Download Indications and contraindications for thoracic epidural

Acute Pain (2008) 10, 15—22
Indications and contraindications for thoracic
epidural analgesia in multiply injured patients
Eileen M. Bulger a,∗, William T. Edwards b, Mario de Pinto b,
Patricia Klotz a, Gregory J. Jurkovich a
a
Department of Surgery, University of Washington, Harborview Medical Center,
Seattle, WA, USA
b Department of Anesthesiology, University of Washington,
Harborview Medical Center, Seattle, WA, USA
Received 21 July 2007 ; received in revised form 17 October 2007; accepted 21 October 2007
Available online 21 December 2007
Presented at the American Society Regional Anesthesia and Pain Medicine, 2005 (poster)
KEYWORDS
Rib fractures;
Epidural analgesia;
Pain control
Summary
Background and objectives: Rib fractures are associated with significant morbidity and mortality. Previous studies have demonstrated a significant reduction in
pneumonia and duration of mechanical ventilation with epidural analgesia (EA) following multiple rib fractures. There remains controversy regarding the appropriate
indications and contraindications for EA in multiply injured patients. We sought
to determine the factors underlying the decision to use or not to use EA in these
patients.
Methods: A survey was sent to the directors of pain management services at all American College of Surgeons Committee on Trauma (ACS-COT) designated Level I trauma
centers in the U.S. The survey queried their opinion regarding the appropriateness
of 33 contraindications and eight indications for EA after rib fractures.
Results: The response rate was 43% (81/188). Ninety-five percent of responding
centers indicated that EA is used after rib fractures, but only 15% had guidelines
defining the indications and contraindications. There was general agreement (>80%)
regarding the indications for EA but disagreement regarding the contraindications.
Contraindications were categorised based on the degree of agreement of respondents. The areas of greatest controversy involved minor spine injuries and minor
coagulopathy.
Conclusions: There is wide variability regarding contraindications employed for thoracic epidural analgesia following rib fractures. These data support the need for
evidenced based guidelines to define the use of EA in the multiply injured patient.
© 2007 Elsevier B.V. All rights reserved.
∗
Corresponding author at: Department of Surgery, Box 359796, Harborview Medical Center, 325 9th Avenue, Seattle, WA 98104,
USA. Tel.: +1 206 731 6448; fax: +1 206 731 3656.
E-mail address: [email protected] (E.M. Bulger).
1366-0071/$ — see front matter © 2007 Elsevier B.V. All rights reserved.
doi:10.1016/j.acpain.2007.10.019
16
1. Introduction
Rib fractures have been associated with significant morbidity and mortality following traumatic
injury. The presence of three or more rib fractures
has been associated with increased mortality and
duration of ICU and hospital care [1,2]. A recent
analysis of the National Trauma Databank demonstrated a significant increase in mortality and
pulmonary morbidity for each additional rib fracture [3]. The elderly are particularly susceptible
to complications of rib fractures with nosocomial
pneumonia rates reported as high as 31% [4]. The
pain associated with rib fractures leads to impaired
ventilatory function and thus increases pulmonary
morbidity. Management of these patients is therefore focused on achieving adequate analgesia and
clearance of pulmonary secretions. Previous studies
have demonstrated that epidural analgesia provides
superior pain relief, improved pulmonary function
tests, reduced the risk of developing nosocomial
pneumonia and led to a shorter duration of mechanical ventilation compared to intravenous opioids
[5—9]. Despite these advantages only 2% of patients
with rib fractures in the National Trauma Databank
received epidural analgesia [3]. This may be due
in large part to controversy regarding the indications and contraindications for the use of epidural
analgesia in patients with multiple injuries. We
sought to define the current practice in the United
States by surveying pain service directors at Level
1 trauma centers regarding their current guidelines
for the use of epidural analgesia in this patient
population and to assess the level of agreement
regarding indications and contraindications for its
use.
2. Methods
A list of all Level 1 trauma centers in the United
States was obtained from the American College
of Surgeons Committee on Trauma. A written
survey was sent to the pain service directors
at all centers in September of 2004. Respondents were asked whether epidural analgesia was
used for the management of pain following rib
fractures and if so were there established institutional guidelines regarding the indications and
contraindications for its use. They were asked
to consider seven potential indications and 33
contraindications. They were asked to rank the contraindications on a four point scale as either: (A)
appropriate contraindication, (B) relatively appropriate contraindication but rarely applied (i.e. OK
to place epidural catheter most of the time), (C)
E.M. Bulger et al.
relatively appropriate contraindication and commonly applied (usually not ok to place epidural
catheter) and (D) inappropriate contraindication.
To develop a rank listing of contraindications,
answers A and C were pooled as general agreement that a contraindication was appropriate and
the percent of respondents in this category was
listed in descending order. Indications were ranked
as either appropriate or inappropriate. The indications and contraindications included were based on
our recent experience with a randomised controlled
trial of epidural analgesia in this patient population [5]. Respondents were not asked to suggest
additional indications or contraindications but were
asked to send their institutional guideline if available. Review of these did not reveal any additional
factors. Three mailings of the survey were sent to
non-responders in an effort to improve the response
rate, telephone calls to non-respondents were not
permitted.
3. Results
Responses were received from 81/188 (43%) of US
Level 1 trauma centers. Seventy-seven of the centers indicated that epidural analgesia is used at
their institution for management of pain after rib
fractures (95%). Twelve centers (15%) reported that
they had developed institutional guidelines regarding the indications and contraindications for the
use of epidural analgesia in this patient population.
As illustrated in Table 1, there was general agreement regarding the indications for the use of EA
Table 1 Rank list based on % of respondents supporting each indication
Indication
Support (%)
Inadequate pain control with
systemic analgesics
Patient sedated by systemic
analgesics
≥3 rib fractures
Request from physician team
providing primary post trauma
care
IRB approved research study of
effectiveness of epidural
analgesia for pain relief
Request from nurses providing
primary post trauma care
Demand from physician team
providing primary post trauma
care
98
95
83
83
81
43
36
Epidural analgesia in multiply injured patients
Table 2 Rank list based on % of respondents supporting each contraindication
Contraindication
Support (%)
Platelet count <50 k
Cellulitis at insertion site
Spinal cord injury
Epidural or spinal cord haematoma
INR > 1.5
LMW heparin w/in 8 h
Major TBI (GCS < 8)
Intracranial haemorrhage
Penetrating head injury
Haemodynamic instability
Unable to obtain consent
LMW heparin w/in 12 h
Full spine precautions
Platelet count <80 k
TBI (GCS 8—13)
Patient deeply sedated for vent
Injury to thoracic aorta
Ligament disruption thoracic spine
Ligament disruption cervical spine
Ligament disruption lumbar spine
Unstable pelvic fracture
Normal thoracic spine films, unable to
examine
Transverse process fracture, thoracic
spine
Spinous process fracture, thoracic spine
Normal lumbar spine films, unable to
examine
Transverse process fracture, cervical
spine
Spinous process fracture, cervical spine
Normal cervical spine films, unable to
examine
Respiratory failure w/o impaired
mechanics
Spinous process fracture, lumbar spine
Transverse process fracture, lumbar
spine
1.0 < INR < 1.5
<3 rib fractures
93
92
90
90
90
88
83
81
77
74
69
69
68
65
64
63
62
62
57
52
47
43
43
40
40
38
37
35
35
30
29
24
18
in this setting (Table 1). Of the 33 contraindications evaluated, they were grouped based on the
general level of agreement as shown in Table 2.
In addition, specific survey results are presented
for complications grouped by common classification.
3.1. Contraindications related to
coagulopathy
As shown in Fig. 1, there were six contraindications
that addressed the issue of coagulopathy in trauma
patients. The majority of respondents felt that a
17
platelet count <50,000, INR > 1.5, or administration
of low molecular weight heparin (LMWH) within the
previous 8 h were appropriate contraindications to
placement of a thoracic epidural catheter. Opinions
were mixed regarding a platelet count <80,000 or
administration of LMWH within the previous 12 h.
The majority of respondents did not believe that
INR between 1.0 and 1.5 was an appropriate contraindication.
3.2. Contraindications related to spinal
evaluation
As many trauma patients admitted to the intensive care unit are still undergoing evaluation for
potential spinal injury, we inquired whether the
spine clearance status was an appropriate contraindication to thoracic epidural placement. We
included as contraindications an admission status of full spine precautions and a series of
questions regarding normal imaging at different
spine levels but the inability to evaluate the
patient clinically for pain that may be associated with ligamentous injury. As illustrated in
Fig. 2, the majority of respondents felt that
full spine precaution status was an appropriate contraindication, but there was disagreement
among the other categories with most reporting these as inappropriate or relative but rarely
applied contraindications to epidural catheter
placement.
3.3. Contraindications related to spine
injury
As illustrated in Fig. 3, we defined a series of contraindications based on the degree of documented
spinal injury at the cervical, thoracic, and lumbar
spine levels. The majority of respondents agreed
that documented spinal cord injury or known spinal
or epidural haematomas were appropriate contraindications. However, there was wide variability
in the opinions regarding more minor spinal injuries
including ligamentous disruption and transverse or
spinous process fractures.
3.4. Contraindications related to associated
injuries
As the majority of blunt traumatic injuries leading
to rib fractures result from motor vehicle collisions, associated injuries are common and may
impact the decision to place a thoracic epidural
catheter. Fig. 4 illustrates the responses to contraindications listed in this area. The majority of
18
E.M. Bulger et al.
Fig. 1 Contraindications related to coagulopathy. The distribution of responses regarding the appropriateness of
contraindications to thoracic epidural placement relative to patient coagulopathy is illustrated. Response categories
include: appropriate contraindication, relative contraindication commonly applied, relative contraindication uncommonly applied, inappropriate contraindication, and no response. Abbreviations: INR, international ratio; LMW, low
molecular weight.
respondents agreed that significant traumatic brain
injury and haemodynamic instability were appropriate contraindications. There was less agreement
regarding unstable pelvic fracture, injury to the
thoracic aorta and the need for deep sedation for
ventilator support.
4. Discussion
The use of epidural analgesia in the multiply
injured patient with rib fractures is limited by
several potential contraindications to the placement of an epidural catheter. The risks of catheter
Fig. 2 Contraindications related to spine evaluation. The distribution of responses regarding the appropriateness of
contraindications to thoracic epidural placement relative to patient level of spine evaluation is illustrated. Response
categories include: appropriate contraindication, relative contraindication commonly applied, relative contraindication uncommonly applied, inappropriate contraindication, and no response.
Epidural analgesia in multiply injured patients
19
Fig. 3 Contraindications related to spine injury. The distribution of responses regarding the appropriateness of contraindications to thoracic epidural placement relative to spine injury is illustrated. Response categories include:
appropriate contraindication, relative contraindication commonly applied, relative contraindication uncommonly
applied, inappropriate contraindication, and no response. Abbreviations: C, cervical, T, thoracic; L, lumbar; fx,
fracture.
placement must be weighed against the benefits
from improved pain control and the reduction in
pulmonary morbidity reported in recent studies
[5—10]. The contraindications for thoracic epidural placement relate to the major complications
that have been reported in association with its
use including epidural haematoma and catheter
infection that can lead to epidural abscess. Epidural haematoma has been reported to occur in
<1/100,000 procedures but is reported to be a
greater risk in the setting of coagulopathy [11,12].
In addition, there are concerns regarding the ability to assess the effectiveness of pain control or
the development of these complications in patients
Fig. 4 Contraindications related to associated injuries. The distribution of responses regarding the appropriateness
of contraindications to thoracic epidural placement relative to associated injuries is illustrated. Response categories
include: appropriate contraindication, relative contraindication commonly applied, relative contraindication uncommonly applied, inappropriate contraindication, and no response. Abbreviations: TBI, traumatic brain injury; GCS,
Glasgow coma score; vent, ventilator.
20
E.M. Bulger et al.
with altered mental status and thus patients
with associated traumatic brain injury are often
excluded. Finally, a high proportion of patients
with rib fractures as a result of high-energy blunt
trauma have associated spine injuries that may
interfere with placement of the catheter or raise
concern regarding the development of neurologic
sequelae. In our previous randomised controlled
trial of epidural analgesia vs. intravenous opioids we found that 69% of eligible patients met
an exclusion criteria due to contraindications to
placement of the epidural catheter that had been
established for study purposes. The vast majority of these were due to minor associated spine
injuries. This survey was conducted to determine
the current consensus among pain service directors at Level 1 trauma centers in the United
States regarding the indications and contraindications for epidural catheter placement in these
patients.
This report demonstrates general agreement
regarding the common indications for thoracic
epidural placement but significant disagreement
regarding a number of the contraindications listed.
Fig. 5 Local guideline for assessment and management of patients with multiple rib fractures.
Epidural analgesia in multiply injured patients
A similar survey was recently reported regarding the use of thoracic epidural analgesia in the
United Kingdom [13]. While this study did not
focus on its use in multiply injured patients, it
did report little consensus regarding the degree
of coagulopathy that would be tolerated prior
to catheter placement. This included controversy
regarding the timing of catheter placement relative
to a prophylactic dose of LMWH and disagreement
over the appropriate INR and platelet count for
catheter placement. A subsequent survey evaluated the use of epidural analgesia in an intensive
care setting in England [14]. In this survey, the
presence of subclinical coagulopathy was considered a contraindication to epidural placement by
only 49% of the intensive care units surveyed.
A consensus document has been recently produced regarding the use of regional anesthesia n
anticoagulated patients, but this does not specifically address patients with coagulopathy following
injury [11] These reports coupled with our data
highlight the current lack of consensus regarding the appropriate contraindications for epidural
catheter placement among the critically ill or
injured.
It is our hope that this survey will stimulate the
specialty societies to develop an evidence-based
consensus guideline for the use of thoracic epidural analgesia for management of pain following
rib fracture in the multiply injured patient. We
have developed a local guideline for the providers
in our trauma center that is provided as Fig. 5,
but recognise that this has not been subject to a
national consensus process. As shown, we consider
all patients with ≥3 rib fractures as candidates for
evaluation by our Acute Pain Relief Service (APS).
This service consists of anesthesiologist and midlevel practitioners specialising in the management
of acute pain and available 24/7 for consultation and complex pain management. Patients are
considered for ICU admission if they have any
respiratory compromise, significant pulmonary comorbidity or are >65 years of age. All patients
receive respiratory therapy and initial pain management with intravenous opioids pending assessment
for epidural analgesia. Our absolute and relative
contraindications are noted in Fig. 5. Importantly,
all patients with multiple rib fractures have their
pain managed by APS regardless of whether they
are candidates for epidural analgesia.
The primary limitation to this survey is the
response rate of 43%. There may be a selection
bias introduced by those who chose to respond to
our survey. Despite three mailings of the survey to
non-responders, we were unable to improve this
response rate. The survey only included Level 1
21
trauma centers and thus may not be representative
of the practice in the general community. Level 1
centers, however, generally treat the greatest number of severely injured patients and thus the fact
that only 15% of respondents reported the existence
of guidelines regarding the use of epidural analgesia in multiply injured patients suggests that this
has not been widely recognised as a practice issue.
We believe that our data point to the need for the
development of evidence based guidelines for the
use of thoracic epidural analgesia for the management of patients with rib fractures in the setting of
multiple injuries.
Conflict of interest statement
There is no conflict of interest.
References
[1] Lee RB, Morris Jr JA, Parker RS. Presence of three or more
rib fractures as an indicator of need for interhospital transfer. J Trauma 1989;29(6):795—9, discussion 799—800.
[2] Lee RB, Bass SM, Morris Jr JA, MacKenzie EJ. Three
or more rib fractures as an indicator for transfer to a
Level I trauma center: a population-based study. J Trauma
1990;30(6):689—94.
[3] Flagel BT, Luchette FA, Reed RL, Esposito TJ, Davis
KA, Santaniello JM, et al. Half-a-dozen ribs: the breakpoint for mortality. Surgery 2005;138(4):717—23, discussion
723—715.
[4] Bulger EM, Arneson MA, Mock CN, Jurkovich GJ. Rib
fractures in the elderly. J Trauma 2000;48(6):1040—6, discussion 1046—1047.
[5] Bulger EM, Edwards T, Klotz P, Jurkovich GJ. Epidural
analgesia improves outcome after multiple rib fractures.
Surgery 2004;136(2):426—30.
[6] Mackersie RC, Karagianes TG, Hoyt DB, Davis JW. Prospective evaluation of epidural and intravenous administration
of fentanyl for pain control and restoration of ventilatory function following multiple rib fractures. J Trauma
1991;31(4):443—9, discussion 449—451.
[7] Moon MR, Luchette FA, Gibson SW, Crews J, Sudarshan
G, Hurst JM, et al. Prospective, randomized comparison
of epidural versus parenteral opioid analgesia in thoracic
trauma. Ann Surg 1999;229(5):684—91, discussion 691—682.
[8] Wu CL, Jani ND, Perkins FM, Barquist E. Thoracic epidural
analgesia versus intravenous patient-controlled analgesia
for the treatment of rib fracture pain after motor vehicle
crash. J Trauma 1999;47(3):564—7.
[9] Wisner DH. A stepwise logistic regression analysis of factors
affecting morbidity and mortality after thoracic trauma:
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discussion 804—795.
[10] Block BM, Liu SS, Rowlingson AJ, Cowan AR, Cowan Jr JA,
Wu CL. Efficacy of postoperative epidural analgesia: a metaanalysis. JAMA 2003;290(18):2455—63.
[11] Horlocker TT, Wedel DJ, Benzon H, Brown DL, Enneking FK,
Heit JA, et al. Regional anesthesia in the anticoagulated
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[13] O’Higgins F, Tuckey JP. Thoracic epidural anaesthesia and
analgesia: United Kingdom practice. Acta Anaesthesiol
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[14] Low JH. Survey of epidural analgesia management in general intensive care units in England. Acta Anaesthesiol
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Available online at www.sciencedirect.com
A comparison of regional and general
anaesthesia for total replacement of the hip
or knee
A META-ANALYSIS
S. Hu,
Z.-Y. Zhang,
Y.-Q. Hua,
J. Li,
Z.-D. Cai
From the Second
Military Medical
University, Shanghai,
People’s Republic of
China
„ S. Hu, MD, Orthopaedic
Surgeon
„ Z.-Y. Zhang, MD, Professor
„ Y.-Q. Hua, MD, Orthopaedic
Surgeon
„ J. Li, MD, Orthopaedic
Surgeon
„ Z.-D. Cai, MD, Professor
Department of Orthopaedics
Changhai Hospital, Second
Military Medical University,
168 Changhai Road, Shanghai
200433, People’s Republic of
China.
Correspondence should be sent
to Professor Z.-D. Cai; e-mail:
[email protected]
©2009 British Editorial Society
of Bone and Joint Surgery
doi:10.1302/0301-620X.91B7.
21538 $2.00
J Bone Joint Surg [Br]
2009;91-B:935-42.
Received 16 July 2008;
Accepted after revision 12
March 2009
VOL. 91-B, No. 7, JULY 2009
We performed a meta-analysis to evaluate the relative efficacy of regional and general
anaesthesia in patients undergoing total hip or knee replacement. A comprehensive search
for relevant studies was performed in PubMed (1966 to April 2008), EMBASE (1969 to April
2008) and the Cochrane Library. Only randomised studies comparing regional and general
anaesthesia for total hip or knee replacement were included.
We identified 21 independent, randomised clinical trials. A random-effects model was
used to calculate all effect sizes. Pooled results from these trials showed that regional
anaesthesia reduces the operating time (odds ratio (OR) -0.19; 95% confidence interval (CI)
-0.33 to -0.05), the need for transfusion (OR 0.45; 95% CI 0.22 to 0.94) and the incidence of
thromboembolic disease (deep-vein thrombosis OR 0.45, 95% CI 0.24 to 0.84; pulmonary
embolism OR 0.46, 95% CI 0.29 to 0.80).
Regional anaesthesia therefore seems to improve the outcome of patients undergoing
total hip or knee replacement.
In 2005, more than 375 000 patients underwent
total hip replacement (THR) and more than 530
000 had total knee replacement (TKR) in the
United States.1 Despite the frequency with
which these procedures are carried out, there
remains controversy as to whether they are best
performed under regional anaesthesia using epidural or spinal neuraxial blockade, or general
anaesthesia. In 2000, Rodgers et al2 published a
meta-analysis which addressed the clinical merits of neuraxial blockade for a variety of surgical procedures. However, its place in patients
undergoing joint replacement remains uncertain.
Regional anaesthesia in total joint replacement is claimed to decrease the incidence of
deep-vein thrombosis (DVT) and pulmonary
embolism and to reduce intraoperative bleeding, the need for transfusion and the length of
hospital stay.3-9 It can also increase patient satisfaction especially after one-stage bilateral
THR or TKR.10 Epidural anaesthesia combined with post-operative epidural analgesia
can reduce the physiological stress of surgery
and the incidence of complications as well as
improving the overall outcome of surgery.11
However, other studies have reported contradictory results.12-14 Moiniche et al15 have
shown that there may not be any advantage in
regional techniques. Moreover, spinal and epidural anaesthesia and analgesia may cause
hypotension, motor blockade, urinary retention and pruritus.16 Although there have been
many refinements to reduce such complications, there is still the potential for inadvertent
dural puncture and neurological injury which
may make these techniques less acceptable.11
In addition, many of these studies have been
compromised by small numbers of patients
and, in some cases, the relatively rare occurrence of complications. Consequently, it has
been difficult to draw any conclusions about
the effect of the choice of anaesthesia on the
outcome of joint replacement.
We carried out a meta-analysis to evaluate
the relative efficacy of regional and general
anaesthesia in patients undergoing joint
replacement. We concentrated on THR and
TKR and restricted the regional techniques to
epidural or spinal approaches, to limit the
number of confounding variables.
Materials and Methods
A search of the literature was undertaken using
PubMed (1966 to April 2008), EMBASE (1969
to April 2008) and the Cochrane Library databases using the following keywords: hip
replacement, hip arthroplasty, knee replacement, knee arthroplasty, regional anaesthesia,
epidural anaesthesia, spinal anaesthesia and
general anaesthesia. The terms regional,
epidural, spinal and general anaesthesia were
935
936
S. HU, Z.-Y. ZHANG, Y.-Q. HUA, J. LI, Z.-D. CAI
Table I. Characteristics of the randomised controlled trials of regional versus general anaesthesia in total joint replacement of the
lower limb contributing data to our meta-analysis
Source
Joint studied*
Regional anaesthesia technique
Outcomes studied†
Modig et al3
Modig et al4
Modig et al5
Davis et al6‡
THR
THR
THR
THR
Continuous epidural
Continuous epidural
Continuous epidural
Spinal
Jørgensen et al8
Nielsen et al9
Brueckner et al12
Planes et al13
Mitchell et al14
Borghi et al21‡
TKR
TKR
THR
THR
TKR
THR
Continuous epidural
Continuous epidural
Spinal
Spinal
Continuous epidural
Continuous epidural
Gonano et al24
Lattermann et al25
Kita et al26
THR or TKR
THR
THR
Spinal
Combined spinal and epidural
Continuous epidural
Kudoh et al27
Modig and Karlstrom28
Wulf et al29
Donatelli et al30
TKR
THR
THR
THR or TKR
Spinal
Continuous epidural
Continuous epidural
Continuous epidural
Hole et al31
Jones et al32
THR
THR or TKR
Single-injection epidural
Spinal
Williams-Russo et al33
Keith34
TKR
THR
Continuous epidural
Single-injection epidural
Duration of surgery, blood loss, DVT, PE
Duration of surgery, blood loss, DVT, PE
Duration of surgery, blood loss, DVT, PE
Duration of surgery, blood loss, number of
patients transfused, DVT, PE
DVT, PE
DVT
Duration of surgery, blood loss
Duration of surgery, blood loss, DVT
DVT
Duration of surgery, blood loss, number of
patients transfused
Duration of surgery
Duration of surgery, blood loss
Duration of surgery, blood loss, length of
hospital stay
Duration of surgery, blood loss, PONV
Duration of surgery, blood loss
Duration of surgery, length of hospital stay
Duration of surgery, blood loss, number of
patients transfused
Duration of surgery, PE
Duration of surgery, number of patients transfused, length of hospital stay, DVT, PE mortality
Duration of surgery, blood loss, DVT, PE
Blood loss, number of patients transfused
* THR, total hip replacement; TKR, total knee replacement
† DVT, deep-vein thrombosis; PE, pulmonary embolism; PONV, post-operative nausea and vomiting
‡ the data of the two publications of Davis et al (6, 20) were from the same group as were those presented by Borghi et al (21,22) in
their two publications
linked with ‘or’ and combined using ‘and’ with each subsequent term. Each publication was independently reviewed
by two authors (SH, Z-DC) and the data collected entered
onto a standard sheet. We limited the search to articles published in English. Only randomised, controlled trials which
compared the outcome of elective THR and TKR carried
out under regional anaesthesia with those carried out under
general anaesthesia were included. We included all of these
despite the fact that some did not address all the aspects
that we wished to study. Nonetheless, we read all the original articles carefully and extracted relevant data in order to
decrease publication bias. We also checked the references of
each article for other studies which met all our inclusion
criteria. We extracted the following outcome data from
each study if reported: the operating time, the intraoperative blood loss, the number of patients requiring blood
transfusion, the number of patients with DVT or pulmonary embolism, diagnosed radiologically or clinically, the
length of hospital stay and any deaths.
The data collection was not blinded. A third reviewer
(Z-YZ) compared the two sets of data collection sheets and
any differences were resolved by discussion and reconfirming the data from the original paper. We attempted to contact the authors of a trial if they had published more than
one report on the subject to confirm that the data in each of
their publications were from different groups of patients.
Lastly, we asked authors if they knew of any other relevant
published studies.
Statistical analysis. We only included those outcome
parameters which were presented in numerical format.
Continuous outcome parameters were expressed as the
mean and SD and dichotomous outcomes as the number of
events. The level of significance for all tests was set at a
two-sided p-value of 0.05 and variances were not assumed
to be equal. Patients who had a general anaesthetic were
treated as a control group, and those with regional anaesthesia as an intervention group. The odds ratios (OR) and
the 95% confidence interval (CI) were calculated for
dichotomous outcomes. The standardised mean difference
and the 95% CI were presented for continuous outcomes.
Heterogeneity among studies was tested using the chisquared test. We used a random-effects model to calculate
all effect sizes since it was more conservative and included
both the random variation within the studies and the variation among the different studies. Moreover, the pooled
estimates calculated by the random-effects and fixed-effects
models were similar when there was minimal heterogeneity
between studies. Whenever possible, subgroup analyses
were performed to detect and evaluate clinically significant
differences. All statistical analyses were performed using
the freeware program Review Manager 4.2 (Cochrane
Collaboration, Oxford, United Kingdom).
THE JOURNAL OF BONE AND JOINT SURGERY
A COMPARISON OF REGIONAL AND GENERAL ANAESTHESIA FOR TOTAL REPLACEMENT OF THE HIP OR KNEE
937
Table II. Results of the meta-analysis for all the outcomes of total joint replacement
Heterogeneity
Outcome*
Number of studies SMD or OR (95% CI)†
Z-value p-value
Chi-squared test
p-value
I2(%)‡
Duration of surgery
Intra-operative blood loss
Length of hospital stay
Number of transfusions
DVT
PE
PONV
Mortality
17
12
3
5
10
8
2
2
2.36
2.12
0.57
2.14
2.48
1.9
2.96
0.06
13.99
107.04
4.31
8.94
28.88
11.85
0.19
0.83
0.60
< 0.0001
0.12
0.06
0.0007
0.11
0.66
0.36
0.0
91.6
53.6
55.3
68.8
10.9
0.0
0.0
-0.12 (-0.23 to -0.02)
-0.50 (-0.96 to -0.04)
SMD -0.55 (-2.47 to +1.37)
OR 0.45 (0.22 to 0.94)
OR 0.45 (0.24 to 0.84)
OR 0.46 (0.21 to 1.02)
OR 0.27 (0.11 to 0.64)
OR 0.94 (0.14 to 6.52)
SMD
SMD
0.02
0.03
0.57
0.03
0.01
0.06
0.003
0.95
* DVT, deep-vein thrombosis; PE, pulmonary embolism; PONV, post-operative nausea and vomiting
† SMD, standardised mean difference; OR, odds ratio; 95% CI, 95% confidence interval
‡ inconsistency value, this represents the extent of the heterogeneity
Table III. Subgroup analysis of some of the outcome assessments
Heterogeneity
*
Outcome
Subgroup
Duration of surgery
THR
TKR
†
Number of studies SMD or OR (95% CI)
‡
Z-value p-value Chi-squared test p-value I2(%)§
12
2
SMD
Intra-operative blood loss THR
THR¶
10
8
SMD
Number of transfusions
THR
TKR
4
None
OR 0.35 (0.18 to 0.67)
3.19
0.001
4.16
0.25
27.8
DVT
No TED drug
prophylaxis
TED drug prophylaxis
7
OR 0.27 (0.14 to 0.52)
3.88
0.0001
11.7
0.07
48.7
3
OR 1.07 (0.58 to 1.97)
0.21
0.83
2.78
0.25
28.1
No TED drug
prophylaxis
TED drug prophylaxis
6
OR 0.26 (0.13 to 0.52)
3.87
0.0001
2.2
0.82
0.0
2
OR 1.66 (0.61 to 4.52)
1.0
0.32
0.70
0.40
0.0
PE
SMD
SMD
-0.19 (-0.33 to -0.05) 2.69
-0.02 (-0.21 to +0.17)0.21
0.007
0.84
9.57
0.92
0.57
0.34
0.0
0.0
-0.65 (-1.24 to -0.06) 2.16
-0.48 (-1.13 to 0.17) 1.44
0.03
0.15
103.24
82.8
< 0.0001 91.3
< 0.0001 91.6
* DVT, deep-vein thrombosis; PE, pulmonary embolism
† THR, total hip replacement; TKR, total knee replacement; TED, thromboembolic disease
‡ SMD, standardised mean difference; OR, odds ratio; 95% CI, 95% confidence interval
§ inconsistency value, this represents the extent of the heterogeneity
¶ two trials in which patients in the regional anaesthesia group had a lower blood pressure than those in the general anaesthesia group were excluded
Results
We identified 25 randomised, controlled trials in the English language in which patients had been randomised to
receive either regional or general anaesthesia. Of these, one
in which the data were reported as medians and ranges was
excluded.17 Another three were also excluded. One did not
present data in a form which could be included in the
review18 and the other two included confounding factors,
namely peri-operative hypotension and hip trauma.19,20
Two studies generated more than one publication each, but
were counted only once.6,21-23 Finally, 21 studies were
included in the review3-6,8,9,12-14,21,24-34 (Table I). We
assessed the presence of publication bias by examining funnel plots which displayed the studies included in the metaanalysis in a plot of effect size against sample size. Fortunately, they showed no evidence of publication bias for the
VOL. 91-B, No. 7, JULY 2009
operating time, intraoperative bleeding, rate of transfusion,
and the incidence of DVT and pulmonary embolism.
Whenever possible, we also performed several subgroup
analyses on the hips and knees independently and then
combined them to provide an overall estimate. The results
of the meta-analysis are shown in Tables II and III.
Operating time. Data on the operating time were found in
17 studies with a total of 1483 patients.3-6,12,13,21,24-33
There was a decrease in the length of the operating time
with regional compared with general anaesthesia (standard
mean difference -0.12; 95% CI -0.23 to -0.021; Fig. 1). In
the subgroup meta-analysis, the operating time for THR
under regional anaesthesia was significantly shorter than
that under general anaesthesia (OR -0.19; 95% CI -0.33 to
-0.05), but there was no significant difference between the
two for TKR (OR -0.02; 95% CI -0.21 to 0.17; Table III).
938
S. HU, Z.-Y. ZHANG, Y.-Q. HUA, J. LI, Z.-D. CAI
Study
or sub-category
31
Number of Regional anaesthesia Number of
patients
Mean (SD)
patients
Hole et al
3
Modig et al
Modig et al4
5
Modig et al
Modig and Karlstrom28
6
Davis et al
32
Jones et al
Planès et al13
33
Williams-Russo et al
Wulf et al29
12
Brueckner et al
27
Kudoh et al
22
Borghi et al
25
Lattermann et al
24
Gonano et al
30
Donatelli et al
26
Kita et al
29
15
30
48
14
69
74
61
134
43
16
75
70
7
20
30
16
Total (95% Cl)
751
190.00 (32.00)
147.00 (28.00)
146.00 (22.00)
152.00 (25.00)
132.00 (23.00)
73.00 (13.00)
107.00 (24.00)
73.30 (2.30)
85.00 (33.00)
145.00 (45.00)
101.00 (23.00)
106.70 (31.50)
106.00 (29.00)
95.00 (22.00)
109.00 (26.00)
175.00 (38.00)
71.00 (34.00)
General anaesthesia
Mean (SD)
31
15
30
46
10
71
72
62
128
45
10
75
70
8
20
30
9
Standardised mean difference
(random) 95% CI
207.00 (33.00)
161.00 (35.00)
156.00 (26.00)
150.00 (26.00)
136.00 (30.00)
79.00 (21.00)
112.00 (28.00)
73.70 (2.40)
88.00 (32.00)
136.00 (29.00)
113.00 (39.00)
104.20 (11.80)
112.00 (41.00)
99.00 (26.00)
111.00 (36.00)
168.00 (40.00)
84.00 (34.00)
732
Weight
(%)
Standardised mean difference
(random) (95% CI)
3.94
1.99
4.00
6.39
1.58
9.39
9.90
8.35
17.82
5.95
1.64
10.20
9.50
1.01
2.72
4.07
1.54
-0.52 (-1.03 to 0.00)
-0 .43 (-1.15 to 0.30)
-0.41 (-0.92 to 0.10)
0.08 (-0.33 to 0.48)
-0.15 (-0.96 to 0.66)
-0.34 (-0.67 to -0.01)
-0.19 (-0.52 to 0.13)
-0.17 (-0.52 to 0.19)
-0.09 (-0.33 to 0.15)
0.24 (-0.18 to 0.66)
-0.39 (-1.19 to 0.41)
0.10 (-0.22 to 0.42)
-0.17 (-0.50 to 0.16)
-0.16 (-1.17 to 0.86)
-0.06 (-0.68 to 0.56)
0.18 (-0.33 to 0.68)
-0.37 (-1.19 to 0.45)
100.00
-0.12 (-0.23 to -0.02)
2
Test for heterogeneity: chi-squared = 13.99, df = 16 (p = 0.60), l = 0%
Test for overall effect: Z = 2.36 (p = 0.02)
-1.0
-0.5
0.0
Favours regional anaesthesia
1.0
0.5
Favours general anaesthesia
Fig. 1
Chart showing comparison of the duration of surgery (mean, SD) between the regional and general anaesthesia groups for patients undergoing total
joint replacement.
Study
or sub-category
34
Keith
5
Modig et al
Modig and Karlstrom28
6
Davis et al
Planès et al13
Borghi et al22
Lattermann et al25
Kita et al26
Number of Regional anaesthesia Number of
patients
Mean (SD)
patients
10
48
14
69
61
70
7
16
342.00
1210.00
950.00
512.00
523.00
547.00
629.00
335.00
(59.00)
(490.00)
(300.00)
(266.00)
(29.00)
(99.00)
(525.00)
(381.00)
General anaesthesia
Mean (SD)
9
46
10
71
62
70
8
9
648.00
1680.00
1140.00
706.00
508.00
479.00
563.00
485.00
Standardised mean difference
(random) 95% CI
Weight
(%)
(58.00)
(460.00)
(200.00)
(354.00)
(23.00)
(107.00)
(306.00)
(383.00)
Standardised mean difference
(random) (95% CI)
6.24
14.32
12.17
14.66
14.58
14.66
11.11
12.25
Subtotal (95% Cl)
295
285
Test for heterogeneity: chi-squared = 13.99, df = 7 (p < 0.00001), l2 = 91.6%
Test for overall effect: Z = 1 .44 (p = 0.15)
100. 00
-4
-2
0
Favours regional anaesthesia
2
-4.99 (-6.99 to -3.00)
-0.98 (-1.41 to -0.55)
-0.70
(-1.54 to 0.14)
-0.61 (-0.95 to -0.28)
0.57
(0.21 to 0.93)
0.66
(0.32 to 100)
0.15 (-0.87 to 1.16)
-0.38 (-1.20 to 0.44)
-0.48
(-1.13 to 0.17)
4
Favours general anaesthesia
Fig. 2
Chart showing comparison of intraoperative blood loss (mean, SD) between the regional and general anaesthesia groups for patients undergoing total
joint replacement.
Intra-operative blood loss. Intraoperative blood loss
was reported in 12 studies which included 880
patients. 3-6,13,21,25-28,30,34 In five there was no statistical
difference in the intraoperative blood loss between
regional and general anaesthesia. In another five there
was reduced blood loss with regional anaesthesia. The
remaining two showed increased blood loss. These differences were statistically significant (standardised mean
difference -0.50, 95% CI -.96 to -0.04; Table II).
The pooled data from the ten studies on THR showed
a statistically significant decrease in blood loss in
patients with regional anaesthesia (standardised mean
difference -0.65; 95% CI -1.24 to -0.006; Table III).
However, when we excluded two trials in which patients in
the regional anaesthesia group had a significantly lower
blood pressure than those in the general anaesthesia
group,3,4 there was no significant difference between the
groups (Fig. 2).
Transfusion requirement. Five studies included data on the
number of patients transfused intraoperatively.6,21,30,32,34
Meta-analysis showed that regional anaesthesia reduced
the need for transfusion (OR 0.45; 95% CI 0.22 to 0.94;
Table II). Subset modelling of the THR group showed that
regional anaesthesia reduced the need for transfusion (OR
0.35; 95% CI 0.18 to 0.67; Table III). None of the studies
presented comparable data for the TKR group and
THE JOURNAL OF BONE AND JOINT SURGERY
A COMPARISON OF REGIONAL AND GENERAL ANAESTHESIA FOR TOTAL REPLACEMENT OF THE HIP OR KNEE
Study
Regional anaesthesia
or sub-category
General anaesthesia
(n/N)
Odds ratio (random)
Weight (%)
939
Odds ratio (random)
(n/N)
(95% CI)
No antithrombotic prophylaxis
Modig et al3
5/15
11/15
7.94
0.18
Modig et al4
12/30
23/30
10.47
0.20
(0.03 to 0.62)
Modig et al5
21/48
38/46
11.51
0.16
(0.06 to 0.42)
Davis et al6
9/69
6/74
19/71
3/72
12.00
8.68
0.41
2.03
(0.17 to 0.99)
(0.49 to 8.44)
Jones et al32
Nielsen et al9
(0.0.4 to 0.87)
2/13
10/16
6.18
0.11
(0.02 to 0.67)
Jørgensen et al8
3/17
13/22
8.24
0.15
(0.03 to 0.67)
Subtotal (95% CI)
266
272
65.66
0.27
(0.14, 0.521)
Total events: 58 (regional anaesthesia), 117 (general anaesthesia)
Test for heterogeneity: chi-squared = 11.70, df = 6 (p = 0.07), I2 = 48.7%
Test for overall effect: Z = 3.88 (p = 0.0001)
TED prophylaxis
Mitchell et al14
12/34
10/38
11.16
1.53
(0.56 to 4.18)
7/60
4/62
9.48
1.92
(0.53 to 6.91)
39/97
39/81
13.70
0.72
(0.40 to 1.31)
181
34.34
1.07
(0.58 to 1.97)
100.00
0.45
(0.24 to 0.84)
Planés et al13
Williams-Russo et al33
Subtotal (95% CI)
191
Total events: 58 (regional anaesthesia), 53 (General anaesthesia)
Test for heterogeneity: chi-squared = 2.78, df = 2 (p = 0.25), I2 = 28.1%
Test for overall effect: Z = 0.21 (p = 0.83)
Total (95% CI)
457
453
Total events: 116 (regional anaesthesia), 170 (general anaesthesia)
Test for heterogeneity: chi-squared = 28.88, df = 9 (p = 0.0007) I2 = 68.8%
Test for overall effect: Z = 2.48 (p = 0.001)
0.1
0.2
0.5
1.0
Favours regional anaesthesia
2.0
5.0
10.0
Favours general anaesthesia
Fig. 3
Chart showing comparison of the number of patients with deep-vein thrombosis in the regional and general anaesthesia groups with and without the
administration of thromboembolic disease prophylaxis.
therefore the effect of regional anaesthesia on the need for
transfusion in TKR could not be determined.
Thromboembolic disease. Ten studies presented data on the
incidence of DVT3-6,8,9,13,14,32,33 and eight on pulmonary
embolism.3-6,8,31-33 These two meta-analyses showed that
regional anaesthesia significantly lowered the incidence of
thromboembolic disease when compared with general
anaesthesia (DVT 95% CI 0.24 to 0.84; Fig. 3). Although a
random-effects model did not show the difference
(pulmonary embolism 95% CI 0.21 to 1.02; Table II), it
was identified using a fixed-effects model (pulmonary
embolism 95% CI 0.29 to 0.80; Fig. 4).
However, when subgroup analysis was performed of the
studies in which patients had been given anticoagulants,13,14,31,33 there was no significant difference in the
incidence of thromboembolic disease between the two
groups (DVT 95% CI 0.58 to 1.97; Fig. 3; pulmonary
embolism 95% CI 0.61 to 4.52; Table III).
Post-operative nausea and vomiting. Data on the number
of patients who suffered from this were only given in two
studies24,27 (OR 0.27; 95% CI 0.11 to 0.64; Table II). One
noted that regional anaesthesia reduced its incidence,17 but
pooled data showed significant difference between the two
groups.
VOL. 91-B, No. 7, JULY 2009
Other outcome measurements. Data on mortality were
presented in only two studies13,32 (OR 0.94; 95% CI 0.14
to 6.52; Table II). There was no obvious difference between
regional and general anaesthesia. Meta-analysis was not
performed because of insufficient data.
Three studies recorded the length of hospital stay.29,32,33
There was no discernible difference between the groups
(standardised mean difference -0.55; 95% CI -2.47 to
+1.37; Table II).
Discussion
Our meta-analysis has shown several potential advantages of
regional over general anaesthesia. The former can be beneficial in reducing the duration of surgery, the need for transfusion, post-operative nausea and vomiting and the
incidence of thromboembolic disease (DVT and pulmonary
embolism) in patients undergoing total joint replacement,
particularly THR. There was insufficient evidence to support
or refute the use of regional anaesthesia in decreasing intraoperative blood loss, mortality or length of hospital stay.
Duration of surgery refers to the operating time and not
to the duration of anaesthesia or recovery. Our metaanalysis has shown that regional anaesthesia had only a
minimal effect in reducing the operating time. Sub-group
940
S. HU, Z.-Y. ZHANG, Y.-Q. HUA, J. LI, Z.-D. CAI
Study
or sub-category
Hole et al31
Modig et al3
Modig et al4
Modig et al5
Davis et al6
Jones et al32
Jørgensen et al8
Williamson-Russo et al33
Regional anaesthesia
(n/N)
2/29
4/15
3/30
5/48
0/69
2/74
0/17
10/97
General anaesthesia
(n/N)
Odds ratio (fixed)
(95% CI)
Weight
(%)
0/31
10/15
10/30
15/46
3/71
2/72
1/22
6/81
1.03
17.04
20.91
31.88
7.96
4.58
2.97
13.63
Subtotal (95% CI)
379
368
Total events: 26 (regional anaesthesia), 47 (general anaesthesia)
Test for heterogeneity: chi-squared = 11.85, df = 7 (p = 0.11), I2 = 40.9%)
Test for overall effect: Z = 2.84 (p = 0.005)
100.00
0.1
0.2
0.5
1.0
Favours regional anaesthesia
2.0
5.0
Odds ratio (fixed)
(95% CI)
5.73 (0.26 to 124.51)
0.18
(0.04 to 0.87)
0.22
(0.05 to 0.91)
0.24
(0.08 to 0.73)
0.14
(0.01 to 2.78)
0.97
(0.13 to 7.09)
0.41 (0.02 to 10.69)
1.44
(0.50 to 4.14)
0.48
(0.29 to 0.80)
10.0
Favours general anaesthesia
Fig. 4
Chart showing comparison of the number of patients with pulmonary embolism in the regional and general anaesthesia groups.
analysis indicated that regional anaesthesia significantly
reduced the operating time for THR, a result which was
consistent with that of other recent studies.35 However, this
effect was not seen in patients undergoing TKR. The difference may relate to the use of a thigh tourniquet during
TKR. The tourniquet gives an almost bloodless operating
field which, in turn, may speed up the operation.
The pooled data showed a statistically significant
decrease in blood loss in the regional anaesthesia group.
However, some of the studies were performed 20 years ago
and patients in the regional anaesthesia groups had a significantly lower blood pressure.3,4 A subgroup analysis of the
eight THR studies, showed that there was no significant
difference between the groups when this confounding factor was excluded. This is at odds with recent research by
Mauermann et al.35 The explanation for this discrepancy
may be that the latter included studies in which patients in
the regional anaesthesia group had significant perioperative
hypotension. Therefore we think the result from our subgroup analysis is more appropriate and conclusive. In the
only study for which valid data about intra-operative blood
loss could be extracted there was no significant difference
between the two groups.27 They did not present the data in
a form which could be included in the meta-analysis.
Several other studies did not find any discernible difference
between the two groups.8,18,36 This is easily explained.
Bleeding after TKR, which is performed under tourniquet,
occurs after the period of the anaesthetic effect, into surgical drains. Although we cannot refute the possibility that
regional anaesthesia reduces blood loss in TKR, we contend
that, if there is such an effect, it is probably very small. Data
on the need for transfusion were reported in five studies.6,21,30,32,34 We found that the use of regional anaesthesia
reduced the risk of blood transfusion. The overall blood
loss was not significantly different between the two methods of anaesthesia, but significant differences were found
between the groups as to the need for transfusion. We
believe that the reason for this may be that patients having
regional anaesthesia for a THR are given a plasma
expander more often than those who have general anaesthesia. Consequently, while general anaesthesia for THR
would appear to increase the need for blood transfusion,
patients who have regional anaesthesia either for THR or
TKR require significantly greater amounts of colloid to
maintain their intravascular volume in order to compensate
for sympathetic vasodilatation, thereby apparently reducing the need for blood transfusions.
The prevention of thromboembolic disease is of concern
to all orthopaedic surgeons. Our meta-analysis showed a
protective effect of regional anaesthesia against thromboembolic disease (DVT and pulmonary embolism) in
patients undergoing total joint replacement. A similar effect
has been demonstrated by others.6,9 This finding was also
consistent with the results published by Rodgers et al2
which included over 9500 patients. There are many possible reasons for this effect including altered coagulability,
increased volume flow to the lower limbs, an improved
ability to breathe without pain and a reduction in the surgical stress responses.4,37 However, most of the studies
which favour regional anaesthesia were carried out on
patients who did not have heparin prophylaxis.10 These
findings must be viewed cautiously. A previous review38
showed that regional anaesthesia was inadequate as sole
prophylaxis, although it may reduce the incidence of
thromboembolic disease by 50%.39 However, a recent
review showed that epidural anaesthesia without anticoagulants resulted in a low incidence of venous thromboembolism in patients undergoing THR.40 We suggest that on this
basis regional anaesthesia, when used in conjunction with a
prophylactic anticoagulant, will be more beneficial in
decreasing the rate of thromboembolism, especially in
those patients with risk factors such as varicose veins,
THE JOURNAL OF BONE AND JOINT SURGERY
A COMPARISON OF REGIONAL AND GENERAL ANAESTHESIA FOR TOTAL REPLACEMENT OF THE HIP OR KNEE
malignancy and smoking. old age and the use of oral
oestrogens.6
Our data have shown that the incidence of postoperative nausea and vomiting was significantly lower in
the regional group than in the general anaesthesia group.
Some authors have suggested that this is because regional
anaesthesia provides significantly better post-operative
analgesia,41 which leads to a lower consumption of opioids.
However, the sample size was small and the impact of
regional anaesthesia on post-operative nausea and vomiting was inconclusive.
In our meta-analysis, we failed to confirm that regional
anaesthesia was associated with a reduced length of stay in
hospital or reduced mortality.
Despite the relatively large number of patients studied,
there were several limitations to our study. First, we limited
our meta-analysis to articles in English. Although the effect
of excluding non-English trials on the results of a metaanalysis is unclear, exclusion of such trials may have little
effect on the summary effects of treatment and may actually
give a more conservative estimate of the effect of treatment.42 Secondly, although the data were weighted by trial
size, they were not weighted by the quality of the randomised controlled trials included nor were they assessed in
a blinded fashion. We believe that the quality of the trials
was generally similar, since all were randomised and controlled. We also used a random-effects model for metaanalysis, which assumed some heterogeneity between studies and was thus more stringent in assigning statistical significance than a fixed-effect model. Lastly, although these
data represent most of the randomised evidence available,
the CIs were wide for many outcomes and the summary
estimates of effect (OR and standardised mean difference)
should be interpreted with caution.
In conclusion, our data support the recent trend towards
the increased use of regional anaesthesia. Furthermore, epidural anaesthesia/analgesia has been shown to improve the
post-operative outcomes by relieving pain, reducing pulmonary complications, allowing early mobilisation and shortening the length of hospital stay.11,17,43
941
6. Davis FM, Laurenson VG, Gillespie WJ, et al. Deep vein thrombosis after total
hip replacement: a comparison between spinal and general anaesthesia. J Bone Joint
Surg [Br] 1989;71-B:181-5.
7. Sharrock NE, Haas SB, Hargett MJ, et al. Effects of epidural anesthesia on the
incidence of deep-vein thrombosis after total knee arthroplasty. J Bone Joint Surg
[Am] 1991;73-A:502-6.
8. Jørgensen LN, Rasmussen LS, Nielsen PT, Leffers A, Albrecht-Beste E. Antithrombotic efficacy of continuous extradural analgesia after knee replacement. Br J
Anaesth 1991;66:8-12.
9. Nielsen PT, Jørgensen LN, Albrecht-Beste E, Leffers AM, Rasmussen LS.
Lower thrombosis risk with epidural blockade in knee arthroplasty. Acta Orthop Scand
1990;61:29-31.
10. Schäfer M, Elke R, Young JR, Gancs P, Kindler CH. Safety of one-stage bilateral
hip and knee arthroplasties under regional anaesthesia and routine anaesthetic monitoring. J Bone Joint Surg [Br] 2005;87-B:1134-9.
11. Moraca RJ, Sheldon DG, Thirlby RC. The role of epidural anesthesia and analgesia in surgical practice. Ann Surg 2003;238:663-73.
12. Brueckner S, Reinke U, Roth-Isigkeit A, et al. Comparison of general and spinal
anesthesia and their influence on hemostatic markers in patients undergoing total hip
arthroplasty. J Clin Anesth 2003;15:433-40.
13. Planès A, Vochelle N, Fagola N, Feret J, Bellaud M. Prevention of deep vein
thrombosis after total hip replacement: the effect of low-molecular-weight heparin
with spinal and general anaesthesia. J Bone Joint Surg [Br] 1991;73-B:418-22.
14. Mitchell D, Friedman RJ, Baker JD 3rd. Prevention of thromboembolic disease
following total knee arthroplasty: epidural versus general anesthesia. Clin Orthop
1991;269:109-12.
15. Moiniche S, Hjortso NC, Hansen BL, et al. The effect of balanced analgesia on
early convalescence after major orthopaedic surgery. Acta Anaesthesiol Scand
1994;38:328-35.
16. Gedney JA, Liu EH. Side-effects of epidural infusions of opioid bupivacaine mixtures. Anaesthesia 1998;53:1148-55.
17. Chu CP, Yap JC, Chen PP, Hung HH. Postoperative outcome in chinese patients
having primary total knee arthroplasty under general anaesthesia/intravenous
patient-controlled analgesia compared to spinal epidural anaesthesia/analgesia.
Hong Kong Med J 2006;12:442-7.
18. Nielson WR, Gelb AW, Casey JE, et al. Long-term cognitive and social sequelae of
general versus regional anesthesia during arthroplasty in the elderly. Anesthesiology
1990;73:1103-9.
19. Thorburn J, Louden JR, Vallance R. Spinal and general anaesthesia in total hip
replacement: frequency of deep vein thrombosis. Br J Anaesth 1980;52:1117-21.
20. Davis FM. Anesthesia for hip surgery. Comparative studies of spinal anaesthesia and
general anaesthesia for elective total hip arthroplasty and internal fixation of fractures of the femoral neck in the elderly. University of Otago, 1987 [MD Thesis].
21. Borghi B, Casati A, Iuorio S, et al. Frequency of hypotension and bradycardia during general anesthesia, epidural anesthesia, or integrated epidural-general anesthesia for total hip replacement. J Clin Anesth 2002;14:102-6.
22. Borghi B, Casati A, Iuorio S, et al. Effect of different anesthesia techniques on red
blood cell endogenous recovery in hip arthroplasty. J Clin Anesth 2005;17:96-101.
23. Davis FM, McDermott E, Hickton C, et al. Influence of spinal and general anaesthesia on haemostasis during total hip arthroplasty. Br J Anaesth 1987;59:561-71.
24. Gonano C, Leitgeb U, Sitzwohl C, et al. Spinal versus general anesthesia for
orthopedic surgery: anesthesia drug and supply costs. Anesth Analg 2006;102:524-9.
No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.
25. Lattermann R, Belohlavek G, Witmann S, et al. The anticatabolic effect of
neuraxial blockade after hip surgery. Anesth Analg 2005;101:1202-8.
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3. Modig J, Hjelmstedt A, Sahlstedt B, Maripuu E. Comparative influences of epidural and general anaesthesia on deep venous thrombosis and pulmonary embolism
after total hip replacement. Acta Chir Scand 1981;147:125-30.
4. Modig J, Borg T, Karlstrom G, Maripuu E, Sahlstedt B. Thromboembolism after
total hip replacement: role of epidural and general anesthesia. Anesth Analg
1983;62:174-80.
5. Modig J, Maripuu E, Sahlstedt B. Thromboembolism following total hip replacement: a prospective investigation of 94 patients with emphasis on the efficacy of lumbar epidural anesthesia in prophylaxis. Reg Anesth 1986;11:72-9.
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27. Kudoh A, Takase H, Takazawa T. A comparison of anesthetic quality in propofolspinal anesthesia and propofol-fentanyl anesthesia for total knee arthroplasty in
elderly patients. J Clin Anesth 2004;16:405-10.
28. Modig J, Karlstrom G. Intra- and post-operative blood loss and haemodynamics in
total hip replacement when performed under lumbar epidural versus general anaesthesia. Eur J Anaesthesiol 1987;4:345-55.
29. Wulf H, Biscoping J, Beland B, et al. Ropivacaine epidural anesthesia and analgesia versus general anesthesia and intravenous patient-controlled analgesia with
morphine in the perioperative management of hip replacement. Anesth Analg
1999;89:111-16.
30. Donatelli F, Vavassori A, Bonfanti S, et al. Epidural anesthesia and analgesia
decrease the postoperative incidence of insulin resistance in preoperative insulinresistance subjects only. Anesth Analg 2007;104:1587-93.
31. Hole A, Terjesen T, Breivik H. Epidural versus general anaesthesia for total hip
arthroplasty in elderly patients. Acta Anaesthesiol Scand 1980;24:279-87.
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32. Jones MJ, Piggott SE, Vaughan RS, et al. Cognitive and functional competence
after anaesthesia in patients aged over 60: controlled trial of general and regional
anaesthesia for elective hip or knee replacement. BMJ 1990;300:1683-7.
33. Williams-Russo P, Sharrock NE, Haas SB, et al. Randomized trial of epidural versus general anesthesia: outcomes after primary total knee replacement. Clin Orthop
1996;331:199-208.
34. Keith I. Anaesthesia and blood loss in total hip replacement. Anaesthesia
1977;32:444-50.
35. Mauermann WJ, Shilling AM, Zuo Z. Comparison of neuraxial block versus general anesthesia for elective total hip replacement: a meta-analysis. Anesth Analg
2006;103:1018-25.
36. Kohro S, Yamakage M, Arakawa J, et al. Surgical/tourniquet pain accelerates
blood coagulability but not fibrinolysis. Br J Anaesth 1998;80:460-3.
37. Modig J, Borg T, Bagge L, Salden T. Role of extradural and of general anaesthesia
in fibrinolysis and coagulation after total hip replacement. Br J Anaesth 1983;55:625-9.
38. Feller JA, Parkin JD, Phillips GW, et al. Prophylaxis against venous thrombosis
after total hip arthroplasty. Aust N Z J Surg 1992;62:606-10.
39. Prins MH, Hirsh J. A comparison of general anaesthesia and regional anaesthesia
as a risk factor for deep vein thrombosis following hip surgery: a critical review.
Thromb Haemost 1990;64:497-500.
40. Daniel J, Pradhan A, Pradhan C, et al. Multimodal thromboprophylaxis following
primary hip arthroplasty: the role of adjuvant intermittent pneumatic calf compression. J Bone Joint Surg [Br] 2008;90-B:562-9.
41. Block BM, Liu SS, Rowlingson AJ, et al. Efficacy of postoperative epidural analgesia: a meta-analysis. JAMA 2003;290:2455-63.
42. Juni P, Holenstein F, Sterne J, Bartlett C, Egger M. Direction and impact of language bias in meta-analyses of controlled trials: empirical study. Int J Epidemiol
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43. Ballantyne J, Carr D, de Ferranti S, et al. The comparative effects of postoperative analgesia therapies on pulmonary outcome: cumulative meta-analysis of randomized, controlled trials. Anesth Analg 1998;86:598-612.
THE JOURNAL OF BONE AND JOINT SURGERY
Analgesia following total knee arthroplasty.
Knee reconstruction
Current Opinion in Orthopedics. 18(1):76-80, February 2007.
Trueblood, Andrew a,b; Manning, David W a,b
Abstract:
Purpose of review: Conventional methods of postoperative pain control
for total knee arthroplasty include continuous epidural infusions of
local anesthetic and patient-controlled intravenous narcotics. Dosedependent side effects are common with these modalities and may
result in limited effectiveness and decreased patient satisfaction.
This review intends to detail recent advances in postoperative pain
management after total knee arthroplasty.
Recent findings: Multimodal, or balanced, techniques for
postoperative pain control have been described that simultaneously
utilize multiple analgesics with different mechanisms of action,
additive effects and decreased dose-related side effects. Narcotic
side-effect-sparing modalities include the scheduled use of
acetaminophen, nonsteroidal anti-inflammatory drugs, tramadol,
cryotherapy, and the use of sustained-release oral narcotics. In
addition, regional nerve block is a reproducible technique that
provides more consistent and efficacious analgesia than patientcontrolled intravenous narcotic therapy alone and is associated with
fewer side effects than continuous epidural analgesia.
Summary: Regional nerve block coupled with nonnarcotic analgesics and
combined long and short-acting oral narcotics decreases postoperative
pain, allows for faster functional recovery, and decreases medicationrelated side effects. It may also shorten hospitalization and enhance
patient satisfaction when compared with traditional approaches to
postoperative pain management.
British Journal of Anaesthesia 103 (3): 335–45 (2009)
doi:10.1093/bja/aep208
Advance Access publication July 23, 2009
REVIEW ARTICLE
Does regional anaesthesia improve outcome after total hip
arthroplasty? A systematic review
A. J. R. Macfarlane1 2, G. A. Prasad1, V. W. S. Chan1 and R. Brull1*
1
Department of Anaesthesia and Pain Management, Toronto Western Hospital, University Health Network,
399 Bathurst Street, Toronto, ON, Canada M5T 2S8
2
Present address: Department of Anaesthesia, Glasgow Royal Infirmary, 84 Castle Street, Glasgow G4 0SF, UK
*Corresponding author. E-mail: [email protected]
Total hip arthroplasty (THA) is amenable to a variety of regional anaesthesia (RA) techniques
that may improve patient outcome. We sought to answer whether RA decreased mortality,
cardiovascular morbidity, deep venous thrombosis (DVT) and pulmonary embolism (PE), blood
loss, duration of surgery, pain, opioid-related adverse effects, cognitive defects, and length of
stay. We also questioned whether RA improved rehabilitation. To do so, we performed a systematic review of the contemporary literature to compare general anaesthesia (GA) and RA
and also systemic and regional analgesia for THA. To reflect contemporary surgical and anaesthetic practice, only randomized controlled trials (RCTs) from 1990 onward were included.
We identified 18 studies involving 1239 patients. Only two of the 18 trials were of Level I
quality. There is insufficient evidence from RCTs alone to conclude if anaesthetic technique
influenced mortality, cardiovascular morbidity, or the incidence of DVT and PE when using
thromboprophylaxis. Blood loss may be reduced in patients receiving RA rather than GA for
THA. Our review suggests that there is no difference in duration of surgery in patients who
receive GA or RA. Compared with systemic analgesia, regional analgesia can reduce postoperative pain, morphine consumption, and nausea and vomiting. Length of stay is not reduced and
rehabilitation does not appear to be facilitated by RA or analgesia for THA.
Br J Anaesth 2009; 103: 335–45
Keywords: anaesthesia, general; anaesthetic techniques, regional; analgesia, postoperative;
analgesic techniques, regional; surgery, orthopaedic
Total hip arthroplasty (THA) is amenable to a variety of
regional anaesthesia (RA) techniques. Central neuraxial
blockade (CNB) can provide excellent intraoperative
anaesthesia and prolonged postoperative analgesia.
Peripheral nerve blockade (PNB) avoids some of the
unwanted adverse effects of CNB and allows for targeted
analgesia of the operative limb.6 64 65 The use of continuous PNB has increased as it has the advantage of longer
postoperative analgesia compared with a single-injection
technique.8 31 53
Despite a low rate of complications and apparent
benefits in certain orthopaedic procedures, including better
postoperative analgesia, improved rehabilitation, and a
reduced length of hospital stay, there are disadvantages of
RA.2 – 4 10 14 15 22 49 60 72 76 There is an inherent block
failure rate, even in expert hands.51 Operating theatre
delays and a perceived risk of increased liability are criticisms also often directed at RA.38 52 Other limiting factors
include the training required to develop the necessary
technical skills for successful RA and, more recently, the
expense of ultrasound equipment as this method of nerve
localization increases in popularity. Finally, many patients
are fearful of RA and may have misconceptions about the
technique involved.43
Although RA is increasingly used, the results of large
meta-analyses and randomized controlled trials (RCTs)
comparing general anaesthesia (GA) and RA for major
lower limb orthopaedic surgery often conflict.7 18 44 56 69 77
It is not uncommon for the results of large RCTs to disagree with those of meta-analyses.30 This can be due to
the inclusion of small studies, publication bias, and
sample heterogeneity between different trial populations
and meta-analysis bias.32 40 46 More importantly, many
trials included in recent meta-analyses were originally
published more than 30 yr ago and do not reflect modern
anaesthetic or surgical practice. Landmark articles which
# The Author [2009]. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved.
For Permissions, please email: [email protected]
Macfarlane et al.
compared GA and RA for hip surgery used drugs that are
no longer available.47 48 In the past two decades, surgical
techniques and postoperative patient care have improved
considerably, new thromboembolic prophylaxis regimes
have been introduced, and RA has advanced as a result of
enhanced needle technology, block placement techniques,
catheter design, and infusion pumps.25 27 33 58 63 We have
re-examined existing data66 for relevance and application
to modern anaesthetic practice.
We have performed a systematic review of the literature,
published from 1990 onwards, to ascertain if either RA
was superior to GA or regional analgesia was superior to
systemic analgesia for THA. The specific questions we
sought to answer were whether, when compared with GA
or systemic analgesia, RA or regional analgesia for THA
decreased: (i) mortality, (ii) cardiovascular morbidity, (iii)
deep venous thrombosis (DVT) and pulmonary embolism
(PE), (iv) blood loss, (v) duration of surgery, (vi) pain,
(vii) opioid-related adverse effects, (viii) cognitive defects,
and (ix) length of stay. We also examined whether or not
RA or regional analgesia improved rehabilitation.
Methods
Two of the authors (G.A.P. and R.B.) searched the electronic databases MEDLINE, EMBASE, and the Cochrane
Central Register of Controlled Clinical Trials (from
January 1990 to October 2008) using the following population search terms: ‘total hip replacement’ OR ‘total hip
arthroplasty’ OR ‘hip operation’. These search results were
combined with ‘anaesthesia’ OR ‘analgesia’ using the
Boolean search operator AND. The references of retrieved
articles were hand searched for any relevant articles not
identified in the original search.
The study selection criteria were limited to include only
RCTs, English language, and human adults. Each abstract
was screened to identify studies that had randomized
patients to compare GA or RA for surgery. RCTs comparing
systemic or regional techniques for postoperative analgesia
were also included. Studies were excluded if surgery other
than a joint arthroplasty was performed, or if both hip and
knee arthroplasty were treated as one single study population and data on the patients undergoing knee surgery
were not presented separately in the results.9 26 29 35 73
Studies using opioid-only neuraxial techniques were
excluded.24 71 Finally, studies were excluded if the primary
outcome was not included in the list described above.13 57
The data were extracted onto a templated evidencebased medicine literature review form to assist in the systematic review of full-text articles and data collection.
Data extracted for comparison included year of publication, author, total number of subjects, mean patient age,
per cent male, and co-morbidity. The intervention (specific
RA, regional analgesia technique, or both) and comparator
(GA, specific systemic analgesia technique, or both) were
recorded. The specific outcomes sought in each article
were: (i) mortality, (ii) cardiovascular morbidity (myocardial infarction, arrhythmia, and hypotension), (iii) DVT,
(iv) PE, (v) blood loss, (vi) duration of surgery, (vii)
pain ( pain scores and morphine consumption), (viii)
opioid-related adverse effects (nausea, vomiting, pruritis,
sedation, urinary retention, and respiratory depression),
(ix) cognitive defects, (x) length of stay, and (xi) rehabilitation (range of motion and ambulation). It was noted
whether each outcome was primary or secondary. Each
outcome was then evaluated qualitatively for each intervention and comparator and the data were recorded in
tables. Because there were a limited number of studies
with homogenous design for each outcome, meta-analysis
was not performed.
The methodological quality of each trial was assessed
using several criteria. The likelihood of methodological
bias of each RCT was assessed using the Jadad score,34
which assigns points based on three factors. One point was
given to randomized studies, an additional point was given
if the method of randomization was described and appropriate, and one point was deducted if randomization was
inappropriate. One point was given if a study was doubleblind, and an additional point was given if the blinding
procedure was described and appropriate. One point was
deducted if blinding was inappropriate. One point was
given if the numbers and reasons for withdrawals were
described. The maximum score is 5; trials scoring 3 or
more are generally regarded as having satisfactory methodologic quality. Allocation concealment, which helps
eliminate selection bias, was assessed and defined as adequate, unclear, or inadequate. Finally, whether patient
follow-up rates were ,80% was recorded.
After abstraction of information, a level of evidence was
assigned to the outcomes of each RCT (Level I is a highquality RCT; Level II is a lesser quality RCT, e.g. ,80%
follow-up, no blinding, or improper randomization). Two
authors (A.J.R.M. and R.B.) independently reviewed and
scored each RCT using this methodology.
Results
In total, 18 RCTs were identified that compared either GA
vs RA, systemic vs regional analgesia, or both for THA
(Fig. 1). Ten of these had a Jadad score of 2 or less.
Allocation concealment was unclear in 13 trials and
inadequate in one. Follow-up was adequate in all trials
(Table 1). Two RCTs were considered to provide Level I
evidence.37 65 In total, the studies included 1239 patients.
A summary of the outcomes reported in each trial is provided in Table 2.
Mortality
There were no trials primarily designed to assess differences in mortality after GA or RA for THA. Only two
336
GA vs RA for THA
Total hip arthroplasty OR
Total hip replacement OR
Hip operation
AND
Deep venous thrombosis and pulmonary embolism
Anaesthesia
OR analgesia
639 citations
RCTs only
213 abstracts
Foreign language,
non-adult subjects
166 abstracts
27 full-text articles
18 full-text articles
GA vs RA,
systemic vs regional
analgesia, or both
Data not exclusive for
THA, did not meet
inclusion criteria
Fig 1 Flow chart of screened, excluded and analysed papers.
trials documented mortality as a secondary outcome
(Level II). The follow-up period was 48 h in one study
and 16 days in the other.55 78 There was only one death
reported in 276 patients included in these two studies; no
difference in mortality was detected between the groups in
either study.
The incidence of DVT and PE after THA was evaluated as
a secondary outcome in two trials comparing GA with
RA.20 55 In both of these trials, all patients received
chemical thromboprophylaxis. When comparing EA and
GA with GA alone, there was no difference in the incidence of DVT on postoperative days one to nine, with
warfarin administered to all patients after operation (Level
II).20 Spinal anaesthesia was compared with GA using
three groups which differed with respect to administration
of thromboprophylaxis.55 First, the GA group received preoperative enoxaparin, unlike the two spinal anaesthesia
groups. Secondly, one of the spinal anaesthesia groups
received enoxaparin 1 h after operation. All three groups
received daily enoxaparin from 12 h after operation.
Compared with the GA group, distal DVTs (measured
12– 15 days after operation) were more frequent in the
spinal anaesthesia group who did not received enoxaparin
at 1 h (11% vs 0%, P¼0.013, Level II).55 The incidence
of proximal DVTs did not differ significantly between the
three groups (Level II). This was the only study that examined the incidence of PE, again as a secondary outcome,
but as this was zero in both RA and GA groups, no difference was detected (Level II).55
Blood loss
Cardiovascular morbidity
Six trials examined cardiovascular morbidity, although this
was a primary outcome in only one trial.11 Hypotension
was most commonly studied. GA combined with epidural
anaesthesia (EA), when compared with GA alone, resulted
in significantly more frequent hypotensive episodes, both at
induction (41% vs 23%, P¼0.0049) and intraoperatively
(54% vs 35%, P¼0.04). Intraoperative mean arterial
pressure (80 vs 88 mm Hg, P¼0.037) was also lower in the
combined group (Level II).11 20 However, the effect of epidural analgesia on hypotension after operation varied, and
in three trials, the frequency was either less (0% vs 33%,
P¼0.001, Level I), greater (40% vs 13%, P¼0.01, Level
II), or no different (Level II) when compared with patients
receiving systemic analgesia.37 61 78 The incidence of postoperative hypotension with continuous femoral nerve block
was significantly less (0% vs 40%, P¼0.01, Level II) when
compared with CEA.61 Continuous lumbar plexus block
(CLPB), compared with systemic analgesia, did not affect
the incidence of hypotension (Level II), again when studied
as a secondary outcome however.5 The incidence of bradycardia was assessed in two studies5 78 and was not significantly different with either CEA or CLPB when compared
with systemic analgesia (Level II). Myocardial ischaemia
or significant arrhythmias other than bradycardia was investigated in one study comparing GA with or without lumbar
EA.20 There was no difference between the groups, up to
48 h after operation (Level II). (For further information, see
Supplementary Table 3.)
Ten studies measured intraoperative blood loss. In four of
these, intraoperative blood loss was reduced (ranging from
118 to 595 ml) by RA compared with either GA or systemic analgesia, whereas in the six others, there was no
significant difference.12 19 – 21 55 59 61 64 65 67 Postoperative
blood loss was recorded in seven trials. In two of these,
postoperative blood loss was reduced (ranging from 140 to
517 ml) in the RA group compared with GA or systemic
analgesia, whereas in the five others, there was no difference.12 19 – 21 55 65 67 Blood transfusion was reduced (range
1.3– 1.7 units) in the RA group in two out of the five
studies that measured this outcome.19 – 21 55 61 All studies
were Level II evidence except one Level I study which
demonstrated reduced intra- and postoperative blood loss
using combined GA and LPB compared with GA alone.65
In no case was blood loss significantly greater in the RA
group compared with GA or systemic analgesia. (For
further information, see Supplementary Table 4.)
Duration of surgery
The duration of surgery was not influenced by the type of
anaesthetic for THA (Level II).6 11 12 19 – 21 37 50 55 65 67 68
Postoperative analgesia
We identified 11 RCTs comparing systemic and regional
analgesia for THA and in all but one,61 regional analgesia
reduced pain scores or morphine consumption.5 6 37 45 50 59
64 65 68 78
There was good evidence that, compared with
337
Table 1 Patient characteristic data, design, and breakdown of Jadad score for each trial. *Randomization groups. Age is presented as mean (SD) or median (range) where available. Alloc Conceal, allocation
concealment; SA, systemic analgesia; CPB, continuous psoas block; CS, continuous spinal; CLPB, continuous lumbar plexus block; SNB, sciatic nerve block; GA, general anaesthesia; EA, epidural anaesthesia; FNB,
femoral nerve block; OB, obturator nerve block; CFNB, continuous femoral nerve block; CSE, combined spinal epidural; CPB, continuous psoas block; R, ropivacaine; PCA, patient-controlled analgesia; CEA,
continuous epidural analgesia; N/A, not available; ASA, American Society of Anesthesiologists; †See Remarks
n
Anaesthesia
Analgesia
Age (yr)
% Male
Co-morbidity
Alloc Conceal
Jadad score
Remarks
Becchi and colleagues5
37
36
SA
SA
CPB*
Systemic infusion*†
69 (8)
71 (11)
43
43
ASA I–II; age 61 –82
Adequate
11 001 (3)
Siddiqui and colleagues59
17
17
22
22
GA
GA
SA
SA
CLPB*
I.V. PCA*
Fascia iliaca*
Placebo*
59
52
69
67
(12)
(13)
(10)
(9)
41
53
68
50
ASA I–III; age 18 –80; body mass
index .40 excluded
ASA I–III
Adequate
11 001 (3)
Both CPB and i.v. infusion
continued for 48 h;
†
morphine and ketorolac;
observors and patients
adequately blinded but not
investigators
CLPB
Unclear
11 101 (4)
Eroglu and colleagues21
20
20
EA*
GA*†
CEA
CEA
64 (13)
62 (10)
20
30
Unclear
11 000 (2)
Singelyn and colleagues61
15
15
15
70
70
70
16
15
14
34
34
70
70
70
GA
GA
GA
EA*
EAþGA*
GA*
GA
GA
GA
CS anaesthesia
SA
EA*
EAþGA*
GA*
CFNB*
CEA*
I.V. PCA*
CEA
CEA
I.V. opioid infusion
FNB*
Psoas block*
I.V. PCA*
CS analgesia *
I.V. PCA*
CEA
CEA
I.V. opioid infusion
67
61
66
66
64
64
53
57
58
74
70
66
64
64
33
47
40
46
36
33
63
40
64
38
55
46
36
33
ASA I–III; patients with unstable
angina,
valvular disease, neurologic, or
cerebrovascular
disease excluded
ASA I–II; age 18 –80
Unclear
11 000 (2)
CFNB and CEA continued
for 48 h
ASA I–III
Adequate
11 000 (2)
Drop-outs replaced by a
new randomized
participant
N/A
Unclear
10 101 (3)
ASA I–III; age 50 –85; weight 40 –
100 kg
ASA I–III
Inadequate
11 001 (3)
Adequate
11 000 (2)
Stevens and colleagues64
Borghi and colleagues12
Biboulet and colleagues6
Maurer and colleagues45
Borghi and colleagues
11
(11)
(13)
(15)
(10)
(11)
(10)
(12)
(13)
(14)
(9)
(11)
(10)
(11)
(10)
Modified fascia iliaca
block—injection 1 cm
above the inguinal
ligament. Clonidine and
bupivacaine 0.5% used for
block
Hypotensive anaesthesia in
both groups (mean arterial
pressure 50 –60 mm Hg);
†
total i.v. anaesthesia
CS analgesia continued for
24 h
Same population as in
Borghi and colleagues12
Macfarlane et al.
338
Study
12
11
EA
EA
CEAþplacebo i.v. PCA*
Placebo CEAþi.v. PCA*
66 (9)
62 (6)
25
33
ASA I–III; age 18 –80; weight 50 –90
kg
Unclear
10 111 (4)
Stevens and colleagues65
30
30
43
45
GA
GA
EA*
GA*
LPB*
I.V. PCA*
CEA
I.V. PCA
66 (10)
66 (10)
N/A
N/A
50
50
N/A
N/A
ASA I–III
Unclear
10 111 (4)
ASA I–III; age older than 18 yr
Unclear
10 001 (2)
D’Ambrosio and colleagues19
15
15
15
15
EAþGA*I
EAþGA*II
GA*III
GA*IV
CEA
CEA
Systemic opiates
Systemic opiates
62
67
67
61
(9)
(7)
(9)
(13)
53
60
47
47
ASA I–II
Unclear
10 000 (1)
Dauphin and colleagues20
20
17
11
11
93
89
65
61
62
EAþGA*
GA*
EA*
GA*
GA
GA
SA*I
SA*II
GA*III
I.V./I.M. opioid
I.V./I.M. opioid
CEA*
I.M. morphine*
‘3 in 1’ block*
Systemic opioid*
Acetaminophen
Acetaminophen
Acetaminophen
71
66
73
71
71
70
67
67
67
(7)
(14)
(range
(range
(range
(range
(1)
(1)
(1)
35
41
18
9
47
48
46
52
45
ASA I–III
Unclear
11 001(3)
No apparent exclusions
Unclear
11 000 (2)
N/A
Unclear
10 001 (2)
ASA I–III; age .45 yr; weight .45
kg
Unclear
10 001 (2)
10
10
GAþLPB*
GA
Undisclosed
Undisclosed
N/A
N/A
0
0
Women only
Unclear
10 000 (1)
Wulf and colleagues78
Moiniche and colleagues
50
Uhrbrand and colleagues68
339
Planes and colleagues
55
Twyman and colleagues67
67– 82)
61– 85)
48– 85)
53– 88)
CEA continued for at least
44 h (duration of study);
four patients in placebo
CEA vs two in CEA
received GA
Epidural infusion
continued for 24 h; boluses
thereafter if required;
removed at 48 h
CEA continued for 48 h;
I. Aprotinin 500 000 KIU
preop and 500 000 KIU
h21 intraoperatively; II. No
aprotinin (placebo); III.
Aprotinin 500 000 KIU
preop and 500 000 KIU
h21 intraoperatively; IV.
No aprotinin (placebo)
Epidural for intraoperative
period only
CEA continued for 48 h
I. No additional
enoxaparin; II. Enoxaparin
20 mg 1 h after SA; III.
Enoxaparin 40 mg 12 h
before GA; enoxaparin
12 h after operation and
daily thereafter
GA vs RA for THA
Kampe and colleagues37
Table 2 Outcomes and levels of evidence for each study included in the review. Arrows indicate whether the outcome is no different ($), better (#), or worse (") with RA, regional analgesia, or both compared with
GA, systemic analgesia, or both. *Randomization groups. Mort, mortality; CVS, cardiovascular morbidity; DVT, deep venous thrombosis; PE, pulmonary embolus; Cog Def, cognitive deficit; LOS, length of stay;
Rehab, rehabilitation; SA, spinal anaesthesia; CS, continuous spinal; CLPB, continuous lumbar plexus block; SNB, sciatic nerve block; GA, general anaesthesia; EA, epidural anaesthesia; FNB, femoral nerve block;
CFNB, continuous femoral nerve block; R, ropivacaine; PCA, patient-controlled analgesia; CSE, combined spinal – epidural; CEA, continuous epidural analgesia; MC, morphine consumption; B, bupivacaine
Study
Anaesthesia
Analgesia
Outcomes (levels of evidence)
Mort
Becchi and colleagues5
Siddiqui and colleagues59
Stevens and colleagues
64
Eroglu and colleagues21
Singelyn and colleagues
61
Borghi and colleagues12
340
Maurer and colleagues45
Borghi and colleagues
11
Kampe and colleagues37
Stevens and colleagues
65
Wulf and colleagues78
D’Ambrosio and colleagues
Dauphin and colleagues20
Moiniche and colleagues50
Uhrbrand and colleagues
68
Planes and colleagues55
Twyman and colleagues
67
19
CPB*
I.V. infusion*
CLPB*
I.V. PCA*
Fascia iliaca*
Placebo*
CEA
CEA
CFNB*
CEA*
I.V. PCA*
CEA
CEA
I.V. opioid infusion
FNB*
Psoas block*
I.V. PCA*
CS analgesia*
I.V. PCA*
CEA
CEA
I.V. opioid infusion
CEAþplacebo i.v. PCA*
Placebo CEAþi.v. PCA*
LPB*
I.V. PCA*
CEA
$ (II)
I.V. PCA
CEA
CEA
Systemic opiates
Systemic opiates
I.V./I.M. opioid
I.V./I.M. opioid
CEA*
I.M. morphine*
‘3 in 1’ block*
Systemic opioid*
CFNB*
$ (II)
I.M. opioid*
Undisclosed
Undisclosed
DVT
PE
Blood loss Duration of surgery Pain
$ (II)
# (II)
# (II)
$ (II)
# (II); #MC (II)
# (II)
$ (II)
$ (II); #MC (II) $ (II)
# (II)
$ (II)
Rehab
$ (II)
$ (II)
" (II)
Adverse Cog Def LOS
effects
$ (II)
$ (II)
$ (II) $ (II)
# (II); #MC (II); $ (II)
psoas block only
$ (II) $ (II)
$ (II)
$ (II)
# (II)
# (II)
$ (II)
# (I)
# (I)
$ (II)
# (I); #MC (I)
$ (II)
$ (II)
# (II)
# (II)
" (II); EAþGA group
# (I)
# (I)
" (II)
" (II)
$ (II)
" (II)
# (II)
$ (II)
# (II)
$ (II)
$ (II) $ (II)
# (II)
$ (II)
# (II); $MC (II)
$ (II)
# MC (II)
$ (II)
$ (II)
# (II)
$ (II)
$ (II) $ (II)
Macfarlane et al.
Biboulet and colleagues6
SA
SA
GA
GA
SA
SA
EA*
GA*
GA
GA
GA
EA*
GAþEA*
GA*
GA
GA
GA
CS anaesthesia*
SA*
EA*
GAþEA*
GA*
EA
EA
GA
GA
EA*
GA*
EAþGA*
EAþGA*
GA*
GA*
EAþGA*
GA*
EA*
GA*
GA
GA
GA
GA
GAþLPB*
GA*
CVS
GA vs RA for THA
systemic analgesia, single-shot lumbar plexus block (LPB)
reduced pain scores and morphine consumption but only
for a short duration (Level I).6 65 Continuous LPB,
however, was of benefit for up to 48 h compared with systemic analgesia (Level II).5 59 In three37 50 78 out of four
trials,61 epidural analgesia provided superior pain relief
compared with systemic analgesia. The analgesic benefit
lasted from only 8 (Level I) to 48 h (Level II). Compared
with a placebo injection, a modified fascia-iliaca block
reduced morphine consumption up to 24 h, but not pain
scores (Level II).64 Similarly, a ‘3 in 1’ block also reduced
24 h opioid consumption (Level II) compared with systemic opioid alone.68 Femoral nerve block alone, however,
either as a single shot or continuous infusion was of no
benefit.6 61 Continuous spinal analgesia reduced pain
scores compared with systemic analgesia for the 24 h duration of the infusion (Level II).45 (For further information,
see Supplementary Table 5.)
Adverse effects
Although all adverse effects were analysed as secondary
outcomes, significant reductions in postoperative nausea
(relative risk reduction 85– 93%, Level II)5 45 59 and vomiting (relative risk reduction of 100%, Level I)37 45 were
observed in favour of regional analgesia in four of the
nine studies examining this outcome.5 6 37 45 59 61 64 65 78
In the other five studies, there was no difference between
systemic and regional analgesia. There was no difference
detected in the incidence of pruritis, sedation, urinary
retention, or respiratory depression in the studies that examined these as secondary outcomes.5 6 37 45 59 61 (For further
information, see Supplementary Table 6.)
Cognitive deficit
In the only trial that commented on postoperative cognitive deficit after THA, those patients who received EA had
‘superior mental clarity and cooperativeness’ compared
with the GA group.78 The method of assessment for cognition was unclear.
Length of stay
Four studies measured length of stay (some including time
spent in a rehabilitation centre) as either a primary or a
secondary outcome, but there was no difference between
regional (FNB,6 CFNB,61 and CEA50 61) and systemic
analgesia (Level II). (For further information, see
Supplementary Table 7.)
Rehabilitation
Three studies examined rehabilitation. Outcome measures
included daily hours of ambulation and activity scores,50
time to first ambulation,61 or the different ranges of movement about the hip joint.6 61 In all three RA, regional analgesia, or both provided no benefit compared with GA and
systemic analgesia (Level II). These were all secondary outcomes, and two of the trials were also completely unblinded.
(For further information, see Supplementary Table 8.)
Discussion
The aim of this systematic review was to examine contemporary RCTs, published from 1990 onwards, comparing
either GA and RA or regional and systemic analgesia for
THA. We found insufficient evidence from RCTs alone to
conclude whether anaesthetic technique influenced mortality, cardiovascular morbidity, duration of surgery, or the
incidence of DVT and PE in the setting of routine thromboprophylaxis. Blood loss may be reduced in patients
receiving RA rather than GA for THA. RA does, however,
reduce postoperative pain and also nausea and vomiting.
Length of stay is not reduced and rehabilitation does not
appear to be facilitated by RA or analgesia for THA.
Before further considering the implications of our
review, we accept that there are several limitations. First,
for practical reasons, we chose to include only English
language trials. Although this may have introduced bias, it
has been suggested that excluding trials not published in
English has little effect on summary treatment effect estimates.36 Secondly, we found that 10 of the 18 RCTs evaluated herein had Jadad scores of 2 or less. This was
primarily due to lack of any form of blinding in a number
of the trials. Double-blinding can be difficult to institute
when studying peripheral nerve blocks for systemic analgesia, especially in awake patients, as sham nerve blocks are
often not performed for ethical reasons. The latter notwithstanding the Jadad score is effectively reduced automatically by 2 points for the lack of a double-blinded study
design. Thirdly, there were no large (n.1000) trials identified. The studies included in the present review had sample
sizes varying from only 22 to 210 patients. In trials with
small numbers of subjects, the absence of ‘significant’
differences in secondary outcomes must be interpreted with
caution as these studies are often inadequately powered to
detect such differences.42 We took care to highlight secondary outcomes in the summary tables and these shortcomings are also reflected in the level of evidence scores (i.e.
by definition, Level II). Finally, the purpose of this review
was not to provide recommendations on the preferred mode
of anaesthesia for THA. To do so would have required an
assessment of harm and consideration of other information
such as costs, quality of life, and feasibility. One major
concern with RA for instance is the risk of nerve injury
compared with GA. This is difficult to quantify and has
been addressed elsewhere in the contemporary literature.14
As with any anaesthetic technique, patient co-morbidity
and preference and also expertise of the anaesthesiologist
must also be considered.
The lack of difference in mortality between GA and RA
for THA is unsurprising given the safety of modern
341
Macfarlane et al.
anaesthetic and surgical practice. Much greater numbers
than those included in the two RCTs that we identified
would be required to demonstrate any difference.55 78
Furthermore, neither trial followed up patients beyond the
study period (48 h and 15 days). A large meta-analysis
comparing GA and CNB alone for a variety of surgery
types found that overall mortality was reduced by
one-third [odds ratio (OR) 0.70, 95% confidence interval
(CI) 0.54 – 0.90] in patients allocated to CNB.56 When
each group in this meta-analysis was analysed according
to type of surgery, there was decreased mortality only in
the orthopaedic subgroup.56 Interestingly, overall mortality
was reduced whether or not CNB was continued after
operation. Conversely, combined intraoperative GA and
CNB negated the mortality benefit of CNB alone. In a retrospective review examining postoperative analgesia for
THA, there was no difference in mortality when comparing epidural analgesia and systemic analgesia.77 These
data suggest that intraoperative CNB alone may confer the
most benefit. Indeed, in a meta-analysis comparing CNB
with GA for hip fracture repair, CNB was shown to reduce
1 month mortality in patients undergoing hip fracture
surgery.69 We recognize, however, that the latter
meta-analysis of urgent hip fracture repair, arguably in a
generally sicker group of patients, is not necessarily applicable to patients undergoing elective THA.
Only three trials examined cardiovascular morbidity
other than hypotension, comparing either CLPB or epidural analgesia vs systemic analgesia, or EA and GA vs
GA alone. Although there was no difference in the incidence of ischaemia or arrhythmia between the groups, this
could have been the result of inadequate numbers of
patients. In the meta-analysis described above, there was a
reduction in the incidence of myocardial infarction in the
epidural group, although the CI just reached zero.23 This
significant difference was detected only when all surgical
groups were combined and did not specifically apply to
orthopaedic patients alone. Further RCTs with large
numbers are required to examine whether RA reduces
serious cardiovascular morbidity in elective THA.
We found no difference in the frequency of proximal
DVT in the two trials that compared RA and GA, although
both trials suffered from a combination of inadequate
blinding, underpowering, or both.20 55 Although one trial
found an increased incidence of distal DVT in the RA
group compared with GA, the two groups were not truly
comparable because enoxaparin was administered at
different times in each group. Furthermore, the clinical
importance of distal DVTs is arguably less than that for
proximal clots. Our findings contrast with the results of a
recent meta-analysis where patients undergoing THA with
CNB compared with GA had a significantly lower risk of
DVT (OR 0.27, 95% CI 0.17 – 0.42) and PE (OR 0.26,
95% CI 0.12– 0.56).44 Importantly, however, among the
five trials included in this meta-analysis, all were carried
out before 1989 and none utilized routine
thromboprophylaxis. Although it has been suggested that
CNB may decrease the incidence of DVT either directly
by enhancing lower extremity venous blood flow or by
attenuating the prothrombotic effects of the stress
response, further work is required to ascertain whether RA
offers any additive benefit when used in combination with
contemporary routine thromboprophylaxis. Indeed, one
trial included in our review where all patients received
chemical thromboprophylaxis, but which did not have
DVT as an outcome, found no difference in laboratory
measurements of coagulation between patients who
received GA and RA.21 This lack of difference was similarly reflected in a further trial that did not meet our
inclusion criteria but compared haemostatic markers in
patients undergoing THA with either GA or spinal anaesthesia.13 Again, patients received chemical thromboprophylaxis. Although no difference occurred between GA
and RA in the one trial that examined the incidence of PE,
both the method of randomization and diagnosis of PE
were unclear and there was no blinding of observers.55
Four trials demonstrated reduced blood loss in THA with
RA, whereas in six there was no difference. A recently published meta-analysis found that CNB for THA reduced the
likelihood of transfusion by three-quarters (OR 0.25, 95%
CI 0.11–0.53), although seven of the 10 trials included in
this analysis were published before 1990 and may not reflect
current surgical or anaesthetic practice.28 Interestingly, in
this meta-analysis, no difference in intraoperative blood loss
was detected between RA and GA. This contrasts with a
meta-analysis which found a reduction in intraoperative
blood loss by 275 ml per case (95% CI 180–371 ml) in the
RA group.44 Again, however, of the eight (some quasirandomized only) trials included, seven were published before
1990. With the variety of anaesthetic, analgesic, and thromboprophylaxis regimes in the 10 trials included in our
review, results were not homogeneous enough to pool. Three
trials did compare combined EA and GA vs GA, but even
here there was a confounding factor, such as a statistically
significant difference in arterial pressure between the groups.
With the use of restrictive transfusion strategies now commonplace, and many patients now participating in preoperative blood conservation therapies, it may become more
difficult to demonstrate a significant reduction in transfusion
requirements in primary arthroplasty if the prevalence of
blood transfusion decreases, particularly if this endpoint is
studied as a secondary outcome.
In contrast to our findings, a recent meta-analysis
demonstrated a modest, but significant, decrease in surgical time with CNB compared with GA for THA.44 It is
noteworthy that the definition of operating theatre time
may vary, and the majority of the studies we reviewed did
not consider the total time including anaesthetic intervention. A ‘block room’ or anaesthesia induction room, where
RA is performed before patient transfer, can increase
efficiency and boost cost-savings by reducing
anaesthesia-related time.1 62 74 75
342
GA vs RA for THA
Our review found that regional analgesia reduced postoperative pain in THA. The purpose of our review was not
to specifically compare the different RA or analgesia techniques for THA. This has been addressed elsewhere.23
Choi and colleagues18 recently published a meta-analysis
comparing postoperative epidural analgesia with systemic
analgesia after THA or total knee arthroplasty (TKA) and
concluded that epidural analgesia provided better pain
relief for up to 6 h after operation compared with systemic
analgesia. All patients, however, whether THA or TKA,
were analysed together, despite important differences in
the severity of postoperative pain between these two surgical procedures. Although when THA is examined independently, we found that pain scores were reduced for up to
48 h,50 78 the sole trial of Level I quality demonstrated
that the benefit of epidural analgesia was in fact only
evident for 8 h.37 LPBs appeared to be of benefit but are
arguably associated with more serious complications than
other peripheral nerve blocks such as femoral block.16 17
The lack of benefit of femoral block alone, however, compared with either fascia iliaca or ‘3 in 1’ blocks is not
unsurprising because this block does not provide anaesthesia to the lateral cutaneous nerve of the thigh which
innervates the site of skin incision in THA. Although continuous spinal anaesthesia can provide reliable, titratable
anaesthesia and analgesia, this is not yet used widely due
to frequent technical difficulties, requirement for closer
ward monitoring, and fears of complications such as cauda
equina syndrome.39 70
Like postoperative pain, opioid-related adverse effects,
especially nausea and vomiting, are a major concern to
patients and can delay discharge from hospital.41 54
Unfortunately, however, opioid-related adverse effects are
almost never investigated as a primary outcome. Despite
this we found, primarily Level II evidence, that single shot
and continuous LPB, continuous spinal analgesia, and epidural analgesia (Level I) reduced postoperative nausea and
vomiting.5 37 45 59 A reduction in morphine consumption
was not always associated with a reduction in adverse
effects, but this may be due to inadequate powering. The
five RCTs in which no benefit was observed were all
graded as Level II. These were either inadequately
powered or had poor methodological quality.
We found that RA or regional analgesia does not appear
to significantly shorten length of stay in hospital or hasten
postoperative rehabilitation for THA. This apparent lack of
sustained benefit in the setting of THA is quite different
from RCTs examining the TKA population, which is
likely due to rapidly decreasing pain after THA in comparison with TKA.15 60 Furthermore, postoperative physiotherapy in TKA can exacerbate pain severity. Finally,
many centres performing major joint surgery now
implement clinical pathway protocols. It may become
increasingly difficult to detect differences in length of stay
based on mode of anaesthesia as streamlined care often
results in all patients being discharged at similar times.
In conclusion, we found insufficient evidence from
RCTs alone to conclude whether anaesthetic technique
influenced mortality, cardiovascular morbidity, duration of
surgery, or the incidence of DVT and PE in the setting of
routine thromboprophylaxis. Our systematic review does
suggest that blood loss may be reduced in patients receiving RA rather than GA for THA. Regional analgesia does,
however, reduce postoperative pain and also nausea and
vomiting. Length of stay is not reduced and rehabilitation
does not appear to be facilitated by RA or analgesia for
THA. Sixteen of the 18 RCTs identified were of Level II
quality and therefore further work is required to investigate
whether RA influences the majority of outcomes after
THA.
Supplementary material
Supplementary material is available at British Journal of
Anaesthesia online.
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arthroplasty: a randomized controlled trial. Reg Anesth Pain Med
2007; 32: 393 –8
60 Singelyn FJ, Deyaert M, Joris D, Pendeville E, Gouverneur JM.
Effects of intravenous patient-controlled analgesia with morphine,
continuous epidural analgesia, and continuous three-in-one block
on postoperative pain and knee rehabilitation after unilateral
total knee arthroplasty. Anesth Analg 1998; 87: 88 –92
61 Singelyn FJ, Ferrant T, Malisse MF, Joris D. Effects of intravenous
patient-controlled analgesia with morphine, continuous epidural
analgesia, and continuous femoral nerve sheath block on rehabilitation after unilateral total-hip arthroplasty. Reg Anesth Pain Med
2005; 30: 452 –7
62 Smith MP, Sandberg WS, Foss J, et al. High-throughput operating
room system for joint arthroplasties durably outperforms routine
processes. Anesthesiology 2008; 109: 25 – 35
63 Steele SM, Klein SM, D’Ercole FJ, Greengrass RA, Gleason D. A new
continuous catheter delivery system. Anesth Analg 1998; 87: 228
64 Stevens M, Harrison G, McGrail M. A modified fascia iliaca compartment block has significant morphine-sparing effect after total
hip arthroplasty. Anaesth Intensive Care 2007; 35: 949 – 52
65 Stevens RD, Van Gessel E, Flory N, Fournier R, Gamulin Z.
Lumbar plexus block reduces pain and blood loss associated with
total hip arthroplasty. Anesthesiology 2000; 93: 115– 21
66 Thorburn J, Louden JR, Vallance R. Spinal and general anaesthesia
in total hip replacement: frequency of deep vein thrombosis. Br J
Anaesth 1980; 52: 1117 – 21
67 Twyman R, Kirwan T, Fennelly M. Blood loss reduced during hip
arthroplasty by lumbar plexus block. J Bone Joint Surg Br 1990; 72:
770 – 1
68 Uhrbrand B, Jensen TT, Bendixen DK, Hartmann-Andersen JF.
Perioperative analgesia by 3-in-one block in total hip arthroplasty.
Prospective randomized blind study. Acta Orthop Belg 1992; 58:
417 – 9
69 Urwin SC, Parker MJ, Griffiths R. General versus regional anaesthesia for hip fracture surgery: a meta-analysis of randomized
trials. Br J Anaesth 2000; 84: 450 – 5
70 Van Gessel E, Forster A, Gamulin Z. A prospective study of the
feasibility of continuous spinal anesthesia in a university hospital.
Anesth Analg 1995; 80: 880– 5
71 Viscusi ER, Martin G, Hartrick CT, Singla N, Manvelian G.
Forty-eight hours of postoperative pain relief after total hip
arthroplasty with a novel, extended-release epidural morphine
formulation. Anesthesiology 2005; 102: 1014 – 22
72 Watson MW, Mitra D, McLintock TC, Grant SA. Continuous
versus single-injection lumbar plexus blocks: comparison of the
effects on morphine use and early recovery after total knee
arthroplasty. Reg Anesth Pain Med 2005; 30: 541 – 7
73 Weller R, Rosenblum M, Conard P, Gross JB. Comparison of epidural and patient-controlled intravenous morphine following joint
replacement surgery. Can J Anaesth 1991; 38: 582 – 6
74 Williams BA, Kentor ML, Vogt MT, et al. Economics of nerve
block pain management after anterior cruciate ligament reconstruction: potential hospital cost savings via associated postanesthesia care unit bypass and same-day discharge. Anesthesiology
2004; 100: 697 – 706
75 Williams BA, Kentor ML, Williams JP, et al. Process analysis in
outpatient knee surgery: effects of regional and general anesthesia on anesthesia-controlled time. Anesthesiology 2000; 93:
529 – 38
76 Williams-Russo P, Sharrock NE, Haas SB, et al. Randomized trial
of epidural versus general anesthesia: outcomes after primary
total knee replacement. Clin Orthop Relat Res 1996; 331: 199 – 208
77 Wu CL, Hurley RW, Anderson GF, Herbert R, Rowlingson AJ,
Fleisher LA. Effect of postoperative epidural analgesia on morbidity and mortality following surgery in medicare patients. Reg
Anesth Pain Med 2004; 29: 525 – 33
78 Wulf H, Biscoping J, Beland B, Bachmann-Mennenga B, Motsch J.
Ropivacaine epidural anesthesia and analgesia versus general
anesthesia and intravenous patient-controlled analgesia with morphine in the perioperative management of hip replacement.
Ropivacaine Hip Replacement Multicenter Study Group. Anesth
Analg 1999; 89: 111 – 6
345
“I would have everie man write what he knowes and no more.”– Montaigne
BRITISH JOURNAL OF ANAESTHESIA
Volume 101, Number 3, September 2008
British Journal of Anaesthesia 101 (3): 291–3 (2008)
doi:10.1093/bja/aen232
Editorial I
Haematoma and abscess after epidural analgesia
The survey by Meikle and colleagues1 published in this
month’s British Journal of Anaesthesia highlights the
uncommon but catastrophic complication of epidural haematoma. Although the incidence of symptomatic epidural
haematoma may appear small, amounting, they suggest, to
one case every 2 yr in the UK, it appears that the use of
epidural infusions is increasing, alongside an increase in
prophylactic anticoagulation and low-dependency care of
patients with indwelling epidural catheters.2 The results of
this survey indicate that the incidence of epidural haematoma may, in fact, be significantly higher than suggested
by reported cases, and the ongoing national audit by the
Royal College of Anaesthetists may give us a better indication of the true risk of this complication.
Similar catastrophic injury may result also from epidural
abscess, which has been reported in one UK hospital to
occur with a frequency of 1 in 800, when epidural catheters
were inserted for postoperative pain management.3 Our
experience from forensic practice is that Meikle (and
previous authors) underestimate the incidence of epidural
haematoma considerably, but that the experience of Phillips
and colleagues overestimates the risk of abscess nationally.
The incidence of epidural haematoma and abscess probably
varies in different patient populations; Scott and Hibbard4
reported two haematomas and one abscess after 505 000
epidural blocks in obstetric practice. The incidence in
higher risk patients is likely to be greater. For example,
Ngan Kee and colleagues5 reported a higher incidence after
thoracic epidural analgesia and Okano and colleagues6
noted 11 out of 30 patients with epidural abscesses had an
underlying illness or were receiving steroid therapy.
Two of us (A.R.A. and J.G.H.) have encountered, in
medicolegal practice, 11 cases of epidural haematoma in an
11 yr period (the events occurred between 1997 and 2007)
and eight cases of epidural abscess in a 10 yr period
(between 1995 and 2004). Failure to discontinue epidural
infusions after the presentation of new neurological signs
(especially leg weakness) and failure to recognize the
urgency of diagnosis and surgery after suspicion of epidural
haematoma appear frequently in such cases. In contrast to
epidural haematomas, which usually present during the epidural infusion,7 abscesses often present late and after the
patient has left hospital,3 8 – 10 but for those which present
before discharge and for the large majority of epidural haematomas, our experience is that there is usually a significant
delay before diagnosis because junior surgical trainees,
inexperienced anaesthetists, or both wrongly attribute the
onset of weakness and increasing numbness to the effects
of the local anaesthetic. The infusion is usually continued
for hours,7 and sometimes for several days, before the
opinion of an experienced anaesthetist is sought, resulting
in permanent neurological damage. It is impossible to
educate all trainee surgeons and nurses to recognize the
significance of these clinical signs, and we agree that strict
protocols offer the best solution to early diagnosis, investigation, and treatment.
Although reporting-bias affects the incidence calculated
from reported cases, examination using closed-claim
analysis has similar flaws. Closed-claim analysis allows a
glimpse of cases that would usually not be reported.
However, the technique must also underestimate the true
incidence of complications because not all patients who
suffer complications sue. Patients who decide to sue have
usually suffered a significant and long-lasting injury, and
have been able to secure funding for their claim. In
addition, the true incidence of a complication which leads
to litigation cannot be estimated accurately from the
experience of two individuals. The number of other
patients who have entered litigation proceedings in relation
to epidural haematoma or abscess in the UK in the last
10– 11 yr is unknown.
Another method of estimating the extent of damage
caused by specific anaesthetic techniques is to consider the
costs of claims handled by large insurance or indemnity
organizations. Between April 1995 and October 2005, the
Clinical Negligence Scheme for Trusts (CNST), which
deals with litigation for all NHS hospitals in England,
handled 251 claims associated with epidural blocks.11
# The Board of Management and Trustees of the British Journal of Anaesthesia 2008. All rights reserved. For Permissions, please e-mail: [email protected]
Editorial I
The claims had a total value of £32 346 737 (an average
of £128 871 each). There were lower incidences of brain
damage and fatality in claims related to epidural block
than in those associated with general anaesthesia.
However, there were higher incidences of nerve damage,
paraplegia, partial paralysis, spinal damage, and unnecessary pain. We have been unable to establish how many of
these claims were related to delay in recognizing the
symptoms and signs of epidural haematoma or abscess,
but the size of the settlements suggests that the proportion
of these 251 patients suffering debilitating neurological
injury was not inconsiderable.
Meikle and colleagues1 recommend that patients should
receive neurological observations at least every 4 h and
that these observations should continue for at least 24 h
after removal of the epidural catheter. This recommendation seems valid in view of the previously reported
cases of haematoma and abscess formation after catheter
removal.5 8 12 Every department should have readily available written guidelines regarding the use of neuraxial techniques in patients with potentially altered coagulation.13
The authors also recommend the cessation of the epidural
infusion after the presentation of new neurological signs,
with suspicion of epidural haematoma if these signs do
not resolve. The authors do not recommend a minimum
time interval between the suspicion of haematoma or the
cessation of the infusion and MRI scanning; we suggest
that no more than 4 h should elapse between the onset of
new neurological signs and MRI scanning, and this scan
(and ideally, the patient) should be assessed by an expert.
Should there be a delay in stopping the epidural infusion
after the presentation of new signs, then MRI scanning
may need to take place before the local anaesthetic effect
of the epidural may be expected to resolve.
In hospitals without expertise to carry out surgical
decompression, protocols and procedures need to be in
place to ensure that patients are transferred to a unit where
surgery can be performed within 12 h of the onset of
weakness or increasing numbness to optimize the chance
of recovery. In the absence of focal neurological signs,
conservative management of epidural abscess may be
successful14 – 17 but frequently urgent surgical evacuation
is required.9 18 – 22
Owing to the low incidence of epidural haematoma, we
will never be in a position to introduce true, evidencebased practice. Even if studies of sufficient size are
conducted, their relevance will be limited by constant
evolution in practice. Thus, we are obliged to apply
common-sense and learning to help our patients avoid
a life-damaging event. The relative rarity of epidural haematoma and abscess means that expensive and laborious
additions to current practice are not appropriate, but the
simple measures suggested by Meikle and colleagues need
not be expensive or laborious, and we wholly commend
them to practising anaesthetists in the UK. It is likely that
the introduction of strict protocols would minimize or
prevent the development of permanent and disabling
neurological injury in a considerably larger number of
patients than they suggest.
N. M. Bedforth1
A. R. Aitkenhead2
J. G. Hardman2*
1
Department of Anaesthesia
Queen’s Medical Centre
Nottingham NG7 2UH
UK
2
University Department of Anaesthesia
Queen’s Medical Centre
Nottingham NG7 2UH
UK
*E-mail: [email protected]
References
1 Meikle J, Bird S, Nightingale JJ, White N. Detection and management of epidural haematomas related to anaesthesia in the UK:
a national survey of current practice. Br J Anaesth 2008; 101:
400 – 4
2 Burstal R, Wegener F, Hayes C, Lantry G. Epidural analgesia: prospective audit of 1062 patients. Anaesth Intensive Care 1998; 26: 165–72
3 Phillips JM, Stedeford JC, Hartsilver E, Roberts C. Epidural abscess
complicating insertion of epidural catheters. Br J Anaesth 2002; 89:
778 – 82
4 Scott DB, Hibbard BM. Serious non-fatal complications associated
with extradural block in obstetric practice. Br J Anaesth 1990; 64:
537 – 41
5 Ngan Kee WD, Jones MR, Thomas P, Worth RJ. Extradural abscess
complicating extradural anaesthesia for Caesarean section. Br J
Anaesth 1992; 69: 647 – 52
6 Okano K, Kondo H, Tsuchiya R, Naruke T, Sato M, Yokoyama R.
Spinal epidural abscess associated with epidural catheterization:
report of a case and a review of the literature. Jpn J Clin Oncol
1999; 29: 49– 52
7 Christie IW, McCabe S. Major complications of epidural analgesia after
surgery: results of a six-year survey. Anaesthesia 2007; 62: 335–41
8 Hearn M, Roberts C. Epidural abscess complicating insertion of
epidural catheters. Br J Anaesth 2003; 90: 706 – 7
9 Strong WE. Epidural abscess associated with epidural catheterization: a rare event? Report of two cases with markedly delayed
presentation. Anesthesiology 1991; 74: 943 – 6
10 Sowter MC, Burgess NA, Woodsford PV, Lewis MH. Delayed
presentation of an extradural abscess complicating thoracic extradural analgesia. Br J Anaesth 1992; 68: 103 – 5
11 Catchpole K, Bell D, Johnson S, Boult M. Reviewing the evidence
of patient safety incidents in anaesthetics. Internal Report. The
National Patient Safety Agency, 2006
12 Yin B, Barratt SM, Power I, Percy J. Epidural haematoma after
removal of an epidural catheter in a patient receiving high-dose
enoxaparin. Br J Anaesth 1999; 82: 288 – 90
13 Prophylaxis of venous thromboembolism; spinals and epidurals.
SIGN publication No 62, October 2002. ISBN 1899893 03
2. Available from http://www.sign.ac.uk/guidelines
14 Dysart RH, Balakrishnan V. Conservative management of extradural abscess complicating spinal-extradural anaesthesia for
Caesarean section. Br J Anaesth 1997; 78: 591– 3
292
Editorial II
15 Leys D, Lesoin F, Viaud C, et al. Decreased morbidity from acute
bacterial spinal epidural abscesses using computed tomography
and nonsurgical treatment in selected patients. Ann Neurol 1985;
17: 350 – 5
16 Hanigan WC, Asner NG, Elwood PW. Magnetic resonance
imaging and the nonoperative treatment of spinal epidural
abscess. Surg Neurol 1990; 34: 408 – 13
17 Mampalam TJ, Rosegay H, Andrews BT, Rosenblum ML, Pitts LH.
Nonoperative treatment of spinal epidural infections. J Neurosurg
1989; 71: 208 –10
18 Borum SE, McLeskey CH, Williamson JB, Harris FS, Knight AB.
Epidural abscess after obstetric epidural analgesia. Anesthesiology
1995; 82: 1523– 6
19 Del Curling O, Jr, Gower DJ, McWhorter JM. Changing concepts
in spinal epidural abscess: a report of 29 cases. Neurosurgery
1990; 27: 185 –92
20 Hlavin ML, Kaminski HJ, Ross JS, Ganz E. Spinal epidural abscess:
a ten-year perspective. Neurosurgery 1990; 27: 177 – 84
21 Lange M, Tiecks F, Schielke E, Yousry T, Haberl R, Oeckler R.
Diagnosis and results of different treatment regimens in
patients with spinal abscesses. Acta Neurochir (Wien) 1993; 125:
105 – 14
22 Danner RL, Hartman BJ. Update on spinal epidural abscess: 35
cases and review of the literature. Rev Infect Dis 1987; 9: 265 – 74
British Journal of Anaesthesia 101 (3): 293–5 (2008)
doi:10.1093/bja/aen233
Editorial II
NICE and warm
Inadvertent perioperative hypothermia, defined as core
body temperature 36.08C, is a common consequence of
anaesthesia. Its adverse effects are well known to anaesthetists and include greater intraoperative blood loss and
consequent blood transfusion.1 After operation, inadvertent
perioperative hypothermia can lead to an increased rate of
wound infection,2 morbid cardiac events,3 and pressure
sores,4 and also a longer stay in both recovery and
hospital.5 These are apart from the subjective discomfort
and wound pain which cold and shivering may cause the
patient. Significantly, maintaining normothermia perioperatively can modify these adverse effects.
Despite this knowledge, implementation of warming
strategies remains patchy. An audit in the hospital of one
of the authors (C.M.H.) indicated that there is an incidence
of inadvertent perioperative hypothermia in the region of
20% and that there is inconsistency in the methods of
warming used. There are no active temperature management protocols and, as with anything that may cost money,
there is resistance to more aggressive prevention of inadvertent perioperative hypothermia on economic grounds.
In the USA, where there are guidelines,6 compliance
remains poor. It has been suggested that there are a
number of factors contributing to this: a misguided belief
that forced-air warming can increase the rates of infection,7
surgeons’ complaints of discomfort, inconsistent monitoring
(hindered by the inconsistency between different thermometers and sites of measurement), and a simple lack of
appreciation of the causes and consequences of inadvertent
perioperative hypothermia.8 Additionally, even where
there are standards such as those of the American Society
of Anesthesiologists (ASA),9 they are criticized for being
vague and giving flexibility at the expense of clear
guidance.8
Recognizing the significance of inadvertent perioperative hypothermia and the deficiencies in current practice in
the UK, the National Institute for Clinical Excellence
(NICE) convened a guideline development group to
address the issue. This culmination of the group’s work
came with the publication of the ‘Management of inadvertent perioperative hypothermia in adults’ guideline.10
The guidance is divided into the pre-, intra-, and postoperative phases. Before operation, the key recommendations are that a formal assessment of the risk of
hypothermia should be undertaken for each patient and
that patients themselves should be empowered by being
given information that will help them minimize that risk.
Another important element is that the temperature should
be measured in the hour before surgery. Should it be
,36.08C, unless the operation is life or limb saving, active
warming should be initiated until such time as the patient
is normothermic.
Intraoperatively, the recommendations are that forced-air
warming is commenced as early as possible, preferably in
the anaesthetic room, for any patient having surgery with
an anaesthetic time (i.e. from first anaesthetic intervention
to arrival in recovery) of .30 min, or who has two or
more risk factors for inadvertent perioperative hypothermia. I.V. fluids should be warmed when .500 ml is to be
given.11 12 These recommendations therefore encompass
the majority of operations and infusions.
Monitoring is an integral part of perioperative thermal
management and one that remains neglected.13 The guide
recommends that core temperature should be recorded at
293
Anesthesiology 2005; 103:126 –9
© 2005 American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins, Inc.
A Comparative Study of Sequential Epidural Bolus
Technique and Continuous Epidural Infusion
Kenichi Ueda, M.D.,* Wasa Ueda, M.D., Ph.D.,† Masanobu Manabe, M.D., Ph.D.‡
Background: In this randomized, double-blind study, the
authors compared the effectiveness of a sequential epidural
bolus (SEB) technique versus a standard continuous epidural
infusion (CEI) technique of local anesthetic delivery. Both techniques used the same hourly dose of local anesthetic.
Methods: Sixteen gynecologic patients undergoing abdominal surgery received postoperative epidural analgesia using
0.75% ropivacaine at a dose of 22.5 mg (3 ml) per hour. Patients
were randomly assigned to one of two groups. In the SEB group
(n ⴝ 8), patients received one third of the hourly dose every 20
min as a bolus. In the CEI group (n ⴝ 8), the hourly dose was
administered as a continuous infusion. Analgesia was assessed
by rest pain scored by a visual analog scale and pinprick to
determine the number of separately blocked spinal segments
on each side of the body. Doses of rescue medication for pain
were also recorded.
Results: The median number of blocked spinal segments was
19.5 (range, 18 –24) in the SEB group and 11.5 (range, 10 –18) in
the CEI group (P < 0.001). The median difference in the number
of blocked segments between the right and left sides was 0
(range, 0 –1) in the SEB group and 2 (range, 0 – 6) in the CEI
group (P < 0.04). No patients in the SEB group but one patient
in the CEI group required rescue medication for pain. The visual
analog scale pain score was 0 in both groups except for one
patient in the CEI group during the study period.
Conclusion: The SEB technique with ropivacaine provides
superior epidural block compared with an identical hourly dose
administered as a continuous infusion.
infusion (CEI) to achieve a similar quality of epidural
analgesia.5 Further, Sia and Chong6 found that PCEA
could provide satisfactory epidural analgesia even when
the background infusion was eliminated. These findings
caused us to hypothesize that an intermittent bolus administration with regular intervals independent of patient demand could be superior to CEI for producing
epidural sensory block with better quality. To test this
new epidural delivery mode, we provided postoperative
epidural analgesia by two different techniques, using
identical hourly doses of local anesthetic. One group of
patients received the standard CEI technique. The other
group received a sequential epidural bolus technique
(SEB) in which one third of the hourly dose was administered every 20 min.
Materials and Methods
The study protocol was approved by the Ethics Committee of the Kochi Medical School (Kochi, Japan) and
written informed consent was obtained from each patient. The study group consisted of 16 gynecologic patients with American Society of Anesthesiologists physical status I or II who were scheduled to undergo lower
abdominal surgery. None of the patients had previous
experience with epidural analgesia.
All patients received standardized anesthetic care by
the same anesthesiologist for the surgery. Oral diazepam,
10 mg, was administered 1 h before surgery. The epidural catheter (18 gauge; Portex, Kent, United Kingdom)
was placed before induction of anesthesia, with the
patient in the right lateral decubitus position, at the
T11–T12 or T12–L1 spinal interspace using the paramedian approach. General anesthesia included mask induction with sevoflurane, tracheal intubation, and maintenance with 1.0% end-tidal concentration of isoflurane in
oxygen. Muscle relaxation was facilitated with vecuronium. No opioids were administered. After induction of
general anesthesia, an initial epidural dose of 8 ml lidocaine, 2%, with 1:200,000 epinephrine was administered.
Thereafter, 1 ml lidocaine, 2%, with 1:200,000 epinephrine
was given as a bolus every 10 min until the end of the
surgery. If a patient showed any reaction to the surgical
maneuvers that required more than 1.2% end-tidal concentration of isoflurane to control, we eliminated the case from
the study because of failed epidural block.
At the end of surgery, patients were given either SEB or
CEI according to a computerized random-number generator. Both groups received 0.75% ropivacaine at a dose
of 3 ml/h. In the SEB group (n ⫽ 8), ropivacaine was
CONTINUOUS epidural analgesia now plays an important role in postoperative pain control.1 In the standard
continuous epidural infusion technique (CEI), the initial
dose establishes the requisite extent of analgesia, and
then continuous infusion preserves it. Over time, however, some patients experience diminution of analgesia,
characterized by a reduction in the number of blocked
spinal segments and development of unequal right and
left blockade. In such cases, additional top-up doses are
necessary. The development of patient-controlled epidural analgesia (PCEA) permitted patients to superimpose a limited volume of bolus dosing on continuous
infusion. PCEA was first applied to obstetrics2 and was
then found to be effective in postoperative pain control
that requires a steady level of analgesia.3,4
Interestingly, patients with PCEA required less local
anesthetic than did patients with continuous epidural
* Assistant Professor, ‡ Professor, Department of Anesthesia, † Professor,
Department of Perioperative Care and Medicine, Kochi Medical School.
Received from the Department of Anesthesia, Kochi Medical School, Kochi,
Japan. Submitted for publication October 4, 2004. Accepted for publication
February 28, 2005. Support was provided solely from institutional and/or departmental sources.
Address reprint requests to Dr. Ueda: Department of Anesthesiology, Kochi
Medical School, Nankoku, Kochi, Japan 783-8505. Address electronic mail to:
[email protected]. Individual article reprints may be purchased through the
Journal Web site, www.anesthesiology.org.
Anesthesiology, V 103, No 1, Jul 2005
126
COMPARISON OF EPIDURAL DOSING METHODS
given as a sequential epidural bolus of 1 ml every 20 min.
In the CEI group (n ⫽ 8), ropivacaine was given as a
continuous epidural infusion. Patients were blinded to
the drug administration technique. On arriving at the
postanesthesia care unit, patients were asked to rate
their pain experience on a visual analog scale (VAS).
Only rest pain was assessed by nurses who were not
aware of this study. The patients stayed in the postanesthesia care unit for 3 h to confirm that the pain control
was adequate. In the ward, the patients were allowed to
take diclofenac suppositories as rescue medication from
an independent nurse.
An independent nurse in the ward assessed vital signs
and rest pain score by VAS every 4 h. If a patient experienced hypotension, bradycardia, or bradypnea, epidural infusion was discontinued and the acute pain service team was called for assessment. Hypotension was
defined as a systolic blood pressure of less than 90
mmHg, bradycardia was defined as a heart rate of less
than 50 beats/min, and bradypnea was defined as a
respiratory rate of less than 10 breaths/min.
Anesthesiologists who were unaware of the infusion
mode visited the patients after the 15 h of ropivacaine
infusion. Using a dermatome chart,7 the extent of analgesia was judged by the number of blocked spinal segments as determined by the pinprick method.
To produce the SEB mode, we modified the program
of the standard infusion pump (SP-80RS; Nipro, Osaka,
Japan) so that the pump divided the hourly dose into
three parts and infused each every 20 min as a bolus
(bolus rate of 500 ml/h).
Statistics
A pilot study with 12 patients showed the number of
blocked spinal nerve segments to be 21 ⫾ 3 (mean ⫾
SD) in the SEB group and 13 ⫾ 3 in the CEI group. The
sample size to give a power of 0.8 with an ␣ of 0.05
was 4 when the expected difference was 8 ⫾ 3. The
difference in the number of blocked segments between the right and left sides was 0 ⫾ 0 in the SEB
group and 3 ⫾ 2 in the CEI group. The sample size to
give a power of 0.8 with an ␣ of 0.05 was 7 when the
expected difference was 2 ⫾ 1. Therefore, we decided
to use a sample size of 16. The measured data were
rejected by normality test, so we compared the two
groups by Mann–Whitney rank sum test. Statistical
analysis with SigmaStat 3.0 (SPSS Inc., Chicago, IL)
yielded a significant probability value of less than 0.05.
Continuous data are expressed as medians, with the
ranges given in parentheses.
Results
Table 1 shows the demographic data of the patients
studied. There was no statistical difference in the physAnesthesiology, V 103, No 1, Jul 2005
127
Table 1. Demographic Data of the Patients Studied
n
Age, yr
Height, cm
Body weight, kg
ASA PS, I/II
SEB Group
CEI Group
8
33.5 (21–48)
154 (150–159)
54 (45–68)
7/1
8
33.5 (20–50)
156 (150–162)
53.5 (48–65)
7/1
Values are presented as mean or n, with range in parentheses.
ASA PS ⫽ American Society of Anesthesiologists physical status.
ical status between the two groups. Surgical epidural
block was successful in all patients. No patient in either
group had hypotension, bradycardia, or bradypnea during the study.
Figure 1 shows the extent of sensory blockade obtained after the 15 h of epidural infusion in the study.
SEB produced a larger band of sensory blockade. The
median number of blocked spinal nerve segments in the
SEB group was 19.5 (range, 18 –24), and that in the CEI
group was 11.5 (range, 10 –18) (P ⬍ 0.001). SEB also
significantly improved equal right and left distribution of
sensory blockade. The median difference in the number
of blocked spinal segments between the right and left
sides, expressed by spinal nerve segment, in the SEB
group was 0 (range, 0 –1), and that in the CEI group was
2 (range, 0 – 6) (P ⬍ 0.04).
One patient in the CEI group required rescue medication for left lower abdominal pain. In this patient, there
was a significant difference between the right and left
side analgesia, with segments T8 –L2 blocked on the
Fig. 1. Extent of sensory blockade after 15 h of epidural infusion. In the sequential epidural bolus (SEB) group (n ⴝ 8),
0.75% ropivacaine was given as a sequential epidural bolus of 1
ml every 20 min. In the continuous epidural infusion (CEI)
group (n ⴝ 8), 0.75% ropivacaine was given as a continuous
epidural infusion. The median number of blocked spinal segments was 19.5 (range, 18 –24) in the SEB group and 11.5 (range,
10 –18) in the CEI group (P < 0.001). The median difference in
the number of blocked segments between the right and left
sides was 0 (range, 0 –1) in the SEB group and 2 (range, 0 – 6) in
the CEI group (P < 0.04).
128
UEDA ET AL.
Fig. 2. Spread of contrast medium after
injection of 1 ml iotrolan, 240 mg I/ml.
Epidurograms A and B were taken from
different patients to locate the epidural
catheters, which were placed for chronic
pain management. The length of the arrow represents right- or left-sided spread
of contrast medium. (Courtesy of Masataka Yokoyama, M.D., Department of
Anesthesiology, School of Medicine,
Okayama University, Okayama, Japan.)
right side but only T9 –T11 on the left side. Accordingly,
the pain score at rest by VAS was 0 in both groups,
except for one patient in the CEI group who scored 3 as
the maximum VAS score during the study.
Discussion
In this study, local anesthetic administered as a sequential epidural bolus (SEB) provided greater longitudinal
extension of sensory blockade than continuous epidural
infusion (CEI). The SEB technique also improved equal
right and left distribution of sensory blockade compared
with CEI. We propose some possible explanations.
First, the bolus technique may have a different mode of
spread through the epidural space as compared with
continuous infusion. It is known that some of the epidural local anesthetic is captured by perineural tissue or
removed by blood vessels, making it unavailable for
nerve block.8 A bolus of local anesthetic likely spreads
further longitudinally and bilaterally before such capture
occurs than does continuous infusion.
It seems unlikely that only a 1-ml bolus of local anesthetic would make such a significant difference as compared with continuous infusion. Nonetheless, 1 ml contrast medium (iotrolan, 240 mg I/ml) when given as a
bolus can clearly appreciate an extended area in the
epidural space (fig. 2). This is impossible by continuous
infusion of the medium. Yokoyama et al.9 showed that
the behavior of the local anesthetic and contrast medium
inside the epidural space were well correlated. Therefore, bolus dosing has the potential to increase the
spread of local anesthetic in the epidural space, and a
bolus as small as 1 ml, as used in the current study, might
have contributed to the success of SEB.
Second, proper timing of epidural dosing is key to
maintain effective analgesia. If diminution of the epidural blockade occurs, sensory neural input to the spinal
cord has been shown to accelerate the decline of the
Anesthesiology, V 103, No 1, Jul 2005
block.10 If this occurs, a larger dose of local anesthetic is
required to restore analgesia. If instead the same dose of
anesthetic is used before decay of analgesia, the extent
of analgesia may increase.11 In the current SEB, the bolus
administration might have occurred at regular intervals
before decay of sensory neural block, thereby increasing
the number of sensory-blocked spinal segments.
Ropivacaine, 0.75%, produced profound neural block
sufficient to control pain without the help of opioids in
the current study. Epidural analgesia has commonly
been induced with local anesthetic combined with opioids to increase the quality of analgesia. Adverse effects
of opioids, however, have the potential to cause complications.12 To avoid such adverse effects and also to
clearly define the range of sensory neural block, we
performed epidural block exclusively by local anesthetic. The concentration was decided according to the
recommendation by Sakura et al.13; concentration determines the intensity of sensory block such that a high
concentration and a small volume, rather than a low
concentration and a high volume, are suitable when
profound neural blockade is required. The volume given
to the current patients was to achieve sufficient analgesia with CEI and thereby caused no difference in VAS
pain score between the SEB and CEI groups. Because the
range of blocked segments was so extended with SEB, it
may be possible to reduce the dose of the anesthetic in
SEB. Further studies are needed to establish the optimal
timing, concentration, and volume of anesthetic for SEB
in various conditions.
There are limitations to our study design. First, we
evaluated the epidural-blocked segments at only a single
data point (15 h). We did not study a longer duration of
infusion. This may have been insufficient to ascertain the
effects of SEB. Secondary, the lidocaine used for surgical
anesthesia could have affected our results. We believe
this is unlikely because effective surgical analgesia by 2%
COMPARISON OF EPIDURAL DOSING METHODS
lidocaine with epinephrine lasts for 2–3 h at the most.14
After 15 h, the residual effect of lidocaine is negligible.
Another issue is whether SEB is economical. SEB requires a special infusion pump. To produce the SEB
mode, we modified the operating program of a computer-controlled syringe pump for this study. Multipurpose
infusion pumps equipped with various infusion modes
currently available allow SEB in clinical practice. Such
pumps are more expensive than pneumatic infusion
pumps. However, an electrical pump uses a disposable
plastic reservoir with tubing, which is less expensive
and, as a medical waste product, less bulky than a disposable pneumatic infuser. As a whole, the expense
associated with the infusion pump may not be a drawback of SEB.
SEB would have the potential to replace CEI in various
situations. SEB can be applied to epidural anesthesia
during surgery. Also, it can be combined with PCEA.
Still, the possibility of local anesthetic overdose by programmed dose administration necessitates careful selection of dose and interval and continued assessment by
the anesthesiologist.
In conclusion, SEB improved the quality of sensory
blockade as compared with continuous epidural block in
this study. This infusion mode has the potential to increase the extent of sensory blockade as well as to
decrease unilateral blockade, thereby improving the reliability of epidural analgesia in postsurgical pain control.
The authors thank Masataka Yokoyama, M.D. (Associate Professor of Anesthesiology, Okayama University School of Medicine, Okayama, Japan), for his help in
providing epidurographic pictures. The authors also thank William Hammonds,
M.D. (Professor), and Alan Ross, M.D. (Associate Professor, Department of An-
Anesthesiology, V 103, No 1, Jul 2005
129
esthesia, University of Iowa Hospitals and Clinics, Iowa City, Iowa), for helpful
comments in the preparation of the manuscript.
References
1. Block BM, Lieu SS, Rowlingson AJ, Cowan AR, Cowan Jr, JA Wu CL: Efficacy
of postoperative epidural analgesia. JAMA 2003; 290:2455–63
2. Gambling DR, Yu P, Cole C, McMorland GH, Palmer L: A comparative study
of patient controlled epidural analgesia (PCEA) and continuous infusion epidural
analgesia (CIEA) during labour. Can J Anesth 1988; 35:249–54
3. Silvasti M, Pitkaenen M: Patient-controlled epidural analgesia versus continuous epidural analgesia after total knee arthroplasty. Acta Anaesthesiol Scand
2001; 45:471–6
4. Standl T, Burmeister M-A, Ohnesorge H, Wilhelm S, Striepke M, Gottschalk
A, Horn E-P, Esch JS: Patient-controlled epidural analgesia reduces analgesic
requirements compared to continuous epidural infusion after major abdominal
surgery. Can J Anesth 2003; 50:258–64
5. Antok E, Bordet F, Duflo F, Lansiaux S, Combet S, Taylor P, Pouyau A,
Paturel B, James R, Allaouchiche B, Chassard D: Patient-controlled epidural
analgesia versus continuous epidural infusion with ropivacaine for postoperative
analgesia in children. Anesth Analg 2003; 97:1608–11
6. Sia AT, Chong JL: Epidural 0.2% ropivacaine for labour analgesia: Parturientcontrolled or continuous infusion? Anesth Intensive Care 1999; 27:154–7
7. Barash PG, Cullen BF, Stoelting RK: Clinical Anesthesia, 4th edition. Philadelphia, JB Lippincott, 2001, p 692
8. Bromage PR: Mechanism of action of extradural analgesia. Br J Anesth 1975;
47:199–212
9. Yokoyama M, Hanazaki M, Fujii H, Mizobuchi S, Nakatsuka H, Takahashi T,
Matsumi M, Takeuchi M, Morita K: Correlation between the distribution of
contrast medium and the extent of blockade during epidural anesthesia. ANESTHESIOLOGY 2004; 100:1504–10
10. Ueda W, Sagara Y, Hirakawa M: Role of afferent neural input in regression
of sensory paralysis during epidural block. Anesth Analg 1992; 74:358–61
11. Cousins MJ, Bromage P: Epidural neural blockade, Neural Blockade, 2nd
edition. Edited by Cousins MJ, Bridenbaugh PO. Philadelphia, JB Lippincott,
1988, pp 253–360
12. Jorgensen H, Formsgaard JS, Dirks J, Wetterslev J, Andreasson B, Dahl JB:
Effect of epidural bupivacaine vs combined epidural bupivacaine and morphine on
gastrointestinal function and pain after major gynecological surgery. Br J Anesth
2001; 87:727–32
13. Sakura S, Sumi M, Kushizaki H, Saito Y, Kosaka Y: Concentration of
lidocaine affects intensity of sensory block during lumbar epidural anesthesia.
Anesth Analg 1999; 88:123–7
14. Camann W, Loferski B, Fanciullo G, Stone M, Datta S: Does epidural
administration of butorphanol offer any clinical advantage over the intravenous
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Anesthesiology 2008; 109:664 –74
Copyright © 2008, the American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins, Inc.
Population Pharmacokinetic–Pharmacodynamic Modeling
of Epidural Anesthesia
Erik Olofsen, M.Sc.,* Antonius G. L. Burm, Ph.D.,† Mischa J. G. Simon, M.D., Ph.D.,‡
Bernadette Th. Veering, M.D., Ph.D.,‡ Jack W. van Kleef, M.D., Ph.D.,§ Albert Dahan, M.D., Ph.D.†
Background: In previous studies, the authors reported on the
absorption and disposition kinetics of levobupivacaine and
ropivacaine. The current study was designed to develop a population pharmacokinetic–pharmacodynamic model capable of
linking the kinetic data to the analgesic effects of these local
anesthetics (i.e., sensory neural blockade).
Methods: A disposition compartmental model was fitted to
concentration data of the intravenously administered deuterium-labeled anesthetics, and a model consisting of two parallel
absorption compartments and the identified disposition
compartments was fitted to concentration data of the concomitantly epidurally administered unlabeled anesthetics.
The epidural segments were modeled by individual central
and peripheral absorption compartments and effect sites,
which were fitted to the simultaneously acquired pinprick
data. A covariate model incorporated the effects of age.
Results: The threshold for epidural anesthesia increased
from the lower to the higher segments. The central effect compartment equilibration half-lives were approximately 15 min
for levobupivacaine and 25 min for ropivacaine. For levobupivacaine, age reduced the equilibration half-lives at all segments;
for ropivacaine, age increased the anesthetic sensitivity at segments T12 and higher.
Conclusions: A population pharmacokinetic–pharmacodynamic model was developed that quantitatively described sensory blockade during epidural anesthesia, including the effects
of age. The model may be useful to individualize dose requirements, to predict the time course of sensory blockade, and to
study new local anesthetics.
dent on pharmacokinetic factors. The rate of systemic
absorption of local anesthetics gives some indication of
the relation between neural blockade and the amount of
drug remaining at or near the site of injection. In the past
two decades, we indirectly assessed epidural drug concentrations by estimation of the time course of systemic
absorption from the epidural space in humans.1–5
In our previous studies, the pharmacokinetic data
were analyzed for each individual separately. However,
population pharmacokinetic–pharmacodynamic (PKPD) analysis of epidural anesthesia is important because
it enables the description of both within- and betweensubject variability, enables the development of predictive models, and, consequently, improves therapeutic
outcome.6 Schnider et al.7 developed a population pharmacodynamic model to describe the time course and
blockade level of spinal anesthesia. The objective of the
current study was to develop a population PK-PD model
of epidural anesthesia based on pharmacokinetic absorption profiles. In a first attempt, we applied the model to
levobupivacaine and ropivacaine data and determined
the impact of age on the model parameters.
Materials and Methods
EPIDURAL anesthesia is obtained by the injection of a
local anesthetic drug into the epidural space. The clinical characteristics of the ensuing sensory neural blockade, such as onset time, intensity, and duration, depend
directly on the changes in the concentration of the local
anesthetic at the axonal membrane, which are depen-
Received from the Department of Anesthesiology, Leiden University Medical
Center, Leiden, The Netherlands. Submitted for publication September 11, 2007.
Accepted for publication June 18, 2008. Support was provided solely from
institutional and/or departmental sources.
Study Design
For the development of the epidural PK-PD model,
data were used from two previous studies3,5 on the
epidural injection of levobupivacaine and ropivacaine
(see table 1 for patient characteristics). In these studies,
arterial blood samples were obtained before, during, and
after the epidural injection of the local anesthetic (at the
L3–L4 interspace; table 2). The maximum duration of
sampling was 24 h. When after epidural injection satisfactory anesthetic conditions (i.e., the presence of a
bilateral sensory blockade, assessed by pinprick) were
obtained (usually 15–25 min after the injection), the
same but now deuterium (2H3)–labeled local anesthetic
was administered intravenously (table 2). Blockade assessments were made every 5 min during the first 30
min, every 15 min for the next 3.5 h, and subsequently
every 30 min for the next 6 h. Refer to our previous
publications for further details. For the current study,
there were no additional protocols that needed approval
of an institutional review board.
Address correspondence to Dr. Dahan: Department of Anesthesiology, Leiden
University Medical Center, P5-Q, P.O. Box 9600, 2300 RC Leiden, The Netherlands. [email protected]. Information on purchasing reprints may be found at
www.anesthesiology.org or on the masthead page at the beginning of this issue.
ANESTHESIOLOGY’s articles are made freely accessible to all readers, for personal use
only, 6 months from the cover date of the issue.
Development of the Pharmacokinetic Model
The reanalysis of the pharmacokinetic data from the
previous studies had two aims: (1) to obtain popula-
Additional material related to this article can be found on the
ANESTHESIOLOGY Web site. Go to http://www.anesthesiology
.org, click on Enhancements Index, and then scroll down to
find the appropriate article and link. Supplementary material
can also be accessed on the Web by clicking on the “ArticlePlus” link either in the Table of Contents or at the top of
the Abstract or HTML version of the article.
* Research Associate, † Professor of Anesthesiology, ‡ Staff Anesthesiologist,
§ Professor of Anesthesiology and Chairman. The authors regret the untimely
death of Dr. Toine Burm. They dedicate this work to his memory.
Anesthesiology, V 109, No 4, Oct 2008
664
PK-PD MODELING OF EPIDURAL ANESTHESIA
665
Table 1. Patient Characteristics
Anesthetic
Sex, No. F/M
Age, yr
Weight, kg
Height, cm
No. PK
No. PD*
Levobupivacaine
Ropivacaine
All
8/19
2/22
10/41
55.9 ⫾ 20.0
54.3 ⫾ 16.8
55.1 ⫾ 18.4
76.9 ⫾ 16.4
79.7 ⫾ 12.1
78.2 ⫾ 14.5
173 ⫾ 9.82
177 ⫾ 8.16
175 ⫾ 9.19
27
24
51
24
24
48
Data are mean ⫾ SD or number of patients where appropriate.
* For some of the patients, there were pharmacokinetic (PK) but no pharmacodynamic (PD) data available.
tion pharmacokinetic models for the local anesthetics
levobupivacaine and ropivacaine together with a covariate analysis (to enable individualization at the
pharmacokinetic level) and (2) to obtain optimal individual absorption parameters for a pharmacodynamic
model that describes the effects of those anesthetics
on sensory blockade (and to enable individualization
on the pharmacodynamic level). The pharmacokinetic
analysis was performed in four steps: (1) A threecompartment structural model was fitted to the concentration data of the intravenously administered labeled local anesthetics (fig. 1). (2) A model including
covariate age was developed. (3) A model, consisting
of two parallel absorption compartments and the
model of disposition developed in step 2, was fitted to
concentration data of the epidurally administered unlabeled local anesthetic (fig. 1; note that the disposition parameters were fixed to their empirical bayesian
[see Statistical Analysis section] values obtained in
step 2). (4) A model including covariate age was
developed.
The absorption compartments were characterized by
the following parameters: F1, F2, t½,a1, and t½,a2, denoting the fractions absorbed and absorption half-lives of
the two compartments. We used a parameterization
with F and F=
1 where F1 ⫽ F 䡠 F=
1 and F2 ⫽ F · (1 ⫺ F=
1),
because F, the total absorption, should be around 1, and
interindividual variability in F1 is likely to be counteracted by approximately the same variability in F2.
Development of the Pharmacodynamic Model
The Epidural Segments. Each segment was modeled
by its own central and peripheral absorption compartTable 2. Solutions and Amounts of Local Anesthetics
Administered in the Two Studies on Which the Current
Analysis Is Based
Unlabeled LA
Study
Concentration,
%
Amount,
ml
Dose,
mg
Labeled LA
Dose, mg
Levobupivacaine3
Ropivacaine5
0.75
1
18
15
126
125
23
20
The local anesthetics (LAs) were administered as short infusions: the unlabeled LAs epidurally, the deuterium-labeled LAs intravenously.
Anesthesiology, V 109, No 4, Oct 2008
ments (fig. 1). After a unit dose, the amount of anesthetic
in a central absorption compartment Ac(t), is given by
Ac共t兲 ⫽ F1 · exp共⫺ka1 · t兲 ⫹ F2 · exp共⫺ka2 · t兲, (1)
with ka1 ⫽ log(2)/t½,a1 and ka2 ⫽ log(2)/t½,a2 for convenience. The concentration Cc(t) in a central absorption
compartment after a dose consisting of amount A (fraction of total dose; see Main Assumptions section) of
anesthetic is then described by
Cc共t兲 ⫽ f1 · exp共⫺ka1 · t兲 ⫹ f2 · exp共⫺ka2 · t兲, (2)
with f1 ⫽ F1 䡠 A/Vc and f2 ⫽ F2 䡠 A/Vc, where Vc is the
volume of that central absorption compartment. Effect
sites were postulated to exist at each segment to account
for lags between the absorption compartment concentration and effect, quantified by equilibration rate constant ke0. The effect site concentration Ce(t; ke0) is then
given by
Ce共t; ke0兲
⫽
⫹
f1 · ke0
· exp共⫺ka1 · t兲 ⫺ exp 共⫺ke0 · t兲兲
ke0 ⫺ ka1 共
f2 · ke0
· exp共⫺ka2 · t兲 ⫺ exp 共⫺ke0 · t兲兲 (3)
ke0 ⫺ ka2 共
Epidural blockade (analgesia with respect to pinprick)
was assumed to occur when Ce(t; ke0) exceeds a concentration threshold Cthr (fig. 1).
Types of Observations. The acquired pharmacodynamic data contained three types of observations:
1. an interval (ton, toff) with Ce(ton; ke0) ⱖ Cthr where a
blockade occurred, and Ce(toff; ke0) ⬍ Cthr where the
blockade disappeared;
2. as type 1, but at the last assessment time a blockade
was still present; and
3. there was no blockade at all assessment times.
Although this might seem counterintuitive, a type 3
observation does provide information, because no blockade occurs because Cthr is relatively high, Vc is large,
and/or A is small. With only type 3 observations in the
data set, only a lower limit of Cthr can be determined for
a fixed ke0. Together with type 1 and type 2 observations, type 3 observations do allow for more accurate
estimates of Cthr and ke0. Evidently, also the reverse is
OLOFSEN ET AL.
666
Fig. 1. Schematic diagram of the pharmacokinetic–pharmacodynamic model. By
intravenous administration of a labeled
local anesthetic (LA), its disposition is
identified and described by pharmacokinetic parameters V1 (central volume) and
kij (distribution rate constants between
the compartments; V2 and V3 are derived
parameters). By epidural administration
of the unlabeled LA, its absorption is identified and described by parameters F1, F2,
ka1, and ka2. Assumption 1: At time T ⴝ 0,
the unlabeled LA administered at the
L3–L4 interspace spreads instantaneously
across all segments (for segments T9 and
T10, model details are given). Consequently, there is only drug distribution
between the central absorption compartments for T ⴝ 0, not for T > 0 (dashed
arrows), and there is no distribution between the effect sites via the cerebrospinal fluid (CSF) (dotted arrows). Assumption 2: For T > 0, the local absorption
profiles are identical to the identified
global absorption profile. Consequently,
the two parallel absorption compartments
are equivalent with the central and peripheral absorption compartments as described by parameters Vc, kabs, kcp, and kpc
(Vp is a derived parameter). When the effect site concentration Ce(t) is above a
threshold Cthr, a stimulus S is not perceived because it is blocked (e.g., at T10);
when Ce(t) is below Cthr, it is not blocked
and can be perceived (e.g., at T9).
true: When type 3 observations would be discarded,
estimates of Cthr would be biased downward.
Main Assumptions. According to the pharmacodynamic model, each segment is described by the following six parameters: F1, F2, ka1, ka2, ke0, and Cthr. In
addition, rate constants should be defined that describe
the transport of the anesthetic between segments. However, there were at most only two informative observations per dermatome, and the pharmacokinetic analysis
provides global rather than local absorption process parameters. So there are more parameters than observations. The following assumptions allowed us to proceed
(fig. 1):
1. The longitudinal spread of the anesthetic solution
across the segments of the epidural space occurs
instantaneously.
2. The parameters F1, F2, ka1, and ka2 are equal for each
segment, albeit that F1 and F2 are interpreted with
respect to the fraction of the dose that is present in
each segment after the initial spread.
Under these assumptions, both the local (segmental)
and global (total epidural; obtained by adding all local
absorption profiles) processes are described by the
same parameters as those obtained from the pharmacokinetic analysis. If the local absorption or transport
processes would be subject to large intrasegmental
variability, it is unlikely that the global absorption
Anesthesiology, V 109, No 4, Oct 2008
profile would display such a clear biphasic pattern.1,8
Furthermore, distribution via the cerebrospinal fluid
can be assumed to be minimal.9 We therefore believe
that the postulated assumptions are reasonable.
After the initial spread, the amounts (A) of anesthetic present in each of the segments, and the central
absorption volumes (Vc) at those segments, are not
simultaneously identifiable. Only a combination parameter Athr ⫽ Cthr 䡠 Vc/A can be estimated. For parameter
estimation, we therefore used (cf. equations 1 and 3):
Ae共t; ke0兲
⫽
F1 · ke0
· exp共⫺ka1 · t兲 ⫺ exp 共⫺ke0 · t兲兲
ke0 ⫺ ka1 共
⫹
F2 · ke0
· exp共⫺ka2 · t兲 ⫺ exp 共⫺ke0 · t兲兲 (4)
ke0 ⫺ ka2 共
and assumed that a blockade occurs when Ae(t; ke0) ⱖ
Athr. Parameter Athr is a measure of the anesthetic
sensitivity. With two observations per dermatome, the
remaining unknown parameter, ke0, can be estimated.
Parameters Athr and ke0 were assumed to be lognormally distributed across the population. Because of
the assumptions postulated, they can be estimated for
each of the segments independently. Further details
are given in the appendix.
PK-PD MODELING OF EPIDURAL ANESTHESIA
667
Covariate Analysis
The pharmacokinetic and pharmacodynamic parameters (␪, indexed by i) were multiplied by factors containing log-transformed and centered (at 50) covariate age:
␪i ⫽ ␪pop,i · exp共␣AGE,i · c ⫹ ␩i兲,
(5)
where ␪pop,i denote population (typical) values; c ⫽
log(age/50), ␣AGE,i denote covariate coefficients; and ␩i
denote residual interindividual variabilities.
Statistical Analysis
Statistical analysis of the pharmacokinetic data were
performed with the NONMEM version VI software package (a data analysis program for nonlinear mixed effects
modeling)10 using its routine ADVAN11 for three-compartmental models of the intravenous data and analytical
expressions (for processor time reduction) in $PRED for
the five-compartmental model of the epidural data. Nonzero variance terms of the ␩s were determined for the
population model without covariate age; the structure was
assumed to be the same for the model with the covariate
included (mainly a decrease in variances is to be expected).
Constant relative errors were assumed for the concentration measurements. All numerical results are given with
three significant digits (conform NONMEM output). The
empirical bayesian estimates (provided by NONMEM) of
the disposition parameters were used for the estimation of
the absorption parameters; the empirical bayesian estimates of the absorption parameters were used for the
estimation of the pharmacodynamic parameters.
Statistical analysis of the pharmacodynamic data was
performed using software written in the computer language C by one of the authors (E.O.) using the free GNU
Scientific Library (GSL).㛳 Additional information regarding this is available on the ANESTHESIOLOGY Web site at
http://www.anesthesiology.org. With distributions of
parameters Athr and ke0 postulated, the probability of
observing the data per dermatome can be computed by
integration across the (Athr, ke0) plane where it is possible that the data are as observed. The likelihood of
observing the data are the product of the probabilities of
all observations per dermatome. By maximizing this likelihood, the parameters of the lognormal distributions of
Athr and ke0 can be obtained. (Note that NONMEM cannot be used when the integrand used for integration
across the (Athr, ke0) plane is not continuous.) The
boundaries of the 95% confidence intervals of the parameter estimates were determined by those parameter values that increase the objective function by 3.84 points
(i.e., the likelihood profile method). Further details are
given in the appendix.
The improvement of the model fit by inclusion of
separate parameters for the different anesthetics and
㛳 Available at: http://www.gnu.org/software/gsl. Accessed April 1, 2008.
Anesthesiology, V 109, No 4, Oct 2008
covariate age via forward selection was based on
Akaike’s Information-Theoretic Criterion (AIC).11 The
best model was defined as the one with the lowest value
of the criterion, where AIC ⫽ MVOF ⫹ 2p, where MVOF
is the ⫺2 log-likelihood and p is the number of parameters. The model with the lowest value of the criterion is
assumed to have the best predictive properties.12,13
However, to present a classic measure of the significance
of difference from zero of each of the final covariate
coefficients of the pharmacokinetic models, likelihood
ratio tests were performed (⌬objective function value ⬎
3.84 corresponds to P ⬍ 0.05; ⌬objective function value
⬎ 6.63 corresponds to P ⬍ 0.01). To present a classic
measure of significance of the selected covariate coefficients of the pharmacodynamic models, their 95% confidence intervals were graphically displayed together
with zero ordinate lines.
Except for F=1, lognormal distributions were postulated
for all parameters. The value of F=1 was constrained between 0 and 1, which was accomplished by using the
inverse logit transformation on its ␩.
With distributions of Athr and ke0 available, the probability of blockade at each segmental level can be
determined as a function of time and age. Blockade
probabilities were computed with respect to a standardized dose of 100 mg for ropivacaine and 125 mg
for levobupivacaine.
Results
Pharmacokinetic Analysis
Best, median, and worst model fits of the labeled local
anesthetic concentration data (panels 1, 2, and 3, respectively) according to the coefficient of determination,
together with the corresponding model fits of the unlabeled local anesthetic concentration data, are shown in
figure 2. The worst model fits of the unlabeled local
anesthetic data still provide adequate inputs for the pharmacodynamic models.
Levobupivacaine and ropivacaine disposition parameter estimates are presented in table 3. The only parameter that differed significantly between the two anesthetics was k31. A significant effect of age on V1, and
therefore on elimination clearance, was detected. In
addition, a significant effect of age on intercompartmental distribution rate constant k12 was detected.
Levobupivacaine and ropivacaine absorption parameter estimates are presented in table 4. Parameters t½,a1
and t½,a2 were significantly different between the two
anesthetics. Significant effects of age on t½,a1 and F=1 were
detected. Parameter F was approximately 10% higher
than 1 for both anesthetics (and had small interindividual
variability around it).
OLOFSEN ET AL.
668
Fig. 2. Best, median, and worst model fits
(filled circles; panels 1, 2, and 3, respectively) according to the coefficient of determination (R2) for unlabeled levobupivacaine and ropivacaine concentration
data (panels A and B, respectively), together with the corresponding model fits
of the labeled local anesthetic concentration data (open circles). The numbers in
the subplots denote patient identification
number/R2 unlabeled/R2 labeled.
Pharmacodynamic Analysis
Figure 3 presents the population estimates of t1⁄2,ke0
(converted from the ke0 values for convenience of interpretation) and Athr with their 95% confidence intervals
for each segment separately. Both parameters were significantly different between levobupivacaine and ropivacaine. At the L2 segment level, parameter t1⁄2,ke0 was
approximately 5 min for levobupivacaine and 9 min for
ropivacaine, which approximately doubled at higher and
tripled at lower dermatome levels. Parameter Athr increased from S5 to T5, with the highest overall level for
levobupivacaine. The variabilities in ke0 and Athr were
approximately 45% and 25%, respectively (data not
shown).
Figure 4 presents the effects of age on the population
values. For levobupivacaine, age increase the equilibration rate constants ke0 at all segments. For ropivacaine,
age increased the anesthetic sensitivity Athr at segments
T12 and higher.
The nature of the pharmacodynamic data are such that
the model fits exactly for each individual and dermatome
(with two measurements (onset and offset of effect), and
two parameters (t1⁄2,ke0 and Athr)); only their probability
distributions across the population can be estimated.
The probabilities of blockade (after a dose of 100 mg
ropivacaine and 125 mg levobupivacaine) as a function
of time and age of the patient are presented in figure 5.
The effects of increasing age are clearly visible at the
higher segments (T9 and higher) where the probability
of block dramatically increases, and by the increase of
duration of block. To facilitate the interpretation of figure 5, a three-dimensional view of the blockade probabilities for levobupivacaine in a patient aged 50 yr is
given in figure 6. Additional information regarding this is
available on the ANESTHESIOLOGY Web site at http://www
.anesthesiology.org.
Discussion
We developed a predictive population PK-PD model
of epidural anesthesia and determined its parameters,
taking into account the effects of age, for the local
anesthetics levobupivacaine and ropivacaine. The
pharmacokinetic analysis yielded similar population
parameter estimates with respect to our previous stud-
Table 3. Disposition Pharmacokinetic Model Parameter Estimates for Levobupivacaine and Ropivacaine
Value
SE
␻2
SE
␣AGE
SE
V1
k10
k12
k21
k13
k31,levo
6.85
0.0522
0.152
0.0884
0.0519
0.00732‡
0.404
0.00352
0.0183
0.00670
0.00508
0.000563
0.0352
0.0724
0.0357
0.0241
0.147
0.00973
0.0315
0.0188
0.0111
0.0399
⫺0.193*
0.0949
0.0669
0.0185
⫺0.213
k31,ropi
␴2
0.0137‡
0.00991
0.000782
0.000904
Parameter
0.579†
0.155
0.137
* P ⬍ 0.05, † P ⬍ 0.01, ‡ P ⬍ 0.01 between anesthetics.
kij ⫽ rate constant between compartments i and j; V1 ⫽ volume of central compartment; ␻2 ⫽ variance of first-level random effect; ␴2 ⫽ variance of second-level
random effect.
Anesthesiology, V 109, No 4, Oct 2008
PK-PD MODELING OF EPIDURAL ANESTHESIA
669
Table 4. Absorption Pharmacokinetic Model Parameter Estimates for Levobupivacaine and Ropivacaine
Parameter
Value
SE
t½,a1,levo, min
5.76‡
0.466
t½,a1,ropi, min
t½,a2,levo, min
9.66‡
425‡
0.837
27.4
t½,a2,ropi, min
F
F=1,levo
237‡
1.08
0.193
12.1
0.0122
0.0112
F=1,ropi
␴2
0.221
0.0149
␻2
SE
0.147
0.0281
0.0783
0.0150
0.00475
0.00168
0.127
0.0338
␣AGE
SE
⫺0.666†
0.129
⫺0.337*
0.142
0.0134
0.00141
* P ⬍ 0.05, † P ⬍ 0.01, ‡ P ⬍ 0.01 between anesthetics.
F ⫽ total fraction absorbed; F=1 ⫽ fraction absorbed in compartment 1; t½,a1 and t½,a2 ⫽ absorption half-lives (see text); ␻2 ⫽ variance of first-level random effect;
␴2 ⫽ variance of second-level random effect.
ies. The PK-PD model was able to predict the probability of block and duration of anesthesia per segment.
The covariate analysis showed that age had a significant and clinically important effect on the spread and
duration of analgesia.
We previously determined absorption kinetics after
epidural administration of bupivacaine, levobupivacaine, and ropivacaine.1–5 Stable isotope–labeled analogs were intravenously infused to obtain disposition
kinetics. Subsequently, with the use of the disposition
kinetics and the plasma concentration of the epidurally administered unlabeled local anesthetic, the
absorption kinetics could be obtained by deconvolution. The plasma concentration–time curves of indi-
Fig. 3. Equilibration half-lives and absorption thresholds, with their 95% confidence intervals, at segments S5–T5 of the
two local anesthetics under study. To
guide the eye, dashed lines were drawn at
the parameter values at level L2 (epidural
injection was at the L3–L4 interspace).
Anesthesiology, V 109, No 4, Oct 2008
vidual patients were adequately described by fitting
directly the aggregated model of two parallel firstorder absorption compartments and the disposition
profile (a two- or three-compartmental model). These
analyses allowed the determination of the profiles of
the different local anesthetics and the effects of age.
However, these individual analyses may be hampered by interindividual variability, caused by sex differences and genetic, environmental, and pathophysiologic factors.14 –16 A population approach of these
data may be attractive because it can explain a part of
the wide variability by incorporating covariates, such
as the type of local anesthetic and age. In addition, it
enables the development of models that are able to
670
OLOFSEN ET AL.
Fig. 4. Effect of age on ke0 and Athr at segments S5–T5 as quantified by the respective covariate coefficients (equation 5)
together with their 95% confidence intervals, for the two local anesthetics under
study.
make predictions about certain clinically important
endpoints, such as maximal level and duration of
blockade. This may, consequently, improve therapeutic outcome in future patients.6
Pharmacokinetic Analysis
The current analysis yielded similar results with respect to our previous studies; small differences, however, were apparent. For example, we now observed
that the clearances of the two anesthetics decrease significantly with increasing age.
The observed differences between the absorption
parameters of the two anesthetics can be explained
from their vasoconstrictory and vasodilatory properties.5 The effects of those differences on the concentration in the epidural space after a standardized bolus
dose are shown in figure 7. Levobupivacaine concentration levels are the highest, and this anesthetic could
be called the most efficient in terms of concentration.
This observation has to be linked to the pharmacodynamic potency to determine whether it is also effect
efficient (see Discussion, Pharmacodynamic Analysis
section).
Parameter F, which represents the fraction of the administered dose that is present in the patient’s blood,
should be 1. It was greater than 1 for levobupivacaine
and ropivacaine. Possible explanations are given in our
previous articles3–5; in brief, bioavailability may be overestimated because of the finite experiment time from
which the disposition kinetics (in particular elimination
clearance) are determined.
Pharmacodynamic Analysis
We observed that the sensitivity to the two anesthetics, quantified by an increase of parameter Athr, decreased with segment height. Assuming that the sensitivity of the nerves to the presence of an anesthetic,
and the volume of the central absorption compartments do no differ between segments, this decrease is
due to a smaller amount of anesthetic reaching the
higher segments. The overall Athr is highest for
levobupivacaine. So although the absorption charac-
Fig. 5. Blockade probabilities for the two
local anesthetics (ropivacaine dose 100
mg, levobupivacaine dose 125 mg) and the
effect of age. The size of the dots is proportional to the probability of blockade;
in addition, 90%, 75%, and 50% isoeffect
lines were drawn (solid, heavily, and
lightly dashed lines, respectively).
Anesthesiology, V 109, No 4, Oct 2008
PK-PD MODELING OF EPIDURAL ANESTHESIA
671
Fig. 6. Blockade probabilities for levobupivacaine for age 50 yr as a function of time
and segment level.
teristics cause this anesthetic to be concentration efficient, this is counteracted by its lower sensitivity
(figs. 3 and 7). Ropivacaine was found to have a lower
speed of onset and offset (as expressed by t1⁄2,ke0) than
levobupivacaine. This may be explained by the fact
that the physiochemical properties of ropivacaine are
similar to those of levobupivacaine, apart from its
lower lipid solubility. Because lipid solubility is related to potency, ropivacaine may be less potent.17
The smaller t1⁄2,ke0 in the neighborhood of the L2 segment is probably related to differences in the distribution of the anesthetics in the epidural space close to
the site of injection.
Anatomical and physiologic changes associated with
advancing age may affect the pharmacokinetics and
Fig. 7. Comparison of absorption profiles of levobupivacaine
and ropivacaine in the epidural space (absorption parameters
from table 4).
Anesthesiology, V 109, No 4, Oct 2008
the nerve block characteristics after epidural administration of local anesthetics. A declining number of
neurons, deterioration in myelin sheaths in the dorsal
and ventral roots, changes in the anatomy of the spine,
and intervertebral foramina may contribute to altered
nerve block characteristics after epidural anesthesia.18,19 Furthermore, the number of axons in peripheral nerves decreases with advancing age, and the
conduction velocity diminishes, particularly in motor
nerves.19 –21 With increasing age, changes in the connective tissue ground substances and epidural fat may
result in changes in local distribution, i.e., in the
distribution rate of the local anesthetic from the site of
injection (the epidural space) to the sites of action.18
We observed important age effects for ropivacaine
and levobupivacaine, respectively: (1) Athr decreased
at the higher segment levels (T12 and higher); and (2)
onset and offset of the sensory blockade, as expressed
by parameter t1⁄2,ke0 was faster with increased age. The
most probable mechanism of an increased anesthetic
sensitivity with age is an age-dependent change in the
longitudinal spread of the anesthetics in the epidural
space. This is evident because we observed an increased sensitivity with age mainly at the higher segments. The reduced loss of anesthetic via sclerotic
intervertebral foramina during its rostral spread with
increasing age may explain this observed age effect.
The higher level of analgesia in older patients may as
well be attributed to a greater sensitivity (a lower Athr)
OLOFSEN ET AL.
672
such that with the same local anesthetic concentrations at higher thoracic segments, blockade occurs in
older but not in younger patients. Consequently, to
obtain comparable epidural blocks, smaller doses of
local anesthetic solutions should be administered to
older as compared with younger patients. The effect
of age on the speed of onset and offset of effect is
probably related to changes in epidural fat. Uptake
into extraneural tissues, such as epidural fat, limits the
rate and extent of drug distribution to the nerves and
thereby changes the time profile of clinical potency.22
PK-PD Models of Spinal Anesthesia
To the best of our knowledge, this is the first PK-PD
model developed for lumbar epidural administration
of local anesthetics. There are, however, PK-PD models for spinal anesthesia in pigs and in humans.7,23,24
Shafer et al.23 performed PK-PD modeling of intrathecal neostigmine using cerebrospinal fluid samples and
analgesia (visual analog scale) scores. The pharmacokinetic part of their model included a component to
account for the spatial dimension in the intrathecal
administration–analgesia relation. The pharmacokinetic model developed by Ummenhofer et al.24 consists of four spatially interconnected subunits of four
serially connected compartments to describe drug distribution in each subunit. From microdialysis data, it
was not possible to estimate all model parameters for
all subunits, and some additional assumptions had to
be made. For example, exchange between spinal levels was assumed to occur only via the cerebrospinal
fluid and not via the epidural space. For our model of
epidural anesthesia, we assumed that no exchange
occurs via the cerebrospinal fluid9 and epidural
space, except in the latter during epidural administration. Schnider et al.7 developed a population pharmacodynamic model of spinal anesthesia from pinprick
assessments. Although their model is applicable to
epidural anesthesia, it is unable to predict sensory
blockade at levels lower than the maximum. Furthermore, because they did not take into account pharmacokinetic data (on disposition and absorption) and
hence the local anesthetic concentration, their pharmacodynamic analysis is affected by pharmacokinetic
variability. Although this seems of limited importance
when treating and predicting epidural anesthesia in a
new patient, the inclusion of covariates in the pharmacokinetic model will improve the prediction of
sensory anesthesia in this particular patient.
Critique on Methods
A potential drawback of our model is the underlying
essential assumption that rostral and caudal spread of the
anesthetic in the epidural space is instantaneous and
subsequently remains unchanged (apart from absorp-
Anesthesiology, V 109, No 4, Oct 2008
tion). In reality, the local anesthetic spreads with a certain delay. Incorporation of segment-dependent delay is
not feasible, because we have only two measurements
per dermatome (onset and offset times of blockade).
Note that in reality t1⁄2,ke0 is not the delay to the segments
but the delay from the segment to the effect site (i.e., the
spinal nerve roots). Consequently, we may have slightly
overestimated the value of t1⁄2,ke0.
Furthermore, the results that we present here are valid
for the specific volume of the local anesthetic given as
well as the location of the epidural puncture (L3–L4
interspace). It has been shown that in contrast to dose,
volume per se has little or no effect on sensory block
height and quality of anesthesia.25,26 We expect, however, that the site of injection affects the parameter
values of our model.
The way covariate age was included in the models
allows for a covariate effect in one way only (either a
decrease or an increase). In our previous articles, patients were assigned to age groups; however, this allowed for physiologically unrealistic covariate effects.
There was no intraindividual variability in the pharmacodynamic data because of the nature of the binary
assessments. There was, however, intraindividual uncertainty in the actual times of onset and offset of effect,
depending on the sampling times according to the protocol; this uncertainty will bias the estimates of interindividual variability (␻A2 thr and ␻k2e0) upward.
Conclusions
In conclusion, we developed a predictive PK-PD
model of epidural anesthesia in humans. We were able
to demonstrate the importance of age on the spread of
the sensory blockade as well as on the speed of onset/
offset of blockade. The model allows the study of
various important factors in epidural anesthesia, such
as the site of injection, the volume of the injected
fluid, combined spinal– epidural injections, anestheticopioid interaction, and pregnancy. Furthermore, the model
may be used in the development and study of new local
anesthetics for epidural use.
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GM, Burm AGL: The systemic absorption and disposition of levobupivacaine 0.5%
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G: Pharmacokinetic-pharmacodynamic modeling: Why? Arch Med Res 2000;
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17. Casati A, Putzu M: Bupivacaine, levobupivacaine and ropivacaine: Are they
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19. Ferrer-Brechner T: Spinal and epidural anesthesia in the elderly. Semin
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Appendix
673
Fig. 8. Central and effect site absorption profiles in the epidural
space (solid and hatched curves, respectively) given by equations 1 and 4 with parameter estimates from patient 4210 substituted. The dots denote the effect site absorption Ae(t; ke0) at
onset and offset times ton,1, ton,2, toff,1, and toff,2, respectively.
The anesthetic sensitivity Athr (horizontal line) and central effect site equilibration rate constant ke0 were approximated
from the average (ton, toff) (see text).
the (double) integral of the probability distributions of Athr and ke0
across this area:
Li ⫽
兰
ke0,max
ke0,min
兰
Athr,max共 ke0兲
Athr,min共 ke0兲
NL共Athr;␮Athr, ␻A2 thr兲NL共ke0 ;␮ke0, ␻k2e0兲dAthrdke0
(6)
where NL denotes the fact that Athr and ke0 are normally distributed in
the log-domain and ␮ and ␻2 denote, in NONMEM parlance, typical
population values and variabilities. The integration interval for Athr
depends on ke0, and the integration interval for ke0 is determined by
nonempty Athr integration intervals (fig. 9). The integrals are evaluated
in the log-domain; the inner integral can be numerically approximated
by one of the GSL gsl_cdf_normal routines, and the outer integral can
be numerically approximated by one of the GSL gsl_integration_qag
routines, depending on whether the ke0 range is finite or infinite. The
likelihood of the set of observations is given by the product of equation
7 for each individual.
For a type 2 observation, a blockade is still present at the last
assessment time, so Ae(tend) ⫽ Ae(toff,1) ⱖ Athr and toff,2 is not observed,
which means that the information about Athr and ke0 is not bounded by
the line Ae(toff,2, ke0) in figure 9, and the area of integration therefore
also includes the horizontally shaded part (with ke0 2 0).
For a type 3 observation, Ae(t) ⬍ Athr for all assessment times; only
the maximum value of Ae(tmax) gives information, because if Ae(tmax) ⬍
Athr, Ae(t) ⬍ Athr for all t ⫽ tmax (the observations are not independent,
and function Ae(t) has only one maximum).
Likelihood Function for the Set of Observations
For a type 1 observation, pinprick assessment times yield intervals
(ton,1, ton,2) and (toff,1, toff,2) that constitute the closest intervals
around the actual onset and offset times of effect (fig. 8). The
remaining assessments do not contain any additional information,
because they were always 0 for t ⱕ ton,1 and t ⱖ toff,2, and 1 for ton,2
ⱕ t ⱕ toff,1 (a result of the choice of assessment times with respect
to the rate of change in the effect site absorption profile). Therefore, the uncertainty about whether there is a blockade cannot be
estimated and has to be neglected, but there is uncertainty with
respect to the actual onset and offset times. This uncertainty is
taken into account by the postulated normal probability distributions for the logarithms of Athr and ke0 with variances ␻A2 thr and ␻k2e0,
respectively. Thus, they are a measure of the combination of intraindividual and interindividual variabilities (which cannot be separated). Figure 9 depicts the (Athr, ke0) area for which it is possible
that the observed intervals (ton,1, ton,2) and (toff,1, toff,2) are observed. The likelihood of an observation in individual i is given by
Anesthesiology, V 109, No 4, Oct 2008
Fig. 9. The area of integration is the area bounded by the effect
site absorption profiles for ton,1, ton,2, toff,1, and toff,2 (when
observed) as functions of ke0 (given by equation 4 with fixed
absorption parameters). The dot in the center denotes the (Athr,
ke0) estimate from the average (ton, toff).
OLOFSEN ET AL.
674
The implementation of the integrals in the C program were checked
using Monte Carlo simulation, i.e., by counting the number of samples
from the lognormal distributions of Athr and ke0 that fall within the
region of integration.
The model parameters were estimated by the method of maximum
likelihood, i.e., they are given by those values that maximize L ⫽ 兿iLi
(for all individuals i, equation 6); the maximum was numerically determined by the GSL routine gsl_multimin_fminimizer_nmsimplex.
Blockade Probabilities
Once the distributions of Athr and ke0 are known (their parameters
estimated), the probability of blockade at time t is given by:
P 兵 blockade at t 其
⫽ P 兵 Ae共t; ke0兲 ⱖ Athr其
⫽
兰兰
⬁
Ae共t;ke0兲
0
0
NL共Athr;␮Athr, ␻A2 thr兲NL共ke0;␮ke0, ␻k2e0兲dAthrdke0 (7)
Initial Parameter Values
Suppose that ton,1 ⬇ ton,2 and toff,1 ⬇ toff,2, so that they can be approximated by their averages ton and toff. Then there exists a unique relation
between (ton, toff) and (Athr, ke0); the latter are given by those values that
satisfy Ae(ton; ke0) ⫽ Ae(toff; ke0) ⬅ Athr (using equation 4). They are unique
because Ae(ton; ke0)1 when ke0 1 while Ae(toff; ke0)2 when ke0 1. The
equality is numerically found by the GSL root-finding routine gsl_root_fsolver_brent. Initial parameter values were calculated as the means and variances
of the logarithms of the Athr and ke0 estimates at each dermatome for all
individuals from the type 1 observations.
Anesthesiology, V 109, No 4, Oct 2008
where the population values ␮Athr and ␮ke0 are functions of age as
given by equation 5, and the parameters of Ae(t; ke0) (equation 4)
are given by population estimates of F1, F2, ka1, and ka2, which are
also functions of age. When the population distributions of the
absorption parameters are postulated correctly and/or their variances are small, the bias caused by taking their population estimates
instead of in addition integrating across their respective distributions is assumed to be negligible.
Are epidurals worthwhile in vascular surgery?
Bernadette T. Veering
Department of Anesthesiology, Leiden University
Medical Center, Leiden, The Netherlands
Correspondence to Bernadette T. Veering, MD, PhD,
Department of Anesthesiology, Leiden University
Medical Center, P5-Q, P.O. Box 9600, 2300 RC
Leiden, The Netherlands
Tel: +31 71 52622301; fax: +31 71 5266230;
e-mail: [email protected]
Current Opinion in Anaesthesiology 2008,
21:616–618
Purpose of review
Patients undergoing major vascular surgery are at increased risk for postoperative
complications due to the high incidence of comorbidities in this population.
Epidural anaesthesia provides potential benefits but its effect on morbidity and mortality
is unclear.
Recent findings
Existing studies fail to demonstrate improved clinical outcome and reduced mortality
for epidural anaesthesia or combined epidural/general techniques compared with
general anaesthesia. Postoperative epidural analgesia provides better pain relief and
reduces the duration of postoperative mechanical ventilation.
Summary
Optimization of perioperative care rather than the anaesthetic technique may have
potential benefit in improving postoperative outcome.
Keywords
epidural anaesthesia, outcome, vascular surgery
Curr Opin Anaesthesiol 21:616–618
ß 2008 Wolters Kluwer Health | Lippincott Williams & Wilkins
0952-7907
Introduction
Major vascular surgery is considered to be a high-risk
procedure. It is often applied in elderly patients, who
exhibit many comorbidities such as ischaemic heart
disease, renal insufficiency and diabetes. Many of these
patients are at increased risk for perioperative complications. Consequently, these patients would benefit from
anaesthetic techniques reducing those risks. The question whether epidural or general anaesthesia is preferable
for vascular surgery has been debated for years.
The present review will focus on the probable advantages
of epidural anaesthesia for vascular surgery.
Physiologic effects
The use of epidural anaesthesia provides physiologic
benefits and may attenuate the pathophysiology that
occurs following surgery. This may be associated with
a reduction in perioperative mortality and morbidity
when compared with general anaesthesia.
Thoracic epidural anaesthesia (TEA) covering the cardiac segments (T1–T4) improves an ischaemia-induced
left ventricular dysfunction; reduces electrocardiographic, echocardiographic and angiographic signs of
coronary insufficiency; decreases the incidence of arrhythmias and provides relief of ischaemic chest pain [1].
Local anaesthetics have the capability to block afferent
and efferent signals to and from the spinal cord, thus
0952-7907 ß 2008 Wolters Kluwer Health | Lippincott Williams & Wilkins
suppressing the surgical stress response [2]. Major surgery
is associated with a hypercoagulable state that persists
into the postoperative period. The incidence of thromboembolic complications is lower in patients operated
upon under epidural anaesthesia compared to those given
general anaesthesia [3]. Modulation of the surgically
induced changes in coagulation or fibrinolysis by epidural
anaesthesia might be due to an increased blood flow
with subsequent reduced venous stasis, to effects of
the local anaesthetics themselves and to blunting the
stress response [3,4].
Epidural anaesthesia extending above T12 is associated
with splanchnic sympathetic nervous blockade, resulting
in reduced inhibitory gastrointestinal tone and increased
intestinal blood flow. Perioperative intestinal hypoperfusion is a major contributing factor leading to organ dysfunction. TEA during and after major surgery has been
shown to protect the gut from decreased microvascular
perfusion and to improve the mucosal blood flow, even
under conditions of decreased perfusion pressure [5,6].
TEA with postoperative thoracic epidural analgesia has
been shown to shorten the time to first bowel movement
[7] and the duration of postoperative colonic ileus [8].
Vascular surgery
Various comorbidities associated with advanced age, such
as ischaemic heart disease, renal insufficiency and diabetes are robust, predictors of cardiac complications in
DOI:10.1097/ACO.0b013e32830c6ec8
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Are epidurals worthwhile in vascular surgery? Veering 617
the vascular patient [9]. Cardiac and pulmonary complications remain the main causes of perioperative morbidity associated with major vascular surgery [10].
A commonly asked question is whether the mentioned
physiologic benefits ascribed to epidural anaesthesia will
make a difference in the outcome of vascular surgical
patients.
Aortic surgery
Major vascular surgical procedures are amenable to
epidural anaesthesia combined with general anaesthesia
(EA þ GA). Aortic cross clamping and unclamping are
associated with complex cardiovascular, renal, humoral
and haemostatic changes [11]. During reconstructive aortic
surgery, clamping and unclamping is usually well tolerated
but may produce severe haemodynamic disturbances.
Patients with TEA þ GA to have a more stable haemodynamic course during the critical times of aortic clamping and unclamping with fewer fluctuations in blood
pressure and heart rate [12,13].
With cross clamping both with epidural anaesthesia þ
general anaesthesia and with general anaesthesia alone,
signs of myocardial ischaemia did occur. So the favourable
factor of epidural anaesthesia on the myocardial oxygen
supply–demand relationship did not influence the incidence of intraoperative myocardial ischaemia [14].
Discrepancies exist between studies that have evaluated
the effect of epidural anaesthesia þ general anaesthesia
and postoperative analgesia in comparison with general
anaesthesia and postoperative systemic opioid-based pain
relief on the postoperative cardiac outcome in patients
who underwent elective abdominal aortic surgery. Some
studies [15,16] involving high-risk (e.g. aortic reconstruction) surgery patients have reported significant reductions
in cardiac morbidity associated with the use of intraoperative and postoperative epidural anaesthesia/analgesia
using local anaesthetics and opioids.
Others [13,17–19]didnotdemonstrate adecreaseincardiac
morbidity in patients undergoing aortic reconstructions
treated with intraoperative TEA þ light general anaesthesia. However, epidural anaesthesia and analgesia was
associated with shortened intubation times and ICU stay.
A meta-analysis of 17 studies examining the effect of
postoperative epidural analgesia on postoperative cardiac
morbidity showed a significant reduction in postoperative
myocardial infarction in the epidural group continued for
more than 24 hours [20]. Patients underwent abdominal
and vascular surgery and had a history of preoperative
cardiac morbidity. Subgroup analysis demonstrated that
thoracic epidural analgesia was superior to lumbar epidural
analgesia in reducing postoperative myocardial infarction.
These findings suggest that thoracic epidural anaesthesia
may have a favorable effect on cardiac morbidity, however
more randomized clinical trials are warranted.
A part of postoperative complications is caused by respiratory problems during the early postoperative recovery
period. A meta-analysis by Ballantyne et al. [21] found
that postoperative epidural analgesia was associated with
a decrease in the incidence of atelectasis, pneumonia,
overall pulmonary complications and an increase in the
arterial partial pressure of oxygen, compared with systemic opioid administration. These findings suggest that
postoperative epidural analgesia has a beneficial effect on
pulmonary morbidity.
A recent systemic review showed that epidural analgesia
provides better pain relief and reduces the duration of
tracheal intubation after open abdominal aortic surgery
compared to systemic opioid-based relief [22]. These
findings suggest that epidural pain relief may be advantageous for pulmonary patients undergoing abdominal
aortic surgery.
Peripheral vascular surgery
Studies of Christopherson et al. [23] and of Bode et al. [24]
reported no difference in myocardial ischaemia, major
cardiac morbidity or operative mortality when comparing
epidural anaesthesia and analgesia with general anaesthesia followed by intravenous patient-controlled analgesia (PCA) in patients undergoing lower extremity vascular
surgery. The limitation of both studies was that they were
inadequately powered to detect differences between
anaesthetic techniques. However, a benefit of epidural
anaesthesia over general anaesthesia was a reduction in
the incidence of graft occlusion [4,15,25].
Lower extremity revascularization is performed in patients
with a high incidence of coexistent diseases. Krupski et al.
[26,27] compared the difference in early and late cardiac
morbidity in patients undergoing suprainguinal aortic
operations versus patients undergoing infrainguinal vascular operations. The incidence of early postoperative
cardiac complications was the same in both groups, however cardiac morbidity rates at 2 years were greater for
infrainguinal versus abdominal aortic procedures. This
may be due to a greater prevalence of diabetes and cardiac
morbidities in patients with peripheral vascular diseases.
In both studies the effect of anaesthetic technique on
cardiac morbidity was not investigated.
The major drawbacks of early prospective studies are
methodological flaws, including different regimens of
epidural anaesthesia, different protocols of postoperative
pain treatment, inclusion of small numbers of patients
and possible investigator bias.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
618 Regional anaesthesia
In order to avoid those deficiencies of design and methodology Norris et al. [28] performed a double-masked
randomized controlled trial of 168 patients undergoing
abdominal aortic surgery. In this study strict intraoperative and postoperative protocols were used to guide and
optimize perioperative management and postoperative
analgesia. Participants were allocated into four treatment
groups, two groups received TEA combined with a light
GA followed by either PCA or epidural patient-controlled
analgesia (EPCA) and two groups received GA alone
followed by either PCA or EPCA.
7
Steinbrook RA. Epidural anesthesia and gastrointestinal motility. Anesth
Analg 1998; 86:837–844.
8
Zugel N, Bruer C, Breitschaft K, Angster R. Effect of thoracic epidural
analgesia on the early postoperative phase after interventions on the gastrointestinal tract. Chirurgia 2002; 73:262–268.
9
Lee TH, Marcanonio ER, Mangione CM, et al. Derivation and prospective
validation of a simple index for prediction of cardiac risk of major noncardiac
surgery. Circulation 1999; 100:1043–1049.
The primary outcome was length of stay; secondary
outcomes included selected postoperative morbidities
like pulmonary complications and cardiovascular events.
Cardiac morbidity was defined as myocardial infarction,
angina, congestive heart failure and ventricular tachyarrhythmia. Postoperative outcomes were not influenced
by intraoperative and postoperative anaesthetic regimen. This implies probably that perioperative care of
patients undergoing vascular procedures seems to be
important regardless of the anaesthetic techniques used
[29].
13 Garnett RL, Lindsay P, Cole CW, et al. Perioperative ischaemia in aortic
surgery: combined epidural/general anaesthesia and epidural analgesia vs
general anaesthesia and iv analgesia. Can J Anaesth 1996; 43:769–777.
Conclusion
Existing studies fail to demonstrate improved clinical
outcome and reduced mortality for epidural anaesthesia
or combined epidural/general techniques compared with
general anaesthesia. Large, well designed randomized
clinical trials on a long-term basis are necessary to draw
solid conclusions on the effect of anaesthetic techniques
on eventual outcome after vascular surgery.
However it seems more reasonable that the real aim
should be to improve the perioperative care of vascular
surgery patients rather than to focus on the effect of
the particular anaesthetic technique on patient outcome
following vascular surgery.
References and recommended reading
Papers of particular interest, published within the annual period of review, have
been highlighted as:
of special interest
of outstanding interest
1
2
3
4
5
6
Veering BT, Cousins MJ. Cardiovascular and pulmonary effects of epidural
anaesthesia. Anaesth Intensive Care 2000; 28:620–635.
Kehlet H. Manipulation of the metabolic response in clinical practice. World J
Surg 2000; 24:690–695.
Modig J, Borg T, Bagge L, et al. Role of extradural and of general anaesthesia
on fibrinolysis and coagulation after total hip replacement. Br J Anaesth 1983;
55:625–629.
Rosenfeld BA, Beattie C, Christopherson R, et al. The effect of different
anesthetic regimens on fibronolysis and the developments of postoperative
arterial thrombosis. Anesthesiology 1993; 79:435–443.
Adolphs J, Schmidt DK, Mousa SA, et al. Thoracic epidural anesthesia
attenuates hemorrhage-induced impairment of intestinal perfusion in rats.
Anesthesiology 2003; 99:685–692.
Sielenkamper AW, Eicker K, Van Aken H. Thoracic epidural anesthesia
increases mucosal perfusion in ileum of rats. Anesthesiology 2000; 93:
844–851.
10 Elkouri S, Gloviczki P, McKusick MA, et al. Perioperative complications and
early outcome after endovascular and open surgical repair of abdominal aortic
aneurysms. J Vasc Surg 2004; 39:497–505.
11 Gelman S. The pathophysiology of aortic cross-clamping and unclamping.
Anesthesiology 1995; 82:1026–1057.
12 Mason RA, Newton GB, Cassel W, et al. Combined epidural and general
anaesthesia in aortic surgery. J Cardiovasc Surg 1990; 31:442–447.
14 Dodds TM, Burns AK, DeRoo DB, et al. Effect of anesthetic technique on
myocardial wall motion abnormalities during abdominal surgery. J Cardiovasc
Anesth 1997; 11:129–136.
15 Tuman KJ, McCarthy RJ, March RJ, et al. Effects of epidural anesthesia and
analgesia on coagulation and outcome after major vascular surgery. Anesth
Analg 1991; 73:696–704.
16 Park WY, Thompson JS, Lee KL. Effect of epidural anesthesia and analgesia
on perioperative outcome: a randomized, controlled veterans affairs cooperative study. Ann Surg 2001; 234:560–571.
17 Baron JF, Bertrand M, Barre E, et al. Combined epidural and general
anesthesia versus general anesthesia for abdominal aortic surgery. Anesthesiology 1991; 75:611–618.
18 Davies MJ, Silbert BS, Mooney PJ, et al. Combined epidural and general
anaesthesia versus general anaesthesia for abdominal aortic surgery: a
prospective randomized trial. Anaesth Intensive Care 1993; 21:790–794.
19 Boylan JF, Katz J, Kavanagh BP, et al. Epidural bupivacaine-morphine analgesia
versus patient-controlled analgesia following abdominal aortic surgery: analgesic, respiratory and myocardial effects. Anesthesiology 1998; 89:585–593.
20 Beattie WS, Badner NH, Choi P. Epidural anesthesia and analgesia reduces
postoperative myocardial infarction: a meta-analysis. Anesth Analg 2001;
93:853–858.
21 Ballantyne JC, Carr DB, Deferranti S, et al. The comparative effects of
postoperative analgesic therapies on pulmonary outcome: cumulative metaanalysis of randomized controlled trials. Anesth Analg 1998; 86:598–612.
22 Nishimori M, Ballantyne JC, Low JH. Epidural pain versus systemic opioid
based pain relief for abdominal aortic surgery. Cochrane Database Syst Rev
2006:CD005059.
Important systemic review that shows that epidural analgesia provides better pain
relief and reduces the duration of tracheal intubation after open abdominal aortic
surgery compared with systemic opioid-based relief.
23 Christopherson R, Beattie C, Gottlieb S, et al. Perioperative morbidity in
patients randomized to epidural or general anesthesia for lower extremity
vascular surgery. Anesthesiology 1993; 79:422–434.
24 Bode RH, Lewis KP, Zarich SW, et al. Cardiac outcome after peripheral
vascular surgery: comparison of general and regional anesthesia. Anesthesiology 1996; 84:3–13.
25 Singh N, Sidawy AN, Dezee K, et al. The effects of the type of anesthesia
on outcomes of lower extremity infrainguinal bypass. J Vasc Surg 2006;
44:964–970.
26 Krupski WC, Layug EL, Reilly LM, et al. Comparison of cardiac morbidity rates
between aortic and infrainguinal operations. J Vasc Surg 1992; 15:354–365.
27 Krupski WC, Layug EL, Reilly LM, et al. Comparison of cardiac morbidity rates
between aortic and infrainguinal operations: two-year follow up. J Vasc Surg
1993; 18:609–617.
28 Norris EJ, Beattie C, Perler BA, et al. Double-masked randomized trial
comparing alternate combinations of intraoperative anesthesia and postoperative analgesia in abdominal aortic surgery. Anesthesiology 2001;
95:1054–1067.
An important study demonstrating that no differences in perioperative outcome in
patients undergoing surgery of the abdominal aorta occurred when comparing
TEA þ general anaesthesia followed by either intravenous or epidural patientcontrolled analgesia with general anaesthesia alone followed by either intravenous
or epidural patient-controlled analgesia. Strict intraoperative and postoperative
protocols were used to guide and optimize perioperative management.
29 Rock P. Regional vs GA for vascular surgery patients. ASA annual meeting
refresher course lectures. 2007; 209.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
British Journal of Anaesthesia 102 (6): 739–48 (2009)
doi:10.1093/bja/aep096 Advance Access publication May 6, 2009
REVIEW ARTICLE
Failed spinal anaesthesia: mechanisms, management, and
prevention
P. D. W. Fettes1*, J.-R. Jansson2 and J. A. W. Wildsmith1
1
University Department of Anaesthesia, Ninewells Hospital & Medical School, Dundee DD1 9SY, UK.
2
AstraZeneca R&D SE-151 85, Sodertalje, Sweden
*Corresponding author. E-mail: [email protected]
Although spinal (subarachnoid or intrathecal) anaesthesia is generally regarded as one of the most
reliable types of regional block methods, the possibility of failure has long been recognized.
Dealing with a spinal anaesthetic which is in some way inadequate can be very difficult; so, the
technique must be performed in a way which minimizes the risk of regional block. Thus, practitioners must be aware of all the possible mechanisms of failure so that, where possible, these
mechanisms can be avoided. This review has considered the mechanisms in a sequential way: problems with lumbar puncture; errors in the preparation and injection of solutions; inadequate
spreading of drugs through cerebrospinal fluid; failure of drug action on nervous tissue; and difficulties more related to patient management than the actual block. Techniques for minimizing the
possibility of failure are discussed, all of them requiring, in essence, close attention to detail.
Options for managing an inadequate block include repeating the injection, manipulation of the
patient’s posture to encourage wider spread of the injected solution, supplementation with local
anaesthetic infiltration by the surgeon, use of systemic sedation or analgesic drugs, and recourse
to general anaesthesia. Follow-up procedures must include full documentation of what happened,
the provision of an explanation to the patient and, if indicated by events, detailed investigation.
Br J Anaesth 2009; 102: 739–48
Keywords: anaesthetic techniques, regional; anaesthetic techniques, spinal; complications
Two conditions are, therefore, absolutely necessary to
produce spinal anesthesia: puncture of the dura mater
and subarachnoid injection of an anesthetic agent.
Gaston Labat, 1922
Spinal (intrathecal) anaesthesia is generally regarded as one
of the most reliable of regional block methods: the needle
insertion technique is relatively straightforward, with cerebrospinal fluid (CSF) providing both a clear indication of
successful needle placement and a medium through which
local anaesthetic solution usually spreads readily. However,
the possibility of failure has long been recognized, the
above quote being taken from the work of Gaston Labat,24
the ‘father’ of modern regional anaesthesia. His two conditions for success, although perhaps a little simplistic
when related to current knowledge, still indicate the
essence of the method and provide a starting point for the
consideration of failure, although it may be helpful to
define exactly what this means first. Literally, the word
failure implies that a spinal anaesthetic was attempted, but
that no block resulted; this happens, but perhaps a
commoner outcome is that a block results, but is inadequate
for the proposed surgery. Such inadequacy may relate to
three components of the block: the extent, quality, or duration of local anaesthetic action, often with more than one
of these being inadequate. This review has considered all
three eventualities within the definition of ‘failure’.
Most experienced practitioners would consider the incidence of failure with spinal anaesthesia to be extremely low,
perhaps less than 1%. However, a figure as high as 17% has
been quoted from an American teaching hospital, yet most
of the failures were judged to be ‘avoidable’.28 A survey at
another such institution considered that this high rate was
‘unacceptable’, and recorded the much lower, but still significant, figure of 4%, with ‘errors of judgement’ as the
major factor.32 The clear implication is that careful attention
to detail is vital, and it has been shown that a failure rate of
,1% is attainable in everyday practice.17 Minimizing the
incidence of failure is obviously a pre-requisite for gaining
the benefits of spinal anaesthesia, and prevention must start
with full recognition of the potential pitfalls so that clinical
practice can be tailored to their avoidance.
# The Author [2009]. Published by Oxford University Press on behalf of The Board of Directors of the British Journal of Anaesthesia. All rights reserved.
For Permissions, please email: [email protected]
Fettes et al.
Search strategy
For this review ‘PubMed’ and ‘Google’ databases were
searched using the terms ‘failed regional anaesthesia’,
‘failed regional anesthesia’, ‘failed spinal anaesthesia’, and
‘failed spinal anesthesia’. Relevant articles were retrieved
as were any possibly relevant papers in their reference lists.
Supporting searches were performed on subjects that may
not have been otherwise identified, specific examples being
CSF volume, dural ectasia, and the chemical compatibility
of local anaesthetics with adjuncts.
In addition, searches were made using ‘Planet’ (an
AstraZeneca internal database), ‘Biosis’, ‘Current
Contents’, ‘Embase’, ‘PsycINFO’, ‘Medline’, and ‘Medline
Daily update’, using the terms ‘Failed Spinal Anaesthesia’
and ‘Failed Spinal Anesthesia’ as sole search terms and
‘spinal anesthesia’ or ‘spinal anaesthesia’ or ‘spinal anesthetic’ or ‘spinal cord anesthesia’ or ‘spinal cord anaesthesia’ or ‘anesthesia, spinal’ or ‘anaesthesia, spinal’ and
‘treatment failure’ or ‘therapy failure’, and ‘Intrathecal’.
All papers identified as relevant are included in this review.
Mechanisms and their prevention
Failed lumbar puncture
Inability to obtain CSF, sometimes referred to as a ‘dry
tap’, is the only cause of failure which is immediately
obvious. A needle with a lumen blocked at the outset is a
theoretical possibility, but is most unlikely with modern
equipment. However, both needle and stylet must be
checked for correctness of fit before use, and the needle
should not be advanced without the stylet in place because
160
The Americas
Europe
Asia
Australasia
140
120
Number of reports
In general terms, block failure is usually ascribed to one
of three aspects: clinical technique, inexperience (of the
unsupervised trainee especially), and failure to appreciate
the need for a meticulous approach.10 However, such
broad categories reveal little about the many detailed ways
in which an intrathecal injection can go astray within each
of the five phases of an individual spinal anaesthetic, these
being, in sequence, lumbar puncture, solution injection,
spreading of drug through CSF, drug action on the spinal
nerve roots and cord, and subsequent patient management.
All of the problems involved are well described in the literature, but usually long ago, and many practitioners seem
unaware of the issues involved. For instance, the neuroscience division of AstraZeneca received 562 ‘Product
Defect Notification’ reports in the 6 yr to December 31,
2007, all ascribing failed spinal anaesthetics to ineffective
bupivacaine solution (Fig. 1). Nearly one-third of reports
(179) were from the UK, but virtually every country
where the drug is marketed was represented. However,
analysis showed that the returned material was within the
product’s specification in every case so a formal review,
based on a literature search, was thought to be worthwhile.
100
80
60
40
20
0
1995
2000
Calendar year
2005
Fig 1 Annual numbers of reports of failed spinal anaesthesia with
bupivacaine received by AstraZeneca between January 1, 1993 and
December 31, 2008 plotted according to region of the world.
tissue or blood clot can easily obstruct the fine bore
needles used now. Otherwise, a failed lumbar puncture is
virtually always because of either poor positioning of the
patient or incorrect needle insertion, both factors being
within the control of the anaesthetist. Abnormalities of the
spine (kyphosis, scoliosis, calcification of ligaments, consequences of osteoporosis), obesity, and patient anxiety
make both positioning the patient and needle insertion
more difficult, especially in the elderly. Texts of regional
anaesthesia give more extensive instruction than can be
provided here, and good clinical training is the key to
success, but most difficulties are attributable to lack of
adherence to the basic rules.
Positioning
The patient is placed on a firm surface; the lumbar laminae
and spines are ‘separated’ maximally by flexing the whole
spine (including the neck), the hips, and knees; rotation
and lateral curvature of the spine are avoided; these points
apply to lumbar puncture in both sitting and lateral horizontal positions; the former is usually an easier option in
‘difficult’ patients, but sometimes the reverse is true. The
role of the assistant in achieving and maintaining the
patient in the correct position cannot be underestimated.35
Needle insertion
Although its accurate identification can be difficult using
clinical land-marks, what is judged to be the third lumbar
inter-space is used usually, but examination may indicate
that another is preferable. However, care should be taken
not to venture too cephalad and risk damage to the spinal
cord.33 With the midline approach, insertion should start
precisely in the mid-line, mid-way between the posterior
spines, with the needle shaft at right angles to the back in
both planes. Small, incremental changes in needle angle
740
Failed spinal anaesthesia
should be made only if there is resistance to advancement;
if resistance is met, cephalad angulation should be tried
first, and such angulation may be appropriate from the
start if the patient is unable to flex fully (e.g. the obstetric
patient at term). A degree of caudad angulation is sometimes needed, with a slight lateral direction being required
very rarely. All authorities recommend that the anaesthetist
should have a good knowledge of spinal anatomy and
relate these to changes in tissue resistance as the needle is
advanced so that a mental ‘picture’ of where the needle tip
lies is appreciated.
The above points apply specifically to the midline
approach; lateral or paramedian approaches are preferred
by some,27 especially if the mid-line ligaments are heavily
calcified, but they are inherently more complex techniques.
However, in the face of difficulty, the same basic rules
apply: make sure that the patient is in the correct position
and that the correct angles and insertion technique are
used.
Adjuncts
A calm, relaxed patient is more likely to assume and
maintain the correct position, so explanation (before and
during the procedure) and gentle, unhurried patient handling are vital; light anxiolytic premedication contributes
much to relaxing the patient; local anaesthetic infiltration
at the puncture site must be effective without obscuring
the landmarks, but must include both intradermal and s.c.
injection. Achieving the correct position is a particular
challenge in the patient in pain (e.g. from a fractured hip)
and systemic analgesia (i.v. or inhalation) helps considerably. The aim of such adjuncts is to optimize the patient’s
position and to prevent any movement. As will be discussed later, it takes only slight movement to displace the
needle from its target.
Advances in ultrasound technology are reaching the
stage where it can be used to overcome difficulties with
lumbar puncture, but clinicians will still need to be aware
of the problems and how they should be overcome.
Pseudo-successful lumbar puncture
The appearance of clear fluid at the needle hub is usually
the final confirmation that the subarachnoid space has been
entered. Rarely, however, the clear fluid is not CSF, but
local anaesthetic injected as a ‘top-up’ for an epidural
which then proved inadequate for a Caesarean section, or
even spreading there from the lumbar plexus.26
Unfortunately, a positive test for glucose in the fluid does
not confirm that this fluid is definitely CSF because extracellular fluid constituents diffuse rapidly into fluids
injected into the epidural space. Another, even rarer,
suggested cause of clear fluid appearing at the needle hub,
but not confirming successful lumbar puncture, is a congenital arachnoid cyst.39
Solution injection errors
The appearance of CSF in the needle hub is an essential
pre-requisite for spinal anaesthesia, but it does not guarantee success, which also requires that a fully effective dose
is both chosen and actually deposited in the CSF.
Dose selection
Studies of many factors influencing intrathecal drug spread
have shown that the dose injected, within the range normally used, has only a small effect on the extent of a
spinal anaesthetic, but is far more important in determining the quality and duration of block.20 Overall, the actual
dose chosen will depend on the specific local anaesthetic
used, the baricity of that solution, the patient’s subsequent
posture, the type of block intended, and the anticipated
duration of surgery. Thus, knowledge of the factors influencing intrathecal drug spread and clinical experience with
any particular local anaesthetic preparation are important
guides to choosing an effective dose.
However, the need to guarantee an adequate effect
means that the doses of drugs injected in standard ‘single
shot’ techniques are larger than is strictly necessary,
experience with dose titration during continuous spinal
anaesthesia showing clearly that lower doses are often
effective.21 In attempts to either minimize hypotension,
for example by attempting to produce a unilateral block, or
speed postoperative mobilization, by decreasing duration,
some practitioners use lower doses than is traditional3 (e.g.
5– 10 rather than 15 mg of hyperbaric bupivacaine). Used
correctly, and in appropriate situations, such doses can be
reliable, but they do mean that the margin for error is
reduced and that the consequences of other problems (e.g.
Loss of injectate—see below) will be exaggerated and so
risk an inadequate block. It becomes even more important
to ensure that the whole of that lower dose reaches the
CSF and then spreads properly, remembering that the
‘dead space’ of the needle will contain a significant proportion of what is a small volume to start with.
Loss of injectate
The Luer connection between syringe and needle provides
a ready opportunity for leakage of solution. A particular
variant of this problem being a leak through a defect at
the junction of needle hub and shaft.6 Given the small
volumes involved, the loss of even a few drops may cause
a significant decrease in the mass of drug reaching the
CSF, and thus in its effectiveness. To avoid this, it has
long been conventional teaching that the syringe containing the injectate must be inserted very firmly into the hub
of the needle, and that a subsequent check is made that no
leakage occurs.
Misplaced injection
Needle and syringe must be connected firmly, but great
care should be taken to avoid either anterior or posterior
741
Fettes et al.
displacement of the needle tip from subarachnoid to epidural space, where deposition of a spinal dose of local
anaesthetic will have little or no effect. Fluid aspiration,
after attachment of the syringe, should confirm free flow
of CSF and, thus, that the needle tip is still in the correct
space, but such aspiration may displace the tip unless performed carefully, as may the force of the injection of the
syringe contents. To prevent displacement at any stage, it
has been advocated that the dorsum of one hand should be
anchored firmly against the patient’s back and the fingers
used to immobilize the needle, while the other hand is
used to manipulate the syringe.40 Most practitioners would
recommend aspiration for CSF after the injection to
confirm that correct placement is maintained, and some
advocate that this is done half way through as well
although neither of these practices has been shown to
influence the outcome of the block.32 40
Tip displacement must be guarded against with any type
of spinal needle, but it is a particular issue with the
‘pencil point’ needles now used widely to minimize the
incidence of post-dural puncture headache. The opening at
the end of these needles is proximal to the tip, so only a
minor degree of ‘backward’ movement during syringe
attachment may result in epidural injection as was recognized at an early stage in the widespread use of such
needles.12 The distances involved are of the order of a
millimetre or two, but (as with leakage) misplacement of
only a small amount of solution can have significant
effects. An additional issue with pencil-point needles is
that the opening, being much longer than the bevel of a
Quincke needle, may ‘straddle’ the dura so that some solution reaches the CSF, and some the epidural space
(Fig. 2).41 This may be exaggerated by the dura acting as
a ‘flap’ valve across the needle opening. Initially, CSF
pressure pushes the dura outwards so that aspiration is
successful (Fig. 3A), but subsequent injection pushes the
dura forward and the solution is misplaced (Fig. 3B).
A variant is that the needle tip penetrates the dura, but it
is the arachnoid mater that acts as the flap valve so that a
subdural injection results (Fig. 3C). This misplacement is
usually thought of as leading to excessive spread during
epidural block, but the equivalent phenomenon has been
described after intended subarachnoid injection,37 and is
a recognized complication of myelography.22 Subdural
injection has also been identified as the cause of a failed
block when either epidural11 or subarachnoid15 injection
was intended.
These eventualities, being subtle abnormalities of placement, are impossible to identify at the actual time, but
rotation of the needle through 3608 after the initial
appearance of CSF, and before check aspiration, has
been advocated as a way of minimizing the possibility
of them occurring, the theory being that the rotation
reduces the risk of the membrane edges catching on the
opening.
Inadequate intrathecal spread
The intrathecal spread of a local anaesthetic solution, even
when correctly placed, has truly been described as capricious.7 The factors that affect it are many, but the focus
here will be on those that may result in inadequate spread.
Anatomical abnormality
Intrathecal spread is governed by interplay between solution physical characteristics, gravity, and the configuration of the vertebral canal. Anatomical abnormalities that
lead to problems with spread can be both overt and covert.
The curves of the vertebral column are integral to solution
Epidural
space
Epidural
space
Dura and
arachnoid
Subarachnoid
space
Dura and
arachnoid
A
Cauda
equina
Subarachnoid
space
Cauda
equina
CSF
Aspiration
LA
B
Correct
LA
Epidural
C
LA
LA
LA
Subdural
Incorrect
Fig 2 Possible positions of the tip of a pencil-point needle. If it is
correctly placed (upper picture) all of the local anaesthetic solution will
reach the subarachnoid space, but if the opening ‘straddles’ the dura
(lower picture) some solution will be deposited in the epidural space.
Fig 3 To show how the dura or arachnoid mater may act as a ‘flap’ valve
across the opening of a pencil point needle. During aspiration (A) the
dura/arachnoid are pulled back allowing CSF to enter the needle. During
injection the dura (B) or arachnoid (C) is pushed forward and the local
anaesthetic enters the epidural or subdural space.
742
Failed spinal anaesthesia
spread and any obvious abnormality, kyphosis, or scoliosis, may interfere with the process. Examination of the
patient should reveal whether this might occur, but it is
not possible to predict whether the effect will be excessive
spread or failure.
A very rare possibility, which is not apparent on examination, is that the ligaments that support the spinal cord
within the theca form complete septae and act as longitudinal or transverse barriers to local anaesthetic spread.
This can result in a block that is entirely unilateral2 or of
insufficient cephalad spread. Spinal stenosis or other
pathological lesions might also limit spread, effectiveness,
or both, one such case being attributed to the consequences of previous intrathecal chemotherapy.1 42
Similarly, previous surgery within the vertebral canal may
result in adhesions that interfere with spread.
An interesting ‘abnormality’ considered to have caused
restricted spread in a single patient was a larger than usual
volume of CSF in the lumbar theca.18 Subsequent systematic study has shown that lumbar CSF volume is the
most important factor influencing the variability seen
between individuals in the spread of an intrathecal injection.9 A negative correlation was found between lumbar
CSF volume and the peak sensory level achieved with
hyperbaric bupivacaine when the injection was performed
in both supine and sitting positions. A variation of this
factor is dural ectasia, which is a pathological enlargement
of the dura seen in the majority of patients with Marfan’s
syndrome and in some other connective tissue disorders.25
Solution density
Consistently effective spinal anaesthesia requires that the
practitioner has a good understanding of the factors that
affect intrathecal spread, particularly, but not only, solution density. A solution with a density within the normal
range of that of CSF (‘isobaric’) will virtually guarantee
block of the lower limbs with little risk of thoracic nerve
block and thus hypotension.43 However, plain solutions of
bupivacaine, although often referred to as isobaric, are
actually of sufficiently lower density to be hypobaric,
especially at body temperature. As a result their range of
spread is much less predictable than that of a truly isobaric
preparation, and occasionally the block may be no higher
than the first, or even second, lumbar dermatome when
administered to the non-pregnant supine patient.29
Although the impact of variations in CSF volume has yet
to be studied with these solutions, it seems likely that this
factor may well be a factor in their variability.
Solutions with a density greater than that of CSF
(hyperbaric) move very definitively under the combined
influence of gravity and the curves of the vertebral canal.
Over a hundred years ago, Barker, one of the early pioneers of spinal anaesthesia in the UK, observed that the
addition of glucose to the solution made for a more
reliable effect.4 In the standard scenario, that of a patient
placed supine after the injection of a hyperbaric
preparation at the mid-lumbar level, the solution will
spread ‘down’ the slope under the effect of gravity to pool
at the ‘lowest’ point of the thoracic curve, so exposing all
nerve roots up to that level to an effective concentration of
local anaesthetic. However, if lumbar puncture is performed at the fourth lumbar or the lumbo-sacral interspace
the local anaesthetic may be ‘trapped’ below the lumbar
curve, especially if the patient is in the sitting position
during injection and maintained in that position for a
period thereafter.
This results in a block that is restricted to the sacral segments, just as has been described with a spinal catheter
that passes caudally.31 Prevention relies on avoiding too
low an injection level unless, of course, a deliberate
‘saddle’ block is intended.
Ineffective drug action
The last possible explanation for a failed spinal is that the
solution actually injected reaches the target nerves, but is
inactive or ineffective, with a variety of explanations
being possible.
Identification errors
Spinal anaesthetics are supplied in aqueous solution ready
for injection and there is no opportunity for confusion in
the preparation of the solution itself. However, other optically clear solutions, such as a separate local anaesthetic
for skin infiltration or analgesic adjuvants, are often used
from the same sterile preparation area and the possibility
that confusing them may lead to an ineffective block must
be considered. Recognition of the possibility of such injection errors has led to the widespread use of syringe labelling in anaesthesia, but this is not as easy within a sterile
field as it is on an anaesthetic work station. Attention to
detail is essential, but minimizing the number of ampoules
on the block tray (such as using the same local anaesthetic
for both skin infiltration and spinal) and consistent use
of different sizes of syringe for each component of the
procedure help considerably.
Chemical incompatibility
The mixing of two different pharmaceutical preparations
also raises the possibility of ineffectiveness as a result of
interaction between local anaesthetic and adjuvant. Local
anaesthetics seem to be compatible with most of the
common opioids, but there has been little formal study of
the effects of mixing them, and the situation is even less
definitive with other adjuvants such as clonidine, midazolam, and other more extreme substances. Certainly, there
are no studies of the stability of three or more substances
when mixed together for intrathecal use, a not unknown
practice today. Chemical reaction might generate an
obvious precipitate, but another possibility is that the pH
of the local anaesthetic solution becomes even lower than
it was to start with. This would decrease the concentration
743
Fettes et al.
of the un-ionized fraction that is what diffuses into nerve
tissue and, unless the solution mixes well with CSF, a
decreased effect could result. There is at least one report
indicating that the incidence of failure is greater after the
addition of a vasoconstrictor solution and this could represent an example of this effect.30
Inactive local anaesthetic solution
The older, ester-type local anaesthetics are chemically
labile so that heat sterilization and prolonged storage, particularly in aqueous solution, can make them ineffective
because of hydrolysis and hence they need very careful
handling. Although the more modern amide-linked drugs
(e.g. lidocaine, bupivacaine, etc.) are much more stable
and can be heat sterilized in solution and then stored for
several years without loss of potency, there have been a
number of reports attributing failure of spinal anaesthetics
to inactive drug.8 16 38 44
Local anaesthetic resistance
Very rarely a failed spinal anaesthetic has been attributed
to physiological ‘resistance’ to the actions of local
anaesthetic drugs, although the reports tend to the
anecdotal.5 23 36 45 A history of repeated failure of dental
or other local anaesthetic techniques is accompanied by
speculation that the problem is because of a sodiumchannel mutation that renders the drugs ineffective.
However, no such mutation has ever been described, and
the clinical reports are incomplete, specifically failing to
consider not only the recognized causes of failure, but also
the behaviour of an anxious patient preferring general
anaesthesia as an explanation for the ‘resistance’. Very
detailed investigation would be required for ‘resistance’ to
be accepted as an explanation. As an aside, any patient
giving a history of repeated failures with local anaesthesia
should be managed by an experienced clinician.
Failure of subsequent management
Not all of a patient’s claims of discomfort, or even pain,
during a spinal anaesthetic are the result of an inadequate
injection. A properly performed spinal anaesthetic will
produce complete somatic, and a major degree of autonomic, nerve block in the lower half of the body unless a
specifically restricted method is used. However, ensuring
that this block occurs is only part of the process because
the unaffected components of the nervous system require
consideration and management. Specifically, this relates to
conscious awareness of the clinical setting and of ‘sensations’ transmitted through unblocked nerves, with both
factors possibly making the patient claim that the block
has failed. This may not actually be the case, but patient
management certainly has failed if such a claim is made
when the block is actually as good as it could be.
Lying supine and wide awake while undergoing surgery
is not a pleasant experience, even for the most sanguine of
individuals, and anxiety alone can cause much difficulty.
Further, operating tables are designed for surgical access,
not patient comfort; and intra-abdominal stimuli may
result in afferent impulses in unblocked parasympathetic
and phrenic nerve fibres. The more anxious the patient, the
greater will be the impact of these factors and the more
likely will it be that the patient will fail to cope with the
situation and claim that the anaesthetic has not worked
properly. Expectation plays a part, and good preoperative
patient counselling followed by a supportive approach
from the anaesthetist during the operation is important in
avoiding such problems, but so is the judicious, and
pro-active use of systemic sedative and analgesic drugs.
Sufficient sedation to produce drowsiness, or even sleep
(with appropriate monitoring), is rarely contra-indicated
other than in the obstetric situation, and even there small
doses may occasionally be useful.
Testing the block
In recent years, it has become almost mandatory, certainly
in the obstetric setting, to test the level of block formally
before surgery commences. This apparently sensible precaution may be difficult or impossible to undertake in
some patients (for example the demented patient with a
fractured neck of femur). Excessive focus on testing can
also have a negative impact. Most patients will have some
anxiety about the effectiveness of the injection, and this
will be increased if testing is started too soon.
Conventional practice is to check motor block by testing
the ability to lift the legs, followed by testing of sensory
block to stimuli such as soft touch, cold, or pin prick, all
of which have their proponents. It is advisable to start
testing in the lower segments, where onset will be fastest,
and work upwards. Proving early on that there is some
effect encourages patient confidence; testing too soon does
the opposite.
Even if there is no formal assessment of the level of
block, the clinician must be confident that an adequate
block has been produced. Establishing that the level
of block is appropriate for the projected surgery is often
taken to demonstrate that the quality of block is adequate
also, but this is not always the case if cold or pin-prick
stimuli are used. The observation that the upper block
level is a few dermatomes above which innervate the surgical field (not forgetting the deeper structures) is a good
start, but it does not guarantee that the quality of block is
sufficient. A covert pinch of the site of the proposed surgical incision may be a better indicator of skin analgesia,
and can be reassuring if the block has been slow in onset.
Indeed, there is much to be said, particularly when the
patient is conscious, for asking the surgeon to do the same
with a toothed surgical forceps before incising the skin,10
but surreptitiously and without asking a loaded question
such as ‘Does that hurt?’! The patient is distracted by conversation and an exchange of glances between surgeon
and anaesthetist is all that is needed for surgery to begin.
744
Failed spinal anaesthesia
Catheter and combined techniques
The great majority of spinal anaesthetics involve a single,
through needle injection and, as has been noted, this
requires some certainty about its effectiveness for surgery.
To take advantage of the rapid onset and profound block
of spinal anaesthesia, both continuous and combined
spinal – epidural techniques have been introduced to
increase flexibility. If the catheters are correctly placed,
problems of inadequate spread, quality, and duration of
effect can be dealt with although many of the potential
technical problems outlined above can still apply.
However, both methods require a greater level of skill and
experience to use, the insertion of an intrathecal catheter
can be surprisingly difficult to achieve in some patients
and, as has been mentioned already, can result in the misdirection of the local anaesthetic solution, with the risk of
neurotoxicity.34 It is vital to leave no more than 2 – 3 cm
of catheter within the dura to avoid this. In the combined
technique, it is common to inject a relatively small volume
for the spinal component, so the problems that can result
in a proportion not reaching the subarachnoid space are
very relevant, but at least the epidural catheter can be used
in attempts to rescue the situation.
Management of failure
Failure of a spinal anaesthetic is an event of significant
concern for both patient and anaesthetist even when it is
immediately apparent, but it can have serious consequences (clinical and medico-legal) if the problem only
becomes evident once surgery has started. If there is any
doubt about the nature or duration of the proposed
surgery, a method other than a standard spinal anaesthetic
should be used. The trainee anaesthetist should avoid
over-selling the technique, especially in the early days of
unsupervised practice. Promising that all will be achieved
by one injection leaves no room for manoeuvre, but
offering one injection to reduce pain and a second to
ensure unconsciousness does. If a spinal anaesthetic does
fail in some way, the management options are limited; so,
the first rule is to expend every effort in prevention.
Prevention is better than cure
Having made the decision to use a spinal anaesthetic, the
block should be performed with meticulous attention to
detail as has been indicated above. It is impossible to overemphasize this point.
The failed block
The precise management of the failed block will depend
on the nature of the inadequacy and the time at which it
becomes apparent. Thus, some monitoring of the onset of
the block and correct interpretation of the observations are
both vital. The slower the onset of either motor or sensory
block, the more likely is the block to be inadequate, so the
more detailed this assessment should be. While the onset
of spinal anaesthesia is rapid in most patients, it can be
slow in some; so, ‘tincture of time’ should always be
allowed.10 However, if most of the expected block has not
developed within 15 min, some additional manoeuvre is
almost certainly going to be needed. The possibilities,
their explanations, and suggested immediate responses are
as follows:
(1) No block: the wrong solution has been injected, it has
been deposited in the wrong place, or it is ineffective.
Repeating the procedure or conversion to general
anaesthesia are the only option. If, after operation, the
patient has significant pruritus, it is likely that only an
opioid was injected.
(2) Good block of inadequate cephalad spread: the level
of injection was too low, anatomical abnormality has
restricted spread, or some injectate has been misplaced. If a hyperbaric solution was used, flex the
patient’s hips and knees and tilt the table head down.
This straightens out the lumbar curve, but maintains a
cephalad ‘slope’ and allows any solution ‘trapped’ in
the sacrum to spread further. A variation with the
same aim, but perhaps better suited to the obstetric
situation, is to turn the patient to the full lateral
position with a head down tilt, reversing the side after
2 – 3 min. If a plain (and usually slightly hypobaric)
solution has been used, it may help to sit the patient
up, but beware of peripheral pooling of blood.
If a spinal catheter injection results in inadequate
spread, the response should not be to inject more of
the same solution because dose has minimal effect on
intrathecal spread.20 Either posture should be manipulated as above, or a different baricity of solution
should be tried, or the catheter should be withdrawn
before the injection is repeated.31
(3) Good, but unilateral block: this is most likely because
of positioning, but it is possible that longitudinal ligaments supporting the cord have blocked spread. If the
operation is to be on the anaesthetized limb, then the
surgeon should know that the other leg has sensation,
and the patient should be reassured and closely monitored. Otherwise, turning the patient onto the
unblocked side if a hyperbaric solution was used (or
the reverse for plain solutions) may facilitate spread.
(4) Patchy block (This term is used to describe a block
that appears adequate in extent, but the sensory and
motor effects are incomplete.): causes of inadequate
block are numerous and include all those discussed
above, but the most likely explanation is that the local
anaesthetic was at least partially misplaced, or that the
dose given was inadequate. If this becomes apparent
before surgery starts, the options are to repeat the
spinal injection or to use a greater degree of systemic
supplementation than was planned, the latter being the
745
Fettes et al.
only option after skin incision. It may not be necessary
to recourse to general anaesthesia, sedation, or analgesic drugs often being sufficient especially when
patient anxiety is a major factor. Infiltration of the
wound and other tissues with local anaesthetic by the
surgeon may also be useful in such situations.
(5) Inadequate duration: the most likely explanation is
that for one of several reasons an inadequate dose of
local anaesthetic was delivered to the CSF.
Alternatively, lidocaine (intended for skin infiltration)
was confused for bupivacaine, or the operation has
taken longer than expected. Systemic supplementation
or infiltration of local anaesthetic may tide matters
over, but often the only option is to convert to general
anaesthesia.
Repeating the block
Where no effect at all has followed the injection it seems
reasonable to repeat the procedure, paying close attention
to avoiding the potential pitfalls. In all other situations
besides total failure, there must be some local anaesthetic
in the CSF already, and anxieties relating to several issues
have to be taken into account:
(1) A restricted block may be because of some factor,
probably anatomical, impeding the physical spread of
the solution, and it may have exactly the same impact
on a second injection, resulting in a high concentration
of local anaesthetic at or close to the site of injection.
Cauda equina lesions were described after continuous
spinal anaesthesia when very restricted spread
prompted repeat injections rather than the manipulation of other factors,34 and a similar problem has
been described after repeated needle injection.14 19
(2) Repeat injection, especially in response to a poor
quality block, may lead to excessive spread,13 so it
may be argued that a lower dose should be used to
reduce the risk of this possibility.
(3) A good quality, but unilateral block, might lead to an
attempt to place a second injection into the ‘other’
side of the theca, but the risk of placing the second
dose in the same side must be significant.
(4) Barriers to spread within the subarachnoid space may
also affect epidural spread (and vice versa), so an
attempt at epidural block may not succeed either.
(5) A block of inadequate cephalad spread might be overcome by repeating the injection at a higher level, but
should perhaps only be attempted when the indication
for a regional technique is considerable.
(6) The final concern, particularly applicable to the last
mentioned, but relevant to nearly all situations where
a repeat block might be considered, is that the adjacent
nerve tissue is already affected by local anaesthetic
action so that the risk of direct needle trauma is
increased.
Only some of these problems have actually been
described, most being in the category of theoretical possibilities, but such concerns do reinforce the view that every
effort must be made to ensure that the first injection is
fully effective.
Recourse to general anaesthesia
There are many ways in which an inadequate block might
be ‘rescued’, but there is a limit to how much discomfort
or distress an individual patient can tolerate, so general
anaesthesia must be considered if one or two simple
measures have not rectified matters. Common sense and
clinical experience are usually the best indicators of
exactly when to convert to general anaesthesia, so the
unsupervised trainee can be at a disadvantage. However, it
is far better to make the decision sooner rather than later
and have to deal with a seriously distressed patient. Of
course, explaining later why the anticipated technique had
not been provided can be difficult. It is another reason
why prevention (getting the block right to start with) is the
best approach, but it is also a reason for not ‘over-selling’
the regional approach before operation.
If general anaesthesia is induced to supplement a partially effective spinal anaesthetic, any degree of sympathetic nerve block will make hypotension more likely.
Follow-up initiatives
Clinical follow-up
As with any anaesthetic complication, the details should
be documented fully in the notes, and the patient provided
with an apology and a full explanation after operation.
Giving the patient a written summary of events for presentation to a future anaesthetist can be very helpful, although
care should be taken to prevent medico-legal recourse.
Rarely, inadequate spread has been the first indication of
pathology within the vertebral canal. Therefore, it may be
appropriate to look for symptoms and signs of neurological disease, and involve a neurologist if there is any suspicion of these being present.
It is during the follow-up of a patient in whom no block
was obtained, the possibility of local anaesthetic ‘resistance’ may seem an attractive explanation. As has already
been noted, much wider consideration of the possibilities,
supported by very detailed investigation, is needed than
has been the case in previous reports.
Investigating local anaesthetic effectiveness
Spinal anaesthesia is usually a simple and effective technique, but ‘failure’ can occur at any time and in the hands
of any clinician, no matter how experienced. However, if
the procedure has, apparently, been routine and straightforward concerns can arise that the current supply of local
anaesthetic is defective, especially if two or more such
failures occur in the same hospital within a short period of
time. The preparations which have been most implicated
746
Failed spinal anaesthesia
are those of hyperbaric bupivacaine ( probably because it
is the drug used most commonly at present), with drug
from both major suppliers, Abbott38 and AstraZeneca,8 16
44
being involved. In fact, the chemical stability of the
amide drugs and modern standards of pharmaceutical
manufacture mean that drug inactivity is a most unlikely
cause of a failed spinal anaesthetic, but it remains a possibility which at least has to be eliminated.
As has been suggested, performing skin infiltration with
some of the solution intended for the spinal injection
should demonstrate that it is effective. If the concern continues the operating theatre, pharmacy and anaesthetic
department records should be cross-checked to see
whether other practitioners in the hospital have experienced any problems. Similarly, distributors should be able
to check whether other hospitals which have been supplied
with material from the same batch have reported difficulty.
If such enquiries reveal that others are using the same
material to good effect, the clinician should consider the
advice of those two great authorities, Lee and Atkinson,
on ‘The spinal that does not take’:
10
11
12
13
14
15
16
17
18
All experienced workers have encountered this
occasionally even though accepted procedure has
apparently been followed. Reflection, however,
usually discloses some flaw in technique. In 1907
Alfred E. Barker wrote that for successful spinal
analgesia it is necessary ‘to enter the lumbar dural
sac effectually with the point of the needle, and to
discharge through this, all the contemplated dose of
the drug, directly and freely into the cerebrospinal
fluid, below the termination of the cord’ (Barker,
1907). Failure to follow the details of this advice is
the commonest cause of a poor result.27
19
20
21
22
23
24
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748
 Original Articles
Disclosure of Risks Associated With Regional
Anesthesia: A Survey of Academic Regional
Anesthesiologists
Richard Brull, M.D., F.R.C.P.C.,
Colin J.L. McCartney, M.B.Ch.B., F.R.C.A., F.C.A.R.C.S.I., F.R.C.P.C.,
Vincent W.S. Chan, M.D., F.R.C.P.C., Gregory A. Liguori, M.D.,
Mary J. Hargett, B.Sc., Daquan Xu, M.B., M.Sc., Sherif Abbas, M.D.,
and Hossam El-Beheiry, M.B.B.Ch., Ph.D., F.R.C.P.C.
Background and Objectives: In view of the relatively few large studies available to estimate the rates of
complications following regional anesthesia, we aimed to identify and quantify the risks that academic regional
anesthesiologists and regional anesthesia fellows disclose to their patients before performing central and peripheral
nerve blockade.
Methods: We asked 23 North American regional anesthesia fellowship program directors to distribute a
questionnaire to the regional anesthesiologists and regional anesthesia fellows at their institutions. The questionnaire was designed to capture the risks and corresponding incidences that are routinely disclosed to patients
before performing the most common central and peripheral nerve block techniques.
Results: The total number of respondents was 79 from 12 different institutions. Fifty-eight (74%) respondents disclose risks of regional anesthesia in order to allow their patients to make an informed choice, whereas
20 (26%) disclose risks for medicolegal reasons. For central neural blockade, the most commonly disclosed risks
are headache, local pain/discomfort, and infection. For peripheral nerve blockade, the most commonly disclosed
risks are transient neuropathy, local pain/discomfort, and infection. For both central and peripheral nerve
blockade, the risks most commonly disclosed are also those with the highest-reported incidences.
Conclusions: The risks of regional anesthesia most commonly disclosed to patients by academic regional
anesthesiologists and regional anesthesia fellows are benign in nature and occur frequently. Severe complications of regional anesthesia are far less commonly disclosed. The incidences of severe complications disclosed by
academic regional anesthesiologists and their fellows can be inconsistent with those cited in the contemporary
literature. Reg Anesth Pain Med 2007;32:7-11.
Key Words: Adverse effects, Anesthesia, Epidural, Spinal, Nerve block, Postoperative complications.
C
omplications after regional anesthesia (RA) are
uncommon. Unfortunately, prohibitively large
numbers of patients are required for study in order
See Editorial page 1
From the Department of Anesthesia and Pain Management,
Toronto Western Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada; and Department of
Anesthesia, The Hospital for Special Surgery, Weill Medical College of Cornell University, New York, NY.
Accepted for publication July 25, 2006.
Reprint requests: Richard Brull, M.D., F.R.C.P.C, Department of
Anesthesia, Toronto Western Hospital, 399 Bathurst Street, Toronto,
Ontario, Canada M5T 2S8. E-mail: [email protected]
© 2007 by the American Society of Regional Anesthesia and
Pain Medicine.
1098-7339/07/3201-0001$32.00/0
doi:10.1016/j.rapm.2006.07.005
to capture the true incidences of such complications.1 The American Society of Anesthesiologists
(ASA) Closed Claims Project provides the largest
collection of adverse events associated with modern
RA practice in the United States;2 however, the lack
of a denominator prevents the calculation of incidence. The objective of this study is to identify and
quantify the risks of RA that are routinely disclosed
by academic regional anesthesiologists and their RA
fellows to patients in North American teaching hospitals. The information gathered may complement
the relatively limited data available in the contemporary literature to produce a more accurate representation of the risks associated with RA and allow
other anesthesia practitioners to draw on the experience of experts during preoperative discussions
with their patients. Our hypothesis was that academic regional anesthesiologists and RA fellows
Regional Anesthesia and Pain Medicine, Vol 32, No 1 (January–February), 2007: pp 7–11
7
8
Regional Anesthesia and Pain Medicine Vol. 32 No. 1 January–February 2007
routinely disclose all significant risks and corresponding incidences to their patients before performing central (CNB) or peripheral nerve blockade
(PNB).
Methods
After institutional review board approval (University Health Network, Toronto, Ontario, Canada),
an information letter and questionnaire were sent
by electronic mail to all identifiable regional anesthesia fellowship program directors in North America on November 7, 2005. Twenty-three program
directors were identified from the Regional Anesthesia Fellowship Program listings on the American
Society of Regional Anesthesia and Pain Medicine
website (www.ASRA.com) as well as the recently
published guidelines for RA Fellowship training.3
The program directors were asked to distribute the
questionnaire to “all practicing regional anesthesiologists and RA fellows” at their home institutions
and then return the completed questionnaires by
mail or facsimile. After 8 weeks, a reminder message was sent by electronic mail to those program
directors who had not yet responded to the initial
request.
The questionnaire was primarily designed to capture the risks and corresponding incidences that are
routinely disclosed by the respondents to their patients prior to performing the most common CNB
and PNB techniques. From a list of complications
for each CNB and PNB technique, the respondents
were instructed to select which risks they routinely
disclose to their patients and indicate the corresponding incidence that is disclosed along with each
risk according to a 6-point scale: (1) “greater than
1:10,” (2) “approximately 1:100,” (3) “approximately 1:1,000,” (4) “approximately 1:10,000,” (5)
“approximately 1:100,000,” or (6) “less than
1:1,000,000.” Respondents were encouraged to add
any risks (and corresponding incidences) that did
not appear in the list. Additionally, respondents
were asked to select the “primary reason” for disclosing risks associated with RA from 2 options: (1)
“to allow the patient to make an informed choice”
or (2) “for medicolegal reasons.” Finally, respondents were asked to select whether their institution
required a “written consent form” for (1) “general
anesthesia,” (2) “regional anesthesia,” (3) “combined (general/regional anesthesia),” or (4) none of
the above.
Data analysis was undertaken using SAS Version
8.0 (SAS Institute Inc., Cary, NC). Categorical data
were analyzed by using the chi-square test. Nonparametric data were analyzed by using the Mann-
Whitney U test with the Bonferroni correction for
multiple comparisons.
Results
The program directors from 12 institutions (9
American and 3 Canadian) replied and agreed to
participate in this study. Seven program directors
replied and agreed after the initial e-mail request,
whereas 5 replied and agreed after the reminder
e-mail request. No replies were received from the
program directors of the remaining 11 institutions.
The total number of respondents (questionnaires
returned) was 79 (70 attending anesthesiologists
and 9 RA fellows). Fifty-eight (74%) respondents
answered that the primary reason for explaining
regional anesthetic risks was to allow their patients
to make an informed choice regarding anesthetic
technique, whereas 20 (26%) answered for medicolegal reasons. Among the 12 participating institutions, 8 require a written consent form for anesthesia, whereas the remaining 4 institutions do not.
For all 8 institutions that require a written consent
form for anesthesia, both general anesthesia (GA)
and RA are addressed in a single form. The risks and
corresponding incidences routinely disclosed for
spinal and epidural anesthesia are remarkably similar. For both spinal and epidural anesthesia, the
most commonly disclosed risks are headache, local
pain/discomfort, and infection (Table 1). Severe
complications of CNB, such as paralysis, cardiac
arrest, and death, are far less frequently disclosed.
For PNB, the most commonly disclosed risks are
transient neuropathy, local pain/discomfort, and
infection (Table 2). The 2 exceptions are axillary
block, where bruising is often disclosed (possibly
reflecting the transarterial technique), and ankle
block, where the risk of neuropathy is arguably
rare. For both CNB and PNB, the risks most commonly disclosed are also those with the highest
likelihood of occurrence among all incidences routinely disclosed by our respondents (Tables 1 and
2). When analyzed according to institutional country of origin (United States v Canada), there were
no significant differences for any of the responses in
the questionnaire.
Discussion
Neurological complications of RA can be severe
and potentially devastating to patients and their
families. Candid disclosure and accurate quantification of risks associated with RA are imperative to
protecting both patients and anesthesiologists alike.
Surprisingly, however, the results of our questionnaire suggest that relatively few regional anesthesiologists disclose the severe risks of RA. For exam-
N, number of respondents who routinely disclose specified risk; %, percentage of total respondents who routinely disclose specified risk; incidence, incidence of specified risk routinely
disclosed by respondents. The incidence is expressed as the mode calculated from all responses in aggregate; N/A, not applicable.
20
29
1:105
10
14
1:104
5
7
1:104
14
20
1:103
31
43
1:106
42
57
1:105
41
56
1:103
N/A
69
91
1:102
38
51
1:10
61
82
1:10
54
73
1:105
23
32
1:105
13
18
1:105
10
14
1:104
5
7
1:104
32
43
1:106
44
58
1:105
37
49
1:104
45
59
1:102
69
90
1:102
55
74
1:105
36
48
1:10
Headache
Infection
Bruising
55
73
1:10
Spinal anesthesia
N
%
Incidence
Epidural anesthesia
N
%
Incidence
Paralysis
Peripheral
Neuropathy
(permanent)
Peripheral
Neuropathy
(transient)
Transient
Neurological
Symptoms
Local
Pain/Discomfort
Table 1. Risks of Neuraxial Blockade Disclosed by Regional Anesthesiologists
Seizures
Respiratory
Failure
Cardiac
Arrest
Death
Risk Disclosure for Regional Anesthesia
•
Brull et al.
9
ple, only 58% and 43% of academic regional
anesthesiologists routinely disclose the risks of permanent neuropathy and paralysis, respectively, to
their patients undergoing CNB. Our survey did not
enable us to determine why some anesthesiologists
failed to disclose these risks. One possible explanation for this finding is the potential for discussions
regarding anesthetic risk in the immediate preoperative period to exacerbate the patients’ preoperative
anxiety.4 Additionally, previous studies that have
examined which anesthetic risks patients would
like to know about are conflicting.5,6 Many patients
prefer simple explanations about the main risks and
benefits, although a considerable number of patients wish full-risk disclosure. Nonetheless, anesthesiologists have a duty to accurately disclose the
significant risks of the proposed anesthetic to their
patients, including those that happen relatively frequently (e.g., local pain/discomfort) as well as those
that happen rarely but are severe in nature (e.g.,
permanent neuropathy and paralysis).
The complications of RA and their likelihood presented to the patient by the anesthesiologist likely
influence the patients’ choice of anesthetic technique for their surgery. Disclosing an inflated rate
of complications may cause patients to opt for GA
and forfeit the potential benefits of RA. Alternatively, failing to mention certain complications or
deflating the rate of complications associated with
RA may lead the patient to choose an RA technique
when the patient would have chosen a GA had the
risks been accurately disclosed. Importantly, among
the anesthesiologists who do disclose the severe
risks of CNB, specifically, permanent neuropathy,
paralysis, respiratory failure, seizures, cardiac arrest, and death, the incidences disclosed are generally in keeping with those cited in the contemporary literature.7-10 The single exception is seizures
after CNB, which reportedly occur far less often
(0.12-1.32:10,000)7-9,11 than what is disclosed by
our respondents. For PNB, the contemporary literature suggests that the incidence of severe complications is considerably less common than that disclosed by our respondents. For example, in 2 recent
comprehensive prospective studies of complications
after PNB, yielding 5,412 blocks in aggregate, there
were no cases of permanent neuropathy, 1 case of
seizure (1.8:10,000), and no cases of cardiac arrest
or death.12,13 Similarly, in the large and widely cited
investigation of 43,552 PNBs (excluding lumbar
plexus block) by Auroy and colleagues,9 there were
5 cases of seizure (1.1:10,000) and no cases of cardiac arrest or death. Unfortunately, Auroy’s study
did not provide sufficient detail to determine the
rate of permanent neuropathy after PNB. There are
at least 2 possible explanations for the discrepancy
10
Interscalene block
N
%
Incidence
Infraclavicular block
N
%
Incidence
Axillary block
N
%
Incidence
Femoral block
N
%
Incidence
Popliteal block
N
%
Incidence
Ankle block
N
%
Incidence
Infection
Horner’s
Syndrome
Peripheral
Neuropathy
(transient)
Peripheral
Neuropathy
(permanent)
Paralysis
Seizures
Pneumothorax
Respiratory
Failure
Cardiac
Arrest
Death
42
55
1:102
54
72
1:104
55
71
1:10
57
73
1:102
59
77
1:104
15
21
1:104
29
39
1:103
27
37
1:103
23
32
1:103
13
18
1:105
21
28
1:105
45
69
1:10
39
60
1:102
45
70
1:104
N/A
47
72
1:104
43
66
1:105
N/A
17
28
1:103
29
46
1:103
N/A
11
18
1:105
18
30
1:106
55
75
1:10
55
76
1:10
51
70
1:104
N/A
54
73
1:104
51
70
1:104
N/A
21
30
1:104
N/A
N/A
12
18
1:104
18
26
1:105
51
68
1:10
46
62
1:10
54
73
1:104
N/A
54
71
1:104
48
63
1:104
N/A
18
25
1:104
N/A
N/A
12
17
1:104
19
27
1:105
50
70
1:10
43
61
1:10
53
74
1:105
N/A
53
73
1:104
50
69
1:104
N/A
18
26
1:104
N/A
N/A
11
16
1:104
18
26
1:105
55
79
1:10
43
61
1:10
43
62
1:104
N/A
34
48
1:104
32
45
1:104
N/A
8
12
1:103
N/A
N/A
7
11
1:105
13
19
1:105
Local
Pain/Discomfort
Bruising
54
71
1:10
N, number of respondents who routinely disclose specified risk; %, percentage of total respondents who routinely disclose specified risk; incidence, Incidence of specified risk routinely
disclosed by respondents. The incidence is expressed as the mode calculated from all responses in aggregate; N/A, not applicable.
Regional Anesthesia and Pain Medicine Vol. 32 No. 1 January–February 2007
Table 2. Risks of Peripheral Nerve Blockade Disclosed by Regional Anesthesiologists
Risk Disclosure for Regional Anesthesia
between the incidence of severe complications disclosed by our respondents and that reported in the
literature. The first may be that regional anesthesiologists are less familiar with the contemporary literature than they should be. The second, perhaps
more palatable explanation, is that much of the
available literature is flawed, and the respondents
are drawing on their own clinical experience to
estimate and disclose the incidences of severe complications associated with RA. Indeed, the questionable validity of the available literature limits its role
in guiding discussions of risk with patients. The
largest contemporary studies of risk associated with
RA are restricted to reviews of insurance claims2,7,14
and self-reporting by anesthesiologists,8-10 both of
which can result in misrepresentation of risk.1,15
There are several important limitations of our
study. First, because the distribution of our survey was left to the discretion of the program
directors, we did not determine the total number
of questionnaires distributed and therefore could
not calculate a true “response rate.” Moreover,
the rate of reply by the program directors was
only 12 out of the 23 programs identified; however, it is likely that some of the e-mail contact
information gathered was outdated and/or the
programs inactive or discontinued. Furthermore,
although we recognize that the inclusion of RA
fellows may have skewed our results, any such
bias is likely minimal. Indeed, the number of RA
fellow respondents was very low compared to the
number of attending anesthesiologist respondents. We, nonetheless, believe that including RA
fellows is important because fellows are often the
ones charged with conducting the preoperative
assessment and entering into discussions of risk
with their patients; such discussions should faithfully reflect the practice of their expert instructors, namely the attending anesthesiologists. Finally, the incidence of some complications
disclosed by our respondents may not be generalizable beyond teaching centers. For example,
the incidence of headache routinely disclosed for
either spinal or epidural anesthesia was curiously
similar and questionably high.
In summary, our survey of risk-disclosure practices among academic regional anesthesiologists
and RA fellows revealed that the most commonly
disclosed risks of RA are benign in nature and
occur frequently. Severe complications of RA are
far less commonly disclosed. The incidences of
severe complications disclosed by academic regional anesthesiologists and their fellows can be
inconsistent with those cited in the contemporary
literature.
•
Brull et al.
11
References
1. Auroy Y, Benhamou D, Amaberti R. Risk assessment
and control require analysis of both outcomes and
process of care. Anesthesiology 2004;101:815-817.
2. Lee LA, Posner KL, Domino KB, Caplan RA, Cheney
FW. Injuries associated with regional anesthesia in
the 1980s and 1990s: A closed claims analysis. Anesthesiology 2004;101:143-152.
3. Hargett MJ, Beckman JD, Liguori GA, Neal JM.
Guidelines for regional anesthesia fellowship training. Reg Anesth Pain Med 2005;30:218-225.
4. White SM, Baldwin TJ. Consent for anaesthesia. Anaesthesia 2003;58:760-774.
5. Garden AL, Merry AF, Holland RL, Petrie KJ. Anaesthesia information—What patients want to know.
Anaesth Intensive Care 1996;24:594-598.
6. Lonsdale M, Hutchison GL. Patients’ desire for information about anaesthesia. Scottish and Canadian attitudes. Anaesthesia 1991;46:410-412.
7. Aromaa U, Lahdensuu M, Cozanitis DA. Severe complications associated with epidural and spinal anaesthesias in Finland 1987-1993. A study based on patient
insurance claims. Acta Anaesthesiol Scand 1997;41:445452.
8. Auroy Y, Narchi P, Messiah A, Litt L, Rouvier B,
Samii K. Serious complications related to regional
anesthesia: Results of a prospective survey in France.
Anesthesiology 1997;87:479-486.
9. Auroy Y, Benhamou D, Bargues L, Ecoffey C, Falissard B, Mercier FJ, Bouaziz H, Samii K. Major complications of regional anesthesia in France: The SOS
Regional Anesthesia Hotline Service. Anesthesiology
2002;97:1274-1280.
10. Moen V, Dahlgren N, Irestedt L. Severe neurological
complications after central neuraxial blockades in Sweden 1990-1999. Anesthesiology 2004;101:950-959.
11. Brown DL, Ransom DM, Hall JA, Leicht CH, Schroeder DR, Offord KP. Regional anesthesia and local
anesthetic-induced systemic toxicity: Seizure frequency and accompanying cardiovascular changes.
Anesth Analg 1995;81:321-328.
12. Capdevila X, Pirat P, Bringuier S, Gaertner E, Singelyn F, Bernard N, Choquet O, Bouaziz H, Bonnet F.
Continuous peripheral nerve blocks in hospital wards
after orthopedic surgery: A multicenter prospective
analysis of the quality of postoperative analgesia and
complications in 1,416 patients. Anesthesiology 2005;
103:1035-1045.
13. Fanelli G, Casati A, Garancini P, Torri G. Nerve stimulator and multiple injection technique for upper and
lower limb blockade: Failure rate, patient acceptance,
and neurologic complications. Study Group on Regional Anesthesia. Anesth Analg 1999;88:847-852.
14. Peng PW, Smedstad KG. Litigation in Canada against
anesthesiologists practicing regional anesthesia. A review of closed claims. Can J Anaesth 2000;47:105-112.
15. Cullen DJ, Bates DW, Small SD, Cooper JB, Nemeskal
AR, Leape LL. The incident reporting system does not
detect adverse drug events: A problem for quality improvement. Jt Comm J Qual Improv 1995;21:541-548.
ƒ Editorials
Informed Consent for Regional
Anesthesia: What Is Necessary?
I
n this issue of Regional Anesthesia and Pain Medicine, Brull et al.1 described what
risks were disclosed to patients by academic anesthesiologists and anesthesia
fellows in North American regional-anesthesia fellowship programs in obtaining
informed consent for regional anesthesia. Brull et al.1 found the most commonly
revealed risks were benign in nature and occurred frequently. For central neural
block, the most commonly disclosed risks were headache, local pain/discomfort,
and infection, whereas for peripheral-nerve block, transient neuropathy, local
pain/discomfort, and infection were mentioned. Severe complications of regional
anesthesia, including permanent neurologic injury, paralysis, cardiac arrest, seizures, and death were only infrequently disclosed in the process of informed
consent. For instance, a minority of anesthesiologists described risks of paralysis
(43%), seizures (20%), cardiac arrest (14%), and death (29%) to patients undergoing epidural anesthesia.1 In addition, the authors found that the incidences
of severe complications cited by the anesthesiologists were often inconsistent with
the literature.
Although the results of Brull et al.1 are probably typical of the practice of
regional anesthesia, the results are concerning because of the ethical and legal
requirement for informed consent. Informed consent requires an active communication between the physician and patient, in which the physician explains the
nature and purpose of the proposed procedure and the alternative techniques
available, as well as a description of the risks and benefits of the procedures and
alternatives. The desired outcome is that the patient will have sufficient knowledge to make an educated choice about whether to undergo the proposed procedure or treatment.
What types of risks need to be disclosed during the process of informed
consent? Although the exact information to be transmitted varies from state to
state, most states have adopted a “reasonable patient” standard.2-4 This standard
requires the physician to disclose information that a reasonable patient under
similar circumstances would want to know to make an informed decision. Informed consent requires that a patient have a full understanding of that to which
he or she has consented. The risks that should be disclosed are those that would
be important in deciding whether to undertake the proposed therapy. For regional anesthesia, the disclosure should include both the common, but not severe,
risks (e.g., local pain/discomfort, infection, headache, transient neuropathy) and
the rare, but of major consequences, risks (e.g., seizure, cardiac arrest, permanent
neuropathy, paralysis, and death). Certainly, a patient would want to know a risk
of permanent neuropathy exists after an interscalene block performed for postoperative pain control, especially if he or she were an artist, pianist, or a surgeon.
Interestingly, 3 out of 4 of the programs utilized a written informed consent for
anesthesia, with most addressing general and regional anesthesia on a single form.
Although the Joint Commission on Accreditation of Healthcare Organizations
requires documentation of informed consent, it can be done by handwritten note,
on the surgical consent, or on a separate written anesthesia consent form.2 Many
attorneys believe that a written anesthesia-specific consent form, detailing sedoi:10.1016/j.rapm.2006.10.001
See Brull et al. page 7
Regional Anesthesia and Pain Medicine, Vol 32, No 1 (January–February), 2007: pp 1–2
1
2
Regional Anesthesia and Pain Medicine Vol. 32 No. 1 January–February 2007
lected risks specific to the procedure will help in the defense of a claim for an
injury.4,5 Notations to tailor the informed-consent discussion to a specific patient
help to support the defense of the underlying medical issues.5 Although informed
consent is seldom the major issue of liability in a claim,5,6 in a significant number
of cases, the adequacy of informed consent is included as an additional allegation,
thereby influencing the evaluation, defense, and resolution of a malpractice
claim.5 However, patients can still allege lack of understanding of risks in the
presence of a written consent form.4 Likewise, no scientific evidence indicates that
separate anesthesia written informed consent is better than a handwritten note
plus the written surgical consent.7
In summary, the article by Brull et al.1 brings to our consciousness the need to
further educate our patients of important risks/benefits of all types of anesthesia,
especially regional anesthesia. To make an informed decision, patients require
accurate portrayal of rare, serious complications, as well as the more common
minor ones.
Karen B. Domino, M.D., M.P.H.
Chair, ASA Committee on Professional Liability
Professor, Department of Anesthesiology
University of Washington School of Medicine
Seattle, WA
References
1. Brull R, McCartney CJL, Chan VWS, et al. Disclosure of risks associated with regional
anesthesia: A survey of academic regional anesthesiologists. Reg Anesth Pain Med 2007;
32:7-11.
2. O’Leary CE. Informed consent for anesthesia: Has the time come for a separate written
consent document? ASA Newsl 2006;70:11-12.
3. Manual for Anesthesia Department Organization and Management. Park Ridge, IL: American
Society of Anesthesiologists; 2005:1-18.
4. Bierstein K. Informed consent and the Medicare Interpretive Guidelines. ASA Newsl
2006;70:13-14.
5. Sanford SR. Informed consent: The verdict is in. ASA Newsl 2006;70:15-16.
6. Caplan RA. Informed consent: Patterns of liability from the ASA Closed Claims Project.
ASA Newsl 2000;64:7-9.
7. Cheney FW. A separate written consent document for anesthesia: What is the indication? ASA Newsl 2000;70:17-18.
The Role of Intrathecal Drugs in the Treatment of
Acute Pain
James P. Rathmell,
MD,
Timothy R. Lair,
MD,
and Bushra Nauman,
MD
Department of Anesthesiology, University of Vermont College of Medicine, Burlington, Vermont
Intrathecal opioids are widely used as useful adjuncts
in the treatment of acute and chronic pain, and a number of non-opioid drugs show promise as analgesic
drugs with spinal selectivity. In this review we examine
the historical development and current use of intrathecal opioids and other drugs that show promise for treating pain in the perioperative period. The pharmacology
and clinical use of intrathecal morphine and other opioids is reviewed in detail, including dosing guidelines
O
pioid analgesics have long been recognized as
among the most effective treatments for pain. In
his treatise on gout and rheumatism (1), the 17th
century English physician Thomas Sydenham wrote:
“Among the remedies which it has pleased Almighty
God to give man to relieve his suffering, none is so
universal and so efficacious as opium.”
Despite their nearly universal ability to alleviate
pain, opioids have a number of unpleasant, even lifethreatening, side effects: nausea and vomiting, tolerance, pruritus, urinary retention, and respiratory depression. For thousands of years, these medications
were used without a known mechanism of action until
1971, when a class of highly specific opioid receptors
was identified (2). Soon thereafter, opioid receptors
were localized within the brain (3) and spinal cord (4).
Evidence that direct application of morphine at the
spinal cord level could produce spinally mediated
analgesia soon followed (5). Based on this limited
experimental evidence, Wang et al. (6) administered
bolus intrathecal morphine and Onofrio et al. (7) reported chronic intrathecal morphine infusions, both
working in patients with severe pain associated with
Financial support for preparation of this manuscript was provided by an unrestricted educational grant from Endo Pharmaceuticals, Chadds Ford, Pennsylvania.
Accepted for publication June 22, 2005.
Address correspondence and reprint requests to James P. Rathmell, M.D., Center for Pain Medicine, Fletcher Allen Health Care, 62
Tilley Drive, South Burlington, VT 05403. Address electronic mail to
[email protected].
S30
Anesth Analg 2005;101:S30–S43
for specific surgical procedures and the incidence and
treatment of side effects associated with these drugs.
Available data on the use of non-opioid drugs that have
been tested intrathecally for use as analgesics are also
reviewed. Evidence-based guidelines for dosing of intrathecal drugs for specific surgical procedures and for
the treatment of the most common side effects associated with these drugs are presented.
(Anesth Analg 2005;101:S30 –S43)
advanced cancer; they reported the first observations
of profound and prolonged pain relief with spinal
opioids. Since these first, bold clinical experiments, we
have witnessed a rapid transition from the laboratory
to clinical practice. Intrathecal opioids are now widely
used as useful adjuncts in the treatment of acute and
chronic pain, and a number of non-opioid drugs show
promise as analgesics with spinal selectivity. In this
review, we examine the current use of intrathecal
opioids and other drugs that show promise for treating pain in the perioperative period.
Search Strategy
We performed a MEDLINE search for all indexed
articles published between 1966 and March 2004 using
the search terms “postoperative pain,” “spinal or intrathecal,” “spinal analgesia,” “intrathecal analgesia,”
“acute pain and spinal,” and “postoperative pain and
spinal,” resulting in 1436 articles. The abstracts of all
articles were reviewed to select articles on the development and use of intrathecal drugs that are representative of the current state of our knowledge. Those
articles representing the best available evidence were
selected (e.g., randomized, controlled trials were used
in preference to observational studies when available,
case reports or case series were used only when no
other information was available, and retrospective
analyses were generally omitted); however, there was
no attempt to assign qualitative scores to each article
or to combine the available data quantitatively.
©2005 by the International Anesthesia Research Society
0003-2999/05
ANESTH ANALG
2005;101:S30 –S43
REVIEW ARTICLE
RATHMELL ET AL.
INTRATHECAL DRUGS FOR ACUTE PAIN
S31
Pharmacology
Drug disposition after intrathecal administration varies depending on the lipid solubility of the individual
drug, and the most closely studied drugs are the opioid analgesics. After spinal administration, typically
within the cerebrospinal fluid (CSF) in the lumbar
cistern, the drug is distributed within CSF. Ummenhofer et al. (8) reported a series of elegant experiments
in which the concentration of morphine, fentanyl,
sufentanil, and alfentanil were measured within CSF,
spinal cord, epidural fat, and plasma in anesthetized
pigs after lumbar intrathecal administration. From
their data, they developed a multiple-compartment
pharmacokinetic model that closely simulates the observed pharmacology and explains many of the clinical characteristics of the opioids used for intrathecal
analgesia. The fate of opioids after intrathecal administration is complex (Fig. 1). Intrathecal opioids penetrate the spinal cord and the dura mater to enter the
epidural space. Within the spinal cord, they bind to
nonspecific sites within the white matter as well as to
specific receptors within the dorsal horn. Drug within
the spinal cord eventually reaches the plasma compartment though venous uptake. In the epidural
space, the opioid is sequestered in fat and enters the
plasma compartment via venous uptake. The sum of
these multiple avenues for drug disposition results in
the clinical characteristics observed. Any drug given
intrathecally rapidly redistributes within the CSF; opioid is detectable in the cisterna magna after lumbar
intrathecal administration within 30 min, even with
lipophilic drugs like sufentanil (9). Indeed, all opioids
move within the CSF and this rapid distribution
within the CSF likely accounts for the small, but significant, incidence of respiratory depression that is
observed immediately after lumbar intrathecal injection (Fig. 2) (10).
The lipophilic opioids rapidly traverse the dura
where they are sequestered in the epidural fat and
enter the systemic circulation; they also rapidly penetrate the spinal cord where they bind to both nonspecific sites within the white matter as well as dorsal
horn receptors and eventually enter the systemic circulation as they are cleared from the spinal cord. This
rapid transfer from the CSF to both spinal cord and
the epidural fat accounts for the rapid onset and the
prompt decline in CSF levels of opioid, accounting for
the minimal rostral spread, lack of delayed respiratory
depression, and relatively small dermatomal band of
analgesia seen during chronic administration; vascular uptake accounts for the limited duration of analgesia of lipophilic opioids (Fig. 3).
Morphine, the prototypic hydrophilic opioid, undergoes a similar transfer to both the spinal cord and
Figure 1. Disposition of opioid after intrathecal administration.
After intrathecal administration, the disposition of opioids is complex and multicompartmental. Simultaneously, intrathecal opioids
1) travel cephalad within the cerebrospinal fluid (CSF), 2) enter the
spinal cord, where they may bind to nonspecific sites within the
white matter or specific opioid receptors within the dorsal horn, and
3) traverse the dura mater to enter the epidural space where they
bind to epidural fat. From the spinal cord and epidural space,
opioids enter the plasma compartment through vascular uptake.
The clinical properties of each opioid (speed of onset, duration of
action) and degree of rostral spread result from the sum of effects
for each route. Lipophilic opioids (fentanyl/sufentanil) rapidly
cross the dura, where they are sequestered in fat and gain rapid
access to plasma; they also enter the spinal cord, where they may
bind to nonspecific sites within the white matter as well as specific
receptors within the dorsal horn and then enter the plasma. This
results in rapid onset, limited and brief rostral spread resulting in
early respiratory depression and a narrow band of analgesia surrounding the site of injection, and a relatively short duration of
action. In contrast, the hydrophilic opioid morphine traverses the
dura slowly to the epidural space where it binds little within epidural fat and only slowly enters the plasma. Morphine also enters
the spinal cord and binds little to nonspecific receptors but largely
to specific receptors within the dorsal horn, where uptake into the
plasma occurs slowly. As a result of this limited and slow transfer
from the CSF, morphine remains in relatively large concentration
within the CSF; this results in slow onset, extensive and prolonged
rostral spread resulting in delayed respiratory depression and a
broad band of analgesia surrounding the site of injection, and a
relatively long duration of action.
the epidural space; however, there is limited binding
to fat within the epidural space and limited binding to
nonspecific receptors within the spinal cord white
matter. Transfer to the systemic circulation is likewise
slower than the lipophilic drugs. Concentrations
within the CSF decline more slowly than similar doses
of lipophilic drugs, accounting for the greater degree
of rostral spread, delayed respiratory depression (Fig.
2), and extensive dermatomal analgesia during
chronic administration. This complex pharmacokinetic behavior explains why the location of injection
for intrathecal administration remains an important
determinant in the pattern of analgesia observed (11).
Hydrophilic drugs result in slow onset and a wide
band of analgesia surrounding the site of injection. In
contrast, highly lipophilic drugs transfer rapidly from
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Figure 2. The average onset and duration of respiratory depression
after intrathecal opioid administration. Respiratory depression after
intrathecal administration of lipophilic opioids (fentanyl and sufentanil) results from rostral spread immediately after injection, occurring within the first 20 –30 min after injection. In contrast, the
hydrophilic opioid morphine traverses from the cerebrospinal fluid
(CSF) to the spinal cord and epidural space slowly. There is a small
degree of respiratory depression immediately after injection that is
similar to that seen with the lipophilic drugs and a later and more
prolonged respiratory depression resulting from rostral migration
of morphine within the CSF that peaks at approximately 6 h after
injection and can persist for 18 –24 h.
Figure 4. Spread of analgesia after intrathecal administration in the
lumbar cistern. Values shown in parentheses are octanol:water partition coefficients; a larger value indicates that a drug is more lipid
soluble. Lipophilic opioids result in a narrow band of analgesia
whereas hydrophilic opioids produce a broader band of analgesia.
In contrast, intrathecal administration of a lipophilic drug in the
lumbar cistern results in a broad, but short-lived, band of analgesia
limited to the lumbar dermatomes similar to that seen with chronic
infusion. Despite these differing patterns of analgesia, all opioids
move within the cerebrospinal fluid (CSF) and are detectable in the
CSF adjacent to the brainstem soon after injection. Indeed, lifethreatening respiratory depression has been reported within 20 min
after intrathecal injection of fentanyl, sufentanil, and meperidine
(10).
Figure 3. The average onset and duration of analgesia after intrathecal opioid administration. Lipophilic opioids (fentanyl and
sufentanil) produce rapid onset of analgesia lasting from 2– 4 h,
whereas hydrophilic opioids (morphine) are slower in onset with a
duration of analgesia extending 18 –24 h.
the CSF and result in a broad band of analgesia that is
much shorter in duration and the clinical observation
that analgesia during prolonged infusion is limited to
a narrower band of analgesia surrounding the anatomic site of administration during epidural administration (Fig. 4). The clinical dose range, onset, and
duration of activity for various intrathecal opioids are
shown in Table 1.
Internationally, opioids and adjuvant analgesics are
supplied in varying concentrations and in preparations that include preservatives. Although the toxicity
of the most common preservatives appears to be small
(12), benzyl alcohol and the parabens have been implicated as the cause of neurotoxicity after intrathecal
administration (13).
Morphine
In early trials with intrathecal morphine, doses ranged
from 500 –1000 ␮g and profound sedation and respiratory depression were not uncommon (14). In a carefully controlled study in healthy volunteers, profound
and prolonged respiratory depression was observed
in all subjects who received 600 ␮g of intrathecal morphine (15). In more recent years, several trials have
examined doses as small as 40 ␮g, typically, extending
only as large as 300 ␮g. Indeed, it appears that the
efficacy of doses above this range is often limited by side
effects.
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Table 1. Pharmacologic Properties of Common Opioids used for Intrathecal Analgesia
Opioid
Usual dose range
(␮g)
Onset
(min)
Duration
(h)
IT:IV potency ratio
Morphine
Fentanyl
Sufentanil
100–500
5–25
2.5–10
45–75
5–10
5–10
18–24
1–4
2–6
1:200
1:10
1:10
In recent years, clinical investigation surrounding
use of intrathecal morphine in the perioperative period has centered on establishing the optimal dose for
specific surgical procedures. Rathmell et al. (16) compared the need for supplemental IV morphine via
patient-controlled analgesia after doses of intrathecal
morphine ranging from 0 –300 ␮g after total hip and
knee arthroplasty. After total hip replacement, intrathecal morphine (200 ␮g) provided excellent analgesia. In contrast, the degree of pain experienced after
total knee arthroplasty exceeded the analgesia afforded by even the largest dose of intrathecal morphine (300 ␮g), yet patients who received this dose
nearly universally reported nausea, vomiting, and
pruritus. Intrathecal morphine has been studied as an
analgesic for pain after cesarean delivery (17), various
orthopedic procedures (16), and a range of other surgical procedures (18) from spinal (19) to cardiac surgery (20). Two generalizations emerge. The first and
most important is that the optimal dose of intrathecal
morphine depends on the specific surgical procedure,
with doses ⬍100 ␮g often sufficing for pain control
after cesarean delivery, whereas doses in the area of
500 ␮g may be required for more extensive surgery,
such as thoracotomy or open abdominal aortic aneurysm repair. The best available evidence relating to
optimal dosing for specific procedures is presented in
Table 2. The second generalization is that the incidence of side effects increases in proportion to the
dose administered, with doses in excess of 300 ␮g
producing nausea, vomiting, pruritus, and urinary retention in most recipients. Indeed, there appears to be
a ceiling analgesic effect for intrathecal morphine
above which the risk of side effects outweighs the
benefits of improved analgesia. Despite the excellent
analgesia afforded by use of intrathecal morphine,
carefully controlled studies in high-risk patients have
failed to demonstrate any beneficial effects on outcome in terms of reduced perioperative renal, pulmonary, and cardiac complications or mortality (21). The
prolonged duration of action along with the risk of
late respiratory depression associated with intrathecal
morphine point to the need for hospitalization and
monitoring after administration. This drug is not suitable for ambulatory procedures. Preservative-free
morphine is currently the only drug discussed in this
review that is approved by the United States Food and
Drug Administration for intrathecal use in the treatment of acute pain.
Other Opioids
Fentanyl and Sufentanil
Fentanyl and sufentanil are the best studied and most
commonly used lipophilic drugs for intrathecal delivery. Two major trends in use of these drugs as analgesics have evolved in recent years: the first is a closer
definition of their role as analgesics for labor, delivery,
and postcesarean delivery; the second is the recognition that addition of small doses of lipophilic opioids
during spinal anesthesia for ambulatory procedures
can produce more rapid onset and better quality surgical block and lead to more rapid recovery of motor
function and allow for earlier discharge after surgery.
Both drugs can be summarized as having a rapid
onset of analgesia (10 –15 min) with a short duration of
action (2–5 h).
Bucklin et al. (22) performed a meta-analysis of 7
randomized, controlled trials and concluded that intrathecal opioids (including morphine 200 ␮g, sufentanil 2–10 ␮g, and fentanyl 25 ␮g) provide comparable
analgesia 15–20 min after injection in early labor with
a more frequent incidence of pruritus compared with
epidural local anesthetics. Duration of analgesia depends on the stage of labor. Viscomi et al. (23) found
that 10 ␮g intrathecal sufentanil, combined with
2.5 mg of bupivacaine, provided analgesia that was
significantly shorter in duration in advanced labor
(120 ⫾ 26 min) compared with early labor (163 ⫾
57 min). Intrathecal sufentanil is approximately 4.5
times more potent than intrathecal fentanyl in laboring parturients (24). Single-shot techniques provide
predictable analgesia but of limited duration. In obstetrics, where prolonged labor and operative delivery
often occur, many practitioners now take advantage of
the best of both spinal and epidural techniques using
combined spinal-epidural analgesia (CSE). In a prospective, randomized comparison of CSE versus epidural analgesia for labor, Norris et al. (25) found that
progress and outcome of labor were similar in women
receiving10 ␮g intrathecal sufentanil with 2.0 mg bupivacaine or 10 ␮g epidural sufentanil and 12.5–
25.0 mg bupivacaine followed by continuous epidural
infusion of 0.083% bupivacaine plus 0.3 ␮g/mL sufentanil. Intrathecal opioids also provide effective analgesia after cesarean delivery. In a review of the use of
intrathecal lipophilic opioids as adjuncts for surgical
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Table 2. Optimal Intrathecal (IT) Opioid Dose for Specific Surgical Procedures
Procedure
Optimal IT opioid and dose
Comments
Labor analgesia
Sufentanil 2.5–5 ␮g
Larger doses (⬎7.5 ␮g) are associated with an increased incidence of
Cesarean delivery
Morphine 100 ␮g
fetal bradycardia (129).
Fentanyl (10–40 ␮g) and sufentanil (10–15 ␮g) improve intraoperative
Outpatient procedures under spinal
Fentanyl 10–25 ␮g
analgesia but do not produce significant postoperative analgesia (15).
These intrathecal lipophilic opioids speed onset of block and improve
anesthesia (e.g., knee arthroscopy)
Sufentanil 5–12.5 ␮g
both intraoperative and immediate postoperative analgesia without
Transurethral resection of the prostate
Morphine 50 ␮g
prolonging motor block (18).
This small dose of intrathecal morphine was equivalent to 100 ␮g after
(TURP)
Major orthopedic surgery (e.g., total
Morphine 200–300 ␮g
TURP (130).
Although these doses of intrathecal morphine provide excellent
joint arthroplasty)
analgesia after total hip arthroplasty they are inadequate for pain
relief after total knee arthroplasty, reflecting the greater degree of
Thoracotomy
Morphine 500 ␮g
pain reported by patients undergoing knee replacement (16).
Lumbar intrathecal morphine improves pain relief and reduces but
does not eliminate the need for supplemental IV opioid analgesics
Fast-track cardiac surgery
Morphine 500–600 ␮g (8 ␮g/kg)
(131).
Lumbar intrathecal morphine administered prior to elective cardiac
surgery combined with remifentanil/desflurane anesthesia provided
superior analgesia when compared to a sufentanil/desflurane
Major abdominal/vascular surgery (e.g.,
Morphine 500–600 ␮g
open abdominal aortic aneurysm
anesthetic (132).
Lumbar intrathecal morphine provided more intense analgesia than IV
patient-controlled analgesia with morphine (21).
repair)
spinal anesthesia, Hamber and Viscomi (18) recommended using 20 –30 ␮g fentanyl or 5–7.5 ␮g of sufentanil to supplement bupivacaine spinal anesthesia for
cesarean delivery. The addition of these doses of intrathecal opioid led to faster onset of block, improved
intraoperative and postoperative analgesia that lasted
2-5 h, and decreased nausea and vomiting during
cesarean delivery.
Much recent work has focused on the addition of
intrathecal lipophilic opioids to local anesthetics during spinal anesthesia for brief outpatient surgery. In
this setting, adding fentanyl or sufentanil to bupivacaine or lidocaine results in more rapid onset of block
and improved analgesia, both intraoperatively and for
the first several hours after surgery (18). In efforts to
take advantage of the improved analgesia without
motor blockade, a series of investigations have examined combining lipophilic opioids with small doses of
local anesthetic. Ben-David et al. (26) reported that
patients receiving 20 mg of 0.5% lidocaine in dextrose
with 20 ␮g fentanyl for knee arthroscopy were ready
for discharge an average of 45 min after placement of
the spinal drugs (range, 28 –180 min ). Likewise, addition of fentanyl (10 ␮g) to small doses of hyperbaric
bupivacaine (5 mg) enhanced the quality and duration
of sensory block without prolonging the intensity or
duration of motor block in patients undergoing knee
arthroscopy (27). The addition of intrathecal fentanyl
(10 –25 ␮g) to surgical spinal anesthetics hastens the
onset of surgical anesthesia, enhances intraoperative
analgesia, and provides several hours of postoperative
analgesia without prolonging motor block or delaying
discharge.
Meperidine
Meperidine produces a local anesthetic effect in addition to its properties as an opioid analgesic (28). It has
been reported to provide similar surgical anesthesia
for perineal and lower extremity surgery as the sole
anesthetic compared to bupivacaine (29). The duration
of sensory block after intrathecal administration of
meperidine was 112 ⫾ 19 min in those receiving
1.5 mg/kg compared with 79 ⫾ 27 min in those receiving 1.2 mg/kg; respiratory depression within
5–50 min of administration, hypotension (⬎30% decline in systolic arterial blood pressure), nausea, and
vomiting were all common side effects (30). The addition of meperidine 10 mg to intrathecal bupivacaine
for cesarean delivery was associated with prolonged
postoperative analgesia but with more frequent intraoperative nausea and vomiting (31). Another randomized trial examining use of intrathecal meperidine (15
or 25 mg) for CSE during labor was halted because of
the frequent incidence of the nausea and vomiting
associated with this drug (32). Adding small doses of
meperidine (0.3 mg/kg) to spinal lidocaine also prolongs postoperative analgesia after transurethral resection of the prostate (33). Despite the theoretic appeal of meperidine as a drug that can provide both
opioid and local anesthetic effects, it has gained limited popularity owing to the frequent association with
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nausea and vomiting. Detailed dose-response studies
examining analgesic effects at smaller intrathecal
doses are not available.
Non-Opioids as Adjuvants and Analgesics
for Intrathecal Use
Hydromorphone
Clonidine is a specific ␣2-receptor agonist; ␣2receptors are present within both presynaptic and
postsynaptic terminals of primary afferent nociceptive
neurons within the dorsal horn of the spinal cord.
Spinal ␣2-receptor agonists alter pain transmission by
binding presynaptically to nociceptive A␦ and C fiber
terminals and reducing neurotransmitter release, and
postsynaptically by hyperpolarizing second order
neurons within the dorsal horn (44). Clonidine produces analgesia by activating ␣2-receptors; direct intrathecal administration produces selective spinallymediated analgesia (45,46). Spinal clonidine produces
dose-dependent analgesia with hypotension, bradycardia and sedation; it is not associated with respiratory depression or pruritus (47).
Clonidine has demonstrated effects on reducing
both nociceptive and neuropathic pain in experimental models and in clinical use. Eisenach et al. (48) used
intradermal capsaicin-induced hyperalgesia to produce central hypersensitivity and allodynia and noxious heat to produce acute pain in a series of healthy
volunteers. They found that 150 ␮g of clonidine administered intrathecally, but not IV, relieved pain and
allodynia, supporting a spinal selective mechanism for
analgesia. In a placebo-controlled, randomized study,
patients with severe cancer pain despite large doses of
opioids received epidural clonidine (30 ␮g/h) or placebo (49). Epidural clonidine provided significant pain
relief, particularly in patients with neuropathic pain.
Reports on the use of intrathecal clonidine in the
perioperative period are numerous and collectively
point toward synergistic action with spinal local anesthetics (50) with less urinary retention than spinal
morphine (51). Clonidine has been demonstrated in
numerous studies to prolong sensory and motor
block. Eisenach et al. (47) reviewed the use of
clonidine for regional anesthesia in 1996. Their summary analysis of numerous studies found that
clonidine 75–225 ␮g (average, 146 ␮g) added to spinal
bupivacaine 13.75–15 mg prolonged sensory block
from 2.5 to 3.7 h and motor block from 2.4 to 3.3 h (47).
Clonidine intensifies the degree of sensory block, reduces tourniquet pain (52), and appears to prolong
and intensify the effects of spinal local anesthetic by
altering systemic absorption (53). The degree of sympatholysis and hypotension after typical spinal local
anesthetic doses (e.g., 15 mg bupivacaine) is near maximal; thus, adding intrathecal clonidine results in no
increased hypotension (47). Hemodynamic effects of
clonidine after neuraxial administration begin within
30 min, reach maximum effect within 1–2 h, and last
approximately 6 – 8 h after a single injection (47).
Long-term, continuous infusion of hydromorphone
was not associated with spinal cord toxicity in an
animal model (34) and has gained popularity and
acceptance as an alternative to morphine as an analgesic drug for treatment of chronic pain using continuous intrathecal drug delivery systems (35). Hydromorphone has also been used effectively as a
neuraxial drug for continuous epidural analgesia after
thoracotomy (36), prostatectomy (37), and spinal fusion (38). Liu et al. (37) randomized 16 patients who
had undergone prostatectomy to receive hydromorphone via patient-controlled analgesia either via an
epidural or an IV route and measured the effectiveness and dose requirements. Patients receiving hydromorphone via the IV route required twice as much
hydromorphone as those receiving the same drug via
an epidural route (approximately 2 ␮g · kg⫺1 · h⫺1
versus 4 ␮g · kg⫺1 · h⫺1 in the IV versus epidural
groups, respectively, during hours 3–24 after surgery).
There are only limited data on intrathecal dosing of
hydromorphone in the acute setting. Drakeford et al.
(39) randomized 60 patients undergoing total joint
arthroplasty to receive either saline, morphine 500 ␮g,
or hydromorphone 2 ␮g/kg intrathecally. Both morphine and hydromorphone produced significantly
better postoperative pain relief with similar incidence
of side effects when compared with saline. Like morphine, systemic doses of hydromorphone required to
produce similar analgesia after IV administration are
several hundred times the doses required after intrathecal administration (40) and produce similar duration of analgesia and side effects. The limited available
data suggest that intrathecal hydromorphone 50 –100
␮g produces analgesia and side effects similar to 100 –
200 ␮g of intrathecal morphine with similar side effects and duration of action.
Methadone
The d-enantiomer of methadone is a weak opioid with
low affinity to the N-methyl-d-aspartate (NMDA) receptor, a class of receptors with potential analgesic
effects. However, in the antinociceptive dose range,
the NMDA antagonism does not appear to contribute
to the mechanism of d-methadone analgesia (41).
There are only limited, uncontrolled reports of use of
intrathecal methadone for intrathecal use via continuous infusion for chronic pain (42) and acute postoperative pain (43).
Clonidine
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There are few studies examining clonidine in combination with intrathecal opioids. Sites et al. (54) found
that combining intrathecal morphine (250 ␮g) with
intrathecal clonidine (25 or 75 ␮g) reduced the need
for supplemental analgesics and improved pain control after total knee arthroplasty. Side effects were
similar with the exception that patients receiving
clonidine had more hypotension during the first 6 h
after surgery.
Neostigmine
Spinal administration of neostigmine, an acetylcholinesterase inhibitor, inhibits breakdown of the endogenous neurotransmitter acetylcholine, thereby inducing analgesia (50). Eisenach et al. (55) demonstrated
that acetylcholine has intrinsic analgesic properties,
and that the concentration of acetylcholine in CSF is
increased during painful electrical stimulation. They
further suggested that enhanced amounts of acetylcholine released from preganglionic sympathetic neurons after spinal neostigmine administration may
counteract the sympatholytic actions of local anesthetics or ␣2-agonists (reducing the degree of hypotension) and add a synergistic antinociceptive effect to
spinal ␣2-agonists (55).
In preliminary dose-ranging studies in surgical patients and healthy volunteers, intrathecal neostigmine
10 –50 ␮g provided analgesia (56). Nausea and lower
extremity weakness were common in doses exceeding
100 –150 ␮g, but sedation, pruritus, respiratory depression, and hemodynamic changes did not occur
(57). Adding 6.25–25 ␮g neostigmine to spinal bupivacaine improves sensory and motor block (56), delays
resolution of block (56), and reduces postoperative
analgesic requirements (58). All doses were associated
with a frequent incidence of nausea and vomiting that
was resistant to pharmacologic treatment (56,58).
One study (59) demonstrated that adding 1–5-␮g
neostigmine to 100 ␮g intrathecal morphine improved
analgesia without increasing side effects after gynecological surgery. The incidence of nausea and the prolongation of recovery from spinal anesthesia suggest
that neostigmine is not a useful adjuvant; further examination of small dose neostigmine in combination
with intrathecal opioids is warranted.
Adenosine
Adenosine produces receptor-specific analgesia via
both peripheral and central mechanisms, and adenosine receptors are present in high density within the
dorsal horn of the spinal cord (60). After animal toxicity testing suggested safety, a phase I dose-ranging
trial of 0.25–2 mg of intrathecal adenosine in healthy
volunteers showed no effect on arterial blood pressure, end-tidal carbon dioxide, or neurologic function;
headache and back pain were common side effects
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(61). Adenosine produced no effect on acute thermal
or chemical pain but reduced mechanical hyperalgesia
and allodynia from intradermal capsaicin for at least
24 h (62). Adenosine concentrations in CSF increased
after intrathecal, but not IV, administration of opioids,
suggesting a role for adenosine in spinal opioid receptor activation and analgesia (63). A randomized study
of 25 parturients who received 10 ␮g of intrathecal
sufentanil with or without 500 ␮g of adenosine
showed no differences in the degree or duration of
pain relief (64). Further clinical trials of intrathecal
adenosine are warranted; its role as an analgesic will
likely be limited to injury associated with acute hyperalgesia (e.g., surgery) and treatment of neuropathic
pain (62).
Epinephrine
Adding the vasoconstrictor epinephrine (0.1– 0.6 mg)
to spinal local anesthetics intensifies and extends the
duration of sensory and motor block in a dosedependent fashion (65,66). Epinephrine may produce
both direct analgesia through ␣-adrenergic receptor
binding as well as prolongation of local anesthetic
effect by vasoconstriction and decreased clearance.
Adding epinephrine to intrathecal opioid (sufentanil,
fentanyl) has no effect on the intensity or duration of
analgesia for labor (67,68) but may increase the incidence of nausea and vomiting (67). Using epinephrine
is a safe and effective means of prolonging and intensifying spinal anesthesia, although at the expense of
delayed return of motor function and micturition (69).
Thus, epinephrine is an unsuitable adjunct for use in
the ambulatory setting.
Ketorolac
Cyclooxygenase-2 (COX-2) activity in the spinal cord
plays a key role in sensitization to sensory stimuli
during acute inflammation (70), but intrathecal administration of COX-2 specific inhibitors has minimal
analgesic effects in an incisional model of postoperative pain (71). Studies in experimental animals suggests that COX-1 plays an important role in spinal
cord pain processing and sensitization after surgery
and that spinally administered specific COX-1 inhibitors may be useful to treat postoperative pain (72). In
a phase I safety assessment of intrathecal ketorolac in
volunteers, a single 0.25–2 mg intrathecal dose of ketorolac did not affect sensory or motor function or
deep tendon reflexes, and there were no subjective
sensations, neurologic or otherwise, reported by the
volunteers. Ketorolac did not reduce pain reported
from heat stimuli applied to the lateral calf (73). Intrathecal ketorolac lacks efficacy in normal rats subjected
to acute, noxious heat stimuli but enhances the antinociceptive effects of clonidine (74). Further study is
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needed to define the role of intrathecal ketorolac in
treating acute pain.
Midazolam
There has been much recent attention toward the use
of the benzodiazepine midazolam as an intrathecal
drug in the treatment of both acute and chronic pain.
Yaksh and Allen (75) recently reviewed the existing
animal and human data regarding use of intrathecal
midazolam. Basic science work with ␥-amino butyric
acid suggests that it may play an important role in
regulating primary as well as dorsal (sensory) and
motor horn excitability. Preclinical studies in animal
models have demonstrated significant analgesia without changes in sympathetic outflow. At larger doses
(typically 3 or more times the dose required to produce analgesic effects), reversible degradation of motor strength and coordination appear. Early toxicity
studies in rabbits (76) suggested that midazolam produced significant spinal cord toxicity, even after
single-shot administration in clinically relevant doses.
However, recent animal studies examining the effects
of long-term intrathecal administration of midazolam
showed no discernible toxicity (77). Yaksh and Allen
(75) conclude that current data “. . .support the assertion of a degree of safety for this modality [intrathecal
midazolam] within the doses and concentrations
examined.”
The use of intrathecal midazolam in humans has
been reported in at least 18 peer-reviewed reports
with an estimated 797 patients (75) since 1986. The
overall clinical effects are characterized by an increased duration of sensory and motor block when
administered with spinal local anesthetic, an increase
in time to first request for supplemental analgesia
postoperatively, and a decrease in postoperative analgesic requirements. There appears to be no increase in
adverse effects, including hypotension, bradycardia,
micturition, or nausea/vomiting, when midazolam is
combined with another intrathecal local anesthetic
and/or opioid compared with groups not receiving
intrathecal midazolam. Tucker et al. (78) reported a
prospective observational study of 1100 patients who
underwent various surgical procedures with spinal
anesthesia with or without the addition of 2 mg of
intrathecal midazolam. Intrathecal midazolam was not
associated with an increased risk of symptoms suggestive of neurological impairment, including motor or sensory changes and bladder or bowel dysfunction. Tucker
et al. (79) randomized 30 parturients to receive intrathecal midazolam 2 mg, fentanyl 10 ␮g, or the combination
of both drugs. Labor pain was not altered by midazolam
alone, was modestly reduced by fentanyl alone, and was
reduced most by the combination of the two drugs. They
concluded that intrathecal midazolam enhanced the analgesic effect of fentanyl without increasing maternal or
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fetal adverse effects. Current reports suggest that the use
of midazolam in a dose not exceeding 1–2 mg at a
concentration not exceeding 1 mg/mL, delivered either
alone or as an intrathecal adjuvant, has positive effects
on perioperative pain and does not increase the incidence of adverse events (75). Although current formulations are preservative-free, commercially available stock
solutions of midazolam hydrochloride are supplied in
concentrations of 5 mg/mL at a pH 3.4 –3.6 (75). The
solubility rapidly declines to ⬍1 mg/mL at pH 4.5–5,
and cloudiness (precipitation) has been reported when
the 5 mg/mL is diluted with higher pH saline or CSF
(80).
Complications Associated with Intrathecal
Opioid Use
Pruritus
Pruritus after intrathecal administration of opioids is
common and occurs more often than after systemic
administration. Szarvas et al. (81) reviewed the pathophysiology and treatment of neuraxial opioid-induced
pruritus. The incidence of pruritus after intrathecal
administration of opioid varies from 30% to 100%
(82– 87). The incidence among the commonly used
intrathecal opioids (morphine, fentanyl, sufentanil)
has been reported to be similarly frequent (88,89). The
exact mechanism of neuraxial opioid-induced pruritus
remains unclear (83). Naloxone’s reversibility of pruritus supports the existence of an opioid receptormediated central mechanism. The mechanism does
not appear to be histamine related (90). Pharmacological therapies include antihistamines, 5-HT3-receptor
antagonists, opiate antagonists and combination
agonist-antagonists, propofol, and nonsteroidal antiinflammatory drugs (83). Histamine is not released
and does not appear to be causative (91). Antihistamines are thus unlikely to have any role in prevention.
The sedative properties may be helpful in interrupting
the itch-scratch cycle but without relieving itch sensation (92). Despite its widespread use, diphenhydramine has little demonstrated efficacy in the treatment
of neuraxial opioid-induced pruritus (84,90). Ondansetron has demonstrated efficacy in both prevention
and treatment of pruritus associated with neuraxial
opioids (84,93). The opioid antagonists naloxone and
naltrexone (91), as well as the agonist-antagonist nalbuphine (94), are the most effective drugs for prevention and treatment of neuraxial opioid-induced pruritus. When the pure antagonists are used in larger
doses, they also reverse analgesia (94). Nalbuphine
appears to be the most effective drug when compared
with naloxone, diphenhydramine, and ondansetron
(94,95). Propofol, in subhypnotic doses, has also
proven effective in the prevention and treatment of
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REVIEW ARTICLE RATHMELL ET AL.
INTRATHECAL DRUGS FOR ACUTE PAIN
neuraxial opioid-induced pruritus. Propofol, 10 mg
bolus followed by 30 mg/24h infusion (96) or 10 mg
without infusion (97), markedly reduced the incidence
of pruritus. However, studies in obstetric populations
have failed to show any effect of similar doses of
propofol on neuraxial opioid-induced pruritus (98,99).
Treatment of opioid-induced pruritus remains a challenge. Ondansetron, propofol, and nalbuphine have
proven efficacy in the treatment of neuraxial opioidinduced pruritus (Table 3).
Urinary Retention
Urinary retention after administration of intrathecal
opioids is common. This side effect can be observed
soon after intrathecal injection of morphine and lasts
for 14 –16 h, regardless of the dose used (100). The
incidence of urinary retention appears to be most frequent with intrathecal morphine at ⬃35% (101) and is
more common after neuraxial administration than after IV or IM administration (102). The incidence does
not appear to be dose related but is more frequent
after intrathecal morphine than after lipophilic opioids
(103,27). Indeed, intrathecal sufentanil alone for lithotripsy was associated with a shorter time to voluntary
micturition than spinal lidocaine (104).
Opioids affect urination via several mechanisms including alteration of parasympathetic tone and central
analgesic action, which modify the pain threshold for
the bladder and contribute to retention (100). Urinary
retention secondary to neuraxial opioids is likely related to interaction with opioid receptors located in
the sacral spinal cord. This interaction promotes inhibition of sacral parasympathetic nervous system outflow, which causes marked detrusor muscle relaxation
and an increase in maximal bladder capacity (100).
Naloxone can prevent or reverse urodynamic changes
after neuraxial morphine; however the dose required
may partially or completely reverse analgesia (100).
Nalbuphine may also reverse the urinary effects of
neuraxial morphine (105). If patients are unable to
void for ⱖ6 h, urinary catheterization should be performed to prevent myogenic bladder damage resulting from prolonged distention. Because urinary retention is infrequent with use of lipophilic intrathecal
opioids, they are the preferred adjuvants for outpatient surgery with spinal anesthesia (18).
Nausea and Vomiting
All opioids, regardless of route of administration, can
produce nausea and vomiting. The incidence after
neuraxial administration is approximately 30% (106),
but the incidence varies with the particular opioid
used and, in some settings, also varies with the dose
administered. Intrathecal morphine led to a dosedependent increase in vomiting in volunteers (15) but
caused no increase in nausea and vomiting when
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2005;101:S30 –S43
added to spinal bupivacaine (107,108). Others have
demonstrated a dose-dependent increase in nausea
and vomiting with intrathecal morphine (109,110). Together, these data suggest that intrathecal morphine
does not increase the incidence of nausea and vomiting after major surgery when compared with systemic
administration of morphine, particularly if the dose is
⬍100 ␮g (111). In contrast, fentanyl and sufentanil
have been associated with little or no nausea or vomiting after intrathecal administration of a single dose
(103,112,113).
Nausea and vomiting induced by neuraxial opioids
may be a systemic effect, particularly with lipophilic
opioids, or may be the result of cephalad migration of
drug in the CSF and subsequent interaction with opioid receptors located in the area postrema (111). Sensitization of the vestibular system to motion and decreased gastric emptying produced by opioids may
also play a role.
For shorter or less painful procedures, use of lipophilic opioids will minimize the risk of nausea and
vomiting. Both fentanyl and sufentanil were shown to
decrease the rate of intraoperative nausea and vomiting during cesarean delivery when compared with
local anesthetic alone for spinal anesthesia (18). Dexamethasone and droperidol have been shown to be
effective for prevention of nausea and vomiting after
epidural morphine (114). Combinations of scopolamine and promethazine used as preventative measures decreased the incidence of nausea and vomiting
(111).
Respiratory Depression
The most feared complication of opioid administration is respiratory depression. The pharmacology and
time course of opioid-induced respiratory depression
have been discussed previously in this review (Fig. 2).
The true incidence of clinically significant respiratory
depression is not known, but evidence from smaller
controlled trials and large observational studies confirm that it is infrequent (115). The majority of prospective studies of epidural morphine have not detected clinically significant respiratory depression, but
they are hindered by relatively small sample sizes and
are markedly underpowered to detect such a rare
event (116). Ko et al. (117) reviewed the use of the term
“respiratory depression” and found that there is no
clear definition, leading to difficulty and confusion
when comparing available studies. The incidence is
infrequent for doses commonly used clinically but the
incidence is dose-dependent for both hydrophilic and
lipophilic opioids (118). The incidence of respiratory
depression associated with continuous epidural infusions containing opioids has been estimated from
large observational studies, with estimates ranging
from 0.09% to 0.4% (119 –125). The risk of respiratory
Respiratory depression •
•
•
•
• Different rates for different opioids (morphine ⬎
fentanyl ⫽ sufentanil)
• Likely dose dependent
• Frequent incidence with IV/IM
Nausea and vomiting
Overall estimates: 0.07%–0.49%.
Dose dependent
All opioids can cause
Typically lipophilic early onset (⬍2 h) and
morphine both early and late onset (6–12 h)
As frequent as 35% with morphine
More common than with IV/IM administration
Morphine ⬎ fentanyl/sufentanil
Not dose related
•
•
•
•
Urinary retention
Incidence
Varies from 30%–100%
Increased in parturients
Varies with opioid used
Likely dose dependent
Increased with epinephrine
•
•
•
•
•
Pruritus
Complication
• Risk factors include large dose;
concomitant use of additional
opioid and or sedatives, age ⬎65
yr, opioid naı̈ve patient
• Late onset depression more
apparent with morphine
• There is not an opioid free from
risk
• Inability to void postoperatively is
a multifactorial problem—risk
factors include surgery type
(especially hernia) preexisting
obstructive problems, volume
status, spinal anesthesia with
epinephrine.
• This is ␮- and ␦-receptor mediated
• Intrathecal opioids appear to have
a protective effect against
intraoperative nausea and
vomiting during cesarean delivery
• Opioid antagonist and agonistantagonist including naloxone,
naltrexone and nalbuphine
Commentary
• Propofol may be less effective for
the parturient
• Histamine release does not appear
to be causative
Treatment
• Ondansetron 4–8 mg IV
• Nalbuphine 4 mg IV
• Propofol 10 mg IV bolus ⫹ small dose
infusion
• Infusion of naloxone
• Oral naltrexone
• Use smallest effective dose
May be a systemic effect vs. cephalad
• For ambulatory procedures use
migration in the cerebrospinal fluid
lipophilic opioid instead of morphine.
(CSF) and interaction with opioid
Dexamethasone and droperidol have
receptors in the area postrema.
shown efficacy as well as combinations
Sensitization of the vestibular system to
of scopolamine and promethazine.
motion and decreased gastric emptying
produced by opioids may play a role.
Secondary to rostral spread in CSF
• Prevention: Establish a monitoring
protocol for your institution and train
personnel; a dedicated acute pain
service can establish appropriate
protocols and monitor adverse events
• Opioid antagonists including naloxone,
naltrexone, nalmefene
Exact mechanism unclear. Postulates
include “itch center” in the central
nervous system, medullary dorsal horn
activation, antagonism of inhibitory
transmitters. Modulation of the
serotonergic pathway and involvement
of prostaglandins may be important as
well
Likely related to interaction with opioid
receptors in the sacral spinal cord,
promoting inhibition of sacral
parasympathetic nervous system
outflow. This causes detrusor muscle
relaxation and an increase in maximal
bladder capacity.
Proposed mechanism
Table 3. Incidence, Proposed Mechanisms, and Treatment for Intrathecal Opioid-Related Side Effects
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REVIEW ARTICLE RATHMELL ET AL.
INTRATHECAL DRUGS FOR ACUTE PAIN
depression after epidural or intrathecal opioid is less
than 1%, and limited data suggest that the risk is
similar to that of opioids delivered via the parenteral
route (116). In a double-blind study of healthy volunteers randomly assigned to receive placebo, IV morphine (0.14 mg/kg), or intrathecal morphine (300 ␮g),
depression of the ventilatory response to hypoxia was
similar in magnitude after either IV or intrathecal
morphine but longer lasting after intrathecal administration (126).
Risk factors for the development of respiratory depression include large doses, concomitant use of additional opioids and/or sedatives, administration in
opioid-naı̈ve patients, and age ⬎65 yr (116,122,123).
Detection of respiratory depression after intrathecal
administration of opioid may be difficult. Respiratory
rate may or may not decrease (124), and significant
hypercapnia can occur despite a normal respiratory
rate (124). Pulse oximetry may be valuable (15), but
the most reliable clinical sign of significant respiratory
depression appears to be a depressed level of consciousness (116,124). Protocols for monitoring vary,
but typical duration of monitoring is 18 to 24 h after
intrathecal morphine and 4 to 6 h after intrathecal
fentanyl or sufentanil (124). Lipophilic opioids are
now used more frequently in the ambulatory setting,
where patients are discharged shortly after surgery;
respiratory depression more than 2 h after intrathecal
injection of fentanyl or sufentanil has never been described. Patients can be safely managed on regular
wards when personnel are trained, emergency guidelines are available, patient dosing and selection are
appropriate, and respiratory rate and patient level of
consciousness are checked hourly (124). The efficacy
and safety of spinal opioids in surgical wards are best
assured when these analgesic techniques are used under the supervision of organized acute pain services
(127,128).
Conclusions
Intrathecal administration of opioids can provide excellent pain relief after a wide range of operative procedures, including procedures performed in the ambulatory setting. Understanding of optimal doses for
specific procedures has improved, but side effects remain common. Knowledge of spinally mediated analgesia is evolving rapidly and a number of non-opioid
compounds may prove useful as analgesics that will
reduce side effects and improve treatment for both
nociceptive and neuropathic pain.
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Anaesthesia, 2009, 64, pages 27–31
doi:10.1111/j.1365-2044.2008.05655.x
.....................................................................................................................................................................................................................
Audit of motor weakness and premature catheter
dislodgement after epidural analgesia in major abdominal
surgery
I. Königsrainer,1 S. Bredanger,2 R. Drewel-Frohnmeyer,2 R. Vonthein,3
W. A. Krueger,2 A. Königsrainer,1 K. E. Unertl2 and T. H. Schroeder2
1 Department of General-, Visceral- and Transplantation Surgery, University Hospital Tübingen, Tübingen, Germany
2 Department of Anaesthesiology and Critical Care Medicine, University Hospital Tübingen, Tübingen, Germany
3 Department of Medical Biometry, University Hospital Tübingen, Tübingen, Germany
Summary
In a quality improvement audit on epidural analgesia in 300 patients after major abdominal
surgery, we identified postoperative lower leg weakness and premature catheter dislodgement
as the most frequent causes of premature discontinuation of postoperative epidural infusion. Lower
limb motor weakness occurred in more than half of the patients with lumbar epidural analgesia. In a
second period monitoring 177 patients, lumbar catheter insertion was abandoned in favour of
exclusive thoracic placement for epidural catheters. Additionally, to prevent outward movement,
the catheters were inserted deeper into the epidural space (mean (SD) 5.2 (1.5) cm in Period Two
vs 4.6 (1.3) cm in Period One). Lower leg motor weakness declined from 14.7% to 5.1% (odds
ratio 0.35; 95% confidence interval 0.16–0.74) between the two periods. Similarly, the frequency
of premature catheter dislodgement was reduced from 14.5% to 5.7% (odds ratio 0.35; 95%
confidence interval 0.17–0.72). With a stepwise logistic regression model we demonstrated that the
odds of premature catheter dislodgement was reduced by 43% for each centimetre of additional
catheter advancement in Period Two. We conclude that careful audit of specific complications can
usefully guide changes in practice that improve success of epidural analgesia regimens.
. ......................................................................................................
Correspondence to: Torsten H. Schroeder
E-mail: [email protected]
Accepted: 16 June 2008
Peri-operative analgesic protocols that include a combination of general and epidural analgesia have been
introduced for a wide variety of surgical procedures
to reduce stress response and allow immediate postoperative rehabilitation [1, 2]. Epidural analgesia significantly
reduces the incidence of cardiovascular events, acute
respiratory failure, deep venous thrombosis and gastrointestinal paralysis after major abdominal surgery [3, 4].
Therefore, it is important to maximise efficacy of
postoperative epidural analgesia. Up to 15% of postoperative epidural analgesia failures are due to technical
problems leading to premature dislodgement of the
catheter or disconnection of the infusion. Failures due
to inadequate analgesia despite properly-functioning
catheters account for another 8–12% [5–7]. Such failures
cause patient discomfort and delays in the rehabilitation
process.
2008 The Authors
Journal compilation 2008 The Association of Anaesthetists of Great Britain and Ireland
Audits have proved generally useful in maintaining
standards of care and might be useful in identifying
problems with postoperative epidural therapy, especially
those important in the setting of a local unit. We
conducted an audit of postoperative epidural analgesia in
our unit by first identifying common causes for our
postoperative epidural failures, then initiating new standards and finally monitoring the success of these interventions.
Methods
This project was undertaken to improve the quality of
epidural analgesia in our unit. The Ethics Committee
of the University Hospital Tübingen approved the
conduct of this audit and publication of its results.
The audit was organised in two parts.
27
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I. Königsrainer et al.
Improving epidural analgesia after abdominal surgery
Anaesthesia, 2009, 64, pages 27–31
. ....................................................................................................................................................................................................................
Period One
First, to identify the main reasons for premature cessation
of postoperative epidural analgesia, we retrospectively
analyzed the data of 300 patients in whom epidural
analgesia had been used after major abdominal surgery in
the Department of General, Visceral, and Transplantation
Surgery over a 13-month period.
Conduct of epidural analgesia and anaesthesia
Our local policy is that exclusion criteria for pre-operative
catheter placement are: patient refusal, coagulation disorders, signs of local or systemic infection, and anatomical
abnormalities. Our standard hospital protocol involves identifying the epidural space with the patient
sitting upright, using a midline approach and the lossof-resistance technique to either air or saline. It was our
local policy that either the lumbar or thoracic vertebral
interspace was selected for epidural catheter placement
on the basis of the dermatomal extent of the surgical
procedure and skin incision. Thus, patients scheduled for
colorectal surgery or surgery in the lower pelvic region
received lumbar epidural analgesia, while higher surgical
incisions received thoracic epidural analgesia. The catheter is routinely affixed to the skin at the insertion site
with a dressing consisting of steri-stripesTM (3M Health
Care, St Paul, MN, USA), a porous tape with a small hole
which was closed with an additional piece of tape. The
rest of the catheter is generally taped along the midline
of the patient’s back. Routinely, a test dose of 20 mg
ropivacaine is applied via the catheter. General anaesthesia
is generally induced with thiopentone (5 mg.kg)1) and
sufentanil (0.2 lg.kg)1) and maintained with sevoflurane
in oxygen ⁄ air. According to local guidelines, the patients
received an epidural loading dose of ropivacaine 45 mg
and sufentanil 10 lg followed by continuous epidural
infusion of ropivacaine 30 mg.h)1 and sufentanil
3 lg.h)1. Postoperatively, continuous infusion was
reduced to ropivacaine 12 mg.h)1 and sufentanil
3 lg.h)1 and then titrated according to presence of pain
and sensory block. Additionally, paracetamol 4 g.24 h)1
or metamizole up to 5 g.24 h)1 were prescribed.
Postoperative care and data collection
Postoperatively, patients with epidural catheters were
assigned to the care of an acute postoperative pain service
team. A tracking sheet was initiated by the anaesthesiologist inserting the epidural catheter. The sheet contained
data on catheter placement, patient demographics, and
prescribed epidural drug infusion. Patients were visited
twice daily on the ward by a member of the acute pain
service team. The ‘tracking’ sheet recorded the following:
vital parameters, presence of absence of pain, motor
weakness (modified Bromage scale: 0 = free movement
28
of legs; 1 = knee flexion barely possible-foot lifting
unconfined; 2 = knee flexion impossible-foot lifting
barely possible; 3 = no movement possible), paraesthesia
(i.e. prickling sensations in the lower limbs or body), the
details of the prescribed epidural drug infusion, and any
free-text notes. Motor weakness of the legs was defined as
a Bromage score > 0. We classed ‘insufficient analgesia’
as any state in which unilateral distribution of the epidural
block, or pain as reported on the tracking sheet. The
catheter insertion site was inspected once per day.
According to hospital protocol, the continuous infusion
was stopped no sooner than the fourth postoperative day
or after postoperative ileus had resolved (with the final
decision left to the discretion of the responsible attending
anaesthetist). The epidural catheter was removed when
the tracking sheet confirmed the patient was pain-free.
Period Two
Following the review of the data of Period One, we
changed certain policies and (a) limited catheter placement to thoracic interspaces T8-11, (b) stipulated that
catheters be advanced 1 cm deeper into the epidural
space. Thus, practitioners who had placed their catheters
4 cm into the epidural space in Period One were
instructed to advance them at least 5 cm deep; those
who had placed their catheters 5 cm deep were instructed
to advance them now 6 cm (with an absolute upper limit
in the new guidelines of 6 cm). The remainder of the
protocols for conduct of analgesia and anaesthesia were
unchanged. During this second period 177 patients
received an epidural catheter.
Statistical analysis
Variables are given as mean (SD), median [interquartile
range] or as frequency, as appropriate. Significance of the
differences between the groups was evaluated by univariate comparisons: analysis of variance for continuous
variables and chi-squared tests for discrete data. Nonparametric tests (Wilcoxon, Kruksal–Wallis) were used
where distributions were extremely skewed. Odds ratios
(OR) and estimated 95% confidence intervals (CI) for
single risk factors were stratified by time period. For
quantitative variables the OR per unit, e.g. for one
additional centimetre of catheter advancement, was
estimated by logistic regression. We used a stepwise
variable selection to find a model that described the main
factors involved in an adjusted manner. Calculations were
done with JMP 7.0 [8].
Results
Patient characteristics are listed in Table 1 and suggest
similar populations between the two time periods. The
2008 The Authors
Journal compilation 2008 The Association of Anaesthetists of Great Britain and Ireland
Æ
Anaesthesia, 2009, 64, pages 27–31
I. Königsrainer et al.
Improving epidural analgesia after abdominal surgery
. ....................................................................................................................................................................................................................
Table 1 Patient characteristics, duration of epidural catheter
placement, and surgery details. Values are median [interquartile
(IQ) range], mean (SD) or number (proportion) as indicated.
Age; years
Gender (male:female)
BMI; kg.m)2
ASA; I:II:III (%)
Catheter duration:
Days
Thoraco-abdominal surgery (%)
Upper abdominal surgery (%)
Colorectal surgery (%)
Miscellaneous surgery (%)
Period One
(n = 300)
Period Two
(n = 177)
59 (13)
165 : 132
25.8 (6.3)
7 : 72 : 21
60 (14)
106 : 71
25.1 (5.7)
8 : 64 : 26
4 [3–5]
4
52
31
13
4 [3–4]
3
55
25
17
BMI, Body mass index; ASA, American Society of Anesthesiology.
Period Two
Cases per month
Period One
30
20
Following the change in policy to thoracic placement
only (2.3% of epidural catheters were nonetheless inserted
into a lumbar intervertebral space) there was a significant
reduction in postoperative lower limb motor weakness
(5.1% vs 14.7%; OR 0.35; 95% CI 0.16–0.74). The
percentage of patients with inadequate postoperative
analgesia remained unchanged (10.3% vs 12.2%; OR
0.82; 95% CI 0.45–1.51).
Following the change to deeper catheter placement,
we found epidural catheters inserted 5.2 (1.5) cm in
Period Two vs 4.6 (1.3) cm in Period One. As a result,
the rate of catheter dislodgement was significantly
reduced from 14.5% to 5.7% (OR 0.35; 95% CI 0.17
to 0.72). We further calculated by linear regression that
the OR for catheter dislodgement was reduced by 43%
for every cm of additional catheter advancement into the
epidural space (unit OR 0.57; 95% CI 0.34–0.93)
within Period Two. The frequency of catheter dislodgement was independent of gender, body mass index,
age, site of insertion (thoracic or lumbar), ASA status, or
type of surgery.
10
0
Discussion
1
3
5
7
9
11
13
15
17
19
Month
Figure 1 Monthly postoperative epidural catheter case load
(black line: thoracic epidural catheters, grey line: lumbar epidural catheters) during Period One (13 months) and Period
Two (7 months).
mean duration of catheter placement and the nature of
the surgery performed did not differ significantly between
Period One and Period Two.
In Period One, 19.7% of the epidural catheters were
placed in a lumbar intervertebral space and 80.3% in a
thoracic intervertebral space (Fig. 1). A review of the
database identified postoperative lower limb motor
weakness as the most frequently noted abnormality taken
care of by the acute pain service team (14.7%) (Table 2):
52.4% of patients with epidural catheters placed in a
lumbar intervertebral space developed postoperative
motor weakness of the legs, compared with only 4.8%
of patients with a thoracic epidural catheter.
Table 2 Site and failure rate (by
motor weakness and dislodgement
of catheter) of epidural. Values are
mean (SD) or number (proportion).
CI, confidence interval.
This quality improvement audit achieved a significant
reduction of postoperative leg weakness and premature
catheter dislodgement in patients by promoting the nearexclusive use of thoracic placement of epidural catheters
and by inserting the catheters deeper into the epidural
space.
The use of epidural analgesia for intra- and postoperative pain control has become an important element of
early rehabilitation programs. The occurrence of lower
limb motor weakness frequently impedes patient mobilization and leads to transient discontinuation of epidural
analgesics, increasing patient discomfort. This impairment
of motor function results from the anaesthesia of the
lumbar and sacral plexuses. It has been shown that after
epidural application, the highest concentrations of local
anaesthetic agents are found in the spinal roots and pia
arachnoid. Significant amounts of local anaesthetic are
demonstrated in the peripheral parts of the spinal cord.
Additionally, diffusion of the drugs along the spinal roots
Thoracic:lumbar site; n
Lumbar epidural; %
Motor weakness; %
Catheter dislodgement; %
Epidural catheter depth; cm
Insufficient analgesia; %
2008 The Authors
Journal compilation 2008 The Association of Anaesthetists of Great Britain and Ireland
Period One
(n = 300)
Period Two
(n = 177)
Odds ratio
[95% CI]
p value
241 : 59
19.7
14.7
14.5
4.6 (1.3)
12.2
173 : 4
2.3
5.1
5.7
5.2 (1.5)
10.3
0.11
0.11
0.35
0.35
0.79
0.82
< 0.0001
< 0.0001
0.0013
< 0.0001
0.004
0.57
[0.04–0.33]
[0.04–0.33]
[0.16–0.74]
[0.17–0.72]
[0.64–0.98]
[0.45–1.51]
29
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I. Königsrainer et al.
Improving epidural analgesia after abdominal surgery
Anaesthesia, 2009, 64, pages 27–31
. ....................................................................................................................................................................................................................
into the cerebrospinal fluid and the spinal cord might
affect the two major descending motor pathways that run
downwards superficially at lumbar levels [9–11]. In
contrast, it is unclear whether drug penetration is deep
enough to affect a significant proportion of ascending and
descending tracts and contribute to leg weakness when
local analgesics are injected at thoracic levels [11]. Our
results are consistent with those of previous studies
reporting a rate of leg motor impairment between 40%
and 50% in patients after lumbar epidural analgesia [12].
In our Period One, lumbar epidural analgesia was
preferred at our institution in patients scheduled for
lower pelvic and colorectal surgery. The rationale for
catheter insertion site was that the intervertebral segments
of the affected splanchnic nerves of the inferior mesenteric plexus (L1–L2) are stimulated by lesser pelvis, left
colon, sigmoid, and rectal surgery as well as the dermatomal segments of the laparotomy incision. Additionally,
it seemed reasonable to assume that the danger of direct
nerve damage would be lower with lumbar needle
insertion than it would for thoracic needle insertion
(although we are not aware of published data to
substantiate this).
To reduce the rate of leg motor weakness in Period
Two we considered two possible treatment changes. First,
we could have confined the catheter insertion site to
thoracic levels (based on the considerations above), or
second we could have used lower doses of local
anaesthetics. However, the latter might have led to
insufficient analgesia [13]. Since we were already using a
reasonably low dose of ropivacaine with an opioid, which
has been recommended as an effective postoperative
analgesic after abdominal surgery [13–15], we chose not
to reduce local anaesthetic concentrations further but
instead change the insertion sites to thoracic level. Our
results suggest that thoracic epidural analgesia was as
successful as lumbar epidural analgesia [9, 16].
While our rate of premature catheter dislodgement
(14.5%) during Period One may seem high, comparable
rates are reported by others [6, 17–19]. We considered
this unacceptably high, as it hampered postoperative
rehabilitation and was unpleasant for the patients if a new
catheter placement became necessary. Our intention in
advancing the catheter insertion deeper was to establish a
broader margin for outward catheter mobility during
patient mobilization. One reason for premature catheter
dislodgement is fluid leakage along the outside of the
catheter into the muscles of the back or to the skin [19].
The fluid can accumulate under the adhesive dressing and
loosen the tape fixation to the skin [20]. Towards its tip,
the catheter is usually gripped tightly by the ligamentum
flavum. Due to the presence of a midline septum or
postsurgical adhesions the reduced capacity of the epidural
30
space is easily filled and then a retrograde flow of epidural
solutions could loosen the grip [21]. Moreover, 30–40%
of catheters which are properly placed initially have been
shown to move outwards within the epidural space over
time [22]. Consequently, increasing frequency of dislodgement over the duration of catheterization has been
shown [23, 24]. However, we examined neither the
duration of catheterization before dislodgement nor the
rate of fluid leakage so the main reasons for premature
dislodgement in our study remain unclear.
In a study of epidural analgesia during labour, catheter
insertion to a depth of 7 cm was associated with the
highest rate of insertion complications, while insertion to
a depth of 5 cm was associated with the highest incidence
of satisfactory analgesia [25]. Therefore, we limited the
catheter insertion depth to 5–6 cm. Subcutaneous tunnelling and suture techniques have been used to prevent
outward movement of epidural catheters [22], but are
somewhat invasive and time-consuming. Others have
recommended using an ‘epidural catheter clamp’ to
reduce rates of premature catheter dislodgements from
16% to 4% [17] but we achieved the same effect by simply
advancing the catheter deeper into the epidural space. We
were, though, surprised that a relatively small change in
insertion depth of < 1 cm had such a beneficial effect on
dislodgement.
Our study does have some limitations. While we could
demonstrate a significant reduction of leg motor weakness
and unintentional catheter dislodgements, no data were
collected on end-points such as reduced morbidity, time
to discharge or reduction of the number of unscheduled
patient visits by the members of the postoperative pain
service team. Moreover, this is not an interventional study
but an audit. Generally, results may have been confounded by seasonal variation, the fact the staff were
aware of the audit (i.e. no blinding), staff changes, and
other aspects that we could not control as we might in a
formal study. The data analysis for time Period One was
limited to 13 months. During this time span, a full data set
was available, and no changes in the peri-operative
management occurred. Time Period Two was much
shorter and ended after 7 months because – independent
of this audit – there was a change of the general
anaesthesia induction protocol. We did not think it
correct to include this subsequent data in this audit. While
we assessed occurrence of pain by it being noted on our
tracking charts, we did not use a formal visual analogue
scale so our assessment of this important variable is a
shortcoming. Thus, while we demonstrate improvements
in quality of motor weakness and catheter dislodgement
rates, we cannot show that this is translated into any
benefit in pain control. Nonetheless we can be confident
that there was unlikely to have been a significant increase
2008 The Authors
Journal compilation 2008 The Association of Anaesthetists of Great Britain and Ireland
Æ
Anaesthesia, 2009, 64, pages 27–31
I. Königsrainer et al.
Improving epidural analgesia after abdominal surgery
. ....................................................................................................................................................................................................................
in this measure as a result of the changes we introduced
(Table 2).
In summary, future audits or studies will extend to cover
other surgical disciplines where postoperative lumbar
epidural analgesia is frequent, e.g. urology or gynaecology.
We feel that our rate of 6% for premature catheter
dislodgement remains unacceptably high and there is
room for improvement. Studies assessing combinations of
methods to further reduce this rate (e.g. fixation methods,
epidural catheter clamp, and catheter advancement) are
desirable.
13
14
15
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12 Heid F, Schmidt-Glintzer A, Piepho T, Jage J. Epidural
ropivacaine – where are the benefits? A prospective,
2008 The Authors
Journal compilation 2008 The Association of Anaesthetists of Great Britain and Ireland
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17
18
19
20
21
22
23
24
25
randomized, double-blind trial in patients with retropubic
prostatectomy. Acta Anaesthesiologica Scandinavica 2007; 51:
294–8.
Scott DA, Chamley DM, Mooney PH, Deam RK, Mark
AH, Hagglof B. Epidural ropivacaine infusion for postoperative analgesia after major lower abdominal surgery –
a dose finding study. Anesthesia and Analgesia 1995; 81:
982–6.
Niiyama Y, Kawamata T, Shimizu H, Omote K, Namiki A.
The addition of epidural morphine to ropivacaine improves
epidural analgesia after lower abdominal surgery. Canadian
Journal of Anesthesia 2005; 52: 181–5.
Scott DA, Blake D, Buckland M, et al. A comparison of
epidural ropivacaine infusion alone and in combination with
1, 2, and 4 microg ⁄ mL fentanyl for seventy-two hours of
postoperative analgesia after major abdominal surgery.
Anesthesia and Analgesia 1999; 88: 857–64.
Lee CJ, Jeon Y, Lim YJ, et al. The influence of neck flexion
and extension on the distribution of contrast medium in the
high thoracic epidural space. Anesthesia and Analgesia 2007;
104: 1583–6.
Clark MX, O’Hare K, Gorringe J, Oh T. The effect of the
Lockit epidural catheter clamp on epidural migration:
a controlled trial. Anaesthesia 2001; 56: 865–70.
Liu SS, Allen HW, Olsson GL. Patient-controlled epidural analgesia with bupivacaine and fentanyl on hospital
wards: prospective experience with 1,030 surgical patients.
Anesthesiology 1998; 88: 688–95.
Motamed C, Farhat F, Remerand F, Stephanazzi J,
Laplanche A, Jayr C. An analysis of postoperative epidural
analgesia failure by computed tomography epidurography.
Anesthesia and Analgesia 2006; 103: 1026–32.
Scott DA, Beilby DS, McClymont C. Postoperative analgesia using epidural infusions of fentanyl with bupivacaine.
A prospective analysis of 1,014 patients. Anesthesiology 1995;
83: 727–37.
Collier CB, Gatt SP. Dislodgement of epidural catheters in
labour. Anaesthesia 2001; 56: 604–5.
Burstal R, Wegener F, Hayes C, Lantry G. Subcutaneous
tunnelling of epidural catheters for postoperative analgesia to
prevent accidental dislodgement: a randomized controlled
trial. Anaesthesia and Intensive Care 1998; 26: 147–51.
Scott AM, Starling JR, Ruscher AE, DeLessio ST, Harms
BA. Thoracic versus lumbar epidural anesthesia’s effect on
pain control and ileus resolution after restorative proctocolectomy. Surgery 1996; 120: 688–95.
Tsui BC, Gupta S, Finucane B. Confirmation of epidural
catheter placement using nerve stimulation. Canadian Journal
of Anesthesia 1998; 45: 640–4.
Beilin Y, Bernstein HH, Zucker-Pinchoff B. The optimal
distance that a multiorifice epidural catheter should be
threaded into the epidural space. Anesthesia and Analgesia
1995; 81: 301–4.
31
“I would have everie man write what he knowes and no more.”– Montaigne
BRITISH JOURNAL OF ANAESTHESIA
Volume 102, Number 6, June 2009
British Journal of Anaesthesia 102 (6): 729– 30 (2009)
doi:10.1093/bja/aep085
Editorial I
Spinal anaesthesia: a century of refinement, and failure is still an option
On August 24, 1898, August Bier1 and his assistant
Hildebrandt undertook ‘experiments on [their] own
bodies’ which were part of their historic initial investigations of spinal anaesthesia. Bier’s description of these
experiments is notable for the manner in which he documented the lack of sensibility after injection of cocaine
into Hildebrandt’s subarachnoid space, which included a
burning cigar, a strong blow to the shin with an iron
hammer, and strong pressure and traction on the testicles,
none of which provoked pain. Absent from this report are
descriptions of similar assessments being performed by
Hildebrandt on Bier. This was not out of deference to
Bier, but rather the Pravaz syringe failed to fit on the
needle, and a significant amount of the cocaine intended
for Bier’s subarachnoid space was lost, resulting in a
failed block.
Although the aetiology of this historic failure is no
mystery, a particularly perplexing and frustrating problem
with spinal anaesthesia is the occasional failure to achieve
adequate sensory block, despite an apparently orthodox
injection of an adequate dose of local anaesthetic.
Believing certain subjects to be ‘hyper-resistant’ to spinal
anaesthesia, Sebrechts2 coined the term ‘rachi-resistance’
in 1934 to describe this phenomenon. He postulated that
this aberration reflected a ‘peculiar idiosyncrasy which
renders the nerve roots of certain individuals insensitive or
resistant to the action of anaesthetic solutions’. This
concept garnished a modicum of support, some proponents
proposing that this effect might be due to reduced permeability of the roots.3 However, most were critical,
suggesting such failures more likely reflect inactive solution, or a variety of anatomic variations or abnormalities
such as arachnoid adhesions, unusual arrangements of the
dentate ligament, or a dilated lower end of the thecal
sac.4 – 6 Ultimately, the term ‘rachi-resistance’ disappeared
from the anaesthesia literature.
A review article and two clinical studies in this issue of
the British Journal of Anaesthesia attempt to shed light on
this elusive subject. In their systematic review, Fettes and
colleagues7 dissect the spinal technique into its sequential
components, providing a framework to understand the
mechanisms that may account for failure. Such information is a prerequisite for maximizing success rate, and
for rational clinical management of a failed block. In the
first of two related research papers, Ruppen and colleagues8 explore the cerebrospinal fluid (CSF) concentrations of anaesthetic associated with the development of
adequate spinal anaesthesia after administration of plain
bupivacaine 0.5%. Their principal finding was the enormous range of concentrations (26– 781 mg ml21), which
did not correlate with the level of block. Further, the variability in samples obtained at randomized time-points
between 5 and 45 min post-injection was so large as to
prohibit any meaningful pharmacokinetic assessment. An
even larger variability (3.36 – 1020 mg ml21) was seen in
the second study9 where samples were obtained from
patients who had received the same anaesthetic but had
inadequate anaesthesia. The range of concentrations from
these two studies overlapped, with only four of the 20
failed spinals having a CSF concentration below any
associated with successful spinal anaesthesia.
Although these findings may appear incomprehensible,
they can be understood by appreciating the limitations of
single-site assessments of CSF anaesthetic concentrations,
a point well appreciated and considered by the authors of
these two research papers. Because local anaesthetic will
often distribute unevenly within the subarachnoid space,
the concentration at a single point cannot be used to determine the true volume of distribution, nor can concentrations found below the conus reliably predict those at
more rostral locations servicing clinically relevant dermatomes. Consequently, faced with a relatively low concentration, clinical correlation or imaging is needed to permit
any distinction between a poor injection, a large volume
of CSF below the conus, extensive spread, or an anomalous sample. With the exception of technical failure,
similar considerations apply to interpretation of high
concentrations.
# The Author [2009]. Published by Oxford University Press on behalf of The Board of Directors of the British Journal of Anaesthesia. All rights reserved.
For Permissions, please email: [email protected]
Editorial I
Despite these limitations, there are some interesting
insights that can be gleaned from the data. For example,
the highest concentration in any sample came from a
patient with inadequate anaesthesia, supporting the
concept of maldistribution as an aetiology of failure, a
point highlighted by the authors. A similar observation
was made in a very early study of hyperbaric lidocaine
administered through continuous spinal catheters.10 Of
16 patients receiving an initial injection of lidocaine
150 –200 mg, there was only one failure requiring general
anaesthesia. The anaesthetic concentration in the CSF
sample from this patient was roughly 2 SD above the mean,
and an X-ray demonstrated the catheter to be curled with
the end resting in the cul-de-sac at the level of the second
sacral vertebra. Such findings are also consistent with data
obtained from in vitro investigations modelling subarachnoid anaesthetic distribution.11
That failure from maldistribution cannot be readily distinguished clinically from technical failure has important implications for management of a failed spinal. In such cases,
repetitive injection can distribute in the same pattern, reinforcing the already high concentrations, and potentially resulting in neurotoxic injury. Review of the closed claims
database12 and case reports13 – 15 appear to confirm these concerns. On the basis of these considerations, we previously
made suggestions for management of a failed spinal,12 which
included evaluation of the likelihood of technical error and
adjustment of dosage for the second injection. However,
these recommendations impart significant delay, as one must
allow sufficient time for achievement of near-maximal block
before assessment of sensory anaesthesia. A more efficient—
and probably much safer—alternative is to simply limit the
combined anaesthetic dosage to the maximum reasonable to
administer as a single intrathecal injection.
In four of the failed spinals, there was no detectable
sensory anaesthesia, despite CSF concentrations that
exceeded the lowest value associated with a completely
successful block. And, in one case, the concentration was
above the 5th percentile for successful spinal anaesthesia,
the cut-off (albeit somewhat arbitrary) that the authors
thought should be adequate for successful spinal anaesthesia. Although it is possible that this reflects the limitations
of sampling and errant concentrations obtained in the
study of successful spinals, it is intriguing to consider
the possibility that these patients were actually resistant to
the anaesthetic. Such consideration is more than a theoretical possibility, as there are well-described mutations of the
voltage-gated sodium channel that can profoundly affect
function, including altered sensitivity to anaesthetic.16 17
Further advances in pharmacogenetics might thus identify
genetic diversity as a factor in spinal anaesthetic failure,
justifying a reintroduction of the term ‘rachi-resistance’
into the language of anaesthesia. Who knows, Sebrechts
belief that there are familial tendencies in susceptibility,
and that the ‘the Anglo-Saxon . . . has resistance to larger
doses than the Italian’ might just turn out to be correct.
K. Drasner
University of California
San Francisco
CA 94110
USA
E-mail: [email protected]
References
1 Bier A. Versuche fiber Cocainisirung des Rfickenmarkes. Deutsche
Zeitschriftir Chirurgie 1899; 51: 361 – 9
2 Sebrechts J. Spinal anaesthesia. Br J Anaesth 1934; 12: 4 – 27
3 Black WR, Walters GAB. ‘Rachi-resistance’ and spinal anaesthesia.
Br Med J 1937; 1: 218– 9
4 Lake NC. ‘Rachi-resistance’ and spinal anaesthesia. Br Med J 1937;
1: 297
5 Hewer CL. ‘Rachi-resistance’ and spinal anaesthesia. Br Med J
1937; 1: 360
6 Burke J. ‘Rachi-resistance’ and spinal anaesthesia. Br Med J 1937; 1:
584 – 5
7 Fettes PDW, Jansson JR, Wildsmith JAW. Failed spinal anaesthesia:
mechanisms, management and prevention. Br J Anaesth 2009; 102:
739 – 48
8 Ruppen W, Steiner LA, Drewe J, Hauenstein L, Brugger S,
Seeberger MD. Bupivacaine concentrations in the lumbar cerebrospinal fluid of patients during spinal anaesthesia. Br J Anaesth
2009; 102: 832 – 8
9 Steiner LA, Hauenstein L, Ruppen W, Hampl KF, Seeberger MD.
Bupivacaine concentrations in lumbar cerebrospinal fluid in
patients with failed spinal anaesthesia. Br J Anaesth 2009; 102:
839 – 44
10 Mörch ET, Rosenberg MK, Truant AT. Lidocaine for spinal anaesthesia. A study of the concentration in the spinal fluid. Acta
Anaesthesiol Scand 1957; 1: 105 – 15
11 Rigler ML, Drasner K. Distribution of catheter-injected local
anesthetic in a model of the subarachnoid space. Anesthesiology
1991; 75: 684 – 92
12 Drasner K, Rigler M. Repeat injection after a ‘failed spinal’—at
times, a potentially unsafe practice. Anesthesiology 1991; 75:
713– 4
13 Waters JH, Watson TB, Ward MG. Conus medullaris injury following both tetracaine and lidocaine spinal anesthesia. J Clin
Anesth 1996; 8: 656 – 8
14 Hirabayashi Y, Konishi R, Shimizu R. Neurologic symptom associated with a repeated injection after failed spinal anesthesia.
Anesthesiology 1998; 89: 1294 – 5
15 Loo CC, Irestedt L. Cauda equina syndrome after spinal anaesthesia with hyperbaric 5% lignocaine: a review of six cases of
cauda equina syndrome reported to the Swedish Pharmaceutical
Insurance 1993– 1997. Acta Anaesthesiol Scand 1999; 43:
371– 9
16 Catterall WA, Dib-Hajj S, Meisler MH, Pietrobon D. Inherited
neuronal ion channelopathies: new windows on complex neurological diseases. J Neurosci 2008; 28: 11768 – 77
17 Sheets PL, Jackson JO, Waxman SG, Dib-Hajj SD, Cummins TR. A
Nav1.7 channel mutation associated with hereditary
erythromelalgia contributes to neuronal hyperexcitability and
displays reduced lidocaine sensitivity. J Physiol 2007; 581:
1019– 31
730
Current Anaesthesia & Critical Care 20 (2009) 71–73
Contents lists available at ScienceDirect
Current Anaesthesia & Critical Care
journal homepage: www.elsevier.com/locate/cacc
FOCUS ON: REGIONAL ANAESTHESIA
Role of ultrasound in modern day regional anaesthesia
Narendra Babu Siddaiah, Anand Sardesai*
Addenbrooke’s Hospital, Cambridge University Hospitals NHS Trust, Cambridge CB2 0QQ, United Kingdom
s u m m a r y
Keywords:
Ultrasound
Regional anaesthesia
Nerve block
The aim of any regional anaesthesia technique is to locate target nerves and deposit local anaesthetic
around them. Nerve stimulation using anatomical landmarks has been conventional method of nerve
localisation. With the advance in technology, the use of ultrasound in regional anaesthesia has been
steadily increasing. In addition to localisation of nerves and other structures under direct visualisation,
ultrasound has the potential to reduce complications and minimise the local anaesthetic toxicity by
injecting right dose at the right site. The principles, advantages, disadvantages and applications of
ultrasound have been reviewed in this article.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
emits and receives high-frequency sound waves (greater than
20,000 cycles/s, 20 kHz) and thus ultrasound waves are not audible
to the human ear. Ultrasound frequencies useful in clinical medicine are in the megahertz (MHz) range.5
The ultrasound probe is a transducer that contains crystals
which exhibit piezoelectric effect. Piezoelectricity is the ability of
a substance to convert mechanical energy into electricity and vice
versa. When an electrical current is applied to piezoelectric
crystals (quartz) within the ultrasound probe, they vibrate
resulting in ultrasound waves. As the ultrasound waves pass
through body tissues of different acoustic impedance, the signals
are attenuated. The degree of attenuation of signals depends on
the attenuation coefficient of the tissue. Also, it varies directly
with the frequency of the ultrasound wave and the distance from
the source. Reflected waves are transformed into electrical signals
by the transducer which are processed to generate an image on
the screen.6
Echogenicity or how bright the object appears depends on the
amount of ultrasound reflected back to the probe; the greater the
reflection, the brighter is the image and vice versa. Structures with
high water content like blood let the ultrasound waves pass
through with minimal reflection and so appear black or dark
(hypoechoic). On the other hand, waves are reflected and scattered
by the bone and tendons, hence these appear white or bright
(hyperechoic). With bone, the periosteum appears as a white
hyperechoic line. Structures of intermediate density such as the
liver parenchyma or the thyroid gland reflect less. Hence they
appear grey on the screen.
The depth of the structure from the probe is calculated by the
software accounting for the speed of sound in tissue (1540 m/s on
average) and the time taken for the ultrasound to return.
Nerve blocks have been traditionally done using anatomical
landmarks to guess approximate position of the nerve and then
using either paraesthesia or nerve stimulation to confirm the
proximity of needle to the nerve. This assumes that every person’s
anatomy is same, yet we know that this assumption is wrong. There
are interpersonal variations and also variations in the same person
on different sides of the body.1 It is also assumed with these ‘blind
techniques’ that when local anaesthetic is injected it spreads
uniformly around the nerves which if does not happen results in
block failure. ‘Threshold current’ i.e. the current which indicates
that the position of the stimulating needle is close to the nerve, but
not close enough to cause nerve damage, is relatively poorly
identified.2 It is possible to be actually eliciting paraesthesia or be
intraneural with the needle without producing any motor
response.3,4 Thus the science of nerve stimulation is neither precise
nor perfect.
La Grange and his colleagues first reported the use of ultrasound
for providing nerve block in 1978. They successfully performed
supraclavicular brachial plexus blocks with the help of a Doppler
ultrasound blood-flow detector to identify the subclavial artery.5
2. Principles
Sound that we hear is between the frequency range of 20 and
20,000 Hz (20–20,000 cycles/s). An ultrasound probe (transducer)
* Corresponding author.
E-mail addresses: [email protected] (N.B. Siddaiah), sardesai1@aol.
com (A. Sardesai).
0953-7112/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.cacc.2008.12.004
72
N.B. Siddaiah, A. Sardesai / Current Anaesthesia & Critical Care 20 (2009) 71–73
3. Equipment
For anaesthesia purposes we need an ultrasound machine
which is ideally small in size, portable as it is likely to be shared
between different theatres and different anaesthetists and durable
as it has to move between theatres and by different anaesthetists so
damage during transit is likely.
Colour Doppler is used to differentiate vascular from nonvascular structures. Low frequency probes (3–5 MHz) are useful to
scan deeper structures like liver, gallbladder and kidneys while
a frequency of 4–7 MHz is better for deep structures, such as the
brachial plexus in the infraclavicular region and the sciatic nerve in
adults.
Superficial structures such as the supraclavicular brachial plexus
require high-frequency probes (10–16 MHz) that provide high axial
resolution.
The hard disk should be high capacity with a CD burner in
order to store and edit a large number of images and films 7
although images and video can be stored on external hard disks
as well.
As the competition between manufacturers is increasing and as
the technology improves the machines are getting cheaper while
the image quality is improving. Ultrasound machines used by the
radiologists have multiple probes and softwares. They are useful for
both diagnostic and therapeutic purposes. These are highly
sophisticated, bulky and expensive varying from £100,000 to
£150,000. Whereas a simple portable ultrasound machine for
regional anaesthesia, peripheral arterial and central venous cannulation costs about £15,000.
4. Appearance of peripheral nerve under ultrasound
A single nerve fibre is surrounded by endoneurium. Group of
nerve fibres forms a nerve fascicle. Each nerve fascicle is surrounded by perineurium. Nerve fascicles together form a nerve
which is surrounded by epineurium. Nerve fibres themselves do
not reflect any ultrasound so they appear dark. Only the
connective tissue surrounding the nerve fibres, fascicles and the
nerve itself reflects ultrasound and then appears bright or white.
On transverse (short-axis, nerve in cross-section) view that is
generally used, a nerve is round or oval shaped with internal
hypoechoic (dark) nerve fibres and nerve fascicles surrounded by
the hyperechoic (bright) connective tissue.8 It has been compared
to bunch of drinking straws viewed end on.
In the long-axis view, the probe is parallel to the long axis of the
nerve. In this view nerves appear tubular with parallel bright and
dark bands corresponding to the fascicles and interfascicular
connective tissue respectively.
Roots of the brachial plexus appear hypoechoic in the interscalene and supraclavicular regions more like blood vessels
without any flow. One possible explanation that has been suggested is that the nerves at this level have not grouped into fascicles
yet.8 When the brachial plexus is scanned distally typical appearance of the peripheral nerve is seen.
Nerves vary in shape (round, oval or triangular) and a same
nerve can have different shapes as it passes along different
structures.9
Nerves are fairly mobile structures as demonstrated by
movement of the branches of the sciatic nerve in the popliteal
fossa with foot movement.10 In order to identify the nerve
anatomy in terms of its size, depth and location before the
insertion of needle, a preliminary scan should be performed. This
helps in the assessment of point, angle and direction of needle
insertion.11
5. Advantages of ultrasound guided nerve identification
Nerves can be easily identified. The structures surrounding the
nerve like blood vessels (e.g. saphenous vein)12 can be easily
identified which in turn can help the identification of the
nerves.
Needles can be visualised as a hyperechoic line. In real-time
navigation of ultrasound, the needle can be guided towards
the nerve. This can prevent the risk of inadvertent needle
entry into the blood vessels, pleura13 or structures like spinal
canal.14
Local anaesthetic spread can be seen with the ultrasound so if
inadequate a further injection could be made.15 Incomplete
nerve blocks can be prevented by ensuring circumferential
spread of the local anaesthetic.
Ultrasound can identify the point of division of the nerve.16
This is of help when complete nerve block before the division
of nerve is needed as local anaesthetic can be injected
proximal to the point of division of nerve identified by
ultrasound.
Placement of peripheral nerve catheters under direct
vision.17,18
Ultrasound guided nerve blocks can be a relatively painless
procedure when muscle contraction is avoided without nerve
stimulation.19,20
In blocks such as the 3-in-1 block, it has been demonstrated
that the success rate is higher using ultrasound and that the
dose of local anaesthetic required is lower.21
Faster sensory onset time and longer duration of blocks.15,19
Improved quality of block.22
Less incidence of diaphragmatic paralysis as less volume can be
used for interscalene block.23
No risk of radiation.
Patient groups where ultrasound guided blocks are particularly
useful in:
Children, in whom nerve blocks are performed under
anaesthesia.
Patients with peripheral neuropathy where it is difficult to
elicit nerve stimulus although nerve damage can occur even
without direct nerve needle contact.24
Use of Doppler has been described in obese patients or where
the vascular landmarks can’t be easily identified.25–27
Ultrasound-assisted nerve block has been described for:
Upper limb blocks: brachial plexus block by interscalene,23,28
supraclavicular,13,22
infraclavicular19,29
and
axillary30
approaches.
Lower limb blocks: femoral nerve,15,21 lumbar plexus,31 sciatic
nerve.32
Other nerve blocks: coeliac plexus,33 stellate ganglion,34
pudendal nerve35
Assessment of the depth of the epidural space36 and to assess
the lumbar epidural space during pregnancy.37
Disadvantages of ultrasound guided nerve blocks:
It has the potential to avoid or reduce nerve damage. Whether
it can eliminate damage completely remains to be seen. Patient
related factors and operator errors can still result in nerve
damage.
The ultrasound machines are still expensive although the cost
is coming down.
N.B. Siddaiah, A. Sardesai / Current Anaesthesia & Critical Care 20 (2009) 71–73
6. Summary
Ultrasound has revolutionised the practise of regional anaesthesia. It has helped in a better understanding of the anatomic
variability between patients. It has potential to provide a safe and
reliable nerve block. It remains to be seen how it delivers this
promise.
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