Download SAFETY OF EPIDURAL ANAESTHESIA Eleni Moka

SAFETY OF EPIDURAL ANAESTHESIA
Eleni Moka, Eriphili Argyra, Ioanna Siafaka
Introduction
Every patient wishes to receive anaesthesia care that is safe, in other words, free from risk, not
involving danger or mishap and guaranteed against failure. Anaesthesiologists usually present a
more realistic view to the patient. The personal view of the hoped – for care will be one in which
the clinical outcome is satisfactory and achieved without complications, since performance has not
deviated from the ideal. By this standard, most deviations are trivial or easily corrected by a perfect
process, whereas patient outcome and a reasonably stress-free life for the clinician are objectives
for all anaesthesiologists [1]. Safety of an anaesthetic technique is characterized by avoidance of
complications, minimal percentages of associated risks and numerous primary and secondary
beneficial endpoints, balanced against the inevitable consequences of method – related dangers.
Consequently, prior to any conclusion regarding safety, reliable evidence must be established for
both sides of the anaesthetic technique benefit-and-risk equation [2, 3].
Epidural anaesthesia – analgesia (EAA) has a long and distinguished history. For many clinicians, it
remains an attractive option and a leading anaesthetic – analgesic modality applied in the
perioperative environment [4, 5]. In regard to the benefit side, there is widespread conviction
among anaesthesiologists that EAA offers significant advantages in certain settings, especially those
involving abdominal and thoracic operative procedures [4, 6]. EAA is highly effective for controlling
acute pain after surgery or trauma to the chest, abdomen, pelvis or lower limbs, with its salutary
effects providing an added therapeutic benefit postoperatively. It has been instituted in various
subpopulations, including cardiothoracic, vascular, paediatric and obstetric patients, with optimistic
and promising results. Usually, the combination of excellent pain relief, associated with minimal
side – effects, results in high patient satisfaction, when compared with other methods of analgesia
[4, 6 – 8].
However, the controversy around EAA still continues, particularly with regard to its true impact on
postoperative morbidity and mortality, as well as its safety, mostly due to the fear of rare, but
potentially life – threatening or catastrophic complications [3, 6, 9]. Controversies represent the
debate and dialogue that ensue when clinicians examine the issue of best practice. Taking into
account the other (“darker”) side of the benefit – and – risk equation, unfortunately, the fear of
complications is still held with almost equal intensity, compared to the enthusiasm which initially
escorts EAA beneficial effects. Since there is always risk attached to all anaesthesia methods,
contemporary EAA practice in certain situations has been controversial. In addition, the main factor
which in the past turned our specialty away from EAA has been the difficulty in making a
reasonable risk/benefit analysis about the technique, resulting in clinicians constantly asking
whether epidurals are effective and whether the technique can finally be safe [2 – 4, 6, 9 – 12].
Nowadays, EAA is widely used again and since it is an invasive method, its benefit/risk ratio
deserves to be appraised, in order to help physicians estimate technique safety, make appropriate
choice among other opportunities (general anaesthesia, peripheral nerve blocks, wound infiltration)
and provide objective information to patients, prior to their written informed consent acquisition [5,
6, 13]. In this context, the “ultimate tool” of evidence – based medicine, the Level 1 evidence of
meta-analysis, has shown over the previous years that EAA decreases postoperative morbidity and
mortality [6, 15], as well as pulmonary complications [16], improves bowel recovery [17] and
reduces incidence of myocardial infarctions [18]. However, evidence to support improved outcome
from surgery remains elusive [19, 20], with the exception of aortic surgery, where mortality and
major complications were significantly reduced [21].
Therefore, it is not surprising that research and more or less scientific and emotive debates in this
area continue, even more so in view of reports of safety, complications and the current medicolegal
environment in many countries [5, 6]. EAA complications have been described by many authors,
although our understanding of the numerous risk factors is limited [2, 10 – 14]. Despite their
relatively infrequent occurrence, the fear of EAA complications exceeds their actual incidence [2, 3,
9, 13, 22]. Incidence knowledge could be an essential component of the clinical decision-making,
objective safety judging and consent processes, although there are few good and detailed data,
which can be quoted to support such discussions, leaving both patient and clinicians in quandary.
Figures (ranging from 1:1.000 to 1:100.000 in general) are quoted, but their doubtful validity
questions the ability to obtain genuinely informed consent from patients offered these procedures
[13]. Although it is impossible to prevent all EAA complications, it may be possible to reduce their
occurrence, by avoiding well-defined risk factors and by using a meticulous epidural technique at all
times. Further studies on clarification of risks, complications’ early recognition and on EAA
technique improvement may reduce adverse effects occurrence and improve EAA safety [13, 14,
22].
In the following paragraphs, the general objective is to focus on the clinical aspects of EAA risks in
terms of their incidence, recognition, prevention and management, in an effort to provide
information that will help clinicians to avoid or minimize complications, incurred during technique
application. In this context, EAA provision can be safe, as well as effective, if described risks and
benefits are carefully considered and the Hippocratic axiom “primum non nocere” is kept in mind.
Complications and Safety of EAA: Aetiology – Evaluation of Evidence
EAA complications represent the unexpected or untoward events following the application of the
technique itself or the exposure to anaesthetic agents. They can be classified as simple adverse
events and common or uncommon/rare complications. Some of them are considered minor side
effects, easy to prevent and to manage, that usually do not raise safety concerns. However, others,
resulting from EAA as unexpected outcomes, are of major concern, due to their potential to cause
neurological damage, leading to long-term or permanent disability. Both major and minor EAA
complications are well – known to clinicians and are also well-annotated. They can occur
immediately, or can be delayed. They can be clinically insignificant, or, in rare situations, life –
threatening. Knowledge and attention to the technique can reduce the likelihood for major
complications. The impact of EAA complications in anaesthesia practice is significant because
anaesthesia care is rarely therapeutic and known to carry risks. Furthermore, there is compelling
evidence that adverse outcomes trigger malpractice claims. As a group, anaesthesiologists seem to
accept the blame of complications that may or may not have been caused by EAA itself.
Furthermore, even when the standard of care has been met, juries tend to assign blame more
readily in EAA complicated cases [2, 9 – 14, 22].
EAA complications [2, 6, 9 – 12, 22] may happen in the whole perioperative period, including the
postoperative one and can be the direct or indirect result of the following:
-
the technique itself: usually related to direct or indirect trauma by needle/catheter insertion
and/or catheter presence in the epidural space
the untoward effects of local anaesthetics/adjuvant drugs instilled
local and systemic toxicity results of drugs infused
fatal drug errors
untoward effects resulting from the anticipated or unanticipated physiologic consequences
of local anaesthetic blockade
poor/late/no management of physiologic responses and/or adverse effects (arterial
hypotension – fatal cardiovascular collapse)
intraoperative technical problems/equipment failure
ignorance regarding complications’ anticipation/recognition of precipitating factors
delayed complications’ diagnosis
non – application/delayed application of complications’ preventive measures
lack of experience/education/audit/monitoring
human/behavioural/operator/patient factors
EAA complications have been recognized over 100 years ago and the database concerning such
risks is large but confusing. Studies are scarce, and their results difficult to compare. Due to their
rarity, definite studies on EAA risks remain problematic and the quoted ranges of complications for
severe adverse events still vary widely, because the study methodologies vary, much of the data are
retrospective, and the distinction between permanent and temporary disability is not always clear.
Many complications are known through case reports, and these rare events might not be evenly
distributed within the patient population. Retrospective observational studies/surveys and case
reports are important sources for evaluation, providing valuable information on incidence and
possible associations with confounding factors. Observational data are often clinically relevant, can
have a profound influence on clinical practice when a consensus of opinions is formulated, but,
unlike randomized controlled trials, lack a control group, making it difficult to calculate an accurate
incidence of risk. Because the enormous number of patients needed to perform prospective studies
exceeds feasibility, it is important that retrospective studies try to minimize the inherent weakness
of such study designs. Underreporting is common in retrospective studies, causing underestimation
of risk [2, 3, 6, 9, 10, 14, 22].
Complications and Safety of EAA: Incidence
Fortunately, literature data are reassuring, suggesting that EAA blocks carry a low incidence of
major complications, many of which may resolve in up to six months [13]. Anaesthesiologists’
vigilance has enabled early recognition of these diverse and, in some cases, extremely rare
complications, so that corrective action can be taken to prevent permanent harm. Nonetheless,
permanent disabling injuries following EAA are not so rare that we can ignore the issue. We are
obliged to raise the specter of permanent injury to patients in our discussions, despite its
uncommon incidence [2, 3, 6, 9, 14].
In the perioperative setting, overall permanent disability following EAA has been reported, in large
populations, with some of the best information available coming from Europe, US and Australia [5,
6, 13, 23 – 28]. Prior to examination of studies results, one should not forget the Poisson’s Law
regarding distribution of rare events. Actually, it is a statistical model for situations where the
probability of an event to occur is very law, but the opportunity for such an occurrence is very high.
According to this law, when an event has occurred in a sample size of “n” patients, the sample size
associated with a 95% probability to have a new occurrence is “3n”. If no adverse event occurred in
a population of “n” patients, it can only be conducted that the real incidence does not exceed “3 / n”
[5].
Moen V et al published a huge retrospective study involving 450.00 epidurals (including 200.000 in
obstetric cases) administered in Sweden in a ten – year period. Major EAA complications reported
were 1.37/10.000 patients (1/7.258 in general, 1/25.000 in obstetric population and 1/3.600 in all
other patient groups). The incidence of epidural haematoma was 1/22.000 (approximately
0.45/10.000), being lower in the obstetric patients (1/200.000) and much higher in patients subject
to knee arthroplasty (1/3.600) [23]. Auroy et al provided some information on this topic, through
two studies from France. Even though their data are prospective and large numbers are involved,
information is conflicting and studies were not randomized. After 30.413 epidurals performed, 19
serious events were noticed, including 6, 5 and 1 cases of neurological injury, radiculopathy and
paraplegia respectively, with the incidence of permanent neurological injury being calculated as
0.32/10.000 patients [24, 25]. According to Aromaa et al, based on the claims related to regional
anaeshesia, 9 serious complications were associated with the 170.000 EAA administered in Finland,
from 1987 – 1993 (0.52/10.000 patients) [26]. In the UK, Christie and McCabe retrospectively
recorded 12 major complications after 8.100 perioperative epidurals (1 in 675) in one hospital. This
approximates to 148/100.000 epidurals. As nine patients made a full recovery, permanent injury
was 3 in 8.100 (37/100 000, 95% CI 7.6 – 10.8) [29]. Cameron and colleagues reported similar
results, from a retrospective, single – hospital series, from Australia, with two vertebral canal
haematomas and six epidural abscesses following 8.210 “acute pain” epidurals. One laminectomy
was required and there were no cases of permanent neurological injury. Percentages of vertebral
canal haematoma (24/100.000, 95% CI 3 – 8.8), abscess (73/100.000, 95% CI 2.7 – 15.9),
laminectomy (12/100.000, 95% CI 1 – 6.8), and permanent neurological harm (0/100.000, 95% CI 0
– 4.5) are again broadly consistent with those from previous studies [30]. In a recent prospective
survey, conducted in UK, with denominator (procedures performed) and nominator (complications)
data validation through national databases, severe complications following 293.050 EAA have been
calculated in events/100.00 epidurals, with [95% CI] . Permanent injury after EAA is reported to be
4.2 [2.9 – 6.1]/100.000, with incidence of 17.4 [7.2 – 27.8]/100.000 and 0.6 [0 – 3.4]/100.000 in the
perioperative and obstetrical setting respectively [13].
Subgroup analysis from various studies has shown that elderly, female and orthopaedic patients
carry a considerably higher risk of untoward side-effects and are more exposed to complications,
compared to the obstetric or general population [13, 23, 27, 31]. Perioperative hypotension,
potential coagulation disorders, blood in the needle, pain on injection and difficult block may be
considered as alarm events [6]. Cardiovascular collapses [27] and wrong route drug injection errors
[32] have still to be considered. Severe neurologic events are more often reported in the
perioperative period and are mainly related to spinal haematoma (0.17 – 2.4/10.000), epidural
abscess (0.23 – 7.3/10.000) and permanent or transient traumatic neurological injury (0.17 –
2/10.000) [13, 23 – 30, 33 – 35]. Based on the lessons learned from the ASA Closed Claims Analysis,
haematoma, chemical injury and abscess represent 2%, 7% and 3% of spinal cord claims injury
respectively, with paraesthesia during needle insertion and/or drug injection and multiple attempts
to perform the block being the most important associated factors. These data also suggest that
nerve injury now surpasses brain damage as the second leading injury associated with anaesthesia
claims [2, 36]. In the following paragraphs, in regard with EAA safety only major complications
leading to potential disability will be analyzed.
Adverse Events due to Insertion of Needle/Catheter in the Epidural Space
Dural Puncture
Dural puncture occurs in 0.32 – 1.23% of epidural placements, potentially resulting in a post – dural
– puncture – headache (PDPH). Rarely, subdural haematoma, leading to neurological deterioration
has been described after dural puncture; its incidence may be less with loss of resistance to saline
than to air [2, 11, 12, 33, 37]. There is also a risk of pneumocephalus if air is used, which can result
in serious complications. The use of saline may again help to reduce the incidence of this and other
complications that have been associated with the use of air, notably spinal cord and nerve root
compression, postepidural paraesthesia and venous air embolism. In addition, accidental pleural
puncture during epidural catheter insertion has been described, as has haemothorax. There is
currently a large body of evidences suggesting that liquid must be used instead of air for loss of
resistance technique [11, 12, 38].
Direct Trauma
Direct trauma to the spinal cord, conus medullaris, spinal nerve roots or peripheral nerves ascribed
to the needle or catheter is extremely rare, but has been reported, followed by sensory loss and
less frequently motor deficits. As needle or catheter is advanced in the epidural space, intrinsic
spinal cord lesions may happen, possibly due to direct trauma during the procedure and
subsequent injection of fluid into the spinal cord, producing localized hydromyelia [2, 12, 39]. Auroy
et al found five cases of radiculopathy following 30.413 epidurals. In each of these patients, pain or
paraesthesia was noted on needle insertion or drug administration, with the radiculopathy being in
the same distribution as the associated paraesthesias, suggesting a traumatic mechanism [24, 25].
Pathology of the spine may be a risk factor and the impact of spinal stenosis (often asymptomatic)
has been recently pointed out, warranting further attention [5, 39, 40, 41]. Recent reports
demonstrate that either multimodal causes [42], or a preexisting pathology of the spine [43] may
be responsible for such complications, arising in temporal but not necessarily causal relationship to
EAA [6].
To avoid nerve trauma, careful technique and accurate anatomic knowledge are advised. Literature
reports highlight the problem and are fuelling the ongoing discussion and debate as to whether
patients should remain awake during EAA, to respond to painful stimuli, thus serving as possible
indicators of accidental cord trauma or unrecognized nerve injury. Epidural catheterization is most
frequently performed in the awake patient to avoid this risk of neurological damage and needle
advancement should be stopped if the patient complains of pain. In most adults, spinal cord
terminates at L1 vertebral body; however, in some it may terminate above or below this landmark.
The ability of the clinician to correctly identify lumbar spinous interspaces has been questioned,
using MRI. Only 29% of the interspaces were correctly identified, with 51% of clinicians being at a
higher vertebral level than anticipated and with the spinal cord terminating below L1 in 19% of
subjects. Oblique lateral entry into the ligamentum flavum may direct the needle into the dural cuff
region, resulting in potential nerve trauma and unisegmental paresthesia. This should alert the
clinician against persisting with further needle insertion or catheter threading [2, 4-6, 10 – 12, 22,
44, 45].
Traumatic injury when performing EAA also raises the question about technical skills. A learning
curve exists and manual skills improve with increasing experience. It is considered that residents
show significant improvement over baseline after 25 EAA, whereas at least 60 procedures have to
be performed before obtaining a 90% success rate [46]. Some new methods of training, such as
video technology and/or simulator, can be added to the available educational tools and would be
valuable for improving safety [47, 48]. Ultrasound-guided technique may help to teach and also to
perform EAA, especially when difficulties are awaited in specific population categories (obese
patients, parturients, scoliosis, hyperlordodis etc) [49, 50].
Additionally, many attempts have been made to improve techniques for epidural space localization.
The “membrane – in – syringe” technique, a modification of the loss of resistance technique,
combining loss of resistance to air and saline, allows reliable identification of epidural space,
keeping injection of saline into the space to a minimum [6, 51]. Another experimental innovation is
a device combining a visible and acoustic signal for epidural space identification [52]. Although
these techniques are in an early experimental stage, the simple, objective and reliable technique
for confirmation and accurate placement of an epidural catheter by low current electrical
stimulation has become widely discussed [53-55]. A meta-analysis of available studies, investigating
the ultrasound application as a diagnostic tool for epidural space visualization and its effects on EAA
quality and performance, demonstrated a clear advantage over the use of this imaging technique.
Regarding cost and practicability of these techniques, it has to be shown whether they will find
application in everyday practice [4, 6, 56].
However, one of the important and unanswered questions regarding the ultrasound use to guide
EAA is whether this technique will actually result in a lower incidence or severity of neurologic
complications, versus classical methods of epidural space identification. As with any newer
technique, there will be a learning curve when introducing ultrasound into clinician’s practice and
as such anaesthesiologists will need to be familiar with the anatomical landmarks and cognizant of
the potential artifacts and pitfall errors associated with ultrasound-guided regional anesthesia [4].
Transient Neuropathy
Transient neuropathy after EAA with eventual full recovery occurs more commonly, but is still
relatively infrequent; a recent large, prospective, multicentre series involving 30.413 epidurals
reported five cases of radiculopathy (0.016%), over 50% recovering completely within 3 months.
Results are similar to ones previously published in large studies on transient neuropathy: 4 out of
17.439 patients (0.023%) and 0.013% from a retrospective study of 1.304.214 epidurals. Smaller
studies report an incidence of 0.24 – 0.56%. After certain operations, such as tibial fracture fixation,
EAA has been implicated in a higher incidence of neurological complications. However, a
retrospective study demonstrated no significant association between peroneal nerve palsy
development after total knee replacement, with the use of postoperative EAA [2, 10, 12, 22, 23].
The management of transient or permanent postoperative neurologic sequelae requires the
cooperation of the anesthetist, surgeon, and neurologist. Additionally, the advice of the radiologist
and neurosurgeon may also be sought. Although it is easy to blame epidural presence for an
adverse neurologic outcome, it should be borne in mind that other factors can lead to
demonstrable nerve injury. These include undiagnosed preexisting neurologic disorders; ligation of
nutrient spinal cord vessels during abdominal surgery; injury to the femoral nerve during pelvic
surgery, or to the lateral cutaneous nerve of thigh during retraction close to the inguinal ligament;
or, pressure on the fibular head leading to neuroapraxia of the lateral popliteal nerve. If an adverse
outcome occurs, an attempt to localize the lesion by history and examination should be made.
Bilateral symptoms associated with pain should alert one to the possibility of neuraxial pathology.
Injury at the nerve roots affects both posterior and anterior rami. Preservation of sensation over
the paraspinous muscles suggests a more distal injury. Investigations should include blood cultures
and coagulation studies. Immediate MRI is the gold standard for out ruling central lesions.
Electromyography can be used to determine the site of injury and the degree of axonal loss,
although it can take up to 3 weeks after injury for changes to appear [2, 3, 4-6, 9-11].
Adverse Events due to Insertion/Presence of an Indwelling Catheter in the Epidural Space
Epidural Haematoma
Epidural vessels puncture during catheter placement occurs during 3 – 12% of attempts [12].
Bleeding from an epidural vein may occur during needle/catheter insertion, but is usually selflimiting. However, the subsequent development of a spinal haematoma, defined as symptomatic
bleeding within the spinal neuraxis, which causes neurological damage, is a rare and potentially
catastrophic complication following EAA [10, 22]. Epidural haematoma often occurs spontaneously,
without any relationship with neuraxial anaesthesia. If not detected and treated early, it results in
irreversible paraplegia [10 – 13, 22].
The true incidence of clinically apparent epidural haematoma is unknown, as any study attempting
to quantify it would have to involve an enormous number of patients. The calculated incidence is
approximated to be about 1/150.000 cases of EAA [57]. Because this estimate represents the upper
limit of the 95% confidence interval, the actual frequency should be much less [58, 59]. However,
the series involved in these calculations were conducted before the implementation of routine
perioperative thromboprophylaxis and the risk may increase 15 – fold by concomitant use of
anticoagulant therapy, when appropriate precautions are not taken [60]. In this context, risk rate
may be underestimated, since complications frequency is mainly based on cases reported in the
literature. Recent reports have raised this risk to 1/100.000 after epidural labor analgesia,
1/150.000 in patients who were already receiving heparin or acetylsalicylic acid and 1/70.000 in
patients who had experienced a traumatic spinal tap [57 – 60].
In a study including 1.710.000 patients, the overall incidence of epidural haematomas was around
1/50.000 and increased to 1/3.600 when analysis was restricted to EAA with a catheter for total
knee replacement in women older than 70 years [23]. Other reports calculated the risk to be as
high as 1/3.000 in specific patient subpopulations [3, 9 – 13, 22 – 30, 61]. In a retrospective review,
three neuraxial haematomas were detected in 8.000 EAA, associated with epidural catheter, 2 days
after its insertion [29]. Schroeder et al estimated that spinal haematoma incidence in patients
undergoing EAA in combination with LMWH, in the United States, was 1/3.100 epidural injections
[60]. It is apparent that risk increases substantially in elderly women, in whom epidural catheters
are inserted, concomitantly with anticoagulant therapy and bloody puncture [59]. This high
prevalence could have a double explanation: the frequent dual therapy with antiplatelet agents and
antithrombotic drugs in orthopaedic patients and that, in the past, the majority of Anaesthesia
Society Guidelines that establish a time interval between the administration of the anticoagulant
and the performance of EAA had not been published [62, 63].
Recent case series and epidemiologic surveys suggest that the risk has increased, possibly as a
result of increased use of regional anaesthesia in combination with altered coagulation or of better
reporting of the complication. Overall, the risk of clinically significant bleeding is currently related
not only with concomitant drug administration, but also with procedure – related and additional
personal risk factors. It increases with age, associated abnormalities of the spinal cord or vertebral
column, presence of an underlying coagulopathy, difficulty during needle placement, and an
indwelling neuraxial catheter during sustained anticoagulation (particularly with standard heparin
or low-molecular weight heparin). The need for prompt diagnosis and optimized intervention is also
consistently reported [59, 62, 63].
New anticoagulant and antiplatelet drugs have been introduced recently, giving rise to new
challenges in the management of the anticoagulated patient undergoing EAA. EAA performance
could be considered safe in patients receiving drugs that alter haemostasis, provided there is
appropriate management based on safety intervals, suited to the anaesthetic-analgesic technique
to be carried out and to the characteristics of the anticoagulant. International recommendations for
thromboembolic prophylaxis and EAA application may help the physician to manage safely with
antithrombotic agents when EAA is foreseen. Appropriate guidelines have been prepared by a
number of national societies of anaesthesiologists, but they do not have universal acceptance [3, 9,
10, 12, 22, 59, 61]. The first national recommendations on neuraxial anaesthesia and
antithrombotic drugs were published by the German Society for Anaesthesiology and Intensive
Care in 1997 [64], followed by the American Society of Regional Anesthesia and Pain Medicine
(ASRA) in 1998 [65] and Belgian Anaesthesiologists in 2000 [66]. Since then, new anticoagulant
agents have been introduced and more information, regarding EAA risks with concurrent
anticoagulation, is available [59].
In response to such patient safety issues, the ASRA convened its Third Consensus Conference on
Regional Anesthesia and Anticoagulation. Practice guidelines and recommendations, published in
2010, summarize evidence-based reviews. However, the rarity of spinal hematoma defies a
prospective randomized study, and there is no current laboratory model. As a result, the ASRA
consensus statements represent the collective experience of recognized experts in the field of
neuraxial anesthesia and anticoagulation. These are based on case reports, clinical series,
pharmacology, hematology, and risk factors for surgical bleeding. An understanding of the
complexity of this issue is essential to patient management [62].
Additionally, in 2010, the European Society of Anaesthesiology (ESA) working party on Neuraxial
Anaesthesia and Anticoagulants, composed of academic physicians experienced in this topic,
published guidelines, to assist European anaesthesiologists in their daily clinical practice. The
introduction of new anticoagulants together with recent reports of stent thrombosis in patients
with perioperative cessation of antiplatelet drugs have considerably broadened the issue and made
revision necessary. To overcome deficiencies in content and applicability, the ESA has taken the
initiative to provide current and comprehensive guidelines for the continent as a whole, based on
extensive literature review [63].
Guidelines were designed to optimize both safety and efficacy of prophylaxis in the presence of
EAA. Recommendations and suggestions are drug-specific and usually based on the pharmacologic
profile (pharmacokinetics and pharmacodynamics) of each drug, mainly the time required to reach
maximal concentration, the time to reach maximal antithrombotic activity, the half-life and the
dose regimen. Two important factors also taken into account are how long to delay before
removing catheters and when to restart anticoagulation. The recommendations are usually relevant
to doses used for thrombosis prophylaxis, rather than therapeutic anticoagulation [59, 61 – 63].
All anticoagulants administered can be classified according to their specific target [59, 67 – 69] in
the coagulation pathway:
-
Inhibitors of the initiation of coagulation: factor VIIa/tissue factor pathway inhibitors
Inhibitors of propagation of coagulation: mainly factor Xa (FXa) inhibitors, either direct or
indirect
Inhibitors of fibrin generation: direct and indirect thrombin inhibitors
“Global” inhibitors of the coagulation pathway: antivitamin K drugs and unfractionated
heparin
Interestingly, recommendations for prevention of haemorrhagic complications associated with EAA
in patients given LMWH differ from country – to – country, and across continents. Indeed, in most
European countries, the recommendations are that placement or removal of a spinal or epidural
needle/catheter should be delayed at least 12 h after the last anticoagulant dose, but the
recommendation is to delay 20 h and 10h in France and USA respectively. Subsequent
administration of LMWH is not recommended until 4 h after catheter removal in Europe, but is
considered acceptable after only 2 h in the USA. In France, LMWH therapy is not initiated until 6 h
after surgery in patients having EAA [59, 70].
Recommendations related to EAA and antithrombotic agents vary according to patient
characteristics (age, weight, creatinine clearance and concomitant medications), difficulties
associated with needle puncture, and pharmacokinetics of the anticoagulants. Recommendations
and suggested strategies [59, 61 – 63, 68] can be summarized as follows:





Consider the risk/benefit ratio of EAA for each patient. In general, outcomes sometimes
appear comparable between general and neuraxial anaesthesia.
EAA in patients receiving full anticoagulation continues to be contraindicated.
Concomitant administration of medications affecting haemostasis, such as antiplatelet
agents, NSAIDs, or dextran represents an additional risk of perioperative haemorrhagic
complications, including spinal haematoma.
Appropriate neurological monitoring is essential during postoperative recovery period and
following catheter removal. The final decision to perform EAA in patients receiving drugs
that affect haemostasis has to be taken after careful assessment of individual risks and
benefits.
Preoperative initiation of anticoagulation is not required for efficacy. When begun within
2 h of surgery, anticoagulation may increase major bleeding. For example, fondaparinux is
effective and not associated with an increased risk of major bleeding if started 8 ± 2h after
surgery; but it increases major bleeding without improving efficacy when the drug is started
within 6h after surgery.







The first dose of the anticoagulant after epidural puncture must be administered so as to
ensure an interval of at least 8h between the end of surgery and the peak plasma level of
the drug.
Catheter manipulation and removal carry similar risks to insertion and the same criteria
should apply. For any anticoagulant, the removal of an indwelling neuraxial catheter must
be delayed by an interval of at least two half – lives of the anticoagulant, following the last
peak plasma level. This is when only 25% of the circulating drug remains active, therefore,
offering the optimal risk/benefit ratio. After this interval, elimination slows considerably and
waiting longer only slightly decreases the residual drug concentration. An obvious limitation
to this strategy is the slight residual anticoagulant activity, but it seems a reasonable
compromise between the risk of haemorrhagic complications and the risk of thrombosis.
The next re-injection depends on the time required to reach maximum concentration (Tmax).
The safety interval between the removal of the catheter and the next anticoagulant
administration must be delayed by a period calculated from the haemostasis time minus the
peak plasma level of the drug (the longer the peak level the shorter the time delay). Thus,
the time necessary to optimize haemostasis is about 8h; the minimum safety window can be
estimated as 8h – Tmax.
Fondaparinux can be started between 6 and 8h after end of surgery. An indwelling epidural
catheter should not be removed until 36h (at least two half – lives) after the previous dose,
and the next dose should not be given until 12h after catheter removal. This delay is higher
than suggested by the pharmacokinetics of the drug, but is more convenient. Thus, there
needs to be a window of 48h between two injections of fondaparinux, which is achieved by
skipping one injection.
Dabigatran cannot be administered if EAA with the insertion of a permanent catheter for
postoperative analgesia has been performed. Theoretically and pharmacokinetically, once a
dose of the anticoagulant has been given, the safety time between removal of the catheter
and the next administration of dabigatran would be 36h, but this practice has not been
validated anywhere. Another case would be a bridge from the administration of a lowmolecular weight heparin (LMWH), used for 2 or 3 days, to the administration of the oral
drug, once the epidural catheter has been removed, but it is not fully supported practice.
On the basis of the pharmacokinetics of rivaroxaban, it is possible to perform EAA with an
indwelling catheter for postoperative analgesia. The first dose, with the catheter in place,
will be administered at 6 – 10h after end of surgery. Between drug administration and
catheter removal, it is necessary to wait for an interval of at least 18h. In elderly patients,
due to the prolonged half-life in this specific population, although there is not a particular
recommendation, this time should be longer, and it could be established in 22-26h. In any
case, the minimal interval between catheter removal and next dose of rivaroxaban should
be 4h.
Monitoring of anti – Xa concentrations in the plasma is no longer recommended, because
concentrations do not predict the risk of bleeding.

In order to minimise bleeding complications during EAA, care should be taken to avoid
traumatic puncture. The presence of bleeding during needle puncture and catheter
placement does not necessitate postponement of surgery. If a bloody tap occurs when
intraoperative anticoagulation is planned, postponing surgery should be considered.
Alternatively, catheters can be placed the night before surgery. Anticoagulant therapy
should be delayed for 24h after surgery when bleeding is observed.
Infectious Complications/Febrile and Infected Patients
Infection can be introduced into the epidural space from an exogenous source via contaminated
equipment or drugs, or from an endogenous source, leading to bacteraemia, which seeds to the
insertion site. Alternatively, the catheter can act as a wick through which infection tracks down
from the entry site on the skin to the epidural space. Infection can result in meningitis (if the dura is
breached), arachnoiditis or epidural abscess formation, resulting in cord compression. Risk of
infectious complications could be decreased by strict aseptic conditions during epidural catheter
insertion [2, 4, 6, 9 – 12, 22].
Although serious neuraxial infections after EAA have been reported as rare, epidural abscess
remains a serious complication, because of possible persistent neurological deficits. The incidence
varies from 0.015% to 0.7% according to different studies. Epidural abscess is uncommon, but early
diagnosis and treatment is of paramount importance. Symptoms of epidural abscess usually begin
several days after EAA, or sometimes after months. Clinical signs, duration of symptoms and rate of
neurological deterioration show a high inter – individual variability, with the classic triad (spinal
pain, fever and neurological deficit) often not found, especially not at first presentation to a
physician. Gadolinium – enhanced MRI is the most sensitive, specific and accurate imaging method
[71 – 73].
Patients with epidural abscess usually have a longer mean catheterization time than the population
mean, their majority are immune – compromised by one or more complicating diseases and
associated risk factors (malignancy, diabetes, multiple trauma, chronic obstructive respiratory
disease, chronic renal failure, herpes zozter, chronic alcohol abuse, epidural or steroid injection)
and perioperative anticoagulant therapy has been involved in most cases. There are no reports of
abscess formation in patients with catheters in situ for 2 days or less. The incidence of bacterial
contamination of epidural needles does not seem to increase with difficulty at insertion. The risk of
persistent neurological deficit from an epidural abscess is almost 50%, which may be explained by
the long period from diagnosis to intervention [9, 10, 12, 13, 22, 73].
Available data suggest that serious central neuraxial infections such as arachnoiditis, meningitis and
abscess after EAA are rare. The decision to perform EAA must be made on an individual basis
considering anaesthetic alternatives, technique benefits and risk of CNS infection. Use of a short
term EAA poses little risk to the patient who may become transiently bacteraemic during surgery.
Conversely, EAA in infected or febrile patients may increase the risk of neuraxial infection, and such
a block remains controversial. Many anaesthetists have considered sepsis to be a relative
contraindication for EAA. It is generally recommended that epidural catheterization should not be
performed in patients with untreated bacteraemia, unless there is an overwhelming reason to do
so. Conservatively, all patients with an established local or systemic infection should be considered
at risk for developing neuraxial infection. Small numbers in the studies make it difficult to provide
recommendations. Thus, vigilance must be maintained through monitoring for epidural infection
detection. There should be careful selection of patients currently responding to antibiotic
treatment of their sepsis for which EAA is suggested. Also, the potential unproven risk of neuraxial
infection after intraoperative transient bacteraemia during an obstetric or urological procedure
should be considered. However, short-term catheterization in these patients is probably safe [74].
Catheter Migration
After initial placement of the epidural catheter in the epidural space, the tip of the catheter can
move intrathecally. Similarly, intravenous migration may occur. The incidence of intrathecal or
intravenous migration has been reported to be 0.15 – 0.18% or 0.18% respectively. Both must be
considered before any bolus dose is administered via the epidural catheter, by careful aspiration, to
avoid intravascular injection of local anaesthetics. The interest of doing aspiration test and
administering test dose prior to full injection should be once again strongly underlined. A test dose
containing epinephrine can also provide evidence of intravenous migration by producing transient
tachycardia. These techniques, and the use of low-dose local anaesthetics/opioid infusions, may
help to prevent dramatic complications, such as total spinal anaesthesia, resulting in possible
neurotoxicity and seizures. Unintentional subdural catheter placement or migration can also lead to
a high block requiring intubation [10, 12, 22, 75].
Adverse events related to epidural drug administration
Drug Errors
Most commonly, local anaesthetics, opioids and/or clonidine are infused into the epidural space to
provide postoperative analgesia. All these drugs carry the potential for serious adverse effects. In
addition, occasionally, drug errors occur whereby the wrong drug is administered via the epidural
catheter, sometimes resulting in tragic consequences. The incidence of such cases remains unclear
as there are very few case reports. Glucose, antibiotics, thiopentone, potassium chloride (resulting
in paraplegia) and total parenteral nutrition have all been inadvertently injected. The use of
pharmacy or commercially prepared solutions, extreme care with labeling of epidural catheters and
drugs, checking procedures and the use of dedicated pumps should help avoid these problems [2, 4,
6, 10, 12, 22, 32].
Respiratory Depression
The side effect of most concern with epidural opioids is respiratory depression. Because of the
hydrophilic nature of some opioids, such as morphine, there is an increased tendency for the drug
to remain in the CNS, particularly the cerebrospinal fluid, resulting in possible cephalad spread and
delayed respiratory depression. There is an abundance of literature devoted to neuraxial opioids,
with a reported incidence of respiratory depression ranging between 0.13 – 0.4%. Major risk factors
are age over 70 years and additional opioid administration by other routes. Both the choice of
opioid and the dose of drug given by continuous infusion are important risk factors to cause
delayed respiratory depression. Regular monitoring of respiratory rate and, more importantly, of
level of consciousness appears to be adequate to detect respiratory depression, and is indicated for
up to 12h after a bolus injection of opioids and for the entire duration of a continuous infusion [2, 4,
6, 9 – 14, 22].
Hypotension
Apart from sensory and motor block, epidural local anaesthetics carry sympatholytic effects, due to
sympathetic chain blockade, resulting in hypotension. If the block height reaches the cardiac
outflow between T1 and T5, there may be a marked hypotensive and bradycardic response,
particularly in the presence of hypovolaemia. The degree of hypotension depends on the actual
dose, with lower concentrations causing less effect on blood pressure. Unopposed
parasympathetically mediated bronchoconstriction was suggested as the cause of a case of severe
bronchospasm during EAA. The incidence of hypotension during EAA is 0.7 – 3%, depending on the
concentration used and the criteria for hypotension. The routine use of epidural clonidine up to
900 µg as boluses of 100 µg is likely to produce significant haemodynamic depression and sedation
[2, 4, 9 – 14, 22].
CNS Toxicity
The incidence of CNS toxicity, notably convulsions, as a result of high plasma concentrations of free
LA, was reported to be 0.01 – 0.12% for bupivacaine and 0.3 / 1.000 with lidocaine [12, 22].
Motor Blockade
Excessive lower limb motor blockade with controlled epidural infusions is uncommon, occurring in
only in 3% of cases using low bupivacaine concentrations. If motor blockade does occur, it may
result in development of pressure areas on the heels and deep venous thrombosis. Persistent
motor blockade of one or both lower limbs in a patient receiving EAA should always be treated with
suspicion. Stopping the epidural infusion normally results in neurological improvement within 2h. If
this does not occur, consideration should be given to excluding a spinal haematoma or abscess. EAA
has been blamed in occasional case reports for masking the symptoms of compartment syndrome,
although there have also been cases which were diagnosed successfully during epidural blockade
[10, 12].
Total Spinal Anaesthesia
It can be caused by accidental intrathecal injection of local anaesthetics and remains a potential
hazard of EAA. Testing for S1 motor block 10 min after epidural injection may reliably detect
accidental subarachnoid administration [2, 4, 6, 76].
Cardiac Arrest
Incidence of cardiac arrest following EAA is 0.9/10.000 and is often related to high sensory block,
above T6, concomitant use of sedative agents, or intravenous injection of local anaesthetics.
Epidural test dose is strongly recommended [2 – 6, 12, 77].
Complications and Safety of EAA: Controversies – Risk Factors
Although serious disabling neurological injury post-EAA is fortunately a rare occurrence, certain
conditions predispose patients to these injuries. Some risk factors have been identified, including
advanced age, compromised immunity, diabetis mellitus, blood coagulation disorders, spine
pathology, pre – existing neurological disorders and technical difficulty when performing EAA.
EAA and Immune Compromised Patients
EAA may decrease the risk of infection through attenuation of the stress response and preservation
of immune function. However, patients with altered immune status due to neoplasms, immunesuppression therapy after solid organ transplantation and chronic infection with human
immunodeficiency virus (HIV) or herpes simplex virus (HSV) are often not considered candidates for
neuraxial techniques, because of the risk of infection around the spinal cord or within the spinal
canal. A depressed immune state increases both frequency and severity of infection. The relative
risk of CNS infections in patients with altered immune status compared with the normal host is
unknown. Nevertheless, the decision to perform EAA must be made on an individual basis
considering anaesthetic alternatives, regional anaesthesia benefits and the risk of CNS infection
(which theoretically are more likely to occur in the immune-compromised patient), as well as the
risk of haemorrhagic or neurologic complications.
The attenuated inflammatory response within the immune – compromised patient may diminish
the clinical signs and symptoms often associated with infection. Likewise, the range of
microorganisms causing invasive infection in the immune-compromised host is higher than that
affecting the general population and includes atypical and opportunistic pathogens. Consultation
with an infectious disease specialist is advised to facilitate initiation of early and effective therapy [2,
11, 12, 22].
EAA and Pre – Existing Systemic Neuropathy/Diabetic Polyneuropathy
Peripheral sensory motor neuropathies may occur secondary to a variety of underlying aetiologies,
including metabolic, autoimmune, infectious, or hereditary abnormalities. Of these, diabetes
mellitus is the most common cause of systemic polyneuropathy. The frequency of diabetic
polyneuropathy ranges from 4 – 8% at the time of initial presentation, to approximately 50% in
patients with chronic disease. Ultimately, all asymptomatic patients will likely be found to have
abnormalities of nerve conduction. The pathophysiology of diabetic polyneuropathy is
multifactorial and not completely understood. Any disruption in the supply of essential components
(blood, oxygen, adenosine triphosphate, glucose) to the axon can cause distal axonal degeneration
[2, 10 – 12].
Patients with underlying, chronic, pre-existing neural compromise, including peripheral sensorymotor neuropathy and diabetic polyneuropathy, may be at an increased risk of perioperative nerve
damage after EAA. Neural compromise can result secondary, due to mechanical, ischemic
(peripheral vascular disease or microangiopathy), toxic (chemotherapy), or metabolic (diabetes
mellitus) abnormalities and has been attributed to a physiologic “double – crush”. Patients with
atherosclerosis are especially exposed to neurologic complications following EAA. Spinal infarction
may result from direct tissue and/or vascular injury during insertion. It may be related to severe
hypotension in high risk vascular patients [2, 10 – 12, 31, 78, 79].
Abnormal local anaesthetic diffusion and subsequent neurotoxicity may have been the contributing
factors to the neurological complications. Toxicity differs greatly among local anaesthetics,
bupivacaine being the least toxic. Even though hyperbaric lidocaine is most often associated with
neurotoxicity, all local anaesthetics are potentially neurotoxic. Epinephrine may have a pathogenic
role in the development of neurotoxicity after EAA. Epinephrine alone, or when combined with a
local anaesthetic, may significantly reduce nerve blood flow [11, 12, 22].
EAA and Neurological Disorders
Historically, the use of EAA in patients with pre – existing CNS disorders has been considered
relatively contraindicated. The fear of worsening the neurologic outcome, secondary to mechanical
trauma, local anaesthetic toxicity, or neural ischemia is commonly reported. Many clinicians
completely avoid EAA in patients with pre-existing neurological disorder, because of medico-legal
implications of any increase in postoperative neurologic deficit, with exacerbation of neurological
deficit after EAA. The decision to perform EAA in such patients should be based on the risks and
potential benefits of each individual case. The risks commonly associated with EAA may not be as
frequent as once thought and neuraxial blockade should not be considered an absolute
contraindication within this patient population [2, 10, 12].
Future Perspectives
Providing effective analgesia to patients undergoing major surgery is a daily challenge for most
clinical anaesthesiologists. Methods for safe and effective management of EAA should be based on
the following recommendations, incorporating multiple major factors that should be considered
prior to EAA application, such as patient, clinician, technique, monitoring and audit:
Patient



Written informed consent should be obtained
Careful patient selection, based on a risk/benefit analysis should be performed
EAA application should be done in the absence of absolute contraindications
Clinicians – Staff







EAA should be performed by experienced practitioners
Training Programmes/Protocols/Acute Pain Handbooks are necessary, with particular
attention to
- Recognition/Management of Complications
- Concurrent Thromboprophylaxis/Anticoagulant Therapy
- Access to Members of Acute Pain Service/Acute Pain Team
- 24h Cover
Guidelines on Thromboprophylaxis/Anticoagulant Therapy Application in patients submitted
to EAA should be followed
Risks of doing EAA in surgery associated with perioperative blood coagulation disorders
(liver, vascular, cardiothoracic surgery) must be considered
Particular risks in elderly patients, necessitating aggressive thromboembolic prevention post
– surgery should be considered
EAA in septic patients should be avoided
Risk in immune-compromised and diabetic patients must be taken into account
Technique – Monitoring


















Do strict antiseptic preparation of the skin using alcoholic solutions
Wear mask, sterile gloves and probably gown when performing EAA, aiming in a sterile
technique
Avoid use of repeatedly changing small volume syringes
prefer the use of large volume, pharmacy prepared or commercially produced bags for
continuous infusion
Use identifiable administration sets without injection ports
Connect bacterial filter
Use transparent dressings
Be careful in providing EAA in patients having spine pathology
Stop procedure in case of paraesthesia and/or pain at injection
Be able to forego procedure after multiple failed attempts
Try to confirm the placement of the epidural catheter
Avoid EAA in adult unconscious patients
Do aspiration test and test-dose before full injection of local anaesthetics
Avoid severe arterial hypotension concomitant to EAA
Prefer liquid (normal saline) rather than air for loss of resistance technique
Perform regular monitoring of dynamic pain scores/cardio-respiratory parametres/sedation
scores/dermatomal level/motor blockade
Have a daily look at the insertion point of the catheter (daily inspection of epidural site)
Have an epidural review by the Acute Pain Team twice daily


Remove epidural catheters in the perioperative setting before the 4 th postoperative day
Remember that ultrasound guided EAA may improve safety in certain circumstances
Audit


Audit and Feedback to anaesthetists/nurses/surgeons is necessary
Critical Incident Reporting is mandatory
Conclusions
In an era of evidence-based medicine, further meta-analyses and well-planned large, randomized
trials have to address the controversial issues of EAA regarding safety and postoperative outcome.
EAA might well represent a key factor to improve outcome, reduce hospital stay and thereby
healthcare costs. However, it can cause serious, potentially life-threatening complications and its
safe, effective management requires a coordinated multidisciplinary approach.
A thorough knowledge of anatomy, EAA indications/contraindications meticulous attention to
preparation and block performance and careful selection of drugs and dosage will improve safety.
Recent innovations and developments in techniques and drugs, as well as established guidelines
may further minimize potential errors and harmful complications. Final decision will be based on
the individual risk/benefit balance of all these factors.
Moving forward, improved EAA safety should also include the patient. Informed consent protects
autonomous choice of patient. Disclosure includes information on the nature of the procedure,
potential risks/benefits and alternative treatments. We now have sufficient information on EAA
associated risks and safety. Why not share these data with the patient to help him (or her) decide.
References
1. McIntyre JWR. Regional Anaesthesia Safety. In: Finucane BT, ed. Complications of Regional
Anaesthesia. New York, NY: Springer Science & Business Media, LLC; 2007 (2nd Edition): pp
1-38 (Chapter 1).
2. Gilbert HC. Complications and controversies in regional anaesthesia. In: Schwartz AJ,
Matjasko MJ, Otto CW, ed. American Society of anaesthesiologists (ASA) Refresher Courses.
Philadelphia, PS: Lippincott Williams & Wilkins; 2003: pp 45-64 (Volume 31, Chapter 6).
3. Fischer B. Benefits, risks and best practices in regional anaesthesia. Do we have the
evidence we need? Reg Anesth Pain Med, 2010; 35: 545-548.
4. Hanna MN, Murphy JD, Kumar K, Wu CL. Regional techniques and outcome: What is the
evidence? Curr Opin Anaesthesiol, 2009; 22: 672-677.
5. Beaussier M. Safety of epidural anaesthesia. Highlights in Regional Anaesthesia and Pain
Therapy, 2010.
6. Schug S, Pfluger E. Epidural anaesthesia and analgesia for surgery: Still going strong? Curr
Opin Anaesthesiol, 2003; 16: 487-492.
7. Low J. Epidural anaeshtesia and analgesia in major surgery. Lancet, 2002; 360: 568-569.
8. Kehlet H, Holte K. Epidural anaesthesia and analgesia in major surgery. Lancet, 2002; 360:
568-569.
9. Benhamou D, Auroy Y, Amalberti R. Safety during regional anaesthesia. What do we know
and how can we improve our practice? Reg Anesth Pain Med, 2010; 35: 1-3.
10. Twomey C, Tsui BCH. Complications of epidural blockade. In: Finucane BT, ed. Complications
of Regional Anaesthesia. New York, NY: Springer Science & Business Media, LLC; 2007 (2 nd
Edition): pp 167-192 (Chapter 10).
11. Agarwal A, Kishore K. Complications and controversies of regional anaesthesia: A review.
Indian J Anaesth, 2009; 53: 543-553.
12. Wheatley RG, Schug SA, Watson D. Safety and efficacy of postoperative epidural analgesia.
Br J Anaesth, 2001; 87: 47-61.
13. Cook TM, Counsell D, Wildsmith JA. Major complications of central neuraxial block: Report
on the Third National Audit Project of the Royal College of Anaesthetists. Br J Anaesth, 2009;
102: 179-190.
14. Buggy DJ. Central neuraxial block: Defining risk more clearly (Editorial). Br J Anaesth, 2009;
102: 151-153.
15. Rodgers A, Walker N, Schug S, et al. Reduction of postoperative mortality and morbidity
with epidural or spinal anaesthesia: results from overview of randomised trials. BMJ, 2000;
321: 1493-1497.
16. Ballantyne JC, Carr DB, De Ferranti S, et al. The comparative effects of postoperative
analgesic therapies on pulmonary outcome: cumulative meta-analyses of randomized,
controlled trials. Anesth Analg, 1998; 86: 598-612.
17. Jorgensen H, Wetterslev J, Moiniche S, Dahl JB. Epidural local anaesthetics versus opioidbased analgesic regimens on postoperative gastrointestinal paralysis, PONV and pain after
abdominal surgery. Cochrane Database Syst Rev, 2000; (4): CD001893.
18. Beattie WS, Badner NH, Choi P. Epidural analgesia reduces postoperative myocardial
infarction: A meta-analysis. Anesth Analg, 2001; 93: 853-858.
19. Rigg JR, Jamrozik K, Myles PS, et al. Epidural anaesthesia and analgesia and outcome of
major surgery: A randomised trial. Lancet, 2002; 359: 1276-1282.
20. Peyton PJ, Myles PS, Silbert BS, et al. Perioperative epidural analgesia and outcome after
major abdominal surgery in high-risk patients. Anesth analg, 2003; 96: 548-554.
21. Park WY, Thompson JS, Lee KK. Effect of epidural anesthesia and analgesia on perioperative
outcome: a randomized, controlled Veterans Affairs Cooperative study. Ann Surg, 2001; 234:
560-569.
22. Rosenquist RW. Avoiding complications in regional anaesthesia. In: Finucane BT, ed.
Complications of Regional Anaesthesia. New York, NY: Springer Science & Business Media,
LLC; 2007 (2nd Edition): pp 53-60 (Chapter 3).
23. Moen V, Dahlgren N, Irestedt L. Severe neurological complications after central neuraxial
blockade in Sweden 1990-1999. Anesthesiology, 2004; 101: 950-959.
24. Auroy Y, Narchi P, Messiah A, et al. Serious complications related to regional anesthesia:
results of a prospective survey in France. Anesthesiology, 1997; 87: 479-486.
25. Auroy Y, Benhamou D, Bargues L, et al. Major complications of regional anaesthesia in
France: The SOS Regional Anaesthesia Hotline Service. Anesthesiology, 2002; 97: 1274-1280.
26. 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; 4: 445-452.
27. Horlocker TT. Complications of spinal and epidural anaesthesia. Anesthesiol Clin North Am,
2000; 19: 461-485.
28. Sorensen EJ. Neurological injuries associated with regional anaesthesia. Reg Anesth Pain
Med, 2008; 33: 442-448.
29. Christie IW, McCabe S. Major complications of epidural analgesia after surgery: Results of a
six-year survey. Anaesthesia, 2007; 62: 335-341.
30. Cameron CM, Scott DA, McDonald WM, Davies MJ. A review of neuraxial epidural morbidity:
Experience of more than 8.000 cases at a single teaching hospital. Anesthesiology, 2007; 106:
997-1002.
31. De Tommasso O, Caporuscio A, Tagariello V. Neurological complications following central
neuraxial blocks: Are there predictive factors? Eur J Anaesthesiol, 2002; 19: 705-716.
32. Lanigan CJ. Safer epidural and spinal connectors. Anaesthesia, 2002; 57: 567-571.
33. Giebler RM, Scherer RU, Peters J. Incidence of neurologic complications related to thoracic
epidural catheterization. Anaesthesiology, 1997; 86: 55-63.
34. Popping DM, Zahn PK, Van Aken HK, Dasch B, Boche R, Pogatzki – Zahn EM. Effectiveness
and safety of postoperative pain management: A survey of 18.925 consecutive patients
between 1998 and 2006 (2nd revision). A database analysis of prospective data. Br J Anaesth,
2008; 101: 832-840.
35. Katircioglu K, Hasegeli L, Ibrahimhakkioglu HF, Ulusoy B, Damar H. A retrospective review of
34.109 epidural anaesthetics for obstetric and gynaecologic procedures at a single private
hospital in Turkey. Anesth Analg, 2008; 107: 1742-1745.
36. Lee LA, Posner KL, Domino KB, Caplan RA, Cheney FW. Injuries associated with regional
anaesthesia in the 1980’s and 1990’s. A closed claims analysis. Anesthesiology, 2004; 101:
143-152.
37. Duarte WL, Araujo FS, Almeida MF, Geber DG, de Castro CH. Subdural haematoma after
inadvertent dura matter puncture. Case report. Rev Bras Anestesiol, 2008; 58: 389-390.
38. Wilson M. Epidural endeavour and the pressure principle (Editorial). Anaesthesia, 2007; 62:
319-324.
39. Wilkinson PA, Valentine A, Gibbs JM. Intrinsic spinal cord lesions complicating epidural
anaesthesia and analgesia: Report of three cases. J Neurol Neurosurg Psychiatry, 2002; 72:
537-539.
40. Tetzlaff JE, Dilger JA, Wu C, Smith MP, Bell G. Influences of lumbar spine pathology on the
incidence of paraesthesia during spinal anaesthesia. Reg Anesth Pain Med, 1998; 23: 560563.
41. Horlocker TT. Neuraxial blockade in patients with spinal stenosis: Between a rock and a hard
place. Anesth Analg, 2010; 110: 13-15.
42. Weinberg L, Harvey WR, Marshall RJ. Postoperative paraplegia following spinal cord
infarction. Acta Anaesthesiol Scand, 2002; 46: 469-472.
43. Kararmaz A, Turhanoglu A, Arslan H, et al. Paraplegia associated with combined spinal –
epidural anaesthesia caused by preoperatively unrecognized spinal vertebral metastasis.
Acta Anaesthesiol Scand, 2002; 46: 1165-1167.
44. Neal JM, Bernards CM, Hadzic A, et al. ASRA Practice Advisory on neurologic complications
in regional anaesthesia and pain medicine. Reg Anesth Pain Med, 2008; 33: 404-415.
45. Bernards CM, Hadzic A, Suresh S, et al. Regional anaesthesia in anaesthetized or heavily
sedated patients. Reg Anesth Pain Med, 2008; 33: 449-460.
46. Kopacz DJ, Neal JM, Pollock JE. The regional anaesthesia learning curve. What is the
minimum number of epidural and spinal blocks to reach consistency? Reg Anesth Pain Med,
1996; 21: 182-190.
47. Birnbach DJ, Santos AC, Bourlier RA, et al. The effectiveness of video technology as an
adjunct to teach and evaluate epidural anaesthesia performance skills. Anesthesiology, 2002;
96: 5-9.
48. Friedman Z, Siddiqui N, Katznelson R, Devito I, Bould MD, Naik V. Clinical impact of epidural
anaesthesia simulation on short- and long-term learning curve: High versus low fidelity
model training. Reg Anesth Pain Med, 2009; 34: 229-232.
49. Grau T, Bartusseck E, Conradi R, Martin E, Motsch J. Ultrasound imaging improves learning
curves in obstetric epidural anaesthesia: A preliminary study. Can J Anaesth, 2003; 50: 10471050.
50. Grau T, Leipold R, Conradi R, Martin E. Ultrasound control for presumed difficult epidural
puncture. Acta Anaesthesiol Scand, 2001; 45: 766-771.
51. Lin BC, Chen KB, Chang CS, et al. A “membrane in syringe” technique that allows
identification of the epidural space with saline while avoids injection of air into the epidural
space. Acta Anaesthesiol Sin, 2002; 40: 55-60.
52. Lechner TJ, van Wijk MG, Maas AJ. Clinical results with a new acoustic device to identify the
epidural space. Anaesthesia 2002; 57: 768-772.
53. Tsui BC, Seal R, Koller J, et al. Thoracic epidural analgesia via the caudal approach in
pediatric patients undergoing fundoplication using nerve stimulation guidance. Anesth
Analg, 2001; 93: 1152-1155.
54. Tsui BC, Gupta S, Finucane B. Confirmation of epidural catheter placement using nerve
stimulation. Can J Anaesth, 1998; 45: 640-644.
55. Hayatsu K, Tomita M, Fujihara H, et al. The placement of the epidural catheter at the
predicted site by electrical stimulation test. Anesth Analg, 2001; 93: 1035-1039.
56. Grau T, Conradi R, Martin E, Motsch J. [Ultrasound and local anaesthesia: part III. Ultrasound
and neuroaxial local anaesthesia]. Anaesthesist, 2003; 52: 68-73.
57. Tryba M, Wedel DJ. Central neuraxial block and low molecular weight heparin (enoxaparine):
lessons learned from different dosage regimes in two continents. Acta Anaesthesiol Scand
(Supplementum), 1997; 111: 100-104.
58. Choi S, Brull R. Neuraxial techniques in obstetric and non-obstetric patients with common
bleeding diathesis. Anesth Analg, 2009; 109: 648-660.
59. Rosencher N, Bonnet MP, Sessler DI. Selected new antithtrombotic agents and neuraxial
anaesthesia for major orthopaedic surgery: Management strategies. Anaeshtesia, 2007; 62:
1154-1160.
60. Schroeder DR. Statistics: detecting a rare adverse drug reaction using spontaneous reports.
Reg Anesth Pain Med, 1998; 23: 183-9.
61. Lliau JV, Ferrandis R. New anticoagulants and regional anaesthesia. Curr Opin Anaesthesiol,
2009; 661-666.
62. Horlocker TT, Wedel DJ, Rowlingson JC, et al. Regional anaesthesia in the patient receiving
antithrombotic or thrombolytic therapy: American Society of Regional Anaesthesia and Pain
Medicine Evidence Based Guidelines (Third Edition). Reg Anesth Pain Med, 2010; 23: 95-116.
63. Gogarten W, Vandermeulen E, Van Aken H, Kozek S, Liau JV, Samama CM. Regional
anaesthesia and antithrombotic agents: Recommendations of the European Society of
Anaesthesiology. Eur J Anaesthesiol, 2010; 27: 999-1015.
64. Gogarten W, Van Aken H, Wulf H, et al. Regional anaesthesia and thromboembolism
prophylaxis/anticoagulation. Anaesth Intensivmed, 1997; 38: 623-628.
65. Horlocker TT, Wedel DJ. Anticoagulation and neuraxial block: historical perspective,
anesthetic implications, and risk management. Reg Anesth Pain Med, 1998; 23: 129-134.
66. Anonymous. Belgian Guidelines concerning drug induced alterations of coagulation and
central neuraxial anesthesia. Acta Anaesth Belg 2000; 51: 101-104.
67. Weitz JI, Hirsh J, Samama MM. New antithrombotic drugs. Chest 2008; 133: 234S-256S.
68. Gogarten W. The influence of new antithrombotic drugs on regional anesthesia. Curr Opin
Anesthesiol, 2006; 19: 545-550.
69. Hirsh J, O’Donnell M, Weitz JI. New anticoagulants. Blood, 2005; 105: 453-463.
70. Samama CM, Albaladejo P, Benhamou D, et al. Venous thromboembolism prevention in
surgery and obstetrics: Clinical practice guidelines. Eur J Anaesthesiol, 2006; 23: 95-116.
71. Royakkers AA, Willigers H, van der Ven AJ, et al. Catheter-related epidural abscesses: don’t
wait for neurological deficits. Acta Anaesthesiol Scand, 2002; 46: 611-615.
72. Orlikowski C, Majedi PM, Keil AD. Bacterial contamination of epidural needles after multiple
skin passes. Br J Anaesth, 2002; 89: 922-924.
73. Bluman EM, Palumbo MA, Lucas PR. Spinal epidural abscess in adults. J Am Acad Orthop
Surg, 2004; 12: 155-163.
74. Wedel DJ, Horlocker TT. Regional anaesthesia in the febrile or infected patient. Reg Anesth
Pain Med, 2006; 31: 324-333.
75. Guay J. The epidural test dose: A review. Anesth Analg, 2006; 102: 921-929.
76. Douad Z, Collis RE, Ateleanu B, Mapleson WW. Evaluation of S1 motor block to determine a
safe, reliable test dose for epidural analgesia. Br J Anaesth, 2002; 89: 442-445.
77. Kopp S, Horlocker TT, Warner M, et al. Cardiac arrest during neuraxial anaesthesia:
Frequency and predisposing factors associated with survival. Anesth analg, 2005; 100: 855865.
78. Hebl J, Kopp S, Schroeder D, Horlocker T. Neurologic complications after neuraxial
anaesthesia or analgesia in patients with preexisting peripheral sensorimotor neuropathy or
diabetic polyneuropathy. Anesth Analg, 2006; 103: 1294-1299.
79. Monsel S, Rodesch G, Laloe P, Kuhlman G, Fischler M. Neurologic dysfunction after major
thoracic surgery in a patient with severe arteriosclerosis disease receiving epidural analgesia.
Anesth Analg, 2007; 104: 204-206.