Download dent patients undergoing coronary artery bypass grafting

(Acta Anaesth. Belg., 2015, 66, 49-54)
Spinal anesthesia reduces postoperative delirium in opium dependent patients undergoing coronary artery bypass grafting
O. Tabatabaie (*), N. Matin (*), A. Heidari (**), A. Tabatabaie (***), A. Hadaegh (****),
S. Yazdanynejad (*****) and K. Tabatabaie (****)
Abstract : We investigated the effect of high spinal
­anesthesia on postoperative delirium in opium dependent
patients undergoing coronary artery bypass grafting
(CABG). The study was conducted in a tertiary referral
university hospital on a population of 60 opium dependent patients undergoing CABG surgery. Patients were
divided into two groups based on anesthesia protocol.
One group were given general anesthesia (GA Group),
the other group additionally received intrathecal
­morphine and bupivacaine (SGA Group). Postoperative
delirium (POD) was defined as the main outcome of
­interest. Incidence of POD was significantly higher in
­patients of GA Group as compared with those in SGA
Group (47% and 17% for GA and SGA respectively ; Pvalue = 0.01). Time to extubation was on average 2.2 h
shorter in SGA than in GA (7.1 h and 9.3 h respectively,
P‑value < 0.001). Intrathecal morphine and bupivacaine
reduced the risk of POD after CABG in a population of
opium dependent patients.
Key words : Coronary artery bypass grafting ; opioid
dependence ; delirium ; spinal anesthesia ; intrathecal
morphine ; treatment outcome.
Introduction
Postoperative delirium (POD) is a dreaded
complication of surgery especially coronary artery
bypass grafting (CABG) (1-3) and is independently
associated with increased mortality and morbidity
in post cardiac surgery patients (4-6). Risk factors
for POD include : advanced age, previous cerebrovascular accident (CVA), concomitant peripheral
vascular disease, diabetes mellitus (DM), chronic
renal failure, use of blood products after surgery,
and extended length of intensive care unit stay (1,
6-10).
Postoperative pain is another important risk
factor for POD (11, 12). Opioid drugs have traditionally been used for the control of pain in postoperative patients ; however, opioids especially those
given through an IV route, are associated with an
increased risk of delirium, particularly when high
doses are used, and in older patients (11, 13). This
tradeoff often challenges the anesthesiologists in
cardiac intensive care units (CICU), particularly if
the patient is not opioid naïve (7, 14). Furthermore,
opioid dependence itself is associated with an increased risk of POD in patient undergoing CABG (7,
15). Unfortunately, opioid dependence due to illicit
drug abuse or chronic illnesses requiring long term
opioid therapy has become a widespread problem.
A recent study showed that UK, USA, Russia and
Australia are especially suffering from illicit drug
abuse (> 650 DALY per 100,000 of population) (16). In some parts of the world, a considerable proportion of patients undergoing CABG are
opioid dependent (12-15%), with opium being the
most frequently abused drug (17, 18).
Opioid sparing strategies such as concomitant
use of regional anesthesia are well studied, but only
in opioid naïve populations. Preoperative intrathecal morphine has been shown to reduce the amount
of postoperative opioid consumption and enhance
analgesia in patients undergoing CABG (19-22).
Use of such measure to reduce the risk of postoperative delirium in the population of opioid tolerant
Omidreza Tabatabaie, M.D., M.P.H. ; Nassim Matin, M.D.,
M.P.H. ; Amanollah Heidari, M.D, Associate professor of
cardiothoracic surgery ; Alireza Tabatabaie, medical
student ; Amir Hadaegh, M.D. ; Samira Yazdanynejad,
M.D. ; Kamaloddin Tabatabaie, Assistant professor of
cardiac anesthesia.
(*) Tehran University of Medical Sciences, Tehran, Iran.
(**) Department of cardiothoracic surgery, Ahvaz Jondishapour
University of Medical Sciences, Ahvaz, Iran.
(***) Ahvaz Jondishapour University of Medical Sciences,
Ahvaz, Iran.
(****) Department of anesthesiology, (*****) Department of
psychiatry, Ahvaz Jondishapour University of Medical
Sciences, Ahvaz, Iran.
Correspondence address : Kamaloddin Tabatabaie, Depart­
ment of anesthesiology, Ahvaz Jondishapour University of
Medical Sciences, Ahvaz, Iran.
Tel. : +989126859319. Fax : +986113384941.
E-mail : [email protected]
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o. tabatabaie
patients is reasonable ; however, to this date, no
study has been done with this regard in cardiac
­surgery patients.
The aim of this study was to test the hypothesis
that using a combination of spinal and general anesthesia, in opioid dependent patients undergoing
CABG, would decrease their postoperative pain as
well as opioid consumption, and thus reduce the
­incidence of postoperative delirium.
Patients and methods
This study was an observational retrospective
study. The study setting was a tertiary referral University hospital. Two independent cardiac surgery
teams operate at this center ; however, the anesthesiologist is the same for both teams. Patients are referred to surgical teams by the hospital, so that equal
number of patients is allocated to each team. One
team implemented spinal anesthesia in addition to
general anesthesia (SGA group), while the other
team preferred general anesthesia only (GA group).
The study was approved by the Institutional
Review Board (IRB). Study population consisted of
patients who underwent cardiac surgery between
August 2012 and January 2014. Inclusion criteria
were opium dependence and elective first time
CABG surgery. Opium dependence was defined as
daily use of opium (via ingestion or inhalation) for
the previous 12 months, tolerance to opium, and experiencing withdrawal symptoms with abstinence.
Heroin abusers were not included in this study
because of different and often more severe co­
­
morbidities caused by intravenous use of this drug.
Since opium dependence was rare in our female
­patients, all participants were males.
Patients with CVA history, alcoholism, altered
mental status before the surgery, any cardiac surgery other than CABG, as well as redo and off pump
CABG surgeries were excluded (due to the small
number of cases with those potentially confounding
factors).
Sixty two patients met our inclusion criteria of
whom two were excluded (one had a history of
CVA and the other excluded patient had off pump
CABG). Because patients were divided equally between the two surgical teams operating in the hospital, the resulting 60 patients had been serendipitously divided into two equal 30 patient groups, based
on the implemented anesthesia protocol. Thirty patients were given spinal anesthesia in addition to
general anesthesia (SGA Group), while the remaining 30 received only general anesthesia (GA Group).
et al.
As a part of the standard protocol of the hospital, patients were allowed to use opium while preparing for surgery in hospital (via ingestion only),
but were instructed to discontinue their use 12 h before the procedure. Since the anesthesiologist for
both groups was the same, anesthesia procedures
were similar in both SGA and GA groups except for
the use of spinal anesthesia. Premedication with intramuscular midazolam (5 mg) was administered
30 min before induction of anesthesia. Normal saline (15 mg/Kg) was given preoperatively. Patients
in GA Group were given intravenous midazolam
(0.15 mg/Kg), fentanyl (3 µg/Kg), sodium thiopental (3 mg/Kg) and atracurium (0.5 mg/Kg), while
those in SGA Group received intrathecal bupivacaine (20 mg ; 4 ml of 0.5% solution) and morphine
(0.4 mg) before induction of anesthesia, using a
25 gauge needle in the sitting position. The bevel of
the needle had cephalic orientation and the patients
were put back to supine position immediately after
the injection. Induction of general anesthesia was
performed immediately after the intrathecal injection. Next, the operating table was tilted 15 degrees
head down for ten minutes before returning to operating position, in order to achieve high spinal block.
Continuous infusion of atracurium (0.4 mg/Kg/h),
midazolam (0.1 mg/Kg/h) and fentanyl (2-6 µg/
Kg/h) were used for maintenance of anesthesia.
Systolic blood pressure was maintained between
90-110 mmHg throughout the procedure. Hypotension was anticipated in SGA group due to the sympathetic block and resulting systemic vasodilation,
and was managed with norepinephrine infusion imµg/min). Hypertension episodes
mediately (1-3 during surgery were managed by bolus infusions of
fentanyl (400 µg).
Standard cardiac monitoring was implemented
for all patients. A left radial artery catheter was
placed preoperatively for continuous monitoring of
systemic blood pressure throughout and after surgery. A right subclavian central venous access was
placed for central venous pressure monitoring.
Electrocardiography (EKG) monitoring was performed during and after surgery. All patients were
admitted to CICU after surgery. Patient postoperative pain was managed using intravenous morphine
(2-5 mg) as circumstance arose (PRN). All data
were recorded during and after surgery by the respective service provider, and were retrieved retrospectively for this study from medical records.
POD on the first three days after the surgery
was considered as the main outcome of the study.
Measurements were performed by an anesthesiologist each evening. Confusion assessment method
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Table 1
Demographic characteristics and baseline risk factors of postoperative delirium1,2
SGA (n = 30)
GA (n = 30)
Total (n = 60)
Mean age, years
65 (5.1)
65 (5.6)
65 (5.3)
Preoperative EF1
42 (10.6)
40 (9.6)
41 (10.1)
DM
10 (33%)
8 (26%)
18 (30%)
7 (23%)
9 (30%)
16 (26%)
20 (66%)
22 (73%)
42 (70%)
1
1
HTN1
Smoking history
Male
1
1
Opium abuse
30 (100%)
30 (100%)
60 (100%)
30 (100%)
30 (100%)
60 (100%)
Alcohol use
0
0
0
CVA
0
0
0
IDU
0
0
0
Off-pump surgery
0
0
0
SGA : spinal plus general anesthesia group, GA : general anesthesia group, DM : diabetes mellitus, HTN : hypertension, CPB : cardiopulmonary
bypass, EF : ejection fraction, CVA : cerebrovascular accident, IDU : IV drug abuser, SD : standard deviation.
1
Categorical variables are presented by absolute number of patients and percentages in the parentheses. Continuous variables are given as means
and standard deviations in the parentheses.
2
None of the variables approached statistical significance (p-value < 0.05).
for intensive care unit (CAM‑ICU) was used for
measurement of POD (23, 24). Other variables of
interest were : time to tracheal extubation, post­
operative CVA, survival to hospital discharge, and
postoperative myocardial infarction (MI). Post­
operative MI was defined as EKG changes (new
pathological Q-waves and/or new left bundle branch
block) in the presence of rise of plasma troponin I
levels above five times the upper limit of reference
range during the first 72 hours after the surgery (25).
Postoperative opioid consumption could not be
measured reliably due to continued unrecorded
­opium use by the patients and suboptimal documentation of per required need administered doses of
opioids.
Continuous variables were reported using
means and standard deviations (SD), while categorical variables were described using frequencies and
percent. Chi-square (χ2) and t-test analyses were
performed for comparison of categorical and continuous variables respectively. Statistical Package
of Social Science software (SPSS version 16, IBM,
USA) was used for statistical analyses.
Results
Age and other baseline characteristics of the
study population for each group are shown in
­Table 1. Mean age was 65.3. No significant difference was observed between patients in GA and
SGA groups regarding preoperative ejection fraction (EF) and past medical history.
Procedure-related determinants of postoperative delirium are presented in Table 2. Time to extubation was on average 2.2 h shorter in SGA than in
GA (7.1 h and 9.3 h respectively, P-value < 0.001).
Total intraoperative fentanyl consumption was significantly lower in SGA group as compared to GA
(8 µg/Kg vs. 29 µg/Kg respectively ; P-value < 0.001). Transient episodes of hypotension were significantly higher in SGA group and were managed
with norepinephrine (9 vs. 2, respectively). Contrarily, hypertension episodes were significantly
more common in GA group as compared to SGA (8
vs. 1 respectively). Two patients in each group were
reintubated after initial extubation.
Outcome variables are given in Table 3. Overall, 32% of patients experienced POD by the third
postoperative day. Eighty-four % of POD cases
were diagnosed on the first postoperative day.
­Incidence of POD was significantly higher in
­patients of GA Group as compared with those in
SGA Group on the first postoperative day (40% and
13% for GA and SGA respectively ; P-value = 0.02).
Three patients died after the surgery, two in SGA
Group and one in GA Group (6% vs. 3%, P‑value = 0.55). Postoperative MI and CVA were not
significantly different between groups. There was
no case of ­spinal epidural hematoma.
Discussion
To our knowledge, this is the first study to
evaluate SGA and GA regarding the risk of POD, in
opium dependent patients undergoing CABG.
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et al.
Table 2
Surgery-related risk factors for postoperative delirium
SGA (n = 30)
GA (n = 30)
Total (n = 60)
P-value
3.4 (0.9)
3.6 (1)
3.5 (0.9)
0.4
CPB time, minutes1
95 (7.1)
96 (7.8)
95 (7.4)
0.7
ET, h
7.1 (0.7)
9.3 (1.0)
8.2 (1.4)
< 0.001*
Intraoperative fentanyl, µg/Kg1
8 (1.0)
29 (4.7)
19 (11)
< 0.001*
Hypotension 9 (30%)
2 (6%)
11 (18%)
0.04*
Hypertension
1 (3%)
8 (26%)
9 (30%)
0.02*
Reintubation1
2 (7%)
2 (7%)
4 (7%)
–
Operation time, h
1
1
1
1
SGA : spinal plus general anesthesia group, GA : general anesthesia group, CPB : Cardiopulmonary bypass time in minutes, ET : time to extubation in hours.
1
Categorical variables are presented by absolute number of patients and percentages in the parentheses. Continuous variables are given as means
and standard deviations in the parentheses.
* Statistical significance (p < 0.05).
present paper (Table 2), that patients in SGA group
experience less pain and require lower doses of analgesics, intra- and postoperatively, which make
them less likely to experience POD. This hypothesis
is supported by other studies that state that intrathecal morphine leads to better pain management and
less opioid use during and after CABG (19-21, 28).
The patients with known preoperative confounders of POD (such as CVA and alcoholism)
were not included in the study to improve baseline
comparability between groups (Table 1). Patient allocation by the hospital management could have
improved baseline comparability as well. However,
some of the surgical outcomes such as hypotension
and hypertension episodes were different between
the two groups. Nonetheless, cardio-pulmonary bypass time and operation time were similar (Table 2).
Our small sample size of 60 patients excluded the
possibility of a multivariate analysis to adjust the
effects of the intermediary factors of POD such as
blood pressure and ET differences. Nevertheless,
POD incidence was high (40%) in patients
who received GA. This is higher than results of
most other studies. However, one study put that figure on 80% in opium dependent patients undergoing CABG, far above our outcome. Unlike the present study, Intensive Care Delirium Screening
Checklist was used in that study for detection of
delirium, which could explain the difference to
some extent (15). Interestingly, the incidence rate
was 13% for patients receiving SGA, which is comparable to rates of opioid naive patients undergoing
CABG (2, 7, 26, 27).
This study shows that SGA reduces the incidence of POD in opium dependent patients undergoing CABG. Although the exact mechanism for
POD itself is not yet fully understood, our findings
are in line with the current understanding of the
condition. Since poorly controlled pain as well as
excessive opioid use to treat that pain are two well
established precipitating factors for POD (9, 12,
13), it is possible, as suggested by the results of the
Table 3
Outcome variable and adverse events in the study groups1
SGA (n = 30)
GA (n = 30)
Total (n = 60)
P-value
1,2
POD, day 1
4 (13%)
12 (40%)
16 (26%)
0.02*
POD, day 21,2
5 (17%)
14 (47%)
19 (32%)
0.01*
POD, day 3
5 (17%)
14 (47%)
19 (32%)
0.01*
pMI1
2 (7%)
4 (13%)
6 (10%)
0.39
pCVA
1 (1.7%)
0
1 (1.3)
0.31
Mortality1
2 (6.7%)
1 (3.3%)
3 (5%)
0.55
0
0
0
–
1,2
1
Epidural hematoma
1
SGA : spinal plus general anesthesia group, GA : general anesthesia group, POD : postoperative delirium, pMI : postoperative myocardial
infarction, pCVA : postoperative cerebrovascular accident.
* indicates statistical significance (P-value < 0.05).
1
Categorical variables are given as absolute count and percentages (in the parentheses). Continuous variables are presented as mean and standard
deviations (in the parentheses).
2
Cumulative incidence is given.
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those intermediate surgical outcomes are understandably related to the procedure and anesthesia
protocol, and can be logically related to POD in a
chain of events (i.e. they are mediators, not confounders). For instance, regarding hypertension, patients in GA group could have experienced more
intraoperative pain‑related sympathetic activation
resulting in a rise in blood pressure, which in turn
necessitated more intraoperative opioid use. Contrarily, patients in SGA group did not need any extra
intraoperative fentanyl for pain control due to total
spinal block. However, high spinal block in SGA
group was associated with systemic α1-adrenergic
block and hypotension.
This study also shows a significant reduction
in time to extubation in SGA as compared with GA.
This can be explained by the same hypothesis that
decreased pain and analgesic use also reduce extubation time. POD itself could play a part as well,
since delirious patients often remain intubated for
extended periods. Nevertheless, the effect of SGA
on time to extubation in CABG is a matter of controversy as suggested by a review article (20). Another review found no difference between intrathecal morphine and GA regarding time to extubation ;
however, the same study reported a significant decrease in extubation time with thoracic epidural anesthesia (29). Some studies have found results similar to ours (28, 30). These differences may be caused
by various study designs, different extubation protocols followed by diverse research teams and, most
importantly, differences in study populations.
Other interventions to reduce POD in CABG
patients have been investigated as well. A double
blind clinical trial reported that dexmedetomidine,
an α2-adrenergic receptor agonist, reduces duration
of delirium in post cardiac surgery patients, however, unlike the present study, it concluded that the
incidence of delirium is not reduced with dexmedetomidine as compared with morphine (14). Another study has concluded that pregabalin reduces
the need for opioids and the incidence of POD, although pregabalin use also prolonged extubation
time (31).
The results of the present paper support our
initial hypothesis that, given the much feared hemodynamic instability inherent to SGA (i.e. hypotension) is properly managed, SGA can enhance analgesia, thus reducing extubation time, intraoperative
opioid consumption and postoperative delirium in
opium dependent patients undergoing CABG. The
results of the present paper could justify prospective
randomized clinical trials (RCT) for more conclusive results.
This study has several limitations. The study
population was comprised of only males. This was
because of rarity of female opium dependent patients in our study population. This study does not
take into consideration the amount of opium used
by each patient. This was mainly due to unreliability of patients estimates regarding their opium consumption as well as the fact that opium is not a standard drug and its content cannot be assumed to be
identical in different samples. A sample size of
60 patients may not be able to detect smaller effects
especially uncommon outcomes such as mortality
or CVA. Our small sample size also made confounder adjustment by multivariate analyses unfeasible. However, the most important known confounders were excluded and the two groups were
comparable in that regard. Nonetheless, like any
other non-randomized study, we could not adjust
for unknown confounders. That could only be done
by proper randomization. Importantly, retrospective
studies such as this one are inherently vulnerable to
bias, especially treatment and selection biases.
However, treatments in this study were based on
surgical team (surgeon preference) and not the patients. Future prospective randomized clinical trials
are highly recommended.
Conclusion
Incidence of POD is high in opium dependent
patients after CABG. Intrathecal administration of
bupivacaine and low dose morphine in opioid dependent patients undergoing CABG decreases the
risk of POD and shortens time to extubation. Further randomized clinical trials are recommended to
elucidate long term benefits and adverse effects of
SGA in CABG, especially in opioid dependent patients.
Acknowledgements
We would like to appreciate the hard work of
the staff of the medical record section of our hospital without whom this work would have been
­impossible.
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