Eur J Cardiothorac Surg 2004;26:694-700
© 2004 Elsevier Science NL
Postoperative naproxen after coronary artery bypass surgery: a double-blind randomized controlled trial
Alexander Kulika,
Marc Ruela,c,
Michael E. Bourkeb,
Lynn Sawyera,
John Penningd,
Howard J. Nathanb,
Thierry G. Mesanaa,
Pierre Bédarda,*
a Division of Cardiac Surgery, University of Ottawa Heart
Institute, Ottawa, Ont., Canada
b Division of
Cardiac Anesthesia, University of Ottawa Heart Institute, Ottawa, Ont.,
Canada
c Department of Epidemiology, University
of Ottawa, Ottawa, Ont., Canada
d Department of
Anesthesiology, University of Ottawa, Ottawa, Ont., Canada
Received 5 May 2004;
received in revised form 22 June 2004;
accepted 1 July 2004.
* Corresponding author.
Tel.: +1-613-761-4313; fax: +1-613-761-5107. (E-mail: pbedard{at}ottawaheart.ca).
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Abstract
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Objective: Non-steroidal
anti-inflammatory drugs (NSAIDs) are routinely used after coronary artery
bypass surgery (CABG), yet their effects have seldom been evaluated in
randomized controlled settings. The aim of this study was to examine the
efficacy and safety of a commonly used NSAID, naproxen. We hypothesized
that naproxen would reduce postoperative pain following CABG without
increasing complications. Methods: Patients (N=98)
undergoing primary CABG were randomized to receive naproxen (500mg
q12hx5 doses via suppository started 1h after operation, followed by
oral 250mg q8hx6 doses) or placebo. Standard analgesic and
anti-emetic regimens were available to both patient groups. Interventions
were double-blinded. Primary end-points were postoperative pain measured
before and after chest physiotherapy by visual analog scale and pulmonary
slow vital capacity (SVC). Results: Baseline characteristics were
equivalent between the two groups. Over the first 4 postoperative days,
naproxen decreased pain by 47±17% on average before chest
physiotherapy (P=0.034), and 44±13% after chest
physiotherapy (P=0.0092). Patients who received naproxen
also had better preservation of SVC over the first 4 postoperative days
(mean loss of SVC from baseline: 2.1±0.1 vs. 2.5±0.1l,
naproxen vs. placebo, P=0.0032). This was concomitant with
a lower white blood cell count observed in naproxen patients
(9.2±0.3 vs. 12.7±1.5x109/l, naproxen vs.
placebo, P=0.03). Patients who received naproxen had more
chest tube drainage after 4h postoperatively, but there was no difference
in the incidence or amount of transfusions. There was no difference in
medication use, length of stay, or in the incidence of atrial fibrillation,
azotemia, and other complications. Conclusions: Naproxen is an
effective and low-cost adjunct for optimization of pain control and lung
recovery after CABG. Its use may result in increased chest tube drainage,
but no apparent increase in other
complications.
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1. Introduction
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Inadequate
postoperative analgesia has been recognized as a common problem associated
with suboptimal patient outcomes [1]. Postoperative pain results in autonomic
nervous system stimulation and the release of catecholamines. This can lead
to adverse physiologic consequences, such as an increase in myocardial
oxygen consumption and a higher likelihood of myocardial ischemia
[2]. Furthermore,
immobilization and poor inspiratory effort as a result of inadequately
controlled pain may increase the risk of thromboembolic [3] and pulmonary complications
[4]. Adequate pain control
following cardiac surgery is therefore essential not only with respect to
patient comfort, but also because of important physiologic
benefits.
While opioids provide excellent analgesia, undesirable side
effects such as respiratory depression, sedation and nausea constitute
major limitations. As a result, many surgical centers use non-steroidal
anti-inflammatory drugs (NSAIDs), such as naproxen, as analgesic adjuvants.
The short-term use of NSAIDs in the perioperative period has been
demonstrated to be reliable and safe in carefully selected patients
[5,6]. Compared to other
NSAIDs, naproxen has a low cost, may be administered orally or as a
suppository in the anesthetized patient, and has been shown to have an
acceptable side effect profile in the outpatient setting [7,8].
Although several studies
have reported on the use of NSAIDs after cardiac surgery [9–13], their effects have seldom
been evaluated in randomized controlled settings, and none have examined
the use of naproxen. Therefore, the aim of this study was to examine the
efficacy and safety of naproxen in a prospective, double-blind, randomized,
controlled trial comparing early naproxen administration with placebo as an
adjunct to opioids following coronary artery bypass graft surgery (CABG).
The primary end-points of the study focused on postoperative pain and
pulmonary function, while the secondary end-points related to safety. We
hypothesized that naproxen would reduce postoperative pain following CABG
without increasing postoperative
complications.
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2. Materials and methods
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2.1. Patients
This study was approved by
the Human Research Ethics Board, and written consent was obtained from each
participating patient. Eligible subjects consisted of patients undergoing
non-emergency primary multi-vessel CABG on cardiopulmonary bypass, during
which the non-skeletonized left internal mammary artery (LIMA) was grafted
to the left anterior descending artery and saphenous vein segments were
used for other coronary targets. The left pleural space was routinely
opened in order to ensure a lateral lie of the LIMA. Exclusion criteria
were the following: left ventricle ejection fraction <20%; serum
creatinine >130µmol/l; preoperative use of H2 antagonists,
proton pump inhibitors, steroids, NSAIDs (with the exception of ASA),
narcotics or illicit drugs; a history of peptic ulcer, liver disease or
NSAID allergy; or the inability to provide informed consent for the study.
Patients were excluded from further study drug administration in the
presence of: low cardiac output syndrome with inotrope and/or intra-aortic
balloon pump support for greater than 24h, recurrent ventricular
arrhythmias, intubation for more than 24h, or a postoperative rise in serum
creatinine of more than 25µmol/l from
baseline.
2.2. Anesthesia
All patients
enrolled in the study received a standardized anesthesia regimen. Two
milligrams of oral lorazepam were administered 2h preoperatively, followed
by 10mg of intramuscular morphine 1h before surgery. Anesthesia was induced
with 2–5mg of intravenous midazolam, 0.5–1.0µg/kg of
intravenous sufentanil, 0.6–1.2mg/kg of intravenous rocuronium, and
inhaled isoflurane. Maintenance of anesthesia was achieved with 0.5µg/kg
per h of intravenous sufentanil, 0.5µg/kg per min of intravenous
midazolam, inhaled isoflurane, and intravenous rocuronium as needed.
Anti-fibrinolytics were not used.
2.3. Study protocol
Study patients were randomized preoperatively to receive
either naproxen or placebo after surgery. An unrestricted randomization
schedule was generated using SAS 6.0 software (SAS, Cary, NC). The placebo
and naproxen medications were prepared by the hospital pharmacy and
appeared identical. Medication administration and data collection was
performed in a double-blind manner, such that neither the patient nor the
healthcare personnel were aware of the medication assignment. Following
surgery, patients received either placebo or naproxen 500mg rectal
suppository within 1h after arrival in the recovery room. The suppository
was repeated every 12h for a total of five doses. Patients then received
oral therapy of either placebo or naproxen 250mg three times a day for 2
days (total six doses).
In addition to the study medication, a
standard analgesic regimen was available to all patients. This included
0.5–4.0mg/h of intravenous morphine, titrated to effect by the
attending intensive care unit (ICU) nurse. Oral analgesia was initiated at
the end of postoperative day (POD) one with 1–2 oral tablets of
acetaminophen 325mg plus 30mg codeine phosphate every 4h as needed. In
patients with codeine sensitivities, oral anileridine 25–50mg every
6h was substituted. Peptic ulcer prophylaxis was not used in order to fully
evaluate potential gastrointestinal side effects of the study drug.
Standard anti-emetic regimens were available to both patient
groups.
Packed red blood cells were transfused postoperatively to
anemic patients with evidence of hemodynamic instability, poor organ
perfusion, or hemoglobin levels below 80g/l. Platelets in aliquots of 5
units were transfused postoperatively to patients with platelet counts
below 60,000/µl, or to patients with active bleeding and platelet counts
below 100,000/µl. Fresh frozen plasma, at a dose of 15ml/kg, was
transfused to bleeding patients with an INR>1.5, and to patients with an
INR>2.5 regardless of bleeding. Cryoprecipitate, at a dose of 0.25
units/kg, was transfused to bleeding patients with fibrinogen levels less
than 1.0g/l.
2.4. Study endpoints
The
primary endpoints of the study were postoperative pain and pulmonary
function. Postoperative pain was evaluated using a standard 10-cm visual
analog scale (VAS) [14].
Patients were familiarized with the scale preoperatively, and
postoperatively, pain was assessed using this scale on days 1–4 at
10:00h. Pain was assessed prior to the administration of analgesia, both at
rest and following chest physiotherapy. Postoperative analgesia
requirements were recorded, and total opioid consumption was determined by
converting oral narcotics to parenteral morphine equivalents (i.e. 10mg of
parenteral morphine being equivalent to 75mg of oral anileridine and 300mg
of oral codeine).
Pulmonary function was assessed using slow vital
capacity (SVC), measured preoperatively and daily after surgery at 10:00h
on postoperative days 1–4 using a Respiradyne® II Plus
flow spirometer (Davis and Geck, Markham, Canada). Arterial oxygen
saturations on room air were measured with pulse oximetry and recorded
daily.
Secondary study endpoints related to safety, including chest
tube blood loss, blood product transfusions, wound infection, renal
dysfunction and gastrointestinal complications. Other postoperative data
collected included inotrope use, the duration of intubation, the incidence
of atrial fibrillation, and the use of anti-emetics. Daily postoperative
blood work was also obtained including serum creatinine, hemoglobin
concentration and white blood cell (WBC)
count.
2.5. Statistical analysis
The sample
size was determined by considering that a mean difference in VAS pain score
of at least 1 point would be clinically important, and that ±1 would
correspond to the maximum standard deviation of the VAS scale. Setting a
Bonferroni-adjusted 
value of 0.0125 (i.e. 0.05/4) to
account for repeated measures and a ß value of 0.10, a
minimum of 42 subjects per group were needed.
Data were imported and
analyzed in Intercooled Stata 8 (Stata, College Station, TX). Continuous
data are presented as a mean±standard error of the mean and were
compared between groups using a two-sided Student's t test or
a two-sample Wilcoxon rank-sum test for variables determined to be skewed
by a 1-sample Kolmogorov–Smirnov test. A Pearson
2 test was used for categorical data. VAS scores
and SVC were compared between groups using a two-sided Student's
t test and a one-way analysis of variance (ANOVA) with a
Bonferroni multiple-comparison tests for overall effect estimates.
Statistical significance was set at a P value of <0.05.
Analyses were conducted on an intention-to-treat basis. All patients who
had received at least one dose of study drug were included in the
analysis.
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3. Results
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3.1. Patients
Ninety-eight
patients were randomized (50 naproxen, 48 placebo). Preoperative
characteristics and intraoperative data showed no statistical differences
between the groups, with the exception of the mean number of grafts
performed (Table 1). Nine
patients from the placebo group and seven patients from the naproxen group
were withdrawn from the study prematurely (Fig. 1). Within the placebo group, patients were
withdrawn for the following reasons: one patient suffered a cardiac arrest
in the recovery room, one patient experienced a perioperative myocardial
infarction, one patient had an elevated baseline creatinine level
(115µmol/l), two patients had excessive chest tube output in the
recovery room, and four patients had protocol violations. Of the naproxen
patients that were withdrawn, one patient had a prolonged cardiopulmonary
bypass time, one patient had a perioperative cerebrovascular accident, one
patient had severe anorexia, and four patients had protocol
violations.
3.2. Postoperative pain
Patients who received naproxen had significantly less pain
before chest physiotherapy over the first 4 postoperative days (mean VAS
1.6±0.1 vs. 3.0±0.6, naproxen vs. placebo respectively,
P=0.034) (Fig.
2). Similarly, after chest physiotherapy, patients who received
naproxen had significantly less pain during the first 4 postoperative days
(mean VAS 2.2±0.1 vs. 3.9±0.6, naproxen vs. placebo
respectively, P=0.009) (Fig. 3). However, there was no significant
difference in pain on POD 4 between patients who received naproxen or
placebo (P=0.76 before chest physiotherapy,
P=0.49 after chest physiotherapy). There was also no
significant difference between the two groups in terms of daily opioid
consumption or cumulative opioid intake (63.7±4.0 vs.
64.1±4.9 total morphine equivalents in milligrams, naproxen vs.
placebo respectively,
P=0.96).
3.3. Pulmonary function
Patients who received naproxen had better preservation of
SVC over the first 4 postoperative days (mean loss of SVC from baseline:
2.1±0.1 vs. 2.5±0.1 L, naproxen vs. placebo respectively,
P=0.0032) (Fig.
4). This was associated with a significantly lower WBC count on
POD 2 (9.2±0.3 vs. 12.7±1.5x109/l, naproxen
vs. placebo respectively, P=0.03). There was no difference
observed in postoperative oxygen saturations between the two
groups.
3.4. Blood loss and transfusion
Naproxen use was associated with increased chest tube
drainage during the initial four postoperative hours (1035±88 vs.
732±107ml, naproxen vs. placebo respectively,
P=0.04). There was however no difference in the incidence
of transfusion, or in the amount of blood products administered (Table 2). Patients who received
naproxen had a trend towards receiving less platelet concentrates than
those who received placebo (0.1±0.1 vs. 1.3±0.6 units,
naproxen vs. placebo respectively,
P=0.08).
3.5. Postoperative complications
There was no difference in the rate of
gastrointestinal or renal complications between the placebo and naproxen
groups (Table 3). Two
patients in each group developed a postoperative upper gastrointestinal
bleed (P=0.93). A moderate reduction in serum creatinine
was seen postoperatively in both groups compared to preoperative values
(–7.6±2.4 vs. –8.0±2.2µmol/l, naproxen vs.
placebo, P=0.90). A creatinine rise of 25µmol/l was
noted in five patients in the naproxen group and seven in the placebo group
(P=0.44). There was no difference in medication use,
infection, hospital length of stay, or in the incidence of atrial
fibrillation between the naproxen and placebo
groups.
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4. Discussion
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Postoperative
pain control is important to patients and clinicians alike. The
physiological consequences of suboptimal analgesia following cardiac
surgery can be harmful, contributing to mobility limitations and the
impairment of the hematologic, immune, cardiovascular, and respiratory
systems. Furthermore, a direct relationship has been demonstrated between
poorly controlled pain and the cost of medical care, time spent in an
intensive care unit and hospital length of stay [15].
In this randomized controlled trial
comparing naproxen to placebo as an adjunct to opioids following CABG,
naproxen significantly reduced postoperative pain and improved pulmonary
function compared to placebo. The present data add to that of other studies
which have also illustrated the analgesic effects of NSAIDs after cardiac
surgery. A significant reduction in postoperative pain was demonstrated
with the use of ketorolac [9,10], diclofenac [11] and rectal indomethacin after CABG
[12]. However, unlike
previous trials, this is the first to date to demonstrate an improvement in
both pain control and lung function following CABG using a low-cost NSAID
such as naproxen.
Postoperative pain following CABG occurs as a
result of surgical trauma and inflammation to the thoracic cage and
parietal pleura. Pain is normally transient, and has been reported to be
maximal up to POD 3 [16].
Our results are consistent with this description, and interestingly, in our
study, naproxen was not associated with a reduction in postoperative pain
after POD 3. This data indicate that NSAIDs have the greatest impact in
relieving postoperative pain early in recovery after cardiac surgery.
Although inflammation has been implicated as a possible etiology of
postoperative atrial fibrillation, our results and that of others have not
shown any effect of NSAIDs on the incidence of postoperative atrial
fibrillation [11,17].
Significant changes in pulmonary
function occur following cardiac surgery. After median sternotomy, vital
capacity is significantly reduced, resulting in secretion retention, lobar
collapse, and a predisposition to infection. In this study, naproxen
significantly improved pulmonary SVC postoperatively, consistent with a
previous study using ketorolac [10]. Patients who received naproxen also had a
significantly lower WBC count postoperatively. This suggests that naproxen,
as an adjunct to opioids, may potentially reduce postoperative lung
atelectasis, in accordance with previous work by Gust et al. [17].
NSAIDs have traditionally
been avoided in cardiac surgery because of the older patient population and
the fear of untoward side effects on the gastric, renal and coagulation
systems. By inhibiting prostaglandin secretion, NSAID use can contribute to
gastroduodenal mucosal ulceration. In carefully selected patients however,
the short-term use of NSAIDs in the postoperative period appears safe,
without an increased incidence of gastrointestinal bleeding or peptic
ulceration [5,6]. Routine
peptic ulcer prophylaxis is advocated by most surgeons that prescribe
NSAIDs postoperatively. However, our study illustrated that even in the
absence of peptic ulcer prophylaxis, an increased risk of gastrointestinal
events was not demonstrable. Recently, the use of higher-cost selective
cyclooxygenase-2 inhibitors (COX-2) has been promoted due to the lower
incidence of gastrointestinal events compared to non-selective
cyclooxygenase inhibitors such as naproxen [18]. However, increasing evidence indicates that
COX-2 inhibitors may also be associated with acute gastrointestinal events
[19]. Furthermore, no
significant benefits were demonstrated in a recent randomized study
comparing the use of etodolac (COX-2 inhibitor) versus diclofenac
(non-selective inhibitor) after CABG [11].
Concerns remain regarding
postoperative renal impairment with the use of NSAIDs after cardiac
surgery. However, the incidence of acute renal failure following exposure
to NSAIDs is very uncommon in adults without underlying kidney disease
[20]. Our study suggests
that in patients free of preoperative renal insufficiency, short-term
postoperative naproxen use is not associated with an increased incidence of
renal dysfunction following CABG. This is in agreement with other studies
that have also found no increased risk of postoperative renal impairment
after cardiac surgery in carefully selected patients [12,13].
Through the inhibition of platelet
cyclooxygenase, NSAIDs block the formation of thromboxane-A2 and impair
platelet aggregation, thereby producing a systemic bleeding tendency.
Although the use of NSAIDs may predispose to an increase in perioperative
blood loss, previous trials of NSAIDs after cardiac surgery have failed to
demonstrate this effect [12]. In this study, naproxen use was associated
with increased chest tube drainage during the initial four postoperative
hours. However, this was not associated with an increased rate of
transfusion, and in the current era of routine anti-fibrinolytic use, it is
uncertain whether this effect would be observed or not. Although it is
biologically plausible that delaying the administration of naproxen for
several hours after surgery may reduce perioperative blood loss, this
question cannot be answered within the realm of this study. Also, it is
unclear whether such a delayed approach would affect the early
postoperative pain relief associated with naproxen. Patients who received
naproxen in this study had a trend towards receiving less platelet
concentrates than those who received placebo. Previous work has shown that
NSAIDs can interfere with the anti-platelet effect of aspirin [21]. Through the antagonism of
aspirin-induced platelet dysfunction, naproxen administration may lead to
less perioperative platelet transfusion requirements. Alternatively, the
increase in platelet transfusions in the placebo group may have been
coincidental, contributing to less blood loss in these patients.
The
opioid-sparing effect of NSAIDs has been inconsistently described in the
cardiac surgery literature. Rapanos and colleagues [12] illustrated a reduction in morphine
consumption in the first 24h after administration of rectal indomethacin.
Hynninen et al. [13] showed
an opioid-sparing effect with diclofenac, but neither indomethacin nor
ketoprofen decreased opioid consumption in their trial. Our study failed to
demonstrate an opioid-sparing effect, with no significant difference
between the naproxen and placebo groups in terms of postoperative opioid
consumption. This may have been due to our institution's aggressive
management of postoperative pain, as illustrated by the relatively low VAS
scores. Not infrequently, patients are administered narcotics
around-the-clock as prophylaxis before pain progresses.
Our study was
limited by the absence of a strict nursing protocol for narcotic
administration, impairing our ability to detect an opioid-sparing effect of
naproxen. Because patients undergoing CABG with cardiopulmonary bypass were
selected for this study, our results may not necessarily be generalizable
to all patients undergoing cardiac surgery. Furthermore, with the advent of
COX-2 inhibitors, the applicability of this study to modern postoperative
pain regimens may be questioned. However, COX-2 inhibitors have not been
demonstrated to be safer, more efficacious [11] or cost effective than standard NSAIDs in
the cardiac surgery literature. Irrespective of these potential
limitations, the strengths of this study rest in its randomized
placebo-controlled design, intention-to-treat analysis, and use of a simple
regimen with an inexpensive medication.
In conclusion, the benefits
of early naproxen use in combination with opioids for postoperative
analgesia after cardiac surgery appear to outweigh the risks in carefully
selected patients. Naproxen results in less postoperative pain and faster
recovery of lung function without producing significant side effects. Our
findings support the routine inclusion of an NSAID in the postoperative
pain regimen in all patients in whom specific contraindications do not
exist.
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Acknowledgments
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The authors wish to extend their gratitude and appreciation to nurses Nancy Shore, Sharon Findlay, Denyse Winch and Lynn Gagne, as well as to pharmacist Regis Vaillancourt, for their suggestions and assistance in conducting this study.
The authors have no relationship to disclose pertaining to this research.
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Top
Abstract
1. Introduction
