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Eur J Cardiothorac Surg 2004;26:694-700
© 2004 Elsevier Science NL
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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 Top Abstract 1. Introduction2. Materials and methods3. Results4. DiscussionReferences |
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1. Introduction |
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TopAbstract1. Introduction2. Materials and methods3. Results4. DiscussionReferences |
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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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TopAbstract1. Introduction2. Materials and methods3. Results4. DiscussionReferences |
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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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TopAbstract1. Introduction2. Materials and methods3. Results4. DiscussionReferences |
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4. Discussion |
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TopAbstract1. Introduction2. Materials and methods3. Results4. DiscussionReferences |
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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 have no relationship to disclose pertaining to this research.
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References |
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TopAbstract1. Introduction2. Materials and methods3. Results4. DiscussionReferences |
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