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CARDIOVASCULAR ANESTHESIA

A Comparison of Intrathecal Opioid and Intravenous Analgesia for the Incidence of Cardiovascular, Respiratory, and Renal Complications After Abdominal Aortic Surgery

Marie-Hélène Fléron, MD^*, Richard B. Weiskopf, MD, Michèle Bertrand, MD^*, Stéphane Mouren, MD PhD, Daniel Eyraud, MD^*, Gilles Godet, MD^*, Bruno Riou, MD PhD^*, Edouard Kieffer, MD^*, and Pierre Coriat, MD^*

*Departments of Anesthesiology and Critical Care, and Vascular Surgery, CHU Pitié-Salpêtrière; Department of Anesthesiology, Institut Mutualiste Montsouris, Paris, France; and Department of Anesthesia, Cardiovascular Research Institute, University of California, San Francisco, California

Address correspondence and reprint requests to Richard B. Weiskopf, MD, Department of Anesthesia, C450, Box 0648, University of California, San Francisco, CA 94143–0648, or 94122 for non-US postal delivery. Address e-mail to weiskopf{at}anesthesia.ucsf.edu

	Abstract

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Major surgery evokes a stress response that can produce deleterious consequences, especially in a population at high risk for those complications. We tested the hypothesis that decreasing or eliminating one of the sources of stress by providing intense analgesia in the immediate postoperative period via application of neuraxial opioids would decrease major nonsurgical complications. Two-hundred-seventeen patients scheduled to undergo abdominal aortic surgery were randomly allocated to receive either general anesthesia alone (control) or general anesthesia combined with intrathecal opioid (1 µg/kg sufentanil with 8 µg/kg preservative-free morphine injected at the L4–5 interspace). Postoperative care was identical in the two groups, including patient-controlled analgesia. Each patient provided an assessment of postoperative pain using a visual analog scale. Postopera-tive complications were recorded according to criteria established a priori. The administration of intrathecal opioid provided more intense analgesia than patient-controlled analgesia during the first 24 h postoperatively (P < 0.05). There was no difference between groups for the incidence of combined major cardiovascular, respiratory, and renal complications (P > 0.05) or mortality (P > 0.05). The incidence of myocardial damage or infarction, as defined by abnormal plasma concentration of troponin I, did not differ between the two groups (P > 0.05). In patients undergoing major abdominal vascular surgery, decrease of one contributor to postoperative stress, by provision of intense analgesia for the intraoperative and initial postoperative period, via application of neuraxial opioid, does not alter the combined major cardiovascular, respiratory, and renal complication rate.

IMPLICATIONS: Provision of intense analgesia for the initial postoperative period after major abdominal vascular surgery, via the administration of neuraxial opioid, does not alter the combined incidence of major cardiovascular, respiratory, and renal complications.

	Introduction

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Abdominal aortic surgery is associated with substantial mortality and a substantial incidence of postoperative cardiac, pulmonary, and renal complications (1–3). The response to the stress of this surgery is multifaceted, and includes increased sympathetic tone and circulating catecholamine concentrations, increased heart rate, and hypercoagulability (4,5).

Several studies have focused on therapies designed to modulate the stress response, especially as related to cardiac events. For example, postoperative myocardial ischemia in these patients is associated with tachycardia (6). The administration of a ß-adrenergic antagonist immediately before anesthesia reduces postoperative (but not intraoperative) myocardial ischemia (7), improves long-term survival (8,9) in patients with or at risk for coronary artery disease, and decreases mortality and the incidence of postoperative myocardial infarction in patients with proven coronary artery disease (10).

Fewer studies have addressed the multifactorial production of the stress response. Inflammation, pain, and psychological factors may all contribute to postoperative stress. Studies examining interventions to modify the etiology of the stress response, rather than its consequences, have largely focused on pain, and a single outcome variable. For example, Yeager et al. (11) reported that epidural anesthesia and postoperative analgesia reduce postoperative cardiac complications in a population at high risk for these events. However, those findings have not been confirmed subsequently (12–14). At our institution, Baron et al. (13) could not find a reduction in cardiac or respiratory complications by use of intraoperative thoracic epidural anesthesia in combination with general anesthesia, in comparison with general anesthesia alone, in patients undergoing abdominal aortic surgery.

We postulated that intraoperative and immediate postoperative afferent stimulation from the operative site (pain, inflammation) provides substantial contribution to the stress response and the associated sequelae. In this prospective, randomized study, we tested the hypothesis that blockade of these afferent stimuli, by the administration of neuraxial opioids, in the intraoperative and immediate postoperative periods, would reduce the combined incidence of major cardiac, respiratory, and renal complications after major abdominal aortic surgery.

	Methods

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This study was approved by the Ethics Committee for Human Research of our hospital and performed with written informed consent of all patients. Consecutive patients referred to the Vascular Surgery Unit of Pitié-Salpêtrière Hospital for elective abdominal aortic surgery (aneurysm or occlusive disease), who did not have a contraindication to dural puncture (clinical signs of coagulopathy, localized infection, septicemia, graft infection, previous lumbar spinal surgery), were randomly assigned to one of the two groups by a computer-generated list compiled before the start of the study. Those taking care of the patients were not blinded to patient group assignment.

A preoperative detailed history and physical examination were performed by a staff anesthesiologist. Demographic and clinical data collected included age, body weight, history of previous myocardial infarction, coronary artery disease, hypertension, diabetes mellitus, cardiac failure, chronic obstructive pulmonary disease, cigarette smoking, and preoperative medications. Twelve-lead electrocardiogram (ECG) at rest, respiratory function tests, arterial blood gas analyses, and chest radiograph were obtained in all patients. Preoperative coronary angiography was required for patients presenting with clinical or ECG evidence of unstable or uncontrolled coronary artery disease.

The study was powered to detect a 50% decrease in combined major cardiovascular, respiratory, and renal complications (see below). Two-hundred-seventeen patients who met all inclusion criteria were randomized to receive either balanced anesthesia with IV sufentanil, isoflurane, and 50% nitrous oxide (control group) or intrathecal sufentanil and morphine (IT group) plus isoflurane and 50% nitrous oxide.

Anesthetic Management
One hour before surgery, all patients were premedicated with oral midazolam 5 mg. Patients were given their usual cardiovascular medications, except for angiotensin-converting enzyme inhibitors, because of the intraoperative hypotensive effects of the latter (15). Patients were monitored with a 5-lead ECG using continuous ST segment analysis of leads modified V5, II, and V₅; invasive arterial blood pressure (Solar 7000, Marquette Electronics Inc.); percutaneous oxyhemoglobin saturation (SpO₂); end-tidal CO₂ and anesthetic concentrations; and urine output via a bladder catheter.

Control Group.
After placement of an IV catheter and an IV infusion of 10 mL/kg of an isotonic salt solution, anesthesia was induced with 0.5 µg/kg IV sufentanil, and 1–2 mg/kg IV propofol. Atracurium 0.5 mg/kg IV was administered to facilitate tracheal intubation, and ventilation (10 mL/kg at 12/min) was mechanically controlled to maintain an end-tidal PCO₂ of 30–35 mm Hg. Anesthesia was maintained with 50% nitrous oxide and isoflurane, and sufentanil with an initial rate of 0.5 µg · kg^-1 · h^-1. Isoflurane concentration and sufentanil infusion rates were adjusted as required by clinical conditions, according to heart rate and blood pressure. A continuous infusion of atracurium (0.5 mg · kg^-1 · h^-1) was maintained and adjusted according to the results of stimulation of a median nerve, until closure of the peritoneum.

IT Group.
After placement of an IV catheter and an infusion of 10 mL/kg of an isotonic salt solution, 1 µg/kg sufentanil with 8 µg/kg preservative-free morphine (in 5 mL NaCl 0.9%) was injected via the L4–5 interspace through a 25-gauge Whitacre needle. After 10–15 min, general anesthesia was induced with 1–2 mg/kg IV propofol, and 0.5 mg/kg IV atracurium was given to facilitate tracheal intubation. Ventilation was mechanically controlled, and isoflurane, nitrous oxide, and atracurium were administered as in the control group. In the IT group, sufentanil was not infused continuously; the attending anesthesiologist was allowed to give intermittent doses of 5–10 µg/kg sufentanil, according to the same clinical criteria used in the IT group.

In both groups, fluid administration, blood transfusion management, and vasoconstrictor (ephedrine or neosynephrine) administration were at the discretion of the attending anesthesiologist and were based on hemoglobin concentration (ß-hemoglobin photometer; Hemocue AB, Ängelhom, Sweden), hemodynamic measures (heart rate, arterial blood pressure, and central venous pressure), and ECG findings. Central venous catheters were used in all patients; pulmonary artery catheters were not used. Maximal and minimal values of systolic arterial pressure and heart rate during the operative period were recorded. Forced-warm air devices were used intraoperatively and in the early postoperative period until body temperature reached 36°C. Heparin was administered before the application of the aortic cross-clamp, and was not antagonized with protamine. Tracheal extubation was planned to occur in the intensive care unit (ICU), and not in the operating room; it was supervised by the attending anesthesiologist and was based on clinical evaluation. All patients received supplemental nasal oxygen after tracheal extubation.

Postoperative Management
Postoperative management was identical for all patients. All patients were admitted postoperatively into an ICU for at least 24 h, during which time careful attention was given to pain management. During this period, all patients received supplemental oxygen.

Morphine titration was started at the time of tracheal extubation based on the Visual Analog Pain Score (VAPS) assessed every 10 min (scale from 0 to 100 mm). Intermittent doses of morphine were given every 10 min until the VAPS was reduced to a value <30 mm. A patient-controlled analgesia (PCA) device (Abbott LifeCare PCA Infuser; Abbott Laboratory, North Chicago, IL) was then connected to an IV infusion and set to deliver a 1-mg dose of morphine (1 mg/mL) with a 7-min lock-out time; there was no background infusion of morphine. After initiation of PCA, the VAPS and sedation score (16) were recorded at 2, 4, 12, and 24 h after tracheal extubation. In both groups, patients received 2 g of propacetamol 4 times daily.

ß-adrenergic antagonists were administered IV to maintain heart rate <90 bpm when the patients were in the ICU. When the patients were on the ward, ß-adrenergic antagonists were administered by nasogastric tube twice per day, until oral medication could be administered.

Arterial blood was analyzed for pH and partial pressures of O₂ and CO₂ 1, 4, 12, and 24 h after tracheal extubation. Postoperative assessment in the ICU included standard biochemical assays, arterial blood gas analyses, chest radiographs, 12-lead ECG recordings, and measurement of plasma concentration of troponin I (Tn I) (Stratus®; Dade, Massy, France). The hemodynamic monitoring and treatments, mechanical ventilation, tracheal extubation, and standardized nursing care were under the supervision of the attending anesthesiologist in charge of the ICU. Patients were maintained in the ICU until physicians in charge determined that they could be transferred to the surgical ward.

At our institution, the administration of neuraxial opioids is not permitted outside of the intensive care setting. When the patient was on the surgical ward, postoperative analgesia was achieved with subcutaneous administration of 10 mg of morphine repeated 4–6 times a day and 2 g of propacetamol repeated 4 times a day. Standard biochemical assays, arterial blood gas analyses, chest radiographs, 12-lead ECG recordings, and measurement of plasma concentrations of Tn Ic were performed on the first, second, third, fifth, and seventh postoperative days. In addition, the measurements of Tn Ic were repeated when any value exceeded the upper limit of normal (0.3 ng/mL).

Clinical Outcome
The major clinical outcome variables were determined and defined prospectively. We recorded major cardiovascular, respiratory, and renal morbidity for 30 days after surgery (patients were contacted 30 days after surgery), and within-hospital mortality. Major cardiovascular and respiratory complications were defined as myocardial damage or infarction, congestive heart failure, new cardiac arrhythmia, new segmental or lobar atelectasis, confirmed pneumonia, severe respiratory depression, acute respiratory failure, or renal insufficiency, occurring within 30 days after surgery. All cardiac events were assessed and agreed upon by at least two of the investigators.

Taking into account Tn I values of the reference population in our laboratory (cardiac Tn-I concentration >0.3 is above the 99th percentile of the reference population), and the results of our previous study that established the cut-off value of Tn I associated with impaired 30-day outcome as 0.5 ng/mL in a similar patient population (17), we defined myocardial damage as a postoperative Tn I concentration >0.5 ng/mL on 2 successive measurements with or without associated ECG changes. Myocardial infarction was defined as any increase of Tn I concentration >1.5 ng/mL (17,18). Congestive heart failure was defined as the postoperative requirement for adrenergic agonists to maintain systolic blood pressure >100 mm Hg, associated with classic radiograph changes and an impairment in left ventricular function (ejection fraction <30%) determined by echocardiography. Cardiac arrhythmia was defined as the documented development of supraventricular or ventricular fibrillation or tachydysrhythmia (atrial or ventricular premature contractions).

Major atelectasis was defined as the presence of segmental or lobar atelectasis on chest radiograph. Confirmed pneumonia was defined as the new appearance on radiograph of an infiltrate associated with purulent sputum, a temperature ≥38.5°C, abnormal increase of white blood cell count, and favorable outcome after antibiotic treatment. We prospectively defined major respiratory depression as any clinical need of tracheal reintubation occurring within the first 24 h after anesthesia and requiring mechanical ventilation of the lungs for <24 h. Acute respiratory failure was defined as the need of mechanical ventilation for >24 h in the presence of atelectasis or pneumonia, or the clinical need for tracheal reintubation and mechanical ventilation of the lungs occurring after the first postoperative day.

Renal insufficiency was defined as serum creatinine concentration increase of >50%, or an absolute concentration of ≥200 µm/L (2.26 mg/dL).

The study was powered to enable detection, with an 80% probability and an of 0.05, of a 50% decrease in the combined incidence of major cardiovascular, respiratory, and renal complications, which historically has been approximately 35% at the institution where the study was performed.

The Kolmogorov-Smirnov test was used to assess the Gaussian distribution of variables. Data are expressed as mean ± SD for data with normal distribution, or as median [95% confidence intervals] for data without normal distribution. Data with normal distribution were compared between the two groups by Student’s t-test for unpaired data. Data obtained at multiple times were compared between groups using repeated measures analysis of variance, followed by the Newman-Keuls test. Data not normally distributed were compared by the Mann-Whitney test. Categorical variables were compared between the two groups using Fisher’s exact test. Analyses were performed for both "intention to treat" and the actual treatment received by each patient. Analyses are presented by "intention to treat," unless stated otherwise. All statistical tests were two-tailed, and statistical significance was accepted at P ≤ 0.05.

Statistical analyses were performed with a computer using NCSS 6.0 software (Statistical Solution Ltd., Cork, Ireland)

	Results

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Two-hundred-seventeen patients were enrolled in the study: 112 in the control group and 105 in the IT group. There were no significant differences in the preoperative clinical (Table 1) and biological (Table 2) variables between the two groups. Lumbar puncture could not be performed in three patients in the IT group. These patients were continued in the study, and managed as in the control group. Thus, in the analysis of patients as actually treated, 115 patients were in the control group and 102 in the IT group.

View larger version (12K): [in this window] [in a new window]   Figure 1. Heart rate (HR), mean arterial blood pressure (MAP), and body temperature did not differ (all P > 0.05) between the control group and the group given intrathecal opioid (IT) before anesthesia (CONT), after the induction of anesthesia (IND), after surgical incision (INC), after aortic clamping (CL), after aortic declamping (DCL), and at the end of surgery (END). Data are mean ± SD. NS = not significant.

View larger version (20K): [in this window] [in a new window]   Figure 2. Patient self-rated degree of pain as determined by use of a 100-mm Visual Analog Pain Scale (VAPS), after abdominal aortic surgery was greater in the control than in the intrathecal opioid (IT) group (P < 0.001). Data are mean ± SD.

View larger version (16K): [in this window] [in a new window]   Figure 3. Sedation and ventilatory rate did not differ between the control group (•) and the group given intrathecal opioid () during the initial 24 postoperative hours. Data are mean ± SD. NS = not significant.

	Discussion

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We have found that although the administration of intrathecal opioids in patients undergoing abdominal aortic surgery provides more intense postoperative analgesia than does the administration of IV opioids, the former is not associated with a reduced combined incidence of major cardiovascular, respiratory, and renal complications within 30 days of surgery. The incidence of postoperative myocardial damage/infarction is also not altered. Thus, our hypothesis, that decreasing an important etiology of stress associated with major surgery by the administration of neuraxial opioids in a population at high risk for coronary artery disease would reduce the incidence of major complications, was not supported.

We administered a single dose of intrathecal opioid because it is an established, easily performed method for providing both intra- and early postoperative intensive analgesia, without altering the circulatory status in patients undergoing cardiac and aortic surgery (19–21). Neuraxial opioids reduce stress as judged by reduced plasma concentrations of "stress" hormones (20,22,23) and by a potent analgesic effect (19,21). For example, application of epidural fentanyl results in a smaller plasma concentration of ß-endorphin four hours after thoracotomy than does the administration of IV fentanyl, and a shorter duration of increased plasma cortisol concentration (23). Thus, we reasoned that application of neuraxial opioids in a population at high risk for stress-related major complications would reduce the combined complication rate. We chose to assess the combined incidence of major complications, rather than any single complication, because the overall incidence of major complications is of greater clinical significance inasmuch as a therapy might reduce the incidence of one complication, but increase the incidence of others.

Our results are similar to those reported from our institution by Baron et al. (13) a decade ago. They found similar complication rates in similar patients undergoing abdominal aortic surgery with general plus epidural anesthesia versus general anesthesia alone. We now find that provision of spinal analgesia for the first postoperative day also does not alter the incidence of major nonsurgical complications. Rigg et al. (24) recently reported the results of a multicenter study of 915 patients with at least 1 risk factor for postoperative complications, undergoing a variety of abdominal procedures, and found no difference in mortality or overall complication rate with epidural anesthesia and 72 hours of postoperative epidural anesthesia/analgesia than in patients managed with a general anesthetic and primarily PCA and IV opioids. Only one of eight categories of major complications (respiratory failure) had a less frequent incidence in the epidural group. However, assessment of their results is exceedingly difficult because fully half of their patients in the epidural group did not complete the protocol, and the patients in the general anesthesia group were assessed preoperatively to be at greater risk for complications. Tuman et al. (25) studied 2 groups of 40 patients each allocated to combined general anesthesia plus epidural analgesia, with the latter continued for a mean of 3 postoperative days, or to general anesthesia plus postoperative parenteral opioid after abdominal or lower extremity surgery. They found fewer postoperative vascular occlusions in the epidural group. However, Norris et al. (14) recently reported no differences in morbidity, mortality, or length of hospital stay among four groups of approximately 40 patients each randomly allocated to combinations of general anesthesia, general anesthesia supplemented with epidural analgesia, and both with epidural or IV PCA for at least 72 hours after abdominal aortic surgery. However, that study was sized only to detect differences for length of stay, and not for differences of morbidity or mortality. A recently published meta-analysis (26) examined 17 studies with 1173 patients, concluding that provision of epidural analgesia for 24 hours or more after surgery decreased postoperative myocardial infarction rate (P = 0.049), but that this effect was restricted to postoperative analgesia administered in the thoracic, but not lumbar epidural space. The meta-analysis also noted no effect of epidural analgesia on postoperative mortality. With the exception of the study by Seeling et al. (27), which found no effect of intraoperative epidural anesthesia plus postoperative epidural analgesia on postoperative myocardial infarction in patients undergoing major abdominal surgery, our study examined substantially more patients than did the others. We avoided the problems inherent in a meta-analysis, such as heterogeneity of subjects (risk, operation, enrollment criteria) and methodology (e.g., definitions of and methods of detection of complications).

There are several possible explanations for the lack of demonstrated efficacy in reducing major postoperative complications. Afferent input, such as pain, is not the only contributor to the development of the stress response. Other factors, such as psychological issues and inflammation are of importance. In this study, neither were controlled or treated. Although intrathecally administered opioids successfully substantially blunted afferent pain stimuli better than did IV PCA, altering this single modality may be insufficient to alter the major deleterious outcomes related to stress. Despite statistically significant differences in self-rated pain scores between the group treated with intrathecal opioids and the control group, the latter, of course, was not left without amelioration of their pain. In fact, very careful attention was given to both groups in the ICU, and consequently, the differences in VAPS scores, although statistically significant, were relatively modest. The study of Yeager et al. (11) has been criticized (26) for providing poor analgesia in the patients not given epidural analgesia.

It is also possible that our end points were insufficiently sensitive or even the incorrect choices to enable detection of reduction of stress. We specifically avoided end points without definitive clinical consequences, such as plasma cortisol, catecholamine, or other hormonal concentrations. Had we found that intrathecal opioid administration decreased the postoperative concentrations of one or more of these compounds, we would not have been able to relate that finding directly to a clinically important outcome. Rather, we specifically assessed the clinically important major complications that occur after abdominal aortic surgery, but are thought not to be primarily related to the surgical procedure per se.

We did not include myocardial ischemia as an end point. Although the intraoperative occurrence of myocardial ischemia is associated with increases in the adverse outcome of myocardial damage or infarction, this may be only a reflection of the severity of the patient’s underlying coronary artery disease. Others have recognized that myocardial ischemia is merely a surrogate measure of the potential for adverse cardiac outcomes, rather than an adverse outcome per se (28). Consequently, we did not include myocardial ischemia as a major adverse event, but used a more definitive adverse outcome, myocardial damage or infarction. Furthermore, we relied on serum Tn I concentrations, rather than ECG changes for establishing these diagnoses. This approach, based on very specific biological markers of myocardial cell death, has become a standard for myocardial infarction (28–30) and has been associated with an increased detection rate of postoperative myocardial infarction (30,31) and cardiac complications (17) in comparison to the more conventional approach using ECG or plasma creatine kinase concentrations, implying a greater sensitivity of plasma Tn I concentrations. Our results support these previous observations: only 2 of the 4 patients in the IT group and 3 of the 8 patients in the control group with Tn I plasma concentrations >1.5 ng/mL had ECG changes diagnostic of myocardial infarction. The high sensitivity of plasma Tn I concentration for detection of myocardial infarction (32) allows for earlier diagnosis than does assessment of ECG or plasma creatine kinase changes (29–32). For diagnosis of myocardial damage or acute myocardial infarction, we chose values of plasma Tn I more than the upper limit of normal of our laboratory (0.3 ng/mL) and 1.5 ng/mL, respectively, as has been validated in surgical and medical settings (17,18,30,32). Our finding of myocardial damage/infarction rates of 10.5% in the treated group and 12.5% in the control group is similar to other reports of patients undergoing similar procedures (32,33).

Similarly, for other organs, we chose end points that are not likely to be related to the surgery per se, but those with substantial clinical implications. We chose to assess renal function because stress is a principal activator of the renin-angiotensin system, which can interfere with postoperative renal function (34). An increase of serum creatinine concentration of ≥50% requires a substantial loss of renal glomerular function. We did not use postoperative length of hospital stay as an outcome measure because at our institution, many factors, of which patient readiness is but one, influence this variable.

We included major respiratory complications because they occur frequently after abdominal surgery (35), and neuraxial opioid administration has been reported to decrease their incidence (36). Conversely, application of neuraxial opioids can induce respiratory depression, which infrequently can be severe (37). Postoperative respiratory depression occurred in the IT group as reflected by hypercapnia (Table 5) but was not associated with more frequent tracheal reintubation or more frequent need for the administration of naloxone. The maximal increase in PaCO₂ and the delay for its peak value were in the same ranges as previously reported in volunteers after the administration of 0.4–0.6 mg of intrathecal morphine (37). This level of respiratory acidosis has very limited effects on coronary blood flow and cardiac metabolism of patients with coronary artery disease (35). However, supplemental nasal oxygen is required to avoid hypoxemia (37). The incidence of major respiratory complications was similar in the two groups; however, our study was not powered to detect differences in respiratory complications alone.

The duration of our intervention may not have been adequate to test our hypothesis. The neuraxially administered opioid provided for intraoperative and postoperative analgesia through the initial 16 postoperative hours. The peak incidence of myocardial infarction after surgery is within the first 24 hours (29–31). However, the analgesia provided by our opioids administered intrathecally did not likely cover the entire important period of the etiology of stress contributing to the eventual development of its major clinical consequences. Thus, any putative effect of neuraxial opioids on reduction of stress-related major complications might have been effective for an insufficient period of time. We recognized this potential problem before initiation of this study, but were constrained in extending the neuraxial opioid administration for a longer postoperative period. In our institution, patients given postoperative neuraxial analgesia must be observed in an ICU, and there are an insufficient number of available ICU beds at most times to have guaranteed appropriate care of these patients based solely on study considerations. The duration of the stay in an ICU imposed by an intrathecal administration of opioids is well suited to our setting. Our study would have been unalterably confounded and made uninterpretable by a variable duration of neuraxial administration of opioids that would have been imposed by the logistical issue of being able to retain some, but not all patients in the ICU. Indeed, in a recently published study (24) designed to provide 72 hours of postoperative epidural anesthesia, in the group to be given epidural analgesia, 50% of the patients failed to complete the protocol rendering results of uncertain meaning. Nevertheless, our results do not exclude the possibility that a more protracted application of neuraxial opioids might have produced different findings.

The number of patients studied may have been too small to detect the difference we sought. Historical data from our institution indicated a somewhat more frequent complication rate (approximately 35%) than the observed overall major complication rate of 28% in our study. Thus, although a priori our study was adequately powered, to have had an 80% likelihood to detect a difference between groups ( of 0.05), the observed incidence of complications would have required studying approximately 650 patients to achieve that likelihood of detecting a difference.

Finally, we chose a large reduction of complications (50%) as our a priori outcome measure. It may be argued that we sought too large a reduction, and that it would have been more reasonable to attempt to detect a lesser difference, which many might consider clinically significant. Detection of a 25% reduction of major complications would have required a study of >1200 patients, given the overall major complication rate of 28%; detection of a reduction of 10% of major complications would have required a study of approximately 8000 patients. When designing this study, we judged that we would not be able to achieve these numbers in a reasonable period of time, without clinical practice changing substantially during the course of the study. Such changes might have invalidated the study. Indeed, most of these procedures at our institution are now performed by an endovascular technique, and thus, the population currently undergoing abdominal vascular surgery differs from that in this study. Similarly, we designed this study to be performed at a single center to avoid the heterogeneity imposed by differing surgical and postoperative practices. Despite the limitation of a study designed to detect only the large difference of a 50% reduction of major complications, no similar study has had more than the 100 patients per group that we studied.

Our study was not designed to specifically examine mortality. Overall in-hospital mortality was 4.1%. If the mortality incidence in the two groups is an accurate reflection of the two populations, a study of approximately 750–800 patients would be required with an 80% likelihood to detect a statistically significant difference (with an of 0.05) between the two groups. We also did not design our study to enable detection of changes in the rate of myocardial infarction. If the incidence of myocardial infarction in the two groups is an accurate reflection of the two populations, a study of >8000 patients would be required with an 80% likelihood to detect a statistically significant difference (with an of 0.05) between the two groups.

The lack of blinding in our study deserves comment. We considered this issue when planning this study, but decided that it would not be possible to maintain the blinding because the difference in postoperative pain would be obvious. Therefore, to assess complications, we chose biological markers, which are not subject to observer bias. Nevertheless, although unlikely, bias could have influenced the results. If it did, it is more likely that the bias would have been in favor of a positive effect for neuraxial analgesia (and against the study outcome), because this was our belief and hypothesis.

In summary, within the limits discussed above, we have found, in patients undergoing major abdominal vascular surgery, that provision of more intense analgesia for the initial postoperative period, via the administration of neuraxial opioid in contrast to IV opioid, does not alter the combined incidence of major cardiovascular, respiratory, and renal complications.

	Acknowledgments

 
This study was funded by the Assistance Publique, Hôpitaux de Paris.

	Footnotes

 
Results of this study have been presented, in part, at the European Society of Anesthesiology.

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