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Efficacy of Low-Dose Intrathecal Morphine for Postoperative Analgesia After Abdominal Aortic Surgery: A Double-Blind Randomized Study
Efficacy of Low-Dose Intrathecal Morphine for Postoperative Analgesia After Abdominal Aortic Surgery: A Double-Blind Randomized Study Mike Blay, M.D., Jean-Christophe Orban, M.D., Laurent Rami, M.D., Stéphane Gindre, M.D., Régine Chambeau, M.D., Michel Batt, M.D., Dominique Grimaud, M.D., and Carole Ichai, M.D., Ph.D. Background and Objectives: Several studies suggest that intrathecal morphine (ITM) improves analgesia after aortic surgery. We tested the hypothesis that in combination with multimodal postoperative pain management, low-dose ITM associated with general anesthesia would decrease postoperative analgesic requirements in patients undergoing abdominal aortic surgery. Methods: Thirty patients were randomized to receive either general anesthesia alone or preceded by low-dose ITM (0.2 mg) administration. Patients and providers were blinded to treatment. Postsurgical multimodal pain management was similar in both groups, including parenteral paracetamol, followed by intravenous nefopam and then morphine if not sufficient. Intravenous analgesic requirements, visual analog scale (VAS) scores, and the incidence and severity of side effects were recorded for 48 hours after surgery. Results: Intraoperative data were comparable between the 2 groups, except sufentanil consumption, which was significantly lower in the ITM group when compared with the control group (P ⫽ .023). ITM decreased postoperative total-morphine requirements with respect to both the number of patients who received morphine (4 v 12 patients, P ⫽ .003) and the cumulative dose of morphine administered (0 [0-12.4] v 23 [13.9-45.6] mg, P ⫽ .006). VAS scores at rest were higher in the control group than in the ITM group at awakening (P ⬍ .01), at 4 hours (P ⬍ .01) after surgery, and at 8 hours (P ⬍ .05) after surgery but did not differ between groups after this period. Whereas VAS scores on coughing were higher in the control group at awakening (P ⬍ .01) and 4 hours after surgery (P ⬍ .05), no differences were found between groups from 8 hours after surgery. Conclusion: In patients undergoing abdominal aortic surgery, intrathecal morphine (0.2 mg) improves postoperative analgesia and decreases the need in intraoperative and postoperative analgesics. Further studies are indicated to evaluate the role of ITM in postoperative recovery. Reg Anesth Pain Med 2006;31:127-133. Key Words:
Aortic surgery, Analgesia, Intrathecal morphine, Pain.
I
ntrathecal opioid administration has been used for postoperative analgesia in a variety of surgical specialities, such as obstetrics1-3 and orthopedics.1,4,5 Despite its efficiency and simplicity, administration of intrathecal morphine (ITM) in the preoperative period has been limited by a high incidence of respiratory depression. However, the use of low-dose
From the Department of Anesthesiology and Critical Care East (M.Bl., J.-C.O., L.R., S.G., R.C., D.G., C.I.) and Service of Vascular Surgery (M.Ba.), Saint-Roch Hospital, University of Nice, Nice, France. Accepted for publication November 10, 2005. Reprint requests: Carole Ichai, M.D., Ph.D., Service de Réanimation, Département d’Anesthésie-Réanimation Est, Hôpital Saint-Roch, CHU de Nice, 06000, France. E-mail: [email protected] © 2006 by the American Society of Regional Anesthesia and Pain Medicine. 1098-7339/06/3102-0006$32.00/0 doi:10.1016/j.rapm.2005.11.010
opioids (⬍0.5 mg) reduces the incidence of opioidrelated side effects in young healthy patients.4-6 Elective abdominal aortic surgery is painful, especially during the first postoperative day. In these patients, who often have a wide range of serious comorbidities, a multidisciplinary approach that includes adequate control of postoperative pain appears to improve postoperative recovery.7,8 Only 2 previous studies have evaluated the analgesic effect of ITM in patients undergoing abdominal aortic surgery.9,10 These studies are difficult to interpret and compare because of different postoperative analgesic management9 and a lack of blinding.10 Moreover, these authors administered high doses of ITM (respectively, 0.8 and 0.5 mg). The efficacy of lowdose ITM has never been evaluated in elderly patients, who may be more susceptible to hypoxemic stress. Therefore, we performed this study in elderly patients to assess the analgesic effects of low-dose
Regional Anesthesia and Pain Medicine, Vol 31, No 2 (March–April), 2006: pp 127–133
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ITM during the first 48 hours after elective abdominal aortic surgery. We tested the hypothesis that with a similar postoperative multimodal pain management, a single intrathecal injection of low-dose (0.2 mg) morphine before general anesthesia would reduce postoperative analgesic requirements, while providing adequate analgesia in elderly patients undergoing major vascular surgery.
Methods Patients With the approval of our Hospital Ethical Research Committee, we recruited consecutively all patients scheduled to undergo elective abdominal aortic aneurysm surgery in a prospective, singlecenter, randomized, double-blind clinical trial. Exclusion criteria included (1) chronic respiratory insufficiency, (2) coagulation abnormalities (platelet count less than 100,000/mm3), (3) infection at the puncture site, (4) allergy to morphine, and (5) refusal of spinal anesthesia. After giving written informed consent, patients were randomly allocated to 1 of 2 groups: general anesthesia (control group) and general anesthesia plus intrathecal morphine (ITM group). In total, we recruited 42 patients. Study Protocol Spinal Anesthesia. Before induction of general anesthesia, spinal anesthesia was performed at the L3-L4 or L4-L5 intervertebral space, with the patient in the lateral position. In the ITM group, morphine sulfate was diluted (0.1 mg/mL), and 2 mL of the solution was injected into the subarachnoid space through a 27-gauge Whitacre needle. The control group received a subcutaneous injection of 2 mL of sterile saline through a standard needle. All patients were then placed in the supine position. Patients, intraoperative physicians (anesthesiologists and surgeons), and nurses were blinded to the treatment. Preoperative and Intraoperative Management. All patients were visited on two occasions: 21 days before surgery and the evening before surgery. Coagulation treatments were all stopped 7 days before surgery. The anesthetic management was standardized. Premedication consisted of 6 mg of oral bromazepam 100 minutes before patients were transferred to the operating room. After preoxygenation, general anesthesia was induced with propofol (2 mg/kg) or sodium thiopentone (4 mg/kg), sufentanil (0.1 g/kg), and atracurium (0.6 mg/kg) to facilitate orotracheal intubation. Anesthesia was maintained with nitrous oxide, sevoflurane (0.6% to 1%), and atracurium (0.3 mg/kg/h). Sufentanil
was administered intravenously by a continuous infusion (0.2 to 0.5 g/kg/h). The doses of sevoflurane and sufentanil were adjusted in both groups to maintain hemodynamic stability. Hemodynamic instabilty was defined as a variation in blood pressure or heart rate exceeding 20% from baseline values. Invasive arterial pressure (arterial catheter), heart rate (electrocardiogram), oxygen saturation (SpO2), central temperature, respiratory frequency, ETCO2 (capnograph), and diuresis (bladder catheter) were continuously monitored during anesthesia. A central venous catheter and a nasogastric tube were placed for all patients. Intravenous fluid infusion consisted of 0.9% sodium chloride and additional volume expansion with a mixture of colloid (Gelofusine 4%; B Braun Medical, Boulogne, France) and 6% hydroxyethylstarch (Voluven; Fresenius Kabi, France). Autologous transfusion was performed systematically, and packed red cells were administered according to both intraoperative blood losses and concentration of hemoglobin (-hemoglobin; Hemocue AB, Sweden). Forced-flow warm air devices were used throughout surgery. Two surgeons with a similar technique (transverse incision) performed all operations reported in this study. At the end of the procedure, sevoflurane and nitrous oxide were discontinued. All patients were extubated in the ICU. The tracheal tube was removed when the patients met classic criteria (spontaneous breathing without hypercapnia and stable hemodynamic condition) and normothermia. In case of hypothermia (⬍36°C), sedation (propofol ⫹ sufentanil) and orotracheal intubation were maintained until normothermia was reestablished. Postoperative Management. All patients were admitted into the ICU for 24 to 48 hours. After this period and in the absence of complications, patients returned to their original surgical unit. When the endotracheal tube was removed, all patients received oxygen via a face mask to maintain SpO2 at ⬎94% throughout the study period. Arterial blood gases were measured after the patients regained consciousness and extubation, 4 hours later, then every 6 hours during 24 hours. All patients received i.v. nonfractionated heparin by a continuous infusion to achieve a blood concentration of heparin of between 0.2 to 0.3 U/mL. Patients were asked to rate their pain on the visual analog scale (VAS) at rest and on coughing (graded from 0 to 100) every 4 hours during the first 12 hours, and then every 12 hours until 48 hours. Pain severity was evaluated by nurses blinded to the treatment group. In both groups, 2 analgesics were administered to treat postoperative pain before morphine was required. Paracetamol belongs to the central and peripheral analgesic
Intrathecal Morphine and Abdominal Aortic Surgery
class.11 Nefopam is a nonopioid benzoxazocine central analgesic,12,13 which also inhibits monoamine uptake.14 Both molecules are efficient and commonly used to treat postoperative pain in Europe.15 The postoperative analgesia protocol consisted of a systematic administration of 1 g of i.v. paracetamol at the end of the procedure and every 6 hours after surgery. We considered VAS score above 30 to indicate a persistent pain that required additional analgesia management. In this case, patients received a bolus of 20 mg of i.v. nefopam, followed by a continuous infusion of 120 mg/day. If the patient continued to complain of excessive pain (VAS score ⬎30) 45 minutes after the beginning of the nefopam infusion, additional titration with i.v. morphine was given that consisted of 3 mg of morphine every 10 minutes until the VAS score was less than 30. After the end of the titration, two thirds of the cumulative dose of morphine was administered subcutaneously, followed by half of the dose every 4 hours. This management corresponds to the routine protocol in our institution. Side effects, including hypoxemia (SpO2 ⬍94%) bradypnea (respiratory rate ⬍8/min), hypercapnia (ETCO2 ⬎50 mm Hg), nausea, vomiting, pruritus, and headache were recorded every hour over the 48-hour study period in the ICU. We recorded within-hospital mortality and major postoperative complications that occurred during hospitalization, including congestive cardiac failure, acute renal failure that required extrarenal therapy, pulmonary and urinary infections that required antibiotherapy, lobar atelectasis, unusual delayed transit, and encephalopathy. Statistical Analysis. Nonpublished personal data showed that patients undergoing elective abdominal aortic surgery required a mean dose of 25 ⫾ 5 mg of morphine during the 24 hours after surgery. Comparable data are published from other abdominal surgical studies.16,17 On the basis of these data, we postulated that a total sample size of 30 patients (15 pairs) would be required to detect a 20-mg reduction in the 24-hour morphine consumption with a statistical power of 90% and a significance level of .05. Because of a nonparametric distribution, continuous variables were analyzed by use of a MannWhitney rank-sum test for unpaired comparisons between groups and a Wilcoxon test for intragroup paired comparisons. Chi-square and Fisher exact tests were appropriately used for categorical data. A value of P ⬍ .05 was considered to indicate a statistical significance. Data are presented as mean (SD) for the parametric data, median (25th to 75th percentiles) for data without normal distribution, or as a number (percentage).
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Eligible patients on elective operating list n = 42 Excluded patients n = 10 . 2 contraindications for ITM . 8 refused to participate
Randomized patients n = 32
Control group n = 16
ITM group n = 16 1 withdrew (protocol violation)
1 withdrew (early post-operative death)
Control group 15 patients analyzed
ITM group 15 patients analyzed
Fig 1. Study trial.
Results Forty-two consecutive patients were enrolled over a 12-month period (Fig 1). Ten patients were not randomized because of refusal to participate or ITM contraindication. Thirty-two patients were enrolled and randomized to each group, but 1 patient in each group was excluded from analysis because of early postoperative death related to an acute heart failure in the control group and a protocol violation in the ITM group. Finally, this study included 15 patients in each group. No neurologic or infectious complication resulted from the intrathecal morphine procedure. Patient demographic and intraoperative data were similar between the 2 groups (Tables 1 and 2). The median dose of sufentanil during surgery was significantly lower in the ITM group compared with the control group (0.59 [0.49-0.86] g/kg v 1.11 [0.74-1.53] g/kg, P ⫽ .023). Differences were seen between groups in most data concerning the postoperative period (Table 3). Mortality was comparable between the 2 groups. Although higher in the control group, the number of patients who experienced postoperative complications did not reach significant difference when compared with the ITM group (Table 3). PaCO2 and PaO2 were measured when patients were spontaneously ventilated immediately after extubation, at 4 hours and at every 6 hours, throughout the following 20 hours. These data were similar and remained within the normal range in both groups (Table 4). One patient from each group experienced an episode of hypercapnia that did not require any treatment and disappeared spontaneously.
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Regional Anesthesia and Pain Medicine Vol. 31 No. 2 March–April 2006 Table 1. Demographic and Preoperative Characteristics
Characteristics Age (y) Sex (male) Weight (kg) Preoperative PaCO2 (mm Hg) Preoperative PaO2 (mm Hg) ASA physical status III IV Comorbidities Coronary artery disease Arterial hypertension Hypercholesterolemia Diabetes requiring treatment COPD Therapeutics -adrenergic antagonists ACE inhibitors Ca2⫹ channel antagonists Diuretics Salicylates-antiagregants Statins Type of surgery Aortoaortic tube Aortobiiliac artery graft bypass Aortobifemoral artery graft bypass
Control Group (n ⫽ 15)
Intrathecal Morphine Group (n ⫽ 15)
70 ⫾ 12 14 (93) 71 ⫾ 13 38 ⫾ 4 84 ⫾ 10
71 ⫾ 10 13 (87) 78 ⫾ 12 38 ⫾ 3 80 ⫾ 10
10 (66) 5 (33)
11 (73) 4 (27)
4 (26.7) 8 (53.3) 8 (53.3) 0 (0) 5 (33.3)
7 (46.6) 10 (66.7) 5 (33.3) 1 (6.7) 2 (13)
1 (7) 5 (33.3) 3 (20) 2 (13) 6 (40) 3 (20)
3 (20) 2 (13) 5 (33.3) 5 (33.3) 4 (26.7) 3 (20)
6 (40) 4 (26.6) 5 (33.3)
4 (26.6) 9 (60) 2 (13.3)
NOTE. Values are mean ⫾ SD for symetric continuous variables and number (%) for categorical variables. No significant differences are seen between groups for any variables. Abbreviations: COPD, chronic obstructive pulmonary disease, ACE, angiotensin-converting enzyme.
Cumulative morphine doses (including the titrated dose) after surgery are shown in Figure 2. Morphine requirements were significantly less in patients who received ITM than in the control group throughout the entire study period. Intragroup pairwise comparisons showed that morphine requirements remained negligible and unchanged over time in the ITM group. Conversely, the cumulative median dose of morphine increased significantly from awakening to 36 hours in the control group, but no significant difference was found between 36 and 48 hours after surgery. All patients
Table 3. Postoperative Characteristics and Major Complications During Hospitalization
Characteristics Time to extubation (min) Duration of hospital stay (days) Side effects Pruritus Nausea Vomiting Sleepiness Headache Respiratory depression Number of i.v. rescue morphine titration Survival Major complications Delayed transit (⬎3 days) Infectious pneumonia Lobar atelectasis Congestive heart failure Septic encephalopathy Urinary infection Reintervention for hemorrhage (retroperitoneal hematoma) Total number of complications
Control Group (n ⫽ 15)
Intrathecal Morphine Group (n ⫽ 15)
60 (15–158) 13 (8–15)
83 (30–240) 12 (9–13)
1 (6.6) 5 (33.3) 1 (6.6) 0 (0) 1 (6.6) 0 (0)
4 (26.6) 3 (20) 2 (13.3) 2 (13.3) 0 (0) 0 (0)
12 (80) 13 (86.6)
4 (26.6)* 14 (93.3)
0 (0) 2 (13.3) 1 (6.6) 1 (6.6) 1 (6.6) 1 (6.6)
2 (13.3) 1 (6.6) 0 (0) 0 (0) 0 (0) 0 (0)
1 (6.6) 7 (46.7)
0 (0) 3 (20)
NOTE. Values are median (25th to 75th percentiles) for continuous variables and number (%) for categorical variables. *P ⬍ 0.01 compared with the control group.
except 1 and 2, respectively, in the ITM group and the control group received postoperative nefopam. The number of patients who needed postoperative morphine administration was significantly smaller in the ITM group compared with the control group (4 patients v 12 patients, P ⫽ .003) (Table 3). Moreover, the time to first request of analgesics was significantly longer in the ITM group than in the control group: (4 [1-20.5] hours v 0.5 [0-1] hours, P ⫽ .006) for nefopam and (21 [13.5-30] hours v 3 [1-12.5] hours, P ⫽ .029) for titration of morphine. Pain was relatively well controlled throughout the 48 hours after surgery in both groups, as the VAS scores at rest remained under 30 after the first 4 hours after surgery (Fig 3A). Comparisons be-
Table 2. Intraoperative Characteristics Characteristics
Control Group (n ⫽ 15)
Intrathecal Morphine Group (n ⫽ 15)
Duration of surgery (min) Duration of aortic clamping (min) Intraoperative fluid administration (mL) Packed erythrocytes (units) Autologous transfusion (mL) Intraoperative hemodynamic instability (%) Ephedrine (mg)
180 (180–225) 60 (60–89) 3,500 (2,500–3,500) 0 (0–1.8) 340 (198–493) 8 (53) 3 (0–6)
180 (180–285) 73 (45–90) 3,500 (3,000–4,000) 1 (0–2) 355 (230–450) 7 (46.6) 3 (0–12)
NOTE. Values are median (25th to 75th percentiles) for continuous variables and number (%) for categorical variables. No significant differences are seen between groups for any variables.
Intrathecal Morphine and Abdominal Aortic Surgery
A
Table 4. Postoperative PaO2 and PaCO2 in Patients with Spontaneous Ventilation
PaO2 (mm Hg) Awakening H4 H10 H16 H22 PaCO2 (mm Hg) Awakening H4 H10 H16 H22
Control Group (n ⫽ 15) 128 (103–174) 134 (111–155) 130 (106–134) 123 (98–147) 104 (100–124)
122 (103–133) 126 (111–155) 106 (94–173) 122 (99–154) 126 (102–146)
39 (35–44) 39 (37–42) 38 (38–43) 39 (36–42) 38 (36–40)
41 (39–43) 41 (38–45) 41 (38–43) 40 (37–44) 37 (33–42)
Fig 2. Cumulative morphine consumption during the 48 hours after surgery. Box plots represent median (25th to 75th percentiles), with bars showing the range (10th to 90th percentiles). *P ⬍ .05 between groups; **P ⬍ .01 between groups.
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control group
**
70 50
*
30 10 -10 awakening
B
NOTE. Values are median (25th to 75th percentiles). No significant differences are seen between groups for any variables.
H4
H8
H12
H24
H36
H48
H8
H12
H24
H36
H48
**
90 VAS score on coughing
tween groups showed that VAS scores at rest were significantly higher during the first 8 hours after surgery in the control group compared with the ITM group. From H12 to H48, VAS scores at rest were lower and comparable between both groups. The VAS scores at rest remained low and unchanged over time in the ITM group, whereas they decreased significantly until 8 hours after surgery in the control group. Patients in the control group had significantly higher VAS scores on coughing at awakening and at H4 than those in the ITM group (Fig 3B). From H8 to H48, no significant difference was found for VAS scores on coughing between groups. VAS score on coughing was significantly higher immediately after surgery (awakening) compared with all the following hours in the control group. Patients in the ITM group had unchanged VAS scores on coughing throughout the 48 hours after surgery.
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intrathecal morphine group
90
VAS score at rest
Variable
Intrathecal Morphine Group (n ⫽ 15)
**
•
*
70 50 30 10 -10 awakening
H4
Fig 3. Visual analog scale (VAS) score (A) at rest and (B) on coughing during the 48 hours after surgery. Box plots represent median (25th to 75th percentiles), with bars showing the range (10th to 90th percentiles). *P ⬍ .05 between groups; **P ⬍ .01 between groups.
Discussion The main finding of this study is that preoperative intrathecal low-dose morphine significantly reduces the need for additional morphine during the first 48 hours after elective abdominal aortic surgery. The time of first rescue i.v. analgesic is significantly longer when postoperative multimodal pain management is combined with intrathecal morphine than when used alone. We also found that intrathecal morphine provides superior postoperative analgesia, especially during the first 24 hours after surgery. Finally, intrathecal morphine significantly reduces the intraoperative consumption of sufentanil. Previous studies have shown that preoperative intrathecal morphine improves the quality of postoperative analgesia while it simultaneously reduces postoperative morphine requirements after obstetric1-3 and orthopedic1,5,6 surgery. Recent studies have also demonstrated that low-dose intrathecal morphine provides an effective analgesia without increased respiratory depression after thoracotomy,
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coronary artery bypass,18-22 or major abdominal surgery.23 Despite these previous studies, preoperative intrathecal morphine is still not used routinely in abdominal aortic surgery because of the possibility of increased mortality and morbidity. Indeed, the risk of hemorrhage, respiratory depression, or cardiovascular complications in older patients with more severe comorbidities remains theoretical. Only a few nonblinded studies have demonstrated that spinal analgesia provided adequate analgesia after abdominal aortic surgery.1,9,10,24 Davis9 showed that 0.8 mg of ITM provided an effective and safe early postoperative analgesia in aortic surgery, but postoperative analgesia was not precisely measured, and the method of additional analgesic administration after surgery was different between the 2 groups. In a randomized trial, Fléron et al.10 compared 2 groups of patients undergoing abdominal aortic surgery, who received general anesthesia alone or combined with intrathecal opioid (8 g/kg morphine ⫹ 1g/kg sufentanil). Postoperative pain management was similar in both groups, on the basis of a classic patient-controlled anesthesia after an initial morphine titration. The authors found that intrathecal morphine provided superior analgesia during the first 24 hours after surgery and reduced the need for i.v. morphine during the same period. However, large doses of intrathecal morphine were used in both studies, which led to respiratory depression. Very low doses of ITM (0.05-0.1 mg) provide adequate analgesia with low incidences of side effects in young healthy patients.25 Only 1 study has shown that 0.1 mg of ITM was the optimum dose in elderly patients undergoing arthroplasty.5 We decided to administer 0.2 mg of ITM, which appeared to be the lowest dose sufficient for major painful surgery.16,23 Our study confirms the analgesic efficacy of a low-dose ITM regimen that should not delay tracheal extubation. When we compared our study with previous studies,9,10 we found a more pronounced decrease in postoperative total-morphine consumption and superior analgesia throughout the 48 hours after surgery. Theoretically, the contribution of systemic paracetamol administration followed by a continuous infusion of nefopam before titration of morphine should have applied equally in both groups. However, we can hypothesize a potentiating effect between these analgesics and ITM. Indeed, continuous infusion of nefopam provides adequate analgesia while it spares the dose of morphine in patients undergoing abdominal surgery.15 The peak effect of intrathecal morphine usually occurs between 3 and 7 hours after injection.6,26 As expected from these pharmacologic data, the dura-
tion of improved analgesia was 8 hours in our study. Nevertheless, some studies have shown that intrathecal morphine may also reduce intraoperative pain, which leads to a decrease in intraoperative inhalation agent requirements.27,28 This strongly suggests that the onset of ITM is probably 1 hour or less, which could readily explain our 40% decrease in intraoperative sufentanil requirements. Another explanation is that analgesic effects of ITM may be enhanced in elderly patients.29,30 Our study has some limitations. We included a small number of elderly patients with numerous comorbidities. Thus, we cannot extrapolate our results to other types of patients or surgical procedures. The small number of patients may also be partly responsible for the absence of significant differences between the 2 groups for the frequency of side effects, the time for extubation, the duration of hospital stay, and mortality. However, this study was not designed to investigate these parameters. Finally, we cannot assess the analgesic contribution of paracetamol or nefopam, which might have additive effects with morphine.15 In conclusion, preoperative administration of low-dose intrathecal morphine (0.2 mg) provided superior postoperative analgesia at 48 hours when compared with a multimodal pain-management technique alone in elderly patients undergoing elective abdominal aortic surgery. Intrathecal morphine was associated with a large reduction in both postoperative total-morphine requirements and intraoperative sufentanil consumption. However, we did not observe any difference in the time to tracheal extubation or the duration of hospital stay. Further studies are necessary to evaluate the most appropriate dose of morphine for this type of patient and surgery and to determine the risk/benefit of this technique.
Acknowledgments The authors thank Dr. David Bake, D.M. F.R.C.A. (CHU Necker–Enfants Malades, Paris), and Dr. D.G. Lambert (University of Leicester) for reviewing the paper. The authors are especially grateful to Dr. F. Berthier (Département d’Informatique Médicale, University of Nice) for advice on statistical analysis.
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17. Motamed C, Bouaziz H, Franco D, Benhamou D. Analgesic effect of low-dose intrathecal morphine and bupivacaine in laparoscopic cholecystectomy. Anaesthesia 2000;55:118-124. 18. Liu N, Kuhlman G, Dalibon N, Moutafis M, Levron JC, Fischler M. A randomized, double-blinded comparison of intrathecal morphine, sufentanil and their combination versus IV morphine patient-controlled analgesia for postthoracotomy pain. Anesth Analg 2001;92:31-36. 19. Mason N, Gondret R, Junca A, Bonnet F. Intrathecal sufentanil and morphine for post-thoracotomy pain relief. Br J Anaesth 2001;86:236-240. 20. Alhashemi JA, Sharpe MD, Harris CL, Sherman V, Boyd D. Effect of subarachnoid morphine administration on extubation time after coronary artery bypass graft surgery. J Cardiothorac Vasc Anesth 2000;14: 639-644. 21. Liu SS, Block BM, Wu CL. Effects of perioperative central neuraxial analgesia on outcome after coronary artery bypass surgery. Anesthesiology 2004;101: 153-161. 22. Lena P, Balarac N, Arnulf JJ, Teboul J, Bonnet F. Intrathecal morphine and clonidine for coronary artery bypass grafting. Br J Anaesth 2003;90:300-303. 23. Devys JM, Mora A, Plaud B, Jayr C, Laplanche A, Raynard B, Lasser P, Dabaene B. Intrathecal ⫹ PCA morphine improves analgesia during the first 24 hr after major abdominal surgery compared to PCA alone. Can J Anaesth 2003;50:355-361. 24. Houweling PL, Joosten W. A haemodynamic comparison of intrathecal morphine and sufentanil supplemented with general anaesthesia for abdominal aortic surgery. Eur J Vasc Surg 1993;7:283-290. 25. Yang T, Breen TW, Archer D, Fick G. Comparison of 0.25 mg and 0.1 mg intrathecal morphine for analgesia after cesarean section. Can J Anaesth 1999;46: 856-860. 26. Nordberg G, Hedner T, Mellstrand T, Dahlström B. Pharmacokinetic aspects of intrathecal morphine analgesia. Anesthesiology 1993;79:49-59. 27. Cohen E, Neustein SM. Intrathecal morphine during thoracotomy, Part I: Effect on intraoperative enflurane requirements. J Cardiothorac Vasc Anesth 1993;7: 154-156. 28. Martin-Larrauri R, Mestre C, Barcena A, Canizal JM, de la Torre J. Decrease in isoflurane requirements and of postoperative pain with preanesthetic intrathecal morphine. Rev Esp Anestesiol Reanim 1995;42: 349-351. 29. Pitkanen M, Haapaniemi L, Tuominen M, Rosenberg PH. Influence of age on spinal anesthesia with isobaric 0.5% bupivacaine. Br J Anaesth 1984;56:279282. 30. Cameron AE, Arnold RW, Ghoris MW, Jamieson V. Spinal analgesia using bupivacaine 0.5% plain: Variation in the extent of the block with patient age. Anaesthesia 1981;36:318-323.
Aortic surgery, Analgesia, Intrathecal morphine, Pain.
I
ntrathecal opioid administration has been used for postoperative analgesia in a variety of surgical specialities, such as obstetrics1-3 and orthopedics.1,4,5 Despite its efficiency and simplicity, administration of intrathecal morphine (ITM) in the preoperative period has been limited by a high incidence of respiratory depression. However, the use of low-dose
From the Department of Anesthesiology and Critical Care East (M.Bl., J.-C.O., L.R., S.G., R.C., D.G., C.I.) and Service of Vascular Surgery (M.Ba.), Saint-Roch Hospital, University of Nice, Nice, France. Accepted for publication November 10, 2005. Reprint requests: Carole Ichai, M.D., Ph.D., Service de Réanimation, Département d’Anesthésie-Réanimation Est, Hôpital Saint-Roch, CHU de Nice, 06000, France. E-mail: [email protected] © 2006 by the American Society of Regional Anesthesia and Pain Medicine. 1098-7339/06/3102-0006$32.00/0 doi:10.1016/j.rapm.2005.11.010
opioids (⬍0.5 mg) reduces the incidence of opioidrelated side effects in young healthy patients.4-6 Elective abdominal aortic surgery is painful, especially during the first postoperative day. In these patients, who often have a wide range of serious comorbidities, a multidisciplinary approach that includes adequate control of postoperative pain appears to improve postoperative recovery.7,8 Only 2 previous studies have evaluated the analgesic effect of ITM in patients undergoing abdominal aortic surgery.9,10 These studies are difficult to interpret and compare because of different postoperative analgesic management9 and a lack of blinding.10 Moreover, these authors administered high doses of ITM (respectively, 0.8 and 0.5 mg). The efficacy of lowdose ITM has never been evaluated in elderly patients, who may be more susceptible to hypoxemic stress. Therefore, we performed this study in elderly patients to assess the analgesic effects of low-dose
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ITM during the first 48 hours after elective abdominal aortic surgery. We tested the hypothesis that with a similar postoperative multimodal pain management, a single intrathecal injection of low-dose (0.2 mg) morphine before general anesthesia would reduce postoperative analgesic requirements, while providing adequate analgesia in elderly patients undergoing major vascular surgery.
Methods Patients With the approval of our Hospital Ethical Research Committee, we recruited consecutively all patients scheduled to undergo elective abdominal aortic aneurysm surgery in a prospective, singlecenter, randomized, double-blind clinical trial. Exclusion criteria included (1) chronic respiratory insufficiency, (2) coagulation abnormalities (platelet count less than 100,000/mm3), (3) infection at the puncture site, (4) allergy to morphine, and (5) refusal of spinal anesthesia. After giving written informed consent, patients were randomly allocated to 1 of 2 groups: general anesthesia (control group) and general anesthesia plus intrathecal morphine (ITM group). In total, we recruited 42 patients. Study Protocol Spinal Anesthesia. Before induction of general anesthesia, spinal anesthesia was performed at the L3-L4 or L4-L5 intervertebral space, with the patient in the lateral position. In the ITM group, morphine sulfate was diluted (0.1 mg/mL), and 2 mL of the solution was injected into the subarachnoid space through a 27-gauge Whitacre needle. The control group received a subcutaneous injection of 2 mL of sterile saline through a standard needle. All patients were then placed in the supine position. Patients, intraoperative physicians (anesthesiologists and surgeons), and nurses were blinded to the treatment. Preoperative and Intraoperative Management. All patients were visited on two occasions: 21 days before surgery and the evening before surgery. Coagulation treatments were all stopped 7 days before surgery. The anesthetic management was standardized. Premedication consisted of 6 mg of oral bromazepam 100 minutes before patients were transferred to the operating room. After preoxygenation, general anesthesia was induced with propofol (2 mg/kg) or sodium thiopentone (4 mg/kg), sufentanil (0.1 g/kg), and atracurium (0.6 mg/kg) to facilitate orotracheal intubation. Anesthesia was maintained with nitrous oxide, sevoflurane (0.6% to 1%), and atracurium (0.3 mg/kg/h). Sufentanil
was administered intravenously by a continuous infusion (0.2 to 0.5 g/kg/h). The doses of sevoflurane and sufentanil were adjusted in both groups to maintain hemodynamic stability. Hemodynamic instabilty was defined as a variation in blood pressure or heart rate exceeding 20% from baseline values. Invasive arterial pressure (arterial catheter), heart rate (electrocardiogram), oxygen saturation (SpO2), central temperature, respiratory frequency, ETCO2 (capnograph), and diuresis (bladder catheter) were continuously monitored during anesthesia. A central venous catheter and a nasogastric tube were placed for all patients. Intravenous fluid infusion consisted of 0.9% sodium chloride and additional volume expansion with a mixture of colloid (Gelofusine 4%; B Braun Medical, Boulogne, France) and 6% hydroxyethylstarch (Voluven; Fresenius Kabi, France). Autologous transfusion was performed systematically, and packed red cells were administered according to both intraoperative blood losses and concentration of hemoglobin (-hemoglobin; Hemocue AB, Sweden). Forced-flow warm air devices were used throughout surgery. Two surgeons with a similar technique (transverse incision) performed all operations reported in this study. At the end of the procedure, sevoflurane and nitrous oxide were discontinued. All patients were extubated in the ICU. The tracheal tube was removed when the patients met classic criteria (spontaneous breathing without hypercapnia and stable hemodynamic condition) and normothermia. In case of hypothermia (⬍36°C), sedation (propofol ⫹ sufentanil) and orotracheal intubation were maintained until normothermia was reestablished. Postoperative Management. All patients were admitted into the ICU for 24 to 48 hours. After this period and in the absence of complications, patients returned to their original surgical unit. When the endotracheal tube was removed, all patients received oxygen via a face mask to maintain SpO2 at ⬎94% throughout the study period. Arterial blood gases were measured after the patients regained consciousness and extubation, 4 hours later, then every 6 hours during 24 hours. All patients received i.v. nonfractionated heparin by a continuous infusion to achieve a blood concentration of heparin of between 0.2 to 0.3 U/mL. Patients were asked to rate their pain on the visual analog scale (VAS) at rest and on coughing (graded from 0 to 100) every 4 hours during the first 12 hours, and then every 12 hours until 48 hours. Pain severity was evaluated by nurses blinded to the treatment group. In both groups, 2 analgesics were administered to treat postoperative pain before morphine was required. Paracetamol belongs to the central and peripheral analgesic
Intrathecal Morphine and Abdominal Aortic Surgery
class.11 Nefopam is a nonopioid benzoxazocine central analgesic,12,13 which also inhibits monoamine uptake.14 Both molecules are efficient and commonly used to treat postoperative pain in Europe.15 The postoperative analgesia protocol consisted of a systematic administration of 1 g of i.v. paracetamol at the end of the procedure and every 6 hours after surgery. We considered VAS score above 30 to indicate a persistent pain that required additional analgesia management. In this case, patients received a bolus of 20 mg of i.v. nefopam, followed by a continuous infusion of 120 mg/day. If the patient continued to complain of excessive pain (VAS score ⬎30) 45 minutes after the beginning of the nefopam infusion, additional titration with i.v. morphine was given that consisted of 3 mg of morphine every 10 minutes until the VAS score was less than 30. After the end of the titration, two thirds of the cumulative dose of morphine was administered subcutaneously, followed by half of the dose every 4 hours. This management corresponds to the routine protocol in our institution. Side effects, including hypoxemia (SpO2 ⬍94%) bradypnea (respiratory rate ⬍8/min), hypercapnia (ETCO2 ⬎50 mm Hg), nausea, vomiting, pruritus, and headache were recorded every hour over the 48-hour study period in the ICU. We recorded within-hospital mortality and major postoperative complications that occurred during hospitalization, including congestive cardiac failure, acute renal failure that required extrarenal therapy, pulmonary and urinary infections that required antibiotherapy, lobar atelectasis, unusual delayed transit, and encephalopathy. Statistical Analysis. Nonpublished personal data showed that patients undergoing elective abdominal aortic surgery required a mean dose of 25 ⫾ 5 mg of morphine during the 24 hours after surgery. Comparable data are published from other abdominal surgical studies.16,17 On the basis of these data, we postulated that a total sample size of 30 patients (15 pairs) would be required to detect a 20-mg reduction in the 24-hour morphine consumption with a statistical power of 90% and a significance level of .05. Because of a nonparametric distribution, continuous variables were analyzed by use of a MannWhitney rank-sum test for unpaired comparisons between groups and a Wilcoxon test for intragroup paired comparisons. Chi-square and Fisher exact tests were appropriately used for categorical data. A value of P ⬍ .05 was considered to indicate a statistical significance. Data are presented as mean (SD) for the parametric data, median (25th to 75th percentiles) for data without normal distribution, or as a number (percentage).
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Eligible patients on elective operating list n = 42 Excluded patients n = 10 . 2 contraindications for ITM . 8 refused to participate
Randomized patients n = 32
Control group n = 16
ITM group n = 16 1 withdrew (protocol violation)
1 withdrew (early post-operative death)
Control group 15 patients analyzed
ITM group 15 patients analyzed
Fig 1. Study trial.
Results Forty-two consecutive patients were enrolled over a 12-month period (Fig 1). Ten patients were not randomized because of refusal to participate or ITM contraindication. Thirty-two patients were enrolled and randomized to each group, but 1 patient in each group was excluded from analysis because of early postoperative death related to an acute heart failure in the control group and a protocol violation in the ITM group. Finally, this study included 15 patients in each group. No neurologic or infectious complication resulted from the intrathecal morphine procedure. Patient demographic and intraoperative data were similar between the 2 groups (Tables 1 and 2). The median dose of sufentanil during surgery was significantly lower in the ITM group compared with the control group (0.59 [0.49-0.86] g/kg v 1.11 [0.74-1.53] g/kg, P ⫽ .023). Differences were seen between groups in most data concerning the postoperative period (Table 3). Mortality was comparable between the 2 groups. Although higher in the control group, the number of patients who experienced postoperative complications did not reach significant difference when compared with the ITM group (Table 3). PaCO2 and PaO2 were measured when patients were spontaneously ventilated immediately after extubation, at 4 hours and at every 6 hours, throughout the following 20 hours. These data were similar and remained within the normal range in both groups (Table 4). One patient from each group experienced an episode of hypercapnia that did not require any treatment and disappeared spontaneously.
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Regional Anesthesia and Pain Medicine Vol. 31 No. 2 March–April 2006 Table 1. Demographic and Preoperative Characteristics
Characteristics Age (y) Sex (male) Weight (kg) Preoperative PaCO2 (mm Hg) Preoperative PaO2 (mm Hg) ASA physical status III IV Comorbidities Coronary artery disease Arterial hypertension Hypercholesterolemia Diabetes requiring treatment COPD Therapeutics -adrenergic antagonists ACE inhibitors Ca2⫹ channel antagonists Diuretics Salicylates-antiagregants Statins Type of surgery Aortoaortic tube Aortobiiliac artery graft bypass Aortobifemoral artery graft bypass
Control Group (n ⫽ 15)
Intrathecal Morphine Group (n ⫽ 15)
70 ⫾ 12 14 (93) 71 ⫾ 13 38 ⫾ 4 84 ⫾ 10
71 ⫾ 10 13 (87) 78 ⫾ 12 38 ⫾ 3 80 ⫾ 10
10 (66) 5 (33)
11 (73) 4 (27)
4 (26.7) 8 (53.3) 8 (53.3) 0 (0) 5 (33.3)
7 (46.6) 10 (66.7) 5 (33.3) 1 (6.7) 2 (13)
1 (7) 5 (33.3) 3 (20) 2 (13) 6 (40) 3 (20)
3 (20) 2 (13) 5 (33.3) 5 (33.3) 4 (26.7) 3 (20)
6 (40) 4 (26.6) 5 (33.3)
4 (26.6) 9 (60) 2 (13.3)
NOTE. Values are mean ⫾ SD for symetric continuous variables and number (%) for categorical variables. No significant differences are seen between groups for any variables. Abbreviations: COPD, chronic obstructive pulmonary disease, ACE, angiotensin-converting enzyme.
Cumulative morphine doses (including the titrated dose) after surgery are shown in Figure 2. Morphine requirements were significantly less in patients who received ITM than in the control group throughout the entire study period. Intragroup pairwise comparisons showed that morphine requirements remained negligible and unchanged over time in the ITM group. Conversely, the cumulative median dose of morphine increased significantly from awakening to 36 hours in the control group, but no significant difference was found between 36 and 48 hours after surgery. All patients
Table 3. Postoperative Characteristics and Major Complications During Hospitalization
Characteristics Time to extubation (min) Duration of hospital stay (days) Side effects Pruritus Nausea Vomiting Sleepiness Headache Respiratory depression Number of i.v. rescue morphine titration Survival Major complications Delayed transit (⬎3 days) Infectious pneumonia Lobar atelectasis Congestive heart failure Septic encephalopathy Urinary infection Reintervention for hemorrhage (retroperitoneal hematoma) Total number of complications
Control Group (n ⫽ 15)
Intrathecal Morphine Group (n ⫽ 15)
60 (15–158) 13 (8–15)
83 (30–240) 12 (9–13)
1 (6.6) 5 (33.3) 1 (6.6) 0 (0) 1 (6.6) 0 (0)
4 (26.6) 3 (20) 2 (13.3) 2 (13.3) 0 (0) 0 (0)
12 (80) 13 (86.6)
4 (26.6)* 14 (93.3)
0 (0) 2 (13.3) 1 (6.6) 1 (6.6) 1 (6.6) 1 (6.6)
2 (13.3) 1 (6.6) 0 (0) 0 (0) 0 (0) 0 (0)
1 (6.6) 7 (46.7)
0 (0) 3 (20)
NOTE. Values are median (25th to 75th percentiles) for continuous variables and number (%) for categorical variables. *P ⬍ 0.01 compared with the control group.
except 1 and 2, respectively, in the ITM group and the control group received postoperative nefopam. The number of patients who needed postoperative morphine administration was significantly smaller in the ITM group compared with the control group (4 patients v 12 patients, P ⫽ .003) (Table 3). Moreover, the time to first request of analgesics was significantly longer in the ITM group than in the control group: (4 [1-20.5] hours v 0.5 [0-1] hours, P ⫽ .006) for nefopam and (21 [13.5-30] hours v 3 [1-12.5] hours, P ⫽ .029) for titration of morphine. Pain was relatively well controlled throughout the 48 hours after surgery in both groups, as the VAS scores at rest remained under 30 after the first 4 hours after surgery (Fig 3A). Comparisons be-
Table 2. Intraoperative Characteristics Characteristics
Control Group (n ⫽ 15)
Intrathecal Morphine Group (n ⫽ 15)
Duration of surgery (min) Duration of aortic clamping (min) Intraoperative fluid administration (mL) Packed erythrocytes (units) Autologous transfusion (mL) Intraoperative hemodynamic instability (%) Ephedrine (mg)
180 (180–225) 60 (60–89) 3,500 (2,500–3,500) 0 (0–1.8) 340 (198–493) 8 (53) 3 (0–6)
180 (180–285) 73 (45–90) 3,500 (3,000–4,000) 1 (0–2) 355 (230–450) 7 (46.6) 3 (0–12)
NOTE. Values are median (25th to 75th percentiles) for continuous variables and number (%) for categorical variables. No significant differences are seen between groups for any variables.
Intrathecal Morphine and Abdominal Aortic Surgery
A
Table 4. Postoperative PaO2 and PaCO2 in Patients with Spontaneous Ventilation
PaO2 (mm Hg) Awakening H4 H10 H16 H22 PaCO2 (mm Hg) Awakening H4 H10 H16 H22
Control Group (n ⫽ 15) 128 (103–174) 134 (111–155) 130 (106–134) 123 (98–147) 104 (100–124)
122 (103–133) 126 (111–155) 106 (94–173) 122 (99–154) 126 (102–146)
39 (35–44) 39 (37–42) 38 (38–43) 39 (36–42) 38 (36–40)
41 (39–43) 41 (38–45) 41 (38–43) 40 (37–44) 37 (33–42)
Fig 2. Cumulative morphine consumption during the 48 hours after surgery. Box plots represent median (25th to 75th percentiles), with bars showing the range (10th to 90th percentiles). *P ⬍ .05 between groups; **P ⬍ .01 between groups.
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control group
**
70 50
*
30 10 -10 awakening
B
NOTE. Values are median (25th to 75th percentiles). No significant differences are seen between groups for any variables.
H4
H8
H12
H24
H36
H48
H8
H12
H24
H36
H48
**
90 VAS score on coughing
tween groups showed that VAS scores at rest were significantly higher during the first 8 hours after surgery in the control group compared with the ITM group. From H12 to H48, VAS scores at rest were lower and comparable between both groups. The VAS scores at rest remained low and unchanged over time in the ITM group, whereas they decreased significantly until 8 hours after surgery in the control group. Patients in the control group had significantly higher VAS scores on coughing at awakening and at H4 than those in the ITM group (Fig 3B). From H8 to H48, no significant difference was found for VAS scores on coughing between groups. VAS score on coughing was significantly higher immediately after surgery (awakening) compared with all the following hours in the control group. Patients in the ITM group had unchanged VAS scores on coughing throughout the 48 hours after surgery.
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intrathecal morphine group
90
VAS score at rest
Variable
Intrathecal Morphine Group (n ⫽ 15)
**
•
*
70 50 30 10 -10 awakening
H4
Fig 3. Visual analog scale (VAS) score (A) at rest and (B) on coughing during the 48 hours after surgery. Box plots represent median (25th to 75th percentiles), with bars showing the range (10th to 90th percentiles). *P ⬍ .05 between groups; **P ⬍ .01 between groups.
Discussion The main finding of this study is that preoperative intrathecal low-dose morphine significantly reduces the need for additional morphine during the first 48 hours after elective abdominal aortic surgery. The time of first rescue i.v. analgesic is significantly longer when postoperative multimodal pain management is combined with intrathecal morphine than when used alone. We also found that intrathecal morphine provides superior postoperative analgesia, especially during the first 24 hours after surgery. Finally, intrathecal morphine significantly reduces the intraoperative consumption of sufentanil. Previous studies have shown that preoperative intrathecal morphine improves the quality of postoperative analgesia while it simultaneously reduces postoperative morphine requirements after obstetric1-3 and orthopedic1,5,6 surgery. Recent studies have also demonstrated that low-dose intrathecal morphine provides an effective analgesia without increased respiratory depression after thoracotomy,
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coronary artery bypass,18-22 or major abdominal surgery.23 Despite these previous studies, preoperative intrathecal morphine is still not used routinely in abdominal aortic surgery because of the possibility of increased mortality and morbidity. Indeed, the risk of hemorrhage, respiratory depression, or cardiovascular complications in older patients with more severe comorbidities remains theoretical. Only a few nonblinded studies have demonstrated that spinal analgesia provided adequate analgesia after abdominal aortic surgery.1,9,10,24 Davis9 showed that 0.8 mg of ITM provided an effective and safe early postoperative analgesia in aortic surgery, but postoperative analgesia was not precisely measured, and the method of additional analgesic administration after surgery was different between the 2 groups. In a randomized trial, Fléron et al.10 compared 2 groups of patients undergoing abdominal aortic surgery, who received general anesthesia alone or combined with intrathecal opioid (8 g/kg morphine ⫹ 1g/kg sufentanil). Postoperative pain management was similar in both groups, on the basis of a classic patient-controlled anesthesia after an initial morphine titration. The authors found that intrathecal morphine provided superior analgesia during the first 24 hours after surgery and reduced the need for i.v. morphine during the same period. However, large doses of intrathecal morphine were used in both studies, which led to respiratory depression. Very low doses of ITM (0.05-0.1 mg) provide adequate analgesia with low incidences of side effects in young healthy patients.25 Only 1 study has shown that 0.1 mg of ITM was the optimum dose in elderly patients undergoing arthroplasty.5 We decided to administer 0.2 mg of ITM, which appeared to be the lowest dose sufficient for major painful surgery.16,23 Our study confirms the analgesic efficacy of a low-dose ITM regimen that should not delay tracheal extubation. When we compared our study with previous studies,9,10 we found a more pronounced decrease in postoperative total-morphine consumption and superior analgesia throughout the 48 hours after surgery. Theoretically, the contribution of systemic paracetamol administration followed by a continuous infusion of nefopam before titration of morphine should have applied equally in both groups. However, we can hypothesize a potentiating effect between these analgesics and ITM. Indeed, continuous infusion of nefopam provides adequate analgesia while it spares the dose of morphine in patients undergoing abdominal surgery.15 The peak effect of intrathecal morphine usually occurs between 3 and 7 hours after injection.6,26 As expected from these pharmacologic data, the dura-
tion of improved analgesia was 8 hours in our study. Nevertheless, some studies have shown that intrathecal morphine may also reduce intraoperative pain, which leads to a decrease in intraoperative inhalation agent requirements.27,28 This strongly suggests that the onset of ITM is probably 1 hour or less, which could readily explain our 40% decrease in intraoperative sufentanil requirements. Another explanation is that analgesic effects of ITM may be enhanced in elderly patients.29,30 Our study has some limitations. We included a small number of elderly patients with numerous comorbidities. Thus, we cannot extrapolate our results to other types of patients or surgical procedures. The small number of patients may also be partly responsible for the absence of significant differences between the 2 groups for the frequency of side effects, the time for extubation, the duration of hospital stay, and mortality. However, this study was not designed to investigate these parameters. Finally, we cannot assess the analgesic contribution of paracetamol or nefopam, which might have additive effects with morphine.15 In conclusion, preoperative administration of low-dose intrathecal morphine (0.2 mg) provided superior postoperative analgesia at 48 hours when compared with a multimodal pain-management technique alone in elderly patients undergoing elective abdominal aortic surgery. Intrathecal morphine was associated with a large reduction in both postoperative total-morphine requirements and intraoperative sufentanil consumption. However, we did not observe any difference in the time to tracheal extubation or the duration of hospital stay. Further studies are necessary to evaluate the most appropriate dose of morphine for this type of patient and surgery and to determine the risk/benefit of this technique.
Acknowledgments The authors thank Dr. David Bake, D.M. F.R.C.A. (CHU Necker–Enfants Malades, Paris), and Dr. D.G. Lambert (University of Leicester) for reviewing the paper. The authors are especially grateful to Dr. F. Berthier (Département d’Informatique Médicale, University of Nice) for advice on statistical analysis.
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