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From the Departments of Anesthesiology and Pharmacology, Dalhousie University and Queen Elizabeth II Health Sciences Centre, Halifax, Nova Scotia, Canada.
Address Dr. Richard Hall, Department of Anesthesia, Queen Elizabeth II Health Sciences Centre, 1796 Summer Street, Halifax, Nova Scotia, B3H 3A7 Canada. Phone: 902-473-2328; Fax: 902-473-4828; E-mail: rihall{at}is.dal.ca
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Abstract |
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Methods: In a single centre, open, randomized clinical trial, first time elective CABG surgery patients, < 75 yr, were studied. Control subjects (n=12) received a standardized anesthetic consisting of fentanyl (maximum cumulative dose of 35 µg•kg–1), propofol, and pancuronium. In addition, spinal subjects (n=13) received 1.0 mg (age > 60 yr) or 1.5 mg (age # 59 yr) intrathecal morphine prior to induction of anesthesia. Control subjects received continuous iv morphine at 2 mg•hr–1 on arrival in the ICU with iv bolus morphine supplementation as required while spinal subjects received bolus iv morphine as required. Changes in plasma cortisol and catecholamine concentrations were measured preoperatively, poststernotomy, on admission to ICU, following tracheal extubation, at 0800 hr on the first postoperative day, and 24 and 48 hr after ICU admission.
Results: No differences between groups were detected for demographic variables. The percent change in cortisol concentration relative to preoperative values (control vs spinal; (38 (87) vs –41 (46)%: P < 0.05)) was lower in the spinal group on admission to ICU. The percent change in plasma epinephrine levels (control vs spinal) on admission to ICU (285 (337) vs –10 (37)%) and 0800 hr after surgery (314 (341) vs -4 (37)%) was also significantly different.
Conclusion: Intrathecal morphine only partially attenuated the postsurgical stress response in CABG surgical patients.
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Methods |
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Patients in the intrathecal morphine group <60 yr received 1.5 mg and > 60 yr received 1 mg morphine intrathecally. Induction of anesthesia was with fentanyl up to 10-15 µg•kg–1, propofol up to 2 mg•kg–1 and pancuronium 0.1 mg•kg–1 for muscle relaxation. Following tracheal intubation, anesthesia was maintained via a propofol infusion at 50-200 µg•kg–1•min–1, supplemented by fentanyl to a maximum of 35 µg•kg–1 cumulative dose to maintain mean arterial blood pressure and heart rate within ± 20% of the baseline value obtained at the preoperative visit.
In the ICU, subjects in the control group received 2 mg•hr–1 morphine by continuous iv infusion with additional bolus morphine in amounts of 2 mg as necessary. Subjects in the spinal group received a 2 mg morphine iv bolus when needed for breakthrough pain. Sedation, if required, was provided using propofol.
Stress response was determined by changes in plasma cortisol and catecholamine concentrations. Blood was collected at seven intervals: preoperatively; post-sternotomy; admission to the ICU; at the time of extubation; 0800 hr of the first postoperative day; and at 24 and 48 hr after admission to the ICU. These times were based on likely physiological responses over time and economic limitations.
Catecholamine Analysis: Plasma catecholamine levels were determined using a modification of the methodology of Weicker et al.7 The sensitivity (pg•ml–1) and coefficient of variation (%) for epinephrine was 8 pg•ml–1 and 17%, for norepinephrine 6 pg•ml–1 and 14%, and for dopamine 6 pg•ml–1 and 17%.
Plasma Cortisol Analysis: Plasma cortisol levels were determined using a radioimmunoassay technique (Gamma Coat® Cortisol 125IRIA). The sensitivity was 0.2 µg•dl–1 (0.6 nmol•dl–1) and coefficient of variation was 9%.
For repeated measurements, differences between groups for catecholamine and cortisol levels were analyzed using repeated measures ANOVA. Any test statistic reported as significant was then analyzed post hoc using the Bonferroni t test.
Differences between groups for continuous variables were analyzed using a t test and for discrete variables using Fisher's exact test or chi square analysis.
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. The spinal group received more intraoperative vasopressors such as ephedrine and phenylephrine to support the blood pressure. The total intraoperative dose of fentanyl was not different between groups.
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Discussion |
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During cardiac surgery, activation of the sympathetic nervous system occurs in response to noxious stimuli.8 By blunting the reponse to noxious stimulation, opioids may have a role to play in ameliorating the stress response1,3,4,8,9 but this has been difficult to demonstrate using intrathecal morphine in adults.3
Why might intrathecal opioids fail to completely ameliorate the stress response during cardiac surgery? Catecholamines and other stress hormones may be released by factors other than noxious stimulation e.g. activation of the cytokine network.1 Alternatively, activation of the stress response by noxious stimulation may occur before adequate intrathecal levels of morphine are reached. Support for this hypothesis is provided in this study. Doses of intraoperative fentanyl required to maintain hemodynamic stability were similar between the two groups. The periods of maximum stimuli (e.g. intubation, incision, sternotomy) occur early in the course of surgery and perhaps before adequate levels of intrathecal morphine are achieved (peak onset of activity approximately six hours).5,10 To blunt noxious stimulation occurring at these times, the same amount of intravenous fentanyl would be required whether patients received intrathecal morphine or not. As concentrations of intrathecal morphine increased, this would have a synergistic effect with the previously administered intravenous opioid (hence requirements for more vasoactive agents later on in the course of surgery as occurred in our study) and superior analgesia in the ICU (better VAS score).
In summary, this study demonstrated that intrathecal morphine only partially ameliorated the stress response to cardiac surgery.
Accepted for publication February 2, 2000.
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2 George JM, Reier CE, Lanese RR, Rower JM. Morphine anesthesia blocks cortisol and growth hormone response to surgical stress in humans. J Clin Endocrinol Metab 1974; 38: 736–41.[Medline]
3 Chaney MA, Smith KR, Barclay JC, Slogoff S. Large-dose intrathecal morphine for coronary artery bypass grafting. Anesth Analg 1996; 83: 215–22.[Abstract]
4 Anand KJS, Hickey PR. Halothane-morphine compared with high-dose sufentanil for anesthesia and postoperative analgesia in neonatal cardiac surgery. N Engl J Med 1992; 326: 1–9.[Abstract]
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Etches RC, Sandler AN, Daley MD. Respiratory depression and spinal opioids. Can J Anaesth 1989; 36: 165–85.
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Vandermeulen EP, Van Aken H, Vermylen J. Anticoagulants and spinal-epidural anesthesia. Anesth Analg 1994; 79: 1165–77.
7 Weicker H, Feraudi M, Hagele H, Pluto R. Electrochemical detection of catecholamines in urine and plasma after separation with HPLC. Clin Chim Acta 1984; 141: 17–25.[Medline]
8 Mangano DT, Siliciano D, Hollenberg M et al. Postoperative myocardial ischemia. Therapeutic trials using intensive analgesia following surgery. Anesthesiology 1992; 76: 342–53.[Medline]
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Fitzpatrick GJ, Moriarty DC. Intrathecal morphine in the management of pain following cardiac surgery. A comparison with morphine i.v. Br J Anaesth 1988; 60: 639–44.
10 Nordberg G, Hedner T, Mellstrand T, Dahlstrom B. Pharmacokinetic aspects of intrathecal morphine analgesia. Anesthesiology 1984; 60: 448–54.[Medline]
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