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ANESTHETIC PHARMACOLOGY

Large-Dose Intrathecal Sufentanil Prevents the Hormonal Stress Response During Major Abdominal Surgery: A Comparison with Intravenous Sufentanil in a Prospective Randomized Trial

Paul J. Borgdorff, MD^*, Traian I. Ionescu, MD PhD, Peter L. Houweling, MD PhD^*, and Johannes T. A. Knape, MD PhD

*Department of Anaesthesiology, Diakonessenhuis Hospital, Utrecht, The Netherlands; and Division for Perioperative and Emergency Medicine, University Medical Centre, Utrecht, The Netherlands

Address correspondence and reprint requests to Paul J. Borgdorff, MD, Diakonessenhuis Hospital, PO Box 80250, 3508 TG Utrecht, The Netherlands. Address e-mail to pborgdorff{at}diakhuis.nl

	Abstract

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We studied the effect of large-dose intrathecal sufentanil (ITS) for major abdominal surgery on the hormonal stress response. Forty patients were randomly allocated to receive either IV sufentanil (IVS) or 150 µg of ITS as part of general anesthesia. In the IVS group, adrenocorticotropic hormone (ACTH) and cortisol concentrations were larger than baseline and the ITS group, 60 min after incision and at skin closure. Plasma concentrations of cortisol and ACTH were not different from baseline in the ITS group during surgery. Six hours after skin closure, cortisol concentrations were larger than baseline in both groups. Twenty-four and 48 h after skin closure, ACTH and cortisol values were similar between groups. Norepinephrine concentrations increased after surgery in both groups. Blood glucose levels increased in both groups during and after surgery. Pain scores and morphine consumption during the first 48 h after surgery were lower in the ITS group. The data show that large-dose ITS prevents the intraoperative hormonal stress response in comparison with balanced anesthesia. We speculate that this is due to the highly specific binding of sufentanil to spinal and supraspinal receptors. This technique improves postoperative analgesia when compared with balanced anesthesia.

IMPLICATIONS: This prospective, randomized trial demonstrates that large-dose intrathecal sufentanil (150 µg) as part of combined general and regional anesthesia prevents activation of the hormonal stress response during major abdominal surgery and improves postoperative analgesia in comparison with IV balanced anesthesia.

	Introduction

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The classic hormonal response to trauma is described as activation of the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system interacting with immunological responses (1). Nociceptive stimuli from the site of tissue damage produce responses of different intensity that reflect the severity of the injury (2). These responses, if intense and of long duration, are thought to cause cardiac, pulmonary, renal, or cerebral morbidity; immune suppression; or mortality (3). An important task of the anesthesiologist is, therefore, to prevent this exaggerated stress response.

It has been suggested that the intrathecal (IT) or epidural administration of local anesthetics, with or without opioids, may abolish the stress response in lower abdominal surgery for the duration of the sensory analgesic block (4), but not in upper abdominal surgery (5,6). Unblocked sympathetic (7) or vagal afferents (5), phrenic nerve stimulation (8), and cytokine release from the site of injury (7) have all been implicated in causing stress hormone release. Although it was assumed that a stress-free condition during upper abdominal surgery could be achieved only by using large-dose IV opioid anesthesia, the results are conflicting (9,10). Clinical and experimental results indicate that the IT administration of opioids can be considered a rational method of pain relief (11) as a result of optimal contact with the specific opioid receptors in the spinal cord. It is generally assumed, however, that this technique is not associated with significant perioperative stress modulation (12). In previous studies, it was demonstrated that sufentanil 2 µg/kg IT provides good hemodynamic stability during major vascular surgery (13).

The main goal of this prospective, randomized, blinded study was to study the response of the hormones of the HPA axis, catecholamines, and blood glucose to major abdominal surgery, comparing IV to IT administration of sufentanil, both as part of general anesthesia. The secondary goal was to establish the effect of either technique on postoperative pain scores and morphine consumption.

	Methods

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After approval by the ethics committee, the study was conducted in two centers. Informed consent was obtained from 40 patients between 30 and 65 yr old, ASA physical status I–II, who were undergoing elective major gastrointestinal resection for carcinoma or paraaortic lymph node dissection. Patients with hepatic, renal, pulmonary, neuroendocrine, and cardiovascular diseases were excluded from the clinical trial, as were patients taking medication known to interfere with hemodynamic, hormonal, metabolic, or immunological function. Data from patients sustaining blood loss exceeding 30 mL/kg during surgery were excluded from analysis. One day before the operation, patients received instructions about the use of a patient-controlled analgesia (PCA) device (Pain Management Provider; Abbott Laboratories, North Chicago, IL) and the visual analog scale (VAS) for pain. This scale consisted of an unmarked 100-mm line on which 0 mm represents no pain and 100 mm represents the worst pain imaginable.

The patients did not receive any premedication. Before surgery, the patients were randomized, by drawing sealed envelopes with treatment allocation, into one of two groups to receive IV sufentanil (IVS) or IT sufentanil (ITS) analgesia. Both patients and laboratory staff were blinded to the treatment allocation. After arrival in the operating room, electrocardiogram leads II and V5 were displayed continuously, and a peripheral venous and a radial arterial cannula were inserted. To maintain blinding, in all patients an 18-gauge IT catheter was introduced at L2-3 and threaded 3 to 4 cm into the IT space. The patients were then turned to the supine position. Five minutes thereafter, the following baseline values were recorded at T1: heart rate (HR), systolic arterial blood pressure (SAP), and diastolic arterial blood pressure. Mean arterial blood pressure (MAP) was calculated.

Simultaneously, a blood sample was taken to determine the arterial plasma concentrations of adrenocorticotropic hormone (ACTH), cortisol, epinephrine, norepinephrine, and glucose. All samples in this study were immediately put on ice and centrifuged. They were stored thereafter at –70°C until analysis.

In the IVS group, orotracheal intubation was performed after the induction of general anesthesia with midazolam 0.25 mg/kg, rocuronium 0.5 mg/kg, and sufentanil 50 µg IV and 50% nitrous oxide in oxygen. Sufentanil 20 µg was administered IV every 30 min during surgery. In the ITS group, after the administration of 150 µg of sufentanil IT, general anesthesia was induced by IV midazolam 0.25 mg/kg IV and 50% nitrous oxide in oxygen. Rocuronium 0.5 mg/kg was given to facilitate orotracheal intubation. In both groups, mechanical ventilation of the lungs was adjusted to maintain end-tidal carbon dioxide between 35 and 40 mm Hg. Midazolam 0.07 mg · kg^–1 · h^–1 was administered IV during surgery to ensure adequate depth of anesthesia. If analgesia was considered insufficient during surgery, as indicated by increases compared with baseline in HR (>15 bpm) and SAP (>30 mm Hg), lacrimation, or sweating, 10 µg of sufentanil was injected IV. Increments of rocuronium were injected IV as required.

All patients received lactated Ringer’s solution 15 mL · kg^–1 · h^–1 throughout the operation. We assessed blood loss by measuring suctioned blood and by weighing gauzes and drapes, and we replaced blood with Gelofusine® in a ratio of 1:1 or with packed cells if hemoglobin was <10 g/dL. All fluids were warmed before administration. An upper body Bair Hugger® was used to prevent a marked decrease in body temperature. Hemodynamic measurements, recorded at baseline (T1), were repeated 5 min after orotracheal intubation (T2), 5 min after peritoneal incision (T3), 60 min after peritoneal incision (T4), at skin closure (T5), and at 6 h (T6), 24 h (T7), and 48 h (T8) after skin closure. At the same time intervals, all blood sample measurements were repeated, except for blood glucose at T4. The durations of surgery and mechanical ventilation were recorded. After surgery, all patients received IV fluids at 30 mL · kg^–1 · d^–1 and oral fluids as indicated. All had access to IV analgesia by means of a PCA device containing morphine 0.4 mg/mL. The settings of the PCA device were as follows: no initial loading dose, no continuous background infusion, demand dose 2 mL, lockout period 5 min, and no 4-h maximum. No medication other than the 150 µg of sufentanil in the ITS group was administered through the IT catheter in any patient. The IT catheter was removed 48 h after the end of surgery (14). Peripheral oxygen saturation was recorded continuously after surgery for 24 h. All patients received diclofenac 75 mg every 8 h starting at T6. Pain scores (VAS) were measured in rest and during movement at 6, 24, and 48 h after the end of surgery.

ACTH was measured by using a competitive radioimmunoassay with a polyclonal anti-ACTH antibody (IgG Corp., Nashville, TN), ¹²⁵I-ACTH (CIS Bioindustries, Gif-sur-Yvette, France), and synthetic ACTH (1–39) standard (National Institutes of Health, Bethesda, MD). The interassay coefficient of variation was 14.1% at 28 ng/L (n = 21) and 9.6% at 67 ng/L. Cortisol was measured by using the Abbott TDx analyzer (Abbott Laboratories), a fluorescence polarization immunoassay. The coefficient of variation was 5.6% at 0.23 µmol/L (n = 25). Epinephrine and norepinephrine plasma levels were measured with high-pressure liquid chromatography. Blood glucose was measured on a Vitros 250 clinical chemistry analyzer (Johnson & Johnson Clinical Diagnostics, Inc., Rochester, NY) by using a glucose oxidase method. The interassay coefficient of variation was 1.7% at 4.8 mmol/L.

Data are presented as mean ± SD, except for side effects, which are expressed as incidence. SPSS 11.5 for Windows (SPSS Inc., Chicago, IL) software was used for statistical analysis. Continuous variables were analyzed by using repeated-measures of variance with Bonferroni’s correction. Categorical variables were analyzed by using Fisher’s exact test or ² tests, as appropriate. Because the covariance matrices were not equal across groups, the results of the ACTH plasma concentration were log-transformed before analysis. A P value <0.05 was considered statistically significant.

	Results

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Forty patients were enrolled in the study. One patient in the IVS group had >40 mL/kg blood loss during right hemicolectomy, and there was a violation of protocol in a patient in the ITS group. Data from these patients were excluded from analysis. Preoperative use of medication was limited to ferrous fumarate (two patients in the ITS group) and fluoxetine (one patient in the IVS group). Hemodynamic data were 100% complete; plasma hormone data were 98.4% complete. There were no differences between groups concerning demographic and surgical data (Table 1).

View larger version (21K): [in this window] [in a new window]   Figure 1. A–E, Comparative mean ± SEM plasma levels over time for adrenocorticotropic hormone (ACTH), cortisol, epinephrine, norepinephrine, and glucose for the IV sufentanil group (IVS; and the intrathecal sufentanil group (ITS; •). F and G, Comparative mean ± SEM heart rate and mean arterial blood pressure (MAP) over time for IVS and ITS. *Significantly different from baseline for IVS; significantly different from baseline for ITS; significantly different between groups.T1 = baseline; T2 = after induction; T3 = after incision; T4 = 1 h after incision; T5 = end of surgery; T6, T7, and T8 = 6, 24, and 48 h after T5, respectively.

HR decreased significantly in the IVS group immediately after the induction of general anesthesia (P < 0.01); HR decreased in the ITS group after peritoneal incision (P < 0.001). It remained lower than baseline throughout surgery in both groups (P < 0.01). MAP decreased after induction in both groups (P < 0.01 and P < 0.001 in the IVS and ITS groups, respectively). In the ITS group, MAP remained less than IVS (P < 0.05) from peritoneal incision to skin closure.

Six hours after surgery, plasma cortisol increased significantly in the IVS group compared with baseline values (P < 0.01). Twenty-four hours after skin closure, ACTH plasma levels were less than baseline in the ITS group. Forty-eight hours after surgery, epinephrine plasma levels in the ITS group were significantly less than baseline (P < 0.001). Norepinephrine levels and blood glucose levels were significantly increased in both groups compared with baseline at 24 and 48 h after skin closure. After surgery, HR and MAP were not different from baseline in either group.

No patients in the ITS group received supplemental IVS. The mean ± SD sufentanil consumption differed between groups (IVS, 119 ± 38 µg; versus ITS, 150 ± 0 µg; P < 0.01). Blood loss was not different between groups (IVS, 394 ± 342 mL; versus ITS, 455 ± 607 mL). The duration of analgesia, defined as the time from the administration of sufentanil as part of the induction of general anesthesia to the first request by the patient for analgesia, was significantly longer in the ITS group (417 ± 192 min) compared with the IVS group (226 ± 81 min; P < 0.001). The duration of mechanical ventilation was also significantly longer in the ITS group (307 ± 103 min) compared with the IVS group (210 ± 91 min; P < 0.01).

Figure 2 shows the VAS scores at 6, 24, and 48 h after skin closure. At rest, pain scores were significantly lower in the ITS group 24 h after skin closure (P < 0.05).

View larger version (26K): [in this window] [in a new window]   Figure 2. Mean ± SEM visual analog scale scores at rest and during movement at 6, 24, and 48 h after skin closure (T6, T7, and T8, respectively) for the IV sufentanil group (IVS) and the intrathecal sufentanil group (ITS). Significantly different between groups.

View larger version (35K): [in this window] [in a new window]   Figure 3. Comparative mean ± SEM postoperative morphine consumption for the IV sufentanil group (IVS) and the intrathecal sufentanil group (ITS) for 0–6 h, 6–24 h, and 24–48 h after skin closure. Significantly different between groups for the cumulative 48-h period.

	Discussion

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This study demonstrates the absence of a hormonal stress reaction during major abdominal surgery and improved postoperative analgesia after ITS in comparison to balanced anesthesia. Sympathetic activation was prevented in both groups, as demonstrated by stable catecholamine concentrations. MAP during surgery, however, was lower than baseline only in the ITS group. Kietzmann et al. (15) reported significant increases in catecholamine levels in geriatric patients during major abdominal surgery after the administration of IVS or IV fentanyl. In patients undergoing abdominal hysterectomy, Moller et al. (16) found only partial suppression of cortisol levels when using large-dose IV alfentanil. Both reports are indicative of the limited modulation of the stress response by IV opioids.

The mechanism of the prevention of HPA axis activation by the administration of ITS may lie in its efficacy at the receptor level and physicochemical properties (17–19). Because of its physicochemical properties, ITS is rapidly cleared from the cerebrospinal fluid by blood (18), leading to high plasma levels. It has been recently demonstrated that IT and IV opioids, when given simultaneously, interact in a supraadditive fashion to produce analgesia in rats (20). It is therefore possible that sufentanil, when given IT, acts on both spinal and supraspinal antinociceptive systems. In addition to the rapid systemic uptake, sequestration of sufentanil in the spinal cord lipids (21) necessitates the administration of a large dose of ITS to cover the entire duration of surgery.

Six hours after surgery, cortisol plasma levels in the IVS group were higher than baseline, but there was no significant difference between groups. High cortisol levels at this time are not unexpected, because this is when hormonal and metabolic responses are thought to be most prominent (22). It would seem that during the immediate postoperative period, the inhibition of nociceptive stimuli is not strong enough to prevent some ACTH release. At that time, plasma levels of sufentanil are probably too low to attenuate the hormonal stress responses effectively (18). Although the increases in ACTH levels were not statistically significant in either group, they still caused stimulation of the adrenal cortex. This activation of the surgical stress response in the immediate postoperative phase—and particularly the continuation of ITS in the postoperative period—deserves further assessment. ACTH and cortisol plasma levels were not higher than their preanesthetic levels 24 and 48 hours after skin closure in either group.

Epinephrine plasma levels remained at or less than baseline during surgery in both groups, indicating a continuous inhibition of the adrenal medulla. Norepinephrine plasma levels followed a distinct pattern whereby they remained at baseline values during surgery but increased in both groups after surgery. Blood glucose levels increased to a similar extent in both groups at skin closure and during the entire postoperative period. Apparently, the intraoperative increase does not depend on catecholamine or cortisol release, because epinephrine, norepinephrine, and cortisol levels were low in the ITS group during surgery.

The duration of analgesia was significantly longer in the ITS group and was comparable with previous observations (23). Likewise, the duration of mechanical ventilation was predictably prolonged in the ITS group, although most patients in the IVS group were also mechanically ventilated in the postoperative period. Both observations are indicative of the residence time of sufentanil in the IT space.

Patients in the ITS group experienced less pain at rest than those in the IVS group during the first 24 hours after surgery and needed less morphine for at least 48 hours after surgery. Akural et al. (24) compared postoperative PCA sufentanil consumption in patients receiving a bolus dose of 50 µg of sufentanil epidurally before versus after abdominal hysterectomy and reported less consumption between 8 and 16 hours in the preemptive-administration group. They attributed their findings to reduced wound sensitization. Conversely, Cooper et al. (25) reported acute opioid tolerance after a small dose of IT fentanyl for cesarean delivery. Chapman et al. (26) propose that in this respect, dose size and timing could be significant in the prevention of windup and sensitization. Our study was not designed to demonstrate a preemptive effect of neuraxial block with large-dose sufentanil, but this possible mechanism deserves further investigation. Another explanation of improved postoperative analgesia in the ITS group could be the absence of a perioperative stress response. Although in clinical practice our decisions are led by clinical symptoms such as HR, MAP, and symptoms of sympathetic stimulation, it seems obvious from our study that these are inadequate variables for the level of stress reduction.

The side effects were relatively few and easy to treat. Nausea occurred equally often in both groups. Postdural puncture headache occurred twice in the ITS group, but not in the IVS group.

In conclusion, we have demonstrated that in major abdominal surgery, a single dose of ITS 150 µg—in contrast with IVS—prevents the intraoperative activation of the HPA axis and the sympathetic system in this category of patients. In addition, this technique provides improved analgesia during the first 24 hours after surgery combined with a reduced morphine requirement in the postoperative phase.

	Acknowledgments

 
Supported by a grant from Janssen-Cilag, Berchem, Belgium, and a grant from the Division for Perioperative and Emergency Medicine, University Medical Centre Utrecht, Utrecht, The Netherlands.

	Footnotes

 
Presented in part at the annual meeting of the American Society of Anesthesiologists, Dallas, TX, October 1999.

	References

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