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GENERAL ARTICLES

The Effects of Prostaglandin E₁ on Intraoperative Temperature Changes and the Incidence of Postoperative Shivering During Deliberate Mild Hypothermia for Neurosurgical Procedures

Masahiko Kawaguchi, MD^*, Satoki Inoue, MD^*, Takanori Sakamoto, MD^*, Yoshitaka Kawaraguchi, MD^*, Hitoshi Furuya, MD^*, and Toshisuke Sakaki, MD

Departments of *Anesthesiology and Neurosurgery, Nara Medical University, Nara, Japan

Address correspondence and reprint requests to Masahiko Kawaguchi, MD, Department of Anesthesiology, Neuroanesthesia Research, VA Medical Center, 3350 La Jolla Village Dr., San Diego, CA 92161.

	Abstract

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We investigated the effects of IV prostaglandin E₁ (PGE1) on intraoperative changes of core temperature and the incidence of postoperative shivering in neurosurgical patients undergoing deliberate mild hypothermia. Eighty-three patients were randomly assigned to one of three groups: patients in the control group did not receive PGE1, whereas patients in the PG20 group and PG50 group received PGE1 at a dose of 0.02 and 0.05 µg · kg^-1 · min^-1, respectively. The administration of PGE1 was started just after the induction of anesthesia and continued until the end of anesthesia. Anesthesia was maintained with nitrous oxide in oxygen, sevoflurane, and fentanyl. After the induction of anesthesia, patients were cooled using a water blanket and a convective device blanket. Tympanic membrane temperature was maintained at 34.5°C. During surgical wound closure, patients were rewarmed. Intraoperative changes in tympanic membrane and skin temperatures and the incidence of postoperative shivering were compared among groups. Demographic and intraoperative variables were similar among groups. There were no significant differences in tympanic temperatures among groups at each point during the operation. Skin temperature 30 min after rewarming and just after tracheal extubation was significantly lower in the PG20 group than in the PG50 group. Postoperative shivering was more frequent in the PG20 group (43%) than in the control (13%) and PG50 (17%) groups. These results suggest that the intraoperative administration of PGE1 does not affect changes in core temperature during deliberate mild hypothermia and that PGE1 at a dose of 0.02 µg · kg^-1 · min^-1 may increase the occurrence of postoperative shivering.

Implications: Deliberate mild hypothermia has been proposed as a means of providing cerebral protection during neurosurgical procedures. Vasodilating drugs may be used during deliberate mild hypothermia to maintain peripheral circulation and to enhance the cooling and rewarming rate. In the present study, however, we found no benefit from IV prostaglandin E₁ administration during deliberate mild hypothermia in neurosurgical patients.

	Introduction

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Investigations in laboratory animals have demonstrated that mild hypothermia (2–4°C temperature reduction) is associated with a substantial decrease in histologic damage in models of both global and focal cerebral ischemia (1–3). Deliberate mild hypothermia has been proposed as a means of providing cerebral protection during neurosurgical procedures complicated by cerebral ischemia, such as cerebral aneurysm clipping or arteriovenous malformation resection. Although the effects of mild hypothermia on neurologic outcome in such situations are still unknown (4,5), research into techniques that allow safe management of intraoperative deliberate mild hypothermia seems warranted. This is particularly true because the time available to provide cooling and rewarming is limited.

Prostaglandin E₁ (PGE1) is a potent vasodilator that acts on vascular smooth muscle and that has been used to control blood pressure in patients undergoing neurosurgical procedures, because of its minimal effect on cerebral hemodynamics (6,7). Matsukawa et al. (8,9) reported that the intraoperative administration of PGE1 significantly affected central and peripheral temperatures and decreased the incidence of postoperative shivering during abdominal surgery. We therefore tested the hypothesis that the administration of PGE1 increases the cooling and rewarming rates during deliberate mild hypothermia for neurosurgery and consequently reduces the incidence of postoperative shivering.

	Methods

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After institutional approval and informed consent, 83 patients scheduled to undergo elective neurosurgical procedures in the supine position were enrolled. Patients with symptomatic ischemic heart disease, hepatic or renal disease, or coagulopathy were excluded.

All patients were premedicated with atropine 0.5 mg and famotidine 20 mg IM 30 min preoperatively. Anesthesia was induced with IV thiopental 4–6 mg/kg or propofol 1.5–2.5 mg/kg, fentanyl 1–2 µg/kg, and vecuronium 8 mg. The trachea was intubated, and the lungs were mechanically ventilated. Anesthesia was maintained with 50%–67% nitrous oxide in oxygen, sevoflurane, and supplemental doses of fentanyl. Additional vecuronium was administered as required to maintain one or two mechanical twitches in response to supramaximal train-of-four stimulation of the ulnar nerve at the wrist. Routine monitoring was used. A tympanic membrane probe was inserted in the external auditory meatus on the side opposite of surgery for temperature monitoring by using sterile copper-constantin thermocouple sensors (Mallinkrodt Medical, St. Louis, MO). The probe was taped into place, the aural canal was occluded with cotton, and the external ear was covered with a gauze pad. A skin temperature probe equipped with adhesive (Mallinkrodt Medical) was placed on the surface of the thenar eminence.

A water blanket (American Medical Systems, Cincinnati, OH) was placed under each patient. A convective device blanket (Warm Touch; Mallinckrodt Medical) was applied directly to the ventral body surface. After the induction of anesthesia, active cooling was started. The temperature of the water blanket was set at 15°C, and room-temperature air was circulated by the convective device. Active cooling was stopped at a tympanic membrane temperature of 35°C, and the body temperature was then allowed to decrease. Temperature settings on both the water blanket and the convective device were then adjusted to maintain a target temperature of 34.5°C. After major surgical procedures, such as aneurysm clipping or tumor removal, rewarming was instituted with the water blanket set at 38°C and the convective device at its highest setting (43°C). The arm used to monitor the skin temperature was excluded from the forced-air cover.

Patients were randomly assigned to one of three groups: patients in the control group (n = 31) did not receive PGE1; patients in the PG20 group (n = 28) received IV PGE1 at a dose of 0.02 µg · kg^-1 · min^-1; and patients in the PG50 group (n = 24) received 0.05 µg · kg^-1 · min^-1 IV PGE1. The administration of PGE1 was started just after the induction of anesthesia and continued until the end of anesthesia. Temperatures were recorded at 15-min intervals, starting immediately after the induction of anesthesia when active cooling was started (initial values). Postoperative shivering was evaluated by observers blinded to group assignment and core temperature and was scored as none, mild, moderate, or severe (4).

Morphometric data, clinical data, and changes in temperature among the groups at each time interval were compared using one-way analysis of variance and Scheffé's F-tests. Categorical variables were analyzed by using the 2 or Fisher's exact test. Data are presented as mean ± SD. Differences were considered significant when P < 0.05.

	Results

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Demographic data are shown in Table 1. There were no significant differences in age, gender, weight, height, or coexisting diseases among the three groups. Table 2 shows the comparison of intraoperative variables. There were no significant differences among groups. Intraoperative arterial blood analysis values were also similar among groups (Table 3).

View larger version (32K): [in this window] [in a new window]   Figure 1. Intraoperative changes in tympanic membrane temperature during deliberate mild hypothermia. There were no significant differences among the three groups. Ope end = end of operation; ex = extubation. Data are expressed as mean ± SD.

View larger version (36K): [in this window] [in a new window]   Figure 2. Intraoperative changes in skin temperature during deliberate mild hypothermia. Skin temperature 30 min after rewarming and just after extubation was significantly lower in the PG20 group than in the control group. Ope end = end of operation; ex = extubation. Data are expressed as mean ± SD. * P < 0.05 versus control.

View larger version (30K): [in this window] [in a new window]   Figure 3. Intraoperative changes in heart rate during deliberate mild hypothermia. The heart rate at the beginning of and 15 min after rewarming was significantly higher in the PG20 group than in the control group. Ope end = end of operation, ex = extubation. Data are expressed as mean ± SD. * P < 0.05 versus control.

View larger version (33K): [in this window] [in a new window]   Figure 4. Intraoperative changes in mean arterial blood pressure (MAP) during deliberate mild hypothermia. The MAP 60 and 90 min after the cooling was significantly lower in the PG20 and PG50 groups than in the control group. The MAP 75 and 90 min after the rewarming and at the end of operation was significantly lower in the PG50 group than in the control group. Ope end = end of operation, ex = extubation. Data are expressed as mean ± SD. * P < 0.05 versus control.

	Discussion

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Core hypothermia during general anesthesia develops with three characteristic phases (10–12), which are completely different when extracorporeal circulation is used in cardiac surgery. Initial core hypothermia results from core to peripheral redistribution of body heat when anesthesia inhibits tonic thermoregulation vasoconstriction. Subsequently, heat loss that exceeds metabolic heat production decreases core temperature in a slow, linear fashion. Finally, a core temperature plateau results when resumption of thermoregulatory vasoconstriction decreases cutaneous heat loss and constrains metabolic heat to the core thermal compartment. We hypothesized that vasodilation by PGE1 would enhance the redistribution of body heat and that cutaneous heat loss and would inhibit the thermoregulatory vasoconstriction, resulting in an increased rate of cooling. However, PGE1 did not influence the cooling rate of core temperature during deliberate mild hypothermia in the present study.

Peripheral vasodilation induced by PGE1 might be less than that induced by anesthetics used in the present study and/or may not be efficient in counteracting the active vasoconstriction seen during cooling. Similar observations during mild hypothermic therapy were reported for other vasodilating drugs, such as nicardipine and nitroprusside (13,14). The vasodilatory effects of these drugs may be modified under mild hypothermic conditions. Theard et al. (13) demonstrated that nicardipine was not efficient in counteracting the active vasoconstriction seen during cooling. In contrast, chlorpromazine, an adrenergic blocking drug, has been used extensively to induce hypothermia because it can produce vasodilation even under hypothermic conditions and can enhance the cooling rate during hypothermic therapy (15–17). However, the effect of chlorpromazine on the cooling rate is caused by a central action at the level of the hypothalamus, rather than by a peripheral action (17).

Factors that affect the cooling rate include morphometric characteristics of patients, the presence or absence of vasoconstriction, and the method of cooling (15). Kurz et al. (18) reported that the amount of initial redistribution hypothermia was inversely proportional to the percentage of body fat and the weight to surface area ratio (Wt/SA ratio), and that the cooling rate during the second phase was inversely proportional to the Wt/SA ratio. Intraoperative thermoregulatory vasoconstriction thresholds may be influenced by depth of anesthesia, age, and painful stimulation (19–23). However, because anesthesia and cooling methods were standardized and morphometric data were comparable among the three groups, we believe that the effects of these variables were unimportant in our study.

In our study, the rates of core rewarming were not influenced by the administration of PGE1. Clough et al. (24) tested the hypothesis that thermoregulatory vasoconstriction decreases the cutaneous transfer of applied heat and restricts the peripheral to core flow of heat, thereby delaying and reducing the increase in core temperature. However, the rewarming rate of core temperature (esophagus) was similar during vasoconstriction and vasodilation in anesthetized subjects. Baker et al. (14) also reported that the administration of sodium nitroprusside sufficient to decrease systolic arterial blood pressure by 10% did not speed intraoperative rewarming of tympanic membrane temperature. Their results (14) are compatible with the results obtained in the present study. In contrast, Szmuk et al. (25) reported that residual spinal anesthesia, which maintained lower body vasodilation, significantly increased the rate of postoperative core rewarming (tympanic membrane temperature), which suggests that vasoconstriction decreases peripheral to core heat transfer after general anesthesia.

In the present study, we used PGE1 only at doses of 0.02 and 0.05 µg · kg^-1 · min^-1 and observed no effect on the rate of cooling and rewarming. Large doses of PGE1 may have produced a different result. In a pilot study, we used PGE1 at a dose of 0.1 µg · kg^-1 · min^-1. However, that dose could not be continued in most cases because of unacceptable arterial hypotension.

It was surprising that the incidence of postoperative shivering was significantly more frequent in the PG20 group than in the control and PG50 groups, although the core temperatures at each interval were comparable among the three groups. The mechanisms by which 0.02 µg · kg^-1 · min^-1 PGE1 increased postoperative shivering are unknown. However, there are several possible explanations. Skin temperature in the PG20 group tended to be lower than that in the control and PG50 groups. Skin temperature is an important predictor of postoperative shivering (26,27). Cheng et al. (26) demonstrated that skin and core temperature contribute linearly to the control of shivering and that skin temperature contributed approximately 20% to shivering. Therefore, decreasing skin temperature linearly increases the core temperature threshold for shivering. However, the reasons why skin temperature tended to be lower in the PG20 group are unknown. PGE1 0.02 µg · kg^-1 · min^-1 may increase splanchnic circulation more than peripheral circulation (28). In the present study, we only measured skin temperature on the surface of the thenar eminence. To clarify the relationship between skin temperature and the occurrence of postoperative shivering, area-weighted, mean skin surface temperature or forearm minus fingertip skin surface temperature gradients should be measured in addition to skin blood flow (29).

In summary, the administration of PGE1 did not affect the cooling and rewarming rate of core temperature. Because the skin temperature tended to be lower and the incidence of postoperative shivering significantly higher in patients who received 0.02 µg · kg^-1 · min^-1 of PGE1 compared with the other groups, this dose of PGE1 should be avoided in neurosurgical patients undergoing deliberate mild hypothermia.

	Acknowledgments

 
This work was supported by Grant-in-Aid for Scientific Research C2-08671763 in Japan.

	References

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Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999