Amrinone can accelerate the cooling rate of core temperature during deliberate mild hypothermia for neurosurgical procedures

S. Inoue1, M. Kawaguchi1, T. Sakamoto1, T. Iwata1, Y. Kawaraguchi1, H. Furuya1 and T. Sakaki2

1Department of Anaesthesiology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan. 2Department of Neurosurgery, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan*Corresponding author

Accepted for publication: December 14, 2000


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
We investigated the effects of i.v. amrinone on intraoperative changes of core temperature during deliberate mild hypothermia for neurosurgery. The patients in a control group (n=10) did not receive amrinone and patients in the amrinone group (n=10) received amrinone 5 µg kg–1 min–1 after a loading dose of 1.0 mg kg–1. Anaesthesia was maintained with nitrous oxide in oxygen, propofol and fentanyl. After the induction of anaesthesia, patients were cooled and tympanic membrane temperature was maintained at 34.5°C. After completion of the main surgical procedures, patients were rewarmed in the operating room. Tympanic membrane temperatures between 30 and 90 min after cooling were significantly lower in the amrinone group than in the control group. During cooling, the times taken to cool to 35°C and to the lowest temperature were significantly shorter in the amrinone group than in the control group. These results suggest that i.v. amrinone can accelerate the cooling rate of core temperature during deliberate mild hypothermia for neurosurgical procedures.

Br J Anaesth 2001; 86: 663–8

Keywords: heart, amrinone; complications, hypothermia; surgery, neurological


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Deliberate mild hypothermia has been proposed as a means of providing cerebral protection during neurosurgical procedures that carry the risk of cerebral ischaemia, such as cerebral aneurysm clipping and arteriovenous malformation resection. Although the effects of mild hypothermia on neurological outcome in such situations are still unknown,13 research into techniques that allow the safe management of intraoperative deliberate mild hypothermia seems warranted.

Vasoconstriction limits the core-to-peripheral redistribution of body heat during cooling and peripheral-to-core heat transfer during rewarming. Several investigators have examined the effects of vasodilating agents, such as prostaglandin E1, nicardipine and sodium nitroprusside, on cooling and rewarming during deliberate mild hypothermia.46 However, these agents did not affect intraoperative temperature management during deliberate mild hypothermia. Mild hypothermia not only promotes thermoregulatory vasoconstriction7 but it also decreases cardiac output as a result of depression of left ventricular contractility,8 which may contribute to poor heat regulation. Therefore, intraoperative temperature management may benefit from inotropic therapy as well as vasodilator therapy.

Amrinone is a phosphodiesterase inhibitor that has inotropic and vasodilatory effects.9 It has been used in neurosurgery to treat vasospasm after subarachnoid haemorrhage,10 although its effects on the cerebral circulation are still not fully understood. We tested the hypothesis that the administration of amrinone accelerates the cooling and rewarming rates of core temperature during deliberate mild hypothermia for neurosurgery.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
After institutional approval and informed consent, 20 patients scheduled to undergo elective neurosurgical procedures in the supine position were enrolled. Patients with symptomatic ischaemic heart disease, hepatic disease, renal disease, coagulopathy and patients who were receiving vasodilator medication were excluded. At the commencement of the active cooling, patients with a tympanic membrane temperature greater than 37.0°C or less than 36.0°C were excluded.

All patients received preoperative medication with a histamine type 2 receptor antagonist (roxatidine 75 mg orally 2 h preoperatively). Anaesthesia was induced with propofol 1.5–2.5 mg kg–1, fentanyl 1–2 µg kg–1 and vecuronium 0.15 mg kg–1. The trachea was intubated and the lungs were ventilated mechanically. Anaesthesia was maintained with 50–67% nitrous oxide in oxygen and propofol 3–5 mg kg–1 h–1, and supplemented with doses of fentanyl and vecuronium. Additional vecuronium was administered as required to maintain one or two mechanical twitches in response to supramaximal electrical stimulation of the ulnar nerve at the wrist. Routine monitoring included electrocardiogram, a radial arterial catheter, a non-invasive blood pressure cuff, pulse oximetry and capnogram. A tympanic membrane probe consisting of copper–constantan thermocouple sensors (Mallinckrodt Medical, St Louis, MO, USA) was inserted in the external auditory meatus on the side opposite surgery for temperature monitoring. The probe was then taped in place, the aural canal occluded with cotton and the external ear covered with a gauze pad. Adhesive skin temperature probes (Mallinckrodt Medical) were placed on the ventral surface of the forearm and the tip of the index finger.

A water blanket (RK1000; American Medical Systems, Cincinnati, OH, USA) was placed under each patient. A polyurethane formed pad covered with a cotton sheet (S-K pad; Asahi Medical Co., Osaka, Japan) protected the patient from direct contact with the water blanket. A convective warming/cooling blanket (Warm Touch; Mallinckrodt Medical) was applied directly to the ventral body surface. The arm used to monitor the skin temperature was not covered by the convective blanket. After the induction of anaesthesia, active cooling was started. The temperature of the water blanket was set at 5°C and air at room temperature was circulated through the convective blanket. Active cooling was stopped at a tympanic membrane temperature of 35°C and body temperature was then allowed to drift downwards. The temperature settings of the water blanket and the convective blanket were then adjusted to maintain a target tympanic membrane temperature of 34.5°C (passive cooling). After completion of the major surgical procedures, active rewarming was instituted with the water blanket set at 41°C and the convective blanket at its highest setting (43°C). Active rewarming was stopped at a tympanic membrane temperature of 35.5°C, and body temperature was then allowed to drift upwards. The temperature settings on the water blanket and the convective blanket were then adjusted to maintain a target tympanic membrane temperature of 36°C (passive rewarming). After the operation, the patient’s trachea was extubated in the operating room.

Patients were assigned randomly to one of two groups; patients in the control group did not receive amrinone, and patients in the amrinone group received with a loading dose of amrinone 1.0 mg kg–1 followed by infusion of amrinone 5 µg kg–1 min–1. The administration of amrinone was started just after the induction of anaesthesia and continued until the end of anaesthesia. Loading of amrinone was performed over approximately 5–10 min. Temperatures were recorded at 15 min intervals, starting immediately after induction of anaesthesia, when active cooling was started (initial values). Temperature gradients of the skin surface (forearm minus fingertip) were calculated. As in a previous study, we considered a temperature gradient <0°C to indicate vasodilation.7 Arterial blood samples were analysed for PaO2, PaCO2, pH, base excess and concentrations of haemoglobin, Na+, K+, glucose and lactate with a commercial blood gas analyser (Chiron 860; Chiron, Tokyo, Japan). Blood samples were collected at the initiation of active cooling and when the target temperature was achieved and were analysed immediately after collection.

Data handling and statistical analysis
Active cooling and rewarming rates (°C h–1) were defined as the slopes of the simple regression lines calculated from plotted core temperature values over time from the beginning of cooling to the time when the temperature reached 35°C, and from the beginning of rewarming to the time when the temperature reached 35.5°C.

Comparisons of changes in haemodynamic variables and temperatures between the two groups were performed by two-way analysis of variance for repeated measures followed by Fisher’s protected least significant difference. Other comparisons between the two groups were carried out with the unpaired Student’s t-test for continuous variables and the {chi}2 test for nominal data. The data are expressed as mean (SEM); differences were considered significant with a P value of <0.05.


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patient characteristics and the type of surgery are shown in Table 1. Intraoperative changes in tympanic membrane temperature and skin surface temperature gradient (forearm minus fingertip) are shown in Fig. 1. Tympanic membrane temperatures 30–90 min after the start of active cooling were significantly lower in the amrinone group than in the control group. The temperature gradient 30 min after the start of active cooling was significantly lower in the amrinone group than in the control group. By contrast, during the rewarming period, the tympanic membrane temperature and the temperature gradient at each time interval were similar in the two groups. Table 2 shows a comparison of intraoperative variables. The times taken for active cooling to achieve a core temperature of 35°C and the lowest temperature were significantly shorter in the amrinone group than in the control group. The active cooling rate was significantly greater in the amrinone group than in the control group. However, there were no significant group differences in the rewarming time to reach 35.5°C and the rewarming rate. There were no significant differences in anaesthesia and surgery times, total volumes of intravenous infusions, transfusion, blood loss, urinary output and total doses of fentanyl and propofol.


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Table 1 Patient characteristics and indications for surgery. The control group did not receive amrinone; the amrinone group received a loading dose of amrinone 1.0 mg kg–1 then an infusion of amrinone 5 µg kg–1 min–1. The data are expressed as mean (SEM). OCVD = occlusive cerebrovascular disease
 


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Fig 1 Intraoperative changes in tympanic membrane temperature and skin surface temperature gradient (forearm minus fingertip). Tympanic membrane temperature 30–90 min after cooling was significantly lower in the amrinone (AMR) group than in the control group. The temperature gradient 30 min after the cooling was significantly lower in the amrinone group than in the control group. The amrinone group received a loading dose of amrinone 1.0 mg–1 kg–1 then an infusion of amrinone 5 µg kg–1 min–1; the control group did not receive amrinone. The data are expressed as mean (SEM). Comparisons between the two groups were performed by two-way analysis of variance for repeated measures followed by Fisher’s protected least significant difference test. *P<0.05 versus control group; **P<0.01 versus control group.

 

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Table 2 Intra-operative variables. The control group did not receive amrinone; the amrinone group received a loading dose of amrinone 1.0 mg kg–1 then an infusion of amrinone 5 µg kg–1 min–1. The data are expressed as mean (SEM). Comparisons between the two groups were performed with unpaired Student’s t-test. *Statistically significant difference between the groups (P<0.05)
 
Figure 2 shows the intraoperative changes in heart rate and mean arterial blood pressure. There were no significant differences between the two groups in heart rate at each time interval during the study. The mean arterial blood pressure at the beginning of rewarming was significantly lower in the amrinone group than in the control group.



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Fig 2 Intraoperative changes in heart rate and mean arterial blood pressure. There were no significant differences between the two groups in heart rate at each time interval during the operation. Mean arterial blood pressure at the beginning of the rewarming was significantly lower in the amrinone (AMR) group than in the control group. There were no significant differences between the two groups in heart rate at each time interval during the operation. The amrinone group received a loading dose of amrinone 1.0 mg–1 kg–1 then an infusion of amrinone 5 µg kg–1 min–1; the control group did not receive amrinone. The data are expressed as mean (SEM). Comparisons between the two groups were performed by two-way analysis of variance for repeated measures followed by Fisher’s protected least significant difference test. *P<0.05 versus control group; **P<0.01 versus control group.

 
The results of the arterial blood analyses are shown in Table 3. There were no significant differences between the two groups in pH, PaCO2, PaO2, base excess, haemoglobin, Na+, K+, glucose and lactate before or during mild hypothermia.


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Table 3 Intraoperative arterial blood chemistry variables. The control group did not receive amrinone; the amrinone group received a loading dose of amrinone 1.0 mg kg–1 then an infusion of amrinone 5 µg kg–1 min–1. The data are expressed as mean (SEM). Comparisons between the two groups were performed with unpaired Student’s t-test. NT = normothermia; HT = hypothermia
 

    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
The results of this study reveal that intraoperative administration of amrinone 5 µg kg–1 min–1 after a loading dose of 1.0 mg kg–1 accelerated the cooling rate of the core temperature, although it did not affect the rewarming rate after deliberate mild hypothermia.

Core hypothermia during general anaesthesia develops with three characteristic phases.1113 Initial core hypothermia results from core-to-peripheral redistribution of body heat when anaesthesia inhibits tonic thermoregulatory vasoconstriction. Subsequently, heat loss exceeding metabolic heat production lowers core temperature in a slow, linear fashion. Finally, a core temperature plateau results when the emergence of thermoregulatory vasoconstriction decreases cutaneous heat loss and constrains metabolic heat to the core thermal compartment. We proposed that the combination of the inotropic effect with the vasodilatory effect—the ‘inodilatory effect’—of amrinone would enhance the redistribution of body heat and cutaneous heat loss and would inhibit the thermoregulatory vasoconstriction, resulting in an increase in the cooling rate. Just as we had expected, amrinone accelerated the cooling rate of the core temperature during deliberate mild hypothermia in the present study.

Evidence supporting our proposed mechanism was found in the present study. The forearm minus fingertip skin surface temperature gradient became significantly lower in the amrinone group than in the control group before the tympanic membrane temperature became significantly lower in the amrinone group than in the control group. The temperature gradient is considered to be a measure of peripheral thermoregulatory vasoconstriction.7 14 15 Generally, it is considered that the more positive the temperature gradient the greater is the degree of vasoconstriction, whereas the more negative the temperature gradient the greater is the degree of vasodilation. Thus, we suggest that the inodilatory effect of amrinone inhibits thermoregulatory vasoconstriction, promoting the redistribution of body heat and cutaneous heat loss and resulting in acceleration of the cooling rate of core temperature. However, it is uncertain whether the inotropic or the vasodilatory effect is mainly responsible for this effect, because we did not measure cardiac output or skin blood flow. Shitara et al. demonstrated that dobutamine accelerated the decline of core temperature in volunteers anaesthetized with isoflurane.16 They attributed this to the inotropic and vasodilatory effects of dobutamine. These results are compatible with our results.

In the present study the rewarming of the core temperature was not influenced by the administration of amrinone. Previous investigators have tested the hypothesis that thermoregulatory vasoconstriction decreases cutaneous transfer of applied heat and restricts peripheral-to-core flow of heat, thereby delaying and reducing the increase in core temperature.4 6 17 However, rewarming of the core temperature was not affected by vasodilation by anaesthetics, sodium nitroprusside and prostaglandin E1. We thought that the combined inotropic and vasodilatory effect of amrinone would maintain peripheral circulation and cardiac output, thereby enhancing peripheral heat gain and the peripheral-to-core flow of heat, resulting in an acceleration of the rewarming rate. However, amrinone did not influence the rewarming of the core temperature after deliberate mild hypothermia. The temperature gradient in the two groups showed similar changes during the rewarming phase. The inodilatory effect of amrinone might be modified under mild hypothermic conditions. Alternatively, the dose of amrinone used in this study might have been insufficient to counteract the active vasoconstriction under mild hypothermic conditions. It is interesting to note that postoperative rebound hyperthermia1 was not observed in this study. This may be because of the passive warming method we used.

Factors known to affect cooling and rewarming include the morphometric characteristics of patients, the presence or absence of vasoconstriction, and the method of temperature management.18 Intra-operative thermoregulatory vasoconstriction thresholds may be influenced by the depth of anaesthesia, age, and painful stimulation.1923 In our study, anaesthesia and the method of temperature management were standardized and the morphometric data were similar in the two groups.

It is possible that higher doses of amrinone might affect the rewarming rate. We chose not to use higher doses because of the risk of severe hypotension associated with their use.24 25 In the present study, the mean arterial blood pressure was significantly lower in the amrinone group than in the control group at the start of rewarming, although no patient in either group required treatment for hypotension. However, the possibility of hypotension due to amrinone, especially in patients who demonstrate cardiovascular instability before anaesthesia, should be considered.


    Acknowledgements
 
This work was supported by Grant-in Aid for Scientific Research C2-10671439 and Meiji Seika Kaisha Ltd, Tokyo, Japan.


    References
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
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