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Forced-air warming effectively prevents midazolam-induced core hypothermia in volunteers

Sato, Hiroakia; Yamakage, Michiakib; Okuyama, Katsumia; Imai, Yusukea; Iwashita, Hironobua; Ishiyama, Tadahikoa; Matsukawa, Takashia

European Journal of Anaesthesiology (EJA): July 2009 - Volume 26 - Issue 7 - p 566–571
doi: 10.1097/EJA.0b013e328328f662
Original Articles – General
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Background and objective Midazolam is a commonly used sedative and anaesthetic adjuvant and the agent is known to decrease core temperature by core-to-periphery redistribution of heat. We tested the hypothesis that forced-air warming could effectively prevent midazolam-induced hypothermia.

Methods Six healthy male volunteers were studied over 3 days. On the first day, the volunteers were alert during a 30 min control period with forced-air warming. On the second day, after the volunteers were vasoconstricted, 75 μg kg−1 midazolam was injected intramuscularly and they were covered with a cotton blanket. On the third day, after the volunteers were vasoconstricted, 75 μg kg−1 midazolam was again administered and they were given forced-air warming. Tympanic temperature was measured as the core temperature. Four adhesive skin-surface probes with thermocouples were fixed on the chest, upper right arm, lateral calf and thigh, and both mean skin and body temperatures were calculated. Fingertip perfusion was evaluated using forearm minus fingertip and calf minus toe skin-surface temperature gradients. Thirty minutes after the intramuscular injection of midazolam, the level of sedation in volunteers was measured by a blinded observer according to the alertness/sedation scale.

Results Core temperature significantly decreased by midazolam premedication in a time-dependent manner. Although forced-air warming did not prevent the midazolam-induced transient decrease in core temperature, it increased the temperature to the control level thereafter.

Conclusion We conclude that forced-air warming can effectively prevent midazolam-induced redistribution hypothermia.

aDepartment of Anesthesiology, University of Yamanashi, Faculty of Medicine, Chui, Yamanashi, Japan

bDepartment of Anesthesiology, Sapporo Medical University School of Medicine, Sapporo, Hokkaido, Japan

Received 22 September, 2008

Revised 1 January, 2009

Accepted 4 January, 2009

Correspondence to Michiaki Yamakage, MD, PhD, Assistant Professor, Department of Anesthesiology, Sapporo Medical University School of Medicine, South 1, West 16, Chuo-ku, Sapporo, Hokkaido 060-8543, Japan Tel: +81 11 611 2111x3568; fax: +81 11 631 9683; e-mail: yamakage@sapmed.ac.jp

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Introduction

Perioperative hypothermia commonly occurs during general anaesthesia and major surgery. Because hypothermia causes potentially serious complications [1–7], patients should be maintained in normothermia perioperatively. The hypothermia results mainly from perioperative heat loss and anaesthetic-induced inhibition of normal thermoregulatory control. Initial anaesthetic-induced hypothermia, however, results largely from core-to-periphery redistribution of heat [8,9]. Midazolam is a commonly used sedative and anaesthetic adjuvant. In our previous study [10], we demonstrated that midazolam as premedication significantly decreased core temperature by a comparable aetiology of core-to-periphery redistribution of heat in volunteers. At the same time, we demonstrated that elderly patients receiving midazolam premedication had a risk of becoming more hypothermic both before and after induction of general anaesthesia [11]. In those clinical situations, it is important to seek a way of preventing hypothermia after premedication.

We, therefore, tested the hypothesis that peripheral warming with forced air after intramuscular (i.m.) midazolam [12,13] used as premedication effectively prevents core temperature decrease in volunteers.

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Volunteers and methods

Protocol

With the approval of the Committee on Human Research at the Yamanashi Medical University, Faculty of Medicine, we studied six young healthy male volunteers. None was obese, taking medications, or had a history of thyroid disease, dysautonomia or Raynaud's syndrome.

All studies started at approximately 9: 30 a.m. The volunteers fasted for 8 h before arriving at the air-conditioned laboratory. They were minimally clothed (T-shirt and shorts) and rested supine in a 22–23°C room (relative humidity: 40–60%) during the study. We started the study after the volunteers were spontaneously vasoconstricted at the feet (calf minus toe skin-surface temperature gradient >0) under these conditions [9]. Volunteers were studied, in a random order, over a 3-day study period. On the first day, the volunteers were kept alert during a 30 min control period under force-air warming (Bair Hugger; Augustine Medical Inc., Eden Prairie, Minnesota, USA). On the second day, after the volunteers were vasoconstricted, midazolam (75 μg kg−1) was administered i.m. and they were covered with an unwarmed cotton blanket. On the third day, after the volunteers were similarly and spontaneously vasoconstricted, midazolam (75 μg kg−1) was again administered i.m. under forced-air warming. The disposable blanket of the forced-air warming system or the unwarmed cotton blanket was placed over the entire body except for the head and neck field.

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Measurements

Temperatures were monitored using Mon-a-therm thermocouples (Mallinckrodt Anesthesiology Products, Inc., St Louis, Missouri, USA). The probes were connected to Mallinckrodt Model 6510 two-channel electronic thermometers. These thermometers require no user calibration and have a precision of 0.1°C when used with Mon-a-therm disposable thermocouples. Core temperatures (Ttym) were measured at the right tympanic membrane. The aural probe was inserted until the volunteers felt the thermocouple touch the tympanic membrane; appropriate placement was confirmed when they easily detected a gentle rubbing of the attached wire. The probe was then securely taped in place and the aural canal was occluded with cotton. Four adhesive skin-surface probes were fixed on the chest, upper right arm, lateral calf, and thigh. Mean skin temperature (MST) was calculated as 0.3 × (Tchest + Tarm) + 0.2 × (Tthigh + Tcalf) [14]. Mean body temperature (MBT) was calculated as 0.34 × TMST + 0.66 × Ttym[15]. Fingertip perfusion was evaluated using forearm minus fingertip skin-surface temperature gradients. Perfusion was recorded from the arm and the leg without the blood pressure cuff or pulse oximeter. As in previous studies [9,16], we considered a gradient of greater than 0°C to indicate significant thermoregulatory vasoconstriction.

Thirty minutes after i.m. midazolam, the levels of sedation in the volunteers were assessed by a blinded observer according to the alertness/sedation scale [17]. The sedation scale is composed of four assessment categories: responsiveness, speech, facial expression, and eyes. Responsiveness should be evaluated first. A composite score was assigned corresponding to the lowest levels at which any category was assessed. The composite score level ranged between 5 (alert) and 1 (deep sleep).

Heart rate and oxyhaemoglobin saturation were measured continuously using pulse oximetry (Symphony N-3000; Tyco Healthcare Inc., Mansfield, Massachusetts, USA) and blood pressure was determined oscillometrically at the left arm at the start and end of the study.

The volunteers' height [median (range)] was 165 (162–177) cm, total body weight (TBW) 64 (53–84) kg, and age 33 (27–36) years. The lean body mass (LBM) was 51.1 (44.6–63.6) kg as determined from height (cm) and total body mass (TBM; kg) using the formula LBM = (1.10 × TBM) − 128 × (TBM/height) [2]. Basal surface area was 1.75 (1.59–2.06) m2. Background data 30 min after i.m. midazolam administration did not differ among the three groups tested in this study (Table 1).

Table 1

Table 1

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Data analysis

Haemodynamic responses, ambient temperature, oxyhaemoglobin saturation, and mean skin temperature and MBT under each study condition were averaged among volunteers. Results for each study condition were compared using repeated-measures analysis of variance (ANOVA) and Scheffé's F-tests, or Kruskal–Wallis test. Data were presented as means ± SD or median (± percentile or range). A P value less than 0.05 was considered statistically significant.

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Results

Changes in tympanic membrane temperatures (Ttym) at 0, 10, 20, and 30 min after i.m. midazolam administration are shown in Fig. 1. Ttym in the control group with forced-air warming did not change throughout the study period. Ttym in the group with midazolam administration but without warming significantly decreased in a time-dependent manner. Ttym in the group with midazolam administration and forced-air warming also decreased until 20 min after the midazolam administration; however, it increased thereafter significantly up to the level with the Ttym in the control group without midazolam administration. Mean skin and body temperatures 30 min after i.m. midazolam administration are shown in Fig. 2. Although these temperatures without active warming by forced air did not change significantly (data of 0 elapsed time not shown), those with forced-air warming significantly increased compared with those at the start of the study and were significantly higher than those of volunteers who were not warmed with forced air. Changes in skin-surface temperature gradients (ΔGradarm-fing) using forearm minus fingertip (a) and in skin-surface temperature gradients (ΔGradcalf-toe) using calf minus toe (b) during the study period are shown in Fig. 3. Both of the temperature gradients significantly decreased in all of the groups tested (data of 0 elapsed time were approximately zero) and there were no significant differences in the values among the groups.

Fig. 1

Fig. 1

Fig. 2

Fig. 2

Fig. 3

Fig. 3

Sedation scores 30 min after administration of midazolam in volunteers (with or without forced-air warming) were significantly lower than those without midazolam administration (P < 0.05), and there was no significant difference in the sedation level between the midazolam-treated groups (Table 2).

Table 2

Table 2

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Discussion

The present study showed that i.m. injection of midazolam that produces a slight sedation level [3 (median) in all of the midazolam-treated groups (Table 2)] in young healthy male volunteers decreased body core temperature by approximately 0.5°C. This finding is consistent with the results of our previous studies [10,11]. As indicated in Fig. 3, significant increases in peripheral blood flow and peripheral temperature were observed 30 min after the midazolam administration. This finding indicates that midazolam-induced hypothermia is caused by the core-to-periphery heat distribution induced by midazolam [10,11]. It could also be supported by the results that showed that midazolam minimally impairs thermoregulatory control [18]. The midazolam-induced decrease in core temperature of 0.5°C obtained in the present study may appear small in physiological terms. However, patients receiving midazolam premedication experience further decreases in body temperature due to subsequent induction of general anaesthesia [1] or epidural anaesthesia [2], which causes further redistribution hypothermia as well as disruption of the balance between generation and loss of heat. Therefore, a decrease of 0.5°C resulting only from sedative premedication may lead to hypothermia and necessitates a difficult follow-up active warming. Midazolam-induced vasodilatation makes a patient poikilothermic; thus, controlling the ambient temperature and keeping patients ‘comfortably warm’ is vital following premedication and clinicians need to be aware of this when heavily premedicating their patients.

Perioperative hypothermia is known to adversely affect the prognosis of patients regardless of its severity. Patients with mild hypothermia at the completion of an operation most commonly complain of shivering and chills upon awakening from anaesthesia [19]. Shivering has been reported to result in increases of 300–400% in oxygen consumption relative to the resting state [20], and hypothermia-induced peripheral vasoconstriction, higher norepinephrine concentration, and higher arterial blood pressure in the early postoperative period could be related to cardiovascular morbidity in the perioperative period [21]. Hypothermia produces several adverse effects such as decreased metabolism of drugs, reduced platelet function, and postanaesthetic shivering [4–8,22]. In addition, even mild intraoperative hypothermia has been shown to prolong hospitalization due to increased incidence of surgical wound infection and to increase postoperative myocardial ischaemia [3,9,21]. Therefore, maintenance of normothermia by constant monitoring and active management of the patient's body temperature during the perioperative period is of utmost importance in anaesthetic management [23].

Although forced-air warming did not prevent decreases in core temperature during the first 20 min of midazolam administration, body temperature increased to control levels thereafter. Temperature decreases could not be prevented during the first 20 min because they were caused by core-to-periphery heat redistribution, which cannot be prevented by the simultaneous warming. This decrease in temperature can be prevented only by eliminating differences between the core and peripheral body temperatures by warming the patient prior to induction of anaesthesia [24,25] or using a combination of drugs that prevent decreases in body temperature [11]. Meanwhile, forced-air warming, which has been confirmed to be a useful intraoperative warming device due to its high warming effect [26], not only prevented temperature decreases from 20 min following midazolam administration, but also increased body core temperature to preadministration levels. As can be seen in Figs 2 and 3, this increase was primarily attributed to the heat generated by forced-air warming, rather than peripheral vasoconstriction functioning to maintain body temperature.

Despite these warming effects, forced-air warming did not increase body core temperature in the control group, which was not given midazolam. Because no drugs affecting thermoregulatory control were given to this group, peripheral vasodilatation, redistribution of heat, and increased release of heat from the body including extremities were thought to have occurred as responses to accurately regulate body core temperature, resulting in the absence of temperature increase. These findings indicate that actively warming patients with forced-air warming prior to the administration of sedatives as premedication enables prevention of transient decreases in body temperature.

Finally, a limitation of the present study was that volunteers were relatively young healthy men. In the present study, factors such as fasting and study initiation time were fixed and the study was initiated after exposing volunteers to a relatively cold environment in advance and detecting sufficient peripheral vasoconstriction. Because these conditions reflect those of actual patients, who experience tension prior to premedication and who enter operating rooms covered by a thin blanket that does not provide warmth, the present study can be considered a clinical study and the present findings are thus applicable to clinical practice. Furthermore, in our previous studies [10,11], a relatively small number of volunteers (n = 5–8) were evaluated because thermoregulatory mechanisms are supposed to be controlled tightly and physiological variations should be quite small. Thus, we studied six volunteers and got significant results in the current study, which we believe to be sufficient for our evaluation. However, if a larger number of patients had been studied, we might have demonstrated an actual increase in MBT as heat transfer from the forced-air warming might actually have been facilitated by the vasodilation of the midazolam. A second limitation of our study was that we did not have a placebo group (e.g. i.m. injection of physiological saline or control without forced-air warming) in this study. We, therefore, cannot comment on the spontaneous time course of the core and peripheral temperatures under rather cool conditions. However, it could easily be speculated that the core temperature could have been maintained despite the decrease in peripheral temperatures in a time-dependent manner because i.m. midazolam for premedication minimally impairs thermoregulatory control [18] and the control could regulate the core temperature well by reducing peripheral circulation and by shivering. Finally, midazolam was injected i.m. in this study because i.m. injection of sedation is popular in Asia [12,13]. The difference in the route of sedative administration could have affected the results, especially the time course and degree of temperature changes as the time course and the peak concentration of midazolam in brain would differ by changing the route of sedative administration.

In conclusion, forced-air warming after premedication with midazolam is effective to prevent premedication/sedation-induced redistribution hypothermia.

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Acknowledgements

We would like to thank Professor and Chair Makoto Ozaki, MD, PhD, Department of Anesthesiology, Tokyo Women's Medical University, Tokyo, Japan, for his valuable comments on our study.

The present research was supported solely by institutional and/or departmental sources. None of the authors have any financial interests in products related to this study.

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Keywords:

core temperature; forced-air warming; hypothermia; midazolam; thermoregulation; vasoconstriction

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