Clonidine Produces a Dose-dependent Impairment of Baroreflex-mediated Thermoregulatory Responses to Positive End-expiratory Pressure in Anaesthetised Humans

Summary

Background. Perioperative hypothermia is common and results from anaesthetic-induced inhibition of thermoregulatory control. Hypothermia is blunted by baroreceptor unloading caused by positive end-expiratory pressure (PEEP) and is mediated by an increase in the vasoconstriction threshold. Premedication with clonidine impairs normal thermoregulatory control. We therefore determined the effect of clonidine on PEEP-induced hypothermia protection.

Methods. Core temperature was evaluated in patients undergoing combined general and epidural anaesthesia for lower abdominal surgery. They were assigned to an end-expiratory pressure of zero (ZEEP) or 10 cmH₂O PEEP. The PEEP group was divided into three blinded subgroups: placebo (Clonidine-0), clonidine 150 μg (Clonidine-150), and clonidine 300 μg (Clonidine-300). Placebo or clonidine was given orally 30 minutes before surgery. We evaluated core temperature and thermoregulatory vasoconstriction. We also determined epinephrine, norepinephrine, and angiotensin II concentrations and plasma renin activity.

Results. Core temperature after 180 minutes of anaesthesia was 35.1 ± 0.1°C in the ZEEP group. PEEP significantly increased final core temperature to 35.8 ± 0.2°C (Clonidine-0 group). Clonidine produced a linear, dose-dependent impairment of PEEP-induced hypothermia protection: final core temperatures of 35.4 ± 0.1°C in the clonidine-150 group and 35.1 ± 0.2°C in the Clonidine-300 group. Similarly, clonidine produced a linear and dose-dependent reduction in vasoconstriction threshold: Clonidine-0=36.4 ± 0.1°C, Clonidine-150=35.8 ± 0.1°C, and Clonidine-300=35.4 ± 0.2°C. Plasma norepinephrine and angiotensin II concentrations and renin activity were consistent with the thermoregulatory responses.

Conclusion. Baroreceptor unloading by PEEP normally moderates perioperative hypothermia. However, clonidine premedication produces a linear, dose-dependent impairment of this benefit.

Perioperative hypothermia is common because of the combination of anaesthesia-induced impairment of thermoregulatory vasomotion, a cool operating room environment, and surgical exposure promotion of excessive heat loss.¹ Core hypothermia results initially from an internal redistribution of body heat² and subsequently from heat loss that exceeds metabolic heat production.³ In patients who become sufficiently hypothermic, further reduction in core temperature is limited by re-activation of thermoregulatory vasoconstriction.⁴ Perioperative hypothermia is associated with numerous adverse outcomes including morbid cardiac events, coagulopathy, and impaired immune function.⁵ Hypothermic patients are also prone to surgical wound infections, delayed suture removal, and prolonged hospitalization.⁶ It is therefore routine for anaesthesiologists to prevent perioperative hypothermia unless hypothermia is specifically indicated.

Peripheral vasoconstriction plays a major role in the thermoregulatory response to reduced body temperature. Therefore, non-thermal factors affecting the cardiovascular system might modulate thermoregulatory control. Cardiopulmonary baroreceptors monitor blood pressure and central blood volume. They trigger a reflex that causes vasoconstriction when right atrial transmural pressure (RATP) decreases and vasodilation when RATP increases. We recently reported the severity of perioperative hypothermia can be moderated by applying positive end-expiratory pressure (PEEP) to decrease RATP. PEEP, which unloads baroreceptors, attenuates perioperative hypothermia in lower abdominal surgery in anaesthetised humans by increasing the vasoconstriction threshold (triggering core temperature).⁶ Thermoregulatory vasoconstriction is effective in constraining metabolic heat to the core thermal compartment, thus minimising further core hypothermia.⁴

Clonidine, an α2 adrenergic agonist, is used as a premedication and has a sedative effect; it has both anaesthetic-sparing and favourable haemodynamic properties.⁷ However, clonidine impairs central thermoregulatory control, an impairment that is manifested by reduced vasoconstriction and shivering thresholds.⁸ We, therefore, tested the hypothesis that clonidine premedication produces a dose-dependent impairment of the baroreflex-mediated protective thermoregulatory response to PEEP in anaesthetised humans.

METHODS

With approval of the Kyoto Prefectural University of Medicine Review Board on Human Experiments and written informed consent, we studied a total of 32 patients (ASA Physical Status 1 or 2), aged 20-60 years, scheduled for open lower abdominal surgery. None was obese, febrile, or receiving vasodilators or medications likely to alter thermoregulation; none had a history of thyroid disease or dysautonomia.

Thirty-two Patients were randomly assigned to zero end-expiratory pressure (ZEEP, n=8) or 10 cmH2O positive end-expiratory pressure (PEEP) protocol. Those assigned to PEEP were divided into three groups: placebo group (Clonidine-0, n=8), clonidine 150 μg group (Clonidine-150, n=7), or clonidine 300 μg group (Clonidine-300, n=7). Randomisation was based on computer-generated codes and maintained in sequentially numbered envelopes until just before premedication. Unfortunately, in each of the two Clonidine groups, one patient was excluded due to insufficient data.

Protocol

This study was performed as described previously.^4-6 All operations were performed between 8:00 am and noon. Patients fasted for more than 8 h before the surgery. They were given with a placebo (ZEEP and Clonidine-0 groups), clonidine 150 μg (Clonidine-150 group), or clonidine 300 μg (Clonidine-300 group) with 100 ml of water orally 30 min before entering the operating room. The anaesthesiologists and investigators were blinded to treatment.

Ambient temperature was maintained at 24°C and relative humidity at 40%. We allowed 30 minutes for the patients to become acclimated to the operating room environment; during this time an 18-G catheter was inserted into a left antecubital vein for administration of lactated Ringer's solution at ambient temperature (10 ml·kg^-1·h^-1). A 22-g catheter was inserted into the left radial artery for blood pressure monitoring and blood sampling. Additionally, an epidural catheter was inserted via the L1-L2 or the L2-L3 vertebral interspace with the patient in lateral position.

Anaesthesia was induced by IV administration of 2 mg·kg^-1 propofol and 0.15 mg.kg^-1 vecuronium bromide and was maintained with 0.4% isoflurane and 66% nitrous oxide in oxygen. An IV infusion of vecuronium, initially set to 0.025 mg·kg^-1·h^-1, was adjusted to maintain one or two twitches in response to supermaximal stimulation of the ulnar nerve at the wrist. Mechanical ventilation was adjusted to maintain end-tidal Pco₂ between 35 and 40 mmHg. After an initial dose of 7 ml of 1% lidocaine without epinephrine into the epidural catheter, 0.25% bupivacaine at a rate of 5ml·h^-1 was infused for the reminder of surgery to obtain epidural analgesia. Patients were covered with one cotton sheet. In patients assigned to receive it (Clonidine-0, Clonidine-150, and Clonidine-300), PEEP (10 cmH₂O) was initiated 10 min after the induction of anaesthesia and was maintained for 3 h.

Measurements

Blood pressure, heart rate, oxygen saturation, end-tidal Pco₂, and end-tidal isoflurane concentrations were recorded at 5-min intervals. Upper- and lower-body sensory block levels were evaluated after emergence from anaesthesia by response to cold sensation.

Core temperature, represented by distal oesophageal temperature, was measured with a thermistor (Mon-a-therm, Mallinckrodt, St. Louis, MO), the end of which was inserted one-fourth the distance of the subjects' standing height from the external nares. The thermistor probes were calibrated in the same environment as that of experiments. The resolution of the temperature measurement system was about 0.024 °C. We also recorded forearm-minus-fingertip, skin-temperature gradients.⁹ Briefly, thermistor probes for skin temperature measurement were attached to the right forearm halfway between the elbow and the wrist and to the right index finger (opposite the nail bed). To quantify thermoregulatory peripheral vasoconstriction, we employed a forearm-minus-fingertip temperature gradient, because positive forearm-fingertip temperature gradient is closely correlated with reduction in blood flow in acral regions and less affected by ambient temperature than fingertip temperature alone. Temperatures were recorded at 5-min intervals.

Blood was sampled from the radial artery 20, 90, and 180 minutes after induction of anaesthesia. Samples were immediately centrifuged at 4°C, and aliquots of the plasma were stored at -80°C until assayed. Plasma epinephrine and norepinephrine were measured by high-performance liquid chromatography with an electrochemical detector after alumina extraction. Radioimmunoassay kits were used to evaluate plasma renin activity (Renin RIABEAD; Dainabot, Tokyo, Japan) and plasma angiotensin II concentrations (Angiotensin II, Nichols Institute, CA).

Data Analyses

As in previous studies, we defined the vasoconstriction threshold as the core temperature that triggered a rapid increase in the skin-temperature gradient.⁶ The threshold was determined individually for each patient by an investigator blinded to treatment after the measurement. Once the threshold was reached, thermal responsiveness (gain) was defined by the slope of a regression between the skin-temperature gradient and core temperature in each individual.

Baseline values were averaged over the final 30 minutes before the induction of general anaesthesia. Intraoperative values were presented over time or first averaged within each patient, and then averaged among the patients in each group. Thermal responsiveness (gain) and vasoconstriction thresholds were analyzed with general linear regression models for one-way analysis of variance (ANOVA with one between factor), followed by Scheffé's multiple comparison tests. The effects of clonidine and time on the cardiovascular, thermoregulatory, and hormonal responses were analyzed by general linear regression model procedures for two-way ANOVA with repeated measures (one between and one within factor), followed by Scheffé's multiple comparison tests. Results are presented as means ± SEMs; P < 0.05 was considered statistically significant.

Results

There were no statistically significant differences among the four groups in terms of demographic data, or initial arterial pressure, heart rate, or body temperature (Table 1). Total blood loss and fluid replacement volume at 180 minutes after induction of anaesthesia did not differ significantly among the groups (data not shown). No patient received a blood transfusion. There were no significant differences in gender between the four groups.

Table 1.

Morphometric and Demographic Characteristics and Baseline Core Temperature and Haemodynamic Responses.

	ZEEP	Clonidine-0	Clonidine-150	Clonine-300
Age (yr)	52±3	53±4	47±5	48±4
Weight (kg)	57±4	60±4	54±6	53±4
Height (cm)	160±5	157±4	156±7	156±5
Sex (M/F)	4/4	4/4	3/4	2/5
Mean Arterial Pressure (mmHg)	87±2	90±2	85±4	84±4
Heart Rate (beats per min)	82±2	81±4	82±5	75±8
Core Temperature (°C)	36.8±0.1	36.8±0.1	36.7±0.1	36.9±0.2

Values are expressed as means + SEMs.

Both mean arterial pressure and heart rate in the clonidine-300 group decreased significantly after induction of anaesthesia, compared with the Clonidine-0 group (Table 2).

Table 2.

Intraoperative Haemodynamic, Anaesthetic (at 180 min after induction of anaesthesia), and Thermoregulatory Responses.

	ZEEP	Clonidine-0	Clonidine-150	Clonine-300
Final Mean Arterial Pressure (mmHg)	84±2	82±2	84±2	68±4*
Final Heart Rate (beats per min)	70±3	69±4	70±4	59±4*
End-tidal Isoflurane (%)	0.4±0.1	0.4±0.1	0.4±0.1	0.4±0.1
Final Core Temperature (°C)	35.1±0.1*	35.8±0.2	35.5±0.1*	35.0±0.2*
Vasoconstriction Threshold (°C)	35.5±0.2*	36.4±0.1	35.8±0.1*	35.4±0.2*
Vasoconstriction Gain	9.6±3.3*	17.4±4.3	13.5±4.5	10.5±4.3*

^*Significantly different from Clonidine-0 value. PEEP = positive end-expiratory pressure.

Figure 1 shows core temperature and forearm-fingertip skin temperature gradients as a function of time. The decrease in core temperature in the clonidine-150 group became significantly greater than that in the Clonidine-0 group starting at 150 min; in the clonidine-300 group it was significantly greater at 110 min after induction of anaesthesia. Final core temperature was 35.1 ± 0.1°C in the ZEEP, 35.8 ± 0.2°C in the Clonidine-0, 35.4 ± 0.1°C in the Clonidine-150, and 35.1 ± 0.2°C in the Clonidine-300 group. Clonidine dose-dependently decreased the final core temperature with a significant difference between Clonidine-0 and Clonidine-300 (P < 0.05). The final core temperature in the Clonidine-300 patients was similar to that in the ZEEP patients. The increase in forearm-minus-fingertip temperature gradient was delayed in both clonidine premedication groups; compared with that in Clonidine-0 group, the gradient became significantly smaller in the Clonidine-150 group starting at 80 min and in the Clonidine-300 group starting at 70 min after induction of anaesthesia, (P < 0.05).

Fig 1.

Time course of core temperature (T_es) and the forearm-minus-fingertip temperature gradient (T_forearm - T_fingertip) after induction of anaesthesia. The decrease in T_es in the clonidine-150 and clonidine-300 groups became significantly greater than that in the Clonidine-0 group starting at 150 min and 110 min after induction of anaesthesia, respectively (P < 0.05). The increase in forearm-minus-fingertip temperature gradient was delayed in both clonidine premedication groups compared with that in Clonidine-0 group (P < 0.05). Data are presented as the means ± SEM every 10 min. ZEEP: Control (n=8); Clonidine-0: positive end-expiratory pressure (PEEP) starting 10 min after induction of anaesthesia (n=8); Clonidine-150: PEEP with 150 μg of oral clonidine premedication (n=7); Clonidine-300: PEEP with 300 μg of oral clonidine premedication (n=7).

The vasoconstriction thresholds were 35.5 ± 0.2°C in ZEEP, 36.4 ± 0.1°C in Clonidine-0, 35.8 ± 0.1°C in Clonidine-150, and 35.4 ± 0.2°C in Clonidine-300 (Fig. 2). Patients assigned to the Clonidine-300 group vasoconstricted at significantly lower core temperatures than those in the Clonidine-0 group (P < 0.05). Vasoconstriction occurred at similar core temperature in the ZEEP and Clonidine-300 groups. The gain of vasoconstriction (slope of the forearm-minus-fingertip temperature gradient / core temperature relationship below the threshold) was significantly reduced by clonidine, with the gain of vasoconstriction in the Clonidine-300 group being similar to that in ZEEP group (Table 2).

In patients exposed to PEEP, clonidine linearly reduced the vasoconstriction threshold: [Threshold] = -0.003 [Clonidine] + 36.3, r = 0.73. Clonidine also linearly reduced core temperature 180 minutes after induction of anaesthesia: [Temperature] = -0.002 [Clonidine] + 35.8, r = 0.67 (Figure 3). In patients exposed to PEEP, clonidine linearly reduced plasma norepinephrine concentration: [NE]= -0.0007 [Clonidine] + 0.33, r = 0.69. Clonidine also linearly reduced plasma rennin activity: [PRA] = -0.0007 [Clonidine] + 3.18, r = 0.66, and plasma angiotensin II concentration: [Ang II] = -0.54 [Clonidine] + 158, r = 0.67 (Figure 4). Plasma norepinephrine in the Clonidine-300, and plasma rennin activity and plasma angiotensin II in both clonidine groups were significantly less than those in the Clonidine-0 group (P < 0.05). Clonidine premedication did not significantly reduce plasma epinephrine concentration under PEEP condition.

Fig 3.

In patients exposed to PEEP, clonidine linearly reduced the vasoconstriction threshold: T_es Threshold = 0.003 [Clonidine] + 36.3, r = 0.73. Clonidine also linearly reduced T_es 180 minutes after induction of anaesthesia: Final T_es = 0.002 [Clonidine] + 35.8, r = 0.67. Individual results are shown as closed circles. The mean ± SEM of each group is shown as open squares.

Fig 4.

In patients exposed to PEEP, clonidine linearly reduced plasma norepinephrine concentration: [NE]= -0.0007 [Clonidine] + 0.33, r = 0.69. Clonidine also linearly reduced plasma rennin activity: [PRA] = -0.0007 [Clonidine] + 3.18, r = 0.66, and plasma angiotensin II concentration: [Ang II] = -0.54 [Clonidine] + 158, r = 0.67. Concentrations in each individual are shown as closed circles. The mean ± SEM for each group are shown as open squares. The level of detectability radioimmunoassay kits (Angiotensin II, Nichols Institute, CA) was 3.8 pg?ml^-1. All plasma angiotensin II values were > 5.0 pg?ml^-1(7.9±1.5 pg?ml^-1, mean ±SEM)

Discussion

Clonidine, a selective partial alpha-2 adrenergic agonist, was introduced into clinical practice as an antihypertensive medication more than 25 years ago.^7,10 Clonidine is currently used in the anaesthetic management of surgical patients because of its sedative, analgesic, and anaesthetic sparing properties.⁷ In veterinary practice, alphaã2 adrenergic agonists are used as primary anaesthetics. Alpha-2 adrenergic agonists, which are not subtype selective, give a biphasic blood pressure response: after a short hypertensive phase, arterial pressure falls below the baseline. Alpha-2B adrenergic receptor subtype stimulation causes initial direct vasoconstriction in the peripheral vascular smooth muscle. Also, activation of the α-2A adrenergic receptor subtype leads to a decrease in blood pressure by inhibiting central sympathetic outflow as well as norepinephrine release from sympathetic nerves.^7,10

We previously demonstrated that baroreceptor unloading by PEEP attenuates anaesthetic-induced perioperative hypothermia by increasing the threshold and gain of thermoregulatory vasoconstriction. Relative preservation of thermoregulatory vasoconstriction was associated with sympathetic nervous system activation.⁶ Our current major results are that oral clonidine premedication produces a dose-dependent impairment of the thermoregulatory benefit normally elicited by PEEP; specifically, oral premedication with 300 μg obliterated the thermoregulatory protection normally produced by 10 cm H₂0 PEEP. Several mechanisms may account for the effect of clonidine premedication on thermoregulatory responses by PEEP.

Intravenous α-2 adrenergic agonists, such as clonidine and dexmedetomidine, decrease the thermoregulatory thresholds for vasoconstriction and shivering, producing a dose-dependent impairment of central thermoregulatory control.^8,11 It is therefore likely that clonidine's central inhibition of thermoregulatory control blunts the normal beneficial effects of PEEP. Several anaesthetics decrease the thermoregulatory vasoconstriction threshold in a dose-dependent manner.^12,13 Clonidine also has sedative/hypnotic and analgesic properties.⁷ Alpha-2 adrenoceptor activation produces a potent analgesic response involving both supraspinal and spinal sites. Alpha-2 agonists are able to reduce the MAC of volatile anaesthetics (e.g., MAC for isoflurane by 85% and for halothane by more than 95%). Therefore, clonidine itself might inhibit the thermoregulatory response as an anaesthetic agent, which antagonizes the thermoregulatory effect of baroreceptor unloading by PEEP. Alternatively, relatively higher concentration of isoflurane combined with clonidine in this study may exert more potent inhibitory effect on the thermoregulatory centre, which could overwhelm the effect on the thermoregulatory response by PEEP.

Cutaneous vasodilation induced by clonidine premedication may reduce the core to peripheral temperature gradient and enhance body heat redistribution, which mimics the effect of nifedipine premedication.¹⁴ However, clonidine premedication, which has no subtype selectivity, may produce initial vasoconstriction due to (-2B adrenergic stimulation,¹⁰ which prevents body heat redistribution. In this study, mean arterial pressure in the Clonidine-300 group was significantly decreased, compared with that of the Clonidine-0 group. These results suggest that the vasoconstrictive effect of clonidine was blunted by vasodilation produced by clonidine itself combined with the effect of anaesthetic agents.

Clonidine produces cutaneous vasodilation by reducing sympathetic nerve activity.¹⁵ Applying PEEP (baroreceptor unloading) prevents hypothermia by enhancing peripheral vasoconstriction, which is mediated by activation of the sympathetic nervous system via baroreceptors.⁶ Therefore, clonidine seems to inhibit the thermoregulatory vasoconstriction and the baroreceptor reflex-induced vasoconstriction through the sympathetic nervous system. The plasma norepinephrine and angiotensin II concentrations in the present study, both of which are increased by baroreceptor unloading with PEEP, indicated that clonidine dose-dependently attenuated the sympathetic outflow centrally, sympathetic tone peripherally, or both.

The amount of redistribution hypothermia (reduction in core temperature during the first hour of anaesthesia) was greater with ZEEP than PEEP. However, redistribution was similar with each dose of clonidine in the patients give PEEP. This suggests that clonidine premedication has little effect on core-to-peripheral internal heat redistribution of body heat. The second linear phase of the hypothermia curve results from heat loss exceeding heat production.³ This phase was short in our patients and is thus difficult to evaluate. In contrast, the plateau phase, which results from re-emergence of thermoregulatory vasoconstriction, was a strong function of both PEEP and clonidine dose. An additional factor is that clonidine premedication reduces systemic oxygen consumption which would also contribute to hypothermia.^8,17,18 It is thus likely that both thermoregulatory and metabolic factors contribute. Our study does not allow us to assess the relative contribution of each mechanism, but both appear most prominent during the third (plateau) phase of hypothermia.

Clonidine is a long-lasting drug with a half-life of roughly 12 hours.¹⁹ It is thus unlikely that plasma concentrations decreased much over the study period. A limitation of our study is that we did not measure plasma clonidine concentrations. We thus cannot confirm our assumption that concentrations were twice a great in the Clonodien-300 group as in the Clonidine-150 group. However, linear effects of clonidine on almost all measured responses suggest that plasma concentrations also changed proportionately with dose.

A limitation of this study is that gender is known to influence thermoregulation, and we did not control for this. However, there were no significant differences in gender between the four groups in our present study.

In summary, general anaesthetics profoundly reduce the thresholds for vasoconstriction and shivering. Baroreceptor unloading by PEEP normally moderates the amount of perioperative hypothermia by activating thermoregulatory vasoconstriction at temperatures closer to unanaesthetised values. The mechanism for this protective response appears to be early activation of the sympathetic nervous system. In contrast, clonidine premedication produces a linear, dose-dependent impairment in sympathetic nervous system activation. It also produces a dose-dependent reduction in the vasoconstriction threshold in the presence of PEEP. The consequence is a dose-dependent impairment of the beneficial thermoregulatory effect otherwise provided by PEEP. Premedication with 300 μg of clonidine obliterates the benefit that otherwise results from 10 cm H₂O PEEP.

Fig 2.

The functional relationship between T_forearm - T_fingertip and T_es. Patients assigned to the Clonidine-150 (35.8 ± 0.1°C) and Clonidine-300 (35.4 ± 0.2°C) group vasoconstricted at significantly lower core temperatures than those in the Clonidine-0 group (36.4 ± 0.1°C) (P < 0.05). Data are presented as the means ± SEM.