Mild hypothermia provides substantial protection against cerebral1 – 4 and myocardial ischemia in animals.5,6 In humans, mild hypothermia improves neurologic outcome and reduces mortality after cardiac arrest.6 – 8
Mild hypothermia with core temperatures between 33°C and 34°C is relatively easy to induce during general anesthesia because anesthetics profoundly impair thermoregulatory responses5,9 – 11 such as arteriovenous shunt vasoconstriction and shivering. Other analgesic and sedative drugs, for example, meperidine,6 buspirone,12 dexmedetomidine,13 and clonidine,14 comparably reduce the vasoconstriction and shivering threshold. However, all of these drugs, when used in sufficient concentrations to impair thermoregulatory control, have severe side effects such as sedation and respiratory depression. There is thus considerable interest in identifying drugs that defeat thermoregulatory defenses against hypothermia without causing side effects in awake patients.
Nefopam, a nonsedative analgesic, seems to have important thermoregulatory properties. It is a benzoxazocine compound that is structurally related to orphenadrine and diphenhydramine.7 It is a centrally acting analgesic7,8 with both supraspinal15,16 and spinal sites of action.17,18 Nefopam is neither an opiate nor a nonsteroidal noninflammatory drug19 and does not induce respiratory depression, even in postoperative patients.20 Mechanisms involved in the thermoregulatory effect of nefopam are not clearly established.
Clinical studies indicate that nefopam treats or prevents postoperative shivering.21 – 23 It decreases the shivering threshold without altering the vasoconstriction threshold.24 It might thus be a potent drug for induction of therapeutic hypothermia. However, not only the shivering threshold but also the gain and maximum intensity of a thermoregulatory response define the thermoregulatory properties of a drug and are thus of great clinical importance. Once the shivering threshold is reached, shivering usually progresses quickly to its maximum intensity in a nonsedated and nonanesthetized person. Once maximum intensity for shivering is reached, further cooling is almost impossible. Nefopam might not only delay the shivering threshold but also the gain of shivering, which would allow cooling to even lower core temperatures before maximum intensity of shivering is reached. Furthermore, nefopam might decrease the maximum intensity of shivering, which in itself would foster cooling. Therefore, we evaluated the gain and maximum intensity of shivering with 2 different doses of nefopam.
With approval from the IRB of the University Hospital of Bern and written informed consent, we studied 7 healthy volunteers (5 men and 2 women) on 3 days. Medical history and physical examination were performed. Volunteers who used any medication or reported a history of alcohol or drug abuse were excluded from the study.
Studies started at approximately 8:00 AM. Volunteers fasted for 8 hours and avoided alcohol and drugs for 24 hours before each study day. During the study, volunteers were minimally clothed and rested supine on a standard patient bed equipped with a water mattress. Ambient temperature was maintained between 20°C and 22°C. Volunteers were studied on 3 randomly assigned days, each separated by at least 2 days: (1) control (saline), (2) nefopam at a target plasma concentration of 50 ng/mL (small dose), and (3) nefopam at a target concentration of 100 ng/mL (large dose).
Nefopam was administered IV via the right antecubital vein as bolus plus maintenance regimen. The infusion profile was based on published pharmacokinetic data.24,25 The time to peak plasma concentration was 20 minutes; the mean elimination half-life was approximately 240 minutes. This dosing scheme is intended to rapidly achieve therapeutic concentrations, minimize side effects during the initial phase, and maintain a therapeutic level throughout the study.
A 20-gauge catheter was inserted into a radial artery for blood sampling. To qualify for arterial catheterization, volunteers were required to have no recent wrist trauma, and normal Allen test. Arterial lines were placed by anesthesiologists or physicians experienced in the procedure. If insertion of the arterial line was not possible with 3 attempts, the study was aborted. Blood samples were collected from the arterial line via a 3-way stopcock. After each sample, the arterial line was flushed with 0.9% sodium chloride. The arterial line remained in place for up to 15 hours after nefopam administration for additional blood sampling to further evaluate nefopam pharmacokinetics (unpublished data). We had no complications with the arterial lines.
A 30-cm central venous catheter was inserted with sterile technique by an anesthesiologist in the volunteer's left antecubital vein and used for infusion of cold Ringer lactate solution. During infusion of cold IV fluid, the upper arm was kept warm to avoid discomfort for the volunteers. The central venous catheter was removed after each study day and no complications were observed. Once stable predicted nefopam plasma concentrations were achieved (approximately 30 minutes after start of the infusion), Ringer lactate solution cooled to approximately 4°C was infused via the left antecubital vein on all study days at rates sufficient to decrease tympanic membrane temperature approximately 2.4°C/h, i.e., approximately 0.2°C every 5 minutes. The core temperature cooling rate was restricted to <2.5°C/h because this rate was unlikely to trigger any dynamic thermoregulatory response.3 Fluid was given until the maximum intensity (shivering intensity no longer increases, despite a continued decrease in core temperature) of shivering was identified or a total of up to 60 mL/kg fluid was administered. Throughout the study, the volunteers’ mean skin temperatures were kept at 31°C using a forced-air whole body cover on top of the volunteers and a circulating water mattress under the volunteers. A temperature of 31°C was chosen specifically because this is a skin temperature at which volunteers are vasoconstricted and feel slightly cold but have not yet started to shiver. Choosing this particular mean skin temperature restricts IV fluid amounts. Each thermoregulatory study ended upon detection of maximum intensity of shivering. Subsequently, volunteers were warmed until they were normothermic and comfortable.
An interval of at least 48 hours elapsed between study days; before subsequent treatment, a blood sample was obtained to ensure that nefopam had been eliminated from the previous study day.
Heart rate was measured continuously using an electrocardiogram and oxygen saturation using a pulse oximeter. Blood pressure was determined oscillometrically at 5-minute intervals as well as from the arterial line. Core temperature was recorded from the tympanic membrane (Mallinckrodt Anesthesiology Products, Inc., St. Louis, MO). Tympanic probes were inserted into both ears by the volunteer until the thermocouple touched the tympanic membrane; appropriate placement was confirmed when the volunteer detected a gentle rubbing of the attached wire. Additionally, a temperature difference ≤0.2°C confirmed correct placement. The aural canal was occluded with cotton, the probe taped securely in place, and a gauze bandage was positioned over the external ear. Mean skin-surface temperatures were calculated from measurements at 15 area-weighted sites. Temperatures were recorded at 1-minute intervals from thermocouples connected to Iso-Thermex® thermometers with an accuracy of 0.1°C (Columbus Instruments Corp., Columbus, OH).26
Oxygen consumption, as measured by a Vmax metabolic monitor (Sensor Medics Corp., Yorba Linda, CA), was used to quantify shivering; the system was used in canopy mode on the 3 study days. This system provides measurements with an absolute accuracy of 5% to 10%.27 Measurements were averaged over 1-minute intervals and recorded every minute. A sustained increase in oxygen consumption of 20% identified the shivering threshold. Oxygen consumption is the “gold standard” for shivering intensity because it represents integrated metabolic rate.
We also evaluated known side effects of nefopam such as nausea and vomiting, pain at the injection site, and dry mouth every 30 minutes throughout the study.
Determination of Nefopam Plasma Concentrations
Plasma samples were stored at −20°C until analysis. Before extraction, plasma samples for nefopam analysis were allowed to thaw at room temperature, vortexed, and then centrifuged at 2000 rpm for 5 minutes. To 0.5 mL of plasma, 0.5 mL deionized water, internal standard (imipramine hydrochloride; ICN Biomedicals, Inc., Aurora, OH) and 30 μL orthophosphoric acid were added and vortexed. Samples were analyzed by gas chromatography–mass selective detector (MSD) (model 6890 with a 5972A MSD and automatic injector; Agilent Technologies, Santa Clara, CA). Aliquots of 1 μL were injected in splitless mode onto a Varian FactorFour VF-Xms (Varian, Inc., Palo Alto, CA), 12 m, 0.2-mm inside diameter capillary column with a 0.33-μm film. The helium flow rate was 0.8 mL/min. Operating temperatures of the gas chromatography were: injector 250°C, MSD transfer line 280°C, oven 140°C for 0.2 minute increasing (25°C/min) to 280°C, hold 1 minute. The MSD was operated in the electron impact mode (70 eV) with selected ion monitoring with a dwell time of 100 milliseconds each. Selected ion monitoring ions for quantitation were m/z 225 and 235 for nefopam and internal standard, respectively. The data were processed with proprietary mass spectrometer control software (HP G1701AA; Hewlett-Packard, Palo Alto, CA).
All calibration curves had correlation coefficients ≥0.99. Coefficient of variation of intraday reproducibility (n = 10) was for nefopam at 301, 103, and 10.3 ng/mL blood content 2.0%, 2.2%, and 3.7%, respectively. Coefficient of variation of interday reproducibility at the same concentrations (n = 6) was 4.5%, 5.3%, and 7.4%, respectively. Mean recovery of nefopam (n = 15) at concentrations of 10 to 300 ng/mL was 92.5% (range, 87%–104%). The limit of quantification at a signal-to-noise ratio of 10:1 was 4.4 ng/mL. The limit of detection at a signal-to-noise ratio of 3:1 was 1.3 ng/mL.
A 20% sustained increase in oxygen consumption identified the shivering threshold. The cutaneous contribution to sweating and to vasoconstriction and shivering is linear. We thus used measured skin and core temperatures in °C at the threshold to calculate the core-temperature threshold that would have been observed with a fixed skin temperature of 31°C:
where the fractional contribution of mean skin temperature to the threshold was termed β. TCore(calculated) thus equals the measured core temperature, TCore, plus a small correction factor consisting of β/(1 − β) multiplied by the difference between actual (TSkin) and designated [TSkin(designated)] skin temperatures. We have previously described the derivation, limitations, and validation of this equation. We used a β of 0.2 for shivering. The designated skin temperature was set at 31°C.
The gain of shivering was determined as the slope of oxygen consumption versus core temperature regression during its initial ascent toward the maximum observed value. Slopes were calculated for each volunteer and each study day and then averaged among volunteers. Maximum intensity of shivering was identified by an oxygen consumption that failed to increase further despite continued reduction in core temperature. In both cases, the data series were smoothed using 5-minute running average filters. The shivering threshold, gains, and maximum intensity were determined post hoc by an investigator blinded to treatment and core temperature. Results on the 3 study days were averaged using repeated measures of analysis of variance.
Hemodynamic responses, ambient temperature, relative humidity, and end-tidal PCO2 on each study day were first averaged for each volunteer; data obtained between the onset of shivering and the maximum intensity were included. The resulting values among volunteers were then averaged. Results on the 3 study days were compared using repeated measures of analysis of variance.
Volunteers were aged 27 ± 6 years, weighed 76 ± 12 kg, and were 180 ± 6 cm tall. The volunteers required slightly more fluid for core cooling when nefopam was administered (Table 1). Heart rate was similar on all study days whereas mean arterial blood pressure increased with the large dose of nefopam. However, this increase was small and clinically unimportant. Furthermore, thermal comfort was similar on all 3 days (Table 2). Known side effects of nefopam such as nausea and vomiting and pain at the injection site were not observed in this study. One volunteer experienced dry mouth during the first hour after drug administration.
As per protocol, nefopam plasma levels were 56 ± 10 ng/mL and 99 ± 15 ng/mL for small and large doses, respectively (Table 1). A total amount of approximately 17 mg nefopam was administered on the small-dose day and approximately 32 mg on the large-dose day. According to protocol, skin temperature was ≈31°C on all study days throughout the entire study (Table 2).
The calculated shivering threshold was 35.6°C ± 0.2°C on the control day. As in previous studies, nefopam significantly decreased the shivering threshold with the low and the high dose of nefopam (small dose: 35.2°C ± 0.3°C; large dose: 34.9°C ± 0.5°C; P = 0.0041) (Table 2). However, low and high dose did not differ significantly. The high dose of nefopam also significantly reduced the gain of shivering (control day: 597 ± 235 mL · min−1 · °C−1; small dose: 438 ± 178 mL · min−1 · °C−1; and large dose: 301 ± 134 mL · min−1 · °C−1; P = 0.028) (Fig. 1). The core temperature at maximum intensity of shivering was significantly lower on the small-dose and high-dose days compared with control. Maximum intensity of shivering did not differ among the 3 studies days (Table 2).
Mild hypothermia has been shown to improve outcome after cardiac arrest1,2 and its application has been advised by the International Liaison Committee on Resuscitation28 and the European Resuscitation Council.29 Currently, investigators conducting several clinical trials are studying mild hypothermia in patients with ischemic heart injury, brain trauma, and ischemic stroke. In the majority of studies, hypothermia is induced by anesthetics often in combination with muscle relaxants to suppress shivering. Although anesthetics reduce shivering and vasoconstriction thresholds by 2°C to 3°C, these drugs are, unsurprisingly, not the first choice for induction of mild hypothermia in the awake patient; they cause significant sedation, respiratory depression, and jeopardize airway patency.
Consequently, numerous investigators have searched for other drugs or drug combinations that decrease vasoconstriction and shivering thresholds. One of the most effective antishivering drugs is meperidine.30 Meperidine affects both shivering and vasoconstriction thresholds, but reduces the shivering threshold to a greater extent (by a factor of 2) compared with the vasoconstriction threshold.31 However, when used as a single drug, large plasma concentrations of meperidine are necessary to reduce shivering thresholds below 34°C, leading to sedation and respiratory depression. Smaller doses of meperidine in combination with other drugs (buspirone,12 dexmedetomidine,13 or magnesium32) have proven helpful.
We investigated nefopam, a centrally acting, nonsedative analgesic. Nefopam is neither an opiate nor a nonsteroidal noninflammatory drug.19 Nefopam does not induce respiratory depression, even in postoperative patients.20 Clinical studies indicate that nefopam treats or prevents postoperative shivering.21 – 23 Mechanisms involved in the thermoregulatory effect of nefopam are not clearly established. However, in vitro and in vivo studies indicate that nefopam's analgesic properties are related to its potent inhibition of serotonin (5-hydroxytryptamine), norepinephrine, and dopamine synaptosomal uptake. Monoamines are involved in the thermoregulatory pathways. The balance between modulator 5-hydroxytryptamine and norepinephrine inputs may be responsible for short-term thermoregulatory adaptive modifications of the heat-defense and cold-defense responses, with monoamines promoting hypothermia. Nefopam may therefore promote hypothermia via a monoamine mechanism. Other properties of nefopam may also contribute to its antishivering action. Nefopam may have a direct interaction with α2-adrenoceptors. Nefopam, similar to orphenadrine, is also a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist. Magnesium sulfate and ketamine, which are competitive NMDA receptor antagonists, inhibit postanesthetic shivering. Inhibition of NMDA receptors may thus contribute to the antishivering effect of nefopam. Nefopam is available in Europe, but is not approved by the Food and Drug Administration for use in the United States.
Alfonsi et al.24 showed that moderate doses of nefopam decrease the threshold of shivering to a core temperature of approximately 35°C without affecting the vasoconstriction threshold. Furthermore, side effects, e.g., nausea, pain upon injection, or dry mouth, were minimal and of short duration. Nefopam did not impair ventilation. Although this study defined the shivering threshold, the thermoregulatory response is further described by the gain and maximum intensity of shivering. Gain determines the extent to which the response intensity increases with further deviation of the core temperature from the triggering threshold. Maximum intensity is the maximum response, which even with further deviation from the core temperature remains unchanged. As demonstrated by our study, 100 ng/mL nefopam significantly decreased the gain of shivering but did not affect maximum intensity. Clinically, this is important: once shivering is triggered, core temperature decreases approximately 1°C before the maximum intensity of shivering. An approximate 1°C reduction in the shivering threshold is itself unlikely to be sufficient for induction of therapeutic hypothermia in unanesthetized patients. However, if the gain of shivering is decreased as well, patients probably can be actively cooled until maximum intensity of shivering is reached, which would allow a further reduction of core temperature of 0.5°C to 1.0°C. Furthermore, it is likely that nefopam combined with other drugs will produce substantial thermoregulatory tolerance with minimal side effects. Alfonsi et al.33 recently showed that the combination of nefopam with alfentanil reduces the shivering threshold more than nefopam and the α-agonist clonidine, and the combination of nefopam with alfentanil was more effective than either alfentanil or nefopam alone. Furthermore, induction of hypothermia via internal cooling in combination with skin-surface warming significantly reduces the shivering threshold.34 Thus, the combination of skin warming and nefopam administration might be a powerful approach to therapeutic hypothermia, when hypothermia is induced by internal cooling.
Furthermore, only a few anesthetics or epidural anesthesia decrease the shivering threshold and have an effect on gain of shivering as well. However, neither general nor neuraxial anesthesia are helpful for the purpose of therapeutic hypothermia. Moreover, meperidine, which represents the gold standard for shivering inhibition, fails to reduce gain of shivering. For these reasons, findings of our study are clinically relevant because nefopam is the first drug with a significant effect on the shivering threshold that does not have sedative, respiratory, or hemodynamic effects and that reduces gain of shivering, allowing further core temperature decrease after the shivering threshold is achieved.
For the purpose of our study, we administered a total of approximately 17 mg nefopam on the low-dose day and 32 mg nefopam on the high-dose day. Nefopam reduced both the shivering threshold and the gain of shivering. This is comparable to the study by Alfonsi et al.24 who saw a dose-dependent reduction in the shivering threshold. However, in that study, lower nefopam plasma levels were reached (30 ng/mL blood for the low dose and 60 ng/mL blood for the high dose). Thus, their high dose was similar to our low dose. The shivering threshold for their high dose was 35.3°C, which is comparable to the shivering threshold in our study for the low dose. However, doubling the plasma levels from 50 to 100 ng/mL did not result in a further decrease in the shivering threshold. This suggests that a maximum decrease in the shivering threshold can be reached with a nefopam dose of 50 ng/mL and that a further increase in dose does not result in further threshold reduction. However, we achieved a significant reduction in the gain of shivering with the high dose of nefopam only. Both the reduction in threshold and gain are important for induction and maintenance of therapeutic hypothermia. It is important to note that both of our nefopam doses are still within the therapeutic range of nefopam and, even when administered for long periods of time during therapeutic hypothermia, are not associated with toxic side effects. Administration of doses equivalent to a plasma concentration of approximately 100 ng/mL will achieve the greatest impairment of thermoregulatory defense mechanisms.
In the study by Alfonsi et al., the volunteers were significantly more likely to become nauseated or to complain of pain upon injection or a dry mouth during the study when nefopam was infused. In our current study, we did not see these side effects, most likely because we administered the drug as a target-controlled infusion. We observed a significant increase in arterial blood pressure on the high-dose nefopam day. However, we believe that this increase is not clinically important. Furthermore, this increase might have been only partially attributable to nefopam's effects. In many hypothermia volunteer studies, slight increases in arterial blood pressure at low core temperatures are observed with intense shivering. In the current study, the high dose of nefopam was associated with the lowest core temperatures, which might have contributed to the slight increase in mean arterial blood pressure.
A limitation of our study is that it was conducted in young, healthy volunteers. Results from volunteer studies cannot always be extrapolated to clinical situations. For example, 0.12 mg/kg nefopam seemed to have a greater effect in patients recovering from neurosurgery.35 Indeed, only 2 of 20 patients shivered at a mean core temperature of 33.6°C. However, there were numerous factors that presumably contributed to thermoregulatory inhibition in these patients including residual anesthesia and opioids, cutaneous warming to 36.5°C, and neurosurgery per se.
In summary, the high dose of nefopam significantly reduced the gain of shivering. This reduction, in combination with a reduced shivering threshold, will allow clinicians to cool patients even further when therapeutic hypothermia is indicated. There were no adverse side effects, suggesting that even a relatively high dose of the drug can be used for an extended period of time to suppress thermoregulatory cold responses.
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© 2010 International Anesthesia Research Society
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