Mild therapeutic hypothermia (2°C–4°C) has proven protective against tissue ischemia in every tested animal species and virtually all experimental models.1,2 In humans, hypothermia improves long-term neurological outcomes after out-of-hospital cardiac arrest3,4 and in asphyxiated neonates.5–7 In contrast, it has not proven helpful for brain trauma,8,9 aneurysm surgery,10 or acute myocardial infarction,11 although delayed onset of hypothermia and other issues complicate interpretation of these studies.
Stroke, which has yet to be adequately tested, remains among the most promising uses for therapeutic hypothermia.12 Stroke differs from cardiac arrest and asphyxiated neonates, in that most victims do not require tracheal intubation. Furthermore, neurologists prefer to avoid deep sedation because it interferes with symptom evaluation. To the extent that hypothermia is used for stroke, it must thus be induced without provoking undue discomfort, autonomic activation, or compromising ventilation. The difficulty is that induction of even mild hypothermia provokes thermoregulatory defenses,13 notably arteriovenous shunt constriction and shivering.14,15 Vasoconstriction provokes hypertension,16 but more importantly, shivering increases plasma catecholamine concentrations, worsens hypertension, increases metabolic rate, and is uncomfortable.16,17
An important clinical question is how to pharmacologically prevent shivering without deep sedation and substantial respiratory compromise. One strategy is to take advantage of the 20% cutaneous contribution to autonomic thermoregulatory control18,19 and 50% contribution to thermal comfort20 by combining endovascular cooling with cutaneous warming.21,22 While undoubtedly effective, this strategy reduces the shivering threshold (triggering core temperature) by <1°C. Furthermore, it can only be used in conjunction with invasive catheter-based cooling systems.23,24 In practice, physical cooling needs to be combined with induction of pharmacologic tolerance that substantially reduces the shivering threshold. It is easy to induce thermal tolerance with deep sedation25 or general anesthesia.26 It is challenging to cool patients while maintaining consciousness and adequate ventilation.
Various nonanesthetic drugs reduce the shivering threshold, including tramadol,27 alfentanil,28 clonidine,29,30 dexmedetomidine, dantrolene,31 and doxapram32; however, possibly the best single drug is meperidine,28 which almost uniquely reduces the shivering threshold disproportionately more than the vasoconstriction threshold.33 Meperidine does not sufficiently reduce the shivering threshold to be used as a sole drug. Various drug combinations have been studied to identify additive, or preferably synergistic, combinations that induce substantial thermal tolerance with few side effects. For example, nefopam and alfentanil are additive,34 as are buspirone and dexmedetomidine.35 Even better, buspirone and meperidine act synergistically and are thus especially effective.36
Nefopam, a nonsedative benzoxazocine analgesic, is an effective antishivering drug that does not cause sedation or impair ventilation.37 Combined with meperidine,28,33 nefopam might induce clinically useful thermal tolerance, especially if the antishivering effects of the combination proved additive or synergistic. We determined the interaction between nefopam and meperidine on the shivering threshold in volunteers.
With IRB (Comité de Protection des Personnes, Ile de France VIII, Hôpital Ambroise Paré, Boulogne-Billancourt, France) approval and written informed consent, we studied 10 healthy male volunteers. We evaluated 10 volunteers because similar numbers have been used in previous similar studies and we expected similar baseline variability and treatment effect.34–36 None was obese, taking medication, or had a history of thyroid disease, dysautonomia, or Raynaud syndrome.
The volunteers had a light breakfast and refrained from caffeine for at least 8 hours before the study. To avoid circadian fluctuations, studies were scheduled so that thermoregulatory responses were triggered at similar times on each of the study days. During the studies, the volunteers rested supine and were minimally clothed.
The study was conducted in a single-blind fashion, with volunteers blinded to which drug(s), if any, they were given on each study day. The volunteers were studied on 4 randomly assigned days, each separated by at least 48 hours: (1) control, no drug; (2) nefopam at a target plasma concentration of 0.1 μg/mL (nefopam); (3) meperidine at a target plasma concentration of 0.1 μg/mL (meperidine); and (4) nefopam and meperidine combination at target concentrations of 0.1 μg/mL each (combination).
An 18-cm-long 4.5-Fr catheter (Vygon, Ecouen, France) was introduced through an antecubital vein and used for the infusion of cooled solution. A venous catheter was inserted into the other arm for drug administration. Throughout the study period, mean skin temperature (details below) was maintained at 30°C by adjusting the ambient temperature.
Thermal manipulation began 30 minutes after the study drugs were started. Lactated Ringer’s solution cooled to 4°C was infused at rates sufficient to decrease tympanic membrane temperature 1°C/h to 2°C/h. Fluid was given until the shivering threshold was identified or a total of 70 mL/kg was given. A pediatric forced-air cover connected to a warmer (Warm-Touch, Mallinckrodt, Inc., St. Louis, MO) was rolled around the arm used for cold solution infusion because we have found that local warming reduces local discomfort.
Nefopam and meperidine were infused through an Orchestra Base A (Fresenius Vial Inc., Brezins, France) pump connected to a locally generated software written in Visual Basic 5.0 (Microsoft, Redmond, MA). The nefopam infusion profile was based on published pharmacokinetic data38 and was designed to provide a time to peak plasma concentrations of 20 minutes with a mean elimination half-life of 240 minutes. The infusion rate for the target plasma level of meperidine was based on published pharmacokinetic data and was designed to provide a time to peak plasma concentrations of 10 minutes with a mean elimination half-life of 4.4 hours.39 Both dosing schemes were intended to rapidly achieve therapeutic concentrations, minimize side effects during the initial phase, and maintain a therapeutic level throughout the study.
Drug doses were chosen to: (1) decrease the shivering threshold 0.5°C to 1°C, and (2) minimize toxicity. From previous data, a concentration of 0.1 μg/mL nefopam was chosen to reduce the shivering threshold 0.6°C to 0.7.34,40 For meperidine, a target blood concentration of 0.1 μg/mL was chosen from published data.33 With this dose, a 0.6°C shivering threshold decrease was expected with only minor respiratory depression and minimal sedation.
Heart rate and pulse oximeter saturation were monitored continuously. Arterial blood pressure was determined oscillometrically at the ankle at 10-minute intervals and at the time the shivering threshold was reached (Argus LCM, Schiller, Marne la Vallée, France). Oxygen consumption and carbon dioxide production were measured by a DeltaTrac metabolic monitor (Datex-Ohmeda, Helsinki, Finland). The system was used in canopy mode with measurements averaged over 1-minute intervals and recorded every minute.
Core temperature was measured at the tympanic membrane. The aural probe was inserted until the patients 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, the aural canal occluded with cotton, and the external ear covered with a gauze bandage. Mean skin temperature (T Skin) was calculated from 10 sites, using the formula:41
All temperatures were measured using Ellab thermometers and probes (Ellab, Inc., Copenhagen, Denmark), and results were recorded electronically at 10-second intervals.
Thermoregulatory vasoconstriction was determined by estimating fingertip blood flow, which was evaluated using forearm minus fingertip, skin surface temperature gradients.42 Gradients exceeding 0°C were indicative of vasoconstriction because this gradient corresponds to onset of the core temperature plateau.43 As in numerous previous studies,44,45 shivering was evaluated by a blinded observer and confirmed when a sustained increase in oxygen consumption (VO2) to 25% above the baseline identified significant shivering.
Sedation was evaluated using the responsiveness component of a modified Observer’s Assessment of Alertness/Sedation (OAA/S) score (Table 1) upon completion of the initial loading infusion and at the shivering threshold. Thermal comfort was assessed at each threshold with a 100-mm-long visual analog scale with 50 mm defined as thermal comfort, 0 mm as the most intense imaginable sensation of cold, and 100 mm being the most intense imaginable sensation of warmth. On each study day, sedation score and thermal comfort were obtained: (1) before drug administration; (2) before active cooling started; and (3) at the shivering threshold.
Volunteers were asked about pain upon study drug injection. They were also asked about side effects during the initial loading dose and at 10-minute intervals during drug or placebo infusion until the shivering threshold was identified. Specifically, we asked about pruritus, bradypnea, dizziness, headache, nausea, vomiting, dry mouth, palpitation, and epigastric pain.
The shivering threshold was identified by a sustained increase in oxygen consumption VO2 exceeding 25% lasting at least 3 minutes. The baseline for this analysis was the steady state (≤5% variation) VO2 after drug infusion but before core cooling started. On each study day, hemodynamic and SpO2 data were averaged for each volunteer across the cooling period. These values were then averaged among the volunteers. Core and mean skin temperature data, as well as thermal comfort scores (visual analog scale) at the shivering threshold, were similarly averaged among the volunteers for each study day.
Sedation scores after drug infusion and at the shivering threshold were presented as the number of subjects having modified OAA/S scores of 5, 4, or 3. Results on the 4 study days for each combination were compared by Kruskal-Wallis test and Student-Newman-Keuls tests for post hoc comparison.
The interaction between nefopam and meperidine was evaluated as described by Slinker.46 The study was designed as a 2-factor crossover experiment with 2 levels for each factor: the presence and absence of each of the 2 drugs. Assuming an additive effect, the expected reduction for the combination of nefopam and meperidine was estimated as the sum of the individual effects of nefopam and meperidine for each subject. Specifically, analysis was based on the differences between the control and drug days for each volunteer.
With this model, a statistically significant interaction term between the 2 drugs indicates that they act synergistically (greater than expected effect) or have an infra-additive interaction (less than expected effect). A nonsignificant interaction term indicates that the drugs’ effects on the shivering threshold are additive.
The data were normally distributed. Repeated-measures analysis of variance were used because each volunteer received all 4 treatments. Side effect frequencies were compared with Fisher exact tests. The software used for statistical tests was StatView v. 5.0 (SAS Institute Inc., Cary, NC). Results are expressed as means ± SDs. Differences and the interaction term were considered statistically significant when P < 0.05.
Ten volunteers (24 ± 6 years old), weighing 70 ± 7 kg, and 178 ± 5 cm tall, were each evaluated on 4 study days. The mean initial loading dose of nefopam was 46 ± 0.6 mg (0.64 ± 0.09 mg/kg); the mean loading dose of meperidine was 16.5 ± 1.2 mg (0.25 ± 0.05 mg/kg).
After the loading dose infusion, sedation level, as defined by the modified OAA/S score, heart rate, mean arterial blood pressure, and SpO2 were similar on each study day. All the volunteers were vasoconstricted before the cold fluid infusion was started and remained vasoconstricted throughout the study.
Mean skin temperatures at the shivering threshold were similar on each of the 4 study days. Sedation level at the shivering threshold did not differ among the 4 study days and was of trivial magnitude. Significantly more lactated Ringer’s solution was given on the nefopam and combination study days than on the control day (Table 2).
Nefopam reduced the shivering threshold by 0.7°C ± 0.3°C, from 36.6°C ± 0.3°C on the control day to 35.8°C ± 0.3°C (P < 0.001). Meperidine reduced the shivering threshold by 0.4°C ± 0.3°C, to 36.1°C ± 0.3°C (P < 0.001). The combination of nefopam and meperidine reduced the shivering threshold by only 0.6°C ± 0.4°C, to 35.8°C ± 0.3°C (P < 0.001).
There was a significant interaction between the 2 drugs on the shivering threshold (P < 0.001). The combination of nefopam and meperidine was infra-additive because it reduced the shivering threshold less than would be expected based on the individual effects of each drug (Fig. 1).
Nausea and pain on injection were both significantly more common with nefopam than with no drug or meperidine. Both complications were more common with the combination of nefopam and meperidine (Table 3) than with either drug alone.
No single approved drug appears to sufficiently reduce the shivering threshold in doses that are safe in unintubated humans. (Future drugs based on hydrogen sulfide47 or inhibitors of transient receptor potential receptors48 may prove effective as single agents.) Combinations of existing drugs are thus an attractive strategy for inducing thermal tolerance since efficacy will be enhanced, while presumably limiting the intensity of any particular side effect. Shivering has only been evaluated with a limited number of drug combinations. Most, unsurprisingly, appear to be additive.34,35
For example, the combination of nefopam and alfentanil is additive on the shivering threshold.34 In contrast, our current results suggest that nefopam and meperidine are infra-additive. All opioids impair thermoregulatory control,49,50 but meperidine differs from other opioids in reducing the shivering threshold twice as much as the vasoconstriction threshold.33 This “special antishivering action” of meperidine does not result from the drug’s κ agonist activity or from its anticholinergic activity.51 A possible explanation is that meperidine may have a central α-agonist effect.52 Nefopam analgesia is partially mediated by α receptors,53 and its antishivering action may be as well. However, the infra-additive interaction between meperidine and nefopam probably results from other antishivering effects of each drug.
Nefopam and meperidine each individually reduce the shivering threshold and might thus reasonably be included in antishivering cocktails. However, given their infra-additive relationship, they would not be a prudent combination. In contrast, the combination of meperidine and buspirone is synergistic and well tolerated. It has thus been used in large clinical trials11 and remains a common strategy for induction of hypothermia in unintubated patients. The combination of meperidine and dexmedetomidine is additive. Because doses that are well tolerated sufficiently reduce the shivering threshold,35 it is thus also a reasonable clinical strategy. Other approaches were recently described in a meta-analysis.54
We did not measure plasma drug concentrations. However, we used well-established pharmacokinetic models and computer-controlled administration to target desired concentrations. Meperidine reduced the shivering threshold slightly less than expected (0.4°C vs 0.6°C), but well within experimental error.33 The reduction with nefopam was also as expected based on previous works (0.7°C vs 0.6°C–0.7°C).34,40
Only 10 volunteers participated in our study. However, we used a 4-way crossover design to increase statistical power. Furthermore, thermoregulatory responses are highly reproducible, also increasing statistical power. Our conclusion that nefopam and meperidine are infra-additive is likely correct.
The dose dependence of the shivering threshold has been determined for both meperidine33 and nefopam,37 with both being linear. While it is possible that the interaction differs as a function of dose, it seems quite unlikely that different doses would produce a clinically useful additive or supra-additive effect. We evaluated young, healthy, thin volunteers, which is rarely the target population for therapeutic hypothermia. While it is likely that hypothermia will be easier to induce in elderly patients, the specific thermoregulatory effects of the drugs we evaluated may differ somewhat.
In summary, nefopam reduced the shivering thresholds by 0.7°C ± 0.3°C compared with no drug. Meperidine reduced the shivering thresholds by 0.4°C ± 0.3°C compared with no drug. When combined, the shivering threshold decreased by only 0.6°C ± 0.4°C, which was significantly less than would be expected based on the individual effects of each drug (P < 0.001). The effect of combined nefopam and meperidine on the shivering threshold is infra-additive. The combination of nefopam and meperidine should be avoided for induction of therapeutic hypothermia. Better options would be combinations of drugs that are at least additive (such as buspirone and dexmedetomidine) or even synergistic (such as buspirone and meperidine).
Name: Pascal Alfonsi, MD.
Contribution: This author helped design and conduct the study, analyze the data, and write the manuscript.
Attestation: Pascal Alfonsi has seen the original study data, reviewed the analysis of the data, approved the final manuscript, and is the author responsible for archiving the study files.
Name: Andrea Passard, MD.
Contribution: This author helped design and conduct the study, analyze the data, and write the manuscript.
Attestation: Andrea Passard has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.
Name: Bruno Guignard, MD.
Contribution: This author helped design and conduct the study.
Attestation: Bruno Guinard has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.
Name: Marcel Chauvin, MD.
Contribution: This author helped design and conduct the study, analyze the data, and write the manuscript.
Attestation: Marcel Chauvin has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.
Name: Daniel I. Sessler, MD.
Contribution: This author helped design the study and write the manuscript.
Attestation: Daniel I. Sessler has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.
This manuscript was handled by: Steven L. Shafer, MD.
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