Edwin B. Liem

Dexmedetomidine and Meperidine Additively Reduce the Shivering Threshold in Humans

Background and Purpose— Hypothermia might prove to be therapeutically beneficial in stroke victims; however, even mild hypothermia provokes vigorous shivering. Meperidine and dexmedetomidine each linearly reduce the shivering threshold (triggering core temperature) with minimal sedation. We tested the hypothesis that meperidine and dexmedetomidine synergistically reduce the shivering threshold without producing substantial sedation or respiratory depression. Methods— We studied 10 healthy male volunteers (18 to 40 years) on 4 days: (1) control (no drug); (2) meperidine (target plasma level 0.3 &mgr;g/mL); (3) dexmedetomidine (target plasma level 0.4 ng/mL); and (4) meperidine plus dexmedetomidine (target plasma levels of 0.3 &mgr;g/mL and 0.4 ng/mL, respectively). Lactated Ringer’s solution (≈4°C) was infused through a central venous catheter to decrease tympanic membrane temperature by ≈2.5°C/h; mean skin temperature was maintained at 31°C. An increase in oxygen consumption >25% of baseline identified the shivering threshold. Sedation was evaluated by using the Observer’s Assessment of Sedation/Alertness scale. Two-way repeated-measures ANOVA was used to identify interactions between drugs. Data are presented as mean±SD;P <0.05 was statistically significant. Results— The shivering thresholds on the study days were as follows: control, 36.7±0.3°C; dexmedetomidine, 36.0±0.5°C (P <0.001 from control); meperidine, 35.5±0.6°C (P <0.001); and meperidine plus dexmedetomidine, 34.7±0.6°C (P <0.001). Although meperidine and dexmedetomidine each reduced the shivering threshold, their interaction was not synergistic but additive (P =0.19). There was trivial sedation with either drug alone or in combination. Respiratory rate and end-tidal Pco2 were well preserved on all days. Conclusions— Dexmedetomidine and meperidine additively reduce the shivering threshold; in the small doses tested, the combination produced only mild sedation and no respiratory toxicity.

Anesthetic requirement is increased in redheads

Background:Age and body temperature alter inhalational anesthetic requirement; however, no human genotype is associated with inhalational anesthetic requirement. There is an anecdotal impression that anesthetic requirement is increased in redheads. Furthermore, red hair results from distinct mutations of the melanocortin-1 receptor. Therefore, the authors tested the hypothesis that the requirement for the volatile anesthetic desflurane is greater in natural redheaded than in dark-haired women. Methods:The authors studied healthy women with bright red (n = 10) or dark (n = 10) hair. Blood was sampled for subsequent analyses of melanocortin-1 receptor alleles. Anesthesia was induced with sevoflurane and maintained with desflurane randomly set at an end-tidal concentration between 5.5 and 7.5%. After an equilibration period, a noxious electrical stimulation (100 Hz, 70 mA) was transmitted through bilateral intradermal needles. If the volunteer moved in response to stimulation, desflurane was increased by 0.5%; otherwise, it was decreased by 0.5%. This was continued until volunteers “crossed over” from movement to nonmovement (or vice versa) four times. Individual logistic regression curves were used to determine desflurane requirement (P50). Desflurane requirements in the two groups were compared using Mann–Whitney nonparametric two-sample test; P < 0.05 was considered statistically significant. Results:The desflurane requirement in redheads (6.2 vol% [95% CI, 5.9–6.5]) was significantly greater than in dark-haired women (5.2 vol% [4.9–5.5]; P = 0.0004). Nine of 10 redheads were either homozygous or compound heterozygotes for mutations on the melanocortin-1 receptor gene. Conclusions:Red hair seems to be a distinct phenotype linked to anesthetic requirement in humans that can also be traced to a specific genotype.

Increased sensitivity to thermal pain and reduced subcutaneous lidocaine efficacy in redheads.

Background:Anesthetic requirement in redheads is exaggerated, suggesting that redheads may be especially sensitive to pain. Therefore, the authors tested the hypotheses that women with natural red hair are more sensitive to pain and that redheads are resistant to topical and subcutaneous lidocaine. Methods:The authors evaluated pain sensitivity in red-haired (n = 30) or dark-haired (n = 30) women by determining the electrical current perception threshold, pain perception, and maximum pain tolerance with a Neurometer CPT/C (Neurotron, Inc., Baltimore, MD). They evaluated the analogous warm and cold temperature thresholds with the TSA-II Neurosensory Analyzer (Medoc Ltd., Minneapolis, MN). Volunteers were tested with both devices at baseline and with the Neurometer after 1-h exposure to 4% liposomal lidocaine and after subcutaneous injection of 1% lidocaine. Data are presented as medians (interquartile ranges). Results:Current perception, pain perception, and pain tolerance thresholds were similar in the red-haired and dark-haired women at 2,000, 250, and 5 Hz. In contrast, redheads were more sensitive to cold pain perception (22.6 [15.1–26.1] vs. 12.6 [0–20]°C; P = 0.004), cold pain tolerance (6.0 [0–9.7] vs. 0.0 [0.0–2.0]°C; P = 0.001), and heat pain (46.3 [45.7–47.5] vs. 47.7 [46.6–48.7]°C; P = 0.009). Subcutaneous lidocaine was significantly less effective in redheads (e.g., pain tolerance threshold at 2,000-Hz stimulation in redheads was 11.0 [8.5–16.5] vs. > 20.0 (14.5 to > 20) mA in others; P = 0.005). Conclusion:Red hair is the phenotype for mutations of the melanocortin-1 receptor. Results indicate that redheads are more sensitive to thermal pain and are resistant to the analgesic effects of subcutaneous lidocaine. Mutations of the melanocortin-1 receptor, or a consequence thereof, thus modulate pain sensitivity.

Effect of intra-operative end-tidal carbon dioxide partial pressure on tissue oxygenation.

Postsurgical infection risk is correlated with subcutaneous tissue oxygenation. Mild hypercapnia augments cutaneous perfusion. We tested the hypothesis that peripheral tissue oxygenation increases as a function of arterial PCO2 in surgical patients. Twenty patients were randomly assigned to intra‐operative end tidal PCO2 of 3.99 (control) or 5.99 kPa (hypercapnia). All other anaesthetic management was per protocol. Tissue oxygen partial pressure, transcutaneous oxygen tension, cerebral oxygen saturation, and cardiac output were measured. Mean (SD) subcutaneous tissue oxygen tension was 8.39 (1.86) kPa in control and 11.84 (2.53) kPa hypercapnia patients (p = 0.014). Cerebral oxygen saturation was 55 (4)% for control vs. 68 (9)% for hypercapnia (p = 0.004). Neither cardiac index nor transcutaneous tissue oxygen tension differed significantly between the groups. Mild intra‐operative hypercapnia increased subcutaneous and cerebral oxygenation. Increases in subcutaneous tissue oxygen partial pressure similar to those observed in patients assigned to hypercapnia are associated with substantial reductions in wound infection risk.

Dantrolene Reduces the Threshold and Gain for Shivering

Dantrolene is used for treatment of life-threatening hyperthermia, yet its thermoregulatory effects are unknown. We tested the hypothesis that dantrolene reduces the threshold (triggering core temperature) and gain (incremental increase) of shivering. Healthy volunteers were evaluated on 2 random days: control and dantrolene (≈2.5 mg/kg plus a continuous infusion). In Study 1, 9 men were warmed until sweating was provoked and then cooled until arteriovenous shunt constriction and shivering occurred. Sweating was quantified on the chest using a ventilated capsule. Absolute right middle fingertip blood flow was quantified using venous-occlusion volume plethysmography. A sustained increase in oxygen consumption identified the shivering threshold. In Study 2, 9 men were given cold lactated Ringer’s solution IV to reduce core temperature 2°C/h. Cooling was stopped when shivering intensity no longer increased with further core cooling. The gain of shivering was the slope of oxygen consumption versus core temperature regression. In Study 1, sweating and vasoconstriction thresholds were similar on both days. In contrast, shivering threshold decreased 0.3 ± 0.3°C, P = 0.004, on the dantrolene day. In Study 2, dantrolene decreased the shivering threshold from 36.7 ± 0.2 to 36.3 ± 0.3°C, P = 0.01 and systemic gain from 353 ± 144 to 211 ± 93 mL · min−1 · °C−1, P = 0.02. Thus, dantrolene substantially decreased the gain of shivering, but produced little central thermoregulatory inhibition.

The timing of acupuncture stimulation does not influence anesthetic requirement.

Studies suggest that acupuncture is more effective when induced before the induction of general anesthesia than afterwards. We tested the hypothesis that electro-acupuncture initiated 30 min before the induction reduces anesthetic requirement more than acupuncture initiated after the induction. Seven volunteers were each anesthetized with desflurane on 3 study days. Needles were inserted percutaneously at four acupuncture points thought to produce analgesia in the upper abdominal area and provide generalized sedative and analgesic effects: Zusanli (St36), Sanyinjiao (Sp6), Liangqiu (Sp34), and Hegu (LI4). Needles were stimulated at 2 Hz and 10 Hz, with frequencies alternating at 2-s intervals. On Preinduction day, electro-acupuncture was started 30 min before the induction of anesthesia and maintained throughout the study. On At-induction day, needles were positioned before the induction of anesthesia, but electro-acupuncture stimulation was not initiated until after the induction. On Control day, electrodes were positioned near the acupoints, but needles were not inserted. Noxious electrical stimulation was administered via 25-gauge needles on the upper abdomen (70 mA; 100 Hz; 10 s). The desflurane concentration was increased 0.5% when movement occurred and decreased 0.5% when it did not. These up-and-down sequences continued until volunteers crossed from movement to no movement four times. The P50 of logistic regression identified desflurane requirement. Desflurane requirement was similar on the Control (mean ± sd; 5.2% ± 0.6%), Preinduction (5.0% ± 0.8%), and At-induction (4.7% ± 0.3%; P = 0.125) days. This type of acupuncture is thus unlikely to facilitate general anesthesia or decrease the requirement for anesthetic drugs.

Women with Red Hair Report A Slightly Increased Rate of Bruising, but Have Normal Coagulation Tests

There is an anecdotal impression that redheads experience more perioperative bleeding complications than do people with other hair colors. We, therefore, tested the hypothesis that perceived problems with hemostasis could be detected with commonly used coagulation tests. We studied healthy female Caucasian volunteers, 18 to 40 yr of age, comparable in terms of height, weight, and age, with natural bright red (n = 25) or black or dark brown (n = 26) hair. Volunteers were questioned about their bleeding history and the following tests were performed: complete blood count, prothrombin time/international normalized ratio, activated partial thromboplastin time, platelet function analysis, and platelet aggregation using standard turbidimetric methodology. Agonists for aggregation were adenosine diphosphate, arachidonic acid, collagen, epinephrine, and two concentrations of ristocetin. The red-haired volunteers reported significantly more bruising, but there were no significant differences between the red-haired and dark-haired groups in hemoglobin concentration, platelet numbers, prothrombin time/international normalized ratio, or activated partial thromboplastin time. Furthermore, no significant differences in platelet function, as measured by platelet function analysis or platelet aggregometry, were observed. We conclude that if redheads have hemostasis abnormalities, they are subtle.