Tom Heier

Mild Intraoperative Hypothermia Increases Duration of Action and Spontaneous Recovery ofVecuronium Blockade during Nitrous Oxide-Isoflurane Anesthesia in Humans

We compared the duration of action and recovery times for vecuronium in normothermic and mildly hypothermic patients. Ten patients were actively cooled to a central body temperature near 34.5 degrees C, and ten were maintained at a normothermic central temperature (greater than 36.5 degrees C); temperature was measured in the distal esophagus. Vecuronium 0.1 mg/kg was administered as an intravenous (iv) bolus to all patients, and the evoked mechanical response to train-of-four stimulation was recorded. Five hypothermic and five normothermic patients were allowed to recover spontaneously. In the remaining five in each group, neostigmine (40 micrograms/kg) and atropine (20 micrograms/kg) was administered when the first twitch (T1) height spontaneously recovered to 10% of control (T1 = 10% of the pre-vecuronium twitch tension). Vecuroniums duration of action (from injection of drug until T1 = 10%) was 28 +/- 4 and 62 +/- 8 min during normothermia and hypothermia, respectively (P less than 0.05). The corresponding values for spontaneous recovery from T1 = 10% to TOF ratio greater than 75% were 37 +/- 15 and 80 +/- 24 min (P less than 0.05), and for neostigmine-induced recovery were 10 +/- 3 and 16 +/- 11 min (difference not significant). We conclude that mild hypothermia increases the duration of action of and time for spontaneous recovery from vecuronium-induced neuromuscular blockade.

Temperature-dependent pharmacokinetics and pharmacodynamics of vecuronium.

Background The authors evaluated the influence of temperature on the pharmacokinetics and pharmacodynamics of vecuronium because mild core hypothermia doubles its duration of action. Methods Anesthesia was induced with alfentanil and propofol and maintained with nitrous oxide and isoflurane in 12 healthy volunteers. Train-of-four stimuli were applied to the ulnar nerve, and the mechanical response of the adductor pollicis was measured. Volunteers were actively cooled or warmed until their distal esophageal temperatures were in one of four ranges: < 35.0°C, 35.0–35.9°C, 36.0–36.9°C, and ≥ 37.0°C. With temperature stabilized, vecuronium was infused at 5 &mgr;g · kg−1 · min−1 until the first response of each train-of-four had decreased by 70%. Arterial blood (for vecuronium analysis) was sampled at intervals until the first response recovered to at least 90% of its prevecuronium level. Vecuronium, 20 &mgr;g · kg−1 · min−1, was then infused for 10 min, and arterial blood was sampled at intervals for up to 7 h. Population-based nonlinear mixed-effects modeling was used to examine the effect of physical characteristics and core temperature on vecuronium pharmacokinetics and pharmacodynamics. Results Decreasing core temperature over 38.0–34.0°C decreases the plasma clearance of vecuronium (11.3% per °C), decreases the rate constant for drug equilibration between plasma and effect site (0.023 min−1 per °C), and increases the slope of the concentration–response relationship (0.43 per °C). Conclusions Our results show that reduced clearance and rate of effect site equilibration explain the increased duration of action of vecuronium with reducing core temperature. Tissue sensitivity to vecuronium is not influenced by core temperature.

Efficacy of tactile-guided reversal from cisatracurium-induced neuromuscular block.

Background Because tactile evaluation is the most common form of clinical neuromuscular monitoring, this study examines the relative efficacy of antagonizing residual block at different levels of recovery of the tactile train-of-four (TOF) response. Methods Anesthesia was induced in 64 adults with 2–5 &mgr;g/kg fentanyl and 1–3 mg/kg propofol and maintained with fentanyl, propofol, and nitrous oxide. The tactile response of the adductor pollicis to TOF stimulation was evaluated at one arm, and the mechanomyographic response was recorded at the other. Patients received 0.15 mg/kg cisatracurium and were randomized to receive 0.07 mg/kg neostigmine on reappearance of the first (group I), second (group II), third (group III), or fourth (group IV) tactile TOF response (16 patients per group). Times from administration of neostigmine until the TOF ratio recovered to 0.7 (R0.7), 0.8 (R0.8), and 0.9 (R0.9) were measured. Results Data are presented as median with range in parentheses. R0.7 was 10.3 (5.9–23.4), 7.6 (3.2–14.1), 5.0 (2.0–18.4), and 4.1 (2.4–11.0) min in groups I, II, III, and IV, respectively (P < 0.05, group I > II, III, and IV, group II > IV). R0.8 was 16.6 (8.9–30.7), 9.8 (5.3–25.0), 8.3 (3.8–27.1), and 7.5 (3.0–74.5) min in groups I, II, III, and IV, respectively (P < 0.05, group I > II, III, and IV, group II > IV). R0.9 was 22.2 (13.9–44.0), 20.2 (6.5–70.5), 17.1 (8.3–46.2), and 16.5 (6.5–143.3) min in groups I, II, III, and IV, respectively (no intergroup differences). Ten minutes after neostigmine, a TOF ratio of 0.7 or greater was achieved in 50, 75, 88, and 93% of patients in groups I, II, III, and IV, respectively (P < 0.05 group I > II, III, and IV). At 30 min, a TOF ratio of 0.9 or less was observed in 21, 13, 13, and 7% of patients in groups I, II, III, and IV respectively (no intergroup differences). Conclusions To achieve rapid (within 10 min) reversal to a TOF ratio of 0.7 in more than 87% of patients, three or four tactile responses should be present at the time of neostigmine administration. It was not possible within 30 min to achieve a TOF ratio of 0.9 in all patients, regardless of the number of tactile responses present at neostigmine administration.

Hemoglobin desaturation after succinylcholine-induced apnea : A study of the recovery of Spontaneous ventilation in healthy volunteers

Background Because of the rapid recovery of neuromuscular function after succinylcholine administration, there is a belief that patients will start breathing sufficiently rapidly to prevent significant oxygen desaturation. The authors tested whether this belief was valid. Methods Twelve healthy volunteers aged 18–45 yr participated in the study. After preoxygenation to an end-tidal oxygen concentration greater than 90%, each subject received 5 mg/kg thiopental and 1 mg/kg succinylcholine. Oxygen saturation (Sao2) was measured at both a finger and an ear lobe (beat to beat). During the period of apnea and as they were recovering, the volunteers received continuous verbal reassurance by the investigators. If the Sao2 decreased below 80%, the volunteers received chin lift and, if necessary, assisted ventilation. The length of time the subject was apneic and level of desaturation were related by linear regression analysis. One hour after recovery and again 1 week later, subjects were asked a series of questions regarding their emotional experience. Results In six volunteers, Sao2 decreased below 95% during apnea; in four, Sao2 decreased below 80%, necessitating chin lift and assisted ventilation in three. Apnea time was significantly longer in volunteers who reached Sao2 less than 80% than in those who did not (7.0 ± 0.4 and 4.1 ± 0.3 min, respectively), and there was a significant correlation between the length of time the subject was apneic and the magnitude of desaturation. Conclusions Spontaneous recovery from succinylcholine-induced apnea may not occur sufficiently quickly to prevent hemoglobin desaturation in subjects whose ventilation is not assisted.

Impact of Hypothermia on the Response to Neuromuscular Blocking Drugs

Muscle strength is reduced during hypothermia, both in the presence and in the absence of neuromuscular blocking drugs. A 2°C reduction in body temperature may double the duration of neuromuscular blockade. Central body and muscle temperatures decline in parallel, as long as peripheral vasoconstriction does not occur. A reduction in muscle strength must be expected at a body temperature less than 36°C (corresponding to a muscle temperature of approximately 35°C). Local cooling of the hand may make adductor pollicis twitch tension monitoring less useful during clinical anesthesia. The efficacy of neostigmine is maintained during mild hypothermia. The use of a nerve stimulator is strongly recommended to monitor the effect of neuromuscular blocking drugs during intraoperative hypothermia.

Safety and efficacy of sugammadex for the reversal of rocuronium-induced neuromuscular blockade in cardiac patients undergoing noncardiac surgery

Background and objective The present randomized, safety-assessor blinded, placebo-controlled trial was designed to assess safety and efficacy of sugammadex, a novel selective relaxant-binding agent, in patients with underlying cardiovascular disease undergoing noncardiac surgery. Methods Overall, 116 patients (New York Heart Association class II–III) were randomized and received sugammadex 2.0 mg kg−1 (n = 38), sugammadex 4.0 mg kg−1 (n = 38) or placebo (n = 40) for reversal of rocuronium-induced neuromuscular blockade at reappearance of T2. Safety variables included heart rate, blood pressure and electrocardiogram characteristics, including rate-corrected QT (QTc Fridericia and QTc Bazett) interval. Efficacy was evaluated as time to recovery of the T4/T1 ratio to 0.9 after administration of sugammadex or placebo. Results There were no significant differences between groups in terms of QTc (Fridericia) interval. Three serious adverse events, one in each treatment group, considered to be possibly drug-related according to the investigator, were cases of mild QTc (Bazett) interval prolongation. Blood pressure and heart rate decreased after initiation of anaesthesia and remained stable in all groups up to 10 min after administration of study drug. Blood pressure was significantly higher (P < 0.05) in both sugammadex dose groups compared with placebo at 30 min. The decrease in heart rate from baseline (prestudy drug) was significantly greater in the 2.0 mg kg−1 sugammadex group at 2 and 5 min, and, for both sugammadex groups, the increase at 30 min was greater compared with placebo. Both sugammadex doses resulted in considerably shorter time to recovery of the T4/T1 ratio to 0.9 compared with placebo. Conclusion The findings indicate sugammadex 2.0 and 4.0 mg kg−1 can be given safely and effectively for the reversal of rocuronium-induced neuromuscular blockade in patients with cardiovascular disease undergoing noncardiac surgery.

Rapid Tracheal Intubation with Large-Dose Rocuronium: A Probability-Based Approach

There are situations in anesthesia in which it may be desirable to achieve rapid tracheal intubation with perfect conditions, i.e., no coughing or straining. To determine the dose of rocuronium that gives a high probability of achieving perfect conditions for rapid (within 60 s) tracheal intubation, we administered a range of doses of rocuronium, some larger than used previously. Sixty adults, anesthetized with thiopental 4 mg/kg IV and alfentanil 10 &mgr;g/kg IV, received rocuronium 0.4 to 2.0 mg/kg IV. We used logistic regression to define the relationship of rocuronium dose to probability of achieving perfect intubation conditions. We estimated the doses giving 90% and 95% probability of achieving perfect intubation and used resampling to determine confidence limits for these estimates. Rocuronium 1.85 and 2.33 mg/kg gave, respectively, 90% and 95% probability of perfect intubation conditions. The confidence limits (5th and 95th percentile) for these estimates were 1.15 to 2.31 and 1.23 to 3.22 mg/kg, respectively. In conclusion, it is possible to achieve perfect intubation conditions with large doses of rocuronium, but the long duration of action and expense may limit the usefulness of the technique. Implications We found that it is possible to have a 90% probability of achieving perfect conditions for rapid tracheal intubation with large (up to 2.0 mg/kg) doses of rocuronium. These large doses of rocuronium may be useful in, for instance, head trauma or open globe injuries if succinylcholine is contraindicated.

The Relationship Between Adductor Pollicis Twitch Tension and Core, Skin, and Muscle Temperature during Nitrous Oxide—Isoflurane Anesthesia in Humans

Temperature and volatile anesthetic agents influence neuromuscular transmission. Because mild hypothermia is common during general anesthesia, the authors sought to determine the relationship between the core temperature, adductor pollicis muscle temperature, and the twitch response of the adductor pollicis muscle, during isoflurane anesthesia in 15 patients undergoing elective surgery in which muscle relaxants were not required. Five patients were allowed to cool spontaneously, five were cooled actively, and normothermia was maintained actively in the remaining five. In the normothermic patients (core greater than 36.5 degrees C, muscle greater than 35.7 degrees C), the twitch response of the muscle remained unchanged from control values. In the patients who were cooled passively or actively, a muscle temperature threshold was observed (35.2 degrees C), below which twitch response of the muscle diminished by 10-15%/degrees C decrease in muscle temperature. To ensure that the adductor pollicis muscle temperature remained above 35.2 degrees C, the core temperature had to be maintained above 36 degrees C. A significant linear relationship (P less than 0.05) was found between the adductor pollicis muscle temperature and twitch tension below the threshold for each individual patient in the cooled groups (correlation coefficient range, 0.80-0.99). Thus, there is a temperature-related decrease in adductor pollicis twitch response during isoflurane anesthesia, and the temperature of this muscle should be maintained above 35-35.5 degrees C during studies of neuromuscular transmission. This can be achieved by maintaining core temperature above 36 degrees C.

Pharmacokinetics and Pharmacodynamics of Atracurium in the Elderly

To evaluate the effect of aging on the distribution, clearance, and neuromuscular junction sensitivity to atracurium, the authors determined the pharmacokinetics and pharmacodynamics of atracurium in five healthy elderly subjects (74-76 yr) during halothane-nitrous oxide anesthesia and compared these values to those obtained previously in five healthy young adults (22-44 yr). A brief (6.0-13.0 min) infusion of atracurium was administered until twitch tension was suppressed by approximately 70%, and atracurium plasma concentration and twitch tension data were used to determine pharmacokinetic and pharmacodynamic parameters for each patient. Total clearance (Cltotal) was similar in elderly and young adults. However, clearance via the liver and/or kidney (Clorgan) was lower in elderly patients, whereas clearance due to Hofmann elimination and ester hydrolysis (Clnonorgan) was higher. Volume of distribution at steady state (Vss) was larger in elderly patients. The increase in Vss without an age-related increase in Cltotal resulted in a longer elimination half-life [21.8 (+)/- 3.3 vs. 15.7 (+)/- 2.5 min (mean (+)/- SD)] in elderly patients. The steady state plasma concentration of atracurium required to suppress twitch tension by 50% was similar in elderly and young adults. The authors conclude that the pharmacokinetics, but not the pharmacodynamics, of atracurium differ significantly between elderly and young adults. As a result, repeated doses will be required with similar frequency in young and elderly adults, but recovery from comparable levels of neuromuscular blockade may be slightly prolonged in elderly patients.

Mild intraoperative hypothermia does not change the pharmacodynamics (concentration-effect relationship) of vecuronium in humans

To investigate the effect of mild hypothermia on the neuromuscular junction sensitivity to vecuronium, we determined the pharmacodynamics (concentration-effect relationship) of vecuronium in 10 patients (ASA physical class I or II; age range, 21–46 yr; weight range, 54–104 kg), during isoflurane-nitrous oxide-fentanyl anesthesia. Five were cooled to a mean temperature of 34.4°C and five were maintained normothermic at a mean temperature of 36.8°C. Neuromuscular function was monitored by measuring the evoked mechanical response of the adductor pollicis muscle after supra-maximal train-of-four stimulation of the ulnar nerve at the wrist. Vecuronium, 3 μg·kg−1.min−1, was infused for 10 min, venous blood sampled for 60 min, and twitch tension and plasma concentration data were used to determine pharmacodynamic variables in each patient. Results for the hypothermic and normothermic groups were compared by Mann-Whitney U-test. There were no differences in any pharmacodynamic variable between the hypothermic and normothermic patients. For the hypothermic and normothermic patients, respectively, steady-state plasma concentrations of vecuronium producing 50% neuromuscular block (CSS50) were 73 ± 13 ng/mL (mean ± SD) and 79 ± 31 ng/mL; the rate constants for equilibration of vecuronium between the plasma and the neuromuscular junction (Keo) were 0.27 ± 0.14 per min−1 and 0.26 ± 0.11 per min, and the power functions representing the slope of the concentration-effect relationship (γ) were 5.7 ± 1.9 and 4.4 ± 1.8. We conclude that the pharmacodynamics (concentration-effect relationship) of vecuronium are similar at 34.4 and 36.8°C and that pharmacodynamic factors do not explain the prolongation of action of vecuronium previously observed during mild hypothermia.