James E. Caldwell

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.

Reversal of profound rocuronium-induced blockade with sugammadex: a randomized comparison with neostigmine.

Background: Traditionally, reversal of nondepolarizing neuromuscular blocking agents was achieved using acetylcholinesterase inhibitors, but these are unable to adequately reverse profound blockade. Sugammadex is a novel reversal agent, reversing the effects of rocuronium by encapsulation. This study assessed the efficacy and safety of sugammadex versus neostigmine for reversal of profound rocuronium-induced neuromuscular blockade. Methods: This phase III, randomized study enrolled surgical patients, aged 18 yr or older with American Society of Anesthesiologists physical status I–IV. Patients were randomized to receive sugammadex (4.0 mg/kg) or neostigmine (70 &mgr;g/kg) plus glycopyrrolate (14 &mgr;g/kg). Anesthetized patients received an intubating dose of rocuronium (0.6 mg/kg), with maintenance doses (0.15 mg/kg) as required. Neuromuscular monitoring was performed by acceleromyography. Sugammadex or neostigmine was administered at reappearance of 1–2 posttetanic counts (profound neuromuscular blockade). The primary efficacy parameter was the time from sugammadex or neostigmine–glycopyrrolate administration to return of the train-of-four ratio to 0.9. Results: In the intent-to-treat population (n = 37 in each group), geometric mean time to recovery to a train-of-four ratio of 0.9 with sugammadex was 2.9 min versus 50.4 min with neostigmine–glycopyrrolate (P < 0.0001) (median, 2.7 min vs. 49.0 min). Most sugammadex patients (97%) recovered to a train-of-four ratio of 0.9 within 5 min after administration. In contrast, most neostigmine patients (73%) recovered between 30 and 60 min after administration, with 23% requiring more than 60 min to recover to a train-of-four ratio of 0.9. Conclusions: Recovery from profound rocuronium-induced neuromuscular blockade was significantly faster with sugammadex versus with neostigmine, suggesting that sugammadex has a unique ability to rapidly reverse profound rocuronium neuromuscular blockade.

Onset and duration of rocuronium and succinylcholine at the adductor pollicis and laryngeal adductor muscles in anesthetized humans.

BackgroundRocuronium, a new nondepolarizing muscle relaxant, has a rapid onset of activity and may be suitable as a component of a rapid-sequence Induction of anesthesia. We evaluated a range of doses on onset and duration of effect at the larynx and the adductor pollicis and compared these characteristics with those of succinylcholine. MethodsForty-eight patients aged 18–70 yr, of ASA physical status 1–3, were randomly allocated to receive succinylcholine (1 mg/kg) or one of three doses of rocuronium (0.4, 0.8, or 1.2 mg/kg) during surgery. Anesthesia was induced and maintained with propofol and fentanyl. The trachea was intubated without the use of muscle relaxants, and the cuff of the endotracheal tube placed between the vocal cords. Neuromuscular transmission was monitored by mechanomyography at the laryngeal adductor and adductor pollicis muscles. Muscular activity was evoked with supramaximal stimuli in a train-of-four sequence every 12 s to the anterior branch of the recurrent laryngeal nerve and the ulnar nerve. ResultsAt the laryngeal adductors, peak effect exceeded 99% in all patients given succinylcholine and in none (0%), five (42%), and ten (83%) of those given rocuronium 0.4, 0.8, and 1.2 mg/kg, respectively. At the adductor pollicis, peak effect exceeded 99% in all study patients except two who received rocuronium 0.4 mg/kg (peak effects 91% and 97%). Onset of effect with succinylcholine was significantly more rapid at the laryngeal adductors (34 ± 12 s, mean ± SD) than at the adductor pollicis (56 ± 15 s); this was true also for rocuronium 0.4 mg/kg (92 ± 29 s and 155 ± 40 s for the laryngeal adductors and adductor pollicis, respectively). Onset times were similar at the two muscle groups with rocuronium 0.8 and 1.2 mg·kg-1: 96 ± 29 and 74 ± 36 s with 0.8 mg/kg and 54 ± 30 and 65 ± 21 s with 1.2 mg/kg at the laryngeal adductors and the adductor pollicis, respectively. ConclusionsThe laryngeal adductors are more resistant to the action of rocuronium than is the adductor pollicis. Consequently, the onset of effect of rocuronium, in doses greater than 0.8 mg/kg, is similar to that of succinylcholine at the adductor pollicis but Is significantly delayed compared with that of succinylcholine at the laryngeal adductors.

Pharmacokinetics of rocuronium bromide (ORG 9426) in patients with normal renal function or patients undergoing cadaver renal transplantation.

To determine the effect of end-stage renal disease on the pharmacokinetics of reocuronium bromide (ORG 9426), a new nondepolarizing monoquaternary steroidal neuromuscular blocking drug, the authors administered 600 micrograms/kg rocuronium (2 x ED95) intravenously to ten patients undergoing cadaver renal transplantation and ten healthy patients undergoing elective minor surgery (controls). All patients were anesthetized with nitrous oxide (50-70% in oxygen) and isoflurane (end-tidal concentrations of 1.2 +/- 0.5% and 0.8 +/- 0.2%, mean +/- SD, for control and transplant groups, respectively). Plasma concentrations of rocuronium were determined by capillary gas chromatography. A population-based pharmacokinetic analysis (NONMEM) was used to determine typical values, standard errors, and interindividual variability for the pharmacokinetic parameters and to determine whether these values differed between control and renal transplant patients. Total plasma clearance (2.89 +/- 0.25 ml.kg-1.min-1, mean +/- SE) and volume of the central compartment (76.9 +/- 10.6 ml/kg) did not differ between control and renal transplant patients, whereas volume of distribution at steady state was greater in renal transplant patients (264 +/- 19 ml/kg) than in control patients (207 +/- 14 ml/kg). This resulted in a longer elimination half life in renal transplant patients (97.2 +/- 17.3 min) compared to controls (70.9 +/- 4.7 min). The authors conclude that renal failure and renal transplantation alter the distribution but not the clearance of rocuronium.

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.

The pharmacokinetics and neuromuscular effects of rocuronium bromide in patients with liver disease

To determine the effect of liver disease on the pharmacokinetics of rocuronium, the authors administered 0.6 mg/kg (twice the ED95) to 10 patients with liver disease and compared these results to values in 10 healthy surgical patients. Anesthesia was induced with thiopental and maintained with isoflurane (0.9%-1.1% end-tidal concentration) and nitrous oxide (60%). Venous blood samples were obtained for 6 h after rocuronium injection and plasma concentrations were measured using gas chromatography. Pharmacokinetic differences between groups were determined using a population-based pharmacokinetic analysis (NONMEM). Hepatic impairment did not alter the plasma clearance of rocuronium (217 +/- 21.8 mL/min, mean +/- SE, for both groups), but did increase the volume of the central compartment (5.96 +/- 1.01 L for controls, 7.87 +/- 1.33 L for patients with liver disease) and volume of distribution at steady state (16.4 L for controls, 23.4 L for patients with liver disease). In turn, elimination half-life was longer in patients with liver disease (111 min) compared to controls (75.4 min). The authors conclude that liver disease alters the pharmacokinetics of rocuronium by increasing its volume of distribution. The longer elimination half-life might result in a longer duration of action of rocuronium in patients with liver disease, particularly after prolonged administration. (Anesth Analg 1995;80:754-9)

The pharmacodynamics and pharmacokinetics of vecuronium in patients anesthetized with isoflurane with normal renal function or with renal failure.

The duration of action and the pharmacokinetics of vecuronium were compared in patients with and without renal function. Twenty patients were studied: 12 with renal failure who were to receive kidney transplants from cadaveric donors, and eight with normal renal function. After oral premedication with diazepam, 10 mg, anesthesia was induced with thiopental, 4 mg/kg iv, and maintained with the inhalation of 60% nitrous oxide and 0.9–1.1% isoflurane, end-tidal concentration, in 40% oxygen. The force of thumb adduction in response to supramaximal ulnar nerve stimulation was monitored and recorded. An intravenous bolus of vecuronium, 0.1 mg/kg, was administered after 15 min of a stable end-tidal isoflurane concentration, as measured by mean spectrometry. Venous blood was then sampled at frequent intervals for 4 h following the bolus. Vecuronium concentrations in plasma were quantified by a sensitive and specific gas chromatographic assay. Data were analyzed by nonlinear least squares regression and described by a two-compartment model. The duration of neuromuscular blockade was longer in patients with renal failure than in those with normal renal function. This increased duration may be related to both a decreased plasma clearance duration may be related to both a decreased plasma clearance and a prolonged elimination half-life of vecuronium in the renal failure group.

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.

Muscle Relaxation Does Not Alter Hypnotic Level During Propofol Anesthesia

Electromyographic (EMG) activity can contaminate electroencephalographic signals. Paralysis may therefore reduce the Bispectral Index (BIS) by alleviating artifact from muscles lying near the electrodes. Paralysis may also reduce signals from muscle stretch receptors that normally contribute to arousal. We therefore tested the hypothesis that nondepolarizing neuromuscular block reduces BIS. Ten volunteers were anesthetized with propofol at a target effect site concentration of 3.8 ± 0.4 &mgr;g/mL. A mivacurium infusion was adjusted to vary the first twitch (T1) in a train-of-four to 80%, 30%, 20%, 15%, 10%, 5%, or 2% of the prerelaxant intensity. At each randomly assigned T1, we measured BIS and frontal-temporal EMG intensity. BIS averaged 95 ± 4 before induction of anesthesia, and decreased significantly to 40 ± 5 after propofol administration. However, there were no significant differences at the designated block levels. Frontal-temporal EMG intensity averaged 47 ± 3 dB before induction of anesthesia, and decreased significantly to 27 ± 1 dB after propofol administration. However, there were no significant differences at the designated block levels. These data suggest that the BIS level and EMG tone are unaltered by mivacurium administration during propofol anesthesia.