Ronald D. Miller

Simultaneous modeling of pharmacokinetics and pharmacodynamics: Application to d‐tubocurarine

We propose a model of drug pharmacodynamic response that when integrated with a pharmacokinetic model allows characterization of the temporal aspects of pharmacodynamics as well as the time‐independent sensitivity component. The total model can accommodate extremes of effect. It allows fitting of simultaneous plasma concentration (Cp) and effect data from the initial distribution phase of drug administration, or from any non‐equilibrium phase. The model postulates a hypothetical effect compartment, the dynamics of which are adjusted to reflect the temporal dynamics of drug effect. The effect compartment is modeled as an additional compartment linked to the plasma compartment by a first‐order process, but whose exponential does not enter into the pharmacokinetic solution for the mass of drug in the body. The hypothetical amount of drug in the effect compartment is then related to the observed effect by the Hill equation, a nonlinear sigmoid form. Nonlinear least‐squares data fitting is used for parameter estimation. The model is demonstrated on two different sets of Cp and effect data for the drug d‐tubocurarine (dTC). In 7 normal subjects, the (mean ± SD) rate constant for equilibration of dTC effect (paralysis) and Cp is 0.13 ± 0.04 min−1 and the (mean ± SD) steady‐state Cp required to produce 50% paralysis is 0.37 ± 0.05 µg/ml.

Comparison of rocuronium, succinylcholine, and vecuronium for rapid-sequence induction of anesthesia in adult patients.

BackgroundSuccinylcholine has been the agent of choice when clinical conditions require emergency airway protection during a rapid-sequence induction of anesthesia. Rocuronium, a new nondepolarizing muscle relaxant with a brief onset of action, but devoid of the adverse reactions associated with succinylcholine, may be an alternative to succinylcholine. To test this hypothesis, the authors compared rocuronium with succinylcholine and vecuronium for rapid-sequence induction of anesthesia. MethodsFifty patients, ASA 1–3, were randomly designated to receive one of three intravenous doses of rocuronium (0.6, 0.9, and 1.2 mg/kg), vecuronium (0.1 mg/kg), or succinylcholine (1.0 mg/kg). Patients were premedicated with midazolam and fentanyl, and received 2–7 mg/kg thiopental for induction of anesthesia. Sixty seconds after receiving a muscle relaxant, intubation of the trachea was attempted by a clinician who was blinded to the muscle relaxant administered. Neuromuscular monitoring was established before administration of the muscle relaxant. The time from injection of muscle relaxant until complete ablation of T1 (onset) and recovery of T1 to 25% (duration) were recorded. Tracheal intubating conditions were evaluated, and the presence or absence of fasciculations was noted. ResultsOnset times for patients receiving 0.9 mg/kg (75 ± 28 s) and 1.2 mg/kg rocuronium (55 ± 14 s), and succinylcholine (50 ± 17 s) were similar. Onset times for the groups given 0.6 mg/kg rocuronium (89 ± 33 s) and vecuronium (144 ± 39 s) were significantly longer. Clinical duration of action was longest with 1.2 mg/kg rocuronium, similar with 0.6 and 0.9 mg/kg rocuronium, and vecuronium, and least with succinylcholine. ConclusionsThere is a dose-dependent decrease in onset time with rocuronium. The onset times for the two larger doses of rocuronium were similar to that for succinylcholine, but clinical duration of action with rocuronium was significantly longer. The brief onset time achieved with rocuronium indicates that administration of 0.9–1.2 mg/kg is an acceptable alternative to succinylcholine for rapid-sequence induction of anesthesia.

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.

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.

Elimination of atracurium in humans: contribution of Hofmann elimination and ester hydrolysis versus organ-based elimination

Atracurium, a nondepolarizing muscle relaxant, is eliminated through several pathways, including Hofmann elimination (spontaneous degradation in plasma and tissue at normal body pH and temperature) and ester hydrolysis (catalysis by nonspecific esterases). Because elimination of atracurium occurs in both tissue and plasma, traditional pharmacokinetic models assuming elimination from a single central compartment are inaccurate for atracurium. The authors developed a two-compartment pharnacokinetic model in which hepatic and/or renal elimination occurs from the central compartment (Clorgan), and Hofmann elimination and ester hydrolysis occur from both central and peripheral compartments (Clnonorgan). To determine the in vitro rate constant for Hofmann elimination and ester hydrolysis, atracurium was added to whole blood kept at each patients pH and temperature. The values for this rate constant ranged from 0.0193 to 0.0238 per min. When these values were applied to the pharmacokinetic model, Cltotal, Clorgan, and Clnonorgan were 4.8 ± 1.1, 3.0 ± 0.9, and 1.9 ± 0.6 ml.kg−1. min−1, respectively. The authors conclude that more than one-half of the clearance of atracurium occurs via pathways other than Hofmann elimination and ester hydrolysis.

Clinical Pharmacology of ORG NC45 (NorcuronTM)A New Nondepolarizing Muscle Relaxant

To determine the neuromuscular effects of a new muscle relaxant, ORG NC45 (NorcuronTM), a monoquaternary homologue of pancuronium, 84 ASA Class I or II patients were studied under halothane and nitrous oxideanesthesia. The ED50 (dose of muscle relaxant causing a 50 per cent depression of twitch tension) of pancuronium and ORG NC45 was 0.022 mg/kg (r = 0.90) and 0.015 mg/kg (r = 0.80), respectively, for a potency ratio of 1.5 (0.022/0.015). The duration of action (time from injection to 90 per cent recovery of control twitch tension) was 27 ± 5 min with ORG NC45, 0.02 mg/kg, and 65 ± 16 min with pancuronium in an equivalent dose of 0.03 mg/kg. The increase in duration of neuromuscular blockade from repetitive doses was greater with pancuronium than with ORG NC45. Reversal of an ORG NC45 neuromuscular blockade was accomplished with doses of neostigmine slightly less than those required for pancuronium. Under thiopental-nitrous oxide anesthesia, endotracheal intubation was easily performed using ORG NC45, 0.07–0.14 mg/kg. The duration of action of ORG NC45, 0.07 mg/kg, was about one-third that of pancuronium (0.1 mg/kg). It was concluded that ORG NC45 is more potent and has a shorter duration of action with both initial and repetitive doses than does pancuronium. With these characteristics and the reported lack of cardiovascular effects, the authors believe further clinical trials are warranted.

Vecuronium-induced Neuromuscular Blockade during Enflurane, Isoflurane, and Halothane Anesthesia in Humans

To determine the effect of the commonly used volatile anesthetics on a vecuronium-induced neuromuscular blockade, the authors studied 54 patients anesthetized with 1.2 MAC or 2.2 MAC enflurane, isoflurane, or halothane (MAC value includes contribution from 60% nitrous oxide). During 1.2 MAC enflurane, isoflurane, and halothane, the ED50s (the doses depressing twitch tension 50%) for vecuronium were 12.8, 14.7, and 16.9 μg/kg, respectively. During 2.2 MAC enflurane, isoflurane, and halothane, the ED50s for vecuronium were 6.3, 9.8, and 13.8 μg/kg, respectively (P < 0.05). Time from injection to peak effect was the same for each anesthetic group (6.5 ± 0.5 min, mean ± SD), except for the group given 2.2 MAC enflurane (9.7 ± 0.6 min) (P < 0.05). The duration of a 50% block from injection to 90% recovery was the same for each group (mean 20 ± 4 min), except for the group given 2.2 MAC enflurane (46.5 min) (P < 0.05). The authors conclude that enflurane is the most potent volatile anesthetic, followed by isoflurane and then halothane, in augmenting a vecuronium-induced neuromuscular blockade. Increasing the concentration of volatile anesthetic has less effect on a neuromuscular blockade produced by vecuronium than on one produced by other nondepolarizing relaxants (e.g., pancuronium and d-tubucurarine).

Hypotensive anesthesia for total hip arthroplasty: a study of blood loss and organ function (brain, heart, liver, and kidney).

The authors attempted to determine whether hypotensive anesthesia or the method of inducing hypotension has any effect on postoperative brain, liver, or kidney function and myocardial status following total hip arthroplasty. Thirty patients were anesthetized with halothane–nitrous oxide for total hip arthroplasty and randomly assigned to one of three groups. In two groups mean arterial blood pressure was decreased to 50 torr by high inspired concentrations of halothane (n = 9) or sodium nitroprusside (n = 12). In the third group (n = 9) mean blood pressure was maintained within 20 per cent of control. Intraoperative blood losses decreased from 1,183 ± 172 ml in the normotensive group to 406 ± 102 ml and 326 ± 41 ml in the halothane and nitroprusside hypotensive groups, respectively. Neither method of inducing hypotension nor hypertensive technique affected the results of postoperative tests of cerebral, hepatic, or renal function and myocardial status. These tests were performed before anesthesia and operation and at intervals in the postoperative course. In this small group of patients, deliberate hypotension for total hiparthroplasty added no morbidity and significantly shortened operating time, decreased blood loss, and decreased the number of blood transfusions needed.

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.

A comparison of three methods of hemoglobin monitoring in patients undergoing spine surgery.

BACKGROUND:Hemoglobin values (Hb) can facilitate decisions regarding perioperative transfusion management. Currently, Hb can be determined invasively by analyzing blood via laboratory Co–Oximetry (tHb) or by point-of-care HemoCue (HCue). Recently, a new noninvasive, continuous spectrophotometric sensor (Masimo SpHb) was introduced into clinical practice. We compared the accuracy of the SpHb and HCue with tHb. METHODS:Twenty patients, ages 40 to 80 years, were studied. They received general anesthesia and underwent spine surgery in the prone position. All blood samples were obtained from a radial artery catheter. SpHb, tHb, and HCue were determined immediately after induction of anesthesia, but before the start of surgery and approximately every hour thereafter. Primary outcomes were defined on the basis of the following differences between measures: SpHb − tHb or HCue − tHb. All patients had 3 to 5 observations taken on each measure. Differences and absolute differences were analyzed by several techniques to assess accuracy. We also investigated the relationship between observed differences and the following variables: tHb level, duration of surgery, age, weight, and perfusion index. RESULTS:Data consisted of 78 measurements of SpHb, tHb, and HCue made on the 20 patients. Absolute differences between SpHb and tHb were <1.5 g/dL for 61% of observations, between 1.6 to 2.0 g/dL for 16% and >2.0 g/dL for 22% of the observations. Observed differences displayed significant decreases with time and higher perfusion index values. No systematic relationships were observed with age or weight. Except for 1 value, all of the HCue values were <1.0 g/dL of tHb. CONCLUSIONS:Although HCue was consistently accurate, our data confirm that SpHb often correlated well with tHb values. Yet our study indicates that SpHb may not be as accurate as clinically necessary in some patients. Improved refinement of continuous, noninvasive technology, such as SpHb, could address important clinical requirements.