Altered d-tubocurarine disposition during cardiopulmonary bypass surgery.

Kinetics of the neuromuscular blocker d-tubocurarine (dTc) were investigated in 13 adult patients undergoing surgery involving cardiopulmonary bypass (CPB). Approximately 1 hr before CPB surgery, each received dTc as an intravenous bolus of 0.6 mg/kg and a maintenance infusion of 3 micrograms/kg/min. dTc plasma concentration-time data before CPB did not differ from those reported in normal surgical patients. There was an abrupt discontinuity in the plasma concentration-time profile with the onset of CPB, and both total and free plasma concentrations increased 400% during the period of CPB. Although computer simulations suggest that these rises in dTc plasma concentrations can be attributed to contraction in central compartment volume, there also was decreased renal and total plasma clearance of dTc together with a prolonged elimination 1 1/2, which suggests that clearance processes of dTc are also altered as a result of CPB. A 27% rise in dTc free fraction in plasma during CPB could be attributed to hemodilution associated with the CPB procedure itself. Lower doses of dTc will need to be used in patients undergoing surgery that involves CPB unless the concentration-effect relationship for dTc is so altered that higher concentrations are needed to elicit the same response as in normal patients.

Pharmacokinetics and pharmacodynamics of vecuronium administered by bolus and infusion during halothane or balanced anesthesia.

Vecuronium was administered to two patient groups as a single intravenous dose, 60 micrograms/kg, combined with an infusion, 1 microgram/min/kg. Anesthesia was maintained for the first group with a halothane-nitrous oxide technique; the second group received fentanyl-barbiturate-tranquilizer-nitrous oxide. As the infusion ended, plasma vecuronium concentrations were 0.34 (+/- 0.10) microgram/ml for the halothane group and 0.32 (+/- 0.07) microgram/ml for the fentanyl group, associated with 93% (+/- 8) and 88% (+/- 10) twitch depression, respectively. Vecuronium plasma concentration-time data were combined with the simultaneous intensities of neuromuscular blockade to model the kinetic-dynamic values for each patient. For the halothane group the steady-state volume was 0.21 (+/- 0.04) L/kg, the clearance was 2.9 (+/- 0.1) ml/min/kg, and the elimination half-life was 100 (+/- 36) minutes; for the fentanyl group these were 0.20 (+/- 0.08) L/kg, 3.2 (+/- 0.1) ml/min/kg, and 84 (+/- 43) minutes, respectively. Plasma concentrations associated with 50% blockade averaged 0.2 microgram/ml for both groups. Neither the pharmacokinetics nor the pharmacodynamics of vecuronium in humans differed between these two patient groups.

Gallamine disposition in open-heart surgery involving cardiopulmonary bypass.

Kinetics of gallamine, a neuromuscular blocker, were investigated in 22 adult patients undergoing surgery involving cardiopulmonary bypass (CPB). Approximately 60 min before CPB, 11 patients received 480 mg gallamine IV; the other 11 patients received an initial dose of 240 mg IV, followed by another 240 mg through the pump priming fluid at the start of CPB. In 14 of our patients, the time course of gallamine concentrations in the plasma before, during, and after CPB was similar to that in normal surgical patients, indicating little or no effect of cardiac disease or CPB. In the remaining patients, perturbations were not observed before CPB, but with its onset there were varying changes, typically, rises in gallamine concentration ranging from an alteration during the period of CPB only or during the elimination phase, to an alteration at all times after starting CPB. Although the mechanism for this rise in gallamine plasma concentrations during and after CPB is not known, computer simulations suggest that it is due to a contraction in blood volume or decreased tissue perfusion during the period of extracorporeal circulation. Gallamine disposition differed only moderately in our patients from that in control patients. Therefore, from a kinetic viewpoint, provided that renal function is not impaired, gallamine is not contraindicated in CPB surgery.

Metocurine kinetics in patients undergoing operations requiring cardiopulmonary bypass.

Metocurine kinetics were determined in 10 patients undergoing operations requiring hypothermic cardiopulmonary bypass (CPB) and nine patients of similar age undergoing operations of similar duration but not requiring CPB. The metocurine dosage regimen was a bolus of 0.3 mg/kg given concomitantly with the commencement of an infusion at a rate of 0.04 mg/kg/hr; this regimen was designed to produce and maintain a plasma metocurine concentration associated with 95% depression of the twitch response. Metocurine kinetics were affected minimally by hypothermic CPB. The kinetic parameters including volumes of distribution at steady state of 0.35 L/kg and 0.34 L/kg and elimination clearances of 1.3 ml/min/kg and 1.1 ml/min/kg in the control and CPB groups, respectively, are in agreement with the results of others. Changes in neuromuscular blockade with the onset of CPB and the return to original blockade intensities with rewarming suggest a decreased sensitivity to the effects of metocurine at lower temperatures.

Indocyanine green kinetics characterize blood volume and flow distribution and their alteration by propranolol.

BACKGROUND AND OBJECTIVES: Although indocyanine green can be used to estimate cardiac output and blood volume independently, a recirculatory multicompartmental indocyanine green model enables description of these and additional intravascular events. Our model was used to describe the effect of propranolol on blood volume and flow distribution in humans. METHODS: Indocyanine green disposition was determined twice in four healthy adult men, once during a propranolol infusion that decreased cardiac output. After injection of indocyanine green, arterial blood was collected frequently for 2 minutes and less frequently thereafter. Plasma indocyanine green concentrations were measured by HPLC. The recirculatory pharmacokinetic model incorporates data from both the initial transient oscillations and the later post-mixing portions of the blood indocyanine green concentration versus time curves to characterize not only blood volume and cardiac output but also their distribution among a central blood volume and fast and slow peripheral volumes in lumped parallel circuits. Flow through the central circulation (cardiac output) is described by two parallel Erlang distribution functions generated by two linear chains of compartments in parallel. RESULTS: Propranolol reduced cardiac output from 10.6 to 4.1 L/min. Most of the decrease in cardiac output was at the expense of blood flow to the fast peripheral circuit, which represented nonsplanchnic circulation. Propranolol also reduced the blood volume of the fast peripheral circuit by more than half. CONCLUSION: Our indocyanine green model is able to derive estimates of blood volume and cardiac output, as well as their systemic distribution during different physiologic conditions.

Clinical pharmacokinetics of the non-depolarising muscle relaxants.

Muscle relaxants are of great benefit to the anaesthetist as adjuncts to anaesthesia. These drugs are used to facilitate endotracheal intubation and to reduce muscle tone during surgery, and may also find application in assisting ventilator care in the intensive care situation. The pharmacological effect of the relaxants may be readily assessed by the anaesthetist by means of a variety of techniques to quantify muscular activity in response to electrical stimulation. A number of factors may modify the effects of the muscle relaxants including anaesthetic agents, hypothermia, patient age and disease status and a variety of drugs. The disposition kinetics of the muscle relaxants have been well characterised although information on protein binding and placental transfer is somewhat scanty. A common characteristic of their pharmacokinetics is multicompartmental behaviour. Clearance of the relaxants ranges from total elimination by the kidneys (gallamine) to substantial hepatic clearance (fazadinium), and thus their clearance may be adversely affected by renal or hepatic disease. Dosage regimens have been designed using knowledge of the disposition kinetics of the relaxants to provide for continuous adequate relaxation during prolonged surgical procedures. With the use of sophisticated pharmacokinetic and pharmacodynamic models good relationships have been demonstrated between plasma concentrations of the relaxants throughout the entire range of relaxant response.

Relationship between gallamine plasma concentration and neuromuscular paralysis in surgical patients.

The pharmacodynamics of the neuromuscular blocking drug gallamine were investigated in 10 surgical patients using a constant-rate infusion regimen, and results are compared to those for d-tubocurarine (dTc). Gallamine effect (paralysis)-time data gathered during and following the infusion were fitted to a pharmacodynamic effect model, while paralysis-plasma concentration data gathered during (onset) and following (offset) the infusion were fitted separately to a nonlinear form of the Hill equation. The effect model was most appropriate in characterizing the combined (on and off infusion) effect data. While there was also an excellent characterization of onset and offset data with the Hill equation, the two effect-concentration curves were not superimposable. The mean (+/- S.D.) plasma concentration of gallamine at 50 per cent paralysis during onset of action (Cp50(onset) 8.0 +/- 1.8 micrograms/ml) or that predicted to exist at steady state using the effect model (Cp50(ss) 5.4 +/- 1.4 micrograms/ml). Cp50(offset) and Cp50(ss) did not differ significantly, and there was no significant difference in the power factor (lambda) estimates for the various model fits. Comparison of the pharmacodynamic parameters for gallamine and dTc using the effect model revealed no significant differences in keo, t1/2(keo), and lambda estimates. However, Cp50(ss) for gallamine (5.4 +/- 1.4 micrograms/ml) was nine times higher than that for dTc (0.61 +/- 0.15 micrograms/ml) in absolute terms and seven times higher when compared on a molar basis.

Alcuronium pharmacodynamics in dogs: effect-concentration relationships in the diaphragmatic and limb muscles.

Previous studies suggest that the muscles of the diaphragm are less sensitive to neuromuscular blocking agents than the limb muscles. However, this difference has not been characterized directly in terms of relaxant drug plasma concentrations. The pharmacodynamics of the non-depolarizing muscle relaxant alcuronium were therefore investigated in nine dogs using a constant-rate infusion regimen with simultaneous measurement of muscle paralysis in the limb and diaphragm. Maximum paralysis between 95 and 100% was achieved in both muscle groups, within approximately the same time interval. However, during onset of and offset of effect, the pharmacodynamic parameters ECp50 and ECp95 for the limb muscle were lower than in the diaphragm. From a pharmacodynamic effect model it was also predicted that Css(50) and Css(95) for the limb muscles are half those values for the diaphragm. Thus, the diaphragm is less sensitive to the action of alcuronium than are limb muscles. The half-time for equilibration of alcuronium between plasma and the effect site was two-fold lower for the diaphragm, and the rate of recovery from paralysis in diaphragmatic muscles was twice that observed in limb muscles. Collectively, these data suggest that there is a greater margin of safety in the diaphragmatic muscles and that the response of the peripheral limb muscles to nerve stimulation provides only a conservative index of recovery from competitive neuromuscular block in the diaphragmatic muscles.

The train-of-four count and kinetic-dynamic modelling.

The intraoperative monitoring of neuromuscular blockade usually involves measurement of the muscular responses to motor nerve stimulation. Although researchers have the time and technology to obtain predrug control measurements of the twitch responses, these are seldom available to the clinician. During surgically useful relaxation, there is progressive inhibition of responses to train-of-four (TOF) stimulation in the presence of a nondepolarizing relaxant, and the clinician can count the number of responses to predict the likely time-course of paralysis. At the extremes, a count of four (of four) responses may indicate a need for further relaxant, whereas with profound paralysis, the absence of responses may suggest that reversal with an anticholinesterase may be ineffective. Concentrations in the effect compartment associated with these two extremes of the TOF count are combined with concentration-time profiles of vecuronium with various dose regimens. This study models the effect compartment concentrations associated with vecuronium-induced paralysis, combining them explicitly with the range of concentrations associated with the TOF count to demonstrate the kinetic mechanisms underlying the time-course of paralysis.

Intravenous regional analgesia.

Despite its introduction in 1908, the technique of intravenous regional analgesia did not achieve popularity until it was reintroduced by Holmes in 1963. This simple technique has proved its usefulness in most operative and manipulative procedures on the extremities, including suture of lacerations, tendon repair, abscess incision and fracture work. It is more often used in the upper limb, as the arm requires a lesser total dose of the local anaesthetic agent, and does not have the same potential for precipitation of vascular pathology.

Neuromuscular contributions in eight anaesthesia journals.

Entries in the index issues of eight English-language anaesthesia journals were examined for the years 1950-1990, noting the number of original articles, reviews and editorials. Those which included topics involving neuromuscular blockade were examined in greater detail; these averaged almost one-tenth of the annual totals, despite its eightfold increase over the four decades. During the eighties the strongest research interest involved atracurium, pancuronium, succinylcholine, tubocurarine, and vecuronium, but the share for the long-acting agents was waning by 1990.

Simulating the time-course of clinical paralysis.

This computer program depicts the concentration-time curves for the nondepolarizing neuromuscular blocking agents. It simulates their administration by single and multiple iv injections, and with continuous infusion, alone and in combination. It provides the plasma concentrations related to 75% and 25% depression of the twitch response, using these to calculate clinically useful pharmacodynamic values, such as the duration of surgical relaxation, and the recovery index. These simulations allow the user to contrast the time-course of relaxation to be expected with various dosage regimens.

Heat gain in the treatment of accidental hypothermia.

In two cases of accidental hypothermia, heated humidification of the inspired gases and warming of fluids administered intravenously was associated with an increase in the deep body (core) temperatures at rates of 0-5 degrees to 1-0 degrees C per hour. The first case demonstrated that heat was transferred selectively to the body core, as temperatures here rose during the first three hours of treatment, while skin temperatures remained low. The second patient gained less than 0-1 degrees C per hour when treated "passively" by means of surface insulation with unheated blankets. The introduction of "active" measures was followed by a more rapid gain. It is suggested that heat supplied to the body core by these measures provides effective additions to metabolic production, particularly when the deep body and cardiac temperatures are at their lowest.

Heat balance during surgery involving body cavities.

Three groups of adult patients were anaesthetized for elective intra-abdominal surgery. In one group, patients were ventilated with dry anaesthetic gases, and these patients all lost heat. In the second group humidification was used to annul respiratory heat exchange, and these patients lost heat initially but tended to regain heat during anaesthesia. The third group, in addition to humidification, had surface insulation and all these patients gained heat. It is suggested that conservative methods which negate heat loss are able to prevent hypothermia by the retention of metabolically produced heat.

Control of heat balance during arterial surgery.

Patients were studied to quantitate methods used to prevent heat loss during vascular surgery. A combination of techniques limiting heat loss were shown to prevent hypothermia. In addition it was shown that heat balance in patients undergoing vascular surgery did not differ from that in patients undergoing other forms of surgery.

Mean skin temperature during anaesthesia: an assessment of formulae in the supine surgical patient.

The mean skin temperature was calculated from measurements made in 22 patients under general anaesthesia. The results from 11 different formulae were compared with a system involving 15 temperature sites on the skin, each given a weighting factor in proportion to the fraction of total surface area which it represented. If accuracy is required, the mean skin temperature should be measured in surgical patients using a formula which involves at least 10 skin sites. Incorrect estimation of stored body heat results from an erroneous value for the mean skin temperature, and this occurred more frequently when the number of skin sites was reduced.

Dose-response curves for alcuronium and pancuronium alone and in combination.

Simultaneous administration of pancuronium and alcuronium was used in surgical patients during nitrous oxide-narcotic-barbiturate anaesthesia in order to determine the intensity of neuromuscular blockade. When compared with the results obtained when each of the drugs was given alone, the effect was not greater than the additive. The mean effective dose of pancuronium to produce 95% paralysis was 76 micrograms per kg for the mechanical twitch response and 70 micrograms per kg for the electrical response. The respective mean doses of alcuronium producing that degree of paralysis were 285 and 244 micrograms per kg. Usually the curve derived for the mechanical twitch response was to the right of, and roughly parallel to, that for the electrical response.

Managing journal references with JREF, an IBM-compatible program to simplify manuscript preparation.

JREF is a program which stores, manages and converts journal references. It is intended for the writer of articles and reviews, to simplify the task of keeping card indexes. Entries can be made from downloaded literature searches or from the keyboard. When writing, selections are made from the archival files, for conversion into the specific style of the chosen Journal. All files are ASCII text, accessible to most word processing programs. Once the accuracy of entries has been confirmed, these can be transformed into a perfectly punctuated bibliography.