Computer-controlled infusion of ORG 21465, a water soluble steroid i.v. anaesthetic agent, into human volunteers

ORG 21465 has been found to possess anaesthetic properties in humans and its pharmacokinetics are known. We performed this study to confirm the characteristics associated with its administration and to define its pharmacodynamic profile, in particular to explore the relationship between sedation, anaesthesia, excitation and plasma drug concentrations. A water soluble preparation of ORG 21465 was administered to six male volunteers as a series of three 15-min computer-controlled, pharmacokinetic model-driven infusions targeting three exponentially increasing plasma concentrations: 0.5, 1 and 2 micrograms ml-1. The clinical characteristics of the resultant sedation and anaesthesia were observed. Plasma concentrations of ORG 21465 were measured during and for 500 min after the infusions and the EEG recorded. A sigmoid e-max effect compartment pharmacodynamic model was fitted to the plasma concentrations and an EEG derivative (spectral edge frequency (SEF)). Anaesthesia with ORG 21465 was associated with involuntary movements in all subjects. A steady state concentration of 1180 ng ml-1 depressed SEF by 50%, the Hill factor describing the sigmoid nature of the concentration-response curve was 1.42 and the equilibration rate constant of the biophase was 0.112 min-1. Anaesthesia with ORG 21465 was found to be unsatisfactory because of involuntary movements and slow equilibration with the biophase.      

Clinical experience with ORG NC45 (norcuron) as the sole muscle relaxant

The neuromuscular effects of ORG NC45, used as the sole muscle relaxant, were compared with a succinylcholine-pancuronium sequence in patients during nitrous oxide-fentanyl anaesthesia. The subjects were divided into four groups with ten in each group. After induction of anaesthesia they received either succinylcholine, 1 mg . kg-1 or ORG NC45 in doses of 50, 70 or 90 micrograms . kg-1 and tracheal intubation was done 90 seconds later. Neuromuscular transmission was monitored using train-of-four stimulation. Succinylcholine produced 100 per cent block with uniformly excellent intubating conditions whereas the three doses of ORG NC45 were associated with blocks of 7.5, 18.7 and 30.7 per cent and acceptable conditions in only 30 per cent of subjects. Muscle relaxation was maintained in the NC45 groups with increments of 10 micrograms . kg-1 and in the succinylcholine group with pancuronium, initially as a bolus of 40 micrograms . kg-1, followed by increments of 5 mg . kg-1. All increments were given at 10 per cent recovery of twitch height. The overall requirement to maintain 90 per cent block with pancuronium was 1.1 microgram/kg-1 . min-1 compared with 1.28 microgram . kg-1 . min-1 with ORG NC45. No cumulative effects were seen with either drug during the first hour of neuromuscular blockade. At the end of the operation the neuromuscular block was antagonized with atropine 18 micrograms . kg-1, and neostigmine 36 micrograms . kg-1 and recovery was significantly more rapid with NC45 than pancuronium. We conclude that the lack of cumulation, easy reversibility and lack of cardiovascular effects suggest that NC45 has advantages over currently available non-depolarizing muscle relaxants but that its onset of action is too slow for rapid intubation.     

Pre-oxygenation: an easy method for all elective patients

The transparent plastic facemask has been investigated as a pleasant method of pre-oxygenation for elective non-high risk cases in 60 healthy ASA I or II patients randomly allocated to two groups. The patients in the pre-oxgenated group (n = 30) received 8 litre min-1 oxygen through a plastic facemask for 3 min whereas those in a control group (n = 30) were not pre-oxygenated. In all patients anaesthesia was induced with propofol 2.5 mg kg-1, fentanyl 1 ug kg-1 and atracurium 0.6 mg kg-1. Manual ventilation of the lungs using a Mapleson A breathing system was performed for 2 min with 50% oxygen in nitrous oxide prior to oral intubation. Arterial saturation in the pre-oxygenated group rose significantly from a mean baseline value of 96.4 (+/- 0.9)% to 99 (+/- 0.8)% (P < 0.01) and then remained stable both after induction and intubation: 99.1 (+/- 0.8)% and 98.9 (+/- 1.1)% respectively. In the control group arterial saturation dropped sharply within 20 s following induction to a mean of 89.8 (+/- 3.1)%, and it was 30 s before arterial saturation reached the equivalent value in the pre-oxygenated group as a result of manual inflation of the lungs. An 8 litre min-1 oxygen flow via a standard transparent plastic facemask is a simple, feasible and acceptable method for routine pre-oxygenation for all elective cases.     

Alfentanil v. isoflurane for outpatient arthroscopy

Alfentanil by continuous intravenous infusion and isoflurane have been compared as anaesthetic agents for outpatient arthroscopy. In 42 patients, divided at random into two groups, anaesthesia was induced with methohexitone and vecuronium bromide, and, after intubation, maintained with nitrous oxide 66% in oxygen combined with alfentanil or isoflurane. Alfentanil was given before intubation (1 mg), as a loading dose before starting surgery (50 micrograms kg-1) and by a continuous infusion at a rate of 1 microgram kg-1 min-1. Isoflurane was given in a concentration of 0.9% as a maintenance dose. Awakening from anaesthesia was more rapid with alfentanil than with isoflurane. Recovery tests were applied in the recovery room. Both anaesthetic techniques provided satisfactory anaesthesia and rapid recovery. All patients but one were content with the anaesthesia. The patients who received isoflurane scored better in the recovery tests in the first 3 h, but after 3 h there was no difference between the groups. The alfentanil group showed a higher incidence of nausea and/or vomiting: 45% compared to 14% in the isoflurane group.     

Pharmacokinetics of tramadol in children after i.v. or caudal epidural administration

We have studied the pharmacokinetics of a single bolus dose of tramadol 2 mg kg-1 injected either i.v. or into the caudal epidural space in 14 healthy children, aged 1-12 yr, undergoing elective limb, urogenital or thoracic surgery. Serum concentrations of tramadol and its metabolite O- demethyl tramadol (MI) were measured in venous blood samples at various intervals up to 20 h by non-stereoselective gas chromatography with nitrogen-selective detection. All pharmacokinetic variables were evaluated using a non-compartmental model. After a single i.v. injection (n = 9), the mean elimination half-life of tramadol was 6.4 (SD 2.7) h, with a volume of distribution of 3.1 (1.1) litre kg-1 and total plasma clearance of 6.1 (2.5) ml kg-1 min-1. All of these pharmacokinetic variables were similar to those reported previously in adults. After caudal epidural administration (n = 5), mean elimination half-life was 3.7 (0.9) h, volume of distribution was 2.0 (0.4) litre kg-1 and total clearance was 6.6 (1.9) ml kg-1 min-1. The caudal/i.v. quotient of the AUC was 0.83, which confirms that there is extensive systemic absorption of tramadol after caudal administration. Serum concentrations of MI showed a time course typical of a metabolite after both modes of administration. Serum concentrations of MI after caudal administration were lower than those after i.v. injection.      

High frequency jet ventilation: use of the Bain system for entrainment

The use of a Bain system to convey anaesthetic gases for entrainment during high frequency jet ventilation (HFJV) was evaluated by examining the effect of varying the fresh gas flow (Vf) on the end-tidal carbon dioxide (PECO2) in 46 ASA physical status I and II patients undergoing extracorporeal shock-wave lithotripsy (ESWL). Anaesthesia was induced with methohexitone (1-2 mg.kg-1), fentanyl (1-1.5 micrograms.kg-1) and vecuronium (0.1 mg.kg-1). After endotracheal intubation with a Mallinckrodt Hi-Lo Jet cuffed endotracheal tube, the patient was immersed in a water bath and HFJV at 150 breaths per minute was instituted with an Acutronic AMS 1000 jet ventilator attached to the side channel of the Hi-Lo tube. A Bain system was attached to the proximal end of the endotracheal tube to provide gases for entrainment. Anaesthesia was maintained with an intravenous infusion of methohexitone (5 mg.kg-1.h-1) and 50% nitrous oxide in oxygen for both the jetted and entrained gases. PECO2 was determined at 5-min intervals by a single-breath technique using a calibrated Engstrom Eliza capnograph. Thirty patients were randomly allocated to receive Vf's of 50 (Group 1), 75 (Group 2) and 100 (Group 3) ml.kg-1.min-1, respectively. A further eight patients (Group 4) received a Vf of 100 ml.kg-1.min-1 for 15 min, 75 ml.kg-1.min-1 for the next 15 min and 50 ml.kg-1.min-1 thereafter. In a further group of eight patients (Group 5), Vf was initially 25 ml.kg-1.min-1 for 10 min and was then switched off for the remainder of the procedure.(ABSTRACT TRUNCATED AT 250 WORDS)     

Influence of 0.2 minimum alveolar concentration of enflurane on the ventilatory response to sustained hypoxia in humans

To determine the influence of 0.2 minimum alveolar concentration (MAC) of enflurane on the time course of ventilation during sustained hypoxia, we studied 10 healthy adult volunteers with and without enflurane. The following design was used: end-tidal Po2 was maintained at 13.3 kPa for 8 min, at 6.7 kPa for 20 min and at 13.3 kPa for 8 min. End-tidal Pco2 was held constant throughout at 0.67 kPa above the subject's natural value. Control experiments were conducted with no hypoxia imposed. During the experiment subjects breathed via a mouthpiece from an automated gas mixing system which controlled end- tidal values. Enflurane reduced baseline (euoxic) ventilation from 20.9 (SEM 2.0) litre min-1 to 10.1 (1.0) litre min-1 (ANOVA, P < 0.001). Enflurane reduced the acute ventilatory response to hypoxia (AHVR) from 20.1 (3.3) litre min-1 to 5.0 (1.3) litre min-1 (ANOVA, P < 0.01), and the ventilatory off-response at cessation of hypoxia from 11.7 (2.4) litre min-1 to 1.8 (0.5) litre min-1 (ANOVA, P < 0.02). There was no significant difference in hypoxic ventilatory decline (HVD) without and with enflurane (8.9 (2.4) litre min-1 vs 5.5 (1.1) litre min-1; ANOVA, ns). These results confirm that 0.2 MAC of enflurane suppressed the acute ventilatory response to hypoxia, but had no significant effect on the subsequent ventilatory decline during sustained hypoxia.      

Ketamine decreases plasma catecholamines and improves outcome from incomplete cerebral ischemia in rats.

Central neuroexcitatory receptors (N-methyl-D-aspartate [NMDA], non-NMDA) may affect outcome from cerebral ischemia by altering sympathetic nervous system activity. We tested whether ketamine, an NMDA antagonist, and NBQX, a non-NMDA antagonist, improve outcome from incomplete cerebral ischemia in the rat and whether a change in outcome is related to changes in plasma catecholamines. There were five treatment groups: group 1 (control, n = 10) received a fentanyl infusion at a rate of 25 microgram.kg-1.h-1 and ventilation with 70% N2O in O2. Group 2 (n = 10) received the same anesthetic treatment and were given an intraperitoneal injection of 30 mg/kg NBQX 15 min prior to ischemia. Group 3 (n = 10) received a ketamine infusion of 1.0 mg.kg-1.min-1 and ventilation with room air. Group 4 (n = 10) received a ketamine infusion of 1.5 mg.kg-1.min-1. Group 5 received a ketamine infusion of 1 mg.kg-1.min-1 plus a 6 ml/kg intraperitoneal injection of 40% glucose solution 15 min before the start of ischemia. Ischemia was produced by right common carotid ligation combined with hemorrhagic hypotension to 35 mmHg for 30 min. Blood gases, pH, and skull temperature were controlled during ischemia. Plasma glucose increased during ischemia in all groups but was lower in ketamine-anesthetized rats (groups 3 and 4). Glucose-loaded ketamine-anesthetized rats (group 5) had plasma glucose concentrations similar to the control group. Plasma epinephrine and norepinephrine concentrations were significantly less in ketamine-anesthetized rats (groups 3, 4, and 5) during ischemia compared to controls (P less than 0.05). Neurologic outcome was significantly better (P less than 0.05) in all ketamine-treated rats (groups 3, 4, and 5) compared to the control group, regardless of plasma glucose concentration during ischemia. NBQX did not improve neurologic outcome. These results suggest that ketamine improves neurologic outcome from incomplete cerebral ischemia by a mechanism related to a decrease in plasma catecholamine activity.     

Metabolic effects of low-dose insulin therapy on glucose metabolism in diabetic ketoacidosis

The effect of low-dose insulin treatment (5-10 U/h) on hepatic glucose production (HGP) and peripheral glucose disposal was determined in 5 insulin-dependent diabetes mellitus (IDDM) subjects who were admitted with diabetic ketoacidosis (DKA; plasma glucose 598 +/- 50 mg/dl, blood pH 7.20 +/- 0.06, plasma bicarbonate 12 +/- 2 meq/L). Basal hepatic glucose production (4.3 +/- 0.5 mg.kg-1.min-1) in the DKA patients was 1.5- to 2-fold greater (P less than .01) than in controls (2.1 +/- 0.1 mg.kg-1.min-1) and nonketotic IDDM subjects (2.9 +/- 0.3 mg.kg-1.min-1), whereas tissue glucose disposal was significantly reduced (1.7 +/- 0.1 vs. 2.1 +/- 0.1 mg.kg-1.min-1, P less than .05). After the institution of insulin therapy (1 mU.kg-1.min-1), the plasma glucose concentration fell at the rate of 60 +/- 5 mg.dl-1.h-1 to reach a value of 220 +/- 10 mg/dl, which was maintained constant for 2 h (insulin-clamp technique). Blood pH (7.21 +/- 0.06 to 7.35 +/- 0.05) and plasma bicarbonate (12 +/- 3 to 18 +/- 2 meq/L) both increased during insulin therapy (P less than .01). The decline in plasma glucose concentration during insulin therapy primarily resulted from a suppression of HGP (from 4.3 +/- 0.5 to 1.7 +/- 0.2 mg.kg-1.min-1, P less than .01) and to a lesser extent from the stimulation of tissue glucose disposal (1.7 +/- 0.2 to 2.6 +/- 0.3 mg.kg-1.min-1, P less than .01). At this time, urine glucose excretion decreased from 2.6 +/- 0.2 to 0.6 +/- 0.1 mg.kg-1.min-1.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cumulation and reversal with prolonged infusions of atracurium and vecuronium

A randomized, double-blind study was undertaken to compare the tendencies for cumulation, and reversal characteristics of atracurium (ATR) and vecuronium (VEC) when administered by continuous infusion for long surgical procedures under balanced anaesthesia. Eligible subjects were between 50 and 75 yr of age and were free of neuromuscular disease. Patients in the ATR group (n = 25) received a loading dose of atracurium 0.25 mg.kg-1, followed by an infusion initially set at 5.0 micrograms.kg-1.min-1. In the VEC group (n = 25) patients received a loading dose of vecuronium 0.05 mg.kg-1, followed by an infusion at 1.0 microgram.kg-1.min-1. During surgery, the infusions of both ATR and VEC were titrated in increments or decrements of 12.5% to maintain first twitch (T1) suppression of 90-95%. Neuromuscular block was measured by recording the integrated evoked electromyographic response (EMG) of the first dorsal interosseous muscle in response to supramaximal TOF stimuli on the ulnar nerve. The durations of infusion were similar for the two groups (164 +/- 42 and 183 +/- 67 min for ATR and VEC, respectively). The infusion rates of ATR (mean +/- SD) remained between 4.0 +/- 0.7 and 5.0 +/- 1.0 microgram.kg-1.min-1 throughout the study period. In contrast, a progressive decrease (P less than 0.05) in the infusion rate of VEC, from 1.0 to 0.47 +/- 0.13 micrograms.kg-1.min-1, was observed during the study period. The number of adjustments required to maintain 90-95% T1 suppression decreased between the second and fourth hours of administration, but were similar at corresponding times when comparing the two groups.(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparison of breathing methods for inhalation induction of anaesthesia

We studied healthy female patients, allocated randomly to three breathing regimens for induction of anaesthesia using sevoflurane and oxygen from a co-axial Mapleson D breathing system and a mask, to test the hypothesis that rebreathing reduces the incidence of apnoea associated with loss of consciousness. The non-rebreathing group received sevoflurane in oxygen 6 litre min-1 from the start, doubling in concentration from 0.5% to 8% every 3 breaths. The second group received oxygen 6 litre min-1 for 1 min before sevoflurane was introduced, and the third group received oxygen 3 litre min-1 for 1 min before sevoflurane. The incidence and duration of apnoea were assessed using pneumotachograph and impedance pneumograph recordings, and time to induction of anaesthesia (weight drop) was measured from the time the breathing sequence was started. There was no difference in these times, which were mean 121 (95% confidence values 91-160) s, 117 (69- 201) s and 125 (76-192) s, respectively. There was a significant difference in the incidence of apnoea. No apnoea occurred during induction using oxygen 3 litre min-1. Apnoea occurred in five of 15 patients who did not receive oxygen before sevoflurane and in four of 13 who received oxygen 6 litre min-1 (P < 0.05). No patient showed a reduction in pulse oximeter saturation. We conclude that inhalation induction of anaesthesia can be performed reliably in approximately 3 min using sevoflurane in oxygen 3 litre min-1.      

Comparison of perioperative ketoprofen 2.0 mg kg-1 with 0.5 mg kg-1 i.v. in small children during adenoidectomy

We have investigated if ketoprofen 0.5 mg kg-1 i.v. provided as good analgesia with less adverse effects compared with ketoprofen 2.0 mg kg- 1 i.v. in 107 children, aged 1-7 yr, after adenoidectomy, in a randomized, double-blind, parallel group study design. A standard anaesthetic method was used and all children received fentanyl 1 microgram kg-1 i.v. during induction. Children in group 2.0 received ketoprofen 2.0 mg kg-1 and children in group 0.5, 0.5 mg kg-1 i.v. during induction. If the child was in pain, fentanyl 1 microgram kg-1 was given i.v. as rescue analgesia. We found that ketoprofen provided good analgesia and only 49% of children required fentanyl in the post- anaesthesia care unit. There were no differences between the groups in the number of fentanyl doses, pain scores or frequency of adverse reactions. No serious adverse reactions occurred.      

Ventilatory effects of eltanolone during induction of anaesthesia: comparison with propofol and thiopentone

We recorded the ventilatory effects of eltanolone 0.75 mg kg-1, propofol 2.5 mg kg-1 and thiopentone 4 mg kg-1 at induction of anaesthesia in 76 unpremedicated patients, aged 18-65 yr. Measurements were made using a pneumotachograph incorporated between a close-fitting face mask and a T-piece delivering 35% oxygen. Eltanolone caused significantly less apnoea than propofol (incidence 57% vs 100%) and less reduction in ventilation than propofol (median maximum decrease 4.8 vs 7.8 litre min-1), but the differences between eltanolone and thiopentone were smaller and generally not significant. Ventilatory frequency was maintained well in the eltanolone group.      

The effect of etomidate pretreatment on cerebral high energy metabolites, lactate, and glucose during severe hypoxia in the rat

Etomidate was compared with thiopental with respect to preventing loss of brain high energy metabolites and accumulation of lactate during 20 min of hypoxemia (Pa2 of 16-19 mmHg) in rats with unilateral carotid artery ligation. Male Sprague-Dawley rats, anesthetized with halothane and nitrous oxide (N2O) in oxygen were randomly assigned to one of six groups. A normoxic control group which received 70% N2O in oxygen, a hypoxia group received no iv drug treatment (hypoxia-N2O), and four iv drug treatment groups (N2O was replaced by 70% nitrogen at the start of drug administration). The iv drug groups were treated as follows: hypoxia-etomidate low dose (1 mg.kg-1 iv followed by an infusion at 0.35 mg.kg-1.min-1); hypoxia-etomidate high dose (1 mg.kg-1 then 1.3 mg.kg-1.min-1); hypoxia-thiopental low dose (15 mg.kg-1, then 1.5 mg.kg-1.min-1); and hypoxia-thiopental high dose (15 mg.kg-1, then 5 mg.kg-1.min-1). After hypoxia or a corresponding period in the normoxic group, the brains were frozen in situ for later biochemical analysis. Blood was obtained prior to and at the end of hypoxia and analyzed for glucose. Brain metabolite concentrations on the side ipsilateral to the ligated carotid artery in the normoxia-N2O group were adenosine triphosphate (ATP), 2.76 +/- 0.1, phosphocreatione (PCr) 3.88 +/- 0.12, lactate 2.34 +/- 0.16, and glucose 3.56 +/- 0.28 (mumole.g-1 wet weight, mean +/- SE). There was no significant decrease in ATP in any of the hypoxia groups. PCr decreased by 45% (compared to normoxia-N2O) in the hypoxia-N2O group.(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparison of the effects of sub-hypnotic concentrations of propofol and halothane on the acute ventilatory response to hypoxia

To compare the effects of sub-anaesthetic concentrations of propofol and halothane on the respiratory control system, we have studied the acute ventilatory response to isocapnic hypoxia (AHVR) in 12 adults with and without three different concentrations of propofol and halothane. Target doses for propofol were 0, 0.05, 0.1 and 0.2 of the effective plasma concentration (EC50 = 8.1 micrograms ml-1). Target doses for halothane were 0, 0.05, 0.1 and 0.2 minimum alveolar concentration (MAC = 0.77%). The doses achieved experimentally were 0.01, 0.06, 0.13 and 0.26 of the EC50 for propofol and 0, 0.05, 0.11 and 0.20 MAC for halothane. During the experiment subjects breathed via a mouthpiece from an end-tidal forcing system. End-tidal PO2 (PE'O2) was held at 13.3 kPa for 5 min, and then at 6.7 kPa for 5 min. End- tidal PCO2 (PE'CO2) was held constant at 0.13-0.27 kPa greater than the subject's natural level throughout. The mean values for AHVR with propofol were: 12.8 (SEM 2.4) litre min-1 (0.01 EC50), 10.0 (1.9) litre min-1 (0.06 EC50), 9.8 (2.3) litre min-1 (0.13 EC50) and 4.9 (1.2) litre min-1 (0.26 EC50). The values for AHVR with halothane were: 11.9 (2.4) litre min-1 (0 MAC), 7.8 (1.6) litre min-1 (0.05 MAC), 5.9 (1.2) litre min-1 (0.11 MAC) and 3.2 (1.6) litre min-1 (0.2 MAC). The decline in AHVR with increasing dose for both drugs was statistically significant (ANOVA, P < 0.001); there was no significant difference between the two drugs with respect to this decline. Normoxic ventilation with propofol declined from 13.2 (1.6) litre min-1 (0.01 EC50) to 8.3 (0.9 litre min-1 (0.26 EC50), and with halothane declined from 13.5 (2.0) litre min-1 (0 MAC) to 11.8 (1.6) litre min-1 (0.2 MAC). This was significant for both drugs (ANOVA, P < 0.001).      

Venodilation contributes to propofol-mediated hypotension in humans.

The present investigation explored the possibility that the commonly observed hypotension that occurs during induction of anesthesia with propofol might be related to its ability to produce venodilation. Thirty-six ASA I and II patients who received no premedication were studied. The first 20 patients were divided into two equal groups. Hemodynamic measurements consisted of heart rate, arterial blood pressure, and forearm venous compliance by occlusive plethysmography. Baseline measurements were made in awake patients while resting in a supine position. Repeat measurements were made during steady-state infusions of propofol (2.5 mg/kg bolus injection, followed by a continuous infusion at 200 micrograms.kg-1.min-1) or thiopental (4 mg/kg bolus injection, followed by continuous infusion at 200 micrograms.kg-1.min-1), 10 min after tracheal intubation while patients were artificially ventilated. Both anesthetics resulted in a significant (P less than 0.05) and similar tachycardia; however, propofol produced significant decreases in systolic (-30 +/- 9 mm Hg) and diastolic (-11 +/- 4 mm Hg) arterial blood pressure. Forearm venous compliance was significantly increased during propofol administration but unchanged in patients receiving thiopental. In four additional patients receiving smaller consecutive infusions of propofol (50 and 100 micrograms.kg-1.min-1), significant subtle increases in forearm compliance were also recorded. These increases were not observed in four patients who received placebo infusions. Thus, one mechanism promoting hypotension during propofol anesthesia in humans seems to be related to its direct effects on venous smooth muscle tone and presumably venous return.     

The incidence of myocardial ischemia during anesthesia for coronary artery bypass surgery in patients receiving pancuronium or vecuronium

This study was performed to compare the incidence of prebypass myocardial ischemia in patients receiving fentanyl and enflurane for anesthesia along with either pancuronium or vecuronium. Ninety-eight patients with normal left ventricular function were randomly allocated to receive either pancuronium 0.15 mg.kg-1 or vecuronium 0.15 mg.kg-1 in a double-blind manner after fentanyl 40 micrograms.kg-1 for induction of anesthesia for elective coronary artery bypass grafting (CABG). Premedication included diazepam 0.15 mg.kg-1 po, morphine 0.10 mg.kg-1, and scopolamine 0.005 mg.kg-1 im. Two lead Holter monitor recordings (leads V6 and V9) from the time of arrival in the operating suite to institution of cardiopulmonary bypass were analyzed for ischemia by a cardiologist blinded to the choice of muscle relaxant. Intraoperatively, heart rates greater than 90 beats.min-1 and systolic blood pressure +/- 20% of ward values were treated with propranolol, enflurane, or phenylephrine. Nitroglycerin was infused for ECG signs of ischemia or pulmonary hypertension. After induction of anesthesia the heart rate and cardiac index were consistently decreased in patients receiving vecuronium and also lower in these patients compared with those receiving pancuronium. Thirty-two per cent of patients receiving pancuronium received propranolol for heart rates greater than 90 beats.min-1 versus 7% of those who received vecuronium (P approximately 0.01). Eight patients developed 13 episodes of ischemia after administration of the muscle relaxant: four who received pancuronium (n = 44; 9%) and four receiving vecuronium (n = 54; 7%). Four episodes occurred at induction or tracheal intubation, two in each group. There were four perioperative myocardial infarctions as determined by ECG and CPK-MB levels, two in each group.(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparison of the pharmacodynamics and pharmacokinetics of an infusion of cis-atracurium (51W89) or atracurium in critically ill patients undergoing mechanical ventilation in an intensive therapy unit

We have studied 12 critically ill, sedated patients who required a neuromuscular blocking drug to assist mechanical ventilation in an intensive care unit. Patients were randomized to receive an infusion of cis-atracurium 0.18 mg kg-1 h-1 (group 1, n = 6) or atracurium 0.6 mg kg-1 h-1 (group 2, n = 6) preceded, if necessary, by a bolus dose of 2 x ED95 of the same drug (cis-atracurium 0.1 mg kg-1 or atracurium 0.5 mg kg-1). Neuromuscular block was monitored using an accelerograph and the infusion rate adjusted regularly so that it was possible to detect the first response to train-of-four (TOF) stimulation of the ulnar nerve at the wrist. Blood samples were obtained for estimation of plasma cis-atracurium and laudanosine concentrations (group 1) or the three groups of atracurium isomers and laudanosine (group 2). There was no apparent haemodynamic or allergic response to either drug. The mean infusion time in group 1 was 37.6 h and in group 2, 27.5 h. On termination of the infusion, the time for the TOF ratio to reach 0.7 was similar in the two groups (group 1 = 60 min; group 2 = 62 min). The mean infusion rate of cis-atracurium was 0.19 mg kg-1 h-1 and of atracurium 0.47 mg kg-1 h-1 (expressed as mg of bis-cation): cis- atracurium was 2.5 times more potent than atracurium. Using the NONMEM program, a single compartment pharmacokinetic model was fitted to the plasma concentrations of cis-atracurium and the cis-cis, cis-trans and trans-trans isomers of atracurium. The mean population pharmacokinetic values for cis-atracurium were: volume of distribution (V) = 21,900 (SEM 416) ml; clearance (Cl) = 549 (79) ml min-1; half-life (T1/2) = 27.6 (3.6) min; and for the three groups of atracurium isomers were: cis-cis, V = 15,100 (720) ml, Cl = 449 (42) ml min-1, T1/2 = 23.4 (1.2) min; cis-trans, V = 18,000 (667) ml, Cl = 1070 (43) ml min-1, T1/2 = 11.7 (0.1); trans-trans, V = 13,100 (1280) ml, Cl = 1560 (55) ml min-1, T1/2 = 5.8 (0.4) min. Plasma laudanosine concentrations were lower in the cis-atracurium (peak value 1.3 micrograms ml-1) than in the atracurium (maximum 4.4 micrograms ml-1) group.      

Comparison of the effects of propofol and isoflurane anaesthesia on right ventricular function and shunt fraction during thoracic surgery

I.v. anaesthetic agents, including propofol, have not been shown to inhibit hypoxic pulmonary vasoconstriction (HPV). This may encourage the use of propofol in thoracic surgery where one lung ventilation (OLV) is required. We have compared the effects of maintaining anaesthesia with either isoflurane or propofol infusion on right ventricular function and shunt fraction. We studied 10 patients who received isoflurane and 12 who received propofol. When OLV commenced there was a greater reduction in both mean cardiac index (3.2 (SEM 0.2) to 2.4 (0.1) litre min-1 m-2 for propofol, and 3.4 (0.2) to 3.3 (0.4) litre min-1 m-2 for isoflurane) and right ventricular ejection fraction (0.45 (0.03) to 0.37 (0.02) for propofol, and 0.48 (0.02) to 0.42 (0.02) for isoflurane) in patients who received propofol. Furthermore, these reductions were sustained for longer in the propofol group. However, propofol was not associated with a significant increase in shunt fraction during OLV, which increased threefold in patients who received isoflurane.      

Pharmacokinetics of Propofol Infusions in Critically Ill Neonates, Infants, and Children in an Intensive Care Unit

Background: Propofol is a commonly used anesthetic induction agent in pediatric anesthesia that, until recently, was used with caution as an intravenous infusion agent for sedation in pediatric intensive care. Few data have described propofol kinetics in critically ill children.

Methods: Twenty-one critically ill ventilated children aged 1 week to 12 yr were sedated with 4-6 mg [middle dot] kg-1 [middle dot] h-1 of 2% propofol for up to 28 h, combined with a constant morphine infusion. Whole blood concentration of propofol was measured at steady state and for 24 h after infusion using high-performance liquid chromatography.

Results: A propofol infusion rate of 4 mg [middle dot] kg-1 [middle dot] h-1 achieved adequate sedation scores in 17 of 20 patients. In 2 patients the dose was reduced because of hypotension, and 1 patient was withdrawn from the study because of a increasing metabolic acidosis. Mixed-effects population models were fitted to the blood propofol concentration data. The pharmacokinetics were best described by a three-compartment model. Weight was a significant covariate for all structural model parameters; Cl, Q2, Q3, V1, and V2 were proportional to weight. Estimates for these parameters were 30.2, 16.0, and 13.3 ml [middle dot] kg-1 [middle dot] min-1 and 0.584 and 1.36 l/kg, respectively. The volume of the remaining peripheral compartment, V3, had a constant component (103 l) plus an additional weight-related component (5.67 l/kg). Values for Cl were reduced (typically by 26%) in children who had undergone cardiac surgery.