Albert J. Rutten

Myocardial and cerebral drug concentrations and the mechanisms of death after fatal intravenous doses of lidocaine, bupivacaine, and ropivacaine in the sheep

This paper reports the cardiovascular effects of intentionally toxic intravenous doses of lidocaine, bupivacaine, and ropivacaine and the mechanisms of death. Fatal doses of lidocaine, bupivacaine, and ropivacaine were established in sheep treated with successive daily dose increments of each drug. The mean fatal dose of lidocaine (± SD) was 1450 ± 191 mg (30.8 ± 5.8 mg/kg), that of bupivacaine was 156 ± 31 mg (3.7 ± 1.1 mg/kg), and that of ropivacaine was 325 ± 108 mg (7.3 ± 1.0 mg/kg); thus the ratio of fatal doses was approximately 9:1:2. In four out of four lidocaine-treated animals, respiratory depression with bradycardia and hypotension without arrhythmias were the causes of death. Three out of four bupivacaine-treated animals died after the sudden onset of ventricular tachycardia/fibrillation without hypoxia or acidosis; the fourth died in a similar manner to the lidocaine-treated animals. Three out of five animals given ropivacaine died in a manner resembling the fatal effects of lidocaine-treated animals, but unlike the lidocaine-treated animals, in all three sheep there were also periods of ventricular arrhythmias. The remaining two ropivacaine-treated sheep died as a result of the sudden onset of ventricular tachycardia/fibrillation. The mean percentages of the fatal dose found in the myocardium was 2.8 ± 0.7 for lidocaine-treated animals, 3.3 ± 0.9 for bupivacaine-treated animals, and 2.2 ± 1.4 for ropivacaine-treated animals; the corresponding percentages in whole brain were, respectively, 0.71 ± 0.01, 0.71 ± 0.21, and 0.89 ± 0.27.

Additional work of breathing imposed by endotracheal tubes, breathing circuits, and intensive care ventilators

A disadvantage of spontaneous breathing through an endotracheal tube (ETT) and connector attached to a breathing circuit and/or ventilator (breathing device) is an increase in the work of breathing. The work of breathing associated with ETT of 6 to 9-mm diameter and eight breathing devices was determined, using a lung simulator to mimic spontaneous inspiration at flow rates of 20 to 100 L/min and a tidal volume of 500 ml, at both zero end-expiratory pressure (ZEEP) and 10 cm H2O continuous positive airway pressure (CPAP). Work associated with the breathing devices alone (WCIR) ranged from -0.002 kg.m/L (Servo 900-C ventilator, 7-mm ETT, 20 L/min, ZEEP) to 0.1 kg.m/L (continuous flow circuit, 7-mm ETT, 100 L/min, CPAP), the latter representing 196% of the work of normal breathing. When the devices were attached to ETT, total apparatus work (WAPP) ranged from 0.009 kg.m/L (Mapleson-D circuit, 9-mm ETT, 20 L/min, ZEEP) to 0.25 kg.m/L (Drager EV-A, 6-mm ETT, 100 L/min, ZEEP), the latter representing 490% of the work of normal breathing. This additional work imposed by the ETT varied considerably among devices. Spontaneous breathing through modern ventilators, circuits and ETT imposes a burden of increased work, most of which is associated with the presence of the ETT and connector. Whether this burden represents an impediment to the weaning patient, or has training value for the ultimate resumption of unassisted spontaneous ventilation, remains to be determined.

Hemodynamic and central nervous system effects of intravenous bolus doses of lidocaine bupivacaine and ropivacaine in sheep

Lidocaine hydrochloride (HCI) (80–320 mg), bupivacaine HCl (20–80 mg), and ropivacaine HO (30–120 mg) were administered as intravenous bolus doses to conscious sheep (n = 18; average body weight 45 kg) that had previously placed intravascular cannulae for hemodynamic monitoring and for obtaining blood samples. The mean convulsive doses and arterial blood concentrations were ∼110 mg and 40 mg/L, respectively, for lidocaine HCl, 45 mg and 14 mg/L for bupivacaine HCl, and 60 mg and 20 mg/L for ropivacaine HCl. After subconvulsive doses of each agent, there were minimal cardiovascular effects. After convulsive doses, there were marked increases in heart rate, mean arterial pressure, pulmonary artery pressure, cardiac output, systemic vascular resistance, left ventricular end diastolic pressure, and myocardial contractility. Ventricular fibrillation caused death in two sheep after bupivacaine (80 mg) and in two sheep after ropivacaine (90 and 120 mg) administration. With sublethal doses, the hemodynamic responses to these agents were qualitatively and quantitatively similar when compared with their local anesthetic potencies.

Renovascular interaction of epinephrine, dopamine, and intraperitoneal sepsis.

OBJECTIVE To determine the effect of intraperitoneal sepsis on the systemic and renal actions of the continous infusion of epinephrine or dopamine, and during the concurrent administration of both drugs. DESIGN Prospective, randomized study. SETTING Laboratory at a university hospital. SUBJECTS Seven conscious, chronically catheterized, adult merino sheep. INTERVENTIONS Epinephrine at 40 micrograms/min or dopamine at 2 micrograms/kg/min, or both drugs concurrently were infused for 4 hrs on separate study days in healthy sheep. This protocol was then repeated following the induction of sepsis after the intraperitoneal injection of 10(11) Escherichia coli, 10(12) Bacteroides fragilis, and bran. MEASUREMENTS AND MAIN RESULTS Systemic oxygen delivery (DO2) and consumption were measured using thermodilution cardiac output and measured oxygen content. Renal blood flow was measured using an electromagnetic flow transducer, and creatinine clearance was calculated as the quotient of renal blood flow and the renal extraction ratio of creatinine. Infusion of epinephrine augmented systemic DO2 and mean arterial pressure (MAP) during both healthy and septic studies. Systemic oxygen consumption was only increased during epinephrine infusion in the septic study. During the healthy animal study, renal blood flow was initially decreased during epinephrine infusion, but increased to 36% above baseline (p = .003). However, creatinine clearance remained unchanged. During the experimental sepsis study, the infusion of epinephrine had less marked effects on renal blood flow (unchanged from baseline), while an initial reduction (15 mins) in creatinine clearance (p = .04) was not sustained and had returned to baseline by 3 hrs. Dopamine alone produced no change in systemic oxygen variables or MAP during the studies on healthy or septic animals. Although dopamine produced renal vasodilation and an increase in renal blood flow in the healthy state, these results were not found during the septic state. In addition, concurrent infusion of dopamine with epinephrine did not alter the systemic or renal effects of epinephrine during the healthy or septic states. CONCLUSIONS These results do not support the routine use of low-dose dopamine, and demonstrate a change in renovascular responses to catecholamines during intraperitoneal sepsis. The infusion of epinephrine at 40 micrograms/min had few deleterious effects on the kidney, and augmented both MAP and systemic DO2. Its role as a catecholamine in the management of sepsis may need to be reconsidered.

Postoperative course of plasma protein binding of lignocaine, ropivacaine and bupivacaine in sheep

Abstract— The plasma protein binding of the 2,6‐xylidide local anaesthetic agents lignocaine, ropivacaine and bupivacaine enantiomers was determined by equilibrium dialysis in plasma obtained from chronically catheterized sheep before and up to 21 days after surgery. Three concentrations (1, 5 and 10 mg L−1), were used for each agent. Concentration‐dependent binding was evident for each agent throughout the study period. R(+)‐Bupivacaine was more extensively bound than S(–)‐bupivacaine at the higher concentrations. Compared with pre‐surgery, binding of each agent was less on the first postoperative day but did not differ significantly from days 8 to 21.

Epinephrine infusion in sheep systemic and renal hemodynamic effects

ObjectiveTo evaluate the dose-response effects of graded epinephrine infusions on systemic and renal hemodynamics. DesignProspective, dose-response study. SettingLaboratory at a university hospital. SubjectsThirteen conscious, chronically catheterized, adult merino sheep. InterventionsTen sheep received five infusions of epinephrine (5, 10, 20, and 40 μg/min; the 40-μg/min dose was repeated) and a placebo (saline) on separate days (at least 1 day apart). Each drug infusion was administered for 4 hrs on separate days after a 90-min baseline was established. Plasma catecholamine values and renin activity were measured in an additional three sheep infused with 40 μg/min epinephrine. Measurements and Main ResultsRenal blood flow was measured, using an electromagnetic flow transducer; these data, along with aortic and pulmonary arterial pressure, were continuously recorded after analog-to-digital conversion. Cardiac output was intermittently measured by thermodilution. Epinephrine resulted in a dose-dependent increase in mean arterial pressure (p < .001), and in cardiac output at 30, 60, and 120 mins after the start of the infusion. Concurrently, systemic vascular resistance was initially depressed below baseline, but then gradually increased during the 4-hr infusion period. Although a dose-dependent increase in renal vascular resistance was found, 5− and 10− μg/min of epinephrine failed to alter renal vascular resistance. However, 20− and 40-μg/min of epinephrine increased renal vascular resistance by 77% and 94% respectively, at 10 mins, but these values decreased to 17% and 16% of baseline by 120 mins. Consequently, an early dose-dependent decrease in renal blood flow was also time dependent, with renal blood flow increasing back to or above baseline at all studied infusion rates of epinephrine. ConclusionsUsing a clinically relevant dose regimen, epinephrine increased mean arterial pressure and cardiac output. Renal blood flow decreased transiently, but returned to baseline within 30 to 60 mins. (Crit Care Med 1994; 22:994–1001)

The Hemodynamic Effects of Intravenous Bolus Doses of Meperidine in Conscious Sheep

The hemodynamic effects of 100, 200, and 300 mg of meperidine injected intravenously were studied in five chronically instrumented adult ewes. The maximum rate of increase of left ventricular pressure was decreased, respectively, by 27.4% +/- 3.9%, 37.5% +/- 5.6%, and 31.9% +/- 13.0%, and recovery occurred by 5, 8, and 0.5 min, respectively. Mild central nervous system stimulatory effects (agitation) were observed in three of five sheep at 200 mg and moderate effects (rigor and jumping movements) were observed in four of five sheep at 300 mg. These doses also produced increases in heart rate (43%-64%) and mean arterial blood pressure (17%-27%). At these doses, cardiac output was increased for 0.5 min by approximately 25% without changes in stroke volume and left ventricular stroke work. Coronary blood flow was increased by 44%-81% for 0.5 min. We conclude that, in unpremedicated sheep, meperidine has a brief direct negative inotropic effect on the myocardium, but that at larger doses this is overridden by stimulatory central nervous system (CNS) and indirect hemodynamic effects.

Cardiovascular effects and regional clearances of intravenous ropivacaine in sheep.

The purpose of this study was to determine the cardiovascular effects and the total body and regional clearances of ropivacaine during its continuous intravenous infusion to subtoxic levels in five conscious unrestrained sheep that had been previously prepared with appropriate intravascular cannulas. Ropivacaine HCl·H2O, 1 mg/min, produced constant arterial blood concentrations which ranged from 0.70 to 1.84 mg/L. This caused no appreciable cardiovascular effects. The mean total body clearance (± SD) of ropivacaine was 1.00 ± 0.27 L/min. There was significant clearance of ropivacaine by the liver (0.85 ± 0.32 L/min), gut (0.09 ± 0.07 L/min), and kidneys (0.04 ± 0.03 L/min). There was no significant clearance of ropivacaine by the lungs, brain, heart, or hindquarters. It was concluded that the liver accounts for the majority of ropivacaine clearance.

An assessment of six different pulmonary artery catheters

The performance of three samples each of six brands of flow-directed pulmonary artery (PA) catheters was evaluated. In vivo studies determined the reproducibility of PA waveforms over a range of controlled heart rates when compared to those obtained from a transducer-tipped catheter. In vitro studies determined their frequency response, thermistor accuracy, balloon characteristics, and the maximum infusion rates possible through their proximal lumens. All catheters performed similarly in vivo, with mean errors in systolic and diastolic pressures ranging, respectively, from +9% to -12%, at a HR of 80 beat/min, to +23% and -30% at a HR of 160 beat/min. The resonant frequencies of all catheters in vitro were similar at 12 Hz or less; we were unable to obtain the frequency responses (17 to 32 Hz) claimed by the manufacturers. All thermistors were accurate for clinical use when tested over the temperature range 32 degrees to 42 degrees C. Balloon characteristics and infusion rates varied with some catheter brands. Maximum infusion rates varied from 164 to 383 ml/h when infusing 20% dextrose, and from 95 to 213 ml/h when infusing 35% dextrose.

Stereochemistry and its relevance in anaesthesiology

The fact that drugs may exist in stereoisomeric forms with potentially different pharmacodynamic and pharmacokinetic properties has been a neglected aspect in anaesthesiology. This review provides a basic introduction and examples of both theoretical and practical relevance to this topic.