Influence of hemorrhagic shock on remifentanil: a pharmacokinetic and pharmacodynamic analysis.

BACKGROUND: Hemorrhagic shock is known to alter significantly the pharmacokinetics of fentanyl, an opioid that requires delivery to the liver for metabolism. The authors hypothesized that the pharmacokinetics and pharmacodynamics of remifentanil, an esterase metabolized opioid that does not require delivery to a metabolic organ, would be altered less by hemorrhagic shock that those of fentanyl. METHODS: Sixteen pigs were assigned randomly to control and shock groups. The shock group was bled using an isobaric hemorrhage model. Remifentanil 10 microg x kg(-1) x min(-1) was infused for 10 min to both groups. Arterial samples were collected for remifentanil concentration assay. Pharmacokinetic parameters were estimated using a three-compartment model. The electroencephalogram spectral edge was used as a measure of drug effect. The pharmacodynamics were characterized using a sigmoid inhibitory maximal effect model. RESULTS: Remifentanil blood levels were higher in the shocked group. The central clearance was slower and the central compartment was smaller in shocked animals. No difference between groups was observed in the magnitude or time course of the remifentanil-induced decrease in spectral edge. CONCLUSIONS: Hemorrhagic shock altered the pharmacokinetics of remifentanil, suggesting that less remifentanil would be required to maintain a target plasma concentration. However, because of its rapid metabolism, the impact of hemorrhagic shock on the concentration decline of remifentanil after termination of the infusion was minimal. Hemorrhagic shock did not alter the pharmacodynamics of remifentanil.

Fentanyl pharmacokinetics in hemorrhagic shock: a porcine model.

BACKGROUND: It is common clinical practice to administer reduced doses of opioid to patients suffering from hemorrhagic shock to minimize adverse hemodynamic consequences and to prevent prolonged opioid effect However, the scientific foundation supporting this practice is not well established. The aim of this study was to test the hypothesis that hemorrhagic shock alters both the distribution and clearance of opioids using fentanyl in a porcine isobaric hemorrhage model. METHODS: Eighteen pigs were randomized to shock or control groups. The animals in the shock group were subjected to hemorrhage using an isobaric method. Pigs in both groups received fentanyl (50 microg/kg) intravenously over 5 min. Frequent arterial blood samples were obtained for radioimmunoassay. Each animal's pharmacokinetic parameters were estimated by fitting a three-compartment model to the concentration versus time data Nonlinear mixed-effects population pharmacokinetic models examining the influence of mean arterial pressure and cardiac index were also constructed. Clinical simulations using the final population model were performed. RESULTS: The shock cohort reached substantially higher fentanyl concentrations. The shock group's central clearance and central- and second-compartment distribution volumes were significantly reduced. The most useful population model scaled all pharmacokinetic parameters to mean arterial pressure. The simulations illustrated that hemorrhagic shock results in higher fentanyl concentrations for any given dosage scheme. CONCLUSION: The essential finding of the study is that fentanyl pharmacokinetics are substantially altered by hemorrhagic shock. The reduced opioid requirement commonly observed during hemorrhagic shock is at least partially attributable to pharmacokinetic mechanisms.

Evaluation in volunteers of the VIA V-ABG automated bedside blood gas, chemistry, and hematocrit monitor.

OBJECTIVE: To evaluate the VIA V-ABG (VIA Medical Corp.) point-of-care blood gas and chemistry monitor in healthy human volunteers, with particular emphasis on the measurement of blood gases. METHODS: Experimental conditions were varied by intermittently subjecting volunteers to either isocapnic hypercapnia (end-tidal (ET), PETCO2 = 50+/-2 mmHg, ETPO2 = 130+/-5 mmHg) or isocapnic hypoxia (PETCO2 = 42+/-2, PETO2 + 45+/-2 mmHg) in addition to room air breathing. Measurements by the VIA V-ABG device were compared with paired samples and measurements performed by two ABL Radiometers (505 and 500). Analysis of results includes bias and precision plots and comparison of results with minimal performance criteria as established by CLIA. RESULTS: Nineteen volunteers yielded 222 matched samples. The range of values were 7.32-7.61 for pH, 20.9-51.6 mmHg for PCO2, 27.9-184.5 mmHg for PO2, 134-141 mmol/l for Na, 3.1-4.1 mmol/l for K, and 30.0-50.4% for hematocrit. Bias and precision (+/-2 sd) for pH was 0.01 and 0.04, for PCO2 was 0.4 and 4.8, for PO2 was 1.0 and 17.0, for Na was -0.3 and 5.2, for K was 0.1 and 0.2, and for Hct was 2.0 and 5.4. CONCLUSIONS: Over the range of blood gas values assessed, blood gas measurements by the VIA V-ABG device were clinically acceptable and met minimal performance criteria utilizing current Medicare CLIA proficiency standards. Performance criteria were also met by the VIA V-ABG device for Na, K, and Hct measurements but the range of values was too narrow to allow characterization of clinical acceptability. The VIA V-ABG device appears to perform well compared with the results which have been published for other point-of-care devices. Comparison between different studies investigating point-of-care devices is difficult due to several factors (range of values measured, comparison device, population studied, etc.). Some of these instruments, including the VIA V-ABG device, may serve quite well as point-of-care devices to perform certain tests at the bedside. Whether or not any of these devices can substitute for traditional laboratory blood gas and chemistry measurements remains an issue that is not adequately studied.

Cardiovascular responses to graded doses of three catecholamines during lactic and hydrochloric acidosis in dogs.

We have studied the cardiovascular effects of incremental doses of three catecholamines in dogs subjected to lactic (LAC) and hydrochloric (HCl) acidosis. Fifty-four dogs were allocated randomly to one of three groups: control, LAC and HCl acidosis (n = 18 each group). In the acidotic models, 2 mol litre-1 of lactic acid (4 ml kg-1 h-1) or 2 mol litre-1 of HCl (1 ml kg-1 h-1) was infused i.v. until arterial pH was reduced to 7.00 +/- 0.1. Within each group, six dogs received one of three different drugs in logarithmically incremental doses: adrenaline 0.1, 0.2, 0.4, 0.8, 1.6, 3.2 micrograms kg-1 min-1, noradrenaline 0.1, 0.2, 0.4, 0.8, 1.6, 3.2 micrograms kg-1 min-1 and dobutamine 5, 10, 20, 40, 80, 160 micrograms kg-1 min-1. Cardiovascular variables were monitored, with periodic measurements of plasma electrolyte and lactate concentrations. The pH reduction induced by HCl or lactic acid was associated with a statistically significant increase in mean pulmonary arterial pressure (MPAP), prominent especially in the LAC group where MPAP increased from mean 18 (SD 5) to 27 (6) mm Hg. In the acidotic models, the reduction in myocardial responsiveness to adrenaline or noradrenaline was more prominent than that for the control for corresponding doses of drugs. In the LAC group mean cardiac index decreased significantly from 5.2 (1.8) to 2.2 (0.7) litre min-1 m-2 after infusion of adrenaline 3.2 micrograms kg-1 min-1 and decreased from 5.1 (1.1 to 2.4 (0.9) litre min-1 m-2 after infusion of noradrenaline 3.2 micrograms kg-1 min-1.(ABSTRACT TRUNCATED AT 250 WORDS)

Use of gastric intramucosal pH as a monitor during hemorrhagic shock.

During resuscitation of the patient suffering from hemorrhagic shock, it may be difficult to determine the adequacy of treatment in the acute setting. The objective of these preliminary studies was to determine if monitoring perfusion of the gastrointestinal tract as estimated by gastric intramucosal pH (pHi) is useful as a guide during the treatment of hemorrhagic shock. Dogs were bled using a modified Wigger's method to a mean arterial blood pressure of 50 mmHg, and pHi was determined 30, 60, 90, and 120 min later. Gastric intramucosal acidosis developed within 30 min of induction of hemorrhagic shock. It was also found that pHi decreases with relatively small amounts of blood loss. There was a significant fall in pHi following hemorrhage to a mean arterial pressure of 80 mmHg from a baseline pressure of 100 mmHg. Following the reinfusion of shed blood, the pHi returned to baseline values within 30 min. It is concluded that measurements of pHi may be a useful monitor in the evaluation and initial resuscitation of patients in hemorrhagic shock.

A system for automatic feedback control of plasma potassium concentration.

A system is described for automatic feedback control of plasma potassium concentration in experimental animals. Plasma potassium was monitored continuously and the signal compared with the desired plasma potassium concentration. The resulting error signal controlled the infusion rates of a concentrated potassium chloride solution (50 or 200 mmol litre-1) and a solution of 50% glucose with insulin 200 u litre-1. Plasma potassium was increased or decreased to the desired concentration at various rates, dictated by the controller constants. Increases were achieved significantly faster than reductions. The system may prove useful for elucidating the fate of infused potassium and for determining the optimum rate of insulin infusion in hyperkalaemia. If adapted for clinical use, it may find applications in the management of various abnormalities of potassium homeostasis.

Preservation of the ischemic canine myocardium: a comparison of hypothermia, lidoflazine, and ketanserin.

The purpose of this study was to determine whether ketanserin protects the globally ischemic canine heart and whether such protection, if present, is independent of that provided by hypothermia or calcium channel blockade with lidoflazine. Forty mongrel dogs, anesthetized with halothane, were divided into eight groups of five and subjected to one hour of global myocardial ischemia during hypothermic (30 degrees C; groups 1 to 4) or normothermic (37 degrees C; groups 5 to 8) cardiopulmonary bypass (CPB). Dogs in groups 1 and 5 served as controls with respect to prebypass myocardial protective therapy, and received only placebo (a normal saline bolus) prior to CPB. Before bypass, dogs in groups 2 and 6 received lidoflazine, 1.25 mg/kg intravenously (IV); those in groups 3 and 7 received ketanserin, 5 mg IV bolus, followed by a continuous infusion at 33 microg/min during bypass. Animals in groups 4 and 8 were given both lidoflazine and ketanserin according to the dosing schedules above. No type of pharmacologic or mechanical cardiovascular support was provided after termination of CPB. Postbypass hemodynamic performance and survival of the unsupported animal were assumed to reflect the degree of myocardial protection during CPB. One minute after bypass, mean arterial pressure and cardiac output were decreased in all groups. Cardiac output was lower in groups 5 to 8 (normothermic CPB) than in groups 1 to 4 (hypothermic CPB). After CPB, left ventricular filling pressures were elevated in all groups kept normothermic and in group 3 (hypothermic CPB plus ketanserin). By 15 minutes after CPB, there were no survivors in groups 5, 7, and 8. Sixty percent of animals in group 6 (normothermic CPB plus lidoflazine) survived to the end of the study. Relative odds of survival were increased 110-fold by hypothermia and sevenfold by lidoflazine. Conversely, treatment with ketanserin was associated with an increased likelihood of nonsurvival. It is concluded that, at the doses studied, ketanserin does not protect the canine myocardium against ischemic injury and may exert a detrimental effect when combined with calcium channel blockade in this setting.