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Biomedical subjects

John Butterworth

Publications and source records attributed to John Butterworth.

26 records · Page 2Linked to original sources
PubMed2002

The pharmacokinetics and cardiovascular effects of a single intravenous dose of protamine in normal volunteers.

UNLABELLED: Despite its long use in clinical medicine, protamine concentrations and pharmacokinetics in humans have not been reported. The occasional reoccurrence of anticoagulation after protamine reversal of heparin led us to hypothesize that protamine plasma concentrations decrease rapidly. We developed a method for the measurement of protamine in plasma. Eighteen fit volunteers gave their consent to receive 0.5 mg/kg protamine sulfate administered IV by an infusion pump over 10 min. Heart rate, mean arterial blood pressure, and cardiac output, all measured noninvasively, were recorded and blood samples obtained during and after protamine infusion. Blood plasma was subjected to solid-phase extraction and high-performance liquid chromatography. The administration of protamine was associated with no significant changes in heart rate, mean arterial blood pressure, or cardiac output. Plasma protamine concentrations decreased rapidly, becoming nondetectable within approximately 20 min. Protamine elimination differed significantly between men and women: men had significantly larger areas under the concentration versus time curve. Model-independent pharmacokinetic analysis revealed median (range) values as follows: volume of distribution at steady state, 12.3 (6.9--63.1) L; clearance, 2.2 (1.1--12.1) L/min; and t1/2, 7.4 (5.9--9.3) min. Concentration versus time plots revealed an atypical pattern inconsistent with usual exponential models. The Schwartz-Bayesian criterion identified a one-compartment Michaelis-Menten model and a two-compartment exponential model with irreversible binding as performing better than conventional one- or two-compartmental exponential models; however, performance errors were large with both Michaelis-Menten and exponential models. All models described rapid decreases in protamine blood concentrations. IMPLICATIONS: We developed a method for measurement of protamine in human blood. In volunteers, protamine concentrations decreased rapidly after administration. The rapid disappearance of protamine from the circulation, as defined by a median half-life of 7.4 min, could contribute to cases of "heparin rebound" after initial adequate reversal of heparin.

Adult↗
PubMed2002

Pulmonary artery catheter placement for elective coronary artery bypass grafting: before or after anesthetic induction?

UNLABELLED: Pulmonary arterial catheters (PACs) are often used during and after coronary artery bypass grafting. We hypothesized that placement of a PAC would be faster in anesthetized patients. We further hypothesized that the presence or absence of a PAC during the induction of anesthesia would make no difference in hemodynamics, vasoactive drug use, or IV fluid administration during the induction. Patients (n = 200) undergoing elective coronary artery bypass grafting were assigned to PAC insertion either before or after the induction of anesthesia. Total time for PAC insertion, number of finder needle and venous catheter insertion attempts, incidence of carotid artery puncture, arrhythmias or ST segment changes, arterial blood gas analysis, hemodynamic variables, IV fluids, and vasoactive drugs required during and after the anesthetic induction were recorded. Thirty-two different physicians placed the PACs. PAC placement was faster (10 versus 12 min, P = 0.0003) and required fewer punctures with a finder needle (P = 0.0107) in anesthetized patients. There were no significant differences between groups in hemodynamic values or use of vasoactive or anesthetic drugs or IV fluids during the induction. There were also no significant differences between groups in the incidence of myocardial ischemia, arterial hypoxemia, or hypercarbia. Placement of a PAC before the induction of anesthesia consumes more time and fails to improve hemodynamic stability or lessen vasoactive drug use during the induction of anesthesia. IMPLICATIONS: Insertion of pulmonary artery catheters (PACs) before the induction of anesthesia requires more needle sticks and takes longer than insertion after the induction of anesthesia; moreover, previous PAC insertion has no significant effect on hemodynamics or use of vasoactive drugs or IV fluid associated with the induction of anesthesia.

Aged↗
PubMed2002

Dexmedetomidine-induced sedation in volunteers decreases regional and global cerebral blood flow.

UNLABELLED: Dexmedetomidine is a selective alpha(2)-agonist approved for sedation of critically ill patients. There is little information on the effects of dexmedetomidine on cerebral blood flow (CBF) or intracranial hemodynamics, despite considerable other pharmacodynamic data. We hypothesized that therapeutic doses of dexmedetomidine would decrease CBF. Therefore, nine supine volunteers, aged 24-48 yr, were infused with a 1 micro g/kg IV loading dose of dexmedetomidine, followed by an infusion of 0.2 micro g. kg(-1). h(-1) (LOW DEX) and 0.6 micro g. kg(-1). h(-1) (HIGH DEX). Hemodynamic and CBF (via positron emission tomography) measurements were determined at each experimental time point. Dexmedetomidine decreased both cardiac output and heart rate during and 30 min after drug administration. Blood pressure decreased from 12% to 16% during and after the dexmedetomidine administration. Global CBF was decreased significantly from baseline (91 mL. 100 g(-1). min(-1) [95% confidence interval, 72-114] to 64 mL. 100 g(-1). min(-1) [51-81] LOW DEX and 61 mL. 100 g(-1). min(-1) [48-76] HIGH DEX). This decrease in CBF remained constant for at least 30 min after the dexmedetomidine infusion was discontinued, despite the plasma dexmedetomidine concentration decreasing 40% during this same time period (628 pg/mL [524-732] to 380 pg/mL [253-507]). IMPLICATIONS: Dexmedetomidine-induced sedation decreased cerebral blood flow (CBF) by congruent with 33%, which could be due to direct alpha(2)-receptor cerebral smooth muscle vasoconstriction or to compensatory CBF changes caused by dexmedetomidine-induced decreases in the cerebral metabolic rate.

Adrenergic alpha-Agonists↗
PubMed2002

Pharmacokinetics of tranexamic acid during cardiopulmonary bypass.

BACKGROUND: Tranexamic acid (TA) reduces blood loss and blood transfusion during heart surgery with cardiopulmonary bypass (CPB). TA dosing has been empiric because only limited pharmacokinetic studies have been reported, and CPB effects have not been characterized. We hypothesized that many of the published TA dosing techniques would prove, with pharmacokinetic modeling and simulation, to yield unstable TA concentrations. METHODS: Thirty adult patients undergoing elective coronary artery bypass grafting, valve surgery, or repair of atrial septal defect received after induction of anesthesia: TA 50 mg/kg (n = 11), TA 100 mg/kg (n = 10), or TA 10 mg/kg (n = 10) over 15 min, with 1 mg x kg(-1) x hr(-1) maintenance infusion for 10 h. TA was measured in plasma using high performance liquid chromatography. Pharmacokinetic modeling was accomplished using a mixed effects technique. Models of increasing complexity were compared using Schwarz-Bayesian Criterion (SBC). RESULTS: Tranexamic acid concentrations rapidly fell in all three groups. Data were well fit to a 2-compartment model, and adjustments for CPB were supported by SBC. Assuming a body weight of 80 kg, our model estimates V1 = 10.3 l before CPB and 11.9 l during and after CPB; V2 = 8.5 l before CPB and 9.8 l during and after CPB; Cl1 = 0.15 l/s before CPB, 0.11 l/s during CPB, and 0.17 l/s after CPB; and Cl2 = 0.18 l/s before CPB and 0.21 l/s during and after CPB. Based on simulation of previous studies of TA efficacy, we estimate that a 30-min loading dose of 12.5 mg/kg with a maintenance infusion of 6.5 mg x kg(-1) x hr(-1) and 1 mg/kg added to the pump prime will maintain TA concentration greater than 334 microm, and a higher dose based on 30 mg/kg loading dose plus 16 mg x kg(-1) x h(-1) continuous infusion and 2 mg/kg added to the pump prime would maintain TA concentrations greater than 800 microm. CONCLUSIONS: Tranexamic acid pharmacokinetics are influenced by CPB. Our TA pharmacokinetic model does not provide support for the wide range of TA dosing techniques that have been reported. Variation in TA efficacy from study to study and confusion about the optimal duration of TA treatment may be the result of dosing techniques that do not maintain stable, therapeutic TA concentrations.

Adult↗
PubMed2002

Clinical trial of the neuroprotectant clomethiazole in coronary artery bypass graft surgery: a randomized controlled trial.

BACKGROUND: The neuroprotective property of clomethiazole has been demonstrated in several animal models of global and focal brain ischemia. In this study the authors investigated the effect of clomethiazole on cerebral outcome in patients undergoing coronary artery bypass surgery. METHODS: Two hundred forty-five patients scheduled for coronary artery bypass surgery were recruited at two centers and prospectively randomized to clomethiazole edisilate (0.8%), 225 ml (1.8 mg) loading dose followed by a maintenance dose of 100 ml/h (0.8 mg/h) during surgery, or 0.9% NaCl (placebo) in a double-blind trial. Coronary artery grafting was completed during moderate hypothermic (28-32 degrees C) cardiopulmonary bypass. Plasma clomethiazole was measured at several intervals during and up to 24 h after the end of infusion. A battery of eight neuropsychological tests was administered preoperatively and repeated 4-7 weeks after surgery. Analysis of the change in neuropsychological test scores from baseline was used to determine the effect of treatment. RESULTS: Neuropsychological assessments were completed in 219 patients (110 clomethiazole; 109 placebo). The mean plasma concentration of clomethiazole during surgery was 66.2 microm. There was no difference between the clomethiazole and placebo group in the postoperative change in neuropsychological test scores. CONCLUSION: Clomethiazole did not improve cerebral outcome following coronary artery bypass surgery.

Affect↗
PubMedDate not supplied

Does local anesthetic stereoselectivity or structure predict myocardial depression in anesthetized canines?

BACKGROUND AND OBJECTIVES: It is unclear whether the susceptibility to myocardial depression from an accidental intravascular local anesthetic (LA) administration is associated with LA stereoselectivity or structure. By using direct left ventricular pressure monitoring and echocardiographic indices of contractile function in anesthetized, ventilated dogs, we compared the cardiac depressant effects of bupivacaine, ropivacaine, levobupivacaine, and lidocaine. METHODS: Open-chest dogs were randomized to receive escalating incremental infusions of the 4 local anesthetics until cardiovascular collapse. We assumed a concentration relationship for potency of 4:1 for lidocaine/bupivacaine, ropivacaine, and levobupivacaine. RESULTS: All LAs produced concentration-dependent increases in left ventricular end diastolic pressure (LVEDP) and decreases in dP/dtmax, ejection fraction % (EF), fractional shortening (%) (FS), and cardiac output (CO). When comparing the long-acting agents, the effect was least for ropivacaine. The effective concentration estimates for ropivacaine that produced 35% reductions in dP/dtmax and FS were 4.0 micro g/mL (95% confidence intervals [CI(95)]: 3.1 to 5.2 micro g/mL) and 3.0 micro g/mL (CI (95): 2.1 to 4.2 micro g/mL), respectively. The concentrations of levobupivacaine that produced these same end points of contractile dysfunction were significantly less: 2.4 micro g/mL (CI(95): 1.9 to 3.1 micro g/mL) and 1.3 micro g/mL (CI(95): 0.9 to 1.8 micro g/mL), respectively, and these were not different from bupivacaine. As expected, the concentrations of lidocaine that produced 35% reductions in dP/dtmax and FS were significantly greater than the longer acting agents; 8.0 micro g/mL (CI(95): 5.7 to 11.0 micro g/mL) and 5.5 micro g/mL (CI(95): 3.5 to 8.7 micro g/mL), respectively. CONCLUSIONS: This study suggests that smaller molecular size and possibly a piperidine-free structure as opposed to stereoselectivity may be the more important factor in reducing the risk of LA-induced myocardial depression.

Anesthesia↗