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Biomedical subjects

D R Cook

Publications and source records attributed to D R Cook.

At least 91 records · Page 5Linked to original sources
PubMed1987

Pharmacodynamics and pharmacokinetics of high-dose sufentanil in infants and children undergoing cardiac surgery.

The pharmacodynamic and pharmacokinetic profiles of high-dose sufentanil (15 micrograms/kg) and oxygen were determined in 20 infants and children undergoing repair of congenital heart defects. Sufentanil provided marked hemodynamic stability after an infusion and during the stress periods of incision and sternotomy. Two patients required supplemental nitrous oxide because of an increase in blood pressure greater than 20% of baseline. Mean plasma catecholamine concentrations varied widely among patients and increased, although not significantly, during intraoperative stress. Pharmacokinetic data best fit a two-compartment model. In infants younger than 10 months (group 1) and children older than 10 months (group 2) who were not surface-cooled, elimination half-lives were similar (mean +/- SD, 53 +/- 15 min vs 55 +/- 10 min) as were clearance values (27.5 +/- 9.3 vs 18.1 +/- 10.7 ml X kg-1 X min-1). However, the volumes of distribution were significantly smaller in group 1 compared with group 2 (1.6 +/- 0.46 vs 3.0 +/- 1.3 L/kg). In infants younger than 10 months who were surface-cooled (group 3) elimination half-life was longer (120 +/- 36 min) and volume of distribution larger (3.7 +/- 1.1 L/kg), but clearance rate was similar (21.5 +/- 5.0 ml X kg-1 X min-1) compared with age- and weight-matched infants (group 1).

Anesthesia, Intravenous↗
PubMed1986

Pharmacokinetics of atracurium in anaesthetized infants and children.

The pharmacokinetics of atracurium were studied in infants and children anaesthetized with isoflurane and nitrous oxide in oxygen. There were no significant differences in volume of distribution (area) (139 v. 152 ml kg-1), clearance (5.1 v. 5.3 ml kg-1 min-1), T1/2 alpha (2.1 v. 2.0 min), or T1/2 beta (19.1 v. 20.3 min) between children with normal hepatic and renal function and those with moderately impaired hepatic function presenting for hepatic transplantation. There were significant differences in volume of distribution (area) (176 v. 139 ml kg-1) and in clearance of atracurium (9.1 v. 5.1 ml kg-1 min-1) between infants and children with normal excretory function. In infants the clearance of atracurium in ml m-2 min-1 (153 v. 133) tended to be greater and the T1/2 alpha and T1/2 beta tended to be shorter (1.0 v. 2.0 and 13.6 v. 19.1) than in children with normal excretory function; however, these trends did not reach statistical significance. Plasma laudanosine concentration was around 100 ng ml-1 greater in patients with liver disease than in normal children from 15-45 min following a bolus of atracurium 0.5 mg kg-1.

Anesthesia, Inhalation↗
PubMed1986

Cardiovascular and electroencephalographic effects of laudanosine in "nephrectomized" cats.

We studied a cat model simulating laudanosine accumulation in the "anephric" patient. Cardiovascular effects were seen only with the bolus doses of laudanosine 2 mg kg-1, and at plasma laudanosine concentrations unlikely to be achieved clinically. Similarly, EEG and power spectra analysis showed no evidence of epileptiform activity at all plasma laudanosine concentrations achieved. The non-specific EEG/power spectra changes observed may reflect a direct CNS activity with neurodepression, since laudanosine was shown by its presence in CSF to cross the blood-brain barrier. These EEG changes were observed at plasma concentrations eight to 10 times those observed in humans during infusion of atracurium. Thus, laudanosine accumulation and related CNS or cardiovascular toxicity seem unlikely following atracurium administration in the anephric patient.

Animals↗
PubMed1986

Hemodynamic effects of isoflurane in the newborn piglet: comparison with halothane.

To better understand the mechanism of hypotension and bradycardia that may occur in newborn infants during isoflurane anesthesia, we studied the hemodynamic changes in the major determinants of cardiac output in 15 newborn piglets given 0.5, 1.0, and 1.3 minimal alveolar concentrations (MAC) of isoflurane and in nine sham-instrumented, age-matched control animals. Cardiac output did not differ from the baseline reading or the control group at any isoflurane dose. Mean aortic pressure (MAP) decreased 23-45% in a dose-related manner. Total peripheral resistance index (TPRI) decreased 29% at 0.5 MAC, but did not decline further at higher concentrations. Because the decrease in MAP was offset by a similar reduction in TPRI, cardiac output did not change. Heart rate decreased significantly at 1.3 MAC (-19%). Contractility was depressed at all concentrations: left ventricular dP/dT decreased progressively at 0.5 and 1.0 MAC, and echocardiographic shortening fraction decreased significantly at 1.0 MAC. Left ventricular end-diastolic pressure was not affected. Eight of twelve animals who had bradycardia while breathing isoflurane were atrially paced at their baseline heart rate. Because pacing did not restore MAP, TPRI, and LV dP/dT/DP40 (a contractile index independent of preload and afterload) to control values, bradycardia was not primarily responsible for depression of these variables. At equipotent concentrations, isoflurane reduced MAP and TPRI more than, and cardiac output less than, halothane did in previous studies in this laboratory. Heart rate and dP/dT were decreased to a similar extent by both agents. Blood, heart, and brainstem isoflurane LD:MAC ratios were 2.04, 2.00, and 2.84, respectively, indicating a relatively low margin of safety for isoflurane in young piglets.

Animals↗
PubMed1985

Enflurane, halothane and isoflurane do not inhibit angiotensin converting enzyme activity.

We studied the effect of halothane, enflurane and isoflurane on angiotensin converting enzyme (ACE) activity using [3H]-benzoyl-phenylalanyl-alanyl-proline (BPAP) as a substrate. Isolated rabbit lungs were perfused in a recirculating system in vitro with BPAP in Krebs-Ringer solution. The rate of metabolism and per cent metabolism were determined before and after treatment for 30 minutes with four MAC multiples of enflurane, halothane or isoflurane. The effects of the anaesthetics on ACE activity were determined by calculating per cent inhibition of metabolism of BPAP using data from the control and test period for each lung. The average metabolism of BPAP at 15 minutes during the control period was 76.5 per cent (+/- 1.92 SEM). No anaesthetic significantly inhibited metabolism of BPAP. Likewise there was no effect on BPAP first order kinetics. Although potent inhalation anaesthetics may alter the renin-angiotensin-aldosterone axis, they do not affect this crucial step.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1985

In vitro degradation of atracurium in human plasma.

The degradation of atracurium and the formation of laudanosine was examined in vitro in both Sorensen buffer and human plasma using sensitive, specific high pressure liquid chromatographic assays to determine drug concentrations. At normal physiological pH and temperature, the degradation of atracurium was threefold more rapid in plasma than in buffer. Laudanosine is the major end-product of atracurium degradation in buffer or in plasma; its production is more rapid in plasma than in buffer. Dilution of plasma constituents or the use of diisopropylfluorophosphate (a potent esterase inhibitor), slows the degradation of atracurium and the production of laudanosine. We conclude that, although ester hydrolysis is the major metabolic pathway of atracurium degradation, Hofmann elimination provides a "safety net" in its clinical use.

Atracurium↗
PubMed1985

Cardiovascular and pharmacodynamic effects of high-dose fentanyl in newborn piglets.

To understand better the hemodynamic effects of fentanyl anesthesia on the developing newborn, the authors studied the changes in cardiac output and its four determinants (preload, afterload, heart rate, and contractility) and plasma fentanyl kinetics in newborn piglets following the administration of high-dose fentanyl with or without atropine premedication. Twenty-five healthy farm piglets were divided into four groups. Hemodynamic studies were conducted on five who received 50 micrograms/kg intravenous fentanyl, five controls who received only 0.01-0.03 mg/kg intravenous atropine, and nine who received both agents. Fentanyl pharmacokinetics were determined by radioimmunoassay in six additional piglets. Mean plasma fentanyl concentrations were 25.4, 12.7, and 7.9 ng/ml at 5, 15, and 30 min postbolus, respectively, with an elimination phase half-life of 35.8 min. In piglets given fentanyl alone, the maximum significant (P less than 0.05) hemodynamic changes from baseline occurred at 5 min: mean aortic pressure (MAP) +42%, cardiac output -42%, heart rate -36%, left ventricular end-diastolic pressure +81%, and total peripheral resistance index +93%. The latter four hemodynamic variables were highly correlated with the logarithm of the plasma fentanyl concentration (R2 greater than 0.96, P less than or equal to 0.05). In control animals given atropine alone, only MAP changed significantly (+12-14%) during the study. Contractile indices (echocardiographic shortening fraction and left ventricular peak dP/dT) did not change significantly in any group. Piglets given fentanyl-atropine had no significant hemodynamic change during the study other than a 7-15% increase in MAP.

Anesthesia, Intravenous↗
PubMed1985

Craftsman versus professional: analysis of the controlled drinking controversy.

With the publication of the Pendery et al. follow-up of the Sobells' experimental studies of controlled drinking, serious questions about the relationship of paraprofessionals (i.e., craftsmen) and professionals in the improvement of alcoholism treatment have been raised. The present analysis reexamines the original published data of the controlled drinking studies in light of the Pendery et al. follow-up and draws the conclusion that readers can find support for both the success and failure of the controlled drinking by examining only the Sobells' data. On this basis, a more phenomenological view of alcoholism and alcoholism treatment is suggested as a way out of the schism between the craftsman and the professional, both of whom operate from within a linear, cause-effect mode of thinking.

Alcohol Drinking↗
PubMed1985

Atracurium infusion requirements in children during halothane, isoflurane, and narcotic anesthesia.

We were interested in determining the dose-response relationship of atracurium in children (2-10 yr) during nitrous oxide-isoflurane anesthesia (1%) and the atracurium infusion rate required to maintain about 95% neuromuscular blockade during nitrous oxide-halothane (0.8%), nitrous oxide-isoflurane (1%), or nitrous oxide-narcotic anesthesia. Neuromuscular blockade was monitored by recording the electromyographic activity of the adductor pollicis muscle resulting from supramaximal stimulation at the ulnar nerve at 2 Hz for 2 sec at 10-sec intervals. To estimate dose-response relationships, three groups of five children received 80, 100, 150 micrograms/kg atracurium, respectively. During isoflurane anesthesia, the neuromuscular block produced by 80 micrograms/kg was 23.6% +/- 6.5 (mean +/- SEM), by 100 micrograms/kg was 45% +/- 7.2, and by 150 micrograms/kg was 64% +/- 8.7. The ED50 and ED95 (estimated from linear regression plots of log dose vs probit of effect) were 120 micrograms/kg and 280 micrograms/kg, respectively. At equipotent concentrations, halothane and isoflurane augment atracurium neuromuscular block to the same extent, compared to narcotic anesthesia. Atracurium steady-state infusion requirements averaged 6.3 +/- 0.6 micrograms . kg-1 . min-1 during halothane or isoflurane anesthesia; the requirements during balanced anesthesia were 9.3 +/- 0.8 micrograms . kg-1 . min-1 (P less than 0.05). There was no evidence of cumulation during prolonged atracurium infusion.

Anesthesia, General↗
PubMed1985

Anesthesia for pediatric orthotopic liver transplantation.

The anesthetic management of 68 liver transplantations in 50 pediatric patients is described. The surgical technique is briefly reviewed. The selection of an anesthetic technique was not as important as management of numerous intra-operative problems. Citrate intoxication secondary to massive blood transfusion in the hypothermic anhepatic patient is a major problem, as are coagulation deficiencies. Hyperkalemic cardiac arrest, also a significant hazard, produced the only intraoperative death.

Acid-Base Imbalance↗
PubMed1984

Clinical pharmacology of atracurium in infants.

The neuromuscular effects of atracurium were studied in 25 infants anesthetized with 1.0% end-tidal halothane and N2O-O2. Neuromuscular blockade was monitored by recording the electromyographic activity of the adductor pollicis muscle resulting from supramaximal stimulation of the ulnar nerve at 2 Hz for 2 sec at 10-sec intervals. To estimate dose-response relationships, three groups of five infants received 60, 80, and 100 micrograms/kg atracurium, respectively; another ten infants received 300 micrograms/kg (2 X ED95). The neuromuscular block produced by 60 micrograms/kg was 27% +/- 10.9 (SEM), by 80 micrograms/kg was 34% +/- 8.0 and from 100 micrograms/kg was 70% +/- 8.3. The ED50 and ED95 (estimated from linear regression plots of log dose vs probit of effect) were 85 micrograms/kg and 150 micrograms/kg, respectively. Neuromuscular blockade lasted 23 +/- 1.6 min at 1 X ED95 and 32.5 +/- 5.2 min at 2 X ED95. Changes in heart rate and mean arterial pressure were clinically insignificant.

Adolescent↗
PubMed1984

Hemodynamic effects of halothane in the newborn piglet.

In order to better understand the mechanism of hypotension and bradycardia in newborn infants under halothane anesthesia, we studied the changes in the four determinants of cardiac output in newborn piglets given 0.5 and 1% end tidal halothane. Cardiac index (CI) was measured by thermodilution. Preload was estimated from the left ventricular diastolic dimension determined by echocardiography and from the left ventricular end-diastolic pressure. Total peripheral resistance index was calculated to assess afterload. Contractility was estimated from left ventricular peak dP/dT, and from left ventricular shortening fraction and mean rate of circumferential fiber shortening determined by echocardiography. All indices of contractility decreased to approximately 50% of baseline values during administration of 1% halothane, whereas heart rate (HR) was reduced to 74% of baseline. Preload and afterload did not change significantly. Mean arterial pressure (MAP) and CI decreased to 67% and 74% of control values, respectively. Smaller, proportional reductions in all variables occurred when 0.5% halothane was administered. Control values of MAP were the only measurements significantly related to piglet age. When five additional animals underwent atrial pacing at the control HR during 1% halothane anesthesia, MAP and CI decreased to 66 and 71% of control values, respectively. dP/dT/DP40, a dP/dT point measurement independent of preload and afterload changes, decreased to 49% of control during pacing. Therefore, the major effect of halothane in newborn piglets is its potent negative inotropic action, not peripheral vasodilation or bradycardia.

Aging↗
PubMed1983

Clinical pharmacology of atracurium in paediatric patients.

The potency of atracurium was determined in adolescents and children during nitrous oxide-halothane and nitrous oxide-thiopentone-fentanyl anaesthesia using single dose-response curves. Dose-response curves were parallel. The effective doses producing 95% twitch depression (ED95) (mg kg-1) during nitrous oxide-halothane were larger in younger children than in the adolescents. Halothane (0.8% end-tidal) did not significantly potentiate atracurium when compared with thiopentone-fentanyl. On a microgram m-2 basis there was no difference in the ED95 between patients of different age or those anaesthetized with different techniques. At approximately 95% twitch depression intubating conditions were excellent in all groups. Minimal cardiovascular effects were noted at several multiples of the ED95.

Adolescent↗