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Biomedical subjects

J A Martyn

Publications and source records attributed to J A Martyn.

At least 55 records · Page 3Linked to original sources
PubMed1989

Alteration by burn injury of the pharmacokinetics and pharmacodynamics of cimetidine in children.

We have studied the mechanisms of the increased dosage requirements of the H2-receptor antagonist cimetidine in paediatric burned patients in a pharmacokinetic and pharmacodynamic study. Cimetidine (10-15 mg.kg-1) was given to 21 burned children and multiple blood samples were obtained for determination of plasma cimetidine concentrations and pharmacokinetic analysis. The relation of gastric pH to plasma cimetidine concentrations was studied in five of these children who had nasogastric tubes. In an additional four patients the effects of cimetidine on gastric pH were studied during a continuous infusion of cimetidine, which maintained steady-state plasma cimetidine concentrations above 0.5 microgram.ml-1. The mean (SEM) clearance of cimetidine in burned children was 16.22 ml.kg-1 and cimetidine half-life was 1.06 h. The cimetidine clearance and half-life values were significantly higher in burned children compared with our previously reported values for normal adult patients, 8.2 ml.min.kg-1 and 2.21 h respectively. Endogenous creatinine clearance normalized to 70 kg in burned children was 190 ml.min-1. In burned children 41% of the dose of intact cimetidine was excreted during 8 h of the study compared with 45% excretion during 24 h in healthy adult controls previously reported. The correlation coefficient between creatinine and cimetidine clearances was 0.93 (r2 = 0.85). The plasma concentration of cimetidine needed to increase gastric pH to greater than or equal to 4.0 was greater than or equal to 1.0 micron.ml-1, which contrasts with the value of greater than 0.5 micron.ml-1 required for adult burned patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1989

Neuromuscular blockade with vecuronium in paediatric patients with burn injury.

1. The effect of body surface area (BSA) burn injury on neuromuscular pharmacodynamics of vecuronium was evaluated. 2. The neuromuscular responses of 15 burned children were compared with those in five controls. 3. The effective dose for 50% suppression of twitch tension (ED50) was 34 micrograms kg-1 for patients with less than 40% BSA burn, 55 micrograms kg-1 for 40-60% BSA burn, and 65 micrograms kg-1 for patients with greater than 60% BSA burn. These values were significantly higher than the value for control patients, which was 18 micrograms kg-1. 4. Burn injury induces a resistance to the neuromuscular effects of vecuronium, the magnitude of which is related to burn size.

Adolescent↗
PubMed1988

Anti-curare effect of plasma from patients with thermal injury.

Following severe thermal injury, patients are resistant to non-depolarizing muscle relaxants. Although this resistance has been well documented clinically, little is known about its etiology. We have tested the hypothesis that circulating factors contribute to the decreased potency of neuromuscular blockers following burns. The potencies of d-tubocurarine (2 microM) or pancuronium (2 microM) dissolved in plasma from either burned or control human subjects were tested on the indirectly stimulated (0.2 Hz) rat phrenic nerve-hemidiaphragm preparation. The muscle relaxants produced less neuromuscular blockade when dissolved in plasma from burned patients than when they were dissolved in plasma from controls. Thus, circulating factors are involved in the decreased potency of non-depolarizing neuromuscular blocking drugs.

Adolescent↗
PubMed1988

Evaluation of atracurium neuromuscular blockade in paediatric patients with burn injury.

The neuromuscular effects of atracurium were studied in acutely burned children, and in children at least 3 years after burn injury (controls). Thirty-one children were studied a total of 48 times. During nitrous oxide-narcotic anaesthesia, a single dose of atracurium was administered in each study and the twitch suppression recorded. Dose-response curves were established using least-squares regression techniques. The ED95 of atracurium in children recovered from burn injury was 0.27 mg kg-1, which is similar to that of normal children reported previously. During the first week of burn injury, the ED95 was 0.3 mg kg-1 irrespective of burn size, and was not significantly different from controls. After the first week of injury, in children with 20-60% body surface burn, the ED95 was twice normal, while in those with greater than 60% body surface burn, it probably may be increased up to 3.0 mg kg-1.

Adolescent↗
PubMed1988

Burn injury to rat increases nicotinic acetylcholine receptors in the diaphragm.

Thermal injury induces aberrant responses to neuromuscular (NM) blocking drugs, and it has been speculated that an increase in nicotinic acetylcholine receptors (AchR) may contribute to the altered response. Using the diaphragmatic muscle as a representative of skeletal muscle, the changes in AchR were examined. The diaphragm, rather than limb muscles, was chosen to avoid the effects of wound contracture-induced immobilization and denervation of limb, which can also increase AchR in skeletal muscle. Study of changes in diaphragm also tested the hypothesis that increase in AchR are the result of a generalized systemic effect, and not limited to area of burn. Following a 45-55% body surface area thermal injury to the trunk (not limbs) of rats, AchR changes in the diaphragm were studied at 10, 14, 21, and 28 days after injury and compared to uninjured (control) rats. The AchR changes in the diaphragmatic muscle was assayed using 125I-alpha-bungarotoxin as the specific ligand. At 10, 14, and 21 days after thermal injury, the animals had an arrest in weight growth and the AchR concentration was increased to (mean +/- SE) 155 +/- 15% (P less than 0.02), 160 +/- 16% (P less than 0.003), and 141 +/- 16% (0.05 less than P less than 0.1), respectively, compared to control. At 28 days, probably because of wound healing and burn wound contracture, the size of thermally injured area was significantly (P less than 0.001) reduced to 19 +/- 4% of body surface area, and weight increased (P less than 0.001) compared to preburn weight.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Azathioprine fails to alter the dose-response curve of d-tubocurarine in rats.

Cyclic 3':5' adenosine monophosphate (cAMP) mediated facilitation of neuromuscular (NM) transmission was previously implicated in the mechanisms of the reversal of nondepolarizing NM relaxants by azathioprine (AZA). This interaction of d-tubocurarine (dTC) with AZA was re-examined in rats and correlated to changes in cAMP in the same muscle. Three groups of animals were studied: controls, low-dose AZA (5 mg/kg), and high-dose AZA (50 mg/kg). After AZA or saline administration, dose-response (DR) curves for inhibition of gastrocnemius twitch tension by dTC were constructed. Contralateral gastrocnemius muscle was sampled for cAMP levels. In another group of animals, the response to 5- and 50-mg/kg boluses of AZA was recorded during a steady-state twitch depression maintained with an infusion of dTC. No significant shift in the DR curve of dTC was observed following low- and high-dose AZA. During steady-state twitch depression, high-dose AZA, however, caused a transient reversal of twitch lasting 5-10 min. High-dose AZA caused a significant (P less than 0.006) elevation of cAMP levels (340 +/- 49 pmol/mg prot) compared to control (120 +/- 18) and low-dose (163 +/- 24) AZA groups. These studies, therefore, document transient reversal of twitch tension by 50 mg/kg doses of AZA during a steady-state dTC infusion. On the other hand, AZA administered prior to dTC in low (5 mg/kg) and high (50 mg/kg) doses failed to cause a significant shift in the dTC DR curve. A three-fold increase in skeletal muscle cAMP induced by high-dose AZA does not alter dTC DR curves.

Animals↗
PubMed1987

Beta-adrenoceptor blockade, alpha-stimulation and changes in plasma potassium concentration after suxamethonium administration in dogs.

A study involving 20 mongrel dogs tested the hypotheses that beta-adrenoceptor blockade or alpha-adrenoceptor stimulation may potentiate and prolong the increase in plasma potassium concentration after suxamethonium administration, and that the beta effect is beta 2-receptor mediated. Propranolol 0.5 mg kg-1 altered the time to peak increase in plasma concentration of potassium after suxamethonium, but did not increase peak concentrations. In controls, the maximum change (0.83 mmol litre-1) occurred at 3 min, while in propranolol-treated dogs the peak change (0.96 mmol litre-1 occurred at 30 min. Similar results were obtained when metoprolol 0.25 mg kg-1 and ICI 118551 0.1 mg kg-1 were used, respectively, as selective beta 1- and beta 2-adrenoceptor blockers. The increases in potassium concentration following suxamethonium in the metoprolol group (0.98 mmol litre-1) and the ICI 118551 group (0.82 mmol litre-1) reached maximum concentrations at 30 min compared with the controls (0.79 mmol litre-1) which achieved a maximum at 3 min. Phenylephrine was infused at 8 micrograms kg-1 min-1 to produce alpha stimulation. The infusion alone altered plasma concentrations of potassium, but the haemodynamic changes were such that conclusions as to the effect of alpha-stimulation on release of potassium after suxamethonium could not be reached.

Adrenergic beta-Antagonists↗
PubMed1986

Ventricular volume and ejection fraction in the diagnosis of the aetiology of low cardiac output in burned patients.

Cardiovascular instability following burns may result from either cardiac or non-cardiac causes. We illustrate three cases in whom routine measurements of atrial filling pressures and cardiac output alone did not reflect the adequacy of blood volume or the myocardial performance. In each instance, measurements of ventricular volume and ejection fraction by thermodilution technique or 99mTC ventriculography were useful to determine the actual causes of decreased cardiac output.

Adult↗
PubMed1985

Increased cimetidine clearance in burn patients.

To determine the etiology of the decreased efficacy of cimetidine in burned and critically ill surgical patients, we studied the kinetics and dynamics of the drug in eight burned patients at a mean of 12 days after the burn. The kinetics were compared with those of nine healthy controls. The elimination half-life of cimetidine in burned patients was significantly reduced (2.2 v 1.5 hours), and total clearance significantly increased (8.2 v 13.3 mL/min/kg). Creatinine and total cimetidine clearance were highly correlated with size of the burn. In the patients studied, 63% of the dose was excreted in eight hours, compared with 45% after 24 hours in controls. Gastric pH was maintained at 4 or higher as long as plasma levels of cimetidine were held above 0.5 microgram/mL. Thus, the increased clearance of cimetidine might explain the decreased effectiveness of this drug in burned and possibly other surgical patients. Dose schedules may need to be altered to compensate for the enhanced clearance of this drug.

Adult↗
PubMed1985

Cimetidine and/or antacid for the control of gastric acidity in pediatric burn patients.

A retrospective study was performed to assess the therapeutic efficacy of cimetidine and antacid, alone and in combination, for the control of gastric acidity and bleeding in pediatric burn patients. The frequency of pH values no greater than 3.5 was significantly greater in the cimetidine group than in the antacid group, and the combined regimen did not enhance the effectiveness of therapy. In all groups, pH values no greater than 3.5 were associated with a significantly higher incidence of positive guaiac tests. In four patients studied prospectively, 63% of the administered dose was detected in the urine 8 h later, compared to the previously reported 24-h delay for normal, healthy adults. Rapid clearance of cimetidine might explain the decreased efficacy of this drug in burn patients. Dosage and schedules for antacid prophylaxis in pediatric burn patients require further study.

Antacids↗
PubMed1984

Plasma protein binding of drugs after severe burn injury.

Plasma protein binding in seven severely burned (35% to 85% of body) patients 1 to 25 days after burn injury was examined for two drugs: diazepam (DZ), which binds mainly to serum albumin (ALB), and imipramine (IMI), which binds primarily to alpha 1-acid glycoprotein (AAG). Protein binding was determined by equilibrium dialysis, and AAG concentrations were measured by radial immunodiffusion. AAG concentrations increased from 36 to 99 mg/dl (day 1) to 221 to 268 mg/dl (days 5 to 20). The IMI free fraction values decreased from 11.2%-19.7% to 5.5%-7.8% and correlated well with AAG concentrations. IMI free fraction values were lower in burned patients (10.8% +/- 0.8%) than in healthy controls (15.3% +/- 0.7%). In contrast, DZ free fraction did not correlate with AAG or ALB concentrations. The DZ free fraction ranged from 1.5% to 8.04%, and changes in a given individual did not relate to time after injury. Free fraction of DZ was higher in the burned population (3.5% +/- 0.37%) than in healthy controls (1.25% +/- 0.05%). Basic drugs that are highly bound to AAG may show progressive, increased binding after burn injury, whereas drugs binding to ALB may decrease after burn injury. Such binding changes can alter the interpretation of total serum or plasma drug concentrations.

Adolescent↗
PubMed1984

Potentiation of neuromuscular blockade using a combination of pancuronium and dimethyltubocurarine. Studies in children following acute burn injury or during reconstructive surgery.

The neuromuscular effects of the combined administration of pancuronium and dimethyltubocurarine were evaluated in children undergoing reconstructive surgery (n = 6), or the skin grafting of acute burn wounds: body surface area (BSA) burns less than 40% (n = 5); and BSA burns greater than 40% (n = 6). A dose of pancuronium 0.005 mg kg-1 was considered to be equipotent with dimethyltubocurarine 0.02 mg kg-1, and each dose was defined as being equal to 1 relaxant equivalent (RE). Incremental doses of the combination of pancuronium and dimethyltubocurarine were administered until a 95% depression of twitch height was achieved (ED95). These results were compared with previously published data for pancuronium and dimethyltubocurarine alone. The mean ED95 of the combination in the control population (reconstructive surgery) was 5.1 RE, compared with 10.8 RE and 10.0 RE for pancuronium and dimethyltubocurarine , respectively, administered alone. In the acutely burned population, the mean ED95 for the combination was 9.9 and 15.9 RE, respectively, compared with 26 RE for pancuronium alone in burned patients. In all groups of patients, significantly less total drug was required when the combined therapy was used.

Burns↗
PubMed1983

Cardiovascular effects of midazolam and thiopentone for induction of anaesthesia in ill surgical patients.

The cardiovascular effects of midazolam (0.15 mg kg-1) and thiopentone (3.0 mg kg-1) were compared during induction of anaesthesia in 20 American Society of Anesthesiologists class III patients. In patients given thiopentone (N = 11), cardiac output, mean arterial pressure, heart rate, and systemic vascular resistance all decreased significantly over the course of the study period; mean right atrial pressure rose slightly, and stroke volume remained the same. Patients receiving midazolam (N = 9) experienced similar haemodynamic changes which were significant relative to baseline only for the fall in mean arterial pressure and the rise in mean right atrial pressure at ten minutes. There were no significant differences between the two groups. Midazolam thus appears to be at least as acceptable an induction agent as thiopentone in ill patients, from a haemodynamic point of view.

Anesthesia, Intravenous↗
PubMed1983

Metocurine requirements and plasma concentrations in burned paediatric patients.

A cumulative dose-response study for metocurine was performed on 11 burned and 11 non-burned children during thiopentone, nitrous oxide in oxygen and narcotic anaesthesia. Burned children required a significantly (P less than 0.001) greater dose (three-fold) of metocurine to achieve a given degree of neuromuscular blockade compared with non-burned children. For the same degree of twitch depression, burned children required twice the plasma concentration of metocurine. Despite the larger dose, the recovery time for the twitch was not significantly different in the two groups. It is speculated that there may be fundamental changes at the neuromuscular junction of burned children to account for their resistance to the effect of non-depolarizing neuromuscular blockers.

Anesthesia, General↗