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Biomedical subjects

G A Gronert

Publications and source records attributed to G A Gronert.

At least 55 records · Page 3Linked to original sources
PubMed1993

No dantrolene protection in a dog model of complete cerebral ischaemia.

Intracellular free calcium is believed to play a major role in the ischaemic cascade which leads to cell death. Calcium channel blockers, which in part inhibit the influx of extracellular calcium, have been shown to be neuroprotective in both complete and focal cerebral ischaemia models. Dantrolene, an agent used in the treatment of malignant hyperthermia, is known to inhibit the release of stored intracellular calcium. Assuming that reduced levels of intracellular free calcium would improve neurologic outcome, we studied the neuroprotective potential of dantrolene. A complete cerebral ischaemia model was used to examine ten anesthetized dogs. Five were given intravenous dantrolene and five were given equal volumes of saline prior to the ischaemic event. Simultaneous occlusion of the venae cavae and ascending aorta provided eleven minutes of complete cerebral ischaemia as monitored by electroencephalography. Arterial blood gases and serum glucose levels were drawn prior to ischaemia, 5 and 20 minutes post-ischaemia, and following extubation. Forty-eight hours following the ischaemic event, neurologic outcomes were scored. No significant differences were observed between the two groups. All ten dogs had equally significant increases in serum glucose levels at 5 and 20 minutes post-ischaemia. The average neurologic outcome of the five dantrolene-treated dogs equalled the average of the five controls. These results suggest that dantrolene, alone, is not neuroprotective during complete cerebral ischaemia.

Animals↗
PubMed1993

Succinylcholine causes profound hyperkalemia in hemorrhagic, acidotic rabbits.

Two recent clinical reports suggested that succinylcholine (SCh) may cause severe hyperkalemia in hemorrhagic, acidotic humans. To investigate this, we anesthetized rabbits with halothane and N2O, and inserted venous and arterial catheters. Control rabbits (Group C, n = 4) remained anesthetized and undisturbed. Hemorrhage/profound acidosis (HPA) was accomplished by withdrawal of 25-30 mL/kg of blood and waiting until pHa approximately 7.05 (Group HPA, n = 5). Hemorrhage/minimal acidosis (HMA) was accomplished by withdrawal of 25-30 mL/kg of blood, but acidosis was minimized by not waiting for it to occur and by administering NaHCO3 0-1.4 mEq/kg (Group HMA, n = 4). In a metabolic acidosis group (n = 4), HCl was infused until pHa approximately 7.05. Respiratory acidosis (n = 4) was accomplished by partial obstruction of the endotracheal tube until PaCO2 approximately 120 mm Hg and pHa approximately 7.05. Potassium levels were determined before the above interventions (baseline), immediately before (pre-SCh), and 1, 3, 5, 7, 10, and 13 min after SCh 1 mg/kg intravenously. In Group C, potassium gradually increased from 3.5 +/- 0.2 mEq/L to 4.8 +/- 0.2 mEq/L 13 min after SCh. In Group HPA, potassium increased from 3.8 +/- 0.3 to 7.0 +/- 1.8 mEq/L after hemorrhage/acidosis and then to 11.4 +/- 1.7 mEq/L at 13 min after SCh. The metabolic acidosis group was significantly different from Group C at 7, 10, and 13 min after SCh (maximum at 13 min, 6.8 +/- 1.2 mEq/L).(ABSTRACT TRUNCATED AT 250 WORDS)

Acidosis↗
PubMed1992

Absence of malignant hyperthermia contractures in Becker-Duchenne dystrophy at age 2.

Two 2-year-old males underwent muscle biopsy that established the histopathologic diagnosis of Becker dystrophy in one, and Duchenne dystrophy in the other. Concomitant contracture testing with caffeine or halothane was normal for malignant hyperthermia (MH). The results suggest that acute hypermetabolism or acute rhabdomyolysis during anesthesia, in patients with these disorders, is related to the X-linked myopathy and its associated muscle deterioration, rather than to the autosomal dominant MH.

Age Factors↗
PubMed1992

Up-and-down regulation of skeletal muscle acetylcholine receptors. Effects on neuromuscular blockers.

Multiple factors alter the interaction of muscle relaxants with the NMJ. This review has focused on the aberrant responses caused principally by alterations in AChRs (table 1). Many pathologic states increase (up-regulate) AChR number. These include upper and lower motor neuron lesions, muscle trauma, burns, and immobilization. Pre- or postjunctional inhibition of neurotransmission by drugs or toxins also up-regulate AChRs. These include alpha- and beta-BT, NDMR, anticonvulsants, and clostridial toxins. We speculate that other bacterial toxins also up-regulate AChR. With proliferation of AChRs, agonist drug dose-response curves are shifted to the left. The exaggerated release of potassium when depolarization occurs with the use of agonists such as SCh and decamethonium can be attributed to the increased number of AChR. Thus, SCh should be avoided in patients who are in the susceptible phase (see section V). In the presence of increased AChR, the requirement for NDMR is markedly increased. Thus, the response to NDMR may be used as an indirect estimator of increased sensitivity to SCh (table 1). The most extensively studied pathologic state in which there is a decrease in AChRs is myasthenia gravis; there is immunologically mediated destruction and/or functional blockade of AChRs. The pathophysiologic and pharmacologic changes in LEMS are quite distinct from those of myasthenia gravis. Decreased AChRs in myasthenia gravis result in resistance to agonists and increased sensitivity to competitive antagonists. In conditioning exercise, the perturbed muscles show sensitivity to NDMR that may be due to decreased AChRs. Chronic elevations of ACh observed with organophosphorus poisoning or chronic use of reversible cholinesterase inhibitors results in down-regulation of AChRs. In this condition, SCh should be avoided because its metabolic breakdown would be impaired; the requirement for NDMR may be decreased. All of the varied responses to SCh and NDMR, which are associated with concomitant changes in AChRs, are analogous to drug-receptor interactions observed in other biologic systems.

Animals↗
PubMed1992

Blood gas and catecholamine levels in capture stressed desert bighorn sheep.

Forty-seven bighorn sheep (Ovis canadensis nelsoni) were captured within a 3-day period in December, 1989 as part of a California Department of Fish and Game effort to repopulate historic ranges in California. They were captured on the Mojave Desert in the Kelso Mountains near Old Dad Peak, San Bernardino County, California. Venous blood gases measured at the site of capture demonstrated a severe metabolic acidosis (base deficit, 23 mEq/liter), with no evidence of respiratory acidosis. There were moderately elevated plasma epinephrine (1.25 ng/ml), norepinephrine (2.60 ng/ml), and dopamine (114 pg/ml) levels. These data appear to reflect animals that have been moderately stressed. These acid-base-catecholamine values differ from values in resting domestic sheep, and are similar to those reported in greyhounds after brief strenuous exercise.

Acid-Base Equilibrium↗
PubMed1992

Evaluation of greyhound susceptibility to malignant hyperthermia using halothane-succinylcholine anesthesia and caffeine-halothane muscle contractures.

We investigated Greyhounds because of prior reports of malignant hyperthermia (MH) episodes and because Greyhounds may express high genetic relatedness due to inbreeding for generations. Seven Greyhound and six mongrel dogs were given halothane and succinylcholine anesthesia as a challenge to trigger MH. They also underwent semitendinosus muscle biopsy for contracture study with halothane and caffeine. Measurements in vivo of mixed venous and arterial blood gases, cardiac output by thermodilution, temperature, blood pressure, and pulse rate provided sequential data regarding whole body O2 consumption (product of cardiac output and arterial-mixed venous O2 content difference), acid-base status, and arterial CO2 tension. Greyhounds and mongrels had uniformly similar in vivo and in vitro responses, without evidence for MH. Contracture thresholds were higher than those reported for normal swine and humans (8 mM vs. 4 mM). Information on MH susceptibility in this breed is important for laboratory investigation in Greyhounds as well as to veterinary medicine in general. Neither mongrels nor this group of Greyhounds were obviously susceptible to MH. If all Greyhounds are genetically homologous, then Greyhounds may not be specifically MH susceptible. These findings overall may provide a protocol and baseline normal comparative data for determining MH susceptibility in dogs and other species.

Anesthesia, Inhalation↗
PubMed1992

Determination of sensitivity to metocurine in exercised horses.

On the basis of results in dogs, conditioning exercise may increase sensitivity to nondepolarizing muscle relaxants. Five Thoroughbreds were exercised/conditioned 3 times weekly on a treadmill for 8 months. Increasing maximal rate of O2 consumption verified that the horses were responding to exercise conditioning. Six nonexercised Thoroughbreds served as the control group. Studies were done with horses under general anesthesia by use of halothane during partial paralysis by a brief constant-rate infusion with the muscle relaxant, metocurine iodide. Quantification of degree of paralysis of the hoof twitch (eg, digital extensor) occurred with simultaneous quantification of blood values of metocurine. Pharmacokinetic and pharmacodynamic analyses of the data were done by a nonlinear regression program, using the Hill equation. There were no differences in findings between exercised and nonexercised horses. The mean blood concentration for the 50% paralyzing dose of metocurine was 0.44 +/- 0.11 (SD) microgram/ml in exercised horses, and 0.58 +/- 0.22 microgram/ml in nonexercised horses. Despite evidence for a response to conditioning, a significant change in the sensitivity of the neuromuscular junction to metocurine was not found.

Animals↗
PubMed1991

The onset of disuse-related potassium efflux to succinylcholine.

Disuse atrophy of skeletal muscle produces resistance to nondepolarizing relaxants and increased potassium efflux after the administration of succinylcholine. These changes appear to be due to development of perijunctional and/or extrajunctional receptors (up-regulation). In this study, the authors searched for the earliest detectable appearance of increased potassium efflux in beagles in whom disuse atrophy was simulated. Seven beagles underwent unilateral cast immobilization of a hind limb. Between 4 and 42 days, they periodically received succinylcholine 0.25 mg/kg while anesthetized with thiamylal and nitrous oxide. Sequential bilateral femoral venous samples showed that the casted limb did not manifest potassium release greater than the upper limit of normal (1 mEq/l) until cast immobilization periods of 14 days or longer. When this occurred, the increase in the potassium concentration in the femoral venous blood of the casted limb exceeded that from the noncasted limb by at least 0.7 mEq/l (P less than 0.01). The range for the onset of this response after casting was 14-42 days, the mean 27.2 days, and the standard deviation 9.8 days. These findings imply that up-regulation of skeletal muscle receptors, associated with exaggerated potassium efflux after administration of succinylcholine, is dependent on progressive development of extrajunctional receptors over surface membrane areas beyond the endplate.

Animals↗
PubMed1990

Twitch response in a myopathy with impaired relaxation but no myotonia.

A patient with slow muscle relaxation but without accompanying motor unit or myotonic electrical activity had a unique staircase twitch response to repeated nerve stimulation. During 1-Hz stimulation, twitches recorded by measurement of the ankle dorsiflexor group displayed progressively increasing relaxation times with successive stimuli (37% increase) unlike the progressively decreasing relaxation time of the normal response (12-37% decrease). The response may be diagnostic of this unusual myopathy; the test methods are noninvasive and easily tolerated.

Action Potentials↗
PubMed1989

Ankle dorsiflexor twitch properties in malignant hyperthermia.

A noninvasive method to diagnose malignant hyperthermia (MH) was sought. To this end, in vivo isometric twitch properties of the ankle dorsiflexor muscles were studied in three groups: (1) MH-susceptible patients (n = 12), (2) relatives (n = 12) of MH-susceptible patients who were judged to be MH resistant, and (3) a group of normal volunteers (n = 42) chosen from the community. Twitch properties were studied under resting state conditions and with 1 or 2 Hz stimulation to produce the negative staircase twitch response. There was a high degree of overlap between the ranges of the measured twitch parameters of all groups. Thus, the techniques presented in this study have no value in diagnosing susceptibility to MH. Several physiological features of human isometric twitch properties were demonstrated: (1) slowing of twitch speed with advancing age, (2) strong positive correlation between body weight and twitch torque, and (3) a negative staircase response typical of that described in other mammalian twitch studies.

Adolescent↗
PubMed1989

A comparison of parametric with semiparametric analysis of the concentration versus effect relationship of metocurine in dogs and pigs.

We investigated the ability of two pharmacokinetic modeling techniques to estimate the equilibration delay (i.e., hysteresis) between plasma drug concentration and observed drug effect. The data were from 20 animals (15 dogs, 5 pigs) receiving an infusion of metocurine, a neuromuscular blocking drug. An effect compartment model was used to model the hysteresis and characterize the relationship between drug concentration and effect. The effect compartment model requires identification of ke0, the rate constant of drug elimination from the effect compartment. Two methods were used to estimate ke0. The first technique was to fit the plasma metocurine concentration-time curve to a two-compartment pharmacokinetic model and then to use this pharmacokinetic model, along with the neuromuscular blockade vs. time curve to estimate ke0 and the parameters of a pharmacodynamic model (the Hill equation). The second technique was to directly estimate ke0 by a recently described semiparametric technique that does not require either a pharmacokinetic or pharmacodynamic model, although it does assume that drug flux to and from the effect compartment is a first-order process. This semiparametric technique only estimates a single parameter, ke0. The results from the new semiparametric analysis technique were similar to the results from the parametric analysis. In the few animals where the results differed, the semiparametric analysis produced a better description of the data.

Animals↗
PubMed1989

Combined H1 and H2 receptor blockade attenuates the cardiovascular effects of high dose atracurium in rabbits.

Large doses of atracurium (1.5 mg/kg) (six times the ED95) have been reported to provide adequate conditions for rapid sequence endotracheal intubation within 60 seconds in humans. However, this dose can result in significant histamine release and systemic hypotension. We therefore studied the efficacy of histamine receptor blockade in attenuating this response. Four groups of five rabbits were pretreated as follows: Group I--control, Group II--H1 blockade (1 mg/kg diphenhydramine), Group III--H2 blockade (cimetidine 4 mg/kg), and Group IV--H1 and H2 blockade (diphenhydramine 1 mg/kg and cimetidine 4 mg/kg). All rabbits were anesthetized and then 1.8 mg/kg (six times the rabbit ED95) atracurium was administered. Group I rabbits experienced a decrease in MAP of 12.2 mmHg after one minute, a change that was significantly greater than Group IV in which MAP decreased by 0.8 mmHg (p less than 0.001). H1 or H2 receptor blockade alone was associated with intermediate changes in MAP not significantly different from control. We conclude that combined H1 and H2 receptor blockade attenuates the cardiovascular effects associated with large doses of atracurium in the rabbit and that this combination of antagonist drugs might have similar effectiveness in humans.

Animals↗
PubMed1989

Exercise produces sensitivity to metocurine.

Chronic muscle disuse decreases the sensitivity of skeletal muscle to nondepolarizing relaxants, such as metocurine (MTC). In this study, the authors determined whether chronic conditioning would produce the opposite effect and increase the sensitivity of skeletal muscle to MTC. Five dogs were exercised by daily running over a period of 5 weeks. At the conclusion of this training period, a pharmacokinetic and pharmacodynamic study of the MTC dose-response relationship was performed. The same analysis was performed on four dogs housed in the same kennel who did not undergo conditioning. Neuromuscular blockade was measured and recorded bilaterally in both gastrocnemius muscles while the animal was anesthetized with nitrous oxide and pentobarbital, 30 ml.kg-1. Plasma concentrations of MTC were measured by radioimmunoassay. The MTC concentration estimated in the effect compartment which produced 50% paralysis was 0.114 +/- 0.008 micrograms.ml-1 (mean +/- SD) in exercised dogs and 0.189 +/- 0.038 micrograms.ml-1 in nonexercised dogs, which was significant at P less than 0.005). The MTC concentration versus response curves were parallel. This supports the authors' hypothesis that exercise increases sensitivity to the nondepolarizing muscle relaxant metocurine.

Animals↗
PubMed1989

Malignant hyperthermia in humans--standardization of contracture testing protocol.

Malignant hyperthermia (MH) diagnostic biopsy centers across North America have not previously been standardized in regard to protocols and specific muscles. Recent standardization criteria prompted this study of the vastus and rectus abdominis muscles. This study evaluated changes in contracture tension after electrical stimulation of 271 bundles taken from the vastus (n = 16) and rectus abdominus (n = 19) muscle biopsies of normal individuals when exposed to tissue baths in the absence of and in the presence of caffeine (0.5, 1.0, 2.0, 4.0, 8.0, and 32.0 mM) alone, halothane (1% or 3%) alone, or the combination of halothane (1%) plus caffeine (0.25, 0.5, 1.0, 2.0, 4.0, and 32.0). Caffeine threshold concentration was that concentration of caffeine that produced a 7% increase in tension. Caffeine specific concentration (CSC) and halothane caffeine specific concentration (HCSC) were those concentrations of caffeine alone or of halothane plus caffeine that produced a 1 g increase in tension. The concentration of caffeine alone that increased the contracture tension by 7% averaged 6.7 +/- 0.3 mM for vastus, significantly greater than 4.1 +/- 0.2 mM for the rectus muscle biopsies. Caffeine specific concentration was significantly greater for vastus muscle (7.7 +/- 0.7 mM) than it was for rectus muscle (4.9 +/- 0.4 mM). Three percent halothane alone showed contractures in 3/41 vastus (all less than 0.5 g) and 18/54 rectus muscle bundles (8 greater than 0.5 g). Mean HCSC was statistically significantly greater for vastus muscle (1.9 +/- 0.2 mM) than for rectus muscle (1.2 +/- 0.2 mM).(ABSTRACT TRUNCATED AT 250 WORDS)

Biopsy↗
PubMed1988

Failure of norepinephrine to initiate porcine malignant hyperthermia.

Continuous intravenous infusion in pigs of norepinephrine, to blood concentrations of 140 ng.ml-1, provided a test of the hypothesis that this sympathetic hormone can initiate malignant hyperthermia (MH). This study was performed during nitrous oxide-pentobarbital anesthesia, and in part utilized sodium nitroprusside to maintain normal blood pressure and peripheral perfusion. Metabolic stimulation, or evidence of MH, did not occur in normal or susceptible pigs, as indicated by the lack of increase in both whole body O2 consumption and arterial lactate concentration. Next, in contrast, susceptible pigs manifested MH when exposed to halothane and succinylcholine, while normal pigs did not. We conclude that norepinephrine does not mediate or initiate porcine whole body stress responses characteristic of MH.

Animals↗