Plasma hyperosmolality elevates the internal temperature threshold for active thermoregulatory vasodilation during heat stress in humans.

Plasma hyperosmolality delays the response in skin blood flow to heat stress by elevating the internal temperature threshold for cutaneous vasodilation. This elevation could be because of a delayed onset of cutaneous active vasodilation and/or to persistent cutaneous active vasoconstriction. Seven healthy men were infused with either hypertonic (3% NaCl) or isotonic (0.9% NaCl) saline and passively heated by immersing their lower legs in 42 degrees C water for 60 min (room temperature, 28 degrees C; relative humidity, 40%). Skin blood flow was monitored via laser-Doppler flowmetry at sites pretreated with bretylium tosylate (BT) to block sympathetic vasoconstriction selectively and at adjacent control sites. Plasma osmolality was increased by approximately 13 mosmol/kgH(2)O following hypertonic saline infusion and was unchanged following isotonic saline infusion. The esophageal temperature (T(es)) threshold for cutaneous vasodilation at untreated sites was significantly elevated in the hyperosmotic state (37.73 +/- 0.11 degrees C) relative to the isosmotic state (36.63 +/- 0.12 degrees C, P < 0.001). A similar elevation of the T(es) threshold for cutaneous vasodilation was observed between osmotic conditions at the BT-treated sites (37.74 +/- 0.18 vs. 36.67 +/- 0.07 degrees C, P < 0.001) as well as sweating. These results suggest that the hyperosmotically induced elevation of the internal temperature threshold for cutaneous vasodilation is due primarily to an elevation in the internal temperature threshold for the onset of active vasodilation, and not to an enhancement of vasoconstrictor activity.

Paradoxical ventricular tachycardia and fibrillation after intravenous bretylium therapy. Report of two cases.

Two patients were treated with bretylium tosylate for malignant ventricular arrhythmias after inadequate response to conventional agents. In the first patient, two episodes of ventricular tachycardia requiring cardioversion occurred in close temporal sequence with administering bretylium. With drug rechallenge two days later, ventricular tachycardia recurred within minutes. In the second case, five cardiac arrests due to ventricular tachycardia and fibrillation occurred during several hours after beginning a trial of bretylium maintenance therapy for complex ventricular ectopy. Although transient increases in ectopy after bretylium therapy have been described, presumably due to catecholamine release, the occurrence of life-threatening ventricular arrhythmia leading to cardiac arrest has not previously been emphasized. There is potential for this side effect, and additional caution in the use of this drug should be followed.

Oral and intravenous bretylium disposition.

To compare the oral and intravenous disposition of bretylium tosylate in man, 10 normal male subjects were randomly assigned single doses of 5 mg/kg bretylium tosylate either orally or intravenously and crossed over 2 wk later to the opposite route (20 studies). Each experiment included sampling for drug in serum and urine over 48 hr. Bretylium tosylate was assayed by gas chromatography. Kinetic analysis provided the following mean [coefficient of variation] results: 100FPo, 22.6% [40.2%]; ClrIV, 300 ml/min [27.8%]; ClrPo, 1.268 mg/min [54.8%]; ClBIV, 299 ml/min [31.9%]; f, 101% [8.7%]; Vdss, 3.37 l/kg [30.5%]; lambda lIV 0.0510 [12.8%]; lambda lPG, 0.115 [52.7%]hr-1; elimination half-life (t 1/2) after intravenous bretylium tosylate, 13.6 hr, and after oral bretylium tosylate, 6.0 hr (harmonic means). Bretylium tosylate binding to plasma proteins in normal volunteer samples was found to be negligible. The results indicate extensive tissue binding of bretylium tosylate. Oral doses of bretylium tosylate are only partially absorbed. Bretylium tosylate is eliminated entirely by the kidneys as unchanged drug. The greater renal clearance after oral than intravenous bretylium tosylate, and the greater elimination rate constant and shorter oral bretylium tosyulate t 1/2 are of interest but no explanation is available.

Long-term intravenous infusion of antiarrhythmic drugs using a totally implanted drug delivery system.

In vitro and in vivo testing was performed to establish the feasibility of a totally implantable pump system to deliver antiarrhythmic agents. In vitro flow characteristics suggested predictable day to day delivery with acceptably small variations in flow with changes in reservoir volume or temperature. During 3 months of in vitro testing, procainamide and bretylium were found suitable for long-term delivery. Delivery of lidocaine was limited by high viscosity and corrosion of steel elements within the pump. The pump was implanted in a subcutaneous pocket in four dogs. Procainamide (0.5 g/ml), delivered at 4 ml/day (70 mg/kg body weight per day), provided a mean steady state drug concentration of 5.3 micrograms/ml. Bretylium (50 mg/ml), delivered at 8 ml/day (13 mg/kg per day), provided a steady state concentration of 0.8 micrograms/ml (range 0.4 to 1.4). Long-term intravenous administration of therapeutic doses of bretylium and procainamide with this delivery system has been demonstrated in dogs and appears to be feasible in human subjects.

Bretylium tosylate in patients with acute myocardial infarction.

Experience with bretylium tosylate accumulated during a period of over 10 years, during which time greater than 1,500 patients with acute myocardial infarction were treated, is summarized. On the diagnosis of acute infarction, the agent was given by continuous intravenous drip at a rate of 10 mg/kg/24 hours for 5 to 7 days for prophylaxis of ventricular fibrillation. Bretylium administration prevented primary ventricular fibrillation in about 99% of these patients. No undesirable side effects were observed with this protocol, which lessens the initial sympathomimetic effect of the drug while allowing sufficient time for the adrenergic neuronal blocking effect to develop. The beneficial effects of the drug are believed to be due, in part, to a direct electrophysiologic effect on both normal and ischemic myocardium. This effect equalizes the duration of both the effective refractory periods and the ventricular action potentials, and it creates conditions capable of blocking reentrant pathways. Bretylium stabilizes the duration of electrical systole in patients with acute myocardial infarction. Hemodynamic studies during bretylium treatment further confirm the effectiveness of this drug and have prompted additional studies to evaluate its potential as an agent capable of decreasing impedance in acute myocardial infarction.

Bretylium tosylate: profile of the only available class III antiarrhythmic agent.

Bretylium tosylate, the only approved class III antiarrhythmic agent, is a unique quaternary ammonium compound with prominent experimental and clinical antifibrillatory effects. Intravenous bretylium causes a biphasic hemodynamic response; initial norepinephrine release is followed by sympathetic ganglionic blockade. Cardiac output is well maintained. Electrocardiographic intervals are unchanged, and global conduction unchanged or facilitated. With long-term experimental use, proportionate lengthening of ventricular action potential and refractory period occurs. Bretylium is largely eliminated unchanged in the urine, with a long terminal half-life of about 13 hours. Bretylium demonstrates substantial activity in several animal models and clinical circumstances of ventricular fibrillation, including those in which standard antiarrhythmic therapy is ineffective. Bretylium is thus currently approved as a first-line agent for prophylaxis and treatment of ventricular fibrillation, and as a second-line agent for ventricular tachycardia and other prefibrillatory ventricular arrhythmias. In contrast, bretylium's weak antiectopic activity and limited oral absorption make it a poor choice for management of simple ventricular ectopy. Side effects of bretylium are generally limited to its hemodynamic actions (eg, postural hypotension). Nausea may occur with rapid intravenous administration. Emerging clinical concepts emphasize the clinical importance of antifibrillatory action over antiectopic effects alone. Bretylium is thus likely to continue to find increasing usage in the acute management of malignant ventricular arrhythmia.

Bretylium tosylate--induced stabilization of electrical systole duration in patients with acute myocardial infarction.

The electrical systole duration (QTc), heart rate, and the QTc/QTt ratio were studied during the hospital course of an uncomplicated AMI in 13 patients treated with bretylium tosylate (10 mg/mg/24 hr over 5 days since confirmation of AMI) and in 19 controls. The QTc/QTt ratio showed prolongation of electrical systole duration in control subjects with a maximal value at the second day after AMI. QTc increased in these patients from day 1 to day 2 after AMI (402 +/- 4 msec vs. 430 +/- 3 msec, p less than 0.05) and decreased in the following days (p less than 0.05). During hospitalization cardiac rate was constant in both groups. In contrast, patients treated with bretylium tosylate showed a stable duration of QTc and the QTc/QTt ratio did not indicate prolongation of electrical systole duration. After drug discontinuation a slight increase in QTc duration was noticed (391 +/- 6 msec vs. 413 +/- 5 msec, p less than 0.05). These observations may contribute to the understanding of the antiarrhythmic action of bretylium and would indicate its usefullness in AMI patients with prolonged QTc and high risk of life-threatening arrhythmias.

Pediatric cardiopulmonary resuscitation.

Pediatric cardiopulmonary resuscitation refers to those measures used to restore ventilation and circulation in children. This article defines how cardiopulmonary resuscitation in infants, children, and adolescents differs from cardiopulmonary resuscitation in adults and delineates the drugs and dosages to be used in the resuscitation of pediatric patients.

[Etiologies of electric storm]. / Etiologies de l'orage électrique.

The electrical storm is defined as recurrent ventricular tachycardia or fibrillation leading to cardiac shock occurring two or more times within 24 hours and usually requiring cardioversion or defibrillation. Recent advances in our understanding of this severe arrhythmia and its pharmacological treatment have improved the prognosis of these patients. The authors review several clinical syndromes of the electrical storm and the treatment of each.

[An analysis of the mechanism of the effect of intragastric calcium and magnesium on the release of gastrin and insulin in dogs]. / Analiz mekhanizmu vplyvu intrahastral'noho kal'tsiiu i mahniiu na vyvil'nennia hastrynu ta insulinu u sobak.

The experiments have been carried out on four intact awake dogs to study the influence of intragastric introduction of deionized water, 5 mmol/l of calcium and magnesium chloride solutions in a dose of 3 ml/kg on release of gastrin and insulin into blood. It is stated that during the first 4 min after infusion of deionized water the release of gastrin decreases by 89 +/- 32 conventional units (c.u.), CaCl2 exerts a more pronounced inhibitory effect (168 +/- 36 c.u.), while MgCl2, on the contrary, increases the gastrin release by 398 +/- 92 c.u. Atropin (0.03 mg/kg, subcutaneous injection, 10 min before infusion) absolutely takes away the gastrin-stimulating effect of magnesium, but it has almost no influence on the gastrin-inhibitory effect of calcium. The latter can be taken away by 62% by ornid (5 mg/kg subcutaneously, 20 min before infusion). Preliminary anaesthesia of the stomach mucosa by trymecain or novocain absolutely remove the effect of both calcium and magnesium. Insulin release remained significantly unchanged in any series of experiments.

Oral vitamin C enhances the adrenergic vasoconstrictor response to local cooling in human skin.

Local administration of ascorbic acid (Asc) at a supraphysiological concentration inhibits the cutaneous vasoconstrictor response to local cooling (LC). However, whether orally ingesting Asc inhibits the LC-induced vasoconstrictor response remains unknown. The purpose of the present study was to examine the acute influence of oral Asc on the adrenergic vasoconstrictor response to LC in human skin. In experiment 1, skin blood flow (SkBF) was measured by laser-Doppler flowmetry at three sites (forearm, calf, palm). The three skin sites were locally cooled from 34 to 24°C at -1°C/min and maintained at 24°C for 20 min before (Pre) and 1.5 h after (Post) oral Asc (2-g single dose) or placebo supplementation. Cutaneous vascular conductance (CVC) was calculated as the ratio of SkBF to blood pressure and expressed relative to the baseline value before LC. Oral Asc enhanced (P < 0.05) the reductions in CVC in the forearm (Pre, -50.3 ± 3.3%; Post, -57.8 ± 2.2%), calf (Pre, -52.6 ± 3.7%; Post, -66.1 ± 4.3%), and palm (Pre, -46.2 ± 6.2%; Post, -60.4 ± 5.6%) during LC. The placebo did not change the responses at any site. In experiment 2, to examine whether the increased vasoconstrictor response caused by oral Asc is due to the adrenergic system, the release of neurotransmitters from adrenergic nerves in forearm skin was blocked locally by iontophoresis of bretylium tosylate (BT). Oral Asc enhanced (P < 0.05) the reductions in CVC at untreated control sites but did not change the responses at BT-treated sites during LC. In experiment 3, to further examine whether adrenergically mediated vasoconstriction is enhanced by oral Asc, 0.1 mM tyramine was administered using intradermal microdialysis in the forearm skin at 34°C in the Pre and Post periods. Oral Asc increased (P < 0.05) the tyramine-induced reduction in CVC. These findings suggest that oral Asc acutely enhances the cutaneous vasoconstrictor responses to LC through the modification of adrenergic sympathetic mechanisms.

Different vascular responses in glabrous and nonglabrous skin with increasing core temperature during exercise.

To elucidate the characteristics of vasomotor control in glabrous and nonglabrous skin during dynamic exercise, we compared the vascular responses in both areas to increasing core temperature during the cycle exercise for 30 min at different intensities in the range 20-60% of peak oxygen consumption (VO(2peak)) in a total of 13 male and four female subjects in two experimental protocols. Skin blood flow was monitored using laser Doppler flowmetry. In protocol 1, the slope of the relationship between esophageal temperature (T (es)) and cutaneous vascular conductance (CVC) in the early phase of the exercise decreased (P < 0.05) with increasing exercise intensity at glabrous sites (palm) but not nonglabrous sites (dorsal hand). In protocol 2, to examine whether a difference in vascular responses in the two areas is due to the adrenergic vasoconstrictor system, the release of norepinephrine from adrenergic nerves in forearm and palmar skin was blocked locally by iontophoresis of bretylium tosylate (BT). The administration of BT diminished completely the change of CVC in the palm during the exercise but did not alter the response in the forearm compared with the untreated site. In the two areas, neither the T (es) threshold for vasodilation nor the change in CVC above the threshold in the middle and late phase of the exercise was influenced by the intensity of the exercise. These results suggest that, in the early phase of the exercise, light-to-moderate exercise reduces in an intensity-dependent manner the thermal sensitivity for vasodilation in glabrous skin but not nonglabrous skin via an adrenergic vasoconstrictor pathway.

Sympathetic, sensory, and nonneuronal contributions to the cutaneous vasoconstrictor response to local cooling.

Previous work indicates that sympathetic nerves participate in the vascular responses to direct cooling of the skin in humans. We evaluated this hypothesis further in a four-part series by measuring changes in cutaneous vascular conductance (CVC) from forearm skin locally cooled from 34 to 29 degrees C for 30 min. In part 1, bretylium tosylate reversed the initial vasoconstriction (-14 +/- 6.6% control CVC, first 5 min) to one of vasodilation (+19.7 +/- 7.7%) but did not affect the response at 30 min (-30.6 +/- 9% control, -38.9 +/- 6.9% bretylium; both P < 0.05, P > 0.05 between treatments). In part 2, yohimbine and propranolol (YP) also reversed the initial vasoconstriction (-14.3 +/- 4.2% control) to vasodilation (+26.3 +/- 12.1% YP), without a significant effect on the 30-min response (-26.7 +/- 6.1% YP, -43.2 +/- 6.5% control; both P < 0.05, P > 0.05 between sites). In part 3, the NPY Y1 receptor antagonist BIBP 3226 had no significant effect on either phase of vasoconstriction (P > 0.05 between sites both times). In part 4, sensory nerve blockade by anesthetic cream (Emla) also reversed the initial vasoconstriction (-20.1 +/- 6.4% control) to one of vasodilation (+213.4 +/- 87.0% Emla), whereas the final levels did not differ significantly (-37.7 +/- 10.1% control, -37.2 +/- 8.7% Emla; both P < 0.05, P > 0.05 between treatments). These results indicate that local cooling causes cold-sensitive afferents to activate sympathetic nerves to release norepinephrine, leading to a local cutaneous vasoconstriction that masks a nonneurogenic vasodilation. Later, a vasoconstriction develops with or without functional sensory or sympathetic nerves.

Pharmacokinetics of bretylium in man after intravenous administration.

The pharmacokinetic profile of bretylium was studied in four normal male volunteers using a new sensitive EC-GC procedure for its quantitative in biological fluids. The plasma concentrations and urinary excretion rates following the constant i.v. infusion of a single 4 mg/kg dose of bretylium tosylate declined biexponentially and the data were fitted to a two-compartment model with a renal and a nonrenal route of elimination. The drug had a mean half-life (t1/2 beta) of 7.8 hr and apparent volume of distribution (Vd, beta) of 8.18 liters/kg. The renal clearance, which was 6 times that of the glomerular filtration rate, accounted for almost 84% of the total body clearance and correlated linearly with the subjects' creatinine clearance. The observed side effects of bretylium were mild and similar to those of other adrenergic blocking agents.

Massive intravenous bolus bretylium tosylate.

A 30 mg/kg (2-gm) intravenous bolus of bretylium tosylate was administered to a patient with recurrent ventricular tachycardia and fibrillation. After successful defibrillation the patient exhibited marked hypertension followed by protracted refractory hypotension. There was no further ventricular ectopy in spite of a very low cardiac index. A bretylium level of 8,800 ng/ml is the highest reported in man from a single bolus injection. This case demonstrates the exaggerated hemodynamic response to massive intravenous bolus bretylium tosylate.

Intravenous bretylium overdose.

An 81.5-mg/kg intravenous overdose of bretylium tosylate was administered to a 74-year-old patient after resuscitation from inferior wall myocardial infarction and cardiac arrest. The patient exhibited prolonged neurological depression with eventual neurological recovery. This case demonstrates the central nervous system depression that can occur with bretylium overdose. The emergency physician should be aware of this effect and avoid ending lifesaving measures because of apparent brain death in patients with bretylium overdose.