Potential time savings by prehospital administration of activated charcoal.

OBJECTIVE: Activated charcoal (AC) has been proven useful in many toxic ingestions. Theoretically, administration of AC in the prehospital environment could save valuable time in the treatment of patients who have sustained potentially toxic oral ingestions. The purpose of this study was to determine the frequency of prehospital AC administration and to identify time savings that could potentially result from field AC administration. METHODS: Adult patients with a chief complaint of toxic ingestion who had complete emergency medical services (EMS) and emergency department (ED) records and no medical treatment (gastric emptying, AC administration) prior to EMS arrival were eligible for inclusion. Data obtained from EMS and ED records included time of EMS departure from the scene, time of EMS arrival at the ED, and time of administration of AC in the ED. Since most EMS agencies in this system do not insert gastric tubes, patients requiring gastric tube placement for administration of AC were excluded. RESULTS: Twenty-nine of 117 (24.8%) adult patients received oral AC with no other intervention. None of the 117 patients received AC in the prehospital setting. The EMS transport time for these patients ranged from 5 to 43 minutes (mean 16.2 +/- 9.7 minutes). The delay from ED arrival to AC administration ranged from 5 to 94 minutes (mean 48.8 +/- 24.1 minutes), and was more than 60 minutes for 14 (48.2%) of the patients. The total time interval from scene departure to ED AC administration ranged from 17 to 111 minutes (mean 65.0 +/- 25.9 minutes). CONCLUSIONS: In a selected subset of patients who tolerate oral AC, prehospital administration of AC could result in earlier and potentially more efficacious AC therapy. Prospective study of the benefits and feasibility of prehospital AC administration is indicated.

Pharmacodynamic modeling of digoxin-induced bradycardia.

Digoxin-induced bradycardia in dogs was used to evaluate several pharmacodynamic models. Digoxin plasma concentrations and response were monitored in beagle dogs administered either 0.05 or 0.025 mg/kg of digoxin iv as an infusion over 5 min. The models investigated were the linking model, the linear model, the effect compartment model, and the inhibitory model. Regression procedures for investigating the effect compartment model were conducted with Emax (the maximal response, where response was the percentage decrease in heart rate) as a variable with an upper bound of 100%, with a constant value of 100%, or alternately with a constant value equal to the maximal observed response. Based on statistical criteria the effect model using Emax as a variable was found to be the best model for describing digoxin-induced bradycardia. For the effect compartment model, CPss(50) (concentration at steady state that will produce 50% of the maximal response) ranged from 3.8-9.8 ng/ml; delta (exponent describing the steepness of the concentration-response relationship) ranged from 0.6-7.1. The implication of these models in understanding concentration-effect relationships are discussed.

Temperature dependence of phenytoin-protein binding in serum: effects of uremia and hypoalbuminemia.

Phenytoin-protein binding was determined as a function of temperature in uremic patients with normal albumin and in uremic patients with hypoalbuminemia. Free phenytoin levels were determined in ultrafiltrates (MPS-1; Amicon, Lexington, MA, U.S.A.) from serum equilibrated at either 20, 25, 30, 35, or 40 degrees C. Scatchard analyses showed significant differences in phenytoin-protein binding affinity as a function of temperature. Linear regression plots of free phenytoin versus temperature showed the slopes of the uremic and uremic with hypoalbuminemia patients (0.546 and 0.535, respectively) to be 3 times that of patients with normal renal function (0.174). Free phenytoin was analyzed in 150 patients with normal renal function in whom the total phenytoin was in the range of 38.0-80.8 mumol/L. The ultrafiltrate, prepared at 22 +/- 0.5 degrees C, resulted in free phenytoin levels in the range of 3.2-8.3 mumol/L. We have established this as the therapeutic range for the patient population seen at this medical center.

Effects in mice of testosterone and dihydrotestosterone on platelet aggregation in injured arterioles and ex vivo.

Mice were implanted subcutaneously with placebo pellets, or with pellets containing either testosterone (T) or dihydrotestosterone (DHT). Eight to 19 days later platelet aggregation was produced in pial or mesenteric arterioles by injuring their endothelium with a noxious light/dye stimulus. The onset of platelet aggregation was significantly shortened in the mesenteric arterioles of male mice following implantation of 1.0 mg T or 0.1 mg DHT. However no effect was observed in females, nor did T or DHT alter aggregation in pial arterioles of either sex. Ex vivo studies showed that sodium arachidonate produced greater aggregation of platelets in plasma from testosterone treated males compared with controls. No effect of testosterone was observed ex vivo in platelets from females. These ex vivo results paralleled in vivo data from mesenteric vessels, but not from pial vessels. Moreover DHT failed to influence aggregation ex vivo in either sex. Thus enhanced aggregation observed in vivo in mesenteric arterioles of androgen treated males may not reflect direct action of androgen on the platelet. Rather enhanced aggregation may reflect hormonal action on endothelium or adjacent tissue. In addition to the preceding studies we tested the hypothesis that testosterone's action was due to its conversion to estradiol. This was considered because our data with T and mesenteric vessels resembled that previously reported by us with estradiol. However only minimal elevations in plasma estradiol levels resulted from testosterone treatment.

Myocardial metabolism and regional myocardial blood flow in the canine left ventricle following twenty minutes of circumflex artery occlusion and reperfusion.

The recovery of high energy phosphate stores (ATP plus phosphocreatine) was examined following various periods of reperfusion after 20 min circumflex artery occlusion in the open-chest dog. Transmural tissue samples were obtained from the posterior wall of the left ventricle of control dogs, after 20 min occlusion and after 1, 5, 10, 15 and 20 min reperfusion. Significant reductions in high energy phosphate stores were observed in the subepicardium (41.6% of control) and subendocardium (31.3% of control) after occlusion. Upon reperfusion, recovery was rapid and exceeded control by 65.4% (91.0 v. 55.0 microns/g dry wt) in the subendocardium, but only by 2.6% (72.2 v. 70.4, mumg/g dry wt) in the subepicardium and was due mainly to recovery of phosphocreatine. Regional myocardial blood flow was studied in a separate, but identical, series of experiments. During occlusion, posterior wall blood flow was reduced by 54% (0.85 +/- 0.04 to 0.37 +/- 0.04, ml/g/min) in the subepicardium and by 94.7% (1.13 +/- 0.05 to 0.06 +/- 0.005, ml/g/min) in the subendocardium. Reperfusion produced a rapid recovery including overshoot of blood flow compared to control blood flow. Peak blood flow occurred one minute after release of the occlusion becoming 3.34 +/- 0.16 ml/g/min in the subepicardium and 2.39 +/- 0.13 ml/g/min in the subendocardium. Blood flow in both levels returned to control flow after 15 min reperfusion. These results indicate that metabolic recovery of high energy phosphate stores occurred within 5 min of restoration of blood flow in this model.

Effects on labile metabolites of temporal delay in freezing biopsy samples of dog myocardium in liquid nitrogen.

Sudden hypothermia utilising liquid nitrogen has been used for immediate inhibition of metabolic reactions and preservation of labile compounds in heart muscle. It has been suggested that this rapid transfer of tissue into liquid nitrogen, within 1 to 2 s, is essential for accurate assessment of internal milieu conditions. We tested this hypothesis in normal dogs by measuring phosphocreatin, ATP, glycogen, and lactate concentrations in transmural layers of a core biopsy taken from the posterolateral wall of the left ventricle frozen immediately in liquid nitrogen or held at room temperature for varying times up to 300 s before freezing the tissue. The earliest significant change occurred in phosphocreatine levels after 60 s; only phosphocreatine demonstrated any changes within the first 120 s. These studies indicate that a delay of up to 30 s may be tolerated before freezing tissue without any change occurring in these labile metabolites.

Transmural metabolic gradients in the normal dog left ventricle: effect of right atrial pacing.

The effects of atrial pacing on tissue metabolite levels known to be sensitive to ischemia were examined. Anesthetized dogs were thoracotomized and a pacing electrode was sutured to the right atrium. Pacing at rates of 200 or 250 beats/min (10 animals per group) was performed for 15 min after base-line hemodynamic data had been obtained. At the end of the pacing period, a transmural biopsy was taken, frozen in liquid nitrogen, and sectioned into subepicardial, midmyocardial, and subendocardial layers. ATP, phosphocreatine, lactate, and glycogen were extracted and analyzed. Significant (P less than 0.001) transmural gradients of each of these metabolites existed in the control group. Pacing had no significant (P greater than 0.2) effect on any metabolite from layer to layer at 200 or 250 beats/min. However, indices of heart work (i.e., contractility (dP/dt), stroke work, and stroke volume) demonstrated significant reductions (P less than 0.01) due to pacing, while circumflex artery blood flow increased more than twofold (P less than 0.001) at the highest rate. These data suggest that physiologic autoregulation occurred during pacing and protected the subendocardium from stress-induced ischemic insult.

Reduced high-energy phosphate levels in rat hearts. I. Effects of alloxan diabetes.

Significant alterations in heart carbohydrate and lipid metabolism are present 48 h after intravenous injection of alloxan (60 mg/kg) in rats. It has been suggested that uncoupling of oxidative phosphorylation occurs in the alloxanized rat heart in vivo, whereas normal oxidative metabolism has been demonstrated in alloxan-diabetic rat hearts perfused in vitro under conditions of adequate oxygen delivery. We examined the hypothesis that high-energy phosphate metabolism might be adversely affected in the alloxan-diabetic rat heart in vivo. Phosphocreatine and ATP were reduced by 58 and 45%, respectively (P is less than 0.001). Also, oxygen-dissociation curves were shifted to the left by 4 mmHg, and the rate of oxygen release from blood was reduced by 21% (P is less than 0.01). Insulin administration normalized heart high-energy phosphate compounds. ATP production was accelerated in diabetic hearts perfused in vitro with a well-oxygenated buffer. These studies support the hypothesis that oxidative ATP production in the alloxan-diabetic rat heart is reduced and suggest that decreased oxygen delivery may have a regulatory role in the oxidative metabolism of the diabetic rat heart.

Transmural gradients in ischemic canine left ventricle: effects of blood reflow on glycolytic intermediates.

Following two and four hours of left ventricular ischemia, 20 minutes of blood reflow cannot produce a complete return to normal oxidative metabolism in ischemic canine myocardium. Glycolysis remains increased and aerobic metabolism is most extensively depressed in the subendocardium.

Reduced high-energy phosphate levels in rat hearts. II. Effects of sodium cyanate.

The effects of increased blood-oxygen affinity, due to carbamylation of hemoglobin in vivo, on aerobic metabolism in the heart were studied in rats. Adult male rats were injected intraperitoneally 3 times weekly for 10 wk with sodium cyanate (60 mg/kg). Significant derangement of blood-oxygen interaction was observed. Oxygen-dissociation curves were left shifted by 13 mmHg (35.1-21.8), and the overall deoxygenation rate (k) was reduced 41% (6.142-3.624; s(-1)); P is less than 0.001 for each parameter. Heart ATP and PCr levels were reduced (ATP: 19.4-16.7; PCr: 15.0-11.0, mum/g dry wt; P is less than 0.001 for each). In addition, glycogen levels fell (161.4-112.9, mum C6/g dry wt; P is less than 0.001). Myocardial lactate levels increased 54% (2.6-4.0, mum/g dry wt; P is less than 0.01) in the cyanate-treated group. These findings strongly suggest a hypoxia-induced activation of glycolysis as a consequence of altered oxidative metabolism in rats treated with sodium cyanate.

Inability of selenium to affect creatine metabolism in rat muscle.

1. Two groups of adult rats were placed in a metal-free environment and pair-fed with selenium-supplemented and Se-deficient diets. 2. After 5 months the animals were killed and skeletal muscle concentrations of creatine, creating phosphate, ATP, protein and Se were determined. 3. Se deficiency was indicated by the low Se content of the skeletal muscle from the deficient animals, but no changes were found in the amounts of the other components. 4. These results suggest that Se may not be involved in creatine metabolism and that Se deficiency may not be concerned independently in the development of nutritional dystrophy, where changes are found in the levels of protein, creatine, creatine phosphate and ATP.

Reduced myocardial ATP and creatine phosphate in diabetes: role of 2,3-diphosphoglycerate.

Observations are presented which suggest that myocardial cellular hypoxia may account for the reduction in myocardial ATP and CP in the ketoacidotic diabetic state. It is suggested that reduced 2,3-diphosphoglycerate adversely affects oxygen release from the red blood cell, thereby leading to myocardial cellular hypoxia.