Robert G. Peterson

Acute carbamazepine toxicity resulting from overdose

Four patients with an acute overdose of carbamazepine were examined with serial blood level determinations. The clinical spectrum consisted of coma, respiratory depression, seizures, myoclonus, nystagmus, hyperreflexia, hyporeflexia, delayed gastric emptying with cyclic coma, ataxia, sinus tachycardia, and atrioventricular conduction delay. Carbamazepine elimination half-lives varied from 10 to 29 hours, and in one case carbamazepine-l0, 11-epoxide was measured and had a half-life of 24 hours.

D-Penicillamine therapy of acute arsenic poisoning

Severe poisoning resulting from single ingestions of rodenticides, herbicides, or insecticides containing arsenic have been frequently recognized. We record three cases of solubilized arsenic trioxide poisoning in Navajo Indian children and one case of sodium arsenate ingestion in an infant. One fatality occurred during dimercaprol therapy prior to initiation of therapy with D-penicillamine. Three survivors were treated with 2.3-dimercaprol intramuscularly and with oral D-penicillamine. The use of D-penicillamine in arsenic poisoning has not been generally appreciated. Excretion data from the three children are presented which document the effectiveness of D-penicillamine, administered orally in four daily doses of 25 mg/kg/dose, in the therapy of arsenic intoxication. Excretion data for the trace metals, zinc and copper, during D-penicillamine chelation therapy are also reported.

Toxicity of acetaminophen overdose

Symptoms of toxicity following overdose of acetaminophen (APAP), now a common household medication, occur 24 to 48 hours following ingestion. Toxicity is mainly to the liver but, while data has implicated a minor metabolite, the precise mechanism is not known. Toxicity is likely to occur after a minimum ingestion of 140 mg/kg, but the toxic dose may vary as a function of individual glutathione levels. Since the early clinical picture is not diagnostic, APAP plasma levels must be measured. Supportive care alone has resulted in a 5% to 10% mortality with a high incidence of hepatic toxicity. Treatment within 10 to 12 hours following ingestion with any therapeutic agent reduced mortality to zero and diminished liver toxicity. N-acetylcysteine is an investigational new drug for treating APAP toxicity and can ethically be used if the patient is first enrolled in the current nationwide evaluation. Recommended treatment steps in a suspected APAP poisoning are 1) emesis or lavage; 2) plasma APAP determination; 3) obtain treatment protocol from the Rocky Mountain Poison Center; 4) history of use of other pharmacologic agents, and 5) diuresis, alkalinization or hemodialysis, as in aspirin poisoning, are contraindicated.

Asymptomatic Theophylline Overdose

A case of severe theophylline overdose is described in which clinical signs of toxicity initially were minimal despite extremely high serum drug levels. Hemodialysis was performed because of the risk of seizures and cardiac arrhythmias. The predialysis, dialysis, and postdialysis half-lives were 13.1, 4.3, and 6.7 hours, respectively. Corresponding total body clearance values were 23.8, 72.5, and 46.3 ml/kg/h. The patient showed apparent saturation kinetics of theophylline clearance at high serum levels. Hemodialysis is effective for enhancing the removal of theophylline.

Phenothiazine-induced ventricular tachycardia following acute overdose

The chronic use of phenothiazine is known to result in ventricular arrhythmias in certain patients. The occurrence of cardiac abnormalities following acute phenothiazine overdose is less well documented. Phenothiazine-induced ventricular tachycardia, when it occurs in the overdose situation, may be refractory to conventional antiarrhythmic drugs. We present a case in which the usual therapy was unsuccessful. Only after a transvenous pacemaker was inserted was the patients condition reversed.

PHARMACOLOGY OF INTRAVENOUS VITAMIN E IN THE VERY LOW BIRTHWEIGHT (VLBW) NEWBORN

Vitamin E (VE) has been used via the oral or in route in VLBW infants; however, the intravenous route is often preferred. The pharmacokinetics of intravenous VE have not been reported.Prior to an infant study, we measured VE pharmacokinetics in 8 adult cats after an intravenous infusion. Results showed a mean T½ of 73.0 hours, volume of distribution based on area (VD) of 0.59 l/kg and total plasma clearance (PC) of 4.5 mg/k/hr.We then measured serum VE levels in six VLBW newborns after a one-hour infusion of 10 mg/kg (dl-α-tocopherol, Hoffman-LaRoche) via peripheral vein. Serum was obtained at 0, 0.5, 2, 6, 12, 24, 48, 72, 96 and 120 hours and then intermittently up to 28 days post infusion. Serum VE levels were measured by HPLC. Kinetic analysis was done using a multicompartment fitting with an exact, least squares program on a digital computer. All infants were n.p.o. and intubated for respiratory distress. Their mean BW was 920 grams and G.A. was 27 weeks. Select serum VE levels in mg/l:The mean T½ was 282 ± 164 hrs., VD was 0.373 ± 0.098 l/kg, and PC was 1.27 ± .46 ml/k/hr. There was no change in liver function as assessed by clinical course, SGOT or bilirubin. Serum lipid concentrations were stable. Dosing recommendations can be based on these data.

Laetrile and pregnancy.

Pregnancy in a woman who took laetrile as daily intramuscular injections during the last trimester resulted in a live, term infant. No laboratory or clinical evidence of elevated cyanide or thiocyanate, a pricipal metabolite, could be detected. Neurological evidence of chronic cyanide exposure may not be recognizable in infancy, and long-term follow-up is indicated.

DISEASE SEVERITY AS A FACTOR IN ELIMINATION OF TOBRAMYCIN (TOBRA) IN PATIENTS WITH CYSTIC FIBROSIS (CF)

To obtain therapeutic “peak” and “trough” concentration of tobra, many CF patients require ↑ dose/kg and ↑ frequency of drug administration. The basis for this is unclear. Tobra clearances after a single 60 mg/m2 IV infusion were studied in 11 stable CF patients with mild to very severe disease to investigate factors which might modify tobra kinetics. The mean age was 16.5 years±3.5; range 10-22, with a mean NIH score of 63±19; range 32-94. The mean % weight for height was 93.1±17.5; range 63.1-122. The lung disease was mild to severe; mean FVC 70.2±23.570 predicted;, range 36-99; mean FEV1 53.4±27.570 predicted; range 17-97. The data could best be described by a two compartment model for drug elimination. Dosing based upon body surface area minimized the effect of malnutrition on attainment of therapeutic levels (mean peak 7.6±1.4mg/l). The half life (T½%) range was 1.24-2.52 hr, the volume of distribution (VD) range was 0.102-0.401 I/kg, the plasma clearance (TPC) range was 43-110 ml/kg/hr and the mean % dose recovered in urine by 24 hours was 78.7±18.5. VD and TPC were ↑ in patients with lower FVC, FEV1 % predicted; those with more severe disease (ps <0.02, strong correlation coefficients). NIH score (contains FVC) also correlated inversely but less strongly (ps< 0.05). Creatinine and inulin clearances correlated only with T½ and VD respectively. Age, nutrition, and PAH clearance did not correlate. Thus, all CF patients are not the same in terms of tobra kinetics. These varied with the disease severity. This suggests that the severity of disease, not just the presence of CF, is the major factor for altered tobra kinetics.

Clonidine — Recurrent Apnea following Overdose

Recurrent episodes of apnea are described in two children following overdosage of clonidine. Respiratory depression and apnea requiring intubation may not occur for up to 2½ hours following ingestion of clonidine. Hypotension was absent in one case, suggesting opposition to centrally mediated effects by peripheral alpha-agonistic activity in the presence of high serum concentrations of clonidine. General symptoms and treatment of clonidine overdosage are discussed.

16 N-ACETYLCYSTEINE THERAPY OF CHILDHOOD ACETAMINOPHEN OVERDOSE

573 cases of acetaminophen (APAP) ingestion (277 in children under 5 years) have occurred in the Rocky Mountain Region. There were four deaths, all in the adolescent age group, prior to 1976. A multiclinic open national study of N-acetylcysteine (NAC) therapy of APAP overdose since Sept., 1976 has resulted in 88 cases of APAP ingestion in the less than 5 year old. Of these, only 16 had taken more than 140mg/kg by history and would be considered to be at risk for toxicity. Two of these children, in fact, had evidence for toxicity by SGOT elevation and toxic plasma level.Adolescents and young adults, in contrast, contributed 146 cases of APAP overdose with 56 cases in the 12 to 16 year group and 90 cases between the ages of 17 and 21 years. These cases were divided according to time following ingestion and first NAC dose as: I- 0 to 10 hours; II- 10 to 24 hours; and III- no NAC therapy. The data regarding peak SGOT values (IU/L) in each group are given below.