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Background: Clonidine ingestions (A) and gastrointestinal decontamination (B) in children deserve special consideration. Case Series A: Clinically, clonidine toxicity mimics opiate overdose. Therefore, it is not surprising that naloxone has been administered in an attempt to reverse clonidine-induced hypotension, bradycardia, coma, and apnea. Case reports reveal inconsistent reversal of central nervous system (CNS) and cardiovascular (CV) effects following the administration of naloxone to toddlers who have ingested clonidine. There are multiple variables in these case reports. Varying doses of naloxone, frequently determined by weight, were administered. Varying degrees of coma, hypotension, and bradycardia were present at the time that naloxone was administered. Cardiovascular response was not differentiated from CNS response. Discussion: Animal research indicates that clonidine causes hypotension by inhibiting the imidazoline-preferring receptors in the ventrolateral medulla oblongata but clonidine causes sedation by inhibiting the alpha-2 adrenoreceptors in the locus cereleus. Large doses of clonidine are required to inhibit the metabolic activity of catecholaminergic neurons within the locus cereleus. Therefore the clinical picture (sedation) is partially determined by ingested dose of clonidine. Central alpha-2 receptor agonists such as clonidine may cause release of beta-endorphin. Both sympathetic tone and adrenoreceptors in the locus cereleus are inhibited by beta-endorphin. A genetic predisposition may determine the resting tone of the sympathetic nervous system as well as the release of endogenous opiates in response to clonidine. There may be genetically predetermined 'responders' and 'nonresponders.' Clinical presentation at the time of administration of naloxone, genetic predisposition and individual response to the actions of naloxone contribute to the inconsistent reversal of CV and CNS toxicity. The clinical question that has not yet been answered is whether there is a dose of naloxone that would reverse the toxic effects of clonidine in all patients. There is very little evidence that large doses of naloxone would be harmful in these patients. Hypertension myth: The myth of hypertension following naloxone administration can be clarified by analysis of the three case reports supporting this myth. Administration of atropine and paralytic agents prior to the administration of naloxone contribute to the hypertension that occurred following naloxone administration. Yet many practicing pediatricians do not use naloxone in the setting of clonidine intoxication due to the concern of subsequent hypertension. The lack of evidence for naloxone-induced hypertension in the setting of clonidine intoxication needs to be disseminated to practicing clinicians. Receptor physiology: Receptor physiology may be different in children and adults. One of the clinical aspects to be considered is whether children should be treated with larger doses of drugs that affect receptors. Case Series B: Certain aspects of gastrointestinal decontamination require special consideration in children. Aspects include: conflicting opinions regarding the indications for syrup of Ipecac administration, reasons that gastric lavage is seldom, if ever, indicated in children, the risk:benefit ratio of administering single-dose activated charcoal (SDAC) to children, multiple-dose activated charcoal (MDAC) and the misconception regarding the dangers of administering charcoal with sorbitol to children. Conclusion: The risk:benefit ratio of administration of syrup of Ipecac, gastric lavage, SDAC and MDAC may be different in children than in adults. Some poisons, such as cellular toxins, require special consideration., Seger D. Department of Medicine and Emergency Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, [...]

Background: The efficacy of Dantrolene in the treatment of drug-induced hyperthermia is controversial. Dantrolene acts directly on skeletal muscle where it inhibits release of calcium from the sarcoplasmic reticulum and reduces intracellular calcium, which leads to muscle relaxation. Dinitrophenol (DNP) causes hyperthermia by uncoupling oxidative phosphorylation in the mitochondria. This decreases available ATP and increases the free [Ca.sup.++] within the cell, leading to muscle contraction. Because of the hypermetabolic state it can induce, DNP is marketed on the internet for body building and weight loss. Case: A thirty-year old male presented to an emergency department following ingestion of DNP. He was diaphoretic, flushed, and tachycardic. Serum creatine phosphokinase concentration was 62,000 IU/L. His body temperature reached 108[degrees]F and was decreased to 104[degrees]F with cooling blankets. Twenty minutes following Dantrolene administration his body temperature decreased to 100.8[degrees]F. Repeated doses of dantrolene were needed to maintain a stable body temperature. Two other DNP cases resulting in death from hyperthermia have been reported to our center in the past three years. Both of these patients remained hyperthermic despite cooling blankets. Conclusion: Mortality in DNP toxicity is caused by life-threatening hyperthermia. Uncoupling of oxidative phosphorylation causes DNP-induced hyperthermia which may be ameliorated by Dantrolene. Further investigation is needed., Kumar S, Barker K, Seger D. Vanderbilt University Medical [...]

Background: Supratherapeutic vancomycin infusions of 300-400 mg/kg were inadvertently administered to three premature neonates (AR, DH, SP). Reported beta-elimination half-life (T1/2) of normal dosing of vancomycin in neonates is 13.4-33.7 hours (hr). A T1/2 of 35 hr was reported in an iatrogenically-overdosed premature neonate. Multiple dose activated charcoal (MDAC) was given to enhance elimination in our 3 patients. Case Series: Following vancomycin infusion, three neonates developed apnea, hypotension, flushed skin, and inflamed infusion, sites. Initial vancomycin levels were: AR--287.7 mcg/mL (wt 3120 g), DH--371.4 mcg/mL (wt 690g), and SP--357.2 mcg/mL (wt 1275g). MDAC (1 g/kg every 4 hours) was given for 24 hours to patient AR and 48 hours to patients DH and SP. TI/2 for vancomycin pre- and post-MDAC (see Table). Conclusions: MDAC reduced the beta-T 1/2 of vancomycin in 2 of 3 preterm neonates. T1/2 in the 3rd neonate during MDAC was less than previously reported in neonatal overdose. T1/2 reduction was greatest in AR who received the highest mg/kg dose of AC. MDAC should be considered for treatment of vancomycin toxicity. Patient T 1/2 pre-MDAC T 1/2 during MDAC AR 5.3 hours (during therapeutic dosing) 1.9 hours DH 14 hours (following overdose) 7.3 hours SP 5.3 hours (during therapeutic dosing) 5.2 hours Abstract 204. Barker K (1), Ford M (2), Wright K (3), Seger D (1). (1) Vanderbilt University Medical Center, Nashville TN, (2) Carolinas Medical Center, Charlotte NC, (3) University of Tennessee Medical Center, Knoxville TN, Barker K (1), Ford M (2), Wright K (3), Seger D (1). (1) Vanderbilt University Medical Center, Nashville TN, (2) Carolinas Medical Center, Charlotte NC, (3) University of Tennessee Medical [...]

Study objective: To examine the clinical presentation and outcome of patients treated in the ED or toxicology clinic for suspected brown recluse spider bites. Methods: We assembled a retrospective case series of patients at a southeastern US university hospital. Our study group comprised 111 patients with suspected brown recluse spider bites treated during a 30-month period. Our main outcome measures were the need for skin grafting and the development of other complications. Results: The mean age of our subjects was 34+/-17 years. Thirteen patients (12%) brought the spider to the hospital, 22 (20%) saw a spider at the time of the bite, and an exclusively clinical diagnosis was made in the remaining 76 (68%). Most wounds (59%) involved the leg. At the time of presentation, 81% had central discoloration and 37% necrosis. Sixteen patients (14%) were systemically ill, and 6 (5%) were admitted to the hospital. Most (86%) were treated with antibiotics. Dapsone was infrequently used (9%) and had usually been prescribed before the patient's presentation to our ED. Only three patients (3%; 95% confidence interval, 1% to 8%) required skin grafting. Mild hemolytic anemia developed in one patient, and another had mild hemolysis and a mild coagulopathy; neither patient was taking dapsone. No deaths or serious complications occurred in our study group. Conclusion: In our series, long-term outcome after brown recluse spider bite was good. Serious complications were rare, as was the need for skin grafting. Because the vast majority of bites heal with supportive care alone, aggressive medical therapy does not appear warranted. [Wright SW, Wrenn KD, Murray L, Seger D: Clinical presentation and outcome of brown recluse spider bite. Ann Emerg Med July 1997;30:28-32.]

The cell adhesion protein vitronectin (Vn) was previously shown to be the major target in human blood for an extracellular protein kinase A, which is released from platelets upon their physiological stimulation with thrombin and also prevails as an ectoenzyme in several other types of blood cells. Because plasma Vn was shown to have only one protein kinase A phosphorylation site (Ser378) but to contain approximately 3 mol of covalently bound phosphate, and because human serum and blood cells were shown to contain also a casein kinase II (CKII) on their surface, we studied the phosphorylation of Vn by CKII attempting to find out whether such phosphorylation modulates Vn function, an acid test for its having a physiological relevance. Here we show (i) that the CKII phosphorylation of Vn has a Km of 0.5-2 microM (lower than the Vn concentration in blood, 3-6 microM), (ii) that it is targeted to Thr50 and Thr57, which are vicinal to the RGD site of Vn, and (iii) that the phosphorylation of Thr57 facilitates the phosphorylation of Thr50. The maximal stoichiometry of the CKII phosphorylation of plasma Vn was found to be low, which, in principle, could be due to its partial prephosphorylation in vivo. However, for the detection of a functional modulation, we needed a comparison between a fully phosphorylated Vn (at Thr57 and Thr50) and a nonphosphorylated Vn. Therefore, we expressed Vn in a baculovirus system and show (i) that the CKII phosphorylation of wt-Vn enhances the adhesion of bovine aorta endothelial cells; (ii) that the double mutant T50E/T57E (in which the neutral Thr residues are replaced by the negatively charged Glu residues considered analogs of Thr-P) has a significantly enhanced capacity to promote cell adhesion and to accelerate cell spreading when compared with either wild-type Vn or to the neutral T50A/T57A mutant; and (iii) that, at least in the case of bovine aorta endothelial cells, the T50E/T57E mutant exhibits an enhanced adhesion, which seems to be due to an increased affinity toward the alphav beta3 Vn receptors.