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 NACCT- Toronto, Canada - September 11th - 16th, 2008 |
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Dr. Anthony Pizon, Dr. David Jang, Dr. Henry Wang
Presentation Date: Saturday, September 13th, 2008,
Location: Session 2 - Toxicity & Laboratory
Time: 5p to 6p
Abstract
Title: The effect of Acetadote on prothrombin time in plasma samples from healthy subjects
A F Pizon1, D H Jang1 and H E Wang1. 1University of Pittsburgh-Affiliated Residency in Emergency Medicine, Pittsburgh, PA, United States.
Background>: N-acetylcysteines (NAC) ability to artificially elevate prothrombin time (PT) in patients has been debated. This may alter management if a clinician is following the PT as a marker of liver damage after acetaminophen toxicity. The purpose of this study is to evaluate the ability of NAC to alter measurement of PT in human plasma.
Methods: A single blood draw was obtained from 33 volunteer subjects. The plasma sample from each subject was divided into four 1 ml aliquots. Each subject acted as their own control. The remaining three 1 mL aliquots had 5 L of decreasing concentrations of NAC, as Acetadote (Cumberland Pharmaceuticals, Nashville, TN), added. The serial concentrations of Acetadote (20, 10, and 2%) were created in order to maintain the same volume of drug added to each plasma sample. The dilution of the samples never exceeded 0.5% and no correction for the PT was made. After mixing Acetadote with the plasma samples, this made 3 concentrations of Acetadote (250, 500, 1000 mg/L) plus the control. All samples were mixed and incubated at 37 C for one hour. PTs were obtained on all samples and analyzed using the fix regression for continuous variables.
Results: Acetadote was found to have a linear dose-dependent effect upon the measurement of PT. Means for the control, 100, 500, 1000 mg/L were 13.9 (SD=1.01), 14.2 (SD=1.08), 15.5 (SD=1.21), 17.4 (SD=1.72) secs, respectively. At the 1000 mg/L concentration, two PTs exceeded 22 sec and 50% of the samples exceeded 17 sec. All Acetadote concentrations were significantly higher than the control (p<0.001).
Discussion: Previous studies describe the effect of NAC on PT in vivo and in vitro. These studies were either underpowered or used non-physicologic concentrations of NAC. The 1000 mg/L samples approximate Acetadote levels during the bolus while the other concentrations represent levels obtained later in the infusions. Not only were physiologic concentrations of NAC used, the appropriate power to detect a clinically significant difference in PT was obtained.
Conclusion: Using an in vitro model of human plasma, Acetadote was found to have a clinically significant linear dose-dependent effect on the measurement of PT.
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Dr. Michael Lynch, Dr. Kenneth Katz, Dr. Cliffton Callaway, Dr. Eric Logue, Dr. Anthony Pizon
Date: September 14th
Time: 9a to 3p
Abstract
Abtract # 167: Survival of verapamil-poisoned rats treated with triiodothyronine
M J Lynch1, 2, K D Katz1, 2, C Callaway2, E Logue2 and A F Pizon1, 2. 1Division of Medical Toxicology, University of Pittsburgh Medical Center, Pittsburgh, PA, United States and 2Department of Emergency Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, United States.
Background: The aim of this study was to evaluate the potential vasopressor effect of triiodothyronine(T3) in verapamil-poisoned rats. T3 mechanisms of action include: potentiation of endogenous catecholamines, improving aerobic metabolism and direct vasopressor activity. T3 has significantly decreased vasopressor requirements in critically-ill patients but has never been evaluated for verapamil toxicity.
Methods: Based on a power calculation to demonstrate an increase of 10mmHg SBP, 2 groups of 5 Sprague Dawley rats were anesthetized, intubated and poisoned with an initial bolus and then continuous infusion of IV verapamil to maintain SBP of 55mmHg. The groups were randomized to then receive either IV NSS or T3 infusions over 60minutes. T3 dose was 0.4 g/kg bolus, followed by 1.6 g/kg/24hr doubled every 2 minutes titrated to clinical effect, based on accepted resuscitation guidelines in critically-ill children. Outcome measures were SBP and survival. SBP, HR were continually recorded via arterial catheter and ECG leads. Normothermia was maintained.
Results: All rats expired during the 60 minute period without any clinically significant difference between control and study groups.
Discussion: This study was performed because 1) verapamil toxicity is highly lethal 2) no specific antidote for verapamil poisoning exists and 3) T3 has been reported to possess potent vasopressor effects in humans. However, despite rapidly escalating T3 doses, no significant increase in SBP was demonstrated compared with controls. The study had several limitations. The rats were significantly poisoned with verapamil using a continuous infusion throughout the study which ultimately led to death in all animals. Therefore, minute T3 effects may have been unrecognized. Also, T3 may have delayed vasopressor effects which may not have been adequately evaluated during the 60 minute period. It is also unknown whether T3 could act synergistically with other commonly used vasopressors.
Conclusion: T3 monotherapy has no appreciable vasopressor effect in verapamil-poisoned rats.
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Dr. Michael Lynch, Dr. Matthew Krasowski, Dr. Anthony Pizon
Date: September 15th
Time: 9a - 3p
Abstract
Abstract # 54: Coma Following Toxic Topiramate Ingestion
M J Lynch1, A F Pizon1 and M Krasowski2. 1Division of Medical Toxicology, University of Pittsburgh, Pittsburgh, PA, United States and 2Department of Pathology, University of Pittsburgh, Pittsburgh, PA, United States.
Background: Topiramate, a sulfamate-substituted monosaccharide anticonvulsant, is being used with increasing frequency for a variety of neurologic and psychiatric disease due to its benign safety profile. Data regarding the toxicity and toxicokinetics of topiramate in acute overdose is limited. A case of massive, acute ingestion resulting in the highest reported topiramate level is presented.
Case Report: A 37 yo woman presented with normal vital signs and coma unresponsive to naloxone. Family found bottles of topiramate, ibuprofen, and hydrocodone/acetaminophen. She was intubated for airway protection, given 3.5mg lorazepam IV for facial and neck muscle twitching, and transferred to a tertiary care facility. No additional sedation was required for 24 hours on the ventilator. The patient was extubated on day 2, but confusion, dysarthria, and imbalance continued until day 3. Serial serum topiramate levels were 356.6mcg/ml(5-20), 173.6, 61.2, and 44 at 1615 day 1, 0955 day 2, and 0841, 1555 day 3, respectively. Serum half-life was 15.79h overall, and 17.01, 15.025, and 15.188h for each measurement. She presented with a nonanion gap metabolic acidosis (pH 7.31, HCO3 16mEq/L) which persisted throughout her hospitalization. Urine pH was 9.0. Serum ibuprofen level drawn upon presentation was 12mcg/ml(5-50). Urine GC/MS revealed only topiramate, ibuprofen, and caffeine. Acetaminophen and salicylate levels were undetectable.
Case Discussion:A massive topiramate ingestion led to a prolonged coma with normal vital signs and a nonanion gap acidosis. This consistent with topiramate s mechanism of action: GABA agonism, kainate/AMPA antagonism and carbonic anhydrase inhibition. The highest previously reported level was 170mcg/ml which resulted in death. Coma of the severity reported in the above patient has not been previously reported. Toxicokinetic evaluation revealed preserved first order kinetics with a serum t1/2 of 15.79h. Despite the large ingestion and significant presenting symptoms, the patient recovered fully with supportive intensive care alone.
Conclusion: Massive acute topiramate ingestion may lead to prolonged coma which resolves with supportive care.
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Dr. Michael Lynch, Dr. Robert Cannon
Date: September 16th
Time: 9a - 3p
Abstract
Abtract # 61: Crotalidae polyvalent immune Fab (CroFab) Therapy for Crotalus durissus terrificus Envenomation
Background: The Crotalus durissus subspecies account for ~10% of snake envenomations in Brazil, however no cases of envenomation by these species have been reported in North America. Consequently, no human data exists regarding its treatment with crotalidae polyvalent immune Fab (CroFab), the most widely used and available commercial antivenin in the United States. A case of an exotic snake owner suffering envenomation of moderate severity by a privately owned Crotalus durissus terrificus (cascavel) treated effectively with CroFab is presented.
Case Report: Thirty-six year old man presented to the Emergency Department(ED) within one hour of suffering a bite to his left index finger from his cascavel. In that time, he described progressive pain and swelling to his midforearm as well as mild subjective diplopia and perioral paresthesias without objective neurologic deficits. Due to his progressive local symptoms and early systemic neurologic symptoms, antivenin therapy with CroFab was instituted. Serum fibrinogen(fib) was 249mg/dl(205-508) on presentation. PT/INR were 14.2s(11.6-14.3) and 1.1(0.9-1.1). Following administration of 6 vials of IV CroFab begun 45 minutes after presentation, he had no progression of symptoms, but repeat fib was 104. An additional 6 vials were administered to gain control. Ensuing fib was 153. Maintenance therapy with 2 vials every 6 hours for 3 doses was given. Repeat fib was 267 prior to discharge. PT and INR peaked at 15.9 and 1.3, respectively following the first 6 vials then normalized. CBC and platelets were normal throughout. Maximum CPK was 1085IU/L. Repeat labs 7 days following envenomation, 5 days after discharge, were PT/INR 17.8, 1.5 and fib 53. CBC remained unremarkable. Hand and arm pain were slowly improving. Follow up labs 3 days later showed PT/INR 14.1, 1.1 and fib 156. The patient's symptoms continued to improve over the following weeks with no long term sequelae.
Case Discussion: The specific antivenin to C. d. terrificus is not available in the U.S., but CroFab is partially derived from Mojave toxin, antigenically similar to crotoxin. CroFab administration in this patient led to a halt in symptomatic progression and improvement in hemotoxicity which did rebound following cessation of therapy indicating a beneficial therapeutic effect.
The neurotoxic, myotoxic, and hemotoxic effects seen in C. d. terrificus envenomation are reminiscent of the clinical presentation in Crotalus scutulatus scutulatus(Mojave rattlesnake). In fact, crotoxin and Mojave toxin share antigenemic properties allowing antiserum to crotoxin to have neutralizing effect on Mojave toxin. In Brazil, specific C. d. terrificus antivenin is used to treat envenomation, but is not available in the U.S. CroFab does not include C. durissus spp., but is partially derived from C. s. scutulatus making it likely to be effective given the similarities in toxin structure in these species. This patient did demonstrate a halt to symptomatic progression as well as improvement in hemotoxicity with CroFab administration which did rebound following cessation of therapy indicating a beneficial therapeutic effect in moderate toxicity.
Crotalus durissus venom has neurotoxic, myotoxic, and hemotoxic activity mediated by crotoxin, crotamine, and a thrombin-like enzyme among others. Cranial nerve deficits progressing to respiratory paralysis as well as rhabdomyolysis leading to myoglobinuric renal failure incur most of the morbidity and mortality associated with envenomation while hypofibrinogenemia rarely leads to hemorrhagic sequelae. Thrombocytopenia and coagulopathy are reported less frequently. In Brazil, envenomation is treated with specific C. d. terrificus antivenom that is not available in the U.S. However, the toxic mechanism of crotoxin is similar to that of Mojave toxin with shared antigenic properties. C. d. terrificus antivenom neutralizes Mojave toxin. The clinical presentation of envenomations by these two species is also
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Abstracts from the 2007 NACCT in New Orleans, LA
Dextromethorphan-Induced Serotonin Syndrome
Schwartz AR, Pizon AF, Brooks DE. University of Pittsburgh School of Medicine, Pittsburgh,
PA, USA.
Background: The ability of dextromethorphan (DXM) to potentiate serotonin levels and lead
to serotonin syndrome (SS) is well known but few case reports are published. Due to the ubiquitous
use of selective serotonin reuptake inhibitors (SSRI) and DXM, SS associated with
these drugs (taken in combination) should be common. The lack of published cases suggests
therapeutic doses of these drugs are not enough to cause SS. We present two cases of SS associated
with supra-therapeutic doses of DXM and therapeutic levels of a SSRI. Case
Report: Case One: A 20 YO man was found confused after a suspected ingestion of aripiprazole,
benztropine, escitalopram and DXM. Physical examination was notable for tachycardia
(HR 168), hyperthermia (102.0 F), tremor, and rigidity and clonus in his lower extremities
only. Head CT, EEG and routine blood work were normal. He was treated with IV lorazepam,
PO cyprohyptadine and IV fluids. GC-MS confirmed nicotine, chlorpheniramine, escitalopram
and DXM. Serum drug levels from admission revealed a DXM level of 950 ng/mL (norma <
l5), escitalopram 23 ng/mL (normal < 200), chlorpheniramine 430 ng/mL (normal < 20) and
undetectable levels of aripiprazole and benztropine. He made a complete recovery within 24
hours. Case Two: A 6 YO boy, recently started on sertraline, was found lethargic and confused
with an empty bottle of DXM elixir. Physical examination revealed: tachycardia (HR 118),
mild hypertension (140/69), hyperthermia (100.6 F), and rigidity with clonus in his lower
extremities only. He was intubated for airway protection and sedated with fentanyl and versed.
Head CT, routine blood work and drug screen were normal (negative). GC-MS confirmed
DXM and caffeine. Serum drug levels from admission revealed a DXM level of 2820 ng/mL
and sertraline of 12.5 ng/mL (normal < 200). He was extubated and neurologically intact
within 15 hours of admission. Conclusion: To our knowledge, this is the first case series to
use serum levels of DXM and a SSRI to confirm DXM-induced SS. Our cases suggest supratherapeutic
DXM doses with a therapeutic amount of a SSRI are required for SS. More work is
needed to answer this question more completely.
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Prolonged CNS Toxicity in a Child with Lamotrigine Poisoning
Dlugopolski PR,1 Katz KD,1 Krenzelok EP.1,2 1Pittsburgh Poison Center, University of Pittsburgh
Medical Center, Pittsburgh, PA, USA; 2Schools of Pharmacy and Medicine, University of
Pittsburgh, Pittsburgh, PA, USA.
Background: Lamotrigine (Lamictal) is an anticonvulsant that is also used off-label to treat a
variety of neurological and psychiatric disorders. Only one other case report involving pediatric
lamotrigine toxicity has been published. We report a documented unintentional pediatric exposure to lamotrigine that resulted in a prolonged symptomatic post-exposure period. Case
Report: A four year-old male ingested a minimum of 600 mg and a maximum of 1000 mg of his
mother’s lamotrigine tablets. The child’s mother contacted the poison center at one hour postexposure
and reported that he was drowsy and “shaking all over”. He was referred to an emergency
department for evaluation and observed for a period of eight hours post-exposure and discharged.
Due to the presence of persistent symptoms at 19.5 hours post-exposure, the mother took
the child to the pediatrician’s office for further evaluation. The pediatrician reported to the poison
center that the child had slurred speech, was shaking and having difficulty walking. There was no
history of re-exposure to lamotrigine. The child was transferred immediately to a specialty children’s
hospital. At 23 hours post-exposure the child was noted to have ataxia, tremors, dysphagia
and irritability. Vital signs and laboratory values were within normal limits at this time. By 30
hours post-exposure he was asymptomatic and discharged the following day. A lamotrigine serum
concentration of 18.9 mcg/ml (therapeutic: 4–5 mcg/ml) was present at 25 hours postexposure.
Case Discussion: This child ingested a maximum of 1000 mg, which exceeds significantly
the normal starting pediatric dose of 25 mg. He exhibited toxic effects within one hour that
were consistent with the rapid and complete absorption of lamotrigine and remained symptomatic
for nearly 30 hours post-exposure which is expected since the half-life of lamotrigine is 25–35
hours. He recovered uneventfully with minimal supportive care. Conclusion: Lamotrigine poisoning
in children may cause prolonged mental status changes.
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