UMEM Educational Pearls - By Hong Kim

Category: Toxicology

Title: Sugar for sulfonylurea-induced hypoglycemia? Try octreotide.

Keywords: sulfonylurea, hypoglycemia, octreotide (PubMed Search)

Posted: 7/28/2015 by Hong Kim, MD (Emailed: 7/31/2015) (Updated: 5/27/2024)
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Oral hypoglycemic agents (e.g. sulfonylureas) can cause symptomatic hypoglycemia. Unlike metformin, sulfonylureas stimulate the release of insulin from beta-cells (in pancreas) in response to serum glucose level.

 

ED management of hypoglycemia involves:

  1. Dextrose (D50 50mL via IV) administration if symptomatic: e.g. altered mental status
  2. Feeding: food items that are more substantial than juice: e.g. food tray or sandwich
  3. Serial finger stick glucose check

 

However, for recurrent hypoglycemia (> 3 episodes of hypoglycemia), think about octreotide, rather than starting a dextrose (D5) infusion.

 

For example, D5 infusion at 150 mL/hour has only 7.5 gm of dextrose (calculation: D5% = 5gm/100 mL). One gram of dextrose contains about 4 calories (equivalent to one piece of Skittles) So, with a D5 infusion at 150 mL/hour, you are giving your patients 8 pieces of Skittles per hour. A bottle of Snapple lemon ice tea (non-diet) has more calories (150 calories in 16 oz. or 473 mL)! 

 

Octreotide 50 mcg SQ (q6 hour) injection will decrease the insulin release from the beta-cell by blocking the voltage-gated Ca channel on the beta-cell.

 

All patient who received octreotide in the ED requires admission to the hospital for observation. Patients can be safely discharge from the hospital when finger stick glucose level remains normal for 24 hours after the last dose of octreotide.

 

Bottom line: In sulfonylrea-induced recurrent hypoglycemia, administer octreotide, rather than continuous infusion of dextrose (D5) solution.



Category: Toxicology

Title: How did physostigmine get a bad rap?

Keywords: physostigmine, anticholinergic toxicity, TCA overdose, asystole (PubMed Search)

Posted: 7/16/2015 by Hong Kim, MD (Updated: 5/27/2024)
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Physostigmine is a cholinergic agent (acetylcholine esterase inhibitor) that can be used to reverse anticholinergic toxicity. Its use has been declining since the publication of several case reports of physostigmine induced cardiac arrest in tricyclic antidepressant (TCA) overdose.

 

The first case report (and often cited) was by Pental P. et al. (Ann Emerg Med 1980), who presented 2 cases (32 and 25 year old) of asystole after administration of physostigmine (2 mg) in severe TCA overdose. These two cases both had widened QRS interval (120, 240 msec) due to TCA poisoning. Bradycardia preceded the asystole.

 

The second case report (Shannon M Pediatr Emerg Care 1998) reported a 15 year-old girl with QRS widening (120 msec) received 2 mg of physostigmine and developed severe bradycardia and then asystole.

 

Another case series (Knudson K et al. BMJ 1984) of 41 patients with overdose of maprotiline showed that physostigmine administration was associated with higher incidence of seizures. No asystole was noted.

 

Today physostigmine is contraindicated in TCA poisoning. But if we think about it, physostigmine administration probably wasn’t a good idea in the first place. Correcting anticholinergic toxicity of TCA has limited benefit; mortality from TCA overdose is usually associated with cardiac toxicity (Na-channel blockade) and should be treated with NaHCO3 administration

 

Physostigmine still has a role in treating isolated anticholinergic toxicity  (e.g. diphenhydramine, benztropine, dimenhydrinate, scopolamine, jimson weed overdose). Prior to physostigmine administration:

 

  1. Get a screening EKG to demonstrate there is no evidence of Na-channel blockade. Even diphenhydramine can cause Na-channel blockade and seizures in severe OD.
  2. Have atropine at bedside. Physostigmine is a cholinergic agent. When given too much, your patient will develop cholinergic toxicity.
  3. Administer 0.5 mg IV over 3-5 min. repeat as needed (every 3-5 min) to max dose of 2.0 mg for clinical effect (improvement of mental status).

 

Bottom line: If you suspect isolated anticholinergic toxicity, think about physostigmine. Like any medication, risk and benefit of administration should be considered prior to administration. 

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Category: Toxicology

Title: K2 strikes back: A surge in synthetic cannabinoid use.

Keywords: Synthetic cannabinoid, K2 (PubMed Search)

Posted: 6/18/2015 by Hong Kim, MD (Updated: 5/27/2024)
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Recently, there has been a surge in synthetic cannabinoid in the U.S., including the Baltimore area. According to U.S. poison control center data, there has been 229% increase in calls related to SC between January to May of 2015 compared to similar time period in 2014.

 

The most commonly reported adverse/clinical effects included:

  • Agitation: 35.3%
  • Tachycardia: 29%
  • Drowsiness/lethargy: 26.3%
  • Vomiting: 16.4%
  • Confusion: 16.4%

 

End-organ injuries have been also reported in case reports, including AKI, seizure, MI, and CVA.

 

Synthetic cannabinoid includes a list of chemical compounds that are structurally different compared to THC – the active compound in marijuana. However, they possess full CB1 (cannabinoid) receptor agonism effect, unlike the THC, which is a partial CB1 receptor agonist. 

 

These chemicals (particularly JWH series) were originally synthesized to study the effect of cannabinoid receptors. Overall, it is difficult to identify the compound and the dose within each packets of SC.

 

Commonly marketed names include: Spice, K2, K9, herbal highs, Scooby snax, WTF.

Table. Identified synthetic cannabinoids

Chemical name

Chemical origin

JWH-018; JWH-073; JWH-250

Laboratory of J.W. Huffman

CP47,497; CP47,497-C8; CP59,540; cannabicyclohexanol

Pfizer laboratory

HU-210

Hebrew University laboratory

Oleamide

Fatty acid

UR-144

CB2 receptor agonist

XLR-11, AKB-48, AM-2201, AM-694

 

 

Management: Majority of the patients with acute SC intoxication mostly requires supportive care, including benzodiazepine for acute agitation. However, ED providers should be mindful of potential end-organ injury. 

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Category: Toxicology

Title: why is your patient blue? xenobiotic-induced methemoglobinemia

Keywords: methemoglobinemia, methylene blue (PubMed Search)

Posted: 5/20/2015 by Hong Kim, MD (Emailed: 5/21/2015) (Updated: 5/21/2015)
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Methemoglobin (MetHb) is produce when Fe+2 in heme is oxidized to Fe+3 under oxidative stress (caused by mediation and chemicals). MetHb does not bind to oxygen and thus decrease RBC’s O2 carrying capacity.

Among medication, overdose of local anesthesia - benzocaine, dapsone, and phenazopyridine are often implicated. (Table 1)

Think about methemoglobinemia in presence of low pulse oximetry (~85%) with lack of response to supplemental oxygen, cyanosis, dyspnea, etc. (see Table 2 – signs and symptoms of MetHb) in patients who are taking or overdosed on medication listed in Table 1.

Diagnosis: CO-oximetry detects toxin-induced hemoglobinopathies, including COHb and MetHb.

Treatment: Methylene blue (1 mg/kg over 5 min) in symptomatic patients or MetHb level > 25%. Resolution of methemoglobinemia should be noted in 30 – 60 min.

G6PD deficiency: Prevalence in the U.S. is 4-7% with highest prevalence in African American population (11%). Methylene blue causes hemolytic anemia in patients with G6PD deficiency within 24 hours of administration. However, G6PD status is often unknown in ED patients.  When caring for patients with known G6PD deficiency and methemoglobinemia, providers must carefully consider the risk and benefit of treating MetHb (including severity of poisoning/MetHb) with methylene blue.

Table 1. Causes of MetHb

Medication

 

Chemicals

Benzocaine, Lidocaine, Prilocaine

Aniline dye

Dapsone

Chlorobenzene

Phenazopyridine

Organic nitrites (e.g. isobutyl nitrite)

Nitroglycerin

Naphthalene

Nitroprusside

Nitrates (well water contamination)

Quinones (Primaquine & Chloroquine)

Nitrites (food preservatives)

Sulfonamides

Silver nitrate

Nitric oxide

Trinitrotoluene

Amyl nitrite

 

 

Table 2. Signs and symptoms

MetHb level (%)

Signs and symptoms

1-3% (normal)

 

·  None

3-15%

·  Low pulse oximetry (<90%)

·  Gray cutaneous coloration

15-20%

·  Chocolate brown blood

·  Cyanosis

20-50%

·  Dizziness, syncope

·  Dyspnea

·  Weakness

·  Headache

50-70%

·  CNS depression, coma, seizure

·  Dysrhythmias

·  Tachypnea

·  Metabolic acidosis

>70%

·  Death

·  Hypoxic injury

 



Category: Toxicology

Title: When should NAC be stopped after an acute acetaminophen poisoning?

Keywords: acetaminophen toxicity, NAC, hepatic toxicity (PubMed Search)

Posted: 3/19/2015 by Hong Kim, MD (Updated: 5/27/2024)
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Elevation of AST or ALT >1000 after acute ingestion of acetaminophen indicate hepatic toxicity. N-acetylcysteine (NAC) is an effective treatment for acute acetaminophen poisoning. However, in a setting a significant transaminitis, (> 1000s) NAC infusion is continued beyond the routine 21-hour protocol.

 

Currently, there is no specific guideline or “level” of AST or ALT where discontinuing NAC is deemed safe and appropriate.

 

A recent retrospective study (n = 37 patients with 343 pairs of AST/ALT) evaluated AST/ALT ratio as a possible indicator for discontinuing NAC infusion after an acute acetaminophen induced hepatic toxicity.

 

This study found that post peak AST/ALT ratio of < 0.4 had sensitivity of 99% for identifying patients with resolving hepatic injury.

 

This finding requires validation prior to clinical application but this may be the first step to identifying a safe indicator to help guide clinician when NAC can be discontinued safely.

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Category: Toxicology

Title: Can Hydroxocobalamin be administered via intraosseous access for acute cyanide toxicity?

Keywords: intraosseous, hydroxocobalamin, cyanide poisoning (PubMed Search)

Posted: 1/15/2015 by Hong Kim, MD (Updated: 5/27/2024)
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Hydroxocobalamin is an effective cyanide antidote when administered intravenously. Although intraosseous (IO) access is often used in critically ill patients with difficult or delayed IV access, the efficacy of IO administration has not been investigated until recently.

In a recent randomized animal study, acute cyanide toxicity was induced in two groups of swine where 150 mg/kg Hydroxocobalamin was administered via IV vs. IO. The survival rate, reversal of hypotension, and laboratory results were similar between the IV and IO group.

The finding of this study suggest that IO administration of Hydroxocobalamin is as efficacious as IV administration and its administration in acute cyanide toxicity should not be delayed due to lack of IV access when IO access is available.

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It is believed that administration of beta-blocker administration in patients with cocaine chest pain will produced increased vasoconstriction due to “unopposed alpha effect.”

 

Several retrospective studies on the use of beta-blocker in patients with cocaine-induced chest pain concluded the use of beta-blocker to be safe.

 

So is the unopposed alpha effect just a theory?

 

Lange RA et al. 1990 Ann Internal Med

Design: randomized, double-blind, placebo controlled trial.

 

30 (38- 68 years old) patients undergoing cardiac catherization for chest pain evaluation were studied.

 

Cocaine (intranasal administration) resulted in:

  • Increased myocardial oxygen demand
  • Increased coronary vascular resistance 22%
  • Decreased coronary sinus blood flow: 10%

 

Administration of propranolol (intracoronary infusion) resulted in additional:

  • Increase coronary vascular resistance 19%
  • Decrease coronary sinus blood flow by 15%
  • No additional change in myocardial oxygen demand

 

Complete coronary occlusion observed in 1 patient with ST elevation

Epicardial coronary arterial segment constriction >10% in 5 patients.

 

Bottom Line: Lange RA et al. 1990 demonstrates that the “unopposed alpha effect” does occur in coronary artery when beta-blocker is administered in a setting of acute cocaine exposure.  Overall, the use of beta-blocker in the ED management of cocaine-induce acute chest pain is not a prudent option.  It is unknown if the cocaine dose, last use of cocaine (days), or CAD history influence the “safety” of beta-blocker initiation/use during inpatient hospitalization.

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Category: Toxicology

Title: Identification of cyanide poisoning in smoke inhalation victims.

Keywords: Cyanide, smoke inhalation, lactate (PubMed Search)

Posted: 11/28/2014 by Hong Kim, MD (Updated: 5/27/2024)
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Cyanide poisoning is rare but highly lethal. Cyanide exposure can occur during residential fire (most common source of exposure) where combustion of synthetic materials (i.e. plastic and polyurethane) releases cyanide gas as well as other toxic gases, including carbon monoxide. Although carbon monoxide poisoning can be readily identified by CO-Hb level using CO-oximetry, serum/blood cyanide level is not readily available for acute management.

 

However, elevated lactate level (> 10 mmol/L ) has shown to be highly correlated with toxic level of cyanide (40 micromol/L or 1 mg/L) in smoke inhalation victims (Baude FJ et al. N Engl J Med 1991;325:1761-6).

  • Sensitivity: 87%
  • Specificity: 94%
  • Positive predictive value: 95%

 

Bottom line: when managing smoke inhalation victims, think about cyanide poisoning in addition to carbon monoxide poisoning and check the lactate level. Lactate > 10 mmol/L is suggestive of cyanide poisoning and should be treated with hydroxocobalamin. 

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Category: Toxicology

Title: Valproic acid toxicity

Keywords: valproic acid (PubMed Search)

Posted: 10/16/2014 by Hong Kim, MD (Updated: 5/27/2024)
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Valproic acid (VPA) is often used to treat seizure disorder and mania as a mood stabilizer. The mechanism of action involves enhancing GABA effect by preventing its degradation and slows the recovery from inactivation of neuronal Na+ channels (blockade effect).

 

VPA normally undergoes beta-oxidation (same as fatty acid metabolism) in the liver mitochondria, where VPA is transported into the mitochondria by carnitine shuttle pathway.

 

In setting of an overdose, carnitine is depleted and VPA undergoes omega-oxidation in the cytosol, resulting in a toxic metabolite.

 

Elevation NH3 occurs as the toxic metabolite inhibits the carbomyl phosphate synthase I, preventing the incorporation of NH3 into the urea cycle.

 

Signs and symptoms of acute toxicity include:

  • GI: nausea/vomiting, hepatitis
  • CNS: sedation, respiratory depression, ataxia, seizure and coma/encephalopathy (with serum concentration VPA: > 500 mg/mL)

 

Laboratory abnormalities

  • Serum VPA level: signs of symptoms of toxicity does not correlate well with serum level.
  • NH3: elevated
  • Liver function test: elevated AST/ALT
  • Basic metabolic panel: hypernatremia, metabolic acidosis
  • Complete blood count: pancytopenia

 

Treatment: L-carnitine

  • Indication: hyperammonemia or hepatotoxicity
  • Symptomatic patients: 100 mg/kg (max 6 gm) IV (over 30 min) followed by 15 mg/kg IV Q 4 hours until normalization of NH3 or improving LFT
  • Asymptomatic patients: 100 mg/kg/day (max 3 mg) divided Q 6 hours.

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Category: Toxicology

Title: "Food poisoning": How do you like your fish?

Keywords: ciguatera, scromboid, tetrodotoxin (PubMed Search)

Posted: 9/18/2014 by Hong Kim, MD
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Food poisoning can occur with many different food groups/items, as well as how the food is prepared, handled or stored.

There are three specific “food poisonings” associated with fish consumption can cause serious toxicity/illness beyond GI symptoms: Ciguatera, Scrombroid, tetrodotoxin (puffer fish)

 

Ciguatera

  • Endemic to warm tropical water and bottom reef dwelling large carnivorous fish: grouper, red snapper, barracuda, amberjack, parrot fish, etc. (> 500 species).
  • Toxin: ciguatoxin: opens voltage gated Na channel
  • Produced by dinoflagellates (gambierdiscus toxicus) and bioaccumulates in large fish through food chain (eating small fish).

Symptoms:

  • GI symptoms: n/v/d and abdominal pain
  • Hot/cold reversal
  • Paresthesia of tongue/lip >> extremities
  • Dental pain: “loose teeth”

May progress to develop…

  • T wave changes, bradycardia, hypotension
  • Respiratory paralysis and pulmonary edema

Treatment: supportive care and mannitol in presence of severe neurologic symptoms (limited evidence).

 

Scrombroid

  • Endemic in (dark meat) fish living in temperate or tropical water: amberjack, skipjack, tuna, mackerel, albacore, mahi mahi, etc.
  • Associated with poor refrigeration/storage after catching fish.
  • Histidine in tissue is converted to histamine by bacteria on the fish skin.

 

Symptoms:

  • GI symptoms: n/v/d and abdominal pain
  • Upper body flushing
  • Puritis, urticarial and perioral swelling can occur
  • Palpitation and mild hypotension

 

Tx: H1/H2 blockers and supportive care

Serious reactions: treat like allergic/anaphylactic reaction

 

Tetrodotoxin

  • Ingestion of improperly prepared puffer fish (fugu) sushi (or bite from blue ring octopus)
  • Toxin: tetrodotoxin: blocks voltage gated Na channel.
  • Highest concentration in liver and ovary.

 

Symptoms:

  • GI: n/v/d
  • Progressive paresthesia and weakness (bulbar-> extremities), ataxia
  • Ascending paralysis and respiratory distress/paralysis
  • Dysrythmia and hypotension
  • Mental status preserved.

 

Treatment: supportive care and intubated if needed.



Metformin is the first line medication for the treatment of type II diabetes. A rare complication of chronic metformin use is MALA.

  • Incidence: 2-9 cases per 100,000 patients
  • Mortality: 30-50%

The association between metformin accumulation and development of lactic acidosis is controversial as patients with suspected MALA experience concurrent illnesses such as sepsis/septic shock, tissue hypoxia, and/or organ dysfunction (especially renal failure).

  • Greater than 90% of metformin (unchanged) is eliminated by the kidney.
  • Metformin accumulation (from renal failure) leads to inhibition of complex I of the electron transport chain.1,2
  • A case series of 66 patients MALA experienced severe lactic acidosis (pH: 6.91+ 0.18; lactate 14.36+ 4.9 mmol/L) and renal failure (Cr 7.24 + 3.29 mg/dL)3
  • Prodromal GI symptoms in 77%
  • Clinical findings at time of admission/presentation:
  • AMS/coma: 57%
  • Dyspnea/hyperventilation: 42%
  • Hemodynamic shock: 39%
  • Hypotension (SBP < 100 mmHg): 23%
  • No correlation between lactate and metformin level.
  • Risk factors
    • Renal failure (metformin accumulation)
    • Elderly population (higher mortality)
    • Cardiac or respiratory insufficiency causing central hypoxia
    • Sepsis/septic shock
    • Liver disease
    • IV contrast use (resulting in renal insufficiency)
  • Treatment: emergent hemodialysis

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NAC is an effective antidote against acetaminophen (APAP) toxicity in preventing acute hepatotoxicity. It provides cysteine that is essential for glutathione synthesis and its availability is rate limiting.

Currently, PO and IV formulation is available in the U.S. Regardless of the route, NAC is equally effective in preventing APAP induced acute hepatotoxicity when administered within 8 hours after single acute ingestion. 1

Adverse effects of NAC

1.     Anaphylactoid reaction

a.     More frequently reported with IV administration and during the first regimen of NAC (150 mg/kg over 60 min) administration. (dose and rate dependent)

b.     Higher risk of anaphylactoid reaction in patients with negative APAP vs. patients with elevated APAP level.2

c.      Management: Benadryl as needed and slow infusion rate.

2.     Hyponatremia in children if inappropriate volume of diluent (D5W) used. Dose calculator: http://acetadote.com/dosecalc.php

3.     Laboratory: increase Prothrombin time (PT).3

4.     Fatality from iatrogenic NAC overdose has been reported.

 

Advantage of IV NAC

1.     Convenience

2.     100% bioavailability

3.     Shorter hospital length of stay

4.     Minimum GI symptoms (nausea & vomiting) compared to PO route

 

Indication of IV NAC

1.     Severe hepatotoxicity or fulminant liver failure

2.     APAP poisoning during pregnancy

3.     Unable to tolerate PO intake (nausea, vomiting, altered mental status)

However many clinicians administer IV NAC for their advantages over PO NAC.

 

 Take home message:

1.     PO and IV NAC are equally effective when administered within 8 hours after single acute ingestion.

2.     Anaphylactoid reaction is frequently encountered AE during the infusion of 1st NAC regimen and patients with negative/low APAP level may be at higher risk.

3.     No emergent need to start NAC in presumed acetaminophen overdose patients prior to obtaining APAP level.

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Currently, no effective reversal agent for new oral anticoagulants (e.g. direct thrombin inhibitor, dabigatran, and factor Xa inhibitors: rivaroxaban and apixaban) exists for emergent management of hemorrhagic complications.

 

Boehringer Ingelheim, the manufacturer of dabigatran, is developing an antibody fragment (Fab) against dabigatran as a reversal agent.1

 

A small ex-vivo porcine study demonstrated partial reversal of anticoagulation effects, measured by PT, aPTT, clotting time, clot formation time and maximum clot firmness, of dabigatran by PCC and activated PCC, while dabigatran-Fab achieved complete reversal. Recombinant fVIIa did not reverse the anticoagulation effect of dabigatran.2

 

Caution should be exercised when interpreting these finding as reversal of laboratory values does not necessarily correlate with clinical effect/outcome. However, dabigatran-Fab holds promise as an effective reversal agent of dabigatran.

 

Dabigatran-Fab is still under development and is not available/approved for clinical use.

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Category: Toxicology

Title: Predictors of esophageal injury in caustic ingestion?

Keywords: caustic ingestion; esophageal injury (PubMed Search)

Posted: 4/17/2014 by Hong Kim, MD (Updated: 5/27/2024)
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Caustic ingestion can potentially cause significant esophageal and/or gastric injury that can lead to significant morbidity, including death.

 

Endoscopy is often performed:

·      To determine the presence of caustic injury.

·      To determine the severity of caustic injury (grade: I to III).

 

Grade

Tissue finding

Sequela

I

•  Erythema or edema of mucosa

•  No ulceration

No adverse sequela

IIa

•  Submucosal ulceration and exudates

•  NOT circumferential

No adverse sequela

IIB

•  Submucosal ulceration and exudates

•  Near or circumferential

Stricture > 70%

IIII

•  Deep ulcers/necrosis

•  Periesophageal tissue involvement

Acute

Perforation and death

Chronic

Strictures and increased cancer risk

 

·      Placement of orogastric or nasograstic tube for nutritional support if needed (grade IIb and III)

 

Evidence for predictor of esophageal injury (frequently cited) comes from mostly studies involving pediatric population and unintentional ingestion:

1.     Gaudreault et al. Pediatrics 1983;71:767-770.

o   Studied signs/symptoms: nausea, vomiting, dysphagia, refusal to drink, abdominal pain, drooling or oropharyngeal burn

o   Presence of symptoms: Grade 0/I lesion: 82%; Grade II: 18%

o   Absence of symptoms: Grade 0/I: 88%; Grade II: 12%

2.     Crain et al. Am J Dis Child. 1984;138(9):863-865

o   Presence of 2 or more (vomiting, drooling and stridor) identified all (n=7) grade II and III lesion.

o   Presence of 1 or no symptoms: no grade II/III lesions

o   Stridor alone associated with grade II/III lesions (n=2)

o   10% of patients without oropharyngeal burns had grade II/III lesions.

3.     Gorman et al. Am J Emerge Med 1990;10(3):189-194.

o   Two or more symptoms: vomiting, dysphagia, abdominal pain or oral burns

o   Sensitivity: 94%; specificity 49%

o   Positive predictive value 43% ; negative predictive value: 96%

o   Stridor alone (n=3): grade II or greater lesion

4.     Previtera et al. Pediatric Emerg Care 1990;6(3):176-178.

o   Esopheal injury in 37.5% of patients without oropharyngeal burn

o   Grade II/III injury: 8 patients

 

Available data suggests that there are no “good” or reliable predictors for esophageal injury.

 

However, high suspicion for gastrointestinal injury should be considered with GI consultation for endoscopy in the presence of

·      Stridor alone

·      Two or more sx: vomiting, drooling or stridor (Crain et al)

·      Intentional suicide attempt



Category: Toxicology

Title: Valproic acid toxicity

Keywords: Valproic acid (PubMed Search)

Posted: 10/16/2014 by Hong Kim, MD (Emailed: 5/27/2024)
Click here to contact Hong Kim, MD

Valproic acid (VPA) is often used to treat seizure disorder and mania as a mood stabilizer. The mechanism of action involves enhancing GABA effect by preventing its degradation and slows the recovery from inactivation of neuronal Na+ channels (blockade effect).

VPA normally undergoes beta-oxidation (same as fatty acid metabolism) in the liver mitochondria, where VPA is transported into the mitochondria by carnitine shuttle pathway.

In setting of an overdose, carnitine is depleted and VPA undergoes omega-oxidation in the cytosol, resulting in a toxic metabolite.

Elevation NH3 occurs as the toxic metabolite inhibits the carbomyl phosphate synthase I, preventing the incorporation of NH3 into the urea cycle.

Signs and symptoms of acute toxicity include:

  • GI: nausea/vomiting, hepatitis
  • CNS: sedation, respiratory depression, ataxia, seizure and coma/encephalopathy (with serum concentration VPA: > 500 mg/mL)

Laboratory abnormalities

  • Serum VPA level: signs of symptoms of toxicity does not correlate well with serum level.
  • NH3: elevated
  • Liver function test: elevated AST/ALT
  • Basic metabolic panel: hypernatremia, metabolic acidosis
  • Complete blood count: pancytopenia

Treatment: L-carnitine

  • Indication: hyperammonemia or hepatotoxicity
  • Symptomatic patients: 100 mg/kg (max 6 gm) IV (over 30 min) followed by 15 mg/kg IV Q 4 hours until normalization of NH3 or improving LFT
  • Asymptomatic patients: 100 mg/kg/day (max 3 mg) divided Q 6 hours.

Show References