Suits and Cases: Potential Pitfalls in the management of

Poisoned Patients

John Kashani DO

St. Josephs Regional Medical Center

New Jersey Poison Center

Case 1

• An 18 year old female, with a past medical history significant for asthma and depression, presents to the ED for shortness of breath

• She has a respiratory rate of 34, is diaphoretic, is actively vomiting and appears confused

Case 1

• Her blood pressure is 90/54, Heart rate is 150 and a rectal temperature is 102

.

farenheit and pulse oximetry is 99% on supplemental oxygen

• Her mother states that this is the worst asthma attack she has ever had

• She is emergently intubated

Case 1

• Shortly after being intubated she seizes and develops ventricular fibrilation

• Despite your best efforts she dies

• An autopsy is requested by the family

• A post mortem salicylate level was 150mg/dL

Introduction

• Salicylates are the most widely used analgesic, anti-pyretic and anti-inflamatory and is the standard for the comparison and evaluation of others

• Because salicylates are so widely available the potential for misuse is often underappreciated

Introduction

• The physician taking care of the salicylate intoxicated patient must be familiar with the pathophysiology, pharmakokinetics, potential pitfalls, and treatment options

Sources of Salicylates

• Found in Willow bark (Salix alba vulgaris)• Available in a multitude of

formulas/preparations– Over-the-counter (pepto-bismol)– Topical preparation (wart removal)– Combinations (excedrin, fiorinal,

percodan)– Other (oil of wintergreen)

Pharmakokinetics

• Peak levels – Regular preparations – Enteric coated– Liquids preparations– Overdose

• Distribution• Metabolism• Excretion

Distribution

• Volume of distribution (Vd)

– Apparent volume the drug is dissolved in

– Measured in Liters or Liters/Kg

• not a real volume

Salicylates: Toxic Dose

• Therapeutic Range: 10–20 mg/kg

• Mild Toxicity: 150 mg/kg

• Moderate Toxicity: 150-300 mg/kg

• Severe Toxicity: > 300 mg/kg

Inflamatory Mediators

• Inhibits cyclooxygenase

– Decrease in prostaglandins

– Increase leukotrienes

• Increases microvascular permeability

acetyl-CoA

oxaloacetate citrate

isocitrate

-ketoglutarate

succinyl-CoAsuccinate

fumarate

malateNAD+

NADH

NAD+

NADH

NAD+

NADH

FAD

FADH2

pyruvate

CO2

CO2

CO2

NAD+

NADH

matrix

Glucose

Pyruvate Lactate

2 ATP

ALT

Muscle

Alanine

Liver

Alanine

Pyruvate

Glucose

NH2

Urea6 ATP

4 ATP

X

Respiration

• Uncouples oxidative phosphorylation– Disrupts hydrogen ion gradient– Unable to generate ATP using electron

transport• Increased oxygen consumption,

increased heat production, increased metabolic rate, decreased ATP production, increased CO2 production

R-COOH

matrix

intermembrane space

H+ H+ H+ H+ H+ H+ H+ H+

H+ H+

H+

R-COOHR-COO-

R-COO-

I

matrix

intermembrane space

II

Q

4H+

4H+

III

4H+

4H+

IV

CytC

O2 H2O

2H+

2H+

succinate

NADH + H+

ATP + H2O

ADP + Pi + H+

3H+

3H+

R-0H

R-0H

R-0- + H+

H+

R-0-

H+

heat

Metabolic

• Increased lipolysis

• Increased production of ketones

– Ketonuria present in almost all overdose patients

Ketone bodies

Acetyl CoA

Fatty Acids

Metabolic

• Hyperglycemia in acute setting

– Glycogenolysis

– May cause glucosuria

• Hypoglycemia may subsequently develop

Metabolic

• Causes a respiratory alkalosis

– Due to respiratory center stimulation

– Increase in respiratory rate and depth

Hematologic

• Platelet dysfunction• Inhibition of Vitamin K dependent

clotting factors• II, VII, IX, X, Protein C, Protein S

• Hypoprothrombinemia

Gastrointestinal Effects

• Nausea

• Vomiting

• Gastritis

• Pylorospasm

Neurologic• Occurs from metabolic derangements and

salicylate CNS levels– Agitation, irritability– Tinnitus

• Occurs at levels of 20-45 mg/dL– Lethargy

Laboratories

• Salicylate Level

– An Level of 100 mg/dL is extremely worrisome (impending doom)

– Chronic Levels of > 30 mg/dL are concerning

• Difficulty in interpretation due to variable Vd

Laboratories

• Levels should be obtained every 1 to 2 hours until downward trend is observed

• Do not rely on a single level• Levels < 20mg/dl and a downward trend

can be medically cleared

Case 2

• A 35 year old male presents to the emergency department for profound weakness, bradycardia and emesis

• An I stat potassium is 8.5mg/dL and an EKG show a sine wave pattern

• IV Calcium chloride is administered and he develops ventricular fibrilitation shortly thereafter

Case 2

• Despite your best efforts he dies

• The wife said he has no medical problems, but was recently doing a “cleansing diet” that included herbal teas

Introduction

• Digitalis and digitalis like cardiac glycosides (DG’s) are found in a variety plants, toads and pharmaceutical agents

• Dried powders and extracts have been used for centuries for medicinal agents and as arrow poisons

Pharmacokinetics

• Peak serum concentrations occur in minutes with IV dosing and 1-2 hours after an oral dose

• The VD is initially small and increases following a two phase compartment model– Higher in infants and neonates and

lower in the elderly

Pharmacokinetics

• Tissue distribution takes 6-12 hours

• Digoxin crosses the placenta with fetal levels approaching that of the mother

• Elimination

– Hepatic metabolism

– Urinary excretion of unchanged drug

Pathophysiology

• Cardiac glycosides inhibit the sodium potassium atp-ase

– Responsible for pumping two sodium ions out of the cell for every two potassium ions in to the cell

3 Na+

2 K+

Na-KATPase Na+

Ca++

SR

Ca++

Ca++

Ca++

Ca++Ca++

Ca++

Ca++

Ca++

Ca++Ca++

ATPase

Ca++

myocardium

-90 mv

K+

Na+

Na+

Na+

Ca++

Na+

3 Na+

2 K+

Na-KATPase Na+

Ca++

SR

Ca++

Ca++

Ca++

Ca++Ca++

Ca++

Ca++

Ca++

Ca++Ca++

ATPase

Ca++

myocardium

-90 mv

K+

Na+

Na+

Na+

Na+

Na+

Na+

Na+Na+

Na+

Na+

Na+

Ca++

Na+

3 Na+

2 K+

Na-KATPase Na+

Ca++

SR

Ca++

Ca++

Ca++

Ca++Ca++

Ca++

Ca++

Ca++

Ca++Ca++

ATPase

Ca++

myocardium

-90 mv

K+

Na+

Na+

Na+

Na+

Na+

Na+

Na+

Na+

Na+Na+

Na+

Ca++

Ca++

Ca++

Ca++

Ca++

Ca++

Ca++

Ca++

Ca++

Ca++

Ca++

Ca++

Ca++

Ca++

Ca++Ca++

Ca++

Na+

3 Na+

2 K+

Na-KATPase Na+

Ca++

SR

Ca++

Ca++

Ca++

Ca++Ca++

Ca++

Ca++

Ca++

Ca++Ca++

ATPase

Ca++

myocardium

-90 mv

K+

Na+

Na+

Na+

Na+

Na+

Na+

Na+

Na+

Na+Na+

Na+

Ca++

Ca++

Ca++

Ca++

Ca++

Ca++

Ca++

Ca++

Ca++

Ca++

Ca++

Ca++

Ca++

Ca++

Ca++Ca++

[Ca++]Ca++

Na+

Inhibition of Na-K-ATPase

[Nai+]

[Cai++]

heart

contractility

3 Na+

2 K+

Na-KATPase Na+

Ca++

SR

Ca++

Ca++

Ca++

Ca++Ca++

Ca++

Ca++

Ca++

Ca++Ca++

ATPase

Ca++

muscle

-90 mv

K+

Na+

Na+

Na+

Na+

Na+

Na+

Na+

Na+

Na+Na+

Na+

Ca++

Ca++

Ca++

Ca++

Ca++

Ca++

Ca++

Ca++

Ca++

Ca++

Ca++

Ca++

Ca++

Ca++

Ca++Ca++

[Ca++]

[K+]

Ca++

Na+

Inhibition of Na-K-ATPase

[Nai+]

[Ko+]

hyperkalemia

[Cai++]

skeletal muscleheart

contractility

3 Na+

2 K+

Na-KATPase Na+

Ca++

SR

Ca++

Ca++

Ca++

Ca++Ca++

Ca++

Ca++

Ca++

Ca++Ca++

ATPase

Ca++

myocardium

-90 mv

K+

Na+

Na+

Na+

Ca++

Na+

3 Na+

2 K+

Na-KATPase Na+

Ca++

SR

Ca++

Ca++

Ca++

Ca++Ca++

Ca++

Ca++

Ca++

Ca++Ca++

ATPase

Ca++

myocardium

-90 mv

K+

Na+

Na+

Na+

Na+

Na+

Na+

Na+

Na+

Na+Na+

Na+

Ca++

Ca++

Ca++

Ca++

Ca++

Ca++

Ca++

Ca++

Ca++

Ca++

Ca++

Ca++

Ca++

Ca++

Ca++Ca++

Ca++ Ca++

Ca++

Ca++

Na+

3 Na+

2 K+

Na-KATPase Na+

Ca++

SR

Ca++

Ca++

Ca++

Ca++Ca++

Ca++

Ca++

Ca++

Ca++Ca++

ATPase

Ca++

myocardium

-90 mv

K+

Na+

Na+

Na+

Na+

Na+

Na+

Na+

Na+

Na+Na+

Na+

Ca++

Ca++

Ca++

Ca++

Ca++

Ca++

Ca++

Ca++

Ca++

Ca++

Ca++

Ca++

Ca++

Ca++

Ca++Ca++

Ca++ Ca++

Ca++

Ca++

Na+

-90 mv

premature beat or ectopic focus

increased automoticity

late afterdepolarizations

Inhibition of Na-K-ATPase

[Nai+]

[Ko+]

hyperkalemia

[Cai++]

skeletal muscleheart

contractility

automoticity

premature beatsescape rhythmsV-tach, V-fib

rise in Nai+

and Cai++

Baroreceptors

Carotidsinus

receptorsCN IX Vagus Nerve

Aortic arch

receptors

Vagal Tone

Bradycardia AV blocksAsystole

Vagus Nerve

Increasedbaroreceptor

firing

CNS

Parasympathetic

Sympathetic

SVRCO

IncreasedArterial

Pressure

(-)(-)

Baroreceptors

Inhibition of Na-K-ATPase

[Nai+]

[Ko+]

hyperkalemia

[Cai++]

skeletal muscleheart

contractility

premature beatsescape rhythmsV-tach, V-fib

firing

baroceptors

vagal tone

bradycardia, AV blocks, asystole

automoticity

rise in Nai+

and Cai++

rise in Nai+

and Cai++

Devils Advocate

• Treatment of Hyperkalemia in a patient with unrecognized digitalis toxicity

– 80 yr old female presents to the ED with AMS, hyperkalemia and bradycardia

– Treated with intravenous pacing and IV calcium chloride

J Toxicol Clin Toxicol. 2003;41(4):373-6

Devils Advocate

• A toxicological Surprise

– A 42 year old man was admitted to a medical service for CP, nausea and vomiting

– Heart rate was 35, EKG showed total AV block

– Potassium was 5.7mmol/L

Lancet. 2000 Oct 21;356(9239):1406.

Devils Advocate

• He was treated for a myocardial infarction

• A transvenous pacer was inserted with an increase in his heart rate to 70 BPM

• A serum digoxin level was 365ng/mL (therapeutic range 10-30)

Lancet. 2000 Oct 21;356(9239):1406.

Digoxin in herbal Supplements

• Digoxin Toxicity in a 26 year-old woman taking a herbal dietary supplement

– Presented to an ED with chest pain

– Initially her heart rate was 70 BPM and BP was 112/59

– Her heart rate dropped to 39 and BP dropped to 59/36J Am Osteopath Assoc. 2001 Aug;101(8):444-6

Digoxin in herbal Supplements

• EKG showed the absence of P waves

• She was given a NS fluid bolus and placed in the trendelenberg position

• Her BP and heart returned to her original baseline

• A digoxin level was 0.9ng/mL

J Am Osteopath Assoc. 2001 Aug;101(8):444-6

Digoxin in herbal Supplements

• She confessed to consuming a tea that contained:

– Skullcap herb, wood betony herb, black cohosh root, hops flowers, valerian root and cayenne pepper fruit

J Am Osteopath Assoc. 2001 Aug;101(8):444-6

Case 3

• A 36 year old female, with a past medical history for depression and chronic back pain, presents to the ED for back pain

• She states that Demerol is the only medication that relieves her pain

• Reluctantly, you write an order for Demerol

Case 3

• Two hours after the administration of Demerol she develops tachycardia, AMS and myoclonus

• You believe that she developed serotonin syndrome

• A NGT is placed in preparation for the administration of cyproheptadine

Case 3

• She has a self limited seizure, vomits and has a decrease in her O2 sat

• She is intubated using etomidate and succinylcholine

• A post intubation x-ray shows a right upper lobe consolidation

• She dies on hospital day 6 from complications of aspiration pneumonia

Serotonin Syndrome

• Drug Induced Disorder• Variable alterations in

– cognition-behavior– neuromuscular activity– autonomic nervous system function

• Increased CNS serotonin neurotransmission at 5-HT1A and 5-HT2A receptors

Serotonin Receptors

• The largest and most diverse of all neurotransmitter systems– 5HT1 – 5HT7

• Each receptor class may contain many subclasses

• 5HT1A - presynaptic and postsynaptic• 5HT1D - presynaptic and postynaptic

5HT2A - postsynaptic

Serotonin Syndrome

• No gender predilection

• Idiosyncratic in nature

• Patients are not more likely to develop SS following an overdose than they are while taking therapeutic doses

• SS is a diagnosis of exclusion

Precipitants

– Addition of second serotonergic drug usually at therapeutic doses

– Increasing primary drug

• Inherited / Acquired

– Reduction in endothelial MAOA activity

– Genetic variation

Serotonergic Agents

• Inhibit 5-HT uptake

• Enhances 5-HT release

• Inhibits 5-HT breakdown

• Metabolized to 5-HT

• 5-HT1A agonist

• Enhances 5-HT receptor response to stimulation

L-tryptophan

5-hydroxytrytophan

5-HT

TPH

AAD

5-HT

5-HT receptors 1-7

MAO

5-HIAA

5-HT1A, D

-

X

X

Inhibit 5-HT Uptake

• Specific SRIs• Non-specific SRIs - clomipramine, trazodone• TCAs• Meperidine• Dextromethorphan• Pentazocine• Tramadol• Dexfenfluramine

Enhance 5-HT Release

• Lithium

• Levodopa, dopamine

• MDMA

• Cocaine

• Amphetamines

• Fenfluramine

• Dexfenfluramine

5-HT1 Agonists

• LSD

• Buspirone

• Sumatriptan

• Dihydroergotamine

Serotonergic Agents

• Inhibits 5-HT breakdown

– MAOIs

• Metabolized to 5-HT

– Tryptophan

• Enhances 5-HT1A receptor response to stimulation

– Lithium

Drug Combinations

• All MAOI combinations• Dextromethorphan and SSRI• Lithium and SSRI• Trazodone and SSRI• Tramadol and SSRI• Trazodone and Buspirone• Selegiline and SSRIs or TCAs• Switching from 1 SSRI to another SSRI

Serotonin Syndrome Associated with Monotherapy

• Clomipramine

• Fluvoxamine

• Venlafaxine

• MDMA

• Sertraline

Clinical Manifestations

• Cognitive and behavioral

– Confusion (54%)

– Agitation (35%)

– Coma (28%)

– Hypomania (15%)

– Seizures (14%)

– Hallucinations (6%)Mills K. Serotonin Syndrome A Clinical Update. Critical Care Clinics, Volume 13:4 Oct 1997

Clinical Manifestations

• Autonomic Dysfunction

– Blood Pressure Lability (47%)

– Hyperthermia (46%)

– Diaphoresis (46%)

– Tachycardia (41%)

– Mydriasis (26%)

– Diarrhea (12%) Mills K. Serotonin Syndrome A Clinical Update. Critical Care Clinics, Volume 13:4 Oct 1997

Clinical Manifestations

• Neuromuscular Abnormalities– Myoclonus (57%) – Hyperreflexia (55%) – Rigidity (49%)– Tremor (49%) – Incoordination (38%) – Shivering (25%) – Nystagmus (13%)– Seizures (14%)

Mills K. Serotonin Syndrome A Clinical Update. Critical Care Clinics, Volume 13:4 Oct 1997

Sternbach’s Suggested Diagnostic Criteria

• Coincidental with the addition of or increase in known serotonergic agents to an established medications regimen - at least 3 of the following– agitation, diaphoresis, diarrhea, fever,

hyperreflexia, incoordination, MS changes, myoclonus, shivering, tremor

• Other etiologies (infections, metabolic, withdrawal) have been ruled out

• A neuroleptic agent has not been started or increased in dosage

Other Criteria

• Hegerl Criteria

• Dursun Criteria

• Randomski Criteria

• Mills Criteria

• Hunters Decision Rules

• MOFO Criteria

Time course

• Usually abrupt

• Occurring within hours after initiation of new serotonergic agent

• 2/3 of cases resolves within 24 hours

Treatment

• Five basic management principles

– Supportive care

– Discontinue serotinergic agents

– Anticipate potential complications

– Administer antiserotinergic agents

– Reassess the need for reinstituting pharmacotherapy

Treatment

• Antipyretics are generally ineffective

• Benzodiazepines are the initial choice for relieving muscle spasm

• No specific antidotes for SS

• Most symptoms resolve in 12 – 24 hours

Cyproheptadiene

• Cyproheptadine (periactin)

– Most consistently effective

– Blocks postsynaptic 5HT1A and 5HT2

receptors

– Only available orally (syrup, tablet)

– Also has antimuscarinic and antihistaminc properties

Case 4

• A 54 year old male presents to the ED with a rash that has been getting progressively worse over that past week and a half

• He also offers complaints of chills, nausea, vomiting and diarrhea

• Past medical history is significant for seizure disorder and hypertension

Case 4

• His medications include phenytoin and lisinopril

• He is febrile with a temperature of 102.c, tachycardic at a ventricular rate of 130, hypotensive with a sys BP of 80, RR 24

• His white count is 28,000 with a left shift, HG: 19, HCT: 45, Platelets 52

Case 4

• Na+ 156, K+ 5.4, Cl- 92, NaHco3- 12,

• BUN: 60, CR 5.2 and glucose is 220

• His LFTS are markedly elevated and he has a creatinine of 3.2

• His phenytoin level 0.5mcg/mL

• He is loaded with IV phenytoin in the ED

Case 4

• One hour after the administration of phenytoin he drops his blood pressure and becomes apneic

• He is subsequently intubated and is transferred to the ICU

• He dies on Hospital day 7 from multi-system organ failure

Introduction

• Anticonvulsant hypersensitivity syndrome (ACHS) is a rare, potentially fatal multisystem disorder that occurs after exposure to phenytoin, carbamazepine, phenobarbital, felbamate and lamotrigine

Signs and Symptoms

• ACHS commonly begins within one to four weeks after starting therapy, but may present as late as three months

• ACHS may occur within hours of a previously sensitized individual

• ACHS is not related to the dose or serum concentration

Signs and Symptoms

• Most commonly ACHS begins with a fever, followed by a rash and variable degrees of lymphadenopathy

• The fever usually ranges from 38 – 40.C

• The Rash may develop concurrently or shortly after the fever

Signs and Symptoms

• The Rash is commonly described as an exanthem with or without pruritus

• The upper extremities, face and trunk are usually first affected

• Periorbital edema, exudative tonsillitis, pharyngitis, oral ulcerations and conjunctivitis may be seen

Signs and Symptoms

• Rarely, more severe skin reactions may occur (SJS, TEN, EM)

– Usually in the setting of repeated exposures or continued use

• Tender lymphadenopathy is commonly seen

Signs and Symptoms

• The Liver is the most common organ involved

• The CNS, heart, lungs, renal system and thyroid gland may be involved– Patients may present with elevated

transaminases, alkaline phosphatase, PT and bilirubin

• The hepatitis is usually mild and anicteric

Signs and Symptoms

• The degree of hepatitis is related to the time between the onset of symptoms and the discontinuation of the offending agent

• Liver biopsies reveal periportal inflammation with or without necrosis

• The majority of patients recover within a few weeks

Signs and Symptoms

• Hematologic abnormalities – Lymphocytosis – Leukocytosis– Eosinophilia– Anemia– Leukopenia – Thrombocytopenia– Aplastic anemia

Pathophysiology

• The anticonvulsants implicated in ACHS all have in common an aromatic benzene ring that is metabolized by cytochrome p450 to an arene oxide

• Arene oxides are highly electrophilic and covalently bind to macromolecules to disrupt cellular function

Pathophysiology

• Arene oxides may also form neoantigens that trigger an immunologic response

• These metabolites are highly unstable and under normal conditions can be detoxified by one of several routes

Diagnosis

• Usually based on history of drug exposure and clinical examination

– Atypical lymphocytes

– Eosinophilia

– Elevated liver enzymes

– hyperbilirubinemia

Treatment

• The mainstay of treatment is discontinuation of the offending agent and supportive care

• Severe skin reactions are best managed in a burn center

• Strict attention must be paid to maintaining fluid and electrolyte balance

Thank You