General Approach to the Poisoned Patient

1
General Approach to the Poisoned Patient

• Presented by Dr. Levy
• Prepared by
• Dr. Trey Woods D.O.
• Emergency Medicine
• St. Josephs Health Center
• Warren Ohio

2
Comic Relief

• .

3
Objectives

• Supportive care is main means to decrease
  morbidity and mortality
• Learn about gastric decontamination
• Learn and know all antidotes
• Know toxidromes and treatment

4
What this lecture is not. . .

• A comprehensive review of all of toxicology
• Though important it will also not cover
  envenomations, medications like oral
  hypoglycemics, blood pressure medications,
  lithium, or caustics

5
Why do we discuss toxicology?

• In practice, toxicology makes up 5-30 of your
  cases
• Inservice and written boards, about 8
• Oral boards, about 15

6
Toxic Trivia 1

• About 2-4 million toxic exposures annually
• Fewer than 1 of overdose patients that reach the
  hospital result in fatality
• But 13-35 mortality if arrive in deep coma
• One fourth of suicide attempts are via drugs
• More than half of exposures, lt6 yo
• Toxin-related deaths on the rise

7
Its Not Just Swallowing Pills

• Ingestions account for 79 of exposures
• Others
• 7 dermal
• 6 ophthalmologic
• 5 inhalations
• 3 stings and bites
• .3 injection

8
EPIDEMIOLOGYThe Ten Most Lethal Poisons

• Analgesics
• Antidepressants
• Sedative/Hypnotics
• Stimulants/Street Drugs
• Cardiovascular Drugs
• Clinical Toxicology Forum Vol 5 Num 2

• Alcohols
• Gases and Fumes
• Asthma Therapies
• Chemicals
• Hydrocarbons

9
Toxic Trivia II

• Leading causes of pharmaceutical death
• Analgesics
• Tricyclic antidepressants
• Sedative/hypnotics
• Stimulants and street drugs
• Cardiovascular drugs
• Alcohols

10
7 Mechanisms of Toxicity

• 1. Interfere with O2 transport or tissue
  utilization of oxygen
• (example cyanide, CO)
• 2. Affect CNS
• (example cocaine, sedatives)
• 3. Affect ANS
• (example organophosphates)

11
7 Mechanisms of Toxicity

• 4. Affect lungs
• (example paraquat)
• 5. Affect cardiovascular system
• (example TCA, Ca channel blockers)
• 6. Direct local damage
• (example acids, bases)
• 7. Delayed effects on liver or kidneys
• (example acetaminophen, metals)

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Principles of Toxicology

• Reduce exposure
• Reduce absorption
• Increase elimination
• Know when to intervene
• Give supportive care
• Give specific therapy and antidotes when
  appropriate

13
Lets start by...

• A basic review of the initial approach to the
  following patient. . .

14
Your patient. . .

• 29 year old man
• found down
• EMS transports
• Reports from scene he took something
• No pill bottles on scene
• No family with him
• Roommates that found him are long gone
• He is now in your ED

15
You are never going to know exactly what he took.
. .

• What do I do with him?
• What do I order?
• How do I treat him?
• How do I decontaminate him?
• Do I give him an antidote?
• When can he go to psych?

16
You can. . .

• Start with the basics
• Airway, breathing, circulation
• Get a better history
• Get EMS to get pill bottles, tell you what they
  do know (found outside, inside, garage)
• Call friends, family, neighbors
• Call psych or primary MD to see what he is on
  regularly
• Get him to tell you
• Always remember that suicidal patients (just like
  everyone else) can lie so be skeptical of their
  history

17
General ApproachABCs of Toxicology

• A-Antidotes and alter absorption (in some
  instances prior to airway-decontamination with
  organophosphates to protect others, cyanide
  toxicity where antidotes are lifesaving)
• B-Basics ABCs
• C-Change metabolism (NAC, ethanol)
• D-Distribute differently (calcium gluconate, O2)
• E-Elimination (diuresis, dialysis, hemoperfusion)

18
Obtaining the History

• Remember the AMPLE history
• Allergies, Medications, Past medical and surgical
  history,
• Last meal, Events leading to presentation
• When in a jam, remember the Ps
• Paramedics
• Parents
• Pals
• Physicians
• Pharmacists
• History may prove UNRELIABLE

19
Toxicologic Physical Exam

• CNS level of arousal, GCS, pupils, behaviour,
  neurologic exam
• CVS rate, rhythm
• Resp pattern, depth, wheezing
• GI bowel sounds, distention
• Skin color, temp, signs of trauma
• Odors

20
Physical Exam

• Vitals (temperature, resp. rate,HR, BP)
• Mental status, bowel sounds, pupillary response,
  skin findings
• Often times no significant physical findings,
  especially if exposure early
• Beware of changes
• Odors may give clue to substance
• Look for easily recognizable toxidromes

21
PHYSICAL EXAMINATIONTemperature

• HYPOTHERMIA (COOLS)
• Carbon Monoxide
• Opiates
• Oral Hypoglycemics, insulin
• Liquor
• Sedative Hypnotics
• Emergency Medicine June 1996 79-88

22
PHYSICAL EXAMINATIONTemperature

• HYPERTHERMIA (NASA)
• Neuroleptic Malignant Syndrome, nicotine
• Antihistamines
• Salicylates, sympathomimetics
• Anticholinergics, Antidepressants
• Emergency Medicine June 1996 79-88

23
PHYSICAL EXAMINATIONHeart Rate

• Bradycardia (PACED)
• Propanolol (B Blockers), poppies (opiates)
• Anticholinesterase drugs
• Clonidine, calcium channel blockers
• Ethanol, other alcohols
• Digoxin
• Emergency Medicine June 1996

24
PHYSICAL EXAMINATIONHeart Rate

• Tachycardia (FAST)
• Free base (cocaine)
• Anticholinergics, antihistamines, amphetamines
• Sympathomimetics, solvents
• Theophylline
• Emergency Medicine June 1996

25
PHYSICAL EXAMINATIONBlood Pressure

• Hypotension (CRASH)
• Clonidine, calcium channel blockers
• Reserpine, other antihypertensives
• Antidepressants, aminophylline
• Sedative-hypnotics
• Heroin, other opiates
• Emergency Medicine June 1996

26
PHYSICAL EXAMINATIONBlood Pressure

• Hypertension (CT SCAN)
• Cocaine
• Thyroid supplements
• Sympathomimetics
• Caffeine
• Anticholinergics, amphetamines
• Nicotine
• Emergency Medicine June 1996

27
PHYSICAL EXAMINATIONRespiratory Rate

• Hypoventilation (SLOW)
• Sedative-hypnotics
• Liquor
• Opiates
• Weed (marijuana)
• Emergency Medicine June 1996

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PHYSICAL EXAMINATIONRespiratory Rate

• Hyperventilation (PANT)
• PCP, paraquat, pneumonitis
• ASA
• Non cardiogenic pulmonary edema
• Toxin-induced metabolic acidosis
• Emergency Medicine June 1996

29
PHYSICAL EXAMINATIONNeurological Exam - Pupil
Size

• Miosis ( COPS)
• Cholinergics, clonidine
• Opiates, organophosphates
• Phenothiazines, pilocarpine, pontine bleed
• Sedative-hypnotics
• Emergency Medicine June 1996

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PHYSICAL EXAMINATIONNeurological Exam Pupil
Size

• Mydriasis (AAAS)
• Antihistamines
• Antidepressants
• Anticholinergics
• Sympathomimetics
• Emergency Medicine June 1996

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PHYSICAL EXAMINATIONSKIN

• Flushed/Red Appearance
• Anticholinergics
• Boric Acid
• Carbon Monoxide (rare)
• Cyanide (rare)

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PHYSICAL EXAMINATIONSKIN

• Diaphoretic Skin (SOAP)
• Sympathomimetics
• Organophosphates
• Acetylsalicylic acid
• Phencyclidine
• Dry Skin
• Antihistamines
• Anticholinergics
• Emergency Medicine June 1996

33
PHYSICAL EXAMINATIONDrugs That Cause
SeizuresOTIS CAMPBELL

• Organophosphates
• Tricyclic Antidepressants
• Isoniazid, insulin
• Sympathomimetics
• Camphor, cocaine
• Amphetamines
• Methylxanthines
• Emergency Medicine June 1996

• PCP
• Benzodiazepine withdrawal
• Ethanol withdrawal
• Lithium, lidocaine
• Lead, lindane

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Odors as Clues to Toxins

• Acetone acetone, acidosis
• Alcohol NOT with ethylene
• glycol
• Bitter almonds cyanide
• Hemp (burnt rope) marijuana
• Garlic arsenic
• Rotten eggs disulfiram, H2SO4

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Now you are ready to order diagnostic studies. . .

• Want to evaluate
• Acid base status
• Renal function
• Liver function
• Cardiac conduction
• EKG
• Drug levels
• Based on history or clinical findings
• Any toxin specific findings
• CK for cocaine, NH3 for valproate, etc

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Useful lab values

• Calculate the anion gap
• AGNa-(HCO3Cl)

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Anion Gap Acidosis

• Mmethanol,metoformin,massive ingestions
• U uremia
• D DKA
• P paraldehyde
• I iron, INH
• L lactic acidosis (CO,CN)
• E ethylene glycol
• S salicylates, strychnine

38
Useful lab values

• Osmolar gapmeasure serum osmolality-calculated
  serum osmolality
• Calculated2Naglucose/18BUN/2ethanol/6
• Normal gap lt10 (nl 285-295)
• Causes Osmolar Gap
• ME DIE (methanol, mannitol, ethanol, diuretic,
  isopropyl, ethylene glycol)

39
Directed Toxicology Tests

• Comatose Tox screen, glu, NH4, CT scan, CSF
  analysis
• Respiratory toxin ABG, CXR, spirometry,
  pulse ox
• Cardiac toxin EKG, ECHO, cardiac enzymes,
  hemodynamic monitoring

40
EKG

• An ECG should be performed on all patients who
  are symptomatic or who have been exposed to
  potentially cardiotoxic agents
• Evaluate QRS and QTC, presence of blocks, rhythm
• QTc gt 450 and a QRS gt 100 can be concerning for
  toxin induced (eg TCAs) cardiac abnormalities

41
Radiographs

• Limited usefulness
• CHIPES
• Chloral hydrate, Ca
• Heavy metals
• Iron, iodides
• Phenothiazines
• Enteric coated
• Slow release
• Packers/ stuffers
• Aspiration

42
Tox Screens

• Toxic screening is rarely necessary when patients
  with a non-intentional ingestion are asymptomatic
  or have clinical findings that are consistent
  with the medical history.
• However, screening for acetaminophen and
  salicylates is strongly recommended for patients
  with an uncertain history or intentional
  poisoning few early signs may be present
  following lethal doses of these agents, and
  specific treatments are available and highly
  effective if implemented early.

43
Tox Screens

• Quantitative urine specimens are superior to
  blood specimens since drug metabolites can be
  detected 2-3 days post exposure
• Urine screen specifically designed for drugs of
  abuse
• A positive or negative screen does not
  necessarily rule in or rule out an overdose

44
Tox Screens

• False Positives
• Amphetamines pseudoephdrine
• TCAs cyclobenzaprine, carbazepine,
  phenothiazines, diphenhydramine
• PCP ketamine, detromethorphan
• False Negatives
• Dilute urine
• Methadone opiod screens
• MDMA amphetamines

45
Specific drug levels

• Quantitative blood tests should be limited to
  those drugs for which levels can predict
  subsequent toxicity or guide specific therapy
• E.g., iron, lithium, acetaminophen, ASA,
  theophylline, digoxin

46
Toxic Timebombs

• Acetaminophen
• Mushrooms
• Toxic alcohols
• Sustained released preps (calcium channel
  blockers, beta blockers, lithium)
• Drug packet ingestion (heroin, cocaine)
• Oral hypoglycemic agents
• Fat soluble organophosphates
• Enteric coated preps
• MAOs
• Heavy metals

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Or. . .

• Establish a pattern to his symptoms
• Toxic syndrome
• Also known as a
• TOXIDROME

48
Toxidromes

• Not every drug fits into a broad based category
• Lots of meds have unique effects not easily
  grouped
• Physiologic fingerprints that occur in the form
  of syndromes or groups of symptoms which are
  observed to occur together in response to
  exposure to one of a pharmacologically similar
  group of agents
• Useful in determining the class of agents
  involved in an unknown poisoning
• 5 Basic Toxidromes
• Sympathomimetic
• Opiate
• Anticholinergic
• Cholinergic
• Seditive Hypnotic

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Toxidromes Sympathomimetic
50
Sympathomimetics

• Cocaine
• Methamphetamine/Amphetamines
• Ecstasy (MDMA)
• ADHD meds like ritalin, adderal
• Ephedrine
• Caffeine

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Why do they do what they do?

• Excessive SYMPATHETIC stimulation involving
  epinephrine, norepinephrine and dopamine
• Excessive stimulation of alpha and beta
  adrenergic system

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What goes wrong?

• Tachycardia /- arrythmias
• Hypertension /- ICH
• Hyperthermia,
• mydriasis,
• convulsions, diaphoresis, seizure,
• central nervous system (CNS) excitation
• psychosis,
• Rhabdomyolysis
• Mimics Anticholinergic except WET compared to DRY
• Diaphoresis and normal bowel sounds with
  sympathomimetic toxidrome
• Dry skin and absent bowel sounds with
  anticholinergic toxidrome

53
What do you do about it?

• Supportive care
• Monitor airway, diagnose ICH, rhabdo
• IVF for insensible loses and volume repletion
• Benzos, benzos, benzos, benzos
• BP mgmt if severe
• NEVER GIVE BETA BLOCKERS

54
Toxidrome Opiate
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Opiates / Opioids

• Opiate derived directly from the opium poppy
• morphine and codeine
• Opioids much broader class of agents that are
  capable of producing opium-like effects or of
  binding to opioid receptors
• Heroin
• Methadone
• meperidine
• Hydrocodone
• oxycodone

56
What goes wrong

• Triad of
• Coma
• Miosis (not always seen demerol actually
  dilates)
• Respiratory depression
• Peripheral vasodilation, hypotension
• Flushing (histamine)
• Bronchospasm
• Pulmonary edema
• Seizures (meperidine, propoxyphene)
• Hypothermia
• Bradycardia

57
What do you do about it?

• Competitive opioid antagonist Naloxone
• Goal of return of spontanous respirations
  sufficient to ventilate the patient appropriately
  
• May have to re-dose as opiates may act longer
  than antagonist
• There are other longer acting opioid antagonists
  such as nalmefene and naltrexone but these are
  not often used

58
Toxidrome Anticholinergic
59
Better way to remember it. . .

• Hot as Hades - Fever
• Fast as a Hare - Tachycardia
• Dry as a Bone Lack of diaphoresis
• Red as a Beet Flushed skin
• Mad as a Hatter Delerium
• Full as a Tick Urinary retention
• Blind as a Bat Mydriasis

60
What do you do about it?

• Supportive care
• IVF to replace insensible losses from agitation,
  hyperthermia
• Benzos to stop agitation
• Physostigmine
• Induces cholinergic effects
• Short acting
• May help with uncontrollable delirium
• Do not use if ingestion not known
• Danger with TCAs
• Dont use in patients with CHB

61
Toxidrome Cholinergic
62
Why do they do what they do?

• Block acetylcholinesterase from working
• End up with excess of acetylcholine in synapses
• Leads to excess stimulation of the muscarinic and
  nicotinic systems

Normal
63
What goes wrong?

• D - Diarrhea
• U - Urination
• M - Miosis
• BBB Bradycardia, Bronchorrhea, Bronchospasm
• E - Emesis
• L - Lacrimation
• S Salivation, Seizures

64
What goes wrong?

• S - Salivation
• L - Lacrimation
• U - Urination
• D - Diaphoresis
• G - Gasterointestinal upset
• vomiting, diarrhea
• E - Eye
• miosis

65
What else goes wrong?

• Nicotinic effects
• M- Mydriasis
• T - Tachycardia
• W - Weakness
• (t) H - Hypertension
• F -Fasiculations

66
What do you do about it?

• Antagonize muscarinic symptoms
• Atropine
• Stop aging of enzyme blockade
• 2-PAM
• Prevent and terminate seizures
• Diazepam
• Supportive care

67
Toxidrome Sed-Hypnotic
68
Why do they do what they do?

• Different agents have different mechanisms
• Many interfere in the GABA system

69
What goes wrong?
70
What goes wrong?

• CNS depression, lethargy
• Can induce respiratory depression
• Can produce bradycardia or hypotension

71
What do you do about it?

• Supportive care
• Be wary of the benzo antidote Flumazinil
• Is an antagonist at the benzo receptor
• RARELY INDICATED
• If seizures develop either because of benzo
  withdrawal, a co-ingestant or metabolic
  derangements, have to use 2nd line agents,
  barbiturates, for seizure control

72
So back to our patient. . .

• Agitated, pupils 8 mm, sweaty, HR 140s, BP
  230/130
• Sympathomimetic
• Unarousable, RR 4, pupils pinpoint
• Opiate
• Confused, pupils 8mm, flushed, dry skin, no bowel
  sounds, 1000 cc output with Foley
• Anticholinergic
• Vomiting, urinating uncontrollably, HR 40, Pox
  80 from bronchorrhea, pupils 2 mm
• Cholinergic
• Lethargic, HR 67, BP 105/70, RR 12, pupils
  midpoint
• Sedative Hypnotic

73
Management

• Most toxic exposures will get better simply with
  meticulous supportive care
• Not everybody needs the full court press
• Issues to address
• frequent assessment
• decontamination
• enhancement of elimination
• Antidotes
• disposition

74
Frequent Assessment

• Do they need to be here at all?
• Beware of the Stable patient
• Consider possible polysubstance exposures
• Be prepared for deterioration
• IV access
• Cardiac monitor
• Pulse oximetry

75
So basic approach

• Airway, breathing, circulation
• Establish IV, O2 and cardiac monitor
• Consider coma cocktail
• Thiamine, D50, Narcan
• Evaluate history and a thorough physical exam
• Look at vitals, pupils, neuro, skin, bowel
  sounds. . .
• Gives you hints regarding the general class of
  toxins
• Guides your supportive care
• Draw blood / urine for testing
• Time to consider decontamination options

76
Decontamination or How do I get the poison out
of your body?

• Induce vomiting Ipecac
• Take out pills from the stomach Lavage
• Adsorb the toxins in the gut Charcoal
• Flush out the system Whole Bowel

77
Decontamination Methods

• Aim is to prevent absorption and minimize
  exposure
• Many standard practices now virtually extinct
• Forced emesis, forced lavage, charcoal anytime
• Removal of contaminated clothing, substances on
  skin or in eyes
• Charcoal
• Gastric lavage
• Whole Bowel Irrigation

78
Ipecac

• Emetine and Cephaeline
• Induces emesis
• Rarely if ever still recommended for HOME use
• DOES NOT HAVE A ROLE IN ED CARE

79
Decontamination Methods

• Gastric lavage
• Used far less now than in past
• Having your stomach pumped, with large tube
  inserted into stomach, suctioned, and lavaged
• Risk of perforation, aspiration, and simply not
  working
• Contraindicated in comatose or seizing patients,
  unprotected airways, extended release preparations

80
Gastric Lavage

• Can be a brutal procedure
• Indication life threatening ingestions that
  occurred within one hour
• Airway protection is key
• Limited indications
• Lots of complications

81
Charcoal

• Basically, everybody gets a dose
• Works to adsorb substances to its matrix
• Not for metals, caustics
• Generally safe, few contraindications
• Aspiration, bowel obstruction
• Dosing 1g/kg po dose, /- single dose of cathartic

82
Charcoal

• Works by substances being adsorbed to the
  surface, which is size dependent
• Window of opportunity around one hour post
  ingestion
• Has some indications for multiple dosing
• drugs that have enterohepatic circulation
• drugs that can be eliminated by gut dialysis

83
Charcoal Contraindications

• Charcoal doesnt bind CHARCOAL
• Caustics and corrosives
• Heavy metals
• Alcohols
• Rapid absorption (cyanide, strychnine)
• Chlorine and iodine
• Other agents insoluble in water
• Aliphatics (petroleum distillates)
• Laxatives (Mg, K, Na)

84
Charcoal Contraindications

• Loss of protective reflexes
• drugs likely to cause rapid depressed
  consciousness or early seizures
• infants lt 6 months of age
• ingested foreign body
• neurologically impaired
• absent bowel sounds or obstruction
• unstable patients

85
Multi-dose CharcoalEnterohepatic Circulation

• Chloral hydrate
• colchicine
• digitalis preparations
• glutethimide
• isoniazid
• methaqualone

• NSAIDS
• phencyclidine
• phenothiazines
• phenytoin
• salicylates
• TCAs

86
Multi-dose CharcoalGut Dialysis

• Pretty Damn Short QTc
• Phenobarbital
• Dapsone
• Salicylates
• Quinine
• Theophylline
• Carbemazepine

87
Whole Bowel

• Isotonic polyethylene glycol electrolyte
  solutions (GoLytely)
• Large volumes ingested wash the substances
  through the bowel
• cleanses gut of intoxicants
• PEG solutions at 2 Liters/hour
• effective for use in LA preparations, body
  packers/stuffers, and some substances poorly
  absorbed by charcoal (ex iron)
• contraindicated if hematemesis, ileus,
  obstruction, perforation, or peritonitis
• Dose in volume sufficient to create clear rectal
  effluent

88
WBI

• Dosing
• 1-2 LITERS/HOUR
• Have to use an NG tube

89
Enhancement of Elimination

• In other words, get rid of the toxin faster
• Cathartics - used, but no study showing benefit
• Alkalinization salicylates
• Hemodialysis
• Hemoperfusion

90
Hemodialysis

• Invasive, time consuming procedure
• Patients unstable despite supportive treatment
• Drugs must be amenable to hemodialysis
• Must have small volume of distribution (ie, drug
  must be in plasma, not tissues)
• Low protein binding, low molecular weight
• Water-soluble

91
Substances amenable to hemodialysis or
hemperfusion

• LET ME SAV P
• Lithium
• Ethylene glycol
• Theophylline
• MEthanol
• Salicylates
• Atenolol
• Valproic acid
• Potassium, paraquat

92
Complications of hemodialysis

• Bleeding at venous puncture site
• hypotension
• DVT
• Bleeding due to systemic anticoagulation
• Infection
• Air embolus

93
One more mneumonic for Hemodialyzable susbtances

• I STUMBLE (the common ones)
• Isoniazid
• Salicylates
• Theophylline
• Uremia
• Methanol
• Barbiturates
• Lithium
• Ethylene glycol

94
Antidotes

• Very limited number of antidotes given the vast
  array of pharmaceuticals and chemicals
• Coma Cocktail
• glucose
• thiamine
• naloxone
• NOT flumazenil

95
Common Antidotes

• Toxin
• APAP
• Tricyclics
• Opiates
• Organophosphates
• Heavy metals
• Iron
• Digoxin
• Beta-blocker
• Calcium channel blockers
• Cyanide

• Antidote
• N acetylcysteine
• Na bicarbonate
• Naloxaone
• 2 PAM
• BAL
• Desferoxamine
• Dig Fab (Digibind)
• Glucagon
• Calcium, glucagon, gluc/insulin
• Sodium nitrite, sodium thiosulfate,
  hydroxycobalamine

96
Common Antidotes

• Toxin
• Methanol, ethylene glycol
• Methemoglobinemia
• Anticholinergics
• Isoniazid
• Snakebites

• Antidote
• Fomepizole (Antizole)
• Methylene blue
• Physostigmine
• Pyridoxine
• Antivenom

97
Observation Period

• Normal labs, normal EKG, normal exam, no history
  of extended release drug
• Approximately 6 hours
• Extended release medications, buprorion, oral
  hypoglycemics involved
• Depending on agent, 12-24 hours

98
High Risk Patients (ICU wannabees)

• Needs circulatory or respiratory support
• altered mental status gt 3 hours
• seizures
• arrhythmia
• second or third degree heart block
• widened QRS
• unresponsive to verbal stimuli
• arterial pCO2 gt 45 mmHg

99
Disposition

• Home if stable after appropriate evaluation and
  observation period, unintentional or simple
  gesture with support structure
• Psychiatry evaluation if intentional, or risk to
  harm self or others
• Admission if unstable, long-acting or sustained
  release, needing therapies

100
So back to your patient. . .

• How do I treat him
• Good supportive care, good physical examination
• How do I decontaminate him
• Charcoal as long as he is not an aspiration risk
• What do I order
• Chem, ASA, APAP, EKG at a minimum
• Do I give him an antidote
• Coma cocktail, others as indicated by labs
• When can he go to psych?
• Observe for 6 hours and re-evaluate

101
A few more cases
102
First some Comic Relief

• .

103
CASE ONE

• 24 year old male brought in by family
• 3 day history of confusion, not eating
• Vitals T 38.5C HR96/min BP 100/50 RR 20

104
CASE ONE

• What else do we need to know ??
• History of presenting illness
• Meds/All/Imm
• Past medical/surgical history
• Other
• Physical exam

105
CASE ONE

• What is going on ?
• WHY ?
• What do we need to do ?

106
NEUROLEPTIC MALIGNANT SYNDROME

• Rare, life-threatening
• Reaction to neuroleptic medication
• All anti-psychotics may precipitate
• - typical or atypical
• - potent neuroleptics most frequent

107
NEUROLEPTIC MALIGNANT SYNDROME

• Classic Symptoms
• Fever
• Altered Mental Status
• Muscle Rigidity
• Autonomic Dysfunction
• Heterogeneous syndrome
• Average onset 4-14 days after initiation of
  therapy
• May occur at any time

108
NEUROLEPTIC MALIGNANT SYNDROME

• Pathophysiology
• Dopamine D2 receptor antagonists
• Nigrostriatum muscle rigidity
• Hypothalamus altered thermoregulation
• Sympathetic nervous system activation or
  dysfunction
• J Neurol Neurosurg Psychiatry 1995 Mar 58(3)
  271-3

109
NEUROLEPTIC MALIGNANT SYNDROME

• Frequency
• 0.07-0.2
• Mortality
• 5-11.6
• Respiratory failure, CV collapse, arrhythmias,
  renal failure, DIC
• Sex
• Male female 21
• Age
• No age predilection
• Benzer Jan 18 2002

110
NEUROLEPTIC MALIGNANT SYNDROMEHISTORY

• Recent treatment with neuroleptics
• Within past 1-4 weeks
• Chronic use, increased dose, newly instituted
• Fever
• Above 38 C
• Muscle Rigidity

111
NEUROLEPTIC MALIGNANT SYNDROMEHISTORY

• At Least 5 of the Following
• Change in mental status
• Tremor
• Tachycardia
• Hypertension/Hypotension
• Diaphoresis/sialorrhea
• Incontinence
• Leukocytosis
• Increased CK or urine myoglobin
• Metabolic acidosis
• EXCLUSION OF OTHER SYSTEMIC DISEASE

112
NEUROLEPTIC MALIGNANT SYNDROMEPHYSICAL
EXAMINATION

• Altered Mental Status
• Hyperthermia
• Autonomic Instability
• Tachycardia, hypertension, hypotension
• Generalized Muscle Rigidity
• Tremor

113
NEUROLEPTIC MALIGANT SYNDROMEINVESTIGATIONS

• Laboratory
• CBC, electrolytes, BUN, creatinine
• Calcium, magnesium, phosphate
• Liver Function
• PT, PTT
• CK
• Blood cultures
• Urine urinalysis, urine myoglobin
• ABG
• Toxicology screening

114
NEUROLEPTIC MALIGNANT SYNDROMEINVESTIGATIONS

• Imaging Studies
• Chest X-ray
• CT Head
• Procedures
• Lumbar Puncture
• Rule out meningitis

115
NEUROLEPTIC MALIGNANT SYNDROME TREATMENT

• ABCS
• Stop all neuroleptics
• IV fluid rehydration
• Reduce Temperature
• Cooled IV fluids
• Cooling blankets
• Ice packs
• Pharmacotherapy

116
NEUROLEPTIC MALIGNANT SYNDROME PHARMACOTHERAPY

• Benzodiazepines
• Dopamine Agonists
• Bromocriptine
• Levodopa/Carbidopa
• Reverse dopamine blockade
• Skeletal Muscle Relaxants
• Dantrolene
• Inhibits calcium release from sarcoplasmic
  reticulum
• Neuromuscular blockade

117
NEUROLEPTIC MALIGNANT SYNDROME

• Consider the diagnosis
• Institute prompt therapies
• Patient/family education
• Risk for recurrence

118
Comic Relief
119
CASE TWO

• 24 year old female brought in by family
• GCS 13/15
• HR 110/min BP 100/52 RR 12/min T 36C
• Able to indicate she took overdose
• Suicidal

120
CASE TWO

• What else do we need to know ??
• What do we need to do ??

121
CASE TWO

• What else do we need to know ??
• Who
• What
• When
• Where
• Why
• How
• How much ?

122
CASE TWO

• What do we need to do ??
• O2/IV/monitors
• A
• B
• C
• D
• Disability
• Decontaminate
• E
• Exposure
• Head to Toe Exam

123
CASE TWO

• Investigations
• CBC
• Electrolytes, BUN, creatinine
• Liver Function
• ASA, acetaminophen, ETOH
• Serum osmolality
• BHCG
• EKG

124
TRICYCLIC ANTIDEPESSANTS

• Wide usage
• Depression, sleep, chronic pain, enuresis
• Most prevalent in females
• Age prevalence 20-29 years
• 2-3 in hospital mortality
• 70 out of hospital mortality
• Biittner Dec 11 2001

125
TRICYCLIC ANTIDEPRESSANTS

• Pharmacokinetics
• Peak levels 2-6 hours post ingestion
• Highly lipophilic
• Crosses blood-brain barrier
• Large tissue levels
• Elimination hepatic oxidation
• Average t1/2 24 hours
• Up to 72 hours in overdose

126
TRICYCLIC ANTIDEPRESSANTS

• Toxicity
• 10mg/kg life-threatening
• 1 gram commonly fatal
• Desipramine
• Most potent sodium channel blocker

127
TRICYCLIC ANTIDEPRESSANTS

• Pathophysiology
• Antihistaminic
• Antimuscarinic
• Inhibit alpha-adrenergic receptors
• Inhibit amine uptake
• Sodium channel blockade
• Potassium channel blockade
• GABA receptor antagonist

128
TRICYCLIC ANTIDEPRESSANTS

• Physical Findings
• Confusion, hallucinations, seizures
• Hypotension
• Tachycardia
• Mydriasis
• Dry mucous membranes and skin
• Decreased bowel sounds
• Urinary retention

129
TRICYCLIC ANTIDEPRESSANTS EKG FINDINGS

• RAD of terminal 40 ms of QRS in limb leads
• Sign of TCA exposure and toxicity
• R wave in aVR 3mm or greater
• Sign of toxicity and potential adverse outcome
• AV blocks
• Bundle branch blocks
• J Emerg Med 1990 Sep-Oct 8(5) 597-605

130
TRICYCLIC ANTIDEPRESSANTSEKG FINDINGS

• Widening of QRS gt 100ms
• Predictor of adverse outcome
• Indication for treatment
• Seizure/Dysrhythmia risk
• QRSlt100ms low
• QRSgt100ms moderate
• QRSgt160ms high
• Tintinalli ( 5th Edition)

131
TRICYCLIC ANTIDRESSANTSEKG FINDINGS

• Normal
• Sinus Tachycardia
• Prolongation PR, QRS, QT intervals
• Ventricular dysrhythmias

132
TRICYCLIC ANTIDEPRESSANTSTREATMENT

• A
• B
• C
• D
• Decontaminate
• Charcaol
• Gastric Lavage

133
TRICYCLIC ANTIDEPRESSANTSTREATMENT

• Cardiovascular Agents
• Sodium Bicarbonate
• QRS gt 100 ms
• Dysrhythmias
• Cardiac arrest
• Hypotension
• Also
• Seizures
• Acidosis (pHlt7.0)
• J Emerg Med11336 1993

134
TRICYCLIC ANTIDEPRESSANTSTREATMENT

• Cardiovascular Agents
• Norepinephrine
• Beta 1 and Alpha agonist
• Dopamine
• Avoid Type Ia (quinidine, procainaminde,
  disopyramide) and Type IC (ecainide, flecainide,
  propafenone)
• Inhibit fast sodium channels

135
TRICYCLIC ANTIDEPRESSANTSTREATMENT

• Anticonvulsants
• Benzodiazepines
• Lorazepam
• Midazolam
• Diazepam
• Phenobarbital
• Seizures refractory to benzodiazepines
• Propofol
• Avoid Phenytoin

136
COMIC RELIEF

• .

137
CASE THREE

• 3 year old male brought in by his mother
• 8 hour history of intractable nausea and vomiting

138
CASE THREE

• History
• Visiting friends earlier in the day
• Acute onset completely asymptomatic prior
• No fever, no URI symptoms, no rash
• Multiple episodes of vomiting and diarrhea
• No Blood
• No travel history, infectious contacts
• Healthy
• Immunizations UTD
• No medications, allergies

139
CASE THREE

• REMEMBER
• Ask about potential toxicologic exposure
• Prescription medications
• Herbal preparations
• Vitamins
• Cleaners, detergents, solvents, paints
• Plants
• Etc.

140
IRON TOXICITY

• Leading cause of toxicologic deaths lt 6 years old
• Pediatr Ann 1996
• Pathophysiology
• Corrosive Toxicity
• GI tract
• Hypovolemia fluid and blood loss
• Cellular Toxicity
• Uncouples oxidative phosphorylation
• Mitochodrial dysfunction and cell death
• Liver significantly affected
• Also heart, lungs, kidneys, hematologic system

141
IRON TOXICITY

• Toxic Doses
• Non-toxic lt20 mg/kg
• Moderate 20-60 mg/kg
• Severe gt 60 mg/kg
• Lethal 180-300 mg/kg
• Peak Levels
• Chewable 4-6 hours
• Enteric coated erratic

142
IRON TOXICITY

• Maintain High Index of Suspicion
• Vomiting and diarrhea
• Especially hemorrhagic
• Hyperglycemia and metabolic acidosis
• During/following episode of abdominal pain and
  gastroenteritis

143
IRON TOXICITYPHYSICAL EXAMINATION

• Five Stages of Iron Toxicity
• Stage One
• 0-12 hours
• GI symptoms
• Abdominal pain
• Vomiting, diarrhea
• Shock
• /- Leukocytosis, Hyperglycemia

144
IRON TOXICITY

• Stage Two
• 6-24 hours
• Quiescent stage
• BEWARE !
• Stage Three
• 24-72 hours
• Multiple Organ Failure
• Altered LOC
• Respiratory failure
• Cardiovascular Collapse
• Liver Failure

145
IRON TOXICITY

• Stage Four
• 2-5 days
• Hepatic Failure
• Hypoglycemia
• Coagulopathy
• Stage Five
• Days
• Obstructions
• Gastric outlet
• intestinal

146
IRON TOXICITYLABORATORY INVESTGATIONS

• CBC, electrolytes, Bun, creatinine
• Glucose
• Liver function, PT, PTT
• ABG
• Lipase
• Type and Screen, Crossmatch
• Abdominal xray
• Iron is radiopaque

147
IRON TOXICITYLABORATORY INVESTIGATIONS

• Serum iron level
• 3 5 hours post ingestion
• lt 350 ug/dl minimal
• 350-500 ug/dl moderate
• 500 ug/dl severe
• Repeat at 6-8 hours
• Erratic absorption

148
IRON TOXICITYMANAGEMENT

• ABCs
• Fluid resuscitation
• Decontamination
• Charcaol
• Ineffective
• Whole bowel irrigation
• Exchange transfusion
• severe

149
IRON TOXICITYMANAGEMENT

• Deferoxamine
• Binds elemental iron
• 100mg to 9.35mg elemental iron
• 15 mg/kg/hr
• Renal excretion
• Urine turns vin rose color
• Infusion usually for 24 hours

150
IRON TOXICITY MANAGEMENTINDICATIONS FOR
DEFEROXAMINE

• Serum iron gt 500 ug/dL
• Rising serum iron levels
• Sustained GI symptoms
• Metabolic acidosis
• Hypotension
• J Toxicol Clin Toxicol 1996 34 (5) 485-89

151
Comic Relief
152
CASE FOUR

• 17 year old female
• Nausea, vomiting, diarrhea
• Blurred vision, seeing yellow and green halos
• Took grandmothers heart pills

153
CASE FOURINITIAL ASSESSMENT

• Monitored room
• O2/IV Monitor
• Vitals T 36 C, HR 50/min BP 90/60 RR 18/min
  O2 sats 96 room air
• EKG

154
EKG ON ARRIVAL
155
DIGOXIN TOXICITY

• First described in 1785
• Ellenhorns Medical Toxicology 2nd Ed 1997
  451-456
• Medication error and toxic effects account for
  44 of preventable cardiac arrests
• Digoxin most common
• JAMA 265 2815, 1991.

156
DIGOXIN TOXICITYPATHOPHYSIOLOGY

• Therapeutic effects
• Inhibits Na/K Pump
• Increase intracellular sodium and calcium
• Increase extracellular potassium
• Increases myocardial contraction
• Direct and indirect effects on SA and AV nodes
• Increase vagal and decrease sympathetic actvity
• Purkinje Fibers
• Slow phase 0 depolarization and conduction
  velocity
• Decrease action potential duration
• Enhanced automaticity
• Rosen 5th edition

157
DIGOXIN TOXICITYPATHOPHYSIOLOGY

• Toxic Levels
• Paralyze Na/K pump
• Hyperkalemia
• Depress generation of SA node impulses
• Decrease conduction through AV node
• Myocardium very sensitive
• Electrical and mechanical stimuli
• Virtually any dysrhythmia or conduction block
• Rosen 5th Edition

158
DIGOXIN TOXICITY CAUSES

• Acute overdose
• Deteriorating renal function, dehydration
• Electrolyte disturbances
• Toxic effects on Na/K pump
• Hyperkalemia most common exacerbant
• Acidosis
• Depresses Na/K pump
• Myocardial Ischemia
• Suppresses Na/K pump
• Alters myocardial automaticity
• Schreiber May 23 2001

159
DIGOXIN TOXICITYSYMPTOMS

• Constitutional Symptoms
• CNS
• Headache, confusion, dizziness, delerium,
  agitation, paresthesias, seizures (rare)
• CVS
• Palpitation, syncope
• Gastrointestinal
• Nausea, vomiting, anorexia, diarrhea
• Ocular
• Disturbances of color vision
• Tendency to yellow-green
• Halos and scotomas
• Blurred vision
• photophobia

160
DIGOXIN TOXICITY TREATMENT

• ABCS
• Decontamination
• In overdose
• Charcoal
• Correct electrolyte and acid-base disturbances
• Potassium, sodium, magnesium
• Calcium contraindicated unless profoundly
  hypocalcemic

161
DIGOXIN TOXICITYTREATMENT

• Atropine
• For bradydysrhythmias
• Pacing
• External may be safer than transvenous
• Irritable myocardium
• May induce tachydysrhythmias
• Clin Tox 31 261 1993

162
DIGOXIN TOXICITYTREATMENT

• Digoxin-Fab Fragments (Digibind)
• Digoxin-specific antibody fragments
• From IgG of sheep immunized with digoxin
• One vial 40 mg of digoxin-specific antibodies
• Doses
• Chronic Toxicity
• digoxin level (ng/mL) x weight (kg) / 100
  number of vials
• Acute Toxicity
• Amount ingested (mg) x 0.8 /0.5 number of vials
• Schreiber May 23, 2001

163
DIGOXIN TOXICITYTREATMENT

• Indication for Digitalis Antibody Fragments
• Severe ventricular dysrhythmias
• Hemodynamically significant bradydysrhythmias
• Unresponsive to atropine
• Serum potassium gt 5.0 mEq/L or rising levels
• Rapidly progressive rhythm disturbances
• Coingestion of cardiotoxic drugs
• B blockers, TCAs etc.
• Ingestion of plants containing cardiac glycosides
  plus dysrhythmias
• Acute ingestion gt 10 mg plus any of the above
• Level gt 6 ng/mL plus ant of the above
• Rosen 5th Edition

164
CHRONIC VERSUS ACUTE TOXICITY

• CHRONIC
• Higher mortality
• Potassium low/normal
• Ventricular dysrhythmias
• More common
• Usually elderly
• Often need Fab
• Underlying heart disease
• Increases morbidity and mortality

• ACUTE
• Lower mortality
• Potassium normal/high
• Bradycardia/AV block
• More common
• Usually younger
• Often do well without Fab
• Absence of heart disease
• Decreases morbidity and mortality

165
Case 5

• A 21-year-old female is brought to the ED by her
  boyfriend when he learned that she had ingested
  approximately 30 X 325 mg tabs of acetaminophen
  in an attempted suicide.
• He was unaware of any prior medical or
  psychiatric problems but reports that she was
  seen in another ED several days earlier for
  persistent headaches.
• The patient provided some history stating that
  she wanted to kill herself but denies any
  co-ingestion. She c/o stomach ache

166
Case 5

• On physical exam the patient was diaphoretic,
  pale and suffering from abdominal distress.
• VS BP 95/70 mm Hg P 100/min RR 20/min, and
  T98.6 F
• The exam was otherwise unremarkable except for
  mid-epigastric abdominal tenderness.
• She was given charcoal and a 4-hour
  acetaminophen level was 215 mcg/mL

167
APAP

• Name 4 metabolic pathways of APAP and the
  proportion of APAP metabolized by each pathway in
  a normal adult host with a therapeutic ingestion.

168
Metabolic pathways of APAP

• Hepatic glucuronide conjugation(40-65) 90
• Hepatic sulfate conjugation(20-45)
• ? inactive metabolites excreted in the urine.
• Excretion of unchanged APAP in the urine (5).
• Oxidation by P450 cytochromes (CYP 2E1, 1A2, and
  3A4) to NAPQI (5-15)
• ? GSH combines with NAPQI
• ? nontoxic cysteine/mercaptate conjugates
• ? excreted in urine.

169
(No Transcript)
170
Acetaminophen (APAP) Overdose

• Most absorption 2º, even after OD
• Peak concentration 4º then hepatic metabolism
• 90 elimination 3 routes conjugation w/
  gluconroide (40-67) or sulphate (20-46), or
  oxidation via CP450 or similar enzyme then
  conjugation
• Oxidation by CP450 or subfamily CYP2E1--gt very
  reactive electrophile NAPQI (aka
  N-acetyl-p-benzoquinoeimine)

171
Acetaminophen

• It is the toxic metabolite that causes liver
  injury
• See saturation of glucoronidation and sulfonation
  pathways (major pathways)
• Metabolism shifts to minor pathways cytochrome
  P450 metabolism requires glutathione, which
  depletes rapidly
• Toxic metabolite accumulates
• Direct hepatocellular toxicity

172
APAP level
Use the nomogram to help decide who needs
treatment Must be between 4-24 hours from single
acute ingestion of non-extended release product
173
4 stages APAP-induced Hepatic Injury post
ingestion

• Stage 1 pre-injury 1st 24º, no specific Sx
  N/V, anorexia, diaphoresis, malaise... common in
  1st 8º
• Stage 2 onset Liver injury 24º (12 to 36º after
  OD). If sever may be 8º N/V, RUQ/mid-epigastric
  pain
• Stage 3 Max liver injury 3-4 days. Sx vary
  fulminant hepatic failure encephalopathy, coma,
  coagulopathy, hypoglycemia, metab acidosis,
  haemorrhage, ARDS
• Risk renal injury ? 25 w/ severe toxicity vs. 2
  w/o hepatotoxicity

174
4 stages APAP-induced Hepatic Injury post
ingestion

• Stage 4 Recovery Liver Enzymes to baseline 5-7
  days, longer w/ severe injury. Histologicly-
  months
• Regeneration of liver is complete w/o chronic
  dys-fxn

175
Acetaminophen

• Toxic ingestion 140 mg/kg (7-10 g in adults)
• 4 hr level gt 140 potentially toxic
• N-acetylcysteine (NAC) Prevents binding of BNAPQI
  to heaptic macromolecules)
• May also reduce NAPQI back to acetaminophen
• Oral and IV preps available
• Safe in pregnancy
• Charcoal does not limit effectiveness
• Still indicated in presentations gt 24 hrs

NAC provides a cofactor needed to make inert
metabolites of APAP/Lack of this cofactor results
in the production of hepatotoxic intermediary
metabolites
176
APAP

• Tx with NAC if
• 4, 6 or 8h level above the R-M tx line ? full
  course NAC.
• If all levels are below the tx line and the 8h
  APAP level is less than 50 of tx line ? D/C home
  (NYPC).
• If the 8h APAP line is btw 50 of tx line and tx
  line ? NAC. for 24-36h and D/C once APAP lt10 or
  transaminases normal (NYPC).
• If the 6-hour level is greater than the 4-hour
  level, begin NAC therapy.
• More prolonged monitoring of levels may be
  necessary if the patient has food in the stomach
  or co-ingestants that delay gastric emptying.

177
APAP

• What percent of pts whose APAP level falls above
  the upper line of the Rumack-Matthew normogram
  will develop hepatotoxicity?
• (defined as elevation of the plasma
  transaminases above 1,000 U/L)

178
APAP pts w/ hepatotoxicity

• 60

179
Tx for Acetaminophen Toxicity

• N-acetylcysteine (NAC) serves as both glutathione
  precursor substitute
• NAC may ? NAPQI formation ? non-toxic sulfation
• NAC improves survival in pts w/
  acetaminophen-induced fulminant liver failure,
  even long after initial metabolism
• Possible MOA for survival benefit ? oxygen
  delivery/uptake by tissues, change in
  microcirculation, scavenging ROS ? cerebral
  edema

180
NAC

• Oral NAC
• The FDA approved oral dosing regimen is 140 mg/kg
  as the loading dose, then 70 mg/kg every 4 hours
  for 17 doses starting 4 hours after the loading
  dose.
• Oral NAC is irritating to the gastrointestinal
  track and should be diluted to a final
  concentration of no more than 5 to reduce the
  risk for vomiting.
• The oral form of NAC has an unpleasant odor and
  taste that can also affect compliance with
  administration.
• IV NAC (Acetadote)
• adult dosage regimen for the IV formulation is a
  loading dose of 150 mg/kg in 200 mL of 5
  dextrose given over 15 to 30 minutes. The
  maintenance dose follows at 50 mg/kg in 500 mL of
  5 dextrose given IV over 4 hours then 100 mg/kg
  in 1000 mL of 5 dextrose given IV over 16
  hours2.
• Adjustments are required for children and
  patientsat risk for fluid overload

181
Disposition

• Contact poison control center
• Fulminant Hepatic failure, need ICU, frequent
  Neuro checks, glucose measurements, VS monitoring
• Early contact Liver transplant center if Liver
  failure
• Serum PH lt 7.3 after resuscitation likely to die
  w/o transplant.

182
Last one
183
Case 6 Ill tell you if you tell me

• Setting Mid-March 2006 _at_ RAH ER, sidekick to Dr.
  Rabin, called to T3
• 61 yr old obese female who looks unwell, slumped
  in bed, with some increased work of breathing
• Patients eyes are closed, shes not answering
  questions, but responds to commands
• While trying to take some history, she states
  Ill tell you if you tell me

184
What did she just say?

• Your initial reaction is?
• 1. Here we go again- another patient for Kendra
  to laugh at me about
• 2. I bet shed open her eyes to look at me if I
  was Tom Griffin
• 3. Where the hell is Bob Moosally when you need
  him
• 4. This patient is sick and ?confused
  vitals, chemstrip, IV, O2, monitor.

185
Initial management

• Vitals T 37, HR 117, RR 26, BP 109/55,
• Sats 86 on RA, c/s 6.2
• Treatment
• O2 NRM
• IV NS TKVO
• Intubation kit at bedside
• Investigations
• CBC and diff, lytes, BUN, Cr, LFTs, Troponin,
  Lactate
• Toxicology Screen, serum osmolarity
• Blood culture urine cultures
• ABG
• ECG
• CXR (portable)

186
The story (the short version)

• Daughter-in-law states patient seldomly seeks
  medical attention
• Unwell X 3d with nausea and emesis and increasing
  SOB and WOB
• Big smoker, but not known to be ETOH/drug abuser
• Longstanding problems with sore back that she was
  taking Tylenol for with increased dosing over the
  last few days
• No history of trauma
• Brought her to hospital because today she was
  having trouble breathing, confused, slurring her
  speech, and ataxic

187
Deep thoughts?

• Preliminary DDx?
• COPD Exacerbation
• CNS problem
• Sepsis
• GI problem
• Toxidrome

188
More collateral

• SHx
• 1-3 ppd smoker/ 75 p.yr.hx
• No Etoh/recreational drugs

• PmHx
• COPD
• HTN
• DM II
• Low back pain