Intern Report 8.16

internreport

Case Discussion presented by Wissam Rhayem, MD

 

Chief Complaint:  “Chest Pain”

History of Present Illness:

This is a 26 y/o male prisoner presenting with a chief complaint of chest pain and palpitations.

The patient has a history of Wolff-Parkinson-White and poly-substance abuse. He states that he takes 20-40 mg of Xanax daily along with any Ativan, Klonopin, and Seroquel that he can obtain. The story is unclear, but the patient claims that he has been taking Xanax while in prison. The patient has been in prison for the last 9 days. He denies nausea, vomiting, headache, diarrhea, constipation, visual changes, fever, chills, or difficulty breathing.

Medications: Xanax 20-40 mg daily; Ativan; Klonopin; Seroquel; none are prescription

PMH: Wolff-Parkinson-White

Social History: + cannabis; + cigarettes; + alcohol weekly

 

Physical Exam:

VITALS: BP 127/80 HR 104 bpm T 36.1°C RR 16 bpm SpO2 98%

General: severe distress; agitated; not oriented

HEENT: pupils 3 mm; PERRL; EOMI; atraumatic

CV: regular rate and rhythm; no murmurs, rubs, or gallops

Pulmonary: breath sounds are clear bilaterally without rales, rhonchi or wheezing.

GI: soft, nontender, nondistended; no palpable masses

Musculoskeletal: no deformity; full ROM in all four extremities

Skin: no cyanosis; good perfusion in all four extremities; palpable pulses in all extremities

Neuro: not oriented; uncooperative; no focal deficits; normal deep tendon reflexes

Psych: uncooperative; agitated; labile mood; hostile; belligerent; pressured speech

Labs/Studies:

EKG: no delta wave; shortened PR interval; normal sinus rhythm

BMP: Na 139; K 4.0; Cl 104; CO2 30; BUN 11; Creatinine 0.99; Glucose 117

CBC: WBC 9.1; HgB 14.7; Hct 44.2; Plt 220

UDS: + BZDA; + cannabinoids

TROP: < 0.017 x 2

 

Medical Course:

While the patient is waiting for transfer to CDU,  his mental status begins to deteriorate. Now at 24 hours after initial presentation, he starts having visual hallucinations and becoming very agitated and delirious. He is demanding “footballs” and “candy bars.” The patient is screaming and is very verbally abusive. He is tugging violently at his restraints and is fighting to get out of bed. He does not respond to an initial 10 mg of IV Valium (diazepam). He is then given 10 mg, then 20 mg, then 40 mg, then 80 mg of IV Valium, each 5 minutes apart, until light sedation is achieved. At this point, he reports that his chest pain has resolved.

After about 90 minutes of sleep the patient sits straight up in bed, screaming for a urinal. The patient is now tachycardic and hypertensive. He is given a urinal and voids 900 mL of urine. Tachycardia and hypertension immediately resolve. He is noted to have tongue fasciculations and hand tremors at this time. He starts to become extremely agitated again and is given 20 mg, then 40 mg, then 80 mg, and then 160 mg of IV Valium each 5 minutes apart until he sleeps. A foley is placed to avoid further urinary retention.

Hospital pharmacy warns that they are running out of Valium. A propofol drip is then started. In the process of starting the drip, the patient becomes agitated again and requires 40 mg of IV Valium, followed by another 40 mg of IV Valium 5 minutes later. The drip is started at 20 mcg/kg/min. The patient is lightly sedated at this point, but continues trying to get out of bed. The drip is increased to 30 mcg/kg/min and the patient achieves light sleep. He is asleep soundly and snoring but responds to verbal stimuli. Saturations remain at 98% without supplementary oxygen. He is admitted to the MICU.

 

Questions:

1. Which of these is indicated in treatment of acute benzodiazepine overdose?

A. activated charcoal

B. gastric lavage

C. flumazenil

D. naloxone

E. supportive care

 

2. What are sequelae of benzodiazepine withdrawals?

A. agitation

B. seizures

C. hallucinations

D. nausea

E. all of the above

 

3. Which BZDA has a risk of propylene glycol poisoning when given IV for prolonged periods?

A. ativan/lorazepam

B. versed/midazolam

C. xanax/alprazolam

D. klonopin/clonazepam

E. onfi/clobazam

 

Bonus:

4. What is the approximate LD50 of Valium (diazepam)?

A. 1 mg/kg

B. 10 mg/kg

C. 100 mg/kg

D. 1000 mg/kg

E. unknown

 

Answers:

1. E

2. E

3. A

4. E

Discussion:

GOAL: The benzodiazepines are a class of medications that are critical to the armamentarium of emergency medicine physicians. In order to never harm a patient, it is important to touch up on some important facts and continue to think critically about the medication and the patient every single time one places an order for a benzodiazepine. Learning the short-term and long-term effects as well as the limitations of medications allows physicians to be more confident when using these medications.

1. Which of these is indicated in treatment of benzodiazepine overdose?

E. SUPPORTIVE CARE

We are taught in our didactic teachings and USMLE exams that Flumazenil is the antidote for benzodiazepine overdose. Yet, in the setting of the Emergency Department, there is relatively little utility to Flumazenil, for more than one reason. Primarily, Flumazenil has been known to lower seizure threshold in chronic Benzodiazepine users, and this is a risk that is just not worth taking when the patient rarely needs anything more than supportive care. Additionally, there is rarely a situation during which we can be fully confident that the patient we are treating has no other co-ingestions in addition to the benzodiazepines, and there are many documented cases in literature demonstrating seizures in patients with co-ingestions that receive Flumazenil.

There is no place for gastric lavage or activated charcoal in the treatment of benzodiazepine overdose. In fact, in treatment of benzodiazepine overdose without co-ingestion of another drug or alcohol, the patient is likely to benefit most from simple supportive therapy with IV fluids and airway protection. If the patient is not responding well, or requires a rapid return of mental status, such as in the case of accidental iatrogenic overdose, the patient may be treated with Flumazenil. Flumazenil may be given in boluses of 0.3 mg IV spaced at 5 minute intervals for a maximum of 3 mg/hr.

2. What are the sequelae of benzodiazepine withdrawals

E. ALL OF THE ABOVE

Benzodiazepines themselves work at the GABA receptors of cell membranes, allowing for an increase in opening frequency of the chloride ion channel, which hyper polarizes the cell, therefore causing an increased potentiation of the GABA neurotransmitter’s overall inhibitory properties. Therefore, sudden lack of the drug after prolonged use causes a hyperactive state so to speak. The patient may become incredibly agitated or aggressive, even psychotic. Patients can have hallucinations, seizures, insomnia, muscle spasms, and delirium.

3. Which BZDA has a risk of propylene glycol poisoning when given IV for prolonged periods?

A. ATIVAN/LORAZEPAM

Propylene glycol is used as a diluent in the formulation of IV preparations of both Ativan (lorazepam) and Valium (diazepam) to help dissolve the drug into the solution. The prolonged IV administration of either of these two drugs causes an increase in the concentrations of propylene glycol, which causes a constellation of symptoms of toxicity much like that of ethylene glycol. These begin with CNS depression, seizures, coma, and GI irritation. This can follow with tachypnea, pulmonary edema, tachycardia, hypertension, pneumonitis, or shock. Finally, the toxicity affects the kidneys, causing flank pain, hematuria, oliguria, or proteinuria. This can be fatal, and therefore avoiding the use of these two medications in prolonged IV administration is recommended.

4. What is the approximate LD50 of Valium (diazepam)?

E. UNKNOWN

It is true that this is truly unknown. Mice have an LD50 of ~700 mg/kg whereas rats have nearly ~1200 mg/kg. The important point is that Valium has an incredibly high therapeutic index of 1000:1, meaning the lethal dose is 1000 times higher than the effective dose. This is a comforting fact when administering such large doses as was given above. As patients are supportively monitored, there is often times recovery without permanent symptoms from acute intoxication. There are cases of acute ingestion of 2000 mg and 500 mg of diazepam with suicidal intent documented in case studies in 1978. The patients both fell into moderately deep comas but awoke with just supportive care and were discharged from the hospital within 48 hours of admission.

References:

Rapid Recovery From Massive Diazepam Overdose. David J. Greenblatt, MD; Elaine Woo, MD; Marcia Divoll Allen, RN; Paul J. Orsulak, PhD; Richard I. Shader, MD. JAMA. 1978;240(17):1872-1874.

Fatal seizures after flumazenil administration in a patient with mixed overdose. Haverkos, DiSalvo, Imhoff. Ann Pharmacother. 1994 Dec;28(12):1347-9.

Tox Time… Consult of the Week (COW)

COWj
Aimee Nefcy, MD
Fellow-in-training, Detroit PCC

 

The Bitter Truth

A 2 year old male was brought to the ER by family for decreased responsiveness. According to them, he was visiting Grandma’s house and had been seen in the back yard eating some red berries, a sample of which they have brought to the ER. He vomited once at home and then became rapidly lethargic. In the ER, he was initially unresponsive, then vomited twice and became agitated. He was bradycardic to 56 bpm and had a BP of 64/31. He was given atropine with improved vitals (117, 136/96). He was sedated, paralyzed, and intubated. Laboratory values were all within normal limits. In the ICU his BP was 90/45, HR 100. He was extubated after less than 12 hours. After extubation he had normal vital signs, but he remained drowsy yet agitated and confused. He had another episode of emesis, then improved. A photo of the plant was sent by the ER doc to the Toxicologist on call, and is shown here.

bitterj

 

1)    Ingestion of what type of plant should you worry about with a bradycardic, hypotensive, vomiting patient?

2)    What lab test available to the ER could be potentially helpful in diagnosing this?

3)    What tests are needed to determine the need for administration of a potential antidote?

4)    What is the plant shown here?

 

Answers:

1)    Digitalis-like plants, which commonly contain cardioactive steroids. The toxidrome for this extremely varied class of plants is identical for all: GI upset followed by bradycardia and cardiac dysrhythmias leading to cardiac arrest. Not all CAS’s are equipotent, however; eg, Convallaria majalis, Lily-of-the-valley, is relatively benign compared to Nerium oleander. Another consideration might be toxicity from organophosphate pesticides applied topically to the ingested plant, but sludge symptoms should be very prominent on exam.

2)    CAS’s in non-dig plants have some cross-reactivity with the digoxin assay, although the lab level does not correlate to the serum levels of the non-dig-CAS ingested. Children should have negative dig levels, and a detectable dig level is considered diagnostic of ingestion of a CAS.

3)    Additional labs needed to judge the severity of CAS toxicity include a potassium level (K>5 50% mortality, K>5.5 100% mortality without DSFab) and an EKG to evaluate for arrhythmias. Any of these, with or without symptomatic bradycardia, should prompt treatment with DSFab. DSFab has a limited ability to bind non-dig-CAS, therefore much larger doses are needed to treat a suspicious plant ingestion. Typically, 20-30 vials are needed depending on the severity of toxicity (compared to chronic digoxin needing 1-4 vials, and acute digoxin needing <10). Any CAS plant ingestion without GI symptoms, hyperkalemia, or EKG changes after 6hrs of observation in the ED can be cleared medically.

4)    Solanum dulcamara, known as woody or climbing nightshade, or bittersweet. This is a very common plant in Michigan, and is seen ubiquitously. The berries look and smell like little tomatoes and are seen in late summer to autumn. Solanine is the primary toxin, which has been shown in vitro to have acetylcholinesterase inhibition; there have been no reports of cholinergic toxicity, however. The primary toxicity is GI upset without CNS effects. The parts of the plant that are toxic are the leaves, fruits, stems, and shoots. This is in contrast to deadly nightshade, Atropa belladonna, which causes an antimuscarinic toxidrome.

Outcome: His symptoms were not felt to be consistent with this plant, which primarily causes GI upset. His dig level was negative. This patient’s sister had a history of being on carbamazepine, and he had detectable levels in his serum (thus depriving Aimee of her first-ever solanine-toxicity-causing-cholinergic-symptoms case report – so disappointed!). Within 24hrs of presentation he was back to baseline and was discharged with no permanent sequelae.

Recall that carbamazepine is a tricyclic anticonvulsant, and like other TCAs it tends to cause an antimuscarinic toxidrome with additional sodium-channel blockade. It is not clear why this patient was so bradycardic on presentation; possible confounders include coingestions, or maybe hypoxia from a seizure or aspiration.

COW A1.2

COW

*CASE OF THE WEEK*

HPI: 2-year-old boy with a history of eczema presents after a possible clonidine ingestion. The mother states that she put the child ton bed and upon checking on him later in the night, found him with an open pill bottle of 0.1 mg clonidine tablets. She apparently had left her purse reachable to the child. She is not sure if and how many pills the child ingested. Incident occurred at 11:00PM. The mother noticed the patient became lethargic and limp;  therefore, she brought him to the SG ED.

ROS: unable to obtain

PMH: Eczema

PSH: None

Meds: None

Social History: Lives at home with mother, shots UTD

Do you have a list of medications in the home?

Physical Exam

Blood pressure: 116/62, Pulse 123, Temperature 36.7, respiratory rate 20.

General:  Well nourished, Well developed, difficult to arouse with stimulation

Eye: Pupils are small, 2  mm, equal and reactive.

HENT:  Normocephalic, Atraumatic.

Respiratory:  Lungs CTA bilaterally.

Cardiovascular:  Tachycardic, S1 auscultated, S2 auscultated, No rub, No murmur, No gallop, Good pulses equal in all extremities, Normal peripheral perfusion, No edema.

Gastrointestinal:  Soft, Non-tender, Non-distended, Normal bowel sounds, No organomegaly.

Musculoskeletal:  Normal range of motion, No swelling, No deformity.

Integumentary:  Warm, Dry.

Neurologic:  Normal deep tendon reflexes, Not alert,  No clonus or other abnormal movements, Moving all four extremeties, Non focal exam.

LABS: 

ABG: 7.29/32/86/15

White count 6, hgb 10.9

APAP, salicylate undetectable

Electrolytes normal; What was the AG?

QUESTION 1:

ANSWER: G. Clonidine is a peripheral and central alpha 2 and imidazoline agonist that inhibits sympathetic outflow from the CNS leading to hypotension, bradycardia, and depressed mental status. In overdose, clonidine can initially cause peripheral vasoconstriction and hypertension due to peripheral alpha 2 agonism. The hypertension is usually asymptomatic and can last for many hours.   The hypertension  may be abruptly followed by hypotension. If in the rare instance hypertension needs to be controlled, phentolamine is the drug of choice. However, a short-acting calcium channel blocker may be utilized (more sound then an alpha blocker for an alpha agonist?). Beta 2 agonists (albuterol, clenbuterol) leads to vascular smooth muscle relaxation and cardiac stimulation leading to hypotension and tachycardia.  Adenosine antagonists (caffeine, theophylline) causes hypotension, tachycardia, and  seizures. Yohimbine is an alpha 2 antagonist (see answer to next question).

QUESTION 2:

ANSWER: B. Dexmedetomidine (Precedex ®) is a central alpha2 and imidazoline agonist that is increasing in popularitydue to its sympatholytic, analgesic, sedative properties, and its “lack of respiratory depression”.  High doses of dexmedetomidine lead to bradycardia, hypertension, and hypotension. Abrupt discontinuation of dexmedetomidine can lead to hypertension, tachycardia and agitation similar to a “clonidine withdrawal” syndrome.  Etomidate and thiopental are GABA agonists, propofol is a GABA agonist and NMDA antagonist, and ketamine is a pure NMDA antagonist.

QUESTION 3:

ANSWER: B.  Imidazolines agonize the  imidazoline receptor found presynaptically that reduces sympathetic outflow from the CNS. Technically, Imidazolines and clonidine both agonize alpha2 and imidazoline receptors and imidazoline receptors may be more responsible for hypotension.  ImidAZOLE-ring chemicals are found in antifungals (e.g. fluconazole) and midazolam. Methylxanthines (e.g. caffeine, theophylline) release catecholamines (leading to mostly B1 and B2 receptor agonism), antagonize adenosine (CNS stimulation and seizures), and inhibit phosphodiesterase.  Non-dihydropyridines (diltiazem and verapamil) are calcium channel blockers and will lead to hypotension and bradycardia, as will beta antagonists, but through a different mechanism than clonidine.

BONUS QUESTION 4:

ANSWER: C.  Yohimbine and tolazoline are alpha adrenergic antagonists. Case reports are conflicting about tolazoline’s effectiveness.  Aconitine is the toxin found in monkshood and acts as a sodium channel opener. Briefly, toxicity appears similar to digoxin toxicity with paresthesias and without hyperkalemia.  Cytisine is a nicotinic agonist found in the mescal bean, broom, and golden chain.  Cyproheptadine is an antihistamine,  serotinin antagonist, and antimuscarinic agent which is employed clinically for serotonin syndrome.

Hospital Course:

Upon arrival the patient was noted to be lethargic. Although the patient would respond to vigorous stimulation, the patient would become obtunded when not being stimulated. Thus, the patient was intubated for airway protection and sedated with ketamine and midazolam.  He was transferred to the Children’s PICU.

The patient was extubated the following day.  His lowest heart rate was 58. Blood pressure remained normal and stable.

TEACHING POINTS

  • Clonidine has been used for a variety of clinical purposes including: withdrawal treatment (opioids, etoh, benzos, and tobacco) and treatment of mania, ADHD, Tourette Syndrome, tics, hypertension, PTSD, motor spasticity, and rigidity from administration of large doses of opioid.
  • Other pharmacologically similar centrally acting alpha agonists include alpha-methydopa, guanfacine, tizanidine (Zanaflex ®) and guanabenz
  • Imidazolines are often employed as topical vasoconstrictors and more recently are used as antihypertensive agents (SEE TABLE BELOW)
  • Clonidine and dexmedetomidine not only stimulate alpha2 receptors presynaptically, but they also bind to imidazoline receptors.
  • Stimulation of alpha2 and imidazoline receptors, likely through various mechanisms, inhibit the release of noradrenaline and are often thought of as “sympatholytics”

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Presented by Dr. Andrew King. 

COW – Q 1.2

COW

*CASE OF THE WEEK*

HPI: 2-year-old boy with a history of eczema presents after a possible clonidine ingestion. The mother states that she put the child ton bed and upon checking on him later in the night, found him with an open pill bottle of 0.1 mg clonidine tablets. She apparently had left her purse reachable to the child. She is not sure if and how many pills the child ingested. Incident occurred at 11:00PM. The mother noticed the patient became lethargic and limp;  therefore, she brought him to the SG ED.

ROS: unable to obtain

PMH: Eczema

PSH: None

Meds: None

Social History: Lives at home with mother, shots UTD

Do you have a list of medications in the home?

Physical Exam

Blood pressure: 116/62, Pulse 123, Temperature 36.7, respiratory rate 20.

General:  Well nourished, Well developed, difficult to arouse with stimulation

Eye: Pupils are small, 2  mm, equal and reactive.

HENT:  Normocephalic, Atraumatic.

Respiratory:  Lungs CTA bilaterally.

Cardiovascular:  Tachycardic, S1 auscultated, S2 auscultated, No rub, No murmur, No gallop, Good pulses equal in all extremities, Normal peripheral perfusion, No edema.

Gastrointestinal:  Soft, Non-tender, Non-distended, Normal bowel sounds, No organomegaly.

Musculoskeletal:  Normal range of motion, No swelling, No deformity.

Integumentary:  Warm, Dry.

Neurologic:  Normal deep tendon reflexes, Not alert,  No clonus or other abnormal movements, Moving all four extremeties, Non focal exam.

LABS: 

ABG: 7.29/32/86/15

White count 6, hgb 10.9

APAP, salicylate undetectable

Electrolytes normal; What was the AG?

QUESTION 1:

QUESTION 2:

QUESTION 3:

BONUS QUESTION 4:

Presented by Dr. Andrew King. 

COW – answer 1.1

COW

*CASE OF THE WEEK*

You are working your first overnight shift at your new job right out of residency. Part of your contract is to cover a smaller satellite facility with limited resources that takes a steep dive at night.

The triage nurse rolls by your station with a young woman in a wheelchair. The nurse is moving with purpose, which makes you a little nervous. The patient is bent over and holding her abdomen. She holds an emesis basin on her lap.  It looks like there is a small amount of blood present.

She seems sleepy but arousable and is unable to give much of meaningful history.

The nurse gets her in bed and points to her gravid uterus. She grimaces and puts the patient on the monitor.

Her husband arrives. He says that she has been depressed and withdrawn recently, not sure why. She texted him an ambiguous farewell message a few hours ago. He hands you an empty bottle of prenatal vitamins.  He says that she just bought this a couple of days ago and is concerned that she took all of them.

ROS: Postive for abdominal pain and hematemesis, decreased mental status

PMHx:

Unknown

PSHx

Unknown

Meds:

? prenatal vitamins

SHx

Unknown

FHx

Unknown

Physical Examination:

P 110  BP 95/60  RR 12  T 36.5

Fetal heart tones are 135 bpm via bedside ultrasound

General: Young woman, lying in bed, fetal position, sleepy but arousable

HEENT: PERRL, EOMI, MMM

Neck: supple, no LAD

Heart: Tachycardic, clear S1 and S2. No murmurs. No extra heart sounds

Lungs: clear

Abdomen: Gravid uterus, about 30 cm from pubic bone

Extremities: Thready pulses. No c/c/e

Neuro: Sleepy. Follows commands. MAE x 4. Normal reflexes at knees and ankles. No rigidity.

LABORATORIES:

Na 138

K 3.4

Cl 108

HCO3 16

Glucose 168

WBC 16K

Hgb 9.8

Hct 29

Plt 233K

VBG 7.28/25/152

QUESTION #1: You are concerned about overdose. What component of the prenatal vitamin is most concerning?

A. Vitamin A
B. Folinic acid
C. Calcium
D. Iron
E. ascorbic acid

ANSWER: D. Because hypervitaminosis A can cause both toxicity in the mother and the fetus, prenatal vitamins are specifically formulated with reduced amounts of vitamin A.  Iron toxicity is the most concerning component of prenatal vitamins in overdose.

QUESTION #2: Which is not an indication for deferroxamine?

A. 2 hour iron level >300
B. 4 hour iron level >500
C. Metabolic acidosis
D. Lethargy/AMS

ANSWER: A. Deferroxamine should be considered in patient looks ill, has repetitive vomiting, lethargy, hypotension, metabolic acidosis, and an iron level >500 ug/dL. 4-6 Hour levels are preferred, however, iron poisoning is a clinical diagnosis. Clinicians should not rely on a single measurement and a normal iron level does NOT rule out toxicity.

QUESTION #3: What are potential adverse reactions of deferroxamine?

A. Discolored urine
B. Hypotension
C. ALI/ARDS
D. Ototoxicity
E. A and B
F. B and C
G. All of the above

ANSWER: F.  Deferoxamine chelates free iron throughout the body and minimizing disruption of oxidative phosphorylation and improves metabolic acidosis. Interestingly, deferoxamine does not chelate a large amount of iron; however, the small amount of free iron it does chelate leads to significant clinical improvement. Chelation of iron creates ferrioxamine and is eliminated by the kidneys. Ferrioxamine SHOULD cause a reddish color of the urine (so-called vin-rose urine). Deferoxamine should be started, titrated up, and continued while the patient remains ill.  Hypotension is rate-related. Cases of ALI and ARDS are usually described in those with prolonged therapy (>36-72 h of therapy).

History:

  • In the 1990s iron was the leading cause of poisoning deaths, at least reported to the Poison Center, among children < 6.
  • Ironically, this paralleled an effort to be more vigilant in prescribing prenatal iron
  • FDA required warning labels, blister packaging and limits on the # of pills dispensed
  • The requirement of industry to use blister packs have been subsequently overturned.

Pharmacology

  • Because iron is a transition metal, it can accept and donate electrons relatively easily and this feature is utilized in many biochemical process, most notably in the electron transport chain, myoglobin and hemoglobin.
  • The body cannot actively excrete iron, therefore, total body iron is regulated by absorption.
  • In iron-deficient states, iron uptake by the duodenum can increase to 95%.
  • In therapeutic dosing, certain functions are saturated and further uptake is limited, however, in overdose, oxidation and disruption of the GI mucosa allows iron to be absorbed by its concentration gradient.
  • Toxicity depends on the amount of ELEMENTAL IRON anticipated to be absorbed.
  • Calculating the amount of elemental iron in a given supplement depends on the molecular weight of the compound. See the table below for the percent elemental iron per formulation (Adapted from Goldfrank’s Chapter 40, table 40-1).
Formulation % elemental iron
Ferrous chloride 28
Ferrous fumarate 33
Ferrous gluconate 12
Ferrous lactate 19
Ferrous sulfate 20
  • Chewable vitamins tend to have lower concentration of elemental iron (10-18 mg) per tablet when compared to prenatal vitamins (65 mg) and, accordingly, fatalities have not been reported.

Pathophysiology:

  • Iron generates oxidative stress via the Fenton reaction and the Haber-Weiss cycle.

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  • These reactive oxygen species oxidize membrane lipids and damage GI epithelium.
  • Once absorbed, iron binds to circulating proteins, mainly transferrin
  • Once saturated, “free” iron is free to distribute to the various organs.

Free iron leads to metabolic acidosis by two main mechanisms:

  1. Disruption of ox-phos (buffer lost, usual H+ not incorportated into ATP)
  2. Ferric iron + 3H2O à Fe(OH)3 + 3 H+

Clinical Manifestations:

  • AS A MEMORY TOOL ONLY, you can think about the clinical manifestations in 5 stages:

Stage 1: GI distress from local tissue damage in the gut. Gi bleeding, bowel necrosis and hemodynamic instability.  Without vomiting in the first 6 hours, UNLIKELY TO GET SICK

Stage 2: “latent stage”.  GI symptoms have resolved  but develop AMS, metabolic acidosis,  and tachycardia.  THEY WILL APPEAR ILL.

Stage 3: “Shock stage” Coagulopathy, seizures, coma.

Stage 4: Hepatic failure

Stage 5: Chronic issues: GI scarring and stricture

Testing:

  • NOT ALL FORMULATION ARE RADIOPAQUE
  • Liquid and chewable formulations often will not show up on plain radiography
  • Follow electrolytes, ABG or VBG, lactate, coags, WBC (may suggest toxicity), APAP/Salicylate, EKG

DIAGNOSIS:

  • Diagnosis remains clinical
  • Peak iron levels are thought to occur between 2-6 hours post ingestion
  • Serum [Fe] 300-500 à GI and moderate systemic toxicity
  • Serum [Fe] 500-1000 à severe systemic toxicity and shock
  • Serum [Fe] >1000 à high likelihood of death
  • MUST FOLLOW SEQUENTIAL LEVELS, NOT A RULE OUT TEST
  • TIBC (total iron binding capacity) and ferritin are not useful, may lead to confusion, and not recommended

MANAGEMENT:

  • ABCs
  • IV fluids
  • Whole bowel irrigation
  • For patients with retained iron despite WBI may require EGD and/or surgical removal
  • Antidotal therapy

DEFEROXAMINE

  • Deferoxamine + Fe3+ à ferioxamine à Excreted by kidneys
  • Consider treatment if patient looks ill, has repetitive vomiting, lethargy, hypotension, metabolic acidosis, iron level >500 ug/dL
  • Intravenous administration should be increased to 15mg/kg/h.
  • Continue therapy until patient is clinically well.
  • Could consider dialyzing at the same time (animal studies exist)
  • ADVERSE EFFECTS:
  • Hypotension is rate-limiting factor
  • ALI and ARDS
  • PREGNANCY IS NOT A CONTRAINDICATION

Dispo:

  • AAPC guidelines are as follows
  • >40 mg/kg adult formulation or severe or persistent symptoms (alterations in level of consciousness, hematemesis, and bloody diarrhea, persistent vomiting), refer to ED (use pre-pregnancy weight for pregnant women)
  • All children’s chewable vitamins manage at home unless persist vomiting/diarrhea warrant IV fluids
  • All patients with carbonyl iron or polysaccharide-iron complex remain at home
  • Observe for six hours; if asymptomatic à home
  • Otherwise, admit

For pregnant patients: TREAT MOTHER as above.

COW – v1.1

COW

*CASE OF THE WEEK*

You are working your first overnight shift at your new job right out of residency. Part of your contract is to cover a smaller satellite facility with limited resources that takes a steep dive at night.

The triage nurse rolls by your station with a young woman in a wheelchair. The nurse is moving with purpose, which makes you a little nervous. The patient is bent over and holding her abdomen. She holds an emesis basin on her lap.  It looks like there is a small amount of blood present.

She seems sleepy but arousable and is unable to give much of meaningful history.

The nurse gets her in bed and points to her gravid uterus. She grimaces and puts the patient on the monitor.

Her husband arrives. He says that she has been depressed and withdrawn recently, not sure why. She texted him an ambiguous farewell message a few hours ago. He hands you an empty bottle of prenatal vitamins.  He says that she just bought this a couple of days ago and is concerned that she took all of them.

ROS: Postive for abdominal pain and hematemesis, decreased mental status

PMHx:

Unknown

PSHx

Unknown

Meds:

? prenatal vitamins

SHx

Unknown

FHx

Unknown

Physical Examination:

P 110  BP 95/60  RR 12  T 36.5

Fetal heart tones are 135 bpm via bedside ultrasound

General: Young woman, lying in bed, fetal position, sleepy but arousable

HEENT: PERRL, EOMI, MMM

Neck: supple, no LAD

Heart: Tachycardic, clear S1 and S2. No murmurs. No extra heart sounds

Lungs: clear

Abdomen: Gravid uterus, about 30 cm from pubic bone

Extremities: Thready pulses. No c/c/e

Neuro: Sleepy. Follows commands. MAE x 4. Normal reflexes at knees and ankles. No rigidity.

LABORATORIES:

Na 138

K 3.4

Cl 108

HCO3 16

Glucose 168

WBC 16K

Hgb 9.8

Hct 29

Plt 233K

VBG 7.28/25/152

QUESTION #1: You are concerned about overdose. What component of the prenatal vitamin is most concerning?

A. Vitamin A
B. Folinic acid
C. Calcium
D. Iron
E. ascorbic acid

QUESTION #2: Which is not an indication for deferroxamine?

A. 2 hour iron level >300
B. 4 hour iron level >500
C. Metabolic acidosis
D. Lethargy/AMS

QUESTION #3: What are potential adverse reactions of deferroxamine?

A. Discolored urine
B. Hypotension
C. ALI/ARDS
D. Ototoxicity
E. A and B
F. B and C
G. All of the above

Toxicology

Musings On Charcoal

By Dr. Bram Dolcourt

Recently I’ve gotten a few “Huh?” thrown my way when I tell people that…

I am actively discouraging the routine use of charcoal for acute overdoses.

The teaching has generally been to give charcoal in the face of an overdose. To many, what I’m saying is a bit surprising. Believe it or not, the American Academy of Clinical Toxicology recommends against routine charcoal use. I thought I’d write a few musings about how and why we recommend using it when we do.

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The theory: Activated charcoal has a very high surface area. It will bind and hold a drug (xenobioic), preventing absorption. This will reduce the delivered dose to the patient and reduce toxicity.

Reality: There is very little evidence for the use of activated charcoal. It is occasionally useful and has potential for morbidity. Few patients who claim to have overdosed on a xenobiotic benefit from charcoal.

Who should get it?

For the undifferentiated intoxicated patient, charcoal should only be considered early in the ingestion. Generally, charcoal needs to make physical contact with the xenobiotic in order to absorb it. Once past the pylorus, the chance that charcoal will mix with the xenobiotic is fairly low. The stomach usually empties within 1 hour, although it may be as long as 2. Liquid preparations are absorbed too quickly for charcoal to have significant absorption.stomach

Some xenobiotics may reduce GI motility and prolong the useful window for charcoal. A few authors recommend giving charcoal up to 4 hours post-ingestion. While there is no specific evidence, what is clear is that to have a beneficial effect, charcoal needs to be given early in the ingestion for a non-liquid preparation, generally within 1-2 hours and certainly not beyond 4 hours.

That time frame is for the general case.  There are two other mechanisms of action that allow for alternate dosing for charcoal. First, some xenobiotics are reabsorbed and excreted into the bile (enterohepatic recirculation) or into the stomach (enterogastic recirculation). Charcoal can interrupt this recirculation and reduce the elimination half-life. Secondly, just as dialysis uses a membrane to separate substances from blood, the gut lumen can be used as a membrane to separate substances from blood. Amenable xenobiotics will cross from the blood, across the gut, into charcoal on the enteric side.

There is good evidence for using charcoal for 5 drugs: phenobarbital, carbamzepine, theophyllne, dapsone and qunine (quinidine). These are “Category A drugs.” For these xenobiotics the elimination half-life is reduced when charcoal is given.  Multiple doses of charcoal can further increase the elimination rate for these drugs.

Multidose charcoal works for other xenobiotics, although the evidence is not as good (these are not called Category B drugs, BTW). Phenytoin, glipizide, aspirin (in high concentration), valproic acid, cyclosporine, amitriptyline, and colchicine are all potentially amenable to multidose charcoal.

How much should I give?

Several authors recommend giving 1 g per kg of charcoal, orally. Following this recommendation means that a child who ingests grams of a potentially lethal xenobiotic will receive less charcoal than an adult who eats a few milligrams of something moderately toxic. When placed in that context, it becomes clear the appropriate dose of charcoal should be in relation to the amount of the xenobiotic ingested, with the gram per kilogram being a ceiling dose.

Realistically, you want a 10:1 ratio, gram per gram, of charcoal to xenobiotic for optimal absorption. More is not helpful. Many patients only need a few mouthfuls of charcoal, as opposed to 50 or 100 grams. Consider a digoxin overdose; even for a massive ingestion of 100 tablets, one would likely only need to give 1.25 g of charcaol, which translates to about 6 ml. For a similar ingestion of amlodipine, one would only need to give approximately 50 ml of charcoal, or about 1/5 of the standard dose. It is very clear that we are giving most patients far too much charcoal.

For multidose charcoal, the dosage is less clear. Typically we recommend ½ gram per kg, up to 25 grams, ever 4 hours. This recommendation goes against what I said above. This is probably more than is necessary, however as the indications for multidose charcoal are quite different, we can get away with it.

Why wouldn’t I give charcoal?

All people aspirate to some degree, every day. Usually this isn’t a big deal as it is a small amount. However, in the face an altered mental status or vomiting, people aspirate more. A nasogastric tube also may worsen the risk, as the lower esophageal sphincter is held open. An endotracheal tube may reduce, but does not eliminate, aspiration. The sepsis literature is quite clear that intubated patients still aspirate and I can certain attest to suctioning charcoal out of the ET of many intubated patients.

Charcoal is mostly benign, however it may cause a pneumonitis when aspirated. The additional of sorbitol may worsen the pneumonitis. Charcoal comes in a significant volume; 50 grams of charcoal is usually in 240 ml of total volume. Rapidly instilling this volume can trigger vomiting due to stomach distention. While you want the charcoal to go in as early as possible, rapidly squirting it down an NG tube, can be counter productive and result in respiratory compromise.

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A second and unusual complication may result from too much or two frequent multidose charcoal. In the setting of an ileus, multidose charcoal has resulted in charcoal bezoars. The charcoal was, effectively, compressed into briquettes, inside the gut lumen, resulting in obstruction.

The last complication comes from the sorbitol that is packaged with some charcoal. As there is little evidence for the benefits of using charcoal, there is even less for adding sorbitol (or any cathartic). The idea is that sorbitol increases transit time, removing the xenobiotic more quickly. Sorbitol also increases the total water content of the charcoal stool and may reduce the already small risk of a charcoal bezoar, but is of unproven benefit.

The issue comes about from inducing diarrhea and causing depletion in total body water and electrolytes. One of the ways a xenobiotic kills is by causing cardiovascular collapse. Inducing volume depletion, by osmotically drawing water into the gut, may worsen an already sick patient’s cardiovascular status. Electrolytes travel with water, resulting in an electolyte disturbance. Pediatric patient have developing severe metabolic disturbances from multiple doses of charcoal with sorbitol. Other decontamination strategies, such as urine alkalinization rely on a normal electrolyte profile, and charcoal with sorbitol may actually be counter-productive.

Tell me when I should use charcoal!

Like any drug, the astute clinician must weigh the risks and benefits of charcoal. First and foremost, a clinician needs to consider the lethality and potential morbidity associated with an overdose. Good supportive care has saved more lives than charcoal ever will. I may be so bold as to say that no one has every lived or died purely because of the prompt or lack of application of charcoal. What charcoal may do is moderate toxicity. For a non-lethal or unlikely to be lethal overdose, charcoal may not be needed. For a very lethal overdose, charcoal may reduce the toxicity so that very aggressive and attentive care could save the patient’s life.

Second, the clinician needs to examine the alternate therapies available. If there is a very good antidote or treatment available, charcoal is unlikely to add any benefits; the patient is going to fine either way.

Third, the clinician needs to consider how well the xenobiotic binds to charcoal. For any of the Category A drugs or the other listed medications, charcoal should be strongly considered as toxicity can be reasonably modulated. For metals, such as iron, or electrolytes, such as lithium, there is no potential benefit. For all others, the benefit is questionable.

Finally, patient factors need to be considered. A patient who is unconscious with a tenuous airway, there is a significant risk of charcoal aspiration; especially as an NG tube is needed. An aspiration and charcoal pneumonitis may be worse than the effects of the xenobiotic. Other patient factors to keep in mind: GI anatomy (bariatic surgery), age, co-operation (restraining and forcing down an NG tube on an agitated patient can be problematic), etc.

Can you give me some examples of what you would do?

Keep in mind that these are made up examples and may not encompass all issues, but here goes:

1)            A young patient presenting 1-hour post ingestion of 10-20 tablets of extra strength acetaminophen.

This patient is a possible candidate for activated charcoal. The patient is presenting early and doesn’t have any obvious contraindications.  This would be a 10 gram ingestion, thus using the 10:1 ratio, you would like to give 100 grams of charcoal, but probably can’t due to patient weight. The charcoal may prevent the patient from crossing the “possible toxicity” line on the Rumack-Matthew’s Nomogram, thus you may be able to prevent an admission. This ingestion is unlikely to be lethal and there is a very good antidote, so charcoal is probably not going to reduce morbidity or mortality.

2)            A young patient with a large ingestion of carbamazepine. The patient is sleepy.

I would give this patient charcoal at any point during the ingestion and I would repeat doses every 4 hours. Carbamazepine is a Category A drug and very amenable to charcoal. It is also cardiotoxic, with significant risk for lethality. On the minus side, carbamazepine decreases mental status. The patient’s airway will need to be watched, but this patient will likely benefit from multidose activated charcoal.

3)            A patient presents 1 hour after taking 10-20 risperidone tablets

This patient is not likely to benefit from charcoal and there is potential risk for harm. This is not likely to be lethal ingestion, and if it is, it will be from respiratory compromise or aspiration. Abnormal vitals and other derangements respond well to supportive care. Risperidone is a respiratory depressant, thus this patient may lose the airway with a full stomach, risking aspiration.

4)             A patient who was found down after binging on diazepam and alcohol.

Charcoal is probably not indicated for this patient. This patient is not presenting early and will likely get very little, if any, benefit from charcoal. The patient has a decreased mental status with significant risk of vomiting and aspiration. As long as the patient is breathing, and the airway protected, s/he is at little risk of morbidity or mortality. Endotracheal intubation would likely be the optimal strategy for a patient presenting like this, who needs intervention.

Final thoughts…

Charcoal can be beneficial, but is not the end all treatment for the intoxicated patient. It should be given, not as a reflex, but after careful thought, articulating the expected benefit. The dose should be 10:1 ratio of charcoal to xenobiotic. Charcoal should be avoided when the ingested xenobiotic is not expected to cause morbidity or mortality after other care. The risk/benefit ratio of charcoal needs to be assessed in the context of patients with factors that may predispose to aspiration.

Dr Bram Dolcourt is an Assistant Professor in the Department of Emergency Medicine at Wayne State University in Detroit, MI.  He completed a fellowship in Toxicology in 2009