UMEM Educational Pearls - By Bryan Hayes

Pathophysiology: Angiotensin converting enzyme (ACE) catalyzes the conversion of angiotensin I to angiotensin II.  It also degrades bradykinin.  Thus, ACE inhibitors have the effects of decreasing angiotensin II and increasing bradykinin.  In the presence of ACE inhibition, bradykinin can accumulate and interact with vascular bradykinin B2 receptors, causing vasodilation, increased vascular permeability, increased c-GMP, and release of nitric oxide.

Treatment: Even though we generally treat with standard allergic reaction medications, none counteract the mechanism causing the problem.  Steroids, H1-blockers, and H2-blockers should still be considered but may not alter the progression.  Airway monitoring and management is paramount.

Several patients have recently presented with a medication history including tapentadol (Nucynta), the newest opioid formulation.  It is approved for treatment of acute moderate-severe pain.  Here are some key points:

• Mechanism similar to tramadol: mu-receptor agonist, also inhibits norepinephrine reuptake
• Potency stronger than tramadol, but less then morphine
• Usual dose is same as tramadol 50-100 mg every 4-6 hours prn pain
• Schedule II controlled substance, similar to morphine/oxycodone (tramadol is not a controlled substance)
• Overdose should present like other opioids, but potentially also including tachycardia, serotonergic effects, and seizures (similar to tramadol)

Kiwi fruit and latex share several antigens in common.  Thus, individuals who are allergic to either kiwi or latex may also suffer hypersensitivity reactions to the other material.

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For patients with normal renal function, enoxaparin dosing for treatment of VTE is 1 mg/kg subcut every 12 hours OR 1.5 mg/kg subcut every 24 hours.

Studies have evaluated dosing for patients weighing up to 190 kg and found the 1 mg/kg q 12 hours dose to be safe and effective.  It can even be used for patients heavier than 190 kg, but anti-Xa monitoring is recommended.

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Several medications/chemicals can cause unique toxicologic reactions in pediatric patients.

• Ethanol: hypoglycemia.  Reported with ethanol levels as low as 20 mg/dL.
• Clonidine and imidazolines: central nervous system effects.  Agents such as tetrahydrozoline, oxymetazoline, naphazoline, and clonidine can cause CNS depression, respiratory depression, bradycardia, miosis, and hypotension.
• Benzyl alcohol: gasping syndrome.  Preservative which has been removed from most medications and IV flush solutions used in neonates.  Syndrome includes severe metabolic acidosis, encephalopathy, respiratory depression, and gasping.
• Chloramphenicol: gray baby syndrome.  Broad-spectrum antibiotic not used frequently in U.S.  Syndrome includes abdominal distension, vomiting, metabolic acidosis, progressive pallid cyanosis, irregular respirations, hypothermia, hypotension, and vasomotor collapse.

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Sulfamethoxazole (SMX)/trimethoprim (TMP) is the treatment of choice for PCP pneumonia. The IV formulation has been unavailable for almost a year due to shortage. It is contraindicated in patients with sulfa allergy. Here are the alternatives with adverse effects. You'll quickly see why pentamidine should generally be reserved for those with sulfa allergy and G6PD deficiency.

Mild-to-moderate disease:

1. Primaquine 15-30 mg PO PLUS Clindamycin 600 mg IV or 300-450 mg PO
2. Dapsone 100 mg PO PLUS TMP 5 mg/kg PO
3. Atovaquone suspension 750 mg PO

Moderate-to-severe disease:

1. Primaquine 15-30 mg PO PLUS Clindamycin 600 mg IV or 300-450 mg PO
2. Pentamidine 4 mg/kg IV

Adverse Effects:

• Primaquine: Rash, fever, methemoglobinemia, hemolytic anemia (check for G6PD deficiency)
• Clindamycin: Rash, diarrhea, Clostridium difficile colitis, abdominal pain
• Dapsone: Rash, fever, gastrointestinal upset, methemoglobinemia, hemolytic anemia (check for G6PD deficiency)
• TMP: Rash, gastrointestinal distress, transaminase elevation, neutropenia
• Atovaquone: Rash, fever, transaminase elevation
• Pentamidine: Nephrotoxicity, hyperkalemia, hypoglycemia, hypotension, pancreatitis, dysrhythmias, transaminase elevation

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Many consider Paracelsus (1493–1541) as the father of modern toxicology.

• He was the first to emphasize the chemical nature of toxic agents.
• He stressed the need for proper observation and experimentation regarding the true response to chemicals.
• He underscored the need to differentiate between the therapeutic and toxic properties of chemicals when he stated in his Third Defense, "What is there that is not poison? All things are poison and nothing [is] without poison. Solely, the dose determines that a thing is not a poison."

The introduction of the dose–response concept might have been his most important contribution to toxicology, meaning that everything is toxic at the right dose (even oxygen and water).

Many patients report an allergy to iodinated RCM, sometimes adding to the complexity of diagnostic decision making.  Here are a few pearls to help:

• Seafood or shellfish allergy is NOT a risk factor for IHR to RCM
• Iodine and iodide are small molecules that do NOT cause anaphylactic or anaphylactoid reactions
• Life-threatening reactions occur in only 0.004 to 0.04 percent of nonionic low osmolality RCM infusions
  • Our radiology department uses primarily iohexol (Omnipaque) for IV contrast with a low osmolality of 844
  • Iodixanol (Visipaque) is the iso-osmotic alternative with an osmolality of 290

Bottom line: Despite the lack of cross reactivity with shellfish/iodine allergies AND the very low risk associated with today’s low osmolality agents, premedication is still indicated in patient’s with a history of IHR to RCM.

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The Rumack-Matthew nomogram is a well studied and validated tool to help assess the potential for liver toxicity following acute acetaminophen poisoning.  Here is a brief review of when it is best utilized.

• Prior to 4 hours post-ingestion: Not helpful to determine likelihood for toxicity.  Only use is to confirm an ingestion took place.
• Between 4 and 24 hours post-ingestion: Plot the patient's level vs. time after ingestion.  If above the toxicity line, treat with acetylcysteine.
• More than 24 hours post-ingestion: Any elevated acetaminophen level is toxic and should be treated with acetylcysteine.

Outside-the-box situations:

• Chronic exposures: Nomogram not indicated.
• Overdoses with co-ingestants that slow GI motility (e.g., opioids, diphenhydramine) OR extended release products (e.g., Tylenol Arthritis): If the level at 4 hours post-ingestion is not toxic, repeat it at 8 hours post-ingestion.  If either level is toxic, treat with acetylcysteine.

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Most cases of normal anion gap metabolic acidosis result from either urinary (RTA) or gastrointestinal HCO₃^- losses (diarrhea).  A number of xenobiotics can also cause this disorder:

1. Acetazolamide
2. Acidifying Agents: Ammonium chloride, arginine hydrochloride, hydrochloric acid, lysine hydrochloride
3. Cholestyramine
4. Toluene
5. Topiramate (Topamax)

• Ingestion of concentrated hydrogen peroxide (H2O2) has been associated with venous and arterial gas embolic events, hemorrhagic gastritis, gastrointestinal bleeding, shock, and death.
• Although H2O2 is generally considered a benign ingestion in low concentrations (OTC is 3%), case reports have described serious toxicity following high concentration exposures.
• Hyperbaric oxygen (HBO) has been used with success in managing patients suffering from gas embolism with and without manifestations of ischemia.
• A recent poison center case record review confirmed previous findings.
  • It identified 11 cases of portal gas embolism. In 10 cases 35% H2O2 was ingested and in 1 case 12% H2O2 was ingested. All abdominal CT scans demonstrated portal venous gas embolism in all cases. Hyperbaric treatment was successful in completely resolving all portal venous gas bubbles in nine patients (80%) and nearly resolving them in two others. Ten patients were able to be discharged home within 1 day, and one patient had a 3.5-day length of stay.
• Bottom Line: In a patient with a history of hydrogen peroxide ingestion, have a low threshold for CT scan.  HBO therapy is an effective treatment modality.

French LK, et al. Hydrogen peroxide ingestion associated with portal venous gas and treatment with hyperbaric oxygen: a case series and review of the literature. Clinical Toxicology 2010;48:533–38.

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Emerging evidence supports using intravenous fat emulsion (Intralipid) therapy for various drug overdoses, particularly those that are lipophilic.  Within seconds to minutes of administration, toxic cardiovascular effects are reversed, including return of spontaneous circulation in cardiac arrest patients.  Central nervous system effects also tend to improve.

Lipophilic agents for which there has been success include:

• Calcium channel blockers (verapamil, diltiazem, amlodipine)
• Beta blockers
• Bupropion
• Quetiapine
• Lamotrigine
• Sertraline
• TCA's
• Diphenhydramine

Bottom line: Consider intralipid therapy early in the course of a hemodynamically unstable patient with suspected overdose.  Give a bolus of 1.5 mL/kg of 20% lipid emulsion over 1-2 minutes.

In the setting of acute cyanide poisoning, it is virtually impossible to obtain a timely cyanide level to help assess toxicity.  However, there are two diagnostic tests that can help confirm your diagnosis.

1. Anion gap metabolic acidosis with elevated lactate
2. Narrowing of the venous-arterial PO₂ gradient

Remember cyanide halts cellular respiration meaning the cells cannot utilize oxygen.  Therefore, the venous PO₂ should be about the same as the arterial PO₂.  The cells then switch to anaerobic metabolism, thereby producing lactate.

If benzodiazepines and supportive care fail to improve agitation and correct vital signs, several case reports indicate the successful use of cyproheptadine, an antihistamine with nonspecific antagonist effects at 5-HT_1A and 5-HT_2A receptors.

Cyproheptadine is available in 4 mg tablets or 2 mg/5 mL syrup. When administered as an antidote for serotonin syndrome, an initial dose of 8-12 mg is recommended, followed by 2 mg every two hours until clinical response is seen. Cyproheptadine is only available in an oral form, but it may be crushed and given through a nasogastric tube.

Cyproheptadine may lead to sedation, but this effect is consistent with the goals of management. It may also produce transient hypotension due to the reversal of serotonin-mediated increases in vascular tone. Such hypotension usually responds to IV fluids. Cyproheptadine is rated category B for safety in pregnancy by the FDA.

In a patient with toxin-induced bradycardia and hypotension, here is a quick differential to help identify the responsible substance:

• Beta blockers
• Calcium channel blockers
• Cholinergics
• Clonidine (and other alpha-2 agonists)
• Digoxin (and other cardiac glycosides)
• Opioids
• Sedative hypnotics (such as benzodiazepines and barbiturates)

Less commonly seen causes include: magnesium, propafenone, and plant toxins (aconitine, andromedotoxin, veratrine).

Physostigmine has been used extensively in the fields of anesthesiology and emergency medicine.  The only use of physostigmine with sound scientific support is for the management of patients with an anticholinergic syndrome, particularly those without cardiovascular compromise who have an agitated delirium.  In this population, physostigmine has an excellent risk-to-benefit profile.

• Try benzodiazepines first.  They last longer and may diminish the need for physostigmine.
• Obtain ECG.  If there are signs of sodium channel blockade (QRS prolongation), do not use physostigmine.
• Administer 1-2 mg via slow IV push/infusion over at least 5 minutes.
• Have atropine available at the bedside.
• Effects last about 1 hour.

We are all familiar with the classic ECG abnormalities caused by the sodium channel blocking properties of tricyclic antidepressants (QRS interval widening, R wave in aVR, S wave in I and aVL, and rightward deviation in terminal 40 msec of QRS). Here are some other medications that also block cardiac sodium channels in a similar manner:

• Cocaine
• Diphenhydramine
• Cyclobenzaprine (Flexeril)
• Carbamazepine (Tegretol)
• Phenothiazines
• Propoxyphene
• Class 1A antidysrhythmics (quinidine, procainamide, disopyramide)
• Class 1C antidysrhythmics (encainide, flecainide, propafenone, moricizine)
• Amantadine

Many drugs/toxins cause nystagmus, particularly in overdose.  Vertical, horizontal, or rotary nystagmus may be noted.

The most common drug/toxin overdoses that cause nystagmus are the following:

• Anticonvulsants (phenytoin, carbamazepine, valproic acid, lamotrigine, topiramate)
• Ethanol
• Lithium
• Dextromethorphan
• Phencyclidine (PCP)
• Ketamine
• Lysergic acid diethylamide (LSD)

According to the Food Allergy and Anaphylaxis Network, the eight most common food allergies, which account for 90% of the food allergies in the U.S., are: dairy, soy, wheat, shellfish, fish, peanut, tree nut, and egg.

Several medications are formulated with these ingredients and should be avoided in patients with reported allergies.

• Propofol is a lipid emulsion that contains egg.  Avoid in patient with hypersensitivity to eggs, egg products, soybeans, or soy products.
• Ipratropium ± albuterol (Atrovent, Combvient®) inhalers may contain soy lecithin.  This can cause allergic reactions in patients with allergy to soy lecithin or related food products (e.g., soybean and peanut).  Nebulizer solutions (e.g., Duoneb®) seem to be free from this issue.
• Progesterone (Prometrium®) capsules contain peanut oil.

With all of the post-transplant patients we see in the ED, a refresher on the toxicities associated with the most common immunosuppressant medications is warranted.

Cyclosporine (Sandimmune^® and Neoral^®/Gengraf^®) and tacrolimus (Prograf^®) are both calcineurin inhibitors that inhibit activation and proliferation of T-lymphocytes and IL-2.

-          Major concerns: Nephrotoxicity, drug interactions (CYP3A4)

-          Adverse Effects:

o       Electrolyte abnormalities: ­K+, ¯Mg+, ­glucose

o       CNS: HA, tremor (statistically higher with tacrolimus)

o       CV: HTN, ­ lipids (increased with cyclosporine)

o       End organ: hepatotoxicity, nephrotoxicity

o       Cosmetic (cyclosporine specific): hirsutism, gingival hyperplasia, acne

Sirolimus/Rapamycin (Rapamune^®) is an M-tor inhibitor that inhibits T-lymphocyte activation and proliferation.

-          Major concerns: Drug interactions (CYP3A4)

-          Adverse Effects:

o       Delayed wound healing

o       Leucopenia, thrombocytopenia

o       Hypercholesterolemia