We are excited and proud to introduce a new series as part of the recently announced ALiEMU: Capsules: Practical Pharmacology for the EM Practitioner.
The Capsules series’ primary focus is bringing Emergency Medicine pharmacology education to the bedside. Our expert team distills complex pharmacology principles into easy-to-apply concepts. It’s our version of what-you-need-to-know as an EM practitioner. We hope you enjoy it.
I was recently the author of a PV card for management of Salicylate Toxicity, which had some discrepancy with expert opinion. The point of contention was in regards to measurement of urine pH vs serum pH for alkalinization. In preparing the first version of the card, I began with notes from a recent toxicology rotation, and expanded by examining textbooks and review articles. Although there was mention of serum pH measurement, numerous sources emphasized urine alkalinization as the primary endpoint for the treatment of aspirin toxicity. Therefore I choose to include this on the size-limited PV card.
Despite review by numerous peers and colleagues, not long after publication we were met with concern from prominent toxicologists regarding an oversight in mentioning serum alkalinization. Utilizing the strengths of our blog and social media we were immediately able to initiate a discussion with experts on the topic.
Dr. Lewis Nelson of NYU was able to clarify that by prioritizing serum alkalinization, we will avoid the cerebral toxicity that is the primary etiology of mortality. Serum alkalinization should also facilitate urine alkalinization as well as allow time to arrange for hemodialysis. Dr. Bram Dolcourt from Detroit expanded that serum alkalinization and normokalemia alone do not guarantee an optimal urine pH and suggest measurement of both urine and serum. From Twitter, Dr. David Juurlink from Toronto also recommended measurement of both, stating his forthcoming publication will expand on the topic. Our own ALiEM clinical pharmacist Dr. Bryan Hayes also assisted with expert insight as I was revising the PV card.
As the ALiEM-CORD virtual fellow, I have had the challenging task of collaborating with experts in my field, while still very much in a learner role myself. I was fortunate enough to have been featured on a site that has a robust commenting system and pride in peer review, even if it is post-publication. There is certainly content on the web that may be inaccurate or ‘less-accurate’, and consumers of both FOAM and conventional publications, as always, should remain critical and review multiple sources. There is a broad range in teaching and practice based on region, and when we work together we can identify what is truly best practice. Hopefully this conversation and the forthcoming publication on the topic will translate into changes in practice and in the textbooks in the coming years. Luckily, utilizing the strengths of our medium, we are able to publish these corrections today.
For those curious, here was the original version 1.
On a Friday night shift, an ambulance brings you a 52 year-old man who had an episode of syncope at a local club. EMS found him confused and hypoxic with poor skin color. The patient was placed on oxygen via face mask en route to your ED without clinical improvement. On exam, you note a blue discoloration of his extremities, and his chest x-ray and ECG are unremarkable. You draw blood, which appears very dark, and an ABG demonstrates pH 7.39, PCO2 41, and PO2 176.
Figure 1. Blue foot
Figure 2. Dark arterial blood
You suspect that your patient has methemoglobinemia, so you order a methemoglobin level which comes back at 37%. The patient receives antidotal therapy, and, on further interviewing, ultimately explains that he had been using amyl nitrate “poppers” at the club prior to arrival.
Hemoglobin is a protein tetramer, with each subunit consisting of an iron-containing heme group. Normally, the iron in heme exists in a reduced state as ferrous iron (Fe 2+). Methemoglobinemia occurs when some proportion of this ferrous iron is oxidized to produce ferric iron (Fe 3+). 1 This oxidation renders the effected heme groups unable to carry oxygen. Even though not every heme group is oxidized, every heme group in the same hemoglobin tetramer is affected by so-called cooperative binding: oxidized heme molecules induce conformational changes in hemoglobin which increase the un-oxidized heme’s affinity for oxygen. As a result, the oxygen–hemoglobin dissociation curve shifts to the left, and oxygen is less readily released to tissues.
Methemoglobinemia is essentially a functional anemia with normal cardiopulmonary function. Because the cardiovascular system must still circulate these inactivated hemoglobin containing red blood cells, a methemoglobin level of 34% has more effects than if the patient had lost 34% of their blood. The resulting cellular hypoxia leads to a range of end organ dysfunction and clinical signs: gray discoloration, dyspnea, fatigue, acidosis, dysrhythmia, seizure, coma, and ultimately death. Co-morbid anemia as well as cardiopulmonary disease will exacerbate symptoms.
Methemoglobinemia is not always the result of exogenous substances. Normal oxidative metabolism results in a small amount of endogenously produced methemoglobin (usually < 1%). This process is kept in check by NADH methemoglobin reductase, which uses NADH to reduce methemoglobin back to hemoglobin. Genetic deficiencies in this enzyme, as well as alterations in hemoglobin, can lead to congenital methemoglobinemia. 2,3 Infants under 4 months of age are also at increased risk of methemoglobinemia due to immature activity levels of this enzyme. When oxidative stress overwhelms the NADH reduction pathway, methemoglobin levels rise and patients turn blue.
| Aniline dyes | Nitrates, Nitrites | Sulfa drugs |
| Benzocaine, Lidocaine | Phenazopyridine | Trinitrotoluene |
| Dapsone | Prilocaine | Quinones |
| Naphthalene |
Additionally, extremes of age, anemia, diarrhea, hospitalization, malnutrition, renal failure, and sepsis are predisposing factors.
Methemoglobinemia should be suspected in patients with low pulse oximetry who do not respond to supplemental oxygen. Low SpO2 readings occur because pulse oximeters utilize light absorption at 660 and 940 nm to calculate the ratio of oxy-hemoglobin to deoxy-hemoglobin in blood. Methemoglobin absorbs light at both of those wavelengths, thus the presence of these additional hemoglobin species makes SpO2 calculation inaccurate. 4 Arterial blood gas measurement of PO2 is not affected by methemoglobin, resulting in a normal (and often elevated due to supplemental oxygen) calculated SaO2. Whenever there is dissociation between the PO2 and the SpO2, a hemoglobinopathy should be suspected. Additionally, arterial blood has been described as “chocolate brown” with degree of color change correlating to methemoglobin level. 5
Asymptomatic patients with low levels of methemoglobinemia (10% or less) may be managed conservatively by removing oxidizing drugs and arranging follow up. 1 In patients with dapsone-associated methemoglobinemia, administration of cimetidine has been associated with reduced methemoglobin levels. 6 Symptomatic patients or patients with elevated levels of methemoglobin (25% or more) usually require antidotal treatment with methylene blue.
Methylene blue is reduced by NADPH reductase to leukomethylene blue in RBCs, which subsequently reduces methemoglobin to hemoglobin. In this way, though stores of NADH are exhausted, NADPH functions as a reducing agent. Dosing is 1-2 mg/kg of methylene blue administered intravenously over 5 minutes. Though an initial drop in pulse oximeter reading (due to the blue color of the antidote) is expected, cyanosis and methemoglobinemia should improve over the following hour.
Figure 3. Methylene blue antidote
Figure 3. Intravenous administration of methylene blue
While conflicting data exist, many consider G6PD-deficiency (and resulting low levels of NADPH) to be a relative contraindication to methylene blue therapy; treatment failures and hemolysis have been reported in patients with G6PD-deficiency who received high doses of methylene blue. 7 Where methylene blue is not available or contra-indicated, ascorbic acid 0.5 g IV every six hours has been described, but clinical relevance remains uncertain. 8 If treatment fails, consider decontamination to remove remaining oxidant drugs, repeat administration of methylene blue, exchange transfusion, and/or hyperbaric oxygen therapy.
Excited delirium syndrome is defined as “a syndrome of uncertain etiology characterized by delirium, agitation, and hyperadrenergic autonomic dysfunction”.1 You may have encountered a patient like this in the ED or prehospital setting. Although the etiology is impossible to determine in many cases, stimulant abuse and other drugs are involved in a majority of cases. An 8% mortality has been ascribed to Excited Delirium Syndrome, resulting from hyperthermia, severe metabolic acidosis, and cardiovascular collapse.
Limited intravenous access is a common conundrum in the Emergency Department, with heavy implications for medication administration. Of particular concern, are the profoundly septic patients that necessitate multiple timely therapies, which require tying up a line – fluids, pressors, several antibiotics, etc. The shift away from less central line (i.e. triple lumen) placement for initial resuscitation, may serve to further exacerbate this issue.
In January 2014, ALiEM featured a must-read post by Bryan Hayes regarding proper dosing of vancomycin in the emergency department, including a special note related to the recommendations regarding consideration of loading doses of vancomycin ranging from 25 to 30 mg/kg in adult patients who are critically ill with a high suspicion for MRSA infection.
Patients with acute salicylate toxicity can rapidly decompensate and require clinicians to understand the pathophysiology of what is going on. First a respiratory alkalosis occurs with non-specific symptoms of vomiting and dizziness. Then an anion-gap metabolic acidosis also occurs with headache, tinnitus, and confusion. Below lists the core set of labs to obtain and treatment strategies by our stellar ALiEM-CORD Social Media and Digital Scholarship Fellow, Dr. Sam Shaikh.