Serum Levels Can Be Deceiving

Figure: serum levels, salicylate, absorption, overdose, North American Congress of Clinical Toxicology, poisoning, toxicology, sepsis, diabetic ketoacidosis, viral pneumonia, hypovolemia, respiratory distress, hypoxia, gastrointestinal tract, stomach, small intestine, ASA level, pharmacokinetics, NSAID, blood pressure, hemodialysis, toxicokinetics, ibuprofenFigureThe 2023 North American Congress of Clinical Toxicology was held in Montreal recently, which is probably my favorite North American city for a conference. Room and board are surprisingly affordable, Mont Royal is the best urban park in the world, and poutine—the distinctly Québécois mixture of French fries, cheese curds, and rich brown gravy—is justification for the discovery of statins. Besides potatoey deliciousness, the conference also gave us these important presentations. Pitfall: Thinking an InitialNegative Salicylate Level RulesOut Significant Exposure Salicylate overdose is one of the poisonings most feared by seasoned medical toxicologists, for good reason. For one, classic signs and symptoms of salicylate toxicity can mimic other serious conditions—sepsis, diabetic ketoacidosis, viral pneumonia—easily leading to missed diagnoses. Secondly, many salicylate patients present with severe hypovolemia and may be down four to six liters or more. Renal elimination of salicylate will be impaired if this deficit is not repleted expeditiously. On the other hand, patients can develop acute respiratory distress syndrome and hypoxia if fluid repletion is too aggressive. Finally, absorption of salicylate from the gastrointestinal tract is erratic and unpredictable, requiring frequent measurement of salicylate levels (typically every two hours at first). Absorption from the stomach and small intestine is rapid with peak serum levels typically achieved within one to two hours when a therapeutic dose of salicylate is ingested. Absorption can be delayed after a significant overdose, however, with peak levels occurring much later. This can be due to bezoar formation, co-ingestants such as anticholinergics or opioids that delay gastric emptying, pylorospasm, and use of enteric-coated and sustained-release products. Many emergency physicians would be surprised to learn that salicylate absorption after overdose might be so delayed that the initial serum salicylate level may be undetectable. A recent retrospective review of records from a single regional poison center, for example, found 11 cases where the initial serum ASA level drawn within four hours of presentation was undetectable, despite a subsequent level being 30 mg/dL or more. (Clin Toxicol. 2019;57[2]:137; https://tinyurl.com/4z6xvyj5.) The longest interval between reported ingestion and an undetectable ASA level was 225 minutes in those 11 patients. The delay from ingestion to first detectable serum salicylate level, however, can be much more dramatic, as illustrated in a case presented at NACCT 2023 by Stacey Bangh, PharmD, and her colleagues from the Minnesota Poison Control System. A young woman presented to the emergency department 30 minutes after reportedly ingesting 78 325-mg ASA tablets. She was asymptomatic except for nausea and received a single dose of activated charcoal. The regional poison center signed off on the case after serum ASA levels drawn at 2.5, 5.5, and seven hours after ingestion were undetectable (<5 mg/dL) and the patient remained asymptomatic. Fortunately, the treating team drew an additional level at 12 hours, which came back at 31 mg/dL. Levels peaked at 55 mg/dL 21 hours after ingestion. The patient was on a 1:1 hold the entire time and ingestion after presentation was deemed unlikely. Similar delays to initial detectable ASA levels have been reported in the medical literature, though such cases are rare, and it is not clear from existing evidence what the optimal protocol is for obtaining ASA levels following intentional overdose. It is evident that an initial undetectable level within four hours of ingestion should absolutely not rule out clinically significant ASA ingestion. Pitfall: Not Realizing thatPharmacokinetics Can Changein Massive Overdose Imagine this clinical scenario. A young woman is brought to your emergency department after ingesting 180 g of ibuprofen at an unspecified time. She is obtunded with a blood pressure of 94/40 mm Hg, a pulse of 111 bpm, and a respiratory rate of 26 bpm. She receives orogastric lavage, activated charcoal, and aggressive supportive care, but her condition continues to deteriorate, with worsening shock and acidosis. The team consults the regional poison center, which recommends instituting emergent hemodialysis. A medical student who has been observing mentions that UpToDate states that extracorporeal removal of NSAIDs via hemodialysis is ineffective due to the high degree of protein-binding characteristics of all NSAIDs. Just such a case was presented at NACCT 2023 by Ryan Fuchs, MD, et al., also from the Minnesota Poison Control System. The patient received more than two hours of intermittent hemodialysis, which markedly improved her hemodynamics and dramatically decreased the dose of pressors required to support hemodynamics. Does intermittent hemodialysis enhance the removal of ibuprofen? I agree with the authors that the answer is unclear, but it might be effective for increasing elimination. This brings up a very important point: Pearl: Toxicokinetics are notNecessarily the Sameas Pharmacokinetics Studies of drug elimination by intermittent hemodialysis are often done on patients with renal failure on chronic hemodialysis who are given small therapeutic amounts of drug X before their session. Very little of a highly protein-bound drug such as ibuprofen will be free and available for removal by intermittent hemodialysis in this situation. But after massive overdose, the protein-binding sites can become saturated and excess drug will be unbound and readily removed by dialysis. I agree with the authors that it was not clear in their case if the patient's striking improvement after intermittent hemodialysis was from drug removal, improvement in severe acidosis (pre-treatment pH 7.07), or both. And to be fair, UpToDate points out later in its discussion of NSAID overdose that hemodialysis may be indicated in these cases to reverse acidosis or to compensate for renal insufficiency. The key lesson here for emergency physicians is not to be surprised if the consulting regional poison center recommends intermittent hemodialysis in cases of massive overdose from NSAIDs or other highly protein-bound drugs DR. GUSSOW is a voluntary attending physician at the John H. Stroger Hospital of Cook County in Chicago, an assistant professor of emergency medicine at Rush Medical College, a consultant to the Illinois Poison Center, and a lecturer in emergency medicine at the University of Illinois Medical Center in Chicago. Follow him on X @poisonreview, and read his past columns at http://bit.ly/EMN-ToxRounds. Share this article on X and Facebook. Access the links in EMN by reading this on our website: www.EM-News.com. Comments? Write to us at [email protected].

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