Chiefs’ Inquiry Corner – 2/7/22

February 7, 2022

Chief residents of the NYU Langone Internal Medicine Residency give quick-and-easy, evidence-based answers to interesting questions posed by house staff, both in their clinics and on the wards.

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 Hemolysis refers to the release of hemoglobin and other intracellular components of erythrocytes into the extracellular space of blood. It can occur both in vivo and in vitro – in vivo referring to a result of disease or true hemolytic anemia, and in vitro referring to a number of procedures related to specimen handling. In vivo hemolysis has a large differential, but this comprises an estimated 2% of hemolyzed samples. In vitro hemolysis can be related to phlebotomy technique – incorrect needle size, improper tube mixing, incorrect filling of tubes, prolonged tourniquet. It could also be associated with extreme temperatures, delayed processing, and prolonged storage. Depending on your local lab, they may have various methods of identifying hemolyzed samples. Some rely on visual inspection, which compares a centrifuged sample to a color chart showing corresponding concentrations of free hemoglobin; visual assessment can be highly inaccurate. Many analyzers are now capable of automated assessments using a hemolysis index that has been standardized. When it comes to reporting, some labs choose to simply note that the sample must be rechecked without reporting any values. However, this can lead to delay in diagnosis of true in vivo hemolysis. Many labs opt to report the values but denote that the sample was hemolyzed. So – if you don’t have any concern for true hemolysis, the cause of hemolysis could be anything from the point of puncture all the way to the time of sample processing.

References: Hemolyzed Specimens: Major Challenge for Identifying and Rejecting Specimens in Clinical Laboratories
   This question is actually more complicated than you may initially think – the safety and efficacy of newer potassium binders has been established more recently (namely Patiromer and Lokelma/sodium zirconium cyclosilicate (SZC)) (check out the HARMONIZE trial if interested in Lokelma specifically, which we have on formulary). The U.S. Food and Drug Administration and the European Medicines Agency have approved patiromer and SZC for the treatment of hyperkalemia in patients receiving RAAS inhibition. Some practical guidance for when to consider initiation of these agents was recently published in JACC – the idea being that we know there is evidence for ACE/ARBs and MRAs, so in theory we would expect patients to benefit if the use of a potassium binder can help them remain on RAAS inhibition or prevent dose reduction. They suggest considering starting one of these agents when the K+ is greater than 5.0, depending on the clinical scenario – whether it is initiating these therapies or considering discontinuation or dose reduction. However, while this idea in theory makes sense, we do not yet have evidence-based indications for this practice. Two studies are currently ongoing that will help answer that question. The DIAMOND study will evaluate the potential of patiromer to improve outcomes by enabling HF patients, with or without CKD, to be treated with RAAS inhibition in accordance with HF treatment guidelines. The PRIORITIZE-HF (Potassium Reduction Initiative to Optimize RAAS Inhibition Therapy With Sodium Zirconium Cyclosilicate in Heart Failure) study will evaluate whether SZC may enable target-dose RAAS inhibition uptitration if HF patients.

References: Abnormalities of Potassium in Heart Failure: JACC State-of-the-Art Review
 Older treatment options for acute hyperkalemia included sodium or calcium polystyrene sulfonate (SPS/CPS), nonspecific organic polymer resins associated with significant side effects and questionable efficacy. Lokelma, a newer agent, is a non-absorbed zirconium silicate that preferentially captures potassium in exchange for hydrogen and sodium. In vitro, Lokelma has a high affinity for potassium ions, even in the presence of other cations such as calcium and magnesium. Its specificity for potassium is attributed to its chemical composition and structure, with micropore diameters roughly equivalent to the diameter of an unhydrated potassium ion. It has an estimated >25-fold selectivity for potassium over calcium or magnesium, compared with SPS. Studies have demonstrated its capacity to bind potassium in localized environmental conditions mimicking the entire GI tract, including acidic conditions of the duodenum. Compared with nonselective organic exchange resins that function in the colon where potassium concentration is the highest, zirconium silicate is highly selective for potassium and may bind as early as the upper GI tract where high amounts (but lower concentrations) of potassium are present, likely explaining the rapid effect observed consistently and its ability to reliably increase fecal potassium excretion.

References: Pharmacodynamics and pharmacokinetics of sodium zirconium cyclosilicate [ZS-9] in the treatment of hyperkalemia