Sunday, December 14, 2014

Heparin-induced hyperkalemia

Heparin and low molecular weight heparins (LMWH) are some of the many medications that have been identified to cause hyperkalemia.  When looking for more information about this in the prescribing information, Lexicomp, and Micromedex, there is a paucity of information.  

The prescribing information does not mention potassium at all, merely stating that suppression of aldosterone synthesis has been reported, whereas the other sources give rates from <1% to 8%.  The following will discuss the typical time course and extent of changes in potassium identified in some studies, the proposed mechanism for these effects, and risk factors.

Proposed mechanism

The mechanism for hyperkalemia has not clearly been determined but is thought to be due to the suppression of aldosterone synthesis.  Though the specific mechanism seems to differ between heparin and the LMWHs, suppressing aldosterone synthesis causes natriuretic and potassium-retaining effects.  

Under normal circumstances, aldosterone is released from the zona glomerulosa in the adrenal cortex and stimulates sodium reabsorption and potassium and hydrogen ion secretion.  This occurs in response to various stimuli including angiotensin II, ACTH, hyperkalemia, low sodium intake, and decreased intravascular volume. 

Heparin has not been shown to significantly change the clearance or binding activity of aldosterone but has been shown to decrease plasma and urinary aldosterone concentrations due to inhibition of aldosterone production.  This is evident as patients that are administered angiotensin II or have acute volume depletion essentially have an absent aldosterone response when heparin is present.  Because heparin decreases aldosterone production even in primary hyperaldosteronism (where the renin-angiotensin system is already suppressed), it is proposed that heparin has some direct inhibition of aldosterone biosynthesis in addition to its angiotensin receptor antagonist activity.  Narrowing of the zona glomerulosa has been seen in patients using long-term heparin but no other obvious histologic changes have been noted in the zona fasciculata, zona reticularis, or other endocrine glands. 

Further supporting this theory is that the heparin-mediated sodium and potassium effects do not occur in patients in whom aldosterone is already suppressed (salt-loaded patients) or those receiving exogenous aldosterone support (patients on chronic steroids).

These aldosterone inhibitory effects have been seen with low dose unfractionated heparin in addition to LMWH.

Evidence summary

Most of the evidence for heparin-induced hyperkalemia is limited to case studies, case series, and a few prospective trials (none of which are placebo controlled).  One prospective study with unfractionated heparin examined 154 patients being treated for DVT.  Hyperkalemia (defined ≥5.5 mEq/L in this study) occurred in 8.4% of patients, when measured at days 5-7 and 10-14.  Regarding LMWHs, one prospective study including nearly 100 patients treated with enoxaparin found significant increases in potassium levels at day 3 of treatment.  In this study, levels rose by >0.5 mEq/L in 24% of patients and exceeded 5.0 mEq/L in 9% of patients.  It is notable that this study excluded patients with renal impairment (SCr >1.3 mg/dL) as well as those who recently initiated medications known to affect potassium levels.

Generally, these prospective studies and the smaller case series have shown that unfractionated heparin and LMWH, even when given at prophylaxis doses, results in hyperkalemia in up to 7%-9% of patients within the first 14 days of therapy.  Increases occur as early as 1-3 days, achieve maximal effect in 3-5 days, and start to resolve within 1-3 days after discontinuation.

Risk factors for heparin-induced hyperkalemia include diabetes mellitus, renal impairment, hematomas, and other conditions that alter the balance of the renin-angiotensin aldosterone system.  Other medications that increase this risk include ACEIs, ARBs, beta-blockers, potassium-sparing diuretics, and potassium supplements, among others.

Take home points:

  • Heparin and LMWH can cause hyperkalemia in up to 9% of patients, at both prophylactic and treatment doses
  • Time of onset: within 1-3 days
  • Maximal effect: 3-5 days
  • Time to resolution: within 1-3 days of discontinuation
  • Hyperkalemia is due to direct and indirect effects on the adrenal gland, causing a reduction in aldosterone production
  • For an earlier discussion about the use of sodium polystyrene sulfonate in managing hyperkalemia, click on the link.

Heparin [package insert].  New York, NY: Pfizer Labs; 2013.
Hall JE, Granger JP, Jones DW, Hall ME. Chapter 69. Pathophysiology of Hypertension. In: Fuster V, Walsh RA, Harrington RA. eds. Hurst's The Heart, 13e. New York, NY: McGraw-Hill; 2011. Accessed December, 2014.
Oster JR, Singer I, Fishman LM.  Heparin-induced aldosterone suppression and hyperkalemia.  Am J Med  1995;98:575-86.
Gonzalez-Martin G, Diaz-Molinas MS, Martinez Am, et al.  Heparin-induced hyperkalemia: a prospective study.  Int J Clin Pharmacol Ther Toxicol  1991;29:446-50.
Koren-Michowitz M, Avni B, Michowitz Y, et al.  Early onset of hyperkalemia in patients treated with low molecular weight heparin: a prospective study.  Pharmacoepidemiol Drug Saf  2004;13(5):299-302.

photo by michaelnpatterson

1 comment:

  1. this is such a helpful post medically and also to help me write on the disease for affordable dissertation writing. thank you for posting with such a thorough post with proper content


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