Heparin is the most frequently used drug for treatment and prophylaxis of deep venous thrombosis. Common side effects, including thrombocytopenia, bleeding, and cutaneous hypersensitivity, are often recognized early and effectively treated.1-3 Heparin-induced hyperkalemia (HIH) is a relatively unusual side effect that can lead to mortality if unrecognized and left untreated. Greater than normal potassium (K) levels occur in 7%-8% of general hospitalized patients who are on subcutaneous heparin.1, 4 Substantial hyperkalemia is usually associated with the presence of compounding factors such as diabetes mellitus, renal insufficiency, and certain medications.1-12 To increase awareness of HIH and of those patients at greatest risk, we present two cases of documented HIH, including what we believe are among the first reported cases confirmed by drug rechallenge.
The first case involved a 68-yr-old woman with a new onset of right cortical stroke. The patient's past medical history was significant for untreated hypertension over approximately 10 yr, tobacco use, and alcohol abuse. Admission laboratory values at the acute care hospital revealed a K level of 3.6 mg/dl (reference values, 3.6-5.0 mg/dl), a blood urea nitrogen (BUN) level of 26 mg/dl (reference values, 6-33 mg/dl), and a creatinine level of 2.2 mg/dl (reference values, 0.6-1.5 mg/dl; see Fig. 1). The patient was taking no medications before admission. Beginning on day 1 of hospital admission, she received twice daily 5000 units of heparin subcutaneously, 1 g of sucralfate, and 250 mg of ticlopidine hydrochloride, and daily 30 mg of nifedipine. By day 2, laboratory tests revealed a K of 5.1 mg/dl, a BUN of 37 mg/dl, and a creatinine of 2.1 mg/dl. The patient spent 6 days in the acute care hospital for evaluation and was diagnosed with mild renal insufficiency. On day 6, the patient was transferred to an acute inpatient rehabilitation unit. She was kept on the same medications, with the exception of the dose of 5000 units of heparin being increased from twice daily to 3 times daily. A 7-day course of sulfamethoxazole-trimethoprim, at a renal adjusted dose, was also started on day 6 for a urinary tract infection. The K level on day 6 was 5.3 (sodium, 136 mg/dl; BUN, 52 mg/dl; and creatinine, 2.4 mg/dl). By day 15, the K level had peaked at 6.4 mg/dl (sodium, 138 mg/dl; BUN, 58 mg/dl; and creatinine, 4.2 mg/dl) and required Kayexalate and intravenous (IV) fluids. The patient's heparin was stopped on day 15, and the K level returned to 4.6-5.1 mg/dl for the next 10 days. Because of a perceived high risk of deep venous thrombosis and with the patient's permission, the dose of 5000 units of heparin subcutaneously twice daily was restarted on day 31, resulting in an increase in her K level to 5.4 mg/dl by day 36. The heparin was discontinued on day 36, and her K level returned to 4.2 mg/dl by day 38 with the use of fluids and medication. The patient's sodium values ranged from 132 to 141 (reference range, 136-143) mg/dl during this period. There was no evidence of ongoing use of other causative drugs, dehydration, or concomitant medical conditions that could have explained the above changes.
Case 2 involved a 70-yr-old man with a new onset of right medullary stroke and past medical history of diabetes and curative rectal cancer surgery. Previous medications taken at home included an oral hypoglycemic agent and salicylic acid. Heparin was begun at 5000 units subcutaneously twice daily on day 1 in the hospital with the following admission laboratory levels: K, 4.1 mg/dl; BUN, 8 mg/dl; and creatinine, 1.0 mg/dl. Sulfamethoxazole-trimethoprim (double strength) was begun twice daily on day 4 to treat a diagnosed case of urinary tract infection, and was continued for 10 days. On day 5, the patient was transferred to an acute rehab unit with a K of 5.5 mg/dl, a BUN of 18 mg/dl, and creatinine of 1.2 mg/dl. On day 18, the patient's K level peaked at 6.5 mg/dl, with a BUN of 36 mg/dl, a creatinine of 2.6 mg/dl, and a sodium of 130 mg/dl; the patient required Kayexalate, glucose, and IV fluids. Notably, the patient had been given Kayexalate twice during the previous week for hyperkalemia of unclear cause. Dehydration from Kayexalate, heparin-induced natruresis, and poor oral intake were believed to be the cause of the increased BUN and creatinine levels. Heparin was stopped on day 18, and the patient's laboratory levels returned to the following on day 21: K, 4.1 mg/dl; BUN, 9 mg/dl; and creatinine, 1.0 mg/dl. With the patient's permission, heparin was restarted on day 24, at which time the K was 5.7 mg/dl, the BUN 20 mg/dl (normal), and the creatinine 1.3 mg/dl. By day 28, when the heparin was stopped, the patient's K was 5.0 mg/dl, BUN 20 mg/dl, and creatinine 1.1 mg/dl, without the use of IV fluids or Kayexalate. Sodium values ranged from 128 to 140 mg/dl during the admission.
Heparin-induced hyperkalemia has been repeatedly documented over the years. Hypoaldosteronism has been the presumed cause of the hyperkalemia.2, 4, 5, 7-11 We present the first two cases of HIH with the use of low dose subcutaneous heparin that are confirmed by drug rechallenge. Low molecular weight and unfractionated standard heparin have both been documented to cause a dose-related hypoaldosteronism.1, 2, 4-6, 13 Both cases reported here developed HIH on 5000 units of standard heparin subcutaneously on a twice daily or 3 times daily schedule for deep venous thrombosis prophylaxis.
The exact mechanism by which heparin causes HIH remains controversial. Likely, concomitant causes of HIH include decreased aldosterone production, decreased steroidogenesis, and reduction of number and affinity of angiotensin II receptors in the zona glomerulosa.2-5, 7, 9, 10, 12, 14-16 Although patients who receive heparin have reduced aldosterone levels, most patients are able to compensate (i.e., through increased renin production) to maintain normal potassium values.1-5, 8, 10, 11 Therefore, there is a need to identify medical conditions that may predispose patients to HIH secondary to underlying deficits in the renin-angiotensin-aldosterone axis. Disease processes known to predispose patients to HIH include diabetes, renal insufficiency, type 4 renal tubular acidosis, and metabolic acidosis.1-12 In patients with HIH, the inability to increase renin in the face of decreasing aldosterone leads to hyperkalemia.4-11
In case 1, it can be hypothesized that mild renal insufficiency secondary to chronic hypertension likely did not allow the patient's kidneys to compensate for the heparin-induced hypoaldosteronism. In case 2, the patient, who had a normal renal profile, likely had a common underlying diabetic condition of hyporeninemic hypoaldosteronism which led to uncompensated hyperkalemia. The onset of hyperkalemia in our patients occurred in time frames that are consistent with the literature.1, 4-11, 14 Sodium loss and K retention are detectable by 1-3 days and are at maximal levels by 3-5 days.4, 10 Aldosterone suppression also occurs in 2-3 days, with markedly decreased levels by 4-6 days.4, 10
There are also medications that are known to predispose patients to HIH, including angiotensin-converting enzyme inhibitors, diuretics, nonsteroidal anti-inflammatory drugs, and K loads or K-sparing diuretics.1, 4-11 These drugs act by interfering with mineral corticoid metabolism. A unique and convincing argument for presenting these two cases was the lack of medications and concomitant medical complications during our drug rechallenges.
As with all case reports and retrospective reviews, alternative explanations are possible. In critical review of both cases, there is a possibility that sulfamethoxazole-trimethoprim may have at least contributed to the patients' initial hyperkalemia. This does not, however, explain why the K level continued to reach hyperkalemic peaks while the patients were on heparin (Fig. 1). In case 2, initial dehydration could be confounding the first peak of hyperkalemia. However, the second peak of K level was in the face of improving BUN and creatinine levels to normal levels and is consistent with causal effect of heparin (Fig. 2). More data points, perhaps daily, would have been ideal to better delineate responses to heparin. Although rechallenge was warranted because of high risk for deep venous thrombosis, longer rechallenge to document sustained hyperkalemia would have been convincing, but unethical. Finally, concomitant measurements of renin and aldosterone would be helpful to confirm the supporting literature presented in the above discussion.
In summary, there have been 19 previous case reports of HIH. We present the first two known cases of HIH confirmed by drug rechallenge to emphasize the potential serious side effects of heparin even at the low doses used for deep venous thrombus prophylaxis. Early identification and treatment of patients at risk for HIH can reduce the related morbidity and mortality. General recommendations for hospitalized patients starting on heparin include monitoring serum sodium and K during the first 3-5 days, and at least weekly thereafter. More frequent monitoring is necessary for patients at increased risk or for patients starting one of the medications known to predispose to hyperkalemia. Finally, if heparin is the cause of hyperkalemia, sodium and K levels should return to normal ranges within 3-5 days after discontinuing heparin.
We thank Max Reif of University of Cincinnati Medical Center Department of Nephrology for review and recommendations. Thanks also to Melita Wells for expert technical assistance in preparing this article.
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