Hypoglycemia Linked to Trimethoprim-Sulfamethoxazole Use in a Patient with End-Stage Renal Disease

James K. Burks, MDProfessor of Medicine

Mini Gopalan, MD

Internal Medicine

Odessa, Tex

Case Presentation

A 41-year-old Hispanic man with HIV infection and renal failure secondary to focal segmental glomerulosclerosis and hypertension was admitted with acute-onset shortness of breath and pleuritic chest pain. He was taking trimethoprim/sulfamethoxazole 160 mg/800 mg (TMP/SMX; Bactrim DS, Septra DS), 1 tablet daily; amlodipine (Amvaz, Norvasc), 5 mg/day; and metoclopramide (Reglan), 5 mg/day. His chest x-ray showed increased vascular congestion and left lower-lobe haziness. Levofloxacin (Levaquin) and furosemide (Lasix) were administered, and he continued taking his other medications. On admission, his creatinine concentration was 6.1 mg/dL (normal, 0.6-1.2 mg/dL) and blood urea nitrogen (BUN), 65 mg/dL (normal, 8-23 mg/dL).

Four days after admission, the creatinine level rose to 8.8 mg/dL and the BUN level to 83 mg/dL (creatinine clearance, 6 mL/min; normal, 75-125 mL/min). The patient was unresponsive, diaphoretic, and in a generalized seizurelike situation. He was given diazepam (Valium), with no response. An Accu-Chek test showed an immeasurable blood glucose level. Laboratory testing revealed a serum glucose concentration of 12 mg/dL. The patient was given 2 ampules of dextrose 50% in water, and he regained consciousness with no residual neurologic deficits. Laboratory testing showed: serum C-peptide, 5.7 ng/mL; serum cortisol, 39 ?g/dL; and serum insulin, 113 ?U/mL.

His medications were reviewed at this point, to ensure that he had not been given oral hypoglycemics. The TMP/SMX was discontinued. An intravenous (IV) dextrose 5% in water drip was started, but the patient continued to be hypoglycemic, requiring an injection of dextrose 50% in water. The infusion was changed to dextrose 10% in water. The entire hypoglycemic episode lasted for approximately 15 hours, after which the dextrose infusion was discontinued. The patient subsequently began hemodialysis and was given TMP/SMX 80 mg/400 mg (Bactrim, Septra) once daily. He had no further episodes of hypoglycemia.

Discussion

Hypoglycemia is a clinical syndrome in which low levels of plasma glucose eventually lead to neuroglycopenia.¹ Symptoms can be autonomic, such as diaphoresis, palpitations, tremulousness, anxiety, or nausea. Neuroglycopenic symptoms include blurred vision, difficulty speaking, confusion, fatigue, generalized seizures, and coma. Since the symptoms of hypoglycemia are nonspecific, Whipple's triad is often used to make the diagnosis of a hypoglycemic disorder. This triad includes (1) a low plasma glucose concentration, (2) symptoms consistent with hypoglycemia, and (3) reversal of these symptoms when the blood glucose level returns to normal.

Causes of hypoglycemia

Hypoglycemia can cause significant morbidity and may be lethal if severe or prolonged. Causes include endocrine deficiencies, such as of growth hormone, cortisol, glucagon, or epinephrine. Other etiologies include insulinomas, extrapancreatic tumors (eg, sarcoma), renal cancer, and autoimmune hypoglycemia, to name a few. Drugs, including those used to treat diabetes, and alcohol abuse are most often implicated as causes of hypoglycemia. Many conditions increase the risk of hypoglycemia, including renal or hepatic impairment, sepsis, prolonged fasting, inanition, and old age.²

Hypoglycemia in association with renal failure is well documented. Spontaneous uremic hypoglycemia has been attributed to diminished renal gluconeogenesis, impaired glycogenolysis, impaired renal insulin degradation and clearance, deficiency of the precursors of gluconeogenesis, and deficiency of immediate counterregulatory hormones. Additional precipitating factors include alcohol consumption, sepsis, chronic malnutrition, concomitant liver disease, congestive heart failure (CHF), and associated endocrine deficiency.³ In uremic hypoglycemia, neuroglycopenic manifestations predominate because of frequent autonomic nervous system dysfunction and a lack of catecholamine release. Suspect hypoglycemia in any patient with renal failure who exhibits changes in mental or neurologic status.

The pathogenesis of hypoglycemia in association with renal failure is frequently complex and involves multiple mechanisms. In a study of 56 patients with end-stage renal disease who were hospitalized with hypoglycemia over a 10-year period, the most common etiology was drug-induced (46% of patients).⁴ Sepsis was a contributing factor in 39% of all patients, and severe malnutrition was responsible for another 7%.

When evaluating patients with uremic hypoglycemia, first exclude drugs known to cause it (Table). In a study of 1418 cases of drug-induced hypoglycemia, sulfonylureas were the most common inciting drug, accounting for 63% of cases.⁵ Alcohol, propranolol HCl (Inderal), and salicylates were responsible for 19% of cases; and quinine, pentamidine (Pentam), ritodrine HCl (Yutopar), and disopyramide (Norpace) for 7%. Other medications that may cause hypoglycemia include colchicine, lithium (Eskalith, Lithobid), ganciclovir (Cytovene), fluoxetine HCl (Prozac, Sarafem), halothane, phenytoin (Dilantin), furosemide, selegiline HCl (Carbex, Eldepryl), and imipramine HCl (Tofranil).^6,7

Sulfonamides were first noted to cause hypoglycemia in 1942, when they were used to treat typhoid fever. This paved the way for the development of the sulfonylureas used to treat diabetes mellitus. SMX is structurally similar to sulfonylureas in its possessing an amine group attached to a sulfur molecule. It has been postulated that SMX induces hypoglycemia by stimulating the pancreatic islet cells to secrete insulin.⁸ The elevated serum C-peptide and insulin levels in our patient substantiate this mechanism. In addition, the parent compounds as well as the metabolites of TMP and SMX are excreted in the urine. However, only the parent compounds of the drugs are excreted in the bile.⁹ In patients with normal renal function, the plasma half-lives of TMP and SMX are approximately 11 and 9 hours, respectively. These half-lives are prolonged in renal dysfunction.¹⁰

Spontaneous hypoglycemia in patients with impaired renal function has been reported previously, but serum insulin levels were normal in those cases. Our patient had inappropriately high plasma concentrations of insulin and C-peptide. Malnutrition, a risk factor for hypoglycemia, does not cause elevated insulin levels. In addition, our patient's nutritional intake had been adequate, and his weight had been stable over the past 3 months (body mass index, 25.5). Also, serum glucose concentrations after fasting are not significantly decreased because of higher ketone body metabolism. Afactor that may have contributed to our patient's condition is the increased risk of TMP/SMX toxicity noted in patients infected with HIV.¹¹

Furthermore, CHF can contribute to hypoglycemia by hepatic congestion, but it does not cause elevated insulin levels, and there was no evidence of hepatic congestion in our patient. Insulinomas can cause elevated insulin and C-peptide levels, but the absence of additional episodes of hypoglycemia minimizes the likelihood in this patient. Although serum levels of SMX were not measured in our patient, they were probably elevated, accounting for the hyperinsulinemia and prolonged hypoglycemia.

Our patient was subsequently rechallenged with TMP/SMX after he began hemodialysis. He had no further episodes of hypoglycemia, however, since we used a reduced dosage of TMP/SMX, adjusted for his renal function.

Peritoneal dialysis is ineffective in eliminating TMP/SMX, with one study showing a mean half-life of TMP of 28 hours and of SMX of 12.5 hours in patients on continuous ambulatory peritoneal dialysis.¹² Hemodialysis removes moderate amounts of both SMX and TMP, reducing the half-lives of both drugs to normal values.¹³ In hemodialysis patients, 50% of the maintenance dose of TMP/SMX should be supplemented after each dialysis session, because 57% of SMX is removed in a 4-hour hemodialysis session.¹⁴

Management of hypoglycemia

If hypoglycemia is determined to be drug-induced, the offending medication should be discontinued. Oral glucose can be used to treat mild hypoglycemic episodes, but hypoglycemia caused by insulin secretagogues is usually prolonged, depending on the halflife of the drug. Glucagon mobilizes hepatic glycogen and induces hepatic gluconeogenesis. Higher blood glucose levels stimulate the pancreatic beta-cells to secrete more insulin, which lowers blood glucose levels, making it a temporizing measure. Glucagon has a slower onset of action than IV glucose and is used when IV access is unavailable.

Frequent monitoring of blood glucose is recommended in patients with hypoglycemia. In refractory cases, such as with sulfonylurea overdose, octreotide acetate (Sandostatin) may suppress insulin release and restore euglycemia. Octreotide acts by inhibiting insulin secretion from the pancreatic beta-cells and inhibiting glucagon secretion. Diazoxide (Hyperstat) can also be used but has many adverse effects, including Stevens-Johnson syndrome, hirsutism, hypotension, and fluid retention. It acts by inhibiting insulin release from the beta-cells and increasing insulin clearance. The half-life of SMX is 6 to 12 hours. If there are risk factors, such as impaired clearance because of renal dysfunction, prolonged fasting conditions, malnutrition, or the use of excessive doses, hypoglycemia may be prolonged (about 12 hr) and warrants hospital admission.¹⁵

Conclusion

Severe hypoglycemia has been reported as an unusual adverse reaction of TMP/SMX therapy, especially in patients with renal insufficiency. Physicians should be aware that TMP/SMX may cause reversible, prolonged hypoglycemia, particularly when renal function is compromised. This case demonstrates the need to adjust the dose of TMP/SMX for renal function, and to closely monitor patients for hypoglycemia.

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