Propranolol treatment was recently reported to be successful for the management of severe infantile hemangioma. Known adverse effects of propranolol treatment include transient bradycardia, hypotension, hypoglycemia, and bronchospasm (in patients with underlying spastic respiratory illnesses), which led to a general recommendation to gradually increase propranolol dosage and closely monitor patients' hemodynamics at the onset of therapy. To date, no serious or unexpected adverse effects that required specific intervention have been reported. In this report, we describe the case of a 17-week-old female preterm infant who presented with a large, ulcerated, cutaneous-subcutaneous hemangioma of the right lateral thoracic wall, which we treated successfully with propranolol. A few days into therapy, a potentially life-threatening adverse effect, severe hyperkalemia, was observed and required treatment with loop diuretics, fluids, and nebulized salbutamol to normalize her serum potassium levels. This therapy could be gradually tapered and finally discontinued only after several weeks of propranolol treatment. Our case report indicates that, at least during the initial phase of the propranolol treatment of infantile hemangioma, close monitoring of serum electrolytes, besides the monitoring of hemodynamics and blood glucose, is necessary.
Infantile hemangiomas are the most common soft-tissue tumors of infancy.1 They have a heterogenous clinical presentation and vary from small and spontaneously involuting to massive, ulcerating, secondarily infected, and generally problematic tumors.1 Recently, treatment with propranolol, a nonselective β1- and β2-blocker, has been reported to be successful for the management of such problematic infantile hemangiomas.2,–,4 This novel treatment has demonstrated rapid tumor reduction within days of therapy leading to overall improvement of symptoms.
Because of known possible adverse effects of propranolol, such as transient bradycardia, hypotension, hypoglycemia (especially in newborns), and bronchospasm (in patients with underlying spastic respiratory illnesses), a gradual increase of dosage (starting dosage: 1 mg/kg per day, increased to 2 mg/kg per day after 24 hours if no complications occur) and close monitoring of patients' hemodynamics at the onset of therapy were generally recommended in Germany.5 Furthermore, before initiating propranolol therapy, it is recommended to rule out hypoglycemic conditions and underlying cardiac or pulmonary conditions.
The majority of case reports of propranolol treatment for infantile hemangioma either do not mention adverse effects or stated that the patients had none.3,6,–,12 Seldom-reported adverse effects include asymptomatic hypoglycemia,13 transient hypotension,4,13,14 asymptomatic and transient bradycardia,15 wheezing,4 somnolence, gastroesophageal reflux, rash, and respiratory syncytial virus infection exacerbation.16 In the cases of rash, wheezing, and 1 instance of transient hypotension, propranolol therapy was discontinued. All reported adverse effects resolved without specific therapy.
Here, we present a case of severe hyperkalemia that occurred within a few days after initiation of propranolol treatment of a large infantile hemangioma; describe our management protocol; and discuss possible causes of the hyperkalemia.
A 17-week-old female preterm infant was presented to us with a large cutaneous-subcutaneous hemangioma located on the right lateral thoracic wall. The infant was born at 28 weeks of gestation via cesarean delivery (because of placental insufficiency). Her birth weight was 735 g. Postnatal management included intubation, administration of surfactant, and ventilation over a period of 3 days, followed by continuous positive airway pressure ventilation support for another day. No major complications occurred throughout this period.
Five days after birth, a small hemangioma on the infant's right lateral chest wall was noted. The hemangioma was frequently monitored thereafter, but initially no therapy was undertaken. However, the hemangioma grew progressively cutaneously and subcutaneously, and at the time of presentation to our clinic, it was 11 × 8 × 1.5 cm, ulcerated, and superinfected (Fig 1A). A Doppler ultrasound examination revealed a massive hemangioma with deep underlying prominent blood vessels. To diagnose organ involvement and define the extent of the hemangioma, gadolinium-enhanced MRI was performed. The MRI revealed pronounced contrast enhancement in the skin that spread deep into the intercostal musculature and a 3-mm enhancement on the pleura. Pronounced drainage veins with increased caliber, compared with contralateral veins, were observed on the ipsilateral side of her thorax. No single feeding artery could be identified. In addition, a solitary 3-mm faint contrast enhancement was observed in the liver (Fig 2).
After a cardiologic workup, which included electrocardiography and echocardiography, revealed no contraindications for propranolol therapy, 1 mg/kg per day of propranolol divided into 3 doses was started orally and increased to 2 mg/kg per day on day 2. Heart rate, blood pressure, and blood glucose and electrolyte levels were monitored regularly. Except for transient hypotension on day 8 during sleep (67/25 mm Hg), which was treated with intravenous fluids, the patient's hemodynamics were stable throughout the treatment period. Parallel to the initiation of propranolol therapy, a systemic infection with fever, increased white blood cell count (maximum: 19 × 103/μL), and an elevated C-reactive protein level (maximum: 58.7 mg/L) developed (Fig 3). The wound swab revealed growth of Staphylococcus aureus. The infection was treated intravenously with cefuroxime according to antibiogram results. Enzymatic debridement of necrotic tissue was performed daily,17,18 and the ulcerated hemangioma was covered with an antiseptic dressing. These procedures were performed under analgesia, as manipulation was extremely painful.
After 72 hours of therapy, a significant increase of the patient's serum potassium levels without electrocardiographic changes was noted (Fig 3). When potassium levels exceeded 6 mmol/L, intensive antihyperkalemia therapy was initiated. A single intravenous bolus of 1 mg/kg furosemide followed by 1 mg/kg per day intravenous furosemide, fluids, and nebulized salbutamol 6 times daily led to normalization of the patient's serum potassium levels. Her diuresis and serum creatinine levels remained normal. Because a remarkable macroscopic reduction in size and thickness of the hemangioma was noted and the patient responded and tolerated the antihyperkalemia therapy well, and given the rapid growth of the hemangioma (which was progressively ulcerating), we opted for the continuance of propranolol therapy. An attempt to reduce the furosemide dose on the second day resulted in prompt elevation of serum potassium levels (Fig 3). In the following days, stable potassium levels were achieved with furosemide 0.8 mg/kg per day, divided in 3 doses. Intravenous furosemide therapy was replaced by oral furosemide on day 10. Salbutamol inhalation was discontinued on day 9. Her plasma lactate dehydrogenase level was elevated (372 U/L), and her plasma uric acid level was within the normal range (27 mg/L) (Fig 3).
Our patient was discharged with normal and stable serum potassium levels under 0.5 mg/kg per day furosemide, and her ulcerations and systemic infection had healed. At follow-up, furosemide could finally be discontinued 47 days after initiation of the therapy. Her serum potassium levels remained within the normal range thereafter. The hemangioma continued to regress (Fig 1B), and propranolol therapy was terminated after 5 months of treatment.
Until recently, the standard first-line therapy for severe infantile hemangiomas was systemic administration of corticosteroids.1 This therapy has a rather slow therapeutic response and a nonresponder rate that varies from 6% to 31%, depending on applied corticosteroid dosage (dose > 3 mg/kg per day: higher response rate; dose < 3 mg/kg per day: lower response rate).19,20 Adverse effects, which are more prominent as the dose increases, include cushingoid facies, personality changes, gastric irritation, fungal infection, transient diminished longitudinal growth, transient diminished weight gain, persistent hypertension, hyperglycemia, and hypothalamic-pituitary-adrenal axis suppression.21,–,23 Furthermore, rapid discontinuation of corticosteroid therapy leads to a rebound effect and regrowth of the treated hemangioma.1,19,20 Second- and third-line treatment options are vincristine and interferon α, which are both neurotoxic and associated with serious adverse effects.1,20
Propranolol therapy is a novel treatment option for severe infantile hemangiomas. Several case reports have revealed rapid and substantial regression of these hemangiomas. Because of potential adverse effects that generally accompany β-blocker therapy, such as hypotension and bradycardia, hospitalization and basic hemodynamic monitoring (electrocardiography and noninvasive blood pressure monitoring) of patients in the initial phase of propranolol therapy is recommended.6 As mentioned above, no serious adverse effects requiring specific therapy have yet been reported. In our patient, severe hyperkalemia (without pathologic electrocardiographic changes) was observed 4 days into propranolol therapy. Specific therapeutic measures were required to normalize her potassium levels. A systemic infection coincided with the introduction of propranolol therapy and necessitated antibiotic therapy. The patient's kidney functions remained normal throughout this period and evidently did not impair potassium excretion.
Although there has been considerable experience with propranolol in pediatric cardiology, hyperkalemia is not a documented adverse effect of propranolol therapy.24,25 However, propranolol has been reported to impair the β2-receptors via uptake of potassium into cells whilst renal potassium excretion remains intact.26 In this manner, propranolol slows the normalization of exercise-induced hyperkalemia during recovery from exercise in healthy adults.27,–,29 Hyperkalemia is also not a registered adverse effect of cefuroxime therapy.30
The proposed mechanisms of action of propranolol in the treatment of infantile hemangioma are the induction of apoptosis, inhibition of angiogenesis, and alteration of vascular tone.31 Propranolol induces apoptosis in capillary endothelial cells in vitro,32 and a massive and abrupt breakdown of cells is a known cause of hyperkalemia.33,34 Massive lysis of malignant cells typically also induces hyperuricemia, hyperphosphatemia, and hypocalcemia33,35 and is frequently observed after the initiation of cytotoxic therapy in patients with hematologic malignancies. This condition is known as the tumor lysis syndrome (TLS) and is well defined for malignant diseases. Malignant cells differ, however, from normal cells in their up-to-fourfold-higher phosphorus content and high nucleic acid content,36 which could explain why our patient had no other signs of TLS. Furthermore, our patient was treated with intravenous fluids and diuretics, which is also standard therapy for the prevention of TLS, as it enhances urine flow and promotes excretion of metabolites and ions.37
The rapid macroscopic shrinkage of the hemangioma remains unequivocal clinical evidence of tumor regression/lysis. The hypothesis that our patient's hyperkalemia was the result of both elevated potassium load caused by tumor lysis and impaired potassium uptake into cells caused by β-blockade seems plausible. It is noteworthy that after visible shrinkage of the hemangioma, the patient's potassium levels normalized and permitted furosemide tapering while the patient was still being treated with propranolol.
Hyperkalemia is a serious but treatable complication when diagnosed early. To our knowledge, this is the first report of a potentially life-threatening complication of propranolol treatment for infantile hemangioma. Our case strongly indicates that close monitoring of patients' electrolyte status, in addition to blood glucose and hemodynamic monitoring, is required.
- Accepted August 9, 2010.
- Address correspondence to Helena Pavlaković, MD, Department of Anatomy and Cell Biology, University Hospital Göttingen, Kreuzbergring 36, D-37075 Göttingen, Germany. E-mail:
FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.
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- Copyright © 2010 by the American Academy of Pediatrics