LAUSR

Sleep is an essential component of childhood development, the result of complex neurophysiologic processes of activation, and suppression of the neural pathways.1 These pathways are constantly developed and refined over the first few months to years of life and subject to many individual and environmental factors. Not surprisingly, up to 25% of the children under 5 years of age experience sleep difficulties.1 This number may very well be underestimated, as only a subset of sleeping problems come to medical attention, typically being accepted as a variant of normal development. Therefore, sleeping difficulties observed in the context of patients treated with betablockers raised the question if this was a drugrelated phenomenon or a childhood developmental variant. Propranolol, owing to its lipophilicity, has the ability to cross the bloodbrain barrier and interfere with the melatonin secretion potentially leading to sleep disturbances.2 An additional potential mechanism could be increased wakefulness due to lower blood sugar levels. The magnitude of the problem in infants with infantile hemangioma on systemic propranolol is hard to appreciate, ranging from 12%14%.37 In a systematic review comparing all current and historical treatments for infantile hemangioma, propranolol had a higher association with CNS sideeffects and sleeping difficulties compared to other nonsteroidal modalities (RR = 1.4 and RR = 1.63, respectively).8 As most are parental reports, the severity, frequency, and persistence of the problems is not easily quantifiable, even in controlled studies. What has been observed though is that sleeping difficulties may be severe enough in some cases to be the main reason for treatment discontinuation.9 In an attempt to understand this issue, Frost et al10 designed a prospective study using a validated questionnaire, Brief Infant Sleep Questionnaire (BISQ), and a bracelet actigraph (measuring movement as a surrogate marker of wakefulness) 1 week before propranolol initiation and 5 weeks after. They concluded that there was no evidence of increased sleep disturbance in patients treated with propranolol. While on the surface, their conclusion is reassuring, the study had limitations well acknowledged by the authors such as very small sample size, very few patients participating in the actigraphy portion (10/55), and very short duration of followup (5 weeks). Additionally, the BISQ questionnaire lacks granularity and tends to emphasize sleeping issues that are in the normal variant range of developmental problems (“Is the sleep problem a small problem or none at all?”). The fact that the last daily dose of propranolol was administered in early afternoon in this study may have been the biggest confounder. Propranolol's peak plasma concentrations occur after 12 hours after administration, and the elimination halflife is approximately 36 hours. If given in the early afternoon, less propranolol will be in the blood stream at night, potentially causing less sleep disturbance. Moreover, two separate pharmacokinetic studies demonstrated that irregular twice daily dosing with as short as a 6hour interval does not affect propranolol's efficacy.11,12 In fact, this is probably the stronger conclusion I would derive from the study. Instead of reassurance about propranololrelated sleeping issues a definitive answer would require a significantly larger sample size one message of the study should be that if sleep disturbances occur, dosage modifications, with earlier administration well before the standard nighttime dosing, should be tried first before considering discontinuation or switching to another less lipophilic betablocker.