Recently published studies evaluate treatments for common problems in children

December 2006

In previous years, the December issue of Pharmacology Consult has included discussions of the year’s drug approvals.

In 2006, several drug products useful to the pediatric population were approved by the FDA: Gardasil, Merck (quadrivalent human papillomavirus, approved June 2006), Rotateq, Merck (live oral pentavalent rotavirus vaccine, approved February 2006), Elaprase, Shire (idursulfase, for treatment of mucopolysaccharidosis II/Hunter Syndrome, approved July 2006), and Myozyme, Genzyme (alglucosidase alfa, for treatment of Pompe disease/glycogen storage disease type II, approved April 2006).

Of these new approvals, Gardasil and Rotateq are likely to be the most commonly used by general pediatric practitioners. Because these two new vaccine products have previously been reviewed and discussed extensively in Infectious Diseases in Children this year, the focus of this month’s column will be highlights of the 2006 medical literature.

Hot air to treat head lice

An interesting study was published in November which evaluated a nonchemical method of treating head lice. Goates and colleagues tested six different methods of delivering hot air therapy to 169 children and adults with head lice. This study quickly found its way to the lay press, and pediatricians may be receiving questions about this treatment.

Children aged 6 years and older and their parents were recruited from elementary schools in Utah. Each patient’s hair was combed with a LiceMeister comb (National Pediculosis Association) until living lice were found. One side of the subject’s head was combed until no more lice or eggs were found. The entire scalp was then treated with one of six methods and the opposite side of the scalp was combed for a similar amount of time for lice and eggs. The study researchers said each study patient served as his or her own control.

The six different treatment methods, all completed in the patient’s home, were: 1) bonnet-style hair dryer (combined airflow of two bonnet-style hair dryers); 2) handheld blow-dryer: diffuse heating (hair divided in 10 sections with a clip and treated separately and with gradual movement for 3 minutes); 3) handheld blow-dryer: directed heating (hair divided into 20 sections with a clip and treated separately and stationary for one minute); 4) wall-mounted dryer (a detached wall-mounted blow dryer, similar to that found in public restrooms, with hose attached to the nozzle and used as 3) above); 5) LouseBuster with sections (custom built hot air blower with attached hose and used as 3) above); 6) LouseBuster with hand piece (custom built hot air blower with custom built hand piece and teeth, pulled through the patient’s hair).

The methods differed by volume of air blown and temperature, with methods 4 through 6 delivering more air than the bonnet-style and hand-held devices (range 9-103 cu ft/min). Mean temperature of air delivered ranged from 54.8°C to 60.8°C. Method 2) delivered the hottest air, and the LouseBuster methods delivered air with a temperature of 58.4°C-58.8°C. Treatment effectiveness was determined by comparison of viable lice and eggs removed from pretreatment and posttreatment sides of each patients scalp.

All six methods resulted in high egg mortality (>88%). They differed in the ability to kill live lice, ranging from 10.1% (bonnet-style hair dryer) to 80.1% (LouseBuster with hand piece). Control rates of lice mortality ranged from 2.8% to 14.9%. The study researchers state they envision this product to be used not in the home but by health care providers or perhaps school administrators. Three of the seven authors have financial associations with the hot air delivery devices used in this study.

Thus, while the results of this study are interesting and potentially of value, they are limited by several methodological factors. This study was not conducted in a randomized or blinded manner. The potential for bias certainly exists as several of the study authors have a vested financial interest in a positive outcome for the custom-built devices. The use of each patient as control and treatment may not be as valid as comparison of a treatment and placebo group, or comparison of hot hair delivery with conventional treatment (eg, malithione or permethrin). Other considerations of using this treatment include the costs and practicality of treatment in a clinician’s or school-based office, versus self-treatment in the home with current drug (OTC or prescription) treatments. Before hot air treatment can be recommended, additional studies, using appropriate methodology to limit bias, should be conducted.

Diphenhydramine for infant sleep – the TIRED study

Although there is no published evidence supporting the use of antihistamines for sleep in infants, surveys of primary care pediatricians reveal that nearly 50% recommend them to parents of children younger than 2 years of age. Because of this dichotomy, researchers conducted the TIRED study – the Trial of Infant REsponse to Diphenhydramine. This was a controlled randomized, double-blind, trial of infants aged 6-15 months.

Infants were eligible for study enrollment if they awoke two or more times a night. Diphenhydramine or identically appearing placebo was dosed at 1 mg/kg, given 30 minutes prior to bedtime, for seven days. The primary outcome measure was dichotomous: a parental report of improvement in the number of night awakenings requiring parental assistance. A power analysis indicated that 38 infants was necessary to be enrolled in each study group; however, a study analysis conducted prior to complete study enrollment revealed a lack of effectiveness of diphenhydramine, and the study was stopped early.

Of 22 infants receiving diphenhydramine, only one had improved sleep, compared with three of 22 infants receiving placebo. Why did diphenhydramine, one of the most sedating antihistamines available, not improve sleep for the infants enrolled in this study? The study researchers speculate on several reasons: diphenhydramine may have produced low-level hyperactivity that was not noticeable (antihistamines may possibly cause paradoxical stimulatory effects); the dose used, 1 mg/kg, was conservative (normal dosage range – 1-1.5 mg/kg), and may have been insufficient; or, as adherence was not objectively measured, it is possible not all doses were administered.

Although no other studies evaluating diphenhydramine in infants have been published, a study evaluating diphenhydramine (compared to dextromethorphan and placebo) in children 2-18 years of age for treatment of nocturnal cough and sleep found no effect of diphenhydramine (Paul, 2004). These studies contrast with a study published in 1976 of diphenhydramine given to children 2-12 years of age with sleep disorders, in which diphenhydramine was effective. Thus, despite the apparently common practice of administering diphenhydramine to infants for sleep, evidence from well-done scientific studies to support this use is lacking.

Adverse drug effects and errors

Published in October in the Journal of the American Medical Association was an important national surveillance of adverse drug events in nonhospitalized patients. Although the results of this study are most applicable to the adult population, it deserves mention as all ages were evaluated.

Researchers used data collected from the 2004 to 2005 National Electronic Injury Surveillance System-Cooperative Adverse Drug Event Surveillance project to assess the frequency and characteristics of adverse drug events leading to emergency department visits in the United States. Sixty-three hospitals participated in this surveillance system. An adverse drug event case was defined as an emergency department visit for a condition that the treating physician explicitly attributed to the use of a drug or drug-specific effect.

Over the two-year study period, 21,298 adverse drug event cases were reported, equating to 2.4 individuals per 1,000 population treated in emergency departments. Older individuals (>65 years) were most likely to sustain adverse drug events. The pediatric group evaluated included ages 0-4 years and 5-17 years. For the 0-4 year category, the annual population rate of adverse drug events was 4.3 per 1,000, which exceeded the rate for the entire population (2.4 per 1,000). This rate dropped dramatically to 1.0 per 1,000 for the 5-17 year category. Unfortunately, the researchers did not relate age categories to specific drugs or adverse events.

For the entire population, central nervous system agents and systemic antimicrobial agents were the leading therapeutic category to result in adverse drug events. Insulins, warfarin and amoxicillin were the leading specific drugs overall to cause adverse drug events. It is possible that amoxicillin and other antibiotics accounted for many of the adverse drug events in the 0-4 year category (eg, gastrointestinal adverse effects or pseudoallergic rashes), although this is speculative, as no drug-specific data were given for young children.

Lastly, a report recently published in The Annals of Pharmacotherapy analyzed 32 studies that noted dosing errors as the most common type of medication error. Often, the dosing errors were 10-fold errors. Most of the studies reviewed were completed in pediatric hospitals. Drug classes most commonly implicated were antibiotics and sedatives. The most important message from these studies may be that all health care practitioners providing care for pediatric patients should check drug doses, a relatively simple procedure.

For more information:

• Budnitz DS. National surveillance of emergency department visits for outpatient adverse drug events. JAMA. 2006;296:1858-66.
• Ghaleb MA. Systematic review of medication errors in pediatric patients. Ann Pharmacother. 2006;40:1766-76.
• Goates BM. An effective nonchemical treatment for head lice: a lot of hot air. Pediatrics. 2006;118:1962-70.
• Merenstein D. The trial of infant response to diphenhydramine. Arch Pediatr Adolesc Med. 2006;160:707-12.
• Paul IM. Effect of dextromethorphan, diphenhydramine, and placebo on nocturnal cough and sleep quality for coughing children and their parents. Pediatrics 2004;114:e85-e90.