Relationship between zolpidem concentrations and sleep parameters in pediatric burn patients

Abstract

Zolpidem is a short-acting non-benzodiazepine hypnotic that is used to improve sleep architecture in patients with burn injuries. This study evaluated the relationship between zolpidem administration and sleep parameters in a cohort of children with severe burn injuries. Standard age-based zolpidem dosing practices were employed. Polysomnography data were recorded at 30-second intervals throughout the night. Serum concentrations of zolpidem were measured at 0, 1, 2, 4, 5, 6, and 8 hours after administration of the first dose. The relationship between zolpidem concentrations and sleep parameters was evaluated using Markov mixed-effects pharmacodynamic models. Ten children received two doses of zolpidem at 22:00 and 02:00 hours. The median total amount of sleep was 361.0 (interquartile range [IQR]: 299.0-418.5) minutes; approximately 65% of the normal reference value for an 8-hour period. Slow-wave and rapid eye movement (REM) sleep were also dramatically reduced (18-37% of normal). With two doses of zolpidem, stage 2 sleep was 99% of normal levels. Higher peak zolpidem concentrations were associated with increased stage 2 sleep (r = .54; P = .04). Despite this, a median of 120.0 (IQR: 99.5-143.5) transitions between nocturnal sleep stages were recorded, with a median of 55.5 (IQR: 36-75) night-time awakenings per patient. In pediatric burn patients, higher zolpidem serum concentrations were associated with restoration of stage 2 sleep to normal levels. Nonetheless, slow-wave and REM sleep were profoundly depressed with frequent transitions between sleep stages, suggesting that alternative hypnotic agents may be required to restore normal sleep architecture in severely burned children.

Figures

Figure 1

Distribution of sleep stages for 10 severely burned children who received zolpidem. Each participant had polysomnographic measurements obtained every 30 seconds for the duration of the night. The total duration of sleep was approximately 65% of normal age- and gender-matched reference values. This was primarily because of markedly lower amounts of slow-wave and rapid eye movement (REM) sleep than would be expected for healthy children. Two doses of zolpidem effectively restored the amount of stage 2 sleep to normal levels. The sleep patterns observed in these children exhibit signs of sleep fragmentation, including more than 50 nocturnal awakenings, which has been previously reported among children with severe burn injuries.

Figure 2

The probability of transiting between sleep stages changes following zolpidem administration. The x-axis represents the total duration of the night-time and is scaled from 0 (initial sleeplessness) to 1 (final awakening), as a proportion of the 8-hour study period. Solid black lines depict the predicted transition probabilities within the next 30 seconds for severely burned children who received zolpidem (shaded grey areas represent the 95% confidence intervals). Black arrows indicate the timing of the second administration of zolpidem. Administration of the second dose of zolpidem was associated with an increased likelihood of transitioning from stage 1 to stage 2 sleep. The second dose of zolpidem was also associated with a decrease in the likelihood of waking from stage 1 sleep. In contrast, the second dose of zolpidem was associated with a reduced likelihood of transitioning from stage 1 sleep to slow-wave and rapid eye movement (REM) sleep.