Apneic episodes

An MRL of 0.1 ppm was derived for intermediate inhalation exposure (15-364 days) to trichloroethylene. This MRL was based on a study by Arito et al. (1994a) in which male JCL-Wistar rats were exposed to 0, 50, 100, or 300 ppm trichloroethylene for 6 weeks, 5 days/week, 8 hours/day. A LOAEL of 50 ppm was observed for decreased wakefulness during exposure, and decreased postexposure heart rate and slow wave sleep. Another study with rats found an increase in sleep-apneic episodes and cardiac arrhythmias after exposure to trichloroethylene (Arito et al. 1993). These results corroborate similar effects observed in humans exposed to trichloroethylene, as described in the previous paragraph, as well as evidence of organic solvent-induced sleep apnea in humans (Edling et al. 1993 Monstad et al. 1987, 1992 Wise et al. 1983). 

The apneic episode is terminated by a reflex action in response to the fall in blood 02 saturation that causes a brief arousal during which breathing resumes. 

Amikacin may have been the causative agent in an apneic episode in an infant on peritoneal dialysis (1). 

Apneic episodes have been reported in patients given sufentanil (SEDA-20, 81) (SEDA-21, 89). Respiratory arrest occurred 55 minutes after epidural and intrathecal sufentanil and bupivacaine (SEDA-18, 82). 

Splanchnic oxygen delivery in neonates during apneic episodes was studied by Petros et al. [145], while peripheral... 

The metliylenetetraliydrofolate reductase enzyme reduces 5,10-methylenetetrahydrofolate to form 5-methyltetrahy-drofolate, which provides methyl groups necessary for homocysteine remetliylation to methionine. The severity of the enzyme defect and of clinical symptoms varies considerably. Completely absent enzyme activity results in neonatal apneic episodes, myoclonus leading to coma, and death, whereas partial deficiency may result in mental retardation and seizures. Premature cardiovascular disease or peripheral neuropathy could be the only manifestation. A common polymorphism (677C>T) is associated with enzyme thermal lability and mild elevation of homocysteine in the presence of folate insufficiency, implicating a risk for both vascular disease and neural tube defects. ... 

FIGURE 27.1 Distribution of apneic episodes per day. The fraction of all patient days is represented by each level of apneic episodes. 

The study enrolled 97 infants of gestational ages of 24-33 weeks admitted to the neonatal intensive care unit of Connecticut Children s Medical Center (Hartford, CT) (3). Twenty-eight infants were studied prospectively, 69 retrospectively. The neonates were studied from birth up to a maximum of 18.286 postnatal weeks. Data on daily apneic episodes were obtained on approximately 5000 patient-days for 95 of the neonates. Figure 27.1 shows a distribution of the number of apneic episodes per day across all neonates and postnatal days studied. The mean (SD) number of spells per day was 1.93 (2.91). TTie range was 0-30 episodes per day. Figure 27.2 depicts the time course of the mean daily episode count with respect to postnatal age. The frequency increases up to approximately 1.5 weeks and declines gradually as the infants mature. 

A population PK and PK/PD analysis was performed to develop a model for the time course of theophyUine concentrations and for the time course and exposure-response of apneic episodes to treatment with theophylline (3). Results of the population pharmacokinetics of theophylline will not be presented. 

FIGURE 27.2 Mean (+SD) apneic episodes per day by postnatal age. Error bars are +1 standard deviation. Postnatal days for which episodes were recorded in only one neonate are excluded. 

APPLICATION OF POISSON-BASED POPULATION ANALYSIS TO APNEIC EPISODE DATA... 

Apnea of prematurity generally resolves as the neonate matures and approaches typical term age. Therefore, the PK/PD model must account for this trend with respect to time. Figure 27.2 showed the time course of apneic episode frequency. The number of daily episodes increased after birth with a peak between 1 and 2 weeks on average. A gradual decline was observed thereafter. A number of functional forms were considered to describe this profile, but two of the models evaluated are presented here. The first model, TCI (Eq. (27.15)), included a zero-order progression rate of episode frequency and a first-order resolution rate of episode frequency. In the second model, TC2 (Eq. (27.16)), the progression and resolution rates were both treated as first-order processes. Note that the use of resolution is meant to imply lessening of disease severity with maturity, not resolution of a specific apneic episode. 

FIGURE 27.7 Subject level predicted versus observed daily apneic episode counts, base model. Predicted number of apneic episodes per day versus observed apneic episodes per day. The line is the line of identity. The predictions are based on individual estimates of X, the Poisson mean. The predictions are individualized as they arise from the subject level realization of rj, the interindividual random effect. 

The use of a biexponential equation with postnatal age as the time scale permits some practical interpretation of the time course component of the final PD model. Table 27.2 presents the peak spell frequency, the time to achieve peak frequency, and the model predicted resolution half-time of apnea in absence of therapy. The resolution half-time defines the number of days of postnatal maturation that transpire before the daily spell frequency is reduced by one-half. The influence of hyaline membrane disease on resolution half-time is readily apparent. The most premature neonates with HMD have the slowest time to maximum episode counts and have the highest frequency of apnea. A 24 week gestational age infant with HMD requires an additional 7 days for a maturational reduction in spell count of one-half. The half-time of apnea onset is approximately 2.5 days. On average, the greatest severity of apnea would occur at approximately 1 postnatal week. Figure 27.10 depicts the baseline apneic episode frequency versus postnatal age for each gestational age in the present study. The predictions of daily spell count are population predictions, calculated using the final parameter estimates for PRE, and... 

FIGURE 27.9 Predicted and observed average daily apneic episode count versus postnatal age. The average daily apneic episode count was calculated as the mean across all neonates for each postnatal day. The observed data are represented by the solid circles, the plus denotes average conditional predictions from the base PD model, and the open circles represent the average conditional predictions from the final PD model. 

FIGURE 27.10 Model predicted baseline apneic episode frequency. The population prediction of the baseline daily apneic episode counts in the absence of drug effect. The population estimates are calculated using the final PD model parameter estimates in the biexponential function describing the time course of neonatal apnea. Each line represents a gestational age the top line represents a 24 week gestation infant, the bottom line a 35 week gestation infant. 

In contrast, hypnotic doses of benzodiazepines may worsen sleep-related breathing disorders by adversely affecting control of the upper airway muscles or by decreasing the ventilatory response to CO2. The latter effect may cause hypoventilation and hypoxemia in some patients with severe COPD, although benzodiazepines may improve sleep and sleep structure in some instances. In patients with obstructive sleep apnea (OSA), hypnotic doses of benzodiazepines may exaggerate the impact of apneic episodes on alveolar hypoxia, pulmonary hypertension, and cardiac ventricular load. Caution should be exercised with patients who snore regularly partial airway obstruction may be converted to OSA under the influence of these drugs. 

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