In 2009 we reported the fatal case of a toddler who had received codeine after adenotonsillectomy for obstructive sleep apnea syndrome. The child was an ultra-rapid metabolizer of cytochrome P4502D6 (CYP2D6). We now report 3 additional fatal or life-threatening cases from North America. In the 2 fatal cases, functional gene duplications encoding for CYP2D6 caused a significantly greater production of potent morphine from its parent drug, codeine. A severe case of respiratory depression in an extensive metabolizer is also noted. These cases demonstrate that analgesia with codeine or other opioids that use the CYP2D6 pathway after adenotonsillectomy may not be safe in young children with obstructive sleep apnea syndrome.
We report here the case of an infant who developed life-threatening rigid-chest syndrome after receiving an accidental overdose of methadone. The child responded to narcotic reversal. Pediatric physicians should be aware of this possible complication.
Fatal opioid toxicity occurred in a developmentally delayed child aged 5 years 9 months who was inadvertently administered high doses of hydrocodone for a respiratory tract infection. The concentration of hydrocodone in postmortem blood was in the range associated with fatality; however, hydromorphone, a major metabolite catalyzed by cytochrome P450 2D6 (CYP2D6), was not detected when using mass spectrometry. Genetic analysis revealed that the child had a reduced capability to metabolize the drug via the CYP2D6 pathway (CYP2D6*2A/*41). Coadministration of clarithromycin (a potent cytochrome P450 3A4 inhibitor) for an ear infection and valproic acid for seizures since birth further prevented drug elimination from the body. This case highlights the interplay between pharmacogenetic factors, drug-drug interactions, and dose-related toxicity in a child.
Ethylmorphine, an opiate that is partially metabolized to morphine, is a common ingredient in antitussive preparations. We present a case where a 10-month-old boy was administered ethylmorphine in the evening and found dead in bed the following morning. Postmortem toxicological analyses of heart blood by gas chromatography-mass spectrometry and liquid chromatography-mass spectrometry revealed the presence of ethylmorphine and morphine at concentrations of 0.17 muM (0.054 mg/L) and 0.090 muM (0.026 mg/L), respectively. CYP2D6 genotyping showed that the deceased had an extensive metabolizer genotype, signifying a "normal" capacity for metabolizing ethylmorphine to morphine. The autopsy report concluded that death was caused by a combination of opiate-induced sedation and weakening of respiratory drive, a respiratory infection, and a sleeping position that could have impeded breathing. This is the first case report where the death of an infant has been linked to ethylmorphine ingestion.
Naloxone is a pure opioid antagonist specifically indicated for respiratory depression due to opioid exposure. There is not enough data on safety of naloxone, especially in extremely preterm neonates. We report the case of a preterm neonate (gestation 27 weeks and 3 days, birth weight 485 g) who developed cardiac arrest following treatment with naloxone (dose 100 mcg/kg) for a tenfold morphine overdose on day 7 while being ventilated for respiratory distress syndrome. Asystolic cardiac arrest occurred immediately after administering naloxone and required full resuscitation, including adrenaline and external chest compression. Recovery from the cardiac arrest was complete. However, the neonate died on day 45 of life due to unrelated causes. Reports of similar adverse effects of the drug in adults as well as data from animal models raise concerns about safety of naloxone, especially in preterm neonates, given the lack of data on the pharmacokinetics of the drug in this high-risk population. Possible explanations for the adverse event under such a scenario include an idiosyncratic reaction, hypoxia, direct myocardial depressant effect and sympathoadrenal interactions. Awareness of this rare but potentially lethal complication of naloxone is necessary to optimise the response to such an adverse event.
OBJECTIVES: Organic solvent exposure has been shown to cause hearing loss in animals and humans. Less is known about the risk of hearing loss due to solvent exposures typically found in US industry. The authors performed a retrospective cohort study to examine the relationship between solvent exposure and hearing loss in US aluminium industry workers.
METHODS: A cohort of 1319 workers aged 35 years or less at inception was followed for 5 years. Linkage of employment, industrial hygiene and audiometric surveillance records allowed for estimation of noise and solvent exposures and hearing loss rates over the study period. Study subjects were classified as "solvent exposed" or not, on the basis of industrial hygiene records linked with individual job histories. High frequency hearing loss was modelled as both a continuous and a dichotomous outcome.
RESULTS: Typical solvent exposures involved mixtures of xylene, toluene and/or methyl ethyl ketone (MEK). Recorded solvent exposure levels varied widely both within and between jobs. In a multivariate logistic model, risk factors for high frequency hearing loss included age (OR = 1.06, p = 0.004), hunting or shooting (OR = 1.35, p = 0.049), noisy hobbies (OR = 1.74, p = 0.01), baseline hearing level (OR = 1.04, p<0.001) and solvent exposure (OR = 1.87, p = 0.004). A multivariate linear regression analysis similarly found significant associations between high frequency hearing loss and age (p<0.001), hunting or shooting (p<0.001), noisy hobbies (p = 0.03), solvent exposure (p<0.001) and baseline hearing (p = 0.03).
CONCLUSION: These results suggest that occupational exposure to organic solvent mixtures is a risk factor for high frequency hearing loss, although the data do not allow conclusions about dose-response relationships. Industries with solvent-exposed workers should include such workers in hearing conservation programs.
Through pure-tone audiometry, we studied the course of hearing recovery in 24 ears of 20 men (ages 18-48 years) who had acute acoustic sensorineural hearing loss (ASHL). All subjects were members of the Japanese Self-Defense Force. The hearing level in 5 ears returned to normal, the hearing level of 13 ears recovered but was not within the normal range, and the hearing level of 6 ears was unchanged. The time from noise exposure to presentation was longer in patients with unchanged hearing than in other patients. Recovery of hearing was poorest at 4,000 Hz, followed by 8,000 and 2,000 Hz. We concluded that hearing in patients with acute ASHL is likely to return to normal when the hearing level at 4,000 Hz recovers gradually; partial recovery of hearing is expected when the hearing level at 4,000 Hz reaches an early plateau.
OBJECTIVES: To (1) estimate noise-induced permanent threshold shift (NIPTS) values from the data of the 1968-1972 Occupational Noise and Hearing Survey (ONHS); (2) compare these NIPTS estimates to NIPTS predictions from an international standard (ISO-1999); (3) determine why excess risk estimates based on the ONHS are so much higher than those based on ISO-1999.
DESIGN: The ONHS raw data were acquired from the National Institute for Occupational Safety and Health. Binaural average thresholds from 0.5 to 6 kHz were calculated for each of 1291 noise-exposed subjects (80 to 94 dBA, for up to 30 yr, all tested just before their shifts) and 665 non-noise-exposed control subjects (mostly office workers, tested throughout the work day). "Screened" subjects had had no prior significant noise exposure and had no evidence of other ear disease, whereas "excluded" subjects had failed one or more screening criteria. Twenty exposure groups were created (based on exposure level, exposure duration, and screened versus excluded status) and compared with 20 age-matched control groups. The median difference statistic estimated median NIPTS.
RESULTS: Median NIPTS estimates in the 3 to 6 kHz region were generally consistent with the NIPTS predictions of ISO-1999. At lower frequencies, especially at 0.5 and 1 kHz, the ONHS estimates were significantly larger than the ISO-1999 predictions, even for exposures below 90 dBA, but these differences did not increase systematically with exposure level and duration.
CONCLUSIONS: High-frequency median NIPTS estimates from ONHS data are consistent with the predictions of ISO-1999. Differences between exposed and control low-frequency thresholds in the ONHS are higher than predicted by ISO-1999, but these differences probably are related more to socioeconomic or test procedure effects than to occupational noise exposure. These low-frequency effects explain why excess risk estimates from the ONHS are higher than those based on ISO-1999.
BACKGROUND: Much of what is known about the exposure-response relationship between occupational noise exposures and hearing loss comes from cross-sectional studies conducted before the widespread implementation of workplace hearing conservation programmes. Little is known about the current relationship of ambient noise exposure measurements to hearing loss risk.
AIM: To examine the relationship between rates of high frequency hearing loss and measured levels of noise exposure in a modern industrial workforce.
METHODS: Ten-year hearing loss rates were determined for 6217 employees of an aluminium manufacturing company. Industrial hygiene and human resources records allowed for reconstruction of individual noise exposures. Hearing loss rates were compared to ANSI 3.44 predictions based on age and noise exposure. Associations between hearing loss, noise exposure, and covariate risk factors were assessed using multivariate regression.
RESULTS: Workers in higher ambient noise jobs tended to experience less high frequency hearing loss than co-workers exposed at lower noise levels. This trend was also seen in stratified analyses of white males and non-hunters. At higher noise exposure levels, the magnitude of hearing loss was less than predicted by ANSI 3.44 formulae. There was no indication that a healthy worker effect could explain these findings. The majority of 10 dB standard threshold shifts (STS) occurred in workers whose calculated ambient noise exposures were less than or equal to 85 dBA.
CONCLUSIONS: In this modern industrial cohort, hearing conservation efforts appear to be reducing hearing loss rates, especially at higher ambient noise levels. This could be related to differential use of hearing protection. The greatest burden of preventable occupational hearing loss was found in workers whose noise exposure averaged 85 dBA or less. To further reduce rates of occupational hearing loss, hearing conservation programmes may require innovative approaches targeting workers with noise exposures close to 85 dBA.
In 2009 we reported the fatal case of a toddler who had received codeine after adenotonsillectomy for obstructive sleep apnea syndrome. The child was an ultra-rapid metabolizer of cytochrome P4502D6 (CYP2D6). We now report 3 additional fatal or life-threatening cases from North America. In the 2 fatal cases, functional gene duplications encoding for CYP2D6 caused a significantly greater production of potent morphine from its parent drug, codeine. A severe case of respiratory depression in an extensive metabolizer is also noted. These cases demonstrate that analgesia with codeine or other opioids that use the CYP2D6 pathway after adenotonsillectomy may not be safe in young children with obstructive sleep apnea syndrome.
