Although several studies have identified possible risk factors for poor neurodevelopmental outcomes in children undergoing anesthesia and surgery, few have been able to make definitive associations, given the complex nature of neurodevelopment and the many potential factors that affect it.
“The FDA has highlighted some risk factors for neurodevelopmental delay in children,” said George M. Hoffman, MD, professor and chief of anesthesia at the Children’s Hospital of Wisconsin and Medical College of Wisconsin, both in Milwaukee. “These include age less than 3 years, exposure to multiple anesthetics and prolonged anesthesia exposure of greater than three hours.
“Our primary question was this: Are these risk factors specific for neurodevelopmental delays or are they related to overall mortality?” he said. “The specific aim of our study was to characterize the risk factors for mortality and morbidity following anesthesia and surgery in a population of children undergoing care in a large, regional children’s health system.”
The investigators hypothesized that the risk factors of age and multiple or prolonged exposure to anesthesia and surgery would be related to what they called the “hard outcome of mortality” and not uniquely linked to neurodevelopment.
To elucidate this possible relationship, Dr. Hoffman and his colleagues investigated the records of 61,088 children who underwent 104,237 cases (average, 1.73±2.3 cases per patient; range, one to 87 cases) at the institution and its outpatient center between 2013 and 2016. On average, patients were aged 5.4±9.7 years, weighed 19.6±30.4 kg, and had an ASA physical status of 2.2±0.84.
“Thirty-nine percent had an ASA score of greater than II, 25% were less than 2 years of age, and 18% were less than 10 kg,” he added. The median anesthesia time was 62 minutes, the median average anesthetic exposure was two per patient, and the median cumulative anesthesia time was approximately 100 minutes. A number of variables were extracted, including age, ASA physical status score, individual and cumulative anesthesia duration, number of cases, and the interval between the date of service and the date of death, if applicable.
At the 2017 annual meeting of the American Society of Anesthesiologists (abstract BOC04), Dr. Hoffman revealed that 400 patients in the cohort died, yielding a patient mortality rate of 0.65% (95% CI, 0.59%-0.72%). The overall case mortality risk was:
- 0.135% (95% CI, 0.11%-0.16%) at 48 hours;
- 0.539% (95% CI, 0.49%-0.59%) at 30 days; and
- 2.62% (95% CI, 2.52%-2.72%) at an average follow-up of 800 days.
Death occurred at a median of 147±320 days (range, zero to 1,483 days) after any case, at 172±465 days after the first case, and at 20±90 days after the last case.
“There was, not unexpectedly, a very strong relationship between the ASA physical status score and mortality rate,” Dr. Hoffman said. Perhaps not surprisingly, ASA physical status correlated with exposure to multiple and prolonged procedures. Younger age, case duration and the number of cases were thus also related to mortality.
“We also looked at previously described risk factors for poorer neurodevelopmental outcomes,” Dr. Hoffman said. Mortality odds ratios were:
- 1.80 (95% CI, 1.67-1.95) for age less than 3 years;
- 16.2 (95% CI, 14.9-17.6) for ASA physical status greater than III;
- 2.09 (95% CI, 1.88-2.31) for anesthesia duration longer than three hours;
- 19.1 (95% CI, 16.6-22.0) for number of cases greater than three; and
- 9.96 (95% CI, 9.00-11.0) for cumulative anesthesia duration longer than three hours.
“These factors were then entered into a multivariable logistic regression,” Dr. Hoffman explained. “In general, we found that the effect of ASA physical status risk was reduced in this analysis, as were age effects and the effects of the individual FDA selectors.” The regression also revealed that greater cumulative case time and multiple cases remained risk factors, whereas longer duration for each individual case was not a risk factor. The cutoff age for higher risk was younger than 2 years.
Risk Factors Pertinent to Mortality, Neurodevelopment
“In summary,” he said, “exposure to anesthesia and surgery identified children at significantly longer term risk of mortality at 30 days. Age, ASA physical status score and multiple/prolonged exposures all had associations with higher mortality risk in univariable analysis. After controlling for ASA physical status score, multiple exposures and cumulative exposure time had small, incremental effects on mortality.
“So the risk factors for mortality were similar to those risk factors previously identified for neurodevelopmental delay. These factors select a subpopulation of children with higher disease burden, which is associated not only with potential neurodevelopmental impairment but also with mortality,” Dr. Hoffman added.
Peter J. Davis, MD, professor of anesthesiology at the Children’s Hospital of Pittsburgh of UPMC, did not find the results of the study particularly surprising. He said they provide another important piece of an evolving research puzzle. “Based on these findings, we can say that maybe what causes neurocognitive impairment are the underlying disease processes in the patient that may get manifested when an anesthetic is administered.” Dr. Davis, who serves on the advisory board of Anesthesiology News, added, “So if they have their illness and they’ve had an anesthetic, that becomes the foundation for developing neurocognitive impairment.”