Benzodiazepine Exposure Can Predict Delirium in Critically Ill Children

Age, severity of illness and benzodiazepine exposure are the strongest predictors of delirium in critically ill children. According to a new study, given the prevalence of delirium in this vulnerable population, studies targeting benzodiazepine exposure as a potentially modifiable target are warranted to reduce the burden of cognitive impairment.

“Unfortunately, delirium is extremely prevalent among critically ill children,” said Heidi Smith, MD, MSCI, a pediatric anesthesiologist at Vanderbilt University Medical Center, in Nashville, Tenn. “Our study has demonstrated that younger age, higher severity of illness and, more importantly, benzodiazepine exposure are independent risk factors for increased delirium duration. Benzodiazepine administration was also significantly associated with the transition to delirium the day following drug exposure.”

As Dr. Smith reported at the 2016 annual meeting of the International Anesthesia Research Society (abstract S-95), the recently validated test, the PreSchool Confusion Assessment Method for the ICU (psCAM-ICU), designed for use in children 6 months to 5 years of age, has demonstrated an alarming prevalence of delirium. Approximately 44% of critically ill children in this population and over 50% of children younger than 2 years of age experience delirium during their ICU stay (Crit Care Med 2016;44:592-600).

Long-Term Cognitive Impairment

Studies also have shown that benzodiazepine exposure is a key risk factor for not only delirium in adults, but also long-term cognitive impairment in survivors of critical illness (N Engl J Med 2013;369:1306-1316; Anesthesiology2006;104:21-26).

“This is a poignant realization,” Dr. Smith said, “because currently the foundation of sedation in the pediatric ICU setting is benzodiazepine administration. Understanding the relationship between benzodiazepine exposure with delirium and long-term cognitive outcomes in children is paramount.”

For this prospective cohort study, Dr. Smith and her colleagues enrolled critically ill patients aged 6 months to 5 years who were admitted to the pediatric medical ICU (PICU) and pediatric cardiac ICU (PCICU) of a tertiary medical center.

Patients were evaluated for delirium using the psCAM-ICU for up to 14 daily assessments while in the ICU.

Of the 300 patients enrolled (median age, 20 months), 43% required mechanical ventilation, and 44% had at least one positive delirium assessment.

Age, severity of illness and higher benzodiazepine exposure were all significantly associated with longer duration of delirium, Dr. Smith reported.

Benzodiazepine use also was the strongest risk factor for transitioning to delirium. In multinomial models, increased benzodiazepine exposure was significantly associated with a higher likelihood of being delirious the day after compared with having normal mental status, the researchers noted.

Long-Term Effects of Delirium

“Our study demonstrates that benzodiazepine exposure is associated with an increased ICU length of stay, and there have been other, smaller studies that suggest delirium is associated with both longer ICU and hospital length of stay in children,” she explained. “But, even more important is the relationships between critical illness, delirium and sedation on the development of long-term cognitive impairment for arguably the most fragile population—our children.”

For Dr. Smith, the next phase of research for pediatric providers should involve further delineation of these relationships as well as advocating the benefits of avoiding the onset of delirium in the first place.

“Some of this may be attributable to critical illness,” she said, “but there are definitely cases of delirium that are associated with iatrogenic risk factors; those are the things that we really need to focus on as clinicians.”

Dr. Smith explained that delirium management is directed at treating the behaviors reflected by a sick brain. Although there is not “one” drug that can reverse the presence of delirium acutely, she asserted that providers can still take steps in the ICU to decrease the development or severity of delirium while effectively treating critical illness.

“We have to become really inventive about the way that we manage pain and anxiety in children rather than solely relying on sedation when in the ICU,” she said, “especially when they are on mechanical ventilation. We need better strategies for liberating them from the ventilator as quickly as possible.”

Intensivists Must Alter Goals

The proven relationship between delirium and long-term cognitive impairment in adults leaves obvious concern for a population whose brains are still maturing.

“What happens to children, who are on a steep curve of neurodevelopment, when they have a critical illness and develop delirium?” Dr. Smith asked.

In a study of delusional memory after ICU or critical illness, Gillian Colville, BSc, MPhil, CPsychol, a psychologist from London, showed that approximately one-third of children who survive critical illness have delusional memories of their ICU experience (Am J Respir Crit Care Med 2008;177:976-982). According to this study, children with delusional memories are more likely to have been exposed to high levels of benzodiazepines and opioids, and to later demonstrate higher post-traumatic stress disorder scores.

“A better understanding of the long-term effects of both critical illness and delirium on children will push us all to become more vigilant in changing practice to improve care,” Dr. Smith said. “As intensivists, we may think that we have done a good job if we can get the child out of the ICU breathing on their own … but, for a long time, we have failed to see that ‘A’ students now go home to become ‘C’ students, younger children have delay in normal development and still others continue to suffer psychologically.

“The goal must shift to not only treat critical illness, but consider and protect the brain as much as possible during this battle. Illustrating the prevalence of delirium and associated risk factors such as benzodiazepine exposure is the beginning. Now we go back to work to determine those strategies to change the status quo,” she concluded.