Sedation Practices in Pediatric Patients with Acute Lymphoblastic Leukemia

Five-year survival rates for children diagnosed with pediatric acute lymphoblastic leukemia (ALL) now exceed 90%. An estimated 20% to 40% of survivors, however, develop neurocognitive late effects. These can be very subtle changes in learning, including effects on executive function, working memory, processing speed, and visual-motor abilities. Specialized testing with a neuropsychologist helps to identify these needs.

“Interest in the risk of neurocognitive deficits for children treated for ALL with contemporary treatment regimens has tended to focus on the effects of chemotherapy directed to the central nervous system,” says Jean M. Tersak, MD, a hematologist/oncologist at UPMC Children’s Hospital of Pittsburgh, principal investigator with the Children’s Oncology Group (COG), and professor of pediatrics at the University of Pittsburgh School of Medicine, who studies late effects, quality of life, and neurocognitive outcomes in survivors of childhood cancer. 

Given the excellent survival rate in this population, it is important to consider other factors that may contribute to some patients' observed neurocognitive changes. One such factor is the use of repeated sedation for lumbar puncture procedures in patients with ALL.

To learn more about pediatric oncologists’ sedation practices in patients with ALL, Dr. Tersak and her colleagues conducted an electronic survey of individuals in leadership roles at 103 COG member institutions. The study, published in February 2020 in Pediatric Blood & Cancer, is the first to quantify the prevalence of sedation of ALL patients in COG institutions, which treat more than 90% of all the children and adolescents diagnosed with cancer each year in the United States.

Developing Brain

Studies in animal models suggest that sedation and general anesthesia may harm the developing brain. Data from human studies are scant, making this an under-represented area of investigation.  Since 2017, the U.S. Food and Drug Administration (FDA) has required drug manufacturers to include a warning on the labels of anesthetic and sedative agents indicating that repeated or lengthy use of these agents in children aged under three years or in women in the third trimester of pregnancy "may affect the development of children's brains."

“Children undergoing treatment for ALL are sedated or anesthetized numerous times,” says Dr. Tersak. "They are sedated when undergoing magnetic resonance imaging (MRI) or computed tomography (CT) scans, biopsies, bone marrow aspirations, or port placement. However, the most frequent reason for sedation is lumbar puncture. Over two to three years of treatment, a child with ALL probably undergoes about 30 lumbar punctures.”

Advantages and Risks

The researchers received responses from 64 institutions of the 103 institutions surveyed (62%). These institutions reported seeing a total of about 2,018 new ALL diagnoses annually (mean per institution 31.5, range 3–110). Across all responding institutions, more than 95% of children with ALL were sedated when receiving lumbar punctures. 

The most commonly used forms of sedation––reported by more than 85% of all responding institutions––were propofol alone (reported by 36 institutions, or 56%) or propofol in conjunction with midazolam, an opioid, or both (reported by 20 institutions, or 31%). Three institutions (5%) reported using midazolam and an opioid without propofol. Others reported using ketamine alone, ketamine and propofol, ketamine/midazolam or fentanyl/midazolam, or general anesthesia.  

"We already have evidence that methotrexate––a mainstay modality in ALL treatment––may have neurotoxic effects, particularly in younger children," says Dr. Tersak. “Repeated exposure to sedation may add to the existing neurocognitive risks associated with methotrexate.” 

Unanswered Questions

More research is needed to compare the long-term effects of different sedating agents, particularly in younger children who are repeatedly exposed to these agents, indicates Dr. Tersak. 

“Are there critical age periods when children are most vulnerable to the adverse effects of sedation exposure? Do all sedating agents impact the developing brain equally?  Is it possible to deliver agents at the same time as the sedation to protect the brain? Are there effective alternatives to sedation, such as the use of relaxation or distraction techniques?” she says. “We do not currently know the answers to these questions.”

The dramatic improvement in survival rates for childhood ALL has resulted in a large population of survivors. This presents an opportunity to begin to study such questions as outlined above.  A better understanding of sedation practices in children with ALL provides a foundation to build upon, to investigate which methods are the safest, including the potential long-term neurocognitive outcomes.

References

Nugent BD, Davis PJ, Noll RB, Tersak JM. Sedation Practices in Pediatric Patients With Acute Lymphoblastic Leukemia. Pediatr Blood Cancer. 2020 Feb; 67(2): e28037.

Further Reading

U.S. Food and Drug Administration. FDA Drug Safety Communication: FDA Approves Label Changes for Use of General Anesthetic and Sedation Drugs in Young Children. 2017 April 27. https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-approves-label-changes-use-general-anesthetic-and-sedation-drugs