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. Author manuscript; available in PMC: 2025 Aug 1.
Published in final edited form as: J Clin Oncol. 2024 Apr 11;42(22):2671–2679. doi: 10.1200/JCO.23.01989

The impact of propofol exposure on neurocognitive outcomes in children with high-risk B acute lymphoblastic leukemia: A Children’s Oncology Group study

Sarah Alexander 1, John A Kairalla 2, Sumit Gupta 1, Emily Hibbitts 2, Hannah Weisman 3, Doralina Anghelescu 4, Naomi J Winick 5, Kevin R Krull 6, Wanda L Salzer 7, Michael J Burke 8, Lia Gore 9, Meenakshi Devidas 10, Leanne Embry 11, Elizabeth A Raetz 12, Stephen P Hunger 13, Mignon L Loh 14, Kristina K Hardy 15
PMCID: PMC11616431  NIHMSID: NIHMS2024876  PMID: 38603641

Abstract

Purpose

Many children treated for acute lymphoblastic leukemia (ALL) develop long-term neurocognitive impairments. Increased risk of these impairments is associated with treatment and demographic factors. Exposure to anesthesia is an additional possible risk factor. This study evaluated the impact of cumulative exposure to anesthesia on neurocognitive outcomes among a multicenter cohort of children with ALL.

Patients and Methods:

This study was embedded in AALL1131, a Children’s Oncology Group phase 3 trial for patients with high-risk B-ALL. In consenting patients aged 6-12 years, prospective uniform assessments of neurocognitive function were performed during, and at one year post completion of therapy. Exposure to all episodes of anesthetic agents was abstracted. Multivariable linear regression models determined associations of cumulative anesthetic agents with the primary neurocognitive outcome reaction time/processing speed (age-normed) at 1-yr off-therapy, adjusting for baseline neurocognitive score, age, sex, race/ethnicity, insurance status (as a proxy for socioeconomic status) and leukemia risk group.

Results:

144 children, 76 (52.8%) males, mean age of 9.1 (min-max, 6.0-12.0) years at diagnosis underwent a median of 27 anesthetic episodes (min-max, 1-37). Almost all patients were exposed to propofol (140/144, 97.2%), with a mean cumulative dose of 112.3 mg/kg. One year post therapy, the proportion of children with impairment (Z-score ≤ −1.5) was significantly higher compared to a normative sample. In covariate-adjusted multivariable analysis, cumulative exposure to propofol was associated with a 0.05 Z-score decrease in reaction time/processing speed per each 10mg/kg propofol exposure (p=0.03).

Conclusion:

In a multicenter and uniformly treated cohort of children with B-ALL, cumulative exposure to propofol was an independent risk factor for impairment in reaction time/processing speed one year post therapy. Anesthesia exposure is a modifiable risk and opportunities to minimize propofol use should be considered.

Background

Ninety percent of children with acute lymphoblastic leukemia (ALL) treated in high-income countries are cured. 1 Curative therapy: however, comes with risks of long-term side effects, including neurocognitive impairments in executive function, attention, and working memory.1–6 Neurocognitive impairments in survivors of ALL have lifelong consequences of decreased health-related quality of life, and risks for academic, cognitive, and behavioral problems.7,8

Known risk factors for neurocognitive impairments in children treated with contemporary ALL therapy without cranial radiation include exposure to intrathecal and systemic methotrexate, younger age at diagnosis, lower socioeconomic status, female sex, and acute neurotoxicity during active treatment.5,6,9–11 Exposure to anesthesia is an additional potential risk factor, supported by animal data, which have demonstrated that exposure to anesthetic agents at developmentally sensitive times is associated with neurotoxicity.12–14 In children without cancer, evidence linking anesthesia exposure at young ages and subsequent neurocognitive impairments has been mixed, with limitations of the data including lack of specific information on anesthetic agents used and their dosage, inclusion of populations with only a single limited exposure, and by assessments of only a subset of cognitive outcomes.15–26

In children with cancer, for whom treatment typically includes multiple episodes of anesthesia, the available data are limited. In two studies of children with medulloblastoma, cumulative anesthesia frequency and duration were identified as independent risk factors for neurocognitive impairment.27,28 A large single-center study of survivors of childhood ALL found that increased risk of long-term neurocognitive dysfunction was strongly associated with greater exposure to propofol and fluranes as well as with cumulative anesthesia duration.29 In children receiving cancer therapy that itself carries risks of neurotoxicity, determining the impact of anesthesia is complex but potentially even more important as children with prior central nervous system toxicity may be particularly vulnerable to additional events that impact brain function.30

Children with ALL undergo multiple procedures including central venous catheter placement, bone marrow aspirates, and lumbar punctures (LPs). During therapy for high-risk B acute lymphoblastic leukemia (B-ALL) on current Children’s Oncology Group (COG) protocols, patients will undergo 24-31 LPs for the administration of intrathecal therapy. A recent survey of anesthetic practices at COG institutions described regimens used for patients receiving intrathecal therapy for ALL with more that 95% routinely using some form of sedation or anesthesia and with at least 87% routinely using regimens containing propofol.31

Identifying whether anesthetic exposure impacts neurocognitive outcomes may allow for modifications in anesthetic practice and improvement of neurocognitive outcomes for children with ALL. The primary aim of this study was to determine whether cumulative exposure to propofol is associated with increased risk for neurocognitive deficits one year after completion of therapy among a large multicenter cohort of children treated uniformly for high-risk B-ALL on COG AALL1131, accounting for known medical and demographic risk factors.

Methods

Patients

COG AALL1131 was a phase 3 trial for patients >1 to <31 years of age with high or very high-risk B-ALL. Eligibility, treatment, and survival outcomes of AALL1131 have been previously reported.32 Briefly, patients were treated with a 4-drug induction regimen followed by chemotherapy according to a modified Berlin-Frankfurt-Münster treatment plan. In addition, some patients initially treated on COG AALL0932 for standard-risk B-ALL identified as having high risk features were enrolled on AALL1131. . Following induction, patients with high-risk ALL were randomly assigned to receive intrathecal methotrexate (IT-MTX) or intrathecal triple therapy (ITT; methotrexate, hydrocortisone, and cytarabine). In May 2018, the high-risk stratum was closed when results of a futility analysis indicated that treatment with ITT would not be statistically superior to treatment with IT-MTX. Participants with very high-risk status were randomized to one of the following three arms for Consolidation and Delayed Intensification therapy: treatment with fractionated cyclophosphamide (CPM) and etoposide (Experimental Arm 1); treatment with clofarabine, CPM, and etoposide (Experimental Arm 2); or treatment with fractionated cytarabine, CPM, and mercaptopurine (Control Arm). In September 2014, Experimental Arm 2 was closed because of excessive toxicity.

AALL1131 included a prespecified secondary aim to evaluate the prevalence of cognitive deficits as measured by a computerized battery, Cogstate, at one year from the time of completion of therapy, to describe the trajectory of neurocognitive decline from baseline to one-year post-completion of therapy, and to evaluate predictors of both deficits and decline. Eligibility criteria for this optional study included age 6 to <13 years at diagnosis, primary language of English, French or Spanish, no known history of neurodevelopmental disorders (such as Down syndrome and Fragile X), and no significant visual impairment that would prevent computer use. In addition, patients included in the anesthesia exposure study were required to have completed leukemia directed treatment on AALL1131, and to have completed neurocognitive assessments at the baseline timepoint) and at one-year post completion of therapy.

AALL1131 was approved by the Pediatric Central Institutional Review Board (IRB) and participating center IRBs. Written informed consent and assent (if applicable) for the ancillary study was obtained after induction therapy.

Neurocognitive assessments

Uniform neurocognitive assessments were conducted using performance-based testing (Cogstate), and parent-reported executive functioning using the Behavior Rating Inventory of Executive Functioning (BRIEF).33 Cogstate is a computerized battery of tasks assessing various aspects of neurocognitive functioning in children and adults (www.cogstate.com). Cogstate tasks are semi-automated, requiring a trained proctor (e.g., nurses, research coordinators, etc.) and approximately 30 minutes of testing time. Tests are designed to minimize variability attributable to cultural factors and practice effects with repeated administration,34 Cogstate has been used in multiple recent pediatric oncology trials35. Five tasks were used in the current study: Detection (simple reaction time/processing speed), Identification (visual attention), One-Card Learning (visual learning), One-back (working memory), and Groton Maze Learning (executive functioning). Z-scores were computed for each task using available age-based normative data, with lower scores indicating worse performance.

The BRIEF is an 86-item questionnaire measure completed by caregivers to characterize children’s everyday executive functioning skills in domains describing behavior regulation (e.g., inhibiting impulses), emotion regulation (e.g., making transitions), and cognitive regulation (e.g., time management, organization, and planning).

Retrospective anesthesia exposure data collection

Manual chart review was completed by trained clinical research associates at each treating site. All episodes of anesthesia, defined as events that included procedural sedation, moderate or deep sedation, or anesthesia were abstracted from time of study enrollment to one year post completion of chemotherapy. For each episode, data collected included the patient’s weight, the name, dose, and route of each anesthetic agent, start and stop time of the anesthetic, and the reason for anesthesia, including invasive procedures and diagnostic imaging. For each patient, all episodes of CTCAEv4 grade 3 and higher neurotoxic events, days receiving care in an intensive care unit and days on a ventilator were recorded. Submitted data was centrally reviewed to ensure validity and completeness.

Statistical Analysis

For each patient, the number of anesthetic events, the total cumulative exposure to each anesthetic agent adjusted for weight, and the total cumulative duration of anesthesia were calculated. Outcomes were compared by patient characteristics using Wilcoxon rank-sum tests. The primary outcome of interest was age-adjusted reaction time/processing speed (Cogstate Detection task score) at one year off-therapy, controlling for the Detection task score at the first time point. Our key predictors of interest were the cumulative doses of each primary anesthetic agent as well as the total cumulative duration of anesthesia. Our primary analysis used multivariable linear regression models to determine the association of cumulative anesthetic agents with the primary neurocognitive outcome while adjusting for baseline (within 3 months of diagnosis) score and other key potential covariates: age at diagnosis, biologic sex, insurance status, race/ethnicity, and leukemia risk group. Secondary analyses used similar models to examine the other neurocognitive outcomes listed above. A p < 0.05 was considered significant for all comparisons.

RESULTS

There were 483 eligible patients who consented to participate in the embedded longitudinal neurocognitive study. Of these, 144 (29.8%) completed leukemia directed treatment on AALL1131, had available anesthesia records, completed neurocognitive assessments at baseline and one year post end of leukemia therapy, and were included in this analysis. These patients differed from the larger sample of patients only in that they were more likely to be from a non-US-based institution (14.6% v 6.8%, p = .04); there were no differences in age at diagnosis, biological sex, race/ethnicity, insurance status, ALL risk group, or CNS status (appendix, Table A1).

Patients were treated at 71 COG institutions in the US, Canada, Australia, and New Zealand. Median age was 9.1 years (IQR interval = 7.6-10.7), and 76 (52.8 %) were males. The majority of patients were non-Hispanic White (n=79, 54.9%) (Table 1)Patients were identified as having HR ALL (n=106, 73.6%) or VHR ALL (n=38, 26.4%). The majority of patients had no evidence of leukemia in the spinal fluid at diagnosis (CNS1). Three patients had CNS3 disease and subsequently received cranial radiation. Of note, none of the patients who received cranial radiation required anesthesia for the delivery of the radiation therapy.

Table 1.

Participant demographics and treatment characteristics

Patient characteristics, N (%) N =144
Age at diagnosis,
 6-9 years 84 (58.3)
 10-12 years 60 (41.7)
Biologic sex- n (%)
 Male 76 (52.8)
 Female 68 (47.2)
Race/ethnicity
 White, non-Hispanic 79 (54.9)
 All others, known 54 (37.5)
 Unknown 11 (7.6)
Insurance status
 Non-US 21 (14.6)
 US private 65 (45.1)
 US public 46 (31.9)
 Unknown/self-pay 12 (8.3)
Leukemia risk group assignment
 High risk 106 (73.6)
 Very high risk 38 (26.4)
CNS status at diagnosis
  1 125 (86.8)
  2 13 (9.0)
  3 3 (2.1)
  Unknown 3 (2.1)
Treatment with cranial radiation 3 (2.1)
Neurological adverse event (grade3+) 5 (3.5)
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Five patients had CTCAE version 4 grade 3 or higher neurological adverse events during therapy. These included events of reversible posterior leukoencephalopathy syndrome (n=2), encephalopathy (n=1), leukoencephalopathy (n=1) and stroke (n=1). In addition, 22 patients required ICU level care during the treatment period for a median number of 3 days per episode. Of these, two required brief ventilator support for a mean of one day.

The median number of anesthetic episodes per patient was 27 (min-max, 1-37) (Table 2). The most common indication for anesthesia was LP, with or without the administration of intrathecal therapy. Additional treatment-related invasive procedures requiring anesthesia included bone marrow aspirates and biopsies, and central line placements and removals. A small number of patients required anesthesia for diagnostic imaging. Anesthesia episodes for indications other than direct oncology-related procedures and diagnostic imaging included procedures such as bronchoscopy, endoscopy, dental and dermatology procedures and orthopedic surgery.

Table 2:

Anesthetic episodes amongst the 144 patients from study enrolment through one year post completion of leukemia therapy

Median number per patient Range
Number of anesthetic episodes 27 1-37
 Episodes for invasive procedure
    LP/IT 24 0-32
    BMA 2 0-4
    CVL placement 1 0-3
    CVL removal 1 0-3
 Episodes for diagnostic imaging 0 0-2
 Episode for other indications* 0 0-4
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*

Anesthesia episodes for indications other than direct oncology related procedures and diagnostic imaging included bronchoscopy, endoscopy and dental and dermatology procedures and orthopedic surgery

Almost all patients (140/144; 97%) received propofol, with a mean cumulative exposure among these of 112.3 mg/kg (Table 3). There was no significant difference in exposure between males and females. Patients who were 6-9 years old compared to 10-12 years of age had a higher propofol dose per episode (5.1 mg/kg versus 4.3 mg/kg, p=0.016). Patients with a race and ethnicity other than non-Hispanic White had a lower cumulative propofol dose compared to patients that were non-Hispanic White (96.2 mg/kg versus 121.9 mg/kg, p=0.05) (Table 4). There were no other significant differences in cumulative dosing or dose per anesthetic episode as a function of demographic or medical predictors.

Table 3:

Cumulative anesthesia exposures

Exposure Participants receiving agent, n (%) Mean cumulative exposure Median cumulative exposure
Intravenous agent (mg/kg) Dose (mg/kg or microgram/kg)/patient Dose (mg/kg or microgram/kg)/patient
  Propofol 140 (97.2) 112.3 109.2
  Fentanyl* 131 (91.0) 10.6 6.0
  Midazolam 90 (62.5) 0.4 0.2
  Morphine 42 (29.2) 0.2 0.1
  Ketamine 29 (20.1) 6.4 2.8
  Dexmedetomidine * 26 (18.1) 1.1 0.4
  Hydromorphone 14 (9.7) 0.02 0.01
  Meperidine 3 (2.1) 9.9 13.0
Inhalational agent episode, n Mean episodes per patient Median episodes per patient
  Nitrous oxide 41 (28.5) 4.9 2.0
  Flurane 74 (51.4) 5.3 3.0
Anesthesia time, hours - Mean anesthesia time per patient Median anesthesia time per patient
  Total time 11.3 11.1
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*

Doses for these agents are in micrograms/kg; flurane episodes include those with exposure to isoflurane, sevoflurane or desflurane. Total anesthesia time is described for the 137 patients with data available.

Table 4.

Demographic features and exposure of the 140 patients who received propofol.

Demographic factor N Cumulative propofol dose (mg/kg), mean P value* Number of episodes, mean Dose (mg/kg) per episode, mean P value*
Age (yrs)
 6-9 81 118.4 24.1 5.1
 10-12 59 103.8 0.14 24.4 4.3 0.016
Biological Sex
 Male 72 118.4 25.0 4.8
 Female 68 105.8 0.31 23.4 4.7 0.95
Race/ethnicity
 Non-Hispanic white 77 121.9 25.3 4.9
 All others 52 96.2 0.051 22.6 4.4 0.12
 Unknown 11 120.9 24.5 5.0
Insurance status
 Non-US 21 121.37 27.6 4.5
 US private 63 112.3 0.25 24.6 4.4 0.95
 US public 45 114.4 23.1 5.0
 Unknown/self pay 11 86.3 20.6 4.4
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*

Wilcoxon rank-sum tests for two group comparisons and Kruskal-Wallis tests for >2 group comparisons

For anesthesia episodes limited to only those required for LP (with or without IT chemotherapy), among patients receiving propofol, the mean dose per kilogram of propofol was 91.4 mg/k, whereas the mean dose for LP (with or without IT therapy) with an additional procedure was 12.7mg/kg and for procedures other than LPs was 10.7mg/kg. Propofol administered for LPs (with or without IT chemotherapy) alone accounted for 80% (91.4/114.8 mg/kg) of the total mean dose per kilogram administered. For these episodes the propofol dose per kilogram per episode did not increase over time with a mean first episode dose of 4.0 mg/kg and a final episode dose of 4.1 mg/kg.

At the first timepoint within 3 months of diagnosis, the proportion of children with neurocognitive impairments (age-adjusted Z-scores ≤ −1.5) in reaction time/processing speed, attention and working memory was significantly higher compared to the standardization sample (14.1% versus 8.4%, p=0.01; 17.7% versus 7.7%, p<0.001; 15.7% versus 7.9%, p< 0.001, respectively; Appendix Figure 1). At the final timepoint (one year post completion of therapy), the proportion of children with impairment had increased, and was again significantly higher compared to the standardization normal population in the same domains of reaction time/processing speed (24.2% versus 8.4%, p<0.001), attention (27.8% versus 7.7%, p<0.001) and working memory (13.5% versus 7.9%, p=0.01).

After accounting for the Detection task score at baseline, age at diagnosis, biological sex, race/ethnicity, insurance status and leukemia risk group, cumulative exposure to propofol was associated with poorer reaction time/processing speed at 1-year post completion of therapy, with a decrease of 0.05 Z-score per 10 mg/kg increase in propofol exposure (95th CI 0.005, 0.09; p=0.03). (Table 5) This association was not identified with any of the other anesthesia-related exposures, including episodes of flurane exposure or total anesthesia time. Additionally, there was no significant association with risk of impairment in other domains assessed by Cogstate, specifically sustained attention, working memory and executive function or by the BRIEF measures. (Table 6)

Table 5.

Impact of cumulative exposure to propofol on reaction time/processing speed on year post completion of leukemia therapy, multivariable analysis accounting for baseline neurocognitive score, age, sex, race/ethnicity, insurance status and leukemia risk group.

Parameter Adjusted mean difference (SE) P-value
Age at dx (years) 0.09 (0.07) 0.22
Sex Female
(ref=Male)		 0.07 (0.22) 0.76
Race/Ethnicity
(ref=non-Hispanic White)		 Overall test (2df): 0.69
 All others −0.17 (0.29) 0.56
 Unknown 0.20 (0.40) 0.62
Insurance Status (ref=US Private) overall test (3df): 0.16
 US Public −0.30 (0.30) 0.32
 Non-US 0.45 (0.35) 0.20
 Unknown −0.75 (0.50) 0.14
ALL risk group VHR
(ref=HR)		 0.26 (0.26) 0.33
T1 Z-score 0.45 (0.10) <0.0001
Cumulative propofol (10mg/kg) −0.05 (0.02) 0.029
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Table 6.

Adjusted associations for anesthesia exposure type with Cogstate outcome

Reaction time/processing speed (detection task) Sustained attention (identification) Working memory (one back accuracy) Executive function (Groton maze)
Beta* (SE) P-value Beta (SE) P-value Beta (SE) P-value Beta (SE) P-value
Propofol (10mg/kg) −0.05 (0.02) 0.029
 −0.04 (0.02) 0.06 −0.05 (0.03) 0.15 −0.01 (0.02) 0.51
Fentanyl (μ/kg) 0.02 (0.01) 0.11
 0.01 (0.01) 0.52 0.01 (0.02) 0.65 −0.01 (0.01) 0.23
Midazolam (mg/kg) 0.05 (0.22) 0.83
 0.14 (0.21) 0.52 0.22 (0.32) 0.51 0.20 (0.18) 0.27
Nitrous episodes 0.04 (0.03) 0.12 0.04 (0.03) 0.12 0.01 (0.04) 0.83 −0.01 (0.02) 0.77
Flurane episodes −0.04 (0.02) 0.09 0.001 (0.02) 0.95 0.01 (0.03) 0.84 −0.02 (0.02) 0.39
Total hours −0.01 (0.02) 0.69 −0.003 (0.02) 0.90 −0.05 (0.03) 0.11 −0.01 (0.02) 0.53
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*

Adjusted mean difference in multivariable model adjusting for age at diagnosis, sex, race/ethnicity, insurance status, leukemia risk group, and baseline neurocognitive scores

DISCUSSION

This multicenter study of patients aged 6 to 12 years with B-ALL examined the impact of anesthesia exposures on neurocognitive functioning one year from the end of leukemia directed therapy. We identified that cumulative dose of propofol was associated with reduced reaction time/processing speed over time as measured by Cogstate, a performance-based assessment. Difficulties with processing speed can impact children’s academic and interpersonal functioning; when children take longer to process information, they also require more time to solve problems, formulate responses, and process social information in real time.

A previously published single center study of a cohort of survivors of childhood ALL described the impact of anesthesia exposure on neurocognitive outcomes.29 In this study of 217 patients treated between 2000 and 2010 who were evaluated a median of 7-years post therapy, patients had a similar number of anesthesia exposures (26.9) and a cumulative mean propofol dose (148.4 mg/kg) to the present study. In contrast, the methods of measurement of neurocognitive function, the definition of neurocognitive impairment, and the time post therapy were different between the two studies. Despite these differences, the findings are similar with the prior study identifying an association between cumulative propofol dose and global neurocognitive impairment, with the most substantive deficits in processing speed.

Cognitive efficiency is highly dependent on the quality of neural networks supported by white matter development throughout childhood and into adulthood. Evidence from structural and functional imaging studies indicate that survivors of pediatric ALL show smaller white and gray matter volumes, reduced cortical thickness, and lower efficiency of neural processing.3,29,36,37 Changes to white matter microstructure and function in particular, has been associated with weaker processing speed and cognitive efficiency in survivors of ALL.38–41 It is possible that cumulative anesthesia exposure contributes to global axonal injury or alteration in myelination over time, and that reduced processing speed is an early indicator of this process. Importantly, we used a measure of simple reaction time in our study, which is highly sensitive to processing and fine motor speed, both of which are white matter dependent. As such, it may be that our results reflect the earliest detectable changes among the broader phenotype of cognitive late effects that develop over time in many survivors. Additional follow up with this cohort using a larger battery of traditional neurocognitive tasks is being conducted and will clarify whether the early anesthesia-related changes are associated with broader neurocognitive difficulties and functional impairment over time.

Anesthesia, including propofol, is essential in supporting children through painful procedures required for treatment of children with cancer. Unique to the treatment of children with ALL is the requirement for multiple sequential LPs for the administration of intrathecal chemotherapy, which can be associated with both pain and anxiety. In this study, of the 140 patients receiving propofol, 79% of the mean cumulative propofol exposure was for LPs alone. Historically, children underwent these repeated procedures without anesthesia, often with significant distress and the need for physical restraint. To provide comfort for these repeated procedures, pediatric oncology practice evolved to include the routine use of sedation, most often with benzodiazepines and opiates followed by the current widespread practice of propofol anesthesia.42

Alternatives to the use of propofol to reduce pain and anxiety in children undergoing serial LPs for the administration of intrathecal chemotherapy have been described. Prompted by the COVID-19 pandemic and the consequent impacts on access to anesthesia, one center described reducing the percentage of children who received propofol anesthesia by 50% with the implementation of a program including education and simulation with the patient, topical lidocaine, pre-procedure anxiolytic medication (oral lorazepam or IV midazolam) and the option of a guardian and child life practitioner presence during the procedure. 43 Other centers have reported using nitrous oxide, though there remain theoretical concerns about the use of this anesthetic agent in children receiving intrathecal methotrexate.44,45 Developmentally appropriate non-pharmacological interventions including distraction, hypnosis and music have also demonstrated efficacy although are not widely implemented care.46,47

In this study, patients for whom race and ethnicity data were available and who had race and ethnicity other than non-Hispanic White had lower cumulative exposure to propofol. Standard practice for the use of propofol for sedation and anesthesia is to titrate the dose to effect. Possible physiologic explanations for this observation includes evidence of variability in propofol pharmacodynamics associated with race.48 In a study of adult patients undergoing minor surgical procedures, the dose of propofol required for sedation, measured as the loss of verbal response, was significantly lower in black patients compared to white patients. 49 In adult patients receiving the same dose of propofol, Kenyan Africans compared to Caucasians had significantly longer time to recovery from sedation, as measured by time to eye opening and response to verbal commands. 50 Additionally in pediatric patients undergoing lumbar punctures, there is data suggesting that children who are overweight or obese require less propofol.51 Data for body mass index across observation timepoints were not collected in our cohort; however in healthy children in the US, rates of obesity are substantially higher in Hispanic and non-Hispanic Black children than in non-Hispanic White or Asian children.52 In addition to physiologic differences it is possible that systemic biases, including lack of equity of care between sites and lack of equity for individual patients within a center by race and ethnicity contributed to this finding. Further work to understand the possible physiologic and non-physiologic reasons for differences in dosing of propofol in children with ALL by race and ethnicity given emerging evidence that unconscious bias can sometimes impact clinical decision making is clearly warranted.53

This study involved patients with HR and VHR ALL ages 6 to 12 years. The impact of anesthesia may be more substantive in a younger patient cohort receiving similar therapy given that white matter microstructure supporting efficient processing is less mature. 54 Conversely, patients with standard risk ALL who are ages 1 to10 years treated with Children’s Oncology Group protocols, undergo fewer LPs for IT therapy, ranging from 18 to 20 compared to 24 to 31 the patients receiving higher risk therapy. Other indications for treatment related anesthesia would be expected to be similar. Further study in younger children and those undergoing therapy for standard risk ALL will be critical in understanding the generalizability of these results. The current standard risk COG ALL trial includes an embedded neurocognitive aim, utilizes Cogstate as the measurement tool for neurocognitive assessment and includes a one year off therapy timepoint. Replicating the analysis in that cohort will be critical.

This study has several additional limitations. First, although longitudinal neurocognitive assessments were collected prospectively, the anesthesia data were collected retrospectively and not all data elements were available on all patients in each episode. Second, the frequency of exposure to anesthetic agents other than propofol was inadequate to exclude an impact on neurocognitive function. Third, the cohort included in this study was similar to the larger neurocognitive embedded study cohort when analyzed for age, biologic sex, race and ethnicity, insurance status, leukemia risk group and CNS status. (appendix). It is possible that there are additional unmeasured differences between the two groups. Fourth, as has been done in prior studies, insurance status was used as a proxy for socioeconomic status but is not a direct measure. Lastly, the predictive value of Cogstate identified neurocognitive impairments post ALL therapy on long term function remains to be defined.

In this multicenter study, cumulative propofol dose was an independent risk factor for impairment in neurocognitive function, specifically reaction time/processing speed, in children one year post completion of therapy for B-ALL. Propofol exposure is a potentially modifiable risk and opportunities to minimize use, when feasible, in patients with ALL should be considered.

Supplementary Material

PV Appendix Table 1
PV Appendix Figure 1

Appendix Figure 1. The proportion of children with impairments (age-adjusted population normative scores ≥ 1.5 standard deviations below the mean) in reaction time/processing speed, attention and working memory comparing the population expected scores (dark green) and scores in the cohort of children with ALL (light green)

Context summary.

Key objective

Is cumulative exposure to propofol a risk factor for neurocognitive impairment in children treated for acute lymphoblastic leukemia?

Knowledge generated:

In children aged 6-12 treated for high-risk acute lymphoblastic leukemia, cumulative exposure to propofol is associated with risk of impairment in processing speed when measured one year post completion of therapy.

Relevance (written by Dr. Smita Bhatia):

These findings suggest that consideration should be given to minimizing exposure to propofol in order to prevent short-term cognitive impairment in children between the ages of 6 and 12 diagnosed with high-risk ALL.

ACKNOWLEDGMENTS

This study was supported by R01CA212190, as well as by grants supporting activities of the Children’s Oncology Group (NCTN Operations Center Grant U10CA180886, NCTN Statistics & Data Center Grant U10CA180899, and NCORP UG1CA189955). EAR is a KiDS of NYU Foundation Professor at NYU Langone Health. SPH is the Jeffrey E. Perelman Distinguished Chair in Pediatrics at the Children’s Hospital of Philadelphia. MLL is an Endowed Professor of Pediatric Cancer Research, The Aldarra Foundation Endowed Chair, Bill and June Boeing, Founders. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Neurological Disorders and Stroke, National Cancer Institute, or the National Institutes of Health. This work was performed while KKH was a full-time employee of Children’s National Hospital.

Support:

This study was supported by the NCTN Operations Center and NCTN Statistics and Data Center (NIH U10CA180886, U10CA180899), and NCORP UG1CA189955, the American Lebanese Syrian Associated Charities, St Baldrick’s Foundation and R01CA212190

Footnotes

Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Parts of this work were presented at the American Society of Hematology meeting, December 2022, New Orleans, LA

Data sharing statement:

The Children’s Oncology Group Data Sharing policy describes the release and use of COG individual subject data for use in research projects in accordance with National Clinical Trials Network (NCTN) Program and NCI Community Oncology Research Program (NCORP) Guidelines. Only data expressly released from the oversight of the relevant COG Data and Safety Monitoring Committee (DSMC) are available to be shared. Individual-level de-identified datasets that would be sufficient to reproduce results provided in a publication containing the primary study analysis can be requested from the NCTN/NCORP Data Archive at https://nctn-data-archive.nci.nih.gov/. Data are available to researchers who wish to analyze the data in secondary studies to enhance the public health benefit of the original work and agree to the terms and conditions of use. Requests for access to COG protocol research data should be sent to: datarequest@childrensoncologygroup.org. Data are available to researchers whose proposed analysis is found by COG to be feasible and of scientific merit and who agree to the terms and conditions of use.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

PV Appendix Table 1
NIHMS2024876-supplement-PV_Appendix_Table_1.docx (15.1KB, docx)
PV Appendix Figure 1

Appendix Figure 1. The proportion of children with impairments (age-adjusted population normative scores ≥ 1.5 standard deviations below the mean) in reaction time/processing speed, attention and working memory comparing the population expected scores (dark green) and scores in the cohort of children with ALL (light green)

NIHMS2024876-supplement-PV_Appendix_Figure_1.pptx (74.5KB, pptx)

Data Availability Statement

The Children’s Oncology Group Data Sharing policy describes the release and use of COG individual subject data for use in research projects in accordance with National Clinical Trials Network (NCTN) Program and NCI Community Oncology Research Program (NCORP) Guidelines. Only data expressly released from the oversight of the relevant COG Data and Safety Monitoring Committee (DSMC) are available to be shared. Individual-level de-identified datasets that would be sufficient to reproduce results provided in a publication containing the primary study analysis can be requested from the NCTN/NCORP Data Archive at https://nctn-data-archive.nci.nih.gov/. Data are available to researchers who wish to analyze the data in secondary studies to enhance the public health benefit of the original work and agree to the terms and conditions of use. Requests for access to COG protocol research data should be sent to: datarequest@childrensoncologygroup.org. Data are available to researchers whose proposed analysis is found by COG to be feasible and of scientific merit and who agree to the terms and conditions of use.

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