A pediatric emergency care research node within the PECARN network
Principal Investigators
Thomas Chun, MD, MPH
Co-Principal Investigator
Hasbro Children’s Hospital, Providence, RI
Claudia R. Morris, MD
Co-Principal Investigator
Emory University, Atlanta, GA
Hospital Emergency Department Affiliates (HEDA)
Mark Griffiths, MD
HEDA Principal Investigator
Emory University, Atlanta, GA
Jacqueline Grupp-Phelan, MD, MPH
HEDA Co-Principal Investigator
University of California, San Francisco, San Francisco, CA
Aaron Kornblith, MD
HEDA Co-Principal Investigator
University of California, San Francisco, San Francisco, CA
Mark Zonfrillo, MD, MSCE
HEDA Principal Investigator
Hasbro Children’s Hospital, Providence, RI
Pediatric Mental Health and Suicidality
Both the Ask Suicide-Screening Questions (ASQ) and the Computerized Adaptive Screen for Suicidal Youth (CASSY) instruments are appropriate for pediatric suicidality screening. For the small subset of patients with psychiatric symptoms, the CASSY tool shows greater predictive validity.
Importance Screening adolescents in emergency departments (EDs) for suicidal risk is a recommended strategy for suicide prevention. Comparing screening measures on predictive validity could guide ED clinicians in choosing a screening tool.
Objective To compare the Ask Suicide-Screening Questions (ASQ) instrument with the Computerized Adaptive Screen for Suicidal Youth (CASSY) instrument for the prediction of suicidal behavior among adolescents seen in EDs, across demographic and clinical strata.
Design, Setting, and Participants The Emergency Department Study for Teens at Risk for Suicide is a prospective, random-series, multicenter cohort study that recruited adolescents, oversampled for those with psychiatric symptoms, who presented to the ED from July 24, 2017, through October 29, 2018, with a 3-month follow-up to assess the occurrence of suicidal behavior. The study included 14 pediatric ED members of the Pediatric Emergency Care Applied Research Network and 1 Indian Health Service ED. Statistical analysis was performed from May 2021 through January 2023.
Main Outcomes and Measures This study used a prediction model to assess outcomes. The primary outcome was suicide attempt (SA), and the secondary outcome was suicide-related visits to the ED or hospital within 3 months of baseline; both were assessed by an interviewer blinded to baseline information. The ASQ is a 4-item questionnaire that surveys suicidal ideation and lifetime SAs. A positive response or nonresponse on any item indicates suicidal risk. The CASSY is a computerized adaptive screening tool that always includes 3 ASQ items and a mean of 8 additional items. The CASSY’s continuous outcome is the predicted probability of an SA.
Results Of 6513 adolescents available, 4050 were enrolled, 3965 completed baseline assessments, and 2740 (1705 girls [62.2%]; mean [SD] age at enrollment, 15.0 [1.7] years; 469 Black participants [17.1%], 678 Hispanic participants [24.7%], and 1618 White participants [59.1%]) completed both screenings and follow-ups. The ASQ and the CASSY showed a similar sensitivity (0.951 [95% CI, 0.918-0.984] vs 0.945 [95% CI, 0.910-0.980]), specificity (0.588 [95% CI, 0.569-0.607] vs 0.643 [95% CI, 0.625-0.662]), positive predictive value (0.127 [95% CI, 0.109-0.146] vs 0.144 [95% CI, 0.123-0.165]), and negative predictive value (both 0.995 [95% CI, 0.991-0.998], respectively). Area under the receiver operating characteristic curve findings were similar among patients with physical symptoms (ASQ, 0.88 [95% CI, 0.81-0.95] vs CASSY, 0.94 [95% CI, 0.91-0.96]). Among patients with psychiatric symptoms, the CASSY performed better than the ASQ (0.72 [95% CI, 0.68-0.77] vs 0.57 [95% CI, 0.55-0.59], respectively).
Conclusions and Relevance This study suggests that both the ASQ and the CASSY are appropriate for universal screening of patients in pediatric EDs. For the small subset of patients with psychiatric symptoms, the CASSY shows greater predictive validity.
Brent DA, Horowitz LM, Grupp-Phelan J, et al. Prediction of Suicide Attempts and Suicide-Related Events Among Adolescents Seen in Emergency Departments. JAMA Netw Open. 2023;6(2):e2255986. Published 2023 Feb 1. doi:10.1001/jamanetworkopen.2022.55986
Screening for suicidality assumes consistent answers about suicidality, whether asked directly (using the word “suicidal”) or indirectly (describing suicidality without stating the actual word). In a diverse population of almost 6,000 adolescent ED patients from 13 hospitals, adolescents were asked about suicidality using both direct and indirect questioning. 6.2% responded yes to only 1 version to the question but not the other. This discrepancy suggests that screening tools need both direct and indirect questioning about suicidality.
Background: Clinical assessments are a primary method for ascertaining suicide risk, yet the language used across measures is inconsistent. The implications of these discrepancies for adolescent responding are unknown, which is troubling as multiple research areas (i.e. on culture, mental health language, and suicide communication) indicate individuals from varying sociodemographic backgrounds may communicate differently regarding mental health concerns. The aims of the current study are to investigate whether a geographically diverse sample of adolescents respond differently to directly and indirectly phrased suicide attempt questions (i.e. directly phrased includes the term ‘suicide’ and indirectly asks about suicidal behavior without using ‘suicide’), and to examine whether sociodemographic factors and history of mental health service usage relate to endorsement differences.
Methods: Participants were N = 5909 adolescents drawn from the Emergency Department Screening for Teens at Risk for Suicide multi-site study. The lifetime suicide attempt was assessed with two items from an adapted version of the Columbia Suicide Severity Rating Scale (C-SSRS; Posner et al., 2008): (1) a directly phrased question asking about ‘suicide attempts’ and (2) an indirectly phrased question providing the definition of an attempt.
Results: An adolescent majority (83.7%) consistently reported no lifetime suicide attempt across items, 10.1% consistently reported one or more lifetime attempts across items, and 6.2% of adolescents responded discordantly to the items.
Conclusions: Multivariable models indicated multiple demographic and mental health service variables significantly predicted discordant responding, with a notable finding being that father/stepfather education level at or below high school education predicted endorsing only the direct question.
Hatkevich C, Grupp-Phelan J, Brent D, et al. Understanding adolescent responses to differently worded suicide attempt questions: results from a large US pediatric sample. Psychol Med. 2022;52(12):2309-2318. doi:10.1017/S0033291720004213
The following self-reported items predicted adolescent suicide attempts within 3 months:
- Current and past suicide ideation
- Past suicidal behavior
- Total negative life events
- School or social connectedness
Background: Concerns have been raised about the utility of self-report assessments in predicting future suicide attempts. Clinicians in pediatric emergency departments (EDs) often are required to assess suicidal risk. The Death Implicit Association Test (IAT) is an alternative to self-report assessment of suicidal risk that may have utility in ED settings.
Methods: A total of 1679 adolescents recruited from 13 pediatric emergency rooms in the Pediatric Emergency Care Applied Research Network were assessed using a self-report survey of risk and protective factors for a suicide attempt, and the IAT, and then followed up 3 months later to determine if an attempt had occurred. The accuracy of prediction was compared between self-reports and the IAT using the area under the curve (AUC) with respect to receiver operator characteristics.
Results: A few self-report variables, namely, current and past suicide ideation, past suicidal behavior, total negative life events, and school or social connectedness, predicted an attempt at 3 months with an AUC of 0.87 [95% confidence interval (CI), 0.84-0.90] in the entire sample, and AUC = 0.91, (95% CI 0.85-0.95) for those who presented without reported suicidal ideation. The IAT did not add significantly to the predictive power of selected self-report variables. The IAT alone was modestly predictive of 3-month attempts in the overall sample ((AUC = 0.59, 95% CI 0.52-0.65) and was a better predictor in patients who were non-suicidal at baseline (AUC = 0.67, 95% CI 0.55-0.79).
Conclusions: In pediatric EDs, a small set of self-reported items predicted suicide attempts within 3 months more accurately than did the IAT.
Brent DA, Grupp-Phelan J, O’Shea BA, et al. A comparison of self-reported risk and protective factors and the death implicit association test in the prediction of future suicide attempts in adolescent emergency department patients [published online ahead of print, 2021 May 5]. Psychol Med. 2021;1-9. doi:10.1017/S0033291721001215
Sexual minority youth had higher rates of lifetime suicide ideation (61.5%) and suicidal thoughts in the past month (36.6%) compared to heterosexual youth (21.2% and 9%, respectively). Depression, bullying victimization, and sexual abuse seem the most significant risk factors, and parent-family connectedness and positive affect were most protective.
Background: Differences in risk and protective factors (e.g., victimization, abuse, social support) have been used to explain elevated rates of suicidal ideation and suicide attempts in sexual minority youth (SMY) relative to heterosexual peers. However, little is known regarding how risk and protective factors may explain suicide risk differences among subgroups of SMY. The aims of this study were to 1) examine differences in prevalence and severity for suicide risk and protective factors among SMY, and 2) explore whether risk and protective factors are differentially associated with suicidal ideation and suicide attempts for SMY subgroups.
Methods: Participants were 6,423 adolescents (ages 12-17) recruited from 14 Emergency Departments across the United States who completed an assessment of suicide risk and protective factors. SMY were 20% of the sample (n = 1,275) and categorized as bisexual (8%), gay/lesbian (2%), mostly straight (5%), or other sexual minority (5%).
Results: Bisexual youth had elevated rates of suicidal ideation and attempts, more risk factors (e.g., bullying victimization, depression), and fewer protective factors (e.g., parent-family connectedness, positive affect) relative to mostly straight and other sexual minority youth. Bisexual and gay/lesbian youth only differed in parent-family connectedness (lower among bisexual youth). Depression and parent-family connectedness had weaker associations with suicidal ideation for bisexual youth.
Limitations: Emergency departments were not nationally representative. Study design was cross-sectional, preventing causal inferences.
Conclusions: Interventions seeking to mitigate risk factors and promote protective factors are greatly needed for SMY and may benefit from tailoring to address unique stressors for sexual minority subgroups.
Horwitz AG, Grupp-Phelan J, Brent D, et al. Risk and protective factors for suicide among sexual minority youth seeking emergency medical services. J Affect Disord. 2021;279:274-281. doi:10.1016/j.jad.2020.10.015
This technical report accompanies a joint policy statement from the American Academy of Pediatrics, American College of Emergency Physicians, and the Emergency Nurses Association to improve the care of children with mental and behavior health emergencies.
Mental and behavioral health (MBH) visits of children and youth to emergency departments are increasing in the United States. Reasons for these visits range from suicidal ideation, self-harm, and eating and substance use disorders to behavioral outbursts, aggression, and psychosis. Despite the increase in prevalence of these conditions, the capacity of the health care system to screen, diagnose, and manage these patients continues to decline. Several social determinants also contribute to great disparities in child and adolescent (youth) health, which affect MBH outcomes. In addition, resources and space for emergency physicians, physician assistants, nurse practitioners, and prehospital practitioners to manage these patients remain limited and inconsistent throughout the United States, as is financial compensation and payment for such services. This technical report discusses the role of physicians, physician assistants, and nurse practitioners, and provides guidance for the management of acute MBH emergencies in children and youth. Unintentional ingestions and substance use disorder are not within the scope of this report and are not specifically discussed.
Saidinejad M, Duffy S, Wallin D, et al. The Management of Children and Youth With Pediatric Mental and Behavioral Health Emergencies [published online ahead of print, 2023 Aug 16]. Pediatrics. 2023;e2023063256. doi:10.1542/peds.2023-063256
Both the Ask Suicide-Screening Questions (ASQ) and the Computerized Adaptive Screen for Suicidal Youth (CASSY) instruments are appropriate for pediatric suicidality screening. For the small subset of patients with psychiatric symptoms, the CASSY tool shows greater predictive validity.
Importance Screening adolescents in emergency departments (EDs) for suicidal risk is a recommended strategy for suicide prevention. Comparing screening measures on predictive validity could guide ED clinicians in choosing a screening tool.
Objective To compare the Ask Suicide-Screening Questions (ASQ) instrument with the Computerized Adaptive Screen for Suicidal Youth (CASSY) instrument for the prediction of suicidal behavior among adolescents seen in EDs, across demographic and clinical strata.
Design, Setting, and Participants The Emergency Department Study for Teens at Risk for Suicide is a prospective, random-series, multicenter cohort study that recruited adolescents, oversampled for those with psychiatric symptoms, who presented to the ED from July 24, 2017, through October 29, 2018, with a 3-month follow-up to assess the occurrence of suicidal behavior. The study included 14 pediatric ED members of the Pediatric Emergency Care Applied Research Network and 1 Indian Health Service ED. Statistical analysis was performed from May 2021 through January 2023.
Main Outcomes and Measures This study used a prediction model to assess outcomes. The primary outcome was suicide attempt (SA), and the secondary outcome was suicide-related visits to the ED or hospital within 3 months of baseline; both were assessed by an interviewer blinded to baseline information. The ASQ is a 4-item questionnaire that surveys suicidal ideation and lifetime SAs. A positive response or nonresponse on any item indicates suicidal risk. The CASSY is a computerized adaptive screening tool that always includes 3 ASQ items and a mean of 8 additional items. The CASSY’s continuous outcome is the predicted probability of an SA.
Results Of 6513 adolescents available, 4050 were enrolled, 3965 completed baseline assessments, and 2740 (1705 girls [62.2%]; mean [SD] age at enrollment, 15.0 [1.7] years; 469 Black participants [17.1%], 678 Hispanic participants [24.7%], and 1618 White participants [59.1%]) completed both screenings and follow-ups. The ASQ and the CASSY showed a similar sensitivity (0.951 [95% CI, 0.918-0.984] vs 0.945 [95% CI, 0.910-0.980]), specificity (0.588 [95% CI, 0.569-0.607] vs 0.643 [95% CI, 0.625-0.662]), positive predictive value (0.127 [95% CI, 0.109-0.146] vs 0.144 [95% CI, 0.123-0.165]), and negative predictive value (both 0.995 [95% CI, 0.991-0.998], respectively). Area under the receiver operating characteristic curve findings were similar among patients with physical symptoms (ASQ, 0.88 [95% CI, 0.81-0.95] vs CASSY, 0.94 [95% CI, 0.91-0.96]). Among patients with psychiatric symptoms, the CASSY performed better than the ASQ (0.72 [95% CI, 0.68-0.77] vs 0.57 [95% CI, 0.55-0.59], respectively).
Conclusions and Relevance This study suggests that both the ASQ and the CASSY are appropriate for universal screening of patients in pediatric EDs. For the small subset of patients with psychiatric symptoms, the CASSY shows greater predictive validity.
Brent DA, Horowitz LM, Grupp-Phelan J, et al. Prediction of Suicide Attempts and Suicide-Related Events Among Adolescents Seen in Emergency Departments. JAMA Netw Open. 2023;6(2):e2255986. Published 2023 Feb 1. doi:10.1001/jamanetworkopen.2022.55986
Screening for suicidality assumes consistent answers about suicidality, whether asked directly (using the word “suicidal”) or indirectly (describing suicidality without stating the actual word). In a diverse population of almost 6,000 adolescent ED patients from 13 hospitals, adolescents were asked about suicidality using both direct and indirect questioning. 6.2% responded yes to only 1 version to the question but not the other. This discrepancy suggests that screening tools need both direct and indirect questioning about suicidality.
Background: Clinical assessments are a primary method for ascertaining suicide risk, yet the language used across measures is inconsistent. The implications of these discrepancies for adolescent responding are unknown, which is troubling as multiple research areas (i.e. on culture, mental health language, and suicide communication) indicate individuals from varying sociodemographic backgrounds may communicate differently regarding mental health concerns. The aims of the current study are to investigate whether a geographically diverse sample of adolescents respond differently to directly and indirectly phrased suicide attempt questions (i.e. directly phrased includes the term ‘suicide’ and indirectly asks about suicidal behavior without using ‘suicide’), and to examine whether sociodemographic factors and history of mental health service usage relate to endorsement differences.
Methods: Participants were N = 5909 adolescents drawn from the Emergency Department Screening for Teens at Risk for Suicide multi-site study. The lifetime suicide attempt was assessed with two items from an adapted version of the Columbia Suicide Severity Rating Scale (C-SSRS; Posner et al., 2008): (1) a directly phrased question asking about ‘suicide attempts’ and (2) an indirectly phrased question providing the definition of an attempt.
Results: An adolescent majority (83.7%) consistently reported no lifetime suicide attempt across items, 10.1% consistently reported one or more lifetime attempts across items, and 6.2% of adolescents responded discordantly to the items.
Conclusions: Multivariable models indicated multiple demographic and mental health service variables significantly predicted discordant responding, with a notable finding being that father/stepfather education level at or below high school education predicted endorsing only the direct question.
Hatkevich C, Grupp-Phelan J, Brent D, et al. Understanding adolescent responses to differently worded suicide attempt questions: results from a large US pediatric sample. Psychol Med. 2022;52(12):2309-2318. doi:10.1017/S0033291720004213
The following self-reported items predicted adolescent suicide attempts within 3 months:
- Current and past suicide ideation
- Past suicidal behavior
- Total negative life events
- School or social connectedness
Background: Concerns have been raised about the utility of self-report assessments in predicting future suicide attempts. Clinicians in pediatric emergency departments (EDs) often are required to assess suicidal risk. The Death Implicit Association Test (IAT) is an alternative to self-report assessment of suicidal risk that may have utility in ED settings.
Methods: A total of 1679 adolescents recruited from 13 pediatric emergency rooms in the Pediatric Emergency Care Applied Research Network were assessed using a self-report survey of risk and protective factors for a suicide attempt, and the IAT, and then followed up 3 months later to determine if an attempt had occurred. The accuracy of prediction was compared between self-reports and the IAT using the area under the curve (AUC) with respect to receiver operator characteristics.
Results: A few self-report variables, namely, current and past suicide ideation, past suicidal behavior, total negative life events, and school or social connectedness, predicted an attempt at 3 months with an AUC of 0.87 [95% confidence interval (CI), 0.84-0.90] in the entire sample, and AUC = 0.91, (95% CI 0.85-0.95) for those who presented without reported suicidal ideation. The IAT did not add significantly to the predictive power of selected self-report variables. The IAT alone was modestly predictive of 3-month attempts in the overall sample ((AUC = 0.59, 95% CI 0.52-0.65) and was a better predictor in patients who were non-suicidal at baseline (AUC = 0.67, 95% CI 0.55-0.79).
Conclusions: In pediatric EDs, a small set of self-reported items predicted suicide attempts within 3 months more accurately than did the IAT.
Brent DA, Grupp-Phelan J, O’Shea BA, et al. A comparison of self-reported risk and protective factors and the death implicit association test in the prediction of future suicide attempts in adolescent emergency department patients [published online ahead of print, 2021 May 5]. Psychol Med. 2021;1-9. doi:10.1017/S0033291721001215
Sexual minority youth had higher rates of lifetime suicide ideation (61.5%) and suicidal thoughts in the past month (36.6%) compared to heterosexual youth (21.2% and 9%, respectively). Depression, bullying victimization, and sexual abuse seem the most significant risk factors, and parent-family connectedness and positive affect were most protective.
Background: Differences in risk and protective factors (e.g., victimization, abuse, social support) have been used to explain elevated rates of suicidal ideation and suicide attempts in sexual minority youth (SMY) relative to heterosexual peers. However, little is known regarding how risk and protective factors may explain suicide risk differences among subgroups of SMY. The aims of this study were to 1) examine differences in prevalence and severity for suicide risk and protective factors among SMY, and 2) explore whether risk and protective factors are differentially associated with suicidal ideation and suicide attempts for SMY subgroups.
Methods: Participants were 6,423 adolescents (ages 12-17) recruited from 14 Emergency Departments across the United States who completed an assessment of suicide risk and protective factors. SMY were 20% of the sample (n = 1,275) and categorized as bisexual (8%), gay/lesbian (2%), mostly straight (5%), or other sexual minority (5%).
Results: Bisexual youth had elevated rates of suicidal ideation and attempts, more risk factors (e.g., bullying victimization, depression), and fewer protective factors (e.g., parent-family connectedness, positive affect) relative to mostly straight and other sexual minority youth. Bisexual and gay/lesbian youth only differed in parent-family connectedness (lower among bisexual youth). Depression and parent-family connectedness had weaker associations with suicidal ideation for bisexual youth.
Limitations: Emergency departments were not nationally representative. Study design was cross-sectional, preventing causal inferences.
Conclusions: Interventions seeking to mitigate risk factors and promote protective factors are greatly needed for SMY and may benefit from tailoring to address unique stressors for sexual minority subgroups.
Horwitz AG, Grupp-Phelan J, Brent D, et al. Risk and protective factors for suicide among sexual minority youth seeking emergency medical services. J Affect Disord. 2021;279:274-281. doi:10.1016/j.jad.2020.10.015
This technical report accompanies a joint policy statement from the American Academy of Pediatrics, American College of Emergency Physicians, and the Emergency Nurses Association to improve the care of children with mental and behavior health emergencies.
Mental and behavioral health (MBH) visits of children and youth to emergency departments are increasing in the United States. Reasons for these visits range from suicidal ideation, self-harm, and eating and substance use disorders to behavioral outbursts, aggression, and psychosis. Despite the increase in prevalence of these conditions, the capacity of the health care system to screen, diagnose, and manage these patients continues to decline. Several social determinants also contribute to great disparities in child and adolescent (youth) health, which affect MBH outcomes. In addition, resources and space for emergency physicians, physician assistants, nurse practitioners, and prehospital practitioners to manage these patients remain limited and inconsistent throughout the United States, as is financial compensation and payment for such services. This technical report discusses the role of physicians, physician assistants, and nurse practitioners, and provides guidance for the management of acute MBH emergencies in children and youth. Unintentional ingestions and substance use disorder are not within the scope of this report and are not specifically discussed.
Saidinejad M, Duffy S, Wallin D, et al. The Management of Children and Youth With Pediatric Mental and Behavioral Health Emergencies [published online ahead of print, 2023 Aug 16]. Pediatrics. 2023;e2023063256. doi:10.1542/peds.2023-063256
Pediatric Social Determinants of Health
The validated National Institute of Alcohol Abuse and Alcoholism (NIAAA) 2-question screening tool assesses alcohol use risk in pediatric EDs. This tool identified that even adolescents at low risk for alcohol use were associated with later cannibis use disorder.
Background: Alcohol and cannabis use frequently co-occur, which can result in problems from social and academic impairment to dependence (i.e., alcohol use disorder [AUD] and/or cannabis use disorder [CUD]). The Emergency Department (ED) is an excellent site to identify adolescents with alcohol misuse, conduct a brief intervention, and refer to treatment; however, given time constraints, alcohol use may be the only substance assessed due to its common role in unintentional injury. The current study, a secondary data analysis, assessed the relationship between adolescent alcohol and cannabis use by examining the National Institute of Alcohol Abuse and Alcoholism (NIAAA) two question screen’s (2QS) ability to predict future CUD at one, two, and three years post-ED visit.
Methods: At baseline, data was collected via tablet self-report surveys from medically and behaviorally stable adolescents 12-17 years old (n = 1,689) treated in 16 pediatric EDs for non-life-threatening injury, illness, or mental health condition. Follow-up surveys were completed via telephone or web-based survey. Logistic regression compared CUD diagnosis odds at one, two, or three-year follow-up between levels constituting a single-level change in baseline risk categorization on the NIAAA 2QS (nondrinker versus low-risk, low- versus moderate-risk, moderate- versus high-risk). Receiver operating characteristic curve methods examined the predictive ability of the baseline NIAAA 2QS cut points for CUD at one, two, or three-year follow-up.
Results: Adolescents with low alcohol risk had significantly higher rates of CUD versus nondrinkers (OR range: 1.94-2.76, p < .0001). For low and moderate alcohol risk, there was no difference in CUD rates (OR range: 1.00-1.08). CUD rates were higher in adolescents with high alcohol risk versus moderate risk (OR range: 2.39-4.81, p < .05).
Conclusions: Even low levels of baseline alcohol use are associated with risk for a later CUD. The NIAAA 2QS is an appropriate assessment measure to gauge risk for future cannabis use.
Linakis JG, Thomas SA, Bromberg JR, et al. Adolescent alcohol use predicts cannabis use over a three year follow-up period. Subst Abus. 2022;43(1):514-519. doi:10.1080/08897077.2021.1949665
Economic disparities from a lower household income do not seem to result in a more severe course of acute gastroenteritis for pediatric patients (3 months to 4 years old), as defined by need for more post-discharge revisits, hospitalizations, or IV rehydration.
Objective: To determine if low household income is associated with disease severity following emergency department (ED) discharge in children with acute gastroenteritis (AGE).
Methods: We conducted a secondary analysis employing data collected in 10 US-based tertiary-care, pediatric EDs between 2014 and 2017. Participants were aged 3 to 48 months and presented for care due to AGE. Income status was defined based on 1) home ZIP Code median annual home income and 2) percentage of home ZIP Code households below the poverty threshold. The primary outcome was moderate-to-severe AGE, defined by a post-ED visit Modified Vesikari Scale (MVS) score ≥9. Secondary outcomes included in-person revisits, revisits with intravenous rehydration, hospitalization, and etiologic pathogens.
Results: About 943 (97%) participants with a median age of 17 months (interquartile range 10, 28) completed follow-up. Post-ED visit MVS scores were lower for the lowest household income group (adjusted: -0.60; 95% confidence interval [CI]: -1.13, -0.07). Odds of experiencing an MVS score ≥9 did not differ between groups (adjusted odds ratio: 0.91; 95% CI: 0.54, 1.52). No difference in the post-ED visit MVS score or the proportion of participants with scores ≥9 was observed using the national poverty threshold definition. For both income definitions, there were no differences in terms of revisits following discharge, hospitalizations, and intravenous rehydration. Bacterial enteropathogens were more commonly identified in the lowest socioeconomic group using both definitions.
Conclusions: Lower household income was not associated with increased disease severity or resource use. Economic disparities do not appear to result in differences in the disease course of children with AGE seeking ED care.
Chun TH, Schnadower D, Casper TC, et al. Lack of Association of Household Income and Acute Gastroenteritis Disease Severity in Young Children: A Cohort Study. Acad Pediatr. 2022;22(4):581-591. doi:10.1016/j.acap.2021.07.009
Analysis of 33 U.S. hospitals in the Pediatric Health Information System during 2013-17 showed a rise in pediatric firearm inpatient and ICU admissions by 14 and 12% annually over the 5-year period, respectively. Patients in the Midwest and South comprised over 75% of the firearm-related inpatient admissions.
None available
Doh KF, Sheline EK, Wetzel M, Xiang Y, Morris CR, Simon HK. Pediatric firearm and motor vehicle collision injuries in the United States: Diverging trends. Am J Emerg Med. 2022;53:59-62. doi:10.1016/j.ajem.2021.12.029
This is the first large ED-setting survey to assess substance use for adolescents (age 14-17). They are relatively comparable to national surveys conducted in schools and door-to-door interviews. 18% report having drank alcohol within the past 30 days. Also they have tried marijuana (28.5%), cigarette smoking (19.2%), cocaine (5.1%), opioids (1.3%), methamphetamines (1.2%), and LSD/PCP (2.1%) during their lifetime.
Objectives: The aim of this study was to understand the prevalence of alcohol and other substance use among teenagers in generalized samples.
Methods: This study compared the alcohol and other substance use of adolescents enrolled in a screening study across 16 Pediatric Emergency Care Applied Research Network emergency departments (EDs) (ASSESS) with those sampled in 2 nationally representative surveys, the Youth Risk Behavior Surveillance System (YRBSS) and the National Survey of Drug Use and Health (NSDUH). The analysis includes 3362 ASSESS participants and 11,142 YRBSS and 12,086 NSDUH respondents.
Results: The ASSESS patients had a similar profile to the NSDUH sample, with small differences in marijuana and cocaine use and age at first tobacco smoking and smoking within the last 30 days and higher use of snuff or chewing tobacco. The YRBSS participants had higher rates of using marijuana, snuff/chewing tobacco, methamphetamine, and hallucinogens and higher smoking rates compared with ASSESS and NSDUH.
Conclusions: Adolescents visiting Pediatric Emergency Care Applied Research Network EDs have substantial rates of substance use, similar to other nationally representative studies on this topic, although not as high as a school-based survey. Future ED studies should continue to investigate adolescent substance use, including exploring optimal methods of survey administration.
Chun TH, Chernick LS, Ahmad FA, et al. Adolescent Substance Abuse Risk: A Comparison of Pediatric Emergency Care Applied Research Network Emergency Department Patients and 2 Nationally Representative Samples. Pediatr Emerg Care. 2021;37(9):e560-e564. doi:10.1097/PEC.0000000000001763
This survey focuses on pediatric injury prevention from household firearms. Gun owners seem to underestimate their child’s ability to access firearms. 14% of children of gun owners reported that they could acquire a gun that day (compared to 4% of children of non-gun owners). Also alarmingly, 59% of surveyed children could not differentiate photos of an actual versus a toy gun.
Locked-up and unloaded firearm storage is a tenet of injury prevention campaigns to decrease children’s access to firearms. This study cohort describes the reported presence of, storage mechanisms for, and children’s perceived access to firearms. Parent-child dyads (n = 297) were recruited from pediatric emergency departments in Atlanta, GA. Gun owners were 25% of cohort; 53% reported storing some firearms insecurely. Gun owners were more likely to believe their child could access a firearm versus non–gun owners (11% vs 3%).
Children of gun owners versus non-gun owners indicated increased ability to acquire a gun (14% vs 4%). Fifty-nine percent of children could not identify a real versus toy gun in a picture.
This study highlights a plurality of parents storing firearms insecurely with a significant portion of children reporting gun access and demonstrating inability to recognize actual guns. This disconnect points to the importance of public health interventions to decrease access to firearms in this vulnerable population.
Doh KF, Morris CR, Akbar T, et al. The Relationship Between Parents’ Reported Storage of Firearms and Their Children’s Perceived Access to Firearms: A Safety Disconnect. Clin Pediatr (Phila). 2021;60(1):42-49. doi:10.1177/0009922820944398
The validated National Institute of Alcohol Abuse and Alcoholism (NIAAA) 2-question screening tool assesses alcohol use risk in pediatric EDs. This tool identified that even adolescents at low risk for alcohol use were associated with later cannibis use disorder.
Background: Alcohol and cannabis use frequently co-occur, which can result in problems from social and academic impairment to dependence (i.e., alcohol use disorder [AUD] and/or cannabis use disorder [CUD]). The Emergency Department (ED) is an excellent site to identify adolescents with alcohol misuse, conduct a brief intervention, and refer to treatment; however, given time constraints, alcohol use may be the only substance assessed due to its common role in unintentional injury. The current study, a secondary data analysis, assessed the relationship between adolescent alcohol and cannabis use by examining the National Institute of Alcohol Abuse and Alcoholism (NIAAA) two question screen’s (2QS) ability to predict future CUD at one, two, and three years post-ED visit.
Methods: At baseline, data was collected via tablet self-report surveys from medically and behaviorally stable adolescents 12-17 years old (n = 1,689) treated in 16 pediatric EDs for non-life-threatening injury, illness, or mental health condition. Follow-up surveys were completed via telephone or web-based survey. Logistic regression compared CUD diagnosis odds at one, two, or three-year follow-up between levels constituting a single-level change in baseline risk categorization on the NIAAA 2QS (nondrinker versus low-risk, low- versus moderate-risk, moderate- versus high-risk). Receiver operating characteristic curve methods examined the predictive ability of the baseline NIAAA 2QS cut points for CUD at one, two, or three-year follow-up.
Results: Adolescents with low alcohol risk had significantly higher rates of CUD versus nondrinkers (OR range: 1.94-2.76, p < .0001). For low and moderate alcohol risk, there was no difference in CUD rates (OR range: 1.00-1.08). CUD rates were higher in adolescents with high alcohol risk versus moderate risk (OR range: 2.39-4.81, p < .05).
Conclusions: Even low levels of baseline alcohol use are associated with risk for a later CUD. The NIAAA 2QS is an appropriate assessment measure to gauge risk for future cannabis use.
Linakis JG, Thomas SA, Bromberg JR, et al. Adolescent alcohol use predicts cannabis use over a three year follow-up period. Subst Abus. 2022;43(1):514-519. doi:10.1080/08897077.2021.1949665
Economic disparities from a lower household income do not seem to result in a more severe course of acute gastroenteritis for pediatric patients (3 months to 4 years old), as defined by need for more post-discharge revisits, hospitalizations, or IV rehydration.
Objective: To determine if low household income is associated with disease severity following emergency department (ED) discharge in children with acute gastroenteritis (AGE).
Methods: We conducted a secondary analysis employing data collected in 10 US-based tertiary-care, pediatric EDs between 2014 and 2017. Participants were aged 3 to 48 months and presented for care due to AGE. Income status was defined based on 1) home ZIP Code median annual home income and 2) percentage of home ZIP Code households below the poverty threshold. The primary outcome was moderate-to-severe AGE, defined by a post-ED visit Modified Vesikari Scale (MVS) score ≥9. Secondary outcomes included in-person revisits, revisits with intravenous rehydration, hospitalization, and etiologic pathogens.
Results: About 943 (97%) participants with a median age of 17 months (interquartile range 10, 28) completed follow-up. Post-ED visit MVS scores were lower for the lowest household income group (adjusted: -0.60; 95% confidence interval [CI]: -1.13, -0.07). Odds of experiencing an MVS score ≥9 did not differ between groups (adjusted odds ratio: 0.91; 95% CI: 0.54, 1.52). No difference in the post-ED visit MVS score or the proportion of participants with scores ≥9 was observed using the national poverty threshold definition. For both income definitions, there were no differences in terms of revisits following discharge, hospitalizations, and intravenous rehydration. Bacterial enteropathogens were more commonly identified in the lowest socioeconomic group using both definitions.
Conclusions: Lower household income was not associated with increased disease severity or resource use. Economic disparities do not appear to result in differences in the disease course of children with AGE seeking ED care.
Chun TH, Schnadower D, Casper TC, et al. Lack of Association of Household Income and Acute Gastroenteritis Disease Severity in Young Children: A Cohort Study. Acad Pediatr. 2022;22(4):581-591. doi:10.1016/j.acap.2021.07.009
Analysis of 33 U.S. hospitals in the Pediatric Health Information System during 2013-17 showed a rise in pediatric firearm inpatient and ICU admissions by 14% and 12% annually over the 5-year period, respectively. Patients in the Midwest and South comprised over 75% of the firearm-related inpatient admissions.
None available
Doh KF, Sheline EK, Wetzel M, Xiang Y, Morris CR, Simon HK. Pediatric firearm and motor vehicle collision injuries in the United States: Diverging trends. Am J Emerg Med. 2022;53:59-62. doi:10.1016/j.ajem.2021.12.029
This is the first large ED-setting survey to assess substance use for adolescents (age 14-17). They are relatively comparable to national surveys conducted in schools and door-to-door interviews. 18% report having drank alcohol within the past 30 days. Also they have tried marijuana (28.5%), cigarette smoking (19.2%), cocaine (5.1%), opioids (1.3%), methamphetamines (1.2%), and LSD/PCP (2.1%) during their lifetime.
Objectives: The aim of this study was to understand the prevalence of alcohol and other substance use among teenagers in generalized samples.
Methods: This study compared the alcohol and other substance use of adolescents enrolled in a screening study across 16 Pediatric Emergency Care Applied Research Network emergency departments (EDs) (ASSESS) with those sampled in 2 nationally representative surveys, the Youth Risk Behavior Surveillance System (YRBSS) and the National Survey of Drug Use and Health (NSDUH). The analysis includes 3362 ASSESS participants and 11,142 YRBSS and 12,086 NSDUH respondents.
Results: The ASSESS patients had a similar profile to the NSDUH sample, with small differences in marijuana and cocaine use and age at first tobacco smoking and smoking within the last 30 days and higher use of snuff or chewing tobacco. The YRBSS participants had higher rates of using marijuana, snuff/chewing tobacco, methamphetamine, and hallucinogens and higher smoking rates compared with ASSESS and NSDUH.
Conclusions: Adolescents visiting Pediatric Emergency Care Applied Research Network EDs have substantial rates of substance use, similar to other nationally representative studies on this topic, although not as high as a school-based survey. Future ED studies should continue to investigate adolescent substance use, including exploring optimal methods of survey administration.
Chun TH, Chernick LS, Ahmad FA, et al. Adolescent Substance Abuse Risk: A Comparison of Pediatric Emergency Care Applied Research Network Emergency Department Patients and 2 Nationally Representative Samples. Pediatr Emerg Care. 2021;37(9):e560-e564. doi:10.1097/PEC.0000000000001763
This survey focuses on pediatric injury prevention from household firearms. Gun owners seem to underestimate their child’s ability to access firearms. 14% of children of gun owners reported that they could acquire a gun that day (compared to 4% of children of non-gun owners). Also alarmingly, 59% of surveyed children could not differentiate photos of an actual versus a toy gun.
Locked-up and unloaded firearm storage is a tenet of injury prevention campaigns to decrease children’s access to firearms. This study cohort describes the reported presence of, storage mechanisms for, and children’s perceived access to firearms. Parent-child dyads (n = 297) were recruited from pediatric emergency departments in Atlanta, GA. Gun owners were 25% of cohort; 53% reported storing some firearms insecurely. Gun owners were more likely to believe their child could access a firearm versus non–gun owners (11% vs 3%).
Children of gun owners versus non-gun owners indicated increased ability to acquire a gun (14% vs 4%). Fifty-nine percent of children could not identify a real versus toy gun in a picture.
This study highlights a plurality of parents storing firearms insecurely with a significant portion of children reporting gun access and demonstrating inability to recognize actual guns. This disconnect points to the importance of public health interventions to decrease access to firearms in this vulnerable population.
Doh KF, Morris CR, Akbar T, et al. The Relationship Between Parents’ Reported Storage of Firearms and Their Children’s Perceived Access to Firearms: A Safety Disconnect. Clin Pediatr (Phila). 2021;60(1):42-49. doi:10.1177/0009922820944398
Pediatric Sickle Cell Disease
Intranasal fentanyl, which does not require an IV line, seems an ideal initial parenteral analgesic for pediatric patients with sickle cell pain crises, because it is associated with a 9x greater odds of discharge from the emergency department.
Children with sickle cell disease (SCD) commonly experience vaso-occlusive pain episodes (VOE) due to sickling of erythrocytes, which often requires care in the emergency department. Our objective was to assess the use and impact of intranasal fentanyl for the treatment of children with SCD-VOE on discharge from the emergency department in a multicenter study. We conducted a cross-sectional study at 20 academic pediatric emergency departments in the United States and Canada. We used logistic regression to test bivariable and multivariable associations between the outcome of discharge from the emergency department and candidate variables theoretically associated with discharge. The study included 400 patients; 215 (54%) were female. The median age was 14.6 (interquartile range 9.8, 17.6) years. Nineteen percent (n = 75) received intranasal fentanyl in the emergency department. Children who received intranasal fentanyl had nearly nine-fold greater adjusted odds of discharge from the emergency department compared to those who did not (adjusted odds ratio 8.99, 95% CI 2.81-30.56, p < .001). The rapid onset of action and ease of delivery without intravenous access offered by intranasal fentanyl make it a feasible initial parenteral analgesic in the treatment of children with SCD presenting with VOE in the acute-care setting. Further study is needed to determine potential causality of the association between intranasal fentanyl and discharge from the emergency department observed in this multicenter study.
Rees CA, Brousseau DC, Ahmad FA, et al. Intranasal fentanyl and discharge from the emergency department among children with sickle cell disease and vaso-occlusive pain: A multicenter pediatric emergency medicine perspective [published online ahead of print, 2023 Jan 6]. Am J Hematol. 2023;10.1002/ajh.26837. doi:10.1002/ajh.26837
Only 48% of patients presenting to the ED in a sickle cell vaso-occlusive pain crisis received parenteral opioids within the recommended ≤60 minutes of arrival. The subset of children who received intranasal fentanyl more likely reached this 60-minute benchmark.
Unlike prior published papers, there was no association between a delay in initial parenteral opioid administration and higher odds for hospitalization.
An open-access correspondence letter
Rees CA, Brousseau DC, Ahmad FA, et al. Adherence to NHLBI guidelines for the emergent management of vaso-occlusive episodes in children with sickle cell disease: A multicenter perspective. Am J Hematol. 2022;97(11):E412-E415. doi:10.1002/ajh.26696
Low glutamine plasma levels are associated with hemolytic anemias, such as sickle cell disease. Low levels of plasma arginine, whose precursor is glutamine, is associated with sickle cell vaso-occlusive pain severity. This is the first study to demonstrate that oral glutamine increases glutamine and arginine levels in plasma and erythrocytes.
Objectives: L-Glutamine is FDA-approved for sickle cell disease (SCD), yet the mechanism(s)-of-action are poorly understood. We performed a pharmacokinetics (pK) study to determine the metabolic fate of glutamine supplementation on plasma and erythrocyte amino acids in patients with SCD.
Design: A pK study was performed where patients with SCD fasting for > 8 h received oral L-glutamine (10 g). Blood was analyzed at baseline, 30/60/90 min/2/3/4/8 hrs. A standardized diet was administered to all participants at 3 established time-points (after 2/5/7hrs). A subset of patients also had pK studies performed without glutamine supplementation to follow normal diurnal fluctuations in amino acids.
Setting: Comprehensive SCD Center in Oakland, California RESULTS: Five patients with SCD were included, three of whom performed pK studies both with and without glutamine supplementation. Average age was 50.6 ± 5.6 years, 60% were female, 40% SS, 60% SC. Plasma glutamine levels increased significantly after oral glutamine supplementation, compared to minimal fluctuations with diet. Plasma glutamine concentration peaked within 30-min of ingestion (p = 0.01) before decreasing to a plateau by 2-h that remained higher than baseline by 8 h. Oral glutamine also increased plasma arginine concentration, which peaked by 4-h (p = 0.03) and remained elevated through 8-h. Erythrocyte glutamine levels began to increase by 8-h, while erythrocyte arginine concentration peaked at 4-h.
Conclusions: Oral glutamine supplementation acutely improved glutamine and arginine bioavailability in both plasma and erythrocytes. This is the first study to demonstrate that glutamine therapy increases arginine bioavailability and may provide insight into shared mechanisms-of-action between these conditionally-essential amino acids.
Morris CR, Kuypers FA, Hagar R, et al. Implications for the metabolic fate of oral glutamine supplementation within plasma and erythrocytes of patients with sickle cell disease: A pharmacokinetics study. Complement Ther Med. 2022;64:102803. doi:10.1016/j.ctim.2022.102803
Pediatric patients who present to the ED with a sickle cell pain crisis seem to have a higher admission rate if they received an IV normal saline bolus in this retrospective 20-site multicenter study. A prospective study is needed to assess correlation.
Vaso-occlusive pain events (VOE) are the leading cause of emergency department (ED) visits in sickle cell anemia (SCA). This study assessed the variability in use of intravenous fluids (IVFs), and the association of normal saline bolus (NSB), on pain and other clinical outcomes in children with SCA, presenting to pediatric emergency departments (PED) with VOE. Four-hundred charts of children age 3-21 years with SCA/VOE receiving parenteral opioids at 20 high-volume PEDs were evaluated in a retrospective study. Data on type and amount of IVFs used were collected. Patients were divided into two groups: those who received NSB and those who did not. The association of NSB use on change in pain scores and admission rates was evaluated.
Among 400 children studied, 261 (65%) received a NSB. Mean age was 13.8 ± 4.9 years; 46% were male; 92% had hemoglobin-SS. The IVFs (bolus and/or maintenance) were used in 84% of patients. Eight different types of IVFs were utilized and IVF volume administered varied widely. Mean triage pain scores were similar between groups, but improvement in pain scores from presentation-to-ED-disposition was smaller in the NSB group (2.2 vs 3.0, P = .03), while admission rates were higher (71% vs 59%, P = .01). Use of NSB remained associated with poorer final pain scores and worse change in pain scores in our multivariable model.
In conclusion, wide variations in practice utilizing IVFs are common. NSB is given to >50% of children with SCA/VOE, but is associated with poorer pain control; a controlled prospective trial is needed to determine causality.
Carden MA, Brousseau DC, Ahmad FA, et al. Normal saline bolus use in pediatric emergency departments is associated with poorer pain control in children with sickle cell anemia and vaso-occlusive pain. Am J Hematol. 2019;94(6):689-696. doi:10.1002/ajh.25471
This publication announces the phase 3 trial, studying the use of IV arginine in the management of vaso-occlusive episodes for patients with sickle cell disease.
Background
Despite substantial illness burden and healthcare utilization conferred by pain from vaso-occlusive episodes (VOE) in children with sickle cell disease (SCD), disease-modifying therapies to effectively treat SCD-VOE are lacking. The aim of the Sickle Cell Disease Treatment with Arginine Therapy (STArT) Trial is to provide definitive evidence regarding the efficacy of intravenous arginine as a treatment for acute SCD-VOE among children, adolescents, and young adults.
Methods
STArT is a double-blind, placebo-controlled, randomized, phase 3, multicenter trial of intravenous arginine therapy in 360 children, adolescents, and young adults who present with SCD-VOE. The STArT Trial is being conducted at 10 sites in the USA through the Pediatric Emergency Care Applied Research Network (PECARN). Enrollment began in 2021 and will continue for 5 years. Within 12 h of receiving their first dose of intravenous opioids, enrolled participants are randomized 1:1 to receive either (1) a one-time loading dose of L-arginine (200 mg/kg with a maximum of 20 g) administered intravenously followed by a standard dose of 100 mg/kg (maximum 10 g) three times a day or (2) a one-time placebo loading dose of normal saline followed by normal saline three times per day at equivalent volumes and duration as the study drug. Participants, research staff, and investigators are blinded to the participant’s randomization. All clinical care is provided in accordance with the institution-specific standard of care for SCD-VOE based on the 2014 National Heart, Lung, and Blood Institute guidelines. The primary outcome is time to SCD-VOE pain crisis resolution, defined as the time (in hours) from study drug delivery to the last dose of parenteral opioid delivery. Secondary outcomes include total parental opioid use and patient-reported outcomes. In addition, the trial will characterize alterations in the arginine metabolome and mitochondrial function in children with SCD-VOE.
Discussion
Building on the foundation of established relationships between emergency medicine providers and hematologists in a multicenter research network to ensure adequate participant accrual, the STArT Trial will provide definitive information about the efficacy of intravenous arginine for the treatment of SCD-VOE for children.
Trial registration
The STArT Trial was registered in ClinicalTrials.gov on April 9, 2021, and enrollment began on June 21, 2021 (NCT04839354).
Rees, C.A., Brousseau, D.C., Cohen, D.M. et al. Sickle Cell Disease Treatment with Arginine Therapy (STArT): study protocol for a phase 3 randomized controlled trial. Trials 24, 538 (2023). https://doi.org/10.1186/s13063-023-07538-z
Intranasal fentanyl, which does not require an IV line, seems an ideal initial parenteral analgesic for pediatric patients with sickle cell pain crises, because it is associated with a 9x greater odds of discharge from the emergency department.
Children with sickle cell disease (SCD) commonly experience vaso-occlusive pain episodes (VOE) due to sickling of erythrocytes, which often requires care in the emergency department. Our objective was to assess the use and impact of intranasal fentanyl for the treatment of children with SCD-VOE on discharge from the emergency department in a multicenter study. We conducted a cross-sectional study at 20 academic pediatric emergency departments in the United States and Canada. We used logistic regression to test bivariable and multivariable associations between the outcome of discharge from the emergency department and candidate variables theoretically associated with discharge. The study included 400 patients; 215 (54%) were female. The median age was 14.6 (interquartile range 9.8, 17.6) years. Nineteen percent (n = 75) received intranasal fentanyl in the emergency department. Children who received intranasal fentanyl had nearly nine-fold greater adjusted odds of discharge from the emergency department compared to those who did not (adjusted odds ratio 8.99, 95% CI 2.81-30.56, p < .001). The rapid onset of action and ease of delivery without intravenous access offered by intranasal fentanyl make it a feasible initial parenteral analgesic in the treatment of children with SCD presenting with VOE in the acute-care setting. Further study is needed to determine potential causality of the association between intranasal fentanyl and discharge from the emergency department observed in this multicenter study.
Rees CA, Brousseau DC, Ahmad FA, et al. Intranasal fentanyl and discharge from the emergency department among children with sickle cell disease and vaso-occlusive pain: A multicenter pediatric emergency medicine perspective [published online ahead of print, 2023 Jan 6]. Am J Hematol. 2023;10.1002/ajh.26837. doi:10.1002/ajh.26837
Only 48% of patients presenting to the ED in a sickle cell vaso-occlusive pain crisis received parenteral opioids within the recommended ≤60 minutes of arrival. The subset of children who received intranasal fentanyl more likely reached this 60-minute benchmark.
Unlike prior published papers, there was no association between a delay in initial parenteral opioid administration and higher odds for hospitalization.
An open-access correspondence letter
Rees CA, Brousseau DC, Ahmad FA, et al. Adherence to NHLBI guidelines for the emergent management of vaso-occlusive episodes in children with sickle cell disease: A multicenter perspective. Am J Hematol. 2022;97(11):E412-E415. doi:10.1002/ajh.26696
Low glutamine plasma levels are associated with hemolytic anemias, such as sickle cell disease. Low levels of plasma arginine, whose precursor is glutamine, is associated with sickle cell vaso-occlusive pain severity. This is the first study to demonstrate that oral glutamine increases glutamine and arginine levels in plasma and erythrocytes.
Objectives: L-Glutamine is FDA-approved for sickle cell disease (SCD), yet the mechanism(s)-of-action are poorly understood. We performed a pharmacokinetics (pK) study to determine the metabolic fate of glutamine supplementation on plasma and erythrocyte amino acids in patients with SCD.
Design: A pK study was performed where patients with SCD fasting for > 8 h received oral L-glutamine (10 g). Blood was analyzed at baseline, 30/60/90 min/2/3/4/8 hrs. A standardized diet was administered to all participants at 3 established time-points (after 2/5/7hrs). A subset of patients also had pK studies performed without glutamine supplementation to follow normal diurnal fluctuations in amino acids.
Setting: Comprehensive SCD Center in Oakland, California RESULTS: Five patients with SCD were included, three of whom performed pK studies both with and without glutamine supplementation. Average age was 50.6 ± 5.6 years, 60% were female, 40% SS, 60% SC. Plasma glutamine levels increased significantly after oral glutamine supplementation, compared to minimal fluctuations with diet. Plasma glutamine concentration peaked within 30-min of ingestion (p = 0.01) before decreasing to a plateau by 2-h that remained higher than baseline by 8 h. Oral glutamine also increased plasma arginine concentration, which peaked by 4-h (p = 0.03) and remained elevated through 8-h. Erythrocyte glutamine levels began to increase by 8-h, while erythrocyte arginine concentration peaked at 4-h.
Conclusions: Oral glutamine supplementation acutely improved glutamine and arginine bioavailability in both plasma and erythrocytes. This is the first study to demonstrate that glutamine therapy increases arginine bioavailability and may provide insight into shared mechanisms-of-action between these conditionally-essential amino acids.
Morris CR, Kuypers FA, Hagar R, et al. Implications for the metabolic fate of oral glutamine supplementation within plasma and erythrocytes of patients with sickle cell disease: A pharmacokinetics study. Complement Ther Med. 2022;64:102803. doi:10.1016/j.ctim.2022.102803
Pediatric patients who present to the ED with a sickle cell pain crisis seem to have a higher admission rate if they received an IV normal saline bolus in this retrospective 20-site multicenter study. A prospective study is needed to assess correlation.
Vaso-occlusive pain events (VOE) are the leading cause of emergency department (ED) visits in sickle cell anemia (SCA). This study assessed the variability in use of intravenous fluids (IVFs), and the association of normal saline bolus (NSB), on pain and other clinical outcomes in children with SCA, presenting to pediatric emergency departments (PED) with VOE. Four-hundred charts of children age 3-21 years with SCA/VOE receiving parenteral opioids at 20 high-volume PEDs were evaluated in a retrospective study. Data on type and amount of IVFs used were collected. Patients were divided into two groups: those who received NSB and those who did not. The association of NSB use on change in pain scores and admission rates was evaluated.
Among 400 children studied, 261 (65%) received a NSB. Mean age was 13.8 ± 4.9 years; 46% were male; 92% had hemoglobin-SS. The IVFs (bolus and/or maintenance) were used in 84% of patients. Eight different types of IVFs were utilized and IVF volume administered varied widely. Mean triage pain scores were similar between groups, but improvement in pain scores from presentation-to-ED-disposition was smaller in the NSB group (2.2 vs 3.0, P = .03), while admission rates were higher (71% vs 59%, P = .01). Use of NSB remained associated with poorer final pain scores and worse change in pain scores in our multivariable model.
In conclusion, wide variations in practice utilizing IVFs are common. NSB is given to >50% of children with SCA/VOE, but is associated with poorer pain control; a controlled prospective trial is needed to determine causality.
Carden MA, Brousseau DC, Ahmad FA, et al. Normal saline bolus use in pediatric emergency departments is associated with poorer pain control in children with sickle cell anemia and vaso-occlusive pain. Am J Hematol. 2019;94(6):689-696. doi:10.1002/ajh.25471
This publication announces the phase 3 trial, studying the use of IV arginine in the management of vaso-occlusive episodes for patients with sickle cell disease.
Background
Despite substantial illness burden and healthcare utilization conferred by pain from vaso-occlusive episodes (VOE) in children with sickle cell disease (SCD), disease-modifying therapies to effectively treat SCD-VOE are lacking. The aim of the Sickle Cell Disease Treatment with Arginine Therapy (STArT) Trial is to provide definitive evidence regarding the efficacy of intravenous arginine as a treatment for acute SCD-VOE among children, adolescents, and young adults.
Methods
STArT is a double-blind, placebo-controlled, randomized, phase 3, multicenter trial of intravenous arginine therapy in 360 children, adolescents, and young adults who present with SCD-VOE. The STArT Trial is being conducted at 10 sites in the USA through the Pediatric Emergency Care Applied Research Network (PECARN). Enrollment began in 2021 and will continue for 5 years. Within 12 h of receiving their first dose of intravenous opioids, enrolled participants are randomized 1:1 to receive either (1) a one-time loading dose of L-arginine (200 mg/kg with a maximum of 20 g) administered intravenously followed by a standard dose of 100 mg/kg (maximum 10 g) three times a day or (2) a one-time placebo loading dose of normal saline followed by normal saline three times per day at equivalent volumes and duration as the study drug. Participants, research staff, and investigators are blinded to the participant’s randomization. All clinical care is provided in accordance with the institution-specific standard of care for SCD-VOE based on the 2014 National Heart, Lung, and Blood Institute guidelines. The primary outcome is time to SCD-VOE pain crisis resolution, defined as the time (in hours) from study drug delivery to the last dose of parenteral opioid delivery. Secondary outcomes include total parental opioid use and patient-reported outcomes. In addition, the trial will characterize alterations in the arginine metabolome and mitochondrial function in children with SCD-VOE.
Discussion
Building on the foundation of established relationships between emergency medicine providers and hematologists in a multicenter research network to ensure adequate participant accrual, the STArT Trial will provide definitive information about the efficacy of intravenous arginine for the treatment of SCD-VOE for children.
Trial registration
The STArT Trial was registered in ClinicalTrials.gov on April 9, 2021, and enrollment began on June 21, 2021 (NCT04839354).
Rees, C.A., Brousseau, D.C., Cohen, D.M. et al. Sickle Cell Disease Treatment with Arginine Therapy (STArT): study protocol for a phase 3 randomized controlled trial. Trials 24, 538 (2023). https://doi.org/10.1186/s13063-023-07538-z
Professor and Digital Innovation Lab Director
Department of Emergency Medicine
University of California, San Francisco
@M_Lin