Sepsis remains a major cause of childhood mortality worldwide (1,2). In developed nations, the mortality risk associated with pediatric septic shock has decreased from 50% to 60% in the 1950–1960s to 5–10% currently (3–5). Although this statistic represents a paramount achievement for pediatric critical care medicine, it ignores the increasing morbidity burden of children surviving sepsis (6). With recognition that critical illness begins and ends outside of the ICU and hospital (7), clinicians and researchers alike are increasingly interested in long-term, patient-centered, clinically meaningful outcomes for critically ill patients. Previous investigations have reported increased risk for chronic disability, hospital readmission, and late mortality for children surviving sepsis, but these studies were frequently limited by small sample size, lack of baseline status quantification, and/or variable time intervals for follow-up evaluation(s) (8–13).
Accordingly, Specific Aim 1 of the Life After Pediatric Sepsis Evaluation (LAPSE) (R01HD073362) prospective, cohort-outcome investigation was conducted to characterize critically ill children with contemporary, community-acquired septic shock and to describe the trajectory of mortality and health-related quality of life (HRQL) morbidity among those who survived. LAPSE investigators hypothesized that critically ill children with septic shock would demonstrate long-term mortality and significant HRQL morbidity during the year following admission for the sepsis event. A companion article examines critical illness variables associated with long-term death or persistent, serious HRQL disability among children initially surviving septic shock (14).
MATERIALS AND METHODS
Performance Sites, Study Conduct, Study Participants, Definitions
Twelve U.S. academic PICU research teams (eFig. 1, Supplemental Digital Content 1, http://links.lww.com/CCM/F145) enrolled critically ill children with septic shock into the investigation. Details of performance sites, principal investigators, co-principal investigators, research coordinators, and allied research personnel are summarized in the acknowledgment section. Research coordinators continuously screened PICU admissions for potential study participants. Complete inclusion and exclusion criteria are provided in eText 1 (Supplemental Digital Content 1, http://links.lww.com/CCM/F145). Responsible attending physicians directed hemodynamic resuscitation, antimicrobial administration, mechanical ventilation, renal replacement therapy, extracorporeal life support, blood product transfusion, and nutritional management that were not mandated by the study protocol. Institutional review boards approved the study for each performance site, and parents provided written permission prior to patient participation. Developmentally appropriate patients were requested to provide assent for their own continued study participation following PICU discharge.
All patient participants exhibited septic shock that was operationally defined as documented or suspected infection with onset within 48 hours of hospital admission; and presence of greater than or equal to 2 systemic inflammatory response syndrome criteria (15), including abnormal leukocyte count/differential and/or abnormal body temperature; and requirement for fluid resuscitation and vasoactive-inotropic support that was initiated within 72 hours of hospital admission and within 48 hours of PICU admission. At enrollment, research coordinators collected data related to demographics, infectious disease, chronic comorbid conditions (16) (eText 2, Supplemental Digital Content 1, http://links.lww.com/CCM/F145), and immunodeficiency (eText 3, Supplemental Digital Content 1, http://links.lww.com/CCM/F145). Patients were assessed for initial illness severity using Pediatric Risk of Mortality (PRISM)–IV (17) and Pediatric Logistic Organ Dysfunction (PELOD)–2 score around PICU admission (18). Durations of vasoactive-inotropic support, mechanical ventilation, and PICU and hospital stay were recorded.
Patients were serially assessed by research staff for functional status utilizing Pediatric Cerebral Performance Category (PCPC) and Pediatric Overall Performance Category (POPC) (19) and the Functional Status Scale (FSS) (20) at study entry (reflecting baseline pre-sepsis status during the month prior to PICU admission), study day 7, and study day 28 or hospital discharge, whichever occurred first. Similarly, participating families completed serial parent-proxy assessments of their child’s HRQL utilizing the Pediatric Quality of Life Inventory (PedsQL), 4.0 Generic Core Scales (21,22) or PedsQL Infant Scales (23) or the Stein-Jessop Functional Status Scale (short form, 14 item, double element, FSII-R) (24). Parents selected the HRQL instrument that they believed provided the most meaningful assessment for their child. HRQL was assessed at study entry (reflecting baseline pre-sepsis status), study day 7 and 1, 3, 6, and 12 months following PICU admission for the septic shock event. Both surveys employ a 0–100 point scale. For consistency, magnitude of HRQL morbidity is reported in multiples 4.5 points, a minimal clinically important difference (MCID) established for PedsQL (21), but not FSII-R. Detailed methodology for serial assessments of functional status and HRQL is provided in eText 4 (Supplemental Digital Content 1, http://links.lww.com/CCM/F145).
Data Collection, Organization, and Analysis
Clinical data related to PICU admission were entered into an electronic data capture system provided by the data coordinating center at the University of Utah (OpenClinica, LLC, Waltham, MA). Data managers monitored data quality throughout the study. Parent-proxy HRQL assessments were entered into a separate database managed by the Seattle Children’s Research Institute (DatStat, Seattle, WA).
Interval or continuous variables are reported as medians and interquartile ranges, while variables collected categorically are summarized with counts and percentages. Sample size calculations for this investigation are detailed in eText 5 (Supplemental Digital Content 1, http://links.lww.com/CCM/F145). Bar graphs provide longitudinal summaries for PedsQL and FSII-R, as well as PCPC/POPC and FSS at each study time point for which data were collected. Differences in long-term outcomes, focused on change from baseline status, were measured using standard statistical tests such as the Wilcoxon rank-sum test, Fisher exact test, and the Cochran-Armitage test for trend. To account for potential bias due to loss of follow-up, longitudinal HRQL data were also analyzed utilizing multiple imputation techniques as discussed in eText 6 (Supplemental Digital Content 1, http://links.lww.com/CCM/F145).
Analyses were performed using SAS 9.4 (SAS Institute, Cary, NC) and R Version 3.4.4 (The R Foundation for Statistical Computing, Vienna, Austria). p values are based on a two-sided alternative with p values of less than 0.05 considered significant. Results are reported according to STrengthening the Reporting of OBservational studies in Epidemiology Guidelines for cohort studies (25).
The study flow diagram, Figure 1, and eTable 1 (Supplemental Digital Content 1, http://links.lww.com/CCM/F145) summarize exclusions and the number of patients with complete change from baseline survey information available for each study time point. From January 1, 2014, to June 30, 2017, 838 patients were screened, 632 were eligible, 570 (90%) were approached, 392 (62% of those eligible) were enrolled, and 389 provided complete baseline clinical data. Cumulative study enrollment and hospital survival are summarized graphically in eFigure 2 (Supplemental Digital Content 1, http://links.lww.com/CCM/F145). Of the enrolled patients with complete baseline data, 35 of 389 died (9%) during hospitalization and an additional 16 of 389 subjects died (4%) during the 1-year follow-up.
Table 1 summarizes demographics, illness severity, and resource utilization for the study cohort. Separate summaries are provided for all patients and for those completing a baseline HRQL survey, as only the latter group (n = 358) was used for subsequent change from baseline analyses. With broad overall age distribution, proportion of male patients exceeded females by 4%. Children with chronic conditions comprised 51% of the cohort; 18% were immunocompromised. Durations of vasoactive-inotropic infusion and mechanical ventilation support (median [Q1–Q3]) were 3.0 days (2.0–6.0 d) and 8.0 days (5.0–14.0 d); and durations of PICU and hospital stay were 9.4 days (5.6–15.4 d) and 15.7 days (9.2–26.0 d). Additional data indicated that patients’ health insurance status (n = 351) was primarily private insurance (44%) or Medicaid (55%). Prior to hospitalization, 95% of patients resided at their home. At month 1 follow-up, 146 of 235 patients (62%) were residing at home, while 88 of 235 (37%) remained hospitalized. Among all enrolled patients, 89 of 389 (23%) were hospitalized for more than 28 days. Cohort infection characteristics are summarized in eTables 2 and 3 (Supplemental Digital Content 1, http://links.lww.com/CCM/F145). Bacterial infection, viral infection, combined bacterial and viral infection, and no infection were documented in 49%, 45%, 20%, and 32% among all enrolled patients, respectively.
Functional Status Changes
Figure 2 and eTable 4 (Supplemental Digital Content 1, http://links.lww.com/CCM/F145) summarize graphically and numerically changes in PCPC and POPC scores over time. At baseline, only 38% of patients exhibited normal POPC. Median Baseline POPC score was 2.0 (1.0–3.0), while median change in POPC was 0.0 (0.0–1.0) comparing baseline and day 28/hospital discharge. Assuming normality, a mean change in POPC of 0.6 was observed with 95% CI (0.5–0.7) indicating a significant deterioration in functional status (p < 0.001). At day 28/hospital discharge, 85 of 384 children (22%) exhibited poor gross functional status (POPC ≥ 3 and an increase of ≥ 1 from baseline).
Figure 3 and eTable 5 (Supplemental Digital Content 1, http://links.lww.com/CCM/F145) summarize graphically and numerically changes in FSS scores over time. Baseline FSS (n = 389) was 6.0 (6.0–12.0), with normal FSS status recorded (% of patients) for the following dimensions: communication (65.3%), feeding (64.5%), mental status (74.3%), motor function (63.8%), respiratory status (78.7%), and sensory function (79.7%). At day 28/hospital discharge (n = 359), total FSS increased to 9.0 (6.0–15.0) (p < 0.001), again documenting a significant deterioration of functional status. eTable 5 (Supplemental Digital Content 1, http://links.lww.com/CCM/F145) summarizes itemized data for all FSS dimensions and substantiates a deterioration in communication, feeding, mental status, motor function, respiratory and sensory function, during hospitalization for pediatric septic shock.
Health-Related Quality of Life Changes
Less than 10% of subjects provided assent for self-report of HRQL. Accordingly, parent proxy-report is described for all HRQL data. Most families, 227 of 364 (62%), selected the PedsQL instruments for HRQL assessments. Baseline and month 1 absolute PedsQL scores were 78.3 (65.9–92.4) (n = 222) and 64.7 (47.8–81.9) (n = 142), respectively. Median change for PedsQL, comparing Baseline and month 1, was –11.0 (–29.2 to 5.55) (p < 0.001), reflecting a significant deterioration in HRQL. Assuming normality, an estimated mean change of –12.2 with 95% CI (–16.3 to –8.08) was observed. This CI reflects at least a MCID deterioration in PedsQL at month 1.
Figure 4A and eTable 6 (Supplemental Digital Content 1, http://links.lww.com/CCM/F145) display graphical and numerical percentages of patients failing to return to their baseline PedsQL over the 1-year follow-up, utilizing multiples of 4.5 points, the MCID for this HRQL instrument. Additional plots of PedsQL longitudinal data are presented in eFigure 3 (Supplemental Digital Content 1, http://links.lww.com/CCM/F145). At 1, 3, 6, and 12 month assessments, 56%, 41%, 32%, and 38% of patients assessed with PedsQL remained at least 4.5 points (1 × MCID) below their baseline HRQL, while 40%, 16%, 15%, and 17% remained at least 18.0 points (4 × MCID) below their baseline HRQL.
Some families, 137 of 364 (38%), selected the FSII-R instrument because they considered it more meaningful and relevant to their children, who typically manifested significant developmental delay. Baseline and month 1 absolute FSII-R scores were 71.4 (60.7–83.4) (n = 136) and 73.1 (60.7–82.1) (n = 93), respectively. Median change for FSII-R, comparing baseline and month 1, was 0.0 (–10.7 to 10.7) (p = 0.93). Assuming normality, an estimated mean change of –1.1 with 95% CI (–5.3 to 3.0) was observed. Figure 4B and eTable 7 (Supplemental Digital Content 1, http://links.lww.com/CCM/F145) display graphical and numerical percentages of patients failing to return to their baseline FSII-R over the 1-year follow-up, again utilizing multiples of 4.5 points for this HRQL instrument. Additional plots of FSII-R longitudinal data are presented in eFigure 4 (Supplemental Digital Content 1, http://links.lww.com/CCM/F145). At 1, 3, 6, and 12 month assessments, 39%, 32%, 27%, and 31% of patients assessed with FSII-R remained at least 4.5 points below their baseline HRQL, while 14%, 14%, 9%, and 19% remained at least 18.0 points below their baseline HRQL.
In total, at 1, 3, 6, and 12 months following PICU admission for the septic shock event, 8%, 11%, 12%, and 13% of patients had died, and among survivors with adequate change from baseline data, 50%, 37%, 30%, and 35% of surviving patients had not regained their baseline HRQL. Patients assessed with the FSII-R instrument, as a whole, seemed to demonstrate less deterioration from and faster recovery to baseline HRQL. Patients assessed with either HRQL instrument appeared to exhibit a plateau in HRQL recovery, months 3–12 (Fig. 4).
Patients Lost to Follow-Up
Inspection of Figure 1 and eTable 1 (Supplemental Digital Content 1, http://links.lww.com/CCM/F145) reveals significant loss to follow-up for the study cohort, despite parental incentives for continued participation. eTable 8 (Supplemental Digital Content 1, http://links.lww.com/CCM/F145) documents that patients who were lost to follow-up at the month 3 assessment exhibited similar initial illness severity as per initial PRISM-IV and PELOD-2 scores, as well as duration of vasoactive-inotropic and mechanical ventilation support and PICU and hospital stay, as compared with patients who completed the month 3 survey. However, patients lost to follow-up accrued higher summation of daily PELOD-2 scores and more frequently required renal replacement therapy and extracorporeal life support. Data analysis employing multiple imputation techniques, to account for patients lost to follow-up, suggests an even greater burden of long-term HRQL morbidity among children surviving septic shock (eFigs. 5 and 6, Supplemental Digital Content 1, http://links.lww.com/CCM/F145). Specifically, imputation tended to predict lower values for missing HRQL measures, consistent with the notion that patients without completed surveys had at least some measures of higher illness severity, and higher illness severity was associated with higher risk for adverse HRQL outcomes.
This investigation reports several significant, novel findings: First, in-hospital and 1-year mortality from community-acquired septic shock were 9% and 13%, but among the survivors, 35% had not yet regained their baseline HRQL 1 year later. Second, for the cohort as a whole, HRQL improved between 1 and 3 months, but further improvement was not apparent over the ensuing 9 months. Accordingly, a 3-month follow-up may represent a pivotal checkpoint relative to monitoring and intervening for post-intensive care syndrome among children surviving septic shock (26,27). Third, 51% of the patients enrolled demonstrated significant chronic comorbid conditions as assessed by the Pediatric Medical Complexity Algorithm, with impaired baseline functional status per POPC and FSS, even though such children comprise only 3% of the overall pediatric population (28). This preponderance of critically ill children with chronic conditions is consistent with national PICU data (29). Although the median baseline score for patients assessed with PedsQL was similar to published norms (30) for generally healthy children, the median baseline score for patients assessed with FSII-R was significantly lower than normative data for chronically ill children (24). These observations confirm that children with chronic conditions bear a disproportionate burden of critical illness, including sepsis. Fourth, patients assessed with FSII-R unexpectedly exhibited less decline from and seemingly faster resolution toward baseline HRQL compared with patients assessed with PedsQL. This finding may relate to differential views of what constitutes HRQL and HRQL recovery among parents of children with severe developmental disability (30). Alternatively, this finding may reflect greater sensitivity to change for the PedsQL instrument. Fifth, fortunately, the majority of children recovered to or exceeded their baseline HRQL 1 year following septic shock. Improved HRQL following acute illness has been previously reported (13) and may relate to actual improvement in HRQL status (e.g., successful chemotherapy, organ transplantation, curative surgery), potential parental recall bias of lower HRQL at baseline, or the acute illness as a life-transforming event (13).
Collectively, this study demonstrates substantial HRQL morbidity among many critically ill children surviving septic shock. Previous investigations have reported increased risk for chronic disability, hospital readmission, and late mortality for children surviving sepsis, but these studies, largely retrospective in design, were variably limited by small sample size, lack of baseline HRQL ascertainment, and/or variable time intervals for follow-up evaluation(s) (8–13). The LAPSE investigation enrolled a moderate-sized, prospectively derived cohort, from 12 tertiary PICUs across the United States. Accordingly, the results are likely to be generalizable among pediatric academic centers, but perhaps not for community hospital PICUs. Children enrolled into LAPSE were assessed for chronic, comorbid conditions (16), and underwent baseline functional status and HRQL evaluations. Establishing a baseline for subsequent HRQL comparisons is feasible and provides the best approach for differentiating the effects of chronic conditions versus acute illness on long-term HRQL morbidity.
This study has several limitations. First, subjects lost to follow-up was problematic, especially because these events were likely not random. Although HRQL and functional status are clearly important outcome measures (31), results from this study highlight the logistical challenges when such outcomes are used for long-term endpoints. A variety of strategies (http://www.improveLTO.com/cohort-retention-tools/) have been suggested and evaluated (32) to maximize subject research participation retention including financial incentives for participants that were employed in the current investigation. Second, this investigation focused on community-acquired pediatric sepsis. It is likely that patients with hospital-acquired sepsis demonstrate a greater burden of acute and chronic comorbidities that may impact short- and long-term outcomes. Third, some would argue that HRQL or functional status should be based on patient-reported data (33,34) (https://www.fda.gov/downloads/drugs/guidances/ucm193282.pdf) utilizing a single instrument. However, the practicality of patient-reported data for critically ill children is limited, as they are frequently very young, routinely sedated, and often developmentally delayed. Furthermore, as the consumers of pediatric healthcare, families are uniquely positioned to provide their perspectives of pediatric HRQL (35). In addition to PedsQL, LAPSE investigators used FSII-R as a measure of HRQL. Although the name FSII-R suggests this instrument is primarily a functional status measure, in fact, it is generally regarded as a validated measure of general health status for children of all ages (36,37), and some parents preferred this tool to describe their child’s situation. Accordingly, in order to maintain involvement of families with children with severe developmental disability and record meaningful parent-proxy information, we offered use of either tool. Ultimately, this decision was likely a strength of the investigation in terms of inclusion and diversity in enrollment and continued study engagement. Trajectories of failure to recover HRQL following pediatric septic shock, presented separately for the two instruments in Figure 4A and B, and eFigures 5 and 6 (Supplemental Digital Content 1,http://links.lww.com/CCM/F145) appear remarkably similar. Fourth, recall bias, as was used to establish baseline HRQL for this investigation, is a limitation inherent in any retrospective evaluation. However, parents were informed of the importance of accuracy for this baseline assessment, at a time when they were not overtly stressed, typically following resuscitation and stabilization of their child.
This investigation provides the first longitudinal description of long-term mortality and clinically relevant, enduring HRQL morbidity among children encountering community-acquired septic shock. Pediatric septic shock is not only life threatening in terms of ongoing risk for mortality, but also life-altering among children surviving their septic shock. All-cause 28-day mortality alone no longer articulates the entire story of pediatric septic shock outcomes. In addition to ensuring survival from septic shock, optimizing a child’s long-term HRQL is an equally important goal for pediatric septic shock critical care.
The Life After Pediatric Sepsis Evaluation (LAPSE) Investigators thank all subjects and families for participating in the LAPSE investigation. The following is a summary of LAPSE Performance Sites, Principal Investigators (PI), Co-investigators (CI), Research Coordinators (RC), and Allied Research Personnel: Children’s Hospital of Michigan, Detroit, MI: Kathleen L. Meert, PI; Sabrina Heidemann, CI; Ann Pawluszka, RC; Melanie Lulic, RC. Children’s Hospital of Philadelphia, Philadelphia, PA: Robert A Berg, PI; Athena Zuppa, CI; Carolann Twelves, RC; Mary Ann DiLiberto, RC. Children’s National Medical Center, Washington, DC: Murray Pollack, PI; David Wessel, PI; John Berger, CI; Elyse Tomanio, RC; Diane Hession, RC; Ashley Wolfe, RC. Children’s Hospital of Colorado, Denver, CO: Peter Mourani, PI; Todd Carpenter, CI; Diane Ladell, RC; Yamila Sierra, RC; Alle Rutebemberwa, RC. Nationwide Children’s Hospital, Columbus, OH: Mark Hall, PI; Andy Yates, CI; Lisa Steele, RC; Maggie Flowers, RC; Josey Hensley, RC. Mattel Children’s Hospital, University of California Los Angeles, Los Angeles, CA: Anil Sapru, PI; Rick Harrison, CI, Neda Ashtari, RC; Anna Ratiu, RC. Children’s Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA: Joe Carcillo, PI; Michael Bell, CI; Leighann Koch, RC; Alan Abraham, RC. Benioff Children’s Hospital, University of California, San Francisco, San Francisco, CA: Patrick McQuillen, PI; Anne McKenzie, RC; Yensy Zetino, RC. Children’s Hospital of Los Angeles, Los Angeles, CA: Christopher Newth, PI; Jeni Kwok, RC; Amy Yamakawa, RC. CS Mott Children’s Hospital, University of Michigan, Ann Arbor, MI: Michael Quasney, PI; Thomas Shanley, CI; CJ Jayachandran, RC. Cincinnati Children’s Hospital, Cincinnati, OH: Ranjit Chima, PI; Hector Wong, CI; Kelli Krallman, RC; Erin Stoneman, RC; Laura Benken, RC; Toni Yunger, RC. St Louis Children’s Hospital, Washington University, St Louis, MO: Alan Doctor, PI; Micki Eaton, RC. Seattle Children’s Hospital, Seattle Children’s Research Institute (LAPSE Follow-up Center), University of Washington, Seattle, WA: Jerry J. Zimmerman, PI; Catherine Chen, RC; Erin Sullivan, RC; Courtney Merritt, RC; Deana Rich, RC; Julie McGalliard; Wren Haaland; Kathryn Whitlock; Derek Salud. University of Utah (LAPSE Data Coordinating Center), Salt Lake City, UT: J. Michael Dean, PI; Richard Holubkov, CI; Whit Coleman, RC; Samuel Sorenson, RC; Ron Reeder; Russell Banks; Angie Webster; Jeri Burr; Stephanie Bisping; Teresa Liu; Emily Stock; Kristi Flick. Texas A&M University, College Station, TX: James Varni.
1. Weiss SL, Fitzgerald JC, Pappachan J, et al.; Sepsis Prevalence, Outcomes, and Therapies (SPROUT) Study Investigators and Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) Network: Global epidemiology of pediatric severe sepsis: The sepsis prevalence, outcomes, and therapies study. Am J Respir Crit Care Med 2015; 191:1147–1157
2. Kissoon N, Uyeki TM. Sepsis and the global burden of disease in children
. JAMA Pediatr 2016; 170:107–108
3. Hartman ME, Linde-Zwirble WT, Angus DC, et al. Trends in the epidemiology of pediatric severe sepsis*. Pediatr Crit Care Med 2013; 14:686–693
4. Ruth A, McCracken CE, Fortenberry JD, et al. Pediatric severe sepsis: Current trends and outcomes from the Pediatric Health Information Systems database. Pediatr Crit Care Med 2014; 15:828–838
5. Balamuth F, Weiss SL, Neuman MI, et al. Pediatric severe sepsis in U.S. children
’s hospitals. Pediatr Crit Care Med 2014; 15:798–805
6. Simon DW, Clark RS, Watson RR. No pain, no gain in pediatric sepsis?*. Pediatr Crit Care Med 2014; 15:264–266
7. Angus DC, Carlet J; 2002 Brussels Roundtable Participants: Surviving intensive care: A report from the 2002 Brussels Roundtable. Intensive Care Med 2003; 29:368–377
8. Buysse CM, Raat H, Hazelzet JA, et al. Surviving meningococcal septic shock
: Health consequences and quality of life in children
and their parents up to 2 years after pediatric intensive care unit discharge. Crit Care Med 2008; 36:596–602
9. Czaja AS, Zimmerman JJ, Nathens AB. Readmission and late mortality
after pediatric severe sepsis. Pediatrics 2009; 123:849–857
10. Bronner MB, Knoester H, Sol JJ, et al. An explorative study on quality of life and psychological and cognitive function in pediatric survivors of septic shock
. Pediatr Crit Care Med 2009; 10:636–642
11. Edmond K, Dieye Y, Griffiths UK, et al. Prospective cohort study of disabling sequelae and quality of life in children
with bacterial meningitis in urban Senegal. Pediatr Infect Dis J 2010; 29:1023–1029
12. Als LC, Nadel S, Cooper M, et al. Neuropsychologic function three to six months following admission to the PICU with meningoencephalitis, sepsis, and other disorders: A prospective study of school-aged children
. Crit Care Med 2013; 41:1094–1103
13. Killien EY, Farris RWD, Watson RS, et al. Health-related quality of life
among survivors of pediatric sepsis. Pediatr Crit Care Med 2019; 20:501–509
14. Zimmerman JJ, Banks R, Berg RA, et al. Critical Illness Factors Associated With Long-Term Mortality
and Health-Related Quality of Life
Morbidity Following Community-Acquired Pediatric Septic Shock
. Crit Care Med 2020; 48:319–328
15. Goldstein B, Giroir B, Randolph A; International Consensus Conference on Pediatric Sepsis: International pediatric sepsis consensus conference: Definitions for sepsis and organ dysfunction in pediatrics. Pediatr Crit Care Med 2005; 6:2–8
16. Simon TD, Cawthon ML, Stanford S, et al.; Center of Excellence on Quality of Care Measures for Children
with Complex Needs (COE4CCN) Medical Complexity Working Group: Pediatric medical complexity algorithm: A new method to stratify children
by medical complexity. Pediatrics 2014; 133:e1647–e1654
17. Pollack MM, Holubkov R, Funai T, et al.; Eunice Kennedy Shriver
National Institute of Child Health and Human Development Collaborative Pediatric Critical Care Research Network: The pediatric risk of mortality
score: Update 2015. Pediatr Crit Care Med 2016; 17:2–9
18. Leteurtre S, Duhamel A, Salleron J, et al.; Groupe Francophone de Réanimation et d’Urgences Pédiatriques (GFRUP): PELOD-2: An update of the PEdiatric logistic organ dysfunction score. Crit Care Med 2013; 41:1761–1773
19. Fiser DH, Long N, Roberson PK, et al. Relationship of pediatric overall performance category and pediatric cerebral performance category scores at pediatric intensive care unit discharge with outcome measures collected at hospital discharge and 1- and 6-month follow-up assessments. Crit Care Med 2000; 28:2616–2620
20. Pollack MM, Holubkov R, Glass P, et al.; Eunice Kennedy Shriver
National Institute of Child Health and Human Development Collaborative Pediatric Critical Care Research Network: Functional status
scale: New pediatric outcome measure. Pediatrics 2009; 124:e18–e28
21. Varni JW, Burwinkle TM, Seid M, et al. The PedsQL 4.0 as a pediatric population health measure: Feasibility, reliability, and validity. Ambul Pediatr 2003; 3:329–341
22. Aspesberro F, Fesinmeyer MD, Zhou C, et al. Construct validity and responsiveness of the pediatric quality of life inventory 4.0 generic core scales and infant scales in the PICU. Pediatr Crit Care Med 2016; 17:e272–e279
23. Varni JW, Limbers CA, Neighbors K, et al. The PedsQL™ infant scales: Feasibility, internal consistency reliability, and validity in healthy and ill infants. Qual Life Res 2011; 20:45–55
24. Stein RE, Jessop DJ. Functional status
II®. A measure of child health status. Med Care 1990; 28:1041–1055
25. von Elm E, Altman DG, Egger M, et al.; STROBE Initiative: The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: Guidelines for reporting observational studies. J Clin Epidemiol 2008; 61:344–349
26. Watson RS, Choong K, Colville G, et al. Life after critical illness in children
-toward an understanding of pediatric post-intensive care syndrome. J Pediatr 2018; 198:16–24
27. Anderson-Shaw L. Surviving severe sepsis: Is that enough? Crit Care Med 2016; 44:1603–1604
28. Cohen E, Kuo DZ, Agrawal R, et al. Children
with medical complexity: An emerging population for clinical and research initiatives. Pediatrics 2011; 127:529–538
29. Edwards JD, Houtrow AJ, Vasilevskis EE, et al. Chronic conditions among children
admitted to U.S. pediatric intensive care units: Their prevalence and impact on risk for mortality
and prolonged length of stay*. Crit Care Med 2012; 40:2196–2203
30. Rennick JE, Childerhose JE. Redefining success in the PICU: New patient populations shift targets of care. Pediatrics 2015; 135:e289–e291
31. Merritt C, Menon K, Agus MSD, et al. Beyond survival: Pediatric critical care interventional trial outcome measure preferences of families and healthcare professionals. Pediatr Crit Care Med 2018; 19:e105–e111
32. Treweek S, Pitkethly M, Cook J, et al. Strategies to improve recruitment to randomised trials. Cochrane Database Syst Rev 2018; 2:MR000013
33. United States Department of Health and Human Services: Patient-Reported Outcome Measures. Office of Communications, Division of Drug Information, Center for Drug Evaluation and Research. 2009Silver Spring, MD, Food and Drug Administration.
34. Sprangers MA, Aaronson NK. The role of health care providers and significant others in evaluating the quality of life of patients with chronic disease: A review. J Clin Epidemiol 1992; 45:743–760
35. Varni JW, Limbers CA, Burwinkle TM. Parent proxy-report of their children
’s health-related quality of life
: An analysis of 13,878 parents’ reliability and validity across age subgroups using the PedsQL 4.0 Generic Core Scales. Health Qual Life Outcomes 2007; 5:2
36. Keenan HT, Runyan DK, Nocera M. Longitudinal follow-up of families and young children
with traumatic brain injury. Pediatrics 2006; 117:1291–1297
37. Da Costa D, Bann CM, Hansen NI, et al.; National Institute of Child Health and Human Development Neonatal Research Network: Validation of the Functional Status
II questionnaire in the assessment of extremely-low-birthweight infants. Dev Med Child Neurol 2009; 51:536–544