Abstract
Objectives:
Acute disorders of consciousness (DoC) in pediatric severe sepsis are associated with increased risk of morbidity and mortality. We sought to examine the frequency of and factors associated with DoC in children with sepsis induced organ failure.
Design:
Secondary analysis of the multicenter Phenotyping Sepsis-Induced Multiple Organ Failure Study (PHENOMS).
Setting:
Nine tertiary care pediatric intensive care units (PICUs) in the United States.
Patients:
Children <18 years of age admitted to a PICU with severe sepsis and at least one organ failure during a PICU stay.
Interventions:
None.
Measurements and Main Results:
The primary outcome was frequency of DoC, defined as Glasgow Coma Scale (GCS) < 12 in the absence of sedatives during an ICU stay, among children with severe sepsis and the following: single organ failure, non-phenotypeable multiple organ failure (MOF), MOF with one of the PHENOMS phenotypes (Immunoparalysis [IPMOF], Sequential Liver Failure [SMOF], Thrombocytopenia [TAMOF]), or MOF with multiple phenotypes. A multivariable logistic regression analysis was performed to evaluate the association between clinical variables and organ failure groups with DoC. Of 401 children studied, 71 (18%) presented with DoC. Children presenting with DoC were older (median, 8 vs. 5 years, p=0.023), had increased hospital mortality (21% vs. 10%, p=0.011), and more frequently presented with both any MOF (93% vs. 71%, p<0.001) and Macrophage Activation Syndrome (14% vs. 4%, p=0.004). Among children with any MOF, those presenting with DoC most frequently had non-phenotypeable MOF and IPMOF (52% and 34%, respectively). In the multivariable analysis, older age (odds ratio 1.07 [95% confidence interval 1.01-1.12]) and any MOF (3.22 [1.19-8.70]) were associated with DoC.
Conclusions:
One of every five children with severe sepsis and organ failure experienced acute DoC during their PICU stay. Preliminary findings suggest the need for prospective evaluation of DoC in children with sepsis and MOF.
Keywords: Neurological manifestations, Sepsis, Multiple Organ Dysfunction, Pediatrics
INTRODUCTION
Sepsis is prevalent among critically ill children and is a major cause of death and disability (1-3). Recent multicenter trials show that the in-hospital mortality rates for children with community acquired sepsis and sepsis induced multiple organ failure (MOF) were three and five times higher, respectively, than that of all PICU patients (4-6). To date, there have been no interventional trials in children with sepsis-associated MOF that have successfully validated treatments to improve overall outcomes (7). In response, a new approach using computable clinical phenotypes from patient characteristics, laboratory values, organ injury patterns, and outcomes have been suggested as entry criteria in precision medicine trials (8). Clinical phenotypes may have specific mechanistic underpinnings that could potentially support targeted interventions. The multicenter, prospective Phenotyping Sepsis-Induced Multiple Organ Failure (PHENOMS) study discovered three clinical phenotypes, Immunoparalysis associated MOF (IPMOF), Sequential Liver Failure associated MOF (SMOF), and Thrombocytopenia associated MOF (TAMOF), that may require unique treatment approaches.
Neurological manifestations associated with sepsis are also common and represent a cohort at even further increased risk of unfavorable outcomes such as mortality, delayed neurodevelopment, impaired cognitive function, decline in school performance and lower intelligence (2, 9, 10). In a multicenter observational study of children with community acquired sepsis, nearly half experienced a neurologic sign or event such as electrographic seizure, anisocoria, or ischemia on brain imaging (11). A study in children with multiple organ dysfunction syndrome due to any etiology revealed four distinct clinical phenotypes, including one with severe, persistent encephalopathy (12). The frequency of neurologic dysfunction and contributing clinical and disease characteristics have yet to be explored in children with sepsis-induced MOF.
One objective of this study was to determine the frequency of acute disorders of consciousness (DoC) (13) in the PHENOMS cohort of children with severe sepsis by organ failure phenotype. We further analyzed the association of patient, clinical, and laboratory characteristics as well as PHENOMS phenotypes with DoC occurrence during ICU stay. We hypothesized that children with sepsis-induced organ dysfunction would frequently experience DoC, and that DoC would be associated with specific PHENOMS phenotypes.
MATERIALS AND METHODS
Design and Setting.
This is a secondary analysis using the de-identified dataset from the completed parent PHENOMS study (5R01GM108618-04). The multi-center U.S. study (n=9) enrolled 401 children <18 years of age admitted to a PICU with severe sepsis with and without MOF. This study was approved by the central Institutional Review Boards (IRB) for 8 centers and the data coordinating center and two individual IRBs. The central IRB (University of Utah Institutional Review Board) approval number was IRB_00070976 on 9/18/2014 for CPCCRN (Collaborative Pediatric Critical Care Research Network) 047: Biomarker Phenotyping of Pediatric Sepsis and Multiple Organ Failure (PHENOMS). The University of Pittsburgh Institutional Review Board approval number was PRO14050608 on 6/17/2014 for Biomarker Phenotyping of Pediatric Sepsis and Multiple Organ Failure (PHENOMS), Version 1.00, May 12, 2014. The Washington University in St. Louis Human Research Protection Office approval number was IRB ID# 201502145 on 4/14/2015 for Biomarker Phenotyping of Pediatric Sepsis and Multiple Organ Failure (PHENOMS Study). Procedures were followed in accordance with the ethical standards of the responsible committee on human experimentation (institutional or regional) and with the Helsinki Declaration of 1975.
Inclusion and Exclusion Criteria.
As previously published, patients were recruited from 2015 to 2017 if they had a suspected diagnosis of sepsis, evidence of at least one organ failure based on a modified Organ Failure Index (OFI) (14), an existing indwelling central venous or arterial catheter for blood draws and were between the ages of 44 weeks gestation and 18 years old. Exclusion criteria included a lack of commitment to aggressive care. Our study utilized its original dataset of 410 children with further exclusion if empiric phenotype (n=9) data were missing (eFigure 1).
Data Collection
All data for this study, including patient characteristics, sepsis course, patient outcomes, and laboratory results were previously collected in the parent study. CPCCRN site coordinators are trained research professionals who collected data with rigor, using standardized case report forms developed with the central data coordinating center. Laboratory testing was performed biweekly during the PICU stay and was used to assign phenotype. Maximum blood ferritin, C-reactive protein (CRP), and sFas Ligand concentrations, as well as minimum whole blood ex vivo lipopolysaccharide-stimulated TNF-α response throughout the PICU stay were reported (6).
Children were initially grouped by single organ failure versus MOF. Those with MOF were further divided into the following: one of the three empiric PHENOMS phenotypes (Immunoparalysis associated MOF [IPMOF], Sequential Liver Failure associated MOF [SMOF], and Thrombocytopenia associated MOF [TAMOF]), MOF with more than one empiric PHENOMS phenotype, or non-phenotypeable MOF. They were also grouped by presence or absence of an DoC. (13). In this study, DoC was defined in the study Case Report Form as a Glasgow Coma Scale (GCS <12 in the “absence of sedatives” recorded on any day throughout PICU stay and taken from the modified OFI in the parent study (14). GCS scores on presentation to the PICU were unreliable as prior sedative use was not reported.
Outcome Measures.
The primary aim of the study was to quantify the frequency of DoC throughout PICU stay in children with severe sepsis by organ failure phenotype. Our secondary aim was to explore the patient, clinical, and laboratory characteristics associated with DoC.
Data Analysis.
Baseline admission, clinical, and laboratory characteristics and outcomes were analyzed using Wilcoxon Rank Sum for continuous data and Fisher Exact for categorical data. Univariate logistic regression models were constructed to analyze associations with DoC. Covariates with p < 0.05 on univariate regression were included in a multivariable logistic regression model to analyze for adjusted associations with DoC. Missing data was not imputed. Stata 16 was used for data analysis.
RESULTS
Patient characteristics and clinical details of children with and without DoC
Of the 401 patients meeting study criteria, median (interquartile range) age was 5.6 (1.4-12.3) years and 45% were female (Table 1). Seventy-one (18%) children had DoC recorded on at least one day throughout their PICU stay, and median age among those with DoC was higher (8.0 years vs. 5.1 years, p=0.023) than those without DoC. Seventy-six (76%) of children with DoC during their PICU stay had their first recorded GCS<12 in the absence of sedatives on their initial study day of sepsis induced organ failure (eFigure 2). Forty-eight (12%) pediatric patients did not survive to hospital discharge, with a greater percentage among children presenting with DoC (21% vs. 10%, p=0.011) (Table 2). Children with DoC more frequently had a documented bacterial infection (94% vs. 83%, p=0.016), and less frequently had a viral infection (27% vs. 54%, p<0.001). They were also more likely to require mechanical ventilation (99% vs. 89%, p=0.007) and continuous renal replacement therapy (CRRT) (21% vs. 11%, p=0.029) while in the PICU.
Table 1.
Baseline admission characteristics by acute disorders of consciousness (DoC) status
| n (%) or median (interquartile range) |
Overall (n=401) |
No DoC (n = 330) |
DoC (n = 71) |
|---|---|---|---|
| Sex | |||
| Male | 222 (55.4) | 182 (55.2) | 40 (56.3) |
| Female | 179 (44.6) | 148 (44.9) | 31 (43.7) |
| Age,years | 5.6 (1.4-12.3) | 5.1 (1.2-11.5) | 8.0 (2.0-13.5) |
| Race | |||
| White | 270 (72.0) | 232 (70.3) | 38 (53.5) |
| Black | 83 (22.1) | 59 (17.9) | 24 (33.8) |
| Other | 22 (5.9) | 16 (4.9) | 6 (8.5) |
| Ethnicity,Hispanic or Latino | 66 (17.1) | 53 (16.1) | 13 (18.3) |
| Comorbidity | |||
| Immune Dysfunction | 109 (27.2) | 88 (26.7) | 21 (29.6) |
| Cardiovascular Disease | 58 (14.5) | 43 (13.0) | 15 (21.1) |
| Chromosomal Abnormality | 57 (14.2) | 49 (14.9) | 8 (11.3) |
| Gastrointestinal | 25 (6.2) | 22 (6.7) | 3 (4.2) |
| Metabolic | 19 (4.7) | 15 (4.6) | 4 (5.6) |
| Hematologic | 8 (2.0) | 6 (1.8) | 2 (2.8) |
| Renal Disease | 6 (1.5) | 5 (1.5) | 1 (1.4) |
| Other PICU diagnoses | |||
| Steroid Use | 59 (14.7) | 47 (14.2) | 12 (16.9) |
| Post-Operative | 49 (12.2) | 41 (12.4) | 8 (11.3) |
| Trauma | 6 (1.5) | 3 (0.9) | 3 (4.2) |
| Malnutrition | 1 (0.3) | 1 (0.3) | 0 (0.0) |
Table 2.
Clinical details during the pediatric intensive care unit stay by DoC status
| n (%) or median (interquartile range) |
Overall (n=401) |
No DoC (n = 330) |
DoC (n = 71) |
p e |
|---|---|---|---|---|
| Organ Support | ||||
| ECMO | 30 (7.5) | 22 (6.7) | 8 (11.3) | 0.211b |
| Duration (days) | 10.0 (6.0-14.0) | 11.0 (6.0-15.0) | 7.5 (3.0-9.5) | 0.080 a |
| Mechanically ventilated | 363 (90.5) | 293 (88.8) | 70 (98.6) | 0.007 b |
| Duration (days) | 9 (6.0-16.0) | 9 (6.0-16.0) | 9 (6.0-17.0) | 0.989 a |
| CRRT | 51 (12.7) | 36 (10.9) | 15 (21.1) | 0.029 b |
| Duration (days) | 8.0 (5.0-15.0) | 7.5 (4.0-15.0) | 9.0 (5.0-14.0) | 0.747 a |
| Nitric Oxide | 92 (22.9) | 77 (23.3) | 15 (21.1) | 0.757 b |
| Duration (days) | 5 (3.0-9.0) | 5 (3.0-9.0) | 5 (2.0-12.0) | 0.975 a |
| Infections at Eligibility | ||||
| Bacterial | 341 (85.0) | 274 (83.0) | 67 (94.4) | 0.016 b |
| Viral | 197 (49.1) | 178 (53.9) | 19 (26.8) | <0.001 b |
| Fungal | 20 (5.0) | 13 (3.9) | 7 (9.9) | 0.064b |
| Protozoal | 3 (0.8) | 3 (0.9) | 0 (0.0) | 1.000 b |
| Outcomes | ||||
| ICU Length of Stay,days | 12 (7.0-20.0) | 12 (6.0-20.0) | 12 (7.0-25.0) | 0.453 a |
| ICU Mortality | 44 (11.0) | 30 (9.1) | 14 (19.7) | 0.019 b |
| Hospital Length of Stay,days | 19 (11.0-35.0) | 19 (11.0-35.0) | 21 (12.0-38.0) | 0.833 a |
| Hospital Mortality | 48 (12.0) | 33 (10.0) | 15 (21.1) | 0.011 b |
| Organ Failure Category | ||||
| Single Organ Failure | 100 (24.9) | 95 (28.8) | 5 (7.0) | <0.001 b |
| Multiple Organ Failure | 301 (75.1) | 235 (71.2) | 66 (93.0) | <0.001 b |
| MOF, no Phenotype | 200 (49.9) | 163 (49.4) | 37 (52.1) | 0.697 b |
| MOF, IPMOF | 85 (21.2) | 61 (18.5) | 24 (33.8) | 0.006 b |
| MOF, TAMOF | 37 (9.2) | 26 (7.9) | 11 (15.5) | 0.067 b |
| MOF, SMOF | 7 (1.8) | 4 (1.2) | 3 (4.2) | 0.109 b |
| MOF, 2+ Phenotypes | 25 (6.2) | 18 (5.5) | 7 (9.9) | 0.176 b |
| Macrophage Activation Syndrome | 24 (6.0) | 14 (4.2) | 10 (14.1) | 0.004 b |
| Lab values | ||||
| Ferritinc, ng/mlc | 260.0 (121.0-741.0) | 237.5 (121.5-672.3) | 349.0 (118.0-1193.6) | 0.098 a |
| C-reactive proteinc, mg/dlc | 11.1 (4.2-20.0) | 10.9 (4.0-19.4) | 11.6 (5.5-21.6) | 0.214 a |
| sFAS ligandc, pg/mlc | 54.7 (34.9-85.4) | 55.3 (36.4-85.8) | 53.4 (32.9-84.4) | 0.387 a |
| TNF-alphad, pg/mld | 321.1 (73.3-800.9) | 341.0 (78.2-818.6) | 250.8 (57.1-653.2) | 0.442 a |
Wilcoxon Rank-Sum Test
Fisher’s Exact Test
Maximum throughout PICU stay
Minimum whole blood ex vivo lipopolysaccharide-stimulated TNF-alpha values throughout PICU stay
No adjustments for multiple comparisons
DoC, Disorders of Consciousness; ECMO, Extracorporeal membrane oxygenation; CRRT, Continuous Renal Replacement Therapy; SFAS, soluble FAS ligand; TNF, tumor necrosis factor; ICU, intensive care unit; MOF, Multiple Organ Failure; IPMOF, Immunoparalysis Associated Multiple Organ Failure; TAMOF, Thrombocytopenia Associated Multiple Organ Failure; SMOF, Sequential Liver Failure Associated Multiple Organ Failure
The frequency of DoC was greater among children with overall MOF compared to single organ failure (22% vs. 5%, p<0.001) (Figure 1). Among PHENOMS phenotypes, children with DoC had the highest frequency of non-phenotypeable MOF and IPMOF (52% and 34%, respectively) (Figure 2). They were also more likely than those without DoC to present with Macrophage Activation Syndrome (14% vs. 4%, p=0.004) (Table 2).
Figure 1. Frequency of DoC among each PHENOMS phenotype.
DoC, Disorders of Consciousness; MOF, multiple organ failure; IPMOF, Immunoparalysis Associated Multiple Organ Failure; TAMOF, Thrombocytopenia Associated Multiple organ failure; SMOF, Sequential Liver Failure Associated Multiple Organ Failure
Figure 2. Frequency of patients in each organ failure group by DoC status.
DoC, Disorders of Consciousness; MOF, multiple organ failure; IPMOF, Immunoparalysis Associated Multiple Organ Failure; TAMOF, Thrombocytopenia Associated Multiple organ failure; SMOF, Sequential Liver Failure Associated Multiple Organ Failure
Laboratory characteristics of children with and without DoC
Children with and without DoC had similar median maximum ferritin levels (349 ng/mL vs 238 ng/mL, p=0.098) throughout their stay in the PICU (Table 2). Median maximum CRP (12 mg/dL vs. 11 mg/dL), maximum sFAS Ligand (53 pg/mL vs. 55 pg/mL), and minimum whole blood ex vivo lipopolysaccharide-stimulated TNF-alpha (341 pg/mL vs. 251 pg/mL) levels were also similar between the two groups, all p>0.05.
Association between DoC and patient characteristics, laboratory values, and phenotypes
In univariate logistic regression, older age (odds ratio [95% confidence interval]; 1.05 [1.01-1.10]), mechanical ventilation (8.84 [1.19-65.53]), CRRT (2.19 [1.12-4.26]), bacterial infection (3.42 [1.20-9.77]), and fungal infection (2.67 [1.02-6.95]) were associated with greater odds of DoC, p<0.05 (Table 3). DoC was also associated with greater odds of Macrophage Activation Syndrome (3.70 [1.57-8.71]) and any MOF (5.34 [2.08-13.66]), as well as the PHENOMS phenotypes IPMOF (2.25 [1.28-3.96]) and TAMOF (2.14 [1.00-4.57]), all p<0.05 (Table 3).
Table 3.
Univariate and Multivariable Logistic Regression for DoC status
| Univariate | Multivariable | |||||
|---|---|---|---|---|---|---|
| Variable | Odds Ratio | 95% CI | p-value | Odds Ratio | 95% CI | p-value |
| Age | 1.05 | [1.01, 1.10] | 0.018 | 1.07 | [1.01, 1.12] | 0.011 |
| Mechanical ventilation | 8.84 | [1.19, 65.53] | 0.033 | 8.84 | [0.93, 70.70] | 0.059 |
| Any Multiple Organ Failure | 5.34 | [2.08, 13.66] | <0.001 | 3.22 | [1.19, 8.70] | 0.021 |
| MOF, no Phenotype | 1.11 | [0.67, 1.86] | 0.678 | |||
| MOF, IPMOF | 2.25 | [1.28, 3.96] | 0.005 | 1.32 | [0.68, 2.54] | 0.407 |
| MOF, TAMOF | 2.14 | [1.00, 4.57] | 0.048 | 0.90 | [0.35, 2.31] | 0.820 |
| MOF, 2+ Phenotypes | 1.90 | [0.76, 4.73] | 0.170 | |||
| Macrophage Activation Syndrome | 3.70 | [1.57, 8.71] | 0.003 | 4.06 | [1.36, 12.08] | 0.012 |
DoC, Disorders of Consciousness; MOF, multiple organ failure; MOF, multiple organ failure; IPMOF, Immunoparalysis Associated Multiple Organ Failure; TAMOF, Thrombocytopenia Associated Multiple organ failure; SMOF, Sequential Liver Failure Associated Multiple Organ Failure
In the multivariable logistic regression analysis controlling for the covariates above, older age (1.07 [1.01-1.12], p=0.011), any MOF (3.22 [1.19-8.70], p=0.021), and Macrophage Activation Syndrome (4.06 [1.36, 12.08], =0.012) remained associated with greater odds of DoC (Table 3).
DISCUSSION
In this secondary analysis of the PHENOMS dataset of children with severe sepsis induced organ dysfunction, we found that 18% presented with DoC (as defined by a GCS < 12 in the absence of sedatives at any time during PICU admission). DoC was more frequently seen in children with MOF compared to those with single organ failure, and among children with DoC, non-phenotypeable MOF was most common. Children with DoC were also found to present more frequently with macrophage activation syndrome. Notably, older age and children with any MOF during their ICU stay were independent risk factors associated with greater odds of DoC.
DoC in pediatric sepsis and organ failure may occur secondary to one or a combination of inflammation, endothelial dysfunction of the blood-brain barrier, neurotransmitter abnormalities, systemic hypoxia, and hypotension (11). However, little evidence exists regarding the frequency of, risk factors for, and impact of neurologic manifestations in critically ill children with sepsis and organ failure. Our secondary analysis of the 2017 PHENOMS cohort found that nearly one fifth of all patients with severe sepsis present with DoC while in the PICU; however, this is likely an underestimate of the true number of children with severe neurologic dysfunction for the following reasons. First, our definition of DoC does not account for those with severe CNS suppression who had received sedatives (16). Our dataset was also limited to evaluation of GCS <12, but GCS 12-14 may be clinically important as well. Furthermore, our study showed that DoC was associated with older age. However, GCS scores may be less sensitive in detecting DoC for those under 3 years of age, potentially underestimating DoC in infants and toddlers (17, 18).
Our findings support emerging research on the increasing importance of neurologic manifestations in children with sepsis and MOF. Our study’s overall frequency of children with severe sepsis and DoC was less than the Life After Pediatric Sepsis Evaluation (LAPSE) observational cohort in which half of the children with community acquired sepsis had neurologic manifestations according to the Pediatric Cerebral Performance Category Scale (4). However, in conjunction with the study’s finding of an increased risk of mortality or severe deterioration in health-related quality of life at 3 months among children with community acquired sepsis (4), our study found an association between increased hospital mortality and DoC among children with sepsis and organ failure. Additionally, in an analysis of a general PICU population with MODS, 19% of children had a newly defined study phenotype of persistent, severe encephalopathy, characterized primarily by higher neurologic pSOFA scores among other laboratory values. This phenotype was also associated with a higher 28-day mortality than the other study defined phenotypes (12). The three original, empiric PHENOMS phenotypes did not include specific neurologic criteria, but DoC among patients were seen throughout all of them in this secondary analysis. In particular, greater than half of children with DoC had MOF but without an empiric PHENOMS phenotype during the ICU stay. This finding, along with the increased frequency of both hospital mortality and macrophage activation syndrome among those with DoC, suggest the need to further study and develop pediatric sepsis phenotypes that include neurologic criteria and mechanistically informed interventions for future precision trials.
Clinical implications of our study include the importance of careful neurological monitoring in children presenting with severe sepsis with MOF. Optimal definitions for and frequencies of DoC along with other specific neurologic manifestations, their implications in sepsis, and best practices in neuromonitoring and management require further study. A recent secondary analysis of the SPROUT (sepsis prevalence, outcomes, and therapies) study found worse outcomes among children with neurologic dysfunction and greater percentages of death or new impairment among children with recorded neurologic dysfunction later in their sepsis course (19). Therefore, early and continued identification of DoC in the setting of severe sepsis and MOF may help guide interventional trial eligibility and personalized treatments to improve long term outcomes. However, definitive predictors of DoC in children with severe sepsis is currently lacking. In our cohort, we failed to identify an association between inflammatory marker levels and DoC, which may be down to sample size. In contrast, a recently discovered pediatric phenotype containing neurologic status (PedSep-B) had increased C-reactive protein levels (15). In addition, a prospective single center study of 24 children with septic shock and moderate-severe encephalopathy (defined using electroencephalography) found increased mean serum biomarker levels of neuron specific enolase, glial fibrillary acidic protein, and S100b concentrations compared to control patients (20). With regards to imaging, a longitudinal single center brain imaging study showed a preponderance of lesions including volume loss and white matter lesions in children with sepsis who underwent CT or MRI for clinical indications (21). At this time, repeated neurologic examination may be the most feasible and sensitive method to assess for severe neurologic dysfunction or DoC.
There are several limitations of our study that must be taken into consideration. First, as mentioned previously, DoC was defined using GCS, which is limited especially in infants (22). GCS scoring was not modified for children who are mechanically ventilated, potentially leading to more children labeled as having DoC due to low verbal GCS scores. In addition, the GCS score used to define DoC was recorded at any time throughout PICU course. It is possible that GCS, which was recorded in the “absence of sedatives” was influenced by prior sedatives, influencing recording of a lower score. While it would have been beneficial to use GCS score solely upon PICU admission to better guide entry criteria in precision medicine trials, admission GCS was unreliable given lack of information on sedation and neuromuscular blockade status. However, it is still worth noting that 76% of patients with DoC had their first GCS<12 in the absence of sedatives recorded on their first study day of sepsis induced organ failure. Next, the secondary analysis study design did not include data on neuroimaging, electroencephalography, specific neurological serum biomarkers, or sedative use which may have provided more information towards definitive predictors of neurologic dysfunction. Finally, our study did not include data about longitudinal neurology, neurologic outcomes, or functional health outcomes to assess the long-term impacts of DoC in children with severe sepsis and organ failure.
CONCLUSION
Acute DoC were prevalent among critically ill children with sepsis and MOF. These preliminary findings contribute to the increasing importance of neurologic dysfunction in pediatric sepsis and suggest the need for further study of its role in sepsis and MOF phenotypes used for precision trials and in clinical care.
Supplementary Material
INFORMATION BOXES.
Research in Context
Sepsis with multiple organ failure (MOF) is a major cause of child death and disability. Neurological manifestations associated with sepsis are common and may further increase risk of unfavorable outcomes.
A multicenter, prospective study discovered three clinical sepsis phenotypes that may require unique treatment approaches.
Frequency of neurologic dysfunction leading to acute DoC (Glasgow Coma Scale score < 12) and contributing clinical and disease characteristics have not yet been explored in children with sepsis-induced MOF
What this Study Means
In our multicenter cohort in the United States, nearly one of every five children with severe sepsis and organ failure presented with DoC throughout their PICU stay.
DoC in children with sepsis-induced MOF may represent an important additional component for consideration in clinical phenotypes requiring targeted monitoring and treatment considerations.
Optimal definitions for and frequencies of DoC along with other specific neurologic manifestations, their implications in sepsis, and best practices in neuromonitoring and management require further study.
ACKNOWLEDGMENTS
We thank the CPCCRN research coordinators, site investigators, and data coordinating center personnel for their work in PHENOMS. We would also like to thank all the ICU staff for assisting with patient recruitment and exceptional clinical care. Finally, we would like to thank children and families in PHENOMS for their generosity to further knowledge within the field of pediatric critical care medicine.
Financial support used for the study, including any institutional departmental funds:
Supported, in part, by grant R01GM108618 (to Dr. Carcillo) from the National Institutes of General Medical Sciences, by 5U01HD049934-10S1 from the Eunice Kennedy Shriver National Institutes of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services and the following cooperative agreements: U10HD049983, U10HD050096, U10HD049981, U10HD063108, U10HD63106, U10HD063114, U10HD050012, and U01HD049934.
Copyright Form Disclosure:
Dr. Cheung received funding from the Deans Summer Research Program (University of Pittsburgh School of Medicine). Dr. Kernan received funding from the National Institutes of Child Health and Human Development (NICHD) (K12HD047349). Drs. Berg, Pollack, Wesssel, Meert, Hall, Newth, Doctor, Shanley, Harrison, Reeder, Holubkov, and Fink’s institutions received funding from the National Institutes of Health (NIH). Drs. Berg, Zuppa, Pollack, Wessel, Meert, Hall, Newth, Shanley, Harrison, Banks, Reeder, Holubkov, Carcillo, and Fink received support for article research from the NIH. Drs. Zuppa, Banks, and Carcillo’s institutions received funding from the NICHD. Dr. Hall received funding from Abbvie and Kiadis. Drs. Hall and Fink received funding from the American Board of Pediatrics. Dr. Doctor’s institution received funding from the Department of Defense and KaloCyte. Dr. Holubkov received funding from Pfizer and the Physicians Committee for Responsible Medicine. Dr. Carcillo’s institution received funding from the National Institute of General Medical Sciences. Dr. Fink’s institution received funding from the Neurocritical Care Society. The remaining authors have disclosed that they do not have any potential conflicts of interest.
Footnotes
Financial disclosures and conflicts of interest for each of the authors:
Drs. Carcillo’s, Berg’s, Wessel’s, Pollack’s, Meert’s, Hall’s, Doctor’s, Cornell’s, Harrison’s, Zuppa’s, Reeder’s, Banks’s, Newth’s, Shanley’s, and Holubkov’s, and Notterman’s institutions received funding from the National Institutes of Health (NIH). Dr. Hall received funding from Abbvie (service as a consultant [active]) and LaJolla Pharmaceuticals (service as a consultant [completed]). He is a consultant for the American Board of Pediatrics Pediatric Critical Care Subboard. He receives licensing income from Kiadis. Dr. Fink’s institution received funding from the National Institutes of Health and Neurocritical Care Society. She is a consultant for the American Board of Pediatrics Pediatric Critical Care Subboard. Dr. Holubkov serves on Data Safety Monitoring Boards for Pfizer.
The remaining authors have disclosed that they do not have any potential conflicts of interest.
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