Limited data exist about the international burden of severe sepsis in critically ill children.
To characterize the global prevalence, therapies, and outcomes of severe sepsis in pediatric intensive ...care units to better inform interventional trials.
A point prevalence study was conducted on 5 days throughout 2013-2014 at 128 sites in 26 countries. Patients younger than 18 years of age with severe sepsis as defined by consensus criteria were included. Outcomes were severe sepsis point prevalence, therapies used, new or progressive multiorgan dysfunction, ventilator- and vasoactive-free days at Day 28, functional status, and mortality.
Of 6,925 patients screened, 569 had severe sepsis (prevalence, 8.2%; 95% confidence interval, 7.6-8.9%). The patients' median age was 3.0 (interquartile range IQR, 0.7-11.0) years. The most frequent sites of infection were respiratory (40%) and bloodstream (19%). Common therapies included mechanical ventilation (74% of patients), vasoactive infusions (55%), and corticosteroids (45%). Hospital mortality was 25% and did not differ by age or between developed and resource-limited countries. Median ventilator-free days were 16 (IQR, 0-25), and vasoactive-free days were 23 (IQR, 12-28). Sixty-seven percent of patients had multiorgan dysfunction at sepsis recognition, with 30% subsequently developing new or progressive multiorgan dysfunction. Among survivors, 17% developed at least moderate disability. Sample sizes needed to detect a 5-10% absolute risk reduction in outcomes within interventional trials are estimated between 165 and 1,471 corrected patients per group.
Pediatric severe sepsis remains a burdensome public health problem, with prevalence, morbidity, and mortality rates similar to those reported in critically ill adult populations. International clinical trials targeting children with severe sepsis are warranted.
Delayed antimicrobials are associated with poor outcomes in adult sepsis, but data relating antimicrobial timing to mortality and organ dysfunction in pediatric sepsis are limited. We sought to ...determine the impact of antimicrobial timing on mortality and organ dysfunction in pediatric patients with severe sepsis or septic shock.
Retrospective observational study.
PICU at an academic medical center.
One hundred thirty patients treated for severe sepsis or septic shock.
None.
We determined if hourly delays from sepsis recognition to initial and first appropriate antimicrobial administration were associated with PICU mortality (primary outcome); ventilator-free, vasoactive-free, and organ failure-free days; and length of stay. Median time from sepsis recognition to initial antimicrobial administration was 140 minutes (interquartile range, 74-277 min) and to first appropriate antimicrobial was 177 minutes (90-550 min). An escalating risk of mortality was observed with each hour delay from sepsis recognition to antimicrobial administration, although this did not achieve significance until 3 hours. For patients with more than 3-hour delay to initial and first appropriate antimicrobials, the odds ratio for PICU mortality was 3.92 (95% CI, 1.27-12.06) and 3.59 (95% CI, 1.09-11.76), respectively. These associations persisted after adjustment for individual confounders and a propensity score analysis. After controlling for severity of illness, the odds ratio for PICU mortality increased to 4.84 (95% CI, 1.45-16.2) and 4.92 (95% CI, 1.30-18.58) for more than 3-hour delay to initial and first appropriate antimicrobials, respectively. Initial antimicrobial administration more than 3 hours was also associated with fewer organ failure-free days (16 interquartile range, 1-23 vs 20 interquartile range, 6-26; p = 0.04).
Delayed antimicrobial therapy was an independent risk factor for mortality and prolonged organ dysfunction in pediatric sepsis.
Sepsis is a complex process defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. It is associated with significant morbidity and mortality rates in both ...adults and children, and emphasis has been placed on its early recognition and prompt provision of antimicrobials. Owing to limitations of current diagnostic tests (i.e., poor sensitivity and delayed results), significant research has been conducted to identify sepsis biomarkers. Ideally, a biomarker could reliably and rapidly distinguish bacterial infection from other, noninfectious causes of systemic inflammatory illness. In doing so, a sepsis biomarker could be used for earlier identification of sepsis, risk stratification/prognostication, and/or guidance of antibiotic decision-making. In this minireview, we review one of the most common clinically used sepsis biomarkers, procalcitonin, and its roles in sepsis management in these three areas. We highlight key findings in the adult literature but focus the bulk of this review on pediatric sepsis. The challenges and limitations of procalcitonin measurement in sepsis are also discussed.
The purpose of our study was to describe children with life-threatening bleeding.
We conducted a prospective observational study of children with life-threatening bleeding events.
Twenty-four ...childrens hospitals in the United States, Canada, and Italy participated.
Children 0-17 years old who received greater than 40 mL/kg total blood products over 6 hours or were transfused under massive transfusion protocol were included.
Children were compared according bleeding etiology: trauma, operative, or medical.
Patient characteristics, therapies administered, and clinical outcomes were analyzed. Among 449 enrolled children, 55.0% were male, and the median age was 7.3 years. Bleeding etiology was 46.1% trauma, 34.1% operative, and 19.8% medical. Prior to the life-threatening bleeding event, most had age-adjusted hypotension (61.2%), and 25% were hypothermic. Children with medical bleeding had higher median Pediatric Risk of Mortality scores (18) compared with children with trauma (11) and operative bleeding (12). Median Glasgow Coma Scale scores were lower for children with trauma (3) compared with operative (14) or medical bleeding (10.5). Median time from bleeding onset to first transfusion was 8 minutes for RBCs, 34 minutes for plasma, and 42 minutes for platelets. Postevent acute respiratory distress syndrome (20.3%) and acute kidney injury (18.5%) were common. Twenty-eight-day mortality was 37.5% and higher among children with medical bleeding (65.2%) compared with trauma (36.1%) and operative (23.8%). There were 82 hemorrhage deaths; 65.8% occurred by 6 hours and 86.5% by 24 hours.
Patient characteristics and outcomes among children with life-threatening bleeding varied by cause of bleeding. Mortality was high, and death from hemorrhage in this population occurred rapidly.
We present a series of 6 critically ill children with multisystem inflammatory syndrome in children. Key findings of this syndrome include fever, diarrhea, shock, and variable presence of rash, ...conjunctivitis, extremity edema, and mucous membrane changes.
Sepsis and septic shock are major causes of morbidity, mortality, and health care costs for children worldwide, including >3 million deaths annually and, among survivors, risk for new or worsening ...functional impairments, including reduced quality of life, new respiratory, nutritional, or technological assistance, and recurrent severe infections. Advances in understanding sepsis pathophysiology highlight a need to update the definition and diagnostic criteria for pediatric sepsis and septic shock, whereas new data support an increasing role for automated screening algorithms and biomarker combinations to assist earlier recognition. Once sepsis or septic shock is suspected, attention to prompt initiation of broad-spectrum empiric antimicrobial therapy, fluid resuscitation, and vasoactive medications remain key components to initial management with several new and ongoing studies offering new insights into how to optimize this approach. Ultimately, a key goal is for screening to encompass as many children as possible at risk for sepsis and trigger early treatment without increasing unnecessary broad-spectrum antibiotics and preventable hospitalizations. Although the role for adjunctive treatment with corticosteroids and other metabolic therapies remains incompletely defined, ongoing studies will soon offer updated guidance for optimal use. Finally, we are increasingly moving toward an era in which precision therapeutics will bring novel strategies to improve outcomes, especially for the subset of children with sepsis-induced multiple organ dysfunction syndrome and sepsis subphenotypes for whom antibiotics, fluid, vasoactive medications, and supportive care remain insufficient.
Initial success with chimeric antigen receptor-modified T cell therapy for relapsed/refractory acute lymphoblastic leukemia is leading to expanded use through multicenter trials. Cytokine release ...syndrome, the most severe toxicity, presents a novel critical illness syndrome with limited data regarding diagnosis, prognosis, and therapy. We sought to characterize the timing, severity, and intensive care management of cytokine release syndrome after chimeric antigen receptor-modified T cell therapy.
Retrospective cohort study.
Academic children's hospital.
Thirty-nine subjects with relapsed/refractory acute lymphoblastic leukemia treated with chimeric antigen receptor-modified T cell therapy on a phase I/IIa clinical trial (ClinicalTrials.gov number NCT01626495).
All subjects received chimeric antigen receptor-modified T cell therapy. Thirteen subjects with cardiovascular dysfunction were treated with the interleukin-6 receptor antibody tocilizumab.
Eighteen subjects (46%) developed grade 3-4 cytokine release syndrome, with prolonged fever (median, 6.5 d), hyperferritinemia (median peak ferritin, 60,214 ng/mL), and organ dysfunction. Fourteen (36%) developed cardiovascular dysfunction treated with vasoactive infusions a median of 5 days after T cell therapy. Six (15%) developed acute respiratory failure treated with invasive mechanical ventilation a median of 6 days after T cell therapy; five met criteria for acute respiratory distress syndrome. Encephalopathy, hepatic, and renal dysfunction manifested later than cardiovascular and respiratory dysfunction. Subjects had a median of 15 organ dysfunction days (interquartile range, 8-20). Treatment with tocilizumab in 13 subjects resulted in rapid defervescence (median, 4 hr) and clinical improvement.
Grade 3-4 cytokine release syndrome occurred in 46% of patients following T cell therapy for relapsed/refractory acute lymphoblastic leukemia. Clinicians should be aware of expanding use of this breakthrough therapy and implications for critical care units in cancer centers.
Study objective Recognition of pediatric sepsis is a key clinical challenge. We evaluate the performance of a sepsis recognition process including an electronic sepsis alert and bedside assessment in ...a pediatric emergency department (ED). Methods This was a cohort study with quality improvement intervention in a pediatric ED. Exposure was a positive electronic sepsis alert, defined as elevated pulse rate or hypotension, concern for infection, and at least one of the following: abnormal capillary refill, abnormal mental status, or high-risk condition. A positive electronic sepsis alert prompted team assessment or huddle to determine need for sepsis protocol. Clinicians could initiate team assessment or huddle according to clinical concern without positive electronic sepsis alert. Severe sepsis outcome defined as activation of the sepsis protocol in the ED or development of severe sepsis requiring ICU admission within 24 hours. Results There were 182,509 ED visits during the study period, with 86,037 before electronic sepsis alert implementation and 96,472 afterward, and 1,112 (1.2%) positive electronic sepsis alerts. Overall, 326 patients (0.3%) were treated for severe sepsis within 24 hours. Test characteristics of the electronic sepsis alert alone to detect severe sepsis were sensitivity 86.2% (95% confidence interval CI 82.0% to 89.5%), specificity 99.1% (95% CI 99.0% to 99.2%), positive predictive value 25.4% (95% CI 22.8% to 28.0%), and negative predictive value 100% (95% CI 99.9% to 100%). Inclusion of the clinician screen identified 43 additional electronic sepsis alert–negative children, with severe sepsis sensitivity 99.4% (95% CI 97.8% to 99.8%) and specificity 99.1% (95% CI 99.1% to 99.2%). Electronic sepsis alert implementation increased ED sepsis detection from 83% to 96%. Conclusion Electronic sepsis alert for severe sepsis demonstrated good sensitivity and high specificity. Addition of clinician identification of electronic sepsis alert–negative patients further improved sensitivity. Implementation of the electronic sepsis alert was associated with improved recognition of severe sepsis.
Urinary biomarkers are superior to serum creatinine for defining onset and extent of kidney injury. This study classifies the temporal predictive ability of biomarkers for vancomycin-induced kidney ...injury (VIKI) as defined by histopathologic damage. Male Sprague-Dawley rats (
= 125) were randomized to receive 150 to 400 mg/kg of body weight/day vancomycin via once or twice daily intraperitoneal injection over 1, 3, or 6 days. Urine was collected once during the 24 h prior to euthanasia or twice for rats treated for 6 days. Receiver operating characteristic (ROC) curves were employed to assess the urinary biomarker performances of kidney injury molecule 1 (KIM-1), clusterin, osteopontin (OPN), cystatin C, and neutrophil gelatinase-associated lipocalin (NGAL) to predict histopathologically defined VIKI (using a national standard pathological assessment scheme from hematoxylin and eosin stained kidneys). Urinary KIM-1, clusterin, and OPN outperformed cystatin C and NGAL with regard to sensitivity and specificity. For the earliest injury, urinary KIM-1 (area under the receiver operating characteristic curve AUC, 0.662;
< 0.001) and clusterin (AUC, 0.706;
< 0.001) were the most sensitive for predicting even low-level histopathologic damage at 24 h compared to NGAL. KIM-1 and clusterin are the earliest and most sensitive predictors of VIKI. As injury progresses, KIM-1, clusterin, and OPN best define the extent of damage.
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