Permissive versus restrictive temperature thresholds in critically ill children with fever and infection: a multicentre randomized clinical pilot trial.

BACKGROUND: Fever improves pathogen control at a significant metabolic cost. No randomized clinical trials (RCT) have compared fever treatment thresholds in critically ill children. We performed a pilot RCT to determine whether a definitive trial of a permissive approach to fever in comparison to current restrictive practice is feasible in critically ill children with suspected infection. METHODS: An open, parallel-group pilot RCT with embedded mixed methods perspectives study in four UK paediatric intensive care units (PICUs) and associated retrieval services. Participants were emergency PICU admissions aged > 28 days to < 16 years receiving respiratory support and supplemental oxygen. Subjects were randomly assigned to permissive (antipyretic interventions only at ≥ 39.5 °C) or restrictive groups (antipyretic interventions at ≥ 37.5 °C) whilst on respiratory support. Parents were invited to complete a questionnaire or take part in an interview. Focus groups were conducted with staff at each unit. Outcomes were measures of feasibility: recruitment rate, protocol adherence and acceptability, between group separation of temperature and safety. RESULTS: One hundred thirty-eight children met eligibility criteria of whom 100 (72%) were randomized (11.1 patients per month per site) without prior consent (RWPC). Consent to continue in the trial was obtained in 87 cases (87%). The mean maximum temperature (95% confidence interval) over the first 48 h was 38.4 °C (38.2-38.6) in the restrictive group and 38.8 °C (38.6-39.1) in the permissive group, a mean difference of 0.5 °C (0.2-0.8). Protocol deviations were observed in 6.8% (99/1438) of 6-h time periods and largely related to patient comfort in the recovery phase. Length of stay, duration of organ support and mortality were similar between groups. No pre-specified serious adverse events occurred. Staff (n = 48) and parents (n = 60) were supportive of the trial, including RWPC. Suggestions were made to only include invasively ventilated children for the duration of intubation. CONCLUSION: Uncertainty around the optimal fever threshold for antipyretic intervention is relevant to many emergency PICU admissions. A more permissive approach was associated with a modest increase in mean maximum temperature. A definitive trial should focus on the most seriously ill cases in whom antipyretics are rarely used for their analgesic effects alone. TRIAL REGISTRATION: ISRCTN16022198 . Registered on 14 August 2017.

Mortality and morbidity in community-acquired sepsis in European pediatric intensive care units: a prospective cohort study from the European Childhood Life-threatening Infectious Disease Study (EUCLIDS).

BACKGROUND: Sepsis is one of the main reasons for non-elective admission to pediatric intensive care units (PICUs), but little is known about determinants influencing outcome. We characterized children admitted with community-acquired sepsis to European PICUs and studied risk factors for mortality and disability. METHODS: Data were collected within the collaborative Seventh Framework Programme (FP7)-funded EUCLIDS study, which is a prospective multicenter cohort study aiming to evaluate genetic determinants of susceptibility and/or severity in sepsis. This report includes 795 children admitted with community-acquired sepsis to 52 PICUs from seven European countries between July 2012 and January 2016. The primary outcome measure was in-hospital death. Secondary outcome measures were PICU-free days censured at day 28, hospital length of stay, and disability. Independent predictors were identified by multivariate regression analysis. RESULTS: Patients most commonly presented clinically with sepsis without a source (n = 278, 35%), meningitis/encephalitis (n = 182, 23%), or pneumonia (n = 149, 19%). Of 428 (54%) patients with confirmed bacterial infection, Neisseria meningitidis (n = 131, 31%) and Streptococcus pneumoniae (n = 78, 18%) were the main pathogens. Mortality was 6% (51/795), increasing to 10% in the presence of septic shock (45/466). Of the survivors, 31% were discharged with disability, including 24% of previously healthy children who survived with disability. Mortality and disability were independently associated with S. pneumoniae infections (mortality OR 4.1, 95% CI 1.1-16.0, P = 0.04; disability OR 5.4, 95% CI 1.8-15.8, P < 0.01) and illness severity as measured by Pediatric Index of Mortality (PIM2) score (mortality OR 2.8, 95% CI 1.3-6.1, P < 0.01; disability OR 3.4, 95% CI 1.8-6.4, P < 0.001). CONCLUSIONS: Despite widespread immunization campaigns, invasive bacterial disease remains responsible for substantial morbidity and mortality in critically ill children in high-income countries. Almost one third of sepsis survivors admitted to the PICU were discharged with some disability. More research is required to delineate the long-term outcome of pediatric sepsis and to identify interventional targets. Our findings emphasize the importance of improved early sepsis-recognition programs to address the high burden of disease.

Attitudes towards fever amongst UK paediatric intensive care staff.

The role played by fever in the outcome of critical illness in children is unclear. This survey of medical and nursing staff in 35 paediatric intensive care units and transport teams in the United Kingdom and Ireland established attitudes towards the management of children with fever. Four hundred sixty-two medical and nursing staff responded to a web-based survey request. Respondents answered eight questions regarding thresholds for temperature control in usual clinical practice, indications for paracetamol use, and readiness to participate in a clinical trial of permissive temperature control. The median reported threshold for treating fever in clinical practice was 38 °C (IQR 38-38.5 °C). Paracetamol was reported to be used as an analgesic and antipyretic but also for non-specific comfort indications. There was a widespread support for a clinical trial of a permissive versus a conservative approach to fever in paediatric intensive care units. Within a trial, 58% of the respondents considered a temperature of 39 °C acceptable without treatment. CONCLUSIONS: Staff on paediatric intensive care units in the United Kingdom and Ireland tends to treat temperatures within the febrile range. There was a willingness to conduct a randomized controlled trial of treatment of fever. What is known: • The effect of fever on the outcome in paediatric critical illness is unknown. • Paediatricians have traditionally been reluctant to allow fever in sick children. What is new: • Paediatric intensive care staff report a tendency towards treating fever, with a median reported treatment threshold of 38 °C. • There is widespread support amongst PICU staff in the UK for a randomized controlled trial of temperature in critically ill children. • Within a trial setting, PICU staff attitudes to fever are more permissive than in clinical practice.

Intracranial pressure and cerebral perfusion pressure responses to head elevation changes in pediatric traumatic brain injury.

OBJECTIVES: To determine the effect of and dynamic interaction between head elevation on intracranial pressure and cerebral perfusion pressure in severe pediatric traumatic head injury. DESIGN: Prospective, randomized, interventional cohort study. SETTING: Two tertiary pediatric critical care referral units. PATIENTS: Ten children admitted with severe traumatic brain injury defined as Glasgow Coma Score ≤ 8 necessitating intracranial pressure monitoring (10 yrs ± 5 SD; range 2-16 yrs). INTERVENTIONS: Head elevation was randomly increased or decreased between 0 and 40 degrees from baseline level (30 degrees) in increments or decrements of 10 degrees. MEASUREMENTS AND MAIN RESULTS: Intracranial pressure and arterial blood pressure were continuously recorded in combination with time-stamped clinical notations. Data were available for analysis in eight subjects (seven males and one female; mean age, 10 yrs ± SD 5; range, 2-16 yrs) during 18 protocol sessions. This resulted in a total of 66 head-of-the-bed challenges. To compare results for a given change in head-of-the-bed elevation across age, we transformed head-of-the-bed angle to change in height (cm) at the level of Monro's foramen. An increase in head elevation of 10 cm resulted in an average change in intracranial pressure of -3.9 mm Hg (SD ± 3.2 mm Hg; p < .001), whereas cerebral perfusion pressure remained unchanged (0.1 ± 5.6 mm Hg; p = .957). Individual subjects showed marked variability in intracranial pressure change (range, -8.4 to +1.9 mm Hg/10 cm). The overall regression analysis for intracranial pressure response was change in intracranial pressure = -0.39/cm Δh, r2 = 0.42, and p < .001, where Δh is the change in vertical height at the level of foramen of Monro attributable to a change in the head of the bed. CONCLUSIONS: In severe pediatric traumatic brain injury, the relationship between change in head of the bed and change in intracranial pressure was negative and linear. The lowest intracranial pressure was usually, but not always, achieved at highest head-of-the-bed angles. The effect size of a head-of-the-bed angle change depended, in part, on the subject's height. In contrast, cerebral perfusion pressure was mostly unaffected by head-of-the-bed changes.

Genetic variability in complement activation modulates the systemic inflammatory response syndrome in children.

OBJECTIVE: To determine the impact of genetic variability in complement activation on early development of the systemic inflammatory response syndrome (SIRS) in general pediatric critical care. DESIGN: Prospective, observational, cohort study. SETTING: A tertiary pediatric intensive care unit in the United Kingdom. PATIENTS: Children with at least one organ failure expected to stay in the intensive care unit >12 hrs, or an expected death within 12 hrs. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 299 children were genotyped for functional polymorphisms in the complement activation cascade. We identified complement factor H as an important independent genetic modifier of SIRS/sepsis. Homozygosity for the complement factor H Y402H polymorphism, which is thought to reduce complement inhibition, was associated with less frequent SIRS/sepsis (the adjusted odds ratio for the homozygous variant complement factor H Y402H [CC] carriers was 0.3, 95% confidence interval, 0.1-0.7, p = .005). We also confirmed that structural and promoter variant mannose-binding lectin genotypes are a risk factor for SIRS/sepsis in pediatric critical care (adjusted odds ratio, 2.5; 95% confidence interval, 1.3-5.0, p = .008). Both findings were independent of clinical characteristics and other potentially confounding genetic polymorphisms in the innate immune system. CONCLUSIONS: Functional polymorphisms in the complement activation cascade modify the risk for early SIRS/sepsis in general pediatric critical care. The complement factor H Y402H variant allele is protective, whereas the mannose-binding lectin variant polymorphisms increase risk. A genotype that permits vigorous complement activation to an infectious or inflammatory insult may offer protection from development of systemic inflammation.

Pediatric tracheostomy: A large single-center experience.

OBJECTIVES: To describe the epidemiology, specifically the indications, complications, and outcomes, of pediatric tracheostomies performed in one tertiary referral unit. METHODS: Single-center retrospective cohort study of pediatric patients undergoing tracheostomy between May 2010 and May 2018 at the Newcastle upon Tyne Hospitals, United Kingdom. RESULTS: One hundred seventy-two pediatric tracheostomies were performed during the study period with a median age of 141 (interquartile range [IQR] 51-484) days. The most common primary indication was long-term ventilation (38.4%, 66 of 172), followed by weaning from ventilation in cardiac patients (22.1%, 38 of 172). Only 5.2% (9 of 172) of our cohort underwent tracheostomy for subglottic stenosis. The vast majority of tracheostomies were performed electively, with just 6.4% (11 of 172) performed as an emergency procedure. Early and late complication rates were 9.8% (15 of 153) and 40.0% (61 of 153), respectively. Tracheostomy decannulation was successful in 44.4% of children (68 of 153). The median duration the tracheostomy was in situ was 397 (IQR 106-708) days. All-cause mortality was 22.1% (38 of 172), with tracheostomy-related mortality at 1.2% (2 of 172). CONCLUSION: We report one of the largest contemporary case series of pediatric tracheostomies. Present-day pediatric tracheostomy is primarily performed as an elective procedure in ventilated children under the age of 1 year. Pediatric tracheostomy should be considered as a long-term intervention in many children. Nevertheless, a large proportion of children are ultimately decannulated. It is important to acknowledge the significant morbidity associated with this intervention and the small-but-present risk of tracheostomy-related mortality. LEVEL OF EVIDENCE: 4 Laryngoscope, 130:E375-E380, 2020.

Angiotensin-converting enzyme D allele does not influence susceptibility to acute hypoxic respiratory failure in children.

OBJECTIVE: The D allele of the I/D polymorphism in the angiotensin-converting enzyme (ACE) gene has been associated with an increased risk of ARDS in critically ill adults and severity of bronchopulmonary dysplasia in pre-term infants. We hypothesised that the presence of the hypoxia-associated ACE D allele would increase susceptibility to acute hypoxic respiratory failure (AHRF) in a cohort of critically ill children. DESIGN AND SETTING: Single-centre prospective observational cohort study. PATIENTS: Children under 16 years of age requiring admission to a tertiary general PICU. MEASUREMENTS AND RESULTS: A total of 216 Caucasian patients were enrolled. Thirty (13.9%) children developed AHRF and 13 were diagnosed with ARDS (6.0%). There was no significant difference in ACE D allele frequency between patient groups with or without AHRF (0.53 vs. 0.54). CONCLUSIONS: Variation in ACE activity does not influence the development of paediatric AHRF. This may reflect a different pathogenesis from adult ARDS.

Genetic polymorphisms in the endotoxin receptor may influence platelet count as part of the acute phase response in critically ill children.

PURPOSE: To determine if common polymorphisms in the endotoxin recognition complex influence the acute phase response as determined by the development of the systemic inflammatory response syndrome (SIRS) and platelet count on admission. METHODS: This was a prospective observational cohort study. Paediatric intensive care patients (n = 913) were genotyped for common functional polymorphisms in the endotoxin recognition complex, including Toll-like receptor 4 (TLR4). We also selected potentially confounding polymorphisms in other genes of the innate immune system. SIRS was defined by age-specific consensus criteria. Platelet counts were recorded on admission. RESULTS: The development of SIRS was primarily determined by the nature of the insult, but carriers of TLR4 variant alleles had lower platelet counts than children with wild-type genotype [mean +/- standard error of the mean (SEM) 143 +/- 7 vs. 175 +/- 4; p = 0.0001)--independent of other innate immune system polymorphisms. These findings were validated using a patient cohort of 1,170 adults with coronary artery disease. Carriers of TLR4 polymorphisms with a history of myocardial infarction (n = 573) had lower platelet counts than those with the wild-type genotype (217 +/- 7 vs. 237 +/- 2.8; p = 0.021). CONCLUSIONS: Our results show that TLR4 variant alleles are associated with lower platelet counts across a range of ages and precipitating insults but that they do not influence the incidence of SIRS. This result may reflect redundancy and 'robustness' in the pathways leading to SIRS or the lack of specificity of this endpoint. Platelet count may vary with TLR4 genotype because it may be sufficiently sensitive and more linearly related to inflammation than other markers or, alternatively, there may be a direct TLR4-mediated platelet effect.