David Inwald

OBJECTIVE: To describe the prespecified analysis plan for Protocolized Evaluation of Permissive Blood Pressure Targets vs. Usual Care (PRESSURE), a trial comparing a permissive mean arterial pressure (MAP) target above the age-specific fifth centile with usual care in critically ill children. DESIGN: Pragmatic, open, multicenter, parallel group randomized controlled trial with integrated economic evaluation. SETTING: Twenty-one PICUs in the United Kingdom. PATIENTS: Infants and children older than 38 weeks corrected gestational age to 16 years, accepted to a participating PICU, on invasive mechanical ventilation (IMV) and receiving vasoactive drugs for hypotension. INTERVENTION: Adjustment of hemodynamic support to achieve a permissive MAP target greater than the fifth centile for age during IMV. MEASUREMENTS AND MAIN RESULTS: The primary outcome is a composite 30-day mortality and duration of IMV, and it will be analyzed with a two-sample rank-sum test. Components will also be analyzed separately. Sensitivity analyses will adjust for adherence, and subgroup analyses will test interactions with baseline covariates. Secondary analyses will compare mortality at various time-points, duration of survival, time to liberation from IMV, functional status changes, receipt of renal replacement therapy and length of stay. The health economic analysis will follow the intention-to-treat principle and report the mean (95% CI) incremental costs, quality-adjusted life years and cost-effectiveness up to 12 months. CONCLUSIONS: Results will be reported following this plan through peer-reviewed publications and conference presentations.

Lightning strike is rare, with a reported incidence of around 1:100,000. There are few reports of survival after cardiac arrest due to lightning strike. We report the case of a 12-year-old male survivor. Though he had a prolonged out of hospital cardiac arrest and initial poor systolic function, widespread ST segment elevation on electrocardiography, and elevated cardiac troponin I, he survived with a good cardiac and neurological outcome.

Background: In the past decade, molecular diagnostic syndromic arrays incorporating a range of bacterial and viral pathogens have been described. It is unclear how paediatric intensive care unit (PICU) staff diagnose lower respiratory tract infection (LRTI) and integrate diagnostic array results into antimicrobial decision-making. Methods: An online survey with eleven questions was distributed throughout paediatric intensive care societies in the UK, continental Europe and Australasia with a total of 755 members. Participants were asked to rate the clinical factors and investigations they used when prescribing for LRTI. Semi-structured interviews were undertaken with staff who participated in a single-centre observational study of a 52-pathogen diagnostic array. Results: Seventy-two survey responses were received; most responses were from senior doctors. Whilst diagnostic arrays were used less frequently than routine investigations (i.e. microbiological culture), they were of comparable perceived utility when making antimicrobial decisions. Prescribers reported that for arrays to be clinically impactful, they would need to deliver results within 6 h for stable patients and within 1 h for unstable patients to inform their immediate decision to prescribe antimicrobials. From 16 staff interviews, we identified that arrays were helpful for the diagnosis and screening of bacterial LRTI. Staff reported it could be challenging to interpret results in some cases due to the high sensitivity of the test. Therefore, results were considered within the context of the patient and discussed within the multidisciplinary team. Conclusions: Diagnostic arrays were considered of comparable value to microbiological investigations by PICU prescribers. Our findings support the need for further clinical and economic evaluation of diagnostic arrays in a randomised control trial. Trial registration: Clinicaltrials.gov, NCT04233268. Registered on 18 January 2020.

Purpose: Respiratory infections are the most common reason for admission to paediatric intensive care units (PICU). Most patients with lower respiratory tract infection (LRTI) receive broad-spectrum antimicrobials, despite low rates of bacterial culture confirmation. Here, we evaluated a molecular diagnostic test for LRTI to inform the better use of antimicrobials. Methods: The Rapid Assay for Sick Children with Acute Lung infection Study was a single-centre, prospective, observational cohort study of mechanically ventilated children (> 37/40 weeks corrected gestation to 18 years) with suspected community acquired or ventilator-associated LRTI. We evaluated the use of a 52-pathogen custom TaqMan Array Card (TAC) to identify pathogens in non-bronchoscopic bronchoalveolar lavage (mini-BAL) samples. TAC results were compared to routine microbiology testing. Primary study outcomes were sensitivity and specificity of TAC, and time to result. Results: We enrolled 100 patients, all of whom were tested with TAC and 91 of whom had matching culture samples. TAC had a sensitivity of 89.5% (95% confidence interval (CI₉₅) 66.9–98.7) and specificity of 97.9% (CI₉₅ 97.2–98.5) compared to routine bacterial and fungal culture. TAC took a median 25.8 h (IQR 9.1–29.8 h) from sample collection to result. Culture was significantly slower: median 110.4 h (IQR 85.2–141.6 h) for a positive result and median 69.4 h (IQR 52.8–78.6) for a negative result. Conclusions: TAC is a reliable and rapid adjunct diagnostic approach for LRTI in critically ill children, with the potential to aid early rationalisation of antimicrobial therapy.

Background: Broad-spectrum antimicrobial therapy is a key driver of antimicrobial resistance. Here, we aimed to review indications for antimicrobial therapy, determine the proportion of suspected bacterial infections that are confirmed by culture, and assess the time taken for microbiology test results to become available in the paediatric intensive care unit (PICU). Methods: A single-centre prospective observational cohort study of 100 consecutive general PICU admissions from 30 October 2019 to 19 February 2020. Data were collected from the hospital medical record and entered into a study database prior to statistical analysis using standard methods. Results: Of all episodes of suspected infection, 22% of lower respiratory tract infection, 43% of bloodstream and 0% of central nervous system infection were associated with growth on microbiology culture. 90% of children received antimicrobial therapy. Hospital-acquired infection occurred less commonly than primary infection, but an organism was grown in a greater proportion (64%) of cultures. Final laboratory reports for negative cultures were issued at a median of 120.3 hours for blood cultures and 55.5 hours for endotracheal tube aspirate cultures. Conclusions: Despite most critically children receiving antimicrobial therapy, infection was often not microbiologically confirmed. Novel molecular diagnostics may improve rationalisation of treatment in this population.

Background: Broad-spectrum antimicrobial therapy is a key driver of antimicrobial resistance. Here, we aimed to review indications for antimicrobial therapy, determine the proportion of suspected bacterial infections that are confirmed by culture, and assess the time taken for microbiology test results to become available in the paediatric ICU (PICU). Methods: A single-centre prospective observational cohort study of 100 consecutive general PICU admissions from 30 October 2019 to 19 February 2020. Data were collected from the hospital medical record and entered into a study database prior to statistical analysis using standard methods. Results: Of all episodes of suspected infection, 22% of lower respiratory tract infection, 43% of bloodstream and 0% of central nervous system infection were associated with growth on microbiology culture. Ninety percent of children received antimicrobial therapy. Hospital-acquired infection occurred less commonly than primary infection, but an organism was grown in a greater proportion (64%) of cultures. Final laboratory reports for negative cultures were issued at a median of 120.3 h for blood cultures and 55.5 h for endotracheal tube aspirate cultures. Conclusions: Despite most critically children receiving antimicrobial therapy, infection was often not microbiologically confirmed. Novel molecular diagnostics may improve rationalization of treatment in this population.

Objective There is recent interest in the association between hyperchloremic metabolic acidosis and adverse outcomes. In vitro, hyperchloremia causes renal vasoconstriction and fall in glomerular filtration rate (GFR). The objective of this retrospective, observational study is to examine associations between chloride level at admission to pediatric intensive care (PICU) and worst GFR and requirement for renal replacement therapy. Materials and Methods All admissions to PICU between 2009 and 2019 who received invasive mechanical ventilation and had blood gas analysis performed were included. Data analyzed included patient characteristics (age, gender, diagnosis, pediatric index of mortality [PIM]-2 score); results of initial blood gas; and maximum serum creatinine (then used to calculate minimum GFR). Primary outcome measure was worst GFR during PICU stay. Secondary outcome measures were requirement for renal replacement therapy and PICU mortality. Multivariable regression analysis was used to assess if admission chloride level was independently predictive of minimum GFR during PICU stay and to examine associations between hyperchloremia (>110 mEq/L) at admission and requirement for renal replacement therapy after adjustment for confounders. Results Data were available for 2,217 patients. Median age was 16.4 months and 39% of patients were hyperchloremic at admission to PICU. Admission chloride level was independently predictive of worst GFR during PICU stay after adjustment for known confounders. Patients with hyperchloremia were not more likely to require renal replacement therapy or die than patients with normochloremia. Conclusion Prospective studies are necessary to determine if high chloride, specifically chloride containing resuscitation fluids, have a causal relationship with poor outcomes.

Background: Broad-spectrum antimicrobial therapy is a key driver of antimicrobial resistance. Here, we aimed to review indications for antimicrobial therapy, determine the proportion of suspected bacterial infections that are confirmed by culture, and assess the time taken for microbiology test results to become available in the paediatric intensive care unit (PICU). Methods: A single-centre prospective observational cohort study of 100 consecutive general PICU admissions from 30 October 2019 to 19 February 2020. Data were collected from the hospital medical record and entered into a study database prior to statistical analysis using standard methods. Results: Of all episodes of suspected infection, 22% of lower respiratory tract infection, 43% of bloodstream and 0% of central nervous system infection were associated with growth on microbiology culture. 90% of children received antimicrobial therapy. Hospital-acquired infection occurred less commonly than primary infection, but an organism was grown in a greater proportion (64%) of cultures. Final laboratory reports for negative cultures were issued at a median of 120.3 hours for blood cultures and 55.5 hours for endotracheal tube aspirate cultures. Conclusions: Despite most critically children receiving antimicrobial therapy, infection was often not microbiologically confirmed. Novel molecular diagnostics may improve rationalisation of treatment in this population.

Neisseria meningitidis , the causative agent of meningococcal disease (MD), evades complement-mediated clearance upon infection by ‘hijacking’ the human complement regulator factor H (FH). The FH protein family also comprises the homologous FH-related (FHR) proteins, hypothesized to act as antagonists of FH, and FHR-3 has recently been implicated to play a major role in MD susceptibility. Here, we show that, next to FH and FHR-3, the circulating levels of all FH family proteins are equally decreased during pediatric MD. We did not observe a specific consumption of FH or FHR-3 by N. meningitidis during the first days of infection and the levels recovered over time. MD severity associated predominantly with a loss of FH. Strikingly, loss of FH and FHRs associated strongly with renal failure, suggesting insufficient protection of host tissue by the FH protein family. Retaining higher levels of FH family proteins may thus limit tissue injury during MD.