Optic nerve sheath diameter and its association with brain swelling in pediatric cerebral malaria: a retrospective study.

Introduction: Mortality in pediatric cerebral malaria (CM) in low- and middle-income countries (LMICs) is associated with brain swelling on magnetic resonance imaging (MRI); however, MRI is unavailable in most LMICs. Optic nerve sheath diameter (ONSD) measurement is an inexpensive method of detecting increased intracranial pressure compared with the invasive opening pressure (OP). Our primary objective was to determine if increased ONSD correlated with brain swelling on MRI in pediatric CM. Our secondary objective was to determine if increased ONSD correlated with increased OP and/or poor neurological outcome in pediatric CM. We hypothesized that increased ONSD would correlate with brain swelling on MRI and increased OP and that ONSD would be higher in survivors with sequelae and non-survivors. Methods: We performed a retrospective chart review of children aged 0-12 years in Blantyre, Malawi, from 2013 to 2022 with CM as defined by the World Health Organization. Brain swelling on admission MRI was characterized by brain volume scores (BVS); severe swelling was scored as 7-8, mild-to-moderate as 4-6, normal as 3. The admission ONSD was measured via ultrasound; it was defined as abnormal if it was >4.5 mm in children >1 year and >4 mm in children <1 year. Favorable outcome was defined as a normal neurological exam on discharge in survivors. The primary and secondary objectives were evaluated using Spearman's correlation; and the demographics were compared using chi-square and the Kruskal-Wallis test (Stata, College Station, TX, USA). Results: Median age of the 207-patients cohort was 50 months [interquartile range (IQR) 35-75]; 49% (n = 102) were female. Of those, 73% (n = 152) had a favorable outcome, and 14% (n = 30) died. Twenty-nine (14%) had a normal BVS, 134 (65%) had mild-to-moderate swelling, and 44 (21%) had severe swelling. ONSD was elevated in 86% (n = 178) of patients, while 12% of patients had increased OP. There was a weakly positive correlation between BVS and ONSD (r = 0.14, p = 0.05). The median ONSD was not significantly different compared by discharge outcome (p = 0.11) or by BVS (p = 0.18). Conclusion: ONSD was not a reliable tool to correlate with BVS, neurological outcome, or OP in children with CM. Future studies to identify alternative methods of early identification of CM patients at highest risk for morbidity and mortality are urgently needed.

Transcranial Doppler ultrasound velocities in a population of unstudied African children with sickle cell anemia.

The greatest burden of sickle cell anemia (SCA) globally occurs in sub-Saharan Africa, where significant morbidity and mortality occur secondary to SCA-induced vasculopathy and stroke. Transcranial Doppler ultrasound (TCD) can grade the severity of vasculopathy, with disease modifying therapy resulting in stroke reduction in high-risk children. However, TCD utilization for vasculopathy detection in African children with SCA remains understudied. The objective was to perform a prospective, observational study of TCD findings in a cohort of children with SCA from the Democratic Republic of the Congo, Zambia, and Malawi. A total of 770 children aged 2-17 years without prior stroke underwent screening TCD. A study was scored as low risk when the time-averaged maximum of the mean (TAMMX) in the middle cerebral artery or terminal internal carotid artery was <170 cm/s but >50 cm/s, conditional risk when 170-200 cm/s, and high risk when >200 cm/s. Low-risk studies were identified in 604 children (78%), conditional risk in 129 children (17%), and high risk in three children (0.4%). Additionally, 34 (4%) were scored as having an unknown risk study (TAMMX <50 cm/s). Over the course of 15 months of follow-up, 17 children (2.2%) developed new neurologic symptoms (six with low-risk studies, seven with conditional risk, and four with unknown risk). African children with SCA in this cohort had a low rate of high-risk TCD screening results, even in those who developed new neurologic symptoms. Stroke in this population may be multifactorial with vasculopathy representing only one determinant. The development of a sensitive stroke prediction bundle incorporating relevant elements may help to guide preventative therapies in high-risk children.

Post hospital admission blood lactate measurements are associated with mortality but not neurologic morbidity in children with cerebral malaria.

BACKGROUND: In children with cerebral malaria (CM) admission blood lactate has previously guided intravenous fluid therapy and been validated as a prognostic biomarker associated with death. The usefulness of post-admission measurements of blood lactate in children with CM is less clear. The strength of association between blood lactate and neurological sequelae in CM survivors, as well as the optimal duration of post-admission measurements of blood lactate to identify children at higher risk of adverse outcomes is unknown. METHODS: A retrospective cohort study of 1674 Malawian children with CM hospitalized from 2000 to 2018 who had blood lactate measurements every 6 h for the first 24 h after admission was performed. The strength of association between admission lactate or values measured at any time point in the first 24 h post-admission and outcomes (mortality and neurological morbidity in survivors) was estimated. The duration of time after admission that lactate remained a valid prognostic biomarker was assessed. RESULTS: When lactate is analysed as a continuous variable, children with CM who have higher values at admission have a 1.05-fold higher odds (95% CI 0.99-1.11) of death compared to those with lower lactate values. Children with higher blood lactate at 6 h have 1.16-fold higher odds (95% CI 1.09-1.23) of death, compared to those with lower values. If lactate levels are dichotomized into hyperlactataemic (lactate > 5.0 mmol/L) or not, the strength of association between admission lactate and mortality increases (OR = 2.49, 95% CI 1.47-4.22). Blood lactate levels obtained after 18 h post-admission are not associated with outcomes. Similarly, the change in lactate concentrations through time during the first 24 h of hospital admission is not associated with outcomes. Blood lactate during hospitalization is not associated with adverse neurologic outcomes in CM survivors. CONCLUSIONS: In children with CM, blood lactate is associated with death but not neurologic morbidity in survivors. To comprehensively estimate prognosis, blood lactate in children with CM should be assessed at admission and for 18 h afterwards.

DON in pediatric cerebral malaria, a phase I/IIA dose-escalation safety study: study protocol for a clinical trial.

BACKGROUND: Despite treatment with highly effective antimalarial drugs, malaria annually claims the lives of over half a million children under 5-years of age in sub-Saharan Africa. Cerebral malaria (CM), defined as Plasmodium falciparum infection with coma, is the severe malaria syndrome with the highest mortality. Studies in the CM mouse model suggest that a T cell-mediated response underlies CM pathology, opening a new target for therapy in humans. This trial aims to establish the preliminary safety of one such novel therapy, the glutamine antagonist 6-diazo-5-oxo-L-norleucine (DON). METHODS: In this phase I/IIa dose-escalation clinical trial, a single dose of intravenous (IV) DON is administered to three participants groups-healthy adults and adults with uncomplicated malaria, then pediatric participants with CM-to primarily assess safety. The secondary objective of this trial is to assess pharmacokinetics of DON over a range of doses. The open-label adult portion of the trial enrolls 40 healthy adults concurrently with 40 adults with uncomplicated malaria. Cohorts of 10 participants receive a single IV dose of DON with doses escalating between cohorts from 0.1 mg/kg, 1.0 mg/kg, 5.0 mg/kg, to 10 mg/kg. Following subsequent safety review, a randomized, double-blind, and placebo-controlled pediatric study enrolls 72 participants aged 6 months to 14 years with CM. The pediatric portion of the study minimally spans three malaria seasons including a planned interim analysis after 50% of pediatric enrollments. The first half of pediatric participants receive DON 0.1 mg/kg, 1.0 mg/kg, or placebo. Dosing for the second half of pediatric participants is informed by the safety and preliminary efficacy results of those previously enrolled. The pediatric portion of the study has an exploratory outcome evaluating the preliminary efficacy of DON. Efficacy is assessed by diagnostics predictive of CM outcome: electroencephalography (EEG), magnetic resonance imaging (MRI), and transcranial doppler (TCD), measured before and after DON administration. All participants with malaria receive standard of care antimalarials in accordance with local guidelines, regardless of study drug dose group. DISCUSSION: This preliminary safety and efficacy study evaluates DON, a candidate adjunctive therapy for pediatric CM. If results support DON preliminary safety and efficacy, follow-up phase II and III clinical trials will be indicated. TRIAL REGISTRATION: This trial was registered on ClinicalTrials.gov on 28 July 2022 (NCT05478720).

MRI-Based Brain Volume Scoring in Cerebral Malaria Is Externally Valid and Applicable to Lower-Resolution Images.

BACKGROUND AND PURPOSE: Children with cerebral malaria have an elevated risk of mortality and neurologic morbidity. Both mortality and morbidity are associated with initially increased brain volume on MR imaging, as graded by the Brain Volume Score, a subjective ordinal rating scale created specifically for brain MRIs in children with cerebral malaria. For the Brain Volume Score to be more widely clinically useful, we aimed to determine its independent reproducibility and whether it can be applicable to lower-resolution MRIs. MATERIALS AND METHODS: To assess the independent reproducibility of the Brain Volume Score, radiologists not associated with the initial study were trained to score MRIs from a new cohort of patients with cerebral malaria. These scores were then compared with survival and neurologic outcomes. To assess the applicability to lower-resolution MRI, we assigned Brain Volume Scores to brain MRIs degraded to simulate a very-low-field (64 mT) portable scanner and compared these with the original scores assigned to the original nondegraded MRIs. RESULTS: Brain Volume Scores on the new cohort of patients with cerebral malaria were highly associated with outcomes (OR for mortality = 16, P < .001). Scoring of the simulated degraded images remained consistent with the Brain Volume Scores assigned to the original higher-quality (0.35 T) images (intraclass coefficients > 0.86). CONCLUSIONS: Our findings demonstrate that the Brain Volume Score is externally valid in reproducibly predicting outcomes and can be reliably assigned to lower-resolution images.

Noninvasive Neuromonitoring Modalities in Children Part I: Pupillometry, Near-Infrared Spectroscopy, and Transcranial Doppler Ultrasonography.

BACKGROUND: Noninvasive neuromonitoring in critically ill children includes multiple modalities that all intend to improve our understanding of acute and ongoing brain injury. METHODS: In this article, we review basic methods and devices, applications in clinical care and research, and explore potential future directions for three noninvasive neuromonitoring modalities in the pediatric intensive care unit: automated pupillometry, near-infrared spectroscopy, and transcranial Doppler ultrasonography. RESULTS: All three technologies are noninvasive, portable, and easily repeatable to allow for serial measurements and trending of data over time. However, a paucity of high-quality data supporting the clinical utility of any of these technologies in critically ill children is currently a major limitation to their widespread application in the pediatric intensive care unit. CONCLUSIONS: Future prospective multicenter work addressing major knowledge gaps is necessary to advance the field of pediatric noninvasive neuromonitoring.

Description of spatiotemporal patterns of infectious salmon anemia virus (ISAV) detections in marine Atlantic Salmon farms in Newfoundland and Labrador.

OBJECTIVE: The objectives of this study were to describe spatiotemporal patterns of infectious salmon anemia virus (ISAV) detections in marine salmonid production sites in the province of Newfoundland and Labrador in Canada. METHODS: Infectious salmon anemia virus surveillance data between 2012 and 2020 from the province of Newfoundland and Labrador were used. Data comprised a total of 94 sampling events from 20 Atlantic Salmon Salmo salar production sites in which ISAV was detected. Using linear regression models, factors influencing time to detection (days from stocking to first ISAV detection) and time to depopulation (days from first detection to production site depopulation) were investigated. RESULT: Based on 28 unique cases, site-level annual incidence risk of ISAV detection ranged from 3% to 29%. The proportion of ISAV detection by PCR in fish samples ranged from 2% to 45% annually. Overall, ISAV variants from the European clade were more common than variants from the North American clade. The type of ISAV clade, detections of ISAV in nearest production sites based on seaway distances, and year of infectious salmon anemia cases were not associated with time to first ISAV detection. Time to depopulation for sites infected with the ISAV-HPRΔ variant was not associated with ISAV North American or European clades. CONCLUSION: Our results contribute to the further understanding of the changing dynamics of infectious salmon anemia detections in Newfoundland and Labrador since its first detection in 2012 and will likely assist in the design of improved disease surveillance and control programs in the province.

Cerebral Metabolic Crisis in Pediatric Cerebral Malaria.

Cerebral metabolic energy crisis (CMEC), often defined as a cerebrospinal fluid (CSF) lactate: pyruvate ratio (LPR) >40, occurs in various diseases and is associated with poor neurologic outcomes. Cerebral malaria (CM) causes significant mortality and neurodisability in children worldwide. Multiple factors that could lead to CMEC are plausible in these patients, but its frequency has not been explored. Fifty-three children with CM were enrolled and underwent analysis of CSF lactate and pyruvate levels. All 53 patients met criteria for a CMEC (median CSF LPR of 72.9 [interquartile range [IQR]: 58.5-93.3]). Half of children met criteria for an ischemic CMEC (median LPR of 85 [IQR: 73-184]) and half met criteria for a nonischemic CMEC (median LPR of 60 [IQR: 54-79]. Children also underwent transcranial doppler ultrasound investigation. Cerebral blood flow velocities were more likely to meet diagnostic criteria for low flow (<2 standard deviation from normal) or vasospasm in children with an ischemic CMEC (73%) than in children with a nonischemic CMEC (20%, p = 0.04). Children with an ischemic CMEC had poorer outcomes (pediatric cerebral performance category of 3-6) than those with a nonischemic CMEC (46 vs. 22%, p = 0.03). CMEC was ubiquitous in this patient population and the processes underlying the two subtypes (ischemic and nonischemic) may represent targets for future adjunctive therapies.

Point-of-care Ultrasound to Assess Hemodynamic Contributors to Acute Kidney Injury in Pediatric Patients With Cerebral Malaria: A Pilot Study.

BACKGROUND: Acute kidney injury is common in severe malaria and is independently associated with mortality. The pathogenesis of acute kidney injury (AKI) in severe malaria remains incompletely understood. Ultrasound-based tools such as point-of-care ultrasound (POCUS), ultrasound cardiac output monitors (USCOMs) and renal arterial resistive index (RRI) can be used to detect hemodynamic and renal blood flow abnormalities contributing to AKI in malaria. METHODS: We conducted a prospective study of Malawian children with cerebral malaria to determine the feasibility of using POCUS and USCOM to characterize hemodynamic contributors to severe AKI (Kidney Disease: Improving Global Outcomes stage 2 or 3). The primary outcome was feasibility (completion rate of study procedures). We also assessed for differences in POCUS and hemodynamic variables for patients with or without severe AKI. RESULTS: We enrolled 27 patients who had admission cardiac and renal ultrasounds and USCOM. Completion rates were high for cardiac (96%), renal (100%) and USCOM studies (96%). Severe AKI occurred in 13 of 27 patients (48%). No patients had ventricular dysfunction. Only 1 patient in the severe AKI group was determined to be hypovolemic ( P = 0.64). No significant differences in USCOM, RRI or venous congestion parameters were detected among patients with and without severe AKI. Mortality was 11% (3/27) with the 3 deaths occurring in the severe AKI group ( P = 0.056). CONCLUSIONS: Ultrasound-based cardiac, hemodynamic and renal blood flow measurements appear to be feasible in pediatric patients with cerebral malaria. We were unable to detect hemodynamic or renal blood flow abnormalities contributing to severe AKI in cerebral malaria. Larger studies are needed to corroborate these findings.

Capacity Building in Pediatric Critical Care-Global Health Research and Education: The Blantyre Experience.

Pediatric critical care medicine (PCCM), as it is practiced in high-income countries, is focused on specialized medical care for the most vulnerable pediatric patient populations. However, best practices for provision of that care globally are lacking. Thus, PCCM research and education programming can potentially fill significant knowledge gaps by facilitating the development of evidence-based clinical guidelines that reduce child mortality on a global scale. Malaria remains a leading cause of pediatric mortality worldwide. The Blantyre Malaria Project (BMP) is a research and clinical care collaborative that has focused on reducing the public health burden of pediatric cerebral malaria in Malawi since 1986. In 2017, the requirements of a new research study led to the creation of PCCM services in Blantyre, creating the opportunity to establish a PCCM-Global Health Research Fellowship by BMP in collaboration with the University of Maryland School of Medicine. In this perspective piece, we reflect on the evolution of the PCCM-Global Health research fellowship. Although the specifics of this fellowship are out of the scope of this perspective, we discuss the context allowing for the development of this program and explore some early lessons learned to consider for future capacity-building efforts in the future of PCCM-Global Health research.

Transcranial doppler velocities in a large healthy population of African children.

Background and purpose: Transcranial doppler ultrasound (TCD) is a tool that diagnoses and monitors pathophysiological changes to the cerebrovasculature. As cerebral blood flow velocities (CBFVs) increase throughout childhood, interpretation of TCD examinations in pediatrics requires comparison to age matched normative data. Large cohorts of healthy children have not been examined to develop these reference values in any population. There is a complete absence of normative values in African children where, due to lack of alternate neuroimaging techniques, utilization of TCD is rapidly emerging. Materials and methods: A prospective study of 710 healthy African children 3 months-15 years was performed. Demographics, vital signs, and hemoglobin values were recorded. Participants underwent a complete, non-imaging TCD examination. Systolic (Vs), diastolic (Vd), and mean (Vm) flow velocities and pulsatility index (PI) were calculated by the instrument for each measurement. Results: Vs, Vd, and Vm increased through early childhood in all vessels, with the highest CBFVs identified in children 5-5.9 years. There were few significant gender differences in CBFVs in any vessels in any age group. No correlations between blood pressure or hemoglobin and CBFVs were identified. Children in the youngest age groups had CBFVs similar to those previously published, whereas nearly every vessel in children ≥3 years had significantly lower Vs, Vd, and Vm. Conclusions: For the first time, reference TCD values for African children are established. Utilization of these CBFVs in the interpretation of TCD examinations in this population will improve the overall accuracy of TCD as a clinical tool on the continent.

Adherence to severe malaria treatment guidelines in children at a Ugandan regional hospital: a baseline assessment for a malaria treatment quality improvement project.

BACKGROUND: Malaria is one of the most common causes of hospital admission and death in children under the age of five. The World Health Organization (WHO) has issued guidelines for the identification and treatment of severe malaria. Evidence has shown that adherence to standardized malaria treatment protocols improves outcomes. As a baseline assessment in preparation for a malaria treatment quality improvement project, this study aimed to determine adherence to the WHO severe malaria treatment guidelines in children at a Ugandan Regional Referral Hospital. METHODS: A retrospective review was performed on a convenience sample of children discharged between June 2021 and March 2022 from the Mbale Regional Referral Hospital Paediatrics Ward with a diagnosis of severe malaria. Data were collected using a standardized case report form. Demographics, presenting symptoms, laboratory results, treatments, length of stay, and mortality were extracted. Comparison of treatments received to items recommended in the WHO guidelines was undertaken to determine adherence. RESULTS: 147 patients were included. The median age was 5 years (IQR 2-7 years), and 55% were male. The most common features of severe malaria were haemoglobinuria (49%), haemoglobin < 5 mg/dL (34%), and altered mentation (24%). Median hospital length of stay was 3 days (IQR 2-4 days), and the mortality rate was 27% (n = 40). Overall adherence to all aspects of the WHO severe malaria guidelines was achieved in 3% (n = 4) of patients. The most common areas of deficiency were not testing to confirm malaria diagnosis (34%) and inadequate administration of artesunate (82%). Fewer than the three recommended doses of artesunate occurred in 22% of patients. Additionally, a delay in the administration of the second dose occurred in 67% (n = 78) and in the third dose in 77% (n = 71) of patients. While the recommended time between doses is 12 h, the median interval between dose one and dose two was 15 h (12-20) and the median interval from dose two to dose three was 17 h (14-25). CONCLUSIONS: Current adherence to severe malaria treatment guidelines in children at this Ugandan regional referral hospital is poor, but this study has identified target areas for improvement.

Catheter-associated deep vein thrombosis in children with severe traumatic brain injury: A single-center experience.

BACKGROUND: This study was performed to describe the single-center experience of deep vein thrombosis (DVT) in children with severe traumatic brain injury (sTBI) who were mechanically ventilated with a central line, and to identify potentially modifiable risk factors. It was hypothesized that children with DVT would have a longer duration of central venous line (CVL) and a higher use of hypertonic saline (HTS) compared to those without DVT. PROCEDURE/METHODS: This was a retrospective study of children (0-18 years) with sTBI, who were intubated, had a CVL, and a minimum intensive care unit (ICU) stay of 3 days. Children were analyzed by the presence or absence of DVT. HTS use was evaluated using milliliter per kilogram (ml/kg) of 3% equivalents. Univariable and multivariable logistic regression models were used to determine which factors were associated with DVT. RESULTS: Seventy-seven children met inclusion criteria, 23 (29.9%) had a DVT detected in an extremity. On univariable analysis, children with DVT identified in an extremity had prolonged CVL use (14 vs. 8.5 days, p = .021) and longer duration of mechanical ventilation (15 vs. 10 days, p = .013). HTS 3% equivalent ml/kg was not different between groups. On multivariable analysis, mechanical ventilation duration was associated with DVT detection in an extremity, whereas neither CVL duration nor HTS use had an association. CONCLUSIONS: There was a high incidence of extremity DVT detected in children with sTBI who received invasive mechanical ventilation and had a CVL. HTS administration was not associated with DVT detection in an extremity.

Organ Dysfunction Among Children Meeting Brain Death Criteria: Implications for Organ Donation.

OBJECTIVES: Over 70% of pediatric organ donors are declared deceased by brain death (BD) criteria. Patients with these devastating neurologic injuries often have accompanying multiple organ dysfunction. This study was performed to characterize organ dysfunction in children who met BD criteria and were able to donate their organs compared with those deemed medically ineligible. DESIGN: Retrospective cohort study. SETTING: PICU at a quaternary care children's hospital. PATIENTS: Patients with International Classification of Diseases , 9th Edition codes corresponding to BD between 2012 and 2018 were included. MEASUREMENTS AND MAIN RESULTS: Demographics, comorbidities, Pediatric Risk of Mortality (PRISM)-III, and injury mechanisms were derived from the medical record. Organ dysfunction was quantified by evaluating peak daily organ-specific variables. Fifty-eight patients, from newborn to 22 years old, were included with a median PRISM-III of 34 (interquartile range [IQR], 26-36), and all met criteria for multiple organ dysfunction syndrome (MODS). Thirty-four of 58 BD children (59%) donated at least one organ. Of the donors (not mutually exclusive proportions), 10 of 34 donated lungs, with a peak oxygenation index of 11 (IQR, 8-23); 24 of 34 donated their heart (with peak Vasoactive Inotrope Score 23 [IQR, 18-33]); 31 of 34 donated kidneys, of whom 16 of 31 (52%) had evidence of acute kidney injury; and 28 of 34 patients donated their liver, with peak alanine transferase (ALT) of 104 U/L (IQR, 44-268 U/L) and aspartate aminotransferase (AST) of 165 U/L (IQR, 94-434 U/L). Organ dysfunction was similar between heart and lung donors and respective medically ineligible nondonors. Those deemed medically ineligible to donate their liver had higher peak ALT 1,518 U/L (IQR, 986-1,748 U/L) ( p = 0.01) and AST 2,200 U/L (IQR, 1,453-2,405 U/L) ( p = 0.01) compared with liver donors. CONCLUSIONS: In our single-center experience, all children with BD had MODS, yet more than one-half were still able to donate organs. Future research should further evaluate transplant outcomes of dysfunctional organs prior to standardizing donation eligibility criteria.

Multiple Organ Dysfunction Syndrome and Pediatric Logistic Organ Dysfunction-2 Score in Pediatric Cerebral Malaria.

Malaria resulted in an estimated 627,000 deaths in 2020, the majority of which occurred in children under 5 years of age. Cerebral malaria (CM) is a severe manifestation of the disease with case fatality rates of up to 40%. Autopsies in children with CM have demonstrated sequestration of Plasmodium falciparum parasites in the brain as well as multiple other organs. Thus, multiple organ dysfunction syndrome (MODS) may be present in pediatric patients with CM, but its frequency and association with mortality have not been evaluated. This is a retrospective study of data collected prospectively from children with CM admitted in Blantyre, Malawi. Physical examination findings and laboratory values necessary to calculate a Pediatric Logistic Organ Dysfunction-2 (PELOD-2) score, a validated method that quantifies organ dysfunction in critically ill children, were abstracted. A total of 145 patients were included. Mortality was 15% (n = 22). Ten patients (7%) had single organ dysfunction, 36 (25%) had two organs involved, 68 (47%) had dysfunction of three organs, and 31 (21%) patients had four organs affected. Beyond neurologic dysfunction, other organ systems involved included hematologic (77%), renal (61%), cardiovascular (44%), and respiratory (1%). The median PELOD-2 score on admission was 4 (interquartile range [IQR] = 3-6) in survivors and 6.5 (IQR = 5-10) in the nonsurvivors (P < 0.0001). Admission PELOD-2 score predicted mortality with an area under the curve of 0.75. MODS is widespread in pediatric patients with CM. Objectively identifying children with MODS, and therefore at an increased risk of mortality, may allow for the allocation of limited resources.

Mechanisms of Transcranial Doppler Ultrasound phenotypes in paediatric cerebral malaria remain elusive.

BACKGROUND: Cerebral malaria (CM) results in significant paediatric death and neurodisability in sub-Saharan Africa. Several different alterations to typical Transcranial Doppler Ultrasound (TCD) flow velocities and waveforms in CM have been described, but mechanistic contributors to these abnormalities are unknown. If identified, targeted, TCD-guided adjunctive therapy in CM may improve outcomes. METHODS: This was a prospective, observational study of children 6 months to 12 years with CM in Blantyre, Malawi recruited between January 2018 and June 2021. Medical history, physical examination, laboratory analysis, electroencephalogram, and magnetic resonance imaging were undertaken on presentation. Admission TCD results determined phenotypic grouping following a priori definitions. Evaluation of the relationship between haemodynamic, metabolic, or intracranial perturbations that lead to these observed phenotypes in other diseases was undertaken. Neurological outcomes at hospital discharge were evaluated using the Paediatric Cerebral Performance Categorization (PCPC) score. RESULTS: One hundred seventy-four patients were enrolled. Seven (4%) had a normal TCD examination, 57 (33%) met criteria for hyperaemia, 50 (29%) for low flow, 14 (8%) for microvascular obstruction, 11 (6%) for vasospasm, and 35 (20%) for isolated posterior circulation high flow. A lower cardiac index (CI) and higher systemic vascular resistive index (SVRI) were present in those with low flow than other groups (p < 0.003), though these values are normal for age (CI 4.4 [3.7,5] l/min/m2, SVRI 1552 [1197,1961] dscm-5m2). Other parameters were largely not significantly different between phenotypes. Overall, 118 children (68%) had a good neurological outcome. Twenty-three (13%) died, and 33 (19%) had neurological deficits. Outcomes were best for participants with hyperaemia and isolated posterior high flow (PCPC 1-2 in 77 and 89% respectively). Participants with low flow had the least likelihood of a good outcome (PCPC 1-2 in 42%) (p < 0.001). Cerebral autoregulation was significantly better in children with good outcome (transient hyperemic response ratio (THRR) 1.12 [1.04,1.2]) compared to a poor outcome (THRR 1.05 [0.98,1.02], p = 0.05). CONCLUSIONS: Common pathophysiological mechanisms leading to TCD phenotypes in non-malarial illness are not causative in children with CM. Alternative mechanistic contributors, including mechanical factors of the cerebrovasculature and biologically active regulators of vascular tone should be explored.

Transcranial Doppler Ultrasound, a Review for the Pediatric Intensivist.

The use of transcranial Doppler ultrasound (TCD) is increasing in frequency in the pediatric intensive care unit. This review highlights some of the pertinent TCD applications for the pediatric intensivist, including evaluation of cerebral hemodynamics, autoregulation, non-invasive cerebral perfusion pressure/intracranial pressure estimation, vasospasm screening, and cerebral emboli detection.

Descriptive epidemiology of variants of infectious salmon anaemia virus in four Atlantic salmon farms in Newfoundland and Labrador, Canada.

An incursion of infectious salmon anaemia virus (ISAV) was detected in 2020 in southern Newfoundland, Canada. This resulted in an outbreak affecting four marine farms stocking Atlantic salmon (Salmo salar L.) vaccinated against ISAV. This study provides the first description of epidemiologic characteristics of an ISAV outbreak in 2020 and 2021, and detected ISAV variants at the population level. Fish kidneys were screened for ISAV by real-time RT-PCR and non-negative samples were submitted for genotyping and further diagnostic testing. Nine distinct ISAV variants were identified: five European and three North American (NA) HPRΔ ISAV, and one NA-HPR0 ISAV variant. A notable finding was the concurrent detection of both an HPR0 and an HPRΔ ISAV variant in one individual fish. In two farms, both European and NA variants were simultaneously detected, while in the other two farms either NA or European variants were identified, but not both together. Generally, mortality increases followed rises in ISAV prevalence and cycle threshold values on RT-PCR decreased with time. Epidemiologic descriptions of ISAV outbreaks in Atlantic Canada contributes to the understanding of local disease dynamics and identification of changes thereof. Such insights are essential for the strengthening of disease management plans.

The Burden of Critical Illness in Hospitalized Children in Low- and Middle-Income Countries: Protocol for a Systematic Review and Meta-Analysis.

Background: The majority of childhood deaths occur in low- and middle-income countries (LMICs). Many of these deaths are avoidable with basic critical care interventions. Quantifying the burden of pediatric critical illness in LMICs is essential for targeting interventions to reduce childhood mortality. Objective: To determine the burden of hospitalization and mortality associated with acute pediatric critical illness in LMICs through a systematic review and meta-analysis of the literature. Data Sources and Search Strategy: We will identify eligible studies by searching MEDLINE, EMBASE, CINAHL, and LILACS using MeSH terms and keywords. Results will be limited to infants or children (ages >28 days to 12 years) hospitalized in LMICs and publications in English, Spanish, or French. Publications with non-original data (e.g., comments, editorials, letters, notes, conference materials) will be excluded. Study Selection: We will include observational studies published since January 1, 2005, that meet all eligibility criteria and for which a full text can be located. Data Extraction: Data extraction will include information related to study characteristics, hospital characteristics, underlying population characteristics, patient population characteristics, and outcomes. Data Synthesis: We will extract and report data on study, hospital, and patient characteristics; outcomes; and risk of bias. We will report the causes of admission and mortality by region, country income level, and age. We will report or calculate the case fatality rate (CFR) for each diagnosis when data allow. Conclusions: By understanding the burden of pediatric critical illness in LMICs, we can advocate for resources and inform resource allocation and investment decisions to improve the management and outcomes of children with acute pediatric critical illness in LMICs.

Comparison of Intracranial Pressure Measurements Before and After Hypertonic Saline or Mannitol Treatment in Children With Severe Traumatic Brain Injury.

Importance: Hyperosmolar agents are cornerstone therapies for pediatric severe traumatic brain injury. Guideline recommendations for 3% hypertonic saline (HTS) are based on limited numbers of patients, and no study to date has supported a recommendation for mannitol. Objectives: To characterize current use of hyperosmolar agents in pediatric severe traumatic brain injury and assess whether HTS or mannitol is associated with greater decreases in intracranial pressure (ICP) and/or increases in cerebral perfusion pressure (CPP). Design, Setting, and Participants: In this comparative effectiveness research study, 1018 children were screened and 18 were excluded; 787 children received some form of hyperosmolar therapy during the ICP-directed phase of care, with 521 receiving a bolus. Three of these children were excluded because they had received only bolus administration of both HTS and mannitol in the same hour, leaving 518 children (at 44 clinical sites in 8 countries) for analysis. The study was conducted from February 1, 2014, to September 31, 2017, with follow-up for 1 week after injury. Final analysis was performed July 20, 2021. Interventions: Boluses of HTS and mannitol were administered. Main Outcomes and Measures: Data on ICP and CPP were collected before and after medication administration. Statistical methods included linear mixed models and corrections for potential confounding variables to compare the 2 treatments. Results: A total of 518 children (mean [SD] age, 7.6 [5.4] years; 336 [64.9%] male; 274 [52.9%] White) were included. Participants' mean (SD) Glasgow Coma Scale score was 5.2 (1.8). Bolus HTS was observed to decrease ICP and increase CPP (mean [SD] ICP, 1.03 [6.77] mm Hg; P < .001; mean [SD] CPP, 1.25 [12.47] mm Hg; P < .001), whereas mannitol was observed to increase CPP (mean [SD] CPP, 1.20 [11.43] mm Hg; P = .009). In the primary outcome, HTS was associated with a greater reduction in ICP compared with mannitol (unadjusted ß, -0.85; 95% CI, -1.53 to -0.19), but no association was seen after adjustments (adjusted ß, -0.53; 95% CI, -1.32 to 0.25; P = .18). No differences in CPP were observed. When ICP was greater than 20 mm Hg, greater than 25 mm Hg, or greater than 30 mm Hg, HTS outperformed mannitol for each threshold in observed ICP reduction (>20 mm Hg: unadjusted ß, -2.51; 95% CI, -3.86 to -1.15, P < .001; >25 mm Hg: unadjusted ß, -3.88; 95% CI, -5.69 to -2.06, P < .001; >30 mm Hg: unadjusted ß, -4.07; 95% CI, -6.35 to -1.79, P < .001), with results remaining significant for ICP greater than 25 mm Hg in adjusted analysis. Conclusions and Relevance: In this comparative effectiveness research study, bolus HTS was associated with lower ICP and higher CPP, whereas mannitol was associated only with higher CPP. After adjustment for confounders, both therapies showed no association with ICP and CPP. During ICP crises, HTS was associated with better performance than mannitol.