Efficacy and Safety of Garadacimab in Combination with Standard of Care Treatment in Patients with Severe COVID-19.

BACKGROUND: Garadacimab, a fully human IgG4 monoclonal antibody, inhibits the kallikrein-kinin pathway at a key initiator, activated coagulation factor XII (FXIIa), and may play a protective role in preventing the progression of COVID-19. This phase 2 study evaluated the efficacy and safety of garadacimab plus standard of care (SOC) versus placebo plus SOC in patients with severe COVID-19. METHODS: Patients hospitalised with COVID-19 were randomised (1:1) to a single intravenous dose of garadacimab (700 mg) plus SOC or placebo plus SOC. Co-primary endpoint was incidence of endotracheal intubation or death between randomisation and Day 28. All-cause mortality, safety and pharmacokinetic/pharmacodynamic parameters were assessed. RESULTS: No difference in incidence of tracheal intubation or death (p = 0.274) or all-cause mortality was observed (p = 0.382). Garadacimab was associated with a lower incidence of treatment-emergent adverse events (60.3% vs 67.8%) and fewer serious adverse events (34 vs 45 events) versus placebo. No garadacimab-related deaths or bleeding events were reported, including in the 45.9% (n = 28/61) of patients who received concomitant heparin. Prolonged activated partial thromboplastin time (aPTT), and increased coagulation factor XII (FXII) levels were observed with garadacimab versus placebo to Day 14, whilst FXIIa-mediated kallikrein activity (FXIIa-mKA) was suppressed to Day 28. CONCLUSION: In patients with severe COVID-19, garadacimab did not confer a clinical benefit over placebo. Transient aPTT prolongation and suppressed FXIIa-mKA showed target engagement of garadacimab that was not associated with bleeding events even with concomitant anticoagulant use. The safety profile of garadacimab was consistent with previous studies in patients with hereditary angioedema. GOV IDENTIFIER: NCT04409509. Date of registration: 28 May, 2020.

Prospective observational study of early respiratory management in preterm neonates less than 35 weeks of gestation.

BACKGROUND: Current guidelines for management of respiratory distress syndrome (RDS) recommend continuous positive airway pressure (CPAP) as the primary mode of respiratory support even in the most premature neonates, reserving endotracheal intubation (ETI) for rescue surfactant or respiratory failure. The incidence and timing of ETI in practice is poorly documented. METHODS: In 27 Level III NICUs in the US (n = 19), Canada (n = 3) and Poland (n = 5), demographics and baseline characteristics, respiratory support modalities including timing of ETI, administration of surfactant and caffeine/other methylxanthines, and neonatal morbidities were prospectively recorded in consecutive preterm neonates following written parental consent. Infants were divided into three groups according to gestational age (GA) at birth, namely 26-28, 29-32 and 33-34 weeks. Statistical comparisons between groups were done using Chi-Square tests. RESULTS: Of 2093 neonates (US = 1507, 254 Canada, 332 Poland), 378 (18%) were 26-28 weeks gestational age (GA), 835 (40%) were 29-32 weeks, and 880 (42%) were 33-34 weeks. Antenatal steroid use was 81% overall, and approximately 89% in neonates ≤32 weeks. RDS incidence and use of ventilatory or supplemental oxygen support were similar across all sites. CPAP was initiated in 43% of all infants, being highest in the 29-32-week group, with a lower proportion in other GA categories (p < 0.001). The overall rate of ETI was 74% for neonates 26-28 weeks (42% within 15 min of birth, 49% within 60 min, and 57% within 3 h), 33% for 29-32 weeks (13 16 and 21%, respectively), and 16% for 33-34 weeks (5, 6 and 8%, respectively). Overall intubation rates and timing were similar between countries in all GAs. Rates within each country varied widely, however. Across US sites, overall ETI rates in 26-28-week neonates were 30-60%, and ETI within 15 min varied from 0 to 83%. Similar within 15-min variability was seen at Polish sites (22-67%) in this GA, and within all countries for 29-32 and 33-34-week neonates. CONCLUSION: Despite published guidelines for management of RDS, rate and timing of ETI varies widely, apparently unrelated to severity of illness. The impact of this variability on outcome is unknown but provides opportunities for further approaches which can avoid the need for ETI.

Acetazolamide therapy for metabolic alkalosis in critically ill pediatric patients.

OBJECTIVE: Despite a paucity of supporting literature, acetazolamide is commonly used in critically ill children with metabolic alkalosis (elevated plasma bicarbonate [pHco-3] and pH). The objective of this study was to assess the change in 18 hours after initiation of acetazolamide therapy. DESIGN: Retrospective study. SETTING: PICU of an urban, tertiary-care children's hospital. PATIENTS: Mechanically ventilated children (≤ 17 yr) with metabolic alkalosis (pHco-3 ≥ 35 mmol/L). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of 153 consecutively screened patients, 61 patients (29 female patients) were enrolled: 18 cardiac patients (after congenital heart disease repair) and 43 noncardiac patients. The cardiac patients were younger than the noncardiac patients (median [interquartile range] age, 0.6 mo [0.3-2.5 mo] vs 7.4 mo [2.8-39.9 mo]; p < 0.00001) and had higher preacetazolamide baseline diuretic scores and urine output. The pHco-3 levels 18 hours after initiation of acetazolamide were reduced in the cohort as a whole (40.2 ± 4.8 to 36.2 ± 5.6 mmol/L; p < 0.001) and in the noncardiac patients, but they were unchanged in the cardiac patients. The PCO2 remained unchanged after acetazolamide in both subgroups. Because young age and presence of cardiac disease were potential confounders, the 20 noncardiac patients who are 6 months old or younger were compared with the cardiac subgroup and demonstrated reduced pHco-3 after acetazolamide and lower preacetazolamide baseline diuretic score and urine output. CONCLUSION: Acetazolamide reduces pHco-3 concentration in critically ill, mechanically ventilated children overall, but it did not do so in cardiac patients in our cohort, even in comparison with noncardiac patients of a similar age. These findings do not support the current use of acetazolamide for metabolic alkalosis in critically ill children with congenital heart disease. Further study is required to determine why these cardiac patients respond differently to acetazolamide than noncardiac patients and whether this response impacts important clinical outcomes, for example, weaning mechanical ventilation.

An under-recognized benefit of cardiopulmonary resuscitation: organ transplantation.

OBJECTIVE: For many patients who suffer cardiac arrest, cardiopulmonary resuscitation does not result in long-term survival. For some of these patients, the evolution to donation of organs becomes an option. Organ transplantation after cardiopulmonary resuscitation is not reported as an outcome of cardiopulmonary resuscitation and is therefore overlooked. We sought to determine the number and proportion of organs transplanted from donors who received cardiopulmonary resuscitation after a cardiac arrest in the United States and to compare survival of organs from donors who had cardiopulmonary resuscitation (cardiopulmonary resuscitation organs) versus donors who did not have resuscitation (noncardiopulmonary resuscitation organs). DATA SOURCE: We retrospectively analyzed a nationwide, population-based database of all organ donors and recipients from the United Network for Organ Sharing between July 1999 and June 2011. STUDY SELECTION: We queried the database for all organs from deceased donors between July 1999 and June 2011. Organs from living donors (n = 76,015), all organs with missing cardiopulmonary resuscitation data (n = 59), and organs procured following a circulatory determination of death (n = 12,030) were excluded. DATA EXTRACTION: We report donor demographic data and organ survival outcomes among organs from donors who received cardiopulmonary resuscitation (cardiopulmonary resuscitation organs) and donors who had not received cardiopulmonary resuscitation (noncardiopulmonary resuscitation organs). Graft survival of cardiopulmonary resuscitation organs versus noncardiopulmonary resuscitation organs was compared using Kaplan-Meier estimates and stratified log-rank test. DATA SYNTHESIS: In the United States, among the 224,076 organs donated by donors who were declared dead by neurologic criteria between 1999 and 2011, at least 12,351 organs (5.5%) were recovered from donors who received cardiopulmonary resuscitation. Graft survival of cardiopulmonary resuscitation organs was not significantly different than that of noncardiopulmonary resuscitation organs. CONCLUSIONS: At least 1,000 organs transplanted per year in the United States (> 5% of all organs transplanted from patients declared dead by neurologic criteria) are recovered from patients who received cardiopulmonary resuscitation. Organ recovery and successful transplantation is an unreported beneficial outcome of cardiopulmonary resuscitation.

Development of a bedside tool to predict time to death after withdrawal of life-sustaining therapies in infants and children.

OBJECTIVES: To generate a preliminary bedside predictor of rapid time-to-death after withdrawal of support in children to help identify potential candidates for organ donation after circulatory death. DESIGN: Retrospective chart review. SETTING: Pediatric intensive care unit of an academic children's hospital. PATIENTS: All deaths in the pediatric intensive care unit from May 1996 to April 2007. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Among 1389 deaths, 634 patients underwent withdrawal of support and 518 with complete data regarding demographics, life-supportive therapies, and end-of-life circumstances were analyzed. Three hundred seventy-three (72%) patients died within 30 mins of withdrawal and 452 (87%) died within 60 mins. Using multiple logistic regression, significant predictors of death within 30 or 60 mins (typical cut-off times for organ donation) were identified and a predictor score was generated. Significant predictors included: age 1 month or younger; norepinephrine, epinephrine, or phenylephrine >0.2 µg/kg/min; extracorporeal membrane oxygenation; and positive end-expiratory pressure >10 cmH2O; and spontaneous ventilation. Possible scores for the 30-min predictor ranged from -17 to 67; a score ≤-9 predicted a 37% probability of death ≤ 30 mins, whereas a score ≥ 38 predicted an 85% probability of death within 30 mins. For the 60-min predictor, scores ranged from -21 to 38; score ≤-10 predicted a 59% probability of death within 60 mins and a score ≥ 16 predicted a 98% probability of death within 60 mins. CONCLUSIONS: This tool is a reasonable preliminary predictor for death within 30 or 60 mins after withdrawal of support in terminally ill or injured children and might assist in identifying potential pediatric candidates for donation after circulatory death, although prospective validation is required.

Cerebrospinal fluid biomarkers versus glasgow coma scale and glasgow outcome scale in pediatric traumatic brain injury: the role of young age and inflicted injury.

The Glasgow Coma Scale (GCS) and Glasgow Outcome Scale (GOS) are widely used clinical scoring systems to measure the severity of neurologic injury after traumatic brain injury (TBI), but have recognized limitations in infants and small children. Cerebrospinal fluid (CSF) concentrations of neuron-specific enolase (NSE) and S100B show promise as markers of brain injury. We hypothesized that the initial GCS and 6-month GOS scores would be inversely associated with CSF NSE and/or S100B concentrations after severe pediatric TBI. Using banked CSF obtained during ongoing studies of pediatric TBI, NSE and S100B were determined in CSF collected within 24 h of trauma from 88 infants and children with severe TBI (GCS < or = 8) versus 20 non-injured controls. Victims of inflicted (iTBI) and non-inflicted TBI (nTBI) showed similar (>10-fold) increases in both NSE and S100B versus control. Both markers showed overall significant, inverse correlation with GCS and GOS scores. In subgroup analysis, both markers correlated significantly with GCS and GOS scores only in older (>4 years) victims of nTBI; no correlation was found for patients < or =4 years old or victims of iTBI. While confirming the overall correlations between GCS/GOS score and CSF NSE and S100B seen in prior studies, we conclude that these clinical and CSF biomarkers of brain injury do not correlate in children < or =4 years of age and/or victims of iTBI. Although further, prospective study is warranted, these findings suggest important limitations in our current ability to assess injury severity in this important population.

Characterization of the effects of adenosine receptor agonists on cerebral blood flow in uninjured and traumatically injured rat brain using continuous arterial spin-labeled magnetic resonance imaging.

Hypoperfusion after traumatic brain injury may exacerbate damage. Adenosine, a vasodilator, regulates cerebral blood flow (CBF). Treatment with adenosine receptor agonists has shown benefit in experimental CNS trauma; however, their effects on CBF after injury remain undefined. We used magnetic resonance imaging to assess CBF in uninjured rats both early and at 24 h after intrahippocampal administration of either the nonselective adenosine receptor agonist 2-chloroadenosine (2-CA, 12 nmol) or the A(2A)-receptor agonist 2-p-(2-carboxyethyl)-phenethylamino-5'-N-ethylcarbox-amidoadenosine (CGS 21680, 6 nmol). We also assessed the effects of these agents on cerebral metabolic rate for glucose (CMRglu). We then assessed the effect of 2-CA on CBF at 3.5 to 5 h after controlled cortical impact (CCI). Injection of 2-CA into uninjured rat brain produced marked increases in CBF in ipsilateral hippocampus and cortex versus vehicle (P<0.05); CBF increases persisted even at 24 h. Measurement of hippocampal levels of 2-CA showed persistent increases to 24 h. CGS 21680 produced even more marked global increases in CBF than seen with 2-CA (2-6-fold versus vehicle, P<0.05 in 10/12 regions of interest (ROIs)). Neither agonist altered CMRglu versus vehicle. After CCI, 2-CA increased CBF in ipsilateral hippocampal and hemispheric ROIs (P<0.05 versus vehicle), but the response was attenuated at severe injury levels. We report marked increases in CBF after injection of adenosine receptor agonists into uninjured rat brain despite unaltered CMRglu. 2-Chloroadenosine produced enduring increases in CBF in uninjured brain and attenuated posttraumatic hypoperfusion. Future studies of adenosine-related therapies in CNS injury should address the role of CBF.

Continuous versus intermittent cerebrospinal fluid drainage after severe traumatic brain injury in children: effect on biochemical markers.

Drainage of cerebrospinal fluid (CSF) is routinely used in the treatment of severe traumatic brain injury (TBI), either continuously or intermittently in response to increases in intracranial pressure (ICP). There has been little study of the effect of CSF drainage method on the biochemistry, pathophysiology or outcome of TBI in adults or children. Having previously reported that a variety of markers of injury or repair increase in CSF after severe TBI, we chose to evaluate directly the effect of CSF drainage method on the biochemistry and volume of CSF drained as well as ICP. We hypothesized that concentrations of these markers would be similar in CSF drained continuously vs intermittently. We compared CSF levels of markers of neuronal injury (neuron specific enolase, [NSE]), glial injury (s100B), inflammation (interleukin-6 [IL-6]), and regeneration (vascular endothelial growth factor [VEGF]) (measured by ELISA) in 80 CSF samples from 19 severely injured children whose CSF was drained continuously (n = 13) versus intermittently (n = 6) as part of standard care in two institutions. Compared to continuous CSF drainage, intermittent drainage of CSF was associated with twofold greater CSF concentrations of NSE, s100B, IL-6 and VEGF (p < 0.05) and with about half the volume of CSF removal than continuous drainage (p = 0.002). The resulting elimination (concentration x volume) of these biochemicals, however, was not influenced by drainage method. Patients treated with continuous drainage had lower mean ICPs than those with intermittent drainage (13.6 +/- 0.69 vs. 21.8 +/- 0.95 mm Hg, p < 0.0001). We conclude that the method of CSF drainage greatly affects concentrations of CSF markers after TBI and may influence ICP. The influence of method on CSF marker concentration must be kept in mind when interpreting studies of CSF biomarkers. The striking difference in biomarker concentration, CSF volume drained, and ICP suggests the need for a randomized trial directly comparing these two approaches in infants and children with severe TBI.

Vascular endothelial growth factor is increased in cerebrospinal fluid after traumatic brain injury in infants and children.

OBJECTIVE: Vascular endothelial growth factor (VEGF) is an important regulator of angiogenesis, the formation of which is triggered by hypoxia, cytokines, and growth factors and is also induced by activation of the adenosine 2B receptor. VEGF is neuroprotective in several models of experimental brain injury and is increased in brain after traumatic brain injury (TBI) in humans and experimental animals. Adenosine is a neuroprotective purine metabolite that increases in cerebrospinal fluid (CSF) after clinical TBI in children. We hypothesized that VEGF levels would 1). be increased in CSF after TBI in infants and children, and 2). be preceded by increases in CSF adenosine. To test this hypothesis, we designed a case-control study to compare the CSF of infants and children after severe TBI with that of uninjured children. METHODS: Using an Institutional Review Board-approved protocol, we compared CSF concentrations of VEGF (by enzyme-linked immunosorbent assay) and adenosine (by high-performance liquid chromatography) in 73 samples from 14 infants and children with severe TBI (Glasgow Coma Scale score

Adolescent asystolic syncope.

When the etiology of syncope is considered, age is a major parameter. Breath-holding spells are thought of as an entity of early childhood, whereas neurogenic syncope is limited to older children and adults. Both entities, however, involve a similar derangement of the autonomic nervous system. We report an adolescent with a history of breath-holding spells presenting to our institution with neurogenic syncope. Her response to vagal stimulation is consistent with that seen by other investigators in both entities. We propose that pallid breath-holding spells and neurogenic syncope are the same entity.

Potential for liver and kidney donation after circulatory death in infants and children.

OBJECTIVE: To determine the potential effect of organ donation after circulatory death (DCD) on the number of kidney and liver donors in a PICU. PATIENTS AND METHODS: All deaths in the PICU of an academic, tertiary care children's hospital from May 1996 to April 2007 were retrospectively reviewed. Patient demographics, premortem physiology, and end-of-life circumstances were recorded and compared with basic criteria for potential organ donation. A sensitivity analysis was performed to examine the effect of more strict physiologic and time criteria as well as 3 different rates of consent for donation. RESULTS: There were 1389 deaths during 11 years; 634 children (46%) underwent withdrawal of life support, of whom 518 had complete data and were analyzed. There were 131 children (25% of those withdrawn, 9% of all deaths) who met basic physiologic and time criteria for organ donation (80 kidney; 107 liver). Consideration of consent rates in sensitivity analysis resulted in an estimated 24 to 85 organ donors, an increase of 28% to 99% over the 86 actual brain-dead donors during the same time period. Assuming historical rates of organ recovery, these DCD donors might have produced 30 to 88 additional kidneys and 8 to 56 additional livers, an increase of 21% to 60% in kidney donation and 13% to 80% in livers above the number of organs recovered from brain-dead donors. CONCLUSIONS: Although relatively few children may have been eligible for DCD, they might have increased the number of organ donors from our institution, depending greatly on consent rates. DCD merits additional discussion and exploration.

Reliability and validity of the Pediatric Intensity Level of Therapy (PILOT) scale: a measure of the use of intracranial pressure-directed therapies.

OBJECTIVE: To test the reliability and validity of the Pediatric Intensity Level of Therapy (PILOT) scale, a novel measure of overall therapeutic effort directed at controlling intracranial pressure (ICP) in the setting of severe (Glasgow Coma Scale of