Calcium use during paediatric in-hospital cardiac arrest is associated with worse outcomes.

AIM: To evaluate associations between calcium administration and outcomes among children with in-hospital cardiac arrest and among specific subgroups in which calcium use is hypothesized to provide clinical benefit. METHODS: This is a secondary analysis of observational data collected prospectively as part of the ICU-RESUScitation project. Children 37 weeks post-conceptual age to 18 years who received chest compressions in one of 18 intensive care units from October 2016-March 2021 were eligible. Data included child and event characteristics, pre-arrest laboratory values, pre- and intra-arrest haemodynamics, and outcomes. Outcomes included sustained return of spontaneous circulation (ROSC), survival to hospital discharge, and survival to hospital discharge with favourable neurologic outcome. A propensity score weighted cohort was used to evaluate associations between calcium use and outcomes. Subgroups included neonates, and children with hyperkalaemia, sepsis, renal insufficiency, cardiac surgery with cardiopulmonary bypass, and calcium-avid cardiac diagnoses. RESULTS: Of 1,100 in-hospital cardiac arrests, median age was 0.63 years (IQR 0.19, 3.81); 450 (41%) received calcium. Among the weighted cohort, calcium use was not associated with sustained ROSC (aOR, 0.87; CI95 0.61-1.24; p = 0.445), but was associated with lower rates of both survival to hospital discharge (aOR, 0.68; CI95 0.52-0.89; p = 0.005) and survival with favourable neurologic outcome at hospital discharge (aOR, 0.75; CI95 0.57-0.98; p = 0.038). Among subgroups, calcium use was associated with lower rates of survival to hospital discharge in children with sepsis and renal insufficiency. CONCLUSIONS: Calcium use was common during paediatric in-hospital cardiac arrest and associated with worse outcomes at hospital discharge.

N-acetylcysteine reduces brain injury after delayed hypoxemia following traumatic brain injury.

Preclinical investigations into neuroprotective agents for traumatic brain injury (TBI) have shown promise when administered before or very early after experimental TBI. However clinical trials of therapeutics demonstrating preclinical efficacy for TBI have failed to replicate these results in humans, a lost in translation phenomenon. N-acetylcysteine (NAC) is a potent anti-oxidant with demonstrated efficacy in pre-clinical TBI when administered early after primary injury. Utilizing our clinically relevant mouse model, we hypothesized that NAC administration in a clinically relevant timeframe could improve the brain's resilience to the secondary insult of hypoxemia. NAC or vehicle administered daily starting 2 h prior to hypoxemia (24 h after controlled cortical impact) for 3 doses in male mice reduced short-term axonal injury and hippocampal neuronal loss. Six month behavioral assessments including novel object recognition, socialization, Barnes maze, and fear conditioning did not reveal performance differences between sham controls and injured mice receiving NAC or saline vehicle. At 7 months after injury, NAC administered mice had reduced hippocampal neuronal loss but no reduction in lesion volume. In summary, our preclinical trial to test the neuroprotective efficacy of NAC against a secondary hypoxic insult after TBI demonstrated short and long-term neuropathological evidence of neuroprotection but a lack of detectable differences in long-term behavioral assessments between sham controls and injured mice limits conclusions on its impact on long-term neurobehavioral outcomes.

Delayed Hypoxemia after Traumatic Brain Injury Exacerbates Long-Term Behavioral Deficits.

Hypoxemia during initial stabilization of patients with severe traumatic brain injury (TBI) has been associated with poorer outcomes. However, the effects of delayed hypoxemia occurring during intensive care post-TBI on outcome is unclear. Pre-clinical models of TBI have rarely shown cognitive or behavioral deficits beyond 6 weeks post-injury and commonly have not included modeling of secondary insults. We have previously developed a murine model of TBI followed by delayed hypoxemia to model the secondary insult of hypoxemia and brain hypoxia occurring in the intensive care setting. Understanding long-term effects of delayed hypoxemia post-TBI in our murine model is critical for future testing of candidate therapeutics targeting secondary brain hypoxia. For this study, forty 5-week-old male mice were randomized to controlled cortical impact (CCI; N = 24) or sham surgery (N = 16). One day later, awake animals were randomized to 60 min of hypoxemia or normoxemia. Six months after initial injury, animals underwent behavior testing (Morris water maze, social interaction, and tail suspension) before euthanasia for immunohistochemistry (IHC) assessments. At 6 months post-injury, mice experiencing CCI and hypoxemia (CCI+H) had longer swim distances to the hidden platform (51 cm) compared to CCI alone (26 cm) or sham animals (22 cm). During social interaction assessments, CCI + H mice spent less time interacting with novel stimulus mice (79 sec) than CCI alone (101 sec) or sham animals (139 sec). CCI + H had larger lesion volumes compared to CCI alone (14.0% vs. 9.9%; p < 0.003). Glial fibrillary acidic protein IHC at 6 months post-injury demonstrated increased astrogliosis in the ipsilateral white matter of CCI + H compared to CCI alone. To summarize, this clinically relevant model of delayed hypoxia post-TBI resulted in long-term behavioral deficits and evidence of exacerbated structural injury.

Delayed Hypoxemia Following Traumatic Brain Injury Exacerbates White Matter Injury.

Hypoxemia immediately following traumatic brain injury (TBI) has been observed to exacerbate injury. However, it remains unclear whether delayed hypoxemia beyond the immediate postinjury period influences white matter injury. In a retrospective clinical cohort of children aged 4-16 years admitted with severe TBI, 28/74 (35%) patients were found to experience delayed normocarbic hypoxemia within 7 days of admission. Based on these clinical findings, we developed a clinically relevant mouse model of TBI with delayed hypoxemia by exposing 5-week old (adolescent) mice to hypoxic conditions for 30 minutes starting 24 hours after moderate controlled cortical impact (CCI). Injured mice with hypoxemia had increased axonal injury using both ß-amyloid precursor protein and NF200 immunostaining in peri-contusional white matter compared with CCI alone. Furthermore, we detected increased peri-contusional white matter tissue hypoxia with pimonidazole and augmented astrogliosis with anti-glial fibrillary acidic protein staining in CCI + delayed hypoxemia compared with CCI alone or sham surgery + delayed hypoxemia. Microglial activation as evidenced by Iba1 staining was not significantly altered by delayed hypoxemia. These clinical and experimental data indicate the prevention or amelioration of delayed hypoxemia effects following TBI may provide a unique opportunity for the development of therapeutic interventions to reduce axonal injury and improve clinical outcomes.

Hepatic Mucormycosis Mimicking Veno-occlusive Disease: Report of a Case and Review of the Literature.

The clinical history of a 12-year-old boy with trisomy 21 who suffered from relapsed pre-B cell acute lymphocytic leukemia with clinical symptoms of hepatic veno-occlusive disease and death is reported. The postmortem findings were significant for hepatic mucormycosis with selective involvement of the central veins, sinusoids, and portal tracts resulting in obstruction of the outflow tract and massive hepatocellular necrosis. Hematogenous dissemination of mucormycosis causing acute splenitis and hemorrhagic intestinal necrosis were also observed. To our knowledge, mucormycosis invasion of the central veins, sinusoids, and portal tracts by fungal hyphae resulting in a syndrome mimicking hepatic veno-occlusive disease has not been previously reported.

Decompressive craniectomy reduces white matter injury after controlled cortical impact in mice.

Reduction and avoidance of increases in intracranial pressure (ICP) after severe traumatic brain injury (TBI) continue to be the mainstays of treatment. Traumatic axonal injury is a major contributor to morbidity after TBI, but it remains unclear whether elevations in ICP influence axonal injury. Here we tested the hypothesis that reduction in elevations in ICP after experimental TBI would result in decreased axonal injury and white matter atrophy in mice. Six-week-old male mice (C57BL/6J) underwent either moderate controlled cortical impact (CCI) (n=48) or Sham surgery (Sham, n=12). Immediately after CCI, injured animals were randomized to a loose fitting plastic cap (Open) or replacement of the previously removed bone flap (Closed). Elevated ICP was observed in Closed animals compared with Open and Sham at 15 min (21.4±4.2 vs. 12.3±2.9 and 8.8±1.8 mm Hg, p<0.0001) and 1 day (17.8±3.7 vs. 10.6±2.0 and 8.9±1.9 mm Hg, p<0.0001) after injury. Beta amyloid precursor protein staining in the corpus callosum and ipsilateral external capsule revealed reduced axonal swellings and bulbs in Open compared with Closed animals (32% decrease, p<0.01 and 40% decrease, p<0.001 at 1 and 7 days post-injury, respectively). Open animals were also found to have decreased neurofilament-200 stained axonal swellings at 7 days post-injury compared with Open animals (32% decrease, p<0.001). At 4 weeks post-injury, Open animals had an 18% reduction in white matter volume compared with 34% in Closed animals (p<0.01). Thus, our results indicate that CCI with decompressive craniectomy was associated with reductions in ICP and reduced pericontusional axonal injury and white matter atrophy. If similar in humans, therapeutic interventions that ameliorate intracranial hypertension may positively influence white matter injury severity.

Risk factors associated with infections and need for permanent cerebrospinal fluid diversion in pediatric intensive care patients with externalized ventricular drains.

BACKGROUND: Externalized ventricular drains (EVDs) are commonly used in pediatric intensive care units (PICU) but few data are available regarding infection rates, infection risks, or factors associated with conversion to permanent cerebrospinal fluid (CSF) diversion. METHODS: Retrospective observational study of patients managed with EVDs admitted to a tertiary care PICU from January 2005 to December 2009. RESULTS: Three hundred eighty patients were identified. Neurologic diagnostic groups were externalization of existing shunt in 196 patients (52 %), brain tumor in 122 patients (32 %), intracranial hemorrhage in 23 patients (6 %), traumatic brain injury in 17 patients (5 %), meningitis in 9 patients (2 %), or other in 13 patients (3 %). Six percent of all patients (24/380) had new infections associated with EVD management for an infection rate of 8.6 per 1,000 catheter days. The median time to positive cultures was 7 days (interquartile range 4.75, 9) after EVD placement. Patients with EVD infections had significantly longer EVD duration 6 versus 11.5 days (p = 0.0001), and higher maximum EVD outputs 1.9 versus 1.5 mL/kg/h (p = 0.0017). Need for permanent CSF diversion was associated with higher maximum EVD drainage (1.3 vs. 1.6 mL/kg/h p < 0.0001), longer EVD duration (5 vs. 4 days, p < 0.005), and younger age (4.5 vs. 8 years, p < 0.02) but not intracranial hypertension (72 vs. 82 % of patients, p = 0.4). CONCLUSIONS: In our large pediatric cohort, EVD infections were associated with longer EVD duration and higher maximum EVD output. Permanent CSF diversion was more likely in patients with higher maximum EVD drainage, longer EVD duration, and younger age.

Bi-caval dual lumen venovenous extracorporeal membrane oxygenation and high-frequency percussive ventilatory support for postintubation tracheal injury and acute respiratory distress syndrome.

Bi-caval dual lumen venovenous extracorporeal membrane oxygenation (VV-ECMO) as a nonoperative approach to postintubation tracheal injury has not been described. We report the case of a 7-year-old boy who sustained a postintubation tracheal injury, developed acute respiratory distress syndrome from aspiration and viral pneumonitis, and was supported on bi-caval dual lumen VV-ECMO for 16 days until the trachea healed without surgical repair. Before ECMO decannulation, high-frequency percussive ventilation using a volumetric diffusive respiration ventilator was used for lung recruitment and airway clearance without disruption of the healed trachea. The use of ECMO to allow for lower mean airway pressure during initial healing and high-frequency percussive ventilation for lung recruitment and secretion clearance is a promising strategy to allow nonoperative tracheal injury repair in critically ill patients with multiple comorbidities.