Resolution of insulin resistance, lactic acidosis, and decrease in mechanical support requirements in patients post orthotopic heart transplant with the use of long-acting insulin glargine.

OBJECTIVE: This study investigates the efficacy of using a long-acting insulin analog, along with the infusion of regular insulin, in achieving appropriate glycemic control and correcting lactic acidosis in patients post orthotopic heart transplant who demonstrate severe lactic acidosis and insulin resistance. METHODS: This was a retrospective study of two cohorts (IRB FLA 20-003) of patients post orthotopic heart transplant with severe lactic acidosis and insulin resistance who were admitted to a tertiary intensive care unit and treated with (group 1) or without long-acting insulin analog (group 2) within the first 24 h of admission to the intensive care unit. Insulin resistance is defined as the requirement for intravenous regular insulin infusion of more than 20 units/h without the ability to achieve appropriate serum glucose level (120-180 mg /dL). Severe lactic acidosis is defined as arterial lactic acid of more than 10 mmol/L. The following parameters were investigated: time to correct lactic acidosis, duration of postoperative mechanical ventilation, the need for periprocedural mechanical circulatory support, and 28-day mortality. RESULTS: The 28-day mortality was zero in both groups. Two patients required periprocedural mechanical support in group one, and ten patients required mechanical support in group two (RR = 0.224, 95%, confidence interval 0.052-0.95, Z = 2.029, p = 0.042). Three patients required tracheostomy in group one, and four patients required tracheostomy in group two (RR 0.84, 95 confidence interval 0.20-3.48, Z = 0.23, P = 0.81). Wilcoxon rank-sum test was used to compare time to correct lactic acidosis, with lactic acid resolution being faster in group one ([Formula: see text]1 = 19.7 h, SD ± 12.6 h [Formula: see text]2 = 29.3 h, SD ± 19.6 h, Z-value - 2.02, p-value 0.043). The duration of mechanical ventilation was less in group one ([Formula: see text]1 = 29 h, SD ± 12.7 h, [Formula: see text]2 = 55.1 h, SD ± 44.5 h, Z-value: - 1.92, p-value 0.05). CONCLUSION: Administration of low-dose long-acting insulin glargine led to the resolution of the lactic acidosis, insulin resistance, and decreased requirements for pressor and inotropic support, which led to decreased need for mechanical circulatory support.

The Use of Dornase Alfa in the Management of COVID-19-Associated Adult Respiratory Distress Syndrome.

OBJECTIVE: Currently, management of acute respiratory distress syndrome (ARDS) in COVID-19 infection with invasive mechanical ventilation results in poor prognosis and high mortality rates. Interventions to reduce ventilatory requirements or preclude their needs should be evaluated in order to improve survival rates in critically ill patients. Formation of neutrophil extracellular traps (NETs) during the innate immune response could be a contributing factor to the pulmonary pathology. This study suggests the use of dornase alfa, a recombinant DNAse I that lyses NETs, to reduce ventilatory requirements and improve oxygenation status, as well as outcomes in critically ill patients with ARDS subsequent to confirmed or highly suspected COVID-19 infection. DESIGN: A single-institution cohort study. Setting. Intensive care unit in a tertiary medical center. Patients. Adult patients with acute respiratory distress syndrome (ARDS) admitted to the ICU with confirmed COVID-19 infection. Intervention. Treatment with aerosolized dornase alfa. Measurements and Main Results. Of 39 patients evaluated, most patients had improvement in oxygenation measured by increase in the PaO2/FiO2 ratio, reduction in ventilatory support or other supportive oxygen requirements, and partial resolution of bilateral opacities visible on CXR, as well as improved outcome. CONCLUSIONS: Administration of inhalational dornase alfa via a filtered nebulizer medication system or through an adapter in a ventilator circuit should be considered in all COVID-19-positive patients with ARDS as early in the disease course as possible.

Physiologic Improvement in Respiratory Acidosis Using Extracorporeal Co2 Removal With Hemolung Respiratory Assist System in the Management of Severe Respiratory Failure From Coronavirus Disease 2019.

OBJECTIVES: About 15% of hospitalized coronavirus disease 2019 patients require ICU admission, and most (80%) of these require invasive mechanical ventilation. Lung-protective ventilation in coronavirus disease 2019 acute respiratory failure may result in severe respiratory acidosis without significant hypoxemia. Low-flow extracorporeal Co2 removal can facilitate lung-protective ventilation and avoid the adverse effects of severe respiratory acidosis. The objective was to evaluate the efficacy of extracorporeal Co2 removal using the Hemolung Respiratory Assist System in correcting severe respiratory acidosis in mechanically ventilated coronavirus disease 2019 patients with severe acute respiratory failure. DESIGN: Retrospective cohort analysis of patients with coronavirus disease 2019 mechanically ventilated with severe hypercapnia and respiratory acidosis and treated with low-flow extracorporeal Co2 removal. SETTING: Eight tertiary ICUs in the United States. PATIENTS: Adult patients supported with the Hemolung Respiratory Assist System from March 1, to September 30, 2020. INTERVENTIONS: Extracorporeal Co2 removal with Hemolung Respiratory Assist System under a Food and Drug Administration emergency use authorization for coronavirus disease 2019. MEASUREMENTS AND MAIN RESULTS: The primary outcome was improvement in pH and Paco2 from baseline. Secondary outcomes included survival to decannulation, mortality, time on ventilator, and adverse events. Thirty-one patients were treated with Hemolung Respiratory Assist System with significant improvement in pH and Pco2 in this cohort. Two patients experienced complications that prevented treatment. Of the 29 treated patients, 58% survived to 48 hours post treatment and 38% to hospital discharge. No difference in age or comorbidities were noted between survivors and nonsurvivors. There was significant improvement in pH (7.24 ± 0.12 to 7.35 ± 0.07; p < 0.0001) and Paco2 (79 ± 23 to 58 ± 14; p < 0.0001) from baseline to 24 hours. CONCLUSIONS: In this retrospective case series of 29 patients, we have demonstrated efficacy of extracorporeal Co2 removal using the Hemolung Respiratory Assist System to improve respiratory acidosis in patients with severe hypercapnic respiratory failure due to coronavirus disease 2019.

Brain perfusion abnormalities in patients with compromised venous outflow.

Elevated intracranial intravenous pressure is not routinely measured in clinical practice. Indirect evidence of increased venous pressure is reflected in the size change of the cerebral sinuses and the presence of venous infarctions. The purpose of this study is to evaluate the role of brain perfusion venous time-density curves in the diagnosis of cerebral venous hypertension. A retrospective review of four cases in which increased cerebral intravenous pressure was reflected in abnormal time-density curves on CT brain perfusion studies was completed. The abnormal venous time-density curves correlated with clinically increased intravenous pressure and normalized after treating the underlying pathology. Abnormal venous outflow affects brain perfusion. This could be identified on a CT brain-perfusion study based on characteristic venous time-density curves. These curves may appear quite similar even when the underlying etiologies are different. Normalization of the venous time-density curves may be observed after the underlying pathology was treated.

Detectable levels of cytochrome C and activated caspase-9 in cerebrospinal fluid after human traumatic brain injury.

BACKGROUND: The intrinsic pathway of apoptosis has been proposed as one mechanism of cell death after traumatic brain injury (TBI). This study tested the hypothesis that cytochrome c and activated caspase-9 are released into the cerebrospinal fluid (CSF) after severe TBI and that their presence correlates with mitochondrial injury and severity of neurologic outcome. METHODS: Nine adult patients with severe TBI (GCS < or = 8) underwent placement of intraventricular catheters for monitoring and management of intracranial pressure. CSF was sampled at catheter insertion (2-26 h after injury) and at intervals of 24, 48, and 72 h thereafter. Control samples were obtained from patients undergoing spinal anesthesia (ASA1). CSF levels of cytochrome c and activated caspase-9 were measured using ELISA. RESULTS: Cytochrome c was detected in 18 (51.4%) samples, in the range of 0.08-5 ng/ml; mean value for cytochrome c was 0.44 ng/ml (SD +/- 0.632). Activated caspase-9 was detected in 10 samples (28.6%); mean value was 0.28 ng/ml (SD +/- 0.39). R (s) between cytochrome c and Glasgow outcome score (GOS) was -0.25 (P = 0.14), and between GOS and activated caspase-9 was -0.35 (P = 0.04). R calculated based on linear regression of activated caspase-9 and cytochrome c concentrations was 0.18. Control CSF samples had no detectable levels of either marker (detection level for cytochrome c was 0.08 ng/ml and 0.20 for activated caspase-9). CONCLUSIONS: We concluded that activated caspase-9 and cytochrome c are present in the CSF of patients with severe TBI. Activated caspase-9 shows weak correlation with poor neurologic outcome.

Experimental model of brainstem stroke in rabbits via endovascular occlusion of the basilar artery.

BACKGROUND: Basilar artery thrombosis remains a significant clinical problem, and no reproducible animal model has been established to study the stroke within the vertebrobasilar distribution. We report a study designed to pilot test a novel model of brainstem stroke in rabbits, created by selective endovascular occlusion of the basilar artery. METHODS: Basilar artery occlusion was induced in 8 New Zealand white rabbits by injection of the autologous clot through the microcatheter positioned within the distal vertebral artery. Animals were divided into subgroups (I and II) based on the length of produced ischemia (3 and 6 hours, respectively). Magnetic resonance (MR) imaging of the brain and MR angiography of the intracranial vessels were performed before the procedure, and at 3 hours after induced ischemia for groups I and II, with continued imaging up to 6 hours for group II, with diffusion-weighted images acquired approximately every 30 minutes. Animals were killed at the end of the 3-hour (group I) or 6-hour (group II) ischemia time. RESULTS: Brainstem stroke was successfully induced in all animals, with pathological changes documented in all cases. The earliest changes of ischemia on MR diffusion-weighted images were identified at only 4.5 hours of basilar artery occlusion. CONCLUSION: These results suggest that a reproducible model of brainstem stroke can be induced in rabbits using selective endovascular occlusion of the basilar artery. The availability of such a model, integrated with state-of-the-art imaging techniques, holds promise for preclinical investigations of emergent therapeutic approaches in stroke.

Role of transcranial Doppler in optimizing treatment of cerebral vasospasm in subarachnoid hemorrhage.

This study was undertaken to evaluate the role of transcranial Doppler ultrasonography in arterial blood pressure management during hypervolemia/hypertension/ hemodilution therapy in patients with vasospasm from subarachnoid hemorrhage and correlate this data with neurologic outcome. The study included 18 adult patients, Hunt and Hess grades III-IV. Complete neurologic assessment was performed. Transcranial Doppler indices were calculated by standard formulas. On the basis of our results, resistance area product can be used to estimate the optimal arterial blood pressure in hypervolemia/hypertension/hemodilution therapy. An increase in the cerebral blood flow index was associated with better performance on neurologic examination. Estimated cerebral perfusion pressure from transcranial Doppler data analysis showed poor correlation with cerebral perfusion pressure derived from direct measurement of intracranial pressure in patients with cerebral vasospasm (rho = 0.15; 95% CI, 0.11-0.39; P = .2590).

Nitrotyrosine as an oxidative stress marker: evidence for involvement in neurologic outcome in human traumatic brain injury.

BACKGROUND: Oxidative stress has been indicated as a mechanism of secondary neuronal injury in traumatic brain injury (TBI). Nitrotyrosine in the cerebrospinal fluid (CSF) may be an in vivo marker of oxidative nitric oxide damage. We tested the hypothesis that increased levels of nitrotyrosine correlate with poor neurologic outcomes in patients with TBI and attempted to identify the source of increased CSF nitrotyrosine. METHODS: This institutional-review-board-approved study included 10 adults with severe closed TBI (Glasgow Coma Scale score <8) and no documented hypoxic brain injury. These patients underwent routine evaluation and, when indicated, placement of an intraventricular catheter. CSF samples (n = 27) were collected 2 to 72 hours after TBI and were also obtained from four healthy individuals. Nitrotyrosine levels were measured, and immunohistochemistry was performed. Neurologic follow-up extended to 1 month after injury. RESULTS: Nitrotyrosine was not detected in the control samples but was detected in 13 CSF samples from 7 TBI patients (range, 22.4-97.6 nM/mL). Seven patients had poor outcomes, and, in each, nitrotyrosine was detected. Nitrotyrosine immunoreactivity was detected in neurons and glia and confirmed in brain homogenate. CONCLUSION: Oxidative stress contributes to secondary brain injury in patients with TBI. Poor neurologic outcome is associated with increased levels of nitrotyrosine in the CSF. Identifying patients or the stage at which oxidative stress is more active using CSF markers of oxidative injury may help in the development of more targeted treatments.

Expression of cellular FLICE inhibitory proteins (cFLIP) in normal and traumatic murine and human cerebral cortex.

Cellular Fas-associated death domain-like interleukin-1-beta converting enzyme (FLICE) inhibitory proteins (cFLIPs) are endogenous caspase homologues that inhibit programmed cell death. We hypothesized that cFLIPs are differentially expressed in response to traumatic brain injury (TBI). cFLIP-alpha and cFLIP-delta mRNA were expressed in normal mouse brain-specifically cFLIP-delta (but not cFLIP-alpha) protein was robustly expressed. After controlled cortical impact (CCI), cFLIP-alpha expression increased initially then decreased to control levels at 12 h, increasing again at 24-72 h (P<0.05). cFLIP-delta expression was decreased in brain homogenates by 12 h after CCI, then increased again at 24 to 72 h (P<0.05). cFLIP-delta immunostaining was markedly reduced in injured cortex, but not hippocampus, at 3 to 72 h after CCI. In cortex, reduced cFLIP-delta staining was found in TUNEL-positive cells, but in hippocampus TUNEL-positive cells expressed cFLIP-delta immunoreactivity. cFLIP-delta was increased in a subset of reactive astrocytes in pericontusional cortex and hippocampus at 48 to 72 h. Low levels of both cFLIP isoforms were detected in human cortical tissue with no TBI, from four patients undergoing brain surgery for epilepsy and <24 h post mortem from three patients without CNS pathologic assessment. In cortical tissue surgically removed <18 h after severe TBI (n=3), cFLIP-alpha expression was increased relative to epilepsy controls (P<0.05) but not relative to post-mortem controls. The data suggest differential spatial and temporal regulation of cFLIP-alpha and cFLIP-delta expression that may influence the magnitude of cell death and further implicate programmed mechanisms of cell death after TBI.

Upregulation of the Fas receptor death-inducing signaling complex after traumatic brain injury in mice and humans.

Recent studies have implicated Fas in the pathogenesis of inflammatory, ischemic, and traumatic brain injury (TBI); however, a direct link between Fas activation and caspase-mediated cell death has not been established in injured brain. We detected Fas-Fas ligand binding and assembly of death-inducing signaling complexes (DISCs) [Fas, Fas-associated protein with death domain, and procaspase-8 or procaspase-10; receptor interacting protein (RIP)-RIP-associated interleukin-1beta converting enzyme and CED-3 homolog-1/Ced 3 homologous protein with a death domain-procaspase-2] by immunoprecipitation and immunoblotting within mouse parietal cortex after controlled cortical impact. At the time of DISC assembly, procaspase-8 was cleaved and the cleavage product appeared at 48 hr in terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling-positive neurons. Cleavage of caspase-8 was accompanied by caspase-3 processing detected at 48 hr by immunohistochemistry, and by caspase-specific cleavage of poly(ADP-ribose) polymerase at 12 hr. Fas pathways were also stimulated by TBI in human brain, because Fas expression plus Fas-procaspase-8 interaction were robust in contused cortical tissue samples surgically removed between 2 and 30 hr after injury. To address whether Fas functions as a death receptor in brain cells, cultured embryonic day 17 cortical neurons were transfected with an adenoviral vector containing the gene encoding Fas ligand. After 48 hr in culture, Fas ligand expression and Fas-procaspase-8 DISC assembly increased, and by 72 hr, cell death was pronounced. Cell death was decreased by approximately 50% after pan-caspase inhibition (Z-Val-ALa-Asp(Ome)-fluoromethylketone). These data suggest that Fas-associated DISCs assemble in neurons overexpressing Fas ligand as well as within mouse and human contused brain after TBI. Therefore, Fas may function as a death receptor after brain injury.