Tag Archives: Basic and Translational Research

Effects of Epinephrine on Cerebral Oxygenation during CPR

Epinephrine has been presumed to improve cerebral oxygen delivery during cardiopulmonary resuscitation (CPR), but animal and registry studies suggest that epinephrine-induced capillary vasoconstriction may decrease cerebral capillary blood flow and worsen neurological outcome. The effect of epinephrine on cerebral oxygenation during CPR has not been documented in the clinical setting. Therefore, Deakin et al examined the effect of epinephrine on cerebral brain oxygenation during in-hospital cardiac arrest.

They found that 1 mg intravenous epinephrine, administered during advanced life support resuscitation, was not associated with a clinically significant change in cerebral tissue oxygenation.

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Cellular Mechanisms of Prevention of Ischemia-Reperfusion Injury

Ischemic preconditioning is the phenomenon whereby brief periods of sublethal ischemia protect against a subsequent, more prolonged, ischemic insult. In remote ischemic preconditioning, ischemia to one organ protects other organs at a distance. Olenchock et al created mouse models to ask if inhibition of the alpha-ketoglutarate-dependent dioxygenase Egln1, which senses oxygen and regulates the hypoxia-inducible factor transcription factor, could suffice to mediate local and remote ischemic preconditioning.

Using somatic gene deletion and a pharmacological inhibitor, they found that inhibiting Egln1 systemically or in skeletal muscles protects mice against myocardial ischemia-reperfusion injury.

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Dysbiosis Across Multiple Body Sites in Critically Ill Adult Surgical Patients

Current evidence suggests that symbiosis of commensal microflora play a significant role in health and illness. The effect that commensal microflora play in critical care is less well known. Yeh et al set out to assess the dynamics of colonization of critically ill surgical and trauma patients. The authors examined 32 critically ill surgical and trauma patients in a major tertiary care intensive care unit (ICU) and collected information on bacterial colonization at gastrointestinal, tracheal, urinary, oral, and skin sites.

Over the course of the study (and in comparison to healthy controls) colonization in the ICU group showed a decrease in diversity of microflora across multiple sites and a change in colonization from non-pathogenic to pathogenic bacteria.

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Chronic Hypoxemia in Children with CHD Mars Airway Epithelial Na+ Transport

Ambient hypoxia impairs the airway epithelial Na+ transport, which is crucial in lung edema reabsorption. Whether chronic systemic hypoxemia affects airway Na+ transport has remained largely unknown. Kaskinen et al have therefore investigated whether chronic systemic hypoxemia in children with congenital heart defect affects airway epithelial Na+ transport, Na+ transporter-gene expression, and short-term lung edema accumulation.

They found that the impaired airway epithelial amiloride-sensitive Na+ transport activity in profoundly hypoxemic children with cyanotic congenital heart defect may hinder defense against lung edema after cardiac surgery.

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Can Changes in Plasma Glycoproteins Predict Mortality in Severe Sepsis?

Sepsis remains a major cause of mortality in the intensive care unit. Numerous studies have attempted to elucidate the exact pathophysiology of sepsis at the cellular level, including identifying specific proteins in common pathways associated with survival. Although prior studies have had promising but limited success, the recent development and utilization of advanced genomic and proteomic databases have yielded intriguing findings that may link particular proteins and mechanisms to sepsis mortality. DeCoux et al used glycoprotein analysis to determine whether changes in plasma glycoproteins may predict mortality in severe sepsis.

This study ultimately identified proteins linked to patient outcomes and provided insight into unexplored mechanisms that can be investigated for the identification of novel therapeutic targets.

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GCR Expression in Critically Ill Children with Cardiovascular Dysfunction

Various efforts have been made to better understand the interplay of glucocorticoid receptor (GCR) expression and critical illness, but many unknowns remain. Shibata et al hypothesized that a subset of critically ill children with cardiovascular (CV) collapse would demonstrate decreased expression of GCR and would have more severe illness (based on Pediatric Risk of Mortality [PRISM] III measurements) and more organ failure than critically ill children with no CV collapse.

In a comparison of these two groups, the investigators discovered a statistically significant decrease in GCR expression in CD4+ and CD8+ cells in critically ill children with CV failure. They also discovered that this diminished expression could be found in patients with higher PRISM III scores and those with greater organ failure burden. Ultimately, this study’s findings suggest that the lack of GCR expression in critically ill patients could serve as a risk factor for worsening severity of illness and CV failure.

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Examining the Efficacy of L-citrulline Supplementation

Chronic lung disease in neonates and infants can lead to progressive hypoxia-induced pulmonary hypertension. The development of pulmonary hypertension has been associated with increasing mortality in certain infants, and the therapies available are inadequate. Fike et al set out to determine whether starting L-citrulline (in newborn piglets) after the onset of pulmonary hypertension inhibits disease progression and improves nitric oxide production by recoupling endothelial nitric oxide synthase.

The authors found that oral L-citrulline treatment started after disease onset improves nitric oxide production by recoupling endothelial nitric oxide synthase and inhibits the further development of chronic hypoxia-induced pulmonary hypertension in this piglet model. This is an important translational study with novel treatment implications. Some clinical studies have already been done using prophylactic L-citrulline supplementation. However, more work using the supplement after the physiologic insult has occurred are clearly needed, and this study provides a strong background for further investigation.

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Mitochondrial Defects in PBMCs of Children with Sepsis

Mitochondrial dysfunction has been implicated in the pathogenesis of organ injury related to the sepsis syndrome. This can be seen in the condition known as cytopathic hypoxia, wherein oxygen delivery is maintained, but the mitochondria are unable to efficiently convert this delivered oxygen to adenosine triphosphate (ATP) production. An energy deficit consequently arises. In adults, this diminished ability to produce adequate ATP has been demonstrated in peripheral blood mononuclear cells (PBMCs) of septic patients. Mitochondrial defects in PBMCs of septic children have not been previously described. Weiss et al sought to correlate defects in mitochondrial oxygen consumption and mitochondrial membrane potential in the PBMCs of children with septic shock of clinical severity. Twenty-eight children with septic shock were approached for consent. Ultimately, data from 13 patients were compared to those of 11 control subjects.

The authors found that mitochondrial dysfunction occurs in PBMCs from critically ill children with septic shock and multiple organ dysfunction syndrome. While this study has limitations related to the choice of cells studied, the timing of sampling and the numbers of patients, mitochondrial dysfunction in these patients is a significant finding that warrants further research.

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Reduced Microstrain and Improved Alveolar Recruitment Using APRV

Ventilator-induced lung injury (VILI) exacerbates acute lung injury by causing additional atelectrauma and volutrauma at the microanatomical level. Kollisch-Singule and colleagues designed a randomized, nonblinded laboratory animal study to investigate alveolar microstrain of subpleural alveoli during dynamic inflation and deflation. The authors hypothesized that airway pressure release ventilation (APRV), with a prolonged plateau pressure (Phigh) and minimal time at end-expiratory release pressure (Plow), would minimize microstrain.

The authors found that an APRV termination of peak expiratory flow rate to peak expiratory flow rate ratio of 75% resulted in significantly less alveolar microstrain and improved alveolar recruitment. The methodology established in this study will likely prove useful in future large animal and clinical studies designed to investigate the optimal mechanical breath profiles for the prevention of VILI.

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Nitric Oxide Synthase: Key Factor for Vascular Dysfunction in Sepsis

Previous experimental work has demonstrated that excessive nitric oxide (NO) is produced during sepsis and is a key mechanism for vascular dysfunction. The amount of NO produced appears to be directly related to hypotension and decreased responsiveness to vasoconstrictors. Three nitric oxide synthase (NOS) isoforms may contribute to hypotension during sepsis, but most studies suggest that the majority of NO is produced by nitric oxide synthase 2 (NOS-2). Nardi and colleagues sought to define the contribution of nitric oxide synthase 1 (NOS-1) and its relationship with the main vascular effector of NO, soluble guanylate cyclase (sGC), in an animal model of sepsis.

The investigators found that NO production by NOS-1 has an important role in sepsis-induced vascular dysfunction. Limitations of this study include the nature of the sepsis model and the fact that the NOS-1 and sGC association was established only in smooth muscle.  This work may some day be clinically relevant for septic patients with refractory hypotension if the results can be replicated in humans.

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What Effect Do Corticosteroids Have on the Genomic Response of Pediatric Septic Shock?

The use of steroids in patients with inotrope/pressor–resistant septic shock is controversial in both adult and pediatric populations. While these patients’ hemodynamics may improve with adjunctive steroid treatment, the metabolic and immune costs may negate a definitive survival benefit. However, little has been written about the effects glucocorticoids have on global gene expression in patients with septic shock. Wong and colleagues address this topic by using a transcriptomics approach to characterize the genomic response of pediatric patients in septic shock who have received glucocorticoids. They found that the administration of corticosteroids in pediatric septic shock is associated with additional repression of genes corresponding to adaptive immunity. They did not comment on actual immune suppression, though, as qualitative evaluations of immunity were not performed.

Ultimately, steroid use in catecholamine-resistant septic shock — even in seemingly low doses — can have significant consequences in a patient’s ability to fight an initial infection or even subsequent nosocomial infections unrelated to the patient’s illness severity or infecting organism. This fact, coupled with the absence of definitive outcome benefits, should give pediatric critical care practitioners pause before prescribing steroids in children with septic shock.

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