Deficient mitochondrial biogenesis in critical illness: cause, effect, or epiphenomenon?

Recent studies indicate that mitochondrial dysfunction plays a role in the pathogenesis of a number of disease states. The importance of these organelles in shock and multiple organ dysfunction is of particular interest to those caring for the critically ill. Mitochondria have their own unique DNA (mtDNA) that encodes 13 essential subunits of electron transport chain enzymes, two ribosomal RNAs and 22 transfer RNAs. Importantly, mtDNA is especially susceptible to deletions, rearrangements and mutations because it is not bound by histones and lacks the extensive repair machinery present in the nucleus. The study by Côté et al. in this issue of Critical Care examines changes in mtDNA in critically ill patients. The results support further investigation into the role of mtDNA in the critically ill

Multisociety Task Force For Critical Care Research: Key issues and recommendations: Executive summary

Background: Research in critical care extends from the bench to the bedside, involving multiple departments, specialties, and funding organizations. Because of this diversity, it has been difficult for all stakeholders to collectively identify challenges and establish priorities

Chronic hypoxemia increases myocardial cytochrome oxidase

ObjectiveCyanotic patients have potentially decreased tissue oxygen tension. Cytochrome oxidase catalyzes the reduction of oxygen and is integral to adenosine triphosphate production. Cytochrome oxidase subunit I, the active site, is encoded by mitochondrial DNA. Using a newborn swine model of chronic hypoxemia, we evaluated ventricular cytochrome oxidase subunit I mRNA and protein expression and assessed cytochrome oxidase activity.MethodsThirty-two newborn piglets underwent thoracotomy and placement of a pulmonary artery–to–left atrium shunt or sham operation. Two weeks later, partial pressure of arterial oxygen, hematocrit, and left ventricular shortening fraction values were compared with baseline values. Northern blot hybridization and protein immunoblotting for ventricular cytochrome oxidase subunit I were performed. Cytochrome oxidase kinetic activity was measured. Heme a,a3 content and turnover number were determined. Significance was assessed with a t test.ResultsBaseline partial pressure of arterial oxygen and hematocrit values were similar. Hypoxemic piglets had a lower partial pressure of arterial oxygen of 38 ± 10 mm Hg (P < .001) and higher hematocrit value of 31.4% ± 2.9% (P < .001) compared with a partial pressure of arterial oxygen of 140 ± 47 mm Hg and hematocrit value of 24.6% ± 3.9% after the sham operation. Baseline and postprocedure left ventricular shortening fraction were similar within and between groups. Chronic hypoxemia increased right ventricular and left ventricular cytochrome oxidase I mRNA and protein by more than 1.4-fold. Cytochrome oxidase activity increased significantly in hypoxemia by 2.5-fold compared with that seen after the sham operation. Heme a,a3 content and turnover number increased by 1.5-fold during hypoxemia.ConclusionsChronic hypoxemia increases cytochrome oxidase I message, protein expression, and activity. The increase in kinetics was due to increased enzyme content and catalytic activity. This is a possible adaptive mechanism that might preserve organ function during chronic hypoxemia

Enhanced Hsp70 Expression Protects against Acute Lung Injury by Modulating Apoptotic Pathways

The Acute respiratory distress syndrome (ARDS) is a highly lethal inflammatory lung disorder. Apoptosis plays a key role in its pathogenesis. We showed that an adenovirus expressing the 70 kDa heat shock protein Hsp70 (AdHSP) protected against sepsis-induced lung injury. In this study we tested the hypothesis that AdHSP attenuates apoptosis in sepsis-induced lung injury

Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock, 2012

OBJECTIVE: To provide an update to the "Surviving Sepsis Campaign Guidelines for Management of Severe Sepsis and Septic Shock," last published in 2008. DESIGN: A consensus committee of 68 international experts representing 30 international organizations was convened. Nominal groups were assembled at key international meetings (for those committee members attending the conference). A formal conflict of interest policy was developed at the onset of the process and enforced throughout. The entire guidelines process was conducted independent of any industry funding. A stand-alone meeting was held for all subgroup heads, co- and vice-chairs, and selected individuals. Teleconferences and electronic-based discussion among subgroups and among the entire committee served as an integral part of the development. METHODS: The authors were advised to follow the principles of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system to guide assessment of quality of evidence from high (A) to very low (D) and to determine the strength of recommendations as strong (1) or weak (2). The potential drawbacks of making strong recommendations in the presence of low-quality evidence were emphasized. Recommendations were classified into three groups: (1) those directly targeting severe sepsis; (2) those targeting general care of the critically ill patient and considered high priority in severe sepsis; and (3) pediatric considerations. RESULTS: Key recommendations and suggestions, listed by category, include: early quantitative resuscitation of the septic patient during the first 6 h after recognition (1C); blood cultures before antibiotic therapy (1C); imaging studies performed promptly to confirm a potential source of infection (UG); administration of broad-spectrum antimicrobials therapy within 1 h of the recognition of septic shock (1B) and severe sepsis without septic shock (1C) as the goal of therapy; reassessment of antimicrobial therapy daily for de-escalation, when appropriate (1B); infection source control with attention to the balance of risks and benefits of the chosen method within 12 h of diagnosis (1C); initial fluid resuscitation with crystalloid (1B) and consideration of the addition of albumin in patients who continue to require substantial amounts of crystalloid to maintain adequate mean arterial pressure (2C) and the avoidance of hetastarch formulations (1B); initial fluid challenge in patients with sepsis-induced tissue hypoperfusion and suspicion of hypovolemia to achieve a minimum of 30 mL/kg of crystalloids (more rapid administration and greater amounts of fluid may be needed in some patients (1C); fluid challenge technique continued as long as hemodynamic improvement is based on either dynamic or static variables (UG); norepinephrine as the first-choice vasopressor to maintain mean arterial pressure ≥65 mmHg (1B); epinephrine when an additional agent is needed to maintain adequate blood pressure (2B); vasopressin (0.03 U/min) can be added to norepinephrine to either raise mean arterial pressure to target or to decrease norepinephrine dose but should not be used as the initial vasopressor (UG); dopamine is not recommended except in highly selected circumstances (2C); dobutamine infusion administered or added to vasopressor in the presence of (a) myocardial dysfunction as suggested by elevated cardiac filling pressures and low cardiac output, or (b) ongoing signs of hypoperfusion despite achieving adequate intravascular volume and adequate mean arterial pressure (1C); avoiding use of intravenous hydrocortisone in adult septic shock patients if adequate fluid resuscitation and vasopressor therapy are able to restore hemodynamic stability (2C); hemoglobin target of 7-9 g/dL in the absence of tissue hypoperfusion, ischemic coronary artery disease, or acute hemorrhage (1B); low tidal volume (1A) and limitation of inspiratory plateau pressure (1B) for acute respiratory distress syndrome (ARDS); application of at least a minimal amount of positive end-expiratory pressure (PEEP) in ARDS (1B); higher rather than lower level of PEEP for patients with sepsis-induced moderate or severe ARDS (2C); recruitment maneuvers in sepsis patients with severe refractory hypoxemia due to ARDS (2C); prone positioning in sepsis-induced ARDS patients with a PaO (2)/FiO (2) ratio of ≤100 mm Hg in facilities that have experience with such practices (2C); head-of-bed elevation in mechanically ventilated patients unless contraindicated (1B); a conservative fluid strategy for patients with established ARDS who do not have evidence of tissue hypoperfusion (1C); protocols for weaning and sedation (1A); minimizing use of either intermittent bolus sedation or continuous infusion sedation targeting specific titration endpoints (1B); avoidance of neuromuscular blockers if possible in the septic patient without ARDS (1C); a short course of neuromuscular blocker (no longer than 48 h) for patients with early ARDS and a PaO (2)/FI O (2) 180 mg/dL, targeting an upper blood glucose ≤180 mg/dL (1A); equivalency of continuous veno-venous hemofiltration or intermittent hemodialysis (2B); prophylaxis for deep vein thrombosis (1B); use of stress ulcer prophylaxis to prevent upper gastrointestinal bleeding in patients with bleeding risk factors (1B); oral or enteral (if necessary) feedings, as tolerated, rather than either complete fasting or provision of only intravenous glucose within the first 48 h after a diagnosis of severe sepsis/septic shock (2C); and addressing goals of care, including treatment plans and end-of-life planning (as appropriate) (1B), as early as feasible, but within 72 h of intensive care unit admission (2C). Recommendations specific to pediatric severe sepsis include: therapy with face mask oxygen, high flow nasal cannula oxygen, or nasopharyngeal continuous PEEP in the presence of respiratory distress and hypoxemia (2C), use of physical examination therapeutic endpoints such as capillary refill (2C); for septic shock associated with hypovolemia, the use of crystalloids or albumin to deliver a bolus of 20 mL/kg of crystalloids (or albumin equivalent) over 5-10 min (2C); more common use of inotropes and vasodilators for low cardiac output septic shock associated with elevated systemic vascular resistance (2C); and use of hydrocortisone only in children with suspected or proven "absolute"' adrenal insufficiency (2C). CONCLUSIONS: Strong agreement existed among a large cohort of international experts regarding many level 1 recommendations for the best care of patients with severe sepsis. Although a significant number of aspects of care have relatively weak support, evidence-based recommendations regarding the acute management of sepsis and septic shock are the foundation of improved outcomes for this important group of critically ill patients