Simon J. Finney

Referral to an Extracorporeal Membrane Oxygenation Center and Mortality Among Patients With Severe 2009 Influenza A(H1N1)

CONTEXT Extracorporeal membrane oxygenation (ECMO) can support gas exchange in patients with severe acute respiratory distress syndrome (ARDS), but its role has remained controversial. ECMO was used to treat patients with ARDS during the 2009 influenza A(H1N1) pandemic. OBJECTIVE To compare the hospital mortality of patients with H1N1-related ARDS referred, accepted, and transferred for ECMO with matched patients who were not referred for ECMO. DESIGN, SETTING, AND PATIENTS A cohort study in which ECMO-referred patients were defined as all patients with H1N1-related ARDS who were referred, accepted, and transferred to 1 of the 4 adult ECMO centers in the United Kingdom during the H1N1 pandemic in winter 2009-2010. The ECMO-referred patients and the non-ECMO-referred patients were matched using data from a concurrent, longitudinal cohort study (Swine Flu Triage study) of critically ill patients with suspected or confirmed H1N1. Detailed demographic, physiological, and comorbidity data were used in 3 different matching techniques (individual matching, propensity score matching, and GenMatch matching). MAIN OUTCOME MEASURE Survival to hospital discharge analyzed according to the intention-to-treat principle. RESULTS Of 80 ECMO-referred patients, 69 received ECMO (86.3%) and 22 died (27.5%) prior to discharge from the hospital. From a pool of 1756 patients, there were 59 matched pairs of ECMO-referred patients and non-ECMO-referred patients identified using individual matching, 75 matched pairs identified using propensity score matching, and 75 matched pairs identified using GenMatch matching. The hospital mortality rate was 23.7% for ECMO-referred patients vs 52.5% for non-ECMO-referred patients (relative risk [RR], 0.45 [95% CI, 0.26-0.79]; P = .006) when individual matching was used; 24.0% vs 46.7%, respectively (RR, 0.51 [95% CI, 0.31-0.81]; P = .008) when propensity score matching was used; and 24.0% vs 50.7%, respectively (RR, 0.47 [95% CI, 0.31-0.72]; P = .001) when GenMatch matching was used. The results were robust to sensitivity analyses, including amending the inclusion criteria and restricting the location where the non-ECMO-referred patients were treated. CONCLUSION For patients with H1N1-related ARDS, referral and transfer to an ECMO center was associated with lower hospital mortality compared with matched non-ECMO-referred patients.

Pulmonary vascular and right ventricular dysfunction in adult critical care: current and emerging options for management: a systematic literature review

IntroductionPulmonary vascular dysfunction, pulmonary hypertension (PH), and resulting right ventricular (RV) failure occur in many critical illnesses and may be associated with a worse prognosis. PH and RV failure may be difficult to manage: principles include maintenance of appropriate RV preload, augmentation of RV function, and reduction of RV afterload by lowering pulmonary vascular resistance (PVR). We therefore provide a detailed update on the management of PH and RV failure in adult critical care.MethodsA systematic review was performed, based on a search of the literature from 1980 to 2010, by using prespecified search terms. Relevant studies were subjected to analysis based on the GRADE method.ResultsClinical studies of intensive care management of pulmonary vascular dysfunction were identified, describing volume therapy, vasopressors, sympathetic inotropes, inodilators, levosimendan, pulmonary vasodilators, and mechanical devices. The following GRADE recommendations (evidence level) are made in patients with pulmonary vascular dysfunction: 1) A weak recommendation (very-low-quality evidence) is made that close monitoring of the RV is advised as volume loading may worsen RV performance; 2) A weak recommendation (low-quality evidence) is made that low-dose norepinephrine is an effective pressor in these patients; and that 3) low-dose vasopressin may be useful to manage patients with resistant vasodilatory shock. 4) A weak recommendation (low-moderate quality evidence) is made that low-dose dobutamine improves RV function in pulmonary vascular dysfunction. 5) A strong recommendation (moderate-quality evidence) is made that phosphodiesterase type III inhibitors reduce PVR and improve RV function, although hypotension is frequent. 6) A weak recommendation (low-quality evidence) is made that levosimendan may be useful for short-term improvements in RV performance. 7) A strong recommendation (moderate-quality evidence) is made that pulmonary vasodilators reduce PVR and improve RV function, notably in pulmonary vascular dysfunction after cardiac surgery, and that the side-effect profile is reduced by using inhaled rather than systemic agents. 8) A weak recommendation (very-low-quality evidence) is made that mechanical therapies may be useful rescue therapies in some settings of pulmonary vascular dysfunction awaiting definitive therapy.ConclusionsThis systematic review highlights that although some recommendations can be made to guide the critical care management of pulmonary vascular and right ventricular dysfunction, within the limitations of this review and the GRADE methodology, the quality of the evidence base is generally low, and further high-quality research is needed.

Specific C-Terminal Cleavage and Inactivation of Interleukin-8 by Invasive Disease Isolates of Streptococcus pyogenes

Lethal necrotizing fasciitis caused by Streptococcus pyogenes is characterized by a paucity of neutrophils at the site of infection. Interleukin (IL)-8, which is important for neutrophil transmigration and activation, can be degraded by S. pyogenes. Blood isolates of S. pyogenes were better able to degrade human IL-8 than throat isolates. Degradation of IL-8 was the result of a single specific cleavage between 59glutamine and 60arginine within the IL-8 C-terminal alpha helix. Cleaved IL-8 reduced neutrophil activation and migration. IL-8-cleaving activity was found in partially purified supernatant of a necrotizing fasciitis isolate, and this activity was associated with an approximately 150-kDa fraction containing S. pyogenes cell envelope proteinase (SpyCEP). IL-8-cleaving activity corresponded with the presence of SpyCEP in the supernatant. Cleavage of IL-8 by S. pyogenes represents an unprecedented mechanism of immune evasion, effectively preventing IL-8 C-terminus-mediated endothelial translocation and subsequent recruitment of neutrophils.

Acute kidney injury after cardiac surgery according to Risk/Injury/Failure/Loss/End-stage, Acute Kidney Injury Network, and Kidney Disease: Improving Global Outcomes classifications

PURPOSE The epidemiology of acute kidney injury (AKI) after cardiac surgery depends on the definition used. Our aims were to evaluate the Risk/Injury/Failure/Loss/End-stage (RIFLE) criteria, the AKI Network (AKIN) classification, and the Kidney Disease: Improving Global Outcomes (KDIGO) classification for AKI post-cardiac surgery and to compare the outcome of patients on renal replacement therapy (RRT) with historical data. METHODS Retrospective analysis of 1881 adults who had cardiac surgery between May 2006 and April 2008 and determination of the maximum AKI stage according to the AKIN, RIFLE, and KDIGO classifications. RESULTS The incidence of AKI using the AKIN and RIFLE criteria was 25.9% and 24.9%, respectively, but individual patients were classified differently. The area under the receiver operating characteristic curve for hospital mortality was significantly higher using the AKIN compared with the RIFLE criteria (0.86 vs 0.78, P = .0009). Incidence and outcome of AKI according to the AKIN and KDIGO classification were identical. The percentage of patients who received RRT was 6.2% compared with 2.7% in 1989 to 1990. The associated hospital mortality fell from 82.9% in 1989 to 1990 to 15.6% in 2006 to 2008. CONCLUSIONS The AKIN classification correlated better with mortality than did the RIFLE criteria. Mortality of patients needing RRT after cardiac surgery has improved significantly during the last 20 years.

Bench-to-bedside review: Sepsis, severe sepsis and septic shock – does the nature of the infecting organism matter?

International guidelines concerning the management of patients with sepsis, septic shock and multiple organ failure make no reference to the nature of the infecting organism. Indeed, most clinical signs of sepsis are nonspecific. In contrast, in vitro data suggest that there are mechanistic differences between bacterial, viral and fungal sepsis, and imply that pathogenetic differences may exist between subclasses such as Gram-negative and Gram-positive bacteria. These differences are reflected in different cytokine profiles and mortality rates associated with Gram-positive and Gram-negative sepsis in humans. They also suggest that putative anti-mediator therapies may act differently according to the nature of an infecting organism. Data from some clinical trials conducted in severe sepsis support this hypothesis. It is likely that potential new therapies targeting, for example, Toll-like receptor pathways will require knowledge of the infecting organism. The advent of new technologies that accelerate the identification of infectious agents and their antimicrobial sensitivities may allow better tailored anti-mediator therapies and administration of antibiotics with narrow spectra and known efficacy.

Pathophysiology of pulmonary hypertension in acute lung injury

Acute lung injury (ALI) and acute respiratory distress syndrome are characterized by protein rich alveolar edema, reduced lung compliance, and acute severe hypoxemia. A degree of pulmonary hypertension (PH) is also characteristic, higher levels of which are associated with increased morbidity and mortality. The increase in right ventricular (RV) afterload causes RV dysfunction and failure in some patients, with associated adverse effects on oxygen delivery. Although the introduction of lung protective ventilation strategies has probably reduced the severity of PH in ALI, a recent invasive hemodynamic analysis suggests that even in the modern era, its presence remains clinically important. We therefore sought to summarize current knowledge of the pathophysiology of PH in ALI.

Sepsis since the discovery of Toll-like receptors: disease concepts and therapeutic opportunities.

Objective:Sepsis and its sequelae are the leading cause of death in critically ill patients. Discovery in the late 1990s of Toll-like receptors as primary sensors of microbial infection led to significant advances in understanding the pathogenesis of sepsis, including emerging differences between Gram-positive and Gram-negative infection and the potential for the manipulation of Toll-like receptors for the treatment of sepsis. This review describes these advances. Methods:Bibliographic search of the literature since 1999, with particular emphasis on the conceptual and therapeutic implications of Toll-like receptors for patients with systemic sepsis. Results and Conclusions:Toll-like receptors initiate the inflammatory processes that underlie the clinical response to infection and therefore represent an important putative target for therapeutic intervention.

Severe sepsis and Toll-like receptors

Severe sepsis dominates the mortality of non-cardiac intensive care units. The ingenious Toll-like receptor (TLR) system can recognise many infectious organisms through relatively few receptors to trigger pro-inflammatory and anti-inflammatory cytokine release. Further complexity arises from positive and negative signalling feedback loops. Severe sepsis may be a consequence of an inappropriately excessive response or inadequate endogenous negative feedback. Therapies targeting these pathways are currently being evaluated. Alternatively, in clinical scenarios such as compensatory anti-inflammatory response syndrome, chronic viral sepsis or inadequate vaccine function, TLR signalling may be inadequate. TLR agonists may augment the innate response and are being investigated.

Arterial carboxyhemoglobin level and outcome in critically ill patients.

Objective:Arterial carboxyhemoglobin is elevated in patients with critical illness. It is an indicator of the endogenous production of carbon monoxide by the enzyme heme oxygenase, which modulates the response to oxidant stress. The objective was to explore the hypothesis that arterial carboxyhemoglobin level is associated with inflammation and survival in patients requiring cardiothoracic intensive care. Design:Prospective, observational study. Setting:A cardiothoracic intensive care unit. Patients:All patients admitted over a 15-month period. Interventions:None. Measurements and Main Results:Arterial carboxyhemoglobin, bilirubin, and standard biochemical, hematologic, and physiologic markers of inflammation were measured in 1,267 patients. Associations were sought between levels of arterial carboxyhemoglobin, markers of the inflammatory response, and clinical outcome. Intensive care unit mortality was associated with lower minimum and greater maximal carboxyhemoglobin levels (p < .0001 and p < .001, respectively). After adjustment for age, gender, illness severity, and other relevant variables, a lower minimum arterial carboxyhemoglobin was associated with an increased risk of death from all causes (odds risk of death, 0.391; 95% confidence interval, 0.190–0.807; p = .011). Arterial carboxyhemoglobin correlated with markers of the inflammatory response. Conclusions:Both low minimum and high maximum levels of arterial carboxyhemoglobin were associated with increased intensive care mortality. Although the heme oxygenase system is protective, excessive induction may be deleterious. This suggests that there may be an optimal range for heme oxygenase-1 induction.

A modified technique for insertion of dual lumen bicaval cannulae for venovenous extracorporeal membrane oxygenation

PurposeVenovenous extracorporeal membrane oxygenation is used increasingly in adults with severe acute reversible respiratory failure. Cannulation is associated with a risk of vascular damage or cardiac perforation.Methods and resultsThis report describes a modified technique of insertion for dual lumen bicaval cannulae. We have adopted the technique on 25 occasions and had no incidence of vascular damage or cardiac perforation.ConclusionWe suggest that the technique may mitigate the risk of guidewire looping during insertion of the dilators/cannula and thereby reduce the risk of perforation of the right ventricle.