Contemporary Management of Cardiogenic Shock: A RAND Appropriateness Panel Approach.

BACKGROUND: Current practice in cardiogenic shock is guided by expert opinion in guidelines and scientific statements from professional societies with limited high quality randomized trial data to inform optimal patient management. An international panel conducted a modified Delphi process with the intent of identifying aspects of cardiogenic shock care where there was uncertainty regarding optimal patient management. METHODS: An 18-person multidisciplinary panel comprising international experts was convened. A modified RAND/University of California Los Angeles appropriateness methodology was used. A survey comprising 70 statements was completed. Participants anonymously rated the appropriateness of each statement on a scale of 1 to 9: 1 to 3 inappropriate, 4 to 6 uncertain, and 7 to 9 appropriate. A summary of the results was discussed as a group, and the survey was iterated and completed again before final analysis. RESULTS: There was broad alignment with current international guidelines and consensus statements. Overall, 44 statements were rated as appropriate, 19 as uncertain, and 7 as inappropriate. There was no disagreement with a disagreement index <1 for all statements. Routine fluid administration was deemed to be inappropriate. Areas of uncertainty focused panel on pre-PCI interventions, the use of right heart catheterization to guide management, routine use of left ventricular unloading strategies, and markers of futility when considering escalation to mechanical circulatory support. CONCLUSIONS: While there was broad alignment with current guidance, an expert panel found several aspects of care where there was clinical equipoise, further highlighting the need for randomized controlled trials to better guide patient management and decision making in cardiogenic shock.

Human reliability analysis of bronchoscope-assisted percutaneous dilatational tracheostomy: implications for simulation-based education.

BACKGROUND: Teaching and assessing clinical procedures requires a clear delineation of the individual steps required to successfully complete the procedure. For decades, human reliability analysis (HRA) has been used to identify the steps required to complete technical procedures in higher risk industries. However, the use of HRA is uncommon in healthcare. HRA has great potential supporting simulation-based education (SBE) in two ways: (1) to support training through the identification of the steps required to complete a clinical procedure; and (2) to support assessment by providing a framework for evaluating performance of a clinical procedure. The goal of this study was to use HRA to identify the steps (and the risk associated with each of these steps) required to complete a bronchoscope-assisted percutaneous dilatational tracheostomy (BPDT). BPDT is a potentially high-risk minimally invasive procedure used to facilitate tracheostomy placement at the bedside or in the operating theatre. METHODS: The subgoals, or steps, required to complete the BPDT procedure were identified using hierarchical task analysis. The Systematic Human Error Reduction and Prediction Approach (SHERPA) was then used to identify potential human errors at each subgoal, the level of risk and how these potential errors could be prevented. RESULTS: The BPDT procedure was broken down into 395 subgoals, of which 18% were determined to be of high-risk. The most commonly identified remediation strategies for reducing the risk of the procedure included: checklist implementation and audit, statutory and mandatory training modules, simulation training, consultant involvement in all procedures, and fostering a safety-focused hospital culture. CONCLUSION: This study provides an approach for how to systematically identify the steps required to complete a clinical procedure for both training and assessment. An understanding of these steps is the foundation of SBE. HRA can identify 'a correct way' for teaching learners how to complete a technical procedure, and support teachers to give systematic and structured feedback on performance.

Role of Pulmonary Embolism Response Team in patients with intermediate- and high-risk pulmonary embolism: a concise review and preliminary experience from China.

Intermediate- and high-risk pulmonary embolism (PE) is a life-threatening medical emergency with high morbidity and mortality. Many of the treatment options for PE involve clinicians from multiple disciplines. Pulmonary Embolism Response Teams (PERTs) have been developed to coordinate the multidisciplinary team of clinicians to streamline the decision making process and develop individualised treatment plans in a timely fashion. The first PERT was established in 2012 and subsequently multiple centres worldwide have introduced this model for the management of intermediate- and high-risk PE. In this review, we evaluate the organisational structure and algorithms of different PERT services and compare data from pre- and post-PERT services to determine the impact of PERT on outcomes. We consider the cost and time implications of this multidisciplinary 24-hour service and suggest areas for further research and review.

Endothelial protective factors BMP9 and BMP10 inhibit CCL2 release by human vascular endothelial cells.

Bone morphogenetic protein 9 (BMP9) and BMP10 are circulating ligands that mediate endothelial cell (EC) protection via complexes of the type I receptor ALK1 and the type II receptors activin type-IIA receptor (ACTR-IIA) and bone morphogenetic type II receptor (BMPR-II). We previously demonstrated that BMP9 induces the expression of interleukin-6, interleukin-8 and E-selectin in ECs and might influence their interactions with monocytes and neutrophils. We asked whether BMP9 and BMP10 regulate the expression of chemokine (C-C motif) ligand 2 (CCL2), a key chemokine involved in monocyte-macrophage chemoattraction. Here, we show that BMP9 and BMP10 repress basal CCL2 expression and release from human pulmonary artery ECs and aortic ECs. The repression was dependent on ALK1 and co-dependent on ACTR-IIA and BMPR-II. Assessment of canonical Smad signalling indicated a reliance of this response on Smad4. Of note, Smad1/5 signalling contributed only at BMP9 concentrations similar to those in the circulation. In the context of inflammation, BMP9 did not alter the induction of CCL2 by TNF-α. As CCL2 promotes monocyte/macrophage chemotaxis and endothelial permeability, these data support the concept that BMP9 preserves basal endothelial integrity.

Guidelines on the management of acute respiratory distress syndrome.

The Faculty of Intensive Care Medicine and Intensive Care Society Guideline Development Group have used GRADE methodology to make the following recommendations for the management of adult patients with acute respiratory distress syndrome (ARDS). The British Thoracic Society supports the recommendations in this guideline. Where mechanical ventilation is required, the use of low tidal volumes (<6 ml/kg ideal body weight) and airway pressures (plateau pressure <30 cmH2O) was recommended. For patients with moderate/severe ARDS (PF ratio<20 kPa), prone positioning was recommended for at least 12 hours per day. By contrast, high frequency oscillation was not recommended and it was suggested that inhaled nitric oxide is not used. The use of a conservative fluid management strategy was suggested for all patients, whereas mechanical ventilation with high positive end-expiratory pressure and the use of the neuromuscular blocking agent cisatracurium for 48 hours was suggested for patients with ARDS with ratio of arterial oxygen partial pressure to fractional inspired oxygen (PF) ratios less than or equal to 27 and 20 kPa, respectively. Extracorporeal membrane oxygenation was suggested as an adjunct to protective mechanical ventilation for patients with very severe ARDS. In the absence of adequate evidence, research recommendations were made for the use of corticosteroids and extracorporeal carbon dioxide removal.

The effects of pleural fluid drainage on respiratory function in mechanically ventilated patients after cardiac surgery.

BACKGROUND: Pleural effusions occur commonly after cardiac surgery and the effects of drainage on gas exchange in this population are not well established. We examined pulmonary function indices following drainage of pleural effusions in cardiac surgery patients. METHODS: We performed a retrospective study examining the effects of pleural fluid drainage on the lung function indices of patients recovering from cardiac surgery requiring mechanical ventilation for more than 7 days. We specifically analysed patients who had pleural fluid removed via an intercostal tube (ICT: drain group) compared with those of a control group (no effusion, no ICT). RESULTS: In the drain group, 52 ICTs were sited in 45 patients. The mean (SD) volume of fluid drained was 1180 (634) mL. Indices of oxygenation were significantly worse in the drain group compared with controls prior to drainage. The arterial oxygen tension (PaO2)/fractional inspired oxygen (FiO2) (P/F) ratio improved on day 1 after ICT placement (mean (SD), day 0: 31.01 (8.92) vs 37.18 (10.7); p<0.05) and both the P/F ratio and oxygenation index (OI: kPa/cm H2O=PaO2/mean airway pressure×FiO2) demonstrated sustained improvement to day 5 (P/F day 5: 39.85 (12.8); OI day 0: 2.88 (1.10) vs day 5: 4.06 (1.73); both p<0.01). The drain group patients were more likely to have an improved mode of ventilation on day 1 compared with controls (p=0.028). CONCLUSIONS: Pleural effusion after cardiac surgery may impair oxygenation. Drainage of pleural fluid is associated with a rapid and sustained improvement in oxygenation.

MiR-181a: a potential biomarker of acute muscle wasting following elective high-risk cardiothoracic surgery.

INTRODUCTION: Acute muscle wasting in the critically ill is common and associated with significant morbidity and mortality. Although some aetiological factors are recognised and muscle wasting can be detected early with ultrasound, it not possible currently to predict in advance of muscle loss those who will develop muscle wasting. The ability to stratify the risk of muscle wasting associated with critical illness prior to it becoming clinically apparent would provide the opportunity to predict prognosis more accurately and to intervene at an early stage. MicroRNAs are small non-coding RNAs that modulate post-transcriptional regulation of translation, some are tissue specific and can be detected and quantified in plasma. We hypothesised that certain plasma microRNAs could be biomarkers of ICU acquired muscle weakness. METHODS: Plasma levels of selected microRNAs were measured in pre- and post-operative samples from a previously reported prospective observational study of 42 patients undergoing elective high-risk cardiothoracic surgery, 55% of whom developed muscle wasting. RESULTS: The rise in miR-181a was significantly higher on the second post-operative day in those who developed muscle wasting at 1 week compared to those who did not (p = 0.03). A rise in miR-181a of greater than 1.7 times baseline had 91% specificity and 56% sensitivity for subsequent muscle wasting. Other microRNAs did not show significant differences between the groups. CONCLUSION: Plasma miR-181a deserves further investigation as a potential biomarker of muscle wasting. Additionally, since mir-181a is involved in both regulation of inflammation and muscle regeneration and differentiation; our observation therefore also suggests directions for future research.

Pulmonary venous hypertension and mechanical strain stimulate monocyte chemoattractant protein-1 release and structural remodelling of the lung in human and rodent chronic heart failure models.

INTRODUCTION: The burden of chronic heart failure (HF) is rising owing to an increased survivorship after myocardial infarction (MI). Pulmonary structural remodelling in patients with HF may protect against oedema while causing dyspnoea, the predominant symptom associated with HF. The cellular and molecular mechanisms underlying these processes in HF are poorly understood. We hypothesised that pulmonary venous hypertension (PVH) following MI provides a mechanical stimulus for structural remodelling of the lung via monocyte chemoattractant protein-1 (MCP-1). METHODS: Human lung microvascular endothelial cells (HLMVEC) and Ea.Hy 926 cells exposed to cyclic mechanical strain (CMS) in vitro were analysed for MCP-1 expression and activation of signalling intermediates. HF was induced in Sprague-Dawley rats 16 weeks after MI; a cohort was rescued with AAV9.SERCA2a gene therapy to reduce PVH. RESULTS: HLMVEC and Ea.Hy 926 cells exposed to CMS upregulated MCP-1 gene expression and protein release in an extracellular-signal-regulated kinase (ERK) 1/2 dependent manner. Supernatants from these experiments stimulated fibroblast (human fetal lung fibroblast -1) and pulmonary artery smooth muscle cell proliferation and differentiation. Total lung collagen, a marker of structural remodelling, and MCP-1 gene expression were increased in the lungs of rats with post-MI HF. SERCA2a gene therapy that attenuated PVH after MI was associated with lower levels of lung collagen and MCP-1 gene expression in the lung. CONCLUSIONS: Mechanical strain associated with PVH may stimulate pulmonary structural remodelling through ERK 1/2 dependent induction of MCP-1. These findings provide insights into the pathophysiology of lung remodelling in HF and highlight novel, potential therapeutic targets.

Methemoglobin-induced signaling and chemokine responses in human alveolar epithelial cells.

Diffuse alveolar hemorrhage is characterized by the presence of red blood cells and free hemoglobin in the alveoli and complicates a number of serious medical and surgical lung conditions including the pulmonary vasculitides and acute respiratory distress syndrome. In this study we investigated the hypothesis that exposure of human alveolar epithelial cells to hemoglobin and its breakdown products regulates chemokine release via iron- and oxidant-mediated activation of the transcription factor NF-κB. Methemoglobin alone stimulated the release of IL-8 and MCP-1 from A549 cells via activation of the NF-κB pathway; additionally, IL-8 required ERK activation and MCP-1 required JNK activation. Neither antioxidants nor iron chelators and knockdown of ferritin heavy and light chains affected these responses, indicating that iron and reactive oxygen species are not involved in the response of alveolar epithelial cells to methemoglobin. Incubation of primary cultures of human alveolar type 2 cells with methemoglobin resulted in a similar pattern of chemokine release and signaling pathway activation. In summary, we have shown for the first time that methemoglobin induced chemokine release from human lung epithelial cells independent of iron- and redox-mediated signaling involving the activation of the NF-κB and MAPK pathways. Decompartmentalization of hemoglobin may be a significant proinflammatory stimulus in a variety of lung diseases.

Sustained elevation of circulating growth and differentiation factor-15 and a dynamic imbalance in mediators of muscle homeostasis are associated with the development of acute muscle wasting following cardiac surgery.

OBJECTIVES: Acute muscle wasting in the critically ill is common and causes significant morbidity. In a novel human model of acute muscle wasting following cardiac surgery, known or potential circulating modulators of muscle mass--insulin-like growth factor-1, myostatin, and growth and differentiation factor-15--were measured over a week. It was hypothesized that patients who developed acute muscle wasting would show distinct patterns of change in these mediators. DESIGN: A prospective longitudinal observational study of high-risk elective cardiac surgical patients identifying, by ultrasound, those developing muscle wasting. SETTING: Tertiary cardiothoracic referral center: Royal Brompton Hospital, London, UK. PATIENTS: Forty-two patients undergoing elective high-risk cardiothoracic surgery. INTERVENTIONS: Circulating insulin-like growth factor-1, myostatin, and growth and differentiation factor-15 were assayed preoperatively and over the first week postoperatively. The ability of growth and differentiation factor-15 to cause muscle wasting in vitro was determined in C2C12 myotubes. MEASUREMENTS AND MAIN RESULTS: Of the 42 patients, 23 (55%) developed quadriceps atrophy. There was an acute decrease in insulin-like growth factor-1 and unexpectedly myostatin, known mediators of muscle hypertrophy and atrophy, respectively. By contrast, plasma growth and differentiation factor-15 concentrations increased in all patients. This increase in growth and differentiation factor-15 was sustained at day 7 in those who developed muscle wasting (day 7 compared with baseline, p<0.01), but recovered in the nonwasting group (p>0.05). Insulin-like growth factor-1 did not recover in those who developed muscle wasting (day 7 compared with baseline, p<0.01) but did in the nonwasting group (p>0.05). Finally, we demonstrated that growth and differentiation factor-15 caused atrophy of myotubes in vitro. CONCLUSION: These data support the hypothesis that acute muscle loss occurs as a result of an imbalance between drivers of muscle atrophy and hypertrophy. Growth and differentiation factor-15 is a potential novel factor associated with muscle atrophy, which may become a therapeutic target in patients with ICU acquired paresis and other forms of acute muscle wasting.

Strategies to reduce ventilator-associated lung injury (VALI).

Optimal management of the acute respiratory distress syndrome (ARDS) requires prompt recognition, treatment of the underlying cause and the prevention of secondary injury. Ventilator-associated lung injury (VALI) is one of the several iatrogenic factors that can exacerbate lung injury and ARDS. Reduction of VALI by protective low tidal volume ventilation is one of the only interventions with a proven survival benefit in ARDS. There are, however, several factors inhibiting the widespread use of this technique in patients with established lung injury. Prevention of ARDS and VALI by detecting at-risk patients and implementing protective ventilation early is a feasible strategy. Detection of injurious ventilation itself is possible, and potential biological markers of VALI have been investigated. Finally, facilitation of protective ventilation, including techniques such as extracorporeal support, can mitigate VALI.

Influenza-related pneumonia.

Influenza-related pneumonia encompasses both primary viral pneumonia and secondary bacterial pneumonia, which may be difficult to differentiate clinically. A high index of suspicion, prompt initiation of antiviral and antibiotic therapy, and appropriate escalation to secondary/critical care are key to improving outcome.

BMP-9 induced endothelial cell tubule formation and inhibition of migration involves Smad1 driven endothelin-1 production.

BACKGROUND: Bone morphogenetic proteins (BMPs) and their receptors, such as bone morphogenetic protein receptor (BMPR) II, have been implicated in a wide variety of disorders including pulmonary arterial hypertension (PAH). Similarly, endothelin-1 (ET-1), a mitogen and vasoconstrictor, is upregulated in PAH and endothelin receptor antagonists are used in its treatment. We sought to determine whether there is crosstalk between BMP signalling and the ET-1 axis in human pulmonary artery endothelial cells (HPAECs), possible mechanisms involved in such crosstalk and functional consequences thereof. METHODOLOGY/PRINCIPAL FINDING: Using western blot, real time RT-PCR, ELISA and small RNA interference methods we provide evidence that in HPAECs BMP-9, but not BMP-2, -4 and -6 significantly stimulated ET-1 release under physiological concentrations. This release is mediated by both Smad1 and p38 MAPK and is independent of the canonical Smad4 pathway. Moreover, knocking down the ALK1 receptor or BMPR II attenuates BMP-9 stimulated ET-1 release, whilst causing a significant increase in prepro ET-1 mRNA transcription and mature peptide release. Finally, BMP-9 induced ET-1 release is involved in both inhibition of endothelial cell migration and promotion of tubule formation. CONCLUSIONS/SIGNIFICANCE: Although our data does not support an important role for BMP-9 as a source of increased endothelial ET-1 production seen in human PAH, BMP-9 stimulated ET-1 production is likely to be important in angiogenesis and vascular stability. However, increased ET-1 production by endothelial cells as a consequence of BMPR II dysfunction may be clinically relevant in the pathogenesis of PAH.

Biomarkers of acute lung injury: worth their salt?

The validation of biomarkers has become a key goal of translational biomedical research. The purpose of this article is to discuss the role of biomarkers in the management of acute lung injury (ALI) and related research. Biomarkers should be sensitive and specific indicators of clinically important processes and should change in a relevant timeframe to affect recruitment to trials or clinical management. We do not believe that they necessarily need to reflect pathogenic processes. We critically examined current strategies used to identify biomarkers and which, owing to expedience, have been dominated by reanalysis of blood derived markers from large multicenter Phase 3 studies. Combining new and existing validated biomarkers with physiological and other data may add predictive power and facilitate the development of important aids to research and therapy.

Translational research: what does it mean, what has it delivered and what might it deliver?

PURPOSE OF REVIEW: In this article, we review recent developments in translational research in the fields of acute lung injury, acute kidney injury and sepsis with a focus on emerging biomarkers and outline future advances in the field. RECENT FINDINGS: There is currently a significant and unmet need for high quality translational research in critical care. The emergence of '-omics' technologies and sophisticated imaging techniques have resulted in a rapid growth of emerging biomarkers. Biomarkers would ideally provide early and reliable endpoints for proof of concept in clinical trials and inform clinical decision making through earlier and more precise diagnosis and risk stratification. SUMMARY: Despite significant investment in basic science and time-consuming clinical trials, the majority of pharmacological interventions developed for critical illness have yet to translate into measurable clinical benefit. Future validation and qualification of emerging biomarkers allied to advances in pharmacogenomic profiling have the potential to provide valuable clinical information while accurately phenotyping patients enrolled in future clinical trials.

Human models of acute lung injury.

Acute lung injury (ALI) is a syndrome that is characterised by acute inflammation and tissue injury that affects normal gas exchange in the lungs. Hallmarks of ALI include dysfunction of the alveolar-capillary membrane resulting in increased vascular permeability, an influx of inflammatory cells into the lung and a local pro-coagulant state. Patients with ALI present with severe hypoxaemia and radiological evidence of bilateral pulmonary oedema. The syndrome has a mortality rate of approximately 35% and usually requires invasive mechanical ventilation. ALI can follow direct pulmonary insults, such as pneumonia, or occur indirectly as a result of blood-borne insults, commonly severe bacterial sepsis. Although animal models of ALI have been developed, none of them fully recapitulate the human disease. The differences between the human syndrome and the phenotype observed in animal models might, in part, explain why interventions that are successful in models have failed to translate into novel therapies. Improved animal models and the development of human in vivo and ex vivo models are therefore required. In this article, we consider the clinical features of ALI, discuss the limitations of current animal models and highlight how emerging human models of ALI might help to answer outstanding questions about this syndrome.

A stepwise approach to justify phase III randomized clinical trials and enhance the likelihood of a positive result.

Multiple time-consuming, expensive, and negative phase III clinical trials involving many thousands of patients have been undertaken in critical care and continue to be funded. The vast majority of these clinical trials are negative. Furthermore, phase III studies frequently fail to achieve their planned recruitment target. Often such studies are based on small pilot studies with inadequate phase II trial data and limited mechanistic data to provide a sound scientific rationale. The body of research required to justify undertaking a phase III trial in the critically ill population has not been defined adequately. In particular, guidance on the design of phase II studies for evaluating treatments in the critically ill population is needed. Research to inform critical care practice will progress more efficiently and effectively if this can be achieved. The following article presents a template on the minimum evidence required to justify phase III clinical trials in the critically ill population.

Mechanical ventilation induces changes in exhaled breath condensate of patients without lung injury.

INTRODUCTION: Measurement of biomarkers in exhaled breath condensate (EBC) may be useful for monitoring lung inflammation and injury in mechanically ventilated patients. The aim of this study was to analyze changes in biomarkers of inflammation in EBC associated with prolonged mechanical ventilation. METHODS: EBC samples were collected from critically ill patients weaning from mechanical ventilation without lung disease and from healthy nonsmokers. The following parameters were measured: pH after helium deaeration, nitrogen oxide and 8-isoprostane concentrations. RESULTS: EBC was obtained from 10 patients and 20 controls. Ventilation time before the start of sample collection was 250 (85-714)h. The post-deaeration pH of EBC samples was significantly lower in ventilated patients than controls (7.50 [7.28-7.70] vs 8.07 [7.60-8.40]; P=0.008). Ventilation time before sample collection inversely correlated with pH (r=-0.636; P=0.048). A significantly higher concentration of nitrogen oxide (muM) was seen in ventilated patients vs controls (66.22 [22.26-83.13] vs 15.06 [10.73-23.30]; P=0.002), whereas levels of 8-isoprostane (pg/mL) were not significantly different between both groups (5.73 [4.0-11.4] vs 9.09 [6.63-11.43]; P=0.169). The nitrogen oxide concentration correlated negatively with dynamic compliance (r=-0.952; P<0.001) and positively with respiratory rate (r=0.683; P=0.029). CONCLUSIONS: EBC analysis is a non-invasive technique that can be used to monitor ventilated patients. Mechanically ventilated patients had higher EBC acidity and nitrogen oxide concentrations. Duration of ventilation correlated with breath condensate pH.