Influence of reduced diffusing capacity and FEV1 on outcome after cardiac surgery.

BACKGROUND: Impaired lung function is a well-known risk factor in cardiac surgery patients and reduced forced expiratory volume in 1 second (FEV1 ) is associated with increased mortality. However, there is limited knowledge regarding the influence of impaired diffusing capacity of the lungs for carbon monoxide (DLCO) in unselected cardiac surgery patients. The aim of this study was to investigate the association of impaired DLCO and/or reduced FEV1 on post-operative mortality and morbidity in cardiac surgery patients. METHODS: In a prospective cohort study, 390 patients scheduled for elective cardiac surgery underwent preoperative lung function test including spirometry and DLCO measurements. We defined reduced FEV1 as FEV1 below lower limit of normal (LLN) and impaired DLCO as DLCO <60% of predicted. RESULTS: Mortality within 1 year (90-570 days) was significantly higher in patients with impaired DLCO (12% vs 3%, P = .010) and with reduced FEV1 (9% vs 3%, P = .028). Mortality was higher in patients with impaired DLCO both in the presence and absence of FEV1  < LLN. In multivariate analysis, only impaired DLCO [OR: 3.3, 95% confidence interval (CI) 1.4-7.5; P = .005] and age (OR: 1.1 per year, 95% CI 1.0-1.2; P = .001) were independent predictors of the combined outcome of mortality and prolonged intensive care unit (ICU) stay. Impaired DLCO was also associated with post-operative respiratory complications. CONCLUSION: In patients undergoing elective cardiac surgery, preoperative impaired FEV1 and DLCO were associated with increased mortality and morbidity. In multivariate analysis, only DLCO and age were independent predictors of a combined outcome of mortality and prolonged ICU stay.

Citrate NMR peak irreproducibility in blood samples after reacquisition of spectra.

BACKGROUND: In our metabolomics studies we have noticed that repeated NMR acquisition on the same sample can result in altered metabolite signal intensities. AIMS: To investigate the reproducibility of repeated NMR acquisition on selected metabolites in serum and plasma from two large human metabolomics studies. METHODS: Two peak regions for each metabolite were integrated and changes occurring after reacquisition were correlated. RESULTS: Integral changes were generally small, but serum citrate signals decreased significantly in some samples. CONCLUSIONS: Several metabolite integrals were not reproducible in some of the repeated spectra. Following established protocols, randomising analysis order and biomarker validation are important.

Pulmonary artery perfusion versus no perfusion during cardiopulmonary bypass for open heart surgery in adults.

BACKGROUND: Available evidence has been inconclusive on whether pulmonary artery perfusion during cardiopulmonary bypass (CPB) is associated with decreased or increased mortality, pulmonary events, and serious adverse events (SAEs) after open heart surgery. To our knowledge, no previous systematic reviews have included meta-analyses of these interventions. OBJECTIVES: To assess the benefits and harms of single-shot or continuous pulmonary artery perfusion with blood (oxygenated or deoxygenated) or a preservation solution compared with no perfusion during cardiopulmonary bypass (CPB) in terms of mortality, pulmonary events, serious adverse events (SAEs), and increased inflammatory markers for adult surgical patients. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, Science Citation Index Expanded, and advanced Google for relevant studies. We handsearched retrieved study reports and scanned citations of included studies and relevant reviews to ensure that no relevant trials were missed. We searched for ongoing trials and unpublished trials in the World Health Organization International Clinical Trials Registry Platform (ICTRP) and at clinicaltrials.gov (4 July 2017). We contacted medicinal firms producing preservation solutions to retrieve additional studies conducted to examine relevant interventions. SELECTION CRITERIA: We included randomized controlled trials (RCTs) that compared pulmonary artery perfusion versus no perfusion during CPB in adult patients (≧ 18 years). DATA COLLECTION AND ANALYSIS: Two independent review authors extracted data, conducted fixed-effect and random-effects meta-analyses, and calculated risk ratios (RRs) or odds ratios (ORs) for dichotomous outcomes. For continuous data, we have presented mean differences (MDs) and 95% confidence intervals (CIs) as estimates of the intervention effect. To minimize the risk of systematic error, we assessed risk of bias of included trials. To reduce the risk of random errors caused by sparse data and repetitive updating of cumulative meta-analyses, we applied Trial Sequential Analyses (TSAs). We used GRADE principles to assess the quality of evidence. MAIN RESULTS: We included in this review four RCTs (210 participants) reporting relevant outcomes. Investigators randomly assigned participants to pulmonary artery perfusion with blood versus no perfusion during CPB. Only one trial included the pulmonary artery perfusion intervention with a preservation solution; therefore we did not perform meta-analysis. Likewise, only one trial reported patient-specific data for the outcome "pulmonary events"; therefore we have provided no results from meta-analysis. Instead, review authors added two explorative secondary outcomes for this version of the review: the ratio of partial pressure of oxygen in arterial blood (PaO2) to fraction of inspired oxygen (FiO2); and intubation time. Last, review authors found no comparable data for the secondary outcome inflammatory markers.The effect of pulmonary artery perfusion on all-cause mortality was uncertain (Peto OR 1.78, 95% CI 0.43 to 7.40; TSA adjusted CI 0.01 to 493; 4 studies, 210 participants; GRADE: very low quality). Sensitivity analysis of one trial with overall low risk of bias (except for blinding of personnel during the surgical procedure) yielded no evidence of a difference for mortality (Peto OR 1.65, 95% CI 0.27 to 10.15; 1 study, 60 participants). The TSA calculated required information size was not reached and the futility boundaries did not cross; thus this analysis cannot refute a 100% increase in mortality.The effect of pulmonary artery perfusion with blood on SAEs was likewise uncertain (RR 1.12, 95% CI 0.66 to 1.89; 3 studies, 180 participants; GRADE: very low quality). Data show an association between pulmonary artery perfusion with blood during CPB and a higher postoperative PaO2/FiO2 ratio (MD 27.80, 95% CI 5.67 to 49.93; 3 studies, 119 participants; TSA adjusted CI 5.67 to 49.93; GRADE: very low quality), although TSA could not confirm or refute a 10% increase in the PaO2/FiO2 ratio, as the required information size was not reached. AUTHORS' CONCLUSIONS: The effects of pulmonary artery perfusion with blood during cardiopulmonary bypass (CPB) are uncertain owing to the small numbers of participants included in meta-analyses. Risks of death and serious adverse events may be higher with pulmonary artery perfusion with blood during CPB, and robust evidence for any beneficial effects is lacking. Future randomized controlled trials (RCTs) should provide long-term follow-up and patient stratification by preoperative lung function and other documented risk factors for mortality. One study that is awaiting classification (epub abstract with preliminary results) may change the results of this review when full study details have been published.

Preoperative pulmonary function in all comers for cardiac surgery predicts mortality†.

OBJECTIVES: Although reduced lung function and chronic obstructive pulmonary disease (COPD) is associated with higher risk of death following cardiac surgery, preoperative spirometry is not performed routinely. The aim of this study was to investigate the relationship between preoperative lung function and postoperative complications in all comers for cardiac surgery irrespective of smoking or COPD history. METHODS: Preoperative spirometry was performed in elective adult cardiac surgery patients. Airflow obstruction was defined as the ratio of forced expiratory volume in 1 s (FEV1)/forced vital capacity ratio below the lower limit of normal (LLN) and reduced forced ventilatory capacity defined as FEV1

Lung Protection Strategies during Cardiopulmonary Bypass Affect the Composition of Bronchoalveolar Fluid and Lung Tissue in Cardiac Surgery Patients.

Pulmonary dysfunction is among the most frequent complications to cardiac surgeries. Exposure of blood to the cardiopulmonary bypass (CPB) circuit with subsequent lung ischemia-reperfusion leads to the production of inflammatory mediators and increases in microvascular permeability. The study aimed to elucidate histological, cellular, and metabolite changes following two lung protective regimens during CPB with Histidine-Tryptophan-Ketoglutarate (HTK) enriched or warm oxygenated blood pulmonary perfusion compared to standard regimen with no pulmonary perfusion. A total of 90 patients undergoing CPB were randomized to receiving HTK, oxygenated blood or standard regimen. Of these, bronchoalveolar lavage fluid (BALF) and lung tissue biopsies were obtained before and after CPB from 47 and 25 patients, respectively. Histopathological scores, BALF cell counts and metabolite screening were assessed. Multivariate and univariate analyses were performed. Profound histological, cellular, and metabolic changes were identified in all patients after CPB. Histological and cellular changes were similar in the three groups; however, some metabolite profiles were different in the HTK patients. While all patients presented an increase in inflammatory cells, metabolic acidosis, protease activity and oxidative stress, HTK patients seemed to be protected against severe acidosis, excessive fatty acid oxidation, and inflammation during ischemia-reperfusion. Additional studies are needed to confirm these findings.

Lung Protection Strategies during Cardiopulmonary Bypass Affect the Composition of Blood Electrolytes and Metabolites-A Randomized Controlled Trial.

Cardiac surgery with cardiopulmonary bypass (CPB) causes an acute lung ischemia-reperfusion injury, which can develop to pulmonary dysfunction postoperatively. This sub-study of the Pulmonary Protection Trial aimed to elucidate changes in arterial blood gas analyses, inflammatory protein interleukin-6, and metabolites of 90 chronic obstructive pulmonary disease patients following two lung protective regimens of pulmonary artery perfusion with either hypothermic histidine-tryptophan-ketoglutarate (HTK) solution or normothermic oxygenated blood during CPB, compared to the standard CPB with no pulmonary perfusion. Blood was collected at six time points before, during, and up to 20 h post-CPB. Blood gas analysis, enzyme-linked immunosorbent assay, and nuclear magnetic resonance spectroscopy were used, and multivariate and univariate statistical analyses were performed. All patients had decreased gas exchange, augmented inflammation, and metabolite alteration during and after CPB. While no difference was observed between patients receiving oxygenated blood and standard CPB, patients receiving HTK solution had an excess of metabolites involved in energy production and detoxification of reactive oxygen species. Also, patients receiving HTK suffered a transient isotonic hyponatremia that resolved within 20 h post-CPB. Additional studies are needed to further elucidate how to diminish lung ischemia-reperfusion injury during CPB, and thereby, reduce the risk of developing severe postoperative pulmonary dysfunction.

Pulmonary artery perfusion versus no pulmonary perfusion during cardiopulmonary bypass in patients with COPD: a randomised clinical trial.

INTRODUCTION: Absence of pulmonary perfusion during cardiopulmonary bypass (CPB) may be associated with reduced postoperative oxygenation. Effects of active pulmonary artery perfusion were explored in patients with chronic obstructive pulmonary disease (COPD) undergoing cardiac surgery. METHODS: 90 patients were randomised to receive pulmonary artery perfusion during CPB with either oxygenated blood (n=30) or histidine-tryptophan-ketoglutarate (HTK) solution (n=29) compared with no pulmonary perfusion (n=31). The coprimary outcomes were the inverse oxygenation index compared at 21 hours after starting CPB and longitudinally in a mixed-effects model (MEM). Secondary outcomes were tracheal intubation time, serious adverse events, mortality, days alive outside the intensive care unit (ICU) and outside the hospital. RESULTS: 21 hours after starting CPB patients receiving pulmonary artery perfusion with normothermic oxygenated blood had a higher oxygenation index compared with no pulmonary perfusion (mean difference (MD) 0.94; 95% CI 0.05 to 1.83; p=0.04). The blood group had also a higher oxygenation index both longitudinally (MEM, p=0.009) and at 21 hours (MD 0.99; CI 0.29 to 1.69; p=0.007) compared with the HTK group. The latest result corresponds to a difference in the arterial partial pressure of oxygen of 23 mm Hg with a median fraction of inspired oxygen of 0.32. Yet the blood or HTK groups did not demonstrate a longitudinally higher oxygenation index compared with no pulmonary perfusion (MEM, p=0.57 and 0.17). Similarly, at 21 hours there was no difference in the oxygenation index between the HTK group and those no pulmonary perfusion (MD 0.06; 95% CI -0.73 to 0.86; p=0.87). There were no statistical significant differences between the groups for the secondary outcomes. DISCUSSION: Pulmonary artery perfusion with normothermic oxygenated blood during cardiopulmonary bypass appears to improve postoperative oxygenation in patients with COPD undergoing cardiac surgery. Pulmonary artery perfusion with hypothermic HTK solution does not seem to improve postoperative oxygenation. TRIAL REGISTRATION NUMBER: NCT01614951; Pre-results.

Detailed statistical analysis plan for the pulmonary protection trial.

BACKGROUND: Pulmonary dysfunction complicates cardiac surgery that includes cardiopulmonary bypass. The pulmonary protection trial evaluates effect of pulmonary perfusion on pulmonary function in patients suffering from chronic obstructive pulmonary disease. This paper presents the statistical plan for the main publication to avoid risk of outcome reporting bias, selective reporting, and data-driven results as an update to the published design and method for the trial. RESULTS: The pulmonary protection trial is a randomized, parallel group clinical trial that assesses the effect of pulmonary perfusion with oxygenated blood or Custodiol™ HTK (histidine-tryptophan-ketoglutarate) solution versus no pulmonary perfusion in 90 chronic obstructive pulmonary disease patients. Patients, the statistician, and the conclusion drawers are blinded to intervention allocation. The primary outcome is the oxygenation index from 10 to 15 minutes after the end of cardiopulmonary bypass until 24 hours thereafter. Secondary outcome measures are oral tracheal intubation time, days alive outside the intensive care unit, days alive outside the hospital, and 30- and 90-day mortality, and one or more of the following selected serious adverse events: pneumothorax or pleural effusion requiring drainage, major bleeding, reoperation, severe infection, cerebral event, hyperkaliemia, acute myocardial infarction, cardiac arrhythmia, renal replacement therapy, and readmission for a respiratory-related problem. CONCLUSIONS: The pulmonary protection trial investigates the effect of pulmonary perfusion during cardiopulmonary bypass in chronic obstructive pulmonary disease patients. A preserved oxygenation index following pulmonary perfusion may indicate an effect and inspire to a multicenter confirmatory trial to assess a more clinically relevant outcome. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01614951, registered on 6 June 2012.

Pulmonary perfusion with oxygenated blood or custodiol HTK solution during cardiac surgery for postoperative pulmonary function in COPD patients: a trial protocol for the randomized, clinical, parallel group, assessor and data analyst blinded Pulmonary Protection Trial.

BACKGROUND: Five to thirty percent of patients undergoing cardiac surgery present with chronic obstructive pulmonary disease (COPD) and have a 2- to 10-fold higher 30-day mortality risk. Cardiopulmonary bypass (CPB) creates a whole body systemic inflammatory response syndrome (SIRS) that could impair pulmonary function. Impaired pulmonary function can, however, be attenuated by pulmonary perfusion with oxygenated blood or custodiol HTK (histidine-tryptophan-ketoglutarate) solution. METHODS/DESIGN: The Pulmonary Protection Trial (PP-Trial) randomizes 90 patients undergoing CPB-dependent cardiac surgery to evaluate whether pulmonary perfusion with oxygenated blood or custodiol HTK solution reduces postoperative pulmonary dysfunction in COPD patients. Further, we aim for a non-randomized evaluation of postoperative pulmonary function after transcatheter aortic-valve implantation (TAVI). The primary outcome measure is the oxygenation index measured from anesthesia induction to the end of surgery and until 24 hours after anesthesia induction for a total of six evaluations. DISCUSSION: Patients with COPD may be impaired by hypoxemia and SIRS. Thus, prolonged recovery and even postoperative complications and death may be reflected by the degree of hypoxemia and SIRS. The limited sample size does not aim for confirmatory conclusions on mortality, cardiovascular complications or risk of pneumonia and sepsis, but the PP-Trial is considered an important feasibility trial paving the road for a multicenter confirmatory trial. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01614951.

Glucagon-like peptide-1 (GLP-1) reduces mortality and improves lung function in a model of experimental obstructive lung disease in female mice.

The incretin hormone glucagon-like peptide-1 (GLP-1) is an important insulin secretagogue and GLP-1 analogs are used for the treatment of type 2 diabetes. GLP-1 displays antiinflammatory and surfactant-releasing effects. Thus, we hypothesize that treatment with GLP-1 analogs will improve pulmonary function in a mouse model of obstructive lung disease. Female mice were sensitized with injected ovalbumin and treated with GLP-1 receptor (GLP-1R) agonists. Exacerbation was induced with inhalations of ovalbumin and lipopolysaccharide. Lung function was evaluated with a measurement of enhanced pause in a whole-body plethysmograph. mRNA levels of GLP-1R, surfactants (SFTPs), and a number of inflammatory markers were measured. GLP-1R was highly expressed in lung tissue. Mice treated with GLP-1R agonists had a noticeably better clinical appearance than the control group. Enhanced pause increased dramatically at day 17 in all control mice, but the increase was significantly less in the groups of GLP-1R agonist-treated mice (P < .001). Survival proportions were significantly increased in GLP-1R agonist-treated mice (P < .01). SFTPB and SFTPA were down-regulated and the expression of inflammatory cytokines were increased in mice with obstructive lung disease, but levels were largely unaffected by GLP-1R agonist treatment. These results show that GLP-1R agonists have potential therapeutic potential in the treatment of obstructive pulmonary diseases, such as chronic obstructive pulmonary disease, by decreasing the severity of acute exacerbations. The mechanism of action does not seem to be the modulation of inflammation and SFTP expression.