Nucleated red blood cells as a prognostic marker for mortality in patients with SARS-CoV-2-induced ARDS: an observational study.

BACKGROUND: The presence of nucleated red blood cells (NRBCs) in the peripheral blood of critically ill patients is associated with poor outcome. Evidence regarding the predictive value of NRBCs in patients with SARS-CoV-2-induced acute respiratory distress syndrome (ARDS) remains elusive. The aim of this study was to evaluate the predictive validity of NRBCs in these patients. METHODS: Daily NRBC values of adult patients with SARS-CoV-2-induced ARDS were assessed and their predictive validity for mortality was statistically evaluated. A cut-off level based on the patient's maximum NRBC value during ICU stay was calculated and further specified according to Youden's method. Based on this cut-off value, further analyses such as logistic regression models and survival were performed. RESULTS: 413 critically ill patients with SARS-CoV-2-induced ARDS were analyzed. Patients who did not survive had significantly higher NRBC values during their ICU stay compared to patients who survived (1090/µl [310; 3883] vs. 140/µl [20; 500]; p < 0.0001). Patients with severe ARDS (n = 374) had significantly higher NRBC values during ICU stay compared to patients with moderate ARDS (n = 38) (490/µl [120; 1890] vs. 30/µl [10; 476]; p < 0.0001). A cut-off level of NRBC ≥ 500/µl was found to best stratify risk and was associated with a longer duration of ICU stay (12 [8; 18] vs. 18 [13; 27] days; p < 0.0001) and longer duration of mechanical ventilation (10 [6; 16] vs. 17 [12; 26] days; p < 0.0001). Logistic regression analysis with multivariate adjustment showed NRBCs ≥ 500/µl to be an independent risk factor of mortality (odds ratio (OR) 4.72; 95% confidence interval (CI) 2.95-7.62, p < 0.0001). Patients with NRBC values below the threshold of 500/µl had a significant survival advantage over those above the threshold (median survival 32 [95% CI 8.7-43.3] vs. 21 days [95% CI 18.2-23.8], log-rank test, p < 0.05). Patients who once reached the NRBC threshold of ≥ 500/µl during their ICU stay had a significantly increased long-term mortality (median survival 489 days, log-rank test, p = 0.0029, hazard ratio (HR) 3.2, 95% CI 1.2-8.5). CONCLUSIONS: NRBCs predict mortality in critically ill patients with SARS-CoV-2-induced ARDS with high prognostic power. Further studies are required to confirm the clinical impact of NRBCs to eventually enhance decision making.

[Ventilation concepts under extracorporeal membrane oxygenation (ECMO) in acute respiratory distress syndrome (ARDS)]. / Beatmungskonzepte unter extrakorporaler Membranoxygenierung bei akutem Lungenversagen.

Extracorporeal membrane oxygenation (ECMO) is often the last resort for escalation of treatment in patients with severe acute respiratory distress syndrome (ARDS). The success of treatment is mainly determined by patient-specific factors, such as age, comorbidities, duration and invasiveness of the pre-existing ventilation treatment as well as the expertise of the treating ECMO center. In particular, the adjustment of mechanical ventilation during ongoing ECMO treatment remains controversial. Although a reduction of invasiveness of mechanical ventilation seems to be reasonable due to physiological considerations, no improvement in outcome has been demonstrated so far for the use of ultraprotective ventilation regimens.

Treatment of Acquired von Willebrand Disease due to Extracorporeal Membrane Oxygenation in a Pediatric COVID-19 Patient with Vonicog Alfa: A Case Report and Literature Review.

Acquired von Willebrand disease (aVWD) is frequently observed in patients with the need for extracorporeal membrane oxygenation (ECMO). aVWD can be treated by plasma-derived concentrates containing factor VIII (FVIII) and/or von Willebrand factor (VWF) and recombinant VWF concentrate as well as adjuvant therapies such as tranexamic acid and desmopressin. However, all of these therapeutic options possibly cause thromboembolism. Therefore, the optimal treatment remains uncertain. This report presents a case of a 16-year-old patient suffering from severe acute respiratory distress syndrome due to coronavirus disease 2019 with the need of ECMO support. Our patient developed aVWD under ECMO therapy characterized by loss of high-molecular-weight multimers (HMWM) and severe bleeding symptoms following endoscopic papillotomy due to sclerosing cholangitis. At the same time standard laboratory parameters showed hypercoagulability with increased fibrinogen level and platelet count. The patient was successfully treated with recombinant VWF concentrate (rVWF; vonicog alfa; Veyvondi) combined with topic tranexamic acid application and cortisone therapy. rVWF concentrate vonicog alfa is characterized by ultra-large multimers and absence of FVIII. Patient could be successfully weaned from ECMO support after 72 days. Multimer analysis 1 week after ECMO decannulation showed an adequate reappearance of HMWM.

Effect of patient-ventilator asynchrony on lung and diaphragmatic injury in experimental acute respiratory distress syndrome in a porcine model.

BACKGROUND: Patient-ventilator asynchrony during mechanical ventilation may exacerbate lung and diaphragm injury in spontaneously breathing subjects. We investigated whether subject-ventilator asynchrony increases lung or diaphragmatic injury in a porcine model of acute respiratory distress syndrome (ARDS). METHODS: ARDS was induced in adult female pigs by lung lavage and injurious ventilation before mechanical ventilation by pressure assist-control for 12 h. Mechanically ventilated pigs were randomised to breathe spontaneously with or without induced subject-ventilator asynchrony or neuromuscular block (n=7 per group). Subject-ventilator asynchrony was produced by ineffective, auto-, or double-triggering of spontaneous breaths. The primary outcome was mean alveolar septal thickness (where thickening of the alveolar wall indicates worse lung injury). Secondary outcomes included distribution of ventilation (electrical impedance tomography), lung morphometric analysis, inflammatory biomarkers (gene expression), lung wet-to-dry weight ratio, and diaphragmatic muscle fibre thickness. RESULTS: Subject-ventilator asynchrony (median [interquartile range] 28.8% [10.4] asynchronous breaths of total breaths; n=7) did not increase mean alveolar septal thickness compared with synchronous spontaneous breathing (asynchronous breaths 1.0% [1.6] of total breaths; n=7). There was no difference in mean alveolar septal thickness throughout upper and lower lung lobes between pigs randomised to subject-ventilator asynchrony vs synchronous spontaneous breathing (87.3-92.2 µm after subject-ventilator asynchrony, compared with 84.1-95.0 µm in synchronised spontaneous breathing;). There were also no differences between groups in wet-to-dry weight ratio, diaphragmatic muscle fibre thickness, atelectasis, lung aeration, or mRNA expression levels for inflammatory cytokines pivotal in ARDS pathogenesis. CONCLUSIONS: Subject-ventilator asynchrony during spontaneous breathing did not exacerbate lung injury and dysfunction in experimental porcine ARDS.

Extreme obesity is a strong predictor for in-hospital mortality and the prevalence of long-COVID in severe COVID-19 patients with acute respiratory distress syndrome.

Acute Respiratory Distress Syndrome (ARDS) is common in COVID-19 patients and is associated with high mortality. The aim of this observational study was to describe patients' characteristics and outcome, identifying potential risk factors for in-hospital mortality and for developing Long-COVID symptoms. This retrospective study included all patients with COVID-19 associated ARDS (cARDS) in the period from March 2020 to March 2021 who were invasively ventilated at the intensive care unit (ICU) of the University Hospital Dresden, Germany. Between October 2021 and December 2021 patients discharged alive (at minimum 6 months after hospital discharge-midterm survival) were contacted and interviewed about persistent symptoms possibly associated with COVID-19 as well as the quality of their lives using the EQ-5D-5L-questionnaire. Long-COVID was defined as the occurrence of one of the symptoms at least 6 months after discharge. Risk factors for mortality were assessed with Cox regression models and risk factors for developing Long-COVID symptoms by using relative risk (RR) regression. 184 Patients were included in this study (male: n = 134 (73%), median age 67 (range 25-92). All patients were diagnosed with ARDS according to the Berlin Definition. 89% of patients (n = 164) had severe ARDS (Horovitz-index < 100 mmHg). In 27% (n = 49) extracorporeal membrane oxygenation was necessary to maintain gas exchange. The median length of in-hospital stay was 19 days (range 1-60). ICU mortality was 51%, hospital mortality 59%. Midterm survival (median 11 months) was 83% (n = 55) and 78% (n = 43) of these patients presented Long-COVID symptoms with fatigue as the most common symptom (70%). Extreme obesity (BMI > 40 kg/m2) was the strongest predictor for in-hospital mortality (hazard ratio: 3.147, confidence interval 1.000-9.897) and for developing Long-COVID symptoms (RR 1.61, confidence interval 1.26-2.06). In-hospital mortality in severe cARDS patients was high, but > 80% of patients discharged alive survived the midterm observation period. Nonetheless, most patients developed Long-COVID symptoms. Extreme obesity with BMI > 40 kg/m2 was identified as independent risk factor for in-hospital mortality and for developing Long-COVID symptoms.Trial registration DRKS-ID DRKS00027856.

Enhancing Anticoagulation Monitoring and Therapy in Patients Undergoing Microvascular Reconstruction in Maxillofacial Surgery: A Prospective Observational Trial.

BACKGROUND: In reconstructive surgery, loss of a microvascular free flap due to perfusion disorders, especially thrombosis, is a serious complication. In recent years, viscoelastic testing (VET) has become increasingly important in point-of-care (POC) anticoagulation monitoring. This paper describes a protocol for enhanced anticoagulation monitoring during maxillofacial flap surgery. OBJECTIVE: The aim of the study will be to evaluate, in a controlled setting, the predictive value of POC devices for the type of flap perfusion disorders due to thrombosis or bleeding. VET, Platelet monitoring (PM) and standard laboratory tests (SLT) are comparatively examined. METHODS/DESIGN: This study is an investigator-initiated prospective trial in 100 patients undergoing maxillofacial surgery. Patients who undergo reconstructive surgery using microvascular-free flaps will be consecutively enrolled in the study. All patients provide blood samples for VET, PM and SLT at defined time points. The primary outcome is defined as free flap loss during the hospital stay. Statistical analyses will be performed using t-tests, including the Bonferroni adjustment for multiple comparisons. DISCUSSION: This study will help clarify whether VET can improve individualized patient care in reconstruction surgery. A better understanding of coagulation in relation to flap perfusion disorders may allow real-time adaption of antithrombotic strategies and potentially prevent flap complications.

Predictive ability of viscoelastic testing using ClotPro® for short-term outcome in patients with severe Covid-19 ARDS with or without ECMO therapy: a retrospective study.

BACKGROUND: SARS-CoV-2 infections are suspected to trigger the coagulation system through various pathways leading to a high incidence of thromboembolic complications, hypercoagulation and impaired fibrinolytic capacity were previously identified as potentially mechanisms. A reliable diagnostic tool for detecting both is still under discussion. This retrospective study is aimed to examine the prognostic relevance of early viscoelastic testing compared to conventional laboratory tests in COVID-19 patients with acute respiratory distress syndrome (ARDS). METHODS: All mechanically ventilated patients with COVID-19 related ARDS treated in our intensive care unit (ICU) between January and March 2021 were included in this study. Viscoelastic testing (VET) was performed using the ClotPro® system after admission to our ICU. Prevalence of thromboembolic events was observed by standardized screening for venous and pulmonary thromboembolism using complete compression ultrasound and thoracic computed tomography pulmonary angiography at ICU admission, respectively. We examined associations between the severity of ARDS at admission to our ICU, in-hospital mortality and the incidence of thromboembolic events comparing conventional laboratory analysis and VET. ECMO related coagulopathy was investigated in a subgroup analysis. The data were analyzed using the Mann-Whitney U test. RESULTS: Of 55 patients enrolled in this study, 22 patients required treatment with ECMO. Thromboembolic complications occurred in 51% of all patients. Overall hospital mortality was 55%. In patients with thromboembolic complications, signs of reduced fibrinolytic capacity could be detected in the TPA assay with prolonged lysis time, median 460 s (IQR 350-560) vs 359 s (IQR 287-521, p = 0.073). Patients with moderate to severe ARDS at admission to our ICU showed increased maximum clot firmness as a sign of hypercoagulation in the EX-test (70 vs 67 mm, p < 0.05), FIB-test (35 vs 24 mm, p < 0.05) and TPA-test (52 vs 36 mm, p < 0.05) as well as higher values of inflammatory markers (CRP, PCT and IL6). ECMO patients suffered more frequently from bleeding complications (32% vs 15%). CONCLUSION: Although, the predictive value for thromboembolic complications or mortality seems limited, point-of-care viscoelastic coagulation testing might be useful in detecting hypercoagulable states and impaired fibrinolysis in critically ill COVID-19 ARDS patients and could be helpful in identifying patients with a potentially very severe course of the disease.

Changes in lung aeration and respiratory function after open abdominal surgery: A quantitative magnetic resonance imaging study.

BACKGROUND: Atelectasis is one of the most common respiratory complications in patients undergoing open abdominal surgery. Peripheral oxygen saturation (SpO2 ) and forced vital capacity (FVC) are bedside indicators of postoperative respiratory dysfunction. The aim of this study was to describe the changes in lung aeration, using quantitative analysis of magnetic resonance imaging (MRI) and the diagnostic accuracy of SpO2 and FVC to detect postoperative atelectasis. METHODS: Post-hoc analysis of a randomized trial conducted at a University Hospital in Dresden, Germany. Patients undergoing pre- and postoperative lung MRI were included. MRI signal intensity was analyzed quantitatively to define poorly and nonaerated lung compartments. Postoperative atelectasis was defined as nonaerated lung volume above 2% of the total lung volume in the respective MRI investigation. RESULTS: This study included 45 patients, 27 with and 18 patients without postoperative atelectasis. Patients with atelectasis had higher body mass index (p = .024), had more preoperative poorly aerated lung volume (p = .049), a lower preoperative SpO2 (p = .009), and a lower preoperative FVC (p = .029). The amount of atelectasis correlated with preoperative SpO2 (Spearman's ρ = -.51, p < .001) and postoperative SpO2 (ρ = -.60, p < .001), and with preoperative FVC (ρ = -.29, p = .047) and postoperative FVC (ρ = -.40, p = .006). A postoperative SpO2 ≤ 94% had 74% sensitivity and 78% specificity to detect atelectasis, while postoperative FVC ≤ 50% had 56% sensitivity and 100% specificity to detect atelectasis. CONCLUSION: SpO2 and FVC correlated with the amount of postoperative non-aerated lung volume, showing acceptable diagnostic accuracy in bedside detection of postoperative atelectasis.

Characteristics and outcomes of sepsis patients with and without COVID-19.

BACKGROUND: The aim of this study was to describe and compare clinical characteristics and outcomes in critically ill septic patients with and without COVID-19. METHODS: From February 2020 to March 2021, patients from surgical and medical ICUs at the University Hospital Dresden were screened for sepsis. Patient characteristics and outcomes were assessed descriptively. Patient survival was analyzed using the Kaplan-Meier estimator. Associations between in-hospital mortality and risk factors were modeled using robust Poisson regression, which facilitates derivation of adjusted relative risks. RESULTS: In 177 ICU patients treated for sepsis, COVID-19 was diagnosed and compared to 191 septic ICU patients without COVID-19. Age and sex did not differ significantly between sepsis patients with and without COVID-19, but SOFA score at ICU admission was significantly higher in septic COVID-19 patients. In-hospital mortality was significantly higher in COVID-19 patients with 59% compared to 29% in Non-COVID patients. Statistical analysis resulted in an adjusted relative risk for in-hospital mortality of 1.74 (95%-CI=1.35-2-24) in the presence of COVID-19 compared to other septic patients. Age, procalcitonin maximum value over 2 ng/ml, need for renal replacement therapy, need for invasive ventilation and septic shock were identified as additional risk factors for in-hospital mortality. CONCLUSION: COVID-19 was identified as independent risk factor for higher in-hospital mortality in sepsis patients. The need for invasive ventilation and renal replacement therapy as well as the presence of septic shock and higher PCT should be considered to identify high-risk patients.

Point of care coagulation management in anesthesiology and critical care.

Point of care (POC) devices are increasingly used in the ICU and in anesthesia. Besides POC-devices for blood gas analysis, several devices are available for coagulation measurements. Although basic principles for thromboelastographic measurements are not novel, some promising developments were made during the last decade improving both user-friendliness and measurement reliability. For instance, POC measurements of activated clotting time (ACT) for heparin monitoring is still regarded as standard-of-care in cardiac interventions and surgery. In the field of anesthesia and intensive care medicine, POC-devices for thromboelastographic and platelet aggregation measurements are widely used. Their impact in case of bleeding and patient blood management for cardiothoracic and trauma surgery is well known. Moreover, there are promising concepts for anticoagulation monitoring including new oral anticoagulant drugs. Coagulation POC-devices may also identify patients at specific risk for thromboembolic events quickly. On the other hand, benefits of POC-devices need to be balanced against limitations, which include technical restrictions and operator related errors, mainly affecting reproducibility and interpretation of results. Therefore, it is recommendable to consider results of POC-coagulation testing in comparison to standard laboratory tests (SLT). Nevertheless, in urgent or emergency situations POC results enable fast decision making to optimize patient care.

COVID-19 and Intracranial Hemorrhage: A Multicenter Case Series, Systematic Review and Pooled Analysis.

INTRODUCTION: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) profoundly impacts hemostasis and microvasculature. In the light of the dilemma between thromboembolic and hemorrhagic complications, in the present paper, we systematically investigate the prevalence, mortality, radiological subtypes, and clinical characteristics of intracranial hemorrhage (ICH) in coronavirus disease (COVID-19) patients. METHODS: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we performed a systematic review of the literature by screening the PubMed database and included patients diagnosed with COVID-19 and concomitant ICH. We performed a pooled analysis, including a prospectively collected cohort of critically ill COVID-19 patients with ICH, as part of the PANDEMIC registry (Pooled Analysis of Neurologic Disorders Manifesting in Intensive Care of COVID-19). RESULTS: Our literature review revealed a total of 217 citations. After the selection process, 79 studies and a total of 477 patients were included. The median age was 58.8 years. A total of 23.3% of patients experienced the critical stage of COVID-19, 62.7% of patients were on anticoagulation and 27.5% of the patients received ECMO. The prevalence of ICH was at 0.85% and the mortality at 52.18%, respectively. CONCLUSION: ICH in COVID-19 patients is rare, but it has a very poor prognosis. Different subtypes of ICH seen in COVID-19, support the assumption of heterogeneous and multifaceted pathomechanisms contributing to ICH in COVID-19. Further clinical and pathophysiological investigations are warranted to resolve the conflict between thromboembolic and hemorrhagic complications in the future.

An Automated Electronic Screening Tool (DETECT) for the Detection of Potentially Irreversible Loss of Brain Function.

BACKGROUND: A major reason for the low number of organ donors in Germany is a deficit in the recognition of patients who may have impending irreversible loss of brain function (ILBF) in hospitals capable of organ retrieval. METHODS: We used anonymized data from the German Organ Procurement Organization (Deutsche Stiftung Organtransplantation, DSO) to compare two 12-month periods (a reference period and an evaluation period) before and after the implementation of an electronic screening tool (DETECT) at the University Hospital Dresden (UKD) with four other university hospitals without tool implementation (comparative cohort). DETECT is intended to aid in the recognition of potentially impending ILBF. The study endpoints encompassed patients with potentially unrecognized ILBF, patients with recognized ILBF, organ donations performed, and reports to the DSO. Changes in absolute risk were compared with Breslow-Day tests. RESULTS: 309 patients who died with primary or secondary brain lesions were identified in the UKD in the reference and evaluation periods (164 and 145 patients, respectively), and 1060 (529, 531) in the comparative cohort. In the UKD, the number of unrecognized cases of possibly impending ILBF was 14/164 (8.54%) in the reference period and 1/145 (0.69%) in the evaluation period, yielding an absolute reduction of 7.85% (95% confidence interval [--3.36; --12.33]); by contrast, in the comparative cohort, there was a 0.55% absolute increase between the two periods ([--2.21; 3.30]; p = 0.002 for the comparison between the two cohorts). Only minor differences in absolute risk change were seen with regard to the probability of recognized ILBF (7.09% [0.29; 13.88] vs. 2.42% [1.18; 6.01]; p = 0.234), organ donation (4.70% [--0.89; 10.28] vs. 0.55% [--2.17; 3.26]; p = 0.214), or reporting to the DSO (4.17% [--1.77; 10.11] vs. 2.22% [--1.44; 5.89; p = 0.447); these changes may have arisen by chance. CONCLUSION: These findings suggest that the use of DETECT can help to reduce the deficit in the recognition of patients with impending or manifest ILBF.

Comparative effects of neurally adjusted ventilatory assist and variable pressure support on lung and diaphragmatic function in a model of acute respiratory distress syndrome: A randomised animal study.

BACKGROUND: Variable assisted mechanical ventilation has been shown to improve lung function and reduce lung injury. However, differences between extrinsic and intrinsic variability are unknown. OBJECTIVE: To investigate the effects of neurally adjusted ventilatory assist (NAVA, intrinsic variability), variable pressure support ventilation (Noisy PSV, extrinsic variability) and conventional pressure-controlled ventilation (PCV) on lung and diaphragmatic function and damage in experimental acute respiratory distress syndrome (ARDS). DESIGN: Randomised controlled animal study. SETTING: University Hospital Research Facility. SUBJECTS: A total of 24 juvenile female pigs. INTERVENTIONS: ARDS was induced by repetitive lung lavage and injurious ventilation. Animals were randomly assigned to 24 h of either: 1) NAVA, 2) Noisy PSV or 3) PCV (n=8 per group). Mechanical ventilation settings followed the ARDS Network recommendations. MEASUREMENTS: The primary outcome was histological lung damage. Secondary outcomes were respiratory variables and patterns, subject-ventilator asynchrony (SVA), pulmonary and diaphragmatic biomarkers, as well as diaphragmatic muscle atrophy and myosin isotypes. RESULTS: Global alveolar damage did not differ between groups, but NAVA resulted in less interstitial oedema in dorsal lung regions than Noisy PSV. Gas exchange and SVA incidence did not differ between groups. Compared with Noisy PSV, NAVA generated higher coefficients of variation of tidal volume and respiratory rate. During NAVA, only 40.4% of breaths were triggered by the electrical diaphragm signal. The IL-8 concentration in lung tissue was lower after NAVA compared with PCV and Noisy PSV, whereas Noisy PSV yielded lower type III procollagen mRNA expression than NAVA and PCV. Diaphragmatic muscle fibre diameters were smaller after PCV compared with assisted modes, whereas expression of myosin isotypes did not differ between groups. CONCLUSION: Noisy PSV and NAVA did not reduce global lung injury compared with PCV but affected different biomarkers and attenuated diaphragmatic atrophy. NAVA increased the respiratory variability; however, NAVA yielded a similar SVA incidence as Noisy PSV. TRIAL REGISTRATION: This trial was registered and approved by the Landesdirektion Dresden, Germany (AZ 24-9168.11-1/2012-2).

Non-canonical chemical feedback self-limits nitric oxide-cyclic GMP signaling in health and disease.

Nitric oxide (NO)-cyclic GMP (cGMP) signaling is a vasoprotective pathway therapeutically targeted, for example, in pulmonary hypertension. Its dysregulation in disease is incompletely understood. Here we show in pulmonary artery endothelial cells that feedback inhibition by NO of the NO receptor, the cGMP forming soluble guanylate cyclase (sGC), may contribute to this. Both endogenous NO from endothelial NO synthase and exogenous NO from NO donor compounds decreased sGC protein and activity. This effect was not mediated by cGMP as the NO-independent sGC stimulator, or direct activation of cGMP-dependent protein kinase did not mimic it. Thiol-sensitive mechanisms were also not involved as the thiol-reducing agent N-acetyl-L-cysteine did not prevent this feedback. Instead, both in-vitro and in-vivo and in health and acute respiratory lung disease, chronically elevated NO led to the inactivation and degradation of sGC while leaving the heme-free isoform, apo-sGC, intact or even increasing its levels. Thus, NO regulates sGC in a bimodal manner, acutely stimulating and chronically inhibiting, as part of self-limiting direct feedback that is cGMP independent. In high NO disease conditions, this is aggravated but can be functionally recovered in a mechanism-based manner by apo-sGC activators that re-establish cGMP formation.

Effects of variable versus nonvariable controlled mechanical ventilation on pulmonary inflammation in experimental acute respiratory distress syndrome in pigs.

BACKGROUND: Mechanical ventilation with variable tidal volumes (VT) may improve lung function and reduce ventilator-induced lung injury in experimental acute respiratory distress syndrome (ARDS). However, previous investigations were limited to less than 6 h, and control groups did not follow clinical standards. We hypothesised that 24 h of mechanical ventilation with variable VT reduces pulmonary inflammation (as reflected by neutrophil infiltration), compared with standard protective, nonvariable ventilation. METHODS: Experimental ARDS was induced in 14 anaesthetised pigs with saline lung lavage followed by injurious mechanical ventilation. Pigs (n=7 per group) were randomly assigned to using variable VT or nonvariable VT modes of mechanical ventilation for 24 h. In both groups, ventilator settings including positive end-expiratory pressure and oxygen inspiratory fraction were adjusted according to the ARDS Network protocol. Pulmonary inflammation (primary endpoint) and perfusion were assessed by positron emission tomography using 2-deoxy-2-[18F]fluoro-d-glucose and 68Gallium (68Ga)-labelled microspheres, respectively. Gas exchange, respiratory mechanics, and haemodynamics were quantified. Lung aeration was determined using CT. RESULTS: The specific global uptake rate of 18F-FDG increased to a similar extent regardless of mode of mechanical ventilation (median uptake for variable VT=0.016 min-1 [inter-quartile range, 0.012-0.029] compared with median uptake for nonvariable VT=0.037 min-1 [0.008-0.053]; P=0.406). Gas exchange, respiratory mechanics, haemodynamics, and lung aeration and perfusion were similar in both variable and nonvariable VT ventilatory modes. CONCLUSION: In a porcine model of ARDS, 24 h of mechanical ventilation with variable VT did not attenuate pulmonary inflammation compared with standard protective mechanical ventilation with nonvariable VT.

Periodic Fluctuation of Tidal Volumes Further Improves Variable Ventilation in Experimental Acute Respiratory Distress Syndrome.

In experimental acute respiratory distress syndrome (ARDS), random variation of tidal volumes (VT ) during volume controlled ventilation improves gas exchange and respiratory system mechanics (so-called stochastic resonance hypothesis). It is unknown whether those positive effects may be further enhanced by periodic VT fluctuation at distinct frequencies, also known as deterministic frequency resonance. We hypothesized that the positive effects of variable ventilation on lung function may be further amplified by periodic VT fluctuation at specific frequencies. In anesthetized and mechanically ventilated pigs, severe ARDS was induced by saline lung lavage and injurious VT (double-hit model). Animals were then randomly assigned to 6 h of protective ventilation with one of four VT patterns: (1) random variation of VT (WN); (2) P04, main VT frequency of 0.13 Hz; (3) P10, main VT frequency of 0.05 Hz; (4) VCV, conventional non-variable volume controlled ventilation. In groups with variable VT , the coefficient of variation was identical (30%). We assessed lung mechanics and gas exchange, and determined lung histology and inflammation. Compared to VCV, WN, P04, and P10 resulted in lower respiratory system elastance (63 ± 13 cm H2O/L vs. 50 ± 14 cm H2O/L, 48.4 ± 21 cm H2O/L, and 45.1 ± 5.9 cm H2O/L respectively, P < 0.05 all), but only P10 improved PaO2/FIO2 after 6 h of ventilation (318 ± 96 vs. 445 ± 110 mm Hg, P < 0.05). Cycle-by-cycle analysis of lung mechanics suggested intertidal recruitment/de-recruitment in P10. Lung histologic damage and inflammation did not differ among groups. In this experimental model of severe ARDS, periodic VT fluctuation at a frequency of 0.05 Hz improved oxygenation during variable ventilation, suggesting that deterministic resonance adds further benefit to variable ventilation.

Association between pre-operative biological phenotypes and postoperative pulmonary complications: An unbiased cluster analysis.

BACKGROUND: Biological phenotypes have been identified within several heterogeneous pulmonary diseases, with potential therapeutic consequences. OBJECTIVE: To assess whether distinct biological phenotypes exist within surgical patients, and whether development of postoperative pulmonary complications (PPCs) and subsequent dependence of intra-operative positive end-expiratory pressure (PEEP) differ between such phenotypes. SETTING: Operating rooms of six hospitals in Europe and USA. DESIGN: Secondary analysis of the 'PROtective Ventilation with HIgh or LOw PEEP' trial. PATIENTS: Adult patients scheduled for abdominal surgery who are at risk of PPCs. INTERVENTIONS: Measurement of pre-operative concentrations of seven plasma biomarkers associated with inflammation and lung injury. MAIN OUTCOME MEASURES: We applied unbiased cluster analysis to identify biological phenotypes. We then compared the proportion of patients developing PPCs within each phenotype, and associations between intra-operative PEEP levels and development of PPCs among phenotypes. RESULTS: In total, 242 patients were included. Unbiased cluster analysis clustered the patients within two biological phenotypes. Patients with phenotype 1 had lower plasma concentrations of TNF-α (3.8 [2.4 to 5.9] vs. 10.2 [8.0 to 12.1] pg ml; P < 0.001), IL-6 (2.3 [1.5 to 4.0] vs. 4.0 [2.9 to 6.5] pg ml; P < 0.001) and IL-8 (4.7 [3.1 to 8.1] vs. 8.1 [6.0 to 13.9] pg ml; P < 0.001). Phenotype 2 patients had the highest incidence of PPC (69.8 vs. 34.2% in type 1; P < 0.001). There was no interaction between phenotype and PEEP level for the development of PPCs (43.2% in high PEEP vs. 25.6% in low PEEP in phenotype 1, and 73.6% in high PEEP and 65.7% in low PEEP in phenotype 2; P for interaction = 0.503). CONCLUSION: Patients at risk of PPCs and undergoing open abdominal surgery can be clustered based on pre-operative plasma biomarker concentrations. The two identified phenotypes have different incidences of PPCs. Biologic phenotyping could be useful in future randomised controlled trials of intra-operative ventilation. TRIAL REGISTRATION: The PROtective Ventilation with HIgh or LOw PEEP trial, including the substudy from which data were used for the present analysis, was registered at ClinicalTrials.gov (NCT01441791).

Kinetics of plasma biomarkers of inflammation and lung injury in surgical patients with or without postoperative pulmonary complications.

BACKGROUND: Postoperative pulmonary complications (PPCs) are common after major abdominal surgery. The kinetics of plasma biomarkers could improve identification of patients developing PPCs, but the kinetics may depend on intraoperative ventilator settings. OBJECTIVE: To test whether the kinetics of plasma biomarkers are capable of identifying patients who will develop PPCs, and whether the kinetics depend on the intraoperative level of positive end-expiratory pressure (PEEP). DESIGN: A preplanned substudy of a randomised controlled trial. SETTING: Operation room of five centres. PATIENTS: Two hundred and forty-two adult patients scheduled for abdominal surgery at risk of developing PPCs. INTERVENTIONS: High (12 cmH2O) versus low (≤2 cmH2O) levels of PEEP. MAIN OUTCOME MEASURES: Individual PPCs were combined as a composite endpoint. Plasma samples were collected before surgery, directly after surgery and on the fifth postoperative day. The levels of the following were measured: tumour necrosis factor (TNF)-α, interleukin (IL)-6 and IL-8, the soluble form of the Receptor for Advanced Glycation End-products (sRAGE), Surfactant Protein (SP)-D, Clara Cell protein (CC)-16 and Krebs von den Lungen 6 (KL6). RESULTS: Blood sampling was complete in 242 patients: 120 patients in the high PEEP group and 122 patients in the low PEEP group. Increases in plasma levels of TNF- IL-6, IL-8 and CC-16, and a decrease in plasma levels of SP-D were greater in patients who developed PPCs; however, the area under the receiver operating characteristic curve was low for all biomarkers. CC-16 was the only biomarker whose level increased more in patients who had received high levels of PEEP. CONCLUSION: In patients undergoing abdominal surgery and at risk of developing PPCs, plasma levels of biomarkers for inflammation or lung injury showed distinct kinetics with development of PPCs, but none of the biomarkers showed sufficient prognostic value. The use of high levels of PEEP was associated with increased levels of CC-16, suggesting lung overdistension. TRIAL REGISTRATION: The PROVHILO trial, including this substudy, was registered at clinicaltrials.gov (NCT01441791).