Causes of Hypoxemia in COVID-19 Acute Respiratory Distress Syndrome: A Combined Multiple Inert Gas Elimination Technique and Dual-energy Computed Tomography Study.

BACKGROUND: Despite the fervent scientific effort, a state-of-the art assessment of the different causes of hypoxemia (shunt, ventilation-perfusion mismatch, and diffusion limitation) in COVID-19 acute respiratory distress syndrome (ARDS) is currently lacking. In this study, the authors hypothesized a multifactorial genesis of hypoxemia and aimed to measure the relative contribution of each of the different mechanism and their relationship with the distribution of tissue and blood within the lung. METHODS: In this cross-sectional study, the authors prospectively enrolled 10 patients with COVID-19 ARDS who had been intubated for less than 7 days. The multiple inert gas elimination technique (MIGET) and a dual-energy computed tomography (DECT) were performed and quantitatively analyzed for both tissue and blood volume. Variables related to the respiratory mechanics and invasive hemodynamics (PiCCO [Getinge, Sweden]) were also recorded. RESULTS: The sample (51 ± 15 yr; Pao2/Fio2, 172 ± 86 mmHg) had a mortality of 50%. The MIGET showed a shunt of 25 ± 16% and a dead space of 53 ± 11%. Ventilation and perfusion were mismatched (LogSD, Q, 0.86 ± 0.33). Unexpectedly, evidence of diffusion limitation or postpulmonary shunting was also found. In the well aerated regions, the blood volume was in excess compared to the tissue, while the opposite happened in the atelectasis. Shunt was proportional to the blood volume of the atelectasis (R2 = 0.70, P = 0.003). V˙A/Q˙T mismatch was correlated with the blood volume of the poorly aerated tissue (R2 = 0.54, P = 0.016). The overperfusion coefficient was related to Pao2/Fio2 (R2 = 0.66, P = 0.002), excess tissue mass (R2 = 0.84, P < 0.001), and Etco2/Paco2 (R2 = 0.63, P = 0.004). CONCLUSIONS: These data support the hypothesis of a highly multifactorial genesis of hypoxemia. Moreover, recent evidence from post-mortem studies (i.e., opening of intrapulmonary bronchopulmonary anastomosis) may explain the findings regarding the postpulmonary shunting. The hyperperfusion might be related to the disease severity.

Quantification of Bile Acids in Cerebrospinal Fluid: Results of an Observational Trial.

(1) Background: Bile acids, known as aids in intestinal fat digestion and as messenger molecules in serum, can be detected in cerebrospinal fluid (CSF), although the blood-brain barrier is generally an insurmountable obstacle for bile acids. The exact mechanisms of the occurrence, as well as possible functions of bile acids in the central nervous system, are not precisely understood. (2) Methods: We conducted a single-center observational trial. The concentrations of 15 individual bile acids were determined using an in-house LC-MS/MS method in 54 patients with various acute and severe disorders of the central nervous system. We analyzed CSF from ventricular drainage taken within 24 h after placement, and blood samples were drawn at the same time for the presence and quantifiability of 15 individual bile acids. (3) Results: At a median time of 19.75 h after a cerebral insult, the concentration of bile acids in the CSF was minute and almost negligible. The CSF concentrations of total bile acids (TBAs) were significantly lower compared to the serum concentrations (serum 0.37 µmol/L [0.24, 0.89] vs. 0.14 µmol/L [0.05, 0.43]; p = 0.033). The ratio of serum-to-CSF bile acid levels calculated from the respective total concentrations were 3.10 [0.94, 14.64] for total bile acids, 3.05 for taurocholic acid, 14.30 [1.11, 27.13] for glycocholic acid, 0.0 for chenodeoxycholic acid, 2.19 for taurochenodeoxycholic acid, 1.91 [0.68, 8.64] for glycochenodeoxycholic acid and 0.77 [0.0, 13.79] for deoxycholic acid; other bile acids were not detected in the CSF. The ratio of CSF-to-serum S100 concentration was 0.01 [0.0, 0.02]. Serum total and conjugated (but not unconjugated) bilirubin levels and serum TBA levels were significantly correlated (total bilirubin p = 0.031 [0.023, 0.579]; conjugated bilirubin p = 0.001 [0.193, 0.683]; unconjugated p = 0.387 [-0.181, 0.426]). No correlations were found between bile acid concentrations and age, delirium, intraventricular blood volume, or outcome measured on a modified Rankin scale. (4) Conclusions: The determination of individual bile acids is feasible using the current LC-MS/MS method. The results suggest an intact blood-brain barrier in the patients studied. However, bile acids were detected in the CSF, which could have been achieved by active transport across the blood-brain barrier.

Oral Drug Absorption and Drug Disposition in Critically Ill Cardiac Patients.

(1) Background: In critically ill cardiac patients, parenteral and enteral food and drug administration routes may be used. However, it is not well known how drug absorption and metabolism are altered in this group of adult patients. Here, we analyze drug absorption and metabolism in patients after cardiogenic shock using the pharmacokinetics of therapeutically indicated esomeprazole. (2) Methods: The pharmacokinetics of esomeprazole were analyzed in a consecutive series of patients with cardiogenic shock and controls before and after elective cardiac surgery. Esomeprazole was administered orally or with a nasogastric tube and once as an intravenous infusion. (3) Results: The maximum plasma concentration and AUC of esomeprazole were, on average, only half in critically ill patients compared with controls (p < 0.005) and remained lower even seven days later. Interestingly, esomeprazole absorption was also markedly compromised on day 1 after elective surgery. The metabolites of esomeprazole showed a high variability between patients. The esomeprazole sulfone/esomeprazole ratio reflecting CYP3A4 activity was significantly lower in critically ill patients even up to day 7, and this ratio was negatively correlated with CRP values (p = 0.002). The 5'-OH-esomeprazole and 5-O-desmethyl-esomeprazol ratios reflecting CYP2C19 activity did not differ significantly between critically ill and control patients. (4) Conclusions: Gastrointestinal drug absorption can be significantly reduced in critically ill cardiac patients compared with elective patients with stable cardiovascular disease. The decrease in bioavailability indicates that, under these conditions, any vital medication should be administered intravenously to maintain high levels of medications. After shock, hepatic metabolism via the CYP3A4 enzyme may be reduced.

Feasibility of Continuous Infusion of Cefiderocol in Conjunction with the Establishment of Therapeutic Drug Monitoring in Patients with Extensively Drug-Resistant Gram-Negative Bacteria.

BACKGROUND AND OBJECTIVE: Resistance to antibacterial substances is a huge and still emerging issue, especially with regard to Gram-negative bacteria and in critically ill patients. We report a study in six patients infected with extensively drug-resistant Gram-negative bacteria in a limited outbreak who were successfully managed with a quasi-continuous infusion of cefiderocol. METHODS: Patients were initially treated with prolonged infusions of cefiderocol over 3 h every 8 h, and the application mode was then switched to a quasi-continuous infusion of 2 g over 8 h, i.e. 6 g in 24 h. Therapeutic drug monitoring (TDM) was established using an in-house liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. RESULTS: Determined trough plasma concentrations were a median of 50.00 mg/L [95% confidence interval (CI) 27.20, 74.60] and steady-state plasma concentrations were a median of 90.96 mg/L [95% CI 37.80, 124]. No significant differences were detected with respect to acute kidney injury/continuous renal replacement therapy. Plasma concentrations determined from different modes of storage were almost equal when frozen or cooled, but markedly reduced when stored at room temperature. CONCLUSIONS: (Quasi) continuous application of cefiderocol 6 g/24 h in conjunction with TDM is a feasible mode of application; the sample for TDM should either be immediately analyzed, cooled, or frozen prior to analysis.

Association of the C-terminal 42-peptide fragment of alpha-1 antitrypsin with the severity of ARDS: A pilot study.

BACKGROUND: Acute respiratory distress syndrome is a life-threatening condition with a hospital mortality rate of up to 40%. Biomarkers related to the pathophysiology of ARDS may not only identify patients at risk but may also serve as potential therapeutic targets. This study examined the association between the proteolytic C-terminal 42-peptide fragment of alpha-1 antitrypsin and ARDS severity. METHODS: The 42-peptide fragment and interleukin-6 levels were measured in 21 patients with mild-to-moderate ARDS and 47 patients with moderate-to-severe ARDS on days 1, 3, and 5 after diagnosis/admission to the intensive care unit. To elucidate the association between both biomarkers and the PaO2/FiO2 ratio, the concentrations of both biomarkers were compared between the two groups, and a multivariate regression analysis was performed. RESULTS: The concentrations of both biomarkers were higher in patients with moderate-to-severe ARDS. While the PaO2/FiO2 ratio increased from day 1 to day 3, the concentrations of both biomarkers decreased. Multivariate regression analysis revealed negative associations between the PaO2/FiO2 ratio and both the C-terminal 42-peptide of alpha-1 antitrypsin and interleukin-6 on day 1 (beta: -0.138, p = 0.052; beta: -0.096, p = 0.004) and on day 3 (beta: -0.157, p = 0.045; beta: -0.106, p = 0.043). INTERPRETATION: The C-terminal 42-peptide of alpha-1 antitrypsin is a new biomarker associated with ARDS severity. Its predictive value in identifying patients at risk of developing moderate-to-severe ARDS must be investigated in additional, independent prospective studies.

A reduced glycine-to-taurine ratio of conjugated serum bile acids signifies an adaptive mechanism and is an early marker of outcome in acute respiratory distress syndrome.

The accumulation of Bile Acids (BA) in serum is a common finding in critically ill patients and has been found in patients with Acute Respiratory Distress Syndrome (ARDS), where liver and biliary function could be essentially affected by the underlying disease process and subsequent therapeutic measures. We hypothesized that the glycine-to-taurine conjugation ratio (G/T-ratio) is predictive of outcome in ARDS patients and would support our previously published hypothesis that the BA profile reflects a (mal-) adaptive response of bile acid production when suffering from a disease or syndrome such as ARDS. In 70 patients with ARDS, we determined conjugated BA fractions from protein precipitated serum samples using a LC-MS/MS method and calculated the G/T-ratios, which were then compared with a healthy control group. In patients with ARDS, the G/T-ratio was markedly lower compared to the control group, due to an increase in taurine-conjugated BA. The G/T ratio was lowest on the day of diagnosis and increased steadily during the following days (control = 3.80 (2.28-4.44); day 0 = 1.79 (1.31-3.86); day 3 = 2.91 (1.71-5.68); day 5 = 2.28 (1.25-7.85), significant increases were found between day 0 and day 3 (p = 0.019) and between day 0 and day 5 (p = 0.031). G/T-ratio was significantly correlated with SAPS II score on day 0 (p = 0.009) and day 3 (p = 0.036) and with survival (p = 0.006). Regarding survival, the receiver-operator characteristic revealed an area-under-the-curve of 0.713 (CI 0.578-0.848), the Youden index revealed a G/T-ratio cut-off level of 2.835 (sensitivity 78.4%, specificity 63.2%). Our findings further support our previously published hypothesis that alterations in BA profiles represent adaptive mechanisms in states of severe disease. Our current study adds the finding of an increase in taurine-conjugated BA expressed by a decrease in the G/T-ratio of conjugated BA in serum. The G/T-ratio on day 3 using a threshold G/T-ratio of 2.8 was even associated with survival (p = 0.006); these results are yet to be confirmed by subsequent studies.

End-Tidal to Arterial Pco2 Ratio as Guide to Weaning from Venovenous Extracorporeal Membrane Oxygenation.

Rationale: Weaning from venovenous extracorporeal membrane oxygenation (VV-ECMO) is based on oxygenation and not on carbon dioxide elimination. Objectives: To predict readiness to wean from VV-ECMO. Methods: In this multicenter study of mechanically ventilated adults with severe acute respiratory distress syndrome receiving VV-ECMO, we investigated a variable based on CO2 elimination. The study included a prospective interventional study of a physiological cohort (n = 26) and a retrospective clinical cohort (n = 638). Measurements and Main Results: Weaning failure in the clinical and physiological cohorts were 37% and 42%, respectively. The main cause of failure in the physiological cohort was high inspiratory effort or respiratory rate. All patients exhaled similar amounts of CO2, but in patients who failed the weaning trial, [Formula: see text]e was higher to maintain the PaCO2 unchanged. The effort to eliminate one unit-volume of CO2, was double in patients who failed (68.9 [42.4-123] vs. 39 [20.1-57] cm H2O/[L/min]; P = 0.007), owing to the higher physiological Vd (68 [58.73] % vs. 54 [41.64] %; P = 0.012). End-tidal partial carbon dioxide pressure (PetCO2)/PaCO2 ratio was a clinical variable strongly associated with weaning outcome at baseline, with area under the receiver operating characteristic curve of 0.87 (95% confidence interval [CI], 0.71-1). Similarly, the PetCO2/PaCO2 ratio was associated with weaning outcome in the clinical cohort both before the weaning trial (odds ratio, 4.14; 95% CI, 1.32-12.2; P = 0.015) and at a sweep gas flow of zero (odds ratio, 13.1; 95% CI, 4-44.4; P < 0.001). Conclusions: The primary reason for weaning failure from VV-ECMO is high effort to eliminate CO2. A higher PetCO2/PaCO2 ratio was associated with greater likelihood of weaning from VV-ECMO.

Determination of individual bile acids in acute respiratory distress syndrome reveals a specific pattern of primary and secondary bile acids and a shift to the acidic pathway as an adaptive response to the critical condition.

OBJECTIVES: Cholestasis and elevated serum bile1 acid levels are common in critically ill patients. This study aims to define the specific pattern of bile acids associated with acute respiratory distress syndrome (ARDS) and the changes in pattern over time. METHODS: Prospective observational study. Serum samples of 70 ARDS patients were analyzed for primary bile acids (cholic acid, chenodeoxycholic acid) and secondary bile acids (deoxycholic acid, litocholic acid, and ursodeoxycholic acid) as well as their glycine and taurine glycation products. RESULTS: Primary bile acid levels increased from day zero to day five by almost 50% (p<0.05). This change bases on a statistically significant increase in all primary bile acids between day 0 and day 5 (cholic acid [CA] p=0.001, taurocholic acid [TCA] p=0.004, glycocholic acid [GCA] p<0.001, chenodeoxycholic acid [CDCA] p=0.036, taurochenodeoxycholic acid [TCDCA] p<0.001, glycochenodeoxycholic acid [GCDCA] p<0.001). Secondary bile acids showed predominantly decreased levels on day 0 compared to the control group and remained stable throughout the study period; the differences between day zero and day five were not statistically significant. Non-survivors exhibited significantly higher levels of TCDCA on day 5 (p<0.05) than survivors. This value was also independently associated with survival in a logistic regression model with an odds ratio of 2.24 (95% CI 0.53-9.46). CONCLUSIONS: The individual bile acid profile of this ARDS patient cohort is unique compared to other disease states. The combination of changes in individual bile acids reflects a shift toward the acidic pathway of bile acid synthesis. Our results support the concept of ARDS-specific plasma levels of bile acids in a specific pattern as an adaptive response mechanism.

Biomarkers of Cholestasis and Liver Injury in the Early Phase of Acute Respiratory Distress Syndrome and Their Pathophysiological Value.

BACKGROUND: Impaired liver function and cholestasis are frequent findings in critically ill patients and are associated with poor outcomes. We tested the hypothesis that hypoxic liver injury and hypoxic cholangiocyte injury are detectable very early in patients with ARDS, may depend on the severity of hypoxemia, and may be aggravated by the use of rescue therapies (high PEEP level and prone positioning) but could be attenuated by extracorporeal membrane oxygenation (ECMO). METHODS: In 70 patients with ARDS, aspartate-aminotransferase (AST), alanin-aminotransferase (ALT) and gamma glutamyltransferase (GGT) were measured on the day of the diagnosis of ARDS and three more consecutive days (day 3, day 5, day 10), total bile acids were measured on day 0, 3, and 5. RESULTS: AST levels increased on day 0 and remained constant until day 5, then dropped to normal on day 10 (day 0: 66.5 U/l; day 3: 60.5 U/l; day 5: 63.5 U/l, day 10: 32.1 U/l), ALT levels showed the exact opposite kinetic. GGT was already elevated on day 0 (91.5 U/l) and increased further throughout (day 3: 163.5 U/l, day 5: 213 U/l, day 10: 307 U/l), total bile acids levels increased significantly from day 0 to day 3 (p = 0.019) and day 0 to day 5 (p < 0.001), but not between day 3 and day 5 (p = 0.217). Total bile acids levels were significantly correlated to GGT on day 0 (p < 0.001), day 3 (p = 0.02), and in a trend on day 5 (p = 0.055). PEEP levels were significantly correlated with plasma levels of AST (day 3), ALT (day 5) and GGT (day 10). Biomarker levels were not associated with the use of ECMO, prone position, the cause of ARDS, and paO2. CONCLUSIONS: We found no evidence of hypoxic liver injury or hypoxic damage to cholangiocytes being caused by the severity of hypoxemia in ARDS patients during the very early phase of the disease. Additionally, mean PEEP level, prone positioning, and ECMO treatment did not have an impact in this regard. Nevertheless, GGT levels were elevated from day zero and rising, this increase was not related to paO2, prone position, ECMO treatment, or mean PEEP, but correlated to total bile acid levels.

Contraindications to the Initiation of Veno-Venous ECMO for Severe Acute Respiratory Failure in Adults: A Systematic Review and Practical Approach Based on the Current Literature.

(1) Background: Extracorporeal membrane oxygenation (ECMO) is increasingly used for acute respiratory failure with few absolute but many relative contraindications. The provider in charge often has a difficult time weighing indications and contraindications to anticipate if the patient will benefit from this treatment, a decision that often decides life and death for the patient. To assist in this process in coming to a good evidence-based decision, we reviewed the available literature. (2) Methods: We performed a systematic review through a literature search of the MEDLINE database of former and current absolute and relative contraindications to the initiation of ECMO treatment. (3) Results: The following relative and absolute contraindications were identified in the literature: absolute-refusal of the use of extracorporeal techniques by the patient, advanced stage of cancer, fatal intracerebral hemorrhage/cerebral herniation/intractable intracranial hypertension, irreversible destruction of the lung parenchyma without the possibility of transplantation, and contraindications to lung transplantation; relative-advanced age, immunosuppressed patients/pharmacological immunosuppression, injurious ventilator settings > 7 days, right-heart failure, hematologic malignancies, especially bone marrow transplantation and graft-versus-host disease, SAPS II score ≥ 60 points, SOFA score > 12 points, PRESERVE score ≥ 5 points, RESP score ≤ -2 points, PRESET score ≥ 6 points, and "do not attempt resuscitation" order (DN(A)R status). (4) Conclusions: We provide a simple-to-follow algorithm that incorporates absolute and relative contraindications to the initiation of ECMO treatment. This algorithm attempts to weigh pros and cons regarding the benefit for an individual patient and hopefully assists caregivers to make better, informed decisions.

The Specific Bile Acid Profile of Shock: A Hypothesis Generating Appraisal of the Literature.

BACKGROUND: Bile acid synthesis and regulation of metabolism are tightly regulated. In critical illness, these regulations are impaired. Consequently, the physiologic bile acid pattern in serum becomes disturbed and a disease-specific bile acid profile seems to become evident. METHODS: A literature review was performed and trials reporting the broken-down bile acid pattern were condensed with regard to percent differences in bile acid profiles of defined diseases compared to a human control. RESULTS: Ten articles were identified. Most of the studied bile acid profiles differ statistically significant between disease states, furthermore, neither of the reported disease entities show the same broken-down pattern of individual bile acids. Deoxycholic acid (DCA) was found to be decreased in almost all diseases, except for the two shock-states investigated (cardiogenic shock, septic shock) where it was elevated by about 100% compared to the control. Moreover, the pattern of both examined shock-states are very similar, rendering a specific shock-pattern possible, that we argue could eventually maintain or even worsen the pathological state. CONCLUSION: The specific broken-down bile acid profile of defined diseases might aid in gaining insight into the body's adaptive reaction and the differential diagnosis, as well as in the therapy of disease states in the early course of the disease.

Camostat Mesylate May Reduce Severity of Coronavirus Disease 2019 Sepsis: A First Observation.

Severe acute respiratory syndrome coronavirus 2 cell entry depends on angiotensin-converting enzyme 2 and transmembrane serine protease 2 and is blocked in cell culture by camostat mesylate, a clinically proven protease inhibitor. Whether camostat mesylate is able to lower disease burden in coronavirus disease 2019 sepsis is currently unknown. DESIGN: Retrospective observational case series. SETTING: Patient treated in ICU of University hospital Göttingen, Germany. PATIENTS: Eleven critical ill coronavirus disease 2019 patients with organ failure were treated in ICU. INTERVENTIONS: Compassionate use of camostat mesylate (six patients, camostat group) or hydroxychloroquine (five patients, hydroxychloroquine group). MEASUREMENTS AND MAIN RESULTS: Clinical courses were assessed by Sepsis-related Organ Failure Assessment score at days 1, 3, and 8. Further, viral load, oxygenation, and inflammatory markers were determined. Sepsis-related Organ Failure Assessment score was comparable between camostat and hydroxychloroquine groups upon ICU admission. During observation, the Sepsis-related Organ Failure Assessment score decreased in the camostat group but remained elevated in the hydroxychloroquine group. The decline in disease severity in camostat mesylate treated patients was paralleled by a decline in inflammatory markers and improvement of oxygenation. CONCLUSIONS: The severity of coronavirus disease 2019 decreased upon camostat mesylate treatment within a period of 8 days and a similar effect was not observed in patients receiving hydroxychloroquine. Camostat mesylate thus warrants further evaluation within randomized clinical trials.

Longtime Neurologic Outcome of Extracorporeal Membrane Oxygenation and Non Extracorporeal Membrane Oxygenation Acute Respiratory Distress Syndrome Survivors.

Neurologic complications following acute respiratory distress syndrome (ARDS) are well described, however, information on the neurologic outcome regarding peripheral nervous system complications in critically ill ARDS patients, especially those who received extracorporeal membrane oxygenation (ECMO) are lacking. In this prospective observational study 28 ARDS patients who survived after ECMO or conventional nonECMO treatment were examined for neurological findings. Nine patients had findings related to cranial nerve innervation, which differed between ECMO and nonECMO patients (p = 0.031). ECMO patients had severely increased patella tendon reflex (PTR) reflex levels (p = 0.027 vs. p = 0.125) as well as gastrocnemius tendon reflex (GTR) (p = 0.041 right, p = 0.149 left) were affected on the right, but not on the left side presumably associated with ECMO cannulation. Paresis (14.3% of patients) was only found in the ECMO group (p = 0.067). Paresthesia was frequent (nonECMO 53.8%, ECMO 62.5%; p = 0.064), in nonECMO most frequently due to initial trauma and polyneuropathy, in the ECMO group mainly due to impairments of N. cutaneus femoris lateralis (4 vs. 0; p = 0.031). Besides well-known central neurologic complications, more subtle complications were detected by thorough clinical examination. These findings are sufficient to hamper activities of daily living and impair quality of life and psychological health and are presumably directly related to ECMO therapy.

Minimal-flow ECCO2R in patients needing CRRT does not facilitate lung-protective ventilation.

Extracorporeal CO2 removal (ECCO2R) is intended to facilitate lung protective ventilation in patients with hypercarbia. The combination of continuous renal replacement therapy (CRRT) and minimal-flow ECCO2R offers a promising concept for patients in need of both. We hypothecated that this system is able to remove enough CO2 to facilitate lung protective ventilation in mechanically ventilated patients. In 11 ventilated patients with acute renal failure who received either pre- or postdilution CRRT, minimal-flow ECCO2R was added to the circuit. During 6 h of combined therapy, CO2 removal and its effect on facilitation of lung-protective mechanical ventilation were assessed. Ventilatory settings were kept in assisted or pressure-controlled mode allowing spontaneous breathing. With minimal-flow ECCO2R significant decreases in minute ventilation, tidal volume and paCO2 were found after one and three but not after 6 h of therapy. Nevertheless, no significant reduction in applied force was found at any time during combined therapy. CO2 removal was 20.73 ml CO2/min and comparable between pre- and postdilution CRRT. Minimal-flow ECCO2R in combination with CRRT is sufficient to reduce surrogates for lung-protective mechanical ventilation but was not sufficient to significantly reduce force applied to the lung. Causative might be the absolute amount of CO2 removal of only about 10% of resting CO2 production in an adult as we found. The benefit of applying minimal flow ECCO2R in an uncontrolled setting of mechanical ventilation might be limited.

Patient-Ventilator Interaction During Noninvasive Ventilation in Simulated COPD.

BACKGROUND: During noninvasive ventilation (NIV) of COPD patients, delayed off-cycling of pressure support can cause patient ventilator mismatch and NIV failure. This systematic experimental study analyzes the effects of varying cycling criteria on patient-ventilator interaction. METHODS: A lung simulator with COPD settings was connected to an ICU ventilator via helmet or face mask. Cycling was varied between 10 and 70% of peak inspiratory flow at different breathing frequencies (15 and 30 breaths/min) and pressure support levels (5 and 15 cm H2O) using the ventilator's invasive and NIV mode with and without an applied leakage. RESULTS: Low cycling criteria led to severe expiratory cycle latency. Augmenting off-cycling reduced expiratory cycle latency (P < .001), decreased intrinsic PEEP, and avoided non-supported breaths. Setting cycling to 50% of peak inspiratory flow achieved best synchronization. Overall, using the helmet interface increased expiratory cycle latency in almost all settings (P < .001). Augmenting cycling from 10 to 40% progressively decreased expiratory pressure load (P < .001). NIV mode decreased expiratory cycle latency compared with the invasive mode (P < .001). CONCLUSION: Augmenting the cycling criterion above the default setting (20-30% peak inspiratory flow) improved patient ventilator synchrony in a simulated COPD model. This suggests that an individual approach to cycling should be considered, since interface, level of pressure support, breathing frequency, and leakage influence patient-ventilator interaction and thus need to be considered.