Background. The rationale for using albumin in fluid resuscitation lies in its ability to increase plasma oncotic pressure and optimize hemodynamics and tissue perfusion. However, randomized trials in sepsis have not demonstrated a survival benefit, and the effects of albumin infusion on fluid distribution remain unclear. This study investigates, in healthy pigs, whether albumin infusion modifies Intravascular Fluid Volume (IFV) distribution, compared to crystalloids, and explores albumin kinetics. Methods. Thirty-nine healthy female pigs ventilated for 48 hours were categorized into four groups based on Mechanical Power (MP) (High ~18 J/min vs. Low ~6 J/min) and fluid type (5% albumin vs. balanced crystalloid) to achieve a set fluid balance: MPLOW-Crystalloid; MPLOW-Albumin; MPHIGH-Crystalloid; and MPHIGH-Albumin. Measurements were taken at baseline and six-hourly thereafter. Outcome variables included IFV and albumin kinetics and other physiological variables. Results. No significant differences in IFV were observed over time across groups (Figure 1), and at 48 hours: MPLOW-Crystalloid 1.92 (±0.38) L; MPLOW-Albumin 1.86 (±0.37) L; MPHIGH-Crystalloid 1.72 (±0.40) L; MPHIGH-Albumin 2.10 (±0.58) L; p=0.389. As expected, the theoretical and the actual quantities of albumin in the IFV were higher in the albumin groups compared to the crystalloid groups. Wasted albumin, defined as the difference between theoretical and actual albumin is shown in Figure 2. At 48h, albumin-treated groups demonstrated significantly greater albumin waste, as high as: 62 (±13) % in the MPLOW-Albumin group and 58 (±24) % in the MPHIGH-Albumin group (p<0.001). Groups receiving albumin had a higher volume of ascites: MPLOW-Crystalloids =261 (±380) mL, MPLOW-Albumin =710 (±664) mL, MPHIGH-Crystalloids =144 (±148) mL, and MPHIGH-Albumin =685 (±651) mL (p=0.034) (Figure 3, Panel A). Additionally, the amount of infused albumin was linearly related to the volume of ascites (p<0.001; R2=0.750) (Figure 3, Panel B). Conclusions. The 48h-long administration of albumin was associated with higher quantities of wasted albumin and greater volume of ascites.

The rationale of albumin use lies in its potential to increase oncotic pressure and optimize tissue perfusion. Randomized trials have not demonstrated a survival benefit, and the effects of albumin on volemia remain unclear. This study investigates, in healthy pigs, the effects of a 48-h albumin infusion on intravascular fluid volume, albumin kinetics, and its impact on respiratory function. Thirty-nine healthy female pigs ventilated for 48 h were grouped according to mechanical power (high 18 J/min vs. low 6 J/min) and type of fluid (5

Importance:Albumin supplementation may reduce mortality in patients with septic shock; however, data from randomized clinical trials are limited. Objective:To assess the impact of albumin administration on outcomes in patients with septic shock. Design, Setting, and Participants:This multicenter, open-label randomized clinical trial was conducted between October 21, 2019, and May 2, 2022. Patients from 23 intensive care units in Germany enrolled within 24 hours of the onset of septic shock were followed up for outcome data up to 90 days. The statistical trial report was completed and filed with the federal authorities in December 2023; additional analyses were completed in October 2024. The study was terminated prematurely due to low enrollment rates. Interventions:Protocol group patients received 20% albumin to maintain serum albumin levels of at least 3.0 g/dL for up to 28 days during their intensive care unit admission. The control group received standard fluid administration with crystalloids. Main Outcomes and Measures:The primary end point was 90-day mortality; secondary end points included 28-day, 60-day, intensive care unit and in-hospital mortality, organ dysfunction or failure, total amount of fluid administration and total fluid balance while in the intensive care unit, duration of intensive care and hospital stays, and frequency of adverse events. Results:Of 440 randomized patients (median [IQR] age, 69 [59-78] years; 290 [65.9%] male), 222 received albumin and 218 received standard fluids. Baseline characteristics were comparable. Ninety-day mortality was 43.3% (91 of 210) in the albumin group vs 45.9% (96 of 209) in controls (relative risk, 0.94; 95% CI, 0.76-1.17; P = .71). No significant differences were observed for secondary end points. Conclusions and Relevance:In this randomized clinical trial of patients with septic shock, albumin administration was safe but did not improve 90-day survival. As this trial was prematurely terminated, results remain inconclusive and additional studies are recommended. Trial Registration:ClinicalTrials.gov Identifier: NCT03869385.

QuestionCan the reported potential mortality reduction by albumin replacement in septic shock be confirmed in a randomized clinical trial?FindingsIn a multicenter randomized clinical trial, 440 adults with septic shock were treated with albumin therapy aiming to maintain serum albumin concentrations greater than 3.0 g/dL or with standard fluid therapy. Ninety-day mortality did not differ significantly between the albumin group (43.3%) and the controls (45.9%).MeaningThese results suggest that albumin administration was safe but did not improve 90-day survival in patients with septic shock; results remain inconclusive due to premature trial termination. This randomized clinical trial of patients with septic shock assesses whether albumin reduces 90-day mortality. ImportanceAlbumin supplementation may reduce mortality in patients with septic shock; however, data from randomized clinical trials are limited.ObjectiveTo assess the impact of albumin administration on outcomes in patients with septic shock.Design, Setting, and ParticipantsThis multicenter, open-label randomized clinical trial was conducted between October 21, 2019, and May 2, 2022. Patients from 23 intensive care units in Germany enrolled within 24 hours of the onset of septic shock were followed up for outcome data up to 90 days. The statistical trial report was completed and filed with the federal authorities in December 2023; additional analyses were completed in October 2024. The study was terminated prematurely due to low enrollment rates.InterventionsProtocol group patients received 20% albumin to maintain serum albumin levels of at least 3.0 g/dL for up to 28 days during their intensive care unit admission. The control group received standard fluid administration with crystalloids.Main Outcomes and MeasuresThe primary end point was 90-day mortality; secondary end points included 28-day, 60-day, intensive care unit and in-hospital mortality, organ dysfunction or failure, total amount of fluid administration and total fluid balance while in the intensive care unit, duration of intensive care and hospital stays, and frequency of adverse events.ResultsOf 440 randomized patients (median [IQR] age, 69 [59-78] years; 290 [65.9%] male), 222 received albumin and 218 received standard fluids. Baseline characteristics were comparable. Ninety-day mortality was 43.3% (91 of 210) in the albumin group vs 45.9% (96 of 209) in controls (relative risk, 0.94; 95% CI, 0.76-1.17; P = .71). No significant differences were observed for secondary end points.Conclusions and RelevanceIn this randomized clinical trial of patients with septic shock, albumin administration was safe but did not improve 90-day survival. As this trial was prematurely terminated, results remain inconclusive and additional studies are recommended.Trial RegistrationClinicalTrials.gov Identifier: NCT03869385

Rationale: The pathophysiological relationship among fluid administration, fluid balance, and mechanical ventilation in the development of lung injury is unclear. Objectives: To quantify the relative contributions of mechanical power and fluid balance in the development of lung injury. Methods: Thirty-nine healthy female pigs, divided into four groups, were ventilated for 48 hours with high (∼18 J/min) or low (∼6 J/min) mechanical power and high (∼4 L) or low (∼1 L) targeted fluid balance. Measurements and Main Results: We measured physiological variables (e.g., end-expiratory lung gas volume, respiratory system mechanics, gas exchange, hemodynamics) and pathological variables (i.e., lung weight, wet-to-dry ratio, and histology score of lung injury). End-expiratory lung gas volume, respiratory system elastance, strain, and oxygenation significantly worsened in the two groups assigned to receive high fluid balance, irrespective of the mechanical power received. All four groups had similar lung weights (i.e., lung edema), lung wet-to-dry ratios, and pathological variables. Animals with higher fluid balance developed more ascites, which was associated with a decrease in end-expiratory lung gas volume. Conclusions: Our study did not detect a significant difference in lung injury between high and low mechanical power. Some damage is directly attributable to mechanical power, while additional injury appears to result indirectly from high fluid balance, which reduces end-expiratory lung gas volume, with ascites playing an important role in this process.

Assessing and quantifying recruitability are important for characterizing ARDS severity and for reducing or preventing the atelectrauma caused by the cyclic opening and closing of pulmonary units. Over the years, several methods for recruitment assessment have been developed, grouped into three main approaches: 1) Quantitative CT Scanning: This method accurately measures the amount of atelectatic lung tissue that regains aeration; 2) Regional Gas Volume Measurement: Based on anatomical markers, this approach assesses gas volume within a specified lung region; 3) Compliance-Based Gas Volume Measurement: This technique compares actual gas volume at a given pressure to expected values, assuming respiratory system compliance is constant within the explored pressure range. Additional methods, such as lung ultrasonography and electrical impedance variation, have also been explored. This paper details the distribution of opening and closing pressures throughout the lung parenchyma, which underpin the concept of recruitability. The distribution of recruitable regions corresponds to atelectasis distribution, with the pressure needed for recruitment varying according to whether the atelectasis is “loose” or “sticky.” We also discuss the effects of different PEEP levels on preventing atelectrauma, the importance of keeping some lung areas closed throughout the respiratory cycle, and briefly cover the roles of sigh ventilation, prone positioning, and the closed lung approach.

The selection and intensity of respiratory support for ARDS are guided by PaO2/FiO2. However, ventilator-induced lung injury (VILI) is linked to respiratory mechanics and ventilator settings. We explored whether the VILI risk is related to ARDS severity based on oxygenation. We analysed data on 228 ARDS subjects with PaO2/FiO2 < 200 mmHg, categorized into three severity groups: one based on PaO2/FiO2 ratio, and the others based on tertiles of predictors of VILI: mechanical power ratio (MPR) and driving pressure (DP). In each group of oxygenation-based ARDS severity and MPR and DP tertiles, we measured CT anatomy, gas exchange, respiratory mechanics, VILI prerequisites (lung elastance and lung gas volume), and VILI determinants (tidal volume, PEEP, airway pressures). Predictors of VILI, such as MPR and DP, were similar across ARDS severity groups based on PaO2/FiO2 ratio, while oxygenation remained comparable across different levels of VILI risk defined by MPR and DP. Oxygenation impairment was associated with increased lung weight, recruitability, and reduced well-inflated tissue. In contrast, MPR and DP tertiles affected variables associated with the baby lung size, such as lung gas volume and well-inflated tissue. Mechanical ventilation intensity increased progressively across MPR and DP tertiles, but remained similar across PaO2/FiO2 severity groups. ARDS severity based on oxygenation impairment does not reflect the prerequisites and determinants of VILI. This should prompt a reconsideration of recommending respiratory support based on oxygenation impairment, rather than VILI determinants.

Objectives: The intensity of respiratory treatment in acute respiratory distress syndrome (ARDS) is traditionally adjusted based on oxygenation severity, as defined by the mild, moderate, and severe Berlin classifications. However, ventilator-induced lung injury (VILI) is primarily determined by ventilator settings, namely tidal volume, respiratory rate, and positive end-expiratory pressure (PEEP). All these variables, along with respiratory elastance, are included in the concept of mechanical power. The aim of this study is to investigate whether applied mechanical power is proportional to oxygenation severity. Methods: We analyzed 291 ARDS patients (71 mild, 155 moderate, and 65 severe). We defined low, middle, and high mechanical power by dividing the entire population into tertiles with a similar number of patients. In each oxygenation class, we measured computed tomography (CT) anatomy, gas exchange, respiratory mechanics, mechanical power, and mortality rate. Results: ARDS severity was proportional to lung anatomy impairment, as defined by quantitative CT scans (i.e., lung volume and well-aerated tissue decreased across the ARDS classes, while respiratory elastance increased, as did mortality). Mechanical power, however, was similarly distributed across the severity classes, as the decrease in tidal volume in severe ARDS was offset by an increase in respiratory rate. Within each ARDS class, mortality increased from low to high mechanical power (roughly 1% for each J/min increase). Conclusions: Both lung severity and mechanical power independently impact mortality rates. It is tempting to speculate that ARDS severity primarily reflects the natural course of the disease, while mechanical power primarily reflects the risk of VILI.

Abstract Background Ventilator-induced lung injury (VILI) is one of the side effects of mechanical ventilation during ARDS; a prerequisite for averting it is the quantification of its risk factors associated with a given ventilatory setting. Many clinical variables have been proposed as predictors of VILI, of which driving pressure is the most widely used. In this study, we compared the performance of driving pressure, four times the driving pressure added to respiratory rate (4DPRR) and mechanical power ratio. Results In a study population of 121 previously healthy pigs exposed to harmful ventilation, we compared the association of driving pressure, 4DPRR and mechanical power ratio to lung weight, lung wet-to-dry and total histological score. All the three variables were associated with these outcomes. Driving pressure, 4DPRR and mechanical power ratio increase linearly with the lung weight (adjusted R2 of 0.27, 0.36 and 0.40, respectively), the lung wet-to-dry ratio (adjusted R2 of 0.19, 0.25 and 0.37) and the total histological score (adjusted R2 of 0.26, 0.38 and 0.26). Using a multiple linear regression model with forward analysis, starting with tidal volume and progressively adding respiratory rate and positive end-expiratory pressure, and comparing the topic with the outcome variables, we obtained R2 values, respectively, of 0.07, 0.20, 0.42 for lung weight, 0.09, 0.19, 0.26 for lung wet-to-dry ratio and 0.07, 0.27, 0.43 for total histological score. Conclusions Driving pressure, 4DPRR and mechanical power ratio, were all associated with lung injury in healthy animals undergoing mechanical ventilation.

Background The individual components of mechanical ventilation may have distinct effects on kidney perfusion and on the risk of developing acute kidney injury; we aimed to explore ventilatory predictors of acute kidney failure and the hemodynamic changes consequent to experimental high-power mechanical ventilation. Methods Secondary analysis of two animal studies focused on the outcomes of different mechanical power settings, including 78 pigs mechanically ventilated with high mechanical power for 48 h. The animals were categorized in four groups in accordance with the RIFLE criteria for acute kidney injury (AKI), using the end-experimental creatinine: (1) NO AKI: no increase in creatinine; (2) RIFLE 1-Risk: increase of creatinine of > 50%; (3) RIFLE 2-Injury: two-fold increase of creatinine; (4) RIFLE 3-Failure: three-fold increase of creatinine; Results The main ventilatory parameter associated with AKI was the positive end-expiratory pressure (PEEP) component of mechanical power. At 30 min from the initiation of high mechanical power ventilation, the heart rate and the pulmonary artery pressure progressively increased from group NO AKI to group RIFLE 3. At 48 h, the hemodynamic variables associated with AKI were the heart rate, cardiac output, mean perfusion pressure (the difference between mean arterial and central venous pressures) and central venous pressure. Linear regression and receiving operator characteristic analyses showed that PEEP-induced changes in mean perfusion pressure (mainly due to an increase in CVP) had the strongest association with AKI. Conclusions In an experimental setting of ventilation with high mechanical power, higher PEEP had the strongest association with AKI. The most likely physiological determinant of AKI was an increase of pleural pressure and CVP with reduced mean perfusion pressure. These changes resulted from PEEP per se and from increase in fluid administration to compensate for hemodynamic impairment consequent to high PEEP;

(1) Background: Patients with sepsis following surgical intervention may exhibit fundamental distinctions from those experiencing sepsis without prior surgery. Despite the potential clinical importance of distinguishing these two sepsis subpopulations, dissimilarities, particularly in outcome, between surgical and non-surgical patients have been subject to limited scientific investigations in the existing literature. This study aimed to investigate the differences in mortality and sepsis-associated organ dysfunction between these two groups. (2) Methods: A retrospective analysis was conducted using data from a large cohort of prospectively enrolled patients with sepsis (n = 737) admitted to three intensive care units at University Medical Center Goettingen; patients were categorized into surgical (n = 582) and non-surgical sepsis groups (n = 155). The primary outcomes assessed were 28- and 90-day mortality rates, and secondary endpoints were multiple clinical parameters and measures of sepsis-associated organ dysfunction. (3) Results: Non-surgical patients presented a significantly higher 90-day mortality (37%) compared to surgical sepsis patients (30%, p = 0.0457). Moreover, the non-surgical sepsis group exhibited increased sepsis-associated organ dysfunction, as evidenced by higher average SOFA scores (p < 0.001), elevated levels of serum Procalcitonin (p = 0.0102), and a higher utilization of organ replacement therapies such as ventilation (p < 0.001), vasopressor treatment (p < 0.001), and renal replacement therapy (p = 0.0364). Additionally, non-surgical sepsis patients had higher organ-specific SOFA respiratory (p < 0.001), cardiovascular (p < 0.001), renal (p < 0.001), coagulation (0.0335), and central nervous system (p = 0.0206) subscores. (4) Conclusions: These results suggested that patients with non-surgical sepsis may face distinct challenges and a higher risk of adverse outcomes compared to patients with sepsis following surgical intervention. These findings have important implications for clinical decision-making, patient management, and resource allocation in sepsis care.

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-ter-minal 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 con-centrations 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 -pep-tide 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.

Mechanically ventilated patients suffering from acute respiratory distress syndrome (ARDS) frequently receive aerosolized iloprost. Because of prostacyclin’s short half-life, prolonged inhalative administration might improve its clinical efficacy. But, this is technically challenging. A solution might be the use of inspiration-synchronized vibrating mesh nebulizers (VMNsyn), which achieve high drug deposition rates while showing prolonged nebulization times. However, there are no data comparing prolonged to bolus iloprost nebulization using a continuous vibrating mesh nebulizer (VMNcont) and investigating the effects of different ventilation modes on inspiration-synchronized nebulization. Therefore, in an in vitro model of mechanically ventilated adults, a VMNsyn and a VMNcont were compared in volume-controlled (VC-CMV) and pressure-controlled continuous mandatory ventilation (PC-CMV) regarding iloprost deposition rate and nebulization time. During VC-CMV, the deposition rate of the VMNsyn was comparable to the rate obtained with the VMNcont, but 10.9% lower during PC-CMV. The aerosol output of the VMNsyn during both ventilation modes was significantly lower compared to the VMNcont, leading to a 7.5 times longer nebulization time during VC-CMV and only to a 4.2 times longer nebulization time during PC-CMV. Inspiration-synchronized nebulization during VC-CMV mode therefore seems to be the most suitable for prolonged inhalative iloprost administration in mechanically ventilated patients.

BACKGROUND:Despite recent advances in the clinical management and understanding of sepsis and septic shock, these complex clinical syndromes continue to have high mortality rates. The effect of sex on these diseases' mortality, clinical presentation and morbidity remains controversial. This study aimed to investigate the association of sex with mortality and organ dysfunction in patients with sepsis and septic shock.METHODS:Prospectively enrolled patients with clinically defined sepsis and septic shock in three intensive care units at University Medical Center Göttingen, Germany, were investigated. The primary outcomes were 28- and 90-day mortality, while the secondary endpoints included the evaluation of organ dysfunction as measured by clinical scores and laboratory parameters.RESULTS:A total of 737 septic patients were enrolled, including 373 in septic shock, 484 males, and 253 females. No significant differences in 28- and 90-day mortality were observed in the cohort. However, men with sepsis had significantly higher SOFA scores, SOFA respiratory and renal subscores, bilirubin and creatinine values, and lower weight-adapted urine outputs, indicating higher organ dysfunction compared to women.CONCLUSIONS:Our findings revealed notable differences in organ dysfunction between male and female patients, with males exhibiting more pronounced dysfunction across multiple clinical indicators. These results highlight the potential influence of sex on sepsis disease severity and suggest the need for tailored approaches in sepsis management according to patient sex.

Rationale: In the EOLIA (ECMO to Rescue Lung Injury in Severe ARDS) trial, oxygenation was similar between intervention and conventional groups, whereas (V) over dot(E) was reduced in the intervention group. Comparable reductions in ventilation intensity are theoretically possible with low-flow extracorporeal CO2 removal (ECCO2R), provided oxygenation remains acceptable. Objectives: To compare the effects of ECCO2R and extracorporeal membrane oxygenation (ECMO) on gas exchange, respiratory mechanics, and hemodynamics in animal models of pulmonary (intratracheal hydrochloric acid) and extrapulmonary (intravenous oleic acid) lung injury. Methods: Twenty-four pigs with moderate to severe hypoxemia (PaO2:F-IO2 <= 150 mm Hg) were randomized to ECMO (blood flow 50-60 ml/kg/min), ECCO2R (0.4 L/min), or mechanical ventilation alone. Measurements and Main Results: (V) over dot(O2), (V) over dot(CO2), gas exchange, hemodynamics, and respiratory mechanics were measured and are presented as 24-hour averages. Oleic acid versus hydrochloric acid showed higher extravascular lung water (1,424 +/- 419 vs. 574 +/- 195 ml; P < 0.001), worse oxygenation (Pa-O2:F-IO2 = 125 +/- 14 vs. 151 +/- 11 mm Hg; P, 0.001), but better respiratory mechanics (plateau pressure 27 +/- 4 vs. 30 +/- 3 cm H2O; P= 0.017). Both models led to acute severe pulmonary hypertension. In both models, ECMO (3.7 +/- 0.5 L/min), compared with ECCO2R (0.4 L/min), increased mixed venous oxygen saturation and oxygenation, and improved hemodynamics (cardiac output= 6.0 +/- 61.4 vs. 5.2 +/- 1.4 L/min; P= 0.003). (V) over dot(O2) and (V) over dot(CO2), irrespective of lung injury model, were lower during ECMO, resulting in lower Pa-CO2 and (V) over dot(E) but worse respiratory elastance compared with ECCO2R (64 +/- 27 vs. 40 +/- 8 cm H2O/L; P<0.001). Conclusions: ECMO was associated with better oxygenation, lower (V) over dot(O2), and better hemodynamics. ECCO2R may offer a potential alternative to ECMO, but there are concerns regarding its effects on hemodynamics and pulmonary hypertension.

The amount of energy delivered to the respiratory system is recognized as a cause of ventilator-induced lung injury (VILI). How energy dissipation within the lung parenchyma causes damage is still a matter of debate. Expiratory flow control has been proposed as a strategy to reduce the energy dissipated into the respiratory system during expiration and, possibly, VILI. We studied 22 healthy pigs (29 +/- 2 kg), which were randomized into a control (n = 11) and a valve group (n = 11), where the expiratory flow was controlled through a variable resistor. Both groups were ventilated with the same tidal volume, positive end-expiratory pressure (PEEP), and inspiratory flow. Electric impedance tomography was continuously acquired. At completion, lung weight, wet-to-dry ratios, and histology were evaluated. The total mechanical power was similar in the control and valve groups (8.54 +/- 0.83 J.min(-1) and 8.42 +/- 0.54 J.min(-1), respectively, P = 0.552). The total energy dissipated within the whole system (circuit + respiratory system) was remarkably different (4.34 +/- 0.66 vs. 2.62 +/- 0.31 J/min, P < 0.001). However, most of this energy was dissipated across the endotracheal tube (2.87 +/- 0.3 vs. 1.88 +/- 0.2 J/min, P < 0.001). The amount dissipated into the respiratory system averaged 1.45 +/- 0.5 in controls versus 0.73 +/- 0.16 J.min(-1) in the valve group, P < 0.001. Although respiratory mechanics, gas exchange, hemodynamics, wet-to-dry ratios, and histology were similar in the two groups, the decrease of end-expiratory lung impedance was significantly greater in the control group (P = 0.02). We conclude that with our experimental conditions, the reduction of energy dissipated in the respiratory system did not lead to appreciable differences in VILI. NEW & NOTEWORTHY Energy dissipation within the respiratory system is a factor promoting ventilator-induced lung injury (VILI). In this animal study, we modulated the expiratory flow, reducing the energy dissipated in the system. However, this reduction happened mostly across the endotracheal tube, and only partly in the respiratory system. Therefore, in healthy lungs, the advantage in energy dissipation does not reduce VILI, but the advantages might be more relevant in diseased lungs under injurious ventilation.