Amado‑Rodríguez et al. Ann. Intensive Care (2021) 11:132 https://doi.org/10.1186/s13613‑021‑00919‑0 RESEARCH Open Access Biotrauma during ultra‑low tidal volume ventilation and venoarterial extracorporeal membrane oxygenation in cardiogenic shock: a randomized crossover clinical trial Laura Amado‑Rodríguez1,2,3* , Cecilia Del Busto1,2, Inés López‑Alonso2,3, Diego Parra1,2, Juan Mayordomo‑Colunga2,3,4, Miguel Arias‑Guillén3,5, Rodrigo Albillos‑Almaraz1,2, Paula Martín‑Vicente2,3,6, Cecilia López‑Martínez2,3, Covadonga Huidobro2,3, Luigi Camporota7, Arthur S. Slutsky8 and Guillermo M. Albaiceta1,2,3,6 Abstract Background: Cardiogenic pulmonary oedema (CPE) may contribute to ventilator‑associated lung injury (VALI) in patients with cardiogenic shock. The appropriate ventilatory strategy remains unclear. We aimed to evaluate the impact of ultra‑low tidal volume ventilation with tidal volume of 3 ml/kg predicted body weight (PBW) in patients with CPE and veno–arterial extracorporeal membrane oxygenation (V–A ECMO) on lung infammation compared to conventional ventilation. Methods: A single‑centre randomized crossover trial was performed in the Cardiac Intensive Care Unit (ICU) at a ter‑ tiary university hospital. Seventeen adults requiring V–A ECMO and mechanical ventilation due to cardiogenic shock were included from February 2017 to December 2018. Patients were ventilated for two consecutive periods of 24 h with tidal volumes of 6 and 3 ml/kg of PBW, respectively, applied in random order. Primary outcome was the change in proinfammatory mediators in bronchoalveolar lavage fuid (BALF) between both ventilatory strategies. Results: Ventilation with 3 ml/kg PBW yielded lower driving pressures and end‑expiratory lung volumes. Overall, there were no diferences in BALF cytokines. Post hoc analyses revealed that patients with high baseline levels of IL‑6 showed statistically signifcant lower levels of IL‑6 and IL‑8 during ultra‑low tidal volume ventilation. This reduction was signifcantly proportional to the decrease in driving pressure. In contrast, those with lower IL‑6 baseline levels showed a signifcant increase in these biomarkers. Conclusions: Ultra‑low tidal volume ventilation in patients with CPE and V–A ECMO may attenuate infammation in selected cases. VALI may be driven by an interaction between the individual proinfammatory profle and the mechan‑ ical load overimposed by the ventilator. Trial registration The trial was registered in ClinicalTrials.gov (identifer NCT03041428, Registration date: 2nd February 2017). *Correspondence: lar@crit‑lab.org 1 Unidad de Cuidados Intensivos Cardiológicos, Hospital Universitario Central de Asturias, Avda de Roma s/n, 33011 Oviedo, Spain Full list of author information is available at the end of the article © The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. Amado‑Rodríguez et al. Ann. Intensive Care (2021) 11:132 Page 2 of 10 Keywords: Extracorporeal membrane oxygenation, Ventilator‑induced lung injury, Mechanical ventilation, Pulmonary oedema, Respiratory mechanics Background ultra-low tidal volume strategy with tidal volume of Distribution of tidal volume (Vt) within lung paren- 3 ml/kg PBW in patients with CPE who were on V–A chyma determines the regional distribution of forces ECMO. experienced by the tissue. When end-inspiratory stretch is high or functional residual capacity is low, Materials and methods leading to recruitment/de-recruitment phenomena, Study design excessive mechanical loads may promote tissue damage Tis single-centre, prospective, randomized, cross- and infammation [1]. In patients with the acute respir- over trial was registered in Clinicaltrials.gov (identifer atory distress syndrome (ARDS), ventilator-associated NCT03041428) and performed according to CONSORT lung injury (VALI) contributes to lung infammation statement (CONSORT checklist available as Additional and is one major determinant of outcomes [2]. Calfee fle 1). All procedures performed were in accordance with et al. identifed two ARDS subphenotypes that may the ethical standards of the institutional and/or national beneft from diferent ventilatory approaches, accord- research committee (Comité de Ética de la Investigación ing to their proinfammatory profle [3]. del Principado de Asturias, REF 22/17) and with the 1964 In spite of diferent pathophysiological mechanisms, Helsinki Declaration and its later amendments. Informed alveolar fooding caused by hydrostatic mechanisms consent was obtained from each patients’ next of kin. in patients with cardiogenic pulmonary oedema (CPE) may produce similar respiratory system mechanics to Patients those observed in patients with ARDS [4, 5]. A recent From February 2017 to December 2018, all mechanically report illustrates that patients with congestive heart ventilated patients receiving V–A ECMO in the Car- failure are exposed to driving and plateau pressures diac Intensive Care Unit at Hospital Universitario Cen- similar to those with ARDS [6]. However, the efects tral de Asturias were screened. Inclusion criteria, other of this mechanical load on regional infammation in than mechanical ventilation and V–A ECMO support, patients with CPE, in which the infammatory response were: cardiogenic shock (defned as systemic hypoper- may not be so activated as in ARDS, have not been fusion with systolic blood pressure below 90 mmHg in studied. spite of fuid resuscitation and inotropes, evidence of Reduced tidal volume is the mainstay of the ventila- distant organ failure—defned as Organ-Specifc SOFA 2 tory management of ARDS [7], where decreases in driv- score ≥ 2 [14]—and/or cardiac index < 2.2 l/min/m , ing pressures have been related to lower risk of death, and corresponding to Stages C to D in the SCAI con- with the lower threshold for this beneft still unclear. sensus defnition [15]) and CPE (defned as impaired Low tidal volumes may decrease alveolar ventilation, gas exchange with a PaO2/FiO2 lower than 300, bilateral increasing CO2 levels, and produce atelectasis and infltrates in chest X-ray with pulmonary capillary wedge patient-ventilator dyssynchronies [8]. Several authors pressures (PCP) > 18 mmHg and/or echocardiographic have proposed the use of ultra-low tidal volume strat- signs of congestive heart failure). Exclusion criteria were egies with tidal volumes of 3 ml/kg, predicted body age < 18-year, immunosuppression, history of chronic weight (PBW) [9, 10] and extracorporeal gas exchange respiratory diseases, known or suspected acute lung to remove CO 2 and possibly improve oxygenation [11]. injury from other causes (pneumonia, atelectasis, mas- Veno-venous extracorporeal membrane oxygenation [9] sive pleural efusion), haemodynamic instability refrac- permits this ventilatory strategy and can lead to better tory to therapy, do-not resuscitate orders or a terminal outcomes in patients with very severe ARDS [10, 12]. condition. Intraaortic balloon pump was inserted via Patients with CPE due to severe ventricular dysfunc- femoral artery in all the cases [16]. Patients were followed tion may require extracorporeal cardiopulmonary sup- up to hospital discharge. port with veno-arterial ECMO (V–A ECMO) [13] and may also beneft from ultra-low tidal volume strategies, Outcomes assuming a similar respiratory mechanics and risk of Te primary endpoint was the bronchoalveolar lavage VALI as ARDS patients do, due to alveolar fooding. fuid (BALF) interleukin (IL)-6 concentration after each We conducted a prospective study aimed to evalu- ventilatory strategy. Additionally, a set of infammatory ate changes in lung infammation in response to an cytokines were determined in the obtained samples. Amado‑Rodríguez et al. Ann. Intensive Care (2021) 11:132 Page 3 of 10 Secondary outcomes were the impact of the ventilatory (LegendPLEX assay panel, BioLegend, USA), following strategy on respiratory mechanics and on haemodynamic the manufacturer’s instructions. variables. Planned post hoc analyses included com- Patients were classifed as hyperinfamed or non- parisons of subgroups according to driving or plateau hyperinfamed based on IL-6 concentration on BALF pressures or IL-6 levels during conventional protective during ventilation with 6 ml/kg PBW. Using data from a ventilation (6 ml/kg PBW). previous study [17], an optimal cut-of point of 680 pg/ml to discriminate between patients with and without ven- tilation-related lung infammation was identifed (Addi- Intervention and measurements tional fle 2: Figure S1A, B). PBW was calculated as 45.5 [0.91 (centimetres of + Sample size calculation height − 152.4)] for females; and 50 + [0.91 (centimetres of height − 152.4)] for males. Before inclusion, patients Based on the BALF IL-6 levels measured in a previous were ventilated with tidal volumes of 6–8 ml/kg PBW study in patients with ARDS and low strain [17], the and plateau pressures below 28 cmH 2O. After inclusion, study was designed to detect a diference of 100 pg/ml in patients were ventilated using a constant-fow, volume- the change of IL-6 levels (matched pairs), with a standard controlled mode for 24 h with a tidal volume of 6 or 3 ml/ deviation of 100 pg/ml. With 95% power and a 5% type-I kg PBW, applied in random order. After the frst 24 h in error, the required sample size was 17 patients. the initial strategy, tidal volume was modifed by 1 ml/kg PBW per hour until it achieved the target for the consec- Statistical analysis utive ventilatory strategy.