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Protecting the Right Ventricle in ARDS: The Role of Prone Ventilation

  • Vasileios Zochios
    Affiliations
    University Hospitals Birmingham National Health Service Foundation Trust, Department of Critical Care Medicine, Queen Elizabeth Hospital, Edgbaston, Birmingham, UK

    Perioperative Critical Care and Trauma Trials Group, Institute of Inflammation and Ageing, Centre of Translational Inflammation Research, University of Birmingham, Birmingham, UK
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  • Ken Parhar
    Affiliations
    Department of Critical Care Medicine, University of Calgary, Calgary, Canada
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  • Antoinne Vieillard-Baron
    Affiliations
    Assistance Publique-Hôpitaux de Paris, University Hospital Ambroise Paré, Intensive Care Unit, Section Thorax-Vascular Disease-Abdomen-Metabolism, Boulogne-Billancourt, France

    Faculty of Medicine Paris Ile-de-France Ouest, University of Versailles, Saint-Quentin en Yvelines, France

    INSERM U-1018, CESP, Team 5(EpReC, Renal and Cardiovascular Epidemiology), Villejuif, France
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Published:February 08, 2018DOI:https://doi.org/10.1053/j.jvca.2018.01.007
      ACUTE RESPIRATORY DISTRESS SYNDROME (ARDS) is associated with high mortality (up to 46%) despite best standards of supportive care.
      • Bellani G.
      • Laffey J.G.
      • Pham T.
      • et al.
      Epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in 50 countries.
      One of the major determinants of mortality in severe ARDS is hemodynamic instability, in particular pulmonary vascular dysfunction and right ventricular (RV) dysfunction/failure
      • Bull T.M.
      • Clark B.
      • McFann K.
      • et al.
      Pulmonary vascular dysfunction is associated with poor outcomes in patients with acute lung injury.
      • Boissier F.
      • Katsahian S.
      • Razazi K.
      • et al.
      Prevalence and prognosis of cor pulmonale during protective ventilation for acute respiratory distress syndrome.
      ; however, cardiopulmonary interactions in the context of ARDS are not understood fully. In most ARDS studies, RV failure is defined as “acute cor pulmonale” (ACP), which refers to an abrupt increase in RV afterload. On echocardiography, this is characterized by septal dyskinesia and RV dilatation with a ratio of RV end-diastolic area (RVEDA) to left ventricular end-diastolic area (LVEDA) >0.6 and >1 for severe ACP.
      • Jardin F.
      • Dubourg O.
      • Bourdarias J.P.
      Echocardiographic pattern of acute cor pulmonale.
      • Mekontso Dessap A.
      • Boissier F.
      • Charron C.
      • et al.
      Acute cor pulmonale during protective ventilation for acute respiratory distress syndrome: Prevalence, predictors, and clinical impact.
      A recent risk score developed for the prediction of ACP in ARDS demonstrated several important clinical and physiologic parameters: (a) pneumonia as a cause of ARDS, (b) ratio of arterial oxygen partial pressure to fractional inspired oxygen (PaO2/FiO2) <150 mmHg, (c) arterial carbon dioxide partial pressure (PaCO2) ≥48 mmHg, and (d) driving pressure ≥18 cm H2O.
      • Mekontso Dessap A.
      • Boissier F.
      • Charron C.
      • et al.
      Acute cor pulmonale during protective ventilation for acute respiratory distress syndrome: Prevalence, predictors, and clinical impact.
      The aforementioned variables have a statistically significant correlation with development of ACP with a reported incidence of 19%, 34%, and 74% in ARDS patients with risk scores of 2, 3, and 4, respectively.
      • Mekontso Dessap A.
      • Boissier F.
      • Charron C.
      • et al.
      Acute cor pulmonale during protective ventilation for acute respiratory distress syndrome: Prevalence, predictors, and clinical impact.

      Pathophysiology of RV Injury in ARDS

      Pulmonary vascular dysfunction and RV injury are characterized by increased pulmonary vascular resistance (PVR), pulmonary hypertension, and uncoupling between the RV and pulmonary circulations. ARDS-related pathophysiologic factors contributing to this include the following: hypoxic/hypercapnic pulmonary vasoconstriction, imbalance of vasoactive mediators (eg, increased endothelin-1 levels) and increased vasomotor tone, development of intravascular microthrombi, extrinsic vessel compression (due to reduction in lung volume, interstitial edema, and atelectasis), and pulmonary vascular remodeling.
      • Price L.C.
      • McAuley D.F.
      • Marino P.S.
      • et al.
      Pathophysiology of pulmonary hypertension in acute lung injury.
      • Moloney E.D.
      • Evans T.W.
      Pathophysiology and pharmacological treatment of pulmonary hypertension in acute respiratory distress syndrome.
      • Morimont P.
      • Lambermont B.
      • Desaive T.
      • et al.
      Right ventriculoarterial coupling in acute respiratory distress syndrome (ARDS) and expected benefits of CO2 removal therapy [abstract].
      These factors are related to mechanical ventilation and pulmonary mechanics with a negative impact on RV function in ARDS (alveolar vessel collapse leading to increased RV afterload): extremes of lung volume and imbalance between overdistension and recruitment,
      • Shekerdemian L.
      • Bohn D.
      Cardiovascular effects of mechanical ventilation.
      • Paternot A.
      • Repessé X.
      • Vieillard-Baron A.
      Rationale and description of right ventricle-protective ventilation in ARDS.
      • Repessé X.
      • Charron C.
      • Vieillard-Baron A.
      Acute cor pulmonale in ARDS: Rationale for protecting the right ventricle.
      • Vieillard-Baron A.
      • Loubieres Y.
      • Schmitt J.M.
      • et al.
      Cyclic changes in right ventricular output impedance during mechanical ventilation.
      • Jardin F.
      • Vieillard-Baron A.
      Is there a safe plateau pressure in ARDS? The right heart only knows.
      plateau pressure (alveolar end-inspiratory pressure) >27 cm H2O,
      • Jardin F.
      • Vieillard-Baron A.
      Is there a safe plateau pressure in ARDS? The right heart only knows.
      and driving pressure (plateau pressure minus total positive end-expiratory pressure) >18 cm H2O.
      • Boissier F.
      • Katsahian S.
      • Razazi K.
      • et al.
      Prevalence and prognosis of cor pulmonale during protective ventilation for acute respiratory distress syndrome.
      • Mekontso Dessap A.
      • Boissier F.
      • Charron C.
      • et al.
      Acute cor pulmonale during protective ventilation for acute respiratory distress syndrome: Prevalence, predictors, and clinical impact.

      RV Function during Prone Ventilation—Evaluating the Evidence

      Correction of hypoxemia/hypercapnia along with pressure and volume-limited mechanical ventilation potentially could minimize the adverse heart–lung interactions in ARDS. Prone mechanical ventilation has been used as a strategy to improve oxygenation and respiratory mechanics in the most severe form of ARDS (PaO2/FiO2 <150 mmHg) when conventional modes of ventilation fail. Early randomized trials showed a consistent association between prone ventilation and improvement in gas exchange, but no clear mortality benefit.
      • Gattinoni L.
      • Tognoni G.
      • Pesenti A.
      • et al.
      Effect of prone positioning on the survival of patients with acute respiratory failure.
      • Guerin C.
      • Gaillard S.
      • Lemasson S.
      • et al.
      Effects of systematic prone positioning in hypoxemic acute respiratory failure: A randomized controlled trial.
      • Voggenreiter G.
      • Aufmkolk M.
      • Stiletto R.J.
      • et al.
      Prone positioning improves oxygenation in post-traumatic lung injury—a prospective randomized trial.
      One might argue that this is because the proning sessions were of short duration (6-8 hours), ventilatory strategies used were nonprotective, and there was supine/prone crossover.
      • Gattinoni L.
      • Tognoni G.
      • Pesenti A.
      • et al.
      Effect of prone positioning on the survival of patients with acute respiratory failure.
      • Guerin C.
      • Gaillard S.
      • Lemasson S.
      • et al.
      Effects of systematic prone positioning in hypoxemic acute respiratory failure: A randomized controlled trial.
      • Voggenreiter G.
      • Aufmkolk M.
      • Stiletto R.J.
      • et al.
      Prone positioning improves oxygenation in post-traumatic lung injury—a prospective randomized trial.
      Vieillard-Baron et al. examined the effect of prone ventilation on RV function, using transesophageal echocardiography (before and after the first 18-hour session of proning) in 42 patients with severe ARDS (defined as PaO2/FiO2 <100 mmHg).
      • Vieillard-Baron A.
      • Charron C.
      • Caille V.
      • et al.
      Prone positioning unloads the right ventricle in severe ARDS.
      Acute cor pulmonale was present in 50% of the cohort, and prone position ventilation was associated with a significant reduction in plateau pressure and PaCO2, with associated improvement in RV function (reduced RVEDA/LVEDA ratio and septal dyskinesia).
      • Vieillard-Baron A.
      • Charron C.
      • Caille V.
      • et al.
      Prone positioning unloads the right ventricle in severe ARDS.
      Joswiak et al. showed that in patients with moderate to severe ARDS receiving pressure-limited low-tidal-volume ventilation, who are preload dependent, proning was associated with a decrease in RV afterload, increased cardiac index, and significant reduction in RVEDA/LVEDA ratio.
      • Jozwiak M.
      • Teboul J.L.
      • Anguel N.
      • et al.
      Beneficial hemodynamic effects of prone positioning in patients with acute respiratory distress syndrome.
      The PROSEVA (Proning Severe ARDS patients) randomized controlled trial demonstrated that prone positioning patients with a PaO2/FiO2 <150 mmHg subjected to low-tidal-volume ventilation and neuromuscular blockade confers significant mortality benefit (16.8% absolute reduction in 28-day all-cause mortality compared to the supine group).
      • Guerin C.
      • Reignier J.
      • Richard J.C.
      • et al.
      Prone positioning in severe acute respiratory distress syndrome.
      The “prone ventilation” arm of PROSEVA had fewer cardiac arrests and more cardiac failure-free days at 28 days after recruitment, which could suggest that the RV-protective effect of prone positioning may contribute to survival benefit.
      Five systematic reviews and meta-analyses based on individual or grouped data from randomized controlled trials (including PROSEVA) have shown that patients with moderate to severe ARDS are likely to benefit from early prone positioning; none of the studies, however, explored cardiovascular outcomes.
      • Beitler J.R.
      • Shaefi S.
      • Montesi S.B.
      • et al.
      Prone positioning reduces mortality from acute respiratory distress syndrome in the low tidal volume era: A meta-analysis.
      • Sud S.
      • Friedrich J.O.
      • Adhikari N.K.
      • et al.
      Effect of prone positioning during mechanical ventilation on mortality among patients with acute respiratory distress syndrome: A systematic review and meta-analysis.
      • Bloomfield R.
      • Noble D.W.
      • Sudlow A.
      Prone position for acute respiratory failure in adults.
      • Lee J.M.
      • Bae W.
      • Lee Y.J.
      • et al.
      The efficacy and safety of prone positional ventilation in acute respiratory distress syndrome: Updated study-level meta-analysis of 11 randomized controlled trials.
      • Munshi L.
      • Del Sorbo L.
      • Adhikari N.K.J.
      • et al.
      Prone position for acute respiratory distress syndrome. A systematic review and meta-analysis.
      The recently published APRONET (ARDS Prone Position Network)

      Guérin C, Beuret P, Constantin JM, et al. A prospective international observational prevalence study on prone positioning of ARDS patients: The APRONET (ARDS Prone Position Network) study [published online ahead of print December 7, 2017]. Intensive Care Med. https://doi.org/10.1007/s00134-017-4996-5.

      study is the first multicenter international prospective prevalence study dedicated specifically to the use of prone positioning. APRONET enrolled 735 ARDS patients (Berlin Definition)
      • Ranieri V.M.
      • Rubenfeld G.D.
      • et al.
      ARDS Definition Task Force
      Acute respiratory distress syndrome: The Berlin Definition.
      from 20 countries (141 intensive care units) and showed that 32.9% of severe ARDS patients are being prone positioned. Prone ventilation is associated with significant improvement in gas exchange and a decrease in driving pressure, known to be a risk factor for ACP and an independent predictor of mortality in ARDS.
      • Bellani G.
      • Laffey J.G.
      • Pham T.
      • et al.
      Epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in 50 countries.
      • Mekontso Dessap A.
      • Boissier F.
      • Charron C.
      • et al.
      Acute cor pulmonale during protective ventilation for acute respiratory distress syndrome: Prevalence, predictors, and clinical impact.
      • Amato M.B.
      • Meade M.O.
      • Slutsky A.S.
      • et al.
      Driving pressure and survival in the acute respiratory distress syndrome.
      Of note, the 2 main reasons for not prone positioning patients in the APRONET study were (1) hypoxemia being not severe enough to justify prone positioning, based on the clinicians’ judgment (PaO2/FiO2 <150 mmHg had the lowest odds ratio for predicting the risk for not prone positioning); and (2) hemodynamic instability.

      Guérin C, Beuret P, Constantin JM, et al. A prospective international observational prevalence study on prone positioning of ARDS patients: The APRONET (ARDS Prone Position Network) study [published online ahead of print December 7, 2017]. Intensive Care Med. https://doi.org/10.1007/s00134-017-4996-5.

      The latter suggests that intensive care specialists may not be aware that changes in cardiovascular physiology associated with prone position in ARDS are advantageous, in particular reversal of RV-pulmonary artery (PA) uncoupling, and RV unloading during prone positioning could confer a mortality benefit.
      • Vieillard-Baron A.
      • Charron C.
      • Caille V.
      • et al.
      Prone positioning unloads the right ventricle in severe ARDS.
      • Jozwiak M.
      • Teboul J.L.
      • Anguel N.
      • et al.
      Beneficial hemodynamic effects of prone positioning in patients with acute respiratory distress syndrome.
      However, a major concern remains: It may be difficult for intensivists to distinguish between ACP and other potential mechanisms of circulatory failure, such as vasodilatory shock as seen in sepsis. This dilemma highlights the value of critical care echocardiography in this setting.
      In cases of ARDS complicated by refractory hypercapnia despite prone ventilation, extracorporeal devices could be considered to mitigate the deleterious effects of hypercapnia on the RV (increased RV afterload and RV-PA uncoupling). In particular, venovenous extracorporeal CO2 removal (ECCO2R) offers CO2 clearance and facilitates ultraprotective ventilation (tidal volume of 4 mL/kg predicted body weight and reduction in plateau pressure).
      • Terragni P.P.
      • Del Sorbo L.
      • Mascia L.
      • et al.
      Tidal volume lower than 6 ml/kg enhances lung protection: Role of extracorporeal carbon dioxide removal.
      In an experimental porcine ARDS model, Morimont et al. showed that institution of ECCO2R effectively reduced hypercapnia during protective ventilation, reduced PVR and mean PA pressure, and improved RV-PA coupling.
      • Morimont P.
      • Guiot J.
      • Desaive T.
      • et al.
      Veno-venous extracorporeal CO2 removal improves pulmonary hemodynamics in a porcine ARDS model.
      However, given the experimental and observational nature of current evidence pertaining to the use of ECCO2R, it cannot be recommended as an accepted therapeutic measure or routine adjuvant therapy to prone ventilation in ARDS and RV protection at this time.
      • Morelli A.
      • Del Sorbo L.
      • Pesenti A.
      • et al.
      Extracorporeal carbon dioxide removal (ECCO2R) in patients with acute respiratory failure.
      Feasibility and safety of prone positioning for ARDS in the context of cardiothoracic surgery has not been tested in randomized controlled trials. In fact, 2 of the PROSEVA trial exclusion criteria were recent sternotomy and lung transplantation.
      • Guerin C.
      • Reignier J.
      • Richard J.C.
      • et al.
      Prone positioning in severe acute respiratory distress syndrome.
      Retrospective data suggest that prone positioning can be applied safely as a bridge to recovery in lung transplantation recipients with refractory hypoxemia secondary to primary graft dysfunction, and it is associated with a decrease in vasoactive drug support.
      • Riera J.
      • Maldonado C.
      • Mazo C.
      • et al.
      Prone positioning as a bridge to recovery from refractory hypoxaemia following lung transplantation.
      A proportion of lung transplant candidates have preoperative RV dysfunction/failure secondary to chronic lung disease, which may be worsened by perioperative ARDS.
      • Schulman L.L.
      • Leibowitz D.W.
      • Anandarangam T.
      • et al.
      Variability of right ventricular functional recovery after lung transplantation.
      It is therefore reasonable that prone ventilation be considered in this cohort of patients.

      Mechanisms of RV Unloading During Prone Positioning in ARDS

      The physiological effect of prone positioning on the RV and pulmonary circulation can be explained by the following potential mechanisms:

      Reduction in Pulmonary Vascular Tone

      The ventral–dorsal transpulmonary pressure difference is reduced during prone positioning, and as ventilation becomes more homogeneous and the distribution of perfusion remains constant (in supine and prone positions), intrapulmonary shunt decreases and oxygenation improves.
      • Gattinoni L.
      • Taccone P.
      • Carlesso E.
      • et al.
      Prone position in acute respiratory distress syndrome. Rationale, indications, and limits.
      The homogenous pulmonary aeration during prone positioning leads to reduced regional stress and strain and better carbon dioxide clearance.
      • Gattinoni L.
      • Taccone P.
      • Carlesso E.
      • et al.
      Prone position in acute respiratory distress syndrome. Rationale, indications, and limits.
      The reduction in hypoxic/hypercapnic pulmonary vasoconstriction results in decreased PVR, a decrease in RV afterload, and improved RV-PA coupling.
      • Gattinoni L.
      • Taccone P.
      • Carlesso E.
      • et al.
      Prone position in acute respiratory distress syndrome. Rationale, indications, and limits.
      • Guerin C.
      • Baboi L.
      • Richard J.C.
      Mechanisms of the effects of prone positioning in acute respiratory distress syndrome.

      Reduction in Driving Pressure

      Driving pressure, a surrogate currently used for dynamic lung stress, can be calculated as the difference between plateau pressure (end-inspiratory alveolar pressure) and total positive-end expiratory pressure (PEEP), and reflects the pressure generated in the respiratory system by the tidal volume.
      • Amato M.B.
      • Meade M.O.
      • Slutsky A.S.
      • et al.
      Driving pressure and survival in the acute respiratory distress syndrome.
      • Chiumello D.
      • Carlesso E.
      • Brioni M.
      • et al.
      Airway driving pressure and lung stress in ARDS patients.
      It has been shown that when high PEEP is applied during prone ventilation, the associated reduction in tidal hyperinflation and alveolar cyclic recruitment/derecruitment results in a reduction in driving pressure,
      • Cornejo R.A.
      • Díaz J.C.
      • Tobar E.A.
      • et al.
      Effects of prone positioning on lung protection in patients with acute respiratory distress syndrome.
      a reduction in pulmonary capillary and extra-alveolar vessel compression, and a drop in PVR.
      • Vieillard-Baron A.
      • Loubieres Y.
      • Schmitt J.M.
      • et al.
      Cyclic changes in right ventricular output impedance during mechanical ventilation.

      Increase in Central Blood Volume

      During prone ventilation there is an increase in central blood volume due to the shift of blood from the splanchnic into the thoracic circulation, which may induce recruitment of pulmonary microvasculature, increase in pulmonary capillary wedge pressure, and reduction in PVR and RV afterload.
      • Jozwiak M.
      • Teboul J.L.
      • Anguel N.
      • et al.
      Beneficial hemodynamic effects of prone positioning in patients with acute respiratory distress syndrome.
      • Gattinoni L.
      • Taccone P.
      • Carlesso E.
      • et al.
      Prone position in acute respiratory distress syndrome. Rationale, indications, and limits.
      This probably is true especially in patients with preliminary relative or absolute hypovolemia.

      Protection Against Ventilator-Induced Lung Injury

      Injurious mechanical ventilation can further exacerbate RV dysfunction in ARDS. It is assumed that cyclic interruption and exaggeration of pulmonary blood flow during high-pressure ventilation may cause pulmonary microvascular injury, leading to cor pulmonale.
      • Cornejo R.A.
      • Díaz J.C.
      • Tobar E.A.
      • et al.
      Effects of prone positioning on lung protection in patients with acute respiratory distress syndrome.
      Recent data suggest that not only is the RV dysfunction the consequence of VILI, but also it could promote in part such a ventilator-induced lung injury (VILI).
      • Katira B.H.
      • Giesinger R.E.
      • Engelberts D.
      • et al.
      Adverse heart-lung interactions in ventilator-induced lung injury.
      • Vieillard-Baron A.
      • Dreyfuss D.
      Ventilator-induced lung injury: Follow the right direction! Another piece of the puzzle in the ventilator-induced lung injury epic.
      The protective effect of prone positioning against VILI potentially could be explained by ventilatory homogeneity, a decrease in tidal hyperinflation, and homogenous distribution of strain.
      • Gattinoni L.
      • Taccone P.
      • Carlesso E.
      • et al.
      Prone position in acute respiratory distress syndrome. Rationale, indications, and limits.
      • Guerin C.
      • Baboi L.
      • Richard J.C.
      Mechanisms of the effects of prone positioning in acute respiratory distress syndrome.
      • Chiumello D.
      • Carlesso E.
      • Brioni M.
      • et al.
      Airway driving pressure and lung stress in ARDS patients.
      • Cornejo R.A.
      • Díaz J.C.
      • Tobar E.A.
      • et al.
      Effects of prone positioning on lung protection in patients with acute respiratory distress syndrome.
      • Katira B.H.
      • Giesinger R.E.
      • Engelberts D.
      • et al.
      Adverse heart-lung interactions in ventilator-induced lung injury.
      In conclusion, a substantial body of evidence supports the pivotal role of prone positioning in reducing mortality outcomes in severe ARDS. RV failure is a predictor of mortality in ARDS, and therefore monitoring and protecting the RV should be made an integral part of a heart and lung protective strategy in severe ARDS. The recommended RV-protective ventilatory goals (driving pressure <18 cm H2O, PaCO2 <48 mmHg, and PaO2/FiO2 >150 mmHg)
      • Mekontso Dessap A.
      • Boissier F.
      • Charron C.
      • et al.
      Acute cor pulmonale during protective ventilation for acute respiratory distress syndrome: Prevalence, predictors, and clinical impact.
      • Repessé X.
      • Charron C.
      • Vieillard-Baron A.
      Acute cor pulmonale in ARDS: Rationale for protecting the right ventricle.
      could be met with prone ventilation and no need for recruitment maneuvers and titrated high PEEP, recently found to be associated with mortality.

      Writing Group for the Alveolar Recruitment for Acute Respiratory Distress Syndrome Trial (ART) Investigators, Cavalcanti AB, Suzumura ÉA, et al. Effect of lung recruitment and titrated positive end-expiratory pressure (PEEP) vs low PEEP on mortality in patients with acute respiratory distress syndrome: A randomized clinical trial. JAMA 201710;318:1335-45.

      Adequately powered and well-designed randomized controlled trials should test the hypothesis that prone positioning ARDS patients with severe RV dysfunction regardless of PaO2/FiO2 ratio improves patient-centred outcomes.

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