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In an excellent review from early 2016, Gattinoni and Quintel note that ventilator induced lung injury [VILI] is better considered ventilation induced lung injury because VILI can develop during spontaneous breathing . To support this claim, they reference a classic experimental study from the late 1980s by Mascheroni and colleagues . In this oft-cited work from over 30 years ago, 16 sheep had sodium salicylate injected into their cisterna magnae to trigger central hyperventilation. These sheep developed clinical respiratory distress syndrome typified by both diminished arterial oxygenation and respiratory system compliance, coupled with abnormal chest x-rays and grossly injured lungs. Another 10 sheep had salicylate injected into their cisterna magnae, however, they were sedated, paralyzed and placed on mechanical ventilation with normal tidal volume. None of the latter sheep developed lung injury over the same time frame. Appropriately, the authors concluded that, in their experimental paradigm, hyperventilation caused acute lung injury.
Roughly 10 years later, a fascinating case report by Kallet et al. described a patient with acute respiratory distress syndrome [ARDS] who developed hydrostatic pulmonary edema when significant respiratory effort developed after being switched to lower lung volume ventilation . This mechanical model supported previous literature on negative pressure pulmonary edema  and later data showing how blood flow and alveolar ‘corner vessels’ contribute to VILI.
More recently, a review by Brochard and colleagues coined the term ‘patient self-inflicted lung injury’ or P-SILI to encompass the aforementioned pathophysiology . As well, they argue that instituting mechanical ventilation is not simply supportive, but also prophylactic – as it was for the sheep in the investigation by Mascheroni and colleagues. But others have highlighted beneficial aspects of spontaneous breathing in hypoxemic respiratory failure . Accordingly, lung injury initiation by spontaneous efforts has been a hotly-debated topic, especially with regards to non-invasive support . How can the beneficial and detrimental aspects of patient effort be reconciled in acute respiratory distress syndrome? Is there an underlying mechanism? Should these findings change management?
Spontaneous Breathing is Beneficial
Much of the data on spontaneous breathing in ARDS was carried out by comparing either airway pressure release ventilation [APRV] to pressure support [PSV] or APRV with spontaneous efforts to APRV without effort. For example, in experimental lung injury, APRV compared to PSV improved systemic blood flow and ventilation-perfusion matching . In porcine models of mild-to-moderate ARDS, APRV with spontaneous ventilation displayed better hemodynamics and gas exchange with improved end-expiratory lung volume [9, 10]. Using a similar paradigm, APRV produced salutary hemodynamic effects in trauma patients with ARDS  and in trauma patients ‘at risk’ for ARDS . In these investigations, the authors concluded that the beneficial effects of spontaneous breathing in APRV were likely afforded by recruiting non-ventilated lung units. Other animal data comparing pressure-controlled ventilation to pressure-assist control ventilation revealed that spontaneous efforts [i.e. pressure-assist control] showed similar benefits as the APRV data above . Mechanistically, some of the recruitment observed may have been due to active diaphragm ‘breaking’ of lung collapse on expiration ; this might be particularly important in the dorsal, dependent lung regions.
Importantly, this entry is focusing solely on the effects of spontaneous breathing on lung function. The benefits of lighter sedation without paralysis also extend to improved diaphragm function, time on ventilator and prevention of myopathy amongst other potential improvements [15, 16]. These topics are beyond the scope of this brief synthesis.
Spontaneous Breathing is Harmful
In addition to the data discussed at the outset, there is other, direct experimental data revealing potential danger with spontaneous respiratory effort, even when plateau pressure is limited at 30 cm H2O . In porcine, severe lung injury receiving ultraprotective mechanical ventilation with extra-corporeal carbon dioxide removal, spontaneous breathing supplemented with pressure support increased lung inflammation .
A case report from the mid-1980s showed that arterial oxygenation improved following neuromuscular blockade in a young woman with ARDS. Yet, this patient displayed strong contraction of her abdominal muscles during ventilator exhalation, suggesting loss of dependent lung  as the underlying mechanism of hypoxemia.
Perhaps the most compelling, yet indirect, evidence suggesting hazard with spontaneous breathing are the clinical trials that revealed benefit with neuromuscular blockade [NMBA] . In other words, if respiratory effort in ARDS is harmful, then blocking effort with paralysis should improve outcome – which has been demonstrated. For example, Lagneau and colleagues found that neuromuscular blockade to either a train-of-four of 0/4 or 2/4 increased the P/F ratio in patients with moderate ARDS , though these effects occurred within 2 hours, intimating a mechanism similar to the case report described above .
Gainnier and colleagues reported on 56 patients with moderate-to-severe ARDS [P/F ratio less than 150] randomized to either 48 hours of neuromuscular blockade [NMBA] or conventional care . All patients received volume-assist control with appropriately low tidal volume and a ‘lower’ PEEP strategy. Of interest, within 1 hour of randomization, there was no significant difference in oxygenation between the two groups. However, the NMBA group had a higher P/F ratio at 48, 96, and 120 hours after randomization and decreased positive end-expiratory pressure requirements. Accordingly, the temporal trend in gas exchange evoke a mechanism beyond that of simply improving immediate ventilator synchrony.
The same group published on 36 patients randomized to either NMBA or placebo with P/F ratio less than 200 and found that inflammatory markers were diminished in patients who were pharmacologically-paralyzed . The anti-inflammatory effects of NMBA in severe ARDS were also observed retrospectively in the original ARMA trial ; that is, patients with a P/F ratio of less than 120 who received NMBA during the first 72 hours following randomization had lower markers of endothelial, epithelial and general inflammation, as compared to those who did not receive NMBA.
Finally, in 2010, Papazian and colleagues reported a large randomized controlled trial of 340 patients with severe ARDS [defined as P/F ratio less than 150] and found benefit similar to their two publications described above [22, 23, 25]. Importantly, as above, the patients randomized in this trial received a lower PEEP strategy.
Given the conflicting data above and the results of the more recent ROSE trial , how is this reconciled? Does P-SILI actually exist? Are there mechanisms to consider? These questions are touched on in part 2.
Dr. Kenny is the cofounder and Chief Medical Officer of Flosonics Medical; he also the creator and author of a free hemodynamic curriculum at heart-lung.org
- Gattinoni L, Quintel M: How ARDS should be treated. Critical Care 2016, 20(1):1.
- Mascheroni D, Kolobow T, Fumagalli R et al: Acute respiratory failure following pharmacologically induced hyperventilation: an experimental animal study. Intensive care medicine 1988, 15(1):8-14.
- Kallet RH, Alonso JA, Luce JM et al: Exacerbation of acute pulmonary edema during assisted mechanical ventilation using a low-tidal volume, lung-protective ventilator strategy. Chest 1999, 116(6):1826-1832.
- Hodges U, Sumner E: Negative pressure pulmonary oedema. Canadian journal of anaesthesia 1991, 38(4):542.
- Brochard L, Slutsky A, Pesenti A: Mechanical ventilation to minimize progression of lung injury in acute respiratory failure. American journal of respiratory and critical care medicine 2017, 195(4):438-442.
- Güldner A, Pelosi P, de Abreu MG: Spontaneous breathing in mild and moderate versus severe acute respiratory distress syndrome. Current opinion in critical care 2014, 20(1):69-76.
- Grieco DL, Menga LS, Eleuteri D et al: Patient self-inflicted lung injury: implications for acute hypoxemic respiratory failure and ARDS patients on non-invasive support. Minerva anestesiologica 2019, 85(9):1014-1023.
- Putensen C, Räsänen J, López FA et al: Effect of interfacing between spontaneous breathing and mechanical cycles on the ventilation-perfusion distribution in canine lung injury. Anesthesiology: The Journal of the American Society of Anesthesiologists 1994, 81(4):921-930.
- Wrigge H, Zinserling J, Neumann P et al: Spontaneous breathing improves lung aeration in oleic acid–induced lung injury. Anesthesiology: The Journal of the American Society of Anesthesiologists 2003, 99(2):376-384.
- Güldner A, Braune A, Carvalho N et al: Higher levels of spontaneous breathing induce lung recruitment and reduce global stress/strain in experimental lung injury. Anesthesiology: The Journal of the American Society of Anesthesiologists 2014, 120(3):673-682.
- Putensen C, Mutz NJ, Putensen-Himmer G et al: Spontaneous breathing during ventilatory support improves ventilation–perfusion distributions in patients with acute respiratory distress syndrome. American journal of respiratory and critical care medicine 1999, 159(4):1241-1248.
- Putensen C, Zech S, Wrigge H et al: Long-term effects of spontaneous breathing during ventilatory support in patients with acute lung injury. American journal of respiratory and critical care medicine 2001, 164(1):43-49.
- Henzler D, Pelosi P, Bensberg R et al: Effects of partial ventilatory support modalities on respiratory function in severe hypoxemic lung injury. Critical care medicine 2006, 34(6):1738-1745.
- Pellegrini M, Hedenstierna G, Roneus A et al: The diaphragm acts as a brake during expiration to prevent lung collapse. American journal of respiratory and critical care medicine 2017, 195(12):1608-1616.
- deBacker J, Hart N, Fan E: Neuromuscular blockade in the 21st century management of the critically ill patient. Chest 2017, 151(3):697-706.
- Ely EW: The ABCDEF bundle: science and philosophy of how ICU liberation serves patients and families. Critical care medicine 2017, 45(2):321.
- Yoshida T, Uchiyama A, Matsuura N et al: Spontaneous breathing during lung-protective ventilation in an experimental acute lung injury model: high transpulmonary pressure associated with strong spontaneous breathing effort may worsen lung injury. Critical care medicine 2012, 40(5):1578-1585.
- Güldner A, Kiss T, Bluth T et al: Effects of ultraprotective ventilation, extracorporeal carbon dioxide removal, and spontaneous breathing on lung morphofunction and inflammation in experimental severe acute respiratory distress syndrome. Anesthesiology: The Journal of the American Society of Anesthesiologists 2015, 122(3):631-646.
- Coggeshall JW, Marini JJ, Newman JH: Improved oxygenation after muscle relaxation in adult respiratory distress syndrome. Archives of internal medicine 1985, 145(9):1718-1720.
- Yoshida T, Grieco DL, Brochard L et al: Patient self-inflicted lung injury and positive end-expiratory pressure for safe spontaneous breathing. Current opinion in critical care 2020, 26(1):59-65.
- Lagneau F, D'honneur G, Plaud B et al: A comparison of two depths of prolonged neuromuscular blockade induced by cisatracurium in mechanically ventilated critically ill patients. Intensive care medicine 2002, 28(12):1735-1741.
- Gainnier M, Roch A, Forel J-M et al: Effect of neuromuscular blocking agents on gas exchange in patients presenting with acute respiratory distress syndrome. Critical care medicine 2004, 32(1):113-119.
- Forel J-M, Roch A, Marin V et al: Neuromuscular blocking agents decrease inflammatory response in patients presenting with acute respiratory distress syndrome. Critical care medicine 2006, 34(11):2749-2757.
- Sottile PD, Albers D, Moss MM: Neuromuscular blockade is associated with the attenuation of biomarkers of epithelial and endothelial injury in patients with moderate-to-severe acute respiratory distress syndrome. Critical Care 2018, 22(1):63.
- Papazian L, Forel J-M, Gacouin A et al: Neuromuscular Blockers in Early Acute Respiratory Distress Syndrome. New England Journal of Medicine 2010, 363(12):1107-1116.
- National Heart L, Network BIPCT: Early neuromuscular blockade in the acute respiratory distress syndrome. New England Journal of Medicine 2019, 380(21):1997-2008.