The size of the functional lung is highly variable in acute respiratory distress syndrome (ARDS). The elastance of the respiratory system (Ers) is more likely to reflect the functional lung size compared to the predicted body weight. It indicates the degree of lung stiffness and is represented by the pressure required to inflate the lungs. Ers is thus the reciprocal of compliance, the volume change per unit pressure change.
Compliance = Tidal volume / Pplat – PEEP
Pplat – PEEP = driving pressure
Ers = Driving pressure / tidal volume
Considering the relationship between Ers and the functional lung size, would the impact of low tidal volume ventilation on ARDS-related mortality depend on Ers? Would the driving pressure be a more rational target to aim for compared to tidal volumes based on predicted body weight? The recent study by Goligher et al., published recently in the American Journal of Respiratory and Critical Care Medicine, addresses these questions based on data from five previously published randomized controlled trials (RCTs).1
Methods
The study is a secondary analysis of previous RCTs comparing low vs. higher tidal volume ventilation. The authors evaluated the association between Ers and the low tidal volume-related reduction in mortality. Data were extracted from five previous RCTs that compared low vs. higher tidal volume in ARDS. These studies were also included in a previous analysis by Amato et al. that evaluated the impact of driving pressure on mortality in ARDS. The following data were extracted in the present study:
- Treatment assignment (low vs. higher tidal volume)
- Day 60 mortality
- SAPS, APACHE scores
- Ers (driving pressure/tidal volume) – normalized to body weight and expressed as cm H2O/ (ml/kg) (normal Ers: <1 cm H2O/ (ml/kg)
Statistical analysis
The study was based on the hypothesis that the mortality benefit of low tidal volume depends on the Ers. The mortality benefit of a low tidal volume is greater when the Ers is higher; the mortality benefit is less when Ers is lower.
The analysis was based on a Bayesian logistic regression model to calculate the posterior probability of an interaction between tidal volume and Ers on the 60-day mortality. Adjustments were made for the severity of illness, including the PaO2/FiO2 ratio, the APACHE or Simplified Acute Physiology Score, and the mortality rate of the control group in each study.
A Subpopulation Treatment Effect Pattern Plot (STEPP) technique was used for testing the frequentist hypothesis for interaction between tidal volumes and Ers regarding the difference in the absolute risk of mortality.
Results
The authors enrolled 1202 patients from 5 RCTs; complete data were available from 1096 patients (Table 1).
Table 1. RCTs included in the study
| RCT (year) | No: of patients | Low tidal volume arm | Higher tidal volume arm |
| Amato et al. (1998)2 | 53 | 6 ml/kg | 12 ml/kg |
| Brochard et al. (1998)3 | 116 | 6–10 ml/kg | > 10 ml/kg |
| Stewart et al. (1998)4 | 120 | < 8 ml/kg | 10–15 ml/kg |
| Brower et al. (1999)5 | 52 | 8 ml/kg | 10–12 ml/kg |
| Brower et al. (ARDS-net, 2000)6 | 861 | 6 ml/kg | 12 ml/kg |
Four hundred and sixteen patients (38%) died on or before day 60. The mortality benefit of low tidal volume ventilation was related to Ers. As Ers increased, lower tidal volumes progressively reduced the risk of death. There was a 93% posterior probability that the mortality benefit of ventilation with lower tidal volumes varied according to the Ers (posterior median interaction OR, 0.80 per cm H2O/ (ml/kg); 90% Credible Interval, 0.63 to 1.02). The absolute risk reduction (ARR) associated with a lower tidal volume ventilation strategy increased progressively with increasing Ers (Table 2). The mortality benefit of low tidal volume ventilation did not vary with the PaO2/FiO2 ratio
Table 2. The absolute risk reduction (ARR) for mortality associated with low tidal volumes progressively increased with increasing Ers
| Ers (cm H2O/ (ml/kg) | Posterior probability of ARR of at least 1% | More than 5% |
| Less than 2 | 55% | 29% |
| 2–3 | 82% | 58% |
| More than 3 | 92% | 82% |
The investigators used a skeptical prior, assuming that the effect of tidal volume is unlikely to vary meaningfully with Ers. This assumption in the Bayesian method is similar to the null hypothesis in the frequentist method. The Bayes factor for the one-sided null-hypothesis test of no interaction under the skeptical prior was 3.6, suggesting substantial evidence against the null hypothesis (this value is equivalent to P < 0.01 by the frequentist method)
The Subpopulation Treatment Effect Pattern Plot (STEPP) technique was employed for a frequentist hypothesis test of the interaction between the tidal volume strategy and Ers. By this technique, the impact of lower tidal volume ventilation on mortality also varied according to the Ers (interaction, P = 0.02)
Conclusions
The authors concluded that the mortality benefit of low tidal volume ventilation depends on the Ers, with a greater benefit at higher levels of Ers. They also proposed that lung-protective ventilation should primarily target the driving pressure instead of tidal volume.
Furthermore, the authors also observed that the posterior probability of any mortality benefit was low when the Ers was less than 1.5 cm H2O/ (ml/kg). Among patients with Ers less than 1.5 cm H2O/ (ml/kg), the driving pressure was approximately 15 cm H2O in the high tidal volume arm. This finding suggested that when the driving pressure is at or below 15 cm H2O, the likelihood of improved survival from low tidal volume ventilation was low.
Previous studies evaluating driving pressure
Targeting tidal volume based on predicted body weight may seem counterintuitive in ARDS considering that the extent of lung involvement is non-uniform, with a highly variable volume of the ventilatable, “baby lung”. Hence, targeting driving pressure may seem more logical as Ers would more likely reflect the extent of involvement.
In an earlier study on the relevance of driving pressure in mechanically ventilated patients, Amato et al. re-analyzed data of 3562 patients with ARDS from nine RCTs.2 The authors tested tidal volume, Pplat, PEEP, and driving pressure for possible association with survival. They observed that at a constant level of PEEP, mortality increased with an increase in the driving pressure. At a constant driving pressure, a higher Pplat did not increase mortality. Besides, even at similar plateau pressures, mortality decreased with a lower driving pressure. Thus, this study suggested that an increase in the driving pressure was associated with increased mortality, even if the Pplat remained constant.2
In a registry-based cohort study of 13408 patients receiving invasive mechanical ventilation, a daily increment of driving pressure or mechanical power was associated with a significant increase in the hazard of death after adjustment for baseline variables. The association persisted throughout the duration of mechanical ventilation.7
Yehya et al., in a re-analysis of the ALVEOLI and the ExPress trials, aimed to compare the association between changes in the PaO2/FiO2 ratio and driving pressure following protocol-based adjustments in ventilation. When both studies were modeled together, no association was observed between the change in PaO2/FiO2 ratios and mortality; however, change in driving pressure was significantly associated with mortality.8
Dianti et al. performed a meta-regression of nine trials including 4731 patients to evaluate the association of ventilator-induced lung injury (VILI) with tidal volume, driving pressure, and mechanical power. Modified mechanical power did not contribute to the risk of death from VILI compared to driving pressure and tidal volume.
How is Pplat measured during spontaneous breathing?
It is fairly straightforward to perform an inspiratory hold to measure Pplat when no spontaneous respiratory efforts are present. Inspiratory hold in the absence of spontaneous respiratory efforts results in a slight drop in the inspiratory pressure with the cessation of inspiratory flow. This constitutes the Pplat and represents the pressure generated by a static lung volume.
In contrast, inspiratory hold during spontaneous respiratory efforts results in an increase in the airway pressure to the Pplat level (Figure 1). The rise in pressure occurs because the tidal volume during a positive pressure-supported spontaneous breath is generated by two forces – the positive pressure generated by the ventilator and the negative pleural pressure generated by the patient effort. Thus, the static pressure required to generate the larger tidal volume results in an increase in airway pressure to the Pplat level.9,10
Inspiratory hold to measure Pplat in the presence of spontaneous breathing efforts is possible on the pressure support mode in some ventilators (Servo I, Servo S, Draeger-Evita XL). If the ventilator does not allow inspiratory hold in the pressure support mode, the patient may be switched to the pressure-controlled mode.
Summary
- Low tidal volume ventilation based on predicted body weight may be an overly simplistic approach towards lung protective ventilation
- There is emerging evidence that other parameters including driving pressure, transpulmonary pressure, and mechanical power may be more closely linked to clinical outcomes, including survival in ARDS
- Driving pressure is an easily monitored parameter by the bedside; Pplat measurement by applying inspiratory hold is valid in the presence of spontaneous respiratory efforts
- Limiting driving pressures below 15 cm H2O may be an important strategy in the prevention of VILI
- The protective effect of a low tidal volume ventilation strategy is evident only when the Ers is high
- Prospective controlled studies are required that compare driving pressure with tidal volume as the ventilation strategy
References
1. Goligher EC, Costa ELV, Yarnell CJ, et al. Effect of Lowering V t on Mortality in Acute Respiratory Distress Syndrome Varies with Respiratory System Elastance. Am J Respir Crit Care Med. 2021;203(11):1378-1385. doi:10.1164/rccm.202009-3536OC
2. Amato MBP, Meade MO, Slutsky AS, et al. Driving Pressure and Survival in the Acute Respiratory Distress Syndrome. N Engl J Med. 2015;372(8):747-755. doi:10.1056/NEJMsa1410639
3. Brochard L, Roudot-Thoraval F, Roupie E, et al. Tidal volume reduction for prevention of ventilator-induced lung injury in acute respiratory distress syndrome. The Multicenter Trail Group on Tidal Volume reduction in ARDS. Am J Respir Crit Care Med. 1998;158(6):1831-1838. doi:10.1164/ajrccm.158.6.9801044
4. Stewart TE, Meade MO, Cook DJ, et al. Evaluation of a ventilation strategy to prevent barotrauma in patients at high risk for acute respiratory distress syndrome. Pressure- and Volume-Limited Ventilation Strategy Group. N Engl J Med. 1998;338(6):355-361. doi:10.1056/NEJM199802053380603
5. Brower RG, Shanholtz CB, Fessler HE, et al. Prospective, randomized, controlled clinical trial comparing traditional versus reduced tidal volume ventilation in acute respiratory distress syndrome patients. Crit Care Med. 1999;27(8):1492-1498. doi:10.1097/00003246-199908000-00015
6. Brower RG, Matthay MA, Morris A, et al. Acute Respiratory Distress Syndrome Network. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med. 2000;342(18):1301-1308. doi:10.1056/NEJM200005043421801
7. Urner M, Jüni P, Hansen B, Wettstein MS, Ferguson ND, Fan E. Time-varying intensity of mechanical ventilation and mortality in patients with acute respiratory failure: a registry-based, prospective cohort study. The Lancet Respiratory Medicine. 2020;8(9):905-913. doi:10.1016/S2213-2600(20)30325-8
8. Yehya N, Hodgson CL, Amato MBP, et al. Response to Ventilator Adjustments for Predicting Acute Respiratory Distress Syndrome Mortality. Driving Pressure versus Oxygenation. Annals ATS. 2021;18(5):857-864. doi:10.1513/AnnalsATS.202007-862OC
9. Chen L, Jonkman A, Pereira SM, Lu C, Brochard L. Driving pressure monitoring during acute respiratory failure in 2020. Current Opinion in Critical Care. 2021;27(3):303-310. doi:10.1097/MCC.0000000000000827
10. Bellani G, Grassi A, Sosio S, Foti G. Plateau and driving pressure in the presence of spontaneous breathing. Intensive Care Med. 2019;45(1):97-98. doi:10.1007/s00134-018-5311-9
Role of Respiratory Rate. The degree of lung damage depends on pressure and frequency applied. In that sense a lower respiratory rate may be reasonable. But a higher respiratory rate might reduce expiratory time and provide intrinsic PEEP. Higher RR may be associated with less pulmonary inflammation, but increased lung oedema
Thanks Ranjit for our comment. Yes, the respiratory rate may also contribute to ventilator-induced lung injury (VILI). In fact, it is one of the components for the calculation of the mechanical power of ventilation. The other components include tidal volume (TV)/driving pressure (Pplat-PEEP), flow, and the positive end-expiratory pressure (PEEP) level.