PEEP: the early beginnings
In the 1960s, at the Colorado General Hospital, David Ashbaugh and colleagues formed a team to care for patients who required respiratory support. Among the patients who required ventilator support, they identified a few patients who remained severely hypoxic with diffuse lung infiltrates. Mortality was high among these patients; autopsy revealed extensive alveolar collapse and the presence of hyaline membranes. They reported 12 such patients that turned out to be a milestone in the history of medicine – the first report of what we know today as acute respiratory distress syndrome (ARDS) (1).
The Ashbaugh-led team encountered great difficulty in ventilating these patients with poorly compliant lungs using pressure-cycled ventilators available to them as they did not deliver sufficient tidal volumes. A frustrated Ashbaugh stumbled upon an old volume-cycled Engstrom ventilator in the anesthesia department storeroom. They initially used this ventilator in two patients with ARDS, one related to trauma, and the other, secondary to acute pancreatitis. On both occasions, higher tidal volumes were achieved; however, disappointingly, there was little change in the gas exchange. The third patient, with acute hemorrhagic pancreatitis appeared to be similarly unresponsive to volume-cycled ventilation. The team seemed lost for answers, when one of the residents noticed an unfamiliar button labeled “expiratory retard” on the machine. Although the team had no clue regarding what it was meant to do, they decided to push it nevertheless, more out of desperation than conviction. The effect was stunning – there was a dramatic improvement in oxygenation. They had serendipitously pushed the hitherto unknown PEEP button. It came as no surprise that in their 1967 series of 12 patients, among the first seven who did not receive PEEP, there were only two survivors. In contrast, there were three survivors among five patients who received PEEP (1).
Barotrauma vs. volutrauma
The harmful effect of using high ventilation pressures was apparent to clinicians, as many of these patients developed pneumothorax. The damage arising from high pressures was referred to as “barotrauma”. However, would the lungs suffer damage due to ventilation with excessive volumes even if the ventilation pressures were maintained reasonably low? In their historical 1988 study, Dreyfuss et al. evaluated the effect of volume and pressure in a rat lung model.
They ventilated one group of rats with high inflation pressures of 45 cm H2O and tidal volumes of 40 ± 3 ml/kg body weight. In another group, the chest and abdomen were strapped with rubber bands, thus restricting air entry into the lungs. In this second group, they used similar ventilation pressures, but the tidal volume was restricted to 19 ± 1 ml/kg due to the thoraco-abdominal strapping. The rats ventilated with high pressure and high tidal volumes developed pulmonary edema; the rats who were subjected to high pressures, but restricted tidal volumes due to strapping did not. This study demonstrated that lung injury occurred not solely due to barotrauma imposed by increased ventilation pressures; high tidal volume alone can initiate and perpetuate injury even at modest ventilation pressures. High tidal volume-associated lung injury occurred even when the animals were ventilated with an iron lung. Despite the use of negative pressure, the animals still suffered lung injury from ventilation with high tidal volumes (2).
Subsequently, the term “volutrauma” related to ventilation with high tidal volumes was coined in 1992 by Dreyfuss and Saumon. They contended that tidal volume is the key risk factor for ventilation-associated lung injury. This concept was based on the observation that tidal volume is a more reliable indicator of lung stress compared to airway pressure. The rise in airway pressure may be partly contributed to by chest wall stiffness (elastance) (3).
Clinical studies with a low tidal volume strategy
In their 1994 study, Hickling et al. evaluated the effect of low tidal volume ventilation between 4–7 ml/kg while limiting peak pressures to 30–40 cm H2O among patients with ARDS. They allowed the PaCO2 levels to rise. The PaCO2 levels rose to a mean of 66.5 mm Hg while the pH dropped to a mean level of 7.23. No buffers were used to combat the acidosis. Among 53 patients ventilated using this technique, they noted a significantly lower than predicted mortality based on the APACHE II score. This was one of the first studies that suggested improved outcomes using low tidal volumes and “permissive” hypercapnia, as the authors described it (4).
Amato et al. tested the hypothesis of high tidal volume-related lung injury in a randomized controlled trial (RCT) (5). They studied 53 patients with ARDS comparing different ventilatory strategies at two hospitals in Brazil. The control group received what was considered a conventional strategy at that time – a tidal volume of 12 ml/kg, and the lowest PEEP levels for acceptable oxygenation, aiming to normalize of PaCO2 levels. This strategy was compared with a protective ventilatory strategy using a tidal volume of 6 ml/kg, with individualized PEEP levels, set 2 cm H2O above the lower inflection point on the pressure-volume curve. The driving pressures were limited to less than 20 cm H2O in this group. Permissive hypercapnia was accepted as part of the protective strategy. The results were remarkable; the 28-day mortality was 11/29 (37%) with the protective strategy compared with 17/24 (71%) in the conventional group. Weaning from mechanical ventilation was also significantly higher with the protective strategy; besides, the incidence of barotrauma was 42% with conventional ventilation compared to just 7% with the protective strategy. This study was criticized for the inexplicably high mortality of 71% in the control arm. There was a high incidence of critical incidents, including accidental extubations and iatrogenic mortality, that further confounded the findings of this study. Besides, the identification of the lower inflection point from the static pressure-volume curve appeared to be no easy task, often requiring neuromuscular blockade.
These findings contrasted with those of another RCT comparing tidal volumes and ventilation pressures in the same edition of the New England Journal of Medicine of February 5, 1998. Stewart et al. observed no difference in mortality when they compared tidal volumes of 8 ml/kg limiting peak inspiratory pressures to 30 cm H2O compared with tidal volumes of 10–15 ml/kg, allowing the peak inspiratory pressures to rise to 50 cm H2O (6).
The landmark ARDSNet trial
The stage was set for a multicenter, adequately powered RCT to establish the efficacy of a lung-protective ventilation strategy, limiting tidal volumes and ventilation pressures. The landmark ARDSNet study was published on May 4, 2000 (7). It revolved around the comparison of a conventional with a lung-protective ventilation strategy in patients with acute lung injury or ARDS. In the conventional strategy, a tidal volume of 12 ml/kg predicted body weight was employed, limiting the plateau pressure to 50 cm H2O or less; the lung-protective strategy used a tidal volume of 6 ml/kg predicted body weight, aiming to limit plateau pressures to 30 cm H2O. The study was stopped after the enrolment of 861 patients. It was amply clear by this time that high tidal volumes were associated with excessive mortality. The mortality was 31% in the low tidal volume arm compared with 39.8% in the high tidal volume arm. (p = 0.007). The use of low tidal volumes was also associated with significantly higher ventilator-free days. Besides, non-pulmonary organ failure was also less with low tidal volume ventilation. Interestingly, the PaO2/FiO2 was significantly lower in the low tidal volume group on days 1 and 3. This finding underlined the futility of aiming to improve oxygenation using high tidal volumes and ventilation pressures during the early phase of ARDS. As Martin Tobin emphasized in the accompanying editorial, aptly titled the “Culmination of an Era in Research on the Acute Respiratory Distress Syndrome”, the ARDSNet trial underlined the importance of a “gentler form of mechanical ventilation” in ARDS (8).
Injurious ventilatory strategies were also hypothesized to result in the release of inflammatory mediators and neutrophil recruitment in the lung, that may trigger or worsen multi-organ dysfunction, often observed in critically ill patients. This phenomenon was described as biotrauma, and was established later by Ranieri et al (9). They ventilated patients with severe ARDS using a lung protective strategy with tidal volume and PEEP based on the pressure-volume curve. This strategy was compared with a tidal volume based on normalization of PaCO2 values. The tidal volume in PaCO2-based ventilation group was much higher compared to the lung-protective strategy group (11.1 vs. 7.6 ml/kg). The authors demonstrated that the level of inflammatory mediators, including tumor necrosis factor (TNF) alpha and IL-6 were significantly higher in the PaCO2-based ventilation group that used much higher tidal volumes.
Evolution of technology – ventilators
The first generation of positive pressure ventilators were introduced in the 1950s. These early ventilators did not offer the option of patient-initiated breaths, often leading to a lack of synchrony between the man and the machine. Most of these ventilators did not provide any measured variables. The respiratory rate had to be counted manually and the tidal volume could be measured only using an external device. The Engstrom ventilators of yesteryears had a limited monitoring capability, including tidal volume and respiratory rate (Fig. 1); however, there was no facility for patient trigger and the inspiratory: expiratory ratio was fixed at 1:2. The facility for PEEP was introduced in the early 1970s, in the Puritan Bennet ventilators of that era.
Patient-triggered breaths were introduced in the second-generation mechanical ventilators. These were also the first ventilators that incorporated alarms, including high airway pressures, respiratory rate, and tidal volume alarms. The Servo 900 C ventilators were the last of this generation and the first to offer pressure support and pressure-controlled modes (Fig. 2). Breath activation was through pressure-triggering. These hardy, ever-reliable machines were in widespread use in the ICUs of the 1990s.
The third-generation ventilators were microprocessor-controlled. The Servo 300, Puritan Bennett 7200, and Hamilton Veolar were the most popular machines of this generation (Fig. 3). The ventilators of this generation were the first to introduce flow-triggering or “flow-by” aimed to reduce the patient effort required for breath activation. These machines offered most of the modes available on modern ventilators, including synchronized intermittent mandatory ventilation (SIMV) and pressure-regulated volume-controlled modes (PRVC). They provided on screen display of waveforms and loops; besides, a wide range of alarms was included to ensure patient safety. Airway pressure release ventilation (APRV) was also introduced for the first time in some of the third-generation ventilators.
We have come a long way from the iron lung era through the polio epidemics that ushered in the epoch of positive pressure ventilation. While mechanical ventilation saved lives, it was obvious that injudicious application could inflict severe lung injury. The concept of the “baby lung” in ARDS espoused the concept of “protecting” the relatively normal lung from the adverse effects emanating from high volumes and pressures. The futility of using high tidal volumes purely in the pursuit of improved gas exchange also became self-evident. The concept of biotrauma emerged, with organ dysfunction arising from inflammatory mediator release in the lungs. An open-lung strategy optimizing PEEP levels while restricting tidal volumes was established through evidence available from multiple clinical trials. In the meantime, technology also made giant leaps, with the availability of increasingly sophisticated ventilators. Ventilatory modes have been refined, and patient-ventilator interaction has improved with the advent of assist and support modes. The fast pace of advancement in biology and engineering will definitely enable us to offer vastly superior respiratory care to our patients in the future.
1. Ashbaugh DG, Bigelow DB, Levine BE. Acute respiratory distress in adults. Lancet 1967;2:319–323.
2. Dreyfuss D, Soler P, Basset G, Saumon G. High Inflation Pressure Pulmonary Edema: Respective Effects of High Airway Pressure, High Tidal Volume, and Positive End-expiratory Pressure. Am Rev Respir Dis. 1988 May;137(5):1159–64.
3. Dreyfuss D, Saumon G. Barotrauma is volutrauma, but which volume is the one responsible? Intensive Care Med. 1992 Mar;18(3):139–41.
4. Hickling KG, Henderson SJ, Jackson R. Low mortality associated with low volume pressure limited ventilation with permissive hypercapnia in severe adult respiratory distress syndrome. Intensive Care Med. 1990;16(6):372–7.
5. Amato MB, Barbas CS, Medeiros DM, Magaldi RB, Schettino GP, Lorenzi-Filho G, et al. Effect of a protective-ventilation strategy on mortality in the acute respiratory distress syndrome. N Engl J Med. 1998 Feb 5;338(6):347–54.
6. Stewart TE, Meade MO, Cook DJ, Granton JT, Hodder RV, Lapinsky SE, et al. Evaluation of a Ventilation Strategy to Prevent Barotrauma in Patients at High Risk for Acute Respiratory Distress Syndrome. N Engl J Med. 1998 Feb 5;338(6):355–61.
7. 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;8.
8. Tobin MJ. Culmination of an Era in Research on the Acute Respiratory Distress Syndrome. N Engl J Med. 2000 May 4;342(18):1360–1.
9. Ranieri VM, Suter PM, Tortorella C, De Tullio R, Dayer JM, Brienza A, et al. Effect of mechanical ventilation on inflammatory mediators in patients with acute respiratory distress syndrome: a randomized controlled trial. JAMA. 1999 Jul 7;282(1):54–61.
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