Positive End Expiratory Pressure PEEP

Since its proposal by Alan K. Laws in Toronto in the late 1960s, and subsequent publication [35], there have been many descriptions of the titration of PEEP. For the bedside clinician, PEEP is utilized in an attempt to increase the FRC, and has the potential to achieve the following goals:

• Improved oxygenation (permitting lowered FiO2)

• Improved compliance

• Improved hemodynamic status (reduced pulmonary vascular resistance, reduced left ventricular afterload)

• Reduced stretch-induced lung injury (and concomitant lung-to-systemic release of inflammatory factors)

• Elimination of auto-PEEP

While these goals are admirable, they need to be weighed in the context of the potential deleterious effects of excessive PEEP including:

• Barotrauma

• Reduced compliance (if over-inflated)

• Impaired hemodynamic status (reduced right - and maybe left - ventricular preload)

The effects of PEEP on oxygenation and hemodynamics occur rapidly with changes in PEEP, and, therefore, are well appreciated by any bed-side intensivist. An early attempt to titrate the beneficial effects of PEEP on oxygenation against the deleterious effects on hemodynamics represented one of the first attempts to integrate several key ICU parameters in ICU patients [36]. In terms of clinical trials of the application of PEEP in ARDS, three studies are especially important. Amato et al demonstrated that maintenance of PEEP at a level greater than the LIP in a PV curve, as well as utilizing small Vt, was associated with a significantly better survival compared with a strategy consisting of lower PEEP plus higher Vt [17]. Application of 'prophylactic' PEEP was not associated with improved outcome in ARDS [37], and preliminary data from a recently completely study suggest that use of PEEP to induce recruitment is not associated with improved outcome 10[38]. The full data from this study are not yet available, and it is not clear that the applied PEEP resulted in lung recruitment 10[38].

However, several issues have become prominent since then. First, patients with ARDS represent a heterogeneous population in terms of the etiology of their respiratory failure, as well as the 'morphology' of the lung injury. Although most acute forms of lung injury are similar at a microscopic (i.e., histologic) level, wider utilization of bedside respiratory mechanics and Ct scanning [39] has increased our appreciation of different categories of ARDS [40]. Indeed Gattinoni et al. have suggested that the etiology of ARDS is related to the characterization of the subsequent lung mechanics, wherein 'pulmonary' etiology (e.g., aspiration, primary pneumonia) results in ARDS associated with consolidated, non-recruitable lung, whereas 'non-pulmonary' etiology (e.g., sepsis) results in recruitable lung [41]. Second, the protection against stretch-induced lung injury afforded by PEEP is largely accepted in the laboratory literature, spanning multiple experimental models of VILI [42,43]. However, this is far from obvious in the clinical environment, given the mixed outcomes from clinical studies. In this context, timing may be extremely important. A recent clinical study [45], demonstrated that the ability to recruit lungs depends on the timing of the efforts: recruitment is easier in the setting of early lung injury, and is more difficult when injury is more established.

In a recent provocative article, Rouby et al. developed a paradigm for characterizing patients with ARDS [40]. In that paper, the authors outline the importance of early assessment of CT-based morphology and bedside compliance in patients with ARDS. Following this, they outline an approach to optimization of PEEP, based on the slope of the PV curve, as well as the values of the lower and upper inflection points [40]. The rationale for this approach is largely based on their division of ARDS into two basic populations. In cases with diffuse hyperdensities accompanied by a 'high' LIP (>5 cmH2O) and a 'non-compliant' PV curve (slope <<50 ml/cmH2O), higher levels of PEEP are likely to be necessary, and are unlikely to cause problematic hyperinflation. Conversely, where the hyperdensities are focal and accompanied by a 'low' LIP (<5 cmH2O) and a 'compliant' PV curve (slope >50 ml/cmH2O), lower levels of PEEP are likely to be optimal; however, higher levels are likely to cause hyperinflation with the potential for barotrauma.

Finally, the 'titration' of PEEP against either oxygenation (or recruitment) must take into account the experimental findings of Rimensberger et al. [46] who confirmed theoretical predictions based on the differences between the inspiratory vs. expiratory limbs of the PV curve. They reported that whereas high levels of airway pressure (PEEP or continuous positive airway pressure [CPAP]) may be required to 'open' collapsed lungs in an experimental model, far lower levels of PEEP are required to maintain this opened -'recruited'- state. Thus, the early need for high levels of PEEP may not be maintained. Thus, one should not set a high level of PEEP and leave the bedside. Rather, one should apply a high level of PEEP or CPAP (sometimes to very high levels as tolerated by the hemodynamic status), and when improved oxygenation is attained, convert to a lower (but still elevated) level of PEEP, and thereafter titrating downwards to a 'stable' level of PEEP. This process may need to be repeated to progressively higher levels of 'stable' PEEP if oxygenation deteriorates during downward titration of 'stable' PEEP. The clinician will only discover this for each patient by regular - and repeated - titration.

In summary, if oxygenation is the chosen surrogate for recruitment, regular titration of PEEP should be commenced early in the ICU course, and be guided by the morphology and mechanics.

Tidal Volume and Plateau Pressure

Recent clinical trials have provided contradictory results relating to the optimal Vt, plateau pressure, and associated PEEP [14, 17, 19, 47, 48]. Whereas three of these studies found no impact of ventilatory strategy on outcome, two studies did. The clearest evidence of effect has been provided by the studies of Amato et al. [17] and the ARDSnet group [14]. The study by Amato et al. reported that relatively low VT combined with relatively high levels of PEEP resulted in significantly reduced mortality [17]. The ARDnet study reported that a 'low tidal volume' vs. a 'high tidal volume' strategy (as part of a comprehensive ventilatory management protocol that dictated FiO2, plateau airway pressure, and PEEP) was associated with improved patient survival [14]. These two studies are the only randomized controlled trials that demonstrate that mechanical ventilation has an impact on mortality in ARDS, and as such, constitute critically important contributions to the critical care literature. Applying the 'best available' evidence, a clinician might be tempted to conclude that 'on aggregate', lower Vt is generally better than higher Vt. However, titration of Vt in ARDS based on such suppositions may be dangerous for three reasons. First, each of the studies had two experimental groups (only), so that the results are 'binary'. Therefore, we have no clinical basis for interpolation about 'intermediate' ventilatory targets, or for extrapolating towards extremes of Vt. Second, a recent meta-analysis [49] of these studies casts (disputed [50]) doubt on the reliability of the validity of the concerns about 'high' Vt (as opposed to high plateau pressure) and the benefits of 'low' Vt [49]. Finally, a large-scale Australian study of outcome in ARDS, reported (without presenting the data) that there was no correlation between Vt and mortality [51].

In summary, if the alternatives available to a clinician are either of the four treatment groups in the studies by Amato et al. [17] or the ARDSnet [14], then the clinician should definitely opt for one of the respective 'low stretch' group options. This is never the case, however, and the clinician should not at this stage decide that lower Vt is necessarily better for all ranges of Vt; therefore, Vt should not be continually titrated downwards in the absence of due regard to lung recruitment or adequacy of ventilation. Instead, avoidance of high Vt that result in elevated plateau pressures appears appropriate.

Cytokines

Since the late 1960s it has been recognized that lung stretch results in release of inflammatory mediators [52], and this was proposed as a mechanism of hemodynamic depression resulting from mechanical ventilation [53]. Recent work from multiple laboratories has suggested that adverse forms of mechanical ventilation are associated with pulmonary [54] or systemic [55] release of cytokines or bacterial products [56, 57]. From the clinical perspective, these findings have been confirmed, at least in principle. The ARDSnet study reported that systemic circulating interleukin (IL)-6 was higher in the 'high stretch' group [14], and an additional smaller study demonstrated that high PEEP combined with lower Vt resulted in lesser elevations in lung and circulating cytokine release [18]. Nonetheless, not all experimental evidence concurs with the hypothesis that adverse ventilatory strategy results in elevated cytokines [58].

Our group has recently reported that cytokine gene activation is associated with high stretch ventilation, but that such activation occurs well before the development of measurable physiologic lung impairment or before the appearance of pathologic changes in lung histology [59]. Taken together, these data suggest that in the future, plasma cytokine profile might provide an early-warning signal of impending stretch-induced lung injury, thereby mandating a change in ventilatory strategy. In such a way circulating (or bronchoalveolar lavage) cytokines or bacterial products could function as a target for ventilatory titration.

Targeting the Long-term

Much of the foregone discussion has focussed on respiratory issues, or on the integrated physiology of O2 delivery and CO2 control. However, it is increasingly clear that patients do not die from hypoxia perse [60], or indeed from any particular impingement of pulmonary function, including overt barotrauma [61]. Furthermore, the overall ICU mortality from ARDS appears to be fairly consistent over the last decade, and pending a radical change in approach to mechanical ventilation or a new biologically driven therapy, it is difficult to envisage how mortality could improve significantly beyond the current range. Thus, clinicians should expand their focus from mortality statistics to the broader issues of morbidity and quality of life in those patients - the majority - who survive ARDS. Several groups have investigated these issues, and several pertinent findings have been described. The key causes of long-term morbidity disability relate to acquired neuromuscular impairment [62]. In addition, long-term depression and post-traumatic stress disorder may be associated with increased use of sedative or neuromuscular blocking drugs [63]. Finally, the use of low Vt -although associated with less mortality [14, 17] - does not appear to translate into less morbidity in survivors of ARDS [64]. Thus, it will be important for future investigators to explore the biologic basis for long-term disability, and investigate therapeutic and preventive approaches.

Conclusion: Trading Multiple Targets Against Each Other

Although we are rapidly accumulating knowledge about specific questions in critical care, we do not - and will never - have the answers to all possible clinical questions in ventilatory care, much less in critical care in general. Thus, randomized clinical trials will answer isolated questions, and the individual clinician will have to weigh the evidence as applied to specific scenarios. However, frameworks can be constructed to address clinical situations. In terms of targeting parameters in mechanical ventilation, the following approach might be useful:

1. Decide on the single most important immediate issue for the patient, and consider the following (illustrative) examples:

- If the SpO2 is less than 85%, then correction of hypoxemia would be the first priority.

- On the other hand, if the PaCO2 is 11 kPa in the setting of elevated intracranial pressure, then reduction of PaCO2 would be a very high priority.

2. Prioritize among the following parameters or targets (oxygenation, PaCO2, plateau pressure or Vt, hemodynamic depression, lung recruitment, patientventilator synchrony) and rank them in order of importance for the patient.

3. Decide on which parameters will be selected for clinical titration

In summary, the clinician needs to decide which parameter is of immediate - and subsequent - importance, and which scientific literature is applicable. In addition, he/she must decide on which 'trade-offs' are appropriate for the patient in question, and atwhat stage the benefits oftargets such as oxygenation, perfusion, recruitment are worth the cost to the patient of attaining them.

References

1. Mao C, Wong DT, SlutskyAS, KavanaghBP (1999) A quantitative assessment of how Canadian intensivists believe they utilize oxygen in the intensive care unit. Crit Care Med 27:2806-2811

2. Kavanagh BP (1998) Goals and concerns for oxygenation in acute respiratory distress syndrome. Curr Opin Crit Care 4:16-20

3. Bernard GR, Artigas A, Brigham KL, et al (1994) The American-European consensus conference on ARDS. Definitions, mechanisms, relevant outcomes, and clinical trial coordination. Am J Respir Crit Care Med 149:818-824

4. Phang PT, Cunningham KF, Ronco JJ, Wiggs BR, Russell JA (1994) Mathematical coupling explains dependence of oxygen consumption on oxygen delivery in ARDS. Am J Respir Crit Care Med 150:318-323

5. Maldonado A, Bauer TT, Ferrer M, et al (2000) Capnometric recirculation gas tonometry and weaning from mechanical ventilation. Am J Respir Crit Care Med 161:171-176

6. Obrig H, Villinger A (2003) Beyond the visible-imaging the human brain with light. J Cereb Blood FlowMetab 23:1-18

7. Schlosser RL, Voigt B, von Loewenich V (2000) [Cerebral perfusion in newborn infants treated with high-frequency oscillation ventilation]. Klin Padiatr 212:308-311

8. Conference C (1996) Tissue hypoxia. How to detect, how to correct, how to prevent. Am J Respir Crit Care Med 154:1573-1578

9. Wung JT, James LS, Kilchevsky E, James E (1985) Management ofinfants with severe respiratory failure and persistence of the fetal circulation, without hyperventilation. Pediatrics 76:488-494

10. Hickling KG, Henderson SJ, Jackson R (1990) Low mortality associated with low volume pressure limited ventilation with permissive hypercapnia in severe adult respiratory distress syndrome. Intensive Care Med 16:372-377

11. Hickling KG, Walsh J, Henderson S, Jackson R (1994) Low mortality rate in adult respiratory distress syndrome using low-volume, pressure-limited ventilation with permissive hypercap-nia: a prospective study. Crit Care Med 22:1568-1578

12. Bidani A, Tzouanakis AE, Cardenas VJ, Jr., Zwischenberger JB (1994) Permissive hypercapnia in acute respiratory failure. JAMA 272:957-962

13. Feihl F, Perret C (1994) Permissive hypercapnia. How permissive should we be? Am J Respir Crit Care Med 150:1722-1737

14. The Acute Respiratory Distress Syndrome Network (2000) 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 342:1301-1308

15. Laffey JG, Kavanagh BP (1999) Carbon dioxide and the critically ill - too little of a good thing? Lancet 354:1283-1286

16. Laffey JG, Kavanagh BP (2000) Biological effects of hypercapnia. Intensive Care Med 26:133-138

17. Amato MB, Barbas CS, Medeiros DM, et al (1998) Effect of a protective-ventilation strategy on mortality in the acute respiratory distress syndrome. N Engl J Med 338:347-354

18. Ranieri VM, Suter PM, Tortorella C, et al (1999) Effect of mechanical ventilation on inflammatory mediators in patients with acute respiratory distress syndrome: a randomized controlled trial. JAMA 282:54-61

19. Stewart TE, Meade MO, Cook DJ, et al (1998) Evaluation of a ventilation strategy to prevent barotrauma in patients at high risk for acute respiratory distress syndrome. Pressure- and Volume-Limited ventilatory strategy. N Engl J Med 338:355-361

20. Shibata K, Cregg N, Engelberts D, Takeuchi A, Fedorko L, Kavanagh BP (1998) Hypercapnic acidosis may attenuate acute lung injury by inhibition of endogenous xanthine oxidase. Am J Respir Crit Care Med 158:1578-1584

21. Broccard AF, Hotchkiss JR, Vannay C, et al (2001) Protective effects of hypercapnic acidosis on ventilator-induced lung injury. Am J Respir Crit Care Med 164:802-806

22. Sinclair SE, Kregenow DA, Lamm WJ, Starr IR, Chi EY, Hlastala MP (2002) Hypercapnic acidosis is protective in an in vivo model of ventilator-induced lung injury. Am J Respir Crit Care Med 166:403-408

23. Laffey JG, Tanaka M, Engelberts D, et al (2000) Therapeutic hypercapnia reduces pulmonary and systemic injury following In vivo lung reperfusion. Am J Respir Crit Care Med 162:2287-2294

24. Vannucci RC, Towfighi J, Heitjan DF, Brucklacher RM (1995) Carbon dioxide protects the perinatal brain from hypoxic-ischemic damage: an experimental study in the immature rat. Pediatrics 95:868-874

25. Nomura F, Aoki M, Forbess JM, Mayer JE (1994) Effects of hypercarbic acidotic reperfusion on recovery of myocardial function after cardioplegic ischemia in neonatal lambs. Circulation 90:321-327

26. du Plessis AJ, Jonas RA, Wypij D, et al (1997) Perioperative effects of alpha-stat versus pH-stat strategies for deep hypothermic cardiopulmonary bypass in infants. J Thorac Cardiovasc Surg 114:991-1000

27. Holmes JM, Leske DA, Zhang S (1997) The effect of raised inspired carbon dioxide on normal retinal vascular development in the neonatal rat. Curr Eye Res 16:78-81

28. Zhu S, Basiouny KF, Crow JP, Matalon S (2000) Carbon dioxide enhances nitration of surfactant protein A by activated alveolar macrophages. Am J Physiol 278:L1025-L1031

29. Lang JD JR, Chumley P, Eiserich JP, et al (2000) Hypercapnia induces injury to alveolar epithelial cells via a nitric oxide-dependent pathway. Am J Physiol 279:L994-1002

30. Gole MD, Souza JM, Choi I, et al (2000) Plasma proteins modified by tyrosine nitration in acute respiratory distress syndrome. Am J Physiol 278:L961-967

31. Laffey JG, Engelberts D, Kavanagh BP (2000) Buffering hypercapnic acidosis worsens acute lung injury. Am J Respir Crit Care Med 161:141-146

32. Hood VL, Tannen RL (1998) Protection of acid-base balance by pH regulation of acid production. N Engl J Med 339:819-826

33. Abu Romeh S, Tannen RL (1986) Amelioration of hypoxia-induced lactic acidosis by superimposed hypercapnea or hydrochloride acid infusion. Am J Physiol 250:F702-F709

34. Laffey JG, Kavanagh BP (2002) Hypocapnia. N Engl J Med 347:43-53

35. McIntyre RW, Laws AK, Ramachandran PR (1969) Positive expiratory pressure plateau: improved gas exchange during mechanical ventilation. Can Anaesth Soc J 16:477-486

36. Suter PM, Fairley B, Isenberg MD (1975) Optimum end-expiratory airway pressure inpatients with acute pulmonary failure. N Engl J Med 292:284-289

37. Pepe PE, Hudson LD, Carrico CJ (1984) Early application of positive end-expiratory pressure in patients at risk for the adult respiratory-distress syndrome. N Engl J Med 311:281-286

38. NIH (2002) ALVEOLI study: at http://hedwig.mgh.harvard.edu/ardsnet/ards04.html.

39. Gattinoni L, Mascheroni D, Torresin A, et al (1986) Morphological response to positive end expiratory pressure in acute respiratory failure. Computerized tomography study. Intensive Care Med 12:137-142

40. Rouby JJ, Lu Q, Goldstein I (2002) Selecting the right level of positive end-expiratory pressure in patients with acute respiratory distress syndrome. Am J Respir Crit Care Med 165:1182-1186

41. Gattinoni L, Pelosi P, Suter PM, Pedoto A, Vercesi P, Lissoni A (1998) Acute respiratorydistress syndrome caused by pulmonary and extrapulmonary disease. Different syndromes? Am J Respir Crit Care Med 158:3-11

42. Parker JC, Hernandez LA, Peevy KJ (1993) Mechanisms of ventilator-induced lung injury. Crit Care Med 21:131-143

43. Dreyfuss D, Saumon G (1998) Ventilator-induced lung injury: lessons from experimental studies. Am J Respir Crit Care Med 157:294-323

44. Grasso S, Mascia L, Del Turco M, et al (2002) Effects of recruiting maneuvers in patients with acute respiratory distress syndrome ventilated with protective ventilatory strategy. Anesthesiology 96:795-802

45. Suzuki H, PapazoglouK, Bryan AC (1992) Relationship between PaO2 and lung volume during high frequency oscillatory ventilation. Acta Paediatr Jpn 34:494-500

46. Rimensberger PC, Pristine G, Mullen BM, Cox PN, Slutsky AS (1999) Lung recruitment during small tidal volume ventilation allows minimal positive end-expiratory pressure without augmenting lung injury. Crit Care Med 27:1940-1945

47. Brower RG, Shanholtz CB, Fessler HE, et al (1999) Prospective, randomized, controlled clinical trial comparing traditional versus reduced tidal volume ventilation in acute respiratory distress syndrome patients. Crit Care Med 27:1492-1498

48. Brochard L, Roudot-Thoraval F, Roupie E, et al (1998) Tidal volume reduction for prevention ofventilator-induced lung injury in acute respiratory distress syndrome. The Multicenter Trail Group on Tidal Volume reduction in ARDS. Am J Respir Crit Care Med 158:1831-1838

49. Eichacker PQ, Gerstenberger EP, Banks SM, Cui X, Natanson C (2002) Meta-analysis of acute lung injury and acute respiratory distress syndrome trials testing low tidal volumes. Am J Respir Crit Care Med 166:1510-1514

50. Brower RG, Matthay M, Schoenfeld D (2002) Meta-analysis of acute lung injury and acute respiratory distress syndrome trials (letter). Am J Respir Crit Care Med 166:1515-1517

51. Bersten AD, Edibam C, Hunt T, Moran J (2002) Incidence and mortality of acute lung injury and the acute respiratory distress syndrome in three Australian States. Am J Respir Crit Care Med 165:443-448

52. Edmonds JF, Berry E, Wyllie JH (1969) Release of prostaglandins caused by distension of the lungs. Br J Surg 56:622-623

53. Berry EM, Edmonds JF, Wyllie H (1971) Release of prostaglandin E2 and unidentified factors from ventilated lungs. Br J Surg 58:189-192

54. Imai Y, Kawano T, Miyasaka K, Takata M, Imai T, Okuyama K (1994) Inflammatory chemical mediators during conventional ventilation and during high frequency oscillatory ventilation. Am J Respir Crit Care Med 150:1550-1554

55. Chiumello D, Pristine G, Slutsky AS (1999) Mechanical ventilation affects local and systemic cytokines in an animal model of acute respiratory distress syndrome. Am J Respir Crit Care Med 160:109-116

56. Murphy DB, Cregg N, Tremblay L, Engelberts D, Laffey JG, Slutsky AS, Romaschin A, Kavanagh BP (2000) Adverse ventilatory strategy causes pulmonary-to-systemic translocation of endotoxin. Am J Respir Crit Care Med 162:27-33

57. Nahum A, Hoyt J, Schmitz L, Moody J, Shapiro R, Marini JJ (1997) Effect of mechanical ventilation strategy on dissemination of intratracheally instilled Escherichia coli in dogs. Crit Care Med 25:1733-1743

58. Ricard JD, Dreyfuss D, Saumon G (2001) Production of inflammatory cytokines in ventilator-induced lung injury: a reappraisal. Am J Respir Crit Care Med 163:1176-1180

59. Copland I, Engelberts D, Kavanagh BP, Post M (2001) High stretch ventilation causes cytokine gene activation before injury. Am J Respir Crit Care Med 161:A164 (abst)

60. Montgomery AB, Stager MA, Carrico CJ, Hudson LD (1985) Causes of mortality in patients with the adult respiratory distress syndrome. Am Rev Respir Dis 132:485-489

61. Weg JG, Anzueto A, Balk RA, et al (1998) The relation of pneumothorax and other air leaks to mortality in the acute respiratory distress syndrome. N Engl J Med 338:341-346

62. Herridge MS, Cheung AM, Tansey CM, et al (2003) One-year outcomes in survivors of the acute respiratory distress syndrome. N Engl J Med 348:683-693

63. Nelson BJ, Weinert CR, Bury CL, Marinelli WA, Gross CR (2000) Intensive care unit drug use and subsequent quality of life in acute lung injury patients. Crit Care Med 28:3626-3630

64. Orme J Jr, Romney JS, Hopkins RO, et al (2003) Pulmonary function and health-related quality of life in survivors of acute respiratory distress syndrome. Am J Respir Crit Care Med 167:690-694

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