Across the nation, at least 1,500 critically ill patients in intensive care hospital units suffering from acute lung injury (ALI) or respiratory distress syndrome (ARDS), have been subjected to a controversial, unproven, potentially harmful therapy in several clinical trials sponsored by the National Heart, Lung and Blood Institute of the National Institutes of Health (NHLBI-NIH). The trials continue to be conducted at multiple sites of the influential NHLBI-ARDS Network comprising a dozen prestigious academic medical centers. [1]

Critically ill patients with ALI-ARDS require lung-protective mechanical ventilation to enable them to breathe ensuring they get adequate oxygen. The controversy centers on what is the best protective ventilation method for pumping air into lungs–or, more accurately, what ventilation setting provides optimal air volume while maintaining safe plateau pressure—the key to survival. The ARDS Network recommendation involves an unproven method enabling patients to take only short breaths through a mechanical air ventilator. The setting recommended by the ARDS Network is very low (6 mL/ kg of predictable body weight (PBW) tidal volume, VT). But evidence shows that some patients would do better with settings of 8 mL/ kg to 10mL / kg allowing them to take deeper breaths with less exertion.

The ARDS Network setting of choice (6 mL/ kg) is based on the erroneous conclusions drawn from a published flawed experiment (ARMA, 2000) [2] sponsored by the NHLB-NIH. That experiment was conducted between March, 1996 and March, 1999, involving 861 patients. The ARDS Network investigators failed to put the safety and efficacy of the 6 mL/ kg ventilation method to the test against the best clinical practice, which affords patients individualized ventilation settings based on their condition. 

Below, a critical editorial by Dr. Robert M Kacmarek, Head of Respiratory Care Services at Massachusetts General Hospital and professor at Harvard University—the coordinating center for the ARDS Network, calls into question the validity of the ARDS Network recommendation of treating all patients with ALI-ARDS with a fixed, low air ventilation setting (6 mL/ kg).

Dr. Kacmarek was persuaded by compelling evidence—demonstrable by patient discomfort and survival rates–that the ARDS recommendation is unsustainable.

“In my opinion, the cost of using a small (6.4-mL/kg PBW) VT [tidal volume] with these patients, from a WOB [work of breathing] perspective, is too high.”

Since its publication in 2000, in The New England Journal of Medicine, the ARDS Network report about the first study, ARMA, has been the subject of heated controversy. The study has been criticized both for its flawed scientific design, the arbitrary selection of a fixed ventilation setting, and the investigators’ failure to comply with ethical / legal federal regulations and international standards for the protection of human subjects.  Neither the purpose nor the risks—including death—were disclosed to patients or surrogates. In most cases informed consent requirements were violated.

Another NHLBI-NIH funded ARDS Network experiment (ALVEOLI, 2004) was conducted between October, 1999 and February, 2002 at 23 ARDS Network hospitals involving 549 ALI-ARDS patients, all of whom were forced to bear the extra stress involved in the small 6 mL / kg tidal volume ventilation. Both ARMA and ALVEOLI were published in The New England Journal of Medicine (ARMA, 2000, lending them the appearance of legitimacy. [3]

A third ARDS Network experiment (FACTT) is ongoing.

Senior critical care physicians have questioned the (apparently) arbitrary, unsupportable basis underlying the ARDS Network fixed ventilation setting (6 mL /kg) that all ALI-ARDS patients are subjected to—apparently disregarding patients’ condition and plateau pressure. [4]

The updated analyses of the ARMA study data by critics [5] and new evidence from a small study comparing tidal volume and pressure regulated breathing modes, [6] as well as Dr. Kacmarek’s own study, [7] have persuaded him that the "a one size fits all" ARDS Network approach to treating ALI-ARDS patients is unsustainable because it increases stress and discomfort for patients struggling to breathe. When ventilators are set at 6 mL/ kg—as recommended by the ARDS Network—patients are not getting sufficient air and are forced to struggle to survive.  Dr. Kacmarek explains:

"To put this into perspective, the normal inspiratory WOB in a healthy adult breathing through the nose is about 0.4 J/L.  Many have considered inspiratory WOB_1.0 J/L during spontaneous breathing unsustainable and an indication for ventilatory support.  In other words, the WOB performed by these ALI/ARDS patients during assisted ventilation was equivalent to that considered in spontaneously breathing patients as an indication for ventilatory support."

Dr. Kacmarek points out that low mortality in all of the studies he examined was achieved by maintaining “low-end-inspiratory plateau pressure.” Low mortality was NOT achieved by low 6 mL/kg tidal volume, inasmuch as different ventilation volume settings were used. He concludes that by assessing four options for patients with ALI-ARDS, based on the available data, “it would seem safe to allow [tidal volume] VT up to 9 mL/kg if the plateau pressure is maintained below 25 cm H2O. The higher the plateau pressure, the greater the need to maintain a low VT, but in patients with a low plateau pressure, the risks of the alternatives would appear to outweigh the benefits of forcing a VT of 6.0 mL/kg PBW!”

In light of the confirmatory evidence demonstrating that the low volume (6 mL/kg PBW) ventilation setting recommended by the ARDS Network for all ALI-ARDS patients is unsustainable—because it increases patients’ level of exertion and discomfort (i.e., work of breathing) and will likely increase patients’ death rate—

What is the justification for the continued support by the National Heart Lung and Blood Institute of an unethical follow-up study by the ARDS Network (called FACTT) whose protocol forces patients to be treated with the fixed low volume 6 mL/kg ventilation setting?

What is preventing the Office of Human Research Protection—the research ethics oversight agency of the federal government—from intervening?

The FACTT experiment is being conducted on hundreds of critically ill patients with ALI-ARDS —some of who will die for no other reason than being forced to a fixed 6 mL/kg ventilation setting, as required by the FACTT protocol. That setting is based on erroneous conclusions drawn from the original flawed ARDS Network experiment. The error is a result of the investigators’ failure to compare the experimental low 6 mL/kg setting against current practice which affords patients a range of individualized ventilation settings, selected according to their condition.

Failure to include a comparison arm representing the best current practice—as is required under the international standard of the Declaration of Helsinki—rendered the ARMA study nothing more than a physiology experiment in which patients’ lives were sacrificed as two extreme methods of mechanical ventilation were compared—6mL/kg versus 12mL/kg. [8]

Scientists, clinical investigators and government agencies must own up to the fact that patients are being harmed because scientists who made wrong decisions based on a false premise, are reluctant to acknowledge their mistake. They should not be allowed to perpetuate a falsehood that results in harm to patients.

It is unconscionable that the director of the National Institutes of Health and the Office of Human Research Protection have not suspended the FACTT experiment inasmuch as it is both scientifically flawed and immoral.

References:

1.ARDSNet member list: https://ahrp.org/Initiatives/2328/ethicsARDS.php#_edn1 

2. The 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; Vol 342: 1301-1308

3. Brower RG, Lanken PN, MacIntyre N, Matthay MA, Morris A, Ancukiewicz M, Schoenfeld D, Thompson BT; National Heart, Lung, and Blood Institute ARDS Clinical Trials Network. Higher vs. lower positive end-expiration pressures in patients with the acute respiratory distress syndrome. N Engl J Med. 2004 Jul 22;351(4):327-36).

4.. Peter Q. Eichacker, Eric P. Gerstenberger, Steven M. Banks, Xizhong Cui, and Charles Natanson, Meta-Analysis of Acute Lung Injury and Acute

Respiratory Distress Syndrome Trials Testing Low Tidal Volumes, Am J Respiratory Critical Care Medicine, 2002 Vol 166. pp 1510–1514.

5. Deans KJ, Minneci PC, Cui X, et al: Mechanical ventilation in ARDS: One size does not fit all. Crit Care Med 2005; 33:1141–1143; Katherine J. Deans, MD, Peter C. Minneci, MD, Department of Surgery, Massachusetts General Hospital, Boston, MA; Steven M. Banks, PhD, Xizhong Cui, MD PhD, Charles Natanson, MD, Peter Q. Eichacker MD, Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, MD, Letter. Crit Care Med 2006 Vol. 34:264-267.

6. Kallet RH, et alCampbell AR, Dicker RA, Katz JA, Mackersie RC. Work
of breathing during lung-protective ventilation in patients with acute lung injury and acute respiratory distress syndrome: a comparison between volume and pressure-regulated breathing modes. Respir Care 2005;50(12):1623–1631.

7. Kacmarek RM, Wiedemann HP, Lavin PT, Wedel MK, Tu¨tu¨ncu¨ AS,
Slutsky AS. Partial liquid ventilation in adult patients with the acute
respiratory distress syndrome. Am J Respir Crit Care Med 2005 Oct 27.

8. See: AHRP testimonies at: https://ahrp.org/infomail/0603/26.php;
Journal Medical Ethics-BMJ. Letters. http://jme.bmjjournals.com/cgi/eletters/31/9/548

Contact: Vera Hassner Sharav
veracare@ahrp.org

RESPIRATORY CARE DECEMBER 2005 VOL 50 NO 12
Editorials
Lung Protection: The Cost in Some Is Increased Work of Breathing. Is It Too High?

The need for lung-protective ventilation for patients in acute respiratory distress syndrome (ARDS) has been clearly demonstrated by a number of groups, both in animal studies1 and, most importantly, in patient randomized controlled trials. [2–4] Lung-protective ventilation has focused on 2 very specific aspects of ventilation: (1) reduction of end-inspiratory overdistention by limiting end-inspiratory plateau pressure and tidal volume (VT) and (2) elimination of repetitive opening and closing of unstable lung units by the use of appropriately adjusted positive end-expiratory pressure (PEEP). [1] Although controversy does exist over what is the appropriate level of PEEP to avoid injury, [2,4,5] most would support the need to avoid end-inspiratory overdistention by reducing end-inspiratory plateau pressure and VT.1–5 Even in patients initially ventilated without lung injury there seems to be a relationship between VT and development of acute lung injury (ALI) during ventilatory support. [6,7] Gajic et al [6,7] in 2 retrospective analyses, demonstrated the relationship between delivered VT and development of ALI [8] (ratio of arterial partial pressure of oxygen to fraction of inspired  oxygen [PaO2 /FIO2 ] <300mm Hg). Their data would imply that ventilating patients who do not have lung injury with VT > 9 mL/kg increases the risk of developing lung injury during mechanical ventilation. However, those data are retrospective, and actual end-inspiratory plateau pressures were not provided.

As very nicely demonstrated by Kallet and colleagues in this issue of the Journal, the primary cost of maintaining a small VT (6 mL/kg of predicted body weight [PBW]) in some patients is an increase in the work of breathing (WOB). [9] They demonstrated in 14 patients with ALI or ARDS, and who were spontaneously triggering the ventilator, that regardless of which ventilation mode was used (volume-assist/control, pressure-assist/control, or pressureregulated volume control), when VT is maintained at about 6.4 mL/kg PBW, patient WOB exceeds 1.0 J/L. In addition, there was a nonsignificant trend of greater WOB with pressure-assist/control (1.27 _ 0.58 J/L) and pressure-regulated volume control (1.35 _ 0.6 J/L) than with volumeassist/ control (1.09 _ 0.59 J/L).

To put this into perspective, the normal inspiratory WOB in a healthy adult breathing through the nose is about 0.4 J/L. [10] Many have considered  inspiratory WOB _ 1.0 J/L during spontaneous breathing unsustainable and an indication for ventilatory support. [11–13]  In other words, the WOB performed by these [14] ALI/ARDS patients during assisted ventilation was equivalent to that considered in spontaneously breathing patients as an indication for ventilatory support. [11–13] Is the cost of the small, lung-protective VT in these patients too high? This is not an easy question to answer! One problem in answering this question is the lack of airway pressure data. No indication of the end-inspiratory plateau pressure is provided. As discussed by Dreyfuss and Saumon,

[1] it is local overdistention that causes lung injury, defined by transpulmonary pressure.
Without knowing the end-inspiratory plateau pressure it is impossible to even estimate transpulmonary pressure.

The most important question is: Is it beneficial for patients to continue to breathe with this high inspiratory work?   Again, a difficult question to answer. The original ARDS Network data would indicate the answer is yes, but a recent editorial by Deans et al [14] would question that answer. Deans et al determined the mortality of 2,587 patients who meet the original ARDS Network enrollment criteria [4] but were not randomized for various technical reasons. The mortality of these patients was 31.7%, as compared to the 31% mortality of the patients in the 6-mL/kg PBW group. Guess what the VT was in these patients? 10 mL/kg!

Before completing the above discussion, let us consider Petrucci and Iacovelli’s meta-analysis [15] of the 5 published randomized controlled trials that have evaluated lung-protective ventilation, [2,4,16–18] which found that VT did impact mortality among the 1,202 patients in those 5 studies. However, when patients whose plateau pressure was _ 31 cm H2O were evaluated, VT had no significant effect on mortality.

A recent analysis of the actual patient data from those 5 trials, [2,4,16–18] plus the high/low PEEP ARDS Network trial, 5 has been performed by Amato (Marcelo Amato, Pulmonary Division, Hospital das Clınicas, University of Sa˜o Paulo, Brazil, personal communication, 2005). When Amato assessed the actual data from almost 1,800 patients, VT did not have an association with mortality. Mortality was primarily related to plateau pressure! The higher the plateau pressure, the higher the mortality.

In addition, the recent data from the last adult partial liquid-ventilation trial must be considered. [19] That was a negative trial, but the mortality of the control group, who received conventional volume-assist/control, was only 15%—the lowest mortality ever published for a group of ARDS patients. On day one of randomization, the VT of that group was 9 mL/kg PBW, the PEEP was 14 cm H2O, and the plateau pressure was 28 cm H2O. That is the same plateau pressure as in the ARDSNetwork’s 6-mL/kg group [4] on day one, in which the mortality was 31%, and even in the ARDS Network high/low PEEP trial5 the mortality was only 25%. The first question that comes to mind is:  Were different patients studied in the partial-liquid-ventilation study than in the ARDS Network studies?

They most likely were, and from a pulmonary perspective it would appear that the sicker patients were in the partial liquid-ventilation study! Enrollment into the ARDS Network trials required that the PaO2 /FIO2 was _ 300 mm Hg, regardless of PEEP or FIO2 , whereas in the partial-liquid-ventilation study, first, patients were enrolled only if the PaO2 /FIO2 was _ 200 mm Hg, regardless of PEEP or FIO2.

Then patients were placed on a PEEP _ 13 cm H2O and an FIO2 _ 0.5. Only those with a PaO2 _ 300 mm Hg were then randomized! Why the low mortality in all of these studies, despite the use of different VT? The answer is low-end-inspiratory plateau pressure!

Now let’s go back to the Kallet and colleagues [9] data. In my opinion, the cost of using a small (6.4-mL/kg PBW) VT with these patients, from a WOB perspective, is too high.  What are our options when managing patients who clinically clearly have increased WOB, rapid respiratory rate, increased use of accessory muscles of ventilation, retractions, cardiovascular stress, etc? Well, that depends on the end-inspiratory plateau pressure. Plateau pressure is difficult to measure in patients actively participating in ventilatory assistance, but if pressure-assist/control or pressure-regulated volume control is used, plateau pressure can be no higher than the peak airway pressure. It can be argued that high transpulmonary pressure may be developed in actively breathing patients on pressure-assist/control or pressure-regulated volume control, even when the peak pressure is low. But I disagree with that assumption, because with a patient who is actively breathing, the set pressure-assist/control level is never established at the alveolar

level unless inspiratory flow is zero before the end of the breath, which is a very unlikely situation in the highly stressed patient.

The options, then, for these patients are: (1) eliminate the increased ventilatory drive by correcting those issues (eg, oxygenation and temperature) that increase ventilatory drive, (2) sedate the patient to markedly depress respiratory drive, (3) accept the high WOB as a necessary cost of lung protection, or (4) allow the VT to increase.

The most ideal option is number 1, but in ARDS/ALI patients it is frequently difficult to eliminate the cause of the increased drive to breath. Sedation does work in many patients; however, frequently sedation to apnea with paralysis is required to eliminate the high ventilatory drive in ARDS/ALI patients—a scenario that itself causes many additional complications, potentially increasing the duration of mechanical ventilation. Accepting the high WOB increases oxygen consumption and cardiovascular work, frequently resulting in cardiovascular instability, but clearly this is an option in many patients.

Finally, there is the possibility of letting the VT increase, provided the plateau pressure remains low; but how low is low? Based on the available data discussed above, it would seem safe to allow VT up to 9 mL/kg if the plateau pressure is maintained below 25 cm H2O. The higher the plateau pressure, the greater the need to maintain a low VT, but in patients with a low plateau pressure, the risks of the alternatives would appear to outweigh the benefits of forcing a VT of 6.0 mL/kg PBW!

Robert M Kacmarek PhD RRT FAARC
Respiratory Care Services
Massachusetts General Hospital
Harvard Medical School
Boston, Massachusetts

REFERENCES
1. Dreyfuss D, Saumon G. Ventilator-induced lung injury: lessons from experimental studies. Am J Respir Crit Care Med 998;157(1):294–323.

2. 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;338(6):347–354.

3. 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;282(1):54–61.

4. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. The Acute Respiratory Distress Syndrome Network. N Engl J Med 2000;342(18):1301–1308.

5. Brower RG, Lanken PN, MacIntyre N, Matthay MA, Morris A, Ancukiewicz M, et al. Higher versus lower positive end-expiratory pressures in patients with the acute respiratory distress syndrome. N Engl J Med 2004;351(4):327–336.

6. Gajic O, Dara SI, Mendez JL, Adesanya AO, Festic E, Caples SM, et al. Ventilator-associated lung injury in patients without acute lung injury at the onset of mechanical ventilation. Crit Care Med 2004; 32(9):1817–1824.

7. Gajic O, Frutos-Vivar F, Esteban A, Hubmayr RD, Anzueto A. Ventilator settings as a risk factor for acute respiratory distress syndrome in mechanically ventilated patients. Intensive Care Med 2005; 31(7):922–926.

8. Bernard GR, Artigas A, Brigham KL, Carlet J, Falke K, Hudson L, et al. The American-European consensus conference on ARDS. Definitions, mechanisms, relevant outcomes, and clinical trial coordination. Am J Respir Crit Care Med 1994;149 (3 Pt 1):818–824.

9. Kallet RH, Campbell AR, Dicker RA, Katz JA, Mackersie RC. Work of breathing during lung-protective ventilation in patients with acute lung injury and acute respiratory distress syndrome: a comparison between volume and pressure-regulated breathing modes. Respir Care 2005;50(12):1623–1631.

10. Roussos C, Campbell EJM. Respiratory muscle energetics. In: Macklem PT, Mead J, editors. Handbook of physiology. Bethesda, Maryland: American Physiological Society; 1986:487–509.

11. Peters RM, Hilberman M, Hogan JS, Crawford DA. Objective indications for respiratory therapy in post-trauma and post-operative patients. Am J Surg 1972;124(2):262–269.

12. Proctor HJ, Woolson R. Prediction of respiratory muscle fatigue by measurement of the work of breathing. Surg Gynecol Obstet 1973; 136(3):367–370.

13. Henning RJ, Shubin H, Weil MH. The measurement of the work of breathing for the clinical assessment of ventilator dependence. Crit Care Med 1977;5(6):264–268.

14. Deans KJ, Minneci PC, Cui X, Banks SM, Natanson C, Eichacker PQ. Mechanical ventilation in ARDS: one size does not fit all. Crit Care Med 2005;33(5):1141–1443.

15. Petrucci N, Iacovelli W. Ventilation with lower tidal volumes versus traditional tidal volumes in adults for acute lung injury and an acute respiratory distress syndrome. Cochrane Database of Syst Rev 2004; (2):CD003844.

16. Brochard L, Roudot-Thoraval F, Roupie E, Delclaux C, Chastre J, Fernandez-Mondejar E, et al. Tidal volume reduction for prevention of ventilator-induced lung injury in acute respiratory distress syndrome. Am J Respir Crit Care 1998;158(6):1831–1838.

17. Stewart TE, Meade MO, Cook DJ, Granton JT, Hodder RV, Lapinsky SE, et al. Evaluation of a ventilation strategy to prevent barotraumas in patients at high risk for acute respiratory distress syndrome. N Engl J Med 1998;338(6):355–361.

18. Brower RG, Shanholtz CB, Fessler HE, Shade DM, White P, Wiener C, 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.

19. Kacmarek RM, Wiedemann HP, Lavin PT, Wedel MK, Tu¨tu¨ncu¨ AS, Slutsky AS. Partial liquid ventilation in adult patients with the acute respiratory distress syndrome. Am J Respir Crit Care Med 2005 Oct 27; [Epub ahead of print].

LUNG PROTECTION: INCREASED WORK OF BREATHING RESPIRATORY CARE • DECEMBER 2005 VOL 50 NO 12 1615  DECEMBER 2005 VOL 50 NO 12

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