Chief Respiratory Care Mass General Hospital-Harvard-Rejects ARDS Recommendation

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[sSRI-Research] Chief Respiratory Care Mass General

Hospital-Harvard-Rejects ARDS Recommendation

 

 

 

Chief Respiratory Care Mass General Hospital-Harvard-Rejects ARDS

Recommendation

 

ALLIANCE FOR HUMAN RESEARCH PROTECTION (AHRP)

Promoting Openness, Full Disclosure, and Accountability

www.ahrp.org

 

FYI

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:

http://www.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: http://www.ahrp.org/infomail/0603/26.php;

Journal Medical Ethics-BMJ. Letters.

http://jme.bmjjournals.com/cgi/eletters/31/9/548

~~~~~~~~~~~~~~~~~~~~~~~~~

 

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

Clýnicas, 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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