Journal club 6/17: ARDSnet

Our home institution has recently instituted a regular journal club. We will be sharing the notes.

The article

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 SyndromeN Engl J Med. 2000 May 4;342(18):1301-8

What’s the question we’re looking at? Why do we care in CCM?

Does mechanical ventilation with lower tidal volumes and plateau pressures reduce mortality compared to higher tidal volumes/plateau pressures? This directly bears upon the vent settings we select, which we otherwise might presume have no importance other than for comfort and minute ventilation. Historically we used very large tidal volumes to improve oxygenation and ventilation.

What is ARDS?

Syndrome of hypoxia, bilateral infiltrates (looks like heart failure), but non-cardiac cause

What is a plateau pressure?

Airway pressure after a brief inspiratory hold, thus isolating the distending pressure felt within the alveoli from the resistance to airflow in the airways during active inspiration.

What is volutrauma/barotrauma?

Injury to the alveoli caused by overdistention. Some argument about whether it is the excess volume that causes injury or the excess pressure; obviously they tend to go together. The opinion has shifted towards volume nowadays. However, the common vernacular adopted nowadays describes overdistention injury as “volutrauma” and actual ruptures (e.g. pneumothorax) as “barotrauma.” Volutrauma is common in ARDS, since it causes a loss of compliance — the lungs become stiffer, and large portions become walled off by consolidation, forcing vent breaths into the small remaining airspaces, which may only have the capacity for a fraction of a normal breath before becoming injured.

What type of study was this?

A prospective, multi-center, randomized, unblinded, controlled trial.

Concurrent drug trial, ketoconazole vs placebo and lisofylline vs placebo

Who was the study population? What were the inclusion/exclusion criteria?

Enrolled intubated/ventilated patients over three years at 10 academic centers (not clear if enrollment was consecutive), if they had (basically the old consensus ARDS definition):

  •  Acute decrease in P/F ratio to <300 (adjusted for altitude);
  •  Bilateral pulmonary infiltrates on chest radiograph consistent with the presence of edema;
  •  And no clinical evidence of left atrial hypertension or actual PCWP <18.

Excluded if:

  •  >36 hours elapsed since meeting criteria
  •  <18 yrs
  •  Participated in other trials within the last 30 days
  •  Pregnant
  •  Elevated ICP
  •  Neuromuscular disease impairing spontaneous breathing, sickle cell, or severe chronic respiratory disease (hence hard to wean)
  •  Weighed >1kg per cm of height (would be about 400lb for me at 6ft)
  •  Burns >30%
  •  Other conditions with estimated 6-mo mortality >50%
  •  Bone or organ transplantation
  •  Child-Pugh class C liver disease
  •  Not a full code

What was the intervention? What was the control?

Patients randomized by a call-in system to receive either:

Control group

  •  Tidal volume kept between 4–12cc/kg
  •  Plateau pressure kept between 45–50 cm H2O

Treatment group

  •  Tidal volume kept between 4–6cc/kg
  •  Plateau pressure kept between 25–30 cm H2O
  • (up to 8cc/kg okay if “severe dyspnea” and plateau still <30)

 Plateau pressures above goal were okay if tidal volume was at 4 or pH was <7.15.

Were patients blinded? Providers? Evaluators/analysts?

Patients: no, but unclear if they were informed either (intubated)

Providers: presumably no

Analysts: unclear

What is the PRIMARY outcome? Is it clinically significant and patient oriented?

 “First primary outcome”: Death (prior to discharge and “breathing without assistance,” or 180 days)

 “Second primary outcome”: Vent-free days (off vent for 48+ hours) during the first 28-days. (Less days could be due to longer vent time, or early death!)

What were the SECONDARY outcomes?

– Days without…

  •   “Circulatory failure” (SBP <90, or any pressor)
  •   “Coagulation failure” (Plt <80,000)
  •   “Hepatic failure” (bilirubin >2)
  •   “Renal failure” (creatinine >2)

– Incidence of barotrauma (pneumothroax, pneumomediastinum, subcutaneous emphysema, pneumotocele <2cm)

– Plasma interleukin 6 levels

Were the groups initially similar?

Yes (Table 2).

Other than the therapy under investigation, is there any reason why patients might have been treated differently in the two groups, and was this controlled? If not, what effect might it have?

No obvious reason, except perhaps closer attention by providers/nursing, since this was unblinded.

Were there any losses/failures after enrollment, and if so, were they analyzed using intention-to-treat?

31 patients lost, unclear how they were analyzed, seem to have simply been struck from the analysis.

How long was study follow-up, and was this adequate?

28 days for vent liberation, 180 days for mortality, which seems adequate.

What are the results?

Stopped early for efficacy.

861 patients enrolled (out of unclear goal; maybe 1000 projected?)

Mortality: 31.0% (intervention) vs 39.8% (control), p = .007.

Vent-free days: 12 vs 10, p=.007 (but if analyzed only among those who survived, there was no difference, suggesting that this difference was mostly because of the mortality difference)

Alternately put, chance of being off the vent at day 28: 55.0% vs 65.7 (p<.001).

Less days without:

  •  Circulatory failure: 2 fewer days
  •  Coagulation failure: 2 fewer days
  •  Renal failure: 2 fewer days

Barotrauma: similar incidence

Hepatic failure: Not mentioned

Interleukin 6 levels decreased more in intervention group

Mean tidal volumes: 6.2 cc/kg (intervention group) vs 11.8 cc/kg (control group)

Mean plateau pressures: 25 cm H2O (intervention group) vs 32 cm H2O (control group)

Higher PEEPs and worse P/F ratios seen in intervention group for first 3 days; but lower PEEP and better P/F ratios at day 7 (perhaps suggesting if you are a bit permissive with your oxygenation early on but are less damaging to the lungs, it results in better gradients and less disease later).

Higher pCO2 and lower pH in intervention group — as expected due to smaller tidal volumes, but did not seem harmful.

No significant interaction with the other study measures (ketoconazole and lisophylline).

What are the results in terms of absolute risk and NNT?

Absolute risk of death reduced by 8.8%

NNT: 12 patients need to receive this ventilation strategy to prevent 1 death

Who sponsored the study? Any reason to suspect bias? Conflicts of interest among the authors?

National Heart, Lung, and Blood Institute sponsored (a division of NIH, so public money). Participants was a large network (ARDSnet). First author is Brower from Hopkins. Probably no money to be made here, however all researchers and networks intrinsically want to find positive results.

Our take-home

 – Should we be doing this? Yes! Tremendous mortality benefit in a well-designed trial. 17 years old, this should have permeated our practice by now.

 – Unanswered questions (at time of this study): Should we use this prophylactically in patients without ARDS? (I say yes; more recent data exists.) How early do we need to use it? (I say immediately; more recent data exists.) How strictly do we need to follow the protocol? Does this apply to non-pure-ARDS patients (some contusion, some atelectasis, some pneumonitis/pneumonia)?

 – Practical approach: in every patient, at least eyeball the height, get a goal tidal volume, and try to stick fairly close to it. Be more or less strict depending on their risk. If actual ARDS already exists, definitely keep tight tidal volumes if possible. Look at plateau pressures every day and keep under 30.