Week 14 – ARDSNet aka ARMA

“Ventilation with Lower Tidal Volumes as Compared with Traditional Tidal Volumes for Acute Lung Injury and the Acute Respiratory Distress Syndrome”

by the Acute Respiratory Distress Syndrome Network (ARDSNet)

N Engl J Med. 2000 May 4;342(18):1301-8. [free full text]

Acute respiratory distress syndrome (ARDS) is an inflammatory and highly morbid lung injury found in many critically ill patients. In the 1990s, it was hypothesized that overdistention of aerated lung volumes and elevated airway pressures might contribute to the severity of ARDS, and indeed some work in animal models supported this theory. Prior to the ARDSNet study, four randomized trials had been conducted investigating the possible protective effect of ventilation with lower tidal volumes, but their results were conflicting.

Population: patients with ARDS diagnosed within < 36 hrs
Intervention: initial tidal volume 6 ml/kg predicted body weight, downtitrated as necessary to maintain plateau pressure ≤ 30 cm of water
Comparison: initial tidal volume 12 ml/kg predicted body weight, downtitrated as necessary to maintain plateau pressure ≤ 50 cm of water


1) in-hospital mortality
2) ventilator-free days within the first 28 days

1) number of days without organ failure
2) occurrence of barotrauma
3) reduction in IL-6 concentration from day 0 to day 3


861 patients were randomized before the trial was stopped early due to the increased mortality in the control arm noted during interim analysis. In-hospital mortality was 31.0% in the lower tidal volume group and 39.8% in the traditional tidal volume group (p = 0.007, NNT = 11.4). Ventilator free days were 12±11 in the lower tidal volume group vs. 10±11 in the traditional group (n = 0.007). The lower tidal volume group had more days without organ failure (15±11 vs. 12±11, p = 0.006). There was no difference in rates of barotrauma among the two groups. IL-6 concentration decrease between days 0 and 3 was greater in the low tidal volume group (p < 0.001), and IL-6 concentration at day 3 was lower in the low tidal volume group (p = 0.002).

Low tidal volume ventilation decreases mortality in ARDS relative to “traditional” tidal volumes.

The authors felt that this study confirmed the results of prior animal models and conclusively answered the question of whether or not low tidal volume ventilation provided a mortality benefit. In fact, in the years following, low tidal volume ventilation became the standard of care, and a robust body of literature followed this study to further delineate a “lung protective strategy.”

Critics of the study noted that at the time of the study the standard of care/“traditional” tidal volume in ARDS was less than the 12 ml/kg used in the comparison arm. (Non-enrolled patients at the participating centers were receiving a mean tidal volume of 10.3 ml/kg.) Thus not only was the trial making a comparison to a faulty control, but it was also potentially harming patients in the control arm. Here is an excellent summary of the ethical issues and debate regarding this specific issue and regarding control arms of RCTs in general.

Corresponding practice point from Dr. Sonti and Dr. Vinayak and their Georgetown Critical Care Top 40: “Low tidal volume ventilation is the standard of care in patients with ARDS (P/F < 300). Use ≤ 6 ml/kg predicted body weight, follow plateau pressures, and be cautious of mixed modes in which you set a tidal volume but the ventilator can adjust and choose a larger one.”

PulmCCM is an excellent blog, and they have a nice page reviewing this topic and summarizing some of the research and guidelines that have followed.

Further Reading/References:
1. Wiki Journal Club
2. 2 Minute Medicine
3. PulmCCM “Mechanical Ventilation in ARDS: Research Update”
4. Georgetown Critical Care Top 40, page 6

Summary by Duncan F. Moore, MD


“Hydrocortisone Therapy for Patients with Septic Shock”

N Engl J Med. 2008 Jan 10;358(2):111-24. [free full text]

Steroid therapy in septic shock has been a hotly debated topic since the 1980s. The Annane trial in 2002 suggested that there was a mortality benefit to early steroid therapy and so for almost a decade this became standard of care. In 2008 the CORTICUS trial was performed suggesting otherwise.

– inclusion criteria: ICU patients with septic shock onset with past 72 hrs (defined as SBP < 90 despite fluids or need for vasopressors, and hypoperfusion or organ dysfunction from sepsis)
– exclusion criteria: “underlying disease with a poor prognosis,” life expectancy < 24hrs, immunosuppression, recent corticosteroid use

Intervention: hydrocortisone 50mg IV q6h x5 days with taper

Comparison: placebo injections q6h x5 days plus taper


Primary: 28 day mortality among patients who did not have a response to ACTH stim test (cortisol rise < 9mcg/dL)

– 28 day mortality in patients who had a positive response to ACTH stim test
– 28 day mortality in all patients
– reversal of shock (defined as SBP ≥ 90 for at least 24hrs without vasopressors) in all patients
– time to reversal of shock in all patients

In ACTH non-responders (N=233): intervention vs. control 28 day mortality was 39.2% vs. 36.1% (p=0.69)

In ACTH responders (N=254): intervention vs. control 28 day mortality was 28.8% vs. 28.7% (p=1.00); reversal of shock 84.7%% vs. 76.5% (p=0.13)

Among all patients:
– intervention vs. control 28 day mortality was 34.3% vs. 31.5% (p=0.51)
– reversal of shock 79.7% vs. 74.2% (p=0.18)
– duration of time to reversal of shock was significantly shorter among patients receiving hydrocortisone (per Kaplan-Meier analysis, p<0.001; see Figure 2), median time to reversal 3.3 days vs. 5.8 days (95% CI 5.2 – 6.9)

The CORTICUS trial demonstrated no mortality benefit of steroid therapy in septic shock, regardless of a patient’s response to ACTH. Despite the lack of mortality benefit, it demonstrated an earlier resolution of shock with steroids. This lack of mortality benefit sharply contrasted with the previous Annane study. Several reasons have been posited for this including poor powering of the CORTICUS study (it did not reach the desired N=800), CORTICUS inclusion starting within 72 hrs of septic shock vs. Annane starting within 8 hrs, and Annane patients generally being sicker (including their inclusion criterion of mechanical ventilation). Subsequent meta-analyses disagree about the mortality benefit of steroids, but meta-regression analyses suggest benefit among the sickest patients. All studies agree about the improvement in shock reversal. The 2016 Surviving Sepsis Campaign guidelines recommend IV hydrocortisone in septic shock in patients who continue to be hemodynamically unstable despite adequate fluid resuscitation and vasopressor therapy.

Per Drs. Sonti and Vinayak of the GUH MICU (excerpted from their excellent Georgetown Critical Care Top 40): “Practically, we use steroids when reaching for a second pressor or if there is multiorgan system dysfunction. Our liver patients may have deficient cortisol production due to inadequate precursor lipid production; use of corticosteroids in these patients represents physiologic replacement rather than adjunct supplement.”

References / Further Reading
1. Wiki Journal Club
2. 2 Minute Medicine
3. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock (2016), section “Corticosteroids”
4. Annane trial (2002) [free full text]
5. Georgetown Critical Care Top 40 [iTunes / iBooks link]
6. UpToDate,“Glucocorticoid therapy in septic shock”

Summary by Gordon Pelegrin, MD


“Intensive versus Conventional Glucose Control in Critically Ill Patients”

by the Normoglycemia in Intensive Care Evaluation–Survival Using Glucose Algorithm Regulation (NICE-SUGAR) investigators

N Engl J Med 2009; 360:1283-1297. [NEJM free full text]

On the wards we often hear 180 mg/dL used as the upper limit of acceptable for blood glucose, with the understanding that tighter glucose control in inpatients can lead to more harm than benefit. Interestingly, the relevant evidence base comes from ICU populations, with scant direct data in non-ICU patients. The 2009 NICE-SUGAR study is the largest and best among this evidence base.

Population: ICU patients expected to require 3 or more days of ICU-level care
Intervention: “intensive” glucose control = target glucose 81 to 108 mg/dL
Comparison: conventional glucose control = target of less than 180 mg/dL
Outcome: primary = 90-day all-cause mortality rate

6104 patients were randomized to the two arms, and both groups had similar baseline characteristics. 27.5% of patients in the intensive-control group died versus 24.9% in the conventional-control group (OR 1.14, 95% CI 1.02-1.28, p= 0.02). Severe hypoglycemia (< 40 mg/dL) was found in 6.8% of intensive patients but only 0.5% of conventional patients.

Intensive glucose control increases mortality in ICU patients.

Notably, only 20% of these patients had diabetes mellitus, suggesting that much of the hyperglycemia treated in this study (97% of intensive group received insulin, 69% of conventional) was from stress, critical illness, and corticosteroid use. For ICU patients, intensive insulin therapy is clearly harmful, but the ideal target glucose range remains controversial and by expert opinion appears to be 140-180. For non-ICU inpatients with or without diabetes mellitus, the ideal glucose target is also unclear – the ADA recommends 140-180, and the Endocrine Society recommends a pre-meal target of < 140 and random levels < 180.

Further reading:
1. ADA Standards of Medical Care in Diabetes 2016 (skip to page S99)
2. Wiki Journal Club

Summary by Duncan F. Moore, MD