Month: October 2017

Week 17 – PROSEVA

“Prone Positioning in Severe Acute Respiratory Distress Syndrome”

by the PROSEVA Study Group

N Engl J Med. 2013 June 6; 368(23):2159-2168 [free full text]
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Prone positioning had been used for many years in ICU patients with ARDS in order to improve oxygenation. Per Dr. Sonti’s Georgetown Critical Care Top 40, the physiologic basis for benefit with proning lies in the idea that atelectatic regions of lung typically occur in the most dependent portion of an ARDS patient, with hyperinflation affecting the remaining lung. Periodic reversal of these regions via moving the patient from supine to prone and vice versa ensures no one region of the lung will have extended exposure to either atelectasis or overdistention. Although the oxygenation benefits have been long noted, the PROSEVA trial established mortality benefit.

Population:  Patients were selected from 26 ICUs in France and 1 in Spain which had daily practice with prone positioning for at least 5 years.

Inclusion: ARDS patients intubated and ventilated <36hr with severe ARDS (defined as PaO2:FiO2 ratio <150, PEEP>5, and TV of about 6ml/kg of predicted body weight)

(NB: by the Berlin definition for ARDS, severe ARDS is defined as PaO2:FiO2 ratio <100)

Intervention: Proning patients within 36 hours of mechanical ventilation for at least 16 consecutive hours (N=237)

Control: Leaving patients in a semirecumbent (supine) position (N=229)

Outcome:

Primary: mortality at day 28

Secondary: mortality at day 90, rate of successful (no reintubation or use of noninvasive ventilation x48hr) extubation, time to successful extubation, length of stay in the ICU, complications, use of noninvasive ventilation, tracheotomy rate, number of days free from organ dysfunction, ventilator settings, measurements of ABG, and respiratory system mechanics during the first week after randomization

Results:
At the time of randomization in the study, the majority of characteristics were similar between the two groups, although the authors noted differences in the SOFA score and the use of neuromuscular blockers and vasopressors. The supine group at baseline had a higher SOFA score indicating more severe organ failure, and also had higher rate of vasopressor usage. The prone group had a higher rate of usage of neuromuscular blockade.

The primary outcome of 28 day mortality was significantly lower in the prone group than in the supine group, at 16.0% vs 32.8% (P<0.001, NNT = 6.0). This mortality decrease was still statistically significant when adjusted for the SOFA score.

Secondary outcomes were notable for a significantly higher rate of successful extubation in the prone group (hazard ratio 0.45; 95% CI 0.29-0.7, P<0.001). Additionally, the PaO2:FiO2 ratio was significantly higher in the supine group, whereas the PEEP and FiO2 were significantly lower. The remainder of secondary outcomes were statistically similar.

Discussion:
PROSEVA showed a significant mortality benefit with early use of prone positioning in severe ARDS. This mortality benefit was considerably larger than seen in past meta-analyses, which was likely due to this study selecting specifically for patients with severe disease as well as specifying longer prone-positioning sessions than employed in prior studies. Critics have noted the unexpected difference in baseline characteristics between the two arms of the study. While these critiques are reasonable, the authors mitigate at least some of these complaints by adjusting the mortality for the statistically significant differences. With such a radical mortality benefit it might be surprising that more patients are not proned at our institution. One reason is that relatively few of our patients have severe ARDS. Additionally, proning places a high demand on resources and requires a coordinated effort of multiple staff. All treatment centers in this study had specially-trained staff that had been performing proning on a daily basis for at least 5 years, and thus were very familiar with the process. With this in mind, we consider the use of proning in patients meeting criteria for severe ARDS.

References and further reading:
1. 2 Minute Medicine
2. Wiki Journal Club
3. Georgetown Critical Care Top 40, pages 8-9
4. Life in the Fastlane, Critical Care Compendium, “Prone Position and Mechanical Ventilation”
5. PulmCCM.org, “ICU Physiology in 1000 Words: The Hemodynamics of Prone”

Summary by Gordon Pelegrin, MD

Week 16 – COPERNICUS

“Effect of carvedilol on survival in severe chronic heart failure”

by the Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) Study Group

N Engl J Med. 2001 May 31;344(22):1651-8. [free full text]
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We are all familiar with the role of beta-blockers in the management of heart failure with reduced ejection fraction. In the late 1990s, a growing body of excellent RCTs demonstrated that metoprolol succinate, bisoprolol, and carvedilol improved morbidity and mortality in patients with mild to moderate HFrEF, while the only trial of beta-blockade (with bucindolol) in patients with severe HFrEF failed to demonstrate a mortality benefit. In 2001, the COPERNICUS trial further elucidated the mortality benefit of carvedilol in patients with severe HFrEF.

Population: patients with severe CHF (NYHA class III-IV symptoms and LVEF < 25%) despite “appropriate conventional therapy”

Intervention: carvedilol with protocolized uptitration (in addition to pt’s usual meds)

Comparison: placebo with protocolized uptitration (in addition to pt’s usual meds)

Outcomes: all-cause mortality and combined risk of death or hospitalization for any cause


Results:
2289 patients were randomized before the trial was stopped early due to higher than expected mortality benefit in the carvedilol arm. Mean follow-up was 10.4 months. Regarding mortality: 190 (16.8%) of placebo patients died, while only 130 (11.2%) of carvedilol patients died (p = 0.0014) (NNT = 17.9). Regarding mortality or hospitalization: 507 (44.7%) of placebo patients died or were hospitalized, while only 425 (36.8%) of carvedilol patients died or were hospitalized (NNT = 12.6). Both outcomes were found to be of similar directions and magnitudes in subgroup analyses (age, sex, LVEF < 20% or >20%, ischemic vs. non-ischemic CHF, study site location, and no CHF hospitalization within year preceding randomization).

Implication/Discussion:
In severe heart failure with reduced ejection fraction, carvedilol significantly reduces mortality and hospitalization risk.

This was a straightforward, well-designed, double-blind RCT with a compelling conclusion. In addition, the dropout rate was higher in the placebo arm than the carvedilol arm! Despite longstanding clinician fears that beta-blockade would be ineffective or even harmful in patients with already advanced (but compensated) HFrEF, this trial definitively established the role for beta-blockade in such patients.

Per the 2013 ACCF/AHA guidelines, “use of one of the three beta blockers proven to reduce mortality (e.g. bisoprolol, carvedilol, and sustained-release metoprolol succinate) is recommended for all patients with current or prior symptoms of HFrEF, unless contraindicated.”

Of note, there are two COPERNICUS trials. This is the first reported study, in NEJM from 2001, which reports only the mortality and mortality + hospitalization results, again in the context of a highly anticipated trial that was terminated early due to mortality benefit. A year later, the full results were published in Circulation, which described findings such as a decreased number of hospitalizations, fewer total hospitalization days, fewer days hospitalized for CHF, improved subjective scores, and fewer serious adverse events (e.g. sudden death, cardiogenic shock, VT) in the carvedilol arm.

Further Reading/References:
1. 2013 ACCF/AHA Guideline for the Management of Heart Failure
2. COPERNICUS, 2002 Circulation version
3. Wiki Journal Club (describes 2001 NEJM, cites 2002 Circulation)
4. 2 Minute Medicine (describes and cites 2002 Circulation)

Summary by Duncan F. Moore, MD

Week 15 – TRICC

“A Multicenter, Randomized, Controlled Clinical Trial of Transfusion Requirements in Critical Care”

N Engl J Med. 1999 Feb 11; 340(6): 409-417. [free full text]
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Although intuitively a hemoglobin closer to normal physiologic concentration seems like it would be beneficial, the vast majority of the time in inpatient settings we use a hemoglobin concentration of >7g/dL as our threshold for transfusion in anemia. Historically, higher hemoglobin cutoffs were used, often aiming to keep Hgb >10g/dL. In 1999, the landmark TRICC trial was published showing no mortality benefit in the liberal transfusion strategy and even harm in certain subgroup analysis.

Population:

Inclusion: critically ill patients expected to be in ICU > 24h, Hgb ≤ 9g/dL within 72hr of ICU admission, and clinically euvolemic after fluid resuscitation

Exclusion criteria: age < 16, inability to receive blood products, active bleed, chronic anemia, pregnancy, brain death, consideration of withdrawal of care, and admission after routine cardiac procedure.

Intervention: liberal strategy (transfuse to Hgb goal 10-12g/dL, N=420)

Comparison: restrictive strategy (transfuse to Hgb goal 7-9g/dL, N=418)

Primary outcome: 30-day all-cause mortality

Secondary outcomes: 60-day all-cause mortality, mortality during hospital stay (ICU plus step-down), multiple-organ dysfunction score, change in organ dysfunction from baseline

Subgroup analyses: patients with APACHE II score ≤ 20 (i.e. less-ill patients), patients younger than 55, cardiac disease, severe infection/septic shock, and trauma

Results:
The primary outcome of 30-day mortality was similar between the two groups (18.7% vs. 23.3%, p = 0.11). Secondary outcomes of mortality rates during hospitalization were lower in the restrictive strategy (22.2% vs. 28.1%, p = 0.05). 60-day all-cause mortality trended towards lower in the restrictive strategy although did not reach statistical significance (22.7% vs. 26.5 %, p = 0.23). Between the two groups there was no significant difference in multiple-organ dysfunction score or change in organ dysfunction from baseline.

Subgroup analysis was most notable for finding statistically significant benefits for the restrictive strategy in the patients with APACHE II score ≤ 20 and patients younger than 55. In these patients, a restrictive strategy showed decrease in 30-day mortality and a lower multiple-organ dysfunction score. In the subgroups of primary disease process (i.e. cardiac disease, severe infection/septic shock, and trauma) there was no significant difference.

Complications in the ICU were monitored, and there was a significant increase in cardiac events (primarily pulmonary edema) in the liberal strategy compared to the restrictive strategy.

Discussion/Implication:
TRICC showed no difference in 30-day mortality between a restrictive and liberal transfusion strategy. Secondary outcomes were notable for a decrease in inpatient mortality with the restrictive strategy. Furthermore, subgroup analysis showed benefit in various metrics for a restrictive transfusion strategy when adjusting for younger and less-ill patients. This evidence laid the groundwork for our current standard of transfusing to hemoglobin >7g/dL. A restrictive strategy has also been supported by more recent studies. In 2014 the Transfusion Thresholds in Septic Shock (TRISS)