Primecuts – This Week In The Journals

February 25, 2015

By Steven R. Liu, MD

Peer Reviewed

“And the award goes to…” – for those of you who watched the Academy Awards this week, you will have been an admirer of Neil Patrick Harris’ opening, his presence in the audience, and his underwear spoof of “Birdman”. The event made for glamorous viewing, and also included heartfelt speeches from winners about the lingering state of race relations, suicide, and equality for women among some of the topics.

In the journals this week…

Nitric oxide, antihypertensive treatment and acute stroke

From the world of neurology comes another attempt at deciphering the relationship between blood pressure and ischemic stroke. With the not too recent INTERACT2 trial fresh in our collective consciousness, we now have concluded that strict blood pressure control in hemorrhagic stroke improves clinical neurologic outcomes. However, though it has been well described that there is a U-shaped relationship between blood pressure and worsening outcomes post ischemic CVA [1], there has yet to be a definitive study suggesting that controlling that blood pressure in the post-stroke period has any significant changes in outcomes of stroke.

The ENOS Trial, published ahead of print last year, now in this month’s Lancet attempted to demonstrate improved outcomes in a randomized, multicenter, partial factorial, non-blinded trial [2]. The study included patients with either acute ischemic or hemorrhagic stroke with hypertension between SBPs of 140 to 220mmHg. Patients were randomized to be started on transdermal glyceryl trinitrate or nothing with the additional randomization of restarting their home medications to see if there was a difference in modified Rankin scores (assessing functional status post-CVA).

Investigators successfully demonstrated a reduction in blood pressures between the treatment and non-treatment groups of initially 7 mmHg SBP / 3.5 mmHg DBP which was maintained at 10 mmHg / 5 mmHg by the end of treatment phase (p<0.0001 for both). However, the study did not show any significance in modified Rankin score between the two groups (OR 1.01, 95% CI 0.91-1.13, p=0.83). Additionally, there was no difference between median hospital stay or death on discharge; nor was there a statistically significant difference between death or any of the additional functional tests performed (including mini-mental status exam, EuroQol Visual Analogue Score, Verbal Fluency, Health utility status, Zung depression scale, or modified telephone interview for cognitive status) at 90 days.

The authors suggest that this study may be interpreted as “it seems reasonable to withhold blood pressure-lowering drugs until patients with an acute stroke are medically and neurologically stable, and have suitable oral or enteral access to allow safe drug reintroduction”. It further adds, though, to the suggestion that efforts to normalize blood pressure in the setting of acute stroke likely does not change neurologic recovery outcomes.

Driving Pressure and Survival in the Acute Respiratory Distress Syndrome

Mechanical-ventilation strategies that use lower end-inspiratory (plateau) airway pressures, lower tidal volumes (VT), and higher positive end-expiratory pressures (PEEPs) (collectively termed lung-protective strategies) have been associated with survival benefits in randomized clinical trials involving patients with the acute respiratory distress syndrome (ARDS) [3]. In this month’s New England Journal of Medicine, Amato et al. provide us with the proposition that driving pressure (VT / compliance) would be an index more strongly associated with survival than VT or PEEP in patients with acute respiratory distress syndrome (ARDS) [4].

This group derived a survival-prediction model with the use of data from a cohort of 336 patients with ARDS from four early randomized clinical trials testing various strategies of volume-limited ventilation. They then tested and refined their model with data from a validation cohort of 861 patients from a large, randomized trial comparing lower versus higher VT values. Finally, they retested the model with data from a more recent validation cohort of 2365 patients with ARDS enrolled in four randomized trials comparing higher-PEEP versus lower-PEEP strategies. The primary outcome (the dependent variable) was survival in the hospital at 60 days.

In their results section, this group report a strong association between driving pressure and survival even though all the ventilator settings that were used were lung-protective (relative risk of death, 1.36; 95% confidence interval [CI], 1.17 to 1.58; P<0.001). In contrast, further reductions in plateau pressures or VT below these thresholds (plateau pressures ≤30 cm of water and VT ≤7 ml per kilogram of predicted body weight) had no effect on survival. This result stands, however only for ventilation in which the patient is not making respiratory efforts; it is difficult to interpret driving pressure in actively breathing patients.

This group highlights The Acute Respiratory Distress Syndrome Network (ARDSNet) trial, which shows that low VT values per se decrease mortality from ARDS. However, they postulate that the efficacy of this strategy is also critically dependent on other components of the lung-protective bundle (e.g. plateau-pressure limitation, respiratory-rate modification, and hypercapnia). For example, when low VT values were introduced into the lung, improved survival was observed only when large changes in driving pressure (the dependent variable during volume control) were avoided.

This fascinating article is not without drawbacks, however. Indeed, it is a post-hoc observational analysis. Going forward, trials need to be designed in which ventilator changes are linked to achieve changes in driving pressure, in order to determine whether this group’s observations can be translated into changes that may be implemented at the bedside.

High-dose versus Standard-dose Influenza Vaccines in US residents >65

Another research group published in the Lancet sought to establish whether high-dose inactivated influenza vaccine was more effective for prevention of influenza-related visits and hospital admissions in US Medicare beneficiaries than was standard-dose inactivated influenza vaccine [5].

In this retrospective cohort study, the authors identified Medicare beneficiaries aged 65 years and older who received high-dose or standard-dose inactivated influenza vaccines from community pharmacies that offered both vaccines during the 2012–13 influenza season. The primary outcome was probable influenza infection, defined by receipt of a rapid influenza test followed by dispensing of the neuraminidase inhibitor oseltamivir. The secondary outcome was a hospital or emergency department visit, listing a Medicare billing code for influenza. In total, 929 730 recipients of high-dose vaccine and 1 615 545 recipients of standard-dose vaccine were evaluated. Each group was matched well with regards to age and presence of underlying medical conditions.

Results from this study revealed that the high-dose vaccine (1•30 outcomes per 10 000 person-weeks) was 22% (95% CI 15–29) more effective than the standard-dose vaccine (1•01 outcomes per 10 000 person-weeks) for prevention of probable influenza infections (rapid influenza test followed by oseltamivir treatment) and 22% (95% CI 16–27%) more effective for prevention of influenza hospital admissions (0•86 outcomes per 10 000 person-weeks in the high-dose cohort vs 1•10 outcomes per 10 000 person-weeks in the standard-dose cohort). Given the large population in their study, this enabled toe group to show that there was a significant reduction in influenza-related hospital admissions in high-dose compared to standard-dose vaccine recipients – something for us all to perhaps ponder as we order our ‘flu vaccines in clinic.

In other news…

In early February, GlaxoSmithKline began Phase II trials for Ebola vaccination with the ChAd3-ZEBOV vaccine in West Africa in Cameroon, Ghana, Mali, Nigeria, and Senegal, with a plan to start Phase III trials in Guinea, Liberia, and Sierra Leone [6]. As previously reported, the number of Ebloa cases have decreased to 25 in January. Now, the WHO has approved use of ReEBOV Antigen Rapid Test, the first rapid blood test for Ebola, which reports a definitive answer in 12 to 24 hours [7].

In other virologic news, an article in Nature suggests that a new HIV drug, termed the AAV-delivered eCD4-Ig could function like an effective HIV-1 vaccine [8]. In the past, investigators have attempted to develop non-conventional vaccines by inducing immune responses which might prevent viral entry. This new product is a CD4-Ig w/ a small CCR5-mimetic zone which binds to the conserved region of the HIV-1 envelope glycoprotein, preventing viral entry and CD4 binding for more than 40 weeks.

Outbreak! Again, continuing our infectious disease trend. There was a carbapenem-resistant enterobacteriae outbreak at UCLA involving advanced endoscopy [9]. Despite adequate sterilization of the scopes per the manufacturer’s standards, over 100 patients were potentially exposed.

And finally, in a non-infectious update, it appears that drinking dark roast coffee may decrease spontaneous DNA breaks. The studies investigators concluded “that regular coffee consumption contributes to DNA integrity.” [10] Food for thought.

Dr.Steven R. Liu is a 3rd year resident at NYU Langone Medical Center.

Peer Reviewed by Cilian J. White, M.D., Internal Medicine Resident, NYU Langone Medical Center.

Image courtesy of Wikimedia Commons.


1. Bee J, Bath PMW, Phillips SJ, et al. Blood Pressure and Clinical Outcomes in the International Stroke Trial. Stroke. 2002;33:1315-1320.

2. The ENOS Trial Investigators. Efficacy of nitric oxide, with or without continuing antihypertensive treatment, for management of high blood pressure in acute stroke (ENOS): a partial-factorial randomized trial. The Lancet. 2015;385:617-628.

3. 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;342:1301-1308.

4. Marcelo BP, Amato MD, Meade M, et al. Driving Pressure and Survival in the Acute Respiratory Distress Syndrome. N Engl J Med. 2015;372:747-755.

5. Izurieta H, Thadani N, Shay DK, et al. Comparative effectiveness of high-dose versus standard-dose influenza vaccines in US residents aged 65 years and older from 2012 to 2013 using Medicare data: a retrospective cohort analysis. Lancet. 2015;15(3):293-300.

6. Doyle M. “Ebola crisis: First major vaccine trials in Liberia”. BBC News Africa, Feb 2nd, 2015.

7. Gallagher J. “Fifteen-minute Ebola test approved.” BBC News Health, Feb 20th 2015.

8. Gardner MR, Mattenhorn LM, Kondur HR, et al. AAV-expressed eCD4-Ig provides durable protection from multiple SHIV challenges. Nature. 2015. Published online.

9. UCLA statement on notification of patients regarding endoscopic procedures. UCLA Newsroom, Feb 18th 2015.

10. Bakuradze T, Lang R, Hofmann T, et al. Consumption of a dark roast coffee decreases the level of spontaneous DNA stard breaks: a randomized controlled trial. Eur J Nutr. 2015; 54:149-156.