Primecuts-This Week in the Journals

March 13, 2018

By: Brooks Crowe, MD

There was big news last week in the area of mergers and acquisitions.  Cigna, a health care insurer, plans to purchase Express Scripts, a pharmacy benefit manager (PBM) for a total of $52 billion.  Express scripts manages prescription plans for over 80 million people. A similar merger occurred in December when CVS Health (a PBM) announced it would buy the insurer Aetna.

The CEO of Cigna David Cordiani promised the deal would help “improve the affordability and value to the consumer in a more personalized way.” In a country where many patients cannot fill prescriptions due to cost, this sounds like it could be a major breakthrough in decelerating health care spending. Skeptics suggest that both the CVS Health and the Express Scripts agreements benefit shareholders over patients.  The deal is pending federal and state approval over antitrust concerns after two separate large healthcare mergers were blocked last year.1

Now onto recent news in the medical literature:

Septic Shock and Adjunctive Glucocorticoid Therapy

Septic shock carries a very high short-term mortality rate of 20-30% and several interventions are recommended to reduce mortality including IV fluids, rapid administration of antibiotics, and vasoactive medications when needed.2,3 In the past two decades, multiple trials have examined the adjunctive use of corticosteroids in refractory septic shock. In 2002, the Annane trial enrolled approximately 300 patients and demonstrated a significant benefit of hydrocortisone plus fludrocortisone vs. placebo for 28-day all cause mortality in patients with relative adrenal insufficiency based on ACTH stimulation testing.4 However the subsequent CORTICUS trial randomized 499 patients with septic shock to hydrocortisone vs. placebo and showed no survival benefit regardless of the initial result of an ACTH stimulation test. Treatment with steroids did, however, result in a faster reversal of shock.5 The HYPRESS trial randomized 380 patients with severe sepsis without shock and found no difference in progression to septic shock at 14 days with hydrocortisone vs. placebo as well as no difference in mortality at 28 days.6

Recently published in the New England Journal of Medicine (NEJM), the ADRENAL trial performed a multicenter randomized, double-blinded, parallel-group controlled study comparing hydrocortisone vs. placebo in septic shock. Included patients were adults requiring mechanical ventilation meeting two or more Systemic Inflammatory Response Syndrome (SIRS) criteria and requiring vasopressor/inotropic support for over four hours. Notable exclusion criteria included patients receiving systemic steroids for other reasons, administration of etomidate, or patients meeting inclusion criteria for over twenty-four hours. In total, 3,658 patients were studied using intention to treat analysis with 1,832 patients in the hydrocortisone group and 1,826 in the placebo group. Hydrocortisone was administered as a continuous infusion totaling 200mg daily for seven days or until time of ICU discharge or death.

There was no significant difference in the primary outcome of all cause mortality at ninety days between the hydrocortisone and placebo groups (27.9% vs. 28.8% respectively, odds ratio (OR) 0.95, 95% confidence interval (CI) 0.82 to 1.10; p=0.50). Numerous secondary outcomes were analyzed, however the only statistically significant results for hydrocortisone vs. placebo were a faster median time to resolution of shock (median duration, 3 days vs. 4 days respectively; HR 1.32; 95% CI, 1.23 to 1.41; P<0.001), fewer blood transfusions (37% vs. 41.7% respectively; OR 0.82; 95% CI, 0.72 to 0.94; P = 0.004), and a shorter median time to discharge from the ICU (10 days vs. 12 days respectively; HR 1.14; 95% CI 1.06-1.23; P <0.001). Patients in the hydrocortisone group had a shorter duration of initial mechanical ventilation however this lost significance after accounting for episodes of recurrence of ventilation.7

Several limitations of this study exist including that patients receiving etomidate were excluded due to its adrenal-suppressant properties.8 Furthermore, in this trial corticosteroids were administered in a continuous infusion as opposed to bolus dosing as performed in previous trials. An infusion may have led to a slower onset of action and delayed any subsequent effect on septic shock reversal.

A comparative trial published in the same issue of NEJM examined steroids in adults with septic shock. The APROCCHSS trial performed a multicenter, double-blinded, randomized trial comparing hydrocortisone plus fludrocortisone vs. placebo with a primary outcome of all cause mortality at ninety days. In the intention to treat analysis, 1241 ICU patients were included with 614 in intervention group and 627 in placebo group. Eligible patients included those with probable or indisputable septic shock for less than twenty-four hours. Septic shock was defined as microbiologically or clinically documented infection, a Sequential Organ Failure Assessment (SOFA) score of 3-4 for two or more organ systems for over six consecutive hours, and administration of vasopressor therapy for over six hours.   Notable exclusion criteria included duration of septic shock for over 24 hours, high risk of bleeding, or previous treatment with corticosteroids. Lung infection was the most common site of infection for both intervention and placebo groups. The intervention arm received hydrocortisone 50mg IV dosing every six hours plus fludrocortisone 50mcg daily via a nasogastric tube for seven days.

All cause mortality at 90 days was significantly lower in the corticosteroid group compared to placebo (43.0% vs. 49.1% respectively, RR 0.88; 95% CI .78-0.99; P = 0.03). Numerous secondary outcomes showed significant improvement with hydrocortisone plus fludrocortisone including all cause mortality at ICU discharge (41% vs. 35%, RR 0.86) as well as at hospital discharge (45% vs. 39%, RR 0.86), and at 180 days (53% vs. 47%, RR 089). There was also a significant improvement vasopressor-free days at 28 days (mean 15 vs. 17 days, P <0.001) and organ-failure-free days at 28 days (mean 12 vs. 14, P=0.003). Between the intervention and control groups, there was no difference in all cause mortality or ventilator free days at 28 days.9

At this time, multiple trials have examined the use of glucocorticoids in septic shock and its effect on short-term mortality with mixed results. These two recent eagerly anticipated trials discussed above involve the largest study populations to date on this topic and possess strong statistical power to detect any significant effects in comparison to previous studies.   However, these two trials still came to different conclusions regarding short-term mortality. Currently the Surviving Sepsis Campaign Guidelines recommends hydrocortisone administration to restore hemodynamic stability if intravenous fluids and vasopressor therapy are insufficient however this is a weak recommendation.2 While several studies have more consistently shown an improvement in time to resolution of shock, the effect of steroids in sepsis on short-term mortality is an ongoing question that requires further examination.

Choice of Crystalloid Fluids for Resuscitation in the Critically and Noncritically Ill Patients.

The use of crystalloid fluids for intravenous resuscitation is one of the most common medical interventions across different healthcare settings. The most commonly administered crystalloid solution is 0.9% sodium chloride. However balanced crystalloid solutions such as lactated ringer’s more closely match the composition of human plasma.10 The use of saline in large volumes is often associated with hyperchloremic metabolic acidosis and subsequent development of acute kidney injury however balanced solutions are in fact hypotonic in comparison to the extracellular fluid and can lead to metabolic alkalosis among other adverse effects.11 Thus, there has been ongoing question as to the ideal crystalloid solution for fluid resuscitation in the critically ill as well as stable patient.

The recent SALT-ED trial examined balanced crystalloids (lactated Ringer’s solution or Plasma-Lyte A) vs. saline administered while in the emergency department at a single institution and enrolled 13,347 noncritically ill adults who were subsequently admitted but cared for outside of the ICU. Randomization was performed in blocks by alternating fluid types on monthly intervals without blinding where all patients in a given month received one type of fluid. The primary endpoint was hospital-free days at day 28 after admission with multiple secondary outcomes including all cause mortality and adverse effects on renal function. Patients were excluded if they received less than 500ml of intravenous fluids or if they were subsequently admitted to the ICU.

In total, 6,708 patients received balanced crystalloids and 6,639 received saline solutions. There was no significant difference in the number of hospital-free days between the two treatment arms with an adjusted OR for use of balanced crystalloids of 0.98 (95% CI, 0.92 to 1.04; P=0.41). However, use of balanced crystalloids compared to saline did result in a significantly lower rate of composite major adverse renal events at 30 days including death, new renal replacement therapy, or persistent renal dysfunction with creatinine 200% over baseline (4.7% vs. 5.6% respectively; adjusted OR, 0.82; 95% CI, 0.70 to 0.95; P=0.01).12

Overall, the median volume of fluids administered was similar between the two groups (1,089ml balanced crystalloid vs. 1,071ml saline) and approximately 95% of the balanced crystalloid solution administered was lactated ringer’s solution. Key limitations for this study include an unblinded process and that fact that no data was obtained regarding fluid type or volume administered after admission. However, while there was no significant difference in length of stay, the use of balanced crystalloid solution in noncritically ill patients admitted to the hospital may reduce risk of major adverse renal events.

In comparison, the SMART trial investigated crystalloid solutions in critically ill patients. This cluster-randomized, unblinded trial enrolled 7,942 patients to receive balanced crystalloids and 7,860 patients to receive saline. All adult patients admitted to the ICU during the trial period were enrolled in this study.   The median volume of administered fluids between ICU admission and hospital discharge for the balanced crystalloid and saline groups was 1000ml and 1020ml respectively and approximately 95% of patients received only the assigned crystalloid. The primary study outcome was any major adverse renal event within 30 days defined as in hospital death, new onset need for renal replacement therapy, or persistent renal dysfunction with Creatinine >200% of baseline.

The use of balanced crystalloid solution led to a small but significant improvement in the primary outcome as compared to saline (14.3% vs. 15.4%, adjusted OR, 0.90; 95% CI, 082 to 099; P =0.04). For each of the three individual components of the composite primary outcome, there was a trend towards benefit from balanced crystalloids however none of these independent results were statistically significant.13

As in the SALT-ED trial discussed above, the SMART trial was also an unblinded study conducted at a single institution and used a composite primary end point of major adverse renal events rather than mortality. The study also does not provide extensive detail regarding the primary diagnosis upon ICU admission instead only noting the percent of people with sepsis (approx. 15% for each treatment arm) or traumatic brain injury (approx. 8.5-9% for each arm). Despite these limitations, however, there does appear to be a small but statistically significant improvement for major adverse renal events with the use of balanced crystalloid solution in comparison to saline for critically ill adult patients.

Overall, these two articles illustrate that the use of balanced crystalloid solutions in both critically and noncritically ill patients may help reduce risk of adverse major renal events including death, renal replacement therapy, or persistent renal dysfunction however the effect on mortality is unclear.


The SPACE trial recently published in JAMA studied patients cared for at Veteran Affairs primary care clinics with chronic back pain or hip or knee osteoarthritis pain. Overall, 240 patients were randomized to opioid vs. nonopioid treatment protocols. There was no significant difference in pain related function over a twelve-month period between the two groups. This supports the effort to manage chronic musculoskeletal pain with nonopioid treatments and modalities.14


Appropriate screening for prostate cancer in the primary care setting is an ongoing question and a recent trial in JAMA evaluates the effect of single PSA screening vs. standard care without PSA screening. Over 400,000 patients across the United Kingdom were included in this study. Patients in the intervention group received a single PSA test and patients with a result >3.0 ng/ml were offered a prostate biopsy with 85% subsequently undergoing biopsy. Patients in the control group received care as recommended by the National Health Service, which does not recommend routine screening via PSA testing. At 10 years of median follow-up, there was no significant difference in prostate cancer mortality although more low-risk prostate cancers were detected.15


This week, NEJM describes the case of a 44 year-old man who self-managed his own STEMI. The patient is a nurse in remote Australia over 150 km from the nearest medical facility and was the only provider on duty when he began experiencing severe chest pain and dizziness. With consultation via the Emergency Telehealth Service, he self diagnosed an inferior STEMI, performed appropriate ACS management, and ultimately self administered thrombolytics with resolution symptoms and ST elevations.16

Dr. Brooks Crowe is a 2nd year internal medicine resident at NYU Langone Health 

Peer reviewed by David Kudlowitz, MD, Associate Editor of Clinical Correlations

Image courtesy of Wikimedia Commons


[1] Thomas K, Abelson R, Bray C. “Cigna to Buy Express Scripts in $52 Billion Health Care Deal.” New York Times, 8 March 2018.

[2]Angus DC, van der Poll T. Severe Sepsis and Septic Shock. NEJM 2013; 369(9): 840-851.

[3] Rhodes A, Evans LE, Alhazzani W, et al. Surviving Sepsis Campaign: international guidelines for management of sepsis and septic shock: 2016. Crit Care Med 2017;45:486-552.

[4]Annane D, Sebille V, Charpentier C, et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA 2002; 288(7): 862-871.

[5] Sprung CL, Annane D, Keh D, et al. Hydrocortisone therapy for patients with septic shock. NEJM 2008; 358(2):111-24.

[6] Keh D, Trips E, Wirtz SP, et al. Effect of Hydrocortisone on Development of Shock Among Patients With Severe Sepsis: The HYPRESS Randomized Clinical Trial. JAMA 2016; 316(17): 1775-1785.

[7]Venkatesh B, Finfer S, Cohen J, et al. Adjunctive Glucocorticoid Therapy in Patients with Septic Shock. NEJM 2018; 378(9): 797-808.

[8] Wagner RL, White PF, Kan PB, Rosenthal MH, Feldman D. Inhibition of adrenal steroidogenesis by the anesthetic etomidate. NEJM 1984; 310: 1415-21.

[9] Annane D, Renault A, Brun-Buisson C, et al. Hydrocortisone plus Fludrocortisone for Adults with Septic Shock. NEJM 2018; 378(9):809-818.

[10] Myburgh JA, Mythen MG. Resuscitation Fluids. NEJM 2013; 369(13): 1243-1251.

[11] Myburgh, J. Patient-Centered Outcomes and Resuscitation Fluids. NEJM 2018; 378(9): 862-863.

[12] Self WH, Semler MW, Wanderer JP, et al. Balanced Crystalloids versus Saline in Noncritically Ill Adults. NEJM 2018; 378(9): 819-828.

[13] Semler MW, Self WH, Wanderer JP, et al. Balanced Crystalloids versus Saline in Critically Ill Adults. NEJM 2018; 378(9):829-839.

[14] Krebs EE, Gravely A, Nugent S, et al. Effect of Opioid vs Nonopioid Medications on Pain-Related Function in Patients with Chronic Back Pain or Hip or Knee Osteoarthritis Pain – The SPACE Randomized Clinical Trail. JAMA 2018; 319(9):872-882.

[15]Martin RM, Donovan JL, Turner EL, et al. Effect of a Low-Intensity PSA-Based Screening Intervention on Prostate Cancer Mortality – the CAP Randomized Clinical Trial. JAMA 2018; 319(9):883-895.

[16] Lee F, Maggiore P, Chung K. Self-Management of an Inferior ST-Segment Elevation Myocardial Infarction. NEJM 2018; 378(10): 960-961.