Early Use of Norepinephrine in Septic Shock Resuscitation (CENSER): A Randomized Trial

Permpikul C, Tongyoo S, Viarasilpa T, Trainarongsakul T, Chakorn T, Udompanturak S. Am J Respir Crit Care Med. 2019 Feb 1. [Epub ahead of print] [CrossRef][PubMed]

A vocal minority of researchers have advised against delaying vasopressors in septic shock, arguing that norepinephrine, not intravenous fluid, as the most effective initial treatment to correct the loss of vascular tone ("vasoplegia") from septic shock. The authors conducted a Phase II trial evaluating the hypothesis that early low-dose norepinephrine in adults sepsis with hypotension increases shock control by six hours compared with standard care. This single-center, randomized, double-blind, placebo-controlled clinical trial was conducted at Siriraj Hospital, Bangkok, Thailand and enrolled 310 adults diagnosed with sepsis with hypotension. The patients were randomly divided into two groups: early norepinephrine (n=155) and standard treatment (n=155). The primary outcome was shock control rate (defined as achievement of mean arterial blood pressure >65mmHg, with urine flow >0.5mL/kg/h for 2 consecutive hours, or decreased serum lactate >10% from baseline) by 6 hours after diagnosis. The patients in both groups were well matched in background characteristics and disease severity. Median time from emergency room arrival to norepinephrine administration was significantly shorter in early norepinephrine group (93 vs.192 min; P<0.001). Shock control rate by 6 hours was significantly higher in early norepinephrine group (118/155 [76.1%] vs.75/155 [48.4%]; P<0.001). 28-day mortality was not different between groups: 24/155 (15.5%) in the early norepinephrine group versus 34/155 (21.9%) in the standard treatment group (P=0.15). The early norepinephrine group was associated with lower incidences of cardiogenic pulmonary edema (22/155 [14.4%] vs. 43/155 [27.7%]; P=0.004) and new-onset arrhythmia (17/155 [11%] vs. 31/155 [20%]; P=0.03). The authors conclude that early norepinephrine was significantly associated with increased shock control by 6 hours. A much larger U.S-based trial testing early vasopressors in septic shock (CLOVERS) is currently recruiting, with plans to enroll up to 2,300 patients and an expected completion date of June 2021.

Association of Positive Airway Pressure Prescription with Mortality in Patients with Obesity and Severe Obstructive Sleep Apnea: The Sleep Heart Health Study

Lisan Q, Van Sloten T, Marques Vidal P, Haba Rubio J, Heinzer R, Empana JP. JAMA Otolaryngol Head Neck Surg. 2019 Apr 11. [Epub ahead of print] [CrossRef] [PubMed]

The association of positive airway pressure (PAP) with reduced mortality in patients with obstructive sleep apnea (OSA) remains uncertain. This European, NIH-funded, multicenter, population-based cohort study evaluated data from the Sleep Heart Health Study (SHHS), a long-term observational cohort study that included participants between 1995 and 1998, with a mean follow-up of 11.1 years. Analyses were performed in September 2018. Within the SHHS, we compared patients with obesity and severe OSA with (n = 81) and without (n = 311) prescription of PAP therapy, after matching patients from each group by age, sex, and apnea-hypopnea index. Of 392 study participants, 316 (80.6%) were men, and mean (SD) age was 63.1 (11.0) years. Ninety-six deaths occurred; 12 among the prescribed-PAP group and 84 among the nonprescribed-PAP group, yielding crude incidence rates of 12.8 vs 24.7 deaths per 1000 person-years. In Cox multivariate analysis, the hazard ratio (HR) of all-cause mortality for prescribed PAP therapy was 0.38 (95% CI, 0.18-0.81). After propensity matching, the HR of all-cause mortality for prescribed PAP therapy was 0.58 (95% CI, 0.35-0.96). According to survival curves, the difference in mortality appears 6 to 7 years after initiation of PAP therapy. The authors concluded that positive airway pressure prescription is associated with reduced all-cause mortality, and this association appears several years after PAP initiation. If replicated, these findings may have strong clinical implications.

Effect of Glucose Improvement on Spirometric Maneuvers in Patients with Type 2 Diabetes: The Sweet Breath Study

Gutiérrez-Carrasquilla L, Sánchez E, Barbé F, et al. Diabetes Care. 2019 Apr;42(4):617-24. [CrossRef] [PubMed]

 The authors conducted a prospective interventional study to determine if an improvement in glycemic control affects pulmonary function. Sixty patients with type 2 diabetes and forced expiratory volume in 1 s (FEV1) <90% of predicted were studied. Spirometry was performed at baseline and after a 3-month period in which antidiabetic therapy was intensified. Those with an HbA1c reduction of >0.5% were considered to be good responders (n = 35). Good responders exhibited a significant improvement in spirometric values between baseline and the end of the study (forced vital capacity [FVC]: 78.5 + 12.6% vs. 83.3 + 14.7%, P = 0.029]; FEV1: 75.6 + 15.3% vs. 80.9 + 15.4%, P = 0.010; and peak expiratory flow [PEF]: 80.4 6 21.6% vs. 89.2 6 21.0%, P = 0.007). However, no changes were observed in the group of nonresponders when the same parameters were evaluated (P = 0.586, P = 0.987, and P = 0.413, respectively). Stepwise multivariate regression analysis showed that the absolute change in HbA1c independently predicted increased FEV1 (R² = 0.175) and PEF (R² = 0.323). In contrast, the known duration of type 2 diabetes, but not the amelioration of HbA1c, was related to changes in forced expiratory flow between 25% and 75% of the FVC. In type 2 diabetes, spirometric measurements reflecting central airway obstruction and explosive muscle strength exhibit significant amelioration after a short improvement in glycemic control. The reason for the nonsignificant improvement in spirometry with improved type 2 diabetes control was unclear.  

Whole-Genome Sequencing of Pharmacogenetic Drug Response in Racially Diverse Children with Asthma

Mak ACY, White MJ, Eckalbar WL, et al. Am J Respir Crit Care Med. 2018 Jun 15;197(12):1552-64. [CrossRef] [PubMed]

Albuterol, a bronchodilator medication, is the first-line therapy for asthma worldwide. However, there are significant racial/ethnic differences in albuterol drug response. The authors performed whole-genome sequencing pharmacogenetics study from 1,441 children with asthma to identify genetic association with bronchodilator response (BDR). They identified population-specific and shared genetic variants associated with BDR, including genome-wide significant (P < 3.53 × 10−7) and suggestive (P < 7.06 × 10−6) loci near genes previously associated with lung capacity (DNAH5), immunity (NFKB1 and PLCB1), and β-adrenergic signaling (ADAMTS3 and COX18). Functional analyses of the BDR-associated SNP in NFKB1 revealed potential regulatory function in bronchial smooth muscle cells. The SNP is also an expression quantitative trait locus for a neighboring gene, SLC39A8. This study demonstrates that a set of genetic mutations found mostly in children of African-American or Puerto Rican descent may make them less likely to respond to albuterol. This research suggests that a genetic test could be developed to help identify patients who are resistant to albuterol and could benefit from alternative treatments.

Patient Safety Outcomes under Flexible and Standard Resident Duty-Hour Rules and Sleep and Alertness in a Duty-Hour Flexibility Trial in Internal Medicine

Silber JH, Bellini LM, Shea JA, et al. N Engl J Med 2019; 380:905-14. [CrossRef]

Basner M, Asch DA, Shea JA, et al. N Engl J Med 2019; 380:915-23. [CrossRef] [PubMed]

In 2003 the American Council on Graduate Medical Education (ACGME) limited resident work-hour limits. In 2011 the ACGME enacted even more stringent requirements. However, waivers were granted allowing some flexibility in shift length, as well as time off between shifts; caps on weekly hours worked, total days off, and the frequency of overnight call were maintained. Some argued that there was a paucity of evidence to support these changes and some new risks, such as those associated with increased handoffs of care or inadequate educational exposure. The Arizona Thoracic Society was amongst those who urged the ACGME to conduct randomized trials. In today’s edition of the New England Journal the results of two of these trials are reported.

The first report used Medicare claims data to assess patient outcomes. Mortality, readmissions and payments did not differ in programs with flexible hours worked standard hours. The second study found that sleep duration also did not differ in flexible programs as compared with standard programs, with interns in both groups averaging approximately 7 hours of sleep per night. Essentially, interns made up for lost sleep on extended shifts by sleeping more during time off.

A thoughtful editorial by Rosenbaum and Lamas summarizes the data and points out that there may be some downsides to the resident hour restrictions including increased handoffs of care or inadequate educational exposure.