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

Rationale: Recent retrospective evidence suggests the efficacy of early norepinephrine administration during resuscitation; however, prospective data to support this assertion are scarce. Objectives: To conduct a phase II trial evaluating the hypothesis that early low-dose norepinephrine in adults with sepsis with hypotension increases shock control by 6 hours compared with standard care. Methods: This single-center, randomized, double-blind, placebo-controlled clinical trial was conducted at Siriraj Hospital, Bangkok, Thailand. The study 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 ≥65 mm Hg, with urine flow ≥0.5 ml/kg/h for 2 consecutive hours, or decreased serum lactate ≥10% from baseline) by 6 hours after diagnosis. Measurements and Main Results: 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 the early norepinephrine group (93 vs. 192 min; P < 0.001). Shock control rate by 6 hours was significantly higher in the early norepinephrine group (118/155 [76.1%] vs. 75/155 [48.4%]; P < 0.001). The 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). Conclusions: Early norepinephrine was significantly associated with increased shock control by 6 hours. Further studies are needed before this approach is introduced in clinical resuscitation practice. Clinical trial registered with www.clinicaltrials.gov (NCT01945983) (CENSER trial).

Hydrocortisone treatment in early sepsis-associated acute respiratory distress syndrome: results of a randomized controlled trial.

BACKGROUND: Authors of recent meta-analyses have reported that prolonged glucocorticoid treatment is associated with significant improvements in patients with severe pneumonia or acute respiratory distress syndrome (ARDS) of multifactorial etiology. A prospective randomized trial limited to patients with sepsis-associated ARDS is lacking. The objective of our study was to evaluate the efficacy of hydrocortisone treatment in sepsis-associated ARDS. METHODS: In this double-blind, single-center (Siriraj Hospital, Bangkok), randomized, placebo-controlled trial, we recruited adult patients with severe sepsis within 12 h of their meeting ARDS criteria. Patients were randomly assigned (1:1 ratio) to receive either hydrocortisone 50 mg every 6 h or placebo. The primary endpoint was 28-day all-cause mortality; secondary endpoints included survival without organ support on day 28. RESULTS: Over the course of 4 years, 197 patients were randomized to either hydrocortisone (n = 98) or placebo (n = 99) and were included in this intention-to-treat analysis. The treatment group had significant improvement in the ratio of partial pressure of oxygen in arterial blood to fraction of inspired oxygen and lung injury score (p = 0.01), and similar timing to removal of vital organ support (HR 0.74, 95 % CI 0.51-1.07; p = 0.107). After adjustment for significant covariates, day 28 survival was similar for the whole group (HR 0.80, 95 % CI 0.46-1.41; p = 0.44) and for the larger subgroup (n = 126) with Acute Physiology and Chronic Health Evaluation II score <25 (HR 0.57, 95 % CI 0.24-1.36; p = 0.20). With the exception of hyperglycemia (80.6 % vs. 67.7 %; p = 0.04), the rate of adverse events was similar. Hyperglycemia had no impact on outcome. CONCLUSIONS: In sepsis-associated ARDS, hydrocortisone treatment was associated with a significant improvement in pulmonary physiology, but without a significant survival benefit. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT01284452 . Registered on 18 January 2011.

High-flow nasal oxygen cannula vs. noninvasive mechanical ventilation to prevent reintubation in sepsis: a randomized controlled trial.

BACKGROUND: High-flow nasal oxygen cannula (HFNC) and noninvasive mechanical ventilation (NIV) can prevent reintubation in critically ill patients. However, their efficacy in post-extubated sepsis patients remains unclear. The objective of this study was to compare the efficacy of HFNC vs. NIV to prevent reintubation in post-extubated sepsis patients. METHODS: We conducted a single-centre, prospective, open-labelled, randomised controlled trial at the medical intensive care unit of Siriraj Hospital, Mahidol University, Bangkok, Thailand. Sepsis patients who had been intubated, recovered, and passed the spontaneous breathing trial were enrolled and randomly assigned in a 1:1 ratio to receive either HFNC or NIV support immediately after extubation. The primary outcome was rate of reintubation at 72 h after extubation. RESULTS: Between 1st October 2017 and 31st October 2019, 222 patients were enrolled and 112 were assigned to the HFNC group and 110 to the NIV group. Both groups were well matched in baseline characteristics. The median [IQR] age of the HFNC group was 66 [50-77] vs. 65.5 [54-77] years in the NIV group. The most common causes of intubation at admission were shock-related respiratory failure (57.1% vs. 55.5%) and acute hypoxic respiratory failure (34.8% vs. 40.9%) in the HFNC and NIV groups, respectively. The duration of mechanical ventilation before extubation was 5 [3-8] days in the HFNC group vs. 5 [3-9] days in the NIV group. There was no statistically significant difference in the primary outcome: 20/112 (17.9%) in the HFNC group required reintubation at 72 h compared to 20/110 (18.2%) in the NIV group [relative risk (RR) 0.99: 95% confidence interval (CI) (0.70-1.39); P = 0.95]. The 28-day mortality was not different: 8/112 (7.1%) with HFNC vs. 10/110 (9.1%) with NIV (RR 0.88: 95% CI (0.57-1.37); P = 0.59). CONCLUSIONS: Among sepsis patients, there was no difference between HFNC and NIV in the prevention of reintubation at 72 h after extubation. Clinical Trial Registration ClinicalTrials.gov Identifier: NCT03246893; Registered 11 August 2017; https://clinicaltrials.gov/ct2/show/NCT03246893?term=surat+tongyoo&draw=2&rank=3.

Prognostic value of combined magnetic resonance myocardial perfusion imaging and late gadolinium enhancement.

Late gadolinium enhancement (LGE) and myocardial perfusion study by cardiac magnetic resonance (CMR) have a diagnostic and prognostic value in patients with suspected coronary artery disease (CAD). The purpose of this study was to determine the prognostic value of combined myocardial perfusion CMR and LGE in patients with known or suspected CAD. We studied patients with known or suspected CAD. All patients underwent CMR for functional study, myocardial perfusion and LGE. Myocardial ischemia by CMR was defined as a perfusion defect in patients without LGE or a perfusion defect beyond the LGE area. Patients were followed up for cardiovascular outcomes including hard cardiac events (cardiac death or non-fatal myocardial infarction) and major adverse cardiac events (MACE) which included cardiac death, non-fatal myocardial infarction, hospitalization for unstable angina, and heart failure. There were a total of 587 men and 645 women. Average age was 64.6 ± 11.1 years. LGE was detected in 326 patients (26.5%). Myocardial ischemia by CMR was detected in 423 patients (34.3%). Average follow-up duration was 34.9 ± 15.6 months. Univariate analysis showed that age, diabetes, use of beta blocker, left ventricular ejection fraction, left ventricular mass, wall motion abnormality, LGE, and myocardial ischemia are predictors for hard cardiac events and MACE. Multivariable analysis revealed that myocardial ischemia was the strongest predictor for hard cardiac events and MACE. Other independent predictors were age, use of beta blocker, and left ventricular mass. Myocardial ischemia by CMR has an incremental prognostic value for cardiac events in patients with known or suspected CAD.

Prognostic value of late gadolinium enhancement in hypertensive patients with known or suspected coronary artery disease.

To determine the prognosis of a myocardial scar assessed by a late gadolinium enhancement (LGE) technique of cardiac magnetic resonance (CMR) in hypertensive patients with known or suspected coronary artery disease (CAD). Patients with systemic hypertension with known or suspected CAD without a clinical history of myocardial infarction were enrolled. All patients underwent CMR for assessment of cardiac function and LGE. Prognostic data was determined by the occurrence of a hard cardiac endpoint, defined as cardiac death or a non-fatal myocardial infarction, or major adverse cardiac events (MACEs), defined as cardiac death, a non-fatal myocardial infarction, or hospitalization due to heart failure, unstable angina, or life-threatening ventricular arrhythmia. A total of 1,644 patients were enrolled; 48% were males and the mean age was 65 +/- 11 years. The average follow-up time was 863 +/- 559 days. Four hundred fifty-three (28%) patients had LGE. LGE was the strongest and most independent predictor for hard events and MACEs with hazard ratios of 4.77 and 3.38, respectively. Other independent predictors of hard events and MACEs were left ventricular ejection fraction and mass, the use of a beta-blocker, and a history of heart failure. The risk of cardiac events increased as the extent of LGE increased; the hazard ratio was 12.74 for hard events for those with a LGE >20% of the myocardium. LGE is the most important and independent predictor for cardiac events in hypertensive patients with known or suspected CAD.