Prospective evaluation of the efficacy, safety, and optimal biomarker enrichment strategy for nangibotide, a TREM-1 inhibitor, in patients with septic shock (ASTONISH): a double-blind, randomised, controlled, phase 2b trial.

BACKGROUND: Activation of the triggering receptor expressed on myeloid cells-1 (TREM-1) pathway is associated with septic shock outcomes. Data suggest that modulation of this pathway in patients with activated TREM-1 might improve survival. Soluble TREM-1 (sTREM-1), a potential mechanism-based biomarker, might facilitate enrichment of patient selection in clinical trials of nangibotide, a TREM-1 modulator. In this phase 2b trial, we aimed to confirm the hypothesis that TREM1 inhibition might improve outcomes in patients with septic shock. METHODS: This double-blind, randomised, placebo-controlled, phase 2b trial assessed the efficacy and safety of two different doses of nangibotide compared with placebo, and aimed to identify the optimum treatment population, in patients across 42 hospitals with medical, surgical, or mixed intensive care units (ICUs) in seven countries. Non-COVID-19 patients (18-85 years) meeting the standard definition of septic shock, with documented or suspected infection (lung, abdominal, or urinary [in patients ≥65 years]), were eligible within 24 h of vasopressor initiation for the treatment of septic shock. Patients were randomly assigned in a 1:1:1 ratio to intravenous nangibotide 0·3 mg/kg per h (low-dose group), nangibotide 1·0 mg/kg per h (high-dose group), or matched placebo, using a computer-generated block randomisation scheme (block size 3). Patients and investigators were masked to treatment allocation. Patients were grouped according to sTREM-1 concentrations at baseline (established from sepsis observational studies and from phase 2a change to data) into high sTREM-1 (≥ 400 pg/mL). The primary outcome was the mean difference in total Sequential Organ Failure Assessment (SOFA) score from baseline to day 5 in the low-dose and high-dose groups compared with placebo, measured in the predefined high sTREM-1 (≥ 400 pg/mL) population and in the overall modified intention-to-treat population. Secondary endpoints included all-cause 28-day mortality, safety, pharmacokinetics, and evaluation of the relationship between TREM-1 activation and treatment response. This study is registered with EudraCT, 2018-004827-36, and Clinicaltrials.gov, NCT04055909. FINDINGS: Between Nov 14, 2019, and April 11, 2022, of 402 patients screened, 355 were included in the main analysis (116 in the placebo group, 118 in the low-dose group, and 121 in the high-dose group). In the preliminary high sTREM-1 population (total 253 [71%] of 355; placebo 75 [65%] of 116; low-dose 90 [76%] of 118; high-dose 88 [73%] of 121), the mean difference in SOFA score from baseline to day 5 was 0·21 (95% CI -1·45 to 1·87, p=0·80) in the low-dose group and 1·39 (-0·28 to 3·06, p=0·104) in the high-dose group versus placebo. In the overall population, the difference in SOFA score from baseline to day 5 between the placebo group and low-dose group was 0·20 (-1·09 to 1·50; p=0·76),and between the placebo group and the high-dose group was 1·06 (-0·23 to 2·35, p=0·108). In the predefined high sTREM-1 cutoff population, 23 (31%) patients in the placebo group, 35 (39%) in the low-dose group, and 25 (28%) in the high-dose group had died by day 28. In the overall population, 29 (25%) patients in the placebo, 38 (32%) in the low-dose, and 30 (25%) in the high-dose group had died by day 28. The number of treatment-emergent adverse events (111 [96%] patients in the placebo group, 113 [96%] in the low-dose group, and 115 [95%] in the high-dose group) and serious treatment-emergent adverse events (28 [24%], 26 [22%], and 31 [26%]) was similar between all three groups. High-dose nangibotide led to a clinically relevant improvement in SOFA score (of two points or more) from baseline to day 5 over placebo in those with higher cutoff concentrations (≥532 pg/mL) of sTREM-1 at baseline. Low dose nangibotide displayed a similar pattern with lower magnitude of effect across all cutoff values. INTERPRETATION: This trial did not achieve the primary outcome of improvement in SOFA score at the predefined sTREM-1 value. Future studies are needed to confirm the benefit of nangibotide at higher concentrations of TREM-1 activation. FUNDING: Inotrem.

Hydrocortisone in Severe Community-Acquired Pneumonia.

BACKGROUND: Whether the antiinflammatory and immunomodulatory effects of glucocorticoids may decrease mortality among patients with severe community-acquired pneumonia is unclear. METHODS: In this phase 3, multicenter, double-blind, randomized, controlled trial, we assigned adults who had been admitted to the intensive care unit (ICU) for severe community-acquired pneumonia to receive intravenous hydrocortisone (200 mg daily for either 4 or 7 days as determined by clinical improvement, followed by tapering for a total of 8 or 14 days) or to receive placebo. All the patients received standard therapy, including antibiotics and supportive care. The primary outcome was death at 28 days. RESULTS: A total of 800 patients had undergone randomization when the trial was stopped after the second planned interim analysis. Data from 795 patients were analyzed. By day 28, death had occurred in 25 of 400 patients (6.2%; 95% confidence interval [CI], 3.9 to 8.6) in the hydrocortisone group and in 47 of 395 patients (11.9%; 95% CI, 8.7 to 15.1) in the placebo group (absolute difference, -5.6 percentage points; 95% CI, -9.6 to -1.7; P = 0.006). Among the patients who were not undergoing mechanical ventilation at baseline, endotracheal intubation was performed in 40 of 222 (18.0%) in the hydrocortisone group and in 65 of 220 (29.5%) in the placebo group (hazard ratio, 0.59; 95% CI, 0.40 to 0.86). Among the patients who were not receiving vasopressors at baseline, such therapy was initiated by day 28 in 55 of 359 (15.3%) of the hydrocortisone group and in 86 of 344 (25.0%) in the placebo group (hazard ratio, 0.59; 95% CI, 0.43 to 0.82). The frequencies of hospital-acquired infections and gastrointestinal bleeding were similar in the two groups; patients in the hydrocortisone group received higher daily doses of insulin during the first week of treatment. CONCLUSIONS: Among patients with severe community-acquired pneumonia being treated in the ICU, those who received hydrocortisone had a lower risk of death by day 28 than those who received placebo. (Funded by the French Ministry of Health; CAPE COD ClinicalTrials.gov number, NCT02517489.).

Mottling Incidence and Mottling Score According to Arterial Lactate Level in Septic Shock Patients.

OBJECTIVES: Mottling score is estimated from 0-5 according to mottling over the knee and described as clinical evaluation of tissue perfusion. This score was developed with ancient definitions of sepsis without lactate level, a major prognostic parameter when superior to 2 mmol/L. This study describes mottling incidence and mottling score in septic shock patients according to lactate level. MATERIALS AND METHODS: We reanalyzed our prospective study in a French tertiary hospital in the intensive care unit (ICU) which studied mottling score and thermography correlation. Patients admitted to septic shock diagnosis and requiring vasoactive drugs were included. We recorded hemodynamic variables, mottling score, and lactate. Data collection was realized at ICU admission (H0) and after six hours (H6). RESULTS: Forty-three patients were included. Mean age was 67 (±4), mean sequential organ failure assessment (SOFA) score was 11 (8-12), and SAPS II 58 ±20. Mortality rate at day 28 was 30%. Among patients with lactate ≥2 mmol/L, mottling was more prevalent in 82.6% vs 47.4% (p value = 0.016), and at H6 mottling score was higher (p value = 0.009). Although, mottling incidence was not different between dead (85%) and survivors (81%; p value = 0.795). CONCLUSION: A new sepsis definition implies a new epidemiology in mottling according to lactate threshold. Patients with lactate ≥2 mmol/L presented a higher incidence and score of mottling. However, mortality was not influenced by mottling in this study. CLINICAL SIGNIFICANCE: Arterial lactate is a major prognostic parameter when superior to 2 mmol/L.A new definition of sepsis was published in 2016 with a new paradigm and epidemiology of septic shockPatients with lactate ≥2 mmol/L presented a higher incidence and score of mottling.Mottling score is a clinical sign of microcirculatory alteration, related to lactate level in septic shock. HOW TO CITE THIS ARTICLE: Ferraris A, Bouisse C, Thiollière F, Piriou V, Allaouchiche B. Mottling Incidence and Mottling Score According to Arterial Lactate Level in Septic Shock Patients. Indian J Crit Care Med 2020;24(8):672-676.

Mottling score and skin temperature in septic shock: Relation and impact on prognosis in ICU.

INTRODUCTION: Mottling score, defined by 5 areas over the knee is developed to evaluate tissue perfusion at bedside. Because of the subjective aspect of the score, we aimed to compare mottling score and skin temperature in septic shock with infrared thermography in ICU and the correlation to survival. METHODS: We conducted a prospective and observational study in a teaching hospital in France during 8 months in ICU. All patients with sepsis requiring vasoactive drugs were included. We recorded epidemiologic data, hemodynamic parameters, mottling score and skin temperature with a thermic camera of the 5 mottling areas around the knee (temperatures recorded with FLIR™ software) at bedside. Measures were performed at ICU admission (H0) and six hours after initial resuscitation (H6). RESULTS: 46 patients were included. Median age was 69 (60-78), SOFA score 11 (8-12) mean SAPS II was 57±20 and 28-day mortality rate was 30%. Patients with mottling (score≥1), had a skin temperature of the knee significantly lower (30.7 vs 33,2°C p = 0.01 at H6) than patients without mottling (score = 0). Skin temperatures of the knee in mottling groups 1 to 5 were similar at H0 and H6. Neither mottling score nor skin temperature of the knee were associated with prognostic regarding day-28 mortality. CONCLUSIONS: Skin temperature measured with infrared thermography technology around the knee is lower when mottling sign is present and sign microcirculation alterations. This method, compared to standard mottling score is objective and allows data collections. However, this method failed to predict mortality in ICU patients.