Circulating adrenomedullin estimates survival and reversibility of organ failure in sepsis: the prospective observational multinational Adrenomedullin and Outcome in Sepsis and Septic Shock-1 (AdrenOSS-1) study

Background: Adrenomedullin (ADM) regulates vascular tone and endothelial permeability during sepsis. Levels of circulating biologically active ADM (bio-ADM) show an inverse relationship with blood pressure and a direct relationship with vasopressor requirement. In the present prospective observational multinational Adrenomedullin and Outcome in Sepsis and Septic Shock 1 (, AdrenOSS-1) study, we assessed relationships between circulating bio-ADM during the initial intensive care unit (ICU) stay and short-term outcome in order to eventually design a biomarker-guided randomized controlled trial. Methods: AdrenOSS-1 was a prospective observational multinational study. The primary outcome was 28-day mortality. Secondary outcomes included organ failure as defined by Sequential Organ Failure Assessment (SOFA) score, organ support with focus on vasopressor/inotropic use, and need for renal replacement therapy. AdrenOSS-1 included 583 patients admitted to the ICU with sepsis or septic shock. Results: Circulating bio-ADM levels were measured upon admission and at day 2. Median bio-ADM concentration upon admission was 80.5 pg/ml [IQR 41.5-148.1 pg/ml]. Initial SOFA score was 7 [IQR 5-10], and 28-day mortality was 22%. We found marked associations between bio-ADM upon admission and 28-day mortality (unadjusted standardized HR 2.3 [CI 1.9-2.9]; adjusted HR 1.6 [CI 1.1-2.5]) and between bio-ADM levels and SOFA score (p < 0.0001). Need of vasopressor/inotrope, renal replacement therapy, and positive fluid balance were more prevalent in patients with a bio-ADM > 70 pg/ml upon admission than in those with bio-ADM ≤ 70 pg/ml. In patients with bio-ADM > 70 pg/ml upon admission, decrease in bio-ADM below 70 pg/ml at day 2 was associated with recovery of organ function at day 7 and better 28-day outcome (9.5% mortality). By contrast, persistently elevated bio-ADM at day 2 was associated with prolonged organ dysfunction and high 28-day mortality (38.1% mortality, HR 4.9, 95% CI 2.5-9.8). Conclusions: AdrenOSS-1 shows that early levels and rapid changes in bio-ADM estimate short-term outcome in sepsis and septic shock. These data are the backbone of the design of the biomarker-guided AdrenOSS-2 trial. Trial registration: ClinicalTrials.gov, NCT02393781. Registered on March 19, 2015

Complex prescribing in chronic kidney disease: role of the renal pharmacist in kidney supportive care in uncovering hydralazine-related lupus

Background: Herein we describe the presentation of drug-induced lupus in an 89-year-old woman with end-stage kidney disease (estimated glomerular filtration rate (eGFR) 11\ua0mL/min per 1.73\ua0m) who had chosen a conservative non-dialysis pathway of care, and highlight the role of a pharmacist in identifying drug-related problems. Clinical details: Among numerous health conditions, the patient had systemic lupus erythematosus (SLE) that had previously responded to hydroxychloroquine, which had been ceased. Hydralazine was subsequently commenced to control the patient's blood pressure. The combination of ceasing the medicine that controlled the patient's SLE and commencing a medicine that accumulates in patients with reduced renal function and can precipitate SLE resulted in a reactivation of the patient's disease. Outcomes: The pharmacist was pivotal in uncovering the timeline of medication changes and assisting in identifying SLE reactivation. Cessation of the patient's hydralazine and recommencing hydroxychloroquine resulted in the resolution of the symptoms. Conclusion: This case presents the value of an interdisciplinary approach to patient directed symptoms, when prescribing in the very complex clinical context of multiple comorbid conditions for patients with severely reduced renal function

Non-invasive ventilation versus high-flow nasal cannula oxygen therapy with apnoeic oxygenation for preoxygenation before intubation of patients with acute hypoxaemic respiratory failure: a randomised, multicentre, open-label trial

International audienceBACKGROUND: Non-invasive ventilation has never been compared with high-flow oxygen to determine whether it reduces the risk of severe hypoxaemia during intubation. We aimed to determine if preoxygenation with non-invasive ventilation was more efficient than high-flow oxygen in reducing the risk of severe hypoxaemia during intubation. METHODS: The FLORALI-2 multicentre, open-label trial was done in 28 intensive care units in France. Adult patients undergoing tracheal intubation for acute hypoxaemic respiratory failure (a partial pressure of arterial oxygen [PaO2] to fraction of inspired oxygen [FiO2] ratio of \textless/=300 mm Hg) were randomly assigned (1:1; block size, four participants) to non-invasive ventilation or high-flow oxygen during preoxygenation, with stratification by PaO2/FiO2 ratio (\textless/=200 mm Hg vs \textgreater200 mm Hg). Key exclusion criteria were intubation for cardiac arrest, altered consciousness (defined as a Glasgow coma score of less than eight points), other contraindications to non-invasive ventilation (recent laryngeal, oesophageal, or gastric surgery, and substantial facial fractures), pulse oximetry not available, pregnant or breastfeeding women, and refusal to participate. The primary outcome was the occurrence of severe hypoxaemia (pulse oximetry \textless80%) during the procedure, assessed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT02668458. FINDINGS: Between April 15, 2016, and Jan 8, 2017, 2079 patients were intubated in the 28 participating units, and 322 were enrolled. We excluded five patients with no recorded data, two who withdrew consent or were under legal protection, one who was not intubated, and one who had a cardiac arrest. Of the 313 patients included in the intention-to-treat analysis, 142 were assigned to non-invasive ventilation and 171 to high-flow oxygen therapy. Severe hypoxaemia occurred in 33 (23%) of 142 patients after preoxygenation with non-invasive ventilation and 47 (27%) of 171 with high-flow oxygen (absolute difference -4.2%, 95% CI -13.7 to 5.5; p=0.39). In the 242 patients with moderate-to-severe hypoxaemia (PaO2/FiO2 \textless/=200 mm Hg), severe hypoxaemia occurred less frequently after preoxygenation with non-invasive ventilation than with high-flow oxygen (28 [24%] of 117 patients vs 44 [35%] of 125; adjusted odds ratio 0.56, 0.32 to 0.99, p=0.0459). Serious adverse events did not differ between treatment groups, with the most common immediate complications being systolic arterial hypotension (70 [49%] patients in the non-invasive ventilation group vs 86 [50%] patients in the high-flow oxygen group) and chest infiltrate on x-ray (28 [20%] vs 33 [19%]), and the most common late complications being death at day 28 (53 [37%] vs 58 [34%]) and ventilator-associated pneumonia during ICU stay (31 [22%] vs 35 [20%]). INTERPRETATION: In patients with acute hypoxaemic respiratory failure, preoxygenation with non-invasive ventilation or high-flow oxygen therapy did not change the risk of severe hypoxaemia. Future research should explore the effect of preoxygenation method in patients with moderate-to-severe hypoxaemia at baseline. FUNDING: French Ministry of Health