Oxygen consumption is depressed in patients with lactic acidosis due to biguanide intoxication

INTRODUCTION: Lactic acidosis can develop during biguanide (metformin and phenformin) intoxication, possibly as a consequence of mitochondrial dysfunction. To verify this hypothesis, we investigated whether body oxygen consumption (VO2), that primarily depends on mitochondrial respiration, is depressed in patients with biguanide intoxication. METHODS: Multicentre retrospective analysis of data collected from 24 patients with lactic acidosis (pH 6.93 +/- 0.20; lactate 18 +/- 6 mM at hospital admission) due to metformin (n = 23) or phenformin (n = 1) intoxication. In 11 patients, VO2 was computed as the product of simultaneously recorded arterio-venous difference in O2 content [C(a-v)O2] and cardiac index (CI). In 13 additional cases, C(a-v)O2, but not CI, was available. RESULTS: On day 1, VO2 was markedly depressed (67 +/- 28 ml/min/m2) despite a normal CI (3.4 +/- 1.2 L/min/m2). C(a-v)O2 was abnormally low in both patients either with (2.0 +/- 1.0 ml O2/100 ml) or without (2.5 +/- 1.1 ml O2/100 ml) CI (and VO2) monitoring. Clearance of the accumulated drug was associated with the resolution of lactic acidosis and a parallel increase in VO2 (P < 0.001) and C(a-v)O2 (P < 0.05). Plasma lactate and VO2 were inversely correlated (R2 0.43; P < 0.001, n = 32). CONCLUSIONS: VO2 is abnormally low in patients with lactic acidosis due to biguanide intoxication. This finding is in line with the hypothesis of inhibited mitochondrial respiration and consequent hyperlactatemia

Enteral versus intravenous approach for the sedation of critically ill patients: a randomized and controlled trial

Background. ICU patients must be kept conscious, calm, and cooperative even during the critical phases of illness. Enteral administration of sedative drugs might avoid oversedation, and would be as adequate as intravenous for awake patients, with fewer side effects and lower costs. This study compares two sedation strategies, in order to early reach and maintain the light sedation target. Methods. Multicenter, single-blind randomized and controlled trial carried out in 12 Italian ICUs, involving patients with expected mechanical ventilation duration >72 hours at ICU admission and predicted mortality >12% (Simplified Acute Physiology Score II >32 points) during the first 24 ICU hours. Patients were randomly assigned to receive intravenous (midazolam, propofol) or enteral (hydroxyzine, lorazepam, and melatonin) sedation. Primary outcome: percentage of work shifts with an observed Richmond Agitation-Sedation Scale (RASS) = target RASS \ub1 1. Secondary outcomes: protocol feasibility, delirium- and coma-free days, costs of drugs, length of ICU and hospital stay, ICU, hospital, and one-year mortality. Results. 348 patients were enrolled. There were no differences in the primary outcome: enteral 89.8 [74.1-100], intravenous 94.4 [78-100]%, p=0.20. Enteral-treated patients had more protocol violations: 81 (46.6%) vs 7 (4.2%), p<0.01, more self-extubations: 4 (2.4%) vs 14 (8.1%), p=0.03, a lighter sedative target (RASS = 0): 93 [71-100] vs 83 [61-100]%, p<0.01, and lower total costs for drugs: 2.39 [0.75- 9.78] vs 4.15 [1.20 -20.19] \u20ac/day with mechanical ventilation (p=0.01). Conclusions. Although enteral sedation of critically ill patients is cheaper and permits a lighter sedation target, it is not superior to intravenous sedation for reaching the RASS target. Trial registration. ClinicalTrials.gov, Clinical Trial #NCT01360346, registered 25 March 2011, https://clinicaltrials.gov/ct2/show/NCT01360346. Registered on 25 March 2011

Pentraxin 3 in patients with severe sepsis or shock: the ALBIOS trial

Background: The long pentraxin PTX3 is a key component of the humoral arm of innate immunity related to sepsis severity and mortality. We evaluated the clinical and prognostic significance of circulating PTX3 in the largest cohort ever reported of patients with severe sepsis or septic shock. Materials and methods: Plasma PTX3 was measured on days 1, 2 and 7 after randomization of 958 patients to albumin or crystalloids for fluid resuscitation in the multicentre Albumin Italian Outcome Sepsis (ALBIOS) trial. We tested the association of PTX3 and its changes over time with clinical severity, prevalent and incident organ dysfunctions, 90-day mortality and treatment. Results: PTX3 was high at baseline (72 [33\u2013186] ng/mL) and rose with the severity and number of organ dysfunctions (P &lt; 0\ub7001) and the incidence of subsequent new failures. The PTX3 concentration dropped from day 1 to 7, but this decrease was less pronounced in patients with septic shock (P = 0\ub70004). Higher concentrations of PTX3 on day 1 predicted incident organ dysfunctions. Albumin supplementation was associated with lower levels of PTX3 in patients with septic shock (P = 0\ub7005) but not in those without shock. In a fully adjusted multivariable model, PTX3 on day 7 predicted 90-day mortality. Smaller drops in PTX3 predicted higher 90-day mortality. Conclusions: In severe sepsis and septic shock, early high PTX3 predict subsequent new organ failures, while a smaller drop in circulating PTX3 over time predicts an increased risk of death. Patients with septic shock show lower levels of PTX3 when assigned to albumin than to crystalloids