José A. Lorente

Recombinant human platelet-activating factor acetylhydrolase for treatment of severe sepsis: Results of a phase III, multicenter, randomized, double-blind, placebo-controlled, clinical trial

ObjectivePlatelet-activating factor (PAF) and structurally-related oxidized phospholipids are proinflammatory mediators in systemic inflammatory states such as severe sepsis. The enzyme platelet-activating factor acetylhydrolase (PAF-AH) rapidly degrades PAF and oxidized phospholipids into inactive metabolites. Reduced PAF-AH activity has been observed in patients with severe sepsis and may contribute to their systemic inflammatory response and organ dysfunction. A previous clinical trial with recombinant human PAF-AH (rPAF-AH, Pafase) suggested that this treatment may decrease 28-day all-cause mortality in patients with severe sepsis. The current study was undertaken to confirm this result. DesignA prospective, randomized, double-blind, placebo-controlled, multicenter, international trial. SettingOne hundred forty-six intensive care units from nine countries. PatientsApproximately 2,522 patients were planned to be enrolled ≤12 hrs after the onset of severe sepsis. Eligible patients were randomized to receive either rPAF-AH 1.0 mg/kg or placebo administered intravenously once daily for five consecutive days. Measurements and Main ResultsThe study was terminated based on the recommendation of an independent data and safety monitoring committee after the second of three planned interim analyses, and the enrollment of 1,425 patients. rPAF-AH treatment was well tolerated among the 1,261 patients included in the interim analysis (643 rPAF-AH and 618 placebo), but did not decrease 28-day all-cause mortality compared with placebo (25% for rPAF-AH vs. 24% for placebo; relative risk, 1.03; 95% confidence interval, 0.85–1.25; p = .80). There were no statistically significant differences between treatment groups in any of the secondary efficacy end points. The overall incidence of adverse events was similar among rPAF-AH and placebo-treated patients, and no rPAF-AH-treated patients developed antibodies to PAF-AH. ConclusionsrPAF-AH was well tolerated and not antigenic, but did not decrease 28-day all-cause mortality in patients with severe sepsis.

A model for predicting mortality among critically ill burn victims

OBJECTIVEnTo develop a model for predicting mortality among burn victims.nnnMETHODSnAll casualties admitted to our intensive care burn unit (ICBU) with a diagnosis of thermal or inhalation injury were studied. Age, total and full-thickness body surface area (BSA) burned, presence of inhalation injury, gender, mechanism of injury, delay to ICBU admission and mechanical ventilation during the first 72 h were recorded. The 851 participants were randomly divided into derivation (671) and validation (180) sets. From univariate and multivariate logistic regression analyses a mortality predictive equation was derived.nnnRESULTSnMortality was 17.6%. In univariate analysis, all variables were significantly associated with mortality except mechanism of injury and delay to ICBU admission. In multivariate analysis, age, total and full-thickness BSA burned, female gender and early mechanical ventilation were independently associated with mortality.nnnCONCLUSIONSnWe propose a mortality predictive equation for burned victims. In this model, MV and not inhalation injury is a mortality risk factor.

Role of free radicals in vascular dysfunction induced by high tidal volume ventilation

ObjectiveTo demonstrate that increased formation of reactive oxygen (ROS) and nitrogen species (RNS) is involved in VILI-induced vascular dysfunction.MethodsMale Sprague-Dawley anesthetized rats were ventilated for 60xa0min using low VT ventilation [VT 9xa0ml/kg, positive end-expiratory pressure (PEEP) 5xa0cmH2O, nxa0=xa018], and high VT ventilation (VT 35xa0ml/kg, zero PEEP, nxa0=xa018). Arterial pressure and respiratory system mechanics were monitored. Blood samples for the determination of arterial blood gases and lactate concentration were drawn. Vascular rings from the thoracic aortae were mounted in organ baths for isometric tension recording. We studied endothelium-dependent relaxation in norepinephrine-precontracted rings (acetylcholine, 10xa0nM–10xa0μM) and contraction induced by norepinephrine (1xa0nM–10xa0μM) in resting vessels. Vascular rings were preincubated for 30xa0min with Zn–Mn–SOD (100xa0u/ml) or tempol (10−4xa0M) (extracellular and intracellular superoxide scavengers, respectively) or MnTMPyP (10−5xa0M) (a superoxide and peroxynitrite scavenger). The presence of superoxide and nitrotyrosine in aortic rings was evaluated by immunofluorescence.ResultsHigh VT ventilation induced hypotension, systemic acidosis, hypoxemia and hyperlactatemia, as well as impairment in acetylcholine and norepinephrine-induced responses inxa0vitro. Responses to acetylcholine were improved by tempol (Pxa0=xa00.004) and completely corrected (Pxa0<xa00.001) by MnTMPyP. Responses to norepinephrine were also improved by treatment with tempol (Pxa0<xa00.001) and MnTMPyP (Pxa0<xa00.001). However, Zn–Mn–SOD did not improve acetylcholine- or norepinephrine-induced responses. Immunostaining for both superoxide and nitrotyrosine was increased in aortic rings from the high VT group.ConclusionsOur data support a role for intracellular ROS and peroxynitrite in the high VT ventilation-induced vascular dysfunction.

Safety and Pharmacokinetics of Intravenous Zanamivir Treatment in Hospitalized Adults With Influenza: An Open-label, Multicenter, Single-Arm, Phase II Study

Abstract Background.u2003Intravenous zanamivir is a neuraminidase inhibitor suitable for treatment of hospitalized patients with severe influenza. Methods.u2003Patients were treated with intravenous zanamivir 600 mg twice daily, adjusted for renal impairment, for up to 10 days. Primary outcomes included adverse events (AEs), and clinical/laboratory parameters. Pharmacokinetics, viral load, and disease course were also assessed. Results.u2003One hundred thirty patients received intravenous zanamivir (median, 5 days; range, 1–11) a median of 4.5 days (range, 1–7) after onset of influenza; 83% required intensive care. The most common influenza type/subtype was A/H1N1pdm09 (71%). AEs and serious AEs were reported in 85% and 34% of patients, respectively; serious AEs included bacterial pulmonary infections (8%), respiratory failure (7%), sepsis or septic shock (5%), and cardiogenic shock (5%). No drug-related trends in safety parameters were identified. Protocol-defined liver events were observed in 13% of patients. The 14- and 28-day all-cause mortality rates were 13% and 17%. No fatalities were considered zanamivir related. Pharmacokinetic data showed dose adjustments for renal impairment yielded similar zanamivir exposures. Ninety-three patients, positive at baseline for influenza by quantitative polymerase chain reaction, showed a median decrease in viral load of 1.42 log10 copies/mL after 2 days of treatment. Conclusions.u2003Safety, pharmacokinetic and clinical outcome data support further investigation of intravenous zanamivir. Clinical Trials Registrationu2003NCT01014988.

Cyclosporine Use in Epidermal Necrolysis Is Associated with an Important Mortality Reduction: Evidence from Three Different Approaches

Several immunomodulatory agents are used in the treatment of epidermal necrolysis, but evidence of their efficacy is limited. The Autonomous Community of Madrid has two reference burn units to which all patients with epidermal necrolysis are referred. One burn unit has mostly used cyclosporine (CsA), and the other has used non-CsA therapies (mainly high-dose intravenous immunoglobulin). The allocation of patients to one or the other burn unit was mainly based on proximity, resembling a random assignment. Thus, we took advantage of this natural experiment to estimate the mortality risk ratio (MRR) of CsA (nxa0= 26) compared with non-CsA (nxa0= 16) treatment using hospital as an instrumental variable over the period from 2001 to 2015. We also computed the observed versus expected (O/E) MRR in a case series of 49 CsA-treated patients (including 23 patients from other regions treated in Madrid), and using the Score for Toxic Epidermal Necrolysis (i.e., SCORTEN) scale to estimate the expected values. The instrumental variable-based MRR of CsA versus non-CsA was 0.09 (95% confidence intervalxa0= 0.00-0.49). The O/E analysis also showed a reduction in mortality risk (MRROExa0= 0.42; 95% confidence intervalxa0= 0.14-0.99). We identified five other case series of CsA-treated patients providing MRROE and meta-analyzed their results. The pooled MRROE (including from this study) was 0.41 (95% confidence intervalxa0= 0.21-0.80). All three approaches consistently show that CsA reduces the mortality in epidermal necrolysis patients.

Genetic predisposition to acute kidney injury induced by severe sepsis

PURPOSEnThe aim of this study was to demonstrate that candidate gene polymorphisms are associated with an increased risk of acute kidney injury (AKI).nnnMATERIALS AND METHODSnPatients admitted to the intensive care unit with the diagnosis of severe sepsis and an expected intensive care unit length of stay more than 48 hours were included. Genetic polymorphisms studied included angiotensin-converting enzyme insertion/deletion (polymerase chain reaction); tumor necrosis factor α -376, - 308, and -238; interleukin-8 -251; vascular endothelial growth factor (VEGF) +405 and +936; and pre-B-cell colony-enhancing factor -1001 (TaqMan SNP genotyping assay, Life Technologies, Grand Island, NY). Acute kidney injury was defined as the risk, injury, and failure categories, as per the RIFLE (risk, injury, failure, loss, end-stage kidney disease) classification.nnnRESULTSnOne hundred thirty-nine patients were included, 65 of whom developed AKI. In univariate analysis, the VEGF +936 CC and the pre-B-cell colony-enhancing factor -1001 GG genotypes were associated with AKI. In multivariate analysis, Simplified Acute Physiology Score II score (odds ratio [95% confidence interval], 1.06 [1.03-1.09]), chronic arterial hypertension (3.15 [1.39-7.15]), and the presence of the VEGF +936 CC genotype (3.41 [1.19-9.79]) were associated with AKI.nnnCONCLUSIONnThis is the first study demonstrating an association between the VEGF +936 CC genotype and the risk to develop AKI in patients with severe sepsis.

Influence of mechanical ventilation and sepsis on redox balance in diaphragm, myocardium, limb muscles, and lungs

Mechanical ventilation (MV), using high tidal volumes (V(T)), causes lung (ventilator-induced lung injury [VILI]) and distant organ injury. Additionally, sepsis is characterized by increased oxidative stress. We tested whether MV is associated with enhanced oxidative stress in sepsis, the commonest underlying condition in clinical acute lung injury. Protein carbonylation and nitration, antioxidants, and inflammation (immunoblotting) were evaluated in diaphragm, gastrocnemius, soleus, myocardium, and lungs of nonseptic and septic (cecal ligation and puncture 24 hours before MV) rats undergoing MV (n = 7 per group) for 150 minutes using 3 different strategies (low V(T) [V(T) = 9 mL/kg], moderate V(T) [V(T) = 15 mL/kg], and high V(T) [V(T) = 25 mL/kg]) and in nonventilated control animals. Compared with nonventilated control animals, in septic and nonseptic rodents (1) diaphragms, limb muscles, and myocardium of high-V(T) rats exhibited a decrease in protein oxidation and nitration levels, (2) antioxidant levels followed a specific fiber-type distribution in slow- and fast-twitch muscles, (3) tumor necrosis factor α (TNF-α) levels were higher in respiratory and limb muscles, whereas no differences were observed in myocardium, and (4) in lungs, protein oxidation was increased, antioxidants were rather decreased, and TNF-α remained unmodified. In this model of VILI, oxidative stress does not occur in distant organs or skeletal muscles of rodents after several hours of MV with moderate-to-high V(T), whereas protein oxidation levels were increased in the lungs of the animals. Inflammatory events were moderately expressed in skeletal muscles and lungs of the MV rats. Concomitant sepsis did not strongly affect the MV-induced effects on muscles, myocardium, or lungs in the rodents.

Geo-economic variations in epidemiology, patterns of care, and outcomes in patients with acute respiratory distress syndrome: insights from the LUNG SAFE prospective cohort study

BACKGROUNDnLittle information is available about the geo-economic variations in demographics, management, and outcomes of patients with acute respiratory distress syndrome (ARDS). We aimed to characterise the effect of these geo-economic variations in patients enrolled in the Large Observational Study to Understand the Global Impact of Severe Acute Respiratory Failure (LUNG SAFE).nnnMETHODSnLUNG SAFE was done during 4 consecutive weeks in winter, 2014, in a convenience sample of 459 intensive-care units in 50 countries across six continents. Inclusion criteria were admission to a participating intensive-care unit (including transfers) within the enrolment window and receipt of invasive or non-invasive ventilation. One of the trials secondary aims was to characterise variations in the demographics, management, and outcome of patients with ARDS. We used the 2016 World Bank countries classification to define three major geo-economic groupings, namely European high-income countries (Europe-High), high-income countries in the rest of the world (rWORLD-High), and middle-income countries (Middle). We compared patient outcomes across these three groupings. LUNG SAFE is registered with ClinicalTrials.gov, number NCT02010073.nnnFINDINGSnOf the 2813 patients enrolled in LUNG SAFE who fulfilled ARDS criteria on day 1 or 2, 1521 (54%) were recruited from Europe-High, 746 (27%) from rWORLD-High, and 546 (19%) from Middle countries. We noted significant geographical variations in demographics, risk factors for ARDS, and comorbid diseases. The proportion of patients with severe ARDS or with ratios of the partial pressure of arterial oxygen (PaO2) to the fractional concentration of oxygen in inspired air (FiO2) less than 150 was significantly lower in rWORLD-High countries than in the two other regions. Use of prone positioning and neuromuscular blockade was significantly more common in Europe-High countries than in the other two regions. Adjusted duration of invasive mechanical ventilation and length of stay in the intensive-care unit were significantly shorter in patients in rWORLD-High countries than in Europe-High or Middle countries. High gross national income per person was associated with increased survival in ARDS; hospital survival was significantly lower in Middle countries than in Europe-High or rWORLD-High countries.nnnINTERPRETATIONnImportant geo-economic differences exist in the severity, clinician recognition, and management of ARDS, and in patients outcomes. Income per person and outcomes in ARDS are independently associated.nnnFUNDINGnEuropean Society of Intensive Care Medicine, St Michaels Hospital, University of Milan-Bicocca.

Acute respiratory distress syndrome: does histology matter?

Kao et al. have reported in Critical Care the histological findings of 101 patients with acute respiratory distress syndrome (ARDS) undergoing open lung biopsy. Diffuse alveolar damage (DAD), the histological hallmark of ARDS, was present in only 56.4xa0% of cases. The presence of DAD was associated with higher mortality. Evidence from this and other studies indicates that the clinical criteria for the diagnosis of ARDS identify DAD in only about half of the cases. On the contrary, there is evidence that the clinical course and outcome of ARDS differs in patients with DAD and in patients without DAD. The discovery of biomarkers for the physiological (increased alveolocapillary permeability) or histological (DAD) hallmarks of ARDS is thus of paramount importance.

Hemodynamic management of critically ill burn patients: an international survey

Hemodynamic management of critically ill burn patients: an international survey Sabri Soussi, Mette M. Berger, Kirsten Colpaert, Martin W. Dünser, Anne Berit Guttormsen, Nicole P. Juffermans, Paul Knape, Guniz Koksal, Athina Lavrentieva, Thomas Leclerc, José A. Lorente, Ignacio Martin-Loeches, Philipp Metnitz, Olivier Pantet, Paolo Pelosi, Anne-Françoise Rousseau, Folke Sjöberg, Matthieu Legrand and for the ESICM Burn ICU working group