Carlos Ferrando

Open Lung Approach for the Acute Respiratory Distress Syndrome: A Pilot, Randomized Controlled Trial*

Objective:The open lung approach is a mechanical ventilation strategy involving lung recruitment and a decremental positive end-expiratory pressure trial. We compared the Acute Respiratory Distress Syndrome network protocol using low levels of positive end-expiratory pressure with open lung approach resulting in moderate to high levels of positive end-expiratory pressure for the management of established moderate/severe acute respiratory distress syndrome. Design:A prospective, multicenter, pilot, randomized controlled trial. Setting:A network of 20 multidisciplinary ICUs. Patients:Patients meeting the American-European Consensus Conference definition for acute respiratory distress syndrome were considered for the study. Interventions:At 12-36 hours after acute respiratory distress syndrome onset, patients were assessed under standardized ventilator settings (FIO2≥0.5, positive end-expiratory pressure ≥10 cm H2O). If Pao2/FIO2 ratio remained less than or equal to 200 mm Hg, patients were randomized to open lung approach or Acute Respiratory Distress Syndrome network protocol. All patients were ventilated with a tidal volume of 4 to 8 ml/kg predicted body weight. Measurements and Main Results:From 1,874 screened patients with acute respiratory distress syndrome, 200 were randomized: 99 to open lung approach and 101 to Acute Respiratory Distress Syndrome network protocol. Main outcome measures were 60-day and ICU mortalities, and ventilator-free days. Mortality at day-60 (29% open lung approach vs. 33% Acute Respiratory Distress Syndrome Network protocol, p = 0.18, log rank test), ICU mortality (25% open lung approach vs. 30% Acute Respiratory Distress Syndrome network protocol, p = 0.53 Fisher’s exact test), and ventilator-free days (8 [0-20] open lung approach vs. 7 [0-20] d Acute Respiratory Distress Syndrome network protocol, p = 0.53 Wilcoxon rank test) were not significantly different. Airway driving pressure (plateau pressure - positive end-expiratory pressure) and PaO2/FIO2 improved significantly at 24, 48 and 72 hours in patients in open lung approach compared with patients in Acute Respiratory Distress Syndrome network protocol. Barotrauma rate was similar in both groups. Conclusions:In patients with established acute respiratory distress syndrome, open lung approach improved oxygenation and driving pressure, without detrimental effects on mortality, ventilator-free days, or barotrauma. This pilot study supports the need for a large, multicenter trial using recruitment maneuvers and a decremental positive end-expiratory pressure trial in persistent acute respiratory distress syndrome.

Anidulafungin dosing in critically ill patients with continuous venovenous haemodiafiltration

BACKGROUND Anidulafungin is indicated as a first-line treatment for invasive candidiasis in critically ill patients. In the intensive care unit, sepsis is the main cause of acute renal failure, and treatment with continuous renal replacement therapy (CRRT) has increased in recent years. Antimicrobial pharmacokinetics is affected by CRRT, but few studies have addressed the optimal dosage for anidulafungin during CRRT. PATIENTS AND METHODS We included 12 critically ill patients who received continuous venovenous haemodiafiltration to treat acute renal failure. Anidulafungin was infused on 3 consecutive days, starting with a loading dose (200 mg) on Day 1, and doses of 100 mg on Days 2 and 3. Blood and ultradiafiltrate samples were collected on Day 3 (during steady-state) before, and at regular intervals after, the infusion had started. Anidulafungin concentrations were determined with HPLC. RESULTS On Day 3, peak plasma concentrations with the 100 mg dose were 6.2 ± 1.7 mg/L and 7.1 ± 1.9 mg/L in the arterial and venous samples, respectively. The mean, pre-filter trough concentration was 3.0 ± 0.6 mg/L. The mean AUC0-24 values for plasma anidulafungin were 93.9 ± 19.4 and 104.1 ± 20.3mg·h/L in the arterial and venous samples, respectively. There was no adsorption to synthetic surfaces, and the anidulafungin concentration in the ultradiafiltrate was below the limit of detection. CONCLUSION The influence of CRRT on anidulafungin elimination appeared to be negligible. Therefore, we recommend no adjustments to the anidulafungin dose for patients receiving CRRT.

Sevoflurane, but not propofol, reduces the lung inflammatory response and improves oxygenation in an acute respiratory distress syndrome model: a randomised laboratory study.

CONTEXT Acute respiratory distress syndrome is characterised by activation of the inflammatory cascade. The only treatment that reduces the mortality rate associated with this syndrome is lung protective ventilation, which requires sedation of patients. Sedation in critical care units is usually induced intravenously, although there is reason to believe that inhaled anaesthetics are a suitable alternative. Sevoflurane has recently been shown to modulate the lung inflammatory response in a model of lung injury more favourably than propofol. OBJECTIVE The goal of this study was to confirm whether or not sevoflurane is more effective than propofol in ameliorating the inflammatory response in an animal model of acute respiratory distress syndrome. DESIGN A prospective, randomised, controlled study. SETTING Research foundation laboratory at the Hospital Clínico Universitario, Valencia, Spain. EXPERIMENTAL ANIMALS Sixteen Landrace/large white crossbred pigs weighing 30 to 45 kg. INTERVENTIONS Animals were allocated randomly to one of two groups: one sedated with intravenous propofol 5 to 7 mg kg−1 h−1 (group P) and the other with sevoflurane, administered using an AnaConDa device to obtain an end-tidal concentration of 1.5% (group S). Monitoring, lung protective ventilation and anaesthetic management were identical in both groups. MAIN OUTCOME MEASURES The PaO2/FiO2 ratio and cytokine concentrations in bronchoalveolar lavage specimens were determined at 10, 150 and 240 min after confirmation of acute respiratory distress syndrome (PaO2/FiO2 <26.7 kPa). RESULTS At 240 min, median and interquartile range (IQR) concentrations of cytokines in bronchial lavage specimens in group S were lower than those in group P [interleukin-1&bgr; (IL-1&bgr;) 53, IQR 16–140 vs. 311, IQR 183–637 pg ml−1, P = 0.04; tumour necrosis factor-&agr; 347, IQR 161–433 vs. 552, IQR 475–649 pg ml−1, P = 0.04; and IL-6 101, IQR 76–282 vs. 580, IQR 369–701 pg ml−1, P = 0.03]. The polymorphonuclear neutrophil count was also lower in group S (P = 0.007), which also had a higher PaO2/FiO2 ratio. TRIAL REGISTRATION GE-015/09. CONCLUSION In an animal model of acute respiratory distress syndrome, sevoflurane ameliorates the lung inflammatory response and improves oxygenation to a greater extent than propofol.

Rationale and study design for an individualized perioperative open lung ventilatory strategy (iPROVE): study protocol for a randomized controlled trial

BackgroundPostoperative pulmonary and non-pulmonary complications are common problems that increase morbidity and mortality in surgical patients, even though the incidence has decreased with the increased use of protective lung ventilation strategies. Previous trials have focused on standard strategies in the intraoperative or postoperative period, but without personalizing these strategies to suit the needs of each individual patient and without considering both these periods as a global perioperative lung-protective approach. The trial presented here aims at comparing postoperative complications when using an individualized ventilatory management strategy in the intraoperative and immediate postoperative periods with those when using a standard protective ventilation strategy in patients scheduled for major abdominal surgery.MethodsThis is a comparative, prospective, multicenter, randomized, and controlled, four-arm trial that will include 1012 patients with an intermediate or high risk for postoperative pulmonary complications. The patients will be divided into four groups: (1) individualized perioperative group: intra- and postoperative individualized strategy; (2) intraoperative individualized strategy + postoperative continuous positive airway pressure (CPAP); (3) intraoperative standard ventilation + postoperative CPAP; (4) intra- and postoperative standard strategy (conventional strategy). The primary outcome is a composite analysis of postoperative complications.DiscussionThe Individualized Perioperative Open-lung Ventilatory Strategy (iPROVE) is the first multicenter, randomized, and controlled trial to investigate whether an individualized perioperative approach prevents postoperative pulmonary complications.Trial registrationRegistered on 5 June 2014 with identification no. NCT02158923.

Age, PaO2/FIO2, and Plateau Pressure Score: A Proposal for a Simple Outcome Score in Patients With the Acute Respiratory Distress Syndrome.

Objectives: Although there is general agreement on the characteristic features of the acute respiratory distress syndrome, we lack a scoring system that predicts acute respiratory distress syndrome outcome with high probability. Our objective was to develop an outcome score that clinicians could easily calculate at the bedside to predict the risk of death of acute respiratory distress syndrome patients 24 hours after diagnosis. Design: A prospective, multicenter, observational, descriptive, and validation study. Setting: A network of multidisciplinary ICUs. Patients: Six-hundred patients meeting Berlin criteria for moderate and severe acute respiratory distress syndrome enrolled in two independent cohorts treated with lung-protective ventilation. Interventions: None. Measurements and Main Results: Using individual demographic, pulmonary, and systemic data at 24 hours after acute respiratory distress syndrome diagnosis, we derived our prediction score in 300 acute respiratory distress syndrome patients based on stratification of variable values into tertiles, and validated in an independent cohort of 300 acute respiratory distress syndrome patients. Primary outcome was in-hospital mortality. We found that a 9-point score based on patient’s age, PaO2/FIO2 ratio, and plateau pressure at 24 hours after acute respiratory distress syndrome diagnosis was associated with death. Patients with a score greater than 7 had a mortality of 83.3% (relative risk, 5.7; 95% CI, 3.0–11.0), whereas patients with scores less than 5 had a mortality of 14.5% (p < 0.0000001). We confirmed the predictive validity of the score in a validation cohort. Conclusions: A simple 9-point score based on the values of age, PaO2/FIO2 ratio, and plateau pressure calculated at 24 hours on protective ventilation after acute respiratory distress syndrome diagnosis could be used in real time for rating prognosis of acute respiratory distress syndrome patients with high probability.

A Quantile Analysis of Plateau and Driving Pressures: Effects on Mortality in Patients With Acute Respiratory Distress Syndrome Receiving Lung-protective Ventilation.

Objectives: The driving pressure (plateau pressure minus positive end-expiratory pressure) has been suggested as the major determinant for the beneficial effects of lung-protective ventilation. We tested whether driving pressure was superior to the variables that define it in predicting outcome in patients with acute respiratory distress syndrome. Design: A secondary analysis of existing data from previously reported observational studies. Setting: A network of ICUs. Patients: We studied 778 patients with moderate to severe acute respiratory distress syndrome. Interventions: None. Measurements and Main Results: We assessed the risk of hospital death based on quantiles of tidal volume, positive end-expiratory pressure, plateau pressure, and driving pressure evaluated at 24 hours after acute respiratory distress syndrome diagnosis while ventilated with standardized lung-protective ventilation. We derived our model using individual data from 478 acute respiratory distress syndrome patients and assessed its replicability in a separate cohort of 300 acute respiratory distress syndrome patients. Tidal volume and positive end-expiratory pressure had no impact on mortality. We identified a plateau pressure cut-off value of 29 cm H2O, above which an ordinal increment was accompanied by an increment of risk of death. We identified a driving pressure cut-off value of 19 cm H2O where an ordinal increment was accompanied by an increment of risk of death. When we cross tabulated patients with plateau pressure less than 30 and plateau pressure greater than or equal to 30 with those with driving pressure less than 19 and driving pressure greater than or equal to 19, plateau pressure provided a slightly better prediction of outcome than driving pressure in both the derivation and validation cohorts (p < 0.0000001). Conclusions: Plateau pressure was slightly better than driving pressure in predicting hospital death in patients managed with lung-protective ventilation evaluated on standardized ventilator settings 24 hours after acute respiratory distress syndrome onset.

Protection strategies during cardiopulmonary bypass: ventilation, anesthetics and oxygen.

Purpose of review To provide an update of research findings regarding the protection strategies utilized for patients undergoing cardiopulmonary bypass (CPB), including perioperative ventilatory strategies, different anesthetic regimens, and inspiratory oxygen fraction. The article will review and comment on some of the most important findings in this field to provide a global view of strategies that may improve patient outcomes by reducing inflammation. Recent findings Postoperative complications are directly related to ischemia and inflammation. The application of lung-protective ventilation with lower tidal volumes and higher positive end-expiratory pressure reduces inflammation, thereby reducing postoperative pulmonary complications. Although inhalation anesthesia has clear cardioprotective effects compared with intravenous anesthesia, several factors can interfere to reduce cardioprotection. Hyperoxia up to 0.8 FiO2 may confer benefits without increasing oxidative stress or postoperative pulmonary complications. During the early postoperative period, inhalation anesthesia prior to extubation and the application of preventive noninvasive ventilation may reduce cardiac and pulmonary complications, improving patients’ outcomes. Summary Lung-protective mechanical ventilation, inhalation anesthesia, and high FiO2 have the potential to reduce postoperative complications in patients undergoing CPB; however, larger, well powered, randomized control trials are still needed.

WHO Needs High FIO2

World Health Organization and the United States Center for Disease Control have recently recommended the use of 0.8 FIO2 in all adult surgical patients undergoing general anaesthesia, to prevent surgical site infections. This recommendation has arisen several discussions: As a matter of fact, there are numerous studies with different results about the effect of FIO2 on surgical site infection. Moreover, the clinical effects of FIO2 are not limited to infection control. We asked some prominent authors about their comments regarding the recent recommendations.

Pharmacokinetics of anidulafungin during albumin dialysis

In the ICU setting, current guidelines recommend echi-nocandins as the first-line treatment for invasive candi-diasis [1]. Albumin dialysis (AD) has been used in theICU as supportive therapy for hepatic failure, but thistechnique can significantly enhance drug elimination [2].We prescribed anidulafungin for suspected invasivecandidiasis in a patient with severe liver failure treatedwith AD and measured the plasma concentrations of thedrug using high-performance liquid chromatography.This study (GEF-ANI-2010-02) was approved by thelocal ethics committee (INCLIVA, Institute of Research,Valencia, Spain) and written informed consent wasobtained from the patient’s next of kin. An adult patientwas admitted to our ICU with acute liver failure aftermajor hepatectomy for metastasis. The patient was givenanidulafungin (200 mg loading dose on day 1, followedby 100 mg daily) for suspected invasive candidiasis. Onthe fourth day, the patient developed encephalopathyand complained of increasing pruritus. AD using theMolecular Adsorbent Recirculating System (GambroHospal AG, Zurich, Switzerland) was therefore startedwhile waiting for liver function to improve. Arterialblood, urine, and dialysate samples were collected atdifferent times after the first AD session was initiated:before starting the fourth anidulafungin infusion and at0.5, 1, 1.5, 2, 4, 6, and 8 hours after starting the infusion.The last samples (8 hours) were obtained when AD wasfinished. Anidulafungin was well tolerated withoutrelevant adverse effects.The following pharmacokinetic parameters were calcu-lated: area under the concentration curve from 0 to 8 hoursusing the linear trapezoidal rule, and the eliminationhalf-life with noncompartmental analysis. The values forthe peak plasma concentration, the through plasma con-centration, and the time to reach the peak plasma concen-tration were calculated from the observed values (Figure 1).Plasma, urine, and dialysate samples were analysed.The limit of quantification was 0.5 mg/l. No anidulafun-gin levels were measurable in the ultradiafiltrate andurine samples. The peak plasma concentration with the100 mg dose on day 4 was 9.45 mg/l (Figure 1).Only two reports regarding the use of antifungals duringAD were found in the literature, demonstrating that theinfluence of this technique on drug elimination appeared tobe negligible [3,4]. We report the first pharmacokineticstudy of anidulafungin during AD. Although the mainlimitation of our study is the enrolment of only one patientand the sampling being no more than 8 hours, AD appearsto have little influence on the pharmacokinetics of anidula-fungin and an adjustment of the drug dose is probably notrequired. However, further research is needed to confirmour findings.

Extravascular Lung Water Does Not Increase in Hypovolemic Patients after a Fluid-Loading Protocol Guided by the Stroke Volume Variation

Introduction. Circulatory failure secondary to hypovolemia is a common situation in critical care patients. Volume replacement is the first option for the treatment of hypovolemia. A possible complication of volume loading is pulmonary edema, quantified at the bedside by the measurement of extravascular lung water index (ELWI). ELWI predicts progression to acute lung injury (ALI) in patients with risk factors for developing it. The aim of this study was to assess whether fluid loading guided by the stroke volume variation (SVV), in patients presumed to be hypovolemic, increased ELWI or not. Methods. Prospective study of 17 consecutive postoperative, fully mechanically ventilated patients diagnosed with circulatory failure secondary to presumed hypovolemia were included. Cardiac index (CI), ELWI, SVV, and global end-diastolic volume index (GEDI) were determined using the transpulmonary thermodilution technique during the first 12 hours after fluid loading. Volume replacement was done with a strict hemodynamic protocol. Results. Fluid loading produced a significant increase in CI and a decrease in SVV. ELWI did not increase. No correlation was found between the amount of fluids administered and the change in ELWI. Conclusion. Fluid loading guided by SVV in hypovolemic and fully mechanically ventilated patients in sinus rhythm does not increase ELWI.