Daniela Pasero

Effect of a Lung Protective Strategy for Organ Donors on Eligibility and Availability of Lungs for Transplantation A Randomized Controlled Trial

CONTEXT Many potential donor lungs deteriorate between the time of brain death and evaluation for transplantation suitability, possibly because of the ventilatory strategy used after brain death. OBJECTIVE To test whether a lung protective strategy increases the number of lungs available for transplantation. DESIGN, SETTING, AND PATIENTS Multicenter randomized controlled trial of patients with beating hearts who were potential organ donors conducted at 12 European intensive care units from September 2004 to May 2009 in the Protective Ventilatory Strategy in Potential Lung Donors Study. Interventions Potential donors were randomized to the conventional ventilatory strategy (with tidal volumes of 10-12 mL/kg of predicted body weight, positive end-expiratory pressure [PEEP] of 3-5 cm H(2)O, apnea tests performed by disconnecting the ventilator, and open circuit for airway suction) or the protective ventilatory strategy (with tidal volumes of 6-8 mL/kg of predicted body weight, PEEP of 8-10 cm H(2)O, apnea tests performed by using continuous positive airway pressure, and closed circuit for airway suction). MAIN OUTCOME MEASURES The number of organ donors meeting eligibility criteria for harvesting, number of lungs harvested, and 6-month survival of lung transplant recipients. RESULTS The trial was stopped after enrolling 118 patients (59 in the conventional ventilatory strategy and 59 in the protective ventilatory strategy) because of termination of funding. The number of patients who met lung donor eligibility criteria after the 6-hour observation period was 32 (54%) in the conventional strategy vs 56 (95%) in the protective strategy (difference of 41% [95% confidence interval {CI}, 26.5% to 54.8%]; P <.001). The number of patients in whom lungs were harvested was 16 (27%) in the conventional strategy vs 32 (54%) in the protective strategy (difference of 27% [95% CI, 10.0% to 44.5%]; P = .004). Six-month survival rates did not differ between recipients who received lungs from donors ventilated with the conventional strategy compared with the protective strategy (11/16 [69%] vs 24/32 [75%], respectively; difference of 6% [95% CI, -22% to 32%]). CONCLUSION Use of a lung protective strategy in potential organ donors with brain death increased the number of eligible and harvested lungs compared with a conventional strategy. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00260676.

Patient-ventilator interaction and sleep in mechanically ventilated patients: pressure support versus proportional assist ventilation.

Objectives:To understand the role of patient-ventilator asynchrony in the etiology of sleep disruption and determine whether optimizing patient-ventilator interactions by using proportional assist ventilation improves sleep. Design:Randomized crossover clinical trial. Setting:A tertiary university medical-surgical intensive care unit. Patients:Thirteen patients during weaning from mechanical ventilation. Interventions:Patients were randomized to receive pressure support ventilation or proportional assist ventilation on the first night and then crossed over to the alternative mode for the second night. Polysomnography and measurement of light, noise, esophageal pressure, airway pressure, and flow were performed from 10 pm to 8 am. Ventilator settings (pressure level during pressure support ventilation and resistive and elastic proportionality factors during proportional assist ventilation) were set to obtain a 50% reduction of the inspiratory work (pressure time product per minute) performed during a spontaneous breathing trial. Measurements and Main Results:Arousals per hour of sleep time during pressure support ventilation were 16 (range 2–74) and 9 (range 1–41) during proportional assist ventilation (p = .02). Overall sleep quality was significantly improved on proportional assist ventilation (p < .05) due to the combined effect of fewer arousals per hour, fewer awakenings per hour (3.5 [0–24] vs. 5.5 [1–24]), and greater rapid eye movement (9% [0–31] vs. 4% [0–23]), and slow wave (3% [0–16] vs. 1% [0–10]) sleep. Tidal volume and minute ventilation were lower on proportional assist ventilation, allowing for a greater increase in Paco2 during the night. Patient-ventilator asynchronies per hour were lower with proportional assist ventilation than with pressure support ventilation (24 ± 15 vs. 53 ± 59; p = .02) and correlated with the number of arousals per hour (R2 = .65, p = .0001). Conclusions:Patient ventilator discordance causes sleep disruption. Proportional assist ventilation seems more efficacious than pressure support ventilation in matching ventilatory requirements with ventilator assistance, therefore resulting in fewer patient-ventilator asynchronies and better quality of sleep.

High tidal volume is associated with the development of acute lung injury after severe brain injury : An international observational study

Objective:Although a significant number of patients with severe brain injury develop acute lung injury, only intracranial risk factors have previously been studied. We investigated the role of extracranial predisposing factors, including hemodynamic and ventilatory management, as independent predictors of acute lung injury in brain-injured patients. Design:Prospective multicenter observational study. Setting:Four European intensive care units in university-affiliated hospitals. Patients:Eighty-six severely brain-injured patients enrolled in 13 months. Interventions:None. Measurements and Main Results:All patients with severe brain injury (Glasgow Coma Scale score <9) were studied for 8 days from admission. Ventilatory pattern, respiratory system compliance, blood gas analysis, and hemodynamic profile were recorded and entered in a stepwise regression model. Length of stay in the intensive care unit, ventilator-free days, and mortality were collected. Eighteen patients (22%) developed acute lung injury on day 2.8 ± 1. They were initially ventilated with significantly higher tidal volume per predicted body weight (9.5 ± 1 vs. 10.4 ± 1.1), respiratory rate, and minute ventilation and more often required vasoactive drugs (p < .05). In addition to a lower Pao2/Fio2 (odds ratio 0.98, 95% confidence interval 0.98–0.99), the use of high tidal volume (odds ratio 5.4, 95% confidence interval 1.54–19.24) and relatively high respiratory rate (odds ratio 1.8, 95% confidence interval 1.13–2.86) were independent predictors of acute lung injury (p < .01). After the onset of acute lung injury, patients remained ventilated with similar tidal volumes to maintain mild hypocapnia and had a longer length of stay in the intensive care unit and fewer ventilator-free days (p < .05). Conclusions:In addition to a lower Pao2/Fio2, the use of high tidal volume and high respiratory rate are independent predictors of acute lung injury in patients with severe brain injury. In this patient population, alternative ventilator strategies should be considered to protect the lung and guarantee a tight CO2 control.

Randomized Evidence for Reduction of Perioperative Mortality

OBJECTIVE With more than 220 million major surgical procedures performed annually, perioperative interventions leading to even minor mortality reductions would save thousands of lives per year. This international consensus conference aimed to identify all nonsurgical interventions that increase or reduce perioperative mortality as suggested by randomized evidence. DESIGN AND SETTING A web-based international consensus conference. PARTICIPANTS More than 1,000 physicians from 77 countries participated in this web-based consensus conference. INTERVENTIONS Systematic literature searches (MEDLINE/PubMed, June 8, 2011) were used to identify the papers with a statistically significant effect on mortality together with contacts with experts. Interventions were considered eligible for evaluation if they (1) were published in peer-reviewed journals, (2) dealt with a nonsurgical intervention (drug/technique/strategy) in adult patients undergoing surgery, and (3) provided a statistically significant mortality increase or reduction as suggested by a randomized trial or meta-analysis of randomized trials. MEASUREMENTS AND MAIN RESULTS Fourteen interventions that might change perioperative mortality in adult surgery were identified. Interventions that might reduce mortality include chlorhexidine oral rinse, clonidine, insulin, intra-aortic balloon pump, leukodepletion, levosimendan, neuraxial anesthesia, noninvasive respiratory support, hemodynamic optimization, oxygen, selective decontamination of the digestive tract, and volatile anesthetics. In contrast, aprotinin and extended-release metoprolol might increase mortality. CONCLUSIONS Future research and health care funding should be directed toward studying and evaluating these interventions.

Mortality reduction in cardiac anesthesia and intensive care: results of the first International Consensus Conference

There is no consensus on which drugs/techniques/strategies can affect mortality in the perioperative period of cardiac surgery. With the aim of identifying these measures, and suggesting measures for prioritized future investigation we performed the first International Consensus Conference on this topic. The consensus was a continuous international internet‐based process with a final meeting on 28 June 2010 in Milan at the Vita‐Salute University. Participants included 340 cardiac anesthesiologists, cardiac surgeons, and cardiologists from 65 countries all over the world. A comprehensive literature review was performed to identify topics that subsequently generated position statements for discussion, voting, and ranking. Of the 17 major topics with a documented mortality effect, seven were subsequently excluded after further evaluation due to concerns about clinical applicability and/or study methodology. The following topics are documented as reducing mortality: administration of insulin, levosimendan, volatile anesthetics, statins, chronic β‐blockade, early aspirin therapy, the use of pre‐operative intra‐aortic balloon counterpulsation, and referral to high‐volume centers. The following are documented as increasing mortality: administration of aprotinin and aged red blood cell transfusion. These interventions were classified according to the level of evidence and effect on mortality and a position statement was generated. This International Consensus Conference has identified the non‐surgical interventions that merit urgent study to achieve further reductions in mortality after cardiac surgery: insulin, intra‐aortic balloon counterpulsation, levosimendan, volatile anesthetics, statins, chronic β‐blockade, early aspirin therapy, and referral to high‐volume centers. The use of aprotinin and aged red blood cells may result in increased mortality.

Polymyxin-B hemoperfusion inactivates circulating proapoptotic factors

ObjectiveTo test the hypothesis that extracorporeal therapy with polymyxin B (PMX-B) may prevent Gram-negative sepsis-induced acute renal failure (ARF) by reducing the activity of proapoptotic circulating factors.SettingMedical-Surgical Intensive Care Units.Patients and interventionsSixteen patients with Gram-negative sepsis were randomized to receive standard care (Surviving Sepsis Campaign guidelines) or standard care plus extracorporeal therapy with PMX-B.Measurements and resultsCell viability, apoptosis, polarity, morphogenesis, and epithelial integrity were evaluated in cultured tubular cells and glomerular podocytes incubated with plasma from patients of both groups. Renal function was evaluated as SOFA and RIFLE scores, proteinuria, and tubular enzymes. A significant decrease of plasma-induced proapoptotic activity was observed after PMX-B treatment on cultured renal cells. SOFA and RIFLE scores, proteinuria, and urine tubular enzymes were all significantly reduced after PMX-B treatment. Loss of plasma-induced polarity and permeability of cell cultures was abrogated with the plasma of patients treated with PMX-B. These results were associated to a preserved expression of molecules crucial for tubular and glomerular functional integrity.ConclusionsExtracorporeal therapy with PMX-B reduces the proapoptotic activity of the plasma of septic patients on cultured renal cells. These data confirm the role of apoptosis in the development of sepsis-related ARF.

Effect of fenoldopam on use of renal replacement therapy among patients with acute kidney injury after cardiac surgery: a randomized clinical trial

IMPORTANCE No effective pharmaceutical agents have yet been identified to treat acute kidney injury after cardiac surgery. OBJECTIVE To determine whether fenoldopam reduces the need for renal replacement therapy in critically ill cardiac surgery patients with acute kidney injury. DESIGN, SETTING, AND PARTICIPANTS Multicenter, randomized, double-blind, placebo-controlled, parallel-group study from March 2008 to April 2013 in 19 cardiovascular intensive care units in Italy. We randomly assigned 667 patients admitted to intensive care units after cardiac surgery with early acute kidney injury (≥50% increase of serum creatinine level from baseline or oliguria for ≥6 hours) to receive fenoldopam (338 patients) or placebo (329 patients). We used a computer-generated permuted block randomization sequence for treatment allocation. All patients completed their follow-up 30 days after surgery, and data were analyzed according to the intention-to-treat principle. INTERVENTIONS Continuous infusion of fenoldopam or placebo for up to 4 days with a starting dose of 0.1 μg/kg/min (range, 0.025-0.3 µg/kg/min). MAIN OUTCOMES AND MEASURES The primary end point was the rate of renal replacement therapy. Secondary end points included mortality (intensive care unit and 30-day mortality) and the rate of hypotension during study drug infusion. RESULTS The study was stopped for futility as recommended by the safety committee after a planned interim analysis. Sixty-nine of 338 patients (20%) allocated to the fenoldopam group and 60 of 329 patients (18%) allocated to the placebo group received renal replacement therapy (P = .47). Mortality at 30 days was 78 of 338 (23%) in the fenoldopam group and 74 of 329 (22%) in the placebo group (P = .86). Hypotension occurred in 85 (26%) patients in the fenoldopam group and in 49 (15%) patients in the placebo group (P = .001). CONCLUSIONS AND RELEVANCE Among patients with acute kidney injury after cardiac surgery, fenoldopam infusion, compared with placebo, did not reduce the need for renal replacement therapy or risk of 30-day mortality but was associated with an increased rate of hypotension. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00621790.

Reducing Mortality in Acute Kidney Injury Patients: Systematic Review and International Web-Based Survey

OBJECTIVE To identify all interventions that increase or reduce mortality in patients with acute kidney injury (AKI) and to establish the agreement between stated beliefs and actual practice in this setting. DESIGN AND SETTING Systematic literature review and international web-based survey. PARTICIPANTS More than 300 physicians from 62 countries. INTERVENTIONS Several databases, including MEDLINE/PubMed, were searched with no time limits (updated February 14, 2012) to identify all the drugs/techniques/strategies that fulfilled all the following criteria: (a) published in a peer-reviewed journal, (b) dealing with critically ill adult patients with or at risk for acute kidney injury, and (c) reporting a statistically significant reduction or increase in mortality. MEASUREMENTS AND MAIN RESULTS Of the 18 identified interventions, 15 reduced mortality and 3 increased mortality. Perioperative hemodynamic optimization, albumin in cirrhotic patients, terlipressin for hepatorenal syndrome type 1, human immunoglobulin, peri-angiography hemofiltration, fenoldopam, plasma exchange in multiple-myeloma-associated AKI, increased intensity of renal replacement therapy (RRT), CVVH in severely burned patients, vasopressin in septic shock, furosemide by continuous infusion, citrate in continuous RRT, N-acetylcysteine, continuous and early RRT might reduce mortality in critically ill patients with or at risk for AKI; positive fluid balance, hydroxyethyl starch and loop diuretics might increase mortality in critically ill patients with or at risk for AKI. Web-based opinion differed from consensus opinion for 30% of interventions and self-reported practice for 3 interventions. CONCLUSION The authors identified all interventions with at least 1 study suggesting a significant effect on mortality in patients with or at risk of AKI and found that there is discordance between participant stated beliefs and actual practice regarding these topics.

Ventilatory and hemodynamic management of potential organ donors: an observational survey.

Objective:To determine the current standard ventilatory and cardiovascular management in potential organ donors. Design:Prospective, multiple-center, observational survey. Setting:A total of 15 intensive care units in 13 hospitals in Piedmont, Italy. Patients:A total of 34 brain-dead patients enrolled in 6 months. Measurements and Main Results:Demographics and reasons for lung transplant exclusion were recorded. Ventilatory and hemodynamic variables were compared before and after confirmation of brain death. A total of 23 potential donors were ineligible for lung donation based on pulmonary status and age. Of the 11 eligible lung donors, only two donated the lungs because five had Pao2/Fio2 ratios of <300 and four were ineligible for logistic problems. Tidal volume was 10 ± 2 mL/kg, positive end-expiratory pressure was 3.3 ± 2.7 cm H2O, Fio2 was 50% ± 18% before brain death diagnosis, and no changes were made after brain death confirmation. In potential lung donors, apnea tests were performed with apneic oxygenation after disconnection from the ventilator in all cases; tracheal suction was performed with an open circuit in eight cases, and no recruitment maneuvers were performed. Crystalloid infusion was increased after diagnosis of brain death from 187 ± 151 to 275 ± 158 mL/hr (p < .05), and central venous pressure increased from 6 ± 3 to 7 ± 3 mm Hg (p < .05). Inotropic support was used in 24 donors (70%). Conclusions:Five of 11 potential lung donors (45%) had a Pao2/Fio2 ratio of <300, making them ineligible for lung donation. After the diagnosis of brain death, ventilatory management remained the same, no maneuvers for prevention of derecruitment of the lung were performed, and cardiovascular management was modified to optimize peripheral organ perfusion. These data represent the current standard of care for ventilatory management of potential organ donors and may be suboptimal in preserving lung function. LEARNING OBJECTIVES On completion of this article, the reader should be able to: Explain the issues related to harvesting lungs for transplantation. Describe the management of potential lung donors. Use this information in a clinical setting. All of the authors have disclosed that they have no financial relationships with or interests in any commercial companies pertaining to this educational activity. Wolters Kluwer Health has identified and resolved all faculty conflicts of interest regarding this educational activity. Visit the Critical Care Medicine Web site (www.ccmjournal.org) for information on obtaining continuing medical education credit.

Accuracy of plateau pressure and stress index to identify injurious ventilation in patients with acute respiratory distress syndrome.

Background:Guidelines suggest a plateau pressure (PPLAT) of 30 cm H2O or less for patients with acute respiratory distress syndrome, but ventilation may still be injurious despite adhering to this guideline. The shape of the curve plotting airway pressure versus time (STRESS INDEX) may identify injurious ventilation. The authors assessed accuracy of PPLAT and STRESS INDEX to identify morphological indexes of injurious ventilation. Methods:Indexes of lung aeration (computerized tomography) associated with injurious ventilation were used as a “reference standard.” Threshold values of PPLAT and STRESS INDEX were determined assessing the receiver-operating characteristics (“training set,” N = 30). Accuracy of these values was assessed in a second group of patients (“validation set,” N = 20). PPLAT and STRESS INDEX were partitioned between respiratory system (Pplat,Rs and STRESS INDEX,RS) and lung (PPLAT,L and STRESS INDEX,L; esophageal pressure; “physiological set,” N = 50). Results:Sensitivity and specificity of PPLAT of greater than 30 cm H2O were 0.06 (95% CI, 0.002–0.30) and 1.0 (95% CI, 0.87–1.00). PPLAT of greater than 25 cm H2O and a STRESS INDEX of greater than 1.05 best identified morphological markers of injurious ventilation. Sensitivity and specificity of these values were 0.75 (95% CI, 0.35–0.97) and 0.75 (95% CI, 0.43–0.95) for PPLAT greater than 25 cm H2O versus 0.88 (95% CI, 0.47–1.00) and 0.50 (95% CI, 0.21–0.79) for STRESS INDEX greater than 1.05. Pplat,Rs did not correlate with PPLAT,L (R2 = 0.0099); STRESS INDEX,RS and STRESS INDEX,L were correlated (R2 = 0.762). Conclusions:The best threshold values for discriminating morphological indexes associated with injurious ventilation were Pplat,Rs greater than 25 cm H2O and STRESS INDEX,RS greater than 1.05. Although a substantial discrepancy between Pplat,Rs and PPLAT,L occurs, STRESS INDEX,RS reflects STRESS INDEX,L.