Measuring extravascular lung water: animals and humans are not the same

The evolution of extravascular lung water (EVLW) monitoring is an important step forward in the hemodynamic assessment of critically ill patients

Recombinant human activated protein C ameliorates oleic acid-induced lung injury in awake sheep

Introduction: Acute lung injury (ALI) may arise both after sepsis and non-septic inflammatory conditions and is often associated with the release of fatty acids, including oleic acid (OA). Infusion of OA has been used extensively to mimic ALI. Recent research has revealed that intravenously administered recombinant human activated protein C (rhAPC) is able to counteract ALI. Our aim was to find out whether rhAPC dampens OA-induced ALI in sheep. Methods: Twenty-two yearling sheep underwent instrumentation. After 2 days of recovery, animals were randomly assigned to one of three groups: (a) an OA+rhAPC group (n = 8) receiving OA 0.06 mL/kg infused over the course of 30 minutes in parallel with an intravenous infusion of rhAPC 24 mg/kg per hour over the course of 2 hours, (b) an OA group (n = 8) receiving OA as above, or (c) a sham-operated group (n = 6). After 2 hours, sheep were sacrificed. Hemodynamics was assessed by catheters in the pulmonary artery and the aorta, and extravascular lung water index (EVLWI) was determined with the single transpulmonary thermodilution technique. Gas exchange was evaluated at baseline and at cessation of the experiment. Data were analyzed by analysis of variance; a P value of less than 0.05 was regarded as statistically significant. Results: OA induced profound hypoxemia, increased right atrial and pulmonary artery pressures and EVLWI markedly, and decreased cardiac index. rhAPC counteracted the OA-induced changes in EVLWI and arterial oxygenation and reduced the OA-induced increments in right atrial and pulmonary artery pressures. Conclusions: In ovine OA-induced lung injury, rhAPC dampens the increase in pulmonary artery pressure and counteracts the development of lung edema and the derangement of arterial oxygenation

Extravascular lung water assessed by transpulmonary single thermodilution and postmortem gravimetry in sheep

INTRODUCTION: Acute lung injury is associated with accumulation of extravascular lung water (EVLW). The aim of the present study was to compare two methods for quantification of EVLW: transpulmonary single thermodilution (EVLW(ST)) and postmortem gravimetric (EVLW(G)). METHODS: Eighteen instrumented and awake sheep were randomly assigned to one of three groups. All groups received Ringer's lactate (5 ml/kg per hour intravenously). To induce lung injury of different severities, sheep received Escherichia coli lipopolysaccharide 15 ng/kg per min intravenously for 6 hours (n = 7) or oleic acid 0.06 ml/kg intravenously over 30 min (n = 7). A third group (n = 4) was subjected to sham operation. Haemodynamic variables, including EVLW(ST), were measured using a PiCCOplus monitor (Pulsion Medical Systems, Munich, Germany), and the last measurement of EVLW(ST )was compared with EVLW(G). RESULTS: At the end of experiment, values for EVLW(ST )(mean ± standard error) were 8.9 ± 0.6, 11.8 ± 1.0 and 18.2 ± 0.9 ml/kg in the sham-operated, lipopolysaccharide and oleic acid groups, respectively (P < 0.05). The corresponding values for EVLWI(G )were 6.2 ± 0.3, 7.1 ± 0.6 and 11.8 ± 0.7 ml/kg (P < 0.05). Ranges of EVLWI(ST )and EVLWI(G )values were 7.5–21.0 and 4.9–14.5 ml/kg. Regression analysis between in vivo EVLW(ST )and postmortem EVLW(G )yielded the following relation: EVLW(ST )= 1.30 × EVLW(G )+ 2.32 (n = 18, r = 0.85, P < 0.0001). The mean bias ± 2 standard deviations between EVLW(ST )and EVLW(G )was 4.9 ± 5.1 ml/kg (P < 0.001). CONCLUSION: In sheep, EVLW determined using transpulmonary single thermodilution correlates closely with gravimetric measurements over a wide range of changes. However, transpulmonary single thermodilution overestimates EVLW as compared with postmortem gravimetry

Increased Extravascular Lung Water Reduces the Efficacy of Alveolar Recruitment Maneuver in Acute Respiratory Distress Syndrome

Introduction. In acute respiratory distress syndrome (ARDS) the recruitment maneuver (RM) is used to reexpand atelectatic areas of the lungs aiming to improve arterial oxygenation. The goal of our paper was to evaluate the response to RM, as assessed by measurements of extravascular lung water index (EVLWI) in ARDS patients. Materials and Methods. Seventeen adult ARDS patients were enrolled into a prospective study. Patients received protective ventilation. The RM was performed by applying a continuous positive airway pressure of 40 cm H2O for 40 sec. The efficacy of the RM was assessed 5 min later. Patients were identified as responders if PaO2/FiO2 increased by >20% above the baseline. EVLWI was assessed by transpulmonary thermodilution before the RM, and patients were divided into groups of low EVLWI (<10 mL/kg) and high EVLWI (≥10 mL/kg). Results. EVLWI was increased in 12 patients. Following RM, PaO2/FiO2 increased by 33 (4–65) % in the patients with low EVLWI, whereas those in the high EVLWI group experienced a change by only −1((−13)–(+5)) % (P = 0.035). Conclusion. In ARDS, the response to a recruitment maneuver might be related to the severity of pulmonary edema. In patients with incresed EVLWI, the recruitment maneuver is less effective

Recombinant human activated protein C attenuates endotoxin-induced lung injury in awake sheep

Introduction: Acute lung injury often complicates severe sepsis. In Gram-negative sepsis, bacterial endotoxin activates both coagulation and inflammation. Enhanced lung vascular pressures and permeability, increased extravascular lung water content and deteriorated gas exchange characterize ovine endotoxin-induced lung injury, a frequently used model of acute lung injury. Recombinant human activated protein C (rhAPC), with its anticoagulant, anti-inflammatory, fibrinolytic and antiapoptotic effects, reportedly reduces the respiratordependent days and the mortality of patients with severe sepsis. We speculate whether rhAPC antagonizes endotoxin-induced lung injury in sheep. Methods: Two groups of sheep were exposed to Escherichia coli endotoxin (lipopolysaccharide) 15 ng/kg/minute intravenously from 0 to 24 hours; one group received only lipopolysaccharide throughout (n = 8), and the other group received lipopolysaccharide in combination with rhAPC 24 μg/ kg/hour from 4 to 24 hours (n = 9). In addition, one group received rhAPC as above as the only intervention (n = 4), and four sham-operated sheep were used for determination of the α and ε isoforms of protein kinase C in pulmonary tissue. Data were assessed by one-way analysis of variance for repeated measurements. Biochemical data were analyzed using Student's t test, or using the Mann–Whitney U test when appropriate. Results: Infusion of endotoxin caused lung injury, manifested by increments in pulmonary artery pressure, in pulmonary microocclusion pressure, in pulmonary vascular downstream resistance, in pulmonary vascular permeability index, in extravascular lung water index and in deterioration of oxygenation that were all attenuated by infusion of rhAPC. Endotoxemia led to changes in inflammation and coagulation, including pulmonary neutrophil accumulation paralleled by increased TNFα and decreased protein C and fibrinogen in animal plasma, which all improved following infusion of rhAPC. Moreover, rhAPC prevented the translocation of protein kinase C α and ε isoforms from the cytosolic fraction of lung tissue extracts. Conclusion: In awake sheep, rhAPC alleviates endotoxininduced lung injury – as characterized by improvements of oxygenation, coagulation and inflammation, as well as by reversal of pulmonary hemodynamic and volumetric changes

Inhaled aerosolised recombinant human activated protein C ameliorates endotoxin-induced lung injury in anaesthetised sheep

Introduction We recently demonstrated that intravenously infused recombinant human activated protein C (APC) attenuates ovine lipopolysaccharide (LPS)-induced lung injury. In this study, our aim was to find out whether treatment with inhaled aerosolised APC (inhAPC) prevents formation of increased lung densities and oedema and derangement of oxygenation during exposure to LPS. Methods: Sheep were anaesthetised during placement of intravascular introducers. After one to four days of recovery from instrumentation, the animals were re-anaesthetised, endotracheally intubated and mechanically ventilated throughout a six-hour experiment where the sheep underwent quantitative lung computed tomography. Sheep were randomly assigned to one of three groups: a sham-operated group (n = 8) receiving inhaled aerosolised saline from two hours after the start of the experiment; a LPS group (n = 8) receiving an intravenous infusion of LPS 20 ng/kg per hour and, after two hours, inhaled aerosolised saline over the next four hours; a LPS+inhAPC group (n = 8) receiving an intravenous infusion of LPS 20 ng/kg per hour and, after two hours, aerosolised APC 48 µg/kg per hour inhaled throughout the experiment. Data were analysed with analysis of variance; P less than 0.05 was regarded as significant. Results: An infusion of LPS was associated with a reduction of well-aerated lung volume and a rapid fall in arterial oxygenation that were both significantly antagonised by inhaled APC. Pulmonary vascular pressures and extravascular lung water index increased significantly during exposure to LPS, but inhaled APC had no effect on these changes. Conclusions: Inhalation of aerosolised APC attenuates LPSinduced lung injury in sheep by preventing a decline in the volume of aerated lung tissue and improving oxygenation

Comparison of Goal-Directed Hemodynamic Optimization Using Pulmonary Artery Catheter and Transpulmonary Thermodilution in Combined Valve Repair: A Randomized Clinical Trial

Our aim was to compare the effects of goal-directed therapy guided either by pulmonary artery catheter (PAC) or by transpulmonary thermodilution (TTD) combined with monitoring of oxygen transport on perioperative hemodynamics and outcome after complex elective valve surgery. Measurements and Main Results. Forty patients were randomized into two equal groups: a PAC group and a TTD group. In the PAC group, therapy was guided by mean arterial pressure (MAP), cardiac index (CI) and pulmonary artery occlusion pressure (PAOP), whereas in the TTD group we additionally used global end-diastolic volume index (GEDVI), extravascular lung water index (EVLWI), and oxygen delivery index (DO2I). We observed a gradual increase in GEDVI, whereas EVLWI and PAOP decreased by 20–30% postoperatively (P < 0.05). The TTD group received 20% more fluid accompanied by increased stroke volume index and DO2I by 15–20% compared to the PAC group (P < 0.05). Duration of mechanical ventilation was increased by 5.2 hrs in the PAC group (P = 0.04). Conclusions. As compared to the PAC-guided algorithm, goal-directed therapy based on transpulmonary thermodilution and oxygen transport increases the volume of fluid therapy, improves hemodynamics and DO2I, and reduces the duration of respiratory support after complex valve surgery

Perioperative goal-directed hemodynamic therapy based on radial arterial pulse pressure variation and continuous cardiac index trending reduces postoperative complications after major abdominal surgery: a multi-center, prospective, randomized study

IntroductionSeveral single-center studies and meta-analyses have shown that perioperative goal-directed therapy may significantly improve outcomes in general surgical patients. We hypothesized that using a treatment algorithm based on pulse pressure variation, cardiac index trending by radial artery pulse contour analysis, and mean arterial pressure in a study group (SG), would result in reduced complications, reduced length of hospital stay and quicker return of bowel movement postoperatively in abdominal surgical patients, when compared to a control group (CG).Methods160 patients undergoing elective major abdominal surgery were randomized to the SG (79 patients) or to the CG (81 patients). In the SG hemodynamic therapy was guided by pulse pressure variation, cardiac index trending and mean arterial pressure. In the CG hemodynamic therapy was performed at the discretion of the treating anesthesiologist. Outcome data were recorded up to 28 days postoperatively.ResultsThe total number of complications was significantly lower in the SG (72 vs. 52 complications, p = 0.038). In particular, infection complications were significantly reduced (SG: 13 vs. CG: 26 complications, p = 0.023). There were no significant differences between the two groups for return of bowel movement (SG: 3 vs. CG: 2 days postoperatively, p = 0.316), duration of post anesthesia care unit stay (SG: 180 vs. CG: 180 minutes, p = 0.516) or length of hospital stay (SG: 11 vs. CG: 10 days, p = 0.929).ConclusionsThis multi-center study demonstrates that hemodynamic goal-directed therapy using pulse pressure variation, cardiac index trending and mean arterial pressure as the key parameters leads to a decrease in postoperative complications in patients undergoing major abdominal surgery.Trial registrationClinicalTrial.gov, NCT01401283

Epidural anesthesia and postoperative analgesia with ropivacaine and fentanyl in off-pump coronary artery bypass grafting: a randomized, controlled study

<p>Abstract</p> <p>Background</p> <p>Our aim was to assess the efficacy of thoracic epidural anesthesia (EA) followed by postoperative epidural infusion (EI) and patient-controlled epidural analgesia (PCEA) with ropivacaine/fentanyl in off-pump coronary artery bypass grafting (OPCAB).</p> <p>Methods</p> <p>In a prospective study, 93 patients were scheduled for OPCAB under propofol/fentanyl anesthesia and randomized to three postoperative analgesia regimens aiming at a visual analog scale (VAS) score < 30 mm at rest. The control group (n = 31) received intravenous fentanyl 10 μg/ml postoperatively 3-8 mL/h. After placement of an epidural catheter at the level of Th₂-Th₄before OPCAB, a thoracic EI group (n = 31) received EA intraoperatively with ropivacaine 0.75% 1 mg/kg and fentanyl 1 μg/kg followed by continuous EI of ropivacaine 0.2% 3-8 mL/h and fentanyl 2 μg/mL postoperatively. The PCEA group (n = 31), in addition to EA and EI, received PCEA (ropivacaine/fentanyl bolus 1 mL, lock-out interval 12 min) postoperatively. Hemodynamics and blood gases were measured throughout 24 h after OPCAB.</p> <p>Results</p> <p>During OPCAB, EA decreased arterial pressure transiently, counteracted changes in global ejection fraction and accumulation of extravascular lung water, and reduced the consumption of propofol by 15%, fentanyl by 50% and nitroglycerin by a 7-fold, but increased the requirements in colloids and vasopressors by 2- and 3-fold, respectively (<it>P </it>< 0.05). After OPCAB, PCEA increased PaO₂/FiO₂at 18 h and decreased the duration of mechanical ventilation by 32% compared with the control group (<it>P </it>< 0.05).</p> <p>Conclusions</p> <p>In OPCAB, EA with ropivacaine/fentanyl decreases arterial pressure transiently, optimizes myocardial performance and influences the perioperative fluid and vasoactive therapy. Postoperative EI combined with PCEA improves lung function and reduces time to extubation.</p> <p>Trial Registration</p> <p><a href="http://www.clinicaltrials.gov/ct2/show/NCT01384175">NCT01384175</a></p

Rationale and design of the PeriOperative ISchemic Evaluation-3 (POISE-3): a randomized controlled trial evaluating tranexamic acid and a strategy to minimize hypotension in noncardiac surgery

Background For patients undergoing noncardiac surgery, bleeding and hypotension are frequent and associated with increased mortality and cardiovascular complications. Tranexamic acid (TXA) is an antifibrinolytic agent with the potential to reduce surgical bleeding; however, there is uncertainty about its efficacy and safety in noncardiac surgery. Although usual perioperative care is commonly consistent with a hypertension-avoidance strategy (i.e., most patients continue their antihypertensive medications throughout the perioperative period and intraoperative mean arterial pressures of 60 mmHg are commonly accepted), a hypotension-avoidance strategy may improve perioperative outcomes. Methods The PeriOperative Ischemic Evaluation (POISE)-3 Trial is a large international randomized controlled trial designed to determine if TXA is superior to placebo for the composite outcome of life-threatening, major, and critical organ bleeding, and non-inferior to placebo for the occurrence of major arterial and venous thrombotic events, at 30 days after randomization. Using a partial factorial design, POISE-3 will additionally determine the effect of a hypotension-avoidance strategy versus a hypertension-avoidance strategy on the risk of major cardiovascular events, at 30 days after randomization. The target sample size is 10,000 participants. Patients ≥45 years of age undergoing noncardiac surgery, with or at risk of cardiovascular and bleeding complications, are randomized to receive a TXA 1 g intravenous bolus or matching placebo at the start and at the end of surgery. Patients, health care providers, data collectors, outcome adjudicators, and investigators are blinded to the treatment allocation. Patients on ≥ 1 chronic antihypertensive medication are also randomized to either of the two blood pressure management strategies, which differ in the management of patient antihypertensive medications on the morning of surgery and on the first 2 days after surgery, and in the target mean arterial pressure during surgery. Outcome adjudicators are blinded to the blood pressure treatment allocation. Patients are followed up at 30 days and 1 year after randomization. Discussion Bleeding and hypotension in noncardiac surgery are common and have a substantial impact on patient prognosis. The POISE-3 trial will evaluate two interventions to determine their impact on bleeding, cardiovascular complications, and mortality. Trial registration ClinicalTrials.gov NCT03505723. Registered on 23 April 2018