Development and validation of the Efficacy Safety Score (ESS), a novel tool for postoperative patient management.

BACKGROUND: Several reports have shown that postoperative monitoring of general safety and quality issues, including pain treatment, after discharge from recovery is often non-systematic and inadequate. We suggest a new score with assessment of key recovery parameters, as a supportive tool for postoperative care and a call-out algorithm for need of extra help. The aim of this investigation was to validate the score. METHODS: After suggesting a prototype score from a pilot study in 182 postoperative patients, we performed a Delphi process by using international experts to create consensus on the final score contents and called the revised tool the Efficacy Safety Score (ESS). Then, we performed a prospective observational study with the ESS throughout the first 24 h postoperatively in 207 surgical in-patients. We compared ESS with Modified Early Warning Systems (MEWS), and postoperative journal information. We subsequently validated ESS by addressing recognized quality criteria for measurement of health status questionnaires. RESULTS: A call-out value of ESS ≥10 correlated with MEWS > 0 values and journal information about postoperative concerns with a sensitivity of 94% and 92%, respectively. All serious safety issues were identified with the ESS ≥ 10, and a higher number of quality issues were identified than with routine care or MEWS. We obtained positive ratings for six out of seven tested criteria of questionnaire quality; one criterion had an indeterminate rating. CONCLUSION: ESS fulfils suggested criteria for score quality validation and reflects the patient's postoperative status adequately and with high sensitivity. Further clinical trials are warranted to evaluate the usefulness of ESS as a simple tool for assessment of the postoperative safety and quality of patients.

Estimated continuous cardiac output based on pulse wave transit time in off-pump coronary artery bypass grafting: a comparison with transpulmonary thermodilution.

To evaluate the accuracy of estimated continuous cardiac output (esCCO) based on pulse wave transit time in comparison with cardiac output (CO) assessed by transpulmonary thermodilution (TPTD) in off-pump coronary artery bypass grafting (OPCAB). We calibrated the esCCO system with non-invasive (Part 1) and invasive (Part 2) blood pressure and compared with TPTD measurements. We performed parallel measurements of CO with both techniques and assessed the accuracy and precision of individual CO values and agreement of trends of changes perioperatively (Part 1) and postoperatively (Part 2). A Bland-Altman analysis revealed a bias between non-invasive esCCO and TPTD of 0.9 L/min and limits of agreement of ±2.8 L/min. Intraoperative bias was 1.2 L/min with limits of agreement of ±2.9 L/min and percentage error (PE) of 64 %. Postoperatively, bias was 0.4 L/min, limits of agreement of ±2.3 L/min and PE of 41 %. A Bland-Altman analysis of invasive esCCO and TPTD after OPCAB found bias of 0.3 L/min with limits of agreement of ±2.1 L/min and PE of 40 %. A 4-quadrant plot analysis of non-invasive esCCO versus TPTD revealed overall, intraoperative and postoperative concordance rate of 76, 65, and 89 %, respectively. The analysis of trending ability of invasive esCCO after OPCAB revealed concordance rate of 73 %. During OPCAB, esCCO demonstrated poor accuracy, precision and trending ability compared to TPTD. Postoperatively, non-invasive esCCO showed better agreement with TPTD. However, invasive calibration of esCCO did not improve the accuracy and precision and the trending ability of method.

Polymorphisms on PAI-1 and ACE genes in association with fibrinolytic bleeding after on-pump cardiac surgery.

BACKGROUND: Carriers of plasminogen activator inhibitor -1 (PAI-1) -675 genotype 5G/5G may be associated with lower preoperative PAI-1 plasma levels and higher blood loss after heart surgery using cardiopulmonary bypass (CPB). We speculate if polymorphisms of PAI-1 -844 A/G and angiotensin converting enzyme (ACE) intron 16 I/D also might promote fibrinolysis and increase postoperative bleeding. METHODS: We assessed PAI-1 -844 A/G, and ACE intron 16 I/D polymorphisms by polymerase chain reaction technique and direct sequencing of genomic DNA from 83 open heart surgery patients that we have presented earlier. As primary outcome, accumulated chest tube drainage (CTD) at 4 and 24 h were analyzed for association with genetic polymorphisms. As secondary outcome, differences in plasma levels of PAI-1, t-PA/PAI-1 complex and D-dimer were determined for each polymorphism. SPSS® was used for statistical evaluation. RESULTS: The lowest preoperative PAI-1 plasma levels were associated with PAI-1 -844 genotype G/G, and higher CTD, as compared with genotype A/A at 4 and 24 h after surgery. Correspondingly, 4 h after the surgery CTD was higher in carriers of ACE intron 16 genotype I/I, as compared with genotype D/D. PAI-1 plasma levels and t-PA/PAI-1 complex reached nadir in carriers of ACE intron 16 genotype I/I, in whom we also noticed the highest D-dimer levels immediately after surgery. Notably, carriers of PAI-1 -844 genotype G/G displayed higher D-dimer levels at 24 h after surgery as compared with those of genotype A/G. CONCLUSIONS: Increased postoperative blood loss secondary to enhanced fibrinolysis was associated with carriers of PAI-1 -844 G/G and ACE Intron 16 I/I, suggesting that these genotypes might predict increased postoperative blood loss after cardiac surgery using CPB.

Monitoring of anesthetic depth during surgical correction of acquired valvular disorders: single center, randomized trial.

OBJECTIVE: The authors' primary objective was to test the hypothesis that Cerebral State Index (CSI)-guided control of anesthetic depth might reduce the consumption of anesthetics and shorten the duration of ICU and hospital stays after surgical correction of combined valve disorders. DESIGN: Single center, randomized trial. SETTING: City Hospital Number 1 of Arkhangelsk, Russian Federation. PARTICIPANTS: Fifty adult patients with combined valve disorders requiring surgical correction. INTERVENTIONS: The patients were randomized into 2 groups. In the CSI group, anesthetic depth was monitored, and the rate of infusion of propofol was titrated to maintain the depth of anesthesia corresponding to a CSI of 40-60. In the control group, the depth of anesthesia was monitored clinically, and the dosage of propofol was administered according to the recommendations of the manufacturer. MEASUREMENTS AND MAIN RESULTS: All patients received standard perioperative monitoring. Consumption of anesthetics and length of ICU and hospital stays were recorded. Preoperative patient characteristics did not differ significantly between the groups. In the CSI group, average intraoperative doses of midazolam and propofol were reduced by 41% and 19%, respectively (p<0.01). Maintenance of anesthesia guided by CSI shortened the time until fit for ICU discharge by 50% and reduced the lengths of ICU and postoperative hospital stays by 35% and 25%, respectively (p< 0.05). CONCLUSIONS: Monitoring of anesthetic depth reduces the requirements for midazolam and propofol, resulting in a faster recovery and a shorter postoperative ICU and hospital stay after surgical correction of combined valve disorders.

PAI-1 and t-PA/PAI-1 complex potential markers of fibrinolytic bleeding after cardiac surgery employing cardiopulmonary bypass.

BACKGROUND: Enhanced bleeding remains a serious problem after cardiac surgery, and fibrinolysis is often involved. We speculate that lower plasma concentrations of plasminogen activator inhibitor - 1 (PAI-1) preoperatively and tissue plasminogen activator/PAI-1 (t-PA/PAI-1) complex postoperatively might predispose for enhanced fibrinolysis and increased postoperative bleeding. METHODS: Totally 88 adult patients (mean age 66 ± 10 years) scheduled for cardiac surgery, were enrolled into a prospective study. Blood samples were collected pre-operatively, on admission to the recovery and at 6 and 24 hours postoperatively. Patients with a surgical bleeding that was diagnosed during reoperation were discarded from the study. The patients were allocated to two groups depending on the 24-hour postoperative chest tube drainage (CTD): Group I > 500ml, Group II ≤ 500ml. Associations between CTD, PAI-1, t-PA/PAI-1 complex and D-dimer were analyzed with SPSS. RESULTS: Nine patients were excluded because of surgical bleeding. Of the 79 remaining patients, 38 were allocated to Group I and 41 to Group II. The CTD volumes correlated with the preoperative plasma levels of PAI-1 (r = - 0.3, P = 0.009). Plasma concentrations of preoperative PAI-1 and postoperative t-PA/PAI-1 complex differed significantly between the groups (P < 0.001 and P = 0.012, respectively). Group I displayed significantly lower plasma concentrations of fibrinogen and higher levels of D-dimer from immediately after the operation and throughout the first 24 hours postoperatively. CONCLUSIONS: Lower plasma concentrations of PAI-1 preoperatively and t-PA/PAI-1 complex postoperatively leads to higher plasma levels of D-dimer in association with more postoperative bleeding after cardiac surgery.

Inhibitor of neuronal nitric oxide synthase improves gas exchange in ventilator-induced lung injury after pneumonectomy.

BACKGROUND: Mechanical ventilation with high tidal volumes may cause ventilator-induced lung injury (VILI) and enhanced generation of nitric oxide (NO). We demonstrated in sheep that pneumonectomy followed by injurious ventilation promotes pulmonary edema. We wished both to test the hypothesis that neuronal NOS (nNOS), which is distributed in airway epithelial and neuronal tissues, could be involved in the pathogenesis of VILI and we also aimed at investigating the influence of an inhibitor of nNOS on the course of VILI after pneumonectomy. METHODS: Anesthetized sheep underwent right pneumonectomy, mechanical ventilation with tidal volumes (VT) of 6 mL/kg and FiO2 0.5, and were subsequently randomized to a protectively ventilated group (PROTV; n = 8) keeping VT and FiO2 unchanged, respiratory rate (RR) 25 inflations/min and PEEP 4 cm H2O for the following 8 hrs; an injuriously ventilated group with VT of 12 mL/kg, zero end-expiratory pressure, and FiO2 and RR unchanged (INJV; n = 8) and a group, which additionally received the inhibitor of nNOS, 7-nitroindazole (NI) 1.0 mg/kg/h intravenously from 2 hours after the commencement of injurious ventilation (INJV + NI; n = 8). We assessed respiratory, hemodynamic and volumetric variables, including both the extravascular lung water index (EVLWI) and the pulmonary vascular permeability index (PVPI). We measured plasma nitrite/nitrate (NOx) levels and examined lung biopsies for lung injury score (LIS). RESULTS: Both the injuriously ventilated groups demonstrated a 2-3-fold rise in EVLWI and PVPI, with no significant effects of NI. In the INJV group, gas exchange deteriorated in parallel with emerging respiratory acidosis, but administration of NI antagonized the derangement of oxygenation and the respiratory acidosis significantly. NOx displayed no significant changes and NI exerted no significant effect on LIS in the INJV group. CONCLUSION: Inhibition of nNOS improved gas exchange, but did not reduce lung water extravasation following injurious ventilation after pneumonectomy in sheep.

Physiological Changes in Subjects Exposed to Accidental Hypothermia: An Update.

Background: Accidental hypothermia (AH) is an unintended decrease in body core temperature (BCT) to below 35°C. We present an update on physiological/pathophysiological changes associated with AH and rewarming from hypothermic cardiac arrest (HCA). Temperature Regulation and Metabolism: Triggered by falling skin temperature, Thyrotropin-Releasing Hormone (TRH) from hypothalamus induces release of Thyroid-Stimulating Hormone (TSH) and Prolactin from pituitary gland anterior lobe that stimulate thyroid generation of triiodothyronine and thyroxine (T4). The latter act together with noradrenaline to induce heat production by binding to adrenergic ß3-receptors in fat cells. Exposed to cold, noradrenaline prompts degradation of triglycerides from brown adipose tissue (BAT) into free fatty acids that uncouple metabolism to heat production, rather than generating adenosine triphosphate. If BAT is lacking, AH occurs more readily. Cardiac Output: Assuming a 7% drop in metabolism per °C, a BCT decrease of 10°C can reduce metabolism by 70% paralleled by a corresponding decline in CO. Consequently, it is possible to maintain adequate oxygen delivery provided correctly performed cardiopulmonary resuscitation (CPR), which might result in approximately 30% of CO generated at normal BCT. Liver and Coagulation: AH promotes coagulation disturbances following trauma and acidosis by reducing coagulation and platelet functions. Mean prothrombin and partial thromboplastin times might increase by 40-60% in moderate hypothermia. Rewarming might release tissue factor from damaged tissues, that triggers disseminated intravascular coagulation. Hypothermia might inhibit platelet aggregation and coagulation. Kidneys: Renal blood flow decreases due to vasoconstriction of afferent arterioles, electrolyte and fluid disturbances and increasing blood viscosity. Severely deranged renal function occurs particularly in the presence of rhabdomyolysis induced by severe AH combined with trauma. Conclusion: Metabolism drops 7% per °C fall in BCT, reducing CO correspondingly. Therefore, it is possible to maintain adequate oxygen delivery after 10°C drop in BCT provided correctly performed CPR. Hypothermia may facilitate rhabdomyolysis in traumatized patients. Victims suspected of HCA should be rewarmed before being pronounced dead. Rewarming avalanche victims of HCA with serum potassium > 12 mmol/L and a burial time >30 min with no air pocket, most probably be futile.

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

BACKGROUND: 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). METHODS: 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-Th4 before 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. RESULTS: 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 (P < 0.05). After OPCAB, PCEA increased PaO2/FiO2 at 18 h and decreased the duration of mechanical ventilation by 32% compared with the control group (P < 0.05). CONCLUSIONS: 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. TRIAL REGISTRATION: NCT01384175.

Prioritized Brain Circulation During Ergometer Cycling with Apnea and Face Immersion in Ice-Cold Water: A Case Report.

BACKGROUND: Successful cardiopulmonary resuscitation after drowning or avalanche is often attributed to hypothermia-induced decrease in metabolism, which adapts the oxygen demand to the amount supplied under cardiac compression. Four decades ago, we speculated if oxygen-sparing mechanisms like those found in marine mammals, may improve cerebral oxygenation during acute airway blockade in humans. We investigated hemodynamic changes during steady state ergometer cycling with intermittent periods of apnea and face immersion (AFI) in ice-cold water. During AFI, heart rate (HR) dropped by 58% whereas average blood velocity (ABV) determined by means of a Doppler ultrasound velocity meter (UNIDOP University of Oslo, Oslo, Norway) fell by 85% in the radial artery and rose by 67% in the vertebral artery. Similar changes occured in radial artery ABV, albeit more slowly, when the test subject only held his breath while cycling. When he breathed via a snorkel during face immersion, HR remained unchanged while radial artery ABV fell transiently and subsequently returned to its pre-immersion level. These findings later were confirmed by other investigators. Moreover, a recent study revealed that the seal even has a system for selective brain cooling during the dive. CONCLUSION: Our research has confirmed prioritized cerebral circulation during AFI in cold water. We hypothesize that these changes may improve brain oxygenation due both to greater blood flow and possibly also to faster brain cooling, as demonstrated in diving seals.

Rewarming From Hypothermic Cardiac Arrest Applying Extracorporeal Life Support: A Systematic Review and Meta-Analysis.

Introduction: This systematic review and meta-analysis aims at comparing outcomes of rewarming after accidental hypothermic cardiac arrest (HCA) with cardiopulmonary bypass (CPB) or/and extracorporeal membrane oxygenation (ECMO). Material and Methods: Literature searches were limited to references with an abstract in English, French or German. Additionally, we searched reference lists of included papers. Primary outcome was survival to hospital discharge. We assessed neurological outcome, differences in relative risks (RR) of surviving, as related to the applied rewarming technique, sex, asphyxia, and witnessed or unwitnessed HCA. We calculated hypothermia outcome prediction probability score after extracorporeal life support (HOPE) in patients in whom we found individual data. P < 0.05 considered significant. Results: Twenty-three case observation studies comprising 464 patients were included in a meta-analysis comparing outcomes of rewarming with CPB or/and ECMO. One-hundred-and-seventy-two patients (37%) survived to hospital discharge, 76 of 245 (31%) after CPB and 96 of 219 (44 %) after ECMO; 87 and 75%, respectively, had good neurological outcomes. Overall chance of surviving was 41% higher (P = 0.005) with ECMO as compared with CPB. A man and a woman had 46% (P = 0.043) and 31% (P = 0.115) higher chance, respectively, of surviving with ECMO as compared with CPB. Avalanche victims had the lowest chance of surviving, followed by drowning and people losing consciousness in cold environments. Assessed by logistic regression, asphyxia, unwitnessed HCA, male sex, high initial body temperature, low pH and high serum potassium (s-K+) levels were associated with reduced chance of surviving. In patients displaying individual data, overall mean predictive surviving probability (HOPE score; n = 134) was 33.9 ± 33.6% with no significant difference between ECMO and CPB-treated patients. We also surveyed 80 case reports with 96 victims of HCA, who underwent resuscitation with CPB or ECMO, without including them in the meta-analysis. Conclusions: The chance of surviving was significantly higher after rewarming with ECMO, as compared to CPB, and in patients with witnessed compared to unwitnessed HCA. Avalanche victims had the lowest probability of surviving. Male sex, high initial body temperature, low pH, and high s-K+ were factors associated with low surviving chances.

Thromboelastometry for Assessing Risks of Free Flap Thrombosis in Patients Undergoing Microvascular Surgery.

Introduction: Coagulation assessment is often missing in microvascular surgery. We aimed at evaluating the predictive value of thromboelastometry for free flap thrombosis in microvascular surgery patients. Materials and Methods: We enrolled 103 adult patients with traumatic injuries scheduled for microvascular free flap surgery into a prospective observational study. Thirty-six patients with recent trauma underwent surgery within 30 days (ES group), and were compared with 67 trauma patients who underwent surgery later than 30 days (late surgery, LS group) after the injury. Rotational thromboelastometry (RTE) was performed before surgery. Functional fibrinogen to platelet ratio (FPR) ≥ 42 was selected as the main hypercoagulability index. Free flap thrombosis was set as primary outcome. Thrombotic risk factors and duration of surgery related to free flap thrombosis were secondary outcomes. Statistical significance p < 0.05; not significant NS. Results: Six patients (16.7%) in the ES group and 10 (14.9%) in the LS group had free flap thrombosis (NS). In the entire cohort, free flap thrombosis rate increased in the presence of thrombogenic comorbidities (OR 4.059, CI 1.33-12.37; p = 0.014) and prolonged surgery times (OR 1.007, CI 1 - 1.012; p = 0.05). Although hypercoagulability occurred more frequently in the ES group (44.4%) than in the LS group (11.9%; p < 0.001), it was not associated with higher free flap thrombosis rate. In ES group patients with surgery times > 240 min, the risk of free flap thrombosis increased (OR 3.5, CI 1.16-10.6; p = 0.026) with 93.3% sensitivity and 86.7% specificity (AUC 0.85; p = 0.007). In contrast, in LS patients hypercoagulability increased the odds of free flap thrombosis (OR 8.83, CI 1.74-44.76; p = 0.009). Moreover, a positive correlation was found between FPR ≥ 42 and free flap thrombosis rate (r = 0.362; p = 0.003). In the LS group, the presence of thrombogenic comorbidities correlated with free flap thrombosis rate (OR 7, CI 1.591-30.8; p = 0.01). Conclusions: In LS patients with thrombogenic comorbidities, thromboelastometry supports the detection of hypercoagulability and predicts free flap thrombosis risk. In ES patients, postoperative hypercoagulability did not predict free flap thrombosis. Prolonged surgery time should be considered as a risk factor.

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 microg/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 LPS-induced lung injury in sheep by preventing a decline in the volume of aerated lung tissue and improving oxygenation.

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.

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 respirator-dependent 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 microg/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 alpha and epsilon 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 micro-occlusion 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 TNFalpha 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 alpha and epsilon isoforms from the cytosolic fraction of lung tissue extracts. CONCLUSION: In awake sheep, rhAPC alleviates endotoxin-induced lung injury--as characterized by improvements of oxygenation, coagulation and inflammation, as well as by reversal of pulmonary hemodynamic and volumetric changes.

Fibrinolytic System Changes in Liver Surgery: A Pilot Observational Study.

Introduction: Bleeding occurs frequently in liver surgery. Unbalance between tissue plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1) concentrations might increase bleeding. Our aim was to analyze perioperative fibrinolytic changes during liver surgery. Materials and Methods: We evaluated 15 patients for inclusion into a prospective pilot study of liver surgery. We assessed fibrinolysis by plasma PAI-1 and t-PA: before surgery (T1), before Pringle maneuver (PM;T2), at the end of surgery (T3) and 24 h postoperatively (T4), and registered demographic and laboratory data, extent and duration of surgery, hemodynamic parameters, blood loss, and transfused volumes of blood products. Data presented as mean ± SD. Significance at P < 0.05. Results: After exclusion of six patients only undergoing biopsies, we included six women and three men aged 49.1 ± 19.6 years; two patients with liver metastases of colorectal cancer and hepatocellular carcinoma, respectively, two with focal nodular hyperplasia, two with hepatic hemangioma, and one with angiomyolipoma. Six patients underwent PM. PAI-1 plasma concentration (n = 9) rose from 6.25 ± 2.25 at T1 through 17.30 ± 14.59 ng/ml at T2 and 28.74 ± 20.4 (p = 0.007) and 22.5 ± 16.0 ng/ml (p = 0.04), respectively, at T3 and T4. Correspondingly, t-PA plasma concentration (n = 9) increased from 4.76 ± 3.08 ng/ml at T1 through 8.00 ± 5.10 ng/ml (p = 0.012) at T2 and decreased to 4.25 ± 2.29 ng/ml and 3.04 ± 3.09 at T3 and T4, respectively. Plasma t-PA level at T2 was significantly different from those at T1, T3, and T4 (p < 0.004). In PM patients, t-PA levels increased from T1, peaked at T2 (p = 0.001), and subsequently decreased at T3 and T4 (p = 0.011 and p = 0.037), respectively. Mean blood loss was 1,377.7 ± 1,062.8 ml; seven patients received blood products. Patients with higher PAI-1 levels at T3 received more fresh frozen plasma (r = 0.79; p = 0.01) and red blood cells (r = 0.88; p = 0.002). Conclusions: During liver surgery, fibrinolysis increased, as evidenced by rises in plasma PAI-1and t-PA, especially after start of surgery and following PM. Transfused volumes of blood products correlated with higher plasma concentrations of PAI-1. Confirming this tendency requires a larger cohort of patients.

Effects of Constant Flow vs. Constant Pressure Perfusion on Fluid Filtration in Severe Hypothermic Isolated Blood-Perfused Rat Lungs.

BACKGROUND: Victims of severe accidental hypothermia are prone to fluid extravasation but rarely develop lung edema. We hypothesize that combined hypothermia-induced increase in pulmonary vascular resistance (PVR) and a concomitant fall in cardiac output protect the lungs against edema development. Our aim was to explore in hypothermic-isolated blood-perfused rat lungs whether perfusion at constant pressure influences fluid filtration differently from perfusion at constant flow. METHODS: Isolated blood-perfused rat lungs were hanging freely in a weight transducer for measuring weight changes (ΔW). Fluid filtration coefficient (Kfc), was determined by transiently elevating left atrial pressure (Pla) by 5.8 mmHg two times each during normothermia (37°C) and during hypothermia (15°C). The lung preparations were randomized to two groups. One group was perfused with constant flow (Constant flow group) and the other group with constant pulmonary artery pressure (Constant PPA group). Microvascular pressure (Pmv) was determined before and during elevation of Pla (ΔPmv) by means of the double occlusion technique. Kfc was calculated with the formula Kfc = ΔW/ΔPmv/min. All Kfc values were normalized to predicted lung weight (PLW), which was based on body weight (BW) according to the formula: PLW = 0.0053 BW - 0.48 and presented as KfcPLW in mg/min/mmHg/g. At cessation, bronchoalveolar lavage (BAL) fluid/perfusate protein concentration (B/P) ratio was determined photometrically. Data were analyzed with parametric or non-parametric tests as appropriate. p < 0.05 considered as significant. RESULTS: Perfusate flow remained constant in the Constant flow group, but was more than halved during hypothermia in the Constant PPA group concomitant with a more fold increase in PVR. In the Constant flow group, KfcPLW and B/P ratio increased significantly by more than 10-fold during hypothermia concerted by visible signs of edema in the trachea. Hemoglobin and hematocrit increased within the Constant flow group and between the groups at cessation of the experiments. CONCLUSION: In hypothermic rat lungs perfused at constant flow, fluid filtration coefficient per gram PLW and B/P ratio increased more than 10-fold concerted by increased hemoconcentration, but the changes were less in hypothermic lungs perfused at constant PPA.

Activation of Coagulation and Fibrinolysis in Acute Respiratory Distress Syndrome: A Prospective Pilot Study.

INTRODUCTION: Coagulation and fibrinolysis remain sparsely addressed with regards to acute respiratory distress syndrome (ARDS). We hypothesized that ARDS development might be associated with changes in plasma coagulation and fibrinolysis. Our aim was to investigate the relationships between ARDS diagnosis and plasma concentrations of tissue factor (TF), tissue plasminogen activator (t-PA), and plasminogen activator inhibitor-1 (PAI-1) in mechanically ventilated patients at increased risk of developing ARDS. MATERIALS AND METHODS: We performed an ethically approved prospective observational pilot study. Inclusion criteria were patients with PaO2/FiO2 < 300 mmHg admitted to the intensive care unit (ICU) for mechanical ventilation for 24 h, or more, because of one or more disease conditions associated with increased risk of developing ARDS. Exclusion criteria were age below 18 years; cardiac disease. We sampled plasma prospectively and compared patients who developed ARDS with those who did not using descriptive statistics and chi-square analysis of baseline demographical and clinical data. We also analyzed plasma concentrations of TF, t-PA, and PAI-1 at inclusion (T0) and on third (T3) and seventh day (T7) of the ICU stay with non-parametric statistics inclusive their sensitivity and specificity associated with the development of ARDS using receiver operating characteristic curve analysis. Statistical significance: p < 0.05. RESULTS: Of 24 patients at risk, 6 developed mild ARDS and 4 of each moderate or severe ARDS, respectively, 3 ± 2 (mean ± SD) days after inclusion. Median plasma concentrations of TF and PAI-1 were significantly higher at T7 in patients with ARDS, as compared to non-ARDS. Simultaneously, we found moderate correlations between plasma concentrations of TF and PAI-1, TF and PaO2/FiO2, and positive end-expiratory pressure and TF. TF plasma concentration was associated with ARDS with 71% sensitivity and 100% specificity, a cut off level of 145 pg/ml and AUC 0.78, p = 0.02. PAI-1 displayed 64% sensitivity and 100% specificity with a cut off concentration of 117.5 pg/ml and AUC 0.77, p = 0.02. t-PA did not change significantly during the observation time. CONCLUSION: This pilot study showed that increased plasma concentrations of TF and PAI-1 might support ARDS diagnoses in mechanically ventilated patients after 7 days in ICU.

Flagellin from gram-negative bacteria is a potent mediator of acute pulmonary inflammation in sepsis.

Flagellin is a recently identified bacterial product that elicits immune response via toll-like receptor 5. Here, we demonstrate that flagellin is an extraordinarily potent proinflammatory stimulus in the lung during sepsis. In vitro, flagellin triggers the production of interleukin (IL)-8 by human lung epithelial (A549) cells, with 50% of the maximal response obtained at a concentration of 2 x 10(-14) M. Flagellin also induces the expression of ICAM-1 in vitro. Intravenous administration of flagellin to mice elicited a severe acute lung inflammation that was significantly more pronounced than following lipopolysaccharide (LPS) administration. Flagellin induced a local release of proinflammatory cytokines, the accumulation of inflammatory cells, and the development of pulmonary hyperpermeability. These effects were associated with the nuclear translocation of the transcription NF-kappaB in the lung. Flagellin remained active in inducing pulmonary inflammation at doses as low as 10 ng/mouse. In the plasma of patients with sepsis, flagellin levels amounted to 7.1 +/- 0.1 ng/mL. Plasma flagellin levels showed a significant positive correlation with the lung injury score, with the alveolar-arterial oxygen difference as well as with the duration of the sepsis. Flagellin emerges as a potent trigger of acute respiratory complications in gram-negative bacterial sepsis.

Heparin nebulization attenuates acute lung injury in sepsis following smoke inhalation in sheep.

Pseudomonas pneumonia is a common complication of smoke inhalation injury. Airway casts formed from clotted mucous occur frequently in this condition. A recent report shows that intravenous heparin improves oxygenation and reduces lung damage in a sheep model of smoke inhalation. We hypothesized that nebulized heparin could be an effective means of reducing cast formation. Female sheep (n = 19) were surgically prepared for a study of acute lung injury (ALI). After a tracheotomy, 48 breaths of cotton smoke (<40 degrees C) were inflated into the airway. Afterwards, live Pseudomonas aeruginosa (5 x 10(11) CFU) was instilled into the lung. All sheep were mechanically ventilated with 100% O2 and were divided into four groups: a heparin-nebulized group (n = 5; animals received aerosolized heparin [10,000 I.U.] 1 h after the bacterial instillation and subsequently every 4 h thereafter), an intravenous heparin group (n = 5,300 U/kg/23 h, infusion was started 1 h after the injury), a saline-nebulization group (n = 5; animals received inhaled nebulized saline), and a sham injury group (n = 4, treated in the same fashion, but no injury). The animals were sacrificed after 24 h of mechanical ventilation, and lung samples were harvested. Sheep exposed to lung injury presented with typical hyperdynamic cardiovascular changes and a corresponding drop in PaO2. These changes were significantly attenuated in the heparin groups. Histological changes consisting of cellular infiltrates, lung edema, congestion, and cast formation were reduced by heparin. These data suggest that nebulized inhaled heparin is a beneficial therapy for sepsis-induced ALI.

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 (EVLWST) and postmortem gravimetric (EVLWG). 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 EVLWST, were measured using a PiCCOplus monitor (Pulsion Medical Systems, Munich, Germany), and the last measurement of EVLWST was compared with EVLWG. RESULTS: At the end of experiment, values for EVLWST (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 EVLWIG were 6.2 +/- 0.3, 7.1 +/- 0.6 and 11.8 +/- 0.7 ml/kg (P < 0.05). Ranges of EVLWIST and EVLWIG values were 7.5-21.0 and 4.9-14.5 ml/kg. Regression analysis between in vivo EVLWST and postmortem EVLWG yielded the following relation: EVLWST = 1.30 x EVLWG + 2.32 (n = 18, r = 0.85, P < 0.0001). The mean bias +/- 2 standard deviations between EVLWST and EVLWG 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.