Effect of low-dose dexamethasone on extra vascular lung water in patients following on-pump elective primary coronary artery bypass graft surgery.

Background: The primary objective was to compare the effect of a low-dose dexamethasone as against a saline placebo on extravascular lung water index (EVLWI) in patients undergoing elective primary coronary artery bypass surgery. The secondary endpoints were to assess the effect of dexamethasone on other volumetric parameters (pulmonary vascular permeability index, global end diastolic volume index, and intrathoracic blood volume index), Vasoactive Inotrope Scores, hemodynamic parameters and serum osmolality in both groups. Settings and Design: Prospective observational study performed at a single tertiary cardiac care center. Materials and Methods: Twenty patients were randomized to receive either dexamethasone (steroid group, n = 10) or placebo (nonsteroid group, n = 10) twice before the institution of cardiopulmonary bypass (CPB). EVLWI and other volumetric parameters were obtained with the help of VolumeView™ Combo Kit connected to EV 1000 clinical platform at predetermined intervals. Hemodynamic parameters, vasoactive-inotropic Scores, hematocrit values were recorded at the predetermined time intervals. Baseline and 1st postoperative day serum osmolality values were also obtained. Results: The two groups were evenly matched in terms of demographic and CPB data. Intra- and inter-group comparison of the baseline EVLWI including other volumetric and hemodynamic parameters with those recorded at subsequent intervals revealed no statistical difference and was similar. Generalized estimating equation model was obtained to compare the changes between the groups over the entire study period which showed that on an average the changes between the steroid and nonsteroid group in terms of all volumetric parameters were not statistically significant. Conclusions: There were no beneficial effects of low-dose dexamethasone on EVLWI or other volumetric parameters in patients subjected to on-pump primary coronary bypass surgery. Hemodynamic parameters were also not affected. Probably, the advanced hemodynamic monitoring aided in optimal fluid management in the nonsteroidal group impacting EVLW accumulation.

Effects of 6% Tetrastarch and Lactated Ringer's Solution on Extravascular Lung Water and Markers of Acute Renal Injury in Hemorrhaged, Isoflurane-Anesthetized Healthy Dogs.

BACKGROUND: Tetrastarch can cause acute kidney injury (AKI) in humans with sepsis, but less likely to result in tissue edema than lactated Ringer's solution (LRS). OBJECTIVES: Compare effects of volume replacement (VR) with LRS and 6% tetrastarch solution (TS) on extravascular lung water (EVLW) and markers of AKI in hemorrhaged dogs. ANIMALS: Six healthy English Pointer dogs (19.7-35.3 kg). METHODS: Prospective crossover study. Animals underwent anesthesia without hemorrhage (Control). Two weeks later, dogs hemorrhaged under anesthesia on 2 occasions (8-week washout intervals) and randomly received VR with LRS or TS at 3 : 1 or 1 : 1 of shed blood, respectively. Anesthesia was maintained until 4 hour after VR for EVLW measurements derived from transpulmonary thermodilution cardiac output. Neutrophil gelatinase-associated lipocalin (NGAL) and creatinine concentrations in plasma and urine were measured until 72 hour after VR. RESULTS: The EVLW index (mL/kg) was lower at 1 hour after TS (10.0 ± 1.9) in comparison with controls (11.9 ± 3.4, P = 0.04), and at 4 hour after TS (9.7 ± 1.9) in comparison with LRS (11.8 ± 2.7, P = 0.03). Arterial oxygen partial pressure-to-inspired oxygen fraction ratio did not differ among treatments from 0.5 to 4 hour after VR. Urine NGAL/creatinine ratio did not differ among treatments and remained below threshold for AKI (120,000 pg/mg). CONCLUSIONS AND CLINICAL IMPORTANCE: Although TS causes less EVLW accumulation than LRS, neither fluid produced evidence of lung edema (impaired oxygenation). Both fluids appear not to cause AKI when used for VR after hemorrhage in healthy nonseptic dogs.

Influence of Inhaled Amiloride on Lung Fluid Clearance in Response to Normobaric Hypoxia in Healthy Individuals.

Wheatley, Courtney M., Sarah E. Baker, Bryan J. Taylor, Manda L. Keller-Ross, Steven C. Chase, Alex R. Carlson, Robert J. Wentz, Eric M. Snyder, and Bruce D. Johnson. Influence of inhaled amiloride on lung fluid clearance in response to normobaric hypoxia in healthy individuals. High Alt Med Biol 18:343-354, 2017. AIM: To investigate the role of epithelial sodium channels (ENaC) on lung fluid clearance in response to normobaric hypoxia, 20 healthy subjects were exposed to 15 hours of hypoxia (fraction of inspired oxygen [FiO2] = 12.5%) on two randomized occasions: (1) inhaled amiloride (A) (1.5 mg/5 mL saline); and (2) inhaled saline placebo (P). Changes in lung fluid were assessed through chest computed tomography (CT) for lung tissue volume (TV), and the diffusion capacity of the lungs for carbon monoxide (DLCO) and nitric oxide (DLNO) for pulmonary capillary blood volume (VC). Extravascular lung water (EVLW) was derived as TV-VC and changes in the CT attenuation distribution histograms were reviewed. RESULTS: Normobaric hypoxia caused (1) a reduction in EVLW (change from baseline for A vs. P, -8.5% ± 3.8% vs. -7.9% ± 5.2%, p < 0.05), (2) an increase in VC (53.6% ± 28.9% vs. 53.9% ± 52.3%, p < 0.05), (3) a small increase in DLCO (9.6% ± 29.3% vs. 9.9% ± 23.9%, p > 0.05), and (4) CT attenuation distribution became more negative, leftward skewed, and kurtotic (p < 0.05). CONCLUSION: Acute normobaric hypoxia caused a reduction in lung fluid that was unaffected by ENaC inhibition through inhaled amiloride. Although possible amiloride-sensitive ENaC may not be necessary to maintain lung fluid balance in response to hypoxia, it is more probable that normobaric hypoxia promotes lung fluid clearance rather than accumulation for the majority of healthy individuals. The observed reduction in interstitial lung fluid means alveolar fluid clearance may not have been challenged.

Effect of rhubarb on extravascular lung water in patients with acute respiratory distress syndrome.

OBJECTIVE:: The aim of this study was to evaluate the effect of rhubarb on extravascular lung water (EVLW) in patients with acute respiratory distress syndrome (ARDS). METHOD:: A total of 80 patients with ARDS were randomly divided into a treatment group (40 cases) and control group (40 cases). Patients in the treatment group received rhubarb (30.0 g/d) and patients in the control group received conventional therapy for seven consecutive days. Extravascular lung water index (EVLWI) and pulmonary vascular permeability index (PVPI) were determined using pulse contour cardiac output (PiCCO) technology, and the oxygenation index was measured by blood gas analysis at baseline and on days 3, 5 and 7 after treatment. RESULTS:: The oxygenation index was higher and the levels of EVLWI and PVPI were lower after treatment in the two groups; however, these indexes showed significant differences on the 5th and 7th days after rhubarb treatment compared with the results in the control group (p<0.05). CONCLUSION:: Rhubarb can decrease EVLWI and PVPI, and improve oxygenation in patients with ARDS.

Effect of rhubarb on extravascular lung water in patients with acute respiratory distress syndrome

Summary Objective: The aim of this study was to evaluate the effect of rhubarb on extravascular lung water (EVLW) in patients with acute respiratory distress syndrome (ARDS). Method: A total of 80 patients with ARDS were randomly divided into a treatment group (40 cases) and control group (40 cases). Patients in the treatment group received rhubarb (30.0 g/d) and patients in the control group received conventional therapy for seven consecutive days. Extravascular lung water index (EVLWI) and pulmonary vascular permeability index (PVPI) were determined using pulse contour cardiac output (PiCCO) technology, and the oxygenation index was measured by blood gas analysis at baseline and on days 3, 5 and 7 after treatment. Results: The oxygenation index was higher and the levels of EVLWI and PVPI were lower after treatment in the two groups; however, these indexes showed significant differences on the 5th and 7th days after rhubarb treatment compared with the results in the control group (p<0.05). Conclusion: Rhubarb can decrease EVLWI and PVPI, and improve oxygenation in patients with ARDS.

Effect of ß2-adrenergic receptor stimulation on lung fluid in stable heart failure patients.

BACKGROUND: The purpose of this study was to determine: (1) whether stable heart failure patients with reduced ejection fraction (HFrEF) have elevated extravascular lung water (EVLW) when compared with healthy control subjects; and (2) the effect of acute ß2-adrenergic receptor (ß2AR) agonist inhalation on lung fluid balance. METHODS: Twenty-two stable HFrEF patients and 18 age- and gender-matched healthy subjects were studied. Lung diffusing capacity for carbon monoxide (DLCO), alveolar-capillary membrane conductance (DmCO), pulmonary capillary blood volume (Vc) (via re-breathe) and lung tissue volume (Vtis) (via computed tomography) were assessed before and within 30 minutes after administration of nebulized albuterol. EVLW was derived as Vtis - Vc. RESULTS: Before administration of albuterol, Vtis and EVLW were higher in HFrEF vs control (998 ± 200 vs 884 ± 123 ml, p = 0.041; and 943 ± 202 vs 802 ± 133 ml, p = 0.015, respectively). Albuterol decreased Vtis and EVLW in HFrEF patients (-4.6 ± 7.8%, p = 0.010; -4.6 ± 8.8%, p = 0.018) and control subjects (-2.8 ± 4.9%, p = 0.029; -3.0 ± 5.7%, p = 0.045). There was an inverse relationship between pre-albuterol values and pre- to post-albuterol change for EVLW (r2 = -0.264, p = 0.015) and DmCO (r2 = -0.343, p = 0.004) in HFrEF only. CONCLUSION: Lung fluid is elevated in stable HFrEF patients relative to healthy subjects. Stimulation of ß2ARs may cause fluid removal in HFrEF, especially in patients with greater evidence of increased lung water at baseline.

Solnatide Demonstrates Profound Therapeutic Activity in a Rat Model of Pulmonary Edema Induced by Acute Hypobaric Hypoxia and Exercise.

BACKGROUND: The synthetic peptide solnatide is a novel pharmacologic agent that reduces extravascular lung water, blunts reactive oxygen species production, and improves lung function due to its ability to directly activate the epithelial sodium channel. The goal of this study was to investigate the effect of solnatide in pulmonary edema induced by acute hypobaric hypoxia and exercise in rats, which is considered a model for high-altitude pulmonary edema. METHODS: Sprague-Dawley rats were assigned to low-altitude control and eight treatment groups. Animals of all groups were subjected to exhaustive exercise in a hypobaric hypoxic environment simulating an altitude of 4,500 meters, followed by simulated ascent to 6,000 meters. After 48 h at 6,000 meters, rats were given sodium chloride, dexamethasone, aminophylline, p38 mitogen activated protein kinase inhibitor, and NOD-like receptor containing a pyrin domain 3 inhibitor, or one of three different doses of solnatide, once daily for 3 consecutive days. After 3 days, arterial blood gas, BAL fluid, lung water content, and histologic and ultra-microstructure analyses were performed. Tight junction protein occludin was assayed by using immunohistochemistry. RESULTS: Rats treated with solnatide had significantly lower BAL fluid protein and lung water content than high-altitude control rats. Lungs of solnatide-treated rats were intact and showed less hemorrhage and disruption of the alveolar-capillary barrier than those of high-altitude control animals. Occludin expression was significantly higher in solnatide-treated animals, compared with high-altitude control, dexamethasone-, and aminophylline-treated animals. CONCLUSIONS: Solnatide reduced pulmonary edema, increased occludin expression, and improved gas-blood barrier function during acute hypobaric hypoxia and exercise in rats. These results provide a rationale for the clinical application of solnatide to patients with pulmonary edema and exposure to a high-altitude hypoxic environment.

Propranolol Reduces Cardiac Index But does not Adversely Affect Peripheral Perfusion in Severely Burned Children.

PURPOSE: The aim of this study was to quantify the effect of propranolol on hemodynamic parameters assessed using the PiCCO system in burned children. METHODS: We analyzed hemodynamic data from patients who were randomized to receive either propranolol (4 mg/kg/day) or placebo (control), which was initiated as a prospective randomized controlled trial. Endpoints were cardiac index (CI), percent predicted heart rate (%HR), mean arterial pressure (MAP), percent predicted stroke volume (%SV), rate pressure product (RPP), cardiac work (CW), systemic vascular resistance index (SVRI), extravascular lung water index (EVLWI), arterial blood gases, events of lactic acidosis, and mortality. Mixed multiple linear regressions were applied, and a 95% level of confidence was assumed. RESULTS: One hundred twenty-one burned children (control: n = 62, propranolol: n = 59) were analyzed. Groups were comparable in demographics, EVLWI, SVRI, %SV, arterial blood gases, Denver 2 postinjury organ failure score, incidence of lactic acidosis, or mortality. Percent predicted HR, MAP, CI, CW, and RPP were significantly reduced in the propranolol-treated group (P <0.01). CONCLUSIONS: Propranolol significantly reduces cardiogenic stress by reducing CI and MAP in children with severe burn injury. However, peripheral oxygen delivery was not reduced and events of lactic acidosis as well as organ dysfunction was not higher in propranolol treated patients.

Effects of different concentrations of isoflurane pretreatment on respiratory mechanics, oxygenation and hemodynamics in LPS-induced acute respiratory distress syndrome model of juvenile piglets.

PURPOSE: This study was prospectively designed to investigate the effects of different concentrations of isoflurane (ISO) pretreatment on respiratory mechanics, oxygenation, and hemodynamics in lipopolysaccharide (LPS)-induced acute respiratory distress syndrome (ARDS) model of juvenile piglets. METHODS: Twenty-four piglets (9-14 kg, 5-6 weeks old) were randomly assigned to four groups (n = 6): LPS group, which was injected with LPS (20 µg/kg) to induce ARDS; 0.5 ISO-LPS, 1.0 ISO-LPS, and 1.3 ISO-LPS groups, which were pretreated with 0.5, 1.0, and 1.3 minimum alveolar concentrations (MAC) ISO for 30 min before immediate LPS infusion, respectively. After establishment of ARDS, respiratory mechanism, oxygenation and hemodynamics parameters were measured at baseline, and 0, 1, 2, 3, and 4 hours after induction of ARDS. RESULTS: After induction of ARDS, there were increases in alveolar-arterial oxygen difference (A-aDO2), oxygenation index (OI), mean airway pressure (MAP), dead space-to-tidal volume ratio, heart rate (HR), dP/dtmax, extravascular lung water index, pulmonary vascular permeability index, and PaCO2, and decreases in PaO2/FIO2, respiratory rate (RR), dynamic lung compliance (Cdyn), mean arterial blood pressure (MABP) and systemic vascular resistance (SVR) compared with baseline (P(time) < 0.05). Pretreatment with 1.0 and 1.3 MAC ISO alleviated changes in dP/dtmax and PaCO2 at ARDS 0-2 hours, SVR at 0-3 hours, PaO2/FIO2, RR, and MABP at 1-2 hours, HR at 2-3 hours, A-aDO2 at 3-4 hours, and OI at 4 hours (P(group) < 0.05). CONCLUSION: Pretreatment with 1.0 and 1.3 MAC ISO had protective effects on respiratory mechanics, oxygenation, and hemodynamics in piglets with LPS-induced ARDS.

Endogenous acetylcholine increases alveolar epithelial fluid transport via activation of alveolar epithelial Na,K-ATPase in mice.

The contribution of endogenous acetylcholine to alveolar fluid clearance (AFC) and related molecular mechanisms were explored. AFC was measured in Balb/c mice after vagotomy and vagus nerve stimulation. Effects of acetylcholine chloride on AFC in Kunming mice and Na,K-ATPase function in A549 alveolar epithelial cells also were determined. AFC significantly decreased in mice with left cervical vagus nerve transection compared with controls (48.69 ± 2.57 vs. 66.88 ± 2.64, P ≤ 0.01), which was reversed by stimulation of the peripheral (60.81 ± 1.96, P ≤ 0.01). Compared with control, acetylcholine chloride dose-dependently increased AFC and elevated Na,K-ATPase activity, and these increases were blocked or reversed by atropine. These effects were accompanied by recruitment of Na,K-ATPase α1 to the cell membrane. Thus, vagus nerves participate in alveolar epithelial fluid transport by releasing endogenous acetylcholine in the infusion-induced pulmonary edema mouse model. Effects of endogenous acetylcholine on AFC are likely mediated by Na,K-ATPase function through activation of muscarinic acetylcholine receptors on alveolar epithelia.

Comparative effects of propofol and nitroglycerine on efficacy of rewarming in patients undergoing on-pump coronary artery bypass grafting.

OBJECTIVES: To compare the effects of propofol and nitroglycerine (NTG) on the efficacy of rewarming, extra volume added during cardiopulmonary bypass and extravascular lung water (EVLW) in patients undergoing on-pump coronary artery bypass grafting. MATERIALS AND METHODS: A prospective, randomized, blinded trial, twenty adult patients were randomly assigned to receive either NTG infusion (NTG group) or propofol infusion (propofol group) during rewarming. RESULTS: After drop in temperature at the end of surgery and till 24 h were significantly less in propofol group compare to NTG group (P < 0.025). Extra volume added during cardiopulmonary bypass and net crystalloid balance till 24 h was less in the propofol group (P < 0.003). There was no difference in EVLW and postoperative outcome. CONCLUSIONS: Propofol use during moderate hypothermic cardiopulmonary bypass is associated with less after drop in temperature and less requirement of extra fluid during the perioperative period.

TIP peptide inhalation in experimental acute lung injury: effect of repetitive dosage and different synthetic variants.

BACKGROUND: Inhalation of TIP peptides that mimic the lectin-like domain of TNF-α is a novel approach to attenuate pulmonary oedema on the threshold to clinical application. A placebo-controlled porcine model of acute respiratory distress syndrome (ARDS) demonstrated a reduced thermodilution-derived extravascular lung water index (EVLWI) and improved gas exchange through TIP peptide inhalation within three hours. Based on these findings, the present study compares a single versus a repetitive inhalation of a TIP peptide (TIP-A) and two alternate peptide versions (TIP-A, TIP-B). METHODS: Following animal care committee approval ARDS was induced by bronchoalveolar lavage followed by injurious ventilation in 21 anaesthetized pigs. A randomised-blinded three-group setting compared the single-dosed peptide variants TIP-A and TIP-B as well as single versus repetitive inhalation of TIP-A (n = 7 per group). Over two three-hour intervals parameters of gas exchange, transpulmonary thermodilution, calculated alveolar fluid clearance, and ventilation/perfusion-distribution were assessed. Post-mortem measurements included pulmonary wet/dry ratio and haemorrhage/congestion scoring. RESULTS: The repetitive TIP-A inhalation led to a significantly lower wet/dry ratio than a single dose and a small but significantly lower EVLWI. However, EVLWI changes over time and the derived alveolar fluid clearance did not differ significantly. The comparison of TIP-A and B showed no relevant differences. Gas exchange and ventilation/perfusion-distribution significantly improved in all groups without intergroup differences. No differences were found in haemorrhage/congestion scoring. CONCLUSIONS: In comparison to a single application the repetitive inhalation of a TIP peptide in three-hour intervals may lead to a small additional reduction the lung water content. Two alternate TIP peptide versions showed interchangeable characteristics.

Heparin-binding protein (HBP/CAP37) - a link to endothelin-1 in endotoxemia-induced pulmonary oedema?

BACKGROUND: Vascular leakage and oedema formation are key components in sepsis. In septic patients, plasma levels of the vasoconstrictive and pro-inflammatory peptide endothelin-1 (ET-1) correlate with mortality. During sepsis, neutrophils release heparin-binding protein (HBP) known to increase vascular permeability and to be a promising biomarker of human sepsis. As disruption of ET-signalling in endotoxemia attenuates formation of oedema, we hypothesized that this effect could be related to decreased levels of HBP. To investigate this, we studied the effects of ET-receptor antagonism on plasma HBP and oedema formation in a porcine model of sepsis. In addition, to further characterize a potential endothelin/HBP interaction, we investigated the effects of graded ET-receptor agonist infusions. METHODS: Sixteen anesthetized pigs were subjected to 5 h of endotoxemia and were randomized to receive either the ET-receptor antagonist tezosentan or vehicle after 2 h. Haemodynamics, gas-exchange and lung water were monitored. In separate experiments, plasma HBP was measured in eight non-endotoxemic animals exposed to graded infusion of ET-1 or sarafotoxin 6c. RESULTS: Endotoxemia increased plasma ET-1, plasma HBP, and extravascular lung water. Tezosentan-treatment markedly attenuated plasma HBP and extravascular lung water, and these parameters correlated significantly. Tezosentan decreased pulmonary vascular resistance and increased respiratory compliance. In non-endotoxemic pigs graded ET-1 and sarafotoxin 6c infusions caused a dose-dependent increase in plasma HBP. CONCLUSIONS: ET-receptor antagonism reduces porcine endotoxin-induced pulmonary oedema and plasma levels of the oedema-promoting protein HBP. Moreover, direct ET-receptor stimulation distinctively increases plasma HBP. Together, these results suggest a novel mechanism by which ET-1 contributes to formation of oedema during experimental sepsis.

Ulinastatin suppresses burn-induced lipid peroxidation and reduces fluid requirements in a Swine model.

Objective. Lipid peroxidation plays a critical role in burn-induced plasma leakage, and ulinastatin has been reported to reduce lipid peroxidation in various models. This study aims to examine whether ulinastatin reduces fluid requirements through inhibition of lipid peroxidation in a swine burn model. Methods. Forty miniature swine were subjected to 40% TBSA burns and were randomly allocated to the following four groups: immediate lactated Ringer's resuscitation (ILR), immediate LR containing ulinastatin (ILR/ULI), delayed LR resuscitation (DLR), and delayed LR containing ulinastatin (DLR/ULI). Hemodynamic variables, net fluid accumulation, and plasma thiobarbituric acid reactive substances (TBARS) concentrations were measured. Heart, liver, lung, skeletal muscle, and ileum were harvested at 48 hours after burn for evaluation of TBARS concentrations, activities of antioxidant enzymes, and tissue water content. Results. Ulinastatin significantly reduced pulmonary vascular permeability index (PVPI) and extravascular lung water index (ELWI), net fluid accumulation, and water content of heart, lung, and ileum in both immediate or delayed resuscitation groups. Furthermore, ulinastatin infusion significantly reduced plasma and tissue concentrations of TBARS in both immediate or delayed resuscitation groups. Conclusions. These results indicate that ulinastatin can reduce fluid requirements through inhibition of lipid peroxidation.

Treatment of pulmonary edema by ENaC activators/stimulators.

Lungs contain a particular amount of fluid that is crucial for proper lung function. This fluid content is tightly controlled within certain limits. Fluid accumulation in the alveolar airspace impairs gas exchange and represents a lifethreatening condition referred to as pulmonary edema. Ion transport processes by pulmonary epithelia represent a mechanism, responsible for fluid absorption from the airspace. Thus, it is obvious to consider ion transport processes as target for therapeutic interventions in pulmonary edema. The principle mechanism responsible for fluid absorption from the airspace is: Na(+) diffuses through luminal Na(+) channels into epithelial cells and is extruded by Na(+)/K(+)-ATPases at the basolateral side. This process generates an osmotic gradient that represents the driving force for fluid absorption. The rate of Na(+) absorption is limited by the number/activity of Na+ channels in the luminal membrane of alveolar epithelial cells. Although different Na+ channels have been identified, the epithelial Na+ channel (ENaC) is a major player that participates in Na(+)-driven fluid absorption and thus a suitable target for the treatment of pulmonary edema. This article reviews cellular mechanisms by which ENaC activity can be increased in alveolar epithelia (lectins, proteases, ß-adrenoceptors, mineralo-/glucocorticoid-receptors). These mechanisms are involved in regulating ENaC-dependent fluid absorption under physiological conditions. Additionally, pre-clinical as well as some preliminary clinical studies revealed that "ENaC-activators/stimulators" (ß2-adrenoceptor agonists and mineralo-/glucocorticoid-receptor agonists) could be beneficial for therapeutic interventions in patients with pulmonary edema. However, the outcome of subsequently performed multicenter clinical trials with "ENaC-activators/stimulators" for treatment of patients with pulmonary edema was disappointing.

Fluid resuscitation of adults with severe falciparum malaria: effects on Acid-base status, renal function, and extravascular lung water.

OBJECTIVE: To evaluate the efficacy and safety of liberal fluid resuscitation of adults with severe malaria. DESIGN, SETTING, PATIENTS, AND METHODS: Twenty-eight Bangladeshi and Indian adults with severe falciparum malaria received crystalloid resuscitation guided by transpulmonary thermodilution (PiCCO) in an intensive care setting. Systemic hemodynamics, microvascular indices and measures of acidosis, renal function, and pulmonary edema were followed prospectively. RESULTS: All patients were hypovolemic (global end-diastolic volume index<680 mL/m) on enrollment. Patients received a median (range) 3230 mL (390-7300) of isotonic saline in the first 6 hours and 5450 mL (710-13,720) in the first 24 hours. With resuscitation, acid-base status deteriorated in 19 of 28 (68%), and there was no significant improvement in renal function. Extravascular lung water increased in 17 of 22 liberally resuscitated patients (77%); eight of these patients developed pulmonary edema, five of whom died. All other patients survived. All patients with pulmonary edema during the study were hypovolemic or euvolemic at the time pulmonary edema developed. Plasma lactate was lower in hypovolemic patients before (rs=0.38; p=0.05) and after (rs=0.49; p=0.01) resuscitation but was the strongest predictor of mortality before (chi-square=9.9; p=0.002) and after resuscitation (chi-square=11.1; p<0.001) and correlated with the degree of visualized microvascular sequestration of parasitized erythrocytes at both time points (rs=0.55; p=0.003 and rs=0.43; p=0.03, respectively). Persisting sequestration was evident in 7 of 15 patients (47%) 48 hours after enrollment. CONCLUSIONS: Lactic acidosis--the strongest prognostic indicator in adults with severe falciparum malaria--results from sequestration of parasitized erythrocytes in the microcirculation, not from hypovolemia. Liberal fluid resuscitation has little effect on this sequestration and does not improve acid-base status or renal function. Pulmonary edema--secondary to increased pulmonary vascular permeability--is common, unpredictable, and exacerbated by fluid loading. Liberal fluid replacement of adults with severe malaria should be avoided.

Hypertonic solution decreases extravascular lung water in cardiac patients undergoing cardiopulmonary bypass surgery.

OBJECTIVE: To test the hypothesis that the infusion of hypertonic solution would decrease extravascular lung water postoperatively and thus improve pulmonary function. DESIGN: Prospective, randomized, blinded trial. SETTING: Tertiary cardiothoracic referral center. PARTICIPANTS: Twenty-six patients with coronary artery disease who underwent surgery with cardiopulmonary bypass (CPB). INTERVENTIONS: Patients were allocated randomly to receive 4 mL/kg of 7.2% NaCl/hydroxyethyl starch, 200/0.5 (HSH group) or an equal volume of 0.9% NaCl (control group) for 30 minutes starting after anesthesia induction. The extravascular lung water index, hemodynamic and biochemical data, and the rate of complications were analyzed. MEASUREMENTS AND MAIN RESULTS: The extravascular lung water index was significantly lower (7 v 9.5 mL/kg) in the HSH group at the first postoperative day (p < 0.01). The index of arterial oxygenation efficiency was significantly higher at 5 minutes and 2 and 4 hours after cardiopulmonary bypass (CPB) in the HSH group (p < 0.05). The alveolar-arterial oxygen tension difference was significantly lower at 5 minutes and 2 and 4 hours after CPB in the HSH group (p < 0.01). The cardiac index was significantly higher at 5 minutes after infusion in the HSH group (p < 0.05). CONCLUSIONS: The infusion of HSH leads to significant decreases in the extravascular lung water index during and after cardiac surgery and is associated with better preservation of pulmonary function and transient increases in the cardiac index. Further trials are needed to clarify the clinical advantages of hypertonic solution administration in patients undergoing surgery with CPB.

Evaluation of respiratory dysfunction in a pig model of severe acute dichlorvos poisoning.

BACKGROUND: Respiratory failure is the main cause of death in acute organophosphorus pesticide poisoning. In this study, a pulse-induced contour cardiac output monitor was used to evaluate the respiratory status in a pig model of acute dichlorvos poisoning. METHODS: Twenty female pigs were randomly allocated to dichlorvos (n = 7), atropine (n = 7), and control (n = 6) groups. In the dichlorvos group, pigs were administered 80% emulsifiable dichlorvos (100 mg/kg) via a gastric tube. In the atropine group, pigs were similarly administered dichlorvos, and 0.5 hours later, atropine was injected to attain and maintain atropinization. The control group was administered saline solution. Arterial blood gas was measured at 0, 0.5, 1, 2, 4, and 6 hours post-injection. The extravascular lung water index and pulmonary vascular permeability index were recorded by the pulse-induced contour cardiac output monitor. At termination of the study, the animals were euthanized, the lung wet-to-dry weight ratio was determined, and histopathology was observed. RESULTS: In the dichlorvos group, the extravascular lung water index and pulmonary vascular permeability index were substantially increased from 0.5 hours and were particularly high within 1 hour. In the atropine group, these indices increased initially, but decreased from the 1-hour mark. The control group exhibited no obvious changes. In both the dichlorvos and atropine groups, the extravascular lung water index was negatively correlated with partial pressure of oxygen/fraction of inspiration oxygen (PO2/FiO2) and positively correlated with the pulmonary vascular permeability index. Compared with the control group, the lung wet-to-dry weight ratio markedly increased and the histopathological findings obviously changed in the dichlorvos group, but only mildly increased and changed, respectively, in the atropine group. CONCLUSION: The extravascular lung water index is an appropriate and valuable parameter for assessment of respiratory function in acute dichlorvos poisoning.

Inhaled neutrophil elastase inhibitor reduces oleic acid-induced acute lung injury in rats.

RATIONALE: Neutrophil elastases (NE) play an important role in the pathogenesis of acute lung injury (ALI). NE activities are significantly increased in serums and lungs of patients or animals with ALI. Intravenous infusion (IV) of Sivelestat, an NE inhibitor, can reduce ALI. Through inhalation, drugs reach lungs directly and in high concentration. We hypothesized that inhaled Sivelestat would alleviate oleic acid (OA)-induced ALI in rats. METHODS: Rats were anesthetized and mechanically ventilated, and then ALI was induced by OA injection. One hour later, the animals were randomized to receive either Sivelestat (3 mg/kg/h) or saline inhalation. The effect of Sivelestat IV (3 mg/kg/h) was also investigated. All animals were ventilated and observed for 6 h. RESULTS: OA injection increased NE activities in lung tissues and serums. The increase of NE activities in lung tissues and serums markedly reduced by 77%, and 29%, respectively, by the inhalation of Sivelestat; and 53.8%, and 80%, respectively, by Sivelestat IV. Additionally, inhaled Sivelestat resulted in ameliorated lung injury by reducing edema and infiltration of neutrophils in the lung, improved oxygenation and survival. CONCLUSIONS: An over increased NE activity in lungs may play a vital effect in the pathogenesis of OA-induced ALI in rats. Topical application of nebulized Sivelestat, an NE inhibitor, may reduce OA-induced ALI in rats. Sivelestat inhalation can be developed as a novel treatment for ALI.