Role of arachidonic acid metabolites in oleic acid induced pulmonary injury in a canine model. Effect of ketoconazole (thromboxane synthetase inhibitor)

This study was designed to investigate the effects of ketoconazole, a thromboxane synthetase inhibitor, on pulmonary and systemic hemodynamics and pulmonary function in experimental respiratory distress syndrome. Pulmonary artery infusion of oleic acid (PAIOA), 0.1 ml/kg, was used to cause lung injury. Ten dogs were randomized into two groups (Gps): Gp I (n = 5) acted as control, whereas Gp II (n = 5) were treated with IV ketoconazole (2.5 mg/kg bolus then 10 mg/kg/hour for 2.5 hours). Hemodynamics, extravascular lung water (EVLW), serum levels of PGE2, and TxB2 were obtained at baseline (BL) and at 30-minute intervals for 2.5 hours (T30-T150). After 30 minutes of PAIOA the mean arterial pressure (MAP) decreased significantly in both Gps (131 +/- 17 vs. 88 +/- 9 mmHg Gp 1, 119 +/- 9 vs. 79 +/- 8 mmHg Gp II, P less than 0.05); however, while MAP returned to BL values in Gp II, it remained significantly lower throughout the experimental interval in Gp I. Mean pulmonary artery pressure (MAP) was not significantly affected by PAIOA in either Gp, while pulmonary vascular resistance increased significantly from BL at T120 in Gp II. Pulmonary function measured by partial pressure of arterial O2 (PaO2) and extravascular lung water (EVLW) were significantly affected by PAIOA. There was a significant decrease in PaO2 (66 +/- 6 vs. 96 +/- 8 mmHg, Gp I and 60 +/- 7 vs. 100 +/- 6 mmHg, Gp II) as well as an increase in EVLW (604 +/- 61 vs. 135 +/- 9 ml, Gp I and 641 +/- 110 vs. 117 +/- 18 ml, Gp II) in both Gps.(ABSTRACT TRUNCATED AT 250 WORDS)     

Lung water changes after thermal injury. The effects of crystalloid resuscitation and sepsis.

Respiratory failure after thermal injury is common, but the etiologic roles of high volume crystalloid resuscitation, hypoproteinemia, inhalation injury, or sepsis have not been specifically defined in human studies. We used the thermal-green dye double indicator dilution measurement of extravascular lung water (EVLW) to follow daily lung water changes in seven severly burned adult patients, resuscitated with only crystalloid solutions. An average weight gain of 21.3 kg, a 30% increase (p < 0.001), was present two to three days after admission. Admission EVLW for all patients was 7.9 +/- 1.2 ml/kg, (means +/- SD), and EVLW at the time of maximal weight gain was 5.9 +/- 1.4 ml/kg, a 25% decrease (p < 0.05). Admission pulmonary artery wedge pressure (PAWP) was 8 +/- 3 mmHG, which was not significantly different from PAWP of 13 +/- 4 mmHg at the time of maximal weight gain. In the three patients who died of sepsis, their terminal weight averaged 17.8 kg (27%) above their admitting weight (p < 0.01) and EVLW was 26.4 +/- 4.4 ml/kg, a 200% increase (p < 0.02) from admission. Their terminal PAWP averaged 22 +/- 2 mmHg, a 170% increase (p < 0.005). None of these patients had an increase in EVLW until clinical signs of sepsis occurred and the rise in EVLW preceded the rise in PAWP. Calculated mean plasma colloid osmotic pressure (PCOP) on admission was 20.7 +/- 4.9 mmHg; at the time of maximal weight gain, it was 8.6 +/- 1.7 mmHg (p < 0.001). The PCOP-PAWP gradient fell to -4 +/- 4 mmHg (p < 0.001) at the time of maximal weight gain and remained less than +4 mmHg throughout the study period in all patients. We conclude that massive crystalloid resuscitation while maintaining PAWP below 15 mmHg does not cause an increase in EVLW during the first four days after thermal injury. EVLW actually decreases slightly in all patients despite marked weight gain, hypoproteinemia and a negative PCOP-PAWP gradient. EVLW does not correlate with the PCOP-PAWP gradient in either septic or nonseptic periods. Three patients had severe inhalational injury and normal EVLW for the first four postburn days. It therefore appears that significant interstitial edema does not result from inhalational injury. There is also no evidence that thermal injury causes an early increase in pulmonary capillary permeability. The occurrence of sepsis, however, results in rapid accumulation of lung water, without any change in hydrostatic or osmotic forces. This study supports the primary role of sepsis in altering pulmonary capillary permeability with resulting pulmonary edema.     

Effect of pulmonary artery pressure on extravascular lung water in an experimental model of acute lung injury

BACKGROUND: Lung edema can be influenced by hemodynamic changes in pulmonary circulation. The aim of this study was to evaluate, in an experimental model of acute lung injury, the effect on extravascular lung water (EVLW) of an increase in pulmonary artery pressure (Ppa) without changes in cardiac output and wedge pressure. METHODS: Lung edema was produced by an intravenous oleic acid infusion in mixed-breed pigs weighing 25-31 kg, which, after 20 min, were randomly assigned to a control group (100% FiO(2)) (n = 6) or a high Ppa group (21% FiO(2)) (n = 7). An increase in pulmonary artery pressure of at least 40% over baseline was produced in the high Ppa group by alveolar hypoxia. Hemodynamic, ventilatory and gas exchange parameters were collected at regular intervals. Pulmonary, wedge and capillary pressures were measured with a pulmonary artery catheter and the occlusion technique. EVLW was calculated gravimetrically. RESULTS: At 240 min, both gravimetric-measured EVLW and mean pulmonary artery pressures were significantly higher (P < 0.05) in high Ppa animals vs. controls (12.06 +/- 4.21 vs. 7.98 +/- 2.46 ml/kg and 39.0 +/- 1.3 vs. 26.6 +/- 4.7 mmHg, respectively). Cardiac output (6.8 +/- 2.5 vs. 7.3 +/- 1.3) and pulmonary wedge pressures (9.2 +/- 1.7 vs. 9.4 +/- 2.8 mmHg) were similar. A difference was detected in pulmonary capillary pressures [17.0 +/- 3.3 (high Ppa) vs. 13.8 +/- 2.7 mmHg (controls)] but did not reach statistical significance. CONCLUSIONS: In this model, an increase in pulmonary artery pressure by alveolar hypoxia produces an increase in extravascular lung water, probably related to changes in pulmonary capillary pressures.     

Platelet-activating factor in porcine Pseudomonas acute lung injury

We investigated the role of platelet-activating factor (PAF) in acute septic lung injury by examining the effects of the selective PAF antagonist SRI 63-675 and by measuring PAF in lung tissue in the porcine model. Four groups of pigs (15-25 kg) were studied: saline control (C, n = 5); Pseudomonas (Ps, n = 9), given 5 x 10(8) CFU/ml at 0.3 ml/20 kg/min intravenously over 1 hr; SRI (n = 3), given SRI 63-675 in a 40 mg/kg bolus; and SRI + Ps (n = 5). Ps infusion produced a fulminant lung injury characterized by a threefold increase in pulmonary arterial pressure at 30 min and persistent pulmonary hypertension (P less than 0.05 vs C), a significant (P less than 0.05 vs C) decrease in arterial oxygen tension (PaO2) from 60 min, a significant (P less than 0.05 vs C) increase in extravascular lung water (EVLW) from 120 min, and a significant (P less than 0.05 vs C) increase in albumin flux determined scintigraphically as slope index at 150-180 min. Systemic arterial pressure and cardiac index (CI) decreased significantly (P less than 0.05) in the Ps group vs C at 60 and 180 min, respectively. Bolus injection of SRI 63-675 at the time of Ps infusion blocked the early pulmonary hypertension, attenuated the early and late fall in PaO2, ameliorated the increase in EVLW, and prevented the late (150-180 min) increase in albumin flux. SRI 63-675 had minimal effects on Ps-induced hypotension or alterations in CI.(ABSTRACT TRUNCATED AT 250 WORDS)     

Evaluation of the thermal technic for the quantitative measurement of extravascular lung water

To evaluate the accuracy of the method, sequential measurements (n = 159) of extravascular lung water (EVLW) using the thermo-dye double-indicator dilution technique were performed in 22 critically surgical ill patients. Radiographic grading of lung water content served as clinical standard. Normal mean EVLW defined radiographically without evidence of pulmonary edema was 4.8 +/- 1.1 ml/kg. Early interstitial fluid accumulation was quite accurately detected with 6.9 +/- 2.1 ml/kg EVLW (p less than 0.001 vs normal lung water content). The mean EVLW present with definitive interstitial and alveolar edema was 11.5 +/- 3.8 ml/kg and 19.1 +/- 4.5 ml/kg, respectively. Despite some objections to the method (diffusion limitation of the thermal indicator, uneven regional lung perfusion), this technique for measuring EVLW reliably assesses the degree of pulmonary edema. Even when properly performed, chest roentgenograms only confirm gross changes in the lung water content.     

Experimental and clinical study of cardiopulmonary hemodynamics under one-lung ventilation during transthoracic esophagectomy]

Cardiopulmonary hemodynamics in pre- and postoperative period after transthoracic esophagectomy under one-lung ventilation (OLV) was investigated in experimental and clinical studies. In experimental study, 30 mongrel dogs were assigned to one of the groups: Group 1 (n = 10): 2 hour right thoracotomy alone under one (n = 5)- or two-lung ventilation (TLV) (n = 5), Group 2 (n = 10): thoracotomy + esophagectomy, Group 3 (n = 10): esophagectomy + right thoracic vagotomy. For further evaluation of the effect of vagotomy on increase of extravascular lung water (EVLW) on 3rd POD, the following 2 groups were designed as Group 4-1) (n = 5): thoracotomy + right thoracic vagotomy and Group 4-3) (n = 5): esophagectomy + left thoracic vagotomy. In clinical study, 30 patients underwent transthoracic esophagectomy were randomly divided into either OLV or TLV group. Cardiopulmonary hemodynamics and postoperative complications were investigated in pre- and up to 3 POD. 1. Cardiopulmonary parameters and EVLW except PaO2 and shunt ratio were not different between OLV and TLW groups in experimental study. PaO2 of OLV group dropped from the pre-thoracotomy value of 577 +/- 75 mmHg to 98 +/- 47 mmHg. This decrease was significant in comparison with TLV (582 +/- 85 mmHg to 215 +/- 132 mmHg) (p less than 0.05). Shunt ratio increased in the OLV group from 10 +/- 11% to 37 +/- 13%. This increase was also significant in comparison with TLV (24 +/- 10% from 9 +/- 9%) (p less than 0.05). However, both PaO2 and shunt ratio returned to the pre-thoracotomy value after stopping of OLV and showed no difference compared with TLV. 2. EVLW per kg was not different between 5 groups. Values of right to left lung ratio of EVLW in Group 3 and Group 4-3), 1.77 +/- 0.26 and 1.82 +/- 0.26, were greater than that in Group 1, 1.39 +/- 0.17 (p less than 0.05). This difference seems to be caused by increase of permeability of pulmonary capillaries. 3. Cardiopulmonary parameters and postoperative complications were not different between OLV and TLV groups in clinical study. In conclusion, OLV is a desirable procedure, not only for good exposure of the operative filed, but also for its safety regarding the cardiopulmonary hemodynamics. Transthoracic esophagectomy plus vagal branch denervation, which is necessary for aggressive lymphadenectomy around the trachea, increases EVLW and subsequent pulmonary edema compared with thoracotomy alone.     

Does a hyperoncotic cardiopulmonary bypass prime affect extravascular lung water and cardiopulmonary function in patients undergoing coronary artery bypass surgery?

OBJECTIVE: Different types of colloidal priming for cardiopulmonary bypass (CPB) have been used to reduce fluid load and to avoid the fall of plasma colloid osmotic pressure (COP) that leads to edema formation and consequently can cause organ dysfunction. The discussion about the optimal priming composition, however, is still controversial. We investigated the effect of a hyperoncotic CPB-prime with hydroxyethyl starch (HES) 10% (200;0.5) on extravascular lung water (EVLW) and post-pump cardiac and pulmonary functions. METHODS: In 20 randomized patients undergoing elective coronary artery bypass graft surgery (CABG), a colloid prime (COP: 48 mmHg, HES-group, n = 10) and a crystalloid prime (Ringer's lactate, crystalloid group, n = 10) of equal volume were compared with respect to the effects on cardiopulmonary function. Cardiac index (CI), mean arterial pressure (MAP), pulmonary capillary wedge pressure (PCWP), systemic vascular resistance index (SVRI), pulmonary artery pressure (PAP), pulmonary vascular resistance index (PVRI), alveolo-arterial oxygen difference (AaDO(2)), pulmonary shunt fraction (Q(s)/Q(T)), EVLW (double-indicator dilution technique with ice-cold indocyanine green), COP, fluid balance and body weight were evaluated peri-operatively. RESULTS: Pre-operative demographic and clinical data, CPB-time, cross-clamp time and the number of anastomoses were comparable for both groups. During CPB, COP was reduced by 20% in the HES-group (18.9 +/- 3.7 vs. 23.7 +/- 2.2 mmHg, P < 0.05) while it was reduced by more than 50% of the pre-CPB value (9.8 +/- 2.0 vs. 21.4 +/- 2.1 mmHg, P < 0.05) in the crystalloid group (P < 0.05 HES- vs. crystalloid group). Post-CPB EVLW was unchanged in the HES-group but it was elevated by 22% in the crystalloid group (P < 0.05 HES- vs. crystalloid group), CI was higher in the HES-group (3.4 +/- 0.3 vs. 2.7 +/- 0.5l/min, P < 0.05). Fluid balance was less in the HES-group (813 +/- 619 vs. 2143 +/- 538, P < 0.05). Post-operative weight gain could be prevented in the HES-group but not in the crystalloid group (1.5 +/- 1.2 vs. -0.3 +/- 1.5, P < 0.05). No significant differences were seen for MAP, PAP, PCWP, SVRI, PVRI, AaDO(2) and (Q(s)/Q(T)) between the two groups at any time. CONCLUSIONS: Hyperoncotic CPB-prime using HES 10% improves CI and prevents EVLW accumulation in the early post-pump period, while pulmonary function is unchanged. This effect can be of benefit especially in patients with congestive heart failure.     

CD18 adhesion receptors, tumor necrosis factor, and neutropenia during septic lung injury.

Sequestration of neutrophils (PMNs) in the pulmonary microvasculature and associated neutropenia are characteristic features of experimental models of septic lung injury. The etiology of altered PMN kinetics during septic lung injury is uncertain, but may be partially due to increased adhesiveness of activated PMNs to pulmonary endothelium. This study examines the relationship between the expression of PMN CD18 adhesion receptors, the evolving neutropenia, and plasma tumor necrosis factor (TNF) activity in a porcine model of septic lung injury. Acute lung injury was induced by infusion of live Pseudomonas aeruginosa (5 x 10(8) CFU/ml at 0.3 ml/20 kg/min) for 60 min (Group Ps, n = 6). Control animals (Group C, n = 3) received a 60-min infusion of sterile 0.9% saline. CD18 expression of circulating PMNs was measured by quantitative immunofluorescent flow cytometry. Plasma TNF activity was measured by L929 fibroblast cytolytic assay. Group Ps developed a significant neutropenia by 30 min (14.9 +/- 2.5 vs 23.4 +/- 3.3 x 10(3) cells/microliter at baseline, P less than 0.05, ANOVA) with circulating neutrophils exhibiting significantly increased CD18 expression by 60 min (6.34 +/- 0.72 vs 5.01 +/- 0.52 equivalent soluble fluorescence molecules (ESFM) x 10(3) at baseline, P less than 0.05, ANOVA). Group Ps demonstrated a significant increase in plasma TNF activity by 30 min (2.5 +/- 0.9 vs 0.7 +/- 0.3 U/ml at baseline). There was no significant change in PMN count, PMN CD18 expression, or plasma TNF activity in Group C. In complimentary in vitro studies, porcine PMNs stimulated with recombinant human TNF-alpha (n = 5) demonstrated a time- and dose-dependent increase in CD18 expression.(ABSTRACT TRUNCATED AT 250 WORDS)     

Addition of dextran sulfate to blood cardioplegia attenuates reperfusion injury in a porcine model of cardiopulmonary bypass

Objective: Contact of blood with artificial surfaces and air as well as ischemia/reperfusion injury to the heart and lungs mediate systemic and local inflammation during cardiopulmonary bypass (CPB). Activation of complement and coagulation cascades leads to and accompanies endothelial cell damage. Therefore, endothelial-targeted cytoprotection with the complement inhibitor and endothelial protectant dextran sulfate (DXS, MW 5000) may attenuate CBP-associated myocardial and pulmonary injury. Methods: Eighteen pigs (DXS, n=10; phosphate buffered saline [PBS], n=8) underwent standard cardiopulmonary bypass. After aortic cross-clamping, cardiac arrest was initiated with modified Buckberg blood cardioplegia (BCP), repeated after 30 and 60min with BCP containing either DXS (300mg/10ml, equivalent to 5mg/kg) or 10ml of PBS. Following 30min reperfusion, pigs were weaned from CPB. During 2h of observation, cardiac function was monitored by echocardiography and invasive pressure measurements. Inflammatory and coagulation markers were assessed regularly. Animals were then sacrificed and heart and lungs analyzed. Results: DXS significantly reduced CK-MB levels (43.4+/-14.8ng/ml PBS, 35.9+/-11.1ng/ml DXS, p=0.042) and significantly diminished cytokine release: TNFalpha (1507.6+/-269.2pg/ml PBS, 222.1+/-125.6pg/ml DXS, p=0.0071), IL1beta (1081.8+/-203.0pg/ml PBS, 110.7+/-79.4pg/ml DXS, p=0.0071), IL-6 (173.0+/-91.5pg/ml PBS, 40.8+/-19.4pg/ml DXS, p=0.002) and IL-8 (304.6+/-81.3pg/ml PBS, 25.4+/-14.2pg/ml DXS, p=0.0071). Tissue endothelin-1 levels were significantly reduced (6.29+/-1.90pg/100mg PBS, 3.55+/-1.15pg/100mg DXS p=0.030) as well as thrombin-anti-thrombin formation (20.7+/-1.0mug/ml PBS, 12.8+/-4.1mug/ml DXS, p=0.043). Also DXS reduced cardiac and pulmonary complement deposition, neutrophil infiltration, hemorrhage and pulmonary edema (measured as lung water content, 81+/-3% vs 78+/-3%, p=0.047), indicative of attenuated myocardial and pulmonary CPB-injury. Diastolic left ventricular function (measured as dp/dt(min)), pulmonary artery pressure (21+/-3mmHg PBS, 19+/-3mmHg DXS, p=0.002) and right ventricular pressure (21+/-1mmHg PBS, 19+/-3mmHg DXS p=0.021) were significantly improved with the use of DXS. Conclusions: Addition of DXS to the BCP solution ameliorates post-CPB injury and to a certain extent improves cardiopulmonary function. Endothelial protection in addition to myocyte protection may improve post-CPB outcome and recovery.     

Effects of ibuprofen on a pig Pseudomonas ARDS model

The effects of ibuprofen (I) were studied in the Pseudomonas (P) porcine ARDS model. Pigs, 14-26 kg (5 in each group), were anesthetized and ventilated with 0.5 FiO2 and 5 cm H2O PEEP. A control (C) group received saline only, a second group was given P, 1 X 10(8) org/ml at 0.3 cc/20 kg/min, and a third group was given P followed by 12.5 mg I at 20 and 120 min. Pulmonary arterial (PAP), wedge (PWP) and systemic arterial pressures, cardiac output (CO), and thermal-cardiogreen extravascular lung water (EVLW), thromboxane (TxB2), 6-keto-PGF1 alpha, PaO2, PaCO2 were determined every 30 min. Albumin flux was measured with scintigraphic determination of lung:heart radioactivity ratios versus time, called slope index (SI). At 3 hr, P produced marked (P less than 0.05) increases in PAP (18 +/- 7 to 37 +/- 2 mm Hg), TxB2 (471 +/- 513 to 9216 +/- 3615 pg/ml), 6-keto-PGF1 alpha, EVLW (6.4 +/- 1.4 to 14.6 +/- 5.7 mg/kg), and SI (0.4 +/- 0.2 to 1.7 +/- 0.5 X 10(-3) U/min) with decreases in PaO2 (214 +/- 47 to 101 +/- 41 torr), CO and SAP. Ibuprofen caused a rapid clearing of TxB2 and 6-keto-PGF1 alpha associated with a transient decrease in PAP; PaO2 was considerably improved compared to P; however, CO, SAP, EVLW, and SI were unaffected. Prostaglandin blockage temporarily ameliorated the pulmonary hypertension and markedly improved oxygenation in this porcine septic ARDS model, but failed to alter increased permeability, confirming other studies that the increased pulmonary shunt in ARDS is not only dependent upon capillary leak.     

Ibuprofen prevents deterioration in static transpulmonary compliance and transalveolar protein flux in septic porcine acute lung injury

The effects of intravenous ibuprofen on measurements of pulmonary function and alveolar capillary membrane permeability to protein in sepsis-induced porcine acute lung injury (ALI) were studied. Young swine (15-25 kg) were anesthetized, cannulated, and ventilated (5 cm H2O PEEP, 0.5 FIO2, and 15 cc/kg tidal volume). Three groups were studied: septic animals (Ps, n = 10) received Pseudomonas aeruginosa for 1 hr IV, controls (C, n = 9) received 0.9% NaCl, and ibuprofen-treated septic animals (Ps + Ibu, n = 7) received ibuprofen 12.5 mg/kg at 0 and 120 min post Ps. Systemic (SAP) and pulmonary (PAP) arterial pressures, PaO2, cardiac index (CI), static lung compliance (CL), EVLW (thermal cardiogreen), and peripheral white blood cell counts (WBC) were measured. Bronchoalveolar lavage (BAL) was performed for protein and % neutrophil (%PMN) content. Results: Ps produced significant (p less than 0.05) decreases in CL, PaO2, SAP, CI, and peripheral WBC and increases in PAP, EVLW, BAL protein, and %PMN's vs. controls. Ibu prevented the early increase in PAP and attenuated the late increase in PAP and EVLW. Ibu also maintained PaO2, CL, BAL protein, and %PMN's in BAL at control levels, but exhibited no significant effect on peripheral leukopenia. These data strongly suggest that ibuprofen administered before and at 120 min after onset of Pseudomonas infusion improves lung compliance and affects neutrophil function sufficiently to significantly ameliorate many of the physiologic derangements in acute sepsis.     

Treatment of porcine Pseudomonas ARDS with combination drug therapy

A combination drug therapy (Poly-5: ibuprofen 12.5 mg/kg, methylprednisolone 30 mg/kg, cimetidine 150 mg, diphenhydramine 10 mg/kg, and ketanserin 0.2 mg/kg) given at 20 and 120 minutes after starting continuous intravenous Pseudomonas (Ps, 5 X 10(8) CFU/20 kg/min) was studied in three groups of swine: saline control (C, n = 9), Ps alone (Ps, n = 8), and Ps plus Poly-5 (n = 5). PaO2, systemic (SAP) and pulmonary arterial (PAP) pressures, cardiac index (CI), thermal-cardiogreen extravascular lung water (EVLW), pulmonary albumin flux (slope index, SI), and arterial blood serotonin levels (5-HT) were measured. Ps produced significant (p less than 0.05) increases in PAP, EVLW, and SI with decreases in PaO2, CI, and SAP. 5-HT fell significantly compared to baseline. Poly-5 prevented (p less than 0.05) the rise in EVLW and SI and the fall in PaO2 and CI compared to Ps. PAP and SI were maintained at C until 90 and 150 minutes, respectively. SAP fell significantly from C at 30, 60, and 180 minutes. 5-HT was significantly lower than Ps throughout, and significantly lower than baseline at 180 minutes. Combined blockade of arachidonic acid metabolites, histamine, and serotonin receptors prevented hypoxemia, increased pulmonary capillary permeability, and cardiovascular deterioration in this porcine septic ARDS model.     

Measurement of extravascular lung water by double-indicator dilution method amd its clinical assessment

In this study, thermal-dye double-indicator dilution method using Lung water computer (Edwards Laboratories) was used to detect the changes of extravascular lung water (EVLW) in 14 patients, including 8 head injuries, one multiple injury, and 5 burns. The coefficient of variation of multiple readings at the same time was 5.04 +/- 3.64% (M +/- SD, n = 180), so reproducibility was excellent. EVLW showed no correlation with cardiac index, Qs/Qt ratio, PAO2/PaO2 ratio, and PaO2/FiO2 ratio, but did show significant correlation with pulmonary capillary wedge pressure (PCWP) (r = 0.50, n = 54, p less than 0.01). In non-septic period of burn patients, EVLW showed good correlation with COP-PCWP gradient (r = -0.75, n = 54, p less than 0.01), better correlation than with PCWP only. In septic period, it had no correlation with the gradient, probably due to the enhanced pulmonary capillary permeability. Although it is very difficult to determine the threshold of EVLW to diagnose pulmonary edema, the elevation of EVLW appeared earlier than the changes of X-ray films. In estimate of EVLW, we must always take into consideration changes in effective vascular bed and pulmonary capillary permeability. The measurement of EVLW was also of much help in the differential diagnosis of pulmonary edema and other lung diseases.     

Hypertonic saline as a resuscitation solution in hemorrhagic shock: effects on extravascular lung water and cardiopulmonary function

To determine the effect of resuscitation with hypertonic saline on extravascular lung water, seven adult sheep were endotracheally intubated; mean arterial pressure (MAP), pulmonary artery pressure (PAP), pulmonary capillary wedge pressure (PCWP), and central venous pressure (CVP) were monitored. A 5-French, thermistor-tipped catheter was used to measure extravascular lung water (EVLW). Colloid oncotic pressure (COP), serum electrolytes and osmolality, and arterial and mixed venous blood gas tensions were measured. The COP-PCWP gradient and the shunt fraction (Qsp/Qt) were calculated. After baseline measurements, the animals were bled to an MAP of 50 mm Hg (blood volume removed, 16.2 +/- 3.6 ml/kg), which was maintained for 30 min, measurements then being repeated. Three percent sodium chloride solution was infused at 500 ml/15 min until two of three parameters--cardiac output (CO), PCWP, or MAP--were restored to baseline values. Data were recorded again and then 60 min later. No shed blood was reinfused. The total volume of hypertonic saline infused was 39 +/- 19 ml/kg. Pulmonary artery pressure did not vary throughout the study. PCWP, MAP, and CO were significantly lower than baseline (P less than 0.05) 30 min after bleeding but all except MAP returned to baseline with resuscitation. Throughout the study, EVLW did not vary despite a COP-PCWP gradient less than 4 mm Hg. Serum sodium levels and serum osmolality were significantly above baseline values after resuscitation. In this animal model of hemorrhagic shock, infusion of hypertonic saline effected resuscitation without compromising cardiopulmonary function or increasing EVLW.     

Measurement of extravascular lung water in sheep during colloid and crystalloid resuscitation from smoke inhalation

The pathophysiology of pulmonary inhalation injury, a major cause of morbidity and mortality from fires, is poorly understood. To examine the effects of colloid and crystalloid resuscitation on extravascular lung water (EVLW) during a standard smoke inhalation injury, we subjected 12 sheep to 8 minutes of cool pine smoke inhalation. The animals were then resuscitated to a pulmonary capillary wedge pressure (PCWP) of 10 +/- 1.5 mm Hg with either lactated Ringer's solution or plasma protein derivative. EVLW, cardiac output, vascular resistance, colloid oncotic pressure (COP), arterial and pulmonary artery pressures, PCWP, and blood gases were monitored during 4 hours of resuscitation. In colloid-treated animals, EVLW increased from 8.3 +/- 1.2 to 11.1 +/- 0.9 ml/kg with injury; it increased only to 12.5 +/- 1.3 ml/kg during resuscitation. In crystalloid-treated animals, EVLW increased from 8.0 +/- 1.0 to 10.3 +/- 0.8 ml/kg with injury and further increased to 17.4 +/- 1.6 ml/kg during resuscitation, a level significantly higher than that in the colloid group (P less than 0.05). The increases in EVLW were associated with progressive hypoxia, which was worse in the crystalloid group. In the crystalloid group, COP decreased from 27.3 +/- 0.9 to 14.2 +/- 0.4 mm Hg and intravascular driving force (COP-PCWP) dropped from 17.6 to 3.26 +/- 1.5 mm Hg; COP and COP-PCWP were maintained in the colloid group. These data demonstrate that supporting serum COP minimizes the increase in EVLW with smoke inhalation injury and suggests that smoke inhalation does not lead to a dramatic increase in alveolar capillary membrane permeability to protein.     

The measurement of extra vascular lung water using a thermal-sodium double indicator dilution technique in patients undergoing surgery for esophageal cancer

The Extra Vascular Lung Water (EVLW) was measured using the thermal sodium double indicator dilution technique in 21 patients undergoing surgery for esophageal cancer. This measurement is an important parameter in the control of the respiratory function. In the 16 cases without pulmonary complications, the preoperative EVLW was 5.3 +/- 0.2 (mean +/- SEM) ml/kg and the immediate postoperative EVLW was 4.8 +/- 0.4 ml/kg. This change was significant (p less than 0.05), but within 24 hours the EVLW returned to almost the same levels as those recorded before surgery. In only 3 cases, the EVLW were elevated beyond 7.5 ml/kg, but these high EVLW levels did not continue for more than 12 hours. Of the 5 patients with pulmonary complications, only two experienced pulmonary edema. Their preoperative EVLW levels were normal, but the immediate postoperative EVLW levels were significantly elevated beyond 10 ml/kg. These elevated levels were observed before the PaO2, the portable chest roentgenograms and the other test results changed following surgery. The high EVLW levels beyond 7.5 ml/kg continued for 72 hours after surgery. We found no correlation between the EVLW and measureable hemodynamic parameters (Cardiac Index, Pulmonary Wedge Pressure, Colloid Osmotic Pressure-Pulmonary Wedge Pressure gradient) during the observation period. In the other cases with pulmonary complications (2 cases were pneumonia, one was atelectasis with pneumonia), the changes in the EVLW levels were the same as for the cases without pulmonary complications. These results indicate that the EVLW is the optimum parameter for the control of the respiratory function and early diagnosis of pulmonary edema after surgery for esophageal cancer.     

Partial liquid ventilation reduces fluid filtration of isolated rabbit lungs with acute hydrochloric acid-induced edema

BACKGROUND: Hydrochloric acid aspiration increases pulmonary microvascular permeability. The authors tested the hypothesis that partial liquid ventilation has a beneficial effect on filtration coefficients in acute acid-induced lung injury. METHODS: Isolated blood-perfused rabbit lungs were assigned randomly to one of four groups. Group 1 (n = 6) served as a control group without edema. In group 2 (n = 6), group 3 (n = 6), and group 4 (n = 6), pulmonary edema was induced by intratracheal instillation of hydrochloric acid (0.1 N, 2 ml/kg body weight). Filtration coefficients were determined 30 min after this injury (by measuring loss of perfusate after increase of left atrial pressure). Group 2 lungs were gas ventilated, and group 3 lungs received partial liquid ventilation (15 ml perfluorocarbon/kg body weight). In group 4 lungs, the authors studied the immediate effects of bronchial perfluorocarbon instillation on ongoing filtration. RESULTS: Intratracheal instillation of hydrochloric acid markedly increased filtration coefficients when compared with non-injured control lungs (2.3 +/- 0.7 vs. 0.31 +/- 0.08 ml.min(-1). mmHg(-1).100 g(-1) wet lung weight, P < 0.01). Partial liquid ventilation reduced filtration coefficients of the injured lungs (to 0.9 +/- 0.3 ml.min(-1).mmHg(-1).100 g(-1) wet lung weight, P = 0.022). Neither pulmonary artery nor capillary pressures (determined by simultaneous occlusion of inflow and outflow of the pulmonary circulation) were changed by hydrochloric acid instillation or by partial liquid ventilation. During ongoing filtration, bronchial perfluorocarbon instillation (5 ml/kg body weight) immediately reduced the amount of filtered fluid by approximately 50% (P = 0.027). CONCLUSIONS: In the acute phase after acid injury, partial liquid ventilation reduced pathologic fluid filtration. This effect started immediately after bronchial perfluorocarbon instillation and was not associated with changes in mean pulmonary artery, capillary, or airway pressures. The authors suggest that in the early phase of acid injury, reduction of fluid filtration contributes to the beneficial effects of partial liquid ventilation on gas exchange and lung mechanics.     

The effects of tumor necrosis factor and their selective inhibition by ibuprofen.

High doses of tumor necrosis factor (TNF) cause hypotension, metabolic acidosis and, death. At Brigham and Women's Hospital, the effects of a sublethal, 6-hour infusion of TNF (0.57 X 10(5) Units/kg body weight) in twelve anesthetized dogs were studied. The dose caused falls in mean arterial pressure from 153 mmHg to 96 mmHg, pulmonary artery pressure (-4.5 mmHg), central venous pressure (-2.5 mmHg) and pulmonary capillary wedge pressures (-5.25 mmHg). Associated with these responses were a fourfold increase in urine volume (22.4 ml/kg/6 hours as compared to 5.2 ml/kg/6 hours in controls), significant pyrexia (from 38.1 C to 39.5 C, rectal), tachycardia (from 125 to 175 beats/minute), and hypermetabolism. In addition, leukopenia and increased circulating stress hormone concentrations were observed. Blood glucose concentrations fell from 4.68 mM/1 to 3.97 mM/1 (84-71 mg/dl) within 3 hours of TNF infusion, whereas lactate and pyruvate concentrations increased. These alterations occurred in the absence of severe hypotension or acidosis and were similar to changes observed after endotoxin administration or gram-negative septicemia. Pretreatment of the animals with the cyclooxygenase inhibitor ibuprofen abolished most of the hemodynamic changes and attenuated other responses. These findings support the hypothesis that TNF is an important mediator of septic responses and that some of the effects of TNF are mediated via cyclooxygenase pathways.     

Neurogenic pulmonary edema in the acute stage of hemorrhagic cerebrovascular disease

Extravascular lung water (EVLW) was measured by the double-indicator dilution method in 25 patients with hemorrhagic cerebrovascular diseases. EVLW had a significantly positive correlation with both alveolar-arterial oxygen difference (AaDO2) and intrapulmonary shunt. The value of EVLW in the acute stage in 15 patients with increased AaDO2 more than 20 mm Hg was 7.8 +/- 2.2 ml/kg and that in the chronic stage 4 weeks after onset significantly decreased to 4.6 +/- 0.7 ml/kg (P less than 0.001). The value of EVLW in the acute stage in 10 patients with normal AaDO2 less than 20 mm Hg was 4.7 +/- 1.1 ml/kg and that in the chronic stage 4 weeks after onset was 4.5 +/- 0.2 ml/kg. There was no significant difference between them. Pulmonary arterial blood pressure, pulmonary capillary wedge pressure, central venous pressure, cardiac index, systemic vascular resistance index, and pulmonary vascular resistance index in the acute stage in the 25 patients were all within the normal range. Three patients with neurogenic pulmonary edema had markedly increased EVLW without abnormalities in pulmonary arterial blood pressure, pulmonary capillary wedge pressure, central venous pressure, cardiac index, systemic vascular resistance index, and pulmonary vascular resistance index. From these facts, the main cause of the increase in EVLW cannot be explained by left ventricular failure, but can be explained by high permeability pulmonary edema.     

Delayed cyclo-oxygenase blockade reduces the neutrophil respiratory burst and plasma tumor necrosis factor levels in sepsis-induced acute lung injury.

Ibuprofen pretreatment attenuates the enhanced neutrophil (PMN) respiratory burst and reduces increased plasma tumor necrosis factor (TNF) activity in porcine sepsis-induced acute lung injury (ALI). These septic responses have been linked to increased alveolar-capillary membrane (ACM) permeability. This study was designed to establish whether delayed ibuprofen treatment would have the same effect and to examine the relationship between PMN oxidant generation and TNF. Three groups of anesthetized, ventilated pigs (15-25 kg) were used. Group Ps received Pseudomonas aeruginosa (5 x 10(8) CFU/mL at 0.3 mL/20 kg/min) for one hour IV; The control group (Con) received 0.9% NaCl. Group D-Ibu received ibuprofen 12.5 mg/kg as a delayed bolus at 30 minutes and again at 120 minutes after Ps. Protein (BAL-P, microgram/mL) in harvested bronchoalveolar lavage fluid and extravascular lung water (EVLW, mL/kg) were used to estimate the integrity of the ACM. Superoxide anion (O2-) generation (ferricytochrome c reduction) from circulating PMNs and plasma TNF activity (L929 fibroblast bioassay) were measured. The EVLW increased significantly (p less than 0.05), as did BAL-P (p less than 0.01), in the P. aeruginosa-treated animals at 300 minutes. These increases were abolished in Group D-Ibu: EVLW, 6.6 +/- 1.0 baseline vs. 14.6 +/- 2.6 Ps 300 vs. 6.8 +/- 0.9 D-Ibu 300; BAL-P, 175 +/- 28 baseline vs. 984 +/- 186 Ps 300 vs. 284 +/- 42.8 D-Ibu 300. Both enhanced PMN oxidant activity and increased plasma TNF activity were significantly attenuated by delayed ibuprofen treatment. These data support the efficacy of the nonsteroidal anti-inflammatory drug, ibuprofen, when used after the onset of a septic stimulus.