High-frequency oscillatory ventilation does not decrease endothelin release in lung-lavaged rabbits

High-frequency oscillatory ventilation (HFO) has been shown to reduce lung injury and pulmonary arterial pressure (PAP). We hypothesized that HFO leads to decreased endothelin 1 (ET-1) and endothelin 3 (ET-3) release when compared to conventional mechanical ventilation (CMV) in lung-lavaged rabbits. Design: Prospective, randomized, controlled animal study. In 26 adult New Zealand White Rabbits ventilated by CMV or HFO under hypoxemic and normoxemic conditions after lung lavage (CMV-hypo: n=5; CMV-normo: n=8; HFO-hypo: n=7; HFO-normo: n=6) we recorded systemic and PAP, measured blood gases, ET-1 and ET-3 and calculated intrapulmonary venous admixture during a 4-h experiment. ET-1 was significantly increased after lavage (p<0.05) with no further increase until the end of the experiment. Neither pulmonary arterial nor systemic arterial ET-1 differed between CMV and HFO or between hypoxemia and normoxemia. Systemic arterial ET-3, however, was significantly higher in HFO-hypo than in the other two groups ventilated under normoxemic conditions at the end of the experiment (HFO-hypo vs. CMV-normo, p<0.05; HFO-hypo vs. HFO-normo, p<0.05). PAP showed a continuous increase in all groups (p<0.05). We did not find any correlation between PAP and ET-1 or ET-3. Intrapulmonary venous admixture increased in animals ventilated under hypoxemic conditions, whereas it decreased after lung lavage in those ventilated under normoxemic conditions until the end of the experiment (HFO-normo, p<0.05). Conclusions: This study suggests that HFO does not decrease ET-1 and ET-3 release compared to CMV in lung-lavaged rabbits. Hypoxemia, however, may increase ET-3 release from the lungs, leading to an increased intrapulmonary shunt.     

高频振荡通气结合低浓度一氧化氮吸入对急性缺氧大鼠肺动脉高压的作用

目的：观察高频振荡通气（ＨＦＯ）联合低浓度一氧化氮（ＮＯ）吸入对急性缺氧大鼠肺动脉高压的治疗作用。方法：在ＨＦＯ下,经气管插管给大鼠１２％氧３０分钟制成急性缺氧肺动脉高压模型,行肺泡再充气,吸入低浓度ＮＯ（１０、５、２ｍｍｏｌ／Ｌ）对模型动物进行治疗,测定血流动力参数和血气值。结果：２～１０ｍｍｏｌ／Ｌ ＮＯ吸入均可逆转急性缺氧大鼠肺动脉压（ＰＡＰ）,收缩压（ｓＰＡＰ）从４．４４～４．５３ｋＰａ（     

High frequency oscillatory ventilation attenuates the activation of alveolar macrophages and neutrophils in lung injury

BACKGROUND: Recent investigations have shown that leukocyte activation is involved in the pathogenesis of ventilator-associated lung injury. This study was designed to investigate whether the inflammatory responses and deterioration of oxygenation in ventilator-associated lung injury are attenuated by high-frequency oscillatory ventilation (HFO). We analyzed the effects of HFO compared with conventional mechanical ventilation (CMV) on the activation of pulmonary macrophages and neutrophils in 10 female rabbits. RESULTS: After surfactant depletion, the rabbits were ventilated by CMV or HFO at the same mean airway pressure. Surfactant-depletion followed by 4 h mechanical ventilation hindered pulmonary oxygenation in both groups. Impairment of oxygenation was less severe in the HFO group than in the CMV group. In the HFO group the infiltration of granulocytes into alveolar spaces occurred more readily than in the CMV group. Compared with CMV, HFO resulted in greater attenuation of beta2-integrin expression, not only on granulocytes, but also on macrophages. CONCLUSIONS: In the surfactant-depleted lung, the activation of leukocytes was attenuated by HFO. Reduced inflammatory response correlated with decreased impairment of oxygenation. HFO may reduce lung injury via the attenuation of pulmonary inflammation.     

Comparison of high-frequency jet ventilation with conventional mechanical ventilation in saline-lavaged rabbits

A surfactant-depletion lung-injury model was produced in 37 New Zealand white rabbits by saline lavage. During the next 2 to 3 h, rabbits were ventilated with conventional mechanical ventilation (CMV, group 1), high-frequency jet ventilation (HFJV, group 2), or CMV for 1 h followed by HFJV for 2 h (CMV/HFJV, group 3). Survival until planned termination of the protocol was 56%, 77%, and 63% in groups 1, 2 and 3, respectively. Causes of early demise were usually pneumothorax or metabolic acidosis. There were no statistically significant differences among the groups with respect to survival, incidence of pneumothorax or metabolic acidosis. Arterial oxygenation was more efficient with HFJV (group 2) (P[A-a]O2 = 372 +/- 51 torr [mean +/- SE] at 2 h) than with CMV (group 1) (P[A-a]O2 = 512 +/- 18 torr at 2 h, p less than .01). Furthermore, oxygen gas exchange in 3 of 5 group 3 rabbits improved after institution of HFJV. In contrast to previous findings with high-frequency oscillation (HFO), there were no qualitative histologic differences between lungs ventilated with HFJV vs. CMV. Thus, although HFJV produced more efficient gas exchange in this model, it did not improve pulmonary pathology. HFO may be preferable to HFJV in infant respiratory distress syndrome.     

Acute effects of combined high-frequency oscillation and tracheal gas insufflation in severe acute respiratory distress syndrome

OBJECTIVE: In acute respiratory distress syndrome (ARDS), high-frequency oscillation (HFO) improves oxygenation relative to conventional mechanical ventilation (CMV). Alveolar ventilation is improved by adding tracheal gas insufflation (TGI) to CMV. We hypothesized that combined HFO and TGI (HFO-TGI) might result in improved gas exchange relative to both standard HFO and CMV according to the ARDS Network protocol. DESIGN: Prospective, randomized, crossover study. SETTING: A 30-bed university intensive care unit. PATIENTS: A total of 14 patients with early (<72 hrs in duration), severe (PaO2/FiO2 of <150 mm Hg and prerecruitment oxygenation index of 22.8 +/- 1.9 [mean +/- SEM]), primary ARDS. INTERVENTIONS: Patients were ventilated with HFO without (60 mins) and combined with TGI (6.1 +/- 0.1 L/min, 60 mins) in random order. HFO sessions were repeated in inverse order within 24 hrs. HFO sessions were preceded and followed by ARDS Network CMV. Four recruitment maneuvers were performed during the study period. During HFO sessions, mean airway pressure was set at 1 cm H2O above the point of maximal curvature of the respiratory system expiratory pressure-volume curve. MEASUREMENTS AND MAIN RESULTS: Gas exchange and hemodynamics were determined before, during, and after HFO sessions. HFO-TGI improved PaO2/FiO2 relative to HFO and CMV (174.5 +/- 10.4 vs. 136.0 +/- 10.0 and 105.0 +/- 3.7 mm Hg, respectively, p < .05 for both) and oxygenation index relative to HFO (17.1 +/- 1.3 vs. 22.3 +/- 1.7, respectively p < .05). PaO2/FiO2 returned to baseline within 3 hrs after HFO. During HFO-TGI, shunt fraction and mixed venous oxygen saturation improved relative to CMV (0.36 +/- 0.01 vs. 0.45 +/- 0.01 and 77.8% +/- 1.2% vs. 71.8% +/- 1.3%, respectively, p < .05 for both). PaCO2 and hemodynamics were unaffected by HFO sessions. Respiratory mechanics remained unchanged throughout the study period. CONCLUSIONS: In early onset, primary, severe ARDS, short-term HFO-TGI improves oxygenation relative to standard HFO and ARDS Network CMV.     

Interaction of acetylcholine and endothelin-1 in the modulation of pulmonary arterial pressure

OBJECTIVE: The study was designed to investigate the effects of acetylcholine (ACh) on pulmonary circulation with special regard to mediators that could be involved in the mediation of ACh-induced effects. ACh has been reported to induce either vasodilation or vasoconstriction in the pulmonary circulation of different species. DESIGN: Prospective experimental study in rabbits. SETTING: Experimental laboratory in a university teaching hospital. SUBJECTS: Sixty-six adult rabbits of either sex. INTERVENTIONS: The experiments were performed on 66 isolated and ventilated rabbit lungs that were perfused with a cell- and plasma-free buffer solution. ACh was injected in various concentrations after pulmonary artery preconstriction and in untreated lungs. MEASUREMENTS AND MAIN RESULTS: Pulmonary arterial pressure (PAP) and lung weight gain were monitored continuously. Perfusate samples were taken intermittently to determine endothelin-1 (ET-1), thromboxane A2 (TXA2), and prostacyclin (PGI2) concentrations. ACh in final dosages from 10(-5) to 10(-2) M (n = 6 each) was injected into the pulmonary artery of lungs treated with U46619 to induce pulmonary arterial hypertension or was injected into untreated lungs. To analyze the potential mechanisms of action, ACh (10(-5) M) was administered in additional experiments after pretreatment with either ETA receptor antagonist BQ123 (10(-6) M; n = 6) or the cyclooxygenase inhibitor diclofenac (10 microg/mL; n = 6). In preconstricted pulmonary vessels, ACh (10(-3) and 10(-2) M) initially induced a PAP rise for 10 mins followed by a sustained decrease. In untreated lungs, ACh induced an immediate dose-dependent increase in PAP, requiring as long as 30 mins to return to predrug levels. Simultaneously, significantly elevated TXA2 and PGI2 levels were observed. Furthermore, ET-1 was detected in the perfusate, which was free from ET-1 before ACh administration. Pretreatment with BQ123 reduced substantially the ACh (10(-5) M)-induced PAP increase and the release of TXA2 and PGI2. At 5 mins, the PAP maximum was reduced from 18.5 +/- 3.2 mm Hg to 9.9 +/- 0.65 mm Hg by BQ123 pretreatment (p < .01). An inhibition of PAP increase was also observed after diclofenac pretreatment (11.6 +/- 0.4 mm Hg at 5 mins; p < .05). Inhibitory effects at 5 mins were significantly more pronounced in the BQ123 group compared with the diclofenac group. CONCLUSIONS: The effects of ACh on the pulmonary circulation of isolated rabbit lungs depend on ACh concentration and the basal tone of the arterial vasculature. In lungs with a normal pulmonary vascular resistance, ACh administration causes vasoconstriction via the release of ET-1 and TXA2, whereas vasodilation is induced in preconstricted pulmonary vessels.     

Effect of high-frequency ventilation on histamine-induced lung injury in dogs

We compared the effects of high-frequency oscillation (HFO) and conventional mechanical ventilation (CMV) on dynamic lung compliance (Cdyn), venous admixture (Qsp/Qt), cardiac output, and total lung resistance (RL) in seven mongrel dogs with histamine-induced lung injury. Baseline measurements during CMV were followed by iv infusion of histamine at 100 micrograms/min. Cdyn, Qsp/Qt, cardiac output, and RL were measured in triplicate during CMV and then during HFO. Subsequently, at least one complete set of measurements was recorded again on CMV. During HFO, animals were ventilated at 15 Hz with a tidal volume of 70 to 80 ml. CMV was delivered at 15 to 18 breath/min with a tidal volume of 15 ml/kg. Histamine infusion produced a marked fall in Cdyn, a variable rise in RL, an inconsistent but usually progressive rise in Qsp/Qt, and hypotension. A period of ventilation with HFO made no difference in the Cdyn, Qsp/Qt, or cardiac output changes produced by histamine infusion.     

Characterization and distribution of endothelin receptors in the pulmonary circulation: investigation of isolated, perfused, and ventilated rabbit lungs.

The aim of the study was to investigate the distribution of 2 subtypes of endothelin-receptors, mediating the effects of endothelin-1 (ET-1) in the pulmonary circulation. Until now, it is still unclear, whether ET(A) receptors or ET(B) receptors or even both are localized in pulmonary vessels. The experiments were performed on 72 isolated and ventilated rabbit lungs that were perfused with a cell- and plasma-free buffer solution. The arterial pressure and the lung weight gain were continuously registered. Intermittently perfusate samples were taken for determination of thromboxane A2 (TXA2) and prostacyclin (PGI2). The injection of ET-1 (10(-8) M, n = 6) resulted in a biphasic increase in pulmonary arterial pressure (PAP) that was accompanied by the generation of TXA2 and PGI2. Pretreatment with the ET(A)-receptor antagonist LU135252 (10(-6) M, n = 6) suppressed the pressure response after ET-1 application (P < 0.01 at 120 min) and reduced the generation of TXA2 (P < 0.05 at 120 min) and PGI2 (P < 0.05 at 120 min). Pretreatment with the cyclooxygenase inhibitor diclofenac (10 microg/mL; n = 6) also reduced the PAP increase after ET-1 injection. In contrast to this, the pulmonary vascular pressure reaction after ET-1 application was elevated, when ET(B)-receptor antagonist BQ788 (10(-6) M; n = 6) was given. Furthermore, the PGI2 to TXA2 ratio was shifted from 2.3 to 0.9, reflecting a predominance of vasoconstrictive TXA2. The simultaneous application of LU135252 and BQ788 significantly reduced the PAP increase after ET-1 application, but no beneficial effects were observed compared with the application of LU135252 solely. The injection of the ET(B)-receptor agonist sarafotoxin S6c (S6c; 10(-8) M, n = 6) also induced an increase in PAP that was not attenuated by pretreatment with the ET(B)-receptor antagonist BQ788 (10(-6) M, n = 6). LU135252 (n = 6) as well as the application of LU135252 in combination with BQ788 (n = 6) failed to suppress the pressure response after S6c, whereas the cyclooxygenase inhibitor diclofenac (10 microg/mL, n = 6) alone and in combination with LU135252 and BQ788 (n = 6) was able to prevent the PAP increase after S6c injection (P < 0.001). The results demonstrate that the ET-1-induced increase in pulmonary vascular resistance is mainly mediated via ET(A) receptors, whereas ET(B) receptors seem to mediate vasodilation, which was shown by an imbalance of TXA2 and PGI2 generation. On the other hand, the ET(B)-receptor agonist S6c induced vasoconstriction, which was only attenuated by the cyclooxygenase inhibitor diclofenac. From the current results we conclude that, apart from vasoconstrictor ET(A) receptors, at least 2 ET(B)-receptor subtypes are expressed in the pulmonary circulation, one mediating vasoconstriction, which was not blocked by BQ788, and one mediating vasodilation, which was influenced by BQ788.     

Analysis of cardiovascular and pulmonary responses to endothelin-1 and endothelin-3 in the anesthetized cat

Cardiovascular and pulmonary responses to endothelin (ET)-1, ET-3 and neuropeptide Y (NPY) were investigated in the anesthetized cat. ET-1, 0.1 to 1 nmol/kg i.v., decreased or elicited biphasic changes in arterial pressure (AP), whereas ET-3, in the same doses, decreased AP. Both ETs increased cardiac output (CO) and, at the highest doses, a secondary decrease in CO was observed. NPY, 0.3 to 3 nmol/kg i.v., increased AP and at the highest dose decreased CO. All three peptides had inconsistent effects on right ventricular contractile force and increased central venous pressure. ET-1 at lower doses increased heart rate (HR) and, at 1 nmol/kg, caused a biphasic change. ET-3 increased HR, whereas NPY decreased HR. Systemic vascular resistance (SVR) was increased by NPY and decreased by ET-3, whereas ET-1 elicited biphasic changes. ET-1 and ET-3 increased pulmonary arterial pressure, left atrial pressure and caused biphasic changes in pulmonary vascular resistance (PVR). NPY had no significant effect on PAP or PVR. When pulmonary blood flow was maintained constant, ET-1 and ET-3 had only pulmonary vasoconstrictor activity, whereas NPY and the ET analog had no significant effect. The increase in SVR in response to NPY, the decrease in response to ET-3 or the biphasic change in response to ET-1 were not modified by meclofenamate, hexamethonium or propranolol. Increases in HR in response to ET-1 and ET-3 were reduced by the beta receptor and ganglionic blocking agents.(ABSTRACT TRUNCATED AT 250 WORDS)     

Endothelin-1 and asymmetric dimethylarginine in children with left-to-right shunt after intracardiac repair

BACKGROUND: Endothelin-1 (ET-1) is an endogenous vasoconstrictive peptide hormone and asymmetric dimethylarginine (ADMA) acts as an endogenous inhibitor of nitric oxide synthase. We hypothesized that both could contribute to pulmonary hypertension in patients with left-to-right shunt after intracardiac repair. PATIENTS AND METHODS: We prospectively analyzed ET-1 and ADMA plasma levels in 31 patients (m = 16; f = 15) at an age of 0.6 [0.2-27] years (median [range]) with left-to-right shunt (ASD II: n = 12; VSD: n = 11; AVSD: n = 8) presenting with a Qp/Qs of 2.7 [1.4-6.3] and a pulmonary arterial mean pressure (PAP) of 23 [13-57] mmHg. Blood specimens were taken prior to cardiopulmonary bypass (CPB), after weaning from CPB and at 3, 6, 12 and 24 h after CPB. RESULTS: 12/31 patients were found to have pulmonary hypertension prior to intracardiac repair and 11/12 patients showed persistent pulmonary hypertension during the first 24 h after CPB. Patients with pulmonary hypertension at 12 h after CPB showed significant higher plasma ET-1 compared with patients with normal PAP (1.4 [0-7.9] versus 0.5 [0-2.5] pg/ml; P = 0.048 (Mann-Whitney)). Plasma ADMA decreased from 1.3 [0.75-2.3] micromol/l before CPB to 0.7 [0.4-2.1] micromol/l at 12 h (P < 0.05). However patients with pulmonary hypertension did not show different ADMA plasma levels. CONCLUSIONS: Increased plasma ET-1 but not inhibition of nitric oxide synthase by ADMA is associated with pulmonary hypertension after intracardiac repair.     

Endothelin-1 impairs neutrophil respiratory burst and elimination of Escherichia coli in rabbits

OBJECTIVE: During systemic inflammation, elevated levels of endothelin (ET)-1 have been reported. The aim of this study was to investigate the effects of ET-1 on neutrophil (PMN) respiratory burst, phagocytosis, and elimination of Escherichia coli from blood and tissues. DESIGN: Prospective, randomized, controlled trial. SETTING: Experimental laboratory in a university hospital. SUBJECTS: A total of 18 female chinchilla rabbits. INTERVENTIONS: To quantify the clearance process, defined numbers (10(8) colony-forming units) of E. coli were injected intravenously into anesthetized rabbits, 60 mins after onset of continuous 0.2 microg/kg/min ET-1 administration (n = 9) and after saline infusion (control group, n = 9), respectively. To evaluate potential effects of ET-1 on bacterial elimination and killing, blood clearance of E. coli and colonization of different organs were investigated. MEASUREMENTS: Variables monitored were neutrophil respiratory burst and phagocytosis activity, rates of bacterial elimination from the blood, arterial blood pressure, blood gases, serum lactate concentrations, and nitrite and nitrate levels. The animals were killed 3 hrs after bacterial injection and tissue samples of liver, kidney, spleen, and lung were collected for bacterial counts. MAIN RESULTS: Compared with the control group, ET-1 significantly impaired PMN respiratory burst (p < .05) and prolonged elimination of injected E. coli from the blood (p < .01), whereas phagocytosis functions remained unaltered. The reduced PMN burst activity after ET-1 was associated with a higher bacterial colonization of all organs (lung, p < .01; spleen, p < .05). Endothelin-1 induced increases in mean arterial pressure (p < .01) and serum lactate concentrations, whereas nitrite and nitrate levels remained unaltered. CONCLUSION: Endothelin-1 impairs respiratory burst and bacterial clearance from the blood and tissue. Thus, elevated levels of ET-1 during sepsis could induce organ hypoperfusion and cause disturbances in immune functions, increasing the risk of bacterial infections.     

Hemodynamic effects of high-frequency jet ventilation in dogs with a chronically banded pulmonary artery

Two to seven weeks after banding the main pulmonary artery, the hemodynamic effects of high-frequency jet ventilation (HFJV) and conventional mechanical ventilation (CMV) were studied in dogs with and without PEEP. In comparison with CMV, HFJV significantly increased cardiac index, stroke index (SI), left ventricular stroke work index, and oxygen delivery index, and decreased pulmonary vascular resistance index both with and without PEEP; however, there were significant decreases in PaO2 and increases in intrapulmonary physiologic shunt ratio in HFJV without PEEP. SI without PEEP was significantly greater with HFJV when the peak airway pressure was synchronized with the diastole in pulmonary arterial pressure (PAP) than with CMV and with HFJV synchronized with the systole in PAP. These findings suggest that HFJV has hemodynamic advantages over CMV in dogs with chronically banded pulmonary artery and dilated right ventricle.     

Conventional ventilation versus high-frequency oscillation: hemodynamic effects in newborn babies

OBJECTIVE: We conducted a prospective study to assess the hemodynamic effects of conventional mechanical ventilation (CMV) compared with high-frequency oscillation (HFO) in newborn babies with respiratory distress syndrome. METHODS: A total of 18 consecutive term and preterm infants were examined by two-dimensional M-mode and pulsed Doppler echocardiography. RESULTS: Five patients had to be excluded, three of them because of increasing cardiovascular support after initiation of HFO. The remaining 13 infants (seven males, six females) had a median gestational age of 33 wks (range, 25-40) and a birth weight of 2350 g (range, 790-3600). Patients entered the study at 21 hrs (range, 5-69) of life, receiving total maintenance fluid of 90 mL/kg/day (range, 60-120). Five babies (38%) needed continuous inotropic support. HFO was used as a rescue therapy in infants who failed with CMV. In all 13 patients, HFO significantly impaired cardiac performance compared with CMV by decreasing aortic velocity-time integral: median, 10.2 cm (range, 6.0-14.6) vs. 8.3 cm (range, 5.3-12.4; p<.002); stroke volume: median, 3.8 mL (range, 1.6-6.8) vs. 3.2 mL (range, 1.3-5.9; p<.002); and cardiac index: 281 mL/min/kg of body weight (range, 177-579) vs. 200 mL/min/kg of body weight (range, 156-591; p<.002). Fractional shortening was also significantly reduced: median, 0.31% (range, 0.24-0.44) vs. 0.29% (range, 0.20-0.34; p<.01), because of a significantly smaller left ventricular diastolic diameter during HFO: median, 1.4 cm (range, 1.0-1.9) vs. 1.4 cm (range, 0.9-1.8; p<.05), with a median difference of -0.07 cm (range, -0.4-0.2). HFO also causes a significant decrease in heart rate-corrected left ventricular ejection time: median, 0.25 sec (range, 0.23-0.28) vs. 0.23 sec (range, 0.21-0.26; p < .02) and heart rate-corrected velocity of circumferential fiber shortening (Vcfc): median, 1.3 circ/sec (range, 1.0-1.6) vs. 1.2 circ/sec (range, 0.9-1.4; p<.05). Left ventricular end-systolic wall stress (LVESWS; g/cm2) remained stable. The correlation between Vcfc and LVESWS did not show any significance (CMV, r2 = .2; HFO, r2 = .09). The regression line between Vcfc and LVESWS showed a higher y-intercept and steeper slope during CMV than during HFO. Heart rate, mean arterial pressure, and left ventricular systolic diameter remained unchanged. CONCLUSIONS: In newborn babies, HFO significantly decreased left ventricular cardiac output caused by reduced left ventricular filling and HFO decreased contractility at higher mean airway pressures than with CMV.     

Role of neurosympathetic pathways in the vascular response to sepsis

The aim of this study was to determine the role of sympathetic neural activity in the hemodynamic adaptations to sepsis in pigs with an emphasis on circuit adaptations. A fall in resistance to venous return (RVR) was predicted in contrast to what was previously observed in sympathetically intact animals that had no change in RVR.

We anesthetized and ventilated 13 pigs and gave 5 mg/kg of indomethacin. We measured cardiac output (CO) by thermodilution and measured pulmonary arterial (PAP), pulmonary capillary wedge (Pcw), right atria) pressure (Pra), and arterial pressure (MAP). Intermittent inflation of a 50-mL balloon in the right atrium was used to transiently arrest the circulation for the measurement of mean circulatory filling pressure (MCFP). RVR was calculated from (MCFP — Pra)/CO. Animals were divided into two groups; 6 received 10 mg/kg of the ganglionic blocker, hexamethonium and norepinephrine to maintain MAP; 7 had their spinal cords cut at C-2. After baseline measurements, all animals received 10 μg/kg/h of endotoxin for 2 hours, and hemodynamic measurements were repeated. Plasma samples were obtained for measurements of immunoreactive endothelin-1 (ET-1), which was assayed by a radioimmunoassay.

Hexamethonium had no significant effect on hemodynamics except for an increase in heart rate. After endotoxin, MAP and SVR fell, PAP rose, and CO and RVR did not change. Spinal section resulted in an increase in heart rate and small increase in PAP and MCFP After endotoxin, there was a further increase in heart rate, PAP, and MCFP with a marked fall in MAP and CO. RVR increased from 2.1 ± 0.46 after spinal section to 3.6 ± 54 mm · min/L (P < .05). ET -1 in the hexamethonium group (n = 2) rose from 2.21 ± .14 to 11.5 ± 2.1 pg/ml at 2 hours, and in the spinal group (n = 7) from 2.04 ± 0.77 to 6.85 ± 3.9 pg/mL at 45 minutes.

Spinal section resulted in a more profound fall in blood pressure and less increase in MCFP than in previously studied animals with sympathetic nervous system intact, but there was still an increase in RVR and PAP ET-1 is a possible mediator of the increase in RVR and PAP.     

Pharmacological doses of atrial natriuretic peptide ameliorate the acute renal dysfunction induced by systemic hypoxemia

The acute renal effects of systemic hypoxemia and the ability of atrial natriuretic peptide (ANP) to reverse these effects were assessed in seven anesthetized and mechanically ventilated adult rabbits. Throughout the experiment, arterial pH, PaCO2 and HCO3 remained unchanged. Hypoxemia induced a significant increase in rabbit-ANP plasma levels from 151 +/- 26 to 246 +/- 65 pg/ml. During the normoxemic period (PaO2 = 131 +/- 12 mm Hg), glomerular filtration rate (GFR), renal blood flow (RBF), renal vascular resistance (RVR) and urinary sodium excretion (UNaV) were similar in both kidneys. The subsequent hypoxemic period (PaO2 = 30 +/- 1 mm Hg) caused a decrease in right and left kidney function: GFR, -26 +/- 5 and -29 +/- 6%; RBF, -17 +/- 9 and -29 +/- 8%; RVR, +28 +/- 16 and +59 +/- 30%; urine flow rate, -38 +/- 6 and -36 +/- 6%; and UNaV, -51 +/- 7 and -50 +/- 7%, respectively. Human-ANP infusion in the left renal artery (100 ng/min) during sustained systemic hypoxemia induced a significant improvement in GFR (+57 +/- 18%), RBF (+21 +/- 8%), RVR (-20 +/- 7%), urine flow rate (+151 +/- 27%) and UNaV (+270 +/- 48%) in the left experimental kidney, as compared with the preceding hypoxemic period. In contrast, the function of the right control kidney remained impaired.     

Impact of endothelin-1 in endotoxin-induced pulmonary vascular reactions

OBJECTIVES: Elevated endothelin-1 (ET-1) levels have been detected during sepsis. The aim of the study was to examine the role of thromboxane A2 (TXA2) and ET-1 in pulmonary vascular reactions after endotoxin (LPS) challenge. DESIGN: Prospective experimental study in rabbits. SETTING: Experimental laboratory in a university teaching hospital. SUBJECTS: Twenty-four adult rabbits of either sex. INTERVENTIONS: Experiments were performed on 30 isolated and ventilated rabbit lungs, which were perfused with a saline solution containing 10% autologous blood. MEASUREMENTS AND MAIN RESULTS: Pulmonary arterial pressure and lung weight gain were continuously registered. Perfusate samples were drawn intermittently to determine ET-1, TXA2, and prostacyclin (PGI2) concentrations. LPS isolated from Escherichia coli (0.5 mg/mL; n = 6) was added to the perfusate. A marked pulmonary arterial pressure increase followed by massive edema formation after 60 mins was observed after LPS injection. At the same time, elevated TXA2 and PGI2 levels in the perfusate were measured. ET-1 was detected 30 mins after LPS infusion (13.4+/-2.6 fmol/L). Pretreatment with the ET(A) receptor antagonist LU135252 (10(-6) M; n = 6) almost completely suppressed the pressure reaction after endotoxin injection (p < .01 at 50 and 60 mins) and reduced edema formation (p < .05). The cyclooxygenase inhibitor diclofenac (10 microg/mL; n = 6) was as effective as LU135252 in preventing vascular reactions after LPS injection. CONCLUSIONS: Pretreatment with the ET(A) receptor antagonist LU135252 and the cyclooxygenase inhibitor diclofenac reduced pulmonary vascular reactions after LPS challenge. Based on the current data, we conclude that the pulmonary arterial pressure increase and edema formation after LPS injection are related to an ET-1- and TXA2-dependent mechanism.     

Standardized lung recruitment during high frequency and conventional ventilation: similar pathophysiologic and inflammatory responses in an animal model of respiratory distress syndrome

Objective To evaluate standardized lung recruitment strategy during both high frequency oscillation (HFO) and volume-targeted conventional ventilation (CV+V) in spontaneously breathing piglets with surfactant washout on pathophysiologic and inflammatory responses.Design Prospective animal study.Setting Research laboratory.Subjects Twenty-four newborn piglets.Interventions We compared pressure support and synchronized intermittent mandatory ventilation, both with targeted tidal volumes, (PSV+V, SIMV+V) to HFO. Animals underwent saline lavage to produce lung injury, received artificial surfactant and were randomized to one of the three treatment groups (each n=8). After injury and surfactant replacement, lung volumes were recruited in all groups using a standard protocol. Ventilation continued for 6 h.Measurements and main results Arterial and central venous pressures, heart rates, blood pressure and arterial blood gases were continuously monitored. At baseline, post lung injury and 6 h we collected serum and bronchoalveolar lavage samples for proinflammatory cytokines: IL 6, IL 8 and TNF-, and performed static pressure-volume (P/V) curves. Lungs were fixed for morphometrics and histopathologic analysis. No physiologic differences were found. Analysis of P/V curves showed higher opening pressures after lung injury in the HFO group compared to the SIMV+V group (p<0.05); no differences persisted after treatment. We saw no differences in change in proinflammatory cytokine levels. Histopathology and morphometrics were similar. Mean airway pressure (P_aw) was highest in the HFO group compared to SIMV+V (p<0.002).Conclusions Using a standardized lung recruitment strategy in spontaneously breathing animals, CV+V produced equivalent pathophysiologic outcomes without an increase in proinflammatory cytokines when compared to HFO.This study was supported in part by a grant from the Research and Education Fund of Childrens Hospitals and Clinics–St. Paul, Minnesota. Dräger Babylog supplied by Dräger Critical Care Systems, Survanta provided by Ross laboratories.     

Inhaled endothelin A antagonist improves arterial oxygenation in experimental acute lung injury

OBJECTIVES: To study the effects of an inhaled endothelin A (ET(A)) receptor antagonist on hemodynamics and pulmonary gas exchange in experimental acute lung injury (ALI). DESIGN AND SETTING: Prospective, randomized, and controlled study in a university laboratory. PARTICIPANTS AND INTERVENTIONS: Sixteen pigs were ventilated in a volume controlled mode during general anesthesia. ALI was induced by surfactant depletion using repetitive lung lavages until the PaO2/FIO2 ratio was below 100 mmHg. The animals were then randomly assigned to receive either a nebulized ET(A) receptor antagonist (LU-135252, 3 mg/kg, inhaled over 1 h; LU group) or nebulization of saline (5-10 ml inhaled over 1 h) with no further intervention (controls). MEASUREMENTS AND RESULTS: Parameters of hemodynamics and gas exchange were measured for 6 h after induction of ALI. In the LU group intrapulmonary right-left shunting (QS/QT) decreased from 58 +/- 8% at the onset of ALI to 27 +/- 12% 3 h and 24 +/- 9% 6 h after ALI (p < 0.05); PaO2 increased from 55 +/- 12 to 257 +/- 148 mmHg 3 h and 270 +/- 136 mmHg 6 h after ALI. (p < 0.05), whereas in controls QS/QT and PaO2 did not improve over the 6 h after onset of ALI. In the LU group mean pulmonary artery pressure was stable for 6 h after ALI (26-29 mmHg), while in controls it increased from 28 +/- 2 to 41 +/- 2 mmHg (p < 0.05). Inhaled LU-135252 reduced cardiac output by 31 +/- 11% (p < 0.05) and increased systemic vascular resistance by 60 +/- 29 % (p < 0.05), while these parameters remained stable in controls. CONCLUSION: In this porcine model of ALI the inhalation of an ET(A) receptor antagonist improved arterial oxygenation and maintained a stable pulmonary artery pressure without inducing systemic vasodilatation.     

Endothelin receptor blockade in canine oleic acid-induced lung injury

OBJECTIVE: To investigate the effects of endogenous endothelins on pulmonary haemodynamics and gas exchange in oleic acid lung injury. DESIGN: Prospective experimental study in dogs. SETTING: Animal research laboratory in a university teaching hospital. SUBJECTS. Seventeen anaesthetised and ventilated mongrel dogs. INTERVENTIONS: Nine pretreated dogs received an infusion of the endothelin A and B receptor antagonist bosentan (10 mg/kg) started before oleic acid. Eight treated dogs received bosentan started 90 min after oleic acid. Cardiac index (CI) was manipulated by inflating an inferior vena caval balloon or by opening a femoral arterio-venous bypass. MEASUREMENTS AND RESULTS: Pulmonary vascular resistance was defined by measuring the gradient between mean pulmonary artery pressure (MPAP) and occluded PAP (PAOP) at five levels of CI. Intrapulmonary shunt was measured using the inert gas SF(6). Pretreatment with bosentan prevented the oleic acid-induced shift of (MPAP-PAOP)/CI plots to higher pressures, but did not affect the increase in intrapulmonary shunt. Treatment of established oleic acid lung injury with bosentan had no effect. CONCLUSIONS: Pretreatment, but not treatment, with bosentan, in the dose used, blunted the oleic acid-induced increase in pulmonary vascular resistance, suggesting that endothelins contribute to the increase in pulmonary vascular tone in the early stages of oleic acid lung injury.     

Mechanical ventilation with high positive end-expiratory pressure and small driving pressure amplitude is as effective as high-frequency oscillatory ventilation to preserve the function of exogenous surfactant in lung-lavaged rats

OBJECTIVE: To demonstrate that under well-defined conditions, pressure-controlled ventilators (PCV) allow settings that are as good as high-frequency oscillatory ventilators (HFOV) at preserving the function of exogenous surfactant in lung-lavaged rats. DESIGN: Experimental, comparative study. SETTING: Research laboratory of a large university. SUBJECTS: Sixteen adult male Sprague-Dawley rats (280-310 g). INTERVENTIONS: Lung injury was induced by repeated lavage. After last lavage, all animals received exogenous surfactant and were then randomly assigned to two groups (n = 8 per group). The first group received PCV with small pressure amplitudes and high positive end-expiratory pressure. The second group received HFOV. In both groups, an opening maneuver was performed by increasing airway pressure to improve PaO2/F(IO2) to > or =500 torr. MEASUREMENTS AND MAIN RESULTS: Blood gases were measured every 30 mins for 3 hrs. Airway pressures were measured with a tip catheter pressure transducer. At the end of the study period, a pressure-volume curve was recorded and a broncho-alveolar lavage was performed to determine protein content and surfactant composition. The results showed that arterial oxygenation in both groups could be kept >500 torr during the 3-hr study period by using a mean airway pressure of 13+/-3 cm H2O in PCV and 13+/-2 cm H2O in HFOV. Further, there were no differences in the Gruenwald index, protein influx, or ratio of small to large aggregates between the study groups. CONCLUSION: PCV with sufficient level of positive end-expiratory pressure and small driving pressure amplitudes is as effective as HFOV to maintain optimal gas exchange, to improve lung mechanics, and to prevent protein influx and conversion of large into small aggregates after exogenous surfactant therapy in lung-lavaged rats.