Effects of inhaled nitric oxide during permissive hypercapnia in acute respiratory failure in piglets

OBJECTIVE: To look for the effects of inhaled nitric oxide on oxygenation and pulmonary hemodynamics during acute hypercapnia in acute respiratory failure. DESIGN: Prospective, randomized, experimental study. SETTING: University research laboratory. SUBJECTS: Ten piglets, weighing 9 to 13 kg. INTERVENTIONS: Acute respiratory failure was induced by oleic acid infusion and repeated lung lavages with 0.9% sodium chloride. The protocol consisted of three randomly assigned periods with different PaCO2 levels. Tidal volume was reduced to induce hypercapnia. Inspiratory time was prolonged to achieve similar mean airway pressures. During permissive hypercapnia, pH was not corrected. At each PaCO2 period, the animals were ventilated with inhaled nitric oxide of 10 parts per million and without nitric oxide inhalation. MEASUREMENTS AND MAIN RESULTS: Continuous hemodynamic monitoring included right atrial, mean pulmonary arterial, and mean systemic arterial pressures, arterial and mixed venous oxygen saturations, and continuous flow recording at the pulmonary artery. In addition, airway pressures, tidal volumes, dynamic lung compliance and airway resistance, end-tidal CO2 concentrations, and arterial and mixed venous blood gases were measured. Data were obtained at baseline and after lung injury, at normocapnia, at two levels of hypercapnia with and without nitric oxide inhalation. Acute hypercapnia resulted in a significant decrease in blood pH and a significant increase in mean pulmonary arterial pressure. There was no significant change in PaO2 during normocapnia and hypercapnia. Inhaled nitric oxide significantly decreased the mean pulmonary arterial pressure during both hypercapnic periods. It significantly improved oxygenation during both normocapnia and hypercapnia. CONCLUSIONS: Acute hypercapnia resulted in a significant increase in pulmonary arterial pressure without influencing oxygenation and cardiac output. Inhaled nitric oxide significantly reduced the pulmonary hypertension induced by acute permissive hypercapnia but did not influence the flow through the pulmonary artery. Inhaled nitric oxide significantly improved oxygenation in this model of acute lung injury during normocapnia and acute hypercapnia.     

Does airway pressure release ventilation alter lung function after acute lung injury?

BACKGROUND: During airway pressure release ventilation (APRV), tidal ventilation occurs between the increased lung volume established by the application of continuous positive airway pressure (CPAP) and the relaxation volume of the respiratory system. Concern has been expressed that release of CPAP may cause unstable alveoli to collapse and not reinflate when airway pressure is restored. OBJECTIVE: To compare pulmonary mechanics and oxygenation in animals with acute lung injury during CPAP with and without APRV. DESIGN: Experimental, subject-controlled, randomized crossover investigation. SETTING: Anesthesiology research laboratory, University of South Florida College of Medicine Health Sciences Center. SUBJECTS: Ten pigs of either sex. INTERVENTIONS: Acute lung injury was induced with an intravenous infusion of oleic acid (72 micrograms/kg) followed by randomly alternated 60-min trials of CPAP with and without APRV. Continuous positive airway pressure was titrated to produce an arterial oxyhemoglobin saturation of at least 95% (FIO2 = 0.21). Airway pressure release ventilation was arbitrarily cycled to atmospheric pressure 10 times per minute with a release time titrated to coincide with attainment of respiratory system relaxation volume. MEASUREMENTS: Cardiac output, arterial and mixed venous pH, blood gas tensions, hemoglobin concentration and oxyhemoglobin saturation, central venous pressure, pulmonary and systemic artery pressures, pulmonary artery occlusion pressure, airway gas flow, airway pressure, and pleural pressure were measured. Tidal volume (VT), dynamic lung compliance, intrapulmonary venous admixture, pulmonary vascular resistance, systemic vascular resistance, oxygen delivery, oxygen consumption, and oxygen extraction ratio were calculated. MAIN RESULTS: Central venous infusion of oleic acid reduced PaO2 from 94 +/- 4 mm Hg to 52 +/- 9 mm Hg (mean +/- 1 SD) (p < 0.001) and dynamic lung compliance from 40 +/- 6 mL/cm H2O to 20 +/- 6 mL/cm H2O (p = 0.002) and increased venous admixture from 13 +/- 3% to 32 +/- 7% (p < 0.001) in ten swine weighing 33.3 +/- 4.1 kg while they were spontaneously breathing room air. After induction of lung injury, the swine received CPAP (14.7 +/- 3.3 cm H2O) with or without APRV at 10 breaths per minute with a release time of 1.1 +/- 0.2 s. Although mean transpulmonary pressure was significantly greater during CPAP (11.7 +/- 3.3 cm H2O) vs APRV (9.4 +/- 3.8 cm H2O) (p < 0.001), there were no differences in hemodynamic variables. PaCO2 was decreased and pHa was increased during APRV vs CPAP (p = 0.003 and p = 0.005). PaO2 declined from 83 +/- 4 mm Hg to 79 +/- 4 mm Hg (p = 0.004) during APRV, but arterial oxyhemoglobin saturation (96.6 +/- 1.4% vs 96.9 +/- 1.3%) did not. Intrapulmonary venous admixture (9 +/- 3% vs 11 +/- 5%) and oxygen delivery (469 +/- 67 mL/min vs 479 +/- 66 mL/min) were not altered. After treatment periods and removal of CPAP for 60 min, PaO2 and intrapulmonary venous admixture returned to baseline values. DISCUSSION: Intrapulmonary venous admixture, arterial oxyhemoglobin saturation, and oxygen delivery were maintained by APRV at levels induced by CPAP despite the presence of unstable alveoli. Decrease in PaO2 was caused by increase in pHa and decrease in PaCO2, not by deterioration of pulmonary function. We conclude that periodic decrease of airway pressure created by APRV does not cause significant deterioration in oxygenation or lung mechanics.     

Effects of the lazaroid, tirilazad mesylate, on sepsis-induced acute lung injury in minipigs

OBJECTIVE: To assess the effects of the lazaroid, tirilazad mesylate, a potent lipid peroxidation inhibitor, in an animal model of Pseudomonas sepsis. DESIGN: Comparison of four experimental groups: a) saline control; b) Pseudomonas sepsis control; c) tirilazad mesylate control; and d) sepsis with tirilazad mesylate pre treatment. SETTING: University animal laboratory. SUBJECTS: Hanford minipigs (20 to 25 kg), anesthetized with pentobarbital and mechanically ventilated on an FIO2 of 0.4. INTERVENTIONS: Sepsis was induced by infusing Pseudomonas aeruginosa at 1 x 10(6) colony-forming units/kg/min over 120 mins. The tirilazad mesylate-treated group received a 5-mg/kg bolus 30 mins before, and a 3-mg/kg bolus 3 hrs after, the onset of sepsis. Hemodynamics, PaO2, and neutrophil counts were measured for 6 hrs. Thiobarbituric acid reactive material (TBARM) in tissue (lung, liver, and intestine), lung wet/dry weight ratio, lung myeloperoxidase activity, plasma tumor necrosis factor (TNF)-alpha concentrations, protein content, and percent neutrophils in bronchoalveolar lavage fluid were evaluated at the time the animals were killed (6 hrs). MEASUREMENTS AND MAIN RESULTS: Sepsis induced significant systemic hypotension, pulmonary hypertension, hypoxemia, and neutropenia. Sepsis also significantly increased TBARM content, lung wet/dry weight ratio, myeloperoxidase activity, plasma TNF-alpha concentrations, and bronchoalveolar lavage neutrophil percentage. Treatment with tirilazad mesylate significantly attenuated hypoxemia and decreased TBARM content, lung wet/dry weight ratio, myeloperoxidase activity, bronchoalveolar lavage protein, and bronchoalveolar lavage neutrophil percentage, but did not affect sepsis-induced hemodynamics, including systemic hypotension and pulmonary hypertension, plasma TNF-alpha concentrations, or neutropenia. CONCLUSIONS: Pretreatment with the tirilazad mesylate did not change P. aeruginosa sepsis-induced hemodynamic consequences. However, tirilazad mesylate attenuated sepsis-induced acute lung injury.     

Intravenous nitroglycerin in acute respiratory failure of patients with chronic obstructive lung disease, secondary pulmonary hypertension and cor pulmonale

We have studied the hemodynamic effects of an intravenous single dose of nitroglycerin in 13 patients with secondary pulmonary hypertension and Cor Pulmonale, during the acute course of respiratory failure and under assisted ventilation. We observed a significant decrease in systolic, diastolic and mean pulmonary arterial pressures, and in pulmonary resistance and systolic right ventricular work index, without any change in right or left pre-loads. The systolic arterial pressure decreased slightly, without any change in cardiac index or diastolic pressure. The arterial and mixed venous oxygen contents, and the pulmonary shunting ( Qs/Qt) were unchanged. These results suggest that nitroglycerin may be a useful therapy in patients in the acute stages of pulmonary hypertension resulting from chronic lung disease and under assisted ventilation. In addition, the lack of change in cardiac index, intrapulmonary shunting and oxygen content suggests that this decrease in pulmonary resistance is not linked with any deleterious effect in oxygen transfer.     

Cardiorespiratory effects of induction and maintenance of anesthesia with ketamine-midazolam combination, with and without prior administration of butorphanol or oxymorphone

Cardiorespiratory effects of an IV administered bolus of ketamine (7.5 mg/kg of body weight) and midazolam (0.375 mg/kg) followed by IV infusion of ketamine (200 micrograms/kg/min) and midazolam (10 micrograms/kg/min) for 60 minutes was determined in 6 dogs. Ketamine-midazolam combination was administered to dogs on 3 occasions to determine effects of prior administration of IV administered saline solution (1 ml), butorphanol (0.2 mg/kg), or oxymorphone (0.1 mg/kg). The infusion rate of ketamine and midazolam was decreased by 25% for anesthetic maintenance after opioid administration. There were no significant differences in cardiorespiratory variables after saline solution or butorphanol administration; however, oxymorphone caused significant (P < 0.05) increases in mean arterial blood pressure, systemic vascular resistance, and breathing rate. Bolus administration of ketamine-midazolam combination after saline solution caused significant (P < 0.05) increases in heart rate, mean arterial blood pressure, cardiac index, mean pulmonary blood pressure, venous admixture, and significant decreases in stroke index, pulmonary capillary wedge pressure, arterial and mixed venous oxygen tension, arterial oxygen content, and alveolar-arterial oxygen gradient. Opioid administration was associated with significantly (P < 0.05) lower values than was saline administration for heart rate, mean arterial blood pressure, and arterial and mixed venous pH and with higher values for stroke index, pulmonary capillary wedge pressure, and arterial and mixed venous carbon dioxide tension. Prior oxymorphone administration resulted in the highest (P < 0.05) values for mean pulmonary blood pressure, venous admixture, and arterial and mixed venous carbon dioxide tension, and the lowest values for arterial oxygen tension, and arterial and mixed venous pH. Each treatment provided otherwise uncomplicated anesthetic induction, maintenance, and recovery.(ABSTRACT TRUNCATED AT 250 WORDS)     

Detection and clinical pathological significance of the expression of P21, P185, p53 proteins and mutation of ras, p53 genes in transitional cell carcinoma of the bladder

OBJECTIVE: In order to observe the effects of inhaling nitric oxide (NO) on acute lung injury (ALI). METHODS: 24 rabbits divided into 4 groups. Six rabbits injured with intravenous E. Coli endotoxin, then followed by treatment of inhaling 80 ppm NO in inspired gas. Before and after the infusion of endotoxin, the mean pulmonary arterial pressure (mPAP), mean systemic arterial pressure (mPSA) and the PaO2 were examined. The venous methemoglobin (MHb) was measured by using spectrophometer colorimitry. The extravasculur lung water was evaluated with rate of dried to wet lung weight at the end of study. RESULTS: The rabbits injured with endotoxin inhaling 80 ppm NO could rapidly reduce the mPAP, increase the PaO2 and without inducing significant change of mPSA, MHb and extravasculur lung water. CONCLUSIONS: Inhalation of 80 ppm NO can selectively cause pulmonary artery dilatation, reduce mPAP, improve pulmonary gas exchange, without producing system vasodilation and toxic effects to the rabbits.     

Early hemodynamic effects of olprinone hydrochloride after coronary artery bypass grafting

Our purpose was to evaluate the hemodynamic effects of olprinone hydrochloride early after coronary artery bypass grafting (CABG). Fifteen patients undergoing CABG were administered a constant infusion of 0.1 microgram/kg/min of olprinone and continued for 4 hours. No bolus infusion of olprinone was administered before continuous infusion. Systolic systemic arterial pressure, systolic pulmonary arterial pressure, systemic vascular resistance and pulmonary vascular resistance were significantly decreased. There were no significant changes in heart rate, mean central venous pressure, mean left atrial pressure and left ventricular stroke work index. Cardiac index was significantly increased, but a correlation between cardiac index and mixed venous blood oxygen saturation was not found. Double product was significantly decreased, which described above suggest that olprinone achieved improvement of left cardiac function without more myocardial oxygen consumption. Severe transient hypotension (systolic arterial pressure < 80 mmHg) after infusion of olprinone was observed in three patients. Olprinone administered soon after CABG surgery had beneficial effects in terms of improvement of hemodynamic status without more oxygen consumption and reduction of pulmonary vascular resistance. However transient hypotension was a serious clinical problem in patients after open heart surgery, especially in CABG patients who need suitable systolic arterial pressure to keep enough blood perfusion of arterial bypass grafts.     

Overexpression of iron superoxide dismutase in transformed poplar modifies the regulation of photosynthesis at low CO2 partial pressures or following exposure to the prooxidant herbicide methyl viologen

Knowledge of the contributions of arterial and venous transit time dispersion to the pulmonary vascular transit time distribution is important for understanding lung function and for interpreting various kinds of data containing information about pulmonary function. Thus, to determine the dispersion of blood transit times occurring within the pulmonary arterial and venous trees, images of a bolus of contrast medium passing through the vasculature of pump-perfused dog lung lobes were acquired by using an X-ray microfocal angiography system. Time-absorbance curves from the lobar artery and vein and from selected locations within the intrapulmonary arterial tree were measured from the images. Overall dispersion within the lung lobe was determined from the difference in the first and second moments (mean transit time and variance, respectively) of the inlet arterial and outlet venous time-absorbance curves. Moments at selected locations within the arterial tree were also calculated and compared with those of the lobar artery curve. Transit times for the arterial pathways upstream from the smallest measured arteries (200-micron diameter) were less than approximately 20% of the total lung lobe mean transit time. Transit time variance among these arterial pathways (interpathway dispersion) was less than approximately 5% of the total variance imparted on the bolus as it passed through the lung lobe. On average, the dispersion that occurred along a given pathway (intrapathway dispersion) was negligible. Similar results were obtained for the venous tree. Taken together, the results suggest that most of the variation in transit time in the intrapulmonary vasculature occurs within the pulmonary capillary bed rather than in conducting arteries or veins.     

ANP and bradycardic reflexes in hypertensive rats: influence of cardiac hypertrophy

OBJECTIVES: Beta2-integrin (CD11b/CD18) expression, an indicator of neutrophil activation, has been associated with the development of acute respiratory distress syndrome. Leumedins act directly on leukocytes to inhibit the up-regulated expression of beta2-integrins involved in leukocyte adhesion. We examined the effect of such a new anti-inflammatory agent, NPC 15669 (N-[9H-(2,7-dimethylfluorenyl-9-methoxy)-carbonyl]-L-leucine), on neutrophil-mediated acute lung injury in an animal model. DESIGN: Prospective, randomized, blinded, controlled animal study. SETTING: An animal laboratory in a university setting. SUBJECTS: Adult New Zealand rabbits. INTERVENTIONS: After repeated lung lavages with normal saline to induce acute lung injury, anesthetized rabbits were randomly assigned to one of two groups (n = 6 per group): a) treatment group (pretreated with NPC 15669 [10 mg/kg i.v. bolus] 30 mins before lavage, followed by a continuous infusion [5 mg/kg/hr] for the duration [4 hrs] of the experiment); or b) control group (pretreatment and continuous infusion with placebo). All animals were mechanically ventilated with identical pressure settings over 4 hrs and were killed at the end of the experiment. MEASUREMENTS AND MAIN RESULTS: PaO2, PaCO2, and tidal volumes were repeatedly measured and airway pressure settings were noted every 30 mins. At the end of the experiment, lungs were taken out for measurements of the myeloperoxidase content, for conventional histology (hematoxylin and eosin staining), and for intracellular adhesion molecule-1 immunohistostaining. Pretreatment with NPC 15669 profoundly improved oxygenation from a PaO2 of 52 +/- 5 torr (6.9 +/- 0.7 kPa) to 250 +/- 161 torr (33.3 +/- 21.5 kPa) within 60 mins after lung lavage (p < .05). Oxygenation continued to improve throughout the study, reaching a maximal PaO2 value of 395 +/- 98 torr (52.7 +/- 13.1 kPa) at 4 hrs. In the control group, oxygenation remained poor throughout the observation period. PaO2 values differed significantly (51 +/- 20 torr [6.8 +/- 2.7 kPa] vs. 306 +/- 126 torr [40.8 +/- 16.8 kPa], p < .005) at 90 mins and at all subsequent measurements from those values in the NPC 15669 group. Dynamic lung compliance improved significantly 60 to 90 mins after repeated lung lavage. Histology demonstrated markedly less lung damage (hyaline membrane formation and leukocyte infiltration) in treated animals (p < .05) than in controls. CONCLUSIONS: NPC 15669 seems to block inflammatory reactions by inhibiting the sequestration of neutrophils in acute, ventilator-associated lung injury. As a result, gas exchange and total lung compliance improve. Application of this and similar compounds affecting neutrophil adhesion warrants further investigation as a treatment modality for acute lung injury.     

Pressure-flow-volume relationships in pulmonary circulation of normal highlanders

Pulmonary vascular pressures and blood flow were measured with and without unilateral pulmonary arterial occlusion (UPAO) at rest and during exercise in 10 normal highlanders at La Paz, Bolivia (altitude, 3,750 m). In 6 other highlanders at rest and during exercise, pulmonary pressures, flow, and blood volume were measured during air breathing (PIO2 congruent to 100 Torr) and 29-30% oxygen (PIO2 congruent to 150 Torr). During air breathing, pulmonary vascular resistance was elevated at rest and did not change with exercise. Pulmonary arterial pressure rose less at rest with UPAO than during exercise without UPAO, and pulmonary vascular resistance was less in the former. Raising PaO2 to normal sea-level values had no effects on the pulmonary circulation at rest but prevented to a large extent the rise in pulmonary arterial pressure during exercise. Hence pulmonary vascular resistance during exercise was lower with oxygen than without. Thus, hypoxic vasoconstriction contributed to the pulmonary hypertension during exercise in normal highlanders. Circumstantial evidence suggests that this is related to the profound mixed venous hypoxemia caused by exercise in a hypoxic environment.     

Ascorbic acid reduces the endotoxin-induced lung injury in awake sheep

Our aim was to investigate whether ascorbic acid can reduce reactive oxygen metabolite-mediated acute lung injury. The effects of intravenous administration of Escherichia coli endotoxin were studied, with and without ascorbic acid infusion, on haemodynamics, lung lymph flow, cardio-respiratory and neutrophil function in chronically instrumented sheep. Paired experiments were performed on eight sheep in which they received either endotoxin alone (0.5 micrograms kg-1 b.w.) (ET group) or in combination with an ascorbic acid infusion (1 g kg-1 b.w. bolus injection followed by 0.2 g kg-1 h-1 continuous infusion) ET + ASC group) in random order. Four of the animals also received ascorbic acid alone (ASC group). As a result, for the ET + ASC group a general and mostly significant improvement (P < 0.05) in the early hypertensive phase (0-60 min, P values) and in the late permeability phase (2-4 h, *P values) of cardiorespiratory function (mean artery pressure: P/*P = 0.283/0.049; mean pulmonary artery pressure: P/*P = 0.0001/0.0001; mean pulmonary artery wedge pressure: P/*P = 0.012/0.001; right ventricular stroke work index: P/*P = 0.02/0.0001; cardiac index: P/*P = 0.797/0.755; arterial oxygen saturation: P/*P = 0.0059/0.01; arterial-venous difference of oxygen tension: P/*P = 0.011/0.0005), oxygen consumption: P/*P = 0.013/0.035, lung lymph flow: P/*P = 0.562/0.012, lymph/plasma protein ratio: P/*P = 0.304/0.008 and protein clearance: P/*P = 0.56/0.05 was observed in comparison with the ET group.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pulmonary edema in obstetric patients is rapidly resolved except in the presence of infection or of nitroglycerin tocolysis after open fetal surgery

OBJECTIVES: This study was designed to determine the etiology, course, and severity of pulmonary edema in obstetric patients in a tertiary care center. STUDY DESIGN: A retrospective study was carried out on 16,810 deliveries from University of California, San Francisco, 1985-1995. Diagnosis and severity of lung injury were defined by a 4-point system that was based on the chest radiograph, oxygenation, positive end-expiratory pressure, and lung compliance. Resolution of pulmonary edema was defined by improvement in the chest radiograph and hypoxemia (ratio of arterial oxygen tension to inspired oxygen concentration) scores or by extubation. RESULTS: Pulmonary edema developed in 86 patients, or 0.5% of all obstetric cases. It usually showed extensive air space consolidation on the chest radiograph and arterial hypoxemia. Although 43% of the patients had severe pulmonary dysfunction, the average time to resolution of pulmonary edema was 2.4 days. Only 45% of patients required admission to the intensive care unit and only 15% required intubation and positive-pressure ventilation. Patients with infection (mean of 7.2 days) or fetal surgery (mean of 3.8 days) had the most severe, protracted course. CONCLUSION: Although obstetric pulmonary edema is associated with extensive radiographic infiltrates and severe hypoxemia, resolution occurs rapidly in most patients, limiting the need for intensive care support.     

Characteristics of vascular wall cells subjected to dynamic cyclic strain and fluid shear conditions in vitro

Surfactant bolus instillation may be associated with a drop in blood pressure. Platelet-activating factor (PAF) has been found in surfactant preparations. The aim of this study was to evaluate rapid tracheal infusion of surfactant during 5 min as an alternative to bolus instillation and to examine whether a PAF receptor antagonist is able to prevent the decrease in blood pressure. METHODS: Surfactant deficiency was induced in 16 adult rabbits by lung lavages with saline. Six animals received a bolus of a porcine surfactant preparation (Curosurf (CS); 200 mg/kg), labeled with red microspheres to assess pulmonary distribution. In another 5 rabbits, the same amount of labelled CS was instilled by tracheal infusion within 5 min. A third group of 5 animals received 3 mg/kg body weight of the PAF antagonist WEB 2170 before CS bolus instillation. RESULTS: After CS bolus administration, mean PaO2 increased by 44.7 +/- 8.3 kPa (mean +/- SD) within 2 min and remained at this level. Mean arterial blood pressure dropped transiently by 2.3 +/- 2 kPa within 5 min. Pulmonary distribution of surfactant was even. After infusion, mean PaO2 rose by 22.4 +/- 16.3 kPa within 15 min. Blood pressure dropped by 1.8 +/- 1.1 kPa within 15 min. The distribution was extremely uneven. Blood pressure decreases also occurred after pretreatment with PAF receptor antagonist. CONCLUSION: Rapid tracheal infusion of surfactant results in poorer oxygenation, an inhomogeneous distribution and a similar decrease in blood pressure compared to the bolus instillation method. Blood pressure changes could not be prevented by a PAF receptor-specific antagonist.     

Short-term effects of methylene blue on hemodynamics and gas exchange in humans with septic shock

OBJECTIVE: The aim of this study was to investigate the acute effects of methylene blue (MB), an inhibitor of the L-arginine nitric oxide pathway, in patients with septic shock. DESIGN: A prospective, open, single-dose study. SETTING: The medical ICU of a university hospital. PATIENTS: Six patients with severe septic shock. INTERVENTIONS: Complete hemodynamic values were recorded before and 20 min after the infusion of intravenous MB (3 mg kg(-1)). Arterial pressure was then monitored during the next 24 h or until death. MEASUREMENTS AND RESULTS: Methylene blue increased the mean arterial pressure from 69.7 +/- 4.5 to 83.7 +/- 5.1 mmHg (p = 0.028) and the mean pulmonary artery pressure, from 34.3 +/- 7.2 to 38.7 +/- 8.0 mmHg (p = 0.023). Systemic vascular resistance index was increased from 703.1 +/- 120.6 to 903.7 +/- 152.2 dyne.s.cm(-5).m(-2) (p = 0.028) and pulmonary vascular resistance index, from 254.6 +/- 96.9 to 342.2 +/- 118.9 dyne.s.cm(-5) .m(-2) (p = 0.027). The PaO2/FIO2 decreased from 229.2 +/- 54.4 to 162.2 +/- 44.1 mmHg (p = 0.028), without significant modification of intrapulmonary shunting. Heart rate, cardiac index, right atrial pressure, DO2, VO2, oxygen extraction and arterial lactate were essentially unchanged. Sequential measurements of arterial pressure demonstrated a return to baseline level in 2-3 h. All but one patients died, three in shock and two in multiple organ failure. CONCLUSIONS: MB induces systemic and pulmonary vasoconstriction in patients with septic shock, without significant decrease in cardiac index. The worsening of arterial oxygenation following MB injection may limit its use in patients with the adult respiratory distress syndrome. Larger studies are required to determine whether MB improves the outcome of patients with septic shock.     

Effects of hypoxemia and reoxygenation with 21% or 100% oxygen in newborn piglets: extracellular hypoxanthine in cerebral cortex and femoral muscle

OBJECTIVE: To determine whether reoxygenation with an FIO2 of 0.21 (21% oxygen) is preferable to an FIO2 of 1.0 (100% oxygen) in normalizing brain and muscle hypoxia in the newborn. DESIGN: Prospective, randomized, animal study. SETTING: Hospital surgical research laboratory. SUBJECTS: Twenty-six anesthetized, mechanically ventilated, domestic piglets, 2 to 5 days of age. INTERVENTIONS: The piglets were randomized to control or hypoxemia groups. Hypoxemia was induced by ventilating the piglets with 8% oxygen in nitrogen, which was continued until mean arterial pressure decreased to <20 mm Hg. After hypoxemia, the piglets were further randomized to receive reoxygenation with an FIO2 of 0.21 (21% oxygen group, n = 9) or an FIO2 of 1.0 for 30 mins followed by an FIO2 of 0.21 (100% oxygen group, n = 9), and followed for 5 hrs. The piglets in the control group were mechanically ventilated with 21% oxygen (n = 8). MEASUREMENTS AND MAIN RESULTS: We measured extracellular concentrations of hypoxanthine in the cerebral cortex and femoral muscle (in vivo microdialysis), plasma hypoxanthine concentrations, cerebral arterial-venous differences for hypoxanthine, acid base balances, arterial and venous (sagittal sinus) blood gases, and mean arterial pressures. The lowest pH values of 6.91 +/- 0.11 (21% oxygen group, mean +/- SD) and 6.90 +/- 0.07 (100% oxygen group) were reached at the end of hypoxemia and then normalized during the reoxygenation period. Plasma hypoxanthine increased during hypoxemia from 28.1 +/- 9.3 to 119.1 +/- 31.9 micromol/L in the 21% oxygen group (p < .001) and from 32.6 +/0- 14.5 to 135.0 +/- 31.4 micromol/L in the 100% oxygen group (p <.001). Plasma hypoxanthine concentrations then normalized over the next 2 hrs in both groups. In the cerebral cortex, extracellular concentrations of hypoxanthine increased during hypoxemia from 3.9 +/- 2.8 to 20.2 +/- 7.4 micromol/L in the 21% oxygen group (p < .001) and from 5.9 +/- 5.0 to 25.1 +/- 7.1 micromol/L in the 100% oxygen group (p < .001). In contrast to plasma hypoxanthine, extracellular hypoxanthine in the cerebral cortex increased significantly further during early reoxygenation, and, within the first 30 mins, reached maximum values of 24.9 +/- 6.3 micromol/L in the 21% oxygen group (p < .01) and 34.8 +/- 10.9 micromol/L in the 100% oxygen group (p < .001). This increase was significantly larger in the 100% oxygen group than in the 21% oxygen group (9.7 +/- 4.7 vs. 4.7 +/- 2.6 micromol/L, p < .05). There were no significant differences between the two reoxygenated groups in duration of hypoxemia, hypoxanthine concentrations in femoral muscle, plasma hypoxanthine concentrations, pH, or mean arterial pressure. The cerebral arterial-venous difference for hypoxanthine was positive both at baseline, at the end of hypoxemia, and after 30 mins and 300 mins of reoxygenation, and no differences were found between the two reoxygenated groups. CONCLUSIONS: Significantly higher extracellular concentrations of hypoxanthine were found in the cerebral cortex during the initial period of reoxygenation with 100% oxygen compared with 21% oxygen. Hypoxanthine is a marker of hypoxia, and reflects the intracellular energy status. These results therefore suggest a possibly more severe impairment of energy metabolism in the cerebral cortex or an increased blood-brain barrier damage during reoxygenation with 100% oxygen compared with 21% oxygen in this newborn piglet hypoxia model.     

Experimental antitumour activity of S 16020-2 in a panel of human tumours

OBJECTIVE: To compare the effects of inhaled nitric oxide (NO) and extracorporeal membrane oxygenation (ECMO) on oxygenation, hemodynamics, and lymphatic drainage in an oleic acid lung injury model in sheep. DESIGN: Prospective, randomized study. SETTING: Animal research laboratory. ANIMALS: Thirty female sheep, weighing 35 to 40 kg. INTERVENTIONS: Acute lung injury was induced by central venous injection of oleic acid (0.5 mL/kg body weight). A chronic lymph fistula had been prepared through a right thoracotomy 3 days before the experiment. Animals were assigned randomly to the NO group (n = 14) or the ECMO group (n = 16). When a lung injury score of > 2.5 was achieved, the animals were given NO in dosage increments of 2, 5, 10, 20, and 40 parts per million (ppm), or placed on ECMO with an FIO2 of 0.21 (ECMO-21) and then 1.0 (ECMO-100) at the oxygenator. Mechanical ventilator parameters were kept constant to isolate the effects of NO and ECMO on systemic and pulmonary hemodynamics, cardiac output, oxygenation parameters, lymph/plasma protein ratio, and lymph flow. Measurements and calculations were performed after 1 hr at each individual step of NO concentration or FIO2. MEASUREMENTS AND MAIN RESULTS: In the ECMO group, PVRI and MPAP did not change and were significantly different from the NO group. In the NO group, there was a dose-dependent decrease in venous admixture, maximal at 10 ppm NO and decreasing from 40 +/- 6% to 23 +/- 10% (p < .05). This decrease was significantly different from the ECMO group, where there was no change. There was a significant increase in PaO2/FIO2 in the NO group, maximal at 10 ppm NO (84 +/- 11 to 210 +/- 90, p < .05), but a greater increase in PaO2/FIO2 on ECMO-21 (81 +/- 14 to 265 +/- 63) and a further increase on ECMO-100 (398 +/- 100) (p < .05). The lymph/plasma protein ratio remained unchanged in both groups after induction of lung injury by oleic acid. However, lymph flow decreased by 11 +/- 6% in the NO group, whereas it increased by 14 +/- 17% in the ECMO group (p < .05). CONCLUSIONS: In an oleic acid-induced sheep model of acute lung injury, there were significant differences between the effects of NO and ECMO on acute pulmonary hypertension, hypoxemia, hypercarbia, and lymph flow. NO significantly decreases pulmonary hypertension, whereas pulmonary hemodynamics were not substantially affected by ECMO. Both interventions reversed hypoxemia, but ECMO did so to a greater degree, and only ECMO improved hypercarbia. Only NO decreased lymph flow, possibly as an effect of decreased microvascular filtration pressure. This study did not attempt to evaluate the impact of these interventions on ventilatory requirements, barotrauma, or outcome. However, this model suggests that NO therapy may moderate pulmonary hypertension and improve lymph flow in acute lung injury. Clinical studies are needed to assess whether NO therapy might be beneficial in treatment of severe acute lung injury in older children and adults.     

Cardiovascular changes associated with aging: the anesthetic implications

PURPOSE: Elevated arterial lactate concentrations in patients with sepsis have been interpreted as evidence of peripheral, nonpulmonary tissue hypoxia. These patients often develop pulmonary failure manifested by the acute respiratory distress syndrome (ARDS). As the result of tissue hypoxia or inflammation, the lungs of patients with sepsis and ARDS may become a source of lactate release into the circulation. MATERIALS AND METHODS: Pulmonary lactate release was measured in 19 patients with sepsis, arterial lactate > or = 2.2 mm, and gastric mucosal pH > 7.30. A normal gastric mucosal pH served as a marker of adequate splanchnic oxygenation. Pulmonary lactate release was computed as the product of the cardiac index and the difference in plasma L-lactate concentration in simultaneously obtained arterial and mixed venous blood samples. Lung injury was graded with the Lung Injury Score using radiographic and physiologic data. RESULTS: The lungs of patients with minimal or no lung injury (lung injury score <1) produced significantly less lactate than those with moderate or severe lung injury (lung injury score > or = 1) (P < .005). The Lung Injury Score correlated with pulmonary lactate release (r2 = .73; P < .0001). This relationship resulted primarily from increases in mixed venous-arterial lactate differences (r2 = .59). The Lung Injury Score correlated weakly with the cardiac index (r2 = .32). Arterial lactate concentration did not correlate with pulmonary lactate release, systemic oxygen transport, or systemic oxygen consumption. CONCLUSIONS: The lungs of patients with sepsis and ARDS may produce lactate. Pulmonary lactate release correlates with the severity of lung injury. The contribution of pulmonary lactate release should be considered when interpreting arterial lactate concentration as an index of systemic hypoxia.     

VA/Q abnormalities during gram negative sepsis

Hypoxemia in bacterial sepsis develops by mechanisms which are incompletely understood. In this study, we measured pulmonary gas exchange in eight baboons to determine the causes of hypoxemia after infusion of live Escherichia coli (1 x 10(10) CFU/kg) followed by resuscitation with intravenous fluid. VA/Q distributions were measured periodically using the multiple inert gas elimination technique until death or for a maximum of 42 h. After E. coli infusion, dispersion of perfusion (logSDq) increased rapidly and a transient rise in dead space was observed at 6 h coinciding with systemic hypotension and acidosis. The intrapulmonary shunt developed later and reached 27 +/- 6% at 24 h. PaO2 began to decrease at 12 h and correlated with increases in intrapulmonary shunt and logSDq. There was no evidence of diffusion limitation. Lung edema was mild despite aggressive fluid resuscitation. Morphometric analysis of postmortem lungs revealed dramatic intravascular accumulation of granulocytes. There were increases in arithmetic mean thicknesses of epithelium and interstitium. These data indicate that gram negative sepsis with fluid resuscitation causes progressive hypoxemia, primarily due to the development of intrapulmonary shunt and very low VA/Q regions in the lung. The VA/Q abnormalities occur early and likely reflect ongoing cellular responses in pulmonary vasculature and smaller airways in sepsis.     

High-frequency partial liquid ventilation in respiratory distress syndrome: hemodynamics and gas exchange

Partial liquid ventilation using conventional ventilatory schemes improves lung function in animal models of respiratory failure. We examined the feasibility of high-frequency partial liquid ventilation in the preterm lamb with respiratory distress syndrome and evaluated its effect on pulmonary and systemic hemodynamics. Seventeen lambs were studied in three groups: high-frequency gas ventilation (Gas group), high-frequency partial liquid ventilation (Liquid group), and high-frequency partial liquid ventilation with hypoxia-hypercarbia (Liquid-Hypoxia group). High-frequency partial liquid ventilation increased oxygenation compared with high-frequency gas ventilation over 5 h (arterial oxygen tension 253 +/- 21.3 vs. 17 +/- 1.8 Torr; P < 0.001). Pulmonary vascular resistance decreased 78% (P < 0.001), pulmonary blood flow increased fivefold (P < 0.001), and aortic pressure was maintained (P < 0.01) in the Liquid group, in contrast to progressive hypoxemia, hypercarbia, and shock in the Gas group. Central venous pressure did not change. The Liquid-Hypoxia group was similar to the Gas group. We conclude that high-frequency partial liquid ventilation improves gas exchange and stabilizes pulmonary and systemic hemodynamics compared with high-frequency gas ventilation. The stabilization appears to be due in large part to improvement in gas exchange.     

Partitioning of pulmonary vascular resistance in primary pulmonary hypertension

OBJECTIVES: This study sought to determine the site of increased pulmonary vascular resistance (PVR) in primary pulmonary hypertension by standard bedside hemodynamic evaluation. BACKGROUND: The measurement of pulmonary vascular pressures at several levels of flow (Q) allows the discrimination between active and passive, flow-dependent changes in mean pulmonary artery pressure (Ppa), and may detect the presence of an increased pulmonary vascular closing pressure. The determination of a capillary pressure (Pc') from the analysis of a Ppa decay curve after balloon occlusion allows the partitioning of PVR in an arterial and a (capillary + venous) segment. These approaches have not been reported in primary pulmonary hypertension. METHODS: Ppa and Pc' were measured at baseline and after an increase in Q induced either by exercise or by an infusion of dobutamine, at a dosage up to 8 microg/kg body weight per min, in 11 patients with primary pulmonary hypertension. Reversibility of pulmonary hypertension was assessed by the inhalation of 20 ppm nitric oxide (NO), and, in 6 patients, by an infusion of prostacyclin. RESULTS: At baseline, Ppa was 52+/-3 mm Hg (mean value+/-SE), Q 2.2+/-0.2 liters/min per m2, and Pc' 29+/-3 mm Hg. Dobutamine did not affect Pc' and allowed the calculation of an averaged extrapolated pressure intercept of Ppa/Q plots of 34 mm Hg. Inhaled NO had no effect. Prostacyclin decreased Pc' and PVR. Exercise increased Pc' to 40+/-3 mm Hg but did not affect PVR. CONCLUSIONS:ns. These findings are compatible with a major increase of resistance and reactivity at the periphery of the pulmonary arterial tree.