Noninvasive motion ventilation (NIMV): a novel approach to ventilatory support.

A motion platform was developed that oscillates an animal in a foot-to-head direction (z-plane). The platform varies the frequency and intensity of acceleration, imparting periodic sinusoidal inertial forces (pG(z)) to the body. The aim of the study was to characterize ventilation produced by the noninvasive motion ventilator (NIMV) in animals with healthy and diseased lungs. Incremental increases in pG(z) (acceleration) with the frequency held constant (f = 4 Hz) produced almost linear increases in minute ventilation (VE). Frequencies of 2-4 Hz produced the greatest VE and tidal volume (VT) for any given acceleration between +/-0.2 and +/-0.8 G. Increasing the force due to acceleration produced proportional increases in both transpulmonary and transdiaphragmatic pressures. Increasing transpulmonary pressure by increasing pG(z) produced linear increases in VT, similar to spontaneous breathing. NIMV reversed deliberately induced hypoventilation and normalized the changes in arterial blood gases induced by meconium aspiration. In conclusion, a novel motion platform is described that imparts periodic sinusoidal acceleration forces at moderate frequencies (4 Hz) to the whole body in the z-plane. These forces, when properly adjusted, are capable of highly effective ventilation of normal and diseased lungs. Such noninvasive ventilation is accomplished at airway pressures equivalent to atmospheric or continuous positive airway pressure, with acceleration forces less than +/-1 G(z).     

Effects of alveolar hypoxia on the pulmonary circulation and lung mechanics after cromolyn sodium and U-60,257 in lambs.

Because alveolar hypoxia (HYP) triggers pulmonary mast cell degranulation with elaboration of vasoactive mediators such as leukotrienes, we investigated the effects of aerosolized cromolyn sodium (CS), a mast cell stabilizing agent, and U-60,257(U) (a leukotriene blocker) on the circulation, lung mechanics and thromboxane (TXB2) levels in 11 lambs during acute exposure to HYP. Studies were performed in awake, chronically instrumented animals, once after placebo (saline) and again after CS (100 mg; n = 5) or U (90 mg; n = 6). Pulmonary arterial pressure increased 42% during HYP after saline, and 32% and 19% after CS and U, respectively. Pulmonary vascular resistance did not change during HYP after CS or U. Systemic arterial pressure was unchanged after saline and CS but decreased after U; systemic vascular resistance dropped after both CS and U. No changes were seen in tidal volume, lung compliance or airway resistance during HYP after saline or either drug, but minute ventilation increased during HYP in all studies. TXB2 increased during HYP after saline in both studies and was not altered by CS. In contrast, after U, TXB2 decreased. Thus, U more effectively blunted the pulmonary vascular response to HYP than CS and resulted in mild systemic hypotension. The drop in TXB2 after U suggests leukotriene-induced thromboxane synthesis contributes to regulation of pulmonary, and possibly, systemic vasoactivity.     

Periodic acceleration: effects on vasoactive, fibrinolytic, and coagulation factors.

Cellular and isolated vessel experiments have shown that pulsatile and laminar shear stress to the endothelium produces significant release of mediators into the circulation. Periodic acceleration (pG(z)) applied to the whole body in the direction of the spinal axis adds pulses to the circulation, thereby increasing pulsatile and shear stress to the endothelium that should also cause release of mediators into the circulation. The purpose of this study was to determine whether addition of pulses to the circulation through pG(z) would be sufficient to increase shear stress in whole animals and to acutely release mediators and how such a physical maneuver might affect coagulation factors. Randomized control experiments were performed on anesthetized, supine piglets. The treatment group (pG(z)) (n = 12) received pG(z) with a motion platform that moved them repetitively head to foot at +/-0.4 g at 180 cpm for 60 min. The control group (n = 6) was secured to the platform but remained on conventional ventilation throughout the 4-h protocol. Compared with control animals and baseline, pulsatile stress produced significant increases of serum nitrite, prostacyclin, PGE(2), and tissue plasminogen activator antigen and activity, as well as D-dimer. There were no significant changes in epinephrine, norepinephrine, cortisol, and coagulation factors between groups or from baseline values. Pulsatile and laminar shear stress to the endothelium induced by pG(z) safely produces increases of vasoactive and fibrinolytic activity. pG(z) has potential to achieve mediator-related benefits from the actions of nitric oxide and prostaglandins.     

Estradiol improves pulmonary hemodynamics and vascular remodeling in perinatal pulmonary hypertension

Partial ligation of the ductus arteriosus (DA) in the fetal lamb causes sustained elevation of pulmonary vascular resistance (PVR) and hypertensive structural changes in small pulmonary arteries, providing an animal model for persistent pulmonary hypertension of the newborn. Based on its vasodilator and antimitogenic properties in other experimental studies, we hypothesized that estradiol (E(2)) would attenuate the pulmonary vascular structural and hemodynamic changes caused by pulmonary hypertension in utero. To test our hypothesis, we treated chronically instrumented fetal lambs (128 days, term = 147 days) with daily infusions of E(2) (10 microg; E(2) group, n = 6) or saline (control group, n = 5) after partial ligation of the DA. We measured intrauterine pulmonary and systemic artery pressures in both groups throughout the study period. After 8 days, we delivered the study animals by cesarean section to measure their hemodynamic responses to birth-related stimuli. Although pulmonary and systemic arterial pressures were not different in utero, fetal PVR immediately before ventilation was reduced in the E(2)-treated group (2.43 +/- 0.79 vs. 1.48 +/- 0.26 mmHg. ml(-1). min, control vs. E(2), P < 0.05). During the subsequent delivery study, PVR was lower in the E(2)-treated group in response to ventilation with hypoxic gas but was not different between groups with ventilation with 100% O(2). During mechanical ventilation after delivery, arterial partial O(2) pressure was higher in E(2) animals than controls (41 +/- 11 vs. 80 +/- 35 Torr, control vs. E(2), P < 0. 05). Morphometric studies of hypertensive vascular changes revealed that E(2) treatment decreased wall thickness of small pulmonary arteries (59 +/- 1 vs. 48 +/- 1%, control vs. E(2), P < 0.01). We conclude that chronic E(2) treatment in utero attenuates the pulmonary hemodynamic and histological changes caused by DA ligation in fetal lambs.     

Hemodynamic response and oxygen transport in pigs resuscitated with maleimide-polyethylene glycol-modified hemoglobin (MP4).

Cell-free Hb increases systemic and pulmonary pressure and resistance and reduces cardiac output and heart rate in animals and humans, effects that have limited their clinical development as "blood substitutes." The primary aim of this study was to evaluate the hemodynamic response to infusion of several formulations of a new polyethylene glycol (PEG)-modified human Hb [maleimide PEG Hb (MalPEGHb)] in swine, an animal known to be sensitive to Hb-induced vasoconstriction. Anesthetized animals underwent controlled hemorrhage (50% of blood volume), followed by resuscitation (70% of shed volume) with 10% pentastarch (PS), 4% MalPEG-Hb in lactated Ringer (MP4), 4% MalPEG-Hb in pentastarch (HS4), 2% MalPEG-Hb in pentastarch (HS2), or 4% stroma-free Hb in lactated Ringer solution (SFH). Compared with baseline, restoration of blood volume after resuscitation was similar and not significantly different for the PS (103%), HS2 (99%), HS4 (106%), and MP4 (87%) animals but significantly less for the SFH animals (66%) (P < 0.05). All solutions that contained MalPEG-Hb restored mean arterial and pulmonary pressure and cardiac output. Systemic vascular resistance was unchanged, and pulmonary arterial pressure and resistance were increased slightly. Both systemic and pulmonary vascular resistance increased significantly in animals that received SFH, despite less adequate blood volume restoration. Oxygen consumption was maintained in all animals that received MalPEG-Hb, but not PS. Base excess improved only with MalPEG-Hb and PS, but not SFH. Red blood cell O2 extraction was significantly increased in animals that received Hb, regardless of formulation. These data demonstrate resuscitation with MalPEG-human Hb without increasing systemic vascular resistance and support our previous observations in animals suggesting that the efficacy of low concentrations of PEG-Hb in the plasma results from reduced vasoconstriction.     

EDRF inhibition attenuates the increase in pulmonary blood flow due to oxygen ventilation in fetal lambs.

At birth, pulmonary vasodilation occurs during rhythmic distension of the lungs and oxygenation. Inhibition of prostaglandin synthesis prevents pulmonary vasodilation during rhythmic distension of the lungs but not during oxygenation. Because endothelium-derived relaxing factor (EDRF) modulates pulmonary vascular tone at birth, at rest, and during hypoxia in older animals, we hypothesized that EDRF may modulate pulmonary vascular tone during oxygenation in fetal lambs. We studied the responses to N omega-nitro-L-arginine, a competitive inhibitor of EDRF synthesis, in nine near-term fetal lambs and to drug vehicle in six of these lambs and the subsequent responses to in utero ventilation with 95% O2 in these fetal lambs. In all fetal lambs, prostaglandin synthesis was prevented by meclofenamate. N omega-nitro-L-arginine increased pulmonary and systemic arterial pressures by 28% (P < 0.05) and 31% (P < 0.05), respectively, and decreased pulmonary blood flow by 83% (P < 0.05). In the controls, ventilation with 95% O2 increased pulmonary blood flow by 1,050% (P = 0.05) without changing pressures, thereby decreasing pulmonary vascular resistance by 88% (P = 0.05). During N omega-nitro-L-arginine infusion, ventilation with 95% O2 increased pulmonary blood flow by 162% (P = 0.05) and decreased pulmonary vascular resistance by 74% (P = 0.05). This suggests that EDRF may play an important role in modulating resting pulmonary vascular tone in fetal lambs and in the vasodilatory response to ventilation with O2 in utero.     

The effect of repeated intermittent hypoxia on pulmonary vasoconstriction in the newborn

The effect of repeated intermittent hypoxia upon the basal pulmonary vascular tone in the newborn period is unknown. We therefore studied the central hemodynamic response to seven repeated intermittent hypoxic challenges in acutely prepared piglets under 2 weeks of age. Catheters were placed in the aorta, pulmonary artery, and atria, and an electromagnetic flow probe was positioned around the main pulmonary artery. Each hypoxic challenge (Fio2 = 0.14) lasted 5 min, and was separated by an equal duration of ventilation with air. Nine control animals were ventilated with air for 90 min, a period of time equivalent to the seven challenges in the experimental group, and subjected to one hypoxic challenge at the end. Hypoxia uniformly induced pulmonary vasoconstriction. Repeated intermittent hypoxic challenges produced a progressive increase in pulmonary artery pressure and vascular resistance, both during air ventilation and hypoxia. For each challenge, the vascular resistance value achieved during hypoxia was directly related to the immediately preceding air ventilation one, and the magnitude of hypoxic pulmonary vasoconstriction, defined as the incremental change in resistance from air to hypoxia, was not different from the first to the last challenge in the experimental group. In the control group the pulmonary vascular tone did not change during the 90 min of air ventilation, and the single hypoxic challenge induced an increase in pulmonary vascular pressure and resistance similar in magnitude to the first challenge in the experimental group. Indomethacin administration to five experimental animals, after the last challenge, reversed the increase in air ventilation pulmonary artery pressure and vascular resistance.(ABSTRACT TRUNCATED AT 250 WORDS)     

A fetal-instrumented model to study age-specific responses to leukotriene D4 and prostaglandin D2 in unsedated newborn lambs

Sequential studies of the pulmonary vascular response to leukotriene D4 (LTD4) and prostaglandin D2 (PGD2) in the immediate newborn period were performed in lambs, instrumented in utero and delivered vaginally. Compounds were tested in fully conscious 1.5-day-old lambs and the study was repeated 1 week later. Bolus injections of PGD2 (0.05-2.0 micrograms/kg) or LTD4 (0.01-1.0 micrograms/kg) were made into the main pulmonary artery or aorta while pulmonary blood flow and aortic, pulmonary artery, and left and right atrial pressures were monitored continuously. PGD2 was a systemic constrictor regardless of age. In lambs 1.5 days of age, it decreased pulmonary vascular pressure and resistance by 6% (p less than 0.05) and 15% (p less than 0.05), respectively, while 1 week later it increased pulmonary vascular resistance by 18% (p less than 0.05). In contrast, LTD4 was a pulmonary and systemic vasoconstrictor in both the early and late newborn, the threshold dose being between 0.01 and 0.05 micrograms/kg at either age. The decrease in pulmonary blood flow and the increase in pressure and resistance were greater in older animals. In lambs 1.5 days of age, LTD4 (1 micrograms/kg) increased pulmonary vascular resistance by 66.1% (p less than 0.05) and 1 week later by 210% (p less than 0.001). These sequential observations in the same animal indicate that unlike PGD2, LTD4 is a pulmonary vasoconstrictor regardless of age, and its effectiveness increases significantly with age. These results support previous reports that PGD2 action in the pulmonary circulation changes shortly after birth from dilation to constriction.     

Pulmonary haemodynamics during nasal apnoea in rabbits.

Changes in pulmonary haemodynamics, produced during stimulation of the nasal mucosa with xylol fumes, were found in experiments on anaesthetized rabbits. In spontaneously breathing animals, a decrease in the mean blood pressure in the pulmonary artery and an increase in the mean blood pressure in the left atrium occurred in addition to apnoea and bradycardia. Pulmonary vascular resistance fell significantly, whereas systemic vascular resistance rose. Changes in the pulmonary circulation during nasal stimulation in spontaneously breathing rabbits did not differ significantly from changes in artifically ventilated animals.     

Platelet-activating factor modulates pulmonary vasomotor tone in the perinatal lamb

Eight near-term fetal lambs were studiedacutely in utero to determine role of platelet-activating factor (PAF)in the regulation of vasomotor tone in systemic and pulmonarycirculations in the immediate perinatal period. Four fetal lambs werestudied predelivery and 2 h postdelivery to determine circulating PAFlevels. Aortic and pulmonary arterial pressures and cardiac output weremeasured continuously, and systemic and pulmonary vascular resistances were calculated. Left pulmonary arterial blood flow was also measured in four fetal lambs. After delivery and oxygenation, circulating PAFlevels fell significantly. When WEB-2170, a specific PAF-receptor antagonist, was infused to block effect of endogenous PAF in the eightnear-term fetal lambs, systemic vascular resistance fell 30% butpulmonary vascular resistance fell dramatically by 68%. Specificity of WEB-2170 was tested in juvenile lambs and was found tobe very specific in lowering vasomotor tone only when tone was elevatedby action of PAF. Our data show that endogenous PAF levels in the fetuscontribute to maintain a high basal systemic and pulmonary vasomotortone and that a normal fall in circulating PAF levels after birth andoxygenation may facilitate fall in pulmonary vascular resistance atbirth.

     

Atrial natriuretic factor attenuates the pulmonary pressor response to hypoxia

The influence of endogenous and exogenous atrial natriuretic factor (ANF) on pulmonary hemodynamics was investigated in anesthetized pigs during both normoxia and hypoxia. Continuous hypoxic ventilation with 11% O2 was associated with a uniform but transient increase of plasma immunoreactive (ir) ANF that peaked at 15 min. Plasma irANF was inversely related to pulmonary arterial pressure (Ppa; r = -0.66, P less than 0.01) and pulmonary vascular resistance (PVR; r = -0.56, P less than 0.05) at 30 min of hypoxia in 14 animals; no such relationship was found during normoxia. ANF infusion after 60 min of hypoxia in seven pigs reduced the 156 +/- 20% increase in PVR to 124 +/- 18% (P less than 0.01) at 0.01 microgram.kg-1.min-1 and to 101 +/- 15% (P less than 0.001) at 0.05 microgram.kg-1.min-1. Cardiac output (CO) and systemic arterial pressure (Psa) remained unchanged, whereas mean Ppa decreased from 25.5 +/- 1.5 to 20.5 +/- 15 mmHg (P less than 0.001) and plasma irANF increased two- to nine-fold. ANF infused at 0.1 microgram.kg-1.min-1 (resulting in a 50-fold plasma irANF increase) decreased Psa (-14%) and reduced CO (-10%); systemic vascular resistance (SVR) was not changed, nor was a further decrease in PVR induced. No change in PVR or SVR occurred in normoxic animals at any ANF infusion rate. These results suggest that ANF may act as an endogenous pulmonary vasodilator that could modulate the pulmonary pressor response to hypoxia.     

Umbilical cord compression produces pulmonary hypertension in newborn lambs: a model to study the pathophysiology of persistent pulmonary hypertension in the newborn

We investigated the effects of chronic intrauterine hypoxaemia produced by prolonged partial umbilical cord compression on the circulation shortly after birth in lambs. Vascular catheters were inserted in 10 fetal sheep at 120 to 130 days gestation to measure descending aortic blood gases, arterial pH, and arterial O2 saturation. An inflatable silicone rubber balloon cuff was also placed around the umbilical cord. After recovery and the return of descending aortic blood gases to the normal range, the balloon was gradually inflated, decreasing the PaO2 from 21.2 +/- 3.6 to 17.5 +/- 1.3 mm Hg and the arterial O2 saturation from 57.1 +/- 9.2% to 37.2% +/- 5.2. After 14.3 +/- 3.7 days of partial umbilical cord compression, the lambs were delivered by Caesarean section, instrumented to measure systemic and pulmonary arterial, right atrial and pulmonary arterial wedge pressures, pulmonary and systemic blood flows, and mechanically ventilated. Five normal lambs were also studied. From 60 to 120 min after delivery, when compared to normal lambs, the umbilical compression lambs had an increased pulmonary arterial pressure (P less than 0.05) pulmonary vascular resistance (P less than 0.05), and right atrial pressure (P less than 0.05) with similar arterial blood gases. In both groups, hypoxic ventilation produced an increase in pulmonary arterial pressure (P less than 0.05) which on return to room air ventilation decreased to baseline in the normal lambs but not in the umbilical cord compression lambs (P less than 0.05). Prolonged partial umbilical cord compression produces chronic fetal hypoxaemia and pulmonary arterial hypertension after birth. This may represent a model to study the pathophysiology of persistent pulmonary hypertension syndrome.     

Combination Proximal Pulmonary Artery Coiling and Distal Embolization Induces Chronic Elevations in Pulmonary Artery Pressure in Swine

Pulmonary hypertension (PH) is associated with aberrant vascular remodeling and right ventricular (RV) dysfunction that contribute to early mortality. Large animal models that recapitulate human PH are essential for mechanistic studies and evaluating novel therapies; however, these models are not readily accessible to the field owing to the need for advanced surgical techniques or hypoxia. In this study, we present a novel swine model that develops cardiopulmonary hemodynamics and structural changes characteristic of chronic PH. This percutaneous model was created in swine (n=6) by combining distal embolization of dextran beads with selective coiling of the lobar pulmonary arteries (2 procedures per lung over 4 weeks). As controls, findings from this model were compared with those from a standard weekly distal embolization model (n=6) and sham animals (n=4). Survival with the combined embolization model was 100%. At 8 weeks after the index procedure, combined embolization procedure animals had increased mean pulmonary artery pressure (mPA) and pulmonary vascular resistance (PVR) compared to the controls with no effect on left heart or systemic pressures. RV remodeling and RV dysfunction were also present with a decrease in the RV ejection fraction, increase in the myocardial performance index, impaired longitudinal function, as well as cardiomyocyte hypertrophy, and interstitial fibrosis, which were not present in the controls. Pulmonary vascular remodeling occurred in both embolization models, although only the combination embolization model had a decrease in pulmonary capacitance. Taken together, these cardiopulmonary hemodynamic and structural findings identify the novel combination embolization swine model as a valuable tool for future studies of chronic PH.     

Prostanoids and hemodynamics in man before and during cardiopulmonary bypass

The plasma concentration of 6-keto-PGF1 alpha, the stable degradation product of prostacyclin, was similar in the radial and pulmonary arteries and in the coronary sinus before and after the induction of the anesthesia in patients undergoing coronary artery bypass surgery. After the beginning of the mechanical ventilation and anesthesia the pulmonary vascular resistance decreased although no changes were detected in the plasma levels of 6-keto-PGF1 alpha or TXB2. During the prebypass period after the sternotomy and cannulation of the large vessels the plasma level of 6-keto-PGF1 alpha was increased similarly in the radial and pulmonary arteries and even more in the coronary sinus. During the cardiopulmonary bypass the concentration of 6-keto-PGF1 alpha remained at the increased level as compared to the values before the anesthesia. This indicates that pulmonary circulation is perhaps not the main source of prostacyclin in man. The plasma level of TXB2 was increased during the prebypass period significantly only in the coronary sinus, but during the bypass also in the radial artery. The concentration ratio of 6-keto-PGF1 alpha/TXB2 was increased significantly during the prebypass period in the radial and pulmonary arteries. At the same time the pulmonary vascular resistance was, however, returned to the preanesthesia level and was thus not decreased. The vascular resistance in the systemic circulation was increased during the prebypass period. The plasma level of 6-keto-PGF1 alpha or TXB2 in the radial and pulmonary arteries did not correlate significantly with the total vascular resistance in the systemic and pulmonary circulation, respectively. The vascular resistance in the coronary circulation did not correlate significantly with TXB2 level in the radial artery or coronary sinus. There was, however, a slight positive correlation between the blood flow and the concentration of TXB2 in the coronary sinus (r = 0.76, P less than 0.01). Coronary sinus flow did, however, not correlate with the plasma level of 6-keto-PGF1 alpha in the radial artery or coronary sinus. These results indicate that the detected plasma concentrations of prostacyclin and thromboxane A2 have no significant effects on the total vascular resistance in vivo.     

Hemodynamic parameters in a surgical devascularization model of fulminant hepatic failure in the minipig

Animal models of fulminant hepatic failure (FHF) are important for studying the pathophysiology of this process and for evaluation of the efficacy of artificial and bioartificial liver support systems. In experiments, hemodynamic parameters were monitored in a group of minipigs with FHF induced by surgical devascularization, and compared with those in a control group. During the experiment, animals were analgosedated and were on mechanical lung ventilation. Crystalloid and colloidal solutions were administered and norepinephrine in continuous infusion was applied if mean arterial pressure (MAP) decreased below 60 mm Hg despite adequate intravascular volumes. An increase in heart rate, and decreases in MAP and systemic vascular resistance, compared with the baseline, occurred in the FHF group from 6 h after surgery. A comparison of FHF and control groups revealed no significant differences in systemic vascular resistance and MAP until after 12 h after surgery (systemic vascular resistance index: 953 FHF vs. 1658 controls; p < 0.05; MAP: 58.1 FHF vs. 76 controls; p < 0.05). No significant differences in CI were seen between the FHF group and controls. FHF animals survived for about 13 h after surgery, i.e. a period, which we consider long enough to test a support device. The parameters are believed to be quite adequate, as we were able to maintain satisfactory hemodynamic stability in all experimental animals with induced acute hepatic failure.     

Pulmonary hemodynamic responses to in utero ventilation in very immature fetal sheep

Background

The onset of ventilation at birth decreases pulmonary vascular resistance (PVR) resulting in a large increase in pulmonary blood flow (PBF). As the large cross sectional area of the pulmonary vascular bed develops late in gestation, we have investigated whether the ventilation-induced increase in PBF is reduced in immature lungs.

Methods

Surgery was performed in fetal sheep at 105 d GA (n = 7; term ~147 d) to insert an endotracheal tube, which was connected to a neonatal ventilation circuit, and a transonic flow probe was placed around the left pulmonary artery. At 110 d GA, fetuses (n = 7) were ventilated in utero (IUV) for 12 hrs while continuous measurements of PBF were made, fetuses were allowed to develop in utero for a further 7 days following ventilation.

Results

PBF changes were highly variable between animals, increasing from 12.2 ± 6.6 mL/min to a maximum of 78.1 ± 23.1 mL/min in four fetuses after 10 minutes of ventilation. In the remaining three fetuses, little change in PBF was measured in response to IUV. The increases in PBF measured in responding fetuses were not sustained throughout the ventilation period and by 2 hrs of IUV had returned to pre-IUV control values.

Discussion and conclusion

Ventilation of very immature fetal sheep in utero increased PBF in 57% of fetuses but this increase was not sustained for more than 2 hrs, despite continuing ventilation. Immature lungs can increase PBF during ventilation, however, the present studies show these changes are transient and highly variable.     

Circulatory effects of prolonged hypoxia before and during antihistamine.

Five chronically instrumented healthy dogs were exposed to a 5-day period of breathing 10% oxygen in a chamber. The response to hypoxia was found to be time dependent. During the first 24 h of hypoxia the circulatory response was characterized by increases in cardiac output, heart rate, pulmonary and systemic arterial blood pressures, and pulmonary vascular resistance. Systemic vascular resistance increased; left atrial pressure decreased. During the early part of hypoxia the animals became hypocapnic; the arterial blood pH rose significantly. During the rest of the hypoxic period cardiac output, heart rate, and arterial blood pH returned to the control values; pulmonary and systemic arterial pressures and pulmonary vascular resistance remained significantly elevated. Systemic vascular resistance rose; left atrial pressure remained below control. This response to hypoxia was not substantially modified when the experiment was repeated during the administration of the antihistamine promethazine, an H1-receptor blocking agent, in a dose which blocked the pulmonary vasoconstrictor response to small doses of exogenous histamine. The circulatory response to acute hypoxia in five anesthetized dogs was not modified by intravenous administration of metiamide, an H2-receptor blocking agent.     

Increased vasoreactivity and chronic pulmonary hypertension following thoracic irradiation in sheep

Six chronically catheterized sheep were exposed to 1,500-rad whole-lung irradiation and followed for a four-week period. Pulmonary arterial, left atrial and systemic arterial pressures, cardiac output, arterial blood gases, and pH were measured at base line and biweekly following radiation. Pulmonary vasoreactivity to 12% O2, 100% O2, and an analogue of prostaglandin H2 (PGH2-A) was also assessed. Five nonirradiated sheep served as controls. By the 2nd wk following irradiation, pulmonary vascular resistance had doubled. Final pulmonary arterial pressure was increased 50% over the base-line value (base line = 14 +/- 1 cm H2O; final 22 +/- 2; mean +/- SE; P less than 0.05). Arterial PO2 was decreased to approximately 70 Torr throughout the study. In addition, pulmonary vasoreactivity to PGH2-A, but not to breathing 12 or 100% O2, was significantly increased above base line in the irradiated animals (P less than 0.05). Morphometric techniques applied to the lungs in which the pulmonary arterial circulation was distended with barium gelatin mixture, showed extension of muscle into the distal intra-acinar arteries, and a reduction in both the external diameter and the number of barium-filled peripheral arteries in the irradiated animals. Thus thoracic irradiation results in functional and structural changes of chronic pulmonary hypertension and increased pulmonary vasoreactivity to PGH2-A. The structural changes in the peripheral pulmonary arterial bed may contribute to the increased pulmonary vascular reactivity following thoracic irradiation.     

Intratracheal perfluorocarbons diminish LPS-induced increase in systemic TNF-alpha

Perfluorocarbons (PFC) reduce the production of various inflammatory cytokines, including TNF-alpha. The anti-inflammatory effect is not entirely understood. If anti-inflammatory properties are caused by a mechanical barrier, PFC in the alveoli should have no effect on the inflammatory response to intravenous LPS administration. To test that hypothesis, rats (n=31) were administered LPS intravenously and were either spontaneously breathing (Spont), conventionally ventilated (CMV), or receiving partial liquid ventilation (PLV). Serum concentration of TNF-alpha was measured. The pulmonary expressions of TNF-alpha and TNF-alpha receptor 1 protein and of TNF-alpha and ICAM-1 mRNA were determined. LPS caused a significant (P<0.001) increase in serum TNF-alpha. Serum TNF-alpha concentration was similar in LPS/Spont (525+/-180 pg/ml) and LPS/CMV (504+/-154 pg/ml) but was significantly (P<0.001) lower in animals of the LPS/PLV group (274+/-101 pg/ml). Immunohistochemical data on TNF-alpha protein expression showed a LPS-induced increase in TNF-alpha and TNF-alpha receptor 1 expression that was diminished by partial liquid ventilation. PCR measurements revealed a lower expression of TNF-alpha and ICAM-1 mRNA in LPS/PLV than in LPS/CMV or LPS/Spont animals. Semiquantitative histological evaluation revealed only minor alveolar inflammation with no significant differences between the groups. Low serum TNF-alpha concentration in PFC-treated animals is most likely explained by a decreased production of TNF-alpha in the lung.     

Congenital NOS2 deficiency prevents impairment of hypoxic pulmonary vasoconstriction in murine ventilator-induced lung injury

Hypoxic pulmonary vasoconstriction (HPV) preserves systemic arterial oxygenation during lung injury by diverting blood flow away from poorly ventilated lung regions. Ventilator-induced lung injury (VILI) is characterized by pulmonary inflammation, lung edema, and impaired HPV leading to systemic hypoxemia. Studying mice congenitally deficient in inducible nitric oxide synthase (NOS2) and wild-type mice treated with a selective NOS2 inhibitor, L-N(6)-(1-iminoethyl)lysine (L-NIL), we investigated the contribution of NOS2 to the impairment of HPV in anesthetized mice subjected to 6 h of either high tidal volume (HV(T)) or low tidal volume (LV(T)) ventilation. HPV was estimated by measuring the changes of left lung pulmonary vascular resistance (LPVR) in response to left mainstem bronchus occlusion (LMBO). LMBO increased the LPVR similarly in wild-type, NOS2(-/-), and wild-type mice treated with L-NIL 30 min before commencing 6 h of LV(T) ventilation (96% +/- 30%, 103% +/- 33%, and 80% +/- 16%, respectively, means +/- SD). HPV was impaired in wild-type mice subjected to 6 h of HV(T) ventilation (23% +/- 16%). In contrast, HPV was preserved after 6 h of HV(T) ventilation in NOS2(-/-) and wild-type mice treated with L-NIL either 30 min before or 6 h after commencing HV(T) ventilation (66% +/- 22%, 82% +/- 29%, and 85% +/- 16%, respectively). After 6 h of HV(T) ventilation and LMBO, systemic arterial oxygen tension was higher in NOS2(-/-) than in wild-type mice (192 +/- 11 vs. 171 +/- 17 mmHg; P < 0.05). We conclude that either congenital NOS2 deficiency or selective inhibition of NOS2 protects mice from the impairment of HPV occurring after 6 h of HV(T) ventilation.