Fall In Lung Compliance Research Articles

Comparisons of effects of intravenous and inhaled methacholine on airway physiology in a murine asthma model

Airway responses to intravenous (i.v.) and inhaled (i.h.) delivery of methacholine (MCh) in BALB/c and C57BL/6 mouse strains have been compared with and without ovalbumin (OVA)-induced airway inflammation. Bronchial reactivity to MCh was assessed in anaesthetised and tracheostomised animals by using an animal ventilator (flexiVent). We partitioned the response of the lungs into airway and parenchymal components in order to compare the contributions of the airways with those of the lung parenchyma to the pulmonary mechanical responses resulting from different routes of MCh administration. Our results indicate disparate physiological responses. Intravenous MCh delivery induced a higher maximum lung resistance than i.h. MCh in OVA-treated BALB/c mice but not in C57BL/6 mice. Inhaled MCh delivery led to a significantly larger fall in lung compliance and a greater impact on peripheral airways than i.v. MCh in both strains. In conclusion, i.v. and i.h. MCh produced disparate effects in different murine strains and variant responses in inflamed airways and healthy controls. The two methods of MCh delivery have important advantages but also certain limitations with regard to measuring airway reactivity in a murine model of allergic asthma.

CHEMICALLY MODIFIED TETRACYCLINE PREVENTS THE DEVELOPMENT OF SEPTIC SHOCK AND ACUTE RESPIRATORY DISTRESS SYNDROME IN A CLINICALLY APPLICABLE PORCINE MODEL

Sepsis causes more than with 215,000 deaths per year in the United States alone. Death can be caused by multiple system organ failure, with the lung, in the form of the acute respiratory distress syndrome (ARDS), often being the first organ to fail. We developed a chronic porcine model of septic shock and ARDS and hypothesized that blocking the proteases neutrophil elastase (NE) and matrix metalloproteinases (MMP-2 and MMP-9) with the modified tetracycline, COL-3, would significantly improve morbidity in this model. Pigs were anesthetized and instrumented for hemodynamic monitoring and were then randomized to one of three groups: control (n = 3), laparotomy only; superior mesenteric artery occlusion (SMA) + fecal blood clot (FC; n = 7), with intraperitoneal placement of a FC; and SMA + FC + COL (n = 5), ingestion of COL-3 12 h before injury. Animals emerged from anesthesia and were monitored and treated with fluids and antibiotics in an animal intensive care unit continuously for 48 h. Serum and bronchoalveolar lavage fluid (BALF) were sampled and bacterial cultures, MMP-2, MMP-9, NE, and multiple cytokine concentrations were measured. Pigs were reanesthetized and placed on a ventilator when significant lung impairment occurred (PaO2/FiO2 < 250). At necropsy, lung water and histology were assessed. All animals in the SMA + FC group developed septic shock evidenced by a significant fall in arterial blood pressure that was not responsive to fluids. Lung injury typical of ARDS (i.e., a fall in lung compliance and PaO2/FiO2 ratio and a significant increase in lung water) developed in this group. Additionally, there was a significant increase in plasma IL-1 and IL-6 and in BALF IL-6, IL-8, IL-10, NE, and protein concentration in the SMA + FC group. COL-3 treatment prevented septic shock and ARDS and significantly decreased cytokine levels in plasma and BALF. COL-3 treatment also significantly reduced NE activity (P < 0.05) and reduced MMP-2 and MMP-9 activity in BALF by 64% and 34%, respectively, compared with the SMA + FC group. We conclude that prophylactic COL-3 prevented the development of ARDS and unexpectedly also prevented septic shock in a chronic insidious onset animal model of sepsis-induced ARDS. The mechanism of this protection is unclear, as COL-3 inhibited numerous inflammatory mediators. Nevertheless, COL-3 significantly reduced the morbidity in a clinically applicable animal model, demonstrating the possibility that COL-3 may be useful in reducing the morbidity associated with sepsis and ischemia/reperfusion injury in patients.

Effects of thromboxane synthase and cyclooxygenase inhibition on PAF-induced changes in lung function and arachidonic acid metabolism

PAF was administered as an intravenous bolus (0.1 μg/kg) to eight chronically instrumented awake sheep. The effects of pretreatment with an inhibitor of cyclooxygenase (meclofenamate) on PAF-induced changes in lung function were compared to those observed with a specific inhibitor of thromboxane synthase (DP1904). Each animal was studied four times in varied order: PAF alone, PAF + DP1904, PAF + meclofenamate, and DP1904 alone. Saline alone (control), DP1904 alone, and meclofenamate alone did not cause changes in any of the measured variables. DP1904 and meclofenamate significantly attenuated the PAF-induced fall in lung compliance, elevation in peak pulmonary artery pressure, and increased lung lymph flow. Both drugs abolished the PAF-induced increases in lung lymph thromboxane B 2 concentrations. Meclofenamate, but not DP1904, blocked the rise in lymph 6-keto-PGF 1α. Although meclofenamate blocked the rise in lymph PGE 2, DP1904 resulted in levels 2.7 times higher than PAF alone. We conclude that: (1) inhibition of thromboxane synthase is as effective as inhibition of cyclooxygenase in attenuating PAF-induced changes in lung function, and (2) thromboxane synthase inhibition results in augmented production of PGE 2 following PAF administration in vivo.

Effect of tidal volume and frequency on the temporal fall in lung compliance

In this study we have investigated how changes in respiratory frequency and tidal volume in anesthetized dogs affect the fall in dynamic compliance (Cdyn) that occurs with time after a hyperinflation. Results showed that increasing frequency [at controlled arterial (PaCO2)] PCO2 from 16 to 32 breaths/min had no effect on either the rate of fall or the magnitude of the fall up to 1 h after the hyperinflation. However, increasing the tidal volume from 300 to 750 ml abolished the fall in Cdyn from 10 to 50 min after the hyperinflation; the fall within the first 10 min remained unchanged. We also examined the effect of a simulated on the compliance of strips of parenchymal tissue in vitro. This result indicated that in the absence of surface forces, parenchymal tissue demonstrates a fall in compliance, which is complete within 10 min. Overall our findings are consistent with the hypothesis that the fall in Cdyn after hyperinflation is a two-phase process. The initial rapid fall in Cdyn (i.e., within 10 min) may simply represent a passive recovery process from the hyperinflation stress on the parenchymal tissue. The slower fall occurring after 10 min likely results from progressive increases in surface tension, and this increase can apparently be blocked by increases in tidal volume.

Effect of tidal volume and frequency on the temporal fall in lung compliance.

In this study we have investigated how changes in respiratory frequency and tidal volume in anesthetized dogs affect the fall in dynamic compliance (Cdyn) that occurs with time after a hyperinflation. Results showed that increasing frequency [at controlled arterial (PaCO2)] PCO2 from 16 to 32 breaths/min had no effect on either the rate of fall or the magnitude of the fall up to 1 h after the hyperinflation. However, increasing the tidal volume from 300 to 750 ml abolished the fall in Cdyn from 10 to 50 min after the hyperinflation; the fall within the first 10 min remained unchanged. We also examined the effect of a simulated "hyperinflation" on the compliance of strips of parenchymal tissue in vitro. This result indicated that in the absence of surface forces, parenchymal tissue demonstrates a fall in compliance, which is complete within 10 min. Overall our findings are consistent with the hypothesis that the fall in Cdyn after hyperinflation is a two-phase process. The initial rapid fall in Cdyn (i.e., within 10 min) may simply represent a passive recovery process from the hyperinflation stress on the parenchymal tissue. The slower fall occurring after 10 min likely results from progressive increases in surface tension, and this increase can apparently be blocked by increases in tidal volume.

Influence of vagal activity on the neonatal ventilatory response to hypoxemia.

The sustained increase in ventilation (V1) that occurs during acute hypoxemia in adults is not characteristic of the neonate as V1 falls to or below baseline values soon after onset of the hypoxic stimulus. Associated with this decline in V1 is a decrease in tidal volume, lung compliance, inspiratory duration, and an increase in functional residual capacity and respiratory frequency. We hypothesized that hypoxemia induced small airway constriction and pulmonary time constant inequalities resulting in a frequency dependent fall in lung compliance and tidal volume and retention of lung volume. In seven newborn subhuman primates, responses to acute hypoxemia were measured prior to and after administration of atropine methyl bromide to prevent vagally mediated narrowing of peripheral airways. The increase in frequency and fall in inspiratory duration characteristic of the ventilatory decline during hypoxemia was eliminated by the drug but functional residual capacity and lung compliance were unaffected. Also, the initial rise in V1 was blunted or blocked in all subjects. Bilateral vagotomy caused V1 to fall significantly requiring oxygen supplementation but responses to hypoxemia were still biphasic in nature. These findings suggest that cholinergically mediated mechanisms in the airways do not alter effective lung distensibility related to respiratory rate. Acetylcholine may be important at the peripheral chemosensor since cholinergic blockade eliminated the initial ventilatory increase.(ABSTRACT TRUNCATED AT 250 WORDS)

The mechanical properties of the respiratory system during anesthesia.

1. Static compliance of the total respiratory system is decreased during anesthesia, 2. The fall in total static compliance is probably caused by a fall in lung compliance. 3. It seems unlikely that the fall in lung compliance is the primary event. The change in pleural pressures at FRC before and during anesthesia would answer this question, but the data are conflicting. 4. It is more likely that the position of the chest wall pressure-volume curve shifts to the right as a consequence of anesthesia, so that the position of equilibrium for the lung and chest wall at FRC is at a lower volume. The alteration in the chest wall is possibly because of loss of respiratory muscle tone. 5. FRC is reduced. Gas trapping occurs as a secondary event if FRC falls to below CC. 6. Lung compliance falls as a consequence of the fall in FRC, but only if FRC drops below CC, and closure occurs. No data of the correlation of change in lung compliance to the relationship of FRC to CC have been published. 7. A-aDo2 increases because of an increase in the amount of lung where ventilation is reduced compared to perfusion. Areas of zero ventilation (shunt) will also be produced. 8. The changes in lung compliance, FRC, and A-aDo2 appear to have similar characteristics. They are not influenced by depth or type of general anesthesia or the presence of neuromuscular blockade. They appear as soon as anesthesia is induced and are not progressive with time during anesthesia. They are less in the sitting position and in taller, thinner subjects. They appear to be only transiently affected by hyperinflations. 9. The fall in total respiratory system compliance may contribute to the apparent depression of the ventilatory response to carbon dioxide.

A two-phased change in dynamic lung compliance during hemorrhagic hypotension.

AbstractProlonged hemorrhagic hypotension and multiple trauma not involving the lungs can, in patients, induce respiratory failure with a fall in lung compliance and a concomitant increase in the work of breathing (Moore et al. 1969). However, animals experiments have revealed conflicting results concerning the magnitude and direction of change in lung compliance after a hemorrhage. We have studied the effects of 3 hr of hypovolemic systemic hypotension (femoral a. pressure: 50 to 60 mm Hg) on lung mechanics in open chest cats ventilated by positive pressure.Mean dynamic lung compliance (CL) rose during the first 30 min post‐bleeding by 13 ± 5 per cent whereafter CL gradually fell to 26 ± 6 per cent below its initial value, in the third hr of observation. On the basis of our monitoring of vascular parameters and alveolar‐arterial PO2 differences we suggest that the early rise in CL is due to reduced pulmonary blood volume and vascular distending pressure, whereas the later fall in CL is caused by collapse and narrowing of peripheral airways. No signifiant changes in nonelastic (frictional) resistance could be detected during the 3 h observation period.

THE EFFECT OF HYPERVENTILATION ON PULMONARY SURFACE ACTIVITY

SUMMARY The effect of IPPV with and without hyperventilation was studied in five groups of living anaesthetized guineapigs. The respiratory frequency used was in all cases 32 per min and the tidal volume was equal to either 15 per cent of the predicted vital capacity for a period of 15 min or to 75 per cent of the predicted vital capacity for a period of 2 breaths, 5 min, 10 min, or 15 min. Pressure/volume manoeuvres were done on the lungs of each animal at the end of the ventilation period and samples of lung tissue taken for measurement of the stability ratio of expressed lung bubbles. There was a small but non-significant fall in lung compliance and lung stability index following normal ventilation for 15 min. Hyperventilation reduced lung compliance, lung stability index, total lung volume and the bubble stability ratio to a degree which was related to the duration of ventilation. The opening pressure of the lungs and the pressure required to maximally inflate the lungs were increased following hyperventlation.

THE EFFECT OF HYPERVENTILATION ON PULMONARY SURFACE ACTIVITY

SUMMARY The effect of IPPV with and without hyperventilation was studied in five groups of living anaesthetized guineapigs. The respiratory frequency used was in all cases 32 per min and the tidal volume was equal to either 15 per cent of the predicted vital capacity for a period of 15 min or to 75 per cent of the predicted vital capacity for a period of 2 breaths, 5 min, 10 min, or 15 min. Pressure/volume manoeuvres were done on the lungs of each animal at the end of the ventilation period and samples of lung tissue taken for measurement of the stability ratio of expressed lung bubbles. There was a small but non-significant fall in lung compliance and lung stability index following normal ventilation for 15 min. Hyperventilation reduced lung compliance, lung stability index, total lung volume and the bubble stability ratio to a degree which was related to the duration of ventilation. The opening pressure of the lungs and the pressure required to maximally inflate the lungs were increased following hyperventlation.

HUMORAL TRANSMISSION OF CARDIORESPIRATORY CHANGES IN EXPERIMENTAL LUNG EMBOLISM.

Pairs of sheep were connected via a unilateral carotid-jugular anastomosis in fourteen experiments. With the cross circulation open, pulmonary embolism induced in the donor sheep produced a rise in pulmonary arterial pressure, a fall in lung compliance, and an increase in ventilation in the recipient animal. The transmitted effects were more pronounced with barium sulfate lung embolism than with blood clot lung embolism. These observations are consistent with the assumption that in acute experimental lung embolism a humoral agent is being released causing constriction of the lung vessels and airways.

EFFECT OF AMNIOTIC FLUID ASPIRATION ON THE LUNG AND CIRCULATION

The administration of 1-2 ml/kg body weight of human amniotic fluid into the trachea of anesthetized sheep caused a gross fall in lung compliance, an increase in resistance to air flow and severe hypoxemia, but only a slight rise in pulmonary arterial pressure. The changes in lung mechanics, and the hypoxemia, were not affected by forced inflation of the lungs; but after atropine sulphate, adrenaline, or aerosol isoproterenol, forced inflation produced marked improvement. The effects of amniotic fluid aspiration resemble some of the features of the respiratory distress syndrome of the newborn. However, whether sheep amniotic fluid introduced into newborn lamb lungs would have an entirely similar effect remains to be proven.

The lung as the main target organ in the acute phase of transfusion reaction in sheep

Summary Pulmonary complications arising from the transfusion of small amounts of incompatible blood were studied in sheep. The main features of the nonfatal response consisted of a rise in pulmonary arterial and pulmonary arterial wedge pressures (with left atrial pressure unchanged), arterial hypoxemia, fall in lung compliance and hyperventilation. If death occurred it was due to systemic collapse and respiratory arrest. Systemic hypotension in these cases appeared to be due to acute obstructive pulmonary hypertension, whereas arterial hypoxemia resulted from the compliance fall produced by terminal airway closure. The injection or inhalation of isoproterenol resulted in a fall in pulmonary arterial pressure, and a rise in cardiac output, lung compliance and arterial oxygen saturation. In animals with transfusion-induced respiratory arrest and shock (resistant to vasopressor agents), intravenous isoproterenol produced a prompt rise in systemic arterial pressure and restored spontaneous breathing. It is suggested that in incompatible blood transfusion, or in any other situation conducive of massive red cell destruction, a humoral agent is released from the lysed red cells producing airway closure and pulmonary vaso constriction. The latter, if sufficiently severe, may cause systemic collapse. The beneficial effect of isoproterenol appears to be due to its positive inotropic action and to its dilator effect on lung vessels and airways.

Mechanism and pharmacology of endotoxin shock in sheep

The cardiopulmonary consequences of coli-lipopolysaccharide and staphylococcus toxin administration were studied in sheep. Circulatory changes consisted mainly of a marked rise in pulmonary arterial and pulmonary arterial wedge pressure (with left atrial pressure unchanged), and a fall in cardiac output and in systemic arterial pressure. Fall in the latter closely followed the onset of pulmonary hypertension. The respiratory response consisted mainly of a severe fall in lung compliance produced by terminal airway closure. Continued perfusion of the nonventilated alveoli resulted in venous admixture. Premedication with antihistaminic, antiserotonin, or adrenolytic agents failed to affect the response. Norepinephrine or hypertensin administered after toxin injection had virtually no effect while isoproterenol treatment reduced pulmonary arterial pressure, increased cardiac output, arterial oxygen saturation, and, in cases of endotoxin shock, promptly raised systemic arterial pressure. Endotoxin-resistant sheep proved nonresponsive to minor pulmonary embolism and to incompatible blood transfusion. It is suggested that a common mediator agent is responsible for the similar cardiopulmonary consequences of these three diverse conditions.

Effect of isoproterenol in “severe” experimental lung embolism with and without postembolic collapse

The pulmonary hypertension and the fall in lung compliance that follow the intravenous administration of a large dose of barium sulfate emulsion in sheep were significantly reduced by the injection of isoproterenol. The tolerance of sheep to repeated emboli was markedly increased by the continuous infusion of isoproterenol. The protective effect of the drug was less marked than its curative action. In severe postembolic collapse with apnea unrelieved by the administration of pressor substances (norepinephrine and Hypertensin) the injection of isoproterenol promptly restored 9 out of 11 animals. In the intact sheep the pulmonary uptake of injected barium sulfate was virtually complete; this function was unaffected by the administration of isoproterenol. It is suggested that the beneficial action of isoproterenol in experimental lung embolism is due mainly to stimulation of the β-type of adrenergic receptors resulting in a rise in cardiac output and in pulmonary vasodilatation.

Reflex airway reaction to fluid aspiration

The mechanism of the lung mechanics changes after fluid aspiration was investigated in sheep, intubated and lightly anesthetized with thiopentone. The increase in venous admixture after intratracheal injection of fluid while breathing 100% oxygen indicated airway closure as the explanation for the associated gross fall in lung compliance (Cl). Atropine sulfate reduced the Cl fall produced by 1 ml/kg body wt. of fluid to a significantly greater extent than prior vagotomy. In vagotomized animals the reaction to fresh water was potententiated by prostigmine. A nonfoaming fluid with a surface tension of 27 dynes/cm had the same effect as fresh water. The reaction to water was not affected by lysergic acid butanolamide or aerosol tetracaine. Intravenous or aerosol isoproterenol reduced the Cl fall after water. These findings show that fluid aspiration invokes a reflex response of the parasympathetic nervous system, with both central and peripheral components producing closure of lung units. The relation of this reflex to other respiratory reflexes is discussed. When inflation alone was ineffective or lead to deterioration, both atropine and isoproterenol helped to reverse the effects of sea and fresh water. Submitted on March 8, 1962

Experimental amniotic fluid embolism: mechanism and treatment

Cardiorespiratory dynamics were studied in the experimental animal after the intravenous administration of filtered and unfiltered human amniotic fluid. Pulmonary hypertension, a severe fall in lung compliance, and arterial hypoxemia were observed. All these consequences of amniotic fluid embolism could be prevented or abolished by the administration of isoproterenol.

Lung mechanics and resuscitation after fluid aspiration.

Lung mechanics, arterial oxygen saturation (Sao2) and effective pulmonary capillary blood flow (Qe) were measured before and after intratracheal administration of 1—3 ml/kg body wt. of fresh or sea water in 20 intact and 11 vagotomized sheep during light thiopentone anesthesia. A gross fall in lung compliance (Cl) occurred in all animals after introduction of fresh and sea water; the fall was greater in intact than in vagotomized animals. A variable increase in nonelastic resistance was mainly due to blocking of airways by fluid and foam. Fall in Cl appeared to be the consequence of a reaction within the lungs resulting in a widespread closure of the terminal airways, which was influenced by the vagus nerve but not abolished by vagotomy. By relating Cl and Qe, hypoxemia induced by fluid was explained in terms of altered lung mechanics. Forced inflation increased Cl after fresh water and to a greater extent in vagotomized animals, but produced no change after sea water. A method of resuscitation is suggested based on the change in lung mechanics. With the use of 100% oxygen this method restored normal Sao2 independent of amount of fluid in the lung. Submitted on December 28, 1960

Ventilatory responses to embolization of lung

Marked changes in respiratory rate and volume occurred when anesthetized and spontaneously breathing dogs were subjected to pulmonary embolization with barium sulfate. Following embolization, there was a statistically significant fall in lung compliance, and, although a rise in pulmonary air-flow resistance occurred in the majority of instances, this change was not statistically significant. When the dogs were ventilated in approximately the resting tidal range by means of a pump and embolization was carried out, a statistically significant fall in lung compliance as well as a significant rise in pulmonary resistance was seen. Embolization of spontaneously breathing vagotomized animals in three instances revealed a fall in lung compliance and a rise in pulmonary resistance. The experimental observations of others are reviewed and the clinical implications are discussed. Submitted on October 28, 1960