Richard D. Bland

Preparation of chronic lung lymph fistulas in sheep.

Abstract The majority of lung lymph in the sheep drains through a large caudal mediastinal lymph node. At a preliminary operation, we remove the systemic lymph contamination. We obtain lung lymph by cannulating the efferent duct of the node. We use a physiologic test in which we elevate systemic and pulmonary venous pressures separately to show that the origin of the lymph is from the lung. The overall success rate in obtaining lung lymph flow for periods longer than 1 week is less than 50%. Successful animals are excellent models in which to study net lung fluid and protein flow.

Hemodynamic and oxygen transport patterns in surviving and nonsurviving postoperative patients

Invasive hemodynamic monitoring was performed on 220 critically ill surgical patients judged by clinical evaluation to have a high likelihood of surgical complications or death. Patients with markedly abnormal pre-operative hemodynamic values were excluded from analysis. Data were separated into preoperative, intra-operative and postoperative time intervals and the mean value of each variable for each patient at each time period was computed. In comparison to survivors, the nonsurvivors generally had: (a) reduced myocardial performance as judged by lower cardiac index and left ventricular stroke work in the presence of high right and left ventricular filling pressures, (b) reduced pulmonary function (increased alveolar-arterial oxygen content difference and pulmonary shunt fraction), (c) pulmonary vasoconstriction (increased pulmonary artery pressure and pulmonary vascular resistance), and (d) decreased oxygen delivery despite maintenance of normal arterial blood gases and comparable hemoglobin values. Both survivors and nonsurvivors had vital signs usually within the normal range (until the terminal state of nonsurvivors).

Use of physiologic monitoring to predict outcome and to assist in clinical decisions in critically ill postoperative patients

A predictive index based on cardiorespiratory-monitored values of an earlier series of postoperative critically ill patients was tested in prospective clinical trials and found to be reasonably accurate, sensitive, and specific. The hypothesis was tested that the median values of patients who survived life-threatening postoperative conditions, rather than the norms of unstressed, healthy volunteer subjects, constitute a first approximation to the optimal therapeutic goals for critically ill postoperative patients. In a prospective series of 223 consecutive, critically ill postoperative patients, normal values were used as the therapeutic goals of the control patients, whereas the median values of surviving patients were used as the goals of therapy for the protocol group. The clinical conditions of the protocol group were at least as severe as those of the control group, but the mortality was significantly less in the protocol group (12.5 percent) than in the control group (35 percent); the number of life-threatening complications were also greater in the control group. These data suggest that at least half and possibly as much as two thirds of postoperative deaths may be due to physiologic problems that can be identified, described, predicted, and prevented. Therapy for the critically ill patient should be defined by physiologic criteria, and administration of therapy should be monitored to attain prophylactically optimal physiologic goals rather than giving therapy after a deficiency has occurred to attain normal values.

Neonatal Chronic Lung Disease in the Post-Surfactant Era

This is a brief review of neonatal chronic lung disease, sometimes called the ‘new bronchopulmonary dysplasia (BPD)’. The clinical, radiographic and pathological features of this condition have changed considerably in recent years because of major advances in perinatal care, including widespread use of antenatal glucocorticoid therapy, postnatal surfactant replacement and improved respiratory and nutritional support. Authentic animal models, featuring lengthy mechanical ventilation of surfactant-treated, premature neonatal baboons and lambs, have provided important insights on the pathophysiology and treatment of this disease. Lung histopathology after 2–4 weeks of positive-pressure ventilation with oxygen-rich gas results in failed formation of alveoli and lung capillaries, excess disordered elastin accumulation, smooth muscle overgrowth in small pulmonary arteries and airways, chronic inflammation and interstitial edema. Treatment interventions that have been tested in these animal models include nasal application of continuous positive airway pressure, high-frequency mechanical ventilation, inhaled nitric oxide and retinol. The challenge now is to improve understanding of the molecular mechanisms that regulate normal lung growth and development, and to clarify the dysregulation of lung structure and function that occurs with injury and subsequent repair so that effective treatment or prevention strategies can be devised and implemented.

Labor decreases the lung water content of newborn rabbits

To test the prevailing concept that drainage of fetal lung liquid begins after birth, we measured extravascular lung water content of 47 fetal rabbits born at term gestation, with or without prior labor. Rabbits born after labor, either vaginally or operatively, had less water in their lungs than those delivered by cesarean section without preceding labor; there was no difference in lung water content between rabbits born vaginally or operatively after labor. These results suggest that reduction in the volume of fetal lung liquid in rabbits normally begins before birth and depends on the experience of labor, not the mode of delivery.

Prolonged mechanical ventilation with air induces apoptosis and causes failure of alveolar septation and angiogenesis in lungs of newborn mice

Defective lung septation and angiogenesis, quintessential features of neonatal chronic lung disease (CLD), typically result from lengthy exposure of developing lungs to mechanical ventilation (MV) and hyperoxia. Previous studies showed fewer alveoli and microvessels, with reduced VEGF and increased transforming growth factor-beta (TGFbeta) signaling, and excess, scattered elastin in lungs of premature infants and lambs with CLD vs. normal controls. MV of newborn mice with 40% O(2) for 24 h yielded similar lung structural abnormalities linked to impaired VEGF signaling, dysregulated elastin production, and increased apoptosis. These studies could not determine the relative importance of cyclic stretch vs. hyperoxia in causing these lung growth abnormalities. We therefore studied the impact of MV for 24 h with air on alveolar septation (quantitative lung histology), angiogenesis [CD31 quantitative-immunohistochemistry (IHC), immunoblots], apoptosis [TdT-mediated dUTP nick end labeling (TUNEL), active caspase-3 assays], VEGF signaling [VEGF-A, VEGF receptor 1 (VEGF-R1), VEGF-R2 immunoblots], TGFbeta activation [phosphorylated Smad2 (pSmad2) quantitative-IHC], and elastin production (tropoelastin immunoblots, quantitative image analysis of Harts stained sections) in lungs of 6-day-old mice. Compared with unventilated controls, MV caused a 3-fold increase in alveolar area, approximately 50% reduction in alveolar number and endothelial surface area, >5-fold increase in apoptosis, >50% decrease in lung VEGF-R2 protein, 4-fold increase of pSmad2 protein, and >50% increase in lung elastin, which was distributed throughout alveolar walls rather than at septal tips. This study is the first to show that prolonged MV of developing lungs, without associated hyperoxia, can inhibit alveolar septation and angiogenesis and increase apoptosis and lung elastin, findings that could reflect stretch-induced changes in VEGF and TGFbeta signaling, as reported in CLD.

Chronic Lung Injury in Preterm Lambs: Abnormalities of the Pulmonary Circulation and Lung Fluid Balance

Chronic lung disease of early infancy, or bronchopulmonary dysplasia, is a frequent complication of prolonged mechanical ventilation after premature birth. Pulmonary hypertension and edema are common features of this condition, which is often attributed to long-term, repetitive overinflation of incompletely developed lungs. The overall objective of this work was to examine the effects on the pulmonary circulation and lung fluid balance of different ventilation strategies using large versus small inflation volumes in an animal model of bronchopulmonary dysplasia. We studied 16 newborn lambs that were delivered prematurely (124 ± 3 d gestation, term = 147 d) by cesarean section and mechanically ventilated for 3 to 4 wk. Ten lambs were ventilated at 20 breaths/min, yielding a tidal volume of 15 ± 5 mL/kg, and six lambs were ventilated at 60 breaths/min, yielding a tidal volume of 6 ± 2 mL/kg. All lambs received surfactant at birth and had subsequent surgery for closure of the ductus arteriosus and catheter placement to allow serial measurements of pulmonary vascular resistance and lung lymph flow. Chronic lung injury, documented by serial chest radiographs and postmortem pathologic examination, developed in all lambs irrespective of the pattern of assisted ventilation. Pulmonary vascular resistance, which normally decreases during the month after birth at term, did not change significantly from the first to the last week of study. Lung lymph flow, an index of net transvascular fluid filtration, increased with time in lambs that were ventilated at 20 breaths/min, but not in lambs ventilated at 60 breaths/min. Lymph protein concentration decreased with time, indicative of increased fluid filtration pressure, without evidence of a change in lung vascular protein permeability. Postmortem studies showed interstitial lung edema, increased pulmonary arteriolar smooth muscle and elastin, decreased numbers of small pulmonary arteries and veins, and decreased capillary surface density in distal lung of chronically ventilated lambs compared with control lambs that were killed either 1 d (same postconceptional age) or 3 wk (same postnatal age) after birth at term. Thus, chronic lung injury from prolonged mechanical ventilation after premature birth inhibits the normal postnatal decrease in pulmonary vascular resistance and leads to lung edema from increased fluid filtration pressure. These abnormalities of the pulmonary circulation may contribute to the abnormal respiratory gas exchange that often exists in infants with bronchopulmonary dysplasia.

Sequential cardiorespiratory patterns in septic shock.

Sequential hemodynamic and oxygen transport monitoring was performed in 33 patients with septic shock to define the temporal pattern of physiologic events. Measurements taken over a 24-h period before the hypotensive crisis, defined as the lowest initial mean arterial pressure (MAP), were compared to those taken during the 48 h thereafter. In the 24-h period before the hypotensive crisis, there were increases in cardiac index (CI), central venous pressure (CVP), pulmonary capillary wedge pressure (WP), pulmonary vascular resistance index (PVRI), and pulmonary shunt (Qsp/ Qt), but decreases in MAP, systemic vascular resistance index (SVRI) and oxygen delivery (Do2). When sequential cardiorespiratory patterns were examined, oxygen consumption (Vo2) fell transiently to significantly low values 12 h before as well as at the time of the hypotensive crisis. SVRI fell and CI rose to values significantly different from normal in the 4 h before the low MAP. During the subsequent 48 h after the hypotensive crisis, CI, CVP, WP, PVRI and Qsp/Qt remained elevated. Values for MAP, SVRI, Do2, and Vo2 were significantly reduced. These results demonstrate the existence of antecedent cardiorespiratory alterations that precede the hypotensive episode in septic shock and suggest that flow maldistribution in the systemic circulation is an early event with possible pathogenic significance.

High frequency mechanical ventilation in severe hyaline membrane disease an alternative treatment

Twenty-four preterm infants with respiratory failure from severe hyaline membrane disease (HMD) received mechanical ventilation at high respiratory frequencies. The average birthweight of the infants was 1244 ± 301 g, and 7 babies weighed less than 1000 g. The average gestational age was 30 ± 2 weeks, and 6 infants were born at 28 weeks or less. The method of ventilation included (1) respiratory frequencies of 60–110/min, sometimes with brief manual ventilation at more rapid rates, (2) peak inflation pressures (PIP) of less than 35 cm H2O, (3) inspiratory durations of 0.15–0.25 sec, (4) positive end-expiratory pressure (PEEP) of 4–9 cm H2O, and (5) weaning from mechanical ventilation by reducing tidal volume until peak inflation pressure (PIP) reached 20–25 cm H2O, whereupon respiratory frequency was decreased. Paco2 was kept at 30–40 torr and Pao2 at 60–80 torr. Of the infants, 22 survived (92%) with few major complications.

Cardiorespiratory monitoring in postoperative patients: I. Prediction of outcome and severity of illness.

An index for prediction of outcome for use as a measure of the severity of illness was developed by a nonparametric multivariate analysis of cardiorespiratory data from 113 critically ill postoperative general surgical patients. This severity (predictive) index was based on a computerized algorithm that compares a given observed value with the frequency distributions of survivors and nonsurvivors. The difference in the mean values of this index for survivors and nonsurvivors was statistically significant (p less than 0.001) during each stage of shock. Sensitivity of the index in prediction of survival ranged from 70-93% depending upon stage, the specificity of the index ranged from 76-92%, and the predictive accuracy ranged from 87-96%. The severity index is used as a process measure to track the course of critically ill patients and to evaluate the efficacy of alternative therapies.