Jacqueline J. Coalson

Multiple organ system failure and infection in adult respiratory distress syndrome.

Patients with the adult respiratory distress syndrome and multiple organ system failure have a high mortality rate despite extensive supportive therapy. We evaluated the role of multiple organ system failure and infection in 37 consecutive survivors of the syndrome, and 47 consecutive nonsurvivors on whom autopsies were done. Failure of the central nervous, coagulation, endocrine, gastrointestinal, and renal systems was common in all patients but was more frequent in those who died. Major infections occurred in 46 nonsurvivors and 22 survivors. All patients with bacteremia who had a clinically identified site of infection survived, whereas all patients with bacteremia without a clinically identified site of infection died. Autopsy results of the latter group showed infections requiring surgical drainage for complete therapy. Patients clinically septic but without bacteremia and without a clear site of infection were shown at autopsy to have pneumonia. Multiple organ system failure was more common in infected (93%) than noninfected (47%) patients. Vigorous evaluation and treatment of infection in patients with the adult respiratory distress syndrome may improve survival.

Effects of prolonged controlled mechanical ventilation on diaphragmatic function in healthy adult baboons

OBJECTIVE To study diaphragmatic strength and endurance after a prolonged period of mechanical ventilation. DESIGN Prospective animal study. SETTING Animal research laboratory. SUBJECTS Seven uninjured adult baboons (Papio cynocephalus) were anesthetized with ketamine, sedated, paralyzed, and mechanically ventilated. Animals were monitored with pulmonary arterial and peripheral arterial catheters. INTERVENTIONS Mechanical ventilation was provided for 11 days with an FIO2 of 0.21 and tidal volume of 15 mL/kg. Pulmonary function tests, including lung volumes, arterial blood gases, and chest radiographs were also monitored. Nursing care procedures included frequent turning, chest physiotherapy, and endotracheal suction. Antacids and prophylactic antibiotics (intravenous penicillin, topical polymyxin B, and gentamicin sulfate) were administered. In three animals, fishhook electrodes were surgically placed around both phrenic nerves on both day 0 and after 11 days of mechanical ventilation for diaphragmatic stimulation. On day 0, the electrodes were removed after phrenic nerve stimulation studies were performed. After 11 days of mechanical ventilation, animals were electively killed and full autopsy performed. MEASUREMENTS AND MAIN RESULTS Hemodynamic and pulmonary function parameters were measured at baseline and every day during the 11 days of mechanical ventilation. Diaphragmatic strength and endurance were measured on days 0 and 11. Diaphragmatic endurance was determined by an inspiratory resistive loading protocol. There were no significant changes in hemodynamics, lung volumes, or gas exchange during the period of mechanical ventilation. On day 7, the chest radiographs showed patchy lobar atelectasis in six animals, which cleared by day 11 in all but two of the animals. Lung pathology showed mild, focal pneumonitis. By day 11, maximum transdiaphragmatic pressure had decreased by 25% from day 0 and diaphragmatic endurance had decreased by 36%. CONCLUSIONS Eleven days of mechanical ventilation and neuromuscular blockade in healthy baboons resulted in nonsignificant changes in hemodynamics, oxygenation, and/or lung function. However, significant impairment in diaphragmatic endurance and strength were seen. Based on these results, it is likely that prolonged mechanical ventilation by itself impairs diaphragmatic function independent of underlying lung disease.

Ventilatory management of infant baboons with hyaline membrane disease: The use of high frequency ventilation

Abstract: We tested the hypothesis that high frequency oscillatory ventilation (HFOV) would result in decreased pulmonary barotrauma in infants with hyaline membrane disease by comparing HFOV at 10 Hz to conventional positive pressure ventilation with continual distending airway pressure (PPV/PEEP) in premature baboons with hyaline membrane disease. Nineteen baboon fetuses were randomized to one of two treatment groups, delivered at 140 ± 2 days, and, after stabilization and instrumentation of PPV/PEEP, placed in their respective ventilator group. Animals on conventional ventilation were managed by adjustment of tidal volume and frequency (to 1 Hz) to keep PaCO2 below 55 and by adjustment of the mean airway pressure. One of the “HFOV” group died of cardiovascular complications before going on HFOV and was eliminated from data analysis. The remaining HFOV baboons survived the 11-day experimental period without evidence of airleak. Six of the 11 prematures treated with PPV/PEEP developed pulmonary interstitial emphysema and/or pneumothorax and five of the animals died within 48 h. The intergroup differences in airleak were significant (p < 0.05). Mean airway pressure (measured at the proximal airway) was higher initially with HFOV but then was lowered more rapidly than in the PPV/PEEP animals. The arterial to alveolar oxygen ratio rose and the FIO2 could be lowered more rapidly with HFOV than with conventional ventilation. These differences reached significance by 20 h. After 60 h there were no significant differences between HFOV and the PPV/PEEP survivors. HFOV resulted in more uniform saccular expansion, higher arterial to alveolar oxygen ratio, less oxygen exposure, and decreased acute barotrauma when compared to PPV/PEEP. Although initially mean airway pressure was in the HFOV animals this was not associated with measurable baroinjury. These data support the efficacy of HFOV in the treatment of prematures with hyaline membrane disease.

Chronic lung disease in early infancy

Clinical Aspects Historical Perspective: Early Observations and Subsequent Evolution of Bronchopulmonary Dysplasia William H. Northway, Jr. Epidemiology of Bronchopulmonary Dysplasia: Clinical Risk Factors and Associated Clinical Conditions Alma Martinez, Peter Dargaville, and H. William Taeusch Clinical Course and Lung Function Abnormalities During Development of Neonatal Chronic Lung Disease Eduardo Bancalari and Alvaro Gonzalez Radiographic Features of BPD and Potential Application of New Imaging Techniques David K. Edwards and William H. Northway, Jr. Pathology of Chronic Lung Disease of Early Infancy Jacqueline J. Coalson The Usefulness of Bronchoalveolar Lavage in Infants with Evolving Chronic Lung Disease Carl W. White and Leland L. Fan Inflammatory Mediators in Neonatal Lung Disease Christian P. Speer and Peter Groneck Infection in the Pathogenesis of Bronchopulmonary Dysplasia William E. Benitz and Ann M. Arvin Ventilation Strategies and Bronchopulmonary Dysplasia W. Alan Hodson Effect of Respiratory Care Practices on the Development of Bronchopulmonary Dysplasia Michael R. Gomes and Thomas N. Hansen Influence of Surfactant Replacement on Development of Bronchopulmonary Dysplasia Alan H. Jobe Drug Treatment for Established BPD Thomas A. Hazinski Nutritional Issues in Chronic Lung Disease of Premature Infants Ilene R. S. Sosenko, Michael T. Kinter, and Robert J. Roberts Pulmonary Function in BPD and Its Aftermath Eric C. Eichenwald Cardiovascular Abnormalities in Bronchopulmonary Dysplasia Michael Apkon, Rodrigo Nehgme, and George Lister Long-Term Recovery from Bronchopulmonary Dysplasia Solomon Alkrinawi and Victor Chernick The Goal: Prevention of BPD Mildred T. Stahlman Normal and Abnormal Alveolar and Airway Development Unique Features of the Immature Lung that Make It Vulnerable to Injury Scott H. Randell and Stephen L. Young Hormonal Effects on Lung Maturation and Disease Philip L. Ballard and Roberta A. Ballard Mechanisms and Physiological Sequelae of Reactive Species Injury to the Alveolar Epithelium Imad Y. Haddad, Sha Zhu, Samuel J. Tilden, and Sadid Matalon Surfactant in Chronic Lung Injury Richard J. King and Samuel Hagwood The Regulation of the Formation of Pulmonary Alveoli Donald J. Massaro and Gloria D. Massaro Factors Mediating Cell Growth in Lung Injury A. Keith Tanswell, Shilpa Buch, Mingyao Liu, and Martin Post Developmental Airway Structure and Function in Health and Chronic Lung Injury Howard B. Panitch and Thomas H. Shaffer Normal and Abnormal Development of the Lung Circulation and Interstitium Lung Development and the Effects of Chronic Hypoxia Sheila G. Haworth Altered Development of the Pulmonary Circulation in Chronic Lung Injury Marlene Rabinovitch Pulmonary Hypertension in Chronic Lung Disease of Infancy: Pathogenesis, Pathophysiology, and Treatment Steven H. Abman Connective Tissues in Lung Development and Diseases in Early Infancy David J. Riley Pulmonary Edema After Premature Birth: Progression from Acute to Chronic Lung Disease Richard D. Bland and David P. Carlton Mechanisms of Lung Injury and Repair During Development Molecular Mechanisms of Oxygen-Induced Lung Injury Charles Vincent Smith and Stephen E. Welty Assessment of Tissue Injury from Reactive Oxygen Metabolites Michael J. Thomas, Timothy W. Robison, and Henry Jay Forman Chronic Lung Disease of Early Infancy: Role of Neutrophils Diane E. Lorant, Kurt Albertine, and John F. Bohnsack The Role of Pulmonary Macrophages in Chronic Lung Disease of Early Infancy Michael P. Sherman and William E. Truog Oxidants and Antioxidants: What Role Do They Play in Chronic Lung Disease H. Lee Frank and Ilene R. S. Sosenko Proteolytic Enzymes and Their Inhibitor in Lung Health and Disease John R. Hoidal and Mari K. Hoidal Site and Mechanism-Directed Interventions for Tissue Free Radical Injury William R. Berrington, Margaret M. Tarpey, Bruce A. Freeman, and Bruce R. Pitt Models of Lung Injury and Repair During Development Genetic Models for the Study of Autocrine-Paracrine Signaling in Lung Development and Repair Jeffrey A. Whitsett and Thomas R. Korfhagen Animal Models of Chronic Lung Injury Jacqueline J. Coalson, Steven R. Seidner, and Robert A. De Lemos

A baboon model of bronchopulmonary dysplasia. II. Pathologic features

Abstract A light microscopic (LM), transmission electron microscopic (TEM), and scanning electron microscopic (SEM) study was performed on the lungs from seven baboons delivered by cesarean section prematurely (75% of full gestation) and one at full term. Six of the seven premature baboons pursued a clinical course typical of human hyaline membrane disease (HMD) and/or bronchopulmonary dysplasia (BPD). All the animals were supported with mechanical ventilation and exposed to continuous high levels of inspired oxygen. Three animals died early (⩽3 days) of complications and two demonstrated typical light and electron microscopic lesions of hyaline membrane disease. Three baboons survived ⩾ 8 days and developed pathologically confirmed bronchopulmonary dysplasia, characterized by an altered inflation pattern of atelectasis and overdistension/“emphysema,” bronchial and bronchiolar lesions of necrosis, regenerative hyperplastic and/or squamous metaplastic changes, and peribronchiolar fibrosis and early alveolar wall fibrosis. A striking finding was a hyperplastic/obliterative respiratory bronchiolar lesion, most frequently seen in the atelectatic areas. The lungs of these animals lacked pores of Kohn; a feature shared by a study group of untreated baboons with gestation ages of 109 to 180 days. It is suggested that the lack of collateral ventilation, plus the striking hyperplastic-obliterative airway lesion might explain the characteristic feature of atelectasis. The histopathologic features of this model coincide with with those of BPD in the human neonate, with the exception of the hypertensive vascular changes, which may be a time-related lesion. The pathologic findings further support the premise that the premature baboon will be a very useful model in which the primary etiologic consideration of oxygen toxicity and barotrauma can be separated as to their roles in the causation of bronchopulmonary dysplasia.

A baboon model of bronchopulmonary dysplasia: I. Clinical features

Abstract Investigation in bronchopulmonary dysplasia (BPD) has been seriously hampered by the lack of a suitable animal model. The consistent development of BPD in preterm baboons ( Papio cynocephalus ) with hyaline membrane disease (HMD) who were treated with 95–100% inspired oxygen and supported with mechanical ventilation for more than 1 week is reported. One term (173 days) and nine preterm (134–147 days) pregnancies were delivered by cesarean section with birth weights 495–988 g. Amniotic fluid lecithin: sphingomyelin (L/S) ratios ranged from 0.47 to 1.00. The six animals with L/S ratios ⩽ 0.62 developed HMD. The clinical and radiologic course was indistinguishable from HMD in preterm humans. HMD was confirmed pathologically in two animals dying acutely. One of the remaining four was supported with supplemental oxygen as needed and remains a long-term survivor of HMD. The other three were maintained in 95–100% oxygen. A clinical and radiographic picture similar to that of human BPD developed in each and was pathologically confirmed. The preterm baboon appears to be a suitable animal model for investigation of the etiology, pathophysiology, prevention, therapy, and long-term sequelae of HMD and BPD.

The pulmonary ultrastructure in septic shock

Abstract The ultrastructural alterations in the lungs of the monkey after intravenously administered lethal injections of live E. coli organisms or endotoxin are markedly similar. Edema of the perivascular space was seen in all lung tissues examined. Pulmonary capillaries were engorged with polymorphonuclear leukocytes undergoing fragmentation 15 minutes after injections of endotoxin or E. coli organisms. The endothelial cytoplasm contained large vacuoles and many vesicles, but there was no evidence of actual rupture of the cytoplasmic membranes. Endothelial cellular membranes appeared fuzzy and indistinct at sites where polymorphonuclear leukocytes were adhering. Fragmentation and loss of specific granules in polymorphonuclear leukocytes were noted 1 hour postinjection. The loss of specific granules, fragmentation of polymorphonuclear leukocytes, and focal areas of pulmonary edema were observed 4 hours after the injection of endotoxin or live E. coli organisms. In marked contrast to a previous report on the primate administered endotoxin, this investigation revealed no evidence for intravascular coagulation of fibrin and platelet aggregates. The widespread morphological alterations could explain some of the functional derangements previously observed in monkeys in shock.

Diffuse Alveolar Damage in the Evolution of Bronchopulmonary Dysplasia in the Baboon

ABSTRACT: Pulmonary immaturity, oxygen exposure that elicits cellular damage by free radicals, and barotrauma induced by mechanical ventilation are implicated in the pathogenesis of bronchopulmonary dysplasia. In the adult counterpart of adult respiratory distress syndrome, diffuse alveolar damage characterizes a histopathological sequence of lung findings that can occur during the disease course. Although adult respiratory distress syndrome has many etiologies, elevated oxygen exposure is known to be a contributor to the ensuing lung injury. In bronchopulmonary dysplasia, oxygen exposure is thought to be a primary agent of injury. The evolution of the histopothological findings in the premature baboon model of hyaline membrane disease/bronchopulmonary dysplasia was investigated in this study and compared to that in oxygen-treated adult baboons with adult respiratory distress syndrome. Findings from lung specimens of 121 prematurely delivered baboons at 0, 0.5, 1, 2, 3–6, 7–11+ days after delivery document that the premature lung has a delayed and more blunted exudative response when compared to that of human and baboon adults. Saccular edema, not hyaline membranes, is the dominant histopathological finding in the exudative phase of diffuse alveolar damage and occurs later (7–11 days) in infant lungs when compared to comparably treated adult lungs in which maximal exudative changes are seen at 3–6 days. The reparative response in the premature baboon is characterized by saccular wall thickening and fibrosis, with less intramural organization of exudate in saccular/alveolar spaces when compared to adults. The airway changes in the premature are more severe than those seen in adult disease. These findings indicate that diffuse alveolar damage does occur in the immature lung albeit with differing characteristics when contrasted to comparably injured adults.

Survival of primates in LD100 septic shock following steroid/antibiotic therapy.

Abstract This study was designed to determine the effect of steroid/antibiotic treatment on the survival of baboons subjected to LD100 Escherichia coli shock. Fourteen baboons (Papio c. cynocephalus), randomly divided into three groups, were anesthetized and administered 2-hr infusions of LD100 viable E. coli. Group A received E. coli alone; Group B was administered E. coli followed by infusions of both gentamicin sulfate (GS) (18 mg/kg) and methylprednisolone sodium succinate (MPSS) (75 mg/kg) during a 12-hr period. Group C was given E. coli plus GS (18 mg/kg) alone. Groups B and C baboons were also given GS intramuscularly, 4.5 mg/kg at 12 hr and twice daily for 3 days. Insensible fluid loss during the intial 12-hr period was replaced by minimal volumes of saline. Fully treated baboons (Group B) received steroid after 0.7 × 1010 organisms/kg body wt had been administered. All fully treated baboons survived; however, all animals of Groups A and C died within 42 hr. Systemic hypotension observed in every baboon within 2 hr was reversed in Group B animals. Hypoglycemia, hypoinsulinemia, anuria, and extensive adrenal pathology were prevented by steroid/antibiotic treatment. Serum creatinine and blood urea nitrogen concentrations increased in all baboons but returned to normal in the fully treated group. Increased survival may have been due in part to augmented antibacterial activity elicited by (a) improved peripheral distribution of the antibiotic and (b) stimulation of the bone marrow by the steroid. Findings demonstrate that the lethal pathophysiology of E. coli-induced shock is effectively prevented by combined steroid and antibiotic therapy.

Isolation from a Salivary Gland of Granules Containing Renin and Kallikrein

Granules of the submaxillary gland of the white mouse contain both kallikrein and renin. The granules were separated and concentrated in sequential centrifugation procedures. They were more stable at room temperature and in hypertonic sucrose solutions than in the cold or in isotonic solution. The amylase, acid phosphatase, renin, kallikrein, and benzoyl-L-arginine ethyl ester esterase contents of the granules were determined. Kallikrein and renin showed a similar distribution pattern after fractionation. Granular renin released the equivalent of 9.6 μg angiotensin II amide/mg enzyme protein/min from swine serum angiotensinogen. Granular kallikrein liberated from human kininogen the equivalent of 8.4 μg bradykinin/mg enzyme protein/min. Electron micrographs of the isolated granules showed various forms; some were spherical and symmetrical, and others were amorphous.