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[Intensive therapy for multiple organ dysfunction in neonatal infants after cardiosurgical interventions].

This study was undertaken to evaluate the efficiency of complex intensive therapy for multiple organ dysfunction syndrome (MODS) after cardiosurgical interventions at the resuscitative and intensive care unit of the A. N. Bakulev Research Center of Cardiovascular Surgery, Russian Academy of Medical Sciences. In 2003-2004, MODS developed in 70 (37%) of the neonatal infants operated on the heart and vessels. The babies' age ranged from 6 hours of life to 1 month (8.3 +/- 2.1 days of life, their body weight was from 1.7 to 4.1 kg (3.0 +/- 0.49 kg). All the patients were found to have significant renal and respiratory failures. There were more than 4 (4.1 +/- 0.5) failing vital viscera. The use of phosphodiesterase (III) inhibitors in therapy for acute left ventricular insufficiency significantly improved the performance of the left heart whereas nitric oxide inhalation significantly lowered pulmonary pressure in babies with acute right ventricular insufficiency and improved oxygenation in patients with MODS. The efficiency of nitric oxide inhalation in MODS significantly increased when it was used in combination with endotracheal administration of a surfactant and high-frequency oscillatory ventilation. Peritoneal dialysis effectively replaced renal function when acute renal failure (ARF) developed. Nevertheless, the development of ARF in the pattern of MODS is a marker of high mortality (89% in ARF versus 46% in MODS without ARF).

Acute Kidney Injury↗

Ultrastructural changes in the lung alveoli after cardiac surgical operations with the use of cardiopulmonary bypass (CPB).

Cardiac surgical procedures with the use of cardiopulmonary bypass (CPB) are commonly complicated by pulmonary dysfunction. The mechanisms of such injury are not well understood. The aim of the present study is to analyze morphologically (mainly ultrastructurally) alveolar injury, which occurred during cardiac surgical operations involving CPB, equipped with a hollow fiber oxygenator. Our study included 20 patients, aged 45-72, who underwent coronary artery bypass grafting. Lung biopsies were taken from the left upper lobe 20 minutes after stopping CPB. Pre-CPB biopsies served as controls. Tissue specimens used for electron microscopy were processed according to standard procedures. Light microscopy revealed only a few alterations in the terminal part of the respiratory tract. Frank edema was seen in some of the alveoli. Extravasated erythrocytes as well as some neutrophils were present in the alveoli and several alveolar capillaries were congested. Ultrastructural observations confirmed the above mentioned changes. Moreover, in many alveoli, extensive injury to air-blood barrier was observed. Type I pneumocytes and endothelial cells appeared swollen or necrotically changed. The cytoplasm of type II pneumocytes was swollen. In many alveoli, pulmonary surfactant could not distribute over the alveolar surface because of edema. Structures of pulmonary surfactant were also seen in alveolar capillaries. The results of this investigation suggest that CPB is associated with some injury to lung tissue. However, this injury seems to be temporary since all examined patients had an uneventful post-operative course.

Aged↗

Pathogenesis, pathology and pathophysiology of pulmonary sequelae of bronchopulmonary dysplasia in premature infants.

The incidence of bronchopulmonary dysplasia (BPD), defined as oxygen need at 36 weeks of postmenstrual age, is about 30% for infants with birth weights<1000 grams and is now infrequent in infants with >1200 grams birth weight and >30 weeks gestation. The pathogenesis of BPD is multifactorial, with cytokines appearing to play a key role in initiation, propagation and resolution of this process. The pathology of BPD seen in the pre-surfactant era was remarkable for the presence of airway injury, inflammation and parenchymal fibrosis; pathology of "new" BPD reveals more uniform inflation and less marked fibrosis with both small and large airways being free of epithelial metaplasia, smooth muscle hypertrophy and fibrosis. There is, however, an arrest in acinar development.Up to 50% of infants with BPD require readmission to the hospital for lower respiratory tract illness in the first year of life. There are significant effects on lung mechanics, gas exchange and pulmonary vasculature. Pulmonary outcome in BPD include normalization of pulmonary mechanics and lung volumes over time as somatic and lung growth occurs whereas abnormality of the small airway persists. Airway hyper-responsiveness has been reported in long-term survivors of BPD, with no decrease in exercise capacity. The majority of the radiological findings reveal persistence of mild to moderate abnormalities long term. BPD is a result of dynamic processes involving inflammation, injury, repair and maturation. Infants with BPD have significant pulmonary sequelae during childhood and adolescence; whether the pulmonary dysfunction in these patients will predispose them to obstructive lung disease as older adults, remains to be seen.

Bronchopulmonary Dysplasia↗

Intravenous keratinocyte growth factor protects against experimental pulmonary injury.

Keratinocyte growth factor (KGF) administered by intratracheal instillation is well documented to stimulate the proliferation of alveolar and bronchial cells. In the present study, intravenous KGF was also shown to stimulate the proliferation of alveolar and bronchial cells in mice and rats, although to a lesser degree than intratracheal KGF. Despite the decreased potency of intravenous KGF on pulmonary cell 5-bromo-2'-deoxyuridine incorporation compared with intratracheal KGF, intravenous KGF was very effective in preventing experimental bleomycin-induced pulmonary dysfunction, weight loss, and mortality in either mice or rats and experimental hyperoxia-induced mortality in mice. The effectiveness of intravenous administration of KGF in preventing lung injury suggests that the mechanisms of the protective effect of KGF may involve more than pulmonary cell proliferation and also suggests the potential use of systemic KGF for clinical trials in settings of pulmonary injury.

Animals↗

Elective high-frequency oscillatory ventilation versus conventional ventilation in preterm infants with pulmonary dysfunction: systematic review and meta-analyses.

OBJECTIVES: To systematically review the evidence to determine whether the routine use of high-frequency oscillatory ventilation (HFOV) as compared with conventional ventilation (CV) is beneficial or harmful in preterm infants requiring mechanical ventilation for pulmonary failure principally due to respiratory distress syndrome. METHODS: All randomized controlled trials of elective HFOV versus CV in preterm infants <36 weeks' gestation with respiratory failure mainly attributable to respiratory distress syndrome were identified from the literature through a search of MEDLINE, EMBASE, Oxford database of Perinatal trials, and previous reviews including cross-references and abstracts. Meta-analyses using event rate ratios (ERR), event rate difference, and if significant, number needed-to-treat were calculated (95% confidence limits were used for all analyses). Two prespecified subgroup analyses were performed. RESULTS: Four published trials were included. Meta-analyses revealed the following ERR (95% confidence intervals) for HFOV versus CV: mortality at 28 to 30 days, 1.02 (0.76, 1.39); chronic lung disease (CLD) at 28 days, 0.86 (0.73, 1.01); mortality or CLD, 0.9 (0.80, 1. 01); air-leak syndromes, 1.13 (0.97, 1.33); mechanical ventilation at 28 days, 1.06 (0.84, 1.33); supplemental oxygen at discharge, 0. 59 (0.37, 0.92); intraventricular hemorrhage (IVH) all grades, 1.11 (0.95, 1.29); IVH (grades 3 or 4), 1.32 (1.01, 1.72); and periventricular leukomalacia, 1.39 (0.91, 2.13). In the subgroup of trials in which a high volume strategy (HVS) was used the ERR for CLD was 0.53 (0.36, 0.78); mortality or CLD, 0.56 (0.40, 0.77); supplemental oxygen at discharge, 0.57 (0.36, 0.92); IVH (all grades), 0.90 (0.61, 1.33); and IVH (grades 3 or 4), 0.84 (0.39, 1. 84). Results were similar to these for the trials using surfactant. One recent trial suggests that HFOV may reduce the cost of in-hospital care. CONCLUSIONS: The overall meta-analysis is dominated by the HIFI study, which was criticized for its methodology and surfactant was not used. Subsequent studies, most of which used HVS and/or surfactant, have shown benefits in measures of CLD without an increase in rates of IVH. Caution is warranted in interpreting these results because: 1) the treatment is not blinded and this could affect some outcomes; 2) except for one small trial postneonatal survival, lung function, and neurodevelopment have not been reported from HVS trials; and 3) the benefits and disadvantages have not been reported in infants born at different gestational ages or different birth weights. Importantly, results from groups experienced in the use of HFOV may not be readily generalizable.

Barotrauma↗

Effects of intra-uterine growth restriction on the control of breathing and lung development after birth.

1. Low birthweight is now recognized as an important risk factor for early postnatal respiratory illness and it is becoming evident that low birthweight can increase the risk for airway dysfunction in children and adults. Our studies have been aimed at determining how low birthweight, resulting from intra-uterine growth restriction (IUGR), affects the control of breathing and the structural and functional development of the lung. 2. We have measured ventilatory responsiveness to progressive hypoxia and progressive hypercapnia during the first weeks after birth in postnatal lambs in which IUGR was induced by chronic placental insufficiency. It was found that the postnatal increase in ventilatory sensitivity to hypoxia observed in control lambs was diminished in low birthweight lambs; in contrast, the sensitivity to hypercapnia was not affected. In other studies, we found that IUGR caused by maternal anaemia led to elevated CO2 levels during sleep and wakefulness. 3. Our findings suggest that the prenatal development of the brain-stem or respiratory chemoreceptors may be affected by intra-uterine factors associated with IUGR, such as foetal hypoxaemia or hypoglycaemia. It is also possible that the structure of respiratory muscles and, hence, their ability to maintain a high level of ventilation may be affected by IUGR. 4. Recently, we studied the influence of IUGR on foetal lung development, in particular its effects on foetal lung liquid, a major determinant of lung growth, as well as alveolar structure and pulmonary surfactant. Lung liquid secretion and volume, in relation to bodyweight, were unaffected; however, there was evidence of structural and functional immaturity in the lungs. In foetuses exposed to IUGR, the air-blood barrier was thicker and, after birth, the diffusing capacity of the lungs for carbon monoxide was lower. In contrast, surfactant protein gene expression was enhanced, particularly in foetuses with high levels of circulating cortisol. 5. Further studies are needed to characterize the effects of specific types of prenatal compromise on postnatal control of ventilation and lung function, to determine mechanisms underlying these effects and to determine the capacity for postnatal recovery.

Animals↗

Pharmacokinetics, toxicities, and efficacies of sodium stibogluconate formulations after intravenous administration in animals.

The pharmacokinetics and toxicities of free sodium stibogluconate (SSG) and two vesicular formulations of this drug (a nonionic surfactant vesicular formulation of SSG [SSG-NIV] and SSG-NIV-dextran) were determined after treatment with a single intravenous dose in healthy dogs and were related to their antileishmanial efficacies in mice. Analysis of the curves of the concentrations in plasma after intravenous administration of SSG and SSG-NIV in dogs showed that both formulations produced similar antimony (Sb) pharmacokinetics. In contrast, treatment with SSG-NIV-dextran significantly modified the pharmacokinetics of the drug. The elimination half-life was four times longer (280 min) than that observed after administration of SSG (71 min) (P = 0.01), and the volume of distribution at steady state (V(SS)) was also increased (V(SS) for SSG, 0.21 liters/kg; V(SS) for SSG-NIV-dextran, 0.34 liters/kg [P = 0.02]), thus indicating that drug encapsulation favors the distribution of Sb into organs and increases its residence time in tissues. This would explain the superior antileishmanial efficacy of this formulation compared to those of the free drug in mice. No signs of toxicity were found in dogs after SSG and SSG-NIV administration. However, SSG-NIV-dextran treatment was associated with short-term toxicity, demonstrated by the development of chills and diarrhea, which cleared by 24 h postdosing, and hepatic dysfunction at 24 h postdosing (P < 0.05). The levels of all the biochemical parameters had returned to normal at 1 month postdosing. No signs of toxicity were observed in mice treated with all three formulations.

Alanine Transaminase↗

Survivors of acute respiratory distress syndrome: relationship between pulmonary dysfunction and long-term health-related quality of life.

BACKGROUND: Patients who survive acute respiratory distress syndrome (ARDS) often report decreased general health-related quality of life (HRQOL) following hospital discharge. The extent to which this impairment is due to pulmonary or nonpulmonary causes is unclear. We describe the pattern of recovery of patients surviving ARDS to illuminate any relationships between lung spirometry values, pulmonary symptoms, and overall HRQOL. METHODS: Seventy-three survivors of ARDS were enrolled in a 12-month follow-up study as part of a phase III randomized, multicenter trial. Patients were contacted at 3, 6, and 12 months after enrollment to complete generic and disease-specific HRQOL questionnaires and have lung spirometry tests performed. RESULTS: For all domains of the Medical Outcomes Study Short Form-36 (SF-36) and the St. George's Respiratory Questionnaire (SGRQ) at all time intervals, survivors of ARDS had significantly lower scores than age- and sex-matched population values. Over the 12-month follow-up period, we observed significant improvements to the overall Physical Component Score, but the Mental Component Score of the SF-36 and the SGRQ scores were not statistically different. Physical performance measures suggested that by 12 months, 57% had not returned to "normal activity." At 12 months, lung spirometry tests demonstrated mild abnormalities that were stable over time (64% and 49% had <80% predicted forced expiratory volume in 1 sec [Fev1] and forced vital capacity [Fvc], respectively). At 12 months, the forced expiratory volume in 1 sec correlated strongly with the physical function domain of the SF-36 (correlation coefficient = 0.601; p < .01) and moderately with all domains of the SGRQ (correlation coefficient = -0.36, -50; p < .01 in all cases). In addition, there were several strong to moderate correlations between the various domains of the SF-36 and SGRQ. CONCLUSIONS: Survivors of ARDS have considerable respiratory symptoms and reduced HRQOL that is still prevalent at 12 mos following onset of injury. There are significant correlations between lung spirometry, pulmonary symptoms, and overall HRQOL, thus suggesting the acute lung injury/ARDS is causally contributing to the observed long-term outcome.

Adolescent↗