Incidence, outcomes and outcome prediction of unplanned extubation in critically ill children: An 11year experience.

PURPOSE: Unplanned extubation represents loss of control in the ICU, is associated with harm and is used as a measure of quality of care. We evaluated the rates and consequences of unplanned extubation. MATERIALS AND METHODS: Eligible patients were intubated, <18years, and in ICU. Patient, care-related and environmental characteristics were compared in patients who did and did not receive positive pressure ventilation in the 24h after events. Rates are expressed per 100 intubation-days. RESULTS: The 11,310 eligible patient-admissions identified were intubated for 75,519days; 410 (3.39%) patients had 458 unplanned extubation events (0.61 events/100 intubation-days). Annual rates of unplanned extubation reduced from 0.98 in 2004 to 0.37 in 2014. Consequences occurred in 245 (53.5%) events and included cardiac arrest in 9 (2%), bradycardia 52 (11%), and stridor 63 (14%). Positive pressure was provided after 263 (57%) events, and was independently associated with pre-event sedative and muscle relaxant drugs, non-use of restraints, respiratory reason for intubation and recent care by more nurses. CONCLUSION: Unplanned extubation was associated with both significant and no morbidity. Modification of factors including more consistent nurse staffing, restraint use, and increased vigilance in patients with previous events may potentially reduce rates and adverse consequences of unplanned extubation.

Remote ischaemic preconditioning protects against cardiopulmonary bypass-induced tissue injury: a preclinical study.

OBJECTIVES: To test the hypothesis that remote ischaemic preconditioning (rIPC) reduces injury after cardiopulmonary bypass (CPB). DESIGN: Randomised study with an experimental model of CPB (3 h CPB with 2 h of cardioplegic arrest). Twelve 15 kg pigs were randomly assigned to control or rIPC before CPB and followed up for 6 h. INTERVENTION: rIPC was induced by four 5 min cycles of lower limb ischaemia before CPB. MAIN OUTCOME MEASURES: Troponin I, glial protein S-100B, lactate concentrations, load-independent indices (conductance catheter) of systolic and diastolic function, and pulmonary resistance and compliance were measured before and for 6 h after CPB. RESULTS: Troponin I increased after CPB in both groups but during reperfusion the rIPC group had lower concentrations than controls (mean area under the curve -57.3 (SEM 7.3) v 89.0 (11.6) ng.h/ml, p = 0.02). Lactate increased after CPB in both groups but during reperfusion the control group had significantly more prolonged hyperlactataemia (p = 0.04). S-100B did not differ between groups. Indices of ventricular function did not differ. There was a tendency to improved lung compliance (p = 0.07), and pulmonary resistance changed less in the rIPC than in the control group during reperfusion (p = 0.02). Subsequently, peak inspiratory pressure was lower (p = 0.001). CONCLUSION: rIPC significantly attenuated clinically relevant markers of myocardial and pulmonary injury after CPB. Transient limb ischaemia as an rIPC stimulus has potentially important clinical applications.

Gadolinium chloride inhibits pulmonary macrophage influx and prevents O(2)-induced pulmonary hypertension in the neonatal rat.

Newborn rats exposed to 60% O(2) for 14 d demonstrated a bronchopulmonary dysplasia-like lung morphology and pulmonary hypertension. A 21-aminosteroid antioxidant, U74389G, attenuated both pulmonary hypertension and macrophage accumulation in the O(2)-exposed lungs. To determine whether macrophage accumulation played an essential role in the development of pulmonary hypertension in this model, pups were treated with gadolinium chloride (GdCl(3)) to reduce lung macrophage content. Treatment of 60% O(2)-exposed animals with GdCl(3) prevented right ventricular hypertrophy (p < 0.05) and smooth muscle hyperplasia around pulmonary vessels, but had no effect on morphologic changes in the lung parenchyma. In addition, GdCl(3) inhibited 60% O(2)-mediated increases in endothelin-1, 8-isoprostane, and nitrotyrosine residues. Organotypic cultures of fetal rat distal lung cells were subjected to cyclical mechanical strain to assess the potential role of GdCl(3)-induced blockade of stretch-mediated cation channels in these effects. Mechanical strain caused a moderate increase of endothelin-1 (p < 0.05), which was unaffected by GdCl(3), but had no effect on 8-isoprostane or nitric oxide synthesis. A critical role for endothelin-1 in O(2)-mediated pulmonary hypertension was confirmed using the combined endothelin receptor antagonist SB217242. We concluded that pulmonary macrophage accumulation, in response to 60% O(2), mediated pulmonary hypertension through up-regulation of endothelin-1.

4A randomized trial of prolonged prone positioning in children with acute respiratory failure.

STUDY OBJECTIVE: To compare the effect of the prone position (PP) vs supine position (SP) on oxygenation in children with acute respiratory failure (ARF). DESIGN: Prospective, randomized controlled trial. SETTING: A 36-bed pediatric critical-care unit in a tertiary-care, university-based children's hospital. PATIENTS: Ten children (mean [SD] age, 5 +/- 3.6 years) with ARF with a baseline oxygenation index (OI) of 22 +/- 8.5. INTERVENTIONS: Following a period of stabilization in the SP, baseline data were collected and patients were randomized to one of two groups in a two-crossover study design: group 1, supine/prone sequence; group 2, prone/supine sequence. Each position was maintained for 12 h. Lung mechanics and acute response to inhaled nitric oxide were examined in each position. MEASUREMENTS AND MAIN RESULTS: OI was significantly better in the PP compared to the SP over the 12-h period (analysis of variance, p = 0.0016). When patients were prone, a significant improvement in OI was detected (7.9 +/- 5.3; p = 0.002); this improvement occurred early (within 2 h in 9 of 10 patients) and was sustained over the 12-h study period. Static respiratory system compliance and resistance were not significantly affected by the position change. Inhaled nitric oxide had no effect on oxygenation in either position. Urine output increased while prone, resulting in a significantly improved fluid balance (+ 6.6 +/- 15.2 mL/kg/12 h in PP vs + 18.9 +/- 13.6 mL/kg/12 h in SP; p = 0.041). No serious adverse effects were detected in the PP. CONCLUSION: In children with ARF, oxygenation is significantly superior in the PP than in the SP. This improvement occurs early, remains sustained for a 12-h period, and is independent of changes in lung mechanics.

Endothelin-1 and O2-mediated pulmonary hypertension in neonatal rats: a role for products of lipid peroxidation.

We hypothesized that reactive O2 species, or their intermediary products, generated during exposure to elevated O2 lead to pathologic endothelin-1 expression in the newborn lung. Endothelin-1 expression and 8-isoprostane content (an in vivo marker of lipid peroxidation) were examined and found to be elevated (p < 0.05) in the lungs of newborn rats with abnormal lung morphology and pulmonary hypertension, as assessed by right ventricular hypertrophy, after a 14-d exposure to 60% O2. The antioxidant and lipid hydroperoxide scavenger, U74389G (10 mg/kg), given by daily i.p. injection prevented O2-dependent right ventricular hypertrophy (p < 0.05 compared with vehicle-treated controls), but had no effect on abnormal lung morphology. Additionally, we observed that 8-isoprostane caused marked endothelin-1 mRNA up-regulation in vitro in primary rat fetal lung cell cultures. We conclude that reactive O2 species, or their bioactive intermediaries, are causative in O2-mediated pulmonary hypertension and endothelin-1 up-regulation. It is likely that the bioactive lipid peroxidation product, 8-isoprostane, plays a key role in pathologic endothelin-1 expression and pulmonary hypertension during oxidant stress.

Lung recruitment and lung volume maintenance: a strategy for improving oxygenation and preventing lung injury during both conventional mechanical ventilation and high-frequency oscillation.

OBJECTIVE: To determine whether using a small tidal volume (5 ml/kg) ventilation following sustained inflation with positive endexpiratory pressure (PEEP) set above the critical closing pressure (CCP) allows oxygenation equally well and induces as little lung damage as high-frequency oscillation following sustained inflation with a continuous distending pressure (CDP) slightly above the CCP of the lung. MATERIAL AND METHODS: Twelve surfactant-depleted adult New Zealand rabbits were ventilated for 4 h after being randomly assigned to one of two groups: group 1, conventional mechanical ventilation, tidal volume 5 ml/kg, sustained inflation followed by PEEP > CCP; group 2, high-frequency oscillation, sustained inflation followed by CDP > CCP. RESULTS: In both groups oxygenation improved substantially after sustained inflation (P < 0.05) and remained stable over 4 h of ventilation without any differences between the groups. Histologically, both groups showed only little airway injury to bronchioles, alveolar ducts, and alveolar airspace, with no difference between the two groups. Myeloperoxidase content in homogenized lung tissue, as a marker of leukocyte infiltration, was equivalent in the two groups. CONCLUSIONS: We conclude that a volume recruitment strategy during small tidal volume ventilation and maintaining lung volumes above lung closing is as protective as that of high-frequency oscillation at similar lung volumes in this model of lung injury

Distribution of pulmonary blood flow in the perfluorocarbon-filled lung.

OBJECTIVE: Partial liquid ventilation (PLV) improves gas exchange in animal studies of lung injury. Perfluorocarbons (PFCs) are heavy liquids and are therefore preferentially delivered to the most dependent areas of lung. We hypothesised that improved oxygenation during PLV might be the consequence of a redistribution of pulmonary blood flow away from poorly ventilated, dependent alveoli, leading to improved ventilation/perfusion (V/Q) matching. This study investigated whether partially filling the lung with PFC would result in a redistribution of pulmonary blood flow. DESIGN: Prospective experimental study. SETTING: Hospital research institute laboratory. PARTICIPANTS: Six anaesthetised pigs without lung injury. INTERVENTIONS: Animals were anaesthetised and ventilated (gas tidal volume 12 ml/kg, PEEP 5, FIO2 1.0, rate 16). Whilst the pigs were maintained in the supine position, regional pulmonary blood flow was measured during conventional gas ventilation and repeated during PLV. Flow to regions of lung was determined by injection of radioactive microspheres (Co(57), Sn(113), Sc(46)). Measurements were performed with ventilation held at end-expiratory pressure and, in two PLV animals only, repeated with ventilation held at peak inspiratory pressure. RESULTS: During conventional gas ventilation, blood flow followed a linear distribution with the highest flow to the most dependent lung. In the lung partially filled with PFC a diversion of blood flow away from the most dependent lung was seen (p = 0.007), resulting in a more uniform distribution of flow down the lung (p = 0.006). Linear regression analysis (r2 = 0.75) also confirmed a difference in distribution pattern. On applying an inspiratory hold to the liquid-containing lung, blood flow was redistributed back towards the dependent lung. CONCLUSIONS: Partially filling the lung with PFC results in a redistribution of pulmonary blood flow away from the dependent region of the lung. During PLV a different blood flow distribution may be seen between inspiration and expiration. The clinical significance of these findings has yet to be determined.

[High frequency oscillation ventilation compared to conventional mechanical ventilation plus exogenous surfactant replacement in rabbits] / Ventilação de alta freqüência por oscilação comparada a ventilação mecânica convencional associada a reposição de surfactante em coelhos.

OBJECTIVES: (a) to evaluate the effect on oxygenation and ventilation of rabbits with induced surfactant depletion when they are submitted to a conventional mechanical ventilation, plus a small dose of exogenous surfactant; (b) to compare this group with another group submitted to a High Frequency Oscillation (HFO) without exogenous surfactant administration.METHODS: Twenty New Zealand White rabbits weighing (-/+ 3 kg) were anaesthetized and artificially induced to a endogenous surfactant depletion by successively lung lavage with normal saline (aliquots of 25 ml/kg) until to reach a persistent PaO(2) less than 100 mmHg when submitted to a mechanical ventilation in a pressure control mode with a target tidal volume of 10ml/kg, PEEP of 5cm H(2)O, FiO(2) 1.0, respiratory rate 30/min, and inspiratory time of 0.65 s. Then the rabbits were divided in (a) CMV+S group, submitted to a conventional mechanical ventilation plus exogenous surfactant replacement; (b) HFO group, submitted to a High Frequency Oscillation Ventilation. Arterial blood gases were measured at control period, post lung lavage, 15, 16 and 120 minutes after treatment started. The groups were compared using Student t test.RESULTS: The post lung lavage PaO(2) in both groups was lower than 50mmHg (p=0.154), increasing after 15 min of treatment to 254 mmHg (CMV+S) and 288 mmHg (HFO, p=0.626). The PaO(2) at 60 and 120 minutes were higher (p=0.001) in the HFO group (431 e 431 mmHg) when compared with the CMV+S group, which showed a progressive fall (148 e 126 mmHg). At 60 minutes of treatment, the PaCO(2) was lower (p=0.008) in the CMV+S group (29 versus 41 mmHg).CONCLUSIONS: In ARDS animal model a protect mechanical ventilation strategy as HFO by itself promotes a fast and persistent increase in the oxygenation, with superior levels than those observed in animals treated with conventional mechanical ventilation plus exogenous surfactant replacement.

The open lung during small tidal volume ventilation: concepts of recruitment and "optimal" positive end-expiratory pressure.

OBJECTIVES: To test the hypotheses that during small tidal volume ventilation (5 mL/kg) deliberate volume recruitment maneuvers allow expansion of atelectatic lung units and that a high positive end-expiratory pressure (PEEP) above the lower inflection point of the pressure/volume (PV) curve is not necessarily required to maintain recruited lung volume in acute lung injury. DESIGN: Prospective, randomized, controlled animal study. SETTING: An animal laboratory in a university setting. SUBJECTS: Adult New-Zealand rabbits. INTERVENTIONS: We studied a) the relationship of dynamic loops during intermittent positive pressure ventilation to the quasi-static PV curve, and b) the effect of lung recruitment on oxygenation, end-expiratory lung volume (EELV), and dynamic compliance in two groups (n = 4 per group) of lung-injured animals (lung lavage model): 1) the sustained inflation group, which received ventilation after a recruitment maneuver (sustained inflation); and 2) the control group, which received ventilation without any lung recruitment. MEASUREMENTS AND MAIN RESULTS: In the presence of PV hysteresis, a single sustained inflation to 30 cm H2O boosted the ventilatory cycle onto the deflation limb of the PV curve. This resulted in a significant increase in EELV, oxygenation, and dynamic compliance despite equal PEEP levels used before and after the recruitment maneuver. Furthermore, after a single sustained inflation, oxygenation remained high over 4 hrs of ventilation when a PEEP above the critical closing pressure of the lungs, defined as "optimal" PEEP, was used and was significantly higher compared with that in the control group ventilated at equal PEEP without preceding lung recruitment. CONCLUSIONS: The observation that ventilation occurs on the deflation limb of the tidal cycle-specific PV curve allows placement of the ventilatory cycle, by means of a recruitment maneuver, onto the deflation limb of the PV envelope of the optimally recruited lung. This strategy ensures sufficient lung volume recruitment to maintain the lungs during the tidal cycle while using relatively low airway pressures.

Concealed air leak associated with large tidal volumes in partial liquid ventilation.

Current ventilator strategies aim at maintaining an open lung and limiting both peak inspiratory pressures and tidal volumes to avoid alveolar distension. Perfluorocarbons, as well as being excellent solvents for oxygen and carbon dioxide, have the unique properties of being able to recruit dependent lung regions and improve pulmonary mechanics. Optimal ventilator strategies for partial liquid ventilation (PLV) have not yet been clearly defined. In the surfactant-depleted rabbit model, an approach involving a large tidal volume (VT) (15 ml/kg) and lung filled to FRC with perfluorocarbon (PFC) was compared with strategies involving a moderate VT (9 ml/kg) and partially filled lung (6 ml/kg), a moderate VT (9 ml/kg) and lung filled to FRC with PFC, and a large VT (15 ml/kg) and partially filled lung (6 ml/kg). PEEP was maintained at 5 cm H2O except in the moderate VT, partial-filling group, in which a PEEP of 9 cm H2O was used to maintain the rabbits for the duration of the experiment. Oxygenation was satisfactory in all groups, and peak inspiratory pressures were not significantly different. However, five of the 13 animals in the large-VT, PFC-filled lung group died of a pneumothorax prior to completion of the experiment. Of the eight animals in this group surviving the experiment, two had radiographic evidence of pneumothoraces, with an additional three animals having autopsy evidence of air leak. Of the 22 animals in the other groups, all survived with the exception of a single rabbit in the large VT, partial-filling group, which had both radiographic and autopsy evidence of air leak. We conclude that there is a significant risk of barotrauma in a PLV strategy in which a large VT is used in association with a lung filled to FRC with perfluorocarbon. Adequate gas exchange can be achieved with alternative ventilation strategies in combination with PLV.

Lung disease in mice with cystic fibrosis.

The leading cause of mortality and morbidity in humans with cystic fibrosis is lung disease. Advances in our understanding of the pathogenesis of the lung disease of cystic fibrosis, as well as development of innovative therapeutic interventions, have been compromised by the lack of a natural animal model. The utility of the CFTR-knockout mouse in studying the pathogenesis of cystic fibrosis has been limited because of their failure, despite the presence of severe intestinal disease, to develop lung disease. Herein, we describe the phenotype of an inbred congenic strain of CFTR-knockout mouse that develops spontaneous and progressive lung disease of early onset. The major features of the lung disease include failure of effective mucociliary transport, postbronchiolar over inflation of alveoli and parenchymal interstitial thickening, with evidence of fibrosis and inflammatory cell recruitment. We speculate that the basis for development of lung disease in the congenic CFTR-knockout mice is their observed lack of a non-CFTR chloride channel normally found in CFTR-knockout mice of mixed genetic background.

Phenotypic abnormalities in long-term surviving cystic fibrosis mice.

Mouse models for cystic fibrosis (CF) with no CFTR function (Cftr-/-) have the disadvantage that most animals die of intestinal obstruction shortly after weaning. The objective of this research was to extend the lifespan of CF mice and characterize their phenotype. Weanlings were placed on a nutrient liquid diet, and histologic and functional aspects of organs implicated in the disease were subsequently examined. Approximately 90% of Cftr-/- mice survived to 60 d, the majority beyond 100 d. Cftr-/- mice were underweight and had markedly abnormal intestinal histology. The intestinal epithelia did not respond to challenges with agents that raised intracellular cAMP, consistent with the absence of functional CFTR. No lesions or functional abnormalities were evident in the lungs. Liquid-fed Cftr-/- mice were infertile, although some males weaned to a solid diet were fertile before they died. Thus, we have succeeded in using dietary means to prolong the lives of Cftr-/- mice.

Changes in structure, mechanics, and insulin-like growth factor-related gene expression in the lungs of newborn rats exposed to air or 60% oxygen.

Exposure of neonatal rats to > or = 95% O2 for 2 wk, a widely used model of oxidant/antioxidant interactions in neonatal lung injury, results in arrested lung growth without the dysplastic lesions observed in chronic human neonatal lung injury. To determine whether dysplastic lung cell growth would be seen at lesser O2 concentrations, we exposed newborn rats to either 95% O2 for 1 wk followed by 60% O2 for 1 wk, or to 60% O2 for 2 wk. Exposure to 95% O2 for 1 wk profoundly inhibited lung DNA synthesis. Recovery of synthesis did not occur during the 2nd wk in 60% O2, nor were areas of dysplastic growth evident in lung tissue. In contrast, a continuous 2-wk exposure to 60% O2 resulted in a slight increase in lung weight with a significant reduction in lung volume over a range of inflation pressures. Also seen was an overall, but inhomogeneous, reduction in lung cell DNA synthesis. A preliminary analysis of affected cell types suggested that inhibition of DNA synthesis affected endothelial cells more than interstitial cells, whereas DNA synthesis increased in type II pneumocytes. Areas of reduced DNA synthesis were interspersed with patchy areas of parenchymal thickening and active DNA synthesis. These areas of parenchymal thickening, but not other areas, had increased immunoreactive IGF-I and the type I IGF receptor. These data are consistent with a direct effect of O2 on growth factor and growth factor receptor expression in causing dysplastic lung cell growth in chronic neonatal lung injury.

Compliance of the respiratory system in newborn infants pre- and postsurfactant replacement therapy.

Surfactant administration causes a rapid and dramatic improvement in gas exchange, but paradoxically, studies have failed to show an improvement in the mechanical properties of the lung. We have measured dynamic and static (passive flow-volume technique) compliance before and after a single dose of bovine lipid extract surfactant in 22 premature infants with RDS. This had no effect on the measured dynamic compliance. In contrast, surfactant significantly increased static compliance from 0.41 +/- 0.02 to 0.55 +/- 0.04 mL/cm H2O/kg. This improvement was the result of a substantial recruitment of lung volume after surfactant administration. This led us to reduce ventilator pressures, which produced an increase in both dynamic and static compliance, but did not recruit additional volume. We conclude that surfactant causes a substantial increase in static compliance due to volume recruitment, which is consistent with reports of increase in the measured FRC. However, despite this improvement, the compliance is still below our normal range.

Computer-assisted evaluation of some respiratory parameters during voluntary cough.

Three different microcomputers proved to be useful in processing of pressure, flow and volume signals during cough and other respiratory manoeuvres. In young healthy volunteers, values of forced vital capacity, peak expiratory flow and flow at 0.1 s measured during cough were smaller in women than in men due to their smaller body surface and FVC. Compared to forced expiration a sudden and vigorous cough effort, in spite of its shorter duration, resulted in an increased mean flow rate and in similar peak flow reached by expulsion of a smaller volume. Analysis of flow-volume curves indicated higher flow-rates at the beginning (5-10% FEV) and to the end of cough expulsion (65-95% FEV) than in forced expiration. The volume, peak flow and flow 0.1 s from the beginning of inspiration and expiration were practically the same in 5 successive cycles of voluntary cough performed by maximum effort. The mechanisms involved in cough expiration are more automatic than the mechanisms of cough inspiration. A personal computer can be useful for monitoring the increase in PEP, PIP, PEF, PIF, FEV, FIV and in maximum resistance as well as the decrease in compliance observed during cough compared to quiet breathing.