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Nebulised heparin for patients with or at risk of acute respiratory distress syndrome: a multicentre, randomised, double-blind, placebo-controlled phase 3 trial.
Dixon, B, Smith, RJ, Campbell, DJ, Moran, JL, Doig, GS, Rechnitzer, T, MacIsaac, CM, Simpson, N, van Haren, FMP, Ghosh, AN, et al
The Lancet. Respiratory medicine. 2021;(4):360-372
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Abstract
BACKGROUND Mechanical ventilation in intensive care for 48 h or longer is associated with the acute respiratory distress syndrome (ARDS), which might be present at the time ventilatory support is instituted or develop afterwards, predominantly during the first 5 days. Survivors of prolonged mechanical ventilation and ARDS are at risk of considerably impaired physical function that can persist for years. An early pathogenic mechanism of lung injury in mechanically ventilated, critically ill patients is inflammation-induced pulmonary fibrin deposition, leading to thrombosis of the microvasculature and hyaline membrane formation in the air sacs. The main aim of this study was to determine if nebulised heparin, which targets fibrin deposition, would limit lung injury and thereby accelerate recovery of physical function in patients with or at risk of ARDS. METHODS The Can Heparin Administration Reduce Lung Injury (CHARLI) study was an investigator-initiated, multicentre, double-blind, randomised phase 3 trial across nine hospitals in Australia. Adult intensive care patients on invasive ventilation, with impaired oxygenation defined by a PaO2/FiO2 ratio of less than 300, and with the expectation of invasive ventilation beyond the next calendar day were recruited. Key exclusion criteria were heparin allergy, pulmonary bleeding, and platelet count less than 50 X 109/L. Patients were randomly assigned 1:1, with stratification by site and using blocks of variable size and random seed, via a web-based system, to either unfractionated heparin sodium 25 000 IU in 5 mL or identical placebo (sodium chloride 0·9% 5 mL), administered using a vibrating mesh membrane nebuliser every 6 h to day 10 while invasively ventilated. Patients, clinicians, and investigators were masked to treatment allocation. The primary outcome was the Short Form 36 Health Survey Physical Function Score (out of 100) of survivors at day 60. Prespecified secondary outcomes, which are exploratory, included development of ARDS to day 5 among at-risk patients, deterioration of the Murray Lung Injury Score (MLIS) to day 5, mortality at day 60, residence of survivors at day 60, and serious adverse events. Analyses followed the intention-to-treat principle. There was no imputation of missing data. The trial is registered with the Australian and New Zealand Clinical Trials Register, number ACTRN12612000418875 . FINDINGS Between Sept 4, 2012, and Aug 23, 2018, 256 patients were randomised. Final follow-up was on Feb 25, 2019. We excluded three patients who revoked consent and one ineligible participant who received no intervention. Of 252 patients included in data analysis, the mean age was 58 years (SD 15), 157 (62%) were men, and 118 (47%) had ARDS. 128 (51%) patients were assigned to the heparin group and 124 (49%) to the placebo group, all of whom received their assigned intervention. Survivors in the heparin group (n=97) had similar SF-36 Physical Function Scores at day 60 compared to the placebo group (n=94; mean 53·6 [SD 31·6] vs 48·7 [35·7]; difference 4·9 [95% CI -4·8 to 14·5]; p=0·32). Compared with the placebo group, the heparin group had fewer cases of ARDS develop to day 5 among the at-risk patients (nine [15%] of 62 patients vs 21 [30%] of 71 patients; hazard ratio 0·46 [95% CI 0·22 to 0·98]; p=0·0431), less deterioration of the MLIS to day 5 (difference -0·14 [-0·26 to -0·02]; p=0·0215), similar day 60 mortality (23 [18%] of 127 patients vs 18 [15%] of 123 patients; odds ratio [OR] 1·29 [95% CI 0·66 to 2·53]; p=0·46), and more day 60 survivors at home (86 [87%] of 99 patients vs 73 [73%] of 100 patients; OR 2·45 [1·18 to 5·08]; p=0·0165). A similar number of serious adverse events occurred in each group (seven [5%] of 128 patients in the heparin group vs three [2%] of 124 patients in the placebo group; OR 2·33 [0·59 to 9·24]; p=0·23), which were a transient increase in airway pressure during nebulisation (n=3 in the heparin group), major non-pulmonary bleeding (n=2 in each group), haemoptysis (n=1 in the heparin group), tracheotomy site bleeding (n=1 in the heparin group), and hypoxaemia during nebulisation (n=1 in the placebo group). INTERPRETATION In patients with or at risk of ARDS, nebulised heparin did not improve self-reported performance of daily physical activities, but was well tolerated and exploratory outcomes suggest less progression of lung injury and earlier return home. Further research is justified to establish if nebulised heparin accelerates recovery in those who have or are at risk of ARDS. FUNDING Rowe Family Foundation, TR and RB Ditchfield Medical Research Endowment Fund, Patricia Madigan Charitable Trust, and The J and R McGauran Trust Fund.
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Effects of early administration of acetazolamide on the duration of mechanical ventilation in patients with chronic obstructive pulmonary disease or obesity-hypoventilation syndrome with metabolic alkalosis. A randomized trial.
Rialp Cervera, G, Raurich Puigdevall, JM, Morán Chorro, I, Martín Delgado, MC, Heras la Calle, G, Mas Serra, A, Vallverdú Perapoch, I
Pulmonary pharmacology & therapeutics. 2017;:30-37
Abstract
BACKGROUND Metabolic alkalosis (MA) inhibits respiratory drive and may delay weaning from mechanical ventilation (MV). MA is common in CO2-retainer patients that need MV. Acetazolamide (ACTZ) decreases serum bicarbonate concentration and stimulates respiratory drive. This study evaluated the effects of ACTZ on the duration of MV in patients with MA and COPD or obesity hypoventilation syndrome (OHS) intubated with acute respiratory failure. METHODS Multicenter, randomized, controlled, double-blind study, with COPD or OHS patients with MV < 72 h and initial bicarbonate >28 mmol/L and pH > 7.35. Test-treatment, ACTZ 500 mg or placebo, was daily administered if pH > 7.35 and bicarbonate >26 mmol/L. Clinical, respiratory and laboratory parameters were recorded. RESULTS 47 patients (36 men) were randomized. There were no significant differences between groups in comorbidities, baseline characteristics or arterial blood gases at inclusion. The mean difference in the duration of MV between placebo and ACTZ group was 1.3 days (95%CI, -2.1-4.8; p = 0.44). Kaplan-Meier curves showed no differences in the duration of MV (Log-Rank p = 0.41). Between-group comparison of estimated marginal means (CI 95%) during MV were, respectively: PaCO2 55 (51-59) vs 48 (47-50) mm Hg, p = 0.002; bicarbonate concentration 34 (32-35) vs 29 (28-30) mmol/L, p < 0.0001; and minute volume 9.7 (8.9-10.4) vs 10.6 (9.2-12.0) L/min, p = 0.26. There were no severe adverse effects with ACTZ administration. CONCLUSIONS Among patients with MA and COPD or OHS, early treatment with ACTZ did not shorten significantly the duration of MV compared with placebo. TRIAL REGISTRY clinical.trials.gov; NCT01499485; URL:.www.clinicaltrials.gov.
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Targeted therapeutic mild hypercapnia after cardiac arrest: A phase II multi-centre randomised controlled trial (the CCC trial).
Eastwood, GM, Schneider, AG, Suzuki, S, Peck, L, Young, H, Tanaka, A, Mårtensson, J, Warrillow, S, McGuinness, S, Parke, R, et al
Resuscitation. 2016;:83-90
Abstract
BACKGROUND In intensive care observational studies, hypercapnia after cardiac arrest (CA) is independently associated with improved neurological outcome. However, the safety and feasibility of delivering targeted therapeutic mild hypercapnia (TTMH) for such patients is untested. METHODS In a phase II safety and feasibility multi-centre, randomised controlled trial, we allocated ICU patients after CA to 24h of targeted normocapnia (TN) (PaCO2 35-45mmHg) or TTMH (PaCO2 50-55mmHg). The primary outcome was serum neuron specific enolase (NSE) and S100b protein concentrations over the first 72h assessed in the first 50 patients surviving to day three. Secondary end-points included global measure of function assessment at six months and mortality for all patients. RESULTS We enrolled 86 patients. Their median age was 61 years (58, 64 years) and 66 (79%) were male. Of these, 50 patients (58%) survived to day three for full biomarker assessment. NSE concentrations increased in the TTMH group (p=0.02) and TN group (p=0.005) over time, with the increase being significantly more pronounced in the TN group (p(interaction)=0.04). S100b concentrations decreased over time in the TTMH group (p<0.001) but not in the TN group (p=0.68). However, the S100b change over time did not differ between the groups (p(interaction)=0.23). At six months, 23 (59%) TTMH patients had good functional recovery compared with 18 (46%) TN patients. Hospital mortality occurred in 11 (26%) TTMH patients and 15 (37%) TN patients (p=0.31). CONCLUSIONS In CA patients admitted to the ICU, TTMH was feasible, appeared safe and attenuated the release of NSE compared with TN. These findings justify further investigation of this novel treatment.
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Normocapnia following noninvasive ventilation in acute exacerbations and chronic state of obstructive pulmonary disease.
Laier-Groeneveld, G, Gietl, C, Bauer, JU
Journal of physiology and pharmacology : an official journal of the Polish Physiological Society. 2007;(Pt 1):339-44
Abstract
We attempted to decrease PCO2 during noninvasive ventilation (NIV) and studied he effects of this therapy both in acute exacerbations of chronic obstructive pulmonary disease (COPD) and in its chronic state. Ninety six patients (63% male) with COPD and hypercapnia above 6.7 kPa were investigated. The mode and setting of the ventilator had to be chosen to achieve normocapnia. The subgroup of acute exacerbated COPD was separated by pH (<7.35=acute), by HCO3- (<26 mmol/l=acute), and by history (acute=history of recent deterioration). Ventilator settings were the following: tidal volume-972+/-137 ml and frequency-20+/-2.2 (volume preset). Inspiratory pressure was 33.6+/-14.2 mbar and frequency-19.7+/-5.1 (pressure preset). The preference of volume preset ventilators resulted from insufficient maximal pressures of the pressure preset devices. Eighty three percent of the patients became normocapnic while on NIV after 6.8+/-5.7 days. The mean PCO2 decreased from 64+/-13 mmHg to 41+/-6 mmHg (P<0.001). After 4 weeks, 72% of the patients were normocapnic while breathing spontaneously (P<0.001). The subgroups of acute exacerbation were the following: pH 28%, HCO3- 3.1%, and history 68%. All three indicators together were present in 2% of patients. Normocapnia under ventilation and during spontaneous breathing was independent from the subgroup. In conclusion, the study showed that normocapnia can be achieved in COPD under the ventilator and while breathing spontaneously in chronic and acute disease.
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Periodically changing ventilator circuits is not necessary to prevent ventilator-associated pneumonia when a heat and moisture exchanger is used.
Lorente, L, Lecuona, M, Galván, R, Ramos, MJ, Mora, ML, Sierra, A
Infection control and hospital epidemiology. 2004;(12):1077-82
Abstract
OBJECTIVE To analyze the efficacy of periodically changing ventilator circuits for decreasing the rate of ventilator-associated pneumonia when a heat and moisture exchanger (HME) is used for humidification. The Centers for Disease Control and Prevention recommended not changing the circuits periodically. DESIGN Randomized, controlled trial conducted between April 2001 and August 2002. SETTING A 24-bed, medical-surgical intensive care unit in a 650-bed, tertiary-care hospital. PATIENTS All patients requiring mechanical ventilation during more than 72 hours from April 2001 to August 2002. INTERVENTIONS Patients were randomized into two groups: (1) ventilation with change of ventilator circuits every 48 hours and (2) ventilation with no change of circuits. Throat swabs were taken on admission and twice weekly until discharge to classify pneumonia as endogenous or exogenous. RESULTS Three hundred four patients (143 from group 1 and 161 from group 2) with similar characteristics (age, gender, Acute Physiology and Chronic Health Evaluation II score, diagnostic group, and mortality) were analyzed. There was no significant difference in the rate of pneumonia between the groups (23.1% vs 23.0% and 15.5 vs 14.8 per 1,000 ventilator-days). There was no significant difference in the incidence of exogenous pneumonia per 1,000 days of mechanical ventilation (1.71 vs 1.25). There was no difference in the distribution of microorganisms causing pneumonia. CONCLUSIONS Circuit change using an HME for humidification does not decrease pneumonia and represents an unnecessary cost.
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Assessment of exhaled gases in ventilated preterm infants.
Hitka, P, Cerný, M, Vízek, M, Wilhelm, J, Zoban, P
Physiological research. 2004;(5):561-4
Abstract
Hydrogen peroxide (H2O2) production in exhaled air was measured in ventilated preterm newborns at 5, 24 and 48 hours after delivery, using originally designed method of exhaled breath condensate (EBC) collection. H2O2 production in expired gas was 812+/-34 pmol/20 min during the first measurement and then declined to 389+/-21 at 24 hours and 259+/-26 pmol/20 min at 48 hours.
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Gastro-oesophageal reflux in mechanically ventilated patients: effects of an oesophageal balloon.
Orozco-Levi, M, Félez, M, Martínez-Miralles, E, Solsona, JF, Blanco, ML, Broquetas, JM, Torres, A
The European respiratory journal. 2003;(2):348-53
Abstract
Gastro-oesophageal reflux (GOR) and bronchoaspiration of gastric content are risk factors linked with ventilator-associated pneumonia. This study was aimed at evaluating the effect of a nasogastric tube (NGT) incorporating a low-pressure oesophageal balloon on GOR and bronchoaspiration in patients receiving mechanical ventilation. Fourteen patients were studied in a semi-recumbent position for 2 consecutive days. Inflation or deflation of the oesophageal balloon was randomised. Samples of blood, gastric content, and oropharyngeal and bronchial secretions were taken every 2 h over a period of 8 h. A radioactively labelled nutritional solution was continuously administered through the NGT. The magnitude of both the GOR and bronchoaspiration was measured by radioactivity counting of oropharyngeal and bronchial secretion samples, respectively. Inflation of the oesophageal balloon resulted in a significant decrease of both GOR and bronchoaspiration of gastric content. This protective effect was statistically significant from 4 h following inflation throughout the duration of the study. This study demonstrates that an inflated oesophageal balloon delays and decreases gastro-oesophageal and bronchial aspiration of gastric content in patients carrying a nasogastric tube and receiving enteral nutrition during mechanical ventilation. Although the method was found to be safe when applied for 8 h, longer times should be considered with caution.
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Enteral naloxone reduces gastric tube reflux and frequency of pneumonia in critical care patients during opioid analgesia.
Meissner, W, Dohrn, B, Reinhart, K
Critical care medicine. 2003;(3):776-80
Abstract
OBJECTIVE Opioid analgesia impairs gastrointestinal motility. Enteral administration of naloxone theoretically allows selective blocking of intestinal opioid receptors caused by extensive presystemic metabolism. Therefore, we studied the effect of enteral naloxone on the amount of gastric tube reflux, the frequency of pneumonia, and the time until first defecation in mechanically ventilated patients with fentanyl analgesia. DESIGN Prospective, randomized, double-blinded study. SETTING University hospital intensive care unit. PATIENTS Eighty-four mechanically ventilated, fentanyl-treated patients without gastrointestinal surgery or diseases. INTERVENTIONS Patients were assigned to receive 8 mg naloxone or placebo four times daily via a gastric tube during fentanyl administration. MEASUREMENTS AND MAIN RESULTS Thirty-eight patients received naloxone and 43 placebo; three patients were excluded because of protocol violation. Median gastric tube reflux volume (54 vs. 129 mL, p =.03) and frequency of pneumonia (34% vs. 56%, p =.04) were significantly lower in the naloxone group. In both groups, time until first defecation, ventilation time, and length of intensive care unit stay did not differ. There was no difference in fentanyl requirements between the naloxone and the placebo group (7 vs. 6.5 microg/kg/hr, p =.15). CONCLUSIONS Our results provide evidence that the administration of enteral opioid antagonists in ventilated patients with opioid analgesia might be a simple-and possibly preventive-treatment of increased gastric tube reflux and reduces frequency of pneumonia.
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Respiratory acidosis prolongs, while alkalosis shortens, the duration and recovery time of vecuronium in humans.
Yamauchi, M, Takahashi, H, Iwasaki, H, Namiki, A
Journal of clinical anesthesia. 2002;(2):98-101
Abstract
STUDY OBJECTIVE To determine the effects of respiratory acidosis and alkalosis by mechanical ventilation on the onset, duration, and recovery times of vecuronium. DESIGN Randomized, prospective study. SETTING Operating rooms in the Sapporo Medical University Hospital and Kitami Red Cross Hospital. PATIENTS 90 ASA physical status I and II patients undergoing lower abdominal surgery. INTERVENTIONS Patients were randomly allocated to one of three groups by arterial carbon dioxide tension level (PaCO2; mmHg) after induction: hyperventilation group (PaCO2 = 25-35), normoventilation group (PaCO2 = 35-45), and hypoventilation group (PaCO2 = 45-55). Anesthesia was maintained by spinal block with inhalation of 50% to 66% nitrous oxide in oxygen and intermittent intravenous administration of fentanyl and midazolam with tracheal intubation. MEASUREMENTS AND MAIN RESULTS After vecuronium 0.08 mg/kg was given, onset, duration, and recovery time were measured by mechanomyography (Biometer Myograph 2,000, Odense, Denmark). There were significant differences in the duration and recovery time of vecuronium among the normoventilation group (12.7 +/- 3.3 min and 11.8 +/- 2.8 min, respectively), the hyperventilation group (10.6 +/- 3.5 min and 9.2 +/- 2.7 min, respectively; p < 0.01), and the hypoventilation group (14.4 +/- 3.1 min and 15.0 +/- 3.7 min, respectively; p < 0.01) (mean SD). The closest significant correlation in this study was observed between recovery time and arterial blood pH (r = 0.57; p < 0.05). CONCLUSION In humans, duration and recovery times of vecuronium are prolonged in respiratory acidosis and shortened in respiratory alkalosis.
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Early versus late enteral feeding of mechanically ventilated patients: results of a clinical trial.
Ibrahim, EH, Mehringer, L, Prentice, D, Sherman, G, Schaiff, R, Fraser, V, Kollef, MH
JPEN. Journal of parenteral and enteral nutrition. 2002;(3):174-81
Abstract
BACKGROUND This study sought to compare 2 strategies for the administration of enteral feeding to mechanically ventilated medical patients. METHODS The prospective, controlled, clinical trial was carried out in a medical intensive care unit (19 beds) in a university-affiliated, urban teaching hospital. Between May 1999 and December 2000, 150 patients were enrolled. Patients were scheduled to receive their estimated total daily enteral nutritional requirements on either day 1 (early-feeding group) or day 5 (late-feeding group) of mechanical ventilation. Patients in the late-feeding group were also scheduled to receive 20% of their estimated daily enteral nutritional requirements during the first 4 days of mechanical ventilation. RESULTS Seventy-five (50%) consecutive eligible patients were entered into the early-feeding group and 75 (50%) patients were enrolled in the late-feeding group. During the 5 five days of mechanical ventilation, the total intake of calories (2370 +/- 2000 kcal versus 629 +/- 575 kcal; p < .001) and protein (93.6 +/- 77.2 g versus 26.7 +/- 26.6 g; p < .001) were statistically greater for patients in the early-feeding group. Patients in the early-feeding group had statistically greater incidences of ventilator-associated pneumonia (49.3% versus 30.7%; p = .020) and diarrhea associated with Clostridium difficile infection (13.3% versus 4.0%; p = .042). The early-feeding group also had statistically longer intensive care unit (13.6 +/- 14.2 days versus 9.8 +/- 7.4 days; p = .043) and hospital lengths of stay (22.9 +/- 19.7 days versus 16.7 +/- 12.5 days; p = .023) compared with patients in the late-feeding group. No statistical difference in hospital mortality was observed between patients in the early-feeding and late-feeding groups (20.0% versus 26.7%; p = .334). CONCLUSIONS The administration of more aggressive early enteral nutrition to mechanically ventilated medical patients is associated with greater infectious complications and prolonged lengths of stay in the hospital. Clinicians must balance the potential for complications resulting from early enteral feeding with the expected benefits of such therapy.