Number Of Organ Failure-free Days Research Articles

First do no harm: surrogate endpoints and the lesson of β-agonists in acute lung injury

Expanded abstractCitationMatthay MA, Brower RG, Carson S, Douglas IS, Eisner M, Hite D, Holets S, Kallet RH, Liu KD, MacIntyre N, Moss M, Schoenfeld D, Steingrub J, Thompson BT: Randomized, placebo-controlled clinical trial of an aerosolized β-agonist for treatment of acute lung injury. National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network. Am J Respir Crit Care Med 2011, 184:561-568.Backgroundβ2-Adrenergic receptor agonists accelerate resolution of pulmonary edema in experimental and clinical studies of acute lung injury (ALI).MethodsObjective: To determine whether an aerosolized β2-agonist would improve clinical outcomes in patients with ALI.Design: Multi-center, phase III randomized, placebo-controlled clinical trial.Setting: 33 hospitals participating National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network.Subjects: Patients who were intubated and receiving mechanical ventilation, had bilateral infiltrates consistent with edema on frontal chest radiograph, had a ratio of PaO2 to FIO2 (fraction of inspired oxygen) of 300 or less, and not had clinical evidence of left atrial hypertension. A maximum enrolment of 1,000 patients was planned.Intervention: Patients were randomized to receive aerosolized albuterol (5 mg) or saline placebo every 4 hours for up to 10 days.Outcomes: The primary outcome variable was ventilator-free days (VFD). Secondary outcome measures included mortality before hospital discharge on day 60 and day 90, the number of intensive care unit (ICU)-free days and the number of organ failure-free days.ResultsThere were 282 patients enrolled before the trial was stopped for futility after the second interim analysis. The VFDs difference with albuterol treatment was unfavourable by -2.2 days, well past the futility boundary of -0.4 VFDs. VFDs were not significantly different between the albuterol and placebo groups (means of 14.4 and 16.6 days, respectively; 95% confidence interval for the difference, -4.7 to 0.3 days; P = 0.087). Rates of death before hospital discharge and the number of organ failure-free days were also not significantly different between the two groups. The number of ICU-free days was lower in the albuterol group in comparison with the placebo group (means of 13.5 and 16.2 days respectively; 95% confidence intervals for the mean difference, -4.9 to -0.4 days; P = 0.023). Overall, heart rates were significantly higher in the albuterol group by approximately 5 beats/minute in the first 2 days after randomization (P < 0.05), but rates of new onset atrial fibrillation (10% in both groups) and other cardiac dysrhythmias were not significantly different.ConclusionsThese results suggest that aerosolized albuterol does not improve clinical outcomes in ALI patients. Routine use of β2 agonist therapy in mechanically ventilated ALI patients cannot be recommended.

Beta Agonist Lung Injury TrIal-2 (BALTI-2) trial protocol: a randomised, double-blind, placebo-controlled of intravenous infusion of salbutamol in the acute respiratory distress syndrome.

BackgroundThe Acute Respiratory Distress Syndrome (ARDS) is a common cause of respiratory failure in critically ill patients. Experimental studies suggest that treatment with beta agonists may be helpful in ARDS. The Beta Agonist Lung Injury TrIal (BALTI-2) is a multicentre, pragmatic, randomised, double-blind, placebo-controlled clinical trial which aims to determine if sustained treatment with intravenous (IV) salbutamol will improve survival in ARDS.Methods/DesignPatients fulfilling the American-European Consensus Conference Definition of ARDS will be randomised in a 1:1 ratio to receive an IV infusion either of salbutamol (15 μg kg ideal body weight-1 hr-1) or placebo (0.9% sodium chloride solution), for a maximum of seven days. Allocation to randomised groups will use minimisation to ensure balance with respect to hospital of recruitment, age group (<64, 65-84, >85 years) and PaO2/FiO2 ratio (≤6.7, 6.8- 13.2, ≥13.3 kPa). Data will be recorded by participating ICUs until hospital discharge, and all surviving patients will be followed up by post at six and twelve months post randomisation. The primary outcome is mortality at 28 days after randomisation; secondary outcomes are mortality in ICU, mortality in hospital, number of ventilator-free days, number of organ failure-free days, mortality at twelve months post-randomisation, quality of life at six and twelve months, length of stay in ICU, length of stay in hospital, adverse effects (tachycardia, arrhythmia or other side effects sufficient to stop treatment drug). 1,334 patients will be recruited from about fifty ICUs in the UK. An economic evaluation will be conducted alongside the trial.Trial RegistrationCurrent Controlled Trials ISRCTN38366450.

Effects of discontinuing or continuing ongoing statin therapy in severe sepsis and septic shock: a retrospective cohort study

IntroductionRecent publications suggest potential benefits from statins as a preventive or adjuvant therapy in sepsis. Whether ongoing statin therapy should be continued or discontinued in patients admitted in the intensive care unit (ICU) for sepsis is open to question.MethodsWe retrospectively compared patients with severe sepsis and septic shock in whom statin therapy had been discontinued or continued. The primary endpoint was the number of organ failure-free days at day 14. Secondary end-points included hospital mortality and safety. The association of statin continuation with outcome was evaluated for crude analysis and after propensity score matching and adjustment. We also measured plasma atorvastatin concentrations in a separate set of ICU septic patients continuing the drug.ResultsPatients in whom statin therapy had been continued in the ICU (n = 44) had significantly more organ failure-free days (11 [6-14] vs. 6 [0-12], mean difference of 2.34, 95%CI from 0.47 to 5.21, P = 0.03) as compared to others (n = 32). However, there were important imbalances between groups, with more hospital-acquired infections, more need for surgery before ICU admission, and a trend towards more septic shock at ICU admission in the discontinuation group. The significant association of statin continuation with organ failure free days found in the crude analysis did not persist after propensity-matching or multivariable adjustment: beta coefficients [95% CI] of 2.37 [-0.96 to 5.70] (P = 0.20) and 2.24 [-0.43 to 4.91] (P = 0.11) respectively. We found particularly high pre-dose and post-dose atorvastatin concentrations in ICU septic patients continuing the drug.ConclusionsContinuing statin therapy in ICU septic patients was not associated with reduction in the severity of organ failure after matching and adjustment. In addition, the very high plasma concentrations achieved during continuation of statin treatment advocates some caution.

Fluid Therapy for Acute Lung Injury

Source: The National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network. Comparison of two fluid-management strategies in acute lung injury. N Engl J Med. 2006;354:2564–2575; doi:10.1056/NEJMoa062200To evaluate the use of “conservative” versus “liberal” fluid management, investigators for the Acute Respiratory Distress Syndrome (ARDS) network screened 11,512 adult patients in 20 North American centers. Criteria for ARDS were a ratio of the partial pressure of arterial oxygen (PaO2) to the fraction of inspired oxygen (FiO2) of less than 300 and bilateral pulmonary infiltrates on chest radiograph without evidence of left atrial hypertension. Fluid management was guided by assessments using either a pulmonary artery catheter or a central venous catheter. Patients were assessed every 4 hours for blood pressure, urinary output, and either cardiac output or clinical assessment of circulation. The primary outcome was 60-day mortality, and secondary outcomes included ventilator- and ICU-free days as well as number of organ failure days assessed at day 28.One thousand patients were recruited with 503 randomized to “conservative” and 497 to “liberal” fluid management. Patients had similar demographic and hemodynamic characteristics at the time of enrollment. All patients received mechanical ventilation according to the ARDS Network protocol for lower tidal volumes.1Patients in the “liberal” arm had a positive fluid balance each day for the first 7 days of study ranging from 2.5 liters to 483 ml daily, compared to the “conservative” group which had a positive fluid balance only on day 1 of study, and afterwards had slightly negative fluid balance ranging from −144 ml to −408 ml daily. The in-hospital death rate at 60 days was 25% in the “conservative” arm and 28% in the “liberal” arm; however, the “conservative” arm had greater ventilator-free days (15 vs 12) compared to the “liberal” group (P<.01) and more ICU-free days (13 days vs 11 days; P<.001). The number of organ failure-free days was similar between groups with the exception of central nervous system failure, which was more common in the “conservative” group. Of note, although not statistically significant, use of dialysis was more common in the “liberal” fluid management arm (14% vs 10%). The authors concluded that “conservative” fluid management was associated with a decrease in duration of mechanical ventilation and ICU days.Dr. Bratton has disclosed no financial relationship relevant to this commentary. This commentary does not contain a discussion of a commercial product/device. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device.Need for higher airway pressures with mechanical ventilation as well as capillary leak due to inflammatory processes both diminish intravascular volume and cardiac filling pressures and require administration of supplemental fluid to treat hemodynamic compromise. Studies have shown that failure to treat shock in children2 and adults3 increases risk of mortality. However, the present study nicely demonstrates that this initial insult is generally time-limited. Children with severe lung injury, like adult patients, gain fluid but those who gain less water have been shown to have improved survival.4 This report supports use of “conservative” fluid management to minimize positive fluid balance and decrease extravascular lung water leading to improved lung function. The authors showed that in the first day or so of acute respiratory failure all patients required supplemental fluid to support adequate hemodynamics and organ perfusion; however, over time patients tolerated diuretic therapy and lower intravascular filling pressures without development of additional organ failure. Use of less fluid was associated with shorter time of mechanical ventilation and ICU stay.Although pediatric mortality from acute lung injury is lower than for adult patients, recent mortality rates of 22%5 confirm that acute lung injury/ARDS remains an important pediatric critical illness. Application of the present study to pediatric practice requires use of age-appropriate blood pressure and careful assessment of hemodynamic status with a central venous catheter, a common pediatric ICU practice.