A letter in Intensive Care Medicine by Hoeper and colleagues from Hannover describes a small case series of six ARDS patients with severe hypoxaemia who went straight from non-invasive ventilation to awake veno-venous ECMO. All had single organ failure and four were immunocompromised, the latter factor influencing the decision to try to avoid invasive mechanical ventilation. Four of the six patients survived to hospital discharge. A larger multicentre study is being planned.
Here’s a heads up on a major evidence-based medicine event in critical care: the results of two long awaited randomised controlled trials assessing high-frequency oscillation (HFOV) in Acute Respiratory Distress Syndrome (ARDS) have both been published, and the full text is available from the New England Journal of Medicine at the links below.
In summary, the Oscillation for Acute Respiratory Distress Syndrome Treated Early (OSCILLATE)(1) and the Oscillation in ARDS (OSCAR)(2) trials showed no improvement in in-hospital death or 30 day mortality, respectively. OSCILLATE was terminated early on the basis of a strong signal for increased mortality with HFOV.
An editorial discusses some of the reasons why these outcomes were seen, which include among other factors the possibility that they were related to increased requirements for sedation, paralysis, and vasoactive drugs in the HFOV patients that were not offset by improvements in oxygenation and lung recruitment.
BACKGROUND Previous trials suggesting that high-frequency oscillatory ventilation (HFOV) reduced mortality among adults with the acute respiratory distress syndrome (ARDS) were limited by the use of outdated comparator ventilation strategies and small sample sizes
METHODS In a multicenter, randomized, controlled trial conducted at 39 intensive care units in five countries, we randomly assigned adults with new-onset, moderate-to-severe ARDS to HFOV targeting lung recruitment or to a control ventilation strategy targeting lung recruitment with the use of low tidal volumes and high positive end-expiratory pressure. The primary outcome was the rate of in-hospital death from any cause.
RESULTS On the recommendation of the data monitoring committee, we stopped the trial after 548 of a planned 1200 patients had undergone randomization. The two study groups were well matched at baseline. The HFOV group underwent HFOV for a median of 3 days (interquartile range, 2 to 8); in addition, 34 of 273 patients (12%) in the control group received HFOV for refractory hypoxemia. In-hospital mortality was 47% in the HFOV group, as compared with 35% in the control group (relative risk of death with HFOV, 1.33; 95% confidence interval, 1.09 to 1.64; P=0.005). This finding was independent of baseline abnormalities in oxygenation or respiratory compliance. Patients in the HFOV group received higher doses of midazolam than did patients in the control group (199 mg per day [interquartile range, 100 to 382] vs. 141 mg per day [interquartile range, 68 to 240], P<0.001), and more patients in the HFOV group than in the control group received neuromuscular blockers (83% vs. 68%, P<0.001). In addition, more patients in the HFOV group received vasoactive drugs (91% vs. 84%, P=0.01) and received them for a longer period than did patients in the control group (5 days vs. 3 days, P=0.01).
CONCLUSIONS In adults with moderate-to-severe ARDS, early application of HFOV, as compared with a ventilation strategy of low tidal volume and high positive end-expiratory pressure, does not reduce, and may increase, in-hospital mortality. (Funded by the Canadian Institutes of Health Research; Current Controlled Trials numbers, ISRCTN42992782 and ISRCTN87124254, and ClinicalTrials.gov numbers, NCT00474656 and NCT01506401.)
BACKGROUND Patients with the acute respiratory distress syndrome (ARDS) require mechanical ventilation to maintain arterial oxygenation, but this treatment may produce secondary lung injury. High-frequency oscillatory ventilation (HFOV) may reduce this secondary damage.
METHODS In a multicenter study, we randomly assigned adults requiring mechanical ventilation for ARDS to undergo either HFOV with a Novalung R100 ventilator (Metran) or usual ventilatory care. All the patients had a ratio of the partial pressure of arterial oxygen (PaO2) to the fraction of inspired oxygen (FiO2) of 200 mm Hg (26.7 kPa) or less and an expected duration of ventilation of at least 2 days. The primary outcome was all-cause mortality 30 days after randomization
RESULTS There was no significant between-group difference in the primary outcome, which occurred in 166 of 398 patients (41.7%) in the HFOV group and 163 of 397 patients (41.1%) in the conventional-ventilation group (P=0.85 by the chi-square test). After adjustment for study center, sex, score on the Acute Physiology and Chronic Health Evaluation (APACHE) II, and the initial PaO2:FiO2 ratio, the odds ratio for survival in the conventional-ventilation group was 1.03 (95% confidence interval, 0.75 to 1.40; P=0.87 by logistic regression).
CONCLUSIONS The use of HFOV had no significant effect on 30-day mortality in patients undergoing mechanical ventilation for ARDS. (Funded by the National Institute for Health Research Health Technology Assessment Programme; OSCAR Current Controlled Trials number, ISRCTN10416500.
A single case report might not be practice changing, but it’s helpful to know about this option:
A patient with acute intracerebral haemorrhage developed hyoxaemia due to neurogenic pulmonary oedema, accompanied by a labile blood pressure and elevated catecholamine levels.
Nicardipine and other antihypertensive agents including metoprolol, hydralazine, and labetalol were tried without benefit, and the patient continued to deteriorate.
Phentolamine was tried. The introduction, withdrawal, and reintroduction of phentolamine and the clinical status of the patient is described convincingly:
a phentolamine infusion was started at 0.17 mg/min and titrated for BP control. Over 6 h, the FIO2 requirements dropped precipitously, gas exchange improved, and the chest radiograph showed improvement of pulmonary edema. When the hospital supply of phentolamine was exhausted, the clinical status deteriorated rapidly. Within just 15 h of the discontinuation of phentolamine, the PaO2 fell from 166 mm Hg to 66 mm Hg, and FIO2 requirements rose from 60% to 100%. When the phentolamine supply was replenished and the infusion restarted, the same rapid improvement was observed and BP stabilized.
Phentolamine is a potent competitive antagonist at both alpha 1 and alpha 2 receptors . Phentolamine causes a reduction in peripheral resistance through blockade of alpha 1 receptors and possibly alpha 2 receptors on vascular smooth muscle.
Neurogenic pulmonary edema (NPE) is a clinical syndrome characterized by the acute onset of pulmonary edema following a significant CNS insult. The cause is believed to be a surge of catecholamines that results in cardiopulmonary dysfunction. Although there are myriad case reports describing CNS events that are associated with this syndrome, few studies have identified specific treatment modalities. We present a case of NPE caused by an intracranial hemorrhage from a ruptured arteriovenous malformation. We uniquely document a rise and fall of serum catecholamine levels correlating with disease activity and a dramatic clinical response to IV phentolamine.
A previous study (BALTI-1) suggested β-2 agonists may help in ARDS by reducing extravascular lung water. A randomised trial in the UK aimed to recruit 1334 patients to compare intravenous salbutamol infused for seven days with placebo (0.9% saline). However the Data Monitoring and Ethics Committee recommended that the study stop after the second interim analysis of 273 patients because of a significant increase in mortality. It is unclear why salbutamol is harmful, and could be due to lung, cardiovascular, or other metabolic effects, such as activation of the renin-angiotensin aldosterone system affecting fluid balance.
BACKGROUND:In a previous randomised controlled phase 2 trial, intravenous infusion of salbutamol for up to 7 days in patients with acute respiratory distress syndrome (ARDS) reduced extravascular lung water and plateau airway pressure. We assessed the effects of this intervention on mortality in patients with ARDS.
METHODS:We did a multicentre, placebo-controlled, parallel-group, randomised trial at 46 UK intensive-care units between December, 2006, and March, 2010. Intubated and mechanically ventilated patients (aged ≥16 years) within 72 h of ARDS onset were randomly assigned to receive either salbutamol (15 μg/kg ideal bodyweight per h) or placebo for up to 7 days. Randomisation was done by a central telephone or web-based randomisation service with minimisation by centre, pressure of arterial oxygen to fractional inspired oxygen concentration (PaO2/FiO2) ratio, and age. All participants, caregivers, and investigators were masked to group allocation. The primary outcome was death within 28 days of randomisation. Analysis was by intention-to-treat. This trial is registered, ISRCTN38366450 and EudraCT number 2006-002647-86.
FINDINGS:We randomly assigned 162 patients to the salbutamol group and 164 to the placebo group. One patient in each group withdrew consent. Recruitment was stopped after the second interim analysis because of safety concerns. Salbutamol increased 28-day mortality (55 [34%] of 161 patients died in the salbutamol group vs 38 (23%) of 163 in the placebo group; risk ratio [RR] 1·47, 95% CI 1·03-2·08).
INTERPRETATION:Treatment with intravenous salbutamol early in the course of ARDS was poorly tolerated. Treatment is unlikely to be beneficial, and could worsen outcomes. Routine use of β-2 agonist treatment in ventilated patients with this disorder cannot be recommended.
FUNDING:UK Medical Research Council, UK Department of Health, UK Intensive Care Foundation.
A trial by the ARDS Clinical Trials Network of pharmaconutrition for acute lung injury1 was stopped early for futility – outcomes were worse in the intervention group that received the enteral supplementation of n-3 fatty acids, γ-linolenic acid, and antioxidants. It had been hypothesised that the immunomodulatory effects of these supplements would provide clinical benefit in acute lung injury.
An accompanying editorial2 reports benefits of pharmaconutrition in other areas of critical care:
arginine-supplemented diets are associated with reduced infections and lengths of hospital stay in patients undergoing elective operations
glutamine-supplemented parenteral nutrition is associated with reduced infection and mortality in critically ill patients
antioxidant supplementation is associated with reduced mortality among critically ill patients with systemic inflammation.
Context The omega-3 (n-3) fatty acids docosahexaenoic acid and eicosapentaenoic acid, along with γ-linolenic acid and antioxidants, may modulate systemic inflammatory response and improve oxygenation and outcomes in patients with acute lung injury.
Objective To determine if dietary supplementation of these substances to patients with acute lung injury would increase ventilator-free days to study day 28.
Design, Setting, and Participants The OMEGA study, a randomized, double-blind, placebo-controlled, multicenter trial conducted from January 2, 2008, through February 21, 2009. Participants were 272 adults within 48 hours of developing acute lung injury requiring mechanical ventilation whose physicians intended to start enteral nutrition at 44 hospitals in the National Heart, Lung, and Blood Institute ARDS Clinical Trials Network. All participants had complete follow-up.
Interventions Twice-daily enteral supplementation of n-3 fatty acids, γ-linolenic acid, and antioxidants compared with an isocaloric control. Enteral nutrition, directed by a protocol, was delivered separately from the study supplement.
Main Outcome Measure Ventilator-free days to study day 28.
Results The study was stopped early for futility after 143 and 129 patients were enrolled in the n-3 and control groups. Despite an 8-fold increase in plasma eicosapentaenoic acid levels, patients receiving the n-3 supplement had fewer ventilator-free days (14.0 vs 17.2; P = .02) (difference, −3.2 [95% CI, −5.8 to −0.7]) and intensive care unit–free days (14.0 vs 16.7; P = .04). Patients in the n-3 group also had fewer nonpulmonary organ failure–free days (12.3 vs 15.5; P = .02). Sixty-day hospital mortality was 26.6% in the n-3 group vs 16.3% in the control group (P = .054), and adjusted 60-day mortality was 25.1% and 17.6% in the n-3 and control groups, respectively (P = .11). Use of the n-3 supplement resulted in more days with diarrhea (29% vs 21%; P = .001).
Conclusions Twice-daily enteral supplementation of n-3 fatty acids, γ-linolenic acid, and antioxidants did not improve the primary end point of ventilator-free days or other clinical outcomes in patients with acute lung injury and may be harmful.
1. Enteral Omega-3 Fatty Acid, γ-Linolenic Acid, and Antioxidant Supplementation in Acute Lung Injury JAMA. 2011; 306:1574-1581
Prone ventilation can improve refractory hypoxaemia in ARDS but its effects on mortality have not been impressive in some studies which may be underpowered or include patients with less severe hypoxaemia. An updated meta-analysis showed significantly reduced ICU mortality in the four recent studies that enrolled only patients with ARDS, as opposed to ARDS/ALI (odds ratio = 0.71; 95% confidence interval = 0.5 to 0.99; P = 0.048; number needed to treat = 11). There may also be benefit from a greater duration of prone positioning.
The ACURASYS study of atracurium vs placebo in ARDS: three ml rapid intravenous infusion of 15 mg of cis-atracurium besylate or placebo was administered, followed by a continuous infusion of 37.5 mg per hour for 48 hours. There appeared to be benefits in the intervention group, although the mechanisms are not clear. Further studies are needed.
BACKGROUND: In patients undergoing mechanical ventilation for the acute respiratory distress syndrome (ARDS), neuromuscular blocking agents may improve oxygenation and decrease ventilator-induced lung injury but may also cause muscle weakness. We evaluated clinical outcomes after 2 days of therapy with neuromuscular blocking agents in patients with early, severe ARDS.
METHODS: In this multicenter, double-blind trial, 340 patients presenting to the intensive care unit (ICU) with an onset of severe ARDS within the previous 48 hours were randomly assigned to receive, for 48 hours, either cisatracurium besylate (178 patients) or placebo (162 patients). Severe ARDS was defined as a ratio of the partial pressure of arterial oxygen (PaO2) to the fraction of inspired oxygen (FIO2) of less than 150, with a positive end-expiratory pressure of 5 cm or more of water and a tidal volume of 6 to 8 ml per kilogram of predicted body weight. The primary outcome was the proportion of patients who died either before hospital discharge or within 90 days after study enrollment (i.e., the 90-day in-hospital mortality rate), adjusted for predefined covariates and baseline differences between groups with the use of a Cox model.
RESULTS: The hazard ratio for death at 90 days in the cisatracurium group, as compared with the placebo group, was 0.68 (95% confidence interval [CI], 0.48 to 0.98; P=0.04), after adjustment for both the baseline PaO2:FIO2 and plateau pressure and the Simplified Acute Physiology II score. The crude 90-day mortality was 31.6% (95% CI, 25.2 to 38.8) in the cisatracurium group and 40.7% (95% CI, 33.5 to 48.4) in the placebo group (P=0.08). Mortality at 28 days was 23.7% (95% CI, 18.1 to 30.5) with cisatracurium and 33.3% (95% CI, 26.5 to 40.9) with placebo (P=0.05). The rate of ICU-acquired paresis did not differ significantly between the two groups.
CONCLUSIONS: In patients with severe ARDS, early administration of a neuromuscular blocking agent improved the adjusted 90-day survival and increased the time off the ventilator without increasing muscle weakness. (Funded by Assistance Publique-Hôpitaux de Marseille and the Programme Hospitalier de Recherche Clinique Régional 2004-26 of the French Ministry of Health; ClinicalTrials.gov number, NCT00299650.)
A CME article in Critical Care Medicine summarises the literature on ARDS (including its limitations) and provides evidence based recommendations on what to do about severe hypoxaemia. They summarise:
For life-threatening hypoxaemia, initial management with a recruitment manoeuvre and/or high PEEP should be undertaken if plateau airway pressures and lack of barotrauma allow. If not, or if these are not effective, then proceed to the prone position or HFOV. If hypoxemia still persists, then consider the administration of inhaled NO. If NO fails, then glucocorticoids can then be administered. For elevated plateau airway pressures when tidal volumes are 4 mL/kg, consider prone positioning or HFOV. For life- threatening respiratory acidosis, consider the use of a buffer or continuous veno-venous hemofiltration. It is most important to assess for objective physiologic improvement in the appropriate time period for each intervention. If no benefit is evident, then the therapy should be discontinued to minimise harm and delay in the initiation of another therapy. If the patient continues to have life-threatening hypoxemia, acidosis, or elevated plateau airway pressures, then consider ECMO or extracorporeal carbon dioxide removal.
A multicentre randomised controlled trial of 342 adult patients with moderate to severe ARDS assessed the effect of prone ventilation on mortality, and showed no benefit (6-month mortality was 52.7% and 63.2%, respectively (RR, 0.78; 95% CI, 0.53-1.14; P = .19).
The current mortality of 35% associated with acute lung injury (ALI) is roughly three times higher than that associated with ST-segment elevation myocardial infarction. Protective ventilation strategies limiting tidal volumes and plateau pressures improve outcome, but the optimial level of PEEP is debated. In patients with ALI and its more severe form acute respiratory distress syndrome (ARDS), higher levels of PEEP may prevent atelectasis, recruit already collapsed alveolar units, and reduce pulmonary damage by avoiding the cyclical opening and collapse of alveoli.
In a systematic review and meta-analysis of individual-patient data, researchers investigated the association between higher vs lower PEEP levels and patient-important outcomes among adults with acute lung injury or ARDS who receive ventilation with low tidal volumes.
Randomized trials eligible for this review compared higher with lower levels of PEEP (mean difference of at least 3 cm H2O between groups) in critically ill adults with ALI or ARDS. Eligible trials incorporated a target tidal volume of less than 8 mL/kg of predicted body weight in both the experimental and the control ventilation strategies and provided patient follow-up to death or for at least 20 days.
There were 374 hospital deaths in 1136 patients (32.9%) assigned to treatment with higher PEEP and 409 hospital deaths in 1163 patients (35.2%) assigned to lower PEEP (adjusted relative risk [RR], 0.94; 95% confidence interval [CI], 0.86-1.04; P = .25). Treatment effects varied with the presence or absence of ARDS (as opposed to ALI). In patients with ARDS (n = 1892), there were 324 hospital deaths (34.1%) in the higher PEEP group and 368 (39.1%) in the lower PEEP group (adjusted RR, 0.90; 95% CI, 0.81-1.00; P = .049). Rates of pneumothorax and vasopressor use were similar.
The authors conclude that treatment with higher vs lower levels of PEEP was not associated with improved hospital survival overall when ALI/ARDS were considered together, but higher levels were associated with improved survival among the pre-defined subgroup of patients with ARDS.
Higher vs lower positive end-expiratory pressure in patients with acute lung injury and acute respiratory distress syndrome: systematic review and meta-analysis JAMA. 2010 Mar 3;303(9):865-73