Elsevier

The Lancet

Volume 387, Issue 10030, 30 April–6 May 2016, Pages 1867-1878
The Lancet

Series
High-flow oxygen therapy and other inhaled therapies in intensive care units

https://doi.org/10.1016/S0140-6736(16)30245-8Get rights and content

Summary

In this Series paper, we review the current evidence for the use of high-flow oxygen therapy, inhaled gases, and aerosols in the care of critically ill patients. The available evidence supports the use of high-flow nasal cannulae for selected patients with acute hypoxaemic respiratory failure. Heliox might prevent intubation or improve gas flow in mechanically ventilated patients with severe asthma. Additionally, it might improve the delivery of aerosolised bronchodilators in obstructive lung disease in general. Inhaled nitric oxide might improve outcomes in a subset of patients with postoperative pulmonary hypertension who had cardiac surgery; however, it has not been shown to provide long-term benefit in patients with acute respiratory distress syndrome (ARDS). Inhaled prostacyclins, similar to inhaled nitric oxide, are not recommended for routine use in patients with ARDS, but can be used to improve oxygenation in patients who are not adequately stabilised with traditional therapies. Aerosolised bronchodilators are useful in mechanically ventilated patients with asthma and chronic obstructive pulmonary disease, but are not recommended for those with ARDS. Use of aerosolised antibiotics for ventilator-associated pneumonia and ventilator-associated tracheobronchitis shows promise, but the delivered dose can be highly variable if proper attention is not paid to the delivery method.

Introduction

Respiratory diseases account for a large portion of admissions to the intensive care unit. The lungs are unique both in their exposure to the outside environment and as a part of the cardiopulmonary circuit, exposed to the entirety of the body's circulation. Given these attributes, it is logical that inhaled therapies function as treatments for a range of conditions encountered in critical care. Various devices and drug formulations have been developed to specifically target the lung parenchyma, vasculature, and airways. In this Series paper, we discuss the current evidence regarding the use of inhaled therapies in critical care, including high-flow nasal cannulae (HFNC), heliox, nitric oxide, prostacyclins, bronchodilators and steroids, and antibiotics. We systematically searched the literature to provide the basis for this Series paper.

Section snippets

HFNC

The traditional nasal cannulae for oxygen administration is typically used at flows of 2–4 L/min. At these low flows, large dilution occurs with room air and thus the fraction of inspired oxygen (FiO2) is less than 0·4 L/min. Flows greater than 6 L/min can cause much discomfort when breathing in dry oxygen. Unheated bubble humidifiers can be used, but are inefficient and their efficiency decreases with increases in flow. Systems to deliver heated and humidified oxygen at flows as high as 60

Heliox

Helium is a non-toxic noble gas with a density of 0·18 g/m3, which is much lower than oxygen (1·43 g/m3) and nitrogen (1·25 g/m3).24 Heliox is a mixture of helium and oxygen (usually in a helium:oxygen ratio of 80:20 or 70:30). This gas has been used for decades in the care of patients with various respiratory diseases, albeit with little evidence to guide its use. Its low density affords heliox a unique niche in the critical care setting, with potential applications for partial upper airway

Inhaled nitric oxide for hypoxaemic respiratory failure

Nitric oxide (NO) is a colourless and odourless gas, known to be an environmental pollutant and a toxic component of cigarette smoke. NO is formed endogenously in endothelial cells from L-arginine, catalysed by the enzyme NO synthase. In 1987, NO was identified as the molecule that was previously known as endothelial-derived relaxing factor. Shortly thereafter, studies in both animals and people reported that NO, when inhaled, could decrease pulmonary vascular resistance in patients with

Inhaled prostacyclins for hypoxaemic respiratory failure

Endogenous prostacyclin produced by endothelial cells is a prostaglandin in the eicosanoid group of lipids. It functions as an inhibitor of platelet activation and as a vasodilator. Prostacyclin upregulates cyclic AMP (cAMP), triggering smooth muscle relaxation and subsequent vasodilation (figure 4).63, 64 Intravenous synthetic prostacyclin analogues have a non-selective vasodilatory effect and have long been used to treat pulmonary hypertension. Inhaled prostacyclins have a more specific

Inhaled bronchodilators and corticosteroids during mechanical ventilation

Inhaled bronchodilators, including short-acting β agonists (SABAs) and short-acting muscarinic antagonists (SAMAs), have a role in the care of mechanically ventilated patients with reversible airflow obstruction. Results of a 2016 international survey78 indicated that 22% of intubated patients received aerosol therapy, most commonly bronchodilators and steroids.78 Although commonly prescribed, a dearth of evidence is available examining the effectiveness and safety of bronchodilators in this

Aerosolised antibiotics during mechanical ventilation

Aerosolised antibiotics are standard practice for treatment of Pseudomonas aeruginosa infection in patients with cystic fibrosis.93 Ventilator-associated tracheobronchitis and ventilator-associated pneumonia are common in intubated mechanically ventilated patients. There is renewed interest in the use of aerosolised antibiotics for ventilator-associated pneumonia and ventilator-associated tracheobronchitis, fuelled by the emergence of multidrug-resistant pathogens, most often Gram-negative

Conclusions

Although inhaled therapies greatly vary in their use in the intensive care unit, their ability to directly target the lungs in various conditions while potentially avoiding adverse systemic events makes them attractive for treatment purposes. Despite this, evidence regarding their use in the intensive care unit has been scarce. Our recommendations for use of inhaled therapies are in table 2. Given the few proven therapies in highly morbid conditions (eg, ARDS, ventilator-associated pneumonia,

Search strategy and selection criteria

We searched PubMed for articles published in English between Dec 20, 2005, and Dec 17, 2015. We used the search terms “oxygen” in combination with “cannula” and “high flow”; “heliox” in combination with “humans” or “helium” in combination with “oxygen” and “humans”; “hypoxemia” in combination with “nitric oxide” and “humans”; “mechanical ventilation”, “respiratory failure”, or “hypoxemia” in combination with “epoprostenol”, “prostacyclin”, “veletri”, or “iloprost”, in combination with

References (103)

  • I Inglessis et al.

    Hemodynamic effects of inhaled nitric oxide in right ventricular myocardial infarction and cardiogenic shock

    J Am Coll Cardiol

    (2004)
  • MJ Semigran et al.

    Hemodynamic effects of inhaled nitric oxide in heart failure

    J Am Coll Cardiol

    (1994)
  • H Torbic et al.

    Inhaled epoprostenol vs inhaled nitric oxide for refractory hypoxemia in critically ill patients

    J Crit Care

    (2013)
  • PV van Heerden et al.

    Dose-response to inhaled aerosolized prostacyclin for hypoxemia due to ARDS

    Chest

    (2000)
  • CJ De Wet et al.

    Inhaled prostacyclin is safe, effective, and affordable in patients with pulmonary hypertension, right heart dysfunction, and refractory hypoxemia after cardiothoracic surgery

    J Thorac Cardiovasc Surg

    (2004)
  • TA Khan et al.

    A prospective, randomized, crossover pilot study of inhaled nitric oxide versus inhaled prostacyclin in heart transplant and lung transplant recipients

    J Thorac Cardiovasc Surg

    (2009)
  • BM Fuller et al.

    The use of inhaled prostaglandins in patients with ARDS: a systematic review and meta-analysis

    Chest

    (2015)
  • DE Craven et al.

    Contaminated medication nebulizers in mechanical ventilator circuits. Source of bacterial aerosols

    Am J Med

    (1984)
  • MH Kollef et al.

    Patient transport from intensive care increases the risk of developing ventilator-associated pneumonia

    Chest

    (1997)
  • CD Beaty et al.

    Continuous in-line nebulizers complicate pressure support ventilation

    Chest

    (1989)
  • J Leatherman

    Mechanical ventilation for severe asthma

    Chest

    (2015)
  • M Nishimura

    High-flow nasal cannula oxygen therapy in adults

    J Intensive Care

    (2015)
  • M Nishimura

    High-flow nasal cannula oxygen therapy in adults: physiological benefits, indication, clinical benefits, and adverse effects

    Respir Care

    (2016)
  • W Moller et al.

    Nasal high flow clears anatomical dead space in upper airway models

    J Appl Physiol

    (2015)
  • T Mundel et al.

    Mechanisms of nasal high flow on ventilation during wakefulness and sleep

    J Appl Physiol

    (2013)
  • RL Parke et al.

    Effect of very-high-flow nasal therapy on airway pressure and end-expiratory lung impedance in healthy volunteers

    Respir Care

    (2015)
  • RL Parke et al.

    Pressures delivered by nasal high flow oxygen during all phases of the respiratory cycle

    Respir Care

    (2013)
  • G Chanques et al.

    Comparison of three high flow oxygen therapy delivery devices: a clinical physiological cross-over study

    Minerva Anestesiol

    (2013)
  • JP Frat et al.

    High-flow oxygen through nasal cannula in acute hypoxemic respiratory failure

    N Engl J Med

    (2015)
  • PG Jones et al.

    Randomized controlled trial of humidified high-flow nasal oxygen for acute respiratory distress in the emergency department: the HOT-ER study

    Respir Care

    (2016)
  • N Rittayamai et al.

    Use of high-flow nasal cannula for acute dyspnea and hypoxemia in the emergency department

    Respir Care

    (2015)
  • F Stéphan et al.

    High-flow nasal oxygen vs noninvasive positive airway pressure in hypoxemic patients after cardiothoracic surgery: a randomized clinical trial

    JAMA

    (2015)
  • JP Frat et al.

    Sequential application of oxygen therapy via high-flow nasal cannula and noninvasive ventilation in acute respiratory failure: an observational pilot study

    Respir Care

    (2015)
  • N Rittayamai et al.

    High-flow nasal cannula versus conventional oxygen therapy after endotracheal extubation: a randomized crossover physiologic study

    Respir Care

    (2014)
  • SM Maggiore et al.

    Nasal high-flow versus Venturi mask oxygen therapy after extubation. Effects on oxygenation, comfort, and clinical outcome

    Am J Respir Crit Care Med

    (2014)
  • G Hernandez et al.

    Effect of postextubation high-flow nasal cannula vs conventional oxygen therapy on reintubation in low-risk patients: a randomized clinical trial

    JAMA

    (2016)
  • R Miguel-Montanes et al.

    Use of high-flow nasal cannula oxygen therapy to prevent desaturation during tracheal intubation of intensive care patients with mild-to-moderate hypoxemia

    Crit Care Med

    (2015)
  • M Vourc'h et al.

    High-flow nasal cannula oxygen during endotracheal intubation in hypoxemic patients: a randomized controlled clinical trial

    Intensive Care Med

    (2015)
  • MW Semler et al.

    Randomized trial of apneic oxygenation during endotracheal intubation of the critically ill

    Am J Respir Crit Care Med

    (2016)
  • DR Hess

    aerosol therapy during noninvasive ventilation or high-flow nasal cannula

    Respir Care

    (2015)
  • PW Longest et al.

    High-efficiency generation and delivery of aerosols through nasal cannula during noninvasive ventilation

    J Aerosol Med Pulm Drug Deliv

    (2013)
  • BJ Kang et al.

    Failure of high-flow nasal cannula therapy may delay intubation and increase mortality

    Intensive Care Med

    (2015)
  • DR Hess et al.

    The history and physics of heliox

    Respir Care

    (2006)
  • JL Diehl et al.

    Helium in the adult critical care setting

    Ann Intensive Care

    (2011)
  • JP Kress et al.

    The utility of albuterol nebulized with heliox during acute asthma exacerbations

    Am J Respir Crit Care Med

    (2002)
  • P Gerbeaux et al.

    Use of heliox in patients with severe exacerbation of chronic obstructive pulmonary disease

    Crit Care Med

    (2001)
  • P Jolliet et al.

    An international phase III randomized trial on the efficacy of helium/oxygen during spontaneous breathing and intermittent non-invasive ventilation for severe exacerbations of chronic obstructive pulmonary disease (The ECHO ICU Trial)

    Intensive Care Med Exp

    (2015)
  • P Jolliet et al.

    Helium-oxygen versus air-oxygen noninvasive pressure support in decompensated chronic obstructive disease: a prospective, multicenter study

    Crit Care Med

    (2003)
  • SM Maggiore et al.

    A multicenter, randomized trial of noninvasive ventilation with helium-oxygen mixture in exacerbations of chronic obstructive lung disease

    Crit Care Med

    (2010)
  • MF El-Khatib et al.

    Effect of heliox- and air-driven nebulized bronchodilator therapy on lung function in patients with asthma

    Lung

    (2014)
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