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Respiratory failure is a commonly encountered disease process in both the emergency department (ED) and intensive care (ICU) setting. Respiratory failure most frequently results from exacerbations of congestive heart failure (CHF) or chronic obstructive pulmonary disease (COPD), respiratory infections, encephalopathy, or a combination of these etiologies. Obesity, with or without obesity hypoventilation syndrome, reduces respiratory reserve and may accelerate and worsen the severity of respiratory failure.
Noninvasive ventilation (NIV), including high-flow nasal cannula (HFNC) and non-invasive positive pressure ventilation (NIPPV) can provide benefit in multiple disease states causing respiratory failure, and can help selected patients avoid intubation and mechanical ventilation. This review serves to examine the clinical indications for NIV through discussion of the physiologic effects of the modality supported by the most current research.
Physiology and Definitions:
Non-invasive positive pressure ventilation (NIPPV) includes both continuous positive airway pressure (CPAP) ventilation as well as Bi-level positive airway pressure ventilation (bi-level or BiPAP). These modalities exert their therapeutic and physiologic efficacy via application of positive airway pressure during the respiratory cycle. A constant pressure may be applied, as in CPAP, amounting to a non-invasive application of positive end expiratory pressure (PEEP).
Adding an inspiratory positive pressure (IPAP) during inhalation in addition to PEEP creates bi-level ventilation. This IPAP is akin to pressure support ventilation (PSV) in a ventilated patient. It should be noted that the addition of IPAP during bi-level ventilation is the main effector of CO2 clearance during NIV. The pressure differential between IPAP and EPAP is akin to the driving pressure in invasive ventilation (pPlat-PEEP). Monitoring and maintaining a lower driving pressure seems to have lung protective effects during invasive ventilation and clinicians should be mindful of it during NIV. 
A second modality of NIV/PAP is bubble CPAP, which is most effective in children. This type of continuous flow CPAP uses a positive airway pressure (PAP) generated by a pipe immersed in a column of water applied through a nasal cannula. Flow is pushed through the pipe and the level of CPAP correlates to the height of the pipe immersed in water. This form of CPAP is arguably better for small children, whose more delicate alveoli might benefit from the oscillatory CPAP generated by the bubble column. Additionally, being obligate nose breathers and having larger tongues allows for more effective nasal delivered CPAP in this population as much of the PAP applied via nasal prongs in adults is lost when the mouth is opened. 
In high-flow nasal cannula (HFNC) systems, oxygen is admixed with air and applied continuously at up to 60 liters per minute via large bore nasal cannula. High-flow systems allow an admixture approaching 100% oxygen, but in practice the open circuit results in a delivered fraction of inspired oxygen that may vary widely between patients. High-flow oxygen may be considered a mode of non-invasive positive pressure ventilation, as it generates moderate positive end expiratory pressure (PEEP) above the physiologic level. HFNC likely exerts its effect via other mechanisms (discussed below) besides its moderate PEEP. The high-flow system is administered via large bore nasal cannula which help decrease air entrainement.
Physiologic Effects of NIPPV
Positive airway pressure ventilation exerts therapeutic effects via modulation of both cardiorespiratory function and optimization of gas exchange. With regard to gas exchange, PEEP alone generated during CPAP ventilation improves oxygenation by de-nitrogenating the alveoli. Additionally, PEEP stents open airways and prevents dynamic hyperinflation of alveoli. This in turn decreases air trapping due to small airway collapse known as intrinsic PEEP (PEEPi) and reduces dead space ventilation. More alveoli are aerated (i.e., "recruited") and ventilation-perfusion matching is improved.  This is especially useful in COPD, where loss of airway elastic recoil leads to small airway collapse with hypercapnia, or in severe asthma exacerbations, where high PEEPi worsens distress. In this vein, PEEP can be thought of as a method to decrease the “shunt fraction” of the lungs (i.e., the fraction of V/Q mismatch) by optimizing the ventilated segments of the lung.
With the addition of pressure support driving oxygen-enriched air during bi-level ventilation, anatomic dead space can be washed out of CO2 and nitrogen, thus further improving oxygenation and hypercapnia, along with decreased work of breathing.
Thus, choice of modality can be made easier by asking whether the patient needs oxygenation (favoring CPAP) or both oxygenation and ventilation (bi-level) support.
In addition to the beneficial effects on gas exchange, NIPPV also exerts a hemodynamic effect that can be useful in certain disease processes such as pulmonary edema and decompensated CHF. These effects are best observed in patients with poor left ventricle (LV) function, increased cardiac afterload and resultant decreased lung compliance due to pulmonary edema as in a patient with worsening decompensated heart failure. This benefit is derived from the increased positive intrathoracic pressure exerted by NIPPV. Increases in intrathoracic pressure decrease preload delivered to the right heart, and consequently reduce LV preload as well. Notably, there is some mild increase in pulmonary artery pressure from increased intrathoracic pressure exerted by PPV, but this is likely more than balanced by the decrease in hypoxic pulmonary vasoconstriction in a more optimally perfused lung with PPV. 
Subsequent interventricular interdependence and resultant decreased volume delivered to the LV restore Frank-Starling dynamics in the failing left heart. Additionally, increased lung inflation with PAP leads to increasing compliance, which is translated across the lung parenchyma through the LV wall. This augments LV contractility, helping to overcome reductions in LV contractility inherent to a patient with systolic dysfunction, CHF or ischemic myocardium, assisting the failing LV to overcome increased afterload. Coupled with improved oxygenation, decreased LV preload and afterload lead collectively to decreased cardiac work which can be critical during myocardial ischemic events. [5,6]
Unlike CPAP and bi-level, high-flow nasal cannula (HFNC) therapy achieves its effect through several different mechanisms and is more appropriate for pure hypoxemic respiratory failure in those without underlying cardiopulmonary pathology. Chiefly, HFNC provides heated, humidified oxygen at high-flows which contributes to improved oxygenation and washes out anatomic dead space. Changes in airflow in the oropharynx when HFNC is administered result in decreased upper airways resistance and better gas exchange.  Although HFNC is an open system, a PEEP is generated that is equivalent to 0.7 cmH2O/ 10L of flow applied when the mouth is closed for a maximum of around 4 CmH2O which probably contributes to but is not solely responsible for HFNC’s efficacy. Recent studies have also demonstrated that in ICU patients with hypoxemic respiratory failure, HFNC serves to decrease respiratory rate, increase expiratory volume and increase lung compliance . Together these physiologic effects translate not only to improvements in hypoxia but to a decrease in overall work of breathing (WOB).
NIV has many applications in the critically ill patient; most patients in EDs and ICUs who do not require immediate intubation are candidates for a NIV modality. NIV should be avoided however, in those with severe altered mental status, vomiting, or who are rapidly deteriorating and likely to soon need intubation. Caution should be exercised with patients who are in shock, have difficulty tolerating the mask or severe hypoxia. It should be recognized that sometimes the distinction between relative and absolute contraindication is defined by the underlying disease process and patient factors such as resuscitation status.
In COPD, bi-level NIPPV (commonly called BiPAP) is theoretically preferred due to its enhanced ability to wash out dead space. BiPAP decreased intubations in COPD exacerbations from 74% to 26% in one analysis . A meta-analysis suggested that the numbers needed to treat with bi-level NIPPV to prevent intubation and mortality are 5 and 8 respectively. However, recognizing which COPD patients will fail NIV is as important as knowing who will benefit. Multiple studies have shown that acidemia, encephalopathy, and persistent respiratory rate greater than 30 at time 0 and 1 hour after initiation are associated with NIV failure. Underscored here and throughout this review is the importance of close monitoring and re-assessment. [12, 13]
NIV also demonstrates significant benefit in patients with congestive heart failure exacerbations (CHFe) who are in respiratory distress. In particular, CPAP has traditionally been utilized more than bi-level due to the physiology and an element of dogma. In actuality CPAP and bi-level have both been proven to decrease intubation and mortality in multiple studies of acute heart failure; neither has been shown to be superior to the other. The controversy related to bi-level usage arose from a single small, methodologically flawed study in 1997 that demonstrated an increased risk of myocardial infarction when bi-level was used for CHFe.  Subsequent randomized trials and meta-analysis data have shown bi-level ventilation to be safe in CHFe.[16,17]
In asthma, NIV decreased hospitalization (from 36% to 18%) and increased FEV1 in comparison to standard treatment.  NIV appears to have beneficial effects In immunocompromised patients as well. In solid organ transplant patients with respiratory failure, NIV decreased intubation by 50%, and decreased ICU mortality from 50% to 20% in relation to supplemental oxygen alone. When used in immunosuppressed patients including bone marrow transplant, neutropenic, corticosteroid dependent or HIV patients with moderately severe respiratory failure (P:F>200), reductions in intubation and hospital mortality were also noted, compared to standard oxygen therapy. 
NIV is emerging as a useful tool for the pediatric population, although few RCT’s have been conducted. Bi-level NIV has been shown to decrease intubations by 32% (28% vs 60%) in children between 1 and 13 years old with respiratory failure due to pneumonia or asthma. Additionally, vital sign improvement (HR and RR) improved significantly in the bi-level group indicating improved respiratory mechanics.  In children less than 5 years old with respiratory failure a seminal study demonstrated that both high-flow oxygen and bubble CPAP showed mortality benefit (bubble CPAP: 4% vs 13% HiFlo vs 15%) over standard oxygen therapy. Additionally, fewer children experienced treatment failure (intubation or death) in the high-flow or bubble CPAP group in comparison to standard oxygen therapy (6% vs 13% vs 24% respectively). Importantly, this study seems to demonstrate that bubble CPAP and high-flow oxygen are nearly equivalent in terms of benefit.  Other groups have demonstrated that HFNC decreased intubations from 37% to 7% over a 5 year period in PICU patients less than 24 months, specifically in the subgroup with viral bronchiolitis.  This effect is thought to arise from a reduction in respiratory rate associated with HFNC use, as the subset of patients who did best had consistent decreases toward normal over time.
There is controversy regarding the use of NIV in adults with acute respiratory distress syndrome (ARDS). Current guidelines from the IDSA and ATS caution against use of NIV in patients with signs of severe ARDS, in accordance with multiple studies showing approximately 40-60% of these patients fail NIV and require intubation. These failures were associated with increased morbidity and mortality compared to patients who received early intubation. Not surprisingly, patients who have underlying COPD or pulmonary disease tended to do better than those who had hypoxemic respiratory failure without chronic lung disease.  In the subset of patients with moderate ARDS (P:F 100-200) the mortality increase was the steepest (10% increase vs standard care).  Studies examining NIV in ARDS have suggested high driving pressures and expired tidal volumes over 9 ml/kg predict failure, and pointed towards a role for barotrauma in the progression of disease. [27,28]
Although there is significant data to advise against use of NIV in ARDS, a recent study has demonstrated that changing the interface from mask to helmet decreased the incidence of intubation from 61.5% to 18.3% with an NNT of 2.3 for prevention of intubation. In-hospital and 90-day mortality were also cut nearly in half when a helmet device was used rather than a mask.  Another trial (FLORALI) tested HFNC vs. non-rebreather mask vs. NIV by face mask in patients with hypoxemic respiratory failure with P:F<300. Although the intubation rate was not different between arms, the high-risk subgroup of patients with a P:F ratio of <200 showed benefit from HFNC over NIV. In this group, intubation rates decreased significantly from 58% (NIV) to 35% (HFNC). A significant mortality benefit at 90 days also was observed in the high-flow cannula group. Benefits might result from high-flow nasal cannula's better allowance for secretion clearance and decreased barotrauma in comparison to standard NIV. 
CPAP, bi-level and high-flow nasal cannula can be beneficial in respiratory failure from multiple disease processes. Different modalities may have greater benefit in certain disease processes by ameliorating derangements in physiology and augmenting cardiac and respiratory mechanics. Clinicians should consider the preferential use of CPAP in CHF, bi-level in COPD and HFNC in hypoxemic respiratory failure. NIV is beneficial for respiratory failure in most immunocompromised patients and asthmatics, and has shown benefit in children as well. In the case of pure hypoxemic respiratory failure due to moderate to severe ARDS, traditional NIV has been associated with mortality and should be used with caution. However, limited data suggest that in selected patients with hypoxemic respiratory failure due to pneumonia and ARDS, treatment with high-flow nasal cannula can prevent intubation and reduce mortality.
Dr. Anthony J. Hackett
Emergency Medicine Attending Physician
- Amato MB1, Meade MO, Slutsky AS, Brochard L, Costa EL, Schoenfeld DA, Stewart TE, Briel M, Talmor D, Mercat A, Richard JC, Carvalho CR, Brower RG. Driving pressure and survival in the acute respiratory distress syndrome. N Engl J Med. 2015 Feb 19;372(8):747-55. doi: 10.1056/NEJMsa1410639.
- Dewez J, & Broek N. Continuous positive airway pressure (CPAP) to treat respiratory distress in newborns in low- and middle-income countries Tropical Doctor 2017, Vol. 47(1) 19–22
- Odonoghue, F J. “Effect of CPAP on intrinsic PEEP, inspiratory effort, and lung volume in severe stable COPD.” Thorax, vol. 57, no. 6, Jan. 2002, pp. 533–539., doi:10.1136/thorax.57.6.533.
- Leucke, T., & Pelosi, P. (2005). Clinical review: Positive end-expiratory pressure and cardiac output. Critical care, 9(6), 607-621.
- Kato, T., Suda, S., & Kasai, T. (2014). Positive airway pressure therapy for heart failure. World journal of cardiology, 6(11), 1175-1191.
- Agarwal, R. (2005). Non-invasive ventilation in acute cardiogenic pulmonary oedema. Postgraduate Medical Journal, 81(960), 637-643. doi:10.1136/pgmj.2004.031229
- Nishimura, M., High-flow nasal cannula oxygen therapy in adults: physiological benefits, indication, clinical benefits, and adverse effects. Respir Care, 2016. 61(4): p. 529-541.
- Parke, R.L., M.L. Eccleston, and S.P. McGuinness, The effects of flow on airway pressure during nasal high-flow oxygen therapy. Respir Care, 2011. 56(8): p. 1151-1155.
- Mauri, T., Turrini, C., Eronia, N., Grasselli, G., Volta, C. A., Bellani, G., & Pesenti, A. (2017). Physiologic Effects of High-Flow Nasal Cannula in Acute Hypoxemic Respiratory Failure. American Journal of Respiratory and Critical Care Medicine, 195(9), 1207-1215. doi:10.1164/rccm.201605-0916oc
- Brochard, Laurent, et al. “Noninvasive Ventilation for Acute Exacerbations of Chronic Obstructive Pulmonary Disease.” New England Journal of Medicine, vol. 333, no. 13, 1995, pp. 817–822., doi:10.1056/nejm199509283331301.
- Lightowler JV, Wedzicha JA, Elliott MW, Ram FS. Non-invasive positive pressure ventilation to treat respiratory failure resulting from exacerbations of chronic obstructive pulmonary disease: Cochrane systematic review and meta-analysis. BMJ 2003;326(7382):185–189.
- Murugan, R., Mesquita, A., Fernandes, L., Rodrigues, M., & Vereneker, S. Predicting Efficacy and Failure Risk of NonInvasive Positive Pressure Ventilation in Chronic Obstructive Pulmonary Disease Exacerbation through Arterial Blood Gas Analysis. International Journal of Scientific Study, (2015). 3(4), 48-51
- Ko BS, Ahn S, Lim KS, Kim WY, Lee YS, Lee JH. Early failure of noninvasive ventilation in chronic obstructive pulmonary disease with acute hypercapnic respiratory failure. Intern Emerg Med. 2015 Oct;10(7):855-60
- Masip J, Roque M, Sa´nchez B, Ferna´ndez R, Subirana M, Expo´sito JA. Noninvasive ventilation in acute cardiogenic pulmonary edema: systematic review and meta-analysis. JAMA 2005;294(24):3124–3130.
- Mehta S, Jay GD, Woolard RH, Hipona RA, Connolly EM, Cimini DM, Drinkwine JH, Hill NS. Randomized, prospective trial of bilevel versus continuous positive airway pressure in acute pulmonary edema. Crit Care Med. 1997 Apr;25(4):620-8.
- Bellone, Andrea MD; Monari, Alessandra MD; Cortellaro, Francesca MD; Vettorello, Marco MD; Arlati, Sergio MD; Coen, Daniele MD Myocardial infarction rate in acute pulmonary edema: Noninvasive pressure support ventilation versus continuous positive airway pressure. Critical Care Medicine: September 2004 - Volume 32 - Issue 9 - p 1860-1865
- Hui Li, MM, Chunlin Hu, MD, Jinming Xia, MM, Xin Li, MD, Hongyan Wei, MM, Xiaoyun Zeng, MM, Xiaoli Jing, MD. A comparison of bilevel and continuous positive airway pressure noninvasive ventilation in acute cardiogenic pulmonary edema.American Journal of Emergency Medicine: September 2013-Volume 31, Issue , p 1322-1227
- Soroksky A1, Stav D, Shpirer I. A pilot prospective, randomized, placebo-controlled trial of bilevel positive airway pressure in acute asthmatic attack. Chest. 2003 Apr;123(4):1018-25
- Antonelli M1, Conti G, Bufi M, Costa MG, Lappa A, Rocco M, Gasparetto A, Meduri GU. Noninvasive ventilation for treatment of acute respiratory failure in patients undergoing solid organ transplantation: a randomized trial. JAMA. 2000 Jan 12;283(2):235-41.
- Hilbert G, Gruson D, Vargas F, Valentino R, Gbikpi-Benissan G, Dupon M, Reiffers J, Cardinaud JP.Noninvasive ventilation in immunosuppressed patients with pulmonary infiltrates, fever, and acute respiratory failure. N Engl J Med. 2001 Feb 15;344(7):481-7
- Yañez LJ, Yunge M, Emilfork M, Lapadula M, Alcántara A, Fernández C, Lozano J, Contreras M, Conto L, Arevalo C, Gayan A, Hernández F, Pedraza M, Feddersen M, Bejares M, Morales M, Mallea F, Glasinovic M, Cavada G. A prospective, randomized, controlled trial of noninvasive ventilation in pediatric acute respiratory failure. Pediatr Crit Care Med. 2008 Sep;9(5):484-9
- Chisti MJ, Salam MA, Smith JH, Ahmed T, Pietroni MA, Shahunja KM, Shahid AS, Faruque AS, Ashraf H, Bardhan PK, Sharifuzzaman, Graham SM, Duke T. Bubble continuous positive airway pressure for children with severe pneumonia and hypoxaemia in Bangladesh: an open, randomised controlled trial. Lancet. 2015 Sep 12;386(9998):1057-65
- Schibler A, Pham TM, Dunster KR, Foster K, Barlow A, Gibbons K, Hough JL. Reduced intubation rates for infants after introduction of high-flow nasal prong oxygen delivery. Intensive Care Med. 2011 May;37(5):847-52.
- McKiernan C, Chua LC, Visintainer PF, Allen H. high-flow nasal cannulae therapy in infants with bronchiolitis. J Pediatr. 2010 Apr;156(4):634-8
- Carron M, Freo U, Zorzi M, Ori, C. Predictors of failure of noninvasive ventilation in patients with severe community-acquired pneumonia. Journal of Critical Care. 2010 Sep;25(3):540e9-540e14
- Giacomo Bellani et al. Noninvasive Ventilation of Patients with Acute Respiratory Distress Syndrome Insights from the LUNG SAFE Study Giacomo Bellani et al, on behalf of the LUNG SAFE Investigators and the ESICM Trials Group* Am J Respir Crit Care Med. 2017 Jan; 195(1), p 67–77
- Carteaux G1, Millán-Guilarte T, De Prost N, Razazi K, Abid S Failure of Noninvasive Ventilation for De Novo Acute Hypoxemic Respiratory Failure: Role of Tidal Volume. Crit Care Med. 2016 Feb;44(2):282-90.
- Tucci MR, Costa EL, Nakamura MA, Morais CC. Noninvasive ventilation for acute respiratory distress syndrome: the importance of ventilator settings. J Thorac Dis. 2016 Sep;8(9):E982-E986
- Patel BK, Wolfe KS, Pohlman AS, Hall JB, Kress JP. Effect of Noninvasive Ventilation Delivered by Helmet vs Face Mask on the Rate of Endotracheal Intubation in Patients With Acute Respiratory Distress Syndrome: A Randomized Clinical Trial. JAMA. 2016 Jun 14;315(22):2435-41
- Frat JP, Thille AW, Mercat A, Girault C, Ragot S, Perbet S, Prat G, Boulain T, Morawiec E, Cottereau A, Devaquet J, Nseir S, Razazi K, Mira JP, Argaud L, Chakarian JC, Ricard JD, Wittebole X, Chevalier S, Herbland A, Fartoukh M, Constantin JM, Tonnelier JM, Pierrot M, Mathonnet A, Béduneau G, Delétage-Métreau C, Richard JC, Brochard L, Robert R; FLORALI Study Group; REVA Network. High-flow oxygen through nasal cannula in acute hypoxemic respiratory failure. N Engl J Med. 2015 Jun 4;372(23):2185-96
- Lovas A, Nemeth MF, Trasy D, Molnar Z. Lung recruitment can improve oxygenation in patients ventilated in continuous positive airway pressure/pressure support mode. Front Med (Lausanne). 2015 Apr 21;2:25.
 BIPAP is a registered trademark of the Respironics corporation and this modality will be referred to as Bi-level ventilation in this work.