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Noninvasive ventilation as a palliative measure

Gifford, Alex H.

Current Opinion in Supportive and Palliative Care: September 2014 - Volume 8 - Issue 3 - p 218–224
doi: 10.1097/SPC.0000000000000068
RESPIRATORY PROBLEMS: Edited by David C. Currow and Amy P. Abernethy

Purpose of review Dyspnea is a distressing consequence of many unremitting diseases. This review discusses the therapeutic use of noninvasive ventilation (NIV) in advanced illness.

Recent findings NIV continues to be investigated most rigorously in patients with progressive neuromuscular weakness and the combination of emphysema and lung cancer. Data are quite limited on the palliative role of NIV in bronchiectasis and interstitial lung diseases. It remains difficult to identify the subsets of patients with acute-on-chronic respiratory failure who are most likely to benefit from ICU admission, but NIV may particularly help those with hypercapnia. The question of whether general or disease-specific instruments should be used to evaluate the effects of NIV on quality of life is unanswered. Computerized decision aids have been developed to assist providers, patients, and their families with advance care planning.

Summary NIV is an important adjunct to medications for patients with intractable dyspnea. Future research should attempt to clarify the effectiveness of NIV at controlling dyspnea within and outside the hospital. Barriers to its domiciliary application are largely unknown. Processes should be developed to optimize communication among clinicians, patients, and their caregivers around the issues of when to start NIV and how to withdraw it at the end of life.

Pulmonary and Critical Care Medicine, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, USA

Correspondence to Alex H. Gifford, MD, Assistant Professor of Medicine, Section of Pulmonary and Critical Care Medicine, 5C, Dartmouth-Hitchcock Medical Center, One Medical Center Drive, Lebanon, NH 03756-1000, USA. Tel: +1 603 650 5533; fax: +1 603 650 0580; e-mail:

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Positive pressure applied to the airway using devices other than an endotracheal tube constitutes noninvasive ventilation (NIV). NIV can be delivered by nasal, oronasal, and full-face masks, mouthpieces, and helmets [1], with attention to the anatomy and personal preferences of each patient. Responses depend on the pathophysiology and natural history of the condition for which it is prescribed, in addition to patient tolerance and adherence. NIV is a treatment for obstructive, restrictive, and mixed causes of respiratory failure (Fig. 1). In contrast to the other modalities for palliating dyspnea in advanced illness, NIV uniquely couples man and machine, a relationship that evolves commensurately with symptoms and the extent to which patients value its effects on their quality of life. The prospect of starting NIV often yields myriad questions and emotions. In clinical practice, however, the quality and frequency of communication about this and other goals of care varies considerably [2▪].



Box 1

Box 1

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Many patients with chronic obstructive pulmonary disease (COPD) live with severe breathlessness despite aggressive drug therapy. Given that increased ventilatory demand, static and dynamic hyperinflation, and respiratory muscle weakness conspire to cause this symptom in COPD [3], NIV is a frontline treatment. It unequivocally reduces intubation risk during acute exacerbation [4], but is probably underutilized in the home environment despite some cost–effectiveness data in patients with frequent hypercapnic episodes [5▪]. Table 1 summarizes recent studies [6–10] that have examined the effects of NIV on quality of life in COPD.

Table 1

Table 1

Little has been published about the role of NIV in treating dyspnea associated with other obstructive lung diseases, like cystic fibrosis (CF). Most CF studies compare NIV to airway clearance techniques, with a focus on the differences in physiologic parameters [11]. A single randomized crossover trial of overnight NIV vs. inspiration of air by nasal cannula for 6 weeks demonstrated that NIV improved chest symptom scores and Transition Dyspnea Index (TDI) relative to baseline in hypercapnic CF patients [12]. This study and one by Gozal [13] suggest that NIV favorably influences nocturnal gas exchange but not sleep architecture in CF. Whether NIV enhances physical and emotional functioning in non-CF bronchiectasis and asthma complicated by fixed airflow obstruction is unclear.

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Literature regarding the use of NIV for interstitial lung disease (ILD) is almost entirely populated by studies of hospitalized patients facing an initial or recurrent trial of intubation for acute-on-chronic respiratory failure and is beyond the scope of this review. However, an analysis of data from the Scleroderma Lung Study found that dyspnea severity was closely correlated with impairment of quality of life [14], which is also true for idiopathic pulmonary fibrosis (IPF) [15]. The palliative application of NIV to ILD warrants future intellectual efforts.

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Older studies of NIV used for chest wall and neuromuscular disorders (NMDs) are generally descriptive and include patients with various causes of ventilatory failure [16–19], some of which are rare [20,21]. More recent investigations of NIV have been observational in nature or controlled trials in which specific outcomes are evaluated in patients affected by a single disease, namely amyotrophic lateral sclerosis (ALS) [22,23,24▪▪,25] and Duchenne muscular dystrophy (DMD) [26,27▪▪,28]. Several well conducted studies [22,26,29,30] show that NIV improves survival in chest wall and NMDs. Some authors believe that future work in this field should try to explain global disparities in access to NIV [31▪▪].

Mechanisms of dyspnea are complex in chest wall and NMDs, and only a few studies have been undertaken to elucidate relevant neural and chemoreceptive stimuli. Understanding how these signals are generated and centrally processed helps to explain the clinical utility of NIV. Patients with chest wall and NMDs often describe their breathing as shallow or requiring undue work or effort, a consequence of increased neural drive despite normal respiratory system mechanics in most instances [32]. Lanini et al.[33] provoked dyspnea with hypercapnic-hyperoxic rebreathing in 11 patients, most of whom had limb-girdle dystrophy, and 17 healthy controls. These authors identified a good correlation (r = 0.62, P = 0.04) between the slope of Borg score per unit of ventilation and dynamic lung elastance, leading them to conclude that impairment of neuroventilatory coupling explained much of the variation in dyspnea severity among their patients. Interestingly, central motor output and Borg score per unit change in pCO2 were similar in patients and controls, but this may only hold true for dyspnea triggered by an isolated laboratory methodology. Clague et al.[34] also showed that inspiratory effort was unrelated to CO2 tension in myotonic dystrophy.

Nocturnal hypoventilation fragments sleep [35] and is highly prevalent in chest wall and NMDs [36–38]. These facts, coupled with the evidence that the phenomenon causes few respiratory symptoms [29] and occurs even when forced vital capacity (FVC) exceeds 50% predicted [39▪], have led to the incorporation of overnight oximetry into clinical practice guidelines [40]. NIV can mitigate excessive daytime sleepiness and orthopnea in ALS patients with sleep-related arousals [41]. Correction of sleep disturbance has been invoked as the reason for better cognitive performance in NIV-treated ALS patients [42]. Another exploration of quality of life in ALS revealed that NIV helped patients overcome fatigue and feel more in control of their disease [43], but some data [22] suggest that those with poor bulbar function may not derive as much benefit. In several respects, however, NIV successfully palliates distressing aspects of chest wall and NMDs.

Sometimes patients with chest wall and NMDs reach a point in their lives when they no longer wish to be supported by NIV. The healthcare provider has multiple obligations in this situation, not the least of which is discussing how the patient arrived at this conclusion and whether better managing symptoms by untried means is desirable. Autonomy should be validated whenever possible [44]. Dialog around these issues should arguably start early in the disease course, but as Mitsumoto and Rabkin [45▪] highlight in their narrative about a neurologist with ALS, the healthcare provider must be sensitive to the patient's level of mental and physical readiness to withdraw some or all interventions that do not promote comfort. Simonds [2▪] aptly states that patients are often informed about ‘hard’ outcomes of various therapies, with little mention of their burdens. Interactive computer programs can help patients [46] and physicians [47] with advance care planning. Such ‘third-party’ tools might be able to defuse tensions between patient autonomy and physician paternalism.

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Several conditions cause patients with cancer to require some form of assisted ventilation. Bacterial pneumonia is associated with neutropenia, solid tumor, multiple myeloma, less than 3 days since symptom onset, shock, unilateral radiographic abnormalities, and unilateral crackles [48▪▪]. Opportunistic infections tend to arise in patients treated with steroids and those with a history of a lymphoproliferative disorder or hematopoietic stem cell transplant, whereas patients with acute leukemia commonly present with noninfectious respiratory insults [48▪▪]. A minority of hematology-oncology patients experience respiratory failure from pulmonary emboli, alveolar hemorrhage, and cardiogenic pulmonary edema [49,50]. NIV has been employed successfully in cases of lung injury related to chemotherapy agents, notably gefitinib [51], all-transretinoic acid (ATRA) [52,53], and the combination of docetaxel and gemcitabine [54]. People with lung cancer commonly have exacerbations of congestive heart failure (CHF) and COPD as secondary precipitants of respiratory distress [55]. In these situations, NIV could be particularly useful [56]. Difficulties in determining which cancer patients will benefit from the ICU [57] and trends toward better survival [58–60] have informed the opinion that an ‘ICU trial’ should be offered to most patients [61].

Ten years ago, Cuomo et al.[62] prospectively determined that early NIV improved oxygenation and Borg dyspnea score in hypoxemic patients with solid tumors; however, the overall ICU mortality rate was 39%, and 10 of 23 patients (44%) were intolerant to NIV or had progressive physiologic decline that precluded its continuation. A series of 40 patients with advanced cancer and do-not-intubate orders were described as being ‘alert and cooperative’ at the initiation of NIV, but their in-hospital mortality was much higher (85%) than other NIV-treated patients [63]. Depuydt et al.[64▪] reported similar ICU and in-hospital mortality rates for hypoxemic hematology patients initially treated with NIV (71 and 75%, respectively) and invasive positive pressure ventilation (63 and 80%, respectively). Increasing cancer-specific severity of illness score at admission to the ICU and rapid onset of organ failure were the only factors associated with survival [64▪]. On the basis of these high mortality rates, one might conclude that NIV is ineffective and should not be attempted in those with advanced malignancies, but many variables affect prognosis in this setting [65], and the possibility of relieving dyspnea with NIV may be more important to patients and families depending on the primary goals of care [66].

In patients with solid tumors, respiratory failure, and limited life-expectancy, Nava et al.[67▪▪] recently evaluated the acceptability and effectiveness of NIV vs. oxygen in reducing dyspnea and opiate requirements. Randomization was stratified with respect to the presence or absence of hypercapnia (PaCO2 >45 mmHg). Subcutaneous morphine was administered to all patients to reduce breathlessness ratings by at least 1 point on the Borg scale. There were no significant baseline differences in demographic, physiologic, and prognostic parameters between the cohort of 99 patients treated with NIV and the cohort of 101 patients who received oxygen alone. The authors observed that dyspnea ratings fell more rapidly in the NIV group [mean reduction in Borg scale of 0.58, 95% confidence interval (CI) 0.23–0.92, P = 0.0012], especially in patients with hypercapnia. The average total morphine dose was 32.4 mg lower in NIV-treated patients through the first 48 h of treatment. Within the NIV group, survival at 3 and 6 months after discharge was higher among those with hypercapnia (hazard ratio = 0.41). The authors posited that NIV helped this subgroup overcome respiratory muscle fatigue and emphasized that only 11% of all NIV patients discontinued treatment. Azoulay et al.[68] expressed concern that Nava et al.[67▪▪] combined patients with do-not-intubate orders who received NIV with curative intent and those who received NIV exclusively to alleviate dyspnea (i.e., comfort NIV). In their rebuttal, Nava et al. stated that all the study participants had voluntarily chosen to forego all life support, thus defining a single population of patients treated with comfort NIV.

Limited data suggest that the burden of dyspnea at the end of life is similar in patients with hematologic and solid neoplasms. Applying the Edmonton Symptoms Assessment System, Fadul et al.[69] found no difference in the dyspnea scores between two 125-patient cohorts with each type of cancer. Nonetheless, literature concerning NIV use in patients with leukemia and lymphoma is dominated by small case series and retrospective nested control studies, in which NIV was instituted along with other life-sustaining interventions or compared to endotracheal intubation and mechanical ventilation. Piastra et al.[70] saw uniform improvement in oxygenation in four children with leukemia to whom NIV was delivered through a helmet device, but any impact on dyspnea was not provided. In adults with acute respiratory failure predominantly associated with leukemia, Depuydt et al.[71] observed the same in-hospital mortality rate (65.4%) for 26 patients treated with NIV and 52 well matched patients who were intubated. In a retrospective, single-center study of patients with hematologic malignancies treated with NIV or conventional mechanical ventilation, Azoulay et al.[60] noted a significantly lower 30-day mortality rate (43.7 vs. 70.8%, P = 0.008) favoring NIV, but the two 48-patient cohorts differed in several important aspects, including a trend toward more frequent decisions to withdraw support in the mechanical ventilation group (4.1 vs. 14.5%, P = 0.09). Descriptions of the tolerability and subjective effects of NIV on dyspnea are needed in patients with hematologic cancers.

Some concerns have been raised about the risks and limitations of NIV in patients with dyspnea and terminal cancer [72▪▪]. The first of these, whether NIV is prolonging life but not improving its quality, has an ethical basis. A dying patient might request NIV to buy enough time for a loved one to arrive at the bedside. However, clinicians would only appreciate this perspective if they take time to elicit their patient's expectations of NIV and, perhaps more importantly, to convey their opinions about whether NIV will or will not meet those expectations [73]. Azad and Franco [72▪▪] have contended that a reduction in total morphine dose is an inappropriate endpoint for NIV research in cancer patients because this approach does not address variation in opiate responsiveness, tolerance, and susceptibility to side-effects. Secondly, results of single-center clinical trials could reflect institutional biases about the timing and location of NIV delivery, both of which probably contribute to heterogeneous NIV outcomes [74,75]. Finally, NIV can cause complications (see list below) that undermine its intended purpose as a palliative measure [76]. Complications associated with NIV are as follows:

  1. facial skin breakdown;
  2. claustrophobia;
  3. aerophagia;
  4. aspiration;
  5. discomfort (mask, straps, and high pressure settings);
  6. increased dead space;
  7. dryness of mucous membranes;
  8. persistent leak.
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Although a number of diseases culminate in respiratory failure (Fig. 1), NIV has only been extensively studied in chest wall and NMDs, COPD, and cancer. Most of these investigations have focused on mortality as an endpoint rather than patient-reported outcomes and have been conducted in the ICU. Healthcare professionals rarely solicit perspectives on NIV from patients and families until a crisis forces the issue. Resources should be mobilized to explain this inertia; otherwise, we will have to question whether negative or equivocal results of NIV research are simply the consequences of waiting too long to discuss its implementation.

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The research reported in this publication was supported by The Dartmouth Clinical and Translational Science Institute, under award number UL1TR001086 from the National Center for Advancing Translational Sciences (NCATS) of the National Institutes of Health (NIH). The content is solely the responsibility of the author and does not necessarily represent the official views of the NIH. A.H.G. is supported by a Mentored Career Development Program Scholar Award from The Dartmouth Clinical and Translational Science Institute (KL2TR001088).

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Conflicts of interest

A.H.G. has received research support from Novartis Pharmaceuticals Corporation.

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Papers of particular interest, published within the annual period of review, have been highlighted as:

  • ▪ of special interest
  • ▪▪ of outstanding interest
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2▪. Simonds AK. Ethics and decision making in end stage lung disease. Thorax 2003; 58:272–277.

An excellent discussion of the ethical considerations in the use of NIV which emphasizes decision-making principles.

3. Mahler DA. Mechanisms and measurement of dyspnea in chronic obstructive pulmonary disease. Proc Am Thorac Soc 2006; 3:234–238.
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This is the only published study to provide detailed cost estimates associated with home NIV use by COPD patients.

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This registry-based study showed that NIV improved mortality in ALS patients at least 65 years old, although data on quality of life were not presented.

25. Mahajan KR, Bach JR, Saporito L, Perez N. Diaphragm pacing and noninvasive respiratory management of amyotrophic lateral sclerosis/motor neuron disease. Muscle Nerve 2012; 46:851–855.
26. Bach JR, Martinez D. Duchenne muscular dystrophy: continuous noninvasive ventilatory support prolongs survival. Respir Care 2011; 56:744–750.
27▪▪. McKim DA, Griller N, LeBlanc C, et al. Twenty-four hour noninvasive ventilation in Duchenne muscular dystrophy: a safe alternative to tracheostomy. Can Respir J 2013; 20:e5–e9.

Around-the-clock NIV delivered by mask at night and mouthpiece during the day was tolerated by a small cohort of patients with DMD. On the basis of this finding, the authors concluded that continuous NIV is a possible alternative to tracheostomy in this disease.

28. Toussaint M, Soudon P, Kinnear W. Effect of noninvasive ventilation on respiratory muscle loading and endurance in patients with Duchenne muscular dystrophy. Thorax 2008; 63:430–434.
29. Jackson CE, Rosenfeld J, Moore DH, et al. A preliminary evaluation of a prospective study of pulmonary function studies and symptoms of hypoventilation in ALS/MND patients. J Neurol Sci 2001; 191:75–78.
30. Lechtzin N, Scott Y, Busse AM, et al. Early use of noninvasive ventilation prolongs survival in subjects with ALS. Amyotroph Lateral Scler 2007; 8:185–188.
31▪▪. Radunovic A, Annane D, Rafiq MK, Mustfa N. Mechanical ventilation for amyotrophic lateral sclerosis/motor neuron disease. Cochrane Database Syst Rev 2013; 3:CD004427.

These authors call for further study of the health economics of NIV, including personal and socioeconomic factors associated limited access to this intervention.

32. Manning HL, Schwartzstein RM. Pathophysiology of dyspnea. N Engl J Med 1995; 333:1547–1553.
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This study demonstrated that many ALS patients with a forced vital capacity (FVC) greater than 50% experience clinically significant overnight oxyhemoglobin desaturation. The authors conclude that this FVC criterion is not appropriate to determine whether NIV should be instituted; rather, overnight oximetry is probably more helpful.

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A poignant reflection on the personal journey of a neurologist who developed ALS.

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This study refines our understanding of respiratory failure in cancer patients who are admitted to the ICU. Some of these processes would be expected to respond better than others to NIV. These insights may inform future clinical trials of NIV in this population.

49. Meert AP, Close L, Hardy M, et al. Noninvasive ventilation: application to the cancer patient admitted in the intensive care unit. Support Care Cancer 2003; 11:56–59.
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In this study of patients with hematologic malignancies complicated by severe hypoxic respiratory failure, NIV use within 24 h of ICU admission, compared with invasive positive pressure ventilation and supplemental oxygen, did not confer better outcomes.

65. Hampshire PA, Welch CA, McCrossan LA, et al. Admission factors associated with hospital mortality in patients with haematological malignancy admitted to UK adult, general critical care units: a secondary analysis of the ICNARC Case Mix Programme Database. Crit Care 2009; 13:R137.
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67▪▪. Nava S, Ferrer M, Esquinas A, et al. Palliative use of noninvasive ventilation in end-of-life patients with solid tumours: a randomised feasibility trial. Lancet Oncol 2013; 14:219–227.

This multicenter, randomized controlled trial investigated the feasibility of NIV as a palliative measure compared to oxygen in terminally ill patients with solid tumors and distress from acute respiratory failure. The effect of NIV on total morphine dose necessary to reduce dyspnea using the Borg scale was presented as a novel endpoint.

68. Azoulay E, Kouatchet A, Jaber S, et al. Noninvasive ventilation for end-of-life oncology patients. Lancet Oncol 2013; 14:e200–e201.
69. Fadul NA, El Osta B, Dalal S, et al. Comparison of symptom burden among patients referred to palliative care with hematologic malignancies versus those with solid tumors. J Palliat Med 2008; 11:422–427.
70. Piastra M, Antonelli M, Chiaretti A, et al. Treatment of acute respiratory failure by helmet-delivered noninvasive pressure support ventilation in children with acute leukemia: a pilot study. Intensive Care Med 2004; 30:472–476.
71. Depuydt PO, Benoit DD, Vandewoude KH, et al. Outcome in noninvasively and invasively ventilated hematologic patients with acute respiratory failure. Chest 2004; 126:1299–1306.
72▪▪. Azad A, Franco M. Noninvasive ventilation for end-of-life oncology patients. Lancet Oncol 2013; 14:e199–e200.

These authors contend that because Nava et al.[67▪▪] excluded patients if opioids had been used within 2 weeks of enrollment, the study has limited generalizability. Azad and Franco also point out that only hypercarbic patients derived benefit from NIV.

73. Kacmarek RM. Should noninvasive ventilation be used with the do-not-intubate patient? Respir Care 2009; 54:223–229.
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75. Wermke M, Schiemanck S, Hoffken G, et al. Respiratory failure in patients undergoing allogeneic hematopoietic SCT – a randomized trial on early noninvasive ventilation based on standard care hematology wards. Bone Marrow Transplant 2012; 47:574–580.
76. Gay PC. Complications of noninvasive ventilation in acute care. Respir Care 2009; 54:246–257.

amyotrophic lateral sclerosis; cancer; chronic obstructive pulmonary disease; dyspnea; noninvasive ventilation

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