Advanced Chronic Obstructive Pulmonary Disease

Advanced Chronic Obstructive Pulmonary Disease

By the year 2020, chronic obstructive pulmonary disease (COPD) will be the third leading cause of death globally Symptoms in late stages are often worse than those in patients with advanced lung cancer. In the United States, some 250,000 patients with advanced COPD die each year There are two key barriers between a diagnosis of advanced COPD and provision of quality end-of-life (EOL) care: (1) the highly unpredictable disease trajectory and (2) many patients and their caregivers fail to appreciate that COPD is a life threatening disease Episodic exacerbations and incomplete recovery challenge the timing of any supportive intervention in accordance with patients current needs In contrast to the needs-based care approach for patients with cancer, have demonstrated that hospitalized patients with advanced COPD are more likely to receive technological interventions (without establishing prior life support preferences). Moreover, they often die in an intensive care unit (ICU) setting, die with greater symptom burden, and with less input from other services.

 Arguably the greatest challenge to provision of EOL care in COPD is the unpredictable disease trajectory

 Exacerbations causing respiratory failure occur suddenly and unpredictably, and the outcome of those exacerbations is often determined by last-minute decisions regarding life support. This disease trajectory has two important implications;
First, it causes significant prognostication difficulties. Second, unexpected death at the time of an acute exacerbation generates signifi cant communication challenges.

The Study to Understand Prognosis and Preferences for Outcomes and Treatments (SUPPORT) enrolled seriously ill, hospitalised patients in one of five hospitals in the USA with one of nine life-limiting illnesses, including COPD. Compared with patients with lung cancer, patients with COPD were much more likely to die in the intensive care unit (ICU), on mechanical ventilation, and with dyspnoea. These differences occurred despite most patients with COPD preferring treatment focused on comfort rather than on prolonging life. In fact, SUPPORT found that patients with lung cancer and patients with COPD were equally likely to prefer not to be intubated and not to receive cardiopulmonary resuscitation (CPR), yet patients A study in the UK also found that patients with COPD are much less likely to die at home and to receive palliative care services than patients with lung cancer 12 with COPD were much more likely to receive these therapies. Additional studies have documented the poor quality of palliative care and significant burden of symptoms among patients with COPD 13. Healthcare for these patients is often initiated in response to acute exacerbations rather than being initiated proactively based on a previously developed plan for managing their disease 14. A recent study of patients with COPD or lung cancer in the US Veterans Affairs Health System also found that patients with COPD were much more likely to be admitted to an ICU, and have greater lengths of stay in the ICU during their terminal hospitalisation, than patients with lung cancer.

Other impediments to provision of effective palliative care for patients with advanced COPD include: patients limited understanding of treatment options barriers to effective communication due to attitudes of patients, physicians, and other caregivers our limited ability to judge when palliative care services may be helpful.

THE PROGRESSION OF ADVANCED COPD AND DETERMINING WHO NEEDS PALLIATIVE CARE

Prognoses for individual patients with COPD are notoriously inaccurate; only dementia has a less certain 6-month prognosis among the other 19 reasons for hospice referral in the United States The prognostic models used in SUPPORT, which were based on the Acute Physiology and Chronic Health Evaluation II, documented this difficulty. These models showed that, at 5days prior to death, patients with lung cancer were predicted to have <10% chance of surviving for 6months, while patients with COPD were predicted to have >50% chance. Recent efforts to identify disease-specific prognostic models for patients with COPD do improve prognostic accuracy, but do not predict individual short-term survival as well as can be done for many patients with cancer

Initiating EOLC discussions

Physicians should be encouraged to identify patients with COPD for whom discussions about treatment preferences or end-of-life care are especially important. Studies have shown that only a minority of patients with moderate-tosevere COPD have discussed treatment preferences and end-of-life care issues with their physicians and most believe that their physicians do not know their preferences for end-of-life care Improved communication regarding end-of-life care, prognosis and dying needs to be targeted

EOLC discussions
A recent study that examined the perspectives of pulmonologists on communication about end-of-life care for patients with COPD revealed the following;
When respirologists discussed mechanical ventilation for end-stage COPD, the discussions occurred late in the disease trajectory, most commonly taking place in the ICU, with only 23% occurring in the clinic or office It was found that 84% of physicians waited until dyspnea was severe and 75% waited until the FEV1 was <30% pred.

Initiating EOLC discussions

FEV1 <30% predicted Oxygen dependence One or more hospital admissions in the previous year for an acute exacerbation of COPD Left heart failure or other comorbidities Weight loss or cachexia Decreased functional status Increasing dependence on others Age >70yrs

Components of end-of-life care

Their diagnosis and disease process The role of the treatments in improving symptoms, quality of life and duration of life Their prognosis for survival and for quality of life What dying might be like Advance care planning for future medical care and exacerbations

Tips for talking about end-of-life care, prognosis and advance care planning
Initiating discussions about end-of-life care Frame this discussion as an important part of care for all patients with severe COPD Identify whether the patient or someone close to the patient has been seriously ill, whereby they were not able to make their own medical decisions, and use these situations to facilitate discussion Inquire as to whether a family member or other person should be present for the discussion Discussing prognosis Use ask-tell-ask to ask if patients are willing to discuss prognosis, then deliver prognosis, and then confirm understanding Use numeric expressions of risk rather than qualitative statements Frame prognosis as referring to groups of people rather than individuals Explicitly discuss uncertainty in prognostication

Discussing advance care planning

Frame as being important to hope for the best and prepare for the worst If appropriate, clarify that discussing advance care planning with the physician will not diminish the physician's focus on maximising the patient's survival Discuss particular importance of advance directives if patients have strong opinions about use of CPR, mechanical ventilation or other treatments Discuss importance of advance directives if patients have a preference for another person to make medical decisions for them if they are not able and, especially, if that preference does not match the default surrogate decision-maker according to local laws Identify whether there are specific health states that the patient would consider worse than death Explicitly discuss a commitment to nonabandonment Offer patients the opportunity to raise issues about their spirituality or religion that they would like their physicians to be aware of

Symptom prevalence in advanced COPD

Symptom Prevalence Breathlessness 60%88% Fatigue 68%80% Anxiety 51%75% Pain 34%77% Depression 37%71% Insomnia 55%65% Anorexia 35%67% Constipation 27%44%

Acute Dyspnea
For the assessment of levels of acute dyspnea in response to a stimulus such as exercise, several validated instruments are available. The two most commonly used are the visual analog scale (VAS) and the 0 to 10 category-ratio scale (CR-10). 8 Both scales provide descriptors at the ends of the scales as anchors (although a modified CR-10 exists without a ceiling). Use of the VAS requires patients to position their level of dyspnea on a line drawn between two descriptive anchors (e.g., no shortness of breath and maximal shortness of breath). The CR-10 provides numeric choices with corresponding verbal descriptors nonlinearly spaced between 0 and 10.

Chronic level of dyspnea

The Medical Research Council Questionnaire (MRC scale) is a discriminative 5-point scale of dyspnea (1-5 originally, 0-4 in the modified version) that assesses level of disability (e.g., activity limitation) related to dyspnea. The MRC dyspnea scale, particularly when incorporated into a multidimensional index of COPD disease severity such as BODE (a composite index that includes body mass index, airway obstruction, dyspnea, andexercise tolerance) has been demonstrated to better predict mortality and better correlate with health-related quality of life than the standard spirometry measurement of lung function impairment, forced expired volume in 1 second (FEV 1), alone. Two multidimensional dyspnea scales, the Baseline Dyspnea Index (BDI) and the Transition Dyspnea Index (TDI), are interviewer-administered questionnaires that rate initial level of dyspnea (BDI, discriminative) and change in dyspnea over time since baseline (TDI, evaluative). These two scales rate dyspnea in relation to functional impairment, magnitude of difficulty, and magnitude of effort performing daily activities.

Chronic level of dyspnea

The dyspnea domain of the Chronic Respiratory Disease Questionnaire (CRQ, a disease-specific, health-related quality of life instrument) is another well-validated scale that can be used as a discriminative and evaluative instrument to measure chronic levels of dyspnea during activities of daily living. Longer, interviewer-administered (e.g., patients select 5 daily activities from a menu of 25 choices that are most important to them) and standardized, short-form (e.g., activities are prechosen for patients) versions are available. Dyspnea is rated on a 7-point Likert scale for each of the 5 activities. This instrument has been shown to be responsive to change in level of dyspnea following treatment with medications and nonpharmacological interventions, such as pulmonary rehabilitation.

Outline of Therapy approaching EOL

Non Pharmacological Therapy

Reconditioning is central to the benefit provided by pulmonary rehabilitation programs (Lacasseet al 2006). In the end of life phase capacity for exercise reduces, and the four most common approaches are use of a fan, energy conserving measures, breathing techniques and relaxation strategies

Air Therapy
The flow of cool air through the nose, mouth or over the cheek can reduce the perception of dyspnea (Schwartzstein et al 1987; Liss and Grant 1988). It is believed that stimulation of nasal or pharyngeal mucosal receptors or facial receptors in the region of the trigeminal nerve leads to afferent information being projected to the sensory cortex where it alters the central perception of dyspnea. There is extensive anecdotal evidence that patients find benefit from use of a fan, or from standing by an open window. Even with end-stage disease, patients fi nd a small hand-held fan easy to use. It is a cheap piece of equipment that, unlike use of oxygen does not draw untoward There is, to date, only a small amount of research evidence examining the use of a fan (Booth et al 2006); further studies are known to be underway attention to its user, and has no adverse effects.

Energy conservation techniques

Energy conservation techniques reduce dyspnea by reducing demand for ventilation. Strategies include pacing activities, avoiding unnecessary activities, and rest periods or breathing stations during prolonged tasks (Carrieri and Janson 1986). A variety of recommendations have been published that help patients to complete activities of daily living with less effort (Carrieri-Kohlman and Stulbarg 2002). Possible techniques include sitting where possible, avoiding bending by arranging equipment closely and sliding or pushing items instead of lifting. There are no controlled studies evaluating such techniques; observational studies have described patient experiences (Brown et al 1986).

Breathing techniques
The aim of these techniques is to reduce respiratory rate and prolong expiration, while using a gently leaning forward posture that improves the mechanical efficiency of the diaphragm. The most commonly used position is one in which the patient leans forward and supports his/her weight with the armsupper body. Use of the leaning forward position has also been reported to improve inspiratory muscle strength (ONeill and McCarthy 1983) and diaphragmatic function (Sharp et al 1980), reduce the use of accessory muscles, and decrease abdominal breathing (Barach and Beck 1954; Barach 1974; Sharp et al 1980). PLB involves inhalation through the nose followed by a slow exhalation, usually 46 seconds, through pursed lips. It has been shown to decrease air trapping by stenting the airways and preventing dynamic airway collapse (Tiep et al 1986), thus lowering the demand for ventilation by reducing dynamic hyperinflation, which in turn increases tidal volume and improves carbon dioxide elimination (Belman et al 1996; ODonnell et al 2001). It often helps to avert panic attacks that accompany severe breathlessness (Madge and Edmond 2001).

Relaxation techniques
Relaxation techniques and training in anxiety reduction are particularly important with advanced disease. Anxiety increases breathlessness, which in turn contributes to the anxiety, leading to a deteriorating vicious circle (Bailey 2004). Various methods have been described, and techniques should be tailored and adapted for each individual. Methods include progressive muscular relaxation with systematic tensing and relaxing of all muscle groups, visualization and guided imagery, self-hypnosis and distraction by music (Walker 2004; Carrieri-Kohlman 2006). Renfroe (1988) found that taught relaxation techniques in ten COPD patients reduced anxiety more than in a control group that were told to relax without specific instructions. However, benefits were not maintained after the study, a finding confirmed in other studies (Gift et al 1992). Again this supports the view that such techniques should be continually practiced and should be taught well before the end of life phase in order to be of use when need arises.

NMES and Chest wall vibration

NMES over four to six weeks helps to relieve breathlessness in patients with COPD, which may be especially helpful for persons who are not capable of exercise. In accordance with the conclusions of Bausewein et al (44), the evidence supporting neuromuscular electrical muscle stimulation (NMES) is quite strong. All studies showed that NMES improved dyspnea, muscle strength and performance in daily tasks. Chest wall vibration is another nonpharmacological therapy that has strong supportive evidence for relief of breathlessness, although the chest wall vibration studies have only been tested in a laboratory setting. Although the exact process remains to be determined, the underlying mechanism of chest wall vibration is possibly related to the activation of muscle spindles in the intercostal muscles, with consequent modification of respiratory sensations.

Oral and parenteral opioids

The mechanism of action of opioids is poorly understood and these agents may act centrally, peripherally, or by reducing anxiety (Leach 2005). It is well known that opioids reduce ventilatory response to carbon dioxide (Eckenhoff and Oech 1960), hypoxia (Weil et al 1975; Santiago et al 1977), inspiratory flow-resistive loading (Kryger et al 1976), and exercise (Santiago et al 1979). Additionally, it is known that morphine decreases oxygen consumption both at rest and with exercise in healthy individuals (Santiago et al 1979). Most of the controversy revolves around safety concerns (predominantly respiratory depression) amidst the perception of inadequate evidence for the efficacy of opioids in relieving breathlessness in COPD (Pauwels et al 2001; Currow et al 2003) Two early studies with dihydrocodeine demonstrated decreased breathlessness with exercise as measured by well as increased exercise tolerance as measured by treadmill or pedometer in the absence of significant adverse effects (Woodcock et al 1981c; Johnson et al 1983). However, these early reports were followed by two negative studies that demonstrated signifi cant adverse effects and raised the issue of safety (Rice et al 1987; Eiser et al 1991).

 Jennings et al (2002) systematically reviewed all data on the use of opioids through 2001 in an attempt to evaluate the evidence as a whole.

Jennings et al (2002) concluded that there was a definite and highly statistically significant effect of oral or parenteral opioids on the sensation of breathlessness but that the clinical effect was relatively small (approximately 8 mm on a 100 mm VAS with baseline levels of dyspnea of 50 mm).
They gave several reasons for this small effect, including that the opioid doses were often small, doses were not titrated, dosing intervals were long, and single dose studies would not have achieved steady state. Additionally, their evaluation of the data did not suggest that the use of opioids was associated with changes in arterial blood gas measurements or oxygen saturation.

Meta-analysis demonstrated a highly statistically significant effect of oral and parenteral opioids on the sensation of breathlessness (overall pooled effect size 0.31, 95% confidence internval [CI] 0.50 to 0.13, p=0.0008). Exercise tolerance was a secondary outcome. Meta-analysis demonstrated a trend towards an improved effect on exercise tolerance, but the CI crossed zero (0.20, 95% CI 0.42 to +0.03, p not stated).

 The Poole et al (1998) study found no difference in QOL between treatment and placebo. Abernethy et al (2003) published results of a trial using oral morphine in opioid-nave adults with refractory dyspnea.
There was a significant decrease in dyspnea with morphine, with mean improvements in dyspnea intensity of 6.6 mm in the morning (p=0.011) and 9.5 mm in the evening (p=0.006). Relative improvement over baseline dyspnea was 15%22%. Morphine did not depress the respiratory rate (RR; mean RR for morphine vs placebo = 20 [SD 5] vs 21 [SD 4], p=0.143) and no episodes of severe sedation or obtundation were recorded. The main side-effect was constipation (9 vs 1, p=0.021), but neither treatment caused more vomiting, confusion, sedation, or appetite suppression. Those who received morphine also described better sleep at night (p=0.039) despite the fact that the medication was administered each morning.

Suggested protocol for opioid therapy

Initiate opioid therapy with oral immediate-release morphine syrup titrate slowly at weekly intervals over a 4- to 6-week period Start therapy with morphine 0.5 mg orally twice daily for 2 days, and then increase to 0.5 mg orally every 4 h while awake for remainder of week 1 If tolerated and indicated, increase to morphine 1.0 mg orally every 4 h while awake in week 2, increasing by 1.0 mg/week or 25% dosage increments/week until the lowest effective dose that appropriately manages the dyspnea is achieved Once a stable dosage is achieved (ie, no significant dose change for 2 weeks and dyspnea managed), a sustained-release preparation at a comparable daily dose could be considered for substitution If patients experience significant opioid-related side effects such as nausea or confusion, substitution of an equipotent dose of oral hydromorphine could be considered (1 mg hydromorphine = 5 mg morphine) Stool softeners and laxatives should be routinely offered to prevent opioid-associated constipation

Nebulized opioids
The role of nebulized opioids in the management of refractory dyspnea has also been studied. The mechanism by which these agents may act is currently unclear but it has been proposed that there may be a direct local effect on peripheral neural receptors in small airways. Much like the data with oral opioids, the studies are small and the results inconsistent. However, on the whole, the majority of studies failed to demonstrate a benefit, as reported by Jennings et al (2002) in their meta-analysis. At this point, we do not feel that there is adequate evidence to support the use of nebulized opioids in the treatment of refractory breathlessness. Since the size of nebulized droplets is crucial for the activity of inhaled opioids, in the future, newer methods of microdroplet delivery of opioids may result in rapid systemic effects and improved efficacy of this method of drug delivery.

Benzodiazepines
Diazepam was initially reported to be beneficial by Mitchell-Heggs et al (1980) when they published the results of an exploratory study in four patients. However, these results could not be replicated in two subsequent studies (Woodcock et al 1981a; Sen et al 1983) which also raised the issue of safety. Several other investigators chose to re-look at the use of benzodiazepines but with alprazolam, a shorter-acting and potentially less-sedating medication. In one controlled study (Man et al 1986), the investigators found no improvement in breathlessness. However, a benefit was found in a subsequent single case report (Greene et al 1989).

Anxiolytics
Buspirone, a serotonergic anxiolytic agent, has been shown to be a respiratory stimulant in animals (Garner et al 1989; Mendelson et al 1990). Two small studies (Argyropoulou et al 1993; Singh et al 1993) evaluated the effects of buspirone on breathlessness, exercise tolerance, and anxiety in patients with severe COPD. These studies included slightly different patient populations in that Singh et al (1993)required baseline anxiety as measured by the Speilberger State-Trait Anxiety Inventory Scale (STAI) for study enrollment and Argyropoulou et al (1993) did not require any baseline anxiety assessment. The results of the studies conflicted with those of the Argyropoulou et al (1993) study documenting improvement in all three domains and the other study finding no difference. Taken together, these data, while inconsistent, suggest that there may be a role for anxiolytic agents in selected patients with refractory dyspnea.

Phenothiazines
One early study comparing diazepam and promethazine reported increased exercise tolerance and decreased breathlessness with promethazine (Woodcock et al 1981a) but these results were not supported by a subsequent study (Rice et al 1987). Additionally, the Rice et al (1987) study raised concerns about side-effects, including increases in PaCO2 and drowsiness. Light et al (1996) evaluated both promethazine and prochlorperazine in combination with morphine in a double-blind, placebo-controlled study
Morphine and promethazine in combination increased exercise tolerance compared with placebo Morphine and prochlorperazine had a large negative effect on patients mental status while morphine and promethazine produced effects no different from placebo or morphine alone. The increased exercise tolerance seen with the combination of morphine and promethazine was due to a decreased level of dyspnea at a given workload despite the fact that there was no significant difference in Borg scores. Available data, therefore, do not support the routine use of phenothiazines in the management of refractory dyspnea, referring to the beneficial effect of morphine instead.

SSRIs
Smoller et al (1998) reported a case series of seven patients with obstructive lung disease treated with sertraline by their pulmonologists.
All patients reported a decrease in breathlessness and several also reported improvements in exercise tolerance. It is not clear whether SSRIs improve dyspnea and exercise tolerance by relieving anxiety symptoms or by direct effects on respiration.

Many patients with dyspnea out of proportion to their pulmonary compromise experience depression and/or anxiety and there are data to suggest that treatment of these symptoms relieves dyspnea (Burns and Howell 1969). However, there are also animal data suggesting that serotonin acts at the level of the brainstem respiratory center and it may be this action that affects the sensation of dyspnea (Mueller et al 1982). There have been no subsequent studies of SSRIs and currently there is no substantive evidence on which to recommend their use in COPD patients with refractory dyspnea in the absence of an underlying psychiatric indication.

Inhaled furosemide
The rationale behind the use of furosemide includes its inhibitory effect on the cough response induced by low chloride content solutions (Ventresca et al 1990) and a preventive effect of furosemide on bronchoconstriction in asthma (Bianco et al 1988, 1989; Robuschi et al 1989). Inhaled furosemide may also act indirectly on vagally mediated sensory nerve ending in airway epithelium (Chung and Barnes 1992). In healthy subjects, inhaled furosemide has prolonged breath-holding time and the period of no respiratory sensation and has also slowed the development of discomfort during loaded breathing (Nishino et al 2000). A randomized study evaluated the effects of inhaled furosemide vs placebo in exercise-induced dyspnea (as assessed by VAS) with moderate to severe COPD (FEV1 <70%) and moderate-to-severe chronic breathlessness (Ong et al 2004).
Mean dyspnea VAS scores after exercise were lower after inhalation of furosemide (34mm [SD 25] vs 42 [SD 24], p=0.014). Exercise-related FEV1 and FVC also improved after furosemide inhalation (p=0.038 and 0.005, respectively) but not after placebo. Interestingly, no increase in exercise endurance time was noted.

Heliox28
A Phase II crossover study assessed the palliative role of Heliox28 in 12 lung cancer patients with refractory dyspnea (Ahmedzai et al 2004).
The VAS measurements were significantly lower when comparing Heliox28 with medical air (40.2% [SD 4.8] vs 59.3% [SD 5.3], p<0.05) but there was no significant difference between Heliox28 and oxygen (47.0% [SD 5.6]) or between oxygen and medical air. There were also no significant differences in Borg scores. Patients walked farther breathing Heliox28 than breathing oxygen (214.2 m [SD 9.6] vs 174.6 m [SD 11.2], p<0.05) or medical air (128.8 m [SD 10.3], p<0.0001).

The use of Heliox28 in the management of COPD has been explored (Grape et al 1960; Ishikawa and Segal 1973; Jaber et al 2000) but there are no studies evaluating its use in patients with COPD and refractory dyspnea. The results obtained by Ahmedzai et al (2004) suggest that further investigation of Heliox28 in the therapy of COPD patients with refractory dyspnea may be warranted