Whose advance directives are they, after all?

Comment

seasonal influenza virus strains, although their clinical efficacy, safety, cost-effectiveness, production capacity, and stockpiling potential remain to be established. In the meantime, the present study provides impetus to identify whether and under what conditions influenza immune plasma and hyperimmune globulin can benefit patients. Dorothy Scott, Jay S Epstein, *Frederick G Hayden Center for Biologics Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA (DS, JSE); Division of Infectious Diseases and International Health, University of Virginia School of Medicine, Charlottesville, VA 22908, USA (FGH) [email protected] DS’s research group is working on a label-free, virus-free, solid phase assay to measure and quantitate influenza hemagglutinating antibodies in serum and plans to submit an employee invention report for patentability and commercial utility. FGH has been a non-paid consultant to several companies (GlaxoSmithKline, Janssen of Johnson & Johnson, MedImmune, Medivector of Fujifilm, Sanford Applied Biotherapeutics, Shionogi, and Visterra) involved in development of influenza antivirals or therapeutics including antibodies. This Comment reflects the views of the authors and should not be construed to represent the US Food and Drug Administration’s views or policies. JSE declares no competing interests. 1

Luke TC, Kilbane EM, Jackson JL, Hoffman SL. Meta-analysis: convalescent blood products for Spanish influenza pneumonia: a future H5N1 treatment? Ann Intern Med 2006; 145: 599–609.

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Hung IF, To KK, Lee CK, et al. Convalescent plasma treatment reduced mortality in patients with severe pandemic influenza A (H1N1) 2009 virus infection. Clin Infect Dis 2011; 52: 447–56. 3 Mair-Jenkins J, Saavedra-Campos M, Baillie JK, et al, for the Convalescent Plasma Study Group. The effectiveness of convalescent plasma and hyperimmune immunoglobulin for the treatment of severe acute respiratory infections of viral etiology: a systematic review and exploratory meta-analysis. J Infect Dis 2015; 211: 80–90. 4 Wu XX, Gao HN, Wu HB, Peng XM, Ou HL, Li LJ. Successful treatment of avian-origin influenza A (H7N9) infection using convalescent plasma. Int J Infect Dis 2015; 41: 3–5. 5 Beigel JH, Tebas P, Elie-Turenne M-C, et al. Immune plasma for the treatment of severe influenza: an open-label, multicentre, phase 2 randomised study. Lancet Respir Med 2017; published online May 15. http://dx.doi.org/10.1016/ S2213-2600(17)30174-1. 6 Hung IF, To KK, Lee CK, et al. Hyperimmune IV immunoglobulin treatment: a multicenter double-blind randomized controlled trial for patients with severe 2009 influenza A(H1N1) infection. Chest 2013; 144: 464–73. 7 American Association of Blood Banks. Circular of information for the use of blood and blood components, pp 16–18. https://www.aabb.org/tm/coi/ Documents/coi1113.pdf (accessed April 9, 2017). 8 El-Ekiaby M, Vargas M, Sayed M, et al. Minipool caprylic acid fractionation of plasma using disposable equipment: a practical method to enhance immunoglobulin supply in developing countries. PLoS Negl Trop Dis 2015; 9: e0003501. 9 Kreil TR, McVey JK, Lei LS, et al. Preparation of commercial quantities of a hyperimmune human intravenous immunoglobulin preparation against an emerging infectious disease: the example of pandemic H1N1 influenza. Transfusion 2012; 52: 803–09. 10 Sparrow E, Friede M, Sheikh M, Torvaldsen S, Newall AT. Passive immunization for influenza through antibody therapies, a review of the pipeline, challenges and potential applications. Vaccine 2016; 34: 5442–48.

TEK Image/Science Photo Library

Whose advance directives are they, after all?

For more on end of life care see Spotlight page 473

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Living wills and related documents, collectively termed advance directives, arose in the USA in the 1970s. These documents represented, among other things, a hope that the individual’s voice could be heard during a medical emergency. The advent of life-support technologies— especially advanced cardiac life support and mechanical ventilation—and increasing skepticism that the medical establishment had the patients’ best interests at heart had created a crisis. Death could be deformed and patients’ voices stilled.1 Advance directives aspired to solve that crisis. In practice, though, living wills have been disappointing. Their numerous flaws are well known. They rely on impossible prognostic accuracy and an inaccurate understanding of human psychology and the nature of life-threatening illness.2,3 The evidence marshalled in their defense is of low quality; if living wills were pharmaceuticals, they would never gain regulatory approval.3,4 What worries me here is a distinct concern: advance directives might, paradoxically, drown out patients’ voices. Many considerations have framed advance directives. Worry about strain on the economy—sometimes coupled

with disability stigma—saw living wills as mechanisms to conserve precious resources. Conflicts within America’s socalled culture wars dominated many discussions. Advance directives became arguments in societal controversies about abortion, euthanasia, and the meaning of life. At a practical level, the clinicians whose predictions activate advance directives fell prey to pseudo-empathy, which worsened inherent prognostic inaccuracies.2 The traditional focus on informed consent subtly, but powerfully, drew the focus onto specific procedures (relevant to clinicians) rather than the trajectories and experience of illness (relevant to patients). These factors have derailed the noble aspiration of living wills: that medical care during life-threatening illness be personalised. The clinician focus of advance directives is fundamentally misguided. It is time for replacements that reflect patients’ perspectives (figure). For example, take cardiopulmonary resuscitation (CPR), the most dramatic and obvious of the life-support technologies forsworn in advance directives. Since 1991, patients admitted to US hospitals have been asked for advance directives regarding CPR, the notorious code www.thelancet.com/respiratory Vol 5 June 2017

Comment

Clinicians

Policymakers

Patients

Possible perspectives • 7–9 failed episodes of CPR per success is discouraging • Failed CPR feels brutal • Chronic critical illness and disability feel like failure • Clinicians should be careful stewards of resources • Patients and families are in denial about death; it’s a fact of life

Possible perspectives • People near death or with chronic critical illness consume substantial resources • The morality of life or death decisions is important • Older people owe a debt to younger people to limit resource use

Possible perspectives • I only experience the one episode of CPR • If I’m dying, I want to know that and be supported • Time awake and with loved ones is precious to me • While I don’t want to be disabled, it’s not worse than death

Possible questions • How do we limit expensive treatment in the last year of life? • How do we assure success for a given stance in culture wars?

Possible questions • How will I know it’s my time to die? • Who will be with me when I die? • What will dying be like? • Will my family be supported? • How will I be supported during recovery?

Possible questions • Can I stop treatment? • What does successful CPR look like?

Figure: Perspectives and questions for advance directives CPR=cardiopulmonary resuscitation.

status. Clinician perspectives have dominated these conversations. The influential (and negative) SUPPORT trial5 used Do Not Resuscitate (DNR) orders, rather than a patient-centered outcome, as its main outcome, academics complain that television portrays CPR as too successful,6 and videos are now used to persuade people to refuse CPR, independent of life situation.7 But at least half of DNR orders do not reflect the patient’s actual priorities.8 Commonly, patients intend their DNR order to reject life in a permanent vegetative state, which only applies to a small subset of patients after cardiac arrest. As a procedure, CPR is actually one of medicines’ more effective treatments, with a number needed to treat of 2·5–12, depending on the rhythm.9 Many patients would want CPR at those odds, as long as they are not forced into a vegetative state or believe that their life is already near its end. In my experience, most people prefer a trial of resuscitative efforts, with a quick transition to endof-life care if the resuscitation did not result in neurological recovery. One need not be in pathological denial of death to desire such a rescue option. Why then do we clinicians ask people to refuse this specific medical miracle? I believe we clinicians encourage people to refuse resuscitation for three primary reasons. First, CPR will often deform a dying process already underway, regardless of efficacy. Second, clinicians might endorse a false dichotomy—reject CPR or experience a permanent vegetative state afterwards. Finally, clinicians might find CPR brutal, with too many unsuccessful CPR attempts for a single recovery. A focus on clinicians’ ideas about a specific procedure distracts them from the patient and their individual trajectory. Questions about CPR are primarily relevant when death is independently likely. But if life is near its end, that fact is vastly more important than technical www.thelancet.com/respiratory Vol 5 June 2017

questions about chest compressions. By framing the conversation as procedural consent for future CPR, we clinicians might keep a secret (that death is near) even as we think we’ve divulged that very secret. Our priority should not be to restrict specific procedures, but to assure that the support—both medical and non-medical— for those with life-threatening illness honours their personhood. That is the patient-centred goal. I propose that we reboot advance care planning as conversations about personalised care during serious illness (PCSI).2 Because living wills require impossible prognostic certainty, we ought not emphasise future hypotheticals. Instead, we should alert people to socalled clinical crossroads at which concrete medical decisions might shape the final weeks and months of life. A pacemaker or renal dialysis in a frail, elderly patient or prolonged mechanical ventilation for a person with advanced cancer might represent clinical crossroads. People might choose hospice or a do-not-hospitalise status rather than life-support therapy at this crossroads, focusing on living well with what time remains. They might feel that their life will conclude better without artificial supports. For some patients, an Intensive Care Unit stay is the crossroads, at which they will reject a suite of related procedures and avoid inappropriate admission. They might instead choose hospital admission only for easily treatable conditions, with personal preparation for death at home for serious conditions. At clinical crossroads, both medical questions and many personal tasks relevant to the end of life are important.10 Crucially, PCSI attends to life completion tasks and deathbed rituals when the end of life is near, focusing on hoping for the best while preparing for the worst. Because saying goodbye is central to the deathbed, I encourage tender words (a going off to war talk) before 465

Comment

intubation for potentially fatal respiratory failure or highrisk surgery to avoid stealing last words from patients.2 In my experience, being open about mortality and preparing for that possibility together makes time-limited trials of life support and earlier transitions to end-of-life care more natural. In my experience, having completed endof-life tasks limits regrets that might motivate prolonged life support before death. When the framing shifts from clinician to patient, many new patterns of support become available. It’s time for critical care medicine to move toward the meaningful goal: care during life-threatening illness that is deeply personalised to the person whose life is threatened. Samuel M Brown Intermountain Medical Center, Pulmonary and Critical Care Medicine and Center for Humanizing Critical Care, Shock Trauma ICU, Murray, UT 84157, USA [email protected]

The author declares no competing interests. 1

Callahan D. The troubled dream of life: in search of peaceful death. New York, NY: Simon and Schuster, 1993. 2 Brown SM. Through the valley of shadows: living wills, intensive care, and making medicine human. New York, NY: Oxford University Press, 2016. 3 Fagerlin A, Schneider CE. Enough. The failure of the living will. Hastings Cent Rep 2004; 34: 30–42. 4 Silveira MJ, Kim SY, Langa KM. Advance directives and outcomes of surrogate decision making before death. N Engl J Med 2010; 362: 1211–18. 5 The SUPPORT Principal Investigators. A controlled trial to improve care for seriously ill hospitalized patients. The study to understand prognoses and preferences for outcomes and risks of treatments (SUPPORT). JAMA 1995; 274: 1591–98. 6 Diem SJ, Lantos JD, Tulsky JA. Cardiopulmonary resuscitation on television. Miracles and misinformation. N Engl J Med 1996; 334: 1578–82. 7 El-Jawahri A, Podgurski LM, Eichler AF, et al. Use of video to facilitate end-of-life discussions with patients with cancer: a randomized controlled trial. J Clin Oncol 2010; 28: 305–10. 8 Jesus JE, Allen MB, Michael GE, et al. Preferences for resuscitation and intubation among patients with do-not-resuscitate/do-not-intubate orders. Mayo Clin Proc 2013; 88: 658–65. 9 Girotra S, Nallamothu BK, Spertus JA, et al. Trends in survival after in-hospital cardiac arrest. N Engl J Med 2012; 367: 1912–20. 10 Byock I. Dying well: peace and possibilities at the end of life. New York, NY: Riverhead, 1997.

Clinical trial research in focus: time to reflect on the design of exacerbation trials in COPD Jamie Kripke, MINT IMAGES/Science Photo Library

Exacerbations of respiratory symptoms occur frequently and are responsible for much of the morbidity associated with chronic obstructive pulmonary disease (COPD).1 Not all patients with COPD experience exacerbations, but some patients experience frequent exacerbations of their disease.2 One of the main goals of COPD management is to reduce exacerbations, and several drugs have been shown to reduce the number of exacerbations in patients at risk.1 Most of the evidence base for reducing the risk of exacerbations comes from carefully planned efficacy trials in narrowly defined populations, with the 2016 effectiveness trial, The Salford Lung Study, as a notable exception.3 A closer understanding of the evidence base for risk reduction might be required since exacerbation trials have been very carefully designed to maximise the odds of a successful outcome for the drug or drug combination under study, be it an anti-inflammatory drug or a regimen of combined bronchodilators. The full effect of these changes in design might not be obvious, fully acknowledged, or understood. We believe that most clinicians are unaware of how trials might have been engineered to deliver their aims, and that the evidence 466

base in guidelines on which clinicians make decisions might not be relevant to the patients they are caring for. Trials in COPD did not focus on exacerbations as an outcome until the Inhaled Steroids in Obstructive Lung Disease in Europe (ISOLDE) study.4 In this trial, the primary outcome was not met as patients receiving the inhaled corticosteroid, fluticasone propionate, had a decline in FEV1 that did not differ from that seen in the placebo group. However, a change in severity of exacerbations was seen and this observation initiated numerous large studies with exacerbations as primary outcome, examining both inhaled corticosteroids and long-acting bronchodilators. In virtually all subsequent trials, the exacerbations have been defined on the basis of healthcare use, with moderate exacerbations being defined as those events managed with systemic corticosteroids or antibiotics, or both, and severe exacer­bations defined as events requiring hospital admission. In several trials,5 inhaled corticosteroids tended to show greater efficacy in preventing exacerbations that patients’ clinicians would have treated with systemic corticosteroids, compared with all exacerbations www.thelancet.com/respiratory Vol 5 June 2017