Best Practice & Research Clinical Anaesthesiology 27 (2013) 527–543

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Intensive care for the cancer patient – Unique clinical and ethical challenges and outcome prediction in the critically ill cancer patient Timothy James Wigmore, FRCA, FFICM, FCICM, Consultant in Anaesthesia and Intensive Care a, *, Paul Farquhar-Smith, FRCA, PhD, FFPMRCA, FCICM, Consultant in Anaesthesia, Pain Medicine and Intensive Care a, Andrew Lawson, FFARCSI, FANZCA, FRCA, FFPMRCA, MSc, Hon Senior Lecturer b a b

Royal Marsden Hospital, Fulham Rd., London SW3 6JJ, UK Medical Ethics Unit at Imperial College School of Medicine, Exhibition Rd., London SW7 2AZ, UK

Keywords: critical care intensive care bone marrow transplant HSCT solid tumour haematological tumours

With the rising number of cancer cases and increasing survival times, cancer patients with critical illness are increasingly presenting to the intensive care unit. This article considers the unique challenges they pose in terms of oncological-specific disease processes and treatment and reviews current trends in outcome prediction. We also consider the ethical standpoints surrounding the treatment of patients for whom there may be no cure and their subsequent transition to palliative care, should it become necessary. Ó 2013 Elsevier Ltd. All rights reserved.

There were 12.7 million new cancer cases worldwide in 2008 [1] and there are predicted to be 22.2 million new cases annually by 2030 [2]. Cancer is now the major cause of death in the developed world. At the same time, survival times for patients with cancer are improving resulting in a higher number of patients presenting with cancer to hospitals for a longer period of time. This inevitably leads to an increase in demand for intensive care unit (ICU) resources, be it for complications of the disease, of treatment or of co-morbidities.

* Corresponding author. Tel.: þ44 7843106987. E-mail addresses: [email protected], [email protected] (T.J. Wigmore). 1521-6896/$ – see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.bpa.2013.10.002

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There was a time when the onset of critical illness resulted in the almost inevitable demise of a patient with cancer either because of the refusal for admission to ICU that it engendered or because of the inability to treat the underlying cause of the critical illness (often sepsis in the immunosuppressed). However, a combination of drug development, improvements in general intensive care and the publication of data from leading providers showing that good outcomes can be achieved have led to significant change. The overall survival rates for patients with cancer admitted to ICU now approach those of the general population and just as with other patients, it is the severity of physiological derangement at the point of referral and in the subsequent hours and days that has the biggest impact on ICU survival/outcome. That said, ‘cancer’ is a very broad term, representing a number of heterogeneous diseases with very different natural histories and consequent prognoses, and this is reflected in the breakdown of survival rates. Patients with solid tumours generally fare better than those with liquid (predominantly haemato-oncological) tumours, although the latter have also recently experienced similar proportionate improvements in outcomes. Despite these improvements, cancer patients can present unique challenges, the nature of which depends on their tumour type and often on the treatment they have received as a consequence. Cancer treatment and its implications The treatment of cancer can be roughly divided into chemotherapy, radiotherapy or surgery, with many patients receiving a combination of all three. Solid tumour patients, whose mode of presentation to ICU is often following major surgery, may have received neo-adjuvant chemoradiotherapy administered to render the tumour resectable, whilst haemato-oncology patients will commonly present to ICU having had chemotherapy and radiotherapy to induce remission or to ablate their bone marrow prior to stem cell transplantation. Chemotherapeutic agents are generally unselective in their mode of action and affect rapidly dividing cells in particular and hence have effects on the gut, marrow and skin. In addition, they may have organ-specific effects resulting in characteristic toxicity that may result in admission to ICU. Examples include the anthracyclines, doxorubicin and idarubicin that cause acute and chronic (dose-related) cardiotoxicity as does cyclophosphamide. The alkylating agent ifosfamide causes neurotoxicity that presents as an encephalopathy and is thought to be secondary to ifosfamide metabolites (chloracetaldehyde or dicarboxylic acid). It responds to treatment with methylene blue [3]. Bleomycin (an antibiotic derivative) is widely used against squamous cell carcinomas, germ cell tumours (e.g. teratomas) and cancers of the cervix and causes a dose-related pneumonitis/alveolitis in up to 40% of patients due to the generation of oxygen free radicals [4]. All-trans retinoic acid (ATRA) is used in the treatment of acute promyelocytic leukaemia (APML) and can cause differentiation syndrome (previously known as retinoic acid syndrome), a life-threatening constellation of dyspnoea, weight gain and oedema, cardiac and hepatic impairment and renal failure due to a cytokine storm, endothelial injury and microvascular leak. Treatment is with steroids and the withdrawal of the ATRA [5]. Chemotherapy treatment has been revolutionised in recent years by the development of monoclonal antibodies whose action is targeted against tumour-specific ligands or against growth factors, but even in this case they are often not without toxicities. Examples include trastuzumab (Herceptin) which can cause myocardial stunning in a non-dose-dependent fashion that can result in cardiac failure [6]. Bevacizumab (Avastin) is used against non-small-cell lung cancer and colonic cancer and acts by inhibiting vascular endothelial growth factor (VEGF), effectively not only depriving cancers of their blood supply but also risking gastrointestinal (GI) tract perforation [7]. Tyrosine-kinase inhibitors such as sorafenib and sunitinib commonly cause cardiovascular system side effects, including hypertension, myocardial ischaemia and myocardial dysfunction, again because of their effect on angiogenesis and microvascular endothelial function [8]. Radiotherapy is often used in concert with chemotherapy and it causes tissue damage through the production of oxygen free radicals. It can cause both pneumonitis and pericarditis with subsequent lung and myocardial fibrosis, but the context in which it most usually results in an admission to ICU is when total body irradiation is used as part of a myeloablative regime prior to performing a stem cell transplant. Intentional bone marrow failure follows, with the potential for neutropenic sepsis.

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Oncological emergencies Disease or treatment can result in oncology-specific emergencies requiring admission to ICU.  Superior mediastinal syndrome Thymomas, lymphomas (particularly non-Hodgkins), germ cell tumours, sarcomas and lung and breast tumours can all cause compression of the superior/anterior mediastinum with potential for airway and great vessel obstruction [9]. Often the presentation is acute but if a computed tomography (CT) or magnetic resonance imaging (MRI) is available, a reduction in cross-sectional diameter of >50% predicts airway complications [10,11]. Undertaking cross-sectional imaging once the patient is symptomatic is fraught with risk, but if necessary the risk can be reduced by keeping the patient 20–30 head up, or in the lateral or prone positions. Subsequent induction of anaesthesia may lead to airway collapse due to loss of smooth muscle tone in concert with increased central blood and tumour volume (the latter due to their often vascular nature). Intubation may also precipitate cardiovascular collapse secondary to superior vena cava (SVC) or pulmonary vessel compression. The risk of both is worsened with neuromuscular blockade, which should be avoided if possible. Gaseous induction with maintenance of spontaneous ventilation, or an awake fibre-optic intubation if circumstances permit is preferable. If there is a genuine possibility of complete airway obstruction occurring, then the establishment of veno–veno bypass via the femoral route prior to induction provides a way of maintaining oxygenation and perfusion, should that eventuality transpire. It should also be noted that vessel compression will slow passage of drugs administered via vasculature in the upper body and it is therefore advisable to obtain access in the lower half of the body [12,13].  SVC compression Whilst this may occur as part of superior mediastinal syndrome, it often occurs in isolation. The severity of symptomatology depends on the rapidity of its onset (as collaterals often develop in cases that have gradual onset), but it commonly presents with facial and arm swelling, dysphagia and dyspnoea. At the more extreme end of the spectrum, patients may present with stridor and also have cerebral oedema, with consequent decreased consciousness [14]. Management in this setting is generally done with endovascular stenting [15]. Steroids are only indicated if the tumour is steroid sensitive (as with most lymphomas). Radiotherapy, whilst effective in radiosensitive tumours, may take weeks to have an effect [16].  Tumour lysis syndrome Tumour lysis results from the lysis of large numbers of tumour cells, typically in the context of chemoand radiotherapy for bulky tumours such as leukaemias, lymphomas and occasionally solid tumours such as breast and small-cell lung cancer. Subsequent cell death results in the release of intracellular contents and a characteristic combination of metabolic abnormalities: Hyperkalaemia, hypophosphataemia, hypocalcaemia and hyperuricaemia. The last results in the deposition of uric acid crystals in the distal renal tubules and a consequent nephropathy. At-risk patients are commonly administered prophylactic rasburicase (recombinant urate oxidase, which catalyses the production of water-soluble allantoin from insoluble uric acid) in advance of chemotherapy [17]. Allopurinol, a xanthine oxidase inhibitor, is an alternative, but it leads to xanthinuria, which itself is a potential cause of renal failure and is slower to reduce uric acid concentrations [18]. Treatment, should the tumour lysis syndrome occur, is with rasburicase, fluid hydration and renal replacement therapy (RRT) if required. Hypocalcaemia should not be treated unless symptomatic due to the risk of precipitation of calcium phosphate within the renal tubules.  Cardiac tamponade Tamponade can result from (usually rapidly accumulating) pericardial effusions from either local metastasis or lymph node obstruction and is most often seen with breast and lung cancers or with lymphoma. Management is as per that in any other setting.

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 Electrolyte disorders Electrolyte disorders, due to chemotherapy treatment with subsequent diarrhoea or renal dysfunction or paraneoplastic disorders, are relatively common in oncology patients. Hyponatraemia as a result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH) occurs either as part of a paraneoplastic disorder (typically with small-cell lung cancer although other tumours can also be responsible) or with treatment with ifosfamide, vincristine, vinblastine or cyclophosphamide. That with cyclophosphamide may be exacerbated by the concurrent use of fluid loading to reduce the risk of haemorrhagic cystitis [19]. Sodium levels of 10 mmHg is diagnostic. Liver biopsy is also diagnostic, although associated with a high risk of haemorrhage. The management of hepatic SOS has been revolutionised with defibrotide (an anti-thrombotic and fibrinolytic agent) which is used both prophylactically and as treatment [33].  Engraftment syndrome More frequent in autologous than in allogeneic HSCT (7–10% vs. 24 h after autologous HSCT were discharged from hospital but the presence of concurrent hepatic and renal failure, lung injury and inotrope use reduced this figure to 6% [74]. Outcomes are worse for those with allografts, but one way to ameliorate the risk of complications for those patients is to reduce pre-transplant myoablative conditioning which confers a definite survival advantage [75].  Mechanical ventilation The requirement for mechanical ventilation indicates one major organ failure and is one of the most robust predictors of a poor ICU outcome for solid cancer [76,77] and for haematological malignancy patients [54,75–77]. Requiring ventilation for >24 h has been used as a more discerning outcome [76]. Table 3 In-hospital mortality in haematological malignancy. Year

Mortality

Reference

1988 1991 2002 2006 2008 2009 2011

78% 77% 66% 58% 55% 58% 46%

Lloyd-Thomas [61] Yau [62] Maisson [58] Lamia [63] Cuthbertson [64] ICNARC (Hampshire) [65] Bird [56]

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The accuracy of outcome prediction enhancement after a period of intensive care management is discussed later. Non-invasive ventilation (NIV) may be a strategy that mitigates the impact of respiratory failure on outcome. Azoulay, in a retrospective study of 237 cancer patients, suggested that NIV might be protective of death demonstrated with an ICU mortality of 44% in those who received NIV compared to 71% in those who did not [29]. However, others have failed to replicate such an advantage. In 166 patients with haematological malignancies, NIV and invasive ventilation were associated with identical outcomes and endotracheal intubation within 24 h of admission to the ICU was actually associated with reduced mortality [60]. Patients for whom NIV is sufficient may have less lung injury than those who subsequently require invasive ventilation. Therefore, the survival advantage may be related to severity of lung failure rather than the NIV per se. Indeed, a more recent study found that the type of ventilation had no impact on the risk of death in patients with hypoxic respiratory failure [78]. Moreover, in 1302 haematological cancer patients, although NIV improved outcome, mortality was significantly increased when invasive ventilation was required after failure of NIV [79]. Several factors including respiratory rate, delay in commencing NIV, RRT and vasopressor requirement can predict failure of NIV and thus can indicate the optimal timing for invasive ventilation [80]. The imperative for timely ventilatory therapy (whatever mode) is paramount as those patients with respiratory failure whose admission to ICU was delayed for >2 days were independently associated with 28-day mortality [81].  Neutropenia Neutropenia is an intuitive and often quoted risk factor for death in cancer patients [82]: however, others have failed to establish the link between low neutrophil count and outcome [21]. The presence of neutropenia may interact with other factors such as need for invasive ventilation care which dictates a poor prognosis [83]. Nevertheless, even septic shock in cancer patients may not be influenced directly by neutropenia [84]. A multicentre investigation of 717 consecutive cancer patients admitted to the ICU failed to link neutropenia with mortality [77]. Using a different methodology of a matched case–control study, neither neutropenia nor prior chemotherapy had a significant effect on outcome but severity of physiological derangement and organ failure were associated with increased mortality [85].  Renal replacement therapy RRT is associated with higher mortality in non-cancer ICU patients [86]. Cancer patients in ICU have many other reasons for developing ARF in addition to those aetiologies common in the ICU [87]. Requirement for RRT adds to organ failure scores (and RRT with other organ failures worsens prognosis) [43,88]. However, as an independent risk factor the situation is more opaque. In 975 patients on ICU with cancer and renal dysfunction, starting RRT on day 1 of ICU care inferred a lower mortality than RRT commenced any time later [88]. A smaller study investigated 94 cancer patients and found it was not the need for RRT but renal function decline after ICU admission that predicted hospital mortality [43]. Perhaps, as indicated in non-cancer ICU patients, the degree of physiological upset (e.g., Simplified Acute Physiology Score 3; SAPS3) at the time of starting RRT and how this changes with treatment are pivotal to outcome [48].  Other variable risk factors Other risk factors have variously been reported as being associated with an increased risk of death in cancer patients. The evidence for age itself as a risk factor is conflicting and too susceptible to vagaries of local practice [89]. Illness severity is far more important a consideration than age. The concentration of specialities to ‘expert’ centres has occurred in many disciplines and there is some evidence for improved outcome in high-volume ICUs [90]. This has also been shown for haematological cancer patients with acute respiratory failure who have lower mortality in larger volume units [91].

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 Multi-organ failure It is unsurprising that multi-organ failure and the resulting increase in illness severity greatly increase the chance of death in cancer patients on ICU [76,88]. The greater the number of organs failing, the higher the mortality [65,92]. Other factors may interact such as age and pre-existing co-morbidity [88,93]. Organ failure (as well as chest infection) is also predictive of death specifically in cancer patients with sepsis [52]. The utility of measures of organs’ dysfunction and physiological upset for outcome prediction has been improved by assessment after a defined period of full ICU care, rather than assessment on admission [43,94,95] which is more dependent on time in hospital before admission [65]. For 137 haematological patients with hypoxic respiratory failure, increasing measures of organ failure after 24 h of ICU care was a multivariate risk factor for death [78].  Scoring systems Identification and understanding of the risk factors for cancer patients can potentially lead to more effective and efficient prognostic tools. However, commonly used physiological scoring systems and prognostic tools have not been validated against a cancer population. One could argue that the lack of influence of cancer diagnosis on outcome would support the use of non-cancer tools; yet many of these, such as Acute Physiology and Chronic Health Evaluation (APACHE) and Simplified Acute Physiologic Scale (SAPS), tend to underestimate ICU cancer patient mortality [21,65,96–99]. This has led to the development of specific scoring systems for cancer patients such as the Cancer Mortality Model (CMM) but this may overestimate risk of death [97,98,100]. CMM may be more accurate in predicting non-survivors [101]. Interestingly, a SAPS3 score modified for South America appeared to have greater predictive value for cancer patients than the standard SAPS3 [102]. Criticisms of such scoring systems point to the stress on mortality without looking at long-term data and quality of life for survivorship. Moreover, the importance of local admission criteria and thresholds for end-of-life care can question the applicability of these general prognostic tools [103]. Thiery demonstrated limitations of outcome prediction by studying 206 patients assessed for ICU admission [47]. Of the 54 patients considered unfit for admission, 26% were still alive at 30 days compared to 54% who were deemed fit for ICU. Conversely, only 79% of those assessed as being too well for ICU survived 30 days. Similarly, a week after patients had been considered too sick for ICU admission, 66% were still alive [104]. Predictive scoring systems have been shown to be no different from physician opinion and of only moderate accuracy, further questioning the expediency of assessment at admission [105]. To improve the accuracy of outcome prediction and to assist in planned management, intensivists have looked at physiological evaluation after a fixed time of full ICU management. This provides a measure of impact of ICU care on physiology and organ function rather than initial admission assessment more dependent on delay before ICU admission. Sequential Organ Failure Assessment (SOFA) is relatively accurate in predicting outcome for haematological patient [95,106]. Furthermore, Groeger collated and validated a scoring system of 10 categorical variables assessed after 3 days of ICU care [94]. Other studies in septic and neutropenic cancer patients have also showed improved predicative value by consideration of organ dysfunction at day 3 when compared with assessment at admission [107,108]. The evidence base recommends an optimal strategy of early instigation of organ support and assessment of these interventions on organ failure and physiological derangement after a period of ICU management. The prognosis for cancer patients has improved and some of the risk factors once thought to be equivalent to a death sentence need to be reappraised. Cancer patients should not be discriminated on diagnosis alone and as for non-cancer patients, illness severity and organ failure are of key importance. However, triage based on admission illness severity may be more a function of ICU delay and lack prognostic precision. Delayed prognostic scoring more accurately predicts outcome. This may also inform the difficult decisions to change management from a curative to a supportive intent. The initial decision to admit must be taken after multidisciplinary assessment for capacity to benefit, but in many cases reassessment after an elective period of intensive care will be warranted.

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Cancer patients in the ICU: the goals of medicine, justice and need Whilst in many cases, the decision either to provide full support or to transition to a palliative pathway is obvious, there remains a substantial number of cases where this is not the case. This number is potentially growing because of the uncertainties posed by improvements in outcome and difficulty in applying population-derived prognostic factors to individuals. To know whether we are doing what we ought to be doing, we first need to consider what our goals are, the goals of medicine in a general sense but also specifically what the goals are with a patient with malignant disease on ICU. The progress of medicine has brought with it its own problems. Our life expectancy has shot up, but are we both living longer and taking longer to die? Longevity and technology have brought with them a plethora of end-of-life decisions around so-called life-saving technology. Putting patients on lifesupport machines may support life, but for how long and at what cost? What is the purpose of medicine when applied to persons, who may be or are near the end of their lives; is it about improving the quality of life or simply prolonging life whatever the cost? Second, the goals of medicine will also be influenced by political and societal influences and thus will probably change with time and not be universal. The World Health Organization (WHO) defines health as a state of “complete physical mental and social wellbeing” [109]. As a working definition, in practice, this seems untenable as it would intuitively be unachievable in anybody, and is an intuitive impossibility in the cancer patient on ICU! What might be the needs of patients with cancer on ICU? For many, survival is the key but it is highly unlikely that the vast majority of people would wish to survive at any cost. A more realistic need might be to survive to have a reasonable quality of life and leave hospital. The concept of meeting needs as a goal of medicine has also been described in terms of capacity to benefit [110]. If one accepts that a specific patient can gain no benefit, would that justify not offering intensive care? Accepting that our patients have a need for health care does not, however, necessarily mean they must be treated. A right to health care constitutes a claim on services and goods, in this case, a right to ICU care. Is this right tenable? That a need may exist is true, but as has been said it may be contingent on capacity to benefit, which may be arguable. If the patients have no capacity to benefit, then their need is unmeetable and an unmeetable need could not be translated into a right. It is unfortunate then, not unfair, that the need cannot be met. If resources were limited, it might be acceptable to restrict access to intensive care to those who would benefit most or to those whose needs were meetable. If a need cannot be met, then there may not be an obligation to meet it. This has contemporary resonance in the establishment of organisations such as the National Institute for Clinical Excellence. If there is no reliable evidence that a treatment works, then that treatment cannot be said to be able to meet a health-care need and as such its provision is not obligatory. In any medical endeavour, there is a degree of benefit–harm analysis. For example, the side effects of new drugs are weighed against the beneficial effects. This consequentialist (utilitarian, maximising benefit) approach is mirrored in a view of the goals of medicine, that of maximising the quality of life of a population overall. This is exemplified by the quality-adjusted life year (QALY) approach. In essence, the QALY approach looks at cost-effectiveness aggregated over time to produce an integer – a QALY – with which to compare different health-care interventions. Cassel and Neugarten have characterised the goals of medicine around two distinct models, the heroic and the humanistist [111]. The heroic model has as its goals saving life and curing diseases, whereas the humanistic model is concerned primarily with improving the quality of life. Intensive care is perhaps the most ‘heroic’ of medical endeavours. The two goals are not necessarily mutually exclusive though, as measures that have a principal aim of improving quality of life will more often than not prolong life. The difficulty with applying a humanistic goal of medicine is that of making quality of life judgements. Whereas it is possible in conscious autonomous patients to engage them in discussions of quality of life, how do we come to the right conclusions in a ventilated or heavily sedated patient? It is clear that doctors may have a statistical sense of what the quality of life is likely to be for a patient but that could not be used as a reason not to treat a specific patient. On a practical level, six proper goals of medicine have been described [112]. These are: the restoration of health, relief of symptoms, restoration and maintenance of function, saving or prolonging of life, avoiding harm and education and counselling of patients. This would seem to be a good working model of what doctors do on a day-to-day basis. These goals would fit within the four principles’ approach to medical ethics, being subsets of beneficence and non-

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maleficence [113]. In the four principles’ approach, considerations of respect for autonomy and considerations of justice temper these goals of medicine. The balance of beneficence and non-maleficence is perhaps the most relevant aspect of the four principles’ approach in the case of a non-autonomous patient. The beneficent aspect of the care is the attempt to save their lives both at the acute stage and during their period on intensive care. Doctors have a special obligation to benefit their patients but also to avoid harm. Even in patients with advanced malignant disease, short-term survival may in fact be the objective for the patient and their family. As such, ICU care may be considered appropriate on the grounds of beneficence. Active treatment may also have immense symbolic and emotional significance for relatives and staff and may be an expression of society’s desire to help those in greatest need. Considerations of justice form the fourth of the four principles; this will be in terms of the fairness of resource allocation (distributive justice) as well as the fairness of the treatment for their particular disease. Medicine is also about responding to suffering which seems to be an immediate response of those who care for the ill. This has been considered to be a perfect duty. Ignoring suffering according to Emmanuel Levinas “jeopardizes the agent’s moral being” [114]. The British Medical Association (BMA) has declared “The primary goal of medical treatment is to benefit the patient by restoring or maintaining the patient’s health as far as possible, maximising benefit and minimising harm” [115]. The benefits to the patient may include prolonging life but not under all circumstances and quality of life is also a relevant issue. The fact that the expected quality of life that might be obtained can be considered when making treatment decisions has been accepted into UK law. The position of the BMA seems to have a consequentialist thread to it, implicitly involving benefit–harm analysis and rejecting vitalist claims of the sanctity of life. Where the primary goal of medicine cannot be achieved and no net benefit can be achieved, then the BMA consensus is that the justification for treatment no longer stands. Doctors on the whole seem averse to quantification, feeling that it lacks humanity, but we cannot ignore fiscal scarcity anymore than we can ignore symptoms and signs. Morreim has argued that physicians must work within a resource nexus and has introduced the concept of a ‘standard of resource use’ which encompasses the fiscal resources that physicians are expected to use for their patients [116]. Working within this system, physicians would have an implicit obligation to keep one eye on cost. There would be a minimum level of resource that each citizen would be entitled to, and it would seem that above that level the fiduciary responsibilities of the physician are diluted by other considerations. Physicians can neither ‘commandeer resources’ nor are they obliged to, but rather they are obliged first to act as advocates for their patients. Morreim though adds another duty, that of acting as an advocate for all patients to improve resource policies. This second duty implies a shift from the dyadic doctor–patient relationship to a more general duty of a doctor to think beyond the individual patient in front of him. To have an understanding of the broader picture outside the consulting room, Williams has said that “we need to inculcate a sense of statistical compassion” commenting that “behind the mere statistics there are a lot of real people who do have names and addresses and worried loved ones” [117]. This would imply that when a doctor decides to admit a patient to intensive care, he or she must make a sort of calculus of outcome probability and cost-effectiveness. This would seem impossible on a day-to-day basis; yet, in practice doctors often make inferences under conditions of uncertainty to guide decision making [118]. It might then be possible to come to a commonsense best-guess calculation. It should not be true that a physician need take no note of cost when deciding on treatment. There is thus a tension between their role as a fiduciary agent of the patient and a gatekeeper of healthcare resources. Can a physician involved in making what have been termed “tragic choices” be expected to consider cost? [119]. When dealing with limited supplies of highly expensive drugs, doctors do exactly that; this has been acknowledged for some years. The American Thoracic Society (ATS) stated in 1997 “Marginally beneficial intensive care may be justifiably limited on the basis of societal consensus that its cost is too high in relation to the value of its outcome” [120]. Hospitals, doctors and health budgets are societal resources and the ATS has stated, “extraordinary expenditures of resources for marginal gains unfairly compromise the availability of a basic minimum level of health-care services for all” [120]. Issues of cost in this setting are principally concerned with distributive justice and whilst they may be balanced using a utilitarian tool such as the QALY from a deontological perspective, respect

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for autonomy and issues of beneficence, justice and non-maleficence do not lend themselves to a solution based on integers. Decisions about health care are not made on cost alone. End-of-life care for the cancer patient The intensivist, whilst balancing all the above principles, may have additional issues to consider when dealing with the cancer patient. The principal modus operandi of the intensivist is curative. In the patient with cancer, the issues may become more complex. In the ICU, the cancer patient may be being ‘cured’ of complications relating to treatment having supportive care during chemotherapy, treatment of problems unrelated to diagnosis and treatment of the underlying disorder or a form of intensive palliation. However, at some point for many patients, there is a shift from curative to end-oflife care. At this point, critical care and palliative care start to merge. Whilst it may be appropriate to move patients from the ICU to the general ward or hospice, there will be patients in whom such a transfer would be inappropriate where they are not expected to live for long following removal of supportive therapy. There is little empirical data to guide intensivists in the management of end-of-life care on the ICU; decisions are guided by ethical principles and considerations of the clinical situation. Five domains of good end-of-life care have been identified: adequate pain and symptom control, avoidance of inappropriate prolongation of dying, achieving a sense of control, relieving of burdens and strengthening relationships with loved ones [121]. Of prime importance to the dying patient is symptom control, particularly alleviating pain. Beyond that, the intensivist should tailor the degree of sedation to the patient’s wishes both physical and spiritual, in concert with attending relatives and or friends. Whilst the autonomy of the patient should remain, paramount consideration should be given to the needs of those relatives or friends who are in attendance as part of a family-centred approach to the care of the dying. The American College of Critical Care Medicine has published a set of recommendations for end-of-life care; a principal finding was that “Family-centered care, which emphasizes the importance of the social structure within which patients are embedded, has emerged as a comprehensive ideal for managing end-of-life care in the ICU” [122]. The review also stresses the importance of communication with families and the development of a comprehensive bereavement strategy. Across Europe, around 70% of patients who die in ICU have had limitations applied to treatment. Whilst many doctors feel differently about withholding and withdrawing treatment, emotions principally focussed on the active nature of the latter when compared to the former, there is broad-based ethical and philosophical support that clinicians should not believe that there is a relevant distinction between the two. This is founded on the knowledge that the effects of any intervention in this group of patients may often only be determined after a trial of treatment. The act of intentionally actively shortening the dying process is unlawful in the UK, but not in some European jurisdictions. As well as addressing the needs of the patient and the family, the needs of the clinical team looking after the cancer patient dying on the ICU should be addressed. It is often challenging for staff used to the heroic and curative ethic to switch to the palliative. Summary Treatment of the critically ill cancer patient is an increasingly common and complex issue. Whilst the outcomes of such patients have mirrored the general improvement for intensive care as a whole, this improvement has not been consistent, reflecting the fact that cancer is not one simple diagnosis. Many conditions come with specific challenges that require experience and knowledge of the disease process and of its current treatment to maximise benefit. The treatment of the post bone marrow transplant can be particularly difficult and requires a broader view than that which sees all deteriorations as sepsis related. Despite all efforts, there must be a recognition that for some, critical care will not yield a good outcome. Recognising this and avoiding unnecessary suffering is a crucial aspect of the intensivist’s role.

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Practice points  Consideration of pre-existing treatment should be made for all patients presenting as emergencies to the ICU – chemotherapy and radiotherapy can both cause significant cardiovascular/respiratory and immune system effects.  Tumour-induced mediastinal compression can cause cardiovascular or airway collapse on induction. Precautions should be taken in advance.  Tumour lysis syndrome is now relatively easily managed with rasburicase if anticipated and treated early.  Not all cases of respiratory deterioration post bone marrow transplant are due to sepsis. Early bronchoscopic lavage can lead to alternative diagnoses amenable to steroids.  The outcome for critically ill cancer patients has been improving for some time and now approaches that of many other co-morbidities. For the majority of patients, a ‘trial of ICU care’ at the very least is warranted. However, recognising the point at which active treatment becomes death-rather than life-prolonging remains key.

Research agenda  Most of the studies of cancer patients in critical care consider outcome and prognostication in particular groups.  Teasing out what makes the difference in outcome is difficult but important for the future.  The (probably detrimental) effect of a critical care stay on cancer progression has not been explored and needs to be considered.

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