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Table of Contents
SYMPOSIUM ON END OF LIFE CARE
Year : 2011  |  Volume : 1  |  Issue : 2  |  Page : 138-146

An overview of end-of-life issues in the intensive care unit


1 Department of Anesthesiology, Division of Critical Care Medicine, The Ohio State University Medical Center, Columbus OH 43210, USA
2 Department of Anesthesiology, Division of Critical Care Medicine, University of Michigan Health System, Ann Arbor MI 48109, USA

Date of Web Publication12-Sep-2011

Correspondence Address:
Thomas J Papadimos
Department of Anesthesiology, Room 431, The Ohio State University Medical Center, 410 West 10th Avenue, Columbus, Ohio 43210
USA
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2229-5151.84801

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   Abstract 

The population of the earth is aging, and as medical techniques, pharmaceuticals, and devices push the boundaries of human physiological capabilities, more humans will go on to live longer. However, this prolonged existence may involve incapacities, particularly at the end-of-life, and especially in the intensive care unit. This arena involves not only patients and families, but also care givers. It involves topics from economics to existentialism, and surgery to spiritualism. It requires education, communication, acceptance of diversity, and an ultimate acquiescence to the inevitable. Here, we present a comprehensive overview of issues in the care of patients at the end-of-life stage that may cause physicians and other healthcare providers, medical, ethical, social, and philosophical concerns in the intensive care unit.

Keywords: Critical care, death, intensive care units, palliative care


How to cite this article:
Papadimos TJ, Maldonado Y, Tripathi RS, Kothari DS, Rosenberg AL. An overview of end-of-life issues in the intensive care unit. Int J Crit Illn Inj Sci 2011;1:138-46

How to cite this URL:
Papadimos TJ, Maldonado Y, Tripathi RS, Kothari DS, Rosenberg AL. An overview of end-of-life issues in the intensive care unit. Int J Crit Illn Inj Sci [serial online] 2011 [cited 2023 Mar 30];1:138-46. Available from: https://www.ijciis.org/text.asp?2011/1/2/138/84801


   Introduction Top


End-of-life issues in the intensive care unit (ICU) can be difficult from the perspective of the physician. The Society of Critical Care Medicine and the American Thoracic Society indicate that there is a pressing need for physicians working in the critical care environment to intimately understand problems and impediments to physician communication to patients and families, as well as physician performance in the arena of end-of-life. [1],[2] There is a discomfort in confronting mortality in the 21 st century society. [3] In the United Kingdom (UK), the General Medical Council published the recommendation that death should be a specific topic of discussion when a patient is likely to die within the ensuing year. [4],[5] Additionally, in the United States, the American College of Critical Care Medicine has published a consensus statement and concluded that "End-of-Life care is emerging as a comprehensive area of expertise in the ICU and demands the same high level of knowledge and competence as all other area of ICU practice." [1] This is relevant because currently, 58% of the patients in the UK die in hospitals, [6] and in the US, 22% of all deaths occur in the ICU. [1]

It is of paramount importance that a physician recognizes when he/she is dealing with a dying patient. Besides planning for alleviation of symptoms and treatment, an ICU physician must understand decision making and advanced directives, be effective in the interaction with families, understand the influence of religion and spirituality, acknowledge diversity, be facile with palliation and transition to comfort care, communicate well with the primary care team, and enlighten medical students and residents regarding end-of-life issues. Here, we present a structured approach to caring for end-of-life issues, including specific recommendations for this important and increasingly common situation.


   Recognizing The Dying Patient Top


It is important for a physician to recognize the dying patient. This is essential not only because the physician has to be involved with an end-of-life plan, but because only about 45% of patients actually recognize that they are, indeed, dying. [7] Although a majority of people do not wish to die in a hospital, more than half do so. [8] This "unawareness" by the patient may be difficult to address. Physicians overestimate patient survival on a regular basis, especially if they are familiar with the patient. [9] So, when do we transition from support to palliation? This is truly an intellectual challenge. [10] The ability of a physician to prognosticate accurately has a profound influence on patients' and families' decision regarding end-of-life. [11] This can be especially challenging when dealing with non-cancer patients. [12] Clinicians have traditionally based their prognostication on personal impressions or by using various prognostic tools, which include disease specific and performance status measures. [3]

The first involves disease-specific prognostic tools. These tools are usually used in clinical trials, transplantation, and heart failure. [13],[14],[15],[16] However, these are not usually applied at the end-of-life stage.

The second tool that may help predict critically ill patients without considering their illness type involves the use of one of the many performance status measures. [3] Evaluation of performance status assists providers in regards to palliation and hospice, and the supportive care services required at the end-of-life. [17] Stone's Palliative Prognostic Index in cancer patients assists in quantification of breathlessness, delirium, and anorexia. [18] Providers may alternatively use criteria-based models using clinical features of advanced diseases. [3],[13] In the end, the best prognostication may involve evidence-based markers (markers that have been validated experimentally or clinically). [19] Ultimately, it is incumbent upon physicians to be able to recognize the dying patient, irrespective of whether he/she uses such tools.


   Planning For Alleviation of Symptoms, Palliative Care, and Withdrawal of Care Top


Many prominent symptoms are seen in the dying patient, and these should be quickly recognized. The prominent symptoms in the dying patient include, but are not limited to, pain, breathlessness, difficulty managing secretions, restlessness, depression, and dementia. [6],[20] Pain is feared by all patients, but its management, early and aggressively, will lend itself to alleviation. [21],[22],[23] Pain must be assessed with keen attention to the patient. Dosing of pain medications should be scheduled and doses be prescribed "as needed" to ensure pain control. [20] Also, physicians should not put patients into categories and treat them with protocols; treatment must be individualized. [24] For example, if the patient can safely swallow, they should be prescribed oral opioids. As the illness progresses, patients may need intravenous access, but the subcutaneous route should not be overlooked because it will entail less provider oversight and can be just as effective. [6]

Breathlessness is common in end-of-life, especially in aged patients and those with impaired respiratory systems. [25] It is noteworthy that oxygen is no better than compressed air when palliating patients who were dyspneic, [26] although most physicians prefer using oxygen therapy. [27] Oral or injected opioids are effective in relieving breathlessness. [28] When patients are in their terminal state, low doses of benzodiazepines will help enhance the effects of opioids in case of dyspnea. [6]

Difficulty in managing secretions can be upsetting to families. The patient is often unable to cough up secretions, which has been termed as the "death rattle." Suctioning the patient may be of use, especially nasotracheal suctioning. Also, one pharmacotherapeutic approach that can be recommended is the use of an anticholinergic agent. This will result in about 50-80% decrease in the persistence of such "death rattle," [6],[29] a distressing symptom to families. However, when using anticholinergics for treatment of this symptom in a dying patient, physicians should be aware of the potential for central excitation or sedative effects.

Restlessness, or agitation, secondary to pain, hypoxia, or anxiety is another symptom that ICU physicians must manage well. At times, opioid-induced agitation from toxic levels of narcotics may lead to diagnostic confusion with pre-death agitation. [6] Agitation, or restlessness, can occur in 15-85% of patients, depending on the study. [30],[31] Agitation can be severe enough to need intravenous infusions of propofol, midazolam, lorazepam, or dexmedetomidine. [32],[33]

Depression and dementia is frequent with older patients among the broader population of people in the end stages of life. Depression is a common reaction among dying patients, and it can be easily missed in the elderly at the end-of-life stage. [34] Up to 25% of terminally ill cancer patients are depressed. [35] and physicians are known for missing it. [36] Unfortunately, in the ICU, the diagnosis of depressions is difficult to make and often assumed in patients who may have other neurologic sequela related to their illness or prior comorbidities. Among these, dementia is common, and will likely become more prevalent in the coming years because of the aging population trends worldwide. Such patients cannot express their wishes or complain of pain or discomfort. Therefore, they are at higher risk for certain complications, such as pneumonia, before or during, ICU admission. [37]

Maximizing pain relief at the end of life is critical, but can sometimes cause unintended morbidity and even hasten death itself. This has been referred to as the "double effect," and must be understood by clinicians who manage palliative pain. This concept allows physicians to aggressively pursue pain alleviation, while, at the same time, accepting that their good intentions to decrease pain may cause unintentional morbidity in the patient. As long as the intent is not to cause death, but treat pain, this concept has both ethical and legal support. [38],[39],[40]

It has been argued that a doctrine of "double effect" is not required because opioids and sedation when properly administered should not actually hasten death. [41],[42],[43] The nuances of these activities will be debated undoubtedly, but nonetheless, the physician should always be cognizant of how his/her intentions are perceived by family and staff.

Palliative care deals with the relief of suffering. Suffering is not just the alleviation of physical discomfort (pain), but also the relief of psychological, social, and spiritual distress. [44] Cassel has stated that the threatened intactness of a person was a consequence of severe distress and can be defined as suffering. [45] Cassel further emphasized that, although medical care goals are important, alleviation of suffering is as important as the curative effort. [45],[46] In other words, palliation is as important as life-saving interventions, and the terms "transition to comfort care" are fast replacing "withdrawal of care." Furthermore, engagement of a palliative care team early in a critical illness may not only help the patient, but may also be of help to the family in dealing more effectively with the illness of their loved ones, both before and after death. In many institutions, the palliative care team is actually allowed to psychologically and pharmacologically treat family members who "suffer."

Palliative care teams should be engaged at the beginning and the continuation of curative efforts, as well as during withholding or withdrawing care. Engaging a palliative care team to assist during end-of-life in the ICU should not be viewed as an admission of failure on the part of the primary care team (or the ICU team for that matter), but as a valuable adjunct. However, a palliative care team should only be engaged after frank discussions with the family. [2],[47],[48] In effect, the argument can be made that the palliative care team should be involved as part of more patient- and family-centric focus to deliver optimal care for patients who are clearly dying, as well as for patients who have a significant, but uncertain probability of not surviving a hospitalization.

Decisions of whether to withdraw specific types and intensity of care should ideally have involved a patient prior to being unable to communicate, but often still require among the most careful and thoughtful communication with the family and surrogates. This conversation is best pursued early in a physician-patient relationship when an illness has a probability of being terminal. Unfortunately, in the modern critical care unit, this type of physician-patient interaction rarely exists. If a patient does not have the capacity to make a decision, then surrogates and/or a surrogate-medical team should make the decision,taking into consideration the patient's prior wishes, if possible. [49] Withdrawal of care decision tree has an important point of division: patients on mechanical ventilation and those without mechanical ventilation. While the pharmacology employed and communication skills in both scenarios are equally important, mechanical ventilation deserves added comment.

When the patient is being mechanically ventilated, the critical care team should address withdrawal when the following three scenarios present themselves: (1) when benefit to the patient has been exhausted, (2) when mechanical ventilation no longer meets the treatment goals for the patient, and (3) when the topic is rendered for discussion by the patient, family, or a surrogate. [2] Of course, cultural and spiritual needs must be addressed, as well as when and where this will take place, and who needs to be present. The patient and family must be kept comfortable. A continued dialogue and discourse with the family is essential (whether the patient is mechanically ventilated or not).

Other than the essential need of communication with patient and family, there is no "proper" way for withdrawal care of patients on mechanical ventilation. [50],[51],[52],[53],[54],[55] Patients can be terminally weaned (weaning oxygen concentration) or just extubated (removal of endotracheal tube). Empowering the family, and, if possible, the patient, to participate in this decision is crucial. However, the critical care team needs to make an assessment of the family dynamics and find a suitable pathway that will alleviate, or minimize, spiritual and existential suffering.

Opioids and benzodiazepines should be titrated for comfort (as described above). All neuromuscular blockers should be discontinued and evidence of their reversal should be documented before titration of terminal medications. This matter should be emphasized with colleagues who occasionally think that neuromuscular blockers are compassionate to prevent families from seeing patients' having agonal breaths or air-hunger. Signs of dyspnea and pain should be frequently monitored. Physicians must remember to discontinue antibiotics and other treatments that extend life (eg, renal dialysis or vasopressors/inotropes). They must be aware that continued fluid administration may cause pulmonary sequela that contributes to patient and family discomfort. Nonescalation of care becomes an important concept for consideration. Some families may elect to not add new therapies, knowing that such therapies will likely not alter a futile course of care.

It must be noted that guidelines and protocols have been developed for withdrawal of care. [56] These tools also involve suggestions for incorporation of education. Furthermore, the use of checklists demonstrated much less variability in the types and amounts of drugs during withdrawal of care, and the nurses in the study indicated that the checklists and scoring systems used had improved care at the end-of-life. [57]


   Advanced Directives and Decision Making Top


While much of the international community had already addressed a patient's right to self-determination, it was not until November 1990 that The Patient Self Determination Act (PSDA) was passed by the US Congress. This legislation addressed the increased use of advanced directives by requiring Medicare and Medicaid providers to inform patients regarding their rights on this issue. [58] This law gave patients the decision-making power regarding medical care, which besides allowing an advanced directive, allowed refusal of care. Of further note is the fact that this law mandates that institutions discuss advance directives with the patient upon their admission. [59]

Do not resuscitate (DNR) orders, living wills, and the durable power of attorney for healthcare are the instruments seen most frequently in the US. While a DNR order would seem self-explanatory, it varies from state to state as to what it actually means and what can actually be done or not done. A living will, on the other hand, is a legal document that a person uses to make known his/her wishes regarding life-prolonging medical interventions. A durable power of attorney for healthcare allows another individual to make decisions regarding the healthcare of a patient. Sometimes in an advanced directive, the living will and power of attorney for healthcare are combined. Availability of these documents assists the intensivist in guiding families through the intensive care experience. However, only few patients complete such directives, [60],[61],[62],[63],[64] and few understand what they are actually authorizing physicians to do. [65],[66],[67],[68] In an Oregon study, a large proportion of patients in the university clinics did not understand end-of-life options. [66] Furthermore, families and physicians are poor at predicting a patient's end-of-life desires. [69],[70],[71],[72],[73] Additionally, general health, age, and other patient demographics seem to influence the wishes of patients. [74],[75] Having such instruments in place helps physicians manage the end-of-life process, which is increasingly fraught with ethical difficulties.

Decision-making is made easier with advanced directives. Nonetheless, decision-making in the ICU is difficult. Decisions need to be made for patients who have families and surrogates and for those who do not. Today, the paternalistic model of physician decision-making for ICU patients has been replaced with a more patient- and family-centric approach. The shared model of patient autonomy now dominates the ICU environment, except for certain emergency situations. [76],[77] This shared model of decision-making involves more than the physician leaving the patient with a choice after offering several options. The patient may actually want professional inputs in their option model. If the patient is unable to express his/her wishes, there may be a problem in deciding how to proceed. There are studies that demonstrate concordance of family members with those of the patient, if conversations have taken place in advance of the illness, [78],[79] yet there are discordant examples in these same studies. It seems that there is evidence, though, that patients may wish family members and physicians to make a final decision together. [80]

About 5% of deaths in the ICU happen among those who cannot make decisions, or have not made decisions. In this situation, the physician may have to make the decision to limit or withdraw care. A study on homeless people who were not in hospital revealed that nearly 80% of them would like the physician to make the decision. [81] In this scenario, it may be of benefit to convene the institutional ethics committee.

There will be times when there is a disagreement between the clinician and the family. Having a family meeting where there is comprehensive exchange of information and feelings may be useful. Meeting frequently with families and developing milestones regarding the care/treatment plan and expectations of improvement is of immense help. [82] Here also there may be a place for an ethics committee or a palliative care team to facilitate communication between the family, the primary medical team, and the ICU team.


   Religion and Spirituality Top


Religion and spirituality have importance to 88% of patients with advanced cancer. [83] However, these two are not the same. Understanding what spirituality is, especially in relation to religious beliefs, remains a problem because it has diverse definitions. [84],[85] Spirituality is practiced within a framework of religion on many occasions, but it is common outside formal religion. "Spiritual needs are about the need to be valued, to repent and be forgiven, to achieve self-integrity, and to face and accept death". [86] Spirituality separates itself from formal religion in that it deals with beliefs, faith, hope, attitude, and the meaning and purpose of life through reflection and appreciation outside of a particular belief system. [87]

In religious coping, patients use their belief systems to understand their situation and deal with their stress through prayer, meditation, and studies of their religion. [83],[88],[89],[90] ICU physicians should be aware that Phelps et al. have demonstrated positive religious coping (as opposed to negative religious coping, which views illness as a punishment for transgression, which is, in fact, rare) is associated with the use of more intensive life-prolonging healthcare near death. [88] Also, True et al. have associated religious coping with patient preference for resuscitation, mechanical ventilation, and hospitalization when nearing the time of death. [91] After the opinion of a physician, lung cancer patients considered faith as the most important element in their treatment decisions. [92] It has also been demonstrated that patients with optimistic views of their survival receive more intense and heroic care at their end of life, [93],[94] and in minority populations, as there is less advanced end-of-life planning, this may occur because of religious and spiritual considerations. [95],[96],[97] It is noteworthy that most such studies involve Christian populations and that these results cannot be applied in regard to non-Christian populations, and also that the interactions between religion, belief, psychology, and spirituality are difficult to ascertain. [98]

The ability of a critical care team to support a patient's spiritual values and cultural beliefs in the ICU can also be used as a quality indicator in end-of-life efforts/support, and enhance that institution's standing in the community. [99] Physicians must understand and be sensitive to the influence of religion and spirituality upon their patients (and families) decisions in the ICU.


   Diversity Top


Lack of awareness regarding cultural sensitivity and diversity can lead to undesired outcomes and interactions in end-of-life care. [100] While the US healthcare system has adopted the concept of informed consent and The Health Insurance Portability and Accountability Act of 1996 (HIPAA), this framework of the "autonomy paradigm" in the US has not been as widely accepted in other countries and cultures where the "social framework paradigm" may still dominate. [101] In determining end-of-life care and decision, the intensivist must identify the patient's cultural preferences on two key aspects: transmission of information and the individual in decision-making. [102] The screening question of "what do you want to know about your medical condition?" may identify patient preference regarding information disclosure. It is not universal to disclose bad news, such as terminal illness, and many cultures feel it is inhumane, unethical, and disrespectful to inform a patient of such. [103] For example, a majority of US physicians and patients felt that the patient should be informed of a diagnosis of incurable cancer and HIV-status prior to the family, while only a minority of Japanese physicians and patient felt the same. [101] This segues to cultural diversity in end-of-life decision-making: individual-based versus family-based. Communities that value beneficence and non-maleficence over autonomy, tend to support family-based decisions rather than individual-based decisions. [102] Questions such as "do you make your medical decisions?" and "what is your family's role in the decision-making process?" may help identify patients who do or do not want their families to be involved in their care. Multiple surveys have shown a wide range in family involvement in end-of-life care, ranging from 44% to 100%. [104] Furthermore, the roles of individual members in the family unit become even more critical in end-of-life decisions made in the ICUs where surrogates rather than the patients make most decisions.


   End-of-Life Communication Among Medical Teams Top


Communications between critical care teams, the primary medical or surgical teams, and nurses are crucial in end-of-life scenarios. [105],[106] There can be, at times, disagreement between the various medical teams as to identifying when the patient is a "dying" patient, or when to recommend withdrawal of care to the family. Richardson et al. correctly perceive that intensive care is not a linear process and effective patient care efforts are often not forthcoming, despite movements toward team building because decisions remain a "top-down" authoritative process. [107] Medical team training (MTT), as applied through crew resource management (CRM) to decrease morbidity and mortality in the surgical arena, is rapidly gaining popularity and is heavily endorsed by the Joint Commission on the Accreditation of Healthcare Organizations, and its modeling may hold value in the ICU at the end-of-life stages. [108] CRM focuses on safety, efficiency, and morale of people working together, where the input of all is welcomed, where ideas are debated, accepted, or rejected, but people (other healthcare providers) are not. While CRM/MTT has been well demonstrated to reduce surgical mortality through better communication in surgical suites, [109],[110] it seems that time for its application in the ICU has arrived.

While communicating with the family is vital and effective from the medical team perspective, [111] respectful communication between physician colleagues, between physicians and nurses, and other ancillary healthcare personnel can only be helpful to patients and their families at the end of life. Precise and inclusive communication has been demonstrated to increase the understanding of patient care plans in the ICU by the entire team of providers. [112],[113] Members of ICU teams may disagree among themselves and with the primary physicians providing care regarding goals and plans, and may have divergent perceptions of their communication with each other, but they must learn to effectively communicate with each other because "communication openness is also associated with the degree to which they understand patient care goals." [114] Therefore, at the end of life, it is vital that team members freely exchange ideas without trepidation.


   Caring For Those Who Provide Care Top


Attention should also be given to the psychological well-being of the critical care team itself. While the critical care team focuses on the patient and family, as it should, the team should not lose sight of how it is itself affected. Nurses have indicated their unhappiness that critically ill patients frequently did not receive enough medication and that it had caused the nurses moral distress. Good pain control was essential to a good death that was dignified and that the "double effect" of the use of sedative hypnotics and opioids was acceptable to them. [115],[116],[117],[118]

Moral distress, exhaustion, and an increasingly depersonalizing environment can lead to burnout. [119],[120],[121],[122] Increased self-awareness by members of the critical care team is essential to self-health and effective performance. [123] To this end, instruments have been developed to measure provider burnout to assist leaders and administrators in its recognition and need for intervention. [118],[119]


   Medical Students and Residents' Perceptions of Education In End-of-Life Issues Top


Only since the late 1990's, have medical schools stressed on efforts to improve medical student training in end-of-life issues. [124] Sulmasy et al. reported on medical student perceptions regarding the adequacy of end-of-life education in the curriculum. [125] Over an 8-year period, the adequacy of medical school training is these issues reportedly increased from 70.8% to 79.5% regarding death and dying, 34.3% to 55.3% regarding training in pain management, and 59.9% to 74.8% regarding palliative care. [125]

Nearly all medical schools now teach about end-of-life issues because it is required by the Liaison Committee on Medical Education. [126] The question that now arises: are future medical practitioners prepared to be effective in an environment where there is an explosion of aging baby-boomers. It is incumbent on today's ICU physicians to be part of the education of medical students and residents (let alone other allied health practitioners). There has been a tremendous effort to improve teaching of end-of-life issues in the US. [127],[128] Nonetheless, Sulmasy et al. point out that it is sobering that even after a decade of the effort, students report their schools' curricular attention to death and dying, pain management, and palliative care as inadequate. [125]

There is further concern in other curriculum studies that women, Asians, and older students rated their medical school curriculum as inadequate for preparation to face end-of-life issues. [129] Sulmasy et al. found men to be more confident in discussing DNR orders than women, and Asians have reported to have more difficulty with having such conversations with patients. ICU physicians and teachers must not only note that cultural diversity and cultural competency may be important regarding end-of-life issues, but that women, Asians, and older students may more readily recognize teaching deficiencies in the curriculum. [125]

If there is a deficient effort at the medical school level, then the same shortcomings may be applied to residents. In fact, a Canadian study found that although residents found valuable educational opportunities when being involved with dying patients, they felt that they were not supervised adequately and experienced emotional distress while caring for such patients. [130] ICU physicians must provide meaningful, supportive, educational, and emotional experiences for residents in a nurturing environment in regard to end-of-life training and issues.


   Conclusion Top


End-of-life issues in the ICU are of paramount importance. However, end-of-life issues do not just involve matters of resuscitation, status of advanced directives, and making the patient comfortable. Here, existentialism and culture play large roles, not only in regard to the patients, but also as to who is providing the care. Questions such as, "who is this patient, from what walk of life he or she comes?" need to be considered, as well as "who is the physician and his or her life stances or attitudes?"

Recognizing the dying patient seems to be more difficult than physicians care to admit. Knowing when to let go as a provider and helping the family let go of their loved one can be onerous. Furthermore, communication with the family and among medical, nursing, and ancillary health teams is not only challenging and necessary, but it must also be successful. Finally, educating students, physicians, and other staff members in end-of-life matters, allowing them to participate in discussions, and explaining the decision-making process are crucial to successful delivery of care in the ICUs of 21 st century.

 
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9 Which Multicenter Randomized Controlled Trials in Critical Care Medicine Have Shown Reduced Mortality? A Systematic Review
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10 Perspectives of Singaporean patients and caregivers towards quality of life or quantity of life with disease-modifying treatment in the end-of-life setting
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11 Do we have adequate tools and skills to manage uncertainty among patients and families in ICU?
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12 Dying in Intensive Care Units of India: Commentaries on Policies and Position Papers on Palliative & End-of-Life Care
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13 Implementing a palliative approach in the intensive care unit: an oxymoron or a realistic possibility?
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14 Conflicts between healthcare professionals and families of a multi-ethnic patient population during critical care: an ethnographic study
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  In this article
    Abstract
   Introduction
    Recognizing The ...
    Planning For All...
    Advanced Directi...
    Religion and Spi...
   Diversity
    End-of-Life Comm...
    Caring For Those...
    Medical Students...
   Conclusion
    References

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