Symptom Management Series 2.5 ANCC Contact Hours Persistent Hiccups in Advanced Neuro-oncology Patients Findings From a Descriptive Phenomenological Study

Alvisa Palese, MNS, BNS, RN ƒ Giulio Condolo, BNS, RN ƒ Raffaella Dobrina, MS, BNS, RN ƒ Miran Skrap, MD

There is insufficient evidence to guide the treatment of iccup episodes occur when an abrupt, involun- persistent or intractable hiccups; to date, no studies tary spasm of the diaphragm and intercostal have involved advanced neuro-oncological patients who Hmuscles is followed by sudden closure of the have experienced persistent hiccups with the aim of glottis, generating the characteristic onomatopoeic ‘‘hic’’ understanding their experience, gaining insights, and sound.1 The majority of hiccup episodes are benign, of acute contributing to knowledge in the field. A purposeful onset, and self-limited, ceasing within a few minutes1; how- sample of 5 consecutive patients suffering from more ever, when the episodes last for more than 48 hours and than 1 persistent hiccup experience lasting more than less than 1 month, persistent hiccups is diagnosed, and when 48 hours and persisting for less than 1 month, aged at least the episodes last more than 1 month, intractable hiccups is 18 years, able to answer open-ended questions, and 2 who had given informed consent were invited to diagnosed. The intractable or persistent hiccup frequency participate. Recruitment ended when data saturation may range from 4 to 60 per minute, with little intraindi- was achieved. According to the patients’ experience, vidual variability1; its pathogenesis is unclear and, unlike living with persistent hiccups was characterized by other similar neurophysiological mechanisms, is character- 3mainthemes:(a) resignation to its unpredictable ized by diaphragmatic contraction and spasm,1 as documented nature; (b) despair that there is nothing worse than hiccups; by several case reports.3 Hiccup incidence is underestimated.1 and (c) learning to control the pauses. Persistent hiccups According to Jatoi,4 hiccups result in approximately 4000 have a negative impact on patients’ and families’ quality hospitalizations per year in the United States. of life, leading to extreme anguish and to a feeling Hiccups are still considered one of the most distressing of powerlessness when it becomes clear that there is symptoms in the gastroenteric tract, thoracic viscera, and no useful pharmacological therapy. In trying to interrupt 4 hiccups, patients learn to control their pauses, lengthening central nervous systems of advanced cancer patients. In the interval between 1 spasm and the next. Adopting these patients, persistent or intractable episodes of hiccups this palliative effort, patients might reach 4 hiccups/min, may be present, with a negative impact on their quality of with 1 every 15 seconds, achieving an acceptable level life,1 provoking anxiety, exacerbation of depression symp- of symptom discomfort. toms, and/or sleep impairment, which may lead to fatigue and somnolence. Activities of daily living such as eating KEY WORDS and drinking may also be affected, and social interactions worsened.5 Because of its impact, nurses have demonstrated intractable hiccups, neuro-oncology, palliative care, an early interest toward persistent or intractable hiccups, persistent hiccups, phenomenology 6 publishing one of the first articles on the subject in 1966. Although the origin of intractable or persistent hiccup has interested both philosophers and physicians since the time Alvisa Palese, MNS, BNS, RN, is associate professor, Nursing Science, of Hippocrates and Celsus, the exact cause remains a mys- School of Nursing, Udine University, Italy. tery and its purpose unknown.7 Nurses and physicians, in Giulio Condolo, BNS, RN, is clinical nurse, Surgical Unit, Teaching Hospital, their efforts to help patients cope with this debilitating symp- Udine, Italy. tom, adopt pharmacological (eg, baclofen, chlorpromazine) Raffaella Dobrina, MS, BNS, RN, is nurse researcher, Area di Ricerca or nonpharmacological interventions (eg, digital rectal stim- of Trieste, Palliative Unit, Pineta del Carso, Trieste, Italy. ulation, phrenic nerve block with local anesthesia, and other Miran Skrap, MD, is director, Neurosurgery Unit, Teaching Hospital 7-11 Santa Maria della Misericordia, Udine, Italy. folk remedies). Address correspondence to Alvisa Palese, MNS, BNS, RN, Viale In order to support clinical decision making, a Cochrane Ungheria 20, 33100 Udine, Italy ([email protected]). Systematic Review has been recently published on the ef- The authors have no conflicts of interest to disclose. fectiveness of pharmacological and nonpharmacologi- DOI: 10.1097/NJH.0000000000000087 cal interventions on persistent or intractable hiccups of

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any etiology in adults.5 Several databases were consid- adopt to control persistent hiccup episodes? According to ered by researchers (CENTRAL, CDSR, DARE, EMBASE, the research questions, a descriptive phenomenological CINAHL, PsychINFO, and SIGLE), and scientists known perspective was undertaken.13-15 Descriptive phenome- to be carrying out research in the field were contacted for nology involves direct exploration, analysis, and descrip- unpublished data or knowledge of the gray literature. tion of a particular phenomena, aiming at a maximum Only articles based on randomized controlled trial study de- intuitive presentation.13 signs or controlled clinical trials, where adults (918 years) Preliminarily, a large teaching hospital (9900 beds) lo- diagnosed with persistent or intractable hiccups (hiccups cated in northern Italy devoted to the care of neurosurgical lasting 948 hours) were treated with any pharmacological patients with more than 500 cases with brain neoplasm or nonpharmacological intervention, were included. Only each year and offering continuous follow-up to their patients 4 studies involving 305 participants were retrieved and ana- was identified. The internal review board of the hospital ap- lyzed by researchers: all of these studies were aimed at eval- proved the research protocol. According to the protocol, a uating the effectiveness of different acupuncture techniques purposeful sampling method14 was undertaken. Advanced on persistent and intractable hiccups.5 The unknown inci- neuro-oncological patients (a) suffering from more than 1 dence of the phenomena, as well as the potential underap- persistent hiccup experience lasting more than 48 hours preciation of the symptom in clinical practice, renders the and persisting for less than 1 month in the last 2 months, likelihood of large randomized controlled trials improbable.12 (b) aged at least 18 years, (c) able to answer to an open- Methodological issues in the studies were identified by ended interview, and (d) who had given informed consent Cochrane researchers: a high risk of bias, an absence of to be interviewed after hospital discharge, at home, were any comparison of the effects obtained after the interven- approached. Patients with other discomforting symptoms tion with placebo, and an absence of information regarding (eg, persistent hemicranias, nausea, vomiting, pain) and those adverse effects or adverse events. From the systematic re- not discharged at home (eg, in palliative units) were excluded. view, no studies evaluating pharmacological interventions The home was chosen as a setting for the interviews, so that for persistent and intractable hiccups met the inclusion cri- each patient had the opportunity to share his/her experience teria.5 In conclusion, according to the previously mentioned in a calm and familiar environment, in a natural setting, in Cochrane Systematic Review, there is still insufficient evidence the company of family/caregivers when requested. to guide the treatment of persistent or intractable hiccups; Five patients were approached and included in the study high-quality studies based on randomized placebo-controlled during their in-hospital stay; thereafter, an interview was trial designs, of both pharmacological and nonpharmaco- arranged with each of them, to be carried out at home. The logical treatments, are still needed.5 day before the interview date, a researcher telephoned the in- Several cases7-11 are documented in the available liter- terviewers to be certain he/she would be available and well ature that report the effectiveness of interventions in pa- enough, clinically and psychologically, for the interview. tients with persistent or intractable hiccups caused by On the established day, an adequately prepared re- central nervous system disease. However, to our knowledge, searcher at the master’s in nursing science level and with there are no studies involving advanced neuro-oncology previous experience in conducting interviews for quali- patients who have experienced persistent hiccups that focus tative studies visited the patient at home. The open-ended on patients’ experience, which have yielded insights or ad- interview was conducted in the Italian language and was vanced knowledge in the field. Therefore, a qualitative ap- based on 3 main questions (Table 1). The time and length proach was undertaken aimed at helping to develop a of each interview (from 45 up to 75 minutes) were decided hypothesis or a wider understanding of the phenomena of by each patient. A family member was always present, as interest.13 In particular, a phenomenological method was per patient request, without intervening in the interview used to understand the experience of advanced neuro- process. oncological patients who have experienced persistent hic- cups, lasting for more than 48 hours, by means of direct TABLE 1 Open-Ended Questions Guiding reporting in interviews. the Interview Will you share with me your experience with persistent METHODS hiccups? The research questions were the following: (1) What is Will you share your understanding of the causative factors and controlling/inhibition factors of persistent hiccup the experience of advanced neuro-oncological patient episodes? suffering from persistent hiccups? (2) What are the causal and controlling/inhibitors of persistent hiccup episodes Will you share with me your experience with personal as learned by the patient from his/her own experience? strategies/interventions you have adopted to control persistent hiccup episodes? (3) Which strategies/interventions have patients learned to

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Interviews were audio recorded and transcribed in or- patients’ words were included with citation to the particular der to ensure accuracy in the process of data analysis. interview (eg, patient 1) to which they relate. The recruitment of 5 patients went from 2007 through Aiming to obtain credible and consistent findings, each 2011, when data saturation was achieved14,15 as judged phase was conducted simultaneously; in addition, each independently by 2 researchers. phase was performed by the researchers independently, According to the phenomenological orientation as- who then worked closely together in theme triangula- sumed by researchers, which was descriptive, 4-step pro- tion.15 Given that the recruitment process of patients was cesses were undertaken: bracketing, intuiting, analyzing, slow according to the rare occurrence of the phenomena and describing.13,14 To prevent any misconceptions, the re- of interest5,12 and given that patients were suffering from searchers’ opinions and personal convictions were discussed advanced cancer, any suggestions or insights emerging and bracketed in a preliminary fashion.14,15 from each interview after researcher’s immersion in the Researchers with different backgrounds (A.P., expert in transcripts were not verified with the patients during a sec- different research methods in neuroscience nursing; G.C., ond interview. expert in surgical nursing; R.D., expert in palliative nursing care; M.S., senior neurosurgeon) shared their opinions: FINDINGS from their point of view, the experience of persistent hiccups is dramatic for patients who try as many strategies Five patients suffering from an advanced stage of primary as possible to interrupt the hiccup episodes. or metastatic brain tumor, aged 24 to 45 years, participated According to the descriptive phenomenology second (Table 2). According to their experience, living with persis- phase, which is intuiting,13 researchers (A.P., G.C., R.D.) tent hiccups was characterized by 3 main themes. immersed themselves in the phenomena. Their personal Resignation to Its Unpredictable Nature evaluations, as well as opinions, were not included. The Patients reported that episodes of hiccups are different interviewer took notes during the face-to-face interview from other symptoms experienced during the illness and and shared these notes at the end of each interview with in their own lives. Experienced symptoms, such as fever, a second researcher. Then, the audio recording was tran- vomiting, and pain, always had a cause and a predictable scribed and shared. Thereafter, researchers read the entire trajectory according to the participants. Regarding each of description of the experience several times to obtain a these, patients had learned about the possible cause(s) and sense of the whole. the effective intervention(s). Instead, persistent hiccups are not According to the descriptive phenomenology third predictable; they have a beginning without a reasonable cause phase, which is analyzing,13 researchers reread the tran- andneverseemtoend.Patientsreferredtohavingalways scriptions, identified the transitions and units of the expe- wondered about the trigger factors of persistent hiccups, and rience, detected meaning by relating constituents to each despite the experience of numerous episodes (up to 30), they other and to the whole, reflected on the constituents in were not able to find the cause. Only 1 patient reported: the concrete language of the participant, and transformed concrete language into the language or concepts of science IIt starts with coughingI (Patient 1) (researchers words). In the fourth phase of the process, called describing,13 researchers integrated and summa- The inability to detect the trigger factors made hiccupping rized the insights into a descriptive structure (themes) de- a particular ordeal because of the unpredictability, even scribing the meaning of the experience. Examples of the though before each episode there was a sort of onset ‘‘aura’’:

TABLE 2 Participants Attendee Family Caregiver During the Interview Patient ID Gender Age, y Main Diagnosis (Yes/No) and Role 1 Male 45 Advanced stage of primary brain tumor Yes, wife

2 Male 34 Advanced stage of primary brain tumor Yes, wife

3 Male 24 Advanced stage of primary brain tumor Yes, mother

4 Female 30 Advanced stage of primary brain tumor Yes, mother 5 Female 38 Advanced stage of primary brain tumor Yes, husband

Abbreviation: ID, identification number of the patient.

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You feel weirdI (Patient 3) Iit hits continuously, and it’s stressful, it’s bad and debilitatingI (Patient 3) A strange sensationI and that’s when the hiccupping starts. (Patient 5) Iit’s an ugly thing because it doesn’t let you live your lifeI (Patient 1) This unpredictability induced a general alert and patient resignation while impeding adoption of preventive mea- Hiccups were distressing for patients, who felt over- sures. Quality of life is compromised even in periods with- wrought, while involving their family in the suffering: out hiccup episodes because the patients limit themselves in their activities in order to avoid any triggering factor. Pa- Iwhen it happens, I gaze at my parents, while jumping, tients reported that this unpredictability generates constant to find some helpI (Patient 5) tension, even among family members, and the desire to maintain a calm environment to avoid triggering stimuli. Patients perceived families felt despair because they Therefore, even when not present, the hiccup symptom af- felt powerless. They considered hiccups worse than con- fects the patient and the family routine. vulsive crises or epileptic seizures because there were anticonvulsant drugs available to control onset and dura- Despairing: There Is Nothing Worse tion of the events. Experiencing these hiccup symptoms Than Hiccups is much more dramatic than the pain of other symptoms Hiccup onset episodes were immediate in the experience suffered during the cancer illness trajectory. of the participants: they reached a plateau and persisted nonstop over time with a fast pace, as much as 1 hiccup every 6 to 7 seconds. High intensity was reached immediately Learning to Control the Pauses after the first hiccup; the symptom also stopped abruptly. In the initial stage of the hiccup experience, patients at- However, although patients were able to recognize early tempted to block each episode through folk remedies, such on if hiccups would be long lasting, they were not able as squirting lemon juice into the mouth to acidify it, creating to estimate their duration in days, which was highly an abdominal compression, holding their breath, and/or undeterminable: coughing. They collected suggestions and folk remedies adopted by others, searching different sources (eg, Internet), Iand I can’t tell when it will be overI (Patient 3) and experimented with all possible solutions. After this first stage, patients’ attitude started to modify Because of its intensity and duration, persistent hiccups radically. With the growing understanding of the malign had a negative influence on patients’ overall quality of life. nature of the symptom and its invincibility even against Hiccup episodes limited several functions for patients, pharmacological treatments, over time, patients learned to such as breathing, communication, nutrition, and sleep: lengthen the pauses between 1 hiccup and the next and to reduce the number of spasms. Control was achieved through IIt starts, even during the night, I know long and tough the management of air: days will follow, and finally I’ll be exhaustedI with my muscles hurting! (Patient 3) II swallow some air, I take it to here [pointing at the stomach level] and play with it as if I had to regurgitate According to the patients,someepisodesalsomay without emitting any soundI (Patient 3) generate muscle pain, due to the constant stress deter- mined by the hiccup, which shakes the patient’s chest II deflate my abdomen, that is, I press my abdomen to in a visible way. Externally, the chest trembles and patients let the air go back up and outI. Sometimes I’m really air emit a sound they would like to avoid, in order not to dis- packedI. Yes, sometimes I ask my wife to help me turb the family; internally, patients feel shaken by some- press from under the diaphragmI (Patient 4) thing they cannot control. The sound of hiccups seems to reverberate, and the chest cannot rest. Increasing the pauses between hiccups guaranteed an According to the participants, each hiccup episode is improvement in quality of life: during these pauses, patients very tiring, consumes a lot of energy, and creates des- learned to talk, drink, eat, and also rest during the night. perate patients who feel they can no longer control the They recognized this as a palliative solution positively af- symptom. fecting their mood by reducing personal and family despair. This dynamic causes fear, stress, and prostration, in- When patients achieved 15-second pauses, they believed cluding despair: they had reached good symptom control and acceptance. According to the words of patients, from their experience, II get scaredI (Patient 2) they could have ‘‘learned before how to live with the hiccups’’

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(patient 1) without devoting much effort to learn how to ond stage, they found a compromise, understanding that it stop hiccups that are invincible. is not possible to avoid the symptom. In this stage, they de- veloped a problem-based coping strategy,19 managing the DISCUSSION pauses and regretting having spent too much time in at- tempts to stop the hiccups. Patients gradually learned to Patients in their advanced neuro-oncological stage were in- live with the possibility of regaining control over a specific volved in sharing their persistent hiccup experiences. Pa- dimension of the symptom, and during the pauses, they tients were approached in the neurosurgical setting and performed activities of daily living essential to guarantee interviewed at home, in a more natural setting, to capture a better quality of life. and understand in-depth their persistent hiccup experi- Family caregivers did not participate directly in the inter- ence. To our knowledge, no previous phenomenology view, although patients reported that the symptom did not studies have been undertaken in the specific field of persis- only compromise their quality of life but that of the entire tent hiccup and neuro-oncology care. family. If on the one hand support is important for pa- According to the findings, persistent hiccups have a dev- tients,20,21 on the other hand, the perception that hiccup astating impact on the quality of life of patients and their episodes have a devastating effect for the entire family families. Because of the unpredictability of their cause(s) who must change their routine in order to avoid any trigger and duration, persistent hiccups are considered the most factor increases the emotional burden of the patients, as difficult symptom patients have confronted in their lives described in the literature.22 and over the course of the cancer disease. In addition, be- cause of the ineffective pharmacological and nonpharma- Study Limitations and Strengths cological interventions tested by patients, hiccups become The study has several limitations. The recruitment of pa- their most desperate symptom. No trigger factors have been tients was performed across several years, from 2007 to identified for hiccup onset, although hiccups are preceded by 2011, according to the rare nature of the phenomena.3,12 a feeling of discomfort, such as seizure auras. Previously, In addition, patients with advanced neuro-oncology prob- authors have documented that hiccups may be considered lems and persistent hiccups in the last 2 months were as 1 form of infant seizure.17 recruited. Therefore, the themes that emerged have de- The quality of life is compromised both in the absence scribed the experience of patients who have been facing of the episodes and during episodes. In the absence of this symptom for a relatively short time. It would be impor- the episodes, patients and families live in a state of alert tant in the future to develop a multicenter study design, in- in an attempt to avoid any possible trigger; during the volving more hospitals/palliative centers, with the aim to episodes, the hiccups impact the patient’s personal and include more patients. It would be equally interesting family’s daily life activities. The inability to prevent and to also include patients with hiccups secondary to malig- especially stop bouts of hiccups leads to feelings of pow- nancies localized in the gastroenteric tract or thoracic erlessness in both patients and families. Furthermore, to viscera in order to gain a more extensive description of avoid triggers, optimal management of symptoms that may the phenomenon. be controlled is recommended (eg, controlling coughs that In addition, according to their advanced stage of disease, may trigger hiccups). participants were not reinterviewed to understand the impact The experience of the symptom expresses a process of symptoms on quality of life, social relationships, and spir- reflecting the desire to have control over one’s own life18: ituality. In the future, it would be interesting to design studies patients first report trying to stop the episodes; after having involving multiple interviews of the same patient to describe reached personal and family desperation and trying pharma- the experience more in-depth, its evolution over time, the in- cological and nonpharmacological treatments, they have tervention(s) adopted in different stages, and the physical, learned to control the situation by handling the hiccup emotional, and spiritual consequences. pauses, lengthening the interval between 1 spasm and Finally, the extensive research process, which lasted the next. The reduction of spasms per minute may be several years, engaged the same group of researchers for explained by PCO2 increases and cerebral vasoconstric- a long time. Although this may give the opportunity to un- tion.1,9 Adopting this palliative strategy, patients reached derstand the phenomenon more in-depth, the fragmentation 4 hiccups/min, with 1 every 15 seconds, up to an accept- of the research process, because of the slow recruitment of able level of symptom discomfort. In the process of symp- patients, may have compromised the opportunity to study tom control, patients seem to have adopted 2 different the phenomenon in more depth. During the research pro- coping strategies: in the first stage, they adopted an emo- cess, patients had the opportunity to meet researchers in the tional-based coping strategy,19 confronting the situation, hospital setting, and then they were contacted at home by trying to understand its meaning and reacting emotionally, the same researchers who performed the interview, ensur- experiencing fear, depression, and desperation. In the sec- ing continuity in the research process.

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CONCLUSIONS Antonelli M, Leggio L. Baclofen in the treatment of persistent hiccup: a case series. Int J Clinl Prac. 2013;67(9):918-921. This first qualitative study based on the descriptive phe- 4. Jatoi A. Palliating hiccups in cancer patients: moving beyond nomenology method was intended to describe the experi- recommendations from Leonard the lion. JSupportOncol. ence of patients with persistent hiccups at home. In the 2009;7(4):129-130. 5. Moretto EN, Wee B, Wiffen PJ, Murchison AG. Interventions for absence of evidence, qualitative approaches help in the treating persistent and intractable hiccups in adults. Cochrane development of hypotheses or of a more thorough under- Database Syst Rev. 2013;1:CD008768. standing of the phenomena, especially from the point of 6. Simon P. Hiccups. Soins. 1966;11(8):321-326. view of patients. 7. Barajas RFJr1, Chi J, Guo L, Barbaro N. Microvascular de- compression in hemifacial spasm resulting from a cerebellopontine Persistent hiccups cause deep distress and helplessness angle lipoma: case report. Neurosurgery. 2008;63(4):E815-E816; and have a negative impact on the quality of life of individ- discussion E816. uals and families. Patients are negatively impacted before 8. Payne BR, Tiel RL, Payne MS, Fisch B. Vagus nerve stimulation and during the episodes, which are unpredictable and pro- for chronic intractable hiccups. Case report. J Neurosurg. 2005; 102(5):935-937. voke great stress. After a phase in which they attempt to 9. Heymann WR. The Heimlich maneuver for hiccups. JEmerg interrupt the hiccup episode, patients learn to control the Med. 2003;25:107-108. pauses and achieve a frequency that permits them to per- 10. Becker DE. Nausea, vomiting, and hiccups: a review of mechanisms form daily living activities. and treatment. Anesth Prog. 2010;57(4):150-157. Nurses should be aware that hiccups affect patients’ to- 11. Thaci B, Burns JD, Delalle I, Vu T, Davies KG. Intractable hiccups resolved after resection of a cavernous malformation of the medulla tal pain in that they worsen the perceptions of other symp- oblongata. Clin Neurol Neurosurg. 2013;115(10):2247-2250. toms. In the absence of strong evidence for the best hiccup 12. Strickland SA, Berlin JD. Hiccups: underappreciated and under treatment, it is recommended that patients and their care- recognized. J Support Oncol. 2009;7(4):128-129. givers be supported in the identification of their personal 13. Spiegelberg H. Doing Phenomenology, Dordrecht, the Netherlands: Martinus Nijhoff; 1975. best treatment. This could be accomplished through in- 14. Polit DF, Tatano Beck C. Fondamenti di Ricerca infermieristica. depth exploration of patient history both to identify trigger Milano, Italy: McGraw-Hill Education; 2014. and ameliorative factors of bouts of hiccups. Future re- 15. Streubert H, Carpenter D. Qualitative Research in Nursing. Advanc- search may explore the benefit of breathing and air control ing the Humanistic Imperative. Philadelphia, PA: Lippincott; 2009. 16. Rose P, Beepy J, Parker D. Academic rigor in the lived experi- to lengthen the pauses that emerged in our patients. This ence of researchers using phenomenological methods in nursing. may help other patients in their attempts to stop persistent J Adv Nurs. 1995;21:1123-1129. hiccups, while easing their discomfort promptly. 17. Wallace AH, Manikkam N, Maxwell F. Seizures and a hiccup in the diagnosis. J Paediatr Child Health. 2004;40(2):707-708. Acknowledgments 18. Savio A1, Priyalatha A. Lived experience of cancer patients and We are grateful to patients and their families who have wel- their family members in a view to develop a palliative care comed us in their house. Sharing their feelings and experiences guideline for the nursing personnel. BMJ Support Palliat Care. 2014;4(suppl 1):A84. has given us the opportunity to grow our understanding and 19. Dunkel-Shetter C, Feinstein LG, Taylor SE, Falke RL. Patterns of to enrich our professional and personal background. coping with cancer. Health Psychol. 1992;11(1):79-87. 20. Zabalegui A, Cabrera E, Navarro M, Cebria MI. Perceived social References support and coping strategies in advanced cancer patients. JRes 1. Marinella MA. Diagnosis and management of hiccups in the Nurs. 2011;5(4):1-12. patientwithadvancedcancer.J Support Oncol. 2009;7(4): 21. Brown M1, Brock M. The burden of end of life careVpromoting 122-127, 130. the psychological recovery of informal care givers. BMJ Support 2. Chang FY, Lu CL. Hiccup: mystery, nature and treatment. Palliat Care. 2014;4(Suppl 1):A48. Neurogastroenterol Motil. 2012;18(2):123-130. 22. Sacks J. Suffering at end of life: a systematic review of the 3. Mirijello A, Addolorato G, D’Angelo C, Ferrulli A, Vassallo G, literature. JHospPalliatNurs. 2013;15(5):286-297.

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