Supportive Care in Cancer

, Volume 26, Issue 6, pp 1763–1771 | Cite as

Efficacy of two types of palliative sedation therapy defined using intervention protocols: proportional vs. deep sedation

  • Kengo ImaiEmail author
  • Tatsuya Morita
  • Naosuke Yokomichi
  • Masanori Mori
  • Akemi Shirado Naito
  • Hiroaki Tsukuura
  • Toshihiro Yamauchi
  • Takashi Kawaguchi
  • Kaori Fukuta
  • Satoshi Inoue
Original Article



This study investigated the effect of two types of palliative sedation defined using intervention protocols: proportional and deep sedation.


We retrospectively analyzed prospectively recorded data of consecutive cancer patients who received the continuous infusion of midazolam in a palliative care unit. Attending physicians chose the sedation protocol based on each patient’s wish, symptom severity, prognosis, and refractoriness of suffering. The primary endpoint was a treatment goal achievement at 4 h: in proportional sedation, the achievement of symptom relief (Support Team Assessment Schedule (STAS) ≤ 1) and absence of agitation (modified Richmond Agitation-Sedation Scale (RASS) ≤ 0) and in deep sedation, the achievement of deep sedation (RASS ≤ − 4). Secondary endpoints included mean scores of STAS and RASS, deep sedation as a result, and adverse events.


Among 398 patients who died during the period, 32 received proportional and 18 received deep sedation. The treatment goal achievement rate was 68.8% (22/32, 95% confidence interval 52.7–84.9) in the proportional sedation group vs. 83.3% (15/18, 66.1–100) in the deep sedation group. STAS decreased from 3.8 to 0.8 with proportional sedation at 4 h vs. 3.7 to 0.3 with deep sedation; RASS decreased from + 1.2 to − 1.7 vs. + 1.4 to − 3.7, respectively. Deep sedation was needed as a result in 31.3% (10/32) of the proportional sedation group. No fatal events that were considered as probably or definitely related to the intervention occurred.


The two types of intervention protocol well reflected the treatment intention and expected outcomes. Further, large-scale cohort studies are promising.


Palliative sedation therapy Intervention protocol Continuous infusion of midazolam Proportional sedation Deep sedation Definition 



This study was conducted with the cooperation of the palliative care unit of the Seirei Mikatahara General Hospital. The authors would like to thank all the participants. This study was supported by the Japanese Society for the Promotion of Science KAKENHI Grant Number JP16H05212.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.


  1. 1.
    Seow H, Barbera L, Sutradhar R, Howell D, Dudgeon D, Atzema C, Liu Y, Husain A, Sussman J, Earle C (2011) Trajectory of performance status and symptom scores for patients with cancer during the last six months of life. J Clin Oncol 29(9):1151–1158. CrossRefGoogle Scholar
  2. 2.
    Hui D, Santos RD, Chisholm GB, Bruera E (2015) Symptom expression in the last seven days of life among cancer patients admitted to acute palliative care units. J Pain Symptom Manag 50(4):488–494. CrossRefGoogle Scholar
  3. 3.
    Beller EM, van Driel ML, McGregor L, Truong S, Mitchell G (2015) Palliative pharmacological sedation for terminally ill adults. Cochrane Database Syst Rev 1:CD010206Google Scholar
  4. 4.
    Cherny NI, ESMO Guidelines Working Group (2014) ESMO Clinical Practice Guidelines for the management of refractory symptoms at the end of life and the use of palliative sedation. Ann Oncol 25 Suppl 3:iii143–iii152CrossRefGoogle Scholar
  5. 5.
    Cherny NI, Radbruch L, Board of the European Association for Palliative Care (2009) European Association for Palliative Care (EAPC) recommended framework for the use of sedation in palliative care. Palliat Med 23:581–593CrossRefGoogle Scholar
  6. 6.
    Kirk TW, Mahon MM, Palliative Sedation Task Force of the National Hospice and Palliative Care Organization Ethics Committee (2010) National Hospice and Palliative Care Organization (NHPCO) position statement and commentary on the use of palliative sedation in imminently dying terminally ill patients. J Pain Symptom Manag 39:914–923CrossRefGoogle Scholar
  7. 7.
    Verkerk M, van Wijlick E, Legemaate J, de Graeff A (2007) A national guideline for palliative sedation in the Netherlands. J Pain Symptom Manag 34(6):666–670. CrossRefGoogle Scholar
  8. 8.
    Morita T, Bito S, Kurihara Y, Uchitomi Y (2005) Development of a clinical guideline for palliative sedation therapy using the Delphi method. J Palliat Med 8(4):716–729. CrossRefGoogle Scholar
  9. 9.
    Dean MM, Cellarius V, Henry B, Oneschuk D, Librach SL, Canadian Society Of Palliative Care Physicians Taskforce (2012) Framework for continuous palliative sedation therapy in Canada. J Palliat Med 15:870–879CrossRefGoogle Scholar
  10. 10.
    Quill TE (1993) The ambiguity of clinical intentions. N Engl J Med 329:1039e1040CrossRefGoogle Scholar
  11. 11.
    Jansen LA (2010) Disambiguating clinical intentions: the ethics of palliative sedation. J Med Philos 35:19e31CrossRefGoogle Scholar
  12. 12.
    Claessens P, Menten J, Schotsmans P, Broeckaert B (2008) Palliative sedation: a review of the research literature. J Pain Symptom Manag 36(3):310–333. CrossRefGoogle Scholar
  13. 13.
    Papavasiliou ES, Brearley SG, Seymour JE, Brown J, Payne SA, EURO IMPACT (2013) From sedation to continuous sedation until death: how has the conceptual basis of sedation in end-of-life care changed over time? J Pain Symptom Manag 46(5):691–706. CrossRefGoogle Scholar
  14. 14.
    Morita T, Imai K, Yokomichi N, Mori M, Kizawa Y, Tsuneto S (2017) Continuous deep sedation: a proposal for performing more rigorous empirical research. J Pain Symptom Manag 53(1):146–152. CrossRefGoogle Scholar
  15. 15.
    Quill TE, Lo B, Brock DW, Meisel A (2009) Last-resort options for palliative sedation. Ann Intern Med 151(6):421–424. CrossRefGoogle Scholar
  16. 16.
    Swart SJ, van der Heide A, van Zuylen L, Perez RS, Zuurmond WW, van der Maas PJ, van Delden JJ, Rietjens JA (2012) Considerations of physicians about the depth of palliative sedation at the end of life. CMAJ 184(7):E360–E366. CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Seymour J, Rietjens J, Bruinsma S, Deliens L, Sterckx S, Mortier F, Brown J, Mathers N, van der Heide A, UNBIASED consortium (2015) Using continuous sedation until death for cancer patients: a qualitative interview study of physicians’ and nurses’ practice in three European countries. Palliat Med 29(1):48–59. CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Schildmann EK, Schildmann J, Kiesewetter I (2015) Medication and monitoring in palliative sedation therapy: a systematic review and quality assessment of published guidelines. J Pain Symptom Manag 49(4):734–746. CrossRefGoogle Scholar
  19. 19.
    de Graeff A, Dean M (2007) Palliative sedation therapy in the last weeks of life: a literature review and recommendations for standards. Palliat Med 10(1):67–85. CrossRefGoogle Scholar
  20. 20.
    Jacobi J, Fraser GL, Coursin DB, Riker RR, Fontaine D, Wittbrodt ET, Chalfin DB, Masica MF, Bjerke HS, Coplin WM, Crippen DW, Fuchs BD, Kelleher RM, Marik PE, Nasraway SA Jr, Murray MJ, Peruzzi WT, Lumb PD, Task Force of the American College of Critical Care Medicine (ACCM) of the Society of Critical Care Medicine (SCCM), American Society of Health-System Pharmacists (ASHP), American College of Chest Physicians (2002) Clinical practice guidelines for the sustained use of sedatives and analgesics in the critically ill adult. Crit Care Med 30(1):119–141. CrossRefGoogle Scholar
  21. 21.
    Zomorodi K, Donner A, Somma J, Barr J, Sladen R, Ramsay J, Geller E, Shafer SL (1998) Population pharmacokinetics of midazolam administered by target controlled infusion for sedation following coronary artery bypass grafting. Anesthesiology 89(6):1418–1429. CrossRefGoogle Scholar
  22. 22.
    Somma J, Donner A, Zomorodi K, Sladen R, Ramsay J, Geller E, Shafer SL (1998) Population pharmacodynamics of midazolam administered by target controlled infusion in SICU patients after CABG surgery. Anesthesiology 89(6):1430–1443. CrossRefGoogle Scholar
  23. 23.
    Albrecht S, Ihmsen H, Hering W, Geisslinger G, Dingemanse J, Schwilden H, Schüttler J (1999) The effect of age on the pharmacokinetics and pharmacodynamics of midazolam. Clin Pharmacol Ther 65(6):630–639. CrossRefGoogle Scholar
  24. 24.
    Bremer F, Reulbach U, Schwilden H, Schüttler J (2004) Midazolam therapeutic drug monitoring in intensive care sedation: a 5-year survey. Ther Drug Monit 26(6):643–649. CrossRefGoogle Scholar
  25. 25.
    Pecking M, Montestruc F, Marquet P, Wodey E, Homery MC, Dostert P (2002) Absolute bioavailability of midazolam after subcutaneous administration to healthy volunteers. Br J Clin Pharmacol 54(4):357–362. CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Carson MG, Fitch MI, Vachon ML (2000) Measuring patient outcomes in palliative care: a reliability and validity study of the Support Team Assessment Schedule. Palliat Med 14(1):25–36. CrossRefGoogle Scholar
  27. 27.
    Miyashita M, Matoba K, Sasahara T, Kizawa Y, Maruguchi M, Abe M, Kawa M, Shima Y (2004) Reliability and validity of the Japanese version of the Support Team Assessment Schedule (STAS-J). Palliat Support Care 2(4):379–385CrossRefGoogle Scholar
  28. 28.
    Lichtner V, Dowding D, Esterhuizen P, Closs SJ, Long AF, Corbett A, Briggs M (2014) Pain assessment for people with dementia: a systematic review of systematic of pain assessment tools. BMC Geriatr 14:138CrossRefGoogle Scholar
  29. 29.
    Sessler CN, Gosnell MS, Grap MJ, Brophy GM, O’Neal PV, Keane KA, Tesoro EP, Elswick RK (2002) The Richmond Agitation-Sedation Scale: validity and reliability in adult intensive care unit patients. Am J Respir Crit Care Med 166(10):1338–1344. CrossRefGoogle Scholar
  30. 30.
    Benítez-Rosario MA, Castillo-Padrós M, Garrido-Bernet B, González-Guillermo T, Martínez-Castillo LP, González A, Members of the Asocación Canaria de Cuidados Paliativos (CANPAL) Research Network (2013) Appropriateness and reliability testing of the modified Richmond Agitation-Sedation Scale in Spanish patients with advanced cancer. J Pain Symptom Manag 45:1112–1119CrossRefGoogle Scholar
  31. 31.
    Imai K, Morita T, Mori M, Yokomichi N, Fukuta K (2016) Development and linguistic validation of the Japanese version of the modified Richmond Agitation-Sedation Scale. Palliat Care Res 11(4):331–336 (in Japanese). CrossRefGoogle Scholar
  32. 32.
    Oken M, Creech R, Tormey D, Horton J, Davis TE, McFadden ET, Carbone PP (1982) Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 5(6):649–655. CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Elsayem A, Curry Iii E, Boohene J, Munsell MF, Calderon B, Hung F, Bruera E (2009) Use of palliative sedation for intractable symptoms in the palliative care unit of a comprehensive cancer center. Support Care Cancer 17(1):53–59. CrossRefGoogle Scholar
  34. 34.
    Sykes N, Thorns A (2003) The use of opioids and sedatives at the end of life. Lancet Oncol 4(5):312–318. CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2017

Authors and Affiliations

  • Kengo Imai
    • 1
    Email author
  • Tatsuya Morita
    • 2
  • Naosuke Yokomichi
    • 1
  • Masanori Mori
    • 3
  • Akemi Shirado Naito
    • 1
  • Hiroaki Tsukuura
    • 1
  • Toshihiro Yamauchi
    • 1
  • Takashi Kawaguchi
    • 4
  • Kaori Fukuta
    • 5
  • Satoshi Inoue
    • 1
  1. 1.Seirei HospiceSeirei Mikatahara General HospitalHamamatsuJapan
  2. 2.Division of Palliative and Supportive CareSeirei Mikatahara General HospitalHamamatsuJapan
  3. 3.Palliative Care TeamSeirei Mikatahara General HospitalHamamatsuJapan
  4. 4.Department of Practical PharmacyTokyo University of Pharmacy and Life SciencesTokyoJapan
  5. 5.Department of NursingSeirei Mikatahara General HospitalHamamatsuJapan

Personalised recommendations