Incidence and impact of withdrawal of life-sustaining therapies in clinical trials of severe traumatic brain injury: A systematic review

Abstract

Background

Most deaths following severe traumatic brain injury follow decisions to withdraw life-sustaining therapies. However, the incidence of the withdrawal of life-sustaining therapies and its potential impact on research data interpretation have been poorly characterized. The aim of this systematic review was to assess the reporting and the impact of withdrawal of life-sustaining therapies in randomized clinical trials of patients with severe traumatic brain injury.

Methods

We searched Medline, Embase, Cochrane Central, BIOSIS, and CINAHL databases and references of included trials. All randomized controlled trials published between January 2002 and August 2015 in the six highest impact journals in general medicine, critical care medicine, and neurocritical care (total of 18 journals) were considered for eligibility. Randomized controlled trials were included if they enrolled adult patients with severe traumatic brain injury (Glasgow Coma Scale ≤ 8) and reported data on mortality. Our primary objective was to assess the proportion of trials reporting the withdrawal of life-sustaining therapies in a publication. Our secondary objectives were to describe the overall mortality rate, the proportion of deaths following the withdrawal of life-sustaining therapies, and to assess the impact of the withdrawal of life-sustaining therapies on trial results.

Results

From 5987 citations retrieved, we included 41 randomized trials (n = 16,364, ranging from 11 to 10,008 patients). Overall mortality was 23% (range = 3%–57%). Withdrawal of life-sustaining therapies was reported in 20% of trials (8/41, 932 patients in trials) and the crude number of deaths due to the withdrawal of life-sustaining therapies was reported in 17% of trials (7/41, 884 patients in trials). In these trials, 63% of deaths were associated with the withdrawal of life-sustaining therapies (105/168). An analysis carried out by imputing a 4% differential rate in instances of withdrawal of life-sustaining therapies between study groups yielded different results and conclusions in one third of the trials.

Conclusion

Data on the withdrawal of life-sustaining therapies are incompletely reported in randomized controlled trials of patients with severe traumatic brain injury. Given the high proportion of deaths due to the withdrawal of life-sustaining therapies in severe traumatic brain injury patients, and the potential of this medical decision to influence the results of clinical trials, instances of withdrawal of life-sustaining therapies should be systematically reported in clinical trials in this group of patients.

Keywords

Brain injury clinical trial life-sustaining therapy end-of-life

Get full access to this article

View all access options for this article.

References

Coronado

Basavaraju

et al . Surveillance for traumatic brain injury-related deaths—United States, 1997–2007. MMWR Surveill Summ 2011; 60: 1–32.

Zygun

Laupland

Hader

et al . Severe traumatic brain injury in a large Canadian health region. Canadian J Neurol Sci 2005; 32: 87–92.

Teasdale

Jennett

Assessment of coma and impaired consciousness: a practical scale. Lancet 1974; 2: 81–84.

Hukkelhoven

Steyerberg

Rampen

et al . Patient age and outcome following severe traumatic brain injury: an analysis of 5600 patients. J Neurosurg 2003; 99: 666–673.

Myburgh

Cooper

Finfer

et al . Epidemiology and 12-month outcomes from traumatic brain injury in Australia and New Zealand. J Trauma 2008; 64: 854–862.

Turgeon

Lauzier

Simard

et al . Mortality associated with withdrawal of life-sustaining therapy for patients with severe traumatic brain injury: a Canadian multicentre cohort study. CMAJ 2011; 183: 1581–1588.

O’Callahan

Fink

Pitts

et al . Withholding and withdrawing of life support from patients with severe head injury. Crit Care Med 1995; 23: 1567–1575.

Ball

Navsaria

Kirkpatrick

et al . The impact of country and culture on end-of-life care for injured patients: results from an international survey. J Trauma 2010; 69: 1323–1333.

Rocker

Cook

Shemie

. Brief review: practice variation in end of life care in the ICU: implications for patients with severe brain injury. Can J Anaesth 2006; 53: 814–819.

10.

Holloway

Quill

. Treatment decisions after brain injury—tensions among quality, preference, and cost. N Engl J Med 2010; 362: 1757–1759.

11.

Ganz

Benbenishty

Hersch

et al . The impact of regional culture on intensive care end of life decision making: an Israeli perspective from the ETHICUS Study. J Med Ethics 2006; 32: 196–199.

12.

Diringer

Edwards

Aiyagari

et al . Factors associated with withdrawal of mechanical ventilation in a neurology/neurosurgery intensive care unit. Crit Care Med 2001; 29: 1792–1797.

13.

Sprung

Woodcock

Sjokvist

et al . Reasons, considerations, difficulties and documentation of end-of-life decisions in European intensive care units: the ETHICUS Study. Intens Care Med 2008; 34: 271–277.

14.

Smith

. Treatment withdrawal and acute brain injury: an integral part of care. Anaesthesia 2012; 67: 941–945.

15.

Wunsch

Harrison

Harvey

et al . End-of-life decisions: a cohort study of the withdrawal of all active treatment in intensive care units in the United Kingdom. Intens Care Med 2005; 31: 823–831.

16.

Cook

Rocker

Marshall

et al . Withdrawal of mechanical ventilation in anticipation of death in the intensive care unit. N Engl J Med 2003; 349: 1123–1132.

17.

Mayer

Kossoff

. Withdrawal of life support in the neurological intensive care unit. Neurology 1999; 52: 1602–1609.

18.

Cote

Turgeon

Lauzier

et al . Factors associated with the withdrawal of life-sustaining therapies in patients with severe traumatic brain injury: a multicenter cohort study. Neurocrit Care 2013; 18: 154–160.

19.

Cooper

Rivara

Wang

et al . Withdrawal of life-sustaining therapy in injured patients: variations between trauma centers and nontrauma centers. J Trauma 2009; 66: 1327–1335.

20.

Azoulay

Metnitz

Sprung

et al . End-of-life practices in 282 intensive care units: data from the SAPS 3 database. Intens Care Med 2009; 35: 623–630.

21.

Esteban

Gordo

Solsona

et al . Withdrawing and withholding life support in the intensive care unit: a Spanish prospective multi-centre observational study. Intens Care Medicine 2001; 27: 1744–1749.

22.

Cook

Guyatt

Jaeschke

et al . Determinants in Canadian health care workers of the decision to withdraw life support from the critically ill: Canadian critical care trials group. JAMA 1995; 273: 703–708.

23.

Garland

Connors

. Physicians’ influence over decisions to forego life support. J Palliat Med 2007; 10: 1298–1305.

24.

Azoulay

Pochard

Garrouste-Orgeas

et al . Decisions to forgo life-sustaining therapy in ICU patients independently predict hospital death. Intens Care Med 2003; 29: 1895–1901.

25.

Kelly

Hoskins

Holloway

. Early stroke mortality, patient preferences, and the withdrawal of care bias. Neurology 2012; 79: 941–944.

26.

Sprung

Eidelman

Pizov

et al . Influence of alterations in foregoing life-sustaining treatment practices on a clinical sepsis trial: The HA-1A Sepsis Study Group. Crit Care Med 1997; 25: 383–387.

27.

Harhay

Wagner

Ratcliffe

et al . Outcomes and statistical power in adult critical care randomized trials. Am J Resp Crit Care Med 2014; 189: 1469–1478.

28.

Bragge

Synnot

Maas

et al . A state-of-the-science overview of randomized controlled trials evaluating acute management of moderate-to-severe traumatic brain injury. J Neurotrauma 2016; 33: 1461–1478.

29.

Geurts

Macleod

van Thiel

et al . End-of-life decisions in patients with severe acute brain injury. Lancet Neurol 2014; 13: 515–524.

30.

Turgeon

Tetrault

Lauzier

. Manners of dying in ICU clinical trials. Ann Am Thorac Soc 2014; 11: 1612–1613.

31.

Higgins

JPT

Green

(eds). Cochrane handbook for systematic reviews of interventions . The Cochrane Collaboration, http://handbook-5-1.cochrane.org/ (2011, accessed 2 February 2018).

32.

Liberati

Altman

Tetzlaff

et al . The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. PLoS Med 2009; 6: e1000100.

33.

Glanville

Lefebvre

Miles

et al . How to identify randomized controlled trials in MEDLINE: ten years on. J Med Libr Assoc 2006; 94: 130–136.

34.

Wong

Wilczynski

Haynes

. Developing optimal search strategies for detecting clinically sound treatment studies in EMBASE. J Med Libr Assoc 2006; 94: 41–47.

35.

Acosta-Escribano

Fernandez-Vivas

Grau Carmona

et al . Gastric versus transpyloric feeding in severe traumatic brain injury: a prospective, randomized trial. Intens Care Med 2010; 36: 1532–1539.

36.

Baker

Rhind

Morrison

et al . Resuscitation with hypertonic saline-dextran reduces serum biomarker levels and correlates with outcome in severe traumatic brain injury patients. J Neurotrauma 2009; 26: 1227–1240.

37.

Bilotta

Caramia

Cernak

et al . Intensive insulin therapy after severe traumatic brain injury: a randomized clinical trial. Neurocrit Care 2008; 9: 159–166.

38.

Bouderka

Fakhir

Bouaggad

et al . Early tracheostomy versus prolonged endotracheal intubation in severe head injury. J Trauma 2004; 57: 251–254.

39.

Bourdeaux

Brown

. Randomized controlled trial comparing the effect of 8.4% sodium bicarbonate and 5% sodium chloride on raised intracranial pressure after traumatic brain injury. Neurocrit Care 2011; 15: 42–45.

40.

Bourgoin

Albanese

Wereszczynski

et al . Safety of sedation with ketamine in severe head injury patients: comparison with sufentanil. Crit Care Med 2003; 31: 711–717.

41.

Bulger

May

Brasel

et al . Out-of-hospital hypertonic resuscitation following severe traumatic brain injury: a randomized controlled trial. JAMA 2010; 304: 1455–1464.

42.

Clifton

Valadka

Zygun

et al . Very early hypothermia induction in patients with severe brain injury (the National Acute Brain Injury Study: Hypothermia II): a randomised trial. Lancet Neurology 2011; 10: 131–139.

43.

Coester

Neumann

Schmidt

. Intensive insulin therapy in severe traumatic brain injury: a randomized trial. J Trauma 2010; 68: 904–911.

44.

Cooper

Myles

McDermott

et al . Prehospital hypertonic saline resuscitation of patients with hypotension and severe traumatic brain injury: a randomized controlled trial. JAMA 2004; 291: 1350–1357.

45.

Cooper

Rosenfeld

Murray

et al . Decompressive craniectomy in diffuse traumatic brain injury. N Engl J Med 2011; 364: 1493–1502.

46.

Cottenceau

Masson

Mahamid

et al . Comparison of effects of equiosmolar doses of mannitol and hypertonic saline on cerebral blood flow and metabolism in traumatic brain injury. J Neurotrauma 2011; 28: 2003–2012.

47.

Cruz

Minoja

Okuchi

et al . Major clinical and physiological benefits of early high doses of mannitol for intraparenchymal temporal lobe hemorrhages with abnormal pupillary widening: a randomized trial. Neurosurgery 2002; 51: 628–638.

48.

Edwards

Arango

Balica

et al . Final results of MRC CRASH, a randomised placebo-controlled trial of intravenous corticosteroid in adults with head injury-outcomes at 6 months. Lancet 2005; 365: 1957–1959.

49.

Roberts

Yates

Sandercock

et al . Effect of intravenous corticosteroids on death within 14 days in 10008 adults with clinically significant head injury (MRC CRASH trial): randomized placebo-controlled trial. Lancet 2004; 364: 1321–1328.

50.

Hashiguchi

Shiozaki

Ogura

et al . Mild hypothermia reduces expression of heat shock protein 60 in leukocytes from severely head-injured patients. J Trauma 2003; 55: 1054–1060.

51.

Ichai

Armando

Orban

et al . Sodium lactate versus mannitol in the treatment of intracranial hypertensive episodes in severe traumatic brain-injured patients. Intens Care Med 2009; 35: 471–479.

52.

Jiang

et al . Efficacy of standard trauma craniectomy for refractory intracranial hypertension with severe traumatic brain injury: a multicenter, prospective, randomized controlled study. J Neurotrauma 2005; 22: 623–628.

53.

Knoller

Levi

Shoshan

et al . Dexanabinol (HU-211) in the treatment of severe closed head injury: a randomized, placebo-controlled, phase II clinical trial. Crit Care Med 2002; 30: 548–554.

54.

Maas

Murray

Henney

et al . Efficacy and safety of dexanabinol in severe traumatic brain injury: results of a phase III randomised, placebo-controlled, clinical trial. Lancet Neurol 2006; 5: 38–45.

55.

Marmarou

Guy

Murphey

et al . A single dose, three-arm, placebo-controlled, phase I study of the bradykinin B2 receptor antagonist Anatibant (LF16-0687Ms) in patients with severe traumatic brain injury. J Neurotrauma 2005; 22: 1444–1455.

56.

Mazzeo

Brophy

Gilman

et al . Safety and tolerability of cyclosporin A in severe traumatic brain injury patients: results from a prospective randomized trial. J Neurotrauma 2009; 26: 2195–2206.

57.

Meissner

Krapp

Kauf

et al . Thyroid hormone response to moderate hypothermia in severe brain injury. Intens Care Med 2003; 29: 44–48.

58.

Morrison

Baker

Rhind

et al . The Toronto prehospital hypertonic resuscitation—head injury and multiorgan dysfunction trial: feasibility study of a randomized controlled trial. J Crit Care 2011; 26: 363–372.

59.

Olivecrona

Rodling-Wahlstrom

Naredi

et al . Prostacyclin treatment in severe traumatic brain injury: a microdialysis and outcome study. J Neurotrauma 2009; 26: 1251–1262.

60.

Perez-Barcena

Llompart-Pou

Homar

et al . Pentobarbital versus thiopental in the treatment of refractory intracranial hypertension in patients with traumatic brain injury: a randomized controlled trial. Crit Care 2008; 12: R112.

61.

Qiu

Guo

Shen

et al . Effects of unilateral decompressive craniectomy on patients with unilateral acute post-traumatic brain swelling after severe traumatic brain injury. Crit Care 2009; 13: R185.

62.

Seguin

Tanguy

Laviolle

et al . Effect of oropharyngeal decontamination by povidone-iodine on ventilator-associated pneumonia in patients with head trauma. Crit Care Med 2006; 34: 1514–1519.

63.

Szaflarski

Sangha

Lindsell

et al . Prospective, randomized, single-blinded comparative trial of intravenous levetiracetam versus phenytoin for seizure prophylaxis. Neurocrit Care 2010; 12: 165–172.

64.

Tan

Zhu

et al . Effects of probiotics on serum levels of Th1/Th2-cytokine and clinical outcomes in severe traumatic brain-injured patients: a prospective randomized pilot study. Criti Care 2011; 15: R290.

65.

Tanguy

Seguin

Laviolle

et al . Cerebral microdialysis effects of propofol versus midazolam in severe traumatic brain injury. J Neurotrauma 2012; 29: 1105–1110.

66.

Vialet

Albanese

Thomachot

et al . Isovolume hypertonic solutes (sodium chloride or mannitol) in the treatment of refractory posttraumatic intracranial hypertension: 2 mL/kg 7.5% saline is more effective than 2 mL/kg 20% mannitol. Crit Care Med 2003; 31: 1683–1687.

67.

Xiao

Wei

Yan

et al . Improved outcomes from the administration of progesterone for patients with acute severe traumatic brain injury: a randomized controlled trial. Criti Care 2008; 12: R61.

68.

Yurkewicz

Weaver

Bullock

et al . The effect of the selective NMDA receptor antagonist traxoprodil in the treatment of traumatic brain injury. J Neurotrauma 2005; 22: 1428–1443.

69.

Zhao

Zhang

Wang

. Mild hypothermia therapy reduces blood glucose and lactate and improves neurologic outcomes in patients with severe traumatic brain injury. J Crit Care 2011; 26: 311–315.

70.

Zygun

Nortje

Hutchinson

et al . The effect of red blood cell transfusion on cerebral oxygenation and metabolism after severe traumatic brain injury. Crit Care Med 2009; 37: 1074–1078.

71.

Chesnut

Temkin

Carney

et al . A trial of intracranial-pressure monitoring in traumatic brain injury. N Engl J Med 2012; 367: 2471–2481.

72.

Roquilly

Loutrel

Cinotti

et al . Balanced versus chloride-rich solutions for fluid resuscitation in brain-injured patients: a randomised double-blind pilot study. Crit Care 2013; 17: R77.

73.

Maekawa

Yamashita

Nagao

et al . Prolonged mild therapeutic hypothermia versus fever control with tight hemodynamic monitoring and slow rewarming in patients with severe traumatic brain injury: a randomized controlled trial. J Neurotrauma 2015; 32: 422–429.

74.

Stover

Belli

Boret

et al . Nitric oxide synthase inhibition with the antipterin VAS203 improves outcome in moderate and severe traumatic brain injury: a placebo-controlled randomized Phase IIa trial (NOSTRA). J Neurotrauma 2014; 31: 1599–1606.

75.

NICE-SUGAR Study Investigators for the Australian and New Zealand Intensive Care Society Clinical Trials Group and the Canadian Critical Care Trials Group, Finfer

Chittock

et al . Intensive versus conventional glucose control in critically ill patients with traumatic brain injury: long-term follow-up of a subgroup of patients from the NICE-SUGAR Study. Intens Care Med 2015; 41: 1037–1047.

76.

Van Haren

Thorson

Ogilvie

et al . Vasopressin for cerebral perfusion pressure management in patients with severe traumatic brain injury: preliminary results of a randomized controlled trial. J Trauma Acute Care Surg 2013; 75: 1024–1030.

77.

Sinuff

Dodek

You

et al . Improving end-of-life communication and decision making: the development of a conceptual framework and quality indicators. J Pain Symptom Manag 2015; 49: 1070–1080.

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.00 MB

0.01 MB

0.10 MB

0.01 MB

0.20 MB