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

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.

[1]  J. Higgins,et al.  Cochrane Handbook for Systematic Reviews of Interventions , 2010, International Coaching Psychology Review.

[2]  D. Menon,et al.  A State-of-the-Science Overview of Randomized Controlled Trials Evaluating Acute Management of Moderate-to-Severe Traumatic Brain Injury. , 2016, Journal of neurotrauma.

[3]  D. Heyland,et al.  Improving End-of-Life Communication and Decision Making: The Development of a Conceptual Framework and Quality Indicators. , 2015, Journal of pain and symptom management.

[4]  D. Cook,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 , 2015, Intensive Care Medicine.

[5]  Y. Ohashi,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. , 2015, Journal of neurotrauma.

[6]  F. Lauzier,et al.  Manners of dying in ICU clinical trials. , 2014, Annals of the American Thoracic Society.

[7]  F. StoverJohn,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). , 2014 .

[8]  Dylan S. Small,et al.  Outcomes and statistical power in adult critical care randomized trials. , 2014, American journal of respiratory and critical care medicine.

[9]  M. Macleod,et al.  End-of-life decisions in patients with severe acute brain injury , 2014, The Lancet Neurology.

[10]  K. Proctor,et al.  Vasopressin for cerebral perfusion pressure management in patients with severe traumatic brain injury: Preliminary results of a randomized controlled trial , 2013, The journal of trauma and acute care surgery.

[11]  C. Volteau,et al.  Balanced versus chloride-rich solutions for fluid resuscitation in brain-injured patients: a randomised double-blind pilot study , 2013, Critical Care.

[12]  M. Meade,et al.  Factors Associated with the Withdrawal of Life-Sustaining Therapies in Patients with Severe Traumatic Brain Injury: A Multicenter Cohort Study , 2013, Neurocritical Care.

[13]  N. Carney,et al.  A trial of intracranial-pressure monitoring in traumatic brain injury. , 2012, The New England journal of medicine.

[14]  M. Smith,et al.  Treatment withdrawal and acute brain injury: an integral part of care , 2012, Anaesthesia.

[15]  R. Holloway,et al.  Early stroke mortality, patient preferences, and the withdrawal of care bias , 2012, Neurology.

[16]  Xavier Morandi,et al.  Cerebral microdialysis effects of propofol versus midazolam in severe traumatic brain injury. , 2012, Journal of neurotrauma.

[17]  Min Tan,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 , 2011, Critical care.

[18]  J. Soustiel,et al.  Comparison of effects of equiosmolar doses of mannitol and hypertonic saline on cerebral blood flow and metabolism in traumatic brain injury. , 2011, Journal of neurotrauma.

[19]  M. Meade,et al.  Mortality associated with withdrawal of life-sustaining therapy for patients with severe traumatic brain injury: a Canadian multicentre cohort study , 2011, Canadian Medical Association Journal.

[20]  D. Stuss,et al.  The Toronto prehospital hypertonic resuscitation--head injury and multiorgan dysfunction trial: feasibility study of a randomized controlled trial. , 2011, Journal of critical care.

[21]  Le-Xin Wang,et al.  Mild hypothermia therapy reduces blood glucose and lactate and improves neurologic outcomes in patients with severe traumatic brain injury. , 2011, Journal of critical care.

[22]  M. Wald,et al.  Surveillance for traumatic brain injury-related deaths--United States, 1997-2007. , 2011, Morbidity and mortality weekly report. Surveillance summaries.

[23]  J. Ponsford,et al.  Decompressive craniectomy in diffuse traumatic brain injury. , 2011, The New England journal of medicine.

[24]  C. Bourdeaux,et al.  Randomized Controlled Trial Comparing the Effect of 8.4% Sodium Bicarbonate and 5% Sodium Chloride on Raised Intracranial Pressure after Traumatic Brain Injury , 2011, Neurocritical care.

[25]  G. Clifton,et al.  Very early hypothermia induction in patients with severe brain injury (the National Acute Brain Injury Study: Hypothermia II): a randomised trial , 2011, The Lancet Neurology.

[26]  G. Rozycki,et al.  The impact of country and culture on end-of-life care for injured patients: results from an international survey. , 2010, The Journal of trauma.

[27]  Arthur S Slutsky,et al.  Out-of-hospital hypertonic resuscitation following severe traumatic brain injury: a randomized controlled trial. , 2010, JAMA.

[28]  J. Sánchez-Payá,et al.  Gastric versus transpyloric feeding in severe traumatic brain injury: a prospective, randomized trial , 2010, Intensive Care Medicine.

[29]  R. Holloway,et al.  Treatment decisions after brain injury--tensions among quality, preference, and cost. , 2010, The New England journal of medicine.

[30]  J. Szaflarski,et al.  Prospective, Randomized, Single-Blinded Comparative Trial of Intravenous Levetiracetam Versus Phenytoin for Seizure Prophylaxis , 2010, Neurocritical Care.

[31]  R. Hayes,et al.  Safety and tolerability of cyclosporin a in severe traumatic brain injury patients: results from a prospective randomized trial. , 2009, Journal of neurotrauma.

[32]  Maria Inês Schmidt,et al.  Intensive insulin therapy in severe traumatic brain injury: a randomized trial. , 2009, The Journal of trauma.

[33]  Qizhou Jiang,et al.  Effects of unilateral decompressive craniectomy on patients with unilateral acute post-traumatic brain swelling after severe traumatic brain injury , 2009, Critical care.

[34]  L. Morrison,et al.  Resuscitation with hypertonic saline-dextran reduces serum biomarker levels and correlates with outcome in severe traumatic brain injury patients. , 2009, Journal of neurotrauma.

[35]  L. Koskinen,et al.  Prostacyclin treatment in severe traumatic brain injury: a microdialysis and outcome study. , 2009, Journal of neurotrauma.

[36]  J. Ioannidis,et al.  The PRISMA Statement for Reporting Systematic Reviews and Meta-Analyses of Studies That Evaluate Health Care Interventions: Explanation and Elaboration , 2009, Annals of Internal Medicine [serial online].

[37]  E. Mackenzie,et al.  Withdrawal of life-sustaining therapy in injured patients: variations between trauma centers and nontrauma centers. , 2009, The Journal of trauma.

[38]  C. Sprung,et al.  End-of-life practices in 282 intensive care units: data from the SAPS 3 database , 2009, Intensive Care Medicine.

[39]  D. Menon,et al.  The effect of red blood cell transfusion on cerebral oxygenation and metabolism after severe traumatic brain injury* , 2009, Critical care medicine.

[40]  X. Leverve,et al.  Sodium lactate versus mannitol in the treatment of intracranial hypertensive episodes in severe traumatic brain-injured patients , 2009, Intensive Care Medicine.

[41]  J. A. Llompart-Pou,et al.  Pentobarbital versus thiopental in the treatment of refractory intracranial hypertension in patients with traumatic brain injury: a randomized controlled trial , 2008, Critical care.

[42]  Guoming Xiao,et al.  Improved outcomes from the administration of progesterone for patients with acute severe traumatic brain injury: a randomized controlled trial , 2008, Critical care.

[43]  Daryl A Jones,et al.  Epidemiology and 12-month outcomes from traumatic brain injury in australia and new zealand. , 2008, The Journal of trauma.

[44]  F. Bilotta,et al.  Intensive Insulin Therapy After Severe Traumatic Brain Injury: A Randomized Clinical Trial , 2008, Neurocritical care.

[45]  C. Sprung,et al.  Reasons, considerations, difficulties and documentation of end-of-life decisions in European intensive care units: the ETHICUS Study , 2008, Intensive Care Medicine.

[46]  A. Garland,et al.  Physicians' influence over decisions to forego life support. , 2007, Journal of palliative medicine.

[47]  D. Cook,et al.  Brief review: Practice variation in end of life care in the ICU: implications for patients with severe brain injury , 2006, Canadian journal of anaesthesia = Journal canadien d'anesthesie.

[48]  B. Laviolle,et al.  Effect of oropharyngeal decontamination by povidone-iodine on ventilator-associated pneumonia in patients with head trauma* , 2006, Critical care medicine.

[49]  Carol Lefebvre,et al.  How to identify randomized controlled trials in MEDLINE: ten years on. , 2006, Journal of the Medical Library Association : JMLA.

[50]  C. Sprung,et al.  The impact of regional culture on intensive care end of life decision making: an Israeli perspective from the ETHICUS study , 2006, Journal of Medical Ethics.

[51]  N. Knoller,et al.  Efficacy and safety of dexanabinol in severe traumatic brain injury: results of a phase III randomised, placebo-controlled, clinical trial , 2006, The Lancet Neurology.

[52]  M. Bullock,et al.  The effect of the selective NMDA receptor antagonist traxoprodil in the treatment of traumatic brain injury. , 2005, Journal of neurotrauma.

[53]  A. Marmarou,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. , 2005, Journal of neurotrauma.

[54]  Jun Zhang,et al.  Efficacy of standard trauma craniectomy for refractory intracranial hypertension with severe traumatic brain injury: a multicenter, prospective, randomized controlled study. , 2005, Journal of neurotrauma.

[55]  Peter Sandercock,et al.  Final results of MRC CRASH, a randomised placebo-controlled trial of intravenous corticosteroid in adults with head injury—outcomes at 6 months , 2005, The Lancet.

[56]  H. Wunsch,et al.  End-of-life decisions: a cohort study of the withdrawal of all active treatment in intensive care units in the United Kingdom , 2005, Intensive Care Medicine.

[57]  C. Doig,et al.  Severe Traumatic Brain Injury in a Large Canadian Health Region , 2005, Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques.

[58]  P. Sandercock,et al.  Effect of intravenous corticosteroids on death within 14 days in 10 008 adults with clinically significant head injury (MRC CRASH trial): randomised placebo-controlled trial , 2004, The Lancet.

[59]  B. Fakhir,et al.  Early tracheostomy versus prolonged endotracheal intubation in severe head injury. , 2004, The Journal of trauma.

[60]  J. Ponsford,et al.  Prehospital hypertonic saline resuscitation of patients with hypotension and severe traumatic brain injury: a randomized controlled trial. , 2004, JAMA.

[61]  T. Shimazu,et al.  Mild hypothermia reduces expression of heat shock protein 60 in leukocytes from severely head-injured patients. , 2003, The Journal of trauma.

[62]  J. Timsit,et al.  Decisions to forgo life-sustaining therapy in ICU patients independently predict hospital death , 2003, Intensive Care Medicine.

[63]  J. Habbema,et al.  Patient age and outcome following severe traumatic brain injury: an analysis of 5600 patients. , 2003, Journal of neurosurgery.

[64]  Joseph Varon,et al.  Withdrawal of mechanical ventilation in anticipation of death in the intensive care unit. , 2003, The New England journal of medicine.

[65]  L. 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. , 2003, Critical care medicine.

[66]  R. Vialet,et al.  Safety of sedation with ketamine in severe head injury patients: Comparison with sufentanil , 2003, Critical care medicine.

[67]  J. Cruz,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 , 2002, Neurosurgery.

[68]  N. Knoller,et al.  Dexanabinol (HU-211) in the treatment of severe closed head injury: a randomized, placebo-controlled, phase II clinical trial. , 2002, Critical care medicine.

[69]  D. Cook,et al.  Withdrawing and withholding life support in the intensive care unit: a Spanish prospective multi-centre observational study , 2001, Intensive Care Medicine.

[70]  M. Diringer,et al.  Factors associated with withdrawal of mechanical ventilation in a neurology/neurosurgery intensive care unit , 2001, Critical care medicine.

[71]  S. Mayer,et al.  Withdrawal of life support in the neurological intensive care unit , 1999, Neurology.

[72]  C. Sprung,et al.  Influence of alterations in forgoing life-sustaining treatment practices on a clinical sepsis trial , 1997 .

[73]  L. Pitts,et al.  Withholding and withdrawing of life support from patients with severe head injury. , 1995, Critical care medicine.

[74]  G. Guyatt,et al.  Determinants in Canadian health care workers of the decision to withdraw life support from the critically ill. Canadian Critical Care Trials Group. , 1995, JAMA.

[75]  B. Jennett,et al.  Assessment of coma and impaired consciousness. A practical scale. , 1974, Lancet.

[76]  U. Ungerstedt,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). , 2014, Journal of neurotrauma.

[77]  R Brian Haynes,et al.  Developing optimal search strategies for detecting clinically sound treatment studies in EMBASE. , 2006, Journal of the Medical Library Association : JMLA.

[78]  K. Reinhart,et al.  Thyroid hormone response to moderate hypothermia in severe brain injury , 2002, Intensive Care Medicine.

[79]  C. Sprung,et al.  Influence of alterations in foregoing life-sustaining treatment practices on a clinical sepsis trial. The HA-1A Sepsis Study Group. , 1997, Critical care medicine.