## Protocol Section
### Identification Module
**NCT ID:** NCT06429657

**Acronym:** Ketamine

**Brief Title:** Ketamine for Sedation in Severe Traumatic Brain Injury

**Official Title:** Ketamine for Sedation in Severe Traumatic Brain Injury

#### Organization Study ID Info
**ID:** C.2024.025
#### Organization
**Class:** OTHER
**Full Name:** Henry M. Jackson Foundation for the Advancement of Military Medicine
### Status Module
#### Completion Date
**Date:** 2027-06-30

**Type:** ESTIMATED

#### Expanded Access Info
#### Last Update Post Date
**Date:** 2024-05-28

**Type:** ACTUAL

**Last Update Submit Date:** 2024-05-23

**Overall Status:** NOT_YET_RECRUITING

#### Primary Completion Date
**Date:** 2027-01-01

**Type:** ESTIMATED

#### Start Date
**Date:** 2024-06-01

**Type:** ESTIMATED

**Status Verified Date:** 2024-05

#### Study First Post Date
**Date:** 2024-05-28
**Type:** ACTUAL
**Study First Submit Date:** 2024-04-16
**Study First Submit QC Date:** 2024-05-23
### Sponsor Collaborators Module

#### Collaborators

**Class:** FED

**Name:** Uniformed Services University of the Health Sciences

**Class:** FED

**Name:** Brooke Army Medical Center

#### Lead Sponsor

**Class:** OTHER

**Name:** Henry M. Jackson Foundation for the Advancement of Military Medicine

#### Responsible Party

**Type:** SPONSOR

### Oversight Module

**Is FDA Regulated Device:** False

**Is FDA Regulated Drug:** True

**Is US Export:** True

**Oversight Has DMC:** False

### Description Module

**Brief Summary:** This protocol is for an open-label randomized trial evaluating the safety of using ketamine in combination with propofol for sedation versus the standard of care analgosedation in patients admitted to the intensive care unit with severe traumatic brain injury.

**Detailed Description:** Patients meeting eligibility criteria and consent having been obtained by LAR will undergo randomization to either the ketamine with propofol intervention arm or the standard of care control arm.

Patients enrolled in the intervention arm will receive propofol at a rate of 300 mcg/kg/hr (5 mcg/kg/min) with the addition of ketamine at a rate of 1000-5000 mcg/kg/hr (16.67 - 83.33 mcg/kg/min) (using weight at time of admission) with an additional 2 mg/kg (2000 mcg/kg) bolus of ketamine, for sustained ICP elevations over 22mHg for greater than 5 minutes not attributed to other causes (coughing etc.). In the control arm, patients will receive their institutional analgosedation protocol. The sedation protocols will be continued until removal of intracranial pressure monitoring.

This study will take place during the participant's hospital care. The clinical team will administer treatment using standard practices, including all safety precautions available. Side effects will be monitored closely and may decide to discontinue the subject's participation in the study should the subject's health or safety are at risk.

The research team will performed one outpatient follow-up after study intervention ends.

### Conditions Module

**Conditions:**

- Severe Traumatic Brain Injury

- Intracranial Hypertension

- Intracranial Hemorrhage, Hypertensive

**Keywords:**

- TBI

- Severe TBI

- Traumatic Brain Injury

- Sedation

- Ketamine

### Design Module

#### Design Info

**Allocation:** RANDOMIZED

**Intervention Model:** PARALLEL

##### Masking Info

**Masking:** NONE

**Primary Purpose:** TREATMENT

#### Enrollment Info

**Count:** 50

**Type:** ESTIMATED

**Phases:**

- PHASE4

**Study Type:** INTERVENTIONAL

### Arms Interventions Module

#### Arm Group 1

**Description:** Propofol at a rate of 300 mcg/kg/hr (5 mcg/kg/min) with the addition of ketamine at a rate of 1000-5000 mcg/kg/hr (16.67 - 83.33 mcg/kg/min) (using weight at time of admission) with an additional 2 mg/kg (2000 mcg/kg) bolus of ketamine

**Intervention Names:**

- Drug: Ketamine with propofol

**Label:** Ketamine with propofol

**Type:** EXPERIMENTAL

#### Arm Group 2

**Description:** Standard of Care analgosedation of choice using propofol, fentanyl, dexmedetomidine, morphine, hydromorphone, midazolam, or lorazepam.

**Intervention Names:**

- Other: Standard of Care propofol, fentanyl, dexmedetomidine, morphine, hydromorphone, midazolam, or lorazepam

**Label:** SOC propofol, fentanyl, dexmedetomidine, morphine, hydromorphone, midazolam, or lorazepam

**Type:** ACTIVE_COMPARATOR

### Interventions

#### Intervention 1

**Arm Group Labels:**

- Ketamine with propofol

**Description:** Propofol at a rate of 300 mcg/kg/hr (5 mcg/kg/min) with the addition of ketamine at a rate of 1000-5000 mcg/kg/hr (16.67 - 83.33 mcg/kg/min) (using weight at time of admission) with an additional 2 mg/kg (2000 mcg/kg) bolus of ketamine

**Name:** Ketamine with propofol

**Type:** DRUG

#### Intervention 2

**Arm Group Labels:**

- SOC propofol, fentanyl, dexmedetomidine, morphine, hydromorphone, midazolam, or lorazepam

**Description:** Standard of Care analgosedation of choice using propofol, fentanyl, dexmedetomidine, morphine, hydromorphone, midazolam, or lorazepam administered according to the institutional SOC guidelines.

**Name:** Standard of Care propofol, fentanyl, dexmedetomidine, morphine, hydromorphone, midazolam, or lorazepam

**Type:** OTHER

### Outcomes Module

#### Primary Outcomes

**Description:** ICP elevations \> 22 mmHg for greater than 5 minutes.

**Measure:** Number of ICP elevations greater than 22 mmHg for greater than 5 minutes

**Time Frame:** During the maximum 5-day course of study intervention, while patient is sedated and has intracranial pressure monitor in place in the ICU setting

**Description:** Mean ICP

**Measure:** Mean ICP

**Time Frame:** During the maximum 5-day course of study intervention.

#### Secondary Outcomes

**Description:** Total time spent with ICP \>22 mmHg (in minutes).

**Measure:** Total time spent with intracranial pressure (ICP) >22 mmHg

**Time Frame:** During the maximum 5-day course of study intervention.

**Description:** Mean CPP (in minutes).

**Measure:** Mean Cerebral Perfusion Pressure (CPP)

**Time Frame:** During the maximum 5-day course of study intervention.

**Description:** Total time spent with CPP \<60 mmHg (in minutes).

**Measure:** Total time spent with CPP <60 mmHg

**Time Frame:** During the maximum 5-day course of study intervention.

**Description:** Total number of events where CPP \<60 mmHg (in minutes) for greater than 5 minutes.

**Measure:** Total number of events where CPP <60 mmHg for greater than 5 minutes

**Time Frame:** During the maximum 5-day course of study intervention.

**Description:** Relationship between vasopressor infusion dose and mean arterial blood pressure. VDI= (dobutamine dose × 1) + (dopamine dose × 1) + (norepinephrine dose × 100) + (vasopressin × 100) + (epinephrine × 100))/MAP indicating the relationship of high VDI and poor outcome.

**Measure:** Vasopressor dependency index (VDI)

**Time Frame:** During the maximum 5-day course of study intervention.

**Description:** Incidence of seizures (as documented by EEG).

**Measure:** Incidence of seizures

**Time Frame:** During the maximum 5-day course of study intervention.

**Description:** Incidence of cardiac arrhythmias (other than sinus tachycardia).

**Measure:** Incidence of cardiac arrhythmias

**Time Frame:** During the maximum 5-day course of study intervention.

**Description:** Mean heart rate (HR).

**Measure:** Mean heart rate

**Time Frame:** During the maximum 5-day course of study intervention.

**Description:** Incidence of PTSD at 6-month outpatient follow-up.

**Measure:** Incidence of post-traumatic stress disorder (PTSD) in outpatient setting

**Time Frame:** Outpatient follow-up six months after intervention.

**Description:** GOSE-TBI assessment resulting in subjective measure of 0-8 regarding recovery after injury with higher score indicating greatest recovery to pre-injury life, will be conducted at 6-month outpatient follow-up.

**Measure:** Glasgow Coma Outcome Scale extended (GOSE-TBI) scores

**Time Frame:** Outpatient follow-up six months after intervention.

### Eligibility Module

**Eligibility Criteria:** Inclusion Criteria:

* Adults 18-65 years of age
* Severe traumatic brain injury (TBI), with a Glasgow Coma Scale (GCS) ≤ 8, requiring intracranial monitoring
* Placement of intracranial pressure monitor
* Receiving treatment in an intensive care unit (ICU)

Exclusion Criteria:

* Significant cardiovascular disease with recent coronary intervention
* Pregnancy
* Prisoners
* Known allergy to ketamine or propofol

**Maximum Age:** 65 Years

**Minimum Age:** 18 Years

**Sex:** ALL

**Standard Ages:**

- ADULT

- OLDER_ADULT

### Contacts Locations Module

#### Central Contacts

**Contact 1:**

**Email:** marisa.rodriguez.ctr@usuhs.edu

**Name:** Marisa F Rodriguez

**Phone:** 210-851-5779

**Role:** CONTACT

**Contact 2:**

**Email:** martin.cota.ctr@usuhs.edu

**Name:** Martin R Cota, MPH

**Phone:** 301-295-9685

**Role:** CONTACT

### IPD Sharing Statement Module

**IPD Sharing:** NO

### References Module

#### References

**Citation:** Iaccarino C, Carretta A, Nicolosi F, Morselli C. Epidemiology of severe traumatic brain injury. J Neurosurg Sci. 2018 Oct;62(5):535-541. doi: 10.23736/S0390-5616.18.04532-0.

**PMID:** 30182649

**Citation:** Agrawal D, Raghavendran K, Schaubel DE, Mishra MC, Rajajee V. A Propensity Score Analysis of the Impact of Invasive Intracranial Pressure Monitoring on Outcomes after Severe Traumatic Brain Injury. J Neurotrauma. 2016 May 1;33(9):853-8. doi: 10.1089/neu.2015.4015. Epub 2015 Oct 8.

**PMID:** 26414629

**Citation:** Butcher I, Maas AI, Lu J, Marmarou A, Murray GD, Mushkudiani NA, McHugh GS, Steyerberg EW. Prognostic value of admission blood pressure in traumatic brain injury: results from the IMPACT study. J Neurotrauma. 2007 Feb;24(2):294-302. doi: 10.1089/neu.2006.0032.

**PMID:** 17375994

**Citation:** McHugh GS, Engel DC, Butcher I, Steyerberg EW, Lu J, Mushkudiani N, Hernandez AV, Marmarou A, Maas AI, Murray GD. Prognostic value of secondary insults in traumatic brain injury: results from the IMPACT study. J Neurotrauma. 2007 Feb;24(2):287-93. doi: 10.1089/neu.2006.0031.

**PMID:** 17375993

**Citation:** Murray GD, Butcher I, McHugh GS, Lu J, Mushkudiani NA, Maas AI, Marmarou A, Steyerberg EW. Multivariable prognostic analysis in traumatic brain injury: results from the IMPACT study. J Neurotrauma. 2007 Feb;24(2):329-37. doi: 10.1089/neu.2006.0035.

**PMID:** 17375997

**Citation:** Petkus V, Preiksaitis A, Chaleckas E, Chomskis R, Zubaviciute E, Vosylius S, Rocka S, Rastenyte D, Aries MJ, Ragauskas A, Neumann JO. Optimal Cerebral Perfusion Pressure: Targeted Treatment for Severe Traumatic Brain Injury. J Neurotrauma. 2020 Jan 15;37(2):389-396. doi: 10.1089/neu.2019.6551. Epub 2019 Nov 13.

**PMID:** 31583962

**Citation:** Carney N, Totten AM, O'Reilly C, Ullman JS, Hawryluk GW, Bell MJ, Bratton SL, Chesnut R, Harris OA, Kissoon N, Rubiano AM, Shutter L, Tasker RC, Vavilala MS, Wilberger J, Wright DW, Ghajar J. Guidelines for the Management of Severe Traumatic Brain Injury, Fourth Edition. Neurosurgery. 2017 Jan 1;80(1):6-15. doi: 10.1227/NEU.0000000000001432.

**PMID:** 27654000

**Citation:** Cooper DJ, Rosenfeld JV, Murray L, Arabi YM, Davies AR, D'Urso P, Kossmann T, Ponsford J, Seppelt I, Reilly P, Wolfe R; DECRA Trial Investigators; Australian and New Zealand Intensive Care Society Clinical Trials Group. Decompressive craniectomy in diffuse traumatic brain injury. N Engl J Med. 2011 Apr 21;364(16):1493-502. doi: 10.1056/NEJMoa1102077. Epub 2011 Mar 25. Erratum In: N Engl J Med. 2011 Nov 24;365(21):2040.

**PMID:** 21434843

**Citation:** Hawryluk GWJ, Aguilera S, Buki A, Bulger E, Citerio G, Cooper DJ, Arrastia RD, Diringer M, Figaji A, Gao G, Geocadin R, Ghajar J, Harris O, Hoffer A, Hutchinson P, Joseph M, Kitagawa R, Manley G, Mayer S, Menon DK, Meyfroidt G, Michael DB, Oddo M, Okonkwo D, Patel M, Robertson C, Rosenfeld JV, Rubiano AM, Sahuquillo J, Servadei F, Shutter L, Stein D, Stocchetti N, Taccone FS, Timmons S, Tsai E, Ullman JS, Vespa P, Videtta W, Wright DW, Zammit C, Chesnut RM. A management algorithm for patients with intracranial pressure monitoring: the Seattle International Severe Traumatic Brain Injury Consensus Conference (SIBICC). Intensive Care Med. 2019 Dec;45(12):1783-1794. doi: 10.1007/s00134-019-05805-9. Epub 2019 Oct 28.

**PMID:** 31659383

**Citation:** Hutchinson PJ, Kolias AG, Timofeev IS, Corteen EA, Czosnyka M, Timothy J, Anderson I, Bulters DO, Belli A, Eynon CA, Wadley J, Mendelow AD, Mitchell PM, Wilson MH, Critchley G, Sahuquillo J, Unterberg A, Servadei F, Teasdale GM, Pickard JD, Menon DK, Murray GD, Kirkpatrick PJ; RESCUEicp Trial Collaborators. Trial of Decompressive Craniectomy for Traumatic Intracranial Hypertension. N Engl J Med. 2016 Sep 22;375(12):1119-30. doi: 10.1056/NEJMoa1605215. Epub 2016 Sep 7.

**PMID:** 27602507

**Citation:** Oddo M, Crippa IA, Mehta S, Menon D, Payen JF, Taccone FS, Citerio G. Optimizing sedation in patients with acute brain injury. Crit Care. 2016 May 5;20(1):128. doi: 10.1186/s13054-016-1294-5.

**PMID:** 27145814

**Citation:** Stein DM, Hu PF, Brenner M, Sheth KN, Liu KH, Xiong W, Aarabi B, Scalea TM. Brief episodes of intracranial hypertension and cerebral hypoperfusion are associated with poor functional outcome after severe traumatic brain injury. J Trauma. 2011 Aug;71(2):364-73; discussion 373-4. doi: 10.1097/TA.0b013e31822820da.

**PMID:** 21825940

**Citation:** Gardner AE, Dannemiller FJ, Dean D. Intracranial cerebrospinal fluid pressure in man during ketamine anesthesia. Anesth Analg. 1972 Sep-Oct;51(5):741-5. No abstract available.

**PMID:** 4672167

**Citation:** Gibbs JM. The effect of intravenous ketamine on cerebrospinal fluid pressure. Br J Anaesth. 1972 Dec;44(12):1298-302. doi: 10.1093/bja/44.12.1298. No abstract available.

**PMID:** 4650346

**Citation:** Green SM, Andolfatto G, Krauss BS. Ketamine and intracranial pressure: no contraindication except hydrocephalus. Ann Emerg Med. 2015 Jan;65(1):52-4. doi: 10.1016/j.annemergmed.2014.08.025. Epub 2014 Sep 20. No abstract available.

**PMID:** 25245275

**Citation:** Gregers MCT, Mikkelsen S, Lindvig KP, Brochner AC. Ketamine as an Anesthetic for Patients with Acute Brain Injury: A Systematic Review. Neurocrit Care. 2020 Aug;33(1):273-282. doi: 10.1007/s12028-020-00975-7.

**PMID:** 32328972

**Citation:** Laws JC, Vance EH, Betters KA, Anderson JJ, Fleishman S, Bonfield CM, Wellons JC 3rd, Xu M, Slaughter JC, Giuse DA, Patel N, Jordan LC, Wolf MS. Acute Effects of Ketamine on Intracranial Pressure in Children With Severe Traumatic Brain Injury. Crit Care Med. 2023 May 1;51(5):563-572. doi: 10.1097/CCM.0000000000005806. Epub 2023 Feb 21.

**PMID:** 36825892

**Citation:** Dengler BA, Karam O, Barthol CA, Chance A, Snider LE, Mundy CM, Bounajem MT, Johnson WC, Maita MM, Mendez-Gomez PM, Seifi A, Hafeez S. Ketamine Boluses Are Associated with a Reduction in Intracranial Pressure and an Increase in Cerebral Perfusion Pressure: A Retrospective Observational Study of Patients with Severe Traumatic Brain Injury. Crit Care Res Pract. 2022 May 21;2022:3834165. doi: 10.1155/2022/3834165. eCollection 2022.

**PMID:** 35637760

**Citation:** Bebarta VS, Mora AG, Bebarta EK, Reeves LK, Maddry JK, Schauer SG, Lairet JR. Prehospital Use of Ketamine in the Combat Setting: A Sub-Analysis of Patients With Head Injuries Evaluated in the Prospective Life Saving Intervention Study. Mil Med. 2020 Jan 7;185(Suppl 1):136-142. doi: 10.1093/milmed/usz302.

**PMID:** 32074369

**Citation:** Hill GJ, April MD, Maddry JK, Schauer SG. Prehospital ketamine administration to pediatric trauma patients with head injuries in combat theaters. Am J Emerg Med. 2019 Aug;37(8):1455-1459. doi: 10.1016/j.ajem.2018.10.046. Epub 2018 Oct 22.

**PMID:** 30528051

**Citation:** Maheswari N, Panda NB, Mahajan S, Luthra A, Pattnaik S, Bhatia N, Karthigeyan M, Kaloria N, Chauhan R, Soni S, Jangra K, Bhagat H. Ketofol as an Anesthetic Agent in Patients With Isolated Moderate to Severe Traumatic Brain Injury: A Prospective, Randomized Double-blind Controlled Trial. J Neurosurg Anesthesiol. 2023 Jan 1;35(1):49-55. doi: 10.1097/ANA.0000000000000774. Epub 2021 May 13.

**PMID:** 36745167

**Citation:** Dewan MC, Rattani A, Gupta S, Baticulon RE, Hung YC, Punchak M, Agrawal A, Adeleye AO, Shrime MG, Rubiano AM, Rosenfeld JV, Park KB. Estimating the global incidence of traumatic brain injury. J Neurosurg. 2018 Apr 27;130(4):1080-1097. doi: 10.3171/2017.10.JNS17352.

**PMID:** 29701556

**Citation:** Stein SC, Georgoff P, Meghan S, Mizra K, Sonnad SS. 150 years of treating severe traumatic brain injury: a systematic review of progress in mortality. J Neurotrauma. 2010 Jul;27(7):1343-53. doi: 10.1089/neu.2009.1206.

**PMID:** 20392140

**Citation:** Mangat HS, Wu X, Gerber LM, Shabani HK, Lazaro A, Leidinger A, Santos MM, McClelland PH, Schenck H, Joackim P, Ngerageza JG, Schmidt F, Stieg PE, Hartl R. Severe traumatic brain injury management in Tanzania: analysis of a prospective cohort. J Neurosurg. 2021 Jan 22;135(4):1190-1202. doi: 10.3171/2020.8.JNS201243.

**PMID:** 33482641

**Citation:** Howard JT, Stewart IJ, Amuan M, Janak JC, Pugh MJ. Association of Traumatic Brain Injury With Mortality Among Military Veterans Serving After September 11, 2001. JAMA Netw Open. 2022 Feb 1;5(2):e2148150. doi: 10.1001/jamanetworkopen.2021.48150.

**PMID:** 35147684

**Citation:** Rutherford GW, Wlodarczyk RC. Distant sequelae of traumatic brain injury: premature mortality and intracranial neoplasms. J Head Trauma Rehabil. 2009 Nov-Dec;24(6):468-74. doi: 10.1097/HTR.0b013e3181c133d2.

**PMID:** 19940680

**Citation:** Kang HK, Bullman TA. Mortality among U.S. veterans of the Persian Gulf War. N Engl J Med. 1996 Nov 14;335(20):1498-504. doi: 10.1056/NEJM199611143352006.

**PMID:** 8890102

**Citation:** Bollinger MJ, Schmidt S, Pugh JA, Parsons HM, Copeland LA, Pugh MJ. Erosion of the healthy soldier effect in veterans of US military service in Iraq and Afghanistan. Popul Health Metr. 2015 Mar 18;13:8. doi: 10.1186/s12963-015-0040-6. eCollection 2015.

**PMID:** 25798075

**Citation:** Dismuke CE, Walker RJ, Egede LE. Utilization and Cost of Health Services in Individuals With Traumatic Brain Injury. Glob J Health Sci. 2015 Apr 19;7(6):156-69. doi: 10.5539/gjhs.v7n6p156.

**PMID:** 26153156

**Citation:** Bullock MR, Chesnut R, Ghajar J, Gordon D, Hartl R, Newell DW, Servadei F, Walters BC, Wilberger JE; Surgical Management of Traumatic Brain Injury Author Group. Surgical management of acute epidural hematomas. Neurosurgery. 2006 Mar;58(3 Suppl):S7-15; discussion Si-iv.

**PMID:** 16710967

**Citation:** Bullock MR, Chesnut R, Ghajar J, Gordon D, Hartl R, Newell DW, Servadei F, Walters BC, Wilberger JE; Surgical Management of Traumatic Brain Injury Author Group. Surgical management of acute subdural hematomas. Neurosurgery. 2006 Mar;58(3 Suppl):S16-24; discussion Si-iv.

**PMID:** 16710968

**Citation:** Bullock MR, Chesnut R, Ghajar J, Gordon D, Hartl R, Newell DW, Servadei F, Walters BC, Wilberger J; Surgical Management of Traumatic Brain Injury Author Group. Surgical management of traumatic parenchymal lesions. Neurosurgery. 2006 Mar;58(3 Suppl):S25-46; discussion Si-iv. doi: 10.1227/01.NEU.0000210365.36914.E3.

**PMID:** 16540746

**Citation:** Donnelly J, Czosnyka M, Adams H, Cardim D, Kolias AG, Zeiler FA, Lavinio A, Aries M, Robba C, Smielewski P, Hutchinson PJA, Menon DK, Pickard JD, Budohoski KP. Twenty-Five Years of Intracranial Pressure Monitoring After Severe Traumatic Brain Injury: A Retrospective, Single-Center Analysis. Neurosurgery. 2019 Jul 1;85(1):E75-E82. doi: 10.1093/neuros/nyy468.

**PMID:** 30476233

**Citation:** Farahvar A, Gerber LM, Chiu YL, Carney N, Hartl R, Ghajar J. Increased mortality in patients with severe traumatic brain injury treated without intracranial pressure monitoring. J Neurosurg. 2012 Oct;117(4):729-34. doi: 10.3171/2012.7.JNS111816. Epub 2012 Aug 17.

**PMID:** 22900846

**Citation:** Badri S, Chen J, Barber J, Temkin NR, Dikmen SS, Chesnut RM, Deem S, Yanez ND, Treggiari MM. Mortality and long-term functional outcome associated with intracranial pressure after traumatic brain injury. Intensive Care Med. 2012 Nov;38(11):1800-9. doi: 10.1007/s00134-012-2655-4. Epub 2012 Aug 3.

**PMID:** 23011528

**Citation:** Marshall LF, Smith RW, Shapiro HM. The outcome with aggressive treatment in severe head injuries. Part I: the significance of intracranial pressure monitoring. J Neurosurg. 1979 Jan;50(1):20-5. doi: 10.3171/jns.1979.50.1.0020. No abstract available.

**PMID:** 758374

**Citation:** Lowell HM, Bloor BM. The effect of increased intracranial pressure on cerebrovascular hemodynamics. J Neurosurg. 1971 Jun;34(6):760-9. doi: 10.3171/jns.1971.34.6.0760. No abstract available.

**PMID:** 4997951

**Citation:** Akerlund CA, Donnelly J, Zeiler FA, Helbok R, Holst A, Cabeleira M, Guiza F, Meyfroidt G, Czosnyka M, Smielewski P, Stocchetti N, Ercole A, Nelson DW; CENTER-TBI High Resolution ICU Sub-Study Participants and Investigators. Impact of duration and magnitude of raised intracranial pressure on outcome after severe traumatic brain injury: A CENTER-TBI high-resolution group study. PLoS One. 2020 Dec 14;15(12):e0243427. doi: 10.1371/journal.pone.0243427. eCollection 2020.

**PMID:** 33315872

**Citation:** Sheth KN, Stein DM, Aarabi B, Hu P, Kufera JA, Scalea TM, Hanley DF. Intracranial pressure dose and outcome in traumatic brain injury. Neurocrit Care. 2013 Feb;18(1):26-32. doi: 10.1007/s12028-012-9780-3.

**PMID:** 23055087

**Citation:** Wolf S, Mielke D, Barner C, Malinova V, Kerz T, Wostrack M, Czorlich P, Salih F, Engel DC, Ehlert A, Staykov D, Alturki AY, Sure U, Bardutzky J, Schroeder HWS, Schurer L, Beck J, Juratli TA, Fritsch M, Lemcke J, Pohrt A, Meyer B, Schwab S, Rohde V, Vajkoczy P; EARLYDRAIN Study Group. Effectiveness of Lumbar Cerebrospinal Fluid Drain Among Patients With Aneurysmal Subarachnoid Hemorrhage: A Randomized Clinical Trial. JAMA Neurol. 2023 Aug 1;80(8):833-842. doi: 10.1001/jamaneurol.2023.1792. Erratum In: JAMA Neurol. 2023 Aug 1;80(8):873.

**PMID:** 37330974

**Citation:** Cooper DJ, Nichol AD, Bailey M, Bernard S, Cameron PA, Pili-Floury S, Forbes A, Gantner D, Higgins AM, Huet O, Kasza J, Murray L, Newby L, Presneill JJ, Rashford S, Rosenfeld JV, Stephenson M, Vallance S, Varma D, Webb SAR, Trapani T, McArthur C; POLAR Trial Investigators and the ANZICS Clinical Trials Group. Effect of Early Sustained Prophylactic Hypothermia on Neurologic Outcomes Among Patients With Severe Traumatic Brain Injury: The POLAR Randomized Clinical Trial. JAMA. 2018 Dec 4;320(21):2211-2220. doi: 10.1001/jama.2018.17075.

**PMID:** 30357266

**Citation:** Roquilly A, Moyer JD, Huet O, Lasocki S, Cohen B, Dahyot-Fizelier C, Chalard K, Seguin P, Jeantrelle C, Vermeersch V, Gaillard T, Cinotti R, Demeure Dit Latte D, Mahe PJ, Vourc'h M, Martin FP, Chopin A, Lerebourg C, Flet L, Chiffoleau A, Feuillet F, Asehnoune K; Atlanrea Study Group and the Societe Francaise d'Anesthesie Reanimation (SFAR) Research Network. Effect of Continuous Infusion of Hypertonic Saline vs Standard Care on 6-Month Neurological Outcomes in Patients With Traumatic Brain Injury: The COBI Randomized Clinical Trial. JAMA. 2021 May 25;325(20):2056-2066. doi: 10.1001/jama.2021.5561.

**PMID:** 34032829

**Citation:** Skolnick BE, Maas AI, Narayan RK, van der Hoop RG, MacAllister T, Ward JD, Nelson NR, Stocchetti N; SYNAPSE Trial Investigators. A clinical trial of progesterone for severe traumatic brain injury. N Engl J Med. 2014 Dec 25;371(26):2467-76. doi: 10.1056/NEJMoa1411090. Epub 2014 Dec 10.

**PMID:** 25493978

**Citation:** CRASH-3 trial collaborators. Effects of tranexamic acid on death, disability, vascular occlusive events and other morbidities in patients with acute traumatic brain injury (CRASH-3): a randomised, placebo-controlled trial. Lancet. 2019 Nov 9;394(10210):1713-1723. doi: 10.1016/S0140-6736(19)32233-0. Epub 2019 Oct 14. Erratum In: Lancet. 2019 Nov 9;394(10210):1712.

**PMID:** 31623894

**Citation:** Bourgoin A, Albanese J, Wereszczynski N, Charbit M, Vialet R, Martin C. Safety of sedation with ketamine in severe head injury patients: comparison with sufentanil. Crit Care Med. 2003 Mar;31(3):711-7. doi: 10.1097/01.CCM.0000044505.24727.16.

**PMID:** 12626974

**Citation:** Bourgoin A, Leone M, Delmas A, Garnier F, Albanese J, Martin C. Increasing mean arterial pressure in patients with septic shock: effects on oxygen variables and renal function. Crit Care Med. 2005 Apr;33(4):780-6. doi: 10.1097/01.ccm.0000157788.20591.23.

**PMID:** 15818105

**Citation:** Kolenda H, Gremmelt A, Rading S, Braun U, Markakis E. Ketamine for analgosedative therapy in intensive care treatment of head-injured patients. Acta Neurochir (Wien). 1996;138(10):1193-9. doi: 10.1007/BF01809750. Erratum In: Acta Neurochir (Wien) 1997;139(12):1193.

**PMID:** 8955439

**Citation:** Schmittner MD, Vajkoczy SL, Horn P, Bertsch T, Quintel M, Vajkoczy P, Muench E. Effects of fentanyl and S(+)-ketamine on cerebral hemodynamics, gastrointestinal motility, and need of vasopressors in patients with intracranial pathologies: a pilot study. J Neurosurg Anesthesiol. 2007 Oct;19(4):257-62. doi: 10.1097/ANA.0b013e31811f3feb.

**PMID:** 17893578

**Citation:** Sakpal TV. Sample size estimation in clinical trial. Perspect Clin Res. 2010 Apr;1(2):67-9.

**PMID:** 21829786

**Citation:** Military Health System and Defense Health Agency. DOD TBI Worldwide Numbers: Traumatic Brain Injury Center of Excellence; 2022 [Available from: https://health.mil/Military-Health-Topics/Centers-of-Excellence/Traumatic-Brain-Injury-Center-of-Excellence/DOD-TBI-Worldwide-NumbersTraumaticBrain].

**Citation:** Michalczyk, Lukasz, and Lukasz Kaczmarek.

**Citation:** Chan, Kai En, et al.

## Derived Section

### Condition Browse Module - Ancestors

- ID: D000014652

- Term: Vascular Diseases

- ID: D000002318

- Term: Cardiovascular Diseases

- ID: D000001927

- Term: Brain Diseases

- ID: D000002493

- Term: Central Nervous System Diseases

- ID: D000009422

- Term: Nervous System Diseases

- ID: D000006259

- Term: Craniocerebral Trauma

- ID: D000020196

- Term: Trauma, Nervous System

- ID: D000010335

- Term: Pathologic Processes

- ID: D000002561

- Term: Cerebrovascular Disorders

### Condition Browse Module - Browse Branches

- Abbrev: BC14

- Name: Heart and Blood Diseases

- Abbrev: All

- Name: All Conditions

- Abbrev: BC23

- Name: Symptoms and General Pathology

- Abbrev: BC10

- Name: Nervous System Diseases

- Abbrev: BC26

- Name: Wounds and Injuries

### Condition Browse Module - Browse Leaves

- ID: M10024

- Name: Hypertension

- Relevance: LOW

- As Found: Unknown

- ID: M9556

- Name: Hemorrhage

- Relevance: HIGH

- As Found: Hemorrhage

- ID: M21521

- Name: Intracranial Hypertension

- Relevance: HIGH

- As Found: Intracranial Hypertension

- ID: M22113

- Name: Intracranial Hemorrhages

- Relevance: HIGH

- As Found: Intracranial Hemorrhage

- ID: M5207

- Name: Brain Injuries

- Relevance: HIGH

- As Found: Brain Injury

- ID: M628

- Name: Brain Injuries, Traumatic

- Relevance: HIGH

- As Found: Traumatic Brain Injury

- ID: M22112

- Name: Intracranial Hemorrhage, Hypertensive

- Relevance: HIGH

- As Found: Intracranial Hemorrhage, Hypertensive

- ID: M17685

- Name: Wounds and Injuries

- Relevance: HIGH

- As Found: Injury

- ID: M17400

- Name: Vascular Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M5204

- Name: Brain Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M5742

- Name: Central Nervous System Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M9349

- Name: Craniocerebral Trauma

- Relevance: LOW

- As Found: Unknown

- ID: M22023

- Name: Trauma, Nervous System

- Relevance: LOW

- As Found: Unknown

- ID: M5810

- Name: Cerebrovascular Disorders

- Relevance: LOW

- As Found: Unknown

### Condition Browse Module - Meshes

- ID: D000001930

- Term: Brain Injuries

- ID: D000070642

- Term: Brain Injuries, Traumatic

- ID: D000020300

- Term: Intracranial Hemorrhages

- ID: D000019586

- Term: Intracranial Hypertension

- ID: D000020299

- Term: Intracranial Hemorrhage, Hypertensive

- ID: D000006470

- Term: Hemorrhage

- ID: D000014947

- Term: Wounds and Injuries

### Intervention Browse Module - Ancestors

- ID: D000006993

- Term: Hypnotics and Sedatives

- ID: D000002492

- Term: Central Nervous System Depressants

- ID: D000045505

- Term: Physiological Effects of Drugs

- ID: D000018712

- Term: Analgesics, Non-Narcotic

- ID: D000000700

- Term: Analgesics

- ID: D000018689

- Term: Sensory System Agents

- ID: D000018373

- Term: Peripheral Nervous System Agents

- ID: D000058647

- Term: Adrenergic alpha-2 Receptor Agonists

- ID: D000000316

- Term: Adrenergic alpha-Agonists

- ID: D000000322

- Term: Adrenergic Agonists

- ID: D000018663

- Term: Adrenergic Agents

- ID: D000018377

- Term: Neurotransmitter Agents

- ID: D000045504

- Term: Molecular Mechanisms of Pharmacological Action

- ID: D000018686

- Term: Anesthetics, Intravenous

- ID: D000018681

- Term: Anesthetics, General

- ID: D000000777

- Term: Anesthetics

- ID: D000000778

- Term: Anesthetics, Dissociative

- ID: D000018691

- Term: Excitatory Amino Acid Antagonists

- ID: D000018683

- Term: Excitatory Amino Acid Agents

- ID: D000000701

- Term: Analgesics, Opioid

- ID: D000009294

- Term: Narcotics

- ID: D000000759

- Term: Adjuvants, Anesthesia

- ID: D000014151

- Term: Anti-Anxiety Agents

- ID: D000014149

- Term: Tranquilizing Agents

- ID: D000011619

- Term: Psychotropic Drugs

- ID: D000018757

- Term: GABA Modulators

- ID: D000018682

- Term: GABA Agents

- ID: D000000927

- Term: Anticonvulsants

- ID: D000000932

- Term: Antiemetics

- ID: D000001337

- Term: Autonomic Agents

- ID: D000005765

- Term: Gastrointestinal Agents

### Intervention Browse Module - Browse Branches

- Abbrev: AdjAn

- Name: Adjuvants, Anesthesia

- Abbrev: Analg

- Name: Analgesics

- Abbrev: CNSDep

- Name: Central Nervous System Depressants

- Abbrev: All

- Name: All Drugs and Chemicals

- Abbrev: PsychDr

- Name: Psychotropic Drugs

- Abbrev: AntiConv

- Name: Anticonvulsants

- Abbrev: AnEm

- Name: Antiemetics

- Abbrev: Gast

- Name: Gastrointestinal Agents

### Intervention Browse Module - Browse Leaves

- ID: M8418

- Name: Fentanyl

- Relevance: HIGH

- As Found: Scan

- ID: M22662

- Name: Dexmedetomidine

- Relevance: HIGH

- As Found: Twice daily

- ID: M11845

- Name: Midazolam

- Relevance: HIGH

- As Found: Induction

- ID: M10674

- Name: Ketamine

- Relevance: HIGH

- As Found: Provided

- ID: M11982

- Name: Morphine

- Relevance: HIGH

- As Found: Site

- ID: M7275

- Name: Hydromorphone

- Relevance: HIGH

- As Found: Phase 2 Study

- ID: M11140

- Name: Lorazepam

- Relevance: HIGH

- As Found: Zoledronic Acid

- ID: M18307

- Name: Propofol

- Relevance: HIGH

- As Found: Symptoms

- ID: M10043

- Name: Hypnotics and Sedatives

- Relevance: LOW

- As Found: Unknown

- ID: M4032

- Name: Analgesics

- Relevance: LOW

- As Found: Unknown

- ID: M20786

- Name: Analgesics, Non-Narcotic

- Relevance: LOW

- As Found: Unknown

- ID: M20746

- Name: Adrenergic Agents

- Relevance: LOW

- As Found: Unknown

- ID: M3668

- Name: Adrenergic alpha-Agonists

- Relevance: LOW

- As Found: Unknown

- ID: M3673

- Name: Adrenergic Agonists

- Relevance: LOW

- As Found: Unknown

- ID: M20504

- Name: Neurotransmitter Agents

- Relevance: LOW

- As Found: Unknown

- ID: M4107

- Name: Anesthetics

- Relevance: LOW

- As Found: Unknown

- ID: M20766

- Name: Anesthetics, Intravenous

- Relevance: LOW

- As Found: Unknown

- ID: M20761

- Name: Anesthetics, General

- Relevance: LOW

- As Found: Unknown

- ID: M4108

- Name: Anesthetics, Dissociative

- Relevance: LOW

- As Found: Unknown

- ID: M20771

- Name: Excitatory Amino Acid Antagonists

- Relevance: LOW

- As Found: Unknown

- ID: M4033

- Name: Analgesics, Opioid

- Relevance: LOW

- As Found: Unknown

- ID: M12245

- Name: Narcotics

- Relevance: LOW

- As Found: Unknown

- ID: M4089

- Name: Adjuvants, Anesthesia

- Relevance: LOW

- As Found: Unknown

- ID: M16905

- Name: Anti-Anxiety Agents

- Relevance: LOW

- As Found: Unknown

- ID: M14474

- Name: Psychotropic Drugs

- Relevance: LOW

- As Found: Unknown

- ID: M20827

- Name: GABA Modulators

- Relevance: LOW

- As Found: Unknown

- ID: M4246

- Name: Anticonvulsants

- Relevance: LOW

- As Found: Unknown

- ID: M4251

- Name: Antiemetics

- Relevance: LOW

- As Found: Unknown

- ID: M8881

- Name: Gastrointestinal Agents

- Relevance: LOW

- As Found: Unknown

### Intervention Browse Module - Meshes

- ID: D000008874

- Term: Midazolam

- ID: D000005283

- Term: Fentanyl

- ID: D000020927

- Term: Dexmedetomidine

- ID: D000007649

- Term: Ketamine

- ID: D000009020

- Term: Morphine

- ID: D000004091

- Term: Hydromorphone

- ID: D000008140

- Term: Lorazepam

- ID: D000015742

- Term: Propofol

### Misc Info Module

- Version Holder: 2024-05-31
