Study of APRV and ICP in Patients With Severe Traumatic Brain Injury
Conditions: Injury, Brain, Traumatic, Traumatic Brain Injury
Sponsor: University of Maryland, Baltimore

1 
 
Study of APRV and ICP in Patients with Severe Traumatic 
Brain Injury 
NCT 02507973 
Date : 3/24/15 
 
Introduction 
Management of patients with Traumatic Brain Injury (TBI) emphasizes on prevention of secondary 
insults such as hypotension and hypoxemia which negatively impact outcomes 1.  Both hypotension 2-4 
and hypoxemia 5,6 are not only independent risk factors for increased mortality in patients with TBI, but 
also lead to increased intracranial pressure (ICP), which is also another independent risk factor for high 
mortality 4,7-10. 
All patients with severe TBI (Glasgow Coma Scale ≤8) require sedation and mechanical ventilation for 
airway protection, oxygenation and minimization of obnoxious stimuli which may elevate ICP 11.  
Mechanical ventilation, however, carries risks of increasing intrathoracic pressure, airway pressure 
(Paw) and may lead to increased ICP 12,13.   
Airway pressure release ventilation (APRV) is a mode of mechanical ventilation that switches between 
high (PHigh) and low (PLow) continuous positive airway pressure while allowing spontaneous breathing at 
both phases.   Alveolar recruitment and oxygenation occur during PHigh whereas ventilation occurs during 
brief releases to PLow 14,15.   APRV has been used successfully in patients with multisystem trauma 16-19.  
However literature about APRV and patients with severe TBI has been scant as concern that APRV with 
high positive airway pressure could result in elevated ICP still exists.    
Dart et al 16 showed that APRV could be used to improve oxygenation among multisystem trauma 
patients with ARDS or acute lung injuries, without affecting airway pressure (Paw).  The authors 
informally mentioned that several patients with TBI in their studies tolerated APRV well without 
increasing ICP.   Nemer et al reported that pressure-controlled recruitment maneuver with peak 
pressure up to 50 cm H2O for 2 minutes did not increase ICP in patients with subarachnoid hemorrhage 
20.  A single case report published successful oxygenation of a hypoxemic patient with subarachnoid 
hemorrhage using APRV without increase of patient’s ICP 21.  In addition to improving oxygenation, APRV 
was also shown to improve cerebral blood flow and spinal blood flow in animals undergoing APRV with 
spontaneous breathing 22.    
Hypothesis 

2 
 
Therefore, we hypothesize that APRV could be safely used in patients with severe TBI as it does not 
increase their ICP and compromising their Cerebral Perfusion Pressure (CPP), while preventing 
hypoxemia and hypercapnia in these patients. 
Project Primary Goal 
This pilot study, to the best of our knowledge, is the first study that specifically investigates the efficacy 
of APRV among patients with severe TBI.   We aim to investigate whether APRV can safely oxygenate 
patients without compromising their ICP and CPP. 
Study Personnel 
Principal Investigator: Dr. Debora Stein 
Co-investigator: 
Ms. Claire Rosen (point of contact) 
Drs. Thomas Grissom, Quincy Tran, Molly Deane, Michael Anstadt, Peter Hu, Darren Zimmerman, Sara 
Murthi, Maureen McCunn, Dadjati Bajadia. 
Study Methodology 
Methods: 
We will conduct an observational crossover study.  We aim to recruit 50 patients with severe TBI 
requiring intracranial pressure monitoring during their stay at the Neuro Trauma ICU at the R Adams 
Cowley Shock Trauma Center.  Each patient at admission will initially receive a primary mode of 
mechanical ventilation as determined by the attending trauma intensivists.   
12-18 hours after recruitment, continuous monitoring of patients’ ICP and hemodynamic status (ICP, HR, 
RR, SpO2, EtCO2, MAP, CPP, SpO2, and EtCO2) will commence to collect patients’ baseline data for 30 
minutes. Patients will then undergo low tidal volume mechanical ventilation (LOTV), serving as a control 
mode of ventilation, for 2 hours prior to switching back to the primary mode of ventilation for 30 
minutes.   Next, patients will be placed on APRV for 2 hours.  While receiving APRV, patients’ ICP and 
hemodynamic status will be continuously monitored and recorded for comparison and analysis.  After 2 
hours of APRV, patients will be switched back to their previous mode of ventilation and more data are 
collected for another 30 minutes.  This sequence of ventilation is illustrated in figure 1. 
Intracranial pressure will be measured every 15 minutes during the study period.   While undergoing low 
tidal volume ventilation and APRV, patient’s volume statuses and cardiac functions will also be assessed 
using a non-invasive, non-radioactive modality such as Transthoracic Echocardiography.   
Figure 1. Sequence of mechanical ventilation and data collection. 
 Primary  
Vent. 
Low tidal  
volume Vent. 
Primary 
Vent. 
Primary 
Vent. 
APRV 
30 minutes 
        2 hours 
 
    30 minutes 
 
2 hours  
 
30 minutes 

3 
 
 
 
Figure 2. Flow chart of APRV Protocol: 
 
STOP & Switch 
back 
Initial APRV Setting: 
PHigh = previous plateau pressure 
Thigh =  4s if spont. RR ≥ 30 
 
5s if spont. RR 24-30 
 
6s if spont. RR 12-24 
 
4.5s if spont. RR ≤10 
PLow = 0 
TLow = 0.4-0.8 second based on 
flow curve 
SpO2 <92% 
Increase PHigh by 2cm 
Repeat twice PRN if PHigh ≤ 40 cm 
ICP ≥ 20 mm Hg 
CPP ≤ 50 
Change of HR or 
Blood pressure 
≥20% from baseline. 
Any therapeutic 
intervention for ICP
EtCO2 ≥ 35 
Decrease THigh by 0.5 second 
Repeat twice until THigh ≤ 4 
second 
If SpO2 ≥ 92% ⇒ Wean FiO2 
If SpO2 85-92% ⇒ increase THigh  by 0.5s x 2 PRN until Thigh = 8s 
If SpO2 < 85% ⇒ STOP and switch mode of ventilation 
EtCO2 ≥ 35 ⇒ STOP and switch mode of 
ventilation 

4 
 
 
 
Figure 3. Flow Chart for LOTV protocol 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Initial LOTV Setting: 
SIMV + Volume control 
VT = 6ml/kg PBW 
RR = rate to achieve same 
minute ventilation as in primary 
mode of ventilation.  Not to 
exceed 35/minute 
PEEP = 5 cm H2O 
FiO2 = 40% 
PS = 10 cm H2O 
ICP ≥ 20 mm Hg 
CPP ≤ 50 
Change of HR or 
Blood pressure 
≥20% from baseline. 
Any therapeutic 
intervention for ICP 
STOP & Switch back 
SpO2 <92% 
Increase PEEP to 8 
Increase FiO2 to 50% 
If SpO2 ≥ 92% ⇒ Wean FiO2. 
If SpO2 85-92% ⇒ increase PEEP to 10, FiO2 to 60% 
If SpO2 is still < 92% ⇒ STOP and switch mode of ventilation 
EtCO2 ≥ 35 
If RR ≤ 30, increase RR by 4 bpm x2 PRN until maximum of 35 bpm 
If RR ≥ 30, STOP and switch mode 
Pplat > 30 cm H2O 
Decrease VT by 1ml/kg x2 PRN 
(Minimum VT = 4ml/kg) 
STOP and Switch back 
Peak airway pressure > 40 
Pplat > 30 cm H2O or 
Peak airway pressure > 40 
If EtCO2 still ≥ 35 

5 
 
 
 
Inclusion Criteria 
• 
Intracranial pressure monitoring 
• 
Mechanically ventilated 
Exclusion Criteria 
• 
Age < 18 
• 
Pregnant women 
• 
Prisoners 
• 
Initial mode of ventilation = APRV 
• 
Providers’ judgments 
Consent: 
The patients will not be able to consent for themselves, due the severity of their conditions.  We will 
seek consent from legally authorized representative if available or patients’ next-of-kin. 
Outcomes 
• Primary outcome: ICP 
• Secondary outcomes: MAP, CPP, SpO2, EtCO2, any interventions for ICP or for 
hemodynamic instability. 
 
Analysis Plan 
Data Security: 
Patient’s data will be recorded on a standardized Microsoft Excel spreadsheet.  This spreadsheet will 
first be password-protected, then encrypted by commercial 128-bit encryption software 
(www.boxcryptor.com).  The encrypted spreadsheet then will be stored in a secure, password-protected 
online storage with extra security designed for corporation (OneDrive for Business by Microsoft 
Corporation, Redmond WA; https://onedrive.live.com/about/en-nz/business/).   
These measures of security allow maximal collaborations between investigators while enhancing safety 
for patients’ protected health information. 

6 
 
 
Data Analysis: 
We aim to report our findings as following: 
Table 1. Patient Demographics 
    Number of patients 
     Age (years) 
    Gender 
     BMI 
     Mechanism of injury 
          Motor vehicle collision, n (%) 
          Gunshot wound, n (%) 
          Fall, n (%) 
     GCS score 
     ISS 
     Primary mode of mechanical ventilation 
     PaO2/FiO2 ratio 
     ICU length of stay (days) 
     Hospital length of stay (days) 
     Mortality 
 
Table 2. Outcome Measurements 
Dependent Measure 
(Mean, Interquartile) 
Baseline 
  LOTV 
APRV 
Conventional MV 
p-value 
Pre-
APRV 
Post-
APRV 
ICP 
 
 
 
 
 
 
MAP 
 
 
 
 
 
 
CPP 
 
 
 
 
 
 
CVP 
 
 
 
 
 
 
Heart Rate 
 
 
 
 
 
 
Respiratory Rate 
 
 
 
 
 
 
SpOP 
 
 
 
 
 
 
EtCO2 
 
 
 
 
 
 
Volume status by TTE 
 
 
 
 
 
 
Therapeutic 
interventions for ICP, 
blood pressure 
 
 
 
 
 
 
 
Table 3.  Adverse Events 
Patients not 
tolerating APRV 
N, (%) 
 

7 
 
Causes 
N, (%) 
Elevated ICP 
CPP < 50 
Hypoxemia 
Hypercapnia 
Tachycardia 
 
All continuous variables will be reported as mean with interquartile values (IQR). 
Estimated Study Length  
There were 1259 patients with isolated blunt TBI (Abbreviated Injury Scale of brain was ≥ 2 while AIS for 
other body region was ≤ 2) admitted to the R Adams Cowley Shock Trauma Center in 2013. 
Therefore, we estimate that we will be able to recruit 2-3 patients per week.    
Our pilot study is expected to finish recruitment within 6-8 months. 
Target Conferences 
The American Association for the Surgery of Trauma: Sept. 09-12, 2015 
The Society of Critical Care Medicine 44th Congress: January 17-21, 2015 
Budget: 
None 
 
 
 
 
 
 
 
 
 
 

8 
 
 
References 
 
1. Brain Trauma Foundation, American Association of Neurological Surgeons, Congress of Neurological 
Surgeons, et al. Guidelines for the management of severe traumatic brain injury. I. blood pressure and 
oxygenation. J Neurotrauma. 2007;24 Suppl 1:S7-13. doi: 10.1089/neu.2007.9995 [doi]. 
2. Chesnut RM, Marshall SB, Piek J, Blunt BA, Klauber MR, Marshall LF. Early and late systemic 
hypotension as a frequent and fundamental source of cerebral ischemia following severe brain injury in 
the traumatic coma data bank. Acta Neurochir Suppl (Wien). 1993;59:121-125. 
3. Fearnside MR, Cook RJ, McDougall P, McNeil RJ. The westmead head injury project outcome in severe 
head injury. A comparative analysis of pre-hospital, clinical and CT variables. Br J Neurosurg. 
1993;7(3):267-279. 
4. Schreiber MA, Aoki N, Scott BG, Beck JR. Determinants of mortality in patients with severe blunt head 
injury. Arch Surg. 2002;137(3):285-290. doi: soa1149 [pii]. 
5. Jones PA, Andrews PJ, Midgley S, et al. Measuring the burden of secondary insults in head-injured 
patients during intensive care. J Neurosurg Anesthesiol. 1994;6(1):4-14. 
6. Stocchetti N, Furlan A, Volta F. Hypoxemia and arterial hypotension at the accident scene in head 
injury. J Trauma. 1996;40(5):764-767. 
7. Brain Trauma Foundation, American Association of Neurological Surgeons, Congress of Neurological 
Surgeons, et al. Guidelines for the management of severe traumatic brain injury. VIII. intracranial 
pressure thresholds. J Neurotrauma. 2007;24 Suppl 1:S55-8. doi: 10.1089/neu.2007.9988 [doi]. 

9 
 
8. 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;50(1):20-25. doi: 
10.3171/jns.1979.50.1.0020 [doi]. 
9. Saul TG, Ducker TB. Effect of intracranial pressure monitoring and aggressive treatment on mortality 
in severe head injury. J Neurosurg. 1982;56(4):498-503. doi: 10.3171/jns.1982.56.4.0498 [doi]. 
10. Narayan RK, Kishore PR, Becker DP, et al. Intracranial pressure: To monitor or not to monitor? A 
review of our experience with severe head injury. J Neurosurg. 1982;56(5):650-659. doi: 
10.3171/jns.1982.56.5.0650 [doi]. 
11. Brain Trauma Foundation, American Association of Neurological Surgeons, Congress of Neurological 
Surgeons, et al. Guidelines for the management of severe traumatic brain injury. XI. anesthetics, 
analgesics, and sedatives. J Neurotrauma. 2007;24 Suppl 1:S71-6. doi: 10.1089/neu.2007.9985 [doi]. 
12. Nyquist P, Stevens RD, Mirski MA. Neurologic injury and mechanical ventilation. Neurocrit Care. 
2008;9(3):400-408. doi: 10.1007/s12028-008-9130-7 [doi]. 
13. Stevens RD, Lazaridis C, Chalela JA. The role of mechanical ventilation in acute brain injury. Neurol 
Clin. 2008;26(2):543-63, x. doi: 10.1016/j.ncl.2008.03.014 [doi]. 
14. Daoud EG. Airway pressure release ventilation. Annals of Thoracic Medicine. 2007;2(4):176-179. 
doi:10.4103/1817-1737.36556.  
15. Dart BW,4th, Maxwell RA, Richart CM, et al. Preliminary experience with airway pressure release 
ventilation in a trauma/surgical intensive care unit. J Trauma. 2005;59(1):71-76. doi: 00005373-
200507000-00010 [pii]. 

10 
 
16. Maung AA, Luckianow G, Kaplan LJ. Lessons learned from airway pressure release ventilation. J 
Trauma Acute Care Surg. 2012;72(3):624-628. doi: 10.1097/TA.0b013e318247668f [doi]. 
17. Maxwell RA, Green JM, Waldrop J, et al. A randomized prospective trial of airway pressure release 
ventilation and low tidal volume ventilation in adult trauma patients with acute respiratory failure. J 
Trauma. 2010;69(3):501-10; discussion 511. doi: 10.1097/TA.0b013e3181e75961 [doi]. 
18. Andrews PL, Shiber JR, Jaruga-Killeen E, et al. Early application of airway pressure release ventilation 
may reduce mortality in high-risk trauma patients: A systematic review of observational trauma ARDS 
literature. J Trauma Acute Care Surg. 2013;75(4):635-641. doi: 10.1097/TA.0b013e31829d3504 [doi]. 
19. Nemer SN, Caldeira JB, Azeredo LM, et al. Alveolar recruitment maneuver in patients with 
subarachnoid hemorrhage and acute respiratory distress syndrome: A comparison of 2 approaches. J 
Crit Care. 2011;26(1):22-27. doi: 10.1016/j.jcrc.2010.04.015 [doi]. 
20. Marik PE, Young A, Sibole S, Levitov A. The effect of APRV ventilation on ICP and cerebral 
hemodynamics. Neurocrit Care. 2012;17(2):219-223. doi: 10.1007/s12028-012-9739-4 [doi]. 
21. Kreyer S, Putensen C, Berg A, et al. Effects of spontaneous breathing during airway pressure release 
ventilation on cerebral and spinal cord perfusion in experimental acute lung injury. J Neurosurg 
Anesthesiol. 2010;22(4):323-329. doi: 10.1097/ANA.0b013e3181e775f1 [doi]. 
 Daoud EG. Airway pressure release ventilation. Annals of Thoracic Medicine. 2007;2(4):176-179. 
doi:10.4103/1817-1737.36556.