Presentation by Dr. Brian Greenwald at Brain Injury Alliance of New Jersey's 34th Annual Seminar

1. Medical Complexity and
Complications of Patients with
Traumatically Induced Disorders
of Consciousness
Brian D. Greenwald, MD
bgreenwald@jfkhealth.org
Medical Director Center for Head Injuries
Associate Medical Director
JFK Johnson Rehabilitation Institute
Clinical Associate Professor
Rutgers Robert Wood Johnson Medical
School

2. Overview
! Definition
! Outcomes
! Assessment
! Medical Complications
! Mortality

3. Disorders of Consciousness

4. Disorders of Consciousness
Coma
Vegetative State
Minimally Conscious State
Consciousness

5. Disorders of Consciousness
§ Coma
– No eye opening
– No command following
– No recognizable words
– No intentional movement
– Absence of paralytic agents
– Coma results from severe, diffuse dysfunction
of the cerebral cortices and/or underlying
white matter.

6. Disorders of Consciousness
§ Vegetative State/ Unresponsive
Wakefulness Syndrome
– evidence of functional restoration of the
reticular system (e.g. eye opening/
wakefulness)
– No evidence of awareness of self or
environment
– No purposeful or voluntary behavior that is
sustained or reproducible to stimuli
– May see non-voluntary movement
– No evidence of language comprehension or
expression

7. Disorders of Consciousness
• Minimally Consciousness state:
– minimal but definite behavioral evidence of self or environmental
awareness is demonstrated.
– cognitively mediated behavior occurs inconsistently, but is
reproducible or sustained long enough to be differentiated from
reflexive behavior.
– awareness of self and environment on a sustained basis by one
or more of the following:
! following simple commands
! gestural or verbal yes/no responses
! intelligible verbalization
! purposeful behavior.
Giacino JT, et al. Neurology 2002.

9. DOC Outcomes
! 9028 persons enrolled from 1988 to 2009
! N=337 subjects who were not following
commands on admission to rehabilitation
! N=271 (66%) following commands on discharge
! Median of 24 days post rehab admission
! Median of 55 days post injury
Nakase-Richardson R, Whyte J, Giacino JT, Pavawalla S, Barnett SD, Yablon SA,
Sherer M, Kalmar K, Hammond FM, Greenwald B, Horn LJ, Seel R,
McCarthy M, Tran J, Walker WC.
Longitudinal outcome of patients with disordered consciousness in the NIDRR
TBI Model Systems Programs. J Neurotrauma. 2012 Jan 1;29(1):59-65.

10. DOC Outcomes
! Ninety-one (23%) of these subjects also
emerged from PTA during inpatient
rehabilitation
! Of the 128 who did not regain ability to
follow commands during acute
rehabilitation 76% had at 5-year follow-up

11. DOC Outcomes
! Of 337 with at least 1 follow-up visit, 28
(8%) had died by 2.1 years (mean) from
discharge.

12. DOC Outcomes
§ Discharge Placement: Upon discharge,
264 (68%) had a community discharge
(returned to a private residence or group
home)

13. DOC Outcomes
• At 1 or more of the follow-up intervals:
– (19.6%) were capable of living without in-
house supervision
– (18.7%) demonstrated employment potential
either in competitive or sheltered workshop
environments

14. How can I wake this patient
up?

15. Where are they in Spectrum of
DOC?
! Rule out locked in syndrome

16. Disorders of Consciousness
Coma
Vegetative State
Minimally Conscious State
Consciousness

17. ASSESSMENT OF LEVEL OF
CONSCIOUSNESS
§ High rate of mischaracterizing
patients as being in VS instead of
MCS when using non-
standardized evaluation 40%
Schnakers C, et al. BMC Neurology 2009.

18. VS versus MCS
! Severe motor impairment/ apraxia
! Severe language impairment
! Variable level of consciousness
! Looking for subtle findings

20. JFK COMA RECOVERY
SCALE-REVISED (CRS-R)
! Developed to measure small clinical changes in
patients functioning at very low level with TBI and
Non-TBI.
! Provides reliable, valid, assessment of progress or
lack of progress in low level brain injured patients.

21. JFK COMA RECOVERY
SCALE-REVISED (CRS-R)
§ Assesses:
– Auditory
– Visual
– Motor
– Oromotor/ Verbal
– Communication
– Arousal
– Consistent reproducible responses and evidence or
awareness of environment

22. PATIENTS WITH DISORDERS OF
CONSCIOUSNESS WILL RARELY
IMPROVE UNTIL MEDICAL ISSUES
STABILIZE

23. PATIENTS WITH DOC ARE
MEDICALLY COMPLEX
§ Will review the results of 4 studies that address this
§ All studies part of special collection of articles on DOC
published in the Archives of Physical Medicine and
Rehabilitation, October 2013

24. Nakase-Richardson R, et al.
Do rehospitalization rates differ among injury
severity levels in the NIDRR TBI Model Systems
Program?
Arch Phys Med Rehabil, 2013; 94(10): 1884-90.
§ Aims
– Compare incidence and nature of rehospitalization rates at
1-year post-injury for persons with DOC compared to
moderate and severe TBI without DOC.
– Describe rehospitalization rate of persons with DOC over
time.

25. Methods: Subjects
§ Population: 9028 TBI Rehab Admits (1998-2009)
– Excluded:
– 155 - missing motor score on Rehab DRS
– 1062 - missing or not due for 1-year follow-up
– 78 - missing ER GCS
– 2235 - ER GCS 13-15
§ Study Sample N=5528
– N=769 had moderate TBI (ER GCS 9-12)
– N=4363 Severe TBI (ER GCS 3-8)
– N=366 DOC status at RehAdm

26. Procedure
§ Prospective recruitment and evaluation
– TBI Model System Criteria
§ Chart review – Trained TBIMS Staff
– Acute Care Hospitalization
§ Prospective Tracking
– Neurologic and Rehabilitation Course
– Discharge Status/Outcomes
§ Annual 1, 2, & 5 Year Follow-up
• Coding for Maximum of 5 Hospitalizations During
Follow-Up Interval

27. Subject Demographics
MODERATE
N=769
SEVERE
N=4,363
DOC
N=366
Age (quartiles) 24/37/51 21/29/43 21/28/41
Male 73% 76% 73%
Race
White 56% 69% 67%
Black 30% 19% 22%
Hispanic 10% 8% 8%
Other 4% 4% 3%
Education
<12 years 55% 52% 52%
≥ 12 years 45% 48% 48%
Cause of Injury
N Motor (%) 39% 64% 66%
ED GCS 10/11/12 3/3/6 3/3/6
Rehab Admit
GCS
14/14/15 13/14/15 7/9/10
Acute LOS 9/15/24 12/19/29 21/31/42
Rehab LOS 12/17/28 14/22/35 29/48/74

28. Results: Incidence of All Re-hospitalizations within Year
One by Group
MODERATE
N=769
SEVERE
N=4,363
DOC
N=366
Reason N
Rate Per
100/mths
N
Rate Per
100/mths
N
Rate Per
100/mths
Total No. Hosp. 182 2.23 1,232 2.75 169 5.27*†
Rehabilitation (inpatient) 12 0.15 110 0.25 33 1.03*†
Seizures 30 0.37 134 0.30 26 0.81*†
Neuro disorder (non-
seizure)
14 0.17 116 0.26 18 0.56*†
Psychiatric 6 0.07 104 0.23 2 0.06†
Infectious 17 0.21 138 0.31 36 1.12*†
Orthopedic 38 0.46 252 0.56 23 0.72
Gen Health Maint / OB/GYN 25 0.31 160 0.36 11 0.34
Other, not specified above 40 0.49 218 0.49 20 0.62

29. DOC
Subgroup
Year 1
N=285
Year 2
N=245
Year 5
N=134
Complete Follow-
up
N=108
Number
Admits
Rate per
100/mos
Number
Admits
Rate per
100/mos
Number
Admits
Rate per
100/mos
Number
Admits
Rate
Total No. Hosp. 169 4.94 120 4.08 48 2.99 151 2.33
Reason
Rehabilitation (inpt) 40 0.59 17 0.58 2 0.12 26 0.40
Seizures 20 0.29 18 0.61 8 0.50 18 0.28
Neuro disorder
(non-seizure)
8 0.12 7 0.24 5 0.31 12 0.18
Psychiatric 20 0.30 9 0.32 3 0.19 10 0.15
Infectious 24 0.36 13 0.44 8 1.45 19 0.31
Orthopedic 21 0.31 25 0.85 1 0.18 17 0.26
Gen Hlth Maint or
OB/GYN
15 0.22 10 0.34 13 0.80 23 0.35
Other not specified
above
21 0.30 21 0.71 8 0.49 26 0.40
Results: Incidence of Re-hospitalization for DOC subgroup available at follow-up
and the N=108 with consistent follow-up.

30. Nakase-Richardson R, et al: Descriptive
characteristics and rehabilitation outcomes in active
duty military personnel and veterans with disorders
of consciousness with combat and noncombat-
related brain injury. Arch Phys Med Rehabil.
94:1861-9, 2013
§ Polytrauma Centers
§ Retrospective Chart Review
§ Consecutive Admissions from 2003-2009

31. Methods
§ Emergence Criteria of consecutive admissions
– CRS-R (implemented in 2007; program development
conference)
– Object Use (feeding)
– Communication (responding accurately to orientation
questions)
– Note indicating Rancho 4 or higher in absence of
other behavioral measures in progress notes

32. ECP Participant Characteristics
Mechanism of Injury
§ Trauma
– Blast Injury – 22%
– Non-Blast – 64.2%
! MVC
! GSW
! Fall
§ Non-Traumatic – 12.2%
– Anoxia
– Stroke
– Intracranial Infection
Demographics
§ Gender (93.5% male)
§ Age (quartiles)
– 22/25/31
§ Education –
– 73.4% High School
§ Marital Status
– 42.7% Married
– 48.4% Single
– 7.3% Other
PRC BI 2003-2009 (N= 1,654)
ECP (N=121)

33. Active Duty & Veteran Status
§ Veteran Status 17.9%
§ Active Duty - 82.1%
§ Branch:
! Army – 48%
! Marines -26%
! Navy – 14%
! Air Force – 6.5%
! Other (Coast Guard, National Guard) – 4.1%

34. Overall Sample
N=122
Trauma-Blast
N=29
Trauma-Other
N=67
Non-Trauma
N=16
Spasticity 70% (62-78) 70% (52-86) 76% (66-86) 88% (71-100)
Dysautonomia 34% (25-42) 48% (30-66) 27% (16-37) 38% (14-61)
Seizure 30% (22-38) 45% (27-63) 21% (11-31) 19% (0-38)
Shunt Placement 25% (18-33) 31% (14-48) 28% (18-39) 12% (0-28)
Intracranial Infection 22% (15-30) 48% (30-66) 12% (4-20) 0% (--)
Heterotopic
Ossification
16% (10-23) 31% (14-48) 10% (3-18) 13% (0-29)
PE/DVT 14% (8-20) 21% (6-35) 13% (5-22) 0% (--)
Filter Placement 41% (33-49) 55% (37-72) 40% (29-52) 6% (0-18)
Anticoagulation 84% (77-90) 90% (79-100) 82% (73-91) 75% (54-96)
PE/DVT w/
Prophylaxis
11% (4-14) 17% (3-31) 10% (3-18) 6% (0-18)
Rehab Vent 11% (4-14) 17% (3-31) 10% (3-18) 6% (0-18)
Nakase-Richardson R, McNamee S, Howe LLS, Massengale J, Peterson M, Barnett SD, Harris O, McCarthy M, Tran J, Scott
S, Cifu DX. Descriptive Characteristics and Rehabilitation Outcomes in Active Duty Military Personnel and Veterans with
Disorders of Consciousness With Combat- and Non-Combat- Related Brain Injury. Archives of Physical Medicine and
Rehabilitation, 2013; 94(10): 1861-9

35. Ganesh S, et al: Medical co-morbidities in
disorders of consciousness patients and their
association with functional outcomes. Arch
Phys Med Rehabil. 94:1899-907, 2013
§ 68 subjects from 4 urban rehab facilities
§ At least 28 days of unconsciousness
§ Medical complications extracted from medical records
§ One-year FIM outcome scores also recorded

36. Number of complications and 1-
year outcome

37. Whyte J, et al: Medical complications during
inpatient rehabilitation among patients with
traumatic disorders of consciousness. Arch Phys
Med Rehabil, 94(10):1877-1883, 2013
§ Data collected as part of RCT of amantadine vs. placebo
(Giacino, Whyte, Bagiella, et al. Placebo-controlled trial of
amantadine for severe traumatic brain injury. N Engl J
Med, 366(9): 819-26, 2012
§ Recorded as “adverse events”
§ No difference based on treatment assignment, so all
events tallied

38. “ADVERSE EVENT”
§ New onset of symptom, sign, or abnormal laboratory
finding; or
§ Worsening of existing symptom, sign, or abnormal
laboratory finding
§ Adverse events rated for their severity, and “serious
adverse events” defined as transfer to acute care or
major medical/surgical procedure
§ 468 events over 6 weeks, or about .4/week/patient

39. Characteristics of the Sample
N = 184
Demographics
Age: (mean/SD) 36.4 (15.4)
Male: (N/%) 133 (72.3%)
Hispanic/Latino 16 (8.7%)
Race: Asian 2 (1.1%)
Black/African American 16 (8.7%)
White 160 (87)
Other 6 (3.3)
Injury Characteristics
Time from injury to randomization (med/IQ range) 47 (37 – 65)
Time from admission to randomization (med/IQ range) 12 (6 – 19)
Baseline DRS score (mean/SD) 22.0 (2.1)
Baseline CRS-R score (mean/SD) 9.4 (4.1)

40. Complications per Patient

41. Most Common Medical
Complications
Medical Complication
Number of
Events
Percent of all
Events
Percent
"severe"
Hypertonia/spasticity* 39 8.3 12.8
Agitation/aggression* 30 6.4 6.7
Urinary Tract Infection 30 6.4 3.3
Insomina/sleep disturbance* 29 6.2 3.4
Motor restlessness/hyperkinesia* 22 4.7 9.0
Vomiting 20 4.3 10.0
Other abnormal laboratory finding
(including 8 cases of hyponatremia) 17 3.6 5.9

42. Common Complications (cont.)
Medical Complication
Number of
Events
Percent of all
Events
Percent
"severe"
Pneumonia 14 3 64.3
Other GI problem (e.g., GI bleeding,
bowel obstruction, peritonitis) 13 2.8 38.5
Autonomic "storm"/PSH* 12 2.6 25.0
Skin rash 12 2.6 0.0
Diarrhea 12 2.6 8.3
Hydrocephalus* 10 2.1 70.0
Tachycardia 10 2.1 0.0
Upper respiratory tract infection 10 2.1 10.0
Total 280 59.8

43. Acute Care Hospitalizations
Diagnosis Number of Hospitalizations
Pneumonia 7*
Gastritis/gastrointestinal bleeding 2
Osteomyelitis 1
Intracranial bleeding 1
Deterioration in consciousness 1
Cellulitis/sepsis 2*
Corneal infiltrate (worsened) 1
Jejunal tube replacement 1
Bowel obstruction 2
Paroxysmal Sympathetic Hyperactivity 1
* - One additional patient in each category was treated in an integrated ICU without
transfer

44. Hospitalizations (cont.)
Diagnosis Number of Hospitalizations
Hydrocephalus/shunting 2
Tremor 1
Cardiac arrest 1#
Change in craniectomy site 1
Urinary tract infection/sepsis 1
Anemia, leg swelling 1
Vomiting/possible aspiration 1
Increased white blood cell count/seizures 1
Infection/hydrocephalus 1
Peritonitis 2
Total 31
# - death

45. Complications per Study Week

46. Spontaneous Reduction or
Managed Stability?
§ Poisson regression model applied to occurrence of
adverse events
§ No significant impact of age (p = .20), DRS score (p = .
71), or CRS-R score (p = .19).
§ Post-injury week and post-admission week were both
entered into the model.
§ Post-injury week was not significant (p = .83), but post-
admission week was highly significant (p < .0001).

47. Limitations
§ Underestimation
– A substantial minority of the study subjects had
already returned from an acute care transfer when
they were enrolled (and 14.7% were transferred during
the study)
– Chronically unstable patients excluded
– Complications already stable under management not
counted
§ Overestimation
– Close monitoring
– Some “complications” are expected (e.g.,
restlessness/agitation)

48. What we Know
§ Active management, not the mere passage of time,
appears important for controlling rate of complications
§ Occurrence of more complications is associated with
worse outcomes at 1 year

49. What we don’t know
§ Relevance of etiology of DOC
§ Is high rate of medical complications related to DOC?
§ Is poor outcome of those with more complications due to
the effects of those complications per se? or do
particularly severe injuries produce both frequent
complications and poor outcome?

50. Mortality following Traumatic Brain Injury among
Individuals Unable to Follow Commands at the
Time of Rehabilitation Admission: A NIDRR TBI
Model Systems Study.
Greenwald BD, Hammond F, Harrison-Felix CL, Nakase-
Richardson R, Howe LL, Kreider S. J Neurotrauma. 2015
Mar 25. [Epub ahead of print]

51. Mortality after TBI
§ 1.7 million TBIs occur in the United States
annually.
– 1,365,000 are seen in hospital emergency
departments
– 275,000 are hospitalized
– 52,000 TBI-related deaths
– In hospital mortality of 10-51%
– Severe TBI 6 month mortality- 50% (36-58%)
Faul M, et al Centers for Disease Control and Prevention;
2010.

52. Mortality after TBI
! Cohort of individuals with moderate to severe
TBI have a 1.5-3 X’s greater likelihood of death
relative to the general population using standard
mortality ratio (SMR)
! Patient's with Moderate to Severe TBI have a
decrease life expectancy of 6.7 years
! Life expectancy further reduced if impaired
mobility, swallow, tracheostomy

53. TBI Model Systems
! Traumatic Brain Injury Model Systems
(TBIMS) national database (NDB)
! Funded by the US Department of Education
via the National Institute on Disability and
Rehabilitation Research since 1987
! The TBIMS NDB contains information on
subjects treated within the 20 TBIMS centers
funded between 1988 and 2012, which are
located around the US

54. TBI Model Systems
! Moderate to severe TBI
! At least 16 years of age
! present to the Model System’s acute care
hospital within 72 hours of injury
! receive both acute hospital care and
comprehensive rehabilitation in a designated
brain injury inpatient unit within the Model
System
! October 25, 1988 through December 31,
2008, and follow-up dates or death dates
through December 31, 2009

55. Our Study
! Objective: Characterize long-term mortality,
life expectancy, causes of death and risk
factors for death
– Subjects who lack command following at the time
of admission for inpatient TBI rehabilitation (time
to follow simple commands and DRS ratings)
! TBI MS participants- 8,084
! Meeting our criteria-387 (Non-Command
Following group vs. DOC)

56. Standardized Mortality Ratio
! SMR is calculated by number of deaths in
a population divided by the expected
number in the general population. Controls
for gender, race and age.

57. Demographics
§ “Non-command following” group:
– Younger overall
– Longer LOS (injury to rehab DC)
– More days before getting to rehab
– Lower GCS
– Longer PTA
– Longer LOC
– Die Sooner
– Younger at death
– Lower FIM Motor and Cog at rehab admit and DC
– Higher DRS at Rehab admit and DC

58. Comparison of Mortality by Group
Assignment
Entire Sample
n = 8,084
Non Command Following
n = 387
Command following
n = 7,697
Observed deaths 781 (9.7%) 50 (12.9%) 731 (9.5%)
Expected deaths 348 7 341
Standardized Mortality Ratio
(SMR)
2.24 6.9 2.14
SMR Upper Confidence Limit
(CL)
2.09 4.99 1.99
SMR Lower CL 2.40 8.81 2.30
Mean Life Expectancy
reduction
6.6 years 12.2 years 6.2 years
Mean days to death 1,462.27
(SD 1,382.5)
1,124.62
(SD 1,367.64)
1,485.37
(SD 1,381.42)
Mean age at death 60.24 (SD 18.98) 49.30 (SD 17.09) 60.99 (SD 18.88)
DOC group was younger and dies sooner

59. Death Occurrence by Follow-Up
Time Interval
Time Period of Death
Occurrence
Entire Sample
n = 8,084
Non-Command Following
n = 387
Command Following
n = 7,697
Between Rehabilitation
Discharge & 1 Year
171 (22%) 18 (36%) 153 (21%)
Between 1 & 2 years post-
injury
141 (18%) 10 (20%) 131 (18%)
Between 2 & 5 years post-
injury
236 (30%) 12 (24%) 224 (31%)
Between 5 & 10 years post-
injury
167 (21%) 7 (14%) 224 (22%)
After 10 years post-injury 66 (8%) 3 (6%) 63 (9%)

60. Non-Command Following Group
dies sooner following rehabilitation
discharge than their respective
Command Following group, most
markedly noted for the two
youngest age groups.

61. Standard Mortality Ratios by
Comparison Group
Full Sample Non-Command Following Command Following
Cause SMR Lower Upper SMR Lower Upper SMR Lower Upper
Circulatory 1.3 1.11 1.49 4.58 1.74 7.41 1.25 1.05 1.44
External 3.58 2.94 4.23 1.45 -0.56 3.47 3.67 3.01 4.34
Respiratory 3.61 2.93 4.29 17.81 5.47 30.15 3.39 2.73 4.06
Pneumonia 6.37 4.64 8.11 44.28 5.47 83.1 5.84 4.17 7.51
AspiraGon
Pneumonia 14.11 9.06 19.16 38.04 36.52 112.6 13.81 8.79 18.84
Sepsis 10.32 7.34 13.3 49.54 0.99 98.1 9.59 6.69 12.5
Nervous
System 2.42 1.47 3.37 12.61 -4.87 30.09 2.26 1.34 3.18
DigesGve 1.76 1.03 2.5 NA NA NA 1.81 1.05 2.56
Seizures 35.29 19.82 50.75 133.74 -17.6 285.09 31.23 16.38 46.08
Mental 2.71 1.38 4.04 18.37 -7.09 43.84 2.42 1.15 3.69

62. Mortality
! The Non-Command Following Group has
higher mortality for circulatory, all respiratory,
and pneumonia specific causes than the
moderate to severe TBI groups
! The Non-Command Following Group relative
to the general population (similar age, gender
and race/ethnicity) was:
– over 4 times more likely to die of circulatory conditions
– 44 times more likely to die of pneumonia
– 38 times more likely to die of aspiration pneumonia

63. Mortality
§ Non-Command Following Group:
– higher proportion of ill-defined condition
related deaths
– higher proportion of nervous system causes of
death
– lower proportion of digestive condition related
deaths
– higher proportion of seizure related deaths
– higher proportion of dementia related deaths

64. Strengths and limitations
§ Strengths:
– Large sample size with extensive data about
each subject
§ Limitations:
– Generalizability questions:
! Patients admitted to a TBIMS hospital
! TBIMS acute rehab setting
! Follow-up decreases over time

65. Future research needs
§ Better understanding systemic changes
that increase risk of complication and
death both short term and long term
– Immune changes
– Autonomic changes
§ Medical management strategies to prevent
premature death in this population

66. Conclusion
! This study adds to the literature on
mortality, life expectancy, and risk factors
for death and causes of death after
moderate to severe TBI.
! Results could aid in long-term life
planning, resource allocation and
prevention of untimely death in individuals
after TBI.

67. Summary
! Possible to have a good outcome even if
patient initially had DOC on admit to
rehabilitation
! Patients with DOC on admission to
rehabilitation have significantly more
medical complications than patients with
moderate to severe TBI
! Patients with DOC have increased risk of
mortality relative to patients with moderate
to severe TBI

68. Summary
! Many of the medical complications are
brain injury specific and warrant
management by individuals with
specialized expertise as well as easy
access to testing to evaluate for these
complication subspecialists to assist with
management.

69. Thank You