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Abhishek Srivastava et al. Journal IFNR Volume 1, Issue 1
INTRODUCTION
Hypoxic ischemic encephalopathy (HIE) is a
severe type of brain injury that occurs when brain
doesn't receive enough oxygen for a period of time
resulting from insults such as cardiac arrest,
drowning, asphyxiation. Based on prospective
studies, the incidence of cardiac arrest is estimated
to be 50-100 per 100,000 in the general
population1. With improved techniques in
resuscitation and artificial life support, greater
Hyperbaric Oxygen Therapy in Improving Neurological and Funconal
Outcome of Persons with Severe Hypoxic Ischemic Encephalopathy
Abhishek Srivastava
1
, Faiz Mohammed
2
, Navita Purohit Vyas
3
, Tushar Sonawane
4
1. Neurorehabilitaon Specialist & Director, Centre for Physical Medicine & Rehabilitaon, Kokilaben Dhirubhai Ambani Hospital &
Medical Research Instute, Mumbai, Maharashtra, India. 2. Neurorehabilitaon Specialist, Thanal brain and spine medcity, Kannur,
Kerala, India. 3. Rehab, Pain and Palliave Medicine Specialist, Kokilaben Dhirubhai Ambani Hospital & Medical Research Instute,
Mumbai, Maharashtra, India. 4. Physical Medicine & Rehabilitaon, Kokilaben Dhirubhai Ambani Hospital & Medical Research Instute,
Mumbai, Maharashtra, India.
ABSTRACT
Background- The prevalence of severe Hypoxic Ischemic Encephalopathy (HIE) is increasing and their prognosis
for meaningful recovery is poor. Adjunctive Hyperbaric Oxygen therapy (HBOT) has been used in patients with
severe disorder of consciousness but studies to evaluate benefits are scarce. Objective- Evaluate the changes in
level of consciousness, neurological status and functional status in patients with severe hypoxic ischemic
encephalopathy (HIE) who underwent HBOT. Methods- This is a retrospective study involving 54 patients with
severe HIE. Validated outcome scales (Coma Recovery Scale-Revised for level of consciousness, Glasgow Coma
Scale for neurological status, and Glasgow Outcome Scale for functional status) prior to starting HBOT and at
discharge were evaluated. Clinical Data, Duration of injury, Number of HBOT sessions and medical complications
attributed to HBOT were analysed. Wilcoxon sign ranked test was used for statistical analysis. Results- Fifty two
percent patients had change in level of consciousness with 13% achieving consciousness. Fifty percent patients had
improvement in neurologic Status. 35% of patients showed functional improvement with 13% patients achieving
independence for ADLs at discharge. Higher initial GOS score significantly increased the odds of having higher
GCS and level of consciousness at discharge. Younger age, female gender, HBOT session started within a month
of injury and higher GOS score significantly increased the odds of functional recovery at discharge. No major
complications were attributed to HBOT. Conclusions- There is scope for improvement in consciousness,
neurological status, and functional status after severe HIE. HBOT is safe and well tolerated by persons with severe
HIE.
KEYWORDS- Hypoxic Brain Injury, Hypoxic Ischemic Encephalopathy, Disorder of Consciousness, Hyperbaric
Oxygen therapy.
CORRESPONDING AUTHOR
Dr Abhishek Srivastava,
Neurorehabilitation Specialist & Director,
Centre for Physical Medicine & Rehabilitation,
Kokilaben Dhirubhai Ambani Hospital &
Medical Research Institute, Mumbai
Email- 29abhi@gmail.com
Received on- 4
th
May 2024
Published on- 24
th
July 2024
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Abhishek Srivastava et al. Journal IFNR Volume 1, Issue 1
numbers of patients survive with variable degrees
of residual brain injury. Severe hypoxic-ischemic
injury primarily affects the grey matter structures
due to their high metabolic requirement for oxygen
and glucose to supply large number of synapses.
This makes grey matter more susceptible to
hypoxic -ischemic injuries leading to significant
neurologic disability, ranging from mild cognitive
deficits to minimally conscious state (MCS) and
vegetative state (VS) depending on the severity of
damage2,3.
In severe hypoxic brain injury, patients initially
present in a comatose condition which usually
progresses to VS or MCS. It is challenging to
predict the prognosis based on clinical findings at
this time 4. In a large scale study of adults with
post-hypoxic brain injury, 64% patients died, 9%
remained comatose or in an unresponsive
wakefulness syndrome (UWS) and 27% of patients
regained consciousness 5. In a study by Heinz et al
in 2015 with 93 patients , 82% of patients had
disorder of consciousness (DOC) at admission and
75.3% of them had a poor outcome (Barthel Index
<50)6. The primary goal of a rehabilitation
program in severe brain injury is to promote
arousal. There are currently no treatment guidelines
for individuals with DOC but both pharmacologic
as well as non-pharmacologic methods have been
used in clinical practice7,8. Hyperbaric oxygen
therapy (HBOT) is one of those methods, and has
shown to inhibit apoptosis, suppress inflammation,
protect the integrity of blood-brain barrier, and
promote angiogenesis and neurogenesis9.
HBOT is defined as the inhalation of 100% oxygen
under the pressure greater than 1 atmosphere
absolute (ATA). Among neurological conditions,
HBOT has been evaluated among patients of
traumatic and non-traumatic injuries of the brain
with varying results. Some research has shown that
hyperbaric oxygen (HBO) can decrease the rate of
mortality and disability caused by hypoxic-
ischemic encephalopathy (HIE) in neonates10. In
2019, Sankaran et al in their study to assess the
efficacy of hyperbaric oxygen therapy (HBOT) in
patients with hypoxic ischemic encephalopathy
(HIE) did a case control study with 25 patients and
found a significant difference in CRS-R favouring
the HBOT group11. Hyperbaric Oxygen therapy
(HBOT) has been used along with conventional
rehabilitation methods in some centres, but no
large-scale studies are available at present. We
undertook this study to evaluate the changes in
level of consciousness, neurologic status, and
functional status in patients with severe HIE who
underwent HBOT at our centre.
METHODOLOGY
Population
The retrospective study was conducted at the
Neurorehab Unit of a tertiary care hospital. HBOT
registry was searched for patients with severe HIE
(VS or MCS) who underwent adjunctive HBOT
during March 2017- Feb 2020. A total of 63
patients were found and their medical records were
reviewed. 4 patients died during the hospital stay
due to medical complications not related to HBOT
and were excluded. 5 patients’ medical records
were not complete and were excluded from the
study. A Total of 54 patients met the criterion and
were included in the study. Perry TM Monoplace
Chamber was used for providing HBOT under
medical supervision. Hyperbaric oxygen at 2 ATA
pressure was given for 60 minutes per session for 6
days a week for up to a total of 60 sessions
maximum. Pre requisites for starting HBOT was a)
Cardiopulmonary Stability b) Intracranial Pressure
stability c) Disorder of consciousness d) Minimal
suction requirement with at least 2 hours of suction
free periods consistently e) No history of Asthma,
COPD or other chronic lung diseases f) No history
of ear diseases or tympanic perforation g) No
history of uncontrolled seizures h) No active
systemic infection i) No supplemental oxygen
requirement in past 24 hours, and j) Able to
maintain steady blood sugar values.
VALIDATED OUTCOME SCALES
Level of Consciousness was assessed by Coma
Recovery Scale-Revised (CRS-R), Neurological
Status by Glasgow Coma Scale (GCS) and
Functional Status by Glasgow Outcome Scale
(GOS). Level of consciousness was classified into
VS, MCS, or Conscious state as per evaluation of
auditory, visual, motor, verbal, communication,
and arousal functions on CRS-R Scale12.
Neurological Status was classified as Mild injury,
Moderate injury or Severe injury based on total
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Abhishek Srivastava et al. Journal IFNR Volume 1, Issue 1
GCS score of 13-15, 9-12 and less than 9
respectively13. Glasgow Outcome Scale of 2&3
was considered as significant disability requiring
assistance for daily living, and GOS 4&5 as
patients who were independent for ADLs14.
Improvement in level of consciousness was defined
as change in level of consciousness from either VS
to MCS or MCS to consciousness. Improvement in
neurologic status was defined as change in status of
brain injury from severe to moderate, or, moderate
to mild as per total GCS. Improvement in
functional status was defined as change in at least
1 level in GOS scale.
PROCEDURE
Case records of the 54 patients were obtained from
medical records department and analysed.
Demographic data including age, gender, number
of sessions of HBOT undertaken and duration of
hypoxic injury at the time of starting HBOT was
noted. The GCS, GOS and CRS-R scores before
HBOT and at the time of discharge was noted. Any
complications that occurred due to HBOT or that
resulted in missing of HBOT sessions were noted.
To evaluate the role of age, gender, number of
HBOT sessions and duration of brain Injury on
outcome measures, patients were divided into
a) Less than or equal to 45 years and More than 45
years
b) Male or Female gender
c) HBOT started within a month of brain injury or
more than 1 month
d) Patients who took less than 12 sessions and more
than 12 sessions
STATISTICAL ANALYSIS
Analyses were performed using SPSS software for
Windows (version 25, 2007, IBM Corporation,
Armonk, New York, United State). Data was
presented as frequency (%) or Median (minimum-
maximum). Wilcoxon sign ranked test was used to
analyse the difference in values before and after
intervention. Ordinal Regression analysis was used
to compare the differences.
RESULTS
In our study, 68.5% of the participants were males
and 31.5% were females. The mean age was 47.2
years with 48% patients less than or equal to 45
years of age. HBOT was started within 30 days in
44% of patients. Twenty-eight percent of patients
underwent less than 12 sessions with an average of
26.3 sessions per person. (Table 1)
Before starting HBOT, 74% of patients were in VS
and 26% were in MCS. At discharge, 55% of
vegetative state patients showed improvement in
consciousness with 1 patient achieving
consciousness (1.8%). Fifty-four percent of
patients remained in MCS and 13 % of patients
achieved consciousness (able to have a functional
communication or functional object use). (Table 2)
Before starting HBOT, 77% of patients had severe
brain injury (as per GCS) while others had
moderate brain injury. At discharge, only 35%
patients remained in severe brain injury but 52%
patients had moderate injury. Thirteen percent of
patients had only mild injury at discharge. (Table 3)
Before starting HBOT, all the patients had a GOS
score of 2 or 3, implying complete dependence for
activities. At discharge, 13% of patients showed
functional improvements achieving independence
for ADLs (GOS 4 & 5). (Table 4)
A higher GOS prior to starting HBOT significantly
increased the odds of having higher GCS and DOC
at discharge. Younger age, female gender and
HBOT session started within 1 month of brain
injury significantly increased the odds of having
higher GOS at time of discharge.
Ordinal Regression for level of consciousness
showed that an increase in pre-GOS was associated
with an increase in odds of having higher level of
consciousness at discharge (odds ratio = 219.802)
(p<0.001). Age, gender, time at which HBOT was
started, and number of sessions did not influence
the odds of having higher DOC at end line
(p>0.05). Ordinal Regression Analysis for GCS
showed that an increase in pre-GOS was associated
with an increase in odds of having higher post-GCS
(odds ratio = 55.498) (p<0.001). Age, gender,
duration of brain injury and number of sessions did
not influence the odds of having higher GCS at end
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Abhishek Srivastava et al. Journal IFNR Volume 1, Issue 1
line (p>0.05). Ordinal Regression for GOS showed
that the odds of less than or equal to 45 years being
in higher grade of GOS was 6.175 times that of age
more than 45 years (p<0.05), the odds of females
being in higher grade of GOS was 4.417 times that
of males (p<0.05) and the odds of HBOT session
started within 30 days beings in higher GOS was
3.769 times that of when HBOT session started
after the first month of injury (p<0.05).Number of
sessions did not influence the odds of having higher
GOS at end line (pp>0.05). An increase in initial
GOS was associated with an increase in odds of
having higher GCS at discharge (odds ratio =
77.298) (p=0.001).
DISCUSSION
The findings of this study shows that there is scope
for improvements in level of consciousness,
neurological status and functional status in patients
with severe HIE. A similar study with 113 patients,
who underwent rehabilitation but not HBOT had
6% patients achieving favourable functional
outcome (GOS 4,5) 15. Current literature suggests
that only about 10% of HIE survivors achieved a
good neurological outcome at 90 days. A recent
European study indicated that only 5% of cardiac
arrest survivors achieved full neurological recovery
at 30 days 16. Thirteen percent of our patients
achieved favourable outcome which is higher than
what is previously reported in severe HIE. One of
the reasons for better outcomes could be the
selection bias, as only patients who were medically
stable to undergo HBOT were selected in this study.
Also, patients with up to 1-year post HIE were
chosen in this study unlike most other studies
whose cut off were usually 1 month to 6 months.
Variable Frequency
(n=54)
Males [N (%)] 37 (68.5%)
Females [N (%)] 17 (31.5%)
Age (years) (Mean±SD) 47.2 ±16.1
Age ≤45 years [N (%)] 26 (48.1%)
Age ≥46 years [N (%)] 28 (51.9%)
Duration of injury when HBOT
started (days)(Mean±SD)
74±86
HBOT started ≤30 days [N (%)] 24 (44.4%)
HBOT started ≥31 days [N (%)] 30 (55.6%)
Number of HBOT sessions
(Mean±SD)
27±19
Number of HBOT sessions ≤12 [N
(%)]
15 (27.8%)
Number of HBOT sessions ≥13 [N
(%)]
39 (72.2%)
Table 1. Basic characteristics of study participants
Table 2. Level of Consciousness before and after
receiving HBOT
This study is important because it has a larger
sample size and includes only patients with severe
disorder of consciousness (VS and MCS).
Validated outcome measures were chosen to assess
the change in consciousness (CRS-R), neurologic
status (GCS) and Functional status (GOS) before
and after the HBOT program. Also, all patients
received HBOT along with similar
multidisciplinary rehabilitation programs including
physical therapy, occupational therapy, and
swallow therapy.
More than half of the patients in vegetative state
(52%) had change in level of consciousness, half of
the patients (50%) had improvement in neurologic
status while more than a third of them (35%)
Pre-HBOT sessions Post-HBOT Session p value
Freq. % Freq. %
Vegetative State 40 74.1 18 33.3 0.001*
MCS 14 25.9 29 53.7
Conscious - - 7 13
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Abhishek Srivastava et al. Journal IFNR Volume 1, Issue 1
showed at least some functional improvement.
Changes in patient’s abilities like visual tracking,
movements towards auditory stimulus and semi-
purposeful motor movements in patients who
otherwise did not make functional recovery
provided was also perceived as significant progress
by caregivers. The effect of these non-functional
changes on caregivers are understated and needs to
be taken into consideration in rehabilitation.
Table 3. Neurological Status before and after
receiving HBOT
Table 4. Functional Status before and after
receiving HBOT
.
Our results further suggest that GOS might also
serve as a prognostic variable in neurological early
rehabilitation. A higher GOS before HBOT
significantly increased the odds of having better
level of consciousness and neurologic status at
discharge. The results are comparable to the
outcomes demonstrated in other studies using
HBOT for DOC in severe brain injuries. Wang et al
in their meta-analysis of HBOT in TBI found a
higher post-treatment GCS score in the HBOT
group in addition to greater improvement in GOS
and lower mortality, as compared to the control
group17. Bennett et al in their Cochrane review
found that use of HBOT in TBI resulted in a
statistically significant decrease in the proportion
of people with an unfavourable outcome one month
after treatment using the GOS18.
In neurological rehabilitation outcome studies, age
emerges as an important and independent
prognostic factor (e.g. in stroke outcome). We
found that patient less than 45 years of age and
female gender had better chances of functional
recovery than those above 45 years and males
(p<0.05). We did not find any relation between
outcome and number of HBOT sessions taken, but
HBOT when started within 30 days had better
functional outcome (p<0.05).
Four patients were excluded from the study as they
had succumbed to various medical complications
not related to HBOT. While the risk for seizures is
of significant importance in this patient population
due to extensive brain damage and oxygen toxicity,
we did not have this complication in any of our
patients. HBOT was well tolerated in patients with
severe neurological status when complemented
with adequate medical management.
The study has its limitations being a retrospective
study with no control group. The number of HBOT
sessions varied significantly based on patient’s
length of stay and affordability. Outcome measures
were not assessed at a particular timeframe post
hypoxic brain damage but prior to HBOT
commencement and at the time of discharge which
was variable among patients. Patients also received
simultaneous rehabilitation measures which can
also be a confounder. There is clearly a need for
further research using larger number of patients in
a randomized control trial.
CONCLUSION
Patients with severe hypoxic brain injury has
potential for recovery of consciousness, functional
and neurological status with HBOT. Functional
status(GOS score) at time of admission had
predictive value on neurologic status and level on
consciousness at discharge. Younger age, female
gender, and early HBOT had significant effect on
Pre-HBOT sessions Post-HBOT Session p value
Freq. % Freq. %
Severe Injury
(GCS<=8)
42 77 19 35.2 0.001*
Moderate Injury
(GCS 9-12)
12 23 28 51.9
Mild Injury
(GCS 13-15)
- - 7 13
Pre-HBOT sessions Post-HBOT Session p value
Freq. % Freq. %
GOS 2 48 88.9 32 59.3 0.001*
GOS 3 6 11 15 27.7
GOS 4 - - 5 9.2
GOS 5 - - 2 3.7
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Abhishek Srivastava et al. Journal IFNR Volume 1, Issue 1
functional outcome. Large scale randomized
control studies are required.
REFERENCES
1. Fishman GI, Chugh SS, Dimarco JP, et al. Sudden
cardiac death prediction and prevention: report
from a National Heart, Lung, and Blood Institute
and Heart Rhythm Society Workshop. Circulation
2010; 122:2335–48.
2. Huang BY, Castillo M. Hypoxic-ischemic brain
injury: imaging findings from birth to adulthood.
Radiographics. 2008 Mar-Apr;28(2):417-39;
quiz 617. doi: 10.1148/rg.282075066.
3. Nolan JP, Neumar RW, Adrie C, et al. Post-
cardiac arrest syndrome: epidemiology,
pathophysiology, treatment, and prognostication.
2008 Dec;79(3):350-79. doi:
10.1016/j.resuscitation.2008.09.017. Epub 2008
Oct 28.
4. Oddo M, Rossetti AO. Predicting neurological
outcome after cardiac arrest. Curr Opin Crit Care.
2011 Jun;17(3):254-9. doi:
10.1097/MCC.0b013e328344f2ae.
5. Khot S, Tirschwell DL. Long-term neurological
complications after hypoxic-ischemic
encephalopathy. Semin Neurol. 2006
Sep;26(4):422-31. doi: 10.1055/s-2006-948323.
6. Heinz, U.E., Rollnik, J.D. Outcome and
prognosis of hypoxic brain damage patients
undergoing neurological early rehabilitation.
BMC Res Notes 8, 243 (2015).
https://doi.org/10.1186/s13104-015-1175-z.
7. Giacino JT, Katz DI, Schiff ND, et al. Practice
guideline update recommendations summary:
Disorders of consciousness: Report of the
Guideline Development, Dissemination, and
Implementation Subcommittee of the American
Academy of Neurology; the American Congress
of Rehabilitation Medicine; and the National
Institute on Disability, Independent Living, and
Rehabilitation Research. Neurology. 2018 Sep
4;91(10):450-460. doi:
10.1212/WNL.0000000000005926. Epub 2018
Aug8. Erratum in: Neurology. 2019 Jul
16;93(3):135. PMID: 30089618.
8. Eapen BC, Georgekutty J, Subbarao B, Bavishi S,
Cifu DX. Disorders of Consciousness. Phys Med
Rehabil Clin N Am. 2017 May;28(2):245-258.
doi: 10.1016/j.pmr.2016.12.003. Epub 2017 Mar
1.
9. Sanchez EC. Mechanisms of action of hyperbaric
oxygenation in stroke: a review. Crit Care Nurs
Q. 2013; 36:290–298.
10. Liu Z, Xiong T, Meads C. Clinical effectiveness
of treatment with hyperbaric oxygen for neonatal
hypoxic-ischaemic encephalopathy: systematic
review of Chinese literature. BMJ. 2006 Aug
19;333(7564):374.
doi:10.1136/bmj.38776.731655.2F. Epub 2006
May 11. PMID: 16690641.
11. Sankaran R, Radhakrishnan K, Sundaram KR.
Hyperbaric oxygen therapy in patients with
hypoxic ischemic encephalopathy. Neurol India.
2019 May-Jun;67(3):728-731. doi:
10.4103/0028-3886.263236.
12. Lucca, L.F., Lofaro, D., Pignolo, L. et al.
Outcome prediction in disorders of
consciousness: the role of coma recovery scale
revised. BMC Neurol 19, 68 (2019).
https://doi.org/10.1186/s12883-019-1293-7.
13. Teasdale G, Maas A, Lecky F, Manley G,
Stocchetti N, Murray G. The Glasgow Coma
Scale at 40 years: standing the test of time. Lancet
Neurol. 2014 Aug;13(8):844-54. doi:
10.1016/S1474-4422(14)70120-6. Erratum in:
Lancet Neurol. 2014 Sep;13(9):863.
14. Woischneck D, Firsching R. Efficiency of the
Glasgow Outcome Scale (GOS)-Score for the
long-term follow-up after severe brain injuries.
Acta Neurochir Suppl. 1998; 71:138-41. doi:
10.1007/978-3-7091-6475-4_41.
15. Howell K, Grill E, Klein AM, Straube A, Bender
A (2013) Rehabilitation outcome of anoxic-
ischaemic encephalopathy survivors with
prolonged disorders of consciousness.
Resuscitation 84:1409–1415.
16. Gräsner JT, Lefering R, Koster RW et al, EuReCa
ONE-27 Nations, ONE Europe, ONE Registry: A
prospective one month analysis of out-of-hospital
cardiac arrest outcomes in 27 countries in Europe.
Resuscitation. 2016 Aug;105:188-95.
doi:10.1016/j.resuscitation .2016.06.004.
17. Wang F, Wang Y, Sun T, Yu HL. Hyperbaric
oxygen therapy for the treatment of traumatic
brain injury: a meta-analysis. Neurol Sci. 2016
May;37(5):693-701. doi: 10.1007/s10072-015-
2460-2. Epub 2016 Jan 8.
18. Bennett MH, Trytko B, Jonker B. Hyperbaric
oxygen therapy for the adjunctive treatment of
traumatic brain injury. Cochrane Database Syst
Hyperbaric Oxygen Therapy for Severe Hypoxic Ischemic Encephalopathy Outcomes J Ind Fed NR
Page | 17
Abhishek Srivastava et al. Journal IFNR Volume 1, Issue 1
Rev. 2012 Dec 12;12:CD004609. doi:
10.1002/14651858.CD004609.pub3.
CITE THIS ARTICLE:
Srivastava A, Mohammed F, Purohit N, Sonawane T,
Hyperbaric Oxygen Therapy in Improving
Neurological and Funconal Outcome of Persons
with Severe Hypoxic Ischemic Encephalopathy, J Ind
Fed NR, 2024, Aug 2024; 1 (1): 11-17
