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HBOT2016

10th International Symposium

Deploying Hyperbaric Medicine and Adjunctive

Therapies into the Health Care System:

Combining Public Policy and Clinical Outcomes

International Hyperbaric Medical Foundation

Astor Crowne Plaza Hotel

New Orleans, Louisiana

HBOT2016








HBOT2017 11th International Symposium

The Oxygen Revolution: “Healing Across the Spectrum of Disease and Beings” International Hyperbaric Medical Foundation

The Intercontinental Hotel August 18-20, 2017 New Orleans, Louisiana

HBOT2016








HBOT2016








HBOT2017 11th International Symposium

TBI: No Need to Die! A Review of HBOT in Acute Severe Traumatic Brain

Injury with an Extension to Acute Concussion, and an

Update on Chronic Mild TBI.

HBOT2016








HBOT2016








Paul G. Harch, M.D. Clinical Professor Director Hyperbaric Medicine Department University Medical Center LSU School of Medicine New Orleans, Louisiana

TBI, No Need to Die:

Definition of Traumatic Brain Injury:

Traumatic brain injury (TBI) is a nondegenerative, noncongenital insult to the brain from an external mechanical force, possibly leading to permanent or temporary impair- ment of cognitive, physical, and psychosocial functions, with an associated diminished or altered state of consciousness. http://emedicine.medscape.com/ article/326510-overview

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Classification of TBI

1. Mild, Moderate, and Severe TBI:



Review of Brain Cellular Anatomy

1. The brain is composed of:

a. Neurons: cells that do the thinking. b. Glia: cells that generally support and nourish the neurons.


Neurons in red, astrocytes (glia) n green.http://www.

britannica.com/EBchecked/media/118260/Neurons -which-

are-supported-by-glial-cells- such-as-astrocytes

http://www.britannica.com/

http://www.britannica.com/


Review of Brain Tissue Anatomy

1. Neurons and Glia are distributed in:

a. Gray Matter: dense concen- trations of neurons and glia forming the outer sphere of the brain, deep center, and brainstem. b. White Matter: broad bands of axons and glia connecting the gray matter regions of the brain. The cable of the brain. Very fragile (mostly fat. Think: reinforced mayonnaise).


http://www.wellesley.edu/Chemistry/ Chem101/brain/brain.htm

• http://www.sciencedaily.com

• /releases/2007/10/07102512

• 5137.htm

http://www.sciencedaily.com


Statistics

1. 2013 Centers for Disease Control: https://www.cdc.gov/traumaticbraininjury/get_the_facts.html

a. 2.5 million emergency department visits in the U.S.

b. TBI contributed to the deaths of nearly 50,000 people. c. From 2007–2013 TBI-related death rates decreased by 5%. d. In 2012, an estimated 329,290 children (age 19 or younger) were treated in U.S. EDs for sports and recreation-related concussion or TBI. e. From 2001 to 2012, ED visits for sports and recreation concussion/ TBI, doubled in children (≤19 y.o.).

https://health.mil/News/Articles/2017/03/27/Brain-Injury-Awareness-Part-2-Screening-puts-injured-on-right-path-to-recovery


Mortality

1. Conclusion:

Despite 50 years of advances in modern medicine and intensive care techniques, in a recent 7 year span the mortality of acute severe TBI has only decreased by 5%.

http://3. https://www.researchgate.net/publication/221921426_Neurointensive_Care_Monitoring_for_Severe_Traumatic_Brain_Injury

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Components of Injury

1. Primary Injury: a. Direct contact to the head, or the brain contacting the inside of the skull, resulting in: scalp injury, skull fracture, contusion to the brain surface, bleeding. (Mostly gray matter injury). b Acceleration/deceleration: results in shear, stretch, compression, tearing, bleeding. (Mostly white matter injury)


http://neuro.psychiatryonline. Org/article.aspx?articleID=102725

DAI: pink (white matter). Contusions: blue (superficial gray matter; direct bony impact). Subdural Hematomas: purple (frontal and parietal convexities).

http://neuro.psychiatryonline

http://neuro.psychiatryonline


Components of Injury

1. Secondary Injury:

The inflammatory reaction resulting from tissue injury: edema, reduced blood flow, reduced oxygen, excitatory amino acids, free radical damage, lipid peroxidation, vasospasm, hyperglycemia, and cell death.


Edward D. Hall, Overview of

Therapeutics for Traumatic

Brain Injury.

https://www.nap.edu/read/131

21/chapter/26#382


Pathophysiology of Severe TBI

1. Pathophysiology:

a. Mechanical disruption of tissue: Peerless, 1967; Strich, 1961; Adams, 1980.

b. Ischemia: Bouma, 1991, Graham DI, 1978, Siesjo BK, 1996.

c. Hypoxia: Adams, 1980; van den Brink, 1998; Zhi, 1999.

d. Edema: Adams, 1980; Schoettle, 1990; Bullock, 1985.

e. Anaerobic metabolism: Muizelaar, 1989; Vilalta, 2011.

f. Excitatory neurotransmitters/neurochemicals: McIntosh, 1996; Hovda, 1995.

g. Vasospasm: Martin, 1995; Zurynski, 1998.

c. Activation of intravascular clotting and inflammatory cascades: Zhuang,

1993; Schoettle, 1990.



1. Pathophysiology:

a. Mechanical disruption of tissue: Peerless, 1967; Strich, 1961; Adams, 1980.

Diffuse axonal swelling (brown) Axon contraction balls

http://neuropathology-web.

org/chapter4/chapter4b

Contusions_dai_sbs.html

http://moon.ouhsc.edu/

kfung/JTY1/NeuroSim/

Sim05-B-Diss-4-a.htm

http://neuropathology-web



http://moon.ouhsc.edu/



1. Pathophysiology:

b. Ischemia: Bouma, 1991, Graham DI, 1978, Siesjo BK, 1996. Bouma, 1991: 186 acute severe TBI adults, GCS <9, CBF and AVDO2 q6h: 1/3 patients with CBF < 18 cc/ 100g tissue/min in first 6 h. Mortality highest in low CBF patients.



1. Pathophysiology:

c. Hypoxia: Adams, 1980; van den Brink, 1998; Zhi, 1999.

Van den Brink, 1998:

82 patients: acute severe non-penetrating TBI

Continuous intracerebral PO2 monitoring

Findings: low PO2 seen within the first 24h of injury

Early occurrence of values < 10 mm Hg: poor prognosis

Zhi, 1999:

14 acute severe TBI patients w/i 1.5-12h post TBI

Licox oxygen monitor catheter in frontal white matter

Findings: average initial PO2 low (< 10 mm HG) = 8.9 mm Hg

PO2 ≤ 5 significantly associated with poor outcome



1. Pathophysiology:

d. Edema: Adams, 1980; Schoettle, 1990; Bullock, 1985.

Bullock, 1985:

39 acute severe TBI patients

in coma.

19: focal contusion requiring

surgery.

20: diffuse brain injury

Resect pericontusion white

matter in surgical patients (19)

Resect frontal lobe white matter at ICP bolt site in DAI (20)

Measure CT density at prospective surgical site pre-op

Measure specific gravity of resected tissue:

Findings: lower CT density, lower specific gravity



1. Pathophysiology:

d. Edema:

Bullock, 1985.



1. Pathophysiology:

e. Anaerobic metabolism: Vilalta, 2011

30 mod-severe TBI (avg. GCS 6), Microdialysis and Licox catheters

in least injured hemisphere

Measurements 46h post injury: pre/post: 100% O2/2h challenge

Two groups: lactate ≤ or > 3.0 mmol/L.

Findings: 47% with “anaerobic metabolism” (may actually be a combination

of anaerobic metabolism and hyperglycolysis-Reinert, 2000).

post O2: 7% increase glucose, 9% decrease lac/pyruvate

Group 2: decrease lactate, decrease lac/pyruvate.



1. Pathophysiology:

f. Excitatory neurotransmitters/neurochemicals: Hovda, 1995.

“A similar cascade occurs in human head injury, validating the animal model as well as providing new assessment strategies for the management and treatment of brain injury.”



1. Pathophysiology:

g. Vasospasm: Martin, 1995. (Bernouli Effect).

FIG. 1. Mean time course of transcranial Doppler velocities in the middle cerebral artery (triangles) and extracranial internal carotid artery (squares) in patients with (A) and without (B) vasospasm. From Martin NA, Doberstein C, Zane C, et al. J Neurosurg, 1992;77:575-583.



1. Pathophysiology: g. Vasospasm: Martin, 1995. FIG. 2. Severe posttraumatic vasospasm involving the distal internal carotid artery and middle cerebral artery (arrow). From Martin NA, Doberstein C, Zane C, et al. J Neurosurg, 1992; 77:575-583. Vasospasm in 25-40% of severe TBI patients. ICA, MCA, and basilar arteries. Similar to time course in SAH: ≥ 2 days. Appears to be due to extra- vascular blood.



1. Pathophysiology:

h. Activation of intravascular clotting and inflammatory cascades: Schoettle

1990

Rats, focal cortical weight drop (2 groups of difference force) vs. sham

Labeled PMN and rbc injections pre-injury (measure at 2h post injury) or 4h

post injury (measure 8h post injury)

Measure R-L hemisphere difference in brain water and PMN accumulation.

Findings:

PMN accumulation in first 2h post trauma due to increase in blood volume.

Absolute increase in PMN at 8h post trauma and correlation with brain

edema (inflammatory phase of TBI).

Amount of edema proportional to force.



1. Pathophysiology:


1990. Edema proportional to Force:



1. Pathophysiology:


1990: Edema and PMN Accumulation 4-8h post-TBI


HBOT Effects on Pathophysiology of Severe TBI

1. HBOT Effects on Disrupted Tissue: a. No known direct effects, but possibly indirect effects by reduction in edema

(below) and subsequent resolution of distorted anatomy. Also, HBOT is a treatment of wounds in any location and of any duration. In the process of repairing the wounds of TBI there is improvement in the physical mechanical injury to the brain.

1. HBOT Effects on Ischemia:

Rockswold SB, et al. Effects of hyperbaric oxygenation therapy on cerebral metabolism and intracranial pressure in severely brain injured patients. J Neurosurg, 2001;94;403-411 37 severe TBI patients, GCS ≤ 8, mean 5.8. 18 patients with mass lesions that were evacuated surgically 19 patients with diffuse brain injury Mean time from injury to HBOT: 23h (9-49h)



2. HBOT Effects on Ischemia:

HBOT: 1.5 ATA/60 minutes at depth (15 mins. compression and decompression 1st treatment as soon as stable 2nd treatment at least 8h later or the next a.m. and daily until patient could consistently obey commands or was deemed brain dead, upto a maximum of 7 HBOTs. Measure cerebral blood flow: nitrous oxide saturation method. Abnormal blood flow as 2 standard deviations above or below the normal range (33-55 m./100g/min) Normal blood flow was not necessarily physiologically appropriate for that patient. Results: Patients with reduced CBF: HBOT increased CBF 1 and 6h post HBOT. Patients with “normal” CBF: HBOT increased CBF 1h post HBOT (back to baseline at 6h post HBOT) Patients with increased CBF: HBOT decreased CBF 1h and 6h post HBOT



2. HBOT Effects on Ischemia: Rockswold SB, 2001



3. HBOT effects on hypoxia: Rockswold, 2010. 69 patients with acute severe TBI 3 groups within 24h of injury 1.5 ATA HBOT/60 mins. at depth, 94 minutes Total Dive Time. NBO-100%/3h Control, standard care Treatment once/day for 3 consecutive days Measure brain tissue PO2, ICP, CBF, AVDO2, CRMO2, CSF lactate and F2- isoprostane, bronchial alveolar lavage (BAL) fluid interleukin (IL-6 and 8), pretreatment and 1 and 6 h posttreatment. Findings: Significantly increased brain PO2 levels in HBOT and NBO groups: HBOT (223 mm Hg) NBO (86 mm Hg)



3. HBOT effects on hypoxia: Rockswold, 2010.



4. HBOT Effects on Edema/ICP: Rockswold 2001. 37 acute severe TBI patients 23h from injury to first treatment HBOT: 1.5 ATA/60 minutes at depth, TDT 90 minutes 2nd treatment next a.m., at least 8h after first treatment Daily HBOT for 5 additional days (total 7 HBOTs) or until could obey commands or was brain dead. Measure: CBF, AVDO2, CMRO2, CSF lactate, ICP 1h pre and 1h and 6h post each HBOT. Patient divided into 2 groups: ICP > 15 mm Hg pre-HBOT ICP ≤ 15 mm HG pre-HBOT Findings: ICP > 15: ICP dropped then rose above pre-HBOT level during HBOT then decreased 1 and 6h post HBOT progressively. ICP ≤ 15: ICP increased during HBOT and stayed elevated post- HBOT.



4. HBOT Effects on Edema/ICP: Rockswold 2001.



5. HBOT Effects on Anaerobic Metabolism: Holbach, 1974?, Rockswold 2001.

Holbach, 1974? 23 acute severe TBI and 7 acute severe stroke, 3-7d? post event Measure glucose oxidation quotient pre and post NBO, 1.5 ATA, and 2 ATA for 15 minutes each; Findings: aerobic metabolism most balanced at 1.5 ATA. A 15 minute excur- sion to 2.0 ATA resulted in unbalanced metabolism. Rockswold, 2001: 37 acute severe TBI patients 23h from injury to first treatment HBOT: 1.5 ATA/60 minutes at depth, TDT 90 minutes 2nd treatment next a.m., at least 8h after first treatment Daily HBOT for 5 additional days (total 7 HBOTs) or until could obey commands or was brain dead. Measure: CBF, AVDO2, CMRO2, CSF lactate, ICP 1h pre and 1h and 6h post each HBOT. Regardless of pre-HBOT CBF value significant decrease in lactate at 1 and 6h post-HBOT.



5. HBOT Effects on Anaerobic Metabolism: Rockswold 2001.



6. HBOT effects on excitatory neurotransmitters/neurochemicals: Indirect evidence: Meng, 2016. 60 rats: Group 1: surgery/sham TBI Group 2: TBI group Group 3: TBI + HBOT group: 2.2 ATA/60 at depth w/i 2h of TBI, 2nd HBOT ~6h later. Measure in cortex surrounding TBI: Neurological function at 12 and 24h Apoptosis (TUNEL method) Nissl stain for whole neurons Nrf2 protein (transcription inducer for anti-inflammatory, antioxidant, growth factor, calcium homeostasis, and detoxification genes). Findings: HBOT significantly increased expression of Nrf2, reduced apoptotic and injured nerve cells, and improved neurological function scores.



6. HBOT effects on excitatory neurotransmitters/neurochemicals: Indirect evidence: Meng, 2016.

H3 = Histone 3 protein



7. HBOT effects on vasospasm: . Yufu, 1993: Rats, subarachnoid hemorrhage induction 30 minutes later HBOT 2.0 ATA/60 minutes 2h post hemorrhage measure: Na/K ATPase and spin-label studies on synaptosomal membranes. Results: HBOT reversed most of the SAH-induced alterations. Kohshi, 1993: 43 patients with symptomatic vasospasm post aneurysm surgery 3 groups: 17 patients: no infarcts, mild hypertensive hypervolemia + HBOT. 7 patients: infarcts, mild hypertensive hypervolemia + HBOT. 19 patients: mild hypertensive hypervolemia. HBOT: 2.5 ATA/60 at depth, 85mins. TDT, qd or bid x 2-21 (avg 10 HBOTs) Assessments: CT brain for infarcts at 1 month Neurological outcome at 1 month (Modified Glasgow Outcome Scale) Results: 58% good outcome all HBOT (including the 7 with initial infarcts) 76% good outcome in HBOT group without pre-HBOT infarcts) 37% good outcome in control group. 24% infarcts in HBOT group 1 (no pre-HBOT infarcts) 42% infarcts in control group Conclusion: HBOT reduced infarcts in SAH patients with symptomatic vasosp.



7. HBOT effects on vasospasm: .

Kohshi, 1993:



9. HBOT effects on intravascular clotting and inflammatory cascades: No human data, but substantial animal data immediately after TBI and overwhelming animal and some human data on HBOT effects on acute reperfusion injury: Vlodavsky, 2006: Rats, acute dynamic cortical deformation TBI (.6 ATA pressure exposure = negative .4 ATA suction) Control group: no treatment NBO: 100% O2/90 minutes with 1 air break, 3h post TBI, then bid x 3d = 7 treatments total. HBOT: 2.8 ATA/90 minutes with 1 air break, 3h post TBI, then bid x 3d = 7 treatments total. Measure: 4th post-op day apoptosis (TUNEL method) neuroinflammation: PMNs, MMP-2, 9, TIMP-1, 2 (tissue inhibitors of matrix metalloproteinases) Findings: significant decrease in apoptosis, MMP-9, and PMNs compared to NBO and control Conclusions: HBOT decreased secondary cell death and reactive neuroinflammation in acute TBI.



9. HBOT effects on intravascular clotting and inflammatory cascades: Vlodavsky, 2006: (effect on apoptosis in penumbra)



9. HBOT effects on intravascular clotting and inflammatory cascades: Vlodavsky, 2006: (effect on PMNs in penumbra and MMP-9)



9. HBOT effects on intravascular clotting and inflammatory cascades: Meng, 2016: (effect on Nrf2 inflammatory signaling pathway- expressed at 2h post-TBI, peaks at 24h, resolves 3-5h. Absence of Nrf2 increases severity of TBI). 60 rats, Feeney “head bonk” method: Group 1: surgery/sham TBI Group 2: TBI group Group 3: TBI + HBOT group: 2.2 ATA/60 at depth w/i 2h of TBI, 2nd HBOT ~6h later. Measure in cortex surrounding TBI: Nrf2 protein Anti-oxidants: NQO-1 (quinine oxidoreductase 1) and HO-1 (heme oxygenase1) Findings: HBOT significantly increased expression of Nrf2, Ho-1, NQO-1.



9. HBOT effects on intravascular clotting and inflammatory cascades: Meng, 2016: (effect on Nrf2 inflammatory signaling pathway)



Summary: 1. Severe TBI is characterized by: mechanical

disruption of tissue, ischemia, hypoxia, edema/increased ICP, anaerobic metabolism, excitatory neurotransmitters/neurochemicals, vasospasm,

inflammation. 2. HBOT has been shown to treat in both

animals and humans all of the pathophysiological components of acute severe TBI.


HBOT in Acute Severe TBI: Clinical Literature Review

1. Non-controlled studies: a. Mogami,1969: 66 acute coma cases (51 TBI): 2 ATA/1h at depth, qd or bid (6/143 HBOTs at 3 ATA/30 mins.) Clinical, EEG, and ICP improvement at depth inversely proportional to neurological severity, with regression/ rebound post-treatment. b. Hayakawa, 1971: 13 (9 TBI, 4 brain tumor), HBOT 2 ATA/1h. Three patterns of response: 1) decrease in CSF pressure at the beginning of the dive then increase at the end, 2) decrease in pressure that persisted, 3) no change. Second part of experi- ment in dogs with little or no change in pressure or CBF after brain injury. c. Holbach, 1974: 102 acute neurosurgical cases, 52 at 2-3 ATA, 50 at 1.5 ATA. Average 2.62 HBOTs/patient. 43 TBI patients, Avg. 2.44 HBOTs/patient. No other details to study. Findings: All subjects: 48% definite improvement 1.5 ATA 25% definite improvement 2-3 ATA TBI subjects: 40% definite improvement 1.5 ATA 30% definite improvement 2-3 ATA



1. Non-controlled studies: c. Holbach, 1974:

Cause of brain

damage

Number of

treatments

Number of

cases

A B

Definite

Improvement

A B

Slight

Improvement

A B

No

Improvement

A B

Trauma 105 23 20 7 8 5 3 11 9

CVA 135 21 26 5 15 6 4 10 7

Tumor 16 4 3 - 1 1 1 3 1

Infection 3 3 - 1 - - - 2 -

Ischemia 8 1 1 - - - - 1 1

Totals 267 52 50 13 24 12 8 27 18

% - 100 100 25 48 23 16 52 36



1. Non-controlled studies:

d. Artru, 1976-ox tox study:

6 acute severe TBI patients in coma; 9 studies.

12 normals and controls, some wih Multiple Sclerosis

5-47d from coma to study.

HBOT: 2.5 ATA/90 minutes, 1-3 treatments

Measure: CBF, CMRO2, CMRGluc, CMRLac, glucose, lactate, and

CSF PO2, glucose, lactate, pre and 2.33h post HBOT

Findings: CBF increase in some patients and decrease in others

after HBOT due to different effects on normal brain circula-

tion and injured brain circulation.

Arterial PO2 showed a consistent fall after HBOT (i.e., Ox Tox)




d. Artru, 1976-ox tox study:

Partial data table:

Conclusion:

Pulmonary oxygen

toxicity at 2.5 ATA.




e. Holbach, 1977: 14 acute severe TBI patients, continuous rCBF

and EEG recordings. HBOT: room air – 1 ATA O2 – 1.5 ATA O2 –

2.0 ATA O2 – 2.5 ATA O2 – 2.0 ATA O2 – 1.5 ATA O2 – 1.0 ATA O2 –

room air.

Findings: correlation of EEG and rCBF upto 1.5 ATA (decrease in

blood flow, improvement in aerobic glucose metabolism).

Severe deterioration in EEG beginning in first 15 minutes and

significant increase in rCBF (above baseline) in last 15 minutes

at 2.0 ATA and above consistent with oxygen toxicity.



1. Non-controlled studies: f. Holbach, 1977: 23 patients acute severe TBI/7 acute stroke. Air, Oxygen at 1, 1.5, and 2.0 ATA. Measure metabolism. Found metabolism most balanced at 1.5 ATA/35- 40 minutes, less so at 1.0 ATA. Deterioration at 2.0 ATA/15 mins. with hyperglycolysis, increased CSF lactate and pyruvate and lac/ pyruvate ratio, and decreased uptake of O2, (all indicative of anaerobic metabolism). Upon return to room air there was reduced uptake of glucose (evidence of injury.)



1. Non-controlled studies: g. Rockswold, 2001: 37 acute severe TBI patients HBOT: 1.5 ATA/60 minutes qd x 7 maximum. Measure: CBF, AVDO2, CMRO2, CSF lactate, and ICP 1h pre and 1 and 6h post HBOT. Results: see earlier slides for detail, but main findings: HBOT increased CBF and CMRO2 1 and 6h post HBOT in patients with low CBF. HBOT reduced lactate in all patients 1 and 6h post HBOT HBOT reduced ICP 1 and 6h post HBOT in those with ICPs > 15 mm Hg (The effect started reversing by 30 mins.) The effect of each HBOT did not last until the next HBOT (24h). HBOT improved aerobic metabolism. Recommend: shorter (30 minutes) more frequent (q8h) HBOTs



1. Non-controlled studies: g. Rockswold, 2001: 37 acute severe TBI patients



1. Non-controlled studies: Summary HBOT in acute severe TBI a. HBOT possibly beneficial with proper dosing. b. Cerebral glucose metabolism best and clinical outcomes possibly better at 1.5 ATA. c. Cerebral glucose metabolism worse and clinical outcomes possibly worse at 2-3 ATA.



2. Controlled studies a. Holbach, 1974: 99 patients, acute traumatic mid-brain syndrome. HBOT 1.5 ATA/30 minutes x 1-7. Results: 33% mortality in HBO patients, 74% in control group. 33% HBOT with good outcome, 6% control group. b. Artru, 1976: 60 patients, acute TBI/coma, HBOT at 2.5 ATA/60 mins. qd x 10 then 4d break, repeat until recovery of consciousness or death. Results: avg. 4.5d delay to treatment. Only 17/31 received 4 daily HBOTs during the first week due to interruptions: Development of pulmonary symptoms indicating a marked intolerance to OHP: polypnea with expiratory dyspnea, cyanosis at exit of the chamber, and redcuced SaO2 value. These alarming symptoms usually subsided after deompression and sometimes coexisted with an improved neurological condition after the session. Nevertheless, the treatment was interrupted in 5 cases where the intolerance was severe enough to suggest an impending hyperoxic pneumonia. We also interrupted the treatment in six other patients with severe pulmonary infections by fear of aggravating the lesions. Average 10.5 HBOTs/patient. No difference in mortality between groups at one year, but brainstem contusion subgroup (<30 y.o.) had higher rate of recovery consciousness/lower persistent coma.



2. Controlled studies b. Artru, 1976: Average 10.5 HBOTs/patient. No difference in mortality between groups at one year, but brainstem contusion subgroup (<30 y.o.) had higher rate of recovery consciousness/lower persistent coma. Conclusion: Ox Tox, yet partial clinical benefit.



2. Controlled studies

c. Rockswold, 1992: 168 acute mod-severe TBI patients, GCS ≤ 9.

HBOT: 1.5 ATA/60 mins. q8h x 2 weeks or until brain dead.

Results: Avg. 21 HBOTs.

Mortality 17% (HBOT) vs. 32% (control). For GCS 4-6:

mortality 17% (HBOT) vs. 42% (control). For ICP > 20 mm Hg:

mortality 21% (HBOT) vs. 48% (control). HBOT did not result in

an increase in favorable outcome (good recovery and moderate

disablity). 10 patients had HBOT permanently stopped due to

pulmonary ox tox (increasing FiO2 requirement to maintain adeq.

oxygenation.



2. Controlled studies c. Rockswold, 1992:



2. Controlled studies d. Ren, 2001: 55 acute severe TBI patients, GCS ≤ 8. “Randomly divided” into 2 groups that began Rx on 3rd-4th day of TBI: Control group (20 patients): dehydrating, steroid, and anti- biotic medicine. HBOT group (35 patients): dehydrating, steroid, and anti- biotic medicine + HBOT: 2.5 ATA/40-60 minutes, 10 min. air break, x 10 treatments = one course. 1 course q 4d. Avg. 3-4 “courses” = ? 30-40 HBOTs. VERY INTENSIVE HIGH DOSE SCHEDULE. Measure: GCS score, Brain Electrical Activity Mapping (BEAM), Glasgow Outcome Score (GOS) at pre, post 1 course (in the 2nd week), and after 3 courses of HBOT (in the second month) in both groups. GOS after 6 months as well. BEAM judged to be abnormal by one of 4 pre- determined criteria.



2. Controlled studies d. Ren, 2001: Results: GCS: GCS control vs. HBOT: p < 0.01

Group GCS

pre 1

course

HBOT

GCS

post 1

course

HBOT

p value GCS

post 3

courses

HBOT

p value

Control 5.3 8.1 Not

signif.

9.5 Not

signif.

HBOT 5.1 10.1 < 0.01 14.6 < 0.001



2. Controlled studies d. Ren, 2001, Results of BEAM: GOS control vs. HBOT at 6 months: Good recovery/mild disability: 83.7% HBOT vs. 30%, p <.01 Middle-severe disability: 26.3% HBOT vs. 70%, p <.001

Group Abn.

rate pre

1 course

HBOT

Abn.

rate

post 1

course

HBOT

p value Abn.

rate

post 3

courses

HBOT

p value

Control 95% 91% Not

signif.

78% Not

signif.

HBOT 94.3% 69.9 % < 0.01 38% < 0.001



2. Controlled studies d. Ren, 2001: “Mortality or Morbidity”: 26.3% HBOT vs. 70% control group (p < 0.001) Problems: Partly relate to language translation. Details lost. 1. Randomization inequality of groups. 2. The actual dose of HBOT? Very intensive dose at odds with technical work by Holbach. 3. “Mortality or Morbidity”. Since this was an English translation it likely refers to mortality alone.



2. Controlled studies e. Rockswold, 2010: 69 severe TBI patients, GCS ≤ 8, avg. 5.8, w/i 24h of injury HBOT group more severely injured:



2. Controlled studies e. Rockswold, 2010: 3 Groups: HBOT: 1.5 ATA/60 minutes, q24h x 3 NBO: 1 ATA/3h, q24h x 3 Control: standard care Measure: Brain tissue PO2, microdialysis, ICP continuously CBF, AVDO2, CMRO2, CSF lactate and F2-isoprostane, bronchial lavage fluid for IL-6 and 8. Pre-Rx, 1 and 6h post Rx.



2. Controlled studies e. Rockswold, 2010: Results: Brain PO2 increased during Rx in HBO and NBO (223mm hg and 86mm), p < .0001, and following HBOT until the next Rx (p=.003)



2. Controlled studies e. Rockswold, 2010: Results: CBF and CMRO2 increased for 6h w HBOT (p≤ .01)



2. Controlled studies e. Rockswold, 2010: Results: CSF lactate decreased post Rx in HBOT and NBO (p<.05) Dialysate lactate decreased for 5h post Rx w HBOT (p=.017) Microdialysis lactate/ pyruvate (L/P) decreased post Rx in HBOT and NBO (p<.05)



2. Controlled studies e. Rockswold, 2010: Results: CBF, CMRO2, microdialysate lactate, and L/P with greater improvement when brain PO2 ≥ 200 mm Hg achieved during Rx (p < .01) ICP lower after HBOT until the next HBOT (p < .001) vs. control. The treatment effect persisted over all 3 d.



2. Controlled studies e. Rockswold, 2010: Results: No evidence of oxygen toxicity: No increase in CSF F2- isoprostane, microdialysate glycerol, and interleukin bronchial alveolar lavage IL-6 and 8



2. Controlled studies e. Rockswold, 2010: Conclusions: HBOT has a more robust post-Rx effect than NBO on oxidative metabolism related to its ability to produce a brain tissue PO2 > 200 mm Hg. This appears to be a graded dose-response effect. No signs of pulmonary or cerebral oxygen toxicity.



2.Controlled studies f. Rockswold, 2013: Abstract: “…the positive effect of hyperbaric oxygen (HBO2) for severe traumatic brain injury (TBI) occurs after rather than during treatment.” So, they combined HBOT and NBO post HBOT. 42 acute severe TBI patients GCS ≤ 8, avg. 5.7, w/i 24h of injury 2 Groups: HBOT/NBO: 1.5 ATA/60 minutes + 1 ATA x 3h, q24h x 3 Control: standard care Measure: Brain tissue PO2, microdialysis, ICP continuously CBF, AVDO2, CMRO2, CSF lactate/pyruvate, F2-isoprostane, glycerol, bronchial lavage fluid for IL-6 and 8. Pre-Rx, 1 and 6h post Rx. GOS and mortality at 6 months



2. Controlled studies f. Rockswold, 2013: Results, in HBO/NBO group vs. controls: Brain tissue PO2 increased during and post Rx in noninjured and pericontusional brain (p < .0001).



2. Controlled studies f. Rockswold, 2013: Results, in HBO/NBO group vs. controls: Microdialysate lactate in pericontusional brain decreased with in-treatment/ pre-Rx (p = .0003) and post-treatment/pre-Rx (p = .0193)



2. Controlled studies f. Rockswold, 2013: Results, in HBO/NBO group vs. controls: Microdialysate Lac/ Pyruvate decreased in the noninjured brain (p <.0078) post-treatment.



2. Controlled studies f. Rockswold, 2013: Results, in HBO/NBO group vs. controls: ICP lower during treatment and stayed lower until the next Rx (p < .0006).



2. Controlled studies f. Rockswold, 2013: Results, in HBO/NBO group vs. controls: CSF F2-isoprostane decreased at 6h post Rx (p = .0692) No evidence of oxygen toxicity, actually the reverse. Mortality: Absolute 26% reduction in mortality (p= .048) (16% HBO vs. 42% Control: 26/42 = 62% reduction) Morbidity: Absolute 36% improvement in favorable outcome (GOS) Dichotomized GOS (good recovery or moderate disability): 11/19 HBO (58%), 7/21 (33%), 25% absolute improvement (p=.077).



2. Controlled studies f. Rockswold, 2013: Results, in HBO/NBO group vs. controls: Brain tissue PO2 increased during and post Rx in noninjured and pericontusional brain (p < .0001). Microdialysate Lac/Pyruv decreased in the noninjured brain (p <.0078) ICP lower during treatment and stayed lower until the next Rx in (p < .0006). Microdialysate glycerol lower in noninjured and pericontusional brain tissue (p <.001) CSF F2-isoprostane decreased at 6h post Rx (p = .0692) Absolute 26% reduction in mortality (p= .048) Absolute 36% improvement in favorable outcome GOS



Summary Randomized Controlled Studies HBOT in Acute Severe TBI: 1. Animal/clinical basic science, uncontrolled clinical studies, and randomized controlled trials demonstrate efficacy of HBOT with reduction in mortality and improvement in outcomes. No other therapy has shown such a dramatic effect on reduction in mortality in acute severe TBI:

Author Year Dose of HBOT Mortality

Reduction

Holbach 1974 1.5 ATA/60 mins. x

1-7

53%

Artru 1976 2.4 ATA/90 mins. x 0%

Rockswold 1992 1.5 ATA/60 mins. q8h

x 21

47%

Ren 2001 2.5 ATA/40-60 mins.

x 30-40

M or M 70%

HBO vs. 26%

Rockswold 2013 1.5 ATA/60 + 3h

NBO x qd x 3

62%



Summary Randomized Controlled Studies HBOT in Acute Severe TBI:

Essentially,

there is

No Need To Die

of acute severe TBI

without 2-3 HBOTs

in the first 7 days after TBI.


HBOT in Persistent Post-Concussion Syndrome: Clinical Literature

Review

Switch Gears:

Update on the literature of HBOT in persistent post-concussion syndrome. 3 new publications: 1. Wolf, et al. UHM, 2015;42(4):313-332. 2. Churchill, et al. Military Med,

2016;181(5): 40-44. 3. Shandley, et al. UHM, 2017;44(3):257-

269.



Review

1. Wolf, et al. UHM, 2015;42(4):313-332. Cognitive testing and PCL-M analysis ofprevious 2012 study 50 subjects, RCT, 2.4 ATA/90 minutes vs. 1.3 ATA air/90 mins. x 30 treatments. Braincheckers, ImPACT, and PCL-M pre, post, and 6-week post Measure RROI (Relative Risk Of Improvement= % of HBOT improved/% of pseudo-sham improved: %HBOT % air Dark boxes ratio > 1.0, clear boxes ratio < 1.0 (air group better) Results: No significant differences between groups; both groups improved. Subgroup analysis showed improvement in the 2.4 ATA group vs. pseudo-sham on multiple tests. Implication: 2.4 ATA is a good dose for PPCS. Problem: Inconsistent with earlier publications on the same data set showing 2.4 ATA not as good and potentially harmful for PPCS without PTSD.



Review 1. Wolf, et al. UHM, 2015;42(4):313-332. Dark boxes 2.4 ATA better,

Clear boxes 1.3 air better (ratio of 2.4 O2/air < 1, or air/2.4 O2 > 1). 53/138 boxes 2.4 ATA O2=

38% 85/138 boxes air = 62% All tables in the study: HBOT: 165/414 boxes = 40% Air: 249/414 boxes= 60% The article suggests 2.4 ATA is better. Very misleading.



Review 2. Churchill, et al. Military Med, 2016;181(5): 40-44.

72 active duty military, mTBI > 4 months old. Army HOPPS Study

(Miller, et al).

Fort Carson, Fort Gordon, Camp Lejeune, Camp Pendleton

RCT: local care vs. HBOT 1.5 ATA/60 vs. 1.2 ATA air/60 x 40 in 10

weeks.

Measure: standard cognitive tests, symptoms, ANAM pre, 6-

weeks (mid), 13 weeks (~3 weeks post). Report ANAM here:

SRT and PRT.

Results: average 23 months post TBI

“Repeated measures change over time in Simple Reaction Time

and PRT not different among groups. The study may be under-

powered.




On SRT no treatment group deteriorated while the other groups

stayed the same.

On PRT everyone improved then came back to baseline..




On SRT doubling of numbers in impaired category over time. On PRT more impaired in no treatment and air groups. Remember: This is a minority of the ANAM and cognitive tests performed in this study and published elsewhere showing HBOT and air groups both significantly improved compared to no treatment group.



Review 3. Shandley, et al. UHM, 2017;44(3):257-269. Appears to be another publication on the Wolf, et al 2012 study on 50 military members with TBI. 2.4 ATA/90 vs. 1.3 ATA air/90 x 30 over 8 weeks. Measure ImPACT, BrainCheckers, PCL-M, and human neural progenitor stem cells in blood pre, after 5, 10, 15, 20, 25, and 30 HBOTs and 6 weeks post. Correlate stem cells with cognitive improvement. Results: HBO (2.4 ATA) correlated with stem cell mobilization as well as increased cognitive performance. Supports the hypothesis that stem cell mobilization may be required for cognitive improvement in this population. Problems: There is no cognitive data in the study for either group and no comparison of cognitive data between groups. The air group has been shown in other publications to do as well as or better than 2.4 ATA. This study correlates HBOT with stem cell release into the circulation. It says nothing about what is happening in the brain, but says that the cognitive improvements demonstrated with 1.3 ATA do not correlate with stem cell release; there has to be another mechanism. The study is another attempt to establish benefit of 2.4 ATA, the dose that can be achieved only in a hospital-based reimbursed setting. Yet, it



Review

Update on the literature of HBOT in persistent post-concussion syndrome. Conclusion: HBOT is beneficial at 1.5 ATA oxygen and 1.3 ATA air in m TBI PPCS



Review Summary: studies and dose Author Type N Dose (ATA) Outcome

Imaging

Outcome

PPCS

Outcome

PTSD

Outcome

PTSD/PPCS

Harch25

Case Report 1 1.5 O2 + + + +

Wright26

Case Report 2 1.5 O2 + Harch

27 Prospective

Case Series

30 1.5 O2 + + + +

Wolf13

RCT 50 1.3/1.2 air vs.

2.4 O2

+

+

+

+

Boussi- Gross

28 RCT 71 No pressure

1.5 O2

Crossover

0

+

+

0

+

+

Scorza12

(subset Wolf

13)

RCT 50 1.3/1.2 air vs.

2.4 O2

?

- +

++

+

+

Cifu29

RCT 60 2.0P/.21 O2

2.0P/1.5 O2

2.0P/2.0 O2

0

0

0

0

0

+

Walker31

RCT 60 2.0P/.21 O2

2.0P/1.5 O2 2.0P/2.0 O2

? 0*

? 0+

? 0*

Cifu32

RCT 60 2.0P/.21 O2

2.0P/1.5 O2

2.0P/2.0 O2

? 0ǂ

? 0ǂ

? 0ǂ

Miller30

RCT 72 No pressure 1.2 air

1.5 O2

0

+

+

0

+

+

1



Review Summary: studies and dose


HBOT in Acute Concussion Review

Review:

No published literature.

Unreported use at multiple sites in the U.S.

Rationale: same pathology as acute severe TBI, only difference is severity: mass

effect, ICP, macroscopic bleeding, skull fracture, sub-arachnoid hemorrhage.

Patient’s personal experience: 4 family members (1-3 HBOTs in first week),

another 6-10 subjects in the past 15 years.

Colorado: multiple skiers

Chicago: Dr. Denham, large number of patients (see separate lecture).



Conclusion:

Scientific literature strongly supports the use of HBOT at 1.5 ATA for acute severe

traumatic brain injury.

There is

No Need To Die

of acute severe TBI

without 2-3 HBOTs

in the first 7 days after TBI.



Thank You


References

Mechanical disruption of tissue: Peerless SJ, Rewcastle NB: Shear injuries of the brain. Canadian Medical Association J March 11, 1967; 96(10): 577-582. Strich SJ, Oxon DM: Shearing of nerve fibres as a cause of brain damage due to head injury: A pathological study of twenty cases. Lancet August 26, 1961: 443-448. Adams JH, Graham DI, et al: Brain damage in fatal non-missile head injury. J Clin Pathol 1980; 33:1132-1145. Ischemia: Bouma GJ, et al: Cerebral circulation and metabolism after severe traumatic brain injury: The elusive role of ischemia. J Neurosurg 1991; 75: 685-693. Hypoxia: Adams JH, Graham DI, et al: Brain damage in fatal non-missile head injury. J Clin Pathol 1980; 33:1132-1145. van den Brink WA, van Santbrink H, et al: Monitoring brain oxygen tension in severe head injury: The Rotterdam experience. Acta Neurochir 1998; (Suppl)71: 190-194. Zhi DS, Zhang S, Zhou LG: Continuous monitoring of brain tissue oxygen pressure in patients with severe head injury during moderate hypothermia. Surg Neurol 1999; 52:393-396. Edema: Adams JH, Graham DI, et al: Brain damage in fatal non-missile head injury. J Clin Pathol 1980; 33:1132-1145. Schoettle RJ, Kochanek PM, et al: Early polymorphonuclear leukocyte accumulation correlates with the development of posttraumatic cerebral edema in rats. J Neurotrauma 1990; 7(4):207-217. Bullock R, Smith R, et al: Brain specific gravity and CT scan density measurements after human head injury. J Neurosurg 1985; 63: 64-68. Anaerobic metabolism: Muizelaar JP. Cerebral blood flow, cerebral blood volume, and cerebral metabolism after severe head injury. In: Becker DP, Gudeman SK, eds. Textbook of Head Injury, Philadelphia, PA: WB Saunders, 1989: pp. 221-240. Vilalta A, Sahuquillo J, Merino M-A, Poca M-A, Garnacho A, Martinez-Valverde T, Dronavalli M. Normobaric hyperoxia in traumatic brain injury: does brain metabolic state influence the response to hyperoxic challenge? J Neurotrauma, 2011;28:1139-1148. Reinert MI, Hoelper B, Doppenberg E, Zauner A, Bullock R. Substrate delivery and ionic balance disturbance after severe human head injury. Acta Neurochir Suppl, 2000;76:439-44. Send to



References

Excitatory neurotransmitters/neurochemicals: McIntosh TK, Smith DH, Garde E. Therapeutic approaches for the prevention of secondary brain injury. European Journal of Anaesthesiology, 1996;13:291-309 Hovda DA, Lee SM, Smith ML, Von Stuck S, Bergsneider M, Kelly D, Shalmon DE, Martin N, Caron M, Mazziotta J, Phelps M, Becker DP. The neurochemical and metabolic cascade following brain injury: moving from animal models to man. J Neurotrauma, 1995;12(5):903-6. Meng XE, Zhang Y, Li N, Fan DF, Yang C, Li H, Guo DZ, Pan SY. Effects of hyperbaric oxygen on the Nrf2 signaling pathway in secondary injury following traumatic brain injury. Med Sci Monit, 2016;22:284-8 Vasospasm: Martin NA, Doberstein C, Alexander M, Khanna R, Benalcazar H, alsina G, Zane C, McBride D, Kelly D, Hovda D,

Becker D, McArthur D, Zaucha K. Posttraumatic cerebral arterial spasm. J Neurotrauma 1995;12(5):897-901. Zurynski YA, Dorsch NWC: A review of cerebral vasospasm. Part IV. Post-traumatic vasospasm. J Clin Neuroscience April 1998; 5(2):146-154. Yufu K, Itoh T, Edamatsu R, Mori A, Hirakawa M. Effect of hyperbaric oxygenation on the Na+,K(+)-ATPase and membrane fulidity of cerebrocortical membranes after experimental subarachnoid hemorrhage. Neurochem Res, 1993;18(9):1033-9. Kohski K, Yokota A, Konda N, Munaka M, Yasukouchi H. Hyperbaric oxygen therapy adjunctive to mild hypertensive hypervolemia for symptomatic vasospasm. Neurol Med Chir (Tokyo), 1993;33(2):92-9. Activation of intravascular clotting and inflammatory cascades: Zhuang J, Shackford SR, et al: The association of leukocytes with secondary brain injury. J Trauma September 1993; 35(3):415-422. Schoettle RJ, Kochanek PM, Magargee MJ, Uhi MW, Nemoto EM. Early polymorphonuclear leukocyte accumulation correlates with the development of posttraumatic cerebral edema in rats. J Neurotrauma 1990; 7(4):207-217. Vlodavsky E, Palzur E, Soustiel JF. Hyperbaric oxygen therapy reduces neuroinflammation and expression of matrix metalloproteinase-9 in the rat model of traumatic brain injury. Ischemia: Graham DI, Adams JH, Doyle D. Ischemic brain damage in fatal non-missile head injuries. J Neurol Sci, 1978:39:213-234 Siesjo BK, Siesjo P. Mechanisms of secondary brain injury. Eur J Anaesthesiol, 1996;13:247-268.



References

Clinical HBOT-TBI: Mogami H, Hayakawa T, Kanai N, Kuroda R, Yamada R, Ikeda T, Katsurada K, Sugimoto T. Clinical application of hyperbaric oxygenation in the treatment of acute cerebral damage, 1969;31(6):636-643. Hayakawa T, Kanai N, Kuroda R, Yamada R, Mogami H. Response of cerebrospinal fluid pressure to hyperbaric oxygenation. J Neurol Neurosurg Psychiatry, 1971;34:580-86. Holbach KH, Caroli A. Oxygen Tolerance and the Oxygenation State of the Injured Human Brain. In: 5th International Hyperbaric Congress Proceedings, Vol. 1, eds. W.G Trapp, Banister EW, Davison AJ, Trapp PA. Burnaby, Canada, Simon Fraser University, 1974. pps. 350-361. Artru F, Philippon B, Gau F, Berger M, Deleuze R. Cerebral blood flow, cerebral metabolism and cerebrospinal fluid biochemistry in brain-injured patients after exposure to hyperbaric oxygen. Eur Neurol, 1976;14(5):351-64. Holbach KH, Wassmann H, Caroli A. Correlation between electroencephalographical and rCBF changes during hyperbaric oxygenation. In: Proceedings of the Sixth International Congress on Hyperbaric Medicine, ed. Smith G. Aberdeen University Press, Aberdeen, Scotland, 1979. pps. 113-117. Holbach KH, Caroli A, Wassmann H. Cerebral energy metabolism in patients with brain lesions at normo- and hyperbaric oxygen pressures. J Neurol, 1977:217:17-30. Holbach KH, Wassmann H, Kolbert T. Verbesserte reversibilitat des traumatischen mittelhirsyndroms bei Anwendung der hyperbaren oxygenierung. Acta Neurochir, 1974;30:247-256. Artru F, Chacornac R, Deleuze R. Hyperbaric oxygenation for severe head injuries: Preliminary results of a controlled study. Eur Neurol, 1976:14:310-318. Rockswold GL, Ford SE, Anderson DC, Bergman TA, Sherman RE. Results of a prospectibe randomized trial for treatment of severely brain-injured patients with hyperbaric oxygen. J Neurosurg, 1992;76:929-934. Rockswold SB, Rockswold GL, Vargo JM, Erickson CA, Sutton RL, Bergman TA, and Biros MH. Effects of hyperbaric oxygenation therapy on cerebral metabolism and intracranial pressure in severely brain injured patients. J Neurosurg, 2001;94;403-411 Ren H, Wang W, Zhaoming CE. Glasgow Coma Scale, brain electric activity mapping and Glasgow Outcome Scale after hyperbaric oxygen treatment of severe brain injury. Chinese Journal of Traumatology (English Edition), 2001;4(4): 239-241. Rockswold SB, Rockswold GL, Zaun DA, Zhang X, Cerra CE, Bergman TA, Liu J. A prospective, randomized clinical trial to compare the effect of hyperbaric to normobaric hyperoxia on cerebral metabolism, intracranial pressure, and oxygen toxicity in severe traumatic brain injury. J Neurosurg, 2010;112:1080-1094. Rockswold SB, Rockswold GL, Azun DA, Liu J. A prospective, randomized Phase II clinical trial to evaluate the effect of combined hyperbaric and normobaric hyperoxia on cerebral metabolism, intracranial pressure, oxygen toxicity, and clinical outcome in severe traumatic brain injury. J Neurosurg, 2013;118(6):1317-28. Wolf, et al. UHM, 2015;42(4):313-332. Churchill, et al. Military Med, 2016;181(5): 40-44. Shandley, et al. UHM, 2017;44(3):257-269.


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