UHM 2005, Vol. 32, No. 1 – Treatment of severe anemia with HBO2: Evidence-based
A systematic review of the application of
hyperbaric oxygen in the treatment of severe
anemia: An evidence-based approach.
K. W. VAN METER
Department of Medicine, Section of Emergency Medicine, Division of Hyperbaric Medicine, Louisiana State University Health
Sciences Center, New Orleans, Louisiana
Van Meter, KW. A systematic review of the application of hyperbaric oxygen in the treatment of severe
anemia: An evidence-based approach. Undersea Hyperb Med, 2005; 32(1): 61-83. The treatment of severe
anemia with hyperbaric oxygen (HBO2) is one of thirteen indications approved by the Hyperbaric Oxygen
Therapy Committee of the Undersea and Hyperbaric Medical Society for appropriate use of the therapy (1).
This paper systematically reviews the literature reporting the use of HBO2 therapy in the treatment and
management of severe anemia. Increasingly, a trend to use standards of evidence-based medicine to
evaluate the effectiveness of therapeutic interventions in injury and illness is productively with us in
medicine today. At issue is discovery and evaluation of the best evidence available in world medical
literature for evaluation of current treatment of the individual patient. The best evidence is a published
randomized controlled prospective human trial; at the other end of the spectrum, the least valued evidence
is a published expert opinion. In this review thirty-five publications have been reviewed as representing
published results of applying HBO2 in treatment of severe anemia. Each article underwent the evidencebased evaluative grading of the American Heart Association system (AHA), the National Cancer Institute
Patient Data Query system (NCI-PDQ), and the British Medical Journal’s (BMJ) Clinical Evidence system.
Comparative results using the three systems of evaluation are presented in tabular form for the reader. All
publications report a positive result when HBO2 is delivered as treatment for severe anemia. Other
alternatives other than transfusion with autologous or heterologous matched blood products are helpful but
most too have not been the subject of prospective human randomized controlled trials. HBO2 may be used
adjunctively with hematinics, fluorocarbons, and cell wall free polymerized hemoglobin (currently
fluorocarbons and cell wall free polymerized hemoglobin are not available for routine use in the United
States, but both are undergoing advanced stage clinical trials at the time of this review).
INTRODUCTION
More than twelve million units of
blood are transfused in the United States each
year, and slightly over seventy million units
are estimated to be transfused in the world
each year (2). Outside of this clinical demand
are a smaller number of patients with severe
anemia who for religious reason or because of
transfusion complication or incompatibility
cannot be transfused with red blood cells
(RBCs). Some of the reasons for transfusion
complications are as follows (3, 4):
1. Personal discordance through religious belief
2. Acute intra-and extravascular hemolysis from blood group
incompatibility
3. Febrile non-hemolytic transfusion reaction (FNHTR)
4. Both delayed amnestic or primary hemolytic anemia
5. Allergy (from urticaria to anaphylaxis)
6. Transfusion-associated graft-versus-host disease (TAGVHD)
7. Transfusion-related acute lung injury (TRALI)
Copyright © 2005 Undersea and Hyperbaric Medical Society, Inc. 61
UHM 2005, Vol. 32, No. 1 – Treatment of severe anemia with HBO2: Evidence-based
8. Transfusion-transmitted infections (TTI)
9. Both RBC and human lymphocyte antigen (HLA) allosensitization
10. Congestive heart failure
11. Hemosiderosis
12. Long-term transfusion immunomodulation
13. Short-term induction of multiorgan failure (MOF) by RBC-associated lipids and
cytokines (5)
The most important consequence of severe anemia is cellular hypoxia from inadequate delivery
of oxygen to tissues. The oxygen content or carrying capacity of blood (CaO2) is represented by
the formula (6):
CaO2 = (hemoglobin (Hgb) in g/dL x 1.34 Hgb O2 saturation) + PaO2 (mmHg) x 0.003
Systemic circulation oxygen delivery (DO2) is represented by the formula (7):
DO2 = cardiac output ÷ BSA in m2 x CaO2
Transfusion of packed red blood cells (PRBC) after severe anemia, if not contraindicated,
usually becomes appropriate and affords improved DO2 when (8):
1. Hgb is at or below 7 g/dL; (if the patient is in critical care, then below 8 or 9 g/dL)
2. A patient develops an American College of Surgeons (ACS) class II (30-40% blood
loss) or class IV (>40% blood loss) hemorrhage;
3. Following an acute blood loss, the patient has two or more of the following
determinations:
a. ACS class II (15-30% blood loss) hemorrhage;
b. Hypotension;
c. Oliguria;
d. Altered mental status;
4. The patient has an acute myocardial infarct and a hematocrit (Hct) below 33% (9).
Extreme organ damage or dysfunction
by severe anemia may manifest clinically by
altered mental status, hypotension, diarrhea
from ischemic bowel, and oliguria. Another
important concept is the negative after-image
of insufficient DO2, or so-called oxygen debt.
Oxygen consumption (VO2) can be measured
and cumulative debt represented as the time
integral of the difference between VO2
measured during and after hemorrhagic shock
minus the VO2 for the same interval measured
under control conditions (10). In 1961,
Crowell demonstrated that dogs subjected to
severe hemorrhage had certain death, no
matter the resuscitative attempt, if the oxygen
debt was greater than 140 ml/kg. Survival was
62
possible, provided adequate resuscitation, if
the oxygen debt was less than 100 ml/kg (11).
In humans, Shoemaker has demonstrated that
after severe hemorrhage, dying patients had a
maximum cumulative VO2 deficit averaging
33 L/m2. Surviving patients with MOF have a
VO2 deficit averaging 22 L/m2, while
surviving
patients
without
detectable
complications had a maximum cumulative
VO2 deficit of about 9 L/m2. Monitoring VO2
debt to guide therapeutic interventions may
forestall MOF or death (12).
In 1959, Boerema demonstrated
survival of pigs after severe controlled
hemorrhage to Hgb levels of 0.4 to 0.6 g/dL) if
ventilated with 100% O2 and ambient pressure
UHM 2005, Vol. 32, No. 1 – Treatment of severe anemia with HBO2: Evidence-based
was raised to 0.3 MPa. Essentially the animals
were concurrently resuscitated by replacement
of shed blood by a mixture of intravenous 6%
dextran/5% dextrose/Ringers’ lactate solution.
Boerema speculated that the impending
oxygen debt of the insult was relieved by
HBO2 bridging therapy. At the end of the
experiment the animals were re-transfused
with their shed blood and survived (13, 14).
MODELS FOR LITERATURE
ASSESSMENT
This paper utilizes the evidence-based
evaluation system approved by the Undersea
and
Hyperbaric
Medicine
Society’s
Hyperbaric Oxygen Therapy Committee
already used in previously published
evaluations (15). It also relies on the evidencebased evaluation schemes of the AHA (16),
the NCI-PDQ (17), and the BMJ clinical
evidence (18).
The reader is encouraged to become
familiar with these grading scales by
reviewing the given references. A simplified
or thumbnail summary table of these evidencebased evaluative scales is presented below (CT
= controlled trial; RCT = randomized
controlled trial; CS = case studies).
AHA (16)
Level
Class
. Statistically
significant RCT
2. Statistically
insignificant
3. CT nonrandomized
4. CS nonrandomized
historic
5. Case series
6. Animal or
mechanical
model studies
7. Reasonable
extrapolation
from existing
data
8. Common
sense or standard
of practice
1. Standard of
care backed
by RCT
II.a. Probable
II.b. Accepted
and useful
III. Harmful
IV.
Indeterminate
NCI-PDQ (17)
1.i. RCT double-blinded
1.ii. RCT not doubleblinded
2. CT but not randomized
3.i. CS population
based/consecutive
3.ii. CS not populationbased/consecutive
3.iii. CS not populationbased/not consecutive
63
BMJ Clinical Evidence (18)
1. Beneficial
2. Likely to be beneficial
3. Trade off between benefits
and harm
4. Unknown effectiveness
5. Unlikely to be beneficial
6. Likely to be ineffective or
harmful
UHM 2005, Vol. 32, No. 1 – Treatment of severe anemia with HBO2: Evidence-based
The NCI-PDQ and the BMJ clinical evidencebased rating scales cannot be used for animal
studies (19). The Gottlieb scale to evaluate the
use of HBO2 therapy in treatment of severe
anemia will be mentioned briefly in the
discussion section of this paper. Literature was
searched utilizing PubMed and the Institute for
Scientific Information Current Contents
Database, utilizing the following search word
combinations: hyperbaric oxygen/hemorrhage;
hyperbaric
oxygen/anemia;
hyperbaric
oxygen/shock. Additionally, the Journal of
Hyperbaric Medicine (and its antecedent
Undersea Baromedical Research and the
Journal of Hyperbaric Oxygen Therapy) and
the Proceedings of the International Congress
on Hyperbaric Medicine were hand-searched.
Pertinent literature from footnotes of literature
in the above search was also hand-searched.
Some of the articles in the Proceedings of the
International
Congress
on
Hyperbaric
Medicine had nearly duplicate articles in peer
reviewed journals (13,14,20,21,22). The same
search method was used for the word
combination blood transfusion-clinical trial.
No completed trials were found that compared
blood transfusion to the alternative of fluid
resuscitation coupled with HBO2, normobaric
oxygen (NBO2) or normobaric air (NBA).
Clinical trials comparing blood transfusion
with fluorocarbon or stroma-free polymerized
hemoglobin are still ongoing (23).
1.
2.
3.
4.
5.
SUMMARY OF ANIMAL STUDIES OF
HBO2 TREATMENT OF SEVERE
ANEMIA
Research in hemorrhagic shock
advanced further with the development of
shock models for animals across species in an
attempt to produce a uniform result. Wiggers’
model removed or returned shed blood to the
animal to maintain a uniform mean arterial
pressure (MAP) during the experiment (24). It
was incorporated in most of the early HBO2
animal shock research. These studies
demonstrated longer survival times for HBO2
treated animals as compared to NBO2 or NBA
control animals to produce level 6A class IIb
AHA evidence of efficacy. (Table 1-see
Appendix I).
Another approach was to bleed animals
to a predetermined Hgb level (13). Yet another
was to remove a predetermined quantity of
blood per unit weight of the animal (25).
Again, both of these approaches demonstrated
longer survival times for HBO2 treated animals
as compared to NBO2 or NBA control animals
resulting in level 6A, class IIb AHA evidence
of efficacy (Table 1).
Taking the composite best approach of
data in the articles reviewed in this evidencebased review of animal research into the use of
HBO2 in acute blood loss anemia, the
following guidelines for uniform reporting are
suggested:
Clear statement of experiment with animal species, researchers’ names and
affiliation, abstract, key words, introduction, methods (to include statement of
institutional animal care use committee approval [IACUC]), results, discussion,
and footnotes and/or references;
Statement of calculated estimated oxygen debt accumulated by each animal;
Statement of resuscitation fluids used (type, quantity, flow rate, and route);
Statement of the total treatment time in minutes, treatment depth in Mpa, and
compression and decompression rates for the treatment tables used; clear
statement of breathing mix administered to animals during the treatment;
Clear statement of number of animals in each treatment group, whether they were
randomized, and how the animals were selected and randomized for each group;
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UHM 2005, Vol. 32, No. 1 – Treatment of severe anemia with HBO2: Evidence-based
6.
7.
8.
9.
10.
11.
12.
13.
Statement of hemorrhage model chosen and why it might best translate
experimental efficacy to treatment effectiveness;
Statement of whether the experiment incorporated reinfusion of shed blood; if so,
when, at what rate, how much, and how the shed blood was anticoagulated;
Statement of whether the animals were anticoagulated or not;
Statement of each animal’s baseline Hgb at the onset of the experiment and after
immediate stabilization after hemorrhage and at stated post-insult survival
interval;
Statement of post-hemorrhagic insult time interval that was used to state the
survival rate of each animal group;
The study should record BP and body temperature during the immediate
hemorrhagic insult intervention phase of the experiment;
Animals randomized to at least the following groups:
a. NBA with hemorrhage;
b. NBA without hemorrhage;
c. NBO2 with hemorrhage;
d. HBO2 with hemorrhage;
If serum bacterial or histologic markers are used to reflect injury or recovery it is
desirable to have animals randomized to the following groups:
a. NBA with and without hemorrhage;
b. HBA with SEFIO2 normalized to 21% oxygen with and without
hemorrhage;
c. NBO2 with and without hemorrhage;
d. HBO2 with and without hemorrhage.
HUMAN STUDIES IN THE USE OF HBO2
THERAPY IN SEVERE ANEMIA
In the instance of severe anemia, most
clinical reports focus on Jehovah’s Witnesses
who seek other options to RBC transfusion.
The single case reports and case series provide
enough evidence by AHA, NCI-PDQ, and
BMJ evaluation criteria to justify the use of
HBO2 therapy to allow patients to survive
hemorrhagic or hemolytic insults which
clearly otherwise would have been fatal.
The best published series for the use of
HBO2 therapy for treatment severe anemia
draws from Hart (54). Hart also offers more
current criteria for selection of patients and
indications for HBO2 therapy; in this instance
first by accumulating oxygen debt and lastly
by impending or actual organ failure (55):
1. Oxygen debt higher than 9 L/kg;
2. Advent of systolic blood pressure lower than 90 mmHg or the need of vasopressors to
maintain blood pressure;
3. Development of altered mental status (AMS);
4. Development of acute coronary syndrome (ACS);
5. Development of signs/symptoms of ischemic bowel.
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UHM 2005, Vol. 32, No. 1 – Treatment of severe anemia with HBO2: Evidence-based
Hart
advocates
HBO2
therapy
treatment at 0.2 to 0.3 MB/90 minutes with
surface intervals (SI) determined to provide
adequate
pulsed
oxygen
to
reduce
accumulating oxygen debt, symptomatology or
signs
of
ischemia.
Hematinics
and
erythropoetin are also recommended.
Treatment of severe anemia with HBO2
therapy should be early to address
accumulating oxygen debt and pulsed to
prevent oxygen toxicity. Waiting to address
only the development of signs or symptoms of
end organ injury is least desirable.
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
An illustrative comparison could be
drawn with treatment of musculoskeletal
compartment syndrome, which should begin
early when the manometric pressure of the
compartment begins to close the capillary beds
rather than when the signs and symptoms of
pain, paresis, pallor, paresthesia, and
pulselessness develop (5 “P”s) (54). (See
Table 2 – Appendix II).
The
best
elements of each case report or case series
report reviewed were collected. For the future,
based on this evidence-based review of the
literature each patient report should minimally
have the following data included in each case:
Statement of author names and affiliation, abstract, key words, introduction with
statement of need or not for institutional board reporting, case presentations,
discussion and references;
Patient age, gender, and weight;
Illness or injury causing the severe anemia;
Statement of patient co-morbidity;
Statement of patient’s preference on blood transfusion;
Lowest Hgb recorded during patient’s illness;
Pre-morbid Hgb and/or pre-hemorrhage Hgb;
Whether transfusion of blood products occurred and if so, number of units;
Statement of type and quantity of blood products given over time;
Statement of generic type dose and timing of adjunctive hematinics;
Statement of HBO2 treatment table used to include elements of descent
time/ascent time, bottom time, air break duration, surface interval duration, and
breathing mixes used;
Statement of estimated accumulated oxygen debt of the patient after hemorrhagic
or hemolytic insult;
Statement of extent and duration of hypotension and other signs/symptoms or
serum or electrophysiologic marker of organ damage;
Statement of presence or absence of altered mental status during acute illness.
DISCUSSION
Resuscitation of severe anemia by
blood transfusion is a conventional gold
standard of medical practice. Interestingly,
transfusion of blood products for exceptional
blood loss by evidence-based evaluation is not
based on the best levels of evidence, but rather
on standard practice (2,3,4). A thumbnail
sketch of evidence-based evaluation schemes
utilized in this paper focused on the use of
transfused blood severe anemia would be as
follows:
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UHM 2005, Vol. 32, No. 1 – Treatment of severe anemia with HBO2: Evidence-based
Evaluation of blood transfusion in severe anemia
AHA
Level
8
NCI-PDQ
Class
3.iii. – useful based on case
reports and case series
BMJ Evidence
Trade off between benefits and
harm
II.b. – accepted
and useful
Clearly to date perfluorocarbon replacement or stroma-free unpolymerized or
polymerized hemoglobin have not yet attained better evidence-based ratings (2).
Evaluation of stroma-free unpolymerized or polymerized Hgb on treatment of severe anemia
AHA
Level
2 and 6
NCI-PDQ
Class
Indeterminate
1.i. and 3.iii. – useful based on
case reports and preliminary pilot
clinical trials
BMJ Evidence
Trade off between benefits and
harm
Evaluation of perfluorocarbons in treatment of severe anemia
AHA
Level
2 and 6
NCI-PDQ
Class
Indeterminate
1.i. and 3.iii. – useful based on
case reports and preliminary pilot
clinical trials
In resuscitation of patients with severe
anemia, HBO2 therapy addresses the clinical
resolution of oxygen debt well. The therapy
does not conflict with the concomitant use of
hematinics (i.e., vitamin B complex, vitamin c,
BMJ Evidence
Trade off between benefits and
harm
iron, and erythropoetin), fluorocarbons, or
stroma-free polymerized Hgb. Harmful side
effects of HBO2 are rare and safety in the
hospital setting has been very good to date in
the United States (62,63).
Evidence-based evaluation of the use of HBO2 therapy for patients with severe anemia
AHA
Level
5, 6, 6b
NCI-PDQ
Class
3iii
BMJ Evidence
Likely to be beneficial
II.b. –
Accepted and
useful
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UHM 2005, Vol. 32, No. 1 – Treatment of severe anemia with HBO2: Evidence-based
With the Gottlieb evaluative scale
referenced earlier, the rating for HBO2 in
treatment severe anemia which is 45 on a
possible scale of 70 points (Gottlieb scale
ratings of 35-56 provide sufficient evidential
guidance for acceptance of clinical use of a
therapeutic modality). In the very later part of
the twentieth century, as well as for today,
resuscitation medicine has relied heavily on
the AHA Clinical Evidence Scheme to
recommend clinical approach in resuscitation
and if the resuscitation was successful then in
aftermath critical care (16). The majority of
the commonly used drugs of interventions
used in resuscitation are of AHA level 5 or 6
evidence and effectiveness class II.b. or better.
For instance, epinephrine, when used in
cardiopulmonary arrest, is at the time of the
writing of this paper an AHA level 5 and 6,
class
indeterminate
drug
(64).
In
cardiopulmonary arrest, epinephrine has a
lesser evaluative score than HBO2 has in
resuscitation of severe anemia.
CONCLUSION
In conclusion, the use of HBO2 to treat
severe anemia (when blood products may not
be used) is an established and effective option,
especially when the alternative is severe organ
injury or death. Additionally, the use of HBO2
as a bridging therapy in severe trauma or
illness to successfully treat accumulating
oxygen debt until shed blood or transfusion of
allotypic RBCs can be accomplished. For lack
of availability of HBO2 units in emergency
department and critical care areas, this
application is rarely used. HBO2 provides a
practical treatment option in an emergency
department or critical care setting for
resuscitation of patient with life-threatening
oxygen debt.
In the United States, the Center for
Medicare and Medicaid Services (CMS)
approves reimbursement of HBO2 in the
management of severe anemia. Likewise CMS
has given approval for the hyperbaric
physician to multitask in the concurrent care of
multiple patients in the hospital hyperbaric
unit. Where HBO2 treatment facilities are in
areas of critical care, this will allow hospital
intensivists and emergency physicians to costeffectively provide twenty-four hour a day
availability of HBO2 therapy for treatment of
severe anemia. As hyperbaric facilities become
more and more a part of hospital critical care
areas, pulsed HBO2 to periodically reduce
accumulating oxygen debt in severe anemia
will be increasingly used. HBO2 works by
easily understood mechanisms in this instance
with a good safety records as advanced by
evidence-based analysis (61).
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Bitterman H, Reissman P, Bitterman N, et al. Oxygen therapy in hemorrhagic shock. Circ Shock 1991;33:183-191.
Wen-Ren L. Resection of aortic aneurysms under 3 ATA of hyperbaric oxygenation. In: Bakker DJ, Cramer JS, eds.
Proceedings of the Tenth International Congress on Hyperbaric Medicine. Flagstaff: Best Publications, 1992:94-95.
Marzella L, Yin A, Darlington D, et al. Hemodynamic responses to hyperbaric oxygen administration in a rat model of
hemorrhagic shock. Circ Shock 1992;37:12.
Adir Y, Bitterman N, Katz E, et al. Salulary consequences of oxygen therapy or long-term outcome of hemorrhagic
shock in awake, unrestrained rats. Undersea Hyperb Med 1995;22:23-30.
Yamashita M, Yamashita M. Hyperbaric oxygen treatment attenuates cytokine induction after massive hemorrhage. Am
J Physiol Endocrin Metab 2000;278:E811-E816.
Hart GB, Lennon PA, Strauss MB. Hyperbaric oxygen in exceptional acute blood loss anemia. J Hyperbar Med
1987;2:205-210.
Hart GB. Hyperbaric oxygen and exceptional blood loss anemia. In: Kindwall EP, Whalen HT, eds. Hyperbaric
Medicine Practice, 2nd Edition Revised. Flagstaff: Best Publishing, 2002:744-751.
Matsen FA, Winquist RA, Krugmire RB. Diagnosis and management of compartment syndromes. J Bone Joint Surg
1980;62:286-291.
Ledingham IM. Hyperbaric oxygen in shock. Anes Clinics 1969;7:819-839.
Amonic RS, Cockett ATK, Lonhan PH, et al. Hyperbaric oxygen therapy in chronic hemorrhagic shock. JAMA
1969;208:2051-2054.
Hart GB. Exceptional blood loss anemia. JAMA 1974;228:1028-1029.
Myking O, Schreinen A. Hyperbaric oxygen in hemolytic crisis. JAMA 1974;227:1161-1162.
Meyerstein N, Mazor D, Tsach T, et al. Resistance of human red blood cells to hyperbaric oxygen under therapeutic
conditions. J Hyperbar Med 1989;4:1-5.
Young BA, Burns JR. Management of the severely anemic Jehovah’s Witness. Ann Int Med 1992;119:170.
McLaughlin PL, Cope TM, Harrison JC. Hyperbaric oxygen therapy in management of severe acute anemia in a
Jehovah’s Witness. Anesthes 1999;54:891-895.
Poss ME, Yolton DP, Yolton RL, et al. Myopia associated with hyperbaric oxygen therapy. Optometry Vision Sci
1996;73:487-494.
Youngberg JT, Meyers AM. Complications from hyperbaric oxygen therapy. Ann Emerg Med 1990;19:1356-1357.
American Heart Association. International guidelines 2000 for cardiopulmonary resuscitation (CPR) and emergency
cardiac care (ECC): part 6, advanced cardiovascular life support: section 7, algorithm approach to ACLS emergencies.
Circ 2000;102(suppl I):I136-I165.
70
71
1963
5.
1959
3.
1962
1959
2.
4.
1943
1.
Date
Cowley RA
(29)
Attar S (28)
Boerema I
(13,14)
Burnet W
(27)
Frank HA
(26)
Author
Canine
Canine
Porcine
Rat
Animal
species
Canine
Controlled study:
1. NBA with hem group
(n=30)
2. HBO2 with hem 0.3
MPa/150 min group (n=19)
3. HBO2 without hem 0.3
MPa/150 min group (n=13)
Controlled study:
1. NBA group (n=30)
2. HBO2 0.3 MPa/90
minutes group (n=25)
1. paper relied-on nonHBO2 controls from results
of independent authors in
the same model
2. controlled study of 3
HBO2 0.3 MPa 150-180
min treatment group
(n=18)
Controlled study:
1. NBA/120 min group
(n=25)
2. HBO2 0.2 Mpa/120 min
group (n=25)
Controlled study:
1. HBO2 0.3 MPa/ 75
min group (n=3)
2. HBO2 0.3 MPa with
30°C core temp/ 75 min
group (n=20)
3. NBA group (n=?)
Study groups
Survival at 48 hours
post-hem:
1. NBA with hem
group = 17%
2. HBO2 with hem
group = 74%
3. HBO2 without hem
group = 100%
Wiggers (24) “hypoMAP” model for all
animals
Wiggers (24) “hypoMAP” model for all
animals
All animals were
subjected to variable
volume bleed which
produced Hgb level of
0.4-0.6 g/dL
Survival at 2 hour post
insult, post-hem:
1. non-HBO2 group
(NBA) = 20%
2. HBO2 group = 96%
Survival at 45 minutes
post-hem:
1. HBO2 group =
100%
2. HBO2 +
hypothermic group =
50%
3. NBA group = 0/2
Survival at 48 hours
post-hem:
1. NBA group = 17%
2. HBO2 group = 74%
Survival at 4½ hours
post-hem:
1. non-HBO2 group
(NBA or NBO2) = 0%
2. HBO2 groups =
20%
Survival rates
Intravascular hemolysis
induced by 1 ml/100 g IM
glycerol for all animals
Wiggers (24) “hypoMAP” model for all
animals
Hemorrhagic insult
Level
6A
AHA
Level
6B
AHA
Level
6B
AHA
Level
6A
AHA
6B
Level
AHA
Class
II.b.
Class
II.b.
Class
II.b.
Class
II.b.
Class
Indeter
minate
NA
NCIPDQ
NA
NCIPDQ
NA
NCIPDQ
NA
NCIPDQ
NA
NCIPDQ
NA
BMJ
Evidence
NA
BMJ
Evidence
NA
BMJ
Evidence
NA
BMJ
Evidence
NA
BMJ
Evidence
Thumbnail evidence-based analysis
Table 1. Summary of Published Animal Experiments Investigating the Use of Hyperbaric Oxygen Therapy in Severe Anemia
UHM 2005, Vol. 32, No. 1 – Treatment of severe anemia with HBO2: Evidence-based
1965
8.
1965
1965
7.
9.
1964
6.
Date
Elliot DP
(33)
Cowley RA
(32)
Clark RG
(31)
Blair E (30)
Author
Canine
Canine
Canine
Canine
Animal
species
72
Controlled study:
1. NBA group (n=10)
2. NBO2 group (n=10)
3. NBO2 with ventilator
group (n=10)
4. HBO2 0.28 MPa/100
min group (n=11)
Controlled study:
1. NBA group (n=8)
2. HBO2 0.2 MPa/150 min
group (n=5)
3. NBA + IV bicarb group
(n=6)
Controlled study:
1. NBA group (n=23)
2. HBO2 0.3 MPa/120 min
group (n=19)
Controlled study:
1. NBA group (n=23)
2. HBO2 0.3 MPa/120 min
group (n=19)
Study groups
Wiggers (24) “hypoMAP” model for all
animals
Wiggers (24) “hypoMAP” model for all
animals
Survival at 72 hours
post-hem:
1. NBA group = 10%
2. NBO2 group = 50%
3. NBO2 with
ventilator group =
50%
4. HBO2 group = 73%
Survival at 48 hours
post-hem:
1. NBA group = 22%
2. HBO2 group = 74%
Survival at 18 hours
post-hem:
1. NBA group = 75%
2. HBO2 group =
100%
“Long-term” survival
post-hem:
1. NBA group = 17%
2. HBO2 group = 74%
Wiggers (24) “hypoMAP” model for all
animals
Wiggers (24) “hypoMAP” model for all
animals
Survival rates
Hemorrhagic insult
Level
6A
AHA
Level
6A
AHA
Level
6A
AHA
Level
6A
AHA
Class
II.b.
Class
II.b.
Class
II.b.
Class
II.b.
NA
NCIPDQ
NA
NCIPDQ
NA
NCIPDQ
NA
NCIPDQ
NA
BMJ
Evidence
NA
BMJ
Evidence
NA
BMJ
Evidence
NA
BMJ
Evidence
Thumbnail evidence-based analysis
UHM 2005, Vol. 32, No. 1 – Treatment of severe anemia with HBO2: Evidence-based
10.
1965
Date
Attar S (34)
Author
Canine
Animal
species
Hemorrhagic insult
Wiggers (24) “hypoMAP” model for all
animals
Study groups
Controlled study:
Group I:
1. NBA/150 min subgroup (n=25)
2. HBO2 0.3 Mpa/150 min
subgroup (n=29)
Group II:
Subgroup A
3. NBA/105 min group (n=30)
4. HBO2 0.3 Mpa/105 min group
(n=22)
Subgroup B
5. NBA/120 min group (n=17)
6. NBO2/120 min group (n=25)
7. HBO2/120 min group (n=23)
Subgroup C
8. NBA/150 min group (n=30)
9. HBO2 0.3 MPa/ 0 min group
(n=4)
Subgroup D
10. NBA/240 min group (n=20)
11. HBO2 0.3 MPa/240 min group
(n=24)
Group III:
12. HBO2 0.3 MPa/120 min
started 30 min post-hem group
(n=?)
13. HBO2 0.3 MPa/120 min
started 150 min post-hem group
(n=?)
Group IV:
14. HBO2 0.2 MPa/120 min group
(n=11)
15. HBO2 0.2 MPa/150 min group
(n=?)
16. HBO2 0.3 MPa/120 min
(n=23) see above
17. HBO2 0.3 MPa/130 min (n=4)
see above
Survival at 72 hours
post-hem:
1. NBA group = 20%
2. HBO2 group = 41%
3. NBA group = 66%
4. HBO2 group = 47%
5. NBA group = 29%
6. NBO2 group = 20%
7. HBO2 group = 72%
8. NBA group = 17%
9. HBO2 group = 50%
10. NBA group = 50%
11. HBO2 group =
48%
12. HBO2 30 min posthem = 74%
13. HBO2 150 min
post-hem 50%
14. HBO2 0.2
MPa/120 min = 82%
15. HBO2 0.2
MPa/150 min = 30%
16. HBO2 0.3
MPa/120 min = 72%
17. HBO2 0.3
MPa/150 min = 50%
Survival rates
Class
II.b.
Level
6A
AHA
NA
NCIPDQ
NA
BMJ
Evidence
Thumbnail evidence-based analysis
UHM 2005, Vol. 32, No. 1 – Treatment of severe anemia with HBO2: Evidence-based
73
1965
1965
12.
13.
1965
11.
Date
Navarro RU
(36)
Whalen RE
(35)
Jacobson YG
(20,21,22)
Author
Canine
Canine
Animal
species
Rabbit
Controlled study:
1. NBA/120 min dextran
group (n=15)
2. NBA/120 min dextrose
group (n=15)
3. HBO2 0.35 MPa/120
min dextran group (n=15)
4. HBO2 0.35 MPa/120
min dextrose group
Controlled study:
1. NBA group (n=10)
2. NBO2 group (n=10)
3. HBO2 0.2 MPa/12 hr
(n=10)
Controlled study:
1. NBA group (n=5)
2. NBO2 group (n=5)
3. HBO2 0.35 MPa (n=5)
4. HBO2 0.35 MPa
Study groups
Complete replacement of
blood volume of group 4
animals with dextran
6%/dextrose, 5%/RL
solution to produce a Hct
of 0.5%
Wiggers (24) “hypoMAP” model for all
animals
Wiggers (24) “hypoMAP” model for all
animals
Hemorrhagic insult
Survival at 48 hours
post-hem:
1. NBA group = 0%
2. NBO2 group = 10%
3. HBO2 group = 10%
All groups 100%
survival, but group 4
had increased cardiac
output and decreased
peripheral vascular
resistance
Survival at 48 hours
post-hem after
administration of exp:
1. NBA dextran group
= 26%
2. NBA dextrose
group = 6.6%
3. HBO2 dextran group
= 60%
4. HBO2 dextrose
group = 60%
Survival rates
74
Level
6A
AHA
Level
6B
AHA
Level
6A
AHA
Class
II.b.
Class
Indeter
minate
Class
II.b.
NA
NCIPDQ
NA
NCIPDQ
NA
NCIPDQ
NA
BMJ
Evidence
NA
BMJ
Evidence
NA
BMJ
Evidence
Thumbnail evidence-based analysis
UHM 2005, Vol. 32, No. 1 – Treatment of severe anemia with HBO2: Evidence-based
1970
1970
15.
16.
1969
14.
Date
Oda T (39)
Doi Y (37)
Necas E (38)
Author
Canine
Canine
Animal
species
Rat
75
Controlled study:
1. NBA NS/5% dextran
40/80 min (n=5)
2. HBO2 0.3 MPa/60 min
NS/3% dextran 40 group
(n=5)
3. NBA NS/5% dextran
200 group (n=5)
4. HBO2 0.3 MPa/60 min
NS/6% dextran 200 group
(n=5)
25 ml/kg shed blood
with exchange of NS
designated exchange
followed by continued
bleed to produce a Hct of
18%
Wiggers (24) “hypoMAP” model for all
animals
Group b: Hemorrhage to
Hct of 10%
1b. NBA group (n=3)
2b. HBO2 0.3 MPa/360420 min group (n=4)
3b. NBA group (n=13)
4b. HBO2 0.3 MPa/360420 min group (n=9)
Controlled study:
1. NBA/90 min (120
min) group (n=7)
2. HBO2 0.2 MB/90 min
( 120 min) group (n=7)
Survival at ____ hrs:
1a. NBA with Hct
25% group = 60%
2a. HBO2 with Hct
25% group = 100%
3a. HBO2 with Hct
25% group = 100%
Group a: Hemorrhage to
Hct of 25%
Controlled study:
1a. NBA group (n=5)
2a. HBO2 0.3 MPa/360420 min group (n=3)
3a. HBO2 0.2 MPa/360420 min group (n=2)
Survival rates:
1. NBA dextran 40
group = 100%
2. HBO2 dextran 40
group = 100%
3. NBA dextran 200
group = 100%
4. HBO2 dextran 200
group = 100%
1b. NBA with Hct
10% = 0%
2b. HBO2 with Hct
10% = 100%
3b. NBA with Hct
10% group = 0%
4b. HBO2 with Hct
10% = 100%
Survival at 4½ hours
post-hem:
1. NBA group = 0%
2. HBO2 group =
100%
Survival rates
Hemorrhagic insult
Study groups
Level
6A
AHA
Level
6A
AHA
Level
6A
AHA
Class
Indeter
minate
Class
II.b.
Class
II.b.
NA
NCIPDQ
NA
NCIPDQ
NA
NCIPDQ
NA
BMJ
Evidence
NA
BMJ
Evidence
NA
BMJ
Evidence
Thumbnail evidence-based analysis
UHM 2005, Vol. 32, No. 1 – Treatment of severe anemia with HBO2: Evidence-based
1976
19.
1977
1975
18.
20.
1974
17.
Date
Leonov AN
(43)
Barkova EN
(42)
Norman JN
(41)
Trytyshnkov
IM (40)
Author
Cat
Rat
Animal
species
Rat
76
Controlled study:
1. NBA/60 min group
(n=”?”)
2. HBO2 0.3 MPa/60 min
group (n=”?”)
Non-controlled study:
1. NBA group (n=60)
2. HBO2 0.2 MPa/40 min
group (n=60)
Controlled study:
1. NBA no hem group
2. NBA with hem group
3. HBO2 0.2 MPa/60 min
no hem group
4. immediate HBO2 0.2
MPa/60 min post-hem
group
5. delayed HBO2 0.2
MPa/60 min post-hem
group
(total n=179)
Controlled study:
Study groups
Wiggers (24) “hypoMAP” model for all
animals
2.8% of body weight
blood loss over 30 min
3% body weight
hemorrhage by jugular
blood draw over thirty
minutes
Hemorrhagic insult
Survival rate:
1. NBA group =
increase in brain
ammonia
2. HBO2 group = no
increase in brain
ammonia
Survival rate:
1. NBA group = 0%
2. HBO2 group =
100%
Survival rates:
1. NBA group = 100%
2. NBA with hem
group = 0%
3. HBO2 no hem group
= 100%
4. immediate HBO2
post-hem group =
100%
5. delayed HBO2 posthem group = 0%
Survival rates
Level
6B
AHA
Level
6B
AHA
Level
6A
AHA
Level
6B
AHA
Class
Indeter
minate
Class
II.b.
Class
II.b.
Class
II.b.
NA
NCIPDQ
NA
NCIPDQ
NA
NCIPDQ
NA
NCIPDQ
NA
BMJ
Evidence
NA
BMJ
Evidence
NA
BMJ
Evidence
NA
BMJ
Evidence
Thumbnail evidence-based analysis
UHM 2005, Vol. 32, No. 1 – Treatment of severe anemia with HBO2: Evidence-based
21.
1983
-84
Date
Gross DR
(44,45,46)
Author
Animal
species
Canine
Controlled study:
1. NBA 6% dextran 40
group (n=6)
2. NBA RL group (n=6)
3. NBA 10% dextrose
group (n=6)
4. NBA 6% dextran 70
group (n=6)
5. HBO2 0.28 MPa/93-118
min 6% dextran-40 group
(n=6)
6. HBO2 0.28 MPa/93-118
min RL group (n=6)
7. HBO2 0.28 MPa/93-118
min 10% dextrose (n=6)
8. HBO2 9.28 MPa/93-118
min 6% dextran-70 group
(n=6)
9. HBA 0.6 MPa 6%
dextran-40 (n=6)
10. HBA 0.6 RL group
(n=6)
11. HBA 0.6 MPa 10%
dextran group (n=6)
12. HBO2 0.6 MPa 6%
dextran-70 group (n=6)
Study groups
Wigger (24) “hypoMAP” model for all
animals
Hemorrhagic insult
Survival post-hem:
1. NBA 6% dextran40 group = 100%
2. NBA RL group =
100%
3. NBA 10% dextrose
group = 100%
4. NBA 6% dextran 70
group = 100%
5. HBO2 6% dextran40 group = 100%
6. HBO2 RL group =
100%
7. HBO2 10% dextrose
group = 100%
8. HBO2 6% dextran70 group = 100%
9. HBA 6% dextran40 group = 100%
10. HBA RL group =
100%
11. HBA 10%
dextrose group =
100%
12. HBA 6% dextran70 group = 100%
Survival rates
Level
6A
AHA
Class
Indeter
minate
NA
NCIPDQ
NA
BMJ
Evidence
Thumbnail evidence-based analysis
UHM 2005, Vol. 32, No. 1 – Treatment of severe anemia with HBO2: Evidence-based
77
1991
1992
1992
22.
23.
24.
Date
Marzella L
(49)
Wen-Ren L
(48)
Bitterman H
(47)
Author
Rat
Canine
Animal
species
Rat
Controlled study:
1. NBA/95 min group
(n=6)
2. HBO2 0.3 MPa/95 min
group (n=6)
Controlled study:
1. NBA hem with 90 min
monitoring group (n=”?”)
2. HBO2 hem 15 min then
0.2 MPa/75 min with
monitoring group (n=”?”)
Controlled study:
1. NBA sham group (n=6)
2. NBA + hem group
(n=10)
3. NBO2/90 min + hem
group (n=10)
4. HB nitrox (7/93) 0.3
MPa/190 min + hem group
(n=8)
5. HBO2 0.3 MPa/90 min
sham group (n=6)
6. HBO2 0.3 MPa/90 min +
hem group (n=10)
Study groups
Hemorrhage to 15 ml/kg
Hemorrhage to 60 ml/kg
Hemorrhage within 90
min of 3.2 ml all animals
so designated
Hemorrhagic insult
Survival rates not
provided for groups
1. NBA group: BP
decreased 25%, CO
decreased 25%
2. HBO2 group: BP
increased 10%, CO
decreased 25%
Survival post-hem:
MAP > 40 mmHg for
220 min:
1. NBA sham group =
100%
2. NBA + hem group
= 10%
3. NBO2 + hem group
= 50%
4. HB nitrox + hem
group = 0%
5. HBO2 sham group =
100%
6. HBO2 + hem group
= 100%
Survival rate:
1. NBA group = 0%
2. HBO2 group =
100%
Survival rates
78
Level
6B
AHA
Level
6A
AHA
Level
6A
AHA
Class
Indeter
minate
Class
II.b.
Class
II.b.
NA
NCIPDQ
NA
NCIPDQ
NA
NCIPDQ
NA
BMJ
Evidence
NA
BMJ
Evidence
NA
BMJ
Evidence
Thumbnail evidence-based analysis
UHM 2005, Vol. 32, No. 1 – Treatment of severe anemia with HBO2: Evidence-based
26.
25.
2000
1995
Date
Yamashita M
(51)
Adir Y (50)
Author
Rat
Animal
species
Rat
79
Controlled study:
1. NBA + hem group
(n=15)
2. HBO2 0.3 MPa/60 min
with 30 min
decompression + hem
group (n=10)
3. HBO2 0.3 MPa/60 min
with 30 min
decompression no hem
group (n=10)
Controlled study:
1. NBA no hem group
(n=11)
2. NBA + hem group
(n=10)
3. NBO2 + hem group
(n=10)
4. HBO2 0.3 MPa/90 min
no hem group (n=7)
5. HBO2 0.3 MPa/90 min +
hem group ( n=10)
Study groups
Hemorrhage of 40 ml/kg
over one hour
Hemorrhage 3.2 ml/100
g over 120 min for all
animals so designated
Hemorrhagic insult
Survival at 24 hour/7
day post-hem:
1. NBA no hem group
= 100%/45%
2. HBA hem group =
70%/10%
3. NBO2 hem group =
90%/70%
4. HBO2 no hem group
= 100%/55%
5. HBO2 hem group =
90%/10%
Survival at 24 hours
post-hem:
1. NBA + hem group
= 40%
2. HBO2 + hem group
= 83%
3. HBO2 no hem group
= 100%
Survival rates
Level
6A
AHA
Level
6A
AHA
Class
IIb
Class
Indeter
minate
NA
NCIPDQ
NA
NCIPDQ
NA
BMJ
NA
BMJ
Evidence
Thumbnail evidence-based analysis
UHM 2005, Vol. 32, No. 1 – Treatment of severe anemia with HBO2: Evidence-based
80
1969
1969
1974
1.
2.
3.
Date
Hart GB (57)
Amonic RS
(56)
Diverticulosis with rectal
bleeding with Hgb 2.6
g/dL, AMS, and 90/70 BP
MVA with liver laceration
with Hgb 6.9 g/dL
27 yo
/male
(JW)
S/P resuscitation of
leiomyoma to resolve GI
bleed
Post-op Hct = 10%
3rd post-op day = CHF
Serial HBO2
7th post-op day Hct = 12%
7th post-op week Hct =
42%
Perinatal pelvic hematoma
and pulmonary embolism
with Hgb 3.8 g/dL,
congestive heart failure,
AMS, and 88/40 BP
67 yo
/female
(JW)
27 yo
/female
(JW)
26 yo
/male
(JW)
Iron dextran IM
Serial HBO2 0.2 MPa/90
Yes (pt was
transfused 2
units PRBC’s
on 4th hospital
day after
continued
bleeding)
Iron dextran IM
Serial HBO2 0.2 MPa/90
Iron dextran IM
Serial HBO2 0.2 MPa/90
No
No
Hematinics – yes
Serial 17 cycles of HBO2
0.2 MPa/160 min
(at depth the pt initially
seized when oxygen mask
was removed)
No
Yes
Yes
Yes
Yes
Indeter
minate
5
Class
Indeter
minate
Level
5
AHA
Class
Level
AHA
3.iii.
NCIPDQ
3.iii.
NCIPDQ
Likely to
be
beneficial
BMJ
Evidence
Likely to
be
beneficial
BMJ
Evidence
APPENDIX II - Table 2. Human Case Reports and Series for Use of Hyperbaric Oxygen Therapy in Treatment of Severe Anemia
Pt age
Quantification of
Adjunctive
Adjunctive hematinics
Survival Thumbnail evidence-based analysis
/gender
hemorrhagic insult
Transfusion
And HBO2
Ledingham IM
40 yo
Admission Hgb = 1.5 g/dL Yes (patient
AHA
NCI- BMJ
B12 folic acid, ascorbic
Yes
(55)
/female
PDQ Evidence
Admission BP = 65/?
was transfused
acid
after
Admission sensorium =
HBO2 0.2 Mpa/5 hr + (at
Level Class
Likely to
stabilization by depth the pt would seize
AMS
3.iii. be
completed
at first when oxygen mask
beneficial
5
Indeter
HBO2)
was removed)
minate
Author
81
1974
1987
4.
5.
Date
Hart GB (52)
Myking O (58)
Author
(subgroup
analysis of
those
patients
without
AMS
leaves 19
pts)
6 males
(JW)
20
females
(JW)
55 yo
/female
Pt age
/gender
No
Mean Hct of all 26 patients
= 13% (all with class IV
hem)
No
No
Adjunctive
Transfusion
AIHA with HGB 4.6 g/dL
Failed prednisone with
Hgb falling to 3 g/dL with
AMS
Serial HBO2 x 5 days with
Hgb 5 g/dL
Quantification of
hemorrhagic insult
All had hematinics,
vitamin B12, vitamin c,
iron
All patients averaged 9.6
HBO2 sessions 0.2
MPa/90 min
Prednisone
Serial HBO2 0.26
MPa/240 min QID
tapered to HBO2 0.26
MPa/120 min BID to day
5 with D/C
Adjunctive hematinics
And HBO2
95%
83%
65%
Yes
Survival
Class
Level
5
Level
II.b.
Class
Indeter
minate
5
AHA
Class
Level
AHA
3.iii.
NCIPDQ
3.iii.
NCIPDQ
Beneficial
BMJ
Evidence
Likely to
be
beneficial
BMJ
Evidence
Thumbnail evidence-based analysis
82
1999
1992
7.
8.
1989
6.
Date
McLaughlin PL
(61)
Young BA (60)
Myerstein N
(59)
Author
38 yo
/female
Pt age
/gender
4
individual
human
blood
samples
were
tested for
levels of
GSH, Hct/
free Hgb,
MetHgb
and RBC
volume
Antepartum hemorrhage
with Hgb 2 g/dL
39 day post-bleed
discharge Hgb 7.6 g/dL
Quantification of
hemorrhagic insult
Study groups:
1. Control RBCs, both
fresh and stored samples
2. Low GSH RBCs
induced by diamide in both
fresh and stored samples
3. RBCs exposed to HBO2
0.3 MPa/120 min in both
fresh and stored samples
4. Low GSH RBCs
induced by diamide in both
fresh and stored samples
exposed to HBO2 0.3
MPa/120 min
No
Adjunctive
Transfusion
Vitamin B12, EPO, folic
acid, iron
HBO2 0.3 MPa/90 min
TID tapered to BID over
16 days (total 22 HBO2
sessions)
Adjunctive hematinics
And HBO2
Yes
Yes
II.b.
6
II.b.
5
Class
II.b.
Level
5
AHA
Class
Level
AHA
Class
Level
3.iii.
NCIPDQ
3.iii.
NCIPDQ
NA
Likely to
be
beneficial
BMJ
Evidence
Likely to
be
beneficial
BMJ
Evidence
NA
BMJ
Evidence
AHA
No
damage
or
abnorm
ality
induced
by
HBO2
over
controls
NCIPDQ
Thumbnail evidence-based analysis
Survival
83
9.
2002
Date
Hart GB (53)
Author
20 yo
/female
(JW)
Pt age
/gender
GSW to left chest with left
lung and hemidiaphragm
penetration with spleen,
left kidney and spinal cord
injury
Post-op Hct 18
Post-op intestinal
perforation
Post-op day 28 Hct 22
Quantification of
hemorrhagic insult
No
Adjunctive
Transfusion
EPO
HBO2 0.2 MPa/90 min
TID tapering to BID for a
total of 28 dives
Adjunctive hematinics
And HBO2
Yes
Survival
Class
II.b.
Level
5
AHA
3.iii.
NCIPDQ
Likely to
be
beneficial
BMJ
Evidence
Thumbnail evidence-based analysis