1. health and fitness
2. therapy

Adjunctive effect of hyperbaric oxygen treatment
after thrombolysis on left ventricular function in
patients with acute myocardial infarction
Milica Dekleva, MD, PhD,a Aleksandar Neskovic, MD, PhD, FESC,d Alja Vlahovic, MD,d
Biljana Putnikovic, MD, PhD,b Branko Beleslin, MD, FESC,c and Miodrag Ostojic, MD, PhD, FESC, FACCc
Belgrade, Serbia and Montenegro
Background
The role of hyperbaric oxygen in patients with acute myocardial infarction is controversial, ranging
from not beneficial to having a favorable effect. This randomized study was conducted to further assess the benefit of hyperbaric oxygen treatment after thrombolysis on left ventricular function and remodeling in patients with acute myocardial
infarction.
Methods Seventy-four consecutive patients with first acute myocardial infarction were randomly assigned to treatment with hyperbaric oxygen treatment combined with streptokinase (HBO⫹) or streptokinase alone (HBO⫺).
Results There was a significant decrease of end-systolic volume index from the first day to the third week in HBO⫹
patients compared with HBO⫺ patients (from 30.40 to 28.18 vs from 30.89 to 36.68 mL/m2, P ⬍ .05) accompanied
with no changes of end-diastolic volume index in HBO⫹ compared with increased values in HBO⫺ (from 55.68 to 55.10
vs from 55.87 to 63.82 mL/m2, P ⬍ .05). Ejection fraction significantly improved in the HBO⫹ group and decreased in
the HBO⫺ group of patients after 3 weeks of acute myocardial infarction (from 46.27% to 50.81% vs from 45.54% to
44.05 %, P ⬍ .05).
Conclusions
Adjunctive hyperbaric oxygen therapy after thrombolysis in acute myocardial infarction has a favorable effect on left ventricular systolic function and the remodeling process. (Am Heart J 2004;148:e14.)
Normobaric therapy has been in use for many years
in the treatment of ischemic heart disease.1 When oxygen is breathed in concentrations higher than those
found in the atmospheric air, it is considered to be a
drug. A limited amount of oxygen is dissolved in blood
in normal atmospheric pressure, but under hyperbaric
conditions, it is possible to dissolve sufficient oxygen,
for example, 6%, in plasma to meet the usual requirements of the body. The oxygen physically dissolved in
solution will be utilized more readily than that bound
to hemoglobin, and this effect may normalize or increase oxygen tension in ischemic tissue.1
Calvert et al2 reported that hyperbaric oxygen (HBO)
could be a treatment for neonatal hypoxia-ischemia in
a neonatal rat model and could prevent brain injury. In
From aClinical Medical Center “Dr Dradisa Misovic-Dedinje”, bClinical Medical Center
“Zemun”, cInstitute for Cardiovascular Diseases Clinical Center of Serbia, and dInstitute
for Cardiovascular Diseases, “Dedinje,” Belgrade, Serbia and Montenegro.
Reprint requests: Milica Dekleva, MD, PhD, Clinical Medical Center “Dr Dragisa Misovic-Dedinje.” Department of Echocardiography. Milana Tepica 1 St, 11000 Belgrade,
Serbia and Montenegro.
E-mail: [email protected]
0002-8703/$ - see front matter
© 2004, Elsevier Inc. All rights reserved.
doi:10.1016/j.ahj.2004.03.031
that study, HBO was administered in a chamber for 1
hour at 3 ATA (absolute pressure of 1 atmosphere), 1
hour after hypoxia exposure. Results suggested that
HBO, as a single therapy, is able to attenuate hypoxiaischemia brain insult and offer neuroprotectivity. HBO
reduced neuronal injury with much less atrophy and
apoptosis of immature neurons, resulting in further
improvement of sensorimotor function of neonatal
brain.
The role of HBO in patients with acute myocardial
infarction is controversial, ranging from no beneficial
effect3,4 to a favorable effect.5,6 The only controlled
trial done by Thurston et al,5 in the prethrombolytic
era, revealed a trend but not a statistically significant
decrease in mortality rates, especially in high-risk patients. An animal study conducted by Thomas et al6
proved the hypothesis that a combination of thrombolytic therapy and HBO would be more effective in reducing the size of the myocardial infarction than either
of these modalities alone. Therefore, a randomized pilot trial conducted by Shandling et al7 demonstrated
that adjunctive treatment with HBO appears to be feasible and safe for patients in the acute phase of myocardial infarction. Finally, the Hyperbaric Oxygen and
American Heart Journal
October 2004
2 Dekleva et al
Thrombolysis in Myocardial Infarction (HOT MI) study
demonstrated that treatment with HBO in combination
with thrombolysis might result in an attenuated creatine phosphokinase rise, more rapid resolution of pain,
and improved ejection fraction (EF).8
The following randomized study was designed to
further assess the benefit of thrombolysis in combination with HBO on the remodeling process and left ventricular function preservation in patients with acute
myocardial infarction.
Figure 1
Methods
Study population
The study population consisted of consecutive patients
with first myocardial infarction who met the following criteria: (1) age ⬍70 years, (2) chest pain lasting 30 to 360 minutes, (3) ST-segment elevation ⬎2 mm in ⬎2 contagious electrocardiographic leads, (4) transient creatine phosphokinase
and/or MB isoenzyme increase, and (5) first echocardiogram
performed within 24 hours of the onset of pain.
Exclusion criteria were standard for thrombolysis, including suspected aortic dissection, recent surgery, recent peptic
ulcer, and stroke. Exclusion criteria also included patients
with malignant arrhythmias and severe hemodynamic instability, with Killip classes III and IV, non–rapidly controlled with
intravenous medication, and patients with previous myocardial infarction or bypass surgery. Further exclusions to HBO
were the inability to equilibrate pressure in the middle ear
space secondary to upper respiratory tract infections, otitis
or rhinitis, severe claustrophobia, and chronic obstructive
pulmonary disease.
From 92 patients with acute myocardial infarction originally considered for the study, 18 were subsequently excluded. Five patients were excluded because of rhythm and
hemodynamic instability in the emergency room. Six patients
refused coronary angiography, which also represents exclusion criteria in this study. Three patients refused entry into
the HBO chamber: two because they felt claustrophobia in
the chamber and one because of chronic otitis media. Four
patients had chronic obstructive pulmonary disease with
marked CO2 retention. In patients who started HBO, there
were no complications inside the chamber or after the treatment and no need for urgent decompression. Thus, the final
study population consisted of 74 patients (63 men, 11 women; mean age, 55 ⫾ 7 years).
Study procedure
Streptokinase was administered at the dose of 1.5 mU/L
over 30 to 60 minutes, followed by intravenous heparin infusion. With a random number table, patients were randomly
assigned to streptokinase therapy alone (HBO⫺ group, 37
patients) or streptokinase with HBO (HBO⫹ group, 37 patients). The patients randomly assigned to streptokinase plus
HBO were transferred to the hyperbaric unit in the first 24
hours from the onset of symptoms and after thrombolytic
therapy. The time from cessation of thrombolytic therapy to
HBO ranged from 45 minutes to 18 hours, with average time
of 10 hours (Figure 1). The patients randomly assigned to
Time distribution from thrombolysis to HBO.
HBO were pressurized during a 20-minute period up to 2
ATA. They remained at this pressure during 60 minutes in
the monoplace hyperbaric chamber. Decompression time
was 20 minutes with decreasing pressure change 0.2 ATA/
min. A critical care nurse and cardiologist were in attendance
at all times. By using electrocardiographic cables with 3 terminals, all patients in the chamber were monitored, including electrocardiograms and respiratory traces. Measuring of
noninvasive blood pressure inside the hyperbaric chamber
was done in an automatic reading system, which measures
the pressure displayed from the oscillometric method at preset intervals. All monitoring devices, drug protocols, and
other procedures in the intensive care unit continued when
patients were discharged inside the chamber. Monoplace
chambers exclude possible nurse assistance, so these chambers have an option of emergency decompression within at
least 1 minute, depending on the nature of critical situation.
All patients were assessed clinically at study entry for the
presence or absence of heart failure on the basis of Killip
criteria. Creatine phosphokinase samples were obtained on
admission, every 4 hours for the first 24 hours, and afterward
on daily basis.
Coronary angiography was performed after hospital discharge. Perfusion of the infarct-related artery was assessed by
using criteria from the Thrombolysis In Myocardial Infarction
(TIMI) trial.11 Successful reperfusion was coded as TIMI
grade 3.
Echocardiography
Two-dimensional echocardiography was performed with an
Acuson 128 imaging system on day 1 after thrombolysis or
immediately after thrombolysis plus HBO treatment, on day
2, and after 3 weeks in all patients. All measurements were
performed off-line, calculated from the mean value of 3 best
consecutive cardiac cycles. The physician, who assessed left
ventricular function, was blinded to the random assignment
status of the patient. Left ventricular volumes and EF were
determined from apical 2- and 4-chamber views, using the
Simpson biplane formula. The left ventricular volumes, end-
American Heart Journal
Volume 148, Number 4
Dekleva et al 3
Table I. Demographic, clinical, and angiographic
characteristics of patients
Age (y)
Sex (F/M)
Hypertension
Diabetes mellitus
Smoking
Killip class ⬎2
Time to STK (h)
Anterior MI
Peak CK value (U/L)
Multivessel CAD
TIMI 3 flow
Collaterals
Cardiac mortality
Table II. Medical treatment of patients during in-hospital
period
HBOⴙ
(n ⴝ 37)
HBOⴚ
(n ⴝ 37)
P
value
55 ⫾ 7
8/29
14 (38%)
8 (22%)
30 (81%)
2 (5%)
2.4 ⫾ 1.6
14 (38%)
989 ⫾ 643
19 (51%)
22 (59%)
9 (24%)
0 (0%)
54 ⫾ 8
3/34
13 (35%)
2 (5%)
27 (73%)
5 (14%)
3.0 ⫾ 1.5
16 (43%)
1529 ⫾ 1187
20 (54%)
22 (59%)
9 (24%)
1 (3%)
NS
NS
NS
⬍0.05
NS
NS
NS
NS
⬍0.05
NS
NS
NS
NS
Heparin
Aspirin
Oral anticoagulation
Nitroglycerin IV
Long-acting nitrates
Calcium channel blockers
␤-Blockers
Digitalis
Diuretics
ACE inhibitors
HBOⴙ
(n ⴝ 37)
HBOⴚ
(n ⴝ 37)
P
value
37 (100%)
36 (97%)
5 (14%)
7 (19%)
30 (81%)
1 (3%)
26 (70%)
1 (3%)
3 (8%)
8 (22%)
37 (100%)
36 (97%)
8 (22%)
8 (22%)
31 (84%)
1 (3%)
23 (62%)
1 (3%)
5 (14%)
12 (32%)
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
Figure 2
CAD, Coronary artery disease; CK, creatine phosphokinase; STK, streptokinase.
diastolic and end-systolic, were normalized for body surface
area and expressed as indexes (EDVI and ESVI).12
Statistical analysis
The unpaired t test and ␹2 test were used to test the differences between 2 groups of patients. The paired t test was
used to compare initial left ventricular volume indexes and
EF, with results performed after 3 weeks. Analysis of variance
was used for analyzing repeated measures of left ventricular
volumes indexes, and EF. Probability values of ⬍.05 were
considered statistically significant.
Results
Demographic, clinical, and angiographic data
Patient demographics and clinical and angiographic
data are listed in Table I. There was no significant difference between study groups with regard to the age,
sex, prevalence of hypertension, and smoking history.
According to anamnesis and adjusted analysis for diabetic status at baseline, there were more diabetic patients in the HBO⫹ group, but these distributions have
no obvious influence on the final results. The distribution of localization of myocardial infarction was similar
in both study groups. Patients in both groups were
evenly distributed in either Killip class I or II. With
regard to coronary angiography, there were no significant differences between the two groups in infarction
artery patency, single or multivessel coronary artery
disease, or collateral vessel presence. However, patients receiving thrombolytic therapy alone showed a
higher peak creatine phosphokinase activity compared
with the HBO⫹ group (989 vs 1529 IU, P ⬍ .05).
As shown in Table II, both groups of patients received similar medication before HBO, during their
hospital stay, and at the time of discharge, including
Changes of ESVI in acute myocardial infarction in HBO⫹ and
HBO⫺ groups of patients. Large box/upper border, 75% percentile; large box/lower border, 25% percentile; line in the middle of
the large box, median; small box inside large one, ⫾mean value.
*Confidence interval, 1% to 99%.
ACE inhibitors, anticoagulants, aspirin, ␤-blockers, longacting nitrates, intravenous nitroglycerin, calcium channel
inhibitors, digitalis, and diuretics (P ⫽ not significant).
Left ventricular function and remodeling
In the current study, using serial echocardiography
examinations, we were able to observe the pattern of
changes of left ventricular volumes and EF in respect
to HBO treatment and to compare the baseline values
with subsequent studies up to 3 weeks.
The changes in left ventricular volumes and EF are
presented in Figure 2, Figure 3, and Figure 4. Initial
left ventricular volume indexes and EF were similar in
two study groups (P ⫽ not significant). In patients
treated with thrombolysis only, there were significant
American Heart Journal
October 2004
4 Dekleva et al
Figure 3
to 50.81%). Thus, 3 weeks after acute myocardial infarction, the HBO⫹ group compared with the HBO⫺
group of patients had lower ESVI (28.18 vs 36.68 mL/
m2, P ⬍ .001) (Figure 2) and EDVI (56.2 vs 63.8 mL/
m2, P ⬍ .001) (Figure 3) and higher EF (44.05% vs
50.,81%, P ⬍ .001) (Figure 4).
As shown in the figures, the main effect of HBO was
achieved during the very first days of acute myocardial
infarction, with significant difference in ESVI and EF
on day 2 in favor of the HBO⫹ group. In the subsequent 3-week follow-up period, further changes of left
ventricular function indexes were slight and statistically nonsignificant.
Discussion
Changes of EDVI in acute myocardial infarction in HBO⫹ and
HBO⫺ groups of patients. Large box/upper border, 75% percentile; large box/lower border, 25% percentile; line in the middle of
the large box, median; small box inside large one, ⫾mean value.
*Confidence interval, 1% to 99%.
Figure 4
Changes of EF in acute myocardial infarction in HBO⫹ and
HBO⫺ groups of patients. Large box/upper border, 75% percentile; large box/lower border, 25% percentile; line in the middle of
the large box, median; small box inside large one, ⫾mean value.
*Confidence interval, 1% to 99%.
increases of ESVI (from 30.89 to 36,68 mL/m2) and
EDVI (from 55.87 to 63.82 mL/m2) and decreases of
EF (45.8% to 44.2%) during the first 3 weeks. Conversely, in the HBO⫹ group, EDVI did not change significantly (from 55.68 to 56.24 mL/m2), ESVI decreased significantly (from 30.40 to 28.18 mL/m2), and
EF improved during the follow-up period (from 46.27%
The major original findings of this study relate to the
changes of left ventricular volumes in the time course
estimated by echocardiography. We have shown that
HBO and streptokinase in acute myocardial infarction
reduced left ventricular volumes with associated increase in EF during the first 3 weeks after acute myocardial infarction. In contrast, there was progressive
left ventricular dilation, with no change in EF in patients treated with thrombolysis only.
Comparison with previous studies
Left ventricular dilation in the first 3 weeks of myocardial infarction is determined mostly by the expansion process, infarct-related artery patency, and infarct
localization.11–13,15 Popovic et al16 have shown that
the degree of EDVI increase for the period of 3 weeks
after acute myocardial infarction was 6.0% in patients
treated with streptokinase only. In our study, a similar
increase of EDVI was found in the HBO⫺ group but a
lower degree was found in the HBO⫹ group (55.9 to
63.8 mL/m2, 14.1%, vs 55.7 to 56.2 mL/m2, 0.9%) (P ⬍
.001). Similarly, Chareonthaitawee et al14 have shown
that the degree of ESVI increase in thrombolytictreated patients was 12% in the acute phase, which
correlates well with our results in HBO⫺ patients
(30.1 to 36.7 mL/m2, 21.9%). In contrast, the decrease
of ESVI during 3 weeks (30.4 vs 28.2 mL/m2, 7%) demonstrated a significant benefit of HBO. Concerning EF,
the Intravenous Streptokinase in Acute Myocardial Infarction (ISAM) study demonstrated significant improvement of EF (5.3%) in patients treated with streptokinase compared with the control group.17 This
difference was also seen in the study by White et al13
(10%), the GISSI-2 study18 (2% to 3%), the European
Cooperative study Grupo Trial19 (4%), and the Western
Washington Trial20 (5%). In our study, the difference
in EF was not observed in the HBO⫺ group, but in the
HBO⫹ group, EF significantly increased for 9.8%
(46.3% to 50.8%). A favorable effect of the combination of thrombolysis and HBO on left ventricular EF
has been demonstrated in the HOT MI study by Sta-
American Heart Journal
Volume 148, Number 4
vitsky et al.8 This multicenter study demonstrated
higher values of left ventricular EF at discharge time in
patients treated with adjunctive HBO compared with
control subjects treated with thrombolysis only (48.4%
vs 51.7%).8 Both of these studies reported a benefit of
HBO as a single adjuvant therapy, without repeated
exposure, but Wada et al9,10 showed a protective effect of repetitive HBO against ischemia in a brain experimental model. According to these results, the best
tolerance against neuronal damage of the hippocampus of Mongolian gerbils was induced with pretreatment in 5 sessions of HBO, every other day, compared
with single HBO pretreatment or with ischemic control group.
Regarding prognostic importance of left ventricular
volumes, White et al13 have shown that left ventricular
volumes were clearly associated with death; that is,
ESVI was the most powerful predictor of survival, and
the inclusion of EDVI or EF in a multivariate model
added no further prognostic power.
Myocardial enzymes
Standard reflow with thrombolysis is followed with
significant creatine phosphokinase enzyme leakage or
washout effect, evidenced as an increased total activity
in blood after thrombolysis. In our study, peak creatine phosphokinase level was 35.3% lower in the
HBO⫹ group of patients than in the HBO⫺ group.
Very similar data were reported in a randomized pilot
trial by Shandling et al,7 demonstrating that mean
creatine phosphokinase level at 12 and 24 hours
was reduced in patients given HBO by approximately 35% (P ⫽ .03). An attenuated rise in creatine
phosphokinase (7.5%) in patients treated with
thrombolysis and HBO is one of the main remarks of
the HOT MI study by Stavitsky et al.8 Also, in an animal study conducted by Thomas et al,6 HBO combined with thrombolysis restored 95% of normal oxidative enzyme activity and decreased the release of
creatine phosphokinase into blood, thus better preserving myocardial fiber integrity.
Mechanism of improvement in left ventricular function
In the presence of a critical coronary artery stenosis,
the oxygen demand changes. In these circumstances,
increased dissolved oxygen fraction under hyperbaric
conditions could be enough to meet resting cellular
requirements without any contribution from oxygen
bound to hemoglobin from increased blood flow.1
The quantity of oxygen carried in the plasma and
tissue fluid under hyperbaric conditions in this study is
increased 10-fold compared with breathing room air.
The net effect, with an HBO treatment at 2 ATA absolute pressure, is an approximately 25% enhanced oxygen blood content and consumption and increased
Dekleva et al 5
tissue oxygen diffusion distance by a factor 3 or 4.
Therefore, high oxygen tension and an increased
amount of available tissue oxygen, pressure difference
between ischemic and nonischemic tissue, consequently improved penetration of oxygen into hypoxic
tissues.6 Reduction in heart rate during compression
time that was based on decrease of sympathetic activity could be part of the mechanism of left ventricular
function improvement.5
Tissue oxygen tension remained elevated for some
hours after cessation of HBO treatment.21 Thus, the
tissue remains oxygenated after completion of the
HBO treatment. According to our results, the most
powerful effect was on left ventricular remodeling and
left ventricular function at the first days of acute myocardial infarction. The “late effect” could result in sustained beneficial effects even after decompression, allowing improved myocardial salvage in that group of
patients who have late reperfusion.
Other mechanisms may be responsible for improved
regional wall motion. Through favorable changes in
myocardial oxygen supply and demand, HBO improved contraction of hibernating myocardium after
myocardial infarction that is indicated in the study
conducted by Swift et al.21 In our study, the increase
of global left ventricular function is followed by improvement of global systolic function in HBO⫹ patients compared with the HBO⫺ group.
During left ventricular remodeling, there are structural changes in coronary microcirculation followed by
decreased capillary density, with enlarged diffusion
distances for oxygen and disturbed perfusion of the
capillary bed.22 Microvascular obstruction after reperfusion may be the consequence of low or no reflow
phenomena. These obstructive myocardial zones have
a great influence on the left ventricular remodeling
process and left ventricular function.23,24 Favorable
effects of HBO in decreasing leukocyte endothelial adherence and improvement of angiogenesis is also a
contributory mechanism.23,25
There was initially concern that an increase in free
oxygen radicals, occurring by the high oxygen tension
state of HBO treatment, would emphasize tissue reperfusion injury.1,25 However, the results from our study
do not suggest that this mechanism occurs to any noticeable clinical sign in patients treated with 2 ATA
HBO protocol. Recent and present investigators have
shown that HBO lessens or may inhibit reperfusion
injury by protection of oxidative metabolism in reperfusion-stunned myocardium.23,25,26 Results of the studies conducted by Wada et al showed an HBO effect on
immunoreactivity to apoptosis-regulating protein
(Bc1-2, Bax) and manganese superoxide dismutase (Mn
SOD), a radical scavenging system. This protective
mechanism of repeated HBO pretreatment induced
tolerance against ischemic neuronal damage in gerbil
6 Dekleva et al
hippocampus. Protection against mitochondrial alterations after ischemia through Mn SOD and/or Bc1-2
expression may be related to induction of ischemic
tolerance by HBO.10,27
Study limitations
The data apply to the patients treated only with
streptokinase, and the results may be different for the
patients treated with other lytic agents or combination
therapies.
Because HBO treatment requires additional logistic
support, we excluded from the study high-risk patients
with severe heart failure as well as patients with significant electrical complications, who may actually have
the greatest benefit from combined HBO and thrombolysis therapy.
In the current study, the time from streptokinase to
HBO treatment was prolonged because of the distance
between hyperbaric unit and the coronary care unit.
A larger group of patients treated with HBO after
thrombolysis may demonstrate event-free survival benefits, as compared with those treated with thrombolysis alone.
Clinical implications
Our data indicate the adjunctive effect of HBO after
thrombolysis, resulting in attenuated creatine phosphokinase rise and improvement of left ventricular
function in the acute phase of myocardial infarction.
Repeated HBO sessions during the acute phase of myocardial infarction could be of great importance by inducing ischemic tolerance and attenuating left ventricular remodeling. Further multicenter clinical trials are
needed to evaluate possible improvement of event-free
survival and mortality rates.
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