Microbubbles: The Invisible Killer by
It is well established in surgical procedures
above the heart, such as in the head and neck, where the pressure is less
than one atmosphere, that an invasive procedure may let air in. This is
one reason why surgeons must be particularly careful when operating on the
brain, and why the head of the bed is tilted down when inserting or removing
a central line from the jugular or subclavian veins. Air embolism may also
occur during other types of surgery such as Cesarean section and orthopedic
procedures. Cases have even been reported as a result of sexual intercourse
during late pregnancy.
What is not as well known is the ability
of microbubbles to bypass the body's natural protective systems. Once microemboli
reach the brain they can fuse together forming a larger bubble resulting
in aphasia, coma, stroke, and even death. Increasingly popular interventional
procedures which allow air to enter via the femoral and renal arteries were
once considered safe. The problem we face even today is medical students
are taught that it is anatomically and physiologically impossible for an
air bubble to reach the brain if said procedure is being done below the
heart. As a result, hemodialysis, and renal artery stenting (RAS) patients
needlessly suffer symptoms of air embolism. Compounding the problem, much
of this goes unreported due to "ageism" on the part of the medical community.
Being that most dialysis and renal stenosis patients are of advanced years
and of deteriorating health, decreased mental capacity, dementia, and stroke
are assumed to be unrelated to the procedure. This is indeed unfortunate.
There is solid evidence as far back as
1944 which demonstrates that air bubbles in the form of Microbubbles have
the ability to enter the cerebral circulatory system and embolize the brain.
The challenge researchers have been facing is they had no way to accurately
measure the presence and size of microbubbles and thereby determine a cut-off
point as to what size bubble can make it past the bodies natural protective
systems. Thanks to modern ultrasound Doppler systems that is all changing.
1986 D.F. Gorman and D.M. Browning, while doing research for the Royal Australian
Navy, discovered that, "gas introduced as microbubbles into the femoral
artery of upright rabbits caused cerebral arterial gas embolism with gas
entering cerebral arterioles in cylindrical configurations...
Gas microbubbles infused into the
femoral artery of head-up rabbits distributed against aortic flow to
embolize the brain circulation. Conversely, regardless of infusion
volume, no gas entered the cerebral vessels of rabbits maintained in a head
down posture... We knew this was not was not due to mechanical problems
with the infusion lines because, "cerebral arterial gas emboli were produced
in these animals when reverted to the head-up posture...
These observations are consistent with other reports of arterial gas emulous
distribution... They support the role of a head-down posture in the treatment
of arterial gas embolism. (9,41,81)
In 2005 Michal Barak, MD; and Yeshayahu
Katz, MD, DSc reported, "there is a dynamic, constant process of small bubbles
fusing to create large bubbles, and large bubbles splitting into many small
ones; thus, a few “harmless” microbubbles could coalesce into one injurious
large bubble. The microbubble travels in the blood stream until it is lodged
in the microcirculation. Circulating in the blood stream, microbubbles lodge
in the capillary bed of various organs. Although arterial air emboli could
reach any organ, occlusion of cerebral and cardiac circulation is particularly
deleterious because these systems are highly vulnerable to hypoxia and go
through irreversible cellular damage. The result of such an event may be
massive brain ischemia and stroke or myocardial ischemia and infarction.
Both could be fatal... Arterial air may have direct access to the cerebral
circulation. Venous air may also readily cause cerebral air embolism in
the presence of a patent foramen ovale.2,3"
"Now there is a growing body of knowledge that small amounts of
air in the form of microbubbles are not benign. Please see the post from
July 2008 about a new report of damage from these microbubbles.
To read this post, click here."
For many years, we have known the dangers of
introducing large amounts of air into the circulatory system. Air can
enter during catheter insertion, tubing changes or disconnection and
catheter removal. Usually the air travels to the lungs where it produces
respiratory symptoms, but it can also move to the brain where it
produces neurological problems. These outcomes can be catastrophic for
the patient and nurses have learned to employ all means to prevent this
Cerebral Vasoreactivity and Arterial Gas Embolism
D. F. GORMAN and D. M. BROWNING
School of Underwater Medicine, Royal Australian Navy
Infusion of gas microbubbles into the femoral artery of upright
rabbits caused significant but transient hypertension . respiratory depression,
cardiac bradyarrythmia, inhibition of cerebrovascular autoregulation to
blood pressure changes, and cerebral arterial gas embolism with entrapment
of long emboli in arterioles of 50-200 um in diameter . Compression of casualties
with cerebral arterial gas embolism in a recompression chamber within 5
min of onset of symptoms usually results in rapid, complete recovery (4—11)
Gas Infusion Technique
Gas was introduced into the femoral artery as microbubbles of less than
200um diameter by using a fine hypodermic needle 0.025 ml i.d. at an infusion
rate of 0.2 ml/s (12, 45) . Three milliliter of normal saline were infused
at 0.1 mils to clear all gas from the arterial line.
New Zealand white rabbits (weighing 2-5 kg) were anesthetized with air and
halothane... A tracheotomy was performed below the larynx to allow intubation....
Three ECG electrodes were implanted in the animal's chest to provide a continuous
record on a multichannel recorder... The right femoral artery was isolated
by dissection and intubated with a 3-cm plastic cannula. This was connected
via a three-way tap to a pressure transducer and the multichannel recorder
that displayed systolic, diastolic, and mean blood pressure and to an infusion
I. Local cerebral circulatory arrest studies
a. Five rabbits were fixed to a frame in a head-up posture at 45° to the
horizontal. A single 5-ml saline infusion was given in a method identical
to that described for the gas microbubble infusion. This was followed by
5-ml air infusions as microbubbles, given at 2-min intervals until gas entered
the cerebral circulation under view and caused local circulatory arrest.
Blood pressure, heart rate, respiratory rate, and vessel diameter were recorded
throughout the procedure.
b. Five rabbits were prepared as above, except that they were kept in a
horizontal posture and a catheter was inserted into the left jugular vein
draining the cranial contents. This catheter was connected to a heparinized
loop that included a graduated air trap, and was reintroduced into the jugular
vein at its distal end. Gas microbubble infusions occurred as above with
gas being allowed to escape into the graduated air trap. The amount of gas
collected was recorded as a percentage of the total volume of gas microbubbles
infused into the femoral artery.
c. Five rabbits were fixed to a frame in a head-down posture at 45° to the
horizontal. Five-milliliter air infusions as microbubbles were given at
2-min intervals until either local cerebral circulatory arrest was effected
by gas embolism or until 15ml of gas had been infused . If no cerebral arterial
gas emboli occurred with animals in the head-down posture they were reverted
to a head-up posture at 45 0 to the horizontal . If after a period of 5
min no gas emboli had spontaneously entered the cerebral circulation, a
further 5 ml of air was infused as microbubbles into the femoral artery.
The animals were monitored throughout the procedure as for the first group
Local cerebral circulatory arrest studies
Gas introduced as microbubbles into the femoral artery of upright rabbits
caused cerebral arterial gas embolism with gas entering cerebral arterioles
in cylindrical configurations. No discrete microbubbles were observed. Conversely,
regardless of infusion volume, no gas entered the cerebral vessels of rabbits
maintained in a headdown posture. This was not due to mechanical problems
with the infusion lines because cerebral arterial gas emboli were produced
in these animals when reverted to the head-up posture.
Gas microbubbles infused into the femoral artery of head-up rabbits distributed
against aortic flow to embolize
the brain circulation. Conversely, cerebral arterial gas emboli were
never observed in head-down rabbits . These observations are consistent
with other reports of arterial gas embolus distribution (21, 49, 60, 74-76)
and with the frequency of neurological involvement in divers and submariners
who develop arterial gas emboli (4, 7-9, 56, 76-80). They also support the
role of a head-down posture in the treatment of arterial gas embolism (9,
Michal Barak, MD; and Yeshayahu Katz, MD, DSc
*From the Department of Anesthesiology (Dr. Barak), Rambam
Medical Center, Haifa; and Bruce Rappaport Faculty of Medicine
(Dr. Katz), Technion-Israel Institute of Technology, Haifa,
Manuscript received January 17, 2005; revision accepted April
18, 2005. Correspondence to: Yeshayahu Katz, MD, DSc, Department
of Anesthesiology, HaEmek Medical Center, Afula 18101,
Israel; e-mail: email@example.com
embolism is a known complication of various invasive procedures, and its
management is well established. The consequence of gas microemboli, microbubbles,
is under recognized and usually overlooked in daily practice... Microbubbles
originate mainly in extracorporeal lines and devices, such as cardiopulmonary
bypass and dialysis machines... Circulating in the blood stream, microbubbles
lodge in the capillary bed of various organs... In this review, we present
evidence of the biological and clinical detrimental effects of microbubbles
as demonstrated by studies in animal models and humans, and discuss management
of the microbubble problem with regard to detection, prevention, and treatment.
(CHEST 2005; 128:2918–2932)
...Our natural tendency is to overlook minute particles,
some of which are invisible, believing them to be harmless. However, solid
data show that microbubbles are of clinical importance.
Our knowledge of the consequences of small quantity air
emboli is lacking. The cutoff point
between the occurrence of a major catastrophic episode and subtle but unequivocally
symptoms is yet undefined. An arbitrary definition of microbubble size may
be erroneous since only a bubble of a diameter smaller than the capillary
can travel through the circulatory system without leaving an imprint and
be accepted as safe.4 Furthermore, in the biological setting, there is a
dynamic, constant process of small bubbles fusing to create large bubbles,
and large bubbles splitting into many small ones;
thus, a few “harmless”
microbubbles could coalesce into one injurious large bubble.
The microbubble travels in the blood stream until it is
lodged in the microcirculation. During its course, the bubble is compressed
against the endothelial capillary wall, causing functional stripping of
endothelial cells and an increase of large-pore radii.28
Clinical Consequences of Circulating Microbubbles
The clinical outcome of air embolism depends on the size
of the bubble, location (organ/tissue), general status, and comorbidity
of the patient, plus many known and unknown factors.55 Large air embolism
is usually disastrous, both in the venous and arterial circulation.56–58
The natural course of a large venous embolism is migration into the pulmonary
circulation and obstruction of the right ventricular outflow, acute increased
resistance to the right ventricle and diminished left ventricular preload,
followed by cardiovascular collapse.1,59 Air emboli in arterial vessels
cause symptoms of end-artery obstruction and tissue ischemia and necrosis.
Although arterial air emboli could reach any organ,
occlusion of cerebral and cardiac circulation is particularly deleterious because these systems
are highly vulnerable to hypoxia and go through irreversible cellular damage.
The result of such an event may be massive brain
ischemia and stroke or
myocardial ischemia and infarction. Both could be fatal. The detection of
such catastrophic events and resuscitative measurements are well known.1,60,61
Less is known about the results of small air emboli in the venous or arterial
circulation. A small quantity of microbubbles may be clinically silent,
while recurrent exposure to microbubbles causes a slow smoldering chronic
effect that is difficult to detect but has important consequences. The patient’s comorbidity may also influence the outcome of circulating air emboli. When
there is a right-to-left shunt, venous air emboli may traverse to the arterial
circulation and cause organ ischemia. Such a course of events is termed
paradoxical air embolism,62 and there are a few mechanisms by which it may
occur. One is passage of gas through a cardiac right-to-left shunt into
the systemic circulation. The prevalence of a cardiac right-to-left shunt
ranges between 15 to 40% in various studies,63,64 usually as a result of
patent foramen ovale but may be caused by other cardiac
anatomic anomalies... A right-to-left shunt might also be
extra-cardiac, mostly from dilatation of pulmonary vessels, causing an intrapulmonary
shunt in ARDS. In many cases the existence of such a shunt is unknown to
the patient or physician, and the risk of paradoxical emboli is not taken
Almost every invasive procedure
may cause the introduction of microbubbles into the blood stream.77
Of course, the more invasive and interventional the procedure, the greater
is the risk of microbubble generation.
The incidence of cognitive dysfunction at 1 week following
cardiac surgery is approximately twice that of noncardiac surgery.89...
Roach and colleagues81 calculated the additional cost of in-hospital neurologic
morbidity after cardiac surgery as approximately $400 million annually.
They estimated that true costs, including long-term out-of-hospital medical
and rehabilitative services, probably result in additional expenditures
ranging from 5 to 10 times narrow in-hospital costs, or $2 to $4 billion
As far back as 1975, there was evidence of pulmonary microembolization during
Microbubbles originate from the dialysis tubes or filter
flow in the venous vasculature and are trapped in the pulmonary circulation.
Thus, the hemodialysis patient may suffer both acute and chronic lung injury
due to a microbubble shower.
The damage caused by microbubbles may be more detrimental
in case of cardiac or extracardiac right to left shunt, which may be found
in up to 40% of the population.64 In those cases, air emboli may enter the
cerebral circulation and cause varying degrees of neurologic damage.119
Indeed, the above noted clinical studies106–109 that described microemboli
during dialysis had either no patient with a shunt108,109 or did
not report that detail in the study.106,107 Nevertheless, it is reasonable
to believe that a patient with a right-to-left shunt is at higher risk for
neurologic morbidity as a result of venous air embolism during hemodialysis.
Cerebral atrophy and deterioration of neurocognitive functions in chronic
hemodialysis patients is a recognized problem that correlates with the duration
of dialysis treatment.120–122
Diving and Decompression Sickness
DCS is an accurate example of humans exposed to microbubbles
in the circulation, and thus can demonstrate the clinical presentation of
that event.... The neurologic manifestations are attributed to bubble embolization
in the CNS. Again, clinical studies140,141 suggest that subclinical cerebral
damage occurs in divers, raising the possibility that microbubble damage
is underdiagnosed due to difficulties in detection and not because they
are not present.
The treatment of large air emboli is well established. 1,60,61 Little is
written about the management of microbubble injury. While the detection
of large air emboli is easy, usually manifested by acute cardiovascular
collapse or sudden overt deterioration of the neurocognitive or motor functions,
catastrophic in nature, the presentation of a microbubble event is more
subtle and difficult to detect.
Hyperbaric Oxygen should be employed as soon as
possible after the insult, although delayed treatment is also helpful.168
We have presented published data concerning the microbubble phenomenon and
its detrimental consequences. Indeed, the microbubble event and its
significance have been proved in open-heart surgery and DCS. However, it
awaits clinical confirmation in other conditions such as hemodialysis and
rapid fluid infusion. To date, there is a limited knowledge about the management
of the microbubble events. Nevertheless, acknowledgment of the problem
is the first step in the path toward finding a solution. Contemporary technology
offers us tools to cope with various difficulties. The best way to utilize
highly developed technology is in cooperation between scientists and engineers
in search of a resolution for a recognized problem. The problem of
microbubbles awaits a breakthrough technological solution that will provide
their detection and elimination, facilitating better care for the patient.
M. Barak and Y. Katz Microbubbles: Pathophysiology and Clinical Implications
Chest, October 1, 2005; 128(4): 2918 - 2932.
C. M. Muth and E.
S. Shank Gas Embolism
N. Engl. J. Med., February 17, 2000; 342(7): 476 - 482. [Full
J. E. Souders, J.
B. Doshier, N. L. Polissar, and M. P. Hlastala Spatial distribution of venous gas emboli in the lungs
J Appl Physiol, November 1, 1999; 87(5): 1937 - 1947.
B. Butler and M.
Kurusz Review article : Gaseous microemboli: a review
Perfusion, April 1, 1990; 5(2): 81 - 99. [PDF]
Cerebral Air Embolism Resulting from Invasive Medical Procedures
Treatment With Hyperbaric Oxygen (Full
From the United States Air Force
School of Aerospace
Medicine, Brooks AFB, and the Department of General
Surgery, Wilford Hall USAF Medical Center,
Lackland AFB, San Antonio, Texas
BRIAN P. MURPHY, CAPT, USAF, MC
FRANCIS J. HARFORD, COL, USAF, MC
FREDERICK S. CRAMER, COL, USAF, MC
The introduction of air into the venous or arterial circulation
can cause cerebral air embolism, leading to severe neurological deficit
or death. Air injected into the arterial circulation may have direct access
to the cerebral circulation. A patent foramen ovale provides a right-to-left
shunt for venous air to embolize to the cerebral arteries. The ability of
the pulmonary vasculature to filter air may be exceeded by bolus injections
of large amounts of air. Sixteen patients underwent hyperbaric oxygen therapy
for cerebral air embolism. Neurological symptoms included focal motor deficit,
changes in sensorium, and visual and sensory deficits.
FROM 1970 TO 1984, 16 cases of cerebral air embolism resulting
from invasive medical procedures were treated with hyperbaric oxygen at
the United States Air Force School of Aerospace Medicine... All patients
underwent hyperbaric oxygen therapy in a large multiplace chamber accompanied
by a physician... Eight of 16 patients (50%) became asymptomatic while undergoing
or shortly after completing hyperbaric therapy. Five patients had partial
resolution of symptoms (31%). Three patients had no response; two of these
died while in the hyperbaric chamber and the third was left with a severe
neurological deficit. Overall mortality was 13%.
Arterial air may have direct access to the cerebral circulation.
Venous air may also readily cause cerebral air embolism in
the presence of a patent foramen ovale.2,3 A recent autopsy study found
a 27.3% incidence of patent foreamen ovale in the general population, and
an incidence of 34% in the first 3 decades of life.4 If a bolus of air lodges
in the pulmonary arteries and causes obstruction to pulmonary outflow, a
hemodynamically significant right-to-left shunt (see illus. 1) through a
patent foramen ovale is likely to occur, with subsequent cerebral air embolism.
The pulmonary arterioles and capillaries are generally considered
an effective filter for thrombi, platelet aggregates, and fat emboli,
but trapping of air may not be so
effective.5 Marquez reported a fatal cerebral air embolism resulting
from a neurosurgical procedure in which postmortem examination detected
no intracardiac septal defects.6 Butler demonstrated in a canine model that
the lung is normally a very effective filter for air bubbles of
greater than 22 micrometers
in diameter when infused slowly.7 (see
Microbubbles by M. Barak & Y. Katz in CHEST) However, a bolus injection
of 30 cc of air into a central vein
exceeded the filtering capacity
of the lung and produced embolization through the left heart and into the
Prevention of cerebral air embolism by meticulous technique
in the performance of invasive procedures and preservation of the integrity
of in-dwelling vascular access catheters is essential. However, the steady
growth in the application of percutaneous and endoscopic procedures, total
parenteral nutrition, cancer chemotherapy, hemodynamic monitoring, and other
invasive procedures will continue to provide opportunities for the accidental
injection of air. Hyperbaric oxygen therapy is based on sound physiologic
principles of compression of air bubbles and delivery of high doses of oxygen
to ischemic neurologic tissues. With an increasing number of hyperbaric
chambers in both civilian and military medical facilities, physicians should
be aware of the benefits of hyperbaric oxygen in cerebral air embolism and
pursue prompt treatment in symptomatic cases.
8. Spencer MP, Oyama Y. Pulmonary capacity for dissipation of
venous gas emboli. Aerospace Med 1971; 42:822-827.
complicating obstetric or gynecologic procedures.
Case reports and review of the literature
Gas embolism is a rare life-threatening
complication of obstetric or gynecologic
procedures, arising as a result of gas bubbles
being introduced into the circulation via
severed blood vessels. Extensive brain damage
and acute cardiovascular collapse will lead
to a fatal outcome. A favourable outcome
depends on early diagnosis and prompt treatment.
Hyperbaric oxygenation, which reduces bubble
size and increases the supply of oxygen
to hypoxic tissues, is the definitive treatment
for gas embolism. We report four cases of
gas embolism complicating obstetric or gynecologic
procedures which were treated at the Israel
Naval Medical Institute followed by an updated
review of the literature.
Background: Massive arterial air embolism is a rare but
devastating complication of cardiac operations. Several treatment modalities
have been proposed, but hyperbaric oxygen is the specific therapy. Methods:
The Israel Naval Medical Institute is the only referral hyperbaric center
in this country for acute care patients. We reviewed our experience in the
hyperbaric oxygen treatment of massive arterial air embolism during cardiac
operations. Results: Seventeen patients were treated between 1985 and 1998.
Eight patients (47.1%) experienced a complete neurologic recovery; 6 patients
(35.3%) remained unconscious at discharge, and 3 patients (17.6%) died.
When massive arterial air embolism is diagnosed during
the operation, radiologic studies of the brain provide very little information
and may cause an unnecessary delay of treatment.16 In the different situation,
at which a neurologic deficit is diagnosed the first time in the intensive
care unit, but the cause is uncertain, radiologic study will probably be
the next step. Macroemboli were found in the brain several hours17 and even
days after an embolic event.18 Delayed treatment with HBO for systemic air
embolism was reported,19 including cases of cardiac operations, 20,21 and
recovery might be achieved. Therefore HBO therapy should be given even after
a long delay. The exact limit of this delay is unknown.
In summary, HBO is the specific treatment for massive arterial air embolism
during cardiac operations. It should be administered as soon as possible
after the end of the operation.