Following Cardiac Surgery
April 4-5, 2002
Mary Woodward Lasker Center,
National Institutes of Health
[Main][Abstracts][Agenda (PDF 30
David J. Madden, Ph.D.
Measurable decline in cognitive function occurs during
normal human aging even in the absence of significant disease. Research has
been particularly concerned with the identification of age-related change in
the component processes of cognitive abilities. Comparisons between younger and
older adults' performance on cognitive tasks have consistently revealed
age-related deficits in episodic (context-dependent) memory, which appears to
reflect older adults' difficulty in generating and maintaining successful
encoding and retrieval strategies. An important contributing factor appears to
be a generalized age-related slowing of virtually all stages of information
processing. Exceptions to age-related cognitive decline, however, are also
evident. Even when response speed is measured, the activation and retrieval of
semantic (context-independent) information is often comparable for younger and
older adults. Some aspects of visual selective attention are also resistant to
age-related decline. This mosaic of age-related cognitive change interacts with
health status variables in ways that are at present not well defined. Evidence
indicates that mild hypertension may lead to subtle cognitive deficits that are
more apparent for middle-aged adults than for older adults. To understand the
neurocognitive effects of cardiac surgery it will be necessary to take into
account the age of the patient, the type of cognitive ability being tested, and
health status prior to surgery.
- Craik, F. I. M., & Salthouse , T. A. (Eds.),
The handbook of aging and cognition (2nd ed.). Mahwah, NJ: Erlbaum.
- Kausler, D. H. (1991). Experimental psychology,
cognition, and human aging (2nd ed.). New York: Springer-Verlag.
COGNITIVE CHANGES AFTER CARDIAC SURGERY: STATEMENT OF
Ola Selnes, Ph.D.
Short-term cognitive changes after CABG, primarily
involving memory functions, have long been recognized. Until recently, the
long-term outcomes after CABG have received less attention. Newman and
colleagues reported a high incidence of decline from pre-surgical performance
to 5 years, with 42% of their patients performing below their baseline.
Similarly, in a cohort of CABG patients followed prospectivel for 5 years,
Selnes et al. found significant decline in multiple cognitive domains between 1
and 5 years. These observations raise the possibility that the late decline in
cognitive performance may be causally linked to events during the cardiac
surgery. We have previously hypothesized that the pathophysiology of cognitive
changes after CABG may be multifactorial, including nonspecific effect of
surgery, anesthesia, hypopefusion and microemboli. The aditional role of risk
factors or cerebrovascular disease in poducing late cognitive decline s
currently being investigated.
- Selnes OA, Royall RM, Grega MA, Borowicz LM, Jr.,
Quaskey S, McKhann GM. Cognitive changes 5 years after coronary artery bypass
grafting: is there evidence of late decline? Arch Neurol 2001;
- Selnes OA, Goldsborough MA, Borowicz LM, Enger C,
Quaskey SA, McKhann GM. Determinants of cognitive change after coronary artery
bypass surgery: a multifactorial problem. Ann Thorac Surg 1999;
PATHOLOGIC BASIS OF NEUROLOGIC SEQUELAE FOLLWING
Challa VR, M.D.
Permanent mild-to-severe intellectual and/or cognitive
dysfunction are found in 16-38% of patients following heart surgery with
cardiopulmonary bypass (CPB). Our research efforts for the past 11 years have
been directed towards explaining the pathologic basis of the neurologic damage.
We believe that evidence incriminates minute fatty microemboli as the major
source of brain injury. We have identified millions of these emboli in the
brain arterioles at autopsy in 22 patients who died after CPB. These emboli
were not found in 38 adult control brains with hypertension or leukoaraiosis or
Alzheimer's disease and no history of open-heart surgery. These 10-70 um emboli
appear as Small Capillary and Arteriolar Dilatations (SCADs) in alkaline
phosphatase-stained celloidin sections. Neuropathologists using routine
paraffin-embedded, hematoxylin-eosin stained, 5 um sections can not detect
these emboli. More recently, we demonstrated a directly proportional
relationship between the time length of CPB and the number of these emboli.
They appear to be slowly cleared in about 2 weeks or more. They are
fat-soluble, and frequently show birefringence of a particulate nature.
Elemental analysis using laser microprobe mass spectrometry (n=8) has shown
that there is increased concentration of aluminum (Al) and silicon (Si) in the
SCADs and surrounding neuropil. We found 10 times the number of SCADs in brain
arterioles (p=<.005) of dogs in which shed blood from the thoracic cavity
was returned to the circulation after filtration through a cardiotomy
reservoir. It appears that most lipid microemboli to the brain during CPB are
due to cardiotomy suction. These emboli contain Al and Si which are toxic to
neural parenchyma. We recommend that long-term multicenter studies be
undertaken to determine the residual pathologic effects of microemboli in
patients who undergo major open heart surgery. (Supported by NIH grants
NS20618, NS27500 and 1-PO1-AG05119)
- Challa VR, Lovell MA, Moody Dm, Brown WR,
Reboussion DM, Markesbery WR. Laser microprove mass spectrometric study of
Aluminum and Silicon in brain emboli related to cardiac surgery. J Neuropathol
Exp Neurol 1998:57:140-7
- Brown WR, Moody DM, Challa VR, Stump DA, and Hammon
JW: Lon-g-er duration of CPB is associate with greater numbers of cerebral
microemboli. Stroke; 2000; 31: 707-713.
SYMPOSIUM ON NEUROCOGNITIVE CHANGES FOLLOWING CARDIAC
Alison Baird, M.D., Ph.D.
Pre- and post-operative brain and vascular
imaging has an important role in the understanding of the mechanisms of brain
injury after cardiac surgery, as well as in the identification of high-risk
patients, prediction of outcome and the monitoring of therapeutic
interventions. In earlier studies of brain injury after cardiac surgery
conventional magnetic resonance imaging (MRI) and MR angiography (MRA)
sequences were used to evaluate the effect of vascular stenoses and prior
ischemic lesions on tolerance to the procedure and to study brain edema and
post-operative stroke. Other imaging approaches include: functional MRI and
positron emission tomography (PET) activation studies; serial measurements of
brain volumes; measurement of tissue perfusion, hypoxia, metabolism and novel
molecules with PET and single photon emission computed tomography (SPECT);
imaging of cerebral metabolites with MR spectroscopy. But to date, no brain
imaging method has clearly emerged that could be used as a marker of brain
injury post-cardiac surgery.
New functional sequences MRI (including
diffusion-weighted imaging [DWI}, MR perfusion imaging and MRA) have given
valuable new insights into the understanding of the pathophysiology of ischemic
stroke. These sequences are now widely available and provide high-resolution
images in a scanning time of around 20 to 30 minutes. On DWI lesions as small
as 0.5mm in diameter are detectable. Lesion volume on DWI has been used as an
outcome measure in several trials of neuroprotective agents in stroke, although
this application is somewhat controversial because of variable correlations of
lesion volumes with clinical severity. After vascular interventions such as
carotid angioplasty silent DWI lesions have been detected in up to 20% of
patients. Recently the first results using these newer functional MRI
techniques have been reported in a small series of patients with stroke and
encephalopathy after cardiac surgery. It is possible that this methodology may
also detect brain injury that leads to cognitive decline after cardiac surgery.
But this needs to be systematically studied with pre and post-operative
imaging, clearly defined neuropsychological correlations of imaging changes and
with controls. The attraction of the MRI methodology is that is widely
available, repeatable and fast to obtain, relative to other imaging methods
which are unlikely to be practical on a large scale. Imaging also has an
important role in the pre-operative imaging of the heart and aorta for
potential sources of embolism. The identification of the highest risk patients
and subsequent modification of the surgical technique could significantly
reduce the incidence of post-operative neurological complications.
- Baird AE, Dambrosia J, Janket S-J, Eichbaum Q,
Chaves C, Silver B, Barber PA, Darby D, Parsons M, Davis SM, Caplan LR, Edelman
RR, Warach S (2001). A three-item scale for the early prediction of stroke
recovery. Lancet 357: 2095-2099.
- Staroselskaya I, Chaves C, Silver B, Linfante I,
Edelman RR, Caplan L, Warach S, Baird AE (2001). Relationship between magnetic
resonance arterial patency and perfusion-diffusion mismatch in acute ischemic
stroke and its potential clinical use. Arch Neurol 58: 1069-74.
NEUROCOGNITIVE CHANGES FOLLOWING CARDIAC SURGERY
William A. Baumgartner, M.D.
Several thousand patients in the
United States undergo cardiac surgery. This entails procedures for coronary
artery disease, valvular heart disease, congenital heart disease, aortic
disease, transplantation and a variety of other combined procedures. In
evaluating coronary artery bypass surgery alone, this procedure has
demonstrated improved long-term survival compared to medical therapy for
patients with significant coronary artery disease. In addition to survival,
there is a significant improvement in the quality of life with reduction of
angina and recurrent cardiac procedures.
Neurologic injury is a significant
risk for patients undergoing cardiac surgery. The spectrum of neurologic injury
involves: stroke, (0.8%-5.2%) neurocognitive changes (30-79% at 2 weeks and
24-57% at 6 months), depression, encephalopathy, delirium, and confusion
Stroke is predominantly related to emboli from the
heart, aortic wall, its major branches to the head, or due to decreased flow
secondary to hypoperfusion of potentially compromised areas of the brain. The
mechanism for neurocognitive deficits, encephalopathy and decreased level of
consciousness however, are probably multifactorial. These can include
hypoperfusion, micro-emboli, metabolic derangements due to acid-base imbalance,
general anesthesia, and initiation of an inflammatory state. Our laboratory
investigations have suggested the role of glutamate excitotoxicity as the
mechanism of neurologic injury, especially when the technique of deep
hypothermic circulatory arrest is used.
This review will summarize the current status of
operative techniques involved in current-day cardiac surgery. These include
off-pump coronary artery bypass grafting (OPCAB), influence of a single versus
double cross clamp, use of echocardiographic imaging to detect aortic
atherosclerosis and air (specific for valve, aortic, and transplant
procedures), use of carbon dioxide in certain procedures and a brief
description of techniques specific for patients undergoing deep hypothermic
circulatory arrest for aortic disease.
Off -Pump Coronary Artery Bypass Grafting
introduction of OPCAB surgery, the scientific community has an opportunity to
study the influence of cardiopulmonary bypass as it pertains to these
neurologic sequelae. Several clinical studies have been reported and published.
These studies report a variety of findings, many contradictory with one
another. There are no consistent findings favoring one technique over the
other.(1-10) To-date, there has not been a randomized study comparing these two
operative techniques. Recently a randomized study (OPCAB vs. standard CABG) has
been proposed, designed and initiated within the Veterans Administration system
to address this question. What has been lacking in most clinical studies that
have been previously reported is an adequate control group of patients which
would control for the major operative procedure including general anesthesia
with or without the use of cardiopulmonary bypass. Potential trade off in the
OPCAB operation is a decrease in the number of coronary arteries that are
bypassed, unknown long-term patency of bypass grafts, and isolated reports of
ascending aortic dissection.(11) The incidence of neurologic injury between the
two groups is also conflicting. One recent study from the Cleveland Clinic
demonstrated a decrease in the number of bypass grafts performed in the OPCAB
group with similar mortality and stroke seen in both groups.(12) There was
however a significant reduction in encephalopathy in the OPCAB group compared
to standard coronary artery bypass grafting.
Influence of the Aortic Cross Clamp
involved in aortic cross clamping vary within institutions and from surgeon to
surgeon. The use of an aortic cross clamp is necessary for performance of
standard coronary artery bypass grafting. A partial occlusion clamp is then
applied to the ascending aorta for placement of the proximal vein graft
anastomosis. There has been an increasing use of a single aortic cross clamp
for both distal and proximal anastomoses. This adds a brief incremental period
of ischemia to the operation, but potentially results in less neurologic
injury. Like the OPCAB technique, there are few randomized studies, although
the concept intuitively seems appropriate. We have looked at the influence of a
single clamp technique at Johns Hopkins over the past couple of years. The data
is predominantly that of a single surgeon whose operative technique has not
changed during the period of study. Unfortunately, like most reported studies,
this one was not randomized. Although there was a trend towards less stroke
with the single clamp technique (1.1% versus 2.9%) this was not significant.
However, if one compared neurologic injury (stroke, encephalopathy, seizure,
delirium) there was a significant difference in incidence favoring the single
clamp technique (3.2% versus 9.6%). There have been a variety studies reported
in the literature favoring the use of a single clamp technique.
Use of Echocardiography
Use of epi-aortic
echocardiography has been advocated by Dr. Kouchoukos and associates.(13,14) He
has demonstrated the increased sensitivity of this technique over palpation
alone. This technique is fairly easy to carry out in the operating room but
does require a number of probes and machines if multiple procedures are
occurring simultaneously. Use of transesophageal echocardiography has become
very routine in the current era of cardiac surgery. Its use can detect aortic
atherosclerosis particularly in the aortic arch and descending thoracic aorta.
Unfortunately, its ability to detect atherosclerotic plaque in the ascending
aorta is limited due to inadequate visualization of the aorta in this area.
Transesophageal echocardiography has been demonstrated
to be helpful detecting air following a procedure in which the heart has been
opened.(15) This has become a fairly reliable method to "de-air." For the past
few years, we have been using a constant insufflation of carbon dioxide into
the pericardial well. In our experience this has decreased the incidence of
postoperative air as detected by transesophageal echo.
Deep Hypothermic Circulatory Arrest
particular topic will be addressed in detail by Dr. Jonas in a subsequent
session. In regards to operative technique, there are a few points to make in
regards to use of deep hypothermic circulatory arrest in adult patients. The
first is that our laboratory investigations suggest that the neurocognitive
deficits may be the result of glutamate excitoxicity and thereby could
potentially be prevented by pharmacologic intervention. To-date there has been
no drug compatible with clinical use. Diazoxide a potassium dependent ATP
channel opener, is being clinically investigated to determine its efficacy in
reducing neurologic injury associated with cardiac surgery.
In a recent report to the American Surgical
Association in April of 2001, Dr. Bavaria and his group reported on 104
consecutive patients who underwent repair of acute Type A dissection using
hypothermic circulatory arrest.(16) The overall in hospital mortality was 9%.
Only 5% developed a new CVA following repair. These outstanding results were
attributed to a number of changes made in the operative management of these
patients. These included intraoperative transesophageal echocardiography,
retrograde cerebral perfusion, hypothermic circulatory arrest established after
5 minutes of EEG silence in neuromonitored patients, after 45 minutes of
cooling in non-neuromonitored patients, and use of EEG for monitoring purposes
during the operation.
The entire area of neurocognitive changes
following cardiac surgery is influenced by the assessment of these outcomes.
Experts in this area should develop a concensus in regards to study design,
types of tests used and techniques of evaluations. There does appear to be some
long-term decline in neurocognitive function following coronary artery bypass
surgery. The clinical significance of this decline is unknown. Likewise the
causal relationship between the operation and the decline is not validated.
However, based upon these studies there is evidence suggesting that
cardiopulmonary bypass contributes to this decline. A prospective study
controlling for both general anesthesia and cardiopulmonary bypass is needed to
better define the etiology of neurologic injury.
It appears that stroke will continue to be a major
cause of morbidity and mortality in patients undergoing cardiac surgery,
irregardless of technique employed. Further refinement of specific operative
techniques such as OPCAB, anastomosis stapling techniques and the use of
sophisticated imaging techniques to detect aortic atherosclerosis will be the
thrust of investigational research in the future. Appropriate use of future
phamacologic agents may also mitigate neurologic injury.
- Hernandez F, et al. In-hospital outcomes of
off-pump versus on-pump coronary artery bypass procedures; a multi-center
experience. Presented at the Society of Thoracic Surgeons, January, 2001.
- Magee MJ, et al. The elimination of cardiopulmonary
bypass improves early survival in multivessel coronary artery bypass patients.
Presented at the Society of Thoracic Surgeons, January, 2001.
John M Murkin, M.D.
Advanced age, peripheral
vascular disease, previous stroke or carotid stenosis, and diabetes are
important patient risk predictors, while emergency surgery, complex
valve/coronary operations, and ascending aortic and/or aortic arch procedures
are surgical factors, all of which are associated with increased risk of stroke
and central nervous system (CNS) injury. Whether individual genetic
susceptibility (eg. allele Apoe4) increases risk of injury remains an
intriguing hypothesis. The use of a preoperative risk index score (eg.
Perioperative Stroke Risk Index) can be an important tool to identify patients
at greatest risk of perioperative stroke, potentially allowing interventional
strategies (eg. epiaortic scanning, neurological monitoring, selective brain
cooling) to be employed. Much work remains to be done in this area, however.
Direct epiaortic ultrasound scanning (EAS) would
increasingly appear to be the 'gold standard' for intraoperative detection of
aortic atheromatosis, and if associated with appropriate surgical
modifications, is associated with improved CNS outcomes. Alternatively,
screening with transesophageal echo (TEE) can reliably assess the descending
aorta and detection of descending atherosclerosis should trigger direct EAS.
Precisely what to do and how best to manage unexpected ascending aortic
atheromatosis remains unclear, and is an area worthy of much more study.
Similarly, optimal cannulation sites (eg. axillary vs femoral arteries vs
ascending aorta vs distal aortic arch) and type of aortic cannula (eg.
intraaortic filter, differential cerebral perfusion, flow diffusor) have not
been well studied.
As a categorical statement,
intravenous anesthetics are associated with proportionately decreased cerebral
blood flow (CBF) and cerebral metabolic rate (CMR), while inhalational
anesthetics increase or do not change CBF while decreasing CMR. While various
laboratory studies have demonstrated a cerebroprotective potential for many
anesthetic agents (eg, thiopental, propofol, isoflurane), none have reliably
demonstrated clinically effective cerebroprotection despite several clinical
trials. Overall it does not appear that anesthetic agents appreciably influence
the incidence or extent of perioperative CNS injury. Similarly, several studies
to date have investigated the cerebroprotective efficacy of calcium channel
blockers (eg. nimodipine) with no beneficial CNS effects identified.
Meta-analysis suggests that administration of serine protease inactivators is
associated with a decrease in perioperative stroke in cardiac surgical
Because cerebral emboli are felt to
account for a significant proportion of neurological deficits following CPB,
unnecessary elevations of CBF have the potential to directly increase delivery
of microgaseous and microparticulate emboli into the cerebral circulation.
During CPB principles of optimal management are thus aimed at preservation of
appropriate CBF, and maintenance of cerebral flow/metabolism coupling. CO2 is a
potent cerebral vasodilator and will directly increase CBF. This response is
maintained during hypothermia, profoundly influencing CBF and disrupting
cerebral autoregulation. This is the rationale for use of alpha-stat
pH-management which avoids cerebral hyperemia and preserves cerebral
flow/metabolism coupling rather than pH-stat management during moderate
hypothermic CPB. In several prospective randomized trials alpha-stat
pH-management has been shown to result in decreases in the incidence of
cognitive and neurological dysfunction.
In a prospective study in infants undergoing surgical
repair of congenital heart defects using deep hypothermic circulatory arrest
(DHCA), use of pH-stat strategy was associated with lower postoperative
morbidity, shorter time to first electroencephalographic activity, and
numerically fewer seizures (though not statistically significantly less),
compared with those infants managed using alpha-stat. It appears then, that in
contrast to continuous perfusion during moderate hypothermic or normothermic
CPB, reperfusion injury rather than cerebral embolization per se, may be a
greater factor in postoperative injury following DHCA. There is no similar data
in adults undergoing DHCA. In the presence of cerebral reperfusion (eg.
following DHCA), pH-stat may thus be more advantageous especially in
non-atherosclerotic patients (eg.infants), potentially because of more
homogeneous brain cooling and mitigation of calcium-related reperfusion injury.
Cerebral hypoperfusion is also
detrimental and can independently or synergistically exacerbate brain injury.
To this end, preservation of cerebral perfusion pressure (CPP) should focus not
only on elevating mean arterial pressure (MAP) but also on recognizing cerebral
venous outflow obstruction (eg. atrial cannula-mediated) via monitoring
proximal superior vena cava pressure (eg. via introducer port of pulmonary
artery catheter). Specific patient factors (eg. hypertension, age, diabetes,
carotid stenosis) may predicate a higher CPP and/or hematocrit requiring
individualized neuromonitoring (eg. EEG, NIRS).
Hyperthermia, Hyperglycemia and DHCA
factors such as rate of rewarming, cerebral hyperthermia, and hyperglycemia can
exacerbate CNS injury possibly by increasing release of various excitotoxins
(eg. glutamate), as well as producing an exponential increase in CMR and
substrate requirements. Monitoring of brain temperatures (eg. jugular bulb
and/or nasopharyngeal thermistry, as well as avoidance of CPB aortic inflow
temperatures > 37oC, can avoid cerebral hyperthermia and exacerbation of CNS
injury. Preliminary evidence suggests that maintaining lower brain temperatures
in the postoperative period may also have salutary effects on CNS injury.
During DHCA, effective brain cooling and avoidance of premature rewarming (eg.
ice packs to head) appear to be the most important interventions. Use of
electroencephalographic (EEG) monitoring, jugular bulb thermistry and jugular
O2 saturation may all be useful endpoints for optimal brain cooling. Retrograde
cerebral perfusion may have moderate additional CNS benefits, but this is
debatable and more likely a result of improved brain cooling rather than
because of metabolically effective cerebral perfusion. As discussed above,
optimal pH-management in adults during DHCA remains unclear.
Hyperglycemia is associated with increased brain
injury likely through development of intracellular lactic acidosis and
impairment of energy-dependent neuronal ion pumps Surprisingly small amounts of
intraoperative glucose, on the order of 100 g (eg. about 2 L D5W) --
particularly if administered during CPB -- have been shown to produce
significant hyperglycemia with average peak serum glucose values in the range
of 31 mmol/L (438 mg/dL). This effect is multifactorial and reflects acute
glucose intolerance in the form of insulin suppression, stress hormone-induced
gluconeogensis, and impaired glucose excretion as a consequence of enhanced
renal tubular resorption. The result is that without tight intraoperative
control of perioperative blood glucose, hyperglycemia can and does occur in
virtually all CPB patients receiving glucose-containing solutions. Aggressive
blood glucose management is associated with better CNS outcomes specifically,
and with improved patient outcomes overall (eg. wound infection, renal
failure). Avoidance of glucose in CPB prime and cardioplegic solutions, and
frequent blood glucose monitoring and aggressive management of hyperglycemia
during the perioperative period are all advocated.
Effective deairing to minimize microgaseous emboli in
the presence of open-chamber procedures is currently not clinically achievable,
though pre-closure CO2 insufflation into the ventricular chambers and
image-directed ventricular aspiration would appear to be potentially effective
INTRAOPERATIVE CEREBRAL MONITORING
The purpose of intraoperative cerebral monitoring is
to provide timely information to the surgical team regarding the status of the
brain. The definition of Atimely@ is the critical factor that determines the
usefulness of the information. Unfortunately, most monitoring modalities are
akin to fire alarms which tell you that the fire is in progress and the best
that can be achieved is to limit the damage. Current cerebral monitoring tools
provide information on a continuum from Adamage is about to happen@ to Athis is
the extent of the injury@.
The best Aneuroprotection@ is the prevention of brain
injury which begs the question of exactly what we should be monitoring. Should
we be looking for indications of acute brain insult or for the etiologic
factors that either cause or exacerbate the damage? Brain injury associated
with cardiac surgery is secondary to focal or global ischemia due to either
hypoperfusion or embolization. The extent of the injury can be affected by the
temperature of the tissue when the insult occurs, inflammatory processes, and
the type and level of anesthetic and pharmacological interventions before,
during and after the insult.
Direct intraoperative cerebral monitoring
methodology can be subdivided into three categories based upon the timeliness
and usefulness of the information: Immediately clinically relevant, technically
relevant and research relevant. If we broaden the question to Amonitoring for
neuroprotection@, then a very useful fourth category can be added and includes
monitoring for the precursors of injury. Table 1 grossly catalogues current
cerebral monitoring methods under these four headings. Clinically relevant
information directs therapeutic interventions for the patient on the suegical
the table (i.e. low SjVO2). Technically relevant information is feedback that
will improve surgical methods that will benefit future patients (i.e. changing
clamping method to reduce embolic load). Research tools provide data which will
eventually improve overall outcome (i.e. optimizing CBF). Neuroprotection
monitoring uses non-cerebral monitoring modalities to either prevent or
ameliorate brain injury in the patient on the table (i.e. filter deterioration
allowing more emboli to pass). There is considerable overlap in the
||Arterial line Embolus Detection
|Jugular Venous Bulb O2 Sats
||Arterial line temperature-rate change
and final temp
|Blood product utilization
||Retinal Fluorescein Angiography
||New MRI methods*
To protect the brain from insult during
cardiopulmonary bypass three major areas need to addressed:
- 1. Aortic manipulation. Macroemboli from the aorta
are a major cause of neurologic injury. Reduced aortic manipulation and
epiaortic scanning reduce macroemboli.
- 2. Temperature management. Emboli are delivered via
the blood. The proportion of cardiac output delivered to an autoregulated brain
is a function of temperature. Therefore the number of emboli delivered to the
brain can be reduced by manipulating temperature.
- 2a. The size of a neurologic foci is related to
temperature. The actual brain temperature at the time of the lesion affects the
size of the penumbra. Hyperthermia is to be avoided. The rate of temperature
change is also relevant. The temperature of the arterial inflow is the best
indicator of brain temperature.
- 3. The return of shed and processed blood has a
variety of negative effects. For example, the return of fatty emboli via
cardiotomy suction and increased inflammatory processes.
Protecting the brain does not necessarily mean it has
to be directly monitored. Monitoring for the conditions which may cause or
exacerbate a cerebral lesion may be more neuroprotective if the information is
used to maintain a favorable environment for the brain.
- Hammon JW, Stump DA, Kon ND, Cordell AR, Hudspeth
As, Oacks TE, Brooker RF, Rogers At, Hilbawi R, coker LH, Troost BT. Risk
Factors and solutions for the development of neurobehavorial changes after
coronary artery bypass granfting. Ann Thorac surgeon 1997; 63: 1613-1618.
- Stump DA, Brown WR, Moody DM, Rorie KD, Manuel JC,
Kon ND, Butterworth JF, Hammon JW. Microemboli and neurologic dysfunction after
cardiovascular surgery. Semin Cardiothrorac Vasc Anesth 1999; 3 (1):47-55
BLOOD BORNE AND GENERATED MICROEMBOLI
Edmunds Jr., M.D.
Cognitive defects associated with open cardiac surgery
and/or the use of extracorporeal perfusion (including circulatory and
respiratory assist applications) may be produced by ischemia, hypoxia, toxins
and apoptosis, but a leading cause is the production and circulation of
microemboli. Microemboli are defined as emboli less than 500 microns in
diameter. The major types of microemboli are gas emboli, foreign material and
emboli generated from blood elements. The cardiotomy suction system, retained
air within the heart, stopcocks and bubble oxygenators are the most important
sources of gas emboli. Inert particles in blood aspirated from the wound,
particulate matter from the perfusion circuit and emboli composed of fat and/or
denatured protein, which are largely produced in the wound and cardiotomy
suction system, are major sources of foreign microemboli. Fibrin; platelet,
leukocyte-leukocyte and leukocyte-platelet aggregates; and red cell debris
account for most microemboli produced by blood elements.
Prebypass filtration, micropore filters within
cardiotomy reservoirs, membrane oxygenators and use of arterial line filters
reduce, but do not eliminate microemboli. Pore sizes for cardiotomy filters
range from 20-40 microns and are 170 microns in arterial line filters; thus
even if 100 percent efficient (which filters are not), countless microemboli
enter and block systemic arterioles and capillaries. Pressure gradients
pre-empt smaller pore sizes.
Contact with the wound and perfusion circuit activates
five plasma protein systems and five different blood cells. As a result,
thrombin is generated and fibrin is formed despite large doses of heparin. One
consequence of platelet, neutrophil and monocyte activation is the formation of
aggregates and microparticles. Hemolysis contributes to red cell debris.
Strategies to reduce the production of microemboli
from blood elements include attempts to discover a non thrombogenic material
that can be fabricated; tissue engineering; coating or formulating biomaterials
to be less thrombogenic; and development of reversible inhibitors of selected
blood elements. "Blood anesthesia" is a useful term to describe reversible,
selective inhibition of blood elements during cardiac surgery and all
applications of extracorporeal perfusion, including the artificial heart and
temporary and destination left ventricular assist devices.
- Edmunds LH Jr, Stenach N. Blood-Surface Interface.
In Cardiopulmonary Bypass ed. By. GP Gravlee, RF Davis, M Kurusz, JR Utley.
Lippincott, Williams and Wilkins, Philadelphia, 2000, p149-66.
- Hessel EA II, Hill AG. Circuitry and Cannulation
Techniques. In Cardiopulmonary Bypass ed. By. GP Gravlee, RF Davis, M Kurusz,
JR Utley. Lippincott, Williams and Wilkins, Philadelphia, 2000, p69-104.
Richard Jonas, M.D.
This presentation will review the challenges and the
advantages of studying the neurological morbidity of cardiopulmonary bypass in
a pediatric population.
Problems in Studying Neurological Morbidity of
Cardiopulmonary Bypass in Children
The wide variability and heterogeneity of congenital
heart disease complicates the assessment in children of the neurological
morbidity of cardiopulmonary bypass. There is a wide spectrum of congenital
anomalies and within each anomaly a wide spectrum of severity. Many different
procedures are employed for correction of these anomalies.
Another important problem is the lack of uniform
testing modalities in children who are of different ages both at the time of
surgery as well as at the time of assessment. The young age at which surgery is
presently undertaken prevents subjects from acting as their own control through
pre and postoperative studies.
Recent advances in understanding of genetic
associations with congenital heart anomalies have demonstrated frequent
association of microdeletions such as 22 q 11 with conotruncal anomalies as
well as with developmental delay. Until all such genetic associations with
developmental delay are defined studies will need to include a large number of
subjects to eliminate outliers with genetically determined developmental
A wide range of equipment is applied for congenital
heart surgery as it is only a recent development that oxygenators designed
specifically for neonates and young infants have been available. Although total
priming volumes have decreased tremendously over the last 10 years there is
still a marked disparity between the blood volume of the neonate and total
circuit volume. The major changes that have occurred in equipment and
techniques over the last 10 years reduce the relevance of previous studies of
developmental outcome in pediatric patients.
Advantages of Studying Neurological Morbidity of
Cardiopulmonary Bypass in Children
Despite the problems listed above, the absence of
atherosclerotic cerebrovascular disease and micro and macroembolization of
debris mean that the pediatric patient undergoing cardiopulmonary bypass is a
useful subject to improve understanding of non embolic bypass related factors
in causation of neurological morbidity of bypass. At Children's Hospital Boston
extensive laboratory studies and randomized prospective clinical trials have
been undertaken over the last 14 years. These studies strongly suggest that the
combination of hypothermia, alkaline pH and hemodilute perfusate as well as
marginal flow rates interact in an additive fashion to importantly limit oxygen
delivery during bypass. Cognitive studies of high altitude mountaineers who
climb without oxygen have previously documented the occurrence of permanent
cognitive dysfunction secondary to hypoxia but without obvious manifestations
of brain injury.
Deep hypothermic circulatory arrest is an extreme
example of flow rate and temperature manipulation that continues to be widely
used in pediatric cardiac surgery and is also being used with increasing
frequently for adult aortic surgery. Laboratory studies strongly suggest that
use of a higher hematocrit and the pH stat strategy increase the safe duration
of hypothermic circulatory arrest and should be applied both in adults as well
as in children.
Although there are a number of proponents of
normothermic cardiopulmonary bypass there are few data available to support
this approach. At least one prospective randomized trial in adults demonstrated
a worse outcome with normothermic bypass because of a higher stroke
There are many aspects of neuroprotection of the child
undergoing cardiopulmonary bypass that need study. Both catastrophic brain
injury such as choreoathetosis and stroke as well as more subtle degrees of
cognitive decline are of enormous importance when they occur in the young
- Belling DC, Wypij D, du plessis AJ, Rappaport LA,
Riviello J, Jonas RA, Newburger JW. Development and neurologic effects of alpha
stat versus pII stat strategies for deep hypothermic cardiopulmonary bypass in
infants. J Thorac cardiovasc surg 2001; 121:374-383.
- Bellinger DC, Wypij D, Kuban KC, Rappaport LA,
Hickey PR, Wernovsky G, Jonas RA, Newburger JW. Developmental and neurological
status of children at 4 years of age after heart surgery with hypothermic
circulatory arrest or low flow. Circulation1999;100:526-532.
PERFUSION, OXYGENATION AND DYSREGULATION
S. Prough, M.D.
Because of the high incidence of neurocognitive
disorders after cardiac surgery, the integrity of cerebral blood flow and
cerebral metabolism during cardiopulmonary bypass is important. During
cardiopulmonary bypass, multiple physiologic factors are modified, including
pulsatile flow, body temperature, hematocrit, and arterial blood gases. During
the past twenty years, investigators have repeatedly studied the cerebral
circulation during cardiopulmonary bypass in experimental animals and in humans
undergoing cardiac surgery. Techniques used have included Xenon133 clearance,
the Kety-Schmidt technique, transcranial Doppler ultrasonography and jugular
venous bulb oxyhemoglobin saturation. Accumulated data support the following
generalizations: During cardiopulmonary bypass, cerebral blood flow responds as
expected to reductions in body temperature and hematocrit. During hypothermic
cardiopulmonary bypass, the cerebral metabolic rate for oxygen is reduced as
During hypothermic cardiopulmonary bypass with alpha-stat
management of PaCO2, cerebral pressure autoregulation is well maintained.
During hypothermic cardiopulmonary bypass with pH-stat management of PaCO2,
cerebral pressure autoregulation is impaired, consistent with relative
hypercarbia. Frank global cerebral ischemia is rare during cardiac surgery in
the absence of severe hypotension or cardiac arrest. Major focal episodes of
cerebral ischemia are rare during cardiac surgery. During cardiopulmonary
bypass in patients with severe cerebral vascular disease, mean arterial
pressure should be maintained at a higher level to limit the likelihood of
focal cerebral ischemia. Conditions that produce relative luxury perfusion
increase the delivery of experimental microemboli to the cerebral circulation.
Rapid rewarming after hypothermic cardiopulmonary bypass is associated with
jugular venous desaturation under certain circumstances.
- O'Dwyer C, Prough DS, Johnston WE. Determinants of
Cerebral Perfusion During Cardiopulmonary Bypass. J Cardiothoracic and Vascular
- Schell RM, Kern FH, Greeley WJ et al. Cerebral
Blood Flow and Metabolism
During Cardiopulmonary Bypass. Anesth Analg
Myron D. Ginsberg, M.D.
Hypothermia and rewarming represent major modulators
of brain metabolism in the context of cardiac surgery. Issues of particular
relevance relate to the rate and ultimate extent of rewarming, whether
(inadvertent) cerebral hyperthermia is induced during rewarming, how these
factors contribute to the production of neurocognitive or other abnormalities,
and how to arrive at optimal management parameters.
In the settings of both cerebral ischemia and
traumatic brain injury, the extent of injury is strikingly susceptible to
alterations of brain temperature, as demonstrated convincingly in experimental
as well as clinical investigations. Hypothermia is neuroprotective while
hyperthermia significantly increases the extent of damage. For example, in
patients with acute ischemic stroke, a 1oC rise in temperature doubles the odds
of poor outcome. Moreover, the susceptibility of the injured brain to
temperature-induced exacerbation of damage may persist for even days. Brain
temperature, when directly measured (or estimated, for example, by jugular
venous bulb temperature), is typically higher than core body temperature; thus,
reliance upon core temperature measurements alone may underestimate the extent
of cerebral hyperthermia. Experimentally, mild hyperthermia has been shown to
exacerbate both functional and structural neurologic injury after deep
hypothermic circulatory arrest. In astrocyte culture, mild hyperthermia after
deep hypothermia leads to increased extracellular levels of the potentially
excitotoxic neurotransmitter glutamate.
Neurocognitive changes after cardiac surgery may
involve a number of metabolic mediators. Deserving of consideration are:
oxygen-related mechanisms (e.g., primary tissue hypoxia vs. oxygen radical
production and "reperfusion injury"), the role of neutrophils in
radical-mediated injury, the release of multiple neurotransmitters and
-modulators (e.g., glutamate, glycine, GABA, adenosine), altered brain water
and ionic homeostasis, blood-brain barrier dysfunction, ischemic
depolarizations, and secondary energy failure. Each of these represents a
potential target for prophylactic neuroprotection.
- Ginsberg MD, Busto R: Combating hyperthermia in
acute stroke. A significant clinical concern. Stroke 29: 529-534, 1998.
- Shum-Tim D, Nagashima M, Shinoka T, Bucerious J,
Nollert G, Lidov HG, duPlessis A, Laussen PC, Jonas RA: Postischemic
hyperthermia exacerbates neurologic injury after deep hypothermic circulatory
arrest. J Thorac Cardiovasc Surg 116: 780-792, 1998.
NEUROCOGNITIVE DECLINE FOLLOWING CPB
Cognitive decline following cardiopulmonary bypass may
have various etiologies including focal infarction due to macroemboli, diffuse
ischemic or inflammatory injury due to microemboli, or conceivably reperfusion
effects. Risk factors for cognitive decline are similar to stroke risk factors,
suggesting that cardiovascular status contributes mechanistically to the
outcome. The composition of microemboli includes microbubbles from the bypass
circuit, lipid from scavenged blood from the surgical cavity, and
fibrin-platelet complexes. Several studies have shown that neurocognitive
decline is correlated with embolic load as determined by ultrasound monitoring,
duration on bypass, and interventions that increase overall cerebral blood
flow. But while reducing perfusion pressure or CBF can reduce emboli, it has
also been hypothesized that the impact of microemboli may be adversely affected
by reduced clearance at low flow. Preliminary perfusion MRI data obtained in
our laboratory demonstrate that despite any embolization, CBF is generally
increased postoperatively. Some of this increase may be in response to anemia,
since current practice limits transfusion and crystalloid in the bypass circuit
produces significant hemodilution. Thus, increased numbers of microemboli may
continue to be delivered to the brain, and the reduced oxygen carrying capacity
of the blood may produce hypoxia in regions at risk. The effects of an abrupt
reduction in hemoglobin concentration are also unknown. Postoperative MRI has
additionally shown brain swelling and increased water diffusion suggesting
vasogenic edema, perhaps with blood brain barrier breakdown, findings that are
atypical for acute ischemia. Suggested areas for further exploration include
the development of animal models of cognitive impairment following CPB for the
purposes of identifying the critical pathophysiological mechanisms involved,
monitoring for emboli during the postoperative period, and further elucidation
of the effects of profound anemia on oxygen delivery and cognitive function in
- Caplan, L.R., Hennerici, M., Impaired clearance of
emboli (washout) is an important link between hypoperfusion, embolism, and
ischemic stroke. Arch Neurol,1998, 55(Nov): p. 1475-1482.
- Hindmand, B.J. and Todd, M.M., Improving Neurologic
Outcome after Cardiac Surgery. Anesthesiology, 1999 90(May): 1243-7
INFLAMMATORY AND COAGULANT CASCADES IN ISCHEMIC BRAIN
David J. Pinsky, M.D.
There is increasing recognition that both short and
long-term cognitive changes occur following cardiac surgery (1). Although the
causes are likely to be multifactorial, certain prototypical features of the
cerebral microvasculature may predispose to neuronal injury in the setting of
cardiopulmonary bypass procedures. The brain is critically dependent on
continual nutritive flow of blood, and the quiescent microvasculature exhibits
a number of features which maintain blood fluidity. Procoagulant mediators,
such as tissue factor, are sequestered abluminally in the subendothelium, and
others such as vonWillebrand factor are sequestered in discrete endothelial
intracytoplasmic storage organelles. Critical endothelial transmembrane
proteins such as CD39 actively catabolize vasoactive and prothrombotic
mediators. There is scant expression of glycoprotein adhesion receptors,
ensuring smooth and nonadherent passage of circulating leukocytes. When blood
flow is interrupted, even for relatively brief periods, such as may occur with
low flow secondary to bypass or macro- or micro-emboli, the microvasculature
undergoes a major phenotypic shift, becoming prothrombotic (2) and inflamed
(3). Proinflammatory cytokines synthesized locally or within the bypass
circuitry can contribute to upregulation of adhesion receptors such as ICAM-1
and E-selectin in the cerebral microvasculature, leading to autoamplification
of inflammatory cascades, leukocyte accumulation, microvascular obstruction,
and neuronal injury. Upregulation of inflammatory cascades secondary to low
flow may be potentiated by the brisk cytokine response to cardiopulmonary
bypass (4). This is dominated by release of TNF and interleukins -6, -8, and
10, the latter of which may exert an anti-inflammatory function. Complement
activation, which is a well documented consequence of cardiopulmonary bypass,
may be particularly injurious to neurons, particularly those subjected to low
flow conditions (5). Rapid accretion of intravascular, platelet-rich thrombi
may occur in situ secondary to endothelial retraction and exposure of blood to
procoagulant subendothelial matrix, loss of critical anticoagulant molecules,
induced expression of procoagulant mediators, and suppression of endogenous
fibrinolytic cascades. The shift in the vascular phenotype at locations
downstream from the site of primary vascular occlusion likely represents a
critical feature contributing to ischemic cerebral injury. Restoration of blood
flow may not only restore nutritive flow to the region, but bring in activated
leukocytes, elicit complement activation, and promote the formation of reactive
oxygen intermediates, which can be directly injurious or which can trigger de
novo transcription of inflammatory mediators. Because the vascular phenotype is
modulated in predictable ways following cessation of intraluminal flow and the
onset of low flow represents a discrete, anticipated event in the setting of
cardiac surgery, this opens up significant possibilities for preoperative
- Newman MF, JL Kirchner, B Phillips-Bute, V Gaver,
H Grocott, RH Jones, DB Mark, JG Reves, & JA Blumenthal: Longitudinal
assessment of neurocognitive function after coronary artery bypass surgery. N.
Engl. J. Med. 344: 395-402, 2001.
- Connolly ES Jr, CJ Winfree, TA Springer, Y Naka, H
Liao, SD Yan, DM Stern, RA Solomon, J-C Gutierrez-Ramos, & DJ Pinsky:
Cerebral protection in homozygous null ICAM-1 mice after middle cerebral artery
occlusion: role of neutrophil adhesion in the pathogenesis of stroke. J. Clin.
Invest. 97:209-216, 1996.
PHARMACOLOGICAL STRATEGIES FOR NEUROPROTECTION FROM
THROMBOEMBOLIC EVENTS ASSOCIATED WITH CARDIAC INTERVENTIONS
Feuerstein, M.D., Ms.C., F.A.H.A.
Thromboembolic events leading to acute and chronic
cerebrovascular consequences are well documented after cardiac interventions.
In addition to acute brain damage (strokes), long-term cognitive deficits may
lead to dementia with chronic disability at substantial cost burden to the
individual and the health system. Strategies for prevention and treatments of
cerebrovascular events associated with cardiac interventions have not been
formulated as yet. In this review, three layers of prophylactic and therapeutic
options will be proposed. I. Effective anti-thrombotic pharmacology; II. Acute
treatment of cerebrovascular events peri-operative; III. Long term therapeutic
and reconstructive strategies to prevent and arrest vascular dementia and
The first pharmacological strategy, anti-thrombotic
agents, must include combination of anti-coagulants, ant platelet agents and
possibly fibrinolytics agents. In this respect, effective anti-coagulation with
UFH/LMWH , anti-platelet agents (ASA/clopidogrel) and tPA are currently
available. New anti-thrombotic agents such as selective thrombin (IIa) or FXa
inhibitors could become available within 3-5 years. In addition, the role of
GPIIb/IIIa antagonists as adjunct anti-thrombotic therapy during vascular
interventions supports the possibility that such agents (ReoPro=abciximab,
integrelin=eptifibatide or aggrastat-tirofiban) may be useful agents to enhance
the limited efficacy of ASA/clopidogrel anti-platelet combination.
The second pharmacological strategy, protecting the
brain tissue under distress due to acute ischemia, may include molecular
targets that are rapidly presenting toxic effects, which in the context of
neuronal distress (hypoxia/hypoglycemia) may induce death signals. Three
categories of targets carry the potential to be rapidly tried as
neuroprotective agents in the context of cardiac interventions: 1.
Excitotoxic neurotransmitters (glutamate; glycine) modulators; 2. Ion channels
(Ca+2, Na+) antagonists, and 3. oxygen radicals scavengers (ROR might be
associated with hypoxia and reoxygenation of ischemic brain tissue). These
molecular targets present immediate opportunities in the form of
pharmacological agents that have been introduced into advanced clinical
development (e.g., NMDA or glycine antagonists; ion channels blockers) for
treatment of ischemic brain injury. While such agents have failed in clinical
trials for acute ischemic stroke when treatment commenced > 6 hrs post
ictus, the elective nature of most of the cardiac interventions may allow for
treatment to start at the peri-operative time frame where the respective
antagonists can be delivered in ''real time' relative to the cerebrovascular
The third pharmacological strategy that needs to be
considered in combating cerebrovascular consequences to thromboembolic events
associated with cardiac intervention are aimed to mitigate secondary
pathophysiological consequences of brain injury as well as enhancing
regenerative and reconstructive capacities. Inflammation (1) is a major
reaction that presents itself shortly after brain ischemia or trauma.
Ant-inflammatory agents might therefore be of use to diminish secondary damage.
In this respect, highly specific and inhibitors of TNT, such as TACE inhibitors
need to be tried. Regenerative agents such as growth factors that enhance
neuronal sprouting, or factors that may induce tolerance to I jury could well
In summary, there are multitude opportunities for
pharmacological interventions aimed at preventing or circumventing
cerebrovascular consequences to thromboembolic events peri-cardiac procedures.
Several pharmacological agents are already available for clinical trials as
monotherapy or combination therapy.
- Wang X., Feuerstein GZ. Role of immune and
inflammatory mediators in CNS Injury. Drug News and Perspectives.
- King SB, Montalescot G., reducing the Risk of
Vascular Disease: Anti-Platelet Therapy in the New Millennium. Clin Cardiol 23
(Suppl VI) VI-1-VI-2, 2000.