Cerebral effects of cardiopulmonary
bypass in adults
S Singh BM FRCP FRCA
P Hutton BSc PhD MB ChB FRCA
Both prospective and retrospective studies
have examined the incidence of cerebral injury
following cardiac surgery. The typically reported
frequency of stroke varies from 1% to 6% but
pre-existing factors coupled with valve surgery
can increase this figure to 9%. Once a CVA has
occurred, the death rate rises for CABG procedures to 20% compared with a mortality for all
CABG patients of 2–4%.
The multicentre study of the Perioperative
Ischaemia Research Group classified neurological injury into type 1 (cerebral deaths, non-fatal
strokes, transient ischaemic attacks) or type 2
(new intellectual deterioration at discharge or
seizures). Of > 2000 patients undergoing CABG,
6.1% had a neurological injury (3.1% type 1, 3%
type 2). Independent predictors of type 1 injury
included proximal aortic atherosclerosis, history
of neurological disease, advancing age, hypertension and diabetes mellitus. For type 2 outcomes,
predictors included age, systolic hypertension,
excess alcohol intake and pulmonary disease. Of
the patients undergoing combined CABG and
open ventricle procedures, adverse neurological
injury occurred in 16% (8.4% type 1, 7.3% type
2). The predictors were similar to those for
CABG alone. These data have been used to
develop a stroke risk index which is able to predict an individual’s risk of stroke following
CABG surgery.
However, neurocognitive dysfunction without
focal signs has been recorded as being much
more common than the above results would suggest. Its assessment is based on tests of memory,
new learning ability, psychomotor speed, attention and concentration. Each of these tests attempt
to reflect different aspects of the cerebral cortex.
Deficits in neurocognitive function may be classified as short-term or long-term. Short-term
recoverable deficits are extremely common with
reported incidences of 10–80% at hospital
P Hutton BSc PhD MB ChB FRCA
Professor of Anaesthesia, University
Department of Anaesthesia &
Intensive Care, North 5a, Queen
Elizabeth Hospital, Edgbaston,
Birmingham B15 2TH
Tel: 0121 627 2060
Fax: 0121 627 2062
British Journal of Anaesthesia | CEPD Reviews | Volume 3 Number 4 2003
© The Board of Management and Trustees of the British Journal of Anaesthesia 2003
115
Cardiopulmonary bypass (CPB) provides both
gas exchange and organ perfusion. It allows the
heart to be stopped and cardiac surgery to proceed
under optimal conditions. Although there have
been significant refinements in technology, CPB
is not a normal physiological state. It is responsible for adverse effects on a number of organ systems including the development of coagulopathies and pulmonary, neurological, renal and
immune dysfunction.
This article concentrates on the cerebral effects
of CPB during coronary artery bypass grafting
(CABG) and valve surgery. The spectrum of
cerebral dysfunction associated with cardiac
surgery varies from well-defined cerebral death,
non-fatal cerebrovascular accidents, coma and
encephalopathy to less specific neurocognitive
dysfunction and postoperative delirium. Patients
can also develop seizures, ophthalmological
abnormalities and primitive reflexes.
Although there is an impressive literature on
the effects of CPB on cerebral function, there are
still few clear evidence-based recommendations
that can be made. Most recommendations are
based on common sense (e.g. maintaining oxygenation, avoiding severe hypotension).
Type and epidemiology of
cerebral injury
Cerebral injury following cardiac surgery
remains a significant problem. In part, this is due
to the changing characteristics of the cardiac surgical population with the percentage of patients
undergoing CPB aged > 70 years increasing 7fold over a 15-year period. Advanced age is associated with multiple co-morbidities including diabetes, hypertension, advanced aortic atherosclerosis, carotid artery stenosis and previous neurological disease. All of these factors predispose the
elderly population to a greater risk of cerebral
injury following CPB.
DOI 10.1093/bjacepd/mkg115
Key points
World-wide, thousands
of patients each year suffer cerebral morbidity
following cardiopulmonary bypass.
Hypoperfusion and
emboli are key aetiological factors.
Strong, evidence-based
recommendations to
reduce cerebral injury
are lacking.
Maintaining perfusion
pressures, normoglycaemia and careful rewarming may reduce
risk.
Pharmacological therapies to reduce cerebral
injury are being developed.
S Singh BM FRCP FRCA
Consultant in Cardiothoracic
Anaesthesia and Critical Care,
University of North Staffordshire,
Stoke-on-Trent
Cerebral effects of cardiopulmonary bypass in adults
discharge. However, these may be more related to sleep deprivation, pain and analgesic effects rather than structural brain injury.
Long-term deficits after CPB have a reported incidence of
5–20%. These may represent permanent brain injury but many are
subtle and only detected by detailed assessment. The wide variation in reported incidence reflects differences between the tests
chosen, definitions of abnormalities, timing of testing and statistical analysis. In addition, there are differences between retrospective and prospective studies. To address these problems, international consensus conferences were held in 1994 and 1997. These
have led to an agreement on the battery of tests to be used, their
timing and the definition of an abnormal result. Although deficits
are common postoperatively, it needs to be remembered that many
patients when tested pre-operatively also exhibit cognitive defects.
In summary, although the chances of having a significant longterm postoperative deficit are low, with over 800 000 patients undergoing CABG world-wide each year, thousands will suffer from postoperative cerebral morbidity. Globally, this results in substantial
social, economic and medical consequences requiring prolonged
rehabilitation. Table 1 summarises the odds ratios for various risk
factors for neurological injury and neuropsychiatric changes.
Biochemical markers of cerebral injury
Injury to the brain results in the release of biochemical substances from damaged neurones, glial and Schwann cells. A
number of chemical markers have been evaluated in CSF and
blood including neurone-specific enolase, creatine phosphokinase brain isoform and S-100β protein.
The S-100β protein is derived from glial cells. Following a cerebral insult, increased concentrations are found in CSF and blood.
In stroke, concentrations correlate with infarct volume and neurological outcome. Studies show that concentrations rise during and
after cardiac surgery. They appear to be related to a number of variables including age, bypass time, embolic load and type of cardiac
surgery (higher in intracardiac procedures). Although its presence
is associated with postoperative neurocognitive impairment, its
specificity for neurological injury has yet to be established.
However, presently, it is the most promising biochemical marker
of neural damage.
Determinants of cerebral blood flow
Cardiopulmonary bypass is not a physiological state. There is
a loss of pulsatile flow together with changes in temperature,
haematocrit (Hct), mean arterial pressure (MAP) and PaCO2.
All these factors affect CBF which, in turn, impacts on cerebral oxygen delivery.
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Table 1 Adjusted odds ratio (95% confidence intervals) for major neurological injury and neuropsychiatric changes associated with risk factors following CPB
Risk factor
Major
neurological
injury
Aortic atherosclerosis
Previous CVA
Intra-aortic balloon pump
Diabetes mellitus
Unstable angina
Hypertensive/systolic > 180 mmHg
Age per additional decade
Previous CPB
Alcohol abuse
Pre-operative arrhythmia
4.5 (2.5–8.1)
3.2 (1.7–6.2)
2.6 (1.2–5.6)
2.6 (1.5–4.6)
1.8 (1.0–3.3)
2.3 (1.2–4.5)
1.75 (1.3–2.4)
Neuro
psychiatric
changes
3.5
2.2
2.2
2.6
2.0
(1.4–8.6)
(1.6–3.0)
(1.1–4.2)
(1.3–5.5)
(1.1–3.5)
Adapted from Roach GW, Kanchuger M, Mangano CM et al.Adverse cerebral
outcomes after coronary bypass surgery. N Engl J Med 1996; 335: 1857–63
Arterial pressure
There has been conflicting evidence as to the relationship
between MAP during CPB and neurological outcome. Many
of the early studies had methodological weaknesses. Some
were retrospective, lacked a control group and there was
short-term neurological follow-up. Today, the CPB management techniques employed have changed and the patient population undergoing cardiac surgery s older with more risk factors for stroke. Thus, it may not be valid to apply conclusions
from the early studies to present circumstances.
Under normal physiology, autoregulation ensures that CBF
(approximately 50 ml min–1 per 100 g of tissue) remains relatively constant (MAP of 50–150 mmHg). Beyond these limits,
blood flow becomes pressure-dependent. Studies in the 1980s
suggested that, during moderate hypothermic CPB, there was a
left shift in the autoregulatory curve such that CBF was maintained at MAPs as low as 30 mmHg. However, more recent laboratory animal work has cast doubt on this.
In 1995, a prospective randomised study examined the effects
of different MAP on neurological and cardiac outcome. Patients
were randomised to a lower (50–60 mmHg) or higher (80–100
mmHg) MAP during hypothermic CPB and their outcomes
assessed at 6 months. The overall incidence of combined cardiac
and cerebral complications was significantly lower in the higher
pressure group (4.8% versus 12.9%; P = 0.03).There was also a
non-significant trend to lower stroke rates in the higher pressure
group (2.4% versus 7.2%), even though in this group a mean
MAP of only 70 mmHg was achieved, as opposed to the target
of 80–100 mmHg. Subsequent analysis showed that MAP of 60
mmHg was the point at which morbidity increased. It was also
British Journal of Anaesthesia | CEPD Reviews | Volume 3 Number 4 2003
Cerebral effects of cardiopulmonary bypass in adults
noted that the higher pressure was protective only in patients
with more advanced cerebrovascular disease or aortic arch disease. Additional animal work subsequently has suggested that
cerebral oxygen delivery becomes compromised at MAP < 50
mmHg.
In summary, this area remains contentious, with many units
regarding 50 mmHg as the minimum preferred level of perfusion pressure with higher pressures for those with known atherosclerotic disease.
Table 2 Summary of patient and procedural factors affecting neurological
outcome after CPB
Patient factors
Procedural factors
Age
Male sex
Existing poor ventricular function
Intercavity thrombus
Diabetes mellitus
Previous CVA
Carotid stenosis
Severe atherosclerosis
Genetic factors
Macro-embolism
Micro-embolism
Valve surgery
Cerebral hypoperfusion
Long CPB time
Hyperglycaemia
Poor temperature control
Systemic inflammatory response
Carbon dioxide
Under normal circumstances, PaCO2 is an important determinant
of CBF. A rise in PaCO2 results in an increase in CSF hydrogen ion
concentration which, in turn, leads to cerebral vasodilatation with
a resultant increase in CBF. Conversely, hypocapnia results in
cerebral vasoconstriction and, if sufficiently profound, cerebral
ischaemia may develop. A reduction in PaCO2 from 5 kPa to 4.3
kPa results in a 30% reduction in CBF. Most studies indicate that
CO2 reactivity is preserved during CPB, implying that it is important to maintain CO2 haemostasis.
Temperature and haematocrit
In health, CBF autoregulates oxygen delivery to match cerebral
oxygen demand (approximately 3 ml min–1 per 100 g of tissue at
37°C) in a process known as flow-metabolism coupling. The
most important determinant of cerebral oxygen demand is temperature. A fall in temperature from 37°C to 27°C results in
> 50% decrease in cerebral metabolic rate together with a proportional decrease in CBF. However, greater decreases in temperature have more complex effects on CBF, some of which are
mediated by viscosity changes. Below 22°C, CBF and metabolism uncouple due to cerebral vasoparesis.
Haematocrit is an important determinant of blood viscosity.
The decrease in Hct associated with the haemodilution of CPB
results in decreased vascular resistance and an increase in CBF.
However, with progressive haemodilution, a point is reached
(critical Hct) where cerebral oxygen delivery is inadequate to
meet cerebral oxygen demand. This is also dependent on temperature which controls the metabolic rate. The critical Hct for different temperatures has been investigated in animal studies. In
dogs undergoing CPB at 38°C, 28°C and 18°C the minimum Hct
was found to be 19%, 15% and 11%, respectively.
Mechanisms and prevention of cerebral injury
The major final common pathways of permanent cerebral injury
associated with CPB are embolisation and cerebral hypoperfusion
which result in localised or generalised inadequate cerebral oxygen delivery. It is also becoming recognised that the inflammatory effects of CPB and genetic factors may also have an aetiological role. A summary of procedure and patient related factors is
given in Table 2.
Anti-coagulation and pump technology
Effective anticoagulation is essential to prevent embolisation in the
bypass circuit. Standard therapy is heparin 300 units kg–1 to
achieve a target ACT > 400 sec. Patients who have heparin resistance, often due to antithrombin III deficiency, will require additional doses of heparin in the first instance. However, if
600 units kg–1 fail to raise the ACT > 400 sec, then antithrombin III
concentrate or FFP will be required to achieve adequate anticoagulation. For those receiving aprotinin, current practice is to raise the
celite-ACT > 750 sec (or kaolin-ACT > 500 sec). Patients should
be fully heparinised before joining the CPB circuit and pump suction should be discontinued before protamine is administered.
The universal use of membrane oxygenators and high quality
arterial filters has greatly reduced the micro-embolic load and,
therefore, neurological morbidity. The type of CPB pump also
has an impact on postoperative cerebral function. The roller
pump is used most commonly. It is very reliable but causes cell
damage and spallation. Spallation is the release of plastic
microparticles from the inner wall of the CPB tubing which can
then enter the systemic circulation and cause micro-embolisation.
Spallation does not occur with centrifugal pumps and some
recent studies have suggested that they cause significantly fewer
micro-emboli and neurological complications.
Standard CPB produces non-pulsatile flow. Pulsatile flow is
possible, although technically more complex and expensive to
achieve. The majority of studies have not shown improvements
in clinical outcome with pulsatile perfusion. Therefore, non-pulsatile perfusion remains the standard for CPB with typical flow
rates of 2.0–2.4 litre min–1 m–2.
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Cerebral effects of cardiopulmonary bypass in adults
Embolisation and operative procedure
Embolisation has been demonstrated to occur in vivo by transcranial Doppler echocardiography and retinal fluorescein angiography
and also in vitro by histological examination of the brain following
cardiac surgery. Macroscopic emboli obstruct flow in larger blood
vessels and tend to cause focal injury whereas microscopic emboli
tend to cause more diffuse injury, the severity of which is related to
the embolic load.
One of the most important sources of emboli is atheroma of the
proximal aorta; its presence has been repeatedly correlated with
stroke. Although this atheroma may be detected by palpation,
detection rates are improved by the use of transoesophageal and
epi-aortic ultrasound. Detection of significant localised atheromas
should modify sites of aortic cannulation, placement of the cross
clamp and proximal bypass graft anastomoses. Management of the
severely or diffusely diseased aorta is more controversial. It may
involve femoral bypass return together with the avoidance of crossclamping and the use of fibrillatory cardiac arrest and profound
hypothermia.
Other sources of emboli include air, foreign material, cellular
aggregates, fat, calcium and other debris. Valve operations which
involve opening the chambers of the heart carry a much greater
embolic risk from particles and air (despite meticulous de-airing of
the ventricular chambers). Emboli may enter the systemic circulation during aortic cannulation, removal of the cross clamp and separation from CPB. The aggressive use of the pump sucker can significantly increase the number of emboli.
Prolonged duration of CPB appears to be associated with poorer
neurological outcome, especially if > 2 h. This may be due to an
increased embolic load to the brain or reflect the complexity of the
surgical procedure which carries a greater risk of macro-embolisation.
Off-pump or beating heart CABG surgery has developed over
the last few years to avoid the cerebral and other complications of
CPB. It is estimated that 20% of CABG operations in the US are
now performed as off-pump procedures. Using this technique,
there is a substantial reduction in cerebral emboli together with
lower concentrations of the S-100β protein. Recent randomised
control trials comparing off- to on-pump CABG surgery suggest
less neurocognitive dysfunction with the off-pump technique.
Temperature
Hypothermia has been utilised for neurological and myocardial
protection in cardiac surgery for many decades. As described earlier, a reduction in temperature decreases the cerebral oxygen
demand, inhibits the release of excitatory neurotransmitters such as
glutamate and attenuates the depletion of adenosine triphosphate.
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Several studies have compared hypothermic and normothermic
bypass with respect to neurological outcomes. Although there has
been conflicting evidence, it appears that strict adherence to normothermia may increase neurological risk whereas mild hypothermia (nasopharyngeal temperature 33–35°C) does not.
Hyperthermia is a risk with re-warming because temperature
probes may underestimate cellular brain temperature. Even 2°C of
hyperthermia can have a significant adverse effect on neuronal
function. Rapid re-warming can lead to gases coming out of solution and jugular venous desaturation. It is clear, therefore, that rewarming needs to be done carefully and gradually with avoidance
of hyperthermia. During re-warming, the patient should be perfused with a blood temperature at or < 37°C and a maximal gradient of 7°C between the bypass heat exchanger and patient’s
nasopharyngeal temperature. This is essential to produce even temperature gradients throughout the brain and minimise bubble formation following gas exchange.
Associated medical conditions
Despite a lack of definitive evidence, common sense would suggest that hypoperfusion may be related to inadequate perfusion
pressures, especially in patients with diabetes, hypertension and
significant carotid stenosis. Hypertension and diabetes occurs in
55% and 25% of cardiac surgery patients, respectively; both are
important risk factors for cerebral injury in the general population
and those undergoing cardiac surgery. Both conditions result in the
narrowing of cerebral arteries with a reduction in the ischaemic tolerance of neuronal tissue. Long-term diabetics can also have
altered autoregulation of CBF.
Despite best efforts, perfusion pressure sometimes falls to < 50
mmHg during CPB. This, along with altered autoregulation and
narrowing of vessels, predisposes patients with hypertension,
diabetes and carotid stenosis to hypoperfusion and cerebral
ischaemia. Areas of the brain that are most susceptible are the
border zones between the territories supplied by the three main
cerebral arteries thus producing the so-called watershed infarction which is most common in the parieto-occipital region.
Hyperglycaemia is also associated with a worse neurological
outcome in animal and human studies of cerebral ischaemia and
infarction. This is related to the increased intracellular acidosis
due to anaerobic metabolism. Therefore, due to the risk of cerebral ischaemia during CPB, it seems prudent to maintain normoglycaemia intra-operatively.
Acid–base management
The two strategies for acid-base management are alpha-stat and
pH-stat. In alpha-stat management, no correction is made for the
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Cerebral effects of cardiopulmonary bypass in adults
patient’s temperature. With pH-stat management, temperature-corrected data are used and normocapnia is maintained during hypothermia by the addition of CO2. In adults undergoing moderate hypothermia, it appears that alpha-stat has better neurological outcomes
because autoregulation is better maintained; there is less cerebral
hyperaemia and this reduces the embolic load to the brain. In children, the athero-embolic mechanism for cerebral injury does not
apply. They frequently undergo deep hypothermic circulatory arrest
(DHCA). In these circumstances, pH-stat management may lead to
a better neurological outcome due to improved brain cooling, better
oxygen delivery due to a greater blood flow and a ight shift of the
oxyhaemoglobin dissociation curve, and less reperfusion injury. The
most appropriate strategy for adults undergoing DHCA has not yet
been established.
Inflammation
It is well known that CPB produces a whole-body inflammatory
response which can lead to multi-organ injury. The inflammatory
response involves activation of the both the humoral and cellular
components of blood. There is activation of the complement, fibrinolytic, coagulation and kallikrein systems. Humoral activation
causes activation of the vascular endothelium which results in the
expression of adhesion molecules. This promotes adhesion and
aggregation of neutrophils to the endothelium and their subsequent
activation. Neutrophil degranulation results in the release of proteolytic enzymes, cytokines and oxygen free radicals which lead to
direct cellular damage with disruption of normal membrane physiology, increased capillary permeability and interstitial fluid accumulation. There may also be capillary obstruction due to neutrophil
and platelet aggregation leading to local ischaemia. This systemic
inflammatory response syndrome following bypass is known to
cause pulmonary, renal and coagulation abnormalities. It is possible that it may also be partly responsible for cerebral dysfunction.
Genetic factors
There is evidence that some patients undergoing cardiac surgery
may have a genetic predisposition to neurocognitive dysfunction
following CPB. Possession of apolipoprotein E-ε4 allele is known
to be a genetic marker for late onset Alzheimer’s disease and is
associated with a worse outcome following head injury and subarachnoid haemorrhage.
Astudy of patients undergoing CPB, multivariate linear regression
analysis demonstrated a significant association between the apolipoprotein E-ε4 allele and cognitive dysfunction at hospital discharge
and 6 weeks after surgery. It is hypothesised that these patients have
impaired neuronal mechanisms of maintenance and repair.
Pharmacological interventions
Many drugs have been evaluated as neuroprotective agents in cardiac surgery. It has been hypothesised that drugs that reduce the
cerebral metabolic rate and, therefore, oxygen demand may provide cerebral protection. In this context, thiopentone, propofol and
other anaesthetic agents have been investigated but none were
found to reduce neurological morbidity.
Following cerebral ischaemia, there is a sequence of metabolic
events that can lead to neuronal destruction. For example, there is
an excessive release of glutamate which binds to N-methyl Daspartate (NMDA) receptors. This results in the opening of ligandgated ion channels which permit the intracellular entry and accumulation of calcium. This leads to the activation of proteases, lipases and nucleases that cause intracellular damage and death. Drugs
that interrupt these destructive pathways may, therefore, provide a
degree of neuroprotection. Remacemide (NMDA receptor antagonist) has been evaluated in a double-blind randomised study of
patients undergoing CABG surgery. It was shown to produce a
small, but statistically significant, improvement in neuropsychological outcome. A double-blind randomised trial of nimodipine
(calcium channel blocker) in patients undergoing valve replacement failed to show any neurocognitive benefits up to 6 months
after surgery.
Other therapeutic agents that may be able to inhibit ischaemic
pathways are being developed. These include neuronal nitric
oxide synthase inhibitors and monoclonal antibodies to the
adhesion molecules mediating neutrophil–endothelium binding.
Key references
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Gravlee GP, Davis RF, Kurusz M, Utley JR. (eds) Cardiopulmonary Bypass:
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Hogue CW, Sundt TM, Goldberg M, Barner H, Dávila-Román VG. Neurological
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Newman SP, Harrison MJG. (eds) The Brain and Cardiac Surgery: Causes of
Neurological Complications and their Prevention.Amsterdam: Harwood, 2000
Roach GW,Kanchuger M,Mangano CM et al.Adverse cerebral outcomes after
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Selnes OA, Goldsborough MA, Borowicz LM, McKhann GM. Neurobehavioural sequelae of cardiopulmonary bypass. Lancet 1999; 353: 1601–06
Tardiff BE, Newman MF, Saunders AM et al. Preliminary report of a genetic basis
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See multiple choice questions 85–87.
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