Cerebral hyperperfusion syndrome (CHS) is a complication that occurs after carotid endarteretomy (CEA) or carotid artery angioplasty and stent placement (CAS). The clinical manifestations include frontotemporal and periorbital throbbing headache (sometimes diffuse); oculofacial pain; nausea, vomiting, impaired consciousness, cerebral edema, and visual impairment; epilepsy; neurological impairment; and intracranial or subretinal hemorrhage. The diagnosis of CHS is mainly based on non-specific symptoms and signs, and in clinical work, it is easily misdiagnosed as a common complication before and after carotid surgery, such as cerebrovascular embolism and thrombosis. This paper presents a review of the etiology, pathophysiology, diagnosis and treatment of CHS.
1.Epidemiology
Most patients will experience an asymptomatic increase in ipsilateral cerebral blood flow (20-40% above the basal value) after CEA, which usually lasts for several hours. In some patients, the postoperative cerebral blood flow exceeds basal values by 100-200%, and this increase often peaks 3-4 days after surgery and decreases to a stable state 6-7 days after surgery, sometimes lasting 1-2 weeks. CHS can occur on any day within 4 weeks after CEA, and most studies report that it occurs within a few hours to a few days after the procedure, with the incidence varying widely depending on the study sample size, patient enrollment, and diagnostic criteria, ranging from 0.2% -18.9%. -18.9%.
2. Normal intracranial vasoregulation
Under normal conditions, when the body circulating blood pressure is between 60-160 mmHg, the brain relies on carbon dioxide and self-regulation to maintain the blood supply. Carbon dioxide mainly regulates small arteries (0.5-1.0mm), and has no significant effect on vessels larger than 2.5mm in diameter. Self-regulation of the cerebral vasculature includes both myogenic and neurogenic regulation. The role of myogenic regulation is to control cerebral blood flow by depolarizing smooth muscle cells to constrict the vasculature when blood pressure rises and intravascular pressure increases. When blood pressure rises beyond the range of myogenic regulation, vascular self-regulation relies mainly on sympathetic autonomic nerves distributed in the epicardium. Sympathetic nerves constrict blood vessels when blood pressure rises, producing neurogenic regulation, and this vascular regulation produced by the corresponding innervated nerves is called vascular neurocoupling. The sympathetic nerve distribution in the vertebrobasilar system is relatively sparse, and sympathetic protection is relatively weak, so CHS is more likely to occur than in other areas.
3.Pathophysiology of CHS
Three mechanisms may play a role in the development of hyperperfusion and CHS.
(1) Impaired cerebrovascular self-regulation, which cannot counteract the increase in cerebral blood flow after CEA
This theory is supported by the fact that those with reduced cerebrovascular reactivity and decreased reserve function are prone to CHS. In these patients, the average blood flow velocity of the ipsilateral middle cerebral artery is pressure-dependent after CEA and cannot effectively counteract the fluctuation of blood pressure. Reducing the pressure of the body circulation can normalize the blood flow velocity of the middle cerebral artery, reduce cerebral blood flow, and patients’ symptoms can often be relieved. A variety of factors lead to imbalance in the self-regulatory mechanism of the cerebral vasculature. (1) The preoperative hypoperfusion region has a reduced cerebrovascular self-regulatory capacity, and carotid artery blockade during CEA further aggravates the impairment of cerebrovascular self-regulatory capacity. (ii) The endothelial function of the cerebral vasculature was impaired preoperatively. Experimental damage to the carotid endothelium reduces or even causes complete derangement of myogenic self-regulatory function. Carotid stenosis is often associated with concomitant diseases such as hypertension and diabetes mellitus, and vascular endothelial damage caused by hypertension or diabetes mellitus is often accompanied by varying degrees of regulatory dysfunction. NO is an important cardiovascular chemical mediator that causes increased vasodilation and permeability in the cerebral vasculature, leading to impaired vascular self-regulation and involvement in CHS. ④Oxygen radicals. a short carotid artery block during CEA generates a large amount of oxygen radicals. Current studies have demonstrated that these free radicals can damage endothelial cells, cause vascular self-regulatory dysfunction, and promote the occurrence of CHS. Clinical studies have confirmed that the application of free radical scavengers can reduce the risk of developing hyperperfusion after surgery. ⑤ Another possible risk factor is the pH value. Improper acid-base handling during vascular surgery often promotes the occurrence of hyperperfusion, indicating the presence of factors that lead to imbalance of vascular self-regulation. Studies have confirmed that elevated postoperative carbon dioxide concentrations impair vascular self-regulation and further aggravate hyperperfusion.
(2) Impaired pressure perception reflex
Under normal conditions, the pressure-sensing reflex acts as a buffer against rapid changes in arterial pressure in the circulation, but local nerve destruction after CEA results in impaired pressure-sensing reflexes, which cannot effectively counteract the increase in blood pressure in the circulation, leading to an increased blood supply to the brain.
(3) Trigeminal vascular reflex disorder
Under normal conditions, the trigeminal vascular reflex system has a cerebral protective effect, which restores blood vessels to normal tone after stimulation with vasoconstrictor substances; it is involved in regulating the release of vasoactive substances that lead to increased cerebral perfusion, and its above-mentioned effects are inhibited after trigeminal ganglion resection.
4.Pathology
After the onset of CHS, a large amount of fluid leaks out into the stellate cells and interstitium surrounding the capillaries. To prevent intracranial hemorrhage, cell permeability increases and fluid is exchanged inside and outside the cells by cytocytosis. This edema eventually leads to a balance of intra- and extracellular hydrostatic pressure, and the lesions are most pronounced in the less sympathetic distribution of the vertebrobasilar system. autopsy findings in CHS patients are similar to those in malignant hypertensive encephalopathy, including edema and hyperplasia of endothelial cells, extravasation of red blood cells, and fibrin necrosis.
5. Risk factors for CHS
A variety of factors contribute to the development of CHS. Reduced cerebrovascular functional reserve, postoperative hypertension, and hyperperfusion are the most important risk factors. Patients with decreased cerebral blood flow and cerebral reserve function before surgery are more likely to experience prolonged hyperperfusion after surgery. Blood pressure control is a core component of the prevention and treatment of CHS.
6. Imaging and functional examinations of CHS.
CT, MRI and transcranial Doppler (TCD) are the most frequently used imaging methods. Other methods include single photon emission computerized tomography (SPECT) and PET, and electroencephalogram (EEG) is more commonly used to determine the patient’s responsiveness to ischemia during carotid surgery, but is of little significance for the diagnosis of CHS.
(1) CT
CT is of limited value in the preoperative examination of carotid surgery, as it cannot detect all risk factors for CHS. early after the onset of CHS, when SPECT has suggested the presence of hyperperfusion, routine cranial CT may show no abnormalities. after the onset of CHS CT generally shows diffuse or patchy white matter edema; occupying effects; and varying degrees of ipsilateral hemorrhage on CEA. Because the sympathetic distribution of the vertebrobasilar system is more sparse and relatively less resistant to CHS, the white matter edema is most pronounced at the top of the occipital region of the posterior circulatory system.
(2) MRI
For ischemic lesions, MRI is far more sensitive than CT, while MRA can evaluate intracranial and extracranial vessels noninvasively, therefore, MRI is suitable for preoperative detection of risk factors for CHS. abnormal manifestations of MRI include white matter edema; focal infarction; and limited or extensive hemorrhage. New MRI techniques can be applied to detect cerebrovascular reactivity, such as dynamic magnetization rate enhancement MRI and perfusion-weighted MRI. diffusion-weighted MRI is more sensitive than conventional MRI for the detection of ischemic lesions based on the difference in the diffusion rate of water molecules. In one study, diffusion-weighted and perfusion-weighted MRI were performed in four patients who developed symptoms after CEA. Diffusion-weighted MRI showed no abnormal findings, whereas perfusion-weighted MRI showed a difference in blood flow between the bilateral cerebral hemispheres. Perfusion-weighted scans are not a quantitative test and cannot calculate the absolute value of the difference in blood flow between the cerebral hemispheres.
(3) TCD
TCD uses a specific probe to measure the blood flow velocity in the middle cerebral artery. TCD can show direct and real-time information about middle cerebral artery blood flow, and it can be used to obtain information about the presence of preoperative hypoperfusion, cerebrovascular reactivity, and the occurrence of postoperative hyperperfusion and arterial embolism. In patients who have developed CHS, TCD typically shows a 150-300% increase in ipsilateral middle cerebral artery flow velocity, with correction of hyperperfusion and subsequent improvement in clinical symptoms following a decrease in blood pressure. In addition to measuring middle cerebral artery flow velocity, TCD also measures the resistance index (RI) [Pourcelot′s index RI = (maximum systolic flow velocity – minimum diastolic velocity)/maximum systolic flow velocity] and the pulsatility A decrease in PI represents an increase in diastolic flow and a decrease in vascular resistance, while a decrease in RI means a decrease in distal vascular resistance. Ogsawara et al. reported that increased peak flow velocity and pulsatility after CEA clamp release was a good predictor of sustained hyperperfusion in the postoperative period. The sensitivity and specificity of TCD combined with SPECT for the diagnosis of hyperperfusion was 100%. However, up to 10% of patients cannot complete TCD because of the lack of adequate bone windows, and the results also have a certain false-negative rate. However, TCD is the most convenient to use and can be used for preoperative, intraoperative, and postoperative testing.
(4) EEG
EEG is widely used to assess the response of the brain after carotid artery block during CEA to determine whether a diverter tube is needed. after CEA, in patients who develop reperfusion epilepsy, EEG can show normal waveforms or diffuse waveform slowing. in patients with CHS, even in the absence of epilepsy or after the end of epilepsy, EEG can still show unidirectional epileptiform discharges that indicate the presence of local brain EEG is not very helpful in identifying the presence of CHS.
(5) PET
O15-labeled H20 PET can be used to assess the presence of hypoperfusion before CEA or hyperperfusion after CEA, and PET can assess blood flow, metabolism, and edema with good accuracy, but there are not enough studies to clarify the relationship between hyperperfusion and CHS confirmed by PET.
(6) SPECT
SPECT can be used to detect the reserve function of cerebral blood flow before surgery and the presence of hyperperfusion after surgery. there is a high correlation between the high uptake of brain tissue in SPECT and the abnormal findings in postoperative CT scans. when other tests cannot distinguish whether the symptoms are caused by ischemia or hyperperfusion, SPECT can help in the differential diagnosis. with the progress of imaging and analysis techniques, the differential ability of SPECT will With the progress of imaging and analysis technology, the discriminatory ability of SPECT will be further improved.
(7) Transcranial local oxygen saturation monitoring
When the oxygen consumption of the brain and the oxygen saturation of the body circulation are stable, an increase in the local oxygen saturation of the brain indicates an increase in cerebral blood flow. Cerebral blood flow can be measured by NIR spectroscopy. Recent studies have reported an extremely strong linear relationship between increased local oxygen saturation of the brain and increased cerebral blood flow after CEA. Using SPECT results as a standard, the sensitivity and specificity of transcranial local cerebral saturation for detecting hyperperfusion is 100%.
(8) Ocular inflation volume tracing method
Ophthalmic artery blood flow is a good indicator to understand cerebral artery blood flow. Ocular inflation volume tracing is simple and easy to perform. Clinical studies have confirmed that if the ophthalmic artery blood flow increases by more than 204% after CEA, the risk of CHS is high.
(9) Contrast-enhanced transcranial real-time color ultrasound
A study used contrast-enhanced transcranial real-time color ultrasound to diagnose the presence of hyperperfusion after CEA and to predict the occurrence of CHS. the experimental results showed that the sensitivity of the mean middle cerebral artery flow velocity/preoperative value ≥1.5 at 4 days after surgery was 100% and the specificity was 84% for the diagnosis of CHS.
7.Prevention of CHS
Prevention of CHS includes choosing the appropriate time of surgery, type of anesthesia and anesthetic drugs, controlling hypertension and pre-giving oxygen free radicals.
(1) Selection of the time of surgery
If surgery is performed within a short period of time (within 3 to 4 weeks) after an infarction, there is a higher risk of postoperative hemorrhage from foci of cerebral softening due to hyperperfusion, especially in large or progressive infarcts. However, a recent analysis of data from the European Carotid Surgery Trial and the North American Symptomatic Carotid Surgery Trial showed that the greatest benefit from CEA was obtained for patients with stable neurological symptoms when performed within 2 weeks of an ischemic event. This contradicts the theory of bleeding due to increased hyperperfusion with surgery within two weeks. Recent (within 3 months) contralateral carotid CEA has also been reported to increase the risk of CHS, so a history of contralateral surgery is also a consideration in the timing of the procedure.
(2) Type of anesthesia
The current randomized trials have not fully confirmed whether CHS is more likely to occur after CEA under local or general anesthesia, and some trials have shown significantly higher flow velocities in the middle cerebral artery after blocking clamp release in the local anesthesia group than in the general anesthesia group. Whether this phenomenon means that the ipsilateral circulation is better protected, better tolerated, or more susceptible to CHS remains unclear from the available studies. During general anesthesia, different anesthetic drugs have different effects on cerebral blood flow and self-regulation, and the appropriate anesthetic drug and dose should be carefully selected. High doses of volatile halogenated anesthetics may contribute to the development of CHS. Isoflurane is a volatile anesthetic with less vasodilatory effects at doses that achieve the same anesthetic effect and is therefore the anesthetic of choice for neurosurgical procedures. The effects of isoflurane on cerebral metabolism and self-regulation are dose-dependent and also affect cerebrovascular self-regulation at high doses. N2O has minimal effects on cerebral blood flow, intracranial pressure, and cerebral blood volume, and N2O at concentrations below 70% has little effect on cerebrovascular self-regulation. However, NO in combination with volatile anesthetics such as isoflurane can cause cerebral vasodilation, an effect that is enhanced with increasing concentrations of isoflurane. Isoproterenol is routinely used in patients who have developed CHS, and it may have some effect on cerebral metabolism, thus restoring blood flow to the brain in a normal direction. At the same time, isoproterenol counteracts the increase in blood pressure caused by catecholamines and does not affect cerebrovascular autoregulation and vasoactivity to carbon dioxide.
(3) Blood pressure control
Preoperative blood pressure control is important for the prevention of CHS. Some drugs increase blood flow in the cerebral circulation while decreasing pressure in the body circulation, and some drugs have little effect on blood flow in the cerebral circulation. The choice of drug is significant for postoperative blood pressure control (see Treatment of CHS). For those with well-controlled preoperative blood pressure, there are no studies showing the need to switch from previous medications to those that have no effect on cerebral blood flow.
(4) Pre-administration of free radical scavengers
Free radicals generated during CNS reperfusion can cause post-ischemic hyperperfusion. Edaravone inhibits lipid epoxidation process and vascular endothelial damage, improves cerebral edema and tissue damage. Recent studies have shown that edaravone (60 mg added to 100 ml saline intravenously) given 30 minutes before carotid artery block can reduce the incidence of post-operative hyperperfusion after CEA.
8.Treatment of CHS
(1) Lowering the blood pressure of body circulation
①Drug selection
Patients with CHS have blood pressure-dependent cerebral blood flow, and CHS symptoms can be relieved immediately after blood pressure in the body circulation is lowered. Theoretically, antihypertensive drugs that have no direct effect on cerebral blood flow or can start cerebral vasoconstriction are beneficial for CHS. Clinically used antihypertensive drugs, such as direct vasodilators (represented by sodium nitroprusside and nitroglycerin) and calcium blockers are not suitable for patients with CHS. Angiotensin II converting enzyme inhibitors and blockers increase cerebral perfusion. Studies have shown that chronic cardiac insufficiency with long-term captopril use increases cerebral blood flow despite a decrease in mean arterial pressure, making ACEI and ARB drugs unsuitable for CHS patients. β-receptor antagonists reduce arterial pressure and have little effect on intracranial pressure within the range of cerebrovascular self-regulation. α1β-receptor antagonist labetalol has no direct effect on cerebral blood flow and reduces cerebral perfusion pressure The α1β receptor antagonist labetalol has no direct effect on cerebral blood flow, reduces cerebral perfusion pressure and mean arterial pressure by approximately 30%, and is effective in CHS. The α2 receptor antagonist colistin agonizes α2 adrenoceptors in the postsynaptic membrane of the delayed brain, resulting in reduced central sympathetic impulse efference and reduced peripheral vascular resistance, and also activates peripheral vascular α2 receptors, resulting in reduced catecholamine release, thus reducing blood pressure heart rate and cardiac output. It can be used after CEA. Preservation of brainstem sensitivity to pressure receptor control is another feature of colistin.
In the treatment of CHS, labetalol and colistin are the more appropriate drugs, while other antihypertensive drugs may aggravate the symptoms.
②Timing of treatment
Blood pressure should be strictly controlled until the self-regulation of the brain is fully restored. The recovery time of the brain’s self-regulatory mechanism varies from person to person, and it is difficult to determine how long the treatment should be. Some experts recommend treatment for up to 6 months after surgery. Some use equal Doppler flow signals in both intracranial hemispheres as a criterion for the end of treatment. Most experts believe that TCD is appropriate for follow-up after hyperperfusion.
(2) Local nerve block
According to the hypothesis of the role of trigeminal vascular reflex pathway in the occurrence of CHS, local application of anesthetics for neuromuscular blockade can be an attempt for CHS treatment, but the effect remains to be observed.
(3) Treatment of cerebral edema
Treatment of cerebral edema includes the application of sedative drugs, short periods of transitional ventilation, treatment of hyperthermia, application of mannitol, hypertonic saline and barbiturates. Although the effect of these drugs on the treatment of simple cerebral edema is positive, there is a lack of sufficient studies to show that these drugs are beneficial for CHS, and glucocorticoids may be helpful in the treatment of CHS.
(4) Anticonvulsant therapy
Current treatment studies do not recommend the routine prophylactic application of anticonvulsants. Some scholars recommend the prophylactic application of anticonvulsants when periodic unilateral epileptiform discharges are present on the EEG. Prophylactic application is indicated when patients present with unilateral headache and focal neurological deficits due to CHS. Anticonvulsants must be given when there is a definite seizure.
(5) Anticoagulation and antiplatelet drugs
In case of seizures after CEA, all kinds of anticoagulants should be discontinued. To prevent other cardiovascular complications, antiplatelet drugs should continue to be used.
9.Prognosis of CHS
The prognosis is related to whether the diagnosis and treatment are timely and accurate. Some studies have shown that most patients recover completely (possibly related to earlier diagnosis and treatment); some studies have shown that 30% of patients with CHS (severe CHS or late diagnosis) do not recover completely and have residual neurological symptoms; some studies have even reported mortality rates as high as 50%. Although the incidence of intracranial hemorrhage is low, when it does occur, the consequences are often severe.
CHS is a unique postoperative complication of carotid surgery, and with the widespread availability of conventional and interventional carotid procedures, the number of postoperative CHS cases will gradually increase.