MRI-demonstrated BBB disruption after cardiac surgery occurred in almost half the patients in our sample. The incidence of HARM was higher among patients who received gadolinium within 24 hours of surgery. Because of the short plasma distribution and elimination half-life of gadolinium (0.2 ± 0.13 hours and 1.6 ± 0.13 hours, respectively), our findings suggest that the BBB may open during or soon after heart surgery and close shortly thereafter. Animal studies show that the BBB opens soon after ischemia. In an MCA occlusion (MCAO) rat model, brain sucrose uptake, a marker of BBB disruption, increased 3 hours after reperfusion, was maximal at 48 hours, and persisted for up to 14 days.32
In another study, gadolinium enhancement of the ventricles ipsilateral to stroke was seen on FLAIR within 1 hour of reperfusion in rats subject to MCAO, suggesting that the blood-CSF barrier can be disrupted within minutes of onset of ischemia, and this enhancement increases by 24 hours. At 48 hours parenchymal enhancement on T1 was evident, suggesting a more widespread BBB opening.23
In humans with stroke HARM can be seen within the first 6 hours of symptom onset, and persists for up to 5 days.17
The clinical relevance of HARM in cardiac surgery patients is unclear, as our patients did not have evidence of neurologic or cognitive dysfunction at the time of gadolinium administration -when the integrity of the BBB was evaluated- or at the time of the MRI scan. Further studies are needed to determine if BBB disruption after heart surgery is clinically relevant and if it occurs because of focal or global ischemia, reperfusion injury, changes in the level of matrix metalloproteinases, or inflammatory mechanisms. Our findings suggest that such studies should focus on the first 24 hours after surgery.
The incidence of DWI lesions in our series is higher than previously reported.1-7
Several features of our MRI sequences may explain this higher incidence: we used thin slices to decrease partial volume averaging with normal tissue on CSF; used short echo time to decrease T2 loss; used a DTI sequence with 13-15 directions instead of a conventional DWI sequence to increase averaging and signal-to-noise; and, on the 1.5 T scanner, used a twice refocused spin echo to decreased eddy currents.
In our patients, most DWI lesions were cortical. The clinical relevance of such small DWI lesions seen after invasive procedures, however, remains unknown.33
Case studies have shown that over time some of these lesions may become invisible on 3D T1-weighted and FLAIR images, but still lead to a loss of gray matter.34
These small cortical lesions may be another pathway to cortical atrophy and may explain why some patients undergoing cardiac surgery develop cognitive impairment.
In our study, we did not find an association between HARM and DWI lesions. Cerebral ischemia and reperfusion are associated with opening of the blood brain barrier, which has been described in patients with transient symptoms without DWI lesions.18
A proposed mechanism for BBB disruption after ischemia of any duration is activation of inflammatory cascades and proteolytic enzymes.25, 3
5 The effect of ischemia on BBB disruption may be diffuse.26
HARM is not always related to the site of ischemia.17, 21
In addition, in patients undergoing cardiac surgery, the procedure activates a systemic inflammatory response and the production of immune mediators that may contribute the development of acute and chronic neurological dysfunction and disruption of the blood brain barrier, a process also seen in patients with traumatic brain injury and hemorrhagic and ischemic stroke. 36, 37
Future studies are needed to clarify the role of different immune mediators in the genesis of HARM in these patients.
The use of cardiopulmonary bypass (CPB) may lead to disruption of the BBB, perhaps on the basis of a systemic inflammatory response.9, 11
Case series suggest that neurologic complications are less when the CABG is done off-pump, but clinical trials have not confirmed this observation. 38, 39
In our series, the proportion of patients with DWI lesions and HARM was similar in patients who had an off-pump CABG as those who had an on-pump procedure (CABG or valve replacement). The reasons why patients who have an off-pump procedure have disruption of the BBB are not clear and merit further study looking at serum biomarkers of inflammation and levels of different matrix metalloproteinases.
Our study has some limitations, hence our findings are preliminary and require replication in a larger prospective study. Our sample was small, and the lack of association between HARM and DWI lesions may be a type II error rather than a definitive finding. It is possible that some of the DWI lesions were present before surgery, but only one of the nine participants who had a pre-surgical MRI had DWI lesions at baseline. Breathing high oxygen concentration may lead to CSF hyperintensity on FLAIR due to the T1 shortening effect of oxygen, a phenomenon described only in intubated patients and volunteers breathing 100% O2
, and in that case the CSF enhancement is global and severe. 40, 41
We do not have information about the use of supplemental oxygen in our patients, but we know that none was intubated or using a non-rebreather mask, so we assume that any HARM was not due to high CSF oxygen concentration. Patients were subject to a variety of surgical procedures, but because of the sample size we cannot determine whether features inherent to each surgery played an etiologic role in the development of brain changes. Finally, we do not have longitudinal follow-up data to determine the clinical implications of BBB disruption shortly after cardiac surgery.
In conclusion, almost half the patients undergoing cardiac surgery have evidence of HARM and three quarters have acute lesions on DWI after surgery, and BBB disruption is more prevalent in the first 24 hours after surgery. These findings suggest that MRI can be used as an imaging biomarker to assess therapies that may protect the BBB in patients undergoing heart surgery.