Neurological damage due to coagulation and fat release during cardiopulmonary bypass

Introduction

Cardiac surgery with cardiopulmonary bypass (CPB) has been associated with a higher risk of neurologic and neuropsychological deficits than other major types of surgery [1]. Different etiologic mechanisms have been proposed to account for these deficits [2,3,4,5]. First, inadequate perfusion of the brain circulation has been proposed as a factor of brain damage. Second, CPB produces a systemic inflammatory response that may give rise to renal and pulmonary dysfunction, but the effect on the brain has attracted less attention [6,7]. Although a causal relationship has been suggested between the inflammatory response and cognitive dysfunction [8], no clear evidence exists. Third, emboli are formed during CPB by air, clotting activity or cell aggregation and fat release. Partly, these emboli are captured by the various filters in the circuit, but reorganization of smaller emboli might still occur. By comparing several studies in which markers for brain damage were used, these three major mechanisms are discussed.

Ischemia

During routine CPB at moderate hypothermia, a flow of 2.5 l/min m² is applied. The question arises regarding whether this flow is sufficient under the stress-inducing circumstances. During CPB a whole-body inflammatory response is induced, with release of vasoactive substances, which is often shown by hypotension. Simultaneously, a number of hormones are released, which, under physiologic circumstances, would result in an increased heart rate and subsequent increased flow. The relatively low flow during CPB has been proposed to compensate insufficiently, and thus to result in relative hypoperfusion of organs, including the brain. Although not yet proven, this could be a factor of importance to induce brain damage. Additionally, brain damage might be induced to a greater extent in patients undergoing Fallot corrections by the preceding relative hypoxemia, with SaO2 of less than 85% changing into 100% saturation with concomitant generation of oxygen radicals resulting in ischemia-reperfusion damage [9].

Low temperatures seem to protect the brain, however, because a comparison of CPB with circulatory arrest in infants at a temperature of < 18 °C with continuous flow at moderate hypothermia, did not show differences in S100β release.

Inflammation

The systemic inflammatory reaction (SIR) is recognized as one of the factors that causes neuropsychological dysfunction after CPB. We evaluated the relationship between the SIR and S100β release.

One hundred patients undergoing coronary artery bypass grafting were studied. Inflammatory markers were determined at several time points during and after the operation. Correlation analysis between maximum levels of the different markers and S100β release were performed.

No overall association was found between the maximum levels of the inflammatory markers and S100β release. Remarkably, the concentrations of S100β were low as compared with previous published results.

In this context, the question arises regarding whether S100β is capable of identifying patients with cerebral dysfunction after CPB. We evaluated whether perioperative release of S100β after coronary artery surgery with CPB could predict early or late neuropsychological impairment [10]. Patients underwent cognitive testing on a battery of 11 tests preoperatively, before discharge from hospital and 3 months later. No significant correlation was found between S100β release and neuropsychological measures at either 5 days or 3 months postoperatively. In this group of patients with limited release of S100β we found no evidence to support the suggestion that early release of S100β may reflect long-term neurological injury capable of producing cognitive impairment.

Cardiotomy suction

In order to exclude noncerebral sources of S100β no cardiotomy suction or retransfusion of shed mediastinal blood was used in the previously described study on 100 patients. The low concentrations of S100β indicate a significant contribution of noncerebral sources of S100β in previous studies, or a dominant role of cardiotomy suction blood in the induction of cerebral damage.

Despite heparinization of patients increases in markers for activation of clotting, such as prothrombin fragment 1 + 2 (F1 + 2), thrombin-antithrombin (TAT) and fibrinopeptide A (FPA), have been reported [11]. In general, most activation products are observed in the late period of the operation, which is thought to result from consumption of heparin, rewarming of the patients after a period of cooling, or to intensified pericardial suction of shed blood.

There is mounting evidence that suction blood is the major source of increased activation of the clotting system, which even enhances the clotting and fibrinolytic process after retransfusion of suction blood into the systemic circulation.

In infants a high percentage of multiple system organ failure after CPB has been observed, which correlated with increased blood activation [12]. Patients undergoing tetralogy of Fallot are considered to be more prone to blood activation than ventricle septum defect (VSD) patients, because of the more extended surgery and intensified suction in combination with increased bleeding due to pre-existing disturbed hemostasis and blood dilution during CPB. Moreover, this shed blood in infants cannot be discarded due to the low circulating volume.

Microembolic particles produced by increased clotting activity may obstruct the microcirculation of the brain. Moreover, suction blood contains fat particles, which are not removed completely by screen filters and which are also reported to be related to the occurrence of small capillary and arteriolar dilatations in the brain [13].

We found a significant correlation between the brain damage marker S100β and F1 + 2 concentrations, indicating activation of the clotting system, as well as between S100β and glycerol, indicating free fat in the circulation.

F1 + 2 was found to a higher extent in Fallot than in VSD, which corresponded with higher S100β concentrations.

Conclusion

We conclude that brain damage during CPB in infants may be induced by activation of the clotting system and by release of glycerol during operation, resulting in embolization of brain arterioles. Particularly in patients undergoing tetralogy of Fallot, this process may lead to brain damage.