**3.1 Pathophysiology of post bypass exacerbation of PH**

Post bypass pulmonary vasoconstriction has been demonstrated in a variety of experimental models as well as in the clinical setting and there is increased evidence that the severity of the vasoconstriction correlates with the extent of cardiopulmonary bypass (CPB)-induced endothelial injury (Riedel, 1999).

Endothelial injury and dysfunction is promoted by acidosis, hypoxia, shear stress from increased pulmonary blood flow (left-to-right intracardiac shunts), and fibrin from thromboembolism. Leukocyte activation, oxygen free radicals such as superoxide, hydroxyl radicals and peroxynitrate, tumor necrosis factor α, interleukin-1, elastases and inflammatory mediators are involved in this process.

The most important mechanism underlying this endothelial dysfunction in the setting of cardiac surgery could be ischemia/reperfusion injury, with associated inflammatory cell and complement activation. Ischemia/reperfusion injury due to inadequate flow in the bronchial circulation plays a pivotal role in the exacerbation of post-CPB PH (Matuschak, 1999).

In summary, intraoperative pulmonary vasoconstriction is a result of complex interactions between various perioperative factors: *preoperative status* of the pulmonary vascular bed (valvular pathology, shear stress), *intraoperative vasospastic stimuli* (hypoxia, hypercarbia, acidosis, ischemia/reperfusion injury, inflammatory mediators, free radical formation, pulmonary leukosequestration, excess thromboxane or endothelin production and microemboli) and *postoperative factors* (atelectasis, adrenergic tone, hypoxic pulmonary vasoconstriction). Preexisting pulmonary hypertension, increased pulmonary blood flow states, in combination with intraoperative hypoxia, acidosis, hypothermia, and microembolism may exacerbate CPB-induced pulmonary hypertension.

The final result of this pathophysiology is the imbalance between vasoconstrictor and vasodilator factors at the pulmonary vascular bed, that is reduction in prostacyclin (PGI2) and NO levels and an increase in thromboxane A2, catecholamines, adhesion molecules and endothelin levels.

This can culminate to a life- threatening situation and disconnecting the patient from the extracorporeal circulation may prove particularly laborious, because of right ventricular failure.

Moreover, after discontinuation from bypass there is need for heparin reversal and this is accomplished by the administration of protamine. Protamine administration is commonly associated with hypotension due to systemic vasodilatation. This is suggested to be mediated by the release of NO (Raikar, 1996). A rare reaction brought about by protamine administration, which may be mediated by the release of complement pathway anaphylatoxins (C3a and C5b) and / or cyclooxygenase products (e.g. thromboxane A2), may lead to catastrophic pulmonary hypertension and subsequent right ventricular failure.
