**Protamine**

290 Perioperative Considerations in Cardiac Surgery

hemodynamic changes as their primary end-points. Various pharmacological agents were studied: inhaled prostacyclin I2 (iPGI2), inhaled nitric oxide (iNO), heparinase, protamine and intravenous vasodilators including prostaglandin E1 (PGE1), nitroglycerin (NTG), nitroprusside, milrinone, enoximone, dobutamine, oral sildenafil, beraprost and oxygen. Findings on pharmacological and non-pharmacological approaches for the treatment of PH

Acute pulmonary embolism during cardiac surgery can lead to PH and, in some cases, evolve into CTEPH. Pulmonary thromboembolectomy, when surgically indicated, can help control PH and is currently the only curative treatment in patients with CTEPH (Jamieson & Nomura, 2000; Jamieson et al., 2003) (Fig. **6**). In case of CTEPH, evaluation of the feasibility of surgery mainly depends on the location of the obstruction (central vs. more distal pulmonary arteries) (Dartevelle et al., 2004). Patients who are not candidates for surgery may also benefit from PH-specific medical therapy, however, the use of these medications in CTEPH requires further evaluation in randomized controlled trials (Jais et al., 2008; Rubin et

The rationale for systemic anticoagulant therapy for chronic lung embolism in patients with PH may be justified by well-recognized risk factors for venous thromboembolism, such as heart failure, a sedentary lifestyle, and a thrombophilic predisposition (Bjornsson & Edwards, 1985). However, no data actually support anticoagulant therapy specifically in patients with PH. Warfarin has been evaluated in only two nonrandomized studies, one retrospective and the other prospective, involving a small number of patients (Fuster et al.,

As discussed, CPB causes pulmonary damage during surgery through different mechanisms, potentially leading to PH but, more frequently, it contributes to the exacerbation of PH caused by other factors during the surgical procedure. In this context, patients can benefit from PH-specific medical therapy (Table **2**) and prophylactic treatments

In 62 patients with preoperative PH (PVR > 125 dyn·sec·cm-5 immediately before induction of anesthesia) Solina *et al*. (Solina et al., 2001) explored the dose-responsiveness of 10, 20, 30 and 40 ppm of iNO administered upon termination of CPB in comparison to an intravenous bolus of 50 mg/kg of milrinone given 15 minutes before separation from CPB followed by a 0.5 mg/kg/min regimen administered in the operating room thereafter. Treatment with iNO was associated with significant reductions in PVR at all doses but no improved benefit was observed for doses higher than 10 ppm. No significant difference was observed

between iNO and milrinone in terms of reduction in PVR and inotropic requirement.

The same team compared 20 and 40 ppm of iNO to the same dose of intravenous milrinone in 45 patients after cardiac surgery (Solina et al., 2000). Study drugs were administered upon termination of CPB for a 24h-period in the intensive care unit (ICU). The group receiving 20 ppm iNO had a significantly higher MAP while the group receiving 40 ppm had higher

for PH use in cardiac surgery, which will be discussed later in this chapter.

in cardiac surgery will be discussed together in this section.

**4.1.1 Pre-capillary Pulmonary embolism** 

al., 2006; Suntharalingam et al., 2008).

1984; Rich et al., 1992).

**Cardiopulmonary bypass** 

**4.1.2 Capillary** 

The administration of protamine can be associated with severe PH followed by RV failure. This condition requires immediate treatment. In coronary artery bypass graft (CABG) patients (*n*=3800), Ocal *et al.* (Ocal et al., 2005), two therapeutic approaches were compared for the treatment of the protamine reaction observed in 68 of them (1.8%). One group received iPGI2 and the other intravenous NTG in addition to standard vasoactive agents. The iPGI2 group showed improved hemodynamics and only 14 patients (39%) had to return to CPB compared with all 30 patients (100%) in the NTG group. A trend towards a shorter length of stay in the ICU and reduced mortality was observed in the iPGI2 group, but the numbers were too small to achieve statistical significance.

In order to avoid protamine reaction, heparinase I, a heparin degrading enzyme, was compared to protamine in a multicenter randomized controlled trial (Stafford-Smith et al., 2005). The prevention of protamine-induced PH was also explored as a secondary endpoint. Heparinase I was not associated with a reduction in bleeding or reduction in the need for intervention in the treatment of PH.

#### **Lung diseases and/or hypoxia**

Low CO during cardiac surgery may affect the pulmonary circulation, potentially leading to hypoxia and worsen PH and RV failure. Thus, an acute perioperative low-output state should be reversed whenever possible before clinical manifestation of chronic hypoperfusion and organ dysfunction.

Khan *et al*. (Khan et al., 2009) compared iNO to iPGI2 in 25 heart and lung transplant recipients with PH, refractory hypoxia, or RV dysfunction. Patients were randomized to iNO (20 ppm) or iPGI2 (20,000 ng/ml) as initial treatment in the operating room, followed by a crossover to the other agent after 6 hours. Both iNO and iPGI2 reduced PAP and central venous pressure (CVP), and improved cardiac index (CI) and mixed venous oxygen saturation on initiation of therapy. At the 6-hour crossover trial, there were no significant differences between groups in the reduction of PAP and CVP, and the improvement of CI and mixed venous oxygen saturation on initiation of therapy. Neither iNO nor iPGI2 affected the oxygenation index or systemic blood pressure.

In the case of chronic hypoxia, supplemental oxygen may be indicated to maintain arterial oxygen saturation at a level above 90 percent (Rubin & Rich, 1997).

In the presence of lung disease, improvement of symptoms of PH may be obtained using basic therapy for PH, for instance, therapy for chronic obstructive pulmonary disease COPD and corticosteroids for interstitial lung disease. Antibiotic therapy for pneumonia as well as elimination of ventilation/perfusion mismatch from and atelectasis can also help control PH.

Chest drainage is required in patients with elevated intrathoracic pressure resulting from accumulated air or blood. However, chest closure may be associated with hemodynamic instability in patients requiring long procedures associated with prolonged CPB due to myocardial edema. The solution to this "thoracic compartment syndrome" consists in leaving the chest temporarily opened in order to reduce surrounding pressures until edema recedes.
