**3. CPB and weaning**

**2. Monitoring and induction of general anesthesia**

ance can be very helpful (see **Table 2**).

136 Heart Transplantation

present with an empty stomach [6].

PA radial Invasive arterial pressure (peripheral) PA fem Invasive arterial pressure (central)

PAC (pulmonary artery catheter) PAPs, PAPm, PAPd, sVO2

TEE Biventricular function, shape of ventricular septum, filling, air etc.

correlation, adequate tissue perfusion, brain perfusion

CVP Central venous pressure ECG 12 lead electrocardiography SpO2 Oxygen saturation levels

**Device Measure**

NIRS ScvO2

LAP LV filling pressure

**Table 2.** Standard monitoring.

Timing to get the patient ready to receive the new organ is crucial because the ischemia of the

Everyone in the theater should wear sterile surgical gown, hat, mask, and sterile gloves for any procedure on the patient especially because he will go under immune deficiency. Once the patient is in the theater, he will be connected to multiparametric monitor, with the 12 lead ECG and oximetry probe. Two peripheral venous lines are placed (generally 18G for iv sedation and 14G for rapid fluid infusion), and an arterial catheter, generally 20G, is placed into the radial or humeral artery. When the patient is very unstable, an arterial catheter is placed in the left femoral artery, to estimate central to peripheral arterial pressure gradients. Placement of an arterial line can be very difficult in patients with previous implantation of LVADs as bridge to transplant, due to the absence of arterial pulse. In such situations, ultrasound guid-

Induction of general anesthesia usually starts just with the final acceptance of the donor organ. Drugs used for general anesthesia should impact the less possible on hemodynamics. A rapid sequence induction is preferred since recipients are always very stressed and sometimes not

Midazolam (10–15 mg) or etomidate (20 mg) are preferred to propofol for hypnosis, due to the less impact on hemodynamics. Opioids like fentanyl or sufentanil are preferred for the same reason ("stress-free anesthesia"), with an induction dose of 0.2–0.4 mcg/kg for sufentanil and 2–4 mcg/kg for fentanyl. Continuous infusion analgesia remifentanil is preferable for the less impact on renal function since it is metabolized by plasmatic esterase. This is particularly important in patients with low cardiac output and preexisting renal failure. Remifentanil will be turned off and replaced by morphine or tramadol (30 mg/die and 300 mg/die, respectively), before moving to the intensive care unit. Mean term muscle relaxant rocuronium (1 mg/kg) is usually the first choice for rapid sequence induction. Sometimes short-term cisatracurium

donor heart should be as short as possible to avoid the ischemia-reperfusion injury.

If the graft is not carried out into the organ care system (OCS), the ischemic time is crucial and the risk of ischemic/reperfusion injury is proportionally high, with possible dramatic increase of blood lactate levels and decrease of the graft global function. This is the reason why we must ensure adequate glycemia control, urine output, and, in general, an optimal tissue perfusion during CPB. This means to guarantee an adequate oxygen delivery (DO2 ), which means to keep MAPs about 60–80 mmHg and Hb levels at least about 8–9 mg/dL. When the aorta is unclamped, VF can occur (50% of patients). A shock delivery (10–30 J) followed by lidocaine bolus (when VF is refractory to electrical therapy) will take to resolution of the arrhythmia and return to sinus rhythm. In case of sinus bradycardia, temporary epicardial pacing will ensure adequate heart rate (100–110 bpm). Due to limited muscular mass, the ability of the right ventricle (RV) to increase contractility is limited and a temporary pacing at about 110 bpm will increase RV output and will overpace possible arrhythmias. Surgeons will also place a left atrial catheter for continuous measurement of the left atrial pressure (LAP) as an indicator of the left ventricle performance and stiffness. This value, together with CVP, PAPs, MAPs, and SvO2, will influence the posttransplantation hemodynamic management. Throughout this period, it will be mandatory to ensure adequate MAPs and diastolic pressure to allow adequate coronary perfusion, while maintaining medium-low preload pressures (CVP < 12 mmHg, LAP/PCWP < 12 mmHg). The biventricular assessment with transesophageal echocardiography should be done simultaneously.

Pharmacological tools for CPB weaning will include the following [**Tables 3** and **4**]:


Possible side effects of these selective inhalation drugs are inhibition of platelet activation and aggregation and inhibition of leucocyte adhesion.

• Levosimendan (0.1–0.2 mcg/kg/min) has also been reported to reverse low cardiac output after heart transplantation [10], although its use has not been shown to reduce cardiac surgery mortality [11].

After having unclamped the aorta and before weaning from CPB, about 1 hour of assistance to the new heart is provided. During this period, an adequate temperature is achieved (36–36.5°C measured by nasopharyngeal temperature probe). Vigilance calibration is performed by providing Hb levels and SvO2 from gas analysis; it gives results about the indexed cardiac output, pulmonary vascular resistances, and systemic peripheral vascular resistances, indexed on the patient weight. PAPs are shown on the monitor together with CVP, LAP, MAPs, and ECG. The PAVR (pulmonary artery vascular resistance) equals: PAVR = [80 × (mean pulmonary artery pressure – pulmonary + capillary wedge pressure)/cardiac output] (normal value 100 dynes/cm−<sup>5</sup> ).

**Drug Average dosage Advantages Side effects**

Slowly reduce CPB flow (careful monitoring CVP, TEE, LAP) Check/change drug infusion rate

Sustain SVR and arterial pressure (if necessary) Norepinephrine

Hb level 11 g/dl

Reduce PVR (if necessary) iNO (20–40 ppm)

Support graft Milrinone (0.2–0.5 mcg/kg/min)

Pacing with 110–120 bpm Increase of HR increases CI, avoid overload

Maintain DO2

272 ml/min/m2

level

Maintain regular rhythm and A-V synchrony

**Table 3.** Practice guide to wean from CPB.

110 bpm

vasopressin

K+ /Mg+ Pacing

Raise in pump flow Raise Hb level Raise O2 sat Decrease body temp

Dopamine (4–6 mcg/kg/min) Epinephrine (0.05–0.25 mcg/kg/min)

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Isoprenaline (0.02–0.04 mcg/kg/min)

Inhalatory milrinone (5 mg) for 15 min

Inhalatory iloprost (10–20 ng)

Check chamber filling Check contractility

Norepinephrine Up to 0.15 mcg/kg/min Contrast vasodilatation Increase PVR Levosimendan 0.1–0.2 mcg/kg/min Support RV overload Vasodilation

i-NO 20–40 ppm Reduce PVR (if not fixed) i-Milrinone 5 mg/15 min Reduce PVR (if not fixed) i-Iloprost 20–30 mcg/15 min Reduce PVR (if not fixed) Methylene blue 0.5–2 mg/kg Contrast vasodilation

**Table 4.** Inotropes/vasoactive: average therapeutic dosage to support hemodynamics.

Milrinone 0.2–0.5 mcg/kg/min Support RV overload Arrhythmias, raise O2

Epinephrine 0.05–0.25 mcg/kg/min Support RV overload Tachycardia, arrhythmias, raise O2

Vasopressin 2.5–5 U/h Contrast vasodilatation Increase SVR impair forward flow

demand

vasodilation

of LVAD

demand,

The TPG (transpulmonary gradient) equals: TPG = mPAP − PCWP (normal value 6 mmHg).

A TPG > 15 mmHg is considered at high risk to develop early postoperative RV dysfunction [7]. The reason for RV dysfunction development may be found in the background of the donor heart. Especially when young and comparably small, it may not easily adapt to the already existing pulmonary hypertension in the recipient. Furthermore, as a result of a long ischemia and CPB time, with ischemia-reperfusion injury, RV dilates, becomes ischemic, and further reduces its own contractility. In this case, we need to adjust the amount of inotropes, chronotropes, and pulmonary vasodilators given, basing also on transesophageal echocardiography that can show the biventricular systolic-diastolic function and fluid responsiveness. Once the patient is stable and the heart rate is appropriate, we can start ventilation and slowly decrease the pump flow until 0.5–1 L/min. At that point, we come out from bypass. During CPB weaning, the heart should be loaded with caution because RV is very sensitive to distension. Echocardiographic parameters to asses the RV behavior will be RVFAC (fractional area change), leftward shift of


**Table 3.** Practice guide to wean from CPB.

• Isoprenaline at low-moderate dose (0.02–0.04 mcg/kg/min): it is the first choice in heart transplantation due to the positive chronotropic effect; it helps to guarantee a heart rate of 100–110 bpm. If it does not work, do not go beyond 0.04 mcg/kg/min, in order to avoid

• Adrenaline (0.02–0.2 mcg/kg/min): it provides inotropic support to the new heart, espe-

• Milrinone (0.2–0.5 mcg/kg/min) or other phosphodiesterase inhibitors (enoximone at 5–8 mcg/kg/min): they increase contractility especially of the right ventricle, while decreasing pulmonary vascular resistances. They both increase intracellular levels of cAMP, but they also decrease the systemic vascular resistances (SVR), so that the patient may benefit from low-moderate noradrenergic support in addition. If systemic peripheral resistances are really low, selective pulmonary vasodilators, aimed to decrease RV afterload without affecting peripheral resistances, are a better choice: inhaled nitric oxide (iNO) at 20–40 ppm [9, 17]) or aerosolized prostaglandins (iloprost 20 mcg/15 min, repeated after 4 hours).

Possible side effects of these selective inhalation drugs are inhibition of platelet activation

• Levosimendan (0.1–0.2 mcg/kg/min) has also been reported to reverse low cardiac output after heart transplantation [10], although its use has not been shown to reduce cardiac

After having unclamped the aorta and before weaning from CPB, about 1 hour of assistance to the new heart is provided. During this period, an adequate temperature is achieved (36–36.5°C measured by nasopharyngeal temperature probe). Vigilance calibration is performed by provid-

pulmonary vascular resistances, and systemic peripheral vascular resistances, indexed on the patient weight. PAPs are shown on the monitor together with CVP, LAP, MAPs, and ECG. The PAVR (pulmonary artery vascular resistance) equals: PAVR = [80 × (mean pulmonary artery pressure – pulmonary + capillary wedge pressure)/cardiac output] (normal value 100 dynes/cm−<sup>5</sup>

The TPG (transpulmonary gradient) equals: TPG = mPAP − PCWP (normal value 6 mmHg). A TPG > 15 mmHg is considered at high risk to develop early postoperative RV dysfunction [7]. The reason for RV dysfunction development may be found in the background of the donor heart. Especially when young and comparably small, it may not easily adapt to the already existing pulmonary hypertension in the recipient. Furthermore, as a result of a long ischemia and CPB time, with ischemia-reperfusion injury, RV dilates, becomes ischemic, and further reduces its own contractility. In this case, we need to adjust the amount of inotropes, chronotropes, and pulmonary vasodilators given, basing also on transesophageal echocardiography that can show the biventricular systolic-diastolic function and fluid responsiveness. Once the patient is stable and the heart rate is appropriate, we can start ventilation and slowly decrease the pump flow until 0.5–1 L/min. At that point, we come out from bypass. During CPB weaning, the heart should be loaded with caution because RV is very sensitive to distension. Echocardiographic parameters to asses the RV behavior will be RVFAC (fractional area change), leftward shift of

from gas analysis; it gives results about the indexed cardiac output,

).

hypotensive effects. In this case, switching to atrial pacing is the best choice.

cially to the right ventricle, which is the one more at risk of failure.

and aggregation and inhibition of leucocyte adhesion.

surgery mortality [11].

138 Heart Transplantation

ing Hb levels and SvO2


**Table 4.** Inotropes/vasoactive: average therapeutic dosage to support hemodynamics.


circulation. In case of low response to a full dose of heparin, we can achieve an adequate ACT by administering antithrombin III (AT3), especially when AT3 plasma levels are less than 70%. From 0.5 to 5% of patients with end-stage heart disease can develop HIT (heparin-induced thrombocytopenia), due to repeated heparin exposures related to the placement of IABP, LVADs, or frequent catheter procedures. Alternative anticoagulation, with direct thrombin inhibitors (bivalirudin and argatroban), [8] is recommended in such patients. At the end of organ implantation, once the aortic and right atrium cannulas are removed, we need to guarantee an appropriate heparin reversal with protamine (50 mg of protamine every 50 mg of heparin). We also give the patient 2 g of tranexamic acid at the induction of general anesthesia and 2 g (25–50 mg/kg) with protamine in association with 1 g of gluconate calcium, to avoid hyperfibrinolysis and replace calcium deficiency. Severe bleeding is not a rare condition especially in patients with previous heart surgery. Particularly, in patients with LVADs as bridge to transplant, severe bleeding can often occur due to the large wound area and pretreatment with multiple anticoagulants and platelet inhibitors. If hemostasis is insufficient and the patient is still bleeding, we need to check for coagulation disorders via ROTEM (i.e., hyperfibrinolysis, coagulation factor deficiency, and hypofibrinogenemia) or via TEG and correct the specific deficiency (prothrombin complex concentrate for clotting factor deficiency or fibrinogen concentrate for hypofibrinogenemia). We prefer this approach instead of large dose of fresh frozen plasma, in order to avoid TACO (transfusion-associated circulatory overload), TRALI (transfusion-related lung injury), immune modulation, and increased risk of infections.

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Almost 90% of heart transplants are due to ischemic or dilatative cardiomyopathy and men over 40 years of age are the most involved. They all need a special care and a multimodal approach, even because not only cardiovascular balance but also respiratory care, fluid man-

Patients incoming from the operating room have to be placed in an isolated single bed room to avoid contamination, since they will undergo immunosuppressive therapy. Everyone in contact with them must wear mask, cup, and sterile gown and do routine sterile hand washing. Invasive hemodynamic monitoring, including systemic arterial pressure, right atrial pressure, pulmonary artery pressure through the PAC, and left atrial pressure, should be immediately

Twelve lead ECG at the arrival is mandatory to check heart rhythm disorders. Bradyarrhythmias and supraventricular arrhythmias are the most frequent and should be related to inotropic and chronotropic support, hypovolemia, and electrolyte disorders. If atrial fibrillation occurs, an acute rejection should be considered and a 500 mg bolus of methylprednisolone should be administered, eventually followed by amiodarone (300 mg iv bolus in 30 min) for pharmacological cardioversion and rate control. In case of failure of pharmacological cardioversion, we can try electrical cardioversion. Sinus bradycardia can be

agement, and immune system modulation impact on the overall survival.

**6. Intensive care management**

**6.1. ICU admission**

reconnected in the room.

**Table 5.** Inotropic score.

IAS (interatrial septum) or "fluttering" of IVS (interventricular septum) during end-diastole, TAPSE(tricuspid annular plane systolic excursion), and MPI (myocardial performance index).

Basic ventilation strategies to reduce pulmonary artery resistances such as hyperoxia and moderate hyperventilation are mandatory. Ventilation should be set at 60–100% FiO<sup>2</sup> , 6–8 ml/ kg TV (tidal volume), and low-moderate PEEP (5–6 cmH<sup>2</sup> O), after recruitment maneuver, with the intention to prevent lung atelectasis [12].

Chest closure can be very critical for hemodynamics. In some rare cases (i.e., 2.5%), primary graft failure can occur [13], and it is responsible for more than 30% of early deaths after cardiac transplantation. Clinical onset of primary graft failure is with hypotension, low cardiac output, high preload pressures (PVC, LAP, and wedge pressure), and biventricular failure. When necessary, a temporary IABP (intra-aortic balloon pump), as first step, and then peripheral (femoral vein-femoral artery) or central (left atrium, right atrium, aorta) VA-ECMO (venousarteriosus extracorporeal membrane oxygenation) should be taken into account, whenever hemodynamics remain unsatisfactory despite high inotropic support (**Table 5**) [14].
