**3. Hemodynamic stabilization and monitoring**

The primary goal of hemodynamic monitoring is to prevent inadequate cardiac filling and the subsequent tissue hypoperfusion, and also to avoid overloading leading to congestion of the lungs and sinusoids and hence allograft dysfunction [8]. The intravascular volume, cardiac output (CO), and systematic vascular resistance (SVR) are important parameters vital in determining the success of a LT. The treatment becomes even more complicated when renal and/or heart failure, portopulmonary hypertension, or hepatopulmonary syndromes are also present [9].

Successful management of patients with end-stage liver disease (ESLD) requires a complete understanding of their hemodynamic profile that is often characterized by high cardiac output (CO) with decreased systemic vascular resistance, depleted intravascular volume, and compensatory tachycardia with concomitant renal vasoconstriction and dilutional hyponatremia, due to excessive production of vasodilators during the development of hepatic failure [10]. Following LT, vasodilation and hyperdynamic circulation remain until the graft begins to function and excretes excess vasodilatory agents that are almost completely restored after 6 months [11].

Upon the arrival of a liver transplant recipient in the ICU, advanced monitoring, which estimates CO and volume status, additionally to standard hemodynamic monitoring, that is electrocardiogram, pulse-oximetry, and invasive blood pressure, are deemed essential [12].

Hemodynamic depression may be the result of hypovolemia, prolonged reperfusion syndrome, cardiac dysfunction, either caused by pre-existing or emerging ischemic cardiomyopathy, and metabolic disorders such as acidosis, hypocalcaemia, hypothermia, vasodilation due to sepsis, or graft dysfunction.

**193**

*Management of Patients with Liver Transplantation in ICU*

The assessment of the intravascular volume is of vital importance given that volume status can be affected by contradictory factors such hypovolemia or hypervolemia, both detrimental for graft and patient survival. Restoring volume status, a continually dynamic parameter, and achieving optimal CO are crucial in order to maintain the delicate balance between preload optimization and avoidance of

Hypovolemia, possibly due to continued bleeding, occult or overt, inadequate fluid replacement and/or loss in the third space, can lead to reduced preload and CO and hence hypoperfusion resulting in additional lesions in the newly transplanted liver [14]. The aim is to replace the intravascular fluid and maintain the circulating blood volume. There is still controversy over the type of fluids administered, with crystalloids gaining ground against the colloids (hydroxyl ethyl starches), which have been associated with renal injury and increased mortality in critically ill patients [15], a conclusion that is not supported by convincing evidence in LT. Nevertheless, the appropriate crystalloid should be carefully selected taking into account its special characteristics and based on its metabolism, electrolyte composition, pH and osmolarity, and considering patients' status [16]*.* Albumin (Alb) administration as a replacement fluid has been a matter of debate. In some centers, a large amount of Alb is exogenously administered following the LT to support circulatory stability. Moreover, a concentration of 25 g/L is considered necessary for the immunosuppressive drugs to be effective [17]. Beneficial properties were attributed to Alb in recent studies; whereas, postoperative hypoalbuminemia has been linked to the development of acute kidney injury (AKI) [18]. It has been found that during LT there is translocation of Alb, probably to the interstitial space, which persists until the third postoperative day and whose role has not been clearly clarified [19]. Certain centers choose to replace two-thirds of the required fluids with crystalloids and one-third of drain losses with albumin [14]. Although, blood and blood products transfusion strategies vary between institutions, it is considered that postoperative hematocrit (Hct) values, ranging between 25 and 30%, are safe for adequately transporting O2 to the new graft [14]. The rational use of blood products depends on the monitoring of the coagulation mechanism. Whole-blood viscoelastic tests, such as thromboelastogram (TEG) and rotational thromboelastometry (ROTEM), that illustrate each step of thrombus formation and fibrinolysis are useful tools to guide transfusions and drug administration (anti-fibrinolytics, coagulation factors) [20, 21] by limiting the number of transfusions, as there has been an association between them and increased morbidity/mortality, prolonged stay in the hospital, postoperative sepsis, increased risk of acute rejection, and hepatic artery thrombosis [22–24]. Hypervolemia occurs either from intraoperative over-resuscitation or coexistence of renal dysfunction. It can result in capillary leak syndrome with loss of fluids in the third space, further congestion and graft edema due to vascular permeability disorder, caused by ischemia/reperfusion injury (I/R) that is more pronounced in grafts with higher preservation injury, greater steatosis, or in older donors [7, 25]. Studies also indicate that massive administration of fluids and blood is a risk factor for complications of the respiratory system postoperatively and is correlated with increased mortality [26]. On the contrary, conservative resuscitation strategy and negative fluid balance during the first three postoperative days, if hemodynamic stability has been achieved, act protectively. Codes et al. [27] concluded that a continuous positive balance in the first 4 days after surgery correlates with the development of ΑΚΙ and the need for renal replacement therapy (RRT). Goal directed therapy (GDT) strategy, which has been successfully applied in major surgical interventions, is proposed. It aims at maintaining an adequate supply of O2 to the end organs by a bundle of measures including fluid titration in conjunction with blood transfusions as well as administration of vasopressors and/or inotropic agents [28]. The hemodynamic

*DOI: http://dx.doi.org/10.5772/intechopen.89435*

pulmonary edema [13].

*Liver Disease and Surgery*

transplantation [7].

ing improved endpoint results.

**2. General principles**

Additionally, recipients are sicker, given that priority of graft allocation is based on higher MELD scores, older and with co-morbidities such as metabolic syndrome, cardiac disease, and diabetes mellitus [5, 6]. Postoperative liver transplant patient care requires careful accounting of the recipient's pre-existing pathophysiology, intraoperative events, and donor's quality. Moreover, the implanted liver represents a unique biological entity that has undergone physiological changes and has to adapt to a new environment. This donor-recipient interaction is the key of a successful

The intensivist's role is essential as a multifaceted approach is critical for optimal

The aim of immediate postoperative support is the adequate O2 supply to tissues

The primary goal of hemodynamic monitoring is to prevent inadequate cardiac

Successful management of patients with end-stage liver disease (ESLD) requires a complete understanding of their hemodynamic profile that is often characterized by high cardiac output (CO) with decreased systemic vascular resistance, depleted intravascular volume, and compensatory tachycardia with concomitant renal vasoconstriction and dilutional hyponatremia, due to excessive production of vasodilators during the development of hepatic failure [10]. Following LT, vasodilation and hyperdynamic circulation remain until the graft begins to function and excretes excess vasodilatory agents that are almost completely restored after 6 months [11]. Upon the arrival of a liver transplant recipient in the ICU, advanced monitoring,

which estimates CO and volume status, additionally to standard hemodynamic monitoring, that is electrocardiogram, pulse-oximetry, and invasive blood pressure,

sion syndrome, cardiac dysfunction, either caused by pre-existing or emerging ischemic cardiomyopathy, and metabolic disorders such as acidosis, hypocalcaemia,

hypothermia, vasodilation due to sepsis, or graft dysfunction.

Hemodynamic depression may be the result of hypovolemia, prolonged reperfu-

filling and the subsequent tissue hypoperfusion, and also to avoid overloading leading to congestion of the lungs and sinusoids and hence allograft dysfunction [8]. The intravascular volume, cardiac output (CO), and systematic vascular resistance (SVR) are important parameters vital in determining the success of a LT. The treatment becomes even more complicated when renal and/or heart failure, portopulmonary hypertension, or hepatopulmonary syndromes are also

and graft by ensuring hemodynamic stabilization, fluid balance, restoration of diuresis, optimal ventilation, and supporting graft function. It should be noted that graft recovery depends primarily on the intrinsic hepatocyte recovery capacity and

secondly on optimizing liver hemodynamics and preventing venous stasis.

**3. Hemodynamic stabilization and monitoring**

transplantation outcomes. The main hurdles to tackle are early recognition and immediate treatment of the hemodynamic and metabolic disorders, restoration of intravascular volume, avoidance of coagulation disorders, optimization of organs function affected by hepatic failure, prophylaxis and treatment of infections, early enteral nutrition, and evaluation of graft function. Technological advances offer the possibility of continuous cardiovascular and allograft function monitoring facilitat-

**192**

present [9].

are deemed essential [12].

The assessment of the intravascular volume is of vital importance given that volume status can be affected by contradictory factors such hypovolemia or hypervolemia, both detrimental for graft and patient survival. Restoring volume status, a continually dynamic parameter, and achieving optimal CO are crucial in order to maintain the delicate balance between preload optimization and avoidance of pulmonary edema [13].

Hypovolemia, possibly due to continued bleeding, occult or overt, inadequate fluid replacement and/or loss in the third space, can lead to reduced preload and CO and hence hypoperfusion resulting in additional lesions in the newly transplanted liver [14]. The aim is to replace the intravascular fluid and maintain the circulating blood volume. There is still controversy over the type of fluids administered, with crystalloids gaining ground against the colloids (hydroxyl ethyl starches), which have been associated with renal injury and increased mortality in critically ill patients [15], a conclusion that is not supported by convincing evidence in LT. Nevertheless, the appropriate crystalloid should be carefully selected taking into account its special characteristics and based on its metabolism, electrolyte composition, pH and osmolarity, and considering patients' status [16]*.* Albumin (Alb) administration as a replacement fluid has been a matter of debate. In some centers, a large amount of Alb is exogenously administered following the LT to support circulatory stability. Moreover, a concentration of 25 g/L is considered necessary for the immunosuppressive drugs to be effective [17]. Beneficial properties were attributed to Alb in recent studies; whereas, postoperative hypoalbuminemia has been linked to the development of acute kidney injury (AKI) [18]. It has been found that during LT there is translocation of Alb, probably to the interstitial space, which persists until the third postoperative day and whose role has not been clearly clarified [19]. Certain centers choose to replace two-thirds of the required fluids with crystalloids and one-third of drain losses with albumin [14]. Although, blood and blood products transfusion strategies vary between institutions, it is considered that postoperative hematocrit (Hct) values, ranging between 25 and 30%, are safe for adequately transporting O2 to the new graft [14]. The rational use of blood products depends on the monitoring of the coagulation mechanism. Whole-blood viscoelastic tests, such as thromboelastogram (TEG) and rotational thromboelastometry (ROTEM), that illustrate each step of thrombus formation and fibrinolysis are useful tools to guide transfusions and drug administration (anti-fibrinolytics, coagulation factors) [20, 21] by limiting the number of transfusions, as there has been an association between them and increased morbidity/mortality, prolonged stay in the hospital, postoperative sepsis, increased risk of acute rejection, and hepatic artery thrombosis [22–24].

Hypervolemia occurs either from intraoperative over-resuscitation or coexistence of renal dysfunction. It can result in capillary leak syndrome with loss of fluids in the third space, further congestion and graft edema due to vascular permeability disorder, caused by ischemia/reperfusion injury (I/R) that is more pronounced in grafts with higher preservation injury, greater steatosis, or in older donors [7, 25]. Studies also indicate that massive administration of fluids and blood is a risk factor for complications of the respiratory system postoperatively and is correlated with increased mortality [26]. On the contrary, conservative resuscitation strategy and negative fluid balance during the first three postoperative days, if hemodynamic stability has been achieved, act protectively. Codes et al. [27] concluded that a continuous positive balance in the first 4 days after surgery correlates with the development of ΑΚΙ and the need for renal replacement therapy (RRT). Goal directed therapy (GDT) strategy, which has been successfully applied in major surgical interventions, is proposed. It aims at maintaining an adequate supply of O2 to the end organs by a bundle of measures including fluid titration in conjunction with blood transfusions as well as administration of vasopressors and/or inotropic agents [28]. The hemodynamic

targets are predefined and specific variables are used to control fluid adequacy, improvement of CO, and tissue perfusion. GDT has beneficial effects compared to liberal fluid administration, reducing postoperative ileus, mechanical ventilation time, and respiratory system complications, as it has been indicated in relevant, although limited, studies [29]. Jiang et al. [30] suggests the individualization of fluid administration in the perioperative period as an optimal recovery strategy. They estimated that transfusions >100 ml/kg and fluid balance ≤−14 ml/kg during the first postoperative days result in prolonged mechanical ventilation, extubation time, and ICU stay. Prudent use of vasopressor agents is proposed since they increase arterial tone and improve perfusion pressure avoiding overload. Noradrenaline (0.01–1 μg/ kg/min) with mixed α-β-adrenergic effects is most commonly administered to maintain CO and organ perfusion. Vasopressin (0.5–0.6 U/h) and terlipressin (1.5 μg/ kg/h) have also been used in recent years because of their modifying effect on visceral circulation, where approximately 37% of the total blood volume is located in cirrhotic patients, and of their ability to reduce pressure in the portal vein [31, 32].

Since there has been no consensus on hemodynamic monitoring in LT yet, there is a number of invasive and noninvasive CO monitors available in order to evaluate hemodynamic fluctuations (**Table 1**) [13, 36].

The pulmonary artery (PAC) catheter has traditionally been used for hemodynamic monitoring in LT. It provides the possibility of measuring the CO by the thermodilution method, which is considered the gold standard, but also the cardiac


**195**

*Management of Patients with Liver Transplantation in ICU*

filling pressures, the CVP, and especially the PCWP for assessing the preload [33]. Numerous studies have shown that static preload measurements are indirect markers of the end diastolic volume and have a poor predictive value for fluid management, improvement of hepatic perfusion, and recovery guidance [34]. Although still under debate, current data favor the use of a modified pulmonary artery catheter, with an incorporated heating coil, that provide continuous measurement of CO (CCO) and right ventricular end diastolic volume (RVEDV) as the more reliable preload indicator. Patients with portopulmonary hypertension are highly benefited from PAC, as it is the method of choice for measuring and monitoring pulmonary

In recent years, interest has shifted to the dynamic parameters and expanding data yielded from existing monitoring of blood pressure to assess the CO, the preload and the afterload. There is technology available to accurately analyze pressure waveforms and sufficient knowledge to generate algorithms that are interpreted by

The PiCCO system (Pulsion Medical System, Munich, Germany) uses the method of transpulmonary thermodilution, single indicator technique, and arterial pulse contour analysis which by means of an algorithm can continuously calculate CO and preload markers: global end diastolic volume (GEDVI), extra vascular lung water index (EVLWI), and intrathoracic blood volume index (ITBVI) which is considered a reliable preload indicator in LT. In transplant patients, the CO measurements deriving from the PiCCO system are consistent with those of PAC [38, 39]. Furthermore, this system offers the capability of functional hemodynamic monitoring by detecting the changes in left ventricular pulse volume caused by changes in preload due to mechanical ventilation. Stroke volume variation (SVV) and pulse pressure variation (PPV) have been used successfully to assess the intravascular volume and fluid responsiveness in critically ill patients [12, 13, 40]. Certain LT studies have concluded that the SVV is a better indicator for RVEDVI than CVP, while a SVV greater than 9% is an indicator of low RVEDVI which means fluid responsiveness [41, 42]. However, there are always limitations deriving from

artery pressures intraoperatively and directly postoperatively [13, 35].

the presence of arrhythmia and mechanical ventilation settings.

order to calibrate the arterial waveform analysis algorithm [40].

discrepancy in cases of significantly low SVR [45, 46].

The LiDCO system (LiDCO Plus, Cambridge, United Kingdom) is similar to the PiCCO system, but in its case the lithium indicator dilution technique is applied in

The Flowtrac/Vigileo system (Edwards Lifesciences, Irvine, CA United States) is a special energy converter that links the arterial line with a CO monitor and uses arterial waveform analysis with an algorithm for real-time CO measurement in conjunction with patient demographics without the need for calibration. However, a poor correlation has been found between findings of waveform analysis CO when compared to PAC thermodilution, mainly in patients with cirrhosis B and C according to Child-Pugh classification [43, 44]. Biais et al. came to the same conclusion, using the recent third generation, FloTrac system, pointing out that there was great

In recent years, the use of transesophageal echocardiography (TEE) has been gaining ground not only because it is considered a noninvasive method, but also because it provides the ability to directly visualize the contractility of the left and right heart, preload status, and differential diagnosis of various pathological conditions such as pulmonary embolism, pleural, or pericardial effusion [47]. The CO can be estimated with measurements of flow across the cardiac valve, left ventricular outflow tract, or the flow in the main pulmonary artery. The ability to instantly display real-time preload is considered its biggest advantage. The functional application of TEE is limited by the risk of rupture of the third or fourth grade esophageal varices, but it is considered a reliable hemodynamic monitoring method when used by experienced intensivists [12, 13].

*DOI: http://dx.doi.org/10.5772/intechopen.89435*

the complex pulse wave morphology [36, 37].

**Table 1.** *Hemodynamic monitoring in LT.*

#### *Management of Patients with Liver Transplantation in ICU DOI: http://dx.doi.org/10.5772/intechopen.89435*

*Liver Disease and Surgery*

targets are predefined and specific variables are used to control fluid adequacy, improvement of CO, and tissue perfusion. GDT has beneficial effects compared to liberal fluid administration, reducing postoperative ileus, mechanical ventilation time, and respiratory system complications, as it has been indicated in relevant, although limited, studies [29]. Jiang et al. [30] suggests the individualization of fluid administration in the perioperative period as an optimal recovery strategy. They estimated that transfusions >100 ml/kg and fluid balance ≤−14 ml/kg during the first postoperative days result in prolonged mechanical ventilation, extubation time, and ICU stay. Prudent use of vasopressor agents is proposed since they increase arterial tone and improve perfusion pressure avoiding overload. Noradrenaline (0.01–1 μg/ kg/min) with mixed α-β-adrenergic effects is most commonly administered to maintain CO and organ perfusion. Vasopressin (0.5–0.6 U/h) and terlipressin (1.5 μg/ kg/h) have also been used in recent years because of their modifying effect on visceral circulation, where approximately 37% of the total blood volume is located in cirrhotic

patients, and of their ability to reduce pressure in the portal vein [31, 32].

hemodynamic fluctuations (**Table 1**) [13, 36].

PiCCO Pulse contour

LiDCO Pulse contour

FlowTrac/Vigileo Pulse contour

TEE Ultrasound,

*Hemodynamic monitoring in LT.*

analysis

analysis

analysis

Doppler

Since there has been no consensus on hemodynamic monitoring in LT yet, there is a number of invasive and noninvasive CO monitors available in order to evaluate

> measures of CO Direct measures of PAP and RVEDVI Gold standard in POPH

Less invasive Continuous CO, SV measures

SVV

status

ITBVI, EVLWI, PPV,

Reliable indicators of fluid responsiveness

Continuous CO, SV measures comparable to PAC measures PPV, SVV

Indicative of volume

No need for calibration Continuous CO, SV measures

PPV, SVV, indicative of volume status

Less invasive Direct visualization of cardiac function and volume status

Invasive CVP, PCWP static pressures measurement Unreliable indicators of volume status, SV and fluid responsiveness

in cirrhosis

in cirrhosis

Not reliable in

Need for recalibration in marked changes of SVR Inaccurate CO measures in Child-Pugh Band C stages

Requires sinus rhythm and certain ventilator setting

Calibration with lithium Inaccurate CO measures in Child-Pugh Band C stages

hyperdynamic circulation with very low SVR

Advanced training is

Risk of rupture in 3rd or 4th grade of esophageal

required

varices

The pulmonary artery (PAC) catheter has traditionally been used for hemodynamic monitoring in LT. It provides the possibility of measuring the CO by the thermodilution method, which is considered the gold standard, but also the cardiac

**Monitors Principle Advantages Limitations**

PAC Thermodilution Accurate continuous

**194**

**Table 1.**

filling pressures, the CVP, and especially the PCWP for assessing the preload [33]. Numerous studies have shown that static preload measurements are indirect markers of the end diastolic volume and have a poor predictive value for fluid management, improvement of hepatic perfusion, and recovery guidance [34]. Although still under debate, current data favor the use of a modified pulmonary artery catheter, with an incorporated heating coil, that provide continuous measurement of CO (CCO) and right ventricular end diastolic volume (RVEDV) as the more reliable preload indicator. Patients with portopulmonary hypertension are highly benefited from PAC, as it is the method of choice for measuring and monitoring pulmonary artery pressures intraoperatively and directly postoperatively [13, 35].

In recent years, interest has shifted to the dynamic parameters and expanding data yielded from existing monitoring of blood pressure to assess the CO, the preload and the afterload. There is technology available to accurately analyze pressure waveforms and sufficient knowledge to generate algorithms that are interpreted by the complex pulse wave morphology [36, 37].

The PiCCO system (Pulsion Medical System, Munich, Germany) uses the method of transpulmonary thermodilution, single indicator technique, and arterial pulse contour analysis which by means of an algorithm can continuously calculate CO and preload markers: global end diastolic volume (GEDVI), extra vascular lung water index (EVLWI), and intrathoracic blood volume index (ITBVI) which is considered a reliable preload indicator in LT. In transplant patients, the CO measurements deriving from the PiCCO system are consistent with those of PAC [38, 39].

Furthermore, this system offers the capability of functional hemodynamic monitoring by detecting the changes in left ventricular pulse volume caused by changes in preload due to mechanical ventilation. Stroke volume variation (SVV) and pulse pressure variation (PPV) have been used successfully to assess the intravascular volume and fluid responsiveness in critically ill patients [12, 13, 40]. Certain LT studies have concluded that the SVV is a better indicator for RVEDVI than CVP, while a SVV greater than 9% is an indicator of low RVEDVI which means fluid responsiveness [41, 42]. However, there are always limitations deriving from the presence of arrhythmia and mechanical ventilation settings.

The LiDCO system (LiDCO Plus, Cambridge, United Kingdom) is similar to the PiCCO system, but in its case the lithium indicator dilution technique is applied in order to calibrate the arterial waveform analysis algorithm [40].

The Flowtrac/Vigileo system (Edwards Lifesciences, Irvine, CA United States) is a special energy converter that links the arterial line with a CO monitor and uses arterial waveform analysis with an algorithm for real-time CO measurement in conjunction with patient demographics without the need for calibration. However, a poor correlation has been found between findings of waveform analysis CO when compared to PAC thermodilution, mainly in patients with cirrhosis B and C according to Child-Pugh classification [43, 44]. Biais et al. came to the same conclusion, using the recent third generation, FloTrac system, pointing out that there was great discrepancy in cases of significantly low SVR [45, 46].

In recent years, the use of transesophageal echocardiography (TEE) has been gaining ground not only because it is considered a noninvasive method, but also because it provides the ability to directly visualize the contractility of the left and right heart, preload status, and differential diagnosis of various pathological conditions such as pulmonary embolism, pleural, or pericardial effusion [47]. The CO can be estimated with measurements of flow across the cardiac valve, left ventricular outflow tract, or the flow in the main pulmonary artery. The ability to instantly display real-time preload is considered its biggest advantage. The functional application of TEE is limited by the risk of rupture of the third or fourth grade esophageal varices, but it is considered a reliable hemodynamic monitoring method when used by experienced intensivists [12, 13].
