**7. Heart rate**

370 Liver Transplantation – Basic Issues

aorta, partial or complete clamping of the abdominal aorta may eliminate pressure

The CVP is often taken to express filling of the right ventricle but CVP is not well correlated with preload to the heart as expressed by its diastolic filling (De Wolf, 2006). A correlation between CO and CVP is established during acute changes in the CBV as induced by headup-tilt (Ogoh *et al.*, 2003) or lower body negative pressure (Murray *et al.*, 1999), while for most patients CO is not related to CVP although there is a relation between CO and diastolic

In order to limit the blood loss during surgery, a strategy of keeping CVP low has been suggested and studies on liver resection patients show a reduction in the blood loss, in morbidity, as in the hospital stay when the intraoperative CVP is kept < 5 mmHg (Jones et al., 1998;Chen et al., 2000). Implementing the same strategy to OLT, one study found that a low CVP increased morbidity as expressed as postoperative renal failure and mortality (Schroeder et al., 2004), while an other study came to the opposite conclusion (Massicotte et al., 2006). We hold it that volume therapy during OLT is better detected by flow related parameters than by vascular pressure(s) (Bundgaard-Nielsen *et al.*, 2007a;Jenstrup *et al.*,

A PAC allows for monitoring pulmonary artery (mean) pressure (PAMP) as well as wedge pressure (PAWP). These values are relevant to patients undergoing OLT since some patients develop both portal and pulmonary hypertension (Krenn & De Wolf, 2008). It remains, however, elusive whether monitoring of PAWP provides advantages over the continuous recording of PAMP. At least it should be considered that a determination of PAWP carries

the risk of rupturing a branch of the pulmonal artery and that is likely to be fatal.

Fig. 5. Pulmonary artery mean pressure (PAMP) (±SD and 5th and 95th percentile) and cardiac output (CO) (±SD) for 33 candidates for OLT at rest and during exercise (P. Nissen,

filling of the heart as indicated by echocardiography (Thys et al., 1987).

recording in the femoral artery.

1995;Ejlersen *et al.*, 1995b).

unpublished)

It is probably without exception that HR is monitored during OLT and deviations in HR in response to variation in CBV are therefore of interest. In textbook descriptions of hypovolaemic shock it is stated often that tachycardia is the arterial baroreceptor response to a low blood pressure (Secher & Bie, 1985). Yet the common, both experimental and clinical finding is that the HR response to central hypovolaemia encompasses three stages (Secher *et al.*, 1992) (Fig. 6).

With a small reduction in CBV, there is a moderate increase in HR, most often to less than 100 bpm and as indicated, the increase in HR may be so small that it does not become statistically significant (Murrell *et al.*, 2009). However, with a 30% reduction of CBV, both HR and MAP decrease as known from a vasovagal syncope and cerebral perfusion and oxygenation become affected (Madsen & Secher, 1999;van Lieshout *et al.*, 2003). Such an incident is fatal if CBV is not restored immediately (Madsen *et al.*, 1998), but with partial restoration of CBV, intense sympathetic activation in response to (central) hypovolaemia elicits a marked increase in HR (>120 bpm) may be in response to cerebral hypoperfusion. Thus, adequate restoration of CBV in stage II of shock secures the well-being of the patient, while manifest tachycardia (stage III) appears to indicate a transition to an irreversible stage of shock since the patient then is likely to need eventually prolonged intensive care and is then exposed to the associated grave prognosis (De Backer D. *et al.*, 2010). It should also be noted that the administration of atropine to treat bradycardia during haemorrhage is likely to enhance the haemorrhage and, thereby, could be fatal (Bertolini, 1995). At any rate, the administration of atropine hinders the use of HR to monitor an eventual volume deficit. In case of a low HR, volume should be administrated with an expected moderate increase in HR before the "resting" HR is established (Fig. 6). Conversely, it should be checked whether any increase in HR is due to an otherwise undetected (small) volume deficit by supplementing (100-200 ml) of volume and thereby keep HR low and the volume administration can then stop when HR does not decrease further.

Fig. 6. Heart rate (HR) and blood pressure (systolic **v** and diastolic **^**) responses of a patient treated for a ruptured abdominal aneurism. At admission the patient had thacycardia and low blood pressure (stage III of hypovolaemic shock). During volume loading a decrease in HR (stage II) is seen followed by an increase (stage I, preshock) as blood pressure began to increase before stable values were reached; beginning and end of the operation indicated by circles. (From Jacobsen & Secher, 1992 with permission)

### **8. Cerebral autoregulation**

Central to this chapter is the ability to secure CBF and ScO2 during the OLT and thereby, presumably, maintain the patient's well being after the operation (Murkin *et al.*, 2007).

Interest in recording CBF or ScO2 for the OLT patient is relevant not only because these variables may be affected by hypotensive events during the operation in case a low blood pressure reflects a reduced CO, but also because some acute liver disease patients demonstrate impaired cerebral autoregulation (Larsen *et al.*, 1999; Nissen P. *et al.*, 2009; Ejlersen *et al.*, 1994) (Fig. 7).

Cerebral perfusion may be followed by transcranial Doppler (TCD) derived middle cerebral artery mean blood velocity (MCA Vmean) (Pott *et al.*, 1995) and evaluation of cerebral tissue flow by clearance of 133Xe has been carried out during OLT(Larsen *et al.*, 1999). However, it remains that NIRS is, by far the most feasible method for routine monitoring of cerebral perfusion during surgery (Nissen *et al.*, 2009a;Steiner *et al.*, 2009). NIRS reflects changes in brain capillary saturation and mitochondrial oxygen tension in response to manipulation of the inspired oxygen and CO2 tensions (Rasmussen *et al.*, 2007) although a potential influence of skin blood flow needs to be considered (Sato et al., 2011).

While a determination of CBF requires extensive apparatus and calculations, the recording of ScO2 is as readily available as the recording of arterial oxygen saturation by pulsoximetry

shock

**1 2 3 4**

Fig. 6. Heart rate (HR) and blood pressure (systolic **v** and diastolic **^**) responses of a patient treated for a ruptured abdominal aneurism. At admission the patient had thacycardia and low blood pressure (stage III of hypovolaemic shock). During volume loading a decrease in HR (stage II) is seen followed by an increase (stage I, preshock) as blood pressure began to increase before stable values were reached; beginning and end of the operation indicated by

Central to this chapter is the ability to secure CBF and ScO2 during the OLT and thereby, presumably, maintain the patient's well being after the operation (Murkin *et al.*, 2007).

Interest in recording CBF or ScO2 for the OLT patient is relevant not only because these variables may be affected by hypotensive events during the operation in case a low blood pressure reflects a reduced CO, but also because some acute liver disease patients demonstrate impaired cerebral autoregulation (Larsen *et al.*, 1999; Nissen P. *et al.*, 2009;

Cerebral perfusion may be followed by transcranial Doppler (TCD) derived middle cerebral artery mean blood velocity (MCA Vmean) (Pott *et al.*, 1995) and evaluation of cerebral tissue flow by clearance of 133Xe has been carried out during OLT(Larsen *et al.*, 1999). However, it remains that NIRS is, by far the most feasible method for routine monitoring of cerebral perfusion during surgery (Nissen *et al.*, 2009a;Steiner *et al.*, 2009). NIRS reflects changes in brain capillary saturation and mitochondrial oxygen tension in response to manipulation of the inspired oxygen and CO2 tensions (Rasmussen *et al.*, 2007) although a potential influence

While a determination of CBF requires extensive apparatus and calculations, the recording of ScO2 is as readily available as the recording of arterial oxygen saturation by pulsoximetry

**Time (hours)**

Blood pressure (mm Hg)

Heart rate (beats/min)

and

**180**

**140**

**100**

 **60**

 **20**

**8. Cerebral autoregulation** 

Ejlersen *et al.*, 1994) (Fig. 7).

circles. (From Jacobsen & Secher, 1992 with permission)

of skin blood flow needs to be considered (Sato et al., 2011).

Fig. 7. Changes in frontal lobe cerebral oxygen saturation (ΔScO2) related to mean arterial pressure (MAP) for three patients undergoing liver transplantation (A) A patient for whom a lower limit of cerebral autoregulation can be defined. (B) A patient who demonstrates no cerebral autoregulation. (C) A patient for whom no lower limit of cerebral autoregulation was detected (From Nissen et al., 2009 with permission)

and builds on the same technology of protons absorbance in the near infrared spectrum (NIRS) (Madsen & Secher, 1999). However in contrast to pulsoximetry, ScO2 is not coupled to the recording of pulse and, thereby, expresses an average rather than a maximal oxygen concentration of the tissue, i.e. of the brain or skeletal muscles. With spatial resolution NIRS, light is sampled at two distances from the emitter to prioritise absorption of light in the deep tissue, for the head assumed to represent the cerebral cortex (ScO2) and over a muscle (SmO2) oxygen saturation of haemoglobin and myoglobin. Yet, a sustained subcutaneous fat deposit may hinder detection of SmO2 and the thenar muscle is ideal for monitoring SmO2 since there is no subcutaneous fat over that muscle group (Thomson et al., 2009).

Thus frontal lobe oxygenation by NIRS is a non-invasive recording of changes in CBF (Madsen & Secher, 1999) with a correlation between ScO2 and MCA Vmean (Steiner *et al.*, 2009). Also changes in ScO2 parallel those in internal jugular venous O2 saturation (Pott *et al.*, 1995;Skak *et al.*, 1997) and NIRS is able to detect cerebral hypoperfusion (Plachky *et al.*, 2004). The NIRS determined ScO2 is based on the absorption of light in the spectra for oxygenated and deoxygenated haemoglobin and reports tissue oxygenation as a percentage of light absorption by oxygenated to total haemoglobin. An emitter generates light at, e.g. 733 and 808 nm and the reflection is registered by two or more optodes placed at a distance of, e.g. 3 and 4 cm from the emitter to allow for the subtraction of reflections derived from superficial tissues of the scalp and the skull for detection of ScO2 (Grubhofer *et al.*, 1997) (Fig. 8). Thus with increasing distance between the emitter and the optodes, light penetrates deeper into the tissues and with evaluation of absorption at two distances (spatial resolution), absorption in deep tissue, i.e. brain, is appreciated.

Fig. 8. Near infrared spectroscopy applied to the brain. Distance between the light emitter and the optodes 3 and 4 cm. By subtracting the superficial from the deeper reflections, oxygenation of brain cortex is appreciated (from Covidien, Denmark with permission)

Of relevance for the recording of ScO2 during OLT, bilirubin absorbs light in the same wavelength as haemoglobin and depending of the wavelength used to derive ScO2, there

and builds on the same technology of protons absorbance in the near infrared spectrum (NIRS) (Madsen & Secher, 1999). However in contrast to pulsoximetry, ScO2 is not coupled to the recording of pulse and, thereby, expresses an average rather than a maximal oxygen concentration of the tissue, i.e. of the brain or skeletal muscles. With spatial resolution NIRS, light is sampled at two distances from the emitter to prioritise absorption of light in the deep tissue, for the head assumed to represent the cerebral cortex (ScO2) and over a muscle (SmO2) oxygen saturation of haemoglobin and myoglobin. Yet, a sustained subcutaneous fat deposit may hinder detection of SmO2 and the thenar muscle is ideal for monitoring SmO2 since there

Thus frontal lobe oxygenation by NIRS is a non-invasive recording of changes in CBF (Madsen & Secher, 1999) with a correlation between ScO2 and MCA Vmean (Steiner *et al.*, 2009). Also changes in ScO2 parallel those in internal jugular venous O2 saturation (Pott *et al.*, 1995;Skak *et al.*, 1997) and NIRS is able to detect cerebral hypoperfusion (Plachky *et al.*, 2004). The NIRS determined ScO2 is based on the absorption of light in the spectra for oxygenated and deoxygenated haemoglobin and reports tissue oxygenation as a percentage of light absorption by oxygenated to total haemoglobin. An emitter generates light at, e.g. 733 and 808 nm and the reflection is registered by two or more optodes placed at a distance of, e.g. 3 and 4 cm from the emitter to allow for the subtraction of reflections derived from superficial tissues of the scalp and the skull for detection of ScO2 (Grubhofer *et al.*, 1997) (Fig. 8). Thus with increasing distance between the emitter and the optodes, light penetrates deeper into the tissues and with evaluation of absorption at two distances (spatial

Fig. 8. Near infrared spectroscopy applied to the brain. Distance between the light emitter and the optodes 3 and 4 cm. By subtracting the superficial from the deeper reflections, oxygenation of brain cortex is appreciated (from Covidien, Denmark with permission)

Of relevance for the recording of ScO2 during OLT, bilirubin absorbs light in the same wavelength as haemoglobin and depending of the wavelength used to derive ScO2, there

is no subcutaneous fat over that muscle group (Thomson et al., 2009).

resolution), absorption in deep tissue, i.e. brain, is appreciated.

may be a negative influence of plasma bilirubin of the detected ScO2 (Madsen *et al.*, 2000). However, even when plasma bilirubin is elevated and the reported ScO2 is low, the derived value reacts on changes imposed by bleeding and changes in PaCO2.

The significant haemodynamic changes associated with OLT may lead to neurological complications and increased mortality in reflection of reduced cerebral vascular resistance in the first hour after reperfusion of the liver exposing the brain to hyperperfusion (Ardizzone et al., 2006). Thus in case of lacking cerebral autoregulation, CFB is affected both by a low and a high blood pressure and during OLT, blood pressure is likely to increase markedly when surgery leads to manipulation of the adrenal gland with, presumably, release of adrenaline into the circulation. Normally CBF is considered to be maintained within a MAP range from approximately 60-150 mmHg (Paulson et al., 1990). However, cerebral perfusion decreases already at a MAP of 80 mmHg when the decrease in blood pressure is caused by a low CBV and thereby a lowered CO (Madsen *et al.*, 1995). On the other hand, cerebral perfusion and ScO2 may be preserved even at a MAP below 40 mmHg if CBV is not affected (Nissen P. *et al.*, 2009) (Fig. 9).

A given MAP therefore does not guarantee that cerebral perfusion is secured leading to the conclusion that CBF or, more likely, ScO2 should be monitored during the operation (Nissen *et al.*, 2009a).

Fig. 9. Cerebral oxygen saturation (ScO2) related to mean arterial pressure (MAP) including data obtained with a maintained central blood volume (CBV) during anaesthesia (broken line) and from subjects for whom the central blood volume was reduced deliberately during head-up tilt (full line). Normogram illustrates distribution of the lowest MAP in the anaesthetized patients (Modified from Nissen et al., 2009 with permission)

Also it is to be considered that administration of phenylephrine in case of a low blood pressure, in an attempt to increase blood pressure to above what is might present the lower limit of cerebral autoregulation, is associated with a decrease rather than with the probably intended increase in ScO2 (Nissen et al., 2010). Alternatively, hypotension should be considered in relation to a decrease in plasma calcium in response to administration of blood products and calcium should be supplemented to restore the physiological level (1.2 mM). However, the use of phenylephrine may be indicated during reperfusion of the donor liver to reduce peripheral vasodilatation and thereby to centralise of blood accumulated in the splanchnic region. Alternatively, the administration of phenylephrine to increase the blood pressure may be replaced by the use of ephedrine that does not demonstrate the same negative influence on ScO2 (Nissen *et al.*, 2010; Meng *et al.*, 2011).

PaCO2 has a significant influence on CBF and PaCO2 is regularly monitored by a continuous recording of the end-tidal CO2 tension to maintain a value of, e.g. 4,5 kPa. In that regard OLT is no exception, but with the reduction of the metabolic rate during the anhepatic phase of the OLT, a given setting of ventilation may lower PaCO2 and ventilation then needs to be reduced in order to maintain CBF and ScO2 (Madsen & Secher, 1999). Conversely, with reperfusion of the donor liver, PaCO2 increases again and often to values that exceed the level established in the dissection phase of the operation. Accordingly, ventilation should be increased at, or likely before reperfusion of the liver in order to prevent cerebral hyperperfusion and ventilation is thereafter gradually reduced towards the end of the operation guided by ScO2 as the CO2 load is eliminated by the exhaled air.

With optodes placed over a muscle NIRS monitors muscle oxygen saturation (SmO2) and decreases before central hypovolaemia affects blood pressure. However, haemorrhagic hypotension is likely to be caused by a Bezold-Jarisch-like reflex including loss of sympathetic activity and, therefore, an increase in muscle blood flow and in turn SmO2 (Madsen *et al.*, 1995). SmO2 effectively detects central hypovolaemia (Soller *et al.*, 2008) (Fig. 2) and supplements, or may be used as an alternative non-invasive monitoring modality to SvO2 for detection of a blood loss. Ideally SmO2 provides for an early warning of ongoing haemorrhage and allows for direction of fluid administration before the blood loss affects CBF and in turn ScO2.
