Key words : Fluid status, Liver donation surgery, Monitoring

Introduction

Living related donor liver transplant (LDLT) is the only available treatment for patients with end-stage liver disease in Egypt. Donor right hepatotomy is not a complication-free procedure, and every effort is needed to increase donor safety.^1,2 Reduction of the central venous pressure (CVP) is known to reduce hepatic congestion and blood loss during liver dissection, but this requires insertion of a central venous catheter.^3-5 Modified anterior liver parenchymal resection with no selective vascular occlusion of the hepatic inflow (the Pringle maneuver) and with the preservation of the middle hepatic vein significantly can reduce ischemic reperfusion injury and hemodynamic instability and lead to a blood transfusion-free surgery.⁶ This could allow for the introduction of intraoperative minimal or noninvasive cardiovascular monitoring, particularly with the increase in the number of laparoscopic hepatotomies performed among donors. Central venous pressure can be affected by several factors and has known risk factors for morbidity and mortality.⁷ Choi and colleagues in 2015 proposed an alternative fluid management algorithm for use during donor hepatectomy based on the stroke volume variation (SVV) changes.⁸ El Sharkawy and colleagues and Mahmoud and colleagues have previously demonst­rated use of a minimally invasive transesophageal Doppler device during liver resection to monitor hemodynamics and to guide fluid intake.^9,10 The primary goal of our present study was to investigate the interrelationships and agreements between both noninvasive plethysmography variability index (PVI, %) and the SVV (%) of the noninvasive Electrical Cardiometry (EC) method with the traditional invasive CVP method. Our secondary goal was to observe the ability of PVI and SVV to monitor intraoperative changes and to discriminate donors with increased blood loss.

Materials and Methods

We conducted a diagnostic test accuracy study, which was approved by the local ethics and research committee of Faculty of Medicine (02412/2017), Menoufia University in Egypt. Inclusion criteria included consecutive adult LDLT donors (18-45 years old) with American Society of Anesthesiologists classification I (ASA I), all of whom provided informed written consent (2017/2018). The law in Egypt permits a relationship with the recipient up to third-degree relatives. The legal age of consent for donation in Egypt is 18 years old when the recipient is a parent; otherwise, it is 21 years old. All cases received final approval from the Supreme Committee of Organ Donation, Ministry of Health and Population in Egypt.¹

Exclusion criteria included non-ASA I donors, cardiovascular/pulmonary diseases, and those scheduled for laparoscopic liver resection. Primary measurements included PVI, stroke SVV of EC, and CVP systemic hemodynamics and blood loss. Monitoring included 5-lead electrocardiography, continuous invasive arterial blood pressure (IBP, mm Hg), and CVP (mm Hg). We also used pulse oximetry, a nerve stimulation monitor, an esophageal tempe­rature monitor, and an anesthesia depth monitor system (BIS Bispectral Index Monitor; Aspect Medical Systems) per protocol.² The noninvasive hemoglobin concentration (Radical 7 Pulse CO-Oximeter, Masimo) and laboratory hemoglobin concentration were monitored during surgery.

Electrical Cardiometry
The 4 electrodes of the EC monitor (ICON Noninvasive Cardiometer, Osypka Medical) were applied after skin sterilization with alcohol swab. The first electrode was applied approximately 5 cm above the left base of the neck, the second on the left base of the neck, the third on the lower left thorax at the level of xiphoid, and the fourth on the lower
left thorax. Patient data and the correct signal
quality were verified by the EC impedance waveform. The monitored EC data included SVV (%), systemic vascular resistance (SVR), and cardiac output (CO).¹¹

Stroke volume variation
The SVV is the difference between stroke volumes during the inspiratory and expiratory phases of positive pressure ventilation. The intrathoracic pressure becomes positive during the inspiratory phase, and this reduces the preload and decreases the stroke volumes in contrast to the expiratory phase. Reference values of SVV are between 10% and 15%, preferably below 13%. Maintenance of a normal SVV is essential for hemodynamic and volume stability to ensure adequate blood supply and oxygen delivery, and SVV measurement is used to assess a patient’s response to intravenous fluid administration.11

Plethysmography variability index
The PVI is calculated by a pulse oximeter (SET, Masimo) from the respiratory variations in the perfusion index. The perfusion index is the percentage amplitude difference between the pulsatile infrared signal and the nonpulsatile infrared signal. The PVI is calculated by measuring changes in the perfusion index (ie, maximum and minimum perfusion indexes [PImax and PImin, respectively]) during the respi­ratory cycle according to the equation, PVI = ([PImax - PImin]/PImax) × 100. Cannesson and colleagues have demonstrated that the PVI is a predictor of fluid responsiveness in the operating room and shown that the cutoff value to discriminate responders from nonresponders to intravascular volume expansion (in terms of an increase of cardiac index) was a PVI >14%.¹² The PVI concentration was measured with a pulse oximetry probe placed on the finger of the donor.

Anesthesia technique and fluid management
The anesthesia technique for LDLT donors was according to standard protocols for our institution.² For fluid management, we performed intravenous fluid loading before induction of anesthesia. Acetated Ringer solution was infused up to a rate of 6 mL/kg/h but was restricted during liver dissection to reduce CVP; otherwise, the infusion was continuous to maintain mean IBP (>60 mm Hg) and urine output (>0.5 mL/kg/h) at all times. During dissection, fluid administration was restricted to avoid extreme elevation in CVP and to reduce CVP to less than 5 mm Hg with fluid restriction alone with no drug interferences. After resection, crystalloids (acetated Ringer solution) were infused to maintain CVP between 5 and 10 mm Hg with an adequate urine output. For this procedure, boluses of 3 mL/kg of 5% albumin would be administered if the CVP were to fall below 5 mm Hg despite crystalloid infusion after liver resection.^13,14 Hemoglobin >10 g/dL was maintained with packed red blood cell transfusion when required.

Surgical technique
Donor right hepatotomy was performed with a
J-shaped incision and with intraoperative cholan­giography to identify bile duct anatomy. The same surgical team performed all the resections. We used a surgical aspiration dissection device (Cavitron Ultrasonic Surgical Aspirator Excel, Valleylab) to perform hepatic anterior parenchymal transection with electrocautery and without temporary occlusion of vascular inflow or outflow.Measurement times were at 10 minutes after anesthesia induction (T0), hourly during dissection phase (T1 to T3), after resection (T4), and at the end of surgery (T5).

Demographic and other data
Demographic data included age (years), sex, weight (kg), and body mass index (BMI, calculated as weight in kilograms divided by height in meters squared). Operative data included type of resection, anesthesia duration (minutes), total urine output (mL), and volume of infused crystalloids and colloids (mL). Blood transfusion requirement (U) and blood loss (mL) were measured by the volume in the suction bottles and the weight of the surgical packs. Intraoperative hemodynamic parameters included heart rate (beats/min), mean IBP (mm Hg), CVP (mm Hg), PVI (%), SVV (%), SVR (dyn.s.cm-5), and CO (L/min).

Sample size calculation
We calculated the minimal sample size based on a study that presented the low-CVP technique and high SVV (10%-20%) as a guide for fluid manage­ment and replaced low CVP with high SVV (%) to reduce blood loss during donor hepatectomy.⁵ We calculated that a sample size of 34 patients was the minimum sample size required to detect an area under the curve of the receiver operating characteristic (ROC) of 0.85, relative to a null value of 0.6, as statistically significant with 80% power and at a significance level of 95% (accepted alpha error = .05).¹⁵ Data were entered into the SPSS program for statistical analyses (version 21). The Kolmogorov-Smirnov test of normality revealed significance in the distribution of the variables, so the method of nonparametric statistics was adopted. Data are described as median values with interquartile ranges. Categorical variables are described as frequency and percentage. Comparisons were performed among related-samples by the Friedman test as an alternative to the one-way analysis of variance with repeated measures.^16,17 The nonparametric Kendall tau correlation (τ) was used.¹⁸ For evaluation of the intraclass correlation coefficient value, the Cicchetti guidelines were used.¹⁹Box and whisker plots and clustered bar charts were used accordingly. An alpha level was set to 5% with a significance level of 95%, and a beta error was accepted at up to 20% with a power of study of 80%.

Results

Data are presented as median interquartile ratios with interquartile ranges (IQR). Thirty-four living related donors for elective LDLT were included in 1 study group; 64.71% were males, with median age of 26 years (IQR, 21-34 years) and BMI of 25.9 (IQR, 24.0-27.1). All donors were living relatives; 20/34 were sons or daughters (58.8%), 8/34 were wives (23.5%), 5/34 were brothers or sisters (14.7%), and 1/34 was a father (2.94%).

Thirty-three donors underwent right hepatotomy, and 1 donor underwent a left hepatotomy. All hepatotomies were performed without transfusion of any blood products. Statistically, the PVI, SVV, and CVP intraoperative values changed significantly during surgery, as shown in Table 1. A positive correlation existed between PVI and SVV values but was considered negligible despite statistical significance (Figure 1). A negative correlation also existed between PVI and CVP (Figure 2) and another negative correlation existed between SVV and CVP values, but all were of negligible degrees (Figure 3). The parameters for PVI, SVV, and CVP reflected a state of normovolemia during liver dissection despite fluid restriction (Figure 4 and Figure 5). Restriction of intravenous fluid intake alone did not succeed to reduce the CVP to less than 5 mm Hg. The ROC values of PVI (%), SVV (%), and CVP (mm Hg) were unable to discriminate donors with blood loss of more than 400 mL at T3 (3 hours after opening the fascia during dissection) as presented in Figures 6, 7, and 8. No agreement was found between the PVI and SVV (P > .05) parameters (Figure 9).

Both standard laboratory hemoglobin and noninvasive hemoglobin concentrations were measured intraoperatively and reflected stable hemoglobin concentrations during surgery. A significant correlation was demonstrated between both methods for hemoglobin measurement (Figure 10). The repeated measures analyses (Friedman test) for mean IBP, heart rate, CO, and SVR were statistically significant (P < .01), but this was not reflected clinically. Hemodynamic stability was reported during surgery at all times (Table 2). Operative data, volume of infused crystalloids (no colloids used), blood loss, and postoperative data of the donors are presented in Table 3.
Surgery was successful, and all donors were discharged safely after a median stay of 2.5 days in the intensive care unit (IQR, 2-3 days) and a median hospital stay of 9 days (IQR, 9-11 days). Nausea and vomiting were among the most common postope­rative complications in the donors (64.7%) (Table 4).

Discussion

Agreements and correlations between central venous pressure, plethysmography variability index, and stroke volume variation
Negligible correlations existed between CVP and both the PVI and the EC-derived SVV readings as presented in the results section. Several researchers have reported controversial and variable correlations during liver surgery in this context between the CVP and other brands and types of minimal/noninvasive cardiovascular monitors available on market. Weak correlations were reported by Lee and colleagues (in 2017) between SVV and the CVP in a group of 42 living liver donors, particularly during profound vasodilation.²⁰ Another study (in 2013) by Vos and colleagues reported that PVI did not correlate with SVV in a group of patients who underwent hepatic resection.²¹

In contrast, a significant correlation was identified by Fu and colleagues between SVV and PVI.22 Harimoto and colleagues and Dunki-Jacobs and colleagues also reported a significant correlation between SVV and CVP.^23,24 Biais and colleagues reported that the SVV readings obtained from the Vigileo system (Edwards Lifesciences) accurately predicted fluid responsiveness in patients who experienced circulatory failure during liver tranplant.²⁵ These variations between the above-mentioned studies and the present study could be caused by the technical differences between SVV measured from an invasive arterial catheter (eg, the Vigileo system) and the SVV derived from the noninvasive bioimpedance technology of the EC adopted in our study. It is important to mention that most of the SVV studies mentioned above were based on the Vigileo arterial pulse-pressure contour analysis system, which requires the use of an arterial blood catheter to measure the blood pressure. Few researchers have studied SVV monitored with EC, which is noninvasive and relies on thoracic electrical bioimpedance during liver surgery. Future research and improvements in technologies of these noninvasive-derived measu­rements are required to further reduce the need for invasive monitoring.^26,27

Multimodal monitoring
In this study, we advocate for the benefits of a multimodal monitoring approach during major surgery. This would avoid the disadvantages of sole dependence on a single monitor target, such as the CVP, the accuracy of which can be affected by multiple factors. Kim and colleagues demonstrated that the CVP readings could be affected by patient position, ventilation, and manipulation during surgery; it was not proved that central venous pressure was an independent predictor for intraope­rative hemorrhage during the donor surgery.²⁸ However, the additional data provided by the EC device, ie, CO and SVR, allows a larger scope of monitoring. A study by Ratti and colleagues (in 2016) demonstrated that intraoperative monitoring of the cardiac preload and CO together with SVV did aid in the treatment of the patients in their study and improved the outcomes of laparoscopic liver surgery compared with the traditional sole monitoring of CVP.²⁹ The CVP method has been challenged by other researchers who used noninvasive or minimally invasive fluid guidance parameters and claimed these methods were better to predict the patient response to fluid administration.^30,31 In 2 recent meta-analysis studies, Marik and colleagues suggested abandonment of the CVP as a guide for fluid therapy.^32,33 In contrast, Cecconi and colleagues asserted that the CVP remains an important guide for fluids despite the variability in fluid resuscitation among critically ill patients.^34,35 Preliminary reports from Kim and colleagues (2011) and Su and colleagues (2012) demonstrated the beneficial role during liver transplant for monitoring and maintaining a high level of SVV to reduce blood loss during surgical procedures on recipients and donors, respectively.^28,36 Among the 93 liver donors studied by Kim and colleagues, 38.7% had a blood loss of ≥700 mL.³⁸ The factors associated with blood loss ≥700 mL were heart rate, SVV, CO, and SVR. Only SVV was found to be an independent predictor of blood loss ≥700 mL. The ROC curve analysis in the study by Kim and colleagues calculated that the optimal cutoff value was 6% or less for the SVV to predict blood loss ≥700 mL. This could explain the reduced blood loss volume in our current study. The SVV measurements during the dissection phase times were 8.00% (range, 7.00%-9.00%) at T2 and 10.0% (range, 8.0%-10.0%) at T3, and all values were above 6%, rather that lower than 6% as suggested by Kim and colleagues. The blood loss in our study was low (400 mL; range, 400-500 mL) compared with the 700 mL reported by Kim and colleagues. This could be due to avoiding a state of extreme hypervolemia (SVV <6%) as a result of the fluid restriction policy adopted in this current study.

As early as 2010, Zimmermann and colleagues found that the SVV measured by the FloTrac/Vigileo system and the PVI measured by Masimo plethysmography waveform analysis both have the potential to serve as valid indicators for fluid responsiveness in patients during mechanically ventilated surgery.³⁷ Fu and colleagues²² in 2012 and Vos and colleagues²¹ in 2013 agreed that the best threshold values to predict fluid responsiveness were >12.5% for SVV and >13.5% for PVI in the real surgical setting. Later, in 2016, Chu and colleagues published their systematic review and meta-analysis of 18 studies among 665 patients and demonstrated that PVI had a reasonable ability to predict fluid responsiveness but that the applicability of PVI may be limited by potential interference from several factors such as arrhythmia and low peripheral perfusion.³⁸ Wu and colleagues in their diagnostic accuracy prospective study (also from 2016) among 31 recipients who underwent LDLT demonstrated that multimodal dynamic preload variables (PPV, SVV, and PVI) predicted stroke volume fluid responsiveness in liver patients.³⁹

The improvements in surgical techniques during the past decade have allowed surgeons to perform donor hepatotomies without blood transfusion in most of the volunteers, and this is considered a step toward the highest safety for donors.⁶ In the present study, we have shown that normovolemia is permissible during liver resection if there is prevention of extreme elevation in CVP or extreme reductions in SVV and PVI. This should improve donor safety and reduce any risk from air embolism during dissection phase when the hepatic sinusoids are open.

Another point demonstrated in our study was the shift toward a laparoscopic-assisted surgical approach during liver resection in high-volume liver transplant centers. This shift may encourage the further adoption of the noninvasive monitor approach during anesthesia.⁴⁰ Shih and colleagues⁴¹ reported that a CVP of less than 5 mm Hg, as previously suggested by several authors, is not always a clinical possibility. Our study agreed with the report from Shih and colleagues, that fluid restriction alone was unable to lower the CVP below 5 mm Hg in most of the volunteers. Shih and colleagues suggested that a CVP of less than 8 mm Hg or SVV of less than 13% is sufficient to reduce the blood loss during donor hepatectomy to 100 mL. Kim and colleagues, as mentioned above, calculated that the optimal cutoff value was 6% or less for SVV to predict blood loss of ≥700 mL.²⁸ However, the ROC analyses for CVP, PVI, and SVV in our study failed to act as discriminators for blood loss during liver resection (P > .05) in contrast to the Shih study, which may be because of the reduction of blood loss to 400 mL. More studies are recommended in this specific population during liver donation surgery.

Seo and colleagues⁴² and Choi and colleagues⁸ have published studies that concluded that mainte­nance of an SVV value between 10% and 20% during liver donor hepatectomy would reduce blood loss during surgery.

Another important aspect to our study is the surgical technique. In our study and in the study by Kim and colleagues,²⁸ the Cavitron Ultrasonic Surgical Aspirator and electrocautery devices were used during liver resection without any temporary occlusion of vascular inflow or outflow, which played an important role to reduce the intraoperative bleeding.

Conclusions

Negligible correlations and poor agreements existed between PVI, SVV, and CVP. Both PVI and SVV were able to present trends for intraoperative changes but were unable to discriminate donors with greater blood loss. With regard to the advancements in laparoscopic liver resection among donors, more studies are needed to develop protocols with noninvasive parameters such as PVI and SVV, particularly in surgery with high blood loss. Adoption of a multimodal monitoring approach would provide additional hemodynamic data such as noninvasive CO and SVR to support intraop­erative management and informed decisions. A transfusion-free liver dissection was possible with permissible normovolemia. The median values during liver dissection of CVP, SVV, and PVI were 8 mm Hg, 10%, and 12%, respectively, despite fluid restriction.

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