Comparison Between 2 Strategies of Fluid Management on Blood Loss and Transfusion Requirements During Liver Transplantation

Author’s Accepted Manuscript Comparison of the Effect of two Strategies of Fluid Management on Blood Loss and Transfusion Requirement During Liver Transplantation Nirmeen A. Fayed, Khaled A. Yassen, Ayat R. Abdulla www.elsevier.com/locate/buildenv

PII: DOI: Reference:

S1053-0770(17)30235-5 http://dx.doi.org/10.1053/j.jvca.2017.02.177 YJCAN4027

To appear in: Journal of Cardiothoracic and Vascular Anesthesia Cite this article as: Nirmeen A. Fayed, Khaled A. Yassen and Ayat R. Abdulla, Comparison of the Effect of two Strategies of Fluid Management on Blood Loss and Transfusion Requirement During Liver Transplantation, Journal of Cardiothoracic and Vascular Anesthesia, http://dx.doi.org/10.1053/j.jvca.2017.02.177 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Comparison of the effect of two strategies of fluid management on blood loss and transfusion requirement during liver transplantation Nirmeen A Fayed MD 1, Khaled A Yassen MD , FFARCSI 1 , Ayat R Abdulla MD2

1

Anesthesia and Intensive care department ,2 Public Health and Community department, National Liver Institute, Menoufia University, Egypt.

Corresponding author Nirmeen A Fayed E-mail: [email protected] Address: National Liver Institute, Menoufia ,Egypt. Mobile: 00201068039021

Objective: to compare the effect of low central venous pressure (LCVP) and transesophageal Doppler (TED) guided fluid management on blood loss and blood transfusion during liver transplantation (LTx). Design: retrospective study Setting: single–institutional, university hospital Participants: Adult recipients of LTx Interventions: Two groups. Control (LCVP G), n=45 with CVP was maintained 40% lower than the preoperative value during the preanhepatic phase. The mean arterial pressure was kept >60 mm Hg. This group was matched with the second group (TED G); n=45, in which a TED protocol was followed with maintaining the systemic vascular resistance (SVR) more than 750dyns-1secm-5. Coagulation defects were corrected following thromboelastometry. Measurements and Main Results: Intraoperative blood loss, blood products, perioperative creatinine, lactate and postoperative patients’ stratification according to AKIN classification were compared. Prior the anhepatic phase, CVP was significantly lower in LCVP G (p < 0.001). TED G tended to have less, but nonsignificant; blood loss, packed red blood cells (RBCs), fresh frozen plasma (FFP) and platelets and received significantly less colloid and higher norepinephrine. Lactate was significantly higher in LCVP G at the end of the anhepatic phase and end of surgery while, urine output in the preanhepatic phase was significantly lower. Creatinine was significantly lower on postoperative day 1, and 3 and AKIN stages were better in POD1 in TED G. Conclusions: During LTx, TED guided fluid management, with norepinephrine used to maintain SVR, was similar to LCVP regarding blood loss and transfusion requirements and has better impacts on Kidney function and lactate.

Introduction Low central venous pressure (LCVP) has been evidenced to minimize blood loss during hepatic surgery, including liver resection1-4 and liver transplantation (LTx)

5-9

. However, this fluid

management strategy remains questionable in the setting of LTx due to many reasons related to the pathophysiology of the end stage liver disease and the CVP reliability to reflect the actual volume status. From the functional point of view, patients with advanced liver cirrhosis have a hypovolemic, hyperactive circulation with decreased arterial blood volume 10, 11. Severe liver disease also, results in abnormal regional blood flow and impaired autoregulation to a variety of organ systems. Laboratory and human evidences have shown changes in cerebral, renal, and mesenteric blood flow when compared to healthy controls 12, 13. Therefore, and in contrast to the patients undergoing liver resection who are considered relatively healthy, the risk of maintaining LTx patients in a hypovolemic state, even for the short time of the induced low CVP, may overcome the benefit of this strategy regarding reduction of blood loss as the intrinsic autoregulation and physiologic reserves are inadequate to maintain organ viability for the relatively brief period. According to Schroeder RA et al., 14 generalizations of other strategies from the world of non-transplant hepatobiliary surgery to the end-stage liver failure patient should be done with caution. This is especially true for volume management strategies. In cirrhotic patients, CVP readings is not a good indicator of the actual volume status neither during fluid restriction nor during volume expansion15 and the traditional target values for CVP failed apparently to exclude hypovolemia in hepatorenal syndrome 16. Intraoperatively, there are further factors that negate the ability of CVP to accurately reflect the intravascular volume 14 in the setting of LTx as positive pressure ventilation, ascites, retractor

and clamp position, surgical technique, intraoperative patient position, catheter position, and cirrhosis related comorbidities as tricuspid valvular pathology, pulmonary hypertension and impaired right ventricular function. The impact of LCVP strategy on the kidneys is especially important as the peritransplant period carries great challenges for the renal function. An incidence of creatinine >1.8 mg/dl was reported in 22% of patients scheduled for LTx recipients of LTx

18

17

. Renal impairment occurs in 4-86% of

. Postoperative renal impairment is an independent risk factor for both30

days and 2 year- mortality, as well as short and long-term survival

19-21

. So the issue of renal

compromise must be seriously considered. Goal- directed therapy (GDT) is a strategy refers to the perioperative monitoring and manipulation of hemodynamic parameters by means of fluids, red blood cells, and inotropic drugs

22

to face the increase in oxygen demand and to prevent organ failure23. Data suggest that

hemodynamic optimization may decrease morbidity and mortality in high-risk surgical patients 24, 25

. In their study, Brienza N et al.

26

have concluded that surgical patients receiving

perioperative hemodynamic optimization are at decreased risk of renal impairment. Transesphageal Doppler (TED) has been successfully approved for optimizing fluid management perioperatively and in intensive care patients described the use of TED as a sole

32

27-31

. During LTx, some study groups have

or in comparison with thermodilution method

33, 34

for

cardiac output monitoring. Maintenance of a stable, adequate circulating blood volume and hemodynamics via esophageal Doppler-guided goal-directed fluid management in Ltx recipients all over the operative period should be useful for ensuring optimal perfusion, and is expected to help avoiding the potential complications of the occult hypovolemia. However, the impact of TED guided fluid management

during LTx on the blood loss and transfusion requirement is not yet studied. In our Institute we had used to follow low CVP strategy to minimize intraoperative blood loss during LTx before the introduction of the TED in our operation rooms as a standard tool for hemodynamic monitoring and fluid management. This change in management left an important question behind, how TED protocol would affect the intraoperative blood loss and the subsequent blood transfusion. In this retrospective study we tried to investigate the hypothesis that the change in fluid management might affect blood loss and subsequent blood transfusion. The primary outcome of this study was to detect the effect of TED guided fluid management protocol, compared to LCVP, on blood loss and transfusion requirement in the setting of LTx. Secondary outcomes included 1st the impact on kidney function as assessed by the changes in the absolute values of intraoperative urine output and the perioperative creatinine, and the changes in the functional category of kidney as assessed by the stage changes according to AKIN (Acute Kidney Injury Network) classifications35. 2nd the changes in perioperative lactate levels as a marker of tissue perfusion and liver eliminating function.

Patients and Methods After Institutional Review Board approval was obtained, the medical and anesthesia records of 167 adult recipients for living donor LTx were retrospectively reviewed. During the period from July 2011 till August 2012, a total number of 46 adult recipients had their operations under LCVP technique. One patient was excluded due to incomplete data. The remaining 45 patients represented the control group (LCVP G) in which CVP was reduced by about 40%14 during the preanhepatic phase by limiting infusion volume, forced diuresis and manipulating the patient's posture. The mean arterial pressure was kept > 60 mm Hg using vasoconstrictors mainly ephedrine boluses. Norepinephrine infusion was used in non- responding cases. Those patients were matched with 45 patients (ratio 1:1) of total number of 121 recipients who had their operations during the period from September 2012 till October 2014. Figure (1) represents a flowchart showing patients of both groups.

Those patients represented the second group (TED

G) , who received intraoperative fluid guided by a TED (Cardio QTM; Deltex Medical, Chichester, UK) protocol

36

depending on optimizing the corrected flow time (FTc) (330-360

msec.) and stroke volume (SV) (60-100 ml) (figure 2) with keeping the SVR more than 750 dyns-1sec m-5 using noradrenaline. The matching was performed regarding the age, MELD score, portal hypertension as defined by presence of ascites and/or varicial bleeding , previous abdominal surgery, duration of surgery, and preoperative hemoglobin (Hb), INR, and platelet count (matched on a range basis). Fluids infused included; Ringer acetate, 6% hydroxyethyl starch (130/0.4, Fresenius, Kabi) with maximum dose 30ml kg-1, and albumin 5%. The rate of infusion was manipulated according to both protocols. Coagulation defects were corrected only when there is uncontrolled surgical bleeding following thromboelastometry. Hb was kept above 8 gm/dl. Cell saver and acute

normovolemic hemodilution were not used in any of our patients. All procedures were performed by one surgical team. Neither venovenous bypass nor any piggyback techniques were used. The same immunosuppressive therapy protocol was followed in all patients. The following parameters were compared between both groups; intraoperative blood loss, blood products and fluid requirements, vasoconstrictors consumption, urine output (UOP) during the preanhepatic phase and total, absolute values of creatinine (preoperatively, and postoperative days 1, 3, 5), and lactate (preoperatively, at the end of anhepatic phase, at the end of surgery, and postoperative days 1, 3). Patients of both groups were stratified in different stages according to AKIN classifications in POD 1,3,5. The readings of heart rate and mean arterial blood pressure for each hour intraoperatively were collected and the means of these readings were compared between both groups.

Statistical Analysis: Considering the intraoperative blood loss as the 1ry outcome, the power of the sample in this study was calculated as 75% depending on the previous similar studies using Power and Sample size Calculation software version 3.1.2 The data has been collected and entered into the computer using SPSS (Statistical Package for Social Science) program for statistical analysis, (version 17; Inc., Chicago. IL). Two types of statistics were done; 1. Descriptive statistics: where quantitative data have been shown as mean, and SD, while qualitative data was expressed as frequency and percent, 2. Analytical statistics: where Chi- square test has been used to measure the association between qualitative variables, Student t-test has been used to compare mean and SD of 2 sets of quantitative normally distributed data, while the Mann- Whitney test was used when this data is not normally

distributed. Multiple linear regression analysis for blood loss as a dependent variable and the statistically significant variables in the comparison of both groups was done. Scatter plots have been plotted for the variables continued to be statistically significant in the multiple regression analysis. Pearson's correlation has been used to study the correlation between two variables having normally distributed data. The P - value will be considered statistically significant when it is < 0.05.

Results Patients’ characteristics and clinical data are described in table (1). Baseline fibrinogen level (mg/dl) was significantly lower in TED G (116±55.11 vs. 163.3±61.03, p<0.05). No significant difference between both groups regarding the end of surgery Hb, INR, fibrinogen and platelet count. Prior the anhepatic phase, CVP (mm Hg) was significantly lower in LCVP G (5.8±0.9 vs. 9.3±1.2, p < 0.001). The hemodynamic data of both groups and the TED findings of TED G are shown in tables (2) and (3). TED G had statistically significantly higher mean intraoperative blood pressure and tended to have lower heart rate when compared to LCVP G. TED G tended to have less, but non-significant; blood loss and RBCs FFPs and platelet transfusion but received significantly more cryoprecipitate (1.96±3.2 vs. 1.22±3.3, p<0.05) and significantly less colloid (L) (3.3±0.73 vs. 3.8± 1.07, p=0.01). Regarding vasoconstrictor consumption; Four patients in LCVP G and 11 in TED G received noradrenaline (p<0.05). On the other hand 15 patients in LCVP G vs 9 patients in TED G received ephedrine (p=0.06) with mean value (mg) 4.77 (8.06) vs 0.86 (2.42) p = 0.002 respectively. Blood products, fluids transfused and vasoconstrictors requirement are shown in table (4). Table (5) shows the perioperative readings of lactate,

creatinine, and UOP at different measuring points. Lactate was significantly higher in LCVP G at the end of the anhepatic phase and the end of the surgery (p <0.001, 0.01 respectively). Creatinine was significantly lower in the TED G on postoperative day1, and 3 (p=0.02, 0.04 respectively). UOP during the preanhepatic phase, but not total UOP was significantly lower in GI (p <0.001).. Table (6) shows comparison between both groups regarding patients distribution according to the AKIN classification. There was statistically significant difference between both groups in the POD1with an incidence of AKI of 64.8% in LCVP G vs 43.2% in the TED G. The comparison was insignificant in POD3, 5. Three patients in LCVP G and one in TED G required postoperative renal replacement therapy. The results of

multivariate linear regression analysis

(Table 7)

defined

only colloid

transfusion and noradrenaline as statistically significant independent variables that influence intraoperative blood loss with p value = 0.0004 and 0.004 respectively. Scatter plot shows that more colloid transfusion (3) was strongly associated (R2 0.63) with more intraoperative blood loss while more noradrenaline consumption (4)

was fairly associated with less intraoperative

blood loss. No significant correlation has been found between CVP and SV at any measuring point in TED G as shown in table (8). None of our patients experienced clinically significant air embolism in LCVP G. And no complications related to TED insertion were recorded. The 3 months survival was 73,3% in LCVP G and 77,7% in the TED and showed non- significant difference (p=0.62)

Discussion: In this retrospective study, the described TED guided fluid management protocol was similar to the LCVP technique regarding its effect on blood loss and subsequent blood transfusion and was accompanied by a better impact on kidney function and lactate profile. To eliminate bias and increase comparability, the 2 groups were matched regarding most of the factors that are suspected to affect blood loss and transfusion requirement during LTx 37-40 The protocol of TED guided fluid management depended on FTc and stroke volume changes. FTc, has been reported to predict fluid responsiveness better than CVP

41

in different surgical

settings in the supine 41,42and prone position 43. In addition, changes in SV index caused by fluid loading correlated with FTc values before fluid loading 41. The hemodynamic factors which prevents adequate filling of the left ventricle and subsequently limit the use of FTc as a guide for fluid management

44

were already excluded in our patients by

being recipients for LTx. FTc is also inversely proportional to afterload45. In TED G, SVR was kept more than 750 dyns1

sec m-5. Therefore, FTc could be a reliable predictor of fluid responsiveness in this study. Except for the cryoprecipitate transfusion which was higher in TED G, the use of the other

blood products was comparable in both groups. This higher use of cryoprecipitate can be explained by the preoperative significantly lower fibrinogen level in the same group. In comparison to the LCVP group in the study of Massicotte L et al. 6,

the LCVP G in this

study had more blood loss and more transfusion requirements. Some differences between both studies may explain this result. First, while Massicotte L et al. restricted blood transfusion in the preanhepatic phase, the current study did not restrict transfusion when indicated in the same phase. Second, the Hb trigger to RBCs transfusion was 61.7 gm/l in Massicotte L et al. study

which is lower than trigger used in our study. Third, we did not use a cell saver (was not available in our hospital at the time of study) or do phlebotomy in any of our patients while Massicotte L et al. used cell saver in 27.6 % and phlebotomy was done in 44.5 % of their patients. Furthermore, the harvested blood of the phlebotomy was retransfused to the patients with its preserved coagulation factors, a cause which may augment coagulation and reduce blood loss and blood products required. Our results regarding blood loss appear to be in a nearer range to that of Feng et al. 9 who reported an estimated total intraoperative blood loss in the LCVP group of 1922 ± 1429 ml and an RBC transfusion of 1200 ± 800 ml. Feng et al. did not use phlebotomy or cell saver, did not restrict blood products in the preanhepatic phase, and depended on laboratory results for coagulation management. Also, it is worth mentioning that Feng et al. used somatostatin as an intravenous continuous infusion which could affect blood loss by lowering the portal pressure. RBCs transfusion in this study, comes also in agreement with the results of Schroeder RA, et al. 7 who reported a mean RBCs transfusion of 3.8 (0.7) units. In this study, there was no significant difference between both groups regarding blood loss. LCVP, through decreasing portal vein pressure and reducing the flow of the portal system and collateral circulation, can eventually reduce blood loss9.Furthermore,the restriction of fluid infusion at the beginning of surgery may help the coagulation function 6.On the other hand, the applied TED protocol could achieve, less (non-significant) intraoperative bleeding through reduction of the total colloid requirement which might decrease bleeding with surgical trauma probably due to decreased venous congestion and portal pressure. The decrease in colloid transfusion with TED guided fluid management was also described by other studies

46, 47

.

Another potential factor that might affect blood loss in TED G would be the higher tendency to

use noradrenaline which could help in reducing fluid requirement and subsequently blood loss as recently concluded by an experimental study 48 Multivariate analysis of the possible independent factors affecting blood loss (those variables which were significantly different when comparing both groups) defined colloid transfusion and noradrenaline consumption as the only significant variables. Baseline fibrinogen level was nonsignificant in this analysis. This can be explained by the intraoperative correction of fibrinogen as evidenced by a corresponding higher cryoprecipitate transfusion in the TED G and the nonsignificant comparison of the fibrinogen level of both groups at the end of surgery. What was surprising in this multivariate linear regression results is the failure of the preanhepatic CVP to be defined as a significant independent predictor of blood loss. This may be explained by the effect of the CVP readings of the TED G and its irrelevant relation to amount of fluids given and vasoconstrictor consumed and subsequent blood loss on the total interpretation. We assume that this effect prevented the supposed strong association between the LCVP values and the decreased blood loss in the LCVP G to be evident. This result gave a strong impression that, although the anesthesia team was not blinded to the CVP values during the management in TED G, they totally ignore the CVP readings as a guide for fluid transfusion. In this study, the absolute values of serum creatinine were significantly lower in TED G when compared to LCVP G in POD 1,3. When interpreting these value changes as stages according to the AKIN criteria, which are found to be a useful tool in the recognition and classification of the severity of renal dysfunction in patients after LTx

49

, we found also a statistically significant

difference between both groups in the POD1 (p= 0.033).

Although the total fluid transfused was higher in the LCVP G, TED G had better renal outcome. In a review, studying the volume of fluid resuscitation and the incidence of acute kidney injury, it was difficult to ascribe benefits of goal- directed therapy to the provision of greater volumes of intravenous fluids as the protocolised GDT did not result in significantly larger volumes of fluid therapy when compared with standard management 50. It seems that the period during which the patients were exposed to LCVP had considerable deleterious effects on kidney function. This can be supported by the statistically significant lower UOP in the preanhepatic phase in the LCVP G. It is widely known that volume depletion is the most important risk factor for the development of post-transplant chronic renal failure

51

. No previous studies compared the effect of LCVP and

TED on renal function during LTx. The available studies compared LCVP and control (normal CVP) during LTx or GDT and control during other kinds of surgeries. Schroeder RA et al. 7, 52 recommended that LCVP should be avoided in patients undergoing LTx as it was associated with increased rates of postoperative renal failure when compared to control. However, Macicotte L et al

53

and Feng et al.9 did not report any detrimental effect on renal function accompanied with

LCVP technique. In a stratified meta-analysis study

54

of perioperative fluid management

strategies in major surgery, renal complications were less common in with GDT. Also in a systematic review

50

of 24 perioperative studies, GDT was associated with decreased risk of

postoperative acute kidney with limited additional fluid given. Besides intraoperative maintenance of an adequate kidney perfusion, the applied TED protocol was accompanied by a significantly higher number of patients who required noradrenaline, a possible factor that may contribute to the explanation of the better renal function. While, norepinephrine infusion can decrease renal blood flow under normal circulatory conditions due to vasoconstriction, 55 it acts differently in conditions with stressed circulation, such that visceral

organ blood flow would increase rather than decrease. So it restores arterial pressure without increasing renal vascular resistance and as such, renal blood flow tends to increase 56 57, In this study, the mean arterial blood pressure in TED G was significantly higher compared to LCVP G. The hyperdynamic state due to vasodilation in liver failure may require the addition of noradrenaline to increase MAP and, therefore, optimize renal perfusion51. Also noradrenaline has been reported as a potential drug to improve

kidney function in cirrhotic patients with

hepatorenal syndrome 16,58, 59 The baseline lactate level in both groups was higher than normal due to impaired lactate clearance by the liver dysfunction60,61. The intraoperative changes in lactate level follow the lactate profile changes in other studies62. During anhepatic phase lactate increased as the hepatic function is completely abolished in all patients, so lactate elimination is almost abolished. Furthermore, the increase in lactate level in this phase is due to the increased lactate production as a result of organ hypoperfusion63. At the end of surgery, lactate tended to decrease compared to other intraoperative readings as the new graft started to eliminate lactate. The comparison of the lactate readings between both groups at just prereperfusion and at the end of surgery showed a significant lower lactate level in the TED G. Orii R et al.,

62

found that the rate of lactate

elimination correlated positively with the graft body weight ratio in the new hepatic phase, while the accumulation of lactate correlate significantly with preoperative bilirubin in the preanhepatic phase. Since the baseline values of these two variables were similar

in both groups, the

significant difference could not be attributed to either of them. Adequate volume management during LTx is a gold standard for improvement of tissue perfusion64. Goal-directed fluid management in TED G helped to optimize tissue perfusion and hence decreasing blood lactate. This result comes into agreement with Chytra I et al

36

, who

found that optimization of intravascular volume using TED in multiple-trauma patients was associated with a decrease in blood lactate levels. The same effect of GDT on lactate level has been reported in other clinical scenarios as hypertensive elderly patients who had gastric cancer surgery65, patients who had high-risk surgery 66, and in the critically ill patient 67. The LCVP technique during LTx allowed significantly earlier tracheal extubation when compared to control groups received standard care in one study68.In the current study, the TED protocol permitted even significantly shorter duration of postoperative mechanical ventilation when compared to LCVP. There were no statistically significant differences between both groups regarding some possible factors that may influence the time till extubation including the duration of surgery, and the amount of the blood products required. The ICU team, who was responsible for the extubation, was following the same policy in all patients. So it is possible to attribute this difference, to some extent, to the less fluid transfusion. In their study of the effect of intraoperative TED- versus CVP-guided fluid therapy during renal transplantation, Srivastava D et al.46 reported a reduced incidence of postoperative complications related to fluid overload in TED group due to the use of a significantly less amount of fluid. Many studies have linked the use of goal-directed fluid management with decreased length of stay 69, 70. In this study, the duration of ICU stay was comparable in both groups. A shorter tracheal extubation time did not change the length of ICU stay in TED G. Actually, early tracheal extubation cannot induce a shorter ICU stay, especially after operations as LTx in which the decision to discharge the patient relies on a fixed protocol considering many different aspects. The 3 month survival between both groups tended to be lower in LCVP G but the comparison was non-significant. Schroeder RA et al.7,52 have reported an increased rates of mortality with LCVP technique in patients undergoing LTx when compared to control.

In this study, no correlation was found between CVP and SV at all measuring points in TED G. This appears to be logic as CVP reflects the pressure on the right side of the heart while SV reflects a volume on the left side of the heart. It has been demonstrated that neither the CVP nor its trend accurately reflected left ventricular preload in response to fluid challenge in hemodynamic instability71,72. One more study

73

found that the total blood volume index

correlate well with stroke volume index but not with the CVP. Another study

47

found no

significant statistical correlation between CVP and FTc values at different measuring time points during liver resection. This study is limited by the following; first, the retrospective design. A future prospective, randomized study is recommended. Second, the small number of the patients, which gave the study a power of 75 %. Third, we neither compare blood loss during the preanhepatic phase, the period during which the CVP was reduced in LCVP G nor compare the incidence of the postoperative pulmonary complications as there were no sufficient available data. Fourth, the practitioners were not blinded to the CVP readings in TED G with the possibility that the CVP values might have an influence on the management in TED G. We can rule out that effect by the significantly higher preanhepatic CVP readings in TED G and also by the non- significant effect of the preanhepatic CVP readings in the multivariate linear regression analysis for blood loss. Fifth, the time period of the study over 3 years might affect to some extent the results interpretation due to possible changes in practice or techniques but this is a remote possibility because our management protocols were almost unchanged during this time period. Conclusion: during living donor LTx, TED guided fluid management, with norepinephrine used to maintain systemic vascular resistance, was similar to LCVP technique regarding the effect on

blood loss and subsequent blood product requirements. Use of TED in this way helped decrease colloid transfusion with better impacts on renal function and lactate profile.

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Legends of the figures

Figure 1. Flowchart showing the numbers of patients assessed and enrolled in the study. LCVP, low central venous pressure; TED, transesophageal Doppler.

Figure 2. Protocol of TED guided fluid management in TED G. FTc; corrected flow time, SV; stroke volume.

Figure 3. Scatter plot showing that more colloid transfusion was strongly associated with more intraoperative blood loss. Predictive significance of colloid transfusion on multivariate analysis was p= 0.0004.

Figure 4. Scatter plot showing that more noradrenaline was associated with less intraoperative blood loss. Predictive significance of noradrenaline on multivariate analysis was p =0.004.

Table 1. Patients’ characteristics and perioperative relevant clinical and laboratory parameters Variable

LCVP G (n=45)

TED G (n=45)

P

Age (Y) Sex (male/female) Etiology HCV n. (%) HCB n. (%) HCC n. (%) HCV+ HCC n. (%) PHT Previous abdominal surgery MELD GBWR

51 ± 5.7 40/5

53± 4.9 39/6

0.11 .72

28 (62.2) 3 (6.7) 4 (8.9) 10 (22.2) 41 (91.1) 2 (4.4) 17.67± 3.68 1.09±0.14

26 (57.8) 5 (11.1) 5 (11.1) 9 (20) 39 (86.7) 1 (2.2) 18.42± 1.69 1.05±0.19

.66 .45 .72 .79 .5 .55 .47 .39

Total bilirubin (mg/dl)

2.57±1.6

2.29±1.81

.51

Baseline Hb (gm/dl) End surgery Hb (gm/dl Baseline INR End surgery INR Baseline platelet count (x109/l) End surgery platelet count (x109/l) Baseline fibrinogen (mg/dl) End surgery fibrinogen (mg/dl) Duration of surgery (H) Duration of anhepatic phase (hour)

10.91± 1.61 8.84 ± 1.69 1.62 ± .42 2.37 ± .51 84.33 ± 41.18 51.22± 15.54 163.30± 61.05 90.83 ± 34.23 10.89±1.86 3.1±0.72

11.21± 1.76 8.63 ± .97 1.72 ± .45 2.41± .62 76.78± 54.45 46.73 ± 15.64 116.56 ± 55.11 84.92 ± 43.20 10.53± 1.70 2.8±0.72

.23 .47 .28 .74 .45 .17 .00 .47 .34 .38

Duration of postoperative MV (hour)) 7.04±3.29 5.78±3.72 .031 Duration of ICU stay (day) 6.83±1.27 6.53±1.92 .39 Data are representes as mean ± SD . LCVP G; low central venous pressure group,TED G ; transesophageal Doppler group, HCV; hepatitis C virus, HCB; hepatitis B virus, HCC; hepatocellular carcinoma,PHT; portal hypertension, MELD; model of end stage liver disease,GBWR; graft body weight ratio, Hb;hemoglobin, MV;mechanical ventilation P < .05 is considered statistically significant difference

Table 2. Hemodynamic parameters and of both groups Variable

LCVP G (n=45)

TED G (n=45)

P

baseline HR (beat/min)

88.65± 4.57

87.6 ± 4.78

.48

Mean Intraoperative HR (beat/min) baseline MAP (mmHg)

93.73 4.89

91.75 4.74

.07

72.6±6.36

73.7±5.84

.35

Mean of Intraoperative MAP (mmHg) CVP (mmHg) Baseline Preanhepatic 30 min post reperfusion End surgery

66.28 ± 4.0

71.48 ± 4.93

.001

10.80±1.42 5.85±.86 11.74± 1.20 9.46± 1.18

10.29± 9.31± 11.44± 9.38±

.11 .00 .23 .73

1.64 1.22 1.13 1.02

Data are representes as mean ± SD. LCVP G;lowcentral venous pressure group,TED G ;transesophageal Doppler group,HR;heart rate, MAP;mean arterial blood pressure . P < .05 is considered statistically significant difference

Table 3. Transesophageal findings at different measuring points in TED G Variable

FTc (msec)

SV (ml)

Baseline Preanhepatic 30 min post reperfusion End surgery

336.0± 6.82 338.84± 10.73 343.07± 7.41 347.78± 7.38

72.51± 71.64± 79.60± 78.09±

SVR (dyns-1sec m-5) 6.47 4.88 4.06 5.00

739.58± 103.15 793.31± 49.57 727.33± 32.60 795.62± 60.39

TED G ;transesophageal Doppler group ,FTc; corrected flow time, SV; stroke volume, SVR systemic vascular resistance

Table 4. Intraoperative blood loss,blood components reqirements,fluid transfusion and vasoconstrictor requirements in both groups Variable

LCVP G (n=45)

TED G (n=45)

P

Blood loss (l) RBCs (U) FFPs (U) Cryoprecipitate (U) Platelets (U) Colloids ( l ) Pre anhepatic Total Albumin Ringer acetate ( l) Vasoconstrictor requirement Noradrinaline no, (%) Ephedrine no, (%)

2.39 ±.680 3.96± 2.211 3.67± 2.232 1.22± 3.306 1.17± 2.719 3.80± 1.072 1.4± .2 5.40± 1.152

2.32 ±.68 3.67± 2.132 4.00± 3.282 1.96± 3.289 1.07± 3.454 .62± .415 3.31± .733 1.44 ± .15 5.08± 1.454

.63 .52 .58 .02 .86 .01 0.3 .24

11 15 4.77 (8.06)

4 9 0.86 (2.42)

0.04 0.06 0.002

Dose mean (SD)

Data are representes as mean ± SD . LCVP G;low central venous pressure group, TED G ; transesophageal Doppler group,RBCs;packed red blood cells,FFPs;fresh frozen plasma. P < .05 is considered statistically significant difference

Table 5. perioperative readings of lactate , creatinine and urine output Variable

Lactete (mg/dl)

Creatinine (mg/dl)

UOP (mlkg-1)

Measuring point Baseline Pre reperfusion End surgery POD1 POD3 Baseline POD1 POD3 POD5 Pre anhepatic Total

LCVP G (n=45) 13.76± 2.203 59.00± 8.022 40.04± 5.202 26.96± 3.098 11.28 ±1.928 .88 ± .277 1.32± .258 1.20± .559 1.17 ± 0.12 .50± .121 1.14± .246

TED G (n=45) 14.09 ±2.875 50.71± 5.247 32.47 ±6.720 25.22± 3.330 10.89± 2.025 .86± .206 1.22± .292 1.03± .313 .92 ± 0.1 .79± .205 1.06± .149

P .542 .001 .01 .19 .345 .749 0.02 0.04 0.06 .000 .068

LCVP G; lowcentral venous pressure group,TED G ; transesophageal Doppler group,POD;postoperative day,UOP;urine output. P < .05 is considered statistically significant difference

Table (6) Comparison between both groups regarding patients’ distribution according to the Acute Kidney Injury Network (AKIN) classification L CVP Variable

AKIN stage

p No.

POD1

POD3

POD5

TED

0 I II III 0 I II III 0 I II III

16 8 18 3 25 8 11 1 32 9 3 1

% 35.2 17.6 39.6 6.6 55 17.6 24.4 2.2 71.1 20 6.7 2.2

No. % 26 11 7 1 36 5 4 0 40 4 1 0

57.8 24.4 15.6 2.2 77.8 13.3 8.9 0.0 88.9 8.9 2.2 0.0

.033

.073

.186

POD; postoperative day. P< 0.05 is considered statistically significant different

Table (7) Mmultivariate linear regression analyses of intraoperative blood loss and the potential independent variables Variable Coefficients Standard Error t Stat Intercept 2288,16 445,26 5,13 Baseline fibrinogen -2,5267 1,130 -2,23 CVP preanhepatic -30,26 35,49 -0,85 Norepinephrine -74,09 25,10 -2,95 Ephedrine -13,21 10,74 -1,22 Total colloid 221,56 60,17 3,68 P<0.05 is considered statistically significant difference

P-value 1,77E-06 0,06 0,39 0,004 0,22 0,0004

Lower 95% 1402,705 -4,7743 -100,84 -124,02 -34,582 101,897

Upper 95% 3173,627 -0,2790 40,3068 -24,17 8,15460 341,228

Table(8). Correlation between stroke volume (SV) and central venous pressure (CVP) in TED G Variable

CVP 1- SV1

CVP 2- SV2

CVP 3- SV3

CVP 4- SV4

Pearson Correlation

.165

.103

.015

.037

P (2-tailed significance)

.279

.501

.924

.807

1; baseline, 2 ; preanhepatic, 3; 30 min post reperfusion, 4; end of surgery. P < .05 is considered statistically significant difference

Patients screened n. =167

Patients managed with LCVP n. = 46

One patient was excluded due to incomplete date

LCVP Group n. = 45

Patients managed with TED n. =121

Matching with patients in LCVP group

TED Group n. = 45

Figure (1) Flowchart showing the numbers of patients assessed and enrolled in the study. LCVP, low central venous pressure; TED, transesophageal Doppler

Figure 2. Protocol of TED guided fluid management in TED G. FTc; corrected flow time, SV; stroke volume.

Figure (3). Scatter plot showing that more colloid transfusion was strongly associated with more intraoperative blood loss. Predictive significance of colloid transfusion on multivariate analysis was p= 0.0004

Figure (4). Scatter plot showing that more noradrenaline was associated with less intraoperative blood loss. Predictive significance of noradrenaline on multivariate analysis was p =0.004