Perioperative Effect of Continuous Infusion of Dexmedetomedine on Indirect Gas Calorimetry Monitoring in Liver Transplantation

As clinicians in operations with significant phases of fluctuations, we are normally concerned about hemodynamic solidity. While anesthesia and intubation is the principal components animating the neuronal and endocrinal responses. Hepatectomy phase have significant blood loss, a hepatic phase is characterized by accumulation of acid metabolites and unclamping, is marked by vasodilatation of the splanchnic bed creating an insufficient preload and critical hemodynamic instability particularly in cirrhotic patients with hyper dynamic circulation and fragile peripheral resistance [1].


Introduction
As clinicians in operations with significant phases of fluctuations, we are normally concerned about hemodynamic solidity. While anesthesia and intubation is the principal components animating the neuronal and endocrinal responses. Hepatectomy phase have significant blood loss, a hepatic phase is characterized by accumulation of acid metabolites and unclamping, is marked by vasodilatation of the splanchnic bed creating an insufficient preload and critical hemodynamic instability particularly in cirrhotic patients with hyper dynamic circulation and fragile peripheral resistance [1]. a modest reduction in heart rate [4]. When dexmedetomidine is administered as a nonstop infusion, it is associated with an expected and stable hemodynamic reaction [5].
Dexmedetomidine 200μg/ vial were diluted to a concentration of 4μg /mL, and infusion started after the induction of anesthesia and continued till the end of surgery. The infusion in both groups had to be decreased or stopped with hemodynamic instability (heart rate <60 beats/min and/or mean blood pressure<60 mmHg), which did not respond to usual management including atropine or vasopressor drugs. All patients received noradrenaline support when indicated. The anesthesia team was blind to the cases that received Dexmedetomidine. After standard monitoring was in place, anesthesia was induced using propofol 2 mg/kg and rocuronium 1.2 mg/kg to facilitate endotracheal intubation. Anesthesia was maintained via desflurane in O 2 /air mixture (FIO 2 = 0.4) and fentanyl as needed, anesthesia level was monitored by keeping spectral entropy (GE Healthcare, Helsinki, Finland) between (40-60). Rocuronium was given via neuromuscular blockade monitoring via accleromyography, NMT module, Dragger, USA), in intermittent boluses according to the clinical needs. Normothermia was achieved with a forced-air warming device. An arterial line was placed in the left radial artery, and a central line was deployed in the right internal jugular.
Settings were adjusted to keep PaCO 2 within normal, (Cardio QTM; Deltex Medical, Chichester, UK) was used for fluids adjustment, inotropic administration, and haemodynamic monitoring; cardiac output(CO), systemic vascular resistance(SVR), protocol of TED [6], base line data were collected continuously in patients operative sheet, blood products were given when clinically indicated guided by rotational thromboelastography (ROTEM) (Pentapharm GmbH, Munich, Germany).no patient received bicarbonate during the study. Patients in need for support received noradrenaline. M-COVX™ (Datex-Ohmeda S/5 Avance workstation™, GE Healthcare, Helsinki, Finland) Metabolic module was used in our operating room and ICU. It consists of a gas analyzer and a spirometer unit and displays oxygen consumption (VO 2 ) and carbon dioxide production (VCO 2 ). Partial pressures of O 2 and CO 2 are measured by the rapid paramagnetic analyzer and infrared analyzer, respectively and inspired tidal volume is measured using a pneumotachograph. RQ can be calculated from the Halden-equation, VCO2 subsequently calculated from RQ as VO2=VCO2/RQ, and EE=3.58xVO2+1.44xVCO2-32.4. Reliability of displayed value of resting energy expenditure REE was assessed after considering the concomitant readings of RQ whose normal values range from 0.69 to 0.98).In each patient haemodynamics, arterial blood gases (ABG), VO2, VCO2, RQ, and EE were measured at baseline (BL), during dissection (DISS), an hepatic (ANH) and reperfusion (REP) phases, and as a protocol all recipients were discharged to I.C.U on mechanical ventilation where the last measure were taken (I.C.U). Data were collected and entered to the computer using SPSS (Statistical Package for Social Science) program for statistical analysis, version 21. Data were entered as numerical or categorical, as appropriate. In the present study α was set to 0.05, and Maximum accepted=20% with a minimum power of the study of 80%.
A sample size of 20 per group would be required in each group to reveal a significant difference in the primary outcome of this RCT which is oxygen consumption (VO 2 ) to detect a mean difference of 20 ml/kg/min and standard deviation of 19.2ml/ kg/min and 15.9ml/kg/min in Dexmedetomedine and control groups respectively. Calculation of sample size was done using (IBM SPSS Sample power) software and was also confirmed using Lenth Java Applets for Power and Sample Size (Computer software). Correction of p value for multiple testing was set p to 0.01 to detect significance (Bonforroni correction of multiple comparisons). So, in the present study an alpha level was set to 1% with a significance level of 99%, and a beta error accepted up to 20% with a power of study of 80%.
Two types of statistics were done:

1.
Descriptive statistics: Quantitative data were shown as mean, SD, and range. Qualitative data were expressed as frequency and percent at 95% confidence interval (95% CI).

2.
Analytical statistics: Chi-square test(X 2 ) were used to measure association between qualitative variables. Student t-test and Mann Whitney U test were done to compare means and SD of 2 sets of quantitative data as appropriate. Paired sample t-test and Wilcox on Signed Ranks Test were done to assess the follow up of quantitative data as appropriate. The results of comparing the correlation between two continuous variables were indicated by the correlation coefficient (r) using correlation analysis. P (probability) value considered to be of statistical significance if it is less than 0.05.

Journal of Anesthesia & Intensive Care Medicine
Demographic, clinical characteristics and main indications for liver transplantation (mainly Hepatocellular carcinoma) are presented in Table 1 that demonstrates no significant differences between the control and DEX groups. Operative data of the included patients as in Table 1 demonstrating operative data in details, blood products and fluids transfusions in both groups.  Continuous indirect calorimetry monitoring revealed insignificant changes in VO 2 and VCO 2 at (BL, dissection, an hepatic phases) but significantly decreased at reperfusion and in I.C.U. in DEX vs C groups (Table 2), with a trend of decrease in DEX group (Figure 1 & 2). EE and RQ showed the same fluctuations consistent with oxygen consumption and carbon dioxide production ( Table  2).  As regarding hemodynamic, heart rate (HR) showed slight decrease in all phases in DEX group but in comparison to C significant changes were recorded at BL, a hepatic, I.C.U phases. Mean arterial pressure (MAP) systemic vascular resistance (SVR), corrected flow time (FTC) were maintained in both groups during different measuring points, and that was the same with cardiac output measurements (CO), (Table 3-5). Delivered for 11.93±2.3hours with significant decrease in both Fentanyl (1241±390/988±202) μg p=0.041and Desflurane consumption (221±52/179±59) ml p=0.016 in C vs. DEX respectively, and non significant Noradrenaline in C/DEX (9.4±1.5/10.3±1.0), P=0.076.  Regarding the ABG follow up during the operation there were no significant changes all over all times of measurements except at reperfusion where pH, HCO 3 showed significant decrease in DEX than C and PaCO 2 showed increase with general tendency of ABG parameters towards acidosis especially in an hepatic and reperfusion stages (Table 4). ICU stay was comparable too, DEX/C (6.95 ±2.53/6.70 ±1.36), P =0.683 (Figures 3-5).

Discussion
The principal finding in the study in National Liver Institute (NLI) revealed that changes of (VO 2 , VCO 2 , RQ and EE) which were significant in DEX vs. control group, and that occurred obviously after reperfusion and few hours later in intensive care admission,

Journal of Anesthesia & Intensive Care Medicine
these changes were consistent with restoration of blood to the implanted graft and were correlated with other well-established metabolic changes including the decrease in HCO 3 and pH due to acid metabolites after unclamping. During liver transplantation, Oxygen consumption decreased rapidly by 25% when clamping blood supply. After the hepatic period, there was a sharp increase of oxygen consumption with successful reperfusion of the allograft Carbon dioxide production fell by 14% and returned to pre an hepatic values after successful declamping [5]. Reperfusion is associated with rapid increase in cardiac output, central venous pressure and a decrease in systemic vascular resistance which when severe constitute the post reperfusion syndrome, It has been previously shown that the increase in whole body oxygen consumption occurs after reperfusion which may reflect oxygen uptake by the Metabolically active graft [7] but also it may be due to the hunger of splanchnic tissues to oxygen during an hepatic phase [8,9] VCO 2 .
This also was supported by Walash et al. [10] who observed significant increase in VO 2 , VCO 2 after reperfusion in uncomplicated transplant patients [10], in the study done by Sayed E et al. [11] entitled Dexmedetomidine infusion during LDLT, there were significant decrease in VO 2 ,VCO 2 in DEX group than control in, an hepatic, reperfusion and end of surgery in liver transplant. In the study done by Tarrtonen et al. [9] before operation Dexmedetomidine and Clonidine caused greater decrease in VCO 2 , VO 2 and EE than placebo and there were no difference in RQ between groups, the maximum decrease in Dexmedetomidine group was 7%. During the operation there were no differences in metabolic variables between groups, though VO 2 and EE were lower in dexmedetomidine and clonidine groups than placebo. After operation VO 2 was lower 17% in Dexmedetomidine and Clonidine groups than placebo, also and EE were lower (17%,19%) respectively compared to placebo. Dex decreases central sympathetic outflow and modify intraoperative cardiovascular and endocrine responses favorably to surgical stimuli and laryngoscopy [12].
The diminishment in tachycardia, hypertension, purposful movement, steady serum catecholamine and its impact on sedation results in diminished entire body metabolism subsequently body oxygen utilization. It has been exhibited that successful absence of pain in the postoperative period can diminish VO 2 by up to 7-8% [10]. These combined effects may contribute to the reduction observed in VO 2 and VCO 2 . The analgesic effects of Dex and the indirect effects of sedation and neuromuscular block might account in part for the reduction in VO 2 . Arslan study results also suggested that Dex has beneficial effects on liver ischemia/ reperfusion [13,14] Similar to walash [10] We also observed that the increase in VCO 2 was correlated with PaCO 2 at reperfusion phase, the increase in PaCO 2 may be explained by release of acids and metabolites and may contribute to the decrease in SVR and the increase in CO in reperfusion more than other phases ,and this was accompanied by metabolic acidosis at the same stage.
The heart rate was seen to be diminished at all measuring points with significant decline in DEX versus C in baseline, an hepatic and I.C.U. stages where the impact of dexmedetomidine on HR was not masked by the surgical stimulation or blood loss. The baroreceptor reflex is all around saved in patients who get dexmedetomidine, and the reflex heart rate reaction to a pressor stimulus is enlarged other than the diminishing in noradrenaline discharge. These outcomes outline that the cardiovascular reaction is evoked for the most part by declines in sympathetic outflow. Dexmedetomidine could bring about cardiovascular sorrow; bradycardia and hypotension [15].
Despite what might be expected Unlugenc et al [16] gave 1 mic/ kg dosage of dexmedetomidine within 10 minutes of induction and they found similar readings in HR within the 10 minutes, though HR and mean blood vessel pressure (MAP) were like qualities found in the placebo group. Alpha 2-agonists diminish the perioperative anesthetic and pain relieving prerequisites, however in the review by Taittonen [17,18] there was no huge distinction between groups. In our study, we utilized entropy to quantify the profundity of anesthesia. Entropy showing reaction Entropy in charge of opioid need and state Entropy in charge of anesthesia required, permits keeping up anesthesia level between (40-60), to avoid the mistakes from relying upon hemodynamics to change inhalational anesthesia [19].
The requirement for more Fentanyl in control group of our review might be right due to the sympatholytic impact of dexmedetomidine intra-operatively and furthermore because of the time lag in ICU till extubation as a protocol in our organization thus the DEX group got the benefit of being sedated by dexmedetomidine. Aho et al. [20] indicated 25% diminishments of support focuses of isoflurane in patients who got dexmedetomidine. Another review found 35% to 50% decreases of isoflurane requirements in patients treated with either low or high dosages of dexmedetomidine and isoflurane without premedication. The utilization of opioids (e.g Fentanyl) decreases minimal alveolar concentration (MAC) of sevoflurane significantly, adding opioids to dexmedetomidine can potentiate its saving impact on inhalational utilization [21] All are steady with our outcomes ,but on the other side a study done by Taittonen [17] revealed insignificant distinction in opioids or I.V. analgesic necessities In a review by Basar et al. [22] who watched that a solitary measurements of dexmedetomidine given before induction of anesthesia diminished thiopental needs without serious hemodynamic impacts or any impact on recovery time. Correspondingly Khan et al. [23], observed additionally that dexmedetomidine diminished isoflurane necessities as an advantage of being sedated by the medication. The fluid volume needed during the intraoperative period to avoid hypotension Journal of Anesthesia & Intensive Care Medicine was insignificantly higher in our dexmedetomidine group, a side effect that may be unfavorable in volume sensitive patients with reduced left ventricular function [24]. This effect might be outweighed, however, by the diuretic effects of α2-adrenoceptor agonists, whose mechanisms may include attenuation of the secretion or effect of antidiuretic hormone, inhibition of renin, or release of natriuretic peptide [25].
Similarly the fluid volume needed during the intra operative period to avoid hypotension was insignificantly higher in the dexmedetomidine group [26]. In our study we recorded more fluids; colloids (1540±1798/1368±337) ml, crystalloids (5775±952/5386±871) ml and Noradrenaline (10±1/9.4±1.5) mg in DEX/C groups non critical statistically, yet may add to stability of mean blood pressure weight as dexmedetomidine has a mild vasodilation effect on SVR and although we have fluctuations in hemodynamics, those were less recognizable and statistically insignificant between groups.
The first study to demonstrate the use of Dexmedetomidine in postoperative agitated LT ICU recipients in comparison with haloperidol, significantly decreased ICU length of stay (LOS) and safely reduced the use of supplemental midazolam. Despite the small number of patients in this study, they believe that dexmedetomidine reduces the rate and duration of intubation. One study on the relationship between intubation and the use of dexmedetomidine reported that dexmedetomidine was more effective in in tubated ICU patients [27]. Compared with other studies regarding Dexmedetomidine, in our study the reason why the intensive care stay was similar between dexmedetonidine and control may be related to other surgical issues [28][29][30][31][32][33].

Conclusion and Recommendation
Dexmedetomidine have a significant depressing effect on metabolim in the form of VO 2 , VCO 2 , EE, which may be used as a method of protection from reperfusion injury (undergoing further study), and even in major hemodynamic fluctuations dexmedetomidine can be used with close monitoring, one of our draw backs that we not assess the suitable dose for hepatic patients, we believe this will need further study in surgeries of less hemodynamic fluctuations. Could not assess the suitable dose for hepatic patients, we believe this will need further study in surgeries of less hemodynamic fluctuations.