Hepatic Protective Effect of Dexmedetomidine after Partial Hepatectomy Surgery: A Prospective Controlled Study.

BACKGROUND: Inflow occlusion of the portal triad is a common blood loss-reducing method during hepatectomy which may induce ischemic-reperfusion injury of the remaining parts of the liver. Dexmedetomidine is used for reducing ischemic-reperfusion injury in hepatectomy. AIM: The aim of this study was to assess the protective effect of dexmedetomidine on liver after partial hepatectomy using inflow occlusion. SETTING AND
DESIGN: This prospective controlled, double-blinded, randomized study included any patients of either sex with age between 20 and 70 years, those in physical status American Society of Anesthesiologists Classes I and II, and those who were planned for partial hepatectomy. PATIENTS AND METHODS: Patients with elective hepatectomy were randomized into dexmedetomidine group, which received dexmedetomidine at 0.3 mg/kg/h, and control group, which received a placebo. STATISTICAL ANALYSIS: Statistical analysis was performed using IBM SPSS software version 18. Data were tested using Kolmogorov-Smirnov test, independent t-test or Mann-Whitney U-test, and Chi-square or Fisher's exact test. The statistical significance was considered at P < 0.05.
RESULTS: Serum albumin, aspartate aminotransferase, alanine aminotransferase, prothrombin time were higher in control group in comparison to dexmedetomidine group. Hypotension duration was lower in control group in comparison to dexmedetomidine group. Vasoconstrictor usage, amount of blood loss, and colloid, crystalloid, and blood given to patients were higher in control group in comparison to the study group.
CONCLUSIONS: Dexmedetomidine can protect the liver during hepatic resection surgery with inflow occlusion with decreasing blood loss and need for blood transfusion.

INTRODUCTION

Inflow occlusion by clamping of the portal triad is a common method for bleeding reduction during hepatectomy. Reperfusion after portal vein occlusion may induce ischemic-reperfusion injury of the remaining parts of the liver with impairment of liver function and other organs.[12]

One of the recent drugs used to attenuate the effect of ischemic-reperfusion injury after inflow occlusion in hepatectomy procedures is dexmedetomidine. It is a selective α2-receptor agonist. It has been studied in ischemic-reperfusion injuries in many organ systems.[3456] Furthermore, it can be used as an anesthetic adjuvant during the surgery to provide good perioperative cardiovascular stability and decreases the intraoperative anesthetic and analgesic requirements.[7]

In previous studies, dexmedetomidine was given in a bolus followed by a maintenance dose as anesthetic adjuvants. Recently, a loading dose is unnecessary in most patients as it may increase the risk of hypotension and bradycardia.[8] These studies also tried to evaluate the protective effect of dexmedetomidine on various organs against ischemic-reperfusion injury using various prognostic nonspecific indicators.[910111213]

The aim of this study was to assess the protective effect of continuous infusion of dexmedetomidine without giving a loading dose on liver functions after inflow occlusion during partial hepatectomy.

PATIENTS AND METHODS

This prospective, controlled, double-blinded, randomized study was created over 1 year and after approval of our Institutional Board Review and informed written consent from every patient was obtained first.

Any patients of either sex with age between 20 and 70 years and patient of American Society of Anesthesiologists Physical Status Classes I and II and planned for partial hepatectomy were included in the study. On the other hand, patient refusal, any renal diseases, cardiac ejection fraction <40%, myocardial infarction within 3 months or any anginal pain within 48 h, fulminant hepatitis, or pulmonary dysfunction were considered as exclusion criteria in the study.

On arrival to the preoperative area, enrolled patients were randomized into a dexmedetomidine (D) group or a control (C) group. The randomization sequence was generated by a computer program and consecutively numbered envelopes providing concealment of random allocation.

All patients were monitored using five leads electrocardiogram, peripheral oxygen saturation, entropy, and arterial pressure were invasively monitored through a radial artery cannula that used also for arterial blood gas sampling. The right internal jugular vein was cannulated using three-lumen catheter for central venous pressure (CVP) measurement, aspiration of air embolism if happened, and rapid infusion of blood or infusion of vasoactive drugs. Urine output was monitored through a urinary catheter right after the induction of anesthesia.

Anesthesia was started with air-oxygen mixture, FIO250%, then propofol 2 mg/kg[14] fentanyl 2 μg/kg, and 1 mg/kg rocuronium. After tracheal intubation, anesthesia was maintained with isoflurane in oxygen Minimum Alveolar Concentration (MAC) 1, fentanyl 1–2 μg/kg/h, and rocuronium 0.3 mg/kg/h. The mean arterial pressure was kept at a target of 75% from its basal value. Ringer's lactate solution was used as primary fluids in volume replacement during the surgery.

In dexmedetomidine (D) group, dexmedetomidine was dissolved in 0.9% sodium chloride with the concentration of 4 mg/mL and infused at 0.3 mg/kg/h.[1415] While in the control (C) group, a maintenance dose from the same syringe at a relevant rate to the treatment group was administered as placebo. The infusion of dexmedetomidine and sodium chloride was started after intubation and stopped when the surgery finished.

After mobilization of the liver, inflow occlusion was achieved by a 4-mm mersilene tape around the portal triad in a standardized manner,[16] and the CVP was maintained at 0–5 mmHg during resections and the surgeons determined the length of continuous inflow occlusion time.

All patients were transferred to postanesthesia care unit after surgery for further observation. Postoperative analgesia was managed by epidural block and patient-controlled analgesia using baseline infusion of morphine 3 mg/h with bloused 1 mg every 5 min according to patient requirement together with 1 g paracetamol every 6 h.

Total bilirubin, albumin, aspartate aminotransferase (AST), alanine aminotransferase (ALT) and prothtombin time postoperative care unit time, and length of hospital stay were recorded were measured at three times as follows: baseline (before surgery), 12, 24 and 48 h after surgery as indicators for liver function state. Duration of anesthesia, surgery, liver ischemia and inoperative hypotension were recorded. Volume of blood loss, colloid and crystalloid given were recorded both intra and postoperative respectively. The number of vasoactive drug usage and length of hospital stay were also recorded.

Sample size

A sample size of this study was calculated using G Power version 3.0.10. Copyright © 1992-2008, Germany. according to differences in postoperative peak AST level in the pilot study of patients undergoing partial hepatectomy with inflow occlusion who received propofol anesthesia with or without dexmedetomidine. It revealed 21 patients in each arm to obtain the power of about 85%. We increased the number of patients up to 25 patients in each group to compensate 20% possible dropouts.

Statistical analysis

Statistical analysis was performed using IBM SPSS for Windows (Chicago, USA), version 18. Data were first tested for normality using the Kolmogorov–Smirnov test. Continuous data were analyzed with the independent t-test or Mann–Whitney U-test, respectively, and expressed as mean ± standard deviation or median and interquartile range. Categorical data were described as frequency or percentage and were analyzed with the Chi-square or Fisher's exact test when appropriate. Statistical significance was considered when P < 0.05.

RESULTS

There were no differences between both groups as regard demographic data and BMI [Table 1].

Table 1

Demographic data and BMI of the studied groups. Data are expressed as mean±SD, number and %

	Control group	Dexmedetomedine group	P
Age (years)	36.40±4.73	38.68±4.96	0.103
Gender M/F (No)	19/6 (76%/24%)	18/7 (72%/28%)	0.747
BMI	28±3.65	27.28±4.02	0.325

Serum total bilirubin and AST were higher in control group when compared to dexmedetomidine group at 12, 24, and 48 h postoperative. Similarly, ALT was higher in the control group at 12 and 24 h postoperative in comparison to dexmedetomidine group. Meanwhile, albumin and prothrombin time (PT) was only lower in the control group than the study group at 12 h postoperative [Table 2].

Table 2

Perioperative liver functions’ results of the studied groups. Data are expressed as mean±SD

	Control group				Dexmedetomedine group
	Basal	12h	24h	48h	Basal	12h	24h	48h
Total bilirubin (mg. L-1)	8.34±0.38	23.22±3.50	29.4±549	29.49±6.82	8.47±0.28	19.34±3.92*	24.33±9.47*	24.18±4.87*
					P0.148	P0.031	P0.044	P0.043
Albumin (gm. L-1)	28.52±1.95	31.21±6.79	28.7±3.87	29.93±2.63	27±0.5	24.95±6.36*	29.08±3.22	31.08±3.64
					P0.201	P0.048	P 0.814	P0.149
Aspartate aminotransferase (IU.L-1)	59.38±9.04	149.5±11.3	201.2±17.67	149.2±20.32	62.39±6.05	136.2±13.60*	183.4±13.38*	130.2±16.04*
					P0.147	P0.029	P0.021	P0.032
Alanine aminotransferase (IU.L-1)	45.56±6.85	156.8±16.38	213.9±21.20	216.5±17.49	48.42±4.88	139.3±14.67*	194.4±17.73*	205.6±10.78
					P0.094	P0.022	P0.039	P0.114
Prothrombin time (sec)	40.28±5.06	118.9±9.62	106±7.34	96.92±6.38	38.25±3.98	137.6±12.3*	113±5.34	96.92±6.89
					P0.121	P 0.227	P0.12	P0.074

*P<0.05 when compared to dexmedetomedine group

Duration of hypotension was longer and the number of vasoconstrictor usage was higher in dexmedetomidine group in comparison to the control group [Tables 3 and 4, respectively]. Meanwhile, the amount of blood loss, colloid, and blood given to the patients on need was lower in dexmedetomidine group when compared to similar amounts recorded in the control group both intraoperative and after the surgery. In the same way, the amount of crystalloids given to the patients were lower in dexmedetomidine group intraoperatively than the amount used in control group but showed no difference postoperatively [Tables 3 and 5, respectively]. The length of hospital showed no differences between both groups when compared together [Table 4].

Table 3

Intraoperative data of the studied groups. Data are expressed as mean±SD

	Control group	Dexmedetomedine group	P
Duration of anesthesia (H)	5.1±1.2	4.9±0.7	0.080
Duration of surgery (H)	5.16±0.89	4.83±0.47	0.110
Ischemic time (min)	20.43±2.58	19.61±1.93	0.213
Duration of hypotension (min)	13.80±3.6	15.66±2.41*	0.037
Size of excised liver (gm)	412.92±47.06	425.40±84.19	0.521
Blood loss (ml)	2492.6±584.40	1815±322.63*	0.013
Colloid given (ml)	1920.24±270.92	1721.20±338.58*	0.026
Crystalloid given (ml)	2805.56±590.78	2506±418.02*	0.044
Blood transfused (ml)	1370.76±182.76	1256.20±189.95*	0.032

*P<0.05 when compared to dexmedetomedine group

Table 4

Vasoconstrictive use and length of hospital saty of the studied groups. Data are expressed as mean±SD, number and %

	Control group	Dexmedetomedine group	P
Vasoconstrictor usage (No)	3 (12%)	9 (28%)*	0.048
Length of hospital stay (days)	5.72±0.38	5.54±0.64	0.069

*P<0.05 when compared to dexmedetomedine group

Table 5

Post-operative blood loss, blood, colloid and crystalloid given in the studied groups. Data are expressed as mean±SD

	Control group	Dexmedetomedine group	P
Blood loss (ml)	1200±350	930±195*	0.042
Colloid given (ml)	1300±200	1000±150*	0.013
Crystalloid given (ml)	2200±100	2100±250	0.338
Blood transfused (ml)	1400±510	1150±420*	0.043

*P<0.05 when compared to dexmedetomedine group

DISCUSSION

Liver dysfunction after hepatic resection encompasses a wide range from a transient rise in liver enzymes to liver failure and death. The features include coagulopathy, hyperbilirubinemia, encephalopathy, and associated multiple organ failure.[17]

Furthermore, liver dysfunction can occur after any major surgery due to periods of intraoperative hypoxia, hypotension, blood transfusions or development of sepsis that can result in liver ischemia, and/or cellular dysfunction. Major blood loss after liver resection with the need for blood transfusion increases the risk of postoperative liver failure and sepsis.[118] Sepsis itself has a detrimental effect on liver function and hepatic cell regeneration.[19]

Especially in diseased liver, functional and regenerative capacity of the liver is reduced and therefore makes it more susceptible to damage.[20] Furthermore, a sinusoidal injury which may occur as a result from small-for-size syndrome and steatosis from chemotherapy reduce the regenerative capacity of the liver cells and therefore increase the likelihood of postoperative failure.[2122] It is related to portal hyperperfusion of the graft, combined with poor venous outflow, resulting in sinusoidal congestion and endothelial dysfunction.[23]

To reduce intraoperative bleeding, vascular occlusive techniques are used by either total occlusion of both inflow and outflow or total inflow occlusion (Pringle maneuver). This limits blood supply to the liver, with limiting the bleeding to hepatic venous pressure only, which itself can be reduced by maintaining a low CVP intraoperatively. Occlusion causes ischemia in the liver remnant,[24] resulting in hepatic ischemia-reperfusion injury with the generation of free radicals and subsequent liver dysfunction. For this reason, the Pringle maneuver is restricted to 45 min in total during the surgery.[2526]

Dexmedetomidine is a new drug which acts selectively on α2-adrenoceptor agonist with an imidazole structure and is up to eight times more selective than clonidine, an α2-agonist, for α2-receptor.[27]

In cases with varying degrees of hepatic impairment (Child-Pugh Class A, B, or C), dexmedetomidine clearance is reduced than in healthy participants. The mean clearance values for participants with mild, moderate, and severe hepatic impairment were 74%, 64%, and 53%, of those observed in the normal healthy participants, respectively. Although dexmedetomidine hydrochloride is dosed to effect, it may be necessary to consider dose reduction depending on the degree of hepatic impairment.[27]

The cardiovascular effects of dexmedetomidine are highly predictable. In the absence of a loading dose, an average of 10% fall in systolic blood pressure, heart rate, and cardiac output has been observed when a dose of 1 μg/kg/h is used. Although the currently licensed dose is 1 μg/kg/h, dexmedetomidine must not be given as a bolus at any time to avoid exaggerated cardiac depression.[9]

In the present study, it was found that total serum bilirubin, alanine transferase, aspartate transferase, and PT were higher in the control group in comparison to the study group.

Previous studies have demonstrated that dexmedetomidine exhibited antiapoptotic and anti-inflammatory effects apart from its anesthetic features.[2829] Moreover, studies in animals have reported organ-protective effects of dexmedetomidine in ischemia-reperfusion injury.[3031] It also reduces the oxidative stress and cellular damage as a result of the imbalance between reactive oxygen species and decreased biological ability of the cell to repair itself.[32] Similarly, the antioxidant and anti-inflammatory effects of dexmedetomidine have been confirmed in various experimental studies.[11]

Furthermore, dexmedetomidine has a protective effect against high N Methyle D Aspartate (NMDA) levels and potent anti-inflammatory capacity.[113133] Dexmedetomidine attenuates interleukin-6 and tumor necrosis factor-α levels. Yang et al., in their research, suggested that therapeutic anti-inflammatory effects of dexmedetomidine might be associated with its α2-adrenergic activity which attenuates inflammation-triggered liver injury.[34]

There is an increasing number of experimental studies that proved the protective effects of dexmedetomidine on pulmonary functions in acute lung injury secondary to sepsis, hemorrhagic shock, ischemia-reperfusion injury, and ventilator-induced lung injury and seriously ill patients in intensive care units.[353637]

In the same way, our previous study showed that dexmedetomidine administration before, but not after, ischemia had dose-dependent protective effects on ischemic-reperfusion-induced intestinal injury, partly by inhibiting inflammatory response and intestinal mucosal epithelial apoptosis through α2-adrenoreceptor activation in a rat model. Similar to the above findings, this study also showed that dexmedetomidine can confer protection on the intestine and liver for clinical patients during hepatic ischemic-reperfusion injury.[38]

Our study proved hepatectomy with inflow occlusion caused postoperative liver injury which could be alleviated by dexmedetomidine. It is probably because the Pringle time in the present study was controlled mostly around 20 min and did not have too much influence on hemodynamic data; moreover, the dosage of dexmedetomidine administration in this study remained conserved compared with animal researches before for the sake of avoiding adverse cardiovascular side-effects, and drug accumulation in patients undergoing liver surgery.[8]

Kocoglu et al. and Hall et al. reported that dexmedetomidine reduced the levels of NMDA and catecholamine in plasma in rats. Therefore, dexmedetomidine may prevent liver ischemic-reperfusion injury through the suppression of catecholamine released by activating presynaptic α2-receptors.[4]

The duration of hypotension was longer and the number of vasoconstrictor usage was higher in dexmedetomidine group in comparison to control group.

Dexmedetomidine by activation of α2-receptors on the locus coeruleus in the central nervous system, promotes a significant reduction in circulating catecholamine, with moderate reduction in heart rate and blood pressure.[39]

By decreasing norepinephrine release and renal sympathetic activity in the presynaptic region, dexmedetomidine enhances blood flow to the kidneys, which leads to vasodilatation. As a result of these effects in response to surgical stress, hypotension and/or bradycardia may occur.[4041]

Our results showed higher occurrence of hypotension and the need for vasoconstrictors among patients of dexmedetomidine infusion groups compared with the placebo group. This effect is similar to the results proved by Balkanay et al. who proved rise in hypotension and/or bradycardia occurrence with dexmedetomidine use.[42]

In contrast, as reported by Dere et al., a significant increase in mean arterial pressure was observed in relation to the control group. This fact may be related to the different regimens of drug administration and associated techniques.[43] The amount of blood loss, colloid, and blood given to the patients on need were lower in dexmedetomidine group when compared to similar amounts recorded in control group both intraoperative and after the surgery. In the same way, the amount of crystalloids given to the patients was lower in dexmedetomidine group intraoperatively than the amount used in control group but showed no difference postoperatively.

Attenuated response of sympathetic nervous system to surgical stress has been suggested as a potential benefit of α2-adrenergic agonists that may lead to hypotension vasodilatation and increases the capacity of great vessels. These all factors may be the cause of reported lower blood loss in patients who received dexmedetomidine group when compared to control group.[44]

Opposite to the current study, Leino et al. in his research stated that however the plasma norepinephrine level was reduced the surgery. It might have an influence on the greater blood loss in the dexmedetomidine group compared to the placebo group since high adrenergic output favors thrombosis.[45]

Limitations

This primitive trial was one of the earliest trials designed to detect liver protective effects of dexmedetomidine, and the dose of given dexmedetomidine was based on other studies on its renal or cardiac protective effect. To overcome this point, multicenter trials using different doses may be conducted at the same time to select the most proper dose. Furthermore, previous similar studies were conducted only on rates, but so long as, there are no contraindications for the use of dexmedetomidine in hepatic impairment, we decided to use it in human; however, there was a lack in comparative date.

CONCLUSION

This study strongly confirms that dexmedetomidine when given preoperatively may potentially protect the liver during hepatic resection surgery with inflow occlusion, also with decreasing blood loss and need for blood transfusion.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.