A growing number of studies suggest that GI malignancies with peritoneal metastasis or malignant ascites are indications for HIPEC, especially in digestive system[10, 11]. A meta-analysis by Sun et al suggests that HIPEC could help to prevent peritoneal recurrence and improve survival of patients with advanced gastric cancer who have received curative tumor resections. Despite its effectiveness has been widely proven by mounting evidence and been included in national cancer guidelines in some European countries, the safety of HIPEC has been controversial. The basis of hyperthermia enhancing chemotherapeutic drugs is related to improving the permeability of drugs to tumor, increasing their cytotoxicity, and delaying their clearance from the abdominal cavity. However, the enhanced effects of hyperthermia and drug toxicity may cause more complications and affect patients prognosis. GI complications after HIPEC ranges from 4 to 19%, the most common ones are anastomotic leaks and fistulas, abdominal abscess and wound infection. Other complications include pleural effusion, pneumonia, acute kidney injury (AKI), hepatic insufficiency, marrow depression, venous thromboembolism and fever[13, 14]. The incidence of AKI after cytoreductive surgery (CRS)-HIPEC have ranged between 2% and 22%. Several cases reported that acute liver failure or necrosis after HIPEC[7, 13]. However, there was no statistical significance of liver fuction in our study. This may reflect the relative good tolerance by decreased hepatic blood flow induced by HIPEC. In terms of pathophysiological changes, hepatic artery blood flow increased when portal blood flow reduced maintain partial hepatic blood flow which followed by adequate liver clearance and oxygen supply. The effect was reversible within 48 hours and did not show up in clinical outcomes.
According to the literatures, HIPEC may damage kidney and liver. In present study, we didn’t find the liver function of the patients was significantly influenced by HIPEC, which could be demonstrated from the fact that the indexes of liver injury, such as AST and ALT, were not notably increased during perioperative period. While the patients' renal function seems to be affected by HIPEC, UA is the final decomposition product of purine metabolism, its elevation may be a biomarker of renal disease risk. UA was obviously increased at the end of HIPEC and the 48 hours postoperation, meanwhile, Cys-C, as a new early indicator of AKI, distinctly increased at 48 hours postoperation. At the same time, BUN and Cr has also changed accordingly. To explore whether Dex has a protective effect on liver and kidney, we observed the distinction between groups with/without Dex. The results showed that Dex did not visibly affect the function of liver, but it could significantly alleviated the elevation of serum UA and Cys-C induced by HIPEC and obviously increases patients’ urine output, which may be related to the inhibition of oxidative stress.
In present study, we explore the incidence of hepatic insufficiency and AKI in GI cancer patients with HIPEC, we found that the classic functional indexes of liver and kidney have no significant changes during perioperative period, whereas, as a new early indicator of AKI, Cys-C distinctly increased at 48 hours after operation. Cys-C is cleared only via the kidney, and early renal microdamage can lead to change in its serum level. Its serum concentration increase upon mild renal injury and further elevated following the disease progresses. Meanwhile, UA was also obviously increased at the end of HIPEC and the 48 hours post-operation. The elevation of UA is related to AKI and chronic kidney disease, which could cause endothelial dysfunction, intrarenal crystal deposition and and impairment of nitric oxide production. So, we considered that HIPEC may potentially damage the kidney, but it is sometimes overlooked. According to the report, the cytotoxicity of applied agents, intra-abdominal hypertension caused by continuous perfusion, and decreased visceral perfusion, associated with renal injury. As HIPEC drugs, cisplatin or oxaliplatin have a higher risk of AKI. In our center, most patients with GI cancer were treated with cisplatin as chemotherapy during HIPEC, including present study, which may be one reason for increased serum Cys-C level. Nevertheless, other factors such as renal hypoperfusion and ischemia caused by intra-abdominal hypertension and heat stress response may play critical roles in the development of AKI[9, 20]. We inferred that the elevated serum Cys-C, Cr, BUN and UA may related to HIPEC-induced oxidative stress, so the alterations of serum MDA and SOD levels were detected, which are good indicators of the oxidative stress. MDA is one of the most important products of lipid peroxidation and a useful biomarker for oxidative stress. SOD is an antioxidant metal enzyme, which plays a crucial role in the balance between oxidation and antioxidant in the body, its activity reflects the antioxidant capacity of organs. We found that MDA was significantly increased immediately after surgery and 48h post-operation, meanwhile SOD was obviously decreased. These may indicate that oxidative stress was involved in HIPEC-induced renal injury.
Dex is a commonly used sedative in clinical anesthesia. Recently, with in-depth study, its organ-protective properties have gradually emerged[22–23]. Numerous date indicate that Dex provides strong protection against tissue damage caused by hypoxia, oxidative stress and inflammation. It can help several organs, such as brain, liver, lung, heart and kidney against oxidative damage. To confirm whether Dex used during HIPEC could provide liver and kidney protection through antioxidant activity, we compared the serum indicators of the two groups of patients with/without Dex at different time points. We observed that Dex could distinctly alleviate the increase of serum Cys-c, UA and MDA, while effectively elevated the level of serum SOD. Therefore, we believe that Dex protects against subsequent renal injury by suppressing intraoperative and postoperative oxidative stress. Furthermore, Dex visibly lowered the BIS values and VAS scores of patients during operation, meanwhile notably slowed their heartbeat. These manifestations above are thought to be related to the anti-sympathetic effect of Dex, which inhibits norepinephrine release and reduces plasma catecholamines. For the same reasons, Dex maintains renal perfusion and preserve tubular function by inhibiting the excitability of renal sympathetic nerve, and reduces renin secretion and improves glomerular filtration by activating adrenergic receptors of renal vasculature and tubules .
Certain limitations in our study need be addressed. This is a small sample study which limits the possibility of us to detect significant differences between groups. Hyperthermia is a crucial component of HIPEC, however, some researchers believe that sublethal hyperthermia may even cause tolerance to subsequent treatment, and that enhanced oxidative stress can significantly improve the chemotherapeutics to eliminate tumors. Dex alleviates oxidative stress whether have an impact on patients’ long-term prognosis requires follow-up. Finally, we did not analyze patients’ postoperative complications.