In this study, we have reviewed the safety and efficacy of postoperative early introduction of tolvaptan for patients with injured liver in the subsequent two cohorts. Postoperative preemptive use of tolvaptan did not increase any morbidity associated with adverse events. Although the incidence of refractory ascites showed no significant difference in both of preliminary and prospective study cohort, use of tolvaptan was associated with better fluid management, avoiding excessive water retention (i.e., increased BW, decreased urine excretion, pleural effusion, etc.).
This is the first study looking at the actual influence of early use of tolvaptan among patients undergoing hepatectomy. None of the patients developed acute kidney injury or required discontinuation of tolvaptan due to the occurrence of adverse events. As summarized in Fig. 3 and Supplementary Fig. 1, postoperative BW was generally well controlled avoiding water retention owing to the strong diuretic effect of tolvaptan. Although there was no significant difference in the total amount of discharge, serum albumin level or eGFR in both of preliminary and prospective study cohort, additional use of albumin infusion and diuretics was required significantly less frequently in both cohort (Table 2 and supplementary Table 2), suggesting that tolvaptan can be safely administered and may be effective for maintaining the fluid balance smoothly after hepatectomy. The U.S Food and Drug Administration has recently made a safety announcement that tolvaptan should not be used for longer than 30 days for patients with liver disease considering potential harmful events. (26) However, the present analysis showed that preemptive use of short-course tolvaptan does not increase the adverse event and it can be used safely even for the patients with diseased liver.
Although necessity of routine use of diuretics after liver surgery would need to be investigated in future studies, in the modern ERAS protocol for patients undergoing liver surgery, excessive fluid infusion should be avoided and early oral intake is recommended to prevent excessive fluid collection in the extravascular space, especially in cirrhotic patients. (7) (8) The serum albumin level could be maintained with less use of additional albumin infusion. Tolvaptan effectively pulls water back into the blood vessels from the renal collecting ducts to increase the output of electrolyte-free urine. In this context, the serum albumin level could be well maintained after liver surgery, as reported for the case of cardiac surgery. (27) From a clinical standpoint, avoidance of excessive retention of water after liver resection could contribute to a reduced incidence of morbidity related to edema, pleural effusion, and refractory ascites. Although there was no difference in the major complication rate between the control group and the two groups with tolvaptan, it was surprising that the incidence of pleural effusion and global complication was less frequent in the validation group, which caused the shortened postoperative hospital stay (Table 2). These observations could be partly attributable to the decreased incidence of fluid retention and respiratory morbidities with the use of tolvaptan. The modified protocol in the validation group should be the most favorable management at this time.
From an oncological standpoint, and adequate choice of aggressive treatment, including repeat hepatectomy(28) (29), locoregional treatment(30) and chemotherapy, is reportedly associated with improved survival in patients with recurrent hepatocellular carcinoma. Because maintained renal function is essential for such aggressive treatment to be carried out for recurrences, renal-protective management is important in the multidisciplinary treatment approach.
The time to reach maximum blood concentration (Tmax) and the half-life time (T1/2) of tolvaptan are about 5.6 hours and 9.1 hours after oral intake (31), respectively. Early administration after surgery appears to contribute to rapid elevation of the blood concentration and appearance of the diuretic effect even before excessive fluid enters the extravascular space. A sufficient intravascular volume and sufficient urine output after surgery would be expected to reduce the need for additional infusion of albumin and use of loop diuretics, which allows appropriate fluid balance to be smoothly maintained.
The limitations of this study include its observational study design and limited sample size. However, all consecutive patients with HCC in injured liver treated during the study period were included to reduce selection bias under constant management protocols as shown in Figs. 1 and 2. The present results demonstrated that tolvaptan can be used safely and provides acceptable outcomes with no increased incidence of any morbidities in patients in undergoing liver surgery. These results warrant a prospective multicenter study to validate the current observations.
In conclusion, tolvaptan can be safely used for postoperative management of patients with liver injury after hepatectomy for HCC and is potentially advantageous in the era of ERAS, owing to its strong diuretic effect and allowing easier control of fluid balance.