This study investigated not only clinical characteristics between frail and pre-/non-frail patients or sarcopenia but also predictive factors related to postoperative complications and CR-POPF. Our findings demonstrated that frailty was a predictive factor of postoperative complications (CD ≧ IIIa), and soft pancreas was an independent and significant predictive factor of CR-POPF after pancreaticoduodenectomy.
Many physicians often observe that some patients can withstand operational stress, while others cannot, despite being of the same chronological age, and they judge instinctively and subjectively whether patients have the physiological reserve to endure operations and postoperative burdens. Although some older patients do not have such reserve to endure surgical stress19, there are appropriate methods for evaluating older surgical patients. Our results revealed that frailty may be a useful predictive factor of postoperative complications in patients undergoing pancreatectomy and may become one of the risk stratification tools to better identify potentially high-risk surgical patients. Unlike sarcopenia, frailty represents not only the skeletal muscle mass and muscle function, but also physical activity in daily living, weight loss, and social isolation6. Thus, frailty is considered a biologic syndrome of decreased reserve and resistance to stressors, resulting from cumulative decline across multiple physiologic systems and causing vulnerability to adverse outcomes 1. Our findings suggested that frailty might be a more effective predictor, compared with sarcopenia, to evaluate potentially high-risk surgical patients, even if these two conditions started to converge because of their close relationship with the aging process6.
Several reports9–11 have revealed that frailty is an important predictor of postoperative morbidity and mortality after pancreatectomy, and our conclusion was also the same as these reports. These studies used the modified frailty index (mFI) to define frailty20, while our study used the J-CHS criteria. The mFI is a simple frailty assessment tool mainly evaluated by the patient’s historical variables, such as history of myocardial infarction, previous coronary operation, chronic obstructive pulmonary disease, or pneumonia. Although it is important to focus on a patient’s historical variables, in this study, we aimed to investigate the relationship between frailty and sarcopenia which is a progressive and generalized skeletal muscle disorder involving the accelerated loss of muscle mass and function. Thus, we adopted the J-CHS criteria, which included similar items to the criteria of sarcopenia, such as grip strength and walking time. Unlike these previous studies, our study focused on the relationship between frailty and sarcopenia. In Table 2, compared with sarcopenia (non-frail) patients, frail patients have pulmonary, neurologic, or cardiac medical histories and diabetes mellitus, which may influence postoperative morbidity and mortality after pancreatectomy. Moreover, frail patients had more postoperative complications with CD ≧ IIIa than sarcopenia (not frail) (P = 0.087). No difference in the occurrence frequency of CR-POPF was found between the two groups, but a significant difference was found in the occurrence frequency of respiratory failure (P = 0.030), which resulted in postoperative mortality in frail patients. Sarcopenia was one of the risk stratification tools to better identify potentially high-risk surgical patients7, but frailty was also a useful predictive factor of postoperative complications and may be an effective risk stratification tool to identify these potentially high-risk surgical patients.
Our report also focused on CR-POPF, which was not discussed in previous reports9–11. CR-POPF remains one of the most life-threatening postoperative complications, and two frail patients in our study, who died within 90 days after pancreaticoduodenectomy, had CR-POPF. The direct cause of death of these patients was acute respiratory failure, but uncontrollable CR-POPF can be a trigger of acute respiratory failure. Frail patients may not have physiological reserve to endure postoperative life-threatening complications, such as CR-POPF. Several reports21,22 considered that the soft texture of the pancreatic parenchyma could contribute to the development of POPF after pancreaticoduodenectomy. A soft pancreas and a small-diameter pancreatic duct preserve exocrine function, which increases the secretion of pancreatic juice and pressure within the pancreaticoenteric lumen22, and our findings were consistent with the findings of these reports. However, the term “soft” was a subjective judgment of surgeons. Moreover, “soft” or “hard” pancreas is associated with pancreatic tissue fibrosis, and several previous studies have attempted to quantify pancreatic fibrosis and have suggested that a pancreas with less fibrosis, more fatty tissues, and more acinar cells was at risk for POPF23. Fujita et al.23 reported a useful approach for quantifying pancreatic tissue objectively by acoustic radiation force impulse imaging, and pancreatic tissue fibrosis was found to be correlated with the overall incidence of POPF. In contrast, POPF after distal pancreatectomy is due to functional distal obstruction by the sphincter of Oddi complex at the ampulla24. Our study did not reveal the predictive factor of CR-POPF after distal pancreatectomy; further studies should be performed to evaluate CR-POPF after distal pancreatectomy.
Compared with frail patients undergoing surgery, surgeons should consider various interventions pre-, intra-, or postoperatively to reduce postoperative complications. Nutritional status and frailty are interrelated25, so preoperative intervention for nutritional status may improve frail status. Two randomized double-blind studies26,27 reported that both exercise and nutrition improved muscle mass, walking ability, and hematological parameters, possibly leading to the reversal of frailty status. In these reports, resistance-type exercise training was effective in improving strength and physical performance in frail patients, and supplements were recommended to be added during exercise training. This preoperative intervention is called “prehabilitation,” which is a collective term to describe preoperative interventions aimed at increasing the physiological reserve of patients prior to surgery. Prehabilitation programs variably include physical, psychological, and nutritional interventions and may reduce the incidence of postoperative complications, shorten hospital stay, and improve health-related quality of life28. Despite the lack of evidence of improved mortality and duration of hospital stay, various beneficial prehabilitation programs for frail surgical patients were reported in a systematic review28; thus, we should consider both exercise and nutritional intervention preoperatively. Conversely, early postoperative nutritional support helps reduce the risk of postoperative complications, especially postoperative early enteral nutrition which improves nutritional status and promotes the functional recovery of the digestive system29. As one of the intraoperative interventions, Gilliland et al.30 recommended that pancreatic cancer patients with moderately decreased albumin levels (< 3.0 mg/dL) or weight loss > 5% should be given jejunostomy feeding tubes intraoperatively to avoid postoperative undesirable patient outcomes associated with insufficient nutritional intervention. Moreover, to avoid postoperative complications, it may be useful to insert an enteral tube after a more invasive surgery, such as pancreaticoduodenectomy, as an early nutritional support for frail patients with poor nutritional status.
In this study, three patients died, and the main cause of death was acute respiratory failure. Postoperative complications (CD ≧ IIIa) in these three patients varied; two of them had CR-POPF. Considering our results, frail patients undergoing pancreaticoduodenectomy should have preoperative prehabilitation, especially respiratory prehabilitation31, to improve nutritional status, strength, physical performance, and frail status. Although a long-duration prehabilitation may result in disease progression, especially that of pancreatic cancer or bile duct cancer, we need to consider a certain duration of prehabilitation. If preoperative frail status does not improve, frail patients may avoid pancreatectomy. Consideration of frailty may be beneficial for the evaluation of operative risk and selection of patients.
This study has several limitations. First, this was a retrospective study and very small scale compared with previous reports because of its single-institution setting; thus, future multi-institutional prospective research studies are needed. Second, soft pancreas was defined by surgeons and was not evaluated objectively. Previous reports22, 23 revealed objective evaluation of pancreatic fibrosis pre- or postoperatively. However, reports revealed a relationship between pancreatectomy and CR-POPF, in which surgeons judged the pancreas as soft or hard subjectively. Third, the definition of frail varies16, 20, 32, 33; thus, our result may be remarkably different according to previous definitions. In our report, we adopted the J-CHS criteria, which was a simple frailty assessment tool, and included similar items to the criteria of sarcopenia. Finally, the timing of measuring physical activity and collection of blood samples were not planned and varied among patients. Furthermore, there were patients who underwent nutrition or exercise intervention after being diagnosed frail, and we did not evaluate the effectiveness after these interventions before pancreatectomy; therefore, future prospective research studies are needed to confirm and evaluate these preliminary findings.