In this retrospective study, we for the first time found the perioperative CUCR was associated with postoperative major complications in pancreatic cancer patient underwent PD, independent of important covariates and confounders. Meanwhile, the CUCR was correlated well with the change of SMA derived from CT scans and can be used as clinical parameter for complication prediction.
It was appealing to risk stratify surgical and critical patients and target those who might benefit the most. Traditionally, performance status and nutritional status were the widely adopted approaches [21–24]. However, the former is relatively subjective and the latter lacks unified standard. BMI was considered to be a prominent factor affecting patient short- and long-term status [25]. In critical patients, a J-shaped association between BMI and mortality was observed [26]. Several observational studies also found worse outcome in ICU patients with lower or extremely higher BMI [27, 28]. But sarcopenic or obese patients may also have normal BMI. Therefore, body composition analysis is increasingly gained attention in nutritional assessment and risk stratification [29]. Martin et al demonstrated skeletal muscle depletion was a powerful prognostic factor, independent of BMI in cancer patients [30]. Similarly, in critical patients, both muscle quantity and quality affect the survival [5, 31]. In surgical patients, preoperative sarcopenia could predict postoperative complications [7–9]. Our present study also revealed baseline skeletal mass has a diagnostic potency in postoperative complication (Fig. 5). However, data acquisition of skeletal muscle or body composition requires CT or special instrument, which limited its clinical application.
Patients with skeletal muscle wasting may display with various phenotypes, such as reduced BMI, cachexia, frailty and deranged biochemical indicator. Two large observational studies have revealed low baseline serum creatinine was an independent predictor for mortality in critical patients [32, 33]. In addition, the alteration of serum creatinine was associated with the short-come mortality in AKI patients [34]. Since urinary creatinine is closely related serum creatinine and its production, it has been reported early low urinary creatinine excretion was a strong risk factor for both short- and long-term mortality in ICU patients without renal dysfunction [16].
Our study has shown serum creatinine concentration reduced by 29.0%, from 69.4 ± 25.8 umol/L to 49.3 ± 26.1 umol/L, and urea concentration increased by 38.6%, from 5.7 ± 2.7 mmol/L to 7.9 ± 2.9 mmol/L, a week after PD in all patients. What potential pathophysiology underlies these changes? Before the reduction of total muscle mass, decreased mitochondrial biogenesis and dysregulated lipid oxidation were observed in critical illness, which was a reflection of compromised skeletal muscle bioenergetic status [35]. Meanwhile, reduced phosphor-creatine content has been demonstrated early in these critical patients [35]. Given the tightly-linked relationship between serum and intramuscular creatine content [13], the early reduction of serum creatinine in our study may result from the altered metabolism and bioenergetic failure in skeletal muscle. The elevating of urea lasted more than ten days after surgery. We considered this was the reflection of skeletal muscle catabolism and amino acid liberation. Thus combining the two divergent markers might distinguish patients with different catabolism extent.
ROC curves shown the cut-off values of CURC in predicting postoperative complication were 71.3 for male and 67.4 for female, respectively. The high CURC group showed higher rate of complication, including POPF and nosocomial infection, and longer span of postoperative time to discharge. Further multivariable analysis revealed the CUCR was the only risk factor for complication after adjusted by sex, age and BMI confounders. This result was consistent with previous studies. In patients with acute kidney injury (AKI), a raised urea to creatinine ratio has been demonstrated to be a risk factor for survival [36, 37]. A large retrospective study reported elevated urea to creatinine ratio was significantly associated with prolonged persistent critical illness after trauma [10]. These changes are an indication of skeletal muscle wasting [32]. As we observed the CURC was correlated well with the change of SMA in L3 level and psoas derived CT-scans. This was in line with the results of Haines’ research which focused on critical trauma patients. They have found the decrease of SMA in L3 and psoas correlated with time elapsed. Of note, in those with persistent critical illness, the rate of muscle decrease was significantly greater and the urea to creatinine ratio at the time of second CT negatively correlated with these muscle areas [10].
What mechanism contributed to the muscle wasting observed in our patients? Systemic inflammation as reflected by elevated CRP levels may have a crucial role in the process. Mechanism studies have shown several cytokines, including TNF-α, IL-1β, and NF-κB activation can cause severe muscle wasting [38–41]. Besides, a close and direct relationship has established between intramuscular inflammation and anabolic signaling [35]. Particularly, in these PD patients, the relatively insufficient insulin could impair the PI3K-AKT-mTOR pathway, which was pivotal for protein synthesis [39]. In addition, major surgery and trauma may increase glucocorticoid level, which is a stronger inducer for muscle wasting [39, 41–43].
In the present study, we demonstrated the dynamic change of several indicators for metabolism and nutrition. Of particular interest, the turning point occurred around 8–12 days after surgery. This metabolic trajectory is akin to those observed in ICU patients. Acute illness always rapidly develops an acute phase which is characterized by metabolic instability and uncontrolled catabolism [44]. During this period, muscle wasting occurs and can hardly be reversed by nutrition support [35, 45, 46]. About one week later, the late phase ensues when anabolism increases and there is restoration of lost body components [44]. This trend implied the shift from catabolism to anabolism, which may provide some information for nutritional support to mitigate muscle wasting. Among these indicators, UCR displayed with a more distinctive change. Hence, it may be referable in the clinical practice, but this required further researches.
In the ROC curve, CUCR and CSMA had a comparable potency in predicting postoperative complication, which is superior to that of BSMA. This result indicates the wasting process is more detrimental than the baseline nutritional conditions. Meanwhile, the higher UCR in patients with CDC ≥ 3 in two weeks after surgery also support this assumption. Indeed, other than CT scan, several methods can be used to quantify the change of skeletal muscle mass [29]. Repeated ultrasonography shows promising results in detecting muscle wasting in several studies [47, 48]. However, tissue edema and interobserver reliability should be taken into consideration when interpret the results [49]. Bioelectrical impedance analysis (BIA) is another non-invasive and easy method to gain insight into body composition [50]. But the accuracy is affected when patients is with large fluids shifts. Therefore, a simpler and reliable test to measure muscle wasting is on demand in the future.
Our present study does have some intrinsic limitations. First, the retrospective research precluded the absolute unification of testing time in perioperative period, hence we employed time interval. Second, even though the initial time and contents of PN show no significant difference, the serum urea and creatinine level could be affected by hypovolemia, bleeding and renal function. Third, the serial CT scans were only available in a subset of included patients, which weakened the association between CUCR and muscle wasting in the study. Finally, we only compared the routine test and short-term outcome in these PD patients. Analysis on histological and molecular markers as well as long-term outcome are required in the future research.