Risk factors for surgery-related muscle quantity and muscle quality loss and their impact on outcome

Resection with curative intent is the treatment of choice for colorectal liver metastasis (CLRM) [1, 2]. Despite advances in surgical techniques and perioperative care, liver resection still causes substantial rates of postoperative morbidity and mortality [3‐5]. Postoperative morbidity may result in prolonged hospital stays, increased healthcare costs, and potentially decreased long-term survival [6, 7]. In recent years, awareness has grown of using body composition variables as predictors for postoperative outcomes in surgery. Studies have demonstrated that low muscle mass referred to as sarcopenia negatively affects postoperative outcomes after resection for CRLM [8, 9], and preoperative sarcopenia is associated with poor overall survival in patients with various solid tumours [10]. In addition, there is increasing evidence that preoperative low muscle radiation attenuation as a measure of muscle quality, also referred as myosteatosis, is also an important prognostic factor for impaired outcome in patients with cancer [11‐13].

Although the impact of preoperative body composition variables has been well described in literature, less studies have investigated the process of surgery-related changes in muscle quantity and quality. Recent reports have suggested that loss of muscle quantity after surgery is associated with decreased quality of life and short-term outcomes [14‐16]. In addition, the negative impact of this so-called surgery-related muscle loss (SML) on long-term survival after pancreatic surgery was recently demonstrated [17]. However, these studies only concern muscle quantity. There is minimal literature describing surgery-related changes in muscle quality [18].

Furthermore, through identifying risk factors for surgery-related loss of muscle quantity and quality, perioperative intervention might prevent or reduce SML and subsequently improve postoperative outcomes. Being aged above 65 years and diabetes were reported to be independent risk factors for clinically relevant loss of muscle quantity within 1 week of gastric cancer surgery [16]. Risk factors for surgery-related loss of muscle quality have not yet been described. The aim of this study is to identify risk factors for surgery-related loss of both muscle quantity and quality after liver resection for CRLM. In addition, we also investigate the impact of surgery-related loss of muscle quantity and quality on overall survival.

The results of the present study demonstrated that more than half of our patients had surgery-related loss of muscle quantity (52%) and/or loss of muscle quality (65%). COPD and diabetes were risk factors for surgery-related loss of muscle quantity. A higher age, open resection and longer operation time were significantly associated with surgery-related muscle quality loss. The rate of postoperative complications was significantly higher in the group with surgery-related loss of muscle quality. Patients with both muscle quantity and quality loss had the lowest survival.

In accordance with the findings of Huang et al. [16] diabetes was an independent risk factor for loss of muscle quantity. Diabetes can have negative effects on skeletal muscle function [22]. The impaired insulin function may cause the loss of body protein, particularly during the katabolic postoperative period [23, 24]. In the current study, patients with COPD also had a greater risk at loss of muscle quantity. Studies have suggested that chronic obstructive COPD causes respiratory and limb muscle dysfunction [25, 26]. However, the mechanisms for how COPD contributes to abdominal muscle atrophy or for surgery-related loss of muscle quantity remain unclear [27, 28]. An underlying mechanism of why these patients were more prone to surgery-related muscle loss might be oxidative stress, which is inherent to pulmonary diseases such as COPD or asthma [29]. The oxidative stress could accelerate the process of muscle loss after surgery. However, due to the relatively small numbers of patients with COPD or diabetes, these results should be interpreted with caution and further research is needed to investigate the prognostic value of these two risk factors. Furthermore, a higher age was an independent predictor for surgery-related loss of muscle quality. Previous studies already found a correlation between a higher age and lower muscle quality [12] and quantity [16, 30, 31]. However, a correlation between a higher age and higher risk at surgery-related muscle loss has not been described before.

In this study, change in muscle quality was determined by the difference in AMA of the psoas on the pre- and postoperative CT-scan. All CTs were acquired after administration of intravenous contrast medium, according to the standard clinical protocol. This increases the radiodensity by 8 Hounsfield Units on average [32]. As all scans are acquired using the same contrast-enhanced protocol, the current results reflect the measurements in clinical setting and their direct usefulness in clinical practice. Low muscle radiation attenuation may be a reflection of increased water content (i.e., muscle edema) but is usually described as a marker for increased intramyocellular triglycerides (i.e., myosteatosis) [33, 34]. Though, in postoperative setting the decrease of muscle radiation attenuation should be interpreted with caution, since it might be influenced by perioperative fluid shifts. However, during the manual outlining of the muscle borders, the abdominal wall muscles in particular appeared to be affected by muscle edema and the presence of hematoma, especially in the operated right side, due to the subcostal incision, while the psoas muscles visually appeared unaffected by the direct surgical trauma and the surrounding fat did not show any edema. Therefore, in this study, it is assumed that the decrease in density is largely caused by myosteatosis and minimally caused by muscle edema.

Aoyama et al. [35] demonstrated that the greatest muscle loss occurs during the first postoperative week, and implied that this phenomenon was mainly because of increased catabolism caused by cytokine production under surgical stress. This mechanism is called the surgical stress response, which is the body’s response to prevent further injury through fluid conservation and substrate mobilisation. The surgical stress response comes with direct and indirect injury during surgery. Indirect surgical trauma occurs through events such as blood loss, alterations in blood pressure, and perfusion. Direct surgical injury is the result of incisions through different layers of the abdominal wall, the mobilisation of organs, and resection of organs or tissue [36]. The response starts with the release of cytokine and inflammatory mediators that control a complex process of metabolic, hormonal, and immunological processes, which subsequently results in the breakdown of muscle protein [37]. For example, surgical stress results in insulin resistance [38]. Myosteatosis has also been associated with insulin resistance, supporting the assumption that a postoperative decrease in muscle radiation attenuation of the psoas can be attributed to myosteatosis [34]. A higher degree of injury results in a higher peak and longer duration of cytokine release, as well as subsequent altered glucose metabolism, protein catabolism, and hormonal dysregulation [39]. Consequently, this leads to greater muscle loss. This explains why we found in our study that open surgery (versus laparoscopic) and a longer duration of the operation presented to be risk factors for surgery-related loss of muscle quality. This knowledge highlights the importance of minimally invasive surgery.

To our knowledge, there is only one previous study that investigated surgery-related changes in muscle quality analysed with abdominal CT-scan on outcome, rather than only muscle quantity [18]. Kobayashi et al. [18] investigated postoperative changes in skeletal muscle mass and muscle quality, and presented that postoperative loss of skeletal muscle quality was an independent risk factor for the recurrence of hepatocellular carcinoma in patients following a hepatectomy for hepatocellular carcinoma. Our study demonstrated that patients without loss of muscle quantity and quality had significantly higher survival than other categories, while patients with both loss of muscle quantity and quality had significantly lower survival. Moreover, in our study the rate of postoperative complications was significantly higher in the group with surgery-related loss of muscle quality. These results emphasizing the need for further investigation into the aetiology and occurrence of surgery-related muscle loss and possible pathways for prevention [40]. Despite it has previous described that postoperative complications rates were higher in patients with surgery-related muscle quantity loss, [16] it is not yet clear whether the significant higher rates of postoperative complications were a cause or effect of surgery-related muscle quantity or quality loss. However, in the light of this: in contrast to other studies, postoperative CT scans in most patients were routinely performed as a standard protocol [9]. In this manner, we prevented the bias that CT scans probably create, because they are performed during a complicated course, which could theoretically influence the percentage of patients with SML.

Through identifying risk factors for SML, a perioperative intervention may prevent or reduce SML and subsequently improve postoperative outcomes. Two important risk factors that contributes to muscle loss are malnutrition and inactivity. After surgery, adequate protein supplementation (1.5 g of protein per kg of body weight/day) can influence the surgical stress response and postoperative catabolism and subsequently treat declines in muscle mass, muscle strength, and functional capacity [41]. Also sufficient physical activity is critical for preventing muscle loss in patients [41, 42]. A combination of adequate protein intake and sufficient exercise has been shown to facilitate muscle gain [43‐45]. Because of the retrospective nature of our study, data on postoperative protein and specific data on the degree of mobilisation of the included patients in our study were lacking. This lack of data are limitations of our research. Further research into postoperative protein intake and physical activity will be essential for setting up a proper and feasible protocol to prevent patients suffering muscle loss [37, 40]. Furthermore, a promising idea might be the application of neuromuscular electrical stimulation to muscles to maintain muscle thickness after surgery [46]. In conclusion, the current study demonstrated that surgery-related loss of muscle quantity or quality is present in more than half of the patients after liver resection for CRLM. Specific risk factors for SML could be identified. Overall survival was lowest in patients with both muscle quantity and quality loss, showing that surgery-related loss of muscle quality and quantity may be used in predicting prognosis. To reduce muscle loss, a perioperative programme focused on adequate protein intake combined with early mobilisation, especially for patients in risk groups, could be the first step.