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Prediction of Postoperative Mortality in Patients with Organ Failure After Gastric Cancer Surgery

Background Scarce data are available on the characteristics of postoperative organ failure (POF) and mortality after gastrectomy. We aimed to describe the causes of organ failure and mortality related to gastrectomy for gastric cancer and to identify patients with POF who are at a risk of failure to rescue (FTR). Methods The study examined patients with POF or in-hospital mortality in Seoul National University Hospital between 2005 and 2014. We identified patients at a high risk of FTR by analyzing laboratory findings, complication data, intensive care unit records, and risk scoring including Acute Physiology and Chronic Health Evaluation (APACHE) IV, Sequential Organ Failure Assessment (SOFA) score, and Simplified Acute Physiology Score (SAPS) 3 at ICU admission. Results Among the 7304 patients who underwent gastrectomy, 80 (1.1%) were identified with Clavien–Dindo classification (CDC) grade ≥ IVa. The numbers of patients with CDC grade IVa, IVb, and V were 48 (0.66%), 11 (0.15%), and 21 (0.29%), respectively. Pulmonary failure (43.8%), surgical site complication (27.5%), and cardiac failure (13.8%) were the most common causes of POF and mortality. Cancer progression (100%) and cardiac events (45.5%) showed high FTR rates. In univariate analysis, acidosis, hypoalbuminemia, SOFA, APACHE IV, and SAPS 3 were identified as risk factors for FTR (P < 0.05). Finally, SAPS 3 was identified as an independent predictive factor for FTR. Conclusions Cancer progression and acute cardiac failure were the most lethal causes of FTR. SAPS 3 is an independent predictor of FTR among POF patients after gastrectomy.


Introduction
Gastrectomy is the mainstay treatment for patients with gastric cancer. The prediction and management of postoperative morbidity become more important as a trend is seen recently in older and more fragile patients [1,2]. Despite significant efforts to reduce complications, the morbidity rate following gastrectomy is reported to be 10-28% [3][4][5][6][7][8][9].
Among postoperative complications of gastric cancer surgery, organ failure and in-hospital mortality after gastrectomy are rare. Based on the Clavien-Dindo classification (CDC) [10], grade IV is defined as life-threatening complications requiring intensive care unit (ICU) management. In addition, grade IVa is defined as single organ dysfunction requiring dialysis, or mechanical ventilation, and grade IVb refers to multiple organ failure. Grade V is defined as the complication-related death of patients. In previous reports, the rates of grade IV and V complications were 0.6-1.1% and 0.1-0.5%, respectively [6,11]. In most other studies addressing postoperative complications after gastrectomy for gastric cancer, grade IV complication rates have not been specifically mentioned [3][4][5]. Reasons for lack of data might cause difficulty in clearly defining the CDC grade IV complications, complexity of ICU treatments, and vast number of other parameters that influence the appropriate classification.
Failure to rescue (FTR) patients with complications account for a substantial proportion of postoperative mortality and is an emerging indicator of the quality of medical care [12,13]. Understanding the factors responsible for FTR helps surgeons predict and avoid operative mortality. However, there are very few studies related to FTR in the field of gastric cancer surgery [14].
Hence, in this study, we described the causes of organ failure and mortality related to gastrectomy for gastric cancer and identified patients with postoperative organ failure who are at a risk of FTR.

Patient population and data source
We screened the Seoul National University Hospital gastric cancer database from 2005 to 2014 and identified patients with postoperative organ failure and in-hospital mortality. A total of 7304 patients underwent gastrectomy for histologically confirmed gastric cancer within the study period. Among these patients, we collected data for patients meeting the following inclusion criteria: 30-day and inhospital mortality (CDC grade V); transfer to ICU because of organ failure (CDC grade IV); and continuous postoperative ICU care for 3 or more days and occurrence of any organ failure (CDC grade IV). Patients who underwent palliative procedures without gastrectomy (e.g., gastro-jejunostomy and explorative laparotomy) or procedures in cooperation with other surgical techniques (e.g., coronary artery bypass graft and abdominal aorta aneurysm operation) were excluded. Patients who underwent combined organ resection (e.g., colon resection, cholecystectomy, and pancreaticoduodenectomy) owing to gastric cancer were included in our analysis.
Demographics, comorbidity, operative procedures, pathological results based on the American Joint Committee on Cancer (AJCC) TNM 7th edition [15], ICU medical record, laboratory data, and postoperative complications were reviewed. Preoperative comorbidity data were collected and graded using the Charlson comorbidity index, which is the most widely used method to determine the overall burden of comorbidities and includes 19 medical conditions with corresponding weights [16]. Complications data based on CDC were collected prospectively through weekly team meetings [10]. The type of complications was divided into two categories: local and systemic. Complications were defined and grouped based on our previous report on complication following gastrectomy [11]. We calculated the time to the development of the first complication as the number of days between the operation and the first documented postoperative complication. This study was approved by the Institutional Review Board of our institution (H-1305-043-488).

Assignment of causes of organ failure and mortality
The causes of organ failure and mortality were systematically described by applying the methodology proposed by Waljee et al. [17]. In this classification, the complication that most commonly contributed to patient's ICU transfer or death was defined as a ''seminal'' complication. We adopted this concept when determining the cause of organ failure and mortality. Based on this classification and clinical relevance and frequency of occurrence, we allocated the cases based on the causes of organ failure and mortality into six categories with slight modifications: pulmonary failure (pneumonia, prolonged ventilator assistance, pulmonary edema, pulmonary thromboembolism, pneumothorax); surgical site complications (hemorrhage and surgical site infection); cardiac complication (myocardial infarction, congestive heart failure, arrhythmia, and unexplained cardiac arrest); cerebrovascular complications (stroke); cancer progression; and other complications (urinary tract infection and suicide). Three attending surgeons (HJ Lee, JH Park, and SY Oh) independently reviewed all medical records including ICU data and determined the cause of organ failure and death. In case of disagreement, the medical record was reviewed by the entire committee. After discussion, a final consensus on the cause of organ failure and death was reached.

Outcomes for risk analysis of failure to rescue
To identify risk factors for FTR, risk scoring including the Charlson comorbidity index, Acute Physiology and Chronic Health Evaluation (APACHE) IV, Sequential Organ Failure Assessment (SOFA; formerly, Sepsis-Related Organ Failure Assessment) score, and SAPS (Simplified Acute Physiology Score) 3; laboratory findings; complication details; and ICU clinical data were reviewed. All clinical and laboratory data references for risk scoring were collected within the initial 24 h after ICU admission. Two patients who died suddenly without ICU care and one patient who committed suicide were excluded from FTR risk analysis.
APACHE IV is a widely used scoring system for assessing the severity of illness and prognosis of ICU patients [18]. This scoring system includes age, chronic health conditions, and physiologic data required to calculate an acute physiology score of APACHE III [19]. This score also involves the primary reason for ICU admission (ICU admission diagnosis), patient's location (admission source), length of stay before ICU admission, need of mechanical ventilation or emergency surgery, PaO 2 /FiO 2 ratio, and whether sedation or paralysis resulted in an inability to assess the Glasgow Coma Scale (GCS).
SAPS 3 is a model for predicting mortality and is one of the several ICU scoring systems. It was designed to provide a real-life prediction of mortality for patients. The model is based on a mathematical model that needs calibration [20]. SAPS 3 represents the arithmetic sum of three boxes: (1) Box I: age, comorbidities, use of vasoactive drugs before ICU admission, intrahospital location before ICU admission, and length of stay in the hospital before ICU admission; (2) Box II: reasons for ICU admission, planned/ unplanned ICU admission, surgical status at ICU admission, anatomical site of surgery, and presence of infection at ICU admission; and (3) Box III: lowest estimated GCS, highest heart rate, lowest systolic blood pressure, highest bilirubin, highest body temperature, highest creatinine, highest leukocytes, lowest platelets, lowest hydrogen ion concentration (pH), and ventilatory support and oxygenation.
The SOFA score is used to track a patient's status during the stay in an ICU in order to determine the extent of a patient's organ function or rate of failure [21]. The score is based on six different sub-scores, one each for the respiratory, cardiovascular, hepatic, coagulation, renal, and neurological systems.

Clinical data related to failure to rescue
In univariate analysis (Table 5), low albumin level and acidosis were significantly different between patients with rescue and FTR (P = 0.026 and P = 0.001, respectively) at initial ICU laboratory findings. In terms of risk scoring methods, APACHE IV, SOFA, and SAPS 3 were significantly associated with the FTR rate (P = 0.001, P \ 0.001, and P \ 0.001, respectively). Complication-related data, including type, timing, and time, to the development of the organ failure were not related to FTR.

Discussion
To our knowledge, this is one of the first reports addressing the causes of organ failure and mortality in patients undergoing gastrectomy for gastric cancer. In this context, we conducted a cohort-based study using large-volume data to be able to describe the causes of organ failure and mortality related to gastrectomy. In addition to comparing outcomes between the rescued and FTR patients, we assessed the risks for in-hospital death. Severe complications (CDC grade C IV) developed in only 1.1% of the patients. The characteristics of these patients were heterogenous in terms of demographics, underlying diseases, and complications. The main causes of organ failure and death were pulmonary failure and surgical site complications that accounted for more than 70%. On the other hand, in relation to the grouped number of patients with organ failure, pulmonary failure had the lowest mortality  rate among the five groups. SAPS 3 risk scoring was the most powerful predictor for FTR in ICU patients. The mortality rate after gastrectomy in this study was 0.29%. The literature reports operative mortality rates that range from 0 to 13%, with higher mortality rates in Western studies (the least reported at 4%) [3-5, 8, 9, 14, 22-25]. The most recently published East Asian, multicenter, randomized controlled trials have reported a very low mortality rate of less than 0.5% [3,24,25], which was similar to that seen in our study.  However, our retrospective analysis included all gastric cancer patients who underwent gastrectomy unlike randomized controlled trials with strict inclusion and exclusion criteria.
Organ failure is organ dysfunction to such a degree that homeostasis cannot be maintained without external clinical intervention. If it involved two or more organ systems, it is defined as multiple organ failure, which is the most common cause of death in the surgical ICU [26]. Most studies on postsurgical morbidity focused on major complications (more than CDC grade III) and mortality. However, there was no analysis of specific details published with a focus on organ failure (grade IV) with or without consecutive mortality (grade V) after gastrectomy for gastric cancer. In this study, we investigated the characteristics of patients with organ failure after gastrectomy. Compared to our previous two studies that dealt with the association of underlying diseases and complications after gastrectomy [27,28], we found a higher prevalence of comorbidities (83.8%, 67/80) that was associated with the development of organ failure. In particular, the proportion of hepatic, pulmonary, cardiac, renal, and neurological underlying diseases were highly related to the patients' vitality. Among the complications, all patients had systemic complications, and the rate of surgical complications such as bleeding or leakage was also high.
To our knowledge, there is no study that classifies the causes of organ failure after surgery. Therefore, we introduced the methodology proposed by Waljee et al. [17] for classifying the cause of death after cancer surgery. Gerestein et al. [29] reported the causes of postoperative mortality after surgery for ovarian cancer. Surgical site complications and pulmonary failure were common causes of mortality in that study. In our study, organ failure was caused by pulmonary failure, surgical site complication, cardiac complication, and cerebrovascular complications, sequentially. Whereas pulmonary failure had a mortality of 8.6%, mortality rate according to the cause of organ failure was the highest in cancer progression (100%), followed by cardiac complications and surgical site infections. These results can be mainly explained by sudden cardiac death, myocardial infarction, and sepsis caused by surgical site infection. In particular, surgical site infections influenced organ failure included bowel leakage, intraperitoneal abscess, bile leakage, and gallbladder abscess.
Although several reports identified patients' factors predicting postoperative death, few reports investigated the risk for FTR among patients who were admitted to the ICU with organ failure. Bartlett et al. [30] investigated specific patient factors associated with mortality after total gastrectomy using the American College of Surgeons National Surgical Quality Improvement Program database. Age [70 years, weight loss, albumin \3 g/dL, and combined resection of the pancreas were independently associated with increased 30-day mortality. Another American study showed that patient characteristics, including age and comorbidity, were highly significant predictors of mortality [31]. Recently, Japanese surgeons have reported a risk stratification study for gastrectomy when treating gastric cancer using a nationwide Web-based database [8,9]. This risk models included age, need for total assistance in activities of daily living, American Society of Anesthesiologists grade 4 or 5, disseminated cancer, preoperative dialysis requirement, cerebrovascular disease history, more than 10% weight loss, uncontrolled ascites, leukocytosis, thrombocytopenia, anemia, hypoalbuminemia, hyponatremia, and elevated alkaline phosphatase level.
In our study, hypoalbuminemia and acidosis were remarkable factors for FTR. Additionally, risk scoring using APACHE IV, SOFA, and SAPS 3 was significantly associated with mortality. Finally, SAPS 3 was identified as an independent predictive factor for FTR among patients with organ failure after gastrectomy. In the acute care surgical field, characteristics of complications such as type of seminal complication and number of complications were reported as significant prognostic factors for FTR [32,33]. However, details about complication (type of 1st complication, duration, timing of complication) did not influence FTR in our study.
Prognostic scoring systems have been developed by the critical care community as an effort to quantify the severity of the illness of a given patient or group of patients [34]. Many prognostic models exist, suggesting that the optimum model has not been established. In particular, few studies have applied risk scoring systems to ICU patients with gastric cancer. The most commonly used adult ICU prognostic scoring systems are APACHE and SAPS. Major revisions of these models were published between 2005 and 2006, namely APACHE IV in 2006 and SAPS 3 in 2005 [18,20]. Moreover, the SOFA score is used to track a patient's status during the stay in an ICU to determine the organ function or rate of failure. In this study, we analyzed these three systems and SAPS 3 was most useful in predicting FTR among gastric cancer patients with organ failure. Unlike other systems, SAPS 3 includes data regarding the anatomical site of surgery, presence of acute infection at ICU admission, and vasoactive drug therapy before ICU admission (Table 1). These factors might contribute to the accuracy of the analysis of gastric cancer patients. Future studies are needed to evaluate the role of risk scoring or benchmarking, performance improvement, resource use, and clinical decision support. According to the SAPS 3 system, the patient prognosis factor can be divided into three categories: (a) previous medical/surgical history, (b) the circumstances of ICU admission, and (c) the degree and presence of physiologic dysfunction, and the prognostic value to resuscitate in each category is 50%, 22.5%, and 27.5%, respectively [20]. More than half of the risk for mortality is already determined when a patient is admitted to the ICU. In order to reduce mortality, it is advisable to correct physiologic indices when a high risk of mortality is suspected as soon as possible and perform prompt assessments to identify patient status. In this system, mortality differs in the etiology for ICU admission; transient organ failure shows a better chance of recovery compared to definite conditions such as intracranial mass or severe pancreatitis.
After gastrectomy, organ dysfunction and death are rare events and are therefore difficult to investigate. We performed analyses with mortality and organ failure of patients after gastric cancer surgery through complementary crossing over review using well-organized data from the large-volume gastric cancer center. Prevention of mortality rate is crucial for control of healthcare quality. Our results are intended to contribute to the management of patients with severe complications leading to death after gastric cancer surgery. This is expected to lead to an improvement in the quality of surgery.
In summary, postoperative organ failure and mortality after gastrectomy have heterogeneous causes. Information on morbidities and causes of organ failure or mortality seems essential for managing fatal complications. Cancer progression and acute cardiac failure were the most lethal causes of FTR. SAPS 3 is an independent predictor of FTR among organ failure patients after gastrectomy. By characterizing fatal morbidity and mortality after gastric cancer surgery, it is possible to provide vital information in efforts to reduce hospital mortality.