Decision analysis supports the use of drain amylase-based enhanced recovery method after esophagectomy

Decision analysis supports the use of drain amylase-based enhanced recovery method after... SUMMARY Postesophagectomy anastomotic leak is a common postsurgical complication. The current standard method of detecting leak is esophagram usually late in the postoperative period. Perianastomotic drain amylase level had shown promising results in early detection anastomosis leak. Previous studies have shown that postoperative day 4 amylase level is more specific and sensitive than esophagram. The purpose of this study is to determine if implementing a drain amylase-based screening method for anastomotic leak can reduce length of stay and hospital cost relative to a traditional esophagram-based pathway. The drain amylase protocol we propose uses postoperative day 4 drain amylase level to direct the initiation of PO intake and discharge. We designed a decision analysis tree using TreeAge Pro software to compare the drain amylase-based screening method to the standard of care, the esophagram. We performed a retrospective review of postesophagectomy patients from a tertiary academic medical center (University hospital Cleveland medical center) where amylase level was measured routinely postoperatively. The patients were separated into amylase-based pathway group and the standard of care group based on their postop management. The length of stay, costs, complications, and leak rate of these two groups were used to inform the decision analysis tree. In the base-case analysis, the decision analysis demonstrated that an amylase-based screening method can reduce the hospital stay by one day and reduced costs by ∼$3,000 compared to esophagram group. To take the variability of the data into consideration, we performed a Monte Carlo simulation. The result showed again a median saving of 0.71 days and ∼$2,500 per patient in hospital cost. A ballistic sensitivity analysis was performed to show that the sensitivity of postoperative day 4 amylase level in detecting a leak was the most important factor in the model. We conclude that implementing an amylase-based screening method for anastomotic leak in postesophagectomy patient can significantly reduce hospital cost and length of stay. This study demonstrates a novel protocol to improve postesophagectomy care. Based on this result, we believe a prospective multicenter study is appropriate. INTRODUCTION Despite improvement in surgical technique, esophagectomy is frequently associated with major morbidity. Anastomotic leak is a common but dreaded complication for which prompt and accurate identification is imperative.1–4 Frequently, care providers will restrict patients from taking oral alimentation until the surgical anastomosis has been surveyed radiographically to exclude a leak.5 Esophagram is the standard radiographic imaging method to detect leak currently, but it is frequently inaccurate and, because leaks often present 5–7 days after operation, it can significantly extend hospital stay.6,7 An alternative screening method for leak is to measure perianastomotic drain amylase. Amylase is secreted by salivary glands and typically is contained in the esophagus only. Presence in a drain outside the esophagus would be suggestive of a leak. Postoperative drain amylase levels offer excellent discrimination of leak, and have been proposed as an early screening method to identify patients at high-risk for anastomotic leak.8,9 We have demonstrated that amylase is more sensitive and specific than esophagram in detecting anastomotic leak after esophagectomy.10 Unlike other studies, which suggest that amylase be used to identify patients at high risk for leak, we believe that drain amylase level may allow for more efficient early identification of otherwise clinically stable patients who are unlikely to leak. These lower-risk patients can then be fed and discharged in an accelerated fashion, potentially saving cost and reducing length of hospital stay. This novel protocol presents an alternative to current standard of care of low risk patients, as other studies have not yet demonstrated a benefit to routine use of drain amylase (relative to standard care) to facilitate early discharge. However, drain amylase levels have been used at our institution to assist in decision-making about allowing early discharge after esophagectomy without esophagram. Herein, we propose a drain amylase-facilitated enhanced recovery method (DRAEM) as a protocol to identify patients after esophagectomy that are appropriate for early discharge (Fig. 1). The clinical and financial benefits from an amylase-based pathway like this will be explored herein. Using our institutional experience of using drain amylase to facilitate early discharge, we performed decision analysis to determine the effect of this proposed care pathway on length of stay and cost of hospitalization as compared with standard of care (STD). Fig. 1 View largeDownload slide Drain amylase-facilitated enhanced recovery method (DRAEM). Fig. 1 View largeDownload slide Drain amylase-facilitated enhanced recovery method (DRAEM). METHODS A decision-analysis model was developed using TreeAge Pro software (TreeAge Software, Inc., Williamstown, MA) (Fig. 2) to compare cost and length of stay between the standard of care (STD) and DRAEM. The primary decision node compared STD to DRAEM management. Patients were included in the DRAEM protocol based on presence of recorded drain amylase levels, and patients with and without esophagrams were included. The patients placed in the DRAEM arm (to determine eligibility for early discharge based on our novel protocol) were subdivided at the first event node into four groups based on patients’ clinical presentation and postoperative day 4 (POD4) drain amylase levels as described in a previous paper: (1) clinical stable with high POD4 amylase (amylase > 125 U/L), (2) clinical stable with intermediate POD4 amylase level (amylase between 31 and 125 U/L), (3) clinical stable with low amylase level (amylase < 31 U/L), and (4) clinical unstable patients with or without amylase level. Clinical stability was defined as hemodynamic stability, normal respiratory, and neurological status, and no signs of severe systemic illness (i.e., sepsis). The management of clinical unstable patients in the DRAEM arm was not limited to POD4 amylase level, and these patients would receive all required imaging including esophagram. Our previous data suggest that POD4 was the earliest postoperative day on which drain amylase level had satisfactory sensitivity and specificity to detect leak. The cutoff values for low amylase and high amylase vales at POD4 were based on a ROC curve analysis (Fig. 3). These cutoff values are based on updated data and reflect a larger patient cohort than previous.10 The low amylase level of 31 U/L had a sensitivity of 83% for any leak and 95% for leaks requiring endoscopic or operative intervention (accuracy 58.6%, NPV 93.7%). The high amylase level of 125 U/L had a specificity of 90% for any leak and leaks requiring endoscopic or operative intervention (accuracy 83.2%, PPV 52.7%). Patients were grouped post-hoc for the purposes of the decision tree. For the period of the retrospective review, there was no formal enhanced recovery pathway in place during the actual care of the patients, but the amylase level was utilized in the management of some patients to facilitate early discharge. The patients placed in the STD arm had all been managed with traditional esophagram on days 5 (for thoracic anastomosis) or 7 (for cervical anastomosis) and were given a diet afterwards unless a leak or a complication was noted. Fig. 2 View largeDownload slide The decision analysis tree comparing the length of stay of DA accelerated care to the standard of care in a cohort of patients who have received esophagectomy. Fig. 2 View largeDownload slide The decision analysis tree comparing the length of stay of DA accelerated care to the standard of care in a cohort of patients who have received esophagectomy. Fig. 3 View largeDownload slide Receiver operating characteristic (ROC) curve of using postoperative day 4 drain amylase level in detecting anastomotic leak in post-esophagectomy patients. The low amylase cutoff value of 31 u/L and the high amylase cutoff value of 125 u/L are indicated. Fig. 3 View largeDownload slide Receiver operating characteristic (ROC) curve of using postoperative day 4 drain amylase level in detecting anastomotic leak in post-esophagectomy patients. The low amylase cutoff value of 31 u/L and the high amylase cutoff value of 125 u/L are indicated. As previous studies have demonstrated that the presence of leak and of other nonleak complications were primary drivers of costs after esophagectomy,11,12 these were utilized as subsequent event nodes in both arms of the tree. Each terminal node had two outcomes of interest: cost and length of stay. We included clinical unstable patients in the DRAEM arm despite not using amylase to determine their care to avoid potential bias from shunting away critical ill patients. For other patients who would have been candidates for the DRAEM arm but were managed with esophagram, cost and length of stay data were inferred. For this group, we assumed that patients would have tolerated a diet on POD 5 in the same manner as they did on POD 7. For patients with low amylase (who were therefore candidates for the enhanced recovery pathway), no leak, and no complications, costs and length of stay were truncated at day 5 and these data included in the low-amylase arm of the DRAEM group. We utilized a retrospective chart review to inform frequency and outcome values of the decision tree. Patients who underwent elective esophagectomy utilizing a gastric conduit from March 2007 to December 31, 2015 at a single academic medical center were included, and were grouped according to event branches. Surgical procedures included ‘open’ and minimally invasive approaches to Ivor–Lewis, transhiatal, thoracoabdominal, and McKeown (three-hole) esophagectomy using standardized surgical technique5 (Table 1). Specifically, omental wrapping of the gastric conduit was performed in the Ivor–Lewis technique but not in the transhiatal or McKeown approach. Anastomotic leak was defined as a full thickness gastrointestinal defect involving the esophagus, anastomosis, staple line, or conduit. Leaks were classified according to ECCG definition into 3 types: Type (I) local defect requiring no change in therapy or treated medically or with dietary modification; Type (II) localized defect requiring interventional but not surgical therapy, e.g., interventional radiology drain, stent, or bedside opening and packing of incision; Type (III) defect requiring unplanned reoperation.13 For the purposes of the decision tree analysis, all leaks were grouped together. Complications captured included unexpected return to operating room, air leak >5 days, atelectasis requiring bronchoscopy, pleural effusion requiring drainage, pneumonia, adult respiratory distress syndrome, respiratory failure, bronchopleural fistula, pulmonary embolism, pneumothorax requiring intervention, initial ventilator support >48 hours, tracheostomy, tracheobronchial injury, arrhythmia requiring treatment, myocardial infarction, deep venous thrombosis, ileus, anastomotic leak, dilation esophagus, conduit necrosis requiring surgery, delayed conduit emptying, Clostridium Difficile infection, transfusion of red blood cells, urinary tract infection, urinary retention requiring catheterization, discharge with Foley catheter, empyema requiring treatment, surgical site infection, sepsis, recurrent laryngeal nerve paresis, delirium, stroke, renal failure, chylothorax, unexpected ICU admission, and death based on definitions from the Society of Thoracic Surgeons,14 and were grouped together. Hospital length of stay (LOS) and cost of hospitalization were collected to inform the terminal nodes. Length of stay included hospital days which occurred due to readmission during the 30 day postoperative period. Costs from readmission for leak or nonleak complication which occurred within 30 days of the esophagectomy were included in total hospital costs. Table 1 Characteristics patients in ‘standard care’ and ‘amylase based’ pathways. Values expressed as median (IQR) or n (%) Standard care (n = 126) Amylase based (n = 153) t-test Age (years) 64.49 [56.87, 74.16] 65.17 [58.43, 74.52] 0.67 Male 95 (75.3) 120 (78.4) 0.55 White 118 (93.7) 144 (94.1) 0.87 Hypertension 78 (61.9) 82 (53.6) 0.18 Coronary artery disease 29 (23.0) 35 (22.9) 0.99 Diabetes 31 (24.6) 30 (19.6) 0.32 COPD 18 (14.3) 21 (13.7) 0.98 Preoperative chemotherapy 69 (54.8) 82 (53.6) 0.86 Preoperative radiation 72 (57.1) 92 (60.1) 0.58 Transhiatal 18 (14.3) 35 (22.9) 0.06 Ivor–Lewis Open 3 (0.24) 6 (3.9) 0.46 MI 13 (10.3) 30 (19.6) 0.03 Three-hole Open 18 (14.3) 13 (8.5) 0.14 MI 74 (58.7) 68 (44.4) 0.02 Thoracoabdominal 0 (0) 1 (0.7) 0.32 Location of anastomosis Neck 110 (87.3) 116 (75.8) 0.015 Chest 16 (12.7) 37 (24.2) Any postoperative complication 73 (57.9) 81 (52.9) 0.41 Atrial fibrillation 18 (14.3) 20 (13.1) 0.74 Pneumonia 21 (16.7) 23 (15.0) 0.71 Anastomotic leak† Type 1 leak 11 (8.7) 10 (6.5) 0.66 Type 2 leak 11 (8.7) 14 (9.2) 0.5 Type 3 leak 8 (6.3) 9 (5.9) 0.9 Standard care (n = 126) Amylase based (n = 153) t-test Age (years) 64.49 [56.87, 74.16] 65.17 [58.43, 74.52] 0.67 Male 95 (75.3) 120 (78.4) 0.55 White 118 (93.7) 144 (94.1) 0.87 Hypertension 78 (61.9) 82 (53.6) 0.18 Coronary artery disease 29 (23.0) 35 (22.9) 0.99 Diabetes 31 (24.6) 30 (19.6) 0.32 COPD 18 (14.3) 21 (13.7) 0.98 Preoperative chemotherapy 69 (54.8) 82 (53.6) 0.86 Preoperative radiation 72 (57.1) 92 (60.1) 0.58 Transhiatal 18 (14.3) 35 (22.9) 0.06 Ivor–Lewis Open 3 (0.24) 6 (3.9) 0.46 MI 13 (10.3) 30 (19.6) 0.03 Three-hole Open 18 (14.3) 13 (8.5) 0.14 MI 74 (58.7) 68 (44.4) 0.02 Thoracoabdominal 0 (0) 1 (0.7) 0.32 Location of anastomosis Neck 110 (87.3) 116 (75.8) 0.015 Chest 16 (12.7) 37 (24.2) Any postoperative complication 73 (57.9) 81 (52.9) 0.41 Atrial fibrillation 18 (14.3) 20 (13.1) 0.74 Pneumonia 21 (16.7) 23 (15.0) 0.71 Anastomotic leak† Type 1 leak 11 (8.7) 10 (6.5) 0.66 Type 2 leak 11 (8.7) 14 (9.2) 0.5 Type 3 leak 8 (6.3) 9 (5.9) 0.9 †According to ECCG consensus definition.12 COPD, chronic obstructive pulmonary disease; MI, minimally invasive. View Large Table 1 Characteristics patients in ‘standard care’ and ‘amylase based’ pathways. Values expressed as median (IQR) or n (%) Standard care (n = 126) Amylase based (n = 153) t-test Age (years) 64.49 [56.87, 74.16] 65.17 [58.43, 74.52] 0.67 Male 95 (75.3) 120 (78.4) 0.55 White 118 (93.7) 144 (94.1) 0.87 Hypertension 78 (61.9) 82 (53.6) 0.18 Coronary artery disease 29 (23.0) 35 (22.9) 0.99 Diabetes 31 (24.6) 30 (19.6) 0.32 COPD 18 (14.3) 21 (13.7) 0.98 Preoperative chemotherapy 69 (54.8) 82 (53.6) 0.86 Preoperative radiation 72 (57.1) 92 (60.1) 0.58 Transhiatal 18 (14.3) 35 (22.9) 0.06 Ivor–Lewis Open 3 (0.24) 6 (3.9) 0.46 MI 13 (10.3) 30 (19.6) 0.03 Three-hole Open 18 (14.3) 13 (8.5) 0.14 MI 74 (58.7) 68 (44.4) 0.02 Thoracoabdominal 0 (0) 1 (0.7) 0.32 Location of anastomosis Neck 110 (87.3) 116 (75.8) 0.015 Chest 16 (12.7) 37 (24.2) Any postoperative complication 73 (57.9) 81 (52.9) 0.41 Atrial fibrillation 18 (14.3) 20 (13.1) 0.74 Pneumonia 21 (16.7) 23 (15.0) 0.71 Anastomotic leak† Type 1 leak 11 (8.7) 10 (6.5) 0.66 Type 2 leak 11 (8.7) 14 (9.2) 0.5 Type 3 leak 8 (6.3) 9 (5.9) 0.9 Standard care (n = 126) Amylase based (n = 153) t-test Age (years) 64.49 [56.87, 74.16] 65.17 [58.43, 74.52] 0.67 Male 95 (75.3) 120 (78.4) 0.55 White 118 (93.7) 144 (94.1) 0.87 Hypertension 78 (61.9) 82 (53.6) 0.18 Coronary artery disease 29 (23.0) 35 (22.9) 0.99 Diabetes 31 (24.6) 30 (19.6) 0.32 COPD 18 (14.3) 21 (13.7) 0.98 Preoperative chemotherapy 69 (54.8) 82 (53.6) 0.86 Preoperative radiation 72 (57.1) 92 (60.1) 0.58 Transhiatal 18 (14.3) 35 (22.9) 0.06 Ivor–Lewis Open 3 (0.24) 6 (3.9) 0.46 MI 13 (10.3) 30 (19.6) 0.03 Three-hole Open 18 (14.3) 13 (8.5) 0.14 MI 74 (58.7) 68 (44.4) 0.02 Thoracoabdominal 0 (0) 1 (0.7) 0.32 Location of anastomosis Neck 110 (87.3) 116 (75.8) 0.015 Chest 16 (12.7) 37 (24.2) Any postoperative complication 73 (57.9) 81 (52.9) 0.41 Atrial fibrillation 18 (14.3) 20 (13.1) 0.74 Pneumonia 21 (16.7) 23 (15.0) 0.71 Anastomotic leak† Type 1 leak 11 (8.7) 10 (6.5) 0.66 Type 2 leak 11 (8.7) 14 (9.2) 0.5 Type 3 leak 8 (6.3) 9 (5.9) 0.9 †According to ECCG consensus definition.12 COPD, chronic obstructive pulmonary disease; MI, minimally invasive. View Large Median cost and median length of stay were calculated for each terminal node of the tree. Cost for each terminal node was ‘normalized’ relative to the cost of STD management with no leak and no other complications (according to hospital policy). The frequencies of occurrence of each arm were modeled from the data obtained from the retrospective review. All the numbers used to create the decision tree were listed in Table 2. The base case analysis was defined as the cost-benefit analysis comparing the length of stay and cost of STD and DRAEM arms using the value for each end nodes listed in the Table 2. The base case analysis represents our best estimation of the true value. Table 2 Base-case characteristics: cost and length of stay. Decision analysis arm Anastomotic leak Other complications Adjusted cost† ($) [average, (min; max)] Length of stay (days) [average, (min; max)] Distribution Standard of care + − 4321 (−3697; 7820) 8 (8;11) Triangular + + 52,231 (36,411; 74,624) 24 (13;27) Triangular − − 0 (−1676; 3385) 7 (7;8) Triangular − + 10,321 (2210; 21,262) 8.5 (8;12.75) Triangular Day 4 low amylase + − 8879 (−6261; 15,907) 11 (7;14) Triangular + + 67,616 (N/A) 27 (n/a) Triangular − − −2764 (−3486; −550) 6 (5;6) Triangular − + 5096 (981; 24,408) 8 (7;12) Triangular Day 4 intermediate amylase + − 4646 (4320; 10,924) 9 (8.5; 11.5) Triangular + + 55,738 (51,231: 96,235) 22.5 (20.25; 34.5) Triangular − − 2275 (−2339; 4246) 7 (7; 8) Triangular − + 9848 (4170; 17,969) 9 (7; 12.5) Triangular Day 4 high amylase + − −2417 (−3718; 3848) 12.5 (10.3; 14) Triangular + + 16,339 (4067, 30,060) 12 (9; 16) Triangular − − 3184 (−1369; 3914) 7 (6.5; 8) Triangular − + 10,810 (6576; 15,044) 13 (10.5; 17) Triangular Not eligible for DA protocol 32,276 (14,501; 57,373) 14 (10;23.5) Triangular Decision analysis arm Anastomotic leak Other complications Adjusted cost† ($) [average, (min; max)] Length of stay (days) [average, (min; max)] Distribution Standard of care + − 4321 (−3697; 7820) 8 (8;11) Triangular + + 52,231 (36,411; 74,624) 24 (13;27) Triangular − − 0 (−1676; 3385) 7 (7;8) Triangular − + 10,321 (2210; 21,262) 8.5 (8;12.75) Triangular Day 4 low amylase + − 8879 (−6261; 15,907) 11 (7;14) Triangular + + 67,616 (N/A) 27 (n/a) Triangular − − −2764 (−3486; −550) 6 (5;6) Triangular − + 5096 (981; 24,408) 8 (7;12) Triangular Day 4 intermediate amylase + − 4646 (4320; 10,924) 9 (8.5; 11.5) Triangular + + 55,738 (51,231: 96,235) 22.5 (20.25; 34.5) Triangular − − 2275 (−2339; 4246) 7 (7; 8) Triangular − + 9848 (4170; 17,969) 9 (7; 12.5) Triangular Day 4 high amylase + − −2417 (−3718; 3848) 12.5 (10.3; 14) Triangular + + 16,339 (4067, 30,060) 12 (9; 16) Triangular − − 3184 (−1369; 3914) 7 (6.5; 8) Triangular − + 10,810 (6576; 15,044) 13 (10.5; 17) Triangular Not eligible for DA protocol 32,276 (14,501; 57,373) 14 (10;23.5) Triangular †Hospital costs are adjusted relative to cost of esophagectomy managed by ‘standard care’ that had no postoperative leak or other complications. View Large Table 2 Base-case characteristics: cost and length of stay. Decision analysis arm Anastomotic leak Other complications Adjusted cost† ($) [average, (min; max)] Length of stay (days) [average, (min; max)] Distribution Standard of care + − 4321 (−3697; 7820) 8 (8;11) Triangular + + 52,231 (36,411; 74,624) 24 (13;27) Triangular − − 0 (−1676; 3385) 7 (7;8) Triangular − + 10,321 (2210; 21,262) 8.5 (8;12.75) Triangular Day 4 low amylase + − 8879 (−6261; 15,907) 11 (7;14) Triangular + + 67,616 (N/A) 27 (n/a) Triangular − − −2764 (−3486; −550) 6 (5;6) Triangular − + 5096 (981; 24,408) 8 (7;12) Triangular Day 4 intermediate amylase + − 4646 (4320; 10,924) 9 (8.5; 11.5) Triangular + + 55,738 (51,231: 96,235) 22.5 (20.25; 34.5) Triangular − − 2275 (−2339; 4246) 7 (7; 8) Triangular − + 9848 (4170; 17,969) 9 (7; 12.5) Triangular Day 4 high amylase + − −2417 (−3718; 3848) 12.5 (10.3; 14) Triangular + + 16,339 (4067, 30,060) 12 (9; 16) Triangular − − 3184 (−1369; 3914) 7 (6.5; 8) Triangular − + 10,810 (6576; 15,044) 13 (10.5; 17) Triangular Not eligible for DA protocol 32,276 (14,501; 57,373) 14 (10;23.5) Triangular Decision analysis arm Anastomotic leak Other complications Adjusted cost† ($) [average, (min; max)] Length of stay (days) [average, (min; max)] Distribution Standard of care + − 4321 (−3697; 7820) 8 (8;11) Triangular + + 52,231 (36,411; 74,624) 24 (13;27) Triangular − − 0 (−1676; 3385) 7 (7;8) Triangular − + 10,321 (2210; 21,262) 8.5 (8;12.75) Triangular Day 4 low amylase + − 8879 (−6261; 15,907) 11 (7;14) Triangular + + 67,616 (N/A) 27 (n/a) Triangular − − −2764 (−3486; −550) 6 (5;6) Triangular − + 5096 (981; 24,408) 8 (7;12) Triangular Day 4 intermediate amylase + − 4646 (4320; 10,924) 9 (8.5; 11.5) Triangular + + 55,738 (51,231: 96,235) 22.5 (20.25; 34.5) Triangular − − 2275 (−2339; 4246) 7 (7; 8) Triangular − + 9848 (4170; 17,969) 9 (7; 12.5) Triangular Day 4 high amylase + − −2417 (−3718; 3848) 12.5 (10.3; 14) Triangular + + 16,339 (4067, 30,060) 12 (9; 16) Triangular − − 3184 (−1369; 3914) 7 (6.5; 8) Triangular − + 10,810 (6576; 15,044) 13 (10.5; 17) Triangular Not eligible for DA protocol 32,276 (14,501; 57,373) 14 (10;23.5) Triangular †Hospital costs are adjusted relative to cost of esophagectomy managed by ‘standard care’ that had no postoperative leak or other complications. View Large A Monte Carlo simulation was performed to assess the effect of the variability of the data on the decision model. This model simulates the variability that might occur if this protocol were performed by other institutions or in a different patient population. This simulation was performed by randomly generating a hypothetical patient cohort of 10,000 postesophagectomy patients. Their length of stay and cost were randomly chosen based on the value distribution defined in Table 2. We also performed a sensitivity analysis to assess the effect of leak rate on the model outcome. The leak rate of POD4 low amylase group was allowed to vary from 1% to 100%. We assumed the leak rates of POD4 intermediate and POD4 high amylase groups would also increase proportionally to that of POD4 low amylase group. Leak rates of intermediate and high amylase level groups were adjusted accordingly in the sensitivity analysis. The adjusting factor was based on the ratio between the leak rates among the three groups in the base-case analysis. All data were analyzed using STATA/SE, Version 14.0 (StataCorp, College Station, TX) and TreeAge (TreeAge Software, Inc., Williamstown, MA). The study was approved by the University Hospitals Cleveland Medical Center Institutional Review Board. RESULTS One hundred and eighty eight (188) patients underwent esophagectomy at our institution during the study period and were classified according to study criteria as defined above. Patient demographics are shown in Table 1. One hundred and twenty six (126) patients were included in the STD arm. One hundred and fifty three (153) were included in the DRAEM arm, including 11 patients who were not eligible for early alimentation but were included in the DRAEM arm to reduce potential bias. Patients in the STD pathway and DRAEM were similar in regards to overall rate of postoperative complications (50% vs. 49%, P = 0.41) and anastomotic leaks (23.8% vs. 23.9%, P = 0.66). Patients in STD pathway had more minimal invasive three-hole esophagectomy performed (58.7% vs. 44.4%, P = 0.02), while DRAEM arm had more minimal invasive Ivor–Lewis esophagectomy performed (30% vs. 13%, P = 0.03). The locations of anastomoses differed as well. DRAEM arm had more anastomoses in the chest than that in STD (24.2% vs. 12.7%, P = 0.015). Sixty one patients (of 153 in the DRAEM group, 40%) had low POD4 drain amylase (<31 U/L). Leak rate for the low amylase group was 10%, including both medically managed (Type I, N = 5, 8.2% of low POD4 group) and procedurally managed leaks (Type 2 and 3, N = 1, 1.6% of low POD4 group). Fifty six patients (37%) were characterized as intermediate amylase group, and their leak rate was 16%, including both medically managed (Type I, N = 3) and procedurally managed leaks (Type 2 and 3, N = 6). The high amylase group included 16% of patients, and demonstrated a leak rate of 60%, including both medically managed (Type I, N = 2) and procedurally managed leaks (Type 2 and 3, N = 12). Base-case analysis and Monte Carlo simulation The decision tree is shown in Figure 2. Based on data obtained from review our institution's use of amylase in postoperative management of patients after esophagectomy, the amylase-based pathway was associated with an improvement in LOS (decrease) of 0.93 days (DRAEM 9.23 day/patient, STD 10.16 day/patient) and a cost saving of $3113 (DRAEM $8243/patient, STD $11,356/patient). To determine if this effect could be extrapolated to a broader cohort, we performed a Monte Carlo simulation. The Monte Carlo simulation confirmed the benefit of the amylase-based protocol after accounting for the potential variation associated with a hypothetical cohort of 10,000 patients, with a median saving of 0.71 days in hospital stay and $2434/patient in cost (Table 3, Fig. 4). Table 3 Monte Carlo simulation of 10,000 patient result. Cost ($/patient) LOS (days/patient) Frequency of being the optimal option based on cost (%) Frequency of being the optimal option based on LOS (%) DRAEM median [10th percentile–90th percentile] $9548 [8122–11,156] 9.67 [9.25–10.12] 85.34 86.55 Standard care median [10th percentile–90th percentile] $12,018 [9662–14,522] 10.38 [9.60–11.12] 14.66 13.45 Cost ($/patient) LOS (days/patient) Frequency of being the optimal option based on cost (%) Frequency of being the optimal option based on LOS (%) DRAEM median [10th percentile–90th percentile] $9548 [8122–11,156] 9.67 [9.25–10.12] 85.34 86.55 Standard care median [10th percentile–90th percentile] $12,018 [9662–14,522] 10.38 [9.60–11.12] 14.66 13.45 LOS, length of stay. View Large Table 3 Monte Carlo simulation of 10,000 patient result. Cost ($/patient) LOS (days/patient) Frequency of being the optimal option based on cost (%) Frequency of being the optimal option based on LOS (%) DRAEM median [10th percentile–90th percentile] $9548 [8122–11,156] 9.67 [9.25–10.12] 85.34 86.55 Standard care median [10th percentile–90th percentile] $12,018 [9662–14,522] 10.38 [9.60–11.12] 14.66 13.45 Cost ($/patient) LOS (days/patient) Frequency of being the optimal option based on cost (%) Frequency of being the optimal option based on LOS (%) DRAEM median [10th percentile–90th percentile] $9548 [8122–11,156] 9.67 [9.25–10.12] 85.34 86.55 Standard care median [10th percentile–90th percentile] $12,018 [9662–14,522] 10.38 [9.60–11.12] 14.66 13.45 LOS, length of stay. View Large Sensitivity to the leak rate in day 4 low amylase group In the sensitivity analysis, DRAEM demonstrated benefits in cost and length of stay relative to STD when the leak rate of POD4 low amylase group less than 20.6% (Fig. 5A). DRAEM dominated STD in sensitivity analysis on LOS when the leak rate of POD4 low amylase group was less than 18.3% (Fig. 5B). Fig. 4 View largeDownload slide Monte Carlo simulation: A) Probability distribution plot of length of stays (days) for Monte Carlo simulation of 10,000 patients comparing the drain amylase accelerated care pathway (DA) versus the standard of care (STD). B) Probability distribution plot of adjusted cost ($) for Monte Carlo simulation of 10,000 patients comparing the drain amylase accelerated care pathway versus the standard of care. Fig. 4 View largeDownload slide Monte Carlo simulation: A) Probability distribution plot of length of stays (days) for Monte Carlo simulation of 10,000 patients comparing the drain amylase accelerated care pathway (DA) versus the standard of care (STD). B) Probability distribution plot of adjusted cost ($) for Monte Carlo simulation of 10,000 patients comparing the drain amylase accelerated care pathway versus the standard of care. Fig. 5 View largeDownload slide A) Sensitivity analysis of leak rate in day 4 low amylase group on the cost of the drain amylase care pathway protocol. Each data point represents the cost of the protocol associated with the each leak rate. The dashed line represents the adjusted cost of the standard care ($11,356). B) Sensitivity analysis of leak rate in day 4 low amylase group on the LOS of the drain amylase care pathway protocol. Each data point represents the LOS of the protocol associated with the each leak rate. The dashed line represents the LOS of the standard care (10.2 days). Fig. 5 View largeDownload slide A) Sensitivity analysis of leak rate in day 4 low amylase group on the cost of the drain amylase care pathway protocol. Each data point represents the cost of the protocol associated with the each leak rate. The dashed line represents the adjusted cost of the standard care ($11,356). B) Sensitivity analysis of leak rate in day 4 low amylase group on the LOS of the drain amylase care pathway protocol. Each data point represents the LOS of the protocol associated with the each leak rate. The dashed line represents the LOS of the standard care (10.2 days). DISCUSSION Esophagectomy is a procedure, which is performed infrequently and is often performed at specialized centers. Data from the National Inpatient Sample suggest that only 1% of hospitals that performed esophagectomy were ‘high-volume hospitals,’ and that these facilities performed a median of 50 esophagectomies per year.15 Enhanced recovery pathways have been used in many surgical disciplines to streamline care and reduce major morbidities,16–19 but few have been studied across institutions due to difficulties in study recruitment. Given this paucity of cases and facilities performing esophagectomy, prospective clinical trials in postoperative care of esophagectomy patients are complex and often impractical. Decision analysis is an analytic method to formally quantify and compare the cost-effectiveness of treatments.20–22 We used the decision analysis technique to quantify the benefit of a drain amylase-based enhanced recovery pathway relative to standard care in terms of cost and length of stay. When applied to the cohort of patients at our institution, universal adoption of this protocol would have reduced median length of stay by 0.93 days and reduced hospital cost by $3113 per patient, a savings of roughly 10% of the total hospitalization. A benefit was also seen in a hypothetical cohort of patients generated in a Monte-Carlo simulation, thereby suggesting that the cost and length of stay savings seen at out institution might also be seen in a different patient population or surgical setting. We believe that the ‘source’ of the cost savings associated with the amylase pathway arose from the early discharge of patients who were categorized as unlikely to leak. Relative to the standard of care, patients without anastomotic leak or other complications had a cost savings of $2764. The savings affected approximately 36% of patients, and translated to the majority of the calculated savings of $3113. Our data also demonstrated a savings among patients with high amylase values who had a leak. This was a smaller group of patients (9.6%), but contributed to cost savings. Moreover, we believed these data spoke to a fundamental benefit to early identification of surgical complications. Early identification and treatment of anastomotic leak was clearly associated with improved outcomes, and corroborate data that the cost of esophagectomy is driven mainly by complications.12 Other studies of accelerated care pathways after esophagectomy used nutritional support, preemptive analgesia, perioperative fluid therapy, and surgical techniques to reduce hospital length of stay, but did not focus on pathways that assess the risk of anastomotic leak.23 The assessment of anastomotic leak was an ideal target for accelerated care pathways given the inaccuracy of esophagram in the assessment of leak. Herein we show that a drain amylase-based care pathway safely allows for earlier discrimination of patients who are more likely or unlikely to leak, thereby reducing hospital costs and length of stay. This analysis suggests that an amylase-based care pathway postesophagectomy might reduce hospital length of stay to a similar extent as adoption of minimally invasive surgical technique, which has recently been shown to be associated with a reduction of hospital length of stay by 1 day in a review of the Society of Thoracic Surgeon's database.24 A possible concern about using amylase to screen for anastomotic leak is the false-negative rate. In our experience, clinically significant anastomotic leaks were uncommon when patients have a low POD4 drain amylase. However, only 1.6% of patients in the low amylase group had clinically significant leak requiring procedural intervention. The majority of the leaks in low amylase groups were occult leaks that did not lead to postoperative morbidity and there were no postoperative mortalities associated with these ‘missed’ leaks. For patients in the intermediate amylase group (amylase level between 31 and 125), we found they had higher leak rate (16%) and more significant leaks (66% type II and III leaks). Our sensitivity analysis suggested that there was benefit of this protocol up to a 20% leak rate in the low risk group. Interestingly, this implies that there may not be cost and LOS benefit to esophagram in the ‘intermediate’ amylase group. Given the prevalence of type II/III leaks, we believe that patients in this group were not sufficiently safe to justify early alimentation and discharge. Comparatively, esophagram has a lower sensitivity than drain amylase, and studies of esophagram demonstrate poor negative predictive value.6,7 An analysis at our intuition showed that amylase was superior to esophagram.10 Furthermore, the amylase test was simple, safe, and easy to obtain, and did not expose patients to potential risk of radiation or contrast aspiration that could occur during esophagram. Therefore, we believe that the false negative rate associated with a low POD4 drain amylase is acceptable in this setting. There are several limitations to this study. As with all other cost-effective studies, the result is limited by the data used to create the model. Our data were collected in a single tertiary care institution with limited number of patients and without randomization. Furthermore, there were differences between the groups, most notably in the location of the anastomosis and the procedures performed. The effect of these differences was partially mitigated by the similar leak rate and complication rate in the STD and DRAEM arms. Nonetheless, there is a possibility of bias in the calculation of costs and LOS. However, intrathoracic anastomotic leak can lead to more significant morbidity than cervical anastomotic leak, and therefore higher intrathoracic anastomosis may be biased to have higher costs and longer LOS. We therefore believe that the effect of this difference is minimal and does not alter our conclusion. DRAEM was not an established protocol for the period of retrospective review, and physician's clinical judgment played a significant role in deciding how patients were treated postoperatively. We used our best judgment to determine if a patient was managed in an accelerated basis or not, and attempted to appropriately categorize patients within the decision tree arms to reflect an accurate distribution of patients and patient management, but classification errors or bias was possible. Furthermore, inferred date of discharge for patients in the DRAEM group may have been affected by factors other than oral alimentation, such as postoperative pain or the occurrence of other complications that result from protocol implementation. We attempted to mitigate this effect by careful chart review, but misclassification of discharge day may have skewed the data. This analysis may underestimate the effect of protocol implementation in institutions in which esophagram was performed later than POD5-7 or in which typical length of stay was longer. We could not explore this institution dependent benefit in this single center analysis. Lastly, we applied amylase thresholds to determine risk of anastomotic leak in a homogenous population, and results may not be reproducible at other institutions. We believe that the benefit of the amylase-based method to evaluate the anastomosis would be valid at other institutions even if the leak rate varied significantly (in either direction). Our data may suggest an even more significant benefit to this protocol at institutions with longer length of stay. Based on the demonstrated benefits of this decision analysis and the hypothetical benefit suggested by the Monte-Carlo analysis, we believe that a prospective study of a drain amylase-based oral alimentation protocol is appropriate. Care pathways have been successfully implemented in other surgical disciplines with significant improvement outcomes. As health care resources become increasingly scrutinized, efforts to reduce hospital length of stay are increasingly important. Approximately 7100 esophagectomies were performed between 2008 and 2015 among institutions participating in the society of thoracic surgeons outcomes database.25,26 If DRAEM were implemented in these institutions, the cost saving could have exceeded $2 million and nearly 6500 hospital days reduced. Drain amylase measurement may be a robust method of determining patients who are candidates for an enhanced recovery pathway, which included early alimentation and discharge. CONCLUSION Our analysis indicates that a drain amylase-based enhanced recovery method could potentially reduce length of stay and cost in postesophagectomy patients when comparing to the standard of care. A prospective, multicenter study should be conducted to further validate the benefit of this method. Notes Author Disclosure Statement: The authors declare that no bias, sources of funding, or financial relationships influenced this work and its conclusions. Dr. Towe has received consultant fees and travel reimbursement from Medtronic. Note: These data were presented at the 12th Annual Academic Surgical Congress in Las Vegas, NV, February 2017. Specific author contributions: Study design: Boxiang Jiang, Vanessa P. Ho, Yaron Perry, Luis Argote-Greene, Philip A. Linden, Christopher W. Towe; Manuscript preparation: Boxiang Jiang, Vanessa P. Ho, Jennifer Ginsberg, Yaron Perry, Luis Argote-Greene, Philip A. Linden, Christopher W. Towe; Data collection: Boxiang Jiang, Vanessa P. Ho, Jennifer Ginsberg, Sue J Fu, Christopher W. Towe; Data analysis: Boxiang Jiang, Vanessa P. Ho, Christopher W. Towe. References 1 Kassis E S , Kosinski A S , Ross P Jr , Koppes K E , Donahue J M , Daniel V C . Predictors of anastomotic leak after esophagectomy: an analysis of the society of thoracic surgeons general thoracic database . Ann Thorac Surg 2013 ; 96 : 1919 – 26 . Google Scholar CrossRef Search ADS PubMed 2 Mahoney J L , Condon R E , Adenocarcinoma of the esophagus . Ann Surg 1987 ; 205 : 557 – 62 . Google Scholar CrossRef Search ADS PubMed 3 Markar S R , Arya S , Karthikesalingam A , Hanna G B . Technical factors that affect anastomotic integrity following esophagectomy: systematic review and meta-analysis . Ann Surg Oncol 2013 ; 20 : 4274 – 81 . Google Scholar CrossRef Search ADS PubMed 4 Li B , Xiang J , Zhang Y , Hu H , Sun Y , Chen H . Factors affecting hospital mortality in patients with esophagogastric anastomotic leak: a retrospective study . World J Surg 2016 ; 40 : 1152 – 7 . Google Scholar CrossRef Search ADS PubMed 5 Cooke D T , Lin G C , Lau C L et al. Analysis of cervical esophagogastric anastomotic leaks after transhiatal esophagectomy: risk factors, presentation, and detection . Ann Thorac Surg 2009 ; 88 : 177 – 85 ; discussion 184–5 . Google Scholar CrossRef Search ADS PubMed 6 Lantos J E , Levine M S , Rubesin S E , Lau C T , Torigian D A . Comparison between esophagography and chest computed tomography for evaluation of leaks after esophagectomy and gastric pull-through . J Thorac Imaging 2013 ; 28 : 121 – 8 . Google Scholar CrossRef Search ADS PubMed 7 Cools-Lartigue J , Andalib A , Abo-Alsaud A , et al . Routine contrast esophagram has minimal impact on the postoperative management of patients undergoing esophagectomy for esophageal cancer . Ann Surg Oncol 2014 ; 21 : 2573 – 9 . Google Scholar CrossRef Search ADS PubMed 8 Berkelmans G H , Kouwenhoven E A , Smeets B J et al. Diagnostic value of drain amylase for detecting intrathoracic leakage after esophagectomy . World J Gastroenterol 2015 ; 21 : 9118 – 25 Google Scholar CrossRef Search ADS PubMed 9 Baker E H , Hill J S , Reames M K et al. Drain amylase aids detection of anastomotic leak after esophagectomy . J Gastrointest Oncol 2016 ; 7 : 181 – 8 . Google Scholar PubMed 10 Perry Y , Towe C W , Kwong J , Ho V P , Linden P A . Serial drain amylase can accurately detect anastomotic leak after esophagectomy and may facilitate early discharge . Ann Thorac Surg 2015 ; 100 : 2041 – 7 ; discussion 2046–7 . Google Scholar CrossRef Search ADS PubMed 11 Goense L , van Dijk W A , Govaert J A , van Rossum P S , Ruurda J P , van Hillegersberg R . Hospital costs of complications after esophagectomy for cancer . Eur J Surg Oncol 2017 ; 43 : 696 – 702 . Google Scholar CrossRef Search ADS PubMed 12 Fu S J , Ho V P , Ginsberg J , et al . Complications, not minimally invasive surgical technique, are associated with increased cost after esophagectomy . Minim Invasive Surg 2016 ; 2016 : 7690632 . Google Scholar PubMed 13 Low D E , Alderson D , Cecconello I et al. International consensus on standardization of data collection for complications associated with esophagectomy: Esophagectomy Complications Consensus Group (ECCG) . Ann Surg 2015 ; 262 : 286 – 94 . Google Scholar CrossRef Search ADS PubMed 14 Society of Thoracic Surgeons . http://www.sts.org/quality-research-patient-safety/national-database/database-managers/general-thoracic-surgery-databa-1 . 2017 . 15 Funk L M , Gawande A A , Semel M E , et al . Esophagectomy outcomes at low-volume hospitals: the association between systems characteristics and mortality . Ann Surg 2011 ; 253 : 912 – 7 . Google Scholar CrossRef Search ADS PubMed 16 Azhar R A , Bochner B , Catto J et al. Enhanced recovery after urological surgery: a contemporary systematic review of outcomes, key elements, and research needs . Eur Urol 2016 ; 70 : 176 – 87 . Google Scholar CrossRef Search ADS PubMed 17 Spanjersberg W R , Reurings J , Keus F , van Laarhoven C J . Fast track surgery versus conventional recovery strategies for colorectal surgery . Cochrane Database Syst Rev 2011 : CD007635 . 18 Gimenez-Mila M , Klein A A , Martinez G , Design and implementation of an enhanced recovery program in thoracic surgery . J Thorac Dis 2016 ; 8 : S37 – 45 . Google Scholar PubMed 19 Jones N L , Edmonds L , Ghosh S , Klein A A . A review of enhanced recovery for thoracic anaesthesia and surgery . Anaesthesia 2013 ; 68 : 179 – 89 . Google Scholar CrossRef Search ADS PubMed 20 Lee L , Sudarshan M , Li C et al. Cost-effectiveness of minimally invasive versus open esophagectomy for esophageal cancer . Ann Surg Oncol 2013 ; 20 : 3732 – 9 . Google Scholar CrossRef Search ADS PubMed 21 Pohl H , Sonnenberg A , Strobel S , Eckardt A , Rösch T . Endoscopic versus surgical therapy for early cancer in Barrett's esophagus: a decision analysis . Gastrointest Endosc 2009 ; 70 : 623 – 31 . Google Scholar CrossRef Search ADS PubMed 22 Adunlin G , Diaby V , Xiao H . Application of multicriteria decision analysis in health care: a systematic review and bibliometric analysis . Health Expect 2015 ; 18 : 1894 – 905 . Google Scholar CrossRef Search ADS PubMed 23 Findlay J M , Gillies R S , Millo J , Sgromo B , Marshall R E , Maynard N D . Enhanced recovery for esophagectomy: a systematic review and evidence-based guidelines . Ann Surg 2014 ; 259 : 413 – 31 . Google Scholar CrossRef Search ADS PubMed 24 Sihag S , Kosinski A S , Gaissert H A , Wright C D , Schipper P H . Minimally invasive versus open esophagectomy for esophageal cancer: a comparison of early surgical outcomes from the society of thoracic surgeons national database . Ann Thorac Surg 2016 ; 101 : 1281 – 9 ; discussion 1288–9 . Google Scholar CrossRef Search ADS PubMed 25 Society of Thoracic Surgeons , General thoracic surgery database , https://www.sts.org/registries-research-center/sts-national-database/general-thoracic-surgery-database . 2017 . 26 Towe C W , Gulack B C , Kim S , et al . Restrictive transfusion practices after esophagectomy are associated with improved outcome: a review of the society of thoracic surgeons general thoracic database . Ann Surg 2018 ; 267 : 886 – 91 . Google Scholar PubMed © The Author(s) 2018. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Diseases of the Esophagus Oxford University Press

Decision analysis supports the use of drain amylase-based enhanced recovery method after esophagectomy

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The International Society for Diseases of the Esophagus
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© The Author(s) 2018. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus.
ISSN
1120-8694
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1442-2050
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10.1093/dote/doy041
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Abstract

SUMMARY Postesophagectomy anastomotic leak is a common postsurgical complication. The current standard method of detecting leak is esophagram usually late in the postoperative period. Perianastomotic drain amylase level had shown promising results in early detection anastomosis leak. Previous studies have shown that postoperative day 4 amylase level is more specific and sensitive than esophagram. The purpose of this study is to determine if implementing a drain amylase-based screening method for anastomotic leak can reduce length of stay and hospital cost relative to a traditional esophagram-based pathway. The drain amylase protocol we propose uses postoperative day 4 drain amylase level to direct the initiation of PO intake and discharge. We designed a decision analysis tree using TreeAge Pro software to compare the drain amylase-based screening method to the standard of care, the esophagram. We performed a retrospective review of postesophagectomy patients from a tertiary academic medical center (University hospital Cleveland medical center) where amylase level was measured routinely postoperatively. The patients were separated into amylase-based pathway group and the standard of care group based on their postop management. The length of stay, costs, complications, and leak rate of these two groups were used to inform the decision analysis tree. In the base-case analysis, the decision analysis demonstrated that an amylase-based screening method can reduce the hospital stay by one day and reduced costs by ∼$3,000 compared to esophagram group. To take the variability of the data into consideration, we performed a Monte Carlo simulation. The result showed again a median saving of 0.71 days and ∼$2,500 per patient in hospital cost. A ballistic sensitivity analysis was performed to show that the sensitivity of postoperative day 4 amylase level in detecting a leak was the most important factor in the model. We conclude that implementing an amylase-based screening method for anastomotic leak in postesophagectomy patient can significantly reduce hospital cost and length of stay. This study demonstrates a novel protocol to improve postesophagectomy care. Based on this result, we believe a prospective multicenter study is appropriate. INTRODUCTION Despite improvement in surgical technique, esophagectomy is frequently associated with major morbidity. Anastomotic leak is a common but dreaded complication for which prompt and accurate identification is imperative.1–4 Frequently, care providers will restrict patients from taking oral alimentation until the surgical anastomosis has been surveyed radiographically to exclude a leak.5 Esophagram is the standard radiographic imaging method to detect leak currently, but it is frequently inaccurate and, because leaks often present 5–7 days after operation, it can significantly extend hospital stay.6,7 An alternative screening method for leak is to measure perianastomotic drain amylase. Amylase is secreted by salivary glands and typically is contained in the esophagus only. Presence in a drain outside the esophagus would be suggestive of a leak. Postoperative drain amylase levels offer excellent discrimination of leak, and have been proposed as an early screening method to identify patients at high-risk for anastomotic leak.8,9 We have demonstrated that amylase is more sensitive and specific than esophagram in detecting anastomotic leak after esophagectomy.10 Unlike other studies, which suggest that amylase be used to identify patients at high risk for leak, we believe that drain amylase level may allow for more efficient early identification of otherwise clinically stable patients who are unlikely to leak. These lower-risk patients can then be fed and discharged in an accelerated fashion, potentially saving cost and reducing length of hospital stay. This novel protocol presents an alternative to current standard of care of low risk patients, as other studies have not yet demonstrated a benefit to routine use of drain amylase (relative to standard care) to facilitate early discharge. However, drain amylase levels have been used at our institution to assist in decision-making about allowing early discharge after esophagectomy without esophagram. Herein, we propose a drain amylase-facilitated enhanced recovery method (DRAEM) as a protocol to identify patients after esophagectomy that are appropriate for early discharge (Fig. 1). The clinical and financial benefits from an amylase-based pathway like this will be explored herein. Using our institutional experience of using drain amylase to facilitate early discharge, we performed decision analysis to determine the effect of this proposed care pathway on length of stay and cost of hospitalization as compared with standard of care (STD). Fig. 1 View largeDownload slide Drain amylase-facilitated enhanced recovery method (DRAEM). Fig. 1 View largeDownload slide Drain amylase-facilitated enhanced recovery method (DRAEM). METHODS A decision-analysis model was developed using TreeAge Pro software (TreeAge Software, Inc., Williamstown, MA) (Fig. 2) to compare cost and length of stay between the standard of care (STD) and DRAEM. The primary decision node compared STD to DRAEM management. Patients were included in the DRAEM protocol based on presence of recorded drain amylase levels, and patients with and without esophagrams were included. The patients placed in the DRAEM arm (to determine eligibility for early discharge based on our novel protocol) were subdivided at the first event node into four groups based on patients’ clinical presentation and postoperative day 4 (POD4) drain amylase levels as described in a previous paper: (1) clinical stable with high POD4 amylase (amylase > 125 U/L), (2) clinical stable with intermediate POD4 amylase level (amylase between 31 and 125 U/L), (3) clinical stable with low amylase level (amylase < 31 U/L), and (4) clinical unstable patients with or without amylase level. Clinical stability was defined as hemodynamic stability, normal respiratory, and neurological status, and no signs of severe systemic illness (i.e., sepsis). The management of clinical unstable patients in the DRAEM arm was not limited to POD4 amylase level, and these patients would receive all required imaging including esophagram. Our previous data suggest that POD4 was the earliest postoperative day on which drain amylase level had satisfactory sensitivity and specificity to detect leak. The cutoff values for low amylase and high amylase vales at POD4 were based on a ROC curve analysis (Fig. 3). These cutoff values are based on updated data and reflect a larger patient cohort than previous.10 The low amylase level of 31 U/L had a sensitivity of 83% for any leak and 95% for leaks requiring endoscopic or operative intervention (accuracy 58.6%, NPV 93.7%). The high amylase level of 125 U/L had a specificity of 90% for any leak and leaks requiring endoscopic or operative intervention (accuracy 83.2%, PPV 52.7%). Patients were grouped post-hoc for the purposes of the decision tree. For the period of the retrospective review, there was no formal enhanced recovery pathway in place during the actual care of the patients, but the amylase level was utilized in the management of some patients to facilitate early discharge. The patients placed in the STD arm had all been managed with traditional esophagram on days 5 (for thoracic anastomosis) or 7 (for cervical anastomosis) and were given a diet afterwards unless a leak or a complication was noted. Fig. 2 View largeDownload slide The decision analysis tree comparing the length of stay of DA accelerated care to the standard of care in a cohort of patients who have received esophagectomy. Fig. 2 View largeDownload slide The decision analysis tree comparing the length of stay of DA accelerated care to the standard of care in a cohort of patients who have received esophagectomy. Fig. 3 View largeDownload slide Receiver operating characteristic (ROC) curve of using postoperative day 4 drain amylase level in detecting anastomotic leak in post-esophagectomy patients. The low amylase cutoff value of 31 u/L and the high amylase cutoff value of 125 u/L are indicated. Fig. 3 View largeDownload slide Receiver operating characteristic (ROC) curve of using postoperative day 4 drain amylase level in detecting anastomotic leak in post-esophagectomy patients. The low amylase cutoff value of 31 u/L and the high amylase cutoff value of 125 u/L are indicated. As previous studies have demonstrated that the presence of leak and of other nonleak complications were primary drivers of costs after esophagectomy,11,12 these were utilized as subsequent event nodes in both arms of the tree. Each terminal node had two outcomes of interest: cost and length of stay. We included clinical unstable patients in the DRAEM arm despite not using amylase to determine their care to avoid potential bias from shunting away critical ill patients. For other patients who would have been candidates for the DRAEM arm but were managed with esophagram, cost and length of stay data were inferred. For this group, we assumed that patients would have tolerated a diet on POD 5 in the same manner as they did on POD 7. For patients with low amylase (who were therefore candidates for the enhanced recovery pathway), no leak, and no complications, costs and length of stay were truncated at day 5 and these data included in the low-amylase arm of the DRAEM group. We utilized a retrospective chart review to inform frequency and outcome values of the decision tree. Patients who underwent elective esophagectomy utilizing a gastric conduit from March 2007 to December 31, 2015 at a single academic medical center were included, and were grouped according to event branches. Surgical procedures included ‘open’ and minimally invasive approaches to Ivor–Lewis, transhiatal, thoracoabdominal, and McKeown (three-hole) esophagectomy using standardized surgical technique5 (Table 1). Specifically, omental wrapping of the gastric conduit was performed in the Ivor–Lewis technique but not in the transhiatal or McKeown approach. Anastomotic leak was defined as a full thickness gastrointestinal defect involving the esophagus, anastomosis, staple line, or conduit. Leaks were classified according to ECCG definition into 3 types: Type (I) local defect requiring no change in therapy or treated medically or with dietary modification; Type (II) localized defect requiring interventional but not surgical therapy, e.g., interventional radiology drain, stent, or bedside opening and packing of incision; Type (III) defect requiring unplanned reoperation.13 For the purposes of the decision tree analysis, all leaks were grouped together. Complications captured included unexpected return to operating room, air leak >5 days, atelectasis requiring bronchoscopy, pleural effusion requiring drainage, pneumonia, adult respiratory distress syndrome, respiratory failure, bronchopleural fistula, pulmonary embolism, pneumothorax requiring intervention, initial ventilator support >48 hours, tracheostomy, tracheobronchial injury, arrhythmia requiring treatment, myocardial infarction, deep venous thrombosis, ileus, anastomotic leak, dilation esophagus, conduit necrosis requiring surgery, delayed conduit emptying, Clostridium Difficile infection, transfusion of red blood cells, urinary tract infection, urinary retention requiring catheterization, discharge with Foley catheter, empyema requiring treatment, surgical site infection, sepsis, recurrent laryngeal nerve paresis, delirium, stroke, renal failure, chylothorax, unexpected ICU admission, and death based on definitions from the Society of Thoracic Surgeons,14 and were grouped together. Hospital length of stay (LOS) and cost of hospitalization were collected to inform the terminal nodes. Length of stay included hospital days which occurred due to readmission during the 30 day postoperative period. Costs from readmission for leak or nonleak complication which occurred within 30 days of the esophagectomy were included in total hospital costs. Table 1 Characteristics patients in ‘standard care’ and ‘amylase based’ pathways. Values expressed as median (IQR) or n (%) Standard care (n = 126) Amylase based (n = 153) t-test Age (years) 64.49 [56.87, 74.16] 65.17 [58.43, 74.52] 0.67 Male 95 (75.3) 120 (78.4) 0.55 White 118 (93.7) 144 (94.1) 0.87 Hypertension 78 (61.9) 82 (53.6) 0.18 Coronary artery disease 29 (23.0) 35 (22.9) 0.99 Diabetes 31 (24.6) 30 (19.6) 0.32 COPD 18 (14.3) 21 (13.7) 0.98 Preoperative chemotherapy 69 (54.8) 82 (53.6) 0.86 Preoperative radiation 72 (57.1) 92 (60.1) 0.58 Transhiatal 18 (14.3) 35 (22.9) 0.06 Ivor–Lewis Open 3 (0.24) 6 (3.9) 0.46 MI 13 (10.3) 30 (19.6) 0.03 Three-hole Open 18 (14.3) 13 (8.5) 0.14 MI 74 (58.7) 68 (44.4) 0.02 Thoracoabdominal 0 (0) 1 (0.7) 0.32 Location of anastomosis Neck 110 (87.3) 116 (75.8) 0.015 Chest 16 (12.7) 37 (24.2) Any postoperative complication 73 (57.9) 81 (52.9) 0.41 Atrial fibrillation 18 (14.3) 20 (13.1) 0.74 Pneumonia 21 (16.7) 23 (15.0) 0.71 Anastomotic leak† Type 1 leak 11 (8.7) 10 (6.5) 0.66 Type 2 leak 11 (8.7) 14 (9.2) 0.5 Type 3 leak 8 (6.3) 9 (5.9) 0.9 Standard care (n = 126) Amylase based (n = 153) t-test Age (years) 64.49 [56.87, 74.16] 65.17 [58.43, 74.52] 0.67 Male 95 (75.3) 120 (78.4) 0.55 White 118 (93.7) 144 (94.1) 0.87 Hypertension 78 (61.9) 82 (53.6) 0.18 Coronary artery disease 29 (23.0) 35 (22.9) 0.99 Diabetes 31 (24.6) 30 (19.6) 0.32 COPD 18 (14.3) 21 (13.7) 0.98 Preoperative chemotherapy 69 (54.8) 82 (53.6) 0.86 Preoperative radiation 72 (57.1) 92 (60.1) 0.58 Transhiatal 18 (14.3) 35 (22.9) 0.06 Ivor–Lewis Open 3 (0.24) 6 (3.9) 0.46 MI 13 (10.3) 30 (19.6) 0.03 Three-hole Open 18 (14.3) 13 (8.5) 0.14 MI 74 (58.7) 68 (44.4) 0.02 Thoracoabdominal 0 (0) 1 (0.7) 0.32 Location of anastomosis Neck 110 (87.3) 116 (75.8) 0.015 Chest 16 (12.7) 37 (24.2) Any postoperative complication 73 (57.9) 81 (52.9) 0.41 Atrial fibrillation 18 (14.3) 20 (13.1) 0.74 Pneumonia 21 (16.7) 23 (15.0) 0.71 Anastomotic leak† Type 1 leak 11 (8.7) 10 (6.5) 0.66 Type 2 leak 11 (8.7) 14 (9.2) 0.5 Type 3 leak 8 (6.3) 9 (5.9) 0.9 †According to ECCG consensus definition.12 COPD, chronic obstructive pulmonary disease; MI, minimally invasive. View Large Table 1 Characteristics patients in ‘standard care’ and ‘amylase based’ pathways. Values expressed as median (IQR) or n (%) Standard care (n = 126) Amylase based (n = 153) t-test Age (years) 64.49 [56.87, 74.16] 65.17 [58.43, 74.52] 0.67 Male 95 (75.3) 120 (78.4) 0.55 White 118 (93.7) 144 (94.1) 0.87 Hypertension 78 (61.9) 82 (53.6) 0.18 Coronary artery disease 29 (23.0) 35 (22.9) 0.99 Diabetes 31 (24.6) 30 (19.6) 0.32 COPD 18 (14.3) 21 (13.7) 0.98 Preoperative chemotherapy 69 (54.8) 82 (53.6) 0.86 Preoperative radiation 72 (57.1) 92 (60.1) 0.58 Transhiatal 18 (14.3) 35 (22.9) 0.06 Ivor–Lewis Open 3 (0.24) 6 (3.9) 0.46 MI 13 (10.3) 30 (19.6) 0.03 Three-hole Open 18 (14.3) 13 (8.5) 0.14 MI 74 (58.7) 68 (44.4) 0.02 Thoracoabdominal 0 (0) 1 (0.7) 0.32 Location of anastomosis Neck 110 (87.3) 116 (75.8) 0.015 Chest 16 (12.7) 37 (24.2) Any postoperative complication 73 (57.9) 81 (52.9) 0.41 Atrial fibrillation 18 (14.3) 20 (13.1) 0.74 Pneumonia 21 (16.7) 23 (15.0) 0.71 Anastomotic leak† Type 1 leak 11 (8.7) 10 (6.5) 0.66 Type 2 leak 11 (8.7) 14 (9.2) 0.5 Type 3 leak 8 (6.3) 9 (5.9) 0.9 Standard care (n = 126) Amylase based (n = 153) t-test Age (years) 64.49 [56.87, 74.16] 65.17 [58.43, 74.52] 0.67 Male 95 (75.3) 120 (78.4) 0.55 White 118 (93.7) 144 (94.1) 0.87 Hypertension 78 (61.9) 82 (53.6) 0.18 Coronary artery disease 29 (23.0) 35 (22.9) 0.99 Diabetes 31 (24.6) 30 (19.6) 0.32 COPD 18 (14.3) 21 (13.7) 0.98 Preoperative chemotherapy 69 (54.8) 82 (53.6) 0.86 Preoperative radiation 72 (57.1) 92 (60.1) 0.58 Transhiatal 18 (14.3) 35 (22.9) 0.06 Ivor–Lewis Open 3 (0.24) 6 (3.9) 0.46 MI 13 (10.3) 30 (19.6) 0.03 Three-hole Open 18 (14.3) 13 (8.5) 0.14 MI 74 (58.7) 68 (44.4) 0.02 Thoracoabdominal 0 (0) 1 (0.7) 0.32 Location of anastomosis Neck 110 (87.3) 116 (75.8) 0.015 Chest 16 (12.7) 37 (24.2) Any postoperative complication 73 (57.9) 81 (52.9) 0.41 Atrial fibrillation 18 (14.3) 20 (13.1) 0.74 Pneumonia 21 (16.7) 23 (15.0) 0.71 Anastomotic leak† Type 1 leak 11 (8.7) 10 (6.5) 0.66 Type 2 leak 11 (8.7) 14 (9.2) 0.5 Type 3 leak 8 (6.3) 9 (5.9) 0.9 †According to ECCG consensus definition.12 COPD, chronic obstructive pulmonary disease; MI, minimally invasive. View Large Median cost and median length of stay were calculated for each terminal node of the tree. Cost for each terminal node was ‘normalized’ relative to the cost of STD management with no leak and no other complications (according to hospital policy). The frequencies of occurrence of each arm were modeled from the data obtained from the retrospective review. All the numbers used to create the decision tree were listed in Table 2. The base case analysis was defined as the cost-benefit analysis comparing the length of stay and cost of STD and DRAEM arms using the value for each end nodes listed in the Table 2. The base case analysis represents our best estimation of the true value. Table 2 Base-case characteristics: cost and length of stay. Decision analysis arm Anastomotic leak Other complications Adjusted cost† ($) [average, (min; max)] Length of stay (days) [average, (min; max)] Distribution Standard of care + − 4321 (−3697; 7820) 8 (8;11) Triangular + + 52,231 (36,411; 74,624) 24 (13;27) Triangular − − 0 (−1676; 3385) 7 (7;8) Triangular − + 10,321 (2210; 21,262) 8.5 (8;12.75) Triangular Day 4 low amylase + − 8879 (−6261; 15,907) 11 (7;14) Triangular + + 67,616 (N/A) 27 (n/a) Triangular − − −2764 (−3486; −550) 6 (5;6) Triangular − + 5096 (981; 24,408) 8 (7;12) Triangular Day 4 intermediate amylase + − 4646 (4320; 10,924) 9 (8.5; 11.5) Triangular + + 55,738 (51,231: 96,235) 22.5 (20.25; 34.5) Triangular − − 2275 (−2339; 4246) 7 (7; 8) Triangular − + 9848 (4170; 17,969) 9 (7; 12.5) Triangular Day 4 high amylase + − −2417 (−3718; 3848) 12.5 (10.3; 14) Triangular + + 16,339 (4067, 30,060) 12 (9; 16) Triangular − − 3184 (−1369; 3914) 7 (6.5; 8) Triangular − + 10,810 (6576; 15,044) 13 (10.5; 17) Triangular Not eligible for DA protocol 32,276 (14,501; 57,373) 14 (10;23.5) Triangular Decision analysis arm Anastomotic leak Other complications Adjusted cost† ($) [average, (min; max)] Length of stay (days) [average, (min; max)] Distribution Standard of care + − 4321 (−3697; 7820) 8 (8;11) Triangular + + 52,231 (36,411; 74,624) 24 (13;27) Triangular − − 0 (−1676; 3385) 7 (7;8) Triangular − + 10,321 (2210; 21,262) 8.5 (8;12.75) Triangular Day 4 low amylase + − 8879 (−6261; 15,907) 11 (7;14) Triangular + + 67,616 (N/A) 27 (n/a) Triangular − − −2764 (−3486; −550) 6 (5;6) Triangular − + 5096 (981; 24,408) 8 (7;12) Triangular Day 4 intermediate amylase + − 4646 (4320; 10,924) 9 (8.5; 11.5) Triangular + + 55,738 (51,231: 96,235) 22.5 (20.25; 34.5) Triangular − − 2275 (−2339; 4246) 7 (7; 8) Triangular − + 9848 (4170; 17,969) 9 (7; 12.5) Triangular Day 4 high amylase + − −2417 (−3718; 3848) 12.5 (10.3; 14) Triangular + + 16,339 (4067, 30,060) 12 (9; 16) Triangular − − 3184 (−1369; 3914) 7 (6.5; 8) Triangular − + 10,810 (6576; 15,044) 13 (10.5; 17) Triangular Not eligible for DA protocol 32,276 (14,501; 57,373) 14 (10;23.5) Triangular †Hospital costs are adjusted relative to cost of esophagectomy managed by ‘standard care’ that had no postoperative leak or other complications. View Large Table 2 Base-case characteristics: cost and length of stay. Decision analysis arm Anastomotic leak Other complications Adjusted cost† ($) [average, (min; max)] Length of stay (days) [average, (min; max)] Distribution Standard of care + − 4321 (−3697; 7820) 8 (8;11) Triangular + + 52,231 (36,411; 74,624) 24 (13;27) Triangular − − 0 (−1676; 3385) 7 (7;8) Triangular − + 10,321 (2210; 21,262) 8.5 (8;12.75) Triangular Day 4 low amylase + − 8879 (−6261; 15,907) 11 (7;14) Triangular + + 67,616 (N/A) 27 (n/a) Triangular − − −2764 (−3486; −550) 6 (5;6) Triangular − + 5096 (981; 24,408) 8 (7;12) Triangular Day 4 intermediate amylase + − 4646 (4320; 10,924) 9 (8.5; 11.5) Triangular + + 55,738 (51,231: 96,235) 22.5 (20.25; 34.5) Triangular − − 2275 (−2339; 4246) 7 (7; 8) Triangular − + 9848 (4170; 17,969) 9 (7; 12.5) Triangular Day 4 high amylase + − −2417 (−3718; 3848) 12.5 (10.3; 14) Triangular + + 16,339 (4067, 30,060) 12 (9; 16) Triangular − − 3184 (−1369; 3914) 7 (6.5; 8) Triangular − + 10,810 (6576; 15,044) 13 (10.5; 17) Triangular Not eligible for DA protocol 32,276 (14,501; 57,373) 14 (10;23.5) Triangular Decision analysis arm Anastomotic leak Other complications Adjusted cost† ($) [average, (min; max)] Length of stay (days) [average, (min; max)] Distribution Standard of care + − 4321 (−3697; 7820) 8 (8;11) Triangular + + 52,231 (36,411; 74,624) 24 (13;27) Triangular − − 0 (−1676; 3385) 7 (7;8) Triangular − + 10,321 (2210; 21,262) 8.5 (8;12.75) Triangular Day 4 low amylase + − 8879 (−6261; 15,907) 11 (7;14) Triangular + + 67,616 (N/A) 27 (n/a) Triangular − − −2764 (−3486; −550) 6 (5;6) Triangular − + 5096 (981; 24,408) 8 (7;12) Triangular Day 4 intermediate amylase + − 4646 (4320; 10,924) 9 (8.5; 11.5) Triangular + + 55,738 (51,231: 96,235) 22.5 (20.25; 34.5) Triangular − − 2275 (−2339; 4246) 7 (7; 8) Triangular − + 9848 (4170; 17,969) 9 (7; 12.5) Triangular Day 4 high amylase + − −2417 (−3718; 3848) 12.5 (10.3; 14) Triangular + + 16,339 (4067, 30,060) 12 (9; 16) Triangular − − 3184 (−1369; 3914) 7 (6.5; 8) Triangular − + 10,810 (6576; 15,044) 13 (10.5; 17) Triangular Not eligible for DA protocol 32,276 (14,501; 57,373) 14 (10;23.5) Triangular †Hospital costs are adjusted relative to cost of esophagectomy managed by ‘standard care’ that had no postoperative leak or other complications. View Large A Monte Carlo simulation was performed to assess the effect of the variability of the data on the decision model. This model simulates the variability that might occur if this protocol were performed by other institutions or in a different patient population. This simulation was performed by randomly generating a hypothetical patient cohort of 10,000 postesophagectomy patients. Their length of stay and cost were randomly chosen based on the value distribution defined in Table 2. We also performed a sensitivity analysis to assess the effect of leak rate on the model outcome. The leak rate of POD4 low amylase group was allowed to vary from 1% to 100%. We assumed the leak rates of POD4 intermediate and POD4 high amylase groups would also increase proportionally to that of POD4 low amylase group. Leak rates of intermediate and high amylase level groups were adjusted accordingly in the sensitivity analysis. The adjusting factor was based on the ratio between the leak rates among the three groups in the base-case analysis. All data were analyzed using STATA/SE, Version 14.0 (StataCorp, College Station, TX) and TreeAge (TreeAge Software, Inc., Williamstown, MA). The study was approved by the University Hospitals Cleveland Medical Center Institutional Review Board. RESULTS One hundred and eighty eight (188) patients underwent esophagectomy at our institution during the study period and were classified according to study criteria as defined above. Patient demographics are shown in Table 1. One hundred and twenty six (126) patients were included in the STD arm. One hundred and fifty three (153) were included in the DRAEM arm, including 11 patients who were not eligible for early alimentation but were included in the DRAEM arm to reduce potential bias. Patients in the STD pathway and DRAEM were similar in regards to overall rate of postoperative complications (50% vs. 49%, P = 0.41) and anastomotic leaks (23.8% vs. 23.9%, P = 0.66). Patients in STD pathway had more minimal invasive three-hole esophagectomy performed (58.7% vs. 44.4%, P = 0.02), while DRAEM arm had more minimal invasive Ivor–Lewis esophagectomy performed (30% vs. 13%, P = 0.03). The locations of anastomoses differed as well. DRAEM arm had more anastomoses in the chest than that in STD (24.2% vs. 12.7%, P = 0.015). Sixty one patients (of 153 in the DRAEM group, 40%) had low POD4 drain amylase (<31 U/L). Leak rate for the low amylase group was 10%, including both medically managed (Type I, N = 5, 8.2% of low POD4 group) and procedurally managed leaks (Type 2 and 3, N = 1, 1.6% of low POD4 group). Fifty six patients (37%) were characterized as intermediate amylase group, and their leak rate was 16%, including both medically managed (Type I, N = 3) and procedurally managed leaks (Type 2 and 3, N = 6). The high amylase group included 16% of patients, and demonstrated a leak rate of 60%, including both medically managed (Type I, N = 2) and procedurally managed leaks (Type 2 and 3, N = 12). Base-case analysis and Monte Carlo simulation The decision tree is shown in Figure 2. Based on data obtained from review our institution's use of amylase in postoperative management of patients after esophagectomy, the amylase-based pathway was associated with an improvement in LOS (decrease) of 0.93 days (DRAEM 9.23 day/patient, STD 10.16 day/patient) and a cost saving of $3113 (DRAEM $8243/patient, STD $11,356/patient). To determine if this effect could be extrapolated to a broader cohort, we performed a Monte Carlo simulation. The Monte Carlo simulation confirmed the benefit of the amylase-based protocol after accounting for the potential variation associated with a hypothetical cohort of 10,000 patients, with a median saving of 0.71 days in hospital stay and $2434/patient in cost (Table 3, Fig. 4). Table 3 Monte Carlo simulation of 10,000 patient result. Cost ($/patient) LOS (days/patient) Frequency of being the optimal option based on cost (%) Frequency of being the optimal option based on LOS (%) DRAEM median [10th percentile–90th percentile] $9548 [8122–11,156] 9.67 [9.25–10.12] 85.34 86.55 Standard care median [10th percentile–90th percentile] $12,018 [9662–14,522] 10.38 [9.60–11.12] 14.66 13.45 Cost ($/patient) LOS (days/patient) Frequency of being the optimal option based on cost (%) Frequency of being the optimal option based on LOS (%) DRAEM median [10th percentile–90th percentile] $9548 [8122–11,156] 9.67 [9.25–10.12] 85.34 86.55 Standard care median [10th percentile–90th percentile] $12,018 [9662–14,522] 10.38 [9.60–11.12] 14.66 13.45 LOS, length of stay. View Large Table 3 Monte Carlo simulation of 10,000 patient result. Cost ($/patient) LOS (days/patient) Frequency of being the optimal option based on cost (%) Frequency of being the optimal option based on LOS (%) DRAEM median [10th percentile–90th percentile] $9548 [8122–11,156] 9.67 [9.25–10.12] 85.34 86.55 Standard care median [10th percentile–90th percentile] $12,018 [9662–14,522] 10.38 [9.60–11.12] 14.66 13.45 Cost ($/patient) LOS (days/patient) Frequency of being the optimal option based on cost (%) Frequency of being the optimal option based on LOS (%) DRAEM median [10th percentile–90th percentile] $9548 [8122–11,156] 9.67 [9.25–10.12] 85.34 86.55 Standard care median [10th percentile–90th percentile] $12,018 [9662–14,522] 10.38 [9.60–11.12] 14.66 13.45 LOS, length of stay. View Large Sensitivity to the leak rate in day 4 low amylase group In the sensitivity analysis, DRAEM demonstrated benefits in cost and length of stay relative to STD when the leak rate of POD4 low amylase group less than 20.6% (Fig. 5A). DRAEM dominated STD in sensitivity analysis on LOS when the leak rate of POD4 low amylase group was less than 18.3% (Fig. 5B). Fig. 4 View largeDownload slide Monte Carlo simulation: A) Probability distribution plot of length of stays (days) for Monte Carlo simulation of 10,000 patients comparing the drain amylase accelerated care pathway (DA) versus the standard of care (STD). B) Probability distribution plot of adjusted cost ($) for Monte Carlo simulation of 10,000 patients comparing the drain amylase accelerated care pathway versus the standard of care. Fig. 4 View largeDownload slide Monte Carlo simulation: A) Probability distribution plot of length of stays (days) for Monte Carlo simulation of 10,000 patients comparing the drain amylase accelerated care pathway (DA) versus the standard of care (STD). B) Probability distribution plot of adjusted cost ($) for Monte Carlo simulation of 10,000 patients comparing the drain amylase accelerated care pathway versus the standard of care. Fig. 5 View largeDownload slide A) Sensitivity analysis of leak rate in day 4 low amylase group on the cost of the drain amylase care pathway protocol. Each data point represents the cost of the protocol associated with the each leak rate. The dashed line represents the adjusted cost of the standard care ($11,356). B) Sensitivity analysis of leak rate in day 4 low amylase group on the LOS of the drain amylase care pathway protocol. Each data point represents the LOS of the protocol associated with the each leak rate. The dashed line represents the LOS of the standard care (10.2 days). Fig. 5 View largeDownload slide A) Sensitivity analysis of leak rate in day 4 low amylase group on the cost of the drain amylase care pathway protocol. Each data point represents the cost of the protocol associated with the each leak rate. The dashed line represents the adjusted cost of the standard care ($11,356). B) Sensitivity analysis of leak rate in day 4 low amylase group on the LOS of the drain amylase care pathway protocol. Each data point represents the LOS of the protocol associated with the each leak rate. The dashed line represents the LOS of the standard care (10.2 days). DISCUSSION Esophagectomy is a procedure, which is performed infrequently and is often performed at specialized centers. Data from the National Inpatient Sample suggest that only 1% of hospitals that performed esophagectomy were ‘high-volume hospitals,’ and that these facilities performed a median of 50 esophagectomies per year.15 Enhanced recovery pathways have been used in many surgical disciplines to streamline care and reduce major morbidities,16–19 but few have been studied across institutions due to difficulties in study recruitment. Given this paucity of cases and facilities performing esophagectomy, prospective clinical trials in postoperative care of esophagectomy patients are complex and often impractical. Decision analysis is an analytic method to formally quantify and compare the cost-effectiveness of treatments.20–22 We used the decision analysis technique to quantify the benefit of a drain amylase-based enhanced recovery pathway relative to standard care in terms of cost and length of stay. When applied to the cohort of patients at our institution, universal adoption of this protocol would have reduced median length of stay by 0.93 days and reduced hospital cost by $3113 per patient, a savings of roughly 10% of the total hospitalization. A benefit was also seen in a hypothetical cohort of patients generated in a Monte-Carlo simulation, thereby suggesting that the cost and length of stay savings seen at out institution might also be seen in a different patient population or surgical setting. We believe that the ‘source’ of the cost savings associated with the amylase pathway arose from the early discharge of patients who were categorized as unlikely to leak. Relative to the standard of care, patients without anastomotic leak or other complications had a cost savings of $2764. The savings affected approximately 36% of patients, and translated to the majority of the calculated savings of $3113. Our data also demonstrated a savings among patients with high amylase values who had a leak. This was a smaller group of patients (9.6%), but contributed to cost savings. Moreover, we believed these data spoke to a fundamental benefit to early identification of surgical complications. Early identification and treatment of anastomotic leak was clearly associated with improved outcomes, and corroborate data that the cost of esophagectomy is driven mainly by complications.12 Other studies of accelerated care pathways after esophagectomy used nutritional support, preemptive analgesia, perioperative fluid therapy, and surgical techniques to reduce hospital length of stay, but did not focus on pathways that assess the risk of anastomotic leak.23 The assessment of anastomotic leak was an ideal target for accelerated care pathways given the inaccuracy of esophagram in the assessment of leak. Herein we show that a drain amylase-based care pathway safely allows for earlier discrimination of patients who are more likely or unlikely to leak, thereby reducing hospital costs and length of stay. This analysis suggests that an amylase-based care pathway postesophagectomy might reduce hospital length of stay to a similar extent as adoption of minimally invasive surgical technique, which has recently been shown to be associated with a reduction of hospital length of stay by 1 day in a review of the Society of Thoracic Surgeon's database.24 A possible concern about using amylase to screen for anastomotic leak is the false-negative rate. In our experience, clinically significant anastomotic leaks were uncommon when patients have a low POD4 drain amylase. However, only 1.6% of patients in the low amylase group had clinically significant leak requiring procedural intervention. The majority of the leaks in low amylase groups were occult leaks that did not lead to postoperative morbidity and there were no postoperative mortalities associated with these ‘missed’ leaks. For patients in the intermediate amylase group (amylase level between 31 and 125), we found they had higher leak rate (16%) and more significant leaks (66% type II and III leaks). Our sensitivity analysis suggested that there was benefit of this protocol up to a 20% leak rate in the low risk group. Interestingly, this implies that there may not be cost and LOS benefit to esophagram in the ‘intermediate’ amylase group. Given the prevalence of type II/III leaks, we believe that patients in this group were not sufficiently safe to justify early alimentation and discharge. Comparatively, esophagram has a lower sensitivity than drain amylase, and studies of esophagram demonstrate poor negative predictive value.6,7 An analysis at our intuition showed that amylase was superior to esophagram.10 Furthermore, the amylase test was simple, safe, and easy to obtain, and did not expose patients to potential risk of radiation or contrast aspiration that could occur during esophagram. Therefore, we believe that the false negative rate associated with a low POD4 drain amylase is acceptable in this setting. There are several limitations to this study. As with all other cost-effective studies, the result is limited by the data used to create the model. Our data were collected in a single tertiary care institution with limited number of patients and without randomization. Furthermore, there were differences between the groups, most notably in the location of the anastomosis and the procedures performed. The effect of these differences was partially mitigated by the similar leak rate and complication rate in the STD and DRAEM arms. Nonetheless, there is a possibility of bias in the calculation of costs and LOS. However, intrathoracic anastomotic leak can lead to more significant morbidity than cervical anastomotic leak, and therefore higher intrathoracic anastomosis may be biased to have higher costs and longer LOS. We therefore believe that the effect of this difference is minimal and does not alter our conclusion. DRAEM was not an established protocol for the period of retrospective review, and physician's clinical judgment played a significant role in deciding how patients were treated postoperatively. We used our best judgment to determine if a patient was managed in an accelerated basis or not, and attempted to appropriately categorize patients within the decision tree arms to reflect an accurate distribution of patients and patient management, but classification errors or bias was possible. Furthermore, inferred date of discharge for patients in the DRAEM group may have been affected by factors other than oral alimentation, such as postoperative pain or the occurrence of other complications that result from protocol implementation. We attempted to mitigate this effect by careful chart review, but misclassification of discharge day may have skewed the data. This analysis may underestimate the effect of protocol implementation in institutions in which esophagram was performed later than POD5-7 or in which typical length of stay was longer. We could not explore this institution dependent benefit in this single center analysis. Lastly, we applied amylase thresholds to determine risk of anastomotic leak in a homogenous population, and results may not be reproducible at other institutions. We believe that the benefit of the amylase-based method to evaluate the anastomosis would be valid at other institutions even if the leak rate varied significantly (in either direction). Our data may suggest an even more significant benefit to this protocol at institutions with longer length of stay. Based on the demonstrated benefits of this decision analysis and the hypothetical benefit suggested by the Monte-Carlo analysis, we believe that a prospective study of a drain amylase-based oral alimentation protocol is appropriate. Care pathways have been successfully implemented in other surgical disciplines with significant improvement outcomes. As health care resources become increasingly scrutinized, efforts to reduce hospital length of stay are increasingly important. Approximately 7100 esophagectomies were performed between 2008 and 2015 among institutions participating in the society of thoracic surgeons outcomes database.25,26 If DRAEM were implemented in these institutions, the cost saving could have exceeded $2 million and nearly 6500 hospital days reduced. Drain amylase measurement may be a robust method of determining patients who are candidates for an enhanced recovery pathway, which included early alimentation and discharge. CONCLUSION Our analysis indicates that a drain amylase-based enhanced recovery method could potentially reduce length of stay and cost in postesophagectomy patients when comparing to the standard of care. A prospective, multicenter study should be conducted to further validate the benefit of this method. Notes Author Disclosure Statement: The authors declare that no bias, sources of funding, or financial relationships influenced this work and its conclusions. Dr. Towe has received consultant fees and travel reimbursement from Medtronic. Note: These data were presented at the 12th Annual Academic Surgical Congress in Las Vegas, NV, February 2017. Specific author contributions: Study design: Boxiang Jiang, Vanessa P. Ho, Yaron Perry, Luis Argote-Greene, Philip A. Linden, Christopher W. Towe; Manuscript preparation: Boxiang Jiang, Vanessa P. Ho, Jennifer Ginsberg, Yaron Perry, Luis Argote-Greene, Philip A. Linden, Christopher W. Towe; Data collection: Boxiang Jiang, Vanessa P. Ho, Jennifer Ginsberg, Sue J Fu, Christopher W. Towe; Data analysis: Boxiang Jiang, Vanessa P. Ho, Christopher W. Towe. References 1 Kassis E S , Kosinski A S , Ross P Jr , Koppes K E , Donahue J M , Daniel V C . 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Journal

Diseases of the EsophagusOxford University Press

Published: May 10, 2018

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