Identifying Perioperative Anesthetic Factors associated with Postoperative Morbidity in Robot-Assisted vs. Open Pancreatoduodenectomy: A Cohort Study

Background: Robot-assisted pancreatoduodenectomy (RAPD) is a challenging procedure for the perioperative anesthesiologist, e.g. because of prolonged pneumoperitoneum exposure and reversed-Trendelenburg positioning. Purpose of this retrospective cohort study is to identify differences in perioperative anesthesia-related factors between RAPD and open pancreatoduodenectomy (OPD) and to determine perioperative anesthetic factors associated with major morbidity (Clavien Dindo ≥ III) after RAPD. Methods: All consecutive patient undergoing pancreatoduodenectomy were retrospectively included during a two year inclusion period. Anesthesia charts were studied on uid management details, rates of vasopressor administration and arterial blood gas results. All factors were compared between both surgical approaches. Within RAPD, factors were subsequently compared between patients with major (Clavien Dindo ≥ III) vs. without major postoperative morbidity and between procedures with high and low intraoperative blood loss. Perioperative factors associated with considerable postsurgical morbidity (Clavien Dindo ≥ III) were identied by constructing a logistic regression model. Results: RAPD was associated with higher administration of intraoperative vasopressors (9.5% of operative time vs. 0% in OPD, p=0.005) and a higher net intraoperative uid balance (2497.6 vs. 1572.3 ml, p<0.001). OPD patients more frequently and quantitatively received colloids compared to RAPD patients (79.0% vs. 51.6%, p<0.001, 1000.0 vs. 500.0 ml, p<0.001). Intraoperative erythrocyte transfusion rate was 6.3% (4/64) for RAPD compared to 30.6% (19/62) for OPD (p<0.001). Colloid administration during surgery and hyperlactatemia after 12 hour postoperative admission were associated with major (Clavien Dindo ≥ III) morbidity after RAPD (OR 5.06 with 95% CI 1.49-17.20, p=0.009 Values are presented as number (proportion) or depending on normality distribution of cases as mean ± SD or median (interquartile range). X n where n represents the number of missing cases. ASA, American Society of Anesthesiologists Classication; BMI, Body Mass Index; CD, Clavien Dindo; CVA, Cerebro Vascular Accident; e-GFR, Estimated Glomerular Filtration Rate; OPD, Open Pancreatoduodenectomy; RAPD, Robot-Assisted Pancreatoduodenectomy; TIA, Transient Ischemic Attack. OPD, Open Pancreatoduodenectomy; RAPD, Robot Assisted Pancreatoduodenectomy.

The optimal intraoperative uid regimen during abdominal (including pancreatic) surgery in relation to postsurgical morbidity is part of ongoing scienti c debate. E.g., the 2018 RELIEF trial described an association between a more restrictive intraoperative net uid balance (median 3.7 liters) and an increased rate of postsurgical kidney injury after major abdominal surgery [5]. Grant et al. however observed no differences in postoperative major morbidity rate after randomizing between either a net liberal (12 ml kg − 1 hr − 1 ) vs. net restrictive (6 ml kg − 1 hr − 1 ) intraoperative uid balance for pancreatectomy surgery, both in a conventional and minimally-invasive approach [6]. RAPD presents several speci c perioperative challenges. The patient is exposed to pneumoperitoneum and placed in reversed-Trendelenburg position during the most of the surgical time. This speci c sequence has previously been described to alter central venous pressure, to increase blood carbon dioxide levels as well as to decrease cardiac output [7][8][9]. Compared to OPD, RAPD is expected to differ in perioperative vasopressor demands and levels of uid administration.
The objective of this retrospective study was rstly to evaluate anesthesia-related differences of RAPD compared to OPD and secondly to identify independent anesthesia-related factors associated with post-RAPD morbidity.

Population and study characteristics
The local Medical Ethics Committee approved the study with waiver for informed patient consent with reference MEC-2019-0090 (Medical Ethics Committee, Erasmus MC University Hospital, Rotterdam, the Netherlands). The study protocol is performed in accordance with the relevant guidelines.
All consecutive patients who underwent pancreatoduodenectomy (either RAPD or OPD) between January 1st 2017 and December 31st 2018 have been retrospectively included for analysis. RAPD has been performed in our tertiary referral center since January 2017. All procedures were undertaken by a dedicated team of two pancreatic surgeons or a pancreatic surgeon together with a pancreatic surgical fellow. RAPD was executed using the Da Vinci Model S robotic surgical device, which was later switched to the Model Xi (Intuitive Surgical Inc., Sunnyvale, CA, USA). OP was performed by or under direct supervision of three experienced consultant pancreatic surgeons. Different consultant anesthesiologists (n = 39) were involved in both surgical modalities.
RAPD is characterized as full-robotic surgery, meaning both the resection and the reconstruction phase were conducted robotically-assisted. Patients were assigned to RAPD based on patient preference and availability of both the robot and the robotic surgical team. Patients were only excluded for RAPD in case of locally advanced pancreatic cancer. All patients were postoperatively admitted to a High Dependency Unit (HDU) or incidentally to an Intensive Care Unit (ICU). Protocols for postoperative management were identical for both units. Digital patient records were reviewed for patient demographics, intra-and postoperative management and postoperative outcome.

Data processing and statistical analysis
Baseline and perioperative factors were primarily analyzed for RAPD and OPD totals. Factors were subsequently compared for RAPD patients with major postsurgical morbidity (CD ≥ III) vs. RAPD patients without major postsurgical morbidity. In order to determine whether anesthetic factors were in uenced by intraoperative blood loss, factors ware also compared for RAPD patients with above vs. below median intraoperative blood loss (referred to as groups of high and low blood loss, respectively).
Normal distribution of numerical data was assessed using a combination of visual inspection of histograms and Q-Q plots and the Shapiro-Wilk test. Numerical data on averages were presented as mean (standard deviation, SD) or median (interquartile range, IQR) as appropriate. Categorical data were presented with frequencies and percentages. An independent sample T-test or Mann-Whitney U-test was performed in comparing numerical data, a χ 2 or Fisher's exact test in categorical data. A logistic regression model was constructed using a backward stepwise approach to identify independent prognostic factors of major morbidity (CD ≥ III) after RAPD. Results herein were presented as odds ratio (OR) with corresponding 95% con dence interval. Throughout the study two-tailed P-values of < 0.05 were considered statistically signi cant. Statistical analysis was carried out using IBM SPSS Statistics (version 24.0, Armonk, NY, USA; IBM Corp.).

RAPD vs. OPD
No differences in age, BMI and baseline medical history could be demonstrated between RAPD and OPD patients (Table 1). Baseline hemoglobin level was lower for OPD (12.6 vs. 13.2 g dl − 1 , p = 0.049).
No differences were observed in major postoperative morbidity rate (CD ≥ III) between both surgical modalities (28/64, 43.8% in RAPD vs. 33/62, 53.2% in OPD, p = 0.373, Table 3). An average Comprehensive Complication Index of 32.7 was observed in RAPD vs. 49.9 in OPD (p = 0.012). Rates of postoperative acute kidney injury were 9/64 (14.5%) for RAPD vs. 6/92 (9.7%) for OPD (p = 0.583). Six patients entered the procedure with pre-existing renal impairment (e-GFR < 60 ml min-1, n = 3 in RAPD and n = 3 in OPD). No further deterioration of kidney injury was observed in any of these patients. Average pain score on postoperative day 1 was 3 for RAPD compared to 1 for OPD (p < 0.001). On postoperative day 3, average pain score was 2 for both RAPD and OPD (p = 0.894). Major (CD ≥ III) vs. without major morbidity after RAPD A higher rate of baseline hypertension was observed in the RAPD group with major postoperative morbidity (17/28, 60.7% vs. 11/36, 30.6% for the RAPD group without major morbidity, p = 0.023, Table 1). Intraoperative colloid administration and blood loss were higher in the RAPD group with major postoperative morbidity (500.0 vs. 0.0 ml, p = 0.002 and 350.0 vs. 200.0 ml, p = 0.047, respectively, Table  4). Average NE dose was higher at the end of surgery for the RAPD group with major postoperative morbidity (0.09 vs. 0.04 µg kg − 1 min − 1 for the RAPD group without major postoperative morbidity, p = 0.726). Upon HDU/ICU admission, lower arterial blood pH as well as higher lactate levels were observed in the RAPD group with major postoperative morbidity (7.32 vs. 7.34, p = 0.017 and 1.7 vs 1.3 mmol l − 1 , in the RAPD group without major postoperative morbidity, respectively). A similar trend was observed after a minimum of 12 hour HDU/ICU admission (7.37 vs. 7.39, p = 0.016 and 1.4 vs. 0.9 mmol l − 1 , respectively).
Hospital stay was doubled in the RAPD group with major postoperative morbidity compared to the RAPD group without major postoperative morbidity (18.0 vs. 7.0 days, p < 0.001, Table 5). Within the 90-day inclusion period, n = 2 (RAPD) patients deceased due to early recurrence of malignant disease.

High vs. low intraoperative blood loss in RAPD
Average intraoperative blood loss was 250 ml in RAPD (Table 2), n = 33 RAPD procedures were characterized by high (≥ 250 ml) vs. 31 RAPD procedures by low (< 250 ml) intraoperative blood loss.
Both operating room and operative time were longer in the RAPD group with high intraoperative blood loss (580.0 vs. 487.0 min., p = 0.001 and 518.0 vs. 410.0 min., p = 0.001, respectively, Table 4) compared to the RAPD group with low intraoperative blood loss. Average NE dose was higher at the end of surgery for the RAPD group with high intraoperative blood loss (0.09 vs. 0.04 µg kg − 1 min − 1 in the RAPD group with low intraoperative blood loss). NE-dose trended to exceed 0.2 µg kg − 1 min − 1 more frequently in the RAPD group of high intraoperative blood loss (134.0 vs. 15.0 min, p = 0.283, and 20.8% vs. 4.0% of operative time in the RAPD group of low intraoperative blood loss, p = 0.431). Upon HDU/ICU admission, lactate levels were higher in the RAPD group of high intraoperative blood loss (1.6 vs. 1.0 mmol l − 1 in the RAPD group of low intraoperative blood loss, p = 0.008). Length of hospital stay was doubled for the RAPD group of high intraoperative blood loss (16.0 vs. 8.0 days in the RAPD group of low intraoperative blood loss, p = 0.002, Table 5). A higher rate of postoperative morbidity was observed in the RAPD group with high intraoperative blood loss (Comprehensive Complication Index of 51.5 vs. 24.2 in the RAPD group with low intraoperative blood loss, p < 0.001). Besides, a higher rate of major postoperative morbidity (CD ≥ III) was observed in the RAPD group of high intraoperative blood loss (20/33, 60.6% vs. 8/31, 25.8% in the RAPD group of low intraoperative blood loss, p = 0.006).

Predictors of major morbidity after RAPD
After univariate logistic regression analysis, anesthesia-related factors independently associated with major morbidity (CD ≥ III) after RAPD were a baseline medical history of hypertension (OR 3.51, 95% CI

Discussion
After comparing perioperative anesthetic factors for RAPD and OPD, RAPD is characterized by higher demands of vasopressor support and higher intra-and postoperative pCO 2 and Hb-levels. Although net intraoperative uid balance and vasopressor demands are higher in RAPD, levels of colloid and erythrocyte transfusion are lower for RAPD compared to OPD. Rates of major postoperative morbidity (CD ≥ III) were similar for the surgical approaches. Within patients who developed major morbidity (CD ≥ III) after RAPD, vasopressor demands and necessity of colloid administration tended to be higher. The need for intraoperative colloid administration and increased postoperative lactate levels were independently associated with major morbidity (CD ≥ III) after RAPD.
Comparing outcomes, the surgical modality itself in uences the development of major morbidity less than patient-related variables. We report a small fraction of patients marked ASA class III and above (11/64, 17.2% in RAPD and 13/62, 22.4% in OPD), compared to earlier studies reporting percentages up to 43.1 and 82.4% [14,15]. This discrepancy might suggest an underrating of ASA grading, in contrast with the 2017 strengthened ASA classi cations [16]. ASA scores in our series are however in concordance with recent ndings of van Roessel et al., reporting 21.8% ASA III patients in a cohort of n = 3341 pancreatoduodenectomy and distal pancreatectomy procedures, using Dutch Nationwide Pancreatic Cancer Audit data [17,18]. Van Roessel et al. predict worse outcome after pancreatoduodenectomy in ASA ≥ III patients (OR 0.59, 95% CI 0.44-0.80, for achieving optimal outcome after pancreatic surgery). In our study ASA class itself was not an individual predictor for postoperative major morbidity (CD ≥ III) where baseline hypertension was (OR 3.51, 95% CI 1. 24-9.92). This nding, compared with higher vasopressor demands in RAPD, implies as association between baseline cardiovascular condition and postoperative outcome after RAPD. However, a medical history of hypertension might comprise several baseline conditional factors with itself a possible in uence on postoperative morbidity (e.g. increased BMI, vascular remodeling or pre-existing renal insu ciency).
A higher need for intraoperative vasopressor administration in RAPD could be explained by differences in patient positioning (reversed-Trendelenburg in RAPD vs. supine in OPD) as well as exposure to pneumoperitoneum, affecting cardiac afterload and cardiac output [7][8][9]. Higher demand for vasopressor administration in RAPD was not necessarily re ected by worse baseline physical condition. Although OPD patients more often received neoadjuvant chemotherapy and baseline hemoglobin levels were lower, no differences in baseline medical condition could be demonstrated between both surgical approaches.
Although the intraoperative use of vasopressors was evident, we feel supported by recently published data that routinely insertion of a central venous catheter is not mandatory in RAPD or OPD patients [19,20].
The 2018 RELIEF Study reported on postoperative outcome after distinct intraoperative uid strategies during major abdominal surgery, differentiating between an either restrictive (median crystalloid + colloid 2177) or liberal (median crystalloid + colloid 3500 ml) net intraoperative uid balance [5]. Whereas no differences were observed in general postoperative outcome between both uid approaches, a liberal intraoperative uid strategy was associated with lower rates of postoperative kidney failure (17/1439, 5.0% for liberal vs. 124/1443, 8.6% for restrictive, p < 0.001). In comparison, we report a median intraoperative uid balance of 2800 ml and a 9/64 (14.5%) rate of postoperative acute kidney injury in RAPD patients. Bannone et al. observed an increased rate of post pancreatoduodenectomy pancreatitis in patients exposed to a near-zero net perioperative uid regime, suggesting a more restrictive perioperative uid balance to be associated with an increased risk of postoperative pancreatic stula [21]. On the contrary, the 2019 meta-analysis by Garland et al. reported an OR of 0.54 (95% CI 0.31-0.94) for major morbidity post pancreatoduodenectomy surgery after following a more restrictive intraoperative uid strategy [22]. The optimal intraoperative uid regime in pancreatoduodenectomy remains point of debate and prospective research should extrapolate this topic to minimally-invasive vs. conventional pancreatoduodenectomy surgery.
We observed an association between the intraoperative administration of colloids and development of major morbidity after RAPD (OR 5.06, 95% CI 1.96-15.14, p = 0.009). This nding is in accordance with Simões, reporting an OR of 1.86 (95% CI 1.03-4307) for development of major postoperative morbidity after the intraoperative administration of colloids (n = 308 elective surgeries for abdominal malignancies, including n = 22 pancreatic surgical procedures) [23]. In our RAPD series of low intraoperative blood loss, surgery hyperlactatemia and development of postoperative pancreatic stula [24]. Average postoperative pain scores during the rst postoperative day were higher in RAPD compared to OPD. The reported rst postoperative day NRS of 3 in RAPD compared to a NRS of 1 in OPD is of limited clinical relevance and therefore not attributable to major morbidity. Besides, this moderate difference can well be explained by the routine application of additional epidural analgesia in OPD, in accordance with previously reported studies on additional epidural analgesia during pancreatoduodenectomy [25].
Our study comprises several limitations. First the retrospective single-center study design covering a relatively high, but still limited number of procedures. Due to the limited number of surgeons, the surgical approach was very standardized. This is in contrast to the perioperative anesthetic care, which was provided by n = 39 different consultant anesthesiologists who followed available protocols with different levels of adherence.

Conclusions
Speci c differences exist in perioperative anesthesia-related factors between RAPD and OPD. RAPD is associated with higher levels of vasopressor drug administration as well as higher net perioperative uid balance. Besides, levels of colloid and erythrocyte transfusion are lower for RAPD compared to OPD.
Baseline hypertension, perioperative colloid administration and increased lactate levels after surgery were associated with higher rates of major morbidity (CD ≥ III) after RAPD. A more restrictive intraoperative uid regime has previously been shown to increase postoperative (nephrogenic) morbidity, present evidence is however contradictory. Current data is insu cient to make speci c recommendations on perioperative anesthetic guidance in RAPD. However, intraoperative hemodynamics including uid strategy might in uence postoperative morbidity and should be the focus of future prospective research.