1. INTRODUCTION
Cancer of the pancreas is one of the most common cancers worldwide. Tumors in the head of the pancreas and periampullary tumors are usually highly fatal, and >95% of patients die from these cancers.1 2 3–5 1 , 6
A 2003 study examined outcomes for 16 patients 80+ years who received PD. The overall mortality rate was 13%, the morbidity rate was 51% and 69% of patients required care in a surgical ICU for a median 8 days.2 7 8
The most common surgical complications associated with PD are pancreatic fistula, delayed gastric emptying, intra-abdominal abscess, bleeding that requires transfusion or reoperation, wound infection, and pleural effusion requiring drainage.9 10 10 , 11 surgical stress response and facilitate recovery after PD. Therefore, we conducted a single institution retrospective cohort study to compare the efficacy and safety of postoperative sedation versus usual care in geriatric patients following PD. We also conducted cellular analysis to confirm our findings.
2. METHODS
2.1. Clinical patient data
The hospital Institutional Review Board approved this retrospective cohort study. Patients who had periampullary lesions and received PD from 2009 to 2018 in our medical center were categorized into the sedation group and control group according the postoperative care strategy. The PD procedure is commonly performed in this institution. All enrolled patients were treated by the same pancreas surgery team. All surgical procedures were performed under surgeons with at least 10 years of experience with the PD procedure. The postoperative care for all enrolled patients was similar except for the use of sedation.
Patients in the sedation group were sent to the ICU with mechanical ventilator support immediately after the operation. A fentanyl citrate pump was prescribed as a postoperative analgesic in the ICU and the Behavioral Pain Scale (BPS), a valid and reliable BPS for use in the ICU,12–15
Patients in the control group underwent early extubation after careful evaluation by the anesthesiologist and received no postoperative sedative medication. Patients were excluded from the control group if they could not afford extubation immediately after the operation. An experienced anesthesiologist performed the evaluation process for postoperative extubation according to the perioperative hemodynamic status. Postoperative pain control included intravenous morphine and oral acetaminophen when the patient could tolerate oral intake.
The general exclusion criteria for all patients were as follows: age younger than 75 years, laparoscopic surgery, robot-assisted surgery, presence of an underlying neurological disorder, past history of head trauma, and long-term therapy with a psychiatric medication or sedative.
All major postoperative complications were recorded, including anastomotic leakage, intra-abdominal bleeding, intra-abdominal abscess, gastroparesis, cardiac events, and pulmonary events. Anastomotic leakage was defined as breakdown and subsequent leakage of digestive system fluid from pancreaticogastrostomy, choledochojejunostomy, or gastrojejunostomy. Intra-abdominal bleeding was defined as positive findings on angiography. Intra-abdominal abscess was defined as a pocket of infected fluid and pus (viscous interior) in the belly confirmed by both abdominal computed tomography and bacterial culture. Gastroparesis was defined as the presence of a nasogastric tube with >500 mL drainage by postoperative day 10. Postoperative cardiac events included newly developed arrhythmia and myocardial infarction. Postoperative pulmonary events comprised newly developed pneumonia, lung atelectasis, acute respiratory distress syndrome, and pulmonary edema found by chest plain film.
The primary endpoints were postoperative complication rate and surgical mortality, defined as postoperative 30-day mortality. The secondary endpoint was postoperative hospital LOS. In addition, delirium status assessed by nurses and patient self-reported pain scores (0-10) were recorded during the first 3 days in the ordinary hospital ward. The average heartbeat difference before and after surgery was also recorded.
Statistically significant between-group baseline characters were considered confounding variables. A propensity score was estimated using a logistic regression model and used to match subjects in each group. A 1:1 matching by propensity score was performed using the nearest neighbor method with a caliper width equal to 0.1 SDs. We also examined the balance in baseline covariates in the matched data using standardized differences.
2.2. Cell experiments
The 16HBE cell line (an immortal human bronchial epithelial cell) was cultured in a dish with RPMI-1640 medium (M&C Gene Technology, Beijing, China) which contained 10% fetal calf serum (Gibco, New York, NY, USA), 100 U/mL penicillin, and 100 mg/mL streptomycin (M&C Gene Technology, Beijing, China) in a humid atmosphere of 5% CO2 and 95% air at 37°C.
16HBE cells were seeded at a density of 2.5 × 105 cells/100 μL/well in 96-well culture plates. The normal control group and different concentrations of H2 O2 (100, 500, 1000, and 2000 μM) were placed for 60 minutes by group in six duplicate wells. Then 50-μL MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; 200 mg/mL) was added to each well. After incubation for 2.5 hours, 200 μL of culture medium and MTT were centrifuged and removed. Then, 180-μL dimethyl sulfoxide (DMSO) was added to each well and placed in the cell incubator for 5 to 10 minutes. After the purple crystals were completely dissolved, each sample was measured at 570 nm using a microplate reader. The above experiment was repeated three times, and the H2 O2 concentration with the cell survival rate closest to 50% was selected as the optimal H2 O2 concentration. Cell viability (%) = (average absorbance value of the H2 O2 -treated group[/average absorbance value of the normal control group) × 100%.
The 16HBE cells collected by centrifugation were planted in a 96-well culture plate at a density of 2.5 × 105 cells/100 μL/well and were randomly divided into 10 groups of six replicate wells in each group. Except for the normal control group, the other groups were pretreated with the corresponding dose of dexmedetomidine or propofol for 24 hours in the normal medium, then 20 μL of H2 O2 (2000 μM concentration) was added for 1 hour to each drug group. The experimental groups were as follows: (1) normal control group, no H2 O2 treatment (C); (2) 2000 μM H2 O2 injury group (H); (3) 10 ng/mL dexmedetomidine + 2000 μM H2 O2 group (H + D 10); (4) 5 ng/mL dexmedetomidine + 2000 μM H2 O2 group (H + D 5); (5) 1 ng/mL dexmedetomidine + 2000 μM H2 O2 group (H + D 1); (6) 0.1 ng/mL dexmedetomidine + 2000 μM H2 O2 group (H + D 0.1); (7) 10 μg/mL propofol + 2000 μM H2 O2 group (H + P 10); (8) 5 μg/mL propofol + 2000 μM H2 O2 group (H + P 5); (9) 1 μg/mL propofol + 2000 μM H2 O2 group (H + P 1); (10) 0.1 μg/mL propofol + 2000 μM H2 O2 group (H + P 0.1). The cell viability of the groups was determined by the MTT method. For all 10 treatment groups, the supernatant was tested for interleukin (IL)-6 levels by ELISA.
2.3. Statistical Analysis
Nominal variables were compared across groups by the chi-square test and Fisher’s exact test. Continuous variables were reported as mean ± SD and compared using the independent t test (parametric values) or Mann-Whitney U test (nonparametric values). A p value of <0.05 was considered statistically significant. All analyses were done using SAS version 6.0 (SAS, Inc., Cary, NC, USA).
3. RESULTS
For 2009-2018, we identified 99 geriatric patients who underwent PD and met the inclusion criteria of the study. From the sedation group, 40 patients (100%) were matched with 40 patients in the control group (Fig. 1 ). The distribution of baseline covariates was adequately balanced in the matched data set (Table 1 ). The mean age of the sedation group was 79.6 years (range: 76-94 years) and that of the control group was 78.6 years (range: 75-84 years). The two groups had no significant differences after matching by preoperative demographic characteristics, including age, gender, body mass index (BMI) and weight loss in the previous 6 months. In addition, the groups did no significantly differ in Eastern Co-operative Oncology Group (ECOG) performance scores, preoperative American Society of Anesthesiologists (ASA) scores, intraoperative blood loss, operation time, or postoperative pathological diagnosis. The mean postoperative ICU LOS for patients in the sedation group was 7.2 ± 1.58 days (range: 6-13 days). The mean actual postoperative ventilation stay for patients in the sedation group was 6. 15 ± 1.58 days (range: 5-12 days).
Table 1: Comparison of baseline characteristics between the sedation and control groups in the original and matched data sets
Fig. 1: Patient selection flow diagram.
Table 2 shows the concomitant diseases of patients in the matched data set. The percentage of patients with concomitant diseases was 85% (n = 34) in the sedation group and 77.5% (n = 31) in the control group, which were not significantly different. The two groups had no significant differences in most comorbidities. However, the sedation group had a significantly higher incidence of diabetes mellitus than the control group (50% vs 20%, p = 0.010).
Table 2: Comorbidities of patients of the sedation and control groups in the matched data set
Table 3 summarizes the clinical outcomes of the matched data set. The percentage of patients with overall complications was 25% (n = 10) in the sedation group and 47.5% (n = 19) in the control group (p = 0.063). Cardiac events, intra-abdominal abscess and intra-abdominal bleeding were slightly more common in the control group than in the sedation group, but the differences were not significant. The incidence of pulmonary events was significantly lower in the sedation group than in the control group (12.5% vs 40%, p = 0.011). Although the two patients with pulmonary complications in the sedation group progressed to respiratory failure, the overall reintubation rate was slightly lower in the sedation group (5% vs 20%, p = 0.091).
Table 3: Clinical outcomes of patients of the sedation and control groups in the matched data set
Further analysis of the clinical outcomes indicated gastroparesis in three patients in the sedation group and 13 patients in the control group (7.5% vs 32.5%, p = 0.012). In addition, one patient in the sedation group had a postoperative intestinal obstruction and underwent surgery for enterolysis on postoperative day 49. Patients in the sedation group had no postoperative events. The two groups had the same surgical mortality rate.
Table 4 shows the quality of life assessment of the matched data set. Patients in the control group had a significantly larger heartbeat difference before and after surgery (7.1 ± 5.3 vs 19.1 ± 8.7, p < 0.001). Patients in the sedation group had a significantly lower pain score in the first 3 days in the ordinary hospital ward compared with the control group (2.8 vs 6.1, p < 0.001). Although three patients in the sedation group had delirium in the first 3 days in the ordinary hospital ward, the two groups had no significant difference in the incidence of postoperative delirium (7.5% vs 2.5%, p = 0.615). Finally, the mean postoperative hospital LOS was similar between groups.
Table 4: Quality-of-life assessment of patients of the sedation and control groups in the matched data set
We tested the anti-inflammatory effect of the sedatives on cell function. H2 O2 treatment significantly decreased cell viability of the 16HBE cell line and increased the IL-6 levels (Figs. 2 and 3 ). According to the MTT assays, the concentrations of propofol and dexmedetomidine produced no cytotoxicity and were avirulent to the 16HBE cell line. Exposure to 2000 μM of H2 O2 for 60 minutes led to about 50% reduction in the cell viability rate. Pretreatment with propofol or dexmedetomidine for 24 hours significantly elevated the cell viability rate in a dose-dependent manner. Pretreatment with propofol or dexmedetomidine also significantly decreased the IL-6 production. The concentration of 5 μg/mL propofol and 1 ng/mL dexmedetomidine had the optimal protective effect.
Fig. 2: Cell viability of the 16HBE cell line. H2 O2 treatment significantly decreased cell viability of the 16HBE cell line. Pretreatment with propofol or dexmedetomidine for 24 h significantly elevated the cell viability rate in a dose-dependent manner. *p < 0.05. HBE = human bronchial epithelial cell.
Fig. 3: IL-6 production of the 16HBE cell line. H2 O2 treatment significantly increased the IL-6 levels of the 16HBE cell line. Pretreatment with propofol or dexmedetomidine significantly decreased IL-6 production. *p < 0.05. IL = interleukin; HBE = human bronchial epithelial cell.
4. DISCUSSION
Periampullary cancers are most common among geriatric patients and most patients with these cancers present with obstructive jaundice. Although biliary decompression before surgical intervention can relieve jaundice and biliary tract infection, most patients have infections when undergoing surgery. In general, elderly patients, particularly those older than 75 years, have more underlying diseases and have a higher risk of postoperative morbidity.1 , 6 surgical stress response is initiated with cytokines produced locally in response to nociceptive stimulation and other factors such as anxiety, fear, and tissue damage.16–20 21–25 surgical stress response in our patients. Our in vitro cell experiments confirmed that adequate use of sedatives could indeed protect the 16HBE cell line from H2 O2 damage and reduce inflammation. Pretreatment of the cell line with propofol or dexmedetomidine significantly elevated the cell viability rate and significantly decreased IL-6 production after H2 O2 damage.
We administered propofol or dexmedetomidine to patients in the sedation group to maintain a RASS of −2 (light sedation) for 5 days after surgery. The RASS can be administered in <20 seconds by many types of health care professionals, requires minimal training, and is highly reliable.26 12 12–15
In a 2003 report, of 16 patients aged 80+ years who underwent PD, 69% required surgical ICU care for a median of 8 days.2 7 27
In our study, the overall complication rate was lower in patients given 5 days of postoperative sedation. Although the sedation group had slightly higher ECOG performance status scores and were significantly more likely to develop diabetes (a well-known surgical risk factor), these results did not negatively affect overall outcomes. Furthermore, patients in the sedation group had significantly fewer pulmonary complications (12.5% vs 40%, p = 0.011). This effect may be related to benefits provided during the sedation and postsedation periods.
Age-related pulmonary changes may increase the risk of aspiration, atelectasis, and pneumonia in elderly patients after surgery.28 , 29 30 31 , 32
Gastroparesis is one of the most common complications after pancreaticoduodenectomy related to the presence of other intra-abdominal complications such as leakage or abscess. Unfortunately, a retrospective analysis found that neither the method of pancreaticojejunostomy (Blumgart procedure or Kakita method) nor the route of gastroenteric reconstruction (anticolic or retrocolic) significantly prevented gastroparesis.33 34 35 34 , 35 surgical stress response , decrease the sympathetic tone, increase the parasympathetic tone, increase peristalsis and increase gastric acid secretion, and thereby improve recovery.
In terms of postoperative quality of life, patients in the sedation group faced a significantly smaller heartbeat variation before and after surgery (7.1 ± 5.3 vs 19.1 ± 8.7, p < 0.001). Greater heartbeat variation increases discomfort and decreases willingness to walk. Patient self-reported pain scores in the first 3 days in the ordinary hospital ward differed significantly between the sedation and control groups (2.8 vs 6.1, p < 0.001). Numerous scales can be used to estimate pain, but none objectively quantify pain intensity or relief. Typically, pain is self-assessed by the patient on a scale of 0 (no pain) to 10 (worst imaginable pain).36–40
The present study had two limitations. One was the relatively small sample size of the retrospective cohort study. More than 75% of patient who received PD in our hospital were younger than 75 years. Also, patients in the initial control group were excluded if they could not afford postoperative extubation. This safety measure excluded many patients and prolonged the case collection period. The other limitation was that this study was not a randomized controlled study. Randomized controlled multicenter trials are needed to validate our findings.
In conclusion, the present study indicated that geriatric patients receiving PD had superior clinical outcomes when given postoperative preemptive light sedation for 5 days. In particular, preemptive sedation reduced the rate of postoperative pulmonary complications and gastroparesis, improved postoperative quality of life, but had no effect on postoperative hospital LOS. Our in vitro cell experiments also demonstrated that adequate treatment with sedatives could protect cells from damage and reduce inflammation. Thus, in experienced institutions, postoperative light sedation in the ICU setting may be a safe and feasible strategy for improving outcomes in geriatric patients following PD.
ACKNOWLEDGMENTS
This study was sponsored by grants from Taipei Veterans General Hospital (V108B-002), Cheng Hsin General Hospital (CY10716, CY10821), and Ten-Chan General Hospital Zhongli to T-H Chen. Dr. Pei-Jiun Tsai received grant support from Taipei Veterans General Hospital (V108B-002), Yen Tjing Ling Medical Foundation (CI-106-20), and the Ministry of Science and Technology (MOST107-2314-B-010-056-MY3). We declare that the sponsors of the study and the authors have no conflicts of interest to report. The funding sources had no role in the study design, data collection, data interpretation, data analysis, or writing of the report. The corresponding authors have full access to all of the data from the study, as well as responsibility for the final decision to submit the manuscript for publication.
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