Intraoperative dexamethasone after pancreatoduodenectomy in pancreatic ductal adenocarcinoma: A retrospective cohort study

Abstract

Background and aims:

The anti-inflammatory effects of dexamethasone may reduce the inflammatory response after pancreatoduodenectomy. The aim of this retrospective observational study was to evaluate the association between intraoperative dexamethasone and postoperative complications in patients undergoing pancreatoduodenectomy with a special focus on patients with pancreatic ductal adenocarcinoma (PDAC).

Methods:

All eligible patients undergoing pancreatoduodenectomy in our hospital between January 2018 and December 2021 (n = 319) were included comparing the postoperative outcomes in patients who received intraoperative dexamethasone (n = 178) to patients not given any intraoperative glucocorticoids (n = 142).

Results:

PDAC was the most common diagnosis (n = 166) and of these patients 92 received intraoperative dexamethasone and 74 no glucocorticoids. Patients with PDAC who received dexamethasone experienced fewer severe Clavien–Dindo complications than those not receiving glucocorticoids (n = 13/92 (14.1%) vs n = 21/74 (28.4%), P = 0.033). Multivariable analyses confirmed that a single dose of dexamethasone was associated with a reduced risk of severe complications in this patient group (odds ratio (OR) 0.40, 95% confidence interval [CI] 0.18–0.91, P = 0.030). When considering all pancreatoduodenectomy patients, no statistically significant differences in postoperative complications were observed. The incidence of postoperative infections was similar between the groups, although postoperative C-reactive protein (CRP) levels were lower in pancreatoduodenectomy patients who received dexamethasone (CRP on the second postoperative day: 102 (69–146) vs 159 (112–208) mg/l, P < 0.001). Patients who received dexamethasone experienced postoperative fever less frequently than those not given an intraoperative glucocorticoid (n = 68/178 (38.4%) vs n = 73/141 (51.8%), P = 0.023). Dexamethasone had no statistically significant influence on overall survival of PDAC patients.

Conclusion:

A single dose of dexamethasone was not associated with decreased postoperative complications across all pancreatoduodenectomy patients. However, within the PDAC subgroup, there were fewer Clavien–Dindo ⩾ 3 complications after dexamethasone compared to no glucocorticoid administration.

Keywords

Dexamethasone anti-inflammation postoperative outcome Clavien–Dindo complications pancreatic ductal adenocarcinoma

Context and relevance

While previous studies have presented mixed results on the role of perioperative corticosteroids in postoperative complications after pancreatoduodenectomy, we provide some further insights. We found that a single dose of intraoperative dexamethasone was associated with a reduction of severe Clavien–Dindo complications in pancreatic ductal adenocarcinoma patients. Dexamethasone also reduced the postoperative fever and C-reactive protein (CRP) levels in the general cohort although it did not show a significant impact on severe complications in overall cohort. Overall, dexamethasone demonstrated minimal adverse effects, supporting its use in pancreatoduodenectomy patients due to its anti-inflammatory and antiemetic properties. This study adds to the evidence for optimizing management in patients undergoing pancreatoduodenectomy.

Introduction

The enhanced recovery after surgery (ERAS) guidelines for pancreatoduodenectomy (PD) patients recommend that all PD patients should receive prophylaxis for postoperative nausea and vomiting (PONV).¹ An effective and inexpensive medicine reducing PONV is dexamethasone (DXM). Surgical patients who receive DXM experience a smoother recovery than those who receive a placebo.² In addition to the antiemetic effect, DXM also possesses analgesic and anti-inflammatory properties. DXM lowers the levels of proinflammatory cytokines and endoplasmic reticular stress, consequently diminishing the inflammatory response.³ These anti-inflammatory effects could theoretically lead to a reduction in postoperative complications and infections. However, DXM also induces peripheral insulin resistance and, as a result, transient hyperglycemia, which could affect the innate immunity of the patients.⁴ A meta-analysis indicated that, despite a short-term hyperglycemia, DXM did not increase postoperative infections or problems with wound healing after general anesthesia.⁵

Studies on DXM in pancreatic surgery patients and its influence on postoperative complications have been somewhat contradictory. Sandini et al. pointed out that DXM was associated with fewer postoperative infectious complications, although it did not influence the overall morbidity in PD patients. Moreover, their study suggested that intraoperative DXM was associated with a better overall survival (OS) in pancreatic ductal adenocarcinoma (PDAC) patients.⁶ However, in the recent PANDEX trial, intraoperative DXM did not lower the incidence of major postoperative complications in PD patients, although DXM showed a trend toward fewer reoperations and shorter hospital stay compared to placebo.⁷

Despite the anti-inflammatory features of DXM, its influence on short-term and long-term outcomes in PD patients remains unclear. In addition, many prior studies have examined all PD patients, a group that is highly heterogeneous. This retrospective study aimed to (1) evaluate whether intraoperative DXM was associated with decreased postoperative complications in both PD patients and the PDAC subgroup; and (2) clarify whether DXM improved the OS in patients with PDAC.

Methods

Patient selection and perioperative care

We included all patients who underwent PD at Helsinki University Hospital from 2018 until 2021. We excluded patients who for any reason received other glucocorticoids than DXM perioperatively and patients whose anesthesiology record was missing. The Institutional Review Board of the Perioperative and Intensive Care Medicine at Helsinki University Hospital approved the study protocol on 30 May 2022. An ethics committee approval was not needed due to the retrospective design of our study.

In 2020, a recommendation for a 10 mg dose of DXM was added to our hospital’s treatment protocol for PD patients. However, throughout the entire study period, the administration of intraoperative DXM was determined at the anesthesiologist’s discretion. Patients received DXM during the early stage of surgery. The surgeon determined the prophylactic antibiotics according to their deliberation. Antibiotic treatment and surgical approaches, including surgical techniques, the use of stents and drains, and application of wound protectors, remained consistent throughout the research period. Postoperative care followed our hospital’s guidelines for PD patients including instructions for fluid management, postoperative nutrition, multimodal pain medication, and mobilization.

Outcomes

Primary endpoint of this study was the frequency of severe Clavien–Dindo complications in PD patients. Secondary endpoints included severe surgical complications, postoperative pancreatic fistulas (POPF), delayed gastric emptying, postoperative infections, mortality, and the length of hospital stay.

Data collection and definitions of postoperative complications

We collected patient data from the institutional electronic database including information on the preoperative characteristics, perioperative medications, postoperative outcomes, and in PDAC patients, the histopathology of the tumor. During the postoperative period, we recorded the laboratory parameters on the first five postoperative days (PODs), the patient’s body temperature, antibiotics administered, and the recovery of the patients. Fever was defined as ⩾38.0°C. CRP levels were measured daily on PODs 2–4, and thereafter as needed.

The postoperative clinical complications were determined according to the Clavien–Dindo classification, whereby grade III–V complications were regarded as severe.⁸ In addition, we separately analyzed severe surgical complications, defined as any surgery-related complications requiring invasive intervention such as radiological drainage, endoscopy, or reoperation, excluding complications caused by internal medical conditions (e.g. cardiac or pulmonary problems). We applied the International Study Group of Pancreatic Surgery (ISGPS) definition for determining POPF (grade B–C)⁹ and delayed gastric emptying (DGE, grade B–C).¹⁰ We also analyzed biliary leakages, the length of hospital stay (LOS), and rehospitalization.

All postoperative infections were analyzed, including sepsis, pneumonia, urinary tract infection, wound infection, and abscesses. Sepsis was defined according to the third international consensus definitions for sepsis.¹¹ Pneumonia was diagnosed when a pulmonary infiltration was radiologically demonstrated, urinary tract infection when a urinary culture was positive, and abscess when seen radiologically. Blood cultures were obtained at the clinician’s consideration, typically when fever exceeded 38°C.

The follow-up time for clinical complications was 90 days and 30 days for infectious complications. Clinical complications included Clavien–Dindo complications, POPFs, DGE, and other surgical complications whereas infectious complications included sepsis, pneumonia, urinary tract infection, wound infection, and abscesses. We calculate the OS of PDAC patients from the date of first treatment (neoadjuvant or surgery) to the date when the patient was last known to be alive or to the time of death. The follow-up time for OS was until the end of November 2024.

In addition, we recorded the consistency of the pancreas from surgical reports and the main pancreatic duct (MPD) size from preoperative CT or MRI scans. We classified the patients as type A–D depending upon the MPD size and pancreatic texture using the ISGPS classification on the risk of a POPF.¹²

Statistical analysis

All statistical analyses were performed using SPSS^® Statistics (version 28; IBM, Inc., Armonk, NY, USA) and R (version 4.2.0; Foundation for Statistical Computing, Vienna, Austria). Continuous variables are presented as medians (interquartile range (IQR) or range). Statistical comparisons between groups were performed using the Mann–Whitney U test with continuous variables. Dichotomized and categorical variables are reported as numerals and percentages, and we employed the Fisher’s exact test or the Fisher–Freeman–Halton test for analyses. We performed analyses using the entire cohort and subgroup analyses for PDAC patients.

We used inverse probability weighting (IPW) based on propensity scores to reduce selection bias. Propensity scores were estimated using logistic regression with age and sex as covariates and treatment as the dependent variable. Stabilized IPW weights were calculated and applied in weighted logistic (svyglm, R survey package) or Cox regression models (svycoxph). Extreme weights (percentiles > 97.5% or <2.5%) were filtered out. This approach enables valid treatment effect estimation with robust standard errors.

Logistic regression was used for univariable and multivariable analyses for associations between severe Clavien–Dindo complications and independent variables. Interactions in the multivariable analyses were considered, but found non-significant. We performed the Kaplan–Meier analysis to calculate the OS in the PDAC patients, and Cox proportional hazard model to assess factors associated with OS. Severe surgical complications, intraoperative DXM, and Clavien–Dindo complications were used as time-dependent variables to address immortal time bias. We estimated the median time from operation to complication to be 5 days. All statistical tests were two-sided, with P < .05 considered statistically significant.

Results

During the study period (2018–2021), 596 patients underwent pancreatic surgery in Helsinki University Hospital, including 354 PDs. After excluding patients who received perioperative glucocorticoids other than DXM or whose anesthesiology record was missing, 319 patients were included in our analysis (Figure 1). DXM was administered to 178 patients intraoperatively, and 141 patients received no glucocorticoids during the perioperative period. In 2018, 16 patients (27.1%), in 2019, 20 patients (26.0%), in 2020, 65 patients (69.9%), and in 2021, 77 patients (85.6%) received intraoperative DXM. PDAC was the most common diagnosis (n = 166), and of these patients, 92 received intraoperative DXM and 74 no glucocorticoids.

Figure 1.

Flowchart of the patients included in the study. Study years were 2018–2021 and the data were collected from the anesthesia reports. Patients who did not receive intraoperative dexamethasone were not administered any other corticosteroid medications either.

Table 1 summarizes the preoperative and perioperative characteristics of patients. The patients’ characteristics were similar except that those who were not given DXM more often received intraoperative acetaminophen than patients who had received DXM. Tumor pathology and oncologic treatment of PDAC subgroup patients are presented in Supplementary Table 1.

Table 1.

Baseline and perioperative characteristics of the patients.

	All patients (n = 319)			PDAC patients (n = 166)
	No DXM(n = 141)	DXM(n = 178)	P value	No DXM(n = 74)	DXM(n = 92)	P value
Age* (in years)	67.8 [25.5–84.6]	69.8 [37.6–82.0]	0.251	67.2 [49.0–79.4]	70.7 [45.3–81.9]	0.078
Female	61 (43.3)	79 (44.4)	0.910	34 (45.9)	42 (45.7)	1.00
BMI (kg/m²)	25.3 [22.3–27.5]	25.6 [23.7–28.4]	0.088	25.1 [21.9–27.5]	25.0 [22.8–28.0]	0.465
ASA classification			0.685			0.136
1	2 (1.4)	1 (0.6)		0 (0.0)	0 (0.0)
2	35 (24.8)	53 (29.8)		12 (16.2)	27 (29.3)
3	95 (67.4)	114 (64.0)		57 (77.0)	59 (64.2)
4	9 (6.4)	10 (5.6)		5 (6.8)	6 (6.5)
Diabetes mellitus	38 (27.0)	43 (24.2)	0.606	24 (32.4)	26 (28.3)	0.611
Smoking	26 (18.4)	34 (19.1)	1.00	16 (21.6)	16 (17.4)	0.555
Intraoperative care
Blood loss (ml)	650 (325–1000)	576 (350–1000)	0.984	700 [400–1016]	675 [400–1200]	0.801
Transfusion	42 (29.8)	46 (25.8)	0.451	26 (35.1)	26 (28.3)	0.401
Acetaminophen	40 (33.3)	40 (22.5)	0.032	27 (36.5)	17 (18.5)	0.013
Diagnosis			0.421
PDAC	74 (52.5)	92 (51.6)
Papilla vater carcinoma	20 (14.2)	19 (10.8)
Cholangiocarcinoma	11 (7.8)	25 (14.0)
IPMN	9 (6.4)	12 (6.7)
Severe dysplasia	11 (7.8)	9 (5.1)
Duodenal carcinoma	4 (2.8)	6 (3.4)
FAP	0 (0.0)	2 (1.1)
Other	12 (8.5)	13 (7.3)

Age data are presented as median (range).

Other data are presented as median [interquartile range, IQR] or number (percentage).

Abbreviations: DXM, dexamethasone; BMI, body mass index; ASA, American Society of Anesthesiologists; PDAC, pancreatic ductal adenocarcinoma; IPMN, intraductal papillary mucinous neoplasm; FAP, familial adenomatous polyposis.

Postoperative clinical complications occurred at similar rates in both study groups (Table 2) but the postoperative CRP values remained lower in the DXM group during the first three PODs. Nevertheless, in the subgroup analyses of PDAC patients, severe Clavien–Dindo complications were more common in patients who had not received intraoperative DXM than in those given DXM (no DXM: n = 21 (28.4%) vs DXM: n = 13 (14.1%), P = 0.033); Table 2. Similarly, severe surgical complications more frequently occurred in PDAC patients not administered DXM (Table 2).

Table 2.

Postoperative outcomes among all patients and pancreatic ductal adenocarcinoma patients.

	All patients (n = 319)			PDAC patients (n = 166)
	No DXM (n = 141)	DXM (n = 178)	P value	No DXM (n = 74)	DXM (n = 92)	P value
Laboratory findings
CRP on POD 2 (mg/l)	159 [112–208]	102 [69–146]	<0.001	154 [119–202]	88 [58–114]	<0.001
CRP on POD 3 (mg/l)	131 [88–201]	106 [62–186]	0.013	125 [87–285]	81 [58–114]	<0.001
CRP on POD 4 (mg/l)	96 [58–156]	95 [49–177]	0.819	84 [54–126]	55 [37–90]	0.003
Clinical outcomes
Clavien–Dindo complications			0.150			0.011
0	9 (6.4)	8 (4.5)		7 (9.5)	4 (4.3)
I	29 (20.6)	49 (27.5)		13 (17.6)	32 (34.8)
II	66 (46.8)	79 (44.4)		33 (44.6)	43 (46.7)
III	34 (24.1)	30 (16.9)		19 (25.7)	9 (9.8)
IV	3 (2.1)	10 (5.6)		2 (2.7)	4 (4.3)
V	0 (0.0)	2 (1.1)		0 (0.0)	0 (0.0)
Clavien–Dindo ⩾ 3	37 (26.2)	42 (23.6)	0.603	21 (28.4)	13 (14.1)	0.033
Severe surgical complications	33 (23.4)	34 (19.1)	0.407	17 (23.0)	10 (10.9)	0.036
POPF	10 (7.1)	21 (11.8)	0.185	3 (4.1)	3 (3.3)	1.00
DGE	26 (18.4)	23 (12.9)	0.211	13 (17.6)	9 (9.8)	0.170
Biliary leakage	7 (5.0)	4 (2.2)	0.364	2 (2.7)	3 (3.3)	1.00
Hospital length of stay	8 [7–12]	8 [7–13]	0.970	8 [7–11]	8 [7–11]	0.525
Rehospitalization	29 (21.5)	29 (18.2)	0.557	19 (26.8)	11 (13.8)	0.046
Infectious complications
Fever in PACU (⩾38^oC)*	39 (40.2)	31 (21.5)	0.002	21 (45.7)	15 (22.1)	0.013
Postoperative fever on ward	73 (51.8)	68 (38.4)	0.023	37 (50.0)	28 (30.8)	0.016
Any infectious complication	42 (29.8)	54 (30.3)	1.00	21 (28.4)	21 (22.8)	0.474
Wound infection	8 (5.7)	16 (9.0)	0.293	7 (9.5)	9 (9.8)	1.00
Pneumonia	16 (11.3)	19 (10.7)	0.859	9 (12.2)	6 (6.5)	0.277
Sepsis	4 (2.8)	6 (3.4)	1.00	2 (2.7)	2 (2.2)	1.00
Urinary tract infection	6 (4.3)	0 (0.0)	0.007	5 (6.8)	0 (0.0)	0.016
Abscess	20 (14.2)	29 (16.3)	0.642	8 (10.8)	8 (8.7)	0.792
Abscess required drainage	7 (5.0)	3 (1.7)	0.114	5 (6.8)	0 (0.0)	0.016
Postoperative blood cultures taken	66 (48.9)	69 (51.1)	0.171	33 (44.6)	27 (29.3)	0.051

Data are presented as median [IQR] or number (percentage). Postoperative pancreatic fistula includes clinically relevant complications (grades B–C). Severe surgical complications were included all complications that required invasive intervention. There were no missing data concerning complications.

Abbreviations: PDAC, pancreatic ductal adenocarcinoma; DXM, dexamethasone; POD, postoperative day; POPF, postoperative pancreatic fistula; DGE, delayed gastric emptying; PACU, postanesthesia care unit.

Excluded patients treated postoperatively in ICU.

The multivariable analyses confirmed that intraoperative DXM was associated with a lower risk for severe Clavien–Dindo complications in PDAC subgroup (odds ratio [OR] 0.40 (95% confidence interval [CI] 0.18–0.91, P = 0.030; Table 3). Specific types of severe Clavien–Dindo complications and severe surgical complications are presented in Supplementary Tables 2 and 3. In addition, in PDAC patients, severe Clavien–Dindo complications reduced the proportion of patients who received adjuvant treatment (CD 0–2, n = 104 (78.8%) vs CD 3–5, n = 23 (67.6%), P = 0.040).

Table 3.

Univariable and multivariable analyses of severe Clavien–Dindo complications.

All patients (n = 319)	Univariable			Multivariable
Factor	OR	95% CI	P value	OR	95% CI	P value
BMI (kg/m²)	1.08	1.01–1.15	0.017	1.08	1.02–1.15	0.015
Diabetes	0.83	0.45–1.56	0.566
Intraoperative dexamethasone	0.78	0.45–1.33	0.355	0.75	0.43–1.31	0.310
Creatinine on POD 3 (umol/l)	1.01	1.00–1.02	0.112	1.01	1.00–1.02	0.162
PDAC patients (n = 166)	Univariable			Multivariable
Factor	OR	95% CI	P value	OR	95% CI	P value
BMI (kg/m²)	1.05	0.96–1.15	0.261	1.07	0.98–1.17	0.173
Diabetes	0.92	0.39–2.15	0.915
Intraoperative dexamethasone	0.39	0.18–0.89	0.024	0.40	0.18–0.91	0.030
Creatinine on POD 3 (umol/l)	1.01	0.99–1.03	0.505	1.00	0.98–1.03	0.783

Risk factor analyses of Clavien–Dindo ⩾ 3 complications. Inverse probability weighting (IPW) based on the propensity scores was used with covariates age and sex, treatment as dependent variable. Risk factor analyses prior to IPW are presented in Supplementary table 4.

Abbreviations: OR, odds ratio; CI, confidence interval; BMI, body mass index; IPW, inverse probability weighting; POD, postoperative day; PDAC, pancreatic ductal adenocarcinoma.

Clinically relevant infectious complications were quite similar in both study groups (Table 2). Urinary tract infections and abscesses, which required drainage, occurred more frequently in patients not administered DXM. Postoperative fever (⩾38.0°C) was more common in patients who had not received intraoperative DXM. Blood cultures were frequently taken but bacteremia was rare with no significant difference between the patient groups (no DXM n = 4 (2.8%) vs DXM n = 8 (4.5%), P = 0.559). We observed no differences in the postoperative need for antibiotics.

We performed subgroup analyses of the whole cohort based on pancreatic texture and MPD size, and identified an inverse association between DXM and postoperative complications in type A patients (not-soft pancreatic texture and MPD > 3 mm, n = 121). In that patient group, severe Clavien–Dindo complications were more common in patients not administered intraoperative DXM (Table 4). We observed no differences in postoperative complications in any other subgroups.

Table 4.

Postoperative complications among ISGPS classification subgroups on the risk of a postoperative pancreatic fistula.

Type A	Patients without DXM (n = 55)	Patients with DXM (n = 66)	P value
Any infectious complication	12 (21.8)	14 (21.2)	1.00
Clavien–Dindo ⩾ 3	17 (30.9)	8 (12.1)	0.014
Severe surgical complications	15 (27.3)	7 (10.6)	0.031
POPF (grade B–C)	1 (1.8)	2 (3.0)	1.00
Type B	Patients without DXM (n = 16)	Patients with DXM (n = 18)	P value
Any infectious complication	6 (37.5)	6 (33.3)	1.00
Clavien–Dindo ⩾ 3	4 (25.0)	6 (33.3)	0.715
Severe surgical complications	3 (18.8)	5 (27.8)	0.693
POPF (grade B–C)	1 (6.3)	1 (5.6)	1.00
Type C	Patients without DXM (n = 25)	Patients with DXM (n = 33)	P value
Any infectious complication	6 (24.0)	12 (36.4)	0.396
Clavien–Dindo ⩾ 3	4 (16.0)	9 (27.3)	0.358
Severe surgical complications	4 (16.0)	8 (24.2)	0.526
POPF (grade B–C)	1 (4.0)	6 (18.2)	0.127
Type D	Patients without DXM (n = 35)	Patients with DXM (n = 49)	P value
Any infectious complication	14 (40.0)	17 (34.7)	0.421
Clavien–Dindo ⩾ 3	9 (25.7)	14 (28.6)	0.809
Severe surgical complications	8 (22.8)	10 (20.4)	0.794
POPF (grade B–C)	6 (17.1)	8 (16.3)	1.00

Data are presented as number (percentage). Type A includes patients with a not-soft pancreatic texture and main pancreatic duct (MPD) size > 3 mm; type B includes patients with a not-soft pancreatic texture and MPD size ⩽ 3 mm; type C includes patients with a soft pancreatic texture and MPD > 3 mm; and type D includes patients with a soft pancreatic texture and MPD ⩽ 3 mm. The information of pancreatic texture or size of MPD was missing in 10 patients in no DXM group and in 12 patients in DXM group.

Abbreviations: ISGPS, International Study Group of Pancreatic Surgery; DXM, dexamethasone; POPF, postoperative pancreatic fistula.

The administration of DXM was not associated with OS in PDAC patients who underwent PD surgery (Figure 2). Median OS was 32 months in patients who received DXM and 38 months in patients not receiving DXM (P = 0.4). Stage ⩾ IIB and occurrence of severe surgical complications were associated with poorer OS in PDAC patients (Supplementary Table 5).

Figure 2.

Overall survival of patients with a pancreatic ductal adenocarcinoma (PDAC). All patients underwent PD surgery. Kaplan–Meier curves indicate no difference in patients with and without intraoperative dexamethasone (P = 0.4).

Discussion

Although intraoperative DXM was not associated with improved postoperative outcomes in all PD patients, our study demonstrated that it was linked to fewer severe Clavien–Dindo complications in PDAC patients. In addition, DXM reduced the postoperative CRP levels and fever in all PD patients. Intraoperative DXM was not associated with better OS in PDAC patients.

In our hospital, intraoperative DXM was included in the treatment protocol for PD patients in the beginning of 2020 according to the general ERAS guidelines given its antiemetic, analgesic, and anti-inflammatory effects.¹ Surgical treatment and the operating surgeons remained consistent throughout the study period, with no differences in the administration of prophylactic antibiotics. Although a meta-analysis had demonstrated that a 4–5 mg dose of DXM was as effective in PONV prophylaxis as an 8–10 mg dose,¹³ we chose to use a 10 mg dose since we aimed at a significant anti-inflammatory effect. An early increase in postoperative CRP levels likely results from inflammation rather than infection. In many studies, as in this study, perioperative glucocorticoid use resulted in lower postoperative CRP levels reflecting an anti-inflammatory effect.¹⁴–¹⁶ Increased postoperative CRP levels have been associated with a higher incidence of pancreatic complications,¹⁷ leading to growing interest in whether the anti-inflammatory properties of glucocorticoids could help reduce these complications.

Studies on the perioperative administration of glucocorticoids and their association with postoperative outcomes have generally yielded mixed results. Previous Finnish RCTs have suggested that perioperative hydrocortisone may reduce severe Clavien–Dindo complications in patients undergoing distal pancreatectomy or PD.^18,19 These trials also linked hydrocortisone with a lower rate of clinically relevant POPF when administered to patients with >40% acini in the pancreatic transection line.¹⁸ However, a recent RCT found no association between hydrocortisone and POPF in this same patient group.²⁰ A systematic review indicated that perioperative glucocorticoid use had a positive impact on morbidity in patients having undergone major pancreatic resections.²¹ In contrast, a retrospective study from Newhook et al.²² did not support this finding. A previous meta-analysis found no overall benefit of perioperative glucocorticoid administration on postoperative outcomes in PD patients but suggested that certain subgroups may experience positive effects of glucocorticoids on postoperative complications,²³ and these aspects warrant further research. This is one of the reasons we chose to assess the outcomes in the PDAC subgroup, alongside those in the overall PD cohort.

In this study, the association between intraoperative DXM and a reduction in postoperative complications was observed in PDAC patients, as well as in those with a wide MPD and not-soft pancreatic texture (type A). However, we cannot explain the underlying mechanisms as to why these patients appear to benefit from the anti-inflammatory effects of DXM. According to the ISGPS classification, type A patients are at the lowest risk for developing a POPF, whereas a narrow (⩽3 mm) MPD and a soft pancreatic tissue increases the risk for postoperative complications.^12,24 The majority of PDAC patients (62.5%) were type A, so these subgroups partially overlapped. The positive association between DXM and reduced complications was observed in complications, which required invasive interventions, such as abscess drainage. A recent RCT demonstrated that a preoperative dose of DXM was associated with a reduction in similar complications in patients undergoing emergency laparotomy.¹⁶ There have been concerns that corticosteroid administration may increase the risk for postoperative anastomotic leakage after lower gastrointestinal surgery, but these harmful effects were specifically associated with long-term use and high doses.²⁵ Although DXM induces a short-term hyperglycemia, no negative association with its use and infectious complications has been observed^15,26,27 as the hyperglycemia can be easily controlled with insulin. A risk factor associated with severe Clavien–Dindo complications in the whole patient cohort was body mass index (BMI). Obesity itself promotes inflammation and dysregulates the autophagy of the cells.²⁸ In general, BMI ⩾ 25 kg/m² seems to increase the risk for postoperative surgical complications and infectious complications in pancreatic surgery patients,^29,30 which may be caused by more difficult surgical conditions and insulin-resistance associated with perioperative hyperglycemia.

This study confirmed our clinical experience of the early postoperative inflammatory reaction in PD patients. The postoperative temperature rose significantly more in patients not administered intraoperative DXM despite they more often received acetaminophen at the end of surgery. DXM has been shown to decrease postoperative fever on the first three PODs in noncardiac surgical patients,²⁶ and our findings support those results. Postoperative fever leads to unnecessary laboratory and radiological examinations and causes additional expenses. Due to fever, almost a half of our PDAC patients had blood cultures taken although bacteremia and sepsis were extremely rare. In the RCT by Chen et al.,⁷ PD patients who received DXM also had lower medical and drug costs compared to the placebo group.

The survival analysis of our study demonstrated that only well-known factors such as higher stage and severe complications had an influence on OS of PDAC patients. Our study failed to illustrate any effect of DXM on survival. Some previous studies indicated that a single dose of DXM significantly improved the OS of pancreatic cancer patients.^6,31 Biochemical studies have demonstrated that the anti-inflammatory effects of DXM could inhibit the migration and tissue invasion of cancer cells and, therefore, impede disease progression, which indeed could have a positive effect on survival.^32,33 There have also been concerns that immunosuppression caused by glucocorticoids could enhance the spread of cancer cells, as in vivo, DXM may decrease cell proliferation and lymphokine production and disturb the apoptosis of neoplastic cells.^34,35 Nevertheless, a single dose of DXM has not been associated with changes in recurrence-free survival or OS in other malignancies.^36,37

The major limitations of our study are attributable to the retrospective study design resulting in inevitable selection bias. The anesthesiologist responsible for the patient decided whether the patient was given DXM although the patient characteristics were similar in both study groups. However, the use of IPW strengthened the validity of our findings by reducing selection bias and confounding in this study. Although the surgical treatment remained consistent across the study years and perioperative care followed the hospital’s protocol, the details of treatment may have varied between the patients. In addition, the sample size of the PDAC subgroup was relatively small limiting any strong conclusions. The research team was not blinded to administration of DXM during the data collection.

Our study highlighted that DXM administration had minimal adverse effects in PD patients when a single intraoperative dose was given. In addition to its antiemetic effect, intraoperative DXM was associated with fewer severe complications in PDAC patients. The anti-inflammatory effect of DXM reduced postoperative fever, and therefore, decreased the redundant laboratory examinations. No associations with DXM and infectious complications were seen nor any impact on survival in PDAC patients. Further prospective studies on intraoperative DXM and short-term postoperative complications in different subgroups of PD patients are needed.

Supplemental Material

sj-docx-1-sjs-10.1177_14574969251371868 – Supplemental material for Intraoperative dexamethasone after pancreatoduodenectomy in pancreatic ductal adenocarcinoma: A retrospective cohort study

Supplemental material, sj-docx-1-sjs-10.1177_14574969251371868 for Intraoperative dexamethasone after pancreatoduodenectomy in pancreatic ductal adenocarcinoma: A retrospective cohort study by Piia Peltoniemi, Harri Mustonen, Katarina Johansson, Inkeri Lehto, Hanna Seppänen and Pertti Pere in Scandinavian Journal of Surgery

Footnotes

Acknowledgements

The authors thank Vanessa Fuller from the University of Helsinki Language Center and a colleague Nora Mattila for their help in proof reading of the manuscript.

Authors contributions

P.P., H.S., and P.P. conceived the study. P.P., K.J., and I.L. collected the relevant data. P.P. and H.M. analyzed the data. All authors participated in interpretation of the results. The manuscript was drafted by P.P. All authors critically revised the manuscript and approved the final version.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The authors are grateful for research funds received from the Cancer Foundation Finland, the Sigrid Jusélius Foundation, Finska Läkaresällskapet, the Finnish Government Subsidy Funding, Helsinki University Hospital, the Paulo Foundation, the Mary and Georg C. Ehrnrooth Foundation, the Scandinavian Society of Anesthesiology and Intensive Care Medicine, Orion Research Foundation, and the Academy of Finland. None of the foundations were involved in the study design or execution.

Supplemental material

Supplemental material for this article is available online.

ORCID iDs

Piia Peltoniemi

Katarina Johansson

Hanna Seppänen

References

Melloul

Lassen

Roulin

, et al: Guidelines for perioperative care for pancreatoduodenectomy: Enhanced recovery after surgery (ERAS) recommendations 2019. World J Surg 2020;44(7):2056–2084.

Mihara

Ishii

, et al: Effects of steroids on quality of recovery and adverse events after general anesthesia: Meta-analysis and trial sequential analysis of randomized clinical trials. PLoS ONE 2016;11(9):e0162961.

Lee

DH.

Synergism between taurine and dexamethasone in anti-inflammatory response in LPS-activated macrophages. Adv Exp Med Biol 2022;1370:31–39.

Turina

Fry

Polk

Jr.

Acute hyperglycemia and the innate immune system: Clinical, cellular, and molecular aspects. Crit Care Med 2005;33(7):1624–1633.

Waldron

Jones

Gan

, et al: Impact of perioperative dexamethasone on postoperative analgesia and side-effects: Systematic review and meta-analysis. Br J Anaesth 2013; 110(2):191–200.

Sandini

Ruscic

Ferrone

, et al: Intraoperative dexamethasone decreases infectious complications after pancreaticoduodenectomy and is associated with long-term survival in pancreatic cancer. Ann Surg Oncol 2018;25(13):4020–4026.

Chen

Wang

Jiang

, et al: The effect of perioperative dexamethasone on postoperative complications after pancreaticoduodenectomy: A multicenter randomized controlled trial. Ann Surg 2024;280:222–228.

DeOliveira

Winter

Schafer

, et al: Assessment of complications after pancreatic surgery: A novel grading system applied to 633 patients undergoing pancreaticoduodenectomy. Ann Surg 2006;244(6):931–7discussion937.

Bassi

Marchegiani

Dervenis

, et al: The 2016 update of the International Study Group (ISGPS) definition and grading of postoperative pancreatic fistula: 11 years after. Surgery 2017;161(3):584–591.

10.

Wente

Bassi

Dervenis

, et al: Delayed gastric emptying (DGE) after pancreatic surgery: A suggested definition by the International Study Group of Pancreatic Surgery (ISGPS). Surgery 2007;142(5):761–768.

11.

Singer

Deutschman

Seymour

, et al: The third international consensus definitions for sepsis and septic shock (Sepsis-3). JAMA 2016;315:801–810.

12.

Schuh

Mihaljevic

Probst

, et al: A simple classification of pancreatic duct size and texture predicts postoperative pancreatic fistula: A classification of the international study group of pancreatic surgery. Ann Surg 2023;277:e597–e608.

13.

De Oliveira

Jr Castro-Alves

Ahmad

, et al: Dexamethasone to prevent postoperative nausea and vomiting: An updated meta-analysis of randomized controlled trials. Anesth Analg 2013;116:58–74.

14.

McSorley

Roxburgh

CSD

Horgan

, et al: The impact of preoperative dexamethasone on the magnitude of the postoperative systemic inflammatory response and complications following surgery for colorectal cancer. Ann Surg Oncol 2017; 24(8):2104–2112.

15.

Toner

Ganeshanathan

Chan

, et al: Safety of perioperative glucocorticoids in elective noncardiac surgery: A systematic review and meta-analysis. Anesthesiology 2017;126(2): 234–248.

16.

Cihoric

Kehlet

Lauritsen

, et al: Preoperative high dose of dexamethasone in emergency laparotomy: Randomized clinical trial. Br J Surg 2024;111: znae130.

17.

Palani Velu

McKay

Carter

, et al: Serum amylase and C-reactive protein in risk stratification of pancreas-specific complications after pancreaticoduodenectomy. Br J Surg 2016;103(5):553–563.

18.

Laaninen

Sand

Nordback

, et al: Perioperative hydrocortisone reduces major complications after pancreaticoduodenectomy: A randomized controlled trial. Ann Surg 2016; 264(5):696–702.

19.

Antila

Siiki

Sand

, et al: Perioperative hydrocortisone treatment reduces postoperative pancreatic fistula rate after open distal pancreatectomy. Pancreatology 2019;19(5):786–792.

20.

Kant

Ahmed

Dama

, et al: Does perioperative hydrocortisone or indomethacin improve pancreatoduodenectomy outcomes? A triple arm, randomized placebo-controlled trial. Ann Hepatobiliary Pancreat Surg 2024;28:350–357.

21.

Kuan

Dennison

Garcea

Outcomes of peri-operative glucocorticosteroid use in major pancreatic resections: A systematic review. HPB 2021;23(12):1789–1798.

22.

Newhook

Soliz

Prakash

, et al: Impact of intraoperative dexamethasone on surgical and oncologic outcomes for patients with resected pancreatic ductal adenocarcinoma. Ann Surg Oncol 2021;28(3):1563–1569.

23.

Liu

Wei

Cao

, et al: The effects of perioperative corticosteroids on postoperative complications after pancreatoduodenectomy: A debated topic of systematic review and meta-analysis. Ann Surg Oncol 2025;32:2856–2858.

24.

Andrianello

Marchegiani

Bannone

, et al: Clinical implications of intraoperative fluid therapy in pancreatic surgery. J Gastrointest Surg 2018;22(12):2072–2079.

25.

Eriksen

Lassen

Gögenur

Treatment with corticosteroids and the risk of anastomotic leakage following lower gastrointestinal surgery: A literature survey. Colorectal Dis 2014;16(5):O154–60.

26.

Corcoran

Kasza

Short

, et al: Intraoperative dexamethasone does not increase the risk of postoperative wound infection: A propensity score-matched post hoc analysis of the ENIGMA-II trial (EnDEX). Br J Anaesth 2017;118:190–199.

27.

Polderman

Farhang-Razi

Van Dieren

, et al: Adverse side effects of dexamethasone in surgical patients. Cochrane Database Syst Rev 2018;8:Cd011940.

28.

Gukovsky

Todoric

, et al: Inflammation, autophagy, and obesity: Common features in the pathogenesis of pancreatitis and pancreatic cancer. Gastroenterology 2013;144(6):1199–1209.

29.

Okano

Hirao

Unno

, et al: Postoperative infectious complications after pancreatic resection. Br J Surg 2015;102(12): 1551–1560.

30.

Aoki

Miyata

Konno

, et al: Risk factors of serious postoperative complications after pancreaticoduodenectomy and risk calculators for predicting postoperative complications: A nationwide study of 17,564 patients in Japan. J Hepatobiliary Pancreat Sci 2017;24(5):243–251.

31.

Call

Pace

Thorup

, et al: Factors associated with improved survival after resection of pancreatic adenocarcinoma: A multivariable model. Anesthesiology 2015;122(2):317–324.

32.

Kim

Hwang

Han

, et al: Dexamethasone inhibits hypoxia-induced epithelial-mesenchymal transition in colon cancer. World J Gastroenterol 2015;21:9887–9899.

33.

Rhim

Mirek

Aiello

, et al: EMT and dissemination precede pancreatic tumor formation. Cell 2012;148:349–361.

34.

Kunicka

Talle

Denhardt

, et al: Immunosuppression by glucocorticoids: Inhibition of production of multiple lymphokines by in vivo administration of dexamethasone. Cell Immunol 1993;149(1):39–49.

35.

Chen

Wang

, et al: Dexamethasone enhances cell resistance to chemotherapy by increasing adhesion to extracellular matrix in human ovarian cancer cells. Endocr Relat Cancer 2010;17(1):39–50.

36.

Cata

Jones

Sepesi

, et al: Lack of association between dexamethasone and long-term survival after non-small cell lung cancer surgery. J Cardiothorac Vasc Anesth 2016;30(4):930–935.

37.

De Oliveira

Jr McCarthy

Turan

, et al: Is dexamethasone associated with recurrence of ovarian cancer? Anesth Analg 2014;118:1213–1218.

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.00 MB

0.02 MB