Воздействие дексаметазона на подстрекательские маркеры хирургического стресса: случайное испытание роботической истерэктомии.

Ethical aspects

The trial was approved by the European Medicines Agency (EUDRACT No. 2021-000874-28), the National Medical Agency (2021–1041858), the National Scientific Committee (S-20210054), the Regional Ethics Committee (De Videnskabsetiske Komitéer for Region Syddenmark) (22/22766), and the Unit of Good Clinical Practice (22.011). The study was registered at ClinicalTrials.gov ( NCT04762381 ) on June 1, 2022.

Data were stored in a closed repository within the Open Patient data Explorative Network (OPEN) at the University of Southern Denmark using a REDCap database (No. 1377). Randomization was performed using Ciba-Geigy random numbers (even or odd) prior to trial initiation and stored in sealed envelopes.

All participants received written and oral information and provided written informed consent. The study was monitored by OPEN in accordance with Good Clinical Practice (GCP) guidelines.

Introduction

Laparoscopic surgery has transformed the landscape of surgical interventions, offering significant advantages such as reduced postoperative pain, faster recovery, and shorter hospital stays. As minimally invasive surgery continues to evolve, optimizing surgical outcomes and enhancing patient experiences remain central goals. One promising approach in this context is the perioperative use of dexamethasone, a corticosteroid with well-established anti-inflammatory properties.

The anti-inflammatory effects of dexamethasone are well documented across various medical contexts, including allergic reactions, autoimmune disorders, and certain malignancies. These properties have generated interest in its application in the surgical setting, where dexamethasone may attenuate the inflammatory response to surgical trauma, reduce tissue damage, alleviate postoperative pain, and accelerate recovery. In addition, dexamethasone exerts immunosuppressive effects by modulating immune cell activity and reducing the release of pro-inflammatory cytokines, which may contribute to a reduced risk of postoperative complications such as infection, adhesion formation, and delayed wound healing [ 1 ]. Consequently, numerous studies have examined the use of dexamethasone in laparoscopic surgery, focusing on aspects such as optimal dosage, timing of administration, and potential adverse effects.

However, the existing literature remains somewhat conflicting, making it difficult for clinicians to draw firm conclusions, and a consistent understanding of dexamethasone’s effects on surgical outcomes in minimally invasive procedures is still lacking. This inconsistency is largely attributable to heterogeneity across surgical types and outcome measures, with reliable evidence primarily limited to the prevention of postoperative nausea and vomiting [ 2 , 3 ]. Nevertheless, multimodal analgesia is an important strategy for reducing postoperative pain [ 4 ]. Systematic reviews have demonstrated the effectiveness of adjunct agents—including ketamine, gabapentin, paracetamol, and nonsteroidal anti-inflammatory drugs—in reducing postoperative pain and/or opioid consumption [ 5 – 7 ]. Accordingly, more rigorous studies are needed to clarify the role of dexamethasone in minimizing surgical stress and improving recovery outcomes, particularly in robotic-assisted procedures.

C-reactive protein (CRP) is widely used in clinical practice as a marker of systemic inflammation and provides valuable insight into the body’s response to surgical trauma, as well as its association with perioperative morbidity. By investigating the addition of dexamethasone to perioperative management, this study seeks to determine whether it offers meaningful benefits for patients undergoing robotic hysterectomy.

To address these gaps in the literature, we aimed to evaluate the effect of dexamethasone in robotic hysterectomy, with a specific focus on its impact on CRP levels as a proxy marker of surgical stress.

Methods

Women scheduled for robotic-assisted hysterectomy were recruited into a randomized, placebo-controlled trial at the Gynecology Outpatient Department, Aabenraa Hospital, Sygehus Sønderjylland, after providing written informed consent. Participants were randomized to receive a single preoperative dose of either saline (placebo) or 24 mg dexamethasone (equivalent to 128 mg methylprednisolone) administered intravenously 15 min before insertion of surgical instruments and after induction of anesthesia to minimize potential blinding bias.

Randomization and preparation of the study medication were performed by an independent third party (a midwife from the Delivery Department) who was not involved in patient recruitment, clinical care, or data handling. The study medication was delivered in identical syringes containing 6 mL of solution, indistinguishable in appearance regardless of content.

Women were eligible for inclusion if they were at least 18 years of age, able to understand Danish, and had no major comorbidities or daily use of morphine or morphine-like substances. Exclusion criteria included insulin-treated diabetes and current or previous malignancy.

Blood samples were obtained at recruitment in the outpatient clinic and postoperatively at 0, 4, 8, 12, and 24 h. At the same time points, pain intensity was assessed using a visual analogue scale (VAS), and postoperative nausea and vomiting, as well as medication use during hospital admission, were recorded. Before surgery and weekly for four weeks postoperatively, participants completed questionnaires assessing pain and medication use. Analgesic and antiemetic consumption was registered during hospitalization and subsequently documented by patient diaries for four weeks after discharge. Patients with a nausea score > 40 on a 0–100 VAS scale received ondansetron 4 mg orally, administered by the ward nurse.

The trial was approved by the European Medicines Agency (EUDRACT No. 2021–000874-28), the National Medical Agency (2021–1041858), the National Scientific Committee (S-20210054), the Regional Ethics Committee (22/22766), and the Unit of Good Clinical Practice (22.011). The study was registered at ClinicalTrials.gov ( NCT04762381 ). Data were stored in a secure repository within the Open Patient data Explorative Network (OPEN) at the University of Southern Denmark using a REDCap database (No. 1377).

Randomization was performed using Ciba-Geigy random numbers (even or odd) generated prior to trial initiation and stored in sealed, numbered envelopes. A total of 150 envelopes were prepared and stored in the medical supply unit. For each participant, the third party opened the corresponding envelope and prepared the syringe labeled either “dexamethasone” or “placebo.” Investigators, clinical staff, outpatient personnel, and participants were all blinded to treatment allocation.

Sample size calculations indicated that 48 participants were required in each group based on the primary outcome, C-reactive protein (CRP), which was expected to increase to approximately 40 mg/L postoperatively, with an anticipated 10% reduction and a standard deviation of 7 mg/L [ 8 – 11 ]. CRP was selected as a marker of surgical stress, pre-specified in the ClinicalTrials.gov registration, and its use was clarified in a publication prior to trial initiation [ 12 ]. Secondary outcomes were identified through a patient involvement process and included clinically relevant recovery parameters.

Statistical analyses were conducted according to the intention-to-treat principle. Unpaired analyses were used where appropriate, including relevant covariates. Women with preoperative use of analgesics were analyzed as a predefined subgroup. Longitudinal changes in outcomes were analyzed using mixed-effects models, with baseline CRP included as a covariate. Dropout participants were compared with included participants as part of an external validation process.

Regression analyses using generalized linear mixed models were performed for both primary and secondary outcomes, with anthropometric variables included as dependent variables. CRP values were log-transformed due to a multiplicative effect. Model assumptions were assessed graphically using residual and normal quantile plots. P -values were based on predefined contrasts to avoid multiple testing. A two-tailed p-value < 0.05 was considered statistically significant. Statistical analyses were performed using STATA-BE version 18. Normally distributed data are presented as mean ± standard deviation (SD), and non-normally distributed data as median (range).

Results

Between May 2022 and February 2024, 128 women were assessed for eligibility. Of these, 112 were included in the final analysis, having complete blood sampling, medication records, and visual analogue scale (VAS) data at all predefined time points. Reasons for exclusion were refusal to participate ( n  = 5), type 1 diabetes mellitus ( n  = 4), inability to speak Danish ( n  = 1), and daily use of prednisolone or morphine ( n  = 1 each). Additional exclusions due to protocol violations included supplemental dexamethasone administration ( n  = 2), diagnosis of gynecological cancer ( n  = 1), and conversion from robotic surgery to laparotomy ( n  = 1). These cases were excluded from the final analysis but are presented and evaluated as a separate dropout group (Table  1 ). Table 1 Clinical variables of women with robotic-assisted hysterectomy by randomization group Variable/group DEXA Placebo All No 54 58 112 Age (years) 48 ± 10 49 ± 9 49 ± 9 Height (cm) 168 ± 6 168 ± 5 168 ± 6 Weight (kg) 82 ± 19 82 ± 15 82 ± 17 BMI (kg/m 2 ) 29 ± 6 29 ± 5 29 ± 5 Smoking 14 13 26 Parity (n) 2 (0–2) 2 (0–2) 2 (0–2) Previous surgery (n) a)  -cesarean section 15 12 27  -conisation 7 6 13  -laparoscopic cholecystectomy 6 6 12  -oophorectomy 2 3 5  -laparoscopy 6 7 13  -hysteroscopy 4 9 13  -Incontinence 3 3 6  -other b) 26 38 64  -none - 14* 6* 20 Medication besides estrogen (n)  -Paracetamol 13 19 32  -NSAID 13 10 23  -other painkillers 10 12 22  -Morphine 0 0 0 Estrogen treatment (n)  -none 44 51 95  -vaginal/oral/both ways 5/5 5/1/1 171 Indication for hysterectomy (n)  - fibroids 23 23 46  - meno-metorrhagia 16 20 37  - dysplasia 5 9 14  - dysmenorrhea 5 6 11  - Gender shift 2 0 2  - prolapse 1 0 1 Comorbidity (n) None n (%) 26 (48) 24 (41) 50 (45) Hypertension 12 7 19 Depression 5 9 14 Asthma 7 6 13 Hypercholesterolemia 4 6 10 Other c) 10 13 23 All data following Gaussian distribution are given as mean ± SD, all non-Gaussian are given as median (range) DEXA Dexamethasone, Hgb Hemoglobin, NSAID Nonsteroidal anti-inflammatory drug, NIDDM Non-Insulin dependent diabetes mellitus, IDDM Insulin-dependent diabetes mellitus a) Some women had more than one previous surgery; b) Other operations: Appendectomies ( n  = 8); Breast reduction ( n  = 4); abdominal plastic ( n  = 3); spine operation ( n  = 3); mastectomy ( n  = 2), knee operation ( n  = 2); nose operation ( n  = 2); hernia operation ( n  = 1); foot operation ( n  = 1); salivary gland operation ( n  = 1); varices operation ( n  = 1); hip operation ( n  = 1); gastric bypass operation ( n  = 1); c) Other comorbidity: Hypo and hyperthyroidism, NIDDM, disseminated sclerosis, epilepsy, neuropathic pain; chronic urticaria; lipothymia; high intracranial pressure; primarily degenerative disease of the central nerve system; chronic back pain; attention deficit hyperactivity disorder; systemic lupus erythematosus; arrhythmia cardialis; mental disorder * p  < 0.05

Table 1 Clinical variables of women with robotic-assisted hysterectomy by randomization group Variable/group DEXA Placebo All No 54 58 112 Age (years) 48 ± 10 49 ± 9 49 ± 9 Height (cm) 168 ± 6 168 ± 5 168 ± 6 Weight (kg) 82 ± 19 82 ± 15 82 ± 17 BMI (kg/m 2 ) 29 ± 6 29 ± 5 29 ± 5 Smoking 14 13 26 Parity (n) 2 (0–2) 2 (0–2) 2 (0–2) Previous surgery (n) a)  -cesarean section 15 12 27  -conisation 7 6 13  -laparoscopic cholecystectomy 6 6 12  -oophorectomy 2 3 5  -laparoscopy 6 7 13  -hysteroscopy 4 9 13  -Incontinence 3 3 6  -other b) 26 38 64  -none - 14* 6* 20 Medication besides estrogen (n)  -Paracetamol 13 19 32  -NSAID 13 10 23  -other painkillers 10 12 22  -Morphine 0 0 0 Estrogen treatment (n)  -none 44 51 95  -vaginal/oral/both ways 5/5 5/1/1 171 Indication for hysterectomy (n)  - fibroids 23 23 46  - meno-metorrhagia 16 20 37  - dysplasia 5 9 14  - dysmenorrhea 5 6 11  - Gender shift 2 0 2  - prolapse 1 0 1 Comorbidity (n) None n (%) 26 (48) 24 (41) 50 (45) Hypertension 12 7 19 Depression 5 9 14 Asthma 7 6 13 Hypercholesterolemia 4 6 10 Other c) 10 13 23 All data following Gaussian distribution are given as mean ± SD, all non-Gaussian are given as median (range) DEXA Dexamethasone, Hgb Hemoglobin, NSAID Nonsteroidal anti-inflammatory drug, NIDDM Non-Insulin dependent diabetes mellitus, IDDM Insulin-dependent diabetes mellitus a) Some women had more than one previous surgery; b) Other operations: Appendectomies ( n  = 8); Breast reduction ( n  = 4); abdominal plastic ( n  = 3); spine operation ( n  = 3); mastectomy ( n  = 2), knee operation ( n  = 2); nose operation ( n  = 2); hernia operation ( n  = 1); foot operation ( n  = 1); salivary gland operation ( n  = 1); varices operation ( n  = 1); hip operation ( n  = 1); gastric bypass operation ( n  = 1); c) Other comorbidity: Hypo and hyperthyroidism, NIDDM, disseminated sclerosis, epilepsy, neuropathic pain; chronic urticaria; lipothymia; high intracranial pressure; primarily degenerative disease of the central nerve system; chronic back pain; attention deficit hyperactivity disorder; systemic lupus erythematosus; arrhythmia cardialis; mental disorder * p  < 0.05

Clinical variables of women with robotic-assisted hysterectomy by randomization group

All data following Gaussian distribution are given as mean ± SD, all non-Gaussian are given as median (range)

DEXA Dexamethasone, Hgb Hemoglobin, NSAID Nonsteroidal anti-inflammatory drug, NIDDM Non-Insulin dependent diabetes mellitus, IDDM Insulin-dependent diabetes mellitus

a) Some women had more than one previous surgery; b) Other operations: Appendectomies ( n  = 8); Breast reduction ( n  = 4); abdominal plastic ( n  = 3); spine operation ( n  = 3); mastectomy ( n  = 2), knee operation ( n  = 2); nose operation ( n  = 2); hernia operation ( n  = 1); foot operation ( n  = 1); salivary gland operation ( n  = 1); varices operation ( n  = 1); hip operation ( n  = 1); gastric bypass operation ( n  = 1); c) Other comorbidity: Hypo and hyperthyroidism, NIDDM, disseminated sclerosis, epilepsy, neuropathic pain; chronic urticaria; lipothymia; high intracranial pressure; primarily degenerative disease of the central nerve system; chronic back pain; attention deficit hyperactivity disorder; systemic lupus erythematosus; arrhythmia cardialis; mental disorder

* p  < 0.05

The included women had a mean age of 48 ± 9 years, a mean parity of 1.6 (range 0–2), and a mean BMI of 29 ± 5 kg/m 2 . Seventeen women were current users of estrogen therapy, with similar distribution between the two groups.

Previous surgical history was comparable between groups. Overall, 57% of participants had undergone previous surgery: 24% had a prior cesarean section, 12% conization, 11% laparoscopic cholecystectomy, 5% oophorectomy, and 2% mastectomy. Regarding analgesic use prior to surgery, 29% of patients used paracetamol and 20% ibuprofen; none used morphine. Indications for robotic hysterectomy included fibroids (41%), menometrorrhagia (37%), dysplasia (13%), and dysmenorrhea (10%). Two women underwent hysterectomy as part of gender-affirming surgery, and one due to pelvic organ prolapse.

Comorbidities among included patients included hypertension (17%), depression (13%), asthma (12%), hypercholesterolemia (9%), and other conditions (8%). Five women had hypothyroidism, four had type 2 diabetes mellitus, three had epilepsy, one had multiple sclerosis, and one had hyperthyroidism. No comorbidities were reported in 45% of the participants.

Preoperative hemoglobin levels, operative time, estimated blood loss, and uterine weight were similar between the two groups (Table  2 ). Baseline pain scores were 0 (range 0–50) on the VAS in both groups. At 24 h postoperatively, median pain scores were 20 (range 0–100) in the dexamethasone group and 20 (range 0–80) in the placebo group. Postoperative nausea and vomiting were significantly less severe in the dexamethasone group at 8 h postoperatively. The primary outcome demonstrated significantly lower CRP levels in the dexamethasone group at both 12 and 24 h postoperatively (Table  2 ). Table 2 Data from baseline until 24 h postoperatively Variable/group DEXA Placebo Included in trial Dropout No 54 58 112 16 Hgb (mg/dl) 8.2 ± 0.7 8.3 ± 1 8.3 ± 0.8 8.2 ± 0.7 Uterine weight (g) 287 (26–1000) 315 (35–1365) 302 (26–1365) 208 (40–2366) Peroperative blood loss (ml) 48 (0–750) 86 (0–1000) 66 (0–1000) 50 (20–1200) Operation time (min) 85 (27–225) 92 (30–270) 89 (27–270) 105 (27–215) Nausea VAS (0–100)  Baseline 0 (0–50) 0 (0) 0 (0–50)  4h 0 (0–40) 0 (0–70) 0 (0–70)  8h 0 (0–30)* 0 (0–70)* 0 (0–70)  12h 0 (0–40) 0 (0–50) 0 (0–50)  24h 0 (0–20) 0 (0–80) 0 (0–80) Pain VAS (0–100)  Baseline 0 (0–50) 0 (0–50) 0 (0–50)  4h 30 (0–70) 20 (0–70) 20 (0–70)  8h 20 (0–60) 30 (0–80) 20 (0–80)  12h 20 (20–80) 30 (0–80) 20(0–80)  24h 20 (0–100) 20 (0–80) 0 (0–80) c-reactive protein (mg/dl)  Baseline 1.5 (0.6–9.5) 1.6 (0.5–47) 1.5 (0.5–47)  4h 1.5 (0.6–9-8) 1.8 (0.5–56) 1.5 (0.5–56)  8h 2.4 (0.6–13) 3.7 (0.6–76) 2.9 (0.6–76)  12h 5.2 (1.2–29)** 9.6 (1.3–113)** 6.8 (1.2–113)  24h 8.1 (3.1–98)** 38.5 (4.6–276)** 22 (3.1–276) Data are given as mean ± SD if Gaussian distributed, otherwise as median (range) Bold types indicate difference between DEXA and placebo group DEXA  Dexamethasone, Hgb  Hemoglobin, VAS  Visual analogue scale * p  < 0.05; ** p  < 0.01, DEXA vs placebo

Table 2 Data from baseline until 24 h postoperatively Variable/group DEXA Placebo Included in trial Dropout No 54 58 112 16 Hgb (mg/dl) 8.2 ± 0.7 8.3 ± 1 8.3 ± 0.8 8.2 ± 0.7 Uterine weight (g) 287 (26–1000) 315 (35–1365) 302 (26–1365) 208 (40–2366) Peroperative blood loss (ml) 48 (0–750) 86 (0–1000) 66 (0–1000) 50 (20–1200) Operation time (min) 85 (27–225) 92 (30–270) 89 (27–270) 105 (27–215) Nausea VAS (0–100)  Baseline 0 (0–50) 0 (0) 0 (0–50)  4h 0 (0–40) 0 (0–70) 0 (0–70)  8h 0 (0–30)* 0 (0–70)* 0 (0–70)  12h 0 (0–40) 0 (0–50) 0 (0–50)  24h 0 (0–20) 0 (0–80) 0 (0–80) Pain VAS (0–100)  Baseline 0 (0–50) 0 (0–50) 0 (0–50)  4h 30 (0–70) 20 (0–70) 20 (0–70)  8h 20 (0–60) 30 (0–80) 20 (0–80)  12h 20 (20–80) 30 (0–80) 20(0–80)  24h 20 (0–100) 20 (0–80) 0 (0–80) c-reactive protein (mg/dl)  Baseline 1.5 (0.6–9.5) 1.6 (0.5–47) 1.5 (0.5–47)  4h 1.5 (0.6–9-8) 1.8 (0.5–56) 1.5 (0.5–56)  8h 2.4 (0.6–13) 3.7 (0.6–76) 2.9 (0.6–76)  12h 5.2 (1.2–29)** 9.6 (1.3–113)** 6.8 (1.2–113)  24h 8.1 (3.1–98)** 38.5 (4.6–276)** 22 (3.1–276) Data are given as mean ± SD if Gaussian distributed, otherwise as median (range) Bold types indicate difference between DEXA and placebo group DEXA  Dexamethasone, Hgb  Hemoglobin, VAS  Visual analogue scale * p  < 0.05; ** p  < 0.01, DEXA vs placebo

Data from baseline until 24 h postoperatively

Data are given as mean ± SD if Gaussian distributed, otherwise as median (range)

Bold types indicate difference between DEXA and placebo group

DEXA  Dexamethasone, Hgb  Hemoglobin, VAS  Visual analogue scale

* p  < 0.05; ** p  < 0.01, DEXA vs placebo

Repeated-measures analyses incorporating BMI, age, operative time, blood loss, and uterine weight as covariates showed significantly lower postoperative nausea and vomiting in the dexamethasone group ( p  = 0.039 unadjusted; p  = 0.02 adjusted). Pain scores did not differ significantly between groups at any time point (Table  2 ).

Changes in CRP over time were also evaluated using repeated-measures analysis, revealing highly significant differences both without and with adjustment for BMI, age, and baseline CRP (both p < 0.001; Fig. 1). Overall, the dexamethasone group exhibited approximately 75% lower CRP levels during the postoperative period.

Among the 112 included patients, three experienced vaginal cuff hematomas (all in the placebo group), and one patient in the dexamethasone group developed ileus due to incarcerated small bowel at the incision site. No cases of superficial or deep wound infection were observed, either abdominally or vaginally.

Dropout analysis revealed no significant differences between included and excluded patients with respect to baseline characteristics or perioperative data within the first 24 h (Table  1 ).

Discussion

Our trial indicated that dexamethasone reduced the rise in C-reactive protein (CRP) in robotic hysterectomy, corresponding to a reduction in the perceived surgical stress response. The intervention with steroids most likely dampened inflammatory activity, edema development, or connective tissue swelling—effects that have also been demonstrated in the context of epidural analgesia [ 11 , 13 ]. Administering the dose after initiation of anesthesia ensured masking, thereby maintaining effective blinding for both patients and healthcare personnel. When given before anesthesia, a dose of 24 mg dexamethasone may cause a transient sensation of euphoria that can be observed by others. This issue was not addressed in several similar trials of dexamethasone in laparoscopic abdominal surgery; consequently, a potential bias may have been introduced.

In previous studies, the most common dexamethasone dose ranged from 6–8 mg, but only a handful reported CRP or other inflammatory markers [ 8 – 10 , 14 – 17 ]. With the exception of two studies, postoperative nausea and vomiting (PONV) was the primary outcome, and secondary outcomes were not powered to detect changes in inflammation [ 15 , 17 ]. Thus, conclusions were largely based on patient-reported outcomes rather than on mechanistic effects related to surgical stress reduction or optimization of minimally invasive procedures. Nevertheless, even with lower doses of dexamethasone, reductions in CRP of 44–75% at 24 h have been reported, findings that we confirm [ 8 – 10 , 14 , 15 ]. From these observations and our own results, one may infer that further reductions in surgical stress are possible. Notably, the CRP levels observed in our study exceeded expectations at the time of sample size calculation [ 12 ].

The anti-inflammatory effects of dexamethasone are particularly relevant in the context of microinvasive surgery, where minimizing inflammation may translate into improved outcomes. Previous studies have demonstrated that preoperative dexamethasone administration can reduce postoperative pain and enhance recovery metrics [ 18 , 19 ]. Its analgesic effects are attributed to modulation of inflammatory pathways and reduced release of pro-inflammatory cytokines [ 20 ]. Furthermore, dexamethasone’s pharmacokinetic profile supports its perioperative use, as its half-life allows for sustained anti-inflammatory effects in the immediate postoperative period [ 21 ]. However, potential risks—such as increased susceptibility to infection and delayed wound healing—must be considered, particularly in major abdominal surgery [ 3 , 22 ]. Careful patient selection and appropriate dosing are therefore essential to maximize benefits while minimizing risks.

CRP is a crude marker of surgical stress, and dexamethasone may not specifically target all aspects of the human stress response, in which innate immune mechanisms likely play a central role. Nevertheless, this knowledge may inform fast-track surgery logistics, especially as robotic-assisted surgery increasingly replaces conventional laparoscopy. Multimodal treatment strategies addressing adjunct medications, surgical technique, and perioperative care are central to this approach. Given the difficulty of isolating the effects of individual variables, proxy measures such as mobilization, length of hospital stay, and symptomatic discomfort are often used. In this context, CRP represents a readily obtainable marker with strong correlation to surgical stress [ 23 ].

Randomization successfully distributed covariates evenly between trial arms, and excluded patients did not differ in key characteristics, supporting the external validity of our findings. Potential bias in the primary outcome was addressed by adjusting for individual baseline CRP levels in the statistical model. None of the baseline characteristics—including age, BMI, uterine weight, operative time, or blood loss—altered the results. Although CRP was associated with BMI at baseline, this relationship disappeared in postoperative measurements (see Supplement 1). This was anticipated, as adiposity is known to induce a low-grade chronic inflammatory state [ 24 ]. In contrast, the stress response to surgery, reflected by rising CRP levels, was evident in both groups (Fig.  1 ). Age and other covariates showed no comparable effects, likely due to the exclusion of patients with significant inflammatory or malignant comorbidities. Fig. 1 Postoperative c-reactive protein after robotic-assisted hysterectomy in 112 women. Dexa: Dexamethasone group, Dexa vs. placebo group p <0.001 (repeated measurments with adjustments)

Postoperative c-reactive protein after robotic-assisted hysterectomy in 112 women. Dexa: Dexamethasone group, Dexa vs. placebo group p <0.001 (repeated measurments with adjustments)

The randomized design represents a major strength of this study, which we underestimated during sample size calculation. We anticipated only a 10% reduction in CRP, whereas the post hoc power calculation reached 99%, supporting future studies aimed at further improving fast-track surgery without increasing postoperative risk. Although comorbidities and predisposing factors showed variability, they were statistically insignificant and may have obscured effects in a smaller cohort. We therefore present results both with and without adjustment to enhance external validity. As robotic-assisted surgery is relatively new, evidence remains limited, necessitating comparisons with conventional laparoscopic surgery rather than direct 1:1 comparisons. Nevertheless, the overall direction of evidence is consistent, and future studies are expected to further evaluate clinical benefits.

Previous reports have described a bubble-like increase in CRP followed by a decrease within 48 h [ 25 ], whereas we observed an exponential increase over the same period in the robotic group. This finding may suggest that robotic surgery induces a distinct or delayed stress response, although no direct comparison between surgical techniques was included in glucocorticoid trials. One interpretation is that robotic hysterectomy elicits a delayed stress response relative to laparoscopy. Although the observed reductions may appear modest, they have been associated with reduced postoperative opioid requirements in practical settings [ 8 – 11 , 13 , 14 , 20 , 26 – 30 ]. Systematic reviews indicate that dexamethasone effectively reduces PONV without increasing surgical site infection risk [ 22 , 31 ] and is associated with decreased opioid consumption [ 31 , 32 ]. While we could not confirm analgesic benefits, we did observe the well-established reduction in PONV. Four-week clinical follow-up revealed few complications and no differences between groups. Due to limited sample size, we were underpowered to assess potential effects on hyperglycemia.

In preparation for this trial, we identified only seven abdominal surgery studies reporting inflammatory markers [ 25 ], leading us to conclude that surgical stress reduction is best assessed using paraclinical measures. Advances in surgical technique, perioperative regimens, and adjunct medications such as dexamethasone have reduced adverse clinical outcomes to a minimum.

Several studies have evaluated perioperative glycemic effects of dexamethasone. Liu et al. administered 20 mg dexamethasone to 135 orthopedic patients and observed a maximal glucose increase of 12 mg/dL (≈0.7 mmol/L) compared with placebo [ 33 ]. A larger study of 4,800 patients, including a diabetic subgroup, found minimal clinical harm when comparing 4–10 mg dexamethasone with placebo [ 34 ]. Interestingly, despite higher rates of hyperglycemia, mortality within 90 days tended to be lower among diabetic patients receiving dexamethasone and was substantially lower in non-diabetic patients [ 34 ]. A meta-analysis of 23 randomized trials in non-cardiac surgery (n ≈ 11,000) reported a maximum glucose difference of 1.5 mmol/L between groups [ 35 ]. Collectively, these findings suggest that a single dexamethasone dose has minimal clinical impact, supporting our decision to omit glycemic assessment in this modestly sized study.

In conclusion, dexamethasone substantially reduced CRP levels, supporting its role in ameliorating surgical stress in robotic-assisted surgery. Dexamethasone represents a valuable adjunct in microinvasive abdominal procedures by reducing postoperative stress and nausea, and its anti-inflammatory properties support its inclusion in multimodal analgesia strategies. Future research should focus on optimizing dosing regimens and evaluating long-term effects across diverse surgical populations.

Supplementary Information

Supplementary Material 1.

Supplementary Material 1.