The effect of dexamethasone in laparoscopic abdominal surgery - a review on inflammatory markers for stress response.

This systemic review includes randomized controlled trials focusing on laparoscopic abdominal surgery with benign indications published between January 1996 and May 2023. This review is developed in accordance with the guidelines from the PRISMA 2020 checklist [ 8 ] and the protocol was published prior to commencing the literature search (PROSPERO, CRD42024421062). It adheres to established guidelines for conducting systematic reviews and meta-analyses by employing a comprehensive search strategy to identify relevant studies from electronic databases, including Medline, Embase, and Cochrane Library and following the recommendations of the PRISMA statement [ 13 ]. The search included ‘Surgery’ or ‘Surgery, abdomen’ or ‘(robot* or da Vinci or Aesopmor Zeus or (remote* adj5 surgery)).ti, ab.’ or ‘Minimal invasive surgery’ or ‘Laparoscopic surgery’ or ‘Keyhole surgery’ and 226 different steroid hormones and randomized controlled trial S1. The search strategy did not include language or date restrictions S1, S2, S3. Three authors (KK, SHK, FFL) independently screened the included publications in COVIDENCE, first as titles and abstracts, later in full text for true randomization and double-blind evaluation, the surgery involved, and the end points (Fig.  1 ). While most excluded studies were thematic irrelevant (85%), those remaining for full-text scrutinizing 37% were either not yet started or finished, had no full text or not a randomized or comparative trial. Papers written with non-Latin letters were also excluded ( n  = 3). Discrepancies in evaluation of the trials were resolved by majority vote among the evaluators. One particular study was excluded because of the public concern about the validity of their data and the recommendation to exclude their work from further scientific consideration [ 14 – 18 ]. After ensuring thematic relevance, contents and design, only those papers dealing with randomized comparative trials with steroids left us with just 44 papers, which were then examined for inflammatory response in general i.e. any inflammation cell studies, secretory products and in particular CRP [ 12 ]. Only seven of the 44 reported on any paraclinical variables associated with inflammation and, thus, surgical stress. Risk of bias was assessed according to the RoB 2 principles (Table  1 ) [ 19 ]. Fig. 1 PRISMA flow chart of reviewed and included studies PRISMA flow chart of reviewed and included studies Table 1 Quality assessment of included studies Author/year Randomization process Deviations from intended interventions Missing outcome data Measurement of the outcome Selection of the reported results Overall RoB Bisgaard 2003 [ 20 ] green green green green green green Sistla 2009 [ 1 ] green green green green green green Viriyaroj 2015 [ 21 ] yellow yellow green green green yellow Barden 2020 [ 22 ] yellow green green green green yellow Schietroma 2010 [ 23 ] green green green green green green Corcoran 2017 [ 24 ] green green green green green green Ionescu 2014 [ 25 ] green green green green green green Green: Low risk of bias; yellow: Some concerns Quality assessment of included studies Green: Low risk of bias; yellow: Some concerns

In total, 588 references were imported for screening and 123 duplicates were removed (Fig.  1 ). Four hundred and sixty five studies were screened by title and abstract of which 394 studies were excluded due to thematic irrelevance, leaving 71 studies to be assessed for eligibility by full text screening. Of these, 26 were excluded either because they were protocol studies ( n  = 8), were not full-text ( n  = 6), did not include laparoscopic procedures ( n  = 3), were not written with Latin characters ( n  = 3, language), add-on dexamethasone (not compared with placebo, n  = 2), were not randomized trials ( n  = 3), publicly raised validity concerns ( n  = 1) or were retracted ( n  = 1). Of the remaining 44 studies, seven reported on inflammatory response outcomes by presenting CRP, neutrophils, interleukins or cell adhesion molecules [ 1 , 20 – 23 , 25 ]. One of these reports had incorporated data from one of the other studies [ 14 ]. The intervention in all seven included studies was a single administration of dexamethasone in two trials 60–90 min before and after the induction of the anesthesia in the remaining five. No further administration was reported. Due to differences in measured outcomes and the low number of studies, no meta-analysis was performed. Too few studies had inflammatory response or surgical stress indicators as their primary outcomes, and among those that reported on CRP, the data could not be combined due to incomplete and heterogeneous reporting. Additionally, the studies included 71% women and the types of surgery varied; one study combined results from abdominal surgery with those from breast surgery [ 22 ]. Although CRP was the most commonly reported outcome, three of the seven included studies used other inflammatory measurements as their outcomes [ 22 , 24 , 26 ]. The trials provided moderate to good quality evidence on postoperative nausea and vomiting. The most common secondary outcomes of the trials were generally classified as having low risk of bias (green rating), while two studies received yellow ratings according to the RoB 2 tool (Table  1 ) [ 21 , 22 ]. These two studies had issues with randomization, and one of them deviated from the intended interventions [ 25 ]. Among the seven included studies, the most frequent type of surgery was cholecystectomy ( n  = 4). The studies included mixed-gender populations, except for those focused on gynecology [ 28 ] and breast surgery [ 22 ]; the latter, of course, was neither abdominal nor laparoscopic (Table  2 ). Most patients were between 40 and 60 years old, and severely obese individuals were not included. Blinding was not reported in one study where blood sampling was the primary outcome, and another study was single-blinded where postoperative nausea and vomiting were the trial’s primary outcomes (Table  2 ).The levels of CRP were 38–60% lower at 24 to 48 h postoperatively after administering 8 mg dexamethasone compared to placebo, most evidently in cholecystectomy surgery. Post-trial calculation indicated that the power of these studies ranged between 60% and 95% (Table  3 ). None of the studies reported administering any steroids in the postoperative period as a routine, nor did they mention using them as a supplementary treatment for postoperative nausea and vomiting. No adverse effect of dexamethasone on postoperative infectious complications or other adverse effects was seen. As for the studies reporting on blood cells and their role in cell adhesion involved in inflammation, they showed an increase in neutrophils and an attenuated decline in lymphocytes with dexamethasone. This reduction was not associated to any clinical outcomes [ 22 , 24 ,  26 ]. Table 2 Included randomized trials on dexamethasone in laparoscopic surgery with inflammatory response reported Author/year/country All pts/ no. of ♀ Inclusions criteria/age/body weight Dexa dose at time preop Operation type Primary/secondary outcome Blinding Randomi-zation Fast track surgery/discharge time Sistla 2009, India [ 1 ] 70/53 Consecutive/40 ± 12 yrs/58 ± 12 kg 8 mg, 90 min Cholecystectomy Less pain, better PEFR/ CRP ↓60% at 24 and 48 h DB, prep by ward nurse Sealed envelope No/48 h Bisgaard 2003, Denmark [ 20 ] 80/60 ASA 1 + 2,/43 yrs (22–72)/26 (20–41) kg/m 2 8 mg, 90 min Cholecystectomy less pain & PONV/ CRP ↓38% at 24 h DB prep by nurse Computer generated 24 h Viriyaroj 2015, Thailand [ 21 ] 80/0 ASA 1 + 2,/ 50 ± 14 yrs/ no data 8 mg, 60–90 min Cholecystectomy Less PONV/ CRP ↓40% at 24 h Single blinded Sealed envelope 24 h Schietroma 2010, Italy [ 23 ] 82/82 ASA 1 + 2/48 yrs (25–67)/no data 8 mg, 90 min Nissen fundoplication Less pain and fatigue/ CRP ↓63% at 48 h, IL-1 and − 6 lower at 6 h DB prep by 3rd party nurse Sealed envelope No/no data Corcoran 2017, Australia [ 24 ] 32/32 ASA 1 + 2/45 yrs (40–48)/27 (21–35) kg/m 2 4 mg, after anesthesia induction Major gynecological (> 90 min) a) Neutrophils, biochemistry: ND/ CRP ↓48% at 24 h, innate immune cells ND DB, prep by 3rd party Computer generated No/48 h Barden 2020 Australia; see Corcoran [ 22 ] 51 + 31 51 pts ASA 1 + 2 + 3/53 yrs, (44–51)/30 (24–37)kg/m 2 +31 pts 45 yrs (40–48)/27 (21–35)kg/m 2 4 or 8 mg, after anesthesia induction Breast reconstruction + Mixed gynecological Specialized lipid mediators of inflammation resolution: ND DB, refers to Corcoran Refers to Corcoran No/48 h Ionescu 2011, Romania [ 26 ] 42/25 ASA 1 + 2/53 ± 14/78 ± 10 kg 4 mg before induction of anesthesia Cholecystectomy IL-6 and − 8 decreased 2 h after surgery/Adhesion molecules slCAM-1 lower No blinding recorded Computer generated 24 h Age and body weight are given as mean ± SD or median (range), a) Hysterectomy ± oophorectomy, salpingectomy, excision of endometriosis ♀ : Women, CRP  C-reactive protein, Dexa  dexamethasone, DB  double blinded, dif  difference, lap  laparoscopy, ND  no difference, PEFR  Peak expiratory flow rate, PONV  Postoperative nausea and vomiting, preop  preoperatively, pts.  patients, yrs  years Included randomized trials on dexamethasone in laparoscopic surgery with inflammatory response reported Age and body weight are given as mean ± SD or median (range), a) Hysterectomy ± oophorectomy, salpingectomy, excision of endometriosis ♀ : Women, CRP  C-reactive protein, Dexa  dexamethasone, DB  double blinded, dif  difference, lap  laparoscopy, ND  no difference, PEFR  Peak expiratory flow rate, PONV  Postoperative nausea and vomiting, preop  preoperatively, pts.  patients, yrs  years Table 3 Post-trial power calculation Author/year/country No. of ♀ dexa + placebo Dexa dose (mg) Variable Outcome measurement Power % Bisgaard, 2003, Denmark [ 20 ] 40 + 40 8 CRP At 24 h (mg/l) 85 Sistla, 2009, India [ 1 ] 36 + 34 8 CRP At 24 h and 48 h (µg/ml) 95 and 95 Schietroma, 2010, Italy [ 23 ] 39 + 39 8 CRP, IL-1 At 48 h mg/dl, at 6 h pg/ml 95, 95 Viriyaroj, 2015, Thailand [ 21 ] 40 + 40 8 CRP At 24 h (mg/l) 65 Corcoran, 2017, Australia [ 24 ] 16 + 15 4 CRP Δ mg/l 60 Barden, 2020 Australia; see Corcoran [ 22 ] 17 + 17 4 17-HDHA Δpg/ml 65 Ionescu, 2011, Romania [ 26 ] 21 + 21 4 sICAM-1, sVCAM-1 Area under the curve 30, 45 Δ: Indicating differences from baseline were compared, ♀: Women CRP  C-reactive protein, dexa  Dexamethasone, HDHA  Hydroxydocosahexaenoic acid, power  The probability of rejecting a false null hypothesis, sICAM  Solubale intracellular cell adhesion molecules, sVCAM  Solubale vascular cell adhesion molecules Post-trial power calculation Δ: Indicating differences from baseline were compared, ♀: Women CRP  C-reactive protein, dexa  Dexamethasone, HDHA  Hydroxydocosahexaenoic acid, power  The probability of rejecting a false null hypothesis, sICAM  Solubale intracellular cell adhesion molecules, sVCAM  Solubale vascular cell adhesion molecules

Our main finding is an effect of dexamethasone on CRP but with several caveats in the interpretation as an indicator of surgical stress response. The advantage of using CRP is its relative ease, so one may wonder why just five of 44 randomized trials (11%) reported on this in laparoscopic abdominal surgery on benign indications. We point to this as an objective method to measure regimens that aim to improve postoperative recovery in a short perspective. The humoral immune response to surgery, like interleukins and other inflammatory proteins, could be detected as early as 6 h and up to 24 h postoperative and was suppressed by dexamethasone in three randomized trial. However, these inflammatory markers are not readily available [ 24 – 27 ]. The benefit of using dexamethasone was reported previously to expedite discharge after laparoscopic surgery, thereby enabling true fast-track regimens [ 2 ]. This benefit, however, was most likely due to a reduction of postoperative nausea, vomiting and fatigue [ 21 , 23 ]. Further, for long-term effects one needs to translate seemingly subtle biomedical changes into an understanding of the underlying mechanisms that improve recovery and postoperative infections following surgical trauma [ 20 , 24 ]. CRP is a general marker in this context and dexamethasone may be highly specific in modulating the inherent human response. This effect is related to the anti-inflammatory action, edema reduction, or shrinkage of connective tissue, as demonstrated even in the effects of epidural steroids [ 22 , 28 ]. The innate immune systems may play a key role for this, too [ 20 , 24 ]. Improving surgical outcomes by minimizing side effects is of utmost importance for patients. However, the trials included lack a sufficient number of patients, adequate power to detect events and observation data beyond the point of discharge. Furthermore, most of these studies focused on other primary outcomes, such as postoperative nausea and vomiting and did not aim to explore the underlying causes of discomfort besides of surgery. Apart from this they differed in laparoscopic surgeries between cholecystectomy ( n  = 4), fondoplication and mixed gynecological surgery and the latter even with breast reconstruction mixed in. Schietroma et al. found in the dexamethasone group reduced levels of CRP, IL-1 and IL-6 as well as lower fatigue scores leading them to conclude that fatigue might be linked to the short-term inflammatory response associated with surgery. This is supported by findings of increased fatigue and reduced sleep following IL-6 infusion in human volunteers [ 29 ]. Dexamethasone has the potential to reduce tissue damage by diminishing the inflammatory response triggered by surgery [ 20 , 24 , 26 ]. Dexamethasone also exerts immunosuppressive effects by modulating immune cell activity and reducing the release of pro-inflammatory cytokines. This mechanism is relevant as it may help lower the risk of infection, adhesion formation, and delayed wound healing. Additionally, identifying targets to reduce the stress response to surgery could potentially lead to further medically induced benefits. Even minimally invasive procedures trigger inflammatory responses, which include a rise in specific inflammatory biomarkers such as CRP, serum amyloid A and fibrinogen. Shear stress and vascular injury initiate the inflammatory process by stimulating the production of pro-inflammatory molecules and activating circulating monocytes [ 14 ]. Future studies should focus on understanding the pathophysiology of the inflammatory response associated with surgical procedures, as well as identifying predictors, risk factors, preventive strategies and therapeutic approaches. While the potential role of anti-inflammatory drugs after certain procedures has been noticed, further validation is needed. Radak et al. suggest using the neutrophil to lymphocyte ratio, platelet count, platelet to lymphocyte ratio and other biomarkers to assess the inflammatory response, which could serve as targets for additional adjuvant treatments [ 14 ]. Glucocorticoids have complex effects on the cellular components of the immune system [ 30 ]. While they induce apoptosis in the treatment of certain malignancies, they also prolong the survival of neutrophils through an anti-apoptotic effect [ 31 , 32 ]. Dexamethasone appears to balance the effects of acute inflammation and its resolution. However, there are concerns that these effects during the perioperative period might increase the risk of infections. The included studies did not provide sufficient data on the side effects of dexamethasone or such reports were too rare to draw safe conclusions. Nevertheless, meta-analyses focusing on potential side effects found no increase in infection rates, delayed healing, glucose intolerance, or adrenal suppression with the use of dexamethasone or methylprednisolone, even at high doses [ 33 – 36 ]. The meta-analysis of the included studies would only include three of the studies as they used similar dosage, measurements and time points in laparoscopic cholecystectomy (Table  3 ). They show unanimously a positive effect by lowering CRP each with a power of 65–95%. However, all infused dexamethasone up to 90 min before anesthesia. If the patient was awake when dexamethasone was provided, the patient and the health personnel could therefore notice the rush; thus, compromising the blinding altogether. The effect on CRP duly showed after 24–48 h, which is credible in the cascade and stereotypical way the surgical stress parameters work [ 12 ]. The other studies reported CRP as differences from baseline, cytokines and area under the curve; noticeable, some were blinded sufficiently so the medicine was given after anesthesia induction. While this review is clear on laparoscopic cholecystectomy and the measurements on follow-up on surgical stress, the studies with mixed gynecological surgery and breast reconstruction were not so clear. For one, the exact mixture of surgery was not detailed and may have blurred the results, at least in comparison to cholecystectomy. Then, the lower dose did not provide an unanimous response that one may speculate in whether it was underpowered, too, by intervention dose and numbers of participants. We acknowledge that the mixture of surgical procedures blur the overall picture as it certainly will provide different surgical stress and variation in outcomes but presumably not change the direction of measured effects. In line with the latter, we conclude that the minor dose of 4 mg may be the explanation for the low power of these studies and strengthen the arguments for a dose-response effect of dexamethasone on surgical stress parameters like CRP. This review focusses on the estimation of surgical stress by different markers and not on differences in surgery. We found no indications that the included studies made sample size calculations before the randomized trial but most had chosen CRP due its simplicity and associations with an inherent character of stress cascade reactions irrespective of its origins. This was the main reason for us to perform a post-hoc power calculation within each individual study as the results in a meta-analysis was deemed meaningless and confusing (Table  3 ). Thus, we acknowledge that the low numbers in each study is an issue for now but can improve when further studies are published. Moreover, we may even restrict our conclusion to be valid for women only, as the majority of included patients were female. Similarly, CRP is a crude proxy end-point that need further qualification on which point in the stress cascade to intervene meaningfully. There is, however, a weakness inherent in the systematic quality assessment in the protocolled manner: The blinding has to be stated and not to referred to other publications, i.e. this automatically gives a ‘yellow’ rating of Barden et al. who refers to Corcoran et al. for further reading and some patients are reported in both publication (Table  1 ). The blinding itself may be compromised by individual biological reactions (in this case ‘rush after dexamethasone’) and observations to the interventions, but the grading does not necessarily include this. These cases, therefore, received a rating of ‘green’, as it uncertain whether the rush was observed, felt or ever happened. We found that surgeries designed for fast-track regimens are not always organized in a way, which yields outcomes of clinical relevance for the patient. As a result, when reporting benefits, the vast majority of the included studies focused on dexamethasone’s effect on postoperative nausea and vomiting. While this outcome is well-established, various factors involved in the organization of an operation - ranging from initial patient information and medication strategies to surgical techniques and postoperative care - all contribute to reducing risk. It is worth mentioning that improved well-being, characterized by the absence of nausea and vomiting, can also result in less pain and greater comfort [ 37 , 38 ]. Multimodal strategies for perioperative treatment are not consistently applied within fast-track regimens, even though approaches such as analgesia have shown their effectiveness in minimally invasive surgery. Additionally, cost-benefit analyses often do not align when considering efficacy and safety from the perspectives of both patients and healthcare systems. In conclusion our review suggests a reduction of surgical stress, as indicated by CRP, by adding dexamethasone in laparoscopic abdominal surgery.

Minimally invasive surgery has revolutionized the field of surgical interventions. Laparoscopic procedures have gained widespread popularity across various surgical specialties due to their numerous advantages such as reduced postoperative pain, faster recovery, and shorter hospital stays. As the demand for minimally invasive techniques continues to rise, there is a constant quest to optimize outcomes and improve patient experiences. However, the use of potential pharmacologic modifiers of stress response in minimal invasive surgery is not yet fully supported by clinical evidence. Moreover, their impact on pain relief, respiratory functions and recovery remains unclear [ 1 ]. Dexamethasone, a synthetic glucocorticoid, and its anti-inflammatory effects on allergic reactions, autoimmune disorders, and malignancies is well documented, which has prompted investigations into its potential benefits in surgical settings. Dexamethasone has emerged as a potential adjunct in the perioperative management of laparoscopic surgery. It may help mitigate tissue damage, reduce postoperative pain, and speed up recovery by dampening the inflammatory reaction triggered by surgery. Additionally, dexamethasone has immunosuppressive properties, modulating immune cell activity and decreasing the release of pro-inflammatory cytokines. This effect is relevant as it may help reduce the risk of infection, adhesion formation, and delayed wound healing. Given the potential benefits, numerous studies have investigated the use of dexamethasone in the context of laparoscopic surgery [ 2 – 5 ]. These studies have explored various aspects, including the optimal dosage, timing of administration, and potential adverse effects associated with dexamethasone use. However, the current literature on this topic is extensive and sometimes conflicting, which is a challenge for clinicians to draw on clear conclusions. A systematic review examining the effects of dexamethasone administered after laparoscopic cholecystectomy found that its postoperative analgesic effects were inconclusive [ 6 ]. Moreover, these effects were examined only as a secondary outcome. The authors concluded that dexamethasone is not recommended for postoperative pain relief, as the optimal dose to reduce pain remains uncertain when used as part of a multimodal drug strategy to manage postsurgical pain. Similarly, the conclusions on the effects and clinical implications of perioperative dexamethasone administration were hindered by variability in surgical procedures. Nevertheless, adjunct agents like ketamine, gabapentin, paracetamol, and nonsteroidal anti-inflammatory drugs was effective in multimodal analgesic approaches, as shown in systematic reviews that demonstrated their benefits in reducing postoperative pain and/or opioid consumption [ 7 – 11 ]. Surgical injury causes a cascade of neuroendocrine, cytokine, acute phase and metabolic responses. Within minutes, the sympathetic nervous system is activated, by adrenaline and noradrenaline leading to tachycardia, hypertension, fever and tachypnea. Concomitantly corticotrophin, growth hormone, and vasopressin are released, stimulating cortisol secretion and affecting the kidney and fluid balance. Then, pro-inflammatory cytokines are released in response to injury and form a complex signaling system for subsequent production of acute phase proteins (in particular c-reactive protein (CRP) from the liver) and increased white cell count and platelets. A review evaluating these various clinical markers of the systemic inflammatory response in surgery concluded that only CRP and interleukin-6 (IL-6) were associated with the extent of surgical injury [ 12 ]. As IL-6 is not routinely measured outside research milieus, CRP is the most common marker used as an objective measure in enhanced recovery after surgery for improved patient outcome. However, no review has previously explored the potential benefit of reducing surgical stress in terms of outcomes such CRP and other inflammatory markers. We address this gap by providing a review focused on the effects of dexamethasone on surgical stress markers in laparoscopic abdominal surgery.

Supplementary Material 1. Search text. Supplementary Material 2. MESH word search. Supplementary Material 3. Assessment of risk of bias. Supplementary Material 1. Search text. Supplementary Material 2. MESH word search. Supplementary Material 3. Assessment of risk of bias.