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Abstract

Objective

The repercussions of ischemia-reperfusion and inflammatory response to surgical injury may compromise the return of physiologic processes in video-laparoscopic surgeries. Dexmedetomidine, as an adjuvant drug in general anesthesia, alters the neuroinflammatory reaction, provides better clinical outcomes in the perioperative period, and may reduce the excessive use of chronic medication in patients with a history of addiction. This study evaluated the immunomodulatory potential of dexmedetomidine on perioperative organ function in video-laparoscopic cholecystectomy patients.

Methods

There were two groups: Sevoflurane and Dexmedetomidine A (26 patients) vs. Sevoflurane and Saline 0.9% B (26 patients). Three blood samples were collected three times: 1) before surgery, 2) 4–6h after surgery, and 3) 24h postoperatively. Inflammatory and endocrine mediators were protocolized for analysis. Finally, hemodynamic outcomes, quality upon awakening, pain, postoperative nausea and vomiting, and opioid use were compared between groups.

Results

We have demonstrated a reduction of Interleukin 6 six hours after surgery in group A: 34.10 (IQR 13.88–56.15) vs. 65.79 (IQR 23.13–104.97; p = 0.0425) in group B. Systolic blood pressure, diastolic blood pressure, and mean arterial pressure was attenuated in group A in their measurement intervals (p < 0.0001). There was a lower incidence of pain and opioid consumption in the first postoperative hour favoring this group (p < 0.0001). We noticed better quality upon awakening after the intervention when comparing the values of peripheral oxygen saturation and respiratory rate.

Conclusions

Dexmedetomidine provided anti-inflammatory benefits and contributed to postoperative analgesia without the depressive side effects on the respiratory and cardiovascular systems commonly observed with opioids.

Trial Registration

Immunomodulatory Effect of Dexmedetomidine as an Adjuvant Drug in Laparoscopic Cholecystectomies, NCT05489900, Registered 5 August 2022—Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT05489900?term=NCT05489900&draw=2&rank=1

Keywords

cholecystectomy laparoscopic immunomodulation dexmedetomidine

Introduction

The adrenergic tone on the immune system determines endocrine-metabolic changes and demonstrates the intercommunication between the neural, glandular effector and immune systems.¹ Although immunosuppression in the perioperative period may increase the risk of infections, the anti-inflammatory effects of some medications may promote benefits in controlling SIRS and imply a favorable immediate postoperative outcome and early hospital discharge.²

The abuse of opioids has become a worldwide public health crisis. Between 2001 and 2006, opioid-related deaths in the United States increased by 345%. Therefore, its controlled use in the postoperative period is of paramount importance.³

Analgesic properties of dexmedetomidine can be attributed to its spinal, supraspinal, and peripheral actions. By acting on alpha-2 adrenergic receptors, mainly on alpha2A subtypes, it promotes neuronal hyperpolarization and reduction of calcium channel activation. It contributes to the decrease of hyperalgesia and allodynia, modulating the maintenance mechanism of chronic pain.⁴

Innate immunity cells are capable of expressing alpha-2 adrenoreceptors on their cell membrane. Blocking adrenergic tone on effector tissues can contribute to the modulation of cytokine production by lymphocytes, macrophages, and monocytes during the stress response and reductions in serum levels of pro-inflammatory cytokines such as IL-6, IL-8, and TNF-α throughout up to 24 h after surgery. The control of immune and inflammatory reactions, with fine tuning between pro- and anti-inflammatory cytokines, is essential to minimize significant pathological damage in various settings such as trauma and cancer.⁵

Several studies have demonstrated the efficacy of dexmedetomidine in controlling postoperative pain. It is associated with improved quality of postoperative recovery and reduced opioid consumption in the immediate postoperative period. These factors make dexmedetomidine an attractive agent for enhanced recovery in surgery (ERAS) protocols and for patients with acute and chronic pain.^6–9 It is further considered in pain management as a strategy to decrease opioid use/abuse and as an adjuvant with other drugs in regional peripheral and neuroaxis blocks to increase analgesic duration.^10–12

The infusion dose was standardized and titration was individualized for the intended clinical objective. This research describes a model of an inflammatory response to surgical injury to evaluate the clinical benefits of the anesthetic-surgical practice of dexmedetomidine administration.

Methods

All surgeries were performed at Gaffrée e Guinle University Hospital, Federal University of the State of Rio de Janeiro (UNIRIO). The Departments of Surgery and Anesthesiology are accredited by the Federal Ministry of Education and the Brazilian Society of Anesthesiology. Patients underwent general anesthesia. The study was conducted after approval by the Ethics and Research Committee of the mentioned hospital in December 2021 with CAAE n° 50,311,621.0.0000.

Sample selection

Patients of both genders aged 18 to 70 years were scheduled for elective laparoscopic cholecystectomy surgery if classified as ASA 1 or 2. Patients consented by signing an informed consent form. Inclusion criteria were symptomatic cholelithiasis refractory to medical and non-surgical care. Exclusion criteria included excessive surgical trauma, for example, when patients scheduled for the laparoscopic procedure had to be converted to open surgery. Additional exclusion criteria were surgery duration greater than 3 hours, patients using illicit drugs and drugs that induce the cytochrome complex P450, patients with renal and hepatic failure, chronic users of corticoids and non-steroidal anti-inflammatory drugs, body mass index (BMI) greater than or equal to 40, heart failure, valvular or ischemic heart disease, and use of tricyclic antidepressants.

Fifty-nine patients were enrolled in the study, but seven were excluded: two patients due to surgery lasting longer than 3 hours, two due to conversion to open surgery, and three due to BMI greater than 40. Computer-generated numbers did randomization. These codes were placed in sealed and numbered envelopes, drawn before the infusion of the solution by the surgeon. The patient was unaware of whether he belonged to the intervention or control group, and codes replaced the participants' registration data to preserve personal information.

Ultimately, 52 patients were eligible, divided into two groups: Sevoflurane and Dexmedetomidine group (n = 26) A vs. Sevoflurane and Saline 0.9% group (n = 26) B. Figure 1

Figure 1.

CONSORT flow diagram.

Standardization of the Anesthetic technique

All patients were connected to standard monitoring recommended by ASA. The attending anesthesiologist recorded the relevant hemodynamic and ventilatory data during the surgical procedure. A 20G BD® peripheral venous access was established for anesthesia and blood sample collection. Group A patients received an initial dose of dexmedetomidine 1 mcg/kg/h for 20 min, followed by 0.3–0.5 mcg/kg/h until surgical closure. Group B patients received 0.9% saline solution until surgical closure. Prophylactic antibiotic: cefazolin 2 g venous was given. The anesthesia protocol included 160 mg propofol, 350 mcg of fentanyl (single dose), 10 mg of cisatracurium on induction, and additional doses according to neuromuscular function monitoring by TOF (equal to zero during surgery). Lidocaine 2% 100 mg was administered for induction, and inhalational sevoflurane was used for anesthetic maintenance at 0.8–1 minimum alveolar concentration (MAC). The dexmedetomidine solution or placebo was turned off at the end of the surgical closure. Ketoprofen 100 mg and dipyrone 3 g were administered intravenously for analgesia during surgery. For prevention of nausea and vomiting, we used ondansetron 8 mg intravenous. During the reversal of the neuromuscular blockade, neostigmine was administered 2 mg and atropine 1 mg IV. We did not use additional doses of opioids intraoperatively. Patients were extubated in the recovery room when the neuromuscular function was reestablished (TOF > 90%), sevoflurane below 0.3 MAC, and tidal volume above 6 mL/Kg. Patients were monitored in the postanesthesia care unit (PACU) and were admitted to the hospital after they were rated according to the modified Aldrete–Kroulik scale¹³ > 9.

Postoperative pain was evaluated by the analog visual pain scale (VAS),¹⁴ where 0 represents the individual without pain and 10 represents the most severe pain. The recorded values were divided into the following pain categories: No pain -0; Light -1 to 3; Moderate -4 to 6; Severe -7 to 10. In the post-anesthetic recovery room, analgesia was complemented with morphine, if necessary, at 0.05 mg/kg if moderate to severe pain. Sample 2 was collected 4–6 hours after the end of the surgery, and sample 3 was collected 24 h after it, before hospital discharge. Patients stayed in the hospital for an average of 24–36 h.

Laboratorial analysis

We measured interleukin-6 (IL-6), cortisol, C-reactive protein, and glycemia in all venous blood samples. The samples were centrifuged at 2000 rpm for 15 min and stored in the biorepository at –80°C in cryotubes in the Immunology and AIDS Research Laboratory at the University Hospital. The measurement of results was performed at the Laboratório do Programa Nacional de Controle de Qualidade (PNCQ) in Rio de Janeiro after six months after the beginning of data collection. For analysis of immunomodulators, serum concentration of IL-6 was determined by electrochemiluminescence immunoassay using the Roche Cobas e411® immunoassay analyzer. The sample was incubated with a specific anti-IL-6 monoclonal antibody labeled with a ruthenium complex and microparticles coated with streptavidin, forming a sandwich complex with the sample antigen. The microparticles were magnetically attached to the surface of an electrode that received an electrical current inducing a chemiluminescent emission, which was measured by a photomultiplier. Results were determined based on a calibration curve explicitly generated by the analyzer.

The serum concentration of CRP was determined by a Roche® immunoturbidimetric assay using the Bioclin 3000 automated analyzer.

Blood glucose values were determined by colorimetric enzymatic assay—GOD–PAP (Trinder) Roche®, using the automatic analyzer Bioclin 3000.

The serum cortisol concentration was determined by chemiluminescence immunoassay (CLIA) Roche®, using the Abbott Architect i1000 immunoassay analyzer.

Organic function

The Return to Spontaneous Ventilation Test¹⁵ evaluated the indirect assessment of lung function before extubation with analysis of current volume values, respiratory rate (RR), peripheral oxygen saturation (SpO2), and expired carbon dioxide fraction. Data were recorded when the exhaled fraction of sevoflurane reached values less than or equal to 0.3 MAC, and patients started spontaneous breathing before extubation. This spontaneous breathing trial is a valuable marker in predicting successful weaning from mechanical ventilation, along with other indexes.¹⁶ However, physicians always incorporate other factors, such as expert clinical judgment, into the final extubation decision.

Bolus schemes assessed requests for amines in the perioperative period according to the frequency of ephedrine use among the groups (Table 2). Hemodynamic changes between the two groups were compared through statistical changes in heart rate (HR), systolic blood pressure (SBP), and diastolic blood pressure (DBP). Baseline values were recorded at the first measurement before drug infusion at 0'. The following values were measured 25 min after induction of anesthesia comprising the infusion, surgical period, and 15 min after extubation (Figure 3).

Riker Sedation–Agitation Scale¹⁷ was applied immediately upon awakening from surgery. It's a tool for measuring the degree of agitation and delirium from a fully sedative state to a highly agitated state. Riker Scale is divided into seven levels, ranging from 1 to 7, with higher scores indicating more significant agitation.

Two factors evaluated the quality of analgesia: the amount of opioid (morphine) used 1 h, 6 h, and 24h after awakening in the anesthetic recovery room on a "yes" or "no" and the gradation of pain measured by AVS at these times after extubation. The incidence of nausea and vomiting was also observed in this period between the groups.

Statistical analysis

Data collection for the study was carried out for six months, obtaining information from 52 patients, assuming equal sizes for the two groups of patients. The sample size was calculated to compare means and proportions between the groups relative to the variables researched, with a statistical power of 80% and a significance level of 5% (p = 0.05).

In evaluating the variables involved in organ function and systemic inflammatory response (SIR), we used the software R version 4.0.3 for data processing. Kolmogorov–Smirnov¹⁸ test did not provide evidence that the variables had a normal distribution. The Chi-square test was used for comparing frequencies and qualitative variables. Means of quantitative variables were compared and tested for significant differences using the Mann-Whitney test.

Results

The demographic and clinical characteristics of the patients included in the study are shown in Table 1, and the results of the non-demographic variables are contained in Table 2. The groups were equivalent for age, sex, height, weight, BMI, comorbidities, and surgical indication.

Table 1.

Demographics and clinical data.

	Control (n = 26)	Intervention (n = 26)	p-value
Sex (Male/Female)	8/18	6/20	0,7546
Age (years)	57,5 (43,3–63)	48 (42,3–60)	0,3598
Height (cm)	162,5 (159–170,2)	164,5 (160,3–169,8)	0,6535
Weight (kg)	71,5 (65,8–79,8)	76 (68–90)	0,3993
BMI (kg/m²)	26,6 (55,5–29,4)	29,9 (24,1–31,6)	0,6049
ASA Status (I/II)	8/18	7/19	1
Surgical indication (biliary polyposis/biliary lithiasis)	2/24	1/25	1
Dose of dexmedetomidine (mcg)	0	120,5 (93 – 159)	-

ASA=American Society of Anesthesiologists/BMI= Body Mass Index.

Table 2.

Results from hypothesis tests for the non-demographic variables of the study.

Inflammatory biomarkers
	Control (n = 26)	Intervention (n = 26)	p-value
IL-6
0 h	1,68 (1,50–2,3)	2,05 (1,50–4,88)	0,2090
6 h	65,79 (23,13–104,97)	34,10 (13,88–56,15)	0,0425
24 h	23,59 (15,18–41,27)	23,20 (7,65–53,23)	0,9149
Cortisol
0 h	10,71 (5,70–16,10)	10,11 (6,83–15,00)	0,8489
6 h	23,18 (14,66–21,61)	20,70 (12,99–27,96)	0,6565
24 h	11,84 (6,65–16,31)	10,97 (6,94–15,66)	0,8852
C reactive protein
0 h	1,55 (1,03–3,13)	4,10 (1,85–13,05)	0,0067
6 h	3,00 (1,63–6,20)	7,30 (3,63–15,45)	0,0075
24 h	36,15 (19,48–52,45)	39,95 (24,05–57,27)	0,6481
Glycemia
0 h	89,00 (83,50–95,75)	79,50 (70,75–86,75)	0,0255
6 h	109,5 (91–126)	106 (97,5–121,2)	1
24 h	106 (96–120,8)	110,5 (93,5–122,5)	0,9535

Perioperative outcome
	Control (n = 26)	Intervention (n = 26)	p-value
Opioide (yes/no)	18/8	2/24	<0,0001
Nausea and vomiting (yes/no)
1 h	8/18	3/23	0,1744
6 h	0/26	0/26	1
24 h	1/25	0/26	1
Ephedrine (yes/no)	3/23	8/18	0,1744
Dose of ephedrine (5 mg induction/10 mg induction/20 mg induction/10mg induction + 10mg maintenance)	2/1/0/0	1/5/1/1	0,329
Postoperative pain (No pain/Slight/Moderate/Severe)
1 h	2/4/10/10	18/5/3/0	<0,0001
6 h	7/12/7/0	9/13/3/1	0,4089
24 h	11/14/1/0	14/11/1/0	0,6977

Spontaneous ventilation return/Riker Scale
	Control (n = 26)	Intervention (n = 26)	p-value
RR	14,50 (12–15)	15 (14–18)	0,0361
TV(ML)	395,0 (375,0–427,5)	387,0 (345–398,5)	0,1325
EFCO2	40 (38–44)	40 (39–44)	0,5361
SpO2	0,97 (0,96–0,98)	0,995 (0,98–1)	0,0002
RICKER	4 (4–4)	4 (4–4)	0,0930

IL-6 - Interleukin-6. Reported measurement units: IL-6 pg/mL; RCP mg/L; glycemia mg/dL; cortisol mcg/dL.

RF= Respiratory Rate/TV= Tidal Volume/EFCO2= expired fraction of carbon dioxide.

Surgical time was similar between groups, lasting less than 3 hours. The incidence of nausea and vomiting was higher in the B group but without reaching statistical significance. Pain and opioid use were higher in the first hour after surgery in the control group. None of the patients developed bradycardia or significant hemodynamic instability requiring suspension of medication infusion in the intraoperative period.

A buffering for IL-6 at 4–6 hours after surgery was found in the intervention group, demonstrating the biological effect of alpha-2 blockade on immune response with statistical significance B [65.79 (IQR 23.13–104.97)] vs. A [34.10 (IQR 13.88–56.15)] p = 0.0425. (Figure 2)

Figure 2.

Boxplot & Graph from the variable IL-6. *Note that the median, represented by the central line of each of the boxplots, at 4–6 hours after surgery, showed more distant values between the control and intervention groups than for the other periods recorded. At the 5% significance level, there was a statistical difference between the groups. #Values observed by each patient for IL-6 for each measurement time between groups.

There was no difference between the groups when serum cortisol and blood glucose levels were compared postoperatively (Table 2). The CRP elevation remained postoperatively in both groups, and results indicated that the intervention with dexmedetomidine alone was not enough to change the endocrine response to surgical trauma.

Hemodynamic variables SBP, DBP, and HR were measured before the procedure (time 0), at induction of anesthesia, during surgery, and upon awakening. As shown in Figure 3, the patients that received the intervention obtained lower blood pressure values, corroborating the sympatholytic effect of dexmedetomidine, with p< 0.0001 from induction to awakening.

Figure 3.

Hemodynamic data.

The administered doses did not cause significant hypotension and bradycardia to the point that the need to stop its infusion occurred. The groups had no statistical difference in ephedrine use (p = 0.329).

The p-values calculated using the Chi-square test for operative outcome variables were significant for opioid necessity and category of postoperative pain 1 h after the procedure. Figure 4 shows the frequencies of measurements for each postoperative pain category that the patient reported between the groups. For the 1 h time, the groups showed a statistical difference in opioid consumption (p< .0001) and pain score (p< .0001) with lower opioid use and lower pain scores in group A( Table 2). There was no difference between the groups for the 4 h and 24 h times.

Figure 4.

Graphs of the incidence of postoperative pain.

The incidence of nausea and vomiting didn’t reach a statistical difference between the groups 1 h, 4 h, and 24h in the postoperative period (Table 2).

During extubation, the analysis of the return to spontaneous ventilation was performed: the parameters RR, B = 14.50(IQR 12–15) vs. A = 15(IQR 14–18) p = 0.0361 and SpO2, B = 0.97 (IQR 0.96–0.98) vs. A = 0.995 (IQR 0.98–1) p = 0.0002 showed statistical relevance.

There was no difference in the scores of sedation and agitation by the Riker scale immediately after extubation between the groups (p = 0.0930). Most patients had a peaceful and collaborative awakening.

Discussion

IL-6 is a marker of the inflammatory response to surgical trauma that induces synthesis of acute phase reactants by the liver, stimulates neutrophil production in the bone marrow, and promotes differentiation of T helper cell producers of IL-17. Its serum increase directly reflects the magnitude of stress, as in sepsis, resulting in mitochondrial and endothelial dysfunction, implying increased morbidity and mortality. Decreasing IL-6 release may signify control of the surgical stress response.^19–22 We found a buffering in the graph for IL-6, 4–6 hours after surgery in the intervention group, demonstrating the biological effect of alpha-2 blockade on immune response with statistical significance B [65.79 (IQR 23.13–104.97)] vs. A [34.10 (IQR 13.88–56.15)] p = 0.0425.

CRP is an opsonin and activator of cells of the innate immune system, predominantly neutrophils, and has anti-inflammatory and pro-inflammatory properties. This marker is helpful in objectively assessing which components of enhanced recovery after surgery improve outcomes and evaluate the impact of the operative injury on immune function.²³ This study, in contrast, demonstrated that dexmedetomidine treatment alone was insufficient to attenuate postoperative CRP elevation.

Studies have shown that dexmedetomidine did not effectively protect stress hormones (epinephrine).^24,25 This observation may be due to its primary mechanism of action via hyperpolarization of noradrenergic neurons of the locus ceruleus, unlike other drugs.²⁶ However, combined with different adjuvants, such as propofol in a continuous infusion, it can effectively alleviate the stress response of patients undergoing laparoscopic cholecystectomy and potentiate the stabilization of perioperative hemodynamics^.27 Our results also indicated that intervention with dexmedetomidine as a single agent was insufficient to alter the endocrine response to surgical trauma.

Endocrine response control is an essential strategy for controlling postoperative outcomes after trauma. Metabolic and hydroelectrolytic changes resulting from the adrenergic response on the effector endocrine tissue can precipitate harmful events in the susceptible organism. Therefore, multimodal anesthesia, with strategic drugs with different mechanisms of action and regional blocks, is crucial when this goal is pursued.^28,29

The anti-inflammatory cholinergic pathway activation is a survival mechanism to attenuate sympathetic effects during surgical trauma. This vagal pathway suppresses local and systemic inflammation by inhibiting the release of pro-inflammatory mediators, including IL-1β, IL-18, and TNF-α.^30,31 Dexmedetomidine administration before induction of anesthesia, according to Bielka et al.,¹⁰ attenuated the stress response during intubation, pneumoperitoneum, and extubation, contributed to hemodynamic stabilization and reduced the incidence of reaction to the orotracheal tube during extubation. In our study SBP, DBP, and HR values were significantly lower in group A, emphasizing this sympatholytic effect³² (Figure 3).

Study demonstrated that its intraoperative administration during general anesthesia was superior to remifentanil administration, with lower pain scores during the first 24 h postoperatively and lower incidence of hypotension, chills, and PONV.³³ Its antinociceptive effects on somatic and visceral pain when administered via the neuraxial route have been observed, making it an option for use as an adjuvant in the neuroaxis, significantly decreasing postoperative pain intensity and prolonging analgesia.³⁴ For the 1 h time, the groups showed statistical differences in opioid consumption (p< 0.0001) and pain score (p < 0.0001) with less opioid use and lower pain scores in the intervention group (Table 2/Figure 4).

In our study, alpha2 adrenergic agonists showed no superiority over the control group for PONV. The literature highlights, however, a lower incidence of PONV when dexmedetomidine is used.³⁵

Unlike opioids or benzodiazepines, dexmedetomidine can be infused safely, aiming for adequate tracheal extubation. It can protect against adverse respiratory events in specific situations, such as awake craniotomy and intubation, without promoting residual sedation and respiratory depression.^36,37 Close to extubation, the parameters RR and SpO2 were similar between the groups but with lightly higher values in group A.

Dexmedetomidine administration is associated to shorter extubation time and duration of time on mechanical ventilation, and better quality upon awakening of patients, becoming more able to communicate than those who received benzodiazepines or opioids.³⁸ In the immediate postoperative period and upon awakening, there was no difference in the scores of sedation and agitation by the Riker scale immediately after extubation between the groups (p = 0.0930). Most patients awoke peacefully and collaboratively.

Selective and potent agonism to the α2-adrenergic receptor is responsible for these anxiolytic and sedative properties. Activation of supraspinal pre- and post-synaptic α2-adrenergic receptors in the locus coeruleus may influence endogenous sleep-promoting pathways, contributing to potent and effective sedative/analgesic effects.³⁹

Limitations

The study did not analyze the effects of different doses of dexmedetomidine on the dosages of anesthetics and analgesics during surgery. The use of opioids as an analgesic may affect the incidence of PONV, and we could not show whether there was a causal relationship in the small group that reported these symptoms. The sample size may have prevented achieving statistical differences for other variables analyzed.

Future perspectives

Multiple benefits in protecting specific organs and systems are being studied following the administration of dexmedetomidine. Reduction of oxidative stress markers in lung tissue, with attenuation of altered gene expression for mitochondrial fusion, and potential for inhibition of apoptosis, promotion of neurogenesis, and regulation of synaptic plasticity with increased tyrosine kinase B expression in nervous tissue are examples of the therapeutic application of selective alpha2 adrenergic agonist. Studies involving protecting other organs in injury situations are necessary for the scientific community, as they may provide therapeutic and care advances with decreased morbidity and clinical deterioration.

Conclusions

Activation of supraspinal pre- and post-synaptic α2-adrenergic receptors in the locus coeruleus may influence endogenous sleep-promoting pathways, contributing to potent and effective sedative/analgesic effects. The dexmedetomidine association with general anesthesia for laparoscopic cholecystectomy damped the inflammatory response by decreasing the release of IL-6, the primary pro-inflammatory mediator, in the immediate postoperative period. Highly selective alpha-2 agonists in the perioperative period provided analgesic and sympatholytic effects, with respiratory and cardiovascular safety.

Supplemental Material

Supplemental Material - Outcomes of dexmedetomidine as adjuvant drug in patients undergoing videolaparoscopic cholecystectomy: A randomized and prospective clinical trial

Supplemental Material for Outcomes of dexmedetomidine as adjuvant drug in patients undergoing videolaparoscopic cholecystectomy: A randomized and prospective clinical trial by Gustavo Nascimento Silva, Virna Guedes Brandão, Rossano Fiorelli, Marcelo Vaz Perez, Carolina Ribeiro Mello, Daniel Negrini, Kai-Uwe Levandrowski, Rafael Bof Martinelli, and Tatiana Pereira do Amaral dos Reis in International Journal of Immunopathology and Pharmacology

Ethical Statement

Ethical Approval

This Clinical Trial was approved by the Ethics and Research Committee of Gaffrée e Guinle Universitary Hospital from Federal University of the State of Rio de Janeiro (UNIRIO), in December 2021 with CAAE nº 50,311,621.0.0000.

Consent for publication

Informed Consent was obtained from each individual who agreed to participate.

Footnotes

Acknowledgements

The authors would like to thank Cleonice Bento (biomedical researcher, Department of Biomedicine, Federal University of Rio de Janeiro) for her professionalism and critical review, Luiz Cláudio (head of the Laboratory of Research on Immunology and AIDS at GGUH) for storing the samples in appropriate conditions; and the staffs of the Surgery/Anesthesia Division of GGUH, for their support in the logistics of surgical routines and careful patient selection.

Author’s contribution

VGB, GNS, and DN developed the anesthetic protocol, study design, managed the study, collected data, provided the statistical analysis, interpretation of the data, and first draft of the project. RF, KUL, and CRM offered support in writing the first draft of the article, data collection, and conducted the experimental procedures. MVP, RBM, and TPAR provided interpretation of the results, assisted in writing and critical review of the manuscript, examination, and analysis of clinical data, as well as chemical evaluation of inflammatory and endocrine mediators. All the authors read and approved the final version of the manuscript.

Declaration of conflicting interests

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

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the Universidade Federal do Estado do Rio de Janeiro, Resources from the Federal Ministry of Education.

ORCID iD

Gustavo Nascimento Silva

Data Availability Statement

The used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Supplemental Material

Supplemental material for this article is available online.

Appendix

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