This study aims to evaluate the viability of a clinical model of remote ischemic preconditioning (RIPC) and its analgesic effects. It is a prospective study with twenty (20) patients randomly divided into two groups: control group and RIPC group. The opioid analgesics consumption in the postoperative period, the presence of secondary mechanical hyperalgesia, the scores of postoperative pain by visual analog scale, and the plasma levels interleukins (IL-6) were evaluated. The tourniquet applying after spinal anesthetic block was safe, producing no pain for all patients in the tourniquet group. The total dose of morphine consumption in 24 hours was significantly lower in RIPC group than in the control group (
Ischemic preconditioning (IPC) is defined as brief periods of ischemia, interspersed with reperfusion, prior to a sustained period of ischemia. This procedure is performed in order to prepare and protect the cell to the damage caused by a long period of ischemia [
Many surgical and nonsurgical cardioprotective strategies have been developed to reduce the levels of ischemic injury, some more successful than others. In addition to its protective effects in ischemia-reperfusion injury, there is a considerable amount of evidence indicating the effects of IPC in inflammatory conditions of nonischemic nature, probably through a systemic action [
The effects of inflammatory cytokines have been demonstrated in relation to TNF-alpha, which has been identified as the major mediator involved in the development of tolerance to induced IPC [
The remote ischemic preconditioning (RIPC) is achieved by a series of short nonlethal ischemic periods, interspersed with periods of reperfusion in distant tissues, that results in a target organ protection in late ischemic events [
Postoperative pain has inflammatory and nociceptive nature. It results from the interaction between tissue damage and nociceptive sensory receptor stimulation through inflammatory mediators. Thus, considering that the mediators of inflammation are closely related to the reduction of the excitability threshold of the nociceptive primary afferent, and the release of factors related to the inflammatory response can be changed by RIPC, the hypothesis is reasonable that this simple procedure could affect the pain response, producing postoperative analgesia.
This study aims to evaluate the analgesic activity of a clinical model of ischemic preconditioning on postoperative pain resulting from subcostal incision, as well as the influence of this technique in the cytokines levels in the postoperative period.
The study was approved by Walter Cantídio University Hospital’s Scientific Ethical Committee, which is regularly affiliated to National Research Ethics Commission (CONEP) registered with number 015.03.12. The research was conducted in accordance with the Helsinki Declaration and the principles of Good Clinical Practice. The approval was ratified by the Department of Studies of Santa Casa de Misericordia Hospital in Fortaleza.
A randomized controlled trial, partially blind (evaluators of postoperative outcomes did not know the allocation group of patients), with prospective and quantitative nature was developed at Santa Casa de Misericordia Hospital from June 2013 to June 2014. After applying informed consent form, the patients were randomized utilizing sequentially numbered opaque sealed envelopes to one of two groups (ratio 1 : 1) by the study coordinator. The same anesthetic-surgical medical team did all procedures. All included patients were females, between the ages of 20 and 55 years, with cholelithiasis, physical status, ASA I or II (no comorbidities, or with 1 clinical morbidity well-defined and well controlled, according to criteria defined by American Society of Anesthesiology (ASA)). The exclusion criteria were patients under 20 or above 55 years old, those with signs or symptoms suggestive of acute cholecystitis or choledocholithiasis, and subjects with more than one comorbidity or with one comorbidity clinically uncontrolled or poorly defined. We also excluded those subjects who did not properly understood the methods assessment of postoperative pain, those who did not sign the informed consent form, and patients who presented hemodynamic changes or other serious intraoperative complications, as well as those who had an inappropriate spinal block.
The choice of the experimental design was a challenge. There are no clinical studies using remote preconditioning for abdominal surgery. Thus, this model was based on previous studies using the technique in orthopedic surgery [
Pain control in the postoperative period was indirectly assessed by measuring the intravenous morphine consumption during 24 hours. All patients received a predetermined and fixed analgesia with intravenous metamizole (1 g) every 6 hours. The visual analogue scale (VAS) was applied once 24 hours after surgery, asking about pain intensity in three situations: at rest, during deep inspiration, and during cough induction. Two independent investigators, blinded to the study group where the patient was allocated, performed all the postoperative VAS measurements.
The presence of hyperalgesia produced by mechanical stimulation of the area surrounding the incision previously marked was observed 24 hours after the end of the procedure (Figure
Hyperalgesia area.
Von Frey filaments. Colors determine the variation of the force produced by applying the filament.
In order to assess the role of IL-6 in the RIPC effects on acute postoperative pain and hyperalgesia, 5 mL of blood samples was collected in four different moments:
The surgical technique was similar in all patients, performed by the same surgical team and based on classical technique performed for conventional surgery: right subcostal incision. Only three anesthesiologists, experienced in performing spinal blocks, participated in the implementation of standardized anesthesia with a spinal block in L2-L3 space using a needle gauge in the range 26-27, heavy bupivacaine 0.5%, for a total of 15 mg–20 mg (3-4 mL), and 5 micrograms of sufentanil.
Quantitative variables were initially analyzed by the Kolmogorov-Smirnov test to check the normality of distribution. For descriptive statistics, the mean and standard error of the continuous variables were calculated. Intergroup comparisons at each time point were performed by using the unpaired
There were no significant differences in the analysis of the variables: age, weight, duration of surgery, and ASA physical status between the two groups, as shown in Tables
Age, weight, and operative time between groups: expressed as mean values ± standard error of the mean. Analysis: KS test for normal distribution followed by unpaired
Control group | Tourniquet group | |
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Age (years) | 38.70 ± 3.422 | 40.80 ± 3.994 |
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Weight (Kg) | 64.60 ± 2.676 | 67.30 ± 3.337 |
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Operative time (min.) | 72.50 ± 3.819 | 67.00 ± 4.667 |
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Physical state as ASA. Data expressed as absolute numbers of patients in the respective ASA.
ASA I | ASA II | |
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Control group | 7 | 3 |
RIPC group | 6 | 4 |
The overall total morphine consumption in 24 hours was significantly less in tourniquet group compared to the control group which can be shown in Figure
Morphine consumption. Values expressed as mean ± standard deviation of the mean.
Analysis of the evaluation of the intensity of pain at rest and in deep breathing and coughing showed significantly lower VAS scores at Garrote group compared to the control group, as shown in Figures
Intensity of postoperative pain at rest. Values expressed as mean ± standard deviation of the mean.
Intensity of postoperative pain on deep breathing. Values expressed as mean ± standard deviation of the mean.
Intensity of postoperative pain in cough. Values expressed as mean ± standard deviation of the mean.
There were significant differences in IL-6 between the two dosage groupsin the course of time as shown in Figure
Values are expressed as mean + standard deviation of the average IL-6 concentration in the blood sample times (
The data presented in this study demonstrate a significant reduction in postoperative pain in patients undergoing conventional cholecystectomy who were submitted to remote preconditioning ischemic before the surgical procedure. It demonstrates an unprecedented way, the effect of remote ischemic preconditioning over abdominal surgery pain, since in previous publications, the pneumatic cuff was applied directly to the operated member [
During the past two decades, multiple variations on the theme of RIPC have been investigated, encompassing both in vitro and in vivo models. The cardioprotective effect has been the main focus; however RIPC protects the myocardium, but also other parenchymal organs and, notably, the vasculature [
Studies where peripheral limb ischemia is the RPIC stimulus have mostly employed 3 or 4 episodes of 5 min arm and/or leg ischemia interspersed with 5 min reperfusion periods. However, these are empiric choices, the optimal algorithm has not been identified, and it has been postulated that “hyperconditioning” (i.e., an as-yet undefined, excessive number of conditioning episodes) may be deleterious [
The laparoscopic cholecystectomy is considered the gold standard for the surgical treatment of gallstones and is replacing the conventional technique in most services [
This study presents a clinical model of PCIR as a strategy that can be associated with other in the multimodal analgesia resulting in adequate pain control postoperatively [
The higher reduction in morphine consumption postoperatively in RIPC group also needs to be presented as a very relevant finding, facing the possibility of reducing the complications arising from the adverse effects of opioids that increase postoperative morbidity [
An important question to be answered is how could PCIR act to produce analgesia? It has been demonstrated that circulating monocytes play a key role in ischemia/reperfusion injury RIPC downregulating the expression of a broad portfolio of proinflammatory genes in circulating monocytes [
Details of the mechanisms for local release of the protective signal at the remote site and the contributions of neuronal and humoral pathways to the RPCI are not yet clear; however several extracellular signalling molecules, such as adenosine, bradykinin, and opioids, have been identified as mediators and effectors [
Besides that, it seems that in most cases the common final step of the molecular mechanisms involved in preconditioning is the opening of potasium-ATP channels [
In conclusion, this model of remote ischemic preconditioning is feasible to reproduce in clinical setting, improved pain control, and reduced morphine use in postoperative patients undergoing cholecystectomy conventional with nonlaparoscopic technique. The analgesic effect is not related to the inhibition of inflammatory mediator, interleukin 6 production.
The authors declare that there is no conflict of interests regarding the publication of this paper.