Effect of Remote Ischemic Preconditioning on Patient Survival and End Organ Injury During Elective Open Abdominal Aortic Surgery Repair: A Randomized Controlled Trial

Article information Background: Ischemic preconditioning is natural cyto-protective mechanism that can potentially protect end organs from ischemia. In examined instances having major vascular surgery, remote ischemia preconditioning provides straight-forward technique with the ability to set up widespread and systemic protection from significant organ harm. Thus, we have been required to assess clinical usage of remote preconditioning in preparing myocardial and renal protection after elective open Abdominal Aortic Aneurysm [AAA] repair in randomized trial. Aim of the work: The aim of this research had been to examine potential of remote ischemic preconditioning on myocardial and renal protection and patient survival after elective open AAA repair. Patients and Methods: This randomized double blinded clinical trial comparing AAA repair with remote ischemic preconditioning versus conventional AAA repair [control] was done in cardiothoracic and vascular surgery center Mansoura University from October 2022 to May 2023 after approval from institutional review board of Mansoura faculty of Medicine with obtaining a written informed consent from all studied cases. Results: There had been statistically significant variation among studied groups as regard 30-day mortality. Conclusion: Remote ischemic preconditioning improves mortality rate after elective open abdominal aortic surgery repair.


INTRODUCTION
Myocardial and renal injuries commonly contribute to perioperative morbidity and mortality after abdominal aortic surgery.Brief durations of ischemia followed by reperfusion in an organ have been known to give systemic protection from long ischemia, phenomenon known as remote ischemic preconditioning [1] .
After elective abdominal aortic surgery, the most common reason for both early and late mortality has been cardiac-related [1] .Mechanism of myocardial injury remain unclear and evidence exists that most cardiovascular events in vascular surgery cases have been consequence of non-hemodynamically significant stenosis [2] .
Irrespective of the mechanism, studied cases undergoing abdominal aortic surgery remain at high risk for cardiovascular events [3] .Subclinical myocardial injury after major vascular surgery, discovered by increase in cardiac troponin, has been common and has been related to increased mortality [4,5] .
Ischemic preconditioning is a phenomenon that occurs when small period of ischemia has been followed by reperfusion before prolonged ischemic episode, potentially preparing the body to resist cellular damage.Several signal transduction pathways have been activated by the initial ischemia event, maintaining myocyte contractility and function [6] .
Lately, it is illustrated that ischemia at location distal to heart can confer same cellular protection in circulating or neuroprotective mediators released from distant organs subject to ischemia [7] .Other organs at risk of ischemia throughout surgery may benefit systemically from this kind of remote preconditioning [1,8] .
Renal injury, result of hemodynamic variations after application of aortic cross-clamp and ischemia-reperfusion injury after its release, has been common reason for morbidity and mortality after elective abdominal aortic surgery [1, 8]   .Acute renal failure occurs in approximately ten percent of studied cases after elective open abdominal aortic aneurysm [AAA] repair [9] and has been independent predictor of death [1] .
In examined instances having major vascular surgery, remote ischemia preconditioning provides straightforward technique with the ability to set up widespread and systemic protection from significant organ harm.Thus, we have been required to assess clinical usage of remote preconditioning in preparing myocardial and renal protection after elective open AAA repair in randomized trial.
To examine whether remote preconditioning decreases incidence of myocardial, renal injury and survival rate in studied cases undergoing elective open abdominal aortic surgery, we did randomized trial.Studied cases assigned for primary elective open AAA repair had been asked to take part in research at period of scheduling for operation.

PATIENTS AND METHODS
Exclusion criteria: Potential individuals was excluded if they > 90 years old, require concomitant processes other than AAA repair, had experienced acute coronary syndrome or myocardial infraction in 3 months, are incapable of giving informed consent, or taking sulfonylureas oral hypoglycemic agents or nicorandil drug therapy as these agents are revealed to affect preconditioning [10,11] .
Randomization: Computer-generated list of studied cases had been used to randomly assign them to blocks that had been then covered up with numbered, sealed, opaque envelopes.Allocation had been announced by operating surgeon by opening top envelope on morning of operation.Studied cases were blinded to technique and results.Also, data collectors were blinded to technique and results.Assignment of cases and findings was compared and analyzed blind in two groups labeled R and C. Group R: group of AAA repair with remote ischemic preconditioning.Group C: conventional AAA repair [control group].

Procedure
All studied cases were evaluated preoperatively by history taking, clinical testing, basal laboratory investigations [complete blood picture, INR, liver function and kidney function tests], ECG and ECHO.To evaluate valve function, contractility, or existence of aberrant regional wall motion, transthoracic echocardiography was performed on every studied case.cardiologist evaluated studied cases who had cardiac symptoms and then referred them for non-invasive stress testing, while required by the clinical guidelines.Cases had been referred for coronary angiography if the previous evaluation became unfavourable or if their symptoms changed.Subsequently, revascularized studied cases became eligible for inclusion.In lack of preoperative contraindications, β-blockers had been administered.For all studied cases under local anesthesia, radial arterial cannula and central venous line were inserted.Prior to inducing anesthesia, an epidural catheter had been placed into the L3-L4 intervertebral region to cover the region of lower abdomen.
In the remote ischemic preconditioning [RIPC] group, sequential ischemia of upper limbs was induced through applying of noninvasive pressure cuff on the right arm two fingers above cubital fossa and elevating its pressure above the patient systolic pressure by 40 mm hg with ten minutes ischemia time followed by ten minutes reperfusion during which same ischemia is induced in the left arm for 10 minutes then reperfusion for 10 minutes.Ischemia reperfusion was repeated sequentially in both arms with a total ischemia time 20 minutes in each arm with 10 minutes reperfusion in between.Sequential ischemia in both arms will minimize repeated ischemia in a single arm, therefore decreasing potential for trash arm.
Surgical dissection had been completed up until moment surgeon had been getting ready to cross-clamp aorta and access aneurysm sac.At this time, all patients were heparinized.
Serum lactate and ABG were measured after RIPC, and after declamping.Bolus dosages of fentanyl, raising isoflurane concentration, or adding nitroglycerin infusion were used to treat hypertension while clamping.Fluids, bolus ephedrine doses, decreasing isoflurane concentration, and, if necessary, norepinephrine infusion after declamping were used to treat hypotension.Atropine [30 g/kg] had been administered in bolus dosages to treat bradycardia.Cases with surgery above the origin of the renal artery received crystalloids [500-1000 ml], mannitol twenty percent [one hundred ml] and furosemide [forty mg] through thirty min before clamping for renal protection.At end of the procedure and after emergence from anesthesia, cases had been transferred to Intensive Care Unit with close monitoring.
Following surgery, all studied cases received bupivacaine and fentanyl epidural analgesia & studied case-controlled intravenous morphine.In lack of any contraindications, studied cases who had myocardial damage or infarction were then treated routinely with antiplatelet medications [Aspocid] immediately after surgery, betablockers and angiotensin-converting enzyme inhibitors.
Collected data: Basal serum creatinine, cardiac troponin, ABG, serum lactate.ABG and serum lactate before and after declamping.The primary result measure had been myocardial damage described as rise in blood cardiac troponin more than 0.40 ng/ml.
Secondary results involved mortality, kidney damage and myocardial infarction.revised American College of Cardiology/ American Heart Association recommendations described myocardial infarction as TnI spike >1.5 ng/mL with at least 1 of following: typical ischemic symptoms, ECG alterations indicative of ischemia, or new pathological Q-waves.Each morning following surgery, 12-lead ECG were done as required by clinical guidelines.In accordance with recommendations studied cases undergoing major vascular surgery and noncardiac surgery, impaired renal function has been characterized as peak serum creatinine level of > 177 μmol/L [2.0 mg/dL] [5] .Blood specimens was taken preoperatively and on morning of postoperative days; first, third, and seventh day post-operatively.

RESULTS
Table [1] displays that there had been no statistically significant variation among studied groups as regard baseline data.
Table [2] shows that there had been statistically significant difference among studied groups as regard operative data.
Table [3] shows that there had been statistically significant difference among studied groups as regard 30-day mortality.

DISCUSSION
Using a technique called remote ischemic preconditioning, short, intermittent bursts of ischemia & reperfusion [IR] shield distant organs from longer bursts of IR harm.RIPC is carried out with numerous cycles of IR employing blood pressure cuff on studied case's limb in studied cases undergoing heart surgery [12] .
We had been interested in learning which population would profit most from numerous randomized control studies that are done, results of which are diverse.We investigated whether it's necessary to modify RIPC technique for various studied case populations and whether advancements in surrogate markers result in better clinical results.We feel that area under curve decrease in cardiac biomarkers gives superior evidence of cardio-protection than timepoint measurements, which are often used in majority of meta-analyses that have been published up to this point to report on cardiac protection, like at twelve h postintervention [13] .
In this study, we showed that there had been no variation among studied groups as regards baseline data.In a study to assess RIPC versus no preconditioning in prevention of perioperative myocardial infarction throughout open surgery throughout for ruptured abdominal aortic aneurysm, Pedersen et al. [14] found that baseline characteristics had been alike among 2 groups.Murphy et al. [15] discovered that among 62 studied cases presenting for open AAA repair involved in this research; thirty-one studied cases had been randomized to RIPC group and thirtyone studied cases had been randomized to control group [conventional open AAA repair], there had been no statistically significant variation among studied groups as regard baseline data.
In this study we illustrated that there had been no variation among studied groups as regard operative data.Pedersen et al. [14] discovered that utilization of platelets & plasma, as well as time of process, did not significantly change among 2 groups.type of graft [tube/bifurcated] used had been same.Murphy et al. [15] found that Aortic cross-clamp duration, application site, or graft type did not differ significantly from one another.Meybohm et al. [16] found that control and RIPC groups' demographic & surgical data did not significantly change from one another.
In this investigation, we discovered statistically significant variation in thirty-day mortality among analyzed groups.Current detailed meta-analysis by Ali et al. [17] revealed indications of decreased mortality related to ischemic cardiac events & decrease in combined endpoint of significant adverse cardiovascular events, but also shown that incidence of periprocedural myocardial infarction had been decreased by RIPC while had been postprocedural peak release of troponin.Pedersen et al. [14] found that mortality risk decreases of fifteen percent in absolute terms at thirty days, resulting in OR of 0.46 [95% CI 0.22 to 0.99].
More recently, Cheung et al. [22] reported 1st human clinical use of remote conditioning.In this randomized, controlled trial, authors used blood pressure cuff to administer forty fiveminute cycles of lower limb ischemia/ reperfusion to children undergoing heart surgery to induce remote preconditioning.In their investigation, remote preconditioning decreased airway resistance, postoperative inotropic needs, and myocardial damage.These data from randomized, controlled trials support conclusion from our research that remote preconditioning has been reasonable therapeutic approach to lessen ischemia harm in human sensitive organs.
Hu et al. [23] Researchers who investigated use of RIPC for CI-AKI prophylaxis hypothesized that RIPC had been linked to reductions in-hospital mortality & duration of stay.Pei et al. [24] perioperative incidence of CI-AKI in studied cases receiving elective coronary intervention was considerably decreased by RIPC [P = 0.04].
In summary, our research demonstrates that remote ischemia preconditioning reduces mortality after elective open abdominal aortic surgery.