European Journal of Cardiovascular Medicine

Stimulation of the hypothalamus during stress causes the release of adrenocorticotropic hormone (ACTH), resulting in a sudden increase in cortisol. The increased cortisol mobilizes amino acids and fat to form glucose, causes insulin resistance, and thereby increases blood glucose levels by up to 50% above normal. This makes glucose available for energy and the synthesis of other compounds needed for various tissues. Hence, the estimation of blood glucose serves as a reliable indicator for the indirect assessment of the stress response and its modulation by pharmacological agents like alpha-2 agonists.

The stress response to surgical procedures is a major cytokine and neuroendocrine sequel to surgical injury, leading to a rapid increase in catecholamine release and steroid hormone levels. This has been contemplated as a physiological defense mechanism that is an important risk factor for the body's adaptation to noxious insults.

Hypothalamus stimulation during stress results in adrenocorticotropic hormone release, which in turn causes a sudden increase in cortisol levels. Cortisol mobilizes proteins and fat from body stores, rendering them available for glucose synthesis, leading to hyperglycemia. The resulting hyperglycemia can adversely affect patient outcomes by producing hazardous effects on immunity, thus increasing the percentage of postoperative complications. An increase in mean intraoperative blood sugar readings as minimal as 20 mg/dl has been associated with a 30% increase in adverse outcomes.

Laparoscopic surgeries have the privilege of being low-stress-level surgeries with fewer pulmonary complications, but they still cause increased hemodynamic stress responses. Various pharmacological agents have been used to attenuate surgical stress in laparoscopic procedures to improve outcomes, such as nitroglycerin, beta-blockers, opioids, and alpha-2 agonists.

Alpha-2 receptor activation reduces the norepinephrine surge, making it an effective agent to induce sympatholysis. Because of its sympatholytic properties, dexmedetomidine was gradually developed as premedication, aiming to decrease the sympathetic response to perioperative stressful conditions such as laparoscopy and endotracheal intubation. Therefore, monitoring blood sugar levels can reflect the metabolic stress response to surgery and dexmedetomidine's role in blunting this stress response. Dexmedetomidine additionally has an analgesic effect.

The primary goal of this study is to record the influence of perioperative dexmedetomidine administration on the modulation of the neuroendocrine stress response during laparoscopic surgery by analyzing the variation of perioperative serial capillary blood sugar levels.

A randomized controlled clinical trial was conducted in Maharashtra, India. The data of the patients from the from January 2021 to December 2022, were retrieved and assessed. A total of 76 cases (Group D-38, Group S-38) were analyzed after taking informed consent.Sample size was obtained after Appropriate sampling technique : with reference to the study done by Mostafa et al (2018)* .

Sampling method: A consecutive sample of 76 subjects seeking treatment and care at the tertiary carehospital and fulfilling the eligibility (inclusion and exclusion) criteria were selected fromthe Anaesthesia Dept. by convenience sampling method.

Randomization:

The selected sample of subjects (n=76) wererandomised equally to two groups(Studyand Control) using pre-designed, computer generated random allocation plan. Permutedblock randomization method with 19 blocks of size 4 will be used for random assignmentof treatment to groups (each with n=38) by RALLOC software.

Blinding:

This was a double blind randomised controlled trial where both the study subject and theresearcher will be blinded to the treatment assignment.

The ethical clearance was granted by ethics committee.

INCLUSION CRITERION :

• Consented for the study.
• ASA physical status grade I and II patients.
• Age group: 18 - 60 years of either sex.
• Elective laparoscopic surgery under general Anesthesia.
• Surgeries less than 3 hours of duration.

EXCLUSION CRITERION :

• Refusal to participate in study.
• Age group : <18 years and > 60 years.
• Cardiac, pulmonary, liver, kidney or metabolic disorders or was receivingmedications that might affect sympathetic response or hormonal secretions.
• Endocrinological disorder that might affect blood glucose levels such as Cushingsyndrome, hyperthyroidism or were receiving drug therapy significantly affectingblood glucose levels such as corticosteroid therapy
• Diabetes mellitus • Chronic hypertension and patients on ⍺ blockers, β blockers, calcium channel blockers. • Patients allergic to dexmedetomidine • Positive pregnancy test • Allergic to eggs or soy were debarred from surgery • Complicated surgeries with prolonged duration >3 hr.

Total of 76 patients of either sex aged between 18 to 60 years, ASA PS 1 Or 2 posted for elective surgery under general anaesthesia requiring oral endotracheal intubation was recruited for study. Selected sample of subject(n=76) was randomised equally to two groups, viz Group D (n = 38 patients) - Loading dose - 1mcg/kg diluted in 50 ml of NS given over 10 min. Maintenance dose - 0.5mcg/kg/hr by infusion pump till 30 min prior to surgery. Group C (n = 38 patients) - 0.9% Normal saline, same volume and rate as placebo. MATERIAL AND METHODS 32 using pre- designed, computer generated random allocation plan. Permitted block randomisation method with 19 blocks of sizes 4 was used for random assignment of treatment to groups (each with n =38) by RALLOC software.

A day before surgery (Pre-anaesthetic check up) : A day before scheduled operation the patient was visited preoperatively in their wards for a per-anaesthetic check up and patient characteristic including age, sex, weight, height was recorded. After obtaining the history, performing clinical examination and reviewing laboratory investigations (e.g. fasting blood sugars, serum haemoglobin, kidney function test, liver function test, coagulation profile, glycosylated haemoglobin (HbA1C), Chest x ray, Electrocardiogram (ECG) was checked. Patient was taken up for this study after applying exclusion criterion. Written informed consent for surgery, Anesthesia and participation in the study was taken. • All patients were kept nil by mouth for eight hours prior to start of Anesthesia and will be given tab. Pantoprazole 40 mg and Tab. Diazepam 5mg orally night prior to surgery. On the day of surgery : • Review of pre anaesthetic checkup and fitness of anaesthesia for surgical procedure was done in waiting room of OT. • Written informed consent checked and confirmed. • Nil by mouth status was checked. • Hemodynamic parameters were recorded : Blood pressure (SBP, DBP, MAP), Heart rate (HR), SpO2 in waiting room of operation theatre. • Fasting blood glucose levels were checked with glucometer (AccuCheck) in both the groups.• Patients were shifted to operation room on trolley. • Multipara monitors were attached to patient and all baseline parameters of the patient i.e. NIBP(SBP, DBP, MAP), Heart rate, SpO2, ECG were recorded. • IV access with 18/20G IV cannula was secured in both upper limbs. • All patients received IV fluid Ringers lactate infusion followed by administration of Inj. Pantoprazole 40 mg IV. • Group D patients received IV Dexmedetomidine 1mcg/kg diluted in 50 ml of normal saline and group C patients received same volume of normal saline as group D, over 10 min duration before starting induction of anaesthesia. • After proper assessment of airway and anticipation of difficult airway, pre oxygenation with 100%O2 on 8lit/min for 3 min via mask was started. • Sedated with Inj.Midazolam 0.02mg/kg IV + Inj.Fentanyl 2mcg/kg IV. • Induction of anaesthesia achieved with propofol 2mg/kg IV. After confirming with mask ventilation Inj. Atracurium besylate 25 mg IV. Patient was mask ventilated for 3 min after that intubated with direct laryngoscopy using proper sized blade and proper sized Portex cuffed endotracheal tube. Air entry checked on both sides of chest and tube fixed. Maintenance of anaesthesia was done by O2 + N20+ Sevoflurane as inhalation agent. • After tracheal intubation, controlled mechanical ventilation (CMV) was started. For both groups CMV achieved by tidal volume of 8 - 10 ml/kg body weight and respiratory rate of upto 12 -14breaths/min to maintain normocapnea. • Inj. Dexmedetomidine infusion started at maintenance dose of 0.5 mcg/kg/hr using a syringe pump( Fresenius Kabi). • Patient placed in reverse trendelenberg position. Operation performed through 3 abdominal trocars. Intraabdominal pressure was kept at the range of 12-15mmHg.• Supplemental blouses of Atracurium besylate 0.1mg/kg IV were administered every 20 min to maintain muscle relaxation during surgery. • Group C patients received 50ml of 0.9% saline, followed by a saline infusion. • Inj. Dexmedetomidine infusion stopped 30 min prior to expected time of completion of surgery. • Inj. Paracetamol 1gm IV given as analgesic intraoperatively. Inj. Ondansetron 4mg IV given 15 min prior to extubation. • Trocars removed on completion of surgery and trocar ports are infiltrated with Inj. Bupivacaine 0.25% 3cc at each port. • Upon completion of surgery, patients was extubated after adequate reversal of neuromuscular blockade with Inj. Neostigmine 0.05mg/kg IV + Inj. Glycopyrrolate 8mcg/kg IV and fulfilling the extubation criterion. • All patients were transferred to PACU where they were monitored for additional 3 hours. • After transferal to PACU, patients will be observed for any respiratory depression (Respiratory rate) • Patients were observed for sedation in postoperative period at extubation, 1 hr, 3 hr and at 6 hr. • Patient was observed for differences in blood glucose levels between the two groups. • For postoperative analgesia Inj. Diclofenac sodium 75mg IV BD was given in both the groups. Inj. Tramadol 100mg IV will be given for breakthrough pain if required. • At 6th hour since the beginning of surgery was taken as end point of our study.

SPSS 26 version was used and appropriate statistical tests were applied.

TableNo.1Agedistributionofstudypopulation

Graph 1

Tableno.2. Gender wise distribution of study population

Graph 2

Genderwisedistributionwascomparableinboththegroups. Male: Female ratio of 1:1 was maintained in both the groups

Majority i.e. 24 patients in Group D and 29 patients in Group S belongs to 51 - 60 kg weight category.Only1patientinGroupDandnopatientinGroupSbelongsto41-50kgweightgroup.

13patientsingroupDand9patients inGroupSbelongsto61-70kgweightcategory.Mean values of both groups are comparable.

Tableno.4Distributionofstudypopulationaspertypeofsurgery

Graph 4

As far as types of surgeries are concerned most of the patients had undergone Laparoscopic cholecystectomy (15 out of 38 – 40%) followed by Laparoscopic appendectomy (13 out of 38- 34.2%) in the dexmedetomidine group. In control group, majority of the patients are operated for Laparoscopic cholecystectomy(21 outof38-55.2%), followedbyacuteappendicitis(8 outof 38- 21%)

TableNo.5-Comparisonofcapillarybloodglucoselevelsbetween GroupDandGroupS

Inourstudybaselinelevelofmeanbloodglucosewere105.5±5.6inGroupDand99.4±5.8 in GroupC and thesearecomparable.

At 30 min the mean blood glucose levels in control group were raised from baseline which is 106.7 ±4.4 (7.3%↑) as compared to 98.3 ±4.7 (2.2 %↓) in dexmedetomidine group. The rise in control groupat 30 min was due to stress response to laryngoscopy, intubation and pneumoperitoneum which was attenuated by dexmedetomidine in group D.

At 1 hour, the mean blood sugar level was 113.8 ± 5.6 (14.5%↑) in group C vs. 95.9 ± 4.4 (4.6%↓) in group D.

At 2 hours, the mean blood sugar level was 118.7 ± 4.8 (19.4%↑) in group C vs. 98.3 ± 5.7 (2.2%↓) in group D.

Dexmedetomidine infusion was stopped 30 minutes prior to the expected time of completion of surgery in group D.

At 3 hours, the mean blood sugar level in group D was 103.2 ± 5.2 (2.7%↑) compared to 121.6 ± 5.1 (22.3%↑) in the control group. This rise in both groups could be due to the response to extubation.

There was a continuous rise in blood sugar in the control group at all time intervals, which was statistically significant. Blood sugar levels were well controlled in the Dexmedetomidine group.

At 6 hours from the beginning of surgery, there was a rise in mean blood glucose levels in the Dexmedetomidine group, 110.8 ± 5.7 (10.2%↑), compared to the control group, 123.9 ± 5.7 (24.6%↑).

Table6                 -Adverse effects -

In Group D, 2 patients had Bradycardia, 1 patient had hypotension and 1 patient had nausea. In Group S, 4 patients had nausea, 1 patient had vomiting, whereas no other adverse effects were observed.

We studied fresh capillary blood glucose levels using glucostrip test at various time intervals: at baseline (before Dexmedetomidine bolus), at 30 min after induction, 1hr, 2hr, 3hr and 6 hr from beginning of surgery.

NormalFastingbloodsugarlevels asperAmericanDiabeticAssociationare:

Normal:3.9 to 5.4 mmols/l(70to 99 mg/dl) PrediabetesorImpairedGlucoseTolerance:5.5to6.9mmol/l(100to125mg/dl)

Diagnosisofdiabetes:7.0mmol/l(126mg/dl) orabove^[361]70mg/dlto110mg/dland postprandial blood glucose levels are 100 - 126mg/dl.

Inourstudybaselinelevelofmeanbloodglucosewere105.5±5.6inGroupDand99.4±5.8 in GroupC and thesearecomparable.

At 30 min the mean blood glucose levels in control group were raised from baseline which is 106.7 ±4.4 (7.3%↑) as compared to 98.3 ±4.7 (2.2 %↓) in dexmedetomidine group. The rise in control groupat 30 min was due to stress response to laryngoscopy, intubation and pneumoperitoneum which was attenuated by dexmedetomidine in group D.

At1hrmeanbloodsugarlevelin113.8±5.6(14.5%↑)ingroupCVsgroupDwas95.9±

4.4(4.6 % ↓).

At 2 hr mean blood sugar levels in 118.7 ± 4.8 (19.4%↑) in group C Vs 98.3 ± 5.7 (2.2%↓) in group D.

Dexmedetomidine infusionwas stopped 30 min prior to expected time of completion of surgeryin Group D.

At3hr,meanbloodsugarlevelsingroupDwas103.2±5.2(2.7%↑)ascomparedto 121.6±5.1(22.3%↑)incontrolgroup.Thisriseinboththegroupscouldbeduetoresponse to extubation.

There was continuous rise in blood sugar in control group at all time intervals and was statistically significant. Blood sugar levels was well controlled in Dexmedetomidine group.

At 6 hr since the beginning of surgery there was rise in mean blood glucose levels in Dexmedetomidinegroup110.8±5.7(10.2%↑).ascomparedtoincontrolgroup123.9± 5.7(24.6%↑). Intraoperatively in group C there was higher blood glucose reading from 30 min after induction upto 6 hr later as compared to group D which was highly statistically significantat all levels. Ourresultsaresimilartofollowing studies:

Raham Hasan Moustafa et al used same drug dosage of Dexmedetomidine i.e. 1mcg/kg as loading dose and 0.5mcg/kg/hr as infusion dose. They found mean blood glucoselevels:-

At 30 min -88.77 ±14.46Dexmedetomidine group Vs95.3 ± 14.2 in control group. At 1 hr-84.27 ±20.1 in Dexmedetomidine group Vs101.3 ±14.6 in control group* At 2 hr - 81.57 ±19.3 inDexmedetomidine group Vs103.6 ±14.36 in control group*. At 6 hr - 82.53 ±12.95 in Dexmedetomidine group Vs106.97±15.2 in control group*. (*pvalue - <0.001)

Theyfound statisticallyhighlysignificant decrease in blood sugar level at 1hr,2hr,and 6 hr in dexmedetomidine group as compared to control group. Blood sugar increases after surgical stimulation with good correlation between the magnitude of rise in blood sugarand the extent of surgical injury to the tissues

HarsoorS S et alfoundin theirstudy significant reduction in blood glucose level in post op 1 hr in Dexmedetomidine group 136.95 ± 19.76 versus 118.2 ± 16.24 in control group with similar dosage of Dexmedetomidine.

Ivesh Singh et al found increased blood glucose levels during surgery andpostoperatively in both groups. Postoperative increment was significant at 2.5 hr. Postoperative increment at 2.5hr was significantly more pronounced in patients of group C (129.3 ± 19 VS 119.7 ± 24 mg/dl p <0.05).

Soumi Mandal et alstudiedtheeffectofdexmedetomidineindiabeticpatientsundergoing laparoscopic surgeries. They found significant difference in blood glucose levels among Dexmedetomidine group and control group with drug dosage similar to our study. AT30mininmeanbloodsugarinDexmedetomidinegroup109.00±10.51Vs126.53± 6.65incontrolgroup.At60mininDexmedetomidinegroup117.41±8.75Vs137.06± 4.49incontrolgroup.At90min,InDexmedetomidinegroup127.24±6.14Vs146.88± 3.56incontrol group

Kumkum Gupta et al studied the modulation of neuroendocrine stress response by Dexmedetomidine (1mcg/kg) Vs fentanyl (2mcg/kg) premedication during laparoscopic cholecystectomy. They found 20% increase in blood glucose concentration after surgery. Intraoperatively after 30 min mean blood sugars in Dexmedetomidine group 123.2 ±14 Vs 114.7 ±27 in fentanyl group. Postoperativly(2.5 hr) in Dexmedetomidine group 114.6 ±21 Vs 121.3 ± 25 and was statistically significant (p 0.043) Usha Shukla et al used loading dose of dexmedetomidine1mcg/kg (Group D) and fentanyl 2mch/kg (Group F) without infusion dose in laparoscopic surgeries. They found significant blood sugar levels after incision ( 106.50 —6.88 in group D Vs 122.00 ± 13.29in group F Vs 136.30 ± 9.13 in group C)and 6 hrs after induction ( 90.05 ±8.28in Group D Vs 107.10 ± 10.59 in Group F Vs 116.15 ± 4.71 in group C). Hyperglycaemic changes seen after incision were likely to be induced secondary to pneumoperitoneum. The influence of soluble carbon diaoxide on carotid and aortic chemoreceptor enhances the sympathetic outflow mediated by afferent impulses to subcortical centres. Stimulation of sympathetic nervous activity elevates blood glucose primarily by stimulating hepatic glycogenolysis and suppression of insulin secretion.

Ahmed Yacout et al studied the stress response induced rise in blood glucose, cortisol and interleukins. They found that after complete recovery and at first day postoperatively,bloodglucoselevelsareincreasedinbothgroupsbutwithsignificantlylowervaluein

Dexmedetomidine group (98.27 ± 11.55) than control group (132.6 ± 20.26). They also found significantly increased levels of Interleukin - 6 and cortisol in dexmedetomidinegroup and in control group.

In Yasha et al study changes in mean blood glucose levels 45.20% rise from baseline 30 min after intubation, 27.07% rise during 1st hour postoperatively and 11.05% rise during 2nd hour postoperativelyin control group.In Dexmedetomidine group there was significant rise in blood glucose( p<0.05) in blood glucose 30 min post laryngoscopy and intubation. But it was much less than control group.(9.69% Vs 45.2%, p< 0.0001). The percentagerise in blood sugar levels found in their study was not similar to our study.

Yasha Dexmedetomidine produces effective attenuation of stress induced blood glucose levels by its postsynaptic alpha 2 agonist activity, causing significant reduction in releaseof Norepinephrine thereby reducing blood glucose level.

Its administration results in lower level of stress response markers (glucose, cortisol, interleukins)to surgery haas been seen.

In our study increased mean blood sugar levels were seen during and after surgery in Control group as compared to Dexmedetomidine group due to metabolic response to surgical trauma.

In Dexmedetomidine group, 2 patients had bradycardia at 1 hr after induction 44 - 45/min and was treated successfully with inj. Atropine 0.6mg IV, while no patient had bradycardia in control group. 1 patient in Dexmedetomidine group had hypotensionat 1 hr after induction as compared to nonein control group andwas managed with decreasing dial concentration of sevoflurane followed by 200ml IV fluid bolus and inj. Mephentermine 6mg IV. InDexmedetomidinegroup1patienthad nausea.InControlgroup, 4patientshadnauseaand 1 patient had vomiting.Both nausea and vomiting was treated with Inj. Metoclopramide 10mg IV Raham Hasan Moustafa found Nausea in 4 patients of Dexmedetomidine group and 7 patients in controlgroup.Whereasnauseaandvomitingseenin2patientsofcontrolgroup.andonly1patient hadvomitingincontrolgroup.Theydidnotfoundsignificantperioperativeadverseeffectsinboth groups.Nausea,vomiting,sedation,hypotensionandbradycardiaarecommonlyknownadverse effects of Dexmedetomidine.Laparoscopic surgeryisassociated witharemarkablyhighrate ofpost-operativenausea and vomiting (PONV).Number of complications were few in both groups andwere managed easily.

YashaKameshwaretaltheyfound bradycardia in2patientsinDexmedetomidine group and treated with Inj. Atropine 0.6mg IV and no patients had bradycardia in control group. Two patients had tachycardia in both the groups, while hypertension was seen in one patient in control group only. Theyfound dryness of mouth in 3 patientsofGroup D and 2 patients in Group P.

Harsoor S Set al noticed bradycardia in 3 out of 20 patients in Dexmedetomidine which was treated with Inj.Atropine0.6mgIV.There wasnoincidence ofbradycardiainPlacebo group.Ourresultsare comparable withRahamHasan Moustafaetaland Yasha Kameshwar et al.

Thus use of IV Dexmedetomidine in patients undergoing laparoscopic surgeries was successful inattenuatingthehyperglycaemicresponseasamarkerofstressresponse during surgery and immediate postoperative period.

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