COMPARISON OF INTRANASAL DEXMEDETOMIDINE V/S MIDAZOLAM AS A PREMEDICATION IN CHIDREN WITH CONGENITAL HEART DISEASE UNDERGOING CARDIAC SURGERY

Background: The intranasal route is a reliable way to administer preanaesthetics and sedatives to children. The aim of present study was to compare the anxiolytic and sedative effects of intranasal dexemedetomidine and midazolam as a premedication in children with congenital heart disease undergoing cardiac surgery.. Patients and Methods: Fifty chidrens 2-12 years of age group of either sex with congenital heart disease undergoing cardiac surgery were randomly allocated into two groups. examination. Routine investigation – Hb, TLC, DLC, Platelet count, Bleeding time, Clotting time, Fasting blood sugar, Serum Urea and Creatinine, SGOT, SGPT, Chest X ray, ECG, 2D Echo, Angiography. Written informed consent was obtained for performance of general anaesthesia after complete explaination about the study protocol and the procedure.

Dexmedetomidine is a newer highly selective ᾳ₂-adrenergic agonist, approved by FDA in 1999. It possesses hypnotic, sedative, anxiolytic, sympatholytic and analgesic properties without producing significant respiratory depression{5}. It also diminishes intra operative requirement of analgesics and anaesthetics{6}.Dexmedetomidine increases the hemodynamic stability by altering the stress induced sympatho-adrenal responses to intubation{7}.Dexmedetomidine (0.2-1mcg/kg) is tasteless, odourless & painless when administered by intranasal route. It produce sedation, facilitate parental separation, and improve conditions for induction of general anesthesia, while preserving airway reflexes.
Midazolam is the most commonly used premedication in children. Midazolam has sedative, anxiolytic, hypnotic & anterograde amnesic properties. It has been shown to be more effective than parental presence or placebo in reducing anxiety and improving compliance at induction of anesthesia. It can be given for premedication via intranasal route, have rapidly absorbed from nasal mucosa and onset of sedation and analgesia is fast{8}.
Anxiety and psychological trauma due to maternal deprivation are major challenges in childrens during administration of anaesthesia. Preanaesthetic medication in children should be aimed to decrease the anxiety and psychological trauma and also to facilitate the induction of anesthesia without delaying the recovery. The most commonly used drugs are midazolam, dexmedetomidine, ketamine, transmucosal fentanyl and mepredine, promethazine, diazepam, morphine{9}.
The aim of present study was to compare the anxiolytic and sedative effects of intranasal dexemedetomidine and midazolam as a premedication in children with congenital heart disease(eg;-ASD,VSD) undergoing cardiac surgery.

Subject:
Pediatric patients with congenital heart disease posted for cardiac surgery under general anaesthesia.

Study Location:
After attaining ethical committee approval, the study was conducted on children with congenital heart disease undergoing cardiac surgery at Cardiac OT in the Department of Anaesthesiology, S.M.S. Medical College & attached Group of Hospitals, Jaipur after obtaining the written informed consent from all patients.

Sample Size:
The sample size was calculated to be a minimum of 17 subject in each group at alpha error 0.05 and study power 90% to detect expected minimum difference of 1.4 ± 1.2 (as per reference article) in VAS score after 30 minutes of drug administration among the two study groups. Hence for study purpose sample size was enhanced and rounded off to 25 subjects in each of the two groups as per seed article{10}.

Sampling Technique:
The subjects were randomized into the two groups by simple random sampling using sealed envelope method.

Blinding:
This trial was so planned that neither the doctor nor the participant were aware of the group allocation and the drug received. Study drug was prepared by one anaesthetist and after the completion of the procedure he or she has disclosed the name of the study drug. All the observations were noted as proforma.

Study Universe:
The study included 50 patients undergoing cardiac surgery under general anaesthesia.

Procedure:-
On arrival in the operation theatre, fasting status, written informed consent and PAC was checked. Routine non invasive monitors attached and baseline parameters i.e. heart rate (HR), Systolic blood pressure (SBP), Diastolic blood pressure (DBP), Mean arterial pressure (MAP), and SpO₂ were noted. ECG & ETCO₂ were attached to the patient. General assessment for mental status, weight, pulse was recorded.
Demographic data including age, weight, sedation scale before premedication were recorded. The calculated dose of the study drug to the patient was administered in each nostrils divided equally 30 min before induction of anaesthesia. The study drug was administered prefilled in a syringe attached to nasal atomizer. For next 30 min patients were asked to maintain supine position with slight head low. Before induction data were collected for onset of sedation. Sedation score(six points sedation scale), anxiety score, child parent separation score & haemodynamic data(HR, NIBP, PR, RR & SPO2) were recorded at 5, 10, 15, 20, 25 & 30 minutes. IV line secured and IV fluids RL was started at 5ml/kg/hr. IV glycopyrrolate 0.004 mg/kg was given. Induction was done with an induction agent Inj.

817
Etomidate 0.3mg/kg, rocuronium 0.9mg/kg was given. Hemodynamic data were collected just before intubation. Patient were intubated with appropriate size of endotracheal tube and maintained on O2 and inhalational anaesthetic (isoflurane). Hemodynamic data were collected intraop. At the conclusion of surgery patient were shifted to cardiac ICU. Patient were observed for any side effects.

Outcome analysis:-
Qualitative data (Gender, complication) were summarized as number & percentage and analyzed using Chi square test. Continuous variable (HR, SBP etc) were summarized as mean & standard deviation and analyzed using unpaired t test. Ordinal variables (scores) were summarized as median & range and analyzed using Mann Whitney U test.

Statistical analysis:-
Data obtained from predesigned proforma was entered into MS EXCEL sheets and master chart was prepared.
Statistical analysis was performed with the SPSS, version 21 for Windows statistical software package (SPSS inc., Chicago, IL, USA). The Categorical data was presented as numbers (percent) and were compared among groups using Chi square test. The quantitative data was presented as mean and standard deviation and were compared by student t-test. Anova/Kruskal Wallis Test were used to compare the medians of more than two sample. P-value was considered to be statistically significant if less than 0.05.

Discussion:-
Preoperative anxiety (anxiety regarding impending surgical experience) in children is a common phenomenon that has been associated with a number of negative behaviors during the surgery experience (e.g., agitation, crying, spontaneous urination, and the need for physical restraint during anesthetic induction). Preoperative anxiety has also been associated with the display of a number of maladaptive behaviours postsurgery, including postoperative pain, sleeping disturbances, parent-child conflict, and separation anxiety. For these reasons, researchers had soughted out interventions to treat or prevent childhood preoperative anxiety and possibly decrease the development of negative behaviours postsurgery.Iirola et al{11}documented that administration of intranasal dexmedetomidine had a high bioavailablity 65% (35%-93%) and was potentially useful sedative effects in surgical procedures. H Gudmundsdottiretal{12}found that Intranasal administration of midazolam had rapid and reliable onset of action and predictable effects. The absolute bioavailability of midazolam in the nasal formulation was determined to be 64 ± 19% (mean ± standard deviation). With this background 50 patients of ASA grade 2 and 3, aged between 2 to 10 years, wt up to 30 kg with congenital heart disease undergoing cardiac surgery under general anaesthesia were randomly selected after applying inclusion and exclusion criteria. These patients were divided into two groups, group A (Dexmedetomidine group) and group B (Midazolam group).
In our study, sedation score, child parental separation score, anxiety score in both the groups were compared. In addition demographical variables (such as age, gender, ASA grading, wt) and hemodynamic changes (such as heart rate, systolic blood pressure, diastolic blood pressure , mean arterial blood pressure, arterial oxygen saturation and respiratory rate) were compared. Six point sedation scale (Ramsay scale) for sedation score, four point scale for child parental separation score and four point scale for anxiety score were used to compare the groups in this study.The mean age of the patients in A group was 7.00±4.34 years and in B group was 7.68±3.18 years. There was no statistically significant difference between the groups with regards to age (p˃0.05). This helped us to judge the clinical significance of our study as the distribution, metabolism, excretion and action of drug are undoubtedly varied in different age groups. Therefore, clinically insignificant variation in age simply helped to alleviate these confounding factors.
In group A 15 patients were male and 10 patients were female. In group B 15 patients were male and 10 patients were female. There was no statistically significant difference between the groups with regards to gender (p˃0.05). There was no statistically significant difference between the groups with regards to ASA grading (p˃0.05).  Dexmedetomidine produces sedation by stimulating α2-adrenergic receptors in the locus coeruleus, apart from the brain stem involved in the sleep-wake cycle, which reduce central sympathetic outflow, resulting in increased stimulation of inhibitory neurons{14}.Therefore, it causes analgesia and sedation without causing respiratory depression. It produces "cooperative sedation," which means that the sedated patient can still interact with healthcare professionals{15,16}.while midazolam stimulates gamma-aminobutyric acid (GABA) receptors in the cerebral cortex to increase the conductance of chloride ions and hyperpolarization that inhibits normal function of neurons producing sedation.

Anxiety Score:-
In our study, anxiety score was assessed using Four point scale (Table no. 3). We found that anxiety score was lower (less anxiety) in dexmedetomidine group (  2) attained significant and satisfactory sedation with better levels without any adverse effects as compared with intranasal midazolam (3.34±0.9) in children with simple congenital heart disease (ASD, VSD) undergoing cardiac catheterization (p value < 0.05).Ghali AM et al{13} did a comparison of intranasal dexmedetomidine versus oral midazolam as a preanesthetic medication in children.
Intranasal dexmedetomidine (2.94±1.37) appeared to be a better choice for preanesthetic medication than oral midazolam (3.99±1.58) in their study. Dexmedetomidine was associated with lower sedation levels at the time of transferring patients to the OT than children who received oral midazolam (p value 0.042). V. M. Yuenetal{19}found similar results that's coincide with our study. In our study the mean SBP, mean DBP, mean MAP decreased in both the study groups after premedication (Table  no. 6,7,8). There was statistically significant reduction in systolic and diastolic blood pressure and mean arterial blood pressure in group A as compared to group B at 5, 10, 15, 20, 25 and 30 min after premedication (p value < 0.05).In our study, peripheral arterial SpO2 and RR were compared in both groups (Table no. 9 and 10 ) at various time intervals till 30 min after premedication. There were no significant differences observed in both groups (p value > 0.05).
In the current study, the peripheral arterial SpO 2 and RR were well maintained throughout the perioperative observation period in both groups. Dexmedetomidine does not suppress respiratory function, even at high doses{20} while midazolam acts as GABA-mimetic drug, and therefore, it is known to decrease the respiratory drive in a dosedependent manner{18}.
Similar results were reported by Yuen et al{21}. They did a comparison of intranasal dexmedetomidine and oral midazolam for premedication in pediatricanesthesia and found that dexmedetomidine was known to decrease sympathetic outflow and circulating catecholamine levels and was therefore be expected to cause a decrease in HR and SBP{22}.
In addition, this study demonstrated that intranasal dexmedetomidine reduced HR and SBP during the preoperative sedation period compared with the oral midazolam. Children in both groups maintained normal SpO 2 value

Results And Conclusion:-
The following observations were made No significant difference regarding demographic data (age, gender, body weight) was observed. No significant difference regarding ASA grading was observed.
Children in dexmedetomidine group achieved significant higher sedation score and lower anxiety score (more sedated) up to 30 min after drug administration in comparison to midazolam group. Furthermore, the children were satisfactorily separated from parents in dexmedetomidine group when compared to the midazolam group.
Hemodynamic data showed that SBP, DBP, MAP and HR were significantly decreased 5, 10, 15, 20, 25 and 30 min after drug administration in the dexmedetomidine group when compared with the midazolam group.
Peripheral arterial SpO 2 and RR displayed no significant difference between the studied groups throughout the study period.
Finally we conclude that intranasal dexmedetomidine appears to be a better choice for preanesthetic medication than intranasal midazolam in our study. Premedication with intranasal dexmedetomidine attained significant and satisfactory sedation with better parent separation and lower anxiety levels without any adverse effects as compared with intranasal midazolam in children with congenital heart disease undergoing cardiac surgery.