INTRODUCTION:

The anaesthesia for day care has come into existance while in 1984 Society for Ambulatory Anesthesia, “SAMBA,” was established. Increasing financial awareness of 1970¹and the global economic constrains, reduced overall costs of procedure,improved monitoring devices to minimise the adverse effects of anaesthesia on the recovery process,availability of short acting anaesthetic,analgesic and sympatholytic drugs,shorter hospital stay so reduced incidence of nosocomial infections have led to the concept of fast tracking where the post-operative care unit is being bypassed.

The procedure can be performed under general anaesthesia, local anaesthetic block or under sedation of total intravenous anaesthesia (TIVA) in ambulatory surgery/day care surgery/out-patient surgeries where the patient is discharged the same day without overnight hospital stay. TIVA, a process in which induction and maintenance of anaesthesia carried out with intravenous agents only, is advantageous in day care surgery because of rapid recovery without any agitation besides low incidence of post procedure nausea vomiting. Hysteroscopic approach is the most frequently performed gynaecological procedure for diagnostic and therapeutic purpose now-a-days. Hysteroscopy, a form of minimally invasive surgery where a tiny telescope (hysteroscope) is inserted through the cervix into the uterus while the organ is insufflated with normal saline or sorbitol to inspect and examine on a video monitor, the intrauterine pathology if any inside the uterine cavity for the diagnosis and/or surgical intervention. Studies had been done in the day care gynaecological procedures with the drugs propofol, remifentanyl, remimazolam with TIVA but none became popular as a sole anaesthetic agent though to provide a balanced anaesthesia consisting of amnesia, hypnosis and analgesia several drugs can be used as supplements. Therefore, this study was undertaken to evaluate and compare the drugs dexmedetomidine and ketamine as sole agents in TIVA in day care hysteroscopic procedures.

Dexmedetomidine, a sedative analgesic and/or total anaesthetic agent causing no respiratory depression or the need for intubation of trachea in adults and paediatric patients undergoing minimally invasive procedures², has been approved by the federal drug administration. Dexmedetomidine possesses selective alpha adrenoreceptor agonism especially for the 2α receptor subtype and reduces top up requirements without causing significant respiratory depression³, affects the locus caeruleus area which controls respiration and causes modulation of sleep unlike conventional GABAergic sedative drug midazolam. Activation of the α2-adrenergic receptor of central nervous system results in analgesia⁴thus lowering biological stress response and catecholamine secretion resulting in reduction of blood pressure and heart rate to a moderate level. Ketamine, a n-methyl-d-aspartate (NMDA) receptor and glutamate receptor antagonist ,is a dissociative sedative hypnotic drug with potent analgesic properties and sympathomimetic effects on the cardiovascular system.

AIM AND OBJECTIVES:

Aim of this study is to assess and compare the efficacy of single preoperative dose of the drugs dexmedetomidine and ketamine as total intravenous anaesthesia (TIVA)

The objectives are:

· To compare the hemodynamic status

· Requirement of rescue sedative and/or analgesic during the procedure

· Any untoward effect associated with the drugs

· Duration of the procedure

STUDY DESIGN:

This is a prospective randomised double blinded comparative study.

SAMPLE SIZE:

Sample size calculation was performed using openepi.com. Assuming perioperative SBP at 0 min in dexmedetomidine group is 132.88±14.07⁵keeping power at 80% and confidence intervals at 95% (alpha error at 0.05), a sample of 20 patients would be required in each group to detect a minimum of 10% difference in the SBP between the two groups. We included 25 patients in each group to compensate for possible dropouts

STATISTICAL ANALYSIS:

Qualitative data was presented with the help of percentage table, association among the study groups was assessed with the help of Chi-square test. Quantitative data will be presented as mean and standard deviation, comparison among the study groups was done with the help of student t-test. Software used in the analysis was SPSS (Statistical Package for the Social Sciences) 20.0 version and p<0.05 was considered statistically significant.

MATERIAL AND METHODS:

After approval of the Institutional Ethical Committee and informed written consent from each patient, this prospective randomized double blinded study titled “Hysteroscopic Procedure As Day Care Cases Under Tiva With Dexmedetomidine Vs Ketamine” was conducted in the department of Anaesthesia, Acharya Vinoba Bhave Rural Hospital , a unit of Jawaharlal Nehru Medical College (DMIMS) Sawangi Wardha, during the period November 2016 to May 2017.

Inclusion Criteria:

Female patients of ASA grade І or II, age 20-55 years, weight 40-60kg, height 145-155cm, undergoing elective diagnostic hysteroscopic procedures.

Exclusion Criteria:

Emergency surgeries, pregnant or breast feeding patients, significant cardiovascular, hepatic, endocrinal or renal dysfunction, chronic user of α2-agonists, chronic use or addiction to opiates or sedatives, history of alcohol usage (>4 drinks/day), psychiatric or emotional disorder, patients with OSA or BMI greater than 30, history of allergy to egg or soya bean or study drugs or anesthetic medications used in the protocol, patients having difficulty to communicate due to language problem or deafness.

All patients underwent elective procedure of approximately 1h duration, were subjected to thorough pre-anesthetic evaluation and relevant laboratory investigations.

On arrival to the operation theatre multipara monitor, SpO₂, EtCO2 attached, ECG leads connected and base line parameters recorded, 18 gauge IV cannula inserted and Lactated Ringers solution through a drip set 15ml/kg infused.

Premedication:

Inj. Glycopyrrolate 0.01mg/kg and Inj Ondensetron 0.08 mg/kg injected IV at the onset of the procedure before administering the study drugs. After preoxygenation with 100%

After preoxygenation with 100% Oxygen for 3 mins, patients, according to computer-generated randomization were allocated to receive the study drugs as follows:⁶

Group D (n=25) dexmedetomidine 100µg IV

Group K (n=25) ketamine 75mg IV

Both the drugs were diluted with 10mL of normal saline and injected over 10min at the onset of the surgical procedure.

A team member who was not involved in data recording, prepared the syringes containing the acqueous solutions of either dexmedetomidine or ketamine in a double-blind fashion. Both the groups received Inj Midazolam 1.5mg IV immediately after the study drug was administered. Anaesthetic procedure had been maintained on (Hudson) mask ventilation with 30% oxygen and 70% nitrous oxide. Lack of response to verbal command and also RSS⁷ 3 [Fig.1] were considered the point of insertion of hysteroscope. If the target end point was reached before completing the loading infusion, then the infusion was stopped and noted. If any patient in either of the groups had sedation score RSS<3 then rescue bolus IV midazolam 0.01mg kg ^-1 was administered and was repeated if necessary till RSS was 3. Intraoperatively hemodynamic variables as the blood pressure and heart rate were monitored at 2 mins interval for first 10 mins and then every 10 mins till the surgery was over. During the procedure tachycardia (HR >110 beats/min or an increase of more than 20% from the baseline level) treated with midazolam 0.01mg kg ^-1 IV or bradycardia (HR <50 beats/min or a 20% decrease from the baseline) was treated with atropine sulphate 0.6mg IV, any hypotension (MAP value < 60mmHg or 20% less than the baseline) treated with fluid replacement and IV ephedrine hydrochloride 5mg in incremental doses if needed, or HTN (MAP levels > 150mmHg or 20% more from the baseline) treated with propofol 0.5mg kg^-¹ IV. In case of bradypnoea (RR < 8 breaths or less per minute) patient had been woken up and was asked to take deep breaths. Hypoxia or arterial SpO₂ value to <90% was treated by increasing O 2 flow up to 10 liters/min in bag mask ventilation.

Requirement of rescue drug doses such as propofol (0.5 mg kg−1 IV) when RSS was <3,fentanyl(1μg kg−1 IV) when when pain scoring VAS⁸ [Fig.2] was >4 during surgery was recorded, the protocol specified was up to a maximum of three rescue doses each. If at any time, the specified amounts of rescue drugs were exceeded for clinical indication, the sedation procedure was converted to any alternative sedative or anesthetic technique, the study drug was discontinued and the patient was dropped from the study. Complications such as cough, respiratory depression, dizziness, loss of analgesia, restlessness, nausea and vomiting, allergies as skin wheal during the procedure were recorded and compared between the groups. Once the procedure (diagnostic) completed, the hysteroscope was removed and that was the end point of our study. When the patient achieved modified Aldrete score (MAS)⁹ of 9-10 [Fig.3], was considered fit to be discharged to post operative care unit. Post-operative monitoring was done in the recovery room for any adverse effect such as nausea, vomiting, bradycardia, hypotension, oxygen desaturation, restlessness, shivering, abdominal discomfort and if any was treated accordingly.

Fig. 1: Ramsay sedation score (RSS)⁷

Fig. 2: Visual Analogue Scale (VAS) ⁸

Fig. 3: Modified Aldrete score (MAS)⁹

OBSERVATION AND RESULT:

Table 1: Patients' demographic data

Demographics	Group	N	M ± SD	p value
Age (yr)	Dexmedetomidine (D)	25	31.16 ± 8.38	p >0.05 (NS)
Age (yr)	Ketamine(K)	25	32.56 ± 9.05
Weight(kg)	Dexmedetomidine (D)	25	49.24 ± 6.49	p >0.05 (NS)
Weight(kg)	Ketamine(K)	25	51.1 ± 7.07
Height(cm)	Dexmedetomidine (D)	25	148.46 ± 4.74	p >0.05 (NS)
Height(cm)	Ketamine(K)	25	148.36 ±4.41
Duration of procedure (min)	Dexmedetomidine (D)	25	44.04 ± 7.50	p >0.05 (NS)
Duration of procedure (min)	Ketamine(K)	25	45.2 ± 8.22

Table 2: Haemodynamic parameter

Time (min)	Systolic BP			Diastolic BP			Heart rate
	D K			D K			D K
	M ±SD	M ±SD	p	M ±SD	M ±SD	p	M ±SD	M ±SD	p
0	115.1± 7.7	116.8±7.1	0.43	68.8±6.5	72.0± 5.6	0.63	76.4± 5.6	75± 5.0	0.36
2	108.8± 4.6	122.4±4.5	0.0001	65.8±4.2	71.6± 6.4	0.0005	67.8±6.7	78.6±5.3	0.0001
4	110.6± 6.4	127.9±5.3	0.0001	65.2± 4.5	75.3±5.8	0.0001	68.2±8.0	79.8±6.3	0.0001
6	107.5±5.8	127.5±6.1	0.0001	67.0±4.2	76.5±6.8	0.0001	66.7±6.4	82.8±4.6	0.0001
8	109 ± 4.3	127.8±5.0	0.0001	68.9±5.1	76.6±5.1	0.0001	63.8±6.1	79.8±5.4	0.0001
10	106.6± 5.3	128.2± 4.8	0.0001	68.8± 4.7	77.1± 6.7	0.0001	62.9±7.5	81.0±5.0	0.0001
20	106.9±5.4	127.5±5.8	0.0001	70.8± 4.1	80 ± 3.2	0.0001	65.3±5.4	81.8±6.2	0.0001
40	109.9±6.5	128.6±4.4	0.0001	74.7±7.1	81.8± 3.1	0.0001	62.3±8.6	86.6±3.1	0.0001
60	114.9±5.6	127.2± 6.1	0.0001	70 ±3.8	83.2 ±3.4	0.0001	75.1±4.4	81.9±6.9	0.0001

Number of patient in each group 25 ‘p’ value of <0.0001 statistically very highly significant

Table 3: Rescue sedative and analgesic

Rescue Propofol	Dexmedetomodine	M ± SD	Ketamine	M ± SD	p value
Yes/Number	1/24	0.04± 0.20	8/17	0.32 ± 0.48	0.0093 (HS)
No.of top-ups(1/2/3)	0/1/0		4/3/1
Rescue Midazolam
Yes/Number	1/24	0.04 ± 0.20	13/12	0.52 ± 0.51	0.0001 (HS)
No.of top-ups(1/2/3)	1/0/0		9/2/2
Rescue Fentanyl
Yes/Number	2/23	0.08 ± 0.28	1/24	0.04 ± 0.20	0.05609 (NS)
No.of top-ups (1/2/3)	1/1/0		1/0/0

‘p’ value of <0.01 as statistically highly significant (HS). Number of patient in each group 25.

Table 4: Per-operative complication

	D (Dex) (n=25)	K (Ket) (n=25)
Nausea, Vomiting	1(4%)	6 (24%)
Hypotension	0	0
Bradycardia	4 (16%)	0
O₂desaturation	0	3 (12%)
Restlessness	0	8 (32%)
Shivering	0	6(24%)
Abd. discomfort	0	1 (4%)

The haemodynamics at the 0 min (base line value, immediately before applying the study drugs) were not significant statistically and comparable between the groups.The systolic and diastolic blood pressure and heart rate changes in the groups starting from 2mins after the study drugs were injected were statistically very highly significant.The haemodynamics were stable in the group D. [Table 2]

The requirement for rescue sedation propofol and midazolam, rescue analgesic fentanyl and the number of top -up doses were higher in the group K. The difference in the groups D and K as per the requirement are statistically highly significant with rescue propofol and midazolam but insignificant with fentanyl.

Discussion:

Day care gynaecological procedures need short acting anaesthetic agents with the properties of amnesia, hypnosis and analgesia. So we preferred the drugs dexmedetomidine and ketamine in single preoperative dose as total intravenous anaesthesia (TIVA) for this prospective randomized study to asssess and compare the efficacy of the study drugs. At low doses, dexmedetomidine produces dose dependent sedative effect⁶ that mimics natural sleep of stage 2 non-rapid eye movement. Patients remain drowsy but are co-operative and arousable.¹⁰ Dexmedetomidine also has the properties of being sympatholytic, amnestic and analgesic¹¹without causing respiratory depression. The distribution half life of dexmedetomidine is 6 min and terminal elimination half life is 2hr. We followed previous studies for selection of dose of dexmedetomidine to induce sedation in patients who underwent anesthesia.¹² Our study dose of dexmedetomidine 100µg IV over 10 min to induce sedation in patients who underwent anesthesia was used in the range of those used in other studies.^12,13,14Ketamine, a dissociative anaesthetic agent,causes inhibition of sensory perception which is mediated by N-methyl D-aspartate receptor blockade.¹⁵Cardiostimulatory responses like hypertension and/or tachycardia after Ketamine induction and postoperative hallucinations which is reflected as the emergent reaction of Ketamine can be overcome by premedication with benzodiazepine.^16,17The elimination half life of Ketamine has been found to be 2.5-3 hr which is comparable to dexmedetomidine.

Talke P et al.¹⁸ published that dexmedetomidine, because of its sympatholytic effects and ability to decrease circulating catecholamine levels causes decrease in the HR.Taniyama et al.¹⁹ also found in their study statistically significant lower HRs in the dexmedetomidine group . In our study too we observed decrease in HR from the base line value throughout the study period in Group D which is lower than Group K and the comparison is highly significant (p<0.0001), [Table 2, Graph 1] Similarly,the blood pressure (BP) values also showed the same trend as the heart rate[Table 2] in Group D and Group K. In controlling SBP, DBP, dexmedetomidine proved clinical advantages over ketamine. The 'p' value of <0.0001 is statistically highly significant all along the study period barring the base line records where the values ae comparable [Table 2, Graph 2]. In 2013, Devangi A Parikh et al.²⁰ observed in their study lower HR and MAP and their findings support other studies.^21,22The effects of dexmedetomidine are not mediated by the Ỳ aminobutyric system²³so it does not cause respiratory depression. This finding is similar to other studies.^24,25Walker et al.²⁶, stated that Dexmedetomidine is not associated with respiratory depression. Our study also shows similar pattern and there was neitherany evidence of bradyponea in our study groups. RSS, to be assessed, the sedated patients are to be made alert and depending on the response of the patient,the assessor makes a subjective scoring of sedation. Our assessment in the study, was based on the response on painful stimuli which was amenable to the surgical procedure. The rescue drug was then administered as per the requirement (Table 3) in titrable doses. So no extra effort was needed to be taken for assessing the RSS. Additional sedatives and analgesics as rescue drugs if required were provided with midazolam and fentanyl respectively in equivalent doses and were common in both the groups to avoid any bias in our results. Reetu Verma et al.²⁷ in 2014 have demonstrated that in the perioperative period, dexM, without clinically significant respiratory depression provides adequate levels of sedation and observed that rescue analgesia as injection fentanyl was required in less number of patients in dexM group which explains the analgesic property of the drug,that is consistent with the findings of Arain and Ebert²⁸ and Taghinia AH et al.²⁹Similarly,Scheinin B et al.³⁰established that analgesia induced by fentanyl is potentiated by dexmedetomidine. Our study results also support the same and and group D had

less number of requirements for rescue sedation with midazolam and propofol with highly significant statistical ‘p’ value <0.01 though analgesia by fentanyl in group D and group K were statistically insignificant (Table 3). Suzuki M et al.³¹observed that Ketamine, allows a reduction in opioid (morphine) requirements by approximately 40%. Ketamine, at subanesthetic doses has sedative and amnestic properties and analgesic activity.³²Nightmares and hallucinations may occur in 5-30% of patients, at high doses, but occurence is significantly less frequentl at doses < 1 mg·kg⁻¹.³³ Low dose of Ketamine is not associated with respiratory depression.³⁴ In the present study the dose we used was 75mg for all the patients which comes in the dose range of < 2mg kg⁻1. But still 16% had 0₂desaturation intra-operatively, 28% suffered shivering, 24% were restless, 8% felt abdominal discomfort, 24% felt nausea vomiting (Table 4) in the perioperative procedure though only 4% in dexmedetomidine group had nausea. Therewas hemodynamic unstability in the Ketamine group in comparison to the dexmedetomidine one.But none of the subjects in our study developed postoperative hallucinations or nightmares (Table 4). Propofol (2,6-di-isopropylphenol) is a short-acting, hypnotic/amnestic agent administered IV. Since propofol has no analgesic property, fentanyl, a synthetic opiod, related to phenlpiperidine is used in our study as adjuvant to alleviate pain.³⁵ It acts on µ receptors as agonist.In our study, there was a significant difference between the two groups D and K regarding the requirement of propofol as rescue sedative with an increasing trend of using these in Group K [p <0.01, statistically highly significant (HS)] Midazolam, is widely used during monitored anaesthesia care (MAC) because of its sedative, anxiolytic and amnesic effects and a short elimination half life (2 hours). Arellano RJ et al.³⁶published that, for endoscopic, angiographic diagnostic purpose and other minor procedures, Nitrous oxide though is accused of causing increase in PONV but has been confronted with rather it improves post operative pain control.³⁷Beacause nitrous oxide inhibits the NMDA receptor so it might reduce hyperalgesia and tolerance caused by opoid administration. Major side effect of alpha-2-agonist agents is bradycardia, which is mediated by activation of alpha-2-adrenoceptors, especially in the solitarius nucleus tract.³⁸ In our study, there was no intra or post operative adverse effects as respiratory depression,restlessness, though nausea and vomiting was only in 1 patient in dexmedetomidine group (D).So our results were similar to Abdellatif et al³⁹ Ghali et al⁴⁰, Arain and Ebert²⁸, Takimoto et al⁴¹ who had established the sedation safety and reduced adverse effects of dexmedetomidine. Postoperatively, an Aldrete score of 10 was considered to be the end point of study.

CONCLUSION:

So, we can claim that the use of dexmedetomidine in TIVA can be the drug of choice for day care gynaecological procedures. Unlike ketamine, dexmedetomidine having slower onset and offset of sedation,is a safe drug with improved analgesia and sedation with less requirement of narcotic analgesic or sedative in the periperative period, good hemodynamic and recovery profile with clear consciousness and alert state of mind. Very few studies are published regarding its use in day care gynaecological procedures as in TIVA and no study had been found with ketamine in comparison. So this study would possibly help in filling up the void in knowledge.

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Received on 20.12.2020 Modified on 02.07.2021

Research J. Pharm.and Tech 2022; 15(4):1785-1790.

DOI: 10.52711/0974-360X.2022.00299