KARNATAKA, BANGALORE.
SYNOPSIS FOR REGISTRATION OF SUBJECT FOR DISSERTATION
1. / Name of the candidate and address
(in block letters) / DR.SANDEEP KUMAR.
POSTGRADUATE STUDENT
DEPARTMENT OF ANAESTHESIOLOGY
SDM COLLEGE OF MEDICAL SCIENCES & HOSPITAL
MANJUSHREE NAGAR, SATTUR
DHARWAD, KARNATAKA – 580009
2. / Name of the Institution / SDM COLLEGE OF MEDICAL SCIENCES & HOSPITAL
MANJUSHREE NAGAR, SATTUR
DHARWAD, KARNATAKA – 580009
3. / Course of study and subject / M.D (ANAESTHESIOLOGY)
4. / Date of admission to the course / 05-06-2013
5. / Title of the Dissertation / Study of dose related effects of dexmedetomidineon laryngeal mask airway removal in children undergoing herniotomy-Adouble blind randomized study
6. / BRIEF RESUME OF THE INTENDED WORK:
6.1Need for the study:Dexmedetomidine, an α2-adrenergic agonist, was
approved by the U.S. Food and Drug Administration in 1999 for sedation in adults whose airways were intubated in the intensive care unit (ICU) and subsequently it wasapproved in 2008 for sedation for surgical or medical procedures in adultswithout secured airway in non ICU setup.1Dexmedetomidine being a α2 adrenergic receptor agonist potentiates anesthetic effect of all the anesthetic agents irrespectiveof the mode of administration (intravenous, inhalational,regional blockade). Intraoperative administration of dexmedetomidine in lower concentrations has reducedthe requirement of other anesthetic agents; fewer interventions to treat tachycardia; and a reduction in the incidence of myocardial ischemia.2Dexmedetomidine has been used for the sedation of paediatric patients undergoing different type of procedures such as cardiac catheterization and magnetic resonance imaging. Dexmedetomidine was administered in conjunction with local anaesthesia and/or other sedatives.3Dexmedetomidine can be successfully used in pediatric patients for smooth removal of laryngeal mask airway (LMA) and decreasing postoperative respiratory complication and agitation.4Dexmedetomidine 0.75μg/kg administered 15min before extubation, stabilizes hemodynamics and facilitates smooth extubation.5 Not many studies have been conducted to evaluate the efficacy of different doses of dexmedetomidine on LMA removal and post operative recovery in pediatric age group, so there is a need for conducting a study on this which after completion may be of benefit in anaesthesia practice and use of dexmedetomidine in pediatric patients anaesthetized using LMA.
6.2 Review of the literature:
Dexmedetomidine was approved by the Food and Drug Administration at the end of 1999 for use in humans as a short term medication (<24 hours) for anaesthesia and sedation in the intensive care unit. Dexmedetomidinehydrochlorideis the S-enantiomer of medetomidine and is chemically described as (+)-4-(S)-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole monohydrochloride. Dexmedetomidine has a molecular weight of 236.7 and the empirical formula isC13H16N2•HCl and the structural formula is
It exhibits a rapid distribution phase with a distribution half-life (t1/2) of approximately 6 minutes; a terminal elimination half-life (t1/2) of approximately 2 hours; and steady-state volume of distribution (Vss) of approximately 118 liters. Clearance is estimated to be approximately 39 L/hr. Dexmedetomidine exhibits linear kinetics in the dosage range of 0.2 to 0.7μg/kg/hr when administered by i.v. infusion for upto 24 hours. The average protein binding is 94% and is significantly decreased in subjects with hepatic impairment. Dexmedetomidine undergoes almost complete biotransformation with very little unchanged dexmedetomidine excreted in urine and faeces. Biotransformation involves both direct glucuronidation as well as cytochrome P450 mediated metabolism.
Mechanism of action of Dexmedetomidine
The mechanism of action of dexmedetomidine is unique and differs from the currently used sedative drugs. α 2-adrenoceptors are found in many sites through the CNS, however, the highest densities of α 2-receptors are found in the Locus Ceruleus, the predominant noradrenergic nuclei of the brainstem and an important modulator of vigilance. Presynaptic activation of the α 2-adrenoceptor in the Locus Ceruleus inhibits the release of norepinephrine (NE) and results in thesedative and hypnotic effects. In addition, the Locus Ceruleus is the siteof origin for the descending medullospinal noradrenergic pathway, knownto be an important modulator of nociceptive neurotransmission.Stimulation of the alpha2-adrenoceptors in this area terminates thepropagation of pain signals leading to analgesia. Postsynaptic activationof α2-adrenoceptors in the CNS results in decrease in sympatheticactivity leading to hypotension and bradychardia. Also, activation of the α2-adrenoceptors in the CNS results in an augmentation of cardiacvagalactivity. Combined, these effects can produce analgesia, sedationand anxiolysis.
At the spinal cord, stimulation of α2-receptors at the substantiagelatinosa of the dorsal horn leads to inhibition of the firing ofnociceptive neurons and inhibition of the release of substance P. Also,the α2-adrenoceptors located at the nerve endings have a possible rolein the analgesic mechanisms of α2-agonists by preventing NE release.The spinal mechanism is the principal mechanism for the analgesic actionof Dexmedetomidine even though there is a clear evidence for both asupraspinal and peripheral sites of action.
α2-recepots are located on blood vessels where they mediatevasoconstriction, and on sympathetic terminals, where they inhibit NErelease. The responses of activation of α2-adrenoceptors in otherareas include contraction of vascular and other smooth muscles;decreased salivation, decreased secretion, and decreased bowel motility inthe gastrointestinal tract, inhibition of renin release, increased glomerularfiltration, and increased secretion of sodium and water in the kidney;decreased insulin release from the pancreas, decreased intraocularpressure, decreased platelet aggregation and decreased shiveringthreshold by 2°C.7
Mason KP and Lerman J in their review article summarize that dexmedetomidine is an effective sedative for infants and children that only minimally depresses the respiratory system while maintaining a patent airway. However, dexmedetomidine does depress the cardiovascular system. Specifically, bradycardia, hypotension and hypertension occur to varying degrees depending on the age of the child. Dexmedetomidine provides and augments analgesia and diminishes shivering as well as agitation postoperatively. The safety record of dexmedetomidine suggests that it can be used effectively and safely in children, with appropriate monitoring and interventions to manage cardiovascular sequelae”.6
Dexmedetomidine loading dose ranges from 0.3 to 2 µg /kg, and infusion dose ranges from 0.2 to 3 µg/kg/h.3,6
Case reports describe excellent conditions for successful laryngoscopy, rigid bronchoscopy, and tracheal extubation when an infusion of dexmedetomidine 2.5 µg/kg/h is combined with propofol (200 to 250 µg/kg/min) and supplemented with boluses of dexmedetomidine (0.25 to 1 µg/kg) for tracheal reactivity.8
Le. He, X Wang et al concluded that dexmedetomidine infusion produced a dose dependent decrease in end tidal concentration of sevoflurane required for smooth removal of LMA in children aged3- 7 years and was associated with less agitation in post anaesthetic care unit.4
M. Shukry et al. studied the effects of continuous perioperative infusion of
0.2 µg/kg/hr dexmedetomidine on the incidence of emergence delirium in 50children aged 1–10 years scheduled for sevoflurane based general anaesthesia and concluded that the perioperative infusion of 0.2 µg/kg/hr dexmedetomidine decreases the incidence and frequency of emergence delirium in children after sevoflurane based general anaesthesia without prolonging the time to extubate or discharge.9
G. Guler et al. studied60 children (age 3–7 years) randomly assigning them to receive dexmedetomidine 0.5 µg/kg IV or placebo, 5 min before the end of surgery, induction and maintenance of anesthesia was done using sevoflurane. Results showed that the incidence of agitation, pain, cough were significantly less in the dexmedetomidine group. Postoperative vomiting was similar in both groups. Times to emergence and extubation were significantly longer in the dexmedetomidine group. They concluded that 0.5 µg/kg IV dexmedetomidine reduces agitation after sevoflurane anesthesia in children undergoing adenotonsillectomy.10
Ibacache et al studied the effect of dexmedetomidine on recovery characteristics in 90 children aged 1 to 10 yr scheduled to undergo superficial lower abdominaland genital surgery. After inhaled induction with sevoflurane, patients were randomly assigned to receive saline (Group 1), dexmedetomidine 0.15 µg/kg (Group 2), or dexmedetomidine0.3 µg/kg (Group 3). The incidence of agitation was 37% in Group 1, 17% in Group 2, and 10% in Group 3. They concluded that a dose of dexmedetomidine 0.3 µg/kg administered after induction of anesthesia reduces the sevoflurane induced agitation in children and with no adverse effects.11
6.3 Aims and Objectives of the study:
Primary outcome measures:
1)Effects ofdexmedetomidine on complications occurring during LMA removal.
2)Postoperative agitation.
Secondary outcome measures:
1)Intraoperative hemodynamic stability.
2)Emergence time.
3)Respiratory complications.
4)Recovery time.
7. / Materials and Methods:
7.1 Source of data:
Study subjects: Pediatric patients undergoing herniotomy under general anaesthesia at SDM College of Medical Sciences and Hospital, Dharwad, Karnataka during my study period.
Inclusion criteria:
- Pediatric patients in age group 1 to 12 years
- ASA physical status I or II
- Patients undergoing herniotomy under general anaesthesia
- ASA physical status III or IV
- Patients having arrhythmias
- Congenital heart disease
- Respiratory tract infection
- Difficult airway
- Allergic to the medications being used
- No consent for the procedure
Study period: October 2013 to June 2015
Type of Study: A prospective double blinded randomized study
7.2 Methods of collection of data:
Study design: After obtaining permission from the institutional ethical committee and informed consent from the patient’s guardian, patients will be studied in this prospective randomized study. All the patients will be kept nil-per-oral 6 hours for solids, 4 hours semisolids and 2 hours for clear fluids. Sedative premedication midazolam 0.5mg/kg oral will be given 1 hr before surgery. The patients will be randomly allocated into either of the three groups saline (Group S), dexmedetomidine 0.5µg/kg (Group D0.5) or dexmedetomidine 1µg/kg (Group D1) using computer generated random numbers.
In the operation theatre, standard monitoring with electrocardiogram, noninvasive oscillometric blood pressure (NIBP) and pulse-oximetry will be initiated and baseline values will be recorded and continuous monitoring will be done during the whole study.
Anaesthesia will be induced with sevoflurane in oxygen.Appropriate intravenous (IV) access will be secured and started on Ringer’s Lactate (RL). All patients willreceive fentanyl 1μg/kg followed by caudal block with 1ml/kg of 0.25% bupivacaine for perioperative analgesia. LMA of appropriate size will be inserted when jaw relaxation is adequate. The LMA will be selected as size 1 for <5 kg, size 1.5 for 5-10 kg , size 2 for 10-20 kg and size 2.5 for 20 to 30 kg.Soon after insertion of LMA patients will receive 5ml of the study drug drawn in 5 ml syringe given over 10 minute. Group D0.5 will receive dexmedetomidine 0.5 µg/kg ,Group D1 will receive a dexmedetomidine 1 µg/kg and Group S will receive 5 ml of saline.
Anaesthesia will be maintained with sevoflurane in oxygen and nitrous oxide.Sevoflurane concentration will be adjusted in response to hemodynamic response of each patient.
Spontaneous ventilation will be maintained during operation, if patient becomes apnoeic or end tidal carbondioxide rises over 45mmHg ventilation will be assisted manually.
After the surgery has been completed sevoflurane and nitrous would be cut off and waited for emergence with patient breathing on 100% oxygen. LMA will be removed with the cuff inflated when the patient meets recovery criteria i.e. spontaneous eye opening, facial grimace and purposeful arm movements.
The definition of smooth removal will be absence of development of vigorous coughing (coughing >4 timescontinuously), breath holding,LMA biting, gross head movements,teeth clenching, vomitingduring or within one minute of LMA removal.
Any need of airway assistance or adverse events like laryngospasm or desaturation immediately after LMA removal and the appropriate treatment will be documented
Assesment of recovery : Patient will be kept in PACU until they attend an Aldrete score of 9 or more and free from vomiting . The post operative recovery including respiratory complications like laryngospasm, breath holding (more than 20sec), severe coughing( > 4 times continously),desaturation (< 95%), execessive salivation ( requiring suctioning ) would be noted.
Assessment of emergence agitation (EA) :
The incidence of EA will be evaluated using Aonos four point scale;[12] , according to which 1=calm; 2=not calm but could be easily consoled; 3=moderately agitated or restless and not easily calmed; 4=combative, excited, or disoriented, thrashing around. Scores of one and two will be considered as absence of EA, and scores of three and four as presence of EA.
Patients who have pain will be given fentanyl 1μg/kg
Sample size: Minimum of 30 in each of the three groups.
Data collection: Pediatric Patients undergoing herniotomy fulfilling the inclusion criteria will be selected and blinding maintained, data collection using a standardised proforma for all patients.
Statistical Analysis: Descriptive statistics will be applied. Data will be analysed by rates, ratios, percentages and proportions. Chi-square test will be done to find out the association between two attributes. P< 0.05 will be considered to be statistically significant
7.3 Does the study require any investigations or interventions to be conducted on patients or other humans or animals?If so, please describe briefly.
No.The study does not require any investigations or interventions to be done on the patients for the purpose of the study
7.4 Has ethical clearance been obtained from ethical committee of your institution in case of 7.3?
Yes
8. / List of References:
[1].Precedex (dexmedetomidine) package insert. Lake Forest, IL:
Hospira, Inc., 2008.
[2]. Aho M, Lehtinen AM, Erkola O, Kallio A, Korttila K. The effect of intravenouslyadministered dexmedetomidine on perioperative hemodynamics and isoflurane requirements in patients undergoing abdominal hysterectomy. Anesthesiology 1991;74:997-1002.
[3].Shukry M, Miller JA.Update on dexmedetomidine: use in nonintubated patients requiring sedation for surgical procedures.TherClin Risk Manag 2010;6:111–21
[4]. L. He, X. Wang, S. Zheng, Y. Shi. Effects of dexmedetomidine infusion on laryngeal mask airway removal and post operative recovery in children anaesthetized with sevoflurane. Anaesth Intensive Care 2013; 41: 323-28.
[5]. Bindu B, Pasupuleti S, Gowd UP, Gorre V, Murthy RR, Laxmi MB. A double blind,randomized,controlled trial to study effect of dexmedetomidine on hemodynamic and recovery responses during tracheal extubation. Journ of anaesthclinpharma2013; 29( 2):162-67.
[6]Mason KP, Lerman J. Dexmedetomidine in children:Current knowledge and future applications. AnesthAnalg 2011;113:1129-42.
[7]Vanda G, Yazbek K, Marie M. Perioperative uses of dexmedetomidine. M.E.J. Anesth 18 (6), 2006:1043-58.
[8] Seybold JL, Ramamurthi RJ, Hammer GB. The use of dexmedetomidineduring laryngoscopy, bronchoscopy, and tracheal extubation following tracheal reconstruction. PediatrAnesth 2007;17:1212–4.
[9] Shukry M , Clyde MC ,Kalarickal PL, Ramadhyani U. Does dexmedetomidine prevent emergence delirium in children after sevoflurane-based general anesthesia? PediatrAnesth 2005;15:1098-104.
[10] Guler G, Akin A, Tosun Z, Ors S, Esmaoglu A,Boyaci A. Single dose dexmedetomidine reduces agitation and provides smooth extubation after pediatric adenotonsillectomy.PediatrAnesth 2005;15:762-66.
[11] Ibacache ME, Munoz HR, Brandes V, Morales AL.Single-dose dexmedetomidine reduces agitation after
sevoflurane anesthesia in children.AnesthAnalg 2004;98:60-3.
[12]Aono J, Ueda W, Mamiya K, Takimoto E, Manabe M. Greater incidence of delirium during recovery from sevoflurane anesthesia in preschool boys.Anesthesiology.1997;87:1298–300.
9. / Signature of the candidate
10. / Remarks of the guide / Recommended
11. / Name and Designation
11.1 Guide / DR SHYAMSUNDER KAMATH
PROFESSOR
DEPARTMENT OF ANAESTHESIOLOGY
SDM COLLEGE OF MEDICAL SCIENCES & HOSPITAL
MANJUSHREE NAGAR, SATTUR
DHARWAD, KARNATAKA – 580009
11.2 Signature
11.3 Co-Guide / DR RAVI BHAT
ASSOCIATE PROFESSOR
DEPARTMENT OF ANAESTHESIOLOGY
SDM COLLEGE OF MEDICAL SCIENCES & HOSPITAL
MANJUSHREE NAGAR, SATTUR
DHARWAD, KARNATAKA – 580009
11.4 Signature
11.5 Head of the Department / DR RAGHAVENDRA RAO
PROFESSOR AND HEAD OF THE DEPARTMENT
DEPARTMENT OF ANAESTHESIOLOGY
SDM COLLEGE OF MEDICAL SCIENCES & HOSPITAL
MANJUSHREE NAGAR, SATTUR
DHARWAD, KARNATAKA – 580009
11.6 Signature
12. / 12.1 Remarks of the Principal and Chairman
12.2 Signature
PROFORMA
- PATIENT DETAILS:
a)Name:
b)Age/Sex:
c)IP no:
d)Consent
e)Weight/Height:
f)Comorbities:
g)ASA PS:
h)Heart rate: BP: Hb: NPO for:
i)Diagnosis :
j)Surgery:
- ANAESTHESIA DETAILS:
a)Anaesthesia time: Start: End:
b)Surgery time: Start: End:
c)IV access:
d)Fentanyl used:
e)Caudal block details:
f)LMA size and attempts:
g)Study drug infusion: Start: End:
h)If patient required assisted ventilation (time and duration):
i)Intraoperative event of significance (specify):
j)Emergence time:
k)LMA removed at:
l)Recovery time with aldrete score:
- LMA REMOVAL DETAILS
- Smooth:
- Non Smooth: If not smooth then associated with (tick)
Coughing Breath holding
Teeth clenching/tube biting Laryngospasm
Gross movement Desaturation
HEART RATE / BLOOD PRESSURE/RR / SpO2 / Sevoflurane%Before induction
Before LMA insertion
After LMA insertion
5 minutes after insertion
10 minutes
15 minutes
20 minutes
25 minutes
30 minutes
End of surgery
Emergence
After removal
- RECOVERY:
HEART RATE / BLOOD PRESSURE/RR / SpO2 / Sevoflurane%
5 minutes after removal
10 minutes
15 minutes
20 minutes
25 minutes
30 minutes
45 minutes
60 minutes
On discharge
a)Laryngospasm:
b)Breath holding(>20sec):
c)Severe coughing(>4):
d)Desaturation(<95%):
e)Salivation(requiring suction):
f)Agitation score:
Aonos scale:
1=calm
2=not calm but could be easily consoled
3=moderately agitated or restless and not easily calmed
4=combative, excited, or disoriented, thrashing around.
1 and 2-absence of agitation
2 and 3-presence of agitation
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