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Shamnad Madathil1, Deena Thomas1, Ramesh Agarwal1, Parijat Chandra2, Jeeva Sankar1, Anu Thukral1, Ashok K Deorari1
All India Institute Of Medical Sciences, New Delhi
‘NOPAIN ROP’ trial
Intravenous Fentanyl and Intravenous Ketamine for Analgesia During Laser Treatment for Retinopathy of Prematurity (ROP) In
Preterm Infants An Interventional Study
Background
The standard treatment for analgesia during laser therapy in developed nations:
• General anaesthesia (GA)
• Combination of sedation, analgesia and paralysis (SAP)
Neglected in LMIC due to lack of infrastructure and fear of complications
Gilbert C, et al. Arch Dis Child Fetal Neonatal Ed Month 2015.
Analgesic practices during LASER therapy in neonates
Center/
Centers
General
anaesthesia
IV Sedation+
Topical anesthesia
Topical anesthesia
USA(n=351)
Klein et al 2013
In ICU =14%
In OT= 26%
60% 0 %
UK(n=46)
Chen et al 2007
50% 37% 3%
Turkey (n=70)
Sekeroglu et al 2013
72.2% 20.5% 4.5%
India(n=25)
(e-survey, unpublished)
0% 4% 48%
Analgesic options for ROPDrug Dose Duration
of action
Peak effect Advantages Disadvantages
Fentanyl Bolus:0.5 – 4 µg/kg
Infusion:0.3 – 5 µg/kg/hr
30 min 5-15 min • Rapid onset of action
• Better hemodynamic
stability
• Respiratory
depression
• Chest wall rigidity
Ketamine Bolus:
0.5 to 2 mg/kg
Infusion:0.5-1 mg/kg/hr
5- 15 min 1 min • Analgesia
• Amnesia
• Sedation
• Tachycardia
• Rise in ICP and IOP
Morphine Bolus
0.05-0.2 mg/kg
Infusion:
10-30 µg/kg/h
4-5 hour 45- 90 min • Potent analgesia • Respiratory
depression
• Hypotension
Anand KJS et al; Arch Dis Child Fetal Neonatal Ed. 2006Nov;91(6):F448–53.
ObjectivesPrimary
a) Among preterm infants undergoing laser photocoagulation for ROP, to evaluate if the following agents can provide adequate analgesia (at least 90% of enrolled infants having PIPP-R score <7 and crying <5% time) during the procedure:
1. IV Fentanyl: 2 µg /kg followed by 1 µg /kg/h to maximum of 3 µg /kg/h
2. IV Ketamine: bolus of 0.5 mg/kg followed by intermittent bolus doses of 0.5 mg/kg to a maximum of 2 mg/kg
Outcome variable Measurement • % cry time
• Revised PIPP score 5 min before and then every 15 minutes
• Audio recording (Sony ICD-PX240 MP3 Digital Voice IC Recorder
• Video recording of heart rate, SpO2 and facial actions with Digicam (Sony HDR-XR150E Digital video recorder)
Secondary Objectives
a) Side effect profile
b) To formulate optimum analgesia protocol during laser photocoagulation in
preterm infants
Outcome variable
Need for NICU/HDU admission for 24 hours or more post procedure as defined by any of the following
Hemodynamic instability within 24 hours of procedure requiring fluid boluses or vasoactive support
Change in cardiorespiratory stability score post procedure
Feed intolerance post procedure
Urinary retention post procedure
Repeated episodes of apnea
Methodology• Study Design: Randomized Interventional trial
• Study setting: Pediatric HDU, RPC, AIIMS
• Study duration: 14 April 2018 to 10 May 2019
• IEC approved and CTRI (REF/2018/01/016904)
• Inclusion: All infants with type I ROP who were hemodynamically stable, had no
anemia as defined by packed cell volume (PCV) more than 30%, anticipated
duration of procedure is more than 30 minutes, no major morbidities (grade 3-4
IVH, PDA, NEC)
• Exclusion: All infants with major malformations, those on CPAP, MV or sick enough
to require NICU care
Sample Size
Estimated proportion of infants with adequate analgesia 90%
Absolute precision 7.5%
Confidence interval 95%
62 in each of two groups
Randomisation
Sequence generation: Computer generated
Allocation concealment : Sequentially numbered, opaque, sealed envelopes
Blinding: Participant was blinded. Outcome assessors blinded
Methodology
SOP
• Revised PIPP score 5 minutes before (30 sec for ketamine) and then every 15 minutes during the
procedure
• Make video of 30 sec duration every 15 minutes during procedure
Fentanyl Bolus dose of fentanyl at 2 µg/kg over
5min given 15 minutes prior to procedure f/b infusion of 1 µg
/kg/hour.
Ketamine Bolus dose of ketamine 0.5 mg/kg 1
min prior to procedure
SOP
If no response
Fentanyl • Increased dose by 0.5 µg/kg/hour
every 15 minutes to a maximum of 3 µg/kg/hour
Ketamine Intermittent boluses of Ketamine 0.5
mg/kg till a maximum of 2 mg
Study flow
•Refused consent (n=15)
•Anticipated duration of procedure < 30 min (n=59)
•Clinical anemia (n=9)
•No beds for 24hour monitoring (n=66)
•Excluded (n=19)
•Admitted in outside hospital (n=5)
Randomized (n=124)
(n=97) – 1st phase
Assessed for eligibility (n=297)
Fentanyl
(n=51)
Ketamine
(n=46)
Allocation
Analysis
Analyzed (n=51)*
*- 2 excluded for cry duration
outcome
Analyzed (n=46)*
*- 2 excluded for cry duration
outcome
Statistical analysis
• Stata 11.2 (StataCorp, College station, Texas, US).
• Categorical variables: Chi square/Fisher Exact Test.
• Continuous variables: Student t-test/ Wilcoxon rank sum Test
• GEE for multi-point comparison
• P value < 0.05
Results: Baseline characteristicsCharacteristic Fentanyl
(n=51)Ketamine
(n=46)P Value
GA at birth (wk) 29.7 1.9 29.8 1.5 0.90
GA at randomization (wk) 37.8 2.7 39.2 3. 0.02Birth weight (g) 1227.8 280 1202.9 254 0.67
Weight at randomization (g) 2165.8 582 2258.1 658 0.24
Stage of ROP
APROP
Stage 2 plus
Stage 3 plus
Stage 4 plus
ROP sequelae
6 (11.7)
13 (25.5)
25 (49)
6 (11.7)
1 (1.9)
6 (13.0)
9 (19.5)
22 (47.8)
9 (20.4)
1 (2.3)
0.56
Duration of procedure (min) 75(48-90)
59.1(40-91)
0.26
Data represents as n(%), mean ± SD, median (IQR) as applicable
Results
• Proportion of infants with adequate analgesia
Adequate% , (n/N)
95% CI,(%)
Fentanyl 39.2 (20/51) 35.1 - 43.2
Ketamine 21.8 (10/46) 18.1 - 25.3 0
10
20
30
40
50
60
70
80
90
100
Fentanyl Ketamine
Adequate %
39.2
21.8
Secondary outcomesFentanyl (n=51) Ketamine (n=46) P Value
Any episode of apnea
• Intra-procedure
• Post procedure
4 (7.8)
1(1.9)
3 (6.5)
0
0.40
Need for O2 support
• Intra-procedure
• Post procedure
9 (17.6)
1 (1.9)
4 (8.6)
1 (2.1)0.19
0.36
Need for NICU/HDU admission for >24 hours post procedure
2 (3.9) 2 (4.3) 1.00
Change in mean CRI
No change
Change from baseline
49
2
45
1
1.00
Hemodynamic instability requiring inotropes
0 2 (4.3) 0.401
Data represented as n(%)
No difference
INTERIM ANALYSIS
Amendments to protocol
• Dose modification of fentanyl and ketamine by study steering
committee
Fentanyl
2 µg/kg bolus, 15 min before followed
infusion at 2 µg/kg/hr hiked every 15
minutes till 5 µg /kg/hr
Ketamine
Bolus 1 mg/kg IV, 1 min before followed
by boluses of 0.5 mg/kg every 5-10
minutes up to maximum of 4 mg/kg
Study flow – Revised Regimen Phase
•Refused consent (n=15)
•Anticipated duration of procedure < 30 min (n=59)
•Clinical anemia (n=9)
•No beds for 24hour monitoring (n=66)
•Excluded (n=19)
•Admitted in outside hospital (n=5)
Randomized (n=124)
Phase II (n=27)
All infants undergoing LASER therapy for ROP – Assessed for
eligibility(n=297)
Fentanyl
(n=13)
Ketamine
(n=14)
Allocation
AnalysisAnalyzed (n=13) Analyzed (n=14)
Results- Revised regimen phase
Adequate% , (n/N)
95% CI,(%)
Fentanyl 46.1 (6/13)
14.7- 77.5
Ketamine 28.5 (4/14)
12.5 - 55.6
• Proportion of infants with adequate analgesia
0
10
20
30
40
50
60
70
80
90
100
Fentanyl Ketamine
Adeqaute
46.1
28.5
Secondary outcome – Revised regimen phaseCharacteristic Fentanyl (n=13) Ketamine (n=14) P Value
Any episode of apnea• Intra-procedure• Post procedure
4 (30.7)0
0 0.02
Need for O2 support • Intra-procedure• Post procedure
5 (38.4)0
0 0.01
Hemodynamic instability post procedure
1 (7.7) 0 0.48
Need for NICU/HDU admission for >24 hours post procedure
0 0
Change in mean cardiorespiratory stability scoresNo changeChange from baseline
6 (46.1)7 (53.8)
14 (100)0
0.002
Data represents as n(%)
Primary outcomes- Both regimen
Fentanyl (Regimen 215)
Ketamine(Lower dose)
Fentanyl (Regimen 225)
Ketamine(Higher dose)
Proportion of cry (%) 9.5(4.6-20.2)
18.4(8.8-34.4)
7.9(3.1-13.8)
10.1(5.5-12.5)
Mean PIPP-R 2.84 0.34 3.89 0.75 2.66 0.62 2.82 1.34
Proportion of adequate analgesia (%)
39.2(35.1– 43.2)
21.8(18.1 – 25.3)
46.1(14.7 – 77.5)
28.5(12.5 – 55.6)
Data represented as median (IQR), 95% CI as applicable
Discussion
• Lower dose regimens of fentanyl and ketamine provided adequate
analgesia in approximately one third of infants
(39.2% with fentanyl and 21.8% with ketamine)
• Comparable side effect profile, need for 24 hour observation post
procedure in both groups
• With revised regimen, proportion of infants with adequate analgesia were
46.1% (n=6) and 28.5% (n=4) with fentanyl and ketamine
• Increased proportion of infants with side effects with higher dose fentanyl
Strengths & Limitations
• Strengths
• Well conducted study design with rigorous methodology
• Relatively large sample size
• Dosage of fentanyl and ketamine optimized midway targeting adequate analgesia
• Limitations
• Paucity of baseline data and risk factors for ROP because of a predominantly out
born cohort
• Relatively small sample size in revised regimen phase
Conclusion
1. Rate of adequate analgesia as defined in the study: low with all regimens
tested
2. It seems: GA or adequate analgesia with opioids with and without other agents
targeted at complete analgesia in setting of intensive monitoring and facility of
ventilation must be the choice
3. Lower dose fentanyl infusion (2 g/kg bolus followed by IV infusion of 1
g/kg/hour to a maximum of 3 g/kg/hour) was better than lower dose
ketamine with side effects in only 1/5th of neonates
Conclusion
4. Higher dose fentanyl infusion (2 g/kg bolus followed by IV infusion of 2
g/kg/hour to a maximum of 5 g/kg/hour) provided effective analgesia in
higher proportion, but with increased side effects
5. In LMIC settings like India, fentanyl regimens as used in the study can be
considered reasonable alternatives.
6. Future research addressing the issue of adequate pain relief for these preterm
infants particularly from LMIC setting with huge disease burden is the need of
the hour
Thank You