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(e-survey, unpublished)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