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Feasibility of study at single site; changes in clinical practice in opioid use
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| Name | Class |
|---|---|
| University of Ottawa | OTHER |
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Small amounts of sweet tasting sugar water reduces pain in babies during painful blood tests and injections. The investigators do not know if sugar also reduces pain in babies already receiving a continuous infusion of opioid analgesics. This project will help determine if small amounts of sugar water reduce pain in babies already receiving a continuous infusion of opioid analgesic during a heel lance procedure or nasogastric/orogastric (NG/OG) tube insertions. The investigators hypothesize that infants who are receiving opioid analgesics will have lower pain scores during their blood tests (heel lance) or NG/OG tube insertion, when sucrose is given, compared to when water is given.
Background: Sick infants nursed in Neonatal Intensive Care Units (NICU) are exposed to large numbers of repeated painful procedures during their hospitalization [1-6]. Effectively reducing pain during these frequently performed and repeated painful procedures minimizes short term behavioural and physiological responses to pain, and has the potential to reduce long term adverse effects, including altered responses to subsequent pain [7] and increased risk of adverse neurodevelopmental, behavioural, and cognitive outcomes [8] The effectiveness of sucrose and other sweet solutions in the reduction of pain during painful procedures in infants has been well established. Despite the large numbers of randomized controlled trials (RCTs) of sweet solutions for procedural pain reduction in infants, there remain significant knowledge and research gaps. One of the key unanswered questions is whether sweet solutions reduce pain when given with concomitant opioid analgesics [9].
Rationale: Sick infants in hospital need to have blood tests as part of their medical care. Oral sucrose and glucose has shown to effectively reduce behavioural responses to pain and pain scores during commonly performed painful procedures in preterm and term newborn infants and infants up to 12 months of age. However, the investigators do not know if this also works for infants already receiving a continuous infusion of opioid analgesics. The aim is to establish preliminary evidence of the effectiveness of oral sucrose in reducing pain during heel lancing or NG/OG tube insertion when concomitant opioid analgesics are being administered, and to use the pilot data to inform a full scale RCT.
Hypothesis: Infants who are receiving opioid analgesics will have lower pain scores during their blood tests (heel lance) or NG/OG tube insertion, when sucrose is given, compared to when water is given.
Primary Objective: To obtain preliminary data about the effectiveness of sucrose and concomitant opioid analgesics compared to opioid analgesics alone during the painful procedure of heel lancing or NG/OG tube insertion to inform a full scale RCT.
Secondary Objectives: To determine the acceptability of the interventions to infants' parents and to use these results to help us calculate sample size for a subsequent full trial.
Methods: A single-center, randomized, double-blind, placebo controlled pilot trial will be conducted in an urban tertiary care pediatric university-affiliated hospital NICU. The study population is all infants who are inpatients in the Neonatal Intensive Care Unit (NICU) who are receiving a continuous infusion of opioid analgesics and who require a heel lance for the purpose of medically-required capillary blood sampling or a NG/OG tube insertion. Study participants will be randomly allocated to receive 24% sucrose solution or a placebo solution (water). The maximum amount of the study solution will be administered according to the infant's gestational age and according to the hospital's Sucrose policy:
<28 weeks gestation = maximum dose of 0.1 mL; 28-31 weeks gestation = maximum dose of 0.3 mL; 32-35 weeks gestation = maximum dose of 0.5 mL; >36 weeks gestation = maximum dose between 0.5-1.0 mL.
The primary outcome measure is the difference in pain levels during the heel lance procedure or NG/OG tube insertion in the study population as assessed by the Premature Infant Pain Profile (PIPP).
Secondary outcomes will include; i) total crying time; ii) skin conductance activity, a valid, non-invasive, physiological measure of pain and stress in infants.
Statistical analysis: PIPP scores, crying time, and skin conductance activity will be summarized using mean and standard deviation if normally distributed, and median and interquartile range (IQR) if non-normally distributed. An intention to treat analysis will be performed.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Sucrose 24% po | Experimental | 24% sucrose solution. The Children's Hospital of Eastern Ontario (CHOE) pharmacy department will provide syringes labeled "NICU Pain Relief Study" containing a maximum dose of 1 mL of a 24% sucrose solution |
|
| Placebo po | Placebo Comparator | The CHEO pharmacy department will provide a syringe labeled "NICU Pain Relief Study" containing a maximum of 1 ml dose of water (contents almost identical in color, consistency and odor to the sucrose solution) in identical packagings |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| 24% sucrose po solution | Drug | CHEO pharmacy department will provide syringes labeled "NICU Pain Relief Study" containing a maximum of 1 ml dose of a 24% sucrose solution. The maximum amount of the study solution will be administered according to the infant's gestational age and according to the hospital's Sucrose policy. The total amount of the study solution will be divided into a maximum of 5 aliquots and administered throughout the procedure at two minutes prior to the heel lance, immediately prior to the heel lance, and two-minutely intervals until completion of the procedure. |
| Measure | Description | Time Frame |
|---|---|---|
| Premature Infant Pain Profile (PIPP) | The Premature Infant Pain Profile (PIPP), a validated seven-indicator multidimensional pain assessment tool which is extensively used in neonatal pain research. The scale consists of seven indicators including assessment of gestational age and behavioural state (contextual indicators), heart rate and oxygen saturation (physiological indicators), and facial actions-brow bulge, eye squeeze, and nasolabial furrow (behavioural indicators), which are scored on a 0-3 scale and added for a total score of 0-21 Facial expression scores were also recorded on a 0-4 scale using a modified Neonatal Facial Coding System (NFCS) at 30, and 60 seconds following the beginning of the procedure. The modified NFCS coded for the presence (1) or absence (0) of the 4 most common facial expressions in response to acute pain (brow bulge, eye squeeze, nasolabial furrow, and stretch open mouth). High values on both of these scales represent worse outcome (i.e higher pain intensity). | Baseline, day one of blood test |
| Measure | Description | Time Frame |
|---|---|---|
| Total Crying Time | Cry duration is a useful method to determine infant distress in general and to evaluate pain in the infant's environmental context. | Total crying time were recorded as a proportion of the time spent crying over the total length of procedure and/or in the 3 minutes that followed. |
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Inclusion Criteria:
Infants who are inpatients of the NICU:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Denise Harrison, PhD | Children's Hospital of Eastern Ontario | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Children's Hospital of Eastern Ontario | Ottawa | Ontario | K1H 8L1 | Canada |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 7743285 | Background | Barker DP, Rutter N. Exposure to invasive procedures in neonatal intensive care unit admissions. Arch Dis Child Fetal Neonatal Ed. 1995 Jan;72(1):F47-8. doi: 10.1136/fn.72.1.f47. | |
| 18594041 | Background | Carbajal R, Rousset A, Danan C, Coquery S, Nolent P, Ducrocq S, Saizou C, Lapillonne A, Granier M, Durand P, Lenclen R, Coursol A, Hubert P, de Saint Blanquat L, Boelle PY, Annequin D, Cimerman P, Anand KJ, Breart G. Epidemiology and treatment of painful procedures in neonates in intensive care units. JAMA. 2008 Jul 2;300(1):60-70. doi: 10.1001/jama.300.1.60. |
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Consent was obtain for 16 infants to participate, 7 (44%) were not randomized (prior to data collection n=3 infants were weaned off fentanyl, n=3 infants were discharged/transferred, n=1 medical team refused). 9 (12%) infants were randomized. 4 infants were allocated to sucrose and 5 infants were allocated to water.
Between June 2012 and September 2015, 73 infants admitted in the NICU were assessed for eligibility, 50 (69%) were ineligible, of the 23 (32%) infants that were approached, 7 (3%) declined to participate, 16 (70%) provided consent.
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| ID | Title | Description |
|---|---|---|
| FG000 | Sucrose 24% po | 24% sucrose solution. The CHEO pharmacy department will provide syringes labeled "NICU Pain Relief Study" containing a maximum dose of 1 mL of a 24% sucrose solution 24% sucrose po solution: CHEO pharmacy department will provide syringes labeled "NICU Pain Relief Study" containing a maximum of 1 ml dose of a 24% sucrose solution. The maximum amount of the study solution will be administered according to the infant's gestational age and according to the hospital's Sucrose policy. The total amount of the study solution will be divided into a maximum of 5 aliquots and administered throughout the procedure at two minutes prior to the heel lance, immediately prior to the heel lance, and two-minutely intervals until completion of the procedure. |
| FG001 | Placebo po | The CHEO pharmacy department will provide a syringe labeled "NICU Pain Relief Study" containing a maximum of 1 ml dose of water (contents almost identical in color, consistency and odor to the sucrose solution) in identical packagings Placebo po: CHEO pharmacy department will provide syringes labeled "NICU Pain Relief Study" containing a maximum of 1 ml dose of water (almost identical in color, consistency and odor placebo to the sucrose solution in identical packaging) The total amount of the study solution will be divided into 5 aliquots and administered throughout the procedure at two minutes prior to the heel lance, immediately prior to the heel lance, and two-minutely intervals until completion of the procedure |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Sucrose 24% po | 24% sucrose solution. The CHEO pharmacy department will provide syringes labeled "NICU Pain Relief Study" containing a maximum dose of 1 mL of a 24% sucrose solution 24% sucrose po solution: CHEO pharmacy department will provide syringes labeled "NICU Pain Relief Study" containing a maximum of 1 ml dose of a 24% sucrose solution. The maximum amount of the study solution will be administered according to the infant's gestational age and according to the hospital's Sucrose policy. The total amount of the study solution will be divided into a maximum of 5 aliquots and administered throughout the procedure at two minutes prior to the heel lance, immediately prior to the heel lance, and two-minutely intervals until completion of the procedure. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Median |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Premature Infant Pain Profile (PIPP) | The Premature Infant Pain Profile (PIPP), a validated seven-indicator multidimensional pain assessment tool which is extensively used in neonatal pain research. The scale consists of seven indicators including assessment of gestational age and behavioural state (contextual indicators), heart rate and oxygen saturation (physiological indicators), and facial actions-brow bulge, eye squeeze, and nasolabial furrow (behavioural indicators), which are scored on a 0-3 scale and added for a total score of 0-21 Facial expression scores were also recorded on a 0-4 scale using a modified Neonatal Facial Coding System (NFCS) at 30, and 60 seconds following the beginning of the procedure. The modified NFCS coded for the presence (1) or absence (0) of the 4 most common facial expressions in response to acute pain (brow bulge, eye squeeze, nasolabial furrow, and stretch open mouth). High values on both of these scales represent worse outcome (i.e higher pain intensity). | Posted | Median | Inter-Quartile Range | score on a scale | Baseline, day one of blood test |
|
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Sucrose 24% po | 24% sucrose solution. The CHEO pharmacy department will provide syringes labeled "NICU Pain Relief Study" containing a maximum dose of 1 mL of a 24% sucrose solution 24% sucrose po solution: CHEO pharmacy department will provide syringes labeled "NICU Pain Relief Study" containing a maximum of 1 ml dose of a 24% sucrose solution. The maximum amount of the study solution will be administered according to the infant's gestational age and according to the hospital's Sucrose policy. The total amount of the study solution will be divided into a maximum of 5 aliquots and administered throughout the procedure at two minutes prior to the heel lance, immediately prior to the heel lance, and two-minutely intervals until completion of the procedure. |
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Recruitment for this study was difficult due to the tight inclusion criteria. Although consent was provided for 16 infants to participate, only 9 infants were randomized and studied the results may contribute to systematic review data.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Denise Harrison | Children's Hospital of Eastern Ontario | 6137377600 | 6045 | dharrison@cheo.on.ca |
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| ID | Term |
|---|---|
| D010146 | Pain |
| ID | Term |
|---|---|
| D009461 | Neurologic Manifestations |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
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| Placebo po | Drug | CHEO pharmacy department will provide syringes labeled "NICU Pain Relief Study" containing a maximum of 1 ml dose of water (almost identical in color, consistency and odor placebo to the sucrose solution in identical packaging) The total amount of the study solution will be divided into 5 aliquots and administered throughout the procedure at two minutes prior to the heel lance, immediately prior to the heel lance, and two-minutely intervals until completion of the procedure |
|
|
| 19398379 | Background | Harrison D, Loughnan P, Manias E, Johnston L. Analgesics administered during minor painful procedures in a cohort of hospitalized infants: a prospective clinical audit. J Pain. 2009 Jul;10(7):715-22. doi: 10.1016/j.jpain.2008.12.011. Epub 2009 Apr 23. |
| 9430811 | Background | Johnston CC, Collinge JM, Henderson SJ, Anand KJ. A cross-sectional survey of pain and pharmacological analgesia in Canadian neonatal intensive care units. Clin J Pain. 1997 Dec;13(4):308-12. doi: 10.1097/00002508-199712000-00008. |
| Background | Porter FL, Anand KJ. Epidemiology of Pain in Neonates. Research & Clinical Forums 20(4): 9-16, 1998. |
| 14609893 | Background | Simons SH, van Dijk M, Anand KS, Roofthooft D, van Lingen RA, Tibboel D. Do we still hurt newborn babies? A prospective study of procedural pain and analgesia in neonates. Arch Pediatr Adolesc Med. 2003 Nov;157(11):1058-64. doi: 10.1001/archpedi.157.11.1058. |
| 16117561 | Background | Taddio A, Katz J. The effects of early pain experience in neonates on pain responses in infancy and childhood. Paediatr Drugs. 2005;7(4):245-57. doi: 10.2165/00148581-200507040-00004. |
| 15661436 | Background | Grunau RE, Holsti L, Haley DW, Oberlander T, Weinberg J, Solimano A, Whitfield MF, Fitzgerald C, Yu W. Neonatal procedural pain exposure predicts lower cortisol and behavioral reactivity in preterm infants in the NICU. Pain. 2005 Feb;113(3):293-300. doi: 10.1016/j.pain.2004.10.020. |
| 21138786 | Background | Harrison D, Loughnan P, Manias E, Smith K, Johnston L. Effect of concomitant opioid analgesics and oral sucrose during heel lancing. Early Hum Dev. 2011 Feb;87(2):147-9. doi: 10.1016/j.earlhumdev.2010.11.008. Epub 2010 Dec 8. |
| BG001 | Placebo po | The CHEO pharmacy department will provide a syringe labeled "NICU Pain Relief Study" containing a maximum of 1 ml dose of water (contents almost identical in color, consistency and odor to the sucrose solution) in identical packagings Placebo po: CHEO pharmacy department will provide syringes labeled "NICU Pain Relief Study" containing a maximum of 1 ml dose of water (almost identical in color, consistency and odor placebo to the sucrose solution in identical packaging) The total amount of the study solution will be divided into 5 aliquots and administered throughout the procedure at two minutes prior to the heel lance, immediately prior to the heel lance, and two-minutely intervals until completion of the procedure |
| BG002 | Total | Total of all reporting groups |
| days |
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| Age, Continuous | Median | Inter-Quartile Range | gestational age (days) |
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| Sex: Female, Male | Count of Participants | Participants |
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| Type of Procedure | Count of Participants | Participants |
|
| Duration of Procedure | Median | Inter-Quartile Range | seconds |
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| Type of opioid administered | Count of Participants | Participants |
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| Previous use of sucrose | Count of Participants | Participants |
|
| Sucrose 24% po |
24% sucrose solution. The CHEO pharmacy department will provide syringes labeled "NICU Pain Relief Study" containing a maximum dose of 1 mL of a 24% sucrose solution 24% sucrose po solution: CHEO pharmacy department will provide syringes labeled "NICU Pain Relief Study" containing a maximum of 1 ml dose of a 24% sucrose solution. The maximum amount of the study solution will be administered according to the infant's gestational age and according to the hospital's Sucrose policy. The total amount of the study solution will be divided into a maximum of 5 aliquots and administered throughout the procedure at two minutes prior to the heel lance, immediately prior to the heel lance, and two-minutely intervals until completion of the procedure. |
| OG001 | Placebo po | The CHEO pharmacy department will provide a syringe labeled "NICU Pain Relief Study" containing a maximum of 1 ml dose of water (contents almost identical in color, consistency and odor to the sucrose solution) in identical packagings Placebo po: CHEO pharmacy department will provide syringes labeled "NICU Pain Relief Study" containing a maximum of 1 ml dose of water (almost identical in color, consistency and odor placebo to the sucrose solution in identical packaging) The total amount of the study solution will be divided into 5 aliquots and administered throughout the procedure at two minutes prior to the heel lance, immediately prior to the heel lance, and two-minutely intervals until completion of the procedure |
|
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| Secondary | Total Crying Time | Cry duration is a useful method to determine infant distress in general and to evaluate pain in the infant's environmental context. | Posted | Median | Inter-Quartile Range | seconds | Total crying time were recorded as a proportion of the time spent crying over the total length of procedure and/or in the 3 minutes that followed. |
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| 0 |
| 4 |
| 0 |
| 4 |
| EG001 | Placebo po | The CHEO pharmacy department will provide a syringe labeled "NICU Pain Relief Study" containing a maximum of 1 ml dose of water (contents almost identical in color, consistency and odor to the sucrose solution) in identical packagings Placebo po: CHEO pharmacy department will provide syringes labeled "NICU Pain Relief Study" containing a maximum of 1 ml dose of water (almost identical in color, consistency and odor placebo to the sucrose solution in identical packaging) The total amount of the study solution will be divided into 5 aliquots and administered throughout the procedure at two minutes prior to the heel lance, immediately prior to the heel lance, and two-minutely intervals until completion of the procedure | 0 | 5 | 0 | 5 |
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