Inhaled Nitrous Oxide for Pain Relief During Eye Exam in the Pre-term Infant

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Brief Title

Inhaled Nitrous Oxide for Pain Relief During Eye Exam in the Pre-term Infant

Official Title

A Randomized Controlled Trial on the Effectiveness of Inhaled Nitrous Oxide for Pain Relief During ROP Screening Exam in the Pre-term Infant

Brief Summary

      The primary objective of the proposed study is to show that inhaled equimolar mixture of
      oxygen and nitrous oxide (EMONO) will reduce pain associated with retinal exam in the preterm
      infant, as compared to the current standard treatment (oral sucrose and topical anaesthesia).

      The investigators also aim to show that EMONO can be used safely in preterm neonates
      undergoing retinal exam, and will not result in any increase in apnea, bradycardia, or
      desaturation in the 24 hours following the exam. Finally, the investigators aim to show that
      EMONO will keep the infant calm, and make retinal examination easier and less traumatic.
    

Detailed Description

      Methods

        1. Study population:

           Eligible patients will be healthy preterm infants born at 30 0/7 or less than weeks of
           gestation, or weigh less than 1500 grams at birth, requiring retinopathy of prematurity
           (ROP) screening examination as indicated by AAP guidelines.

        2. Recruitment:

      Patients will be recruited at the Royal Victoria Hospital Neonatal Intensive Care Unit.
      Subjects will be enrolled after written informed consent has been obtained from a parent or
      legal guardian. Although a single patient may require multiple retinal exams, each infant
      will only be studied once under this protocol. Total number of eligible patients, as well as
      consent refusals will be recorded during the study period.

      The study will be conducted in two phases. A pilot phase, comprising 9 infants, will be
      performed first. The purpose of the pilot study is to establish the safety of EMONO for this
      indication, evaluate the technical feasibility of administering EMONO in the NICU setting,
      and determining the optimal nasal interface for inhalation. All subjects during the pilot
      phase will receive EMONO.

      40 babies will be recruited for the second phase of the study, and will be randomized to
      either the therapeutic group (EMONO), or the placebo group (50% oxygen/50% nitrogen).

      3. Gas administration:

      All 9 patients in the pilot phase, and patients randomized to the intervention group will
      receive EMONO. The mixture will be obtained by using hospital compressed oxygen and a tank of
      N2O (Praxair Canada Inc, Mississauga, ON). N2O and oxygen will be mixed via a Bird low flow
      nitrous oxide blender (Summit Technologies, Burlington, ON) to obtain a mixture of 50% O2 and
      50% N2O. Subjects in the control group will receive a mixture of 50% O2 and 50% N2. This will
      be produced by mixing hospital air and oxygen through a blender.

      Before the study, a respiratory therapy technician will open both gas valves and one of them
      will be randomly connected to the patient's inhalation device. The research team at the
      bedside will not be able to see which gas output the patient is connected too.

      Study or control gas will be administered by one of three devices during the pilot phase of
      the study: nasal cannula (Airlife Infant Cushion Nasal Cannula, Cardinal Health, McGraw Park,
      IL), a clear plastic infant resuscitation mask, or a clear plastic non-rebreather mask
      (Medium concentration infant oxygen mask, Rusch Medical, Duluth, GA). Three patients will be
      studied with each device, and different gas flows will be used. The optimal inhalation
      device, duration of inhalation, and gas flow will be thus determined and used for the 40
      patients in the 2nd phase of the study.

      4. Randomization:

      The gas administered to each subject will be determined randomly. Sealed opaque envelopes
      will be prepared in advance, each containing one infant's assignment. The envelope will be
      opened by the respiratory therapy technician who sets up the inhalation circuit.

      5. Study protocol:

      All studies will be conducted in the Royal Victoria Hospital NICU. Complete neonatal
      resuscitation equipment, meeting AAP Neonatal Resuscitation Program standards, will be
      available on hand. The following personnel will be present for all studies: a neonatologist
      (usually one of the co-investigators), a licensed respiratory therapist in charge of gas
      administration, two registered nurses experienced in the care of neonates (one nurse
      responsible for restraining the infant and the other for monitoring the baby's vital signs),
      an ophthalmologist experienced in ROP screening who will conduct the retinal exam.

      Studies will be performed in the morning after routine nursing care of the babies. Infants
      will be pre-treated 30 minutes before with phenylephrine 2.5% 1 drop in each eye, and
      cyclopentolate 1.5% 1 drop in each as eye, as done routinely in our unit before eye exams.
      Infants will be placed on cardio-respiratory monitoring using one of the monitors available
      in our unit. All infants will be swaddled and held by a nurse, as is routinely done in our
      unit. The inhalation device will be placed on the infant by the respiratory therapist,
      allowing control or study gas administration. During the pilot phase ocular manipulations
      will not be started until adequate analgesia is obtained, or a maximum of 15 minutes have
      passed. This will allow us to determine the duration of inhalation necessary for effective
      analgesia, and this duration will then be used for the randomized phase of the trial. All
      infants in both groups can receive oral sucrose for pain relief as per unit protocol. A
      pharmacy prepared solution of sucrose 24% will be used. Sucrose will be administered orally
      in pre-prepared 1mL syringes, and given in 0.1 mL aliquots, up to a maximum of 0.3 mL.

      Proparacaine HCl 0.5% eye drops will be instilled and retinal examination will be performed
      by the ophthalmologist, while the infant is held by the bedside nurse. Both nurses present
      will separately score the infant's pain response, before the beginning of examination, during
      the examination, and 2 hours after. Only the first eye examined will be scored, since both
      eyes are examined in rapid succession and the PIPP score will not have time to decrease in
      between both eyes. After completing the exam, the infant will be returned to standard nursing
      care. All infants will be monitored continuously by pulse oximetry 24 hours before and after
      the exam. Additionally, infants in the pilot study phase will undergo a full 24 hour sleep
      study after the exam.

      6. Measurements:

      * Primary outcome: The primary objective is to show decrease of pain response in the
      treatment group as measured by the PIPP (Premature Infant Pain Profile) score. The PIPP score
      is a multidimensional composite pain score developed for evaluating acute procedural pain
      preterm neonates. Its use has been validated in clinical settings, with high intra and
      inter-rater reliability. It measures 7 different elements including physiological parameters,
      facial expression, behaviour and gestational age. Each is evaluated on a scale of 0 to 3,
      yielding a combined score ranging from 0 to 21. In the initial validations studies, baseline
      mean scores in infants were 4.9 ± 1.0, non painful events yielded mean scores of 9.0 ± 0.8,
      while painful heelsticks were measured at 11.0 ± 1.3. All nurses in our unit are fully
      trained in the use of the PIPP score.

      * Secondary outcomes: After each exam, the ophthalmologist will evaluate the ease of
      performing the procedure, as well as the degree of agitation in the infant using a simple
      ordinal scale.

      Heart and respiratory rate will be monitored using one of our NICU integrated monitors:
      Draeger Infinity Gamma XL (Draeger Medical Canada Inc, Richmond Hill, ON), or HP Agilent
      V29C/HP 895 (Hewlett Packard Company, Palo Alto, CA).

      Continuous pulse oximetry will be performed with a Masimo Radical pulse oximeter (Masimo
      Corp., Irvine, CA), and data will be analyzed using ProFox oximetry software (Escondido, CA).

      Infants in the pilot study will undergo a full cardiorespirogram, with continuous measurement
      of heart rate, respiratory impedance, thermistor nasal airflow, and pulse oximetry (Eden
      Trace II and Eden Trace Analysis Software, Mallinckrodt Co, St-Louis, MO). Data will sampled
      at 4 Hz and recorded on a personal computer. Apnea will be defined as absence of airflow for
      15 seconds or more. Drops in oxygen saturation will be measured as total time spent below 88%
      and number of episodes below 88%. It is the policy in our unit to maintain all oxygen
      saturation levels between 88% and 92% for preterm infants.

      7. Data collection:

      The following data will be collected and recorded for all study infants, using patient
      charts, maternal charts, nursing records, and respiratory therapy data sheets: sex,
      birthweight, gestational age at birth, current weight, relevant maternal history and
      antenatal risk factors, previous respiratory care including modes and duration of ventilatory
      support, frequency of apnea and bradycardia, major neonatal complications (hyaline membrane
      disease, persistent ductus arteriosus, bronchopulmonary dysplasia, necrotizing enterocolitis,
      intra-ventricular hemorrhage), medications received including opiates and caffeine. The CRIB
      II score (Clinical Risk Index for Babies) at admission will be computed for infants in the
      study.

      All patient data related to the study will be kept in a locked filing cabinet, in a locked
      office at the Royal Victoria Hospital. Only the co-investigators will have access to this
      data.

      8. Sample size calculation:

      For the pilot study, a total number 9 patients was chosen, to allow three patients to be
      studied with each different nasal inhalation device.

      For the randomized trial portion, data on PIPP scores was reviewed for all eye exams
      performed between September 2006 and February 2007 in our unit. A total of 16 eligible exams
      with complete data were identified. Mean PIPP score was 13.4 ± 3.4. A 25% reduction would
      bring the PIPP score down to 10, which is below the average for painful events as described
      by Ballantyne et al, and is also a clinically reasonable and meaningful target. We calculate
      that it would take approximately 20 patients in each group, control and placebo, to show a
      reduction in PIPP score from 13.4 to 10 using a two sample t-test. A two-tailed alpha level
      of 0.05 was used, with a power of 0.8.

      Data for the Royal Victoria Hospital NICU show approximately 85 infants < 32 0/7 weeks or <
      1500g are admitted per year. We would estimate enrollment in the study would take
      approximately 1 year.

      9. Statistics:

      Continuous numerical data between control and intervention groups will be compared using the
      two-sample t-test for normally distributed variables. The Wilcoxon rank sum test will be used
      for data not distributed normally. Categorical data will be compared using the chi-squared
      test.
    

Study Phase

Phase 3

Study Type

Interventional


Primary Outcome

The primary objective is to show decrease of pain response in the treatment group as measured by the PIPP (Premature Infant Pain Profile) score

Secondary Outcome

 Heart and respiratory rate will be monitored using one of our NICU integrated monitors. Continuous pulse oximetry will be performed with a Masimo Radical pulse oximeter.

Condition

Retinopathy of Prematurity

Intervention

N2O

Study Arms / Comparison Groups

 A
Description:  O2 and N2O

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Other

Estimated Enrollment

40

Start Date

March 2008

Completion Date

April 2010

Primary Completion Date

April 2010

Eligibility Criteria

        Inclusion Criteria:

          -  Requiring retinal exam for ROP screening

          -  Clinically stable

          -  At least 30 0/7 weeks of corrected gestational age at the time of study

          -  Not on mechanical ventilation or CPAP at the time of study

          -  Requiring an inspired concentration of oxygen less than 50%

        Exclusion Criteria:

          -  - Craniofacial malformations

          -  Cyanotic cardiac disease

          -  Hemodynamically significant cardiac lesions

          -  Known pneumothorax or pneumomediastinum

          -  Congenital pulmonary malformations

          -  Neuromuscular disease

          -  Receiving opiates, benzodiazepines or barbiturates at the time of study
      

Gender

All

Ages

32 Weeks - N/A

Accepts Healthy Volunteers

No

Contacts

, , 

Location Countries

Canada

Location Countries

Canada

Administrative Informations


NCT ID

NCT00623220

Organization ID

07-008-PED


Responsible Party

Sponsor-Investigator

Study Sponsor

Nabeel Ali


Study Sponsor

, , 


Verification Date

October 2013