Changes in Vital Signs and Pupil Diameter Related to Pharmacologic Mydriasis in Premature Infants: A Randomized Double Blind Clinical Study

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Brief Title

Changes in Vital Signs and Pupil Diameter Related to Pharmacologic Mydriasis in Premature Infants: A Randomized Double Blind Clinical Study

Official Title

Changes in Vital Signs and Pupil Diameter Related to Pharmacologic Mydriasis in Premature Infants: A Randomized Double Blind Clinical Study

Brief Summary

      Retinopathy of prematurity (ROP) is one of the common anatomic causes of blindness among
      Filipinos, accounting for 47.7% of the cases. With this retinopathy being preventable and
      treatable, ROP screening has been proven to be effective in preventing blindness, which is
      achieved with the usage of mydriatics. Even if the regimen of multiple alternate
      instillations of 0.5% tropicamide and 2.5% phenylephrine is the one recommended by
      international guidelines for ROP screening, the mydriatic regimen used by many of the
      country's institutions is the single instillation of 0.5% tropicamide + 0.5% phenylephrine
      applied via a cotton wick placed in the inferior fornix (SIW). There have been no studies yet
      on the safety and efficacy in premature infants of this mydriatic preparation and method,
      although it is hypothesized that the usage of a cotton wick promotes the possible systemic
      effects of the mydriatic combination used.

      This study then aims to determine the safety and efficacy of different mydriatic regimens in
      premature infants referred for screening of ROP using (1) multiple alternate instillations of
      0.5% cyclopentolate hydrochloride and 2.5% phenylephrine (MAI), (2) single instillation of
      0.5% tropicamide + 0.5% phenylephrine (SI), and (3) single instillation of 0.5% tropicamide +
      0.5% phenylephrine with a cotton wick placed in the inferior fornix (SIW) in a tertiary
      Philippine hospital.

      This study was designed as a randomized, double blind, clinical study which enrolled sixty
      preterm infants referred for ROP Screening from January to July 2011. With instillations via
      MAI, SI, and SIW, systolic blood pressure (SBP), diastolic pressure (DBP), mean arterial
      pressure (MAP), heart rate, and oxygen saturation were monitored from ten minutes prior to
      instillation up to forty-five minutes after instillation. Pupil dilations were also measured
      at the forty-fifth minute.
    

Detailed Description

      I. Introduction Retinopathy of prematurity (ROP) is one of the common anatomic causes of
      blindness among Filipinos, accounting for 47.7% of the cases. With this retinopathy being
      preventable and treatable, ROP screening has been proven to be effective in preventing
      blindness, which is achieved with the usage of mydriatics. Even if the regimen of multiple
      alternate instillations of 0.5% tropicamide and 2.5% phenylephrine is the one recommended by
      international guidelines for ROP screening, the mydriatic regimen usually used by many of the
      country's institutions is the regimen of 0.5% tropicamide + 0.5% phenylephrine applied via a
      cotton wick placed in the inferior fornix. There have been no studies yet on the safety and
      efficacy in premature infants of this mydriatic preparation and method, although it is
      hypothesized that the usage of a cotton wick promotes the possible systemic effects of the
      mydriatic combination used.

      II. Significance It is the aim of this study to evaluate the safety and efficacy of the
      mydriatic regimens we use in our institution and compare it to the recommendation by the UK
      ROP Guidelines. In doing so, this study aims to (1) document vital sign changes in the infant
      during dilation, (2) identify adverse systemic changes due to the mydriatic regimen and (3)
      provide appropriate interventions and recommendations to address these adverse effects. These
      will greatly improve the ROP screening process in our institution.

      III. Objectives The general objective is to determine vital sign changes related to Pupil
      Dilation among preterm infants referred for ROP Screening from Neonatal Intensive Care Unit,
      Pediatric Wards and Eye Instrumentation Center of the Philippine General Hospital (PGH).
      Specifically, its objective is to compare the vital sign changes and mydriasis in (1)
      multiple alternate instillations of 0.5% Cyclopentolate Hydrochloride + 2.5% Phenylephrine
      (MAI) (2) single instillation of 0.5%/0.5% Phenylephrine + Tropicamide (SI) and (3) single
      instillation of 0.5%/0.5% Phenylephrine + Tropicamide with a cotton wick placed in the
      inferior fornix (SIW).

      IV. Methodology This study was designed as a randomized, double blind, clinical study which
      enrolled sixty preterm infants referred for ROP Screening from January to July 2011. Each
      subject was randomly distributed into the standard, instillation, and packing group. To avoid
      observer bias, two investigators were involved per monitoring during dilation. The first
      investigator was assigned only to place the monitoring devices and to administer the
      mydriatics contained in unmarked 1 mL syringe which content was unknown to him.

      The vital signs monitored during dilation were blood pressures (systolic, diastolic and mean
      arterial pressure (MAP)), heart rates and oxygen saturations using the newly calibrated
      Phillips Digital IntelliVue MP20 junior Cardiac monitors. A digital camera and a millimeter
      rule were used to approximate size of pupil dilatation. Measurement of all the vital signs
      and pupil dilation from a subject was derived from a single dilation session only.

      Prior to data collection up to the end of monitoring, other factors that may affect the vital
      signs of the preterm infants were addressed. This included hunger, cold temperature, and
      soiled diapers.

      Baseline vital signs determination was then performed 10 and 5 minutes prior to the first
      drop of mydriatic or proparacaine prior to packing. Additional reading will be done if there
      is a significant difference in the vital signs between 10 and 5 minutes prior to the initial
      drop.

      For the MAI, multiple alternate drops of 0.5% cyclopentolate then 2.5% phenylephrine every 5
      minutes in two doses were instilled (total of 0.2 milliliter of 0.5% cyclopentolate and 0.2
      millimeter of 2.5% Phenylephrine). Vital signs were continuously recorded at time 0, 5, 10,
      15, 20, 25, 30, 35, 40 and 45. At the 45th minute, a lid retractor was placed in the eyes of
      the subject after a drop of topical anesthesia. Pictures of the eyes were taken with a
      millimeter rule to serve as measurement reference.

      For the SI, only a drop of 0.5%/0.5% tropicamide + phenylephrine was properly instilled at
      time 0 (total of 0.1 milliliter). Vital signs were continuously recorded at time 0, 5, 10,
      15, 20, 25, 30, 35, 40 and 45. At the 45th minute, a lid retractor was placed in the eyes of
      the subject after a drop of topical anesthesia. Pictures of the eyes were taken with a
      millimeter rule to serve as measurement reference.

      For the SIW, a cotton wisp soaked with a drop of 0.5%/0.5% tropicamide + phenylephrine was
      placed on the lower fornix in each eye of the infant (total of 0.1 milliliter). The weight of
      the cotton wisp was standardized at 0.02 milligram using a digital weighing scale. Vital
      signs were continuously recorded at time 0, 5, 10, 15, 20, 25, 30, 35, 40 and 45. At the 45th
      minute, a lid retractor is placed in the eyes of the subject after a drop of topical
      anesthesia. Pictures of the eyes were taken with a millimeter rule to serve as measurement
      reference. Pictures were uploaded into the computer monitor for the actual measurement.

      Vital sign changes were monitored using the newly calibrated Phillips Digital IntelliVue MP20
      junior Cardiac monitors. In the presence of significant vital sign changes, immediate
      intervention will be done.

      In the presence of a significant increase in BP or heart rate, the infant will be observed.
      Both changes are expected from undergoing a stressful procedure such as placing a lid
      retractor in measuring the pupil dilation. The infant will be referred to the NICU ROD for
      further work up should tachycardia persist even after the examination. The blood pressure,
      heart rate and sensorium will be continuously monitored so as to avoid any ensuing
      bradycardia.

      In the presence of a significant drop in BP, the infant will be referred to the NICU ROD for
      further work up to determine the possible source. Fluid challenge will be done to check if
      the cause of hypotension is just attributable to hypovolemia. The investigator will determine
      body temperature to check for hypothermia. If hypothermic, slow rewarming will be done by
      placing back the infant inside a close incubator or beside a radiant warmer. Blood glucose
      will be checked for hypoglycemia. Should hyperglycemia be detected, the infant can be started
      on 2cc/kg D5water. Infant will be worked up for infection as well.

      During events of hypoxia or oxygen desaturation of less than 85%, the infant will be given
      supportive ventilation as required. Oxygen saturation will be monitored using the pulse
      oximeter. In the event of an apnea happening, supportive ventilation will be provided
      immediately, together with significant stimulation. The infant will be referred to the NICU
      ROD for possible intubation.

      In the event of bradycardia, significant stimulation will be started on the infant. The
      infant will be referred to the NICU ROD for further work-up to determine the cause. The
      investigator is also to determine body temperature to check for hypothermia. If hypothermic,
      slow rewarming will be done by placing back the infant inside a close incubator or beside a
      radiant warmer. Blood glucose will be determined to check for hypoglycemia. Should
      hyperglycemia be detected, the infant can be started on 2cc/kg D5water. Infant can be worked
      up for infection as well.

      In the event that a subject suffers from any of the abovementioned adverse effects, the
      appropriate interventions cited will be administered free of charge. Should the adverse
      effects believed by the investigators to be secondary to the ROP screening only and
      additional expenses are needed to procure medicines or equipment, the investigators will
      shoulder the expenses. If the medicine or equipment is immediately needed, the relative may
      spend first for them and have the expenses reimbursed with the investigators later. Should
      the amount to procure the said medicine or equipment cannot be produced by the relative, the
      investigators can be immediately contacted to assist the relatives immediately. All other
      expenses will be shouldered by the investigators through reimbursements. Expenses amounting
      to P500 for the medicine and P1000 for the equipment will be shouldered by the investigators.
      Should it exceed these limits, the infant will be referred to any charitable institution for
      further assistance.

      The blood pressure (systole, diastole and MAP), HR and oxygen saturation obtained during
      dilatation were analyzed. They were graphed to determine patterns from baseline up to 45
      minutes. Wilcoxon signed rank test was used to assess statistical significance for oxygen
      saturation, being a non-parametric variable. Poor dilatation among ROP patients with the
      advanced disease will be noted. A subgroup analysis was also done to determine the any
      relationship between the amounts of mydriatic used to the weight of the infant.

      An interim analysis was done within the study to assess if the two mydriatic regimens were
      particularly beneficial or harmful compared to the concurrent standard group. Either the
      Pocock or the Flemming method will be used to decide if this study needed to terminate
      earlier than planned. Unblinding can be done should it be made necessary during the interim
      analysis or during course of the study. This protocol was submitted to the PGH ERB for ethics
      review and approval. It was conducted only upon approval from the ERB. All patient
      information were anonymized and are confidential. There is no funding received by the
      investigators for the conduct of this research.
    

Study Phase

Phase 4

Study Type

Interventional


Primary Outcome

Systolic blood pressure and systolic blood pressure changes

Secondary Outcome

 Successful retinopathy of prematurity screening

Condition

Retinopathy of Prematurity

Intervention

0.5% cyclopentolate and 2.5% phenylephrine

Study Arms / Comparison Groups

 Multiple Alternate Instillation of 0.5% cyclopentolate and 2.5% phenylephrine (MAI)
Description:  20 infants were enrolled in Multiple Alternate Instillation of 0.5% cyclopentolate and 2.5% phenylephrine (MAI)

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

Drug

Estimated Enrollment

60

Start Date

September 30, 2011

Completion Date

September 30, 2011

Primary Completion Date

September 30, 2011

Eligibility Criteria

        Inclusion criteria:

          -  birth weight of less than 1500 g

          -  gestational age of 32 weeks or less

          -  an unstable clinical course who are believed to be at high risk for Retinopathy of
             Prematurity, as assessed by their individual attendings

        Exclusion criteria cited that

          -  infants with cardiac abnormalities directly affecting the heart rate and oxygen
             saturation

          -  infants with inotropic medications

          -  infants with ventilatory support
      

Gender

All

Ages

N/A - 32 Weeks

Accepts Healthy Volunteers

Accepts Healthy Volunteers

Contacts

Roland Joseph D Tan, MD, , 



Administrative Informations


NCT ID

NCT04838665

Organization ID

OVS 2010-08-10-109


Responsible Party

Sponsor

Study Sponsor

University of the Philippines


Study Sponsor

Roland Joseph D Tan, MD, Principal Investigator, University of the Philippines Manila


Verification Date

April 2021