Conditions: Strabismus
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 106
Healthy volunteers: yes

Brief summary:
Determine whether the application of povidone-iodine ophthalmic solution onto the ocular surface causes a change in respiration in children undergoing strabismus surgery with general anesthesia.

Hypothesis: The application of povidone-iodine ophthalmic solution to the ocular surface causes a change in respiration in children during general anesthesia prior to strabismus surgery.

Detailed description:
The study is randomized and single blind. One hundred children were randomly assigned to have either povidone-iodine (group A) or balanced salt solution (BSS) (group B) eye drops instilled into their eyes during anesthesia just prior to strabismus surgery. After induction of anesthesia and insertion of an LMA while the patient was at a steady state of anesthesia and spontaneously breathing sevoflurane in oxygen, 3 drops of either povidone-iodine or BSS was instilled into each eye (right eye first). Respiratory rate was determined by measuring the peak-to-peak interval on the capnograph. This is similar to calculating heart rate by measuring the R-R interval on an ECG. HR, BP, SaO2, EtCO2, and expired sevoflurane were measured in each patient. Medical history information collected included history of prior surgeries, co-existing diseases, or apnea. Appropriate statistical analyses were performed for comparisons between the groups with respect to respiratory rate, HR, BP, expired sevoflurane, and co-existing diseases.

Arms:
arm 1: Group A will receive three drops of povidone-iodine ophthalmic solution in each eye, with the right eye to receive the drops first. arm 2: Group B will receive three drops in each eye of ophthalmic balanced salt solution, with the right eye to receive the drops first.

Interventions: intervention 1: Provodine-Iodine Solution intervention 2: Group B will receive three drops in each eye of ophthalmic balanced salt solution.
Intervention descriptions: intervention 1: Group A will receive three drops of povidone-iodine ophthalmic solution in each eye, with the right eye to receive the drops first. The eye drops will be administered by the study anesthesiologist. After application of either solution to the eyes of the patient, any change in ventilation can be detected and timed by observation of the capnography (end-tidal carbon dioxide) and direct observation of the chest wall with use of the iPhone stopwatch feature again. The capnograph is a standard monitor of respiration used during the administration of general anesthesia. Data collected at this time will include whether or not there was a change in respiration, what this change in respiration was, if assisted ventilation was required, how long assisted ventilation was required (if applicable), HR, BP, RR, SaO2 , ETCO2, InspSevo, and ExpSevo. This study intervention and data collection will take less than 5 minutes. intervention 2: Group B will receive three drops in each eye of ophthalmic balanced salt solution. The eye drops will be administered by the study anesthesiologist. After application of either solution to the eyes of the patient, any change in ventilation can be detected and timed by observation of the capnography (end-tidal carbon dioxide) and direct observation of the chest wall with use of the iPhone stopwatch feature again. The capnograph is a standard monitor of respiration used during the administration of general anesthesia. Data collected at this time will include whether or not there was a change in respiration, what this change in respiration was, if assisted ventilation was required, how long assisted ventilation was required (if applicable), HR, BP, RR, SaO2 , ETCO2, InspSevo, and ExpSevo. This study intervention and data collection will take less than 5 minutes

Protocol document:
Prot_000.pdf: 
Version #3; 08/15/2018 
 
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The effect of povidone-iodine ophthalmic surgical prep solution on respiration in children 
undergoing strabismus surgery with general anesthesia. 
August 15th, 2018 
Michelle Rovner, MD 
NCT\03349515 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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PROTOCOL TITLE: 
The effect of povidone-iodine ophthalmic surgical prep solution on respiration in children 
undergoing strabismus surgery with general anesthesia. 
 
PRINCIPAL INVESTIGATOR: 
Michelle Rovner, MD 
Assistant Professor 
Department of Anesthesia and Perioperative Medicine 
 
 


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1.0 
Objectives / Specific Aims 
 
The objective of this study is to determine whether the application of povidone-iodine 
ophthalmic solution onto the ocular surface causes a change in respiration in children 
undergoing strabismus surgery with general anesthesia.   
Hypothesis:  The application of povidone-iodine ophthalmic solution to the ocular surface 
causes a change in respiration in children during general anesthesia prior to strabismus 
surgery. 
2.0 
Background 
 
 
 
   Primitive neural reflexes are often unmasked during anesthesia.  This is most likely due 
to an imbalance in the effect of anesthetics on inhibitory and excitatory neurons.  The 
oculo cardiac reflex (OCR) is a well-known reflex that occurs when traction is applied to 
an extra-ocular muscle.  The afferent limb of the reflex is mediated by sensory branches of 
the trigeminal nerve and the efferent limb is mediated by the vagus nerve.  Stimulation of a 
branch of the trigeminal nerve causes an increase in vagal activity that can cause a variety 
of changes in heart rate and rhythm.  Although the OCR has been reported to cause 
atrioventricular block, premature ventricular contractions (PVCs), ventricular tachycardia, 
and sinus arrest, bradycardia is the most consistently reported finding during anesthesia.  
The OCR has been known to occur with strabismus surgery for many decades and is 
correlated with traction on the extraocular muscles. 1,2  If the decrease in heart rate is 
significant enough to cause a decrease in cardiac output and/or blood pressure, the 
intravenous administration of glycopyrrolate or atropine effectively increases the heart rate 
in most patients.  Less well-known triggers of the trigemino-vagal reflex during anesthesia 
involve noxious stimuli to the mandible or skull base. 3-5 Changes in respiratory pattern 
(e.g. apnea, dachypnea, and bradypnea) have not been described with the OCR that occurs 
during anesthesia. 
 The diving reflex that occurs in diving birds and mammals is characterized by cessation 
of respiration, decrease in heart rate, and diversion of blood flow to critical organs (brain, 
heart, kidneys) from less critical tissue beds. 6 The diving reflex is initiated in these 
animals when the head and face are submerged resulting in stimulation of the trigeminal 
nerve.  A diving-type reflex has been described in humans, most notably in near-drowning 
victims.  Activation of this reflex may explain the survival of humans, especially children, 


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submerged in cold water for 30 to 40 minutes.  The diving reflex has also been implicated 
in the pathophysiology of sudden infant death syndrome (SIDS).7 Despite the similarity of 
the OCR and the diving reflex, the relationship between the two is unknown. 8,9 
    In 2015, an observational study was published that described apnea after the application 
of povidone-iodine ophthalmic solution on respiration.  All of those children were 
breathing sevoflurane spontaneously via a laryngeal mask airway (LMA).  Why this was 
not observed previously is not clear.  Prior to the introduction of the LMA into clinical 
practice, most children undergoing strabismus surgery underwent tracheal intubation and 
were managed with controlled or assisted ventilation.  A brief period of apnea or changes 
in respiration were, consequently, not obvious.  For the vast majority of children 
undergoing strabismus surgery throughout the United States (including at MUSC), 
standard airway management during anesthesia practice is with an LMA.  The predominant 
inhaled anesthetic administered is sevoflurane. 
    Povidone-iodine solution has become the standard for disinfection of the eye prior to 
surgery. 11, 12 Povidone- iodine solution has been typically formulated as a 10% solution.  
For surgical eye preparations, the 10% solution is diluted to produce a 5% solution.  
Recently, a specially formulated 5% Betadine® ophthalmic solution (manufactured for 
Alcon Laboratories, Fort Worth, Texas by Catalent Pharma Solutions, LLC, Woodstock, 
IL) was introduced and has become a standard for surgical eye preparation.  Ophthalmic 
balanced salt solution (BSS) is an isotonic solution specifically formulated for irrigation of 
eye tissues.  BSS is used in nearly all eye surgeries for irrigation.  These solutions are 
both FDA approved. 
    The objective of this study is to try to begin delineating the physiology of a potential 
reflex change in respiratory pattern initiated by a mechanical or chemical stimulus.  This 
study is the first step in the study of this reflex.  The results of this study will be used to 
develop further studies aimed at complete definition of this reflex. 
 
 
 
3.0 
Intervention to be studied 
 
 
    The effect of the application of povidone-iodine ophthalmic solution on the ocular 
surface on respiration will be compared to the effect on respiration of the application of the 
application of ophthalmic BSS on the ocular surface during general anesthesia.  Both of 
these solutions are FDA approved for use in this manner and this intervention will begin 
once a steady state of anesthesia is achieved by means of the standard of care.  After the 


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induction of general anesthesia and at the time the patient is ready for surgical preparation 
of the eyes, subjects will first have their average peak to peak interval for respiration 
measured at a steady state of anesthesia, using capnography.  This will give us a baseline 
for measuring a change in respiratory rate.  They will then have one of two solutions 
applied to the ocular surface of each eye.  It is this application of eye solution that is the 
main study intervention.  The solution to be used is determined by randomization upon 
enrollment and will either be 3 drops of povidone-iodine ophthalmic solution in each eye 
(Group A) or 3 drops of BSS in each eye (Group B).  The eye solution intervention period 
will take less than 5 minutes and will cause either only a slight delay or no delay in the 
surgical time.  The only other intervention is the collection of data after induction (but just 
prior to IV insertion), as well as before and after the drops of eye solution are delivered. 
 
4.0 
Study Endpoints (if applicable) 
The effect on respiration will be recorded upon application of either the 3 drops of 
povidone-iodine ophthalmic solution or 3 drops of BSS in each eye.  The presence of any 
respiratory effect – specifically a change in respiratory rate – will be the primary endpoint 
for this study.  Changes in respiratory pattern will be detected and measured by 
observation of the capnograph, which measures breath by breath CO2.13, 14  The capnograph 
is a standard monitor employed during the standard administration of general anesthesia. 15 
 
 
5.0 
Inclusion and Exclusion Criteria/ Study Population 
 
Operating room schedules will be screened the day prior to surgery and eligible 
candidates (their families) will be invited to participate in the study on the morning of 
surgery in the preoperative holding area.  The primary reason for including children is that 
strabismus is normally corrected during childhood and strabismus surgery is of importance 
because, as was mentioned previously, the oculo cardiac reflex has been known to occur 
with strabismus surgery.  
 Inclusion Criteria  
• 
Children 17 years and less 
• 
Scheduled for strabismus surgery  
• 
Anesthesia plan includes inhalational induction with sevoflurane and the use of 
a laryngeal mask airway (LMA) with spontaneous ventilation, per the attending 
anesthesiologist. 


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  Exclusion Criteria 
• 
History of an adverse reaction to iodine  
• 
History of any thyroid disease 
• 
Patients who require tracheal intubation, as determined by the attending 
anesthesiologist; e.g. craniofacial anomalies. 
• 
Patients with a contraindication to sevoflurane, such as malignant 
hyperthermia or severe left ventricular dysfunction. 
• 
Inability or unwillingness of the subject or legal guardian/ representative to 
give informed consent. 
6.0 
Number of Subjects 
    We will enroll approximately 110 patients in this study to include 55 patients for 
each randomized ‘treatment’ group.  Please refer to section 12.0 for the justification 
behind this enrollment number.  
7.0 
Setting 
 
 
 
    This study will be conducted solely in the perioperative areas of MUSC. 
 
8.0 
Recruitment Methods 
 
 
     
    The surgical schedule will be reviewed by a member of the study team on the day prior 
to surgery to identify patients undergoing strabismus surgery.  A chart review will be 
performed to ensure that they fall under proper inclusion criteria.  Furthermore, the study 
team will contact the attending anesthesiologist who will be working the potential study 
candidate’s case to make sure the anesthesia plan does not exclude the patient from the 
study.  Patients will be approached on the morning of surgery in the preoperative holding 
area of MUSC by a study team member and the consent process will proceed.       
9.0 
Consent Process 
 
Upon approaching the patient in the perioperative holding area of MUSC, the study will 
be thoroughly explained to the patient (if old enough to comprehend), as well as the family 
of the patient.  The consent and HIPAA forms will be presented and explained and the 
family will be given the opportunity and time to read through the forms.  Any questions 
they might have about the study or either of the forms will be answered by the study 
member and/or the attending anesthesiologist.  The parents or guardian(s) will then be 
asked to sign the consent form, as the patients will be under the age of 18.  If they patient 


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is over the age of 12, they will also be asked to give assent for study participation and the 
proper form for this will be presented to them and explained prior to obtaining their 
signature. 
 
 
10.0 Study Design / Methods 
 
Once it is confirmed that the attending anesthesiologist has both examined the patient 
and decided on an anesthesia plan that aligns with our inclusion criteria, the patient and 
their family will be consented.  If the patient is included in the study, the study member 
will randomize the patient to one of two groups: Group A - povidone-iodine ophthalmic 
solution, or Group B - ophthalmic balanced salt solution.  This randomization will be 
determined using a simple randomization scheme provided by the study’s statistician.  All 
decisions regarding anesthesia care, including the indication for preoperative 
pharmacologic anxiolysis, will be made by the attending pediatric anesthesiologist.  The 
case will then progress as it would without study involvement and the patient would be 
brought into the operating room and anesthesia would be administered.  The standard of 
care course of anesthesia includes: 
• Inhalation induction with oxygen in sevoflurane 
• Insertion of a peripheral intravenous catheter after induction of anesthesia 
• After a suitable depth of anesthesia is achieved, a laryngeal mask airway of 
an appropriate size will be inserted and secured 
    The only deviation from standard of care during the above process is the collection of 
data after induction, just prior to IV insertion.  These data points are heart rate (HR), blood 
pressure (BP), respiratory rate (RR), arterial oxygen saturation (SaO2), end tidal CO2 
(ETCO2), inspiratory sevoflurane (InspSevo), and expiratory sevoflurane (ExpSevo).  This 
data will be collected by a study member in real, intraoperative time.  The collection of 
data will not affect the progression of standard anesthesia practice, as the data collector 
will not be involved in the clinical care of the patient. Once the airway is secured and the 
patient has reached a steady state of anesthesia, the main study intervention will then 
commence.  We first would like to obtain the patient’s average peak to peak interval for 
respiration at this steady state of anesthesia, as measured from the capnography.  To do 
this, the research member in the room for data collection will use the iPhone stopwatch 
application and its ‘lap button’ feature to collect the respiration peak intervals (in seconds) 


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for 5 breaths.  Specifically, at the patient’s peak inspiration (as seen on the capnography), 
the study member will start the stopwatch and proceed to hit the ‘lap’ button for the next 5 
consecutive inspiration peaks.  These data intervals will be recorded on the data sheet after 
the 5 breaths are over, as the intervals are conveniently stored and numbered below the 
stopwatch in the app. We will do this to establish an average baseline respiratory rate for 
each individual patient.  Next, patients who are randomized to Group A will receive three 
drops of povidone-iodine ophthalmic solution in each eye, with the right eye to receive the 
drops first.  Group B will receive three drops in each eye of ophthalmic balanced salt 
solution.  Similarly, the right eye will receive the drops first; the reason being that we 
know that there are differences in sympathetic stimulation on the right side of the face vs 
left (e.g. termination of superventricular tachycardia) and although we don’t know if this 
effects OCR, we chose to standardize right eye first.  The eye drops will be administered 
by the study anesthesiologist.  After application of either solution to the eyes of the patient, 
any change in ventilation can be detected and timed by observation of the capnography 
(end-tidal carbon dioxide) and direct observation of the chest wall with use of the iPhone 
stopwatch feature again.  The capnograph is a standard monitor of respiration used during 
the administration of general anesthesia.  Data collected at this time will include whether 
or not there was a change in respiration, what this change in respiration was, if assisted 
ventilation was required, how long assisted ventilation was required (if applicable), HR, 
BP, RR, SaO2 , ETCO2, InspSevo, and ExpSevo.  This study intervention and data 
collection will take less than 5 minutes and the surgical team will then progress with the 
case as they normally would.   
    Other data to be collected is as follows: 
• Attending anesthesiologist and CRNA 
• Age 
• Weight 
• Sex 
• Co-existing diseases 
• If the patient was a pre-term birth and if yes, the estimated gestational age 
at birth 
• If premedication was given and if yes, what medication and dose 
• If N2O was used during inhalational induction 
 


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12.0 Data Management  
 
    Descriptive statistics by treatment group will be evaluated for all demographic and 
procedural characteristics.  The goal of the study is to determine if there is a significant 
difference in the change in respiratory response immediately following administration of 
saline or povidone-iodine solution in patients undergoing strabismus surgery.  The primary 
outcome is the difference between the peak to peak interval time from the capnograph 
measured before saline or povidone-iodine administration versus after administration.  Pre-
exposure peak to peak interval will be measured as the average time between peaks for five 
breaths prior to administration.  Post-exposure peak to peak interval will only be evaluated 
as the time between the two peaks at saline or povidone-iodine administration.  Differences 
in the change in peak to peak interval time between the saline and povidone-iodine 
exposure groups will be evaluated using a linear regression approach.  The model will 
include a treatment effect and will additionally control for patient age, history of 
prematurity, and use of any pre-medication to account for other factors thought to be 
associated with respiratory rate.  We anticipate no change in peak to peak interval time in 
the saline group with variability of +4 seconds.  A sample size of 50 patients per treatment 
group (100 patients total) provides >80% power to detect an increase in change in peak to 
peak interval of 2.5 seconds in the povidone-iodine group compared to the saline group 
assuming equal variance between the two groups using a 2-sided test with significance 
level set at alpha = 0.05.  If the variability of the povidone-iodine group is larger, for 
example a variability of 8 seconds, compared to 4 seconds in the saline groups we still 
have 80% power to detect an increase in the povidone-iodine group of approximately 4 
seconds. 
Several steps will be taken to ensure that the data collected for this study remains secure 
for the sake of the confidentiality of the patients enrolled.  All study members are CITI 
certified and the anesthesia research staff have received Core Clinical Research Training 
(CCRT).  Any data collected on the physical data sheet will not contain identifiers, but will 
rather contain the study ID number which is connected with patient identifiers on the study 
enrollment log saved on the secure research server.  All data sheets are kept in a locked 
cabinet in the locked research office and all electronic data is stored in the study’s secure 
REDcap database.  All data will remain in the confines of MUSC and will be brought 
down for storage in the research office promptly after data collection.    


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13.0 Provisions to Monitor the Data to Ensure the Safety of Subjects (if applicable) 
 
The Department of Anesthesia’s Data Safety and Monitoring Board (DSMB) will 
review this study biannually.  Any adverse events will be reported to the DSMB and IRB 
per policies in place.  The members of the DSMB for the Department of Anesthesia and 
Perioperative Medicine are Drs. Jerry Reves, John Waller, and Fred Guidry.  These 
physicians are professors at MUSC who have engaged in clinical research throughout their 
careers. 
 
14.0 Withdrawal of Subjects (if applicable) 
     Subjects will be withdrawn from the study if any changes need to be made to the 
anesthesia plan that do not align with the inclusion/ exclusion criteria of the study; 
e.g. if any airway intervention other than an LMA is required at the start of surgery.  
15.0 Risks to Subjects 
 
The risks to the subjects are minimal.  The anesthetics will be standard of care and the 
BSS and povidone-iodine ophthalmic solutions are commonly used eye surgery solutions 
that are safe for the application to the ocular surface in the manner in which we propose, as 
deemed by the FDA.  These solutions are routinely used during strabismus surgery.  As 
stated previously, the duration of the study intervention is very brief (seconds, to 4 
minutes) and will cause minimal, if any, delay in the surgical procedure.  If apnea becomes 
significant (e.g. arterial oxygenation saturation less than 94%, as measured by pulse 
oximetry), assisted or controlled ventilation is very easily provided via the LMA to 
counteract the apnea. 
There is a risk of loss of confidentiality, but the anesthesia research team has safeguards 
in place for keeping patient health information secure and only accessed when absolutely 
necessary.  All data will be stored on a secure server and consent and data forms will be 
held in a locked cabinet in a locked research office. 
Though it is a randomized study, there is not a risk of randomization because neither of 
the possible groups poses any additional risk to the participants. 
 
 
 
 


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16.0 Potential Benefits to Subjects or Others 
 
There is no direct benefit to participants by being enrolled in this research study, but the 
information gained from completing this study may enable pediatric anesthesiologists to 
predict when respiratory changes may occur during the course of strabismus surgery.  
Subsequent studies, based on the findings of this study may determine whether 
pretreatment with glycopyrrolate or atropine may attenuate or prevent changes in 
respiration.  
 
 
17.0 Sharing of Results with Subjects 
 
 
     
    There are no plans to share the results with the subjects or their families.  If, however, 
the patient or family requests such information, it shall be provided after completion of the 
study. 
 
References 
 
 
1. Rodgers A, Cox RG: Anesthetic management for pediatric strabismus surgery: continuing 
professional development.  Can J Anaesth 2010;57:602-17. 
2. Yi C, Jee D: Influence of the anaesthetic depth on the inhibition of the oculocardiac reflex during 
sevoflurane anaesthesia for paediatric strabismus surgery.  Br J Anaesth 2008;101:234-38. 
3. Chowdhury T, Mendelowith D, Golanov E, Spirev T, Arasho B, Sandhu N, Sadr-Eshkevari P, et 
al: Trigemino-cardiac reflex: the current clinical and physiological knowledge.  J Neurosurg 
Anesthesiol 2015;27:136-47. 
4. Lang S, Lanigan DT, van der Wal M: Trigeminocardiac reflexes: maxillary and mandibular 
variants of the oculocardiac reflex.  Can J Anaesth 1991;38:757-60. 
5. Schipke JD, Cleveland S, Caspers C: Computer-assisted paranasal sinus operation induces diving 
bradycardia.  Am J Otolaryngol Head Neck Med Surg 2013;34:353-54. 
6. Foster GE, Sheel AW: The human diving response, its function, and its control.  Scand J Med Sci 
Sports 2005:15:3-12. 
7. Singh GP, Chowdhury T, Bindu B, Schaller B: Sudden infant death syndrome- role of the 
trigeminocardiac reflex: a review. Front Neurol 2016;7:221. 
8. Lemaitre F, Chowdhury T, Schaller B: The trigeminocardiac reflex- a comparison with the diving 
reflex in humans.  Arch Med Sci 2015;2:419-26. 


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9. Folgering H, Wijnheymer P, Geeraedts L: Diving bradycardia is not correlated to the oculocardiac 
reflex.  Int J Sports Med 1983;4:166-69. 
10. Emhardt JD, Haider KM, Plager DA, Grundhoefer DL: Intraoperative apnea in children after 
buffered 5% povidone-iodine site sterilization for strabismus surgery. Pediatr Anes 2015;25:193-
95. 
11. Ciulla TA, Starr MB, Masket S: Bacterial endophthalmitis prophylaxis for cataract surgery: an 
evidence-based update.  Opthalmology 2002;109:13-24. 
12. Apt L, Isenberg S, Yoskimori R, Paez JH: Chemical preparation of the eye in ophthalmic surgery.  
III. Effect of povidone- iodine on the conjunctiva. Arch Ophthalmol 1984;102:728-29. 
13. Bhavani-Shankar K, Moseley H, Kumar AY, Delph Y: Capnometry and anaesthesia.  Can J 
Anaesth 1992; 39: 617-32 
14. Siobal MS: Monitoring exhaled carbon dioxide. Respir Care 2016; 61: 1397-1416 
15. Standards for Basic Anesthesia Monitoring. American Society of Anesthesiologists Committee on 
Standards and Practice Parameters.  
http://asahq/quality-and -practice-management/standards-and-guidelines 

SAP_001.pdf: 
Title: The Effect of Povidone-iodine Opthalmic Surgical Prep Solution on Respiration in Children 
Undergoing Strabismus Surgery with General Anesthesia 
 
NCT03349515 
 
2018 August 15 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis:  An a priori size calculation was conducted prior to the study.  Assuming no 
change in the peak to peak end-tidal CO2 interval time after drop instillation in the saline group, 
and a peak to peak interval time variability of ± 4 seconds, a sample size of 50 patients per 
group (100 patients total) provided > 80% power to detect an increase in change in peak to 
peak interval of 2.5 seconds in the povidone-iodine group compared to the saline group 
assuming equal variance between the two groups using a 2-sided test with significance level at 
α=0.05. 
     Descriptive statistics by treatment group were estimated for patient and procedural 
characteristics.  Differences in peak to peak interval time between the saline and povidone-
iodine exposure groups were examined using a linear mixed model approach.  Based on the a 
priori analysis plan, the model included fixed effects for treatment, breath number, a treatment 
by breath number interaction and a random subject effect to account for correlation between 
measures collected on the same subject.  The model also controlled for factors thought to be 
associated with respiratory rate including age, pre-term birth, history of apnea, and breath 
duration prior to drop installation.  Comparisons in breath duration between treatment groups 
at each of 15 breaths post-drop instillation were estimated from the model using Bonferroni 
corrected  significance. 
     A secondary outcome of interest was occurrence of a significant change in respiration.  
Although apnea has been defined in the literature as a breath duration of 10 to 20 seconds, this 
definition is arbitrary and fails to account for within and between subject variability of breath 
duration.  To account for within and between subject variability, we defined changes in 
respiration as having a breath duration greater than twice the inner-quartile range above the 


75th percentile for breaths within patient for the 10 breaths prior to and 15 breaths after 
instillation of drops.  Associations between occurrence of change in respiration with patient and 
procedural characteristics were evaluated using univariate logistic regression models.  Notably, 
no participants in the saline group experienced a change in respiration; therefore, all additional 
univariate tests were conducted on the subset of patients that received povidone-iodine drops.  
All analyses were conducted in SAS v.9.4 (SAS Institute, Cary NC, USA).