A Mobile Device App to Reduce Prehospital Medication Errors and Time to Drug Preparation and Delivery by EMS During Simulated Pediatric Cardiopulmonary Resuscitation: a Multicenter, Prospective, Randomized, Controlled Trial
Phase: NA
Conditions: Cardiopulmonary Arrest, Resuscitation, Pediatrics, Medication Errors, Emergency Medical Services
Sponsor: Pediatric Clinical Research Platform

Submitted to ClinicalTrials gov on April 15th 2019
Swiss National Science Foundation project funding application 
 
Title of the project: 
Reducing Prehospital Pediatric Medication Errors and Time to Drug Preparation and 
Delivery by EMS in Switzerland: a Multicenter, Prospective, Randomized Controlled Trial. 
 
Submitted to the Swiss National Science Foundation 29.03.2018 
 
 
a. 
Sponsor (within the meaning of the Ordinance on Clinical Trials in Human Research of 20 
September 2013, article 2) 
None. 

Submitted to ClinicalTrials gov on April 15th 2019
1. Summary of the research plan 
Background: Children represent a vulnerable population with specific medical needs compared to 
adults. Preparing intravenous (IV) drugs for critically ill children when required during 
resuscitation is particularly challenging. The urgent need to quickly and accurately prepare such 
drugs in a stressful environment places children at a particularly higher risk for medication errors 
than adults and is time-consuming. These errors are largely related to the need for individual 
specific weight-based drug doses calculation and preparation that vary greatly from birth to 
adolescence. In-hospital medication errors have been reported in 41% of pediatric resuscitation, 
the most common error being incorrect medication dosage in 65% of cases. However, a big 
challenge remains. The rate of errors may indeed be worse in the high-risk prehospital setting 
where care has to be delivered quickly by emergency medical services (EMS), in challenging field 
environments and where resources and providers are limited. Moreover, as paramedics have 
little exposure to critically ill children, they have limited opportunities to administer resuscitation 
drugs at pediatric doses. This may result in potentially life-threatening outcomes. Despite efforts 
to solve this problematic, prehospital preparation and delivery of emergency drugs remain a 
worldwide-unanswered health challenge with major impact on risk of medication errors, 
resuscitation duration, and healthcare economy. 
 
To address this problem, we developed a tablet application, called Pediatric Accurate Medication 
In Emergency Situations (PedAMINES). This app is a supportive tool designed to drive caregivers 
step-by-step and in real-time from preparation to delivery of a wide range of drugs, especially 
those required during resuscitation. We conducted a prior multicentric randomized controlled 
crossover trial granted by the Swiss National Science Foundation in 6 pediatric emergency 
departments in Switzerland during a simulation-based pediatric cardiac arrest scenario. 
Medication errors were reduced from 75.9% to 10.2% by using respectively conventional 
preparation methods or PedAMINES (P<.0001). While using PedAMINES time to drug preparation 
(TDP) and delivery (TDD) were reduced by 147.5 (48%) and 170.5 (39%) seconds respectively 
(both P<.0001). However, the app was not assessed in prehospital settings. 
 
Objectives: we aim to determine whether the use of PedAMINES improves the management of 
acute pediatric prehospital life-threatening conditions in Switzerland by quickly delivering 
expertise in IV drugs administration and by avoiding medication errors. We hypothesize that 
PedAMINES will reduce medication errors, TDP and TDD independently of the existing 
conventional preparation methods used or EMS’ skills. 
 
Method: a multicenter, prospective, unblinded, randomized controlled trial to compare the 
efficacy of PedAMINES vs conventional methods in the preparation of IV emergency medications 
during a video-recorded simulation-based pediatric cardiac arrest scenario. Participants: 120 
paramedics in several EMS all over Switzerland. Randomization: stratified on EMS and 
centralized with a 1:1 allocation ratio. The study is formatted according to the CONSORT-
EHEALTH and the Reporting Guidelines for Health Care Simulation Research statements. 
 
Intervention: each paramedic will be asked to prepare a standardized series of 4 IV emergency 
medications, using either PedAMINES (intervention group) or conventional methods (control 
group). Two questionnaires will be given before and after the scenario to collect paramedics’ 
demographics data and satisfaction. Stress level will be assessed by questionnaire and heart rate 
will be recorded as a stress marker with a fitness watch.  
 
Outcomes: the primary outcome is to measure the absolute number and the rate of medication 
dosage errors committed during drugs preparation sequences until injection in each allocation 
group. The secondary outcomes are the delays in seconds to TDP and TDD in each drug 
completion sequence, as well as other medication errors, perceived and measured stress. 
Acceptability and usability testing of the app will be assessed using a 52-item questionnaire 
based on the unified theory of acceptance and use of technology (UTAUT) model. 
 
Perspectives: PedAMINES might help EMS with different competencies to prepare and deliver 
complicated drugs. This suggests a worthwhile benefit to its use in remote places where 
paramedics are little exposed to pediatric resuscitation but have to use resuscitative drugs 
before to transfer the patient to a tertiary care center. Being able to assess PedAMINES in the 
prehospital setting would be the next step to demonstrate its usefulness in multiple settings 
before to deploy the application all over Switzerland in real situations. It will also standardize 
and unify drugs prescription in Switzerland during the whole pre- and in-hospital resuscitation 
process. Finally, our project will also be beneficial to clinical research in Switzerland by offering a 
common base for further studies on prehospital medication errors. 

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2. Research plan 
2.1 Current state of research in the field 
Despite many advances in the medical field in recent years and in particular in 
emergency medicine, suboptimal quality of resuscitation is still common for both adult 
and pediatric patients1. Currently, the median hospital survival rate from pediatric in-
hospital cardiopulmonary arrest (IHCA) is 36%1, whereas it is below 10% for out-of-
hospital cardiopulmonary arrest (OHCA)2,3. According to the American Heart Association, 
emergency medications such as epinephrine, adenosine or amiodarone have to be 
considered in children undergoing pediatric advanced life support4,5. Many situations do 
also require use of drugs or substrates for acute pediatric problems that require 
pharmacologic intervention to restore vital functions and prevent patients from 
deteriorating (ex: anticonvulsive drugs, dextrose, etc). However, quickly, accurately, and 
safely preparing intravenous (IV) drugs in a stressful environment is particularly 
challenging, error-prone and time-consuming6-9 when required during emergent pediatric 
situations. 
Medication errors: Medication errors are common in pediatric patients. These errors are 
largely due to the need for individual specific weight-based drug doses calculation and 
preparation that vary significantly from birth to adolescence7,10-14, as well as a lower 
dosing-error tolerance15. Whereas emergency medications given to adults being 
resuscitated are typically in prefilled ready-to-inject syringes containing a single dose 
adapted for most patients, majority of drugs given to pediatric patients are provided in 
vials not adapted for this population, leading to the need to manipulate drugs, to adapt 
volumes, concentrations and doses. This often requires micro-calculation for a majority of 
drug concentrations that are initially appropriate for adults rather than children. This 
places children at higher risk than adults for errors7,10,11 and may result in life-
threatening outcomes. The rate of medication errors also increases in emergency care 
requiring various drugs administration where each of which may have its own 
concentration, dose, and volume7. 
 
In the hospital setting, critically ill or injured patients are typically admitted in pediatric 
emergency departments (PEDs). A recent study showed that one in every 32 
prescriptions in a PED contained a tenfold error on the recommended dose7. Medication 
errors have been reported in up to 41% of pediatric cardiopulmonary resuscitations 
(CPR) in PEDs, the most common being incorrect medication dosage, found in up to 65% 
of cases16. Kozer et al showed an error rate of 17% at the prescription level, with up to 
10 times the recommended pediatric dose in more than 3% of the cases17. In the same 
study, 16% of the analyzed syringes showed a 20% dose deviation from the prescribed 
dose and up to 7% showed a deviation of more than 50%. 

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Furthermore, the rate of medication errors may be made worse depending on the 
situation in which the drugs are being given. This is especially true in the high-risk 
prehospital setting where care has to be delivered quickly and where resources are 
limited. A single paramedic is often in charge of determining the patient’s weight, 
choosing the most suitable drug, calculating the drug dose and appropriate volume to 
inject, and administering it to the patient. Several specific aspects of pediatric care in the 
prehospital setting may also increase the risk of medication errors18. The time pressure 
to prepare the drugs on-site adds to the complexity of the process. Compared to children 
who arrive at the emergency department by other means, children transported by 
emergency medical services (EMS) are indeed more likely to require immediate care18. 
Disruptive emotional anxiety and exogenous conditions encountered during prehospital 
pediatric resuscitation, such as challenging field environments and parental stress, may 
also increase cognitive load19,20. Moreover cognitive load has been shown to be higher 
and error-prone when the task is less familiar, as typically seen during CPR21, and 
uncommon like in children19,22. As is the case in the U.S.A.23, pediatric patients are only 
seen in about 7% of EMS calls in Switzerland24. Paramedics have therefore little exposure 
to critically ill children and experience to administer emergency medications at pediatric 
doses25. For instance, it was shown that delivery of epinephrine and dextrose to children 
less than 17 years old by EMS in 26 U.S.A. states accounted for only 3,6% and 0,8% of 
the total adult drug administrations respectively. Consequently, EMS have minimal 
opportunities to gain experience and maintain competence in this skill26,27. This sum up 
to the fact that almost 60% of paramedics report their initial education course as 
deficient pediatric-specific training26. 
 
Therefore, knowing that medication errors still occur in PEDs despite favourable well 
equipped and staffed environments with numerous available safeguards, it is not 
surprising that the aforementioned factors expose EMS to greater opportunities for 
medication error rates and patients harm in the prehospital setting. It has been shown in 
a large study that prehospital medication dosing errors affect approximately 56,000 U.S. 
children treated by EMS each year26. Authors showed that drugs were administered 
outside of the proper dose range in up to 39,8% of more than 5500 children. Among 
other drugs, epinephrine had the highest rates of incorrect doses with 60,9% of 
preparations containing an error, and a mean error overdose of 808%. Among EMS, 55% 
used a Broselow-Luten length-based tape (BLT), while 36% asked the parent or guardian 
to estimate weights, and 2.3% relied on a smart phone app. These results were in 
agreement with those of other studies where providing EMS with ready access to a BLT 
were shown to be insufficient to prevent a high rate of epinephrine errors in the 
prehospital setting with dosing errors exceeding 60 to 70%25,28. In another study 
identifying causes of errors by EMS during a simulated prehospital pediatric emergency, 

Submitted to ClinicalTrials gov on April 15th 2019
the error rate for diazepam and midazolam dosing was 47% and 60% respectively29. 
Underlying causes of errors included incorrect estimation of weight, incorrect use of the 
BLT, incorrect recall of doses, difﬁculty with calculations under stress, mg⁄kg to mg to mL 
conversion errors, inaccurate measurement of volumes, and failure to cross check doses 
between providers29. These results were somehow similar to others reporting that 
paramedics commit dosing errors 49–63% of the time with miscalculation as a primary 
cause11. Even after intervention to instruct EMS in the use of the BLT and precalculated 
drug dosing charts, medication dosing errors remain significant25. This highlights the fact 
that the sole expertise of paramedics helped by conventional conversion methods is not 
sufficient to ensure fast and reliable conversion and preparation of IV emergency 
medications. At this stage, even small errors either in weight estimation or drug 
calculation may have a large detrimental impact on the amount of drug delivered30-32. 
This can be deleterious to critically ill and unstable patients and even prove fatal7. Some 
authors have therefore advocated replacing as much as possible tasks requiring cognitive 
load during CPR by automated actions in order to optimize patient care and diminish 
medication errors21,33. Moreira et al. have shown that the use of color-coded prefilled 
medication syringes in a PED reduced by 17% the risk of medication errors during 
simulated pediatric resuscitations33. However, if prefilled syringes appear to be applicable 
for drugs that can be packaged as ready-to-use medications in PEDs, it is less evident for 
drugs used in the prehospital setting34. The number of drugs available, their chemical 
stability over time35-38, the infrequent EMS calls for children, and the wide range of drug 
doses used in this population would render this solution nonviable and economically 
unjustified. Thus, to date, drugs administered out-of-hospital continue to need upstream 
preparation and medication errors remain a worldwide health challenge with major 
economic impact. 
 
Every minute counts: In resuscitations, time is also a decisive success criterion. It is 
well established that cardiopulmonary resuscitation (CPR) duration is inversely correlated 
to survival. During the first 15 minutes of in-hospital cardiac arrest (INHCA) pediatric 
resuscitation, survival and favorable neurological outcome decrease linearly by 2.1% and 
1.2% per minute, respectively39. Thus, the survival rate for CPR less than 15 minutes is 
estimated at 41 %, while this rate drops to 12% after 35 minutes39. Similarly, among 
pediatric patients with out-of-hospital cardiac arrest (OHCA) with non-shockable initial 
rhythms, each minute delay to epinephrine delivery is associated with 9% decrease in 
the odds of survival40,41. Regrettably, in the prehospital setting, the majority of patients 
receive epinephrine more than 10 minutes after EMS arrival40,41. The chain of survival 
therefore critically relies on early prehospital initiation and efficient resuscitation by 
EMS42, onsite administration of certain drugs without delay40,41,43,44 before a rapid 
transfer to PED and advanced care. 

Submitted to ClinicalTrials gov on April 15th 2019
2.2 Current state of our own research 
PedAMINES: Following a user-centered and evidence-based approach45, our group 
composed of PED physicians and nurses, as well as software developers and ergonomists 
has developed a tablet app called Pediatric Accurate Medication in Emergency Situations 
(PedAMINES). This app is a supportive tool designed to drive caregivers step-by-step and 
in real-time from preparation to delivery of a wide range of drugs, especially those 
required during resuscitation. The app development was mainly guided by requirements 
built on our clinical experience, CPR observations and focus groups46.  In an in-hospital 
pilot randomized trial, we have shown that medication errors were reduced from 70% to 
0% (P<.001) by using PedAMINES when compared with conventional methods. Time to 
drug preparation (TDP) and delivery (TDD) were decreased by 180 and 177.3 seconds 
respectively (P=.002)47. Results were by far better than those, already consequent, 
obtained with the on-site presence of clinical pharmacist during pediatric CPRs associated 
with a 25% decrease in medication errors16.  
Granted by the Swiss National Science Foundation (SNSF #32003B_169348/1), we 
next conducted in 2017 a multicentric opened randomized controlled crossover trial in 6 
PEDs in Switzerland with the same simulation-based scenario with more than 120 nurses 
(forthcoming publication). Medication errors were reduced from 75.9% to 10.2% by 
using PedAMINES when compared with conventional methods (P<.0001), while using 
PedAMINES TDP and TDD were reduced by 141.8 (43.9%) and 161.9 (39.0%) seconds 
respectively (both P<.0001, Figure 1). Participants rated the overall perceived 
satisfaction using PedAMINES to be 9.4 (95% CI 9.3-9.6) on a 10-point Likert scale. 
 
Fig 1. Boxplots of elapsed time to drug preparation (TDP) and to drug delivery (TDD) in intervention group 
(PedAMINES) and control group (conventional method) in both periods of the SNSF crossover study. Time is 
expressed in seconds. Solid horizontal lines denote median and interquartile ranges; the whiskers go down to 
the smallest value and up to the largest; + denotes mean. Red open circles denote each individual value. Time 
is expressed in seconds. P-values are the result of Mann-Whitney test. **** P<.0001. 
TDP
TDP
TDD
TDD
0
200
400
600
800
1000
Time [s] 
****
****
Study Period 1 (Dopamine)
Time to...
TDP
TDP
TDD
TDD
0
200
400
600
800
Time to...
Time [s] 
Study Period 2 (Norepinephrine)
PedAMINES
Conventional method
****
****
**** P<.0001

Submitted to ClinicalTrials gov on April 15th 2019
PedAMINES is much more than just a calculator. The app lists all the available 
resuscitation drugs, either for direct IV or continuous infusion, with doses automatically 
adapted to the weight or age of the patient entered when starting the app. The list can 
be expanded and customized according to users’ need and to local drugs habits 
internationally. Drugs (concentration, volume, etc.) are fully editable to adjust for each 
center internationally. Safety of the app (doses, calculations, etc.) is guaranteed both by 
the calculation algorithm created and checked by the developers’ team and by the data 
edited by each user. By a simple touch, any of the listed drugs can be selected and the 
exact amount to prepare is clearly displayed making calculations useless (Figure 2). This 
is based on the app’s ability to automatically calculate the optimal weight-based drug 
dose, independently of the user competency in this domain. Multiple drugs can be 
prepared and run in parallel. All actions performed are stored locally on the device in 
historic files to preserve information that can be retrieved at any time for debriefing or 
medicolegal purposes. Historic files can also be erased or safely exported and saved in 
electronic health records. PedAMINES is so simple to use and powerful that even 
inexperienced users may use it after a 5-minutes training session. This was particularly 
obvious in our SNSF granted study where distribution of individual delays was less spread 
with PedAMINES than with the conventional method (Figure 1). This suggests a 
worthwhile benefit to its use in the prehospital setting where paramedics are infrequently 
exposed to pediatric CPR but have to use resuscitative drugs before to transfer the 
patient to a tertiary care center. 
 
Fig 2. PedAMINES application screenshot 
Need for a trial: To our knowledge, PedAMINES is the first scientifically validated app to 
improve drug preparation during in-hospital pediatric CPR and able to sustain cognitively 
users during this process. However, a big challenge remains. To date, very few pediatric 
studies of medication errors and error prevention strategies have been performed in 

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prehospital settings, particularly in regard to the care of pediatric patients18,26. This 
translates into suboptimal knowledge and delivery of pediatric prehospital care. It 
remains to be determined whether the use of PedAMINES will improve the management 
of prehospital life-threatening conditions in prehospital setting, where EMS are either 
little or not exposed to pediatric resuscitation. As research in this area is scarce, results 
generated from this study will be of great importance. They might be sufficient to change 
and improve the pediatric prehospital emergency care practice and increase survival rate. 
Importantly, PedAMINES might become an efficient tool to standardize and unify CPR’s 
drugs prescription during the whole pre- and in-hospital resuscitation process in 
Switzerland. A large multi-center randomized trial is therefore needed to assess this 
assumption in the prehospital setting. 
2.3 Detailed research plan 
2.3.1. Choice of comparators 
In Switzerland, EMS providers have autonomy in emergency situations and a delegated 
authority to prepare emergency medications. They should therefore be regarded as 
medication prescribers for the purpose of studying medication errors in the prehospital 
setting. The current, conventional method used to prepare such drugs relies on the use 
of the BLT, protocols or precalculated drug dosing charts.  
In our pilot and SNSF studies PedAMINES has been validated as an efficient tool to 
reduce medication errors and delays in CPR. Its selection as comparator is therefore 
justified. 
2.3.2. Objectives and hypothesis 
We aim to determine whether the prehospital use of PedAMINES by EMS in Switzerland 
reduces medication errors, as well as TDP and TDD. 
Research hypothesis: Herein, we hypothesize that PedAMINES reduces medication errors 
and TDP and TDD independently of existing conventional preparation methods (i.e. 
precalculated drug dosing charts) or EMS’ skills.  
Primary objective: To determine whether prehospital use of PedAMINES during pediatric 
resuscitation reduces medication preparation errors compared with conventional 
methods. 
Secondary objective: To determine whether prehospital use of PedAMINES during 
pediatric resuscitation reduces dosing deviations and other types of errors (see below) 
compared with conventional methods. To determine if PedAMINES leads to a shorter time 
in direct IV drugs preparation (TDP) and delivery (TDD). 
 

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2.3.3. Study design 
The study is a prospective, multicenter, randomized controlled trial with 2 parallel groups 
comparing PedAMINES46,47 with conventional precalculated drug dosing charts used by 
EMS in the preparation of direct IV drugs during a standardized simulation-based 
pediatric cardiac arrest scenario. The drug dosing charts is presented as a spreadsheet, 
enabling the preparation of the commonly ordered concentrations of emergency 
medications at varying dose ranges based on the patient’s weight. To calculate the 
composition of the drug to inject, one first selects the desired drug dosage to be 
delivered in mg/kg. The next step is to calculate the milliliters of drug based on the 
weight of the patient to be diluted with compatible fluids (sodium chloride 0.9%, etc) in a 
syringe. For the purpose of the study, we will not select drugs that can be directly drawn 
from the vial without calculation and dilution. 
The multicentric setting of the study will involve 15 Swiss EMS (Cantons of Geneva, 
Vaud, Neuchâtel, Fribourg, Jura, Zurich, Bern, Basel, Lucern, Ticino). To ensure optimal 
quality of reporting, the trial is formatted according to the Consolidated Standards of 
Reporting Trials Statement for Randomized Controlled Trials of Electronic and Mobile 
Health Applications and Online TeleHealth (CONSORT-EHEALTH)48 and the Reporting 
Guidelines for Health Care Simulation Research49 
2.3.4. Inclusion and exclusion criteria 
Registered paramedics are eligible for inclusion in this study. Participants must know how 
to prepare IV drug injections, and be willing and able to grant written informed consent. 
Written informed consent will be obtained from all the participants before their voluntary 
involvement.  
 
2.3.5. Intervention 
2.3.5.1. Interventions 
The scenario in this study is a short, approximately 20-minute, standardized highly 
realistic pediatric resuscitation simulation on a wireless high-fidelity manikin (Laerdal 
New SimBaby). The SimBaby represents a realistic 1-year-old boy. The choice of 
selecting this manikin is directed by our willingness to simulate resuscitation in a young 
child requiring pediatric drug dosage, and also to take advantage of its wireless 
properties allowing its use in pre-hospital conditions. This simulator provides all 
functionalities that are relevant to assess the research questions, including chest 
compression, ventilation, vascular access, seizure, as well as realistic and interactive vital 
signs. To date, high-fidelity simulation has become essential to study resuscitations skills 
and technologies that cannot be practiced during both prehospital and in-hospital 

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resuscitations because interindividual diversity among patients and their diseases make 
CPR studies hard to standardize in critical situations50. When skills are assessed with 
simulations, errors are made more visible than during actual pediatric prehospital 
resuscitations29. Moreover, by standardizing the scenario and environment, we will avoid 
effect modifiers by preventing the influence of undesired variables on the outcomes. To 
date, none of the results obtained from simulation-based CPR studies disagreed with 
those obtained from studies in real life. 
Consistent with standard emergency medicine practice, we will create resuscitation 
teams. Two members from the study team, remaining the same along the whole study 
period, will assist the study participant. A Pediatric Advanced Life Support (PALS) 
instructor-certified emergency pediatrician will lead the resuscitation, and a nurse playing 
the role of a second paramedic will assist with resuscitation by performing chest 
compressions and bag-valve mask ventilation according to the pediatrician instructions, 
but not drug dose calculation or preparation. Participants will be informed before the 
scenario starts that these 2 people are study team members. Both study team members 
will guide each participant through a series of predefined key steps, blinded to the 
participant, following a standardized resuscitation scenario (see below). The physician 
will order the medications and allow progression through the scenario only once 
predefined milestones have been reached, regardless of the occurrence of errors or time 
to achieve them. The study-specific training and standardization of both study team 
members is ensured through their involvement in the pilot study47 and previous SNSF 
study and by following the predefined scenario. A certified technician will operate the 
simulator. 
On the day of participation, paramedics will complete a survey collecting data regarding 
their demographics, care training, and simulation and computer experience. After 
random allocation, each participating paramedic will receive a standardized 5-minute 
training session on how to use the PedAMINES app. Paramedics will remain unaware of 
drugs that will be used and specific endpoints of the study during this training session. 
The simulation manikin characteristics are then presented. The paramedics will then be 
asked to perform the pediatric resuscitation scenario. This scenario is standardized to 
follow the same chronological progression and range of difficulty to ensure each 
participant is exposed to exactly the same case, with similar challenges in decision 
making and treatment preparation provided on the same manikin. The uniform delivery 
of the scenario all along the study will minimize confounders. Study team members will 
only adapt to progression speed of participants through the scenario by maintaining a 
stressful resuscitation atmosphere. The scenario will be videorecorded and conducted in a 
simulated children room in each area in order to increase realism. High levels of realism 
are known to immerse participants in the simulated experience and prevent confounding 

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variables that might potentially affect the way individuals perform50. The simulated room 
will be exclusively devoted to the simulation to prevent unexpected interruption or 
external stimuli. Portable monitoring alarms will be activated to increase realism and 
stress. All usual EMS resuscitation equipment will be at the disposal of the paramedic. In 
both allocation groups, the decision to use or not use any equipment will remain personal 
as in real life. Neither pilot testing nor repetitions will be permitted. There will be neither 
interventions nor educational adjuncts prior to or after the study period. Once the 
experiment completed, the paramedic will be required to recall and describe precisely 
how he prepared the drugs in order to verify that the drug names and original doses 
prescribed by the physician were correctly understood to assess the presence of 
comprehension bias.  
Resuscitation scenario: the untimed portion of the simulation starts by turning on the 
video cameras and the fitness watch. The paramedic and both investigators (the 
confederate paramedic and the physician) wait outside the room where they are 
supposedly dispatched. The team will be invited to enter the room by the father 
(simulated by the technician operating the manikin). A clinical statement to recognize the 
life-threatening condition of the patient, including his weight and age, is then given by 
the father as follows: “Here is Junior, a 12-kg, 1 and a half year old boy who suddenly 
collapsed 15 minutes ago. Oral tricyclic antidepressant as well as antidiabetic pills from 
his grandmother were found in is mouth and on the ground of his room. He is 
unconscious, pale and does not breathe”. At this moment, the physician asks the 
participant to take a central pulse. Because of the invariable absence of a pulse, the 
latter is asked to assist the physician to perform a 2-min full course massage and 
ventilation (15:2 ratio) maneuver to increase his own stress level (massage carried out 
by the participant). During this time, the physician asks the confederate paramedic to 
place a 4-derivation electrocardiogram on the manikin, an upper arm blood pressure 
monitor, a digital pulse oximeter and defibrillator’s patches. Then the physician asks to 
change roles; the confederate paramedic has to carry out the massage while the 
participant has to get a peripheral vascular access on the manikin’s right hand. At this 
time, an asystole rhythm is recognized and verbalized by the physician. On the basis of 
the American Heart Association pediatric cardiac arrest algorithm for asystole4, a bolus of 
epinephrine is ordered by the physician and the timed scenario begins. The participant 
must prepare and administer the drug with the help of PedAMINES (intervention group) 
or following the conventional method. ROSC ensues with generalized tonic-clonic 
seizures. The physician says: “The patient has now a return of spontaneous circulation 
with a pulse but with seizures. This patient needs an IV bolus of midazolam right now”. 
The seizures stop 15 seconds after administration of the drug. At this time the physician 
asks the participant to perform a finger stick to obtain a blood sample. The glucometer 
reports a blood sugar of 0.8 mmol/L. The physician says: “the patient has a severe 

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hypoglycemia” and prompts the participant to prepare and inject an IV bolus of dextrose 
10%. Return of a state of consciousness ensues with normal vital signs, but a wide QRS 
on EKG-monitoring. The physician says: “This child needs an IV bolus of sodium 
bicarbonate 1 mEq/kg”. As soon as this last medication is administered, the physician 
asks for transport and the scenario ends. The cameras and the watch are turned off 1 
minute later. The measured deviation between the amount of drug delivered and the 
actual prescribed dose will be measured by the amount of drug in the syringe. As 
everything is video-recorded, we will be able to verify and measure the exact amount of 
drug and concentration in the syringe after the scenario. During the whole scenario, the 
physician, the confederate paramedic and the operator will maintain a stressful 
resuscitation atmosphere (monitoring alarms are on, the primary assessment (ABCDE) is 
often repeated, vital signs are frequently reported aloud and the father repeatedly 
verbalizes his dismay). 
2.3.5.2. Criteria for discontinuing or modifying interventions 
The time needed to complete the full scenario was set to only a 20 minutes period for 
each participant and will be booked weeks ago to ensure availability of the participants 
without repercussion on their normal duty. All participants will receive full permission 
from their hierarchy to participate to the study. Using simulation-based CPR scenario 
makes our study highly feasible without risks for patients or participants.  
2.3.5.3. Adherence 
The study will take place during a 1-week period in each EMS and will occupy each 
paramedic for a single 60-minute period. Thanks to our experience gathered in previous 
studies, we anticipate a very low rate of drop-outs or loss of follow-up. To ensure the 
presence of participants on the day of participation, shift-working paramedics will be 
randomly recruited 1 month before the start of the study by a blinded noninvestigator. 
They will be informed of the upcoming simulation study but not of its purpose and 
outcomes. Each paramedic will be rewarded individually by an amount of 50.- CHF for its 
participation to the study. Adherence of the collaborating EMS to our study will be 
reinforced by their citation in further publications and by a privileged access to the 
PedAMINES app. 
2.3.5.4. Concomitant care 
The paramedics will be allowed to use their current, conventional method of preparing 
direct IV drugs, even if it differs between EMS. This will avoid introducing evaluation bias 
on the baseline ability of paramedic to prepare drugs “as usual” if allocated in the group 
without PedAMINES. This will also test the absolute capacity of the app to reduce 
medication errors and drugs delays, indifferently of the prior traditional method used. 

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However, participants will not be allowed to use any other drug support device and the 
scenario will remain secret until it starts to avoid upstream drugs preparation’s refresh.  
 
2.3.6. Outcomes 
Primary outcome measures: The primary outcome will be to measure, in each 
allocation group, the number of medication dosing errors committed during each drug 
preparation sequence until injection. According to Marcin et al. and Moreira et al, we 
defined a emergency medication dose administration error as more than 10% deviation 
from the correct weight dose9,12. 
Secondary outcome measures: The secondary outcomes will be to measure, in each 
allocation group, the followings variables:  
A) Errors that might be encountered during drug preparation, such as: 1) the amount of 
drug taken in mL and deviation from the one prescribed on the drug dosing charts or the 
app, 2) the amount in mL of saline solution taken to dilute the drug, and deviation from 
the one prescribed, 3) final drug concentration in mg/ml obtained and deviation from the 
one prescribed, 4) correct or wrong drug chosen by the paramedics compared to the one 
prescribed on the drug dosing charts or the app (the drugs chosen will be recorded for 
every participant in order to find any systematic or repetitive error), 5) correct or wrong 
air purge out of the syringe before injection, 6) correct or wrong labeling of the filled 
syringe, 7) detection or not of error(s) by the paramedics, 8) stage of error(s) detection: 
before or after injection, and 9) aseptic errors. These measures of medication errors 
were selected as they were considered to be the most common sources of medication 
errors as evidenced in the pediatric medication error literature and meta-analysis17,51,52.  
B) The time points of the drug preparation, in each allocation group, such as: 1) time in 
seconds between the end of the drug prescription by the physician and the syringe filled 
with the drug (TDP), 2) TDP plus time in seconds between TDP and injection (TDD). TDP 
and TDD are relevant temporal values described in the resuscitation literature39,53. 
C) Questionnaires: at the end of the scenario, a 6-item questionnaire using a 10-point 
Likert scale (scored from one to ten to avoid neutral answers) will be provided to the 
participants. The questionnaire measures (1) the overall stress perceived, (2) the stress 
perceived during each drug preparation sequence with PedAMINES and with the 
conventional method(s), and (3) the satisfaction about the preparation method used 
during the resuscitation scenario. Acceptability and usability testing of the app will be 
assessed using a 52-item questionnaire based on the unified theory of acceptance and 
use of technology (UTAUT) model54. UTAUT provides a useful tool to assess the likelihood 
of success for new technology introductions and helps to understand the drivers of its 
acceptance. 

Submitted to ClinicalTrials gov on April 15th 2019
D) Heart rate (HR) as a stress marker: a baseline HR before the beginning of the 
scenario as well as continuous HR monitoring of each participant reflecting his or her 
stress level will be recorded during the scenario. Mean delta HR values (difference 
between HR peak values and baseline HR) will be obtained during some small segments 
of scenario and correlated to the scenario phases and the preparation methods used.  
 
2.3.7. Patients Timeline 
On-site staff in every collaborating EMS will organize participation of paramedics to the 
study. No informations about the ongoing study will be given to the paramedics at this 
stage. The best study period will be matched with study coordinators. The paramedics 
will be spread throughout 1 week in order to link up the several scenarios. On scheduled 
weeks, the study coordinators will visit the collaborating EMS, provide trial informations 
to participants before they begin the scenario, and assessment of eligibility will be 
verified. Participants will then sign the informed consent. They will be asked to complete 
an anonymised demographic questionnaire and confirm their willingness to participate. If 
it’s the case, they will pursue with a 5-minute learning session to the use of PedAMINES 
given by the investigators. Then, each participant will be randomly allocated to study 
arms. Immediately after the randomization, the paramedic will start the scenario. 1) the 
overall stress perceived during the scenario and during each drug preparation, and 2) the 
satisfaction about the preparation method used. The total study period to enroll all 
paramedics in the various EMS will take 12 months.  
Table 1. PedAMINES timeline protocol for forms and procedures 
 
Study Period 
Pre-
enrollment 
Enrollment / consent 
Pre-study baseline / 
allocation 
20-minute 
scenario 
Closeout 
Time point 
–t2 
–t1 
0 
t1 
tx 
  ENROLMENT: 
  Invitation to participate 
X 
 
 
 
 
  Eligibility screen 
 
X 
 
 
 
  Informed consent form 
 
X 
 
 
 
  Demographic questionnaire 
 
 
X 
 
 
  PedAMINES learning session 
 
 
X 
 
 
  Randomization 
 
 
X 
 
 
  INTERVENTION : 
  Group A (with PedAMINES) 
 
 
 
X  
 
  Group B (with conventional method) 
 
 
 
X  
 
  Termination questionnaire 
 
 
 
 
X 
  ASSESSMENTS : 
  Medication errors 
 
 
 
X  
 
  Time at prescription 
 
 
 
X  
 
  Time to drug preparation (TDP) and delivery (TDD) 
 
 
 
X  
 
 

Submitted to ClinicalTrials gov on April 15th 2019
2.3.8. Sample size 
The primary objective of this study is to detect a difference in proportions of medication 
errors between groups (with PedAMINES vs without PedAMINES). The expected 
proportion of errors made without PedAMINES is 60%11. We consider that a difference of 
30% in the proportion of medication errors is sufficient to modify the practice. Therefore, 
the sample size was calculated to reach a statistical power of 90% in detecting an 
absolute difference of at least 30% in proportions of medication errors between 
intervention groups. With a two-sided risk alpha of 0.05, the needed sample size is 56 
paramedics per arm of the study. To prevent a potential loss of power due to 
misspecification of assumptions, 60 paramedics will be recruited per randomized group 
(total sample size: 120 paramedics). 
2.3.9. Recruitment 
2.3.9.1. Recruitment strategies 
We already have the study participation approval of the different EMS. Each collaborating 
EMS will organize a dedicated time slot for the study to be run and paramedics to be 
available at the defined period. In case of unavailability of a paramedic at the selected 
date, the collaborating EMS will handle to replace him. The investigators and 
collaborating EMS will be in close contact by phone/email to guarantee availability of the 
paramedics. 
2.3.9.2. Feasibility of recruitment 
The number of available paramedics will be guaranteed by the collaborating EMS knowing 
their absolute workforces and the paramedics working shifts. Given the calculated sample 
size, the number of paramedics is affordable. 
2.3.10. Assignment of intervention 
2.3.10.1. Allocation sequence 
A single randomization of the participants (paramedics) will be done using an online 
computing web randomisation service55 to generate the randomisation list. With this 
method, paramedics will be randomly assigned to either group A (using PedAMINES) or 
to group B (conventional preparation methods) with a single, constant 1:1 allocation 
ratio. One randomization list per EMS center will be produced (randomization stratified on 
center) and block of random size will be used to generate the randomization lists. 
2.3.10.2. Concealment mechanism 
Allocation concealment will be ensured with http://www.sealedenvelope.com and will not 
be released until the paramedics start the scenario.  

Submitted to ClinicalTrials gov on April 15th 2019
2.3.10.3. Implementation 
The allocation sequence will be generated by http://www.sealedenvelope.com and the 
randomization lists will remain with it for the whole duration of the study, ensuring that 
the investigators couldn’t influence the lists. The paramedics will be enrolled and 
assigned to the allocation groups by the investigators of the study on the day of the 
simulation. 
2.3.11. Blinding 
2.3.11.1. Blinding 
Blinding to the purpose of the study during recruitment will be maintained to minimize 
preparation bias. The paramedics will be unblinded after randomization. The study team 
members will be revealed just before the scenario starts, and video reviewing will be 
done without blinding by both video reviewers but independently and blindly from one 
another. 
2.3.11.2. Emergency unblinding 
At the time of the simulation, paramedics and investigators are not blinded. Since our 
study is held on a high-fidelity manikin, the patients or paramedics incur no risk. 
2.3.12. Data collection 
2.3.12.1. Data collection methods 
Research using simulation has a valid and reliable investigative methodology to study 
factors affecting human and systems performance in health care has been reviewed50. In 
this project, we will use simulation as an investigative methodology to assess the primary 
and secondary outcomes described above. 
All the actions (ie, primary and secondary outcomes) performed by the paramedics 
during the scenario will be automatically recorded and stored by the responsive simulator 
detectors (Leardal SimBaby) and by 3 GoPro Hero 5 Black edition (GoPro Inc) video 
cameras. The setup of the 3 cameras will be standardized to record at a resolution of 
1080p, at 90 frames per second, wide field of view, and with a 16:9 aspect ratio. 
Cameras position will be standardized. The first camera will be placed in a head strap on 
the paramedic’s head with an inclination of 45° downwards to film the front scene. The 
second camera will be placed on a tripod in front of the nurse and the manikin, slightly 
above the head height, with an inclination of 90° downwards to film the place where the 
drugs will be prepared. The third camera will be placed on a tripod 1 meter away from 
the paramedic on his or her left (if right-handed) or right (if left-handed) and at the level 
of the navel to film the scene on the side. All actions performed with PedAMINES will be 
automatically saved locally in log files for further analysis. The validity and reliability of 

Submitted to ClinicalTrials gov on April 15th 2019
the app has been assessed in a prior study47. Participants’ HR will be recorded during the 
entire resuscitation scenario with the HR monitor on a Polar A360 watch (Polar Electro 
Oy). The data will be stored on the wristwatch itself with further analysis being 
accomplished offline. On-site, the investigators will double-check that the questionnaires 
are fully and accurately filled.  
2.3.12.2. Retention 
Our study offers the advantage of being very short in duration, around 60 minutes per 
paramedic. Therefore, neither follow-up nor retention plans will be necessary. The 
intervention protocol is highly standardized, and paramedic deviation from protocol in 
terms of drug preparation is a parameter that is of interest in our study (ie, in terms of 
medication errors or delays in drug preparation). 
2.3.13. Data management 
Data collected during the interventions will be entered in EpiData database (EpiData, 
software v3.1, EpiData Association, Denmark) by the investigators of the study, in 
anonymised form. To avoid assessment bias, 2 evaluators will then independently review 
the video recordings. In case of disagreement, a third independent evaluator will help 
reach a consensus. In order to assess interrater reliability on video reviewing, a kappa 
score will be calculated.  
2.3.14. Statistical methods 
2.3.14.1. Statistical method for primary and secondary outcomes 
Primary outcome: proportion of medication errors 
The proportion of medication errors is the proportion of paramedics committing a 
medication error. For each type of medication (epinephrine, midazolam, dextrose 10%, 
sodium bicarbonate), the proportion of medication errors will be reported with 95% 
confidence intervals (CI, Clopper-Pearson’s method) when PedAMINES is used and when 
the conventional preparation method is used. The difference in proportion of medication 
errors between preparation methods will also be reported with 95% CI (exact method). 
The association between the preparation methods (PedAMINES versus conventional 
method) and the risk of error will be assessed by using a logistic regression model with 
mixed effects to account for the repetition of measures among paramedics. A random 
intercept will be introduced in the model. The model will be adjusted for the type of 
medication since the risk of error can vary across medications. 
Secondary outcomes: 
a) Proportion of other errors: 

Submitted to ClinicalTrials gov on April 15th 2019
The proportions for other types of errors (the choice of drug, air purge in the syringe, 
labeling of the filled syringe, aseptic errors) will be analyzed in a similar manner as for 
the primary outcome. 
b) Deviation from the correct weight-based dose: 
For each of the 4 drugs prepared, errors will be measured by the deviation from the 
amount of drug taken, the amount of saline solution taken to dilute the drug, the final 
concentration and the correct weight-based dose. Absolute deviation will be analyzed for 
each type of medication. The mean (or median) difference in deviation obtained with 
PedAMINES and with the conventional preparation method will be reported with 95% CI 
(or inter-quartile interval). A t-test or a Mann-Whitney’s test will be used for comparing 
preparation methods. 
c) Time to drug preparation (TDP) and delivery (TDD): 
For TDD and TDP, the mean times will be reported with 95% CI for each preparation 
methods and for each type of medication. The mean difference between preparation 
methods will also be reported with 95% CI. The association between the preparation 
methods and TDP and TDD will be assessed by using a linear regression model with 
mixed effects to account for the repetition of measures among paramedics. A random 
intercept will be introduced in the model. The model will be adjusted for the type of 
medication since TDP and TDD can vary across medications.  
2.3.14.2. Statistical methods for additional analysis 
For the primary and secondary outcomes, logistic regression analyses will be conducted 
to test a difference in rates of errors between urban EMS (defined as a primary EMS 
agency in a area populated with 50,000 or more people in the immediate proximity of a 
tertiary care PED)56 and rural EMS (i.e. EMS agency not included within an urban area) 
with PedAMINES and with the conventional preparation method. In a GEE logistic 
regression model, an interaction between interventions and urban/rural EMS will be 
tested to investigate a potential modification of the efficacy of PedAMINES in rural area 
compared with urban area. Results will also be correlated to the EMS exposition (i.e. total 
number of emergency calls per year per EMS divided by the number of paramedics 
working in that EMS). Analyses of primary and secondary outcomes will be conducted in 
paramedics with more or les than 10 years of experience. 
Means and standard deviations will be determined for stress and satisfaction scores 
(Likert scale) of individuals for each questionnaire item as well as for the UTAUT 
questionnaire and reported with descriptive statistics. Pearson correlations will be 
computed between the HR measures obtained with the watch and the scenario phases for 
each of the drugs and preparation methods used. 

Submitted to ClinicalTrials gov on April 15th 2019
2.3.14.3. Analysis population and missing data 
Data will be analyzed according to the intention-to-treat principle. Due to the nature of 
the interventions, we expect to have no missing data. In case of missing data, a 
complete case analysis will be conducted and no multiple imputations is planned. 
2.3.15. Interim analysis 
We will not perform interim analyses since our trial has a short duration and no potential 
serious outcomes. 
2.3.16. Access to data 
Data will be anonymised and safely stored in triplicate on secured hard disk drives and 
will be kept in locked cabinets, centralized at the Geneva Children’s hospital. Project 
principal investigators - responsible applicant and co-applicants described above - will 
have direct full access to the data sets. The project collaborating EMS members will be 
blinded of any identifying participant information. Only anonymised and summarized data 
will be submitted as part of the statistical analysis. This method was applied in our prior 
SNSF study and was 100% reliable and responsiveness. 
 
2.3.17. Dissemination policy 
2.3.17.1. Dissemination of study results 
The study results will be released to the participating EMS and the general medical 
community via peer-reviewed journal publications and national / international 
congresses. The results will be disseminated regardless of the magnitude or direction of 
effect. An individual collaborating EMS will be authorized to report the data collected from 
its center alone, provided that he quotes the methods, general results and authorship of 
the main project.  
2.3.17.2. Reproducibility 
After publication, we will deliver the full study protocol, deidentified patients data set and 
statistical code to an appropriate data archive for sharing purposes. 
 
 
 
 
 
 
 
 
 
 
 

Submitted to ClinicalTrials gov on April 15th 2019
2.4. Study schedule and milestones 
 
 
 
2.4.2. Date of completion of preparation phase 
01.01.2019 
2.5. Importance and impact 
EMS will greatly benefit from our project by reducing the overall medication errors and 
time to resuscitation. By extrapolation and according to Hansen et al.40, although survival 
rate has complex and numerous components, every single minute saved in the 
preparation of emergency medications thanks to the use of PedAMINES in the prehospital 
setting will lead to an increase in odds of survival of 9%. Moreover its ease-of-use, small 
factor size and mobility, customizable list of drugs and its cost-benefits advantages 
render PedAMINES an absolute essential must have medical application in any EMS. 
Being able to assess PedAMINES in Swiss EMS is the next step to demonstrate its 
usefulness in the high-risk and poorly investigated prehospital setting before to deploy 
the application all over Switzerland in real situations. To date, PedAMINES is the only 
scientifically validated app to assist medical prescriptions in life-threatening conditions. 
Our project will also be beneficial to clinical research by offering a common base for 
further studies on prehospital drugs prescription and medication errors. Because 
PedAMINES drugs list is customizable, unifying the emergency drugs prescription at the 
national level will standardize the therapeutic doses used and facilitate further clinical 
trials on actual or future drugs. Our results will be published in peer-reviewed journals 
and presented at national and international scientific conferences.  
 
2.6. Commercial interest 
The Geneva University Hospitals and some applicants (S.M., J.N.S., F.E., C.L. and A.G.) 
are the owners of the app PedAMINES that is available on the Google Play Store and the 
App Store. These applicants, as well as the Geneva University Hospitals, therefore 
declare a limited direct financial interest to market this app (for R&D only; less than 9.-).  
Preparation phase 
Study year 1 
Study year 2 
 
Milestones:  
 
Study preparation 
Duration: 2 months 
 
- Workshops with EMS heads to prepare study 
venue in their centers 
- On-site collaborating EMS visits to prepare the 
study venue (material and drugs availability, 
paramedics availability…) 
- Invitation to paramedics to participate to the 
study 
-  Wireless manikin SimBaby™ and accessories 
purchased and available 
- Data management system ready 
- Web-based centralized randomization ready 
(www.sealedenvelope.com) 
- Transports for amenities and investigators booked 
- Hotels for investigators booked 
 
Milestones:  
 
Study realization 
Duration: 12 months 
 
Including: 
- All participants enrollment and participation: 1 
week per EMS center  
- Data management: 2 weeks per collaborating EMS 
- 20% extra time for unexpected incidents 
(technical incident, paramedics unavailability…)  
 
 
 
Milestones:  
 
Data analysis 
Duration: 4 months 
 
- Videos reviewing and analysis 
- Data management  
 
Statistics 
Duration: 1 month, full time 
 
Study closure  
Workshop with study partners 
 
Redaction of the study 
Duration: 5 months 
- Final analysis of endpoints 
- Manuscripts writing 
 
Dissemination 
Congress and networking 
Number of participants 
included after 12 months: 
 
 
120 (full enrollment 
completed) 
 
 

Submitted to ClinicalTrials gov on April 15th 2019
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