Clinical trial NCT04392362
Conditions: Supra-ventricular Tachycardia
Sponsor: University of Pretoria
Start date: 2018-04-01; Completion date: 2020-12-16
Enrollment: 30 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Study to compare non inferiority of giving adenosine with the simplified method vs the AHA method

Detailed description:
tle: A randomised controlled trial of the standard versus a simplified adenosine administration method in the treatment of adult patients with supra- ventricular tachycardia (SVT

Arms: arm 1: Method of giving adenosine at 6mg then 12mg repeated twice to abort svt Intervention is giving the drug in a simplified method mixing it with 20 ml saline as a whole flush arm 2: Giving adenosine Ising the recommended AHA two syringe method
Interventions: intervention 1: Adenosine
Intervention descriptions: intervention 1: A vial of adenosine with 6mg

Protocol documents:
Prot_SAP_000.pdf: 
Page 1 of 19 
 
 
                    
University of Pretoria 
Faculty of Health Sciences 
School of Medicine 
 
  
Title: A randomised controlled trial of the standard 
versus a simplified adenosine administration method 
in the treatment of adult patients with supra-
ventricular tachycardia (SVT)   
 
 
 
Degree: MMed Emergency medicine 
 
 
 
 
Author:  Amanda Makhubela 
Student number: 99106699 
Contact details: 
Address:  41 Frangipani Chantelle 0182 
Tel:   
 
 
012 354 1000 
Cell:  
 
 
0722746091 
E-mail: 
 
0795274287@vodamail.co.za 
 
Supervisor: 
 
Prof. A. Engelbrecht 
 
E-mail address:  dries.engelbrecht@up.ac.za  
 
 
 
 
14 February 2018 


Page 2 of 19 
 
1. EXECUTIVE SUMMARY 
 
Adenosine is a naturally occurring endogenous nucleoside which is frequently used 
as a first line therapy for patients experiencing an episode of supraventricular 
tachycardia (SVT). It works by suppressing the sinoatrial and atrioventricular nodal 
conduction time and thereby terminating re-entrant tachycardias. Adenosine 
undergoes rapid biotransformation and has a half-life of less than 10 seconds. 
Elimination occurs through cellular uptake in red blood cells and the vascular 
endothelium. Because of these characteristics adenosine has to be administered 
through rapid intravenous administration and must be followed by a bolus of saline. 
The current method of adenosine administration as suggested by the American 
Heart Association (AHA) and taught on advanced life support courses in South-
Africa and elsewhere is cumbersome and frequently leads to maladministration by 
healthcare workers. The aim of this project is to test if a simplified method of rapid 
intravenous adenosine administration is not as effective as the AHA recommended 
method. Patients who present with an episode of re-entry SVT will be randomized 
into an intervention and control group. The intervention group will receive adenosine 
by a simplified method in which Adenosine will be combined with a saline flush. The 
control group will receive Adenosine via the standard recommended method by the 
AHA. The primary outcomes of this study will be the conversion rate to sinus rhythm 
in the intervention vs. control group. Side effect and complication rates in both 
groups will also be compared. The outcome of this study may lead to wider 
acceptance of a simplified and more elegant more convenient method of Adenosine 
administration and improved health care provider and patient satisfaction. It may 
further lead to a change in the current teaching on Adenosine administration in 
advanced life support courses.    
 
 
 
 
 


Page 3 of 19 
 
2. INTRODUCTION 
 
Supraventricular tachycardia (previously referred to as paroxysmal supraventricular 
tachycardia) due to various reentry mechanisms is a relatively common presentation 
to emergency departments. The incidence is around 35 per 100 000 per year, with a 
prevalence of 2.25 cases per 1000 in the general population of the United States of 
America.1 
 
Intravenous adenosine is the drug of choice given rapidly intravenously when the 
SVT does not respond to vagal maneuvers. The initial recommended dose for adult 
patients is 6mg over 1-3 seconds through a large vein, followed by a 20ml saline 
flush.  Up to two follow up doses of 12mg each can be given if the arrhythmia fails to 
convert.2  
 
The popular ring bound 2010 Handbook of Emergency Cardiovascular Care for 
Healthcare Providers of the American Heart Association® describe the technique of 
rapid intravenous administration of adenosine as follows: 
 
Injection Technique.3 
 
• Record rhythm strip during administration. 
• Draw up adenosine dose (6 or 12mg) and flush (20ml Normal Saline) in 2 
separate syringes. 
• Attach both syringes to the IV injection port closest to patient. 
• Clamp IV tubing above injection port. 
• Push IV adenosine as quickly as possible (1-3 seconds) 
• While maintaining pressure on the adenosine plunger, push NS flush as 
rapidly as possible after adenosine 
• Unclamp IV tubing.  
 
This technique requires training and co-ordination to be successful and problems 
arise when the adenosine, upon rapid injection enters the larger syringe with the 
saline flush instead of the vein of the patient; when the saline flush inadvertently 
enters the adenosine syringe; disconnection of the syringes resulting in fluids 
squirting outside the line and possibly into the eyes of healthcare providers or the 
patient. Such is the complexity that  the Advanced Cardiac Life Support Instructors in 
South-Africa often recommend that a second person should assist to stabilize the 
syringe connections and also turning the three way stop connector.  
 
The research question arises then that in adult patients with re-entry SVT is a 
simpler method of intravenous adenosine administration (intervention) not inferior to 
the AHA method (control) to achieve conversion to sinus rhythm (outcome)? 
 
This study will compare a much simpler technique of rapid intravenous 
administration of adenosine with the above mentioned technique. The simplified 
technique entails combining the adenosine with the saline flush in a 20ml syringe 
given as a rapid bolus. Conversion rates to sinus rhythm and complication rates for 
the two techniques will be compared.  


Page 4 of 19 
 
Adenosine has had significant electrophysiological effects on cardiac conduction 
since 1929.4     In one animal study, adenosine produced atrioventricular block and 
sinus bradycardia in several mammalian species including dogs.4 A calcium channel 
blocker, verapamil was the drug of choice for the treatment of SVT. However, 
adenosine has been shown to be as effective as verapamil, with fewer serious side 
effects, particularly hypotension.5 The conversion rate in this trial was 93.4% for the 
Adenosine group and 90.6% for the verapamil group where patients were treated 
with up to two doses of their assigned drug. This difference was not statistically 
significant. Adenosine also had more rapid onset of action than verapamil and was 
eliminated much faster from the system. Verapamil has an elimination half-life of 4 to 
8 hours.22  
 
Adenosine was found to be safe in arrhythmias such as Wolff-Parkinson-White syndrome in 
which verapamil caused significant complications like ventricular fibrillation and cardiac 
arrest.6 The American Heart Association has recommended adenosine as the first-line 
treatment for SVT in adult patient since the early 1990’s.7 It has also been shown to be safe 
in unstable patients with SVT, where instability was defined as patients with a blood 
pressure of less than 90 mm Hg, pulmonary edema, chest pain or an altered mental 
status.8  
 
A Medline search using search terms including adenosine, supraventricular tachycardia, 
intravenous administration and dilution was performed, and articles relevant to this 
research project included a landmark study by DiMarco in which adenosine was compared 
with verapamil and with a placebo, adenosine doses were followed by a saline flush.5 
Neither the volume nor the method of administration of the flush are mentioned. In an 
earlier study by DiMarco a 10ml saline flush was used9 and the results were ground 
breaking for the effectiveness of adenosine for SVT. Increasing doses of adenosine were 
assessed in 46 patients with SVT. Patients underwent electrophysiological studies to 
determine the mechanisms of arrhythmia. Sixteen patients had AV reciprocating with 
accessory pathways and all 16 converted on adenosine. Thirteen out of 13 patients with AV 
nodal reentry tachycardia also converted. Adenosine was not effective in patients with atrial 
fibrillation (AF), atrial flutter and intra-atrial reentrant tachycardia.  
 
Varying volumes of saline were used in studies that investigated conversion rates for pre-
hospital SVT using adenosine at 6, 12 and 18 mg as a rapid IV bolus given over 1 to 2 
seconds followed by a 30ml saline flush.10   Overall conversion rates improved from 32.4% 
to 59.1% after the introduction of adenosine. 
 
The relatively low conversion rate in some studies was ascribed to the poor accuracy of 
ECG interpretation by paramedics despite additional educational measures. Adenosine 
was administered inappropriately in cases of atrial fibrillation, atrial flutter and ventricular 
arrhythmia. In spite of transient side effects such as shortness of breath, flushing and 
dizziness, no serious complications were noted in any patients irrespective of the 
arrhythmia treated. 
 
 
 
 
 
 


Page 5 of 19 
 
The comparison of adenosine and verapamil in the pre-hospital setting over two periods 
was also studied11. Six milligram of adenosine, followed by 12mg after 1 to 2 minutes if the 
initial dose was unsuccessful in rhythm conversion was used followed by a 10ml saline 
flush. Findings were a 78% conversion rate (25 of 32 patients) compared to an 82% 
conversion rate for verapamil (9 out of 11 patients). In this study paramedics were under 
supervision of base hospital physicians who may have been reluctant to order verapamil 
because of its side effects and safety profile. This may have led to a low number of patients 
in the verapamil period of the trial. This study also showed that paramedics and base 
hospital physicians misdiagnosed the presenting arrhythmia in 30 of 73 cases (41%) 
compared with cardiologists. This study was further limited by the small sample size. 
 
 
Another study compared the rate of recurrence of SVT in a group given oral Verapamil post 
successful conversion with intravenous adenosine to a group not given verapamil after 
adenosine converted SVT in the ED.1 Verapamil is a calcium channel blocker that inhibits 
the influx of calcium proportionately to the plasma concentration. It has a half-life of 3 to 6 
hours with insignificant amount of metabolites as well as elimination via extra-renal routes. 
It is used to control arrhythmias by decreasing SA nodal firing and slowing down AV nodal 
conducts. 
In this study the recurrence of SVT was statistically significantly lower (p= 0.042) in the 
adenosine/verapamil group vs the adenosine only group between 30 and 120 minutes after 
treatment. Although in the rest of the follow up period there was no further recurrence was 
seen in the two groups.1 
 
Another pre-hospital study by showed the safety and efficacy of intravenous adenosine for 
pre-hospital treatment for SVTs.12 This study was a prospective case series carried out 
over a 10 month period. All patients with a pre-hospital field diagnosis of PSVT were 
included. Patients who were excluded were pregnant, younger than 14 years, older than 85 
years of if they had a recent history of ingestion of dipyridamole or carbamazepine. 
 
 Adenosine was administered in doses of 6 mg followed by a flush of 5ml normal saline or 
ringers lactate. Two doses of 12 mg adenosine again followed by a 5ml flush of normal 
saline or ringers lactate were given with first failure to convert. Of the 41 patients included 
in the study 31 were correctly diagnosed. Most of the misdiagnosed cases had atrial 
fibrillation. Of the 31 cases correctly diagnosed as PSVT 28 converted to sinus rhythm after 
adenosine (90.3%). 16 (57.1%) required a single dose, 9 required one additional dose 
(32.1%) and three required two additional doses (10.8%). This study was interesting since 
it indicates that adenosine can be very effective (90.3% conversion rate) even when a 
much smaller saline flush is used than the 20ml flush that is recommended by the AHA.3 
No adverse effects were found in the patients who had atrial fibrillation who received 
adenosine. In fact it was found that the temporary AV block assisted in the diagnosis of AF. 
This study was limited by its design which lacked a control group and by the small sample 
size.  
 
In the above mentioned studies, saline or ringers lactate flushes ranging from 5ml to 30ml 
were used after adenosine administration. We did not come across any studies were 
adenosine were administered without a saline or ringers lactate flush.   
 
 
 


Page 6 of 19 
 
The inclusion and exclusion criteria for the three pre-hospital studies mentioned above are 
compared in table 1 below. These inclusion and exclusion criteria are significant to our 
study since it was made on clinical grounds similar to what we plan for our study. In the 
studies of DiMarco, electrophysiological measures were used which will not be feasible in 
our study.  
 
 
Table 1: The inclusion and exclusion criteria table 
Study: 
Conversion rates fo
Pre-hospital PSVT 
with addition of ade
nosine10 
A comparison of ad
nosine and verapam
for treatment of SVT
in the prehospital  
setting11 
IV adenosine as first  
line management  
of SVT without  
Physician control12 
Inclusion criteria:  
Age 18 years or olde
presumed diagnosis 
of PSVT by EMT 
PSVT definition: 
Regular narrow com-
plex tachycardia be- 
tween 140 and 250 
beats / minute. 
 
Protocol for SVT: 
QRS duration less  
Than .12s and regu- 
lar rhythm.  
QRS rate between  
160 and 240.  
Did not respond to va- 
gal maneuvers. 
Regular narrow com- 
plex tachycardia. 
Rate equal to or grea- 
ter than 160/ minute 
Exclusion criteria: 
• Pregnancy 
• Taking carbamaz
pine or dipyridamole 
• Known allergy to 
•  adenosine.  
• Systolic BP < 90 
• Altered mental sta
• Chest pain 
• Diaphoresis 
• Possible MI 
• The above patien
• Received electrica
cardioversion if th
met the ECG criteria 
• Pregnancy 
• <14yrs; > 85yrs 
• Recent ingestion of  
Carbamazepine or d
pyridamole.  
• Unstable patients as
in the Madsen study  
• received electrical  
cardioversion.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Page 7 of 19 
 
Table 2: Co morbid conditions included in the studies 
Study 
 
 
Postural 
 modification to the standard 
Valsalva manoeuvre for 
emergency  
treatment of supraventricular 
tachycardias (REVERT): a 
randomized controlled trial23 
 
Oral verapamil in paroxysmal
supraventricular tachycardia 
Recurrence control: a  
randomized clinical trial24 
 
Co morbid conditions • Prev SVT Dx 
• Prev SVT not Dx 
• Prev ablation Rx 
• COPD 
• Pneumonia 
• IHD 
• Diabetes 
• Hypertension 
• Valvular heart 
    lesion 
 
• Hypertension 
• IHD 
• Diabetes Mellitus 
• Obstructive lung  
disease 
 
 
A number of studies and case presentations that related to the importance of the type of 
intravenous access needed for effective adenosine administration were found. Although an 
animal study on piglets showed that adenosine was effective when given through an 
intraosseous line13, human case studies did not support this finding.  Goodman and Lu14 
described two cases of infants that presented with SVT’s refractory to vagal maneuvers. 
Intravenous placement was difficult in both cases and intraosseous access was achieved. 
Administration of adenosine in increasing doses did not convert the arrhythmias. In both 
cases the patient was referred for expert assistance. In the first case an IV line was 
obtained and the patient converted after one intravenous dose of adenosine followed by a 
saline flush. In the other case a central line was placed in the right femoral vein and again 
the patient’s arrhythmia converted to sinus rhythm after a single dose of adenosine and 
flush. This suggested that the intraosseous route was not effective for adenosine 
administration.  
 
In a case study described by Connor, the importance of the diameter of the intravenous 
cannula was highlited.15 A 15-year old male patient presented with a SVT of 180 beats per 
minute. The patient reported having had similar previous episodes. The parents forewarned 
the emergency department doctor that high doses of adenosine were usually required for 
cardioversion and that the most recent episode required 18 mg. A large 18 G green 
cannula was inserted and 6 mg of adenosine was given followed by a 20 ml flush of normal 
saline. The patient experienced chest pain and breathlessness, which abated when sinus 
rhythm was restored within 10 seconds. The patient had never before experienced similar 
symptoms during adenosine administration. However, it became clear that yellow 24 G 
intravenous cannulae had been used on the previous occasions. This case suggested that 
smaller gauged cannulae do not facilitate sufficient flow rates and therefore necessitate 
repeated and higher dosages of adenosine.   
 


Page 8 of 19 
 
Another study in McIntosh-Yellin16 looked at peripheral vs. central administration of 
adenosine in 30 subjects.  These patients underwent electrophysiological studies 
and received adenosine via the central and peripheral lines. Peripheral injections 
were given via an IV line in the upper extremity and central infusions were given 
through a catheter positioned in the right atrium. The site of administration was 
randomized and each subject received adenosine via both routes. Adenosine was 
administered in increasing increments of 3, 6, 9 and 12 mg until the tachycardia 
terminated. Responses to peripheral administration were compared with those 
centrally administered.  
 
Tachycardia was terminated in 11 patients with 3 mg (37%), in 10 (33%) with 6 mg, 
in 4 (13%) with 9 mg and in 5 (17%) with 12 mg. In contrast, after central 
administration, 23 episodes of tachycardia (77%) were terminated with 3 mg, 6 
(20%) with 6 mg and 1 (3%) with 9 mg; none required 12 mg. Lower doses of 
adenosine were needed with central administration. Sixty-three percent of the 
subjects required a lower dose. This study concluded that the initial dose for central 
administration of adenosine should be 3 mg. A case study that documented a severe 
prolonged (13s) episode of bradycardia in a patient that received 12 mg of 
adenosine via a central line was also found in the literature.17 The patient also 
experienced severe agitation and chest pain. The AHA recommended that patients 
should receive an initial dose of 3 mg of adenosine when it is administered through a 
central line.2 
 
We identified two studies that determined the stability of adenosine inside various 
diluents inside syringes and bags. Ketkar18 compared the stability of adenosine in 
saline, ringers lactate and dextrose in polypropylene syringes and polyvinyl (PVC) 
bags at three temperatures. It was shown with high performance liquid 
chromatographic analysis that adenosine 3 mg / ml was stable in polypropelene 
syringes and PVC bags for 7days at 25 ºC, 14 days at 5 ºC, and 28 days at -15 ºC. 
Lower concentrations were stable for longer. Fungal growth was only found after 
many days (10 and 16) in dextrose solutions. 
 No fungal growth or change in liquid appearance was detected where adenosine 
was diluted in saline or ringers lactate.  Adenosine was also found to be stable and 
compatible with saline by Kaltenbach.19  
 
In the clinical experience of the researcher and colleagues in the field of emergency 
medicine, drawing up adenosine with the flush is as effective as using the AHA 
method of two syringes. By doing a web-search it was discovered that Bryan Hayes, 
Pharm D20, advocated this simplified technique on Academic Life in Emergency 
Medicine (ALiEM) a well-known emergency medicine website. On this blog he 
motivates the simplified technique citing the following reasons why it is effective: “the 
major advantage to this approach is that it obviates the need for any syringe 
switching or stopcock swiveling. There’s no need for additional flushes since your 
diluted adenosine syringe doubles as the flush. If you don’t have 20 ml syringes, you 
can still add the adenosine to one of the two 10 ml saline flushes and get the same 
effect. Flush volumes as low as 5 ml have been effective.” 


Page 9 of 19 
 
Only one study could be found in the literature that compared a simplified technique 
of adenosine administration with a “standard” technique. It is not clear if the standard 
technique refer to the technique described in the 2010 Handbook of Emergency 
Cardiovascular Care for Healthcare Providers of the American Heart Association®.  
 
This study, which was published in Korean, is not well known since it is rather 
difficult to translate into English and therefore difficult to critically appraise .21 From 
the English abstract of the article the following information was obtained. The 
purpose of the study was to observe the success rate, the average dose and the 
complications associated with a “convenient” method of adenosine administration for 
paroxysmal supraventricular tachycardia. A non-blinded, randomized, prospective 
study was conducted from January 1999 to June 2001. Sixty-five Cases were 
enrolled during this period. Thirty-five cases received adenosine by the standard 
method. The standard method is not described in the abstract and is not clear from a 
Google translation of the main text. Thirty cases received adenosine by a 
“convenient” method. 
 
 This method is described as a mixture of 6 mg adenosine in 15 ml of normal saline. 
The results from this study indicated that a success rate of 80% was achieved in the 
standard method group and 85.7% was achieved in the group that received 
adenosine via the “convenient” method. The difference was not statistically 
significant (p = 0.39). No significant complications were found in the patients who 
received adenosine via the “convenient” method.  
 
Dipyridamole, carbamazepine, B-blockers, digoxin, verapamil and diltiazem may 
potentiate the action of adenosine while theophylline and caffeine antagonize the 
antiarrhythmic effects of adenosine.2,22 Adenosine should not be used for irregularly 
irregular tachyarrhythmias, especially when the QRS complex is widened. This is 
because of the possibility of initiating atrial fibrillation with a very rapid ventricular 
rate in a patient with pre-excitation such as WPW.2  
 
According the South African Medicines Formulary (SAMF), adenosine should only be 
given if cardiac monitoring and resuscitation is available.22  
We hope that our study will clarify whether a simple technique of adenosine 
administration by mixing it with the flush solution is not inferior to the method 
described in the 2010 Handbook of Emergency Cardiovascular Care for Healthcare 
Providers of the American Heart Association®. 
 
 
 
 
 
 


Page 10 of 19 
 
3.  AIM AND OBJECTIVES: 
 
Aim: To investigate if a simplified method of IV adenosine administration is not 
inferior to the standard AHA method of IV adenosine administration.  
 
Objectives:  
1) To determine the proportion of patients who converted to sinus rhythms in the 
simplified vs. the standard method of adenosine administration.  
 
2) To determine the number of complications in the simplified vs. the standard 
method of adenosine administration. 
  
3) To determine the types of side effects in the simplified vs. the standard group of 
adenosine administration.  
 
4) To determine the time to conversion to a sinus rhythms in the simplified vs. the 
standard method of adenosine administration.  
 
 
Hypothesis: Our hypothesis is that the simplified method of IV adenosine 
administration is not inferior to the standard AHA method of IV adenosine 
administration. 
 
H0 (Null Hypothesis): A simplified method of IV adenosine administration is inferior to 
the standard AHA method of IV adenosine administration.  
 
H1 (Research Hypothesis): A simplified method of IV adenosine administration is not 
inferior to the standard AHA method of IV adenosine administration.  
 
 
4. METHODS 
 
In our study a simplified method of adenosine administration will be compared to the 
standard AHA recommendation. This will be a non-inferiority study.  
 
4.1.  STUDY DESIGN 
 
Prospective, non-blinded, non-inferiority, randomized controlled trial.  
 
4.2.  SETTING 
 
Two Tertiary academic hospitals (Steve Biko Academic Hospital and Kalafong 
Academic Hospital) will be used for the study, as well as two Life private hospitals 
(Eugene Marais and Wilgers Hospital). Patients presenting to the emergency 
departments (ED’s) and admitted to the cardiology / internal medicine wards will be 
included. 
 


Page 11 of 19 
 
4.3. PATIENT SELECTION 
 
Sampling strategy: Due to the relatively scarce nature of SVT in adult patients with 
an estimated incidence of 1 case per week per institution all new cases of SVT that 
meets the inclusion criteria will be included in the study. Patients may be included in 
the trial more than once if they have a repeat episode of re-entry SVT more than four 
hours after return to sinus rhythm.  
 
Inclusion criteria:  
 
• All EKGs must have been sent via whatsapp messenger to Prof Engelbrecht 
to validate SVT before inclusion 
• Age: 18 years to 85 years. 
• Presumed diagnosis of re-entry SVT. 
• Re-entry SVT not responsive to two valsalva attempts lasting 15 to 30 
seconds.  
 
Definition of suspected re-entry SVT:  
The spontaneous onset of a regular narrow complex (QRS duration less than 0.12s) 
tachycardia greater than 150 and up to 240 beats per minute. 
 
Exclusion criteria: 
 
• Patients who are clinically too unstable to give consent: 
o Impaired consciousness 
o Significant chest pain, shortness of breath or pulmonary oedema 
o Systolic blood-pressure below 90mmHg 
 
• ECG features:  
o QRS width more than 0.12 seconds (3 blocks on ECG paper) 
o R-R interval irregular  
• Known allergy to adenosine 
• Recent ingestion of dipyridamole, carbamazepine or theophylline. 
• Ingestion of caffeine in the previous 2 hours. 
• Acute asthma attack 
• Heart transplant 
• Patients who were already included in the trial who suffer a second episode of 
re-entry tachycardia less than 4 hours after the first episode.  
 
Randomization procedure: 
To increase the power of the study for the anticipated low numbers of patients, a 2:1 
randomization procedure of the simplified vs. the standard procedure will be 
followed.  
10 envelopes will be randomized at a time into research and control groups for the 
four participating sites to be used by the principal investigator. These envelopes will 
be containing instructions on either of the two administration methods.  
 
 


Page 12 of 19 
 
For each of the four sites, one third of the prepared envelopes will contain 
instructions on the standard AHA method of IV adenosine administration and the 
remaining two thirds will contain instructions on the simplified method of IV 
adenosine administration.  
 
 
These envelopes will be sealed and will have no external indication of which method 
is described inside. The sealed envelopes will then be thoroughly shuffled and 
thereafter numbered from 1 to 10 at a time. Each new patient enrolled will receive 
the next number. Numbers may not be skipped.   
 
 
Treatment will be administered by medical officers and registrars from the 
emergency department of Steve Biko and Kalafong Hospitals; by registrars from the 
department internal medicine at Steve Biko and Kalafong Hospitals; or by the ED 
doctor on duty at the two Life private hospitals ( Eugene Marais and Wilgers 
Hospitals). Only doctors who received training on the protocol by the principal 
investigator will be allowed to enrol patients and administer the treatment. Training 
sessions will be organized by the principal investigator at Steve Biko and Kalafong 
hospital prior to the enrolment of the first patient.  
 
 
The treating medical practitioner of patients who agree to participate in this trial will 
receive a randomized envelope. He will administer adenosine according to the 
instruction given inside the envelope and document demographic data as well as the 
conversion rate to sinus or other rhythms as well as any side effects or complications 
on a case report form (CRF), which will also be in the envelope. The CRF and 
informed consent will then be collected by the investigator.  
 
4.4. 
MEASUREMENTS 
 
For each patient the ECG rhythm of standard lead II will be monitored continuously 
with a monitor-defibrillator throughout the management of the patient. An ECG 
rhythm strip will be printed for at least 15 seconds before and 1 minute after each 
adenosine administration.2 
 
Outcome measurements: 
 
A successful outcome will be defined as an ECG rhythm conversion from re-entry 
SVT to sinus rhythm for at least 10 minutes.  Sinus rhythm will be defined as regular 
ECG rhythm in standard lead II of between 60 and 100 beats per minute where each 
p-wave is followed up by a QRS complex.  
 
 
A failed outcome will be defined as a persistent re-entry SVT or conversion to an 
alternative arrhythmia that requires rescue therapy after up to three doses of 
Adenosine.  
 


Page 13 of 19 
 
Outcomes will be adjudicated by the treating clinicians who will receive training on 
the protocol of the trail including ECG analysis. Post hoc analysis will be done by the 
investigators.  
 
Conversion rate to sinus rhythm will be determined for each technique. The number 
of doses needed per case will be recorded.  
 
Additional measurements: 
 
The initial heart rate and the systolic blood pressure will be recorded. These 
measurements will be repeated 1 to 2 minutes after each dose of adenosine is 
administered.  
 
 
The heart rate and systolic blood pressure will be measured with electronic blood 
pressure devices. These measurements will be taken irrespective of whether rhythm 
change took place or not.  
 
Side effects or complications will be documented.  
  
Safety and monitoring: 
Several trials have demonstrated that Adenosine is safe and effective in the 
treatment of reentry SVT.5,8-12  As a safety method, all EKGs will be sent via 
whatsapp messenger to Prof Engelbrecht to validate the SVT before inclusion into 
the study who is an expert in EKG interpretations. 
Adenosine should not be used for irregularly irregular tachyarrhythmias, especially 
when the QRS complex is widened. This is because of the possibility of initiating 
atrial fibrillation with a very rapid ventricular rate in a patient with pre-excitation such 
as WPW.2  
 
All clinicians who will enroll patients on this trial will be trained on ECG assessment 
and on how to exclude irregular and wide complex tachycardias.  
 
Measurement of the width of the QRS complex and an assessment of the regularity 
of the R-R intervals will be documented in the clinical notes. Patients with a widened 
QRS complex (ORS width more than 0.12 ms) or an irregular rhythm R-R interval will 
be excluded.  
 
Although life threatening arrhythmias are extremely rare after adenosine 
administration, the availability of a defibrillator is an essential component of this trial. 
The defibrillator will be checked prior to adenosine administration. The defibrillator 
check will be documented in the CRF. 
 
 
 
 
 
 


Page 14 of 19 
 
Failed conversion: 
 
Patients who do not convert to sinus rhythm after three doses of Adenosine or 
convert to a rhythm other than sinus rhythm will be treated with rescue therapy 
according to standard medical guidelines. These treatments may include electrical 
cardioversion, alternative drug therapy, hospital admission or referral to a specialist 
cardiologist.  
 
4.5.  DATA management and ANALYSIS 
 
4.5.1. Statistical considerations 
 
This non-inferiority study assesses standard versus simplified adenosine 
administration in the treatment of adult supraventricular tachycardia patients. 
 
Data will be captured on a paper based data capturing sheet called a case record 
form (CRF). From this form the data will be transferred on to an excel spread sheet 
from which statistical analysis will be performed. Result will be illustrated with tables 
and grafts.  
 
 
 
4.5.2. Sample size 
 
The following assumptions was made in calculating the sample size: a response rate 
of 0.9 for both methods, a noninferiority delta = -0.12 (-12 %) and a 95% one sided 
interval. Randomisation will be 2:1 for the simplified administration method vs. the 
standard method. A sample of 94 and 47 patients (a total of N=151) for the two arms 
of the study respecitvely will be feasible due to the low frequency of the condition. 
This sample size wil result in a power of 80.3% in this study. If the recruitment rate is 
higher than expected, extention of the study to enroll more patients, will be 
considered to further improve the power. 
 
4.5.3. Data analysis 
 
A 90 % two sided confidence interval will be determined for the difference between 
simplified and standard response rates. Should the lower limit of this 95% one sided 
confidence interval (90 % two sided) exceed -0.12 the simplified method will be 
regarded as non-inferior to the standard method. However, should it also be in 
excess of 0, the simplified method will be superior to the standard method. 
 
 
 
 
 
 
 


Page 15 of 19 
 
5.  ETHICAL CONSIDERATIONS 
 
Informed consent will be obtained from all patients who participate in this trial.  
Consent will be obtained from the relevant heads of departments and CEO’s of the 
hospitals to allow enrollment of patients at each of the facilities.  
An application will be made to the Ethics Committee of the University of Pretoria for 
approval of the protocol.  
This trial will be registered as a clinical trial at clinical trials.gov.  
The Medicines control council (MCC) will be notified of this trial.  
 
The CRF’s and any additional paper based or electronic data from this trial will be 
stored at Steve Biko Academic hospital in room 72441 for 10 years. All paper based 
and electronic data will be kept strictly anonymous. No non-clinical personal detail, 
names or hospital numbers will be recorded in the CRF or in any other electronic or 
paper based document.    
 
 
 
 
6.  BUDGET 
 
1. All costs for medications and consumables are part of standard medical care 
that patients would have received irrespective of the trial.  
 
2. A honorarium of R150 will be paid to each clinician who enrolls a patient on 
this trail. A budget of R7500 for this purpose will be obtained from the 
Emergency Medicine Research Fund. This will provide payment for 50 
enrollments. The deficit will be enrolled by the investigators and without 
payment.  
3. All additional costs will be covered by the researcher (± R500 for stationary). 
 
4. Total cost: ± R 8000. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 


Page 16 of 19 
 
7.  TIME LINES AND PROJECT MANAGEMENT 
 
 
Figure 1- The gannt chart 
 
 
 
 
 
 
Dates: 
  
Date: 
Preparing Protocol 
3 Dec ‘17 
Mmed Committee 
Application 
15  Mar ‘18 
Ethics Committee 
Application 
            15  Apr ‘18 
Collecting Data 
15 May '18 
Data Analysis 
1 Jan '19 
Writing up – thesis 
1 Feb '19 
 
0
1
2
3
4
5
6
7
8
9
10
11
Preparing Protocol
Mmed Committee Aplication
Ethics Committee Aplication
Collecting Data
Data Analysis
Writing up - thesis
Timelines
months


Page 17 of 19 
 
8.  CONTRIBUTORS AND AUTHORSHIP ( leader and follower) 
 
 
Name  
Department  
Contribution 
Author or 
acknowledgement 
Dr. Amanda 
Makhubela 
 
Emergency 
Medicine 
Researcher / Main 
Author 
Author 
Prof. Andreas 
Engelbrecht 
Department of 
Family Medicine / 
Division of 
Emergency 
Medicine 
Researcher / Main 
Author 
Co Author 
 
 


Page 18 of 19 
 
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3. American Heart Association. 2010 Handbook of Emergency Cardiovascular 
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Adenosine for paroxysmal supraventricular tachycardia: Dose ranging and 
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7. American Heart Association. Emergency Cardiac Care Committee and 
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