The Impact of 4% Sodium Bicarbonate Additive During Potassium Chloride Replacement on Pain and Incidence of Phlebitis for Adult Patients in a Medical Surgical Unit: A Randomized Double Blinded Controlled Study
Phase: PHASE4
Conditions: Hypokalemia
Sponsor: Baptist Health South Florida

   
Cover Page for Protocol 
 
Official Title: 
The Impact of 4% Sodium Bicarbonate Additive During 
Potassium Chloride Replacement on Pain and Incidence of 
Phlebitis for Adult Patients in a Medical Surgical Unit: A 
Randomized Double Blinded Controlled Study 
NCT Number: 
NCT02082717 
Document Date: 
04 July 2018 
 
 
 
 
 
 

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Title: The impact of 4% sodium bicarbonate additive during intravenous Potassium Chloride replacement 
on pain and incidence of Phlebitis for adult patients in a Medical/Surgical unit: A randomized controlled 
double blinded study. 
Problem Statement and Specific Aims: 
According to the National Council on Potassium in Clinical Practice, potassium depletion is one of the 
most common electrolyte abnormalities found in the clinical setting (Cohn, Kowey, Whelton, & Prisant, 
2000).  Hypokalemia has been found to affect between 20-37% of hospitalized patients depending on 
disease process (Crop, Hoorn, Lindemans, & Zietse, 2007; Hemstreet, Stolpman, Badesch, May & 
McCollum, 2008; Widodo, Setiawan, Chen, Nainggolan, & Santoso, 2006).  In addition, epidemiologic 
research has found that hypokalemia not only can result from an underlying disease but is frequently 
acquired in the hospital due to its high association with gastrointestinal losses and use of diuretics (Crop 
et al., 2007).  Therefore, replacement of potassium becomes a common practice carried out by 
Medical/Surgical nurses caring for patients in acute hospitals.  Although oral potassium replacement is an 
option, patients often require rapid replacement or are unable to be replaced orally.  Once intravenous 
(IV) potassium is initiated, Medical/Surgical nurses are faced with patients experiencing 
chemical/infusion phlebitis and pain at the catheter insertion site regardless of using slow infusion rates 
due to the acidic pH of the solution.  This results in Medical/Surgical nurses seeking evidence-based 
options to reduce these further complications.  Currently, the use of lidocaine with IV potassium chloride 
has been found to reduce pain during infusion (Lim, Khoo, & Tweed, 1992; Morril & Katz, 1988; Pucino 
et al., 1988); however lidocaine has also been linked to chemical phlebitis (Bassan & Sheikh-Hamad, 
1983) and does not assist with preventing the complications from infusing acidic solutions.  Therefore, 
this study is interested in evaluating the use of sodium bicarbonate additive as a neutralizing agent to 
potassium chloride infusion. 
 
The purpose of this study is to examine the impact 4% sodium bicarbonate additive during 
intravenous potassium chloride replacement for adult patients in three Medical/Surgical units.  Using a 
randomized controlled blinded experimental study design, patients who are 21 years or older and alert, 
awake, and oriented at time of enrollment and have been ordered intravenous potassium chloride 
replacement will be recruited from three Medical/Surgical units during the first 24-48 hours of their 
admission. 
The specific aim of the study is: 
Aim 1: To compare patient outcomes (phlebitis, pain at peripheral IV insertion site, frequency of 
changing IV access, and time for administration) between the experimental (4% sodium bicarbonate 
additive during peripheral intravenous potassium chloride replacement therapy ) and control (standard of 
practice of no 4% sodium bicarbonate additive during peripheral intravenous potassium chloride 
replacement therapy) groups.  
Aim 2: To compare number and type of nursing interventions done during peripheral IV potassium 
replacement therapy between the experimental (4% sodium bicarbonate additive during intravenous 
potassium chloride replacement) and control (standard of practice of no 4% sodium bicarbonate additive 
during peripheral intravenous potassium chloride replacement therapy) groups.  
Aim 3: To compare attrition rates and reasons between the experimental (4% sodium bicarbonate additive 
during peripheral intravenous potassium chloride replacement therapy) and control (standard of practice 
of no 4% sodium bicarbonate additive during peripheral intravenous potassium chloride replacement 
therapy) groups.   
 
Significance: 
Hypokalemia, or the low concentration of potassium (below 3.5 mmol/l), is a condition that can result in 
serious adverse effects including disturbances in cardiac conduction along with muscle, kidney, 

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gastrointestinal tract, genitourinary tract, respiratory, and endocrine dysfunction (Asmar, Mohandas, & 
Wingo, 2012; Hemstreet, et al., 2008). Hypokalemia is typically a result of chronic medical conditions 
such as reduced intake of potassium, chronic diuretic therapy, diarrhea, short bowel syndrome, vomiting 
and burns. Although potassium can be replaced orally, IV potassium chloride is utilized in patients that 
need rapid replacement, are showing clinical signs of low potassium, or patients who are unable to orally 
ingest the replacement.  Potassium should always be diluted and slowly administered to reduce the 
likelihood of pain from inflammation of the vein or phlebitis. (Pharmacology for the Prehospital 
Professional, 2011). Yet, even at slow rates of 10 mEq/h phlebitis and pain have been reported in 60% of 
patients (Stephens et al., 1976).  
Peripheral venous cannulation (PVC) is a common procedure carried out in hospital to allow 
rapid and accurate administration of medication (Endacott et al., 2009). In replacing Potassium 
intravenously, nurses need to have intravenous access. In WKBH 3 South/3 North/4 South Medical-
Surgical Telemetry units, nurses often receive orders for Potassium replacement through Intravenous 
route. The majority of these patients have peripheral intravenous access. The intravenous access is often 
started in the Emergency Department and continued once the patient is admitted. The peripheral 
intravenous site is being assessed per protocol for phlebitis once per shift and as needed. 
Once the Physician orders the Potassium replacement intravenously, the Pharmacist prepares the 
medication. The nurse then, starts the infusion via the peripheral intravenous access. Nurses receive 
complaints of burning sensation or pain from patients as soon as the infusion is started. The nurse then 
would try to get an order for Neut (4 % sodium bicarbonate additive solution) to be added to the 
Potassium Chloride solution with the goal to minimize pain during infusion. Neut (4% sodium 
bicarbonate additive solution) is a neutralizing additive solution, a sterile non-pyrogenic solution of 
sodium bicarbonate in water for injection. It is administered by the intravenous route only after addition 
as a neutralizing agent to an acidic large volume parenteral solution. It is indicated for use as an additive 
to raise the pH of acid solutions administered intravenously to reduce the incidence of chemical phlebitis 
and patient discomfort due to vein irritation at or near the site of infusion. (APP Pharmaceuticals, 2008). 
Previous studies have concluded that one of the causes of infusion phlebitis was the pH of the solution 
(Lewis and Hecker, 1985; Kuwahara, et al 1998).  A study conducted by Fujita et al 2000, confirmed that 
with the use of 7% Sodium Bicarbonate, moderate phlebitis was only experienced by 6% of the patients. 
Although cardiovascular abnormalities are rare when KCl is administered at an infusion rate of 
10mEq/hour, phlebitis and pain reportedly occur in 60% of patients (Stephens et al 1976)).   
The mechanism by which KCl causes pain and phlebitis upon I.V. administration is not known. A 
study by Morrill and Katz, 1988 provided evidence that Lidocaine in small doses is effective in reducing 
KCl-induced pain but no literatures have been found on the use of 4% Sodium Bicarbonate to reduce pain 
or phlebitis during intravenous Potassium replacement. This study will test the effects of 4% Sodium 
Bicarbonate additive during intravenous potassium chloride replacement. This study will also look at 
efficacy of 4% Sodium Bicarbonate in reduction and prevention of pain and phlebitis on patients 
receiving intravenous Potassium Chloride replacement. 
 
Methods: 
Staff Education: will include, but not be limited to: (1) an introduction to the study; (2) how potential 
participants will be screened (i.e. only patients that have been ordered peripheral intravenous potassium 
chloride replacement therapy as part of their care which is regardless of research); (3) how participants 
will be identified via sticker on chart; (4) how the intervention will be rolled out in collaboration with 
pharmacy and the medical staff; (5) how data collection will occur; and (6) who to contact if there are any 
questions about the study.   
Recruitment (3 means): 
(1) The resource nurse will be provided a screening tool (please see attached screening flyer) to 
assess for potential participants on admission.  The resource nurse will inform the principal 
investigator and/or designated key personnel either by phone or email that a potential participant 

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has been admitted.  No identifying information will be provided.  The principal investigator or 
designated key personnel will then talk with the resource nurse while on the unit in order to 
determine the potential participant’s location on the unit and the direct patient care nurse assigned 
to her or him.  The principal investigator or designated key personnel will then attempt to enroll 
the potential participant after: (a) the direct patient care nurse initiates contact with the potential 
participant (please see script); and (b) potential participant has agreed to meet with the principal 
investigator or designed key personnel. 
(2) The principal investigator will meet with the resource nurse or patient care supervisor (PCS) on 3 
South/3 North/4 South to determine if any patients meet the inclusion criteria (please see attached 
screening flyer). If the principal investigator identifies a potential participant she will attempt to 
enroll the potential participant after: (a) the direct patient care nurse initiates contact with the 
potential participant (please see script); and (b) potential participant has agreed to meet with the 
principal investigator. 
(3) The designated key personnel will go to 3 South/3 North/4 South  on a daily bases Monday 
through Friday and meet with the resource nurse or patient care supervisor (PCS) to see whether 
potential participants are on the unit, and ask for their room numbers and staff nurse assigned to 
them.  The designated key personnel will then attempt to enroll the potential participant after: (a) 
the direct patient care nurse initiates contact with the potential participant (please see script); and 
(b) potential participant has agreed to meet with the designed key personnel. 
Enrollment Process: 
(1) The study will be explained, consent and HIPAA; in either English or Spanish (which will be 
determined by the participant’s personal choice), will be obtained (please see attached consent) 
after the principal investigator or designated key personnel has answered all questions. The 
potential participant will be provided with about 10 minutes of individual time to review the 
consent.  Each participant will be provided a copy of their signed consent (please see attached). 
(2) Once enrolled the principal investigator or designated key personnel will: (a) contact the 
pharmacy to inform them that a new participant has been enrolled in the research study; (b) place 
a sticker on the chart of the participant (study number and enrollment date); and (c) place the 
participant (medical recorder number and study number provided by pharmacy) into the 
enrollment log.   The pharmacy research team member will then randomize the participant into 
either the experimental group (4% sodium bicarbonate additive during peripheral intravenous 
potassium chloride replacement therapy) or the control group (standard of practice of no 4% 
sodium bicarbonate additive during peripheral intravenous potassium chloride replacement 
therapy) based on a randomization table.  The randomization table will be generated by the 
statistician research team member after IRB approval is obtained by use of the statistical package 
nQuery. The pharmacy research team member will label the potassium replacement IV bags with 
a sticker to identify them as study participants.  This will include the standard of practice of 
labeling the IV bags as potassium replacement and also a label stating “neut study participant” 
but without the designated grouping in order to maintain blinding.  In order to maintain integrity 
of data and reduce bias the participant and direct patient care nurse will not be informed of 
randomization results.  The pharmacy research team member will maintain a record of 
randomization that will be provided to the principal investigator.  
 
a. Participants enrolled in the control group will receive standard of practice which is 
intravenous potassium replacement without the 4% sodium bicarbonate additive at the 
rate ordered by the ordering physician or ARNP for peripheral intravenous potassium 
chloride replacement therapy which will be part of the care of the patient regardless of 
research, and based on the WKBH policy of potassium chloride infusion of no more than 
100ml/hr. Pharmacist prepares, as standard of practice, each bag of 100 ml normal saline 
(NS) with 10mEq potassium chloride. 

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b. Participants enrolled in the experimental group (4% sodium bicarbonate additive during 
peripheral intravenous potassium chloride replacement therapy) will receive the additive 
after pharmacy and/or the designated key personnel (Dr. Soto) coordinates the ordering 
of 4% sodium bicarbonate additive during peripheral intravenous potassium chloride 
replacement therapy.  Pharmacist prepares, when ordered as standard of practice, each 
bag of 100 ml NS with 10mEq Potassium Chloride and 5 ml of 4% sodium bicarbonate 
additive, therefore, this practice will be used for the experimental group.  The rate of 
peripheral intravenous potassium chloride replacement therapy will be ordered by the 
ordering physician or ARNP, for IV potassium chloride replacement therapy which will 
be part of the care of the patient regardless of research, and based on the WKBH policy 
of potassium chloride infusion of no more than 100ml/hr. 
Data Collection: 
(1) Demographics (please see attached) will be collected by the principal investigator or 
designated key personnel after enrollment of patient. 
(2) peripheral intravenous potassium chloride replacement therapy (please see attached) data 
collection form: assessment of peripheral IV insertion site for phlebitis, using the VIP tool, 
and pain, using the Likert 11 point scale will be collected at baseline (prior to any peripheral 
intravenous potassium chloride replacement therapy), at 15 minutes after infusion started, 
every hour until peripheral intravenous potassium chloride replacement therapy is complete, 
and then at completion of replacement.   
a. Visual infusion phlebitis (VIP) tool: The VIP tool was developed by Jackson (1998) 
to assess intravenous sites for early signs of infusion phlebitis.  The tool was 
developed to assess intravenous sites daily; when bolus injections are administered, 
intravenous flow rates are checked or altered; and when solution containers are 
changed (Jackson, 1998). Inter-rate reliability was established as 0.85 or greater 
(unpublished data, Gallant, 1998, 2002) and content validity through consensual 
agreement was established (Gallant & Schultz, 2006).  
b. Pain, Numerical Rating Scale (NRS) Likert 11-point scale: pain assessment using the 
Likert 11-point scale of 0-10 with 0 being no pain, 5 being moderate pain, and 10 
being the worst possible pain is the current standard of practice at WKBH for 
assessing pain in adult patients.   Past research has shown that the NRS is sensitive to 
treatments that are expected to affect pain intensity (Chesney & Shelton, 1976; 
Kaplan, Metzger, & Jablecki, 1983; Keefe, Schapira, Williams, Brown, & Surwit, 
1981; Seymour, 1982; Stenn, Mothersill, & Brooke, 1979) and is easy to use in a 
variety of patients (Melzack & Torgerson, 1971). 
c. Peripheral intravenous potassium chloride replacement therapy (please see attached) 
data collection form will also include: administration start and stop time; nursing 
interventions performed (i.e. IV site change, slowed rate, request for 4% sodium 
bicarbonate additive); and pain medication use prior or during intravenous potassium 
chloride replacement therapy.   
d. Direct patient care nurses (during the education prior to the study) will place the 
collected peripheral intravenous potassium chloride replacement therapy data 
collection form into the provided envelop then seal it and place it in to the box 
labeled “research study’ that will be found in the medication room. 
i. Due to the fact that the patient and nurse will be blinded, number and type of 
nursing interventions and attrition rates of each group will be collected.  
Attrition rates, for this study, are defined by the number of participants that 
are removed from the study due to the direct patient care nurses’ intervention 
of requesting from the pharmacy 4% sodium bicarbonate additive for the 
peripheral intravenous potassium chloride replacement therapy which is a 
standard of practice action for patients complaining of pain during infusion 

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or requesting for the infusion not to have an additive. In this case, or in any 
adverse event, the pharmacist will unblind the patient and the nurse by 
revealing which group the patient is in. 
 
Data Storage: 
(1) All data collection sheets will be coded and not include identifying information.   
(2) The enrollment log(s) will be kept by the research team members in their locked BHSF office 
drawer or filing cabinet.  At the end of the study the enrollment logs will be housed in the 
principal investigator’s locked office drawer or filling cabinet.  Enrollment logs will be kept 
separate from data collection.    Peripheral intravenous potassium chloride replacement 
therapy data collection will be sealed in an envelope and placed in the designated ‘research’ 
box in the medication room.  Then on a weekly basis the envelopes will be collected by a 
member of the research team and given to the co-investigator (Julie Lamoureux).  Data entry 
into the BHSF password protected computer system will be done by the designated research 
team member and then all hard copies will be housed in the principal investigator’s BHSF 
locked office or filling cabinet.  
(3) All demographic and chart review data will be given to the co-investigator (Julie 
Lamoureux). Data entry into the BHSF password protected computer system will be done by 
the designated research team member and then all hard copies will be housed in the principal 
investigator’s BHSF locked office or filling cabinet.  
(4) At the end of the study, all data will be housed in the principal investigator’s locked BHSF 
office drawer or filing cabinet.   
(5) All electronic data will be password protected on the BHSF computers of the research team. 
(6) All data will only be accessible by the research team. 

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Instruments: 
Demographic form: data obtained by the participant about her or his self. 
 
Visual infusion phlebitis (VIP) tool: The VIP tool was developed by Jackson (1998) to assess intravenous 
sites for early signs of infusion phlebitis.  The tool was developed to assess intravenous sites daily; when 
bolus injections are administered, intravenous flow rates are checked or altered; and when solution 
containers are changed (Jackson, 1998). Inter-rate reliability was established as 0.85 or greater 
(unpublished data, Gallant, 1998, 2002) and content validity through consensual agreement was 
established (Gallant & Schultz, 2006).  
 
Pain, Numerical Rating Scale (NRS) Likert 11-point scale: pain assessment using the Likert 11-point 
scale of 0-10 with 0 being no pain, 5 being moderate pain, and 10 being the worst possible pain is the 
current standard of practice at WKBH for assessing pain in adult patients.   Past research has shown that 
the NRS is sensitive to treatments that are expected to affect pain intensity (Chesney & Shelton, 1976; 

7 
 
Kaplan, Metzger, & Jablecki, 1983; Keefe, Schapira, Williams, Brown, & Surwit, 1981; Seymour, 1982; 
Stenn, Mothersill, & Brooke, 1979) and is easy to use in a variety of patients (Melzack & Torgerson, 
1971). 
 
 
Participants: 
Participants will be recruited from one adult acute care hospital (West Kendall Baptist Hospital) within 
Baptist Health South Florida (BHSF) health system; one of the largest not-for-profit hospital systems in 
South Florida.  Initial screen will occur during the first 24-48 hours of the Medical/Surgical admission.  
Inclusion criteria: (1) admitted to the Medical/Surgical unit within the last 24 to 48 hours; (2) alert, 
awake, and oriented times three; (3) aged 21 years old and greater; (4) receiving her or his first peripheral 
intravenous potassium chloride replacement therapy as ordered by her or his physician or ARNP as part 
of her or his care and regardless of research; and (5) potassium level of 3.5 mmol/L or less.  Exclusion 
criteria: (1) patients who have been in the Medical/Surgical unit for more than 48 hours; (2) altered 
mental status defined as not being alert, awake, and oriented times three; (3) patients who have already 
received intravenous potassium chloride replacement during the current admission and with the current 
IV access; (4) patients receiving intravenous Potassium replacement therapy through a central line ; and 
(5) patients that are not ordered potassium replacement by her or his physician as part of their care while 
hospitalized. 
 
The literature indicates that the rate of phlebitis for IV administration of toxic substances is 
substantially higher than with non toxic substances (OR = 5.1).  We computed the sample size needed in 
relation to the main objective of comparing the rate of phlebitis in subjects being administered a toxic 
substance (Potassium IV replacement) to the rate of phlebitis in subjects receiving the same substance but 
with the addition of 4% sodium bicarbonate additive (to neutralize the toxicity). Using an alpha of 0.05 in 
a logistic regression assuming the occurrence of phlebitis without 4% sodium bicarbonate additive at 0.15 
and a multiple correlation between the covariates of 0.2, a total sample size of 150 (75 patients per group) 
would have a power of 80% to detect an odds ratio of 5.0.   
This sample size will yield an 80% power to detect a difference as little as 1.5 unit on a 10-point 
rating scale with unequal variances between the two groups, assuming a ratio of 2.75 between the groups’ 
standard deviations in a Satterthwaite t-test at a two-sided 0.05 level of significance.  It will also yield a 
power of 80% to detect an effect size of 0.46 in the length of administration using a t-test with a 0.05 two-
sided level of significance.  A sample size of 75 per group will also yield 80% power to detect a 
probability of 0.632 that an observation in the experimental group is less than an observation in the 
control group for the frequency of changing the IV, the number of nursing interventions and the rates of 
attrition using Wilcoxon rank-sum test with a 0.05 two-sided significance level.  In addition, considering 
that currently about 85 patients per month receive IV potassium replacement on the Medical/Surgical 
floor, it is expected that the research team will be successfully able to enroll the needed sample.  Although 
by power analysis a total of 150 participants is needed, in order to control for confounding variables the 
sample will be 200 (100 in each group). 
 
 
 
 

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Other Pertinent Information: 
Standard of Practice for Potassium chloride replacement therapy: The Physician or ARNP evaluates the 
Potassium level of the patient and orders potassium replacement therapy for potassium level of 3.5 or 
below. The amount of replacement of potassium intravenously is determined by the patient’s physician or 
ARNP based on patient’s condition and potassium level as standard of practice and the order is provided 
to the direct patient care nurses and pharmacy.  Patients with peripheral IV access may be ordered to 
receive intravenous potassium replacement therapy of 10 mEq/100 ml Normal Saline bag, ordered as one 
or multiple doses depending on the potassium level and patient’s condition. The peripheral intravenous 
site is being assessed per protocol for phlebitis once per shift and as needed.  During potassium chloride 
intravenous replacement direct patient care nurses can initiate nursing interventions including but not 
limited to: changing IV site, slowing rate of infusion, and requesting from the patient’s physician or 
ARNP an order for 4% sodium bicarbonate additive solution.  
 
Study Procedures covered: Those participants in experimental group who will receive up to 4 doses of 
4% sodium bicarbonate will not be charged for those experimental doses.  The Academy of Medical-
Surgical Nurses (AMSN) is sponsoring this study and the cost of 4% sodium bicarbonate to Pharmacy 
will be covered by AMSN. 
 
Limitations 
This study has some limitations.  Firstly, the sample will include patients in a Medical/Surgical units 
admitted for various reasons which can result in varying intravenous drug therapy.  For this reason 
participants will be randomized and only those that have been on the unit for 24-48 hours will be 
approached for enrollment.  Secondly, the direct patient care nurses will be assessing phlebitis and pain at 
IV insertion site which can reduce fidelity of data collection.  Therefore, a reliable and valid tool will be 
used along with initial education and additional education at six months will be provided by the research 
team.   
 
Potential Benefits of the Proposed Research to the Subjects and Others 
While there is no outward benefit to the participant for taking part in the study, the knowledge gained 
from this study will add to the body of nursing knowledge specific to Medical/Surgical nursing as it 
relates to intravenous therapy and patient comfort.  This study will test how 4% sodium bicarbonate 
additive could help reduce or prevent phlebitis and pain which is hospital acquired conditions. In addition, 
it is possible that participants will feel a sense of satisfaction in helping determine if an inter-collaborative 
pharmacist and nurse-drive prevention strategy can help with reducing the rate of phlebitis and pain at the 
IV insertion site of patients receiving potassium replacement.  If the result of this study is positive, it 
could be used as evidence that hospital acquired phlebitis could be prevented or reduced with great 
implications to nursing practice in the decrease of frequency of changing peripheral access, cost-
effectiveness and possible harm to the patient. 
 
 
Tentative Plan for Data Analysis 
Descriptive statistics for demographic and baseline variables will be computed for both groups using 
frequencies and proportions for categorical variables and means, medians, standard deviations and ranges 
for numerical variables.  To compare the differential rate of phlebitis between the two groups, we will 
compute the odds ratio (with a 95% confidence interval) using logistic regression.  Although the 
randomization process aims at eliminating the differences between groups, if the groups end up 
significantly different in baseline variables, those variables will be controlled in the logistic regression.  It 

9 
 
is hypothesized that the variances in pain scales will be different between the two groups.  Therefore, to 
compare the pain level between the groups, we plan on using a Satterthwaite t-test.  An independent t-test 
will be used to compare the length of administration per unit of the medication.  All other variables will 
be compared between groups using Wilcoxon rank-sum tests.  All tests will be performed at the 0.05 level 
of significance unless otherwise specified using Stata 12.1 (StataCorp, Texas). 
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