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JOURNAL OF VASCULAR ACCESS
A simple diagnostic test to confirm correct placement of intravenous catheters before
chemotherapy
--Manuscript Draft--
Manuscript Number: JVA-D-14-00132
Full Title: A simple diagnostic test to confirm correct placement of intravenous catheters before
chemotherapy
Short Title: A simple diagnostic test to confirm correct placement
Article Type: Original Article
Section/Category: Oncology
Keywords: end-tidal carbon dioxide
sodium bicarbonate
chemotherapy
Extravasation
Patient safety
Corresponding Author: ilan keidan, MD
University of Florida
gainesville, florida UNITED STATES
Corresponding Author's Institution: University of Florida
First Author: ilan keidan, MD
Order of Authors: ilan keidan, MD
Erez Ben-Menachem, MBCHB, FANZCA
Raanan Berger, MD
Estela Derazne, M.Sc
Haim Berkenstadt, MD
Manuscript Region of Origin: ISRAEL
Abstract: Context: Vesicant extravasation injuries prevention is difficult as currently no test
objectively confirms intravascular location of a catheter.
Objective: To determine the feasibility and effectiveness of using a single injection of
diluted sodium bicarbonate, while monitoring exhaled carbon dioxide changes, to
reliably confirm correct placement of intravenous catheters
Setting: The study was conducted in the oncology day care clinic at a tertiary care
center
Participants: A selected group of patients with various oncological conditions who
required intravenous chemotherapy.
Intervention: Injection with 20mLs normal saline or 20mLs 4.2% sodium bicarbonate
while monitoring exhaled carbon dioxide.
Design: In each patient a newly inserted peripheral intravenous catheter or newly
accessed central line were deemed positively intravascular if they had good blood
return or most probably intravascular if there was no blood return but they flushed
easily. This clinical diagnosis of correct positioning, was correlated with the results of a
single injection of dilute sodium on the exhaled carbon dioxide, and with the ability of a
blinded observer to report whether sodium bicarbonate or saline was injected
Results: 67 patients were enrolled to the study. 56 had positively intravascular IV
catheter while 11 had most probably intravascular IV catheter. A single injection of
20mLs 4.2% sodium bicarbonate had a positive and clinically detectable response that
was diagnosed with high sensitivity and specificity.
Conclusions: Intravenous injection of 20mls of 4.2% sodium bicarbonate with exhaled
carbon dioxide monitoring can be used to reliably confirm correct intravascular
placement of a catheter intended to be used for chemotherapy.
Suggested Reviewers: Mark Rice, MD
Assoc. prof., University of Florida
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IRB Sheba Medical Center, January 2013
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A simple diagnostic test to confirm correct placement of intravenous catheters
before chemotherapy
Short Title - A simple diagnostic test to confirm correct placement
Ilan Keidan1,2
, Erez Ben-Menachem11
, Raanan Berger3
, Estella Derazne4
, Haim
Berkenstadt1
1 Anesthesiology, Sheba Medical Center , Tel Hashomer, Israel
2 Anethesiology, University of Florida , USA
3 Oncology, Sheba Medical Center, Tel Hasomer, Israel
4 Tel Aviv University, Israel
Corresponding Author:
Name: Dr.I Keidan
Department of Anesthesiology and Intensive Care
Sheba Medical Center
Mailing address: Sheba Medical Center, Tel Hashomer, 52621, Israel
Phone: +972-3-530-2754
Email: ikeidan@anest.ufl.edu
Manuscript
Click here to download Manuscript: bicarb oncology adults 17 june.doc
Click here to view linked References

Abstract:
Purpose: To determine the feasibility and effectiveness of using a single injection of diluted
sodium bicarbonate, while monitoring exhaled carbon dioxide changes, to reliably confirm
correct placement of intravenous catheters
Methods: The study was conducted in the oncology day care clinic at a tertiary care center
And included a selected group of patients with various oncological conditions who required
intravenous chemotherapy. In each patient a newly inserted peripheral intravenous catheter or
newly accessed central line were deemed positively intravascular if they had good blood return
or most probably intravascular if there was no blood return but they flushed easily. This clinical
diagnosis of correct positioning, was correlated with the results of a single injection of dilute
sodium on the exhaled carbon dioxide, and with the ability of a blinded observer to report
whether sodium bicarbonate or saline was injected
Results: 67 patients were enrolled to the study. 56 had positively intravascular IV catheter while
11 had most probably intravascular IV catheter. A single injection of 20mLs 4.2% sodium
bicarbonate had a positive and clinically detectable response that was diagnosed with high
sensitivity and specificity.
Conclusions: Intravenous injection of 20mls of 4.2% sodium bicarbonate with exhaled carbon
dioxide monitoring can be used to reliably confirm correct intravascular placement of a catheter
intended to be used for chemotherapy.
Trial Registration: Registered with clinicaltrials.gov NCT01748097
Key Words : Extrvasation, End-Tidal carbon dioxide, Sodium Bicarbonate,
Chemotherapy, Patient safety

Introduction:
Extravasation of chemotherapeutic agents has the potential to cause significant morbidity.
Consequently, considerable vigilance is required to ensure correct intravascular placement of an
intravenous (IV) catheter; yet definitive confirmation of such placement is often difficult.
Despite awareness of this feared complication, and protocols for prevention, monitoring and
management, vesicant extravasation is a well-known complication of chemotherapy.
Preventative strategies offer the best option for a reduction in extravasation injuries, and
guidelines have been developed by the Oncology Nursing Society and the European Oncology
Nurses Society. Precautions advocated include; use of a recently sited IV catheter, in a large
caliber intact vein, with good return of blood on aspiration of the catheter prior to commencing
an infusion. Patency should be confirmed prior to infusion by flushing 5-10mL of isotonic saline
through the IV catheter and observing for leakage and/or tissue swelling(1). Similar strategies
can be employed for central venous access, with the added complexity that some venous ports
require percutaneous access to be established.
Despite education and promulgation of safety guidelines, extravasation continues to occur and
the incidence is commonly reported to be in the range of 0.1-6% of patients receiving
chemotherapy(2). Although rates may be lower in centrally placed venous access catheters, the
reported incidence for extravasation is up to 2% of patients(3). Subcutaneous infusion ports may
have higher extravasation rates due to misplacement of the percutaneous access needle(4).
Extravasation of vesicants can result in mild cutaneous reactions through to massive tissue

necrosis including necrosis of the hand, arm or breast necessitating washout, debridement of
even free flap surgical repairs(5,6).
Peripheral venous access is often difficult in this patient population due to multiple cannulations
over time, fragile tissues and sclerosis of peripheral veins. In this context extravasation may
result from an inadvertently misplaced catheter that goes unrecognized, rupture of the vein or
from migration of the catheter out of the vein during a bolus or infusion. Equally, central venous
catheters can be misplaced at the time of insertion, migrate out of the vessel lumen or perforate
through the wall of vessel with the potential for intrathoracic extravasation(7).
Given the potential for serious morbidity in patients who already have significant disease burden,
there exists a need to definitively establish correct intravascular placement of vascular access
before infusion of vesicant solutions. We have previously described an innovative technique to
verify correct positioning of peripheral IV catheters in anesthetized, ventilated adult and
pediatric patients(8,9). The technique is based on the observed phenomenon of increased exhaled
carbon dioxide concentration following the IV administration of dilute sodium bicarbonate. A
similar response can be seen in awake, spontaneously breathing patients. Dilute sodium
bicarbonate is utilized to ensure safety of the test.
The exhaled carbon dioxide concentrations are measured using capnography, a common
monitoring technique used routinely by anesthesiologists and others to ensure proper placement
of endotracheal tubes, adjust the parameters of mechanical ventilation, and monitor the incidence
of hypoventilation and apnea in spontaneously breathing patients(10). Continuous capnography

measurement is non-invasive and measurements can be taken via nasal cannula with a side
sampling line. Such devices are now widely utilized in endoscopy units or other locations where
sedation is provided and respiratory patterns need to be monitored, with the device integrated
into standard monitoring machines.
In this study we evaluated the utility and feasibility of this technique in patients presenting to the
oncology clinic and scheduled for chemotherapy.

Methods:
The study was reviewed and approved by the IRB (Sheba Medical Center, Tel Hashomer, Israel).
Signed consent was obtained prior to study enrollment. Inclusion criteria were: age 18-85 years
and a primary or secondary oncological disease that required intravenous chemotherapy.
Exclusion criteria included primary or secondary pulmonary oncological involvement, history of
congestive heart failure or renal failure, or any acid-base abnormalities. After arrival to the out-
patient oncology clinic, patients scheduled for chemotherapy had a 22-gauge IV peripheral
catheter (BD Venflon, NJ, U.S.) inserted in the upper limb or had their central line (PICline or
Port-A-Cath) accessed by the nursing staff. The nurse then categorized the IV catheter as
‘positively intravascular’ if there was good blood return; or ‘most probably intravascular' if
there was no blood return but the IV catheter flushed easily with 10mL normal saline; or as ‘not
intravascular’ when there was no blood return and saline flushing encountered resistance or there
was obvious tissue infiltration. IV catheters considered ‘not intravascular’ were replaced and
rechecked.
A preparation of dilute sodium bicarbonate was made by mixing 8.4% sodium bicarbonate with
sterile water in a 1:1 ratio to create 4.2% sodium bicarbonate. In all patients a bolus of 20 mL of
sodium bicarbonate 4.2% (SB), or 20 mL of normal saline (NS) was injected in a random order
at 10 minute intervals. The heart rate, oxygen saturations and exhaled carbon dioxide levels were
monitored continuously using a portable bedside monitor (Capnostream 20 patient monitor,
Covidien, Dublin, Ireland). Exhaled carbon dioxide sampling was performed using a nasal
cannula connected to a breath sampling line and the end-tidal carbon dioxide levels (maximal
carbon dioxide levels during the expiratory phase) were recorded in 2 second intervals and used

for further data analysis. Patients also had venous blood samples taken prior to commencing
injections, as a baseline, and again after completion of both the NS and SB injections. Samples
were analyzed for pH and electrolytes. Additionally, a blinded observer (nurse taking care of the
patient and not participating in the study) was asked to determine, according to the information
presented on the monitor, whether a SB or NS bolus had been injected. All participants were
asked to report any symptoms related to the injection. All IV sites were inspected after the IV
catheter was removed prior to discharge.
A paired t-test was used to compare differences in exhaled carbon dioxide values from baseline
to peak after intravenous injection of dilute 4.2% sodium bicarbonate and normal saline. 95%
confidence intervals of the mean difference and 95% prediction intervals were calculated.
Statistical analysis was performed using IBM SPSS software (version 21, IBM Corp, Somers,
NY, U.S.).

Results:
Seventy-one patients were enrolled into the study, however 4 patients were excluded secondary
to newly diagnosed pulmonary disease or a recent metabolic derangement. The participants’ age
was 57 ± 15 years, weight was 69 ± 14 kg and BMI was 25.8 ± 3.1 kg/m2
(mean ± standard
deviation). The exhaled carbon dioxide measurements displayed a predictable pattern of change
after an intravenous injection of sodium bicarbonate via the intravascular catheter placed for
chemotherapy (Figure 1). No significant difference in baseline to peak exhaled carbon dioxide
was found during intravenous injection of normal saline. After intravenous injection of dilute
4.2% sodium bicarbonate, exhaled carbon dioxide increased significantly from baseline with a
mean increase of 4.1 ± 1.9 mmHg compared to NS, 0.9 ± 1.8 mmHg (paired t-test p<0.001). The
change from baseline of exhaled carbon dioxide to injection of SB versus NS is depicted in
Figures 2 and 3. The effect on the onset of the exhaled carbon dioxide rise from baseline was
first detected 14 ± 10 seconds (3-4 breaths) from the time of injection and peaked at 27 ± 13
seconds (6-7 breaths) (Table 1). The blinded observer correctly identified the injectate with a
sensitivity and specificity of 89% and 85% respectively and a positive predictive value of 86%.
In 56 out of 67 patients included in the study, the peripheral IV cannula had blood return on
aspiration and was considered ‘positively intravenous’. All these patients had a positive exhaled
carbon dioxide response to dilute 4.2% bicarbonate injection (4.15 + 1.8 mmHg). In 11 out of 67
patients included in the study, the IV cannula was considered ‘most probably’ intravenous and
the exhaled carbon dioxide increased by (4.09 + 2.5 mmHg. One patient had no change in
exhaled carbon dioxide and the IV cannula was replaced. No significant change in blood pH or
electrolytes was detected in venous blood gases. No other adverse effects were detected and the
only side effect reported was a transient light-headedness in one patient.

Discussion:
Extravasation of chemotherapeutic agents is a major patient safety concern. Morbidity may be as
mild as patient discomfort, but may also result in tissue sloughing, skin necrosis, compartment
syndromes and can require surgical debridement, fasciotomy and rarely amputation(11). Such
complications can be devastating to patients already coping with the emotional and physical
strain of their primary disease burden. Given the potential for adverse outcomes, the possibility
for malpractice claims is not inconsequential. The Closed Claims Project showed that 2.1% of all
injury claims, between 1970-2001, were related to peripheral IV catheters and that 54% of such
claims were settled in favor of the plaintiff with compensation ranging from $275 to over $10
million(12).
We have previously investigated the utility of the novel technique described above, using dilute
4.2% sodium bicarbonate, as a method to differentiate safely between an infiltrated and a
correctly sited IV catheter. Previous investigations included safety studies in an animal model
and in the controlled setting of anesthetized ventilated healthy adult and pediatric patients(8,9).
In the current study we evaluated the feasibility of using the same technique in routine clinical
practice in patients receiving chemotherapy. The extension of this technique to oncology patients
is a natural progression given the high volume of patients undergoing outpatient chemotherapy
and the significant risk posed to this cohort of patients by extravasation of anti-neoplastic agents.
In this study, the dilute SB could be differentiated from placebo NS in all cases where the
peripheral IV catheter was correctly positioned. All peripheral IV catheters with good return of
blood were confirmed as correctly placed after a positive exhaled carbon dioxide response to
dilute SB. In ‘questionable’ peripheral IV catheters the correct position was confirmed in 10 out

of 11 patients and these went on to be used without complication. In one patient with a
‘questionable’ peripheral IV catheter, who did not have a rise in exhaled carbon dioxide in
response to the injection of dilute SB, the catheter was considered to be ‘tissued’, was replaced,
and subsequently used without complication, potentially avoiding extravasation injury.
Additionally, injection of dilute SB was well tolerated by all patients.
While the technique we describe has utility in confirming correct IV placement of a peripheral
catheter prior to initiation of chemotherapy is does not prevent extravasation as a result of later
migration of the catheter out of the vessel and into surrounding tissues. As always, during
prolonged infusions, vigilance is mandatory and prompt action required in the event of
extravasation. The safety and utility of this technique in patients with respiratory disease and
metabolic derangements requires further investigation.
In summary, we present a useful technique, using dilute 4.2% sodium bicarbonate to confirm the
correct placement of a peripheral IV catheter prior to initiation of chemotherapy in an adult
outpatient oncology clinic. The test may be applied to all peripheral intravenous catheters, or
only to the ‘questionable’ catheter depending on the preferences of the individual unit. The use
of this simple technique may contribute to ongoing efforts to improve patient safety, reduce
iatrogenic morbidity and prevent litigation.

References:
1. Perez Fidalgo JA, Garcia Fabregat L, Cervantes A, Margulies A, Vidall C, Roila F;
ESMO Guidelines Working Group. Management of chemotherapy extravasation: ESMO-
EONS Clinical Practice Guidelines. Ann Oncol 2012; 23(7 Suppl): vii167-73
2. Schrijvers DL. Extravasation: a dreaded complication of chemotherapy. Ann Oncol
2003; 14s3:iii26-30
3. Narducci F, Jean-Laurent M, Boulanger L, El Bedoui S, Mallet Y, Houpeau JL,
Hamdani A, Penel N, Fournier C. Totally implantable venous access port systems and
risk factors for complications: a one-year prospective study in a cancer centre. Eur J Surg
Oncol 2011; 37:913-8
4. Brothers TE, Von Moll LK, Niederhuber JE, Roberts JA, Walker-Andrews S, Ensminger
WD. Experience with subcutaneous infusion ports in three hundred patients. Surg
Gynecol Obstet 1988; 166:295-301
5. Jahn JC, Shafritz AB. Chemotherapy extravasation injuries. J Hand Surg Am 2012;
37:360-2
6. Vasconcelos I, Schoenegg W. Massive breast necrosis after extravasation of a full
anthracycline cycle. BMJ Case Rep 2013; 18:2013
7. Bozkurt AK, Uzel B, Akman C, Ozguroglu M, Molinas Mandel N. Intrathoracic
extravasation of antineoplastic agents: case report and systematic review. Am J Clin
Oncol 2003; 26:121-3
8. Keidan I, Ben-Menachem E, Barzilai A, Nur I, Berkenstadt H. Intravenous sodium
bicarbonate verifies intravenous position of catheters in ventilated patients. Anesth Analg
2011; 113:279-81

9. Keidan I, Ben-Menachem E, White SE, Berkenstadt H. Intravenous sodium bicarbonate
verifies intravenous position of catheters in ventilated children. Anesth Analg 2012;
115:909-12
10. Oretga R, Connor C, Kim S, Djang R, Patel K. Monitoring ventilation with capnography.
N Engl J Med 2012; 367:e27
11. Gault BT. Extravasation injuries. Br J Plast Surg 1993; 46:91-6
12. Doellman D, Hadaway L, Bowe-Geddes LA, Franklin M, LeDonne J, Papke-O’Donnell
L, Pettit J, Schulmeister L, Stranz M. Infiltration and extravasation: update on prevention
and management. J Infus Nurs 2009; 32:203-11

Table 1: Characteristics of end-tidal carbon dioxide waveform changes after 4.2% sodium
bicarbonate
Figure 1: Illustration of end-tidal CO2 response to injection of 20 mLs 4.2% sodium bicarbonate
in a patient. (Injection started at time 0 while capnography is illustrated for 70 seconds after
injection)
Figure 2: The pattern of end-tidal carbon dioxide change over 120 seconds after the injection of
20 mLs sodium bicarbonate 4.2% in comparison to injection of 20 mLs normal saline. (Mean
and 95% predictive interval).
Figure 3: Percent increase of end-tidal CO2 in 67 patients. Comparison between intravenous
4.2% sodium bicarbonate and normal saline.

Table 1: Characteristics of end-tidal carbon dioxide waveform changes after 4.2% sodium
bicarbonate
Time to first increase
from baseline(seconds)
Time to peak
(seconds)
Time return to
baseline (seconds)
Mean 14 27 63
Median 15 25 65
Standard Deviation 10 13 23
Range 5- 25 5-35 25-100
Table

Figure 1
Click here to download high resolution image

Figure 2

Figure 3

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ilan keidan
05/29/2014
A simple diagnostic test to confirm correct placement of
intravenous catheters before chemotherapy
ilan keidan
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