Peripherally Inserted Central Venous Catheter Insertion Site and Complication Rates in Neonates
Phase: NA
Conditions: Catheterization, Peripheral
Sponsor: University of Calgary

 
 
 
 
Peripherally inserted central venous catheter insertion site and 
complication rates in neonates: a randomized controlled trial 
Principle Investigator: Dr. Amuchou Soraisham 
Co-Investigators: Dr. Sumesh Thomas 
           Dr. Harish Amin 
REB17-2317 
December 5, 2017 
 

PICC insertion site and complication rates in neonates: a RCT                       Soraisham et al 
 
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Peripherally inserted central venous catheter insertion site and complication rates in 
neonates: a randomized controlled trial 
1. Background and rationale 
1.1. PICC lines as ‘life lines’ in neonates 
Peripherally inserted central venous catheters (PICCs) provide lasting venous access to 
deliver total parenteral nutrition (TPN) and medications for neonates receiving intensive care, 
especially in very low-birth-weight infants.1In neonates, PICC lines are commonly inserted at 
the basilic, cephalic, and axillary veins in the upper extremity, the great saphenous and 
popliteal veins in the lower extremity, and the temporal and posterior auricular veins in the 
scalp.2  The incidence of PICC associated complication rates in literature varies from 27 to 
42%.3, 4, 5 The common complications resulting in removal of PICCs include mechanical 
complications such as  line infiltration, line occlusion, thrombosis, 3, 4, 5central line-associated 
bloodstream infection (CLABSI),2–6 and life-threatening complications such as pericardial 
effusion and temponade7–9 and pleural effusion.10, 11 
1.2. PICC related complication reports with site of insertion 
Usually the site of insertion is chosen based on the inserter’s preference and accessibility of 
veins rather than incidence of complications. In adult literature, it has been reported that 
lower extremity PICCs are associated with a higher risk of infection than upper extremity 
PICCs, and it is recommended to avoid femoral sites in adults.12,13 However, studies in 
pediatric patients have demonstrated that femoral catheters have a low incidence of 
mechanical complications and might have an equivalent infection rate to that of non-femoral 
catheters.14,15 In neonates, only a few retrospective studies have reported complication rates 
based on the site of insertion with conflicting results.16-19 In a retrospective study, Hoang et 
al16 reported that upper extremity PICCs had significantly higher rates of coagulase negative 
staphylococcal septicemia and cholestasis as compared to lower extremity PICCs  in 
neonates. Wrightson17 reported no difference in the overall complication rate between upper 
and lower extremity PICCS (27% vs 21%). Presumed sepsis was the most common 
complication requiring PICC removal. Both studies included infants of all gestational ages 
(including term infants) and all the PICCs inserted. It is possible that a higher number of 
PICCs inserted in a single baby may increase the complication rates. Ozkiraz et al18 also 
reported no difference in complications between upper and lower extremity PICCs in very 
low-birth-weight and extremely low-birth-weight infants. Some studies in preterm infants 
recommended avoiding PICCs in the lower limbs, especially at the femoral site because of a 
high incidence of sepsis and thrombosis.2,18 Our retrospective study in Calgary noted that the 
overall rate of catheter-related complications resulting in PICC removal was not significantly 
different between upper and lower extremity PICCs.19 However, there was a 2.4-fold increase 
in odds of line infiltration among upper extremity PICCs, especially on the right side. Line 
occlusion was more common in lower extremity PICCs.  
 
1.3. Non-central catheter tip position associated with complications 
When the tip of PICC is not at the superior or inferior vena cava, it is called non central 
catheter tip position. The mid-clavicular tip position of central lines is more commonly 
associated with line infiltrations.4 In a study by Jain et al,4 non-central PICCs developed more 
complications in less time, leading to non-elective catheter removal. Similarly, Racadio et al 

PICC insertion site and complication rates in neonates: a RCT                       Soraisham et al 
 
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reported a sevenfold increased risk of complications when the catheter tip was non-central in 
pediatric populations.20 Use of high-osmolar TPN solutions infusing through PICC lines 
might have contributed to the infiltrations,19  especially if the catheter tips were non-central 
(midclavicular location). The details of these potential factors are not available from 
retrospective studies. Likewise, catheter tip position has not always been documented in 
retrospective studies.19 
1.4.Thrombosis as a complication of PICC lines 
In adults, it is reported that spontaneous deep venous thrombosis occurs more commonly on 
the left side as compared to the right side.21However, in neonates, there is no uniform policy 
to assess thrombosis. 19 It has been observed that lower extremity PICCs had a higher rate of 
major venous thrombo-embolism especially in neonates with intra-abdominal surgeries.22 
Likewise, infiltration and phlebitis were commonly seen with lower limb PICCs in neonates 
with gastroschisis during silo reduction and within 5 days of abdominal closure.23 
1.5. Relation of catheter insertion site to tip position  
Proximity of insertion site to catheter tip destination has been suggested to be a factor against 
PICC-related complications. Panagiotounakou et al observed that PICCs inserted through 
axillary veins were associated with 12 times less complications and were 7 times electively 
removed due to achievement of full enteral nutrition as compared with the PICCs inserted 
through forearm veins due to proximity of insertion site to catheter tip destination.24 Tsai et al 
reported that culture-proven sepsis was common with femoral PICCs, whereas non-infectious 
complications were common with non-femoral PICCs.25 
Rationale for the study: 
There are no prospective or randomized clinical studies in the literature that have looked at 
the site of PICC insertion and complication rates in neonates. Earlier retrospective studies 
also included all PICC lines irrespective of the timing of insertion or number of catheters 
used on an individual patient. Retrospective studies lack pertinent information to determine 
why the site was chosen and details of complication types. A well-designed prospective 
randomized clinical trial is required to conclusively establish if PICC site placement is a 
factor affecting complications that necessitate non-elective removal of the device. Moreover 
this study will also help in understanding the specific complication such as thrombosis 
related to PICC line. 
  
2. Research Question 
In neonates who require PICC placement as a part of their care in NICU, does complications 
following PICC insertion resulting in early (non-elective) removal of catheter differ based on the 
site of insertion? 
P: Neonates admitted to the NICU  
I: Lower extremity PICCs 
C: Upper extremity PICCs 
O: Any complication necessitating non-elective removal of lines 
T: During the period of PICC insertion 

PICC insertion site and complication rates in neonates: a RCT                       Soraisham et al 
 
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3. Study hypothesis: 
We hypothesize that there is an association between the site of PICC insertion and the 
complications necessitating PICC line removal non-electively and complications rates are 
different between upper extremity and lower extremity PICCs.  
4. Study objective: 
i) 
To examine whether the complications following PICC insertion resulting in early removal 
differ based on the site of insertion 
5. Methods: 
5.1. Study design:  Parallel group, prospective, randomized controlled trial 
5.2. Description of population: All neonates admitted to the level III neonatal intensive care unit 
(NICU), Calgary, Canada (i.e.  Foothills Medical Centre (FMC) and Alberta Children’s Hospital 
(ACH), will be eligible for the study and will be screened for participation. Randomization will 
be done once inclusion criteria are met, in the absence of exclusion criteria and once informed 
consent is obtained. 
5.3. Inclusion criteria: 
 Neonates of all gestational ages admitted to Foothills Medical Centre and Alberta 
Children’s Hospital NICU  
 PICC line insertion planned as part of NICU care 
 Venous access available in both upper(above umbilicus) and lower body  
5.4. Exclusion criteria: 
 Local infection at potential site of insertion  
 Hemangioma, lymphangioma or malformations in the region of insertion 
 Major chromosomal anomalies  
5.5. Randomization:  
Eligible infants will be randomly assigned for upper extremity or lower extremity PICC insertion 
using an allocation ratio of 1:1. We will use blocked randomization of varying block sizes in 
multiples of two. The investigators will be blinded to the block sizes; but the block sizes will 
ensure appropriate balance between both arms. Infants will be stratified into two groups based on 
the gestational age (≤ 32 weeks, >32weeks). Randomization will be performed using computer 
generated software once eligibility is confirmed and informed consent is obtained. A unique 
patient identification number and the randomisation sequence will be generated.  
5.6. Interventions:  
PICC insertion attempts will be made by certified health care providers including transport 
nurses, nurse practitioners and physicians using standard clinical practice guidelines. A 
maximum of two attempts will be allowed in the designated region, following which further 
attempts will be considered in the non-designated region if the inserter is confident of success. 
Number of attempts at insertion and sites of attempts will be recorded as per unit protocol. After 
the catheter is inserted, catheter tip position will be confirmed by radiograph with the limbs in 
standard position as per unit protocol, and repeat radiographs will be taken if there is a 
manipulation. As per unit protocol, the catheter inserter will record the details of the procedure, 
the type of catheter used, and position of catheter following radiographic confirmation in the 
progress note of each infant’s medical chart. Similarly, the bedside nurse also documents this 
information in the nursing chart/Metavision. In addition, the inserter will fill out a one-page 
PICC line tracking sheet for all the lines which includes details such as the indication, date of 
insertion, site of insertion, catheter tip position, and any complications during insertion. Once the 

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PICC is removed, the bedside nurse will complete the PICC tracking sheet, filling in the date and 
the reason for removal of the line.  
The clinical goal is to place the catheter tip in the superior vena cava or inferior vena cava, but 
outside the right atrium. A catheter tip lying beyond the medial end of the clavicle and up to 1 
cm at the junction of right atrium and superior vena cava is considered optimal for upper 
extremity. PICCs with the catheter tip located in the inferior vena cava below the diaphragm are 
considered optimal for lower extremity PICCs. Heparin will be infused in all PICCs as per 
standard unit policy. All catheters will be removed either after completion of intravenous therapy 
or earlier if they develop complications. In all babies an ultrasound will be performed within 72 
hours of PICC line removal by neonatologists trained to perform point of care ultrasound, 
looking for the presence of an occlusive thrombus. If one is detected, consultation to radiology 
and hematology will be requested as per unit protocol.  
6. Study Outcomes: 
6.1. Primary outcome: 
Primary outcome is the presence of any complication which necessitates PICC removal. This 
includes mechanical, central line associated blood stream infections (CLABSI) and major life 
threatening complications. 
i) 
Mechanical complication will be considered present if there is a line infiltration, 
occlusion, phlebitis, and dislodgement, resulting in removal of PICC. 19 
ii) 
Line infiltration will be defined as extravasation of fluid into soft tissue around the 
region of the catheter tip. 19 
iii) Line occlusion will be defined as inability to infuse fluid, resulting in removal of line.19 
iv) Phlebitis will be defined as presence of a linear red streak developing along the 
superficial veins from the catheter insertion site.19 
v) 
Line associated thrombosis will be defined as ultrasound proven evidence of an 
occlusive thrombus in an anatomic location in proximity to the site of PICC. 
vi) CLABSI will be defined according to Center for Disease Control definitions 26, that is, 
(1) confirmed primary bloodstream infection with (2) one of following clinical signs of 
infection (fever, hypothermia, apnea, or bradycardia) and (3) presence of central 
catheter at the time of or within 48 hours before the onset of the infection. 
vii) Major life-threatening complications will include pleural effusion, pericardial effusion 
and cardiac tamponade, retroperitoneal extravasation etc 
6.2. Secondary outcome: Secondary outcome will be time to complication post insertion. This 
will be defined as the interval between PICC line insertion and first detection of complication 
post insertion, expressed in days. 
7. Statistical analysis: 
7.1. Sample size calculation:  
Based on our previous retrospective study, the rate of PICC complication resulting in removal of 
PICC was 30%.19 In order to find a clinically important difference of 10% between PICCs 
inserted through upper extremity and lower extremity, a sample of 153 infants in each group will 
be required at 80% power and alpha error of 5%.  We will recruit 320 infants. . Approximately 200 
-250 PICCs are inserted per year in Calgary NICUs. We expect to complete recruitment over 18 month’s 
period. 
 
 
 

PICC insertion site and complication rates in neonates: a RCT                       Soraisham et al 
 
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7.2. Statistical methods:  
Data will be analyzed using intention-to-treat analysis. Baseline demographics of the study 
population will be described using descriptive statistics. Data will be checked for normality. 
Categorical variables will be presented as counts and percentages and continuous variables as 
mean and standard deviation or median and inter-quartile range if data are not normally 
distributed. Primary outcome, which is the presence of any complication, necessitating PICC 
removal, is a binary outcome where we will use chi-squared test or Fisher exact test. Event rates, 
relative risk and 95% confidence intervals will be reported for primary outcome. Secondary 
outcome, which is the time from PICC insertion to development of complication, is a continuous 
outcome for which two sided independent samples t-test or Mann-Whitney U test, depending on 
if the data is normally distributed or not. Standard deviation and 95% confidence interval will be 
reported for continuous outcomes. We will also calculate time to complication post insertion as 
median time. We will also do multivariate logistic regression analysis to examine the association 
of PICC site and complication rate after adjusting for gestational age, day of PICC insertion and 
illness severity score. P-value <0.05 will be taken as significant. Stata 15 will be used for the 
analysis. 
8. Trial administration: 
8.1. Clinical Site: This multicentre study will be conducted at the Neonatal Intensive Care Unit, 
in Foothills Medical Center and Alberta Children’s Hospital NICU, Calgary, Canada 
8.2. Steering Committee and Local Operations Group: The steering committee will consist of 
two neonatologists, two transport nurses, one Clinical Trials Coordinator and one nurse clinician. 
Along with these, there will be a study physician committed to the trial and a research assistant 
responsible for the daily conduct of the trial including recruitment, informed consent, 
administration of intervention, data collection, and in-servicing of relevant NICU staff.  
8.3. Data Safety Monitoring Board (DSMB): This committee will be made up of two separate 
neonatologists, a statistician, and a unit manager, who will be blinded to the two groups. They 
will function independently from the study investigators. Once half the intended recruitment is 
reached, an interim analysis of clinical outcome data for efficacy and data analysis for expected 
and unexpected adverse events will be done. The DSMB will recommend termination of the trial 
for statistically significant (p<0.001) differences between the intervention groups with respect to 
PICC related complications, mortality, or serious unexpected adverse events. Results of the 
interim analysis will not be disclosed to investigators or study participants but will be published 
along with the DSMB’s recommendations upon completion of the trial. 
8.4. Data Collection: All data collection will be done with the help of a research assistant, 
supervised by a physician who is committed to the study. The study physician will check the data 
collection forms for completeness of data and fill each form separately. The study data will be 
collated and entered into the study database for analysis. Completed data collection forms and all 
the reporting forms will be securely locked in a closed cabinet in the study Principal 
Investigator’s office at FMC. 
8.5. Study Monitoring: The specific committee will ensure that all study procedures are in 
compliance with good clinical practice. It is imperative that the study proposal and all the 
amendments will be approved by the local Research Ethics Board. 
8.6. Data Quality Assurance: Baseline infant demographics, details of PICC insertion and 
maintenance will be obtained from patient chart and electronic medical record. X-ray for PICC 
position and ultrasound reports and images to screen for thrombus will be available in the 

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IMPAX. Details of infusing solution through the PICC line as well as laboratory parameters will 
be available in the electronic medical record.  
8.7. Regulatory Approval: All the interventions used for the conduct of the study has been 
approved by Health Canada, hence no special permissions are required. 
8.8.  Subject Confidentiality: Appropriate measures will be taken to maintain subject 
confidentiality. Although hospital database will have personal identifiers, only the random ID 
will be available in the research database. Privacy of electronic records will be maintained in the 
secure hospital server. Since the intervention cannot be blinded, the most responsible physician 
and the research team will know about any adverse event which occurs. 
8.9. Retention of Records: As per Health Canada and local Research Ethics Board, paper 
records will be maintained for 5 years and electronic records for 7 years before destroying. 
8.10. Documentation of Protocol Deviations: Research staff will be instructed to report all 
protocol violations in a particular reporting form created for the purpose. 
9. Ethical Considerations: 
This study will be conducted in accordance with the Good Clinical Practice guidelines and local 
Research Ethics Board requirements. Parents will act as surrogate decision makers for the 
patient.  
10. Feasibility and limitations: 
Major limitation of the study is the large sample size. We expect around 320 babies to be 
enrolled to see an effect. In our retrospective study19, there were around 900 first time PICCs 
over a period of 5 years from 2006- 2010, which gives an average of 180-200 PICCs per year. 
Accordingly, it will take about 1.5-2 years to finish the trial.  
11. Impact of the study: 
The results of this trial will help to figure out if there is an association with increased 
complication rates when PICC lines are inserted through upper or lower extremities. If there is a 
significant difference detected, it will definitely guide the inserter to select the site with fewer 
complications, especially in a neonate with first time PICC insertion, rather than base the choice 
of site of insertion on personal preference and venous accessibility. 
 
 

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