3SITES

Published
Parienti JJ, et al. "Intravascular Complications of Central Venous Catheterization by
Insertion Site". The New England Journal of Medicine. 2015. 373(13):1220-1229.
PubMed • Full text • PDF

Contents
• 1 Clinical Question
• 2 Bottom Line
• 3 Major Points
• 4 Guidelines
• 5 Design
• 6 Population
o 6.1 Inclusion Criteria
o 6.2 Exclusion Criteria
o 6.3 Baseline Characteristics
• 7 Interventions
• 8 Outcomes
o 8.1 Primary Outcomes
o 8.2 Secondary Outcomes
o 8.3 Adverse Events
o 8.4 Subgroup Analysis
• 9 Criticisms
• 10 Funding
• 11 Further Reading

Clinical Question
In critically ill patients requiring central venous access, how do complications vary by
central venous catheter (CVC) access site?

Bottom Line
In this study with limited generalizability to US academic centers, subclavian insertion
was associated with fewer bloodstream infections and DVTs compared to jugular and
femoral approaches, but was balanced by more mechanical complications including
pneumothorax.

Major Points
Central venous catheters (CVCs) are associated with infrequent but potentially severe
complications, including catheter-related bloodstream infection (CRBSI), DVT, and
pneumothorax. A 2001 French randomized study demonstrated that subclavian insertion
was associated with fewer infectious and thrombotic complications than femoral
insertion, but internal jugular (IJ) insertion was not studied.
A 2012 meta-analysis of mostly nonrandomized studies suggested that the subclavian
approach may be associated with fewer infectious complications than femoral or IJ
insertions. However, it concluded that a randomized trial was necessary to confirm the
rates of these complications by access site.

The 2015 3SITES study was a multicenter, randomized trial designed to investigate
whether subclavian, IJ, or femoral access was associated with a difference in the rate of
major catheter-related complications. The primary outcome of major catheter-related
complications was defined as CRBSI or symptomatic DVT, and were adjudicated by a
committee unaware of randomization. A total of 3,027 patients with 3,471 catheters
were studied. Major complications at the subclavian, IJ, and femoral insertion sites
occurred at a rate of 1.5, 3.6, and 4.6 events per 1,000 catheter-days, respectively
(P=0.02). Mechanical complications, including pneumothorax, accounted for 18, 12,
and 6 events in the subclavian, jugular, and femoral groups, respectively (P=0.047).
Fewer mechanical complications occurred in patients whose CVC was inserted with
ultrasound guidance, although use of ultrasonography was not randomized. The
investigators conclude that a subclavian approach reduces the risk of catheter-associated
complications.

The validity of this conclusion needs some consideration. Importantly, mechanical

complications such as pneumothorax were not considered primary outcome events. As
such, the 3SITES primary analysis cannot speak to whether the reduction in the primary
outcome achieved by subclavian access is outweighed by an increase in mechanical
complications. This was partly addressed in an analysis of the composite rate of the
primary outcome plus grade ≥3 mechanical complications between insertion site groups,
which found the complication rate was similar between approaches (subclavian 3.1%,
jugular 3.7%, and femoral 3.3%). Ultimately, this suggests that rates of significant
complications do not vary widely by insertion site and thus an optimal insertion site
probably doesn't exist.

In addition to these findings, several caveats pertain to this study's generalizability.

First, this study defined CRBSI as colonization of the catheter tip by ≥1000 cfu/mL of
the same organism recovered from a peripheral blood culture. While this is a common
research definition, it is more stringent than the published IDSA guidelines.

Second, while using published French and US guidelines for preventing CRBSIs, this
study did not employ antibiotic-impregnated or tunneled catheters, which may reduce
the frequency of CRBSIs.

Third, the catheters were inserted by experienced physicians who previously had placed
at least 50 catheters, which differs from the routine practice at many US academic
centers who allow supervised medical students, interns, and junior residents to perform
these procedures as a matter of routine.

As a final observation, 3SITES suggests that the notion of the "dirty femoral catheter" is
becoming a relic of the past. While 3SITES demonstrated more frequent catheter tip
colonization with femoral compared to subclavian (HR 3.4; P<0.001) and jugular
approaches (HR 1.6; P=0.003), this did not translate to a clinically significant increase
in risk of CRBSI when compared to subclavian (HR 3.4 with a confidence interval
which includes 1.0; P=0.048) or jugular approaches (HR 0.9; P=0.81). This finding is
consistent with a 2012 meta-analysis.

Guidelines
As of November 2015, no guidelines have been published that reflect the results of this
trial.

Design
• Multicenter, randomized, controlled trial
• N=3,027 ICU patients with 3,471 catheters
o Subclavian (n=1,016)
o Jugular (n=1,284)
o Femoral (n=1,171)
• Setting: 10 ICUs from 4 university and 5 community hospitals in France
• Enrollment: 2011-2014
• Median follow up: 5 days
• Analysis: Intention-to-treat
• Primary outcome: Major catheter-related complications (bloodstream infection
or symptomatic DVT)
• Secondary safety outcome: Major mechanical complications

Population
Inclusion Criteria

• Age ≥18 years

• Admitted to the ICU
• Required central venous access
• Had at least 2 acceptable insertion sites (femoral, jugular, or subclavian)

Exclusion Criteria

None provided in manuscript.

Baseline Characteristics

• Demographics: Age 63, 64% male, BMI 26

• Comorbidities: T2 DM 19.7%, Cancer: 9.7%, AIDS: 1.3%; SAPS II 56.1
• Antibiotic therapy: 55%; anticoagulation therapy: 30%; parenteral nutrition:
6.2%
• Skin antiseptics: Alcoholic chlorhexidine 44%, alcoholic povidone-iodine 43%,
aqueous povidone-iodine 10%
• Use of anatomical landmarks to guide insertion: subclavian (86%) vs. femoral
(74%) vs. jugular (33%)
• Catheter insertion time quicker in femoral group (11.6 mins) vs. others (12.7
mins)
 • Insertion failure: femoral 5.3% vs. jugular 7.7% vs. subclavian 14.7%
• Reason for removal: no longer needed 58%, death 18.5%, suspected catheter
infection: 12%
• Mean duration of catheterization: 6.3 days

Interventions
• Somewhat complex randomization to insertion site.
o Patients with 3 available sites were randomized in 1:1:1 ratio to available
site (subclavian, jugular, or femoral)
o Patients with only 2 available sites were randomized in a 1:1 ratio to one
of the 2 available sites.
• Randomization was stratified according to ICU and according to the use of
antibiotics versus no therapy
• All ICUs used the French Haute Autorite de Sante checklist and US guidelines
for preventing catheter-related infections
• Maximal sterile barrier precautions were used
• Catheterization was achieved by means of the Seldinger technique with the use
of anatomical landmarks or ultrasound guidance, which was not randomized
• Within 2 days of catheter removal, compression ultrasound was used to detect
asymptomatic or confirm symptomatic catheter-related DVT

Outcomes
Primary Outcomes

Catheter-related bloodstream infection or symptomatic DVT

Femoral vs. subclavian: 25 vs. 8 (HR 3.5; 95% CI 1.5-7.8; P=0.003)
Jugular vs. subclavian: 23 vs. 11 (HR 2.1; 95% CI 1.0-4.3; P=0.04)
Femoral vs. jugular: 33 vs. 30 (HR 1.3; 95% CI 0.8-2.1; P=0.30)

Secondary Outcomes

Bloodstream infection
Femoral vs. subclavian: 11 vs. 4 (HR 3.4; 95% CI 1.0-11.1; P=0.048)
Jugular vs. subclavian: 13 vs. 6 (HR 2.3; 95% CI 0.8-6.2; P=0.11)
Femoral vs. jugular: 15 vs. 21 (HR 0.9; 95% CI 0.5-1.8; P=0.81)
Catheter tip colonization
Femoral vs. subclavian: 107 vs. 39 (HR 3.4; 95% CI 2.4-5.0; P<0.001)
Jugular vs. subclavian: 104 vs. 42 (HR 2.5; 95% CI 1.7-3.5; P<0.001)
Femoral vs. jugular: 145 vs. 121 (HR 1.6; 95% CI 1.2-2.0; P=0.003)
Symptomatic DVT
Femoral vs. subclavian: 15 vs. 5 (HR 3.4; 95% CI 1.2-9.3; P=0.02)
Jugular vs. subclavian: 10 vs. 6 (HR 1.8; 95% CI 0.6-4.9; P=0.29)
Femoral vs. jugular: 20 vs. 9 (HR 2.4; 95% CI 1.1-5.4; P=0.04)

Adverse Events

Major mechanical complications (pneumothorax, arterial injury, hematoma)

 Femoral vs. subclavian: 6 vs. 18 (HR 0.3; 95% CI 0.1-0.8; P=0.03)
Jugular vs. subclavian: 12 vs. 22 (HR 0.5; 95% CI 0.3-1.1; P=0.09)
Pneumothorax: 4 vs. 14 (statistics not given)
Femoral vs. jugular: 7 vs. 13 (HR 0.5; 95% CI 0.2-1.4; P=0.19)

Subgroup Analysis

• None of the preplanned subgroup analyses showed a significant interaction for

the primary outcome
• For mechanical complications, there was a significant interaction between the
use of ultrasonography and the comparison between the femoral and jugular
group (P=0.007) with the difference increasing when ultrasound was not used to
guide catheter insertion
• For mechanical complications, there was a nonsignificant trend for an
interaction between the use of ultrasonography and the comparison between the
femoral and subclavian group (P=0.07), with the difference increasing when
ultrasound was not used to guide catheter insertion

Criticisms
• By not including mechanical complications in the primary outcome, it is
difficult to determine whether the reduction in the primary outcome achieved by
subclavian access is outweighed by an increase in mechanical complications.
• The short-term nature of the study precludes analysis of longer-term and
potentially more relevant outcomes such as mortality and length of ICU stay.
• Ultrasound guidance was not randomized and therefore its effect is uncertain.
Results may not be generalizable to settings in which ultrasound guidance is
either uniformly used or unavailable.

Funding
• Supported by a grant from the Hospital Program for Clinical Research, French
Ministry of Health

Further Reading
1.

• Merrer J, et al. Complications of femoral and subclavian venous catheterization in

critically ill patients: a randomized controlled trial. JAMA. 2001 Aug 8;286(6):700-7.
• • Parienti JJ, et al. Meta-analysis of subclavian insertion and nontunneled central
venous catheter-associated infection risk reduction in critically ill adults. Crit Care Med.
2012 May;40(5):1627-34.
• • Mermel LA, et al. Clinical practice guidelines for the diagnosis and management of
intravascular catheter-related infection: 2009 Update by the Infectious Diseases Society
of America. Clin Infect Dis. 2009 Jul 1;49(1):1-45.
• • Veenstra DL, et al. Efficacy of antiseptic-impregnated central venous catheters in
preventing catheter-related bloodstream infection: a meta-analysis. JAMA. 1999 Jan
20;281(3):261-7.
• Marik PE, et al. The risk of catheter-related bloodstream infection with femoral
venous catheters as compared to subclavian and internal jugular venous catheters: a
systematic review of the literature and meta-analysis. Crit Care Med. 2012
Aug;40(8):2479-85.