Review Article. Complications associated with peripheral or central routes for central venous cannulation. Summary. Methods

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1 doi: /j x Review Article Complications associated with peripheral or central routes for central venous cannulation A. Pikwer, 1 J. Åkeson 2 and S. Lindgren 3 1 Specialist Registrar and PhD Student, 2 Consultant and Professor, Department of Clinical Sciences Malmö, Anaesthesiology and Intensive Care Medicine, Skåne University Hospital, Lund University, Malmö, Sweden 3 Consultant, Department of Anaesthesiology and Intensive Care Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden Summary We undertook a review of studies comparing complications of centrally or peripherally inserted central venous catheters. Twelve studies were included. Catheter tip malpositioning (9.3% vs 3.4%, p = ), thrombophlebitis (78 vs 7.5 per indwelling days, p = ) and catheter dysfunction (78 vs 14 per indwelling days, p = 0.04) were more common with peripherally inserted catheters than with central catheter placement, respectively. There was no difference in infection rates. We found that the risks of tip malpositioning, thrombophlebitis and catheter dysfunction favour clinical use of centrally placed catheters instead of peripherally inserted central catheters, and that the two catheter types do not differ with respect to catheterrelated infection rates.... Correspondence to: Dr A. Pikwer andreas.pikwer@med.lu.se Accepted: 21 August 2011 Peripherally inserted central catheters (PICCs) are gradually replacing conventionally inserted tunnelled or non-tunnelled central venous catheters in several clinical settings. The PICC concept is far from new. As early as in 1912, a technique using upper extremity veins for central access was described, but from the 1940s the subclavian and jugular veins became the most common routes for central venous catheterisation [1]. It was not until the early 1970s that the use of PICCs became widespread, despite poor clinical outcome [2 4]. Some years later the results were improved with the introduction of specially designed silicone or polyurethane catheters for peripheral insertion, mainly intended for chemotherapy and parental nutrition [5, 6]. At this time teams of nurses specialised in PICC insertion emerged [7]. The increasing use of PICCs has, however, raised concerns [8, 9]. Although these catheters are inserted via peripheral veins, routine management to prevent complications differs markedly from that of conventional peripheral catheters, since the dimensions and locations of the tip of PICCs are similar to those of centrally placed catheters. Use of PICCs instead of central lines has been advocated on the basis of presumed cost and time benefits and fewer mechanical complications, despite a lack of convincing scientific evidence. During the last two decades several studies have been published regarding the rate of complications associated with PICCs and central lines. We undertook a systematic review of comparative studies assessing complications of centrally and peripherally inserted central venous catheters in various patient categories. Methods Studies published in English during the period comparing complication rates for centrally inserted central venous catheters (including non-tunnelled and tunnelled catheters and subcutaneous central venous access ports) and PICCs in adult patients were considered for inclusion. The MEDLINE database was used to identify eligible studies using the MESH search terms PICC, catheterisation, peripheral adverse effects and catheterisation, central venous adverse effects. Two reviewers (AP and SL) assessed independently the titles and abstracts of all eligible studies to determine if they met the criteria for inclusion. No search Anaesthesia ª 2011 The Association of Anaesthetists of Great Britain and Ireland 65

2 Pikwer et al. Complications with central and peripheral central lines was made for unpublished data. The same two reviewers extracted data independently from the studies. Extracted data included numbers and characteristics of patients, types of catheters, study setting and design, whether or not diagnostic criteria were met, risks of bias, catheter indwelling time periods and complications including the main endpoints: catheter malpositioning; thrombophlebitis; catheter-associated infection; and catheter dysfunction, as well as pneumothorax (the latter was specific for centrally placed catheters). Data regarding thrombophlebitis, catheter-associated infection or catheter dysfunction were only included if mean catheter indwelling time periods could be determined. For dichotomous data, we calculated the odds ratios (OR) and risk ratios (RR) with 95% CI using the Mantel Haenszel random effects model and weighted averages. The significance level of the overall effect was calculated for the OR of each complication. Review Manager (RevMan) version 5.1 (The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Denmark) was used for statistical analysis. Results A total of 448 studies were found in the initial search. On assessment for eligibility, 436 studies were found not to meet the criteria for inclusion (Fig. 1). The remaining 12 studies, published between 1986 and 2011 and reporting 3116 PICCs, 2193 non-tunnelled and 819 tunnelled or venous access port centrally inserted lines, were included. The mean (range) group sizes were 260 (15 807) for PICCs, 244 (31 713) for non-tunnelled and 164 (13 285) for tunnelled or venous access port lines. All catheters were made of polyurethane or silicone and had predominantly one, two or three channels. The majority of PICCs (58%) were inserted by nurses, Figure 1 Flow chart of study inclusion process. whereas all central lines were inserted by physicians (anaesthesia or surgery house officers, residents, or fellows). The main characteristics of the included studies are summarised in Table 1. Nine studies compared PICCs with non-tunnelled central lines and five studies compared PICCs with tunnelled central lines or venous access ports. Study settings and definitions of clinical outcome were found to differ considerably between the studies. Two studies included only intensive care patients, and only one study was randomised (and scored three on the Jadad scale). The remaining eleven studies have inherent risks of selection bias due to their non-randomised design. Furthermore, outcome data were not assessed blindly, and in five studies the numbers of PICCs and centrally placed lines were unequal (ratio of two or more). The complications of centrally or peripherally inserted central venous catheters are summarised in Table 2. Radiographic malpositioning of the catheter tip (as determined by five studies reflecting 432 PICCs and 641 centrally placed lines) occurred more often after PICC placement (9.3% vs 3.4%; OR 3.76 (95% CI ); RR 3.39 (95% CI ); p = ; Fig. 2). Thrombophlebitis (seven studies, based on PICC and central-placed line indwelling days) was reported more often with PICCs (78 vs 7.5 per indwelling days; OR 5.82 (95% CI ); RR 5.76 (95% CI ); p = ; Fig. 3). There was no difference in the catheter-associated infection rate (nine studies reflecting PICCs and centrally placed line indwelling days) (22 vs 17 per indwelling days; OR 0.83 (95% CI ); RR 0.83 (95% CI ); p = 0.74; Fig. 4, for PICCs and central lines, respectively). Catheter dysfunction (six studies, reflecting PICC and centrally placed line indwelling days) occurred more often during PICC use (78 vs 14 per indwelling days; OR 6.02 (95% CI ); RR 5.76 (95% CI ); p = 0.04; Fig. 5). The incidence of pneumothorax in patients undergoing centrally placed line insertion was reported in six studies [10 15] and was 16 events in 1481 insertions (1.1% (95% CI %)). The total complication rate including catheter malposition, thrombophlebitis, catheter-associated infection, catheter dysfunction and pneumothorax (all 12 studies, reflecting 3116 PICCs and 3013 centrally placed lines) was higher for PICCs (17% vs 10%; OR 2.02 (95% CI ); RR 1.76 (95% CI ); p = 0.003; Fig. 6). Discussion In this systematic review of twelve studies assessing complication rates of PICC vs centrally placed central lines we found that the available data favour central lines over 66 Anaesthesia ª 2011 The Association of Anaesthetists of Great Britain and Ireland

3 Pikwer et al. Complications with central and peripheral central lines Anaesthesia 2012, 67, Table 1. Main characteristics and diagnostic criteria used in studies assessing complications from centrally or peripherally inserted central venous catheters. Study Al Raiy et al. [27] prospective, diverse units Catheter type (n; mean indwelling period) Catheters used for PICC (n = 622; 9 days) CVC* (n = 638; 8 days) Diagnostic criteria used Malposition Thrombophlebitis Infection Venous access Positive blood culture (organism not associated with infection at other site) Catheter dysfunction Alhimyary et al. [10] PICC (n = 135; 10 days) CVC*, (n = 135; 8 days) Parenteral nutrition Tip position not in superior vena cava Phlebitis or Sepsis; not further specified Catheter occlusion or leakage Bonizzoli et al. [28] prospective, post-icu PICC (n = 114; 35 days) CVC* (n = 125; 22 days) Venous access Thrombosis on ultrasound 7, 15 and 30 days after insertion Cowl et al. [11] Randomised prospective, diverse units PICC (n = 51; 9 days) CVC*, (n = 51; 10 days) Total parenteral nutrition Tip position not in superior vena cava Phlebitis or confirmed by ultrasound or venography Local or systemic symptoms or positive blood culture Catheter occlusion or leakage Duerksen et al. [12] PICC (n = 209; 11 days) CVCà (n = 285; 13 days) Parenteral nutrition Tip position not in superior vena cava Phlebitis or confirmed by ultrasound or venography Positive blood culture Leakage Giuffrida et al. [13] prospective, ICU PICC (n = 472; 5 days) CVC* (n = 713; 6 days) Routine monitoring; total parenteral nutrition; vasopressors àà Symptoms; not further specified àà Gunst et al. [24] Retrospective, ICU PICC (n = 37; 12 days) CVC* (n = 263; 8 days) Routine monitoring; total parenteral nutrition; vasopressors Symptom of infection and positive catheter tip culture and positive blood culture of the same organism Kim et al. [29] Non-randomised prospective, diverse units PICC (n = 24; ) CVC (n = 155; ) Chemotherapy àà Mollee et al. [30] PICC (n = 807; 52 days) CVCà (n = 320; 30 days) Chemotherapy Positive blood culture (organism not associated with infection at other site) Anaesthesia ª 2011 The Association of Anaesthetists of Great Britain and Ireland 67

4 Pikwer et al. Complications with central and peripheral central lines Table 1. (Continued). Diagnostic criteria used Catheter dysfunction Malposition Thrombophlebitis Infection Catheter type (n; mean indwelling period) Catheters used for Study Catheter occlusion; catheter embolus; or damage to external portion of catheter Exit wound or port pocket infection or suspected catheter infection Phlebitis or symptomatic central confirmed by ultrasound Antibiotic therapy; chemotherapy; parenteral or hyperalimentation PICC (n = 555; 21 days) CVC (n = 283; 174 days) Smith et al. [14] Chemotherapy àà PICC (n = 15; ) CVC** (n = 13; ) Snelling et al. [15] Positive blood culture (organism not associated with infection at other site) Chemotherapy Phlebitis or confirmed by venography PICC (n = 75; 24 days) CVC*, (n = 31; 19 days) Worth et al. [25] prospective, diverse units *non-tunnelled CVC; subclavian catheters; ànon-tunnelled and tunnelled CVC and venous access ports; non-tunnelled CVC and venous access ports; tunnelled CVC and venous access ports; **tunnelled CVC; 20% femoral catheters; ààmain outcome but diagnostic criteria not specified. CVC, central venous catheter; ICU, intensive care unit;, not reported; PICC, peripherally inserted central catheter. PICCs for tip malpositioning, thrombophlebitis and catheter dysfunction. There was no difference in catheter-associated infection rates. Use of PICCs is widespread and has increased despite little evidence of greater safety than with conventional centrally placed central lines. The presumed lower risk of some complications associated with central cannulation, such as pneumothorax and carotid or subclavian arterial cannulation, have been used as a reason to favour PICCs [9]. A greater risk of long-term complications associated with PICC use may, however, have been overlooked in earlier non-comparative studies. Previous reviews supporting PICC use have not adequately considered long-term complications [16]. A well-designed recent review challenges the use of PICCs in surgical in hospital patients [9]. This study is, to our knowledge, the only systematic review of all the available articles comparing, in different patient categories, the full spectrum of relevant complications associated with the use of PICCs and centrally placed lines. For short-term catheter use, the catheter tip position is probably of little clinical importance [17]. For long-term use, the catheter tip position is, however, more important because of the increased risks of central [18], pulmonary embolism [19] and catheter dysfunction [20] when the tip is not positioned in the right atrium or lower part of the superior vena cava. Catheter malpositioning is, according to our review, almost three times more common after PICC insertion compared with centrally placed line insertion. In clinical practice, malpositioning is demonstrated on a post-procedural x-ray and usually results in further procedures associated with additional time expenditure, risks and patient discomfort. Cowl et al. concluded that in the elderly the proposed cost advantages of PICCs over central lines are partly outweighed by the costs associated with frequent malpositioning and complicated re-cannulations [11]. Thrombophlebitis due to indwelling central catheters may result in patient inconvenience, need for anticoagulation therapy (with its attendant side-effects), early catheter removal, re-cannulation and higher costs. Most venous thromboses are asymptomatic but they may, nevertheless, later result in pulmonary embolism [19], or in vascular stenosis rendering subsequent venous access more difficult [21]. Venous stenosis is of particular concern in patients in whom long-term venous access may be required (for example, patients with short-bowel syndrome or chronic renal failure). We found the incidence of thrombophlebitis to be ten times higher during PICC use than during centrally placed catheter use. Catheter-related infection is an important clinical issue associated with high costs and increased morbidity and mortality [22]. Based on non-comparative studies, it has been proposed that catheter-related infections are more common 68 Anaesthesia ª 2011 The Association of Anaesthetists of Great Britain and Ireland

5 Pikwer et al. Complications with central and peripheral central lines Anaesthesia 2012, 67, Table 2. Complications of centrally or peripherally inserted central venous catheters. Study Catheter type (n) Total indwelling days Malposition events (%) Events (%); rate per indwelling days Thrombophlebitis Infection Dysfunction Al Raiy et al. [27] PICC (622) (2); 23 CVC (638) (2); 24 Alhimyary et al. [10] PICC (135) (4) 3 (2); 22 0 (0) 0 5 (4); 36 CVC (135) (3) 0 (0); 0 2 (1); 19 0 (0); 0 Bonizzoli et al. [28] PICC (114) (27); 77 CVC (125) (10); 44 Cowl et al. [11] PICC (51) (10) 8 (16); (4); 41 8 (16); 166 CVC (51) (2) 1 (2); 19 3 (6); 56 2 (4); 38 Duerksen et al. [12] PICC (209) (10) 25 (12); (1); 9 29 (14); 131 CVC (285) (2) 12 (4); 33 8 (3); 22 5 (2); 14 Giuffrida et al. [13] PICC (472) (12); (0.4); 9 35 (7); 151 CVC (713) (3); 41 0 (0); 0 66 (9); 149 Gunst et al. [24] PICC (37) (3); 22 CVC (263) (5); 60 Kim et al. [29] PICC (24) 8 (33) CVC (155) 10 (6) Mollee et al. [30] PICC (807) (9); 18 CVC (320) (17); 55 Smith et al. [14] PICC (555) (9); (8); (12); 55 CVC (283) (1); (12); 7 11 (4); 2 Snelling et al. [15] PICC (15) 2 (13) CVC (13) 2 (15) Worth et al. [25] PICC (75) (19); (16); 66 CVC (31) (6); 34 6 (19); 103 CVC, central venous catheter;, not reported; PICC, peripherally inserted central catheter. Figure 2 Forest plot of peripheral (PICC) vs centrally placed (CVC) lines for catheter malpositioning. with centrally placed catheters [23]. We found that there was no difference in the odds ratio for this complication between the two routes. The two largest studies reviewed [24, 25] report diverging results. Mollee et al. [24] and Smith et al. [25] found infection rates of 1.8 and 4.7, and of 3.8 and 0.67 cases per 1000 indwelling catheter days, respectively, for PICCs and centrally placed lines. One possible explanation for these opposing results is the strong selection bias, reflected in unequal ratios of catheter types used and in different clinical definitions of catheter-associated infection. Catheter dysfunction, mainly caused by catheter occlusion or leakage and often requiring catheter removal and reinsertion, occurs more than five times more often with PICCs. The greater risk of catheter dysfunction or malpositioning with PICCs may reflect their greater length and smaller diameter, and the higher incidence of thrombophlebitis is probably associated with the use of a peripheral insertion site where considerably smaller vessels are used for cannulation and the intravascular route to the central circulation is necessarily longer [3, 5, 26]. The higher risks of malpositioning, thrombophlebitis and catheter dysfunction associated with PICC insertion and use must be weighed against more infrequent, but potentially severe, complications such as pneumothorax or arterial injury associated Anaesthesia ª 2011 The Association of Anaesthetists of Great Britain and Ireland 69

6 Pikwer et al. Complications with central and peripheral central lines Figure 3 Forest plot of peripheral (PICC) vs centrally placed (CVC) lines for thrombophlebitis. Figure 4 Forest plot of peripheral (PICC) vs centrally placed (CVC) lines for catheter-associated infection. Figure 5 Forest plot of peripheral (PICC) vs centrally placed (CVC) lines for catheter dysfunction. Figure 6 Forest plot of peripheral (PICC) vs centrally placed (CVC) lines for all complications. with central venous cannulation. The overall complication rate was found to be two times higher for PICCs compared with centrally placed lines even after including pneumothorax in the calculation. Like other reviews, our review is at risk of bias in relation to the studies included. In the studies themselves, selection bias may be an important factor as only one study was randomised. Different definitions of various complica- 70 Anaesthesia ª 2011 The Association of Anaesthetists of Great Britain and Ireland

7 Pikwer et al. Complications with central and peripheral central lines Anaesthesia 2012, 67, tions studied may further reduce the credibility of our review. However, our use of a random effects model may have compensated, in part, for this. In conclusion, we found that there are few comparative studies of complications associated with the use of PICCs vs centrally placed lines, and that all studies but one are at risk of selection bias due to their non-randomised design. We found that the risks of tip malpositioning, thrombophlebitis and catheter dysfunction favour clinical use of centrally placed catheters instead of PICCs, and that the two catheter types do not differ with respect to catheter-related infection rates. Competing interests No external funding and no competing interests declared. References 1. Kalso E. A short history of central venous catheterization. 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