1 INTRODUCTION

Central venous catheters (CVCs) are routinely placed in hematologic patients, providing an access point for drug administration, laboratory testing, and parenteral nutrition. These patients are frequently pancytopenic and have been reported to be at higher risk for catheter-related complications such as bleeding and catheter-related infections (CRIs).1, 2 In the last decade, routine improvements of CVC insertion and management, such as ultrasound-guided catheter placement and the introduction of hygiene bundles, have been implemented worldwide.3, 4 These measurements have been shown to decrease the incidence of CVC-associated complications and overall hospital costs.1, 3, 5 A few studies have been published outlining mechanical and infectious CVC-related complications in hematologic patients. However, those studies were either small, or the CVC insertion in the studies was mainly performed without ultrasound guidance and included only tunneled silicone CVCs.2, 6 Therefore, we designed this retrospective observational study with the primary aim of investigating the prevalence and incidence of CVC-related mechanical and infectious complications after insertion of nontunneled, noncoated CVCs in a cohort of hematologic patients. The secondary aim was to explore factors potentially associated with CVC complications. We hypothesized that hematologic patients have a high risk of both mechanical and infectious complications after CVC insertions and that several risk factors for complications can be identified.

2 METHODS

This study was approved by the Swedish Ethical Review Authority (dnr 2014/916 and 2018/866). The requirement for written informed consent was waived. The study was carried out at the Department of Intensive and Perioperative Care at Skåne University Hospital, Lund, Sweden. The manuscript was prepared according to the STROBE guidelines for observational studies.7 Details on the study methods are presented in Figure 1. The subclavian vein was the preferred site of CVC insertion, since the patients were considered at high risk of infection and because the CVC was expected to remain in situ for more than a week.

Flow charts describing the study methods. All inserted catheters together with the daily inspections and their management was documented in the patient's electronical file. Detailed data on catheter insertion and management, together with all microbiological data, were manually extracted and analyzed. Every patient had the right to opt out from the study. a Blood samples were obtained within 24 h prior to cannulation, and prophylactic coagulation enhancement was considered in patients with preprocedural coagulopathy, defined as platelet count 9/L, prothrombin time (PT-INR) > 1.8, or APTT > 43 s (equal to more than 1.3× upper normal value). bCDC, central dialysis catheter; CVC, central venous catheter. Management of catheters is described in reference [13] (Thorarinsdottir et al.). cAll catheter insertions and any preprocedural complication were documented in the electronic medical chart using a standardized CVC insertion template described in reference [12] (Björkander et al.). dNonantimicrobial transparent catheter dressings (TegadermTM; 3M) were changed every fifth day or more frequently if needed. Once the old dressing was removed, the insertion site was cleaned with 0.9% saline solution and washed with 0.5% chlorhexidine/70% alcohol (SCHA) solution. eThe CVCs were removed after site treatment with 0.5% chlorhexidine/70% alcohol (SCHA) solution and the distal 5 cm of the catheter was cut and submerged in a culture tub, which was sonicated in 10 ml of broth. 0.1 ml of the broth was quantitatively cultured on blood agar plates. Growth of >102 CFU/catheter was considered significant colonization. The BACT/ALERT system (BioMérieux) was used for blood cultures. All bottles were incubated until microbial growth was detected or for a maximum of 5 days. gElectronic medical records of all patients eligible for inclusion were manually reviewed, and relevant data were extracted and entered in the research database (Microsoft Access, version 2016) 2.1 Outcomes

The primary outcomes were moderate and severe mechanical complications and infectious complications.

Mechanical complications included bleeding complications, arterial puncture, pneumothorax, arrhythmia, and nerve injury/rhizopathy within 48 h of insertion. Severity of mechanical complication was graded according to the Common Terminology Criteria for Adverse Events (CTCAE, Version 5.0)8 and further classified into mild, moderate, and severe as demonstrated in Table 1.

TABLE 1. Mechanical complications classified according to their severity, based on the terms defined by the Common Terminology Criteria for Adverse Events Severity of mechanical complication Complications Mild Bleeding grade 1a Arrhythmia grades 1–2b Transient rhizopathy Moderate Bleeding grade 2c Severe Bleeding grades 3–4d Pneumothorax Arrhythmia grades 3–4e Persistent rhizopathy

Infectious complications were defined in accordance with recent publications based on the definitions used by the Centers for Disease Control and Prevention.9-11

2.1.1 Suspected catheter-related infection (sCRI)

Either a positive catheter tip culture or a positive peripheral blood culture together with at least two of three systemic inflammatory response syndrome (SIRS) criteria at the removal of the CVC (fever >38°C or <36°C, heart rate > 90 beats per min, respiratory rate > 20 breaths per min). Leukocytopenia or leukocytosis was not considered an SIRS criterion because hematologic patients already have disturbed leukocyte counts due to reasons other than infections.

and

no likely infectious cause other than the catheter.

and

no likely noninfectious cause, for example, drug- or transfusion-related adverse reaction, venous thromboembolism, or mucositis.

or

local inflammation and signs of infection.

Catheter-related bloodstream infection (CRBSI): Growth of the same microorganism on both the catheter tip and in peripheral blood (within 48 h prior to the removal of the CVC) together, with at least two of four SIRS criteria (three in the current study) with no likely explanation for a cause other than the catheter.

2.2 Statistical analyses

The sample size was based on the number of available patients during the study period. Results were expressed as a median (interquartile range) for continuous variables and a number (percentage) for categorical variables. When comparing binary variables, the chi-square test was applied. To evaluate the associations between independent variables and grades 2–4 bleeding and CRI, univariable and multivariable logistic regression analyses were applied. The selection of independent variables in the regression analyses was based on results from previous studies12, 13 and the significant results in the univariate analysis were further analyzed in a multivariable analysis. The Hosmer-Lemeshow test was used to test the goodness of fit for multivariable testing. p < .05 was considered significant and all tests were two-tailed. All analyses were performed using SPSS 25 (SPSS Inc/IBM).

3 RESULTS

Baseline characteristics of patients and CVCs are presented in Table 2. In summary, a total of 589 catheter insertions were performed in 387 patients, during the study period of 71 months. The majority of catheters inserted were single lumen 469/589 (80%) and most catheters were inserted in the subclavian vein 433/589 (74%). Of all patients (n = 387), 256 (66%) were men and the most common diagnosis was acute myeloid leukemia 153/387 (40%).

TABLE 2. Characteristics of central venous catheters and patients Catheter characteristics Central venous catheters inserted, total 589 (100) Days with catheter 25 [9.0–43] Type of catheter CVC 564 (96) Central dialysis catheter 25 (4.2) Site of insertion Subclavian vein 433 (74) Internal jugular vein 150 (25) Femoral vein 5 (0.8) Missing 1 (0.2) Number of lumens 1 469 (80) 2 33 (6.0) 3 12 (2.0) 4 6 (1.0) 5 14 (2.0) Central dialysis catheter 25 (4.0) Missing 30 (5.0) Number of needle passes 1 385 (66) 2 85 (14) 3 38 (6.0) >4 26 (4.0) Missing 55 (10) Ultrasound guidance 415 (70) Reason for removal Ceased usage 373 (63) Suspected or confirmed infection 89 (15) Patient death 49 (8.0) Catheter malfunction 10 (2.0) Accidental removal 10 (2.0) Mispositioning 11 (2.0) Confirmed venous thrombosis 3 (0.5) Mechanical complication (bleeding) 2 (0.5) Missing 42 (7.0) Preprocedural coagulopathyb 219 (37) Missing data 20 (3.4) Patient characteristics Patients, total 387 Age, years 57 [41–68] Male gender 256 (66) Body mass index (BMI) 25 [23–29] Body temperature at time of catheter insertion (°C) 37.1 [36.6–37.4] Hepatosplenomegalyc 124 (32) Diagnosis Acute myeloid leukemia (AML) 153 (40) Acute lymphoblastic leukemia (ALL) 50 (13) Lymphoproliferative neoplasms/lymphoma 48 (12) Myeloma 34 (9.0) Acute promyelocytic leukemia (APL)d 22 (5.0) Myelodysplastic syndrome (MDS) 15 (4.0) Myeloproliferative neoplasms (MPN) 12 (3.0) Othere 53 (14) 3.1 Outcomes

Detailed data on outcomes per insertion site are presented in Table 3.

TABLE 3. Outcomes per site of insertion Outcome

Subclavian

n = 433

Internal jugular

n = 150

Femoral

n = 5

Total

n = 589

Mechanical complications Bleeding gradeb 1 77 (18) 12 (8.0) 0 (0) 89 (15) 2 33 (7.6) 16 (11) 1 (20) 50 (8.5) 3 8 (1.8) 0 (0) 0 (0) 8 (1.4) 4 2 (0.5) 1 (0.7) 0 (0) 3 (0.5) Aggregated grades 2–4 43 (10) 17 (11) 1 (20) 61 (10) Pneumothorax 3 (0.7) 0 (0) 0 (0) 3 (0.5) Arrythmias Mild 3 (0.7) 0 (0) 0 (0) 3 (0.5) Moderate–severe 0 (0) 0 (0) 0 (0) 0 (0) Nerve injury Mild 4 (0.9) 1 (0.7) 0 (0) 5 (0.8) Moderate–severe 0 (0) 0 (0) 0 (0) 0 (0) Prevalence of mechanical complications Mild mechanical complicationsc 84 (19) 13 (8.7) 0 (0) 97 (16) Moderate mechanical complicationsd 33 (7.6) 16 (11) 1 (20) 50 (8.5) Severe mechanical complicationse 13 (3.0) 1 (0.7) 0 (0) 14 (2.4) Infectious complications f Days with catheter, total 16077 2692 40 18814 Catheter days 28 [17–53] 13 [5–27] 7 [5–12] 25 [9–43] sCRI prevalence, n (%) 53 (12) 15 (10) 0 (0) 69 (12)g sCRI incidence/1000 catheter days 3.3 5.6 0 3.7 CRBSI prevalence, n (%) 9 (2.0) 3 (2.0) 0 (0) 12 (2.0) CRBSI incidence/1000 catheter days 0.56 1.11 0 0.64 3.2 Mechanical complications

In 64/589 (11%) of all insertions, a moderate 50/589 (8.5%) or severe 14/589 (2.4%) mechanical complication occurred. Ultrasonography was used in the majority of insertions that resulted in grades 2–4 bleeding 46/61 (75%) but did not show statistical significance in the univariable logistic regression analysis and was therefore not included in the multivariate analysis.

Arterial punctures occurred in 18/589 (3.1%) insertions, where 4/18 (22%) resulted in grades 3–4 bleeding and 4/18 (22%) in grade 2 bleeding. Out of all grades 2–4 bleedings, 8/61 (13%) occurred after an arterial puncture. Detailed data on preprocedural coagulopathy and correction of hemostasis is described in Figure 2 and File S1.

The Venn Diagram shows the relationship between preprocedural coagulation defects and the correction of hemostasis. The total number of isolated coagulopathies are presented separately, whereas the number of cases receiving any pro-coagulative treatment before insertion are presented within brackets, as explained in the figure above. Two hundred and two cases presented isolated platelet count 9 L, two cases presented isolated PT-INR > 1.8, and three cases had an isolated APTT > 43 s. For more details on the preprocedural correction of coagulopathy, see File S1. APTT, activated partial thromboplastin time; PT-INR, prothrombin time-international normalized ratio.

In the multivariable logistic regression analyses for both grades 2–4 bleeding and sCRI, the goodness of fit showed a valid chi-square value (p > .05) for all outcomes. Detailed results of the uni- and multivariable regression analyses on grades 2–4 bleeding are shown in Tables 4 and 5. The results of the univariable regression analyses were used to identify variables for the multivariable analyses. Corrected or uncorrected preprocedural coagulopathy (p < .001), number of needle passes (p = .008), and arterial puncture (p = .004) were all independently associated with grades 2–4 bleeding in the multivariable analysis.

TABLE 4. Univariable regression analyses for each outcome variables. Independent variables were chosen based on previous studies. Highlighted variables were further analyzed in a multivariable regression analysis (Table ) Independent variables Early grades 2–4 bleeding, n = 61 No Yes Univariable analysese n = 528 n = 61 OR 95% CI p value Body mass index 26 [23–29] 26 [23–29] 0.998 0.945–1.054 .933 Male gender 233 (44) 23 (38) 1.305 0.756–2.252 .339 Hepatosplenomegaly 486 (92) 59 (96) 2.549 0.602–10.804 .204 Operator experience >5 year 355 (67) 43 (70) 1.237 0.644–2.377 .523 Male operator 406 (77) 49 (80) 1.227 0.632–2.381 .545 Number of needle passesa 1 [1–2] 1 [1–2] 1.317 1.070–1.620 .009 Site of insertion Subclavian vein 390 (74) 43 (70) 0.845 0.472–1.515 .572 Internal jugular vein 133 (25) 17 (28) 1.147 0.634–2.077 .649 Femoral vein 4 (8.0) 1 (2.0) 2.183 0.240–19.854 .488 Left sided CVC insertion 297 (57) 34 (56) 0.971 0.569–1.656 .914 Number of lumens 1 [1–1] 1 [1–1] 0.975 0.779–1.220 .823 Ultrasound guidance 369 (70) 46 (75) 1.321 0.717–2.436 .372 Arterial puncture 10 (2.0) 8 (13) 7.819 2.959–20.661 .000 Coagulopathyb 171 (32) 36 (59) 2.931 1.704–5.039 .000 Diagnosis AMLc at CVCd insertion 260 (49) 28 (46) 0.875 0.514–1.488 .621 Independent variables Suspected catheter-related infections (sCRI), n = 69 No Yes Univariable analysese n = 520 n = 69 OR 95% CI p value Body mass index 26 [23–29] 27 [25–30] 1.040 0.993–1.089 .097 Male gender 281 (54) 52 (75) 2.602 1.465–4.619 .001 Total catheter days 27 [13–47] 28 [19–48] 1.002 0.995–1.010 .549 Number of needle passes 1 [1–2] 1 [1–2] 1.185 0.957–1.467 .120 Site of insertion Subclavian vein 380 (73) 53 (77) 1.220 0.675–2.205 .509 Internal jugular vein 135 (25) 15 (22) 0.792 0.433–1.450 .450 Number of lumens 1 [1–1) 1 [1–1] 0.685 0.470–1.000 .050 Arterial puncture 16 (23) 2 (3.0) 0.940 0.212–4.180 .936 Bleedingd 185 (36) 30 (43) 1.393 0.838–2.317 .202 Coagulopathyb 187 (36) 20 (29) 0.707 0.408–1.226 .217 Diagnosis AMLc at CVC insertion 246 (48) 42 (60) 1.733 1.037–2.895