Concerns have been raised by readers about the accuracy and validity of the data reported in the November 1, 2005, Journal of Clinical Oncology (JCO) article by Abdelkefi et al, entitled "Randomized Trial of Catheter-Related Bloodstream Infection by Continuous Infusion of Low-Dose Unfractionated Heparin in Patients With Hematologic and Oncologic Disease" (J Clin Oncol 23:7864–7870, 2005). When asked by JCO to provide evidence that the study was conducted, including primary source documents demonstrating that data were appropriately collected and analyzed, neither the authors nor the institution where the research took place was able to provide this information. Rather, the author informed JCO that the primary data were lost and not recoverable. Because JCO has no means of establishing the data or demonstrating that research results presented in this article are reproducible, JCO is publishing this Expression of Concern.

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Randomized Trial of Prevention of Catheter-Related Bloodstream Infection by Continuous Infusion of Low-Dose Unfractionated Heparin in Patients With Hematologic and Oncologic Disease

From the Centre National de Greffe de Moelle Osseuse; and Tunisia Institut National de la Santé Publique, Tunis, Tunisia

Address reprint requests to Abderrahman Abdelkefi, MD, Centre National de Greffe de Moelle Osseuse, Rue Jebel Lakhdar, 1006 Bab Saadoun, Tunis, Tunisie; e-mail: aabdelkefi{at}yahoo.fr

	ABSTRACT

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PURPOSE: Infection is a serious complication of central venous catheters in immunocompromised patients. Catheter-related infection may be caused by fibrin deposition associated with catheters. Interventions designed to decrease fibrin deposition have the potential to reduce catheter-related infections. The purpose of this study was to evaluate the role of low-dose unfractionated heparin in preventing catheter-related bloodstream infection in patients with hemato-oncological disease.

PATIENTS AND METHODS: This study was a randomized, controlled trial in which patients with nontunneled catheters were randomly assigned to receive either intravenous unfractionated heparin (continuous infusion of 100 U/kg per day) or 50 mL/day of normal saline solution as a continuous infusion (control group). Heparin was continued until the day of discharge. Catheter-related bloodstream infection was defined according to Infectious Disease Society of America guidelines.

RESULTS: Two hundred and eight patients were randomly assigned. Four patients were excluded after assignment. Ultimately, 204 patients were analyzed. Catheter-related bloodstream infection occurred in 6.8% (7 of 102 catheters) of those in the heparin group (2.5 events per 1,000 days) and in 16.6% (17 of 102 catheters) of those in the control group (6.4 events per 1,000 days) (P = .03). No other risk factors were found for the development of catheter-related bloodstream infection. Four and five patients experienced severe bleeding in the heparin and control groups, respectively (P = .2). We did not observe heparin-induced thrombocytopenia.

CONCLUSION: The use of continuous infusion of low-dose unfractionated heparin (100 U/kg per day) can be a practical and economical approach to the prevention of catheter-related bloodstream infection in patients with hemato-oncological disease.

	INTRODUCTION

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Central venous lines (CVLs) are commonly used in patients with hemato-oncological disease for indications such as monitoring of hemodynamics and administration of blood products, chemotherapy, parenteral nutrition, and infusion fluids.^1-5 Complications of catheterization include mechanical (arterial puncture, pneumothorax), thrombotic, and infectious complications.⁶

Studies have shown that catheter-related infection may be a result of fibrin deposition associated with catheters.^7-9 The relation of infection with fibrin deposition has been reported in experimental/in vitro studies.^7-9 Recently, Lordick et al¹⁰ showed in hemato-oncological patients a close correlation between catheter-related thrombosis and infection. Interventions designed to decrease fibrin deposition and thrombus formation have the potential to reduce catheter-related infections.

We have conducted a prospective randomized controlled trial to evaluate the role of low-dose unfractionated heparin (UFH) prophylaxis in preventing catheter-related bloodstream infection (CRBI) in patients with hemato-oncological disease.

	PATIENTS AND METHODS

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Study Design
This prospective randomized controlled study was conducted between May 2002 and June 2004 at the National Center for Bone Marrow Transplantation in Tunis, Tunisia. The study protocol was approved by the local medical ethical committee, and written informed consent was obtained from the patients or their legal representatives.

Patient Population
Patients were eligible for the study if they were between 4 and 60 years of age and had a nontunneled CVL. Exclusion criteria were the presence of a CVL at admission, a catheterization for less than 7 days, a contraindication to the use of subclavian catheterization because of major blood-coagulation disorders (ie, platelet count < 50 x 10⁹/L, disseminated intravascular coagulation), and an absence of catheter-tip culture at the time of catheter removal.

Randomization
Before CVL insertion, patients were randomly assigned to receive either prophylactic intravenous UFH (continuous infusion of 100 U/kg per day, with a maximal dose of 10,000 U/day) or 50 mL/day of normal saline solution as a continuous infusion (control group). UFH continued until the day of discharge. All CVLs were removed before discharge.

UFH was discontinued for any severe bleeding episode defined as CNS bleeding, which is bleeding that results in a decrease in hemoglobin of more than 2 g/dL in a 12-hour time period.

A platelet-transfusion threshold of 20 x 10⁹/L was adopted. Coagulation parameters (particularly partial thromboplastin time [PTT]) were routinely performed (twice a week). PTT-adjusted doses were not given.

CVL Characteristics
CVLs were externalized, nontunneled, polyurethane double-lumen catheters (Arrow International, Reading, PA). Catheter sizes were chosen appropriate to age (5- or 7-F diameter). The physician wore a mask, cap, sterile gloves, and surgical gowns and used large sterile drapes. The skin insertion site was disinfected with povidone iodine.

All CVLs were placed in the subclavian vein by infraclavicular approach by the same physician in the operating room. Catheters were inserted percutaneously by using the Seldinger technique.¹¹ The CVL tip was confirmed radiographically to lie in the superior vena cava. Study catheters were not exchanged over guidewires.

The insertion sites were covered with a transparent sterile dressing (Tegaderm; 3M Health Care Ltd, St Paul, MN). Catheter care included changing of the dressing under aseptic conditions every 6 days.

Microbiologic Methods
After rigorous antiseptic cleansing of the skin and the hub with povidone iodine, at least two sets of blood cultures were drawn in case of fever (> 38°C x 2 over at least 1 hour) and just before (< 1 hour) catheter removal. Blood samples for culture were obtained simultaneously from the catheter hub of the CVL and a peripheral vein. For each blood-culture set, a 20-mL blood sample was drawn aseptically and inoculated into aerobic and anaerobic bottles (Vital-Duo; bio-Mérieux, Marcy l'Etoile, France), immediately taken to the microbiology laboratory, and placed in the automatic positive-culture detector (Vital; bio-Mérieux).

The identity of isolates from peripheral and CVL positive blood cultures was assessed on the basis of colonial morphology, species identification, and identical antibiogram.

Catheters were removed aseptically, at the discretion of primary care physicians, if they were no longer needed or if infection was suspected. A 5-cm segment of the removed catheter tip was aseptically cut and delivered to the microbiology laboratory for quantitative culture according to Brun-Buisson et al.¹²

Definitions and Diagnosis
CRBI was defined according to Infectious Disease Society of America guidelines¹³: bacteremia or fungemia in a patient who has an intravascular device and 1 positive result of culture of blood samples obtained from the peripheral vein, clinical manifestations of infection (eg, fever, chills, and/or hypotension), no apparent source for bloodstream infection (with the exception of the catheter), and a positive result of quantitative ( 10² colony-forming units per catheter segment) catheter culture, whereby the same organism (species and antibiogram) is isolated from a catheter segment and a peripheral blood sample.

The principal investigator determined whether infections were catheter related and had no knowledge of "the assigned arm" at the time of adjudication of the reference standard definition.

Catheter-Related Thrombosis
In our study, all patients were systematically examined by ultrasonography just before, or less than 24 hours after, catheter removal and in case of clinical signs of thrombosis. Two radiologists performed the ultrasonography and were unaware of the allocation of the patients. In case of disagreement between the two radiologist, a third expert opinion was sought. The ultrasound examination was performed bilaterally. Clinical follow-up took place for 8 weeks after CVL removal.

Data Collection
Standardized data-collection forms were completed for all patients. These data included demographic characteristics, underlying disease, therapy, catheter-insertion and -removal date, body side of CVL location (right, left), body mass index, prior mediastinal irradiation, duration of insertion (in minutes), number of attempts at placement, mechanical complications, and use of catheter for administration of parenteral nutrition, asparaginase, and/or supportive care (transfusions, antibiotics).

Additional data recorded were the presence of local signs and symptoms of infection at the catheter-insertion site (eg, swelling, warmth, tenderness, or purulent discharge), the duration of fever, the neutrophil count on the day of insertion, the duration of neutropenia, signs of catheter-related thrombosis (eg, arm or neck pain, localized erythema, arm swelling, or dilated superficial collateral veins), bleeding events, and occurrence of heparin-induced thrombocytopenia (HIT).

The diagnosis of HIT was accepted in the case of either the demonstration of heparin-dependent immunoglobulin G (IgG) antibodies or, when this search could not be performed, the combination of the following features: (1) the absence of any other obvious clinical explanation for thrombocytopenia; (2) the occurrence of thrombocytopenia at least 5 days after heparin start; and (3) either the normalization of the platelet count within 10 days after heparin discontinuation or the earlier patient's death resulting from an unexpected thromboembolic complication.¹⁴

Statistics
We found that CRBI occurred in 20% of patients without heparin prophylaxis (unpublished observations). We estimated that only 5% of the catheters would present a CRBI in the case of UFH prophylaxis. Randomly assigning 85 patients to each group would allow detection of this difference in CRBI rate with 80% power and a two-tailed significance level of 5%. No interim analysis was performed.

Variables between heparin and control groups were compared by an uncorrected ² test or, when appropriate, Fisher's exact test for categorical variables and the Wilcoxon test for continuous variables. The same statistical tests were performed to identify the influence of age, sex, underlying disease, therapy, body side of CVL location (left, right), duration of insertion, number of attempts at placement, duration of catheterization, use of UFH prophylaxis, neutrophil count on the day of catheterization, duration of severe neutropenia (absolute neutrophil count < 0.5 x 10⁹/L), use of the catheter for administration of parenteral nutrition, and catheter-related thrombosis for the development of a CRBI.

Because randomization produced two groups of patients with comparable baseline characteristics, no indication of positive or negative confounding needed to be controlled for with multivariate-analysis models. Statistical significance was established at = .05. All P values are two-tailed.

	RESULTS

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Patient Population
A total of 210 consecutive patients were eligible (Fig 1) during the 26-month study period; 208 patients were randomly assigned (two refused random assignment). Four patients (2%) were excluded after assignment (two in the heparin group and two in the control group) because of catheter-insertion failure. Ultimately, 204 patients were analyzed.

View larger version (4K): [in this window] [in a new window]   Fig 1. Flow of patients through the trial. Two patients refused random assignment, and four patients experienced insertion failures.

CRBI occurred in 6.8% (7 CRBIs in 102 CVLs) of those in the heparin group (2.5 events per 1,000 days) and 16.6% (17 CRBIs in 102 CVLs) of those in the control group (6.4 events per 1,000 days) (P = .03). Prophylactic UFH significantly decreased CRBIs by 59% (relative risk, 0.41; 95% confidence interval, 0.18 to 0.95).

The microorganisms involved in CRBIs were coagulase-negative Staphylococcus (five cases in the heparin group and 10 cases in the control group), Staphylococcus aureus (one case in the control group), Candida albicans (one case in the heparin group), Pseudomonas aeruginosa (one case in the heparin group and one case in the control group), and Klebsiella oxytoca, Enterobacter cloacae, Escherichia coli, Stenotrophomonas maltophilia, and Corynebacterium spp (one case each, respectively, in the control group). Only one death (in the control group, from Stenotrophomonas maltophilia) was attributed to CRBI. The CVL was removed in all patients with CRBI, and an appropriate systemic antimicrobial therapy was administered. Choice and duration of antimicrobial therapy depended on the isolated pathogen, the resistance pattern, and the presence of complications such as deep-seated infections.

Incidence of Catheter-Related Thrombosis
Twelve catheter-related thromboses (12 of 204: two in the heparin group and 10 in the control group; P = .017) were observed. The median number of days between the insertion of the CVL and diagnosis of catheter-related thrombosis was 23 days (range, 9 to 35 days): heparin group, 25 days (range, 14 to 25); control group 23 days (range, 9 to 35). Catheter-related thrombosis and CRBI coincided in two patients and were not significantly correlated (P = .6) (Table 3).

Toxicity
Four and five patients experienced severe bleeding in the heparin and control groups, respectively (P = .7): (CNS bleeding [n = 1], gastrointestinal bleeding [n = 1], and hematuria [n = 2] in the heparin group, and CNS bleeding [n = 1[, hematuria [n = 3], and gastrointestinal bleeding [n = 1] in the control group). Only one patient, in the control group, died of severe bleeding (CNS bleeding).

The low-dose UFH (100 U/kg per day) that we used did not prolong the PTT and did not increase the red blood cell and platelet requirements. The median number of units of packed red blood cells was 6 (range, 0 to 56) and 8 (range, 0 to 65) in the heparin and control groups, respectively (P = .6). The median number of single-donor units of platelets was 5 (range, 0 to 43) and 6 (range, 0 to 47) in the heparin and control groups, respectively (P = .7).

Besides bleeding, there were no other adverse effects clearly ascribable to the use of UFH; particularly, there was no HIT. In the heparin group, only 10 patients (9.8%) have been tested for heparin-dependent IgG antibodies; none were detected. All patients in the heparin group developed a platelet decrease of at least 30%. Thrombocytopenia was explained as a reaction to chemotherapy. Furthermore, we noted a normalization of the platelet count in all cases without heparin discontinuation.

	DISCUSSION

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CVLs are an integral part of modern medical practice, and their advantages are beyond doubt. Nevertheless, data from the National Nosocomial Infection Surveillance system (United States) between January 1992 and February 1998 showed that CRBI is the third most frequent nosocomial infection and accounted for 14% of all nosocomial infections.¹⁵ CRBIs prolong hospital stays from 7 to 21 days and account for an estimated increase in hospital costs of $3,000 to $40,000 per patient.^16-18 In addition, an estimated 10% to 20% attributable mortality resulting from nosocomial CRBI has been reported.¹⁶

Besides the aseptic measures for both the insertion of the catheter and its maintenance, many different approaches have been attempted to decrease CVL infections: heparin-coated catheters,^19,20 antimicrobial- and antiseptic-impregnated CVLs,^21,22 and prophylactic urokinase administration.²³

The National Nosocomial Infection Surveillance system reported an average of 5.3 CRBIs per 1,000 catheter-days in a medical-surgical intensive care unit.²⁴ In our study, we observed 24 CRBIs (11.7%) in 204 CVLs. This represents an incidence of 4.2 episodes of CRBI per 1,000 catheter-days. The incidence of CRBIs per 1,000 catheter-days was 2.5 in the heparin group and 6.4 in the control group (P = .03).

Studies have shown that catheter-related infection may be a result of fibrin deposition associated with catheters.^7-9 Interventions designed to decrease fibrin deposition and thrombus formation have the potential to reduce catheter-related infections. Recently, Dillon et al²³ showed that urokinase administration every 2 weeks significantly reduced infectious events in external catheters compared with heparin administration.

Seven randomized studies^19,25-30 have been performed to assess the safety and efficacy of heparin (either as an infusion or bonded to CVL) on central venous CRBI. Although a meta-analysis³¹ of four studies^19,25-27 that looked at heparin as either an infusion or bonded to CVL showed a strong trend for a reduction in CRBI with the use of heparin, these studies used variable definitions of catheter-related infections.

In a recent randomized study, heparin-bonded CVLs reduced catheter-related bacteremia in critically ill children.²⁸ Nevertheless, there has been some concern expressed in the literature as to the duration that the heparin bonding exists and the degree to which the heparin elutes out of the catheter.

Another randomized trial²⁹ compared in critically ill children the incidence of CRBI between heparin-coated catheters and those coated with a synergistic combination of chlorhexidine and silver sulfadiazine. The incidence of CRBI per 1,000 catheter-days was 3.24 in heparin-coated catheters and 2.6 in chlorhexidine and silver sulfadiazine–coated catheters (P = .79).

Most of these studies have been in vitro,¹⁹ concerned critically ill patients,^28,29 or involved long-term tunneled CVLs.³⁰

Evidence-based data on anticoagulant prophylaxis in hematology patients with CVLs is limited. Indeed, clinicians are reluctant to prescribe anticoagulant prophylaxis routinely because of a concern for bleeding complications in this vulnerable population.

Our study is the first randomized trial that shows that a low dose of UFH (100 U/kg per day) is safe and effective to prevent CRBI (short-term nontunneled percutaneous CVLs) in patients with hemato-oncological disease.

Furthermore, the effectiveness of low-dose UFH prophylaxis, which is well known for hepatic veno-occlusive disease,³² has been demonstrated in the prevention of catheter-related thrombotic complications in a recent randomized study.³³ Indeed, there seems to be a close relationship between catheter-related thrombosis and infection.^10,34 However, data from this current study do not support this association.

After bleeding complications, HIT is the most important complication of UFH.^35,36 In our study, the prophylactic use of intravenous UFH (100 U/kg per day) in hemato-oncological patients did not cause additional bleeding or HIT.

Variables that may be significant for the development of CRBI (eg, age, sex, underlying disease, therapy, side of venous puncture, duration of insertion, number of veins punctured, duration of catheterization, neutrophil count on the day of catheterization, duration of severe neutropenia, use of catheter for administration of parenteral nutrition, and coexisting catheter-related thrombosis) were analyzed. The absence of UFH prophylaxis was the only risk factor for the development of CRBI.

In conclusion, the use of a continuous infusion of low-dose UFH (100 U/kg per day) can be a practical and economical approach to the prevention of CRBI in patients with hemato-oncological disease.

	Authors' Disclosures of Potential Conflicts of Interest

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The authors indicated no potential conflicts of interest.

	NOTES

 
Authors' disclosures of potential conflicts of interest are found at the end of this article.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
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29. Carrasco MN, Bueno A, de las Cuevas C, et al: Evaluation of a triple-lumen central venous heparin-coated catheter versus a catheter coated with chlorhexidine and silver sulfadiazine in critically ill patients. Intensive Care Med 30:633-638, 2004[CrossRef][Medline]

30. Henrickson KJ, Axtell RA, Hoover SM, et al: Prevention of central venous catheter-related infections and thrombotic events in immunocompromised children by the use of vancomycin/ciprofloxacin/heparin flush solution: A randomized, multicenter, double-blind trial. J Clin Oncol 18:1269-1278, 2000[Abstract/Free Full Text]

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33. Abdelkefi A, Ben Othman T, Kammoun L, et al: Prevention of central venous line-related thrombosis by continuous infusion of low-dose unfractionated heparin, in patients with haemato-oncological disease: A randomized controlled trial. Thromb Haemost 92:654-661, 2004[Medline]

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35. Hentschel R, Wiescholek U, Lengerke J von, et al: Coagulation-associated complications of indwelling arterial and central venous catheters during heparin prophylaxis: A prospective study. Eur J Pediatr 158:S126-129, 1999 [suppl 3]

36. Warkentin TE, Levine MN, Hirsh J, et al: Heparin-induced thrombocytopenia in patients treated with low-molecular-weight heparin or unfractionated heparin. N Engl J Med 332:1330-1335, 1995[Abstract/Free Full Text]

Submitted January 3, 2005; accepted July 27, 2005.

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