COPD, 00:16, 2013 ISSN: 1541-2555 print / 1541-2563 online Copyright Informa Healthcare USA, Inc. DOI: 10.3109/15412555.2013.

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ORIGINAL RESEARCH

Efcacy of Low Molecular Weight Heparin in Patients with Acute Exacerbation of Chronic Obstructive Pulmonary Disease Receiving Ventilatory Support
Yongbing Qian, Hui Xie, Rui Tian, Kanglong Yu, and Ruilan Wang
COPD Downloaded from informahealthcare.com by JHU John Hopkins University on 10/17/13 For personal use only. Department of Critical Care Medicine, Afliated First Peoples Hospital, Shanghai Jiao Tong University School of Medcine, Shanghai, China

Abstract
Introduction: Severe and acute exacerbation of chronic obstructive pulmonary disease (COPD) is associated with a high mortality. Since COPD is an airway inammatory disease, and heparin has shown anti-inammatory effects in previous studies, we evaluated the clinical effect of low molecular weight heparin (LMWH; nadroparin) in COPD patients admitted into the hospital due to acute exacerbations. Methods: Sixty-six patients admitted to the intensive care unit (ICU) were randomly divided into control group (n = 33) and LMWH group (n = 33). The control group received conventional treatment, including oxygen therapy (non-invasive or conventional mechanical ventilation), anti-infection, atomization expectorant, spasmolysis, anti-asthmatics, and nutritional support. The LMWH group received the same treatment plus LMWH for 1 week. The levels of plasma C-reactive protein, interleukin-6, and brinogen were measured. The main outcomes were duration of mechanical ventilation, length of ICU stay, and hospital stay. Results: There were no signicant differences between the groups with respect to demographics, severity of illness, and gas exchange variables. The levels of plasma C-reactive protein, interleukin-6, and brinogen were signicantly decreased in the LMWH group. LMWH signicantly reduced the mean duration of mechanical ventilation (6.6 days vs. 3.8 days; p < 0.01), the length of ICU stay (8.5 days vs. 5.6 days; p < 0.01) and hospital stay (14.3 days vs. 11.3 days; p < 0.01). Conclusions: The addition of LMWH to standard therapy benets COPD patients with acute exacerbation.

Introduction
Chronic obstructive pulmonary disease (COPD) is characterized by minimally reversible airow obstruction and progressive incapacity, and is the 4th leading cause of death worldwide (1). The prevalence of COPD is slowly rising in recent years; an epidemiologic study estimated a two-fold increase in deaths in the next 20 years (2). Acute exacerbation is the rst leading cause of decompensation, hospital admission, and death in patients with COPD (35). Heparin is a member of the glycosaminoglycans family, and one of the most often used anticoagulant drugs (6). Heparin is currently used to prevent and treat venous thrombosis and pulmonary embolism, arterial thrombosis in patients presenting with acute myocardial infarction. It prevents rethrombosis after thrombolysis, and prevents thrombosis in extracorporeal circuits and hemodialysis (7). Although heparin is primarily used as an 1

Keywords: low-molecular-weight heparin, inammation, chronic obstructive pulmonary disease, acute exacerbation Correspondence to: Ruilan Wang, Intensive Care Unit, Shanghai First peoples Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China, phone: 021-37798528, fax: 021-37798528, Email: wangruilan66@gmail.com

Qian et al. anticoagulant, it has shown anti-inammatory activities in experimental and clinical studies (8,9). Heparin may serve as an endogenous anti-inammatory molecule involved in the control and resolution of inammatory responses (10). Several clinical trials in various inammatory diseases support the anti-inammatory eect of heparin (1113). Heparin and related compounds have shown clinical benet to patients with bronchial asthma, ulcerative colitis, and burns (14). Given that COPD is an airway inammatory disease, we hypothesized that heparin may have some therapeutic benet in patients with acute exacerbation of COPD. The aim of the present study was to evaluate the eects of low molecular weight heparin (LWMH; nadroparin (5000 U per day 1 week, subcutaneously)) in COPD patients with acute exacerbation. Patients who were treated with non-invasive mechanical ventilation were considered to need tracheal intubation if they met any of the following criteria: pH < 7.20; pH = 7.207.25 on 2 separate measures 1 hour apart; hypercapnic coma (Glasgow Coma Scale = 8 and a PaCO2 = 60 mm Hg); a PaO500 < 45 mm Hg despite a maximum tolerated fraction of inspired oxygen; and/or cardiac arrest (16). Patients with conventional mechanical ventilation were screened each morning to assess recovery from respiratory failure and to determine whether or not they should be weaned from mechanical ventilation. In patients with non-invasive mechanical ventilation, weaning was considered successful if after at least 3 hours of breathing without ventilator assistance the following criteria were met: an arterial oxygen saturation > 90% with a fraction of inspired oxygen < 40%; a pH > 7.35; and a respiratory rate < 35 breaths/min. C-reactive protein was measured using an automated clinical analyzer (Abbott Architect ci8200; Abbott Laboratories, Abbott Park, IL, USA) with the minimum detectable concentration of 5 mg/L. IL-6 levels were measured using the Quantikine Highsensitivity ELISA Commercial Kit (R&D Systems, Minneapolis, MN, USA) with the minimum detectable concentration of 0.039 pg/mL. Fibrinogen was assessed using a coagulation analyzer (Sysmex CA-7000; DadeBehring) according to the Clauss method and calculated from ethylenediamine tetra-acetic acid to citrate plasma values with the minimum detectable concentration of 0.3 g/L.

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Methods
Subjects Sixty-six patients with acute exacerbation of COPD were enrolled in this study. The eligible subjects should be older than 50 years, with at least 10 packyears smoking history, a FEV1 < 60% predicted at the time of inclusion or an inability to perform spirometry due to dyspnea, and an admitting diagnosis of acute exacerbation of COPD (dened as an acute increase in dyspnea, sputum volume, and/or sputum purulence without other attributable cause). Patients were excluded if they had acute heart failure, abnormal coagulation function, severe immune dysfunction, liver or kidney failure. The study was approved by the Medical Ethics Committee for Clinical Trials at Shanghai First Peoples Hospital of Shanghai Jiaotong University, which complied with the ethical guidelines of the 1975 Declaration of Helsinki. Informed consent was obtained from each patient before the study. Study design and protocol Sixty-six patients were randomized into the standard therapy group (control group) or LMWH plus standard therapy group (LMWH group) with equal number. At the time of admission, all subjects received the standardized therapy, including non-invasive ventilation, albuterol and ipratropium bromide, nutritional support, and antibiotics (15). Patients were then randomized using blocks of two randomization protocol into control group receiving standardized therapy and the LMWH group receiving standardized therapy plus nadroparin (5000 U daily 1 week subcutaneously, the prophylactic dose). Each eligible patient was sequentially assigned to either treatment group according to a randomization table generated in advance by our in-house statisticians. The study design was open-labeled, and the treatment assignment was not blind to the investigators, attending physicians, nurses, or patients.

Statistical analysis Continuous variables were expressed as the mean standard deviation and compared between groups using the Students t-test, and variables with a non-normal distribution were compared with the MannWhitney test. Categorical variables were compared with 2 test or Fishers exact test. All statistical analyses were performed using statistical software (SPSS 14.0; SPSS, Inc., Chicago, IL, USA). Statistical signicance was dened as p < 0.05.

Results
COPD is associated with cigarette smoking and old age (17); therefore, all recruited patients were older than 50 years with 10 years of smoking history. The patient demographics and baseline characteristics are summarized in Table 1. There was no signicant dierence in the baseline values between the two treatment groups, including age, gender, weight, height, smoking history, baseline PaO2, baseline PaCO2, and SAPS II score. All of the patients in LMWH group completed the 1-week treatment, and no death occurred during this period. The plasma C-reactive protein levels decreased over time in the LMWH group and were signicantly lower
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Efcacy of LMWH with AECOPD LMWH group on day 3 (p < 0.01) compared to the control group (Figure 1). The clinical outcomes were summarized in Table 2. Compared to the standard therapy (control group), treatment with LMWH plus standard therapy (LMWH group) signicantly reduced the mean duration of mechanical ventilation (6.6 days vs. 3.8 days; p < 0.01), the length of ICU stay (8.5 days vs. 5.6 days; p < 0.01) and hospital stays (14.3 days vs. 11.3 days; p < 0.01). Failure of non-invasive mechanical ventilation was not signicantly reduced in LMWH group (13% vs. 22%; p = 0.39). In-ICU mortality was similar in the LMWH and control groups (9% vs. 12%; relative risk, 1.37; 95% CI, 0.153.52; p = 0.69). There was no dierence in the incidence of adverse eects between these two groups. No thromboenblic or major bleeding events occurred in either group, but clinically signicant non-major bleeding events were found in 1 patient (3.0%) in the LWMH group and in 2 (6.1%) in the control group (95% CI, 0.045.61; p = 0.55). All non-major bleeding events were hematomas at the injection site. In LMWH group, 23 patients (22/23) were treated with non-invasive mechanical ventilation (NIMV) and 10 patients (10/23) with conventional mechanical ventilation (CMV), compared to 22 patients (22/33) with

Table 1. Baseline characteristics of the 66 patients according to treatment assignment Control Characteristics Age, years Sex, male/female Weight, Kg Height, cm Smokers, current/former Baseline PaO2, mmHg Baseline PaCO2, mmHg SAPS II (n = 33) 66.3 6.3 19/14 60.3 8.7 167.0 8.4 22/11 62.5 7.4 91.0 11.3 36.2 5.2 LMWH (n = 33) 65.5 4.5 18/15 58.9 5.4 164.5 6.5 16/17 64.2 7.7 90.5 12.9 34.7 4.7 p-Value 0.56 0.80 0.43 0.18 0.14 0.35 0.85 0.22

Data are presented as mean SD; PaO2, oxygen tension in arterial blood; PaCO2, carbon dioxide tension in arterial blood.

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than the control group on days 3 (p < 0.01) and 6 (p < 0.01). The IL-6 levels were signicantly lower in the LMWH group on days 3 (p = 0.00) and 6 (p = 0.00) compared to the control group. The brinogen levels were signicantly lower in the LMWH group on days 3 (p = 0.02) and 6 (p < 0.01) compared to the control group. The white blood cell count was signicantly lower in the

Figure 1. Mean levels of C-reactive protein (CRP) (A), Interleukin-6 (IL-6) (B), Fibrinogen (C) and white blood cell count (WBC) (D) at selected time points after treatment. The error bars indicates standard errors. (*p < 0.05, and **p < 0.01, for comparison with control group). www.copdjournal.com

Qian et al.

Table 2. Outcome measures Control Outcome Duration of mechanical ventilation, d NIMV CMV Length of ICU stay, d NIMV CMV Length of hospital stay, d NIMV CMV In-ICU mortality, No. (%) COPD Downloaded from informahealthcare.com by JHU John Hopkins University on 10/17/13 For personal use only. NIMV CMV Failure of NIMV, No. (%) (n = 33) 6.6 3.7 4.9 1.8 (n = 22) 9.7 4.3 (n = 11) 8.5 3.0 7.2 1.8 (n = 22) 11.4 3.1 (n = 11) 14.3 3.8 13.0 3.4 (n = 22) 16.8 3.1 (n = 22) 4/33 1/22 (n = 22) 3/11 (n = 11) 5/22 LMWH (n = 33) 3.8 2.2 3.0 0.9 (n = 23) 5.7 3.1 (n = 10) 5.6 1.8 4.8 0.7 (n = 23) 7.4 2.3 (n = 10) 11.3 2.0 10.6 1.7 (n = 23) 13.1 1.7 (n = 10) 3/33 1/23 (n = 23) 2/10 (n = 10) 3/23 p-Value 0.001 0.000 0.026 0.000 0.000 0.004 0.000 0.004 0.003 0.689 0.974 0.696 0.396

Data are presented as mean SD unless specied otherwise. CMV, Convention mechanical ventilation; NIMV, noninvasive mechanical ventilation; ICU, intensive care unit.

NIMV and 11 patients (11/33) with CMV in control group. The clinical outcomes in each subgroup were summarized in Table 2. Either in NIMV or CMV subgroup, the mean duration of mechanical ventilation, the length of ICU stay, and hospital stays were signicantly reduced in LMWH group compared to the control group.

Discussion
This study evaluated the eects of LMWH in addition to the standard treatment in COPD patients with acute exacerbations. The results demonstrated that 1 week of LMWH treatment had a positive anti-inammatory eect, as evidenced by decreased CRP, IL-6, and brinogen levels. The length of ICU and hospital stays were also reduced. Airway and systemic inammation occurs in patients with COPD (18). Stable COPD is associated with low-grade systemic inammation manifested by an increase in blood leukocyte count, acute-phase proteins (CRP and brinogen), and inammatory cytokines (1921). IL-6 and acute-phase proteins levels further increase during acute exacerbations of COPD and decline again during the recovery (20, 22). Clinical studies and animal experiments found an increase in the expression of neutrophil adhesion molecules and changes in neutrophil functions (2325). Heparin modulates some of the pathophysiologic eects of endotoxin and TNF-, such as neutrophil migration, edema formation, pulmonary hypertension, and hypoxemia (26). In addition, heparin has been shown to suppress specic neutrophil functions, such as superoxide generation and chemotaxis in vitro, and eosinophil migration (27). One of the proposed mechanisms underneath the anti-inammatory

actions of heparin is the binding of glycosaminoglycan to adhesion molecules on the surface of activated ECs (endocytes) and/or leukocytes (26). Heparin inuences immunologic responses and inhibits L- and P-selectin-mediated adhesion and TNF- production by macrophages (26, 28). Several recent studies have demonstrated the anti-inammatory activity of heparin (29, 30). In animal models, heparin disaccharide inhibits TNF- production by macrophages and decreases the immune inammation (2931). The antiinammatory activity of heparin has been conrmed by small clinical trials involving patients with a range of inammatory diseases, including rheumatoid arthritis, bronchial asthma and inammatory bowel disease (3235). A hypercoagulable state exists in COPD patients; therefore heparins anti-coagulant eect may add more benet to COPD patients (36). Thus, heparin may have both anti-inammatory and anticoagulant eects. In 2006, Brown et al. (37) reported that subcutaneously administrated LMWH (enoxaparin) once daily for 12 weeks in combination with conventional therapy provide additional clinical benet, such as blood gas tension, dyspnea, and supplemental salbutamol use, to COPD patients (37). Most recently, Shi et al. (38) reported that addition of LMWH to the conventional therapy (oxygen inhalation, spasmolysis, asthma relief, cough relief and sputum reduction) signicantly improves the pulmonary functions in COPD patients with acute exacerbation. Our study showed that 1 week administration of heparin in combination with conventional therapy reduced the inammatory molecules levels and the hospital and ICU stay of COPD patients with acute exacerbation, further supporting the clinical benet of heparin in COPD.
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Efcacy of LMWH with AECOPD This study is the rst eort to evaluate the ecacy of a LMWH (nadroparin) in COPD patients with acute exacerbations in combination with standard therapy. Our observations suggest that further investigation is warranted to evaluate the use of heparin and related drugs in the treatment of COPD patients with acute exacerbations.
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Acknowledgment
Thanks to the Shanghai Young Physician Training Fund sponsored by Shanghai Medicine and Health Development Foundation for sponsorship to Y.Q.

Declaration of Interest Statement

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The authors report no conicts of interest. The authors alone are responsible for the content and writing of the paper.

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