Heparin nebulization attenuates acute lung injury in sepsis following smoke inhalation in sheep

Pseudomonas pneumonia is a common complication of smoke inhalation injury. Airway casts formed from clotted mucous occur frequently in this condition. A recent report shows that intravenous heparin improves oxygenation and reduces lung damage in a sheep model of smoke inhalation. We hypothesized that nebulized heparin could be an effective means of reducing cast formation. Female sheep (n = 19) were surgically prepared for a study of acute lung injury (ALI). After a tracheotomy, 48 breaths of cotton smoke (<40 degrees C) were inflated into the airway. Afterwards, live Pseudomonas aeruginosa (5 x 10(11) CFU) was instilled into the lung. All sheep were mechanically ventilated with 100% O2 and were divided into four groups: a heparin-nebulized group (n = 5; animals received aerosolized heparin [10,000 I.U.] 1 h after the bacterial instillation and subsequently every 4 h thereafter), an intravenous heparin group (n = 5,300 U/kg/23 h, infusion was started 1 h after the injury), a saline-nebulization group (n = 5; animals received inhaled nebulized saline), and a sham injury group (n = 4, treated in the same fashion, but no injury). The animals were sacrificed after 24 h of mechanical ventilation, and lung samples were harvested. Sheep exposed to lung injury presented with typical hyperdynamic cardiovascular changes and a corresponding drop in PaO2. These changes were significantly attenuated in the heparin groups. Histological changes consisting of cellular infiltrates, lung edema, congestion, and cast formation were reduced by heparin. These data suggest that nebulized inhaled heparin is a beneficial therapy for sepsis-induced ALI.     

Nebulized anticoagulants limit coagulopathy but not inflammation in pseudomonas aeruginosa-induced pneumonia in rats

Disturbed alveolar fibrin turnover is a characteristic feature of pneumonia. Inhibitors of coagulation could exert lung-protective effects via anticoagulant (inhibiting fibrin deposition) and possibly anti-inflammatory pathways, but could also affect host defense. In this randomized controlled in vivo laboratory study, rats were challenged intratracheally with Pseudomonas aeruginosa, inducing pneumonia, and randomized to local treatment with normal saline (placebo), recombinant human activated protein C (rh-APC), plasma-derived antithrombin (AT), heparin, or danaparoid. Induction of P. aeruginosa pneumonia resulted in activation of pulmonary coagulation and inhibition of pulmonary fibrinolysis, as reflected by increased pulmonary levels of thrombin-AT complexes and fibrin degradation products and decreased pulmonary levels plasminogen activator activity. Pseudomonas aeruginosa pneumonia was accompanied by systemic coagulopathy, since systemic levels of thrombin-AT complexes increased, and systemic levels of plasminogen activator activity decreased. Although rh-APC and plasma-derived AT potently limited pulmonary coagulopathy, neither heparin nor danaparoid affected net pulmonary fibrin turnover. Recombinant human APC also displayed systemic anticoagulant effects. Neither bacterial clearance nor pulmonary inflammation was affected by anticoagulant therapy. Nebulization of rh-APC or plasma-derived AT attenuated pulmonary coagulopathy, but not bacterial clearance or inflammation, in a rat model of P. aeruginosa pneumonia.     

Heparin/N-acetylcysteine: An adjuvant in the management of burn inhalation injury : A study of different doses

Purpose

Nebulized heparin may reduce fibrin cast formation and reduce the degree of airway obstruction in burn inhalation injury.

Methods

Twenty-nine patients admitted to burn intensive care unit (ICU) within 24 hours of burn inhalation injury were included in this prospective double-blinded randomized study. Group H5 received nebulized heparin sulfate 5,000 IU, and group H10 received nebulized heparin sulfate 10,000 IU. Heparin was given in alternation with N-acetylcysteine every 2 hours. Lung injury score assessed daily for 7 days was the primary outcome. Duration of mechanical ventilation, coagulation profile, length of ICU stay, and mortality were the secondary outcomes.

Results

Median lung injury scores were significantly lower in group H10 on days 5 (1.9 vs 1), 6 (1.4 vs 0.5), and 7 (1.3 vs 0.5). Group H10 had also a lower duration of mechanical ventilation than did group H5 (P = .037). The groups had no significant difference in coagulation parameters, length of ICU stay (P = .17), and mortality (P = .6).

Conclusions

Nebulized heparin 10,000 IU decreased lung injury scores and duration of mechanical ventilation but had no effect on length of ICU stay and mortality. Moreover, nebulized heparin 10,000 IU was safe and had no effect on coagulation parameters.     

Bronchoalveolar hemostasis in lung injury and acute respiratory distress syndrome

Summary. Enhanced intrapulmonary fibrin deposition as a result of abnormal broncho‐alveolar fibrin turnover is a hallmark of acute respiratory distress syndrome (ARDS), pneumonia and ventilator‐induced lung injury (VILI), and is important to the pathogenesis of these conditions. The mechanisms that contribute to alveolar coagulopathy are localized tissue factor‐mediated thrombin generation, impaired activity of natural coagulation inhibitors and depression of bronchoalveolar urokinase plasminogen activator‐mediated fibrinolysis, caused by the increase of plasminogen activator inhibitors. There is an intense and bidirectional interaction between coagulation and inflammatory pathways in the bronchoalveolar compartment. Systemic or local administration of anticoagulant agents (including activated protein C, antithrombin and heparin) and profibrinolytic agents (such as plasminogen activators) attenuate pulmonary coagulopathy. Several preclinical studies show additional anti‐inflammatory effects of these therapies in ARDS and pneumonia.     

Heparin, thrombin and Factor Xa inhibitors

Direct and indirect coagulation inhibitors are used to inhibit the activity of the serine proteases of the coagulation system. Indirect inhibitors act via antithrombin and heparin cofactor II. The main representatives are heparins, lowmolecular-weight heparins, fondaparinux, idraparinux and danaparoid. They bind to antithrombin and potentiate the inactivation of factor Xa and other serine proteases. Direct thrombin inhibitors bind reversibly to thrombin without cofactor. Anticoagulants are determined by global and specific anticoagulant methods. New anticoagulants are developed such as oral factor Xa inhibitors, oral thrombin inhibitors, antibody against activated factor VII, recombinant tissue pathway inhibitor to improve inhibition of blood coagulation or to induce nonanticoagulant effects (e. g. activated protein C in septicaemia). New anticoagulant methods are developed to improve and specify the anticoagulant effect of anticoagulants in thromboembolic diseases.     

Pulmonary coagulopathy as a new target in therapeutic studies of acute lung injury or pneumonia--a review

OBJECTIVES: To review the involvement of coagulation and fibrinolysis in the pathogenesis of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS), pulmonary infection, and ventilator-induced lung injury (VILI). DATA SOURCE: Published articles on experimental and clinical studies of coagulation and fibrinolysis in ALI/ARDS, pneumonia, and mechanical ventilation. CONCLUSIONS: Alveolar fibrin deposition is an important feature of ALI/ARDS and pulmonary infection. The mechanisms that contribute to disturbed alveolar fibrin turnover are localized tissue factor-mediated thrombin generation and depression of bronchoalveolar urokinase plasminogen activator-mediated fibrinolysis, caused by the increase of plasminogen activator inhibitors. These effects on pulmonary coagulation and fibrinolysis are regulated by various proinflammatory cytokines and are similar to those found in the intravascular spaces during severe systemic inflammation. Some studies also suggest that pulmonary coagulopathy is a feature of VILI. Recent studies have demonstrated the beneficial effect of anticoagulant therapy in sepsis. Theoretical considerations suggest that this anticoagulant therapy will benefit patients with primary lung pathology including VILI, but clinical studies are needed to examine this hypothesis before such therapy is to be advocated as a standard of care in critically ill patients.     

Aerosolized alpha-tocopherol ameliorates acute lung injury following combined burn and smoke inhalation injury in sheep

Victims of fire accidents who sustain both thermal injury to the skin and smoke inhalation have gross evidence of oxidant injury. Therefore, we hypothesized that delivery of vitamin E, an oxygen superoxide scavenger, directly into the airway would attenuate acute lung injury postburn and smoke inhalation. Sheep (N = 17 female, 35 +/- 5 kg) were divided into 3 groups: (1) injured, then nebulized with vitamin E (B&S, Vitamin E, n = 6); (2) injured, nebulized with saline (B&S, Saline, n = 6); and (3) not injured, not treated (Sham, n = 5). While under deep anesthesia with isoflurane, the sheep were subjected to a flame burn (40% total body surface area, 3rd degree) and inhalation injury (48 breaths of cotton smoke, <40 degrees C). All groups were resuscitated with Ringer lactate solution (4 mL/kg/%burn/24 h) and placed on a ventilator [positive end-expiratory pressure (PEEP) = 5 cm H2O, tidal volume = 15 mL/kg] for 48 h. B&S injury halved the lung alpha-tocopherol concentrations (0.9 +/- 0.1 nmol/g) compared with sham-injured animals (1.5 +/- 0.3), whereas vitamin E treatment elevated the lung alpha-tocopherol concentrations (7.40 +/- 2.61) in the injured animals. B&S injury decreased pulmonary gas exchange (PaO2/FiO2 ratios) from 517 +/- 15 at baseline to 329 +/- 49 at 24 h and to 149 +/- 32 at 48 h compared with sham ratios of 477 +/- 14, 536 +/- 48, and 609 +/- 49, respectively. Vitamin E treatment resulted in a significant improvement of pulmonary gas exchange; ratios were 415 +/- 34 and 283 +/- 42 at 24 and 48 h, respectively. Vitamin E nebulization therapy improved the clinical responses to burn and smoke inhalation-induced acute lung injury.     

Nebulised heparin: a new approach to the treatment of acute lung injury?

The administration of heparin by nebulisation has been proposed for the 'local' treatment of pulmonary coagulation disturbances in acute lung injury (ALI). Alveolar and lung micro-vascular fibrin accumulation and breakdown inhibition indeed play a central role in the development and clinical course of this disease. Preclinical studies provide some evidence of the beneficial effects of heparin inhalation in several animal models of ALI. Clinical investigations are sparse, and trials such as the one presented by Dixon and colleagues in a recent issue of Critical Care are welcome as they provide insight into the possible clinical use of nebulised heparin in this situation. This phase 1 trial involved 16 patients with early ALI, and showed the feasibility of the approach. In addition, non-significant changes in respiratory functions and systemic anticoagulant effects were documented with the four doses tested. The study of Dixon and colleagues adds to data that helps pave the way towards a possible clinical use of heparin by nebulisation in ALI. It remains to be clarified in which clinical situations, at what time points and with which dosages the best chances exist for a beneficial effect on the prognosis of these patients.     

Combined anticoagulants ameliorate acute lung injury in sheep after burn and smoke inhalation

Burn and smoke inhalation-related multiple organ dysfunction is associated with a severe fall in the plasma concentration of antithrombin. Therefore the aim of the present study was to test the hypothesis that intravenous administration of recombinant human antithrombin in combination with aerosolized heparin will ameliorate acute lung injury in sheep exposed to cutaneous burn and smoke inhalation. Sheep were prepared operatively for study and, 7 days post-surgery, sheep were given a cutaneous burn (40% of total body surface area, third-degree burn) and insufflated with cotton smoke (48 breaths, <40 degrees C) under halothane anaesthesia. After injury, sheep were placed on a ventilator and resuscitated with Ringer's lactate solution. The animals were divided into three groups: sham group (non-injured and non-treated; n=6), saline group (injured and received saline; n=6) and rhAT.iv.+Hep group [injured and treated with rhAT (recombinant human antithrombin) and heparin; n=6]. In the rhAT.iv.+Hep group, rhAT was infused continuously for 48 h starting 1 h post-injury with a dose of 0.34 mg.h(-1).kg(-1) of body weight and heparin (10000 units) was aerosolized every 4 h starting at 1 h post-injury. The experiment lasted 48 h. Haemodynamics were stable in sham group, whereas the saline-treated sheep developed multiple signs of acute lung injury, including decreased pulmonary gas exchange, increased inspiratory pressures, extensive airway obstruction and increased pulmonary oedema. These pathological changes were associated with a severe fall in plasma antithrombin concentration, lung tissue accumulation of leucocytes and excessive production of NO. Treatment of injured sheep with anticoagulants attenuated all of the pulmonary pathophysiology observed. In conclusion, the results provide definitive evidence that anticoagulant therapy may be a novel and effective treatment tool in the management of burn patients with concomitant smoke inhalation injury.     

Aerosolized anticoagulants ameliorate acute lung injury in sheep after exposure to burn and smoke inhalation

OBJECTIVE: Acute lung injury is a detrimental complication for victims of burn accidents. Airway obstruction plays an important role in pulmonary dysfunction in these patients. In this study, we tested the hypothesis that aerosolized anticoagulants will reduce the degree of airway obstruction and improve pulmonary function in sheep with severe combined burn and smoke inhalation injury by preventing the formation of airway fibrin clots. DESIGN: Prospective, randomized, controlled, experimental animal study. SETTING: Investigational intensive care unit at a university hospital. SUBJECTS: Adult female sheep. INTERVENTIONS: After 7 days of surgical recovery, sheep were given a cutaneous burn (40% of total body surface, third degree) and insufflated with cotton smoke (48 breaths, <40 degrees C) under halothane anesthesia. After injury, sheep were placed on ventilators and resuscitated with lactated Ringer's solution. Sheep were randomly divided into five groups: sham, noninjured and nontreated (n = 6); control, injured and aerosolized with saline (n = 6); recombinant human antithrombin (rhAT) + heparin, injured and aerosolized with rhAT (290 units for each) and heparin (10,000 units for each) (n = 6); rhAT, injured and aerosolized with rhAT alone (290 units for each; n = 5); and heparin, injured and aerosolized with heparin alone (10,000 units for each; n = 5). rhAT and heparin were aerosolized every 4 hrs, starting at 2 hrs postinjury. MEASUREMENTS AND MAIN RESULTS: Cardiopulmonary hemodynamics were monitored during a 48-hr experimental time period. Control sheep developed multiple signs of acute lung injury. This pathophysiology included decreased pulmonary gas exchange and lung compliance, increased pulmonary edema, and extensive airway obstruction. These variables were stable in sham animals. The aerosolization of rhAT or heparin alone did not significantly improve deteriorated pulmonary gas exchange. However, aerosolization of these anticoagulants in combination significantly attenuated all the observed pulmonary pathophysiology. CONCLUSIONS: The results provide definitive evidence that aerosolized rhAT and heparin in combination may be a novel treatment strategy for pulmonary pathology in burn victims with smoke inhalation injury.     

Nebulized antibiotics in mechanically ventilated patients: roadmap and challenges

Introduction: Nebulized antibiotics use has become common practice in the therapeutics of pneumonia in cystic fibrosis patients. There is an increasing interest in their use for respiratory infections in mechanically ventilated (MV) patients in order to a) overcome pharmacokinetic issues in the lung compartment with traditional systemic antibiotic use and b) prevent the emergence of multi-drug-resistant (MDR) pathogens.

Areas covered: The beneficial effects of antibiotic nebulization in MV patients e.g. increasing efficacy, reduced toxicity and prevention of resistance are described. Physicochemical parameters of optimal lung deposition, characteristics of currently available nebulizers, practical aspects of the procedure, including drug preparation and adjustments of ventilator and circuit parameter are presented. Antibiotics used in nebulized route, along with efficacy in various clinical indications and safety issues are reviewed.

Expert commentary: The safety of nebulization of antibiotics has been proven in numerous studies; efficacy as adjunctive treatment to intravenous regimens or as monotherapy has been demonstrated in ventilator-associated pneumonia or ventilator-associated tracheobronchitis due to MDR or susceptible pathogens. However, due to the heterogeneity of studies, multiple meta-analyses fail to demonstrate a clear effect. Clarification of indications, standardization of technique and implementation of clinical practice guidelines, based on new large-scale trials will lead to the optimal use of nebulized antibiotics.     

Coagulopathy and its management in patients with severe burns

Severe burn injury is associated with systemic coagulopathy. The changes in coagulation described in patients with severe burns resemble those found patients with sepsis or major trauma. Coagulopathy in patients with severe burns is characterized by procoagulant changes, and impaired fibrinolytic and natural anticoagulation systems. Both the timing of onset and the severity of hemostatic derangements are related to the severity of the burn. The exact pathophysiology and time course of coagulopathy are uncertain, but, at least in part, result from hemodilution and hypothermia. As the occurrence of coagulopathy in patients with severe burns is associated with increased comorbidity and mortality, coagulopathy could be seen as a potential therapeutic target. Clear guidelines for the treatment of coagulopathy in patients with severe burns are lacking, but supportive measures and targeted treatments have been proposed. Supportive measures are aimed at avoiding preventable triggers such as tissue hypoperfusion caused by shock, or hemodilution and hypothermia following the usually aggressive fluid resuscitation in these patients. Suggested targeted treatments that could benefit patients with severe burns include systemic treatment with anticoagulants, but sufficient randomized controlled trial evidence is lacking.     

Alternatives to unfractionated heparin for anticoagulation in cardiopulmonary bypass

Despite the progress made in the development of cardiopulmonary bypass (CPB) equipment, systemic anticoagulation with unfractionated heparin and post-bypass neutralization with protamine are still used in most perfusion procedures. However, there are a number of situations where unfractionated heparin, protamine or both cannot be used for various reasons. Intolerance of protamine can be addressed with extracorporeal heparin removal devices, perfusion with (no) low systemic heparinization and, to some degree, by perfusion with alternative anticoagulants. Various alternative anticoagulation regimens have been used in cases of intolerance to unfractionated heparin, including extreme hemodilution, low molecular weight heparins, danaparoid, ancrod, r-hirudin, abciximab, tirofiban, argatroban and others. In the presence of heparin-induced thrombocytopenia (HIT) and thrombosis, the use of r-hirudin appears to be an acceptable solution which has been well studied. The main issue with r-hirudin is the difficulty in monitoring its activity during CPB, despite the fact that ecarin coagulation time assessment is now available. A more recent approach is based on selective blockage of platelet aggregation by means of monoclonal antibodies directed to GPIIb/IIIa receptors (abciximab) or the use of a GPIIb/IIIa inhibitor (tirofiban). An 80% blockage of the GPIIb/IIIa receptors and suppression of platelet aggregation to less than 20% allows the giving of unfractionated heparin and running CPB in a standard fashion despite HIT and thrombosis. Likewise, at the end of the procedure, unfractionated heparin is neutralized with protamine as usual and donor platelets are transfused if necessary. GPIIb/IIIa inhibitors are frequently used in interventional cardiology and, therefore, are available in most hospitals.     

Effects of manganese superoxide dismutase nebulization on pulmonary function in an ovine model of acute lung injury

Smoke inhalation injury is a major cause of morbidity and mortality in thermally injured individuals. There is evidence of increased oxygen free radical activity, e.g., superoxide, in association with smoke inhalation injury. Because superoxide dismutase converts the reactive superoxide radical to peroxide, we hypothesized that nebulization of manganese superoxide dismutase (Mn-SOD) into the airway might attenuate pulmonary dysfunction secondary to smoke inhalation injury. The present study was designed as a prospective, controlled, and randomized laboratory experiment to determine the effects of aerosolized Mn-SOD on lung fluid balance, as indexed by changes in pulmonary microvascular permeability, lung lymph flow (Q(L)), and gas exchange in an established and clinically relevant ovine model of smoke inhalation injury. Fifteen female Merino sheep were chronically instrumented with a femoral arterial, a Swan-Ganz, and a left atrial catheter. In addition, the right caudal mediastinal lymph node was cannulated to measure Q(L) (mL.h(-1)). Pneumatic occluders were placed around the right pulmonary veins for the determination of the reflection coefficient (sigma). After 7 days of recovery, sheep were randomly allocated to (a) an untreated control group (4 groups of 12 breaths of cotton smoke), (b) an injured group treated with nebulized Mn-SOD (5 mg/kg), and (c) an injured group that received only the vehicle (nebulized saline). Nebulization was performed 1 h and 12 h after smoke inhalation. Mn-SOD nebulization attenuated the increase in both filtration coefficient and sigma and significantly decreased lung tissue conjugated dienes. However, there were no differences in Q(L), PaO2/FiO2 ratio, and bloodless lung wet/dry weight ratio between groups. Although Mn-SOD nebulization attenuated the loss of protein, it failed to improve lung edema and pulmonary gas exchange, thereby limiting its clinical use.     

Nebulized antithrombin limits bacterial outgrowth and lung injury in Streptococcus pneumoniae pneumonia in rats

Introduction  

Disturbed alveolar fibrin turnover is a cardinal feature of severe pneumonia. Clinical studies suggest that natural inhibitors of coagulation exert lung-protective effects via anticoagulant and possibly also anti-inflammatory pathways. Intravenous infusion of the natural anticoagulants increases the risk of bleeding. Local administration may allow for higher treatment dosages and increased local efficacy while at the same time reducing the risk of bleeding. We evaluated the effect of nebulized anticoagulants on pulmonary coagulopathy and inflammation in a rat model of Streptococcus pneumoniae pneumonia.     

重度烟雾吸入致大鼠急性肺损伤的免疫应答及其机制探讨

目的分析重度烟雾吸入致吸人性急性肺损伤(ALI)对大鼠肺自然免疫及特异性免疫反应。方法分别复制一氧化碳(CO)浓度为2×10~(-3)(低浓度)和4×10~(-3)(高浓度)重度烟雾吸入致大鼠吸人性ALI模型。观察染毒后0～24 h大鼠肺组织病理学变化;检测支气管肺泡灌洗液(BALF)中致炎及抗炎细胞因子的浓度;用流式细胞仪检测外周血及BALF中淋巴细胞亚群数,BALF中CD45~+淋巴细胞和非淋巴细胞数量以及CD4~+/CD8~+变化。结果肺组织病理学检查证实染毒后可致明显肺损伤。染毒2 h BALF中肿瘤坏死因子-α(TNF-α)呈一过性升高,高浓度组较低浓度组更明显,之后下降;4 h白细胞介素-6(IL-6)、γ-干扰素(IFN-γ)开始升高,其中IL-6低浓度组较高浓度组明显,IFN-γ高浓度组较低浓度组明显,至12 h达高峰,24 h开始下降,但仍高于正常对照组水平(P＜0．05或P＜0．01);6～24 h IL-10与正常对照组比较均显著升高,尤以24 h明显(P＜0．05或P＜0．01)。外周血及BALF中CD4~+、CD8~+、自然杀伤细胞、B细胞及总T细胞均较正常对照组明显下降(P＜0．05或P＜0．01)。BALF中CD45~+淋巴细胞数和CD4~+/CD8~+均较正常对照组明显减少,非淋巴细胞数较正常对照组明显增多,且高浓度组较低浓度组变化趋势明显(P＜0．05或P＜0．01)。结论重度烟雾吸入致吸入性ALI的过程中伴有持续且过度的肺自然免疫反应,这种自然免疫反应部分由活化的中性粒细胞及巨噬细胞所介导;而肺特异性免疫反应受到明显的抑制。     

Diagnosis and management of heparin-induced thrombocytopenia

Heparin use is ubiquitous, wherein 1 to 5% of patients exposed to standard unfractionated heparin develop thrombocytopenia due to antibodies to a complex of heparin and platelet factor 4. Classic features include onset of thrombocytopenia after 5 to 10 days of ongoing heparin exposure, a 50% fall in the platelet count from baseline, resolution of the thrombocytopenia 5 to 10 days after cessation of heparin and a high risk of thrombosis noted in 30 to 75% of patients with heparin-induced thrombocytopenia (HIT) in terms of every-other-day platelet-count monitoring in patients on standard unfractionated heparin. And those patients developing thrombocytopenia necessitate an accurate, readily accessible diagnostic test for HIT. Diagnosis has been recently facilitated by the development of an enzyme-linked immunsorbent assay (ELISA) test for the heparin–P4 antibody complex, although this test carries a relatively low specificity. Widespread use of the ELISA demonstrates a relatively high prevalence of the antibody in patients exposed to heparin in certain settings, such as cardiopulmonary bypass, wherein a quarter of patients have a positive ELISA of unclear significance. Once HIT is diagnosed, the high risk of thrombosis necessitates empiric anticoagulation with an antithrombin such as argatroban or lepirudin, or the heparinoid danaparoid. Additional agents under further study include the antithrombin bivalirudin and the pentasaccharide fondaparinux. Future issues in HIT include increasing awareness for HIT, improving the specificity of HIT testing and the development of new anticoagulants for HIT that will enable out-patient management.     

Disseminated intravascular coagulation

Disseminated intravascular coagulation (DIC) is an acquired syndrome characterized by systemic formation of microthrombi and fibrin deposition in the vasculature. Cancer is one of the leading cause of DIC, which often complicates bleeding tendency and organ dysfunction. Even though DIC therapy is expectant, it is still important, since the bleeding tendency limits the quality of patients' life remarkably. Heparin, low molecular weight heparin, danaparoid, protease inhibitors for coagulation factors and antithrombin III are the choices for DIC. However, since the selection of the drugs is different depending on the basal disease, it is important to understand the pathophysiology of the individual situation. In general, protease inhibitors is recommended for 'fibrinolysis dominant DIC' like DIC associated with leukemia and terminal stage solid cancer, in contrast, danaparoid and antithrombin III are the first choice for 'coagulation dominant DIC' like sepsis. Supplement of concentrated platelets and fresh frozen should be limited for the patients whose primary disease can be controlled.     

Anticoagulant modulation of inflammation in severe sepsis

Inflammation and coagulation are so tightly linked that the cytokine storm which accompanies the development of sepsis initiates thrombin activation and the development of an intravascular coagulopathy. This review examines the interaction between the inflammatory and coagulation cascades, as well as the role of endogenous anticoagulants in regulating this interaction and dampening the activity of both pathways. Clinical trials attempting to improve outcomes in patients with severe sepsis by inhibiting thrombin generation with heparin and or endogenous anticoagulants are reviewed. In general, these trials have failed to demonstrate that anticoagulant therapy is associated with improvement in mortality or morbidity. While it is possible that selective patients who are severelyill with a high expected mortality may be shown to benefit from such therapy, at the present time none of these anticoagulants are neither approved nor can they be recommended for the treatment of sepsis.     

Diagnosis and management of heparin-induced thrombocytopenia

Heparin use is ubiquitous, wherein 1 to 5% of patients exposed to standard unfractionated heparin develop thrombocytopenia due to antibodies to a complex of heparin and platelet factor 4. Classic features include onset of thrombocytopenia after 5 to 10 days of ongoing heparin exposure, a 50% fall in the platelet count from baseline, resolution of the thrombocytopenia 5 to 10 days after cessation of heparin and a high risk of thrombosis noted in 30 to 75% of patients with heparin-induced thrombocytopenia (HIT) in terms of every-other-day platelet-count monitoring in patients on standard unfractionated heparin. And those patients developing thrombocytopenia necessitate an accurate, readily accessible diagnostic test for HIT. Diagnosis has been recently facilitated by the development of an enzyme-linked immunosorbent assay (ELISA) test for the heparin-P4 antibody complex, although this test carries a relatively low specificity. Widespread use of the ELISA demonstrates a relatively high prevalence of the antibody in patients exposed to heparin in certain settings, such as cardiopulmonary bypass, wherein a quarter of patients have a positive ELISA of unclear significance. Once HIT is diagnosed, the high risk of thrombosis necessitates empiric anticoagulation with an antithrombin such as argatroban or lepirudin, or the heparinoid danaparoid. Additional agents under further study include the antithrombin bivalirudin and the pentasaccharide fondaparinux. Future issues in HIT include increasing awareness for HIT, improving the specificity of HIT testing and the development of new anticoagulants for HIT that will enable out-patient management.