Intensive therapy of DIC-syndrome in patients with acute renal insufficiency caused by long-term crush syndrome

Impairment of parenchymatous organs, primarily kidneys, responsible for their dysfunction in crush syndrome results in many respects from disseminated intravascular coagulation (DIC). It is also associated with hemorrhagic complications. It is demonstrated that treatment modalities aimed at arrest of DIC syndrome (plasmapheresis, heparin, dysaggregation drugs, transfusions of large amounts of fresh frozen plasma) stopped bleeding and septic shock in 12 patients with crush syndrome following the earthquake in Armenia (1988).     

Disseminated intravascular coagulation in meningococcal sepsis. Case 7

We report on a man (age: 49 years), who died from severe meningococcal sepsis with disseminated intravascular coagulation (DIC), multiple organ dysfunction syndrome and extended skin necrosis. We discuss in detail the pathophysiology of the activation of coagulation and fibrinolysis during sepsis. The article discusses new therapeutic concepts in the treatment of disseminated intravascular coagulation in meningococcal sepsis, too.     

Tissue factor production not balanced by tissue factor pathway inhibitor in sepsis promotes poor prognosis

OBJECTIVE: To determine the precise relationship among tissue factor, tissue factor pathway inhibitor (TFPI), and neutrophil elastase in sepsis, as well as to test the hypothesis that low TFPI concentrations are not sufficient to prevent tissue factor-dependent intravascular coagulation, leading to multiple organ dysfunction syndrome and death. DESIGN: Prospective, cohort study. SETTING: General intensive care unit of tertiary care emergency department. PATIENTS: Thirty-one consecutive patients with sepsis, classified as 15 survivors and 16 nonsurvivors. Ten normal, healthy volunteers served as controls. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Tissue factor antigen concentration (tissue factor), TFPI, neutrophil elastase, and global variables of coagulation and fibrinolysis were measured on the day of diagnosis of sepsis, severe sepsis, and septic shock and days on 1-4 after diagnosis. The number of systemic inflammatory response syndrome criteria that patients met and the disseminated intravascular coagulation score were determined simultaneously. The results of these measurements were compared between the survivors and the nonsurvivors. In the nonsurvivors, significantly higher concentrations of tissue factor and neutrophil elastase were found compared with the survivors and control subjects. However, the TFPI values showed no difference between the two groups. No correlation was found between the peak concentrations of tissue factor and TFPI. Disseminated intravascular coagulation scores and numbers of the SIRS criteria met by the survivors significantly decreased from day 0 to day 4, but those of the nonsurvivors did not improve during the study period. The nonsurvivors showed thrombocytopenia and higher numbers of dysfunctioning organs than did the survivors. CONCLUSIONS: We systematically elucidated the relationship between tissue factor and TFPI in patients with sepsis, severe sepsis, and septic shock. Activation of tissue factor-dependent coagulation pathway not adequately balanced by TFPI has important roles in sustaining DIC and systemic inflammatory response syndrome, and it contributes to multiple organ dysfunction syndrome and death. High concentrations of neutrophil elastase released from activated neutrophils may explain, in part, the imbalance of tissue factor and TFPI in sepsis.     

脓毒症抗凝治疗的现实与未来

脓毒症是感染诱发的宿主反应失调所导致危及生命的器官功能障碍的一种临床综合征,通常伴有凝血功能障碍的发生。脓毒症诱发的微血管内血栓形成具有"双刃剑"的作用。感染局部的微血管内血栓形成能够发挥免疫血栓的防御功能,促进病原微生物的清除,对机体是有利的。相反,弥散性微血管内血栓形成是脓毒症相关多器官功能障碍的重要发病机制,为脓毒症的抗凝治疗提供了充足的理论基础。尽管针对脓毒症抗凝治疗的临床研究尚存在争议,但并不能因此而全面否定抗凝治疗对脓毒症的价值。我们应当全面评估脓毒症患者的凝血功能障碍,寻找抗凝治疗的合适时机以及可能受益的人群,并采用优化的抗凝治疗策略,为脓毒症的抗凝治疗寻求更为合理有效的方案。     

Heparin treatment in thrombin-induced disseminated intravascular coagulation in the baboon

BACKGROUND AND METHODS: We postulated that low-dose heparin (10 IU/kg.hr) administered as a continuous iv infusion may prevent or ameliorate the induction of thrombin-induced disseminated intravascular coagulation in baboons under general anesthesia. In a nonrandomized experiment lasting 8 hrs, animals were divided into three groups: 11 received thrombin only (group A); ten were pretreated with heparin before thrombin administration (group B); and 15 received heparin 2 hrs after disseminated intravascular coagulation was induced with thrombin (group C). All animals were monitored hemodynamically and coagulation tests were performed hourly. Tests included the following: one-stage prothrombin ratio; activated partial thromboplastin time; fibrinogen and fibrin degradation products; thrombin time; plasma fibrinogen level; antithrombin III and activated clotting time. After the acute phase of the experiment, the animals were observed for 6 days and a postmortem examination was performed on a survivor of each group. RESULTS: Six (55%) group A animals died within 6 days, while there were no deaths in group B and one animal (7%) died in group C. In group C, the administration of heparin could not normalize the clotting profile, but the mortality rate was significantly less than in group A. The prophylactic administration of heparin in group B prevented the induction of disseminated intravascular coagulation. The postmortem findings were of interest, but no statistically valid conclusions could be made, as only one autopsy was done for each group. However, the results suggest that heparin pretreatment may protect against lung edema and liver necrosis. CONCLUSIONS: The results suggest that heparin, in a dose of 10 IU/kg.hr iv, could possibly be safely used in patients at high risk of developing disseminated intravascular coagulation and in those patients with established disseminated intravascular coagulation.     

Elevated nucleosome levels in systemic inflammation and sepsis

OBJECTIVE: Multiple organ dysfunction syndrome is a frequent complication of severe sepsis and septic shock and has a high mortality. We hypothesized that extensive apoptosis of cells might constitute the cellular basis for this complication. DESIGN: Retrospective study. SETTING: Medical and surgical wards or intensive care units of two university hospitals. PATIENTS: Fourteen patients with fever, 15 with systemic inflammatory response syndrome, 32 with severe sepsis, and eight with septic shock. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We assessed circulating levels of nucleosomes, specific markers released by cells during the later stages of apoptosis, with a previously described enzyme-linked immunosorbent assay in these 69 patients with fever, systemic inflammatory response syndrome, severe sepsis, or septic shock. Severity of multiple organ dysfunction syndrome was assessed with sepsis scores, and clinical and laboratory variables. Elevated nucleosome levels were found in 64%, 60%, 94%, and 100% of patients with fever, systemic inflammatory response syndrome, severe sepsis, or septic shock, respectively. These levels were significantly higher in patients with septic shock as compared with patients with severe sepsis, systemic inflammatory response syndrome, or fever, and in nonsurvivors as compared with survivors. In patients with advanced multiple organ dysfunction syndrome, nucleosome levels correlated with cytokine plasma levels as well as with variables predictive for outcome. CONCLUSIONS: Patients with severe sepsis and septic shock have elevated plasma levels of nucleosomes. We suggest that apoptosis, probably resulting from exposure of cells to excessive amounts of inflammatory mediators, might by involved in the pathogenesis of multiple organ dysfunction syndrome.     

Bench-to-bedside review: Thrombocytopenia-associated multiple organ failure – a newly appreciated syndrome in the critically ill

New onset thrombocytopenia and multiple organ failure (TAMOF) presages poor outcome in critical illness. Patients who resolve thrombocytopenia by day 14 are more likely to survive than those who do not. Patients with TAMOF have a spectrum of microangiopathic disorders that includes thrombotic thrombocytopenic purpura (TTP), disseminated intravascular coagulation (DIC) and secondary thrombotic microanigiopathy (TMA). Activated protein C is effective in resolving fibrin-mediated thrombosis (DIC); however, daily plasma exchange is the therapy of choice for removing ADAMTS 13 inhibitors and replenishing ADAMTS 13 activity which in turn resolves platelet: von Willebrand Factor mediated thrombosis (TTP/secondary TMA).     

Bench-to-bedside review: Thrombocytopenia-associated multiple organ failure – a newly appreciated syndrome in the critically ill

New onset thrombocytopenia and multiple organ failure (TAMOF) presages poor outcome in critical illness. Patients who resolve thrombocytopenia by day 14 are more likely to survive than those who do not. Patients with TAMOF have a spectrum of microangiopathic disorders that includes thrombotic thrombocytopenic purpura (TTP), disseminated intravascular coagulation (DIC) and secondary thrombotic microanigiopathy (TMA). Activated protein C is effective in resolving fibrin-mediated thrombosis (DIC); however, daily plasma exchange is the therapy of choice for removing ADAMTS 13 inhibitors and replenishing ADAMTS 13 activity which in turn resolves platelet: von Willebrand Factor mediated thrombosis (TTP/secondary TMA).     

The presence of superantigens and complex host responses in severe sepsis may need a broad therapeutic approach.

Patients with sepsis can progress into septic shock, disseminated intravascular coagulation, and multiorgan dysfunction syndrome. Various materials secreted by or released from microorganisms such as bacteria initiate these processes. In some bacteria, certain antigens and toxins may cause a 100-fold greater or supernormal activation of monocytes and T lymphocytes, leading to activation of the cascade systems in the host. This can explain the extremely rapid progress of the sepsis into septic shock seen in some patients. In Group A streptococci, more than 100 different toxins have been identified, about 5 of which (superantigens) cause an extremely fast immunological response. Because the toxins and antigens can activate so many different cascade systems in the host, the clinical picture is extremely complex, and little benefit is derived from therapy, which interferes with only 1 or 2 of the parameters in the patient with sepsis. Instead, reversal of the septic shock requires the removal or inhibition of several toxins or substances activating the cascade systems. A broader therapeutic approach may be the use of apheresis (plasma exchange).     

人工肝支持系统成功抢救妊娠急性脂肪肝合并多器官衰竭患者1例报道

目的 分析妊娠急性脂肪肝患者的病例特点、抢救措施及预后,提高对此病的认识及早期诊治水平.方法 回顾性分析1例妊娠急性脂肪肝合并多器官衰竭患者病情演变以及抢救治疗情况,并结合相关文献分析讨论.结果 患者以妊娠晚期出现重度黄疸伴消化道症状起病,常规保肝、退黄等治疗未能逆转病情,并迅速出现肺、肝、肾等多器官衰竭以及DIC等严重并发症,经积极终止妊娠、辅助呼吸及人工肝支持系统等综合抢救最终病情缓解,并经肝组织病理检查明确诊断.结论 妊娠急性脂肪肝病情凶险,极易并发多器官衰竭,早期诊断,多学科、全方位综合救治是提高本病成功抢救的关键.     

Severe disseminated intravascular coagulation caused by congestive heart failure and left ventricular thrombus.

We present a patient who visited emergency department owing to the skin manifestation of disseminated intravascular coagulation. Recent anterior myocardial infarction induced congestive heart failure and left ventricular thrombus, which were considered to be the cause of disseminated intravascular coagulation. Anticoagulant therapy with heparin and warfarin was used successfully to treat the disseminated intravascular coagulation and left ventricular thrombus.     

产科弥漫性血管内凝血33例临床分析

目的：探讨产科弥漫性血管内凝血(DIC)的诊断、治疗、抢救的方法。方法：回顾性分析在本院发生的33例产科DIC的资料。结果：33例产科DIC抢救成功29例，成功率87．9％。结论：早期正确诊断，及时去除诱因，适时结束分娩，及时切除子宫，合理应用肝素，输入大量新鲜血，补充凝血因子及抗纤溶药是治疗的关键。     

Coagulation disorders in septic shock

Abnormalities in coagulation and fibrinolysis are frequently observed in septic shock. The most pronounced clinical manifestation is disseminated intravascular coagulation. Recent studies in human volunteers and animal models have clarified the early dynamics and route of activation of both coagulation and fibrinolytic pathways. In healthy subjects subjected to a low dose of either endotoxin or TNF an imbalance in the procoagulant and the fibrinolytic mechanisms is apparent, resulting in a procoagulant state. Also in patients with septic shock a dynamic process of coagulation and fibrinolysis is ongoing with evidence of impaired fibrinolysis. These abnormalities have prognostic significance; the extent of disturbances of coagulation and fibrinolysis is related to the development of multiple organ failure and death.     

恶性抗磷脂综合征的临床研究进展

恶性抗磷脂综合征是1992年由Asherson提出的一种系统性自身免疫性疾病,临床以短期内进行性多脏器损伤、组织病理学证实有多发小血管栓塞及血清抗磷脂抗体滴度增高为特点。本病虽不足抗磷脂综合征发病的1%,但死亡率可达50%。未来的研究除考虑在血小板持续下降的情况下如何贯彻抗凝治疗外,应更关注于如何维持长期临床缓解、提高生存率的研究。     

Severe falciparum malaria: an important cause of multiple organ failure in Indian intensive care unit patients

OBJECTIVE: To study the incidence and severity of multiple organ dysfunction in severe falciparum malaria. DESIGN: Prospective, observational study. SETTING: Intensive care unit of a tertiary care university hospital. PATIENTS: Three hundred one consecutive patients with severe falciparum malaria admitted during the 30-month study period. INTERVENTIONS: Daily assessment of clinical and biochemical variables required for calculating the Sequential Organ Failure Assessment (SOFA) score. MEASUREMENTS AND MAIN RESULTS: Central nervous system failure was present in 121 patients (53 deaths). Renal failure occurred in 91 patients (48 deaths), and 33 required dialysis. Severe thrombocytopenia occurred in 114 patients (seven required platelet transfusion), and 19 patients had thrombocytopenia and disseminated intravascular coagulation; all required component therapy; 229 patients received blood transfusion for severe hemolytic anemia. Hepatic failure occurred in 77 patients (38 deaths). Respiratory failure developed in 79 patients and carried the worst outcome (70 deaths). It occurred later in the course of the illness (mean, 3.1 days; p <.001) compared with cerebral, renal, and coagulation failure (mean, 1.3-2.3 days). Regardless of the organ system involved, only 11 of 172 patients with one or no organ failure died (6.8%), whereas mortality rate increased to 48.8% in 129 patients with multiple organ failure. Other abnormalities associated with poor outcome included seizures in 54 patients (56% mortality rate), metabolic acidosis in 167 (40% mortality rate), hypoglycemia in 88 (39% mortality rate), and hemoglobinuria in 190 (33% mortality rate). Sixty patients had quinine toxicity requiring dosage reduction. Bacterial sepsis occurred in 39 patients (35 deaths) and accounted for 85% of deaths occurring after day 7. Twenty-three pregnant women had no significant difference in outcomes. Overall mortality rate was 24.6% (301 patients, 74 deaths). CONCLUSIONS: Malaria is an important cause of multiple organ failure in India. Mortality rate is 6.4% when one or fewer organs fail but increases to 48.8% with failure of two or more organs. However, outcomes are better than for similar degrees of organ failure in sepsis.     

Coagulation dysfunction in sepsis and multiple organ system failure

In patients diagnosed with sepsis, severe sepsis or septic shock, cytokine-mediated endothelial injury, and TF activation initiate a cascade of events that culminate in the development of coagulation dysfunction characterized as procoagulant and antifibrinolytic. This abnormal state predisposes the patient to develop microvascular thrombosis, tissue ischemia, and organ hypoperfusion. Multiple organ dysfunction syndrome may be a product of this pertubation in coagulation regulation. Treatments aimed at correcting this coagulation dysfunction have met with mixed success. Current data suggest that AT III replacement therapy has limited efficacy in adults with severe sepsis. In contrast, adult patients diagnosed with severe sepsis and organ failure and treated with aPC (drotrecogin alfa activate) have a significantly reduced risk of death when compared with placebo-treated patients. A phase III trial examining the efficacy of protein C replacement therapy in pediatric patients with severe sepsis and organ failure is underway.     

16例产后出血并发弥漫性血管内凝血的治疗

目的：探讨产后出血并发弥漫性血管内凝血（DIC）的诊断和治疗。方法：对2000年1月-2005年12月间治疗的16例产后大出血并发DIC病例进行分析。结果：16例产后出血并发DIC的患者中抢救成功14例，2例抢救后因并发多脏器功能衰竭而死亡。结论：积极治疗产后出血，对DIC早诊断，早治疗，祛除病因，果断切除子宫，积极补充凝血因子，慎重使用肝素是抢救成功的关键。     

Symmetrical peripheral gangrene in critical illness

Symmetrical peripheral gangrene (SPG) is a disabling complication that affects a small proportion of patients who survive critical illness. Its pathogenesis reflects profoundly disturbed procoagulant-anticoagulant balance in susceptible tissue beds secondary to circulatory shock (cardiogenic, septic). There is a characteristic SPG triad: (a) shock (hypotension, lactic acidemia, normoblastemia, multiple organ dysfunction), (b) disseminated intravascular coagulation (DIC), and (c) natural anticoagulant depletion (protein C, antithrombin). In recent years, risk factors for natural anticoagulant depletion have been identified, most notably acute ischemic hepatitis (“shock liver”), which is seen in at least 90% of patients who develop SPG. Moreover, there is a characteristic time interval (2–5 days, median 3 days) between the onset of shock/shock liver and the beginning of ischemic injury secondary to peripheral microthrombosis (“limb ischemia with pulses”), reflecting the time required to develop severe depletion in hepatically-synthesized natural anticoagulants. Other risk factors for natural anticoagulant depletion include chronic liver disease (e.g., cirrhosis) and, possibly, transfusion of colloids (albumin, high-dose immunoglobulin) lacking coagulation factors. A causal role for vasopressor therapy is unproven and is unlikely; this is because critically ill patients who develop SPG do so usually after at least 36–48 hours of vasopressor therapy, implicating a time-dependent pathophysiological mechanism. The most plausible explanation is a progressive time-dependent decline in key natural anticoagulant factors, reflecting ongoing DIC (“consumption”), proximate liver disease whether acute or chronic (“impaired production”), and colloid administration (“hemodilution”). Given these evolving concepts of pathogenesis, a rationale approach to prevention/treatment of SPG can be developed.     

Coagulation, fibrinolysis, and kallikrein systems in sepsis: relation to outcome

Fatal multiple organ failure after severe infection may be related to an early activation of protease cascade systems. This study aimed to relate changes in coagulation, fibrinolysis, and kallikrein to shock and outcome. Of 53 patients with severe infection, 30 did not develop shock, 12 survived septic shock, and 11 died from organ failure after septic shock. No patient had overt disseminated intravascular coagulation. We measured 17 components of the coagulation/fibrinolysis/kallikrein pathways on admission and on the next 2 days. High values for fibrinogen, factor VIII:C, von Willebrand factor antigen, and D-dimer were seen in all patients; factor XII, prekallikrein, factor VII, antithrombin, protein C, and fibronectin were low. The patients thus appeared to be hypercoagulable. These disturbances were more pronounced in septic shock survivors, who also had low plasminogen and antiplasmin, indicating ongoing fibrinolysis. Nonsurvivors of sepsis were distinguished mainly by high plasminogen activator inhibitor values; this suggests an impaired functional fibrinolysis in fatal sepsis, with possible therapeutic implications. Cryoprecipitate infusion increased the fibronectin concentration, but did not influence the other factors studied.     

Apheresis of plasma compounds as a therapeutic principle in severe sepsis and multiorgan dysfunction syndrome.

During sepsis there is an increase in the plasma content of several compounds, e.g., bacterial toxins, cytokines, cell debris, free hemoglobin and myoglobin. In blood, these compounds activate various cascade systems, which in large amounts or in more vulnerable patients lead to a disseminated intra-vascular coagulopathy (DIC) with multiorgan dysfunction syndrome (MODS) and death, despite conventional intensive care unit therapy. Therapeutic attempts to reverse these conditions have so far been of limited benefit. These effects have mainly been focused on lowering the blood concentration of single substances such as tumor necrosis factor. By the use of low-and high-flux hemodialysis filters, usually only small amounts of these substances are removed. By the use of plasmapheresis or plasma exchange, the extent of removal is considerably increased. The efficacy varies between the techniques (centrifugation vs. filtration or adsorption) and has also different influences on e.g. the complement system. This report describes these techniques and the therapeutical possibilities given by them. In small trials, blood or plasma exchange has been used as rescue therapy in critically ill patients with a progressive MODS and DIC. A survival of about 80% of the patients has been reported in these studies and the use of combined therapy will be discussed. Controlled trials are required in this field.