Disseminated intravascular coagulation in sepsis.

Disseminated intravascular coagulation (DIC) has been considered a rather rare syndrome characterized by severe bleeding. In fact, both of these beliefs are wrong. Bleeding is fairly rare in DIC. The clotting parameters are usually normal unless the DIC is fulminating. It is usually thought that fibrinogen may be low or absent in DIC. However, afibrinogenemia is rare. Fibrinogen is usually high in DIC because of the high rate of fibrinogen manufacture by the liver in response to stress. DIC is very common and most cases are never diagnosed. This is because it has been hard to find fibrin thrombi in autopsy cases and because acute severe bleeding is uncommon. The reason fibrin thrombi are rare may be because they have been lysed by endogenous fibrinolytic enzymes before the autopsy. The appearance of endogenous fibrinolytic response could be a defense mechanism to lyse the microclots of DIC. In fact, this response is often successful. This defense can be aided by the administration of plasminogen activators that will lyse the clots. Heparin has been used for the treatment of DIC but has proved useless and is, in fact, dangerous. This is because heparin will not dissolve clots and may actually promote platelet agglutination. Administration of plasminogen activators will actually prevent bleeding diathesis.

A shock toxin that produces disseminated intravascular coagulation and multiple organ failure.

OBJECTIVE: To introduce a new concept in the etiology and treatment of traumatic and septic shock. It describes 3 types of shock: (1) hypovolemic shock, (2) traumatic shock, and (3) septic shock. BACKGROUND: The mortality of septic shock in both total number and mortality rate has been increasing over the past 40 years despite major advances in diagnosis and treatment, including a number of "magic bullets." Trauma is the No. 1 cause of death in persons under the age of 44 and the No. 3 cause of all deaths. Traumatic shock has been assumed to be caused by hypovolemia; however, many traumatic shock patients die with a normal blood volume, usually after several days. Septic shock in pigs using an injection of killed Escherichia coli organisms produced disseminated intravascular coagulation (DIC). Control pigs treated with plasminogen activator survived. Septic shock in humans also treated with plasminogen activator showed excellent results. Traumatic shock studied in pigs showed excellent results with plasminogen activator. A normal blood volume was maintained with the use of intravenous fluids. Traumatic shock in humans also treated by plasminogen activator showed excellent results. The improvement in PaO2 and other parameters demonstrated in these studies provides a new possibility in the treatment of trauma and/or sepsis induced acute respiratory distress syndrome (ARDS). DIC is almost always present in traumatic and septic shock and probably in the course of ARDS and multiple organ failure. The DIC is probably initiated by tissue cell or bacterial cell destruction, which liberates a thrombogenic aminophospholipid that forms the inner layer of all cell walls.

Treatment of severe acute respiratory distress syndrome: a final report on a phase I study.

Adult respiratory distress syndrome (ARDS) has a high mortality. Its only effective treatment is respiratory therapy. If this fails mortality is probably 100 per cent. No other treatment for ARDS has proved effective including "magic bullets." Twenty patients suffering from ARDS secondary to trauma and/or sepsis failed to respond to treatment with mechanical ventilation and positive end-expiratory pressure. On the assumption that disseminated intravascular coagulation initiates ARDS by occluding the pulmonary microcirculation with microclots, the patients were treated with plasminogen activators. The patients responded with significant improvement in partial pressure of oxygen in arterial blood. No bleeding occurred and clotting parameters remained normal. We conclude that ARDS can be safely treated with plasminogen activator.

Traumatic shock alias posttrauma critical illness.

Trauma is the most common cause of death under the age of 45. Many trauma patients die of multiple organ failure, especially acute respiratory distress syndrome. The basic cause of traumatic shock has only partially been elucidated. Data resources include research papers on the subject of trauma and shock from 1875 to the present. These papers numbered more than 40,000. Almost all of the papers proposed that traumatic shock was due to hypovolemia. The concept of a shock toxin as promulgated during World War I is correct. This toxin is a thrombogenic aminophospholipid that occurs only on the inner layer of all cell membranes and is liberated by cell destruction. It causes disseminated intravascular coagulation, which may obstruct the microcirculation of any and all organs producing multiple organ failure by microclots. These microclots may be lysed by plasminogen activator and circulation to the organs restored.

A review of septic shock.

The mortality of septic shock, both in percentage of septic shock cases and total number of septic shock cases, has been increasing over the past several decades. This is despite major advances in diagnosis and treatment. The basic cause of traumatic and septic shock has only partially been elucidated. This review presents information about the basic cause and mechanism of septic shock as well as a new treatment based on this information. Data sources include research papers on the subject of septic shock from 1875 until the present. These papers numbered more than 10,000, most of which are not included in the reference list because many are duplicative. The main result of the review of literature is that all of a wide variety of treatments of septic shock have not resulted in a lowering of mortality, but in fact have increased it. Another toxin (in addition to endotoxin and its secondarily induced host mediators) is proposed. This toxin causes disseminated intravascular coagulation, which may obstruct the microcirculation of any and all organs, producing multiple organ failure by microclots. These microclots may be lysed by plasminogen activator and circulation to the organs restored.

The etiology and treatment of traumatic and septic shock.

Disseminated intravascular coagulation can cause multiple organ failure including adult respiratory distress syndrome by obstruction of visceral microcirculation by microclots. It was reasoned that if a clot causes vascular obstruction, lysing the clot by a plasminogen activator would be of value.

Traumatic and septic shock alias post-trauma critical illness.

BACKGROUND: The mortality associated with septic shock, both in percentage of septic shock cases and total number of septic shock cases, has been increasing over the past several decades. This is despite major advances in diagnosis and treatment. The basic cause of traumatic and septic shock has been only partially elucidated. METHODS: Data sources include research papers on the subject of traumatic and septic shock from 1875 to the present. These papers numbered over 10 000, few of which are included in the reference list because many are duplicative or negative. Over 1000 articles were reviewed which documented the unsuccessful search for a treatment for septic shock based on the theory that septic shock is due to endotoxin and its secondarily induced host mediators. These references are available from the author. RESULTS: and conclusion The concept of a shock toxin in trauma and sepsis as promulgated during World War I is correct. This toxin is a thrombogenic aminophospholipid which occurs only on the inner layer of all cell membranes and is liberated by cell destruction. It causes disseminated intravascular coagulation which may obstruct the microcirculation of any or all organs, producing multiple organ failure by microclots. These microclots may be lysed by plasminogen activator and circulation to the organs restored.

Effect of urokinase on disseminated intravascular coagulation.

Our study evaluated the possible therapeutic effect of urokinase in treating the microthrombiotic effects of disseminated intravascular coagulation by assisting the activation of endogenous plasminogen. Twenty-six pigs were anesthetized, intubated, mechanically ventilated, and surgically catheterized. Septic shock was induced in all 26 pigs by an intravenous infusion of heat-killed Escherichia coli. The pigs were divided into two sets of experiments: in experiment 2 (n = 14), one-half received an intravenous dose of urokinase 1 h after heat-killed E. coli infusion and in experiment 3 (n = 12) one-half received an intravenous bolus dose and a continuous drip of urokinase 2 h after heat-killed E. coli infusion. The untreated pigs served as controls. Hemodynamic parameters, blood chemistries, and blood gases were analyzed. Urokinase given 1 h after bacterial toxin infusion significantly restored blood flow, resulting in an increase in cardiovascular and pulmonary function and improved survival rate (43% control vs. 100% treated, 24-h experimental period). Treatment given after 2 h showed some significant effect on pulmonary function; however, within 10 h of E. coli infusion, mortality rates in control and treated groups were 100 and 83%, respectively. Early administration of urokinase after onset of disseminated intravascular coagulation restored blood flow and helped resolve organ damage.

The effect of heparinization on intra-abdominal infection and acute pulmonary failure.

UNLABELLED: Acute severe purulent peritonitis is still a very life-threatening disease condition. The primary cause of death is multiple organ failure (MOF) where acute respiratory distress syndrome (ARDS) is the initial trigger. Studies have shown that heparin has a cytoprotective effect and stimulates an increase in cardiopulmonary function systematically. METHODS: Twenty-one Sprauge Dawley rats were used as an animal model by puncturing the distal wall of intestine and ligating the appendix without interfering with the continuity of intestinal tract. In the formal experiments, 100 rats were divided into two groups and equal amounts of distilled water was given intraperitoneally. Total mortality and early mortality rate were recorded. Abdominal autopsies and blood gas analyses were performed and lung tissue samples were taken for light and electronic microscope analyses. RESULTS: The mortality rate was not statistically significant. But early death rate, the average survival times and the rate of abscess formation were significantly lower in the heparin treated group. The histological study of the experimental specimen showed that in the control group, the incidence of ARDS was higher and there was a more severe ARDS-like change, especially polymorphonuclear neutrophil leukocytes infiltration into alveolar and interstitial spaces. Blood gas analysis demonstrated the beneficial aspects of heparin administration. CONCLUSIONS: Heparin can increase the early survival rate and increase the survival time of rats with experimental acute severe purulent peritonitis, and proves to be beneficial in preventing infection induced lung injury during sepsis. We conclude that the effect of heparin on the survival rate is related to less pulmonary function deterioration, thereby preventing ARDS and the triggering of MOF.

Comparison of bacterial translocation during traumatic shock and hemorrhagic shock in rats.

UNLABELLED: Traumatic shock has been classified as a kind of hypovolemic shock similar to hemorrhagic shock. Since bacterial translocation has been observed in shock, this study investigated the difference in bacterial translocation during traumatic shock and hemorrhagic shock, and considered this effect on lung injury during sepsis. METHODS: Forty-eight male or female Sprague-Dawley rats were divided into 2 groups, hemorrhagic shock and traumatic shock. Bacterial translocation, endotoxin, and blood gas were evaluated. Alterations of the lungs morphologically and functionally were observed. RESULTS: Traumatic shock induced more bacterial translocation and endotoxemia from the gut. Blood gas analysis shows a more severe disorder in traumatic shock than in hemorrhagic shock. Pathological morphologic changes of lungs were more severe in traumatic shock than in hemorrhagic shock. CONCLUSIONS: Traumatic shock cause more bacterial translocation and endotoxemia which subsequently caused serial pathological alterations in lung morphologically and functionally than pure hemorrhagic shock does. These results suggest that this trauma activates more severe mechanism to damage lungs.

A new approach to the treatment of experimental septic shock.

Previous work has shown that disseminated intravascular coagulation (DIC) may produce multiple organ failure, including adult respiratory distress syndrome, by obstruction of visceral micro circulation by microclots DIC can be produced by sepsis. This study tests the ability of a plasminogen activator to prevent death from an intravenous injection of killed Escherichia coli by causing lysis of the microclots. Subjects were two groups of 8 pigs each with body weight of 60-70 lbs. Killed Escherichia coli were injected IV in 16 pigs. Invasive monitoring was used to record physiologic data during the 5.0-hr experimental period. Urokinase injected 20 min after the injection of Escherichia coli organisms significantly prevented mortality, acidosis, and development of blood incoagulability. We conclude that plasminogen activator can significantly prevent fatal Escherichia coli (septic) shock without causing bleeding.

A long term follow-up of one of the first arterial homografts.

OBJECTIVE: To report a successful long term homograft of an artery. EXPERIMENTAL DESIGN: Surgical arterial homograft with a long term follow up. SETTING: General surgery wards of two general hospitals. PATIENTS: 2 patients, one with a recurrent sarcoma of the thigh, the other with an osteogenic sarcoma of the humerus. INTERVENTION: Surgical removal of all tissue of the groin including femoral and external iliac artery and vein, femoral nerve, lymphatics, muscle and ligaments. Arterial replacement with homograft from second patient. RESULTS: Successful function of arterial homograft for 40 years. CONCLUSIONS: It is possible that arteries could be added to the list of organs that are harvested for transplantation.

Trauma, sepsis, and disseminated intravascular coagulation.

Disseminated intravascular coagulation (DIC) was first observed clinically in a case of sepsis following severe trauma. It was postulated that the observed clotting defect and bleeding were due to the using up of clotting factors in an episode of intravascular clotting. It was also postulated that the multiple organ failure observed was due to obstruction of the microcirculation of the organs by microclots. Evidence for this process was worked out in many animal studies. It was then postulated that if these microclots could be lysed before organ necrosis was produced, organ failure could be prevented. This prevention was shown to be possible in animals. It was then tried in humans using plasminogen activators, and the approach was found to be effective. Using a low dose of plasminogen activator over a 24-hour period caused no changes in the coagulation profile or bleeding.

Fibrinolytic agents: a new approach to the treatment of adult respiratory distress syndrome.

Nineteen patients suffering from adult respiratory distress syndrome (ARDS) secondary to trauma or sepsis, or both, failed to respond to treatment with mechanical ventilation with oxygen and positive end-expiratory pressure. On the premise that ARDS may be caused by the microclots of disseminated intravascular coagulation obstructing the pulmonary microcirculation, the patients were treated with either streptokinase or urokinase. Eighteen patients responded with significant improvement in PaO 2 value. No bleeding occurred and clotting parameters remained normal.

Organ damage in shock, disseminated intravascular coagulation, and stroke.

Disseminated intravascular coagulation (DIC) may cause multiple organ failure. Although DIC may cause capillary occlusion in any and all organs, the lungs, liver, kidneys, gut, heart and brain are particularly affected. Focal brain necrosis can also be caused by DIC. Fibrinolytic therapy will often restore significant blood flow to the capillaries of the lungs. This results in significant increase in lung function because the lung is more resistant to actual necrosis and will resume function once circulation is restored. Administration of fibrinolytic therapy will also prevent liver and kidney failure if started within four hours after trauma. This therapy, when given in low doses intravenously over a twenty-four hour period, has little effect on the coagulation mechanism, and abnormal bleeding, therefore, has not been a concern. It is speculated that if plasminogen activators are effective and safe for treating the intravascular clots of DIC, then perhaps they would be effective in treating other types of intravascular coagulation in the brain, such as various types and degrees of stroke.

Prevention of adult respiratory distress syndrome with plasminogen activator in pigs.

Death from traumatic shock has been associated with loss of blood externally or internally. However, many patients die after trauma, even though blood volume restoration is adequate. Death is often due to pulmonary failure (adult respiratory distress syndrome [ARDS]). Death and ARDS have been associated with disseminated intravascular coagulation (DIC) and microclots in the lungs. Dissolution of the microclots after trauma can be achieved by activation of endogenous plasmin. Nine pigs were anesthetized for 48 h. Trauma was administered by 60 standard blows to each thigh resulting in a bruise of muscle but no skin, bone, or major vessel injury. Nutrition and respiration were maintained at normal levels. All nine pigs died with severe lung pathology and low PaO2. Ten other traumatized pigs were treated with a plasminogen activator iv 4 h after trauma. Five of these were treated with tissue plasminogen activator (tPA) and five with urokinase. All treated pigs survived 48 h and maintained a normal PaO2. Autopsy showed minimal lung pathology.