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Diagnosis.
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Clinical features of shock and infection are present.
A. Systemic signs: Rigors, fever (hypothermia is noted in 5-10 % of patients), petechiae, leukocytosis, or leucopenia with a shift to the left may be noted.
B. Localized signs: Abdominal tenderness, perirectal and extensive pneumonia may be present. Localized symptoms and signs may be absent, however, especially if the patient is immunocompromised, very young, or very old. Typical sites of occult infection include the urinary tract, billiary system, pelvis, retroperitoneum, and perirectal area.
C. Other signs: hyperventilation with hypocapnia is common. The presence of infection should be confirmed by microscopic examination, culture, or other definitive test.
In toxic shock syndrome, toxins from localized staphylococcal colonization or infection cause severe hypotension or shock associated with a diffuse red rash (which later desquamates) and other symptoms and signs (nausea, vomiting, diarrhea, thrombocytopenia). The majority of cases have occurred within 5 days of onset of a menstrual period in women, using tampons; however, any type of staphylococcal infection may produce this syndrome. The clinical diagnosis is supported by recovery of Staphylococcus aureus from the vagina, wounds or elsewhere.
Treatment
Medical measures:
Volume replacement. As in hypovolemic shock, a balanced salt solution should be used for initial fluid replacement. Colloids should not be used, because capillary endothelial permeability is increased in the shock state, which allows colloid solutions to pass into the interstitial space, thus worsening interstitial edema. The amount of fluid administered follows the same guidelines governing fluid replacement in severe hypovolemic shock. In general < 1-2 l given over 30-60 minutes will improve blood pressure and urine output; further administration of fluids depends on clinical response (urine output, blood pressure, and pulse) and measurements of central venous pressure or, preferably, pulmonary arterial wedge pressure.
Antibiotic therapy. Antibiotic treatment should be specific for the causative organism, but the etiologic agent may not be known at the onset of shock. Prompt empirical treatment with antibiotics, using widespectrum, specific and organotropic agents (Cefmetazol, Cefperamid, Ceftizoxim, Norfloxacin, Aztreonam). Doses and rate of entering depend on severity of the process.
Surgical measures: Surgical measures are more effective, especially in case of combined treatmenrt (antibiotics, fluid replacement measures and removing of the cause of infection, treatment and drainage of adjacent area.
Special measures:
1. Corticosteroids. Recent studies have shown conclusively that administration of pharmacologic doses of glucocorticoids has no beneficial effect on patients with septic shock and may even be harmful. Therefore, high-dose corticosteroids should not be used as adjunctive therapy in septic shock.
2. Heparin. Disseminated intravascular coagulation may occur in septic shock. If treatment of septic shock is successful, consumption of coagulation factors usually ceases and rapid regeneration of these factors occurs. If coagulation studies confirm the presence of persistent disseminated intravascular coagulation (prolonged prothrombin and partial thromboplastin times, decreased number of platelets, depressed fibrinogen levels, and the presence of fibrin degradation products) give heparin, 100 units/kg intravenously to start, followed by 10-40 units/kg/h by continious intravenous administration (infusion pump preferred).
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General Sepsis
This is a generalized form of puerperal infection.
Septicaemia is a grave systemic sepsis characterized by propagation of microbes through the entire body by the circulating blood. From the foci of septic infection the microbes are carried to various organs and tissues of the body to form new foci of infection there; this condition is named septicopyemia. It is rather difficult to distinguish this condition in clinical practice because the reasons and clinical picture are common.
The onset of the disease is marked by a chill, elevation of temperature up to 40-41 degrees, and a sudden worsening of the general condition of the patient. The woman becomes apathic and sleepy, she complains of headache, abnormal excitement and delirium often develops. The pulse is small and accelerated up to 120-130 beats/min. The tongue is dry and coated; the skin is also dry, with a greyish or yellowish tint, frequently affected by eruption. Diarrhea is frequent. The extremities are often cyanotic due to cardiac disfunction. Inoculation of nutrient medium with a blood sample may be used to reveal the agent responsible for the development of septic condition. The disease is often fatal even with modern treatment. Septic shock develops very often. The most important clinical features of septic shock are: arterial hypotension (90/60 mm Hg and less), tachycardia (110 beats per minute and over), hyper- or hypothermia (39º C, or less than 36º C), leukocytosis (15, 000 and over) or leukopenia (less than 4, 000), hypovolemia.
The treatment must be intensive and urgent. It consists in the following:
· Artificial pulmonary ventilation.
· Catheterization of the subclavian vein.
· Promedol 2 ml of 1% solution, dimedrol 2 ml of 1% solution intravenously.
· Disintoxication: infusions of saline solutions, frozen plasma, albumin, rheopolygluckin, rheogluman, polygluckin - summarily 40-45 ml/kg of body weight for twenty four hours intravenously droppingly.
· Diuretics by indication.
· Hydrocortisone 500 mg intravenously, or prednisolon 120 mg.
· Strophanthin 0. 5–1 ml of 0. 05% solution.
· Vasodilators: euphylline 2. 4% - 10 ml, papaverine 2% - 2 ml, etc.
· Antihistamines: suprastin, pipolphen intravenously.
· Antibiotics: thienam, cephperaxon with megadoses intravenously.
· Immunocorrectors: antistaphylococcal gamma-globulin, antistaphylococcal plasma.
After stabilization of hemodynamics surgical treatment is absolutely indicated: removing of the source of infection (uterus, adnexa).
Anaphylactic Shock
Anaphylactic shock is a catastrophic and frequently fatal type of allergic reaction that occurs within minutes after parenteral (rarely oral) administration of drugs or nonhuman proteins, including foods, sera, or venoms. In cases obviously caused by injections of drugs or sera there is seldom any reason for delayed treatment.
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Diagnosis
Symptoms and signs include marked apprehension, generalized urticaria or edema, back pain, a choking sensation, cough, bronchospasm, or laryngeal edema.
In severe cases, hypotension, loss of consciousness, dilatation of the pupils, incontinence, and convulsions may be present; sudden death may occur.
Three modes of presentation of anaphylaxis based on the most conspicuous presenting features are recognized; however, any combination of these may occur:
· Urticaria or angioedema that may be associated with upper airway obstruction and laryngeal edema;
· bronchospasm, or
· vascular collapse (severe hypotension).
Treatment
Treatment should be started as soon as anaphylaxis is suspected; do not wait until it is fully developed.
Position: Place the conscious patient in a comfortable position, and ensure unimpeded ventilation. The unconscious patient should be placed supine, in a level or slightly head-down position (do this as quickly as possible).
Airway: Give supplemental osygen by mask or nasal prongs at a rate of 5-10 l/min. If the patient is not breathing, assist ventilation with a bag-mask until endotracheal intubation can be performed. If equipment for insertion of an endotracheal tube is not available or if intubation is unsuccessful because of airway obstruction by laryngeal edema, cricothyrotomy may be necessary.
Intravenous access: Insert an intravenous catheter, and begin infusion of a balanced salt solution or normal saline, 0/5–1 l over 30 minutes, with further administration governed by blood pressure and urine output.
Drugs: Epinephrine (adrenalin) is the drug of choice for emergency use and should be given as soon as anaphylactic shock is suspected or diagnosed. It may be necessary to supplement epinephrine with antihistaminic drugs or corticosteroids and – in intense bronchospasm – with intravenous aminophylline (euphylline).
Aqueous adrenalin: For mild anaphylaxis, give adrenaline, 0. 3-0. 5 mg (0. 3-0. 5 ml of 1: 1000 solution) intramuscularly. An additional 0. 2-0. 3 ml of 1: 1000 solution can be infiltrated around the sting or injection site (with or without tourniquet proximally) to delay absorption of antigen. For severe anaphylaxis, adrenalin should be administered intravenously or via an endotracheal tube; give 1-5 ml of 1: 10. 000 solution. Repeat every 10 minutes if symptoms continue or recur. A continious infusion may be necessary in some patients.
Diphenilhydramine: Give diphenilhydramine (Benadryl, many others), 50 mg intravenously or intramuscularly, early in treatment.
Glucocorticoid: A soluble glucocorticoid preparation should be given as an adjunct to adrenaline.
Beta-agonist aerosol: If bronchospasm is present, give metaproterenol or other beta-agonist inhalant solutions, 0. 1-0. 5 ml in 3-5 ml of sterile saline, every 30-60 minutes.
Aminophylline: For severe bronchospasm, give aminophylline, 6 mg/kg as a loading dose in 50-100 ml of saline by intravenous infusion over 30 minutes.
Prevention
Inquire carefully about any history of drug allergy before giving drugs. In drunk, unconscious, or obtunded patients, search for a card specifying drug allergies or medical conditions requiring special attention. Be cautious when administering parenteral medication to patients with a history of drug allergy. If there is a history of previous reaction to the agent to be injected, use an alternative drug whenever possible. Give intravenous injections slowly, and observe individuals who have received parenteral medication for at least 30 minutes after injection.
Recurrent episodes of anaphylaxis may occur 12-24 hours after the initial episode: therefore, patients who have experienced life-threatening anaphylaxis should be hospitalized for observation and treatment.
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Amniotic Fluid Embolism
Introduction
Amniotic fluid embolism is a rare obstetric emergency in which amniotic fluid, fetal cells, hair, or other debris enter the maternal circulation, causing cardiorespiratory collapse and shock.
The condition is rare - probably many cases are unrecognized, the diagnosis being erroneously attributed to obstetric shock, postpartum hemorrhage, or acute pulmonary edema. The process is more similar to anaphylaxis than to embolism, and the term anaphylactoid syndrome of pregnancy has been suggested too.
Mortality
Maternal - about 75% of deaths are a direct result of the effects of embolism, and the rest are of hemorrhage.
Fetal - mortality is high; 50% of deaths occur in uterus.
Etiology
· Strong uterine contractions
· Hydramnios
· Large fetus
Predisposing Factors
· High incidence of operative delivery
· Intrauterine fetal death
· Multiparity
· Meconium in amniotic fluid
· History of allergies
Pathophysiology: The pathophysiology of amniotic fluid embolism is poorly understood. Amniotic fluid and fetal cells enter the maternal circulation, triggering a 2-phase process. In phase I, pulmonary artery vasospasm with pulmonary hypertension and elevated right ventricular pressure cause hypoxia. Hypoxia causes myocardial and pulmonary capillary damage, the left heart fails, and acute respiratory distress syndrome develops.
Women who survive the above events may enter phase II. This is a hemorrhagic phase characterized by massive hemorrhage with uterine atony and disseminated intravascular coagulation (DIC); however, fatal consumptive coagulopathy may be the initial presentation.
Clinical Features
The main clinical signs are:
· Respiratory distress
· Cyanosis
· Cardiovascular collapse
· DIC
· Coma
· Death
Amniotic fluid embolism usually occurs during labor but has occurred during abortion, abdominal trauma, and amnioinfusion. A woman in the late stages of labor becomes acutely dyspneic with hypotension; she may experience seizures quickly followed by cardiac arrest. Massive DIC-associated hemorrhage follows and then death. Most patients die within an hour of onset. In case reports patients are described as developing acute shortness of breath, sometimes with a cough, followed by severe hypotension. The following signs and symptoms are indicative of possible amniotic fluid embolism:
· Hypotension: Blood pressure may drop significantly with loss of diastolic measurement.
· Dyspnea: Labored breathing and tachypnea may occur.
· Seizure: The patient may experience tonic-clonic seizures.
· Cough: This is usually a manifestation of dyspnea.
· Cyanosis: As hypoxia/hypoxemia progresses, circumoral and peripheral cyanosis and changes in mucous membranes may manifest.
· Fetal bradycardia: In response to the hypoxic insult, fetal heart rate may drop to less than 110 beats per minute (bpm). If this drop lasts for 10 minutes or more, it is a bradycardia. A rate of 60 bpm or less over 3-5 minutes may indicate a terminal bradycardia.
· Pulmonary edema: This is usually identified on chest film.
· Cardiac arrest
· Uterine atony: Uterine atony usually results in excessive bleeding after delivery. Failure of the uterus to become firm with bimanual massage is diagnostic.
Diagnosis (Definitive)
· the demonstration of the components of amniotic fluid in the maternal circulation,
· histology of the lungs shows edema, alveolar hemorrhages, and emboli consisting of squamous cells, fat, mucin, bile, and lanugo hair.
The diagnosis has traditionally been made at autopsy when fetal squamous cells are found in the maternal pulmonary circulation; however, fetal squamous cells are commonly found in the circulation of laboring patients who do not develop the syndrome. In a patient who is critically ill, aspirate of the distal part of a pulmonary artery catheter that contains fetal squamous cells is considered suspicious but not diagnostic of amniotic fluid embolism syndrome. Do not neglect other causes of hemodynamic instability.
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Differential Diagnosis
· Thrombotic pulmonary embolism
· Air embolism
· Fat embolism
· Aspiration of gastric contents
· Eclampsia
· Stroke
· Heart failure
· Hemorrhagic shock
· Ruptured uterus
· Inverted uterus
· Anesthetic drug reaction
Laboratory Studies:
· Arterial blood gas (ABG): Expect changes consistent with hypoxia/hypoxemia.
· Decreased pH (reference range = 7. 40-7. 45)
· Decreased PO2 (reference range = 104-108 mm Hg)
· Increased PCO2 (reference range = 27-32 mm Hg)
· Base excess increased
· CBC with platelets
· Hemoglobin and hematocrit levels should be within reference ranges.
· Thrombocytopenia is rare. If platelets are less than 20, 000/µl, or if bleeding occurs and platelets are 20, 000-50, 000/µl, transfuse platelets at 1-3 U/10 kg/d.
· Prothrombin time and activated partial thromboplastin time
· Prothrombin time (PT) is prolonged because clotting factors are used up. Values are institution specific, but intervention is indicated when the PT is 1. 5 times the control value. Administer fresh frozen plasma (FFP) to normalize the PT.
· Activated partial thromboplastin time (aPTT) may be within reference ranges or shortened.
· If fibrinogen is less than 100 mg/dL, administer cryoprecipitate. Each unit of cryoprecipitate raises the fibrinogen level 10 mg/dL.
· Blood type and screen in anticipation of the requirement for a transfusion.
Imaging Studies:
· Chest x-ray posteroanterior and lateral findings are usually nonspecific, but evidence of pulmonary edema may be observed.
Histologic Findings:
· On autopsy, blood vessels in the lungs may show evidence of fetal debris (eg, squamous cells, vernix, mucin).
Procedures:
· Arterial line to accurately measure blood pressure and to obtain ABG readings.
· Pulmonary artery catheter to monitor wedge pressure, cardiac output, oxygenation, and systemic pressures
Management
· in severe cases, there is no effective therapy
· aims are reduction of pulmonary hypertension, increased tissue perfusion, relief of bronchospasm, control of hemorrhage, and general supportive measures
For the purpose the following should be given:
· Oxygen
· Bronchodilators and vasodilators
· Correction of coagulation disorders (plasma, cryoprecipitate)
· Blood transfusion
· Inotropes
· Manual exploration of uterus
· Corticosteroids
· Morphine
· Invasive hemodynamic monitoring
Medicamental Treatment
· Administer oxygen to maintain normal saturation. Intubate if necessary.
· Initiate cardiopulmonary resuscitation (CPR) if the patient arrests. If she does not respond to resuscitation, perform a perimortem cesarean delivery.
· Treat hypotension with crystalloid and blood products. Use pressors as necessary.
· Consider pulmonary artery catheterization in patients who are hemodynamically unstable.
· Continuously monitor the fetus.
· Treat coagulopathy with FFP for a prolonged aPTT, cryoprecipitate for a fibrinogen level less than 100 mg/dL, and transfuse platelets for platelet counts less than 20, 000/µL.
Surgical Care: Perform emergent cesarean delivery in arrested mothers who are unresponsive to resuscitation.
Consultations: Women who survive amniotic fluid embolism will probably require admission to an intensive care department. Left heart failure is a common late occurrence. Additionally, survivors will probably have neurologic sequelae.
· Consult the intensive care service in anticipation of transfer to that unit.
· Consult neurologists as needed if a patient shows signs of neurologic deficits.
Drugs are used in amniotic fluid embolism to stabilize the patient. Pressors are used to maintain blood pressure, and inotropes are used to improve contractility. Use of steroids has been suggested because the process may be immune mediated. Uterotonics may be used to limit postpartum bleeding.
Dopamine (Intropin) - One of several drugs that can be used to maintain perfusion. Dopamine increases myocardial contractility and systolic BP with little increase in diastolic BP. It also dilates the renal vasculature, increasing renal blood flow and GFR.
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Dosage: 2-5 mcg/kg/min IV; titrate to BP and cardiac output.
Contraindications: hypersensitivity; pheochromocytoma; ventricular fibrillation, hypovolemia. Interactions: Phenytoin, alpha- and beta-adrenergic blockers, general anesthesia, increases and prolongs effects of dopamine.
Precautions: Monitor urine flow, cardiac output, pulmonary wedge pressure, and BP during infusion; prior to infusion, correct hypovolemia with either whole blood or plasma, as indicated; monitoring central venous pressure or left ventricular filling pressure may be helpful.
Digoxin (Lanoxin, Lanoxicaps) - Cardiac glycoside that acts directly on the cardiac muscle and conduction system. Digoxin causes an increase in force and velocity of systolic contraction, a slowing of the heart rate, and decreased conduction velocity through the AV node.
Dosage: 0. 5 mg IV quickly, then 0. 25 mg intravenously slowly.
Contraindications: Documented hypersensitivity; ventricular fibrillation; beriberi heart disease; idiopathic hypertropic subaortic stenosis; constrictive pericarditis; carotid sinus syndrome. Interactions: Medications that may increase digoxin levels include, benzodiazepines, captopril, cyclosporine, quinidine, aminoglycosides, oral amiodarone, anticholinergics, erythromycin, felodipine, flecainide, hydroxychloroquine, itraconazole, nifedipine, ibuprofen, indomethacin, tetracycline, tolbutamide, and verapamil; medications that may decrease serum digoxin levels include aminoglutethimide, antihistamines, cholestyramine, neomycin, penicillamine, aminoglycosides, hypoglycemic agents, antineoplastic treatment combinations (eg, carmustine, bleomycin, methotrexate, cytarabine, doxorubicin, cyclophosphamide, vincristine, procarbazine), aluminum or magnesium antacids, rifampin, sucralfate, sulfasalazine, barbiturates, kaolin/pectin, and aminosalicylic acid.
Hydrocortisone (Hydrocortone, Hydrocort, Cortef) - Because amniotic fluid embolism is more similar to an anaphylactic reaction, steroids that mediate the immune responses are recommended.
Dosage: 500 mg intravenously.
Contraindications: Documented hypersensitivity; viral, fungal, or tubercular skin infections. Interactions: Corticosteroid clearance may decrease with estrogens; may increase digitalis toxicity secondary to hypokalemia.
Precautions: Drug-induced adrenocortical insufficiency; drug-induced psychosis; caution in hyperthyroidism, osteoporosis, peptic ulcer disease, cirrhosis, nonspecific ulcerative colitis, diabetes, and myasthenia gravis.
Oxytocin (Pitocin, Syntocinon) – This is most commonly used uterotonic. It decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reversing increased capillary permeability.
Dosage: 10 U intramuscularly or 10-40 U intravenously at 505 ml of 5% solution of glucose.
Contraindications: Documented hypersensitivity; pregnant patients with severe toxemia, unfavorable fetal positions, and a contracting uterus with hypertonic or hyperactive patterns; labor in which vaginal delivery should be avoided as at invasive cervical carcinoma, cord presentation or prolapse, active herpes genitalis, total placenta previa, and vasa previa. Interactions: Pressor effect of sympathomimetics may increase when used concomitantly with oxytocic drugs, causing postpartum hypertension. Precautions: A uterus that is overstimulated can be hazardous to both mother and fetus; hypertonic contractions can occur in a patient whose uterus is hypersensitive to oxytocin, regardless of whether it was appropriately administered; oxytocin has intrinsic antidiuretic effect that when administered by continuous infusion and patient is receiving fluids by mouth, can cause water intoxication.
Methylergometrine (Methylergonovine, Methergine) – It acts directly on uterine smooth muscle, causing a sustained tetanic uterotonic effect that reduces uterine bleeding.
Dosage: 0. 2 mg intramuscularly, may be repeated in a 10-15 min interval for 3 doses.
Contraindications: Documented hypersensitivity; glaucoma, anxiety.
Interactions: Concurrent administration of methylergonovine with vasoconstrictors or other ergot alkaloids may produce additive effect in sepsis, obliterative vascular disease, or hepatic or renal insufficiency
Precautions: Caution in cardiovascular disease, asthma, hypotension or hypertension, adrenal disease, diabetes, renal or hepatic disease, a compromised uterus, and jaundice; do not inject IV (may induce hypertension and bronchospasm).
Dinoprost -- Prostaglandin similar to F2-alpha but has longer duration and produces myometrial contractions that induce hemostasis at placentation site, which reduces postpartum bleeding.
Dosage: 0. 25 mg intramuscularly, it can be repeated in a 10-15min interval; not to exceed 3 doses. Precautions: Caution in cardiovascular disease, asthma, hypotension or hypertension, adrenal disease, diabetes, renal or hepatic disease, a compromised uterus, jaundice.
Complications:
Pulmonary edema is a common occurrence in survivors. Pay close attention to fluid input and output.
Left heart failure may occur. Some sources recommend inotropic support.
Treat DIC with blood components.
Prognosis:
Maternal mortality is 61%.
Most survivors have neurologic deficits.
The intact infant survival rate is 70%. Neurologic status of the infant is directly related to the time elapsed between maternal arrest and delivery.
Disseminated Intravascular Coagulation
Introduction
One of the most severe complications in obstetrical practice is acute disseminated intravascular coagulation (DIC). This is basically a state of increased propensity for clot formation triggered by a variety of stimuli related to such diverse disorders as sepsis, endothelial cell damage (heat stroke, shock), obstetrical complications (abruptio placenta, amniotic fluid embolism) and neoplasias. There may be clinical and laboratory evidence of hypercoagulability, but in acute cases, consumptive coagulopathy with hemorrhagic manifestations may predominate.
Pathophysiology
The normal response to tissue damage is a contained explosion of thrombin generation at the site of injury, which results in coagulation of blood on the surface of damaged microvessels and stops blood loss. In DIC, an unregulated thrombin explosion causes release of free thrombin into the circulation. Widespread microvascular thrombosis produces tissue ischemia and organ damage. In the attempt to maintain vascular patency, excess plasmin is generated so that systemic fibrinogenolysis as well as local fibrinolysis occurs. It is the generation of free thrombin and plasmin within the circulation that leads to the clinical features of DIC, with thrombin and plasmin responsible for the thrombotic and hemorrhagic manifestations, respectively. The diagnosis and treatment of this syndrome require an understanding of its pathophysiology, awareness of the disorders that can trigger it and its early recognition.
The endothelium acts like a fire extinguisher. Functional healthy endothelium concentrates antithrombin molecules on its surface and express thrombomodulin molecules. If thrombin is generated next to healthy endothelium, it is either captured and neutralized by antithrombin or binds to thrombomodulin, which alters its substrate specificity so radically that it is no longer capable of converting fibrinogen to fibrin. Instead, thrombomodulin bound thrombin activates the natural anticoagulant protein C system, which rapidly dismantles the fire. Thus, endothelial bound antithrombin and the protein C system are the extinguishers.
When thrombin is generated at the site of tissue damage, there is no intact endothelium and thus no extinguisher, and explosive thrombin generation causes blood to clot. As the thrombin explosion spreads, it eventually meets intact healthy endothelium outside the area of tissue damage. The explosion is then rapidly ended by the extinguishing properties described above. Hence, the thrombin generation is contained at the site of tissue damage.
DIC occurs when these antagonist systems of coagulation and anticoagulation are not balanced. Any component of the fire may be present in excess or the extinguishers may be damaged or rapidly used up, allowing the thrombin explosion to spread uncontrolled throughout the circulation. The endothelium may be disrupted so that tissue factor is released from tissue damaged by trauma, ischemia, infections, excessive metabolic stress, heat, chemicals, tumors or activation of the complement cascade. Alternatively, white blood cells may release tissue factor into the circulation in response to endotoxins, immune complexes or cancer cells. Snake venoms are capable of activating many components of the hemostatic system. Also, cytokine action may be critical to the development of DIC in many diseases. For example, Interleukin 1 can elicit production of tissue factor by endothelial cells and monocytes while simultaneously reducing the expression of thrombomodulin. Thus, when there is an inflammatory reaction, the hemostatic balance is shifted towards coagulation and away from anticoagulation.
Disseminated intravascular coagulation (DIC) is a life-threatening situation that can arise from a variety of obstetrical. Obstetrical DIC has been associated with a series of pregnancy complications including the following:
· acute peripartum hemorrhage (uterine atony, cervical and vaginal lacerations, and uterine rupture);
· placental abruption;
· preeclampsia/eclampsia/hemolysis, elevated liver enzymes, and low platelet count syndrome;
· retained stillbirth;
· septic abortion and intrauterine infection;
· amniotic fl uid embolism; and acute fatty liver of pregnancy.
DIC syndrome is acquired secondary acute pathology of hemostasis, which accompaines a critical condition. It refers to consumption coagulopathies, in which components of the blood coagulant and anticoagulant systems are consumed. Clinically, DIC of blood can be accompanied by both bleeding and thrombosis in the microcirculation zone with the formation of polyorganism deficiency. Prompt diagnosis and understanding of the underlying mechanisms of disease leading to this complication in essential for a favorable outcome. In recent years, novel diagnostic scores and treatment modalities along with bedside point-of-care tests were developed and may assist the clinician in the diagnosis and management of DIC. Team work and prompt treatment are essential for the successful management of patients with DIC.
The pathophysiology of DIC involves the initiation of coagulation via endothelial injury or tissue injury and the subsequent release of procoagulant material in the form of cytokines and tissue factors. Interleukin-6 and tumor necrosis factor may be the most influential cytokines involved in coagulation activation (via tissue factor) and may be responsible for the end-organ damage that occurs. Further, in the setting of sepsis, neutrophils and their secretory products may promote platelet-mediated fibrin formation.
Two proteolytic enzymes, thrombin and plasmin, are activated and circulate systemically. Their balance determines a bleeding or thrombotic tendency. Thrombin cleaves fibrinogen to form fibrin monomers. Thrombin ultimately potentiates the coagulation cascade and leads to small- and large-vessel thrombosis, with resultant organ ischemia and organ failure. Regulatory mechanisms of the coagulation cascade, such as tissue factor pathway inhibitor (TFPI), antithrombin III, and activated protein C, are largely defective. Plasmin, a component of the fibrinolytic system, is capable of degrading fibrin into measurable degradation products. Plasmin also activates complement. Plasmin and thrombin induce qualitative and quantitative platelet abnormalities.
Clinical Features
History: In addition to the symptoms related to the underlying disease process, ascertain history of blood loss and hypovolemia, such as gastrointestinal bleeding. Look for symptoms and signs of thrombosis in large vessels, such as deep venous thrombosis (DVT), and of microvascular thrombosis, such as renal failure. Bleeding from at least 3 unrelated sites is particularly suggestive of DIC.
· Epistaxis
· Gingival bleeding
· Mucosal bleeding
· Cough
· Dyspnea
· Confusion, disorientation
· Fever
Physical:
· Circulation
· Signs of spontaneous and life-threatening hemorrhage
· Signs of subacute bleeding
· Signs of diffuse or localized thrombosis
· Central nervous system
· Nonspecific altered consciousness/stupor
· Focal deficits are not usually present
· Cardiovascular system
· Hypotension
· Tachycardia
· Circulatory collapse
· Respiratory system
· Pleural friction rub
· Signs of adult respiratory distress syndrome (ARDS)
· Gastrointestinal system
· Hematemesis
· Hematochezia
· Genitourinary system
· Signs of azotemia and renal failure
· Acidosis
· Hematuria
· Oliguria
· Metrorrhagia
· Dermatologic system
· Petechiae
· Purpura
· Hemorrhagic bullae
· Acral cyanosis
· Skin necrosis of lower limbs (purpura fulminans)
· Localized infarction and gangrene
· Wound bleeding and deep subcutaneous hematomas
· Thrombosis
Causes: Causes of DIC can be classified as acute or chronic, systemic or localized. DIC may be the result of a single or multiple conditions.
· Acute DIC
· Infectious
§ Bacterial (eg, gram-negative sepsis, gram-positive infections, rickettsial)
§ Viral (eg, HIV, cytomegalovirus [CMV], varicella, hepatitis)
§ Fungal (eg, histoplasma)
§ Parasitic (eg, malaria)
· Malignancy
§ Hematologic (eg, acute myelocytic leukemias)
§ Metastatic (eg, mucin-secreting adenocarcinomas)
· Obstetric
§ Placental abruption
§ Amniotic fluid embolism
§ Acute fatty liver of pregnancy
§ Eclampsia
· Trauma
· Burns
· Motor vehicle accidents (MVAs)
· Snake envenomation
· Transfusion
· Hemolytic reactions
· Massive transfusion
· Liver disease - Acute hepatic failure
· Prosthetic devices
· Shunts (Denver, LeVeen)
· Ventricular assist devices
· Chronic DIC
· Malignancies
§ Solid tumors
§ Leukemia
· Obstetric
§ Retained dead fetus syndrome
§ Retained products of conception
· Hematologic
§ Myeloproliferative syndromes
§ Paroxysmal nocturnal hemoglobinuria
· Vascular
§ Rheumatoid arthritis
§ Raynaud disease
· Cardiovascular - Myocardial infarction
· Inflammatory
§ Ulcerative colitis
§ Crohn disease
§ Sarcoidosis
· Localized DIC
· Aortic aneurysms
· Giant hemangiomas (Kasabach-Merritt syndrome)
· Acute renal allograft rejection
· Hemolytic uremic syndrome
Laboratory Studies:
· Prothrombin fragment 1 and 2
· Enzyme-linked immunosorbent assay (ELISA) estimates levels of prothrombin fragment (PF) 1 and 2 in the circulations. This provides evidence of factor Xa generation and is easily performed.
· Levels are abnormal in 90% of patients with DIC.
· D-dimer test
· D-dimer is an antigen formed as a result of plasmin lysis of cross-linked fibrin clots.
· The presence of this fragment documents the presence of thrombin (cross-linking) and plasmin (fibrinolysis).
· This monoclonal antibody test has the greatest specificity and is a highly reliable test for diagnosis of DIC.
· Antithrombin III level
· Functional antithrombin III levels decrease in DIC.
· This synthetic substrate assay is a reliable and useful test for diagnosis and therapeutic monitoring.
· Fibrin and fibrinogen degradation products
· Latex particle agglutination test is used to detect fibrinogen and fibrin degradation products (FDPs).
· Degradation products increase as plasmin biodegrades fibrinogen and fibrin.
· This test is not diagnostic of DIC, yet levels are elevated in 85-100% of patients.
· Fibrinopeptide A
· ELISA or radioimmunoassay is used to measure fibrinopeptide A (FPA).
· FPA is a breakdown product of fibrinogen, indicative of thrombin activity.
· Levels are abnormal in 88% of patients with DIC.
· Platelet count
· Platelet counts are invariably decreased. This is usually evident in the peripheral smear.
· Functional deficits in platelets are often present, and further studies are not indicated.
· Fibrinogen
· Thrombin-time–based assay is used to measure fibrinogen levels.
· Levels usually are decreased in DIC.
· Fibrinogen is an acute-phase reactant and initially may be elevated secondary to the primary disease.
· Prothrombin time
· Prothrombin time (PT) tests the extrinsic and common pathways.
· PT may be normal, prolonged, or shortened in DIC.
· It is generally an unreliable test for diagnosis of DIC, and 50-75% of patients have prolonged values.
· Activated partial thromboplastin time
· Activated partial thromboplastin time (aPTT) tests the intrinsic and common pathways.
· Values are unpredictable in DIC.
· It is an unreliable test for diagnosis of DIC, and 50-60% of patients will have prolonged values.
· Thrombin time
· Thrombin time measures the conversion of fibrinogen to fibrin.
· It should be prolonged in DIC.
· Protamine test
· The protamine test is a paracoagulation test that detects fibrin monomers in plasma.
· Fibrin web formation indicates a positive result.
· This test should be positive in patients with DIC.
· Anemia
· Schizocytosis
· Decreased coagulation factors
· Factor V
· Factor VIII
· Factor X
· Factor XIII
· Protein C
· Hemoglobinuria
· Hematuria
· Hematochezia
· No single diagnostic test exists for DIC. DIC is initially suggested by the following combination: a clinical condition consistent with DIC, thrombocytopenia (< 100 X 109/l), prolonged PT and aPTT, and presence of FDP/D-dimer. Other tests listed here also may help to exclude DIC.
Imaging Studies:
· Base diagnostic imaging on the underlying pathologic process as well as suspicion for areas of thrombosis and hemorrhage.
· Perform a bilateral perihilar soft-density chest radiograph if pulmonary injury is present.
Other Tests:
· Base other tests on the underlying pathologic process as well as suspicion for areas of thrombosis and hemorrhage.
Procedures:
· Base procedures on the underlying pathologic process as well as suspicion of areas of thrombosis and hemorrhage.
· Conduct invasive procedures with care because of bleeding complications. Procedures should follow the administration of clotting factor and platelet repletion.
Treatment
Prehospital Care: Monitor vital signs, assess and document extent of hemorrhage and thrombosis, correct hypovolemia, and administer basic hemostatic procedures when indicated.
Emergency Department Care: The cornerstone of DIC management is treatment of the underlying disorder. The following supportive measures are essential:
· Continue prehospital measures.
· Attend to life-threatening issues such as airway compromise or severe hemorrhage.
· Determine the underlying cause of the patient's DIC and initiate therapy. Obtain appropriate imaging studies if necessary.
· Draw specimens for appropriate coagulation studies and other diagnostic laboratory tests.
· Begin anticoagulant therapy if indicated (see Medication).
· Replace blood products as indicated (see Medication).
· RBC transfusion (ie, packed RBCs [PRBCs])
· Platelet concentrates
· Fresh frozen plasma (FFP)
· Cryoprecipitate
· Antithrombin III concentrate
Consultations:
· Consult a hematologist for assistance with diagnosis and management.
· Consult a transfusion specialist or a blood bank; determine the availability of general and specialized blood products that may be necessary for the acute management of fulminant DIC.
· Consult a critical care specialist if multiple organ failure is present.
· Early consultation is indicated for this complicated, life-threatening condition. Obtain other subspecialty consultations as indicated by the patient's primary diagnosis.
Medication
Therapy should be based on etiology and aimed at eliminating the underlying disease. Therapy should be appropriately aggressive for the patient's age, disease, and the severity and location of hemorrhage/thrombosis. Treatment for acute DIC includes anticoagulants, blood components, and antifibrinolytics.
Hemostatic and coagulation parameters should be monitored continuously during treatment. Base therapeutic decisions on clinical and laboratory evaluation of hemostasis. In cases of low-grade DIC, therapy other than supportive care may not be warranted or may include antiplatelet agents or subcutaneous heparin; treatment decisions should be based on clinical and laboratory evaluation of hemostasis. Activated human protein C has been shown to reduce the rate of mortality in the setting of severe sepsis for patients at high risk for death; this should be used cautiously and appropriately, following guidelines for administration.
Drug Category: Anticoagulant agents - These agents are used in the treatment of clinically evident intravascular thrombosis when the patient continues to bleed or clot 4-6 h after initiation of primary and supportive therapy. Thrombosis can present as purpura fulminans or acral ischemia. Take special precaution in obstetric emergencies or massive liver failure. The antiinflammatory properties of antithrombin III may be particularly useful in DIC secondary to sepsis.
Heparin -- Use and dose of heparin is based on severity of DIC, underlying cause, and extent of thrombosis. Monitoring results of therapy is mandatory. Heparin augments antithrombin III activity and prevents conversion of fibrinogen to fibrin. It does not actively lyse but inhibits further thrombogenesis. It prevents reaccumulation of a clot after spontaneous fibrinolysis.
Dosage: 80-100 U/kg SC q4-6h or 20, 000-30, 000 U/d intravenously continuous infusion.
Contraindications: Documented hypersensitivity; subacute bacterial endocarditis; active bleeding; history of heparin-induced thrombocytopenia.
Interactions: Digoxin, nicotine, tetracycline, and antihistamines may decrease effects; aspirin, dextran, dipyridamole, and hydroxychloroquine may increase toxicity.
Pregnancy: Safety for use during pregnancy has not been established.
Precautions: Monitor for localized bleeding or hematoma; it may aggravate hemorrhage; in neonates, preservative-free heparin is recommended to avoid possible toxicity (gasping syndrome) by benzyl alcohol, which is used as preservative; caution in severe hypotension and shock.
Antithrombin III (ATnativ, Thrombate III) – it is used for moderately severe to severe DIC or when levels are depressed markedly. Alpha 2-globulin inactivates thrombin, plasmin, and other serine proteases of coagulation, including factors IXa, Xa, XIa, XIIa, and VIIa. These effects inhibit coagulation.
Dosage. Loading dose of 100 U/kg IV over 3 h; followed by continuous infusion of 100 U/kg/d.
Contraindications: Documented hypersensitivity.
Interactions: It increases anticoagulation effects of heparin.
Pregnancy: Safety for use during pregnancy has not been established.
Precautions: Caution in hypotension; despite measures taken to delete infectious agents from human product, potentially it can still transmit disease or contain unknown infectious agents.
Recombinant Human Activated Protein C - These agents inhibit factors Va and VIIIa of the coagulation cascade. They may also inhibit plasminogen activator inhibitor-1 (PAI-1).
Drotrecogin alfa-activated (Xigris) – It is indicated for reduction of mortality in patients with severe sepsis associated with acute organ dysfunction and at high risk of death. It is a recombinant form of human activated protein C that exerts antithrombotic effect by inhibiting factors Va and VIIIa. It has an indirect profibrinolytic activity by inhibiting PAI-1 and limiting formation of activated thrombin-activatable-fibrinolysis-inhibitor. It may exert antiinflammatory effect by inhibiting human tumor necrosis factor (TNF) production by monocytes, blocking leukocyte adhesion to selectins, and limiting thrombin-induced inflammatory responses within microvascular endothelium.
Dosage: 24 mcg/kg/h IV by continuous infusion over 96 h.
Contraindications: Documented hypersensitivity; increased risk of bleeding (eg, active internal bleeding, recent hemorrhagic stroke, recent intraspinal or intracranial surgery, recent or current trauma, presence of epidural catheter, intracranial neoplasm, cerebral herniation, severe head trauma).
Interactions: None reported; coadministration with drugs that affect hemostasis may increase risk of bleeding (eg, warfarin, heparin, thrombolytics, glycoprotein IIb/IIIa inhibitors).
Pregnancy: Safety for use during pregnancy has not been established.
Precautions: Bleeding is most common serious adverse effect; caution with conditions that increase risk of bleeding including INR > 3, concurrent therapeutic heparin (> 15 U/kg/h), within 6 wk of GI bleeding episode, within 3 d of thrombolytic therapy, within 7 d of platelet inhibitors administration, within 3 months of ischemic stroke, intracranial arteriovenous malformation or aneurysm, known bleeding diathesis, chronic severe hepatic disease; stop infusion if clinically significant bleeding occurs; caution with thrombocytopenia (< 50 x 109/l); chronic severe hepatic disease and known bleeding diathesis not associated with the acute coagulopathy related to sepsis.
Drug Category: Blood components - Blood components are used to correct abnormal hemostatic parameters. These products should be considered only after initial supportive and anticoagulant therapy. Washed PRBCs and platelet concentrates are considered safe in uncontrolled DIC. Specialized blood components (fresh frozen plasma, cryoprecipitate) may interfere with or improve DIC.
PRBCs (washed) – These are preferred to whole blood since they limit volume, immune, and storage complications. Obtain PRBCs after centrifugation of whole blood. Use washed or frozen PRBCs in individuals with hypersensitivity transfusion reactions.
Dosage: 1 unit of PRBCs should raise hemoglobin by 1 g/dL or raise hematocrit by 3%.
Contraindications: Competent adult or legal guardian may refuse blood product; immediate consultation with hospital ethical and legal staff is mandated.
Interactions: None reported.
Pregnancy: Safe in pregnancy.
Precautions: Use CMV-negative units or filtered ones; transfusion reactions and transmission of blood-borne pathogens are a concern; benefits should outweigh risks associated with such products.
Platelet concentrates (Random or single donor, pheresis units) – These are considered safe for use in acute DIC.
Dosage: Based on platelet count and clinical situation.
Contraindications: Competent adult or legal guardian may refuse blood product; immediate consultation with hospital ethical and legal staff is mandated.
Interactions: None reported.
Pregnancy: Safe in pregnancy.
Precautions: Platelets should be CMV-negative or the pheresis units from single donors filtered; benefits should outweigh risks associated with such products.
Fresh frozen plasma (FFP) -- This treatment entails removing blood from body, spinning it to separate cells from plasma, and replacing cells suspended in fresh frozen plasma, albumin, or saline. It contains coagulation factors as well as protein C and protein S. It can be performed using either 2 large-bore peripheral IV sites or multiple lumen central line. FFP may be used as a source of antithrombin-III, and may have benefit in a patient with antithrombin-III level < 60% and severe bleeding. It is recommended with active bleeding and fibrinogen < 100 mg/ml.
Dosage: 15-20 ml/kg IV or based on clinical situation.
Contraindications: Documented hypersensitivity.
Interactions: None reported.
Pregnancy: Safe in pregnancy.
Precautions: Viral contamination and infection are remotely possible but unlikely.
Cryoprecipitate or fibrinogen concentrates -- Not commonly recommended except when fibrinogen is needed.
Dosage: Each bag contains 80-100 U of factor VIII; base administration on fibrinogen levels, antithrombin III levels, and coagulation parameters.
Contraindications: Documented hypersensitivity; uncontrolled DIC with abnormal antithrombin III levels.
Interactions: None reported.
Pregnancy: Safe in pregnancy.
Precautions: Benefits should outweigh risks associated with transfusion therapy; viral contamination and infection are remotely possible although unlikely because of prescreening.
Drug Category: Antifibrinolytic agents -- These agents are used only after all other therapeutic modalities have been tried and deemed unsuccessful. Increase in circulating plasmin and laboratory evidence of decreased plasminogen should be documented. Antifibrinolytics may be useful in cases of DIC secondary to hyperfibrinolysis associated with acute promyelocytic leukemia and other forms of cancer.
Aminocaproic acid (Amicar) – It inhibits fibrinolysis via inhibition of plasminogen activator substances and, to a lesser degree, through antiplasmin activity. The main problem is that thrombi that form during treatment are not lysed, and clinical significance of reducing bleeding is uncertain.
Dosage: Load 5-10 g intravenously slowly; followed by 2-4 g/h IV; not to exceed 30 g/d.
Contraindications: Documented hypersensitivity; evidence of active intravascular clotting process; as aminocaproic acid can be fatal in patients with DIC, it is important to differentiate between hyperfibrinolysis and DIC.
Interactions: Estrogens may cause increase in clotting factors, leading to hypercoagulable state.
Pregnancy: Safety for use during pregnancy has not been established.
Precautions: Do not administer unless definite diagnosis of hyperfibrinolysis has been made; caution in cardiac, hepatic, or renal disease.
Further Inpatient Care:
· Most patients with acute DIC require critical care treatment appropriate for the primary diagnosis, occasionally including emergent surgery.
· Assessment of severity of DIC (DIC score)
· A DIC scoring system has been proposed by Bick to assess the severity of the coagulopathy as well as the effectiveness of therapeutic modalities.
· Clinical and laboratory parameters are measured with regularity (every 8 h).
Further Outpatient Care:
· Patients who recover from acute DIC should follow up with their primary physician or a hematologist.
· Patients with low-grade or chronic DIC may be treated by a hematologist on an outpatient basis after initial assessment and stabilization.
In/Out Patient Meds:
· Outpatient medications may include antiplatelet agents for those with low-grade DIC and/or antibiotics appropriate to the primary diagnosis.
Transfer:
· Patients who are stable enough for transfer should be referred expeditiously to centers with appropriate critical care and subspecialty expertise, such as hematology, blood bank, or surgical centers.
Complications:
· Acute renal failure
· Life-threatening thrombosis and hemorrhage (in patients with moderately severe to severe DIC)
· Cardiac tamponade
· Hemothorax
· Intracerebral hematoma
· Gangrene and loss of digits
· Death
Prognosis:
· The prognosis is influenced most by the underlying condition that led to DIC and the severity of the DIC.
Self Test
1. Which of the following may cause a suspicion on shock?
A. systolic blood pressure of 90 mmHg or less
B. diastolic blood pressure of 90 mmHg
C. systolic blood pressure of 60 mmHg
D. diastolic blood pressure of 60 mmHg or less
2. Blood should not be transfused to patients with hypovolemic shock in whom the hematocrit is:
A. lower than 30-35%
B. higher than 30-35%
C. higher than 25-29%
D. lower than 25%
3. Hetastarch is:
A. colloid solution
B. cristalloid solution
C. inhibitor of fibrinolisis
4. Which of the following is most effective in treatment of septic shock?
A. antibiotic therapy
B. surgical measures
C. corticosteroids
D. combined therapy
5. All the following may be a reason of amniotic fluid embolism, except for:
A. strong uterine contractions
B. hydramnios
C. large fetus
D. low intrauterine pressure
6. Amniotic fluid embolism usually occurs during
A. labor
B. uncomplicated pregnancy
7. The following signs and symptoms are indicative of possible amniotic fluid embolism, except for:
A. hypotension
B. dyspnea
C. cough
D. cyanosis
E. uncoordinated labor pains
8. Antithrombin III levels:
A. decrease in DIC
B. increase in DIC
C. permanent in DIC
9. Blood components should be considered:
A. after initial supportive and anticoagulant therapy
B. before the anticoagulant therapy
10. Fibrinogen levels are usually
A. decreased in DIC
B. increased in DIC
C. non-characteristic of DIC
CHAPTER 39. VIRAL INFECTIONS
Viral syndromes in pregnancy pose variable risks to the unborn fetus. Maternal morbidity and mortality are rare.
Human Immunodeficiency Virus (HIV)
There are two main types of HIV: type 1 (HIV-1) is the most common, with HIV type-2 (HIV-2) found predominantly in West Africa, with some pockets in Angola and Mozambique. While HIV-1 prevalence is increasing in these areas, the prevalence of HIV-2 has remained fairly stable, and the clinical course of HIV-2 disease is slower than that of HIV-1. Dual infection with HIV-1 and HIV-2 is possible, although it has been suggested that HIV-2 infection may confer some protection against HIV-1 acquisition.
Epidemiology
The Joint United Nations Programme on HIV/AIDS (UNAIDS) has estimated that in 2017, approximately 36. 7 million people worldwide (1% of the global adult population aged 15-49 y) were infected with HIV, of which 1. 8 million people were newly infected; 64% of all people living with HIV worldwide live in sub-Saharan Africa. New HIV infection rates are declining globally as a result of efforts to strengthen HIV prevention and treatment programs. Worldwide, new infections among children declined 47% since 2010 as coverage of ART provided to pregnant women rose 29% in the same time. Unfortunately, young women in high-prevalence areas of the world, such as sub-Saharan Africa, continue to remain at high risk for HIV with 26% of new infections occurring in women aged 15-24 years despite this age group making up only 10% of the population.
The human immunodeficiency virus (HIV) causes an incurable infection that leads ultimately to a terminal disease called Acquired immunodeficiency syndrome (AIDS).
Clinical features of AIDS
There are large signs and minor signs.
Large signs: loss of body weight by more than 10% of initial, chronic diarrhea continued during > 1 month (constant or intermittent);
Minor signs: pertinacious, persistent cough continued during > 1 month, generalized itching dermatosis, herpes zoster in previous history, oropharyngeal candidosis, recurrent vaginal candidiasis, chronic persistent or disseminated herpetic infection (herpes simplex), generalized lymphadenopathy, persistent warts and genital ulcers. Fever, a macular erythematous rash, pharyngitis and conjunctivitis are also typical.
Thus, the most common AIDS-presenting illnesses are the following:
· pulmonary: pneumocystis carinii pneumonia, tuberculosis (pulmonary or extra pulmonary);
· neurological: cerebral toxoplasmosis, cryptococcal meningitis, AIDS dementia;
· gastrointestinal: diarrhoea and wasting syndrome which may be due to infection with Cryptosporidium, Microsporidium, Isospors, oropharyngeal candidosis;
· ophthalmic: cytomegalovirus retinitis;
· malignancy: Kaposi’s sarcoma, Non-Hodgkin’s lymphoma;
· systemic: Mycobacterium avium-intracellular complex (MAC) infection.
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