Septic Shock

INTRODUCTION ¡@

Background:

History of infectious diseases

During thousands of years of human existence, epidemic infectious diseases probably were rare, with most infections occurring as a result of trauma or from physical contact with animals. In 2735 BC, Chinese emperor Sheng Nung recorded the use of an herbal remedy to treat fever. Over the next 2 millennia, epidemics of cholera, plague (black death), smallpox, measles, tuberculosis, and gonorrhea spread worldwide, wiping out huge segments of the population. In 1546, Hieronymus Fracastorius suggested germ theory for infections.

John Pringle, a British army surgeon, proposed the concept of antisepsis for the first time. In the 19th century, antiseptic practices lead to a reduction in mortality from puerperal fever from 13.6% to 1.5% in a Vienna hospital. In 1879, Louis Pasteur identified Streptococcus bacteria as the cause of puerperal sepsis. In 1892, Richard Pfeiffer identified the toxin that causes shock in patients. In 1928, Alexander Fleming recognized that his bacterial cultures were killed by a blue mold, Penicillium notatum. Thus, with the discovery of penicillin, a new era began, with antibiotics used to treat bacterial infections. In 1944 in the United States, Waksman discovered that streptomycin was effective in the treatment of tuberculosis.

Further advances in medical sciences in the late 20th century enhanced our understanding of sepsis and septic shock—recognition of inflammatory mediators stimulating nitric oxide production; producing endothelial injury; activating coagulation cascade; and eventually leading to organ ischemia, damage, and, ultimately, death. This knowledge will lead to novel approaches to treat severe sepsis in the future.

Sepsis and septic shock

In 1914, Schottmueller wrote, “Septicemia is a state of microbial invasion from a portal of entry into the blood stream which causes sign of illness.?The definition did not change much over the years because the terms sepsis and septicemia referred to several ill-defined clinical conditions present in a patient with bacteremia. In practice, the terms often were used interchangeably; however, less than one half of the patients with signs and symptoms of sepsis have positive results on blood culture. Furthermore, not all patients with bacteriemia have signs of sepsis; therefore, sepsis and septicemia are not identical. In the last few decades, discovery of endogenous mediators of the host response have led to the recognition that the clinical syndrome of sepsis is the result of excessive activation of host defense mechanisms rather than the direct effect of microorganisms. Sepsis and its sequelae represent a continuum of clinical and pathophysiologic severity.

Serious bacterial infections at any body site, with or without bacteremia, usually are associated with important changes in the function of every organ system in the body. These changes are mediated mostly by elements of the host immune system against infection. Shock is deemed present when volume replacement fails to increase blood pressure to acceptable levels and associated clinical evidence indicates inadequate perfusion of major organ systems, with progressive failure of organ system functions.

Multiple organ dysfunctions, the extreme end of the continuum, are incremental degrees of physiological derangements in individual organs (a process rather than an event). Alteration in organ function can vary widely from a mild degree of organ dysfunction to frank organ failure.

The American College of Chest Physicians (ACCP)/Society of Critical Care Medicine (SCCM) consensus conference definitions of sepsis, severe sepsis, and septic shock (Bone, 1992) are outlined below.

Systemic inflammatory response syndrome (SIRS): The systemic inflammatory response to a wide variety of severe clinical insults manifests by 2 or more of the following conditions:

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Sepsis: This is a systemic inflammatory response to a documented infection. The manifestations of sepsis are the same as those previously defined for SIRS. The clinical features include 2 or more of the following conditions as a result of a documented infection:

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With sepsis, at least 1 of the following manifestations of inadequate organ function/perfusion also must be included:

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Severe sepsis: This is sepsis and SIRS associated with organ dysfunction, hypoperfusion, or hypotension. Hypoperfusion and perfusion abnormalities may include, but are not limited to, lactic acidosis, oliguria, or an acute alteration in mental status. The systemic response to infection is manifested by 2 or more of the following conditions:

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Sepsis-induced hypotension (ie, systolic blood pressure <90 mm Hg or a reduction of >40 mm Hg from baseline): This may develop despite adequate fluid resuscitation, along with the presence of perfusion abnormalities that may include lactic acidosis, oliguria, or an acute alteration in mental state.

Septic shock: A subset of people with severe sepsis develop hypotension despite adequate fluid resuscitation, along with the presence of perfusion abnormalities that may include lactic acidosis, oliguria, or an acute alteration in mental status. Patients receiving inotropic or vasopressor agents may not be hypotensive by the time that they manifest hypoperfusion abnormalities or organ dysfunction.

Multiple organ dysfunction syndrome (MODS): This is the presence of altered organ function in a patient who is acutely ill and in whom homeostasis cannot be maintained without intervention.

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Pathophysiology:

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Mediator-induced cellular injury

The evidence that sepsis results from an exaggerated systemic inflammatory response induced by infecting organisms is compelling; inflammatory mediators are the key players in the pathogenesis.

The gram-positive and gram-negative bacteria induce a variety of proinflammatory mediators, including cytokines. Such cytokines play a pivotal role in initiating sepsis and shock. The bacterial cell wall components are known to release the cytokines; these include lipopolysaccharide (gram-negative bacteria), peptidoglycan (gram-positive and gram-negative bacteria), and lipoteichoic acid (gram-positive bacteria).

Several of the harmful effects of bacteria are mediated by proinflammatory cytokines induced in host cells (macrophages/monocytes and neutrophils) by the bacterial cell wall component. The most toxic component of the gram-negative bacteria is the lipid A moiety of lipopolysaccharide. The gram-positive bacteria cell wall leads to cytokine induction via lipoteichoic acid. Additionally, gram-positive bacteria may secrete the super antigen cytotoxins that bind directly to the major histocompatibility complex (MHC) molecules and T-cell receptors, leading to massive cytokine production.

A major role for tumor necrosis factor (TNF) and interleukin (IL)-1 has been demonstrated. Both of these factors also help to keep infections localized, but, once the infection becomes systemic, the effects are detrimental. Circulating levels of IL-6 correlate well with the outcome. High levels of IL-6 are associated with mortality, but its role in pathogeneses is not clear. IL-8 is an important regulator of neutrophil function, synthesized and released in significant amounts during sepsis. IL-8 contributes to the lung injury and dysfunction of other organs. The chemokines (monocyte chemoattractant protein?) orchestrate the migration of leukocytes during endotoxemia and sepsis. The other cytokines that have a supposed role in sepsis are IL-10, interferon-gamma, IL-12, macrophage migration inhibition factor, granulocyte colony-stimulating factor (G-CSF), and granulocyte macrophage colony-stimulating factor (GM-CSF).

The complement system is activated and contributes to the clearance of the infecting microorganisms but probably also enhances the tissue damage. The contact systems become activated; consequently, bradykinin is generated. Hypotension, the cardinal manifestation of sepsis, occurs via induction of nitric oxide. Nitric oxide plays a major role in hemodynamic alteration of septic shock, which is hyperdynamic shock. A dual role exists for neutrophils; they are necessary for defense against microorganisms but also may become toxic inflammatory mediators contributing to tissue damage and organ dysfunction.

The lipid mediators (eicosanoids), platelet activating factor, and phospholipase A2 are generated during sepsis, but their contributions to the sepsis syndrome remain to be established.

Table 1. Mediators of Sepsis

Type Mediator Activity
Cellular mediators Lipopolysaccharide Activation of macrophages, neutrophils, platelets, and endothelium releases various cytokines and other mediators
Lipoteichoic acid
Peptidoglycan
Superantigens
Endotoxin
Humoral mediators Cytokines Potent proinflammatory effect

Neutrophil chemotactic factor

Acts as pyrogen, stimulates B and T lymphocyte proliferation, inhibits cytokine production, induces immunosuppression

Activation and degranulation of neutrophils

Cytotoxic, augments vascular permeability, contributes to shock

Involved in hemodynamic alterations of septic shock

Promote neutrophil and macrophage, platelet activation and chemotaxis, other proinflammatory effects

Enhance vascular permeability and contributes to lung injury

Enhance neutrophil-endothelial cell interaction, regulate leukocyte migration and adhesion, and play a role in pathogenesis of sepsis
TNF-alpha and IL-1b
IL-8
IL-6
IL-10
MIF*
G-CSF
Complement
Nitric oxide
Lipid mediators
Phospholipase A2
PAF?/sup>
Eicosanoids
Arachidonic acid metabolites
Adhesion molecules
Selectins
Leukocyte integrins

*Macrophage inhibitory factor
†Platelet activating factor

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Abnormalities of coagulation and fibrinolysis homeostasis in sepsis

An imbalance of homeostatic mechanisms lead to disseminated intravascular coagulopathy (DIC) and microvascular thrombosis causing organ dysfunction and death (Lorente, 1993; McGillvary, 1998; Levi, 1999). Inflammatory mediators instigate direct injury to the vascular endothelium; the endothelial cells release tissue factor (TF), triggering the extrinsic coagulation cascade and accelerating production of thrombin (Carvalho, 1994). The coagulation factors are activated as a result of endothelial damage, the process is initiated via binding of factor XII to the subendothelial surface. This activates factor XII, and then factor XI and, eventually, factor 10 are activated by a complex of factor IX, factor VIII, calcium, and phospholipid. The final product of the coagulation pathway is the production of thrombin, which converts soluble fibrinogen to fibrin. The insoluble fibrin, along with aggregated platelets, forms intravascular clots.

Inflammatory cytokines, such as IL-1a, IL-1b, and TNF-alpha initiate coagulation by activation of TF, which is the principle activator of coagulation. TF interacts with factor VIIa, forming factor VIIa-TF complex, which activates factor X and IX. Activation of coagulation in sepsis has been confirmed by marked increases in thrombin-antithrombin complex (Levi, 1993) and the presence of D-dimer in plasma, indicating activation of clotting system and fibrinolysis (Mammen, 1998). Tissue plasminogen activator (t-PA) facilitates conversion of plasminogen to plasmin, a natural fibrinolytic.

Endotoxins increase the activity of inhibitors of fibrinolysis, which are plasminogen activator inhibitor (PAI-1) and thrombin activatable fibrinolysis inhibitor (TAFI). Furthermore, the levels of protein C and endogenous activated protein C also are decreased in sepsis. Endogenous activated protein C is an important proteolytic inhibitor of coagulation cofactors Va and VIIa. Thrombin via thrombomodulin activates protein C that functions as an antithrombotic in the microvasculature. Endogenous activated protein C also enhances fibrinolysis by neutralizing PAI-1 and by accelerating t-PA–dependent clot lysis.

The imbalance among inflammation, coagulation, and fibrinolysis results in widespread coagulopathy and microvascular thrombosis and suppressed fibrinolysis, ultimately leading to multiple organ dysfunction and death.

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Circulatory and metabolic pathophysiology of septic shock

The predominant hemodynamic feature of septic shock is arterial vasodilation. Diminished peripheral arterial vascular tone may result in dependency of blood pressure on cardiac output, causing vasodilation to result in hypotension and shock if insufficiently compensated by a rise in cardiac output. Early in septic shock, the rise in cardiac output often is limited by hypovolemia and a fall in preload because of low cardiac filling pressures. When intravascular volume is augmented, the cardiac output usually is elevated (the hyperdynamic phase of sepsis and shock). Even though the cardiac output is elevated, the performance of the heart, reflected by stroke work as calculated from stroke volume and blood pressure, usually is depressed. Factors responsible for myocardial depression of sepsis are myocardial depressant substances, coronary blood flow abnormalities, pulmonary hypertension, various cytokines, nitric oxide, and beta-receptor down-regulation.

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Peripheral circulation during septic shock

An elevation of cardiac output occurs; however, the arterial-mixed venous oxygen difference usually is narrow, and the blood lactate level is elevated. This implies that low global tissue oxygen extraction is the mechanism that may limit total body oxygen uptake in septic shock. The basic pathophysiologic problem seems to be a disparity between the uptake and oxygen demand in the tissues, which may be more pronounced in some areas than in others. This is termed maldistribution of blood flow, either between or within organs, with a resultant defect in capacity to extract oxygen locally. During a fall in oxygen supply, cardiac output becomes distributed so that most vital organs, such as the heart and brain, remain relatively better perfused than nonvital organs. However, sepsis leads to regional changes in oxygen demand and regional alteration in blood flow of various organs.

The peripheral blood flow abnormalities result from the balance between local regulation of arterial tone and the activity of central mechanisms (eg, autonomic nervous system). The regional regulation, release of vasodilating substances (eg, nitric oxide, prostacyclin), and vasoconstricting substances (eg, endothelin) affect the regional blood flow. Development of increased systemic microvascular permeability also occurs, remote from the infectious focus, contributing to edema of various organs, particularly the lung microcirculation and development of acute respiratory distress syndrome (ARDS).

In patients experiencing septic shock, the delivery of oxygen is relatively high, but the global oxygen extraction ratio is relatively low. The oxygen uptake increases with a rise in body temperature despite a fall in oxygen extraction.

In patients with sepsis who have low oxygen extraction and elevated arterial blood lactate levels, oxygen uptake depends on oxygen supply over a much wider range than normal. Therefore, oxygen extraction may be too low for tissue needs at a given oxygen supply, and oxygen uptake may increase with a boost in oxygen supply, a phenomenon termed oxygen uptake supply dependence or pathological supply dependence. However, this concept is controversial because other investigators argue that supply dependence is artifactual rather than a real phenomenon.

Maldistribution of blood flow, disturbances in the microcirculation, and, consequently, peripheral shunting of oxygen are responsible for diminished oxygen extraction and uptake, pathological supply dependency of oxygen, and lactate acidemia in patients experiencing septic shock.

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Multiorgan dysfunction syndrome

Sepsis is described as an autodestructive process that permits the extension of normal pathophysiologic response to infection (involving otherwise normal tissues), resulting in multiple organ dysfunction syndrome. Organ dysfunction or organ failure may be the first clinical sign of sepsis, and no organ system is immune to the consequences of the inflammatory excesses of sepsis.

Circulation

Significant derangement in the autoregulation of circulation is typical in patients with sepsis. Vasoactive mediators cause vasodilatation and increase the microvascular permeability at the site of infection. Nitric oxide plays a central role in the vasodilatation of septic shock. Impaired secretion of vasopressin also may occur, which may permit the persistence of vasodilatation.

Central circulation

Changes in both systolic and diastolic ventricular performance occur in patients with sepsis. Through the use of the Frank Starling mechanism, the cardiac output often is increased to maintain the blood pressure in the presence of systemic vasodilatation. Patients with preexisting cardiac disease are unable to increase their cardiac output appropriately.

Regional circulation

Sepsis interferes with the normal distribution of systemic blood flow to organ systems; therefore, core organs may not receive appropriate oxygen delivery.

The microcirculation is the key target organ for injury in patients with sepsis syndrome. A decrease in the number of functional capillaries causes an inability to extract oxygen maximally; intrinsic and extrinsic compression of capillaries and plugging of the capillary lumen by blood cells cause the inability. Increased endothelial permeability leads to widespread tissue edema of protein-rich fluid.

Hypotension is caused by the redistribution of intravascular fluid volume resulting from reduced arterial vascular tone, diminished venous return from venous dilation, and release of myocardial depressant substances.

Pulmonary dysfunction

Endothelial injury in the pulmonary vasculature leads to disturbed capillary blood flow and enhanced microvascular permeability, resulting in interstitial and alveolar edema. Neutrophil entrapment within the pulmonary microcirculation initiates and amplifies the injury to alveolar capillary membrane. ARDS is a frequent manifestation of these effects. As many as 40% of patients with severe sepsis develop acute lung injury.

Acute lung injury is a spectrum of pulmonary dysfunction secondary to parenchymal cellular damage characterized by endothelial cell injury and destruction, deposition of platelet and leukocyte aggregates, destruction of type I alveolar pneumocytes, an acute inflammatory response through all the phases of injury, and repair and hyperplasia of type II pneumocytes. The migration of macrophages and neutrophils into the interstitium and alveoli produces many different mediators, which contribute to the alveolar and epithelial cell damage.

The acute lung injury may be reversible at an early stage, but, in many cases, the host response is uncontrolled, and the acute lung injury progresses to ARDS. Continued infiltration occurs with neutrophils and mononuclear cells, lymphocytes, and fibroblasts. An alveolar inflammatory exudate persists, and type II pneumocyte proliferation is evident. If this process can be halted, complete resolution may occur. In other patients, a progressive respiratory failure and pulmonary fibrosis develop. The late stage of ARDS is characterized by an aggressive repair process, infiltration with an excess number of fibroblasts, and synthesis of the extracellular matrix (ECM) protein, including collagen. Subsequent deposition of metrics in the alveolar wall impedes gas exchange and results in a restrictive defect leading to irreversible respiratory failure.

Gastrointestinal dysfunction and nutrition

The gastrointestinal tract may help to propagate the injury of sepsis. Overgrowth of bacteria in the upper gastrointestinal tract may aspirate into the lungs and produce nosocomial pneumonia. The gut's normal barrier function may be affected, thereby allowing translocation of bacteria and endotoxin into the systemic circulation and extending the septic response. Septic shock usually causes ileus, and the use of narcotics and sedatives delays the institution of enteral feeding. The optimal level of nutritional intake is interfered with in the face of high protein and energy requirements.

Liver dysfunction

By virtue of the liver's role in the host defense, the abnormal synthetic functions caused by liver dysfunction can contribute to both the initiation and progression of sepsis. The reticuloendothelial system of the liver acts as a first line of defense in clearing bacteria and their products; liver dysfunction leads to a spillover of these products into the systemic circulation.

Renal dysfunction

Sepsis often is accompanied by acute renal failure caused by acute tubular necrosis. The mechanism is by systemic hypotension, direct renal vasoconstriction, release of cytokines (eg, TNF), and activations of neutrophils by endotoxins and other peptides, which contribute to renal injury.

Central nervous system dysfunction

Involvement of the central nervous system (CNS) in sepsis produces encephalopathy and peripheral neuropathy. The pathogeneses is poorly defined.

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Mechanisms of organ dysfunction and injury

The precise mechanisms of cell injury and resulting organ dysfunction in patients with sepsis are not understood fully. Multiorgan dysfunction syndrome is associated with widespread endothelial and parenchymal cell injury because of the falling proposed mechanisms.

Hypoxic hypoxia

The septic circulatory lesion disrupts tissue oxygenation, alters the metabolic regulation of tissue oxygen delivery, and contributes to organ dysfunction. Microvascular and endothelial abnormalities contribute to the septic microcirculatory defect in sepsis. The reactive oxygen sepsis, lytic enzymes, vasoactive substances (nitric oxide), and endothelial growth factors lead to microcirculatory injury, which is compounded by the inability of the erythrocytes to navigate the septic microcirculation.

Direct cytotoxicity

The endotoxin, TNF-alpha, and nitric oxide may cause damage to mitochondrial electron transport, leading to disordered energy metabolism. This is called cytopathic or histotoxic anoxia, an inability to use oxygen even when present.

Apoptosis

Apoptosis (programmed cell death) is the principal mechanism by which dysfunctional cells normally are eliminated. The proinflammatory cytokines may delay apoptosis in activated macrophages and neutrophils, but other tissues, such as the gut epithelium, may undergo accelerated apoptosis. Therefore, derangement of apoptosis plays a critical role in tissue injury of patients with sepsis.

Immunosuppression

The interaction between proinflammatory and anti-inflammatory mediators may lead to an imbalance and inflammatory reaction, immunodeficiency may predominate, or both may be present.

Coagulopathy

Subclinical coagulopathy signified by mild elevation of the thrombin or activated partial thromboplastin time (aPTT) or a moderate reduction in platelet count is extremely common, but overt DIC is rare. Coagulopathy is caused by deficiencies of coagulation system proteins, including protein C, antithrombin 3, and tissue factor inhibitors.

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Characteristics of sepsis that influence outcomes

Clinical characteristics that relate to the severity of sepsis include the following:

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Frequency:
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Mortality/Morbidity: The mortality rate in patients with sepsis varies in the reported series from 21.6-50.8%. Over the last decade, mortality rates seem to have decreased. In some studies, the mortality rate specifically caused by the septic episode itself is specified and is 14.3-20%.

Sex: Most studies of septic shock report a male preponderance. The percentage of male patients varies from 52-66%.

Age: Sepsis and septic shock occur at all ages but most often in elderly patients. At present, most sepsis episodes are observed in patients older than 60 years. Advanced age is a risk factor for acquiring nosocomial blood stream infection in the development of severe forms of sepsis.

CLINICAL ¡@

History: The constitutional symptoms of sepsis usually are nonspecific and include fever, chills, fatigue, malaise, anxiety, or confusion. These symptoms are not pathognomonic for infection and may be observed in a wide variety of noninfectious inflammatory conditions; they may be absent in serious infections, especially in elderly individuals.

Physical: The physical examination should assess the general condition of the patient. An acutely ill, flushed, and toxic appearance is observed universally in patients with serious infections.

Causes: Most patients who develop sepsis and septic shock have underlying circumstances that interfere with the local or systemic host defense mechanisms. The most common disease states predisposing to sepsis are malignancies, diabetes mellitus, chronic liver disease, chronic renal failure, and the use of immunosuppressive agents. In addition, sepsis also is a common complication after major surgery, trauma, and extensive burns.

DIFFERENTIALS ¡@

Acute Renal Failure
Adrenal Crisis
Anaphylaxis
Cardiogenic Shock
Diabetic Ketoacidosis
Disseminated Intravascular Coagulation
Heat Stroke
Hyperthyroidism
Myocardial Infarction
Myocardial Rupture
Neuroleptic Malignant Syndrome
Pulmonary Embolism
Sepsis, Bacterial
Shock and Pregnancy
Shock, Distributive
Shock, Hemorrhagic
Systemic Inflammatory Response Syndrome
Toxicity, Salicylate
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Other Problems to be Considered:

Approach to the initial clinical evaluation of a patient in shock

Any patient presenting with shock must have an early working diagnosis, an approach to urgent resuscitation, and, then, confirmation of the working diagnosis.

Shock is identified in most patients by hypotension and inadequate organ perfusion, which may be caused by either low cardiac output or low systemic vascular resistance. Circulatory shock can be subdivided into 4 distinct classes on the basis of an underlying mechanism and characteristic hemodynamics. These classes of shock should be considered and systemically differentiated before establishing a definitive diagnosis of septic shock.

Hypovolemic shock: Hypovolemic shock results from the loss of blood volume caused by such conditions as GI bleeding, extravasation of plasma, major surgery, trauma, and severe burns. The patient demonstrates tachycardia, cool clammy extremities, hypotension, dry skin and mucus membranes, and poor turgor.

Obstructive shock: Obstructive shock results from impedance of circulation by an intrinsic or extrinsic obstruction. Pulmonary embolism and pericardial tamponade both result in obstructive shock.

Distributive shock: Distributive shock is caused by such conditions as direct arteriovenous shunting and is characterized by decreased resistance or increased venous capacity from the vasomotor dysfunction. These patients have high cardiac output, hypotension, large pulse pressure, a low diastolic pressure, and warm extremities with a good capillary refill. These findings on physical examination strongly suggest a working diagnosis of septic shock.

Cardiogenic shock: Cardiogenic shock is characterized by primary myocardial dysfunction resulting in the inability of the heart to maintain adequate cardiac output. These patients demonstrate clinical signs of low cardiac output, while evidence exists of adequate intravascular volume. The patients have cool clammy extremities, poor capillary refill, tachycardia, narrow pulse pressure, and a low urine output.

WORKUP ¡@

Lab Studies:
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Imaging Studies:
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Procedures:
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Staging: Two well-defined forms of MODS of sepsis exist. In either, the development of acute lung injury or ARDS is of key importance to the natural history, although ARDS is the earliest manifestation in all cases.

TREATMENT ¡@

Medical Care: The treatment of patients with septic shock consists of the following 3 major goals: (1) Resuscitate the patient from septic shock using supportive measures to correct hypoxia, hypotension, and impaired tissue oxygenation. (2) Identify the source of infection and treat with antimicrobial therapy, surgery, or both. (3) Maintain adequate organ system function guided by cardiovascular monitoring and interrupt the pathogenesis of multiorgan system dysfunction.

Surgical Care: Patients with infected foci should be taken to surgery after initial resuscitation and administration of antibiotics for definitive surgical treatment. Little is gained by spending hours stabilizing the patient while an infected focus persists.

Consultations:

MEDICATION ¡@

Proven medical treatments for patients with septic shock are restoration of intravascular volume, hemodynamic support, and broad-spectrum empiric antibiotic coverage. Other medical therapies, while theoretically attractive, do not reduce morbidity or mortality rates.

Drug Category: Vasopressors -- In cardiovascular disorders, they are used for their alpha1 and beta1 properties. They provide hemodynamic support in acute heart failure and shock.

Drug Name
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Dopamine (Intropin) -- Stimulates both adrenergic and dopaminergic receptors. Hemodynamic effect depends on the dose. Lower doses stimulate mainly dopaminergic receptors that produce renal and mesenteric vasodilation. Cardiac stimulation and renal vasodilation is produced by higher doses. After initiating therapy, dose may be increased by 1-4 mcg/kg/min q10-30min until a satisfactory response is attained. Maintenance doses <20 mcg/kg/min usually are satisfactory for 50% of the patients treated.
Adult Dose 1-5 mcg/kg/min IV titrated according to hemodynamic response; not to exceed 20 mcg/kg/min
Pediatric Dose Administer as in adults
Contraindications Documented hypersensitivity; pheochromocytoma; ventricular fibrillation
Interactions Phenytoin, alpha- and beta-adrenergic blockers, general anesthesia, and MAOIs increase and prolong the effects of dopamine
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions Monitor urine flow, cardiac output, pulmonary wedge pressure, and blood pressure during the infusion; prior to infusion, correct hypovolemia, monitor central venous pressure or left ventricular filling pressure
Drug Name
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Epinephrine (Adrenalin) -- Used for hypotension refractory to dopamine. Stimulates alpha- and beta-adrenergic receptors, resulting in relaxation of bronchial smooth muscle, increased cardiac output, and blood pressure.
Adult Dose 1 mcg/min IV titrated according to hemodynamic response; typical dosage range is 1-10 mcg/min
Pediatric Dose 0.1-1 mcg/kg/min IV titrated according to hemodynamic response
Contraindications Documented hypersensitivity; cardiac arrhythmias; angle-closure glaucoma; local anesthesia in areas such as fingers or toes because vasoconstriction may produce sloughing of tissue; during labor (may delay second stage of labor)
Interactions Increases toxicity of beta- and alpha-blocking agents and halogenated inhalational anesthetics
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions Caution in elderly patients, prostatic hypertrophy, hypertension, cardiovascular disease, diabetes mellitus, hyperthyroidism, and cerebrovascular insufficiency; rapid IV infusions may cause death from cerebrovascular hemorrhage or cardiac arrhythmias
Drug Name
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Norepinephrine (Levophed) -- Used in protracted hypotension following adequate fluid replacement. Stimulates beta1- and alpha-adrenergic receptors, which in turn increases cardiac muscle contractility and heart rate, as well as vasoconstriction. As a result, increases systemic blood pressure and cardiac output. Adjust and maintain infusion to stabilize blood pressure (eg, 80-100 mm Hg systolic) sufficiently to perfuse vital organs.
Adult Dose 0.05-2 mcg/kg/min IV titrated according to hemodynamic response
Pediatric Dose 0.05-0.1 mcg/kg/min IV titrated according to hemodynamic response; not to exceed 1-2 mcg/kg/min
Contraindications Documented hypersensitivity; peripheral or mesenteric vascular thrombosis because ischemia may be increased and the area of the infarct extended
Interactions Atropine sulfate may enhance the pressor response of norepinephrine by blocking the reflex bradycardia caused by norepinephrine; effects increase when administered concurrently with tricyclic antidepressants, MAOIs, antihistamines, guanethidine, methyldopa, and ergot alkaloids
Pregnancy D - Unsafe in pregnancy
Precautions Correct hypovolemia before administering norepinephrine; extravasation may cause severe tissue necrosis; therefore, administer into large vein; use with caution in occlusive vascular disease
Drug Name
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Vasopressin (Pitressin) -- Vasopressor and antidiuretic hormone (ADH) activity. Increases water resorption at the distal renal tubular epithelium (ADH effect). Promotes smooth muscle contraction throughout the vascular bed of the renal tubular epithelium (vasopressor effects). Vasoconstriction increased in splanchnic, portal, coronary, cerebral, peripheral, pulmonary, and intrahepatic vessels.
Adult Dose 0.01-0.1 U/min IV titrated according to response
Pediatric Dose Not established
Contraindications Documented hypersensitivity; coronary artery disease
Interactions Lithium, epinephrine, demeclocycline, heparin, and alcohol may decrease vasopressin effects; conversely, chlorpropamide, urea, fludrocortisone, and carbamazepine are known to potentiate vasopressin effects
Pregnancy B - Usually safe but benefits must outweigh the risks.
Precautions Use with caution in patients diagnosed with cardiovascular disease, seizure disorders, nitrogen retention, asthma, or migraine; excessive doses may result in hyponatremia


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Drug Category: Isotonic crystalloids -- Isotonic sodium chloride (normal saline [NS]) and lactated Ringer (LR) are isotonic crystalloids, the standard IV fluid used for initial volume resuscitation. They expand the intravascular and interstitial fluid spaces. Typically, about 30% of administered isotonic fluid stays intravascular; therefore, large quantities may be required to maintain adequate circulating volume. Both fluids are isotonic and have equivalent volume restorative properties. While some differences exist between metabolic changes observed with the administration of large quantities of either fluid, for practical purposes and in most situations, the differences are clinically irrelevant. No demonstrable difference in hemodynamic effect, morbidity, or mortality exists between resuscitation with either NS or RL.

Drug Name
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Normal saline (NS, 0.9% NaCl) -- Restoration of interstitial and intravascular volume.
Adult Dose Initial: 1-2 L IV, with reassessment of hemodynamic response; amount required during the first few hours typically is 4-5 L
Pediatric Dose Initial: 20 mL/kg IV administered rapidly over 20-30 min; amounts approaching 40 mL/kg may be required during the first few hours; titrate to hemodynamic response
Contraindications Potentially fatal additive edema in brain or lungs; pulmonary edema may contribute to ARDS; hypernatremia
Interactions May decrease levels of lithium when administered concurrently
Pregnancy B - Usually safe but benefits must outweigh the risks.
Precautions Monitor cardiovascular and pulmonary function; stop fluids when desired hemodynamic response is observed or pulmonary edema develops; interstitial edema may occur; caution in congestive heart failure, hypertension, edema, liver cirrhosis, and renal insufficiency
Drug Name
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Lactated Ringer -- Restoration of interstitial and intravascular volume.
Adult Dose Initial: 1-2 L IV, with reassessment of hemodynamic response; amount required during the first few hours typically is 4-5 L
Pediatric Dose Initial: 20 mL/kg IV administered rapidly over 20-30 min; amounts approaching 40 mL/kg may be required during the first few hours; titrate to hemodynamic response
Contraindications Potentially fatal additive edema in brain or lungs; pulmonary edema may lead to ARDS; hypernatremia
Interactions May decrease levels of lithium when administered concurrently
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions Monitor cardiovascular and pulmonary function; stop fluids when the desired hemodynamic response is observed or pulmonary edema develops; interstitial edema may occur; caution in congestive heart failure, hypertension, edema, liver cirrhosis, and renal insufficiency

Drug Category: Colloids -- Used to provide oncotic expansion of plasma volume. They expand plasma volume to a greater degree than isotonic crystalloids and reduce the tendency of pulmonary and cerebral edema. About 50% of the administered colloid stays intravascular.

Drug Name
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Albumin (Buminate) -- Used for certain types of shock or impending shock. Useful for plasma volume expansion and maintenance of cardiac output. A solution of NS and 5% albumin is available for volume resuscitation. Five percent solutions are indicated to expand plasma volume; whereas, 25% solutions are indicated to raise oncotic pressure.
Adult Dose 250-500 mL (12.5-25 g) IV of 5% solution over 20-30 min, with reassessment of hemodynamic response; not to exceed 250 g/48h
Pediatric Dose 4-5 mL/kg (200-250 mg/kg) IV of 5% solution over 30 min, with reassessment of hemodynamic response; not to exceed 6 g/kg/d
Contraindications Documented hypersensitivity; severe congestive heart failure; severe anemia; pulmonary edema; the protein load of 5% albumin tends to exacerbate renal insufficiency, a potential complication of septic shock; do not dilute albumin 25% with sterile water for injection (produces hypotonic solution) because, if administered, may result in life-threatening hemolysis and acute renal failure
Interactions None reported
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions Caution in renal or hepatic failure; may cause protein overload; rapid infusion may cause vascular overload or hypotension; monitor for volume overload; caution in sodium restricted patients; common adverse effects include CHF, hypotension, tachycardia, fever, chills, and pulmonary edema

Drug Category: Antibiotics -- Early treatment with empiric antibiotics is the only other proven medical treatment in septic shock. Use of broad-spectrum and/or multiple antibiotics provides the necessary coverage. In children who are immunocompetent, monotherapy is possible with a third-generation cephalosporin (eg, cefotaxime, ceftriaxone, ceftazidime). An antipseudomonal penicillin or carbapenem is used as monotherapy for adults who are immunocompetent. Penicillinase-resistant synthetic penicillins and a third-generation cephalosporin are used for combination therapy in children. Combination therapy in adults involves a third-generation cephalosporin plus anaerobic coverage (ie, clindamycin, metronidazole) or a fluoroquinolone plus clindamycin. All antibiotics should be administered IV initially.

Drug Name
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Cefotaxime (Claforan) -- Used for treatment of septicemia. Also used for treatment of gynecologic infections caused by susceptible organisms. Third-generation cephalosporin with enhanced gram-negative coverage, especially to E coli, Proteus, and Klebsiella species. Has variable activity against Pseudomonas species.
Adult Dose 1-2 g IV q4h; not to exceed 12 g/d
Pediatric Dose 50 mg/kg IV q8h
Contraindications Documented hypersensitivity
Interactions Probenecid may decrease cefotaxime clearance, causing an increase in cefotaxime levels; furosemide and aminoglycosides may increase nephrotoxicity when used concurrently with cefotaxime
Pregnancy B - Usually safe but benefits must outweigh the risks.
Precautions Adjust dose in patients diagnosed with severe renal impairment; associated with severe colitis
Drug Name
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Ceftriaxone (Rocephin) -- Third-generation cephalosporin with broad-spectrum, gram-negative activity. Lower efficacy against gram-positive organisms. Higher efficacy against resistant organisms. Used for increasing prevalence of penicillinase-producing microorganisms. Inhibits bacterial cell wall synthesis by binding to 1 or more penicillin-binding proteins. Cell wall autolytic enzymes lyse bacteria, while cell wall assembly is arrested.
Adult Dose 1 g IV q8-12h; not to exceed 4 g/d
Pediatric Dose <45 kilograms: 50 mg/kg/d IV divided q12h; not to exceed 2 g/d
>45 kilograms: Administer as in adults
Contraindications Documented hypersensitivity; do not use in neonates with hyperbilirubinemia
Interactions Probenecid may decrease clearance, causing an increase in ceftriaxone levels; coadministration of ethacrynic acid, furosemide, and aminoglycosides may increase nephrotoxicity
Pregnancy B - Usually safe but benefits must outweigh the risks.
Precautions Adjust dose in renal impairment; caution in women who are breastfeeding; potential cross-allergy to penicillin
Drug Name
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Ticarcillin and clavulanate (Timentin) -- Antipseudomonal penicillin plus a beta-lactamase inhibitor that provides coverage against most gram-positive organisms (except variable coverage against Staphylococcus epidermidis and no coverage against methicillin-resistant Staphylococcus aureus [MRSA]), gram-negative organisms, and anaerobes.
Adult Dose <60 kilograms: 75 mg/kg IV q6h
>60 kilograms: 3.1 g IV q4-6h
Pediatric Dose <60 kilograms: 75 mg/kg IV q6h
Contraindications Documented hypersensitivity; severe pneumonia, bacteremia, pericarditis, emphysema, meningitis, and purulent or septic arthritis should not be treated with an oral penicillin during the acute stage
Interactions Tetracyclines may decrease the effects of ticarcillin; high concentrations of ticarcillin in vivo or in vitro may physically inactivate aminoglycosides; probenecid may increase penicillin levels; synergistic effect when administered concurrently with aminoglycosides
Pregnancy B - Usually safe but benefits must outweigh the risks.
Precautions Perform CBCs prior to initiation of therapy and at least weekly during therapy; monitor for liver function abnormalities by measuring AST and ALT during therapy; caution in patients diagnosed with hepatic insufficiencies; perform urinalysis, BUN, and creatinine determinations during therapy and adjust dose
Drug Name
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Piperacillin and tazobactam (Zosyn) -- Inhibits the biosynthesis of cell wall mucopeptide and is effective during the stage of active multiplication. Has antipseudomonal activity.
Adult Dose 3.375 g IV q6h
Pediatric Dose >6 months: 75 mg/kg IV q6h
Contraindications Documented hypersensitivity; severe pneumonia, bacteremia, pericarditis, emphysema, meningitis, and purulent or septic arthritis should not be treated with an oral penicillin during the acute stage
Interactions Tetracyclines may decrease effects of penicillins; high concentrations of piperacillin in vivo or in vitro may physically inactivate aminoglycosides; synergistic effect when administered concurrently with aminoglycosides; probenecid may increase serum penicillin levels
Pregnancy B - Usually safe but benefits must outweigh the risks.
Precautions Perform CBCs prior to initiation of therapy and at least weekly during therapy; monitor for liver function abnormalities by measuring AST and ALT during therapy; urinalysis, BUN, and creatinine determinations should be performed during therapy and adjust dose if these values become elevated
Drug Name
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Imipenem and cilastatin (Primaxin) -- Carbapenem with activity against most gram-positive organisms (except MRSA), gram-negative organisms, and anaerobes. Used for treatment of multiple organism infections in which other agents do not have wide-spectrum coverage or are contraindicated due to their potential for toxicity.
Adult Dose 500 mg IV q6h; not to exceed 4 g/d
Pediatric Dose >3 months: 10-15 mg/kg IV q6h; not to exceed 4 g/d for moderately susceptible organisms
Contraindications Documented hypersensitivity
Interactions When administered concurrently with cyclosporine, the CNS adverse effects of both agents may be increased, possibly because of additive or synergistic toxicity; when used concurrently with ganciclovir, generalized seizures may occur, and it should not be used concomitantly; probenecid may increase toxic potential
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions Adjust dose with impaired renal function and in patients <70 kg; avoid in children <12 y due to CNS toxicity
Drug Name
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Meropenem (Merrem) -- Carbapenem with slightly increased activity against gram-negative organisms and slightly decreased activity against staphylococci and streptococci compared to imipenem. Less likely to cause seizures and superior penetration of blood-brain barrier compared to imipenem.
Adult Dose 1 g IV q8h
Pediatric Dose >3 months: 40 mg/kg IV q8h; not to exceed 6 g/d
Contraindications Documented hypersensitivity
Interactions Probenecid may inhibit the renal excretion of meropenem, increasing meropenem levels
Pregnancy B - Usually safe but benefits must outweigh the risks.
Precautions Pseudomembranous colitis and thrombocytopenia may occur, requiring discontinuation of meropenem; cross-reactivity observed (50%) in patients with penicillin anaphylaxis history; caution in seizures; adjust dose with renal dysfunction
Drug Name
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Clindamycin (Cleocin) -- Primarily used for its activity against anaerobes. Has some activity against Streptococcus species and MSSA.
Adult Dose 600-900 mg IV q8h; not to exceed 4.8 g/d
Pediatric Dose 5-10 mg/kg IV q8h; not to exceed 4.8 g/d
Contraindications Documented hypersensitivity; regional enteritis; ulcerative colitis; hepatic impairment; antibiotic-associated colitis
Interactions Increases duration of neuromuscular blockade induced by tubocurarine and pancuronium
Pregnancy D - Unsafe in pregnancy
Precautions Adjust dose in severe hepatic dysfunction; no adjustment necessary in renal insufficiency; associated with severe and possibly fatal colitis
Drug Name
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Metronidazole (Flagyl) -- Imidazole ring-based antibiotic active against various anaerobic bacteria and protozoa. Usually combined with other antimicrobial agents, except when used for Clostridium difficile enterocolitis, in which monotherapy is appropriate.
Adult Dose Loading dose: 15 mg/kg IV over 1 h (1 g IV for 70-kg adult)
Maintenance dose: 7.5 mg/kg IV over 1 h q6-8h (500 mg for a 70-kg adult), initiated 6 h following loading dose; not to exceed 4 g/d
Pediatric Dose Administer as in adults; use dose based on body weight
Contraindications Documented hypersensitivity; first trimester of pregnancy
Interactions Potentiates the anticoagulant effect of warfarin; agents that alter the hepatic CYP450 system also affect its clearance; as a result, phenytoin and phenobarbital may decrease the half-life of metronidazole; cimetidine may reduce metronidazole clearance and increase its toxicity; metronidazole may decrease lithium and phenytoin clearance, increasing their toxicity; disulfiramlike reaction may occur when used concurrently with orally ingested ethanol (although the risk for most patients is slight, exercise caution)
Pregnancy B - Usually safe but benefits must outweigh the risks.
Precautions Adjust dose in severe hepatic disease; monitor patients for seizures and peripheral neuropathy; common adverse effects include dizziness, headache, nausea, vomiting, and anorexia
Drug Name
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Ciprofloxacin (Cipro) -- Fluoroquinolone with variable activity against Streptococcus species, activity against methicillin-sensitive S aureus and S epidermidis, activity against most gram-negative organisms, and no activity against anaerobes. Synthetic broad-spectrum antibacterial compounds. Novel mechanism of action, targeting bacterial topoisomerase II and IV, thus leading to a sudden cessation of DNA replication. Oral bioavailability is near 100%.
Adult Dose 400 mg IV q12h
Pediatric Dose 10-15 mg/kg IV q12h
Contraindications Documented hypersensitivity
Interactions Antacids, iron salts, and zinc salts may reduce serum levels; administer antacids 2-4 h before or after taking fluoroquinolones; cimetidine and probenecid may increase levels of fluoroquinolones; ciprofloxacin reduces therapeutic effects of phenytoin; probenecid may increase ciprofloxacin serum concentrations; fluoroquinolones may increase serum levels of theophylline, caffeine, cyclosporine, and digoxin (monitor digoxin levels); may increase effects of anticoagulants (monitor PT)
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions In prolonged therapy, perform periodic evaluations of organ system functions (eg, renal, hepatic, hematopoietic); adjust dose in renal function impairment; superinfections may occur with prolonged or repeated antibiotic therapy; do not use in pediatric patients as first-line agent due to cartilage damage in young animals; may cause CNS toxicity
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