AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

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, pandemics 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:

• Temperature greater than 38°C or less than 36°C

• Heart rate greater than 90 beats per minute (bpm)

• Respiratory rate greater than 20 breaths per minute or PaCO₂ less than 32 mm Hg

• White blood cell count greater than 12,000/µL, less than 4000/µL, or 10% immature (band) forms

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:

• Rectal temperature greater than 38°C or less than 36°C

• Tachycardia (>90 bpm)

• Tachypnea (>20 breaths per min)

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

• Alteration in mental state

• Hypoxemia (PaO₂ <72 mm Hg at FiO₂ [fraction of inspired oxygen] 0.21; overt pulmonary disease not the direct cause of hypoxemia)

• Elevated plasma lactate level

• Oliguria (urine output <30 mL or 0.5 mL/kg for at least 1 h)

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:

• Temperature greater than 38°C or less than 36°C

• Heart rate greater than 90 bpm

• Respiratory rate greater than 20 breaths per minute or PaCO₂ less than 32 mm Hg

• White blood cell count greater than 12,000/µL, less than 4000/µL, or 10% immature (band) forms

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.

Pathophysiology

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.

An initial step in the activation of innate immunity is the synthesis de novo of small polypeptides, called cytokines, that induce protean manifestations on most cell types, from immune effector cells to vascular smooth muscle and parenchymal cells. Several cytokines are induced, including tumor necrosis factor (TNF) and interleukins, especially IL-1. Both of these factors also help to keep infections localized, but, once the infection becomes systemic, the effects can also be 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–1) orchestrate the migration of leukocytes during endotoxemia and sepsis. The other cytokines that have a supposed role in

sepsis areIL-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† Eicosanoids
	Arachidonic acid metabolites
	Adhesion molecules Selectins Leukocyte integrins

*Macrophage inhibitory factor

†Platelet activating factor

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.

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.

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.

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.

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.

Characteristics of sepsis that influence outcomes

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

• An abnormal host response to infection

• Site and type of infection

• Timing and type of antimicrobial therapy

• Offending organism

• Development of shock

• Any underlying disease

• Patient's long-term health condition

• Location of the patient at the time of septic shock

Frequency

United States

Since the 1930s, studies have shown an increasing incidence of sepsis. In 1 study, the incidence of bacteremic sepsis (both gram-positive and gram-negative sepsis) increased from 3.8 cases per 1000 admissions in 1970 to 8.7 cases per 1000 admissions in 1987. The incidences of nosocomial blood stream infection in 1 institution from 1980-1992 increased from 6.7 to 18.4 cases per 1000 discharges. The increase in the number of patients who are immunocompromised and an increasing use of invasive diagnostic and therapeutic devices predisposing to infection are major reasons for the increase in incidences of sepsis.

The incidence of sepsis syndrome and septic shock in patients admitted to a university hospital was reportedly 13.6 and 4.6 cases per 1000 persons, respectively. In the United States, 200,000 cases of septic shock and 100,000 deaths per year occur from this disease.

A recently published article reported the incidence, cost, and outcome of severe sepsis in the United States. Analysis of a large sample from the major centres reported the incidence of severe sepsis as 3 cases per 1000 population, and 2.26 cases per 100 hospital discharges. Out of these cases, 51.1% received intensive care admission, an additional 17.3% were cared for in intermediate care or coronary care unit. Incidence ranged from 0.2 cases per 1000 admissions in children to 26.2 cases per 1000 admissions in individuals older than 85 years. The mortality rate was 28.6% and ranged from 10% in children to 38.4% in elderly people. Severe sepsis resulted in an average cost of $ 2200 per case, with an annual total cost of $16.7 billion nationally (Angus, 2001).

International

A Dutch surveillance study reported that 1.36 cases per 100 hospital admissions were secondary to severe sepsis.

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

Section 3 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

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.

• Sepsis or septic shock is systemic inflammatory response secondary to a documented infection. Consequently, sepsis is a continuum of detrimental host responses to infection that ranges from sepsis to septic shock and MODS. The specific clinical features depend on where the patient falls on that continuum. The SIRS is defined by the presence of 2 or more of the following:
• • Temperature greater than 38°C or less than 36°C

  • Heart rate greater than 90

  • Respiratory rate greater than 20 per minute

  • WBC count more than 12,000/µL, less than 4000/µL, or more than 10% bands

• Fever is a common feature of patients with sepsis. The hypothalamus resets so that heat production and heat loss are balanced in favor of a higher temperature. Fever may be absent in elderly patients or patients who are immunosuppressed.
• Chills are a secondary symptom associated with fever, which is a consequence of increased muscular activity that produces heat and raises the body temperature.
• Sweating occurs when the hypothalamus returns to its normal set point and senses the higher body temperature, stimulating perspiration to evaporate excess body heat.
• Alteration in mental function often occurs. Mild disorientation or confusion is especially common in elderly individuals. Apprehension, anxiety, agitation, and, eventually, coma are manifestations of severe sepsis. The exact cause of metabolic encephalopathy is not known; alteration in amino acid metabolism may play a role.
• Hyperventilation with respiratory alkalosis is a common feature of patients with sepsis secondary to stimulation of the medullary respiratory center by endotoxins and other inflammatory mediators.
• The localizing symptoms referable to organ systems may provide useful clues to the etiology of sepsis and are as follows:
• • Head and neck infections - Earache, sore throat, sinus pain, or swollen lymph glands
  • Chest and pulmonary infections - Cough (especially if productive), pleuritic chest pain, and dyspnea
  • Abdominal and GI infections - Abdominal pain, nausea, vomiting, and diarrhea
  • Pelvic and genitourinary infections - Pelvic or flank pain, vaginal or urethral discharge, and urinary frequency and urgency
  • Bone and soft tissue infections - Localized limb pain or tenderness, focal erythema, edema, and swollen joint

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.

• Examine vital signs, and observe for signs of hypoperfusion.
• Carefully examine the patient for evidence of localized infection.
• Ensure that the patient's body temperature is measured accurately and that rectal temperatures are obtained. Oral and tympanic temperatures are not always reliable.
• Fever may be absent, but patients generally have tachypnea and tachycardia.
• Observe patients for systemic signs of inadequate tissue perfusion. In the early stages of sepsis, cardiac output is well maintained or even increased. The vasodilation may result in warm skin, warm extremities, and normal capillary refill (warm shock). As sepsis progresses, stroke volume and cardiac output fall. The patients begin to manifest the following signs of poor perfusion: cool skin, cool extremities, and delayed capillary refill (cold shock).
• The following physical signs help to localize the source of an infection:
• • CNS infection - Profound depression in mental status and signs of meningismus (neck stiffness)
  • Head and neck infections - Inflamed or swollen tympanic membranes, sinus tenderness, pharyngeal erythema and exudates, inspiratory stridor, and cervical lymphadenopathy
  • Chest and pulmonary infections - Dullness on percussion, bronchial breath sounds, and localized crackles
  • Cardiac infections - New regurgitant valvular murmur
  • Abdominal and GI infections - Abdominal distention, localized tenderness, guarding or rebound tenderness, and rectal tenderness or swelling
  • Pelvic and genitourinary infections - Costovertebral angle tenderness, pelvic tenderness, pain on cervical motion, and adnexal tenderness
  • Bone and soft tissue infections - Focal erythema, edema, tenderness, crepitus in necrotizing infections, and joint effusion
  • Skin infections - Petechiae, purpura, erythema, ulceration, and bullous formation

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.

• Origin of infection
• • In most patients with sepsis, a source of infection can be identified, with the exception of patients who are immunocompromised with neutropenia, where an obvious source of infection often is not found.

  • Respiratory tract infection and urinary tract infection are the most frequent causes of sepsis, followed by abdominal and soft tissue infections.

  • The use of intravascular devices is a notorious cause of nosocomially-acquired sepsis.

  • Multiple sites of infection may occur in 6-15% of patients.

• Microorganisms: Prior to the introduction of antibiotics in clinical practice, gram-positive bacteria were the principal organisms causing sepsis. More recently, gram-negative bacteria have become the key pathogens causing severe sepsis and septic shock. The following is a list of pathogens that can infect individual organ systems and lead to severe sepsis and septic shock:
• • Lower respiratory tract infections are the cause of septic shock in 25% of patients. The following are common pathogens:
    • Streptococcus pneumoniae
    • Klebsiella pneumoniae
    • Staphylococcus aureus
    • Escherichia coli
    • Legionella species

    • Haemophilus species

    • Anaerobes

    • Gram-negative bacteria

    • Fungi
  • Urinary tract infections are the cause of septic shock in 25% of patients, and the following are the common pathogens:
    • E coli
    • Proteus species

    • Klebsiella species

    • Pseudomonas species

    • Enterobacter species

    • Serratia species
  • Soft tissue infections are the cause of septic shock in 15% of patients, and the following are the common pathogens:
    • S aureus
    • Staphylococcus epidermidis

    • Streptococci

    • Clostridia

    • Gram-negative bacteria

    • Anaerobes
  • GI tract infections are the cause of septic shock in 15% all patients, and the following are the common pathogens:
    • E coli
    • Streptococcus faecalis
    • Bacteroides fragilis
    • Acinetobacter species

    • Pseudomonas species

    • Enterobacter species

    • Salmonella species
  • Infections of the male and female reproductive systems are the cause of septic shock in 10% of patients, and the following are the common pathogens:
    • Neisseria gonorrhoeae

    • Gram-negative bacteria

    • Gram-negative bacteria

    • Streptococci

    • Anaerobes
  • Foreign bodies leading to infections are the cause of septic shock in 5% of patients, and S aureus, S epidermidis, and fungi/yeasts (Candida species) are the common pathogens.

  • Miscellaneous infections are the cause of septic shock in 5% of patients, and Neisseria meningitidis is the common pathogen.

• Anaerobic pathogens are becoming less important as a cause of sepsis. In one institution, the incidence of anaerobic bacteremia declined by 45% over a 15-year period.

• Fungal infections are the cause of sepsis in 0.8-10.2% of patients with sepsis, and their incidence appears to be increasing.
• Polymicrobial sepsis has become a more prevalent cause of sepsis; the incidence is 5.6-18.4%. The patients with neutropenia particularly are at high risk for polymicrobial infections.
• Risk factors for severe sepsis and septic shock
• • Extremes of age ( <10 y and >70 y)
  • Primary diseases
    • Liver cirrhosis

    • Alcoholism

    • Diabetes mellitus

    • Cardiopulmonary diseases

    • Solid malignancy

    • Hematologic malignancy
  • Immunosuppression
    • Neutropenia

    • Immunosuppressive therapy

    • Corticosteroid therapy

    • Intravenous drug abuse

    • Compliment deficiencies

    • Asplenia
  • Major surgery, trauma, burns
  • Invasive procedures
    • Catheters

    • Intravascular devices

    • Prosthetic devices

    • Hemodialysis and peritoneal dialysis catheters

    • Endotracheal tubes
  • Prior antibiotic treatment
  • Prolonged hospitalization
  • Other factors - Childbirth, abortion, and malnutrition

DIFFERENTIALS

Section 4 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Other Problems to be Considered

The control of intermediary metabolism via feeding and control of circulating blood glucose levels

Identification of the source of infection and the rapid institution of appropriate antibiotics

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.

The following points should be considered for early diagnosis of sepsis:

• Patients with sepsis may present in a myriad of ways and high clinical suspicion is necessary to identify subtle presentations.
  
• Septic patients should be screened for evidence of tissue hypo-perfusion.
  
• Cool or clammy skin, mottling, and elevated shock index (heart rate/systolic blood pressure > 0.9) may be signs of tissue hypo-perfusion.
  
• Lactic acid level greater than 4 mmol/dL has been used as an entry criteria for EGDT and indicator of severe tissue hypo-perfusion.

WORKUP

Section 5 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Lab Studies

• CBC count with differential
• • An adequate hemoglobin concentration is necessary to ensure adequate oxygen delivery in patients with shock. Ensure that the hemoglobin is maintained at a level of 8 g/dL.
  • Platelets, an acute phase reactant, usually increase at the onset of any serious stress. However, the platelet count will fall with persistent sepsis, and DIC may develop.
  • The WBC count and the white cell differential count may predict the existence of a bacterial infection. In adults who are febrile, a WBC count of greater than 15,000/µL or a neutrophil band count of greater than 1500/µL is associated with a high likelihood of bacterial infection.
  • WBC counts of greater than 50,000/µL or less than 300/µL are associated with significantly decreased rates of survival.
  • At regular intervals, obtain metabolic assessment with serum electrolytes, including magnesium, calcium, phosphate, and glucose.
  • Assess renal and hepatic function with the following:
    • Serum creatinine

    • BUN

    • Bilirubin

    • Alkaline phosphate

    • Alanine aminotransferase (ALT)

    • Aspartate aminotransferase (AST)

    • Albumin
  • ABG: Measure serum lactate to provide an assessment of tissue hypoperfusion. Elevated serum lactate indicates that significant tissue hypoperfusion exists with the shift from aerobic to anaerobic metabolism. The higher the serum lactate, the worse the degree of shock and the higher the mortality rate.
  • Assess the coagulation status with prothrombin time (PT) and aPTT. Patients with clinical evidence of a coagulopathy require additional tests to detect the presence of DIC.
  • Blood cultures: The blood culture is the primary means for the diagnosis for intravascular infections (eg, endocarditis) and infections of indwelling intravascular devices. The individuals at high risk for endocarditis are intravenous (IV) drug abusers and patients with prosthetic heart valves.
  • The patients at risk for bacteremia include adults who are febrile with an elevated WBC count or neutrophil band count, elderly patients who are febrile, and patients who are febrile with neutropenia. These populations have a 20-30% incidence of bacteremia.
  • The incidence of bacteremia increases to at least 50% in patients with sepsis and evidence of end-organ dysfunction.
  • Perform a urinalysis and urine culture for every patient who is septic. Urinary infection is a common source for sepsis, especially in elderly individuals. Adults who are febrile without localizing symptoms or signs have a 10-15% incidence of occult urinary tract infection.
  • Obtain secretions or tissue for Gram stain and culture from the sites of potential infection. The Gram stain is the only immediately available test that can document the presence of bacterial infection and guide the choice of initial antibiotic therapy.

Imaging Studies

• Several imaging modalities are used to detect a clinically suspected focal infection, the presence of a clinically occult focal infection, and a complication of sepsis and septic shock.
• Since most patients that present with sepsis have pneumonia, one should obtain a chest radiograph because the clinical examination is unreliable for the detection of pneumonia; especially in elderly patients. Occult infiltrates can be detected by the routine use of chest radiography in adults who are febrile without localizing symptoms or signs and in patients who are febrile with neutropenia and without pulmonary symptoms.
• The chest radiograph results may be normal in early ARDS. The typical findings of noncardiogenic pulmonary edema are bilateral, hazy, symmetric homogenous opacities, which may demonstrate air bronchograms. The margins of pulmonary vessels become indistinct and obscured with disease progression. The usual findings of metastatic pulmonary edema, such as Kerley A or B lines, are not usually observed; a perihilar distribution of opacities is also absent. Furthermore, other findings of cardiogenic pulmonary edema, such as cardiomegaly, vascular redistribution and pleural effusions, also are not present.
• With disease progression, the ground glass opacities change into heterogeneous, linear or reticular infiltrates. Days to weeks later, either persistent chronic fibrosis may develop or the chest radiograph appearance becomes more normal. Periodic chest radiographs during the management of ARDS are particularly important to diagnose barotrauma, adequate postioning of an endotracheal tube and intravascular catheters, and occurrence of nosocomial pneumonia.
• Acquire supine and upright or lateral decubitus abdominal films because they may be useful when an intra-abdominal source of sepsis is suspected.
• Ultrasound is the imaging modality of choice when a biliary tract source is thought to be the source of sepsis.
• Obesity or the presence of excessive intestinal gas markedly interferes with abdominal imaging by ultrasonography; therefore, the CT scans are preferred.
• The CT scan is the imaging modality of choice for excluding an intra-abdominal abscess or the retroperitoneal source of infection.
• When clinical evidence exists of a deep soft tissue infection, such as crepitus, bullae, hemorrhage, or foul smelling exudate, obtain a plain radiograph. The presence of soft tissue gas often dictates surgical exploration.
• Obtain a head CT scan in patients with evidence of increased intracranial pressure (papilledema) and in patients thought to have focal mass lesions (eg, focal defects, previous sinusitis or otitis, recent intracranial surgery).
• If bacterial meningitis is strongly suspected, then a lumbar puncture (LP) should be performed without the delay of obtaining a CT scan. If the opening pressure is elevated, then only enough cerebrospinal fluid (CSF) for culture should be obtained.

Procedures

• If a patient is thought to have meningitis or encephalitis, perform an LP urgently. In patients with an acute fulminant presentation, a rapid onset of septic shock, and a severe impairment of mental status, use this procedure to rule out bacterial meningitis.
• Cardiac monitoring, noninvasive blood pressure monitoring, and pulse oximetry are necessary because these patients often require intensive care admission for invasive monitoring and support.
• Supplemental oxygen is provided during initial stabilization and resuscitation.
• Ensure that all patients in septic shock receive adequate venous access for volume resuscitation. A central venous line also can be used to monitor central venous pressure to assess intravascular volume status.
• Use an indwelling urinary catheter to monitor urinary output, which is a marker for adequate renal perfusion and cardiac output.
• Patients who develop septic shock require a right heart catheterization with a pulmonary artery (Swan Ganz) catheter. This catheter provides an accurate assessment of the volume status of a septic patient. The cardiac output measurement can be obtained; furthermore, determination of mixed venous oxygenation is helpful in determining the status of tissue oxygenation. The right-sided cardiac catheterization will detect those patients (25%) with sepsis and hypotension who have underlying congestive heart failure (usually due to myocardial suppressant factor).
• Most patients with sepsis develop respiratory distress as a manifestation of severe sepsis or septic shock. The lung injury is characterized pathologically as diffuse alveolar damage and ranges from acute lung injury to ARDS. These patients need intubation and mechanical ventilation for optimum respiratory support.

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.

• In the more common form of MODS, the lungs are the predominant, and often the only, organ system affected until very late in the disease. These patients most often present with primary pulmonary disorder (eg, pneumonia, aspiration, lung contusion, near drowning, chronic obstructive pulmonary disease [COPD] exacerbation, hemorrhage, pulmonary embolism). Progression of lung disease occurs to meet the ARDS criteria. Pulmonary dysfunction may be accompanied by encephalopathy or mild coagulopathy and persists for 2-3 weeks. At this time, the patient either begins to recover or progresses to develop fulminant dysfunction in other organ systems. Once another major organ dysfunction occurs, these patients often do not survive.
• The second form of MODS presents quite differently. These patients often have an inciting source of sepsis in organs other than the lung (the common source being intra-abdominal sepsis), extensive blood loss, pancreatitis, and vascular catastrophes. Acute lung injury or ARDS develops early, but dysfunction in other organ systems also develops much sooner. The organ systems affected are hepatic, hematologic, cardiovascular, CNS, and renal. Patients remain in a pattern of compensated dysfunction for several weeks and then either recover or deteriorate further and die.

  Table 2. Criteria for Organ Dysfunction

  Organ System	Mild Criteria	Severe Criteria
  Pulmonary	Hypoxia/hypercarbia requiring assisted ventilation for 3-5 d	ARDS requiring PEEP* >10 cm H2O and FiO2† <0.5
  Hepatic	Bilirubin 2-3 mg/dL or other liver function tests more than twice normal, PT elevated to twice normal	Jaundice with bilirubin 8-10 mg/dL
  Renal	Oliguria ( <500 mL/d or increasing creatinine) 2-3 mg/dL	Dialysis
  Gastrointestinal	Intolerance of gastric feeding for more than 5 d	Stress ulceration with need for transfusion, acalculous cholecystitis
  Hematologic	aPTT >125% of reference range, platelets <50-80,000	DIC
  Cardiovascular	Decreased ejection fraction with persistent capillary leak	Hyperdynamic state not responsive to pressors
  CNS	Confusion	Coma
  Peripheral nervous system	Mild sensory neuropathy	Combined motor and sensory deficit

  *Positive end-expiratory pressure
  †Fraction of inspired oxygen

TREATMENT

Section 6 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

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.

The principles in the management of septic shock, based on current literature, include the following components:

1. Early recognition
2. Early and adequate antibiotic therapy
3. Source control
4. Early hemodynamic resuscitation and continued support
5. Corticosteroids (refractory vasopressor-dependent shock)
6. Drotrecogin alpha (Severely ill if APACHE II > 25)
7. Tight glycemic control
8. Proper ventilator management with low tidal volume in patients with ARDS

• General supportive care: Initial treatment includes support of respiratory and circulatory function, supplemental oxygen, mechanical ventilation, and volume infusion. Treatment beyond these supportive measures includes antimicrobial therapy targeting the most likely pathogen, removal or drainage of the infected foci, treatment of complications, and interventions to prevent and treat effects of harmful host responses. Source control is essential for the following reasons:

• Identifying and obtaining source control is an essential component of sepsis management.



• In general, the source of sepsis needs to be removed, drained, or otherwise eradicated.

• Administer supplemental oxygen to any patients with sepsis who also have hypoxemia or are in respiratory distress.
• If the patient's airway is not secure, the gas exchange or acid-base balance is severely deranged, and if evidence of respiratory muscle fatigue exists or if the patient appears markedly distressed, perform an endotracheal intubation.
• Patients in septic shock generally require intubation and assisted ventilation because respiratory failure either is present at the onset or may develop during the course of the illness.
• Correction of shock state and abnormal tissue perfusion is the next step in the treatment of patients with septic shock.

• Hemodynamic support of septic shock
  
  
  • Shock refers to a state of inability to maintain adequate tissue perfusion and oxygenation, ultimately causing cellular, and then organ system, dysfunction. Therefore, the goals of hemodynamic therapy are restoration and maintenance of adequate tissue perfusion to prevent multiple organ dysfunction.
  
  
  
  • Careful clinical and invasive monitoring is required for assessment of global and regional perfusion. A mean arterial pressure (MAP) of less than 60 mm Hg or a decrease in MAP of 40 mm Hg from baseline defines shock at the bedside.
  
  
  
  • Elevation of the blood lactate level on serial measurements of lactate can indicate inadequate tissue perfusion.
  
  
  
  • Mixed venous oxyhemoglobin saturation serves as an indicator of the balance between oxygen delivery and consumption. A decrease in maximal venous oxygen (MVO₂) can be secondary to decreased cardiac output; however, maldistribution of blood flow in patients experiencing septic shock may artificially elevate the MVO₂ levels. An MVO₂ of less than 65% generally indicates decreased tissue perfusion.
  
  
  
  • Regional perfusion in patients with septic shock is evaluated by adequacy of organ function. The evaluation includes evidence of myocardial ischemia, renal dysfunction manifested by decreased urine output or increased creatinine, CNS dysfunction indicated by a decreased level of consciousness, hepatic injury shown by increased levels of transaminases, splanchnic hypoperfusion manifested by stress ulceration, ileus, or malabsorption.
  
  
  
  • The hemodynamic support in septic shock is provided by restoring the adequate circulating blood volume, and, if needed, optimizing the perfusion pressure and cardiac function with vasoactive and inotropic support to improve tissue oxygenation.

• Intravascular volume resuscitation

• • Hypovolemia is an important factor contributing to shock and tissue hypoxia; therefore, all patients with sepsis require supplemental fluids. The amount and rate of infusion are guided by an assessment of the patient's volume and cardiovascular status. Monitor patients for signs of volume overload, such as dyspnea, elevated jugular venous pressure, crackles on auscultation, and pulmonary edema on the chest radiograph. Improvement in the patient's mental status, heart rate, MAP, capillary refill, and urine output indicate adequate volume resuscitation.
  
  
  
  • Large volumes of fluid infusions are required as initial therapy in patients with septic shock. Administer fluid therapy with predetermined boluses (500 mL or 10 mL/kg) titrated to the clinical end points of heart rate, urine output, and blood pressure. Continue fluid resuscitation until the clinical end points are reached or the pulmonary capillary wedge pressure exceeds 18 mm Hg. The volume resuscitation can be achieved by either crystalloid or colloid solutions. The crystalloid solutions are 0.9% sodium chloride and lactated Ringer solution. The colloids are albumin, dextrans, and pentastarch. Clinical trials have failed to show superiority of either crystalloids or colloids as the resuscitation fluid of choice in septic shock. However, 2-4 times more volume of crystalloids than colloids are required, and crystalloids take a longer time to achieve the same end points, whereas the colloid solutions are much more expensive.
  
  
  
  • Data from several studies suggest that formation of pulmonary edema is no different with crystalloids compared to colloids when the filling pressures are maintained at a lower level. However, if the higher filling pressures are required for maintenance of optimal hemodynamics, crystalloids may increase extravascular fluid fluxes because of a decrease in plasma oncotic pressure.
  
  
  
  • In some patients, clinically assessing the response to volume infusion may be difficult. By monitoring the response of the central venous pressure or pulmonary artery occlusion pressure to fluid boluses, the physician can assess such patients. A sustained rise in filling pressure of more than 5 mm Hg after a volume is infused indicates that the compliance of the vascular system is decreasing as further fluid is being infused. Such patients are susceptible to volume overload, and further fluid should be administered with care.
  
  
  • Early goal-directed management of sepsis: In a study by Rivers et al, 263 patients treated in an emergency department were randomized to either a standard care control group or an aggressive care therapy arm for their initial 8 hours of treatment. Patients in the therapy arm provided aggressive resuscitation via to reach a central venous pressure to 8- 12 mm Hg, organ perfusion pressure maintained by keeping mean arterial pressure (MAP) 65-90mm Hg using either vasopressors or vasodilators, and contractility with dobutamine to keep central venous O₂ saturation (ScvO₂) greater than 70% after transfusion to hematocrit greater than 30%. This treatment strategy resulted in a 16% improvement in mortality.
     
• Vasopressor supportive therapy

• • If the patient does not respond to several liters of volume infusion with isotonic crystalloid solution (usually 4 L or more) or evidence of volume overload is present, the depressed cardiovascular system can be stimulated by inotropic and vasoconstrictive agents. When proper fluid resuscitation fails to restore hemodynamic stability and tissue perfusion, initiate therapy with vasopressor agents. These agents are dopamine, norepinephrine, epinephrine, and phenylephrine. These agents are vasoconstricting drugs that maintain adequate blood pressure during life-threatening hypotension and preserve perfusion pressure for optimizing flow in various organs.
  
  
  
  • The mean blood pressure required for adequate splanchnic and renal perfusion (MAP of 60 or 65 mm Hg) is based on clinical indices of organ function. Dopamine is the most commonly used agent for this purpose. Treatment usually begins at a rate of 5-10 mcg/kg/min IV, and the infusion is adjusted according to the blood pressure and other hemodynamic parameters. Often, patients may require high doses of dopamine (as much as 20 mcg/kg/min). Presently, norepinephrine is the preferred drug because dopamine is known to cause unfavorable flow distribution.
  
  
  
  • If the patient remains hypotensive despite volume infusion and moderate doses of dopamine, a direct vasoconstrictor (eg, norepinephrine) should be started at a dose of 0.5 mcg/kg/min and titrated to maintain a MAP of 60 mm Hg. While potent vasoconstrictors (eg, norepinephrine) traditionally have been avoided because of their adverse effects on cardiac output and renal perfusion, data from animal and human studies reveal that norepinephrine can reverse septic shock in patients unresponsive to volume and dopamine. These patients require invasive hemodynamic monitoring with arterial lines and pulmonary artery catheters. Vasopressors may cause more harm than good if administered to patients whose inadequate intravascular volume is not restored (ie, a patient "whose tank is not filled").
     
• The following is a brief review of the mechanism of action and utility of drugs used for hemodynamic support of septic shock:

• • Dopamine: A precursor of norepinephrine and epinephrine, dopamine has varying effects according to the doses infused. A dose of less than 5 mcg/kg/min results in vasodilation of renal, mesenteric, and coronary beds. At a dose of 5-10 mcg/kg/min, beta1-adrenergic effects induce an increase in cardiac contractility and heart rate. At doses of about 10 mcg/kg/min, alpha-adrenergic effects lead to arterial vasoconstriction and elevation in blood pressure. Dopamine is effective in optimizing MAP in patients with septic shock who remain hypotensive after volume resuscitation. The blood pressure increases primarily as a result of inotropic effect and, thus, will be useful in patients who have concomitant reduced cardiac function. The undesirable effects are tachycardia, increased pulmonary shunting, potential to decrease splanchnic perfusion, and increase in pulmonary arterial wedge pressure.
  
  
  
  • Norepinephrine
    
    
    • This agent is a potent alpha-adrenergic agonist with minimal beta-adrenergic agonist effects. Norepinephrine can increase blood pressure successfully in patients with sepsis who remain hypotensive following fluid resuscitation and dopamine. The dose of norepinephrine may vary from 0.2-1.5 mcg/kg/min, and large doses as high as 3.3 mcg/kg/min have been used because of the alpha-receptor down-regulation in sepsis.
    
    
    
    • In patients with sepsis, indices of regional perfusion (eg, urine flow) and lactate concentration have improved following norepinephrine infusion. Two recent trials have shown that a significantly greater proportion of patients treated with norepinephrine were resuscitated successfully, as opposed to the patients treated with dopamine. Therefore, norepinephrine should be used early and should not be withheld as a last resort in patients with severe sepsis who are in shock.
    
    
    
    • The concerns about compromising splanchnic tissue oxygenation have not been proven; the studies have confirmed no deleterious effects on splanchnic oxygen consumption and hepatic glucose production, provided adequate cardiac output is maintained.
       
  • Epinephrine: This agent can increase MAP by increasing cardiac index and stroke volume, along with an increase in systemic vascular resistance and heart rate. Epinephrine may increase oxygen delivery and oxygen consumption and decreases the splanchnic blood flow. Administration of this agent is associated with an increase in systemic and regional lactate concentrations. The use of epinephrine is recommended only in patients who are unresponsive to traditional agents. The undesirable effects are an increase in lactate concentration, a potential to produce myocardial ischemia, development of arrhythmias, and a reduction in splanchnic flow.
  
  
  
  • Phenylephrine: This agent is a selective alpha1-adrenergic receptor agonist that is used primarily in anesthesia to increase blood pressure. Although studies are limited, phenylephrine increased MAP in patients who were septic hypotensive with increased oxygen consumption. However, the concern remains about its potential to reduce cardiac output and lower heart rate in patients with sepsis. Phenylephrine may be a good choice when tachyarrhythmias limit therapy with other vasopressors.
  
  
  
  • Inotropic therapy: Although myocardial performance is altered during sepsis and septic shock, cardiac output generally is maintained in patients with volume-resuscitated sepsis. Data from the 1980s and 1990s suggest a linear relationship between oxygen delivery and oxygen consumption (pathologic supply dependency), indicating that the oxygen delivery likely was insufficient to meet the metabolic needs of the patient. However, recent investigators have challenged the concept of pathologic supply dependency, suggesting that elevating cardiac index and oxygen delivery (hyperresuscitation) was not associated with improved patient outcome. Therefore, the role of inotropic therapy is uncertain, unless the patient has inadequate cardiac index, mean arterial pressure, mixed venous oxygen saturation, and urine output despite adequate volume resuscitation and vasopressor therapy.
  
  
  
  • Renal-dose dopamine: In the setting of circulatory shock of any etiology, several well-designed clinical trials have failed to demonstrate any beneficial effects of low dose dopamine to improve renal blood flow and support renal function. Dopamine at a dose of 2-3 mcg/kg/min is known to initiate diuresis by increasing renal blood flow in healthy animals and volunteers. Multiple studies have not demonstrated a beneficial effect of prophylactic or therapeutic low-dose dopamine administration in patients with sepsis who are critically ill. Considering the real side effects of dopamine infusion, the use of renal dose dopamine should be abandoned.
     
• Empirical antimicrobial therapy

• • Initiate this therapy early in patients experiencing septic shock. However, antibiotics have little effect on the clinical outcome for at least 24 hours. The selection of appropriate agents is based on the patient's underlying host defenses, the potential sources of infection, and the most likely culprit organisms. If the patient is "antibiotic experienced," strongly consider the use of an aminoglycoside rather than a quinolone or cephalosporin for gram-negative coverage. Knowing the antibiotic resistance patterns of both the hospital itself and its referral base (ie, nursing homes) is important. Antibiotics must be broad-spectrum agents and must cover gram-positive, gram-negative, and anaerobic bacteria because the different classes of these organisms produce an identical clinical picture of distributive shock.
  
  
  
  • Administer the antibiotics parenterally, in doses adequate to achieve bactericidal serum levels. Many studies find that the clinical improvement correlates with the achievement of serum bactericidal levels rather than the number of antibiotics administered.
  
  
  
  • Include coverage directed against anaerobes in patients with intra-abdominal or perineal infections. Antipseudomonal coverage is indicated in patients with neutropenia or burns or in patients who acquired sepsis while hospitalized. Patients who are immunocompetent usually can be treated with a single drug with broad-spectrum coverage, such as a third-generation cephalosporin. Patients who are immunocompromised typically require dual broad-spectrum antibiotics with overlapping coverage. Within these general guidelines, no single combination of antibiotics is clearly superior to others.
  
  
  • The following points should always be kept in mind:
  
  
  • Early, empiric antibiotic coverage is essential with narrowed spectrum when culture results are available.
  
  
  
  • Waiting until cultures are back is an invalid reason to withhold antibiotics.
  
  
  
  • Only 30% of patients with presumed septic shock have positive blood cultures.
  
  
  
  • Twenty-five percent of presumed septic shock patients remain culture negative from all sites, but mortality with culture positive counterparts is similar.
     
• Recombinant human activated protein C

• • The inflammatory mediators are known to cause activation of coagulation inhibitors of fibrinolysis, thereby causing diffuse endovascular injury, multiorgan dysfunction, and death. Activated protein C is an endogenous protein that not only promotes fibrinolysis and inhibits thrombosis and inflammation but also may modulate the coagulation and inflammation of severe sepsis. Sepsis reduces the level of protein C and inhibits conversion of protein C to activated protein C. Administration of recombinant activated protein C inhibits thrombosis and inflammation, promotes fibrinolysis, and modulates coagulation and inflammation.
  
  
  
  • A recent publication by the Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study group demonstrated that the administration of recombinant human activated protein C (drotrecogin-alpha, activated) resulted in lower mortality rates (24.7% vs 30.8%) in the treated group compared with placebo. Treatment with activated drotrecogin-alpha was associated with reduction in the relative risk of death by 19.4% (95% CI, 6.6-30.5) and an absolute reduction in risk of death by 6.1%, (P=.005).
     
• Corticosteroids: Although theoretical and experimental animal evidence exists for the use of large doses of corticosteroids in those with severe sepsis and septic shock, all randomized human studies (except 1 from 1976) found that corticosteroids did not prevent the development of shock, reverse the shock state, or improve the 14-day mortality rate. Therefore, no support exists in the medical literature for the routine use of high doses of corticosteroids in patients with sepsis or septic shock. A meta-analysis of 10 prospective, randomized, controlled trials of glucocorticoid use did not report any benefit from corticosteroids. Therefore, high-dose corticosteroids should not be used in patients with severe sepsis or septic shock.

• Although further studies await further confirmation, current recommendations are as follows:
  
  
  • Drotrecogin alpha (activated protein C) is the only widely accepted drug specific to the therapy of sepsis.
  
  
  
  • Drotrecogin alpha should be considered for patients with APACHE II scores greater than 25.
  
  
  
  • The main side effect of Drotrecogin alpha is bleeding.
     
• Stress-dose glucocorticoids: Recent trials (Briegel, 1999; Cartlet, 1999) demonstrated positive results of stress-dose administration of corticosteroids in patients with severe and refractory shock. Although further confirmatory studies are awaited, stress-dose steroid coverage should be provided to patients who have the possibility of adrenal suppression.



• The following key points summarize use of corticosteroids in septic shock:

• • Older, traditional trials of corticosteroids in sepsis were unsuccessful likely because of high doses and poor patient selection.
  
  
  
  • Recent trials with low-dose (physiologic) dosages in select patient populations (vasopressor dependent and possibly relative adrenal insufficiency) have resulted in improved outcome.
  
  
  
  • Corticosteroids should be initiated for patients with vasopressor-dependent septic shock.
  
  
  
  • A cosyntropin stimulation test may be performed to identify patients with relative adrenal insufficiency defined recently as failure to increase levels > 9 mcg/dL
  
  
  • Tight glycemic control:
    
    
    • Tight glycemic control has recently become a prominent emphasis in the care of critically ill patients, and recent data has been extrapolated to potentially apply to septic populations. A 2001 Belgian study of surgical intensive care unit (ICU) patients that remained in the ICU for more than 5 days showed a 10% mortality benefit in those with tighter glycemic control. The glucose levels for these patients were maintained from 80-110 mg per dL through the use of intensive insulin therapy. The benefit of glycemic control appears to result more from aggressive avoidance of the detrimental effects of hyperglycemia rather than the potential therapeutic effect of insulin.
    
    
    
    • Based on the current evidence, the Surviving Sepsis Campaign recommends maintaining a glucose level of less than 150 mg/dL, although the logic behind choosing this level is unclear (Dellinger, 2004). Van den Berge documented benefit only once glucose levels were maintained below 110 mg/dl, with increased mortality when blood glucose levels were allowed to reach 130-150 mg/dl. This same group recently finished a large prospective study in medical patients (NEJM, 2006) documenting similar benefits in these patients.
    
    
    
    • Tight glycemic control has been shown to improve mortality in both postoperative surgical patients including, and particularly, those with sepsis and in-medical ICU patients.
    
    
    
    • The Surviving Sepsis Campaign recommends that glucose levels in the septic patient should be kept at less than 150 mg/dL although the published evidence supports controlling blood glucose between 80 and 110 mg/dL.
    
    
    
    • Tight glycemic control is not without risks. In the elderly (>75 years of age) and in those patients with liver failure, excessive hypoglycemic reactions limits its use. Furthermore, to be effective, glycemic control needs to be protocol driven and run by the bedside caregiver, usually the bedside nurse.
       
• Experimental and other therapies include nonadrenergic vasopressors and inotropes. The clinical utility of several of these agents remains unproven despite several studies indicating their beneficial effect on hemodynamic instability.
  
  
  • Dopexamine: This agent has beta 2-adrenergic and dopaminergic effects without any alpha-adrenergic activity and is known to increase splanchnic perfusion. A few small studies have shown that dopexamine increases cardiac index and heart rate and decreases systemic vascular resistance in a dose-dependent manner. The hepatic blood flow and gastric intramucosal pH improve, but results are not reproducible consistently. This drug appears to be promising for patients with sepsis and septic shock, but superiority over the other drugs has not been demonstrated. Dopexamine continues to be an experimental medication in the United States.
  
  
  
  • Vasopressin: This agent may be useful in patients with refractory septic shock; however, minimal studies have been conducted. In patients with septic shock, infusion of 0.04 U/kg/min of vasopressin resulted in improved MAP secondary to peripheral vasoconstriction.
  
  
  
  • Phosphodiesterases inhibitors: Inamrinone (formerly amrinone) and milrinone are inotropic agents with vasodilating properties, and each has a long half-life. The mechanism of action occurs via phosphodiesterase inhibition. These medications are beneficial in cardiac pump failure, but their benefit in patients experiencing septic shock is not well established. Furthermore, these agents have a propensity to worsen hypotension in patients with septic shock.
  
  
  
  • Nitric oxide inhibitor: This agent is a potent endogenous vasodilator. Excessive nitric oxide production, because of the cytokines and other mediators, induces vasodilation and hypotension in patients with sepsis. Nitric oxide is synthesized from endogenous L-arginine by the enzyme nitric oxide synthase. Inhibitors of nitric oxide synthase (N-monomethyl-l-arginine, L-NMMA) in sepsis augment mean arterial pressure, decreased cardiac output, and increased systemic vascular resistance. Inordinate mortality was the cause of early termination of a randomized trial of nitric oxide synthase inhibition with L-NMMA. The clinical benefit of this therapeutic approach in patients with sepsis remains unproven.
  
  
  
  • Anti-inflammatory therapy: The rationale for anti-inflammatory therapy is that blocking the production of inflammatory mediators may ameliorate the deleterious host inflammatory response and, hence, may limit the tissue injury.
  
  
  
  • Ibuprofen: Despite promising results in animal studies, the use of ibuprofen has not been proven of any benefit in patients with septic shock.
  
  
  
  • Antiendotoxin treatment: The insight that endotoxin, a lipid-polysaccharide compound found in the cell wall of gram-negative bacteria, plays a key role in initiating the humoral cascade observed in septic shock led to the hypothesis that neutralizing the circulating endotoxin with IV administration of an antiendotoxin antibody might be beneficial. Several products have been developed and investigated by carefully conducted human trials. To date, no proven benefit to these agents has been observed. Other methods of extracorporeal elimination of endotoxin, polyclonal antiendotoxin antibodies, or monoclonal antiendotoxin antibodies showed neither improvement in short-term survival nor amelioration of sepsis in humans with septic shock. Trials with some of these compounds are ongoing, and, despite a tendency towards benefit, efficacy data are lacking.
  
  
  
  • Anticytokine treatment: Serum levels of TNF and IL-1 are elevated in patients with septic shock. Both produce hemodynamic effects that duplicate those found in sepsis. Many studies indicate that both the mediators play key roles in sepsis and septic shock, and some think that TNF may be the central mediator in sepsis. As is the case with antiendotoxin antibodies, antibodies to TNF or IL-1 were hypothesized to be useful in patients with septic shock. However, anti-TNF or anti–IL-1 antibodies have yet to be shown to improve the outcome in sepsis or septic shock. Cytokines are the major mediators of inflammatory cascade. Antibodies or blocking medications against TNF, interleukins, and their receptor blockers have been developed and have undergone clinical trials. In 1997, Zeni conducted a meta-analysis and selected 21 trials representing a total of 6429 patients. A small but insignificant beneficial effect was demonstrated.
  
  
  
  • Miscellaneous treatment: Several other experimental interventions and therapies have undergone clinical trials for sepsis. Although several of these may have shown benefit, no convincing evidence suggests that these therapies are efficacious. A long list of these interventions or therapies exists; the important ones include intravenous immunoglobulins, interferon gamma, antithrombin-3 infusion, naloxone, pentoxifylline, growth hormone, G-CSF, and hemofiltration or extracorporeal removal of endotoxins. None of these agents was efficacious in properly designed controlled clinical trials.

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

• Patients who do not respond or who are in septic shock require an intensive care unit facility for continuous monitoring and observation. Consultation with a critical care physician or internist with expertise is appropriate.
• Consultation with an appropriate surgeon should be sought for patients with suspected or known infected foci, especially patients with a suspected abdominal source. Some of these common foci of infection include intra-abdominal sepsis (perforation, abscesses), empyema, mediastinitis, cholangitis, pancreatic abscesses, pyelonephritis or renal abscess from ureteric obstruction, infective endocarditis, septic arthritis, soft tissue infection, and infected prosthetic devices.

MEDICATION

Section 7 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

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.