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eMedicine - Septic Shock : Article by Sat Sharma, MD, FRCPC, FACP, FCCP, DABSM http://intranet.santa.lt/thesaurus/REZIDENTUI/Valvular/septic%20shock.htm[11/20/09 8:33:20 AM] Home | Specialties | Resource Centers | Learning Centers | CME | Contributor Recruitment March 21, 2007 Articles Images CME Advanced Search Consumer Health Link to this site You are in: eMedicine Specialties > Medicine, Ob/Gyn, Psychiatry, and Surgery > Critical Care Septic Shock Last Updated: December 8, 2006 Rate this Article Email to a Colleague Get CME/CE for article Synonyms and related keywords: sepsis, distributive shock, severe sepsis, systemic inflammatory response syndrome, SIRS, multiple organ dysfunction syndrome, acute respiratory distress syndrome, ARDS AUTHOR INFORMATION Section 1 of 11 Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Pictures Bibliography Author: Sat Sharma, MD, FRCPC, FACP, FCCP, DABSM , Program Director, Associate Professor, Department of Internal Medicine, Divisions of Pulmonary and Critical Care Medicine, University of Manitoba; Site Director of Respiratory Medicine, St Boniface General Hospital Coauthor(s): Steven Mink, MD , Head, Section of Pulmonary Medicine, Professor, Department of Internal Medicine, St Boniface Hospital, University of Manitoba, Canada Sat Sharma, MD, FRCPC, FACP, FCCP, DABSM, is a member of the following medical societies: American Academy of Sleep Medicine , American College of Chest Physicians , American College of Physicians-American Society of Internal Medicine , American Thoracic Society , Canadian Medical Association , Royal College of Physicians and Surgeons of Canada , Royal Society of Medicine , Society of Critical Care Medicine , and World Medical Association Editor(s): Cory Franklin, MD, Professor, Department of Medicine, Rosalind Franklin University of Medicine and Science; Director, Division of Critical Care Medicine, Cook County Hospital; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; John L Brusch, MD, FACP, Assistant Professor of Medicine, Harvard Medical School; Consulting Staff, Department of Medicine and Infectious Disease Service, Cambridge Health Alliance; Timothy D Rice, MD, Associate Professor, Departments of Internal Medicine and Pediatrics and Adolescent Medicine, Saint Louis University School of Medicine; and Michael R Pinsky, MD, Professor of Critical Care Medicine, Bioengineering, Anesthesiology, University of Pittsburgh School of Medicine, University of Pittsburgh Medical Center Disclosure Quick Find Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Pictures Bibliography Click for related images. Related Articles Acute Renal Failure Adrenal Crisis Anaphylaxis Cardiogenic Shock Diabetic Ketoacidosis Disseminated Intravascular Coagulation Heatstroke Hyperthyroidism Myocardial Infarction Myocardial Rupture

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eMedicine - Septic Shock : Article by Sat Sharma, MD, FRCPC, FACP, FCCP, DABSM

http://intranet.santa.lt/thesaurus/REZIDENTUI/Valvular/septic%20shock.htm[11/20/09 8:33:20 AM]

Home | Specialties | Resource Centers | Learning Centers | CME | Contributor Recruitment

March 21, 2007

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You are in: eMedicine Specialties > Medicine, Ob/Gyn, Psychiatry, and Surgery > CriticalCare

Septic ShockLast Updated: December 8, 2006

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Synonyms and related keywords: sepsis, distributive shock, severe sepsis, systemicinflammatory response syndrome, SIRS, multiple organ dysfunction syndrome, acuterespiratory distress syndrome, ARDS

AUTHOR INFORMATION Section 1 of 11 Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous PicturesBibliography

Author: Sat Sharma, MD, FRCPC, FACP, FCCP, DABSM, Program Director, AssociateProfessor, Department of Internal Medicine, Divisions of Pulmonary and Critical CareMedicine, University of Manitoba; Site Director of Respiratory Medicine, St BonifaceGeneral Hospital

Coauthor(s): Steven Mink, MD, Head, Section of Pulmonary Medicine, Professor,Department of Internal Medicine, St Boniface Hospital, University of Manitoba, CanadaSat Sharma, MD, FRCPC, FACP, FCCP, DABSM, is a member of the following medicalsocieties: American Academy of Sleep Medicine, American College of Chest Physicians,American College of Physicians-American Society of Internal Medicine, AmericanThoracic Society, Canadian Medical Association, Royal College of Physicians andSurgeons of Canada, Royal Society of Medicine, Society of Critical Care Medicine, andWorld Medical Association

Editor(s): Cory Franklin, MD, Professor, Department of Medicine, Rosalind FranklinUniversity of Medicine and Science; Director, Division of Critical Care Medicine, CookCounty Hospital; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine;John L Brusch, MD, FACP, Assistant Professor of Medicine, Harvard Medical School;Consulting Staff, Department of Medicine and Infectious Disease Service, CambridgeHealth Alliance; Timothy D Rice, MD, Associate Professor, Departments of InternalMedicine and Pediatrics and Adolescent Medicine, Saint Louis University School ofMedicine; and Michael R Pinsky, MD, Professor of Critical Care Medicine,Bioengineering, Anesthesiology, University of Pittsburgh School of Medicine, University ofPittsburgh Medical Center

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INTRODUCTION Section 2 of 11 Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous PicturesBibliography

Background:

History of infectious diseases

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

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

Further advances in medical sciences in the late 20th century enhanced our understanding ofsepsis and septic shock—recognition of inflammatory mediators stimulating nitric oxideproduction; producing endothelial injury; activating coagulation cascade; and eventuallyleading to organ ischemia, damage, and, ultimately, death. This knowledge will lead to novelapproaches 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 ofentry into the blood stream which causes sign of illness.” The definition did not changemuch over the years because the terms sepsis and septicemia referred to several ill-definedclinical conditions present in a patient with bacteremia. In practice, the terms often wereused interchangeably; however, less than one half of the patients with signs and symptoms ofsepsis have positive results on blood culture. Furthermore, not all patients with bacteriemiahave signs of sepsis; therefore, sepsis and septicemia are not identical. In the last fewdecades, discovery of endogenous mediators of the host response have led to the recognitionthat the clinical syndrome of sepsis is the result of excessive activation of host defensemechanisms rather than the direct effect of microorganisms. Sepsis and its sequelaerepresent a continuum of clinical and pathophysiologic severity.

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

NeurolepticMalignantSyndrome

PulmonaryEmbolism

Sepsis, Bacterial

Shock andPregnancy

Shock,Distributive

Shock,Hemorrhagic

SystemicInflammatoryResponseSyndrome

Toxicity,Salicylate

ContinuingEducation

CME availablefor this topic.Click here totake this CME.

Patient Education

Shock Center

Blood andLymphaticSystem Center

Public HealthCenter

Shock Overview

Sepsis (BloodInfection)Overview

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

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 awide 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/mL, less than 4000/mL, or 10% immature(band) forms

Sepsis: This is a systemic inflammatory response to a documented infection. Themanifestations of sepsis are the same as those previously defined for SIRS. The clinicalfeatures 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/perfusionalso must be included:

Alteration in mental state

Hypoxemia (PaO2 <72 mm Hg at FiO2 [fraction of inspired oxygen] 0.21; overtpulmonary 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, orhypotension. Hypoperfusion and perfusion abnormalities may include, but are not limited to,lactic acidosis, oliguria, or an acute alteration in mental status. The systemic response toinfection 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

Sepsis (BloodInfection)Causes

Sepsis (BloodInfection)Symptoms

Sepsis (BloodInfection)Treatment

CardiopulmonaryResuscitation(CPR)

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

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

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

Multiple organ dysfunction syndrome (MODS): This is the presence of altered organfunction in a patient who is acutely ill and in whom homeostasis cannot be maintainedwithout intervention.

Pathophysiology:

Mediator-induced cellular injury

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

The gram-positive and gram-negative bacteria induce a variety of proinflammatorymediators, including cytokines. Such cytokines play a pivotal role in initiating sepsis andshock. The bacterial cell wall components are known to release the cytokines; these includelipopolysaccharide (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 cytokinesinduced in host cells (macrophages/monocytes and neutrophils) by the bacterial cell wallcomponent. The most toxic component of the gram-negative bacteria is the lipid A moiety oflipopolysaccharide. The gram-positive bacteria cell wall leads to cytokine induction vialipoteichoic acid. Additionally, gram-positive bacteria may secrete the super antigencytotoxins that bind directly to the major histocompatibility complex (MHC) molecules andT-cell receptors, leading to massive cytokine production.

An initial step in the activation of innate immunity is the synthesis de novo of smallpolypeptides, called cytokines, that induce protean manifestations on most cell types, fromimmune effector cells to vascular smooth muscle and parenchymal cells. Several cytokinesare induced, including tumor necrosis factor (TNF) and interleukins, especially IL-1. Both ofthese 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 theoutcome. High levels of IL-6 are associated with mortality, but its role in pathogeneses isnot clear. IL-8 is an important regulator of neutrophil function, synthesized and released insignificant amounts during sepsis. IL-8 contributes to the lung injury and dysfunction ofother organs. The chemokines (monocyte chemoattractant protein–1) orchestrate themigration of leukocytes during endotoxemia and sepsis. The other cytokines that have asupposed role in sepsis are IL-10, interferon-gamma, IL-12, macrophage migrationinhibition factor, granulocyte colony-stimulating factor (G-CSF), and granulocyte

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macrophage colony-stimulating factor (GM-CSF).

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

The lipid mediators (eicosanoids), platelet activating factor, and phospholipase A2 aregenerated during sepsis, but their contributions to the sepsis syndrome remain to beestablished.

Table 1. Mediators of SepsisType Mediator Activity

Cellularmediators

Lipopolysaccharide

Activation of macrophages, neutrophils, platelets,and endothelium releases various cytokines andother mediators

Lipoteichoic acidPeptidoglycanSuperantigensEndotoxin

Humoralmediators

Cytokines Potent proinflammatory effect

Neutrophil chemotactic factor

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

Activation and degranulation of neutrophils

Cytotoxic, augments vascular permeability,contributes to shock

Involved in hemodynamic alterations of septicshock

Promote neutrophil and macrophage, plateletactivation and chemotaxis, other proinflammatoryeffects

Enhance vascular permeability and contributes tolung injury

Enhance neutrophil-endothelial cell interaction,regulate leukocyte migration and adhesion, andplay a role in pathogenesis of sepsis

TNF-alpha and IL-1bIL-8IL-6IL-10MIF*G-CSFComplementNitric oxideLipid mediatorsPhospholipase A2PAF†

EicosanoidsArachidonic acidmetabolites

AdhesionmoleculesSelectinsLeukocyteintegrins

*Macrophage inhibitory factor†Platelet activating factor

Abnormalities of coagulation and fibrinolysis homeostasis in sepsis

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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 thevascular endothelium; the endothelial cells release tissue factor (TF), triggering the extrinsiccoagulation cascade and accelerating production of thrombin (Carvalho, 1994). Thecoagulation factors are activated as a result of endothelial damage, the process is initiated viabinding of factor XII to the subendothelial surface. This activates factor XII, and then factorXI 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 ofthrombin, which converts soluble fibrinogen to fibrin. The insoluble fibrin, along withaggregated platelets, forms intravascular clots.

Inflammatory cytokines, such as IL-1a, IL-1b, and TNF-alpha initiate coagulation byactivation of TF, which is the principle activator of coagulation. TF interacts with factorVIIa, forming factor VIIa-TF complex, which activates factor X and IX. Activation ofcoagulation in sepsis has been confirmed by marked increases in thrombin-antithrombincomplex (Levi, 1993) and the presence of D-dimer in plasma, indicating activation ofclotting 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 activatorinhibitor (PAI-1) and thrombin activatable fibrinolysis inhibitor (TAFI). Furthermore, thelevels of protein C and endogenous activated protein C also are decreased in sepsis.Endogenous activated protein C is an important proteolytic inhibitor of coagulation cofactorsVa and VIIa. Thrombin via thrombomodulin activates protein C that functions as anantithrombotic in the microvasculature. Endogenous activated protein C also enhancesfibrinolysis by neutralizing PAI-1 and by accelerating t-PA–dependent clot lysis.

The imbalance among inflammation, coagulation, and fibrinolysis results in widespreadcoagulopathy and microvascular thrombosis and suppressed fibrinolysis, ultimately leadingto multiple organ dysfunction and death.

Circulatory and metabolic pathophysiology of septic shock

The predominant hemodynamic feature of septic shock is arterial vasodilation. Diminishedperipheral arterial vascular tone may result in dependency of blood pressure on cardiacoutput, causing vasodilation to result in hypotension and shock if insufficiently compensatedby a rise in cardiac output. Early in septic shock, the rise in cardiac output often is limited byhypovolemia and a fall in preload because of low cardiac filling pressures. Whenintravascular volume is augmented, the cardiac output usually is elevated (the hyperdynamicphase of sepsis and shock). Even though the cardiac output is elevated, the performance ofthe heart, reflected by stroke work as calculated from stroke volume and blood pressure,usually is depressed. Factors responsible for myocardial depression of sepsis are myocardialdepressant substances, coronary blood flow abnormalities, pulmonary hypertension, variouscytokines, nitric oxide, and beta-receptor down-regulation.

Peripheral circulation during septic shock

An elevation of cardiac output occurs; however, the arterial-mixed venous oxygen differenceusually is narrow, and the blood lactate level is elevated. This implies that low global tissueoxygen 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

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demand in the tissues, which may be more pronounced in some areas than in others. This istermed maldistribution of blood flow, either between or within organs, with a resultantdefect in capacity to extract oxygen locally. During a fall in oxygen supply, cardiac outputbecomes distributed so that most vital organs, such as the heart and brain, remain relativelybetter perfused than nonvital organs. However, sepsis leads to regional changes in oxygendemand and regional alteration in blood flow of various organs.

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

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

In patients with sepsis who have low oxygen extraction and elevated arterial blood lactatelevels, 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, andoxygen uptake may increase with a boost in oxygen supply, a phenomenon termed oxygenuptake supply dependence or pathological supply dependence. However, this concept iscontroversial because other investigators argue that supply dependence is artifactual ratherthan 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 experiencingseptic shock.

Multiorgan dysfunction syndrome

Sepsis is described as an autodestructive process that permits the extension of normalpathophysiologic response to infection (involving otherwise normal tissues), resulting inmultiple organ dysfunction syndrome. Organ dysfunction or organ failure may be the firstclinical sign of sepsis, and no organ system is immune to the consequences of theinflammatory 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 thesite 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 ofvasodilatation.

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 tomaintain the blood pressure in the presence of systemic vasodilatation. Patients withpreexisting cardiac disease are unable to increase their cardiac output appropriately.

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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. Adecrease in the number of functional capillaries causes an inability to extract oxygenmaximally; intrinsic and extrinsic compression of capillaries and plugging of the capillarylumen by blood cells cause the inability. Increased endothelial permeability leads towidespread tissue edema of protein-rich fluid.

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

Pulmonary dysfunction

Endothelial injury in the pulmonary vasculature leads to disturbed capillary blood flow andenhanced microvascular permeability, resulting in interstitial and alveolar edema. Neutrophilentrapment within the pulmonary microcirculation initiates and amplifies the injury toalveolar capillary membrane. ARDS is a frequent manifestation of these effects. As many as40% of patients with severe sepsis develop acute lung injury.

Acute lung injury is a spectrum of pulmonary dysfunction secondary to parenchymal cellulardamage characterized by endothelial cell injury and destruction, deposition of platelet andleukocyte aggregates, destruction of type I alveolar pneumocytes, an acute inflammatoryresponse 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 producesmany 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 hostresponse is uncontrolled, and the acute lung injury progresses to ARDS. Continuedinfiltration occurs with neutrophils and mononuclear cells, lymphocytes, and fibroblasts. Analveolar inflammatory exudate persists, and type II pneumocyte proliferation is evident. Ifthis process can be halted, complete resolution may occur. In other patients, a progressiverespiratory failure and pulmonary fibrosis develop. The late stage of ARDS is characterizedby an aggressive repair process, infiltration with an excess number of fibroblasts, andsynthesis of the extracellular matrix (ECM) protein, including collagen. Subsequentdeposition of metrics in the alveolar wall impedes gas exchange and results in a restrictivedefect leading to irreversible respiratory failure.

Gastrointestinal dysfunction and nutrition

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

Liver dysfunction

By virtue of the liver's role in the host defense, the abnormal synthetic functions caused byliver dysfunction can contribute to both the initiation and progression of sepsis. The

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reticuloendothelial system of the liver acts as a first line of defense in clearing bacteria andtheir products; liver dysfunction leads to a spillover of these products into the systemiccirculation.

Renal dysfunction

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

Central nervous system dysfunction

Involvement of the central nervous system (CNS) in sepsis produces encephalopathy andperipheral 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 sepsisare not understood fully. Multiorgan dysfunction syndrome is associated with widespreadendothelial and parenchymal cell injury because of the falling proposed mechanisms.

Hypoxic hypoxia

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

Direct cytotoxicity

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

Apoptosis

Apoptosis (programmed cell death) is the principal mechanism by which dysfunctional cellsnormally are eliminated. The proinflammatory cytokines may delay apoptosis in activatedmacrophages and neutrophils, but other tissues, such as the gut epithelium, may undergoaccelerated apoptosis. Therefore, derangement of apoptosis plays a critical role in tissueinjury of patients with sepsis.

Immunosuppression

The interaction between proinflammatory and anti-inflammatory mediators may lead to animbalance and inflammatory reaction, immunodeficiency may predominate, or both may bepresent.

Coagulopathy

Subclinical coagulopathy signified by mild elevation of the thrombin or activated partialthromboplastin time (aPTT) or a moderate reduction in platelet count is extremely common,

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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:

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

The incidence of sepsis syndrome and septic shock in patients admitted to a universityhospital was reportedly 13.6 and 4.6 cases per 1000 persons, respectively. In theUnited States, 200,000 cases of septic shock and 100,000 deaths per year occur fromthis disease.

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

Internationally: A Dutch surveillance study reported that 1.36 cases per 100 hospitaladmissions were secondary to severe sepsis.

Mortality/Morbidity: The mortality rate in patients with sepsis varies in the reported seriesfrom 21.6-50.8%. Over the last decade, mortality rates seem to have decreased. In some

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studies, the mortality rate specifically caused by the septic episode itself is specified and is14.3-20%.

Sex: Most studies of septic shock report a male preponderance. The percentage of malepatients 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 riskfactor for acquiring nosocomial blood stream infection in the development of severe forms ofsepsis.

CLINICAL Section 3 of 11 Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous PicturesBibliography

History: The constitutional symptoms of sepsis usually are nonspecific and include fever,chills, fatigue, malaise, anxiety, or confusion. These symptoms are not pathognomonic forinfection 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 documentedinfection. Consequently, sepsis is a continuum of detrimental host responses toinfection that ranges from sepsis to septic shock and MODS. The specific clinicalfeatures depend on where the patient falls on that continuum. The SIRS is defined bythe 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/mL, less than 4000/mL, or more than 10% bands

Fever is a common feature of patients with sepsis. The hypothalamus resets so thatheat production and heat loss are balanced in favor of a higher temperature. Fever maybe absent in elderly patients or patients who are immunosuppressed.

Chills are a secondary symptom associated with fever, which is a consequence ofincreased muscular activity that produces heat and raises the body temperature.

Sweating occurs when the hypothalamus returns to its normal set point and senses thehigher body temperature, stimulating perspiration to evaporate excess body heat.

Alteration in mental function often occurs. Mild disorientation or confusion isespecially common in elderly individuals. Apprehension, anxiety, agitation, and,eventually, coma are manifestations of severe sepsis. The exact cause of metabolicencephalopathy is not known; alteration in amino acid metabolism may play a role.

Hyperventilation with respiratory alkalosis is a common feature of patients with sepsissecondary to stimulation of the medullary respiratory center by endotoxins and otherinflammatory mediators.

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The localizing symptoms referable to organ systems may provide useful clues to theetiology of sepsis and are as follows:

Head and neck infections - Earache, sore throat, sinus pain, or swollen lymphglands

Chest and pulmonary infections - Cough (especially if productive), pleuriticchest pain, and dyspnea

Abdominal and GI infections - Abdominal pain, nausea, vomiting, and diarrhea

Pelvic and genitourinary infections - Pelvic or flank pain, vaginal or urethraldischarge, and urinary frequency and urgency

Bone and soft tissue infections - Localized limb pain or tenderness, focalerythema, edema, and swollen joint

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

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 rectaltemperatures 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 stagesof sepsis, cardiac output is well maintained or even increased. The vasodilation mayresult in warm skin, warm extremities, and normal capillary refill (warm shock). Assepsis progresses, stroke volume and cardiac output fall. The patients begin tomanifest the following signs of poor perfusion: cool skin, cool extremities, anddelayed 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, sinustenderness, pharyngeal erythema and exudates, inspiratory stridor, and cervicallymphadenopathy

Chest and pulmonary infections - Dullness on percussion, bronchial breathsounds, 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, pelvictenderness, pain on cervical motion, and adnexal tenderness

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Bone and soft tissue infections - Focal erythema, edema, tenderness, crepitus innecrotizing infections, and joint effusion

Skin infections - Petechiae, purpura, erythema, ulceration, and bullous formation

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

Origin of infection

In most patients with sepsis, a source of infection can be identified, with theexception of patients who are immunocompromised with neutropenia, where anobvious source of infection often is not found.

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

The use of intravascular devices is a notorious cause of nosocomially-acquiredsepsis.

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 septicshock. The following is a list of pathogens that can infect individual organ systemsand lead to severe sepsis and septic shock:

Lower respiratory tract infections are the cause of septic shock in 25% ofpatients. 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 thefollowing are the common pathogens:

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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 thefollowing 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 thefollowing 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 septicshock in 10% of patients, and the following are the common pathogens:

Neisseria gonorrhoeae

Gram-negative bacteria

Gram-negative bacteria

Streptococci

Anaerobes

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

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

Anaerobic pathogens are becoming less important as a cause of sepsis. In oneinstitution, the incidence of anaerobic bacteremia declined by 45% over a 15-yearperiod.

Fungal infections are the cause of sepsis in 0.8-10.2% of patients with sepsis, andtheir incidence appears to be increasing.

Polymicrobial sepsis has become a more prevalent cause of sepsis; the incidence is5.6-18.4%. The patients with neutropenia particularly are at high risk for polymicrobialinfections.

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

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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 Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous PicturesBibliography

Acute Renal Failure Adrenal Crisis Anaphylaxis Cardiogenic Shock Diabetic Ketoacidosis Disseminated Intravascular Coagulation Heatstroke 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

Other Problems to be Considered:

The control of intermediary metabolism via feeding and control of circulating blood glucoselevels

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 tourgent resuscitation, and, then, confirmation of the working diagnosis.

Shock is identified in most patients by hypotension and inadequate organ perfusion, whichmay be caused by either low cardiac output or low systemic vascular resistance. Circulatoryshock can be subdivided into 4 distinct classes on the basis of an underlying mechanism andcharacteristic hemodynamics. These classes of shock should be considered and systemically

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differentiated before establishing a definitive diagnosis of septic shock.

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

Obstructive shock: Obstructive shock results from impedance of circulation by an intrinsic orextrinsic obstruction. Pulmonary embolism and pericardial tamponade both result inobstructive shock.

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

Cardiogenic shock: Cardiogenic shock is characterized by primary myocardial dysfunctionresulting in the inability of the heart to maintain adequate cardiac output. These patientsdemonstrate clinical signs of low cardiac output, while evidence exists of adequateintravascular 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 isnecessary 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 bloodpressure > 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 EGDTand indicator of severe tissue hypo-perfusion.

WORKUP Section 5 of 11 Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Pictures Bibliography

Lab Studies:

CBC count with differential

An adequate hemoglobin concentration is necessary to ensure adequate oxygen delivery in patients withshock. 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, theplatelet 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/mL or a neutrophil band count of greater

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than 1500/mL is associated with a high likelihood of bacterial infection.

WBC counts of greater than 50,000/mL or less than 300/mL are associated with significantly decreasedrates 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 lactateindicates that significant tissue hypoperfusion exists with the shift from aerobic to anaerobicmetabolism. The higher the serum lactate, the worse the degree of shock and the higher the mortalityrate.

Assess the coagulation status with prothrombin time (PT) and aPTT. Patients with clinical evidence of acoagulopathy 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 forendocarditis 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 orneutrophil 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-organdysfunction.

Perform a urinalysis and urine culture for every patient who is septic. Urinary infection is a commonsource for sepsis, especially in elderly individuals. Adults who are febrile without localizing symptomsor 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 Gramstain is the only immediately available test that can document the presence of bacterial infection andguide the choice of initial antibiotic therapy.

Imaging Studies:

Several imaging modalities are used to detect a clinically suspected focal infection, the presence of a clinicallyoccult focal infection, and a complication of sepsis and septic shock.

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Since most patients that present with sepsis have pneumonia, one should obtain a chest radiograph because theclinical examination is unreliable for the detection of pneumonia; especially in elderly patients. Occultinfiltrates can be detected by the routine use of chest radiography in adults who are febrile without localizingsymptoms 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 pulmonaryedema are bilateral, hazy, symmetric homogenous opacities, which may demonstrate air bronchograms. Themargins of pulmonary vessels become indistinct and obscured with disease progression. The usual findings ofmetastatic pulmonary edema, such as Kerley A or B lines, are not usually observed; a perihilar distribution ofopacities 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 appearancebecomes more normal. Periodic chest radiographs during the management of ARDS are particularly importantto diagnose barotrauma, adequate postioning of an endotracheal tube and intravascular catheters, andoccurrence 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 byultrasonography; therefore, the CT scans are preferred.

The CT scan is the imaging modality of choice for excluding an intra-abdominal abscess or the retroperitonealsource of infection.

When clinical evidence exists of a deep soft tissue infection, such as crepitus, bullae, hemorrhage, or foulsmelling 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 inpatients thought to have focal mass lesions (eg, focal defects, previous sinusitis or otitis, recent intracranialsurgery).

If bacterial meningitis is strongly suspected, then a lumbar puncture (LP) should be performed without thedelay 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 acutefulminant presentation, a rapid onset of septic shock, and a severe impairment of mental status, use thisprocedure to rule out bacterial meningitis.

Cardiac monitoring, noninvasive blood pressure monitoring, and pulse oximetry are necessary because thesepatients 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 centralvenous 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

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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 cardiacoutput measurement can be obtained; furthermore, determination of mixed venous oxygenation is helpful indetermining 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 myocardialsuppressant factor).

Most patients with sepsis develop respiratory distress as a manifestation of severe sepsis or septic shock. Thelung injury is characterized pathologically as diffuse alveolar damage and ranges from acute lung injury toARDS. 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 orARDS 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 affecteduntil 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 ARDScriteria. Pulmonary dysfunction may be accompanied by encephalopathy or mild coagulopathy and persists for2-3 weeks. At this time, the patient either begins to recover or progresses to develop fulminant dysfunction inother 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 inorgans 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 otherorgan 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 weeksand then either recover or deteriorate further and die.

Table 2. Criteria for Organ DysfunctionOrgan System Mild Criteria Severe Criteria

Pulmonary Hypoxia/hypercarbia requiring assistedventilation for 3-5 d

ARDS requiring PEEP*>10 cm H2O and FiO2

<0.5

HepaticBilirubin 2-3 mg/dL or other liverfunction tests more than twice normal,PT elevated to twice normal

Jaundice with bilirubin 8-10 mg/dL

Renal Oliguria (<500 mL/d or increasingcreatinine) 2-3 mg/dL Dialysis

Gastrointestinal Intolerance of gastric feeding for morethan 5 d

Stress ulceration with needfor transfusion, acalculouscholecystitis

Hematologic aPTT >125% of reference range,platelets <50-80,000 DIC

Cardiovascular Decreased ejection fraction withpersistent capillary leak

Hyperdynamic state notresponsive to pressors

CNS Confusion ComaPeripheral Mild sensory neuropathy Combined motor and

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nervous system sensory deficit*Positive end-expiratory pressure†Fraction of inspired oxygen

TREATMENT Section 6 of 11 Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Pictures Bibliography

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

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

1. Early recognition2. Early and adequate antibiotic therapy3. Source control4. Early hemodynamic resuscitation and continued support5. Corticosteroids (refractory vasopressor-dependent shock)6. Drotrecogin alpha (Severely ill if APACHE II > 25)7. Tight glycemic control8. 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 supportivemeasures includes antimicrobial therapy targeting the most likely pathogen, removal or drainage of theinfected foci, treatment of complications, and interventions to prevent and treat effects of harmful hostresponses. 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 inrespiratory distress.

If the patient's airway is not secure, the gas exchange or acid-base balance is severely deranged, and ifevidence of respiratory muscle fatigue exists or if the patient appears markedly distressed, perform anendotracheal intubation.

Patients in septic shock generally require intubation and assisted ventilation because respiratory failureeither 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 withseptic shock.

Hemodynamic support of septic shock

Shock refers to a state of inability to maintain adequate tissue perfusion and oxygenation, ultimatelycausing cellular, and then organ system, dysfunction. Therefore, the goals of hemodynamic therapy arerestoration 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

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mean arterial pressure (MAP) of less than 60 mm Hg or a decrease in MAP of 40 mm Hg from baselinedefines shock at the bedside.

Elevation of the blood lactate level on serial measurements of lactate can indicate inadequate tissueperfusion.

Mixed venous oxyhemoglobin saturation serves as an indicator of the balance between oxygen deliveryand consumption. A decrease in maximal venous oxygen (MVO2) can be secondary to decreasedcardiac output; however, maldistribution of blood flow in patients experiencing septic shock mayartificially elevate the MVO2 levels. An MVO2 of less than 65% generally indicates decreased tissueperfusion.

Regional perfusion in patients with septic shock is evaluated by adequacy of organ function. Theevaluation includes evidence of myocardial ischemia, renal dysfunction manifested by decreased urineoutput or increased creatinine, CNS dysfunction indicated by a decreased level of consciousness,hepatic injury shown by increased levels of transaminases, splanchnic hypoperfusion manifested bystress ulceration, ileus, or malabsorption.

The hemodynamic support in septic shock is provided by restoring the adequate circulating bloodvolume, and, if needed, optimizing the perfusion pressure and cardiac function with vasoactive andinotropic support to improve tissue oxygenation.

Intravascular volume resuscitation

Hypovolemia is an important factor contributing to shock and tissue hypoxia; therefore, all patients withsepsis require supplemental fluids. The amount and rate of infusion are guided by an assessment of thepatient's volume and cardiovascular status. Monitor patients for signs of volume overload, such asdyspnea, elevated jugular venous pressure, crackles on auscultation, and pulmonary edema on the chestradiograph. Improvement in the patient's mental status, heart rate, MAP, capillary refill, and urine outputindicate adequate volume resuscitation.

Large volumes of fluid infusions are required as initial therapy in patients with septic shock. Administerfluid therapy with predetermined boluses (500 mL or 10 mL/kg) titrated to the clinical end points ofheart rate, urine output, and blood pressure. Continue fluid resuscitation until the clinical end points arereached or the pulmonary capillary wedge pressure exceeds 18 mm Hg. The volume resuscitation can beachieved by either crystalloid or colloid solutions. The crystalloid solutions are 0.9% sodium chlorideand lactated Ringer solution. The colloids are albumin, dextrans, and pentastarch. Clinical trials havefailed to show superiority of either crystalloids or colloids as the resuscitation fluid of choice in septicshock. However, 2-4 times more volume of crystalloids than colloids are required, and crystalloids takea 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 crystalloidscompared to colloids when the filling pressures are maintained at a lower level. However, if the higherfilling pressures are required for maintenance of optimal hemodynamics, crystalloids may increaseextravascular fluid fluxes because of a decrease in plasma oncotic pressure.

In some patients, clinically assessing the response to volume infusion may be difficult. By monitoringthe response of the central venous pressure or pulmonary artery occlusion pressure to fluid boluses, thephysician can assess such patients. A sustained rise in filling pressure of more than 5 mm Hg after avolume is infused indicates that the compliance of the vascular system is decreasing as further fluid isbeing infused. Such patients are susceptible to volume overload, and further fluid should beadministered with care.

Early goal-directed management of sepsis: In a study by Rivers et al, 263 patients treated in an emergency

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department were randomized to either a standard care control group or an aggressive care therapy arm fortheir initial 8 hours of treatment. Patients in the therapy arm provided aggressive resuscitation via to reach acentral venous pressure to 8- 12 mm Hg, organ perfusion pressure maintained by keeping mean arterialpressure (MAP) 65-90mm Hg using either vasopressors or vasodilators, and contractility with dobutamine tokeep 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 systemcan be stimulated by inotropic and vasoconstrictive agents. When proper fluid resuscitation fails torestore hemodynamic stability and tissue perfusion, initiate therapy with vasopressor agents. Theseagents are dopamine, norepinephrine, epinephrine, and phenylephrine. These agents are vasoconstrictingdrugs that maintain adequate blood pressure during life-threatening hypotension and preserve perfusionpressure for optimizing flow in various organs.

The mean blood pressure required for adequate splanchnic and renal perfusion (MAP of 60 or 65 mmHg) is based on clinical indices of organ function. Dopamine is the most commonly used agent for thispurpose. Treatment usually begins at a rate of 5-10 mcg/kg/min IV, and the infusion is adjustedaccording to the blood pressure and other hemodynamic parameters. Often, patients may require highdoses of dopamine (as much as 20 mcg/kg/min). Presently, norepinephrine is the preferred drug becausedopamine is known to cause unfavorable flow distribution.

If the patient remains hypotensive despite volume infusion and moderate doses of dopamine, a directvasoconstrictor (eg, norepinephrine) should be started at a dose of 0.5 mcg/kg/min and titrated tomaintain a MAP of 60 mm Hg. While potent vasoconstrictors (eg, norepinephrine) traditionally havebeen avoided because of their adverse effects on cardiac output and renal perfusion, data from animaland human studies reveal that norepinephrine can reverse septic shock in patients unresponsive tovolume and dopamine. These patients require invasive hemodynamic monitoring with arterial lines andpulmonary artery catheters. Vasopressors may cause more harm than good if administered to patientswhose 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 supportof septic shock:

Dopamine: A precursor of norepinephrine and epinephrine, dopamine has varying effects according tothe doses infused. A dose of less than 5 mcg/kg/min results in vasodilation of renal, mesenteric, andcoronary beds. At a dose of 5-10 mcg/kg/min, beta1-adrenergic effects induce an increase in cardiaccontractility and heart rate. At doses of about 10 mcg/kg/min, alpha-adrenergic effects lead to arterialvasoconstriction and elevation in blood pressure. Dopamine is effective in optimizing MAP in patientswith septic shock who remain hypotensive after volume resuscitation. The blood pressure increasesprimarily as a result of inotropic effect and, thus, will be useful in patients who have concomitantreduced 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 remainhypotensive following fluid resuscitation and dopamine. The dose of norepinephrine may varyfrom 0.2-1.5 mcg/kg/min, and large doses as high as 3.3 mcg/kg/min have been used because ofthe alpha-receptor down-regulation in sepsis.

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In patients with sepsis, indices of regional perfusion (eg, urine flow) and lactate concentrationhave improved following norepinephrine infusion. Two recent trials have shown that asignificantly greater proportion of patients treated with norepinephrine were resuscitatedsuccessfully, as opposed to the patients treated with dopamine. Therefore, norepinephrine shouldbe used early and should not be withheld as a last resort in patients with severe sepsis who are inshock.

The concerns about compromising splanchnic tissue oxygenation have not been proven; thestudies have confirmed no deleterious effects on splanchnic oxygen consumption and hepaticglucose production, provided adequate cardiac output is maintained.

Epinephrine: This agent can increase MAP by increasing cardiac index and stroke volume, along withan increase in systemic vascular resistance and heart rate. Epinephrine may increase oxygen deliveryand oxygen consumption and decreases the splanchnic blood flow. Administration of this agent isassociated with an increase in systemic and regional lactate concentrations. The use of epinephrine isrecommended only in patients who are unresponsive to traditional agents. The undesirable effects are anincrease in lactate concentration, a potential to produce myocardial ischemia, development ofarrhythmias, and a reduction in splanchnic flow.

Phenylephrine: This agent is a selective alpha1-adrenergic receptor agonist that is used primarily inanesthesia to increase blood pressure. Although studies are limited, phenylephrine increased MAP inpatients who were septic hypotensive with increased oxygen consumption. However, the concernremains 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, cardiacoutput generally is maintained in patients with volume-resuscitated sepsis. Data from the 1980s and1990s suggest a linear relationship between oxygen delivery and oxygen consumption (pathologicsupply dependency), indicating that the oxygen delivery likely was insufficient to meet the metabolicneeds of the patient. However, recent investigators have challenged the concept of pathologic supplydependency, suggesting that elevating cardiac index and oxygen delivery (hyperresuscitation) was notassociated with improved patient outcome. Therefore, the role of inotropic therapy is uncertain, unlessthe patient has inadequate cardiac index, mean arterial pressure, mixed venous oxygen saturation, andurine output despite adequate volume resuscitation and vasopressor therapy.

Renal-dose dopamine: In the setting of circulatory shock of any etiology, several well-designed clinicaltrials have failed to demonstrate any beneficial effects of low dose dopamine to improve renal bloodflow and support renal function. Dopamine at a dose of 2-3 mcg/kg/min is known to initiate diuresis byincreasing renal blood flow in healthy animals and volunteers. Multiple studies have not demonstrated abeneficial effect of prophylactic or therapeutic low-dose dopamine administration in patients with sepsiswho are critically ill. Considering the real side effects of dopamine infusion, the use of renal dosedopamine should be abandoned.

Empirical antimicrobial therapy

Initiate this therapy early in patients experiencing septic shock. However, antibiotics have little effect onthe clinical outcome for at least 24 hours. The selection of appropriate agents is based on the patient'sunderlying host defenses, the potential sources of infection, and the most likely culprit organisms. If thepatient is "antibiotic experienced," strongly consider the use of an aminoglycoside rather than aquinolone or cephalosporin for gram-negative coverage. Knowing the antibiotic resistance patterns ofboth 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 thedifferent 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

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studies find that the clinical improvement correlates with the achievement of serum bactericidal levelsrather 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 acquiredsepsis while hospitalized. Patients who are immunocompetent usually can be treated with a single drugwith broad-spectrum coverage, such as a third-generation cephalosporin. Patients who areimmunocompromised 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 areavailable.

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, butmortality 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 isan endogenous protein that not only promotes fibrinolysis and inhibits thrombosis and inflammation butalso may modulate the coagulation and inflammation of severe sepsis. Sepsis reduces the level ofprotein C and inhibits conversion of protein C to activated protein C. Administration of recombinantactivated protein C inhibits thrombosis and inflammation, promotes fibrinolysis, and modulatescoagulation and inflammation.

A recent publication by the Recombinant Human Activated Protein C Worldwide Evaluation in SevereSepsis (PROWESS) study group demonstrated that the administration of recombinant human activatedprotein C (drotrecogin-alpha, activated) resulted in lower mortality rates (24.7% vs 30.8%) in thetreated group compared with placebo. Treatment with activated drotrecogin-alpha was associated withreduction in the relative risk of death by 19.4% (95% CI, 6.6-30.5) and an absolute reduction in risk ofdeath by 6.1%, (P=.005).

Corticosteroids: Although theoretical and experimental animal evidence exists for the use of large doses ofcorticosteroids in those with severe sepsis and septic shock, all randomized human studies (except 1 from1976) found that corticosteroids did not prevent the development of shock, reverse the shock state, or improvethe 14-day mortality rate. Therefore, no support exists in the medical literature for the routine use of highdoses 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 ofsepsis.

Drotrecogin alpha should be considered for patients with APACHE II scores greater than 25.

The main side effect of Drotrecogin alpha is bleeding.

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Stress-dose glucocorticoids: Recent trials (Briegel, 1999; Cartlet, 1999) demonstrated positive results ofstress-dose administration of corticosteroids in patients with severe and refractory shock. Although furtherconfirmatory studies are awaited, stress-dose steroid coverage should be provided to patients who have thepossibility 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 andpoor patient selection.

Recent trials with low-dose (physiologic) dosages in select patient populations (vasopressor dependentand 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 insufficiencydefined 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 illpatients, and recent data has been extrapolated to potentially apply to septic populations. A 2001Belgian study of surgical intensive care unit (ICU) patients that remained in the ICU for morethan 5 days showed a 10% mortality benefit in those with tighter glycemic control. The glucoselevels for these patients were maintained from 80-110 mg per dL through the use of intensiveinsulin therapy. The benefit of glycemic control appears to result more from aggressive avoidanceof the detrimental effects of hyperglycemia rather than the potential therapeutic effect of insulin.

Based on the current evidence, the Surviving Sepsis Campaign recommends maintaining aglucose 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 maintainedbelow 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 surgicalpatients including, and particularly, those with sepsis and in-medical ICU patients.

The Surviving Sepsis Campaign recommends that glucose levels in the septic patient should bekept at less than 150 mg/dL although the published evidence supports controlling blood glucosebetween 80 and 110 mg/dL.

Tight glycemic control is not without risks. In the elderly (>75 years of age) and in those patientswith 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 bedsidenurse.

Experimental and other therapies include nonadrenergic vasopressors and inotropes. The clinical utilityof several of these agents remains unproven despite several studies indicating their beneficial effect onhemodynamic 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 haveshown that dopexamine increases cardiac index and heart rate and decreases systemic vascularresistance in a dose-dependent manner. The hepatic blood flow and gastric intramucosal pH

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improve, but results are not reproducible consistently. This drug appears to be promising forpatients with sepsis and septic shock, but superiority over the other drugs has not beendemonstrated. Dopexamine continues to be an experimental medication in the United States.

Vasopressin: This agent may be useful in patients with refractory septic shock; however, minimalstudies have been conducted. In patients with septic shock, infusion of 0.04 U/kg/min ofvasopressin resulted in improved MAP secondary to peripheral vasoconstriction.

Phosphodiesterases inhibitors: Inamrinone (formerly amrinone) and milrinone are inotropic agentswith vasodilating properties, and each has a long half-life. The mechanism of action occurs viaphosphodiesterase inhibition. These medications are beneficial in cardiac pump failure, but theirbenefit in patients experiencing septic shock is not well established. Furthermore, these agentshave a propensity to worsen hypotension in patients with septic shock.

Nitric oxide inhibitor: This agent is a potent endogenous vasodilator. Excessive nitric oxideproduction, because of the cytokines and other mediators, induces vasodilation and hypotensionin patients with sepsis. Nitric oxide is synthesized from endogenous L-arginine by the enzymenitric oxide synthase. Inhibitors of nitric oxide synthase (N-monomethyl-l-arginine, L-NMMA) insepsis augment mean arterial pressure, decreased cardiac output, and increased systemic vascularresistance. Inordinate mortality was the cause of early termination of a randomized trial of nitricoxide synthase inhibition with L-NMMA. The clinical benefit of this therapeutic approach inpatients with sepsis remains unproven.

Anti-inflammatory therapy: The rationale for anti-inflammatory therapy is that blocking theproduction of inflammatory mediators may ameliorate the deleterious host inflammatory responseand, hence, may limit the tissue injury.

Ibuprofen: Despite promising results in animal studies, the use of ibuprofen has not been provenof any benefit in patients with septic shock.

Antiendotoxin treatment: The insight that endotoxin, a lipid-polysaccharide compound found inthe cell wall of gram-negative bacteria, plays a key role in initiating the humoral cascadeobserved in septic shock led to the hypothesis that neutralizing the circulating endotoxin with IVadministration of an antiendotoxin antibody might be beneficial. Several products have beendeveloped and investigated by carefully conducted human trials. To date, no proven benefit tothese agents has been observed. Other methods of extracorporeal elimination of endotoxin,polyclonal antiendotoxin antibodies, or monoclonal antiendotoxin antibodies showed neitherimprovement in short-term survival nor amelioration of sepsis in humans with septic shock. Trialswith some of these compounds are ongoing, and, despite a tendency towards benefit, efficacy dataare 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 indicatethat both the mediators play key roles in sepsis and septic shock, and some think that TNF maybe the central mediator in sepsis. As is the case with antiendotoxin antibodies, antibodies to TNFor 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. Cytokinesare the major mediators of inflammatory cascade. Antibodies or blocking medications againstTNF, interleukins, and their receptor blockers have been developed and have undergone clinicaltrials. In 1997, Zeni conducted a meta-analysis and selected 21 trials representing a total of 6429patients. A small but insignificant beneficial effect was demonstrated.

Miscellaneous treatment: Several other experimental interventions and therapies have undergoneclinical trials for sepsis. Although several of these may have shown benefit, no convincingevidence suggests that these therapies are efficacious. A long list of these interventions or

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therapies exists; the important ones include intravenous immunoglobulins, interferon gamma,antithrombin-3 infusion, naloxone, pentoxifylline, growth hormone, G-CSF, and hemofiltration orextracorporeal removal of endotoxins. None of these agents was efficacious in properly designedcontrolled clinical trials.

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

Consultations:

Patients who do not respond or who are in septic shock require an intensive care unit facility for continuousmonitoring and observation. Consultation with a critical care physician or internist with expertise isappropriate.

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 tissueinfection, and infected prosthetic devices.

MEDICATION Section 7 of 11 Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Pictures Bibliography

Proven medical treatments for patients with septic shock are restoration of intravascular volume, hemodynamicsupport, and broad-spectrum empiric antibiotic coverage. Other medical therapies, while theoretically attractive, donot 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

Norepinephrine (Levophed) -- Used in protractedhypotension following adequate fluid replacement.Stimulates beta1- and alpha-adrenergic receptors, which inturn increases cardiac muscle contractility and heart rate, aswell as vasoconstriction. As a result, increases systemicblood pressure and cardiac output. Adjust and maintaininfusion to stabilize blood pressure (eg, 80-100 mm Hgsystolic) sufficiently to perfuse vital organs.

Adult Dose 0.05-2 mcg/kg/min IV titrated according to hemodynamicresponse not to exceed 10 mcg/kg/min

Pediatric Dose 0.05-0.1 mcg/kg/min IV titrated according to hemodynamicresponse; not to exceed 1-2 mcg/kg/min

ContraindicationsDocumented hypersensitivity; peripheral or mesentericvascular thrombosis because ischemia may be increasedand the area of the infarct extended

Interactions

Atropine sulfate may enhance the pressor response ofnorepinephrine by blocking the reflex bradycardia causedby norepinephrine; effects increase when administeredconcurrently with tricyclic antidepressants, MAOIs,antihistamines, guanethidine, methyldopa, and ergot

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alkaloids

Pregnancy D - Safety for use during pregnancy has not beenestablished.

Precautions

Correct hypovolemia before administering norepinephrine;extravasation may cause severe tissue necrosis; therefore,administer into large vein; use with caution in occlusivevascular disease

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

Dopamine (Intropin) -- Stimulates both adrenergic anddopaminergic receptors. Hemodynamic effect depends onthe dose. Lower doses stimulate mainly dopaminergicreceptors that produce renal and mesenteric vasodilation.Cardiac stimulation and renal vasodilation is produced byhigher doses. After initiating therapy, dose may beincreased by 1-4 mcg/kg/min q10-30min until a satisfactoryresponse is attained. Maintenance doses <20 mcg/kg/minusually are satisfactory for 50% of the patients treated.

Adult Dose Starting at 1-5 mcg/kg/min IV titrated according tohemodynamic response; not to exceed 20 mcg/kg/min

Pediatric Dose Administer as in adults

Contraindications Documented hypersensitivity; pheochromocytoma;ventricular fibrillation

InteractionsPhenytoin, alpha- and beta-adrenergic blockers, generalanesthesia, and MAOIs increase and prolong the effects ofdopamine

Pregnancy C - Safety for use during pregnancy has not beenestablished.

Precautions

Correct hypovolemia before starting infusion; Tachycardiamay limit its use. Monitor urine flow, cardiac output,central venous pressure and pulmonary artery occlusionpressure, and blood pressure during the infusion.

Drug Name

Epinephrine (Adrenalin) -- Used for hypotension refractoryto dopamine or norepinephrine. Stimulates alpha- and beta-adrenergic receptors, resulting in relaxation of bronchialsmooth muscle, increased cardiac output, and bloodpressure.

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 hemodynamicresponse

Contraindications

Documented hypersensitivity; cardiac arrhythmias; angle-closure glaucoma; local anesthesia in areas such as fingersor toes because vasoconstriction may produce sloughing oftissue; during labor (may delay second stage of labor)

Interactions Increases toxicity of beta- and alpha-blocking agents andhalogenated inhalational anesthetics

Pregnancy C - Safety for use during pregnancy has not been

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established.

Precautions

Caution in elderly patients, may cause excessive pulmonaryvasoconstriction; caution in patients with prostatichypertrophy, hypertension, cardiovascular disease, diabetesmellitus, hyperthyroidism, and cerebrovascularinsufficiency; rapid IV infusions may cause death fromcerebrovascular hemorrhage or cardiac arrhythmias

Drug Name

Vasopressin (Pitressin) -- Vasopressor and antidiuretichormone (ADH) activity. Increases water resorption at thedistal renal tubular epithelium (ADH effect). Promotessmooth muscle contraction throughout the vascular bed ofthe 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 responsePediatric Dose Not established

Contraindications Documented hypersensitivity; coronary artery disease

Interactions

Lithium, epinephrine, demeclocycline, heparin, and alcoholmay decrease vasopressin effects; conversely,chlorpropamide, urea, fludrocortisone, and carbamazepineare known to potentiate vasopressin effects

Pregnancy B - Safety for use during pregnancy has not beenestablished.

PrecautionsUse with caution in patients diagnosed with cardiovasculardisease, seizure disorders, nitrogen retention, asthma, ormigraine; excessive doses may result in hyponatremia

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 intravascularand interstitial fluid spaces. Typically, about 30% of administered isotonic fluid stays intravascular; therefore, largequantities may be required to maintain adequate circulating volume. Both fluids are isotonic and have equivalentvolume restorative properties. While some differences exist between metabolic changes observed with theadministration of large quantities of either fluid, for practical purposes and in most situations, the differences areclinically irrelevant. No demonstrable difference in hemodynamic effect, morbidity, or mortality exists betweenresuscitation with either NS or RL.

Drug Name Normal saline (NS, 0.9% NaCl) -- Restoration of interstitialand intravascular volume.

Adult DoseInitial: 1-2 L IV, with reassessment of hemodynamicresponse; amount required during the first few hourstypically is 4-5 L

Pediatric DoseInitial: 20 mL/kg IV administered rapidly over 20-30 min;amounts approaching 40 mL/kg may be required during thefirst 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 administeredconcurrently

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Pregnancy B - Usually safe but benefits must outweigh the risks.

Precautions

Monitor cardiovascular and pulmonary function; stop fluidswhen desired hemodynamic response is observed orpulmonary edema develops; interstitial edema may occur;caution in congestive heart failure, hypertension, edema,liver cirrhosis, and renal insufficiency

Drug Name Lactated Ringer -- Restoration of interstitial andintravascular volume.

Adult DoseInitial: 1-2 L IV, with reassessment of hemodynamicresponse; amount required during the first few hourstypically is 4-5 L

Pediatric DoseInitial: 20 mL/kg IV administered rapidly over 20-30 min;amounts approaching 40 mL/kg may be required during thefirst 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 administeredconcurrently

Pregnancy C - Safety for use during pregnancy has not beenestablished.

Precautions

Monitor cardiovascular and pulmonary function; stop fluidswhen the desired hemodynamic response is observed orpulmonary 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 toa greater degree than isotonic crystalloids and reduce the tendency of pulmonary and cerebral edema. About 50% ofthe administered colloid stays intravascular.

Drug Name

Albumin (Buminate) -- Used for certain types of shock orimpending shock. Useful for plasma volume expansion andmaintenance of cardiac output. A solution of NS and 5%albumin is available for volume resuscitation. Five percentsolutions are indicated to expand plasma volume; whereas,25% solutions are indicated to raise oncotic pressure.

Adult Dose250-500 mL (12.5-25 g) IV of 5% solution over 20-30 min,with reassessment of hemodynamic response; not to exceed250 g/48h

Pediatric Dose4-5 mL/kg (200-250 mg/kg) IV of 5% solution over 30min, with reassessment of hemodynamic response; not toexceed 6 g/kg/d

Contraindications

Documented hypersensitivity; severe congestive heartfailure; severe anemia; pulmonary edema; the protein loadof 5% albumin tends to exacerbate renal insufficiency, apotential complication of septic shock; do not dilutealbumin 25% with sterile water for injection (produceshypotonic solution) because, if administered, may result inlife-threatening hemolysis and acute renal failure

Interactions None reported

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Pregnancy C - Safety for use during pregnancy has not beenestablished.

Precautions

Caution in renal or hepatic failure; may cause proteinoverload; rapid infusion may cause vascular overload orhypotension; monitor for volume overload; caution insodium restricted patients; common adverse effects includeCHF, hypotension, tachycardia, fever, chills, andpulmonary edema

Drug Category: Antibiotics -- Early treatment with empiric antibiotics is the only other proven medical treatmentin septic shock. Use of broad-spectrum and/or multiple antibiotics provides the necessary coverage. In children whoare 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 areimmunocompetent. Penicillinase-resistant synthetic penicillins and a third-generation cephalosporin are used forcombination therapy in children. Combination therapy in adults involves a third-generation cephalosporin plusanaerobic coverage (ie, clindamycin, metronidazole) or a fluoroquinolone plus clindamycin. All antibiotics shouldbe administered IV initially.

Drug Name

Cefotaxime (Claforan) -- Used for treatment of septicemia.Also used for treatment of gynecologic infections causedby susceptible organisms. Third-generation cephalosporinwith enhanced gram-negative coverage, especially to Ecoli, Proteus, and Klebsiella species. Has variable activityagainst Pseudomonas species.

Adult Dose 1-2 g IV q4h; not to exceed 12 g/dPediatric Dose 50 mg/kg IV q8h

Contraindications Documented hypersensitivity

Interactions

Probenecid may decrease cefotaxime clearance, causing anincrease in cefotaxime levels; furosemide andaminoglycosides may increase nephrotoxicity when usedconcurrently with cefotaxime

Pregnancy B - Usually safe but benefits must outweigh the risks.

Precautions Adjust dose in patients diagnosed with severe renalimpairment; associated with severe colitis

Drug Name

Ceftriaxone (Rocephin) -- Third-generation cephalosporinwith broad-spectrum, gram-negative activity. Lowerefficacy against gram-positive organisms. Higher efficacyagainst resistant organisms. Used for increasing prevalenceof penicillinase-producing microorganisms. Inhibitsbacterial cell wall synthesis by binding to 1 or morepenicillin-binding proteins. Cell wall autolytic enzymeslyse 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 exceed2 g/d>45 kilograms: Administer as in adults

Contraindications Documented hypersensitivity; do not use in neonates withhyperbilirubinemia

Interactions

Probenecid may decrease clearance, causing an increase inceftriaxone levels; coadministration of ethacrynic acid,furosemide, and aminoglycosides may increase

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nephrotoxicityPregnancy B - Usually safe but benefits must outweigh the risks.

Precautions Adjust dose in renal impairment; caution in women whoare breastfeeding; potential cross-allergy to penicillin

Drug Name

Ticarcillin and clavulanate (Timentin) -- Antipseudomonalpenicillin plus a beta-lactamase inhibitor that providescoverage against most gram-positive organisms (exceptvariable coverage against Staphylococcus epidermidis andno coverage against methicillin-resistant Staphylococcusaureus [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 Administer as in adults

Contraindications

Documented hypersensitivity; severe pneumonia,bacteremia, pericarditis, emphysema, meningitis, andpurulent or septic arthritis should not be treated with anoral penicillin during the acute stage

Interactions

Tetracyclines may decrease the effects of ticarcillin; highconcentrations of ticarcillin in vivo or in vitro mayphysically inactivate aminoglycosides; probenecid mayincrease penicillin levels; synergistic effect whenadministered concurrently with aminoglycosides

Pregnancy B - Usually safe but benefits must outweigh the risks.

Precautions

Perform CBC counts prior to initiation of therapy and atleast weekly during therapy; monitor for liver functionabnormalities by measuring AST and ALT during therapy;caution in patients diagnosed with hepatic insufficiencies;perform urinalysis, BUN, and creatinine determinationsduring therapy and adjust dose

Drug Name

Piperacillin and tazobactam (Zosyn) -- Inhibits thebiosynthesis of cell wall mucopeptide and is effectiveduring the stage of active multiplication. Hasantipseudomonal activity.

Adult Dose 3/0.375 g (piperacillin 3 g and tazobactam 0.375 g) IV q6h

Pediatric Dose <6 months: Not established>6 months: 75 mg/kg IV q6h

Contraindications

Documented hypersensitivity; severe pneumonia,bacteremia, pericarditis, emphysema, meningitis, andpurulent or septic arthritis should not be treated with anoral penicillin during the acute stage

Interactions

Tetracyclines may decrease effects of penicillins; highconcentrations of piperacillin in vivo or in vitro mayphysically inactivate aminoglycosides; synergistic effectwhen administered concurrently with aminoglycosides;probenecid may increase serum penicillin levels

Pregnancy B - Usually safe but benefits must outweigh the risks.Perform CBC counts prior to initiation of therapy and atleast weekly during therapy; monitor for liver function

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Precautions abnormalities by measuring AST and ALT during therapy;urinalysis, BUN, and creatinine determinations should beperformed during therapy and adjust dose if these valuesbecome elevated

Drug Name

Imipenem and cilastatin (Primaxin) -- Carbapenem withactivity against most gram-positive organisms (exceptMRSA), gram-negative organisms, and anaerobes. Used fortreatment of multiple organism infections in which otheragents do not have wide-spectrum coverage or arecontraindicated due to their potential for toxicity.

Adult Dose 500 mg IV q6h; not to exceed 4 g/d

Pediatric Dose<3 months: Not established>3 months: 10-15 mg/kg IV q6h; not to exceed 4 g/d formoderately susceptible organisms

Contraindications Documented hypersensitivity

Interactions

When administered concurrently with cyclosporine, theCNS adverse effects of both agents may be increased,possibly because of additive or synergistic toxicity; whenused concurrently with ganciclovir, generalized seizuresmay occur, and it should not be used concomitantly;probenecid may increase toxic potential

Pregnancy C - Safety for use during pregnancy has not beenestablished.

Precautions Adjust dose with impaired renal function and in patients<70 kg; avoid in children <12 y due to CNS toxicity

Drug Name

Meropenem (Merrem) -- Carbapenem with slightlyincreased activity against gram-negative organisms andslightly decreased activity against staphylococci andstreptococci compared to imipenem. Less likely to causeseizures and superior penetration of blood-brain barriercompared to imipenem.

Adult Dose 1 g IV q8h

Pediatric Dose <3 months: Not established>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 mayoccur, requiring discontinuation of meropenem; cross-reactivity observed (50%) in patients with penicillinanaphylaxis history; caution in seizures; adjust dose withrenal dysfunction

Drug NameClindamycin (Cleocin) -- Primarily used for its activityagainst anaerobes. Has some activity against Streptococcusspecies and MSSA.

Adult Dose 600-900 mg IV q8h; not to exceed 4.8 g/d

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Pediatric Dose 5-10 mg/kg IV q8h; not to exceed 4.8 g/d

Contraindications Documented hypersensitivity; regional enteritis; ulcerativecolitis; hepatic impairment; antibiotic-associated colitis

Interactions Increases duration of neuromuscular blockade induced bytubocurarine and pancuronium

Pregnancy D - Unsafe in pregnancy

PrecautionsAdjust dose in severe hepatic dysfunction; no adjustmentnecessary in renal insufficiency; associated with severe andpossibly fatal colitis

Drug Name

Metronidazole (Flagyl) -- Imidazole ring-based antibioticactive against various anaerobic bacteria and protozoa.Usually combined with other antimicrobial agents, exceptwhen used for Clostridium difficile enterocolitis, in whichmonotherapy is appropriate.

Adult Dose

Loading dose: 15 mg/kg IV over 1 h (1 g IV for 70-kgadult)Maintenance dose: 7.5 mg/kg IV over 1 h q6-8h (500 mgfor a 70-kg adult), initiated 6 h following loading dose; notto exceed 4 g/d

Pediatric Dose Administer as in adults; use dose based on body weightContraindications Documented hypersensitivity; first trimester of pregnancy

Interactions

Potentiates the anticoagulant effect of warfarin; agents thatalter the hepatic CYP450 system also affect its clearance;as a result, phenytoin and phenobarbital may decrease thehalf-life of metronidazole; cimetidine may reducemetronidazole clearance and increase its toxicity;metronidazole may decrease lithium and phenytoinclearance, increasing their toxicity; disulfiramlike reactionmay occur when used concurrently with orally ingestedethanol (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 forseizures and peripheral neuropathy; common adverseeffects include dizziness, headache, nausea, vomiting, andanorexia

Drug Name

Ciprofloxacin (Cipro) -- Fluoroquinolone with variableactivity against Streptococcus species, activity againstmethicillin-sensitive S aureus and S epidermidis, activityagainst most gram-negative organisms, and no activityagainst anaerobes. Synthetic broad-spectrum antibacterialcompounds. Novel mechanism of action, targeting bacterialtopoisomerase II and IV, thus leading to a sudden cessationof DNA replication. Oral bioavailability is near 100%.

Adult Dose 400 mg IV q12hPediatric Dose 10-15 mg/kg IV q12h

Contraindications Documented hypersensitivityAntacids, iron salts, and zinc salts may reduce serum

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Interactions

levels; administer antacids 2-4 h before or after takingfluoroquinolones; cimetidine and probenecid may increaselevels of fluoroquinolones; ciprofloxacin reducestherapeutic effects of phenytoin; probenecid may increaseciprofloxacin serum concentrations; fluoroquinolones mayincrease serum levels of theophylline, caffeine,cyclosporine, and digoxin (monitor digoxin levels); mayincrease effects of anticoagulants (monitor PT)

Pregnancy C - Safety for use during pregnancy has not beenestablished.

Precautions

In prolonged therapy, perform periodic evaluations of organsystem functions (eg, renal, hepatic, hematopoietic); adjustdose in renal function impairment; superinfections mayoccur with prolonged or repeated antibiotic therapy; do notuse in pediatric patients as first-line agent due to cartilagedamage in young animals; may cause CNS toxicity

FOLLOW-UP Section 8 of 11 Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Pictures Bibliography

Further Inpatient Care:

Maintaining adequate tissue oxygenation

Patients with severe sepsis or septic shock have hypermetabolism, maldistribution of blood flow, and,possibly, suboptimal oxygen delivery; therefore, attempts at detecting and correcting tissue hypoxiamust be made. Lactic acidosis is an indication of either global ischemia (inadequate oxygen delivery) orregional (organ-specific) ischemia. Calculation of pH in the gastric mucosa by gastric tonometry maydetect tissue hypoxia in the splanchnic circulation, this technique has not been validated extensively andis not available widely.

Although initial aggressive resuscitation to maximize oxygen delivery improves outcome (early goal-directed therapy), manipulation of oxygen delivery to deliver supraphysiologic oxygen to the tissueswith blood transfusion, fluid boluses, or use of inotropes once organ dysfunction has developed has notimproved the outcome in patients who are critically ill. Hayes et al (1994) reported a higher mortalityrate in patients with sepsis who were maintained on high levels of oxygen delivery. In patients withseptic shock, the inability to increase oxygen consumption and to decrease lactate levels most likely is aconsequence of impaired oxygen extraction or inability to reverse anaerobic metabolism. Boostingoxygen delivery to supranormal levels does not reverse these pathophysiologic mechanisms after thedevelopment of organ injury.

A trial of increasing oxygen delivery is recommended in patients who have evidence of tissue hypoxia.If augmentation of oxygen delivery is associated with reduction in serum lactate levels and improvedtarget organ perfusion, these interventions may be continued. On the other hand, adequate clinicalparameters, such as a mean arterial pressure, normal cardiac index, and adequate urine output, should bemaintained irrespective of the concerns about supply dependence.

The major focus of resuscitation from septic shock is supporting cardiac and respiratory functions. The otherorgan systems also may require attention and support during this critical period.

Temperature control: Fever generally requires no treatment, except in patients with limitedcardiovascular reserve, because of the increased metabolic requirements. Antipyretic drugs and physicalcooling methods, such as sponging or cooling blankets, may be used to lower the patient's temperature.

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Metabolic support: Patients with septic shock develop hyperglycemia and electrolytes abnormalities.Serum glucose should be maintained in the reference range with insulin infusion. Hypokalemia,hypomagnesemia, and hypophosphatemia should be measured and corrected if deficient.

Anemia and coagulopathy: Hemoglobin as low as 8.0 g/dL is well tolerated and does not requiretransfusion unless the patient has poor cardiac reserve or demonstrates evidence of myocardial ischemia.Thrombocytopenia and coagulopathy are common in patients with sepsis and do not requirereplacement with platelets or fresh frozen plasma, unless the patient develops active clinical bleeding.

Renal dysfunction: Urine output and renal function must be monitored closely in all patients with sepsis.Any abnormalities should prompt attention to adequacy of circulating blood volume, cardiac output, andblood pressure; these should be corrected if inadequate.

Nutritional support: Patients with septic shock generally have high protein and energy requirements.Although a brief period (several days) without nutrition is not going to cause deleterious effects,prolonged starvation must be avoided. Enteral nutrition is preferred and should be carried out unless thepatient has recently had abdominal surgery. Diminished bowel sounds should not prevent a trial ofenteral nutrition, although motility agents or the use of a small bowel feeding tube may be necessary.The benefits of enteral nutrition are protection of gut mucosa, avoiding translocation of organisms fromthe GI tract, lowering the complication rate, and lowering cost. Early nutritional support is of criticalimportance in patients with septic shock. The enteral route is preferred, unless the patient has an ileus orother intestinal abnormality. Gastroparesis commonly is observed, which can be treated with motilityagents or placement of a small bowel feeding tube.

Glutamine, an essential amino acid influences the mucosal integrity of the gastrointestinal tract.Insufficient levels of glutamine may occur from starvation or lack of enteral feeding, a conditioncommonly observed with total parenteral nutrition. Glutamine deficiency contributes to mucosalatrophy, predisposing translocation of bacteria or endotoxin from the gut lumen. Enteral nutrition withglutamine-containing formulas can prevent this relapse of SIRS in patients on adequate therapy.

Acute respiratory distress syndrome

Acute lung injury or ARDS is a frequent complication of severe sepsis or septic shock, occurring in asmany as 40% of patients with severe sepsis secondary to gram-negative infection. Acute lung injury is aspectrum of pulmonary dysfunction secondary parenchymal cellular damage from multiple etiologies.Acute lung injury and ARDS can be associated with clinical disorders causing direct lung injury, suchas gastric acid aspiration, thoracic trauma, pneumonia, and near drowning, or indirect lung injury,including severe sepsis, acute pancreatitis, drug overdose, reperfusion injury, and severe nonthoracictrauma. Sepsis-associated ARDS carries the abysmal prognosis and has the highest mortality rates.

Definition: The American-European Consensus Conference on ARDS (Bernard, 1994) agreed upon thefollowing definitions of acute lung injury and ARDS. The criteria for acute lung injury include thefollowing: (1) an oxygenation abnormality with an arterial PaO2/FiO2 ratio less than 300, (2) bilateralopacities on chest radiograph compatible with pulmonary edema, and (3) a pulmonary artery occlusionpressure less than 18 mm Hg or no clinical evidence of left atrial hypertension if PaO2 is not available.ARDS is a more severe form of acute lung injury and is defined similarly except that PaO2/FiO2 ratio is200 or less.

ARDS has a reported incidence ranging from 1.5-8.4 cases per 100,000 population per year (Baughman,1996). More recent studies report a higher incidence 12.6 cases per 100,000 population per year forARDS and 18.9 cases per 100,000 population per year for acute lung injury. The mortality rate fromARDS has been documented at approximately 50% in most studies.

Clinical manifestations

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Acute lung injury and ARDS secondary to severe sepsis demonstrate the manifestations ofunderlying sepsis and the associated multiple organ dysfunction. Pulmonary manifestationsinclude acute respiratory distress and acute respiratory failure resulting from severe hypoxemiacaused by intrapulmonary shunting. Fever and leukocytosis may be present secondary to the lunginflammation.

The severity of ARDS may vary from mild lung injury to severe respiratory failure. The onset ofARDS usually is within 12-48 hours of the inciting event. The patients demonstrate severedyspnea at rest, tachypnea, and hypoxemia; anxiety and agitation also are present. A scheme tograde the severity of lung injury, lung injury score has been proposed (Murray, 1988). The lunginjury score is calculated after evaluating the severity of 4 components—the chest roentgenogramscore, hypoxemia score, PEEP score, and respiratory system compliance score. A lung injuryscore of greater than 2.5 is associated with severe lung injury or ARDS.

The frequency of ARDS in sepsis has been reported from 18-38%, the highest with gram-negative sepsis, ranging from 18-25%. Sepsis and multiorgan failure are the most common causeof death in ARDS patients. Approximately 16% of patients with ARDS died from irreversiblerespiratory failure. Most patients who improved, achieved maximal recovery by 6 months, thelung function improves to 80-90% of predicted values.

Pathology of ARDS

The central pathological finding in ARDS is severe injury to the alveolocapillary unit. Followinginitial extravasation of intravascular fluid, inflammation and fibrosis of pulmonary parenchymadevelops into a morphologic picture, termed diffuse alveolar damage (DAD). The clinical andpathological evolution can be categorized into the following 3 overlapping phases (Katzenstein,1986): (1) the exudative phase of edema and hemorrhage, (2) the proliferative phase oforganization and repair, and (3) the fibrotic phase of end stage fibrosis.

The exudative phase occurs in the first week and is dominated by alveolar edema andhemorrhage. The other histological features include dense eosinophilic hyaline membranes anddisruption of the capillary membranes. Necrosis of endothelial cells and type I pneumocytesoccur, along with leukoagglutination and deposition of platelet fibrin thrombi.

The proliferative phase is prominent in the second and third week following onset of ARDS butmay begin as early as the third day. Organization of the intra-alveolar and interstitial exudate,infiltration with chronic inflammatory cells, parenchymal necrosis, and interstitial myofibroblastreaction occur. Proliferation of type II cells and fibroblasts, which convert the exudate to cellulargranulation tissue, occurs; excessive collagen deposition, transforming into fibrous tissue, occurs.

The fibrotic phase occurs by the third or fourth week of the onset, though the process may beginin the first week. The collagenous fibrosis completely remodels the lung, the air spaces areirregularly enlarged, and alveolar duct fibrosis is apparent. Lung collagen deposition increases,microcystic honeycomb formation, and traction bronchiectasis follows.

Pathogenesis: The pathogenesis of sepsis-induced ARDS is a pulmonary manifestation of SIRS. Acomplex interaction between humoral and cellular mediators, inflammatory cytokines and chemokines,is involved in the pathogenesis of ARDS. A direct or indirect injury to the endothelial and epithelialcells of the lung increases alveolar capillary permeability, causing ensuing alveolar edema. The edemafluid is protein rich, the ratio of alveolar fluid edema to plasma is 0.75-1.0 compared with patients withhydrostatic cardiogenic pulmonary edema, where the ratio is less than 0.65. Injury to type IIpneumocytes decreases surfactant production; furthermore, the plasma proteins in alveolar fluidinactivate the surfactant previously manufactured. These enhance the surface tension at the air-fluidinterfaces, producing diffuse microatelectasis.

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Management of sepsis-related ARDS

The management of ARDS primarily is supportive; the pharmacological and other innovativetherapies have not proven to be very beneficial. The general supportive management includesadequate treatment of underlying sepsis with appropriate antibiotics and surgical management ifindicated. Appropriate fluid management to lower the intravascular volume without affecting thecardiac output and organ perfusion may be beneficial. The fluid manipulation often requiresinvasive hemodynamic monitoring. The goals of mechanical ventilation include improvement ingas exchange, reduction in work of breathing, avoiding oxygen toxicity, minimizing high airwaypressures, avoiding further lung damage, and allowing the injured lung to heal.

A lung protective and pressure-limited ventilatory strategy has been shown to improve survivalrates and lower rates of barotrauma. Current recommendations are to use a tidal volume of 5-8mL/kg, a longer inspiratory time, and not to exceed a transpulmonary pressure of 30 cm H20.Permissive hypercapnia may ensue but is tolerated, which may occur with the use of lesser tidalvolumes. The use of PEEP may reduce or prevent ventilator-induced lung injury. Sufficient PEEPto recruit atelectatic alveolar units and to increase lung volumes so that respiration happens on themost compliant part of the pressure volume curve is recommended. In clinical practice, this canbe achieved by measuring plateau pressures and calculation of lung compliance at different levelsof PEEP. The use of prone positioning and nitric oxide may prove to be beneficial in the shortterm; these interventions have not been shown to improve survival rates.

High-dose corticosteroids, although not useful in early management of ARDS, have been reportedto improve survival in patients who have unresolving ARDS. In a study by Meduri et al (1998),prolonged administration of methylprednisolone in patients with unresolving ARDS wasassociated with improvement and reduced mortality. For the treatment group versus the placebogroup, the mortality rate for the treatment group was 0 (0%) of 16 versus 5 (62%) of 8 for theplacebo group in the ICU. The rate of infections, including pneumonia, was similar in bothgroups.

Transfer:

Patients with sepsis initially are observed on the wards or in the emergency department. After initial attemptsat stabilization, transfer the patient to the ICU for invasive monitoring and support.

Deterrence/Prevention:

Patients with impaired host defense mechanisms are at a greatly increased risk for developing sepsis.

The main etiologies of impaired host defenses are as follows:

Chemotherapeutic drugs

Malignancy

Severe trauma

Burns

Diabetes mellitus

Renal or hepatitic failure

Advanced age

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Ventilatory support and invasive catheters further worsen the risk of infection. Avoiding the use of cathetersor removing them as soon as possible may prevent severe sepsis.

Prophylactic antibiotics in the perioperative phase, particularly following gastrointestinal surgery, may bebeneficial.

The use of topical antibiotics around invasive catheters and as part of dressing for patients with burns ishelpful.

Maintenance of adequate nutrition, administration of pneumococcal vaccine in patients who have had asplenectomy, and early enteral feeding are other preventive measures.

Prevention of sepsis with topical or systemic antibiotics is suggested for high-risk patients. Use ofnonabsorbable antibiotics in the stomach to prevent translocation of bacteria and occurrence of bacteremia is acontroversial issue. Numerous trials have been performed over the years using either the topical antibioticsalone or a combination of topical and systemic antibiotics. A systemic review by Nathens (1997), presented nobenefit in medical patients but showed a reduced mortality rate in surgical trauma patients. The beneficialeffect was from a combination of systemic and topical antibiotics, predominantly by reducing lowerrespiratory tract infections in treated patients.

Complications:

Acute lung injury leading to ARDS is a major complication of patients with severe sepsis and septic shock.Incidence of ARDS is approximately 18% in patients with septic shock.

Acute renal failure occurs in 40-50% of patients with septic shock. Acute renal failure complicates therapyand worsens the overall outcome.

DIC occurs in 40% of patients with septic shock.

Death occurs in 40-50% of patients with septic shock.

Prognosis:

Several clinical trials have documented a mortality rate of 40-75% in patients with septic shock. The poorprognostic factors are advanced age, infection with a resistant organism, impaired host immune status, poorprior functional status, and continued need for vasopressors past 24 hours. Development of sequential organfailure, despite adequate supportive measures and antimicrobial therapy, is a harbinger of poor outcome. Themortality rates were 7% with SIRS, 16% with sepsis, 20% with severe sepsis, and 46% with septic shock(Brun-Buisson, 2000).

In 1995, a multicenter prospective study published by Brun-Buisson (1995) reported a mortality rate of 56%during ICU stays and 59% during hospital stays. Twenty-seven percent of all deaths occurred within 2 days ofthe onset of severe sepsis, and 77% of all deaths occurred within the first 14 days. The risk factors for earlymortality in this study were higher severity of illness score, the presence of 2 or more acute organ failures atthe time of sepsis, shock, and a low blood pH (<7.3).

Patient Education:

For excellent patient education resources, visit eMedicine's Shock Center, Blood and Lymphatic SystemCenter, and Public Health Center. Also, see eMedicine's patient education articles Shock, Sepsis (BloodInfection), and Cardiopulmonary Resuscitation (CPR).

MISCELLANEOUS Section 9 of 11 Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Pictures Bibliography

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Medical/Legal Pitfalls:

Sepsis is the most common cause of shock in most ICUs and is a leading cause of death.

Recognition of septic shock requires features of systemic inflammatory response (eg, mental changes;hyperventilation; distributive hemodynamics; hyperthermia or hypothermia; reduced, elevated, or left shift ofWBCs) in addition to a potential source of infection.

Patients in septic shock require immediate cardiorespiratory stabilization with a large volume of fluidsintravenously, infusion of vasoactive drugs, and, often, endotracheal intubation and mechanical ventilation.

Intravenous empirical antibiotic therapy directed at all potential infectious sources should begin immediately.

Infectious processes requiring drainage or debridement should be treated surgically expeditiously, even thoughthe patient does not appear stable, because the patient may not improve without the emergent surgicaltreatment.

The effects of drugs used to support hemodynamics of patients with sepsis have adverse effects on splanchniccirculation; therefore, the ideal hemodynamic therapy in these patients is not known. Following adequate fluidresuscitation, therapy with dopamine may be initiated, followed by norepinephrine when dopamine fails. Thealternate approach is initiating therapy with norepinephrine and using dobutamine if inotropic support isneeded.

Manipulation of oxygen delivery by increasing cardiac index either has shown no improvement or hasworsened morbidity and mortality. Routine use of hemodynamic drugs to improve cardiac output tosupranormal is not recommended.

Epinephrine use as a single agent is not recommended for patients with septic shock. Epinephrine impairssplanchnic circulation and tissue perfusion.

Lactic acidosis of septic shock usually causes anion gap metabolic acidosis. Administration of bicarbonatetherapy has the potential to worsen intracellular acidosis. Correction of acidemia using sodium bicarbonate hasnot improved hemodynamics in patients who are critically ill with increased blood lactate. The above notwithstanding, bicarbonate therapy has been used for pH of less than 7.2 or bicarbonate of less than 9 mmol/L,although no data to support this practice exist.

Special Concerns:

A continuum of severity exists from sepsis to septic shock and multiorgan failure. The clinical spectrumusually begins with infection that potentially leads to sepsis and organ dysfunction. In one study, 2527 patientswere evaluated, 26% developed sepsis, 18% developed severe sepsis, and 4% developed septic shock. Theincidence of positive results on blood culture was 17% in patients with sepsis and 69% in patients with septicshock.

The pathogenesis of septic shock and multiorgan failure occurs from mediators produced because of the host'simmune response. Despite encouraging data from animal studies, immunosuppressive agents, such as high-dose corticosteroids, have not shown any benefit in humans.

Recent research has focused on modifying the host response to sepsis by infusion of antibody against gram-negative endotoxin, infusion of gamma globulin, monoclonal antibodies against TNF-alpha, blockage ofeicosanoid production, blockade of IL-1 activity, and inhibition of nitric oxide synthase. These approacheshave demonstrated modest success in animal experimentation but cannot be recommended for general use atthis time.

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A septic patient admitted to the ICU should be monitored carefully to prevent and treat the infectiouscomplications. These events may perpetuate the SIRS or trigger relapse of sepsis after the initial improvement.These infectious complications include sinusitis, urinary tract infection, intravascular catheter–relatedinfections, acalculous cholecystis, and translocation of bacteria or endotoxin from gut lumen. As several ofthese ailments fail to manifest clinically, a high index of suspicion is crucial for early diagnosis and treatment.

PICTURES Section 10 of 11 Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Pictures Bibliography

Caption: Picture 1. Venn diagram showing overlap of infection, bacteremia, sepsis,systemic inflammatory response syndrome (SIRS), and multiorgan dysfunction.

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Picture Type: GraphCaption: Picture 2. A 26-year-old woman developed rapidly progressive shock associatedwith purpura and signs of meningitis. The blood culture confirmed Neisseria meningitidis.The skin manifestation is characteristic of severe meningococcal infection and is calledpurpura fulminans.

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Picture Type: PhotoCaption: Picture 3. Gram stain of blood showing presence of Neisseria meningitidis.

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Picture Type: PhotoCaption: Picture 4. Acute respiratory distress syndrome (ARDS), commonly observed inseptic shock as a part of multiorgan failure syndrome, is pathologically diffuse alveolardamage (DAD). This photomicrograph shows an early stage (exudative stage) of DAD.

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Picture Type: PhotoCaption: Picture 5. Acute respiratory distress syndrome (ARDS), commonly observed inseptic shock as a part of multiorgan failure syndrome, is pathologically diffuse alveolardamage (DAD). This is a high-powered photomicrograph of an early stage (exudativestage) of DAD.

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Picture Type: PhotoCaption: Picture 6. This photomicrograph shows a delayed stage (proliferative ororganizing stage) of diffuse alveolar damage (DAD). Proliferation of type II pneumocyteshas occurred, hyaline membranes are present, and collagen and fibroblasts are present.

Click to see detail

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Picture Type: PhotoCaption: Picture 7. This photomicrograph shows a delayed stage (proliferative ororganizing stage) of diffuse alveolar damage (DAD). This is fibrin stain showingcollagenous tissue, which may develop into the fibrotic stage of DAD.

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Picture Type: PhotoCaption: Picture 8. Acute respiratory distress syndrome (ARDS) in a patient whodeveloped septic shock secondary to toxic shock syndrome.

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Picture Type: X-RAYCaption: Picture 9. Bilateral airspace disease and acute respiratory failure in a patient withgram-negative septic shockThe source of sepsis was urosepsis.

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Picture Type: X-RAYCaption: Picture 10. A 45-year-old woman is admitted to the intensive care unit withseptic shock secondary to spontaneous biliary peritonitis. She subsequently developed acuterespiratory distress syndrome (ARDS) and multiorgan failure.

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Picture Type: X-RAYCaption: Picture 11. An 8-year-old boy developed septic shock secondary toBlastomycosis pneumonia. Fungal infections are a rare cause of septic shock.

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Picture Type: X-RAYCaption: Picture 12. A 28-year-old woman who is a previous intravenous drug user (HIV-negative status) developed septic shock secondary to bilateral pneumococcal pneumonia.

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Picture Type: X-RAY BIBLIOGRAPHY Section 11 of 11 Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Pictures Bibliography

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NOTE:Medicine is a constantly changing science and not all therapies are clearly established. New research changes drug and treatment therapies daily. The authors,editors, and publisher of this journal have used their best efforts to provide information that is up-to-date and accurate and is generally accepted within medicalstandards at the time of publication. However, as medical science is constantly changing and human error is always possible, the authors, editors, and publisher orany other party involved with the publication of this article do not warrant the information in this article is accurate or complete, nor are they responsible for omissionsor errors in the article or for the results of using this information. The reader should confirm the information in this article from other sources prior to use. In particular,all drug doses, indications, and contraindications should be confirmed in the package insert. FULL DISCLAIMER

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