Sepsis - Pro-Inflammatory and Anti-Inflammatory Responses (Contributions to Microbiology)

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The clinical observations used to argue that immunosuppression occurs in sepsis patients surviving the initial inflammatory cascade [ 1 ] are in essence that patients develop nosocomial infections due to opportunistic pathogens, including reactivated chronic viral infections, and that patients who die after sepsis have unresolved foci of infection. These underpinning observations require further consideration.

These multiply-instrumented, high-intensity care, bed-bound, vulnerable patients often have breaches in their integument and mucous membranes airways, surgical sites, indwelling catheters and perturbed microbiomes from antibiotic treatments. Overgrowth of antibiotic-resistant microorganisms and barrier defects predispose them to secondary infections, even without overt defects in their immune defenses [ 70 ]. Additionally, reactivation of herpes simplex virus HSV and cytomegalovirus CMV may have some clinical relevance in critically ill patients.

Whether CMV could cause immune compromise itself, be a reflection of immune compromise, or simply be an indicator of poor outcome in patients with sepsis remains unclear [ 71 ]. Reactivation of oro-labial HSV is extremely common in sepsis, and HSV can frequently be detected in respiratory secretions. However, acyclovir treatment had no impact on the outcome in patients with HSV bronchopneumonitis [ 72 ]. Of greater relevance to predisposition to nosocomial infection in sepsis patients remaining in ICUs for prolonged periods are physical breaches in innate immune system barriers.

Intravascular catheters, endotracheal tubes with consequently increased dead space, and increased gastric pH due to peptic ulcer prophylaxis regimens are all, along with broad-spectrum antibiotics, potent promoters of nosocomial infection. Post-mortems PMs identifying unresolved infection foci are not reliable proof that patients are dying of sepsis. Pneumonia is frequently present in patients in whom supportive care is withdrawn due to failure to thrive. Where pneumonia has been found more frequently at PM than was appreciated ante-mortem, the extent of pulmonary involvement was not quantified [ 73 ].

In this series, there was clear agreement by clinical and PM assessment that MOF was the commonest cause of death [ 73 ].

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These data call into question the relevance of unresolved, PM infection in patients dying in the ICU as a direct indicator of immunosuppression following as a direct consequence of previous sepsis. If the patients die with infectious foci and altered immune status, it does not mean they die because of them. The authors claimed that overall mortality was lower in the treated group compared with historical controls.

GM-CSF has been demonstrated to be able to restore some immune status parameters. However, a meta-analysis concluded that GM-CSF did not significantly reduce in-hospital mortality, although it significantly increased infection recovery [ 76 ]. Although no adverse effects were reported, it is worth recalling a case report of a patient who developed a fatal adult respiratory distress syndrome after GM-CSF treatment [ 77 ]. IL-7 is another cytokine that is promoted for the treatment of sepsis and that is supported by murine and human ex vivo tissue data [ 1 , 80 ].

However, one wonders whether systemic treatment with any immunostimulating cytokine may act on tissue leukocytes boosting the inflammatory process while boosting immune status as well. In this perspective, the attempt to treat peripheral mononuclear cells of sepsis patients ex vivo with IL-2 before re-injecting them is an interesting approach that prevents the delivery of this cytokine to the bloodstream, allowing it to act strictly on the desired cells [ 86 ].

Rather than repeating the mistakes of past experimental treatments for sepsis in which therapies were developed after successful preclinical models that may be far from mimicking human disease, it would be ideal to proceed in the future with new treatments in which extensive human data are available prior to embarking on expensive licensure studies.

Furthermore, identifying currently licensed drugs with tolerable safety profiles as potential sepsis agents leap-frogs costly drug development and early-phase human studies. In animal models, extant licensed drugs, such as chloroquine [ 87 ] and androstenenediol [ 51 ], have successfully restored immune status. Most interestingly, in the latter case, the treatment protected mice against polymicrobial sepsis and boosted altered ex vivo cytokine production observed with peripheral blood cells and spleen macrophages, dampening production observed with alveolar macrophages and Kupffer cells.

A similar compartmentalized adapted specificity was reported with estradiol [ 88 ]. Other approaches involve pro-resolving lipid mediators [ 89 ], although it is uncertain whether they may also adversely boost immune status. The recently recognized aspirin-triggered lipoxins, anti-inflammatory mediators of inflammation resolution, make aspirin a possible inexpensive agent for both prevention and treatment of sepsis. Considerable observational cohort data show improvements in mortality in patients with sepsis pretreated with aspirin [ 90 ].

This approach is being prospectively studied as part of an aspirin primary prevention trial. Could other immunomodulatory approaches be considered with less putative dangerous consequences on inflamed tissues.

Is boosting the immune system in sepsis appropriate?

Still, very little is known of its effect on leukocytes present in different compartments. The cell surface molecules containing in their intracytoplasmic domain an immunoreceptor tyrosine-based inhibition motif - such as programmed death-1 PD-1 , B and T lymphocyte attenuator BTLA , and cytotoxic T-lymphocyte antigen 4 CTLA-4 - could also be interesting targets for new therapeutic approaches. The expression of PD-1 on T cells and its ligand PD-L1 on monocytes is upregulated in critically ill [ 95 ] or septic shock [ 96 ] patients.

Increased expressions were associated with increased occurrence of secondary nosocomial infections and mortality after septic shock [ 97 ]. Not only are PDdeficient mice markedly protected from the lethality of sepsis, accompanied by a decreased bacterial burden and suppressed inflammatory cytokine response [ 98 ], but also blockade of PD-1 or PD-L1 improves survival in a murine model of sepsis, reverses immune dysfunction, inhibits lymphocyte apoptosis, and attenuates organ dysfunction [ 99 — ].

The relevance of these observations in human settings is still needed. Enhanced CTLA-4 expression was demonstrated more frequently in patients with sepsis than in non-infected critically ill patients or control subjects [ ], and blocking CTLA-4 improved survival in bacterial and fungal experimental sepsis [ , ].

However, the use of such an approach seems tricky since, in animal models at high dose, anti-CTLA-4 could worsen survival [ ], and the use of Abatacept a soluble CTLA-4 dimerized with an Fc fragment of immunoglobulin led to increased survival in invasive pneumococcal infection [ ]. In contrast, these mice displayed enhanced susceptibility to endotoxin-induced shock [ ]. New therapeutic approaches to treat sepsis should take into consideration that the immune status of leukocytes in the peripheral blood might be quite different from those present in inflamed tissues.

We believe that a systemic approach to immune stimulation is not appropriate if immune cells are boosted generally, independent of their location. This is the challenge we have to address if we wish to avoid further decades of disillusionment. New therapeutic interventions should address both the events in the tissues that lead to organ failure and the altered immune status of leukocytes restricted to some specific compartments. Lancet Infect Dis , J Immunol , J Exp Med , Curr Eye Res , Cytokine , Annu Rev Immunol , Immunol Lett , Kalinski P: Regulation of immune responses by prostaglandin E2.

A randomized, controlled, double-blind, multicenter clinical trial. TNF-alpha MAb sepsis study group. JAMA , Crit Care Med , Shock , J Trauma , Spight D, Trapnell B, Zhao B, Berclaz P, Shanley TP: Granulocyte-macrophage-colony-stimulating factor-dependent peritoneal macrophage responses determine survival in experimentally induced peritonitis and sepsis in mice. Eur J Immunol , Surgery , Mol Med , Immunity , Am J Pathol , Glynne PA, Evans TJ: Inflammatory cytokines induce apoptotic and necrotic cell shedding from human proximal tubular epithelial cell monolayers.

Kidney Int , Ann Surg , Lancet , Lab Invest , Chest , J Endotoxin Res , 7: Eur Cytokine Netw , Crit Care , R J Clin Invest , Crit Care , 9. Circulation , J Trauma Acute Care Surg , Correlation to CD64 and CD14 antigen expression. Clin Exp Immunol , Cell Host Microbe , J Endotoxin Res , Zurovsky Y, Eligal Z: Reduction of risk following endotoxin injection in unilaterally nephrectomized rats. Exp Toxicol Pathol , Cytokine , 8: Raschke RA, Garcia-Orr R: Hemophagocytic lymphohistiocytosis: a potentially underrecognized association with systemic inflammatory response syndrome, severe sepsis, and septic shock in adults.

Infect Immun , PloS One , 9: e J Infect Dis , Osawa R, Singh N: Cytomegalovirus infection in critically ill patients: a systematic review. Anesth Analg , Nature Med , 3: The Severe Burns Study Group. Verhoef G, Boogaerts M: Treatment with granulocyte-macrophage colony stimulating factor and the adult respiratory distress syndrome. Am J Hematol , J Biol Chem , PLoS One , 6: e Blood , J Inflamm Lond , 9: Arthritis Rheum , J Leukoc Biol , Medicinskaya Immunol , 2: Arch Surg , J Appl Physiol , Nature , Crit Care , R8.

Sodhi A, Paul S: Involvement of mitogen-activated protein kinases in the signal transduction pathway of bone marrow-derived macrophage activation in response to in vitro treatment with thymosin alpha 1. Int Immunopharmacol , 2: Braz J Med Biol Res , Mediators Inflamm , J Lab Clin Med , Download references. Correspondence to Jean-Marc Cavaillon. J-MC and DE wrote the review. DA read and amended it. All authors read and approved the final manuscript.

Reprints and Permissions. Host pattern recognition receptors can be divided into three groups: secreted, endocytic and signaling Mannose-binding lectin and C-reactive protein, are prototypical secreted PRRs that bind to microbial cell membrane components leading to complement activation. Endocytic PRRs such as macrophage mannose receptor are located on the surface of phagocytes and facilitate the phagocytosis of pathogens Ten human TLRs have been discovered on the surface of various cells including phagocytes.

Unlike TLRs which are cell membrane bound, NOD1 and NOD2 are intracellular proteins found in epithelial, monocytes, dendritic cells and granulocytes where they bind to bacterial peptidoglycan moieties The diversity of ligands for TLRs and NODs permit the detection and subsequent response to a broad range of infections In general, cytokines are signaling molecules which can be classified as either pro or anti-inflammatory. These signaling molecules augment a series of local and systemic inflammatory responses and engage various components of the immune and coagulation systems including: acting on the hypothalamus to induce fever; stimulation of bone marrow to release neutrophils; activation of endothelium to promote extravasation of phagocytes and complement to the site of infection; triggering of hepatocytes to synthesize C-reactive protein which binds cell wall components of bacteria, fungi and parasites; and the promotion of platelet-endothelial adhesion with clot formation In addition to IL-1 and TNF other prominent pro-inflammatory cytokines and immune modulators involved in the immune response to infection include IL-8, IL and interferon gamma.

Absolute pro-inflammatory cytokine deficiencies can predispose the host to overwhelming infection and death while excessive amounts can cause damage to the host. Thus, the systemic effects of cytokines including vasodilatory shock and disseminated intravascular coagulation have been implicated in the pathogenesis of sepsis. Paradoxically, infection induces host production of anti-inflammatory mediators. Traditionally, this immunosuppressive response was thought to curb inflammation during the recovery phase of infection.

More recent evidence suggests that normally pro and anti-inflammatory signaling pathways are activated simultaneously and serve to concentrate the immune response at the site of insult all the while limiting systemic immune activation Circulating IL which inhibits phagocyte activation and cortisol which inhibits cytokine synthesis by monocytes are both increased in the setting of infection.

Similarly, blood levels of both IL-1 receptor agonist and soluble IL-6 receptors are also elevated with infection thereby limiting the systemic effect of their respective pro-inflammatory ligands Inflammatory markers in bronchial washings of patients with Acute Respiratory Distress Syndrome ARDS with paired blood samples from the same host are consistent with this dichotomous model of inflammation at the site of infection and systemic immunosuppression Sepsis may progress to cardiovascular collapse and multiple organ dysfunction that culminate in death or residual organ failure.

Vascular endothelial dysfunction is central to the development of the hypotension and end organ injury in sepsis. Nitric oxide NO , a signaling molecule and potent vasodilator, is produced by nitric oxide synthase NOS present in vascular endothelium and smooth muscles cells. Administration of NOS inhibitors to septic patients reverses shock, but also increased mortality secondary to widespread tissue ischemia Vasopressin deficiency which is frequently present in septic patients may contribute to septic shock and organ dysfunction at the vascular endothelial level In addition to systemic hypotension, maldistribution of blood flow between organ systems has also been implicated as a contributory factor in sepsis 2.

Microvascular dysfunction secondary to activation of the coagulation system and the formation of micro thrombi further impairs oxygen and nutrient delivery at the cellular level. Even when blood flow is believed to be adequate there is evidence that tissues are unable to optimally extract oxygen. This may in part be due to decreased mitochondrial function In addition to the direct effect on the vasculature, sepsis directly impairs cardiac performance which further compromises organ perfusion. The usual hemodynamic profile of septic shock includes high cardiac output, low mean arterial pressure and tachycardia.

Left ventricular function is depressed as evidenced by a decrease in the ejection fraction. Elevated levels of troponin may be observed in sepsis; however the cause myocardial dysfunction is not ischemia as coronary blood flow is maintained When a patient with SIRS develops concomitant shock it imperative that the hypotension be further defined as therapies for various types of shock differ greatly. There are four broad shock states: hypovolemic, distributive, cardiogenic, and extracardiac obstructive shock. The various shock states can be distinguished by characteristic hemodynamic profiles and clinical characteristics.

Each type of shock will be briefly reviewed in the context of a differential diagnosis for a patient presenting in septic shock. Hypovolemic shock is caused by a decrease in circulating blood volume. The decrement in blood volume can be either hemorrhagic in origin e. The patient in hypovolemic shock presents with tachycardia and hypotension. Extremities are cool to touch and cyanotic related to a low cardiac output state. Patients exhibit signs of hypovolemia such as collapsed neck veins and oliguria or anuria. Similar findings can be seen in early septic shock when a vasodilatory response to overwhelming infection leads to a relatively hypovolemic picture.

Distributive shock is characterized by vasodilatation with either normal or elevated cardiac output. Classically, patients will present with warm extremities and tachycardia although decompensated distributive shock may be notable for extremities which are cool to touch. Organ injury is due to the inadequate cardiac preload, maldistribution of blood flow and may be further worsened by the inability to utilize oxygen adequately on a cellular level Besides sepsis, anaphylaxis or neuralgic injury with loss of autonomic nervous system function can also cause distributive shock; therefore, allergen exposure or spinal cord injury should be considered when a patient presents with a clinical picture consistent with distributive shock.

Cardiogenic shock results from inadequate tissue perfusion due to cardiac dysfunction. It is characterized by a low cardiac output and a high systemic vascular resistance in the setting of normo- or hypervolemia. In the setting of the septic patient it is important to consider primary cardiac issues in the differential of the shock state since underlying heart disease can complicate the management of the septic patient. In addition, septic shock can have primary cardiac depressive effects which will effect the presentation of the patient.

Extracardiac obstructive shock can be divided into two broad categories: increased intrathoracic pressure and intrinsic vascular flow obstruction. The primary effect of both categories can be either pump failure if cardiac output is compromised or loss of preload if blood return to the heart is compromised. As a result, extracardiac obstructive shock can present as a primarily cardiogenic shock type picture when the inciting event leads to primary cardiac failure or it can also present as a hypovolemic picture when preload is lost, or a mixture of the two.

Increases in intrathoracic pressure leading to a shock state can be seen in the setting of a tension pneumothorax or as a result of positive pressure ventilation such as in obstructive lung disease with air trapping and the progressive rise of auto peep. Intrinsic vascular flow obstruction can be seen in massive pulmonary embolism, cardiac tamponade, and severe pulmonary hypertension.

It is important to consider these issues in the differential diagnosis of the septic patient as some of these are mechanical issues which can be corrected expeditiously leading to rapid hemodynamic improvement. Focal neurologic deficits and seizures are rare and the brain appears anatomically normal on imaging unless patients have pre-existing disease that enhances the likelihood of ischemia induced focal pathology.

The etiology of this impaired level of consciousness is multifactorial and includes decreased cerebral perfusion and oxygen extraction. How sepsis causes diffuse alveolar epithelial injury is unclear. As lung function and hypoxia worsen tissue perfusion and oxygenation are compromised. ARDS can readily be confused with diffuse pneumonia, or can be complicated by secondary pneumonia, and thus much ARDS is in fact a mixed picture with overlapping pathologies. Global cardiac depression is common in sepsis as described above.

Nonetheless, it is important that clinicians be cognizant of the fact that patients with preexisting coronary artery disease can suffer regional ischemia and infarction in the setting of sepsis Oliguria and renal failure are common complications of sepsis. Renal dysfunction is caused by the shunting of blood away from the renal vascular bed to other vital organs.

Oliguria may resolve with fluid resuscitation. Renal failure associated with sepsis is usually reversible. However, many other causes of renal dysfunction can complicate clinical presentation and outcome, such as contrast nephropathy, drug toxicity, diabetes, or hypertension.

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Hypoperfusion of the GI tract in sepsis can increase intestinal permeability which is associated with the onset of multiple organ dysfunction syndrome Mucosal hypoperfusion can lead to ulceration and increase the risk of GI bleeding. These consequences of sepsis can influence the efficacy of enteral nutrition, and the access of bowel flora to lymphatics and capillaries. Patients with sepsis need a careful history and physical examination. While laboratory assessment and monitoring provides invaluable and sometimes essential information for diagnosis and for therapeutic monitoring, failure to assess the history and failure to examine the patient carefully can lead to unnecessary therapies with resulting toxities, and to failure to initiate appropriate therapy promptly, thus reducing the likelihood of a successful outcome.

History can direct diagnosis in many obvious ways. Pre existing medical conditions ureteral calculi , immunosuppression chronic corticosteroids, recent human stem cell transplant are examples of the myriad of information that a skilled history can elicit. Physical examination is also vital to an informed management strategy.

Imaging studies are increasingly important for localizing the source of infection. Computer assisted tomography CAT scans and magnetic resonance imaging MRI are more and more standardized for patients who can be transported and safely monitored for the procedure. Consideration must also be given to the advantage and toxicities of contrast agents. Such imaging is vital for providing diagnostic clues based on patterns or disease, or providing targets for aspiration or biopsy.

Such imaging is also essential for recognizing obstructions of vital structures such as bronchi or ureters, for identifying collections of purulence or foreign bodies that must be removed. For patients with sepsis, severe sepsis, or septic shock, any potential source of infection should be carefully assessed. Bronchoscopy, lumbar punctures, sinus aspirations, soft tissue aspirations or biopsies, and lymph node biopsies are among the many invasive techniques that are a standard component of an effective search for the causative process and identification of the causative organism.

Any purulent discharge needs to be examined by direct microscopy and culture. Similarly, suspicious body fluids, secretions, and excretions should be similarly examined, such as sputum, urine, stool, or CSF. Tissue biopsies of skin, lung, lymph nodes, or aspiration of collections are clearly important. Microbiology laboratories are more and more likely to be distant from the area of patient care. Despite this, clinicians must communicate with the laboratory to assure that specimens are collected and transported properly, and that the optimal stains and cultures are performed.

As diagnostic and therapeutic interventions become more feasible for viruses, fungi, fastidious bacteria, optimal management requires increasingly sophisticated diagnostic approaches. Blood cultures are an important part of a diagnostic evaluation. The likelihood that useful information will be derived from blood cultures depends on selecting patients with a reasonable likelihood of having organisms in their blood stream. A patient with a likely viral infection, or a patient who is stable with a bacterial infection and doing well on antimicrobial therapy, by definition, is unlikely to be bacteremic or fungemic.

Obtaining a blood culture on such a patient is more likely to yield a contaminant than a true pathogen, potentially causing unnecessary drugs, unnecessary expense, and unnecessary toxicity. Thus, care must be exercised in choosing which patients to draw blood cultures on, when to draw cultures, and what types of cultures to obtain.

Blood cultures should ideally be obtained before new antimicrobial therapy is started. Obtaining blood cultures prior to starting or switching antibiotics will increase the likelihood that such cultures will identify the causative agent. However, obtaining cultures show not substantially delay the initiation of potentially life saving therapy.

Some blood culture systems will require inoculation of two bottles, but others require one or three bottles for routine use.

[Full text] Pro-inflammatory agents released by pathogens, dying host cells, and n | JIR

The suggested quantity of blood should be drawn: suboptimal ratio of media to blood, or suboptimal volume of blood will reduce the yield of cultures. Extra bottles must be inoculated for special pathogens such as viruses, certain fungi, certain zoonoses and mycobacteria. The yield of blood cultures, once a high risk patient and an appropriate time e. Current guidelines for evaluating fever in the intensive care unit now recommend three cultures be drawn rather than two cultures based on the relationship between blood culture yield and volume of blood When blood cultures are drawn, at least two sets should be drawn.

Molecular tests on blood and body fluids are an increasingly important part of the diagnostic armamentarium, especially for viruses and fungi. Gene probes for tuberculosis, rapid tests for influenza or RSV virus, or PCR for hepatitis B or C or for HIV are examples of molecular techniques that are becoming routine aspects of patient evaluation. Serial serologies are useful diagnostically, but results rarely come back in time to influence acute management.

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There has also been interest in surrogate markers for the presence of sepsis. While antimicrobial therapy can be life saving, some patients cannot be successfully treated without removing or draining the site of infection. When patients have septic shock due to an infected catheter, patients are far more likely to have a successful outcome if the catheter is promptly removed. Foreign bodies such as biliary stints, urinary stints, Foley catheters, chest tubes, or ventriculostomies must usually be removed to optimize outcome.

There are, however, some specific syndromes and specific pathogens that can be treated medically if there is an urgent need to do so, without removing the foreign body. Collections of purulent fluid must be drained in most situations. Urosepsis associated with an obstructed ureter, a pneumonia with an associated empyema, a liver abscess, or a renal abscess are examples of collections that must be drained to optimize outcome.

How that drainage is accomplished depends on the location, the infection, and the patient. In some situations needle drainage is adequate; in other situations more extensive surgical drainage is required. In some situations, such as brain abscesses and liver abscesses, medical therapy alone can be successful, but such an approach requires judgment, careful evaluation of the literature, with focus on how ill the patient is and what the risks and benefits of the technical options are.

For some patients, there is no urgency to start therapy until the offending pathogen is identified. For others with severe sepsis or septic shock, empiric therapy is life saving, i. Table 4 provides some potential empiric regimens for the therapy of septic shock. Many possible regimens could be used with similar results. The choice in each situation depends on the pathogens likely to cause a specific infectious syndrome, knowledge of organisms the host has been colonized with, consideration of what antibiotics the patient has recently been exposed to, local epidemiologic trends in pathogens and resistance patterns, and patient ability to tolerate specific agents.

Thus, antibiotic coverage for MRSA should be universally considered, i. Candida is the fourth most common pathogen causing blood stream infections in intensive care units. For patients with severe sepsis or septic shock, the initiation of appropriate therapy is urgent. Thus, initial regimens need to be broad in order to be certain that the causative agent is treated. The initial regimen can subsequently be narrowed when the causative agent is definitively identified.

The initial agent must be infused into the patient promptly, and not merely ordered in the computer: the system involved in transferring a cognitive plan to administer antibiotics to the successful infusion into the patient involves many steps that require the medical, nursing, pharmacy and information technology programs to work cohesively. In most hospitals, a substantial number of patients do not receive their antibiotics within minutes of an order being written.

For septic shock in particular, clinicians must work with nursing and pharmacy to assure that the patient has enough ports for infusion, that infusion times of individual drugs are considered in their selection and prioritization. Thus, once a clinical diagnosis of severe sepsis or septic shock has been established, patients should receive a full course of therapy usually days unless another cause of the syndrome has been conclusively identified.

Once the causative pathogen has been conclusively identified and antibiotic susceptibility results have been obtained, the broad empiric regimen can usually be narrowed. Clinicians must recognize, however, that certain infectious syndromes may be polymicrobial. Finding a single organism in the bloodstream does not invariably indicate that only a single organism is involved.

Thus, judgment is required in determining whether to narrow the spectrum of antibiotic therapy. There has been considerable debate in the past about the use of bactericidal antibiotics versus bacteristatic drugs. However, there is no clinical evidence support this preference. There has also been debate regarding the desirability of combination therapy versus combination therapy for treatment of a specific pathogen.

Combination therapy is a logical strategy in terms of assuring that the breadth of coverage include all likely pathogens when patients are severely ill, and there is no margin for error. However, for treating specific pathogens, there are few examples in which combination therapy is superior to monotherapy when modern, potent agents are used The optimal duration of antibiotic therapy has not been studied for most types of sepsis, severe sepsis, and septic shock. The duration of therapy will be determined by the rapidity of host improvement, host immunologic status, presence of undrained purulence or unremoved foreign bodies.

While days in non neutropenic patients with no undrained focus is often recommended, there is little data on which to base this recommendation on. Moreover, there are situations where shorter courses are clearly effective The optimal drugs for specific microorganisms isolated in septic patients can be found in other chapters in this book.

The four essential components of early therapy for patients with sepsis or septic shock are: source control, prompt administration of empiric antibiotics that take into account the most likely pathogen and anti-microbial sensitivity, fluid and vasopressor administration to maintain organ perfusion and source control i. Several adjunctive therapies are also commonly used although the evidence supporting their efficacy is less convincing. Severe sepsis or septic shock requires fluid resuscitation in order to maintain perfusion of vital organs Hydroxyethyl starch is not recommended since it is associated with higher rates of renal failure 9.

Fluid resuscitation should be guided by hemodynamic monitoring preferably with an arterial line and a central venous catheter , and evidence of end organ perfusion e. If resuscitation goals are not being promptly achieved after several liters of fluid or if clinical evidence of pulmonary edema develops then vasopressor therapy should be administered via a central line. Norepinephrine has emerged as the standard vasopressor agent for septic shock although other vasopressors are used including dopamine less commonly epinephrine Nonetheless, adjunctive vasopressin therapy should be considered as a rescue maneuver in patients with septic shock who are not responding to either norepinephrine or dopamine alone The use of glucocorticoids in sepsis is controversial.

Meta-analysis has shown that low doses hydrocortisone to mg daily for 5 to 7 days confer a mortality benefit in severely septic patients In light of these data, a reasonable approach is to consider low dose glucocorticoid therapy in severely ill septic shock patients who are not improving i. Once steroid therapy is initiated, there should be a low threshold for suspecting occult secondary infections as bacteremic patients on steroids will not consistently mount a fever response In two subsequent trials of intensive insulin therapy, including one study which specifically enrolled severe septic patients, there was no mortality benefit due to intensive insulin therapy.

In light of the absence of reproducible benefit and the potential harm, intensive insulin therapy is not recommended for septic patients. Early goal directed therapy EGDT in sepsis is defined as prompt fluid resuscitation targeting optimal central venous pressure, mean arterial pressure and central venous oxygenation saturation ScvO2 While the benefit of treating septic patients in a timely fashion is self-evident, the evidence that measuring ScvO2 is beneficial is less than compelling.

In the only prospective trial of EGDT patients in the treatment arm differed from the controls in one aspect: a catheter capable of measuring ScvO2 was used to guide red blood cells transfusions or dobutamine administration. This one positive trial contrasted with the only other prospective trial evaluating titrating therapy to ScvO2 albeit in critically ill patients which showed no benefit. Analysis of these trials and other data cast doubt as to the contribution of ScvO2 monitoring to patient outcome Thus, at this time such ScvO2 catheters should not be considered necessary for achieving optimal outcome despite their inclusion in well publicized guidelines and bundles Activated protein C drotrecogin alfa is a component of the coagulation cascade and functions as an inhibitor of factors Va and VIIIa thereby promoting fibrinolysis.

In addition, drotrecogin alfa has anti-inflammatory properties and is capable of inhibiting proinflammatory cytokine production. Low plasma levels of protein C occur in septic patients Based upon the results of a single randomized controlled trial, this adjunctive therapy was approved for patients in septic shock who had a severity of illness score APACHE II greater than 25 within 24 hours of the onset of shock 3. Drotrecogin alfa is administered as a 96 hour infusion. An increased risk of serious bleeding including intracerebral hemorrhage, however, has been observed in all trials of drotrecogin alfa Pending the results of an ongoing confirmatory trial of PROWESS-SHOCK , drotrecogin alfa has the potential to cause serious bleeding and should be viewed as an optional therapy in patients with sepsis and a high likelihood of death.

Acute Inflammation

Sepsis is a major cause of morbidity and mortality in the United States. Recognition of sepsis, severe sepsis or impending septic shock in the emergency department and in hospitalized patients remains a challenge that requires clinical judgement. Management principles for patients with distributive shock focus on an expeditious response involving source control, antimicrobial therapy, fluids, vasopressors and adjunctive therapies. Health care providers and medical facilities have an obligation to develop a systems based approach to assure that therapy is prompt, coordinated, and comprehensive in order to provide optimal patient outcome.

Drotrecogin alfa activated for adults with severe sepsis and a low risk of death. N Engl J Med 13 : , Abraham E, Singer M. Mechanisms of sepsis-induced organ dysfunction.

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