3. Plan de marketing estratégico de TOUS
3.3 Análisis de la competencia (PORTER)
3.3.2 Teoría de Porter
The most common categories of illness associated with fever of unknown origin are infectious diseases, noninfectious inflamma- tory diseases, malignancies, and miscellaneous causes (Figure 1). The most common infectious cause is tuberculosis. In patients with HIV infection, approximately 80% will have an additional infection causing the fever. No cause for fever of unknown origin is found in approximately 25% of patients.
If no infectious cause is identified, further evaluation is direct- ed toward autoimmune diseases, connective tissue diseases, and granulomatous disorders (i.e., sarcoidosis). In the miscellaneous category, thyroiditis, pulmonary embolism, drug fever, and facti- tious fever need to be considered.
For fever of unknown origin, additional investigation beyond that for persistent fever is necessary (see Table 1). Some experts recommend a fever diary to monitor and record the fever pattern. HIV antibody (and viral load if fever is of recent onset), erythro- cyte sedimentation rate, and CT of the chest and abdomen are often added. If this fails to identify a source, repeated questioning and examinations are warranted.
Treatment
Seizures, birth defects, brain damage, and death have been attrib- uted to fever, as well as jeopardizing myocardial and pulmonary function in patients with underlying disease. However, evidence for such direct harm is lacking, whereas consistent evidence of the beneficial effects of fever exists. When antipyretics are adminis- tered, studies have shown prolonged time to crusting in varicella infection, and viral shedding is increased and neutralizing anti- body production is suppressed in herpes zoster and rhinoviral infections. Cooling blankets have been shown to increase oxygen consumption (by induced shivering) and cause coronary artery vasospasm. Antipyretics are not without adverse effects: aspirin has gastrointestinal and renal effects and acetaminophen has liver and renal effects. Despite the lack of evidence that fever is harmful, and evidence demonstrating potential deleterious effects of treat- ing fever, antipyretic therapy may be considered for patient com- fort and is considered safe when appropriate dosing guidelines are followed. If the decision is made to treat a patient’s fever, dosing should be around the clock to avoid discomfort from cyclical sweats during PGE-2 inhibition and chills as the set-point returns upward. Empiric antibiotic therapy is guided by the most likely source. In stable patients without localizing signs, empiric antibi- otic therapy is typically withheld. In unstable patients without localizing signs, empiric broad spectrum antibiotics may be initi- ated (see Chapter 46).
Book Enhancement
Go to www.acponline.org/essentials/infectious-disease-section .html to review a table of infection mimics that can present with fever. In MKSAP for Students 4, assess yourself with item 4 in the
Infectious Disease Medicinesection.
Table 1. Minimal Diagnostic Evaluation for Persistent Fever
• Comprehensive history • Physical examination
• Complete blood cell count and differential • Blood film reviewed by hematopathologist
• Routine blood chemistry (including lactic dehydrogenase, bilirubin, and liver enzymes)
• Urinalysis and microscopy • Blood (x3) and urine cultures
• Anti-nuclear antibodies (ANA), rheumatoid factor • Human immunodeficiency virus antibody
• Cytomegalovirus IgM antibodies; heterophil antibody test (if consistent with mononucleosis-like syndrome) • Q-fever serology (if exposure risk factors exist) • Chest radiography
• Hepatitis serology (if abnormal liver enzyme test result)
From Mourad O, Palda V, Detsky AS. A comprehensive evidence-based approach to fever of unknown origin. Arch Intern Med. 2003;163:545-51; with permission.
Bibliography
Bleeker-Rovers CP, Vos FJ, de Kleijn EM, et al.A prospective multicen- ter study on fever of unknown origin: the yield of a structured diagnostic protocol. Medicine (Baltimore). 2007;86:26-38. [PMID: 17220753]
Mourad O, Palda V, Detsky AS. A comprehensive evidence-based approach to fever of unknown origin. Arch Intern Med. 2003;163:545- 51. [PMID: 12622601]
Approach to Fever • 173
Figure 1 Cause of fever of unknown origin over past 40 years. (From Mourad O, Palda V, Detsky AS. A comprehensive evidence-based approach to fever of
174
A
pproximately 750,000 cases of severe sepsis occur in the United States each year. The mortality rate ranges from 20% to 50%. By 2020, there will be more than 1 million cases of sepsis per year in the United States, resulting in 215,000 deaths. Early diagnosis of sepsis syndrome and early goal-direct- ed therapy reduces mortality.Sepsis is a complex dysregulation of both inflammation and coagulation. Primary cellular injury may result directly from infec- tion or when a toxic microbial stimulus (e.g., endotoxin) initiates a deleterious host inflammatory response. A network of inflam- matory mediators is generated, including TNF-α, IL-1, and other cytokines and chemokines that activate leukocytes, promote leukocyte-vascular endothelium adhesion, and induce endothelial damage. Endothelial damage, a key component of sepsis patho- physiology, leads to tissue factor expression and activation of the tissue factor-dependent clotting cascade with subsequent forma- tion of thrombin such that microaggregates of fibrin, platelets, neutrophils, and erythrocytes impair capillary blood flow, decreas- ing oxygen and nutrient delivery to tissues. In addition, cytokines stimulate nitric oxide release, smooth muscle relaxation, and sys- temic vasodilation, leading to impaired oxygen delivery and anaer- obic metabolism on a cellular level. The most severe manifesta- tions of this process include disseminated intravascular coagulation and metabolic (lactic) acidosis.
Higher levels of circulating and intracellular TNF-α, IL-1, IL-6, and soluble adhesion molecules, which are markers for acti- vated or damaged endothelium, have been more common in older compared with younger patients with sepsis. Increasing age is also associated with rising circulating levels of IL-6 and D-dimer, acti-
vated factor VII, and other coagulation factors, indicating activa- tion of inflammatory and coagulation pathways.
Diagnosis
In 1992, the American College of Chest Physicians and the Society of Critical Care Medicine issued standardized definitions for various severe infections that constitute the sepsis syndrome. Four entities were defined: systemic inflammatory response syn- drome (SIRS), sepsis, severe sepsis, and septic shock (Table 1). The definitions provide a simple and practical framework for iden- tifying these disorders. They are a continuum, with a stepwise increase in mortality from SIRS to septic shock. SIRS criteria are relatively nonspecific and can be present in many shock states (Table 2). The presence of the SIRS criteria should place sepsis on the differential and lead to an investigation for infection.
The initial evaluation of the septic patient includes a rapid yet thorough history and physical examination, with emphasis on identifying a possible source of infection. The vital signs are cru- cial to determining the stability of the patient and require contin- uous monitoring, including blood pressure, pulse, respiratory rate, and oxygen saturation.
Laboratory evaluation is focused on finding evidence for end- organ dysfunction related to the sepsis (e.g., renal failure, liver dys- function, disseminated intravascular coagulation, mental status changes). It includes a complete blood count with differential, electrolytes, creatinine, urinalysis, liver chemistry tests, coagula- tion parameters, and a random serum cortisol level to inform deci- sion making on need for adjunctive corticosteroid therapy. Serum lactate level should be measured because it has been correlated with the degree of global tissue hypoxia and the severity of sepsis. Lactate level >4 mmol/L implies significant tissue hypoxia. Obtain cultures of blood, urine, sputum, and any other sites of potential infection as soon as the diagnosis of sepsis is suspected. Obtain x- rays and other imaging studies as directed by patient symptoms.
Chapter 46
Sepsis Syndrome
Charin L. Hanlon, MD
Table 1. Definitions of Systemic Inflammatory Response Syndrome, Sepsis, Severe Sepsis, and Septic Shock
Systemic inflammatory response syndrome (SIRS) Two or more of the following:
Temperature >38.0°C (100.4°F) or <36°C (96.8°F). Heart rate >90/min.
Respiration rate >20/min or arterial blood PaCO2<32 mm Hg. Leukocyte count >12,000/µL or <4000/µL with 10% bands
(in absence of other known cause of these conditions).
Sepsis Systemic inflammatory response syndrome in response to confirmed infectious process. Severe sepsis Sepsis associated with organ dysfunction, hypoperfusion, or hypotension. Hypoperfusion and
hypotension abnormalities may include, but are not limited to, lactic acidosis, oliguria, or an acute alteration in mental status.
Therapy
Almost universally, patients are admitted to the hospital if they meet SIRS criteria. If patients have sepsis, severe sepsis, or septic shock, they are managed in the intensive care unit setting. Early goal-directed therapy refers to the concept of early restoration of hemodynamic stability during the first 6 hours of hospitalization (Table 3). This therapy serves to balance oxygen delivery with oxygen demand to prevent tissue hypoxia. The goals of treatment are a central venous pressure (CVP) of 8-12 mm Hg, mean arte- rial pressure (MAP) >65 mm Hg ([(2× diastolic) + systolic] / 3), urine output >0.5 mL/kg/hr, and central venous oxygen satura- tion (SvcO2) >70%. To achieve the CVP goal of 8-12 mm Hg
requires placement of a central venous catheter attached to a pres- sure transducer, measuring the pressure in the superior vena cava or right atrium. Either crystalloid or colloid is given aggressively until the CVP goal is obtained. There is no evidence-based bene- fit for one fluid replacement over another. Initially, a 500-1000 mL bolus of fluid is given and the CVP monitored to direct sub- sequent fluid replacement. If the fluid challenge fails to achieve a mean arterial pressure >65 mm Hg, vasopressors are added. Source control is crucial initially. This includes removal of sources of infection, such as indwelling catheters, drainage of abscesses, and surgical debridement of wounds, done promptly upon the diagnosis of sepsis.
During the initial stabilization, peripheral oxygen consump- tion is estimated by measuring central venous oxygen saturation from blood obtained from the superior vena cava. If the superior
vena cava oxygen saturation is <70%, oxygen carrying capacity needs to be increased. This is done by transfusion if the hematocrit is <30% or with inotropic agents to increase cardiac output.
Currently accepted therapy consists of treating the underlying illness and administering antibiotics directed against the causative pathogen. The septic patient requires early, empiric broad-spectrum antibiotics, which are narrowed when culture results are avail- able and antimicrobial drug sensitivities are known. In selecting empiric antibiotics, recognize that gram-positive infections now cause most cases of sepsis but gram-negative infections are still prevalent, and fungal infections must be considered in the high risk patients (e.g., neutropenic and transplant patients receiving immunosuppression therapy). Antibiotics should be initiated within 1 hour of the sepsis diagnosis.
Vasopressors are included as part of early goal-directed thera- py if the mean arterial pressure is <65 mm Hg after the initial fluid resuscitation. The most commonly used vasopressor for septic shock is norepinephrine. It is a potent peripheral vasoconstrictor reversing the endotoxin-induced vasodilation that is the hallmark of septic shock. Dopamine is also acceptable but is associated with more tachycardia and arrhythmia because it acts as an alpha- and beta-agonist. Vasopressin has been investigated in severe shock resistant to other vasopressor agents and may be associated with some benefit. Vasopressin is avoided in patients with cardiac dys- function because it commonly depresses cardiac output.
Recombinant human activated protein C (aPC or drotrecogin alfa) significantly reduces mortality rates in patients with severe sepsis. Patients who benefited most from receiving aPC had a high
Sepsis Syndrome • 175
Table 2. Differential Diagnosis of Shock Disease Notes
Septic shock Characterized by high cardiac output (early) that can become depressed (late), low systemic vascular resistance, and low filling pressures. Fever, leukocytosis, and source of infection are characteristically present.
Cardiogenic shock Typically occurs in acute coronary syndromes, in valve dysfunction, or from cardiac tamponade. Characteristics include cardiogenic pulmonary edema, high filling pressures, low cardiac index, and high systemic vascular resistance. ECG is useful in evaluating patients with suspected sepsis to exclude acute coronary syndrome. Echocardiogram is also useful in this regard.
Hypovolemic shock Characterized by low cardiac output, high systemic vascular resistance, and low cardiac filling pressures. Patients may have a history of hemorrhage, but other causes of volume depletion may be causal, such as with severe diarrhea.
Anaphylactic shock Clinical presentation includes urticaria, angioedema, or both; shortness of breath and wheezing; stridor due to laryngeal edema; pulmonary edema; and hypotension. As may be seen in severe sepsis, the systemic vascular resistance is typically low, and the cardiac output elevated. Diagnosis is made when the typical signs and symptoms occur shortly after exposure to a suspected antigen. Treatment with epinephrine should be part of the initial management. Corticosteroids and antihistamines are also indicated.
Neurogenic shock/spinal shock Occurs in spinal cord injury or other severe CNS injury. Thought to be caused by failure of the autonomic nervous system; as a result, it is associated with a low systemic vascular resistance and typically bradycardia. Bradycardia and hypotension in a patient with spinal cord injury should raise suspicion for this syndrome.
Adrenal crisis Adrenal crisis may be difficult to distinguish from septic shock on clinical grounds. Patients with adrenal crisis often have shock and abdominal symptoms (tenderness, nausea, vomiting) and may have fever. In addition, weakness, fatigue, lethargy, and confusion are common. Patients may have hyponatremia and hyperkalemia suggesting adrenal insufficiency. If adrenal insufficiency is suspected, testing of adrenal function should be initiated without delay.
Obstructive shock Characterized by hypotension, tachycardia, and low cardiac output and may mimic septic shock. Causes of obstructive shock include cardiac tamponade, pulmonary embolism, and tension pneumothorax. All of these diagnoses are life- threatening and should be excluded without delay.
risk of death as determined by a severity-of-illness scoring system such as APACHE II >25 (Acute Physiology and Chronic Health Evaluation II), or with the greatest degree of organ failure. Bleeding complications were significantly increased in patients taking aPC, with 3.5% of participants who received aPC devel- oping severe bleeding compared with 2% of participants who received placebo.
Historically, the use of corticosteroids has had mixed results in the treatment of septic shock. Initial studies of high-dose corti- costeroids found an increase in morbidity and mortality. Recently, moderate doses have been used with success. Evidence now sup- ports the use of corticosteroids (hydrocortisone 300 mg/d or equivalent) in septic shock for those patients who have relative adrenal insufficiency. This term is used to describe patients who have inadequate cortisol response to their septic condition and is defined as a random cortisol level of <15 µg/dL or a failure to increase by >9 µg/dL after administration of 250 µg of cosyn- tropin (ACTH stimulation test). Dexamethasone will not interfere with the cortisol assay and can be given until the stimulation test is completed. Corticosteroids are usually continued until the shock state is resolved and are then tapered over approximately a week. Higher doses of corticosteroids are avoided. In the absence of shock, corticosteroids are not be used in the treatment of sepsis. No benefit of corticosteroid therapy is seen in patients with a ran- dom cortisol >34 µg/dL.
Hyperglycemia and insulin resistance are common in the crit- ically ill. Following initial stabilization, blood glucose is maintained <150 mg/dL by continuous insulin infusion if glucose is otherwise difficult to control. Tight glucose control has been proven to ben- efit patients with other forms of critical illness, including diabetics
with acute myocardial infarctions or stroke, and post-surgical patients requiring mechanical ventilation, but its benefit to med- ical patients with severe sepsis has not been proven.
Deep vein thrombosis prophylaxis is given with either low- dose unfractionated heparin or low-molecular-weight heparin. Mechanical compression devices are an alternative if there is a con- traindication to anticoagulation. Stress ulcer prophylaxis is given with proton pump inhibitors or histamine-2 receptor blockers.
Book Enhancement
Go to www.acponline.org/essentials/infectious-disease-section .html to access a table of the key elements in the history and physical examination of a patient with sepsis, an algorithm on the resuscitation of a patient with sepsis, and to view an exam- ple of livedo reticularis and meningococcemia. In MKSAP for
Students 4, assess yourself with items 5-6 in the Infectious
Disease Medicinesection.
Bibliography
American College of Physicians.Medical Knowledge Self-Assessment Program (MKSAP) 14. Philadelphia: American College of Physicians; 2006.
Dellinger RP, Carlet JM, Masur H, et al.Surviving Sepsis. Campaign guidelines for management of severe sepsis and septic shock. Crit Care Med. 2004;32:858-73. [Erratum in: Crit Care Med. 2004;32:1448. Correction of dosage error in text. Crit Care Med. 2004;32:2169-70. [PMID: 15090974]
O’Brien JM Jr, Ali NA, Aberegg SK, Abraham E. Sepsis. Am J Med. 2007;120:1012-22. [PMID: 18060918]
176 • Infectious Disease Medicine
Table 3. Treatment for Sepsis Agent Notes
Crystalloids Restores intravascular volume, which is depleted in patients with severe sepsis. Improves cardiac output, organ perfusion, and mortality in severe sepsis. Commonly given as repeated rapid bolus infusions as long as the patient remains in shock or on vasopressors and continues to show a beneficial response without major adverse effects. May require 4-6 L during initial stabilization.
Antibiotic therapy (fourth- Early appropriate antibiotic therapy is associated with improved outcomes. Appropriate empiric therapy should be initiated generation cephalosporin, rapidly, even if the source of infection is unknown. A more appropriate, source-directed antibiotic selection should be extended-spectrum initiated if the source is known or becomes known. For example, add vancomycin if MRSA is suspected; add double antipseudomonal coverage with an IV fluoroquinolone or aminoglycoside if a highly resistant gram-negative pathogen is suspected; add penicillin, carbapenem) clindamycin if toxic shock syndrome is suspected; consider additional agents such as fluoroquinolones, macrolides,
tetracyclines, antifungal agents, and antiviral agents depending on the clinical presentation.
Norepinephrine Improves blood pressure and cardiac output. Associated with less tachycardia than other vasopressors with -effects. More effective than dopamine in refractory septic shock. Currently considered by many to be the first choice of vasopressors for patients with septic shock.
Dobutamine Improves cardiac output. May be used in combination with a vasopressor to increase cardiac output if it is inappropriately low. Vasopressin Improves blood pressure in patients with septic shock. Because vasopressin works on receptors other than adrenergic
receptors, it may be useful in refractory septic shock treated with high-dose adrenergic vasopressors. No randomized controlled trials exist to show a mortality benefit in this setting.
Drotrecogin alfa Replaces activated protein C, which is depleted in severe sepsis. Activated protein C has antithrombotic, profibrinolytic, anti-inflammatory, and antiapoptosis properties. Improves survival in patients with severe sepsis at high risk of death. Mild increase in the incidence of serious bleeding.