الفهرس 
PATHOPHYSIOLOGY OF PAINOnly 14 pages are availabe for public view
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Abstract
Sepsis is defined as the presence of an infection accompanied by systemic inflammatory response syndrome. Systemic inflammatory response syndrome is defined as the presence of 2 or more of the following: temperature greater than 38°C (100.4°F) or less than 36°C (96.8°F); pulse rate greater than 90 beats/min; respiratory rate greater than 20 breaths/min (or PaCO2 less than 32mmHg); and WBC count greater than 12,000/mm3 or less than 4,000/mm3, or greater than 10% immature band forms. Severe sepsis is defined as the presence of sepsis and 1 or more organ dysfunctions. Septic shock is defined as the presence of sepsis and refractory hypotension.
The incidence of sepsis increased 3-fold between 1979 and 2000. The reasons for this growing incidence likely include an increasingly elderly population, increased recognition of disease, increased performance of invasive procedures and organ transplantation, increased use of immunosuppressive agents and chemotherapy, increased use of indwelling lines and devices, and increase in chronic diseases such as end-stage renal disease and HIV.
A series of pathogenic events are responsible for the transition from sepsis to severe sepsis/septic shock. The initial reaction to infection is a neurohumoral, generalized pro- and anti-inflammatory response. This begins with a cellular activation of monocytes, macrophages, and neutrophils that interact with endothelial cells through numerous pathogen recognition receptors.
Among the most commonly cited signs of sepsis are fever, tachycardia, dyspnea and tachypnea, and raised C-reactive protein (CRP) concentrations; other symptoms include rigors and confusion. To diagnose severe sepsis/septic shock as early as possible, it is necessary to recognize historical, clinical, and laboratory findings that are indicative of infection, organ dysfunction, and global tissue hypoxia. The presence of immune-compromising conditions and prosthetic devices such as intravenous lines, heart valves, and urinary catheters increases infection risk.
Procalcitonin is a 116 amino acid peptide that has an approximate MW of 14.5 kDa and belongs to the calcitonin (CT) superfamily of peptides. It can be divided into 3 sections including the amino terminus of the PCT region, immature calcitonin, and calcitonin carboxyl-terminus peptide-1 (CCP-1, also called katacalcin). Early in the evolution of the inflammatory response, cytokines such as TNF-α and IL-6 rise within the first 1 to 3 hours. However, these cytokines only remain elevated for up to 8 hours. Hyperprocalcitoninemia in systemic inflammation or infection occurs within 2 to 4 hours, often reaches peak concentrations in 8 to 24 hours, and persists for as long as the inflammatory process continues. The half-life of PCT is approximately 24 hours; therefore, concentrations normalize fairly quickly with the patient’s recovery.
Procalcitonin determinations have been found valuable in identifying whether inflammation following an organ transplant is due to bacterial infection or organ rejection also, Serum PCT was the best parameter to distinguish patients with acute bacterial arthritis from patients with crystal induced arthritis or rheumatoid arthritis.
Uncomplicated cardiac surgery induces a postoperative increase in serum PCT levels. Peak PCT levels are reached within 24 hours postoperatively and return to normal levels within the first week also, PCT is useful in differentiating acute graft rejection after heart and/or lung transplantation from bacterial and fungal infections. PCT levels typically remain unchanged after acute rejection but increase markedly after bacterial and fungal infections.
Serum PCT levels may be a sensitive and specific measure for early diagnosis of acute pyelonephritis and determination of the severity of renal parenchymal involvement.
PCT <0.5 ng/mL is considered normal, whereas levels >10 ng/mL are considered significantly elevated. Serum concentrations between 2 to 10 ng/mL are considered suggestive of sepsis, whereas PCT concentrations between 0.5 to 2 ng/mL indicate the possibility of sepsis but do not rule out other causes of elevated PCT.
However, not every sick patient with elevated PCT has sepsis, elevations of PCT are seen in many clinical settings, including inhalation injury, trauma, surgery, pancreatitis, heat stroke, and some cancers. Typically, PCT ranges between 2 to 3 ng/mL in these settings; however, the concentration in severe cases may climb as high as 10 to 20 ng/mL.
The use of a combination of markers often produces a screening or diagnostic test with better sensitivity and specificity than a test based on a single marker. For example, IL-6 in combination with CRP appears to be a valuable parameter in the early diagnosis of pediatric infections.
Early goal-directed resuscitation has been shown to improve survival for emergency department patients presenting with septic shock, Resuscitation is directed toward:
Central venous pressure 8–12 mmHg
Mean arterial pressure (MAP) ≥65mm Hg
Urine output ≥0.5 mL/kg/hr
Central venous (superior venacava) or mixed venous oxygen saturation≥70% or ≥65%, respectively.
Intravenous antibiotic therapy should be started as early as possible and within the first hour of recognition of septic shock and severe sepsis without septic shock. Antimicrobial regimen should be reassessed daily to prevent the development of resistance, to reduce toxicity, and to reduce costs. Appropriate cultures should be obtained before antimicrobial therapy is initiated if such cultures do not cause significant delay in antibiotic administration.
Fluid resuscitation is recommended with either natural/artificial colloids or crystalloids; Fluid resuscitation initially targets a central venous pressure of ≥8 mm Hg (12 mm Hg in mechanically ventilated patients).
Vasopressor therapy is required to sustain life and maintain perfusion in the face of life-threatening hypotension, even when hypovolemia has not yet been resolved. The titration of norepinephrine to as low as MAP 65 mmHg has been shown to preserve tissue perfusion also; dobutamine infusion should be administered in the presence of myocardial dysfunction.
Intravenous hydrocortisone should be given only to adult septic shock patients after it has been confirmed that their blood pressure is poorly responsive to fluid resuscitation and vasopressor therapy.
Once tissue hypoperfusion has resolved and in the absence of extenuating circumstances, such as myocardial ischemia, severe hypoxemia, acute hemorrhage, cyanotic heart disease, or lactic acidosis, red blood cell transfusion should occur when hemoglobin decreases to <7.0 g/dL (<70 g/L) to target a hemoglobin of 7.0 –9.0 g/dL (70–90 g/L) in adults.
For patients with suspected infections, either at admission to the intensive care unit or during their stay in the unit, Procalcitonin guided antibiotic treatment substantially lowers antibiotic exposure and is non-inferior to standard care with respect to outcomes.