Sepsis syndromes span a clinical continuum with variable prognosis. Septic shock, the most severe complication of sepsis, carries high mortality. In response to an inciting agent, pro-inflammatory and anti-inflammatory arms of the immune system are activated in concert with the activation of monocytes, macrophages, and neutrophils that interact with the endothelium through pathogen recognition receptors to elaborate cytokines, proteases, kinins, reactive oxygen species, and nitric oxide. As the primary site of this response, the endothelium not only suffers microvascular injury but also activates the coagulation and complement cascades which further exacerbate vascular injury, leading to capillary leak. This cascade of events is responsible for the clinical signs and symptoms of sepsis and progression from sepsis to septic shock. The ability to balance pro-inflammatory responses to eradicate the invading microorganism with anti-inflammatory signals set to control the overall inflammatory cascade ultimately determines the degree of morbidity and/or mortality suffered by the patient. Judicious and early antimicrobial administration, sepsis care bundle use, and early goal-directed therapies have significantly and positively impacted sepsis-related mortality. However, early identification remains the best therapeutic tool for sepsis treatment and management.
The 2009 European Prevalence of Infection in Intensive Care (EPIC II study) determined that gram-negative bacterial infections far exceed other etiologies as the most common cause of sepsis syndromes with a frequency of 62%, followed by gram-positive infections at 47%. An increase in the prevalence of the latter may be attributable to the performance of more invasive procedures and increased incidence of nosocomial infections. Predominant micro-organisms isolated in patients include Staphylococcus aureus (20%), Pseudomonas (20%), and Escherichia coli (16%). Predominant sites of infection include respiratory (42%), bloodstream (21%), and genitourinary (10%). These data need to be assessed in the context of knowing that over a third of patients never grow positive cultures.
The influence of bacterial strain and site of infection on mortality was illustrated in a large meta-analysis. In this study, gram-negative infections were overall associated with higher mortality. However, gram-positive bacteremia with Acinetobacter or pneumonia with Staphylococcus carried a 40% mortality with Pseudomonal pneumonia carrying the highest mortality at 70%.
Sepsis syndromes caused by multidrug-resistant bacterial strains (methicillin-resistant Staphylococcus (MRSA), vancomycin-resistant enterococci (VRE)) are on the rise with a current incidence of up to 25%; viruses and parasites cause far fewer cases and are identified in 2% to 4% of cases.
Risk factors that predispose to sepsis include:
Annually, the rate of this debilitating condition is rising by almost 9%. The incidence of sepsis and severe sepsis have risen over the past decade from approximately 600,000 to over 1,000,000 hospitalizations per year from 2000 through 2008. Accompanying this trend has been a rise in healthcare expenditure, making sepsis the most expensive healthcare condition in 2009, accounting for 5% of total United States hospital costs. The case-fatality for patients with sepsis has been declining due to advances in sepsis management provided by the Surviving Sepsis Campaign. The United States Nationwide Inpatient Sample (NIS) from 2009 through 2012 showed a mortality rate declined from 16.5% to 13.8%. However, severe sepsis continues to rank amongst the most common causes of death in hospitalized patients. Moreover, up to 25% of patients with severe sepsis and 50% of patients with septic shock will suffer mortality. However, overall mortality from sepsis syndromes can vary from 30% to 50%  depending on demographic factors such as age, race, sex, co-morbid conditions, and the presence of organ dysfunction. For example, in-patient mortality was predicted most by number and degree of organ injury with the strongest predictors being respiratory, cardiovascular, hepatic, and neurologic failure.
Sepsis is a clinical state that falls along a continuum of pathophysiologic states, starting with a systemic inflammatory response syndrome (SIRS) and ending in multiorgan dysfunction syndrome (MODS) before death.
The earliest signs of inflammation are heralded by the following:
The presence of two of these four clinical signs is necessary for the diagnosis of systemic inflammatory response syndrome. After that, systemic inflammatory response syndrome with an infectious source suffices the clinical definition for sepsis.
With the development of hypotension, tissue demands are not adequately met by tissue oxygenation, and the patient is now defined to be in severe sepsis. The decline in peripheral vascular perfusion and oxygenation leads to cellular and metabolic derangements, most notably a shift from aerobic respiration to anaerobic respiration with ensuing lactic acidosis. Tissue hypoperfusion may also be manifested by signs of end-organ damage, such as pre-renal azotemia or transaminitis. The difference in oxygen supply and demand can be monitored during resuscitation by trending the mixed venous oxygen saturation from a central line in the superior vena cava (SVC), when available.
When sepsis-induced hypotension remains refractory to initial management with fluid resuscitation, septic shock ensues. Septic shock is distinguished from other shock states as a distributive type of shock. The action of a combination of inflammatory mediators (histamine, serotonin, super-radicals, lysosomal enzymes) elaborated in response to bacterial endotoxins leads to a marked increase in capillary permeability and a concomitant reduction in peripheral vascular resistance. This translates not only into a reduction in afterload but also in preload from a decline in venous return from third-spacing. The resulting reduction in stroke volume is accommodated initially by an elevation in heart rate, i.e., compensated septic shock. As a result, the patient is in a hyperdynamic state that is characteristic of septic shock.
Clinically, patients, have a dynamic precordium with tachycardia and bounding peripheral pulses. They are warm to the touch and have a reduction in capillary refill (flash cap refill). This is described as warm shock. As shock progresses, elevated catecholamine production leads to an increase in peripheral vascular resistance as the body attempts to shunt blood away from non-vital tissues (gastrointestinal (GI) tract, kidneys, muscle, and skin) to the vital tissues (brain and heart). This is described as cold shock. Understanding the pathophysiology and continuum of septic shock is imperative in initiating appropriate treatment measures.
Functionally, septic shock is defined by persistent hypotension despite adequate fluid resuscitation from 60 ml/kg to 80 mL/kg of either crystalloid or colloid fluid. At this point, the initiation of appropriate vasoactive medications such as beta-adrenergic or alpha-adrenergic drugs is of utmost importance. The progression of organ dysfunction despite high-dose vasoactive administration defines the state of multi-organ dysfunction syndrome (MODS) which carries a mortality as high as 75%. While the exact circumstances predicting poor prognosis and death have been difficult to determine, immunologic dissonance (exaggerated proinflammatory response) versus immunologic paralysis (exaggerated anti-inflammatory response) have been purported to play a role.
Early Signs and Symptoms
Sepsis is defined as systemic inflammatory response syndrome plus an infectious source. Therefore, earlier on in the presentation of sepsis, patients present with the following vital sign changes:
Signs and Symptoms of Severe Sepsis Severe sepsis is defined as sepsis and end-organ dysfunction. At this stage, signs, and symptoms may include:
Patients progressing to septic shock will experience signs and symptoms of severe sepsis with hypotension. Of note, at an early "compensated" stage of shock, blood pressure may be maintained, and other signs of distributive shock might be present, for example, warm extremities, flash capillary refill (less than one second), and bounding pulses, also known as warm shock. This stage of shock, if managed aggressively with fluid resuscitation and vasoactive support, can be reversed. With the progression of septic shock into the uncompensated stage, hypotension ensues, and patients may present with cool extremities, delayed capillary refill (more than three seconds), and thready pulses, also known as cold shock. After that, with continued tissue hypoperfusion, shock may be irreversible, progressive rapidly into multiorgan dysfunction syndrome and death.
Findings in sepsis, severe sepsis, and septic shock are as follows :
Patients should be placed on continuous cardiopulmonary monitoring to allow close observation of vital signs. A thorough assessment of end-organ function and peripheral perfusion should be undertaken to determine where along the pathophysiologic continuum of sepsis they may fall. This should include a Glasgow Coma Scale (GCS) or mental status assessment, urine output measurement, or lactate/mixed venous saturation determination (with central lines). Regardless of where along the continuum patients are, all patients should have drawn a complete blood count with differential (CBC-d), source cultures (blood, urine, tracheal (if intubated), wound), and a urinalysis. Depending on the severity of presentation and age of the patient a lumbar puncture may be indicated, for example, patients with signs of encephalitis or meningitis or febrile pediatric patients under six weeks of age. The addition of C-reactive protein or procalcitonin, both acute-phase proteins, may be helpful in distinguishing viral from bacterial sepsis, with the latter showing steeper elevations in these proteins. A complete chemistry panel with liver function test, disseminated intravascular coagulation (DIC) panel, and an arterial blood gas are additional labs that may provide important information on the severity of sepsis syndrome in a patient.
At least two sets of blood cultures are recommended prior to administration of antibiotics. However, less than 40% of blood cultures are positive.
A chest x-ray may reveal signs of pneumonia or ARDS. Plain x-rays of the extremities may reveal the presence of gas in tissues if the patient has necrotizing fasciitis. Ultrasound may be used to evaluate the gallbladder. CT scan is used to assess the abdomen for abscess, bowel perforation or ischemia.
Management of Shock 
Enhancing Host Response
While central lines are not required for the resuscitation of patients with septic shock, they provide an accurate means of monitoring CVP and mixed venous oxygen. Remember that CVP and MVO2 are most accurate from a central line that lies within the right atrium; lower extremity central lines do not provide the most accurate data for monitoring these indices of resuscitation. Regarding the need for central venous access for administration of vasoactive agents, a recent study showed that both dopamine, norepinephrine, and phenylephrine at high doses could be safely administered via peripheral venous access.
Of note, early goal-directed therapy (EGDT) has not been shown to confer a survival benefit in more recent studies. All studies comparing EGDT to standard practice have shown an increase in the administration of crystalloid and packed red blood cells in the first six hours and the placement of central lines. Furthermore, survival was influenced most by the maintenance of blood pressure independent of the type of fluid or vasoactive used and not CVP or MVO2. That said, the Surviving Sepsis Campaign guidelines continue to support EGDT as the standard of practice for the management of severe sepsis and septic shock.
The placement of an arterial line becomes important in the management of vasoactive-refractory shock for close monitoring of blood pressure and tissue oxygenation status via regular blood gasses with key attention to lactate levels and pO2.
Patients with sepsis have high metabolism and thus prolonged starvation should be avoided. Early nutrition can help protect gut mucosa and prevent translocation of organisms from the GI tract into the systemic circulation.
Septic shock is a serious illness and despite all the advances in medicine, it still carries high mortality which can exceed 40%. Mortality does depend on many factors including the type of organism, antibiotic sensitivity, number of organs affected and patient age. The more factors that match SIRS, the higher the mortality. Data suggest that tachypnea and altered mental status are excellent predictors of poor outcome. Finally, prolonged use of inotropes to maintain blood pressure is also associated with adverse outcomes. Even those who survive are left with significant functional and cognitive deficits.
The management of septic shock is best done with an interprofessional team that includes ICU nurses. The key is early diagnosis and resuscitation to maintain end-organ perfusion. The type of fluid for resuscitation has little bearing on outcomes but the key is to maintain adequate perfusion pressure. Patients with sepsis are prone to many complications which have high mortality. Thus, close monitoring and prevention of these complications are vital. The primary disorders like diabetes, renal or liver failure must be treated. Drugs which affect the immune system should be discontinued. The dietitian should be consulted as there is good evidence that early enteral nutrition is beneficial. The nurse should ensure DVT and pressure sore prophylaxis. The nurse should also monitor all catheters for infection and remove those that are not needed. The pharmacists should follow culture results and ensure that the patient is on organism sensitive antibiotics. Clinicians should maintain aseptic techniques during procedures and hand washing should be practiced. The entire team should communicate with each other to ensure that the patient is receiving optimal care.
The outcomes of septic shock depend on patient age, associated comorbidities, renal function, need for dialysis, requiring mechanical ventilation and response to treatment.
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