SEPSIS UPDATES

DEFINITIONS :

• Sepsis exists on a continuum of severity ranging from infection and bacteremia to sepsis and septic shock, which can lead to multiple organ dysfunction syndrome (MODS) and death.

• The definitions of sepsis and septic shock have rapidly evolved since the early 1990s .

• The systemic inflammatory response syndrome (SIRS) is no longer included in the definition since it is not always caused by infection.

DEFINITIONS :

• Systemic inflammatory response syndrome :(SIRS) criteria to identify those with sepsis has fallen out of favor since it is considered by many experts that SIRS criteria are present in many hospitalized patients who do not develop infection, and their ability to predict death is poor when compared with other scores such as the SOFA score .

• It is a form of dysregulated inflammation. It was previously defined as two or more abnormalities in T, HR, respiration, or WBC .

• SIRS may occur in several conditions related, or not, to infection. Noninfectious conditions classically associated with SIRS include autoimmune disorders, pancreatitis, vasculitis, thromboembolism, burns, or surgery.

DEFINITIONS :

• Early sepsis — Infection and bacteremia may be early forms of infection that can progress to sepsis.

• There is no formal definition of early sepsis. • Monitoring those suspected of having sepsis is critical for its

prevention.

• All patients with infection or bacteremia are at risk of developing sepsis and represent early phases in the continuum of sepsis severity:

●Infection is defined as the invasion of normally sterile tissue by organisms resulting in infectious pathology.

●Bacteremia is the presence of viable bacteria in the blood.

First International Consensus Definitions for Sepsis and Septic Shock (1991)

• In the 1991 definitions (reviewed in 2001) sepsis is defined as a systemic inflammatory response to a new infection, and severe sepsis is defined as sepsis associated with organ dysfunction, hypoperfusion, or hypotension.

• Sepsis with hypoperfusion is defined by the presence of acute circulatory failure: arterial hypotension (SBP <90 mmHg, reduced by >40 mmHg from baseline or [MAP] of <65 mmHg), or other evidence of hypoperfusion, such as serum lactate >2 mmol/L (>18 mg/dL).

• Septic shock is defined as being present when hypoperfusionpersists for at least 1 hour despite adequate fluid resuscitation and is unexplained by other causes.

Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) 2016

• Sepsis has been redefined as life-threatening organ dysfunction caused by a dysregulatedhost response to a new infection.

• Septic shock has also been redefined as a subset of sepsis in which particularly profound circulatory, cellular, and metabolic abnormalities are associated with a greater risk of mortality than with sepsis alone.

EPIDEMIOLOGY

• Incidence — In the late 1970s, it was estimated that 164,000 cases of sepsis occurred in the United States (US) each year .

• Rates are increasing

●One national database analysis of discharge records from hospitals in the US estimated an annual rate of more than 1,665,000 cases of sepsis between 1979 and 2000 .

EPIDEMIOLOGY

• Another retrospective population-based analysis reported increased rates of sepsis and septic shock from 13 to 78 cases per 100,000 between 1998 and 2009 .

• A retrospective analysis of an international database reported a global incidence of 437per 100,000 person-years for sepsis between the years 1995 and 2015.

EPIDEMIOLOGY

• In an analysis of 27 academic hospitals, between 2005 and 2014 rates of septic shock determined by clinical criteria increased from 12.8 to 18.6 per 1000 hospital admissions and mortality decreased from 55 to 51 percent .

• The increased rate of sepsis is thought to be a consequence of advancing age, immunosuppression, and multidrug-resistant infection .

• It is also likely to be due to the increased detection of early sepsis from aggressive sepsis education and awareness campaigns.

EPIDEMIOLOGY

• The incidence of sepsis varies among the different racial and ethnic groups, but appears to be highest among African-American males .

• The incidence is also greatest during the winter, probably due to the increased prevalence of respiratory infections .

• Older patients ≥65 years of age account for the majority (60 to 85 percent) of all episodes of sepsis; with an increasing aging population, it is likely that the incidence of sepsis will continue to increase in the future.

EPIDEMIOLOGY

• Pathogens :• Gram positive bacteria are most frequently identified in patients . • Cases of Gram negative sepsis remains substantial. • The incidence of fungal sepsis has increased over the past decade, but

remains lower than bacterial sepsis . • In half of cases of sepsis, an organism is not identified (culture negative

sepsis) .

• Disease severity : The severity of disease appears to be increasing . • The proportion of patients with sepsis who also had at least one

dysfunctional organ increased from 26 to 44 percent between 1993 and 2003 .

• The most common manifestations of severe organ dysfunction were acute respiratory distress syndrome, acute renal failure, and disseminated intravascular coagulation .

ETIOLOGY

• Causative agents vary significantly depending on the region, hospital size, season, and type of unit (neonatal, transplantation, oncology, or haemodialysisunits).

• Pathogenic organisms are identified in only around half of cases of sepsis.Where organisms are identified, bacteria (gram-positive and gram-negative) are identified as the causative organism in approximately 90% of cases, with gram-positive bacteria and fungal infections increasing in frequency.

ETIOLOGY

• Since the mid-1980s, the frequency of gram-positive sepsis (mainly caused by Staphylococcus aureus, coagulase-negative staphylococci, enterococci, and streptococci) has surpassed that of gram-negative sepsis (mainly caused by Enterobacteriaceae, especially Escherichia coli and Klebsiella pneumoniae, and by Pseudomonas aeruginosa).

• However, E coli remains the most prevalent pathogen causing sepsis.

• Some experts believe that the host response to some viral infections so closely mimics sepsis that it should be considered .

ETIOLOGY

• In the UK, a study in sepsis published in November 2015 highlighted that nearly 75% of cases of sepsis arose as a result of community-acquired infection , where the causative organisms will be sensitive, frequently endogenous bacteria.

• But the resistance patterns of organisms continue to change and can differ greatly according to region. For example, in one large multi-centre European study, >50% of isolates in ICU were methicillin-resistant S aureus(MRSA).

ETIOLOGY

• Over the last 2 decades, vancomycin-resistant enterococci(VREs) have emerged, with >10% of enterococci being VREs.

• The significant number of E coli isolates that are now resistant to amoxicillin/clavulanic acid (around 40%).

• MRSA is also increasingly prevalent in the community, with community-acquired MRSA presenting as a severe pneumonia, often with cavitation, in patients with a recent coryzal illness.

• In the UK, sepsis is the most common direct cause of maternal death, ahead of venous thromboembolism.

ETIOLOGY

• The leading fungal pathogen causing sepsis has been identified as Candida.

• In a European point-prevalence study, fungi were isolated from 17% of ICU patients with nosocomial infection.

• Fungi are more prevalent as isolates in patients with secondary or tertiary peritonitis, withCandida identified in up to 20% of patients with GI tract perforation.

• Risk factors include faecal soiling of the peritoneum, recurrent GI perforation, immunosuppressive therapy for neoplasm or in post-transplant patients, and the presence of inflammatory diseases. These patients carry a high risk of mortality.

SITE OF INFECTION

• The respiratory tract accounted for 44.4 - 60%.

• the bloodstream 20%

• abdomen 26%

• skin 14%

• urinary system 12 - 20.8 %.

• In 20% to 30% of patients, a definite source of infection is not found.

Sequential (sepsis-related) Organ Failure Assessment (SOFA)

Sequential (sepsis-related) Organ Failure Assessment (SOFA)

• It was initially designed to sequentially assess the severity of organ dysfunction in patients who were critically ill from sepsis.

• Since multiple organ dysfunction is common in critically ill patients, it has since been used to predict mortality in those with organ failure from other causes including those with acute liver failure from acetaminophen overdose, chronic liver failure , and cancer, as well as in patients who have undergone cardiac surgery or hematopoietic stem cell transplant .

Sequential (sepsis-related) Organ Failure Assessment (SOFA)

• SOFA uses simple measurements of major organ function to calculate a severity score. The scores are calculated 24 hours after admission to the ICU and every 48 hours thereafter (thus, the term "Sequential" Organ Failure Assessment).

• The mean and the highest scores are most predictive of mortality.

• Scores that increase by about 30 percent are associated with a mortality of at least 50 %.

Sequential (sepsis-related) Organ Failure Assessment (SOFA)

• The SOFA severity score is based upon the following measurements of organ function :

●Respiratory system – the ratio of arterial oxygen tension to fraction of inspired oxygen (PaO2/FiO2)

●Cardiovascular system – the amount of vasoactivemedication necessary to prevent hypotension

●Hepatic system – the bilirubin level

●Coagulation system – the platelet concentration

●Neurologic system – the Glasgow coma score

●Renal system – the serum creatinine or urine output

Identification of early sepsis (qSOFA)

• The 2016 SCCM/ESICM task force have described this assessment score for patients outside the intensive care unit as a way to facilitate the identification of patients potentially at risk of dying from sepsis.

• This score is a modified version of the Sequential (Sepsis-related) Organ Failure Assessment score (SOFA) called the quickSOFA (qSOFA) score.

• A score ≥2 is associated with poor outcomes due to sepsis.• The qSOFA score is easy to calculate since it only has three components,

each of which are readily identifiable at the bedside and are allocated one point:●Respiratory rate ≥22/minute●Altered mentation●Systolic blood pressure ≤100 mmHg

qSOFA

• The qSOFA score was originally validated in 2016 as most useful in patients suspected as having sepsis outside of the (ICU) .

• It is validated in the emergency department (ED) and confirmed to be less valuable in the ICU setting .

• Among 879 patients presenting to the ED with suspected infection, the predictive validity of qSOFA for in hospital mortality was similar to that of the full SOFA score (3 percent mortality for qSOFA and SOFA scores less than 2 versus 24 and 18 percent mortality for qSOFA and SOFA scores greater than or equal to 2, respectively).

• In addition, qSOFA was superior to the systemic inflammatory response syndrome criteria (SIRS) .

• Further studies that demonstrate improved clinically meaningful outcomes due to the use of qSOFA compared to clinical judgement are warranted before it can be routinely used to predict in hospital mortality

qSOFA

• The SOFA score does not diagnose sepsis, identify those whose organ dysfunction is truly due to infection, or determine individual treatment strategies or individual outcome.

• The SOFA score helps identify patients, as a group, who potentially have a high risk of death from infection.

• The quick SOFA (qSOFA) score is a tool to help identify patients with early sepsis outside of the ICU.

• Patients are assigned one point each for the following clinical features which can be easily measured at the bedside: RR ≥22/min, altered mentation, and SBP ≤100 mmHg.

• Patients with two or more of these features were reported to have a poor outcomes from sepsis.

qSOFA

• Sepsis – Sepsis is now defined as life-threatening organ dysfunction caused by a dysregulated host response to infection.

• As an organ dysfunction score, SOFA can be used to identify those whose organ dysfunction is "life-threatening" such that an increase in the SOFA score ≥2 is associated with a mortality of ≥10 percent.

• Septic shock – Patients with a SOFA score ≥2 who also have a vasopressor requirement and an elevated lactate >2 mmol/L (>18 mg/dL)despite adequate fluid resuscitation have a predicted mortality of 40 percent.

qSOFA

• There are no clear guidelines to help the clinician identify the presence of infection or to causally link an identified organism with sepsis.

• The clinician is reliant upon clinical suspicion derived from the signs and symptoms of infection as well as supporting radiologic and microbiologic data and response to therapy.

• The term severe sepsis, which originally referred to sepsis that was associated with tissue hypoperfusion (eg, elevated lactate, oliguria) or organ dysfunction (eg, elevated creatinine, coagulopathy) , is no longer used since the 2016 sepsis and septic shock definitions include patients with evidence of tissue hypoperfusion and organ dysfunction.

qSOFA

• Septic shock — Septic shock is a type of vasodilatory or distributive shock.

• Septic shock is defined as sepsis that has circulatory, cellular, and metabolic abnormalities that are associated with a greater risk of mortality than sepsis alone .

• Clinically, this includes patients who fulfill the criteria for sepsis who, despite adequate fluid resuscitation, require vasopressors to maintain a mean arterial pressure (MAP) ≥65 mmHg and have a lactate >2 mmol/L (>18 mg/dL).

• Per predictions from the SOFA score, patients who fulfill these criteria for septic shock have a higher mortality than those who do not (≥40 versus ≥10 percent).

Multiple organ dysfunction syndrome

• (MODS) refers to progressive organ dysfunction in an acutely ill patient, such that homeostasis cannot be maintained without intervention.

• It is at the severe end of the severity of illness spectrum of both infectious (sepsis, septic shock) and noninfectious conditions (eg, SIRS from pancreatitis).

• MODS can be classified as primary or secondary:●Primary MODS is the result of a well-defined insult in which

organ dysfunction occurs early and can be directly attributable to the insult itself (eg, renal failure due to rhabdomyolysis).●Secondary MODS is organ failure that is not in direct response to the insult itself, but is a consequence of the host's response (eg, acute respiratory distress syndrome in patients with pancreatitis).

Multiple organ dysfunction syndrome

• There are no universally accepted criteria for individual organ dysfunction in MODS. However, progressive abnormalities of the following organ-specific parameters are commonly used to diagnose MODS and are also used in scoring systems (eg, SOFA ) to predict ICU mortality

• ●Respiratory – Partial pressure of arterial oxygen (PaO2)/fraction of inspired oxygen (FiO2) ratio

• ●Hematology – Platelet count• ●Liver – Serum bilirubin• ●Renal – Serum creatinine (or urine output)• ●Brain – Glasgow coma score• ●Cardiovascular – Hypotension and vasopressor requirement• In general, the greater the number of organ failures, the higher the

mortality, with the greatest risk being associated with respiratory failure requiring mechanical ventilation.

RISK FACTORS

• The risk factors for septic shock were the fifth leading cause of years of productive life lost due to premature mortality . Risk factors for sepsis include the following :

• Intensive care unit admission – Approximately 50 percent of intensive care unit (ICU) patients have a nosocomial infection .

• Bacteremia – Patients with bacteremia often develop systemic consequences of infection. In a study of 270 blood cultures, 95 percent of positive blood cultures were associated with sepsis, or septic shock .

• Advanced age (≥65 years) – is an independent predictor of mortality due to sepsis.

• Immunosuppression – Comorbidities that depress host-defense (eg, neoplasms, renal failure, hepatic failure, AIDS, asplenism) and immunosuppressant medications are common among patients with sepsis, or septic shock.

RISK FACTORS

• Diabetes and cancer – Diabetes and some cancers may alter the immune system, result in an elevated risk for developing sepsis, and increase the risk of nosocomial sepsis.

• Community acquired pneumonia – Severe sepsis (as defined by the old definition) and septic shock develop in approximately 48 and 5 percent, respectively, of patients hospitalized with community-acquired pneumonia .

• Previous hospitalization – Hospitalization is thought to induce an altered human microbiome, particularly in patients who are treated with antibiotics. Previous hospitalization has been associated with a three-fold increased risk of developing sepsis in the subsequent 90 days . Patients with hospitalizations for infection-related conditions, especially Clostridium difficile infection, are at greatest risk.

RISK FACTORS

• Genetic factors – genetic factors can increase the risk of infection.

• Genetic studies of susceptibility to infection have initially focused on defects of antibody production, or a lack of T cells, phagocytes, natural killer cells, or complement. Recently, genetic defects have been identified that impair recognition of pathogens by the innate immune system, increasing susceptibility to specific classes of microorganisms .

CLINICAL PRESENTATION

• Symptoms and signs : are nonspecific but may include the following:

• ●Symptoms and signs specific to an infectious source (eg, SX of pneumonia, pain and purulent exudate in a surgical wound may suggest an underlying abscess).

• ●Arterial hypotension (eg, [SBP] <90 mmHg, [MAP] <70 mmHg, an SBP decrease >40 mmHg, or less than two standard deviations below normal for age).

• A sphygmomanometer may be unreliable in hypotensive patients, an arterial catheter may be needed.

• ●Temperature >38.3 or <36ºC.• ●Heart rate >90 beats/min or more than two SD above the normal value for age.• ●Tachypnea, respiratory rate >20 breaths/minute.

• ●Signs of end-organ perfusion:• •Warm, flushed skin may be present in the early phases of sepsis. As sepsis

progresses to shock, the skin may become cool due to redirection of blood flow to core organs.

• Decreased capillary refill, cyanosis, or mottling may indicate shock.

CLINICAL PRESENTATION

• •Additional signs of hypoperfusion include altered mental status, obtundation or restlessness, and oliguria or anuria.

• •Ileus or absent bowel sounds are often an end-stage sign of hypoperfusion.

• These findings may be modified by preexisting disease or medications. As examples, older patients, diabetic patients, and patients who take beta-blockers may not exhibit an appropriate tachycardia as blood pressure falls.

• Younger patients frequently develop a severe and prolonged tachycardia and fail to become hypotensive until acute decompensation later occurs, often suddenly.

• Patients with chronic hypertension may develop critical hypoperfusion at a higher blood pressure than healthy patients (ie, relative hypotension).

Laboratory signs• Nonspecific and may be associated with

abnormalities due to the underlying cause

• Leukocytosis or leukopenia

• Normal WBC with >10% immature forms.

• Hyperglycemia

• CRP> standard deviations above normal

• Hypoxemia PAO2/FIO2 <300

• Acute oliguria

• Cr increase >0.5 mg/dl

• Coagulation abn INR >1.5 OR APTT>60

• Thromboytopenia <100.000/microl

Laboratory signs

• ●Hyperbilirubinemia (plasma total bilirubin >4 mg/dL or 70 micromol/L).

• ●Adrenal insufficiency (eg, hyponatremia, hyperkalemia), and the euthyroid sick syndrome can also be found in sepsis.

• ●Hyperlactatemia (An elevated serum lactate (eg, >2 mmol/L) can be a manifestation of organ hypoperfusionin the presence or absence of hypotension and is an important component of the initial evaluation, since not readily distinguish sepsis from nonseptic systemic inflammation .

• elevated lactate is associated with poor prognosis .• A serum lactate level ≥4 mmol/L is consistent with, but not

diagnostic of, septic shock.

Laboratory signs

• ●Plasma procalcitonin more than two standard deviations above the normal value (not routinely performed in many centers) –Elevated serum procalcitonin levels are associated with bacterial infection and sepsis .

• Evidence for the prognostic value of procalcitonin is unclear and its use in the identification of sepsis is excluded from many guidelines.

• Combined changes in procalcitonin and lactate levels may be highly predictive of outcome between 24 and 48 hours, and may aid prognostication and the decision to reduce duration of antimicrobial therapy.

• Seldom used in practice.

CLINICAL PRESENTATION

• Imaging — non specific except those associated with infection in a specific site (eg, pneumonia on chest radiography, fluid collection on computed tomography of the abdomen).

• Microbiology — +ve culture is highly supportive of the diagnosis of sepsis but is not necessary.

• A culprit organism is frequently not identified in up to 50 percent of patients who present with sepsis nor is a positive culture required to make a decision regarding treatment with empiric antibiotics.

DIAGNOSIS

• Its a constellation of clinical, laboratory, radiologic, physiologic, and microbiologic data is typically required for the diagnosis of sepsis and septic shock.

• The diagnosis is often made empirically at the bedside upon presentation, or retrospectively when followup data returns (eg, positive blood cultures in a patient with endocarditis) or a response to antibiotics is evident.

• The identification of a culprit organism, although preferred, is not always feasible since in many patients no organism is ever identified.

• In some patients this may be because they have been partially treated with antibiotics before cultures are obtained.

• PACs are difficult to interpret and rarely placed in patients with suspected sepsis.

Management of sepsis

• The early administration of fluids and antibiotics is the cornerstone of management for patients with sepsis and septic shock.

• Therapeutic priorities for patients with sepsis or septic shock include:●Early initiation of supportive care to correct physiologic abnormalities, such as hypoxemia and hypotension .●Distinguishing sepsis from systemic inflammatory response syndrome (SIRS) because, if an infection exists, it must be identified and treated as soon as possible .

• This may require appropriate antibiotics as well as a surgical procedure (eg, drainage).

Management of sepsis

• EARLY MANAGEMENT — The first priority is stabilization of their airway and breathing. Next, perfusion to the peripheral tissues should be restored and antibiotics administered .

• Stabilize respiration — Supplemental oxygen should be supplied to all patients with sepsis and oxygenation should be monitored continuously with pulse oximetry.

• Intubation and mechanical ventilation may be required to support the increased work of breathing that typically accompanies sepsis, or for airway protection since encephalopathy and a depressed level of consciousness frequently complicate sepsis .

• Chest radiographs and arterial blood gas analysis should be obtained following initial stabilization. These studies are used in combination with other clinical parameters to diagnose acute respiratory distress syndrome (ARDS), which frequently complicates sepsis.

Assess perfusion

• Clinical signs of impaired perfusion include the following:• ●Hypotension – Hypotension is the most common

indicator that perfusion is inadequate ( [SBP] <90 mmHg, mean arterial pressure <70 mmHg, decrease in SBP >40 mmHg)., an arterial catheter may be inserted if blood pressure is labile or restoration of arterial perfusion pressures is expected to be a protracted process .

• Attempts to insert an arterial line should not delay the prompt management of shock.

• ●Signs of poor end-organ perfusion

• ●Elevated lactate .

Restore perfusion

• Establish venous access — Venous access should be established as soon as possible in patients with suspected sepsis.

• pulmonary artery catheters (PACs) should not be used in the routine management of patients with severe sepsis or septic shock.

• PACs increase complications and have not been shown to improve outcome .

• Interventions to restore perfusion — The rapid restoration of perfusion is predominantly achieved by the administration of intravenous fluids, usually crystalloids.

• Modalities such as vasopressor therapy, inotropic therapy, and blood transfusion are added, depending on the response to fluid resuscitation, evidence for MI, and presence of anemia.

Goals of initial resuscitation

• The goal of fluid resuscitation is early restoration of perfusion to prevent or limit multiple organ dysfunction, as well as to reduce mortality.

• The term "early goal-directed therapy" (EGDT) refers to the administration of intravenous fluids within the first six hours of presentationusing physiologic targets to guide fluid management.

• EGDT has gained widespread acceptance in clinical practice but the optimal targets are unknown.

Goals of initial resuscitation

• Early goal-directed therapy targets :

• Mean arterial pressure (MAP) ≥65 mmHg (MAP = [(2 x diastolic) + systolic]/3)

• Urine output ≥0.5 mL/kg/hour

• Static or dynamic predictors of fluid responsiveness, eg, CVP 8 to 12 mmHg or the radial artery pulse pressure (dynamic measurement).

• Central venous (superior vena cava) oxyhemoglobin saturation (ScvO2) ≥70 percent (when central access is available) or mixed venous oxyhemoglobin saturation (SvO2) ≥65 percent (if a pulmonary artery catheter is being used).

Goals of initial resuscitation

• Lactate clearance should be followed as a target in patients with sepsis to ensure a trend that demonstrates adequate clearance with therapy.

• The lactate clearance is defined by the equation [(initial lactate - lactate >2 hours later)/initial lactate] x 100.

• The lactate clearance and interval change in lactate over the first 12 hours of resuscitation has been evaluated as a potential marker for effective resuscitation.

Goals of initial resuscitation• ●Other – Dynamic indices have been studied as a

potential target to guide fluid management in sepsis.

• Respiratory changes in the vena caval diameter, radial artery pulse pressure, aortic blood flow peak velocity, and brachial artery blood flow velocity are considered dynamic hemodynamic measures.

• Dynamic measures are more accurate predictors of fluid responsiveness than static measures, as long as the patients are in sinus rhythm and passively ventilated with a sufficient tidal volume.

Goals of initial resuscitation

• For actively breathing patients or those with irregular cardiac rhythms, an increase in the cardiac output in response to a passive leg-raising maneuver (measured by echocardiography, arterial pulse waveform analysis, or pulmonary artery catheterization) is a sensitive and specific predictor of fluid responsiveness .

• Large randomized studies will be needed its routine recommendation.

Intravenous fluids

• Fluid therapy should be administered in well-defined (eg, 500 mL), rapidly infused boluses .

• Volume status, tissue perfusion, blood pressure, and the presence or absence of pulmonary edema must be assessed before and after each bolus.

• Intravenous fluid challenges can be repeated until blood pressure and tissue perfusion are acceptable, pulmonary edema ensues, or fluid fails to augment perfusion.

• Careful monitoring is essential because patients with sepsis may develop noncardiogenic pulmonary edema ( [ARDS]).

Intravenous fluids

• Fluid overload is common in patients with sepsis and is associated with the increased performance of medical interventions (eg, diuresis, thoracentesis).

• The effect of fluid overload and such interventions on mortality and functional recovery is unclear .

• while the early, aggressive fluid therapy is appropriate in sepsis and septic shock, fluids may be unhelpful or harmful when the circulation is no longer fluid-responsive.

Intravenous fluids

• In patients with sepsis, intravascular hypovolemia is typical and may be severe, requiring rapid fluid resuscitation.

• Volume — The optimal volume of resuscitative fluid is unknown. • Several studies of early goal directed therapy reported

intravenous fluid infusions targeted to physiologic endpoints and resulted in volumes ranging from 3 to 5 liters.

• Initial bolus : (20-30 ML/KG)

• Rapid, large volume infusions of intravenous fluids are indicated as initial therapy for severe sepsis or septic shock, unless there is coexisting clinical or radiographic evidence of heart failure.

Choice of fluid

• Evidence from randomized trials and meta-analyses have found no convincing difference between using albumin solutions and crystalloid solutions (eg, normal saline, Ringer’s lactate) in the treatment of sepsis or septic shock, but they have identified potential harm from using pentastarch or hydroxyethyl starch rather than a crystalloid solution .

• Its recommended to use a crystalloid solution instead of albumin solution because of the lack of clear benefit and higher cost of albumin.

• Giving a sufficient quantity of intravenous fluids rapidly and targeting appropriate goals is more important than the type of fluid chosen.

Vasopressors

• Vasopressors are second line agents in the treatment of sepsis and septic shock; we prefer intravenous fluids as long as they increase perfusion without seriously impairing gas exchange .

• Intravenous vasopressors are useful in patients who remain hypotensive despite adequate fluid resuscitation or who develop cardiogenic pulmonary edema.

• In most patients with septic shock,Its prefer to use norepinephrine

• phenylephrine (a pure alpha-adrenergic agonist) is useful when tachycardia or arrhythmias preclude the use of agents with beta-adrenergic activity (eg, norepinephrine).

Initial resuscitation

• There is conflicting evidence on the use of additional therapies, such as inotropic therapy or red blood cell transfusion.

• These are targeted at increasing the cardiac output to improve tissue perfusion and thereby raise the central venous (superior vena cava) oxyhemoglobin saturation toward normal (ScvO2 ≥70 percent).

• Their use should be limited to those with refractory shock in whom the ScvO2 remains <70 percent after optimization of intravenous fluid and vasopressortherapy.

Initial resuscitation

• Inotropic therapy — A trial of inotropic therapy may be warranted in patients who have refractory shock who also have diminished cardiac output .

• Inotropic therapy should not be used to increase the cardiac index to supranormal levels .

• Dobutamine is the usual inotropic agent . At low doses, dobutamine may cause the blood pressure to decrease because its peripheral effects can dilate the systemic arteries.

• However, as the dose is increased, blood pressure usually rises because cardiac output increases out of proportion to the fall in peripheral vascular resistance.

Initial resuscitation

• Red blood cell transfusions — red blood cell transfusion is reserved for patients with a hemoglobin level ≤7 g /dl. Exceptions include suspicion of concurrent hemorrhagic shock or active myocardial ischemia.

• No differences in the outcomes and adverse effects between the restrictive transfusion strategy (goal HB >7 g/dL) and the liberal strategy (the HB ≤9 g/dL ).

• Data from randomized studies of EGDT that use RBC transfusion as part of the protocol for treating patients with sepsis are conflicting. While one trial initially reported a mortality benefit from EGDT that included transfusing patients to a goal hematocrit >30 (hemoglobin level 10 g/dL) , two similarly designed studies published since then reported no benefit to this strategy .

CONTROL OF THE SEPTIC FOCUS

• Prompt identification and treatment of the primary site or sites of infection are essential .

• This is the primary therapeutic intervention, with most other interventions being purely supportive. Antibiotics should be administered within the first six hours of presentation or earlier.

• Identification of the septic focus — A careful history and physical examination may yield clues to the source of sepsis and help guide microbiologic evaluation . As an example, sepsis arising after trauma or surgery is often due to infection at the site of injury or surgery.

• The presence of a urinary or vascular catheter increases the chances that these are the source of sepsis.

CONTROL OF THE SEPTIC FOCUS

• Gram stain of material from sites of possible infection may give early clues to the etiology of infection while cultures are incubating.

• Urine should be routinely analyzed via dipstick for leukocyte esterase, Gram stained, and cultured; sputum should be examined in a patient with a productive cough; and an intra-abdominal collection in a postoperative patient should be percutaneously sampled under ultrasound or other radiologic guidance.

• Blood should be drawn from two distinct venipuncture sites and inoculated into standard blood culture media (aerobic and anaerobic). For patients with a vascular catheter, blood should be obtained both through the catheter and from another site .

• If invasive candida or aspergillus infection is suspected, serologic assays for 1,3 beta-D-glucan, galactomannan, and anti-mannan antibodies, if available, may provide early evidence of these fungal infections.

Antimicrobial regimen

• Intravenous antibiotic therapy should be initiated within the first six hours or earlier (eg, within one hour), after obtaining appropriate cultures, since early initiation of antibiotic therapy is associated with lower mortality .

• The choice of antibiotics can be complex and should consider the patient's history (eg, recent antibiotics received , comorbidities, clinical context (eg, community- or hospital-acquired), Gram stain data, and local resistance patterns .

Antimicrobial regimen

• Poor outcomes are associated with inadequate or inappropriate antimicrobial therapy (ie, treatment with antibiotics to which the pathogen was later shown to be resistant in vitro) .

• They are also associated with delays in initiating antimicrobial therapy, even short delays (eg, an hour).

• When the potential pathogen or infection source is not immediately obvious, broad-spectrum antibiotic coverage directed against both gram-positive and gram-negative bacteria (eg, Staphlococcus aureus, Klebsiellapneumoniae, Streptocuccus pneumoniae).

Antimicrobial regimen

• Staphylococcus aureus is associated with significant morbidity if not treated early in the course of infection . There is growing recognition that (MRSA) is a cause of sepsis not only in hospitalized patients, but also in community dwelling individuals without recent hospitalization.

• It is recommend that severely ill patients presenting with sepsis of unclear etiology be treated with intravenous vancomycin (adjusted for renal function) until the possibility of MRSA sepsis has been excluded.

• Potential alternative agents to vancomycin (eg, daptomycin for non-pulmonary MRSA, linezolid, ceftaroline) should be considered for patients with refractory or virulent MRSA, or a contraindication to vancomycin.

Antimicrobial regimen

• If Pseudomonas is an unlikely pathogen: combining vancomycin with one of the following:

• ●Cephalosporin, 3rd generation (eg, ceftriaxone or cefotaxime) or 4th generation (cefepime ), or

• ●Beta-lactam/beta-lactamase inhibitor (eg, piperacillin-tazobactam, ticarcillin-clavulanate), or

• ●Carbapenem (eg, imipenem or meropenem)

• If Pseudomonas is a possible pathogen :combining vancomycin with two of:• ●Antipseudomonal cephalosporin (eg, ceftazidime, cefepime), or• ●Antipseudomonal carbapenem (eg, imipenem, meropenem), or• ●Antipseudomonal beta-lactam/beta-lactamase inhibitor (eg, piperacillin-

tazobactam, ticarcillin-clavulanate), or• ●Fluoroquinolone with good anti-pseudomonal activity (eg, ciprofloxacin), or• ●Aminoglycoside (eg, gentamicin, amikacin), or• ●Monobactam (eg, aztreonam)

Antimicrobial regimen

• Selection of two agents from the same class, for example, two beta-lactams, should be avoided.

• local susceptibility patterns.• After culture results and antimicrobial susceptibility data

return:therapy be pathogen- and susceptibility-directed, even if there has been clinical improvement while on the initial antimicrobial regimen.

• In patients with gram negative pathogens, its recommend use a single agent with proven efficacy and the least possible toxicity, except in patients who are either neutropenic or whose sepsis is due to a known or suspected Pseudomonas infection .

Antimicrobial regimen

• The duration of therapy is typically 7 to 10 days, although longer courses may be appropriate in patients who have a slow clinical response, an undrainable focus of infection, or immunologic deficiencies .

• In patients who are neutropenic, antibiotic treatment should continue until the neutropenia has resolved or the planned antibiotic course is complete, whichever is longer.

• In non-neutropenic patients in whom infection is thoroughly excluded, antibiotics should be discontinued to minimize colonization or infection with drug-resistant microorganisms and superinfection with other pathogens.

Anti-fungal regimens

• Invasive fungal infections occasionally complicate the course of critical illness in non-neutropenic patients, especially when the risk factors are present: surgery, parenteral nutrition, prolonged antimicrobial treatment, septic shock or multisite colonization with Candida spp.

• However, studies do not support the routine use of empiric antifungals in this population.

• Several empirical anti-fungal treatments have been studied:• Untargeted empiric antifungal therapy possibly reduced fungal

colonization and the risk of invasive fungal infection but did not reduce all-cause mortality.

• The routine administration of empirical antifungal therapy is not generally warranted in non-neutropenic critically-ill patients.

ADDITIONAL THERAPIES

• Glucocorticoids : most likely to be beneficial in patients who have severe septic shock (defined as a systolic blood pressure <90 mmHg) that is unresponsive to adequate fluid resuscitation and vasopressor administration.

• Nutrition :• Nutritional support improves nutritional outcomes in critically ill

patients, such as body weight and mid-arm muscle mass. • However, it is uncertain whether nutritional support improves important

clinical outcomes (eg, duration of mechanical ventilation, length of stay, mortality), or whether there is a validated role for specific supplements.

• Venous thromboembolism prophylaxis• Intensive insulin therapy : The targeted blood glucose levels between

140 and 180 mg/dL (7.7 to 10 mmol/L). • External cooling or antipyretics — Controlling fever during sepsis and

septic shock has potential benefits and adverse effects, the net effects of which are uncertain.

Potential therapy

• A number of potential therapies for sepsis appear promising in animal models, but have not yet been adequately studied in humans.

• These include toll-like receptor antagonists and neutralizing antibodies, talactoferrin, interferon gamma, macrophage migration inhibition factor neutralizing antibody, and a synthetic peptide that inhibits bacterial superantigen-induced expression of certain proinflammatory genes.

• Other potential therapies for sepsis have been studied in humans, but have provided conflicting results and require additional investigations to clarify their effects.

• These include polyclonal intravenous (IVIG), hemoperfusion through adsorptive materials or membranes, plasma exchange, whole blood exchange, coupled plasma filtration adsorption, (GM-CSF), hemofiltration, anticoagulants, naloxone, pentoxifylline, and statins.

• Potential therapies that require further validation of benefit in patients with septic shock include therapy with the short-acting beta blocker,esmolol.

In-hospital morbidity and mortality

• Sepsis has a high mortality rate. Rates depend upon how the data are collected but estimates range from 10 to 52 percent

• Sepsis is responsible for 6 percent of all deaths but may be higher. Mortality rates increase linearly according to the disease severity of sepsis .

• In one study, the mortality rates of SIRS, sepsis, and septic shock were 7, 16, and 46 percent, respectively . In another study, the mortality associated with sepsis was ≥10 percent while that associated with septic shock was ≥40 percent .

• Mortality appears to be lower in younger patients (<44 years) without comorbidities (<10 %)

• Several studies have reported decreasing mortality rates over time.• Patients admitted with sepsis also developed more ICU-acquired

infections including infection with opportunistic pathogens, hinting at possible immune suppression.

Long-term prognosis

• Following discharge from the hospital, sepsis carries an increased risk of death (up to 20 percent) as well as an increased risk of further sepsis and recurrent hospital admissions (up to 10 percent are readmitted).

• Most deaths occur within the first six months but the risk remains elevated at two years . Patients who survive sepsis are more likely to be admitted to acute care and/or long term care facilities in the first year after the initial hospitalization, and also appear to have a persistent decrement in their quality of life .

• The most common diagnoses associated with readmission at 90 days are heart failure, pneumonia, acute exacerbations of chronic obstructive pulmonary disease, and urinary tract infections

• Higher rates of readmission with subsequent infection and sepsis may be associated with previous hospitalization for an infection, particularly infection with clostridium difficile

• Another database analysis reported that a previous diagnosis of sepsis was a leading cause of readmissions when compared with myocardial infarction, chronic obstructive pulmonary disease, heart failure, and pneumonia [.

• Sepsis survivors may also be at increased risk of major cardiovascular events and stroke when compared with patients hospitalized with nonsepsis diagnosis

Prognostic factors

• Clinical characteristics that impact the severity of sepsis and, therefore, the outcome include the host's response to infection, the site and type of infection, and the timing and type of antimicrobial therapy.

• Host-related — Anomalies in the host's inflammatory response may indicate increased susceptibility to severe disease and mortality. As examples, the failure to develop a fever (or hypothermia) and the development of leukopenia, thrombocytopenia, hyperchloremia, a patient's comorbidities, age, hyperglycemia, and hypocoagulability have all been associated with poor outcomes .

• Failure to develop a fever (defined as a temperature below 35.5ºC) was more common among non-survivors of sepsis than survivors (17 versus 5 percent) .Leukopenia (WBC < 4000/mm3) was similarly more frequent among non-survivors than survivors (15 versus 7 percent) in a Gram negative sepsis and a platelet count<100,000/mm3 was found to be an early prognostic marker of 28-day mortality patients with septic shock. In another retrospective analysis of critically ill septic patients, hyperchloremia (Cl ≥110 mEq/L) at 72 hours after ICU admission was independently associated with an increase in all-cause hospital mortality .

Prognostic factors

• A patient's comorbidities and functional health status are also important determinants of outcome in sepsis .

• Risk factors for mortality include new-onset atrial fibrillation , an age above 40 years , and comorbidities such as AIDS , liver disease , cancer , alcohol dependence , and/or immune suppression.

• Age is probably a risk factor for mortality because of its association with comorbid illnesses, impaired immunologic responses, malnutrition, increased exposure to potentially resistant pathogens in nursing homes, and increased utilization of medical devices, such as indwelling catheters and central venous lines .

• Admission hyperglycemia, was found in one prospective observational study of 987 patients with sepsis to be associated with an increased risk of death (hazard ratio 1.66) that was unrelated to the presence of diabetes .

• Inability to clot has also been associated with increased mortality. In one prospective study of 260 patients with sepsis, indicators of hypocoagulability using standard and functional levels of fibrinogen, were associated with a six-fold increase in the risk of death.

Site of infection

• The site of infection in patients with sepsis may be an important determinant of outcome, with sepsis from a urinary tract infection generally being associated with the lowest mortality rates .

• One study found that mortality from sepsis was 50 to 55 percent when the source of infection was unknown, gastrointestinal, or pulmonary, compared with only 30 percent when the source of infection was the urinary tract . Another retrospective, multicenter cohort study of nearly 8000 patients with septic shock reported similar results with the highest mortality in those with sepsis from ischemic bowel (78 percent) and the lowest rates in those with obstructive uropathy-associated urinary tract infection (26 percent) .

• Approximately 50 percent of patients with sepsis are bacteremic at the time of diagnosis according to one study.

Type of infection

• Sepsis due to nosocomial pathogens has a higher mortality than sepsis due to community-acquired pathogens.

• Increased mortality is associated with bloodstream infections due to methicillin-resistant staphylococcus aureus , non-candidal fungus , candida , methicillin-sensitive staphylococcus aureus , and pseudomonas , as well as polymicrobial infections .

• When bloodstream infections become severe (eg, septic shock), regardless of whether the pathogens are Gram-negative or Gram-positive bacteria ,the outcome is similar.

Prognostic factors

• Antimicrobial therapy — The early administration of appropriate antibiotic therapy (ie, antibiotics to which the pathogen is sensitive) has a beneficial impact on bacteremic sepsis .

• Adequate antibiotic therapy was associated with a 50 percent reduction in the mortality rate compared to antibiotic therapy to which the infecting organisms were resistant .

• Prior antibiotic therapy (ie, antibiotics within the past 90 days) may be associated with increased mortality, at least among patients with Gram negative sepsis .

• Restoration of perfusion — Failure to aggressively try to restore perfusion early (ie, failure to initiate early goal-directed therapy) may also be associated with mortality . A severely elevated lactate (>4 mmol/L) is associated with a poor prognosis in patients with sepsis with one study reporting a mortality of 78 percent in a population of critically ill patients, a third of whom had sepsis.

THANK YOU

• During hospital admission, sepsis may increase the risk of acquiring a subsequent hospital-related infection. One prospective observational study of 3329 admissions to the ICU reported that ICU-acquired infections occurred in 13.5 percent admissions of patients with sepsis compared with 15 percent of non-sepsis ICU admissions [73]. In patients with a sepsis admission diagnosis, secondary infections were mostly catheter-related blood stream infections (26 percent), pneumonia (25 percent), or abdominal infections (16 percent), compared with patients with non-sepsis admission where pneumonia was the most common ICU-acquired infection (48 percent). In both groups, patients who developed ICU-acquired infection were more severely ill on admission (eg, higher Acute Physiologic and Chronic Health Evaluation [APACHE] IV and Sequential Organ Failure Assessment scores and more shock on admission) and had higher mortality at day 60. However, the contribution of developing a secondary infection was small.

•Timing and duration — The early administration of fluid appears to be more important than volume or type of fluid in reducing mortality associated with sepsis. Based upon evidence from randomized studies and meta-

analyses, we favor the initiation of fluid resuscitation within sixhours of presentation. Once the targets of resuscitation are met and perfusion is restored, fluids can be reduced or stopped, and occasionally patients can be

diuresed, when necessary. Resolution of sepsis and septic shock can take as little as a few hours or can be protracted to days or weeks.

•A 2008 meta-analysis of randomized trials that initiated resuscitation targeting specific physiologic endpoints reported that compared to standard care, only trials that initiated resuscitation within 24 hours of the onset of

sepsis showed a mortality benefit (39 versus 57 percent, odds ratio 0.50, 95% CI 0.37-0.69) [66]. In contrast, analysis of randomized trials that initiated therapy more than 24 hours after the onset of sepsis found no

difference in mortality (64 versus 58 percent for standard resuscitation, odds ratio 1.16, 95% CI 0.60-2.22).•There are two possible outcomes following the interventions described above:•●Inadequate perfusion – Despite aggressive therapy, the patient may have persistent hypoperfusion and

progressive organ failure. This should prompt reassessment of the adequacy of the above therapies, antimicrobial regimen, and control of the septic focus, as well as the accuracy of the diagnosis and the possibility that

unexpected complications or coexisting problems have intervened (eg, pneumothorax following CVC insertion).•●Adequate perfusion – Patients who respond to therapy should have the rate of fluid administration reduced or

stopped, and vasopressor support weaned. Patients should also continue to have their clinical and laboratory parameters followed closely. These include blood pressure, arterial lactate, urine output, creatinine, platelet count, Glasgow coma scale score, serum bilirubin, liver enzymes, oxygenation (ie, arterial oxygen tension or

oxyhemoglobin saturation), and gut function (table 4). Reevaluation is indicated if any of these parameters worsen or fail to improve.

•Protocol-directed therapy — Protocols targeted at the use of a combination of physiologic

endpoints to guide fluid management in patients with sepsis and septic shock are common practice

[17-19,49,50,61-63]. Typically, they combine the EGDT targets (ScvO2, CVP, MAP (calculator 1) and urine output, lactate) for fluid management with

early administration of antibiotics, both within the first six hours of presentation.

•There is conflicting evidence regarding the value of protocol-based therapy for sepsis