With a few exceptions infected pancreatic necrosis , current guidelines recommend the rapid institution of source control measures following initial resuscitation in all cases where there is a definite focus of infection that is amenable to such measures. Recent advances in radiological techniques and the development of percutaneous interventions have offered what is sometimes an equally effective and less invasive surgical alternative to source control.
Procalcitonin has received significant attention over the last two decades as a biomarker for sepsis. It is a precursor of calcitonin—a regulatory hormone involved in calcium homeostasis. It is usually undetectable in healthy individuals. Although the physiological role of procalcitonin has not yet been established, it has been suggested that it is produced by hepatocytes and macrophages in response to certain inciting factors like infection, trauma, surgery, and cancer.
Evidence suggests that the procalcitonin level is a practical biomarker for the early diagnosis of sepsis but must be used in conjunction with other clinical evidence. In , the PRORATA trial demonstrated a decreased duration of antibiotic therapy in critically ill patients managed according to a procalcitonin level-guided antibiotic treatment algorithm, without a significant mortality benefit.
The lack of a benefit on mortality, duration of inpatient and ICU stay, and rates of C. As part of the Protein C Worldwide Evaluation in Severe Sepsis PROWESS trial completed in , an analysis was performed of 19 biomarkers that are associated with systemic host response in sepsis and their relation to disease severity and outcome.
Baseline levels and change in levels of these markers over the course of the disease indicated that day survival in severe sepsis is associated with decreased inflammation, endothelial injury, and thrombin generation, as well as the replenishment of anticoagulant factors. Another study that looked specifically at thyroid function tests as potential predictors of poor outcome in sepsis failed to demonstrate any prognostic effect of the thyroid function panel.
Plasma BNP concentration has been found to function as a reliable biomarker for the identification of patients developing sepsis-induced myocardial depression. At present, there is no single test that can be said to predict mortality with a high degree of sensitivity and specificity. The above described markers are still not ready to be deployed widely in various clinical settings.
As discussed above, the severity of sepsis and the outcomes in sepsis and septic shock are dependent on the nature of infection and the inflammatory response it provokes. This has led to the development of targeted agents that limit the inflammatory and coagulatory cascade while preserving their benefits.
The most well-known and widely used class of immunomodulatory agents is glucocorticoids, which have a generalized depressant effect on immune and vascular response to infection. Newer, more targeted modalities aimed at specific components of these pathways have been developed over the last two decades. Other agents including platelet activating factor PAF and IL-1 receptor antagonists have also failed to show significant benefit. A combination of vitamin C, hydrocortisone, and thiamine as an adjunctive therapy in sepsis has shown promising results in recent experimental and clinical studies.
Vitamin C is known to have antioxidant properties, hydrocortisone has a known theoretical synergistic effect with vitamin C, and thiamine prevents vitamin C crystallization at high doses. A retrospective study published in Chest in demonstrated a reduction in overall sepsis mortality 8. It was also noted to facilitate the more rapid weaning of vasopressors and prevented progression of multiorgan dysfunction, especially acute kidney injury.
However, prospective, multicenter, randomized clinical trials are still required before proper recommendations on the use of the vitamin C protocol in sepsis can be issued. However, given the promising results with what are inexpensive, relatively safe and readily available medications, further investigation is certainly warranted.
A meta-analysis of five randomized controlled trials RCTs on this subject by Liu et al. The use of polyclonal intravenous immunoglobulins IVIg has been studied over the last two decades with a number of clinical trials aimed at assessing their efficacy in sepsis and septic shock. A recent Cochrane meta-analysis of these trials has been unable to demonstrate a clear and definite mortality benefit with the use of polyclonal immunoglobulins in well-designed trials. Only the trials designated with a high-risk of bias appeared to show a mortality benefit.
Trials involving IgM-enhanced polyclonal immunoglobulin therapy did appear to show some reduction in mortality day mortality of These trials have been limited by their small size and significant heterogeneity.
The only large-scale clinical trial involving IVIg did not show any mortality benefit with its use. Based on the above, the Surviving Sepsis Campaign guidelines of recommend against the use of intravenous immunoglobulins in sepsis. Blood purification through the removal or inactivation of endotoxins and inflammatory cytokines has also been investigated to determine if it can be used as additional supportive therapy in sepsis.
The most studied method is hemoadsorption, in which blood is passed through adsorbent membranes most commonly polymyxin B for the removal of endotoxins. However, the mortality data seems to be heavily weighted by polymyxin B hemoadsorption studies from Japan. Other smaller, non-blinded trials have shown no benefit.
Other techniques of blood purification include plasma exchange in which plasma is separated from whole blood, removed, and then replaced with crystalloids and coupled plasma filtration adsorption CPFA which is a combination of plasma filtration and hemadsorption.
CPFA did not show a beneficial effect on hospital mortality or other end points like organ dysfunction in septic shock. Immunostimulation is another potential area for future drug development. Immunostimulatory therapy is predicated on the theory that sepsis and critical illness produces an immunosuppressed state and the resulting nosocomial infections contribute significantly to overall mortality.
In a small study of nine patients, Docke et al. Granulocyte colony-stimulating factor G-CSF therapy is known to augment neutrophil function and number and thereby enhance the immune defenses of the host.
However, multiple studies have found no overall benefit in G-CSF therapy in patients with pneumonia and sepsis. Sepsis remains a significant burden on health systems worldwide. However, the advances made in understanding its pathogenesis and the extensive efforts at framing guidelines for its effective management in the last 20 years exceed anything that has been done before.
There has been no magic bullet for the management of sepsis. However, measures such as prompt use of antibiotics and hemodynamic resuscitation, appropriate ventilator use, and judicious transfusion of blood products have played a significant role in decreasing morbidity and mortality. The use of newer, precision modalities like immunomodulators, while currently in a nascent stage of development, offer a promising field of inquiry.
The definition of sepsis continues to be a contested subject with the latest guidelines abandoning the previously used SIRS criteria and proposing a more complex definition based on multiorgan dysfunction and SOFA scores. It is hoped that this will improve the accuracy of sepsis diagnosis for clinical, epidemiological, and hospital coding purposes.
It remains to be seen if there will be wider adoption and implementation of these recommendations by healthcare facilities and providers. National Center for Biotechnology Information , U. Published online Mar Author information Article notes Copyright and License information Disclaimer. Email: ude. Received Sep 9; Accepted Feb This article has been cited by other articles in PMC.
Abstract There has been a significant evolution in the definition and management of sepsis over the last three decades. Definition Over the years, our understanding of the complex pathophysiology of sepsis has improved, and so has our ability to define sepsis. Table 1. Definitions of sepsis. Severe sepsis: Sepsis associated with organ dysfunction, hypoperfusion, or hypotension; hypoperfusion and perfusion abnormalities may include, but not limited to, lactic acidosis, oliguria, or an acute alteration in mental status Septic shock: Sepsis-induced, with hypotension despite adequate fluid resuscitation along with the presence of perfusion abnormalities that may include, but not limited to, lactic acidosis, oliguria, or an acute alteration in mental status; patients who are receiving inotropic or vasopressor agents may not be hypotensive at the time that perfusion abnormalities are measured.
Open in a separate window. Table 2. Pathophysiology of sepsis There has been a marked evolution in our understanding of the molecular pathobiology and immunology of sepsis. Innate immunity and inflammatory mediators The first step in the initiation of the host response to the pathogen is the activation of innate immune cells, constituted primarily by macrophages, monocytes, neutrophils, and natural killer cells. Dysregulation of hemostasis In sepsis, there is an intersection between the inflammatory and hemostatic pathways, with the simultaneous activation of both the inflammatory and the coagulation cascades.
Immunosuppression Interestingly, the initial proinflammatory state of sepsis is often superseded by a prolonged state of immunosuppression. Cellular, tissue, and organ dysfunction The underlying mechanism behind tissue and organ dysfunction in sepsis is the decreased delivery to and utilization of oxygen by cells as a result of hypoperfusion.
Management of sepsis Before , there were no evidence-based guidelines for early management of severe sepsis and septic shock. Care bundles Bundles are the group of treatments that are built around the best evidence, and they have known to produce greater benefit when implemented together than as individual therapies. Measure initial serum lactate ii. Obtain blood cultures prior to antibiotics iii.
Administer broad-spectrum antibiotics iv. Apply vasopressors for hypotension unresponsive to initial fluid resuscitation to maintain MAP more than or equal to 65 mmHg ii. Initial resuscitation Sepsis and septic shock are medical emergencies. Crystalloid solution versus colloid solution in resuscitation In sepsis, due to the release of several vasodilatory mediators, peripheral vasodilation and increased membrane permeability are observed.
Lactate clearance In sepsis, oxygen debt ensues because of the mismatch between the oxygen demand and the delivery with global tissue hypoxia. Blood transfusion in severe sepsis In sepsis, organ dysfunction is attributed to insufficient tissue perfusion and oxygen delivery.
Management of infection An essential component of the initial management of sepsis is the prompt commencement of appropriate antibiotic therapy and source control. Role of procalcitonin Procalcitonin has received significant attention over the last two decades as a biomarker for sepsis.
Markers of adverse outcome As part of the Protein C Worldwide Evaluation in Severe Sepsis PROWESS trial completed in , an analysis was performed of 19 biomarkers that are associated with systemic host response in sepsis and their relation to disease severity and outcome.
Newer modalities of treatment As discussed above, the severity of sepsis and the outcomes in sepsis and septic shock are dependent on the nature of infection and the inflammatory response it provokes. Conclusion Sepsis remains a significant burden on health systems worldwide.
References 1. Mortality related to severe sepsis and septic shock among critically Ill patients in Australia and New Zealand, — JAMA ; 13 : — National inpatient hospital costs: the most expensive conditions by payer, Statistical Brief August, Outcomes of the surviving sepsis campaign in intensive care units in the USA and Europe: a prospective cohort study.
Lancet Infect Dis ; 12 12 : — Sepsis and septic shock: a history. Crit Care Clin ; 1 : 83— Changing definitions of sepsis. Turk J Anaesthesiol Reanim ; 45 3 : — Chest ; 6 : — Crit Care Med ; 31 : — The third international consensus definitions for sepsis and septic shock Sepsis JAMA ; 8 : — Intensive Care Med ; 22 7 : — Remick DG. Pathophysiology of sepsis.
Am J Pathol ; 5 : — Host—pathogen interactions in sepsis. Lancet Infect Dis ; 8 1 : 32— Esmon CT. The interactions between inflammation and coagulation.
Br J Haematol ; 4 : — Circ Shock ; 33 3 : — Protein C degradation in vitro by neutrophil elastase. Biol Chem Hoppe Seyler ; 11 : — Plasminogen activator and plasminogen activator inhibitor I—release during experimental endotoxaemia in chimpanzees: effect of interventions in the cytokine and coagulation cascades.
Clin Sci ; 88 5 : — J Immunol ; 11 : — Shock ; 14 3 : — Lower levels of whole blood LPS-stimulated cytokine release are associated with poorer clinical outcomes in surgical ICU patients. Surg Infect ; 4 2 : — Sepsis-induced tissue hypoperfusion.
Vieillard-Baron A. Septic cardiomyopathy. Ann Intensive Care ; 1 1 : 6. Left ventricular systolic and diastolic function in septic shock. Intensive Care Med ; 23 5 : — Persistent preload defect in severe sepsis despite fluid loading: a longitudinal echocardiographic study in patients with septic shock. Chest ; 5 : — Crit Care ; 20 1 : Physiologic patterns in surviving and nonsurviving shock patients: use of sequential cardiorespiratory variables in defining criteria for therapeutic goals and early warning of death.
Arch Surg ; 5 : — A trial of goal-oriented hemodynamic therapy in critically ill patients. N Engl J Med ; 16 : — Prospective trial of supranormal values of survivors as therapeutic goals in high-risk surgical patients. Chest ; 94 6 : — Elevation of systemic oxygen delivery in the treatment of critically ill patients. N Engl J Med ; 24 : — Effect of maximizing oxygen delivery on morbidity and mortality rates in critically ill patients: a prospective, randomized, controlled study.
Crit Care Med ; 21 6 : — Multiple organ failure syndrome in the s: systemic inflammatory response and organ dysfunction. JAMA ; 3 : — Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med ; 19 : — Widespread microvascular thrombosis contributes to multi-organ failure, resulting in a progressive cycle of maladaptive immune response, dysregulated coagulation, and deepening critical illness.
Organ perfusion is impaired not only by abnormalities in macrovascular flow oxygen circulation , but also by direct effects on the microcirculation oxygen distribution and the mitochondria oxygen processing.
A complex interplay between the endothelium, vascular smooth muscle, and the cellular components of blood is largely responsible for capillary blood flow, nutrient delivery, exchange of products of cellular respiration, and coagulation and immune function. Toxic products of infection, pro-inflammatory mediators, reactive oxygen species ROS , activated host leukocytes, and inducible nitric oxide synthase all exert direct effects on vascular tone, integrity, and endothelial cell signalling, leading to increased venous capacitance and massive capillary leak.
Clinically, these contribute to impaired cardiac filling pressures that can be partially restored by volume resuscitation. However, conventional measures of fluid balance and effective circulating volume do not fully reflect the substantial extravasation of fluids due to endothelial dysfunction, which can persist beyond initial resuscitation.
Loss of normal autoregulatory function in end-organ tissue beds also contributes to maldistribution of blood flow, with hyperaemia at some sites and hypoperfusion at others. Flow limitations are only part of the problem. Taken together, these changes result in a persistent anaerobic metabolism and lactic acidosis even after the restoration of adequate circulating volume.
These microcirculatory and mitochondrial abnormalities are undetected by conventional haemodynamic measurements. Septic patients often manifest single or multiple organ failures, which share characteristic pathophysiological mechanisms.
Mortality in these patients has been shown to roughly double for each additional organ system failure. Recovery of organ failures, where possible, is largely accomplished by reversal of the underlying insult and associated host inflammatory response. Half of these cases are due to sepsis. For several reasons, the pathophysiology of septic AKI is incompletely understood. Ethical restrictions preclude widespread biopsy collection from critically ill patients, so histopathological data are limited.
More recent animal and human studies have called into question the theory that septic AKI involves renal hypoperfusion and tubular ischaemia. Septic shock is typically a hyperdynamic hypotensive state. While septic AKI is typically attributed to renal hypoperfusion, this may not actually be the case.
Animal data have revealed that hyperdynamic septic subjects often have increased renal blood flow, as the renal arterioles undergo the same dilation as the systemic vasculature. Septic AKI may therefore be misclassified, due instead to hyperaemic renal failure, with tubular cell injury and dysfunction due primarily to non-haemodynamic factors [ 10 ]. These may include the cytokines, coagulation factors, and other inflammatory and neuroendocrine mediators circulating in supranormal concentrations in septic patients.
Renal parenchymal cells express TLR, which may be directly activated by endotoxin. TNF, one of the principal inflammatory cytokines released after TLR activation, is also bound in increased quantities to renal parenchymal receptors in animals with experimentally induced septic AKI [ 10 ].
Thus, the dysfunction seen in septic AKI may result from both remote activation and local propagation. Indirect evidence for this is seen in studies of remote effects of single organ injury, for example the development of AKI in rabbits with acute respiratory distress syndrome who are ventilated with injurious tidal volumes, or the initiation of in vitro apoptosis of renal tubular cells treated with plasma from burn patients [ 11 ].
This type of crosstalk between the kidneys and remotely failing organs suggests that our concept of AKI in sepsis as primarily a problem of renal perfusion is relatively rudimentary. Renal tubular cell apoptosis is likely one of the non-haemodynamic mechanisms underlying septic AKI [ 12 ]. In contrast to ischaemic necrosis, apoptosis is triggered by intercellular signals and results in an organized sequence of steps that terminally extinguish cell function.
Prevention of this sequence of events requires more than simply restoration of renal perfusion pressure. Identification of the signals responsible for the initiation of renal tubular cell death may allow the prevention of their release or blockade of their interaction with receptors in vulnerable renal tissues. Given its exposure to both the external environment and the systemic circulation, the lung can be both a primary site of infection or suffer collateral damage during sepsis.
The extent and fragility of the pulmonary parenchyma renders it vulnerable to circulating mediators and chemical and mechanical disruption. Multiple direct and indirect inflammatory aetiologies can lead to acute pulmonary parenchymal injury, manifested by impaired alveolocapillary membrane integrity and non-cardiogenic pulmonary oedema.
With local infections, TLR activation leads to microbial clearance or, if overwhelmed, necrosis and apoptosis of parenchymal cells. This results in amplified local leukocyte activation, endothelial dysfunction, and interstitial oedema, as well as activation of platelets and coagulation factors. Progressive parenchymal dysfunction manifests as pulmonary shunt with refractory hypoxemia, contributing to multi-organ dysfunction.
Sepsis disrupts normal cardiovascular function through overlapping effects on myocardial function, vascular tone, and capillary integrity. Although commonly understood as a subtype of distributive shock, sepsis also involves features of hypovolemic and cardiogenic shock. Systemic presence of inflammatory cytokines contributes to peripheral arterial dilation, diffuse capillary leak, decreased contractility, and reflex tachycardia.
Patients generally exhibit diastolic hypotension and decreased mean arterial pressure. Myocardial dysfunction in sepsis manifests as biventricular dilation, decreased ejection fraction, diastolic dysfunction, and decreased cardiac output [ 13 ]. These reversible abnormalities are present even during the hyperdynamic phase of shock.
Increased nitric oxide generation and dysregulation of intracellular calcium flux are theorized to contribute to cardiomyocyte dysfunction, via unclear mechanisms. Initial biventricular dilation is postulated as a compensatory Frank-Starling response to decreased vascular resistance. However, as with this and other changes in myocardial function during sepsis, it is not clear which are abnormal and which may be protective e.
Both left and right ventricular function can be impaired in sepsis, the latter being further compromised by increased pulmonary vascular resistance in the case of acute lung injury. To date, most studies of myocardial dysfunction in sepsis have evaluated systolic changes. Diastolic dysfunction also occurs, but it is technically more difficult to assess via echocardiography. As with other organ systems, myocardial dysfunction is likely not simply attributable to ischaemia, illustrated by thermodilution studies demonstrating normal or even supranormal coronary flow.
Microcirculatory dysfunction is among the postulated mechanisms. Structural myocardial structural changes also occur during sepsis, including leukocyte infiltration, interstitial oedema, collagen deposition, and mitochondrial damage, with unclear reversibility and functional consequences. As elsewhere, endothelial dysfunction and TLR activation on circulating leukocytes play central roles, as do locally generated ROS.
The resultant interstitial oedema and inflammation are attributed to both leukocyte activation and the direct effects of toxic microbial products, though the degree to which each is responsible for myocardial dysfunction remains unclear.
Furthermore, mitochondrial structural and functional abnormalities are seen in human autopsy specimens, though cardiomyocyte apoptosis has thus far primarily been seen in vitro. As little as one cell layer separates normally sterile tissues from a dense collection of faecal bacteria. Translocation of these microbes or their components is thought to play a role in the initiation or perpetuation of systemic inflammation in critically ill patients.
Although the precise mechanisms remain unclear, hypomotility of the gut may contribute to this development [ 14 ]. Systemic effects of infection are known to affect gastrointestinal motility, likely due to a combination of effects on the enteric nervous system, sympathetic and vagal input, resident leukocytes, macrophages, and mast cells, and smooth muscle.
It is not known whether these occur directly or are mediated by leukocyte signalling, and little is known about the specific associated TLR pathways. Data suggest that tachypnea and altered mental status are excellent predictors of poor outcomes.
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. Primary disorders like diabetes, renal or liver failure must be treated. Drugs that 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. This book is distributed under the terms of the Creative Commons Attribution 4. Turn recording back on.
National Center for Biotechnology Information , U. StatPearls [Internet]. Search term. Affiliations 1 University of Nebraska Medical Center. Continuing Education Activity Sepsis syndromes span a clinical continuum with variable prognoses.
Introduction Sepsis syndromes span a clinical continuum with variable prognoses. Pathophysiology 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: Fever temperature higher than 38 C or hypothermia temperature less than 36 C. History and Physical 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: Fever, temperature higher than 38 C, or hypothermia, temperature lower than 36 C.
Tachycardia with a heart rate higher than 90 beats per minute in adult patients or less than two standard deviations for age in pediatric patients. Tachypnea with respiratory rate greater than 20 breaths per minute in adult patients or more than two standard deviations for age in pediatric patients.
Initial empiric anti-infective therapy should have activity against all likely pathogens and adequate penetration of source tissue. First-line vasoactive agents epinephrine in cold shock versus norepinephrine in warm shock when fluid-refractoryNote: dopamine as a first-line agent has fallen out of favor given its inhibitory effect on the HPA axis, namely prolactin and growth hormone, which can confer immunologic dysfunction [20].
Complications ARDS. Enhancing Healthcare Team Outcomes The management of septic shock is best done with an interprofessional team that includes ICU nurses. Review Questions Access free multiple choice questions on this topic. Comment on this article. References 1. Severe sepsis and septic shock: review of the literature and emergency department management guidelines. Ann Emerg Med. Infection rate and acute organ dysfunction risk as explanations for racial differences in severe sepsis.
International study of the prevalence and outcomes of infection in intensive care units. Rangel-Frausto MS. The epidemiology of bacterial sepsis. Infect Dis Clin North Am. New method of classifying infections in critically ill patients. Crit Care Med. The epidemiology of sepsis in the United States from through N Engl J Med.
Septicemia in U. Hospitals, Statistical Brief The epidemiologic characteristics, temporal trends, predictors of death, and discharge disposition in patients with a diagnosis of sepsis: A cross-sectional retrospective cohort study. J Crit Care.
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