Evolving Concepts in Sepsis and Septic Shock (Perspectives on Critical Care Infectious Diseases)

Evolving Concepts in Sepsis and Septic Shock

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When sepsis is present, an unregulated systemic response that may progress to multiple organ failures. Survivors of sepsis may have persistently compromised organ function, which may result in symptoms such as dyspnea, fatigue, depression, and impaired functional status [ 8 ].

Genetic Susceptibility to Infection and Sepsis

The term cognitive impairment refers to clinically significant abnormalities in one or more brain functions. Many critically ill patients have significant chronic neurocognitive impairments at 2 months, 6 months, 9 months, 1 year, 2 years, and up to 6 years.

The impairments improve during the first months post-hospital discharge. The economic burden is enormous: Age-adjusted rates for severe sepsis hospitalization and mortality increased annually by 8. The financial burden caused by sepsis continues to be enormous. Physician and nursing education along with the implementation of hospital screening tools have allowed for the early treatment of sepsis and severe sepsis. Nursing orientation includes recognition of sepsis as well as annual recertification. At the physician level, annual training through lectures and simulation sessions are needed.

Success is achieved with the use of screening tools that are available to the nursing staff as well as incorporation of practice alerts that are accessible to all providers. According to results of the Multiple Urgent Sepsis Therapies MUST protocol, there were improvements in outcomes in the intervention group that received algorithmbased treatment when compared to the standard therapy. In the MUST study, patients who met criteria for severe sepsis underwent a pathway of treatment that involved alerting a sepsis team, which included the ICU attending and resident, an emergency room attending and resident, and nursing bed supervisor.

In addition to alerting the key providers, this approach involved empiric antibiotics, fluid resuscitation, insulin therapy, as well as ventilation if applicable. Patients in the treatment arm were noted to have received more fluids 4. A key advancement in the management of sepsis has been linking treatment to early diagnosis through screening processes and early identification.

With the advent of the electronic medical record EMR , simple algorithms can be written to alert the provider of abnormalities in either vital sign of laboratory findings which may be an early warning sign of sepsis. Sepsis alarms notify the provider that the patient, based on numerical values screened from vital signs and laboratory findings may warrant diagnostic or therapeutic intervention Figure 1.

Shown is an example of an automated alert given in the EMR for a patient meeting the criteria for sepsis. Note that orders normally associated with septic patients are available and ready for use. Routine screening of the potentially infected seriously ill patient for severe sepsis may lead to early identification of sepsis and allow implementation of early therapy to include early administration of antibiotics, early and adequate fluid resuscitation [ 14 ].

Early identification has been documented to improve outcomes in septic patients [ 14 ]. The use of appropriate organism is sensitive antibiotics as an early intervention has been shown to have a positive effect on outcome Table 1. B Probability of hospital mortality is estimated using the generalized estimating equation population averaged logistic regression model and is based on the subject having the following characteristics: C Antibiotics administered in the first hour are the referent group and thus the odds ratio by definition is 1.

Introduction

Severely septic patients at the time of presentation are typically significantly volume depleted, and although fluid resuscitation is a mainstay in the treatment of sepsis the recommendations of which type of fluid and how much to use are debated. Crystalloids have been traditionally used as the initial resuscitation fluid in patients with septic shock. A study published in , compared cystalloids with albumin as a general resuscitation fluid in ICU patients and included a large cohort of patients.

There was no difference in outcome between the two fluids, however, subset analysis showed better outcome with albumin in patients with severe sepsis and septic shock. A subsequent meta-analysis also favored albumin. Publications comparing hetastarch with crystalloids reveal increased mortality, increased renal replacement therapy, or no difference in outcomes when hetastarch is used and therefore hetastarch is not recommended. The Surviving Sepsis Campaign recommends that when large amounts of fluids are required to maintain MAP, that albumin be added to the fluid resuscitation regimen.

Choices of cystalloids include normal saline, an unbalanced, i. Normal saline predisposes patients to hyperchloremic metabolic acidosis, with potential for adverse effects [ 18 ]. A before and after study of critically ill patients showed that balanced versus unbalanced fluid solution was associated with a lower incidence of acute kidney injury 8. Since there have not been any randomized trials to compare balanced and unbalanced solutions, no definitive answer is currently available [ 20 ].

When the pathophysiology of septic shock is considered the presence of capillary leak and venodilatation Figure 2 [ 21 ] leads to decreased blood return preload to the right ventricle and subsequently to the left ventricle. The pathophysiology of septic shock is considered the presence of capillary leak and venodilatation. Therefore, the nature of the pathophysiology of septic shock lends to the need for fluid resuscitation to reestablish intravascular volume, stroke volume and cardiac output which decreased in the early unresuscitated phase of septic shock.

The current CMS measures recommend that same amount, i. As body weight increases past ideal body weight there in increase in vascular space. However, the proportion of increase in intravascular space relateive to increase in body weight in obesity does not maintain the same relationship as is present in someone with ideal body weight. Sophisticated formulas have been created to allow one to better calculate what the intravascular space would be in obesity and morbid obesity.

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However, for the purposes of a sepsis performance improvement program the use of such a sophisticated formula is counterproductive. While the question of fluid requirements is easy to answer, the treatment itself is a little more challenging. The amount of fluids required for successful resuscitation and replacement of intravascular volume is no different for this patient from other patients.

Because the capillary leak and venous capacitance increase would be the same with the same amount of sepsis pathophysiology, this patient has the same intravascular fluid replacement needs as someone without ESRD. However, because the kidneys are non-functioning, the result of over-resuscitation with fluids must be considered, as described below. Theoretically, the patient requires the same amount of fluid therapy to reach the baseline status which is elevated filling pressures which produce benefit in allowing compensation for the cardiomyopathy with higher end-diastolic volume increasing contractile force due to the Starling principle.

This is tolerated to some degree because the lymphatic system increases its drainage capability as a compensatory mechanism. As with ESRD patients, over-resuscitation is more of a problem due to underlying cardiomyopathy. Furthermore, because further decrease in myocardial contractility occurs in the majority of patients with septic shock, this group of patients will have more cardiac dysfunction than the group of patients without cardiomyopathy at baseline and will be more likely to need or benefit from dobutamine added to norepinephrine.

In both scenarios, because the same degree of septic shock requires the same amount of fluid resuscitation but with increased risk of hypoxemia with over-resuscitation, a logical approach is to use smaller boluses of fluid, repeating again and again, while observing for any deterioration in oxygenation until fluid replacement is judged to be adequate. The problem with linking this association to cause and effect is that patients with greater severity of septic shock will by definition have greater capillary leak and greater venodilation and require greater amounts of fluid resuscitation.

Therefore, it is hard to separate out the downside of fluids with the need for high amounts of fluid resuscitation to maintain intravascular volume and hemodynamic stability in the most severe patients. This interstitial fluid if potentially problematic in lung, brain, and kidney and subacutely could lead to an impediment to organ recovery, i. Balance of vasopressors and fluids to maintain MAP. One can maintain MAP by either increasing left ventricular preload and stroke volume with more aggressive fluid resuscitation versus use of higher doses of vasopressors to achieve MAP with arteriolar and vasoconstriction.

One intervention increases MAP by increasing flow and the other intervention increases perfusion pressure with vasoconstriction. It is likely that for every patient there is an ideal mix of fluid resuscitation and vasopressors to achieve MAP. Unfortunately, in we do not know what that mixture is for any individual patient.

As one resuscitates a patient with acute kidney injury due to sepsis it is important to keep renal perfusion pressure in mind and the potential for increasing MAP should be considered in the presence of higher CVP. A study by LeDoux et al.

There was no difference in systemic oxygen metabolism, skin microcirculatory blood flow, urine output, or splanchnic perfusion as the MAP increased Table 3 [ 22 ]. Effects of perfusion pressure on tissue perfusion in septic shock. Crit Care Med ; Another study looked at variables associated with better outcome in septic shock and identified a MAP of 65 mmHg area under the curve as the strongest predictor of good outcome.

When septic shock patients continue to be hypotensive despite adequate intravascular volume repletion the hypotension must come from two potential sources, vasodilation and depressed cardiac contractility. Therefore, the optimum vasopressor would have both inotropic and vasopressor activity. Three drugs satisfy this requirement, norepinephrine, dopamine, and epinephrine. The SOAP trial published in revealed a strong trend toward better outcome with norepinephrine and increased arrhythmias with dopamine, and therefore dopamine has fallen into disfavor as a choice for vasopressor therapy.

The underlying principle, systemic induction of maintenance and repair processes by stressors, such as cytotoxic agents or radiation, seems to be a general phenomenon, as demonstrated in C. These results indicate that tolerance can be pharmaceutically enhanced and that the principle of hormesis—a general fitness benefit of low doses of a stressor—is applicable to counter infections and sepsis Over the past century, however, the predominant medical interventions against infectious diseases have involved targeting resistance mechanisms, e.

But this strategy comes at the expense of drug resistance against many classes of antibiotics Moreover, whereas this strategy has proven to be very successful against a broad range of infectious diseases, it has often failed in the treatment of sepsis Futile antibiotic therapy in sepsis is a common phenomenon, even if the pathogen is tested sensitive to the given drug.

This underlines the need for host-directed supportive therapies. In this connection, disease tolerance mechanisms emerge as therapeutic targets in the treatment of infectious diseases and offer fundamentally novel concepts in the treatment of sepsis 4 , 32 , 34 , Exploiting disease tolerance to counter sepsis also seems promising in view of increasing antibiotic resistance, as it does not generate selective pressure and cannot be opposed by antimicrobial resistance development. Thus, tolerance strategies are considered more stable 30 , Moreover, as tissue damage triggered by an excessive immune response is suggested to be the predominant cause of multi-organ failure, which results in poor disease outcome, damage control and repair mechanisms are promising targets for new therapeutic interventions.

In these tolerance settings, stabilizing organ functions has priority and pathogen eradication might be insufficient. However, unrestricted tolerance carries the risk of creating persistent reservoirs of pathogens in the host population 44 , 47 — To reduce this risk, therapeutically used tolerance responses have to be strictly controlled.

Timing and extent of tolerance induction seem of eminent importance. Pathogen persistence and dissemination might be prevented by suppressing tolerance mediators or by provoking specific immune responses. Finally, pathogen persistence mechanisms might be affected directly to clear an infection and re-achieve balanced tolerance and resistance. Immunity and cellular metabolism are intricately connected, as the proteins PI3K, Akt, mTOR, HIF1alpha, and PKC are not only well described mediators of resistance responses but also drive energy-demanding anabolic processes, including glucose storage, protein synthesis, and proliferation.

In contrast, disease tolerance is closely connected to cellular maintenance reactions, including the unfolded protein response and autophagy. Both processes are predominantly controlled by the signaling mediator AMPK. Apparently, both defense mechanisms become dysregulated during sepsis. Whereas excessive activation of resistance responses can lead to immunopathology, inappropriate disease tolerance might entail fulminant infection or long-term pathogen persistence. The interpretation of sepsis as collapsing tolerance and resistance responses obtains increasing support by recent experimental data, in which mTOR and AMPK, as their master regulators, play central roles: For example, mortality of septic mice could be drastically decreased after treatment with the specific mTOR inhibitor rapamycin 50 and the mTOR—HIF1alpha pathway is required for metabolic activation of trained monocytes Reduced mortality of septic mice by treatment with either mTOR inhibitors or AMPK activating agents could thus be interpreted as either directly or indirectly suppressing excessive resistance reactions promoted by mTOR.

However, recent studies report opposed effects.

Publication - Chapter

Under certain conditions, stimulation of AMPK by metformin significantly increases the mortality of septic mice 57 , indicating that the effects are context- and dose-dependent. The intricate connection of metabolism, resistance responses, and disease tolerance suggests a mechanism for controlled resource allocation to either immunity or repair processes. Aggravating factors, such as comorbidities or environmental stresses, contribute to pushing disease tolerance and resistance out of this delicate equilibrium. Key signal mediators connect stress responses to metabolism and can serve to explain a balance between damage and repair processes in immune cells and the majority of parenchymal cells.

We hypothesize that dysregulated signaling and metabolic functions, which govern resistance responses and disease tolerance, are the common underlying cause of septic organ failure. Whereas AMPK is considered a key mediator of disease tolerance, mTOR and connected pathways regulate resistance responses and the metabolic reprogramming connected to immune activation.

The recognition of the close interrelation between metabolism and host defense mechanisms opens new perspectives to sepsis treatment. Most notably, stimulating disease tolerance during sepsis might be a strategy to support patients in surviving septic shock. The fundamental concept of the hormetic nature of mild-to-moderate stress has been observed as a highly conserved phenomenon across kingdoms.

Applying such principles, e. However, timing and targeting of such interventions will be challenging. Manipulation of the relevant signals is likely to produce cell- and tissue-specific side effects. Hence, before signaling mediators can be used therapeutically, it will be necessary to overcome the significant hurdles posed by these multifunctional signaling molecules. Nanoparticle-based targeted drug-delivery 21 , 22 , 59 might help to specifically tackle this problem. The manipulation of key signaling pathways can be expected to significantly add to armamentarium of sepsis therapy, in particular, in the light of increasing antibiotic resistance.

All authors contributed to manuscript revision, read and approved the submitted version. MB declares that he is co-founder and share-holder of a company aiming to develop PI3K inhibitors for target-specific treatment of organ dysfunction. RW holds patents related to the therapeutic use of PI3K inhibitors. All other authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. National Center for Biotechnology Information , U. Journal List Front Immunol v.

Published online Jun This article was submitted to Inflammation, a section of the journal Frontiers in Immunology. Received Dec 18; Accepted Jun The use, distribution or reproduction in other forums is permitted, provided the original author s and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

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Abstract Development of organ dysfunction discriminates sepsis from uncomplicated infection. Introduction The advent of the new sepsis-3 definition, published in prompted a reappraisal of organ dysfunction as the hallmark of sepsis. Septic Shock, Sepsis-Related Dysoxia, and Energy Crisis Severe metabolic dysregulation and circulatory failure are central to the definition of septic shock 1 , 3 and sepsis mortality rises dramatically when there is cardiovascular impairment 8 , 9.

Open in a separate window. End Organ Failure—Insights from Systems Medicine A paradigmatic example of sepsis-related organ failure is excretory dysfunction of the liver. Altered Signaling in Sequential Stress Events and by Comorbidities Liver dysfunction also strongly challenges overall metabolic and immunological homeostasis in the critically ill and frequently promotes progression to multi-organ failure.

Therapeutic Strategies Derived from Stress Biology That tolerance to infections is not exclusively linked to the immune system was further substantiated by the finding that anthracyclines, long known as chemotherapeutic agents, attenuated lung injury in a rodent model of sepsis Outlook—Purposeful Manipulation of Signals Mediating Damage and Repair The recognition of the close interrelation between metabolism and host defense mechanisms opens new perspectives to sepsis treatment.

Conflict of Interest Statement MB declares that he is co-founder and share-holder of a company aiming to develop PI3K inhibitors for target-specific treatment of organ dysfunction. The third international consensus definitions for sepsis and septic shock Sepsis Toward an epidemiology and natural history of SIRS systemic inflammatory response syndrome. Intensive Care Med Disease tolerance as a defense strategy. Hepatic induction of cholesterol biosynthesis reflects a remote adaptive response to pneumococcal pneumonia. The role of mitochondrial dysfunction in sepsis-induced multi-organ failure.

Metabolic adaptation establishes disease tolerance to sepsis. Merx MW, Weber C. Sepsis and the heart. Hyperlactatemia is an independent predictor of mortality and denotes distinct subtypes of severe sepsis and septic shock. J Crit Care Opal SM, van der Poll T. Endothelial barrier dysfunction in septic shock. J Intern Med Survival in critical illness is associated with early activation of mitochondrial biogenesis.

Stress and mTORture signaling. Broad defects in the energy metabolism of leukocytes underlie immunoparalysis in sepsis. Nat Immunol The causes of obvious jaundice in South West Wales: Apoptotic cell death in patients with sepsis, shock, and multiple organ dysfunction. Crit Care Med Liver dysfunction and phosphatidylinositolkinase signalling in early sepsis: PLoS Med 9: The liver in sepsis: Curr Opin Crit Care Novel strategies for the treatment of sepsis.

Nat Med 9: The phosphatidylinositol 3-kinase signaling pathway exerts protective effects during sepsis by controlling C5a-mediated activation of innate immune functions. J Immunol Elevation of serum sphingosinephosphate attenuates impaired cardiac function in experimental sepsis. Sci Rep 6: Cell type-specific delivery of short interfering RNAs by dye-functionalised theranostic nanoparticles. Nat Commun 5: Cargo—carrier interactions significantly contribute to micellar conformation and biodistribution.

NPG Asia Mater 9: Circulating neutrophil dysfunction in acute liver failure. The effect of underlying clinical conditions on the risk of developing invasive pneumococcal disease in England. J Infect

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