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New Consensus Definitions for Sepsis and Septic Shock: Implications for Treatment Strategies and Drug Development?

Michael Berry 1

Brijesh V. Patel 2,3

Stephen J. Brett 3,4

1. Imperial School of Anaesthesia

2. Adult ICU, Royal Brompton and Harefield NHS Foundation Trust

3. Section of Anaesthesia, Pain Medicine and Intensive Care, Department of Surgery and Cancer, Imperial College London

4. Centre for Perioperative Medicine and Critical care Research, Imperial College Healthcare NHS Trust

Abstract:

Sepsis continues to escape a precise diagnostic definition. The most recent consensus definition, termed Sepsis-3, highlights the importance of the maladaptive and potentially life threatening host response to infection. After briefly reviewing the history and epidemiology of sepsis, we go onto describe some of the challenges encountered classifying such a heterogenous disease state. In the context of these new definitions for sepsis and septic shock, we explore current as well as potentially novel therapies and conclude by mentioning some of the controversies of this most recent framework.

Key points:

The third international consensus definitions for Sepsis and Septic Shock take into account the latest pathophysiological understanding of sepsis, highlighting the importance of the life-threatening organ dysfunction caused by a dysregulated host response to infection.

These advances in understanding the complexities of sepsis are not mirrored pharmacologically, where fluids, antibiotics and vasoactive medications continue to form the mainstay of therapy.

Sepsis-3 aims to improve both the accuracy of the nomenclature of sepsis as well as improve clinical care. Important questions remain in regards to the clinical applicability of this latest framework.

Introduction

The new Sepsis-3 consensus definitions firmly acknowledge the role of the host response to infection [1]. In this article we review the pathophysiology and epidemiology of sepsis with respect to the new definitions and explore some of the historical challenges that characterise the nomenclature of sepsis. We touch upon current and emerging therapies as well as some of the research against the backdrop of Sepsis-3. Our account concludes by highlighting some of the controversies of this new consensus framework.

Sepsis overview - pathology & epidemiology

A satisfactory clinical definition of sepsis remains elusive and it continues to be an imprecise diagnostic term since its first description by the ancient Greeks [2,3]. Etymologically sepsis means to decay or to putrefy. The language defining sepsis has been riddled by heterogeneous terminology and various criteria have been put forward attempting to facilitate early identification and allow definitive diagnosis [4].

Thus, sepsis continues to be a descriptive and varied syndrome without at present, a validated gold standard criterion or established diagnostic test, consequently leading to huge variations in reported incidence and mortality rates [5]. However, there is little doubt that sepsis is common worldwide, transcending age, geography, race or pre-existing health status [6,7,8]. The Centers for Disease Control and Prevention (CDC) has conservatively estimated the annual incidence of severe sepsis to be 50-100 cases per 100,000 persons, with absolute numbers averaging about 1,141,000 cases of sepsis in the United States for 2008 [6,8,9]. Figures for the United Kingdom have recently estimated 200,000 cases of sepsis a year [10]. Although these figures are in the context of ever increasing incidence rates internationally, they are not free of controversy. The lack of consistency in defining sepsis, organ dysfunction and septic shock, possible reporting bias fueled by incentivised coding, as well as previous under reporting make the data difficult to interpret. Complicating matters further, improvements in diagnosis and the increasing ability to care for the most critically ill patients may further explain the huge variations in sepsis incidence [1,5]. Despite the true incidence of sepsis remaining unknown there is little argument that mortality remains high with a mortality rate of 35% quoted for the United Kingdom [10,11,12]. This is mirrored by figures from the United States that put mortality between 30-50% making it the leading cause of death and morbidity in intensive care units [6,7,8]. The escalating cost of treating sepsis is measured in billions of dollars yearly in the United States alone, expenses most often incurred during weeks or month-long admissions in critical care units [8,9]. Moreover, sepsis is now being increasingly recognized to contribute to a significantly reduced quality of life in those who survive their acute illness, with neuromuscular weakness, reduced functional status, depression, anxiety and post-traumatic stress syndrome commonly reported [13]. Unlike many other epidemic diseases, treatment for sepsis is non-specific and is largely based on supportive care including oxygen, intravenous fluids, antibiotics, vasopressors, inotropes and mechanical organ support, along with surgical or radiological source control where possible. There are currently no clinically approved biological agents that modify the pathophysiology and specifically target sepsis [14].

Against this backdrop, the biology of sepsis continues to be incompletely understood. Complex pathophysiology in response to infection is at play, involving both pro- and anti-inflammatory pathways as well as a whole array of non-immunological mechanisms [15]. It is increasingly becoming clear that sepsis is an intricate syndrome characterised by the pathogen as well as the host response. Thus, sepsis is now thought of as organ dysfunction driven by a dysregulated host response secondary to infection. The advances made in understanding the pathophysiology of sepsis have been fundamental in the creation of the new Sepsis-3 guidelines. [1].

History of the sepsis definition

The difficulty of defining sepsis accurately and consistently is well documented [4,5]. In everyday clinical language the terminology surrounding sepsis is used in a whole variety of ways and is commonly used colloquially to mean severe infection or infection generally. The first real attempt to define a set of clinical parameters characterising patients with sepsis came in 1989 when Roger Bone and colleagues proposed the term sepsis syndrome (Table 1.) [4].

|Sepsis syndrome criteria |

|Hypothermia 38.3°C |

|Tachycardia >90 beats/min |

|Tachypnoea >20 breaths/min |

|Clinical evidence of an infection site |

|The presence of at least one end-organ demonstrating inadequate perfusion or dysfunction |

|Table 1. |

Following on from the sepsis syndrome concept, the American College of Chest Physicians (ACCP) and the Society of Critical Care Medicine (SCCM) convened a consensus conference in 1991 attempting to create a set of standardized definitions [16]. According to the ACCP-SCCM, infection was defined as a microbial phenomenon characterized by the invasion of microorganisms or microbial toxins into normally sterile tissues [16]. The key term, which emerged at the end of this conference was the Systemic Inflammatory Response Syndrome, known as SIRS. SIRS followed on from the sepsis syndrome using clinical values to identify physiological features consistent with inflammation considered a hallmark feature of sepsis [4,16]. The SIRS criteria were established, by consensus, as the presence of at least two of four clinical criteria (Table 2.) [16].

|Systemic inflammatory response syndrome |

|Body temperature >38°C or 90 beats/min |

|Respiratory rate >20 breaths/min or hyperventilation with a PaCO2 12,000/mm3 or 2 mmol/L (18 mg/dl) despite adequate volume resuscitation [1]. Currently no study has presented statistically significant survival benefit of one vasopressor over another. Hence, the choice of vasopressor in septic shock remains empiric [41].

A recent meta-analysis has demonstrated a 11% reduction in 28-day all cause mortality with noradrenaline compared to dopamine; dopamine demonstrating a twofold increase in arrhythmias, which may account for the difference in mortality [41,42,43]. No mortality benefit was identified in the comparison of noradrenaline and adrenaline, a finding corroborated in other head to head trials [42,44]. No statistically significant improvement in mortality was observed in a comparison between vasopressin and adrenergic vasopressors (noradrenaline, dopamine), although, an overall trend towards reduced mortality with noradrenaline was seen in all comparisons [41,45]. Most recently the VANISH study examining the use of early vasopressin versus noradrenaline again showed no improvement in mortality. However, despite not being the primary endpoint a significant reduction in use of renal replacement therapy in the vasopressin group was observed [46].

Overall, the literature is complex and should be interpreted with caution. Many trials use differing clinical outcomes and comparators, making firm conclusions about side effects, length of stay, ventilator free days etc. almost impossible. Moreover, data regarding clinical and haemodynamic measurement have been reported inconsistently, large variations in concomitant fluid administration between trials have been noted, as well as considerable heterogeneity in the source of sepsis [41, 42]. Trials investigating novel vasopressors such as Selepressin (NCT02508649) are currently eagerly awaited but are unlikely to address all the uncertainties surrounding vasopressors in sepsis [47]. Based on current trial data the surviving sepsis guidelines recommend noradrenaline as first line therapy in septic shock. [21].

Biologicals. Currently there continues to be no approved drug specifically targeting sepsis [14]. With the emerging complexities in the pathophysiology of sepsis it is highly unlikely that a single therapeutic agent will provide the magic bullet [24]. Recent advances in molecular diagnostics, biomarkers, genomics and novel pharmacological agents have hailed some promise in the research arena but are not yet clinical reality [14].

Biomarkers & molecular markers. Current diagnosis of sepsis relies on non-specific physiological criteria and microbiologically led pathogen detection. Biomarkers presently available to clinicians offer no diagnostic certainty to fundamental questions such as [48]:

• Which patients need antibiotics (infection vs inflammation)?

• Is therapy effective?

• Do these positive microbiology results represent infection or colonisation?

• How long should therapy last?

This diagnostic uncertainty has very real clinical implications potentially delaying the administration of antibiotics or increasing the overuse of antimicrobial agents [48]. Therefore, there is an increasing need for new sepsis biomarkers that can aid clinicians in rapid therapeutic decision making, risk stratification and monitoring response to therapy. It is hoped that it will not only improve management of sepsis but also drive drug development [48].

By definition, sepsis biomarkers should reflect the biology of sepsis. A large number of biomarkers have been studied in a variety of research settings and many have demonstrated some propensity to be clinically useful but invariably suffer from some drawback or other [49]. Most biomarkers can be broadly categorised into biochemical (e.g. complement, coagulation system), cellular elements (e.g. neutrophils, macrophages) and mediators (e.g. cytokines, chemokines).

Cytokines and chemokines for example have some value in the assessment of the inflammatory response but lack discriminative power to differentiate between infectious and non-infectious inflammation [48-50].

Coagulation factors (protein C, protein S, antithrombin) have been studied but are limited by the fact that these are frequently activated in other disease states such as trauma, cancer and obstetrics [50]. Soluble receptors and cell surface markers such as triggering receptor expressed on myeloid cells 1 (sTREM-1) have showed some promise but have not yet been prospectively evaluated in large trials [51].

Questions also remain around procalcitonin (PCT) and C-reactive protein (CRP), which are currently the only biomarkers in widespread clinical use. Both CRP and PCT have limited abilities to distinguish sepsis from other inflammatory conditions or to predict outcome [46-49].

Overall, more than 170 different biomarkers have been assessed for potential use in sepsis, predominantly focusing on prognostic markers as opposed to diagnostic markers. Unfortunately, none of the biomarkers are sufficiently established to be of immediate clinical use [50,51]. A combination of several sepsis biomarkers may be more effective but this requires further research [51]. Thus, the disconnect remains between the calls for early diagnosis/treatment and the current diagnostic tools available.

Novel pharmacological agents. Similarly to biomarkers there are a whole range of therapeutic agents described in the literature but none are currently in routine clinical use [14]. One of the difficulties in translating promising laboratory results into clinical benefit is related to modeling. Animal models are frequently used but poorly replicate sepsis in humans [23]. Validated and more clinically relevant animal models are needed to understand the disease process and improve the selection of specific pathophysiological mechanisms [23].

Nonetheless, there are a number of therapeutic agents, which are being trialed targeting various inflammatory pathways, bacterial toxins or the endogenous immune system and clinically applicable results are awaited by researchers as well as clinicians. Currently the ATHOS study (NCT02338843) is recruiting for a phase 3 trial looking at the use of angiotensin in catecholamine refractory shock. High dose ascorbic acid, novel IgM enriched immunoglobulin (NCT02655133) as well as L-carnitine (NCT01665092) are just some of the ongoing studies hoping to reveal new and clinically useful insights [52-54].

Finally, endotoxin (lipopolysaccharide; LPS) is perhaps the best studied and one of the most potent initiators and mediators of the host response in sepsis. A variety of approaches have been tried to target endotoxin therapeutically including extracorporeal devices to remove endotoxin. A recent press release by the company manufacturing these devices claims promising results but full publication is awaited [55].

Drugs to facilitate and maximise recovery. It is increasingly recognised that survivors of intensive care suffer from significant physical, cognitive and psychological morbidity referred to by some as the post intensive care syndrome [56]. Critical illness myopathy is a major complication and patients may face long-term disability. The pathophysiology of critical illness myopathy involves: impaired myocyte excitability due to ion channel dysfunction, mitochondrial dysfunction, proteolysis and impaired protein as well as calcium homeostasis [57]. These processes lead to disruption or loss of the contractile unit within the myocyte - a process that is exacerbated by axonal neuropathy. The pathophysiology of these mechanisms is thought to be triggered by inflammatory mediators, electrolyte and metabolic derangements, endocrine imbalances, steroids and disuse [57].

For now various non-pharmacological approaches to prevent muscle disuse are the main strategy, such as avoidance of sedation, weaning from mechanical ventilation and early mobilization. There is current interest in tackling neuromuscular loss using optimized approaches to feeding (NCT02358512) and there is early translational work looking at molecular targets [57,58]. Overall Sepsis-3 is unlikely to impact on neuromyopathy directly other than earlier diagnosis and treatment of sepsis, which could ultimately lead to earlier recovery.

Concluding remarks

Redefining syndromes creates exciting headlines and the new Sepsis-3 guidelines have been no different, highlighting the plight of patients with sepsis worldwide. Importantly, these latest definitions reflect the most current understanding of the pathogenesis of sepsis emphasizing the role of the dysregulated host response following infection. Furthermore, the importance of early identification of both sepsis and the patients who have the greatest risk of deterioration is re-iterated [1]. However, one of the main merits of this newest conceptual framework is an attempt to unify and codify the language of sepsis. Standardisation of definitions and clinical criteria is crucial in enabling a consistent terminology in studies and clinical trials. Another possible benefit of more rigorous nomenclature is greater epidemiological accuracy. Figures around sepsis incidence and mortality vary hugely and greater clarity in defining sepsis is thought to be key in addressing this issue [1]. Particularly the overlap between SIRS criteria and infection is believed to have led to a large increase in sepsis diagnoses [59]. Despite potential benefits the Sepsis-3 definitions have raised significant questions in the literature and have not been free of controversy.

• The new sepsis criteria aim to encompass all aspects of sepsis (infection, host response and organ dysfunction), whilst being easily measurable and applicable to all clinical areas [1]. Yet, the SOFA score, as stated, offers little as a tool for patient management but merely characterises the septic patient in the intensive care unit. It is a useful and well-known metric in the critical care environment for predicting mortality. Unfortunately its role outside the intensive care unit seems less certain and confusingly is discussed under the heading “Clinical criteria to identify patients with sepsis” [1].

• The introduction of the quick SOFA (qSOFA c.f. box 1) score has provoked considerable debate [59,60]. It is crucial to appreciate that the qSOFA score is not part of the Sepsis-3 definition. Rather it is an operational prompt conceived to identify patients with suspected infection who are likely to have poor outcomes. Again questions arise how well an outcome prediction tool serves as a sepsis screen.

• Although Sepsis-3 acknowledges the lack of validation of the qSOFA tool clinicians have questioned why prior to promoting the use of a new tool, prospective modeling has not been undertaken [60,61].

• These deliberations are particularly pertinent given that in non-critical care patients, SOFA and SIRS perform identically in predicting mortality with an area under the curve of 0.79; 95% CI, 0.78-0.80 vs. 0.76; 95% CI, 0.75-0.77 and sensitivities of 68% and 64% respectively [1,62].

• Adopting new definitions and diagnostic criteria takes time as well as training and very real concerns have been voiced regarding the management of sepsis whilst these new definitions are being understood as well as implemented [61,63] .

There is little doubt that redefining a heterogeneous concept such as sepsis with its variable presentations and complex pathophysiological features is a daunting task. In light of the existing controversies the following understanding offers a pragmatic approach to the newest sepsis definitions:

1. In the face of new organ dysfunction consider infection as a possible underlying cause

2. Investigate the cause of organ dysfunction

3. Sepsis management and referral to critical care where appropriate

Nonetheless, both the clinical utility of the new Sepsis-3 definition and the future of SIRS remain to be seen and much of the struggle with sepsis continues, encapsulated in the two quotes below:

“Advances in the treatment of fever … have not kept pace with the rapid progress in our knowledge of the etiology. In the present condition of bacteriology we may expect great things in the near future, but meanwhile we jog along without any fixed aim, too often carried away by winds of doctrines and wild theories” [64]. (William Osler, 1896)

“As the physicians say it happens in hectic fever, that in the beginning of the malady it is easy to cure but difficult to detect, but in the course of time, not having been either detected or treated in the beginning, it becomes easy to detect but difficult to cure”

(Niccolò Machiavelli, The Prince, 1532 )

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Figure legend:

Table 1: Definition of sepsis syndrome

Table 2: Systemic inflammatory response syndrome

Table 3: Sepsis syndromes

Table 4: Heterogeneity between sepsis trials

Box 1: Sepsis-3 definitions adapted from the consensus guideline

-----------------------

Box. 1 Sepsis-3 terminology adapted from the consensus guideline [1]:

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

• Organ dysfunction can be identified as an acute change in total SOFA score of 2 points consequent to infection

• The quick SOFA (qSOFA) i.e. alteration in mental status, systolic blood pressure d"100mmHg or a respiratoryuent to infection

The quick SOFA (qSOFA) i.e. alteration in mental status, systolic blood pressure ≤100mmHg or a respiratory rate ≥22/min is a tool designed to identify patients with a suspected infection who are likely to have a prolonged ICU stay or die

• Septic shock is described using the following criteria: persistent hypotension requiring vasopressors to maintain MAP >65mmHg and a serum lactate >2mmol/l despite adequate volume resuscitation

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