Sepsis is change and flows ever onwards

KEYWORDS:

• Sepsis
• septic shock
• biomarker
• host response
• organ dysfunction
• heat shock protein
• metabolism
• innate immunity
• guidelines
• bundles

‘Everything changes and nothing stands still’

Heraclitus of Ephesus (530-470 BC)

The ancient philosopher Heraclitus of Ephesus (530–470 BC) said that life is like a river. The peaks and troughs, pits and swirls, are all part of the ride. Nature is change and flows ever onwards. Change and death are common features of the natural world. Similarly, we are flux. We are and are not. Everything changes, and sepsis definitions, guidelines, biomarkers, and pathways’ key roles have changed many times since Heraclitus’ time.

Sepsis changes; septic shock flows; remaining major preventable causes of mortality [1]. Our knowledge and understanding of how sepsis causes organ injury at a molecular, cellular, or organ level have been significantly advanced the last few years. Sepsis guidelines’ updates constitute an effort to support and preserve organ perfusion and function together with anti-infective agents [2]. Early recognition of sepsis and timely resuscitation restore organ perfusion and decrease mortality [3]. Best outcomes, though, require organized emergency medicine, transport medicine, and critical care medicine systems. Frequent reassessment, aggressive ongoing resuscitation, eradication of infection, and host factors constitute critical outcome determinants. Institutions are now challenged to implement their own adopted or home-grown bundles for recognition, resuscitation, stabilization, and performance recommendations [4].

Biomarkers may serve as indicators for screening, diagnosis, risk stratification, monitoring response, bioenergetics failure, and altered rate of cell apoptosis [5,6]. Last decades, the concept of targeted molecular therapies to intervene the pathobiology process, so as to intercept the dysregulated host response, grew enthusiasm. Results of interventions in humans aiming at a variety of inflammation pathways, immunomodulation, bacterial virulence factors, and the coagulation cascade were not so optimistic and provided conflicting data [7]. The new sepsis definition emphasizes the imbalance in immune response, which provokes uncontrolled inflammation, either excessive or inadequate, giving the essence of dysregulated host response, acknowledging that ‘regulated’ host response is still unstated. There is now evidence that pro- and anti-inflammatory responses are activated simultaneously, being coordinated by immune molecular signals and influenced by the genetic and phenotypic diversity of bacteria [8]. This diversity might explain why the immunomodulatory effects of glutamine and heat shock protein (HSP)-72 on purified septic cell populations in animal and experimental studies could not be reproduced in human trials [9,10]. Similarly, procalcitonin-guided antimicrobial escalation either did not improve patients’ survival [11], leading to organ failures and prolonged intensive care unit (ICU) length of stay [12], or guided antibiotic therapy and surgical interventions [11] reduced the duration of treatment and decreased mortality [13]!

Recently, important immunological, hormonal, and metabolic responses have been reported in sepsis pathobiology [14]. Low VO₂, VCO₂, and a hypometabolic pattern predominate the acute phase of sepsis, associated with organ failure and increased mortality [15]. Serum cortisol, prolactin, and extracellular HSP72, and HSP90, expressing the innate immune response, are rapidly increased in adult [16] and pediatric sepsis [17]. Concurrently, a 50% decline of CD14/human leukocyte antigen - antigen D related (HLA-DR) expression is associated with repressed expression of intracellular HSP72 and HSP90 on monocytes and neutrophils [18]. These changes are associated with an acute inflammatory response, shown by an increased CD64 neutrophil expression, and severe metabolic deregulation (high glucose and triglycerides combined with low cholesterol, high-density lipoprotein [HDL], and low-density lipoprotein [LDL] levels) [19]. Recent studies indicate that these alterations might have been induced by hyperpyrexia (heat shock) rather than endotoxin [20].

New definitions (Sepsis-3) [21] and guidelines (Surviving Sepsis Campaign 2016) [22] for adult sepsis and septic shock have been recently published. The systemic inflammatory response syndrome (SIRS) has been suddenly eliminated. The old definition of ‘sepsis’ (infection and SIRS) was shown to be unable to define a life-threatening condition arising, when the body’s response to an infection injures its own tissues and organs, and has been abounded. Instead, the latest quick sepsis-related organ failure assessment (qSOFA) as a clinical scoring system plays an important role in identifying infected adult patients who are highly likely to develop sepsis or septic shock [23]. Apparently, the use of qSOFA in the emergency department setting resulted in greater prognostic accuracy for in-hospital mortality than did either SIRS or severe sepsis [24]. The new definition of sepsis ‘life-threatening organ dysfunction caused by a dysregulated host response to infection’ encompasses infection as the key initiator, corresponding to the old ‘severe sepsis’ definition. The ‘organ dysfunction’ shifts patients into the higher mortality risk category, distinguishing patients with sepsis from patients with a simple infection. The ‘life threatening’ gives a straightforward prognostic outcome among ICU patients with infection [25]. Finally, regardless of new sepsis definition release, there is an alternative perspective that septic shock is a distinct sepsis phenotype rather than a gauge of sepsis severity. There is no high-level evidence to support this. However, this is a challenge for sepsis investigators to identify if such a difference exists.

The updated guidelines recommend frequent reevaluation and patient-specific tailoring of hemodynamic therapy, correcting the uncertainty induced by the early-goal-directed resuscitation for septic shock trials [26]. Adherence to the bundles has been associated with a marked reduction in the odds of death [27]. Within 1-h empirical combined antibiotic treatment and early infection source control are the mainstays of therapy in patients with septic shock. Recommended practice suggests dosing strategies based on pharmacokinetic/pharmacodynamic principles in patients with sepsis when such tests are available. The new guidelines also recommend patient-centered resuscitation approach; frequent reassessment of hemodynamic status, preferably with dynamic variables, should guide additional fluid administration after the initial fluid bolus, predict fluid responsiveness, and determine the type of shock if the clinical diagnosis does not lead to clear diagnosis [22].

Unlike previous editions, the 2016 iteration of the adult guidelines does not include recommendations for the care of pediatric septic shock; they are expected in 2017 [4,28]. Recently, from the Delphi process, the European Society of Pediatric and Neonatal Intensive Care defined the pediatric refractory septic shock (RSS) by including the worst scores of vaso-inotrope dependency, arterial lactate, and the presence of myocardial dysfunction [29]. Accordingly, in conjunction with invasive blood pressure and hemodynamic monitoring, bedside echocardiography provides additional crucial information, which may lead to the recognition of septic myocardial dysfunction and uncorrected hypovolemia in pediatric patients who remain in fluid-resistant septic shock [30]. Using the multimodal monitoring for hemodynamic categorization and management of pediatric septic shock, early goal-directed therapy using intermittent ScvO₂ monitoring may also reduce mortality and improve organ dysfunction [31]. A double-blind prospective randomized controlled trial showed that early administration of peripheral or intraosseous epinephrine, as first-line vasoactive drug in pediatric septic shock, is associated with increased survival compared to dopamine, which is associated with increased mortality and health care-associated infection [32]. Vasopressin and terlipressin, which have been used as last-line therapy in RSS in children, did not show any benefit in terms of mortality and length of stay and suggest an increased risk for ischemic events [33]. In contrast, therapeutic plasma exchange might be an effective adjunct therapy in RSS with multiple dysfunction syndromes by removing toxic mediators and replacing deficient factors using donor plasma [34].

Hopefully, as medical knowledge rapidly evolves, our thinking and practice will change. Sepsis-cohort trials may be supplemented by host genome sequencing based on the clinical phenotype analyses. Since the core problem in sepsis rests in host’s response, newer methods of patient recruitment, prevention strategies, and management approaches will be individually tailored, identifying subgroups of patients who may benefit from specific treatments. Recently, it was shown that sepsis is associated with increased cortisol concentrations and human glucocorticoid receptor expression related to stress-activated biomolecules and organ dysfunction, possibly implying no need for exogenous steroids [35]. It is expected that future research will focus on interventions through multiple downstream pathways concurrently; identification of the entire proximal regulatory pathway; and development of strategies to optimize host’s response by enhancing barrier function and bioenergetics [36]. Considering the complex immune response of each host, the development of large-scale biological databases based on proteomics, metabolomics, genomics, cellular assays, and bioinformatics will move the sepsis field onwards.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

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Funding

This paper was not funded.