Spectrum Defined by the International Consensus Conference on Pediatric Sepsis and Organ Dysfunction:
SIRS- 2 or more of the following:
Core Temperature >38.5 or <36 C
Tachycardia or Bradycardia (>2 SD above age or <10%ile)
Tachypnea (RR >90th %ile) or need for mechanical ventilation
WBC elevated or decreased for age (or >10% immature neutrophils)
SIRS + infection (or suspected infection)
Sepsis + CV dysfunction or ARDS or 2 other dysfunctional organs
Sepsis + CV dysfunction
New Definitions for adult sepsis (JAMA 2016, Sepsis-3):
Inciting factor (infection, trauma, pancreatitis, etc.) leads to marked inflammatory response
Pattern Recognition Receptors (PRR) on immune cells recognize Pathogen Associated Molecular Patterns (PAMPs):
TLR4 recognizes lipopolysaccharide (LPS) (gram negative bacteria)
TLR2 recognizes lipotechoic acid (gram positive bacteria)
PAMP binding to PRR leads to phagocytosis of the infectious agent with subsequent amplification, proliferation, and secretion of cytokines.
NF-KB is central to the signal transduction pathways and serves as a master switch for proinflammatory gene expression
TNF-alpha: its rise is temporally associated with shock, can induce shock in and of itself in experimental models. TNF-alpha inhibition failed to improve outcomes in sepsis (Lorente, Shock 2005).
IL-1B: Similar to TNF-alpha, major early cytokine in sepsis response, clinical trials failed to demonstrate efficacy in improving outcomes for sepsis
IL-6: Increases during sepsis, levels correlated with outcomes in sepsis. Tried utilizing as a stratification marker in sepsis but has failed in the clinical realm
IL-10: Most well known anti-inflammatory cytokine, downregulates inflammation, may be partially responsible for the Compensatory Anti-Inflammatory Response Syndrome (CARS) or subsequent immunoparalysis after sepsis
Altered mental status
Impaired perfusion (prolonged capillary refill or flash capillary refill)
Differentiate between cold and warm shock (the same patient may transition in/out of warm/cold shock)
Cold Shock: More common in younger children. Poor peripheral perfusion, clamped down, delayed capillary refill, cool peripheral extremities. Likely reflects poor cardiovascular function (ie as a result of myocardial depressant factors) with subsequent increase in SVR to maintain blood pressures
Warm Shock: More common in older patients. Vasoplegia with loss of systemic vascular resistance. Hyperdnyamic heart (increased cardiac output to compensate for poor SVR) with bounding pulses, flash capillary refill. Low diastolic blood pressures.
International Sepsis Guidelines 2016; Pediatric Sepsis Guidelines (2020)
Early Goal Directed Therapy remains the framework for initial resuscitation of patients with septic shock (though some criticism remains regarding limitations such as the study being from a single site, the author caring for patients in the interventional arm, and concerns regarding vested interests in the oximeter catheters used in the trial).
More recent large multi-center RCTs of protocolized therapy (in the US, UK, and Australia/New Zealand) have failed to show a significant difference over approaches which utilized less blood transfusions, central venous catheters, and vasoactive agents. (PROCESS, PROMISE, and ARISE)
In light of the results of these recent trials, EGDT and the protocol below (intended for adult patients in the ED) should be thought of as a framework for treating sepsis, rather than a strict guideline
Aggressive volume resuscitation: Boluses of isotonic fluid (over 5-15 minutes) given IV push in 20cc/kg aliquots up to and over 60 cc/kg until perfusion improves or hepatomegaly/rales develop
Some recent evidence suggesting treatment with balanced fluids (i.e. lactated Ringer's) may be preferable to normal saline with associated improvements in outcome (Raghunathan, CCM 2014)
RCT's have also demonstrated improved outcomes with balanced solutions vs. saline in critically ill adults (Semler et al, NEJM 2018)
Other studies (Stenson et al, PCCM 2018) have shown hyperchloremia (i.e. from normal saline boluses) is independently associated with worse outcomes in pediatric sepsis. (Hyperchloremic IV solutions: Have We Seen Enough?)
Age related MAP goals (ie roughly >40 for newborns, >45 for infants, >50 for toddlers, >60 for children, >65 for adolescents/adults)
Establish central venous access and monitor central venous oxygen saturations as a marker of systemic oxygen delivery with goal ScvO2 >70% as well as central venous pressure
Transfusions for Hgb <10 gm/dl if ScvO2 persistently below 70% (newer data suggests thresholds of <7 gm/dl are safe for adult patients with septic shock)
Fluid Refractory Shock: Vasoactive Agents (epinephrine for cold shock, norepinephrine for warm shock, dopamine if only inotrope readily available) to achieve MAP, ScvO2 goals
A Brazilian study of 120 pediatric patients with septic shock (double blind RCT) found higher rates of death and hospital acquired infection rates with dopamine vs epinephrine though generalizability is limited (Ventura et al, CCM 2015)
Vasoactive Inotropic Score
Catecholamine Resistant Shock: Begin hydrocortisone therapy (shock doses often 2 mg/kg IV q6hrs up to 50 mg IV q6 in adults) although CORTICUS and ADRENAL did not show improved outcomes with hydrocortisone. This was in contrast to an initial study by Annane (JAMA 2002). Some physicians advocate obtaining cortisol levels or performing cortisol stimulation tests although the evidence supporting the use of random cortisol or ACTH stimulation to identify patients that may benefit from hydrocortisone has been mixed at best. Hence, until further evidence is available, some physicians advocate for using hydrocortisone (50 mg/m2/day or 12.5 mg/m2 IV q6) in patients with persistent hypotension despite adequate fluid resuscitation and vasoactive therapy and forgoing cortisol or ACTH stimulation assays (as you would use hydrocortisone in this group regardless of what the results are and hydrocortisone is likely not indicated in patients well supported with fluid therapy and vasoactives).
Consider milrinone if normal blood pressures and ScvO2 <70%
Vasopressin is often used as a 3rd vasoactive agent. As an agonist for the V1 receptor, it functions via a different mechanism than epinephrine or norepinephrine (beta and adrenergic receptors) and can increase SVR via vasoconstriction. Two of the major studies of vasopressin are VASST (Russel, NEJM 2008) which showed no significant difference compared to NE in adults with septic shock and Choong, AJRCC 2009 which looked specifically at 65 patients with pediatric vasodilatory shock and found no differences in clinical outcomes (though the authors cite concern re: a trend toward increased mortality in the vasopressin group)
Source Control: Early administration of appropriate antibiotics is directly associated with improved survival (up to 7% increased mortality per hour of delay in antibiotic therapy-Kumar et al, CCM 2006).
A recent meta-analysis by Sterling et al showed no increased mortality in the pooled odds ratios for each hourly delay from less than 1 to more than 5 hours in antibiotic administration from severe sepsis/shock recognition (Sterling et al, CCM 2015) in adult patients.
In the PICU population, Weiss et al, CCM 2014 showed an escalating risk of mortality with each hour delay from sepsis recognition to antimicrobial administration, reaching statistical significance at 3 hours. Odds ratios for PICU mortality were 3.92 (1.27-12.06) and 3.59 (1.09-11.76) with more than 3 hour delay to initial and first appropriate antibiotics, respectively.
Reduce oxygen demand: mechanical ventilation, sedation, paralysis as needed
CRRT, Consideration of Therapeutic Plasma Exchange for TAMOF, and ECMO for refractory septic shock
Immune Modulation: Anti TNF-alpha, Anti-IL1, and Activated Protein C (PROWESS and RESOLVE Trials) have been investigated and shown not to improve outcomes in patients with septic shock. Unfortunately, many targeted immunomodulatory therapies have shown initial promise but none have shown consistent benefit in patient trials.
There is significant interest in stratifying pediatric septic shock (a heterogenous group) using biomarkers. Wong et al. have begun this work with PERSEVERE
Concept of immunoparalysis with initial proinflammatory response and subsequent compensatory anti-inflammatory response (CARS) that may be exaggerated.
CARS thought to be mediated by antinflammatory cytokines such as IL-10 and may be a result of epigenetic changes regulating gene transcription (See Figure below)
May be responsible for the roughly 6% late death seen in pediatric sepsis (50% of the total death rate appears to be this "late" death category)- See Figure below.
Late death in Pediatric Sepsis, from Czaja et al, Pediatrics 2009
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