Sepsis

Definition

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)
  • SEPSIS
    • SIRS + infection (or suspected infection)
  • SEVERE SEPSIS
    • Sepsis + CV dysfunction or ARDS or 2 other dysfunctional organs
  • SEPTIC SHOCK
    • Sepsis + CV dysfunction
New Definitions for adult sepsis (JAMA 2016, Sepsis-3):





Pathophysiology

  • 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


Clinical Presentation

  • Fever
  • Hypothermia
  • Tachypnea
  • Tachycardia
  • Leukocytosis
  • Leukopenia
  • Thrombocytopenia
  • 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. 

Treatment

  • International Sepsis Guidelines 2016; Pediatric Sepsis Guidelines (2017)
  • 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)
  • 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)



  • Catecholamine Resistant Shock: Begin hydrocortisone therapy (shock doses often 2 mg/kg IV q6hrs) although CORTICUS 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 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 a RCT bH
  • 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

Complications

  • 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




References

1) J.A. Lorente, J.C. Marshall: Neutralization of tumor necrosis factor in preclinical models of sepsis. Shock. 1 (Suppl 24):107-119 2005

2) P.Y. Bochud, M. Bonten, O. Marchetti, T. Calandra: Antimicrobial therapy for patients with severe sepsis and septic shock: an evidence-based review. Crit Care Med. 32 (Suppl 11):S495-512 2004

3) ProCESS Investigators, Yealy DM, Kellum JA, Huang DT, Barnato AE, WeissfeldLA, Pike F, Terndrup T, Wang HE, Hou PC, LoVecchio F, Filbin MR, Shapiro NI, Angus DC. A randomized trial of protocol-based care for early septic shock. N Engl J Med. 2014 May 1;370(18):1683-93. doi: 10.1056/NEJMoa1401602. Epub 2014 Mar 18.

4) ARISE Investigators; ANZICS Clinical Trials Group, Peake SL, Delaney A, Bailey M, Bellomo R, Cameron PA, Cooper DJ, Higgins AM, Holdgate A, Howe BD, Webb SA, Williams P. Goal-directed resuscitation for patients with early septic shock. N Engl J Med. 2014 Oct 16;371(16):1496-506.

5) Holst LB, Haase N, Wetterslev J, Wernerman J, Guttormsen AB, Karlsson S,Johansson PI, Aneman A, Vang ML, Winding R, Nebrich L, Nibro HL, Rasmussen BS, Lauridsen JR, Nielsen JS, Oldner A, Pettilä V, Cronhjort MB, Andersen LH, Pedersen UG, Reiter N, Wiis J, White JO, Russell L, Thornberg KJ, Hjortrup PB, Müller RG, Møller MH, Steensen M, Tjäder I, Kilsand K, Odeberg-Wernerman S, Sjøbø B, Bundgaard H, Thyø MA, Lodahl D, Mærkedahl R, Albeck C, Illum D, Kruse M, Winkel P, Perner A; TRISS Trial Group; Scandinavian Critical Care Trials Group. Lower versus higher hemoglobin threshold for transfusion in septic shock. N Engl J Med. 2014 Oct 9;371(15):1381-91.

6) Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, Sevransky JE, Sprung CL, Douglas IS, Jaeschke R, Osborn TM, Nunnally ME, Townsend SR, Reinhart K, Kleinpell RM, Angus DC, Deutschman CS, Machado FR, Rubenfeld GD, Webb SA, Beale RJ, Vincent JL, Moreno R; Surviving Sepsis Campaign Guidelines Committee including the Pediatric Subgroup. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med. 2013 Feb;41(2):580-637.

7) R.S. Watson, J.A. Carcillo: Scope and epidemiology of pediatric sepsis. Pediatr Crit Care Med. 6 (Suppl 3):S3-52005

8) R.S. Hotchkiss, I.E. Karl: The pathophysiology and treatment of sepsis. N Engl J Med. 348 (2):138-150 200312519925

9) R.S. Hotchkiss, C.M. Coopersmith, J.E. McDunn, T.A.Ferguson: The sepsis seesaw: tilting toward immunosuppression. Nat Med. 15 (5):496-497 2009 19424209

10) S. Nadel, B. Goldstein, M.D. Williams, et al.:Drotrecogin alfa (activated) in children with severe sepsis: a multicentre phase III randomised controlled trial.Lancet. 369 (9564):836-843 2007

11) J.A. Carcillo, A.L. Davis, A. Zaritsky: Role of early fluid resuscitation in pediatric septic shock. Jama. 266(9):1242-1245 1991

12) H.R. Wong, N. Cvijanovich, G.L. Allen, et al.: Genomic expression profiling across the pediatric systemic inflammatory response syndrome, sepsis, and septic shock spectrum. Crit Care Med. 37 (5):1558-1566 2009

13) E. Rivers, B. Nguyen, S. Havstad: Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med. 345 (19):1368-1377 2001

14) D. Vlasselaers, I. Milants, L. Desmet, et al.: Intensive insulin therapy for patients in paediatric intensive care: a prospective, randomised controlled study. Lancet. 373(9663):547-556 2009 19176240

15) C.L. Sprung, D. Annane, D. Keh, et al.: Hydrocortisone therapy for patients with septic shock. N Engl J Med. 358(2):111-124 2008

16) Sterling SA, Miller WR, Pryor J, Puskarich MA, Jones AE. The Impact of Timing of Antibiotics on Outcomes in Severe Sepsis and Septic Shock: A Systematic Review and Meta-Analysis. Crit Care Med. 2015 Sep;43(9):1907-15.