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Septic shock

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Septic shock
SpecialtyInfectious diseases, intensive care medicine Edit this on Wikidata

Septic shock is a serious medical condition that occurs when sepsis, which is organ injury or damage in response to infection, leads to dangerously low blood pressure and abnormalities in cellular metabolism.[1] The primary infection is most commonly by bacteria, but can also be by fungi, viruses, or parasites, and can be located in any part of the body, but most commonly in the lungs, brain, urinary tract, skin, or abdominal organs.[2] It can cause multiple organ dysfunction syndrome (formerly known as multiple organ failure) and death.[3] Its most common victims are children, immunocompromised individuals, and the elderly, as their immune systems cannot deal with infection as effectively as those of healthy adults. Frequently, patients suffering from septic shock are cared for in intensive care units. The mortality rate from septic shock is approximately 25–50%.[3]

Definition

Septic shock is a subclass of distributive shock, a condition in which abnormal distribution of blood flow in the smallest blood vessels results in inadequate blood supply to the body's tissues, resulting in ischemia and organ dysfunction. Septic shock refers specifically to distributive shock due to sepsis as a result of infection.

Septic shock can be defined as sepsis-induced hypotension that persists despite treatment with intravenous fluids.[4] Low blood pressure reduces tissue perfusion pressure, causing the tissue hypoxia that is characteristic of shock. Cytokines released in a large scale inflammatory response result in massive vasodilation, increased capillary permeability, decreased systemic vascular resistance, and hypotension. Finally, in an attempt to offset decreased blood pressure, ventricular dilatation and myocardial dysfunction occur.

Septic shock can be regarded as a stage of SIRS (Systemic Inflammatory Response Syndrome), in which sepsis, severe sepsis and multiple organ dysfunction syndrome (MODS) represent different stages of a pathophysiological process. If an organism cannot cope with an infection, it may lead to a systemic response - sepsis, which may further progress to severe sepsis, septic shock, organ failure, and eventually result in death.

According to current guidelines, requirements for diagnosis with sepsis are "the presence (probable or documented) of infection together with systemic manifestations of infection".[4] These manifestations may include:

  • Tachypnea (high respiratory rate), which is defined as more than 20 breaths per minute, or when testing blood gas, a PaCO
    2     less than 32 mmHg, which signifies hyperventilation.
  • White blood cell count either significantly low, (< 4000 cells/mm3) or elevated (> 12000 cells/mm3).
  • Tachycardia (rapid heart rate), which in sepsis is defined as a rate greater than 90 beats per minute.
  • Altered body temperature: Fever > 38.0 °C (100.4 °F) or hypothermia < 36.0 °C (96.8 °F)

Documented evidence of infection, may include positive blood culture, signs of pneumonia on chest x-ray, or other radiologic or laboratory evidence of infection. Signs of end-organ dysfunction are present in septic shock, including kidney failure, liver dysfunction, changes in mental status, or elevated serum lactate.

Septic shock is diagnosed if there is refractory hypotension (low blood pressure that does not respond to treatment). This means that intravenous fluid administration alone is not enough to maintain a patient's blood pressure. Diagnosis of sepsis-induced hypotension is made when systolic blood pressure is less than 90mm Hg, a mean arterial pressure (MAP) is less than 70 mm Hg, or a systolic blood pressure decreases 40 mm Hg or more without other causes for hypotension.[4]

Causes

Septic shock is a result of a systemic response to infection, and can be a response to multiple infectious causes; septicemia may be present but septic shock can occur without septicemia.[5] The precipitating infections which may lead to septic shock if severe enough include, but are not limited to, appendicitis, pneumonia, bacteremia, diverticulitis, pyelonephritis, meningitis, pancreatitis, necrotizing fasciitis, and mesenteric necrosis.[6][7]

Sepsis is a constellation of symptoms secondary to infection that manifest as disruptions in heart rate, respiratory rate, temperature and white blood cell count. If sepsis worsens to the point of end-organ dysfunction (renal failure, liver dysfunction, altered mental status, or heart damage), then the condition is called severe sepsis. Once severe sepsis worsens to the point where blood pressure can no longer be maintained with intravenous fluids alone, then the criteria have been met for septic shock.

Pathophysiology

The pathophysiology of septic shock is not entirely understood, but it is known that a key role in the development of severe sepsis is played by an immune and coagulation response to an infection. Both pro-inflammatory and anti-inflammatory responses play a role in septic shock.[5]

Most cases of septic shock are caused by gram-positive bacteria,[8] followed by endotoxin-producing gram-negative bacteria, though fungal infections are an increasingly prevalent cause of septic shock.[4] Toxins produced by pathogens cause an immune response; in gram-negative bacteria these are endotoxins, which are bacterial membrane lipopolysaccharides (LPS).

gram-positive sepsis

In gram-positive bacteria, these are exotoxins or enterotoxins, which may vary depending on the species of bacteria. These are divided into three types. Type I, cell surface-active toxins, disrupt cells without entering, and include superantigens and heat-stable enterotoxins. Type II, membrane-damaging toxins, destroy cell membranes in order to enter and include hemolysins and phospholipases. Type III, intracellular toxins or A/B toxins interfere with internal cell function and include shiga toxin, cholera toxin, and anthrax lethal toxin.

gram-negative sepsis

In gram-negative sepsis, free LPS attaches to a circulating LPS-binding protein, and the complex then binds to the CD14 receptor on monocytes, macrophages, and neutrophils. Engagement of CD14 (even at doses as minute as 10 pg/mL) results in intracellular signaling via an associated "Toll-like receptor" protein 4 (TLR-4). This signaling results in the activation of nuclear factor kappaB (NF-κB), which leads to transcription of a number of genes that trigger a proinflammatory response. It was the result of significant activation of mononuclear cells and synthesis of effector cytokines. It also results in profound activation of mononuclear cells and the production of potent effector cytokines such as IL-1, IL-6, and TNF-α. TLR-mediated activation helps to trigger the innate immune system to efficiently eradicate invading microbes, but the cytokines they produce also act on endothelial cells. There, they have a variety of effects, including reduced synthesis of anticoagulation factors such as tissue factor pathway inhibitor and thrombomodulin. The effects of the cytokines may be amplified by TLR-4 engagement on endothelial cells.

In response to inflammation, a compensatory reaction of production of anti-inflammatory substances such as IL-4, IL-10 antagonists, IL-1 receptor and cortisol occurs. This is called Compensatory Anti-inflammatory Response Syndrome (CARS).[9] Both the inflammatory and anti-inflammatory reactions are responsible for the course of sepsis and are described as MARS (Mixed Antagonist Response Syndrome). The aim of these processes is to keep inflammation at an appropriate level. CARS often leads to suppression of the immune system, which leaves patients vulnerable to secondary infection.[5] It was once thought that SIRS or CARS could predominate in a septic individual, and it was proposed that CARS follows SIRS in a two-wave process. It is now believed that the systemic inflammatory response and the compensatory anti-inflammatory response occur simultaneously.[9]

At high levels of LPS, the syndrome of septic shock supervenes; the same cytokine and secondary mediators, now at high levels, result in systemic vasodilation (hypotension), diminished myocardial contractility, widespread endothelial injury and activation, causing systemic leukocyte adhesion and diffuse alveolar capillary damage in the lung activation of the coagulation system, culminating in disseminated intravascular coagulation (DIC). The hypoperfusion from the combined effects of widespread vasodilation, myocardial pump failure, and DIC causes multiorgan system failure that affects the liver, kidneys, and central nervous system, among others. Severe damage to liver ultrastructure has been recently noticed by treatment with cell-free toxins of Salmonella.[10] Unless the underlying infection (and LPS overload) is rapidly brought under control, the patient usually dies.

Treatment

Treatment primarily consists of the following:

  1. Volume resuscitation[11]
  2. Early antibiotic administration[11]
  3. Early goal directed therapy[11]
  4. Rapid source identification and control
  5. Support of major organ dysfunction
  6. Sequestration of lipopolysaccharides

Treatment guidelines call for the administration of broad-spectrum antibiotics within the first hour following recognition of septic shock. Prompt antimicrobial therapy is critically important, as risk of dying increases by approximately 10% for every hour of delay in receiving antibiotics.[8] Time constraints do not allow the culture, identification and testing for antibiotic sensitivity of the specific microorganism responsible for infection. Therefore, combination antimicrobial therapy, which covers a wide range of potential causative organisms, is tied to better outcomes.[8]

Because lowered blood pressure, in septic shock contributes to poor perfusion, fluid resuscitation is an initial treatment to increase blood volume. Crystalloids such as normal saline and lactated Ringer's solution are recommended as the initial fluid of choice, while the use of colloid solutions such as hydroxyethyl starch have not shown any advantage or decrease in mortality. When large quantities of fluids are given, administering albumin has shown some benefit.[8]

Among the choices for vasopressors, norepinephrine is superior to dopamine in septic shock.[12] Norepinephrine is the preferred vasopressor, while epinephrine can be added to norepinephrine when needed. Low-dose vasopressin may also be used as an addition to norepinephrine, but is not recommended as a first-line treatment. Dopamine can cause rapid heart rate and arrhythmias, and is only recommended in combination with norepinephrine in those with slow heart rate and low risk of arrhythmia. In the initial treatment of hypotension in septic shock, the goal of vasopressor treatment is a mean arterial pressure (MAP) of 65 mm Hg.[8]

A controversial approach is to use β-Blocker therapy. It may attenuate the deleterious effects of β-adrenergic receptor stimulation in septic shock. Microvascular blood flow alterations are frequent in patients with sepsis and are more severe in patients with a worse outcome.[13] Heart rate control by a titrated esmolol infusion in septic shock patients was associated with maintenance of stroke volume and a preserved microvascular blood flow.[14] It has also shown a trend toward an improvement of the microcirculation on a piglet model of septic shock.[15] A study has shown that the use of esmolol versus standard care was associated with reductions in heart rates to achieve target levels, without increased adverse events. An improvement in mortality was observed, but as it was a secondary clinical outcomes, it warrants further investigation.[16]

Antimediator agents may be of some limited use in severe clinical situations however are controversial:[17]

  • Low dose steroids (hydrocortisone) for 5 – 7 days led to improved outcomes.[18][19]
  • Recombinant activated protein C (drotrecogin alpha) in a 2011 Cochrane review was found not to decrease mortality and thus was not recommended for use.[20] Other reviews however comment that it may be effective in those with very severe disease.[17] The first and only activated protein C drug, drotrecogin alfa (Xigris), was voluntarily withdrawn in October 2011 after it failed to show a benefit in patients with septic shock, including the more severe disease subgroups.

Sequestration of lipopolysaccharides

A technique that has shown success and is currently used in Japan [citation needed], if not elsewhere [where?] , involves sequestering the lipopolysacharides that effectively cause septic shock. The antibiotic toraymyxin coincidentally does this, but is also too toxic to be administered. The Japanese technique binds this toraymixin to an immobile material like polystyrene, and pass the blood over it, but this isn't always practical. Recent peer-reviewed research has found a substance EVK-203 derived from the very same spermine found in semen, to bind to lipopolysaccharids which, so far, seems to be non-toxic as well.[21][22]

Epidemiology

Sepsis has a worldwide incidence of more than 20 million cases a year, with mortality due to septic shock reaching up to 50 percent even in industrialized countries.[23]

According to the US CDC, septic shock is the 13th leading cause of death in the United States, and the #1 cause of deaths in intensive care units. There has been an increase in the rate of septic shock deaths in recent decades, which is attributed to an increase in invasive medical devices and procedures, increases in immunocompromised patients, and an overall increase in elderly patients. Tertiary care centers (such as hospice care facilities) have 2-4 times the rate of bacteremia than primary care centers, 75% of which are hospital-acquired infections.

The process of infection by bacteria or fungi can result in systemic signs and symptoms that are variously described. Approximately 70% of septic shock cases were once traceable to gram-negative bacteria that produce endotoxins; however, with the emergence of MRSA and the increased use of arterial and venous catheters, gram-positive bacteria are implicated approximately as commonly as bacilli. In rough order of increasing severity, these are bacteremia or fungemic; septicemia; sepsis, severe sepsis or sepsis syndrome; septic shock; refractory septic shock; multiple organ dysfunction syndrome, and death.

35% of septic shock cases derive from urinary tract infections, 15% from the respiratory tract, 15% from skin catheters (such as IVs); over 30% of all cases are idiopathic in origin.

The mortality rate from sepsis is approximately 40% in adults, and 25% in children, and is significantly greater when left untreated for more than 7 days.[24]

References

  1. ^ The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016;315(8):801-810. doi:10.1001/jama.2016.0287
  2. ^ Jui, Jonathan (2011). "Ch. 146: Septic Shock". In Tintinalli, Judith E.; Stapczynski, J. Stephan; Ma, O. John; Cline, David M.; et al. (eds.). Tintinalli's Emergency Medicine: A Comprehensive Study Guide (7th ed.). New York: McGraw-Hill. pp. 1003–14. Retrieved December 11, 2012 – via AccessMedicine. {{cite book}}: External link in |chapterurl= (help); Unknown parameter |chapterurl= ignored (|chapter-url= suggested) (help); Unknown parameter |subscription= ignored (|url-access= suggested) (help)
  3. ^ a b Kumar, V.; Abbas, A.K.; Fausto, N.; et al., eds. (2007). Robbins Basic Pathology (8th ed.). Saunders, Elsevier. pp. 102–3. ISBN 9781416029731.
  4. ^ a b c d Surviving Sepsis Campaign Guidelines Committee including The Pediatric Subgroup; Dellinger, R.P.; Levy, M.M.; Rhodes, A.; Annane, D.; Gerlach, H.; Opal, S.M.; Sevransky, J.E.; Sprung, C.L.; Douglas, I.S.; Jaeschke, R.; Osborn, T.M.; Nunnally, M.E.; Townsend, S.R.; Reinhart, K.; Kleinpell, R.M.; Angus, D.C.; Deutschman, C.S.; Machado, F.R.; Rubenfeld, G.D.; Webb, S.; Beale, R.J.; Vincent, J.-L.; Moreno, R. (2013). "Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock: 2012" (PDF). Critical Care Medicine. 41 (2): 580–637. doi:10.1097/CCM.0b013e31827e83af. PMID 23353941 – via Surviving Sepsis Campaign. {{cite journal}}: Unknown parameter |displayauthors= ignored (|display-authors= suggested) (help)
  5. ^ a b c Angus, Derek C.; van der Poll, Tom (2013). "Severe Sepsis and Septic Shock". New England Journal of Medicine. 369 (9): 840–851. doi:10.1056/NEJMra1208623. ISSN 0028-4793. PMID 23984731.
  6. ^ "Bowel necrosis associated with early jejunal tube feeding: A complication of postoperative enteral nutrition". Arch Surg. 141 (7): 701–4. July 2006. doi:10.1001/archsurg.141.7.701. PMID 16847244. {{cite journal}}: Cite uses deprecated parameter |authors= (help)
  7. ^ "Enteral nutrition associated non-occlusive bowel ischemia". J Korean Surg Soc. 83 (3): 171–174. September 2012. doi:10.4174/jkss.2012.83.3.171. PMC 3433554. PMID 22977764. {{cite journal}}: Cite uses deprecated parameter |authors= (help)
  8. ^ a b c d e Martin, G.S. (2012). "Sepsis, severe sepsis and septic shock: changes in incidence, pathogens and outcomes". Expert Review of Anti-infective Therapy. 10 (6): 701–6. doi:10.1586/eri.12.50. PMC 3488423. PMID 22734959.
  9. ^ a b Adib-Conquy, Minou; Cavaillon, Jean-Marc (2008). "Compensatory anti-inflammatory response syndrome". Thrombosis and Haemostasis. doi:10.1160/TH08-07-0421. ISSN 0340-6245.
  10. ^ YashRoy, R.C. (June 1994). "Liver damage by intra-ileal treatment with Salmonella 3,10:r:- extract as studied by light and electron microscopy". Indian Journal of Animal Sciences. 64 (6): 597–99 – via ResearchGate.(animal study).
  11. ^ a b c Levinson, A.T.; Casserly, B.P.; Levy, M.M. (April 2011). "Reducing mortality in severe sepsis and septic shock". Seminars in Respiratory and Critical Care Medicine. 32 (2): 195–205. doi:10.1055/s-0031-1275532. PMID 21506056.
  12. ^ Vasu, T.S.; Cavallazzi, R.; Hirani, A.; Kaplan, G.; Leiby, B.; Marik, P.E. (March 24, 2011). "Norephinephrine or dopamine for septic shock: A systematic review of randomized clinical trials". Journal of Intensive Care Medicine. 27 (3): 172–8. doi:10.1177/0885066610396312. PMID 21436167 – via PubMed. {{cite journal}}: Unknown parameter |displayauthors= ignored (|display-authors= suggested) (help)
  13. ^ De Backer, Daniel (2002). "Microvascular Blood Flow Is Altered in Patients with Sepsis". American Journal of Respiratory and Critical Care Medicine. 166 (166, 1): 98–104. doi:10.1164/rccm.200109-016oc. PMID 12091178.
  14. ^ Morelli, A (September 2013). "Microvascular effects of heart rate control with esmolol in patients with septic shock: a pilot study". Critical Care Medicine. 41 (41(9):): 2162–8. doi:10.1097/CCM.0b013e31828a678d. PMID 23873274.{{cite journal}}: CS1 maint: extra punctuation (link)
  15. ^ Jacquet-Lagrèze, Matthias (2015). "Gut and sublingual microvascular effect of esmolol during septic shock in a porcine model". Critical Care. 19 (4): 19:241. doi:10.1186/s13054-015-0960-3. PMID 26041462.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  16. ^ Morelli, A (October 23, 2013). "Effect of heart rate control with esmolol on hemodynamic and clinical outcomes in patients with septic shock: a randomized clinical trial". JAMA. 310: 1683–91. doi:10.1001/jama.2013.278477.
  17. ^ a b Sandrock, C.E.; Albertson, T.E. (February 2010). "Controversies in the treatment of sepsis". Seminars in Respiratory and Critical Care Medicine. 31 (1): 66–78. doi:10.1055/s-0029-1246290. PMID 20101549.
  18. ^ Annane, D.; Sebille, V.; Charpentier, C.; Bollaert, P.E.; Francois, B.; Korach, J.M.; Capellier, G.; Cohen, Y.; Azoulay, E.; Troche, G.; Chaumet-Riffaut, P.; Bellissant, E. (August 21, 2002). "Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock". JAMA. 288 (7): 862–71. doi:10.1001/jama.288.7.862. PMID 12186604. {{cite journal}}: Unknown parameter |displayauthors= ignored (|display-authors= suggested) (help)
  19. ^ Foëx, B.A. (October 11, 2004). "Do low dose steroids improve outcome in septic shock?". BestBETs.
  20. ^ Martí-Carvajal, AJ; Solà, I; Lathyris, D; Cardona, AF (13 April 2011). "Human recombinant activated protein C for severe sepsis". The Cochrane database of systematic reviews (4): CD004388. doi:10.1002/14651858.CD004388.pub4. PMID 21491390.
  21. ^ Nguyen, T.B.; Adisechan, A.K.; Suresh Kumar, E.V.K.; Balakrishna, R.; Kimbrell, M.R.; Miller, K.A.; Datta, A.; David, S.A. (2007). "Protection from endotoxic shock by EVK-203, a novel alkylpolyamine sequestrant of lipopolysaccharide". Bioorganic & Medicinal Chemistry. 15 (17): 5694–709. doi:10.1016/j.bmc.2007.06.015. PMC 2039869. PMID 17583517. {{cite journal}}: Unknown parameter |displayauthors= ignored (|display-authors= suggested) (help)
  22. ^ Burns, M.R.; Wood, S.J.; Miller, K.A.; Nguyen, T.; Cromer, J.R.; David, S.A. (2005). "Lysine–spermine conjugates: Hydrophobic polyamine amides as potent lipopolysaccharide sequestrants". Bioorganic & Medicinal Chemistry. 13 (7): 2523–36. doi:10.1016/j.bmc.2005.01.038. PMID 15755654. {{cite journal}}: Unknown parameter |displayauthors= ignored (|display-authors= suggested) (help)
  23. ^ "Researchers make blood poisoning breakthrough". Phys.org. June 4, 2010.
  24. ^ Huether, S.E.; McCance, K.L., eds. (2008). Understanding Pathophysiology (4th ed.). ISBN 9780323049900.[page needed]
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