Septic shock

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Septic shock
The Sick Girl by Gabriël Metsu
SpecialtyInfectious disease
SymptomsEarly: Temperature > 38 °C (100.4 °F), fast heart rate, narrow pulse pressure[1][2]
Worsens: Confusion, bluish skin[2]
ComplicationsAcute respiratory distress syndrome, multiple organ dysfunction syndrome[2]
CausesInfection[2]
Risk factorsDiabetes, cancer, liver or kidney problems, corticosteroid use, burns, poor immune function, extremes of age[2]
Diagnostic methodBased on MAP < 65 mmHg and lactate < 2 mmol/L despite fluids[3]
Differential diagnosisOther types of shock, disseminated intravascular coagulation, adrenal crisis, drug overdose[1][2]
TreatmentAntibiotics, removing infected tissue, intravenous fluids, norepinephrine[2]
DeathsRisk > 40%[4]

Septic shock is a severe form of sepsis in which blood pressure remains low and lactate is greater than 2 mmol/L (>18 mg/dL) despite sufficient intravenous fluids.[4][3] Initial symptoms may include a temperature greater than 38 °C (100.4 °F) or less than 36 °C (96.8 °F), fast heart rate, narrow pulse pressure, and increased respiratory rate.[1][2] More severe symptoms may include confusion and bluish skin.[2] Complications can include acute respiratory distress syndrome and multiple organ dysfunction syndrome.[2]

The most common type of infection is bacterial, with gram-negative bacterial infections present in 62% of cases and gram-positive bacterial infections present in 47% of cases.[2] In less than 5% of cases viruses or parasites are involved.[2] The most common locations of infections are the lungs (42%), blood (21%), and urine (10%), though in a third of cases the location is unclear.[2] Risk factors for sepsis include diabetes, cancer, liver or kidney problems, corticosteroid use, burns, poor immune function, and extremes of age.[2] It is a type of distributive shock.[5]

Treatment involves early goal-directed therapy, with the use of antibiotics, removing infected tissue, intravenous fluids, and vasoactive agents such as norepinephrine.[2] Other measures may include mechanical ventilation and corticosteroids.[2] Severe sepsis occurs in about 750,000 people (300 per 100,000) a year in the United States.[6][7] The risk of death is greater than 40% and some who survive are left with long term disability.[4][7]

Signs and symptoms

Thrombocytopenia with purpura on right hand in person with septic shock

Initial symptoms may include a temperature greater than 38 °C (100.4 °F) or less than 36 °C (96.8 °F), fast heart rate, narrow pulse pressure, and increased respiratory rate.[1][2] More severe symptoms may include confusion a bluish skin.[2] Complications can include acute respiratory distress syndrome, multiple organ dysfunction syndrome, and disseminated intravascular coagulation.[2]

Causes

Septic shock is a result of a systemic response to infection or multiple infectious causes. The precipitating infections that may lead to septic shock if severe enough include but are not limited to appendicitis, pneumonia, bacteremia, diverticulitis, pyelonephritis, meningitis, pancreatitis, necrotizing fasciitis, MRSA and mesenteric ischemia.[8][9]

According to the earlier definitions of sepsis updated in 2001[10], sepsis is a constellation of symptoms secondary to an infection that manifests as disruptions in heart rate, respiratory rate, temperature, and white blood cell count. If sepsis worsens to the point of end-organ dysfunction (kidney 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 criterion has 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.[11] Septic shock involves a widespread inflammatory response that produces a hypermetabolic effect. This is manifested by increased cellular respiration, protein catabolism, and metabolic acidosis with a compensatory respiratory alkalosis.[12]

Most cases of septic shock are caused by gram-positive bacteria,[13] followed by endotoxin-producing gram-negative bacteria, although fungal infections are an increasingly prevalent cause of septic shock.[12] Toxins produced by pathogens cause an immune response; in gram-negative bacteria these are endotoxins, which are bacterial membrane lipopolysaccharides (LPS).

Gram-positive

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 includeF 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

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).[14] 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.[11] 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.[14]

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, activation causing systemic leukocyte adhesion and diffuse alveolar capillary damage in the lung, and 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 other organ systems. Recently, severe damage to liver ultrastructure has been noticed from treatment with cell-free toxins of Salmonella.[15] Unless the underlying infection (and LPS overload) is rapidly brought under control, the patient usually dies.

The ability of TLR4 to respond to a distinct LPS species are clinically important. Pathogenic bacteria may employ LPS with low biological activity to evade proper recognition by the TLR4/MD-2 system, dampening the host immune response and increasing the risk of bacterial dissemination. On the other hand, such LPS would not be able to induce septic shock in susceptible patients, rendering septic complications more manageable. Yet, defining and understanding how even the smallest structural differences between the very similar LPS species may affect the activation of the immune response may provide the mechanism for the fine tuning of the latter and new insights to immunomodulatory processes.[16]

Diagnosis

According to current guidelines, requirements for diagnosis with sepsis are "the presence (probable or documented) of infection together with systemic manifestations of infection".[12] These manifestations may include:

  • Tachypnea (fast rate of breathing), which is defined as more than 20 breaths per minute, or when testing blood gas, a PaCO
    2     less than 32 mm Hg, 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 low blood pressure (BP) that does not respond to treatment. This means that intravenous fluid administration alone is not enough to maintain a patient's BP. Diagnosis of septic shock is made when systolic blood pressure is less than 90 mm Hg, a mean arterial pressure (MAP) is less than 70 mm Hg, or a systolic BP decrease of 40 mm Hg or more without other causes for low BP.[12]

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 tissues, resulting in ischemia and organ dysfunction. Septic shock refers specifically to distributive shock due to sepsis as a result of infection.

Septic shock may be defined as sepsis-induced low blood pressure that persists despite treatment with intravenous fluids.[12] 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 low blood pressure. Finally, in an attempt to offset decreased blood pressure, ventricular dilatation and myocardial dysfunction occur.

Septic shock may 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.

Treatment

Treatment primarily consists of:

  1. Intravenous fluids[17]
  2. Early antibiotics[17]
  3. Early goal directed therapy[17]
  4. Rapid source identification and control
  5. Support of organ dysfunction

Fluids

Because lowered blood pressure in septic shock contributes to poor perfusion, fluid resuscitation is an initial treatment to increase blood volume. Patients demonstrating sepsis-induced hypoperfusion should be initially resuscitated with at least 30 ml/kg of intravenous crystalloid within the first three hours.[9] 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.[13]

Antibiotics

Treatment guidelines call for the administration of broad-spectrum antibiotics within the first hour following recognition of septic shock. Prompt antimicrobial therapy is important, as risk of dying increases by approximately 10% for every hour of delay in receiving antibiotics.[13] Time constraints do not allow the culture, identification, and testing for antibiotic sensitivity of the specific microorganism responsible for the infection. Therefore, combination antimicrobial therapy, which covers a wide range of potential causative organisms, is tied to better outcomes.[13] Antibiotics should be continued for 7–10 days in most patients, though treatment duration may be shorter or longer depending on clinical response.[14]

Vasopressors

Among the choices for vasopressors, norepinephrine is superior to dopamine in septic shock.[18] Norepinephrine is the preferred vasopressor, while epinephrine may be added to norepinephrine when needed. Low-dose vasopressin also may be used as an addition to norepinephrine, but is not recommended as a first-line treatment. Dopamine may 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 low blood pressure in septic shock, the goal of vasopressor treatment is a mean arterial pressure (MAP) of 65 mm Hg.[13] In 2017, the FDA approved angiotensin II injection for intravenous infusion to increase blood pressure in adults with septic or other distributive shock.[19]

Methylene blue

Methylene blue has been found to be useful for this condition.[20][21][22][23] Although use of methylene blue has mostly been in adults it has also been shown to work in children.[24][25] Its mechanism of action is thought to be via the inhibition of the nitric oxide-cyclic guanosine monophosphate pathway.[26] This pathway is excessively activated in septic shock. Methylene blue has been found to work in cases resistant to the usual agents.[27] This effect was first reported in the early 1990s.[28][29]

Other

While there is tentative evidence for β-Blocker therapy to help control heart rate, evidence is not significant enough for its routine use.[30][31] There is tentative evidence that steroids may be useful in improving outcomes.[32]

Tentative evidence exists that Polymyxin B-immobilized fiber column hemoperfusion may be beneficial in treatment of septic shock.[33] Trials are ongoing and it is currently being used in Japan and Western Europe.[34]

Recombinant activated protein C (drotrecogin alpha) in a 2011 Cochrane review was found not to decrease mortality and to increase bleeding, and thus, was not recommended for use.[35] Drotrecogin alfa (Xigris), was withdrawn from the market in October 2011.

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.[36]

According to the U.S. Centers for Disease Control, septic shock is the thirteenth leading cause of death in the United States and the most frequent cause of death 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 may 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 fungemia; 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), and more than 30% of all cases are idiopathic in origin.

The mortality rate from sepsis, especially if it is not treated rapidly with the needed medications in a hospital, is approximately 40% in adults and 25% in children. It is significantly greater when sepsis is left untreated for more than seven days.[37]

References

  1. ↑ 1.0 1.1 1.2 1.3 ATLS - Advanced Trauma Life Support - Student Course Manual (10 ed.). American College of Surgeons. 2018. p. 51. ISBN 78-0-9968262.
  2. ↑ 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 2.11 2.12 2.13 2.14 2.15 2.16 2.17 2.18 Mahapatra, S; Heffner, AC (January 2020). "Septic Shock". PMID 28613689. {{cite journal}}: Cite journal requires |journal= (help)
  3. ↑ 3.0 3.1 "Sepsis Definitions and Diagnosis • LITFL • CCC Sepsis". Life in the Fast Lane • LITFL • Medical Blog. 3 November 2020. Archived from the original on 18 January 2021. Retrieved 5 January 2021.
  4. ↑ 4.0 4.1 4.2 Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, et al. (February 2016). "The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3)". JAMA. 315 (8): 801–10. doi:10.1001/jama.2016.0287. PMC 4968574. PMID 26903338.
  5. ↑ International Trauma Life Support for Emergency Care Providers (8 ed.). Pearson Education Limited. 2018. p. 175. ISBN 978-1292-17084-8.
  6. ↑ Ronco, Claudio; Bellomo, Rinaldo; Kellum, John A. (2009). Critical Care Nephrology. Elsevier Health Sciences. p. 831. ISBN 978-1-4160-4252-5. Archived from the original on 2021-08-29. Retrieved 2021-01-05.
  7. ↑ 7.0 7.1 FCCM, Joseph E. Parrillo, MD; MS, R. Phillip Dellinger, MD (2013). Critical Care Medicine: Principles of Diagnosis and Management in the Adult. Elsevier Health Sciences. p. 339. ISBN 978-0-323-08929-6. Archived from the original on 2021-08-29. Retrieved 2021-01-05.
  8. ↑ Melis M, Fichera A, Ferguson MK (July 2006). "Bowel necrosis associated with early jejunal tube feeding: A complication of postoperative enteral nutrition". Arch Surg. 141 (7): 701–4. doi:10.1001/archsurg.141.7.701. PMID 16847244.
  9. ↑ 9.0 9.1 Gwon JG, Lee YJ, Kyoung KH, Kim YH, Hong SK (September 2012). "Enteral nutrition associated non-occlusive bowel ischemia". J Korean Surg Soc. 83 (3): 171–4. doi:10.4174/jkss.2012.83.3.171. PMC 3433554. PMID 22977764.
  10. ↑ for the International Sepsis Definitions Conference; Levy, Mitchell M.; Fink, Mitchell P.; Marshall, John C.; Abraham, Edward; Angus, Derek; Cook, Deborah; Cohen, Jonathan; Opal, Steven M. (2003). "2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference". Intensive Care Medicine. 29 (4): 530–538. doi:10.1007/s00134-003-1662-x. ISSN 0342-4642. PMID 12664219.
  11. ↑ 11.0 11.1 Angus DC, van der Poll T (August 2013). "Severe sepsis and septic shock". N. Engl. J. Med. 369 (9): 840–51. doi:10.1056/NEJMra1208623. PMID 23984731.
  12. ↑ 12.0 12.1 12.2 12.3 12.4 Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, et al. (February 2013). "Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012". Crit. Care Med. 41 (2): 580–637. doi:10.1097/CCM.0b013e31827e83af. PMID 23353941.
  13. ↑ 13.0 13.1 13.2 13.3 13.4 Martin GS (June 2012). "Sepsis, severe sepsis and septic shock: changes in incidence, pathogens and outcomes". Expert Rev Anti Infect Ther. 10 (6): 701–6. doi:10.1586/eri.12.50. PMC 3488423. PMID 22734959.
  14. ↑ 14.0 14.1 14.2 Adib-Conquy M, Cavaillon JM (January 2009). "Compensatory anti-inflammatory response syndrome". Thromb. Haemost. 101 (1): 36–47. doi:10.1160/TH08-07-0421. ISSN 0340-6245. PMID 19132187.
  15. ↑ 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. Archived from the original on 2021-08-29. Retrieved 2014-03-12 – via ResearchGate.(animal study).
  16. ↑ Korneev KV, Arbatsky NP, Molinaro A, Palmigiano A, Shaikhutdinova RZ, Shneider MM, et al. (2015). "Structural Relationship of the Lipid A Acyl Groups to Activation of Murine Toll-Like Receptor 4 by Lipopolysaccharides from Pathogenic Strains of Burkholderia mallei, Acinetobacter baumannii, and Pseudomonas aeruginosa". Front Immunol. 6: 595. doi:10.3389/fimmu.2015.00595. PMC 4655328. PMID 26635809.
  17. ↑ 17.0 17.1 17.2 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.
  18. ↑ Vasu TS, Cavallazzi R, Hirani A, Kaplan G, Leiby B, Marik PE (2012). "Norepinephrine or dopamine for septic shock: systematic review of randomized clinical trials". J Intensive Care Med. 27 (3): 172–8. doi:10.1177/0885066610396312. PMID 21436167.
  19. ↑ Commissioner, Office of the. "Press Announcements - FDA approves drug to treat dangerously low blood pressure". www.fda.gov. Archived from the original on 2017-12-22. Retrieved 2017-12-22.
  20. ↑ Jang DH, Nelson LS, Hoffman RS (2013) Methylene blue for distributive shock: a potential new use of an old antidote. J Med Toxicol 9(3):242-249
  21. ↑ Baldo CF, Silva LM, Arcencio L, Albuquerque AAS, Celotto AC, Basile-Filho A, Evora PRB (2018) Why Methylene Blue have to be always present in the tocking of emergency antidotes. Curr Drug Targets 19(13):1550-1559
  22. ↑ McCartney SL, Duce L, Ghadimi K (2018) Intraoperative vasoplegia: methylene blue to the rescue! Curr Opin Anaesthesiol. 31(1):43-49
  23. ↑ Booth AT, Melmer PD, Tribble B, Mehaffey JH, Tribble C (2017) Methylene blue for vasoplegic syndrome. Heart Surg Forum 20(5):E234-E238
  24. ↑ Rutledge C, Brown B, Benner K, Prabhakaran P, Hayes L (2015) A novel use of methylene blue in the pediatric ICU. Pediatrics 136(4):e1030-4
  25. ↑ Volpon LC, Evora PRB, Teixeira GD, Godinho M, Scarpelini S, Carmona F, Carlotti APCP (2018) Methylene blue for refractory shock in polytraumatized patient: A case report. J Emerg Med 55(4):553-558
  26. ↑ Da Silva PS, Furtado P (2018) Methylene blue to treat refractory latex-induced anaphylactic shock: a case report. A A Pract 10(3):57-60
  27. ↑ Lo JC, Darracq MA, Clark RF (2014) A review of methylene blue treatment for cardiovascular collapse. J Emerg Med 46(5):670-679
  28. ↑ Schneider F, Lutun P, Hasselmann M, Stoclet JC, Tempé JD (1992) Methylene blue increases systemic vascular resistance in human septic shock. Preliminary observations. Intensive Care Med 18(5):309-11
  29. ↑ Preiser JC, Lejeune P, Roman A, Carlier E, De Backer D, Leeman M, Kahn RJ, Vincent JL (1995) Methylene blue administration in septic shock: a clinical trial. Crit Care Med 23(2):259-264
  30. ↑ Chacko CJ, Gopal S (2015). "Systematic review of use of β-blockers in sepsis". J Anaesthesiol Clin Pharmacol. 31 (4): 460–5. doi:10.4103/0970-9185.169063. PMC 4676233. PMID 26702201.
  31. ↑ Sanfilippo F, Santonocito C, Morelli A, Foex P (2015). "Beta-blocker use in severe sepsis and septic shock: a systematic review". Curr Med Res Opin. 31 (10): 1817–25. doi:10.1185/03007995.2015.1062357. PMID 26121122.
  32. ↑ Annane, Djillali; Bellissant, Eric; Bollaert, Pierre Edouard; Briegel, Josef; Keh, Didier; Kupfer, Yizhak; Pirracchio, Romain; Rochwerg, Bram (6 December 2019). "Corticosteroids for treating sepsis in children and adults". The Cochrane Database of Systematic Reviews. 12: CD002243. doi:10.1002/14651858.CD002243.pub4. ISSN 1469-493X. PMC 6953403. PMID 31808551.
  33. ↑ Mitaka C, Tomita M (October 2011). "Polymyxin B-immobilized fiber column hemoperfusion therapy for septic shock". Shock. 36 (4): 332–8. doi:10.1097/SHK.0b013e318225f839. PMID 21654557.
  34. ↑ Ronco C, Klein DJ (June 2014). "Polymyxin B hemoperfusion: a mechanistic perspective". Crit Care. 18 (3): 309. doi:10.1186/cc13912. PMC 4077196. PMID 25043934.
  35. ↑ Martí-Carvajal AJ, Solà I, Gluud C, Lathyris D, Cardona AF (December 2012). "Human recombinant protein C for severe sepsis and septic shock in adult and paediatric patients". Cochrane Database Syst Rev. 12: CD004388. doi:10.1002/14651858.CD004388.pub6. PMC 6464614. PMID 23235609.
  36. ↑ "Researchers make blood poisoning breakthrough". Phys.org. June 4, 2010. Archived from the original on June 6, 2011. Retrieved June 5, 2010.
  37. ↑ Huether, S.E.; McCance, K.L., eds. (2008). Understanding Pathophysiology (4th ed.). ISBN 9780323049900.[page needed]

External links

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External resources
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