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Basics ⬇

Outline

BASICS

Definition!!navigator!!

  • Endotoxemia is a clinical syndrome characterized by the presence of endotoxin in the blood, generalized inflammatory response, and systemic effects. Endotoxin (LPS) is a heat-stable toxin associated with the lipid portion of the outer layer of cell membranes in Gram-negative bacteria. Endotoxemia occurs when either Gram-negative bacteria or the LPS gain access to the systemic circulation
  • The term systemic inflammatory response syndrome (SIRS) is used to describe the clinical manifestation of endotoxemia
  • Endotoxemia occurs through a cascade of events. First, LPS is absorbed from severe localized or disseminated Gram-negative bacterial infection or as free LPS through hypoperfused or inflamed damaged epithelial surfaces. Once in the systemic circulation, LPSs interact with blood constituents or can be removed by macrophages in liver, spleen, or pulmonary vasculature. This is initiated when the LPS-binding protein complexes are bound by the pattern recognition receptors of the inflammatory cells. This complex activates the MyD88 adaptor protein in the equine monocytes, resulting in proinflammatory effects. Therefore, LPS is a potent stimulus of the host inflammation, leading to activation of defense mechanisms that initiate overzealous inflammatory processes causing the manifestations seen in endotoxemia, which are determined by the effects of inflammatory mediators (TNF, IL-1, IL-6, IL-8, IL-10, TXA2, PGE2, PAF, LTB4, kinins, oxygen-derived free radicals, etc.)
  • The main effects are endothelial dysfunction, hemodynamic changes, neutrophil activation, coagulopathy, complement activation, acute phase response, shock, and organ failure

Systems Affected!!navigator!!

Cardiovascular

  • Reduced myocardial contractility
  • Vascular endothelial damage resulting in permeability changes, fluid leakage, and DIC

GI

Impaired mucosal perfusion may cause mucosal sloughing, allowing bacterial translocation and further LPS absorption.

Hepatobiliary

Hepatic ischemia may cause hepatocellular enzyme increases, and alter hepatic function.

Renal

Acute renal failure may result from reduced renal blood flow.

Respiratory

Pulmonary edema and pulmonary thromboembolism may occur.

Signs!!navigator!!

Early

  • Fever
  • Depression
  • Tachycardia
  • Pale mucous membranes
  • Rapid CRT
  • Tachypnea and/or labored respiration

Late

  • Tachycardia or bradycardia
  • Poor peripheral pulses
  • Hypotension
  • Dark mucous membranes
  • Prolonged CRT
  • Cool extremities
  • Hypothermia
  • Peripheral edema
  • Abdominal pain
  • Diarrhea
  • Ileus
  • Laminitis
  • Abortion
  • Petechial and ecchymotic hemorrhages
  • Death

Neonates

Decreased suckling and weakness.

Causes!!navigator!!

GI Disorders

LPS normally gains access to the blood through compromised mucosa that may also allow translocation of Gram-negative bacteria.

Neonatal Sepsis

Localized or disseminated infectious focus causing Gram-negative bacteremia or release of LPS into the circulation.

Risk Factors!!navigator!!

  • The equine is particularly susceptible to sepsis secondary to GI disease, metritis, pneumonia and pleuropneumonia, and neonatal sepsis
  • Failure of transfer of passive immunity and high-risk pregnancies in neonatal septicemia

Diagnosis ⬆ ⬇

Outline

DIAGNOSIS

The diagnosis is usually made based on appreciation of the primary disease process with a high risk of endotoxemia and the presence of the above-mentioned clinical signs in combination with clinicopathologic laboratory findings. A chemiluminescent endotoxin assay has been used to measure endotoxin activity in horses with colic.

Differential Diagnosis!!navigator!!

  • Hypovolemic shock
  • Cardiogenic shock

CBC/Biochemistry/Urinalysis!!navigator!!

  • Initially, there is a neutropenia due to vascular margination (may be < 1000/µL; 109 cells/L). This is followed by a neutrophilic leukocytosis with a left shift, due to induction of myeloid proliferation in the bone marrow. Toxic changes are usually present in the neutrophils
  • Hemoconcentration (increased PCV and total plasma protein)
  • Hyperproteinemia initially due to hemoconcentration, but may decrease significantly with GI losses
  • High hepatocellular enzymes and bilirubin due to ischemic hepatic injury
  • Azotemia may be due to renal or prerenal azotemia associated with blood volume depletion
  • Initial hyperglycemia followed by hypoglycemia

Other Laboratory Tests!!navigator!!

Coagulation Profile

  • Prolongation of the activated partial thromboplastin time and partial thromboplastin time
  • Increased fibrinogen degradation products
  • Thrombocytopenia
  • Decreased plasma fibrinogen
  • Decreased antithrombin III

Blood Gas Analysis

  • •Hypoxemia
  • •Acid–base disturbances; metabolic acidosis due to decreased peripheral perfusion and hypoxemia

Diagnostic Procedures!!navigator!!

Aerobic and anaerobic blood cultures.

Treatment ⬆ ⬇

TREATMENT

The ideal treatment for endotoxemia is prevention. Close monitoring to prevent the development of the cascade of events should be instituted. Treatment should be initiated quickly and should be aimed at stabilization with aggressive symptomatic therapy, inhibition of endotoxin release into circulation, controlling the inflammatory response, and providing supportive care while establishing tissue perfusion, scavenging of LPS, and management of coagulopathy. If the source of sepsis can be identified, it should be addressed.

Medications ⬆ ⬇

Outline

MEDICATIONS

Drug(s) of Choice!!navigator!!

Fluid Therapy and Cardiovascular Support

  • Fluid therapy—restoration of the circulating blood volume is the most important factor in restoring peripheral perfusion. Balanced electrolyte solutions such as lactated Ringer's solution or 0.9% sodium chloride; in foals, dextrose should be added to the fluid therapy. Rates of 10–20 mL/kg/h to severely compromised horses. Use caution not to overhydrate and cause pulmonary edema. Foals and adults with low plasma protein levels are particularly susceptible
  • Colloidal solutions (whole blood, plasma, hetastarch, dextrans) can be used to maintain the fluid in the vascular space. They should be initiated when plasma proteins are <4 g/dL, 40 g/L
  • Colloids should be from a commercial source or from appropriate donors (Aa and Qa isoantibody negative)
  • 7.5% hypertonic saline solution 4 mL/kg for rapid volume expansion
  • Sodium bicarbonate to treat severe metabolic acidosis that does not correct with volume expansion. Adult—0.5 mEq × body weight (kg) × (base deficit); give half the dose slowly IV over 20 min. Give the rest of the dose in crystalloid fluids over 4 h if necessary. Foals—0.7 mEq × body weight (kg) × (base deficit); then follow the same regimen as above
  • Inotropic agents can be given to increase systemic blood pressure when it drops to <60 mmHg. Dopamine hydrochloride—1–5 µg/kg/min by continuous IV administration but its use in horses is questioned. Dobutamine—titrated from 0.5–1 µg/kg/min by continuous IV administration in adult horses and 1–3 µg/kg/min in foals
  • Oxygen therapy if hypoxia and respiratory distress are present

Inhibition of Endotoxin Release

  • Antimicrobials should be initiated soon after samples for culture have been obtained when a primary bacterial infection is suspected. Initially, broad-spectrum antimicrobials should be selected pending the results of the culture and susceptibility. Commonly used drugs include aminoglycosides, third-generation cephalosporins, potentiated sulfonamides, and expanded-spectrum penicillins. However, the use of aminoglycosides and carbapenems is suggested given they cause minimal LPS release from bacteria
  • The use of antimicrobials for endotoxemia resulting from gastroenteritis is debatable
  • Removal of infected tissues or fluids may be helpful

Inhibition of Mediator Synthesis

Corticosteroids

The use of corticosteroids is controversial in horses. In humans, low-dose corticosteroids are now used in the treatment of septic shock with an increase in survival rate without increasing adverse events, while administration of high-dose corticosteroids is discouraged. Whether corticosteroids will provide similar benefit in horses remains to be determined.

NSAIDs

  • NSAIDs are used for attenuation of the inflammatory cascade by inhibiting cyclooxygenase
  • Flunixin meglumine (0.5 mg/kg every 8–12 h or 0.25 mg/kg every 6–8 h) appears to have the most potent antiendotoxic effects
  • NSAIDs inhibit vasodilator PGs; therefore, care must be taken with regard to renal damage

Scavenger of LPS

Immunotherapy (Hyperimmune Antisera or Plasma)

  • O-chain-specific antiserum is not clinically useful due to the antigenic diversity in this region
  • Different Gram-negative bacteria share common core antigens; therefore, antibodies are aimed at the LPS core. The use of J5 hyperimmune plasma (4.4 mL/kg) is controversial due to inconsistent efficacy in different studies

Polymyxin B

  • Cationic polypeptide antibiotic used to bind the lipid A portion of LPS
  • It is nephrotoxic and neurotoxic; caution is advised
  • Reduced toxicity is achieved if the drug is administered as a conjugate with Dextran-70
  • Current recommendation of IV administration of 1000–6000 U/kg every 8–12 h up to 4 or 5 times is based on experimental studies. Its efficacy in clinical equine cases has not been critically evaluated

Contraindications!!navigator!!

  • Glucocorticoids may be contraindicated in horse with severe bacterial infection or exhibiting signs of laminitis
  • Caution is advised when polymyxin B is administered to dehydrated, hypovolemic, and azotemic patients given its neurotoxicity and nephrotoxicity

Precautions!!navigator!!

NSAID toxicity may result in GI ulceration and renal ischemia.

Possible Interactions!!navigator!!

Sodium bicarbonate and dopamine cannot be administered in the same IV line.

Alternative Drugs!!navigator!!

  • Pentoxifylline
  • DMSO
  • Lidocaine in CRI
  • Ketamine in CRI

Follow-up ⬆ ⬇

Outline

FOLLOW-UP

Patient Monitoring!!navigator!!

  • Vital parameters should be closely monitored
  • Blood gas analysis and pulse oximetry to measure oxygenation and acid–base balance
  • PCV, serum total protein, albumin, serum electrolytes, hepatocellular enzymes, BUN, and serum creatinine should be monitored

Possible Complications!!navigator!!

  • Laminitis
  • Electrolyte and acid–base disturbances
  • Pulmonary edema
  • Pulmonary thromboembolism
  • DIC
  • Renal dysfunction
  • Hepatic dysfunction
  • GI ischemia and bacterial translocation
  • Vasculitis and peripheral edema
  • Cardiac arrest

Miscellaneous ⬆ ⬇

Outline

MISCELLANEOUS

Synonyms!!navigator!!

  • Endotoxic shock
  • Gram-negative sepsis

Abbreviations!!navigator!!

  • BUN = blood urea nitrogen
  • CRI = constant rate infusion
  • CRT = capillary refill time
  • DIC = disseminated intravascular coagulation
  • GI = gastrointestinal
  • IL = interleukin
  • LTB4 = leukotriene B4
  • LPS = lipopolysaccharide
  • NSAID = nonsteroidal anti-inflammatory drug
  • PAF = platelet-activating factor
  • PCV = packed cell volume
  • PG = prostaglandin
  • TNF = tumor necrosis factor
  • TXA2 = thromboxane A2

Suggested Reading ⬆ ⬇

Kelmer G. Update on treatments for endotoxemia. Vet Clin North Am Equine Pract 2009;25:259–270.

Moore JN, Vandenplas ML. Is it the systemic inflammatory response syndrome or endotoxemia in horses with colic? Vet Clin North Am Equine Pract 2014;30:337–351.

Author(s) ⬆

Author: Olimpo Oliver-Espinosa

Consulting Editors: Henry Stämpfli and Olimpo Oliver-Espinosa