The Systemic Inflammatory Response Syndrome

CHAPTER 189 The Systemic Inflammatory Response Syndrome



Elizabeth A. Carr


In 1914, Schottmueller defined septicemia as “a state of microbial invasion from a portal of entry into the blood stream which causes signs of illness.” It should follow that the term sepsis would be applied to a set of clinical parameters found in a patient with underlying septicemia. However, the label sepsis is often inappropriately used to describe the clinical signs in patients that may or may not have an underlying bacterial infection as the inciting cause. In an effort to make the nomenclature more precise, the term systemic inflammatory response syndrome (SIRS) was coined to define the clinical syndrome (i.e., the clinical signs of sepsis) that can result from a wide variety of clinical insults, including, but not limited to, bacterial invasion. The term sepsis should be reserved for patients with clinical signs of SIRS resulting from bacterial invasion and infection. The confusion regarding nomenclature emphasizes the fact that although the underlying trigger may differ, the pathophysiologic response and clinical manifestation of sepsis and SIRS are similar and may be impossible to differentiate at times.


The most common cause of SIRS in adult horses is endotoxemia resulting from increased absorption of endotoxin, or lipopolysaccharide (LPS), from the lumen of the large intestine. In foals the most common cause of SIRS is septicemia or severe localized bacterial infection. Other causes include ischemia-hypoxemia, burns or smoke inhalation, severe localized infections (peritonitis, pleuritis), and severe trauma or bleeding (as in pulmonary infarction).


Whether the initial triggering insult is endotoxin, sepsis, or smoke inhalation, the result is activation of multiple physiologic cascades (inflammatory, complement, and coagulation) designed to localize and destroy the injurious agent at the site of injury.


As mentioned, the most common cause of SIRS in adult horses is endotoxemia, which typically develops as the result of increased absorption of LPS across the intestinal wall. The lumen of the equine large bowel contains large quantities of endotoxin, and the integrity of the mucosal barrier is critical in preventing its absorption. The integrity of this barrier is maintained by epithelial tight junctions, soluble factors, and resident microbial flora that normally colonize the bowel wall. In the normal state, small quantities of LPS are absorbed and scavenged by liver macrophages (Kupffer cells) and circulating anti-LPS antibodies. Injury to the wall, whether ischemic, infectious, or infiltrative in origin, results in loss of barrier integrity and absorption of increased quantities of endotoxin, with subsequent overwhelming of normal scavenging mechanisms.


After gaining entry into the systemic circulation, the lipid-A moiety of LPS is bound to circulating LPS-binding protein (LBP) and shuttled to the surface of an immune effector cell. The LPS-LBP complex interacts with cell surface receptor CD14 and triggers phosphorylation of Toll-like receptor-4 (TLR4) and activation of the nuclear transcription factor-κβ (NF-κβ). Activation of NF-κβ results in transcription of pro-inflammatory molecules, including tumor-necrosis factor-alpha (TNF-α), interleukins, chemokines, and growth factors. These cytokines stimulate neutrophil adhesion, diapedesis, and migration to the site of injury. Once there, activated neutrophils release additional cytokines, reactive oxygen species, and enzymes. In addition, endothelial cells are stimulated to express novel surface receptors and tissue factor as well as produce additional soluble molecules that result in activation of the coagulation and complement cascades. Cytokines also affect the hypothalamic setpoint (resulting in fever), alter hormone production and metabolic responses (resulting in a hypermetabolic state with protein calorie wasting), trigger insulin resistance, and induce hepatic production of acute-phase proteins. Altered neurotransmitter release at the tissue level secondary to local injury and inflammation affects motility and secretion, and neurotransmitter molecules can act as proinflammatory molecules locally as well as induce more wide-ranging systemic effects via sensory afferents to the central nervous system (CNS).


In concert with the upregulation of the inflammatory, coagulation, and complement cascades, there is production of anti-inflammatory mediators designed to limit the spread and severity of the pro-inflammatory response. Anti-inflammatory cytokines, such as interleukin-10 (IL-10) and lipoxins, act by downregulating phagocytic cell activity and inhibiting other pro-inflammatory molecules.


The goal of this multifaceted response is to confine or eliminate the insulting agent (pro-inflammatory response) while limiting excessive and widespread inflammation (anti-inflammatory response). Systemic inflammatory response syndrome results when the pro-inflammatory response is uncontrolled and excessive as a result of amplification of the positive feedback loop between cytokines and inflammatory cells. Activation of coagulation and fibrinolysis, designed to limit the spread of a focal injury, can also compromise organ perfusion and function when amplified. The effect is widespread changes in vascular integrity (increased permeability of endothelium), a hypercoagulable state that leads to development of microthrombi in small vessels and organ dysfunction, altered cardiovascular function, decreased cardiac contractility, vasodilation, and perfusion deficits. If unchecked, these systemic derangements can lead to organ dysfunction and failure, cardiovascular shock, and death.



CLINICAL SIGNS


In humans the clinical definition of SIRS is detection of two or more of the following: fever or hypothermia, tachycardia, tachypnea, and leukocytosis or leukopenia. This clinical definition is broad and arguably could encompass cases that do not have true SIRS. In horses additional clinical signs commonly seen with SIRS include injected or “toxic”-appearing mucous membranes with prolonged capillary refill time. In severe cases, tachycardia is accompanied by more profound evidence of circulatory compromise such as poor peripheral pulse quality, poor jugular refill, and cool extremities. Laboratory data often reveal hyperlactatemia, hypoxemia, and hypocapnia (secondary to increased ventilatory rate). These findings, in conjunction with low central venous pressure, are indications of hypovolemia, poor perfusion, and decreased oxygen delivery to the tissues. Additional clinical signs vary, depending on the cause of SIRS. In foals with septicemia, clinical signs associated with a localized infection, such as pneumonia with signs of respiratory compromise, or enteritis with signs of ileus and malabsorption or colic, may be seen. In adult horses with SIRS resulting from a gastrointestinal disorder, signs of ileus (reflux or colic), malabsorption, and electrolyte wasting may be seen. Consequently treatment for SIRS must be tailored to the underlying disease process. General treatment options for endotoxemia or SIRS are discussed later in this chapter; treatments targeted for specific etiologies have been well described and are not detailed here.



TREATMENT



Intravenous Fluids and Colloids


Depending on the duration of illness and the underlying cause (e.g., pneumonia versus severe colitis with large-volume diarrhea), fluid deficits in horses with SIRS can range from mild dehydration to severe hypovolemic shock. Fluid deficits result from increased losses such as can occur with ileus and large-volume reflux, diarrhea secondary to enterocolitis, or third-space sequestration as can develop with 360-degree volvulus of the large colon. Sick, febrile horses frequently have low water consumption, which exacerbates the water deficits. In addition to losses or decreased intake, SIRS affects both vascular integrity (increased permeability) and tone (decreased vasoconstrictive responses) as well as cardiac function. Consequently, whereas total body water volume may remain unchanged, there can be a decrease in effective circulating volume. Clinical findings associated with the alteration in cardiovascular integrity and function includehemoconcentration, hypoalbuminemia, and hypotension as well as inefficient cardiovascular compensatory responses.


In a horse with normal colloid oncotic pressure and normal vascular integrity, isotonic crystalloids are a useful and effective fluid for rapid restoration of circulating volume and tissue perfusion. If needed, 20 L of crystalloids can easily be given in less than an hour through a 12-gauge intravenous (IV) catheter and large-bore tubing. However, because electrolytes are rapidly diffusible across the endothelium, 75% to 80% of infused crystalloids will redistribute to the interstitium and intracellular spaces within an hour of infusion. In horses with increased vascular permeability, the percentage of redistribution can be even higher and can result in interstitial edema and further exacerbation of oxygen delivery deficits. Hypertonic saline is also an effective fluid for rapid, transient restoration of effective circulating volume. The high tonicity of hypertonic saline (7.2% NaCl solution) results in approximately 4 L of expansion in intravascular volume for every 1 L infused. Hypertonic saline can be easily carried for administration in the field before referral. The extravascular fluid volume is pulled from the interstitium (in response to the gradient in tonicity between interstitium and plasma) and from third spaces (such as intraluminal ingesta in the gastrointestinal tract). Similar to isotonic crystalloids, the volume expansion associated with administration of hypertonic saline is short lived, and additional fluid therapy is required to maintain volume expansion.

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May 28, 2016 | Posted by in EQUINE MEDICINE | Comments Off on The Systemic Inflammatory Response Syndrome

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