Elizabeth A. Carr
Systemic Inflammatory Response Syndrome
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 abnormalities found in a patient with underlying septicemia. However, the label sepsis is often inaccurately used to describe the clinical signs in patients that may or may not have an underlying bacterial infection as an 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 or 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 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 common result is activation of multiple physiologic cascades (inflammatory, complement, and coagulation) designed to localize and destroy the injurious agent.
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 colonize the healthy 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 the 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 proinflammatory molecules, including tumor necrosis factor-α (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 to 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 through sensory afferents to the central nervous system.
In concert with the upregulation of the inflammatory, coagulation, and complement cascades, antiinflammatory mediators are produced to limit the spread and severity of the proinflammatory response. Antiinflammatory cytokines, such as interleukin-10 (IL-10) and lipoxins, act by downregulating phagocytic cell activity and inhibiting other proinflammatory molecules.
The goal of this multifaceted response is to confine or eliminate the insulting agent (via the proinflammatory response) while limiting excessive and widespread inflammation (via the antiinflammatory response). Systemic inflammatory response syndrome results when the proinflammatory 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 worsening 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 in this chapter, although 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., fluid loss in a horse with pneumonia differs dramatically from that in a horse with severe colitis and 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 high-volume reflux, diarrhea secondary to enterocolitis, or third-space sequestration such 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 include hemoconcentration, hypoalbuminemia, and hypotension, as well as ineffective 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 be given rapidly through a 12-gauge intravenous 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 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. The extravascular fluid volume is pulled into the vascular space from cells, the interstitium (in response to the gradient in tonicity between interstitium and plasma), and 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 administration is required to maintain the volume expansion. In addition to its volume-expanding effects, hypertonic saline administration decreases bacterial translocation, leukocyte activation, endothelial cell adhesion molecule expression, and intestinal damage and increased short-term survival in a rat model of strangulated small bowel obstruction.
Colloids are solutions containing molecules of large molecular weight (such as albumin) that do not freely pass through healthy capillary membranes. Infusion of colloids results in increased plasma colloid osmotic pressure and favors movement of fluid into the vascular space, in accordance with the Starling principle. Natural colloids include plasma, concentrated albumin, and whole blood. Synthetic colloids available in the United States include hetastarch, dextran, and oxyglobin. Synthetic colloids have the advantage of ease of use and storage. Hetastarch is the most commonly used synthetic colloid in equine medicine and consists of a heterogeneous population of amylopectin molecules ranging in size from 30 to 2300 kDa. Attachment of hydroxyethyl groups to the glucose chains retards metabolism by amylase, permitting longer circulation time. The larger molecules of hetastarch may act as “plugs” in leaky vessel walls, effectively decreasing permeability defects and further fluid losses associated with SIRS.
In 2011, a large volume of research on hetastarch was retracted because of author misconduct. Subsequent to this retraction, a large-scale review of randomized controlled trials comparing hetastarch with other resuscitative fluids (excluding the retracted work) found an increased risk for renal injury and mortality in patients receiving hetastarch. Subsequent to this review, the U.S. Food and Drug Administration has issued a warning on the use of this synthetic colloid in adults (humans) with sepsis, preexisting renal disease, and other critical illness. Administration of hetastarch has also been associated with prolongation of prothrombin time and partial thromboplastin time in horses, and horses at risk for bleeding should undergo monitoring of coagulation parameters. Natural colloids have the advantage of providing albumin, antibodies, complement, and clotting factors, but disadvantages are that initiation of treatment will be delayed while products thaw, and infusions must be administered slowly because of the risk for allergic or anaphylactic reactions. The colloid oncotic pressure of commercial plasma is less than that of presently available synthetic products, so on a per-liter basis, synthetic colloids are more effective in restoring and maintaining plasma volume.
Blood is also a useful colloid; however, time is required for collection of fresh whole blood, and unless the recipient is anemic or has acute hemorrhage (requiring replacement of red blood cell mass and oxygen-carrying capacity), the benefits of blood administration do not outweigh those of plasma.
The choice of replacement fluid and volume administered depends on the severity of the deficits and other clinicopathologic findings. In a horse with severe hypovolemia and normal to high values for colloid oncotic pressure, initial treatment with hypertonic saline (2 to 4 mL/kg), followed by administration of isotonic crystalloids, can rapidly restore circulating volume while emergency treatment is instituted. If colloid oncotic pressure falls or signs of improved cardiovascular function are not seen (e.g., a decrease in the heart rate and capillary refill time and an increase in extremity temperatures, central venous pressure, jugular refill, and urine output), infusion of colloids should be considered to try to improve circulating volume and perfusion. Typical therapy would begin with a bolus dose of about 10 mL/kg, followed if necessary by continuous rate infusion at 1 mg/kg per hour, with total dose not to exceed 20 to 25 mL/kg per day. Frequent clinical monitoring, with particular attention paid to jugular fill, central venous pressure, urine production, and blood pressure, is critical for assessing response to fluid therapy.
Nonsteroidal Antiinflammatory Drugs
Nonsteroidal antiinflammatory drugs (NSAIDs) are the most commonly used drugs in treatment of endotoxemia and sepsis in horses. These drugs block the cyclooxygenase (COX) enzyme responsible for metabolism of membrane lipids to many of the proinflammatory mediators seen in acute inflammatory disorders. There are three isoforms of COX enzymes, with the functions of COX-1 and COX-2 being best described; COX-1 is constitutively expressed, whereas COX-2 expression is upregulated in response to injury. Nonsteroidal antiinflammatory drugs vary in their selectivity for the COX enzyme isoforms. Flunixin meglumine, a nonspecific COX enzyme inhibitor, has long been a staple in the treatment in endotoxemia, sepsis, and other critical illness in the horse. Treatment with flunixin meglumine results in improvement in clinical variables (e.g., decreased heart rate, temperature, and colic symptoms) and laboratory values (improvement in hyperlactatemia, hypoxemia, and acidosis) in both experimentally induced and natural endotoxemia in horses. Although production of proinflammatory mediator is blocked at the lower end of the dosage range (0.25 mg/kg), administration of a dose of 1.1 mg/kg appears to ameliorate clinical signs and more effectively blocks production of proinflammatory molecules. The potential to block severe pain and mask signs of surgical colic at the higher dosage has not, in the author’s opinion, been a concern, and given the superior effect of flunixin in controlling and minimizing clinical and laboratory derangements, administration of 0.5 to 1.1 mg/kg every 12 hours is recommended over administration of a lower dose given every 6 to 8 hours. Given its nonspecific COX selectivity, flunixin meglumine will retard the recovery of ischemic injured bowel, resulting in an increase in permeability to LPS, compared with that in untreated injured bowel. In contrast, treatment with firocoxib (0.09 mg/kg, IV, every 24 hours), a COX-2 selective NSAID, allowed recovery of injured bowel permeability while also providing analgesia and antiinflammatory benefits similar to flunixin in one study. Further work is needed to determine its suitability for treatment of horses with sepsis and SIRS.
Toxic effects of NSAIDs include gastrointestinal ulcer formation and renal toxicosis. Minimizing the duration of treatment with NSAIDs while maintaining adequate hydration is important for avoiding adverse effects. Monitoring trends in serum total protein and creatinine concentrations is useful in assessing intestinal and renal toxicity, respectively, because small changes in either, in the absence of other causes, would indicate potential toxicosis.