By the mid‐1990s, sepsis syndrome had evolved into the nomenclature of systemic inflammatory response syndrome (SIRS). It was discovered that the body can respond to noninfectious insults and tissue injury in the same exaggerated manner that it does to microbial pathogens, with an almost identical pathophysiology [5]. In sepsis, pathogen‐associated molecular patterns (PAMPs), expressed by the pathogen, stimulate pattern recognition receptors (PRRs) in the host. With noninfectious diseases, damaged tissues also release endogenous mediators, such as alarmins and damage‐associated molecular pattern (DAMP) molecules (such as heat shock proteins, HMGB‐1, ATP, and DNA). These will stimulate the toll‐like receptor, PRRs or other receptor systems that typically respond to microbes and activate immune cell responses [6–8]. A list of proinflammatory cytokines associated with SIRS is provided in Table 1.1. Figure 1.1 provides a schematic of many of the proinflammatory changes that occur in this syndrome.

Soon the one‐hit and two‐hit models of MODS caused by SIRS were recognized in humans; one hit results from an initial massive insult (traumatic, metabolic, infectious), culminating in early SIRS and MODS. The two hits occur when a severely injured patient is successfully resuscitated, followed by a second inflammatory insult which amplifies SIRS and results in MODS [9,10]. It was discovered that an antiinflammatory response occurred after the initial inflammatory response as well. This compensatory antiinflammatory response syndrome (CARS) is characterized by increased appearance of antiinflammatory cytokines and cytokine agonists found in the circulation [11]. These antiinflammatory mediators were found for days or weeks after the proinflammatory mediators had gone [12]. Macrophage dysfunction is a significant contributor to CARS, with a decreased capacity to present antigens and release proinflammatory cytokines [13]. It was found that the T‐cells are defective and depleted due to apoptosis and decreased proliferation [14]. In addition, there is an increase in the suppressor cell populations [15]. Many of the cytokines released during CARS are listed in Table 1.1. Figure 1.2 provides a schematic of many of the antiinflammatory changes that occur during this process.

It was determined that the production of proinflammatory and antiinflammatory cytokines occurs simultaneously, with antiinflammatory gene expression paralleling the increased expression of proinflammatory genes [16]. It was then proposed that the induction of SIRS and CARS occurs simultaneously [17]. The emergence of myeloid‐derived suppressor cells (MDSCs) results in suppression of T‐cell responses through increased production of nitric oxide and reactive oxygen species. The increase in MDSCs is proportional to the severity of the inflammatory insult [17].

Although the pathophysiology has not been clearly defined for the SIRS‐CARS phenomenon, the basic hemodynamic consequences have been identified. Once the mediators have entered the circulation, the progression and complications are similar for each inciting disease: peripheral vascular dilation, increased capillary permeability, and depressed cardiac function. Three forms of shock are known to occur simultaneously in these patients: hypovolemic, distributive, and cardiogenic (see Figure 1.3). Once shock ensues, MODS is likely to occur if aggressive patient support has been delayed.

Many research and clinical trials have been conducted in laboratory animals and humans looking for a single best therapy that would be effective in treating most patients with the SIRS‐CARS phenomenon, with minimal success. Since inflammation and immune suppression have been found to be occurring simultaneously, each patient is more likely to be experiencing their own unique combination of immune stimulation and suppression. This makes a standardized protocol for therapy extremely difficult to formulate until further knowledge is acquired. Emphasis is no longer primarily directed at methods to stop exaggerated proinflammatory responses but is instead placed on supporting the patient and searching for new methods that prevent prolonged immunosuppression or restore immune function [18].

Sepsis, the SIRS‐CARS phenomenon (referred to simply as SIRS from here on), and MODS remain tremendous obstacles to the successful treatment of critically ill small animals. A “back to basics” approach is critical for any patient with the potential for inflammatory changes. Several basic yet key principles that can be used to guide patient assessment and care are listed in Box 1.1. Problems within the major organ systems should be anticipated in advance, with appropriate diagnostic, therapeutic, and monitoring efforts employed early, rather than waiting for a problem to surface and reacting to it. The Rule of 20 was developed to assist the critical care team in thoughtfully and carefully assessing these patients. Table 1.2 lists common problems to anticipate under each parameter of the Rule of 20 in patients with SIRS. Sample forms that can be used when applying the Rule of 20 are provided in Figures 1.4 and 1.5.

Rule of 20 parameter	Anticipated problems
Fluid balance	Hypovolemia; vasodilation, increased capillary permeability
Albumin, COP	Hypoalbuminemia; loss through capillaries and catabolic state; reduced COP and extravasation of fluid from vasculature
Blood pressure	Hypotension; hypovolemia and impaired cardiac performance, peripheral vasodilation
Glucose	Hypoglycemia; increased consumption, decreased intake; can affect vascular tone and cardiac performance
Electrolytes	Hypokalemia; any disorder is possible with fluid imbalances, catabolic state, and depressed nutritional intake
Acid–base	Metabolic acidosis associated with poor perfusion and elevated lactate is common
Oxygenation/ventilation	Hypoxemia possible if pulmonary edema from inflammatory vascular changes or poor cardiac performance
Coagulation	Thrombocytopenia (declining trend); some form of DIC due to mediator‐induced vasculitis, activation of serine proteases, and insufficient antithrombin
Red blood cells	Anemia from disease or erythrocytosis from dehydration; frequent blood sampling can result in anemia
Heart rate, rhythm, contractility	Tachycardia in dogs with poor perfusion, bradycardia in cats with poor perfusion; arrhythmias if poor perfusion; depressed myocardial contractility with circulating mediators
Neurological status	Depressed level of consciousness from perfusion changes, hypoxemia if present, circulating mediators, metabolic changes or underlying disease
Urinary tract status	Azotemia if poor perfusion or dehydration; impaired renal function if prolonged hypotension or nephrotoxic drugs
WBC, immune status	Impaired immune function, lymphopenia possible, susceptible to nosocomial infections
Gastrointestinal status	Gastric paresis, ileus; third body fluid spacing into bowel; bacterial translocation if no enteral feeding
Nutrition	Catabolic state and early malnutrition anticipated; bacterial translocation without enteral feeding
Drugs	Altered volume of distribution, metabolism and excretion
Body temperature	High if active inflammation; low in cats with poor perfusion or dogs with difficult‐to‐resuscitate shock
Pain control	Pain is anticipated with all critical illness and deserves analgesic support; critical early in shock resuscitation
Wound and bandage care	Possible source of pathogens requiring close monitoring of wound sites and bandage changes
Nursing care and TLC	Must receive the right treatment at the right time in the right amount; anticipate problems, be ready; provide TLC

COP, colloidal osmotic pressure; DIC, disseminated intravascular coagulation; TLC, tender loving care; WBC, white blood cell.