Monitoring and Intervention for the Critically Ill Small Animal: The Rule of 20

CHAPTER 1

An introduction to SIRS and the Rule of 20

Rebecca Kirby

(Formerly) Animal Emergency Center, Gainesville, Florida

Introduction to the Rule of 20 and inflammatory response syndromes

Heat stroke, peritonitis, parvovirus diarrhea, systemic lymphosarcoma, leptospirosis, massive trauma, gastric dilation‐torsion, aspiration pneumonia, pancreatitis, immune‐mediated disease, and postoperative laparotomy are but a sampling of the multitude of potentially life‐threatening disorders that can affect the small animal intensive care unit (ICU) patient. These and other disorders share a common pathophysiology: an inciting stimulus initiates the production and release of circulating mediators that cause systemic inflammatory changes.

Inflammation can be defined as a localized protective response elicited by injury or destruction of tissues that serves to destroy, dilute, or wall off both the injurious agent and the injured tissue [1]. Chemical mediators are released in response to an inciting antigen and initiate the innate immune response that causes inflammation. The classic signs of inflammation are heat, redness, swelling, pain, and loss of normal function. These are manifestations of the physiological changes that occur during the inflammatory process: (1) vasodilation (heat and redness), (2) increased capillary permeability (swelling), and (3) leukocytic exudation (pain). The initial inflammatory response to a localized insult is good, serving to localize the problem, destroy an offending pathogen, clean up damaged tissues, and initiate the healing process.

However, many ICU patients develop a negative trajectory when the inflammatory mediators and their response have systemic consequences. When this occurs due to an infection, it is called sepsis, and when it progresses, it often results in multiple organ dysfunction syndrome (MODS) or multiple organ failure (MOF).

It might appear logical that an overwhelming infectious agent could stimulate systemic inflammation. Yet, an almost identical clinical progression has been commonly observed in response to conditions that are not due to infection (such as trauma, surgery, and certain metabolic diseases). The term sepsis syndrome was first used to describe this in human patients when they appeared to be septic but had no obvious source of infection [2–4].

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.

Table 1.1 Inflammatory and hemostatic mediators of severe sepsis and their effects.

Adapted from: Balk RA, Ely EW, Goyette RE. Stages of infection in patients with severe sepsis. In: Sepsis Handbook, 2nd edn. Thomson Advanced Therapeutics Communication, 2004, pp 24–31.

Figure 1.1 A schematic of some of the major consequences of the proinflammatory component of systemic inflammatory response syndrome (SIRS). Many cells produce proinflammatory mediators, including monocytes, macrophages, and endothelial cells. The interaction of an antigen (microbial or tissue based) with its receptor will cause the stimulation of protein kinase C and the production of cytokines. Cytokines in the circulation will interact with their specific receptor on other cells and stimulate the production of more cytokines. In addition to the release of cytokines (IFN, IL‐1, TNF), the arachidonic acid cascade is stimulated and produces PG, PAF, and leukotrienes. Reactive oxygen species are produced as well. Some of the consequences include degranulation of white cells, endothelial damage, stimulation of coagulation, white blood cell chemotaxis and adherence in capillaries, and increased phagocytosis of Ags. Ag, antigen; IFN, interferon; IL, interleukin; O2., superoxide radicals; PAF, platelet activating factor; PG, prostaglandins; TNF, tumor necrosis factor; TLR, toll‐like receptor; TTP, tissue thromboplastin; VIIa, activated factor VII.

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.

Figure 1.2 A schematic of some of the major consequences of the antiinflammatory component of the compensatory antiinflammatory response syndrome (CARS). Red dotted lines depict inhibitory actions, blue solid lines depict stimulatory action. T‐cells, monocytes, and macrophages are the primary cells affected. The same antigens (microbial or tissue based) that stimulate the proinflammatory response can also stimulate the antiinflammatory cascades. The antiinflammatory mediators will block the production of many of the proinflammatory cytokines (red triangle and red dotted lines). TNF and IL‐1 receptors are found in the circulation and will bind and inactivate TNF and IL‐1 proinflammatory mediators. Ag, antigen; IFN, interferon; IL, interleukin; IL‐1R, interleukin‐1 receptor; iNOS, inducible nitric oxide synthetase; O2., superoxide radicals; PD‐1, programmed death‐1; TGF‐β, tissue growth factor‐beta; TLR, toll‐like receptor; TNF, tumor necrosis factor; TNFR, tumor necrosis factor receptor.

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.

Figure 1.3 A schematic depicting the presence of proinflammatory (blue) and antiinflammatory (yellow) mediators released concurrently (green), causing hemodynamic changes that result in three simultaneous forms of shock.

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.

Table 1.2 Common problems to anticipate for each parameter of the Rule of 20 in the SIRS patient.

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

Figure 1.4 The Rule of 20. Each parameter should be assessed regularly in any critically ill dog or cat. The order of importance will vary between individual patients. COP, colloidal osmotic pressure; GI, gastrointestinal, TLC, tender loving care; WBC, white blood cell.

Figure 1.5 Rule of 20 form for recording current patient status, targeted endpoints, and proposed intervention. RBC, red blood cell; WBC, white blood cell.

Box 1.1 Key principles to guide the care of the small animal ICU patient.

Treat the most life‐threatening problem first

Treat the patient, not the numbers

Anticipate the worst and be ready for it

Provide the right treatment, at the right time, in the right amount

Examine the cause of the problem and the effect on the patient

Weigh the pros and cons of every drug and procedure

There is not a drug for every problem – less is best

If it has not been written down, it has not been done

Never ignore your gut feeling

Things are done in the order of importance

The critical care team must remain open to options for the diagnosis and care of the patient when changes in patient status occur and must reconsider differentials when a patient is not progressing as expected. A problems list for the patient should be established and revised at least daily, with options for diagnostic, therapeutic, and monitoring plans for each problem outlined and considered (Figure 1.6). A differential diagnosis list is prepared for each problem and frequently reevaluated with the goal of finding one diagnosis that could be responsible for all the listed problems.

Figure 1.6 An example of a worksheet to ensure that each patient problem has a diagnostic, therapeutic, and monitoring plan. The worksheet has some examples of problems to demonstrate the intention of the form. Each of the problems that the patient has that day should be listed in the left‐hand column. New and unresponsive problems deserve a diagnostic, therapeutic, and monitoring plan written down. After assessing each problem and possible plan, the task of choosing the most efficient means for patient diagnosis and care can be performed. Dx, diagnostic; Mx, monitoring; Rx, therapeutic.

There are many aspects of critical care that are unique to the cat. Challenges occur when treating the cat due to species differences such as their physiological response to shock, the specific methods required for shock resuscitation and the different drug responses, metabolism, and dosing requirements. Knowledge of the traits specific to the cat is mandatory for optimizing their ability to recover from critical illness. These differences are highlighted in each chapter throughout the Rule of 20.

The successful treatment of SIRS and MODS has lead to the emergence of a new syndrome identified in human medicine, the persistent inflammation/immunosuppression catabolism syndrome (PICS) [17]. Secondary nosocomial infections and severe protein catabolism are hallmarks of PICS. This syndrome presents the simultaneous challenge of managing chronic inflammation and immunosuppression. These patients are identified in the surgical ICU after >10 days and have persistent inflammation defined by findings such as elevated C‐reactive protein, lymphopenia (<800/mm³), serum albumin < 3 g/dL, and weight loss >10%.

A study of adult humans suffering severe blunt trauma found that patients with complicated clinical outcomes are exhibiting PICS [19]. These patients were reported as being significantly older and sicker, with persistent leukocytosis but low lymphocyte and albumin levels compared with uncomplicated patients. They expressed significant suppression of myeloid cell differentiation, increased inflammation, decreased chemotaxis, and defective innate immunity compared with uncomplicated patients. Genomic analysis found changes consistent with defects in the adaptive immune response and increased inflammation. Clinical data showed persistent inflammation, immunosuppression, and protein depletion.

Unfortunately, at this time, when PICS is recognized, the course correction is difficult. Therapeutic interventions are geared towards supportive care and treating secondary infections. Further research is needed to identify appropriate multimodal therapies that target specific components of the syndrome [16]. The Rule of 20 now becomes even more important for thoroughly assessing and supporting these critical patients.

Diagnostic and monitoring procedures

The practice of medicine is an art that depends on the ability to successfully acquire and integrate the findings from the patient history, physical examination (PE), and cage‐side point of care (POC) laboratory database. Patients continuously give important information through their physical changes, progression of illness, and clinical signs. Additional diagnostic testing is done to confirm, deny or better define the clinical impressions gained from evaluation of the patient status and underlying disease(s). It is not uncommon for life‐threatening problems to require stabilization before time‐consuming or invasive diagnostic and monitoring procedures are employed.

The history and physical examination

The key to taking a great history is organization. A sample format for obtaining a sequential history pertaining to the small animal ICU patient is presented in Table 1.3. The order in which the topics are addressed is specifically arranged to better direct information gathering while allowing the owner to describe their concerns about their pet.

Table 1.3 Example of a format for obtaining a sequential history relevant to the small animal ICU patient. The recommended sequence of questioning is shown and is directed at controlling the conversation while meeting the needs of the client to tell their story about their pet.

Frequently reported complaints elicited from the history (such as vomiting, inability to walk, diarrhea) require further characterization to localize the disease or indicate the severity of the problem. Discussions about significant historical data pertaining to each of the Rule of 20 topics can be found in the corresponding topic chapter.

Each member of the critical care team will develop his or her own style and routine for performing a PE for individual patients. The key is to be consistent and thorough. A rapid evaluation of the ABCs (Airways, Breathing, Bleeding, Circulation, Consciousness) is the first priority, with intervention provided when potentially life‐threatening problems are identified. Developing a head‐to‐tail system of examination helps to maintain a routine and remain focused. Saving the examination of the body parts most likely related to the presenting complaint to the end of the PE can help prevent distraction and failure to complete the remainder of the PE. It is best to perform the equipment‐dependent examinations at the end of the PE to avoid distraction.

As the PE progresses from head to tail, neurological and orthopedic evaluations are done along with the general PE. Any animal that has had head trauma, loss of consciousness, prolonged seizures, or other indication of intracranial edema or hemorrhage must maintain a normal head position throughout the examination. When an area of pain is identified, examination of that area is postponed and the general PE is continued, followed by a closer assessment of the painful region. Significant PE findings relative to each of the Rule of 20 topics are discussed in the corresponding topic chapter.

Point of care testing

The most important and immediate laboratory assessment of the ICU small animal patient is done at the cage side with POC testing. The minimum database should include the packed cell volume (PCV), plasma total protein (TP), blood glucose, blood urea nitrogen (BUN or creatinine), electrolytes, acid–base status, blood lactate, coagulation profile, blood smear for platelet estimate and red blood cell (RBC) morphology, and urinalysis.

There are several POC data points that, when abnormal, warrant immediate investigation and intervention (indicated by red checkmarks in Table 1.4). The significance of the abnormalities with the possible cause(s), intervention options, and monitoring recommendations are available under the corresponding topic chapters.

Table 1.4 Point of care (POC) blood values of concern.

BUN, blood urea nitrogen; PCV, packed cell volume; TP, total protein; i, ionized.

* (mEq/L = mmol/L).

The microhematocrit tube provides a great deal of data. Figure 1.7 illustrates information that can be obtained from the spun tube, including the PCV, TP, buffy coat, and serum color. The PCV and TP are evaluated together, with the most common interpretation of changes presented in Table 1.5.

Figure 1.7 Schematic of benefits of the microhematocrit tube in POC testing. After the tube has been centrifuged, the top portion contains the total protein fraction, the small white layer is the buffy coat containing the white blood cells and platelets, and the bottom red portion is the packed cell volume. The lower columns serve as a reminder that the color of the plasma should also be noted: normal (straw colored), lipemia, icterus, or hemolyzed are the most common abnormalities.

Table 1.5 Changes in packed cell volume and total protein and their significance.

COP, colloidal osmotic pressure; GI, gastrointestinal; PCV, packed cell volume; SIRS, systemic inflammatory response syndrome; TP, total protein (plasma).

*PCV between 60% and 70% can be normal for sight hounds, ferrets, and animals at high altitudes.

The white layer in the hematocrit tube, between the plasma and the RBCs, consists of the white blood cells (WBCs) and platelets, called the buffy coat. When this is >1–2%, it suggests high WBC counts, and when <1%, low counts. A slide can be made of this layer and the cells examined for morphology, inclusion bodies or parasites. Platelet estimates are best made from a drop of whole heparinized blood rather than the buffy coat. However, if few or no platelets are seen in the buffy coat, further investigation is warranted regarding platelet count. How to perform a platelet estimate is discussed in Chapter 9, Box 9.3. Even when an acceptable platelet count is found at presentation, a repeated estimate should be made after resuscitation. A declining trend in platelet numbers can be one of the first indications of disseminated intravascular coagulation (DIC). This is to be anticipated in dogs and cats with SIRS.

Urine should be collected prior to fluid resuscitation, when possible, especially for patients with likely infectious or metabolic problems. The ability of the kidneys to concentrate urine is reflected by the specific gravity. Glycosuria without hyperglycemia reflects proximal tubular cell damage, a complication of nephrotoxic drugs or renal hypoxia. Urine sediment is evaluated for casts in animals on nephrotoxic drugs or having experienced severe shock. Urine casts present (from acute to chronic) as cellular casts, followed by coarse granular casts, fine granular casts, and finally hyaline casts. Renal tubular and coarse casts may appear before significant elevations in BUN and creatinine.

Clinicopathological laboratory testing

Blood is collected prior to therapy when possible for a complete blood count and serum biochemical profile to be run at a commercial or in‐hospital laboratory. It is often beneficial for the clinical pathologist to look at the blood smear for significant changes in the morphology of the blood cells. These additional data will add to the database and provide more information pertaining to the metabolic status of the patient. Evaluation of renal function, hepatic changes, and white blood cell response to illness is important for every critically ill patient.

Often special tests must be ordered to identify a pathogen, confirm a diagnosis or evaluate the success of treatment in the patient. Common clinicopathological laboratory tests that can be used to better define the cause or impact of a parameter of the Rule of 20 are discussed in each of the corresponding topic chapters.

Diagnostic imaging

Diagnostic imaging will almost always begin with survey radiographs of the affected body area. Orthogonal views are always recommended. Chest and abdominal radiographs are examined for evidence of metastatic disease, organ size, shape and position, and fluid accumulation. Contrast studies can assist in outlining structures or demonstrating dynamic changes.

Ultrasound evaluation provides imaging of the organ structure and differentiation between soft tissue and fluid densities. The focused assessment with sonography in trauma (FAST) techniques for rapid assessment of the chest and abdomen are becoming common triage tools and are outlined in the appropriate topic chapters. Doppler blood flow studies can complement the examination when thrombosis or anomalies of the vasculature are suspected.

Echocardiographic evaluation of the performance and size of the heart chambers provides a noninvasive means of assessing cardiac dynamics. Shunts and heart valve disorders can be more closely evaluated using color flow Doppler techniques. The electrocardiogram (ECG) demonstrates cardiac conduction. Information regarding cardiac assessment is presented in Chapter 11.

Endoscopy, laparoscopy, thoracoscopy, and cystoscopy can each provide images and biopsies and facilitate specific procedures of different organs when indicated. Computed tomography (CT) and magnetic resonance imaging (MRI) with and without contrast can provide more detailed imaging of structures that are poorly defined by ultrasound or radiographs.

Recommendations for diagnostic imaging procedures with suggested techniques (such as contrast studies, FAST examination) are presented for each topic of the Rule of 20 in the corresponding topic chapter.

Monitoring procedures

The PE findings will always provide the most important data regarding the status of the patient. Following the trend of change in every monitored parameter affords more accurate information than assessing a single value. Equipment‐based monitoring can include indirect and direct blood pressure, ECG, pulse oximetry, end‐tidal CO2, central venous pressure, urine output, body temperature, and body weight and is readily available for the small animal patient. Serial assessment of blood values, such as PCV, TP, acid–base status, coagulation times, electrolytes and lactate, reflects patient progress and can guide therapy. More sophisticated procedures, such as pulmonary artery catheters, ScvO2, and calorimetry, are presented as options in the appropriate chapters, with known advantages and disadvantages highlighted. Each topic in the Rule of 20 will require patient monitoring. The recommended monitoring procedures are discussed in each corresponding topic chapter.

Communications and the Rule of 20

Exceptional communication skills are needed to quickly build a good rapport with the pet owner under very stressful and emotional circumstances. From first contact by telephone to final discharge of the patient and follow‐up care, each member of the critical care team must develop a caring and trusting relationship with the pet owner (client). It is important to create an open forum that includes a gentle tone of voice, body language that projects an approachable demeanor, open‐ended questions when taking information, attentive listening to owner concerns, and establishing realistic medical and financial expectations. When successful, the decisions made regarding the medical care of the patient can be a shared process between the owner(s) and the critical care team. More information can be found in the Further reading list at the end of the chapter.

The Rule of 20 is a fluid and dynamic monitoring tool that can be utilized to treat any critical patient. As the knowledge pertaining to the pathophysiology of disease expands, new drugs, new treatments, additional diagnostic tools, and state‐of‐the‐art monitoring methods can be easily inserted into the format. The information gained from the Rule of 20 provides a solid foundation for patient care, as well as for communications among staff and with clients. The Rule of 20 assists the critical care team in providing the structured, thorough, and complete evaluation needed for small animal patients with complex medical problems.

Human medicine has coined the term hospital medicine to describe the discipline concerned with the medical care of acutely ill hospitalized patients. Physicians whose primary professional focus is hospital medicine are called hospitalists [20]. The term criticalist has been used in a similar capacity in veterinary medicine. The hospital medicine concept in some human studies has been associated with decreased mortality and fewer adverse events [21,22]. The Rule of 20 provides an important tool for the critical care team to facilitate reaching similar goals for the veterinary small animal ICU.

References

1. Miller‐Keane Encyclopedia and Dictionary of Medicine, Nursing, and Allied Health, 7th edn. St Louis: Saunders, 2003.

2. Waydhas C, Nast‐Kolb D, et al. Inflammatory mediators, infection, sepsis, and multiple organ failure after severe trauma. Arch Surg. 1992;127(4);460–7.

3. Nuytinck HK, Offermans XJ, et al. Whole body inflammation in trauma patients: an autopsy study. Prog Clin Biol Res. 1987;236A:55–61.

4. Faist E, Baue AE, et al. Multiple organ failure in polytrauma patients. J Trauma. 1983;23(9);775–87.

5. Matzinger P. The danger model: a renewed sense of self. Science. 2002;296(5566);301–5.

6. Zhang Q, Raoof M, et al. Circulating mitochondrial DAMPs cause inflammatory responses to injury. Nature. 2010;464(7285);104–7.

7. Pugin J. Dear SIRS, the concept of ‘alarmins’ makes a lot of sense! Intensive Care Med. 2008;34(2);218–21.

8. Tang D, Kang R, et al. PAMPs and DAMPs: signals that spur autophagy and immunity. Immunol Rev. 2012;249(1);158–75.

9. Moore FA, Moore EE. Evolving concepts in the pathogenesis of postinjury multiple organ failure. Surg Clin North Am. 1995;75(2):2577.

10. Moore FA, Sauaia A, et al. Postinjury multiple organ failure: a bimodal phenomenon. J Trauma. 1996;40(4);501–10.

11. Bone RC. Toward a theory regarding the pathogenesis of the systemic inflammatory response syndrome: what we do and do not know about cytokine regulation. Crit Care Med. 1996;24(1):163–72.

12. Rogy MA, Coyle SM, et al. Persistently elevated soluble tumor necrosis factor receptor and interleukin‐1 receptor antagonist levels in critically ill patients. J Am Coll Surg. 1994;178(2):132–8.

13. Munoz C, Carlet J, et al. Dysregulation of in vitro cytokine production by monocytes during sepsis. J Clin Invest. 1991;88(5):1747–54.

14. Hotchkiss RS, Osmon SB, et al. Accelerated lymphocyte death in sepsis occurring by both the death receptor and mitochondrial pathways. J Immunol. 2005;174(8):5110–18.

15. Fehervari A, Sakaguchi S.CD4+ Tregs and immune control. J Clin Invest. 2004;114(9):1209–17.

16. Xiao W, Mindrinos MN, et al. A genomic storm in critically injured humans. J Exp Med. 2011;208(13):2581–90.

17. Gentile LF, Cuenca AG, et al. Persistent inflammation and immunosuppression: a common syndrome and new horizon for surgical intensive care. J Trauma Acute Care Surg. 2012;72(6):1491–501.

18. Hotchkiss RS, Coopersmith SM, et al. The sepsis seesaw: tilting toward immunosuppression. Nat Med. 2009;15(5);496–7.

19. Vanzant EL, Lopez CM, et al. Persistent inflammation, immunosuppression, and catabolism syndrome after severe blunt trauma. J Trauma Acute Care Surg. 2014;76(1):21–9.

20. Vazirani S, Lankarani‐Fard A, et al. Perioperative processes and outcomes after implementation of a hospitalist‐run preoperative clinic. J Hosp Med. 2012 7(9):697–701.

21. Raghavendra M, Hoeg RT, et al. Management of neutrophic fever during a transition from traditional hematology/oncology service to hospitalist care. World Med J. 2014;113(2):53–8.

22. Tadros RO, Raries, PL, et al. The effect of a hospitalist co‐management service on vascular surgery inpatients. J Vasc Surg. 2015;61(6):1550–5.

Further reading

Silverman J, Kurtz S, Draper J. Skills for Communicating with Patients, 3rd edn. London: Radcliffe Publishing, 2013.

CHAPTER 2

Fluid balance

Rebecca Kirby¹ and Elke Rudloff²

¹ (Formerly) Animal Emergency Center, Gainesville, Florida

² Lakeshore Veterinary Specialists, Milwaukee, Wisconsin

Introduction

Water is the most essential nutrient of the body. It is the transport medium that brings oxygen, solutes, and hormones to the interstitium and delivers waste products to the liver, kidneys, and lungs for breakdown and excretion. In the interstitial space, water facilitates movement of these substances between the capillary and the cell. Within the cell, water provides a medium for organelles and for expansion of the cell membrane. Dissipation of heat occurs through the evaporation of water.

Sixty percent of the body mass (0.6 L/kg) is made up of water [1]. The total body water (TBW) is partitioned into segments according to how water is contained. There are two major compartments where water is located: the intracellular compartment (66% TBW, 0.4 L/kg) and the extracellular compartment (33% TBW, 0.2 L/kg), which are separated by the cell membrane. The extracellular fluid (ECF) compartment is further divided by the vascular membrane into intravascular and interstitial compartments. The interstitial fluid compartment makes up 75% of the ECF compartment (25% of the TBW), and the intravascular fluid compartment makes up 25% of the ECF compartment (8% of the TBW) (see Figure 2.1).

Figure 2.1 Schematic of body water dynamics at the level of the capillary. The Starling’s forces across the capillary membrane favor the retention of water in the capillary due to a higher concentration of colloid molecules (green circles) in the intravascular space compared to the subglycocalyx space. The Pc is the major force favoring fluid movement from the capillary into the interstitium. It is a result of CO and BP. The stroke volume is dependent on the preload, thereby a driving force behind the Pc. Sodium is the primary component of the osmotic pressure in the capillary and interstitium, and is freely permeable to the capillary membrane. It is not freely permeable to the cell membrane (yellow arrow). Potassium provides the major intracellular osmotic force that holds water within the cell. Water is freely permeable to the cellular membrane. The lymphatics pass through the interstitial space and remove water and solutes from the interstitium (creating a negative interstitial pressure) and return them back to the intravascular space via the thoracic duct. The intracellular space contains 66% of the TBW, the interstitium 25% of the TBW and the intravascular space 8% of the TBW. Red cylinder, capillary; blue square, cell; blue arrows, water movement; blue background, interstitial fluid; sodium, yellow circle; potassium, orange circle. CO, cardiac output; COP, colloidal osmotic pressure; EC, endothelial cells; GC, glycocalyx layer; HR, heart rate; Pc, capillary hydrostatic pressure; SV, stroke volume; SVR, systemic vascular resistance; TBW, total body water.

Water moves freely across all membranes (cell and vascular) that separate fluid compartments. Two principles, osmosis and the modified Starling’s equation, govern how water remains within or moves between compartments. Osmosis is the process by which fluid diffuses through a semipermeable membrane from a solution with a low solute concentration to a solution with a higher solute concentration until there is an equal solute concentration on both sides of the membrane. Water moves across the cell membrane between the intra‐ and extracellular compartments by osmosis. Small molecular weight solutes on one side of the semipermeable plasma membrane hold water because they generate osmotic pressure. The primary solutes that generate intracellular osmotic pressure are potassium and magnesium, and the primary solutes that generate extracellular osmotic pressure are sodium, chloride, glucose, and urea [2,3]. When the concentration of solutes changes on one side of the cellular membrane and is no longer equal across the membrane, an osmolar gradient is produced. Water will move from the compartment with the lower solute concentration to the compartment with the higher solute concentration. Any sudden change in osmolality in the intravascular and interstitial compartment can affect the movement of water across the capillary membrane. The capillary membrane is freely permeable to small solutes and water, so any increase in solute concentration (osmolarity) in either extracellular compartment will be short‐lived.

The components of the modified Starling’s equation produce the forces that dictate water movement within the extracellular space (Jv) across the capillary membrane, defined by the following formula [4,5].

The hydrostatic (hydraulic) pressure within the vessel (Pc) is generated by cardiac output (CO) and systemic vascular resistance. Hydrostatic pressure within the interstitium (Pis) is produced by the presence of water within the collagen fibrils and fibroblasts. Colloid osmotic pressure (COP; π) is the osmotic force generated by protein particles (such as albumin, fibrinogen, and globulins) that attract water. The COP within the plasma (πc) is opposed by the COP within the subglycocalyx space (πseg, virtually zero under normal conditions) (see Figure 4.2 in Chapter 4). The movement of colloid particles across the endothelial membrane will be affected by the osmotic reflection coefficient (σ), and the movement of water and particles will be controlled by the filtration coefficient (kf). In normal tissues, the lymphatic circulation is continuously removing fluid and particles from the interstitium (Q lymph), creating a slight negative interstitial pressure that promotes continuous flow of fluid and particles from the intravascular space through the interstitium into the lymphatic system which deposits them back into the intravascular space (via the thoracic duct). The major contributing forces affecting capillary fluid dynamics are illustrated in Figure 2.1.

Fluid balance refers to the state of TBW homeostasis. Euvolemia and euhydration refer to a state of normal water content in the intravascular and interstitial fluid compartments, respectively. Hydration is the taking in of water, and describes the clinical state of TBW. Dehydration is a reduction in water content, when intake through food and water is less than output lost in feces, urine, sweat, and respiratory vapor. Clinically, the term dehydration is used to reflect the state of insufficient water content in the interstitial space. Overhydration is a condition of excess water content in the interstitial and intracellular spaces.

Transmembrane ion pumps and channels regulate the movement of solutes and water in and out of the cell, maintaining cellular and organelle integrity. The primary active pump for solute transport across the cell membrane is the sodium‐potassium pump. Additional membrane pumps and channels regulate the movement of calcium, hydrogen, chloride, magnesium, glucose, and amino acids. These membrane transport systems are present in every cell in every organ, and many require energy to function.

Energy required to drive transmembrane ion exchange is supplied by cleavage of adenosine triphosphate (ATP). In contrast to the 38 ATP molecules that are produced during aerobic metabolism, anaerobic metabolism produces lactate and only two ATP molecules per glucose molecule. Oxygen and glucose are transported from the intravascular space to the cell through a fluid medium. Carried by hemoglobin to the capillaries, oxygen normally diffuses with great ease through the capillary membrane and interstitial space, then into the cells, most of which are located less than 50 micrometers from a capillary.

Perfusion is the delivery of oxygen to the tissues. The conduit for fluid that transports oxygen and glucose is the vascular system. The heart serves as the pump of the conduit. Oxygen delivery is the product of arterial flow and arterial oxygen content. Hemoglobin concentration and hemoglobin oxygen saturation are the prime components of arterial oxygen content, with dissolved oxygen content in plasma being a minor component (see Chapters 8 and 10).

Arterial flow is a product of CO and systemic vascular resistance. Cardiac output is a product of myocardial contraction and heart rate. Venous return, as defined by the Frank–Starling law of the heart, increases the stretch of the heart chambers (preload), which increases the force of myocardial contraction. Factors influencing venous return to the heart include mean circulatory filling pressure, right atrial pressure, and resistance of the arteries (see Chapter 11).

Blood flow is also influenced by pressure differences and compliance within the vascular circuit as well as the viscosity of the fluid medium. Extrinsic and intrinsic regulation of the cardiovascular system also affects blood flow to the tissues. Intrinsic metabolic autoregulation affects local organ blood flow, and is influenced by oxygen availability and the accumulation of metabolic byproducts.

Continuously produced and utilized, adequate ATP production becomes heavily dependent on oxygen availability during high energy output states of critical illness. Optimum ATP production, therefore, depends on both oxygen delivery (DO2) to the cell and oxygen utilization (VO2) by the cell. Other than oxygen supplementation and maintaining adequate hemoglobin concentration, reestablishing and maintaining intravascular fluid volume supports maximum oxygen delivery.

Compensatory neuroendocrine responses are initiated for restoring blood volume and meeting metabolic demands occurring during decreased CO states and increased ATP demands. Hormonal mechanisms control the volume and distribution of TBW and involve the kidney and the brain [6–9]. These mechanisms are continuously adjusting the amount of water retained and lost in response to fluids lost and taken in, balancing TBW. Loss of extracellular water with little or no solute (hypotonic fluid loss) results in an increase in plasma osmolality. This increase is detected by osmoreceptors which send an afferent signal to the hypothalamic paraventricular nuclei and cause the release of antidiuretic hormone (ADH) [10,11]. ADH increases the concentration of aquaporins in the renal collecting ducts, facilitating water reabsorption and therefore concentrating the urine. An increase in plasma osmolality is also detected by the thirst center (near the supraoptic and preoptic nuclei in the anteroventral region of the third ventricle), stimulating the sensation of thirst and an increase in water intake [12].

In the critically ill or injured patient, the mechanisms that balance fluid compartments are challenged and can become impaired. Water deficits result in altered body temperature regulation, neurological dysfunction, electrolyte imbalances, and hypovolemia causing reduced organ perfusion, acute kidney injury, and eventually, death [13,14]. Excess water can result in altered ventilation and lung function, gastrointestinal dysfunction, electrolyte imbalances, and cerebral edema [15]. Movement of water between compartments and into and out of the body can occur rapidly, and is not tolerated in critically ill patients. The normal compensatory responses might not occur as quickly as needed and can be incomplete, inappropriate or ineffective due to end‐organ dysfunction. Frequent assessment of the fluid balance in the critical small animal patient is necessary throughout hospitalization to identify the cause(s) of fluid imbalance, and to make appropriate adjustments in the treatment plan.

Diagnostic and monitoring procedures

Monitoring the fluid balance of a patient should occur on a regular basis since changes can be very drastic over relatively short periods of time. The history and physical examination provide initial insight into problems that can affect or be affected by an altered fluid balance. In hospital point of care (POC) testing, clinicopathological laboratory tests, diagnostic imaging, and monitoring procedures are each assessed in light of the physical status of the patient.

History and physical examination

Historical and presenting problems reported by the owner that can be associated with or affect assessment of water balance include vomiting, diarrhea, respiratory problems, blood loss, trauma, toxin exposure, fever, nasal discharge, heart failure, alterations in water intake and urine output, and exposure to environmental heat extremes. A list of prescribed and over‐the‐counter medications should be reviewed for drugs that might affect water balance (such as diuretics or vasodilators). Recently administered medication (such as ketamine or atropine) can alter mucous membrane moisture without being a reflection of TBW changes.

The physical examination will identify abnormal parameters associated with fluid imbalance, in particular those associated with perfusion and hydration. Parameters that reflect peripheral perfusion include heart rate, mucous membrane (MM) color, capillary refill time (CRT), pulse quality, level of consciousness, and body temperature. Reduction in intravascular volume leads to clinical signs of hypovolemic shock. A progression of shock manifests in alterations in perfusion parameters, listed in Table 2.1. Rectal temperatures represent peripheral body temperatures and are an indirect indicator of the status of peripheral blood flow. Redistribution of blood flow from the periphery to the core with vasoconstriction can give a differential core‐to‐peripheral temperature (see Chapter 17).

Table 2.1 Physical examination and measured parameters that reflect peripheral perfusion in the normal state and during the stages of shock. The presence of three or more variables attributable to a particular stage of shock supports a diagnosis of that state of perfusion.

bpm, beats per minute.

Clinical signs of compensatory shock in the dog can be easily overlooked. The signs of hyperemic mucous membranes, tachycardia, rapid capillary refill time, and normal to increased arterial blood pressure should not be interpreted as normal. The arterial blood pressure is being maintained at the expense of the increased heart rate and mild vasoconstriction. The cat does not typically manifest a compensatory shock response since this stage lasts only seconds to minutes after the initiation of shock in the cat [16].

The state of hydration is in continuous flux, and there is no single parameter that reflects hydration status accurately. Physical examination findings and laboratory indices are used to estimate current hydration status [17]. Physical parameters used to assess hydration include mucous membrane and corneal moisture, skin turgor, and eye position within the orbit (Table 2.2). Two important qualifications must be considered: (1) acute changes in tissue hydration may not be evident on physical examination, since there has not been time for compensatory fluid shifting (underestimating the percentage of dehydration), and (2) older or emaciated animals have poor skin turgor and sunken eyes in their orbit unrelated to their hydration status (overestimating the percentage of dehydration).

Table 2.2 Physical examination findings and the associated estimated percent dehydration (interstitial fluid deficits).

Up to 90% of acute changes in body mass can be attributed to a change in TBW, so that in the critically ill patient, a 1 kg change in body weight may be equivalent to a 1 L change in TBW [18–22]. However, due to third body fluid space accumulation (in the abdominal or pleural spaces, or intestines or uterus) or tissue edema, a change in body weight may not occur even though there is loss of fluids from the intravascular or interstitial space(s). Weighing patients, particularly small patients, every six hours is recommended and is a simple monitoring tool to use when assessing trends of change in fluid balance.

Any systemic inflammatory response syndrome (SIRS) disease (such as sepsis, pancreatitis, trauma, immune‐mediated disease, neoplasia) will have increased capillary permeability as part of the syndrome that can result in fluid extravasation. This can lead to complications associated with hypovolemia, interstitial edema, and third body space fluid accumulation. Abdominal distension, reduced bowel sounds, and short or shallow breaths due to increased pressure on the diaphragm can provide physical evidence of a large accumulation of abdominal fluid. Fluid waves might be felt during abdominal palpation. Pleural fluid accumulation can produce an elevated respiratory rate and effort, and muffled lungs sounds. Pulmonary edema may cause respiratory distress with a rapid, shallow breathing pattern and moist lung sounds heard on auscultation. Edema of the intestines may result in poor gastrointestinal function, altered borborygmi, vomiting or diarrhea.

Box 2.1 Common clinical signs associated with excess interstitial fluid (overhydration) in the dog and cat.

Mild signs

Serous nasal discharge

Chemosis

Polyuria

Hypothermia, shivering

Moderate signs

Increased skin turgor (gelatinous nature)

Tissue edema

Increased respiratory rate and effort

Pleural effusion

Abdominal fluid wave, ascites

Diarrhea

Nausea and vomiting

Acute weight gain

Severe signs

Exophthalmos

Hypertension

Pulmonary moist crackles

Cough

Tachy‐ or bradycardia

Depressed level of consciousness

Areas of the body that have thin membranes, low muscle mass, and/or lack of fat will demonstrate fluid accumulation first. Conjunctival edema (chemosis) is an early sign of fluid intolerance, followed quickly by subcutaneous fluid accumulation around the common calcaneal tendon, intermandibular space, head and neck, and the distal limbs. Box 2.1 lists common clinical signs of overhydration. Causes of interstitial edema or cavitary effusion unrelated to increased capillary permeability include oliguric kidney failure, right‐sided heart failure, and portal hypertension. Hypovolemia may or may not be associated with these problems.

Point of care testing

The minimum POC laboratory database that should be assessed before and during fluid therapy includes the packed cell volume (PCV), total protein (TP) measured by refractometer, creatinine, blood glucose, plasma lactate, serum electrolytes, acid–base status, coagulation times, platelet estimate, and urine specific gravity (USG). Following the trend of change over time is necessary since the infusion of fluids and other forms of therapy will result in changes that may require intervention.

Loss and gain of extracellular water can result in hemoconcentration (increased PCV and TP) or hemodilution (decreased PCV and TP). Hemorrhage should be considered when the PCV and TP are reduced, although patients with acute hemorrhage can have normal or increased PCV as a result of sympathetic‐induced splenic contraction releasing red cells back into the circulation. In that situation, a reduction in the initial TP can be a tell‐tale sign of hemorrhage in a patient with a compatible history. An initial low TP without hemorrhage might reflect hypoalbuminemia and fluid shifts due to a loss of intravascular COP. As fluid resuscitation and rehydration are performed, hemodilution will result in a decrease in both PCV and TP.

Decreased DO2 due to inadequate blood flow caused by hypovolemic shock can result in anaerobic metabolism. Hyperlactatemia, metabolic acidosis, and increased base deficit are usually associated with conditions causing tissue hypoxemia.

Intracellular volume changes cannot be identified on physical examination. The clinician must rely on changes in the effective osmolality of ECF (primarily recognized by changes in sodium concentration) to mark changes in cell volume. Hyponatremia will be associated with movement of water from the ECF into the intracellular fluid (ICF) compartment, and a subsequent increase in intracellular volume. Hypernatremia will be associated with a decrease in intracellular volume (see Chapter 6).

Changes in blood glucose can affect water balance. Hyperglycemia increases plasma osmolarity and can result in increased extracellular water if a patient receives or takes in fluid. Hyperglycemia also induces glycosuria, diuresis, and water loss. A significant loss of TBW can occur when water losses exceed intake, and can result in hypovolemia, dehydration, and hypernatremia (see Chapter 5).

Urine specific gravity is a reflection of the kidney’s functional ability to concentrate urine. The USG can be used during assessment of fluid balance. A low USG in the patient receiving intravascular fluid (IVF) support can be difficult to interpret by itself. An inappropriately low USG in the clinically dehydrated patient, or one with azotemia, may indicate altered kidney function. If the USG is normal to increased in the patient receiving fluid therapy, fluid losses may be exceeding fluid intake and additional fluids may be warranted.

Abnormal clotting times and platelet estimate can cause internal hemorrhage and signs of hypovolemia, necessitating careful titration of intravascular fluids to prevent a sudden increase in hydrostatic pressure and exacerbation of bleeding (see Chapter 9). Patients with hypercoagulable conditions may benefit from fluid therapy to prevent capillary stasis.

Clinicopathological laboratory testing

An automated complete blood count with a manual differential count, a serum biochemical profile, and urinalysis should be reviewed for changes that might impact fluid balance and fluid therapy. Evidence of liver failure (low BUN, hypoalbuminemia, hypoglycemia, increased coagulation times, alterations in serum cholesterol) can be a cause of portal hypertension and a loss of intravascular COP with fluid extravasation into the intestinal interstitium and peritoneal cavity. An elevation in creatinine and reduced USG support renal disease, which can result in water and electrolyte imbalances. Hypertension and fluid retention will occur if oliguria or anuria develops. Hypoalbuminemia lowers intravascular COP and can potentiate fluid loss from the intravascular space (see Chapter 4). Significant proteinuria may signify altered glomerular function and, when severe, can result in hypertension, a relative oliguria, and interstitial edema.

When investigating for causes of a solute‐free water imbalance, the serum osmolarity should be compared to the urine osmolarity. Normal serum osmolarity ranges from 290 to 310 mOsm in the dog and 290 to 330 mOsm in the cat [23]. Urine osmolarity can range between 161 and 2830 mOsm/L in normally hydrated dogs [24] and between 600 and 3000 mOsm/L in normally hydrated cats [25]. As the serum osmolarity rises, the urine osmolarity should also rise when the kidney works to conserve water. When there is an excess of water in the body, the normal kidney will dilute the urine, eliminating extra body water.

Ethylene glycol and other small molecular weight toxins can increase measured plasma osmolarity without increasing calculated plasma osmolarity. This will cause an increased osmolar gap and alter fluid distribution and balance. Many osmolar toxins can be tested for in commercial laboratories.

Diagnostic imaging

Survey thoracic and abdominal radiographs can be examined for signs of intracavitary fluid accumulation. Loss of abdominal detail and abdominal distension on abdominal radiographs are signs suggestive of peritoneal fluid accumulation. Distended pulmonary vessels can be caused by increased pulmonary vascular pressure. Increased interstitial densities and alveolar lung patterns are consistent with fluid accumulation in the lung parenchyma. Pleural fissure lines and retraction of the lungs from the pleural wall with surrounding soft tissue opacity suggest thoracic fluid accumulation. Small caudal vena cava and heart sizes are compatible with hypovolemia (Figure 2.2).

Figure 2.2 Lateral abdominal radiograph of dog with gastric dilation‐volvulus. Note the small size of the vena cava (white arrows) and the cardiac silhouette supportive of insufficient intravascular volume. Volume replacement is critical prior to induction of anesthesia.

Ultrasonography is more specific than radiography for demonstrating peritoneal, pleural, and/or pericardial fluid accumulation, organ structure, tissue edema, vessel size and obstructions to blood flow. Thoracentesis or abdominocentesis for fluid retrieval and sampling can be guided using ultrasonography. Echocardiography can provide important information regarding the role that the heart might have in patients with hypotension or fluid imbalance.

Monitoring procedures

Hemodynamic monitoring can be invasive or noninvasive, continuous or intermittent, physical or biochemical. Perfusion parameters and vital signs should be routinely and repeatedly evaluated from the start of fluid resuscitation until the patient leaves the hospital.

Heart rate can be assessed by pulse palpation, continuous ECG monitoring, direct cardiac auscultation, Doppler blood flow monitoring or by pulse oximetry. Bounding pulse quality can be associated with compensatory shock, anemia, or pain. Weak pulse quality can be associated with decreased CO from decompensatory shock or heart failure, vasodilation, or severe vasoconstriction. Body temperature is an indirect indicator of peripheral blood flow within the tissues. Pain, anxiety, and abnormal body temperature may influence sympathetic tone and should be taken into consideration when assessing perfusion parameters. Indications of successful resuscitation of perfusion deficits include a normalization of heart rate, improved pulse quality, CRT of 1–2 seconds, pink MM color, normalization of body temperature, and improvement in mentation.

Periodic monitoring of arterial blood pressure, central venous pressure (CVP), oximetry, urine output, blood lactate, and venous blood gas can be performed in those patients requiring more extensive monitoring. Arterial blood pressure is a frequently monitored parameter for documenting hypo‐ and hypertension and assessing the success of fluid resuscitation. Arterial blood pressure is an indirect estimation of perfusion and can be a reflection of intravascular volume status when cardiovascular function is normal. Arterial blood pressure should always be assessed in conjunction with heart rate and other parameters of perfusion.

Direct arterial blood pressure monitoring is considered to be the gold standard for blood pressure monitoring. Persistently unstable patients that require intensive monitoring may benefit from direct arterial blood pressure monitoring (see Chapter 3). This technique is invasive and requires skill and specialized equipment. It can be difficult to place an arterial catheter in the hypovolemic or vasconstricted patient, and the use of a transducer and special monitor is required.

Indirect methods for monitoring arterial blood pressure utilize a Doppler or an oscillometric monitor. The indirect method of measuring arterial blood pressure is the most efficient and least expensive means for monitoring arterial blood pressure, but studies correlating indirect to direct methods have shown inconsistent results, especially in cats [26–31]. Indirect arterial blood pressure does not accurately reflect venous return or regional blood flow [32], so the trend of change in indirect arterial blood pressure in conjunction with improved physical perfusion parameters implies a positive response to therapy. Pain, anxiety, cardiac dysrhythmias, and hypothermia may result in blood pressure readings that do not accurately reflect intravascular volume status.

Urine output volumes can provide a nonspecific estimation of perfusion to the kidneys. Normal urine production depends upon adequate renal blood flow