Shock Pathophysiology

3 CE Credits

Elizabeth Thomovsky, DVM, MS, DACVECC Paula A. Johnson, DVM Purdue University

Abstract: Shock, defined as the state where oxygen delivery to tissues is inadequate for the demand, is a common condition in veterinary patients and has a high mortality rate if left untreated. The key to a successful outcome for any patient in shock involves having a clear understanding of the pathophysiology and compensatory mechanisms associated with shock. This understanding allows more efficient identification of patients in shock based on clinical signs and timely initiation of appropriate therapies based on the type and stage of shock identified.

hock is a condition that is commonly seen in practice but Anaerobic metabolism just as commonly is not completely understood. This review

focuses on the body’s compensatory responses to shock and Production and release of lactate, cytokines, prostaglandins, nitric oxide, etc. S the clinical signs to help provide practitioners with a better understanding of what shock is and how it can be categorized. Treatment is

Increased capillary Decreased vasomotor tone discussed in the context ofThomovsky the pathophysiology E, et al. Shock pathophysiology but is .not Compend covered Contin Cellular swelling Thomovsky E, et al. Shock pathophysiology. Compend Contin permeability in depth. Educ Vet 2013;35(8)Educ Vet 2013;35(8). .

Definitions Interstitial edema The first difficulty comes in defining shock. At its most elemental, the definition can be stated as: Cellular dysfunction Circulatory collapse 1 oxygen delivery ≠ oxygen consumption (DO2 ≠ VO2). GI barrier breakdown + translocation of gut bacteria

Glucose Glucose Consumptive coagulopathy Anaerobic AnaerobicMetabolism Metabolism. Pyruvate. Pyruvate Aerobic MetabolismAerobic Metabolism. . cannot entercannot the TCA enter cycle the TCA and enterscycle and enters Pyruvate isPyruvate able to e isnter able to enter the Cori cyclethe Corito form cycle lactate. to form Lactate lactate. Lactate the TCA cyclethe TCA and iscycle and is can be usedcan by bethe used brain by and the heart brain in and heart in Death converted intoconverted large into large the short termthe shortfor energy term,forbut energy it is , but it is amounts ofamounts ATP. of ATP. overall an inefficientoverall an inefficientsource of source of 2 pyruvate2 pyruvate Figure 2. SequelaeFigure 2.of prolongedSequelae anaerobic of prolonged metabolism. anaerobic metabolism. cellular energycellular. energy.

Oxygen Oxygen Oxygen Oxygen Most cases of shock are the result of decreased delivery of blood

to tissues. When blood is not delivered to tissues, oxygen is not

delivered. Oxygen is critical for normal cellular function; when the

TCA cycleTCA cycle Cori cycle Cori cycle tissues do not receive oxygen, normal cellular aerobic metabolism ceases and anaerobic metabolism ensues. As a result, cells are unable to produce adequate amounts of ATP (FIGURE 1) to sustain normal metabolic function, ultimately leading to cellular dysfunc-

tion and death. Additionally, sustained anaerobic metabolism results 2 lactate 2 lactate in the production of cytokines and substances such as lactate and 36 36 2 2 ATP ATP nitric oxide, which further complicate shock (FIGURE 2). ATP ATP Multiple factors determine oxygen delivery to cells (FIGURE 3); however, the simplest way to envision oxygen delivery is to consider the body’s cardiac output as being roughly equivalent to the blood Figure 1. Aerobic versus anaerobic metabolism. TCA = tricarboxylic acid delivered throughout the body. In turn, cardiac output is defined

Figure 1.FigureAerobic 1. versusAerobic anaerobic versus anaerobic metabolism. metabolism. TCA = tricarboxylic TCA = tricarboxylic acid. acid.

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Thomovsky E, et al. Shock pathophysiology. Compend Contin Educ Vet 2013;35(8). Shock Pathophysiology

DO2 = CaO2 x CO It is less common that the body’s demand for oxygen is the driving force for the imbalance (i.e., that cardiac output is com- Preload Afterload pletely normal in a patient in shock). One example of this situation

Contractility is overwhelming infection, in which the infection causes increased

cellular metabolism (and therefore increased cellular oxygen CO = HR x SV demand). Increases in cellular metabolism alone can cause a state of shock before or in addition to the development of decreased

cardiac output secondary to the infection.1,2 CaO2 = (SpO2 x 1.34 x [Hb]) + (0.003 x PaO2) A second example in which cardiac output can be normal in a

Figure 3. The determinants of oxygen delivery in the body. CaO2 = arterial oxygen shock patient is when there is abnormal perfusion of tissues. content, = cardiac output, = oxygen delivery, = concentration of CO DO2 [Hb] When large numbers of cells are bypassed by oxygenated blood, an hemoglobin in the blood, HR = heart rate, PaO = partial pressure of oxygen in Figure 3. The determinants of oxygen delivery in the body. CaO2 = arterial oxygen content, CO =cardiac output, DO = oxygenimbalance delivery, [Hb] = in oxygen demand and delivery develops that can lead arterial blood, SV =stroke volume, SpO = % hemoglobin2 saturation with oxygen. 2 concentration of hemoglobin in the blood, HR = heart2 rate, PaO2 = partial pressure of oxygen in arterial blood, SV =stroke volume,to shock. SpO2 = %1,3–8 In cases of abnormal perfusion, the microcirculation hemoglobin saturation with oxygen. at the capillary and other small (≤100 µm) vessel level is typically as heart rate times stroke volume. Appreciating the interrelationship affected.2,4,7 The microcirculation responds in a variety of ways, between oxygen delivery and cardiac output is critical to under- culminating in increased permeability of the walls of the endo- standing the pathophysiology of shock and guiding treatment. thelium and regions of vasodilation and altered blood flow.4 This

Table 1. Categories, Examples, Basic Definitions, and Pathophysiology of Shock Category of Shock Classic Example Basic Definition Pathophysiology/Events Leading to Shock

Hypovolemic Decreased effective circulating blood Decreased effective circulating volume à decreased venous volume return à decreased stroke volume à decreased cardiac Absolute Absolute: bleeding output and blood delivery to tissues from wound (laceration) Relative Relative: bleeding into third space in body (hemoabdomen, fracture hematoma)

Obstructive Gastric-dilatation Physical impediment to blood flow in Physical blockage to venous return/blood trapped distal to volvulus (dilated large vessels (predominantly veins) obstruction à decreased stroke volume à decreased stomach occludes cardiac output and blood delivery to tissues caudal vena cava)

Cardiogenic Dilated cardiomyopathy Heart unable to pump blood (typically Decreased contractility à decreased cardiac output and caused by lack of contractility) blood delivery to tissues

Distributive Sepsis (Gram-negative Multifactorial (one or more of the following): endotoxemia) 1. Vasodilation, especially peripheral Macrocirculatory vasodilation à blood trapped in periphery Anaphylaxis vessels (both microcirculation + à decreased venous return à decreased stroke volume à macrocirculation) decreased cardiac output and blood delivery to tissues Microcirculatory vasodilation à oxygen arrives at the tissues but is not delivered to the metabolizing cells due to vasodilation-driven shunting of blood away from the cells

2. Increased vessel permeability Increased vessel wall permeability à decreased effective (relative hypovolemia as fluid leaks circulating blood volumeà decreased venous return à out of vessels) decreased cardiac output and blood delivery to tissues

3. Decreased cardiac contractility due Decreased cardiac contractility à decreased cardiac output to effects of cytokine mediators and blood delivery to tissues (sepsis) or platelet activating factor (anaphylaxis)

4. Activation of the coagulation Multiple clot formation à small vessels occluded à system decreased venous return à decreased cardiac output and blood delivery to tissues

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Thomovsky E, et al. Shock pathophysioloShock Pathophysiologygy. Compend Contin Educ Vet 2013;35(8). leads to less blood being delivered to other cells and local hypoxia of the by- Shock (decreased Decreased baroreceptor cardiac output) passed cells. Examples of such derange- activity (aortic and ments in microcirculation include the carotid bodies) systemic inflammatory response syn- 4 ↑[Na] (osmoreceptors); drome (SIRS) and reperfusion injury. Decreased decreased blood volume Additionally, in human medicine, use of Increased SNS baroreceptor (baroreceptors) tone activity (JG coronary artery bypass grafting can apparatus) physically re-route blood away from tis- Adrenal V1 receptors gland Release antidiuretic sues, causing those tissues to suffer from hormone/ vasopressin Epinephrine/ 4 Renin release (posterior pituitary) decreased oxygen delivery. norepinephrine (kidney) In an attempt to encompass and cate- release V2 receptors β1 receptors α receptors gorize the various types of shock, shock is bloodstream typically divided into categories that help Insert aquaporin channels collecting explain why oxygen delivery is not match- Increased heart Vaso- and veno- Angiotensinogen duct kidney  Ang I ing oxygen demand. However, it is im- rate constriction portant to remember that clinical cases of ACE (lungs) Push blood Retain water shock usually do not fall neatly into one back to Ang I  Ang II category and often straddle several cate- Maintain tissue heart gories. The four categories described in perfusion this article are listed in TABLE 1, along with Increase Adrenal venous return gland an explanation of why each category Release meets the basic definition of shock. aldosterone

Increase Compensation for Shock cardiac output Retain Na in distal Regardless of the cause, when tissues are tubules kidney not properly supplied with oxygen, the body attempts to remedy the situation by initiating a series of neural and hormon- ally mediated compensatory mecha- Improve oxygen Increase blood nisms. The end goal of these mechanisms volume delivery to tissues is to increase cardiac output and blood vessel tone in an attempt to better supply the cells with oxygen. These compensa- Figure 4. Compensatory mechanisms in response to shock. ACE = angiotensin-converting Figure 4. Compensatory mechanisms in response to shock. ACE = angiotensin-converting enzyme, enzyme, Ang = angiotensin, JG = juxtaglomerular, [Na] = concentration of sodium, SNS = tory mechanisms can be grouped into Ang = angiotensin, JG = juxtaglomerular, [Na] = concentration of sodium, SNS = sympathetic nervous system. three separate categories: (1) effects ex- sympathetic nervous system. erted within minutes (acute), (2) effects exerted in 10 minutes to 1 hour (moderate), (3) and effects exerted are mediated by the sympathetic nervous system (SNS) and cat- within 1 to 48 hours (chronic).1 In general, the body responds by in- echolamine release and take effect within 30 seconds to a few creasing heart rate, increasing peripheral vascular tone, and attempt- minutes.1 As cardiac output decreases, impulse generation by the ing to increase stroke volume, all in an effort to improve cardiac out- baroreceptors at the carotid sinus and aortic arch in the heart put and keep perfusion to tissues intact. Stroke volume is improved decreases. Under normal conditions, baroreceptor impulses work by increasing the amount of blood returned to the heart (e.g., venous to inhibit the vasoconstrictor center of the medulla and increase return). One way to increase venous return is to shunt blood from stimulation of the vagal center in the brain, leading to vasodilation. small (less important), peripheral vessels to the heart to supply the When the baroreceptor impulses are decreased, the vasomotor myocardium, lungs, and brain. The kidneys provide a second way to center in the brain operates unchecked and SNS signals from the improve venous return by retaining fluid to bolster the total blood brain increase. These increased SNS signals cause release of nor- volume. FIGURE 4 summarizes these various compensatory mecha- epinephrine from the adrenal gland and the nerve endings them- nisms; the following text discusses the compensation in more detail. selves. Norepinephrine binds to α-adrenergic receptors on blood

vessels to cause vasoconstriction and binds to β1-adrenergic re- Acute Compensatory Mechanisms ceptors in the myocardium to cause an increase in heart rate and Catecholamines contractility1,2 (FIGURE 4). Acute compensatory effects are limited to those affecting heart A second important stimulus of catecholamine secretion is rate and redistributing peripheral blood back to the heart. They hypoxemia.2 This can be true hypoxemia, represented by a global

Vetlearn.com | 2013 | Compendium: Continuing Education for Veterinarians™ E3 Thomovsky E, et al. Shock pathophysiology. Compend Contin Thomovsky E, etThomovsky al. Shock pathophysiology.E, et al. Shock pathophysiology. Compend Contin Compend Contin Educ Vet 2013;35(8). EducThomovsky Vet 2013;35(8). E,Educ et al. Vet Shock 2013;35(8). pathophysiology. Compend Contin Educ Vet 2013;35(8).Shock Pathophysiology

Blood vessel Interstitial Space Blood vesselBlood vesselInterstitial InterstitialSpace Space decrease in arterial oxygen content, or relative hypoxemia, caused Blood vessel Interstitial Space by microcirculatory derangements that shunt blood away from tissues. Chemoreceptors that sense the oxygen content of the blood πi are located in the carotid artery and aorta. Those in the carotid πi πi πc πi πc πc fluid net

artery sense decreased oxygen delivery to the brain and, therefore, fluid net net fluid fluid net movement

πc No movement movement net fluid fluid net No stimulate the vasomotor center to increase SNS stimulation regard- No

Pi movement 2 Pi Pi No less of peripheral blood pressures. In the aorta, decreases in periph- Pc Pc Pc Pi eral blood pressure are signaled by decreased baroreceptor stimu- Pc lation and chemoreceptors are activated as a result of decreased oxygen delivery.2 Both baroreceptor and chemoreceptor signals lead A. Normal setting. No net fluid movement into either the interstitial or the vascular A. Normal setting.A. NormalNo net fluidsetting. movementNo net fluid into movementeither the interstitial into either or the the interstitial vascular or the vascular to increased SNS signals from the vasomotor center in the brain. compartment. There is a balance between oncotic pressure and hydrostatic pressure in each compartment.A. Normal setting.Therecompartment. isNo a banetlance fluidThere between movement is a ba oncoticlance into between eitherpressure the oncotic and interstitial hydrostatic pressure or the andpressure vascular hydrostatic in each pressure in each compartment. The blood vessel wall permeability is normal (semipermeable). Oncotic pressure compartmentcompartment.. ThecompartmentThere blood is vessela ba.lanceThe wall blood between permeability vessel oncotic wall is pressurenormalpermeability (semipermeable). and hydrostaticis normal (semipermeable). pressureOncotic inpressure each Oncotic pressure works to hold fluid within a compartment; hydrostatic pressure works to push fluid out of a workscompartment to hold fluid.worksThe within blood to hold a vessel compartment;fluid wall within permeability ahydrostatic compartment; is pressurenormal hydrostatic (semipermeable). works pressureto push fluid worksOncotic out toof pushpressure a fluid out of a Cortisol compartment. compartment.works to holdcompartment.fluid within a compartment; hydrostatic pressure works to push fluid out of a Cortisol is also rapidly mobilized in the acute stages of shock compartment. Blood vessel (within minutes).1 Cortisol is released from the adrenal gland in Blood vesselBlood vesselInterstitialInterstitial Space InterstitialSpace Space response to corticotropin-releasing hormone (CRH) from the Blood vessel Interstitial Space hypothalamus and also by stimulation via adrenocorticotropic hormone.7 Stimuli such as pain and mental or physical stress can πi lead to increases in CRH production. These stimuli are generated πi πi πc in or transmitted through the brain to the hypothalamus. Cortisol πc πc πi π has many effects, and it is not completely understood which effect c Pc Pi is the most important in shock; however, stimulation of glycoge- Pc Pc Pi P P i nolysis and mobilization of fat and protein stores for gluconeo- c Pi 1 genesis are often considered the most important. Release of glucose Net movement fluid into vessel Net movement fluidNet movement into vessel fluid into vessel into the bloodstream provides a readily accessible energy source. Net movement fluid into vessel We believe that the most important effects of this glucose surge Thomovsky E, et al. Shock pathophysiology. Compend Contin B. Immediately after hypovolemia occurs (e.g., immediatelyThomovsky postE, et-hemorrhage). al. Shock pathophysiologyNet fluid movement. Compend Contin B. Immediately B.afterImmediately hypovolemia after occursEduc hypovolemia Vet(e.g., 2013;35(8):E1immediately occurs (e.g.,- postimmediately-hemorrhage). postNet-hemorrhage). fluid movementNet fluid movement are to supply endothelial cells in the blood vessels with energy to into the vascular compartment. The hydrostatic pressure within the blood vessel (Pc) is LESS than intoB. theImmediately vascularinto compartment. after the hypovolemiavascularThe compartment. hydrostatic occurs (Educe.g., Thepressure immediatelyVet hydrostatic 2013;35(8):E1 within postpressurethe -bloodhemorrhage).- within vessel the (Pc)Net blood is fluid LESS vessel movement than (Pc) is LESS than that in the interstitium (Pi) due to hypovolemia. Oncotic pressure (πc) is HIGHER in the blood vessel continue contraction, feed the myocardial cells to continue con- thatinto in thethe vascularinterstitiumthat compartment.in the(Pi) interstitium due to Thehypovolemia. hydrostatic(Pi) due toOncotic hypovolemia.pressure pressure withinOncotic (theπc) bloodis HIGHERpressure vessel ( πin(Pc)) theis isHIGHER blood LESS vessel than in the blood vessel than previously due to depletion of fluid. The blood vessel wall permeability is normal c thanthat p reviouslyin the interstitium thandue topreviously depletion (Pi) due due of to fluid tohypovolemia. depletion. The blood ofOncotic fluid vessel. The pressurewall blood permeability vessel(πc) is HIGHERwall is normalpermeability in the blood is normal vessel traction, and allow brain cells to function in the short term. (semipermeable). (semipermeable).than previously(semipermeable). due to depletion of fluid. The blood vessel wall permeability is normal (semipermeable). Blood vessel Interstitial Space Transcapillary Shifts Blood vessel Interstitial Space A final mechanism that aids in the acute improvement in blood volume is transcapillary shifting of fluid from the interstitium to the vasculature. This happens at the capillary level, primarily in 11 FIGURE 5 cases of hypovolemic shock ( ). When the pressure πi within the capillaries drops secondary to hypovolemia and vaso- πc πi

π fluid net constrictive shunting of blood, Starling’s forces dictate that fluid c movement No net fluid fluid net

will move from an area of higher pressure (the interstitium) into Pc movement Pi No Pc an area of lower pressure (the vessel). Fluid continues to move until Pi the dilution of proteins in the blood vessels (decreasing oncotic pressure in the blood vessel) is balanced with the concentration of proteins in the interstitium (increasing oncotic pressure). Addi- C. Cessation of transcapillary fluid shifting. After a period of net fluid movement into the vascular compartment,C. Cessation the fluid of volumetranscapillary in the interstitial fluid shifting. spaceAfter is decreased a period andof net the fluid hydrostatic movement pressure into the(Pi) vascular tionally, as fluid moves out of the interstitium into the vascular decreases.compartment,Dilution of intravascularthe fluid volume proteins in the occurs interstitial secondary space to is fluid decreased movement and the into hydrostatic the blood pressure (Pi) space, fluid volume and, therefore, pressure decrease in the inter- vessel, decreasingdecreases. capillaryDilution ofoncotic intravascular pressure proteins(πc). Interstitial occurs secondaryoncotic pressure to fluid INCREASES movement into due theto blood concentration of proteins in the interstitial space after fluid moves into the vessel. The blood vessel vessel, decreasing capillary oncotic pressure (πc). Interstitial oncotic pressure INCREASES due to wall permeability is normal (semipermeable). Fluid movement into the blood vessel stops. stitium (decreasing hydrostatic pressure). concentration of proteins in the interstitial space after fluid moves into the vessel. The blood vessel An additional step during transcapillary fluid shifting involves wall permeability is normal (semipermeable). Fluid movement into the blood vessel stops. movement of proteins into the blood from storage sites in the mesen- 11 Figure 5. Transcapillary shifting of fluid during hypovolemic shock. Fluid movement tery and liver. These proteins increase oncotic pressure in the blood is dictated by Starling’s law: Net fluid movement = [Pc – Pi] –δ [πc – πi] where vessels to continue to help draw fluid from the interstitium into blood Pc= hydrostatic pressure in the capillary, Pi= hydrostatic pressure in the interstitium, vessels and maintain the extra fluid within the blood vessels.11 Figureπc= oncotic 5. Transcapillary pressureshifting in the of capillary, fluid during πi hypovolemic = oncotic shock.pressure Fluid in movement the interstitium, is dictated and by Starling’s law: Net fluid movement = [Pc – Pi] – δ[πc – πi] where Pc= hydrostatic pressure in Figure 5. Transcapillary shifting of fluid during hypovolemic shock. Fluid movement is dictated theδ= capillary,the reflection Pi= hydrostatic coefficient. pressure Thein the reflection interstitium, coefficientπc= oncotic pressure essentially in the describescapillary, π the i by Starling’s law: Net fluid movement = [P – P] – δ[π – π ] where P = hydrostatic pressure in =“leakiness” oncotic pressure of the in the blood interstitium, vessel andwalls δ= andthe reflection ctheiri ability coefficient.c toi retain The reflectionproteins,c coefficient electrolytes the capillary, P = hydrostatic pressure in the interstitium, π = oncotic pressure in the capillary, π Moderate Compensatory Mechanisms essentially describes thei “leakiness” of the blood vessel walls and ctheir ability to retain proteins, i and other= oncotic substances pressure inin the the interstitium, lumen of andthe δ=capillary. the reflection In the coefficient. situations The discussed reflection coefficient in The next level of compensation starts within about 10 minutes to electrolytes and other substances in the lumen of the capillary. In the situations discussed in this figure,this figure, theessentially reflection the describes reflection coefficient the is “leakiness” coefficientconsidered of to isthe be bloodnormal.considered vessel to walls be and normal. their ability to retain proteins, 1 hour after the body enters the shock state. electrolytes and other substances in the lumen of the capillary. In the situations discussed in this figure, the reflection coefficient is considered to be normal.

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Shock Pathophysiology

Table 2. Physical Examination Findings at Each Stage of Shocka Physical Examination Finding Compensated Shock Acute Decompensated Shock Late Decompensated Shock

Canine

Temperature ↓ (98°F–99°F) ↓↓ (96°F–98°F) ↓↓↓ (<96°F)

Heart rate ↑↑ (>180 bpm) ↑ (>150 bpm) Normal to ↓ (<140 bpm)

Respiratory rate ↑↑ (>50 bpm) ↑ (>50 bpm) ↑ to normal to agonal Mentation QAR Obtunded Obtunded to stupor

Mucous membrane color Pale Pale Pale to muddy

Capillary refill time <1 sec <2 sec ≥2 sec

Mean arterial blood pressure ↓ to normal (70–80 mm Hg) ↓(50–70 mm Hg) ↓↓ (<60 mm Hg)

Feline

Temperature ↓ (<97°F) ↓↓ (<95°F) ↓↓↓ (<90°F)

Heart rate ↑↑↑ (>240) or ↓ (160–180 bpm) ↑↑ (>200 bpm) or↓↓ (120–140 bpm) ↑ (>180 bpm) or ↓↓↓ (<120 bpm)

Respiratory rate ↑↑↑ (>60 bpm, open-mouth breathing) ↑↑ (>60 bpm) ↑ rate to agonal Mentation QAR Obtunded Obtunded to stupor

Mucous membranes Pale Pale to white Variable (pale to white to muddy)

Capillary refill time <1 sec <2 sec ≥2 sec

Systolic arterial blood pressure ↓ to normal (80–90 mm Hg) ↓(50–80 mm Hg) ↓↓ (<50 mm Hg)

aHypothetical values are given in parentheses to give the reader an idea of the approximate range of values found in each species at each stage of shock. QAR = quiet, alert, responsive

Angiotensin II baroreceptors and stretch receptors (in the right and left atria). Baroreceptors in the juxtaglomerular apparatus near the renal The atrial stretch receptors are active when there is a large volume glomerulus sense decreased blood flow from decreased cardiac in the atria and work to inhibit vasopressin secretion; when the output. This decreases impulse generation in the baroreceptors, atria are less full, more vasopressin is released because of lack of which in turn leads to renin secretion. Renin causes conversion of inhibition. Even small alterations—a 1% change in osmolarity or angiotensinogen to angiotensin I in the bloodstream. Angiotensin a 10% decrease in blood volume—lead to release of vasopressin.7 I is converted to angiotensin II in the lungs under the influence of Other stimuli, including nausea and hypoxia, also develop in patients angiotensin-converting enzyme. Angiotensin II binds to angio- with shock and cause further release of vasopressin.7 Vasopressin tensin receptors on the blood vessels and causes vasoconstriction. binds to V1 receptors on the arterioles, causing vasoconstriction. The vasoconstriction not only improves blood vessel tone to main- As with angiotensin or norepinephrine, this improves vascular tone tain perfusion to the tissues but also, more importantly, forces in an effort to maintain delivery of blood to tissues. Additionally, blood from less important peripheral tissues (including the it increases return of blood from the peripheral tissues to the splanchnic circulation) to the brain and heart to improve venous heart so that venous return and cardiac output are maintained. return and cardiac output.2 Angiotensin II also retains water and sodium in the kidneys to help maintain blood volume through renal Chronic Compensatory Mechanisms artery vasoconstriction, which reduces filtration of blood through If the patient survives the shock situation, the final stages of com- direct effects on the tubules that are not completely elucidated.1 pensation involve replacing the blood volume in the body. This takes place from 1 to 48 hours after insult. Vasopressin Vasopressin is released from the posterior pituitary gland in response Aldosterone to increased osmolarity (i.e., less water and more sodium in the At the same time that angiotensin II is exerting its effects on blood blood that passes by the osmoreceptors in the hypothalamus) or vessels and the kidney, it is also stimulating the adrenal glands to decreased effective circulating blood volume as sensed by the secrete aldosterone from the adrenal gland cortex.1 Aldosterone

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Shock Pathophysiology

Table 3. Physical Examination Findings During Shock States Physical Examination Finding Compensated Shock Acute Decompensated Shock Late Decompensated Shock Canine Rectal During vasoconstriction, peripheral vessels Vasoconstrictive shunting of blood away While vasoconstrictive shunting of blood is temperature such as those in the GI tract are preferentially from the GI tract continues. Simultaneously, still in progress, the largest factor in the constricted. Reduced blood flow to the colon the decreased cardiac output with decreased temperature is the minimal amount leads to a decreased rectal temperature. worsening shock equates to less blood of blood flow being delivered to the colon. being delivered to the colon (and therefore a lower rectal temperature).

Heart rate Activation of β1-adrenergic receptors by As the myocardium receives less oxygen, the Continued reduced myocardial perfusion and epinephrine and norepinephrine leads to heart rate starts to decrease despite continued oxygen delivery leads to decreasing ability of

tachycardia. stimulation by the β1-adrenergic receptors. the heart to contract and a reduced heart rate. Respiratory Multifactorial. Pain and stress lead to As oxygen delivery decreases to the Continued reduced oxygen delivery to the rate tachypnea. Respiratory rate also increases diaphragm and other muscles of diaphragm and other muscles of concurrent with perceived oxygen debt in respiration, the respiratory rate decreases. respiration leads to worsening respiratory the respiratory center in the brain. rate decline. Mentation Brain cells receive enough oxygen to As the cells of the brain receive less Continued reduced oxygen delivery to the function, but the patient is less responsive oxygen delivery, the patient’s mentation brain leads to worsening obtundation. than normal. Pain also alters mentation. declines (obtundation). Mucous Pallor occurs primarily because of Pallor continues because of vasoconstriction Pallor occurs largely because of reduced membrane vasoconstriction and shunting of blood and shunting of blood along with reduced peripheral perfusion. Muddy mucous color away from the periphery. Hyperemia ability to deliver blood to peripheral tissues. membrane color develops when waste develops because of massive release of products of cellular metabolism diffuse vasodilatory mediators such as nitric oxide into capillaries but are not removed from (seen in cases of sepsis and SIRS) the region because of reduced perfusion. Capillary refill Rapid refill caused by increased vascular Blood vessels start to become refractory to Blood vessels lose the ability to constrict time tone (binding by epinephrine, norepinephrine, constriction because of reduced oxygen because of severely decreased oxygen ANG II and vasopressin to receptors on delivery to endothelial cells. Vasodilatory delivery to those cells and the overwhelming vascular endothelium). effectors such as nitric oxide start to influence of vasodilatory signals such as overwhelm vasoconstrictors. nitric oxide. Mean arterial The body is able to maintain near normal Gradual loss of vascular tone occurs Ability to vasoconstrict is lost because of blood pressure, primarily because of vasocon- because of reduced oxygen delivery to the reduced oxygen delivery; reduced cardiac pressure striction. vascular endothelium. output leads to reduced vascular volumes. Feline Temperature Same as canine. Heart rate Cats rarely display tachycardia during shock. Cats in shock are often bradycardic and become more so over time. Cats in compensated shock tend to have heart rates ≤160 bpm, and cats in decompensatory shock tend to have heart rates ≤100 bpm. It is not completely understood why cats respond to shock with relative to absolute bradycardia without first having a discernible period of tachycardia, despite having increases in SNS signals similar to dogs. Respiratory Cats display profound tachypnea that can resemble respiratory distress. It is not completely understood why cats have such a dramatic rate response compared with dogs. However, the lungs are considered the “shock” organ in cats and, as such, receive markedly decreased perfusion during vasoconstrictive conditions, which may contribute to the extreme tachypnea and respiratory distress. Mentation Same as canine. Mucous It is often difficult to visualize color and perform a capillary refill time even in healthy cats. However, it is likely that they follow a similar membranes/ pattern to dogs. capillary refill time Mean arterial Same as canine. blood pressure

SIRS = systemic inflammatory response syndrome;SNS = sympathetic nervous system; ANG II = angiotensin II

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Shock Pathophysiology

increases sodium reabsorption in the distal convoluted tubule of the kidney. Water Shock follows the sodium and is reabsorbed into the blood vessels, increasing blood Opioid pain medications (if indicated) volume. Whenever blood volume is increased, there is improved venous return Cardiogenic

(and therefore cardiac output). Hypovolemic Obstructive Distributive Antidiuretic Hormone Vasopressin has another effect in the body as antidiuretic hormone (ADH). Vaso- pressin and ADH are the same hormone; Administer proximal to the two names reflect the two divergent obstruction effects in the body. When produced, Positive inotropes (dobutamine) ADH binds to V2 receptors in the col- 1 Fluids lecting ducts of the kidney. This induces component Vasodilatory insertion of aquaporin channels into the collecting ducts to allow reabsorption of Vasopressors (dopamine, norepinephrine, vasopressin, water from the ducts. ADH also stimulates Relieve epinephrine) obstruction (if thirst to increase the amount of water in the indicated) Treat body and thereby improve blood volume underlying and venous return. cardiac Patient stabilizes based disease (if on vital statistics, present) Clinical Signs Associated mentation, blood With Shock pressure Building on the basic physiology of the

shock response allows better understand- lize Does not ing of the clinical signs associated with stabilize an animal presenting in shock. Patients Further diagnostics go through three stages of shock: com- (imaging, full More fluids pensatory, acute decompensatory, and blood work) Full PE – look for ongoing late decompensatory. Other terms for hemorrhage these stages are compensatory reversible Positive inotropes Vasopressors (dopamine, vasopressin shock, uncompensated reversible shock, and (dobutamine) – if Check for not already in use norepinephrine) – if not hypoglycemia uncompensated irreversible shock.3 In the already in use compensated stage, by virtue of the various physiologic mechanisms discussed Figure 2. Treatment of shock. PE = physical examination. Figure 6. Treatment of shock. PE = physical examination above, the patient is able to maintain oxygen delivery to the tissues to preserve normal cellular metabolism. In the acute stage of decompensation, compensated shock, the expected mucous membrane color is pale the demand for oxygen is greater than the delivery despite the because of vasoconstrictive shunting of blood away from the mucous action of the physiologic mechanisms; therefore, the cells are forced membranes. However, in some cases, the mucous membranes to switch to anaerobic metabolism, which yields less energy. In the can appear hyperemic.9,10 Hyperemic mucous membranes may later stages of decompensation, inappropriate oxygen delivery be seen in diseases in which vasodilation overwhelms the vaso- continues and the cellular demand for oxygen is not met, causing constriction expected in compensated shock. Notable examples further anaerobic metabolism and less available ATP to the cells. are septic shock and SIRS, in which vasodilatory mediators such In veterinary medicine, determination of the patient’s stage of as nitric oxide and cytokines that directly dilate the blood vessels shock is based largely on the physical examination findings for are produced, leading to vasodilation.9,10 Later, in decompensatory that patient. See TABLE 2 for a summary of the physical examination shock, the pallor seen in SIRS and sepsis patients is caused by a findings found at each stage of shock andTABLE 3 for the reasons lack of blood delivery to the mucous membranes, not vasocon- each finding exists at that stage. strictive mechanisms. The physical examination finding that has the most variability Cats may not display the classic sign of tachycardia seen in in cases of shock is the mucous membrane color. Based purely on dogs. While there is no clear reason for this species difference, the physiologic responses to which a patient is exposed during cats in shock that tend to display bradycardia (heart rate <140

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Shock Pathophysiology

bpm) or relative bradycardia (heart rate <160 bpm) are often septic can obstruct blood vessels) and release cytokines that cause depres- or have SIRS.9,10 sion of the myocardium but also, if untreated, prevent resolution of the patient’s condition. Also complicating the situation is the Treatment fact that improving macrovascular parameters such as heart rate In veterinary medicine, treatment for shock should be aimed at or peripheral blood pressure does not necessarily mean that micro- addressing the basic pathophysiologic mechanisms. Gauging a circulation (capillary perfusion) has been restored.4,8 However, at response to treatment for patients in shock is based on normalizing this time, clinicians do not have a clinically dependable bedside vital parameters and, often, peripheral blood pressure. There are diagnostic test or tool that allows assessment of the microcirculatory very limited options available to clinicians to treat cases of shock response to resuscitation. (FIGURE 6). In any treatment situation, continuous reassessment of the Hypovolemic shock is primarily treated by large-volume fluid patient’s vital parameters and status to determine whether resus- resuscitation. Crystalloid fluid doses for patients in shock are 90 citation efforts have been successful is most important. If the patient mL/kg/h in dogs and 60 mL/kg/h in cats. It is recommended to does not seem to be improving as hoped, continue to administer give one-quarter to one-third of the calculated fluid dose to the treatment as suggested by the patient’s condition, but reassess the animal in a bolus as quickly as possible and then reassess the patient with a complete physical examination to look for indications patient’s vital parameters. The fluid bolus can be repeated as of occult hemorrhage (e.g., into a body cavity or a fracture hema- many times as necessary until the parameters have normalized toma) that would lead to ongoing signs of hypovolemic shock. It or the hourly amount has been met. Further or additional steps is important to document that a refractory patient is not suffering might include administration of boluses of colloids (typically 5 to from hypoglycemia caused by depleted liver stores occurring after 10 mL/kg repeated until the patient is stabilized or to a maximum exuberant cortisol release. Finally, especially in trauma patients, dose of 20 mL/kg for colloids such as hetastarch). if the patient does not improve with resuscitation, imaging of Obstructive shock is treated with fluids administered at shock body cavities is indicated to look further for blood loss or other doses in a vascular location where the fluids will return to the abnormalities, such as pneumothorax, that might decrease venous heart and not be trapped distal to the obstruction. For example, return to the heart and further the shock condition. a patient with gastric dilatation-volvulus (GDV) should receive Shock is a complex interaction between the inciting event and fluid in the cephalic veins, not the lateral saphenous veins. When the body’s compensatory mechanisms. In understanding basic applicable, the clinician should also attempt to relieve the ob- pathophysiology, clinicians should be able to better recognize struction (e.g., surgery to relieve GDV). patients in shock and to logically determine the best steps for Cardiogenic shock does not involve decreased blood volume resuscitation of these patients. and instead is a failure of the heart to effectively pump blood to tissues. It is treated with positive inotropes (e.g., dobutamine) References without fluid therapy. In some cases, drugs that cause vasodilation 1. Hall JE. Circulatory shock. In: Guyton and Hall Textbook of Medical Physiology. 12th and reduce afterload, such as nitroprusside, are also used to improve edi. Philadelphia, PA: Saunders Elsevier; 2011:273-282. cardiac output. It is important to limit or forgo fluid therapy in 2. Bonanno FG. Physiopathology of shock. J Emerg Trauma Shock 2011;4(2):222-232. 3. Brown SGA. The pathophysiology of shock in anaphylaxis. Immunol Allergy Clin patients with cardiogenic shock because the heart may already be North Am 2007;27:165-175. fluid overloaded by shunting of blood to the heart caused by vaso- 4. Elbers PWG, Ince C. Bench-to-bedside review: mechanisms of critical illness—classifying constriction during compensation. microcirculatory flow abnormalities in distributive shock.Crit Care 2006;10:221. Distributive shock is the most difficult form of shock to treat 5. Ben-Shoshan M, Clarke AE. Anaphylaxis: past, present and future. Allergy 2010;66:1-14. because it involves derangement of the microvasculature as well 6. Moranville MP, Mieure KD, Santayana EM. Evaluation and management of shock states: hypovolemic, distributive and cardiogenic shock. J Pharm Pract 2011;24(1):44-60. as the macrovasculature. These patients are treated with shock 7. Woolf PD. Endocrinology of shock. Ann Emerg Med 1986;15:1401-1405. doses of fluids to improve hypovolemia resulting from increases in 8. Szopinski J, Kusza I, Semionow M. Microcirculatory responses to hypovolemic vascular permeability and maldistribution of fluids into the dilated shock. J Trauma 2011;71(6):1779-1787. vessels. Patients also require treatment with drugs to promote 9. Boag AK, Hughes D. Assessment and treatment of perfusion abnormalities in the vasoconstriction, such as vasopressin, dopamine, epinephrine, or emergency patient. Vet Clin North Am Small Animal Pract 2005;35(2):319-342. 10. deLaForcade AM, Silverstein DC. Shock. In: Silverstein DC, Hopper K, eds. norepinephrine and, in some cases, positive inotropes to improve Small Animal Critical Care Medicine. St. Louis, MO: Saunders Elsevier; 2009:41-45. myocardial depression (dobutamine). Finally, the underlying 11. Boulpaep EL. Integrated control of the cardiovascular system. In: Boron WF, Boulpaep cause of the distributive shock must be addressed. Diseases leading EL, eds. Medical Physiology: a Cellular and Molecular Approach. Philadelphia, PA: Elsevier to distributive shock may not only cause hypercoagulability (which Saunders; 2003:574-590.

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Shock Pathophysiology

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1. Which of the following lists the correct variables for 6. Which disease entity would most likely cause cardiogenic cardiac output? shock? a. heart rate, preload, stroke volume, oxygen saturation a. hemoabdomen b. preload, afterload, contractility, heart rate b. third-degree AV block c. hemoglobin, afterload, arterial oxygen content, stroke c. pulmonary thromboembolism volume d. dilated cardiomyopathy

d. stroke volume, arterial oxygen content, hemoglobin, 7. A dog with the following physical examination findings heart rate would be classified in which stage of shock? • Temperature: 94.5°F 2. Acute compensatory mechanisms that work to restore • Heart rate: 120 bpm perfusion to the tissues demonstrate their effects within • Respiratory rate: 60 breaths/min what time frame? • Mentation: obtunded a. days • Mucous membrane color: pale b. minutes • Capillary refill time: >2 sec • Mean arterial pressure: 50 mm Hg c. hours a. Compensated d. months b. Acute decompensated 3. Which of the following compensatory mechanisms does c. Acute compensated not happen within the first 30 minutes after onset of shock? d. Late decompensated a. release of aldosterone 8. Which of the following does not happen during distributive b. increase in heart rate shock? c. increase in sympathetic tone a. decreased cardiac contractility d. release of norepinephrine b. embolization of small blood vessels

4. Which of the following is a stimulus for the release of c. increased contractility catecholamines? d. vasodilation

a. hypernatremia 9. ______is not generally associated with feline shock. b. hypertension a. Tachycardia c. hypoxemia b. Hypotension d. hypercapnia c. Hypothermia d. Tachypnea 5. Which of the following is not a stimulus for the release of vasopressin? 10. ______is a product of anaerobic cellular metabolism. a. increased blood volume a. Vasopressin b. hypoxia b. Glucose c. nausea c. Oxygen d. increased osmolarity d. Lactate

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