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KEY FACTS

CE

712 Vol. 23, No. 8 August 2001

n The hallmark clinical sign of ALI/ARDS is hypoxemia that isrefractory to oxygen treatment.

n The most common risk factorsfor ALI/ARDS in dogs aremicrobial pneumonia, sepsis,and aspiration pneumonia.

n The pathogenesis of ALI/ARDS isextremely complex and involvesnumerous inflammatorymediators as well as cellularresponses.

n The primary goals of therapy forthese respiratory diseases is tofind and eliminate the cause,reduce edema formation, providesupportive care as indicated, andensure adequate systemicperfusion.

*When this article was written, Dr. Carpenter was at Auburn University.

Acute Lung Injury and Acute RespiratoryDistress Syndrome University of Minnesota*

Dewey H. Carpenter, Jr., DVM

Auburn University

Douglass K. Macintire, DVM, DACVIM, DACVECC

Mississippi State University

John W. Tyler, DVM, DACVIM

ABSTRACT: Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are se-vere respiratory diseases that have not been well characterized in veterinary medicine. Despiteextensive research into this area in human medicine over the past 30 years, little is knownabout the exact pathogenesis of this complex syndrome. With the increase in veterinary criti-cal care facilities and the greater number of owners who are willing to enter into extensivetreatment of critically ill animals, there will also be an increase in the number of ALI/ARDScases that are identified and treated. Therefore, it is essential for veterinarians not only to rec-ognize the clinical signs of ALI/ARDS but also to know the risk factors that may predisposepatients to developing these respiratory diseases. Knowledge of the complex pathophysiologyas well as the pathogenesis is also required to anticipate changes in the animal’s condition. Todate, treatment remains primarily symptomatic and is aimed at improving oxygenation. Thisarticle is intended to provide clinicians with a basic understanding of the risk factors, patho-physiology, pathogenesis, clinical signs, and treatments that may help improve the survival ofveterinary patients with ALI/ARDS.

Acute respiratory distress syndrome (ARDS), originally called adult respi-ratory distress syndrome, was first recognized as a clinical disorder in hu-man intensive care patients by Ashbaugh and colleagues in 1967.1 It was

defined as a clinical syndrome characterized by severe hypoxemia refractory tooxygen treatment with patchy bilateral alveolar infiltrates on chest radiographsand low pulmonary compliance.1 Estimates of prevalence in humans range from1.5 to 75 per 100,000 patients; but most experts believe that the actual preva-lence is about 5 to 7 per 100,000.2–6 Most of the disparity in mortality andprevalence studies has come from the varying definitions of ARDS over the past30 years.2–6 In 1994, an American-European Consensus Committee on ARDSdifferentiated acute lung injury (ALI) from ARDS by establishing clinical diag-nostic criteria for each condition.7 Differentiation is based on the ratio of partialpressure of arterial oxygen to fractional inspired oxygen (PaO2:FiO2). A value of

less than 300 indicates ALI and less than 200 indicatesARDS.7 Consequently, all ALI cases do not result inARDS, but all cases of ARDS will result from ALI.

Despite being one of the most researched areas of hu-man medicine in the past 20 years, little is knownabout the exact initiating causes and the best methodsof treatment for ALI/ARDS.2–6 A single inciting eventresponsible for producing the clinical signs of ARDShas not been found. It appears more likely that a multi-tude of events occurs, and any of these can lead to thedevelopment of ALI/ARDS. This supposition wouldcoincide with the multiple unrelated risk factors thatcan lead to the development of this clinical syndrome.

Dogs are used extensively in experimental models forstudying the development of ARDS associated withpancreatitis, paraquat poisoning, ethchlorvynol toxico-sis, trauma, oleic acid injury, and endotoxemia.2–6 How-ever, these studies often look at only a single aspect ofthe entire syndrome, thus making the information lessapplicable to the clinical veterinary setting. In addition,only isolated case reports and review articles have beenpublished in the veterinary literature.8–17

With the advent of more advanced emergency andcritical care facilities as well as an increased availabilityof advanced diagnostic capabilities in veterinary medi-cine, it is likely that more cases of ALI/ARDS will beidentified and treated. However, little is known aboutthe actual prevalence and mortality resulting fromALI/ARDS in dogs. It must be assumed that the mor-tality rate is much higher than is seen in human popu-lations because of the limited long-term ventilatory ca-pabilities in veterinary medicine. More information isneeded to establish the clinical differences between hu-man and canine patients with ALI/ARDS.

RISK FACTORSThere are numerous recognized causes of ALI in hu-

mans. These causes are generally placed into two cate-gories: direct and indirect lung injury.2–6 Commoncauses of direct lung injury in dogs include aspirationof gastric contents, blunt force trauma with pulmonarycontusions, near drowning, inhalation of noxious gases(e.g., smoke inhalation injury), oxygen toxicity, andpneumonia.9,14 These injuries are often progressive, andtheir severity should not be underestimated based oninitial clinical parameters.9

Indirect lung injury in humans commonly resultsfrom systemic inflammatory response syndrome (SIRS)and may or may not be related to sepsis.2–6 In dogs, in-direct or secondary lung injury has been associatedwith sepsis, SIRS, shock, trauma, pancreatitis, parvovi-ral enteritis, organ torsion, and paraquat toxicosis.2,8–17

Parent and colleagues14 identified microbial pneumo-

nia, sepsis, and aspiration pneumonia as the most com-mon risk factors observed in dogs. Other predisposingfactors observed in order of prevalence were nonrespon-sive shock, oxygen toxicity, organ torsion, laryngeal ob-struction secondary to strangulation with a chokechain, pulmonary trauma, and disseminated intravascu-lar coagulation (DIC).14 Of the dogs in this study,14

58% had more than one risk factor present and 33%had three or more risk factors.14 This is comparable tothe increased risk seen in human patients that have twoor more predisposing factors.5

Acute respiratory distress syndrome is now consid-ered a risk factor for the development of SIRS and mul-tisystem organ failure syndrome (MOFS).18 In fact, sev-eral experts believe that ARDS is not a single organfailure syndrome but the first organ to fail in MOFSand is closely followed by liver dysfunction.18 About20% of human patients with ARDS die solely as a re-sult of respiratory complications, and the remainingmortality is attributed to other organ failures.2–6 In theParent et al. study,14 42% of the canine deaths were at-tributable to respiratory dysfunction.

PATHOPHYSIOLOGYThe best method to understand the pathophysiology

of the pulmonary edema associated with ALI/ARDS isStarling’s equation, which defines the normal move-ment of fluid across the pulmonary membranes (Box1). The average osmotic reflection coefficient (σ) isabout 0.7 to 0.8 in normal pulmonary tissue and de-scribes the effectiveness of the endothelium in hinder-ing the passage of solutes (i.e., proteins) from the vas-culature into the interstitium.2,19 The net effect ofStarling’s forces is that fluid and protein move from thevascular space into the interstitial space.2,19 The alveolarbarrier between the epithelium of the alveolus and theinterstitium can be explained with a similar equation inwhich the flow of fluid across the alveolar barrier is es-

Compendium August 2001 Small Animal/Exotics 713

QT = Kf[(Pmv − Pis) − σ(πmv − πis)]QT = Amount of fluid filtered per unit of timeKf = Permeability of vessels to fluidPmv = Hydrostatic pressure of the pulmonary

microvasculaturePis = Hydrostatic pressure of the interstitial spaceσ = Average osmotic reflection coefficientπmv = Osmotic pressure of the pulmonary

microvasculatureπis = Osmotic pressure of the interstitial space

BOX 1Starling’s Equation of Fluid Movement2,19

sentially zero in the normal lung. Fluid tends to remainin the interstitial space of the lungs under normal con-ditions and is removed by the lymphatics.19

In ARDS, σ approaches zero because of a loss of en-dothelial integrity.2 This leads to the uncontrolled flowof fluid and protein into the interstitial space, exceed-ing the capacity of the lymphatic system.2,19 Therefore,fluid begins to accumulate in the pulmonary intersti-tium and the peribronchovascular cuffs. There is alsodamage to the alveolar epithelium, and fluid and pro-teins leak from the interstitium into the alveoli, causingalveolar flooding (Figure 1). This is observed on radi-ographs as a diffuse alveolar pattern.19,20

The reason for the loss of vascular and alveolar integrityhas not been fully defined. The pathogenesis of

ALI/ARDS is extremely complexand involves numerous inflamma-tory mediators as well as cellularresponses (Figure 1). The timecourse, order of events, and inter-actions of these responses are notclearly understood.2–6,18–21 Whetherthere is direct or indirect lung in-jury, the overall effect is an abnor-mal modulation and regulation ofthe inflammatory response thatallows the development of ALI/ARDS.2–6,18–21 This rogue inflam-matory response has both cellularand humoral components.2–6,18–21

The major cellular componentsare the neutrophil and macro-phage; the major humoral com-ponents are tumor necrosis factor(TNF)-α, interleukin (IL)-1, IL-6, and IL-8.2–6,18–21

Cellular ComponentsNeutrophil

Although ALI/ARDS can occur without a primary neu-trophilic component, most incit-ing causes have a strong neu-trophil response.2–6 The role of theneutrophil follows a sequentialpattern. Initially, there is neu-trophil sequestration in the lungs,followed by neutrophil adherence,and finally transmigration intothe interstitium and alveolarspaces.21a The neutrophil providesa nonspecific defense responsethat is as equally capable of de-

stroying invading microbes as it is of mediating host tis-sue damage.2–6 Proteases are released along with oxygenradicals that initiate lipid peroxidation, alter surface prop-erties, prevent normal cellular metabolism, damage cellu-lar DNA, and inactivate α-antitrypsin.2–6 Because α-antit-rypsin is the major antiprotease located in the lung, itsinactivation shifts the antiprotease–protease balance,thereby potentiating the effects of neutrophil proteases.2–6

Macrophages and MonocytesMacrophages comprise more than 90% of the pul-

monary leukocyte population in normal lungs andfunction to regulate the inflammatory and immune re-sponse in ALI/ARDS via the release of numerous medi-ators. TNF-α and IL-1, two of the most critical cy-

714 Small Animal/Exotics Compendium August 2001

Figure 1—The normal alveolus (left) and the injured alveolus in the acute phase of acutelung injury and acute respiratory distress syndrome (right). In the acute phase of this syn-drome, there is sloughing of the bronchial and alveolar epithelial cells with the formationof protein-rich hyaline membranes on the denuded basement membrane. Neutrophils areshown adhering to the injured capillary endothelium and marginating through the inter-stitium into the air space, which is filled with protein-rich edema fluid. (From Ware LB,Matthay MA: Medical progress: The acute respiratory distress syndrome. N Engl J Med342(18):1339, 2000; with permission.)

tokines, are released from the macrophage along withIL-6 and IL-8.2–6 The macrophage can also move intothe interstitial and alveolar spaces and release oxygen-derived free radicals, proteases, and metalloproteinases,further increasing the protease burden of the lungs.2–6

LymphocytesRecent evidence suggests that lymphocytes play a role

in the evolution of ALI/ARDS.3 Lymphocytes undergoactivation, sequestration, adhesion, and chemotaxis inmuch the same manner as the neutrophil and use manyof the same chemotactants.3 Although their function inALI/ARDS is not fully understood, these cells can pro-duce damage similar to that observed in ALI/ARDS;therefore, their role in the disorder needs further inves-tigation.3

Platelets and FibroblastsPlatelet aggregation leads to microvascular emboliza-

tion and the production of various cytokines andeicosanoids. These mediators result in vasoconstrictionand bronchoconstriction and can lead to further vascu-lar and alveolar membrane damage.2–6 Fibroblasts andtype II pneumocytes synthesize and release many com-plement components (e.g., C3, C5).2–6

Humoral ComponentsComplement

Complement can be activated by one of three path-ways (i.e., classical antibody dependent, alternative, orthe newly discovered mannan-binding lectin/mannan-binding lectin–associated serine proteases).22 Followingactivation, the proinflammatory peptides C3a and C5a(commonly called anaphylatoxins) and the membraneattack complex (C5b–9) are formed.22 These lead to

chemotaxis of leukocytes, degranulation of all granulo-cytes, smooth muscle contraction, increased vascularpermeability, and stimulation of the production and re-lease of arachidonic acid metabolites and cytokines.22

CytokinesSeveral different biochemical mediators have been

grouped into the general category of cytokines. Fortu-nately, the primary cytokines involved with ALI/ARDScan be loosely placed into four general functional cate-gories (Table 1). These cell-derived peptides cause alter-ation of one or more functions in target cells, whichelicit a direct effect or stimulate the production of morehumoral mediators (Box 2). Undoubtedly, this is acomplex system and all the cytokines involved havelikely not been identified. TNF-α, IL-1, IL-6, and IL-8are the cytokines suspected of having the greatest im-pact on the development and eventual outcome ofALI/ARDS.2–6

EicosanoidsEicosanoids are the product of arachidonate metabo-

lism and as such are products of membrane phospholipidmetabolism.2–6 There are three major categories depend-ing on the specific metabolic pathway used.2–6

Prostaglandins, including thromboxanes TXA2 and TXB2,and prostacyclins are produced via the cyclooxygenasepathway.2–6 Leukotrienes and epoxides are derived fromthe lipoxygenase and monooxygenase pathways, respec-tively.2–6 The prostaglandins and leukotrienes are suspect-ed to be the major players in the pathogenesis ofALI/ARDS.2–6 Recent evidence indicates that their princi-pal role lies in the modulation of the inflammatoryprocess via stimulation of cytokine synthesis and re-


TABLE 1General Functional Categories of the Primary6

Cytokines Involved with ALI/ARDSCytokine Type Functional Category

Initiation TNF-α, IL-1

Recruitment IL-8; macrophage inflammatorypeptide (MIP)-1, MIP-2; monocytechemotactant factor (MCF)–1,MCF-1α; transforming growthfactor (TGF)–β

Repair TGF-α, TGF-β; platelet-derivedgrowth factor, insulinlike growthfactor

Resolution TGF-β, IL-4, IL-6, IL-10, IL-1receptor agonist

Apoptosis (programmed cell death)Stimulation of other cells to release cytokinesMonocyte, neutrophil, and platelet chemotaxis and

activationCytotoxicity (endothelial and epithelial)Mediated bioactivity (vasoactivity and bronchoactivity)Inhibited surfactant functionElevated production of histocompatibility antigenPrecipitation of angiogenesisStimulation of arachidonate metabolism (production of

eicosanoids)Stimulation of monocyte formation in bone marrowStimulation of leukocyte adhesion to the vascular

endothelium

BOX 2Typical Actions Elicited by Cytokines

Involved in the Pathogenesis of ALI/ARDS6

lease.2–6 Eicosanoids also elicit potent tissue level responses(e.g., vasoconstriction, bronchoconstriction) that indirect-ly damage endothelial and epithelial tissue and furtherpotentiate the pathophysiologic effects of ALI/ARDS.2–6

Other MediatorsEndogenous nitric oxide, growth factors, and pul-

monary neuropeptides (e.g., substance P) are also in-volved in the pathogenesis of ALI/ARDS.2–6 Althoughtheir exact role is not clearly understood, it is knownthat at certain stages of the disease process there is ei-ther an excess or depletion of these mediators.2–6

SurfactantUntil recently, the role of surfactant in the patho-

physiology of ALI/ARDS was not fully appreciated.2–6

Often there is direct damage to type II pneumocytes,leading to a decrease in the surfactant pool.2–6 Oxygenradicals and proteases have been shown to damage thesurfactant molecule, and arachidonic acid metabolitesand cytokines are also known to inhibit the productionand function of surfactant. Plasma leaking into thealveolar spaces can also lead to inactivation of surfac-tant as well as a washing away or dilutional effect thatwill lead to a loss of activity.2–6 Research is currently un-derway to assess the potential role of surfactant therapyin ALI/ARDS.2

PATHOGENESISAcute lung injury/ARDS results from direct or indi-

rect injury to the vascular endothelium or alveolar ep-ithelium. This leads to activation of the humoral andcellular components, which initially begin as a localizedinflammatory response. For some unknown reason, thisresponse expands to involve the entire pulmonary sys-tem. Suspected causes include inappropriately high orlow cytokine production, inappropriate response to sys-temic cytokines, alteration in cytokine metabolism, andreperfusion injury. None of these theories, however, hasbeen proven.23

Activation of inflammatory mediators leads to in-creased permeability of the pulmonary vasculatureand/or alveolar tissue, allowing the free movement of flu-id and protein into the interstitium and/or alveolarspaces.2–6 As the edema increases, more fluid floods thealveoli. Because the alveoli are likely to still be perfused,an increased shunt fraction is produced.2–6 Without ven-tilation, this perfusion produces the hallmark sign ofALI/ARDS, namely hypoxemia refractory to increasingamounts of oxygen.2–6 Additionally, the increase in fluidin the interstitial space acts to decrease the functionalresidual capacity of the lungs and leads to airway closureas well as distal lung atelectasis.20 Congestion in the lungs

also leads to decreased compliance.20 This alteration incompliance decreases the elastic recoil of the lungs aswell as the resting volume of the lungs, thus increasingthe work of breathing.24 This can further complicate thehypoxemia and lead to increased lactic acidosis.2–6

Such a large-scale inflammatory response then allowsmediators to spill over into the systemic circulation,leading to activation of systemic inflammation.2–6 Addi-tionally, hypoxemia can cause hypoxic organ damage,alterations in systemic blood flow, and increased poten-tial for reperfusion injury.2–6 Thus ALI/ARDS can easilylead to the production of SIRS and also multisystemorgan dysfunction and MOFS.2–6

CLINICAL FINDINGSAlthough signs may be delayed for 1 to 3 days, pa-

tients are usually seen within 24 hours of the incitingevent.5 Owner complaints usually include dyspnea,lethargy, anorexia, trauma, or collapse.14 ALI/ARDSmay also develop acutely in critically ill hospitalized pa-tients with underlying risk factors. Physical examina-tion routinely discloses tachypnea, dyspnea, increasedabdominal effort, crackles, and harsh lung sounds.14

Hypotension and fever as well as hypoxemia that is re-fractory to oxygen treatment may also be seen.5 In theearly stages, only dyspnea may be observed.18 The mostcommon radiographic finding is the presence of diffusealveolar infiltrates in all lung lobes5,14 (Figure 2). Thecardiac silhouette and pulmonary vasculature appearnormal, thereby ruling out heart failure.5,18 Bron-choalveolar lavage fluid can show an increased proteinor neutrophil content.2–6,19,25,26

Clinical diagnosis in humans is based on establishingan association with a known risk factor, the timing ofthe onset (acute), no evidence of left atrial hypertension(normally signified by a pulmonary wedge pressure lessthan 18 mm Hg), evidence of diffuse bilateral pul-monary edema, and a PaO2:FiO2 less than 300 mm Hgfor ALI and less than 200 mm Hg for ARDS.2–6 Thisratio indicates how responsive the hypoxemia is to oxy-gen therapy and how much of the hypoxemia resultsfrom the shut fraction. PaO2:FiO2 is a good clinical indi-cator of the severity of ALI. In veterinary medicine, it isuncommon to place a catheter for measuring pul-monary wedge pressure; therefore, it is difficult to meetthe established criteria for diagnosis used in humanmedicine. In veterinary patients, the diagnosis is highlysuggested by finding hypoxemia and alveolar infiltratesin the absence of congestive heart failure. It is better toproceed suspecting a diagnosis of ALI/ARDS and tocontinue to monitor for this syndrome rather than haveit occur unexpectedly.

Common diagnostic differentials include other caus-


es of pulmonary edema (cardiogenic or neurogenic),acute pneumonia, allergic pneumonitis, interstitial fi-brosis, pulmonary lymphoma, pulmonary contusions,and aspiration pneumonia.16,27 Another considerationmight be pulmonary thromboembolic disease.16

TREATMENTTo date, there is no specific treatment for ALI/

ARDS. Management remains supportive and is aimedat treating the underlying cause and maintaining ade-quate oxygen delivery to the tissues. The primary goalsof therapy should be to (1) find and treat the cause, (2)minimize edema accumulation, (3) provide supportivetreatment as indicated, and (4) avoid hypotension, vol-ume overload, oxygen toxicity, and infection.19

Because this disease might potentially lead to othermore life-threatening disorders, the key to successfulmanagement lies in anticipation. Therefore, critical pa-rameters should be assessed at least twice daily to en-sure that the animal’s condition does not deteriorate.Purvis and Kirby28 have developed 20 critical parame-ters that should be monitored when treating animalswith SIRS. Monitoring of these same parametersshould prove beneficial in the treatment of ALI/ARDSor any critically ill patient, provided that the proper re-sponse for each parameter is followed.

Treating the Underlying CauseThe first principle in the management of ARDS is to

locate and treat the underlying cause.2–4 If possible, theinitial insult must be arrested to prevent further activa-tion of the inflammatory response.2–4 An exhaustivesearch for the cause should be conducted,2–4 includingradiography of the thorax and abdomen as well as ab-

dominal ultrasonography.2–4 Intraabdominal sepsis is acommon cause in humans and may be a predisposingfactor in dogs as well.2–4 Surgery should be preformed(if necessary) to drain an abscess, remove necrotic bow-el, resolve a stump pyometra, or treat peritonitis.2–4,9

Clinicians should not be reluctant to perform an ex-ploratory laparotomy on any patient that is acutely illwith lung injury and severely compromised pulmonaryfunction because correction of the underlying causemay be the patient’s only hope for survival.19 Broad-spectrum antibiotics should be started pending resultsof appropriate cultures. If sepsis is suspected or no in-citing cause can be found, broad-spectrum antibioticsshould be started based on the presumption that thereis an unlocated infectious cause.2–4

Monitoring and Supportive Treatment Oxygenation and Ventilation

Some patients with ALI/ARDS may maintain ade-quate oxygenation with spontaneous ventilation; how-ever, supplemental oxygen therapy is needed when thearterial oxygen saturation drops below 90%, PaO2 dropsbelow 60 mm Hg, or when it is beneficial to decreasethe work of breathing.2–4 Oxygen therapy is institutedto achieve three clinical goals: (1) treat the hypoxemia,(2) decrease the work of breathing, and (3) decrease themyocardial workload.24 If the dog is oxygen-responsive(as observed in the early stages of ALI/ARDS), thenone of the four common oxygen delivery methodsshould be used (Table 2).24 The first method is via anoxygen mask. However, many animals will not toleratemask insufflation and, therefore, their oxygen demandwill be increased by their struggling, thereby defeatingthe purpose of the mask (Figure 3A).24,29 The second


Figure 2A—Ventrodorsal Figure 2B—Lateral

Figure 2—Radiographs showing bilateral pulmonary infiltrates consistent with acute lung injury and/or acute respiratory distresssyndrome.

method is nasal insufflation,24,29 which allows patientssome freedom of movement, but FiO2 cannot be deter-mined accurately (Figures 3B and 3C).24,29 An oxygenflow rate of 50 to 100 ml/kg will generally deliver anFiO2 of 0.4.29 Higher FiO2 (greater than 0.5) for morethan 24 hours can lead to oxygen toxicity.29 In this situ-ation, oxygen free radicals can produce direct damageto the lungs, thus providing a second risk factor for thedevelopment of ALI/ARDS. A third method of oxygensupplementation is to use an oxygen cage to provide adefined FiO2 in a controlled environment.24,29 The dis-advantage of this method is that opening the cage fortreatment will cause a loss of the high FiO2 environ-ment.24,29 It is also difficult to maintain proper humidi-ty and temperature without a specialized oxygen cage.A final method is to use intratracheal oxygen by plac-ing an endotracheal tube or transtracheal catheter.24,29

As mentioned previously, prolonged exposure to highlevels of oxygen can result in direct injury to thelungs.24,29 Inspired oxygen levels less than 50% are con-sidered to be safe for long-term ventilation, but clini-cians should not hesitate to use FiO2 greater than 0.5initially.30 To minimize the risk of oxygen radical dam-age to the lungs, it is important to use the lowest levelof oxygen supplementation that will provide a PaO2 be-tween 70 and 90 mm Hg and/or an oxygen saturationby pulse oximeter (SpO2) greater than 90%.24,29

In many patients suffering from hypoxemia causedby shunting and ventilation/perfusion mismatch, posi-tive end-expiratory pressure (PEEP) can provide an al-ternative to increasing the FiO2 to dangerously high lev-els.31 PEEP is a method of increasing the end-expiratory

lung volume by allowing positive pressure to remain inthe airways at the end of expiration.31 PEEP is not amode of ventilation but an addition to other modes ofventilation. For example, intermittent mandatory ven-tilation is a mode of mechanical ventilation that can bemodified with the addition of PEEP. It can be appliedto both spontaneous and mechanically ventilated pa-tients but usually is employed in conjunction with me-chanical ventilation.31 PEEP is primarily indicated forthose conditions in which there is arterial hypoxemiapresent despite adequate ventilation.31 The best PEEPlevels have not been determined. Recommendations areto start with a PEEP of 5 cm water and increase in 3-to 5-cm increments up to a maximum pressure of 15 to20 cm water to achieve an SpO2 greater than 90% witha minimal FiO2 while maintaining a reasonable cardio-vascular status.5 It is important to remember that thehigher the PEEP, the greater the decrease in cardiacoutput and risk of barotrauma to the lungs.

If the patient is suffering from respiratory muscle fa-tigue, respiratory acidosis, or hypercapnia; has difficul-ty with oxygenation (despite high levels of supplemen-tal oxygen); or needs its airway protected fromaspiration, then intubation and mechanical ventilationare indicated5 (Figures 3D and 3E). Assisted controlventilation, which allows the patient to initiate eachbreath with little effort and provides a backup respira-tory rate in case the patient fails to initiate enoughbreaths, is the mode that is most often attempted ini-tially.5 Typically, FiO2 is started at 1.0 and reduced insmall increments to a level that maintains the SpO2

greater than 90%.5 Intermittent mandatory ventila-


TABLE 2Four Common Oxygen Delivery Methods Used in the Treatment of ALI/ARDSa,b

Method Advantage Disadvantage Flow Rate

Oxygen mask Easy to use Animals often struggle, thereby Not establishedincreasing oxygen demand

Nasal insufflation Freedom of movement FiO2 cannot be accurately determined 50–100 ml/kg/min(estimated at 40%)

Oxygen cage Provides defined FiO2 Opening the cage will cause a loss As needed to maintainlevel in a controlled of the established FiO2 desired FiO2

environment

Intratracheal oxygen Allows control of Requires the animal to be under 20–40 ml/kg/min respiration and FiO2 chemical restraint or as needed to with a ventilator maintain FiO2 if

on a ventilatoraUse the lowest FiO2 that will provide a PaO2 between 70 and 90 mm Hg or an SpO2 greater than 90%.bSerial monitoring of the PaO2 and/or SpO2 is necessary to ensure proper management.FiO2 = fractional inspired oxygen; PaO2 = partial pressure of arterial oxygen; SpO2 = oxygen saturation by pulse oximeter.

tion allows the patient to breathe spontaneously, but apositive-pressure breath is delivered by the ventilator atpredetermined intervals.30 Continuous positive pres-

sure ventilation is achieved by having the ventilatorcontrol all aspects of ventilation.31

Serial monitoring of arterial blood gas and continu-ous monitoring of SpO2 values are essential to ensureproper management and treatment.5 Additionally, thesewill serve as guides to ensure that the lowest PEEP andFiO2 are used to prevent further injury to the lungs viabarotrauma or oxygen radical formation.5

Fluid BalanceIn human medicine, two hotly debated views have

emerged in regard to fluid balance.2–4 The first approachis to decrease pulmonary capillary wedge pressure as lowas possible.2–4 This will require the use of vasopressor therapy as well as inotropic agents to main-tain adequate systemic perfusion.2–4 The theory is thatreduction of the pulmonary capillary wedge pressurewill minimize the amount of fluid that will leak acrossthe membranes.2–4 This method requires careful andconstant monitoring to ensure that renal function ismaintained.2–4 The second strategy stems from the evi-


Figure 3A Figure 3B

Figure 3—(A) Nasal maskfor oxygen insufflation.(B) Dog with bilateralnasal oxygen lines in place.(C) Oxygen flow meterwith dehumidifier fornasal oxygen. (D) Typicalaccommodations for a dogduring mechanical ventila-tion. (E) Control panel ofthe Newport Breeze me-chanical ventilator (New-port Medical Instruments,Inc, Newport Beach, CA).

Figure 3C Figure 3D

Figure 3E

A

C

B

D

pressure while avoiding fluid over-load.

Blood PressureThe systolic blood pressure must

remain above 90 mm Hg; more im-portantly, the mean arterial bloodpressure must be maintained above60 mm Hg to ensure adequate re-nal perfusion.28 If hypotension oc-curs, then therapeutic interventionmust be considered.

CoagulationDisseminated intravascular coag-

ulation is a potential sequela ofALI/ARDS; therefore, it is impor-tant to check for coagulation ab-normalities. Daily platelet countsand activated clotting times are theminimum laboratory tests thatshould be performed. Prothrombinand partial thromboplastin time,fibrin degradation products, anti-thrombin III, and fibrinogen canalso be monitored.31 Early in DIC,platelet numbers will decline andcoagulation times will be short-ened. As DIC progresses, coagula-tion times and fibrin degradationproducts increase, whereas an-tithrombin III levels decrease.31

Erythrocytes/HemoglobinBecause ALI/ARDS alters the oxygenation ability of an-

imals, it is important to maintain the hematocrit greaterthan 20% and ideally greater than 30%.5,31 Likewise, he-moglobin should be maintained above 7 to 10 g/dl.

Renal FunctionUrine output, blood urea nitrogen, and serum creati-

nine should be monitored daily, and routine urinalysesshould be performed.31 It is not uncommon for patientsto die as a result of acute renal failure secondary to is-chemic injury during ALI/ARDS; therefore, adequateblood pressure must be maintained.2–5,31 Urine outputshould be at least 1 to 2 ml/kg/hr in patients with ade-quate renal blood flow.

NutritionNutrition is important from the time the animal en-

ters the hospital. Due to the labor of breathing and thehigh metabolic rate from the inflammatory response,


Figure 4—Mechanisms important in the resolution of acute lung injury and acute respi-ratory distress syndrome. On the left side of the alveolus, the alveolar epithelium is be-ing repopulated by the proliferation and differentiation of alveolar type II cells. Resorp-tion of alveolar edema fluid is shown at the base of the alveolus, with sodium andchloride being transported through the apical membrane of type II cells. (From WareLB, Matthay MA: Medical progress: The acute respiratory distress syndrome. N Engl JMed 342(18):1341, 2000; with permission.)

dence that only about 20% of patients that die will doso as a result of pulmonary disease. The remainder diefrom secondary organ failure.2–4 Thus fluid resuscitationis based on maintaining adequate systemic perfusion.2–4

The type of fluid used is also controversial.2–4 Becausecolloids would presumably remain in the vascularspace, they would be the logical choice.32 However,there is evidence that the colloids will leak into the pul-monary interstitium and increase the edema present.2–4

Several studies have not shown any significant benefitfrom using colloids, but others have shown that col-loids will attenuate alveolar flooding and improve gasexchange.33 Commonly, packed erythrocytes are used inanemic animals to obtain the double effect of enhanc-ing both perfusion and oxygen delivery while the rest ofthe fluid deficit is maintained with a mixture of col-loids and crystalloids.2–4 Hemoglobin-based oxygen car-rying solutions could also be used as a colloid and ery-throcyte replacer. We generally use a combination ofcolloid and crystalloid solutions to maintain blood

ALI/ARDS patients are in a negative energy bal-ance.2–5,31 Clinically, this malnutrition can lead to com-promise of host defenses, loss of muscle strength, vis-ceral organ atrophy, pneumonia, sepsis, and evendeath.31 Additional studies have shown that disuse ofthe bowels may also predispose animals to secondarybacterial translocation and sepsis.31 The goal is to pro-vide 25% of the patient’s caloric requirement withinthe first 24 hours and to increase this amount to 75%to 80% within 72 to 96 hours.31 If the patient is willingto eat, then oral supplementation can begin; however, afeeding tube should be used if the animal is unwillingor unable to eat.31

Nursing Care and Patient MobilizationRecumbent patients should be turned and their limbs

manipulated every 4 hours.31 Fecal material and urineshould be removed immediately and all catheter andtube sites should be checked as well as properly labeledto avoid confusion or misuse.31

Pharmacologic TreatmentSeveral studies2–6 indicate that there is little if any ben-

efit in using corticosteroids early in the course ofALI/ARDS, and their use may actually increase the dura-tion of the disease. Furthermore, the use of corticos-teroids in septic patients did not prevent them from de-veloping ALI/ARDS.2–6 Another study34 indicated thatthe use of corticosteroids in the fibroproliferative stage ofARDS reduced mortality and increased the PaO2:FiO2

ratio. Current recommendations in humans are that cor-ticosteroids be used in the latter stages of ARDS.

Inhaled nitric oxide causes vasodilation of pul-monary vasculature, resulting in improvement of theshunt fraction and thus decreasing hypoxia.2–6 Howev-er, nitric oxide can produce severe side effects (e.g.,combining with oxygen to produce nitric acid). It alsoproduces methemoglobinemia and may worsen leakageby increasing vascular permeability. Therefore, it is notrecommended for treatment of ALI/ARDS.2–6

The antioxidants vitamins C and E are oxygen radi-cal scavengers and as such will reduce lung injury.2–6

Overdosing, however, can lead to prooxidant effectsthat will result in increased lung damage.2–6 Ketocona-zole has had limited success in preventing the develop-ment of ALI/ARDS in some small, randomized trialsby functioning as a TXA2 blocker.4 Superoxide dismu-tase and catalase are oxygen radical scavengers thathave been shown to reduce the lung injury associatedwith pancreatitis in dogs.35

OUTCOMEMost human survivors of ALI/ARDS have little im-

pairment following recovery.2–5 In most patients, lungmechanics return to normal within 1 year followingresolution of the acute illness2–4 (Figure 4). In a few sur-vivors, however, there are severe alterations in the nor-mal pulmonary architecture that can lead to thickeningof all pulmonary surfaces. These changes result in a de-creased diffusing capacity and increased dead space.This situation is dangerous and can lead to pronouncedhypoxia and dyspnea during exercise.2–5 To date, thereare no reports in the literature of any dog that has sur-vived ALI/ARDS; therefore, little is known about theoutcome of this disease in dogs.

CONCLUSIONAcute lung injury/ARDS is seldomly reported in vet-

erinary medicine. It is expected that the number of cas-es will continue to rise because of increased awarenessand advances in emergency and critical care medicine.Despite 30 years of research of this syndrome in hu-mans, little is known about the exact pathogenesis ofthis disease. This lack of knowledge has prevented thedevelopment of specific treatment protocols. Support-ive care remains the primary treatment modality, andrecent advances have provided prolonged survival as ev-idenced by the fact that only 20% of patients succumbto ARDS alone. Unfortunately, patients often progressfrom ARDS into SIRS and/or multisystem organ dys-function and/or MOFS, thus resulting in an overallmortality rate of 50% to 70% in humans. Vigilantmonitoring of patients and anticipating rather than re-acting to the changing conditions may serve to lowerthis rate. It is hoped that specific treatments will be-come available in the future to allow for easier treat-ment and improved survival.

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piratory distress in adults. Lancet ii:219–223, 1967.2. Watling SM, Yanos J: Acute respiratory distress syndrome.

Ann Pharmacother 29:1002–1007, 1995.3. Canonico AE, Brigham KL: Biology of acute injury, in The

Lung: Scientific Foundations, ed 2. Philadelphia, Lippincott-Raven Publishers, 1997, pp 2475–2491.

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8. Turk J, Miller M, Broen T, et al: Coliform septicemia andpulmonary disease associated with canine parvoviral enteri-


tis: 88 cases (1987–1988). JAVMA 196:771–773, 1990.9. Frevert CW, Warner AE: Respiratory distress resulting from

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1. Which of the following is not a common risk factor forthe development of ALI/ARDS?a. microbial pneumonia b. sepsisc. aspiration pneumoniad. tracheitis

2. Which of the following cytokines does not have a ma-jor impact on the development of and eventual out-come of ALI/ARDS?a. TNF-α c. IL-1b. IL-2 d. IL-6

3. Inactivation of α-antitrypsin leads to which detrimen-tal event?a. shifting the antiprotease–protease balance, thereby

potentiating the effects of proteases b. oxygen radicals initiating lipid peroxidationc. alteration of normal cellular metabolismd. damage to cellular DNA

4. Which eicosanoids are suspected to be the major play-ers in the pathogenesis of ALI/ARDS?a. prostaglandins d. prostacyclinsb. TXA2 e. a and cc. leukotrienes


CEARTICLE #2 CE TEST

The article you have read qualifies for 1.5 con-tact hours of Continuing Education Credit fromthe Auburn University College of Veterinary Med-icine. Choose the best answer to each of the follow-ing questions; then mark your answers on thepostage-paid envelope inserted in Compendium.

5. What is the hallmark clinical sign of ARDS?a. oxygen-responsive hypoxiab. patchy bilateral pulmonary infiltratesc. non–oxygen-responsive hypoxiad. pulmonary wedge pressure less than 18 mm Hg

6. Which of the following is not required for the clinicaldiagnosis of ARDS?a. evidence of diffuse bilateral pulmonary edemab. alveolar oxygen:inspired oxygen concentration less

than 200 mm Hgc. pulmonary wedge pressure less than 18 mm Hgd. PEEP greater than 5 cm water

7. PaO2:FiO2 ratio is a good clinical indicator of thea. severity of ALI.b. amount of surfactant.c. flow rate of oxygen needed.d. cause of the ALI.

8. An inspired oxygen concentration less than _____% isconsidered safe.a. 55b. 60c. 50d. 1

9. Optimum PEEP levels a. have not been determined.b. should not exceed 15 to 20 cm water.c. maintain SpO2 greater than 90%.d. all of the above

10. Corticosteroids are recommended in the treatment ofwhich phase of ARDS?a. acute phaseb. fibroproliferative phasec. intermediate phased. Steroids should never be used in the treatment of

ARDS.


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