Cardiovascular Dysfunction in Dogs Associated With Critical Illnesses

Introduction

Cardiac dysfunction can be caused by abnormalities in contractility or diastolic stiffness, changes in loading conditions, and heart rate or rhythm or valvular dysfunction.^1,2 A primary cardiac abnormality such as ventricular dysfunction is often suspected when animals are presented with weakness or respiratory compromise.^1,2 However, in some humans, cardiac dysfunction may be a manifestation of other circulatory disturbances. Primary causes of such disturbances are often related to complications of systemic inflammation.^3–8 In addition, acute cardiovascular dysfunction may also occur in humans with primary, stable myocardial abnormalities, who have recently become critically ill from other metabolic disorders.⁷ Septic shock and systemic inflammatory responses are common causes of acute depression of ventricular function in humans.^7–9

Serum from people with sepsis has been shown to contain a factor that decreases contractility in isolated muscle strips.¹⁰ Tumor necrosis factor (TNF) and other cytokines are thought to mediate decreased cardiac contractility by activating inducible nitric oxide synthase.¹⁰ In inflammatory disease, activated leukocytes have also been shown to contribute to ventricular hypocontractility by generation of oxygen free-radical damage.¹¹ Furthermore, clinical studies in critically ill people have shown that cardiac injury is a frequently unrecognized complication.¹² In one study, the incidence of myocardial injury as assessed by troponin-I was unexpectedly high (15% of critically ill patients) and correlated well with increased morbidity and mortality in the intensive care setting.¹² Recognizing acute causes of depressed ventricular function may be more important in critically ill patients, because acute causes are potentially reversible and may affect outcome.^7,8,12 The purpose of this report was to retrospectively evaluate dogs with critical illnesses and left ventricular dysfunction. The hypothesis of the study was that identification of left ventricular dysfunction in critically ill dogs was associated with an unfavorable clinical outcome.

Materials and Methods

The records of dogs admitted to the intensive care unit (ICU) at Washington State University between July 2000 and January 2003 with critical illnesses and left ventricular dysfunction were reviewed. Dogs that required supportive therapy in the ICU were selected. Fluid therapy and constant-rate infusions, blood pressure and central venous pressure monitoring, serial laboratory evaluations, continuous electrocardiographic monitoring, and oxygen therapy were common supportive therapies in this group of dogs. Critical illness was defined as significant metabolic derangements that required intensive care to sustain life or enhance metabolic stability. Dogs that were housed in the ICU for observation purposes (e.g., neurological signs, trauma, or during anesthetic recovery) were not included. If necropsy evaluation and cardiac histopathology were unavailable, breeds of dogs (e.g., Doberman pinscher, boxer, sporting breeds, giant breeds) with an increased incidence of dilated cardiomyopathy were also excluded from the study because of their greater risk of primary cardiac dysfunction. An exception was made for two boxers, one of which underwent a cardiac evaluation 2 weeks prior to the critical illness and one that had extensive follow-up during the recovery period. Sixteen dogs met the criteria for inclusion in this study. The diagnosis and follow-up were recorded for each case. Dogs with unproven diagnoses were excluded.

All dogs had thoracic radiographs as a part of the evaluation of the critical illness. Routine echocardiograms with M-mode and Doppler examinations were performed in selected cases by the same person, using commercially available equipment.^a Four cardiac cycles were averaged to determine the reported value for each measured parameter. Standard normal canine echocardiographic parameters were utilized to evaluate the dogs, as has been previously described.^13–15 Left ventricular systolic dysfunction was defined by determining the percent fractional shortening of the left ventricular cavity by M-mode echocardiography and/or percent ejection fraction as determined by a modified Simpson’s rule.^14,15 A percent fractional shortening of <26% and/or a percent ejection fraction of <46% were used to define left ventricular systolic dysfunction. The authors chose to use a more restrictive definition of left ventricular systolic function, because it was felt that many larger, athletic breeds of dogs may normally demonstrate a lower-end percent fractional shortening. The authors realized that a percent fractional shortening of 26% would likely indicate poorer left ventricular function in a small dog versus a large-breed dog. Dogs that had obvious endocarditis were excluded from the study regardless of ventricular function.

Left ventricular pre-ejection period and pre-ejection period compared to ventricular ejection time have been infrequently reported in dogs.¹⁶ A prolonged pre-ejection period to ejection time ratio was interpreted as reduced pressure generation by the left ventricle, with delayed opening of the aortic valve and delayed onset of ventricular ejection.¹⁶ The normal pre-ejection period to ejection time ratio used was defined as 0.2 to 0.35 based on data from the authors’ echocardiography laboratory. This value was similar to results previously reported in dogs.¹⁶ Dogs with pre-ejection period to ejection time ratios of >0.4 were considered to have systolic dysfunction, which was also similar to reported values in humans.¹⁷ Doppler echocardiography was also utilized to assess left ventricular diastolic function by interrogation of the mitral valve inflow velocities. Mitral valve inflow E to A waveform ratios of <1 were interpreted as diastolic dysfunction in dogs with normal sinus rhythm.^18,19

Results

The signalment, diagnosis, pertinent echocardiographic results, and clinical outcomes are presented in the Table. Despite left ventricular dysfunction, no dog had signs of congestive heart failure. The most common clinical complaint was generalized weakness (n=15). One dog (case no. 3) had tachypnea and radiographic evidence of a generalized, interstitial pulmonary pattern. This dog had the lowest percent fractional shortening (13%) of any dog in the study. Necropsy of this dog did not reveal a primary myocardial problem, and pulmonary histopathology indicated a nonspecific inflammatory process. No other dog showed symptoms or radiographic changes consistent with possible cardiovascular-related pulmonary pathology.

All dogs were thought to be normally hydrated at the time of echocardiographic assessment. Five dogs were judged to be normally hydrated on initial presentation, whereas the remaining 11 dogs received intravenous fluid therapy for a minimum of 24 hours prior to the echocardiographic studies. In addition to reduced percent fractional shortening, other pertinent echocardiographic findings were increased left ventricular pre-ejection period to ejection time ratio (n=6), mitral inflow Doppler E wave to A wave inversion (n=3; 10 dogs were considered tachycardic, creating E/A summation), and gradual aortic valve closure during systole on M-mode echocardiography, suggesting subnormal cardiac output (n=3).

The most common diagnoses in dogs with critical illness and left ventricular dysfunction were bacterial sepsis (n=5) and cancer (n=5). Other conditions diagnosed in affected dogs are listed in the Table. Of the 16 dogs evaluated, 12 (75%) died or were euthanized within 15 days of admission to the hospital. The average time until death was 3.6 days (range 1 to 15 days). Dogs that died or were euthanized in the hospital had necropsy evaluations, with the exception of two dogs that had antemortem diagnoses of lymphosarcoma. Necropsy findings did not reveal gross or histological evidence of cardiac disease in any dog.

Four of the 16 dogs were discharged from the hospital and had follow-up times ranging from 20 days to 2 years. Of the four dogs, one had a diagnosis of lymphosarcoma and was alive at 20 days and undergoing chemotherapy with the local veterinarian. A boxer dog with diagnoses of immune-mediated polyarthropathy, anemia, and hyperglobulinemia was still alive 2 years later. The percent fractional shortening in this dog at the time of admission to ICU was 21%, and 2 years later it was 34%. Two dogs with systemic coccidiomycosis were alive 3.5 and 4 months after discharge and were receiving systemic antifungal therapy.

Discussion

Although primary myocardial disease (e.g., occult dilated cardiomyopathy) could not be completely ruled out in this group of critically ill dogs with left ventricular dysfunction, it was not suspected based on their age, breed, or follow-up evaluations. Ten dogs had necropsy examinations, none of which identified gross or histological cardiac abnormalities. Despite having left ventricular dysfunction, no dogs had signs of congestive heart failure. Fifteen dogs had moderate to severe weakness, but it was unclear how much the cardiac dysfunction contributed to the weakness.

Many dogs of this report had significant systemic inflammatory conditions, particularly bacterial sepsis. Sepsis and other systemic inflammatory diseases are common causes of acute depression of ventricular function in humans, and these critically ill dogs may have been affected similarly.^3–9 Many mechanisms have been identified to explain how systemic illnesses contribute to ventricular dysfunction in humans.^{8–11,20–25} Acute causes of depressed ventricular contractility in people include ischemia, hypoxemia, respiratory and metabolic acidosis, low ionized serum calcium, exogenous toxins, endogenous toxins (e.g., depressant factors generated during sepsis), hypothermia, and hyperthermia.²⁵ Serum from people with sepsis may contain a circulating myocardial depressant factor.¹⁰ Tumor necrosis factor, other cytokines, and activated leukocytes may also contribute to ventricular hypocontractility.¹¹ Early in the septic process, hypoperfusion can be confounded by paralysis of arteriolar smooth muscle and vasodilatation. However, later in the course, the decline in cardiac output, leading to death, involves significantly decreased contractility and increased diastolic stiffness.²⁵

Many similar conditions were found in this group of 16 critically ill dogs. The underlying illnesses of these dogs may also have caused increased oxygen demands as a result of elevations in sympathetic nervous system tone.²⁵ In both humans and animals, sepsis-associated cardiac dysfunction is characterized by ventricular dilatation, decreased ventricular contractility, and diminished relaxation.^28–30 Hypoxemia and anemia may also significantly reduce myocardial oxygen delivery and cause myocardial oxygenation defects.²⁰ Such deficits are often encountered in humans with sepsis and may worsen myocardial hypoxia. When the heart becomes progressively hypoxic, the proportion of oxygen extracted by the heart increases but may not be enough to prevent anaerobic metabolism; thus, myocardial lactic acid production may ensue.²¹ Contractility becomes depressed in lactic acidosis, and the ventricles may acutely dilate.²¹ If oxygen delivery in relation to demand is not corrected quickly, the heart may enter a detrimental positive-feedback loop of decreased contractility, cardiac output, and coronary perfusion that may eventually lead to cardiac arrest. In the experimental canine model, this vicious cycle occurred when arterial saturation fell below 75% (i.e., PaO₂=40 mm Hg).20 In addition to sepsis, other systemic inflammatory syndromes may be linked to cardiac dysfunction in humans, such as advanced neoplasia and immune-mediated disorders.^26,27 In the group of dogs reported here, five had cancer, and two were diagnosed with immune-mediated disorders.

It is important to identify the potential causes of depressed ventricular contractility in critically ill animals, because many factors may significantly contribute to morbidity and mortality. Such factors may also affect animals with primary cardiac diseases when they develop systemic illnesses. It may be especially important to recognize the acute mechanisms of ventricular dysfunction, because they may be reversible.^7,8,12,25 Differentiating acute versus chronic causes of reduced ventricular function may be difficult, particularly in those dogs in which primary heart disease may be encountered. In critically ill dogs that are identified with reduced ventricular function and for which primary myocardial disease is not expected, acute ventricular dysfunction associated with systemic illness should be considered. In addition, dogs with known myocardial disease that also develop severe systemic disorders should not have their poor ventricular function dismissed as solely deterioration of their myocardial disease. In such animals, correction of acute, reversible contributors to decreased muscle contractility may potentially improve outcome.

The treatment regimens for the dogs of this report were quite varied and were not compared. The primary treatment for a critical animal with reduced ventricular function is reversal of the underlying cause, if possible. It would seem prudent that if ischemia and hypoxia are present, then aggressive corrective measures should be instituted. Correction of significant anemia may result in substantial improvement in ventricular function.²⁵ Ideally, attention should be paid to eliminating factors that increase myocardial oxygen demand. In humans, positive inotropic agents are commonly used to enhance myocardial contractility and cardiac output in the critically ill.^12,25 Choosing the lowest level of inotropic support that produces a therapeutic effect is thought to minimize myocardial oxygen demands.^12,25 Alleviating pain or sedating an overly excited animal may diminish increased sympathetic tone and tachycardia.²⁵ In animals with pulmonary disease, respiratory acidosis may be addressed with oxygen therapy and ventilatory support. In animals with metabolic disease, current evidence indicates that alkalinization is of no benefit and may be detrimental in a critically ill patient.³¹ Treatment of myocardial depression from circulating myocardial depressant factors has been attempted in humans with antibodies to endotoxin and TNF, naloxone infusions, and dialysis.²⁵ These therapies appear beneficial in some cases but are still considered experimental.²⁵ Some of the mentioned therapies were utilized in the dogs of this report; however, no published clinical studies have evaluated treatment strategies in dogs with critical systemic illnesses and ventricular dysfunction.

The outcomes reported here suggest that identification of left ventricular dysfunction in dogs with critical illnesses may be a poor prognostic indicator, particularly in those animals with sepsis and cancer. A significant limitation to this report was the lack of a control group with which to compare outcomes. In addition, a follow-up echocardiogram was performed in only one of the four surviving dogs. Clinical studies in critically ill humans have shown that cardiac injury is a frequently unrecognized complication, and it correlates well with increased morbidity and mortality.¹² Thus, aggressively treating any systemically ill dog with unexpected cardiac dysfunction, regardless of clinical presentation, may be prudent. The prevalence of cardiac dysfunction associated with critical illness in animals is unknown. If cardiovascular-related signs are not obvious, many critically ill dogs may not receive a thorough cardiac examination.

Conclusion

This report suggests that left ventricular dysfunction may occur in dogs with critical illnesses. Identification of left ventricular dysfunction in critically ill dogs may be a poor prognostic indicator, particularly in those with sepsis and cancer. Early recognition and treatment of ventricular dysfunction could potentially limit morbidity and mortality in these critically ill dogs. Well-designed, prospective studies to evaluate treatments and outcomes are warranted.