Metabolic and Cardiac Derangements in Canine Babesiosis
Remo Lobetti BVSc (Hons) MMedVet (Med) PhD Dipl ECVIM
Bryanston Veterinary Hospital, South Africa.
Presentation ACVIM 2010
Canine babesiosis is a tick-borne disease caused by the hemoprotozoan parasites of the genus Babesia. Babesia canis and B. gibsoni are responsible for canine babesiosis throughout the world. Babesia canis consists of a group of three different subspecies, namely B. c. canis, B. c. vogeli, and B. c. rossi. Babesia gibsoni is subdivided into 2 subspecies: the North American and Asian subspecies. Three other babesia species that can affect the dog are; (1) a small Babesia that is distantly related to B. gibsoni, but more closely related to B. microti, B. rodhaini, and Theileria equi; (2) a B. microti-like organism; and (3) B. conradae, which is a closely related piroplasm to isolates from wildlife and humans. Babesiosis primarily affects erythrocytes but can involve multiple organs and can range from a relatively mild to a fatal peracute disease. Canine babesiosis can be clinically classified as uncomplicated or complicated with uncomplicated babesiosis being further divided into mild, moderate, or severe disease, depending on the severity of anemia. Complicated babesiosis involves clinical manifestations that are unrelated to the hemolytic disease. Recently described complications of babesiosis are metabolic derangements and cardiac changes.
Abnormal carbohydrate metabolism appears to occur frequently in severe and complicated babesiosis as in one study, dogs with naturally occurring, severe and/or complicated babesiosis showed varying degrees of hypoglycemia, hyperglycemia, hyperlactatemia, and hyperpyruvatemia. In that study 3 of the 5 fatal cases showed concurrent hypoglycemia, hyperlactatemia and hyperpyruvatemia. In babesiosis a significant negative correlation between glucose and lactate but not between lactate and pyruvate has been reported, which is consistent with findings in malaria.
A wide range of lactate: pyruvate (L/P) ratios have been documented in babesiosis, due to variability in both lactate and pyruvate and the fact that they frequently do not change in consistent ways relative to one another. Variable pyruvate and L/P ratios have also been reported in other studies. Factors contributing significantly to variance in L/P ratio in severe adult malaria were creatinine, shock and hyperparasitemia. Normal or close-to-normal L/P ratios have been reported in malaria and sepsis.
Hypoglycemia is a common complication of canine babesiosis with a general prevalence of 9% and increasing to 20% in hospitalized cases. In admitted cases, severe hypoglycemia (< 40mg/dl) was documented in approximately 6% of dogs. Risk factors for hypoglycemia are severe anemia, icterus, young animals under 6 months of age, and vomiting. Toy breeds and pregnant bitches do not appear to be at higher risk for hypoglycemia than other dogs. The importance of hypoglycemia is that it can result in neurological signs and thus misdiagnosed as cerebral babesiosis, which carries a much poorer prognosis.
Hypoglycemia in babesiosis can be caused by increased consumption, decreased intake, decreased production and/or increased losses. Increased glucose consumption can result from hypermetabolism, anaerobic glycolysis, and consumption by the parasites. An increase in non-insulin-mediated glucose consumption can occur in sepsis and trauma. Inflammatory mediators such as TNF trigger increase glucose consumption, particularly in macrophage-rich tissues such as spleen, liver and lung; which then continues despite the hypoglycemic state. As canine babesiosis is a sepsis-like state, hypermetabolism could explain the hypoglycemia.
Hyperinsulinemia as a result of inappropriate insulin secretion may precipitate hypoglycemia, and has been suggested as a possible cause of hypoglycemia in human and murine malaria. In dogs with babesiosis induced hypoglycemia, it has been shown that insulin secretion was appropriately low in the majority of cases with only 2 dogs having inappropriately elevated insulin concentrations. Thus hyperinsulinemia appears to be a rare cause of hypoglycemia in canine babesiosis.
Anorexia has not typically been associated with hypoglycemia in dogs subjected to starvation or children with malaria. Suppression of gluconeogenesis has been suggested in malaria and experimental sepsis, but increased gluconeogenesis can also occur. Increased glycogenolysis and impaired glycogenesis causes depletion of hepatic glycogen in endotoxemic dogs. Hepatic dysfunction has been reported in canine babesiosis and could be associated with reduced gluconeogenesis. Hypoglycemia, however, is rarely associated with liver disease alone.
Humans with severe disease often have persistent hyperlactatemia with blood lactate concentration correlated with the survival rate. Hyperlactatemia is an important finding in patients in septic shock and can be indicative of hypermetabolism (stress lactate), tissue hypoxia (shock lactate), or both. In dogs, blood lactate concentration has been shown to be of prognostic value in patients with gastric dilatation-volvulus and in dogs admitted to intensive care units. Serial blood lactate in dogs with naturally occurring, severe or complicated canine babesiosis has shown hyperlactatemia (> 2.5mmol/l) in 50% of dogs. Measurements significantly associated with mortality were blood lactate concentration >5mmol/l on admission; blood lactate concentration >2.5mmol/l at 8, 16, and 24 hours after admission; and increase or <50% decrease in blood lactate concentration within 8 and 16 hours after admission. Blood lactate concentration persistently >4.4mmol/l indicated a very poor prognosis. Serial blood lactate measurements are useful in predicting survival in dogs with severe and complicated canine babesiosis.
Sepsis, bacteremia, febrile infections, and malaria can all result in elevated blood pyruvate levels and hyperpyruvatemia has been reported to occur in dogs with severe and complicated babesiosis. Although lactate production by malaria parasites has been suggested it is not considered quantitatively important. Hepatic dysfunction, potentially causing reduced lactate clearance, occurs in babesiosis, but organ dysfunction alone seems insufficient to explain elevated lactate in critical illness and sepsis. Impairment of pyruvate dehydrogenase activity could account for accumulation of pyruvate and hence lactate, but studies have reported both increased and decreased pyruvate oxidation.
Cardiac dysfunction in canine babesiosis has traditionally been regarded as a rare complication, with the majority of lesions being reported as incidental findings at autopsy. Recent studies have, however, demonstrated cardiac lesions in canine babesiosis that are of clinical importance.
Biochemical markers are being used more frequently in the diagnosis of myocardial diseases in animals with both atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) being potentially useful markers. ANP is released from the atria in response to increased atrial stretch, whereas BNP is secreted by the ventricles in response to volume and pressure overload. In humans ANP and BNP concentrations are good indicators for the severity of left ventricular dysfunction that occurs with acute myocardial infarction and congestive heart failure. In veterinary medicine elevated ANP concentrations have been reported in dogs with mitral valve regurgitation, heartworm disease, and congestive heart failure. BNP is released as a precursor molecule – pro-BNP, which has a longer half-life in circulation than BNP. A pro-BNP value less than 210 pmol/l is considered negative for heart disease, between 210 and 300, a probability of heart disease, and over 300, indicative of heart disease.
In dogs with babesiosis pro-BNP median values with mild uncomplicated, severe uncomplicated, and complicated babesiosis were 245.5 pmol/l (range 8.5-683.3), 650 (range 260-2028), and 638 (range 310-2214), respectively. These findings imply that dogs with babesiosis have reduced cardiac function and that the dysfunction becomes more severe as the disease severity increases. This myocardial dysfunction occurs either earlier and/or is independent of myocardial damage which can be more subtle.
Cardiac troponins are thin, filament-associated proteins of cardiac muscle that act as the regulatory subunit of the troponin complex associated with the actin thin filament within cardiac myocyte. Troponins are important cardiac biomarkers as they are highly sensitive markers for myocardial cell death. They are more sensitive and persistent indicators of cardiac injury, with high tissue specificity, than other markers even in the presence of marked skeletal muscle injury, liver disease, and renal disease. This is an important consideration in babesiosis, in which renal failure, liver impairment, and rhabdomyolysis can occur.
In canine babesiosis it has been shown that troponin I is a sensitive marker of myocardial injury with the magnitude of elevation of troponin I appearing to be directly proportional to the severity of the disease. Dogs dying of canine babesiosis with histological evidence of myocardial lesions had higher concentrations of troponin I than did dogs that survived.
Dogs with severe and complicated babesiosis are frequently presented in a state of collapse and clinical shock, with the shock resembling the hyperdynamic phase of septic shock. Collapsed dogs with babesiosis may not display classic signs of shock syndrome, partially because of the hemodynamics of hemolytic anemia. The pulse may be bounding or weak; temperature elevated or subnormal; and mucous membranes pale, icteric or congested (haemoconcentration). Babesial shock, like endotoxic shock, may pass through a hyperdynamic stage followed by a hypotensive stage. It has been shown that hypotension occurs frequently in babesiosis and that the presence and severity of hypotension increases with increased disease severity. The presence of hypotension in a large proportion of dogs with complicated babesiosis is consistent with the hypothesis that inflammatory mechanisms play a major role in this disease, and can result in a sepsis-like state. It is likely that hypotension in babesiosis is a combination of vasodilation, reduced vascular volume due to increased vascular permeability and/or dehydration, and myocardial depression. Myocardial infarction can result in vascular pooling and myocardial depression. Thus, a feasible explanation for the hypotension in canine babesiosis would be myocardial pathology. In addition, hypotension can play a role in the pathophysiology of the disease as it has been hypothesized to facilitate parasite sequestration within the capillary beds.
Dogs with babesiosis can show a variety of arrhythmias and ECG abnormalities. Arrhythmias include SA block, sinus arrest, first and second degree AV block, ventricular tachycardia, and VPCs. Reported ECG abnormalities are low R-amplitude, prolonged QRS, ST deviation, large T waves, and notching of the R wave. These ECG changes have been described in dogs with myocardial infarction, ischemia and inflammation and in Chagas disease. Although bradycardia and irregular rhythm in dogs may be poor prognostic indicators, in general the ECG changes do not appear to be related to disease severity or to pathological changes and thus the clinical value of ECG monitoring in canine babesiosis is limited. The only exception to this is the presence of VPCs as they appear to be associated with an elevated troponin I concentration.
Macroscopic cardiac lesions that have been described in dogs with babesiosis include pericardial effusion and pericardial, epicardial and endocardial hemorrhage, involving 1 or more of the chambers. On cardiac histopathology from dogs that succumbed to babesiosis, hemorrhage, necrosis, inflammation and fibrin micro-thrombi in the myocardium have been documented.
This myocardial pathology would result in the ECG changes described above as well elevations in troponin I. Myocardial damage results in left ventricular failure, which can result in hypotension and an expansion of the plasma volume due to homeostatic mechanisms.
Keywords: carbohydrate, glucose, lactate, pyruvate, cardiac biomarkers, blood pressure, ECG.
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