ABSTRACT
Objective
To characterize acid–base disorders in dogs with hyperlactatemia via traditional and semiquantitative approaches, and to investigate the mechanisms of hyperlactatemia and the prognostic significance of metabolic acidosis in these patients.
Design
Retrospective study.
Setting
University teaching hospital.
Animals
A total of 3866 dogs with various diseases and a plasma lactate concentration >2 mmol/L at any timepoint during hospitalization underwent traditional acid–base analysis. Among these patients, 1755 dogs had data available for semiquantitative acid–base evaluation.
Measurements and Main Results
The most common disease associated with hyperlactatemia was gastrointestinal disorders in 1232 of 3866 dogs (29.3%), and the most common mechanism of hyperlactatemia was circulatory shock in 741 (19.1%). The traditional approach identified acid–base abnormalities in 2586 dogs (66.9%), with the most common being primary respiratory acidosis in 609 (15.7%). When considering both primary and mixed disorders, metabolic acidosis was present in 1452 patients (37.5%). When excluding the lactate effect, the semiquantitative approach identified concurrent acidifying and alkalinizing effects in 1241 of 1755 dogs (70.7%). Unmeasured anions, determined via semiquantitative analysis, were the most frequent acidifying effect in 775 dogs (44.1%). Metabolic acidosis, whether primary or as part of a mixed disorder, was associated with increased mortality (682/1452 [46.9%]) compared with patients without metabolic acidosis (479/2414 [19.8%]) (p < 0.001). Similarly, type A hyperlactatemia was associated with higher mortality (374/717 [52.5%]) than type B (227/746 [30.4%]) (p < 0.001).
Conclusions
Acid–base disorders in dogs with hyperlactatemia were frequent and complex, with both acidifying and alkalizing processes often occurring simultaneously. The semiquantitative approach might be a valuable tool to improve our understanding of the underlying mechanisms of metabolic acid–base disorders in these patients. The presence of metabolic acidosis was most frequent in dogs with type A hyperlactatemia and was associated with higher mortality.
Keywords: lactic acidosis, metabolic acidosis, plasma lactate
Abbreviations
- AG
anion gap
1. Introduction
Hyperlactatemia is frequently identified in critically ill human and veterinary patients and is commonly assumed to indicate the presence of lactic acidosis. However, it is becoming increasingly evident that hyperlactatemia can occur independent of a metabolic acidosis [1, 2]. In dogs presented to the emergency room with a plasma lactate concentration >2.5 mmol/L, metabolic acidosis was identified in only 42% of patients [3]. The absence of a metabolic acidosis in patients with hyperlactatemia may be due to the underlying mechanism of lactate production or a concurrent alkalinizing process [4, 5, 6, 7]. Additionally, human and veterinary studies have shown that the prognostic implications of hyperlactatemia vary based on the associated acid–base abnormalities [1, 2, 3]. Mortality is significantly higher in both human and veterinary patients when both hyperlactatemia and metabolic acidosis are present, compared with hyperlactatemia by itself [1, 3].
This notable difference in mortality likely stems from the varying mechanisms contributing to hyperlactatemia, which can be divided into type A, in which oxygen consumption exceeds oxygen delivery, leading to anaerobic metabolism, and type B, in which plasma lactate concentrations increase despite aerobic metabolism. In type A hyperlactatemia, metabolic acidosis results from an imbalance between hydrogen ion production and use. Hydrogen ions from ATP hydrolysis accumulate as mitochondrial proton use decreases under anaerobic conditions. The association with metabolic acidosis in type B hyperlactatemia varies depending on the individual mechanism(s) present. Also, there is limited information on the specific nature of acid–base abnormalities in dogs with hyperlactatemia. Existing studies evaluating acid–base disorders do not focus exclusively on dogs with hyperlactatemia but rather on various disease processes, with subgroups of patients exhibiting increased plasma lactate concentrations [8, 9, 10].
The traditional acid–base approach is convenient for detecting the presence of metabolic acidosis through base excess and anion gap (AG) analysis. However, these parameters correlate poorly with plasma lactate concentration, and multiple coexisting metabolic acid–base processes cannot be identified with the traditional approach [11]. In contrast, the semiquantitative approach offers insight into the individual effects of albumin, phosphorus, lactate, free water, chloride, and other unmeasured ions on acid–base disturbances [8]. The semiquantitative approach evaluates unmeasured anions with the parameter XA‐. As albumin, phosphate, and lactate concentrations are all quantitated individually in this approach, XA‐ reflects any remaining unmeasured anions in the system and is not impacted by hypoalbuminemia like AG is [12]. This approach could be valuable for understanding the individual underlying mechanisms contributing to the metabolic component of dogs with hyperlactatemia.
The primary aim of the current study was to qualitatively and quantitatively evaluate the acid–base status in a large population of hyperlactatemic dogs with various underlying diseases. The secondary objective was to assess the prognostic significance of hyperlactatemia, comparing dogs with and without a metabolic acidosis and distinguishing between type A and type B hyperlactatemia.
2. Materials and Methods
2.1. Case Selection
All plasma lactate concentrations (arterial or venous) measured in dogs at the William R. Pritchard Veterinary Medical Teaching Hospital at the University of California, Davis, between December 1, 2017, and November 30, 2022, were retrieved from the computerized medical record system. Only the first visit was included for analysis if an animal had more than one visit in the study period. Similarly, if a patient had multiple plasma lactate measurements during a single visit, only the first hyperlactatemic sample was considered. Plasma lactate measurements were performed at any time throughout the visit using a point‐of‐care blood gas analyzer1. For this study, admission lactate referred to plasma lactate concentration measured within 4 h of admission to any department within the hospital as previously described [13]. Hyperlactatemia was defined as a plasma lactate concentration >2.0 mmol/L and was further stratified as moderate (2.1–4.0 mmol/L) or severe (>4.0 mmol/L) [1].
2.2. Disease Categories and Mechanisms of Hyperlactatemia
Demographic (age and sex) and physical examination data were recorded. Each medical record was evaluated for evidence of type A and type B mechanisms of hyperlactatemia at the time of plasma lactate measurement. The type A category included diseases causing inadequate tissue oxygen supply, such as circulatory shock, cardiopulmonary arrest, severe anemia, carbon monoxide exposure, severe hypoxemia, and increased muscle activity. The criteria chosen to define each of these mechanisms are shown in Table S1. Type B included patients with adequate tissue oxygen supply diagnosed with the following conditions at the time of plasma lactate measurement: sepsis, neoplasia, liver dysfunction, pheochromocytoma, diabetes mellitus, and specific toxicoses such as albuterol, methylxanthines, 5‐fluorouracil, and xylitol. Neoplasia was defined as all benign or malignant processes diagnosed via histology or cytology, and “neoplasia‐associated hyperlactatemia” included patients diagnosed with neoplasia of any type for which no other identifiable causes of type A or type B hyperlactatemia were found. Medications known to induce type B hyperlactatemia were not recorded. Each patient was assigned to one or more potential mechanisms of hyperlactatemia. Although patients classified as having type A hyperlactatemia could have concurrent type B mechanisms, those classified as having type B hyperlactatemia did not have evidence of type A hyperlactatemia.
Based on a thorough review of the medical records for the underlying disease processes present at the time of plasma lactate measurement, all animals were assigned one or more underlying disease category (Table S2). Additional data retrieved from the medical record included the case outcome, which was defined as alive or dead (euthanized or died in hospital) for that visit.
2.3. Traditional and Semiquantitative Acid–Base Analysis
Bicarbonate and standard base excess were calculated by the blood gas analyzer, using the Henderson–Hasselbalch and Van Slyke equations, respectively. A solubility coefficient in plasma of 0.03 mmol/L/mmHg was used for carbon dioxide. The traditional and semiquantitative acid–base diagnoses were determined based on previously published equations (Tables S3 and S4) [14]. Serum albumin and phosphorus concentrations were measured on a chemistry analyzer2 in grams per deciliter (g/dL) and milligrams per deciliter (mg/dL), respectively. Semiquantitative analysis was performed in a subset of patients in which serum albumin and phosphorus concentrations were measured within 24 h of the plasma lactate measurement. Previously published reference intervals for canine arterial and venous blood gas values were used [15]. The reference intervals of the chemistry analyzer for serum albumin (3.4–4.3 g/dL; 34–43 g/L) and phosphorus concentrations (2.6–5.2 mg/dL; 0.8–1.7 mmol/L) were used. The mid‐normal values used in the traditional and semiquantitative analysis were determined as the central values of the previously mentioned reference intervals.
2.4. Exclusion Criteria
Patients with unspecified sample types (arterial or venous) were excluded from the study. Patients suspected of ethylene glycol toxicosis were also excluded due to the interference with the lactate measurement on the analyzer used for this study [16]. Plasma lactate values obtained under anesthesia or cases with incomplete medical records or blood gas panels (i.e., without sufficient data for traditional acid–base analysis) were excluded. In patients with a plasma chloride concentration >120 mmol/L, medications were reviewed for potassium bromide administration. Patients receiving potassium bromide were excluded due to interference with the chloride measurement on the analyzer [17].
2.5. Statistical Analysis
Data were analyzed for normality with the Shapiro–Wilk test on commercially available software3. Nonnormally distributed data are presented as median with 25th–75th percentiles. The proportion of patients with nonsurvival stratified by plasma lactate concentration, presence of metabolic acidosis, or underlying mechanisms of hyperlactatemia was compared using a Fisher exact test. Similarly, the proportion of patients with metabolic acidosis stratified by mechanisms of hyperlactatemia was compared using a Fisher exact test. The Spearman rank test was used to examine the correlation between AG and the magnitude of hyperlactatemia in all patients and patients with an available plasma albumin concentration. Combined results for arterial and venous plasma lactate concentrations are reported for simplicity. Previously established criteria for interpreting the size of Spearman's rho were used [18]. Briefly, a very strong correlation was defined as |r| ≥ 0.70, a strong correlation as 0.50 ≤ |r| < 0.70, a moderate correlation as 0.30 ≤ |r| < 0.50, a weak correlation as 0.10 ≤ |r| < 0.30, and no correlation when |r|< 0.10.
3. Results
Over the study period, 11,247 lactate concentrations >2 mmol/L were documented in dogs. Of these, 7381 were excluded, representing 5530 from patients with multiple visits or lactate measurements, 1410 collected under anesthesia, 395 that were neither venous nor arterial blood samples, 27 from patients receiving potassium bromide, 17 with incomplete data, and two from cases of ethylene glycol toxicosis. This left 3866 plasma lactate concentration values for analysis (3484 venous and 382 arterial). Three hundred sixty‐six dogs were intact females, 494 intact males, 1493 neutered females, 1509 neutered males, and four with an unknown neuter status. The median [25th–75th percentile] age was 8.0 years [4.0–11.0]. Overall, the median plasma lactate concentration was 3.2 mmol/L [2.5–4.7], and the highest recorded value was 28 mmol/L. Of the 3866 dogs, hyperlactatemia was moderate in 2611 (67.5%) and severe in 1255 (32.5%). In this population, 3004 of 3866 plasma lactate concentrations (77.7%) were measured upon admission to the hospital.
3.1. Underlying Diseases and Possible Mechanisms of Hyperlactatemia
Overall, 2447 of 3866 patients (63.3%) were diagnosed with a single disease. The most common disease processes were gastrointestinal in 1132 patients (29.3%) and respiratory in 926 (24.0%) (Table 1).
TABLE 1.
Comparison of plasma lactate concentration and associated mortality among disease processes in 3866 dogs with hyperlactatemia.
| Underlying disease process, N (%) | Median plasma lactate concentration, mmol/L [25th–75th percentile] | Mortality, N (%) |
|---|---|---|
| Suspected neoplastic disease, N = 297 (7.7) | 4.6 [3.1–7.2] | 165 (55.5) |
| Trauma, N = 143 (3.7) | 3.9 [3.0–7.7] | 50 (34.9) |
| Environmental/toxic, N = 129 (3.3) | 3.9 [2.9–6.0] | 28 (21.7) |
| Unknown, N = 30 (0.8) | 3.5 [2.5–5.5] | 5 (16.6) |
| Hematologic, N = 229 (6.0) | 3.5 [2.6–5.8] | 81 (35.2) |
| Immune mediated, N = 130 (3.4) | 3.3 [2.5–4.8] | 42 (32.3) |
| Respiratory, N = 926 (24.0) | 3.2 [2.5–4.4] | 352 (38.0) |
| Cardiac disease, N = 382 (9.9) | 3.2 [2.5–4.1] | 93 (24.3) |
| Hepatobiliary, N = 428 (11.0) | 3.2 [2.4–4.6] | 150 (35.0) |
| Neoplasia, N = 422 (10.9) | 3.1 [2.5–4.6] | 132 (31.3) |
| Integument/musculoskeletal, N = 264 (6.8) | 3.1 [2.4–4.4] | 83 (31.4) |
| Gastrointestinal, N = 1132 (29.3) | 3.1 [2.4–4.5] | 310 (27.4) |
| Neurologic, N = 873 (22.6) | 3.1 [2.5–4.3] | 235 (26.9) |
| Urinary, N = 426 (11.0) | 3.0 [2.4–4.2] | 157 (36.8) |
| Endocrine, N = 260 (6.7) | 3.0 [2.3–4.1] | 81 (31.5) |
| Ophthalmic, N = 26 (0.7) | 2.9 [2.3–4.4] | 5 (19.2) |
| Reproductive, N = 94 (2.4) | 2.8 [2.3–4.0] | 23 (24.5) |
Note: Individual animals may be assigned to one or multiple categories based on criteria described in Table S2.
Mechanisms known to cause hyperlactatemia were also recorded for each case. An obvious mechanism for hyperlactatemia was identified in 1689 of 3866 dogs (45.8%). Of these 1689 dogs, 717 (42.4%) had one or more type A hyperlactatemia mechanisms exclusively, 746 (44.2%) had one or more type B mechanisms exclusively, and 226 (13.4%) had both types concurrently. The median plasma lactate concentration of patients with exclusively type A mechanisms (5.0 mmol/L [3.3–8.3]) was significantly higher than in those with exclusively type B mechanisms (3.0 mmol/L [2.4–4.2]) (p < 0.001).
The most common mechanism of hyperlactatemia overall was circulatory shock in 741 of 3866 dogs (19.1%), while descriptively, cardiopulmonary arrest was associated with the highest median plasma lactate concentration (12.5 mmol/L [7.6–16.0]) (Table 2). Among cases with suspected type B mechanisms, neoplasia‐associated hyperlactatemia was the most common, present in 227 of 3866 dogs (5.8%), with a median plasma lactate concentration of 2.9 mmol/L [2.4–3.9] (Table 2). A detailed analysis of patients with neoplasia‐associated hyperlactatemia by neoplasia type is available in Table S5.
TABLE 2.
Comparison of plasma lactate concentration and associated mortality among mechanisms that might have contributed to hyperlactatemia in 3866 dogs.
| Suspected mechanism of hyperlactatemia, N (%) | Median plasma lactate concentration, mmol/L [25th–75th percentile] | Mortality, N (%) |
|---|---|---|
| No cause identified, N = 2177 (56.3) | 3.0 [2.4–3.9] | 436 (20) |
| Type A hyperlactatemia | ||
| Cardiopulmonary arrest, N = 45 (1.2) | 12.5 [7.6–16.0] | 42 (93.3) |
| Circulatory shock, N = 741 (19.2) | 5.1 [3.3–8.1] | 398 (53.7) |
| Severe anemia, N = 77 (2.0) | 4.0 [2.7–6.8] | 30 (39.0) |
| Increased muscle activity, N = 92 (2.4) | 4.0 [3.2–5.9] | 37 (40.2) |
| Severe hypoxemia, N = 12 (0.3) | 3.1 [2.4–3.9] | 6 (50.0) |
| Carbon monoxide exposure, N = 3 (0.1) | 3.0 [2.2–4.0] | 0 (0) |
| Type B hyperlactatemia exclusively a | ||
| Neoplasia‐associated hyperlactatemia b , N = 227 (5.8) | 2.9 [2.4–3.9] | 53 (23.3) |
| Sepsis, N = 218 (5.6) | 3.0 [2.4–4.2] | 82 (37.6) |
| Diabetes, N = 110 (2.8) | 2.9 [2.4–3.7] | 33 (30.0) |
| Liver dysfunction, N = 97 (2.5) | 3.1 [2.4–4.6] | 38 (39.2) |
| Specific toxicoses c , N = 15 (0.4) | 5.2 [4.0–8.5] | 0 (0) |
| Pheochromocytoma, N = 7 (0.2) | 3.2 [2.3–4.1] | 3 (42.8) |
Note: Individual animals may be assigned to one or multiple categories based on criteria described in Table S1.
Excludes patients with concurrent type A mechanism of hyperlactatemia.
Dogs in this subcategory do not have any other mechanisms of hyperlactatemia.
Specific toxicoses include patients that ingested methylxanthines, 5‐fluorouracil, xylitol, and albuterol.
3.2. Traditional Acid–Base Analysis
Traditional acid–base analysis in the current study showed an abnormality in 2586 of 3866 patients (66.9%), with one‐third of the dogs having a normal traditional acid–base balance. Simple disorders were seen in 1296 patients (33.5%), whereas mixed disorders were present in 1290 (33.4%) (Table 3). The most common acid–base disorder was a primary respiratory acidosis in 609 of 3866 dogs (15.7%). However, 1476 patients (38.2%) had respiratory acidosis when combining both primary (609/3866 [15.7%]) and mixed disorders (867/3866 [22.4%]). Similarly, a total of 1452 dogs (37.5%) had evidence of metabolic acidosis, either as a primary disorder in 402 (10.4%) or as part of a mixed disorder in 1050 (27.1%). A metabolic acidosis with increased AG was present in 328 of 3866 dogs (8.5%), either as primary in 81 (2.1%) or as part of a mixed disorder in 247 (6.4%). Stratifying patients by mechanisms of hyperlactatemia showed a significantly larger proportion of metabolic acidosis associated with type A (446/717 [64.2%]) than type B mechanism (292/746 [39.1%]) (p < 0.001). A detailed traditional acid–base analysis for hyperlactatemia mechanisms is shown in Table S6.
TABLE 3.
Traditional acid–base diagnosis in 3866 dogs with hyperlactatemia and various underlying disease processes.
| Acid–base diagnosis | Dogs, N (%) |
|---|---|
| Normal acid–base balance | 1280 (33.1) |
| Simple disorders | 1296 (33.5) |
| Metabolic acidosis with increased AG | 81 (2.1) |
| Metabolic acidosis with normal AG | 321 (8.3) |
| Metabolic alkalosis | 65 (1.7) |
| Respiratory acidosis | 609 (15.7) |
| Respiratory alkalosis | 220 (5.7) |
| Mixed disorders | 1290 (33.4) |
| Metabolic acidosis with high AG and respiratory acidosis | 158 (4.1) |
| Metabolic acidosis with normal AG and respiratory acidosis | 522 (13.5) |
| Metabolic acidosis with high AG and respiratory alkalosis | 89 (2.3) |
| Metabolic acidosis with normal AG and respiratory alkalosis | 281 (7.2) |
| Metabolic alkalosis and respiratory acidosis | 187 (4.8) |
| Metabolic alkalosis and respiratory alkalosis | 53 (1.4) |
Abbreviation: AG, anion gap.
3.3. Semiquantitative Acid–Base Analysis
Because hyperlactatemia was an inclusion criterion in this study, all patients had an increased lactate effect. To better assess the presence of other acidifying processes, this lactate effect is not discussed in this section. That is, a patient with hyperlactatemia, increased chloride, and increased unmeasured anions is classified as having two acidotic processes instead of three. Semiquantitative data were available for 1755 dogs, of which 1735 (98.9%) had one or more acid–base abnormality identified with this approach. Additionally, 1241 of 1755 dogs (70.7%) had concurrent alkalotic and acidotic processes. Furthermore, 120 dogs (6.8%) exhibited only acidotic processes, while 374 (21.3%) had only alkalotic processes. The most common acidotic effects were increased XA‐ in 775 (44.1%), increased phosphorus effect in 499 (28.4%), and increased chloride effect in 459 (26.1%). The most common alkalotic effects were increased unmeasured cations in 834 (47.5%) and decreased albumin effect in 831 (47.3%) (Table 4). A detailed semiquantitative acid–base analysis for hyperlactatemia mechanisms is reported in Table S7.
TABLE 4.
Semiquantitative approach to metabolic acid–base diagnosis in 1755 dogs with hyperlactatemia and various underlying disease processes.
| Metabolic acid–base diagnosis | Dogs, N (%) |
|---|---|
| One or more acidotic processes only a | 120 (6.8) |
| One or more alkalotic processes only a | 374 (21.3) |
| Both alkalotic and acidotic processes a | 1241 (70.7) |
| Individual abnormalities identified | |
|
Free water effect Free water effect = 0.25 × (measured [Na+] − mid normal [Na+]) | |
| Increased free water acidosis | 240 (13.7) |
| Decreased free water alkalosis | 517 (29.4) |
|
Chloride effect Chloride effect = mid‐normal [Cl−] − corrected [Cl−] | |
| Increased chloride‐associated acidosis | 459 (26.1) |
| Decreased chloride‐associated alkalosis | 171 (9.7) |
|
Albumin effect Albumin effect = 3.7 × (mid‐normal [albumin] − measured [albumin]) | |
| Increased albumin acidosis | 82 (4.7) |
| Decreased albumin alkalosis | 831 (7.3) |
|
Phosphate effect Phosphate effect = 0.58 × (mid‐normal [phosphorus] − measured [phosphorus]) | |
| Increased phosphorus acidosis | 499 (28.4) |
| Decreased phosphorus alkalosis | 47 (2.7) |
|
Lactate effect Lactate effect = −1 × measured [lactate] | |
| Increased lactate | 1755 (100) |
|
Unmeasured anions effect Unmeasured anions (XA‐) effect = Base excess − sum of effects | |
| Increased unmeasured anions (XA‐) | 775 (44.1) |
| Increased unmeasured cations | 834 (47.5) |
Note: The semiquantitative acid–base diagnoses were determined based on reference intervals presented in Table S4. [albumin] = serum albumin concentration; [Cl−] = plasma chloride concentration; [lactate] = plasma lactate concentration; [Na+] = plasma sodium concentration; [phosphorus] = serum phosphorus concentration; XA‐ = unmeasured anions measured via semiquantitative approach.
The lactate effect is excluded from the count.
In this study population, only 167 of 1755 dogs (9.5%) had an increased AG despite having increased XA‐. Additionally, the correlation between the AG and the magnitude of hyperlactatemia was weak (1751 dogs; r = 0.29, p < 0.001) and remained as such even in patients with normal serum albumin concentration (838 dogs; r = 0.27, p < 0.001).
3.4. Mortality
The overall mortality in the study population was 30.0% (1161/3866), which was higher in patients with severe hyperlactatemia (602/1255 [48.0%]) compared with moderate hyperlactatemia (559/2611 [21.4%]) (p < 0.001). The presence of metabolic acidosis either as a primary disorder or as part of a mixed disorder was associated with increased mortality (682/1452 [46.9%]) compared with patients without metabolic acidosis (479/2414 [19.8%]) (p < 0.001). Similarly, patients with type A hyperlactatemia had higher mortality (374/717 [52.5%]) than patients with type B hyperlactatemia (227/746 [30.4%]) (p < 0.001).
4. Discussion
This study used traditional and semiquantitative approaches to shed light on the complex nature of acid–base imbalances in a large population of dogs with hyperlactatemia. One‐third of the dogs in this study had a normal traditional acid–base balance, and one‐third had metabolic acidosis as part of a simple and mixed disorder. In contrast, in addition to the lactate effect, semiquantitative analysis found one or more acid–base abnormalities in almost all animals, with patients exhibiting complex and variable acid–base changes.
In this population, gastrointestinal disease was the most common disease process, accounting for 29% of cases. This was slightly higher than previous reports in dogs, which ranged from 11% to 19% [3, 13]. This discrepancy may be due to variations in the criteria used to define gastrointestinal diseases across studies. The magnitude of hyperlactatemia within this category varied significantly depending on the underlying gastrointestinal process. The combination of gastrointestinal disease with circulatory shock, as seen in patients with gastric‐dilatation‐volvulus, is expected to be associated with higher plasma lactate concentrations than gastrointestinal disease alone.
Alongside gastrointestinal disorders, respiratory diseases were also frequent in this population, accounting for 24%. This is higher than the 7% reported in a previous study of dogs presenting to an emergency room, which likely reflects different enrollment criteria between the two studies [13]. Respiratory disease may lead to hyperlactatemia via type A mechanisms associated with hypoxemia and increased respiratory muscle oxygen consumption from respiratory distress. Studies have also found that the lung can produce lactate in some disease states, such as asthma and acute lung injury [19, 20]. The relevance of lactate monitoring in patients in respiratory distress is an area that warrants further investigation.
Type A hyperlactatemia arises from inadequate cellular oxygen supply due to increased oxygen demand or reduced oxygen delivery [4]. In this study, circulatory shock was the most common type A mechanism, consistent with a previous report [13]. The increased lactate production during anaerobic metabolism arises from the upregulation of glycolysis for ATP formation, as oxidative phosphorylation is downregulated. This excessive lactate formation is coupled with decreased lactate clearance in anaerobic conditions [21]. Aside from perfusion abnormalities, anaerobic metabolism can occur in conditions such as severe anemia or severe hypoxemia. Numerous veterinary studies have discussed hyperlactatemia in severe hemolytic anemia, with median plasma lactate concentrations ranging from 2.3 to 4.8 mmol/L, similar to our findings [22, 23, 24, 25]. In contrast to the extensive literature on severe anemia, there is a lack of clinical studies investigating the relationship between severe hypoxemia and lactate production. This relationship has only been evaluated in the experimental setting involving anesthetized dogs, which does not consider the combined effect of hypoxemia and increased respiratory muscle activity seen in awake dogs [26]. The current study is the first to describe the presence of moderate hyperlactatemia in an awake population of dogs with naturally occurring severe hypoxemia. Anaerobic metabolism can also occur despite normal oxygen delivery when cellular oxygen demand is increased, such as during intense muscle activity. In these cases, hyperlactatemia can range from moderate to severe, with an 8.7‐fold increase reported in human patients with tonic‐clonic seizures and concentrations reaching up to 33 mmol/L in racing Greyhounds [27, 28]. However, this increase is transient, with plasma lactate concentration generally returning to baseline within 2 h of cessation of muscle activity [27]. Persistent hyperlactatemia beyond this timeframe should prompt the clinician to investigate alternative mechanisms.
Another interesting feature of anaerobic metabolism is its frequent association with metabolic acidosis. When hyperlactatemia and metabolic acidosis occur concurrently, the condition is termed “lactic acidosis.” In our study, lactic acidosis was observed in 37.5% of dogs, similar to a previous report (42%) [3]. Additionally, lactic acidosis was more common in patients with type A mechanisms than type B, highlighting the relationship between anaerobic conditions and metabolic acidosis.
Type B hyperlactatemia is characterized by processes that result in increased plasma lactate concentration despite adequate oxygen availability [4]. The magnitude of hyperlactatemia associated with type B mechanisms in this study was generally lower than with type A. Additionally, among type B mechanisms, neoplasia and sepsis were the most common. While it is well‐established that neoplasms such as lymphoma, leukemia, and carcinoma are associated with severe hyperlactatemia in people, the role of neoplasia in the development of hyperlactatemia in dogs remains unclear [29, 30, 31, 32]. Our study identified 227 dogs for which neoplasia was the sole identifiable mechanism of hyperlactatemia. Neoplasia can be associated with type B hyperlactatemia due to aberrant cellular metabolism as well as the effects of chemotherapeutic drugs, such as glucocorticoids [32, 33].
The development of hyperlactatemia in sepsis is likely multifactorial, involving a combination of type A and B mechanisms. These may include global hypoperfusion, microcirculatory dysfunction, direct mitochondrial injury, and catecholamine‐induced upregulation of aerobic glycolysis [4, 34]. The reported median plasma lactate concentration in dogs with sepsis varies between 1.6 and 2.8 mmol/L [35, 36, 37, 38]. This is slightly lower than the value noted in our population of septic dogs from which patients with type A mechanisms were excluded.
Several drugs and toxicants have been associated with type B hyperlactatemia [4]. Toxicant ingestions identified in this study included methylxanthines, xylitol, albuterol, or 5‐fluorouracil. This category stands out among other type B mechanisms due to its markedly increased plasma lactate concentration compared with other type B causes. The veterinary literature regarding xylitol and 5‐fluorouracil ingestion is limited to a few case reports [39]. In 32 dogs intoxicated with albuterol, similarly increased mean serum lactate concentrations ranging from 3.9 to 5.9 mmol/L were noted, while in 34 dogs with chocolate intoxication, the median plasma lactate concentration was 3.6 mmol/L [40, 41]. Hyperlactatemia associated with these substances is believed to arise from the upregulation of glycolysis or inhibition of the Krebs cycle; however, the degree to which they induce hyperlactatemia remains unclear. Clinicians should be aware of the potential for significant hyperlactatemia in dogs presenting with intoxications involving these compounds.
Interestingly, in 56% of dogs in this study, no obvious mechanism of hyperlactatemia was identified. This may be because various mechanisms of hyperlactatemia were not evaluated in this study, as only the more common mechanisms were considered. It could also reflect a lack of detail or accuracy in the medical records, limiting the ability to identify potential causes. In a retrospective study, it may be difficult to recognize mild abnormalities in cardiovascular status or increased muscle activity associated with agitation or excitement that could lead to hyperlactatemia.
It has been commonly assumed that animals with hyperlactatemia will have a high AG metabolic acidosis [42, 43]. As the results of this study show, high AG metabolic acidosis was an uncommon acid–base diagnosis in this population. An increased AG suggests the presence of unmeasured anions, including lactate, phosphate, and sulfate. However, this method does not allow clinicians to evaluate the specific contribution of each anion to the development of metabolic acidosis. Further, the AG loses sensitivity in its ability to identify unmeasured anions in the face of hypoalbuminemia, which is a common coexisting abnormality in critically ill people and animals [44, 45, 46].
In contrast, the semiquantitative approach allows for the separate assessment of the individual effects of lactate, phosphate, and albumin on the metabolic acid–base balance. Therefore, calculation of unmeasured anions using the semiquantitative approach (XA‐) enables the clinician to separately identify unmeasured anions that are not lactate or phosphate and maintains sensitivity despite hypoalbuminemia. A large proportion of unmeasured cations in the system can also decrease the AG, further reducing its sensitivity to detect unmeasured anions [11, 47]. Additionally, the wide reference interval for AG means that changes in plasma lactate concentration may have to be substantial to increase AG values. In the current study, the AG correlated poorly with the plasma lactate concentration, even in patients with normal serum albumin concentration. This study further reinforces the limitations of the AG method in detecting anions such as lactate and emphasizes the importance of directly measuring the plasma lactate concentration in critically ill dogs. The semiquantitative approach, however, identified unmeasured anions in almost half of the dogs in the current study, similar to previous reports [8, 11].
The acid–base balance of dogs with hyperlactatemia is complex, and there is growing evidence that lactic acidosis often does not account for all of the metabolic acidosis in critically ill patients. In this report, the semiquantitative approach allowed the detection of acidifying mechanisms associated with high concentrations of unmeasured anions XA‐, phosphorus, and chloride. These findings highlight that multiple acidifying processes can coexist in patients with hyperlactatemia, and the concurrent finding of hyperlactatemia and metabolic acidosis cannot be assumed to be a lactic acidosis. This situation is further complicated by the possibility of hyperlactatemia occurring without concurrent acidosis, as previously noted in critically ill people and identified in 63% of dogs in our study [1, 2, 7].
The lack of metabolic acidosis in these patients may be due to hyperlactatemia developing without associated acid accumulation, as seen in some type B causes or coexisting alkalinizing processes. Coexisting alkalizing and acidifying effects are common in critically ill patients. This was observed in 71% of dogs in our study and reported in 55% of dogs and cats presenting to an emergency room [14]. The most common alkalizing effects reported in dogs and critically ill people are hypoalbuminemia, hypochloremia, and unmeasured cations, which include iodine, lithium, calcium, magnesium, and guanidine compounds such as creatinine [6, 7, 14, 47, 48]. The relevance of such a large proportion of patients with unmeasured cations in our population remains unclear. Nevertheless, these counteracting effects could mask the true state of the metabolic component if semiquantitative analysis is not performed. Therefore, it is recommended that metabolic acid–base balance be assessed by the semiquantitative approach in patients with complex disease or acid–base findings that are difficult to reconcile.
In this population, the overall mortality was 30%. The reported mortality for hyperlactatemic dogs with various diseases ranges between 45.3% and 60% [3, 49]. Additionally, in our population, hyperlactatemia with concurrent metabolic acidosis was associated with greater mortality. This is comparable with mortality rates reported in human patients admitted to the ICU and dogs presenting to an emergency room with lactic acidosis [3, 50]. Experimentally, acute metabolic acidosis exerts pH‐dependent deleterious effects on the cardiovascular system by altering myocardial function and catecholamine response [51]. However, it remains to be determined if metabolic acidosis is simply a marker of disease severity or if it directly causes mortality in dogs with hyperlactatemia.
Additionally, in the current study, type A mechanisms were associated with increased mortality compared with type B, a pattern also observed in people presenting to the emergency room [52]. Little information is known on the mortality rate in dogs with hyperlactatemia stratified by mechanisms. Ours is the first study to evaluate the association of mechanisms of hyperlactatemia on mortality in a large population of dogs.
This study has several limitations, most related to its retrospective nature. It limits the accuracy of categorizing primary disease processes or mechanisms of hyperlactatemia. Additionally, the timing of lactate measurement was not standardized. However, most patients had lactate measured within 4 h of presentation, making it relatively uniform given the large population in the analysis. Finally, although semiquantitative evaluation can provide a better understanding of metabolic acid–base balance, it does not consider the interplay of respiratory responses, which is important for a full understanding of acid–base balance. The clinician should be aware of these limitations when using semiquantitative acid–base analysis in animals with complex disease processes.
Additionally, there is currently no universally accepted cutoff for defining hyperlactatemia in dogs. However, several veterinary studies have used 2 mmol/L as a prognostic threshold. This level has been associated with increased mortality in dogs with circulatory shock, respiratory disease, liver dysfunction, diabetes mellitus, hypotension, septic peritonitis, and immune‐mediated hemolytic anemia [13, 22, 36, 53]. We selected 2 mmol/L to align with these studies, given its consistent use as a meaningful prognostic marker across diverse clinical conditions in dogs.
Another limitation of this study is the absence of an internally generated reference interval. While reference intervals from our institution's blood gas analyzer were available, the sample size was limited and may have reflected institution‐specific demographics. We chose to use published reference data from a larger population to capture greater biological variability and provide a more stable estimate of normal values, thereby enhancing the generalizability of our findings. However, this may have introduced variability related to differences in analyzer type and measurement methodology.
A final limitation of this study is the use of the Van Slyke equation to determine base excess for the semiquantitative approach, which is based on human data and has not been validated in dogs. This method may overestimate unmeasured anions compared with the dog‐specific approach described by Constable and Stämpfli [54]. Despite these limitations, the Van Slyke method remains commonly used in veterinary practice, as most blood gas analyzers calculate base excess using this method. Consequently, parameters such as unmeasured anions should be interpreted with caution.
In this large study of dogs with hyperlactatemia, acid–base disorders were frequent and complex. One‐third of dogs with hyperlactatemia had a normal traditional acid–base balance, and a high AG metabolic acidosis was relatively uncommon. Metabolic acidosis was present in one‐third of dogs. It was most frequent in patients with type A mechanisms of hyperlactatemia and was associated with higher mortality when compared with animals without concurrent metabolic acidosis. Semiquantitative analysis identified many acidotic and alkalotic processes in this population, with most animals having multiple acid–base processes present. The findings of this study highlight the complex and variable acid–base balance of dogs with hyperlactatemia and the potential role of semiquantitative acid–base analysis to better guide therapy.
Author Contributions
Laurence M. Saint‐Pierre: conceptualization, writing – original draft, methodology, validation, writing – review and editing. Steven E. Epstein: writing – review and editing, validation, supervision, methodology, conceptualization. Kate Hopper: conceptualization, writing – review and editing, supervision, methodology, validation.
Ethics Statement
The authors confirm that the ethical policies of the Journal, as noted on the Journal's author guidelines page, have been adhered to. No ethical approval was required as this is a retrospective study based on reviewing patients’ medical records.
Conflicts of Interest
Dr. Epstein is an assistant editor of the Journal but participated in the peer review process only as an author. The authors declare no other conflicts of interest.
Supporting information
Supporting Information: vec70148‐sup‐0001‐SuppMat.docx
Endnotes
ABL 800, Radiometer Medical A/S, Copenhagen, Denmark.
Cobas c501; Roche Diagnostics, Indianapolis, IN.
GraphPad Prism 7.0, Graph Pad Software, La Jolla, CA.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Supporting Information: vec70148‐sup‐0001‐SuppMat.docx
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.