Topics in Compan An Med 29 (2014) 71–76
Topical Review
Plasma Lactate Concentration as a Prognostic Biomarker in Dogs With Gastric Dilation and Volvulus Erin Mooney, BVSc (Hons), Dip. ACVECCa, Cameron Raw, BVSc (Hons)b, Dez Hughes, BVSc (Hons), MRCVS, Dip. ACVECCc,n Keywords: dog lactate prognosis prognostic indicator gastric dilation and volvulus gastric necrosis a
Small Animal Specialist Hospital, New South Wales, Australia
b
Rochester Veterinary Practice, Victoria, Australia
Initial and serial plasma lactate concentrations can be used to guide decision making in individual dogs with GDV but care is necessary in phrasing conversations with owners. Published data suggests that survival is more likely and the chance of complications less in dogs with an initial plasma lactate of o4 mmol/L. An initial lactate 4 6 mmol/L makes gastric necrosis and greater expense more likely. However, because of the overlap between groups and the good overall survival rates, exploratory laparotomy should always be recommended irrespective of the plasma lactate concentration. Falls in plasma lactate of greater than ~40% after fluid resuscitation are likely to indicate better survival. If the initial plasma lactate concentration is moderately to severely increased (5- 4 10 mmol/L) and a sustained increase in plasma lactate occurs after fluid resuscitation, the cause should be aggressively pursued. Many dogs with persistent hyperlactatemia over 24-48 hours do not survive. & 2014 Elsevier Inc. All rights reserved.
c Section of Emergency and Critical Care, Veterinary Hospital, University of Melbourne, Victoria, Australia n
Address reprint requests to Dez Hughes, BVSc (Hons), MRCVS, Dip. ACVECC, Section of Emergency and Critical Care, Veterinary Hospital, University of Melbourne, 250 Princes Highway, Werribbee, Victoria 3030, Australia. E-mail: [email protected] (D. Hughes)
Introduction Gastric dilation and volvulus (GDV) is an acute condition of dogs characterized by dilation of the stomach and rotation on its mesenteric axis. Affected dogs may suffer from circulatory shock, and a proportion of dogs develop gastric necrosis. Reported mortality rates for GDV vary between 10% and 33%.1-6 Biomarkers, such as plasma lactate concentration, can help guide prognostication. Understanding lactate physiology and how GDV may cause hyperlactatemia is important, but knowing how to apply the results of studies of prognostic indicators to individual animals is vital so that reasonable and proportionate prognostic information can be provided to pet owners. A low lactate concentration is associated with a high survival rate, whereas more dogs with a higher lactate concentration die; however, there are exceptions in both cases. Hence, advice to owners about their individual pets based on initial lactate concentration should be offered carefully. Based on the published literature, the authors suggest that it is reasonable to inform owners of dogs with GDV and a lactate concentration of 6 mmol/L or above that there is a higher chance of gastric necrosis and other complications and that their hospital stay may be more costly but to be no more definitive than that. If the initial lactate concentration is within reference range or only mildly increased (2-4 mmol/L), then it is appropriate to say that complications are less likely but still possible. If plasma lactate concentration does not fall within the reference range in 24-48 http://dx.doi.org/10.1053/j.tcam.2014.09.005 1527-3369/& 2014 Topics in Companion Animal Medicine. Published by Elsevier Inc.
hours, the clinician should aggressively pursue the underlying reason because survival rates are poor in many cases with prolonged hyperlactatemia.
Lactate Biochemistry and Physiology Glycolysis, which occurs in both the presence and absence of oxygen, takes place in the cytoplasm, converts glucose into pyruvate, and produces 2 moles of adenosine triphosphate (ATP) per moles of glucose. Glycolysis also requires NAD þ which is converted into NADH. When sufficient oxygen is available, pyruvate enters the mitochondria and is used in the tricarboxylic acid cycle and oxidative phosphorylation to produce 36 moles of ATP and regenerate NADH back to NAD þ thereby allowing glycolysis to continue.7 Alternatively, pyruvate can be converted into lactate in the cytosol which also consumes H þ and regenerates NAD þ . The main physiological role of lactate production is to allow glycolysis and cellular energy (ATP) production to continue when cellular energy demands exceed the capacity of aerobic mitochondrial energy production. Although glycolysis produces less ATP on a molar basis than oxidative phosphorylation, it is much faster which allows it to temporarily meet cellular energy requirements. When ATP is converted to adenosine diphosphate (hydrolyzed) to release energy, H þ is also produced. If sufficient oxygen is available, this H þ passes into mitochondria to maintain the proton
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gradient required for the electron transport chain and oxidative phosphorylation. But when cellular oxygen supply is inadequate, H þ ions accumulate in the cytosol. Lactate production from pyruvate minimizes this by consuming H þ . Importantly, lactate is formed as the lactate ion without a concurrent H þ ion. Lactate can then be cotransported out of the cell with an H þ ion by the monocarboxylate transporter thereby further limiting intracellular acidosis. Hence, lactate production does not cause acidosis, it protects against it. Nevertheless, when ATP made from glycolysis is used to release energy, an H þ ion is also generated so there is a 1:1 ratio of H þ and lactate production but they are formed by different processes. That is, hyperlactatemia is directly proportional to H þ but not the cause of the increase. Lactate is also protective because it can be the preferred metabolic fuel for vital tissues such as the brain7 and heart8 and the only fuel for red blood cells which lack mitochondria.
possible mechanisms include reduced erythrocyte flexibility, increased leukocyte activation, altered neurohormonal control of endothelial smooth muscle, enhanced nitric oxide production, and pyruvate dehydrogenase inhibition.23,24 Other events during GDV may contribute to hyperlactatemia. Ischemic tissue within the gastric wall and spleen will produce lactate. Whether this lactate enters the systemic circulation depends on the remaining blood flow. With complete cessation of blood flow, there will be no lactate washout. But low flow or intermittent flow (perhaps from intermittent rotation and derotation of the stomach) will wash lactate from ischemic tissue into the circulating blood volume. Decompression of the stomach via trocarization or orogastric intubation may also allow blood flow and lactate release into the systemic circulation. Gastric necrosis and intestinal ischemia might allow bacterial translocation and bacteremia, leading to sepsis, septic shock, and SIRS. Additionally, dogs with GDV commonly experience cardiac arrhythmias and may have myocardial depression.25,26
Hyperlactatemia Hyperlactatemia occurs whenever the rate of lactate production exceeds that of lactate metabolism and clearance and has been categorized into types A and B.9,10 Type A hyperlactatemia is the most common in emergency and critical care practice and occurs with clinical evidence of a relative or absolute tissue oxygen deficiency. A relative deficiency is usually due to increased muscle activity, for example, exercise, struggling, shivering, trembling, tremors, and seizures.10-12 Exercise-related hyperlactatemia has been reported to range from 4.5 mmol/L in dogs following agility testing13 to greater than 30 mmol/L in racing Greyhounds.14,15 Physiological hyperlactatemia should resolve when muscle activity stops with an half-life of 30-60 minutes.13,14,16 If appropriate resolution does not occur in a clinical patient, a concurrent disease process is likely. An absolute tissue oxygen deficiency is usually due to global hypoperfusion (shock) which may be hypovolemic, obstructive, maldistributive, or cardiogenic in origin or a combination thereof. The reference range for plasma lactate concentration measured in 60 conscious dogs was 0.3-2.5 mmol/L17 but because these dogs underwent repeated sampling, it is likely that some had slightly increased concentrations owing to increased muscle activity. Using an upper limit of 2.0 mmol/L is probably more appropriate in dogs with little muscle activity. Type B hyperlactatemia occurs in the absence of clinical evidence of decreased oxygen delivery and has been subclassified into type B1 associated with underlying disease (in particular, sepsis and systemic inflammatory response syndrome [SIRS], B2 with drugs or toxins, and B3 with congenital or hereditary metabolic defects).10
Hyperlactatemia With GDV Most dogs with GDV have type A hyperlactatemia owing to variable degrees of global hypoperfusion. Most are hypovolemic owing to intragastric fluid sequestration and hemorrhage in dogs with torn gastric vessels. They also have a variable obstructive component owing to reduced venous return because of compression of major intra-abdominal veins such as the caudal vena cava and portal vein by the dilated stomach.18 Some may also have maldistributive shock and type B1 hyperlactatemia owing to sepsis, septic shock, and SIRS. Many underlying mechanisms have been suggested for type B1 hyperlactatemia associated with SIRS and sepsis including skeletal muscle Na þ -K þ -adenosine triphosphatase upregulation,19 mitochondrial dysfunction, cytochrome inhibition,20 increased hepatic lactate production, reduced hepatic lactate extraction,21 impaired tissue oxygen extraction,22 and capillary shunting.22 Other
Plasma Lactate Concentration as a Prognostic Indicator With the increasing realization of its clinical utility and availability of point-of-care lactate analyzers, the measurement of lactate has become more mainstream in veterinary medicine over the past decade. Its prognostic value was recognized in human medicine almost 50 years ago,1 and there are a multitude of clinical and experimental studies documenting its clinical and prognostic utility. Over the years, these have ranged the full gamut of investigations from simple, retrospective, observational studies to prospective, randomized trials of its use to guide therapy. Studies in people have shown prognostic value in trauma,27 sepsis,28 septic shock,28 SIRS,28 cardiac arrest,28 carbon monoxide toxicity,29 head trauma,28 malaria,28 and liver failure.9 Its use is now recommended in the consensus guidelines for sepsis.30 The addition of treatment targeted toward lactate clearance to the Surviving Sepsis Campaign resuscitation bundle reduced mortality risk 2-fold in people with severe sepsis. In addition to dogs with GDV, some degree of prognostic utility has been reported for ill and injured dogs in a veterinary intensive care unit,31 systemically ill dogs receiving fluid therapy,32 and dogs with SIRS,33 immune mediated hemolytic anemia,34 severe soft tissue infections,35 heartworm-associated caval syndrome,36 babesiosis,37,38 and abdominal evisceration.39 Lactate has also been demonstrated to have some limited prognostic value in cats with hypertrophic cardiomyopathy40 and with septic peritonitis.41,42 The Acute Patient Physiologic and Laboratory Evaluation for dogs and cats found lactate to be one of the most significant variables associated with mortality and included lactate in both the full and fast scoring systems for both species.43,44 Despite a wealth of evidence supporting its overall value, the difficulty remains in how we, as clinicians, apply these data to our individual clinical cases. Most veterinary studies show that the population of animals that die has a higher average lactate concentration than the population of animals that survive. Yet, some animals that survive may have very high lactate concentrations and some that die may have mildly increased or even reference range concentrations. This may seem contradictory, but the simple explanation is that, in general, the magnitude of the increase in lactate reflects the severity of lactate production (usually tissue hypoxia) not its reversibility. Whether the individual animal dies or survives depends on the underlying disease process that is associated with a concurrent hyperlactatemia. Consider a dog with simple, uncomplicated, peracute hemorrhage that can be easily stopped and treated such as an acute, appendicular arterial laceration. In this instance, the maximum
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Condition Positive Negative Test outcome
Positive
Positive Predictive Value True positive
Negative False negative
False positive
True positives All test positives
Negative Predictive Value True negative
True negatives All test negatives
Specificity
Accuracy
Sensitivity
True positives True negatives True positives + True negatives Condition positives Condition negatives Total population
plasma lactate concentration would provide information regarding the severity of hypovolemia. If the animal was successfully treated immediately with intravenous fluids, survival would be very likely and hence, lactate would not be associated with prognosis. An even more edifying example is normal exercise. Greyhounds may have plasma lactate concentrations of 10, 20, or even 30 mmol/L because their muscles acutely require more energy than can be produced from oxidative processes. Lactate obviously has no prognostic significance because its production is entirely physiological. In contrast, when hyperlactatemia is associated with a serious and ongoing, life-threatening condition, such as septic peritonitis with a high mortality rate (approximately 40%45), then lactate is more likely to have prognostic value.
Sensitivity True positives/All with condition (True positives and false negatives) or Number with condition detected/Total number with condition.
Specificity True negatives/All negatives (True negatives and false positives) or Number without condition/Total number without condition.
Positive Predictive Value True positive tests/All positive tests (True positives and false positives).
Interpreting Measures of Diagnostic Utility Sensitivity, specificity, positive and negative predictive values, and overall accuracy are the traditional measures of diagnostic utility and have been used in the 4 studies to date on the use of plasma lactate concentration in dogs with GDV. When using a continuous variable, such as lactate, the data must first be analyzed to determine the optimal cutoff point to use. Cutoff points can be chosen to optimize sensitivity, specificity, or both. It is important that the decision making takes into consideration the implications of ruling in or out the condition. Choosing an overly sensitive cutoff will result in more false-positive results and an overly specific cutoff will result in more false-negative results. Because lactate has been repeatedly shown to predict survival better than it predicts death, it may well be better to use 2 different cutoff points: a low one below which most animals survive (or do not have gastric necrosis) and a high one above which survival is less likely and more dogs have gastric necrosis. The drawback with this approach is that it only covers a proportion of all cases. A positive test result, when using a continuous variable, is the cutoff value above or below which a condition does or does not occur. For lactate and GDV, this is usually gastric necrosis vs. no necrosis or death vs. survival.
Negative Predictive Value True negative tests/All negative tests (True negatives and false negatives).
Accuracy Total number of correct tests (True positives þ True negatives)/ Total population.
Literature Review Survival rates for dogs without gastric necrosis may be as high as 98%-100%4,46 whereas those with necrosis that undergo gastric resection may have survival rates as high as 66%-75%.4,47 Dogs with necrosis have more complications and incur higher hospitalization costs.4 Because survival is still reasonable following gastric resection, it is probably inappropriate to prognosticate definitively
Table 1 Reported Overall Survival, Incidence of Gastric Necrosis, and Survival With or Without Gastric Necrosis References
Number of Cases
101 de Papp et al.4* 48 Zacher et al. 64 Green et al.46 84 Santoro Beer 73 et al.47†
Overall Survival, % (n)
Gastric Necrosis, % (n)
86 (87)
37 (37)
77 (49) 88 (74) 89 (65)
41 (26) 19 (16) 16 (12)
Survival Without Necrosis, % (n)
Survival With Necrosis, % (n)
Total Number Euthanized (Died)
Intraoperative Euthanasia Owing to Gastric Necrosis (%)
98 (62/63)
66 (25/38)
11 (3)
3/34 (9)
92 (35/38) 100 (68/68) 93 (57/61)
54 (14/26) 38 (6/16) 75 (8/12)
12 (3) 7 (3) 7 (1)
8/26 (31) 7/10 (70) 3/12 (25)
For comparison, all values are calculated from the total number of dogs undergoing anesthesia and surgery. n
†
One dog excluded owing to euthanasia for financial reasons. Five dogs excluded that were euthanized before surgery.
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Table 2 Initial Lactate in Total Study Population, Survivors, and Nonsurvivors References
All Cases Initial Lactate (mmol/L)
All Cases Initial Lactate (o 6.0 mmol/L)
All Cases Initial Lactate (4 6.0 mmol/L)
Survivors Median Plasma Lactate (Range) (mmol/L)
Nonsurvivors Median Plasma Lactate (Range) (mmol/L)
de Papp et al.4 Zacher et al.48 Green et al.46 Santoro Beer et al.47
3.9* (0.8-14.1) NR 4.0 (0.7-16.9) NR
69% NR 71.4% NR
31% NR 29.6% NR
3.5* (0.8-14.1) 6.2 7 3.2 (0-12.6)† 3.4 (0.7-16.1) 4.5 (0.8-14.4)
8.5* (2.0-13.8) 10.3 7 3.2 (3.9-16.7)† 6.80 (1.4-16.9) 7.9 (5.6-15)
NR, data not reported; SD, standard deviation. n
†
Calculated from reanalysis of original data. Mean 7 SD (mean 7 2 SD ¼ 95% of data).
in any individual patient based on a very high initial plasma lactate concentration, but it may be appropriate to inform owners that complications may be more likely and costs higher. If the initial lactate concentration is within reference range or only mildly increased (2-4 mmol/L), then it is appropriate to say that complications are less likely but still possible. All 4 studies of plasma lactate concentration in dogs with GDV are retrospective.4,46-48 In a retrospective study, all the results have obviously already occurred, so even if they differ, the results are valid and complementary. Differing results from retrospective studies may not only reflect real differences in populations studied but also variations in inclusion and exclusion criteria, methodology, analysis, and the myriad of uncontrolled factors involved in clinical management of dogs with GDV. These include varying duration of clinical signs and severity of hypoperfusion, concurrent diseases such as sepsis or SIRS, preanalytical variability, sample handling, analytical variability owing to differences in analyzers, previous treatment before sample collection (especially fluid therapy), differences in medical and surgical treatment, and decisions to euthanase based on perceived poor prognosis. Arguably, one of the main reasons for the apparent differences between the studies is the statistical methodology employed and how authors chose to represent their findings. Close scrutiny reveals that the data among studies were actually remarkably similar. Overall survival in dogs with GDV (Table 1) ranged from 77%89% which comprised a survival rate of 92%-100% in dogs without gastric necrosis and 38%-75% in dogs with necrosis (including intraoperative euthanasia). Notably, the 2 most recent studies (Green and Santoro Beer) reported half the incidence of presumptive gastric necrosis in dogs undergoing surgery (19% and 16%, respectively) than the other 2 (de Papp and Zacher; 38% and 41%, respectively). Green reported the lowest survival rate for dogs with gastric necrosis (38%) and Santoro Beer the highest (75%). In the study with the lowest survival in dogs with gastric necrosis, 7 of 10 dogs that died were euthanized intraoperatively, and 1 dog with presumptive necrosis that did not have a gastrectomy survived. Both of the studies with the highest survival with gastric necrosis (66% and 75%) are from the same institution. Both of the studies with the lower survival for dogs with gastric necrosis reported more dogs euthanized intraoperatively (31% and 70% vs. 9% and 25%). These findings may represent real differences in the respective populations of dogs with GDV or institutional practices. Nevertheless, the main cause of death across all studies is euthanasia.
Initial Plasma Lactate Concentration as a Predictor of Survival All studies reported initial plasma lactate concentration. Comparison of descriptive statistics (Table 2) reveals that lactate concentrations were largely similar in all studies. Reported survival
with an initial lactate concentration o6.0 mmol/L in the 3 studies where it was reported was 69 of 70 (99%),4 23 of 24 (96%),48 55 of 60 (92%) dogs.46 The main difference was that Green reported lower lactate concentrations in their nonsurvivor group, which were mainly owing to 3 dogs with a lactate concentration of 5-5.9 mmol/L. Zacher's population may have had higher initial plasma lactate concentrations, but the data are presented as mean 7 standard deviation (higher numbers may have raised the mean), so it is difficult to directly compare results. Green's findings agree with those of Zacher using a cutoff point of 9.0 mmol/L. Mortality in dogs with a lactate concentration o9.0 mmol/L was 7 of 68 (10%) and 4 of 40 (10%) respectively. When lactate concentration was 49.0 mmol/L mortality was 3 of 6 (50%) and 11 of 24 (46%). Each study listed different optimal plasma lactate cutoff points for prediction of survival (Table 3); however, methodology and data analysis also differed. de Papp et al. purposely selected a cutoff point to slightly optimize specificity. Zacher and Santoro Beer chose to optimize both sensitivity and specificity. Green reported values that maximize sensitivity for the presence of gastric necrosis and specificity for survival.
Initial Plasma Lactate Concentration as a Predictor of Gastric Necrosis The median and range of reported plasma lactate concentrations in dogs with and without necrosis was similar across studies. It was higher in dogs with gastric necrosis than in those without but, as for survival, there is overlap between the groups (Table 4). Cutoff points for the presence or absence of gastric necrosis in the 2 studies that reported single values4,47 are exactly the same as their cutoff values for survival. This is expected given that the presence or absence of gastric necrosis is the main factor affecting
Table 3 Reported Cutoff Points for Initial Lactate, Percentage Survival, and Sensitivity and Specificity in Dogs With GDV Author
Optimal Lactate Cutoff (mmol/L)
Survival o Survival 4 Sensitivity Cutoff, n (%) Cutoff, n (%) (%)
Specificity (%)
de Papp et al.4 Zacher et al.48 Green et al.46 Santoro Beer et al.47
6.0
69/70 (99)
18/31 (58)
68
86
9.0
36/40 (90)
13/24 (54)
74
73
4.1
41/42 (98)
33/42 (79)
60
91
7.4
NR (95)
NR (70)
75
89
NR, not reported.
E. Mooney et al. / Topics in Companion An Med 29 (2014) 71–76
Table 4 Initial Plasma Lactate Concentration in Dogs With and Without Gastric Necrosis References
de Papp et al.4 Green et al.46 Santoro Beer et al.47 n
Gastric Necrosis Median Plasma Lactate (Range) (mmol/L)
No Gastric Necrosis Median Plasma Lactate (Range) (mmol/L)
6.6 (0.8-10.0)* 6.35 (1.4-16.9) 6.95 (1.9-14.4)
3.3 (1.7-14.1)* 3.4 (0.7-14.8) 4.5 (0.8-15)
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Table 6 Initial, Final, and Changes in Plasma Lactate Concentration in Surviving and Nonsurviving Dogs With GDV Survivors, n ¼ 49 Initial lactate concentration (mmol/L) Final lactate concentration (mmol/L) Absolute change in lactate concentration (mmol/L) Percentage change in lactate concentration (%)
Nonsurvivors, n ¼ 15
6.2 7 3.2 3.3 7 2.3 2.9 7 3.3
10.3 7 3.2 8.0 7 3.3 2.6 7 2.0
49.1 7 28.8
24.6 7 19.4
Range calculated from original data.
survival. The percentage of nonsurvivors with gastric necrosis in each study was 13 of 14 (93%),4 12 of 15 (80%),48 10 of 10 (100%),46 and 4 of 8 (50%).47 Studies differed in their reported optimal cutoff points using initial lactate concentration for prediction of gastric necrosis (Table 5), and the reasons are similar to those for prediction of survival (detailed previously). Choosing to maximize sensitivity for the detection of gastric necrosis will result in more falsepositive results as Green demonstrated (only 28% of dogs above their cutoff point actually had gastric necrosis).
Serial Plasma Lactate Concentration The time taken for “clearance” of lactate from the bloodstream is a logical and reasonable reflection of the overall return of the body to normal energy production from states in which it was inadequate. It is therefore a plausible and compelling indicator of prognosis when the underlying cause of lactate production is pathologic. Plasma lactate concentration is always a balance between ongoing production by tissues vs. metabolism and excretion: it is the net reflection of the rates of tissues releasing lactate and those consuming it. Excretion of lactate by the kidneys does not occur until the renal threshold of 6-8 mmol/L is exceeded.49,50 A component of hyperlactatemia in hypovolemic and septic shock may be due to increased aerobic production owing to epinephrine-induced stimulation of the Na þ /K þ –adenosine triphosphatase pump and its associated energy-producing glycolytic enzymes rather than tissue hypoxia.51,52 Failure of plasma lactate to decrease after appropriate fluid therapy and especially if it remains above the reference interval after 24-48 hours of treatment is often associated with a poor prognosis. Zacher and Green both concluded that serial plasma lactate concentration was a useful prognostic indicator in dogs with GDV. Zacher reported serial measurements before surgery (time interval 82 7 32 minutes; mean 7 standard deviation) whereas Green reported a
Table 5 Cutoff Points for Initial Lactate, Percentage With and Without Gastric Necrosis, and Sensitivity and Specificity in Dogs With GDV References Optimal Lactate Cutoff (mmol/L)
Gastric Gastric Sensitivity Necrosis o Necrosis 4 (%) Cutoff, n (%) Cutoff, n (%)
Specificity (%)
de Papp et al.4 Green et al.46 Santoro Beer et al.47
6.0
15/71 (21)
23/31 (74)
61
88
6.0 2.9 7.4
8/60 (13) 1/30 (3.3) NR
8/24 (33) 15/54 (28) NR
94 50
43 88
NR, not reported.
mixture of presurgical and postsurgical values (median time 6 hours [range: 0.5-12.0 hours]). Zacher reported that survival was significantly lower in dogs with a final lactate concentration 4 6.4 mmol/L (23% vs. 91%), an absolute change in lactate concentration r4 mmol/L (10% vs. 86%), or a percentage change in lactate concentration r 42.5% (15% vs. 100%). They also found significant differences between survivors and nonsurvivors for initial lactate, final lactate, and percentage change in lactate but not for the absolute change (Table 6). Green found that of 40 dogs with an initial plasma lactate concentration 4 2.5 mmol/L, 37 survived, and 70% of these had a fall of 50% within 12 hours. In summary, when used with appropriate understanding and cautious wording in conversations with the owner, initial and serial plasma lactate concentrations can be used to guide decision making in dogs with GDV. A conservative compromise, considering all published data, may be to inform owners of dogs with an initial plasma lactate of o4 mmol/L that survival is more likely and the chance of complications less. An initial lactate 46 mmol/L makes gastric necrosis and greater expense more likely. However, because of the overlap between groups, exploratory laparotomy to identify gastric necrosis should always be recommended irrespective of the plasma lactate concentration. Falls in plasma lactate of greater than 40% after fluid resuscitation are likely to indicate better survival. If plasma lactate increases after fluid resuscitation, the cause should be aggressively pursued. Finally, from the small amount of published data and clinical experience, if the initial plasma lactate concentration is moderately to severely increased (5-10 mmol/L) and increases following fluid therapy, death is likely if the underlying cause cannot be found and treated.
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34. Holahan ML, Brown AJ, Drobatz KJ. The association of blood lactate concentration with outcome in dogs with idiopathic immune-mediated hemolytic anemia: 173 cases (2003-2006). J Vet Emerg Crit Care 20:413–420, 2010 35. Buriko Y, Van Winkle TJ, Drobatz KJ, Rankin SC, Syring RS. Severe soft tissue infections in dogs: 47 cases (1996–2006). J Vet Emerg Crit Care 18:608–618, 2008 36. Kitagawa H, Yasuda K, Kitoh K, Sasaki Y. Blood gas analysis in dogs with heartworm caval syndrome. J Vet Med Sci 56:861–867, 1994 37. Jacobson LS, Lobetti RG. Glucose, lactate, and pyruvate concentrations in dogs with babesiosis. Am J Vet Res 66:244–250, 2005 38. Nel M, Lobetti RG, Keller N, Thompson PN. Prognostic value of blood lactate, blood glucose, and hematocrit in canine babesiosis. J Vet Intern Med 18: 471–476, 2004 39. Gower SB, Weisse CW, Brown DC. Major abdominal evisceration injuries in dogs and cats: 12 cases (1998-2008). J Am Vet Med Assoc 234:1566–1572, 2009 40. Bright JM, Golden AL, Gompf RE, Walker MA, Toal RL. Evaluation of the calcium channel-blocking agents diltiazem and verapamil for treatment of feline hypertrophic cardiomyopathy. J Vet Intern Med 5:272–282, 1991 41. Parsons KJ, Owen LJ, Lee K, Tivers MS, Gregory SP. A retrospective study of surgically treated cases of septic peritonitis in the cat (2000–2007). J Small Anim Pract 50:518–524, 2009 42. Costello MF, Drobatz KJ, Aronson LR, King LG. Underlying cause, pathophysiologic abnormalities, and response to treatment in cats with septic peritonitis: 51 cases (1990-2001). J Am Vet Med Assoc 225:897–902, 2004 43. Hayes G, Mathews K, Doig G, et al. The acute patient physiologic and laboratory evaluation (APPLE) score: a severity of illness stratification system for hospitalized dogs. J Vet Intern Med 24:1034–1047, 2010 44. Hayes G, Mathews K, Doig G, et al. The feline acute patient physiologic and laboratory evaluation (Feline APPLE) score: a severity of illness stratification system for hospitalized cats. J Vet Intern Med 25:26–38, 2011 45. Bentley AM, Otto CM. Comparison of dogs with septic peritonitis: 1988–1993 versus 1999–2003. J Vet Emerg Crit Care 17:391–398, 2007 46. Green TI, Tonozzi CC, Kirby R, Rudloff E. Evaluation of initial plasma lactate values as a predictor of gastric necrosis and initial and subsequent plasma lactate values as a predictor of survival in dogs with gastric dilation—volvulus: 84 dogs (2003-2007). J Vet Emerg Crit Care 21:36–44, 2011 47. Santoro Beer KA, Syring RS, Drobatz KJ. Evaluation of plasma lactate concentration and base excess at the time of hospital admission as predictors of gastric necrosis and outcome and correlation between those variables in dogs with gastric dilation-volvulus: 78 cases (2004-2009). J Am Vet Med Assoc 242:54–58, 2013 48. Zacher LA, Berg J, Shaw SP, Kudej RK. Association between outcome and changes in plasma lactate concentration during presurgical treatment in dogs with gastric dilation—volvulus: 64 cases (2002-2008). J Am Vet Med Assoc 236:892–897, 2010 49. Miller AT, Miller JO. Renal excretion of lactic acid in exercise. J Appl Physiol 1:614–618, 1949 50. Craig FN. Renal tubular reabsorption, metabolic utilization and isomeric fractionation of lactic acid in the dog. Am J Physiol 146:146–159, 1946 51. McCarter FD, James JH, Luchette FA, et al. Adrenergic blockade reduces skeletal muscle glycolysis and Na þ , K þ -ATPase activity during haemorrhage. J Surg Res 99:235–244, 2001 52. Marik PE, Bellomo R. Lactate clearance as a target of therapy in sepsis: a flawed paradigm. Anaesthesiol Perioper Crit Care Med 1:3, 2013
Topical Review
Plasma Lactate Concentration as a Prognostic Biomarker in Dogs With Gastric Dilation and Volvulus Erin Mooney, BVSc (Hons), Dip. ACVECCa, Cameron Raw, BVSc (Hons)b, Dez Hughes, BVSc (Hons), MRCVS, Dip. ACVECCc,n Keywords: dog lactate prognosis prognostic indicator gastric dilation and volvulus gastric necrosis a
Small Animal Specialist Hospital, New South Wales, Australia
b
Rochester Veterinary Practice, Victoria, Australia
Initial and serial plasma lactate concentrations can be used to guide decision making in individual dogs with GDV but care is necessary in phrasing conversations with owners. Published data suggests that survival is more likely and the chance of complications less in dogs with an initial plasma lactate of o4 mmol/L. An initial lactate 4 6 mmol/L makes gastric necrosis and greater expense more likely. However, because of the overlap between groups and the good overall survival rates, exploratory laparotomy should always be recommended irrespective of the plasma lactate concentration. Falls in plasma lactate of greater than ~40% after fluid resuscitation are likely to indicate better survival. If the initial plasma lactate concentration is moderately to severely increased (5- 4 10 mmol/L) and a sustained increase in plasma lactate occurs after fluid resuscitation, the cause should be aggressively pursued. Many dogs with persistent hyperlactatemia over 24-48 hours do not survive. & 2014 Elsevier Inc. All rights reserved.
c Section of Emergency and Critical Care, Veterinary Hospital, University of Melbourne, Victoria, Australia n
Address reprint requests to Dez Hughes, BVSc (Hons), MRCVS, Dip. ACVECC, Section of Emergency and Critical Care, Veterinary Hospital, University of Melbourne, 250 Princes Highway, Werribbee, Victoria 3030, Australia. E-mail: [email protected] (D. Hughes)
Introduction Gastric dilation and volvulus (GDV) is an acute condition of dogs characterized by dilation of the stomach and rotation on its mesenteric axis. Affected dogs may suffer from circulatory shock, and a proportion of dogs develop gastric necrosis. Reported mortality rates for GDV vary between 10% and 33%.1-6 Biomarkers, such as plasma lactate concentration, can help guide prognostication. Understanding lactate physiology and how GDV may cause hyperlactatemia is important, but knowing how to apply the results of studies of prognostic indicators to individual animals is vital so that reasonable and proportionate prognostic information can be provided to pet owners. A low lactate concentration is associated with a high survival rate, whereas more dogs with a higher lactate concentration die; however, there are exceptions in both cases. Hence, advice to owners about their individual pets based on initial lactate concentration should be offered carefully. Based on the published literature, the authors suggest that it is reasonable to inform owners of dogs with GDV and a lactate concentration of 6 mmol/L or above that there is a higher chance of gastric necrosis and other complications and that their hospital stay may be more costly but to be no more definitive than that. If the initial lactate concentration is within reference range or only mildly increased (2-4 mmol/L), then it is appropriate to say that complications are less likely but still possible. If plasma lactate concentration does not fall within the reference range in 24-48 http://dx.doi.org/10.1053/j.tcam.2014.09.005 1527-3369/& 2014 Topics in Companion Animal Medicine. Published by Elsevier Inc.
hours, the clinician should aggressively pursue the underlying reason because survival rates are poor in many cases with prolonged hyperlactatemia.
Lactate Biochemistry and Physiology Glycolysis, which occurs in both the presence and absence of oxygen, takes place in the cytoplasm, converts glucose into pyruvate, and produces 2 moles of adenosine triphosphate (ATP) per moles of glucose. Glycolysis also requires NAD þ which is converted into NADH. When sufficient oxygen is available, pyruvate enters the mitochondria and is used in the tricarboxylic acid cycle and oxidative phosphorylation to produce 36 moles of ATP and regenerate NADH back to NAD þ thereby allowing glycolysis to continue.7 Alternatively, pyruvate can be converted into lactate in the cytosol which also consumes H þ and regenerates NAD þ . The main physiological role of lactate production is to allow glycolysis and cellular energy (ATP) production to continue when cellular energy demands exceed the capacity of aerobic mitochondrial energy production. Although glycolysis produces less ATP on a molar basis than oxidative phosphorylation, it is much faster which allows it to temporarily meet cellular energy requirements. When ATP is converted to adenosine diphosphate (hydrolyzed) to release energy, H þ is also produced. If sufficient oxygen is available, this H þ passes into mitochondria to maintain the proton
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gradient required for the electron transport chain and oxidative phosphorylation. But when cellular oxygen supply is inadequate, H þ ions accumulate in the cytosol. Lactate production from pyruvate minimizes this by consuming H þ . Importantly, lactate is formed as the lactate ion without a concurrent H þ ion. Lactate can then be cotransported out of the cell with an H þ ion by the monocarboxylate transporter thereby further limiting intracellular acidosis. Hence, lactate production does not cause acidosis, it protects against it. Nevertheless, when ATP made from glycolysis is used to release energy, an H þ ion is also generated so there is a 1:1 ratio of H þ and lactate production but they are formed by different processes. That is, hyperlactatemia is directly proportional to H þ but not the cause of the increase. Lactate is also protective because it can be the preferred metabolic fuel for vital tissues such as the brain7 and heart8 and the only fuel for red blood cells which lack mitochondria.
possible mechanisms include reduced erythrocyte flexibility, increased leukocyte activation, altered neurohormonal control of endothelial smooth muscle, enhanced nitric oxide production, and pyruvate dehydrogenase inhibition.23,24 Other events during GDV may contribute to hyperlactatemia. Ischemic tissue within the gastric wall and spleen will produce lactate. Whether this lactate enters the systemic circulation depends on the remaining blood flow. With complete cessation of blood flow, there will be no lactate washout. But low flow or intermittent flow (perhaps from intermittent rotation and derotation of the stomach) will wash lactate from ischemic tissue into the circulating blood volume. Decompression of the stomach via trocarization or orogastric intubation may also allow blood flow and lactate release into the systemic circulation. Gastric necrosis and intestinal ischemia might allow bacterial translocation and bacteremia, leading to sepsis, septic shock, and SIRS. Additionally, dogs with GDV commonly experience cardiac arrhythmias and may have myocardial depression.25,26
Hyperlactatemia Hyperlactatemia occurs whenever the rate of lactate production exceeds that of lactate metabolism and clearance and has been categorized into types A and B.9,10 Type A hyperlactatemia is the most common in emergency and critical care practice and occurs with clinical evidence of a relative or absolute tissue oxygen deficiency. A relative deficiency is usually due to increased muscle activity, for example, exercise, struggling, shivering, trembling, tremors, and seizures.10-12 Exercise-related hyperlactatemia has been reported to range from 4.5 mmol/L in dogs following agility testing13 to greater than 30 mmol/L in racing Greyhounds.14,15 Physiological hyperlactatemia should resolve when muscle activity stops with an half-life of 30-60 minutes.13,14,16 If appropriate resolution does not occur in a clinical patient, a concurrent disease process is likely. An absolute tissue oxygen deficiency is usually due to global hypoperfusion (shock) which may be hypovolemic, obstructive, maldistributive, or cardiogenic in origin or a combination thereof. The reference range for plasma lactate concentration measured in 60 conscious dogs was 0.3-2.5 mmol/L17 but because these dogs underwent repeated sampling, it is likely that some had slightly increased concentrations owing to increased muscle activity. Using an upper limit of 2.0 mmol/L is probably more appropriate in dogs with little muscle activity. Type B hyperlactatemia occurs in the absence of clinical evidence of decreased oxygen delivery and has been subclassified into type B1 associated with underlying disease (in particular, sepsis and systemic inflammatory response syndrome [SIRS], B2 with drugs or toxins, and B3 with congenital or hereditary metabolic defects).10
Hyperlactatemia With GDV Most dogs with GDV have type A hyperlactatemia owing to variable degrees of global hypoperfusion. Most are hypovolemic owing to intragastric fluid sequestration and hemorrhage in dogs with torn gastric vessels. They also have a variable obstructive component owing to reduced venous return because of compression of major intra-abdominal veins such as the caudal vena cava and portal vein by the dilated stomach.18 Some may also have maldistributive shock and type B1 hyperlactatemia owing to sepsis, septic shock, and SIRS. Many underlying mechanisms have been suggested for type B1 hyperlactatemia associated with SIRS and sepsis including skeletal muscle Na þ -K þ -adenosine triphosphatase upregulation,19 mitochondrial dysfunction, cytochrome inhibition,20 increased hepatic lactate production, reduced hepatic lactate extraction,21 impaired tissue oxygen extraction,22 and capillary shunting.22 Other
Plasma Lactate Concentration as a Prognostic Indicator With the increasing realization of its clinical utility and availability of point-of-care lactate analyzers, the measurement of lactate has become more mainstream in veterinary medicine over the past decade. Its prognostic value was recognized in human medicine almost 50 years ago,1 and there are a multitude of clinical and experimental studies documenting its clinical and prognostic utility. Over the years, these have ranged the full gamut of investigations from simple, retrospective, observational studies to prospective, randomized trials of its use to guide therapy. Studies in people have shown prognostic value in trauma,27 sepsis,28 septic shock,28 SIRS,28 cardiac arrest,28 carbon monoxide toxicity,29 head trauma,28 malaria,28 and liver failure.9 Its use is now recommended in the consensus guidelines for sepsis.30 The addition of treatment targeted toward lactate clearance to the Surviving Sepsis Campaign resuscitation bundle reduced mortality risk 2-fold in people with severe sepsis. In addition to dogs with GDV, some degree of prognostic utility has been reported for ill and injured dogs in a veterinary intensive care unit,31 systemically ill dogs receiving fluid therapy,32 and dogs with SIRS,33 immune mediated hemolytic anemia,34 severe soft tissue infections,35 heartworm-associated caval syndrome,36 babesiosis,37,38 and abdominal evisceration.39 Lactate has also been demonstrated to have some limited prognostic value in cats with hypertrophic cardiomyopathy40 and with septic peritonitis.41,42 The Acute Patient Physiologic and Laboratory Evaluation for dogs and cats found lactate to be one of the most significant variables associated with mortality and included lactate in both the full and fast scoring systems for both species.43,44 Despite a wealth of evidence supporting its overall value, the difficulty remains in how we, as clinicians, apply these data to our individual clinical cases. Most veterinary studies show that the population of animals that die has a higher average lactate concentration than the population of animals that survive. Yet, some animals that survive may have very high lactate concentrations and some that die may have mildly increased or even reference range concentrations. This may seem contradictory, but the simple explanation is that, in general, the magnitude of the increase in lactate reflects the severity of lactate production (usually tissue hypoxia) not its reversibility. Whether the individual animal dies or survives depends on the underlying disease process that is associated with a concurrent hyperlactatemia. Consider a dog with simple, uncomplicated, peracute hemorrhage that can be easily stopped and treated such as an acute, appendicular arterial laceration. In this instance, the maximum
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Condition Positive Negative Test outcome
Positive
Positive Predictive Value True positive
Negative False negative
False positive
True positives All test positives
Negative Predictive Value True negative
True negatives All test negatives
Specificity
Accuracy
Sensitivity
True positives True negatives True positives + True negatives Condition positives Condition negatives Total population
plasma lactate concentration would provide information regarding the severity of hypovolemia. If the animal was successfully treated immediately with intravenous fluids, survival would be very likely and hence, lactate would not be associated with prognosis. An even more edifying example is normal exercise. Greyhounds may have plasma lactate concentrations of 10, 20, or even 30 mmol/L because their muscles acutely require more energy than can be produced from oxidative processes. Lactate obviously has no prognostic significance because its production is entirely physiological. In contrast, when hyperlactatemia is associated with a serious and ongoing, life-threatening condition, such as septic peritonitis with a high mortality rate (approximately 40%45), then lactate is more likely to have prognostic value.
Sensitivity True positives/All with condition (True positives and false negatives) or Number with condition detected/Total number with condition.
Specificity True negatives/All negatives (True negatives and false positives) or Number without condition/Total number without condition.
Positive Predictive Value True positive tests/All positive tests (True positives and false positives).
Interpreting Measures of Diagnostic Utility Sensitivity, specificity, positive and negative predictive values, and overall accuracy are the traditional measures of diagnostic utility and have been used in the 4 studies to date on the use of plasma lactate concentration in dogs with GDV. When using a continuous variable, such as lactate, the data must first be analyzed to determine the optimal cutoff point to use. Cutoff points can be chosen to optimize sensitivity, specificity, or both. It is important that the decision making takes into consideration the implications of ruling in or out the condition. Choosing an overly sensitive cutoff will result in more false-positive results and an overly specific cutoff will result in more false-negative results. Because lactate has been repeatedly shown to predict survival better than it predicts death, it may well be better to use 2 different cutoff points: a low one below which most animals survive (or do not have gastric necrosis) and a high one above which survival is less likely and more dogs have gastric necrosis. The drawback with this approach is that it only covers a proportion of all cases. A positive test result, when using a continuous variable, is the cutoff value above or below which a condition does or does not occur. For lactate and GDV, this is usually gastric necrosis vs. no necrosis or death vs. survival.
Negative Predictive Value True negative tests/All negative tests (True negatives and false negatives).
Accuracy Total number of correct tests (True positives þ True negatives)/ Total population.
Literature Review Survival rates for dogs without gastric necrosis may be as high as 98%-100%4,46 whereas those with necrosis that undergo gastric resection may have survival rates as high as 66%-75%.4,47 Dogs with necrosis have more complications and incur higher hospitalization costs.4 Because survival is still reasonable following gastric resection, it is probably inappropriate to prognosticate definitively
Table 1 Reported Overall Survival, Incidence of Gastric Necrosis, and Survival With or Without Gastric Necrosis References
Number of Cases
101 de Papp et al.4* 48 Zacher et al. 64 Green et al.46 84 Santoro Beer 73 et al.47†
Overall Survival, % (n)
Gastric Necrosis, % (n)
86 (87)
37 (37)
77 (49) 88 (74) 89 (65)
41 (26) 19 (16) 16 (12)
Survival Without Necrosis, % (n)
Survival With Necrosis, % (n)
Total Number Euthanized (Died)
Intraoperative Euthanasia Owing to Gastric Necrosis (%)
98 (62/63)
66 (25/38)
11 (3)
3/34 (9)
92 (35/38) 100 (68/68) 93 (57/61)
54 (14/26) 38 (6/16) 75 (8/12)
12 (3) 7 (3) 7 (1)
8/26 (31) 7/10 (70) 3/12 (25)
For comparison, all values are calculated from the total number of dogs undergoing anesthesia and surgery. n
†
One dog excluded owing to euthanasia for financial reasons. Five dogs excluded that were euthanized before surgery.
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Table 2 Initial Lactate in Total Study Population, Survivors, and Nonsurvivors References
All Cases Initial Lactate (mmol/L)
All Cases Initial Lactate (o 6.0 mmol/L)
All Cases Initial Lactate (4 6.0 mmol/L)
Survivors Median Plasma Lactate (Range) (mmol/L)
Nonsurvivors Median Plasma Lactate (Range) (mmol/L)
de Papp et al.4 Zacher et al.48 Green et al.46 Santoro Beer et al.47
3.9* (0.8-14.1) NR 4.0 (0.7-16.9) NR
69% NR 71.4% NR
31% NR 29.6% NR
3.5* (0.8-14.1) 6.2 7 3.2 (0-12.6)† 3.4 (0.7-16.1) 4.5 (0.8-14.4)
8.5* (2.0-13.8) 10.3 7 3.2 (3.9-16.7)† 6.80 (1.4-16.9) 7.9 (5.6-15)
NR, data not reported; SD, standard deviation. n
†
Calculated from reanalysis of original data. Mean 7 SD (mean 7 2 SD ¼ 95% of data).
in any individual patient based on a very high initial plasma lactate concentration, but it may be appropriate to inform owners that complications may be more likely and costs higher. If the initial lactate concentration is within reference range or only mildly increased (2-4 mmol/L), then it is appropriate to say that complications are less likely but still possible. All 4 studies of plasma lactate concentration in dogs with GDV are retrospective.4,46-48 In a retrospective study, all the results have obviously already occurred, so even if they differ, the results are valid and complementary. Differing results from retrospective studies may not only reflect real differences in populations studied but also variations in inclusion and exclusion criteria, methodology, analysis, and the myriad of uncontrolled factors involved in clinical management of dogs with GDV. These include varying duration of clinical signs and severity of hypoperfusion, concurrent diseases such as sepsis or SIRS, preanalytical variability, sample handling, analytical variability owing to differences in analyzers, previous treatment before sample collection (especially fluid therapy), differences in medical and surgical treatment, and decisions to euthanase based on perceived poor prognosis. Arguably, one of the main reasons for the apparent differences between the studies is the statistical methodology employed and how authors chose to represent their findings. Close scrutiny reveals that the data among studies were actually remarkably similar. Overall survival in dogs with GDV (Table 1) ranged from 77%89% which comprised a survival rate of 92%-100% in dogs without gastric necrosis and 38%-75% in dogs with necrosis (including intraoperative euthanasia). Notably, the 2 most recent studies (Green and Santoro Beer) reported half the incidence of presumptive gastric necrosis in dogs undergoing surgery (19% and 16%, respectively) than the other 2 (de Papp and Zacher; 38% and 41%, respectively). Green reported the lowest survival rate for dogs with gastric necrosis (38%) and Santoro Beer the highest (75%). In the study with the lowest survival in dogs with gastric necrosis, 7 of 10 dogs that died were euthanized intraoperatively, and 1 dog with presumptive necrosis that did not have a gastrectomy survived. Both of the studies with the highest survival with gastric necrosis (66% and 75%) are from the same institution. Both of the studies with the lower survival for dogs with gastric necrosis reported more dogs euthanized intraoperatively (31% and 70% vs. 9% and 25%). These findings may represent real differences in the respective populations of dogs with GDV or institutional practices. Nevertheless, the main cause of death across all studies is euthanasia.
Initial Plasma Lactate Concentration as a Predictor of Survival All studies reported initial plasma lactate concentration. Comparison of descriptive statistics (Table 2) reveals that lactate concentrations were largely similar in all studies. Reported survival
with an initial lactate concentration o6.0 mmol/L in the 3 studies where it was reported was 69 of 70 (99%),4 23 of 24 (96%),48 55 of 60 (92%) dogs.46 The main difference was that Green reported lower lactate concentrations in their nonsurvivor group, which were mainly owing to 3 dogs with a lactate concentration of 5-5.9 mmol/L. Zacher's population may have had higher initial plasma lactate concentrations, but the data are presented as mean 7 standard deviation (higher numbers may have raised the mean), so it is difficult to directly compare results. Green's findings agree with those of Zacher using a cutoff point of 9.0 mmol/L. Mortality in dogs with a lactate concentration o9.0 mmol/L was 7 of 68 (10%) and 4 of 40 (10%) respectively. When lactate concentration was 49.0 mmol/L mortality was 3 of 6 (50%) and 11 of 24 (46%). Each study listed different optimal plasma lactate cutoff points for prediction of survival (Table 3); however, methodology and data analysis also differed. de Papp et al. purposely selected a cutoff point to slightly optimize specificity. Zacher and Santoro Beer chose to optimize both sensitivity and specificity. Green reported values that maximize sensitivity for the presence of gastric necrosis and specificity for survival.
Initial Plasma Lactate Concentration as a Predictor of Gastric Necrosis The median and range of reported plasma lactate concentrations in dogs with and without necrosis was similar across studies. It was higher in dogs with gastric necrosis than in those without but, as for survival, there is overlap between the groups (Table 4). Cutoff points for the presence or absence of gastric necrosis in the 2 studies that reported single values4,47 are exactly the same as their cutoff values for survival. This is expected given that the presence or absence of gastric necrosis is the main factor affecting
Table 3 Reported Cutoff Points for Initial Lactate, Percentage Survival, and Sensitivity and Specificity in Dogs With GDV Author
Optimal Lactate Cutoff (mmol/L)
Survival o Survival 4 Sensitivity Cutoff, n (%) Cutoff, n (%) (%)
Specificity (%)
de Papp et al.4 Zacher et al.48 Green et al.46 Santoro Beer et al.47
6.0
69/70 (99)
18/31 (58)
68
86
9.0
36/40 (90)
13/24 (54)
74
73
4.1
41/42 (98)
33/42 (79)
60
91
7.4
NR (95)
NR (70)
75
89
NR, not reported.
E. Mooney et al. / Topics in Companion An Med 29 (2014) 71–76
Table 4 Initial Plasma Lactate Concentration in Dogs With and Without Gastric Necrosis References
de Papp et al.4 Green et al.46 Santoro Beer et al.47 n
Gastric Necrosis Median Plasma Lactate (Range) (mmol/L)
No Gastric Necrosis Median Plasma Lactate (Range) (mmol/L)
6.6 (0.8-10.0)* 6.35 (1.4-16.9) 6.95 (1.9-14.4)
3.3 (1.7-14.1)* 3.4 (0.7-14.8) 4.5 (0.8-15)
75
Table 6 Initial, Final, and Changes in Plasma Lactate Concentration in Surviving and Nonsurviving Dogs With GDV Survivors, n ¼ 49 Initial lactate concentration (mmol/L) Final lactate concentration (mmol/L) Absolute change in lactate concentration (mmol/L) Percentage change in lactate concentration (%)
Nonsurvivors, n ¼ 15
6.2 7 3.2 3.3 7 2.3 2.9 7 3.3
10.3 7 3.2 8.0 7 3.3 2.6 7 2.0
49.1 7 28.8
24.6 7 19.4
Range calculated from original data.
survival. The percentage of nonsurvivors with gastric necrosis in each study was 13 of 14 (93%),4 12 of 15 (80%),48 10 of 10 (100%),46 and 4 of 8 (50%).47 Studies differed in their reported optimal cutoff points using initial lactate concentration for prediction of gastric necrosis (Table 5), and the reasons are similar to those for prediction of survival (detailed previously). Choosing to maximize sensitivity for the detection of gastric necrosis will result in more falsepositive results as Green demonstrated (only 28% of dogs above their cutoff point actually had gastric necrosis).
Serial Plasma Lactate Concentration The time taken for “clearance” of lactate from the bloodstream is a logical and reasonable reflection of the overall return of the body to normal energy production from states in which it was inadequate. It is therefore a plausible and compelling indicator of prognosis when the underlying cause of lactate production is pathologic. Plasma lactate concentration is always a balance between ongoing production by tissues vs. metabolism and excretion: it is the net reflection of the rates of tissues releasing lactate and those consuming it. Excretion of lactate by the kidneys does not occur until the renal threshold of 6-8 mmol/L is exceeded.49,50 A component of hyperlactatemia in hypovolemic and septic shock may be due to increased aerobic production owing to epinephrine-induced stimulation of the Na þ /K þ –adenosine triphosphatase pump and its associated energy-producing glycolytic enzymes rather than tissue hypoxia.51,52 Failure of plasma lactate to decrease after appropriate fluid therapy and especially if it remains above the reference interval after 24-48 hours of treatment is often associated with a poor prognosis. Zacher and Green both concluded that serial plasma lactate concentration was a useful prognostic indicator in dogs with GDV. Zacher reported serial measurements before surgery (time interval 82 7 32 minutes; mean 7 standard deviation) whereas Green reported a
Table 5 Cutoff Points for Initial Lactate, Percentage With and Without Gastric Necrosis, and Sensitivity and Specificity in Dogs With GDV References Optimal Lactate Cutoff (mmol/L)
Gastric Gastric Sensitivity Necrosis o Necrosis 4 (%) Cutoff, n (%) Cutoff, n (%)
Specificity (%)
de Papp et al.4 Green et al.46 Santoro Beer et al.47
6.0
15/71 (21)
23/31 (74)
61
88
6.0 2.9 7.4
8/60 (13) 1/30 (3.3) NR
8/24 (33) 15/54 (28) NR
94 50
43 88
NR, not reported.
mixture of presurgical and postsurgical values (median time 6 hours [range: 0.5-12.0 hours]). Zacher reported that survival was significantly lower in dogs with a final lactate concentration 4 6.4 mmol/L (23% vs. 91%), an absolute change in lactate concentration r4 mmol/L (10% vs. 86%), or a percentage change in lactate concentration r 42.5% (15% vs. 100%). They also found significant differences between survivors and nonsurvivors for initial lactate, final lactate, and percentage change in lactate but not for the absolute change (Table 6). Green found that of 40 dogs with an initial plasma lactate concentration 4 2.5 mmol/L, 37 survived, and 70% of these had a fall of 50% within 12 hours. In summary, when used with appropriate understanding and cautious wording in conversations with the owner, initial and serial plasma lactate concentrations can be used to guide decision making in dogs with GDV. A conservative compromise, considering all published data, may be to inform owners of dogs with an initial plasma lactate of o4 mmol/L that survival is more likely and the chance of complications less. An initial lactate 46 mmol/L makes gastric necrosis and greater expense more likely. However, because of the overlap between groups, exploratory laparotomy to identify gastric necrosis should always be recommended irrespective of the plasma lactate concentration. Falls in plasma lactate of greater than 40% after fluid resuscitation are likely to indicate better survival. If plasma lactate increases after fluid resuscitation, the cause should be aggressively pursued. Finally, from the small amount of published data and clinical experience, if the initial plasma lactate concentration is moderately to severely increased (5-10 mmol/L) and increases following fluid therapy, death is likely if the underlying cause cannot be found and treated.
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