Serial plasma lactate concentrations in 68 puppies aged 4 to 80 days
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Original Study Journal of Veterinary Emergency and Critical Care 15(1) 2005, pp17^21
Serial plasma lactate concentrations in 68 puppies
aged 4 to 80 days
Maureen A. McMichael, DVM, DACVECC, George E. Lees, DVM, MS, DACVIM,
Jennifer Hennessey, BS, Mary Sanders and May Boggess, PhD
Abstract
Objective: To determine a reference range for venous blood lactate concentrations in healthy neonatal dogs.
Design: A prospective cohort study.
Setting: All work was conducted at the College of Veterinary Medicine, Texas A&M University.
Animals: Clinically healthy dogs: 68 puppies and 30 adults.
Measurements and main results: A blood sample was collected from each puppy into lithium heparin via
jugular venipuncture at 4, 10, 16, 28, 70, and 80 days of age. A single venous sample was collected from each
adult dog. Lactate concentration in each sample was measured immediately using an automated analyzer.
Two hundred seventy-seven blood samples were analyzed. Blood lactate concentrations of adult dogs were
1.80 0.84 mmol/L (mean SD). Mean blood lactate concentrations of puppies were significantly higher at
4, 10, 16, and 28 days of age compared with those of adult dogs. The reference range for lactate concentration
for puppies at 4 days of age was 1.07–6.59, and for the puppies from 10 to 28 days of age was 0.80–4.60.
Conclusions: Assessment of perfusion can be challenging in neonates due to normal physiologic variation
and small size. Measurement of lactate is rapid, minimally invasive, and has potential to be a useful marker of
perfusion in neonatal dogs. However, lactate concentrations of neonatal dogs in this study were significantly
higher than those of adult dogs. Reference ranges for venous lactate concentrations in adult dogs should not
be used for puppies younger than 70 days of age.
(J Vet Emerg Crit Care 2005; 15(1): 17–21)
Keywords: hypoperfusion, lactic acidosis, neonatal dogs, perfusion, pyruvate
Introduction ume status.1,2 Hemodynamic parameters can vary
markedly in neonates compared with adults. Pulse
Assessment of perfusion can be challenging in both
quality can be difficult to assess and body temperature
human and veterinary patients, particularly neonates.
is lower in neonatal puppies compared with adults
In veterinary practice, mucous membrane color, capil-
(approximately 96–97 1F [35–36 1C]) and may not reach
lary refill time, heart rate, pulse quality, body temper-
100 1F (37 1C) until 2 weeks of age.3 CVP is higher in
ature, urinary output, and central venous pressure
puppies than in adult dogs and requires placement of a
(CVP) are commonly used to assess perfusion and vol-
central venous catheter. CVP was 8 cm H2O in normal
From the Department of Small Animal Medicine and Surgery, College of
puppies at 1 month of age and decreased to 2 cm H2O
Veterinary Medicine, Texas A&M University, College Station, TX (McMi- by 9 months of age in a study of 5 dogs.4 Concentration
chael, Lees, Hennessey, Sanders) and Department of Statistics, Texas A&M and dilution of urine in response to changes in the ex-
University, College Station, TX (Boggess).
tracellular fluid volume is decreased in neonates and
All work was conducted at the College of Veterinary Medicine, Texas A&M increases with age. In puppies at 2 days of age, the
University. Supported in part by grants from Nestlé Purina PetCare Re-
search, St. Louis, Missouri, and the National Institutes of Health. glomerular filtration rate (GFR) was only 14% of adult
Dr. Boggess’ present address is Stata Corporation, 4509 Lakeway Drive,
dog values and did not normalize until 10 weeks of age
College Station, TX 77845. in one study.5 Therefore, pulse quality, body tempera-
Address correspondence and reprint requests to: ture, CVP, and urine output may be inadequate assess-
Dr. Maureen A. McMichael, Department of Small Animal Medicine and ments of perfusion in neonates.
Surgery, College of Veterinary Medicine, Mail Stop 4474, Texas A&M Uni-
versity, College Station, TX 77843-4474.
Blood lactate concentrations are considered by some
E-mail: mmcmichael@cvm.tamu.edu to be accurate indicators of inadequate tissue perfu-
& Veterinary Emergency and Critical Care Society 2005 17M.A. McMichael et al.
sion.6–8 Lactate concentrations have been shown to be a Samples
superior index of hypoxia when compared with oxygen Blood samples were obtained from the puppies at 4, 10,
delivery (DO2), oxygen consumption (VO2), the oxygen 16, 28, 70, and 80 days of age. These sampling intervals
extraction ratio, and cardiac index (the cardiac output were determined by the nutrition study in which the
per minute per square meter of body surface area) in puppies were enrolled. Since litters were born at
clinical studies of critically ill humans.9,10 In studies different times and several samples were clotted, not
where no significant differences existed between sur- all puppies were sampled at all time points. A 23 g
vivors and non-survivors for DO2 and VO2, blood lac- butterfly catheter attached to a 3 mL syringe was used
tate concentrations were closely correlated with survival for puppies at 4 and 10 days of age. A 22 g needle at-
in humans and are also thought to be a more accurate tached to a 3 mL syringe was used after Day 10. All
prognostic indicator.10,11 Numerous studies suggest that venipuncture was performed by the same technician
lactate measurements are superior to measurement of and there was minimal struggling during restraint. One
CO with regards to predicting outcome in critically ill dog was eliminated from the study due to excessive
humans and that elevated lactate concentrations are struggling during restraint. A single venous blood
linked to increased mortality rates.11–16 sample was taken from each of the 30 adult dogs. Blood
Measurement of lactate concentration is a minimally from all dogs was collected into lithium heparin via
invasive technique that can be accomplished using ve- jugular venipuncture with the animal under minimal
nous blood specimens. restraint, and lactate concentration was measured im-
The purpose of this study was to determine a refer- mediately using an automated analyzer.b Plasma lactate
ence range for venous lactate concentrations in neonatal was assayed in whole blood via a platinum electrode
dogs and to assess whether these values change as the that senses hydrogen peroxide. The conversion of lac-
puppies mature. To the authors’ knowledge, lactate tate and oxygen to pyruvate and hydrogen peroxide
values have not been reported for healthy neonatal was catalyzed by a membrane bound lactate oxidase.
puppies. Electrode performance was analyzed every 2, 4, or
6 hours, depending upon the number of samples run.
Internal standards were used to verify slopes and 3
Materials and Methods
standard solutions with lactate concentrations of
Animals 0.5–1.0, 2.5–3.1, and 7.0–8.4 mmol/L were analyzed dai-
Sixty-eight clinically healthy mixed breed puppies were ly. Precision of the machine was determined by meas-
studied. Each of the puppies had a normal physical uring the 3 known lactate samples daily for 10 days
examination. The puppies were from 10 litters and were giving an intraclass correlation coefficient of 0.9996.
concurrently enrolled in a nutrition study in which the
dams were fed 4 different diets.a Each litter was also fed Statistical analysis
the same diet as the dam when the puppies began to Comparison of lactate concentrations in puppies of dif-
eat solid foods and upon weaning at approximately ferent ages with those of adult dogs was made with 6 2-
6 weeks of age. All diets were formulated to be nutri- sample (unequal variance) t-tests using the Bonferroni
tionally complete for all life stages and identical in total adjustment of the p-value. A p-value of 0.0083 (0.05/6)
fat, protein, nitrogen-free extract, vitamins, and miner- was considered significant. Tests of normality were
als. The protein content was 21% of metabolizable en- carried out using the Shapiro–Wilks test and normal
ergy or 30% on a dry matter basis. The fatty acid probability plots. The adult data were normally dis-
composition varied among the diets. The puppies were tributed and the box plots revealed symmetry without
handled daily from birth and were restrained for sev- outliers. Box plots of the puppy data revealed a few
eral minutes each day beginning at 2 weeks of age to outliers on Day 28 (the 95th percentile was 4.90–6.40).
acclimate them for the study. The research protocol was However, since the t-test is robust to mild deviation
approved by the Laboratory Animal Care Committee, from normality with large sample sizes (over 25) the
Texas A&M University. Venous blood samples were al- assumption of normality was accepted. Three-way
so taken from 30 clinically healthy adult, client-owned analysis of variance (ANOVA) was used to test for the
dogs. All adult dogs were reported to be free of disease influence of birth method (i.e. vaginal versus caesarean
by the owner and were normal on physical examina- delivery), diet, and gender on puppy lactate concentra-
tion. The clinical research protocol was approved by tions for each time point. Confidence intervals (CIs) are
the Clinical Research Review Committee, Texas A&M reported at the 95% level and are calculated using the t-
University. Additional data collected from each puppy distribution. Statistical analyses were performed using
included birth method (i.e. vaginal versus caesarean commercially available software.c Data are reported as
delivery), diet, and gender. mean standard deviation.
18 & Veterinary Emergency and Critical Care Society 2005Venous lactate concentrations
Results adult dogs used in this study are similar to those re-
ported in previous studies of healthy adult dogs.
Blood lactate concentration was 1.80 0.84 mmol/L in
Evans et al. reported a mean lactate concentration of
the 30 clinically healthy adult dogs. A total of 247 blood
1.11 mmol/L (range 0.42–3.58 mmol/L) in 60 healthy
samples from puppies were analyzed. Blood lactate
Beagle dogs, aged 5–9 months.17 Hughes et al. reported
concentration was 3.83 1.38 mmol/L for the puppies
mean lactate concentrations of 1.57 0.47 mmol/L
at 4 days of age. The mean lactate concentration for
from the cephalic vein of 60 normal adult dogs.18
the puppies from 10 to 28 days of age was 2.70
Elevated lactate concentrations can reflect increased
0.95 mmol/L. Lactate concentrations of the puppies were
production, as occurs in hypoperfused states, or de-
significantly higher on days 4, 10, 16, and 28 of age
creased elimination, as occurs in severe liver dis-
compared with those of healthy adults (Table 1). There
ease.19,20 Other sources of elevated blood lactate
was no difference between lactate concentrations of
include alkalosis (due to stimulation of glycolysis), thi-
puppies at 70 or 80 days of age and those of the adult
amine deficiency (prevents pyruvate from entering the
dogs.
mitochondria), and liver failure (the liver is responsi-
The ANOVA showed no evidence of an effect of the 3
ble for clearance of the majority of lactate from the
independent factors, birth method, diet, or gender on
blood).19,20 Resolution of lactic acidosis, however,
lactate concentrations in the puppies.
generally reflects an improvement in cell function re-
The reference range for lactate concentration for pup-
gardless of the initial cause of the elevated lactate
pies at 4 days of age was 1.07–6.59 mmol/L. The 95% CI
concentration and can, therefore, be a valuable prog-
of the lower value was [0.304, 1.842] and the 95% CI of
nostic tool to practitioners. Another cause of increased
the higher value was [5.817, 7.356]. The reference range
lactate production is skeletal muscle lactate which
for lactate concentrations for puppies from 10 to 28
can be increased during struggling, tremoring, or
days of age was 0.80–4.60 mmol/L. The 95% CI of the
seizures.21
lower value was [0.522, 1.082] and the 95% CI of the
Lactate concentrations have been used as indicators
higher value was [4.325, 4.885].
of decreased perfusion and as predictors of the devel-
opment of multiple organ failure in humans.13,16 Lactate
concentrations are also used as prognostic indicators in
critically ill humans and animals.22–25 Lactate has been
Discussion reported in veterinary medicine as a predictor of gastric
In these healthy puppies, venous lactate concentrations necrosis in dogs with gastric dilatation volvulus.26 In
were significantly higher than those of adult dogs for human patients with septic shock, serial determinations
the first 28 days of life. The reference range for the of lactate concentration appear to be good predictors of
lactate concentration of the puppies at 4 days of age the development of multiple organ failure and are used
(1.07–6.59 mmol/L) was higher than the reference range to guide the efficacy of treatment strategies.9 The du-
for the lactate concentration of the puppies from 10 to ration of lactic acidosis appears to be a more accurate
28 days (0.80–4.60 mmol/L). By 70 days of age, lactate predictor than the initial lactate concentration in hu-
concentrations were statistically indistinguishable from mans.27 Plasma lactate concentrations have been re-
those of the adult dogs. Lactate concentrations in the ported as predictors of death in human neonates
requiring extracorporeal membrane oxygenation.28
Lactate concentrations are higher in foals at birth
(2.38 1.03) than at 24 (1.24 0.33) and 48 hours
Table 1: Confidence intervals and t-tests results for comparison
(1.08 0.27) of age.d In a study on baboon newborns,
of puppy with adult lactate values
mean lactate was 2.33 0.26 (SE) 4–6 hours after birth
Mean Std. 95% CI on and decreased to 1.93 0.20 at 6 weeks of age.29 Cer-
Age (days) n (mmol/L) dev difference p-value ebral uptake of lactate was noted at birth but not at 6 and
12 weeks of age in this study.29 In a study of newborn
4 37 3.83 1.38 3.37–4.29 0.0000
10 52 2.57 0.78 2.35–2.79 0.0001 infants, lactate was 2–3 times higher (2.9 0.2 mmol/L)
16 41 3.18 1.05 2.85–3.51 0.0000 in 24 term newborns than it was in those beyond the
28 42 2.56 1.17 2.20–2.93 0.0018 neonatal period, and was even higher in the small for
70 38 1.64 0.69 1.41–1.87 0.4184 gestational age pre-term newborns (4.5 1.2 mmol/L).30
80 37 1.79 0.71 1.55–2.02 0.9580
There are several possible reasons for the higher lac-
Adult 30 1.80 0.84 1.48–2.11
tate concentration in neonates compared with adult
n, number of puppies sampled at that day of age and CI, confidence dogs. In the newborn, the blood brain barrier is perme-
interval. able to lactic acid, which is available to the brain in
& Veterinary Emergency and Critical Care Society 2005 19M.A. McMichael et al.
amounts exceeding that of other metabolites, including shock are not fully functional in neonates.37 Mean ar-
glucose.30,31 In addition, the capacity for hepatic glu- terial blood pressure is lower in puppies (i.e. averages
coneogenesis is quite limited at birth.30 Some have spec- 49 mmHg at 8 weeks of age) and CVP is higher at
ulated that lactate can act as a cerebral metabolic fuel in 4 weeks of age (8 cm H2O).4 Due to normal physiologic
the neonatal period, serving as an alternative fuel during variation and small size, measurement of perfusion can
periods of hypoglycemia.29,32 Studies of newborn ani- be especially difficult in this age group. Lactate may,
mals show that lactate readily enters the brain and therefore, be an ideal marker of perfusion in this clinical
cerebral spinal fluid in the early neonatal period.31 setting. Using these reference ranges for puppies may
Hellmann et al. showed that brain/blood lactate ratios allow clinicians to assess effects of fluid therapy on
declined by 83% during hypoglycemia in neonatal dogs, perfusion in this age group.
indicating that the lactate was being actively consumed Limitations of this study include an absence of lactate
by the brain during the period of hypoglycemia.32 It is measurements between 28 and 70 days of age. Further
possible that lactate is higher during this time period as investigation of lactate concentrations in dogs during
a prophylactic protective mechanism in case the neonate this time period would make it possible to model the
undergoes hypoglycemia. Stohrer et al. suggest that the decline of lactate levels over time. This information
postnatal rise in lactate concentration is secondary to might help to pinpoint the age at which lactate con-
ischemia or reperfusion injury during birth.e centrations normalize. Lactate concentrations in dogs
Lactate concentrations have been shown to vary ac- should be investigated further, particularly during this
cording to sample site in a study of 60 healthy dogs. In time period. Other studies are needed to evaluate lac-
this study, mean lactate concentration was highest when tate concentrations in sick neonatal dogs.
sampled from the cephalic vein (1.57 0.47 mmol/L) In these neonatal dogs, lactate concentration was sig-
followed by the femoral artery (1.43 0.52 mmol/L) nificantly higher than adult values when measured be-
and the jugular vein (1.25 0.49 mmol/L).18 All of the fore 28 days of age. Adult reference ranges for lactate
samples from the puppies in this study were taken from should not be used for lactate concentrations from neo-
the jugular vein so sample site variation should not be natal dogs younger than 28 days of age.
affected.
Struggling during restraint can also increase lactate
concentrations and, although struggling was minimal Acknowledgements
in these puppies, it may have contributed to the ele-
vated lactate concentrations in these puppies.21 The authors thank Dr. John E. Bauer for providing
blood samples obtained from neonatal dogs.
One human study focused on removal of lactate dur-
ing periods of lactic acidosis via hemofiltration or ad-
ministration of dichloroacetate (i.e. stimulates pyruvate
dehydrogenase, thereby increasing oxidation of lactate), Footnotes
but no difference in outcome had been shown.33 The a
Bauer JE, Heinemann KM, Bigley KE, et al. Maternal diet alpha-linolenic
acid during gestation and lactation does not increase canine milk
reason for the elevated lactate (i.e. decreased perfusion) docosahexaenoic acid. J Nutr (in press).
seems to be the determining factor as the elevated lac- b
Nova Stat Profile M, Nova Biomedical, Waltham, MA.
c
tate itself may not be harmful, but may just be a marker Stata Corporation, College Station, TX.
d
Gary Magdesian K. Blood lactate levels in neonatal foals: normal values
of decreased perfusion. and temporal effects in the post-partum period, in Proceedings of the
There are many clinical scenarios requiring fluid re- 9th International Veterinary Emergency Critical Care Symposium. 2003,
p. 782.
suscitation to neonatal puppies (e.g. trauma, shock, e
Stohrer M, Lutz S, Stangassinger M. Antioxidant status of newborn and
etc.). Because it is especially difficult to assess perfusion young animals. Vitamine und Zusatzstoffe in der Ernahrung von
Mensch und Tier. 8. Symposium, 26 and 27. September 2001. Jena/
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