• Open Access

Serial Measurement of Lactate Concentration in Horses with Acute Colitis

Authors

  • S. Hashimoto-Hill,

    1. William R. Pritchard Veterinary Medical Teaching Hospital, School of Veterinary Medicine, University of California, Davis, CA
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  • K.G. Magdesian,

    Corresponding author
    1. Department of Medicine and Epidemiology, School of Veterinary Medicine, University of California, Davis, CA
    • William R. Pritchard Veterinary Medical Teaching Hospital, School of Veterinary Medicine, University of California, Davis, CA
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  • P.H. Kass

    1. Department of Medicine and Epidemiology, School of Veterinary Medicine, University of California, Davis, CA
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  • The study was completed at the University of California, Davis.
  • The results of this study were presented in abstract form at the 2010 American College of Veterinary Internal Medicine Forum, Anaheim, CA.

Corresponding author: K.G. Magdesian, 2180 Tupper Hall, University of California, Davis, Davis, CA 95616; e-mail: kgmagdesian@vmth.ucdavis.edu.

Abstract

Background

Serial measurement of lactate concentration is utilized for therapeutic and prognostic purposes in human critical care. The prognostic value of serial lactate measurement in equine acute colitis warrants investigation.

Hypothesis

Serial lactate concentrations are predictive of outcome in horses with colitis.

Animals

A total of 101 horses with colitis.

Methods

Retrospective study. Plasma l-lactate concentrations were measured at admission and at 4–8 and 24 hours after admission. Associations between admission, early (4–8 hours) and late (24 hours) lactate concentrations, and survival status were determined. The percent reduction in lactate concentration between admission and the early time point, and between admission and the late time point, was calculated. Using a cutoff value, associations between percent reduction in lactate and survival status and associations between percent reduction in lactate and clinical and clinicopathologic data were determined.

Results

There was no association between admission plasma lactate concentration and survival status (P = .26). The 4–8 and 24 hour after admission lactate concentrations were associated with survival status (P = .023, .013, respectively). Lactate cutoffs of ≤2.3 and ≤1.5 mmol/L had the maximum sensitivity and specificity for predicting survival at the 4–8 and 24 hour time points, respectively. When lactate reduction ≥30% at 4–8 hours and ≥50% at 24 hours after admission were used as the cutoffs, the percent reduction of lactate concentration was significantly associated with survival (P = .012 and .019, respectively).

Conclusion and Clinical Importance

The prognostic ability of serial measurement of blood lactate concentration warrants prospective study as a measure of therapeutic response in horses with colitis.

Abbreviations
ANOVA

analysis of variance

CBC

complete blood count

CI

confidence interval

CVP

central venous pressure

GGT

γ-glutamyl transpeptidase

HR

heart rate

LRS

lactated Ringer's solution

MAP

mean arterial pressure

OR

odds ratio

PCV

packed cell volume

RR

respiratory rate

SDH

sorbitol dehydrogenase

SD

standard deviation

SIRS

systemic inflammatory response syndrome

T

rectal temperature

WBC

white blood cells

Acute colitis is a serious disease of horses with a reported case fatality rate of 19–30%.[1, 2] Although hypoperfusion and inflammation are known contributors to the pathophysiology of colitis,[3] studies evaluating biomarkers of tissue perfusion in affected horses are scarce.[4-6] Measurement of blood lactate concentration remains an important marker of systemic hypoperfusion and tissue hypoxia in critically ill patients. It is prognostic in critically ill human patients,[7-10] adult horses with colic and other emergency conditions,[11, 12] and critically ill neonatal foals.[13-16] Reduction of lactate concentration from admission values is a better prognostic indicator than a single lactate measurement in humans with sepsis and after cardiac arrest.[17-19] The percent change in lactate concentration from baseline at admission predicts survival, whereas admission lactate may not.[20, 21] A study of a small number of horses suggested an association between the change in lactate concentration during the study period and survival in a subset of horses with colitis; however, the small number of animals with colitis precluded statistic analysis.[11] There is a need for studies investigating an association between serial lactate measurement and outcome in horses with acute colitis.

The purpose of this study was to examine the association between serial measurements of lactate concentration during the first 24 hours of hospitalization with outcome to discharge in horses with acute colitis. We hypothesized that serial lactate measurement would allow better prediction of survival than admission lactate concentration, and that the magnitude of lactate reduction is prognostic in this population of horses. In addition, we investigated clinical and clinicopathologic factors that may predict persistent hyperlactatemia in these horses.

Materials and Methods

The medical records of horses admitted for acute colitis to the William R. Pritchard Veterinary Medical Teaching Hospital of the University of California Davis Large Animal Isolation facility between January 1, 2003 and May 31, 2009 were reviewed. The cases were included based on the following criteria: >1 year of age, presence of diarrhea looser than cow pie consistency, duration of diarrhea <48 h, and having plasma lactate concentrations measured at admission and at 1 or 2 additional time points (4–8 hours [“early lactate concentration”] after admission, 24 hours [“late lactate concentration”] after admission, or both). Horses euthanized for financial considerations were excluded.

Clinical data used in statistical analysis included age, breed, sex, discharge status (survival versus nonsurvival), admission vital signs (rectal temperature [T], heart rate [HR], and respiratory rate [RR]), and volume and type of crystalloid fluids administered parenterally. Results of admission complete blood count (CBC); jugular venous blood gas analysis including pH, PO2, PCO2, HCO3, and BE; plasma lactate, glucose, and electrolyte concentrations; and plasma chemistry analysis including creatinine and total bilirubin concentrations and SDH and GGT activities, were also collected. CBC (Advia 1201), plasma biochemistry analysis (Hitachi 717,2), venous blood gas, plasma glucose, and lactate analysis (ABL 7053) were performed on automated analyzers. “Lactate” refers to “l-lactate” in this study as the ABL analyzer is l-lactate specific.[22, 23] The lower limit of detection for lactate by this analyzer is 0.5 mmol/L. Differential WBC counts were performed manually. The blood samples for lactate and blood gas measurements were collected anaerobically into a heparinized syringe.

The presence of systemic inflammatory response syndrome (SIRS) was based on meeting ≥2 of the following: (1) hypo- or hyperthermia (T < 36.7°C [98°F] or >38.6°C [101.5°F]), (2) leukopenia or leukocytosis (<5000/μL or >14,500/μL) or >10% band neutrophils, (3) tachycardia (HR >50 beats/min), and (4) tachypnea (RR >25 breaths/min).

Lactate reduction was calculated as the relative difference of admission lactate and lactate at time “χ” using the following formula:[8, 19, 21]

% Lactate reduction = (Lactateadmission − Lactatehourχ) × 100/Lactateadmission

A positive value for % lactate reduction indicates a decrease in lactate concentration relative to admission, and a negative% indicates an increase in lactate concentration at the subsequent time point when compared with the admission value. Two time points were used for time χ in this study: 4–8 hours (“early”) and 24 hours (“late”) after admission.

Statistical Analysis

Survival was defined as discharge from the hospital. Lactate concentrations at 3 time points (admission, 4–8 hours, and 24 hours) were compared between survivors and nonsurvivors, and between cases with and without SIRS, by repeated-measures two-way analysis of variance.

To determine the relationship between reduction in plasma lactate concentration to within reference ranges and survival, cases were also divided into horses that obtained a “normal” lactate and those that did not at the same time points after admission. As a result of the various reference ranges reported for horses, two upper limits were studied (1 and 2 mmol/L).[24, 25] Proportions of survivors were compared by Fisher's exact test with calculation of odds ratios (OR) and 95% CI.

Unconditional exact logistic regression was used to measure the associations between admission, “early” (4–8 hours) and “late” (24 hour) lactate values, fluid type administered (lactated Ringer's solution [LRS] versus nonlactate containing fluids), clinical variables, and results from serum chemistries and CBC on survival status to discharge. Linearity in the log odds was verified for untransformed continuous main effects in the model. To test whether the effects of lactate measurements were modified by fluid type (LRS versus nonlactate containing), interactions by fluid type were evaluated by likelihood ratio tests; P-values <.05 were considered statistically significant. Results are presented as OR and 95% CI. Lactate values with the maximum sum of sensitivity and specificity when using plasma lactate concentration (“early” and “late”) to predict survival status were calculated.

Sensitivity and specificity of various cutoffs (−50, −40, −30, −20, −10, 0, 10, 20, 30, 40, and 50%) for the percent reduction of lactate in predicting survival were calculated. Percent reduction cutoffs with the maximum sum of sensitivity and specificity for predicting survival to discharge were determined for the 2 time points (4–8 hours and 24 hours after admission) as previously reported.[19]

The horses were divided into 2 groups: (1) those with a % reduction of lactate ≥ the cutoff value, for each of the time points; and (2) those which failed to achieve such a reduction at the time points. The horses that had both initial and repeated lactate concentrations ≤2.0 mmol/L were grouped with the horses that successfully reduced lactate regardless of their relative lactate difference value. Survival to discharge between the horses that were able to reduce lactate and those that were unable to do so (at each time point) was compared using Fisher's exact test, with calculation of OR and 95% CI.

Clinical and clinicopathologic variables were compared between horses that were able to reduce lactate and those unable to (for both “early” and “late” time points), and between survivors and nonsurvivors. Data were tested for normality by the Kolmogorov–Smirnov test. Data that were normally distributed were compared by an unpaired t-test; data that were not normally distributed were compared by a Mann Whitney U-test comparison.

Multivariate logistic regression was used to determine potential predictors of a lack of lactate reduction at or above the cutoff values. Similarly, risk factors for survival were determined using multivariate logistic regression including lactate reduction in the model. Percentage reduction of lactate ≥ the cutoff value was included as a categorical variable in the multivariate logistic regression to determine its independent contribution as a predictor of survival. Clinical and clinicopathologic variables that had a P value <.2 in the univariate analysis were included in the multivariate analysis. One model each was determined using lactate reduction at 4–8 hours after admission (Model 1) and lactate reduction at 24 hours after admission (Model 2) as a categorical variable, respectively.

Validation of Serial Lactate Concentration and % Lactate Reduction Cut-Off Values in a Novel Data Set.To validate the calculated optimal cutoff values for serial lactate concentrations and % reduction of lactate at the different time points obtained from the initial study population, another data set from the same hospital (with no overlap of animals) was obtained. This new data set consisted of 28 horses with the same inclusion criteria, but that were admitted to the hospital subsequent to the time period covering the first study (June 1, 2009 to February 28, 2011).

Results

A total of 101 horses met the inclusion criteria. The overall survival rate was 75.2% with 76 survivors. Of 25 nonsurvivors, 23 were euthanized and 2 died.

Lactate Concentration

Eighty-eight horses had lactate concentrations recorded at all 3 time points (admission, 4–8 hours after admission, and 24 hours after admission). Of those, 66 horses (75.0%) survived to discharge. Individual lactate concentrations were not significantly different between survivors and nonsurvivors at any of the time points (P = .20).

With logistic regression analysis evaluating for associations between lactate concentrations, fluid type (LRS versus nonlactate containing), and clinical and clinicopathologic variables with survival, only higher “early” lactate concentrations (P = .023; OR: 0.81; 95% CI: 0.67–0.97) and “late” lactate concentrations (P = .013, OR: 0.58; 95% CI: 0.36–0.90) and higher GGT activity (P = .035; OR: 0.73; 95% CI: 0.47–0.99 for every 10 IU/L increase in GGT) were significantly associated with lower survival to discharge. Admission lactate concentration was not associated with survival (P = .26). Higher HR (P = .056; OR: 0.98; 95% CI: 0.95–1.00) and older age (P = .058; OR: 0.94; 95% CI: 0.88–1.00) were not associated with reduced survival. Only increasing “early” and “late” lactate concentrations retained statistically significant associations with lower survival after multivariate analysis.

An “early” (4–8 hour) plasma lactate concentration of ≤2.3 mmol/L maximized sensitivity and specificity in predicting survival (sensitivity of 81.2% and specificity of 58.3%). A “late” (24 hour) plasma lactate concentration of ≤1.5 mmol/L was determined to have the maximum combination of sensitivity and specificity, with a sensitivity of 79.5% and a specificity of 43.5% for predicting survival. Fifty-seven horses (64.8%) had SIRS, and 29 (33.0%) did not have SIRS as defined in this study. SIRS status could not be assessed in 2 horses due to lack of data. When lactate concentrations were compared between horses with SIRS and horses without SIRS, horses with SIRS had significantly higher lactate concentrations at every time point (P = .015) (Fig 1).

Figure 1.

Plasma lactate concentrations in horses with (■) and without (▲) systemic inflammatory response syndrome. The results are displayed as mean ± SD. *= .021; +P = .018; ‡P < .001.

Lactate Reduction

Data from 93 horses were used for analyses at the “early” time point (4–8 hours after admission). A % lactate reduction cutoff of ≥30% of the admission value had the maximum combination of sensitivity and specificity for prediction of survival. Seventy cases (75.3%) were categorized as able to reduce lactate. The remainder of cases (n = 23; 24.7%) had a % reduction below this cutoff value, and comprised the group that was unable to reduce lactate by this time point. A reduction in lactate concentration of ≥30% was significantly associated with survival. Survival rates of horses that had a reduction in plasma lactate concentration and those that did not by the early time point were 81% and 52%, respectively (P = .012; OR = 4.020; 95% CI = 1.46–11.10).

At the early time point, 49 of 69 survivors and 10 of 24 nonsurvivors had lactate concentration ≤2.0 mmol/L. Twenty-three of 69 survivors and 7 of 24 nonsurvivors had lactate concentration ≤1.0 mmol/L. A lactate concentration ≤2 mmol/L at 4–8 hours of hospitalization was significantly associated with survival (P = .014; OR = 3.43; 95% CI = 1.31–9.00), whereas ≤1 mmol/L was not (P = .80).

Data from 96 horses were used for analyses of the parameters at the “late” time point (24 hours after admission). A lactate reduction cutoff of ≥50% of the admission value had the maximum combination of sensitivity and specificity for prediction of survival at this time point. Seventy-six cases (79.2%) had a reduction in plasma lactate concentration by this time point. The remaining 20 cases (20.8%) did not a have a lactate reduction ≥50%. A reduction in lactate concentration ≥50% was significantly associated with survival. Survival rates of horses that had a reduction in plasma lactate and those that did not by the late time point were 81% and 55%, respectively (P = .019; OR = 3.62; 95% CI = 1.26–10.46).

At the ‘late’ time point, 66 of 73 survivors and 18 of 23 nonsurvivors had lactate concentration ≤2.0 mmol/L. Twenty-eight of 73 survivors and 8 of 23 nonsurvivors had lactate concentration ≤1.0 mmol/L. A lactate concentration ≤1 or ≤2 mmol/L at 24 hours after admission was not significantly associated with survival (P = .81 and .15, respectively).

The clinical and clinicopathologic variables that differed significantly between horses that had a reduction in lactate over time and those that did not at each time point (4–8 hours or 24 hours after admission) are summarized in Table 1. The clinical and clinicopathologic variables that differed significantly between survivors and nonsurvivors included PCV (survivors: 40.7 ± 9.7% versus nonsurvivors: 45.5 ± 8.4%; P = .045) and HR (survivors: 57.0 ± 15.7 bpm versus nonsurvivors: 64.9 ± 21.7; P = .050).

Table 1. The clinical and clinicopathologic variables in horses that did and did not have a 30 or 50% reduction in lactate at each time point (4–8 hours or 24 hours after admission), respectively.
Admission VariableHorses with Lactate Reduction ≥30% by 4–8 hoursHorses That Did Not Reduce Lactate by 4–8 hoursPHorses with Lactate Reduction ≥50% by 24 hoursHorses That Did Not Reduce Lactate by 24 hoursP
  1. HR, heart rate; PCV, packed cell volume; SD, standard deviation.

  2. a

    P < .05.

HR (bpm, mean ± SD or median with interquartile range)56.3 ± 16.270.3 ± 18.3<.001a52.0 (44.0, 68.0)60.0 (54.3, 77.0).024a
Creatinine (mg/dL, median with interquartile range)1.5 (1.1, 2.1)1.8 (1.4, 3.4).0541.5 (1.1, 2.1)1.4 (1.2, 3.4).58
Temperature (°F, mean ± SD)100.8 ± 1.4101.3 ± 1.7.197100.7 ± 1.4101.4 ± 1.2.043a
PCV (%, mean ± SD)42.5 ± 10.241.7 ± 9.4.76840.6 ± 9.746.5 ± 8.4.022a
Band cells (/μL, median with interquartile range)250 (0, 810)620 (91, 1141).260250.5 (0, 685.3)786.5 (479.5, 1372.8).007a
PvO2 (mmHg, mean ± SD); peripheral venous35.1 ± 10.436.5 ± 8.7.5935.0 ± 6.637.4 ± 10.6.34

Multivariate regression analysis showed that increasing HR was the only clinical or clinicopathologic parameter associated with not achieving lactate reduction ≥30% at 4–8 hours after admission (OR: 1.57/10 bpm increase in HR; 95% CI: 1.17–2.10; P = .002). Higher rectal temperature (OR: 1.86/1°F increase in temperature; 95% CI: 1.11–3.11; P = .018), higher PCV (OR: 2.21/10% increase; CI: 1.15–4.22; P = .017), and a band neutrophil count of >300/μL (OR: 5.08; 95% CI: 1.22–21.09; P = .003) were predictors of not achieving lactate reduction ≥50% at 24 h.

Multivariate regression analysis using % lactate reduction and clinical and clinicopathologic data showed that a relative lactate reduction ≥ the cutoff value at either time point (4–8 hours or 24 hours) was the only factor predictive of survival, each in an independent model. In the 1st model, ≥30% lactate reduction at 4–8 hours after admission was the only variable that retained a significant association with survival (OR: 3.35; 95% CI: 1.06–10.65; P = .040). PCV, which was significantly different between survivors and nonsurvivors in the univariate analysis, did not reach statistical significance (OR: 1.70/10% increase in PCV; 95% CI: 0.99–2.90; P = .053). In the 2nd model, ≥50% lactate reduction at 24 hours after admission was the only variable retaining a significant association with survival (OR 3.62; 95% 1.26–10.40; P = .017).

Application of Serial Lactate Concentration Cutoffs and % Reduction of Lactate Concentrations to New Data Set

The new population consisted of 28 horses with acute colitis with a survival rate of 64.3%. The 4–8 hour lactate concentration cutoff of ≤2.3 mmol/L had a sensitivity of 100.0% (95% CI: 71.5–100.00%), and a specificity of 80.0% (95% CI: 28.36–99.49%) in predicting survival to discharge. The 24-hour lactate concentration cutoff of ≤1.5 mmol/L had a sensitivity of 76.5% (95% CI: 50.10–93.19%) and a specificity of 80.0% (95% CI: 44.40–97.50%). When applying the ≥30% cutoff for “early” lactate reduction to the new population, the sensitivity was 90.9% (95% CI: 58.72–99.77%) and the specificity was 50.0% (95% CI: 18.71–81.29%). The ≥50% cutoff for “late” lactate reduction had a sensitivity of 82.4% (95% CI: 56.57–96.20%) and a specificity of 40.0% (95% CI: 5.27–85.34%).

Volume and Types of IV Fluids

The volume of crystalloid fluids administered was not significantly different between horses that had a reduction in plasma lactate concentration and those that did not (P = .60 “early”, P = .14 “late”). The majority of horses received commercial fluids containing acetate (Normosol R or PlasmaLyte A). Thirty-eight horses received lactated Ringer's solution (LRS) alone or in combination with fluids containing acetate, whereas 63 did not receive LRS. There were no interactions or confounding effects between lactate concentrations and fluid type administered, including LRS that contains l-lactate (P = .82 for “early” time point; P = .75 “late”). Similarly, there were no interactions or confounding effects found between % lactate reduction and fluid type administered (P = .23, “early” and P = .53, “late”). There was no significant interaction or confounding effect between fluid type and survival (P = 1.00 at “early” time point, P = .69 at “late” time point).

Discussion

In this study, lactate concentrations at both 4–8 and 24 hours after admission and the % reduction of lactate from baseline were the only clinical or clinicopathologic parameter examined that independently predicted survival to discharge in this group of horses with colitis. In agreement with recent human studies, serial measurement of lactate concentrations was superior to admission lactate concentration alone in predicting outcome in these horses.[18, 20, 21] In this study, horses that failed to achieve lactate reduction at or above cutoff value of 30% in the early phase of hospitalization had higher HRs than horses that were able to reduce lactate. It is reasonable to speculate that tachycardia and hyperlactatemia in the early hospitalization are largely due to hypovolemia. Lack of reduction in lactate concentration in these horses could be due to inadequate volume resuscitation.

Two of the SIRS criteria, body temperature and band neutrophil count, predicted an inability to reduce lactate ≥50% by 24 hours after admission. This finding, along with the fact that horses with SIRS had higher lactate concentrations when compared with those without SIRS, suggests a possible cause-and-effect relationship between inflammation and hyperlactatemia in acute colitis. Potential mechanisms include endothelial dysfunction, activation of the coagulation cascade, and vasodepression, all of which can lead to impaired microcirculation and tissue hypoxia.[26] Interestingly, temperature and band counts were significantly associated with persistent hyperlactatemia in the later time period, but not in the earlier period. This might suggest a possible influence of inflammation on persistent hyperlactatemia during the later phases of hospitalization after initial fluid resuscitation has been completed (assuming this was adequate), whereas hypovolemia might be more important in the period immediately after admission and prior to fluid therapy.

As a result of the retrospective nature of this study, it was not possible to determine whether a reduction in lactate concentration was used as a target for therapy by the attending clinician(s). A higher volume of crystalloids might have improved lactate reduction in some of the horses with persistent hyperlactatemia. Hyperlactatemia secondary to SIRS is perhaps more refractory to simple fluid resuscitation without the use of vasoactive agents or anti-inflammatory medications. The adoption of “goal-directed resuscitation” (quantitative resuscitation) for treatment of human patients with severe sepsis and septic shock has reduced death rates when compared with the therapy based on conventional hemodynamic assessment.[27] The resuscitation endpoints used in human patients with this method generally include CVP of 8–12 mmHg, MAP ≥65 mmHg, urine output ≥0.5 mL/kg/h, and central venous oxygen saturation (SCVO2) ≥70%.[27] A recent human study replaced SCVO2 with serial measurements of lactate using reduction of lactate ≥10% as a target in their goal-directed therapy within 6 hours of initial resuscitation.[28] Prospective studies are needed to evaluate whether lactate reduction as a goal of early therapy will affect outcomes in horses.

In performing logistic regression analysis between fluid type and lactate concentration, and between fluid type and death, there were no significant interactions or associations. A number of published human and dogs studies in both normal subjects and those with hemorrhagic shock have demonstrated that LRS does not have a significant impact on physiologic lactate concentrations, unless patients have lymphoma, or theoretically, hepatic failure.[29, 30]

The serial lactate and % reduction cutoffs found in the original dataset of this study demonstrated high sensitivity and moderate specificity in a new population of horses admitted for acute colitis. This was despite the fact that the new dataset consisted of only 28 horses. The two with highest sensitivity included the 4–8 hours after admission lactate concentration of ≤2.3 mmol/L and the % lactate reduction at 4–8 hours after admission of ≥30%. The highest specificities were for the lactate concentration cutoffs of ≤2.3 and ≤1.5 mmol/L at 4–8 and 24 hours, respectively. Although these cutoffs need to be validated in prospective studies at other institutions, these results suggest that reduction of lactate in the period soon after admission can accurately predict survival. Interestingly, these cutoffs are close to or within what is considered the normal range for healthy horses. They are also consistent with our finding that horses that reached a lactate concentration ≤2 mmol/L in the “early” period had an increased OR for survival.

As plasma lactate has demonstrated prognostic value in equine neonates at various institutions,[13-16] the information provided in this study is potentially relevant to those who treat colitis cases. In fact, a recent study performed at a different hospital suggested a prognostic value of serial lactate measurements in horses with acute colitis, although the number of cases was too few for statistical evaluations.[11] The present study builds upon those preliminary findings.

In conclusion, the present study showed prognostic value of serial lactate measurements and calculation of % reduction of lactate after initial fluid therapy and during the first 24 hours of hospitalization in horses with acute colitis. Lactate reduction as a target of therapy, especially during early fluid resuscitation, warrants prospective studies.

Acknowledgments

The authors acknowledge the staff at the William R. Pritchard Veterinary Medical Teaching Hospital for their assistance in data collection.

This study was not supported by a grant or any other monetary aid.

Footnotes

  1. 1

    Seimens Advia 120; Seimens Corporation, Washington, DC

  2. 2

    Roche/Hitachi; Roche Diagnostics, Indianapolis, IN

  3. 3

    Radiometer ABL 705; Radiometer Medical ApS, Denmark

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