Blood glucose concentrations in critically ill neonatal foals

Reasons for Performing Study: Critical illness is associated with hyperglycemia in humans, and a greater degree and duration of hyperglycemia is associated with nonsurvival. Hypoglycemia is also seen in critically ill humans, and is associated with nonsurvival. This might also be true in the critically ill foal.
Objectives: To investigate the association of blood glucose concentrations with survival, sepsis, and the systemic inflammatory response syndrome (SIRS).
Methods: Blood glucose concentrations at admission (515 foals) and 24 hours (159 foals), 36 hours (95), 48 hours (82), and 60 hours (45) after admission were analyzed. Logistic regression analyses were performed to investigate the association of glucose concentrations with survival, sepsis, a positive blood culture, or SIRS.
Results: 29.1% of foals had blood glucose concentrations within the reference range (76–131 mg/dL) at admission, 36.5% were hyperglycemic, and 34.4% were hypoglycaemic. Foals that did not survive to hospital discharge had lower mean blood glucose concentrations at admission, as well as higher maximum and lower minimum blood glucose concentrations in the 1st 24 hours of hospitalization, and higher blood glucose at 24 and 36 hours. Foals with blood glucose concentrations <2.8 mmol/L (50 mg/dL) or >10 mmol/L (180 mg/dL) at admission were less likely to survive. Hypoglycemia at admission was associated with sepsis, a positive blood culture, and SIRS.
Conclusions and Potential Relevance: Derangements of blood glucose concentration are common in critically ill foals. Controlling blood glucose concentrations may therefore be beneficial in the critically ill neonatal foal, and this warrants further investigation.     

Arterial lactate concentration, hospital survival, sepsis and SIRS in critically ill neonatal foals

REASONS FOR PERFORMING STUDY: Blood lactate concentration has been shown to be a useful clinical indicator in human patients, but has not been formally investigated in critically ill foals. OBJECTIVE: To investigate the association of blood lactate with hospital survival, markers of cardiovascular status, metabolic acid base status, sepsis and systemic inflammatory response syndrome (SIRS). METHODS: A database containing clinical, haematological, plasma biochemical and hospital outcome data on neonatal foals referred to an intensive care unit in 2000-2001 was analysed. Seventy-two foals for which arterial lactate was measured at admission were included in the study. RESULTS: Sixty-one foals had an admission lactate concentration > 2.5 mmol/l. Admission lactate was statistically associated with hospital survival, mean arterial pressure, blood creatinine concentration, bacteraemia, anion gap, lactate concentration at 18-36 h after admission and evidence of SIRS, but not with packed cell volume or heart rate. Lactate at 18-36 h was also associated with survival and evidence of SIRS. Anion gap, base excess, base excess due to unidentified anions (BEua), simplified strong ion gap or bicarbonate correctly classified foals for presence of hyperlactaemia (> 5 mmol/l) in < or = 80% of animals. CONCLUSIONS: Admission blood lactate gives important prognostic information. Lactate should be measured rather than assumed from the anion gap, base excess, BEua, simplified strong ion gap or bicarbonate. POTENTIAL RELEVANCE: Blood lactate concentrations at admission are clinically relevant in neonatal foals and warrant further investigation. This should include the clinical value of measuring changes in lactate in response to treatment.     

Use of pressor therapy in 34 hypotensive critically ill neonatal foals

Background Arginine vasopressin (AVP) is used in human medicine in the management of vasodilatory shock and cardiac arrest, but it is not widely used in equine neonatal intensive care because of concerns about potential side effects and suboptimal efficacy. This retrospective study reports the clinical use of AVP and norepinephrine (NE) in foals with refractory hypotension. Objectives To report the cardiovascular responses and fluid balance in critically ill, hypotensive foals receiving either NE or AVP. Design The medical records of neonatal foals (<7 days of age) from 2000 to 2007 admitted to the Marion duPont Scott Equine Medical Center were reviewed. Results The use of exogenous AVP infusion was associated with a significant increase in mean arterial pressure (MAP) and urinary output, and a significant decrease in heart rate. NE administration was also associated with a significant increase in MAP. Conclusions The findings of this first report of the clinical treatment of foals with refractory hypotension support the use of AVP and NE.     

Intragastric pH in critically ill neonatal foals and the effect of ranitidine

OBJECTIVE: To characterize intragastric pH profiles in critically ill foals and determine whether administration of ranitidine altered pH profiles. DESIGN: Prospective observational study. ANIMALS: 23 hospitalized neonatal foals < or = 4 days of age. PROCEDURE: Intragastric pH was measured continuously for up to 24 hours by use of an indwelling electrode and continuous data recording system. In 21 foals, ranitidine was administered IV. RESULTS: 10 foals had predominantly or exclusively alkaline profiles, 10 had profiles typical of those reported for healthy foals, with periods of acidity (hourly mean pH < 5.0 at least once), and 3 had atypical profiles with periods of acidity. All 10 foals that had intragastric pH profiles typical of healthy foals survived, whereas only 2 foals with alkaline profiles survived, and none of the foals with atypical profiles survived. The effects of ranitidine administration could not be assessed in 13 foals because of a high baseline intragastric pH. In 7 of the remaining 9, ranitidine administration resulted in an alkalinizing response, but this response was often of blunted duration. Ranitidine administration did not appear to alter the intragastric pH profile in the remaining 2 foals. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested that hospitalized critically ill foals often have intragastric pH profiles different from those reported for healthy foals and may respond differently to ranitidine administration than do healthy foals. Many critically ill foals have continuously alkaline intragastric pH profiles, questioning the need for prophylactic administration of ranitidine in all critically ill foals.     

Pharmacokinetics of a high dose of amikacin administered at extended intervals to neonatal foals

OBJECTIVE: To determine disposition kinetics of amikacin in neonatal foals administered high doses at extended intervals. ANIMALS: 7 neonatal foals. PROCEDURE: Amikacin was administered (21 mg/kg, i.v., q 24 h) for 10 days. On days 1, 5, and 10, serial plasma samples were obtained for measurement of amikacin concentrations and determination of pharmacokinetics. RESULTS: Mean +/- SD peak plasma concentrations of amikacin extrapolated to time 0 were 103.1 +/- 23.4, 102.9 +/- 9.8, and 120.7 +/- 17.9 microg/mL on days 1, 5, and 10, respectively. Plasma concentrations at 1 hour were 37.5 +/- 6.7, 32.9 +/- 2.6, and 30.6 +/- 3.5 microg/mL; area under the curve (AUC) was 293.0 +/- 61.0, 202.3 +/- 40.4, and 180.9 +/- 31.2 (microg x h)/mL; elimination half-life (t(1/2)beta) was 5.33, 4.08, and 3.85 hours; and clearance was 1.3 +/- 0.3, 1.8 +/- 0.4, and 2.0 +/- 0.3 mL/(min x kg), respectively. There were significant increases in clearance and decreases in t(1/2)beta, AUC, mean residence time, and plasma concentrations of amikacin at 1, 4, 8, 12, and 24 hours as foals matured. CONCLUSIONS AND CLINICAL RELEVANCE: Once-daily administration of high doses of amikacin to foals resulted in high peak plasma amikacin concentrations, high 1-hour peak concentrations, and large values for AUC, consistent with potentially enhanced bactericidal activity. Age-related findings suggested maturation of renal function during the first 10 days after birth, reflected in enhanced clearance of amikacin. High-dose, extended-interval dosing regimens of amikacin in neonatal foals appear rational, although clinical use remains to be confirmed.     

Blood culture isolates and antimicrobial sensitivities from 427 critically ill neonatal foals

OBJECTIVE: To assist correct decision-making about antimicrobial treatment of equine neonates with septicaemia. DESIGN: Retrospective study of microbial blood culture results obtained from foals less than 7 days of age. METHODS: Microbial blood culture results from foals less than 7 days of age admitted to an intensive care unit between July 1999 and December 2004 were reviewed. Antimicrobial sensitivity was assessed by the Kirby Bauer disc diffusion method. Antimicrobials were defined as an effective first-line choice antimicrobial if greater than 70% of isolates were susceptible. Multiple drug resistance (MDR) was defined as resistance to at least three antimicrobials in different chemical classes or with different mechanisms of resistance. RESULTS: Of the 427 Thoroughbred foals included in the study, a positive blood culture was obtained in 110 foals and 124 microorganisms were isolated. Gram-positive isolates, predominantly Streptococcus/Enterococcus spp, were obtained in 41% of foals. Gram-negative isolates were predominantly of the Enterobacteriaceae family, in particular Escherichia coli. The overall antimicrobial sensitivity of the isolates was low. The Gram-positive organisms had unpredictable sensitivity patterns. MDR was recorded in 32% of isolates. In total, 81% of foals were discharged from hospital and 74.5% of foals with a positive blood culture were discharged. CONCLUSION: With the increasing prevalence of Gram-positive microorganisms and their unpredictable sensitivity patterns, blood cultures remain important in the diagnosis and treatment of equine neonatal septicaemia.     

Relation between pharmacokinetics of amikacin sulfate and sepsis score in clinically normal and hospitalized neonatal foals.

Pharmacokinetic values after IV administration of amikacin sulfate were determined for clinically normal and hospitalized foals during the first week of life. The relations between drug disposition and sepsis score and serum creatinine concentration also were studied. In clinically normal foals, differences in sepsis score, serum creatinine concentration, and pharmacokinetic variables of amikacin were not found between foals 1 to 3 and 4 to 7 days old. In hospitalized foals, sepsis score, serum creatinine concentration, area under the curve, area under the moment curve, and mean residence time were greater, and total clearance was decreased, compared with values in clinically normal foals. Sepsis score and serum creatinine concentration were inversely correlated to amikacin clearance and appeared to be useful indicators of altered drug disposition.     

Pharmacokinetics of amikacin in pony foals after a single intramuscular injection

Six healthy pony foals, from 2 to 11 days of age, were given a single IM injection of amikacin sulfate (250 mg/ml) at a dosage rate of 7 mg/kg of body weight. Serum amikacin concentrations were measured serially over a 24-hour period. The mean peak serum concentration was 14.7 micrograms/ml at 0.5 hour. The elimination rate constant for amikacin was 0.24/hour, the elimination half-life was 3.0 hours, and the apparent volume of distribution was 0.58 L/kg.     

Comparison of viscoelastic coagulation analysis and standard coagulation profiles in critically ill neonatal foals to outcome

Objective – To determine if changes in viscoelastic variables are associated with abnormalities observed in the standard coagulation profile and patient outcome in foals with suspected septicemia. Design – Prospective clinical trial during 2003 and 2004 foal season. Setting – Neonatal intensive care unit at a veterinary teaching hospital. Animals – Thirty critically ill foals <72‐hour‐old admitted sequentially meeting criteria for systemic inflammatory response associated with infection. Interventions – Hemostatic evaluation, using standard coagulation testing and viscoelastic analysis, was performed at admission, 24 hours following admission, and 48 hours following admission in critically ill foals. Standard coagulation tests included platelet count, prothrombin time, activated partial thromboplastin time, fibrinogen, fibrin(ogen) degradation products, and antithrombin. Data collected from viscoelastic analysis included time to initial clot formation (ACT), clot rate, and platelet function. Signalment, blood culture results, clinicopathologic data, and outcome were collected from medical records. Equality of populations test was used to determine associations between coagulation tests and blood culture status/outcome, as well as between viscoelastic parameters and coagulopathy, blood culture status, and outcome. Logistic regression was used to quantify associations. A significance level of P<0.05 was used. Measurements and Main Results – Foals with decreasing clot rate (CR) over the sample period were more likely to be euthanized or die (P=0.02). Foals with prolonged ACT (P=0.03), and decreased CR at admission (P=0.047), were more commonly coagulopathic. Identification of coagulopathy on admission (P=0.02), or persistence of hemostatic dysfunction 48 hours later (P=0.04), was associated with death. Conclusions – Viscoelastic coagulation evaluation could be used in a neonatal intensive care unit setting to further characterize coagulopathy, and identify foals at higher risk for poor outcome.     

Insulin, glucagon, and leptin in critically ill foals

Background: Endocrine dysregulation of hormones of energy metabolism is well documented in critically ill humans, but limited information exists in septic foals. The purpose of this study was to provide information on the hormonal response to energy metabolism in critically ill foals, focusing on insulin, glucagon, and leptin. Hypothesis: Concentrations of insulin, glucagon, leptin, and triglycerides will be higher, whereas glucose concentration will be lower in septic foals than in healthy and sick nonseptic foals. The magnitude of these differences will be associated with severity of disease and nonsurvival. Animals: Forty‐four septic, 62 sick nonseptic, and 19 healthy foals <7 days of age. Methods: In this prospective multicenter cross‐sectional study, blood samples were collected at admission. Foals with positive blood culture or sepsis score ≥12 were considered septic. Results: Septic foals had lower glucose and insulin and higher triglyceride and glucagon concentrations than did healthy foals. Glucagon concentrations were not different between septic foals that died (n = 14) or survived (n = 30). Higher insulin and lower leptin concentrations were associated with mortality. Quantitative insulin‐sensitivity check index was higher in septic foals. Conclusions and Clinical Importance: Energy metabolism and the endocrine response of related hormones in septic foals are characterized by hypoglycemia, hypertriglyceridemia, low insulin concentration, and high glucagon concentration. Leptin and insulin may have prognostic value for nonsurvival in septic foals. The hormonal response related to energy metabolism in critical illness differs between foals and humans.     

Pharmacokinetics and serum concentrations of cephapirin in neonatal foals

Six healthy foals, from 4 to 6 days of age, were given a single IM injection of sodium cephapirin (250 mg/ml) at a rate of 20 mg/kg of body weight. Serum concentrations of cephapirin were measured serially over an 8-hour period. The mean peak serum concentration was 21.2 micrograms/ml at 10 minutes. The overall elimination rate constant was 1.06/hr and the elimination half-life was 0.70 hour. The apparent volume of distribution at steady state was 1.06 L/kg and plasma clearance was 1,105 ml/hr/kg.     

Pharmacokinetics of gallium maltolate after intragastric administration in neonatal foals

OBJECTIVE: To determine the pharmacokinetics of gallium maltolate (GaM) after intragastric administration in healthy foals. ANIMALS: 6 healthy neonatal foals. PROCEDURES: Each foal received GaM (20 mg/kg) by intragastric administration. Blood samples were obtained before (time 0) and at 0.25, 0.5, 1, 2, 4, 8, 12, 24, 36, and 48 hours after GaM administration for determination of serum gallium concentrations by use of inductively coupled plasma mass spectroscopy. RESULTS: Mean +/- SD pharmacokinetic variables were as follows: peak serum gallium concentration, 1,079 +/- 311 ng/mL; time to peak serum concentration, 4.3 +/- 2.0 hours; area under the serum concentration versus time curve, 40,215 +/- 8,420 ng/mL/h; mean residence time, 39.5 +/- 17.2 hours; area under the moment curve, 1,636,554 +/- 931,458 ng([h](2)/mL); and terminal half-life, 26.6 +/- 11.6 hours. The mean serum concentration of gallium at 12 hours was 756 +/- 195 ng/mL. CONCLUSIONS AND CLINICAL RELEVANCE: Gallium maltolate administered via nasogastric tube at a dose of 20 mg/kg to neonatal foals resulted in gallium serum concentrations considered sufficient to suppress growth or kill Rhodococcus equi in macrophages and other infected tissues.     

Pharmacokinetics and pharmacodynamics of pantoprazole in clinically normal neonatal foals

REASONS FOR PERFORMING STUDY: Proton pump inhibitors (PPIs) are a mainstay of treatment for acid-related ulceration in man and horses. Currently, only an oral preparation of omeprazole is approved for use in horses in the USA. Intravenous administration of a PPI would provide a useful therapeutic alternative for those foals in which oral medication is not feasible. OBJECTIVE: To investigate the pharmacokinetics and pharmacodynamics of pantoprazole following i.v. or intragastric administration in healthy neonatal foals. METHODS: Seven healthy foals age 6-12 days at the start of the study were evaluated. Treatments included no drug administration, i.v. pantoprazole (1.5 mg/kg bwt) and intragastric pantoprazole (1.5 mg/kg bwt). Intragastric pH was recorded for 24 h after drug administration for pharmacodynamic evaluation. Plasma pantoprazole concentrations were measured using high-performance liquid chromatography. RESULTS: Plasma concentrations of pantoprazole were detectable at the 5 min sampling point following i.v. or intragastric administration. Bioavailability of intragastric-administered pantoprazole was 41%. Baseline mean hourly pH was 1.5-6.1. There was a statistically significant increase in mean hourly pH relative to untreated foals 2-24 h after i.v. or intragastric pantoprazole administration. CONCLUSIONS: Based on these data, i.v. or intragastric administration of pantoprazole results in a significant, prolonged increase in intragastric pH. POTENTIAL RELEVANCE: The i.v. formulation of pantoprazole may provide a clinically useful alternative means of acid suppression in foals unable to tolerate enteral administration of a PPI, such as those with pyloric outflow obstruction.     

Pharmacokinetics of once-daily amikacin in healthy foals and therapeutic drug monitoring in hospitalized equine neonates

The objectives of this study were to investigate the pharmacokinetics of once-daily amikacin in healthy neonates, to determine amikacin concentrations in hospitalized foals, and to determine the minimum inhibitory concentrations (MICs) of amikacin against gram-negative isolates from blood cultures in septic foals. Median half-life, clearance, and volume of distribution of amikacin in healthy 2- to 3-day-old foals after administration of an intravenous bolus of amikacin (25 mg/kg) were 5.07 hours (4.86-5.45 hours), 1.82 mL/min/kg (1.35-1.97 mL/min/kg), and 0.785 L/kg (0.638-0.862 L/kg), respectively. Statistically significant (P <.05) decreases in area under the curve (14% decrease), mean residence time (19% decrease), and C24h plasma amikacin concentrations (29% decrease) occurred between days 2-3 and 10-11. Plasma amikacin concentrations in healthy foals at 0.5 hours (C0.5h) were significantly higher (P = .02) than those of hospitalized foals. Sepsis, prematurity, and hypoxemia did not alter amikacin concentrations. The MIC at which 90% of all gram-negative isolates from equine neonatal blood cultures were inhibited by amikacin was 4 microg/mL, suggesting that amikacin C0.5h of 40 microg/mL should be targeted to achieve a maximum serum concentration to MIC ratio of 10:1. The proportion of foals with C0.5h 40 microg/mL was significantly higher (P < .0001) in hospitalized foals receiving a dose of amikacin at 25 mg/kg (22/24 or 92%) than in foals receiving a dose at 21 mg/kg (9/25 or 36%), whereas no difference was found in the proportion of foals with C24h concentrations > or = 3 microg/mL between the 2 groups. An initial dose at 25 mg/kg is recommended for once-daily amikacin in equine neonates.     

Serum lactoferrin and immunoglobulin G concentrations in healthy or ill neonatal foals and healthy adult horses

BACKGROUND: Lactoferrin is a colostral glycoprotein with antimicrobial properties. HYPOTHESES: (1) Serum lactoferrin and immunoglobulin G (IgG) concentrations are correlated and increase in healthy foals after ingestion of colostrum; (2) compared to healthy foals, ill foals will have lower lactoferrin concentrations that correlate with their IgG concentration, neutrophil count, the diagnosis of sepsis, and survival; and (3) plasma concentrations of lactoferrin will be less than serum concentrations. ANIMALS: Healthy foals (n = 16), mature horses (n = 10), and ill foals 1-4 days old (n = 111) that were examined for suspected sepsis were used for blood collection. Colostrum was obtained from 10 healthy mares unrelated to the foals. METHODS: Blood was obtained from the healthy foals at birth and 1-3 days of age and from the ill foals at admission. Serum IgG was quantified by single radial immunodiffusion (SRID). Lactoferrin concentrations in colostrum and blood were determined by an enzyme-linked immunosorbant assay. The sepsis score, blood culture results, neutrophil counts, and survival were obtained on ill foals. RESULTS: The mean colostral lactoferrin concentration was 21.7 microg/mL. Compared to values at birth, serum IgG (18+/-2 versus 2,921+/-245 mg/dL, SEM) and lactoferrin (249+/-39 versus 445+/-63 ng/mL, SEM) concentrations were significantly greater in healthy foals 1-3 days old. Serum lactoferrin concentration in 1-3-day-old healthy foals was not different from mature horses or ill foals. IgG and lactoferrin concentrations were significantly correlated only in healthy foals. Serum lactoferrin concentrations were significantly lower in ill neutropenic foals. The serum IgG concentration was significantly lower in ill foals as compared to healthy foals. Only serum IgG was significantly less in ill foals with a positive sepsis score and in nonsurvivors, Plasma lactoferrin concentrations were lower than serum concentrations, although values were significantly correlated. CLINICAL IMPORTANCE: Although both serum IgG and lactoferrin concentrations increase in healthy foals after ingestion of colostrum, only serum IgG is significantly correlated with the sepsis score and outcome.     

Tumor necrosis factor activity in serum from neonatal foals with presumed septicemia.

A study was performed to determine prevalence of tumor necrosis factor (TNF) activity in serum of equine neonates with presumed sepsis and to determine correlation between serum TNF activity and severity and outcome of disease. Twenty foals less than 21 days old were considered suitable for inclusion in this study by satisfying clinical and laboratory criteria suggestive of septicemia. At admission, blood samples were collected from all foals for determination of serum TNF activity, then clinical course and outcome of disease were recorded. Thirty-one clinically normal foals less than 21 days old served as controls for serum TNF activity. Serum TNF activity was estimated by use of an in vitro cytotoxicity bioassay and WEHI 164 clone-13 murine fibrosarcoma cells. Of the 20 foals with presumed sepsis, 5 had high serum TNF activity. Mean heart rate (P less than 0.005), mucosal petechial hemorrhages (P = 0.06), and death rate (P = 0.06) were greater in the group of foals with high serum TNF activity. These foals also had a lower mean neutrophil count (P less than 0.001), greater band-to-segmented neutrophil ratio (P less than 0.0001), and more prevalent neutrophil toxic changes (P = 0.07) than did foals without serum TNF activity (P = 0.02). Joint swelling was more prevalent in foals without serum TNF activity. Results of the study indicate that serum TNF activity is correlated with clinical criteria of sepsis in equine neonates. An association was apparent between disease severity and serum TNF activity in this group of foals with presumed septicemia.