Hypothalamic-Pituitary-Adrenal Axis Dysfunction in Hospitalized Neonatal Foals

Background: Transient hypothalamic-pituitary-adrenal (HPA) axis dysfunction occurs frequently in critically ill humans and impacts survival. The prevalence and impact of HPA axis dysfunction in critically ill neonatal foals are not well characterized.
Hypotheses: (1) HPA axis dysfunction occurs in hospitalized neonatal foals, and is characterized by inappropriately low basal serum cortisol concentration or inadequate cortisol response to exogenous adrenocorticotropic hormone (ACTH); (2) hospitalized foals with HPA axis dysfunction have more severe disease and are less likely to survive than hospitalized foals with normal HPA axis function.
Animals: Seventy-two hospitalized foals and 23 healthy age-matched foals.
Methods: Basal ACTH and cortisol concentrations were measured and a paired low-dose (10 μg)/high-dose (100 μg) cosyntropin stimulation test was performed at admission in hospitalized foals. HPA axis dysfunction was defined as (1) an inappropriately low basal cortisol concentration or (2) an inadequate increase in cortisol concentration (delta cortisol) after administration of cosyntropin, with cut-off values for appropriate basal and delta cortisol concentrations determined from results obtained in healthy age-matched foals.
Results: Forty-six percent of hospitalized foals had an inappropriately low basal cortisol concentration and 52% had an inadequate delta cortisol concentration after administration of the 100 μg dose of cosyntropin. An inadequate delta cortisol response to the high (100 μg) dose of cosyntropin was significantly correlated with shock and multiple organ dysfunction syndrome in hospitalized foals, and with decreased survival in a subgroup of septic foals.
Conclusions and Clinical Importance: HPA axis dysfunction occurs frequently in hospitalized neonatal foals, and negatively impacts disease severity and survival.     

Uveal Inflammation in Septic Newborn Foals

Background: Septicemia in humans is described as a leading cause of uveitis, which eventually can induce blindness. Hypothesis/Objectives: Uveal inflammatory findings could be related to sepsis severity in newborn foals and might be used as an indirect indicator for survival. Animals: Seventy‐four septic foals, 54 nonseptic foals, and 42 healthy foals. Methods: Prospective observational clinical study. A detailed blinded, ophthalmic examination was performed by boarded ophthalmologists on all admitted newborn foals. Foals were grouped as septic (when blood culture resulted positive or the sepsis score was ≥14), nonseptic, and controls. Based on blood culture results, the septic group was subdivided into bacteremic and nonbacteremic foals. Results: Blood culture was performed in 62/74 septic foals, from which 35 (56%) were bacteremic and 27 (44%) were nonbacteremic. Anterior uveitis was diagnosed in a significantly (P < .005) higher number of septic/bacteremic foals (14/35, 40%) than in septic/nonbacteremic foals (5/27, 19%), nonseptic foals (4/54, 7%), and control foals (0%). Anterior chamber fibrin was only observed in 4/14 (29%) septic/bacteremic foals with anterior uveitis. Anterior uveitis was also associated with posterior uveitis in 6/35 (19%) septic/bacteremic foals. The diagnosis of uveitis was related to nonsurvival (P= .001, odds ratio = 6.2, 95% confidence interval = 2.1–18.2). Conclusions and Clinical Importance: Anterior uveitis is highly prevalent in septic newborn foals, especially in those with a positive blood culture, and it should be considered as a survival prognostic factor.     

Capturing the dynamics of systemic Renin‐Angiotensin‐Aldosterone System (RAAS) peptides heightens the understanding of the effect of benazepril in dogs

Mochel, J. P., Peyrou, M, Fink, M, Strehlau, G, Mohamed, R, Giraudel, J. M., Ploeger, B, Danhof, M. Capturing the dynamics of systemic Renin‐Angiotensin‐Aldosterone System (RAAS) peptides heightens the understanding of the effect of benazepril in dogs. J. vet. Pharmacol. Therap.  36 , 174–180. In dogs, activation of the Renin‐Angiotensin‐Aldosterone System (RAAS) is an important feature of congestive heart failure (CHF). Long‐term increases in angiotensin II (AII) and aldosterone (ALD) lead to the progression of heart failure to its end stage. Angiotensin‐converting enzyme inhibitors (ACEIs) are the foremost therapeutic option in the management of CHF. Recent literature has challenged the efficacy of ACEIs, based on modest reduction in urinary aldosterone (UALD) excretion despite marked inhibition of ACE activity. This study was designed to heighten the understanding of the effect of benazepril, a potent ACEI, on the RAAS, using a low‐sodium diet as an experimental model of RAAS activation. Time course profiles of RAAS peptides and related areas under the curve (AUC_{24 hours}) were used for comparison between benazepril and placebo groups. Results indicated substantial changes in the dynamics of these biomarkers. At presumed benazeprilat steady state, significant differences in AUC_{24 hours} of plasma renin activity (+90%), angiotensin I (+43%), and AII (?53%) were found between benazepril and placebo‐treated dogs. ALD decreased by 73% in plasma but only by 5% in urine. In conclusion, despite modest reduction in UALD excretion, benazepril markedly influences RAAS dynamics in dogs.     

Hemostatic and Fibrinolytic Indices in Neonatal Foals with Presumed Septicemia

Thirteen coagulation tests evaluating hemostatic and fibrinolytic indices and serum cytokine and plasma endotoxin concentrations were obtained in 34 foals with a positive sepsis score (septic group) and 46 age-matched healthy foals. Compared to healthy foals, the prothrombin, activated partial thromboplastin, and whole blood recalcification times were significantly longer in septic foals. The fibrinogen and fibrin degradation products concentrations, percent plasminogen, alpha-2 antiplasmin, and plasminogen activator inhibitor activities, and tumor necrosis factor and interleukin-6 activities were greater in septic foals. Protein C antigen and antithrombin III activity were significantly lower in septic foals. Blood cultures were positive for growth and endotoxin was detected in 19 of 29 and 15 of 30 septic foals, respectively. In septicemic foals with detectable endotoxin in the plasma, the prothrombin and activated partial thromboplastin times were significantly longer and the plasminogen and antithrombin III activities were significantly less than in septic foals in which endotoxin was not detected. Twenty-three of the 34 septic foals did not survive. Septic foals that did not survive were most likely to have a positive blood culture in which a gram-negative organism was isolated. Histopathologic evidence of hemorrhage was evident in 11 foals at postmortem examination and thrombosis was identified in 2 foals. The prothrombin time was significantly longer in foals that had multisite hemorrhage at postmortem examination. The results of this study indicate that clinically relevant alternations in hemostatic and fibrinolytic indices occur in neonatal foals with septicemia and that derangements can be correlated with the presence of endotoxin in plasma. Derangements in hemostatic or fibrinolytic indices were helpful in identification of septic foals with increased risk of coagulopathy, but were not helpful in predicting hemorrhage as compared to thrombus formation. Survival of septicemic foals was correlated with gram-negative bacteremia, but not with the presence of endotoxin or coagulopathy.     

Low‐Molecular‐Weight Heparin Dosage in Newborn Foals

Background: Heparin is used in humans as prophylaxis of hypercoagulable states and disseminated intravascular coagulation (DIC). However, babies need a higher heparin dose than do adults. Septic neonate foals are at high risk of hypercoagulable state and DIC, and there is limited objective information about heparin dose for equine neonates. Objective: To assess whether neonate foals require higher dosages of low‐molecular‐weight heparin (LMWH) than adults. Animals: Eighteen healthy and 11 septic neonate foals. Methods: Experimental and clinical studies. Firstly, healthy foals were randomly distributed in 2 groups, 1 receiving 50 IU/kg SC of dalteparin and the 2nd group receiving 100 IU/kg SC of dalteparin, once daily for 3 days. Blood samples were collected before and 3, 6, 27, and 51 hours after the 1st LMWH administration. Plasma antifactor‐Xa activity was measured, together with hemostatic and hematologic parameters used to assess the risk of bleeding. Subsequently, septic foals were treated blindly either with placebo (saline) or 100 IU/kg of dalteparin for 3 days. Plasma antifactor‐Xa activity and other hemostatic parameters were determined before and after treatment. Results: Plasma antifactor‐Xa activity in healthy foals was below prophylactic activity when using the adult dosage (50 IU/kg), whereas prophylactic activities were achieved when using the double dosage (100 IU/kg). No hemorrhagic events and erythrocyte‐related complications were observed with either dosage. In the clinical study, only 4/6 septic foals had plasma antifactor‐Xa activity adequate for prophylaxis. Conclusions and Clinical Importance: Equine neonates require higher dosages of LMWH compared with adults to reach prophylactic heparinemia.     

Impact of Food Restriction on Ovarian Development,RFamide‐Related Peptide‐3 and the Hypothalamic–Pituitary–Ovarian Axis in Pre‐Pubertal Ewes

RFamide‐related peptide‐3 (RFRP‐3), the mammalian ortholog of gonadotropin‐inhibiting hormone, has been implicated as a mediator between reproduction and energy balance. This study aimed to investigate the physiological effects of RFRP‐3 on the process of ovarian development in food‐restricted pre‐pubertal ewes. The results showed that food restriction significantly inhibited the ovarian development and follicular growth. The data of qPCR in the hypothalamic–pituitary–ovarian (HPO) axis showed that food restriction not only upregulated RFRP‐3 mRNA expression but also downregulated the mRNA expression of gonadotropin‐releasing‐hormone receptor, follicle‐stimulating hormone receptor and luteinizing hormone receptor (LHR). Immunohistochemistry of RFRP‐3 in the ovaries suggested that RFRP‐3 may regulate the follicular development. These results suggested that the changes of RFRP‐3 in response to food restriction might influence the HPO axis and inhibit ovarian development.     

Calcium Regulating Hormones and Serum Calcium and Magnesium Concentrations in Septic and Critically Ill Foals and their Association with Survival

Background: Disorders of calcium regulation are frequently found in humans with critical illness, yet limited information exists in foals with similar conditions including septicemia. The purpose of this study was to determine whether disorders of calcium exist in septic foals, and to determine any association with survival.
Hypothesis: Blood concentrations of ionized calcium (Ca²⁺) and magnesium (Mg²⁺) will be lower in septic foals with concomitant increases in parathyroid hormone (PTH), calcitonin (CT), and parathyroid-related peptide (PTHrP) compared with healthy foals. The magnitude of these differences will be negatively associated with survival.
Animals: Eighty-two septic, 40 sick nonseptic, and 24 healthy foals of ≤7 days were included.
Methods: Prospective, observational study. Blood was collected at initial examination for analysis. Foals with positive blood culture or sepsis score ≥14 were considered septic. Foals with disease other than sepsis and healthy foals were used as controls. Hormone concentrations were measured with validated immunoassays.
Results: Septic foals had decreased Ca²⁺ (5.6 versus 6.1 mg/dL, P < .01) and increased serum PTH (16.2 versus 3.2 pmol/L, P < .05), and phosphorus concentrations (7.1 versus 6.3 mg/dL, P < .01). No differences in serum Mg²⁺, PTHrP, and CT concentrations were found. Nonsurviving septic foals (n = 42/82) had higher PTH concentrations (41.1 versus 10.7 pmol/L, P < .01) than survivors (n = 40/82).
Conclusions and Clinical Importance: Septic foals were more likely to have disorders of calcium regulation compared with healthy foals, where hyperparathyroidemia was associated with nonsurvival.     

Serum Cortisol Concentrations in Dogs with Pituitary‐Dependent Hyperadrenocorticism and Atypical Hyperadrenocorticism

Background

Atypical hyperadrenocorticism (AHAC) is considered when dogs have clinical signs of hypercortisolemia with normal hyperadrenocorticism screening tests.

Hypothesis/Objectives

To compare cortisol concentrations and adrenal gland size among dogs with pituitary‐dependent hyperadrenocorticism (PDH), atypical hyperadrenocorticism (AHAC), and healthy controls.

Animals

Ten healthy dogs, 7 dogs with PDH, and 8 dogs with AHAC.

Method

Dogs were prospectively enrolled between November 2011 and January 2013. Dogs were diagnosed with PDH or AHAC based on clinical signs and positive screening test results (PDH) or abnormal extended adrenal hormone panel results (AHAC). Transverse adrenal gland measurements were obtained by abdominal ultrasound. Hourly mean cortisol (9 samplings), sum of hourly cortisol measurements and adrenal gland sizes were compared among the 3 groups.

Results

Hourly (control, 1.4 ± 0.6 μg/dL; AHAC, 2.9 ± 1.3; PDH, 4.3 ± 1.5) (mean, SD) and sum (control, 11.3 ± 3.3; AHAC, 23.2 ± 7.7; PDH, 34.7 ± 9.9) cortisol concentrations differed significantly between the controls and AHAC (P < .01) and PDH (P < .01) groups. Hourly (P < .01) but not sum (P = .27) cortisol concentrations differed between AHAC and PDH dogs. Average transverse adrenal gland diameter of control dogs (5.3 ± 1.2 mm) was significantly less than dogs with PDH (6.4 ± 1.4; P = .02) and AHAC (7.2 ± 1.5; P < .01); adrenal gland diameter did not differ (P = .18) between dogs with AHAC and PDH.

Conclusions and Clinical Importance

Serum cortisol concentrations in dogs with AHAC were increased compared to controls but less than dogs with PDH, while adrenal gland diameter was similar between dogs with AHAC and PDH. These findings suggest cortisol excess could contribute to the pathophysiology of AHAC.     

The Effect of Temperature,Rainfall, and Light Conditions on Hair Cortisol Concentrations in Newborn Foals

The aim of this study was to investigate the possible effects of environmental factors such as temperature, rainfall, and light conditions on hair cortisol concentrations in foals during the perinatal period. The study, performed during three consecutive foaling seasons from January to July, enrolled 219 foals from one farm. Hair samples were collected from each foal immediately after birth and at 30 days of age, and the samples were analyzed by radioimmunoassay to measure the cortisol concentrations. The mean cortisol concentration of hair collected at 30 days of age was significantly (P < .01) lower than that found at birth, but none of the evaluated environmental factors (temperature, rainfall, or day length) influenced the hair cortisol concentrations.     

Efficacy of Low‐ and High‐Dose Trilostane Treatment in Dogs (< 5 kg) with Pituitary‐Dependent Hyperadrenocorticism

Background

Trilostane is commonly used to treat pituitary‐dependent hyperadrenocorticism (PDH) in dogs. There are differing opinions regarding the dose and frequency of trilostane administration in dogs with PDH.

Objectives

To compare the efficacy of 2 trilostane protocols in the treatment of dogs with PDH.

Animals

Sixteen client‐owned dogs with PDH and a body weight <5 kg.

Methods

Prospective observational study. Group A (n=9; low‐dose treatment group) received 0.78 ± 0.26 mg of trilostane/kg PO every 12 h and group B (n = 7; high‐dose treatment group) 30 mg of trilostane/dog PO every 24 h. All of the dogs were reassessed at 2, 4, 8, 12, 16, and 24 weeks after the initiation of treatment.

Results

An improvement in both ACTH‐stimulated serum cortisol concentrations and clinical signs occurred more slowly in group A than in group B; however, after 20 weeks of treatment, 2/7 dog in group B had clinical signs and abnormal laboratory findings consistent with hypoadrenocorticism. At 24 weeks, an improvement in the clinical findings of all of the dogs in both groups was detected.

Conclusions and clinical importance

In dogs with PDH, twice‐daily administration of low‐dose trilostane is an effective approach to the management of PDH. In addition, our results suggest fewer potential adverse effects if trilostane is administered twice daily in the lower dose.     

Plasma C‐Reactive Protein and Haptoglobin Concentrations in Critically Ill Neonatal Foals

Background

Accurate diagnostic markers for sepsis in neonatal foals are needed. Plasma C‐reactive protein concentration (p[CRP]) and haptoglobin concentration (p[Hp]) are well‐established biomarkers of infection in humans, but studies are lacking in foals.

Hypotheses

p[CRP]) and p[Hp] are increased in septic foals compared to sick nonseptic and healthy control foals, and are predictive of survival.

Animals

Eighty critically ill foals (40 septic, 40 sick nonseptic) and 39 healthy control foals <1 week of age.

Methods

Multicenter, prospective observational clinical study. Venous blood was collected at admission from septic and sick nonseptic foals and from clinically healthy foals at 24 h of age. A diagnosis of sepsis was made based on positive blood culture or a sepsis score >11, and p[CRP] and p[Hp] were measured by using ELISA tests. Data were analyzed by using the Mann‐Whitney U‐test and forward stepwise multivariable linear regression. P < .05 was considered significant.

Results

Plasma [CRP] was positively associated with age, serum globulin, adrenomedullin, and bilirubin concentrations, aspartate aminotransferase activity, glutamyl‐transferase activity, band neutrophil count, and rectal temperature, and was increased in foals with toxic neutrophils, enterocolitis, colic, rib fractures and septic arthritis. Surprisingly, p[Hp] was lower in septic foals than in sick nonseptic foals. Neither p[CRP] or p[Hp] was predictive of survival in critically ill foals.

Conclusions and Clinical Importance

Plasma [CRP] increases with inflammation in neonatal foals but is not indicative of sepsis. Single time point, admission sampling of p[CRP] and p[Hp] do not appear to be useful biomarkers for sepsis in foals.     

Blood and Cerebrospinal Fluid α‐Tocopherol and Selenium Concentrations in Neonatal Foals with Neuroaxonal Dystrophy

Background

Equine neuroaxonal dystrophy/equine degenerative myeloencephalopathy (NAD/EDM) is a neurodegenerative disorder affecting genetically predisposed foals maintained on α‐tocopherol (α‐TP)‐deficient diet.

Objective

Intramuscular α‐TP and selenium (Se) administration at 4 days of age would have no significant effect on serum or cerebrospinal fluid (CSF) α‐TP in healthy foals. Serum and CSF α‐TP, but not Se, would be significantly decreased in NAD/EDM‐affected foals during first year of life.

Animals

Fourteen Quarter horse foals; 10 healthy foals supplemented with 0.02 mL/kg injectable α‐TP and Se (n = 5) or saline (n = 5) at 4 days of age and 4 unsupplemented NAD/EDM‐affected foals.

Methods

Complete neurologic examinations were performed, blood and CSF were collected before (4 days of age) and after supplementation at 10, 30, 60, 120, 180, 240, and 360 days of age. Additional blood collections occurred at 90, 150, 210, and 300 days. At 540 days, NAD/EDM‐affected foals and 1 unsupplemented healthy foal were euthanized and necropsies performed.

Results

Significant decreases in blood, CSF α‐TP and Se found in the first year of life in all foals, with most significant changes in serum α‐TP from 4–150 days. Dam α‐TP and Se significantly influenced blood concentrations in foals. Injection of α‐TP and Se did not significantly increase CSF Se, blood or CSF α‐TP in healthy foals. NAD/EDM‐affected foals had significantly lower CSF α‐TP through 120 days.

Conclusions and Clinical Importance

Injection of α‐TP and Se at 4 days of age does not significantly increase blood or CSF α‐TP. Despite all 14 foals remaining deficient in α‐TP, only the 4 genetically predisposed foals developed NAD/EDM.