Plasma adrenocorticotropin, cortisol, and adrenocorticotropin/cortisol ratios in septic and normal-term foals

BACKGROUND: Little information exists on the hypothalamic-pituitary-adrenal axis in septic foals. HYPOTHESIS: The plasma concentrations of adrenocorticotropin (ACTH) and cortisol are expected to be higher in septic foals as compared to normal foals. The concentrations of hormones in septic foals also are expected to differ further depending upon survival. ANIMALS: Twenty-eight control foals and 46 septic foals <14 days of age were included in this study. METHODS: Blood was collected in EDTA once from 28 normal foals born in the University of Georgia or Cornell University equine research herds and from 46 septic foals within 12 hours after admission to 1 of the 3 tertiary care referral centers involved in the study. Septic foal selection was based on a sepsis score of >11 or a positive blood culture. The control foals were age matched to the septic foals in the study. ACTH and cortisol concentrations were measured by a chemiluminescent immunoassay system. RESULTS: Cortisol concentrations in control foals did not vary with age. Septic foals had significantly higher mean ACTH, cortisol, and ACTH/cortisol ratios than did normal foals. Within the septic foal group, 28 foals survived to discharge, and 18 were euthanized or died. The mean age was not significantly different between the septic surviving and nonsurviving foals. The mean ACTH/cortisol ratio was significantly higher in the septic nonsurviving foals as compared to the septic surviving foals. CONCLUSIONS AND CLINICAL IMPORTANCE: Septic foals had higher hormone concentrations as compared to normal foals, which is an expected endocrine response to critical illness. The increased ACTH/cortisol ratio in nonsurviving septic foals in comparison to surviving septic foals could indicate hypothalamic-pituitary-adrenal axis dysfunction at the level of the adrenal gland in critically ill septic foals.     

Critical illness-related corticosteroid insufficiency in a dog with septic shock

Objective – To describe a case of hydrocortisone-responsive hypotension and critical illness-related corticosteroid insufficiency (CIRCI) in a dog with septic shock.
Case Summary – A dog with aspiration pneumonia developed septic shock with pressor-refractory hypotension. A standard ACTH stimulation test was performed that showed a blunted cortisol response consistent with CIRCI. Reversal of shock was achieved within 2 hours of hydrocortisone administration, and complete weaning from pressors was accomplished over the subsequent 8 hours. The patient recovered and was discharged from the hospital. An ACTH stimulation test performed 1 month after hospital discharge showed normal adrenal responsiveness consistent with resolution of CIRCI.
New or Unique Information Provided – This case is the first published report of hydrocortisone-responsive hypotension and transient CIRCI associated with naturally occurring septic shock in a dog.     

Relative adrenal insufficiency in critical illness

Objective: To review the effects of critical illness on hypothalamic–pituitary–adrenal (HPA) function in human and veterinary medicine. Data sources: Data from human and veterinary literature was reviewed. Human data synthesis: Relative adrenal insufficiency (RAI) appears to be common in critically ill human patients with sepsis or septic shock. Hypotension that is refractory to fluid therapy and requires vasopressors is the most common presentation of RAI in the human intensive care unit (ICU). Many investigators now advocate the use of a low‐dose adrenocorticotropin hormone stimulation test to diagnose RAI. It is important to evaluate for the presence of adrenal dysfunction, because current data suggest that treatment with ‘stress’ or low doses of glucocorticoids (200–300 mg hydrocortisone daily) may improve patient outcome in humans. Veterinary data synthesis: There is a paucity of controlled studies in the veterinary literature regarding the effects of critical illness on HPA function. The results of these studies are varied. However, research models of sepsis and hemorrhagic shock suggest the existence of RAI in animals. Prospective clinical studies are needed to further examine pituitary–adrenal response to severe illness in veterinary patients, and to determine if there are therapeutic options, including glucocorticoid administration, which will improve patient outcome in animals. Conclusions: RAI is well documented in critically ill human patients, yet little is known about adrenal dysfunction in veterinary critically ill patients. A small number of studies suggest that RAI may exist in certain subpopulations of veterinary patients. The syndrome of RAI could be considered as a differential diagnosis in seriously ill veterinary patients that fail to respond to appropriate therapy, especially when hypotension refractory to fluid and vasopressor therapy is encountered. This disorder may represent a previously unidentified syndrome in critically ill veterinary patients with important therapeutic implications.     

Glucocorticoid Receptor Density and Binding Affinity in Healthy Horses and Horses with Systemic Inflammatory Response Syndrome

Background

Dysregulation of the hypothalamic‐pituitary‐adrenal (HPA) axis occurs in horses with systemic inflammatory response syndrome (SIRS). Peripheral resistance to glucocorticoids has not been investigated in horses.

Objective

To determine if glucocorticoid receptor (GR) function in horses can be measured using flow cytometry, and to use this information to evaluate HPA axis dynamics.

Animals

Eleven healthy adult horses in parts 1 and 2. Ten horses with SIRS and 10 age and sex matched controls in part 3.

Methods

Flow cytometry was used to evaluate GR density and binding affinity (BA) in 3 healthy horses in part 1. In part 2, exogenous ACTH was administered to eight healthy horses. Their cortisol response and GR properties were measured. In part 3, CBC, serum biochemistry, cortisol and ACTH, and GR properties were compared between controls without SIRS (n = 10) and horses with SIRS (n = 10), and between survivors and nonsurvivors (n = 4 and n = 6 respectively).

Results

Flow cytometry can be used to measure GR properties in equine PBMCs. No correlation was observed between plasma cortisol concentration and GR density or BA in healthy horses (r = −0.145, P = .428 and r = 0.046, P = .802 respectively). Nonsurvivors with SIRS had significantly decreased GR BA (P = .008). Horses with triglyceride concentration > 28.5 mg/dL had increased odds of nonsurvival (OR=117; 95% CI, 1.94–7,060). GR BA <35.79% was associated with nonsurvival (OR = 30.33; 95% CI, 0.96–960.5).

Conclusions and Clinical Importance

Tissue resistance to glucocorticoids contributes to HPA axis dysfunction in adult horses with SIRS. These horses might benefit from treatment with exogenous glucocorticoids.     

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.     

Relative adrenal insufficiency in dogs with sepsis

BACKGROUND: A syndrome of relative adrenal insufficiency has been identified in septic humans, and is associated with hypotension and death. Relative adrenal insufficiency is generally associated with basal serum cortisol concentration within or above the reference range and a blunted cortisol response to adrenocorticotropic hormone administration. It is unknown whether relative adrenal insufficiency occurs in septic dogs. HYPOTHESIS: That relative adrenal insufficiency occurs in septic dogs, and that relative adrenal insufficiency is associated with hypotension and mortality. ANIMALS: Thirty-three septic dogs admitted to a small animal intensive care unit. METHODS: Dogs were included in the study if they had a known or suspected infectious disease and had systemic inflammatory response syndrome. Dogs were excluded if they had disease or medication history expected to affect the hypothalamic-pituitary-adrenal axis. Serum cortisol and endogenous plasma adrenocorticotropic hormone concentrations were measured before, and serum cortisol concentration measured 1 hour after, intramuscular administration of 250 microg of cosyntropin/dog. The change in cortisol concentration (delta-cortisol) before and after cosyntropin administration was determined in each dog. RESULTS: Hypotension was associated with lower delta-cortisol values (OR 1.3; CI 1.0-1.9; P = .029). delta-Cortisol cutoff of 3.0 microg/dL was most accurate for predicting hypotension, survival to discharge, and 28-day survival. The rate of death in dogs with delta-cortisol < or = 3 microg/dL was 4.1 times that of dogs with delta-cortisol > 3 microg/dL (RR 4.1; CI 1.5-12.3; P = .01). CONCLUSIONS AND CLINICAL RELEVANCE: Delta-cortisol < or = 3 microg/dL after adrenocorticotropic hormone administration is associated with systemic hypotension and decreased survival in septic dogs.     

Prognostic value of clinicopathologic variables obtained at admission and effect of antiendotoxin plasma on survival in septic and critically ill foals

This prospective study compared survival rates of critically ill and septic foals receiving 1 of 2 different types of commercial equine plasma and analyzed admission variables as possible predictors of survival. Standardized clinical, hematologic, biochemical, and hemostatic admission data were collected and foals received either conventional commercially available hyperimmune equine plasma or equine plasma specifically rich in antiendotoxin antibodies in a double-blinded, coded fashion. Sepsis was defined as true bacteremia or sepsis score >11. Overall survival rate to discharge was 72% (49/68). Foals that were nonbacteremic and demonstrated a sepsis score of < or = 11 at admission had a 95% (18/19) survival rate. The survival rate to discharge for septic foals was 28/49 (57%), with truly bacteremic foals having a survival rate of 58% (14/24), whereas that for nonbacteremic, septic foals was 56% (14/25). Sensitivity and specificity for sepsis score >11 as a predictor of bacteremia were 74 and 52%, respectively. For the entire study population, a higher survival rate to discharge was documented for those foals receiving hyperimmune plasma rich in antiendotoxin antibodies (P = .012, odds ratio [OR] 6.763, 95% confidence interval [CI]: 1.311, 34.903). Administration of plasma rich in antiendotoxin antibodies also was associated with greater survival in septic foals (P = .019, OR 6.267, 95% CI: 1.186, 33.109). Statistical analyses demonstrated that, among 53 clinical and clinicopathologic admission variables, high sepsis score (P < .001), low measured IgG concentration (P = .01), high fibrinogen concentration (P = .018), low segmented neutrophil count (P = .028), and low total red blood cell numbers (P = .048) were the most significant predictors of overall mortality.     

Ionized Hypocalcemia in Critically Ill Dogs

Background: Ionized hypocalcemia (iHCa) is a common electrolyte disturbance in critically ill people, especially those with sepsis. The cause of the iHCa is not entirely understood and is likely multifactorial. Critically ill people with iHCa have longer hospital stays and higher mortality rates compared to people with normocalcemia. There are no published clinical studies evaluating the incidence and impact of iHCa in critically ill dogs.
Hypothesis: iHCa occurs in critically ill dogs, is more prevalent in dogs with systemic inflammatory response syndrome (SIRS) or sepsis, and is associated with longer hospital stays and higher mortality.
Animals: One hundred and forty-one client-owned dogs admitted to a companion animal intensive care unit (ICU) in a veterinary teaching hospital.
Methods: Prospective observational study of sequentially enrolled dogs. Blood was collected and analyzed within an hour of admission from all dogs presented to the ICU that met study inclusion criteria.
Results: The incidence of iHCa (iCa < 1.11 mmol/L) was 16%. The presence of iHCa was associated with longer ICU ( P = .038) and hospital ( P = .012) stays but not with decreased survival ( P = .60). Dogs with sepsis as defined by ≥3 SIRS criteria and a positive culture were more likely to have iHCa ( P = .050).
Conclusions and Clinical Relevance: In dogs not previously treated with fluids or blood products intravenously, the finding of iHCa upon admission to the ICU predicted a longer duration of ICU and hospital stay. Septic dogs with positive cultures were more likely to have iHCa.     

Plasma D-dimer concentration in sick newborn foals

BACKGROUND: Septicemia is associated with a systemic inflammatory response, hemostatic activation, and disseminated intravascular coagulopathy (DIC). HYPOTHESIS: Increased plasma d-dimer concentration occurs in septic neonates and can reliably detect sepsis or DIC, and predict death in ill neonatal foals. ANIMALS: 40 septic, 41 nonseptic hospitalized foals, and 22 healthy neonates. METHODS: Prospective observational clinical study. Blood samples were collected on admission, at 24-48 hours after admission, and at the time of discharge or euthanasia. Plasma d-dimer concentration, clotting times, antithrombin activity, and fibrinogen concentration were determined. RESULTS: On admission, d-dimer concentration values were significantly higher in septic foals (median, 25-75th percentiles; 568, 245-2013 ng/mL) compared with the nonseptic and healthy groups (386, 175-559 and 313, 152-495 ng/mL, respectively), and in septic foals at the age of 2-7 days compared with similar-age nonseptic foals. By means of samples taken at 24-48 hours of hospitalization and a cut-off value of > 2000 ng/mL, D dimer concentration was significantly associated with the diagnosis of septicemia (odds ratio [OR] = 19.6, 95% confidence interval [95% CI] 1.9-203) and death (OR = 8.7, 95% CI 1.8-43). Owing to a high false-positive prediction rate (71%), a normal d-dimer concentration is better at eliminating the diagnosis of sepsis than an increased d-dimer concentration at predicting sepsis. Fifty percent of septic foals had a diagnosis of DIC, but d-dimer concentration was not significantly associated with the diagnosis of DIC. CONCLUSIONS AND CLINICAL IMPORTANCE: Septic foals showed a marked activation of coagulation and fibrinolytic systems and a high prevalence of DIC. Increased plasma d-dimer concentration is significantly associated with the diagnosis of sepsis.