Blood arginine vasopressin, adrenocorticotropin hormone, and cortisol concentrations at admission in septic and critically ill foals and their association with survival

BACKGROUND: Sepsis is an important cause for neonatal foal mortality. The hypothalamic-pituitary-adrenal axis (HPAA) responses to sepsis are well documented in critically ill humans, but limited data exist in foals. The purpose of this study was to evaluate the HPAA response to sepsis in foals, and to associate these endocrine changes with survival. HYPOTHESIS: Blood concentrations of arginine vasopressin (AVP), adrenocorticotropin hormone (ACTH), and cortisol will be higher in septic foals as compared with sick nonseptic and healthy foals. The magnitude of increase in hormone concentration will be negatively associated with survival. ANIMALS: Fifty-one septic, 29 sick nonseptic, and 31 healthy foals of < or =7 days of age were included. METHODS: Blood was collected at admission for analysis. Foals with positive blood culture or sepsis score > or =14 were considered septic. Foals admitted with disease other than sepsis and healthy foals were used as controls. AVP, ACTH, and cortisol concentrations were measured using validated immunoassays. RESULTS: AVP, ACTH, and cortisol concentrations were increased in septic foals. Septic nonsurvivor foals (n = 26/51) had higher plasma ACTH and AVP concentrations than did survivors (n = 25/51). Some septic foals had normal or low cortisol concentrations despite increased ACTH, suggesting relative adrenal insufficiency. AVP, ACTH, and cortisol concentrations were higher in sick nonseptic foals compared with healthy foals. CONCLUSIONS AND CLINICAL IMPORTANCE: Increased plasma AVP and ACTH concentrations in septic foals were associated with mortality. Several septic foals had increased AVP : ACTH and ACTH : cortisol ratios, which indicates relative adenohypophyseal and adrenal insufficiency.     

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.     

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.     

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.     

Mean platelet component as an indicator of platelet activation in foals and adult horses

BACKGROUND: Mean platelet component (MPC) is a new platelet variable, measured by modern commercial complete blood count analyzers, that is reduced during platelet activation in humans and small animals. HYPOTHESIS: MPC decreases in horses with clinical conditions that cause platelet activation and disseminated intravascular coagulation (DIC). ANIMALS: We obtained 418 CBCs from 100 sick and 20 healthy neonates and 178 sick and 45 sound adult horses. Sick neonates were classified into septic and nonseptic, and DIC and non-DIC groups. Adults were grouped by diagnoses (systemic inflammatory disorders, gastrointestinal problems, and thrombocytopenia). METHODS: MPC together with platelet count, mean platelet volume, platelet distribution width, and platelet component distribution width were measured with a commercial analyzer and compared between the different disease and control groups in neonates and in adults. RESULTS: MPC values were significantly lower in the septic and nonseptic neonates (24.0 +/- 3.5 g/dL and 26.6 +/- 2.6 g/dL, respectively) than in the control group (28.1 +/- 1.7 g/dL). Neonates with DIC had the lowest MPC values (23.8 +/- 6.3 g/dL). MPC values in adult horses were significantly lower in the inflammatory (23.5 +/- 4.7 g/dL), gastrointestinal obstruction (23.0 +/- 5.0 g/dL), enteritis (23.6 +/- 4.6 g/dL), ischemic (23.9 +/- 5.1 g/dL), and thrombocytopenia (20.2 +/- 5.7 g/dL) groups when compared with control horses (26.2 +/- 3.5 g/dL). Other platelet variables were not different between the control and the disease groups. CONCLUSION AND CLINICAL IMPORTANCE: MPC might be a useful variable for quickly and easily detecting platelet activation in sick neonates and adult horses.     

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.     

Incidence and clinical relevance of hyperglycemia in critically ill dogs

BACKGROUND: Hyperglycemia associated with critical illness in nondiabetic human patients is a common occurrence in the intensive care unit (ICU), with a reported incidence as high as 71%. HYPOTHESIS: Hyperglycemia in critically ill dogs increases the risk of morbidity and mortality. ANIMALS: Two hundred forty-five dogs hospitalized in the ICU over a 2-month period were evaluated. METHODS: Prospective observational study was conducted over a 2-month period. All dogs in the ICU had their highest daily blood glucose concentration recorded. All dogs with diabetes were excluded from the study. Hyperglycemia was defined as a blood glucose concentration >120 mg/dL. Dogs with hyperglycemia were monitored for persistence and resolution of hyperglycemia. RESULTS: During the study period, 245 dogs were evaluated, of which 38 (16%) were hyperglycemic. Twenty-six percent (10/ 38) developed hyperglycemia during hospitalization, whereas 74% (28/38) were hyperglycemic at presentation. Length of hospitalization (LOH) was shorter in dogs that presented with hyperglycemia compared with those that developed hyperglycemia during hospitalization (P = .001). Seventy-one percent (27/38) of dogs were discharged from the hospital, whereas the remaining 29% (11/38) died or were euthanatized. Nonsurvivors had significantly higher median glucose concentration (median, 176 mg/dL; range 122-310 mg/dL) than did survivors (median, 139 mg/dL; 121-191 mg/dL; P = .021). CONCLUSIONS AND CLINICAL IMPORTANCE: The incidence of hyperglycemia in this population of dogs was 16%. Dogs that developed hyperglycemia had longer LOH and nonsurvivors had more pronounced hyperglycemia than did survivors.     

Evaluation of serum NT-pCNP as a diagnostic and prognostic biomarker for sepsis in dogs

Background: There is a need for diagnostic biomarkers that can rapidly differentiate dogs with sepsis from dogs with noninfectious forms of systemic inflammatory response syndrome (NSIRS). Objectives: To compare serum NT‐pCNP concentrations among dogs with various forms of sepsis, NSIRS, and healthy controls and to evaluate the use of serum NT‐pCNP for the diagnosis of various forms of sepsis in dogs. Animals: One hundred and twelve dogs including 63 critically ill dogs (sepsis n = 29; NSIRS n = 34) and 49 healthy control dogs. Methods: Prospective clinical investigation. Serum samples were collected for NT‐pCNP measurement from dogs with sepsis or NSIRS within 24 hours of intensive care unit admission or at the time of presentation for healthy dogs. Dogs with sepsis were subclassified based on the anatomic region of infection. Serum NT‐pCNP concentrations were compared among sepsis, NSIRS and healthy groups as well as among sepsis subgroups. The area under the curve (AUC), sensitivity, and specificity for identifying dogs with sepsis were determined. Results: Using a cut‐off value of 10.1 pmol/L, AUC, sensitivity, and specificity of NT‐pCNP for differentiating dogs with sepsis from dogs with NSIRS or healthy control dogs were 0.71 (95% CI, 0.58–0.85), 65.5% (45.7–82.1%), and 89.2% (80.4–94.9%), respectively. Serum NT‐pCNP had poor sensitivity for peritoneal sources of sepsis; AUC [0.92 (0.81–1.0)], sensitivity [94% (71–100%)], and specificity [89% (80–95%)] improved when these dogs were excluded. Serum NT‐pCNP concentration was not associated with survival in the sepsis group. Conclusions and Clinical Importance: Serum NT‐pCNP is a promising diagnostic biomarker for sepsis but is a poor indicator of septic peritonitis.     

Effect of plasma transfusion on neutrophil function in healthy and septic foals

OBJECTIVE: To evaluate the effect of plasma transfusion on phagocytosis and oxidative burst activity of peripheral blood neutrophils from healthy and septic equine neonates with sub-optimal passive transfer of maternal immunity. ANIMALS: Nine healthy and seven septic foals with suboptimal passive transfer of maternal immunity (serum IgG < 8 g/L) presented to participating veterinary hospitals for plasma transfusion, and seven healthy foals less than 7 days of age and with circulating IgG concentrations > or = 8 g/L. PROCEDURE: Foals with serum IgG concentrations < 8 g/L were assessed as healthy or septic. Sepsis was recognised by positive bacterial cultures and/or sepsis scores of > or = 11. All foals received between 1 and 3 L of plasma to boost circulating IgG concentrations to > or = 8 g/L. Serum IgG concentrations were determined before and following transfusion by glutaraldehyde coagulation test and confirmed by single radial immunodiffusion assays. Neutrophil phagocytosis and oxidative burst activity were determined before plasma transfusion and at 0 h, 12 h, 24 h, 48 h and 5 d following treatment. Neutrophil function from seven healthy foals less than 7 d of age and with circulating IgG concentrations of > or = 8 g/L was similarly evaluated on a single occasion. RESULTS: Plasma treatment significantly increased circulating IgG concentrations for healthy and septic foals. Oxidative burst activity of neutrophils from septic foals was significantly increased 5 days following treatment, relative to 0 h post treatment. Other differences were not significant but suggested a transient decrease in phagocytosis by neutrophils from healthy foals and increased phagocytosis by neutrophils from septic foals immediately following transfusion. Oxidative burst activity of neutrophils from septic foals tended to be less than that of healthy foals at all sampling times. Serum IgG concentrations were not correlated with neutrophil phagocytosis, but were correlated with oxidative burst activity. CONCLUSIONS: Plasma transfusion did not improve neutrophil function of healthy foals, suggesting that such treatment may be of equivocal benefit for healthy neonates. Conversely, improved neutrophil function was observed following treatment of septic foals, suggesting that plasma transfusion was beneficial for these foals. Oxidative burst activity of neutrophils from septic foals was lower than that of neutrophils from healthy foals and was significantly improved 5 days post treatment, when compared with values obtained immediately following treatment.     

The effect of intravenous fresh frozen plasma administration on fibrinogen and albumin concentrations in sick neonatal foals

This study investigated the immediate (6 h or less) effects of fibrinogen and albumin contained in transfused equine origin fresh frozen plasma on those proteins when measured in sick neonatal foals. Fibrinogen and albumin concentrations were measured in the administered plasma and in 31 sick foals at admission to a referral neonatal intensive care unit. Additional samples were obtained from the foals at 2 and 6 h following transfusion. No changes in albumin concentration were recognised. The main determinant of fibrinogen concentration following transfusion was the concentration of fibrinogen in the foal at admission. Importantly, intravenous transfusion of equine fresh frozen plasma did not result in immediate (6 h or less) increases or decreases in the fibrinogen concentration in the recipient foals. Fibrinogen from the donor contained within transfused plasma will not directly affect fibrinogen concentrations measured at later times.     

Association of adrenocorticotrophin and cortisol concentrations with peripheral blood leukocyte cytokine gene expression in septic and nonseptic neonatal foals

Background

The hypothalamic‐pituitary‐adrenal (HPA) is influenced by the proinflammatory cytokines IL‐6, IL‐1β, and TNF‐α in critically ill humans. Information about the association of cytokines with the HPA axis in neonatal foals is lacking.

Hypothesis/Objectives

The objectives were to describe for hospitalized septic and nonseptic foals (1) temporal changes in blood concentrations of ACTH, and cortisol, and leukocyte cytokine gene expression, and (2) coassociation of these HPA axis hormones with blood leukocyte cytokine gene expression.

Animals

Hospitalized septic foals (N = 15) and hospitalized nonseptic foals (N = 11).

Methods

Blood samples, obtained from study foals at admission (T = 0), and 24 (T = 1), 48 (T = 2), 72 (T = 3), and 96 (T = 4) hours after admission, were processed to isolate RNA from leukocytes and to harvest plasma and serum for hormone assays. Plasma ACTH and serum cortisol concentrations were determined by radioimmunoassay. Leukocyte mRNA expression of IL‐1β IL‐6, IL‐8, IL‐10, and TNF‐α was determined using RT‐PCR.

Results

Cortisol concentrations were greater (P < .05) in foals at admission than at other time points. The expressions of IL‐8 and IL‐10 mRNA were lower (P < .05) at each time point in septic than in nonseptic foals. Among septic foals, ACTH was positively associated (P = .0026) with IL‐6 mRNA expression.

Conclusions

Sepsis influences secretion of the HPA axis hormones and expression of cytokines in foals. A positive association with the HPA axis and IL‐6 expression was detected. The clinical importance of these findings requires additional study.     

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.     

The effect of omeprazole paste on intragastric pH in clinically ill neonatal foals

REASON FOR PERFORMING STUDY: Administration of omeprazole paste per os to healthy neonatal foals has been shown to effectively increase intragastric pH, but has not been evaluated in sick neonatal foals. OBJECTIVES: To determine the effect of orally administered omeprazole paste on intragastric pH in clinically ill neonatal foals requiring nasogastric intubation. METHODS: Intragastric pH was measured continuously for 24 h using an indwelling electrode and continuous data recording system in hospitalised neonatal foals age < or =2 days. Intragastric pH was measured for 12 h prior to (pretreatment period) and 12 h following (post treatment period) treatment with omeprazole paste (4 mg/kg bwt per os). All foals displayed periods of acidity (pH <4) prior to treatment. Statistical analysis compared pre- and post treatment mean and median intragastric pH, and percentage of time below pH 4. RESULTS: Eight foals were evaluated age 1-3 days, a gestational age of at least 320 days or reported to be full term. The mean (3.19 +/- 1.50 vs. 6.20 +/- 0.93) and median (4.6 +/- 1.7 vs. 6.86 +/- 0.89) pH were significantly higher and the percentage of time below pH 4 (32.25 vs. 1.1%) was significantly lower in the post treatment compared to the pretreatment period. CONCLUSION: Omeprazole paste effectively increases intragastric pH in clinically ill neonatal foals after one dose at 4 mg/kg bwt orally.