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Abstract

Defining and describing the systemic inflammatory response syndrome (SIRS) and sepsis has facilitated recognition and investigation of the complex disease processes involving the host response to infection and trauma. Over the years a variety of definitions of SIRS have been examined and applied to numerous research studies to improve critical care in both human and veterinary clinical practice. This article summarizes the history of the development of the SIRS definition, outlines the pathophysiologic processes that are involved in SIRS, and provides a specific definition for use in foal medicine.

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... 19 Although a variety of criteria have been used to describe SIRS in horses, a recent review outlined specific criteria that expand upon the original definition used in people to potentially improve specificity in foals (subsequently referred to as the equine neonatal SIRS criteria in our study). 20 Several studies in horses have evaluated the relationship between blood glucose or L-lactate concentrations and SIRS, but none have directly correlated SIRS with sepsis, 17,18 in part because of the variability in definitions for sepsis, some of which are dependent on a positive sepsis score or positive blood culture. Thus, validation of SIRS criteria is lacking in equine neonates. ...
... 18,21 Lastly, in the updated sepsis scores, fever was not evaluated as a sole criterion, but rather the rectal temperature was incorporated into the proposed equine neonatal SIRS criteria (Score 2), which is detailed in Figure 1. 20 In addition to the equine neonatal SIRS criteria, the original SIRS criteria also were evaluated in an updated sepsis score (Score 3). Score 3 was identical to Score 2 with the exception that the original SIRS criteria were used. ...
... In Score 3, fever was not evaluated as a sole criterion as the rectal temperature was evaluated within the SIRS criteria; a foal was positive for the original SIRS definition if it had 2 of the following criteria: rectal temperature > 102.68F or< 99.08F, tachycardia (using age-specific values noted in Figure 1), respiratory rate > 56 breaths/ min, or leukocytosis or leucopenia (using age-specific values noted in Figure 1). Thus, each foal included in the study had 3 scores calculated using data from the time of admission: Score 1 (modified sepsis score), 12,13 Score 2 (updated sepsis score with equine neonatal SIRS criteria), 20 and Score 3 (updated sepsis score with original SIRS criteria). 19 ...
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Background The original equine sepsis score provided a method of identifying foals with sepsis. New variables associated with sepsis have been evaluated, but the sepsis score has not been updated. Objectives To evaluate the sensitivity and specificity of 2 updated sepsis scores and the systemic inflammatory response syndrome (SIRS) criteria in regard to detecting sepsis in foals. Animals Two‐hundred and seventy‐three ill foals and 25 healthy control foals. Methods Historical, physical examination, and clinicopathologic findings were used to calculate the original sepsis score and 2 updated sepsis scores. SIRS criteria were also evaluated. Sepsis scores and positive SIRS scores were statistically compared to foals with sepsis. Results One‐hundred and twenty‐six foals were septic and 147 sick‐nonseptic. The original and updated sepsis scores were significantly higher in septic foals as compared to sick‐nonseptic and healthy foals. The sensitivity and specificity of the updated sepsis scores to predict sepsis were not significantly better than those of the original sepsis score. One‐hundred and twenty‐seven of 273 (46.5%) foals met the original SIRS criteria and 88/273 (32%) foals met the equine neonatal SIRS criteria. The original SIRS criteria had similar sensitivity and specificity for predicting sepsis as did the 3 sepsis scores in our study. Conclusions and Clinical Importance The updated sepsis scores did not provide improved ability in predicting sepsis. Fulfilling the original SIRS criteria provided similar sensitivity and specificity in predicting sepsis as the modified sepsis score and might serve as a diagnostic aid in identifying foals at risk for sepsis.
... Infection was confirmed on the basis of positive blood culture, positive culture of samples from local sites of suspected infection, or on the basis of postmortem examination. SIRS diagnosis was made as suggested by Wong and Wilkins [22]. Classification based on sepsis score [23] was not enrolled in our analysis. ...
... Moreover, as mentioned above, different timing of determination from other study protocols should be considered. Stringent inclusion criteria, based on the definition of sepsis, thus implying presence of probable or documented infection plus SIRS and diagnosed by recently reviewed criteria, were adopted to classify foals in this study [21,22,26,27]. This could have affected our results and contributed to differences observed from previous studies [13,14,19]. ...
... 3,[5][6][7][8] The SIRS criteria is much simpler and faster to use than sepsis scores and might serve as a more rapid screening tool for sepsis in neonatal foals. A positive result to the original SIRS criteria has a sensitivity of 60% and specificity of 69% to predict sepsis when compared to other proposed SIRS criteria 3,9,10 and could be more useful for predicting nonsurvival associated with sepsis. 3 Based on the human pediatric literature, an updated SIRS score for foals was proposed but it does not provide an improved ability in predicting sepsis. ...
... 3,11 SIRS criteria for foals of the aforementioned study required the presence of at least 3 of: (1) fever or hypothermia, (2) tachycardia, (3) tachypnea, (4) leukocytosis, leukopenia, >5% band neutrophils, (5) venous blood lactate concentration, or (6) venous blood glucose concentration; at least one of which had to be abnormal temperature or leukocyte count. 9 In adult horses, plasma iron concentration acutely decreases in cases with systemic inflammation. 2 Low iron and high fibrinogen plasma concentrations are both sensitive indicators of systemic inflammation in horses, with sensitivity of 90 and 82%, respectively. ...
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Background Sparse information regarding plasma iron concentration in neonatal foals and its utility as an inflammatory marker in this population has been published. Objectives To determine the physiologic plasma iron concentration in neonatal foals. To assess its utility as an inflammatory marker to predict systemic inflammatory response syndrome (SIRS) and as a prognostic marker. Animals Forty‐seven ill neonatal foals admitted to a referral equine hospital were divided in 2 groups based on the SIRS criteria (24 SIRS and 23 non‐SIRS). Two control groups of 43 hospital and 135 stud farm healthy neonatal foals were also included. Methods Observational prospective study. Data were summarized by mean and its 95% confidence interval and absolute frequency and percentage for quantitative andqualitative variables. One‐way ANOVA, ANCOVA (group and age effects) and Dunnett as posthoc analysis were used to compare plasma iron concentration among groups. Results Neonatal foals with SIRS did not have had any statistically significant different plasma iron concentrations compared to non‐SIRS (P = .56) and stud farm control group (P = .99), 172.8 μg/dL (95% CI; 126.0‐219.6), 193.1 μg/dL (139.1‐247.2), and 181.8 μg/dL (171.3‐192.4), respectively. Plasma iron concentration had a large variability in healthy neonatal foals, and was negatively correlated with age in hospital controls (rho = −0.387) and sick neonatal foals (rho = −0.598) (P < .001). Conclusions and Clinical Importance Plasma iron was not a useful marker of SIRS in neonatal foals and was not associated with outcome.
... [4][5][6][7][8] The case fatality rate of patients in an intensive care unit was found to increase with the number of SIRS criteria met-the SIRS score-as well as with the progression from sepsis to severe sepsis and septic shock, suggesting that the consensus definitions were clinically useful and meaningful. 9 Equine clinicians and researchers were also quick to adopt the human SIRS and sepsis definitions, 10,11 leading to widespread use in research, clinic, and veterinary curriculums. Recently, it was suggested that SIRS should replace the widely used term endotoxemia to describe the clinical status of horses with severe colic. ...
... 12 Despite its widespread use in equine medicine, there is still no adult horse-specific consensus SIRS definition, although such definition was recently proposed for foals. 10 As a result, a wide variety of heterogeneous definitions are currently used, and while most authors follow the original human SIRS definition in terms of numbers of criteria, the cutoffs for each criterion have varied between authors, 13-16 with some also including markers of poor perfusion in their SIRS definition. 15,17 Moreover, to our knowledge, the clinical value of the SIRS concept in terms of prediction of death in adult horses remains unknown. ...
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Background: Despite its widespread use in equine medicine, the clinical value of the systemic inflammatory response syndrome (SIRS) concept in horses remains unknown. Objectives: To study the prognostic value of measures of SIRS in horses and identify the best model of severe SIRS to predict outcome. Animals: A total of 479 consecutive adult horse emergency admissions to a private primary referral practice. Methods: Prospective observational study. All adult horses admitted for emergency treatment over the study period were included. Multivariate logistic regression and stepwise model selection were used. Results: Each of the 4 SIRS criteria was associated with outcome in this population. Thirty-one percent of emergency cases had 2 or more abnormal SIRS criteria on admission and were defined as SIRS cases. SIRS was associated with increased odds of death (odds ratio [OR] = 8.22; 95% CI, 4.61-15.18; P < .001), an effect mainly found for acute gastrointestinal cases. SIRS cases were assigned a SIRS score of 2, 3, or 4, according to the number of abnormal SIRS criteria fulfilled on admission, and SIRS3 and SIRS4 cases had increased odds of death compared to SIRS2 cases (OR = 4.45; 95% CI, 1.78-11.15; P = .002). A model of severe SIRS including the SIRS score, blood lactate concentration, and color of the mucous membranes best predicted outcome in this population of horses. Conclusions and clinical importance: Systemic inflammatory response syndrome is associated with an increased risk of death in adult horses presenting with acute gastrointestinal illnesses. The model of severe SIRS proposed in this study could be used to assess the status and prognosis of adult equine emergency admissions.
... The survival of septicaemic foals varies within a range of 45-81% (Corley and Furr 2003;Slack et al. 2005;Castagnetti and Veronesi 2008). Since intensive care for newborn foals is very expensive, the early prognosis for survival on admission or during the first few hours of hospitalisation should be considered to identify neonates with a higher chance of survival (Castagnetti and Veronesi 2008;Wong and Wilkins 2015). ...
... Although the accuracy of the sepsis score developed by Brewer and Koterba (1988), has been questioned (Corley and Furr 2003;Slack et al. 2005;Castagnetti and Veronesi 2008;Wong and Wilkins 2015;Wong et al. 2018), it remains the best predictor of survival, with the survival rate decreasing as the sepsis score increases (Peek et al. 2004;Wilkins 2018;Wong et al. 2018). ...
Article
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This study aimed to investigate differences in heart rate variability (HRV) between healthy and sick neonatal foals with a variety of diagnosis and to verify whether some HRV parameters could be associated with sepsis and/or survival. Twenty-one foals were included in the study: nine were healthy and 12 were sick. Retrospectively, sick foals were divided into sub-groups (non-septic vs. septic and non-survivor vs. survivor) for statistical analysis. Heart rate was recorded daily for 20 min and a 5-min period was used for heart rate variability analysis. Data on HRV variables were analysed using a linear model. Least-square means with their standard errors were reported, and treatment effects were declared significant at p
... Sepsis was defined as ≥1 of the following: (1) positive blood culture; (2) evidence of localized infection and systemic inflammatory response syndrome (SIRS, Supporting Information 1); 11 (3) sepsis score ≥12; 12 or, (4) presence of multiple infectious sites on necropsy. ...
... 8 Our study included older foals, a different geographical location and different referral hospitals. Additionally, the definition of sepsis was slightly different from that of the original study, because foals with evidence of localized infection and SIRS, 11 presence of multiple infectious sites on necropsy, or both also were included in the our study. Despite broadening the sepsis criteria, our study classified fewer foals as septic (27% versus 38%), indicating that the 2 study populations were in fact different. ...
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Background It is highly desirable to assess the probability of survival in sick neonatal foals upon admission. The foal survival score (FSS) is a published scoring system used to estimate the probability of survival in hospitalized neonatal foals <4 days old. Hypothesis/Objectives To evaluate the ability of the FSS to predict survival in older foals from a geographically different area compared to the original study. Animals Five‐hundred ninety hospitalized neonatal foals ≤14 days of age. Methods Retrospective Danish‐Swedish multicenter study that included details of signalment, history, clinical examination, laboratory results, necropsy findings, and outcome. Scores and score variables were compared between survivors and nonsurvivors using logistic regression. The optimal cutoff and its test parameters were calculated using a receiver operator characteristic curve. Results Prematurity, cold extremities, ≥2 infectious or inflammatory sites, blood glucose concentration, and total white blood cell counts were significantly associated with nonsurvival (P ≤ .02). The optimal cutoff to predict survival was ≥6, resulting in sensitivity 78%, specificity 58%, 92% positive predictive value, and 31% negative predictive value. The test performed equally well in foals <4 days old compared to those 4‐14 days old. Conclusions and Clinical Importance Using the suggested optimal cutoff of ≥6, the FSS performed moderately well and may aid in early determination of prognosis for survival. However, the FSS did perform differently in another population and therefore should be assessed under local conditions so that its diagnostic potential is not overestimated.
... Patients included in this study were neonatal foals (0-2 weeks of age) and adult horses (> 1 year old) admitted to-blocked for review-in the period of March-May 2016 with clinical and laboratory parameters compatible with systemic inflammatory response syndrome (SIRS). Animals were defined as having SIRS if 2 or more of the following criteria were met: tachycardia (heart rate > 40 beats/minute (adults) and > 120 beats/minute (foals)), tachypnea (respiratory rate > 20 breaths/minute (adults) and > 56 breaths/minute (foals)), hyper-or hypothermia (rectal temperature > 38.5˚C or < 37˚C (adults) and > 39.5˚C or < 37.2˚C (foals)), leukocytosis or leukopenia (> 10x10 9 cells/L or < 5x10 9 cells/L (adults) and > 12.5x10 9 cells/L or < 4x10 9 cells/L (foals)), presence of > 10% band neutrophils [16]. ...
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This pilot prospective study reports the feasibility, management and cost of the use of a continuous glucose monitoring (CGM) system in critically ill adult horses and foals. We compared the glucose measurements obtained by the CGM device with blood glucose (BG) concentrations. Neonatal foals (0–2 weeks of age) and adult horses (> 1 year old) admitted in the period of March-May 2016 with clinical and laboratory parameters compatible with systemic inflammatory response syndrome (SIRS) were included. Glucose concentration was monitored every 4 hours on blood samples with a point-of-care (POC) glucometer and with a blood gas analyzer. A CGM system was also placed on six adults and four foals but recordings were successfully obtained only in four adults and one foal. Glucose concentrations corresponded fairly well between BG and CGM, however, there appeared to be a lag time for interstitial glucose levels. Fluctuations of glucose in the interstitial fluid did not always follow the same trend as BG. CGM identified peaks and drops that would have been missed with conventional glucose monitoring. The use of CGM system is feasible in ill horses and may provide clinically relevant information on glucose levels, but there are several challenges that need to be resolved for the system to gain more widespread usability.
... Blood analysis revealed leukopenia (2.8 Â 10 3 cells/mL, reference range, 6.9e14.4 Â 10 3 cells/mL) [7], neutrophils' toxicity and left shift. Blood glucose levels, electrolytes and creatinine values were within normal range. ...
... In our study, dogs with hypothermia were at a greater risk of death than were dogs with hyperthermia. The reason could be that hypothermia is more indicative of shock, followed by multi-organ dysfunction (Wong and Wilkins, 2015). ...
Article
The purpose of this study was to investigate retrospectively the prevalence of the complicated and uncomplicated forms of babesiosis and to evaluate various laboratory and clinical parameters of dogs infected with Babesia canis in order to assess their prognostic value regarding the outcomes of the disease. Medical records, complete blood count and serum biochemical analysis from the animal hospital information system of 240 dogs were reviewed and evaluated retrospectively. Binary logistic regression analysis was used to ascertain correlations between alterations in the obtained parameters and survival probability. The results showed that creatinine levels of more than 5 mg/dL and phosphate levels of more than 3 mmol/L have a highly significant link to death (P ≤ 0.001). Albumin levels of <2.2 g/dL (P = 0.003) and a rectal body temperature below 38 °C (P ≤ 0.001) may also serve as prognostic markers for the severity of the disease. If renal involvement was present, 33.9% of the dogs died, while 40.0% of the dogs died in the presence of pancreatitis. The parameters creatinine, phosphate, albumin and rectal temperature serve as reliable predictive markers of an increased risk of death in the case of an infection with B. canis.
... In a recent review of equine neonatal sepsis, Wong et al. (90) present criteria for SIRS diagnosis based on the presence of 3 of 6 criteria (fever or hypothermia, tachycardia, tachypnea, leukocytosis, or leukopenia, hyperlactatemia, hypoglycemia) tailored to 4 different age categories (newborn, neonate, juvenile, weanling) (90). Wong et al. further stipulate that, as in human pediatrics (91), at least 1 of the criteria must be abnormal temperature or leukocyte count due to the fact that diseases affecting neonates often cause tachycardia and tachypnea. ...
Article
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The most recent definition of sepsis in human medicine can be summarized as organ dysfunction caused by a dysregulated host response to infection. In equine medicine, although no consensus definition is available, sepsis is commonly described as a dysregulated host systemic inflammatory response to infection. Defense against host infection is the primary role of innate immune cells known as neutrophils. Neutrophils also contribute to host injury during sepsis, making them important potential targets for sepsis prevention, diagnosis, and treatment. This review will present both historical and updated perspectives on the systemic inflammatory response (SIRS) and sepsis; it will also discuss the impact of sepsis on neutrophils, and the impact of neutrophils during sepsis. Future identification of clinically relevant sepsis diagnosis and therapy depends on a more thorough understanding of disease pathogenesis across species. To gain this understanding, there is a critical need for research that utilizes a clearly defined, and consistently applied, classification system for patients diagnosed with, and at risk of developing, sepsis.
... Equine systemic inflammatory response syndrome (SIRS), which often develops in horses with colic and colitis, was first defined by referring to the definition of human SIRS [ 8 , 9 ]. In a recent equine medicine, SIRS criteria in foals and adult horses have been presented [8][9][10] . Particularly in adult horses, intestinal diseases complicated with SIRS would be associated with a high risk of death [8] . ...
Article
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Histidine-rich glycoprotein (HRG) is an abundant plasma protein that has been identified in most mammals. We first identified whole genome sequence of equine HRG (eHRG) and succeeded to purify eHRG from plasma of horses. Since HRG interacts with various ligands, this protein is thought to be involved in immune response, coagulation, and angiogenesis. Systemic inflammatory response syndrome (SIRS) is characterized as a non-specific, clinical, pro-inflammatory immune response that damage organs and tissues in the host. Recent reports revealed that blood HRG levels in human patients with SIRS are approximately 50% lower than those in healthy controls, indicating the use of HRG as a biomarker or treatment for SIRS. SIRS is also a serious issue in equine medicine. In this study, we investigated various effects of eHRG on neutrophil functions, including adhesion, migration, phagocytosis, reactive oxygen species (ROS) production, and lysosome maturation using neutrophils isolated from horses. Microscopic observation showed that the addition of eHRG to the culture diminished adhesion of neutrophils stimulated with LPS. Using the Boyden chamber technique, we showed that eHRG reduced neutrophil chemotaxis induced by recombinant human IL-8. Luminol-dependent chemiluminescence assay demonstrated that eHRG restrained the peak of LPS-promoted ROS production from neutrophils. In contrast, eHRG promoted phagocytic activity evaluated with uptake of fluorescent dye conjugated particles, as well as lysosomal maturation assessed using fluorescent staining for lysosomes of equine neutrophils. These results indicated that eHRG acts as a dual regulator of neutrophils in horses.
... • positive blood culture; • positive culture of samples from local sites of suspected infection; • postmortem examination. Systemic inflammatory response syndrome (SIRS) diagnosis was made as suggested by Wong and Wilkins [34]. ...
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There is a wide array of evidence across species that exposure to antibiotics is associated with dysbiosis, and due to their widespread use, this also raises concerns also in medicine. The study aimed to determine the changes on the fecal microbiota in hospitalized neonatal foals administered with broad-spectrum antimicrobials and supplemented probiotics. Fecal samples were collected at hospital admission (Ta), at the end of the antimicrobial treatment (Te) and at discharge (Td). Feces were analysed by next-generation sequencing of the 16S rRNA gene on Illumina MiSeq. Seven foals treated with IV ampicillin and amikacin/gentamicin were included. The mean age at Ta was 19 h, the mean treatment length was 7 days and the mean time between Te and Td was 4.3 days. Seven phyla were identified: Actinobacteria, Bacteroidetes, Firmicutes, Fusobacteria, Proteobacteria, TM7 and Verrucomicrobia. At Ta, Firmicutes (48.19%) and Proteobacteria (31.56%) were dominant. The alpha diversity decreased from Ta to Te, but it was the highest at Td. The beta diversity was higher at Ta than at Te and higher at Td than at Te. An increase in Akkermansia over time was detected. The results suggest that the intestinal microbiota of neonatal foals rapidly returns to a high diversity after treatment. It is possible that in foals, the effect of antimicrobials is strongly influenced or overshadowed by the time-dependent changes in the developing gut microbiota.
... This section included five items: 'rectal temperature' [30], 'heart rate' [31,32], 'respiratory rate' [33], 'reaction to palpation of the painful area' [12] and 'intestinal motility' [27] ( Table 5). Items are scored on a two-point scale (0, 2), except for 'reaction to palpation of the painful area' that is scored by intensity (0, 1, 2). ...
Article
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Prompt pain management is crucial in horses; however, tools to assess pain are limited. This study aimed to develop and pilot a composite scale for pain estimation in foals. The “Foal Composite Pain Scale” (FCPS) was developed based on literature and authors’ expertise. The FCPS consisted of 11 facial expressions, 4 behavioural items, and 5 physical items. Thirty-five pain-free foals (Control Group) and 15 foals experiencing pain (Pain Group) were used. Foals were video-recorded at different time points: the Control Group only at inclusion (C), while the Pain Group at inclusion (T1), after an analgesic treatment (T2), and at recovery (T3). Physical items were also recorded at the same time points. Videos were scored twice by five trained observers, blinded to group and time points, to calculate inter- and intra-observer reliability of each scale item. Fleiss’ kappa values ranged from moderate to almost perfect for the majority of the items, while the intraclass correlation coefficient was excellent (ICC = 0.923). The consistency of FCPS was also excellent (Cronbach’s alpha = 0.842). A cut-off ≥ 7 indicated the presence of pain. The Pain Group scores were significantly higher (p < 0.001) than the Control Group and decreased over time (T1, T2 > T3; p = 0.001). Overall, FCPS seems clinically applicable to quantify pain and improve the judgment of the quality of life in foals, but it needs modifications based on these preliminary findings. Consequently, further studies on a larger sample size are needed to test the feasibility and validity of the refined FCPS.
... All foals were classified as having or not having systemic inflammatory response syndrome (SIRS) using SIRS criteria (Table S4). 27 ...
Article
Background: Serum amyloid A (SAA) has been reported to hold promise as diagnostic and prognostic marker in foals. This has not been investigated thoroughly. Objectives: Evaluate admission SAA concentrations as predictor of sepsis and outcome. Animals: Five hundred and ninety hospitalized foals <14 days old. Methods: Retrospective multicenter study. Foals were scored with sepsis and survival scores, grouped according to health category (septic, sick but nonseptic, uncertain sepsis status) and outcome; septic foals were further categorized according to severity (normal sepsis, severe sepsis, and septic shock). SAA was compared between groups using Mann-Whitney test and Kruskal-Wallis test. Receiver operating characteristic curves identified optimal SAA cut off values for detecting sepsis and predicting outcome. Results: Admission SAA concentrations differed significantly between sick nonseptic foals (312.1 ± 685.4 mg/L) and septic foals (1079.7 ± 1254.5 mg/L) and increased with increasing sepsis score. SAA did not differ between sepsis severity groups. The optimal cut off for sepsis detection was 1050 mg/L (sensitivity 30.2%, specificity 90.7%). Admission SAA concentrations were lower in surviving (435.0 ± 723.6 mg/L) compared to nonsurviving foals (1062.7 ± 1440.1 mg/L) and decreased with increasing survival score. The optimal cut off for nonsurvival prediction was 1250 mg/L (sensitivity 22.1%, specificity 90.8%). Conclusions and clinical importance: SAA concentration was higher in septic foals and nonsurviving foals. Even though optimal cut offs for SAA to detect sepsis and predict outcome had low sensitivity, they had good specificity. SAA can therefore be used as a marker to rule out sepsis and nonsurvival.
... Measurements were routinely performed within 30 minutes of blood collection. Strong ion difference (SID = Na + + plasma potassium (K + ) -plasma chloride (Cl − ) concentrations), anion gap (AG = Na + + K + -Cl − -total carbon dioxing neurological signs during the first 24 hours of life were excluded.Presence or absence of SIRS was assessed as previously described12 on the day of the lowest recorded Na + concentration. In brief, pres- ...
Article
Objective: Hyponatremia and rapid correction of hyponatremia can lead to neurological abnormalities. The objective of the study was to determine whether plasma sodium concentrations (Na+ ) and speed of correction of hyponatremia are significantly associated with neurological abnormalities in foals. Design: Retrospective cohort study 2012 to 2016. Setting: Equine hospital. Animals: One hundred and nine foals <6 months old with hyponatremia (Na+ concentration ≤125 mmol/L). Interventions: Case records were reviewed for any foal with hyponatremia. Clinicopathological findings, presence or absence of neurological signs on the day of the lowest Na+ concentration measured and the following 5 days, diagnosis and outcome were recorded, and changes in Na+ concentration per hour were calculated for up to 5 subsequent days. Logistic regression was used to assess the association between presence or absence of neurological signs, Na+ concentration, other known risk factors for neurological dysfunction in foals, and possible confounders. Measurements and main results: In the final multivariable model, only Na+ (odds ratio [OR]: 0.86; 95% CI 0.79-0.95; P = 0.002) and BUN concentrations (OR: 1.04; 95% CI: 1.02-1.06; P = 0.001) were significantly associated with neurological signs. Changes in Na+ concentrations per hour were not associated with neurological signs on any day after the lowest Na+ concentration had been measured (P = 0.18-0.82), and development of new neurological signs following correction of hyponatremia was not reported in any foal. Conclusions: Na+ concentrations were associated with the development of neurological signs in hyponatremic foals. Increased BUN concentrations might contribute to neurological dysfunction, but further studies are necessary to confirm or refute these findings.
Article
Objective: The aim of this study was to present the incidence and lethality of diseases in foals during the first 10 days following birth by analyzing patient data. Material and methods: Over a period of 6 years, patient data from 393 foals, that had been presented within the first 10 days after birth in a hospital, were evaluated. The number of diseases, the sex of the affected foals and the lethality were documented. Results: A total of 28 diseases were diagnosed, with systemic inflammatory response syndrome (SIRS), meconium impaction and bronchopneumonia being the most frequent diagnoses. The mortality rate for SIRS was 41.8%, for meconium impaction 29.7% and for bronchopneumonia 37.9%. The mean time of death for patients with SIRS was 4.2 ± 2.9 days, for patients with meconium impaction 4.6 ± 3.2 days and for foals suffering from bronchopneumonia 5.2 ± 3.5 days post partum. Conclusion and clinical relevance: Based on the data collection, the frequency and thus the importance of individual disease patterns can be deduced. The information on lethality helps to make predictions for the prognosis of the most common neonatal foal diseases based on first diagnosis.
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La sepsis neonatal equina es el desorden más prevalente en potros menores de 14 días de edad, tiene una mortalidad y comorbilidad alta junto a otras enfermedades que se presentan en el potro, por lo tanto, es necesario hacer un diagnóstico rápido y oportuno, para establecer un tratamiento adecuado. En 1988 se estableció un procedimiento diagnóstico llamado “sepsis score”, han pasado más de 30 años desde que se creó, en este tiempo nuevos horizontes de pruebas paraclínicas en la medicina equina han surgido, entre estos, una variedad de biomarcadores en sepsis. Por tal razón, es importante realizar la actualización de dicho método diagnóstico de sepsis en potros. Los biomarcadores son moléculas, genes u otras características naturales que permiten identificar procesos fisiológicos o patológicos particulares y estos a su vez permiten dar un pronóstico sobre la evolución de la enfermedad y la respuesta al tratamiento. Los nuevos biomarcadores que han tenido mayor investigación en el campo de la elucidación de los efectos sépticos en la fisiología del potro y por tanto probable acogida clínica en la especie equina son: Procalcitonina, Amiloide A Sérico, Endotelina 1, Interleuquinas 6 y 10, Antitrombina, diferentes esteroides, CD14 soluble y triglicéridos. La importancia de estos nuevos biomarcadores y su vinculación dentro de la metodología de diagnóstico de los cuadros de sepsis en potros radica en que podría discriminar la sepsis de otras enfermedades críticas con mayor precisión clínica, además se podría predecir con certeza la respuesta al tratamiento de esta, estableciendo un pronóstico adecuado.
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Blood culture is considered the gold standard test for documenting bacteraemia in patients with suspected bacterial sepsis in veterinary and human medicine. However, blood culture often fails to yield bacterial growth even though the clinical picture is strongly suggestive of bacterial sepsis, or contaminating organisms can overgrow the true pathogen, making accurate diagnosis and appropriate management of this life-threatening condition very challenging. Methodology for collecting blood cultures in equine medicine, and even in human hospitals, is not standardised, and many variables can affect the yield and type of microorganisms cultured. Microbiological culture techniques used in the laboratory and specific sample collection techniques, including volume of blood collected, aseptic technique utilised, and the site, timing and frequency of sample collection, all have substantial impact on the accuracy of blood culture results. In addition, patient-specific factors such as husbandry factors, the anatomical site of the primary infection, and changing microflora in different geographic locations, also can impact blood cultures. Thus, blood cultures obtained in practice may not always accurately define the presence or absence of, or specific organisms causing, bacteraemia in horses and foals with suspected sepsis. Erroneous blood culture results can lead to inappropriate antimicrobial use, which can result in poor outcomes for individual patients and contribute to the development of antimicrobial resistance in the patient's microflora and the environmental microcosm. This review summarises current indications and methodology, and specific factors that may be optimised, for equine blood culture, with particular focus on available literature from neonatal foals with suspected bacterial sepsis. To standardise and optimise blood culture techniques in horses and foals, future research in this area should be aimed at determining the optimal volume of blood that should be collected for culture, and the ideal site, timing, and frequency of sample collection.
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This retrospective case series describes the clinicopathologic findings, diagnoses, treatment, and outcomes of 10 hand-reared newborn giraffe (Giraffa camelopardalis) calves admitted to a university teaching hospital for intensive care. Ten calves (five males, five females; nine reticulated giraffes [Giraffa camelopardalis reticulata], one Masai giraffe [G. c. tippelskirchi]), were admitted under 2 days of age. Inadequate transfer of passive immunity was suspected in 5 of 10 calves based on assessment of serum total solids and globulin values. These calves were treated with oral frozen bovine colostrum and/or intravenous hyperimmune bovine plasma. Diarrhea occurred in 6 of 10 calves and was managed with supportive care, fecal microbiota transplantation, and limiting milk intake (offering 10% body weight [BW] in milk per day, while feeding <2 L per meal at 2- to 4-hr intervals). Less common diagnoses included pneumonia (n = 3) and mycoplasma-associated septic arthritis (n = 1). Eight calves received systemic antimicrobial therapy. Hyperlactatemia (lactate > 5 mmol/L; n = 8) and hypercreatininemia (creatinine > 2.0 mg/dl, n = 7) were the most common presenting laboratory abnormalities, which resolved with intravenous fluid therapy. All neonatal giraffes survived to discharge after a median hospitalization of 9.5 days (range, 5-37 days) and were successfully hand-reared at their place of birth. In conclusion, neonatal giraffe calves can be intensively managed in a hospital environment. Diarrhea was a common clinical problem and can be related to feeding regimens. Intravenous hyperimmune bovine plasma infusion was well tolerated to manage failure of transfer of passive immunity in calves with inadequate colostrum administration. The current study supports that compromised neonatal giraffe calves may carry an excellent prognosis after early, intensive intervention.
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Objective Species-related differences in the prevalence, manifestation, and outcome of neonatal illness may impact management practices of neonatal intensive care. The study aimed to elucidate similarities between disease manifestations and mortality risks of critically ill (CI) neonatal crias and foals admitted to the same referral center. Design A comparative, retrospective cohort evaluation of two species (camelid and equine). Setting The study was conducted in a University hospital. Animals Two hundred and forty-six CI neonatal crias (January 1999 to May 2016) and 356 neonatal foals (February 2001 to May 2016) under 4-week-old were admitted to a university hospital. Intervention All data are presented descriptively and compared between groups using univariate and multivariate analyses. Measurements and Main Results Female crias (142/246, 57.7%) were significantly overrepresented in comparison to fillies (132/352, 37.5%). Congenital defects and transfer failure of passive immunity were more often observed in neonatal crias, while colic, diarrhea, patent urachus, septic arthritis, and omphalitis were significantly more common in CI foals. Overall survival to discharge (excluding fatal congenital defects) was comparable between crias (174/224; 77.8%) and foals (287/347, 82.1%), while crias (26/48; 54.2%) were more likely than foals (21/60; 35%) to die naturally than undergo euthanasia. Lower respiratory disease and indications for oxygen or IV glucose support increased mortality in the multivariate outcome models of both species. Species-specific adaptations of pediatric diagnostic criteria for sepsis were significantly associated with mortality in the multivariate analysis of patients with complete hematological datasets. However, the diagnosis of systemic inflammatory response syndrome (SIRS) did not retain statistical significance as an independent outcome predictor. Conclusions Lower respiratory disease and oxygen or glucose dysregulation increased mortality irrespective of species. However, despite species-specific differences in disease prevalence, the success of intensive care management was comparable.
Chapter
The neonatal foal presenting for general anesthesia is a unique challenge in the equine species. This chapter provides an update to current practices and focused information on specific techniques and conditions related to anesthesia of the neonatal foal while covering some general information. The neonatal period is generally classified as the first four weeks of life and is a period of very rapid physiologic change and adaptation, particularly in the cardiovascular, respiratory, immune, and neurologic systems. Much of the information comes from studies in human neonates, as comparatively, literature on anesthesia of the equine neonate is sparse. The goal of cardiovascular monitoring is assessing the adequacy of circulation and tissue perfusion. Sepsis represents one of the most significant causes of systemic inflammatory response syndrome in neonatal foals. In equine neonates, respiratory disease is one of the most common contributors to patient morbidity and mortality.
Chapter
The ocular examination is greatly underused in the diagnosis of systemic diseases in horses. This chapter aims to allow the equine practitioner to become more aware of the changes that can occur in the eye and be able to use them as diagnostic aids; and to enable the veterinary ophthalmologist to recognize the systemic conditions associated with some ocular diseases in the horse. Ocular clinical signs associated with facial nerve paralysis include ptosis, absence of the menace response, and absence of the palpebral reflex. Ocular onchocerciasis may be diagnosed by the clinical findings suggestive of the parasitic disease. Histopathological examination of skin biopsies from horses with hereditary equine regional dermal asthenia (HERDA) show alterations in the distribution, orientation, and density of collagen fibers, but as HERDA is a dermatologic regional disease, many areas show normal skin.
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The ambulatory practitioner is usually the first to evaluate the equine neonate and must assess the foal and determine its health status. If one or more abnormalities are identified, the practitioner must initiate appropriate treatment and determine whether the foal can be managed successfully on the farm or referred to a specialty centre. This article describes the basic requirements that should be met and the limitations involved in treating compromised neonates on the farm. Treatments for common foal disorders are discussed.
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Improvements in the control of haemorrhage after trauma have resulted in the survival of many people who would otherwise have died from the initial loss of blood. However, the danger is not over once bleeding has been arrested and blood pressure restored. Two-thirds of patients who die following major trauma now do so as a result of causes other than exsanguination. Trauma evokes a systemic reaction that includes an acute, non-specific, immune response associated, paradoxically, with reduced resistance to infection. The result is damage to multiple organs caused by the initial cascade of inflammation aggravated by subsequent sepsis to which the body has become susceptible. This Series examines the biological mechanisms and clinical implications of the cascade of events caused by large-scale trauma that leads to multiorgan failure and death, despite the stemming of blood loss. Furthermore, the stark and robust epidemiological finding—namely, that age has a profound influence on the chances of surviving trauma irrespective of the nature and severity of the injury—will be explored. Advances in our understanding of the inflammatory response to trauma, the impact of ageing on this response, and how this information has led to new and emerging treatments aimed at combating immune dysregulation and reduced immunity after injury will also be discussed.
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Toll-like receptors (TLRs) play crucial roles in the innate immune system by recognizing pathogen-associated molecular patterns derived from various microbes. TLRs signal through the recruitment of specific adaptor molecules, leading to activation of the transcription factors NF-κB and IRFs, which dictate the outcome of innate immune responses. During the past decade, the precise mechanisms underlying TLR signaling have been clarified by various approaches involving genetic, biochemical, structural, cell biological, and bioinformatics studies. TLR signaling appears to be divergent and to play important roles in many aspects of the innate immune responses to given pathogens. In this review, we describe recent progress in our understanding of TLR signaling regulation and its contributions to host defense.
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The concept of a systemic inflammatory response syndrome (SIRS) to describe the complex pathophysiologic response to an insult such as infection, trauma, burns, pancreatitis, or a variety of other injuries came from a 1991 consensus conference charged with the task of developing an easy to apply set of clinical parameters to aid in the early identification of potential candidates to enter into clinical trials to evaluate new treatments for sepsis. There was recognition that a diverse group of injuries produced a common inflammatory response in the host and provided attractive targets for new anti-inflammatory molecules designed to prevent further propagation and/or provide specific treatment. Effective application of these new anti-inflammatory strategies necessitated identification of early clinical markers that could be assessed in real-time and were likely to define a population of patients that would have a beneficial response to the targeted intervention. It was felt that early clinical manifestations might be more readily available to clinicians than more sophisticated and specific assays for inflammatory substances that were systemically released by the network of injurious inflammatory events. Therefore, the early definition of a systemic inflammatory response syndrome (SIRS) was built upon a foundation of basic clinical and laboratory abnormalities that were readily available in almost all clinical settings. With further refinement, it was hoped, that this definition would have a high degree of sensitivity, coupled with a reasonable degree of specificity. This manuscript reviews the derivation, application, utilization, potential benefits, and speculation regarding the future of the SIRS definition.
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Patients subject to major surgery, suffering sepsis, major trauma, or following cardiopulmonary bypass exhibit a systemic inflammatory response. This inflammatory response involves a complex array of inflammatory polypeptide molecules known as cytokines. It is well accepted that the loss of local control of the release of these cytokines leads to systemic inflammation and potentially deleterious consequences including the Systemic Inflammatory Response Syndrome, Multi-Organ Dysfunction Syndrome, shock and death. The Medline database was searched for literature on mechanisms involved in the development of SIRS and potential targets for modifying the inflammatory response. We focus on the novel therapy of cytokine adsorption as a promising removal technology. Accumulating data from human studies and experimental animal models suggests that both pro- and anti- inflammatory cytokines are released following a variety of initiating stimuli including endotoxin release, complement activation, ischaemia reperfusion injury and others. Pro-and anti-inflammatory cytokines interact in a complex and unpredictable manner to influence the immune system and eventually cause multiple end organ effects. Cytokine adsorption therapy provides a potential solution to improving outcomes following Systemic Inflammatory Response Syndrome.
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The reasoning that neural reflexes maintain homeostasis in other body organs, and that the immune system is innervated, prompted a search for neural circuits that regulate innate and adaptive immunity. This elucidated the inflammatory reflex, a prototypical reflex circuit that maintains immunological homeostasis. Molecular products of infection or injury activate sensory neurons traveling to the brainstem in the vagus nerve. The arrival of these incoming signals generates action potentials that travel from the brainstem to the spleen and other organs. This culminates in T cell release of acetylcholine, which interacts with α7 nicotinic acetylcholine receptors (α7 nAChR) on immunocompetent cells to inhibit cytokine release in macrophages. Herein is reviewed the neurophysiological basis of reflexes that provide stability to the immune system, the neural- and receptor-dependent mechanisms, and the potential opportunities for developing novel therapeutic devices and drugs that target neural pathways to treat inflammatory diseases.
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Emerging evidence shows a broad spectrum of biological functions of tissue factor (TF). TF classical role in initiating the extrinsic blood coagulation and its direct thrombotic action in close relation to cardiovascular risks have long been established. TF overexpression/hypercoagulability often observed in many clinical conditions certainly expands its role in proinflammation, diabetes, obesity, cardiovascular diseases, angiogenesis, tumor metastasis, wound repairs, embryonic development, cell adhesion/migration, innate immunity, infection, pregnancy loss, and many others. This paper broadly covers seminal observations to discuss TF pathogenic roles in relation to diverse disease development or manifestation. Biochemically, extracellular TF signaling interfaced through protease-activated receptors (PARs) elicits cellular activation and inflammatory responses. TF diverse biological roles are associated with either coagulation-dependent or noncoagulation-mediated actions. Apparently, TF hypercoagulability refuels a coagulation-inflammation-thrombosis circuit in "autocrine" or "paracrine" fashions, which triggers a wide spectrum of pathophysiology. Accordingly, TF suppression, anticoagulation, PAR blockade, or general anti-inflammation offers an array of therapeutical benefits for easing diverse pathological conditions.
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Neural circuits regulate cytokine production to prevent potentially damaging inflammation. A prototypical vagus nerve circuit, the inflammatory reflex, inhibits tumor necrosis factor–α production in spleen by a mechanism requiring acetylcholine signaling through the α7 nicotinic acetylcholine receptor expressed on cytokine-producing macrophages. Nerve fibers in spleen lack the enzymatic machinery necessary for acetylcholine production; therefore, how does this neural circuit terminate in cholinergic signaling? We identified an acetylcholine-producing, memory phenotype T cell population in mice that is integral to the inflammatory reflex. These acetylcholine-producing T cells are required for inhibition of cytokine production by vagus nerve stimulation. Thus, action potentials originating in the vagus nerve regulate T cells, which in turn produce the neurotransmitter, acetylcholine, required to control innate immune responses.
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It is generally believed that diseases caused by oxidative stress should be treated with antioxidants. However, clinical trials with such antioxidants as ascorbic acid and vitamin E, failed to produce the expected beneficial results. On the other hand, important biomolecules can be modified by the introduction of oxygen atoms by means of non-oxidative hydroxyl radicals. In addition, hydroxyl radicals can reduce disulfide bonds in proteins, specifically fibrinogen, resulting in their unfolding and scrambled refolding into abnormal spatial configurations. Consequences of this reaction are observed in many diseases such as atherosclerosis, cancer and neurological disorders, and can be prevented by the action of non-reducing substances. Moreover, many therapeutic substances, traditionally classified as antioxidants, accept electrons and thus are effective oxidants. It is described in this paper that hydroxyl radicals can be generated by ferric ions without any oxidizing agent. In view of the well-known damaging effect of poorly chelated iron in the human body, numerous natural products containing iron binding agents can be essential in the maintenance of human health. However, beneficial effects of the great number of phytochemicals that are endowed with hydroxyl radical scavenging and/or iron chelating activities should not be considered as a proof for oxidative stress.
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Neonatal sepsis is a major cause of neonatal mortality and morbidity. The current gold standard for diagnosis of sepsis, namely blood culture, suffers from low sensitivity and a reporting delay of approximately 48-72 h. Rapid detection of sepsis and institution of antimicrobial therapy may improve patient outcomes. Rapid and sensitive tests that can inform clinicians regarding the institution or optimization of antimicrobial therapy are urgently needed. The ideal diagnostic test should have adequate specificity and negative predictive value to reliably exclude sepsis and avoid unnecessary antibiotic therapy. We comprehensively searched for neonatal studies that evaluated molecular methods for diagnosis of sepsis. We identified 19 studies that were assessed with respect to assay methodology and diagnostic characteristics. In addition, we also reviewed newer molecular microbiological assays of relevance that have not been fully evaluated in neonates. Molecular methods offer distinct advantages over blood cultures, including increased sensitivity and rapid diagnosis. However, diagnostic accuracy and cost-effectiveness should be established before implementation in clinical practice.
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Cytokines produced by T helper (Th) cells are important in orchestrating the immune response during health and disease. Recent reports indicated that cytokine mRNA expression in foals is often quantitatively lower than that of adult horses suggesting that foal T cells are not fully mature. Here, peripheral blood mononuclear cells from foals and adult horses were stimulated with phorbol 12-myristate 13-acetate and analyzed for intracellular interferon-gamma (IFN-gamma), interleukin-4 (IL-4) and IL-10 production, representing the Th1, Th2 and regulatory TR1 cell phenotypes respectively, by flow cytometry. In agreement with previous reports, all three cytokines were quantitatively reduced in foals compared to adults. However, the balance between Th1 and Th2 cytokines (IFN-gamma/IL-4 ratio) showed a clear Th1-biased response in foals by 6 and 12 weeks of life, while similar IFN-gamma/IL-10 ratios were found in foals and adult horses. By day 5 after birth, intracellular IFN-gamma production by foal CD4+ and CD8+ T cells resembled that in adults. Overall, IL-4 production was low in foals. IL-4+ cells peaked at day 5 of age when IL-4 was mainly produced by IgE+ cells. Relative percentages of IL-4+ Th2 cells were significantly lower in foals at all time points. The data suggested that equine neonates and young foals have an impaired Th2 response, that the immune response of foals is Th1 biased, that IFN-gamma production by Th and cytotoxic T cells is qualitatively similar to adult horses, and regulatory IL-10 production by T cells is developmentally mature in foals during the first three months of life.
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Inflammation caused by infection takes place by the cooperative cascade of cytokines and leukocytes. Tumor necrosis factor, interlukin-1, and interlukin-6 play important roles as proinflammatory cytokines to mediate local inflammation and activate other inflammatory cells e.g. neutrophils, monocytes, and macrophages. At least 15 different low molecular weight cytokine are secreted by activated leukocytes and are responsible for triggering acute phase response in the form of fever, leukocytosis, increased secretion of adreno corticotropic hormones, and production of acute phase proteins. Acute phase proteins are produced in liver under the influence of cytokines, which through blood stream passes to the site of inflammation and kill the pathogens by opsonization and activating complement pathways. The changes in the concentrations of positive acute-phase proteins and negative acute-phase proteins are due to the changes in their production by liver. Three of the best known acute phase proteins are C-reactive protein, serum anyloid A, and haptoglobin. Some disease states are casually related to acute phase proteins. C-reactive protein mediated compliment activation has a key role in some forms of tissue alteration such as cardiac infarction. Elevated S amyloid A levels are seen in chronic arthritis and tuberculosis. Other acute phase proteins show more moderate rise, usually less than fivefold.
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An American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference was held in Northbrook in August 1991 with the goal of agreeing on a set of definitions that could be applied to patients with sepsis and its sequelae. New definitions were offered for some terms, while others were discarded. Broad definitions of sepsis and the systemic inflammatory response syndrome were proposed, along with detailed physiologic parameters by which a patient may be categorized. Definitions for severe sepsis, septic shock, hypotension, and multiple organ dysfunction syndrome were also offered. The use of severity scoring methods when dealing with septic patients was recommended as an adjunctive tool to assess mortality. Appropriate methods and applications for the use and testing of new therapies were recommended. The use of these terms and techniques should assist clinicians and researchers who deal with sepsis and its sequelae.
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The development of equine immunity from the fetus to adulthood is complex. The foal's immune response and the immune mechanisms that they are equipped along with changes over the first months of life until the immune system becomes adult-like are only partially understood. While several innate immune responses seem to be fully functional from birth, the onset of adaptive immune response is delayed. For some adaptive immune parameters, such as IgG1, IgG3, IgG5 and IgA antibodies, the immune response starts before or at birth and matures within 3 months of life. Other antibody responses, such as IgG4, IgG7 and IgE production, slowly develop within the first year of life until they reach adult levels. Similar differences have been observed for adaptive T cell responses. Interferon-gamma (IFN-γ) production by T helper 1 (Th1)-cells and cytotoxic T-cells starts shortly after birth with low level production that gradually increases during the first year of life. In contrast, interleukin-4 (IL-4) produced by Th2-cells is almost undetectable in the first 3 months of life. These findings offer some explanation for the increased susceptibility of foals to certain pathogens, such as Rhodococcus equi. The delay in Th-cell development, and in particular Th2 immunity, during the first months of life also provides an explanation for the reduced responsiveness of young horses to most traditional vaccines. In summary, all immune components of adult horses seem to exist in foals but the orchestrating and regulation of the immune response in immature horses is strikingly different. Young foals are fully competent and can perform certain immune responses but many mechanisms have yet to mature. Additional work is needed to improve our understanding of immunity and immune regulation in young horses, to identify the preferred immune pathways that they are using, and to ultimately provide new preventive strategies to protect against infectious disease.
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Reason for Performing StudyThe use of fentanyl is limited in adult horses in part due to potential for central nervous system excitation. The pharmacokinetics and the plasma concentration related behavioural actions of fentanyl are not described for young foals. Objectives The goal of the current study was to describe the pharmacokinetics and behavioural effects of fentanyl following administration to the same group of foals at 3 different ages. Study DesignExperimental study in healthy foals. Methods Fentanyl was administered intravenously (4 μg/kg) to a group of 9 foals on 3 separate occasions at 6-8, 20-22 and 41-42 days of age. Blood samples were collected prior to administration and at multiple times until 24 h post administration. Blood samples were analysed for fentanyl concentrations and pharmacokinetics determined at each age. Behavioural and physiologic effects were also assessed. ResultsThe average volume of distribution was 3.55, 1.53 and 1.82 L/kg and clearance 50.2, 40.7 and 35.7 ml/min/kg when foals were 6-8, 20-22 and 41-42 days of age, respectively. The elimination half-life was slightly prolonged (49.3 min) at 6-8 days relative to 20-22 and 41-42 days of age (25.8 and 33.7 min, respectively). The primary metabolite detected in blood samples was the same as for adult horses. While the onset and duration varied widely between foals, sedation was observed at all ages studied. Conclusions Fentanyl appears to be consistently well-tolerated following intravenous administration of 4 μg/kg to foals ranging in age from 1-6 weeks. The results of this study support further study of fentanyl for clinical use in foals.
Article
Reasons for performing the studyNeonatal sepsis is a common problem in foals and is a primary cause of death in the post natal period. Transient bacteraemia and subsequent host responses have not been described in the equine neonate. Objectives The primary objective of this study was to determine if transient bacteraemia occurs in foals within the first 72h of life. Additional objectives included description of bacterial organisms associated with transient bacteraemia and concurrent cytokine gene expression in healthy foals. Study designProspective observational study in healthy foals. Methods Blood was aseptically collected for bacterial culture from observed spontaneously born foals at birth and 1, 2, 3, 4, 8, 12, 24, 48 and 72h following birth. Samples taken at birth, 4, 12, 24, 48 and 72h were analysed for interferon gamma (IFN), interleukin (IL)-1, IL-2, IL-6, IL-8, IL-10, IL-18 and monocyte chemotactic protein 1 (MCP1) cytokine gene expression quantified by RT-PCR. ResultsBacteria were cultured from 9 of 70 samples submitted for blood culture. The positive samples were from 4 of the 7 foals, all of which remained healthy throughout and subsequent to the study. All positive blood cultures were from blood samples obtained at 12h of age or earlier and IL-10 elevation coincided with positive blood cultures in healthy foals. Cytokine gene expression fluctuated with age. Conclusions Positive blood cultures suggest transient bacteraemia may occur in healthy foals early in the post natal period. Age corrected normal values may be necessary to interpret cytokine concentration in diseased populations.
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Some veterinarians describe particularly sick horses or neonatal foals as being endotoxemic, whereas others refer to the same animals as having the systemic inflammatory response syndrome. This article reviews the basis for the use of each of these terms in equine practice, and highlights the mechanisms underlying the response of the horse's innate immune system to key structural components of the microorganisms that initiate these conditions, including how some of those responses differ from other species. Current approaches used to treat horses with these conditions are summarized, and caution advised on extrapolating findings from other species to the horse.
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Raymond J., LangleyJennifer L., TipperShannon, BruseRebecca M., BaronEphraim L., TsalikJames, HuntleyAngela J., RogersRichard J., JaramilloDenise, O'DonnellWilliam M., MegaMignon, KeatonElizabeth, KensickiLee, GazourianLaura E., FredenburghAnthony F., MassaroRonny M., OteroVance G., FowlerEmanuel P., RiversChris W., WoodsStephen F., KingsmoreMohan L., SoporiMark A., PerrellaAugustine M. K., ChoiKevin S., Harrod. (2014) Integrative “Omic” Analysis of Experimental Bacteremia Identifies a Metabolic Signature That Distinguishes Human Sepsis from Systemic Inflammatory Response Syndromes. American Journal of Respiratory and Critical Care Medicine 190, 445-455 CrossRef
Article
Neonatal sepsis is a serious and often fatal disease of the foal. Research has documented that the clinical syndrome which results from bacterial infection of the neonate is the result of a widespread and florid inflammatory response which is termed the systemic inflammatory response syndrome (SIRS). Successful treatment of affected individuals is possible, and an important component of the treatment is the proper use of antimicrobials. Proper selection of antimicrobials requires the consideration of several important factors including the infecting organism, toxicity, and route of administration, cost, and metabolism of the antimicrobial. In most cases, antimicrobial treatment can be discontinued when localizing signs of infection are absent, and the temperature and complete blood cell count have been normal for 72 hours.
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Seven critically ill foals that continued to be hypotensive despite fluid resuscitation and the infusion of dobutamine and/or dopamine were treated with an infusion of norepinephrine (noradrenaline). The norepinephrine was administered concurrently with dobutamine, and the combination therapy was titrated by use of indirect mean arterial pressure measurements. The highest dose of norepinephrine used was 1.5 mcg/kg/min. In six foals the administration of norepinephrine was associated with an increase in blood pressure. In one foal the mean arterial pressure did not increase in response to the doses of norepinephrine administered. All of the foals experienced an increase in urine output coincident with the start of the norepinephrine infusion. Three of the foal survived to hospital discharge.
Article
Sick neonatal foals suffer from a variety of endocrine and metabolic derangements that may be related to outcome. There are several hepatic and lipid metabolism blood markers that have never been assessed in neonatal foals. Assess panel of endocrine and metabolic variables in group of sick and healthy neonatal foals in order to describe their relationship with diagnosis and survival. All neonatal foals referred to Unitat Equina-Fundació Hospital Clínic Veterinari during 3 consecutive foaling seasons and a group of healthy foals. Observational prospective study. Blood samples were obtained on admission and, when possible, after 24–48 h of hospitalization and immediately before discharge or death. Measured variables were triglycerides, nonsterified fatty acids, glucose, creatinine, urea, γ-glutamyltransferase, glutamate dehydrogenase (GLDH), insulin, cortisol, bile acids, and adrenocorticotropic hormone (ACTH). ACTH/cortisol and glucose/insulin ratios were calculated. Urea, creatinine, and cortisol had median concentrations in septic and nonseptic foals 2- to 8-fold higher than in the control group (P < .001). Median ACTH concentration in the septic group was approximately 4 times higher than in nonseptic and control foals (P < .001). ACTH/cortisol ratio was significantly lower in sick foals compared to control foals (P < .001). A score was designed including creatinine, GLDH, and cortisol. When ≥2 of these variables were altered (P < .001), the foal had 32 times more risk of dying (OR, 31.7; 95% CI, 7.7–130.3). Plasma creatinine, GLDH, and cortisol should be determined in sick newborn foals on admission because of their association with survival.
Article
The pathophysiology of sepsis and its accompanying systemic inflammatory response syndrome (SIRS) and the events that lead to multiorgan failure and death are poorly understood. It is known that, in septic humans and rodents, the development of SIRS is associated with a loss of the redox balance, but SIRS can also develop in noninfectious states. In addition, a hyperinflammatory state develops, together with impaired innate immune functions of phagocytes, immunosuppression, and complement activation, collectively leading to septic shock and lethality. Here, we discuss recent insights into the signaling pathways in immune and phagocytic cells that underlie sepsis and SIRS and consider how these might be targeted for therapeutic interventions to reverse or attenuate pathways that lead to lethality during sepsis.
Article
To evaluate and compare the gene expression of interleukin(IL)-1β, IL-8, and interferon-γ during the first 72 hours after birth in healthy foals and during the first 72 hours after hospitalization in sick neonatal foals and investigate correlations of clinicopathologic variables with cytokine expressions in healthy and sick neonatal foals. 33 foals < 7 days old (10 healthy foals, 7 foals with sepsis, 6 foals with peripartum asphyxia syndrome, and 12 foals with other diseases [2 with failure of passive transfer of immunity only were not further evaluated]). A blood sample (15 mL) was collected from each foal immediately after birth or hospital admission (0 hours) and at 24 and 72 hours later. Clinicopathologic variables were evaluated, and cytokine gene expression in WBCs was measured with an absolute quantitative real-time reverse transcriptase PCR assay. At all time points, gene expression of interferon-γ was low in all groups. No time-dependent changes in cytokine expressions were detected in healthy or sick foals. Foals with sepsis had significantly higher IL-1β gene expression than did healthy foals, foals with peripartum asphyxia syndrome, or foals with other diseases. At 0 hours, IL-1β expression was correlated with plasma fibrinogen concentration in healthy foals and with the neutrophil-to-lymphocyte ratio in foals with sepsis; IL-8 expression was correlated with monocyte count in foals with sepsis and with arterial pH, plasma fibrinogen concentration, and plasma lactate concentration in foals with peripartum asphyxia syndrome. Data have suggested that evaluation of IL-1β expression in sick neonatal foals could help identify those with sepsis.
Article
Admission L-lactate concentration is a useful and commonly measured biomarker not previously prospectively evaluated in a large multicentre study of critically ill neonatal foals. To evaluate overall outcome and the association of survival and L-lactate concentration at admission ([LAC]ADMIT) by periparturient history, presenting complaint and clinicians' major diagnosis for ill neonatal foals. Thirteen university and private equine referral hospitals enrolled 643 foals over the 2008 foaling season. Case details, historical, clinical and clinicopathological data were entered into standardised spreadsheets then unified for analysis. Overall survival was 79% (505/643). Risk of nonsurvival increased with each 1 mmol/l increase in [LAC]ADMIT (odds ratio 1.14, P < 0.001). Mean arterial pressure had a small (r2 = 19.1) but significant (P < 0.001) association with [LAC]ADMIT. Foals experiencing known dystocia or premature placental separation had increased [LAC]ADMIT (P < 0.001). Single umbilical problems (excluding uroperitoneum), meconium impaction only and failure of passive transfer of immunity only had 100% survival. Six clinicians' major diagnoses had increased odds of nonsurvival for each 1 mmol/l increase in [LAC]ADMIT: 'sepsis'; 'unspecified enterocolitis'; 'unspecified colic'; 'unspecified trauma'; 'immune related (not failure of passive transfer of immunity)' and 'respiratory only'. CONCLUSIONS and potential relevance: Survival of critically ill foals is good but varies with peripartum history, presenting complaint and clinicians' major diagnosis. L-lactate concentration at admission proves its utility as a valuable prognostic biomarker in neonatal foals and its utility appears to vary with peripartum history and clinicians' major diagnosis.
Article
Although the clinical syndrome of sepsis is a major problem in equine neonates, the pathophysiology of this condition remains incomplete. Because the term sepsis describes a broad range of disorders with different underlying causes and often different prognoses, the understanding of this process is further complicated. Continued progress is being made, how-ever, in defining the syndromes associated with sepsis and in elucidating the mechanisms in-volved in these processes. Attempts at modulating the septic process by interfering with the action of bacterial toxins or the production or activity of individual mediators have not been successful, thereby reinforcing that this is a multifactorial response. Fortunately, the complex interactions of intra-and extracellular messengers leading to clinical sepsis continue to be de-fined. An increased understanding of the processes involved in the septic response may aid in the identification of patients with these syndromes as well as improve the effectiveness of treatment regimens. O ne of the most challenging problems faced by equine veterinarians is the management of equine neonates with sepsis. Despite the substantial ad-vances that have been made in the medical management of these foals, the mortality rate remains high. 1 This is due to the fact that sepsis represents a systemic inflammatory response to infection or injury; therefore, it can rapidly progress to septic shock and death despite aggressive treatment. Traditionally, the term septicemia, which is used to refer to this process in equine neonates, de-scribes a systemic disease process involving the presence of pathogenic microor-ganisms and/or their toxins in the blood. 2 The classic presentation of sepsis was that of disseminated gram-negative bacterial infections; however, it has become apparent that an identical syndrome occurs in patients with gram-positive bacte-CE
Article
Background: Relative cortisol insufficiency occurs in septic foals and impacts survival. Serum free (biologically available) cortisol concentration might be a better indicator of physiologic cortisol status than serum total cortisol concentration in foals. Hypotheses: In septic foals, (1) low free cortisol concentration correlates with disease severity and survival and (2) predicts disease severity and outcome better than total cortisol concentration. Animals: Fifty-one septic foals; 11 healthy foals; 6 healthy horses. Methods: In this prospective clinical study, foals meeting criteria for sepsis at admission were enrolled. University-owned animals served as healthy controls. Basal and cosyntropin-stimulated total cortisol concentration and percent free cortisol (% free cortisol) were determined by chemiluminescent immunoassay and ultrafiltration/ligand-binding methods, respectively. Group data were compared by ANOVA, Mann-Whitney U-tests, and receiver operator characteristic curves. Significance was set at P < .05. Results: Basal % free cortisol was highest in healthy foals at birth (58 ± 8% mean ± SD), and was higher (P ≤ .004) in healthy foals of all ages (33 ± 6 to 58 ± 8%) than in adult horses (7 ± 3%). Cosyntropin-stimulated total and free cortisol concentrations were lower (P ≤ .03) in foals with shock (total = 6.2 ± 8.1 μg/dL; free = 3.5 ± 4.8 μg/dL versus total = 10.8 ± 6.0 μg/dL; free = 6.9 ± 3.3 μg/dL in foals without shock) and in nonsurvivors (total = 3.8 ± 6.9 μg/dL; free = 1.9 ± 3.9 μg/dL versus total = 9.1 ± 7.7 μg/dL; free = 5.5 ± 4.4 μg/dL in survivors). Free cortisol was no better than total cortisol at predicting disease severity or outcome in septic foals. Conclusions and clinical importance: Serum free cortisol is impacted by age and illness in the horse. There is no advantage to measuring free over total cortisol in septic foals.
Article
Respiratory measurements and blood-gas and acid-base values are reported in nine term induced foals. Measurements were performed at 2, 15, 30 and 60 mins, 4, 12, 24 and 48 h, and four and seven days after birth. Minute respiratory volume was significantly lower at birth than values from 12 h old. Tidal volume peaked at 60 mins old, while respiration rate decreased significantly at 15 mins after birth. Oxygen consumption was high at birth and decreased to its lowest values at 24 and 48 h. The respiratory exchange ratio and ventilatory equivalent showed few significant changes to seven days, as did the minute alveolar ventilation and physiological deadspace.The blood-gas and acid-base values indicated that the foals rapidly establish adequate pulmonary ventilation within minutes of birth, and that those values changed little from 12 h to seven days after birth. Body position had a significant effect on arterial oxygen tension with Pao2 values in lateral recumbency being, on average, 14 mmHg lower than when the foals were standing.
Article
The purpose of the study was to document the developmental changes in the ventilatory and timing parameters associated with quiet breathing at rest in awake, standing horses during the first year post partum. Tidal volume (VT), breathing frequency, airflow, mechanical timing intervals and minute ventilation (V̇E) were measured serially in foals age 24 h-1 year. In the growing foal, V̇E increased due to a progressive rise in VT, in spite of a pronounced decrease in respiratory frequency. When normalised to body weight (bwt), V̇E7kg declined with maturation in a curvilinear fashion, from mean ± s.d. 848 ± 231 ml/min/kg in the 24 h-old foal, to 155 ± 15 ml/kg/min in the 1-year-old foal. Tidal volume normalised to bwt remained relatively constant during the study period, with the exception that at age 3 weeks and from 2–6 months, VT/kg was significantly lower than the value recorded at age 1 week. The decrease in frequency resulted from prolongation of both inspiratory (TI) and expiratory (TIE) time but there was a disproportionately larger increase in TE compared to TI, which resulted in a significantly lower ratio of TI/TE in older foals. The allometric equation relating VT to bwt suggested that lung growth in the horse is dysanaptic, with increases in overall body size exceeding lung growth in the maturing foal during the first year post partum.
Article
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.
Article
In normal conditions, alveolar macrophage (AM) is the main cell that respond against to bacteria that reach lower airways. However, if the microbial inoculum is too high or too virulent to be stopped by AM alone, these cells recruit polymorphonuclear neutrophils (PMN) into the alveoli from the vascular compartment. Cytokines, such as tumor necrosis factor-alpha (TNF-α), interleukin-1-beta (IL-1β), interleukin-6 (IL-6), and interleukin- 8 (IL-8), secreted by the AM are able to attract PMN enhanced for phagocytosis are ready to destroy the invading pathogens. However, excessive cytokine production has deleterious effects, with a systemic inflammatory response (sepsis) that can lead to multiorganic failure and death. Other cytokines like interleukin-10 (IL-10) balance this response attenuating several inflammatory mechanisms. The inflammatory lung response in pneumonia has been well studied in animals and more recently in humans using bronchoalveolar lavage to measure some inflammatory mediators (TNF-α, IL- 1β, IL-6, IL-8). From these studies, it seems that first, the inflammatory response to pneumonia is compartmentalized for most cytokines (in contrast to ARDS), except for IL-6 which is a general marker of inflammation. On the other hand, C-Reactive-Protein is an acute-phase protein synthesized by the liver through the stimuli of IL-6 that may be also an easy to measure marker of inflammation directly related to IL-6; second, some of these cytokines may be useful as prognostic markers; third, there is no clear relationship between the local lung bacterial burden and the intensity of the inflammatory response; fourth, the administration of G-CSF is a promising therapeutic approach still under clinical investigation. In the future the therapeutic goal in severe pneumonia will probably be to find the exact point at which inflammation is beneficial but not deleterious. The measurement of the inflammatory response could serve for this purpose.
Article
The concept that sepsis is the result of an uncontrolled inflammatory response of the host's innate immune system towards invading pathogens has recently been challenged. Evidence is accumulating that, in addition, host-derived alarm molecules are released during sepsis- and trauma-associated cell death, thus triggering the host's immune response. The identification and characterization of exogenous as well as endogenous danger molecules allowed significant advances in our understanding of the pathophysiology of sepsis and may provide potential targets for therapeutic interventions.
Article
The mechanisms leading to parturition in the horse in many aspects differ from those in other species. Pregnancy is maintained not by progesterone but by 5α-pregnanes and the progestin precursor pregnenolone originates from the fetus. As parturition approaches, the fetal adrenal switches from pregnenolone to cortisol synthesis but it is not known whether cortisol crosses the placenta. We hypothesized that in parallel to fetal cortisol release, cortisol in the maternal circulation increases before foaling and this increase can be determined in both saliva and plasma. In addition, maternal, fetal and neonatal heart rate and heart rate variability were measured. In 25 pregnant mares, saliva for cortisol analysis was collected 4 times daily from 15 days before to 5 days after foaling. In 13 mares, in addition, fetomaternal electrocardiogram (ECG) recordings were made and blood samples for progestin and cortisol analysis were collected once daily. Heart rate (HR) was recorded until 5 days after foaling. The heart rate variability (HRV) variables standard deviation of the beat-to-beat (RR) interval (SDRR) and root mean square of successive RR differences (RMSSD) were calculated. From Days 15 to 4 before parturition, progestin concentration increased (peak 267 ± 42 ng/mL) and decreased thereafter (P < 0.05, day of foaling 113 ± 18 ng/mL). A prepartum increase in maternal cortisol concentrations was evident in blood (P < 0.05) and saliva (P < 0.05) and paralleled the decrease in progestin concentrations. In mares, HR remained constant during the last days of pregnancy but decreased within one day after parturition (P < 0.05) while maternal HRV did not change. In the fetus and neonate, HR increased from before to after birth (P < 0.05) indicating increasing demands on the cardiovascular system with adaptation to extrauterine life.
Article
Pattern recognition receptors (PRRs) on host cells detect pathogens to activate innate immunity which, in turn, initiates inflammatory and adaptive immune responses. Successful activation of PRRs is, therefore, critical to controlling infections and driving pathogen-specific adaptive immunity, but overactivity of PRRs causes systemic inflammation, which is detrimental to the host. Here we review the PRR literature as it relates to horses and speculate on the role PRRs may play in sepsis and endotoxaemia.
Article
A systemic inflammatory response syndrome (SIRS) is frequently observed after traumatic injury. The response is sterile and the activating stimulus is tissue damage. Endogenous molecules, called alarmins, are reputed to be released by injured tissues but the precise identity of these mediators is unclear. This review summarizes current preclinical and clinical evidence for trauma alarmins and their role in innate immune activation. A comprehensive literature review of putative alarmins in tissue damage after traumatic injury was conducted. The presence of SIRS at admission is an independent predictor of mortality after trauma. The primary initiators of the human immune response are unclear. Several endogenous substances display alarmin characteristics in vitro. Preclinical studies demonstrate that blockade of certain endogenous substances can reduce adverse clinical sequelae after traumatic injury. Human evidence for trauma alarmins is extremely limited. The magnitude of acute inflammation is predictive of outcome after trauma, suggesting that an early opportunity for immune modulation may exist. An understanding of the mechanisms of innate immune activation following trauma may lead to new therapeutic agents and improved patient survival.
Article
Human sepsis is thought to be systemic inflammatory response syndrome (SIRS) that is activated by invasive infection. The multiple organ dysfunction syndrome (MODS) is the identified failure of critical organ function in patients that have sustained SIRS. Because SIRS and MODS are consequences of the excessive activation of inflammation, extensive research and numerous clinical trials have pursued treatments that would modify the inflammatory response. This presentation reviews the normal local mechanisms of inflammation and provides a theoretical framework for the transition of the inflammatory process to a systemic level. Clinical trials with biomodulators to block or inhibit inflammation have generally failed to improve the outcomes in patients with severe sepsis, septic shock, and MODS. The role of counter-inflammatory signaling and the newer concept of the cholinergic anti-inflammatory pathway are being investigated, and newer hypotheses are focusing upon the balancing of proinflammatory and counter-inflammatory mechanisms as important directions for newer therapies. It is concluded that failure to define novel and effective treatments reflects fundamental gaps in our understanding of inflammation and its regulation.
Article
Sepsis, the systemic inflammatory response to infection, represents the major cause of death in critically ill veterinary patients. Whereas important advances in our understanding of the pathophysiology of this syndrome have been made, much remains to be elucidated. There is general agreement on the key interaction between pathogen-associated molecular patterns and cells of the innate immune system, and the amplification of the host response generated by pro-inflammatory cytokines. More recently, the concept of immunoparalysis in sepsis has also been advanced, together with an increasing recognition of the interplay between regulatory T cells and the innate immune response. However, the heterogeneous nature of this syndrome and the difficulty of modeling it in vitro or in vivo has both frustrated the advancement of new therapies and emphasized the continuing importance of patient-based clinical research in this area of human and veterinary medicine.
Article
This study aimed to determine whether TNF-α is transferred to equine neonates via colostrum and the relationship between TNF-α and IgG concentrations in the equine neonate. Colostrum, presuckle and postsuckle foal serum samples were collected from healthy mares and their foals. Equine TNF-α ELISA and IgG SRID kits were used to determine the concentrations of TNF-α and IgG, respectively. Statistical analysis was performed using the Spearman rank correlation. TNF-α concentrations in all presuckle foal serum were below the limit of detection in 15/16 foals and increased in postsuckle foal serum to a mean concentration of 7.7 x 10(4) pg/ml. TNF-α concentrations in postsuckle foal serum and colostrum showed significant correlation (rho=0.668; P=0.005). However, TNF-α and IgG concentrations in colostrum or postsuckle foal serum did not correlate (rho<-0.016; P>0.05). Ratios of TNF-α/IgG in colostrum or postsuckle foal serum showed significant correlation (rho=0.750; P=0.0008). These results indicate that TNF-α is transferred to the foal via colostrum absorption and may play a role in early immunity.
Article
Serum concentrations of the proinflammatory cytokines tumor necrosis factor-α (TNF-α), interleukin (IL)-lβ, and IL-6, and the anti-inflammatory cytokine 11–10, and IL-1 receptor antagonists (IL-1ra) and soluble TNF receptors (sTNFRs) were measured in 65 patients with severe sepsis. All patients were evaluated clinically and microbiologically and were followed up for clinical outcome. Levels of both pro- and anti-inflammatory cytokines were significantly elevated in patients with sepsis. Elevated serum IL-10 and TNF-α levels and a high IL-10 to TNF-α ratio were associated with death, whereas higher levels of TNF-α, IL-6, IL-lra, and sTNFR were detected in patients with an early hemodynamic deterioration. Interleukin-10 and IL-10 : TNF-α ratio remained higher in nonsurvivors, whereas IL-10 paralleled the sepsis score. Although both the inflammatory and anti-inflammatory response is profoundly augmented in patients with severe sepsis, the sustained overproduction of the anti-inflammatory cytokine IL-10 is the main predictor of severity and fatal outcome.
Article
Over the past two decades, it has become well accepted that sepsis exhibits two, oftentimes concomitant, inflammatory stages; a pro-inflammatory phase, referred to as the systemic inflammatory response syndrome (SIRS), and an anti-inflammatory phase, called the compensatory anti-inflammatory response syndrome (CARS). Considering that therapeutic interventions designed to attenuate the pro-inflammatory septic response have generally failed, much recent research has gone into understanding how and why septic patients display immunosuppressive characteristics, what the significance of septic immunosuppression may be and if there exists any therapeutic targets within the CARS. Herein, we describe the potential mechanisms of the immunosuppressive/CARS phase of sepsis by discussing what anti-inflammatory agents, receptors and cell populations are currently believed to contribute to CARS.
Article
Toll-like receptors (TLRs) form a family of pattern recognition receptors with at least 11 members in human and 13 in mouse. TLRs recognize a wide variety of putative host-derived agonists that have emerged as key mediators of innate immunity. TLR signaling also plays an important role in the activation of the adaptive immune system by inducing pro-inflammatory cytokines and upregulating costimulatory molecules of antigen presenting cells. Inappropriate activation of TLRs by self-components generated by damaged tissues may result in sterile inflammation. This review discusses the contribution of TLR signaling to the initiation and progression of non-infectious inflammatory processes, such as ischemia and reperfusion (I/R) injury, tissue repair and regeneration and autoimmune diseases. The involvement of TLR signaling in the pathogenesis of sterile inflammation-related diseases may provide novel targets for the development of therapeutics.
Article
There is accumulating evidence in humans and in experimental sepsis that robust activation of the complement system occurs along with development of defects in the innate immune system. In this report we review evidence that the complement activation product, C5a, appears in the plasma of rodents following cecal ligation and puncture (CLP). C5a interacts with its receptors (C5aR, C5L2) on phagocytes (polymorphonuclear neutrophils, PMNs, macrophages), ultimately paralyzing the ERK1/2 pathway of the mitogen-activated protein kinase signaling pathway. C5a is also interactive with its receptors on a variety of other cell types in various organs. Interaction of C5a with receptors on PMNs results in compromised innate immunity, with intense suppression of phagocytosis, chemotaxis and the respiratory burst. Endothelial cells acquire a pro-inflammatory phenotype (increased ICAM-1 and tissue factor expression), while macrophages are primed and produce large amounts of cytokines/chemokines. All of these outcomes are C5a and C5a receptor dependent. CLP also unleashes activation of clotting (and fibrinolytic) factors in a C5a-dependent manner. Finally, thymocytes upregulate C5aR and react with C5a, resulting in apoptosis via the intrinsic (mitochondrial) pathway. Collectively, these findings suggest that interception of C5a in sepsis preserves innate immune functions and may be a strategy for treatment of septic humans.
Article
The systemic inflammatory response syndrome (SIRS) is the predominantly cytokine-mediated, pro-inflammatory response of the host to invading pathogens and is considered the hallmark sign of sepsis. Molecular components of this response can be divided into cytokines, plasma cascades and acute phase proteins while the predominant cellular components are leukocytes and the endothelium. High-throughput genetic profiling studies have led to increased insights into leukocyte regulation during sepsis. New players in the pro-inflammatory cytokine network include interleukin-17, high-mobility group box-1 protein, macrophage migration inhibitory factor, the myeloid-related proteins Mrp8 and Mrp14, and soluble triggering receptor expressed on myeloid cells-1. Activation of coagulation with concurrent downregulation of anticoagulant systems and fibrinolysis are almost universally present in septic patients with SIRS. Increasing evidence points to an extensive cross-talk between inflammation and coagulation, in which the protease-activated cell receptors play an important role. Sepsis causes excessive activation of the complement system in which C5a plays a key part. Further dissection of the role of host-pathogen interactions, the cytokine network, the coagulation cascade, the complement system and their multidirectional interactions in sepsis will pave the way for new treatment targets that can modify the excessive and collective activation of all these systems.
Article
The mammalian TLRs serve as key sensors of PAMPs, such as bacterial LPS, lipopeptides, and flagellins, which are present in microbial cells but not host cells. TLRs have therefore been considered to play a central role in the discrimination between "self" and "non-self". However, since the discovery of their microbial ligands, many studies have provided evidence that host-derived molecules may also stimulate TLR2- or TLR4-dependent signaling. To date, more than 20 of these endogenous TLR ligands have been proposed, which have tended to fall into the categories of released intracellular proteins, ECM components, oxidatively modified lipids, and other soluble mediators. This review aims to summarize the evidence supporting the intrinsic TLR-stimulating capacity of each of these proposed endogenous ligands with a particular emphasis on the measures taken to exclude contaminating LPS and lipopeptides from experimental systems. The emerging evidence that many of these molecules may be more accurately described as PAMP-binding molecules (PBMs) or PAMP-sensitizing molecules (PSMs), rather than genuine ligands of TLR2 or TLR4, is also summarized. The relevance of this possibility to the pathogenesis of chronic inflammatory diseases, tumor surveillance, and autoimmunity is discussed.
Article
Activated protein C (APC) is a natural anticoagulant that plays an important role in coagulation homeostasis by inactivating the procoagulation factor Va and VIIIa. In addition to its anticoagulation functions, APC also has cytoprotective effects such as anti-inflammatory, anti-apoptotic, and endothelial barrier protection. Recently, a recombinant form of human APC (rhAPC or drotrecogin alfa activated; known commercially as 'Xigris') was approved by the US Federal Drug Administration for treatment of severe sepsis associated with a high risk of mortality. Sepsis, also known as systemic inflammatory response syndrome (SIRS) resulting from infection, is a serious medical condition in critical care patients. In sepsis, hyperactive and dysregulated inflammatory responses lead to secretion of pro- and anti-inflammatory cytokines, activation and migration of leucocytes, activation of coagulation, inhibition of fibrinolysis, and increased apoptosis. Although initial hypotheses focused on antithrombotic and profibrinolytic functions of APC in sepsis, other agents with more potent anticoagulation functions were not effective in treating severe sepsis. Furthermore, APC therapy is also associated with the risk of severe bleeding in treated patients. Therefore, the cytoprotective effects, rather than the anticoagulant effect of APC are postulated to be responsible for the therapeutic benefit of APC in the treatment of severe sepsis.