Update on the Management of Neonatal S e p s i s in H o r s e s Jon Palmer,


KEYWORDS  Severe sepsis  Septic shock  Fluid therapy  Antimicrobials  Vasoactive agents  Antimediator therapy  Glucose control  Corticosteroids KEY POINTS  The diagnosis of sepsis, severe sepsis, and septic shock is based on clinical judgment. None of the associated clinical signs or immediately available laboratory findings are specific for sepsis, so management must be initiated before a definitive diagnosis is reached.  As important as selecting the most appropriate antimicrobial is, both early initiation of treatment and insuring the dose and frequency will allow adequate drug levels in the face of sepsis and shock, which will change many aspects of the antimicrobial’s pharmacodynamics.  Plasma therapy may not only deliver useful immunoglobulins and other immunologically important factors but can also serve other important functions, such as aiding in the repair of the damaged endothelial glycocalyx layer, which is vital in preserving fluid balance and volemia in the neonate.  Fluid therapy should follow the “Goldilocks approach.” Too much fluid is dangerous. Too little fluid is dangerous. A balance is needed.  Although many approaches have been tried, no antimediator therapy has been successful in mitigating the damage caused by uncontrolled sepsis and, in fact, many therapies which are based on experimental models would seem be rational have actually increased mortality in clinical trials in man.


Development of a bacterial infection is a common cause of morbidity and mortality in neonatal foals. It is not only the most common cause of fatality during this period but also the most important comorbidity of other neonatal diseases, such as prematurity and neonatal encephalopathy, increasing the risk of a more complicated course and a fatal outcome. The concept of sepsis is ancient, being described by both the Egyptians and Hippocrates,1,2 but it was Schottmueller3 in 1914 who first established a

Graham French Neonatal Section, Connelly Intensive Care Unit, New Bolton Center, University of Pennsylvania, 382 West Street Road, Kennett Square, PA 19348, USA E-mail address: [email protected] Vet Clin Equine - (2014) -–http://dx.doi.org/10.1016/j.cveq.2014.04.005 vetequine.theclinics.com 0749-0739/14/$ – see front matter Ó 2014 Elsevier Inc. All rights reserved.



link between the presence of pathogenic microbes in the bloodstream and the development of systemic symptoms and signs. In Schottmueller’s words, “Septicemia is a state of microbial invasion from a portal of entry into the blood stream which causes signs of illness.” Sepsis, the host’s response to infection, is a continuum of clinical syndromes ranging from signs, such as fever and catabolism secondary to a localized, well-controlled infection, to septic shock with its refractory shock and its accompanying multiorgan dysfunction. Sepsis results from the dysregulation of the systemic host response to cascading inflammatory and anti-inflammatory mediators induced by infecting organisms.4 During the last 2 decades, as the complexities of the sepsis response have begun to be understood, many ideas have emerged aimed at managing clinical sepsis by mitigating the damage caused by the inflammatory response while simultaneously preserving the ability to purge the initiating microbial invaders as well as resist secondary infections. Working from bench to patient side, many initially promising therapies have often fallen flat, which is a reflection of the complexity of the response with multiple redundant pathways making control of the cascading responses problematic. The evidence of efficacy in the treatment of sepsis comes from large blinded clinical studies in adult humans. There is some evidence from human neonatal studies, but unfortunately, there are no adequately powered clinical studies in septic neonatal foals to lend evidence to any of the approaches to therapy. Therefore, at best, evidence has been “borrowed” from human trials to direct many of the clinical approaches to septic neonatal foals. This approach is dangerous because the host response may differ greatly. There is some information from sepsis models in foals and horses, but we need to heed the lesions from human medicine that many of the most promising approaches to managing sepsis based on models have actually resulted in increased fatality rates when used in clinical settings.4,5 Another important lesson to learn from human medicine is the reliance on models that use endotoxin to induce sepsis may result in misplaced confidence in the usefulness of the therapy in clinical situations.5 Although endotoxin models may help in understanding many aspects of sepsis, more clinically relevant models that involve multiple initiators of sepsis are more likely to yield more valuable therapeutic information.2,5 The movement to more clinically realistic models of sepsis would be a big step forward in the development of effective management approaches to equine sepsis. Until then, the most reliable methods to manage sepsis in the neonatal foal will remain grounded on the same cornerstones that were established more than 2 decades ago: infection control (antimicrobials, plasma, drainage when possible), cardiovascular support (fluids, inopressors), respiratory support (intranasal oxygen insufflation/ventilation), and nutritional support.6 THE SEPTIC NEONATAL FOAL

Many terms have been used to define “sepsis” since Schottmueller first established a link between the clinical signs and infection.3 The often interchangeable use of terms, such as infection, septicemia, bacteremia, and sepsis syndrome, has led to some confusion. However, using the concept of sepsis as the host response to infection and a hierarchy of terms based on severity, the associated terminology becomes relatively simple (Box 1).4 In 1991, Bone and colleagues7 coined the concept of systemic inflammatory response syndrome. It is a useful term when describing the pathogens of sepsis but their original definition, based on patient temperature, heart rate, respiratory rate or PCO2, and white blood cell count, was designed to cast a broad net to include as many patients as possible in early sepsis therapeutic trials with the knowledge that the nonspecific nature of the inclusion criteria would mean enrolling many

Management of Neonatal Sepsis in Horses

Box 1 Definitions Infection: a pathologic process caused by the invasion of normally sterile tissue or fluid or body cavity by pathogenic or potentially pathogenic microorganisms. Sepsis: the clinical syndrome defined by the presence of both infection and a systemic inflammatory response. Severe sepsis: sepsis complicated by organ dysfunction, usually acute circulatory failure characterized by hypoperfusion unexplained by other causes and readily corrected by volume resuscitation alone. Septic shock: severe sepsis plus acute circulatory failure characterized by persistent hypoperfusion unexplained by other causes and despite adequate volume resuscitation. Data from Vincent JL. Clinical sepsis and septic shock—definition, diagnosis and management principles. Langenbecks Arch Surg 2008;393:817–24; and Bone RC, Balk RA, Cerra FB, et al. Definition for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Chest 1992;101:1644–55.

patients that did not actually suffer from sepsis. Although more recently the definition has been expanded to a longer list of possible signs as well as the results of blood assays of inflammatory mediators, some have considered the term outdated because understanding of the pathophysiology of sepsis has increased.4 It is of little use in the identification of clinical sepsis in neonatal foals. In 1988, Brewer and Koterba8,9 proposed a foal sepsis score to identify sepsis in hospitalized neonatal foals. Their scoring system has been widely embraced and is a valuable epidemiologic tool, but, as acknowledged in the original paper, has some shortcomings when applied to individual cases. The accuracy and reproducibility of fibrinogen and immunoglobulin G (IgG) levels used in the scheme depend on the technique used. The band count and identification of toxic changes in neutrophils also used in the score are laboratory-dependent. The population used to develop the score had a high incidence of prematurity and placentitis, rendering it less useful for postnatal infections and mature foals. It is unfortunate in the 25 years since the scoring scheme was proposed that it has not been proven in a large independent population, a process necessary to validate any risk scoring scheme.10 In the original population, there were several foals with false negative scores and, in a small population reported by Peek and colleagues,11 the scoring scheme had a sensitivity of 74% in predicting bacteremia. The occurrence of these false negative test results, which have also been anecdotally noted in the author’s neonatal population, is important in light of the importance of initiating early antimicrobial therapy (see later discussion). As noted by Brewer and Koterba,8,9 the sepsis score was developed as an aid to diagnosis but was not intended to be used to direct decisions on the institution of antimicrobial therapy. Some of the false negative cases may be because the examination is performed too early in the clinical course for the expected changes (such as with the delay in increase in fibrinogen) and in others the scoring system may fail because the case comes from a population different from that which produced the scoring system. In the author’s experience, use of the score on an individual case may dangerously delay initiation of antimicrobials. Diagnosing sepsis can be difficult. Blood cultures are useful, but cases are not consistently bacteremic, and rapid identification of blood pathogens is not widely available. None of the clinical signs or common laboratory findings is specific for sepsis. The occurrence of multiple, complex underlying disease processes often




confuses the clinical picture. The ideal marker of infection, which should be sensitive enough to detect the presence of infection in patients with minimal or even no host response, specific enough to discriminate infection from other stimuli that may induce a systemic inflammatory response, should be present early in the course of the disease, should be rapidly and conveniently measured, and should be of prognostic significance, is yet to be identified. Diagnosis must thus rely on a strong clinical suspicion supported by the combined presence of several of the signs of sepsis (Boxes 2 and 3). Box 2 Some indications of sepsis in the neonatal foal Clinical signs  Fever/hypothermia  Tachycardia/inappropriate bradycardia  Tachypnea  Hypoperfusion  Poor pulse quality/poor arterial fill/poor arterial tone  Arterial hypotension (low blood pressure)  Cold legs/hooves  Increased venous capacitance  Decreased urine output  Edema (especially asymmetric edema)  Oral small vessel injection  Coronitis  Nasal/facial erythema/altered skin perfusion  Oral/aural petechia Generalized hematological/inflammatory reaction  Leukopenia/neutropenia (sometimes neutrophilia)  Decreased urine output (not associated with hypoperfusion)  Unexplained lactatemia/increased base deficit Signs of organ dysfunction  Hypoxemia despite intranasal oxygen insufflation (suspect acute lung injury)  Depression/somnolence (in the absence of neonatal encephalopathy)  Unexplained alteration in renal function  Rising creatinine/slow decrease in birth creatinine levels  Low urine output  Isosthenuric urine  Abnormal urinalysis  Hypoglycemia/hyperglycemia  Thrombocytopenia/disseminated intravascular coagulation  Unexplained alteration in liver function tests (hyperbilirubinemia)  Intolerance to feeding (gastrointestinal dysmotility)

Management of Neonatal Sepsis in Horses

Box 3 Organ dysfunction common in sepsis  Cardiovascular  Hypotension  Tachycardia/arrhythmias  Lactatemia (secondary to hypoperfusion)  Cardiac failure  Respiratory  Tachypnea/respiratory distress  Hypoxia/hypercapnia  Acute respiratory distress syndrome  Kidneys—acute kidney injury  Increasing plasma creatinine/slow decrease in birth creatinine levels  Decreasing urine output  Fluid overload  Electrolyte imbalances  Central nervous system—nonfocal septic encephalopathy  Depression  Weakness  Somnolence  Metabolic  Lactatemia (not from anaerobic metabolism)  Loss of glycemic control/hypoglycemia/hyperglycemia  Coagulopathies  Thrombocytopenia  Disseminated intravascular coagulation  Altered adrenal function  Adrenal exhaustion  Loss of receptor sensitivity  Gastrointestinal  Ileus/distention/reflux/dysmotility  Diarrhea Data from Angus DC, van der Poll T. Severe sepsis and septic shock. N Engl J Med 2013;369(9):840–51.

The final arbitrator is clinical judgment based on experience, keeping in mind the importance of early intervention. MANAGEMENT STRATEGIES IN NEONATAL SEPSIS

This discussion focuses on the management of severe sepsis and septic shock because these are the most challenging, and despite the increase in understanding,




continue to have poor outcomes. There has been an increasing realization of the importance of early resuscitation on positive outcomes from severe sepsis and septic shock in man.12–14 The same is undoubtedly true for the neonatal foal. Management of foals with severe sepsis essentially comprises 4 key aspects: infection control, hemodynamic support, immunomodulatory interventions, and metabolic/endocrine support. Infection Control

Control of infection relies on appropriate antimicrobial therapy, plasma therapy, and identification of any infected focus with local treatment when possible. Searches for an infected focus through complete physical examinations and imaging should be made repeatedly. The “big six” locations of sepsis should be kept in mind when trying to identify a source, with the search initially focusing on the umbilical remnants, lungs, gastrointestinal tract, urinary tract, physes/joints, and catheters. Identification of the focus may allow culturing of infected material, directed local therapy (eg, joint flush, physis curettage, removal of catheter), and also may help direct antimicrobial therapy based on typical pathogens found in the area when culture results are not yet available. Antimicrobials

Appropriate antimicrobial therapy should be begun within an hour of development of hypoperfusion in cases with severe sepsis or septic shock.14–17 Initial antimicrobial choice is empiric. The author focuses the choice by keeping track of both community-acquired isolates’ and nosocomial isolates’ sensitivities over the past 3 years and bases his antimicrobial choice on this information, along with any patient-specific clues that may be helpful, such as infection location and recent farm history. In approximately 60% of cases of neonatal foal sepsis, no organisms will be isolated. Once started, antimicrobial drugs should be continued for 7 to 10 days with longer courses considered in patients who have a slow clinical response or immunologic deficiencies, including persistent neutropenia. Biomarkers of infection, such as hyperfibrinogenemia, may be used to determine the need for continued antibiotic therapy.4 Achieving optimal target levels rapidly is as important as early initiation of appropriate antimicrobials.6 Pharmacokinetics are affected by changes that occur during sepsis, so information from drug behavior in normal individuals is of limited value when treating septic foals.18–20 However, there are few studies testing drug levels in septic foals. It should also be recalled that there is no one correct antimicrobial dose because the level achieved will vary depending on many host factors and the level required will vary depending on pathogen characteristics. Therefore, there is no one dose that is appropriate for all situations (Table 1). Plasma therapy

Plasma therapy may also be helpful, although currently there is no evidence to support this notion. Although measuring the IgG may be useful to document low levels because of failure of passive transfer or secondary to sepsis-mediated catabolism, it should not be the deciding factor for giving a plasma transfusion. Despite having a large quantity of IgG acquired from passive transfer, useful antibodies may not be present. The IgG present did not prevent sepsis, but antibodies in the transfused hyperimmune plasma might be helpful. Other factors in plasma may also be helpful. It should be noted that high levels of IgG can be immunosuppressive,21 but in sepsis with its associated catabolism, these levels are rarely reached even with repeated plasma transfusions.

Management of Neonatal Sepsis in Horses

Table 1 Suggested dosing of selected antimicrobials for septic foals Antimicrobial


Frequency Route


Ceftiofur sodium

10 mg/kg



1.6 mg/kg/h



With high doses, should be infused slowly over at least 20 min Begin CRI after a bolus dose



20,000–50,000 U/kg QID


8,000 U/kg/h



Cefuroxime Na

50–100 mg/kg/d


Divided Doses up to 200 mg/kg/d TID, QID used in severe infections

Cefuroxime axetil

30 mg/kg/d


Divided BID, TID


16–20 mg/kg



Ideally drug levels should be measured and dose adjusted with the goal of peak (30 min) >40 mg/mL and trough (23 h) 60 mg/mL and trough (23 h)

Update on the management of neonatal sepsis in horses.

Despite advances in neonatal intensive care sepsis, severe sepsis and septic shock remain the biggest killers of neonatal foals. Management of this se...
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