Abstract
While the mortality rate associated with sepsis in children has fallen over the years, it still remains unacceptably high. The development of both acute cardiac dysfunction and acute kidney injury during severe sepsis is categorized as type 5 cardiorenal syndrome (CRS) and is poorly understood in infants. To address this lack of understanding and the need for an appropriate animal model in which to conduct relevant preclinical studies, we developed a model of infant sepsis-induced CRS in rat pups then evaluated the therapeutic potential of the phosphodiesterase (PDE) 4 inhibitor, rolipram. Rat pups at 17–18-days old were subjected to cecal ligation and puncture (CLP) to induce fecal polymicrobial sepsis. Uptake of Evans Blue dye was used to assess renal microvascular leakage. Intravital videomicroscopy was used to assess renal microvascular perfusion and oxidant generation. Glomerular filtration rate (GFR) was used to assess renal function. Left ventricular (LV) catheterization and echocardiography were used to assess cardiac function. Impairment of both cardiac and renal function developed rapidly following CLP, indicating type 5 CRS. Most notable were the rapid decline in LV diastolic function, the decline in cardiac output, renal microvascular failure, and the decline in GFR. A dose-response study with rolipram determined 0.1 mg/kg, ip as the lowest most efficacious dose to protect the renal microcirculation. Rolipram was then evaluated using a clinically relevant delayed dosing paradigm (a single dose at 6 h post-CLP). With delayed dosing, rolipram restored the renal microcirculation and reduced microvascular leakage but did not reduce oxidant generation in the kidney nor restore GFR. In contrast, delayed dosing with rolipram restored cardiac function. Rolipram also improved 4-days survival. In summary, CLP in the rat pup produces a clinically relevant pediatric model of sepsis-induced CRS. The PDE4 inhibitor rolipram was effective in improving renal microvascular function and cardiac function, which improved mortality. These findings suggest that rolipram should be evaluated further as adjunctive therapy for the septic infant with CRS.
Highlights
In the United States, sepsis is the 6th and 7th leading cause of death in neonates and infants, respectively (Heron, 2015)
The pathophysiology of sepsis-induced-cardiorenal syndrome (CRS) in infants is poorly understood due to limited studies in this patient population and the paucity of studies that have examined sepsis-induced multiple organ dysfunction syndrome (MODS) in age-appropriate animal models. To address this lack of understanding and the need for an appropriate animal model in which to conduct relevant preclinical studies, we developed a model of infant sepsis-induced cold shock in rat pups subjected to cecal ligation and puncture (CLP) (Seely et al, 2011)
Core temperature decreased in pups subjected to CLP as sepsis developed, reaching significance compared to Sham pups at 6 and 18 h (Figure 1A)
Summary
In the United States, sepsis is the 6th and 7th leading cause of death in neonates and infants, respectively (Heron, 2015). Severe sepsis is defined as sepsis with cardiovascular distress and multiple organ dysfunction syndrome (MODS), which increases morbidity and mortality in this understudied patient population (Goldstein et al, 2005; Weiss et al, 2015). The heart and kidneys are two organs commonly affected by sepsis The development of both acute cardiac dysfunction and acute kidney injury during severe sepsis is categorized as type 5 CRS (McCullough et al, 2013). The etiology of sepsis-induced CRS in infants is poorly understood (Jefferies and Goldstein, 2013) but appears to be different than that in adults (Aneja and Carcillo, 2011; Deep et al, 2013; Ranjit et al, 2014; Zaky et al, 2014). The reason for poor outcomes is related to the fact that treatments are not targeted and what supportive care is available is usually begun only after symptoms are present and after organ injury may have already been initiated (Simmons et al, 2012; Fortenberry et al, 2013)
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
