Samir Q. Latifi

Interleukin-10 Controls the Onset of Irreversible Septic Shock

ABSTRACT Lethality from sepsis is believed to be mediated by a proinflammatory cytokine cascade, yet blocking the proinflammatory cytokines tumor necrosis factor alpha (TNF-α) and interleukin-1 (IL-1) fails to prevent mortality in human disease and a mouse model of sepsis induced by cecal ligation and puncture (CLP). The role of the antiinflammatory cytokine IL-10 in the CLP model of sepsis is unclear, with either protective or harmful effects demonstrated, depending upon the time of intervention. We therefore hypothesize that IL-10 functions as a temporal regulator of the transition from early reversible sepsis to the late phase of irreversible shock. Transition from reversible sepsis to irreversible shock in the CLP model was defined as the time when removal of the necrotic cecum by rescue surgery is no longer effective. We subjected IL-10-deficient (IL-10−/−) and wild-type (IL-10+/+) mice to CLP and monitored the progression of sepsis, the onset of irreversible shock, and mortality. Onset of lethality in IL-10−/− mice occurred significantly earlier than in IL-10+/+ mice and was associated with 15-fold-higher serum levels of TNF-α and IL-6. Consistent with these findings, the efficacy of rescue surgery after lethal CLP is lost 10 h earlier in IL-10−/− mice than in IL-10+/+ mice. Treatment with recombinant human IL-10 5 h after CLP significantly improved survival and lengthened the therapeutic window for rescue surgery in both strains of mice. These results demonstrate that IL-10 controls the onset of irreversible septic shock after CLP.

Interleukin 10 extends the effectiveness of standard therapy during late sepsis with serum interleukin 6 levels predicting outcome.

Patients with septic shock often display features of T cell hyporesponsiveness and immune suppression, which, if persistent, are associated with increased mortality. In the murine cecal ligation and puncture (CLP) model of sepsis, we previously reported that early treatment with the anti-inflammatory cytokine interleukin 10 (IL-10) delays the onset of irreversible shock, defined as the time at which rescue surgery to remove the necrotic cecum is no longer effective. Because IL-10 can be immunostimulatory for T cells, we hypothesized that in the CLP model, late IL-10 treatment after removal of the infectious nidus at the onset of irreversible shock would restore T cell responsiveness and increase survival. C57BL/6J mice were subjected to lethal CLP with and without rescue surgery, concurrent with IL-10 treatment, at the onset of irreversible shock. Survival and serum IL-6 levels were measured as markers of the response to treatment. Ten hours after intervention, all groups exhibited T cell hyporesponsiveness marked by impaired interferon (IFN)-γ production by Con A-stimulated splenocytes. IL-6 levels at 10 h were related to outcome independent of treatment. By 25 h after intervention, only the dual treatment group of cecal removal and IL-10 exhibited T cell responsiveness that was similar to pre-CLP levels (P = 0.26) and had a 7-day survival of 90% (P ≤ 0.002 compared with all other groups). Thus, even in the advanced stages of septic shock when standard therapies fail, treatment with IL-10 extends the therapeutic window. For an individual mouse, the efficacy of such treatment may be predicted by an early postintervention IL-6 level.

Pharmacology of inotropic agents in infants and children.

Inotropic agents are drugs which increase the stroke work of the heart at a given pre-load and after-load. All of these agents work through a final common pathway involving the modulation of calcium interactions with various myocardial contractile proteins. The agents employed with pediatric patients include the cardial glycosides, catecholamine beta-agonists and the selective phosphodiesterase III inhibitors. Digoxin is the prototypic cardiac glycoside which has a long history of safe and effective use in infants and children. Its utility in improving right ventricular dysfunction in patients with cor pulmonale leading to biventricular dysfunction makes it ideally suited to the pediatric population. Monitoring digoxin pharmacokinetics in infants is confounded by the presence of an endogenous digoxin-like substance. Nevertheless, the drug is well suited for subacute and chronic myocardial support. In contrast, the catecholamines are the drugs of choice for acute intervention. Their pharmacokinetics permit rapid dosing titration. In infants and children the greatest experience has been accrued with dopamine, a mixed alpha- and beta-agonist but both epinephreine and norepinephrine are being used with increasing frequency as the need for drugs with increased potency and pressor activity becomes more common. The phosphodiesterase inhibitors amrinone and milrinone are the newest additions to our therapeutic armamentarium. In addition to their modest inotropic effects, amrinone and to a greater extent, milrinone offer significant pulmonary vasodilatation as part of their therapeutic package. These effects occur with little or any impact on myocardial oxygen consumpton while their lusitropic effects enhance relaxation in hypertrophied ventricular muscle. Of the two agents milrinone is probably preferred due to its greater therapeutic index and shorter elimination half-life. All of these agents remain important tools in the care of critically ill infants and children. The rational use of these drugs based upon their pharmacokinetic and pharmacodynamic properties is essential to achieve their optimal effects.