Abstract
Several studies have suggested that sympathetic overstimulation causes deleterious effects in septic shock. A previous study suggested that pralidoxime exerted a pressor effect through a mechanism unrelated to the sympathetic nervous system; this effect was buffered by the vasodepressor action of pralidoxime mediated through sympathoinhibition. In this study, we explored the effects of pralidoxime on hemodynamics and survival in rats with peritonitis-induced sepsis. This study consisted of two sub-studies: survival and hemodynamic studies. In the survival study, 66 rats, which survived for 10 hours after cecal ligation and puncture (CLP), randomly received saline placebo, pralidoxime, or norepinephrine treatment and were monitored for up to 24 hours. In the hemodynamic study, 44 rats were randomly assigned to sham, CLP-saline placebo, CLP-pralidoxime, or CLP-norepinephrine groups, and hemodynamic measurements were performed using a conductance catheter placed in the left ventricle. In the survival study, 6 (27.2%), 15 (68.1%), and 5 (22.7%) animals survived the entire 24-hour monitoring period in the saline, pralidoxime, and norepinephrine groups, respectively (log-rank test P = 0.006). In the hemodynamic study, pralidoxime but not norepinephrine increased end-diastolic volume (P <0.001), stroke volume (P = 0.002), cardiac output (P = 0.003), mean arterial pressure (P = 0.041), and stroke work (P <0.001). The pressor effect of norepinephrine was short-lived, such that by 60 minutes after the initiation of norepinephrine infusion, it no longer had any significant effect on mean arterial pressure. In addition, norepinephrine significantly increased heart rate (P <0.001) and the ratio of arterial elastance to ventricular end-systolic elastance (P = 0.010), but pralidoxime did not. In conclusion, pralidoxime improved the hemodynamics and 24-hour survival rate in rats with peritonitis-induced sepsis, but norepinephrine did not.
Highlights
Sepsis is a systemic inflammatory response syndrome secondary to infection
Norepinephrine is recommended as the vasopressor of choice for sepsisinduced hypotension [3]. Responsiveness to this drug and other commonly used vasopressors is markedly reduced in septic shock [4,5,6]; patients who do not respond to vasopressors have extremely high mortality risks [7, 8]
We recently investigated the effects of adrenergic antagonists on the pressor action of pralidoxime in anesthetized normal rats to determine the involvement of the sympathetic nervous system in the pressor action of pralidoxime [14]
Summary
Sepsis is a systemic inflammatory response syndrome secondary to infection. Among sepsisinduced organ dysfunctions, cardiovascular dysfunction is a major contributor to the associated mortality [1, 2]. Norepinephrine is recommended as the vasopressor of choice for sepsisinduced hypotension [3] Responsiveness to this drug and other commonly used vasopressors is markedly reduced in septic shock [4,5,6]; patients who do not respond to vasopressors have extremely high mortality risks [7, 8]. Excluding sympathetic effects by means of adrenergic blockers (guanethidine and phentolamine) did not inhibit the pressor response of pralidoxime, but rather augmented it. In combination with the 200 mg/kg dose, the adrenergic blockers converted the initial vasodepressor response into a pressor response These findings, taken together, indicated that pralidoxime did have a dose-dependent vasodepressor action by mechanisms dependent on intact adrenergic receptor function, and that the pressor effect of pralidoxime was unrelated to the sympathetic nervous system. The latter’s vasodepressive action, mediated by inhibition of the sympathetic nervous system, acted to buffer the pralidoxime’s pressor action
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