What is the clinical evidence from this study?

Study design: Other. Population: Endotoxemia / Sepsis. Intervention: Lipopolysaccharide (LPS) vs. Vehicle (sterile normal saline). Primary outcome: Heart rate variability (HRV) and heart rate (p=<0.01).

August 6, 2009AJP Regulatory Integrative and Comparative Physiology122 citationsOpen Access

Endotoxin depresses heart rate variability in mice: cytokine and steroid effects

Q: What are the key findings of this study?

Administration of endotoxin in mice caused a prolonged period of depressed heart rate variability that temporally correlated with peak expression of multiple cytokines.

KFKaren D. FairchildUniversity of Virginia JSJeffrey J. SaucermanUniversity of Virginia LRLaura L. RaynorUniversity of Virginia

Key Result

Administration of endotoxin in mice caused a prolonged period of depressed heart rate variability that temporally correlated with peak expression of multiple cytokines.

Structured PICO

Does endotoxin administration reduce heart rate variability in mice, and is this effect mediated by cytokines?

Population

Adult male C57BL/6 mice undergoing continuous radiotelemetric monitoring of ECG to evaluate the effects of endotoxin on heart rate variability.

Intervention

Lipopolysaccharide (LPS) at doses ranging from 0.001 to 10 mg/kg intraperitoneally, with or without dexamethasone 0.7 mg/kg pretreatment, or recombinant murine TNFalpha 0.2 mg/kg

Comparator

Vehicle (sterile endotoxin-free normal saline intraperitoneally)

Outcome

Heart rate variability (HRV) measured by time-domain (SDNN, pNN6) and frequency-domain (LF, HF) parameters via continuous radiotelemetrysurrogate

Endotoxin-induced depression of heart rate variability in mice is temporally correlated with cytokine release and can be partially blunted by dexamethasone, suggesting a mechanistic role for cytokines in abnormal HRV during sepsis.

Main Result

Absolute Event Rate: 694% vs 547%

p-value: p=<0.01

Limitations

Animal model using a single dose of endotoxin may not fully translate to the complex condition of human sepsis with replicating pathogens.
Spectral analysis of HRV is an indirect measure of autonomic nervous system function.
Spectral analysis of HRV is an indirect measure of autonomic nervous system function
Cannot completely rule out selective modulation of sympathetic or parasympathetic tone during endotoxemia

Abstract

Heart rate variability (HRV) falls in humans with sepsis, but the mechanism is not well understood. We utilized a mouse model of endotoxemia to test the hypothesis that cytokines play a role in abnormal HRV during sepsis. Adult male C57BL/6 mice underwent surgical implantation of probes to continuously monitor electrocardiogram and temperature or blood pressure via radiotelemetry. Administration of high-dose LPS (Escherichia coli LPS, 10 mg/kg, n = 10) caused a biphasic response characterized by an early decrease in temperature and heart rate at 1 h in some mice, followed by a prolonged period of depressed HRV in all mice. Further studies showed that LPS doses as low as 0.01 mg/kg evoked a significant decrease in HRV. With high-dose LPS, the initial drops in temperature and HR were temporally correlated with peak expression of TNFalpha 1 h post-LPS, whereas maximal depression in HRV coincided with peak levels of multiple other cytokines 3-9 h post-LPS. Neither hypotension nor hypothermia explained the HRV response. Pretreatment with dexamethasone prior to LPS significantly blunted expression of 7 of the 10 cytokines studied and shortened the duration of depressed HRV by about half. Interestingly, dexamethasone treatment alone caused a dramatic increase in both low- and high-frequency HRV. Administration of recombinant TNFalpha caused a biphasic response in HR and HRV similar to that caused by LPS. Understanding the role of cytokines in abnormal HRV during sepsis could lead to improved strategies for detecting life-threatening nosocomial infections in intensive care unit patients.

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