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Does heart rate variability reflect the systemic inflammatory response in a fetal sheep model of lipopolysaccharide-induced sepsis?

ABSTRACT: Fetal inflammatory response occurs during chorioamnionitis, a frequent and often subclinical inflammation associated with increased risk for brain injury and life-lasting neurologic deficits. No means of early detection exist. We hypothesized that systemic fetal inflammation without septic shock will be reflected in alterations of fetal heart rate (FHR) variability (fHRV) distinguishing baseline versus inflammatory response states. In chronically instrumented near-term fetal sheep (n = 24), we induced an inflammatory response with lipopolysaccharide (LPS) injected intravenously (n = 14). Ten additional fetuses served as controls. We measured fetal plasma inflammatory cytokine IL-6 at baseline, 1, 3, 6, 24 and 48?h. 44 fHRV measures were determined continuously every 5?min using continuous individualized multi-organ variability analysis (CIMVA). CIMVA creates an fHRV measures matrix across five signal-analytical domains, thus describing complementary properties of fHRV. Using principal component analysis (PCA), a widely used technique for dimensionality reduction, we derived and quantitatively compared the CIMVA fHRV PCA signatures of inflammatory response in LPS and control groups. In the LPS group, IL-6 peaked at 3?h. In parallel, PCA-derived fHRV composite measures revealed a significant difference between LPS and control group at different time points. For the LPS group, a sharp increase compared to baseline levels was observed between 3?h and 6?h, and then abating to baseline levels, thus tracking closely the IL-6 inflammatory profile. This pattern was not observed in the control group. We also show that a preselection of fHRV measures prior to the PCA can potentially increase the difference between LPS and control groups, as early as 1?h post LPS injection. We propose a fHRV composite measure that correlates well with levels of inflammation and tracks well its temporal profile. Our results highlight the potential role of HRV to study and monitor the inflammatory response non-invasively over time.

SUBMITTER: Durosier LD

PROVIDER: S-EPMC5362269 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

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Does heart rate variability reflect the systemic inflammatory response in a fetal sheep model of lipopolysaccharide-induced sepsis?

Durosier Lucien D LD Herry Christophe L CL Cortes Marina M Cao Mingju M Burns Patrick P Desrochers André A Fecteau Gilles G Seely Andrew J E AJ Frasch Martin G MG

Physiological measurement 20150819 10

Fetal inflammatory response occurs during chorioamnionitis, a frequent and often subclinical inflammation associated with increased risk for brain injury and life-lasting neurologic deficits. No means of early detection exist. We hypothesized that systemic fetal inflammation without septic shock will be reflected in alterations of fetal heart rate (FHR) variability (fHRV) distinguishing baseline versus inflammatory response states. In chronically instrumented near-term fetal sheep (n = 24), we i ...[more]

PMID: 26290042

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Project description:Analysis of heart rate variability (HRV) is a recognized tool in the assessment of autonomic nervous system (ANS) activity. Indeed, both time and spectral analysis techniques enable us to obtain indexes that are related to the way the ANS regulates the heart rate. However, these techniques are limited in terms of the lack of thresholds of the numerical indexes, which is primarily due to high inter-subject variability. We proposed a new fetal HRV analysis method related to the parasympathetic activity of the ANS. The aim of this study was to evaluate the performance of our method compared to commonly used HRV analysis, with regard to i) the ability to detect changes in ANS activity and ii) inter-subject variability. This study was performed in seven sheep fetuses. In order to evaluate the sensitivity and specificity of our index in evaluating parasympathetic activity, we directly administered 2.5 mg intravenous atropine, to inhibit parasympathetic tone, and 5 mg propranolol to block sympathetic activity. Our index, as well as time analysis (root mean square of the successive differences; RMSSD) and spectral analysis (high frequency (HF) and low frequency (LF) spectral components obtained via fast Fourier transform), were measured before and after injection. Inter-subject variability was estimated by the coefficient of variance (%CV). In order to evaluate the ability of HRV parameters to detect fetal parasympathetic decrease, we also estimated the effect size for each HRV parameter before and after injections. As expected, our index, the HF spectral component, and the RMSSD were reduced after the atropine injection. Moreover, our index presented a higher effect size. The %CV was far lower for our index than for RMSSD, HF, and LF. Although LF decreased after propranolol administration, fetal stress index, RMSSD, and HF were not significantly different, confirming the fact that those indexes are specific to the parasympathetic nervous system. In conclusion, our method appeared to be effective in detecting parasympathetic inhibition. Moreover, inter-subject variability was much lower, and effect size higher, with our method compared to other HRV analysis methods.

Project description:Introduction: Fetal heart rate variability (FHRV) evaluates the fetal neurological state, which is poorly assessed by conventional prenatal surveillance including cardiotocography (CTG). Accurate FHRV on a beat-to-beat basis, assessed by time domain and spectral domain analyses, has shown promising results in the scope of fetal surveillance. However, accepted standards for these techniques are lacking, and the influence of fetal breathing movements and gross movements may be especially challenging. Thus, current standards for equivalent assessments in adults prescribe rest and controlled respiration. The aim of this review is to clarify the importance of fetal movements on FHRV. Methods: A systematic review in accordance with the PRISMA guidelines based on publications in the EMBASE, the MEDLINE, and the Cochrane Library databases was performed. Studies describing the impact of fetal movements on time domain, spectral domain and entropy analyses in healthy human fetuses were reviewed. Only studies based on fetal electrocardiography or fetal magnetocardiography were included. PROSPERO registration number: CRD42018068806. Results: In total, 14 observational studies were included. Fetal movement detection, signal processing, length, and selection of appropriate time series varied across studies. Despite these divergences, all studies showed an increase in overall FHRV in the moving fetus compared to the resting fetus. Especially short-term, vagal mediated indexes showed an increase during fetal breathing movements including an increase in Root Mean Square of the Successive Differences (RMSSD) and High Frequency power (HF) and a decrease in Low Frequency power/High Frequency power (LF/HF). These findings were present even in analyses restricted to one specific fetal behavioral state defined by Nijhuis. On the other hand, fetal body movements seemed to increase parameters supposed to represent the sympathetic response [LF and Standard Deviation of RR-intervals from normal sinus beats (SDNN)] proportionally more than parameters representing the parasympathetic response (RMSSD, HF). Results regarding entropy analyses were inconclusive. Conclusion: Time domain analyses as well as spectral domain analyses are affected by fetal movements. Fetal movements and especially breathing movements should be considered in these analyses of FHRV.

Project description:BackgroundAutonomic dysregulation is one of the recognized pathophysiological mechanisms in sepsis, generating the hypothesis that heart rate variability (HRV) can be used to predict mortality in sepsis.MethodsThis was a systematic review of studies evaluating HRV as a predictor of death in patients with sepsis. The search was performed by independent researchers in PubMed, LILACS and Cochrane, including papers in English, Portuguese or Spanish, indexed until August 20th, 2017 with at least 10 patients. Study quality was assessed by Newcastle-Ottawa Scale. To analyze the results, we divided the articles between those who measured HRV for short-term recordings (? 1 hour), and those who did long-term recordings (? 24 hours).ResultsNine studies were included with a total of 536 patients. All of them were observational studies. Studies quality varied from 4 to 7 stars in Newcastle-Ottawa Scale. The mortality rate in the studies ranged from 8 to 61%. Seven studies performed HRV analysis in short-term recordings. With the exception of one study that did not explain which group had the lowest results, all other studies showed reduction of several HRV parameters in the non-survivors in relation to the surviving septic patients. SDNN (Standard deviation of the Normal to Normal interval), TP (Total Power), VLF (Very Low Frequency Power), LF (Low Frequency Power), LF/HF (Low Frequency Power / High Frequency Power), nLF (Normalized Low Frequency Power), ?1/?2 (short-term and long-term fractal scaling coefficients from DFA) and r-MSSD (Square root of the squared mean of the difference of successive NN-intervals) of the non-survivor group were reduced in relation to the survivors in at least one study. Two studies found that SDNN is associated with mortality in sepsis, even after adjusting for possible confounding factors. Three studies performed HRV analysis using long-term recordings. Only one of these studies found difference between surviving and non-surviving groups, and even so, in only one HRV parameter: LogHF.ConclusionsSeveral HRV parameters are reduced in nonsurviving septic patients in short-term recording. Two studies have found that SDNN is associated with mortality in sepsis, even after adjusting for possible confounding factors.

Project description:BackgroundFetal heart rate (FHR) variability is an indirect index of fetal autonomic nervous system (ANS) integrity. FHR variability analysis in labor fails to detect early hypoxia and acidemia. Phase-rectified signal averaging (PRSA) is a new method of complex biological signals analysis that is more resistant to non-stationarities, signal loss and artifacts. It quantifies the average cardiac acceleration and deceleration (AC/DC) capacity.ObjectiveThe aims of the study were: (1) to investigate AC/DC in ovine fetuses exposed to acute hypoxic-acidemic insult; (2) to explore the relation between AC/DC and acid-base balance; and (3) to evaluate the influence of FHR decelerations and specific PRSA parameters on AC/DC computation.MethodsRepetitive umbilical cord occlusions (UCOs) were applied in 9 pregnant near-term sheep to obtain three phases of MILD, MODERATE, and SEVERE hypoxic-acidemic insult. Acid-base balance was sampled and fetal ECGs continuously recorded. AC/DC were calculated: (1) for a spectrum of T values (T?=?1÷50 beats; the parameter limits the range of oscillations detected by PRSA); (2) on entire series of fetal RR intervals or on "stable" series that excluded FHR decelerations caused by UCOs.ResultsAC and DC progressively increased with UCOs phases (MILD vs. MODERATE and MODERATE vs. SEVERE, p<0.05 for DC [Formula: see text]?=?2-5, and AC [Formula: see text]?=?1-3). The time evolution of AC/DC correlated to acid-base balance (0.4<[Formula: see text]<0.9, p<0.05) with the highest [Formula: see text] for [Formula: see text]. PRSA was not independent from FHR decelerations caused by UCOs.ConclusionsThis is the first in-vivo evaluation of PRSA on FHR analysis. In the presence of acute hypoxic-acidemia we found increasing values of AC/DC suggesting an activation of ANS. This correlation was strongest on time scale dominated by parasympathetic modulations. We identified the best performing [Formula: see text] parameters ([Formula: see text]), and found that AC/DC computation is not independent from FHR decelerations. These findings establish the basis for future clinical studies.

Project description:The evaluation of the autonomic cardiac functions may be performed through the analysis of the heart rate variability. Heart rate variability is defined as the fluctuations in the heart rhythm or rate, and represents a useful tool in the evaluation of the autonomic nervous system through the sympathetic and parasympathetic components, as well as its balance and its reflexes on the cardiorespiratory control system. Fetal electrocardiography provides important information regarding the well-being of the fetus since, in human fetuses, there are changes in the behavior of the fetal heart rate during the second and third trimesters of pregnancy due to an increase in parasympathetic activity. Therefore, considering the importance of evaluating fetal viability, this study aims at evaluating the behavior of fetal heart rate and heart rate variability in Dorper sheep, as well as the activity of the autonomic nervous system during fetal life and in newborn lambs. The species is often used in experimental studies and autonomic nervous system activity is a prognostic index, therefore, the diagnosis of modifications in the sympathovagal balance may represent an early index for fetal viability and well-being in lambs. The analyses were performed in 10 Dorper sheep during pregnancy and in 10 lambs after birth until 120 days of age. There was a decrease in the fetal heart rate and heart rate variability indexes during the fifth month of pregnancy, but without statistical significance for the period evaluated. The heart rate of the lambs decreased gradually until they were 21 days old. The indexes SDNN (standard deviation of RR intervals) and RMSSD (square root of the mean of successive differences between adjacent RR intervals) diverged according to age, being high at day 60. Fetal viability is relevant in sheep fetuses to avoid losses during pregnancy and risks to the health of the mother. In the species, there seems to be a predominance of parasympathetic activity starting from the 21st day of age. Heart rate variability may be employed as a tool in the evaluation of the fetus and development of lambs, since changes in its behavior may represent an adverse effect to fetal and neonatal health.

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Does heart rate variability reflect the systemic inflammatory response in a fetal sheep model of lipopolysaccharide-induced sepsis?

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Does heart rate variability reflect the systemic inflammatory response in a fetal sheep model of lipopolysaccharide-induced sepsis?

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