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Jan, Badar U.; Coyle, Susette M.; Macor, Marie A.; Reddell, Michael; Calvano, Steve E.; Lowry, Stephen F.

doi: 10.1097/SHK.0b013e3181b66bf4
Clinical Aspects

Autonomic inputs from the sympathetic and parasympathetic nervous systems, as measured by heart rate variability (HRV), have been reported to correlate to the severity injury and responses to infectious challenge among critically ill patients. In addition, parasympathetic/vagal activity has been shown experimentally to exert anti-inflammatory effects via attenuation of splanchnic tissue TNF-α production. We sought to define the influence of gender on HRV responses to in vivo endotoxin challenge in healthy humans and to determine if baseline HRV parameters correlated with endotoxin-mediated circulating cytokine responses. Young (<30 years of age), healthy subjects (n = 30) received endotoxin (2 ng/kg), and HRV and blood samples were obtained serially thereafter. Plasma cytokines were measured by enzyme-linked immunosorbent assay, and HRV parameters were determined by analysis of serial 5-min epochs of heart rate monitoring. In addition, calculation of multiscale entropy deriving from cardiac monitoring data was performed. The influence of factors such as gender, body mass index, and resting heart rate on HRV after endotoxin exposure was assessed. We found that gender, body mass index, or resting heart rate did not significantly alter the HRV response after endotoxin exposure. Using entropy analysis, we observed that females had significantly higher entropy values at 24 h after endotoxin exposure. Using a serially sampling protocol for cytokine determination, we found a significant correlation of several baseline HRV parameters (percentage of interval differences of successive interbeat intervals more than 50 ms, r = 0.42, P < 0.05; high-frequency variability, r = 0.4, P < 0.05; and low-frequency/high-frequency ratio, r = −0.43, P < 0.05) on TNF-α release after endotoxin exposure.

Department of Surgery, Division of Surgical Sciences, Robert Wood Johnson Medical School, New Brunswick, New Jersey

Received 4 May 2009; first review completed 22 May 2009; accepted in final form 6 Jul 2009

Address reprint requests to Stephen F. Lowry, MD, Department of Surgery, Robert Wood Johnson Medical School, University of Medicine & Dentistry of New Jersey, 125 Paterson St, Suite 7300, New Brunswick, NJ 08903. E-mail:

This work was supported by the National Institutes of Health (grant no. R01 GM34695).

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The acute host response to systemic inflammation includes activation of endocrine and innate immune signals (1) as well as changes in autonomic nervous activity. These overlapping signals initially promote a trajectory for the restoration of normal systemic and tissue functions. Over an extended period, however, the persistence of these signals and an associated acute phase response may also be associated with impaired recovery (2).

Physiological and biochemical measures of the acute systemic inflammatory response demonstrate some interindividual variation of the clinical phenotype. This variability undoubtedly results from endogenous, patient-specific factors, including inherited characteristics, age, and gender (3). These factors also likely interact with preexisting illness and therapies to elicit differing adaptive, host responses and to promote uncertainty regarding the recovery capacity of patients over time. The inability to quantify the summative influences of patient-specific and treatment-modified clinical response dynamics suggests that additional measures of host adaptability are needed.

Several recent studies have reported that surrogate measures of host adaptability and physiologic complexity, including heart rate variability (HRV) and entropy assessments (4-6), may provide insight into the dynamic status of host adaptability during inflammation. Measures of HRV are noninvasive assessments that may reflect real-time alterations of physiologic status (7-9). Under normal circumstances, variability parameters measure homeostatic feedback between organ systems such as the central nervous system and the heart, whereas decreased variability implies physiologic decomplexification (10) that may manifest as diminished organ responsiveness to autonomic signals (11). In addition to HRV, other parameters have been suggested to quantify the physiologic complexity between organ systems including multiscale entropy (12). Entropy measures the disorderliness within data and increases with greater variability between values and decreases with increased regularity between values.

Assessments of time and frequency domain analysis of HRV constitute a noninvasive method to evaluate vagal (8), parasympathetic tone (13), and sympathovagal balance (14-16). It is known that parameters of HRV are influenced by several relevant individual conditions such as age (17, 18), body fatness (19), physical fitness (20), and perhaps genetic background (21). The above-noted time and frequency assessments of HRV analysis have received increasing attention as predictors of outcome risk (6, 22-24) in patients presenting with both sterile and infectious injuries as well as potential adjuncts to the ongoing management of patients with complicated inflammatory states (4, 25). In addition, HRV assessment has been suggested to provide insights into the acute influence of both the sympathetic (26, 27) and the choinergic (28) anti-inflammatory pathways. Consistent with the hypothesis that higher indices of HRV determined parasympathetic activity are associated with attenuation of proinflammatory cytokines production, recent studies (29) have observed reduced TNF-α appearance in an ex vivo endotoxin (LPS) challenge model.

This influence of parasympathetic activity is somewhat surprising given current evidence that the cholinergic anti-inflammatory pathway influences principally tissue-fixed immune cell populations in animal models (28, 30). This lead us to further investigate the relationship of HRV-derived measures of sympathovagal activity and adaptability in a well-described in vivo human endotoxin challenge model (1, 27, 31). We also took the opportunity to further assess the influence of gender differences on HRV responses in this model (32). We hypothesized that individual subject factors such as gender, resting heart rate (HR), and body mass index (BMI) could influence the HRV response after endotoxin exposure. In addition, we hypothesized that some basal HRV parameters, such as those measuring parasympathetic activity, would influence the subsequent cytokine response to in vivo endotoxin (29, 33). To test these hypotheses, we recruited human volunteers and grouped them based on their gender, resting HR, and BMI. We used a serial sampling protocol to quantify HRV and cytokine measures to assess the response after i.v. endotoxin exposure.

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Male (n = 16) and female (n = 14) subjects were recruited by public advertisement and screened for normal health status to participate in a study approved by the institutional review board of the Robert Wood Johnson Medical School. Inclusion criteria for the study were normal general health as demonstrated by medical history and physical examination, complete blood count, and basic metabolic panel within normal laboratory limits. In addition, we limited the age of our subjects (18-30) to eliminate the potentially confounding effects of age on HRV (17, 34) and on cytokine responses to systemic endotoxinemia (35). Exclusion criteria included a history of any acute or chronic disease, arrhythmia, recent history of alcohol, drug or medication intake, pregnancy, or prior exposure to LPS in the experimental setting. Once informed, written consent was obtained; all subjects received an initial recording of HR and electrocardiogram (ECG) to screen for any arrhythmic patterns or irregular heartbeats. Only subjects with a normal standard ECG were considered for admission to the protocol. This study population reported here includes a subset of subjects (n = 4) from a previous report (32) as well as additional subjects accrued since then (n = 26).

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Study design and procedures

On accrual to the study, subjects were admitted to the Center for Translational and Clinical Research at the Robert Wood Johnson Medical School, University of Medicine & Dentistry of New Jersey, the afternoon before the study. At that time, a repeat examination confirmed that no changes in health status had occurred since initial recruitment. Female subjects also underwent a urine test to exclude pregnancy.

Subjects were fasted from midnight of the admission day and given i.v. fluids (5% dextrose and 0.45% sodium chloride; 1 mL/kg per hour) via a peripheral venous catheter. As previously described, a radial arterial catheter was placed (0700 h) the morning of study day (36, 37). The arterial catheter was used to monitor HR and blood pressure as well as for periodic blood sampling at defined time points before and after endotoxin administration. A rectal thermometer was placed for continuous monitoring of core body temperature. As previously described (31, 37), a one-time dose of endotoxin (2 ng/kg, CC-RE, Lot #2) was administered for more than a 1-min period through a separate peripheral i.v. catheter at 0900 h (considered time point 0 h) on study day 1.

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Clinical monitoring

Vital signs, including HR and mean arterial blood pressure, were recorded every 30 min from the arterial monitoring system for the first 6 h (0900-1500 h) and then taken manually at 9, 12, and 24 h after LPS administration. Core temperatures were recorded every 30 min through +6 h via rectal thermometer then orally at 9, 12, and 24 h after LPS administration. At 6 h after LPS bolus, the arterial catheter and the rectal thermometer were removed. The peripheral i.v. catheter-infusing saline solution was removed once each subject tolerated a regular diet. Subjects remained in the study unit overnight and were discharged to go home the following morning after the 24-h after LPS samples were obtained.

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Assessment of HRV

A baseline determination of HRV was obtained at the time of admission (Admit) as well as hourly from 0 to +6 h after endotoxin challenge and at +24 h after LPS. Each recording interval consisted of 2 consecutive 5-min epochs. During such determinations, HR was monitored using a continuous ECG technique with 3 standard limb leads and CardioPro® 2.0 software with 1 Infiniti and 1 Procomp Plus® recorder (Thought Technology, Ltd, Montreal, PQ, Canada). Heart rate variability parameters as well as interbeat intervals were collected using ECG data at a rate of 256 samples/second as previously described (27, 31). In a continuous ECG record, each QRS complex was detected, and the "normal-to-normal" intervals (all intervals between adjacent QRS complexes resulting from sinus node depolarization) were tabulated, thus providing a record of instantaneous HR (15). For each epoch, noise artifact and irregular heartbeats were manually edited by visual inspection and interpolation before calculation of interbeat intervals using the CardioPro software. We analyzed each epoch (31) and excluded complete measurement epochs where events such as extra systolic heartbeats, skipped beats, and other arrhythmias comprised more than 10% of the total epoch. The power spectral density then was calculated using a fast Fourier transformation algorithm (15, 38). All signals were exported in standard ASCII format to Excel and SAS 9.0 (SAS Institute Inc., Cary, NC) for analysis and graphics (31).

Parameters of HRV were analyzed for both time domain and frequency domain measures. Time domain measures included (1) the standard deviation of the average beat-to-beat intervals of more than a 5-min period (SDANN), a measure of total HRV and overall system adaptability, and (2) the percentage of interval differences of successive interbeat intervals more than 50 ms (pNN50), which is generally associated with respiratory sinus arrhythmia and therefore vagus nerve activity. Frequency domain measures included (1) high-frequency variability ([HF] 0.15-0.4 Hz) that correlates with parasympathetic and vagal tone and (2) low-frequency/high-frequency ratio (LF/HF) that is hypothesized to be associated with sympathetic-parasympathetic balance (10, 15, 16).

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Analysis of blood samples

Blood samples were collected at time points −24, 0, 0.5, 1, 1.5, 2, 3, 4, 6, and 24 h in relation to endotoxin administration. Blood-derived plasma was then analyzed by enzyme-linked immunosorbent assay for measurement of the soluble inflammatory markers TNF-α and IL-6. The peak value of these cytokines was determined for each individual. We have previously reported the gender-based cytokine response to endotoxin exposure in a larger study population that did not differ between male and female subjects (32).

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Statistical analysis

Analysis of HRV parameters

Gender differences in parameters of HRV were measured by two-way ANOVA with repeated measures on time using Statistica version 6.1 (StatSoft, Inc, Tulsa, Okla) (39). P values less than 0.05 were considered to be statistically significant. The Pearson product-moment correlation coefficient was calculated to measure the association between baseline parameters of HRV and maximum recorded plasma TNF-α and IL-6 levels.

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Analysis of entropy

Entropy analysis was performed using the multiscale approach suggested by Costa et al. (12) and is shown as sample entropy over increasing scale factors. The pattern length of 2 as well as a similarity factor of 0.15 was used as suggested by prior reports (5, 40).

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Vital signs

Vital sign changes after endotoxin administration were similar to those previously described (32) and are not reported here.

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Serial cytokine levels

These levels were also similar to those previously reported (32) after endotoxin administration and are not reported here.

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Gender influence on HRV

None of the HRV parameters varied at baseline between genders before endotoxin exposure. Consistent with previous observations, in both gender groups, the greatest change in HRV after endotoxin administration occurred between time points 0 and +3 h (27, 31). In measuring HRV from baseline to +24 h, we found that gender was not significantly associated with any measured HRV response to endotoxin (SDANN, pNN50, HF, and LF/HF; P > 0.05; Figs. 1 and 2). There was a trend toward an enhanced autonomic recovery in females measured by a more rapid return to baseline values of parameters of HRV, including pNN50, HF, and LF/HF (Figs. 1 and 2).

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Baseline entropy was not significantly different between males and females at time point 0 h (P > 0.05). At 24 h, multiscale entropy analysis revealed a significant difference in the gender-related response to endotoxin where females had significantly higher entropy over increasing scale factors (P < 0.05). At 24 h after endotoxin administration, males return to baseline entropy values. In females, higher entropy than at baseline was observed (Fig. 3).

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Body mass index

Body mass index was calculated using height and weight data measured on admission. Groups were separated by those with a BMI less than 25 kg/m2 (n = 21) and those with a BMI of 25 kg/m2 or greater (n = 9) according to World Health Organization guidelines (41). Across the modest range of BMI exhibited by our healthy, young subjects, BMI was not correlated with any basal or endotoxin-induced change in parameters of HRV (data not shown).

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Heart rate

Resting HR was measured at time point 0 h, and groups were separated by those with a resting HR less than 70 beats/min (n = 21) and those with a resting HR of 70 beats/min or greater (n = 9). Resting HR, whether assessed as a continuous or dichotomous variable, as above, did not correlate with any basal or endotoxin-induced change in parameters of HRV (data not shown).

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Relationship of basal HRV and peak in vivo TNF-α and IL-6 response

Basal HRV was determined immediately before endotoxin administration and compared with the maximum subsequent plasma TNF-α and IL-6 level. Baseline LF/HF (r = −0.43, P < 0.05), pNN50 (r = 0.42, P < 0.05), and HF (r = 0.4, P < 0.05) demonstrated a significant association with plasma TNF-α level where baseline SDANN (r = 0.19) did not correlate to TNF-α production after endotoxin administration. Given that initial HRV levels did not vary by gender before LPS, the depiction of this relationship combined both genders (Fig. 4). No baseline parameter of HRV (SDANN, r = 0.15; pNN50, r = 0.17; HF, r = 0.17; LF/HF, r = −0.16) was significantly associated with the production of IL-6 after in vivo endotoxin (Fig. 5).

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Recent data support the role of efferent, vagus nerve outflow as a regulator of systemic proinflammatory mediator activity during inflammation and infection (42). As an effector arm of the parasympathetic nervous system, vagal activity may regulate inflammation through several mechanisms. Vagus nerve efferent signals have been shown to reduce production of the proinflammatory cytokine TNF-α via acetylcholine binding to the α-7 subunits of nicotinic receptors on mononuclear phagocytes of the reticuloendothelial system (28, 42, 43). Vagotomy has been demonstrated experimentally to enhance proinflammatory cytokine release in a murine model of i.p. sepsis (44). Pharmacologic activation of nicotinic receptors has also been shown to reduce TNF-α release from alveolar macrophages exposed to LPS (45). We have also recently confirmed that antecedent transcutaneous administration of the known α-7 agonist, nicotine, reduced systemic phenotype and proinflammatory mediator responses to endotoxin in humans (37).

Both parasympathetic and sympathetic nervous system activity contribute to protective host responses during systemic inflammation and sepsis. Although parasympathetic activity may exert anti-inflammatory effects through vagally mediated anti-inflammatory pathways (28), sympathetic activity is also of importance in regulating vascular tone during sepsis (46). The influence of both of these systems can be estimated by parameters of HRV (15). Observations in the literature are divided as to whether relative parasympathetic (28) or sympathetic predominance (22) is beneficial during stress. Interestingly in critically ill patients, increased parasympathetic tone and decreased sympathetic tone have been associated with mortality (22), and specific parameters of HRV measuring parasympathetic tone (HF, pNN50) have been identified as independent predictors of mortality (22) and development of septic shock (23). Other measures of the complex interaction between sympathovagal balance and other regulatory systems, such as those reflected in very low frequency variability, have also been suggested to associate with outcome (47).

Previous studies have suggested that relative enhancement of parasympathetic activity assessed by high-frequency power spectral analysis and time domain components of HRV is inversely correlated with ex vivo blood production of the proinflammatory mediators TNF-α and IL-6 (29). To study this correlation in vivo, we measured the parameters of HRV at time point 0 h (immediately before endotoxin exposure) and sought correlates to maximal in vivo TNF-α and IL-6 production. We detected a correlation between parasympathetic/vagal parameters of HRV (HF and pNN50) and maximal TNF-α level but not for IL-6 response after endotoxin exposure. However, our finding is in contrast to what might be anticipated from the results of prior studies which suggest that greater basal parasympathetic/vagal activity would lead to a lesser proinflammatory mediator response via vagally mediated cholinergic anti-inflammatory pathways (28). Several factors may account for this difference, including the younger age of our subjects compared with the generally older subjects evaluated in prior studies. In addition, prior studies used in vitro incubation to assess peak cytokine production, whereas the current study determined peak in vivo responses with a serial sampling protocol. Interestingly enough, gender differences have been observed in ex vivo studies wherein higher TNF-α and IL-6 levels were detected in male subjects (29). This is consistent with prior ex vivo-stimulated blood observations based on gender (48). By contrast, in a previous report, higher IL-6 monocyte expression was observed among females throughout the circadian cycle (49). These results underscore the blurring of lines that separate proinflammatory and anti-inflammatory signaling mechanisms based on discrete sympathetic and parasympathetic components (33).

It remains to be determined what influence the autonomic nervous system exerts over the dynamic processes that result from stress. A previous study measuring the influence of antecedent epinephrine on endotoxin-induced systemic inflammation in healthy subjects suggests that this catecholamine is associated with a modest reduction in vagally mediated HRV (27). This is consistent with previous studies of this α- and β-agonist in humans (50, 51). However, epinephrine excess was associated with decreased TNF-α levels after endotoxin challenge, and this result seems to contrast to an enhanced production that might result from decreased activity of cholinergic anti-inflammatory pathways. This suggests that autonomic signals regulating cytokine release have a more complex interface with the hormonal and nervous systems than previously appreciated (27).

Gender did not significantly influence parameters of HRV after endotoxin exposure. Because the recruitment process for these studies sought to exclude females that might be in a peri-ovulatory phase of the menstrual cycle, only 1 female subject demonstrated an estradiol level more than 100 pg/mL. This precluded a detailed analysis of the influence of increased estrogen on the systemic response after endotoxin administration. Interestingly, during recovery at 6 h after endotoxin, female subjects exhibited a relative decrease in sympathetic activity, as measured by LF/HF ratio, as well as a trend toward increased vagal tone reflected by increased HF and pNN50. These findings may suggest that females may undergo more rapid autonomic recovery after a limited acute systemic stressor. To further analyze gender-related differences in the time to recovery of autonomic balance, we undertook entropy analysis (12) in these subjects. By this analysis, male subjects returned to baseline physiologic complexity at 24 h, whereas female subjects seemed to exhibit greater entropy values than at baseline. The enhanced autonomic recovery in females at 24 h may be influential in modulating the response to subsequent stressors.

This study was specifically limited to subjects younger than 30 years, and hence it is unlikely that age influenced the parameters of HRV. Adiposity did not influence either time domain or frequency domain parameters of HRV after endotoxin exposure. Physical fitness, based on nonexercise oximetric testing (52), has been associated with increased baseline vagal/parasympathetic profile as determined by increased pNN50 and HF after mental stress versus a nonfit cohort (53). In this study, physical fitness, estimated by a resting HR less than 70 beats/min, did not seem to influence parameters of HRV after endotoxin challenge. Other reports suggest that improved fitness increases both time and frequency domain parameters of parasympathetic activity (54). A recent study has confirmed that an extended period of submaximal exercise training is associated with reduced ex vivo TNF-α production in response to endotoxin (55). Further studies are needed to determine how mechanisms of physical fitness-induced autonomic activity might interact with other humoral modulators of innate immunity to derive these potential benefits.

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There may be age and chronic illness-associated influences (3, 56) that preclude direct extension of our observations to either much older or younger subjects. Age does influence parameters of HRV (17) and endocrine responsiveness (34), although many elderly subjects seem to maintain innate immune activity (35). Female subjects were almost exclusively in a lower estradiol background, and so the influence of increased estrogen cannot be assessed. Nevertheless, this is the first such assessment of this purported relationship using the human endotoxin model and has sought to control for the important confounding effect of age on autonomic activity (17). Our study population included healthy volunteers, and it is unclear whether our observations would differ in subjects with ongoing sterile or infectious stress. Heart rate variability also exhibits circadian variation (57), and it is conceivable that diurnal variations in autonomic function might differentially influence endotoxin responses when assessed at other points in the circadian cycle (58).

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What's New in Shock, April 2010?
Clemens, MG
Shock, 33(4): 341-343.
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Endotoxin; heart rate variability; volunteer; gender; cytokine

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