Septic shock has a poor prognosis; moreover, its presence in the emergency units is growing rapidly (1). Septic shock is characterized by a profound vasodilation and hypotension partially due to the release of nitric oxide and inflammatory mediators and to endothelial disruption (2). Nevertheless, treatments based on vasoconstrictor agents and on anti-inflammatory substances did not produce the expected results (3, 4). This is probably due to the fact that, together with a systemic vasodilation, in these patients the distribution of cardiac output is altered, with a reduction of blood flow to vital organs and to the microcirculation (2). The baroreflex is the system deputed to maintain cardiovascular homeostasis and to preserve blood flow to vital organs (5, 6); nevertheless, little attention has so far been given to the impairment of the baroreflex in this condition (7, 8). Moreover, in septic shock, a direct relationship between baroreflex sensitivity (BRS) and survival time has been reported (9, 10) with a reduced survival time in the presence of a reduced baroreflex function. One could hypothesize that in septic shock BRS is reduced as a consequence of the deactivation of the baroreflex brought about by the reduction in blood pressure (BP) values (5, 6). Nevertheless, in this case, a reflex activation of the sympathetic nervous system (9) would occur with a consequent improvement of the hemodynamics. On the contrary, it seems that in septic shock the reflex adjustments to counteract the BP drop are drastically reduced (7). Therefore, it is possible that the impairment of the baroreflex is produced by other factors than the decrease in BP. The aim of our study was therefore to verify whether endotoxemia per se will influence the baroreceptor reflex independently and before of any endotoxin-driven BP drop. The recognition of such a situation is important as it could open the field to new treatment options, as recently suggested (11). It is difficult to investigate the baroreflex function during endotoxemia without the confounding effects of BP changes. It not only requires a new way to administer the toxin as done so far (i.e., intravenous or intraperitoneal bolus); it also requires an almost continuous monitoring of the baroreflex function, making mandatory techniques based on the spontaneous variability of BP and heart rate rather than traditional methods based on the administration of external stimuli. We therefore continuously recorded the spontaneous baroreflex function before and at various times during and shortly after a continuous infusion of Escherichia coli lipopolysaccharide (LPS). We controlled both the E. coli LPS infusion, so as to activate the inflammatory cascade, and the concomitant saline infusion, to avoid any significant BP reduction. In this way, we could verify whether endotoxemia induces a deactivation of the baroreflex independently and before the occurrence of any BP change.
Animal preparation and experimental protocols
All procedures conformed with the Italian Government regulations on protection of animals used for scientific purposes. The protocol of the study was approved by the ethical committee of the University of Milano-Bicocca.
We studied the effects of LPS infusion on the baroreflex function of 10 Sprague-Dawley rats (Charles River Italia, Calco, Italy) aged 11 to 12 weeks. Moreover, we studied the effects of LPS infusion on inflammatory and anti-inflammatory cytokines in another group of eight Sprague-Dawley rats of the same age.
Baroreflex function evaluation
In each rat, polyethylene catheters were implanted in the femoral artery for BP recording or sampling and in two femoral veins for drug infusions. The catheters were tunneled subcutaneously, exteriorized at the dorsal neck region, and kept patent by flushing with appropriate heparin solution (0.01% vol/vol). After surgery, more than 24 h were allowed for the animal to recover and acclimate to the experimental environment, consisting of a wide cage in which the rat could walk, explore, eat, and drink ad libitum. Rats were studied only if they appeared in good shape and did not show any sign of distress or pain. Moreover, during the recording, noises were avoided, and rats could not see outside their cage. Data were collected during daytime in an unanesthetized condition. The arterial catheter was connected to a pressure transducer (model P23 Dc; Gould-Statham, Oxnard, Calif). The BP signal was displayed on a chart recorder (7D polygraph; Grass Instruments, Quincy, Mass) and tape recorded for offline analysis. Heart rate was visualized from the pulsatile pressor signal via tachographic beat-to-beat conversion.
Escherichia coli LPS (026:b6 serotype) was infused for 20 min at 0.05 mg · kg−1 · min−1. This infusion procedure allowed the concomitant infusion of 1 mL of saline solution, a volume that we had previously observed to be sufficient for maintaining the BP level. Blood pressure was continuously recorded for 110 min, i.e., 30 min before starting the LPS infusion, 20 min during the LPS infusion, and 60 min after the end of the infusion.
These rats were similarly instrumented with catheters in the femoral artery and in two femoral veins. In four rats, blood was withdrawn from the femoral artery at baseline and plasma concentrations of interleukin 6 (IL-6), tumor necrosis factor α (TNF-α), and IL-10 were measured by enzyme-linked immunosorbent assay technique. By applying statistical power analysis on these baseline measures, we estimated the minimum number of rats needed to detect a doubling in cytokine concentrations with statistical significance lower than 5% and statistical power greater than 90%. On the base of power analysis, blood was then withdrawn from the femoral artery in a second group of four rats between 50 and 60 min after LPS infusion. Concentrations of IL-6, TNF-α, and IL-10 were measured for comparison. Two separate groups of animals were considered to avoid BP changes due to blood sampling.
Arterial BP was digitized at 12 bits with a sampling rate of 1,000 Hz. Systolic BP (SBP), diastolic BP (DBP), and mean arterial pressure (MAP) were identified beat by beat from the arterial pressure signal; pulse interval (PI) was calculated as time distance between consecutive systolic peaks (Fig. 1, inset). Two stable segments of data (hereafter indicated as “baseline” and “after” subperiods), each of 10-min duration, were selected for frequency-domain analysis: the first before and the second immediately after the end of infusion. In 9 of the 10 animals, it was also possible to select a third stable period of analysis (“after 2” subperiod) between 50 and 60 min after the end of infusion.
Power spectral analysis
Beat-to-beat data were resampled at 100 Hz. The Welch periodogram was calculated greater than 90% overlapped Hann data windows of 3-minute duration. Spectral lines were estimated between 0.006 and 3 Hz after broad-band smoothing (12). The cross-spectrum between SBP and PI was calculated in a similar fashion, and the squared coherence function was derived as ratio between the squared cross-spectrum and the two autospectra. We defined low-frequency (LF) and high-frequency (HF) bands for heart rate and BP spectra from the position of the two maxima characterizing coherence between SBP and PI at baseline. Accordingly, the LF band ranged between 0.09 and 0.70 Hz and the HF band between 0.70 and 2.1 Hz (Fig. 4). The respiratory rate was estimated as the frequency of the highest spectral peak of the MAP spectrum within the HF band.
The baroreflex function was evaluated both in the frequency domain (transfer function technique) and in the time domain (sequence technique). The transfer function technique was applied at baseline, in the after and after two subperiods. It estimates the BRS by calculating the transfer function between SBP and PI, over frequency bands where the two time series are coherent (LF and HF bands), the level of correlation being presumably due to the baroreflex (13). Transfer functions were obtained from the ratio between SBP and PI cross-spectrum and the root-squared SBP auto-spectrum in the LF band (BRSLF) or in the HF band (BRSHF). In either band, only spectral components with SBP-PI squared coherence modulus greater than 0.3 were considered. Calculation included the average phase between SBP and PI fluctuations (ϕLF and ϕHF) in radiants. Because of the definition as multiples of 2π (a turn angle), phases were scaled between −π and +π. A zero phase indicates that increases or decreases of SBP and PI fluctuations occur synchronously. A negative phase indicates that SBP variations precede PI variations, whereas a positive phase indicates that SBP variations follow PI variations (14). Given the phase ϕ, the delay between PI and SBP oscillations at frequency f, in seconds, is τ = −ϕ/(2πf). Because ϕ is defined as multiples of 2π, τ is also defined up to multiples of the mean heart period, PI. The transfer function technique is based on spectral analysis; thus, this method was applied only on the stationary data segments selected previously for spectral analysis.
The sequence technique was applied, as the transfer function technique, at baseline, in the after and after two subperiods. Moreover, it was used to analyze the baroreflex function during infusion. It is a time-domain method based on the identification of monotonic changes in SBP and in the related PI response (15). Briefly, beat-to-beat series of PI and SBP were scanned in search of SBP ramps, i.e., three or more consecutive heart beats in which SBP showed a progressive increase (+ ramp) or decrease (− ramp) followed after a lag of no more than six beats, by a progressive lengthening (+/+ sequence) or shortening (−/− sequence) of PI, respectively. The slope of the regression line between SBP and PI values in the sequence was taken as a measure of BRS (BRSS+ and BRSS−). Calculation was also made of the slope of SBP ramps. At variance from the transfer function technique, which requires stationarity of the signals, the sequence technique can be also used under nonstationary conditions. This allowed us to assess the baroreflex function even during the nonstationary infusion period of 20 min (hereafter indicated as “infusion”). This was done by applying the sequence technique over seven consecutive nonoverlapped segments of data, each of 3-minute duration, with the first segment starting at the beginning of infusion. In this way, the sequence technique provided the profile of BRSS changes during the whole infusion period.
Changes in MAP, PI, and BRSS between “baseline” and each of the seven data segments during infusion and “after” infusion were assessed by repeated-measures analysis of variance with Dunnett post hoc comparisons.
Differences between “baseline” and “after” subperiods were tested by the nonparametric Wilcoxon matched-pairs test when ϕLF and ϕHF were considered, by paired t test otherwise. Before statistical analysis, logarithmic transformation was applied to spectral powers and SDs, and Fisher z transformation was applied to squared coherence spectra. Unless otherwise indicated, data are present as mean ± SEM. The significance threshold was set at 5%.
During E. coli LPS infusion, rats stopped exploring, eating, or drinking and kept still in a corner of the cage. This altered behavior continued for the whole recording period.
BP and PI
Figure 2 illustrates the changes in MAP and PI during and after infusion of E. coli LPS. Mean arterial pressure showed a decrease between the 12th and the 15th minute after the beginning of the infusion (−10 mmHg, P < 0.03). Thereafter, MAP started to increase again, reaching in the “after” condition almost the same level observed at baseline (79 ± 7 mmHg). Table 1 indicates that after infusion also SBP and DBP mean levels were very similar to baseline levels.
A markedly different trend characterized PI changes. Compared with the baseline value (160 ± 13 ms), PI showed significantly lower values starting from the sixth minute of infusion up to the end of infusion (148 ± 13 ms). Pulse interval remained relatively low after infusion (152 ± 12 ms), even if the difference with baseline was only close to the significance threshold after Dunnett correction for multiple tests.
Figure 3 illustrates the changes occurring in BRS, as estimated by the sequence technique, during and after infusion. BRSS decreased few minutes after the start of LPS infusion, the reduction being already statistically significant 10 min after the beginning of the infusion. BRSS reached its nadir 15 min after the beginning of the infusion, remaining stable at this statistically low value.
Table 2 provides further details on the changes in the baroreflex function after infusion as assessed by the sequence technique. The BRS decreased to less than half the baseline values for either sequence type (+/+ or −/− sequences). In parallel with the reduction of BRSS+ and BRSS−, the slopes of the corresponding SBP ramps increased significantly.
Similar findings were obtained by the transfer function technique, and BRS estimates in the LF and HF frequency ranges decreased significantly up to values about half those at baseline (Table 2). From the transfer function technique, we also obtained information on the SBP-PI phase and coherence modulus. The LPS infusion decreased the SBP-PI coherence in the LF band (Fig. 4) without changing the phase, ϕLF, which remained negative as at baseline (Table 2). Therefore, the delay τ remained positive, being respectively equal to 0.7 s (baseline) and 1.1 s (after) at f = 0.17 Hz, frequency of the coherence peak in the LF band. This means that in the LF band most SBP changes preceded the PI changes both in baseline and after infusion. In contrast, the LPS infusion increased significantly the SBP-PI coherence modulus in the HF band (Fig. 4), changing significantly the SBP-PI phase (Table 2). Therefore, the delay τ at the frequency of the respiratory peak (f = 1.14 Hz) decreased from 0.7 to −0.14 s and after infusion respiratory oscillations of PI preceded respiratory oscillations of SBP.
Although the study was designed to investigate changes in BRS occurring rapidly after the start of LPS infusion, the availability of stationary data segments 50 to 60 min after the end of infusion (“after 2” subperiod) in 9 of the 10 animals allowed us to verify the long-term BRS function. We found that the baroreflex impairment in “after 2” (i.e., long after the end of the infusion) was similar as observed in “after” (i.e., shortly after the end of infusion), and BRSS was equal to 0.72 ± 0.23 ms · mmHg−1 (P = 0.95 vs. “after” by paired t test), BRSLF was equal to 0.33 ± 0.07 (P = 0.18), and BRSHF to 0.54 ± 0.21 (P = 0.59).
BP and PI variability
Compared with baseline, PI spectral powers (Fig. 5, left) decreased significantly at almost all the frequencies after infusion. This change was associated to a significant decrease in overall PI variability, as quantified by a reduction of PI SD from 5.6 ± 0.7 to 3.9 ± 0.5 ms. In contrast, the overall BP variability increased, the change being significant for SBP (Table 1). The increase in BP variability was accompanied by an increase in the HF power in the MAP spectrum (Fig. 5, right), index of BP changes mechanically related to respiration. Unlike HF power, LF power of MAP (index of vascular sympathetic modulation) was significantly reduced after LPS infusion. The breathing rate, indirectly estimated from the HF peaks, was equal to 1.14 ± 0.04 Hz in baseline and did not change significantly after infusion (1.16 ± 0.07, P = 0.78).
Both inflammatory (IL-6, TNF-α) and anti-inflammatory (IL-10) cytokines increased significantly between 50 and 60 min after the end of LPS infusion. The increase amounted to almost 100 times for TNF-α, 20 times for IL-6, and 10 times for IL-10 (Table 3).
Our study was designed to assess changes of BRS in an animal model of E. coli LPS infusion without the confounding effect of BP reduction. The results show that during E. coli LPS infusion (a) the BRS is reduced by more than half the baseline value, thus exhibiting a striking baroreflex impairment and that (b) the baroreflex impairment occurs almost immediately after the beginning of infusion and is maintained thereafter without any recovery even at considerable time distance (50–60 min) from the end of infusion. This has obvious pathophysiological implications because such a striking and prolonged baroreflex impairment deprives the cardiovascular system of a fundamental mechanism to oppose, via suitable autonomic sympathetic activation and vagal inactivation, the hypotension and reduction of vital organ perfusion that endanger survival.
During LPS infusion, the bradycardic response to spontaneous BP increases (+/+ sequences) and the tachycardic response to spontaneous BP reductions (−/− sequences) were impaired to a similarly striking degree, suggesting that the endotoxin disrupts the baroreflex function throughout its stimulus-response curve. The impairment of the baroreflex function is presumably responsible for the increased BP variability, as quantified by the increased SBP SD and slopes of SBP ramps as well as by the greater respiratory peak in the MAP spectrum (this latter reflecting larger BP oscillations mechanically induced by respiration). It may be also responsible for the reduction of overall heart rate variability, as quantified by decreased PI SD and spectral powers over a broad band of frequencies. In fact, a primary function of the baroreflex is to buffer BP variations not only by modulating the vasomotor tone but also by amplifying heart rate (and thus cardiac output) changes (16). The baroreflex impairment is also presumably responsible for the SBP-PI reduction of coherence and inversion of phase in the LF or HF band, which reflect the loss of the baroreflex ability to operate on heart rate (and thus cardiac output) to correct immediately preceding BP alterations (12, 17). It may be also responsible for the decrease in the LF components of BP variability, recognized index of autonomic modulation to the blood vessels: similar changes in SBP and PI spectral powers and LF coherence were, in fact, previously observed in presence of baroreflex impairment (18–20).
The mechanisms involved in the striking and prolonged baroreflex impairment associated with endotoxin infusion are not clarified by our study. Nevertheless, the rapidity of baroreflex impairment suggests a direct effect of the toxin. Toxin infusion, in fact, has been shown to induce the production of nitric oxide and reactive oxygen species (21, 22), molecules known to have direct negative effects on BRS (23, 24). Moreover, important alterations of vascular dynamics (hyporeactivity, reduced vascular compliance) (25) and vascular hypopolarization (26), described during E. coli LPS infusion, could have reduced the stimulus to which baroreceptors respond (23, 27).
However, our study also showed that baroreflex impairment persisted after E. coli infusion was stopped. It is possible, therefore, that, in addition to the endotoxin, other compounds played a role in reducing the baroreflex function. In our study, circulating cytokines were significantly increased even after the end of E. coli infusion. Circulating cytokines, therefore, could have induced an inflammation of the carotid body with a reduction of arterial distensibility (27, 28) and therefore of baroreflex engagement. Another possible explanations for baroreflex impairment could be ascribed to an increase in chemoreceptor activity (28, 29) that has been observed during LPS infusion. Moreover, a central effect of the circulating cytokines cannot be excluded. Our rats, in fact, showed signs of a sickness behavior, an effect that has been ascribed to the presence of cytokines in the brain (30).
Some additional points deserve to be mentioned. One, as indicated before, the infused dose of E. coli LPS was associated with levels of circulating inflammatory cytokines (IL-6, TNF-α) more than 10 times greater than those seen in animals under baseline conditions. This indicates that avoiding the BP fall did not prevent a large increase in cytokines to be achieved. Two, we could not avoid completely a reduction of BP during E. coli LPS infusion. Nevertheless, this reduction was transitional (from the 12th to the 15th minute after the beginning of the infusion) and of a small entity. Moreover, its time profile was completely different from that of the baroreflex impairment. The reduction in BRS in fact started well in advance of the change in BP and did not recover any more even after the recovery of the BP level. Three, a dramatic increase in IL-10 was also present. Interleukin 10 is an anti-inflammatory cytokine known to modulate the proinflammatory response (31). In our study, a high concentration of plasmatic IL-10 may have reduced the inflammatory response that could have been even worse in its absence. Four, previous studies on the baroreflex function during infusion of bacterial endotoxins had limitations that were avoided in the present study (8, 32). A most important limitation was that in previous studies baroreceptors were stimulated and unloaded by vasoactive drug administration. Compared with the high number of baroreflex assessments possible by using spontaneous BP changes and to the high specificity and sensitivity of spontaneous estimates both in time domain or frequency domain (33), the approach based on vasoactive drugs allows collecting only a small amount of data with little chance to investigate the time course of baroreflex alterations and to discriminate smaller differences in baroreflex function.
We documented, therefore, that toxin infusion is responsible for a quick and drastic impairment of the baroreflex function, independent from the level of BP and large enough to alter cardiovascular homeostasis. Reported similarities between rats and humans in integrative mechanisms of BP control (34, 35) suggest that our model describes pathophysiological mechanisms that may be present also in humans. The presence of baroreflex impairment therefore could help the early recognition of endotoxemia.
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Baroreflex; rats; E. coli LPS toxin; cytokines; heart rate variability; blood pressure variability