¹Differential Effects of Propofol and Sevoflurane on Heart Rate Variability

¹Kanaya, N, Hirata, N, Kurosawa, S, Nakayama, M, Namiki, A., Differential Effects of Propofol and Sevoflurane on Heart Rate Variability, Anesthesiology 2003; 98(1): 34-40.

• ¹Overview:

  • The inclusion of this paper allows not only the evaluation of an aspect of the mechanism for propofol-induced effects on sympathetic and parasympathetic tone but also an indication of the type of analysis used to assess baroreflex status. 

    • Advantages of propofol include relatively positive recovery characteristics which include a low incidence of side effects. 

    • On the other hand, propofol induction may be accompanied by hypotension and bradycardia. A hypotensive component may be due to reduced systemic vascular resistance or reduced cardiac output secondary to venous & arterial vasodilation or by baroreflex impairment and depression of myocardial contractility.

  • Given the hypotension and bradycardia, reduced sympathetic tone could explain all of the hemodynamic consequences of propofol administration. 

    • The mechanism for such reduced sympathetic tone remains to be determined. The process may be fairly complicated. 

    • For example, should propofol decreased cardiac sympathetic tone, the agent should reduce heart rate. Sometimes an increasing heart rate may be noted which is insufficient to counteract a large decrease in peripheral sympathetic narrow activity and blood pressure. On the other hand, propofol can cause significant bradycardia even asystole which may not be prevented by prophylactic antimuscarinic drugs. 

    • Taken together, these results indicated a possible differential propofol effect on cardiac and peripheral input of the autonomic nervous system.

  • ²[By way of summary, the most prominent cardiovascular effect of propofol   is reduced arterial blood pressure secondary to reduced systemic vascular resistance (inhibition of sympathetic, alpha receptor-mediated activity) Hypotension may be more apparent than if thiopental is used for induction but propofol-mediated hypotension is attenuated by stimulation due to laryngoscopy and intubation. Hypotension is more likely to occur following large doses with rapid infusion, especially in the elderly patient. The normal arterial baroreflex response to hypotension appears blunted by propofol; furthermore, significant preload reduction can result in  vagal-mediated reflex bradycardia. Most of the time heart rate changes in cardiac output changes will not be clinically significant in the healthy patient. By contrast, those whohave diminished ventricular function may exhibit reduced cardiac output secondary to decreased filling and intropism.]

  • ¹Given the possibility of differential effects on various components of the autonomic nervous system as a result of propofol administration, there is an interest in application of non-invasive techniques to assess the autonomic manifestations of cardiac regulation. One technique involves assessments of oscillatory rhythms inherent in R-R (ECG) intervals. Previous analysis indicates the presence of both low-frequency (LF) and high frequency (HF) oscillations. However, more importantly is that analysis  links LF oscillations to both the the parasympathetic and sympathetic systems; whereas, HF oscillatory patterns are due to the parasympathetic system. Oscillatory rhythms reflected in R-R interval analysis is a way of describing heart rate variability or (HRV). The technical method of quantifying such variability within the frequency-domain or time-domain is called spectral analysis and will not be considered in detail.

• ¹Introduction

  • The  mechanism by which propofol influences heart rate variability has been difficult to assess based on prior studies because those studies did not assess anesthesia depth. In this study BIS monitoring provided information concerning depth of anesthesia. The Bispectral Index represents a single electroencephalogram measure which has been shown to track electroencephalographic changes associated with the different anesthetic states.

  • In addition to propofol, sevoflurane was also evaluated. This agent exhibits a low blood-gas solubility explaining rapid induction and emergence as well as rapid control of anesthetic depth. In patients, sevoflurane often has minimal effects on peripheral sympathetic activity; however, ephedrine-induced increases in heart rate is abolished under sevoflurane anesthesia. Since ephedrine probably acts in part by sympathetic nervous system activation, sevoflurane might have an influence on autonomic (sympathetic or parasympathetic) tone. Accordingly heart rate variability was assessed in the presence of sevoflurane allowing comparison to propofol effects on heart rate variability.

• ¹Methods:

  • This study involved 30 patients who were scheduled for elective oral surgery. Patients were excluded from the study if they had severe ischemic heart disease, diabetes, congestive heart failure, or other pathological conditions expected to affect autonomic function. No patients in the study to medication that affected cardiovascular performance.

  • Upon arrival to the operating room, patient monitoring was instituted using both standard monitoring and BIS monitoring. Patients were studied supine and heart rate monitored using lead II and V of the ECG. Fluid and drug administration was provided by means of an 18-gauge catheter (forearm vein). Inspired O₂ and end-tidal CO₂  were monitored with normal ventilation maintained using IPPV (mask), as needed. BIS decreased gradually following anesthesia induction both with propofol and sevoflurane and based on preliminary data, hemodynamic and heart rate variability measurements were made at BIS values of 80, 60, 40 and 30.

  • ECG R waves were detected electronically and RRI measured and analyzed.

• ¹Results:

  • Study groups were similar (see Table 1, reference 1, below). Baseline values of systolic BP (SBP), diastolic BP (DBP), mean BP (MBP) & HR were similar in both groups (Table 2, reference 1.

• ¹BIS values for the awake state were about 97 for both propofol and sevofluran groups. From anesthesia induction time to BIS value of 30 was about nine minutes for both sevoflurane and propofol groups.

  • Propofol administration reduced, in a BIS-dependent way systolic and diastolic blood pressures as well as mean blood pressure; however, heart rate remained unchanged. 

  • 5% sevoflurane (mask) and induced a mean blood pressure reduction (at BIS value 80) with no additional mean blood pressure reduction at lower BIS values. 

  • No differences in mean blood pressure and heart rate between propofol and sevoflurane groups were noted.

  • Alteration in heart rate variability parameters during propofol or sevoflurane induction are noted below.

 

 

Changes in HF (lhigh frequency) during anesthesia induction: Values--mean +/- SD; *P <0.05 versus awake.  BIS = Bispectral Index (Figure 2; ref 1)

 

• Propofol administration reduced, in a BIS-dependent way systolic and diastolic blood pressures as well as mean blood pressure; however, heart rate remained unchanged. 5% sevoflurane (mask) induced a mean blood pressure reduction (at BIS value 80) with no additional mean blood pressure reduction at lower BIS values. No differences in mean blood pressure and heart rate between propofol and sevoflurane groups were noted.

• Recalling that changes in LF reflects alterations in sympathetic and parasympathetic components of autonomic tone, we note that following propofol , LF does not change from baseline  (except during a transient reduction at BIS 60.) By contrast,LF decreases following sevoflurane, reaching about 40% of baseline at BIS 80. LF decreases to about 20% of baseline at BIS 60, although no further reduction is noted at lower BIS values.

• HF (parasympathetic) decreases following propofol administration in a coordinated matter with the BIS value. On the other hand, sevoflurane inhalation did not change HF. Entropy, the meaning of which will be described later, is decreased by propofol in a way that parallels BIS values. Sevoflurane anesthesia transiently decreased the entropy value only at BIS 80. A way of showing the differential effects is by examining LF/HF ratios. Propofol decreases this ratio only at the lowest this value. Sevoflurane had limited effect on the ratio (note transient decreased at BIS 40.)

• ¹Discussion:

  • The authors first review the principal findings noted as follows:

    •  (1) propofol induction decreased blood pressure, HF or entropy in a BIS-dependent way, although propofol did not affect heart rate LF. 

    • (2) sevoflurane (mask) decreased blood pressure or LF independent of changes in BIS and furthermore sevoflurane did not affect heart rate or HF. 

    • (3) propofol and sevoflurane had limited effect on the LF/HF ratio although sevoflurane perhaps decreased the ratio slightly.

  • Entropy as applied to R-R interval data (RRI) can be used it to quantifying pattern repetition. Larger entropy values correspond to increased randomness or irregularity. This definition is consistent with the thermodynamic use of the term. Smaller entropy values then represent increased patterning (decreased randomness) in the data. Applying this concept to beat-to-beat variation in heart rate is a way of describing more complex models with multiple inputs having varied effects on in this case R-R interval. Recalling that the heart is under parasympathetic-dominant control, the entropy of RRI might reflect variability in parasympathetic modulation of heart rate under both differing physiological states and in response to pharmacological agents that block muscarinic receptors, i.e. pharmacological denervation. Entropy changes, consistent with this idea, tended to be similar to changes in HF.

  • ¹Propofol and heart rate variability

    • Cardiovascular homeostasis is regulated significantly by the autonomic nervous system. Therefore understanding how anesthetic agents modify sympathetic activity is helpful in understanding anesthetic action on the cardiovascular system. Propofol-mediation of blood pressure and heart rate reduction in patients may be due in part to inhibition of sympathetic neuronal activity. By direct measurement, peripheral sympathetic nerve activity is reduced in muscle sympathetic and renal sympathetic models in humans and rabbits, respectively. The effect of propofol in the parasympathetic nerve activity has not been studied in a definitive way.

    • The results reported in this paper indicate that propofol reduces HF but not LF suggestive of the reduction cardiac parasympathetic tone more than sympathetic tone associated by propofol rapid sequence inductions. Clinically, propofol may cause bradycardia, although the underlying mechanism remains to be determined. In this presentation, propofol reduced HF but not LF and this effect occurred without a change in heart rate. Heart rate variability measures and-organ response to peripheral and central coronal inputs which both produce and respond to heart rate and blood pressure changes. Anesthetic drugs may interfere with CNS integration in ways that influence end organ responses.

    • Generally, interpretation of heart rate variability data should consider several factors, according to the authors. These factors include:

      • (1) the ability of the heart to respond appropriately to neural regulation 

      • (2) the ability of sympathetic and parasympathetic neural "rhythms" to reach the heart and 

      • (3) the characteristic no central coronal integration sites to function appropriately. 

    • These factors might be associated with limited or no correlation between heart rate and autonomic tone. Propofol anesthesia induction resulted in greater decreases in muscle sympathetic nerve activity and blood pressure suggesting reduced peripheral sympathetic activity, and also was associated with an increase in heart rate reflecting decreased cardiac parasympathetic activity. A direct negative chronotropic (bradycardic) propofol effect could offset an increase in heart rate response to heart rate variability noted in the study. Other studies have reported reduced cardiac parasympathetic activity following propofol with a small increase in heart rate along with larger reductions in sympathetic nerve activity and BP.

    • Inadequate information about anesthesia depth generally may result in misinterpretation of results since heart rate variability could be observed at a fixed time period following propofol, but not necessarily at a fixed depth of anesthesia. This technical point is important in interpretation of other work which doesn't analytically described or determine anesthetic depth.

  • ¹Sevoflurane and heart rate variability

    • In patients, sevoflurane reduces baroreflex control of heart rate and sevoflurane reduces pressor and the pressor baroreflex sensitivities.

      • In this study sevoflurane reduced LF without changing HF and entropy, consistent with dominant inhibition of the sympathetic side with limited or no effect on the parasympathetic side. 

      • Effects of sevoflurane on sympathetic or parasympathetic nerve activity would depend on the overall autonomic tone during the study. One way of thinking about this is that an anesthetic can directly affect heart rate variability which could be considered static, i.e. just a direct effect as well as causing an effect on the baroreflex which influences heart rate variability dynamically. Accordingly, sevoflurane could have different effects between heart rate variability and baroreflex. In a rabbit model, sevoflurane has different effects on spontaneous efferent sympathetic nerve activity and the baroreceptor-sympathetic reflex. 

• ¹Study Limitations:

  • The authors note some study limitations. 

    • For example, sympathetic and parasympathetic nerve activity was not directly measured. 

    • Also, heart rate variability, despite being routinely used to assess autonomic aspects of neuronal cardiac influence, such changes could reflect effects on the reflex arc as opposed to the autonomic nervous system more generally. 

    • The HF component of heart rate variability is sensitive to or results from respiratory-related vagal modulation of heart rate. Also, HF amplitude decreases with respiratory frequency and increases with tidal volume. Respiratory effects on RRI is associated with tidal volume changes, probably reflecting instability in the ventilatory chemo receptor feedback system. Direct mechanical transfer of tidal volume oscillation in a way that could influence heart rate fluctuations were not considered in this study. As a result of these considerations, the effect of anesthetics on heart rate variability could be underestimated if anesthesia induction decreased respiratory rate and tidal volume. There was an effort to minimize these effects in the present study by trying to maintain steady-state respiration. 

    • An important additional point was that even though BIS values with the same, this fact does not insured equal anesthetic depth between propofol and sevoflurane. BIS exhibits significant variability among anesthetics, although it is considered to be a reasonably effective measure of sedation depth with propofol, midazolam, isoflurane and sevoflurane. The variation in BIS described earlier is not well understood mechanistically; however, in the present study there was no reason to doubt that BIS values were independent of anesthesia depth.

• ¹In summary, the authors conclude that propofol decreases HF and entropy rather than LF in a BIS-dependent way, suggesting that propofol inhibits cardiac parasympathetic tone to a greater extent than sympathetic tone during induction. Accordingly, propofol-mediated bradycardia is not likely due to increased cardiac parasympathetic nerve activity. On the other hand, sevoflurane tends to maintain hemodynamics, HF, and entropy, suggesting that this agent has very limited effects on cardiac parasympathetic tone.

• ¹Kanaya, N, Hirata, N, Kurosawa, S, Nakayama, M, Namiki, A., Differential Effects of Propofol and Sevoflurane on Heart Rate Variability, Anesthesiology 2003; 98(1): 34-40.

• ²Morgan, GE, Mikhail, MS, Murray, MJ, Chapter 8 in Clinical Anesthesiology, 3rd Edition, Lange Medical Books/ McGraw-Hill, p 174, 2002.