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Infants Tolerate Spinal Anesthesia with Minimal Overall Autonomic Changes: Analysis of Heart Rate Variability in Former Premature Infants Undergoing Hernia Repair

Oberlander, Tim F. MD, FRCP(C); Berde, Charles B. MD, PhD; Lam, Kar H. MsEE; Rappaport, L. A. MD; Saul, J. Philip MD

Pediatric Anesthesia

Unlike adults, neonates tolerate high thoracic spinal anesthesia with minimal changes in heart rate (HR) and arterial blood pressure.To examine the potential autonomic regulatory mechanisms which may account for these findings, the relation between short-term heart rate variability (HRV) and respiratory activity was analyzed in a group of eight ASA grade II former premature infants undergoing high thoracic spinal anesthesia for inguinal hernia repairs. Quantitative measures of sympathetic (As) and parasympathetic (Ap) modulation of HR were derived. HR, arterial blood pressure, and a calibrated respiratory signal were recorded during 4.4-min stable epochs in eight subjects 1) preoperatively, 2) postincision after high thoracic spinal anesthesia, and 3) during an active sleep state in the postoperative period. Power spectral analysis of HRV and respiratory power yielded measures of low-frequency power (LFP: 0.02-0.15 Hz) and high-frequency power (HFP: 0.15-0.8 Hz). Transfer function analysis between respiratory activity and HR were used to quantify As and A (p). All subjects had successful high thoracic spinal anesthesia with highest levels ranging from C7-T4. Mean HR, blood pressure, and respiratory power did not change significantly with high thoracic spinal anesthesia. LFP and HFP both decreased significantly, whereas the LFP/HFP ratio remained stable. Group mean As and Ap both decreased, but the changes were not significant. Despite overall cardiovascular stability, HRV decreased with high thoracic spinal anesthesia, but the balance between LFP and HFP remained stable, suggesting that the reflex response to high thoracic spinal anesthesia was predominantly diminished parasympathetic modulation of cardiac function. The expected decrease in HR and blood pressure from the sympatholysis which results from high thoracic spinal anesthesia were apparently offset by withdrawal of cardiac vagal activity.

(Anesth Analg 1995;80:20-7)

Departments of Cardiology, Medicine, Anesthesiology, and Surgery, Children's Hospital, Harvard Medical School, Boston, Massachusetts.

This work was supported by grants from the Whitaker Foundation, Mechanicsburg, PA, a Milton Fund Research Grant from Harvard Medical School, and by National Institutes of Health Grant R01-HL48012-01. Dr. Oberlander was a Clinical Research Fellow of the National Cancer Institute of Canada, and received additional support from a training grant from the Bureau of Maternal and Child Health, National Institutes of Health. Dr. Saul is supported by Clinical Investigators Award, National Institutes of Health Grant K08-HL02380-03. Dr. Berde is supported by the Anesthesia Patient Safety Foundation and the Christopher Cokley Fund.

Accepted for publication August 19, 1994.

Address correspondence and reprint requests to J. Philip Saul, D, Department of Cardiology, Children's Hospital, 300 Longwood Avenue, Boston, MA 02115.

High thoracic spinal anesthesia is a safe and effective alternative to general anesthesia in patients less than 1 yr of age [1,2]. This observation has been made in the absence of intravascular fluid administration prior to the onset of anesthesia. In contrast, the preganglionic sympathetic blockade that results from high spinal anesthesia in adults has been associated with hypotension, nausea, pallor, sweating, and bradycardia [3]. Dohi et al. [4] have suggested that the adverse effects observed in adults are the result of sympathetic withdrawal, possibly combined with an increase in vagal outflow, phenomena which are apparently not typically observed in the neonate or young child undergoing spinal anesthesia. Although the reasons that underlie this finding remain unclear, perhaps cardiovascular stability in infants is due to either a smaller venous capacitance in the lower extremities, leading to less pooling of blood [4], or a relative immaturity of the sympathetic nervous system which results in less dependence on sympathetic control of vasomotor tone [4]. Yet unanesthetized newborn infants have beat-to-beat vagal and sympathetic autonomic control of heart rate (HR) which is both qualitatively and quantitatively similar to adults [5,6].

To investigate potential autonomic regulatory mechanisms that enable infants to tolerate spinal anesthesia, heart rate variability (HRV) and the relationship between respiratory activity and short-term variations of HR (respiratory sinus arrhythmia) were analyzed to quantify the effects of spinal anesthesia on autonomic HR control in a group of former premature infants undergoing hernia repair.

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Methods

After approval by The Children's Hospital Committee on Clinical Investigation and with informed, parental consent, nine (ASA grade II) unpremedicated infants undergoing repair of bilateral inguinal hernias were studied. One infant experienced symptomatic bradycardia requiring treatment during the spinal placement, and therefore was removed from further analysis. All eight remaining infants were born prematurely Table 1. The mean gestational age at birth was 32.6 +/- 1.1 wk, mean postbirth age at the time of the operation was 7.5 +/- 4.1 wk, and mean postconceptual age was 40.0 +/- 4.2 wk. Mean weight was 3.2 +/- 1.1 kg. The trachea of one infant was intubated at birth for 2 days and required supplemental oxygen for 3 more days. In no case was ventilation controlled and no infant had an intraventricular hemorrhage greater than Grade I. Spinal anesthesia was chosen as the sole anesthetic for this group because of concern for the frequent occurrence of apnea following general anesthesia. No sedatives or anticholinergic drugs were used.

Table 1

Table 1

Spinal anesthesia was induced in a standard fashion. Lumbar puncture was performed at the L4-5 interspace. Tetracaine 0.5% hyperbaric with dextrose 1 mg/kg combined with epinephrine 50 micro gram was injected. Within 10 min after injection, the sensory level of anesthesia was ascertained by observing the patient's response to a standardized stimulus delivered by a neuromuscular block monitor to sequentially higher sensory dermatomes. Sensory block was indicated by a lack of behavioral response (movement or cry) to the stimulus.

Infants were studied in an awake alert or active sleep state [7], spontaneously breathing room air and in a supine position. One lead of the surface electrocardiogram (ECG), respiratory activity, and cuff blood pressures were recorded before, during, and after the operation. Standard surface chest electrodes were used to produce continuous ECG and impedance respiratory signals (Hewlett-Packard component monitoring system M1046; Waltham, MA) which were digitally sampled to disk at 360 Hz using a personal computer-based data acquisition system. In addition, a brief recording (3-5 min) of calibrated respiratory flow was recorded simultaneously with the impedance respiratory signal (Bear Neonatal Volume Monitor; NVM-1, Riverside, CA). Impedance based respiratory volumes were normalized to a standard body surface area of 1.73 m2 to enable comparisons between adult and infant respiratory data. Arterial blood pressure was measured using the oscillometric technique (Dinamap; Critikon Inc., Tampa FL), and recorded for this study at approximately 5 min prior to the spinal, and then at 10, 20, 30, and 40 min after the spinal injection.

R waves were detected from the sampled ECG and used to form a smoothed instantaneous 4 Hz time series, as described previously [8]. The impedance and respiratory flow signals were digitally low-pass filtered and decimated online using specialized software to create 4 Hz representations of chest impedance and respiratory volume which were simultaneous with the HR signal. The flow signal was then integrated to yield a calibrated respiratory volume signal, and a 15-s epoch of the volume signal was used as a calibration for the impedance signal by multiplying the entire impedance respiratory signal by the ratio of the SD of the volume signal to that of the impedance signal.

Two 2.2-min segments of HR and respiratory activity were selected from three periods: a preoperative, an intraoperative-postincision, and a recovery period. The segment selection criteria were based on qualitative signal stability, the absence of infant movement, and stable behavioral state [7]. In the preoperative baseline control period, infants were in Active Sleep or Drowsy State [7] sucking on a pacifier. The intraoperative period was selected from a period approximately 20 min after the incision to ensure that each infant would be studied at a similar time and under similar operative conditions. During this time, infants were in Active Sleep sucking on a pacifier. The postincision operative epoch started 20.6 +/- 7.6 min after the spinal was given, and 8.3 +/- 5.4 min after the incision. The incision occurred 12.3 +/- 4.1 min after the spinal injection. To assess the overall effect of the operative and anesthetic stress, a postoperative, recovery room control segment was selected as the first two 2.2-min periods which met the selection criteria following the first 3 consecutive min in Active Sleep after arriving in the recovery room. This occurred 119 +/- 31.6 min after the spinal was given. Within 90-100 min after the spinal anesthetic, the anesthetic level had regressed below T12 as assessed by the Anesthesia Resident, Fellow, or Attending Physician who observed the infants' response to a pinprick and leg movements.

Power spectral estimates [Blackman-Tukey method [8]] of HR were quantified using the area (power) of the spectrum in a low-frequency power region (LFP: 0.02-0.15 Hz) and a high-frequency power region HFP: 0.15-0.8 Hz), as well as by the ratio of LFP and HFP. These variables were chosen because previous work [8] has shown that in adult humans and animals, power at frequencies more than 0.15 Hz is due solely to modulation of cardiac vagal activity, primarily by respiratory activity, while power at frequencies less than 0.15 Hz can be due to modulation of both cardiac vagal and sympathetic activity by a variety of stimuli, including low frequency respiratory activity and the arterial baroreflex. Similar measures of respiratory activity were tabulated from the respiratory power (RP) spectrum to yield LFP-RP (0.02-0.15 Hz), HFP-RP (0.15-0.8 Hz), and LFP-RP/HFP-RP ratio scores.

To determine the contribution of both sympathetic and parasympathetic components to HR modulation, respiratory sinus arrhythmia was quantified by assessing the effect of respiratory activity on HR using transfer function analysis as described previously [8]. Specific measures of cardiac parasympathetic (Ap) and sympathetic (As) control gain were derived from the average coherence weighted transfer function magnitude [9] of the two 2.2-min segments of data chosen for each experimental period in each subject, as described below. Previous work using this technique during pharmacologic and postural autonomic manipulations in adults has demonstrated magnitude and phase plots characteristic of "pure" parasympathetic and "pure" sympathetic modulation of HR [9]. A pure sympathetic HR response (during standing plus atropine) is characterized by a reduced magnitude at high frequencies (>0.10 Hz) and a negative phase slope at low frequencies. In contrast, pure vagal modulation of HR (supine plus propranolol) is characterized by higher magnitude at all frequencies and near 0 degrees phase [9]. The transfer function magnitudes from the pure parasympathetic and sympathetic control states were used to derive the specific Ap and As gain factors for infant autonomic modulation of HR. These gain factors are expressed as a function of the adult-derived average low-frequency magnitude, L, and the average high-frequency, H, as detailed in Equation 1 and Equation 2. Equation 1, Equation 2

CV

CV

CV

CV

It should be noted that these variables can have positive and negative values given the relative presence or absence of low transfer magnitude.

The mean and SD of the HR and power spectra for each study epoch were calculated. Coherence weighted transfer function averages were computed as previously described [9]. To compare the course of individual subjects before and during the spinal anesthesia, nonparametric (Wilcoxon signed rank test) statistics were used. A difference was considered significant when P was less than 0.05. For the purposes of display, individual and coherence weighted group average transfer function estimates of both magnitude and phase for preoperative, operative, and postoperative segments were also computed.

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Results

Spinal anesthesia was administered to the eight study infants without complications. Sensory block was rapidly achieved to a dermatomal level of C7-T4. Oxygen saturation remained 97%-100% for all subjects. Mean HR, systolic pressure, and diastolic pressure remained stable across all study periods Table 2. Respiratory power (L/m2)2 did not change significantly over the course of the three study periods Table 2; however, a large, nonsignificant reduction in respiratory power was observed in the postoperative period.

Table 2

Table 2

Overall, LFP decreased significantly from baseline with spinal anesthesia among all infants (Wilcoxon signed rank test, Z = 2.52; P = 0.01) Table 3. Similarly, HFP decreased in seven of the eight subjects (Z = -2.38; P = 0.02). Importantly, the LFP/HFP ratio did not change significantly with the anesthetic (Z = -0.70; P = 0.48). The sympathetic and parasympathetic gain factors, As and Ap, derived from the transfer function magnitude data, decreased 43.8% and 30%, respectively, from their preoperative levels; however, the differences were not statistically significant [(Z = -0.98; P = 0.33) and (Z = -0.28; P = 0.78), respectively].

Table 3

Table 3

As demonstrated in both the HR time series and autospectra from an individual subject Figure 1, B and C, HRV decreased during the operative period, with a small less obvious increase seen in the postoperative period. Although the respiratory rate slowed and became more regular from the preoperative to the operative period, resulting in a clustering of respiratory power at frequencies between 0.4 and 0.5 Hz, total respiratory power was similar. The reduction in HR power combined with stable respiratory activity resulted in decreased transfer magnitude in the operative period, which in this subject is most obvious at low frequencies. In addition, the phase relation at low frequencies shifted from a negative slope, consistent with a sympathetically mediated delay, to a zero slope, consistent with more vagal HR control. As in this subject decreased from 84.3 to 43.9 [(bpm)/(L/m2)], while Ap remained unchanged (3.9 vs 4.0 [(bpm)/(L/m2)], again consistent with diminished sympathetic modulation of HR, but no significant change in vagal modulation.

Figure 1

Figure 1

Finally, the postoperative period demonstrates the importance of the transfer function analysis which accounts for respiratory activity in evaluating the HRV. The transfer magnitudes and Ap actually increased at most frequencies despite the low HRV, because of the marked reduction in respiratory power. The lack of complete consistency of the data from this subject with the group helps demonstrate why the changes in As and Ap between periods were not statistically significant.

The group transfer functions shown in Figure 2 qualitatively demonstrated the changes in As and Ap from Table 3. Low- and high-frequency magnitude both decreased during the operative period with no obvious change in phase, consistent with the small decrease observed in group mean Ap. During the post-operative period, the magnitude increased at all frequencies, while the phase clustered around 0 degrees, consistent with predominant vagal modulation of HR.

Figure 2

Figure 2

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Discussion

In contrast to adults and older children, the former premature infants in this study undergoing spinal anesthesia to high thoracic levels maintained stable levels of mean HR, mean blood pressure, and respiratory activity, even in the absence of prior fluid loading. Overall HRV (both LFP and HFP) decreased with spinal anesthesia, but the balance between them (LFP: HFP ratio) remained stable, suggesting that in response to the sympathetic block due to spinal anesthesia, there was a reflex reduction in parasympathetic modulation of cardiac function. However, when the effect of respiratory activity on HRV was accounted for, the net autonomic effect remained relatively stable.

Using frequency domain analyses to quantify autonomic function, animal and human studies suggest that low-frequency fluctuations of HR at frequencies between 0.02 and 0.15 Hz result primarily from modulation of both cardiac parasympathetic and sympathetic efferent activity by multiple influences, such as low frequency respiratory activity, and arterial and cardiopulmonary baroreceptor feedback [10]. In contrast, higher frequency fluctuations of HR are almost exclusively mediated by modulation of vagal efferent activity, primarily in response to respiratory activity. Based on these observations and others, HFP can be used to provide a qualitative index of cardiac vagal HR control [11-13], and the ratio of the LFP to the HFP, can provide a measure of cardiac sympathetic HR control [13].

Although the quantitative changes of sympathetic (As) and parasympathetic (Ap) modulation of HR did not reach significance [14-18], the group average transfer functions yielded some qualitative insight into the autonomic changes which accompanied the anesthesia. The group magnitude plots both prior to and during anesthesia demonstrate a low-fequency predominance, while the phase plots at low frequencies show decreasing phase with frequency Figure 2, both findings which suggest a sympathetic predominance at rest and during anesthesia. In addition, both the low- and high-frequency transfer magnitude decreased with anesthesia, suggesting vagal withdrawal consistent with the spectral data. Finally, in the postoperative period, both low- and high-frequency magnitude increased and the low-frequency phase became flat, suggesting an increase in vagal HR modulation postoperatively Figure 2 to levels higher than those observed either pre- or intra-operatively.

Previous reports have indicated that spinal anesthesia which induces sensory block at the C7-T4 level produces effective peripheral vascular sympathetic denervation Figure 3a [19] and substantial, if not total, cardiac sympathetic denervation [3]Figure 3b. These effects on vascular sympathetic efferent activity should decrease peripheral arterial resistance and venous tone, and if the patient has not received prior hydration, decrease central venous volume, right atrial pressure Figure 3c and size Figure 3d, and sinoatrial node stretch Figure 3e. Decreased atrial size should presumably also result in a cardiopulmonary-mediated reflex increase in cardiac vagal activity Figure 3f. In the absence of arterial baroreflex-mediated reflex, withdrawal of cardiac vagal activity, HR should drop, decreasing cardiac output, and further decreasing arterial pressure Figure 3g. Such changes have been noted in adults undergoing spinal anesthesia at the T2 level, with the exception that HR actually remains constant, presumably due to arterial baroreflex-mediated vagal withdrawal [3,19]. Because of these observations, one would expect that sympathetic modulation of HR would also decrease, leading to a drop in LFP, LFP/HFP, and As; however, these spectral variables have not been examined in adults who were not prehydrated. Landry et al. [20] recently examined HR spectral variables in a group of pregnant women undergoing peridural anesthesia (to at least a T-6 level) after prehydration. Despite the absence of a change in mean HR and a small but insignificant drop in arterial pressure, they found a decrease in both LFP and HFP without a change in the LFP/HFP ratio, suggesting isolated withdrawal of vagal modulation of HR which effects both frequency bands, and no significant change in sympathetic modulation which selectively effects low frequencies. Furthermore, if one accounts for the factors which influence HR variations such as respiration, theoretically more specific variables for vagal and sympathetic HR control can be derived, in this case Ap and As[9,10,16-18].

Figure 3

Figure 3

The data from the infants in this study differs from that in adults in two important ways. First, despite the absence of volume loading, neither HR nor arterial pressure changed in these infants. Second, measurement of respiratory activity provided the potential for a more sensitive metric of cardiac vagal and sympathetic modulation than the spectral data alone. The fact that mean arterial pressure remained constant without volume loading and without an increase in HR suggests strongly that there was not a significant decrease in arterial resistance or venous filling induced by the anesthesia Figure 4a. Such a finding could be secondary to diminished capacitance of the peripheral venous bed in the neonate compared to the adult, or less dependence of the neonate on sympathetic vasoconstriction at rest (shaded area, Figure 4c), such that sympathetic block fails to cause a significant fall in arterial pressure. However, the HRV data in the study lend support to the notion that there were autonomic changes from the anesthesia. The observed decrease of both LFP and HFP without a change in the LFP/HFP was similar to that seen in adults [19], and is consistent with an isolated withdrawal of vagal HR modulation. Interestingly, the measures A (p) and As derived from the transfer functions demonstrated moderate decreases in both variables which were not statistically significant, but the qualitative appearance the transfer function suggested diminished vagal and preserved sympathetic modulation. Together, these data suggest that, as with adult patients, the neonate maintains a constant HR through a small, baroreflex-mediated withdrawal of cardiac vagal activity in response to, and offsetting, a small anesthesia-induced decrease in cardiac sympathetic modulation due to incomplete or variable cardiac sympathetic block Figure 4d. The variable nature of the block may be due to inconsistencies in the level of anesthesia C7-T4) in this study.

Figure 4

Figure 4

The hemodynamic stability we observed in reponse to C7-T4 spinal anesthesia is consistent with revious studies in infants and children less than 6 yr of age [4,2,20-22]. Many of these authors have attributed their findings to age-related differences in neural development, in particular, incomplete development of the sympathetic nervous system and a relative maturity of the parasympathetic system at birth [4]. Recent work, however, has demonstrated a functionally competent autonomic system at birth in humans and animals [5,23]. Finley et al. [6] demonstrated a small but significant increase in HR among term human infants in response to a tilt-Table maneuver. This shows that lower limb venous capacitance in neonates is at least large enough to sequester a hemodynamically significant volume of blood during tilt, and that neonates have the ability to mount a cardiac autonomic, probable sympathetic, HR response to a change in central volume. In parallel with this cardiac response, Lagercrantz et al. [24] showed that preterm infants (25-37 wk gestation) were able to significantly increase peripheral resistance in the lower limbs during a tilt procedure, indicating that neonates have at least partially developed sympathetic vascular control. Thus, the possibility that the infants in this study maintain constant HR and arterial pressure through offsetting changes in cardiac sympathetic and vagal control is well supported in the literature.

Several limitations of this study need to be noted. First, the small sample size, in combination with the variability in the level of sensory block, may have reduced the power to detect a significant sympathetic withdrawal during spinal anesthesia. Second, while the impedance measure provided an index of respiratory activity, it was an indirect measure of tidal volume and, despite strict epoch selection criteria, remained sensitive to infant movement artifact, thereby increasing the variance of the signal. Given the limitations of this measure, As and Ap may not have yielded a precise quantification of the relation between respiration and HR. Further, no independent measures of sympathetic activity (e.g., blood flow, vascular resistance, muscle sympathetic nerve activity), vagal activity, central venous pressure, or plasma volume were obtained in this study to validate the As and Ap variables. It is also unclear whether the operation itself influenced the results. The short time interval between the spinal injection and the incision and the operative preparations made it impossible to acquire stable physiologic signals that would have enabled us to compare pre- and postincision autonomic measures to assess a possible confounding influence of the operation. However, given that the post-operative autonomic measures, which had been obtained when the block had regressed to at least T-12, were not significantly different from preoperative baseline values, we were confident that the spinal anesthetic could have been responsible for the autonomic changes observed. Finally, there are significant limitations in quantifying the response of HR to respiratory activity, particularly when the respiratory activity is not broad band [17], as was demonstrated by low coherence in this study Figure 3. However, not accounting for the effects of respiration at all clearly has even more disadvantages [9,10,17].

In conclusion, in contrast to older children and adults [3,25], former premature infants in this and other studies [2,4,20,22] maintain stable levels of mean HR, blood pressure, and respiratory activity when undergoing spinal anesthesia without prehydration. Using spectral analysis of HR and transfer function analysis of HR and respiratory activity, the spinal anesthetic predominantly had a net effect on parasympathetic modulation of HR. The decrease in parasympathetic activity we observed may reflect a reflex response to an initial bradycardia which follows a partial or complete cardiac sympatholysis from the spinal anesthetic and decreased arterial blood pressure. Specifically, a decrease in HR that may occur with a high spinal anesthetic is offset by the decreased vagal activity. Although such findings may account for the overall cardiovascular stability observed among neonates and infants during spinal anesthesia, the developmental mechanisms which enable infants to maintain such stability remain to be determined.

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