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Neuromuscular Block Differentially Affects Immobility and Cortical Activation at Near–Minimum Alveolar Concentration Anesthesia

Doufas, Anthony G., MD, PhD; Komatsu, Ryu, MD; Orhan-Sungur, Mukadder, MD; Sengupta, Papiya, MD; Wadhwa, Anupama, MD; Mascha, Edward, PhD; Shafer, Steven L., MD§; Sessler, Daniel I., MD

Section Editor(s): Durieux, Marcel E.; Gin, Tony

doi: 10.1213/ANE.0b013e3181af631a
Anesthetic Pharmacology: Preclinical Pharmacology: Clinical Pharmacology: Research Reports
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BACKGROUND: Anesthesia-induced immobility and cortical suppression are governed by anatomically separate, but interacting, areas of the central nervous system. Consequently, larger volatile anesthetic concentrations are required to suppress cortical activation than to abolish movement in response to noxious stimulation. We examined the effect of decreased afferent input, as produced by neuromuscular block (NMB), on immobility and cortical activation, as measured by Bispectral index (BIS) of the electrocardiogram, in the presence of noxious stimulation during approximately minimum alveolar concentrations (MACs) of desflurane anesthesia.

METHODS: The effect of NMB on the median effective end-tidal concentration of desflurane (EtDes50, or MACtetanus) for immobility was estimated using the up-and-down method and isolated forearm technique in 24 healthy volunteers. Each volunteer sequentially received saline, mivacurium, and succinylcholine in a randomized order, while EtDes concentration during each of the treatments was determined based on the movement response of the previous volunteer on the same treatment. Nonlinear mixed-effects modeling was used to evaluate the effect of NMB on BIS versus EtDes concentration relationship at baseline and after noxious stimulation, while the frontal electromyogram (EMGBIS) effect on BIS was also modeled as a covariate. Cardiovascular responses to noxious stimulation were compared across treatments.

RESULTS: Succinylcholine and mivacurium significantly reduced MACtetanus (95% confidence interval) from 5.00% (4.85%–5.13%), during saline, to 4.05% (3.81%–4.29%) and 3.84% (3.60%–4.08%), respectively. Noxious stimulation significantly, although minimally, increased BIS response during all treatments. Succinylcholine increased BIS independently of an effect on EMGBIS. Succinylcholine administration increased cardiovascular activity. Interestingly, although cardiovascular reaction to the noxious event was ablated by mivacurium, cortical response, as determined by BIS, was retained.

CONCLUSIONS: Both succinylcholine and mivacurium enhanced immobility during near-MAC anesthesia. All treatments were associated with a small, although significant, BIS increase in response to noxious stimulation, whereas succinylcholine increased BIS independently of noxious stimulation or EMGBIS. Mivacurium suppressed autonomic response to a noxious event.

From the *Department of Anesthesia, Stanford University School of Medicine, Stanford, California; †Outcomes Research Institute, and Department of Anesthesiology and Perioperative Medicine, University of Louisville, Louisville, Kentucky; ‡Departments of Quantitative Health Sciences and Outcomes Research, The Cleveland Clinic, Cleveland, Ohio; §Department of Anesthesiology, Columbia University, New York, New York; ∥Department of Outcomes Research, The Cleveland Clinic, Cleveland, Ohio; and ¶Outcomes Research Consortium, Cleveland, Ohio.

Accepted for publication April 21, 2009.

Supported by the Joseph Drown Foundation, Los Angeles, CA.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Web site (www.anesthesia-analgesia.org).

Steven L. Shafer is Editor-in-Chief of the Journal. The manuscript was handled by James G. Bovill, Guest Editor-in-Chief, and Dr. Shafer was not involved in any way with the editorial process or decision.

Address correspondence and reprint requests to Anthony G. Doufas, MD, PhD, Department of Anesthesia, Stanford University School of Medicine, 300 Pasteur Drive, H3590, Stanford, CA 94305-5640. Address e-mail to agdoufas@stanford.edu.

Afferentation theory proposes that tonic sensory and muscle-spindle activity modulate cerebral function and maintain a state of wakefulness.1 Decreased afferent input by neuraxial anesthesia2,3 or muscle relaxation4,5 has been shown to enhance hypnosis2,4 and immobility.3,5 On the other hand, enhanced muscle afferent activity (hyper-afferentation) by succinylcholine administration,6,7 or acute reversal of neuromuscular block (NMB),8 activates the electroencephalogram (EEG)6,7 and promotes clinical signs of arousal, such as grimacing, sucking, and coughing.8

Suppression of cortical activity (i.e., hypnosis) and immobility, mediated by volatile drugs, is governed by different areas of the central nervous system (CNS)9 and occur at different anesthetic depths. For example, clinical studies demonstrate that supramaximal stimulation at 1 minimum alveolar anesthetic concentration (MAC) is associated with activation of the EEG.10,11 This distinction between hypnosis and immobility is important because the effect of “afferentation” apparently differs as a function of anesthetic depth in nonstimulated patients.12,13 Furthermore, the magnitude of stimulation may also influence the effect of decreased afferentation on the cortical EEG. Thus, NMB may have a different effect on the cortical and subcortical components of anesthesia.

We therefore investigated the effect of NMB on immobility during near-MAC desflurane anesthesia, using the isolated forearm technique in healthy volunteers. We simultaneously evaluated cortical activation, as determined by the Bispectral index (BIS) of EEG, in the subjects before and after the application of a potent noxious stimulus with and without muscle relaxation. We used a nondepolarizing, as well as a depolarizing, drug to examine the effect of enhanced muscle afferent activity produced by the latter. Specifically, we tested the hypotheses that at near-MAC anesthesia: (a) mivacurium will exert a higher impact on immobility than hypnotic end points in response to noxious stimulation, whereas (b) succinylcholine will promote both movement and cortical responses.

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METHODS

With approval from the University of Louisville Human Studies Research Committees and written informed consent, we recruited 25 healthy volunteers of both genders, 18–40 years old. Exclusion criteria were administration of any drug acting on the CNS within 24 h of the study, any contraindication to inhaled induction of anesthesia, and a body mass index exceeding 30 kg/m2.

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Protocol

Volunteers fasted at least 8 h before the study. After application of standard anesthesia monitors, an IV catheter was inserted into an antecubital vein of the nondominant arm. In addition, a noninvasive continuous arterial blood pressure (BP) sensor (Finometer™, FMS, Finapress Medical Systems, Arnhem, The Netherlands) was applied on the index finger of the nondominant hand. A tympanic membrane probe was inserted to continuously monitor core temperature. Forced air warming was used to maintain normothermia.

Anesthesia was induced by inhalation of 6%–8% sevoflurane in oxygen. After loss of eyelash reflex, succinylcholine (0.5–1 mg/kg, IV bolus) was administered and the trachea intubated. Subsequently, the volatile anesthetic was switched to desflurane and maintained at the designated end-tidal concentration (EtDes) (described below) for 40 min. The lungs were mechanically ventilated with 80% oxygen in nitrogen, to maintain end-tidal Pco2 at 30–35 mm Hg.

Anesthetic requirement was determined by the response to noxious electrical stimulation administered via two 25-gauge needles inserted subcutaneously into the lower portion of each anterior thigh. A bilateral 65- to 70-mA, 100-Hz tetanic electrical current, maintained for 10 s, or until movement occurred, was used to provide the noxious stimulus. To prevent desensitization at the needle insertion site, the electrodes were moved rostrally by 1 cm after each stimulation. This experimental method of MACtetanus determination has been previously validated in healthy volunteers and produces highly reproducible MAC values, which are consistently lower than MACincision.14–17

Volunteers were studied for 1 day only. Each study consisted of 3 randomly ordered phases, during which the volunteers received the 3 different treatments: saline, succinylcholine, or mivacurium. Shortly before administration of the muscle relaxant or saline, a tourniquet was inflated over the arm of the dominant hand to a pressure of 150 mm Hg more than the systolic BP (SBP). Volunteers then received 1 mg/kg succinylcholine, 0.15 mg/kg mivacurium, or normal saline (control) as an IV bolus (saline, succinylcholine) or a 60-s infusion (mivacurium). After the bolus (2.5 min), or the end of infusion, the noxious electrical stimulation was applied and a video camera, focused on the isolated arm, recorded the response for 1 min after the initiation of the 10-s stimulus. After the end of the 1-min stimulation/observation period and before the tourniquet was deflated, a nerve stimulator was used to obtain a train-of-four (TOF) measurement from both arms to confirm that: (a) the isolated arm was indeed isolated from the circulation and (b) the contralateral arm demonstrated the expected response after drug administration (i.e., intact TOF after saline, and no TOF response after succinylcholine or mivacurium). Figure 1 presents the main features of the experimental design via its application on the first 3 volunteers.

Figure 1.

Figure 1.

The next phase of the experiment then began at the designated (described below) desflurane concentration. After anesthetic equilibration for 20 min and approximately 10 min before the next stimulation, a TOF measurement was obtained from both arms to document clinical recovery of neuromuscular function.

The first volunteer was assigned to an EtDes concentration of 4.5% for all 3 treatments (saline, succinylcholine, or mivacurium). The EtDes concentration was measured using a Datex AS3 monitor (Datex-Engstrom, Ohmeda, Helsinki, Finland), which was calibrated at the beginning of each study day. If the isolated arm of the first volunteer moved in response to noxious stimulation after a given treatment, the desflurane concentration for the same treatment was increased by 0.5% in the subsequent volunteer. In contrast, the desflurane concentration for the same treatment in the subsequent volunteer was decreased by 0.5% if noxious stimulation did not provoke movement (Fig. 1). This paradigm is referred to as the “Dixon up-and-down” method,18 although its application to a 3-way crossover design is novel.

All volunteers were contacted 24 h after their recovery, by phone, and asked about explicit awareness of any intra-anesthetic event.

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Measurements

Demographic and morphometric variables of the volunteers were recorded. Heart rate (HR), EtDes concentration and Pco2, hemoglobin oxygen saturation (Spo2), and tympanic membrane temperature were measured continuously and recorded at 5-min intervals. BP was determined noninvasively using a cuff applied on the left ankle and recorded every 5 min. However, during a 10-min prestimulation period, BP was measured only by finger plethysmography to avoid any unnecessary stimulation of our volunteers.

BIS of the EEG (3.21 algorithm; Aspect Medical Systems, Newton, MA) data were acquired using the 4 BIS-sensor electrodes and the A-2000 BIS monitor. Frontal electromyogram (EMGBIS) was displayed as the power in the 70- to 110-Hz frequency band, measured in decibels (relative to 0.0001 μV2, interval 30–80 decibels). Sensor impedance was kept <5 kΩ. The smoothening time of the BIS monitor was set at 15 s. BIS data were downloaded offline as 1-min averages. Eleven minutes of BIS and correspondent EMGBIS data were collected during the period before and after the drug administration, as well as after the noxious stimulation. More specifically, we used the 4 min preceding drug administration as baseline, the 2.5 min (saline and succinylcholine) or 3.5 min (mivacurium) between drug administration and noxious stimulation as representing the drug effect, and the 3.5–4.5 min after the noxious stimulation as mainly indicating the effect of the latter on BIS response (see Figs. 2 and 3 for a time course of the events).

Figure 2.

Figure 2.

Figure 3.

Figure 3.

An independent investigator, blinded to the treatment and any other experimental condition, observed the video recordings at the end of each study day and decided a movement/no movement response. Any type of visible movement of the isolated arm was characterized as such. Based on the movement/no movement response for each particular treatment, we adjusted the EtDes concentration for the respective treatments in the next volunteer.

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Data Analysis

Median effective EtDes for immobility (EtDes50 or MACtetanus) estimates were calculated based on Dixon’s approach, which takes the average of the concentrations in the sample as the estimated MACtetanus.19 Bootstrap resampling20 was used to determine confidence intervals for the MACtetanus estimates. One hundred thousand bootstrap samples (simple random samples of size 24 with replacement, retaining the original order of the volunteers in the study) were simulated from the observed data. The first volunteer in each bootstrap sample was thus removed, and 1 observation was added to the end of each bootstrap sample by inferring from the EtDes concentration/response combination for the last observation in the original bootstrap sample what the EtDes concentration would have been.

The bootstrap sampling distributions were used for inferences on MACtetanus for the 3 treatments (saline, succinylcholine, or mivacurium), as well as inferences on the differences in MACtetanus among the 3 treatments. Confidence limits for the sample MACtetanus were taken as the 2.5th and 97.5th quantiles from these distributions. Tests of the difference in MACtetanus among the treatments used a z-statistic calculated as a ratio of the mean difference and the standard deviation of the bootstrap distribution for the difference. The experiment-wide significance level was controlled at 0.05 by implementing Bonferroni adjustment for multiple comparisons.

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BIS Response

Nonlinear mixed-effects modeling (NONMEM VI, GloboMax LLC, Hanover, MD) was used to evaluate the effect of mivacurium and succinylcholine on the relationship between BIS and EMGBIS, before, as well as after, the noxious stimulation, using the nested models approach. Graphs showing the change in BIS and EMGBIS as a function of EtDes, as well as the relationship between BIS and EMGBIS, were used to visually explore associations between these model parameters. The effect of different treatments on the EtDes concentration versus BIS relationship before the occurrence of the noxious stimulation was modeled separately. In the final (full) model, all experimental data were included. During each modeling process, any added parameter was considered significant (χ2 < 0.05) if it produced a reduction of at least 3.84 points in the −2 log likelihood of the model. A detailed description of the NONMEM modeling process for BIS response is provided in the Appendix (see Supplemental Digital Content 1, http://links.lww.com/AA/A12).

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Hemodynamic Response

The maximum values of SBP and HR during a 1-min-long period of continuous recording immediately before and after drug administration, as well as after the application of noxious stimulation, were used in the analysis of hemodynamic response. Based on the Kolmogorov-Smirnov test (α level set at 0.05), these data did not follow a normal distribution. Consequently, Wilcoxon’s signed rank test was used to compare SBP and HR values between same and different phases of the experiment across the 3 drug treatments. Twelve paired comparisons among the different phases of the experiment were performed, which adjusted the α level to 0.05/12 = 0.0041.

Hemodynamic responses, EtDes concentration, BIS, and EMGBIS at baseline (before drug administration) were compared across the different treatments, using Friedman test (nonparametric data) or repeated-measures analysis of variance and then appropriate post hoc tests. Data are presented as median (interquartile range) or mean ± sd, and an α level of 0.05 was used to denote statistical significance.

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RESULTS

One volunteer did not complete the study because of gastric fluid regurgitation during inhaled induction of anesthesia. However, his immediate recovery was uneventful. Twenty-four consecutive subjects (9 women) completed the study. They were 27 ± 6 years old, weighed 75 ± 12 kg, and were 174 ± 7 cm tall.

Before study drug administration, hemodynamic and respiratory variables were similar among the different treatments. Volunteers remained normothermic during all phases of the experiment. By study design (up-and-down method), succinylcholine and mivacurium treatments were associated with lower EtDes concentrations and, as a result, with higher BIS values (Table 1).

Table 1

Table 1

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Immobility

During all NMB treatments, a reliable NMB and an intact TOF response were detected in the perfused and isolated arms, respectively. Both responses were obtained immediately after the end of the observation (video recording) period and before releasing the tourniquet.

Figure 2 shows the crossover EtDes concentrations for the different treatments. Table 2 presents the EtDes50 estimates for immobility (MACtetanus). Saline treatment was associated with a MACtetanus (95% confidence interval) of 5.00% (4.85–5.13). The administration of succinylcholine and mivacurium significantly reduced that value to 4.05% (3.81–4.29) and 3.84% (3.60–4.08), respectively. The difference in MACtetanus between succinylcholine and mivacurium was not statistically significant.

Table 2

Table 2

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BIS Response

A detailed report regarding the NONMEM model and the various parameters that determined the BIS response is provided in the Appendix (see Supplemental Digital Content 1, http://links.lww.com/AA/A12). According to the model, both the EMGBIS and the EtDes concentration had a significant effect on BIS response. Noxious stimulation increased BIS during all treatments (i.e., saline, succinylcholine, and mivacurium), independently of an increase in the EMGBIS activity.

Before the occurrence of noxious stimulation, only succinylcholine had a small (approximately 1 U increase) but significant effect on BIS, which was independent of EMGBIS activity. After the onset of the noxious stimulation, both saline and succinylcholine treatments were associated with an additional significant increase in BIS response of approximately 1 U, for which the inclusion of the EMGBIS and noxious stimulation effects into the model could not fully account.

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Hemodynamic Response

During saline, SBP increased from a median (interquartile range) of 101 (96–109) mm Hg before the noxious stimulation to 125 (102–164) mm Hg after the noxious stimulation (P < 0.001), whereas HR increased from 71 (66–76) bpm to 88 (71–115) bpm (P < 0.001). Succinylcholine administration was associated with a significant increase in SBP from 98 (94–107) mm Hg to 124 (114–153) mm Hg (P < 0.0001), whereas HR increased from 70 (60–75) bpm to 90 (74–112) bpm (P < 0.001). The noxious stimulation did not further increase SBP and HR, which remained significantly higher compared with baseline. During mivacurium, SBP and HR did not change significantly between the pre- and poststimulation period.

None of the volunteers reported awareness of any event during anesthesia.

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DISCUSSION

This is the first study to characterize the effect of NMB on the volatile anesthetic requirements for immobility and cortical anesthetic end points in humans using a potent noxious stimulus. We found that both succinylcholine and mivacurium reduce the anesthetic demand for immobility and they are associated with similar BIS activation patterns in response to noxious stimulation compared with saline treatment.

By using the isolated forearm technique, we found that succinylcholine and mivacurium reduced MACtetanus for desflurane by 19% and 23%, respectively. Our study confirms previous findings by Forbes et al.,5 who showed that pancuronium reduced halothane MACincision by 25%. In contrast, Fahey et al.21 did not manage to show any difference in halothane MACincision among nonparalyzed patients and patients treated with atracurium, vecuronium, or pancuronium. However, the different numbers of isolated extremities, as well as the different starting halothane concentrations in the different patient groups, might raise a concern regarding the accuracy of those MAC estimates.22

Saline treatment was associated with a MACtetanus of 5.0 vol%, which approximates those previously estimated by Greif et al.14 (4.9 ± 0.7 vol%) and Jones et al.17 (4.58 ± 0.6 vol%), using a similar study design but without using the isolated forearm technique. This supports not only the successful isolation of the tested limb in our experiment but also the complete recovery of neuromuscular function in between the administration of the different drug treatments. To provoke movement, we applied tetanic electrical stimulation. As we23 and others24,25 have previously shown, our MACtetanus values were lower than those produced by skin incision in surgical patients (MACincision).

Muscle relaxants do not readily cross the blood-brain barrier26 and therefore do not exert a direct effect on the CNS; an indirect action via an active metabolite of succinylcholine or mivacurium is also unlikely. Hemodynamic stability during and immediately after the administration of mivacurium suggests that little, if any, histamine was released. Furthermore, animal evidence indicates that neuronal histamine release reduces, rather than increases, the MAC of halothane.27 Our findings are thus consistent with the afferentation theory, which proposes that loss of tonic afferent input to the CNS would suppress its activity, resulting in decreased anesthetic requirements.

BIS quantifies the relationship among the underlying sinusoidal components of the EEG28 and is proposed as a surrogate measure of the hypnotic (cortical) component of IV,29 as well as volatile,2,30 anesthetics. Perioperative noxious stimuli alter brain electrical activity31–35 and result in a rightward shift of the BIS versus EtDes concentration response curve,36 whereas 1-MAC anesthesia is not sufficient to suppress BIS,10,11 or auditory-evoked37 potentials, in response to surgical incision. Evidence supports that the magnitude and pattern of this EEG response relate to the underlying anesthetic depth32,33 and are independent of the presence of NMB when stimulation occurs at deeper, rather than lighter, levels of anesthesia.35,38 Our data support these findings; noxious stimulation significantly increased BIS, and this response was independent of muscle relaxation or an EMGBIS effect. Conversely, the effect of succinylcholine on BIS in the pre- and poststimulation period was independent of EMGBIS, whereas noxious stimulation completely accounted for the small increase in BIS during mivacurium treatment. Saline treatment was associated with a high EMGBIS, whereas the latter was almost completely suppressed during the muscle relaxation treatments.

Although increased frontal EMG can distort the BIS calculation via altering its Beta Ratio frequency (30–47 Hz) component,28 it might also reflect a “true” EEG component in the higher frequency range (γ band) because stand-alone EMG using submental,39 as well as temporofrontal,35 recordings have demonstrated a negligible contribution of the facial EMG signal on EEG during anesthesia. The possibility that this high-frequency “EMG” activity could signify conscious processing of information40 during anesthesia is undetermined. Desflurane concentrations just above MACawake are sufficient to suppress recall of information acquired during anesthesia in nonstimulated subjects41; nevertheless, the effect of a noxious arousing stimulus on this process remains to be investigated. Evidence suggests that implicit learning during anesthesia varies as a function of both the hypnotic depth42 and analgesic state.43

Succinylcholine administration increased BIS before and after the application of noxious stimulation. This small but significant effect was independent of EMGBIS activation, and the presence of a “true” EEG component cannot be excluded. These data are in accordance with previous reports supporting the afferentation theory by demonstrating the hyper-afferentative properties of succinylcholine.6,7,44 Succinylcholine- and noxious stimulation-induced EEG activations are not synonymous with conscious awareness, which, according to the theory of neuronal adequacy, previously proposed by Libet et al.,45 would require certain temporal, as well as spatial, neuronal assembly requirements to develop.46

Considerable animal9 and human11 evidence suggests that various inhaled9,11 and IV47 anesthetics prevent movement via a direct action on the spinal cord. However, an indirect MAC-sparing3 and hypnotic-sparing2 effect of epidural anesthesia in humans, as well as the depressed excitability of reticulo-thalamo-cortical arousal mechanisms in an animal model of neuraxial anesthesia,48 reflect an existing interaction between cortical and subcortical levels of the nervous system. Although an effect of NMB on both cortical and subcortical levels of the CNS is a possibility, the administration of a potent noxious stimulation led to a pharmacological separation of the structures governing immobility and cortical anesthetic end points.

Noxious stimulation during near-MAC desflurane was followed by a significant increase in cardiovascular activities. Interestingly, mivacurium suppressed the associated autonomic responses. This effect of mivacurium is in agreement with its effect on immobility and supports the view that cardiovascular responses to noxious stimuli during anesthesia are mainly governed by spinal and supraspinal CNS sites.49 These results are in contrast with the findings by Gibbs et al.,50 who showed that vecuronium administration in rats during infra-MAC anesthesia did not alter hemodynamic response to noxious stimulation.

In conclusion, both succinylcholine and mivacurium reduce the desflurane requirement for immobility during near-MACincision anesthesia, without affecting cortical activation in response to a potent noxious stimulation. Succinylcholine administration is associated with an arousal response, as determined by BIS. Importantly, whereas cardiovascular reaction to a noxious event is ablated by mivacurium, cortical response is retained. The anesthetic requirement might thus be underestimated if based only on signs of autonomic function.

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ACKNOWLEDGMENTS

The authors appreciate the contributions of Marina Varbanova, MD, Ching-Rong Cheng, MD, Dorothea Rosenberger, MD, Jay King, BS (medical student), Teresa V. Joiner, RN, CRC, and Annette Robinson, RN, BSN, all from the Department of Anesthesiology and Outcomes Research Institute at the University of Louisville. The authors thank Joseph F. Antognini, MD, for his input, and Lawrence Saidman, MD, for his constructive critique of the manuscript.

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