Autonomic hyperreflexia (AHR) is a potentially life-threatening hypertensive condition that develops in patients with spinal cord injury (SCI) above the splanchnic outflow, usually at the level of T6.1,2 It is commonly triggered by afferent stimuli below the level of injury, such as a distension of hollow viscera (bladder, bowel, uterus, gallbladder), uterine contraction during obstetric delivery, cutaneous stimulation, and surgical procedures involving pelvic organs or lower extremities.3,4 The extreme hypertension during episodes of AHR may be associated with various signs and symptoms, such as throbbing headaches, intracranial and retinal hemorrhages, pulmonary edema, myocardial infarction, and death.5,6 Moreover, episodes of AHR are commonly associated with not only mild electrocardiographic changes, but also atrial fibrillation and cardiac arrest.7,8
The development of intraoperative AHR and hypertension can be prevented either by general anesthesia, which blunts autonomic reflexes, or regional anesthesia (spinal or epidural), which blocks afferent and autonomic efferent neural impulses.1,9,10 However, we have previously shown that the concentration of an inhaled anesthetic required to block AHR is high enough to cause severe hypotension in SCI patients.11
Opioids significantly reduce the minimum anesthetic concentration (MAC) of potent inhalation anesthetics required to abolish consciousness and to blunt the sympathetic response to skin incision.12,13 Among others, remifentanil is a selective μ-opioid receptor agonist that provides potent analgesia of rapid onset and ultrashort duration,14 and has been shown to be effective in preventing sympathetic responses induced by tracheal intubation and other surgical stimuli.15 Because of its unique pharmacokinetic– pharmacodynamic profile, remifentanil is ideally suited for continuous IV infusion, whereas the use of a target-controlled infusion (TCI) using a computer-driven infusion device has been shown to be more effective in maintaining cardiovascular stability than is the traditional weight-adjusted infusion.16
The spinal cord is one of the major sites of action of opioids,17 although they may also act in the brainstem and forebrain18 and in the periphery.19 After SCI, spinal neural pathways caudal to the injury are reorganized over time (plasticity) in adaptation to a changing environment.20,21 In animals with experimental SCI, systemically administered morphine has a greater effect on rostral wide dynamic range (WDR) neurons than on caudal WDR neurons.22 However, whether opioids should reduce the requirement of sevoflurane to blunt AHR has not been determined. We examined the effects of TCI of remifentanil on the end-tidal concentrations of sevoflurane to block AHR in SCI patients while undergoing transurethral litholapaxy.
The protocol of the study (Fig. 1) was approved by the University Hospital Ethics Committee. Written informed consent was obtained from each patient. In patients who were unable to give consent because of injury, their consent was given by their next of kin.
We enrolled 96 patients with chronic, clinically complete traumatic high SCI (above T6) scheduled to undergo transurethral litholapaxy under general anesthesia. Among them, 82 developed AHR during the first trial of bladder distention and were studied for the second trial. The level and completeness of SCI were assessed in accord with the 1996 American Spinal Injury Association standards.23 Patients whose time interval from injury to operation was <1 month were not included because it takes at least 1 month to develop malignant hypertension of AHR.24
All patients were premedicated with midazolam (0.1 mg/kg, orally) 60 minutes before induction of anesthesia. Upon arrival in the operating room, a 20-gauge catheter was inserted into a radial artery connected to a pressure transducer (Deltran; Utah Medical Products, Midvale, Utah) to continuously monitor arterial blood pressure and to take blood samples. A standard bispectral index (BIS) electrode montage (BIS Sensor-Aspect Medical Systems, Inc., Natick, Massachusetts) was applied to the forehead before induction of anesthesia, and BIS was measured continuously throughout the surgery using a BISXP monitor (model A-2000; 3.31 software version; Aspect Medical Systems, Inc.). Each patient received 500 mL colloid solution (6% hydroxyethyl starch) over 15 to 20 minutes before the procedure to prevent hypotension, and Ringer's lactate solution was maintained at approximately 10 mL · kg−1 · h−1 throughout the study. Anesthesia was induced with IV sodium thiopental 5 to 7 mg/kg, followed by IV rocuronium 0.8 mg/kg after full administration of oxygen. Direct laryngoscopy and tracheal intubation were performed when neuromuscular block had been achieved. Sevoflurane combined with 50% nitrous oxide (N2O) in oxygen was then adjusted to achieve an initial BIS reading of 40 to 50 after a 5-minute “washin” period whereby 2% sevoflurane (inspired) was administered. After induction of anesthesia, all patients were placed into the medium lithotomy position and their lungs mechanically ventilated to maintain end-tidal carbon dioxide tension between 35 and 40 mm Hg. Neuromuscular blockade was carefully controlled by train-of-four monitoring, and additional boluses of rocuronium were administered to maintain 1 response at the orbicularis oculi during the procedure. Routine monitoring included invasive measurement of arterial blood pressure, heart rate (HR), and rhythm using a 5-lead electrocardiogram, and oxygen saturation by pulse oximetry. The end-tidal concentrations of carbon dioxide, sevoflurane, and N2O were measured using a gas analyzer (Capnomac Ultima; Datex, Helsinki, Finland).
When BIS and end-tidal sevoflurane concentrations were stable for at least 20 minutes, the development of AHR in response to bladder distension was determined (the first trial). A cystoscope was inserted into the bladder and a 1.5% glycine solution was slowly infused. In patients showing evidence of AHR, the bladder filling was immediately terminated. When the systolic blood pressure (SBP) exceeded 180 mm Hg, the inspired sevoflurane concentration was rapidly increased by 1% every minute up to the maximum of 4% until SBP decreased to 120 mm Hg. AHR was defined as an increase of SBP 20 to 40 mm Hg more than the value measured 1 minute before the procedure in response to bladder distension during the first trial.25 Before and during the first trial, opioids were not administered.
Patients who had developed AHR during the first trial were allocated to 2 experimental groups that would receive either 1 ng/mL (n = 25) or 3 ng/mL (n = 24) of remifentanil using a computer-generated sequence of numbers for the second trial. A group of 31 patients that did not receive remifentanil served as control, of which 28 were included in our prior study.11
After a rest period of 10 to 20 minutes, during which the hemodynamics returned to baseline values (the value measured 1 minute before initiating the first trial), the remifentanil infusion was set at the designated target-controlled concentration in the remifentanil groups. At the same time, the designated end-tidal concentration of sevoflurane was maintained for at least 20 minutes, and then the procedure was resumed (the second trial). According to its context-sensitive half-time, this equilibration period also allowed for complete equilibration between plasma and effect-site concentrations of remifentanil.14,16 During the equilibration time, the patients were left unstimulated except for positioning, prepping, and draping. TCI plasma-site concentration for remifentanil was achieved using the Orchestra Base Primea® infusion pump (Fresenius, Brezins, France) using Minto pharmacokinetic model.26
The target sevoflurane concentrations for the second trial were determined by the response of the preceding patient in each group using an up-and-down sequential-allocation technique.27 The first patient received 2.0% end-tidal concentration of sevoflurane. When the patient response was positive (an increase in SBP of ≥15% above the value measured 1 minute before the procedure), the end-tidal concentration for the next patient was increased by 0.3%. If the response was negative (SBP increased by <15%), the end-tidal concentration of sevoflurane for the next patient was decreased by 0.3%. The positive response was defined as an increase in SBP of 15% or more,12,28 and subsequent corrections of 0.3% end-tidal concentration of sevoflurane were made per the up-and-down method, which was based on SDs of anesthetic concentrations to block AHR in our preliminary study.11
If hypotension developed (mean arterial blood pressure <65 mm Hg), blood pressure was restored by increasing the IV fluid rate. If the patient did not respond to fluid therapy (mean arterial blood pressure decreased below 50 mm Hg even after a fluid challenge of 300 mL lactated Ringer's solution), the patient was withdrawn from the study, and the same concentration of sevoflurane was administered to the next patient enrolled. At the completion of surgery, the inhaled anesthetic was discontinued, and residual neuromuscular block was antagonized with atropine and neostigmine. All anesthetic procedures were conducted by an anesthesiologist, and data were assessed by a person unaware of the anesthetic concentrations used.
SPB, HR, and BIS values were recorded before induction of anesthesia, at 1 minute before commencement of bladder filling and at 1-minute intervals thereafter for up to 5 minutes after the end of bladder emptying for both the first and second trials. During bladder distension, these variables were defined as their values measured at the time of peak pressure response throughout the period of bladder filling. Arterial blood was sampled during the first trial only before induction of anesthesia, at 1 minute before, and at the end of the bladder distension when SBP reached peak value. The samples were collected into prechilled tubes containing EDTA-Na and were immediately centrifuged at 3000 revolutions per minute for 10 minute at 4°C. The plasma was stored at −70°C until assayed. Concentrations of norepinephrine and epinephrine were measured in duplicates using high-pressure liquid chromatography. The assay sensitivity for each catecholamine was 10 pg/mL, and the within-run precision coefficients of variation were 13.5% and 14.2% for norepinephrine and epinephrine, respectively.29
Data are expressed as number or mean ± SD. Sex data were analyzed using the Fisher exact test. The other demographic data were compared using 1-way analysis of variance. Serial changes in hemodynamic, hormonal, and BIS data during the first trials were analyzed using a 2-way analysis of variance with repeated measures, with time as within-factor measure, group as between-factors measure, and an interaction between time and group. A Scheffé test was used when a significant difference was indicated with analysis of variance. EC50 values (50% effective dose) were obtained by calculating the midpoint concentration of all independent response cross-overs in which a positive response was followed by a negative response.27 The up-and-down sequences were further analyzed using logistic regression in PROBIT procedure to calculate the effective sevoflurane concentrations required for blockade of AHR in 50% and in 95% (EC50 and EC95, respectively) of patients. All analyses were performed using the SPSS 15.0 for Windows statistical package (SPSS, Inc., Chicago, Illinois). A P value <0.05 was considered statistically significant. The goodness of fit of the logistic models was assessed by the Hosmer–Lemeshow test and likelihood ratio test, and there was no evidence of lack of fit in the logistic regression models.
Demographic data and duration of procedures did not differ among the groups (Table 1). The level of lesion was between C4 and T6, with 62 above T1. Among 96 patients initially enrolled the study, 82 (85.4%) developed an AHR during the bladder distention and were studied for the second trial. During the second trial, 2 patients were excluded in whom mean arterial blood pressure decreased to below 50 mm Hg during the administration of target concentration of anesthetics despite the fluid therapy necessitating administration of vasoconstrictors.
Table 2 shows SBP, HR, plasma catecholamine concentrations, and BIS in the first trial. Before anesthesia induction, they did not differ among the groups. SBP and BIS decreased after the induction (P < 0.01) in all groups; the magnitude of the decrease did not differ among the groups. HR and plasma concentrations of norepinephrine did not change in any group. In response to bladder distension, SBP increased significantly by 64 to 68 mm Hg, whereas HR decreased by 13 to 16 beats per minute (bpm), during the first episode of AHR. SBP was higher than 160 mm Hg in 33 (40.2%) of 82 SCI patients during the first trial. Additional sevoflurane was given to those whose SBP was above 180 mm Hg (7 in control, 3 in 1 ng/mL remifentanil group, and 4 in 3 ng/mL remifentanil group). SBP and HR returned to pre-AHR levels after bladder emptying within 10 minutes in most patients; however, the time to recover pre-AHR SBP levels varied (5 to 30 minutes). The hemodynamic responses were associated with a significant increase of plasma norepinephrine concentrations (P < 0.05), the degree of which did not differ among the groups. However, the increase in SBP in response to bladder distension was larger in the quadriplegics (n = 62) than in the paraplegics (n = 18) (69 ± 26 mm Hg vs. 52 ± 20 mm Hg; P = 0.011). In addition, the increase of norepinephrine was also larger in the former, although statistically insignificant (78 ± 63 pg/mL vs. 56 ± 26 pg/mL; P = 0.157). Plasma epinephrine concentrations did not change during bladder distension in any groups.
Figure 2 shows individual responses to bladder distension according to the up-and-down sequence during the second trial. The sevoflurane concentrations required to block AHR in 50% of patients according to the up-and-down method were 3.14% (95% confidence interval, 2.94% to 3.34%) in the control group (panel A), in comparison with 2.64% (2.45% to 2.82%) in 1 ng/mL remifentanil group (panel B; P = 0.0009) and 2.23% (2.05% to 2.40%) in 3 ng/mL remifentanil group (panel C; P = 0.0001).
EC50 and EC95 values of sevoflurane for the blockade of AHR by logistic regression analysis were 3.15% (95% confidence interval, 2.89% to 3.56%) and 3.84% (3.48% to 6.14%) in control, 2.63% (2.46% to 2.84%) and 2.98% (2.80% to 4.00%) in 1 ng/mL remifentanil group, and 2.25% (2.06% to 2.62%) and 2.69% (2.44% to 4.74%) in 3 ng/mL remifentanil group (values include the contribution of 50% N2O). Considering the MAC of sevoflurane described in the age range of the study population30 and the concomitant use of 50% N2O, the combined EC50 and EC95 of sevoflurane for AHR blockade expressed as a multiple of the MAC were 2.28 and 2.67 MAC in the control group, 1.98 and 2.18 MAC in the 1 ng/mL remifentanil group, and 1.76 and 2.01 MAC in the 3 ng/mL remifentanil group. EC50 values calculated by logistic regression were comparable with those determined by up-and-down methodology.
The present study demonstrated that target-controlled concentrations of 1 ng/mL and 3 ng/mL remifentanil reduce the end-tidal concentrations of sevoflurane required to prevent AHR by 16% and 29% in the presence of 50% N2O, respectively. Systemically administered opioids exert their antinociceptive effects through a synergism of spinal and supraspinal opioid systems.31 In SCI, descending inhibitory systems—including opioidergic, noradrenergic, and serotonergic systems—are interrupted. The systemically administered remifentanil may have exerted its suppressive effects on the autonomic responses to visceral nociceptive stimuli by blocking the spinal opioid receptors below the level of injury, apart from its peripheral effects (e.g., heart, sympathetic nerves, and blood vessels).
The sevoflurane concentration to block AHR with no remifentanil was 1.80 MAC in 0.48 MAC N2O in the present study, indicating that a deep level of anesthesia is required to block AHR. Patients with high SCI are very susceptible to hypotension under general anesthesia. Indeed, despite the fluid therapy, mean arterial blood pressure decreased to below 70 mm Hg in 76 (92.7%) of 82 patients using sevoflurane anesthesia to block AHR during the second trial. These hemodynamic swings may be poorly tolerated in high SCI. Because of its low blood gas partition coefficient allowing a rapid adjustment of depth, sevoflurane should be used to acutely increase the concentration immediately before bladder distension in SCI patients. Alternatively, combinations of sevoflurane with other adjuncts (opioids or N2O) may be better choices, because they may enhance the actions of inhalation anesthetics in producing immobility or in preventing autonomic responses in the face of noxious stimulation.12,13,15,28
However, the sevoflurane concentration to block AHR was reduced less by remifentanil in SCI patients in the present study than with that to block cardiovascular responses to skin incisions in a normal population. Albertin et al.13 showed that target-controlled concentrations of 1 and 3 ng/mL remifentanil reduced the requirement of sevoflurane to blunt sympathetic responses to surgical incision by 60% and 92%, respectively, in volunteers. Low efficacy of remifentanil in reducing sevoflurane requirements to block AHR in SCI may be accounted for by several factors. First, remifentanil suppresses the visceral noxious stimuli less effectively than does the somatic. In the spinal cord–transected cat, subarachnoid administration of fentanyl significantly suppressed the noxiously evoked activity of WDR neurons located in the deeper lamina of the spinal dorsal horn (lamina V-type cells), mainly involved in somatic pain.32 It was also shown that activities of the higher-threshold superficial neurons of the posterior spinal cord horn (lamina I-type cells), mainly involved in visceral pain, were affected less by spinal administration of fentanyl than were WDR neurons.33 Second, a down-regulation of μ-opioid receptors in injured dorsal root ganglion neurons34 along with significant functional and morphologic reorganization of spinal cord circuitry below the injury site20,21 may have reduced remifentanil sensitivity in SCI.22 Third, remifentanil pharmacokinetics may differ in SCI.35 We assumed that the kinetic profile of IV remifentanil was appropriate for SCI patients in the present study. However, patients with chronic SCI have been reported to have increased fat mass and reduced lean tissue mass,36 implying a greater volume of distribution for remifentanil. Therefore, the actual effect-site concentrations of remifentanil after a stabilization period of about 20 minutes would have been lower than that predicted for similar normal-weight subjects for a given TCI dose. The lesser efficacy to targeted concentrations of 1 or 3 ng/mL remifentanil may be attributed to altered pharmacokinetics in the present study. However, this is less likely because muscle mass and often blood volume in SCI patients with a lesion above T4 are reduced,36,37 both of which may initially increase plasma concentration of remifentanil. Moreover, the variability in remifentanil pharmacokinetics is considerably less than that for any other IV opioid when a proper adjustment is made.26
The plasma concentrations of norepinephrine significantly increased along with the hypertensive response to bladder distension during the first trial. This finding is consistent with that of Maiorov et al.,38 in which a marked increase in renal sympathetic activity was noted in a rat T5 spinal injury model. Moreover, disruption of descending spinal pathways may result in functional and morphological changes of the sympathetic nervous system caudal to SCI.39 In fact, postinjury dendrite degradation of sympathetic preganglionic neurons, followed by sprouting of local primary unmyelinated nociceptive pelvic afferent C-fibers,20 in conjunction with plasticity of lumbosacral propriospinal neurons projecting to the thoracic cord in the dorsal gray commissure,21 have been demonstrated in SCI rats. Such a spinal remodeling in relaying visceral sensory input to sympathetic preganglionic neurons may underlie a marked capacity for peripheral afferent stimulation of the sympathetic nervous system arising after SCI. Nevertheless, in the present study, the peak norepinephrine concentrations reached during the episode of AHR did not exceed those observed at rest in normal populations. The augmented norepinephrine response may be attributed to a loss of descending inhibitory control that would usually serve to dampen such increases of sympathetic nerve activity,39 and peripheral vascular changes.40,41
On the other hand, plasma catecholamine concentrations, especially epinephrine, were quite low throughout the study in SCI patients than were those in normal subjects. Moreover, plasma epinephrine concentrations were not changed in response to bladder distension, which is consistent with a previous study.42 This hormone may have a minimal role in mediating cardiovascular changes during AHR. Individual variation of catecholamine levels and thus group variation was very uncommon in view of their wide range of normal values. Sympathetic preganglionic neurons to the cardiovascular vascular system exit the spinal cord from T1 to L2, and to the adrenal medulla from T3 to L3.43 Sixty-two patients (77.5%) in the present study lost all their sympathetic outflows (i.e., quadriplegia). Low catecholamine concentrations with minimal variation may be attributed to a diminished function of sympathetic nervous system and adrenal gland in high SCI. However, the increase in SBP in response to bladder distension was larger in the quadriplegics than in the paraplegics, suggesting that the autonomic hyperreflex is not related to a preserved sympathetic nervous activity rostral to the injured site.
The depth of anesthesia was adjusted to maintain BIS at 40 and 50 during the first trials. However, 33 (40.2%) of 82 SCI patients developed hypertension (SBP ≥ 160 mm Hg) during the first trial, and was even >200 mm Hg in 6 patients (7.3%). Hypertension, albeit transient, may be hazardous, particularly in those with limited coronary or myocardial reserve, hypertension, or cerebrovascular diseases.44 Individuals with SCI are particularly at an increased cardiovascular risk.45,46 Moreover, patients with SCI undergoing surgery are increasing along with their increased survival. Caution should be exercised when inhalation anesthetics alone without supplemental opioids or other adjunct medications are used to prevent or treat AHR in patients with high SCI.
Our study has a few limitations. First, somatic responses (e.g., movement) and autonomic responses (e.g., HR and SBP) may be used as clinical end points for assessing depth of anesthesia. However, in patients with SCI, both of these responses are altered, i.e., a paralyzed patient does not move even in the absence of adequate anesthesia, and abnormal spinal reflexes dominate the cardiovascular control.39 A BIS value <50 indicates an adequate depth of hypnosis to prevent recall for a variety of clinical anesthetics.47 Therefore, we used the amount of sevoflurane required to maintain BIS at 40 to 50 irrespective of the adequacy of anesthesia during the first trial. Second, the up-and-down method of Dixon27 assumes that each measurement in a subject is independent and not correlated with any other measurements. A noxious stimulus (bladder distension) was applied twice to 1 subject, so that errors in the results may occur because of intrasubject correlations and fade. However, the preliminary study showed persistent AHR (i.e., not self-extinguished), despite repeated bladder distensions during the procedure that lasted >1 hour.11 Third, we did not measure plasma concentrations of remifentanil during the study. Although the pharmacokinetic model that we used to achieve and maintain a stable plasma concentration of remifentanil has been shown to be adequately accurate in predicting plasma and effect-site concentrations of remifentanil,16,26 SCI may alter the pharmacokinetics of remifentanil. Finally, we did not determine the sevoflurane concentration to block AHR in the absence of N2O because it might be at a clinically unacceptable high concentration and because preprocedural arterial blood pressure might be depressed to levels that may be clinically unacceptable.
In summary, the present study showed that EC50 of sevoflurane to block AHR was 3.1% when administered with 50% N2O, which was reduced to 2.6% and 2.2% with target-controlled concentrations of 1 and 3 ng/mL remifentanil, respectively, in SCI patients undergoing transurethral litholapaxy.
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