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Anesth Analg 2004;99:128-134 © 2004 International Anesthesia Research Society doi: 10.1213/01.ANE.0000114549.17864.36
Michael J. Cousins Section Editor |
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Abstract |
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Intrathecal (IT) clonidine is an effective analgesic, but it also produces hemodynamic depression and sedation which are likely to be related to IT clonidine’s cephalad spread within the cerebrospinal fluid. We hypothesized that IT clonidine’s side effects could be reduced without compromising the duration and quality of analgesia by injecting clonidine IT in a hyperbaric solution and elevating the patient’s trunk. We prospectively randomized 30 elderly patients to receive IT 150 µg of either isobaric (ISO) or hyperbaric (HYPER) clonidine for postoperative analgesia after surgical repair of traumatic hip fracture. Hemodynamics, IV fluid administration, visual analog pain scores, sedation scores, and clonidine cerebrospinal fluid levels were recorded at fixed intervals. Patients in the ISO group required significantly more crystalloid fluid administration (median, 2500 mL; range, 1500–3000 mL) than those in the HYPER group (median, 1500; range, 500–3000 mL) to maintain adequate arterial blood pressure (P < 0.01). Also, the decrease in heart rate was significantly more pronounced in the ISO than in the HYPER group (P < 0.01). The duration of analgesia was significantly larger in the ISO (median, 400 min; range, 115–400 min) than in the HYPER (median, 265 min; range, 205–400 min) group (P < 0.05). Sedation scores did not differ between groups. We conclude that increasing the baricity of IT clonidine solution in the conditions of our experiment reduces hemodynamic side effects but also analgesia from IT administered clonidine.
IMPLICATIONS: In elderly patients after surgical repair of traumatic hip fracture, intrathecal hyperbaric clonidine reduces hemodynamic side effects but also the quality and duration of postoperative analgesia compared with isobaric clonidine.
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Introduction |
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Effective postoperative analgesia can be provided by neuraxially applied local anesthetics (1) or opioids (2), which may be accompanied by unwanted side effects, such as motor block, hypotension, or respiratory depression (3). The
2-adrenergic agonist clonidine produces analgesia by a different mechanism that mimics the effect of endogenously released norepinephrine to stimulate postsynaptic 2 receptors in the spinal cord. Intrathecal (IT) and epidural clonidine provide effective analgesia in volunteers (4), in patients in labor (5), and in those with postoperative pain (6), without inducing respiratory depression or motor block (7). Side effects of spinal clonidine that limit its clinical usefulness include hemodynamic depression and sedation (5,6). Hemodynamic depression is partially related to the extent of sympathetic block from clonidine’s effect at preganglionic sympathetic neurons in the spinal cord, and this explains the more profound hypotension after thoracic than after lumbar clonidine administration in animals (8) and in humans (9). Clinical experience demonstrates that the distribution of local anesthetic solutions in cerebrospinal fluid (CSF) is influenced by drug baricity and patient position. Similarly, the spread of spinally-administered opioids can be influenced by patient position: spinally-administered sufentanil results in high sensory levels when injected in a hypobaric solution in the sitting patient (3), or, when injected in a hyperbaric (HYPER) solution to parturients in the sitting position, it provides pain relief with less pruritus (10,11). Neostigmine, which causes nausea after IT injection by cephalad spread, does so with a reduced incidence when injected in HYPER solution with subjects in the sitting position (12).
In contrast to these other local anesthetic, opioid, and non-opioid analgesics, the effects of baricity on analgesia and side effects from clonidine injected in a HYPER solution with the patient’s trunk elevated have previously not been studied. Because hemodynamic depression and sedation, the most limiting side effects of IT clonidine, are likely to be related to cephalad spread within the CSF, we hypothesized that limiting the cephalad spread of IT clonidine by adding dextrose to the clonidine solution and elevating the patient’s trunk would reduce the incidence of hemodynamic depression and sedation without compromising the quality and duration of postoperative analgesia. Therefore, the aim of our study was to compare mean arterial blood pressure (MAP), heart rate, sedation, and analgesia produced by isobaric (ISO) or HYPER clonidine administered IT for postoperative pain relief after surgery in the lumbar dermatomes (traumatic hip fracture repair).
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Methods |
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After obtaining IRB approval and written, informed consent, we included 30 elderly patients undergoing hip surgery after traumatic hip fractures under general anesthesia in this prospective, randomized, double-blinded study. In addition to the usual contraindications to spinal anesthesia, patients unable to understand the study protocol, those with severe deformities of the spine, those with a history of untreated hypertensive disease, and those receiving treatment with ß-adrenergic blockers were excluded from the study.
Before the induction of general anesthesia, a 23-gauge catheter was introduced 2–3 cm cephalad into the IT space at the L3-4 interspace via a 19.5-gauge Sprotte needle (Pajunk, Geisingen, Germany). Correct catheter position was ensured by free aspiration of CSF. Thereafter, general anesthesia was induced with fentanyl 2 µg/kg, propofol 2 mg/kg, and vecuronium 0.1 mg/kg and was maintained with isoflurane 1%–1.5% with 65% nitrous oxide in oxygen, with intermittent positive pressure ventilation to normocapnia. Preoperative fluid deficits and intraoperative blood loss were replaced with crystalloid solution or red packed cells as appropriate to achieve a postoperative hematocrit of approximately 35% and spontaneous urine production.
The protocol was initiated at first complaint of pain after the operation in the recovery room with the administration of 1 of the 2 2-mL study solutions at room temperature (22°C) via the IT catheter: Group ISO (15 patients) received clonidine 150 µg plus 1 mL of 0.9% saline, and Group HYPER (15 patients) received clonidine 150 µg plus 1 mL of 10% glucose, yielding a 5% HYPER solution. The study solutions were freshly prepared by an anesthesiologist who had no further part in the study. The anesthesiologist who injected the study solution and the investigator were blinded to the baricity of the clonidine solution administered. During and after the injection, patients were positioned supine with the trunk elevated for approximately 15 min at an angle of at least 30°.
Pain, assessed on a 10-cm visual analog scale (VAS); heart rate; MAP; oxygen saturation; respiratory rate; and sedation, assessed on a 10-point scale, anchored at 0 for fully awake and 10 for deeply sedated, were recorded before IT drug administration, then at 5-min intervals for 30 min, and thereafter every 30 min until request for further analgesia. The duration of analgesia was determined as time elapsed between IT clonidine injection and request for further analgesia. The end-point of measurement was at 400 min after drug injection. Therefore, the duration of analgesia represents censored data, and the data are presented as median and range. To assess differences in clonidine concentrations between groups in the CSF at the injection site, CSF samples of eight patients in the ISO group and nine patients in the HYPER group were drawn before and at 30, 60, and 120 min after drug injection. CSF samples were frozen immediately and kept frozen at –80°C until analysis. Clonidine concentrations were determined by high-pressure liquid chromatography with ultraviolet detection (UV-HPLC). This method has an interassay coefficient of variation of 12% at 50 ng/mL and an absolute detection limit of 15 ng/mL and was analyzed with HPLC for clonidine.
In case of hypotension (MAP >20% of baseline values), crystalloid solutions were administered IV in 250-mL increments followed by elevation of the patient’s legs before the use of IV etilefrine. The time until reappearance of pain after IT clonidine was recorded. Thereafter, correct positioning of the catheter was verified by injection of 2 mL of bupivacaine 0.25% through the catheter. After the study period, the catheter was removed by the anesthesiologist, and the patient was sent to the ward. Patients were visited 24 h later to record postdural puncture headache, infection, or neurologic sequelae.
Normal data distribution was first evaluated with the Kolmogorov-Smirnov test. Power analysis revealed that a sample size of 14 patients per group was required to achieve a power of 80% and an of 0.05 for detection of a >30% difference between groups in MAP or IV infusion required to restore hemodynamics. Data are expressed as mean ± SD or median and range, as indicated. The Mann-Whitney U-test was used to compare the duration of analgesia, sedation scores, and the amount of fluid administration between groups. Changes in sedation scores within groups were assessed by Friedman two-way analysis of variance. Unpaired Student’s t-tests were used to compare clonidine CSF levels between groups. Analysis of variance for repeated measurements assessed changes in the quality of analgesia and hemodynamic variables between and within groups. P < 0.05 was considered statistically significant.
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Results |
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The two groups were comparable with respect to age, weight, height, ASA classification, and the number of patients receiving antihypertensive medications (Table 1). All spinal catheters were in the correct position, as evidenced by adequate sensory block after bupivacaine injection through the catheter after the study period. IT clonidine for the treatment of postoperative pain was administered 190 ± 53 min after surgery in the ISO group and 175 ± 56 min after surgery in the HYPER group (not significant).
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MAP decreased significantly from baseline after both ISO and HYPER clonidine without differences between groups (P < 0.001; Fig. 1). Patients in the ISO group required significantly more fluid administration (median, 2500 mL; range, 1500–3000 mL) than those in the HYPER group (median, 1500 mL; range, 500–3000 mL) to maintain adequate MAP (P < 0.01). None of the patients required IV administration of etilefrine to restore MAP. Similarly, heart rate decreased significantly from baseline over time in both groups (P < 0.01). In contrast to MAP, the decrease in heart hate was significantly more in the ISO than in the HYPER group (Fig. 2; P < 0.01). The maximum reduction in heart rate occurred within 90 min after drug injection in both groups, but all episodes resolved spontaneously, and none of the patients required IV atropine.
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Patients who received IT clonidine reported a significant reduction in VAS pain scores within 5 min (Fig. 3; P < 0.001). The analgesic effect over time was more pronounced in the ISO than in the HYPER group (P < 0.05). The median duration of analgesia was significantly longer in the ISO (median, 400 min; range, 115–400 min) than in the HYPER (median, 265 min; range, 205–400 min) group (P < 0.05).
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Patients in both groups were significantly more sedated after IT clonidine injection over time (Table 2; P < 0.01), but sedation scores did not differ between groups. Oxygen saturation and respiratory rate were not influenced by either ISO or HYPER clonidine administration (data not shown).
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Clonidine concentrations in CSF at the level of injection were significantly larger in the ISO group than in the HYPER group at 30, 60, and 90 min after injection (Fig. 4; P < 0.05). Postdural puncture headache, infection, or neurologic sequelae did not occur in any patient.
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Discussion |
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The effect of baricity on drug effects after lumbar IT injection is complex and reflects the chemical characteristics of the drug in question, such as molecular weight and lipophilicity, as well as its site of action, such as nerve roots versus spinal cord dorsal horn. As such, this study provides unique information regarding a small, water-soluble, non-opioid analgesic that acts at the level of the spinal cord dorsal horn. The results indicate that increasing the baricity of the solution according to the conditions of the experiment reduces both side effects and analgesia from IT administered clonidine.
As expected, MAP decreased significantly from baseline in both groups. Although analysis of variance showed no difference in MAP between groups, IV fluid requirements to maintain this MAP were significantly larger in the ISO group. We assume that we would have observed MAP decreasing to a larger degree in the ISO than in the HYPER group if we had not titrated IV fluid, but rather had administered a fixed volume. Our data are in agreement with previous studies that indicated that clonidine 75–450 µg IT decreases MAP up to 45% (13) and that 100–200 µg of clonidine injected for pain relief during labor (5) or for postoperative analgesia after cesarean delivery (6) reduces MAP by 25% and 15%, respectively. Although neuraxial clonidine may be systemically absorbed, leading to reduced sympathetic activity by actions in the brainstem and the periphery (7), neuraxial clonidine also directly decreases MAP by inhibition of preganglionic sympathetic neurons in the spinal cord (14). As a result, the degree of hypotension after neuraxial clonidine is associated with the dermatomal level of injection, with more profound hypotension occurring after thoracic than after lumbar administration (8,9). Although we injected both clonidine solutions at the lumbar level of the spinal cord, caudad spread of HYPER clonidine may mainly occur within CSF, in contrast to minimal spread of ISO clonidine in patients with an elevated trunk. Consistent with this hypothesis, we observed larger CSF concentrations of clonidine at the injection site in the ISO group compared with the HYPER group from 30 to 120 minutes after drug administration, suggesting that HYPER clonidine does not ascend higher than the lumbar spinal level in this setting. Although clonidine is somewhat lipophilic, the much more lipophilic opioid sufentanil migrates relatively large distances in the IT space in ewes (15) and may produce respiratory depression by cephalad spread in humans (3).
Other studies provide evidence that some bothersome central side effects of IT administered opioids or neostigmine, such as pruritus or nausea, could be reduced by injecting the drugs in a HYPER solution and maintaining a head-up patient position (10,12). Our data raise the possibility that IT clonidine’s most bothersome side effect, hypotension, can also be decreased but not abolished by increasing the baricity of the clonidine solution and elevating the patient’s trunk. However, the hemodynamic depression after both ISO and HYPER IT clonidine for postoperative analgesia in elderly patients requires careful hemodynamic monitoring for at least two hours.
Heart rate also decreased significantly from baseline after ISO and HYPER clonidine. Patients in the ISO group experienced a larger decrease in heart rate than those in the HYPER group (Fig. 3), although this difference was not clinically relevant. IT clonidine reduces heart rate minimally after cesarean delivery in doses from 150 to 450 µg and significantly with 100 and 200 µg during labor, without differences between doses. Clonidine decreases heart rate by a presynaptic mediated inhibition of norepinephrine release and by a direct depression of atrioventricular nodal conduction (7) after systemic absorption, which occurs 20 minutes after IT injection in sheep (16). However, the decrease in heart rate correlates only after IV, but not after IT or epidural, clonidine administration with clonidine serum concentrations. The degree of clonidine-induced decrease in heart rate is similar after thoracic and lumbar IT administration in sheep (8) and also after thoracic and lumbar epidural administration in humans (9), arguing for similar rates of systemic absorption after drug injection at different levels.
Because IT clonidine decreases heart rate by systemic absorption and redistribution, it is unclear why ISO clonidine causes a more pronounced decrease in heart rate than HYPER clonidine. One may speculate that our findings, i.e., that restricting the cephalad spread of clonidine induces less bradycardia, could be explained by a decreased area of resorption in the HYPER compared with the ISO group, yielding less systemic drug absorption and, hence, lower clonidine serum levels (17). IT injection of 300 µg of clonidine into sheep yields plasma concentrations between 0.2 and 1 ng/mL (16). Because serum concentrations after the injection of 150 µg of IT clonidine into humans are expected to be far less than the detection limit of the UV-HPLC, we did not measure clonidine serum concentrations in this study. However, no delayed or sustained bradycardia occurred during the observation period, and all bradycardic episodes resolved spontaneously without treatment in elderly postoperative patients.
Age-related alterations in drug dynamics result in increased sensitivity to certain drugs in elderly patients as compared with younger patients because of altered pharmacokinetics and pharmacodynamics and changes in receptor sensitivity or density. Further, normal human aging is associated with a reduction in the baroreflex-mediated response to hypotensive stimuli (18), and consequently, elderly patients may not respond with the same degree of sympathetic activity as younger patients. In rodents, the centrally mediated pressor response to intracerebroventricular clonidine declines with age (19). There is no study comparing the hemodynamic effects of IT clonidine between young and elderly patients. However, the hemodynamic depression caused by 150 µg of IT clonidine in elderly patients in our study was comparable to that in other studies undertaken with young patients (13) and parturients (5,6).
IT clonidine provides dose-dependent postoperative analgesia after cesarean delivery and during the first stage of labor (5,6). We determined that postoperative analgesia from 150 µg of ISO clonidine after surgical repair of traumatic hip fractures in elderly patients lasts 400 minutes (range, 115–400 minutes), which is in agreement with Filos et al.’s (6) results. In contrast to our hypothesis, the analgesic effect over time was less pronounced and the duration of analgesia was shorter in the HYPER compared with the ISO group.
However, although the exact mechanism is unknown, IT HYPER bupivacaine induces shorter analgesia and motor blockade than IT ISO bupivacaine, which makes HYPER bupivacaine a useful anesthetic for ambulatory anesthesia (20). Similarly, the addition of dextrose to IT opiates reduces the duration of analgesia during labor pain (10,11), and HYPER neostigmine injected in the sitting, but not in the lateral decubitus, position (12) does not produce analgesia in volunteers. The exact mechanism by which dextrose reduces analgesia in all the above-mentioned studies remains unknown. Although we did not inject IT dextrose by itself in our study, Gage et al. (10) excluded the possibility of an antianalgesic effect of IT dextrose on IT sufentanil because IT dextrose by itself had a minor analgesic action during labor. One may speculate that the differences in analgesia obtained with different clonidine solutions suggest that glucose interferes with the pharmacokinetics of systemic absorption. However, this seems unlikely because reduced or even absent analgesia occurs with a sitting, but not a lateral, position when dextrose is added to IT sufentanil or neostigmine, respectively (10,12). Most likely, the addition of dextrose to clonidine with the patient’s trunk elevated restricted the cephalad spread of adequate concentrations of clonidine to the site of action—the spinal cord—yielding less analgesia in the HYPER group. In fact, we found clonidine CSF concentrations sampled at a lower lumbar interspace to be significantly smaller in the HYPER compared with the ISO clonidine group.
We did not assess segmental analgesia or hyposensitivity with ISO or HYPER clonidine because epidural (21), but not spinal (6), clonidine produces segmental analgesia. Although clonidine has weak local anesthetic properties in extremely large concentrations in vitro (7), a direct inhibitory effect of clonidine on nerve conduction in clinically relevant doses used for spinal analgesia seems extremely unlikely, because IT clonidine by itself has failed to provide surgical anesthesia, despite doses as large as 450 µg (13).
Because the variability in CSF volumes among patients determines the extent and duration of sensory blockade during spinal anesthesia with local anesthetics (22), we cannot exclude the possibility that differences in lumbosacral CSF volumes in our patients may have contributed to different durations of analgesia. However, the chance that this has happened in the obstetric analgesia studies with opiates (10,11) and also in the neostigmine volunteer study (12) seems quite unlikely, although the possibility of such an error cannot be excluded.
We found a significant increase in sedation scores in both groups from baseline. The baricity of the clonidine solution did not influence the degree of sedation. Our results are in agreement with studies by Filos et al. (6), Malinovsky and Bernard (13), and our group (5), in which dose-dependent sedation was observed. Sedation represents an 2-adrenergic effect, because sedation from epidural clonidine can be reversed by the specific antagonist yohimbine in postoperative patients (23). The sedative-hypnotic effect of 2-adrenergic agonists is caused by actions on the locus caeruleus (7). Our results argue for a systemic absorption and vascular redistribution rather than for a cephalad migration of IT clonidine because the onset of sedation was not delayed in either group.
It is unexpected that two of IT clonidine’s side effects caused by systemic absorption and redistribution—sedation and bradycardia—differed with the baricity of the clonidine solution: HYPER clonidine caused less bradycardia but similar sedation compared with ISO clonidine. We speculate that our selected dose of 150 µg of IT clonidine was too small to induce more sedation in the ISO group compared with the HYPER group. Doses of IT clonidine larger than 150 µg induce dose-dependent sedation in postoperative patients (5,6,13), and we assume that we would have observed differences in sedation scores between ISO and HYPER clonidine with larger doses.
Although mild sedation is a desired side effect in postoperative patients, clonidine alone does not cause profound respiratory depression in adults (24). One report (25) indicated the possibility of respiratory depression when clonidine is combined with local anesthetics for caudal blocks in preterm infants. However, neither respiratory rate nor oxygen saturation was influenced by either ISO or HYPER clonidine in our study.
In conclusion, IT HYPER clonidine injected into elderly patients for postoperative analgesia after surgical repair of traumatic hip fractures diminished the requirement for IV fluid administration to limit decreases in MAP and induced less bradycardia, but analgesia was minor and of shorter duration than after IT isobaric clonidine. Therefore, we do not recommend the addition of dextrose to IT clonidine for postoperative analgesia.
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Acknowledgments |
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Supported in part by a grant from the Max Kade Foundation (New York, NY) and by Grants GM35523 and NS41386 from the National Institutes of Health (Bethesda, MD).
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