The types and dosage of intraoperative opioid administration varied greatly (Table 2), with remifentanil administered at a maintenance infusion rate of 0.1 to 0.5 mcg/kg/h during total intravenous anesthesia.
Age, anesthesia method, duration of surgery, and analgesics other than NSAIDs and hyperosmolar solutions were not associated with chronic postsurgical pain.
Univariate analysis identified the following 7 factors as associated with the severity of chronic postsurgical pain (Table 3): sex, BMI, preoperative tumor-related pain, preoperative NSAID use, intraoperative hypotension, postoperative corticosteroids, and deterioration of JOA score.
The duration of preoperative tumor-related pain ranged from 10 to 108 months, with a median of 36 months. In all, 29 of 50 patients with preoperative tumor-related pain and 6 of 33 patients without received preoperative NSAIDs.
Of 78, 32 patients belonged to the hypotensive group. The duration of defined hypotension ranged from 15 to 315 minutes, with a median of 65 minutes. Intraoperative hypotension was usually maintained for a certain period with deep anesthesia or antihypertensive drugs rather than the use of vasopressors or blood transfusions, except in three patients. Twenty-three of 32 patients in the intraoperative hypotension group were administered antihypertensive drugs (including calcium channel blockers, beta-blockers, prostaglandin E1, nitroglycerin, and dexmedetomidine) to reduce bleeding from the surgical area. Intraoperative hypotension was not related to postoperative JOA score deterioration (P=0.418), nor to the longitudinal length of tumor (P=0.892).
Corticosteroids were administered for a maximum duration of 9 days, with maximum cumulative doses of 2500 mg for methylprednisolone, 12 mg for dexamethasone, and 2400 mg for cortisol. The median NPSI scores in the groups with and without postoperative corticosteroids were 18.7 and 9.5, respectively, and a statistically significant difference was observed (P=0.007).
Seven associated factors obtained from univariate analysis and a traditional risk factor for chronic postsurgical pain9 were included in the multivariate logistic regression analysis: sex, BMI, preoperative NSAID use, preoperative tumor-related pain, intraoperative hypotension, postoperative corticosteroids, and decline in JOA score, in addition to age. Three independent associated factors were identified by logistic regression analysis (Table 4), without interaction between postoperative corticosteroid administration and decline in JOA score.
We examined perioperative associated factors for chronic central pain after intramedullary spinal cord tumor resection as postsurgical pain is so severe as to reduce postoperative QOL in a proportion of patients8 even with little preoperative pain. We identified decline in JOA score, postoperative corticosteroid administration, and intraoperative hypotension as independent predictors of postsurgical pain.
Decline in JOA Score
A decline in JOA score compared with preoperative values was associated with chronic postsurgical pain. These results are consistent with the findings reported in a previous study of 3 patients with cordotomy at upper level of thoracic spine due to malignant astrocytoma.8 NPSI scores of those 3 patients were found to vary greatly (from 2.5 to 31.5). Patients with severe paralysis before surgery are reportedly less likely to develop postsurgical pain compared with patients demonstrating postoperative exacerbation of paralysis. Further studies are required to determine whether this finding is associated with the previous demonstration that the coexistence of tissue damage and hemotoxin results in pain.10
Postoperative corticosteroids use was associated with an increased risk of chronic central pain. This result was contrary to our initial expectations as corticosteroids are occasionally administered to alleviate pain, including acute lumbago from disk herniation and postsurgical pain.11 Thus, we excluded factors with multicollinearity and ascertained that interaction with JOA score a surrogate indicator of tissue injury—was not observed in multivariate analysis. There was no statistical difference between the groups with and without postoperative corticosteroids use regarding 7 factors in univariate analysis as well as age, a traditional risk factor (Table 5).
The predominant reason for postoperative corticosteroids administration was deterioration of neurological findings according to MEP/SEP scores, JOA scores, or manual muscle test. Nonetheless, indications for the administration in our cohort included upper airway edema, supplementation for autoimmune disease, respiratory failure, and coadministration of local anesthetic for trigger point injections, which is occasionally adopted in Japan.
Although this unexpected result must be interpreted with care, corticosteroids should be used cautiously as they may worsen clinical neurological outcomes.12 In animal studies, both the pain-alleviating13 and pain-precipitating effects14 of corticosteroids are reportedly attributable to mechanisms underlying anti-inflammatory and proinflammatory effects on the central nervous system.
The ability of corticosteroids to suppress or augment inflammation depends on the site of action (peripheral tissue or central nervous system), dose, timing, duration of exposure, and the type of glucocorticoid.12 We speculate that the site of action in the present study of spine surgery differed from that in earlier studies,11 which is particularly relevant as low-dose synthetic corticosteroids are unable to cross the blood-brain barrier under normal conditions. The administered dose in the present cohort was apparently higher than that typically administered to alleviate postsurgical pain.11 In addition to the dosage, the rate of administration may be associated with chronic pain. A total amount of 2500 mg methylprednisolone, which was the largest amount in our cohort, was administered to 2 patients for paralysis and for muscle weakness—to 1 with NPSI score of 7, continuously over 26 hours; to the other with NPSI score of 22.7, divided into 3 doses administered once per day, respectively. Timing of administration may also be a related factor. We examined the influence of interval between the end of surgery and first postoperative corticosteroids in 18 patients with both postoperative corticosteroid use and decline in JOA score. Higher NPSI score were observed in patients with an interval >12 hours (P=0.037) when the administration of corticosteroids immediately after surgery was considered to be intraoperative administration.
The results of the present study indicate postoperative corticosteroids are associated with chronic central pain after intramedullary spinal cord tumor resection. Accordingly, the effects of postoperative corticosteroids after resection of intramedullary spinal cord tumors should be monitored closely and warrant further study.
Intraoperative hypotension was associated with chronic postsurgical pain. It was not related to postoperative JOA score deterioration, a surrogate indicator of nerve injury, or to the longitudinal length of tumor, an indicator of extension of tumor in the spinal cord.
Spinal cord blood flow is typically autoregulated in a manner similar to cerebral blood flow15; however, mild hypotension as low as 80% of the preoperative baseline values may result in ischemia.16,17 Although the autoregulation appears to be compromised dependently on the types of anesthetics,18,19 there was no significant difference in the NPSI scores between 2 groups with and without nitrous oxide among patients with intraoperative hypotension (P=0.526). Laminectomy itself has also been reported to precipitate hypoperfusion,20 with one case report describing moderate systemic hypotension during a surgical procedure near the spinal cord leading to hypoperfusion.21 Hypoperfusion, not accompanied with nerve injury detected with the JOA score, may be associated with postsurgical chronic central pain in our study.
In patients who have suffered stroke, glial cells induce secondary inflammation.22 In animal studies, even transient ischemia has been shown to be responsible for remarkable accumulation23 and activation of microglia.24
In addition to deliberate hypotension to reduce intraoperative bleeding, deep anesthesia is required to avoid movement during microscopic surgery without resorting to muscle relaxants, thereby allowing the monitoring of neurological function with MEP. We also demonstrated the importance of maintaining blood pressure at a higher level to reduce the possibility of chronic central pain, while deliberate hypotension is well-known to be contraindicated in patients likely to be vulnerable to ischemia.25
Preoperative pain was not significantly associated with chronic postsurgical pain in multivariate analysis (P=0.082). A distinct feature in our cohort was that preoperative tumor-related pain signified direct stimulation or damage to the sensory system, which is believed to cause central sensitization. There was a trend toward an association between this factor and increased risk of chronic postsurgical pain.
Despite long postoperative intervals, factors related to the acute phase of spinal cord surgery were found to be associated with chronic postsurgical central pain. We speculate that certain processes may occur during the acute phase that trigger either the first step of a chain reaction or a long-lasting event.
In the present study, well-known risk factors for postsurgical pain, such as age and sex, were not found to be associated with chronic central pain.
The small sample size of the present study may affect the ability to detect significant findings. The present study was retrospectively conducted and we did not assess the severity of pain immediately after surgery, psychosocial factors, or persistent inflammatory processes. Expansion in the horizontal plane was not examined as tumors expanded intricately in 3 dimensions to a maximum length of 8 vertebral bodies. Further studies are required to assess the validity of the present findings in larger prospective cohorts.
The results of the present study demonstrate the factors related to the acute phase of intramedullary tumor resection are associated with the subsequent chronic central pain. Specifically, we identified decline in JOA score, postoperative corticosteroids, and intraoperative hypotension as associated with chronic postsurgical central pain. We believe that the present findings will facilitate the development of measures to prevent and alleviate chronic central pain following intramedullary tumor resection.
The present study was carried out as a 2010 multidisciplinary research project for measures to help the handicapped patients (survey study of chronic musculoskeletal pain). The authors thank Naoko Kuzumaki, PhD, Doctor of Pharmacy, Department of Toxicology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, for providing comments on the manuscript and Aya Shigeta, Clinical Engineering Technologist, Medical Engineering Center, Keio University Hospital, for her assistance in collecting and interpreting MEP/SEP data.
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postsurgical pain; central pain; intramedullary spinal cord tumor; perioperative associated factors; corticosteroids
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