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Histological Findings After Long-Term Infusion of Intrathecal Ketamine for Chronic Pain
Vol. 18 No. 3 September 1999
Journal of Pain and Symptom Management
223
Clinical Note
Histological Findings After Long-Term Infusion of Intrathecal Ketamine for Chronic Pain: A Case Report Martin Stotz, MD, Hans-Peter Oehen, MD, and Helmut Gerber, MD Institute of Anesthesiology (M.S., H.G.) and Pathology (H-P.O.), Kantonsspital, Basel, Switzerland
Abstract Ketamine, a selective, noncompetitive N-methyl-D-aspartate (NMDA)-receptor antagonist, is able to alter pain perception at the spinal level. Little clinical data exist on the intrathecal and epidural use of ketamine in chronic pain. Histopathologic findings after intrathecal injection of ketamine with and without preservatives are rarely reported. This outcome was evaluated in a 72-year-old woman with abdominal pain due to cancer who was treated with the intrathecal application of bupivacaine, clonidine, and morphine. We reached satisfactory pain relief with the addition of ketamine to the mixture for 7 days. On postmortem, focal lymphocytic vasculitis close to the catheter injection site was found. This finding has not been described previously after long-term application of ketamine intrathecally. The intrathecal infusion of ketamine with preservative, or the mixture of ketamine, clonidine, morphine, and bupivacaine resulted in isolated lymphocytic vasculitis of the spinal cord and leptomeninges without any clinical signs of neurological deficit. J Pain Symptom Manage 1999;18:223–228. © U.S. Cancer Pain Relief Committee, 1999. Key Words NMDA-receptor antagonist, ketamine, chronic pain, intrathecal infusion, histopathology, side effects
Introduction Ketamine, a selective noncompetitive N-methylacid (NMDA)-receptor antagonist, is able to alter pain perception at the spinal level, regulating the spinal wind-up and receptive field size of the dorsal horn neurons.1 Ketamine inhibits the NMDA receptor by blocking the open channel of neurons and thereby reducing the channel mean open time and the frequency of channel opening due to an allosteric mechanism.2 D-aspartatic
Address reprint requests to: Martin Stotz, MD, Institute of Anesthesiology, Kantonsspital, 4031 Basel, Switzerland. Accepted for publication: November 30, 1998. © U.S. Cancer Pain Relief Committee, 1999 Published by Elsevier, New York, New York
Ketamine has been administered epidurally for pain relief in humans without side effects such as respiratory depression, urinary retention, or pruritus.1,3 Intrathecally administered ketamine has been shown to have some anesthetic effect.4 Although no detrimental neurological symptoms have been noted after spinal administration of ketamine, the neurotoxicity of intrathecal ketamine administration has not been studied clinically.5–9 Few data exist on the epidural and intrathecal use of ketamine in chronic pain patients. In one case series, the addition of ketamine to a morphine–lidocaine–clonidine mixture intrathecally provided sufficient analgesia in four patients with terminal cancer pain without the development of tolerance.10 Yang et al.11 also 0885-3924/99/$–see front matter PII S0885-3924(99)00069-X
224
Stotz et al.
found a significant reduction of intrathecal morphine dosage and pain scores when ketamine was added to the morphine mixture. We report the use of intrathecal ketamine in the management of a patient with intractable cancer pain of the lower abdomen. Postmortem histological evaluation was obtained after long-term intrathecal infusion with commercially available ketamine.
Case Report HM was a 72-year-old Caucasian female with a history of peritoneal malignant mesothelioma diagnosed in 1996. She underwent several laparotomies for tumor debulking, partial resection of the small intestine, and lysis of adhesions. No adjuvant chemotherapy or radiation therapy was undertaken. Pain was initially managed with oral opioid analgesics, a nonsteroidal anti-inflammatory drug, and a psychotropic. She presented in our pain unit with pain consisting of constant burning sensation in the right lower abdomen and intermittent sharp pain in the right inguinal region, probably due to infiltration of the abdominal wall. Her pain scores were increasing and reached a score of 8 on a scale of 10 before hospitalization (day 0). Pain scores and management are detailed in Fig. 1.
Vol. 18 No. 3 September 1999
On presentation, we first used intravenous (IV) patient-controlled analgesia (PCA) with morphine (morphine 2 mg/ml; PCA program: 1 ml/demand, lockout interval 7 min, 4-h limit 20 mg) in addition to continuing the oral analgesic management (pain score 7). On day 8, a CT-guided neurolysis of the celiac plexus was performed without beneficial effect (score 6). Then, a thoracic epidural catheter was placed at T6 and a continuous epidural infusion of bupivacaine 0.125% and morphine (0.04 mg?ml21) was started at a rate of 6–12 ml?h21 (day 14) with minor success (score 6–8). On day 22, we placed an intrathecal catheter (Spinocath, B. Braun Co., Germany) with continuous infusion of a mixture of bupivacaine 0.25% and morphine (0.12 mg?ml21) at a rate of 2–2.5ml? h21 (score 6). The tip of the catheter was placed at the level of T7. Because of unsatisfactory pain relief, we first increased the infusion rate to 3–3.5 ml?h21, which resulted in a sensory level C4 to L2, then increased the morphine dose to 0.3 mg?ml21 and added clonidine to the mixture (3 mg?ml21) with still unsatisfactory pain relief (for detailed management, see Fig. 2). At this point, the patient experienced some motor weakness of the upper extremities and the abdomen without apparent discomfort. Finally, pain relief (score 2) was obtained with the addition (1 mg?ml21) of commercially
Fig. 1. Management trials and related pain scores on pain scale during hospitalization in a 72-year-old patient with pain due to peritoneal malignant mesothelioma.
Vol. 18 No. 3 September 1999
Intrathecal Ketamine for Chronic Pain
225
Fig. 2. Detailed infusion scheme for intrathecal treatment with ketamine.
available ketamine (preservative: benzethonium chloride) to the intrathecal mixture. The mean daily dose of ketamine administered intrathecally was 67.2 mg. After 7 days of intrathecal infusion, the patient developed acute psychotic alterations that were thought to be related to ketamine; no abnormal neurological signs were found. Ketamine was removed from the infusion scheme and i.v. PCA (morphine 2 mg/ml; PCA program: background infusion 0.5 ml/min, lockout interval 5 min, no 4-h limit) was added to the pain management (score 2). The next day, the patient developed a stiff neck with normal peripheral reflexes. The cerebrospinal fluid (CSF) was clear and the analysis showed a cell count of 16?ml21 (normal 0–3), normal glucose, protein, and chloride; no microorganisms were found in microscopic examination and culture. Restitutio ad integrum occurred after 18 hours without treatment. Ten days later, the patient succumbed to her disease (before death, score 3) and autopsy was performed within 41 hours after death with special attention to the spinal cord and leptomeninges. Histological sections were stained with hematoxylin–eosin and Klüver-Barrera.
Histological Findings Histological examination showed focal lymphocytic vasculitis in the medullary tissue, in
the nerves, and in the leptomeninges (Fig. 3) of the thoracic and lumbar spinal cord. The mononuclear infiltrate consisted mainly of lymphocytes. The percentage of vessels showing signs of inflammation was 10% in the medullary tissue, 25% in nerves, and 30% in the leptomeninges of the caudal thoracic segment; others did not show signs of alteration. No other histological changes were observed in medullary tissue. There was no necrosis, hemorrhage, or signs of demyelinization or vacuolization (Fig. 4). There was no vasculitis in other organs or tissues, neither in the brain nor its meninges.
Discussion Neuraxial opioid therapy is often effective in treating cancer pain that has not been adequately controlled by enteral or parenteral treatment.12 The addition of epidural clonidine to opioids has been shown to be particularly efficacious in the treatment of neuropathic pain.13 In this case, we were unable to reach satisfactory pain relief with an intrathecal mixture of bupivacaine, morphine, and clonidine, despite an adequate high sensory level. Fifty mg of intrathecally administered ketamine can produce surgical anesthesia with a sensory blockade lasting for 1 hour.4 The combination of intrathecal and/or epidural keta-
226
Stotz et al.
Vol. 18 No. 3 September 1999
Fig. 3. Severe lymphocytic vasculitis of spinal vessel after long-term intrathecal infusion of ketamine with preservative, normal medullary tissue; stained hematoxylin–eosin.
mine with opioids is intended to avoid side effects by either drug. Two authors have reported the successful addition of commercially available ketamine for treatment of chronic
cancer pain.10,11 The sedative effect after large doses of intrathecal ketamine, which was also seen in our patient, is apparently due to systemic uptake.3,4,14 Psychotic alterations, as seen
Fig. 4. Normal nerve sheaths with central axon, no signs of demyelinization or vacuolization in the same patient; stained Klüver-Barrera.
Vol. 18 No. 3 September 1999
Intrathecal Ketamine for Chronic Pain
in our patient, are common after i.v. or i.m. ketamine administration.15 The histological findings of an isolated lymphocytic vasculitis of the spinal cord and leptomeninges near the catheter tip are surprising. Isolated vasculitis of the central nervous system is rare and may be due to a primary disease such as granulomatous angiitis or due to a secondary manifestation of a group of underlying diseases such as lymphoma, leukemia, or metastatic small cell lung cancer.16 With negative microscopic examination and culture of CSF analysis, an infectious angiitis seems improbable in our case. In addition, no other systemic underlying disease was found at autopsy. Either a drug-related origin of angiitis or immunocomplex-mediated reaction of spinal vessels must be suspected. The intrathecal administration of drugs always carries the potential for neurotoxicity. Comparing magnesium sulfate, saline, and implanted catheter alone, no histological differences were shown in rats after 1 month and repeated injections.17 Low pH and high osmolality can produce parenchymatous necrosis and/or hemorrhage of the spinal cord after single-shot spinal anesthesia with hyperbaric bupivacaine.18 With the pH of the intrathecal mixture infused in our case being 5.46 and the osmolality 299 mosmol/kg, they seem unlikely to be responsible for the observed angiitis. Mild deformation of the spinal cord in sheep was found after repeated injection of clonidine through intrathecal catheters, with signs of local demyelinization at the catheter site, but no leptomeningeal or cord inflammation or other histological changes were seen.19 After single-shot intrathecal administration of ketamine, with and without preservative (benzethonium chloride), in monkeys, BrockUtne et al.5,6 found no inflammatory reactions. The same negative findings are reported by Borgbjerg et al.,8 and they found no histological difference between preservative-free ketamine 1% and saline after repeated intrathecal injections in rabbits. Others have observed radicular demyelinization in rats after repeated intrathecal injections of ketamine 5%, with benzethonium chloride as preservative.20 Malinovsky et al.7 found mild vascular lesions and loss of vessel outline with the preservative chlorobutanol, but not with lidocaine or preservative-free d-ketamine 1% after a single-shot ad-
227
ministration. Recently, a case report has been published noting a subpial vacuolar myelopathy after intrathecal administration of ketamine with preservative.21 Preservative-free ketamine as a racemate or isomers may even have beneficial effects in vitro. Cytoprotective properties in hippocampal neurons22 and nephroprotective effects inhibiting the mesangial cell proliferation at clinically relevant concentrations have been observed.23 In conclusion, satisfactory pain relief was obtained in a patient with intractable cancer pain unresponsive to conventional pain therapy with the addition of commercially available ketamine to an intrathecal mixture of bupivacaine, morphine, and clonidine. Clinically, no neurologic deficits were observed. Postmortem findings of focal lymphocytic vasculitis close to the catheter injection site, without other histological changes after long-term intrathecal infusion, may be related to the preservative benzethonium chloride or the toxicity of the mixture itself.
References 1. Yaksh T. Epidural ketamine: a useful, mechanistically novel adjuvant for epidural morphine? Reg Anesth 1996;21:508–513. 2. Orser B, Pennefather P, MacDonald J. Multiple mechanisms of ketamine blockade of N-methylD-aspartate receptors. Anesthesiology 1997;87:903–917. 3. Ravat F, Dorne R, Baechle J, Beaulaton A, Lenoir B, Palmier B. Epidural ketamine or morphine for postoperative analgesia. Anesthesiology 1987;66: 819–822. 4. Bion J. Intrathecal ketamine for war surgery: a preliminary study under field conditions. Anaesthesia 1984;39:1023–1028. 5. Brock-Utne J, Mankowitz E, Maharaj R, Drowning J. Intrathecal ketamine with preservative-histological effects on spinal nerve roots of baboons. S Afr Med J 1982;61:440–441. 6. Brock-Utne J, Mankowitz E, Kallichurum S, Drowning J. Effects of intrathecal saline and ketamine with and without preservative on the spinal nerve roots of monkeys. S Afr Med J 1982;61:360–361. 7. Malinovsky J, Lepage J, Cozian A, Mussini J, Pinaud M, Souron R. Is ketamine or its preservative responsible for neurotoxicity in rabbit? Anesthesiology 1993;78:109–115. 8. Borgbjerg F, Svensson B, Frigas C, Gordh T. Histopathology after repeated intrathecal injections of preservative-free ketamine in the rabbit: a light and
228
Stotz et al.
Vol. 18 No. 3 September 1999
electron microscopic examination. Anesth Analg 1994;79:105–111.
16. Lie T. Angiitis of the central nervous system. Curr Opin Rheumatol 1991;3:36–45.
9. Abram S. Spinal cord toxicity of epidural and subarachnoid analgesics. Reg Anesth 1996;21:84–88.
17. Chanimov M, Cohen M, Grinspun Y, et al. Neurotoxicity after spinal anaesthesia by serial intrathecal injections of magnesium sulphate. Anaesthesia 1997;52:223–228.
10. Muller A, Lemos D. Cancer pain: beneficial effect of ketamine addition to a morphine–clonidine– lidocaine mixture administered by intrathecal route. Ann Fr Réanim 1996;15:271–276. 11. Yang C, Wong C, Chang J, Ho S. Intrathecal ketamine reduces morphine requirements in patients with terminal cancer pain. Can J Anaesth 1996;43: 379–383. 12. Ballantyne J, Carr D, Berkey C, Chalmers T, Mosteller F. Comparative efficacy of epidural, subarachnoid, and intracerebroventricular opioids in patients with pain due to cancer. Anesth 1996;21:542–556. 13. Eisenach J, DuPen S, Dubois M, Miguel R, Allin D. Epidural clonidine analgesia for intractable cancer pain. Pain 1995;61:391–399.
18. Ganem E, Vianna P, Marques M, Castiglia Y, Vane L. Neurotoxicity of subarachnoid hyperbaric bupivacaine in dogs. Reg Anesth 1996;21:234–238. 19. Eisenach J, Dewan D, Rose J, Angelo J. Epidural clonidine produces antinoception, but no hypotension, in sheep. Anesthesiology 1987;66:496–501. 20. Amiot J, Pallaci J, Vedrenne C, Pellerin M. Spinal toxicity of lysine acetylate and ketamine hydrochloride given by the intrathecal route in the rat. Ann Fr Anesth Réanim 1986;5:462. 21. Karpinsky N, Dunn J, Hansen L, Masliah E. Subpial vacuolar myelopathy after intrathecal ketamine: report of a case. Pain 1997;73:103–105.
14. Nagibu M, Adu-Gyamfi Y, Absood G, Farag H, Gyasi H. Epidural ketamine for postoperative analgesia. Can Anaesth Soc J 1986;33:16–21.
22. Himmelseher S, Pfenninger E, Georgieff M. The effects of ketamine-isomers on neuronal injury and regeneration in rat hippocampal neurons. Anesth Analg 1996;83:505–512.
15. Baer G, Parkas P. Ketamine-induced psychopathological changes in normal volunteers during conditions used for experimental psychoses. Anaesthetist 1981;30:251–256.
23. Jimi N, Segawa K, Minami K, Sata T, Shigematsu A. Inhibitory effect of the intravenous anesthetic, ketamine, on rat mesangial cell proliferation. Anesth Analg 1997;84:190–195.
Journal of Pain and Symptom Management
223
Clinical Note
Histological Findings After Long-Term Infusion of Intrathecal Ketamine for Chronic Pain: A Case Report Martin Stotz, MD, Hans-Peter Oehen, MD, and Helmut Gerber, MD Institute of Anesthesiology (M.S., H.G.) and Pathology (H-P.O.), Kantonsspital, Basel, Switzerland
Abstract Ketamine, a selective, noncompetitive N-methyl-D-aspartate (NMDA)-receptor antagonist, is able to alter pain perception at the spinal level. Little clinical data exist on the intrathecal and epidural use of ketamine in chronic pain. Histopathologic findings after intrathecal injection of ketamine with and without preservatives are rarely reported. This outcome was evaluated in a 72-year-old woman with abdominal pain due to cancer who was treated with the intrathecal application of bupivacaine, clonidine, and morphine. We reached satisfactory pain relief with the addition of ketamine to the mixture for 7 days. On postmortem, focal lymphocytic vasculitis close to the catheter injection site was found. This finding has not been described previously after long-term application of ketamine intrathecally. The intrathecal infusion of ketamine with preservative, or the mixture of ketamine, clonidine, morphine, and bupivacaine resulted in isolated lymphocytic vasculitis of the spinal cord and leptomeninges without any clinical signs of neurological deficit. J Pain Symptom Manage 1999;18:223–228. © U.S. Cancer Pain Relief Committee, 1999. Key Words NMDA-receptor antagonist, ketamine, chronic pain, intrathecal infusion, histopathology, side effects
Introduction Ketamine, a selective noncompetitive N-methylacid (NMDA)-receptor antagonist, is able to alter pain perception at the spinal level, regulating the spinal wind-up and receptive field size of the dorsal horn neurons.1 Ketamine inhibits the NMDA receptor by blocking the open channel of neurons and thereby reducing the channel mean open time and the frequency of channel opening due to an allosteric mechanism.2 D-aspartatic
Address reprint requests to: Martin Stotz, MD, Institute of Anesthesiology, Kantonsspital, 4031 Basel, Switzerland. Accepted for publication: November 30, 1998. © U.S. Cancer Pain Relief Committee, 1999 Published by Elsevier, New York, New York
Ketamine has been administered epidurally for pain relief in humans without side effects such as respiratory depression, urinary retention, or pruritus.1,3 Intrathecally administered ketamine has been shown to have some anesthetic effect.4 Although no detrimental neurological symptoms have been noted after spinal administration of ketamine, the neurotoxicity of intrathecal ketamine administration has not been studied clinically.5–9 Few data exist on the epidural and intrathecal use of ketamine in chronic pain patients. In one case series, the addition of ketamine to a morphine–lidocaine–clonidine mixture intrathecally provided sufficient analgesia in four patients with terminal cancer pain without the development of tolerance.10 Yang et al.11 also 0885-3924/99/$–see front matter PII S0885-3924(99)00069-X
224
Stotz et al.
found a significant reduction of intrathecal morphine dosage and pain scores when ketamine was added to the morphine mixture. We report the use of intrathecal ketamine in the management of a patient with intractable cancer pain of the lower abdomen. Postmortem histological evaluation was obtained after long-term intrathecal infusion with commercially available ketamine.
Case Report HM was a 72-year-old Caucasian female with a history of peritoneal malignant mesothelioma diagnosed in 1996. She underwent several laparotomies for tumor debulking, partial resection of the small intestine, and lysis of adhesions. No adjuvant chemotherapy or radiation therapy was undertaken. Pain was initially managed with oral opioid analgesics, a nonsteroidal anti-inflammatory drug, and a psychotropic. She presented in our pain unit with pain consisting of constant burning sensation in the right lower abdomen and intermittent sharp pain in the right inguinal region, probably due to infiltration of the abdominal wall. Her pain scores were increasing and reached a score of 8 on a scale of 10 before hospitalization (day 0). Pain scores and management are detailed in Fig. 1.
Vol. 18 No. 3 September 1999
On presentation, we first used intravenous (IV) patient-controlled analgesia (PCA) with morphine (morphine 2 mg/ml; PCA program: 1 ml/demand, lockout interval 7 min, 4-h limit 20 mg) in addition to continuing the oral analgesic management (pain score 7). On day 8, a CT-guided neurolysis of the celiac plexus was performed without beneficial effect (score 6). Then, a thoracic epidural catheter was placed at T6 and a continuous epidural infusion of bupivacaine 0.125% and morphine (0.04 mg?ml21) was started at a rate of 6–12 ml?h21 (day 14) with minor success (score 6–8). On day 22, we placed an intrathecal catheter (Spinocath, B. Braun Co., Germany) with continuous infusion of a mixture of bupivacaine 0.25% and morphine (0.12 mg?ml21) at a rate of 2–2.5ml? h21 (score 6). The tip of the catheter was placed at the level of T7. Because of unsatisfactory pain relief, we first increased the infusion rate to 3–3.5 ml?h21, which resulted in a sensory level C4 to L2, then increased the morphine dose to 0.3 mg?ml21 and added clonidine to the mixture (3 mg?ml21) with still unsatisfactory pain relief (for detailed management, see Fig. 2). At this point, the patient experienced some motor weakness of the upper extremities and the abdomen without apparent discomfort. Finally, pain relief (score 2) was obtained with the addition (1 mg?ml21) of commercially
Fig. 1. Management trials and related pain scores on pain scale during hospitalization in a 72-year-old patient with pain due to peritoneal malignant mesothelioma.
Vol. 18 No. 3 September 1999
Intrathecal Ketamine for Chronic Pain
225
Fig. 2. Detailed infusion scheme for intrathecal treatment with ketamine.
available ketamine (preservative: benzethonium chloride) to the intrathecal mixture. The mean daily dose of ketamine administered intrathecally was 67.2 mg. After 7 days of intrathecal infusion, the patient developed acute psychotic alterations that were thought to be related to ketamine; no abnormal neurological signs were found. Ketamine was removed from the infusion scheme and i.v. PCA (morphine 2 mg/ml; PCA program: background infusion 0.5 ml/min, lockout interval 5 min, no 4-h limit) was added to the pain management (score 2). The next day, the patient developed a stiff neck with normal peripheral reflexes. The cerebrospinal fluid (CSF) was clear and the analysis showed a cell count of 16?ml21 (normal 0–3), normal glucose, protein, and chloride; no microorganisms were found in microscopic examination and culture. Restitutio ad integrum occurred after 18 hours without treatment. Ten days later, the patient succumbed to her disease (before death, score 3) and autopsy was performed within 41 hours after death with special attention to the spinal cord and leptomeninges. Histological sections were stained with hematoxylin–eosin and Klüver-Barrera.
Histological Findings Histological examination showed focal lymphocytic vasculitis in the medullary tissue, in
the nerves, and in the leptomeninges (Fig. 3) of the thoracic and lumbar spinal cord. The mononuclear infiltrate consisted mainly of lymphocytes. The percentage of vessels showing signs of inflammation was 10% in the medullary tissue, 25% in nerves, and 30% in the leptomeninges of the caudal thoracic segment; others did not show signs of alteration. No other histological changes were observed in medullary tissue. There was no necrosis, hemorrhage, or signs of demyelinization or vacuolization (Fig. 4). There was no vasculitis in other organs or tissues, neither in the brain nor its meninges.
Discussion Neuraxial opioid therapy is often effective in treating cancer pain that has not been adequately controlled by enteral or parenteral treatment.12 The addition of epidural clonidine to opioids has been shown to be particularly efficacious in the treatment of neuropathic pain.13 In this case, we were unable to reach satisfactory pain relief with an intrathecal mixture of bupivacaine, morphine, and clonidine, despite an adequate high sensory level. Fifty mg of intrathecally administered ketamine can produce surgical anesthesia with a sensory blockade lasting for 1 hour.4 The combination of intrathecal and/or epidural keta-
226
Stotz et al.
Vol. 18 No. 3 September 1999
Fig. 3. Severe lymphocytic vasculitis of spinal vessel after long-term intrathecal infusion of ketamine with preservative, normal medullary tissue; stained hematoxylin–eosin.
mine with opioids is intended to avoid side effects by either drug. Two authors have reported the successful addition of commercially available ketamine for treatment of chronic
cancer pain.10,11 The sedative effect after large doses of intrathecal ketamine, which was also seen in our patient, is apparently due to systemic uptake.3,4,14 Psychotic alterations, as seen
Fig. 4. Normal nerve sheaths with central axon, no signs of demyelinization or vacuolization in the same patient; stained Klüver-Barrera.
Vol. 18 No. 3 September 1999
Intrathecal Ketamine for Chronic Pain
in our patient, are common after i.v. or i.m. ketamine administration.15 The histological findings of an isolated lymphocytic vasculitis of the spinal cord and leptomeninges near the catheter tip are surprising. Isolated vasculitis of the central nervous system is rare and may be due to a primary disease such as granulomatous angiitis or due to a secondary manifestation of a group of underlying diseases such as lymphoma, leukemia, or metastatic small cell lung cancer.16 With negative microscopic examination and culture of CSF analysis, an infectious angiitis seems improbable in our case. In addition, no other systemic underlying disease was found at autopsy. Either a drug-related origin of angiitis or immunocomplex-mediated reaction of spinal vessels must be suspected. The intrathecal administration of drugs always carries the potential for neurotoxicity. Comparing magnesium sulfate, saline, and implanted catheter alone, no histological differences were shown in rats after 1 month and repeated injections.17 Low pH and high osmolality can produce parenchymatous necrosis and/or hemorrhage of the spinal cord after single-shot spinal anesthesia with hyperbaric bupivacaine.18 With the pH of the intrathecal mixture infused in our case being 5.46 and the osmolality 299 mosmol/kg, they seem unlikely to be responsible for the observed angiitis. Mild deformation of the spinal cord in sheep was found after repeated injection of clonidine through intrathecal catheters, with signs of local demyelinization at the catheter site, but no leptomeningeal or cord inflammation or other histological changes were seen.19 After single-shot intrathecal administration of ketamine, with and without preservative (benzethonium chloride), in monkeys, BrockUtne et al.5,6 found no inflammatory reactions. The same negative findings are reported by Borgbjerg et al.,8 and they found no histological difference between preservative-free ketamine 1% and saline after repeated intrathecal injections in rabbits. Others have observed radicular demyelinization in rats after repeated intrathecal injections of ketamine 5%, with benzethonium chloride as preservative.20 Malinovsky et al.7 found mild vascular lesions and loss of vessel outline with the preservative chlorobutanol, but not with lidocaine or preservative-free d-ketamine 1% after a single-shot ad-
227
ministration. Recently, a case report has been published noting a subpial vacuolar myelopathy after intrathecal administration of ketamine with preservative.21 Preservative-free ketamine as a racemate or isomers may even have beneficial effects in vitro. Cytoprotective properties in hippocampal neurons22 and nephroprotective effects inhibiting the mesangial cell proliferation at clinically relevant concentrations have been observed.23 In conclusion, satisfactory pain relief was obtained in a patient with intractable cancer pain unresponsive to conventional pain therapy with the addition of commercially available ketamine to an intrathecal mixture of bupivacaine, morphine, and clonidine. Clinically, no neurologic deficits were observed. Postmortem findings of focal lymphocytic vasculitis close to the catheter injection site, without other histological changes after long-term intrathecal infusion, may be related to the preservative benzethonium chloride or the toxicity of the mixture itself.
References 1. Yaksh T. Epidural ketamine: a useful, mechanistically novel adjuvant for epidural morphine? Reg Anesth 1996;21:508–513. 2. Orser B, Pennefather P, MacDonald J. Multiple mechanisms of ketamine blockade of N-methylD-aspartate receptors. Anesthesiology 1997;87:903–917. 3. Ravat F, Dorne R, Baechle J, Beaulaton A, Lenoir B, Palmier B. Epidural ketamine or morphine for postoperative analgesia. Anesthesiology 1987;66: 819–822. 4. Bion J. Intrathecal ketamine for war surgery: a preliminary study under field conditions. Anaesthesia 1984;39:1023–1028. 5. Brock-Utne J, Mankowitz E, Maharaj R, Drowning J. Intrathecal ketamine with preservative-histological effects on spinal nerve roots of baboons. S Afr Med J 1982;61:440–441. 6. Brock-Utne J, Mankowitz E, Kallichurum S, Drowning J. Effects of intrathecal saline and ketamine with and without preservative on the spinal nerve roots of monkeys. S Afr Med J 1982;61:360–361. 7. Malinovsky J, Lepage J, Cozian A, Mussini J, Pinaud M, Souron R. Is ketamine or its preservative responsible for neurotoxicity in rabbit? Anesthesiology 1993;78:109–115. 8. Borgbjerg F, Svensson B, Frigas C, Gordh T. Histopathology after repeated intrathecal injections of preservative-free ketamine in the rabbit: a light and
228
Stotz et al.
Vol. 18 No. 3 September 1999
electron microscopic examination. Anesth Analg 1994;79:105–111.
16. Lie T. Angiitis of the central nervous system. Curr Opin Rheumatol 1991;3:36–45.
9. Abram S. Spinal cord toxicity of epidural and subarachnoid analgesics. Reg Anesth 1996;21:84–88.
17. Chanimov M, Cohen M, Grinspun Y, et al. Neurotoxicity after spinal anaesthesia by serial intrathecal injections of magnesium sulphate. Anaesthesia 1997;52:223–228.
10. Muller A, Lemos D. Cancer pain: beneficial effect of ketamine addition to a morphine–clonidine– lidocaine mixture administered by intrathecal route. Ann Fr Réanim 1996;15:271–276. 11. Yang C, Wong C, Chang J, Ho S. Intrathecal ketamine reduces morphine requirements in patients with terminal cancer pain. Can J Anaesth 1996;43: 379–383. 12. Ballantyne J, Carr D, Berkey C, Chalmers T, Mosteller F. Comparative efficacy of epidural, subarachnoid, and intracerebroventricular opioids in patients with pain due to cancer. Anesth 1996;21:542–556. 13. Eisenach J, DuPen S, Dubois M, Miguel R, Allin D. Epidural clonidine analgesia for intractable cancer pain. Pain 1995;61:391–399.
18. Ganem E, Vianna P, Marques M, Castiglia Y, Vane L. Neurotoxicity of subarachnoid hyperbaric bupivacaine in dogs. Reg Anesth 1996;21:234–238. 19. Eisenach J, Dewan D, Rose J, Angelo J. Epidural clonidine produces antinoception, but no hypotension, in sheep. Anesthesiology 1987;66:496–501. 20. Amiot J, Pallaci J, Vedrenne C, Pellerin M. Spinal toxicity of lysine acetylate and ketamine hydrochloride given by the intrathecal route in the rat. Ann Fr Anesth Réanim 1986;5:462. 21. Karpinsky N, Dunn J, Hansen L, Masliah E. Subpial vacuolar myelopathy after intrathecal ketamine: report of a case. Pain 1997;73:103–105.
14. Nagibu M, Adu-Gyamfi Y, Absood G, Farag H, Gyasi H. Epidural ketamine for postoperative analgesia. Can Anaesth Soc J 1986;33:16–21.
22. Himmelseher S, Pfenninger E, Georgieff M. The effects of ketamine-isomers on neuronal injury and regeneration in rat hippocampal neurons. Anesth Analg 1996;83:505–512.
15. Baer G, Parkas P. Ketamine-induced psychopathological changes in normal volunteers during conditions used for experimental psychoses. Anaesthetist 1981;30:251–256.
23. Jimi N, Segawa K, Minami K, Sata T, Shigematsu A. Inhibitory effect of the intravenous anesthetic, ketamine, on rat mesangial cell proliferation. Anesth Analg 1997;84:190–195.