Protecting the ischemic spinal cord during aortic clamping. The influence of anesthetics and hypothermia.

Infrarenal circumaortic occlusion devices were operatively placed in 74 New Zealand white rabbits. Two days after operation the animals were randomly assigned to one of seven treatment groups: I, control, n = 23; II, halothane, n = 8; III, thiopental, n = 12; IV, ketamine (30 mg/kg intravenously), n = 6; V, halothane+hypothermia, n = 8; VI, thiopental+hypothermia, n = 12; VII, ketamine+hypothermia, n = 5. In each group, the infrarenal aorta was occluded for 21 minutes. Final neurologic recovery after restitution of blood flow was graded as acute paraplegia, delayed paraplegia (neurologic deficit developing after initial recovery), or normal. Halothane alone was of no benefit. Hypothermia with any anesthetic was completely protective and reduced neurologic deficits to 0% compared with 91% in controls (p less than 0.05). Thiopental and ketamine treatment each reduced acute paraplegia to 17% (as compared with 61% in controls) and increased delayed paraplegia from 30% in controls to 75% and 50%, respectively (p less than 0.05 for thiopental, p = 0.10 for ketamine). The authors interpret the increase in delayed deficits and decrease in acute deficits as being the result of partial spinal cord protection. These findings document that this model of spinal cord ischemia is sufficiently sensitive to identify interventional treatments that protect the ischemic spinal cord.     

Epidural cooling for the prevention of ischemic injury to the spinal cord during aortic occlusion in a rabbit model: determination of the optimal temperature

PURPOSE: This experiment was designed for the determination of the optimal epidural cooling temperature for the allowance of spinal cord protection with minimal side effects during an aortic occlusion-induced spinal cord ischemia model in rabbits. METHODS: Spinal cord ischemia was induced in rabbits with infrarenal aortic occlusion for 40 minutes. Spinal cord cooling was effected with epidural infusion of normal saline solution at the following different temperatures: group 1, 17 degrees C (n = 6); group 2, 24 degrees C (n = 6); group 3, 32 degrees C (n = 6); and group 4, 39 degrees C (n = 3). Sham-operated rabbits without aortic occlusion were used as controls with epidural infusion at healthy body temperature (39 degrees C; n = 3). Motor function was assessed at 48 hours with Tarlov's criteria, and the animals were killed. The spinal cord was sectioned into multiple segments, and semiquantitative histologic scoring (0 to 5) was used to grade ischemic injury. RESULTS: Cooling solution and spinal cord temperatures showed linear correlation (r = 0.95). All the rabbits in groups 1 (except one with mild weakness), 2, and 3 were neurologically intact, and all in group 4 had paraplegia develop (P < .001). One rabbit in group 1 died from increased intracranial pressure (ICP). Mean blood pressure, ICP, and body temperature were similar among the groups. Histology correlated with the clinical findings. In groups 1 and 2, minimal histologic changes were noted. Low-grade ischemic changes were present in group 3 in the low-lumbar and mid-lumbar segments. Severe ischemic injury occurred at the same segments in group 4 (P < .05). CONCLUSION: These study results suggest that in rabbits satisfactory spinal cord protection during aortic occlusion can be achieved at moderate regional hypothermia (24 degrees C). Large volume infusion for the achievement of profound hypothermia may cause deleterious effects of increased ICP and is not warranted.     

Effects of intrathecal bupivacaine in conjunction with hypothermia on neuronal protection against transient spinal cord ischemia in rats

BACKGROUND: Excitotoxic neuronal injury from ischemia may be reduced by local anesthetics. We investigated the neuroprotective effects of intrathecally administered bupivacaine and hypothermia in a rat model of transient spinal cord ischemia. METHODS: PE-10 intrathecal catheter-implanted male Sprague-Dawley rats were randomly assigned to one of four groups: normothermia (NT) and hypothermia (HT) groups (given 15 microl of normal saline) and bupivacaine (B) and bupivacaine-hypothermia (BHT) groups (given 15 mul of 0.5% bupivacaine). Transient spinal cord ischemia was induced by inflation of a 2F Fogarty catheter placed in the aortic arch for 12 min. The rectal temperature was maintained at 37.0 +/- 0.5 degrees C for the NT and B groups, and at 34.5 +/- 0.5 degrees C for the HT and BHT groups. Motor and sensory deficit scores were assessed 2 and 24 h after reperfusion. Lumbar spinal cords were harvested for histopathology and immunoreactivity of heat shock protein 70 (HSP70). RESULTS: After reperfusion, the motor and sensory deficit scores of the NT group were significantly higher than those of the HT (P < 0.05) and BHT (P < 0.001) groups. Significant differences were evident in the motor and sensory deficit scores between the HT and BHT groups at 24 h (P < 0.05). Neuronal cell death and immunoreactivity of HSP70 were frequently observed in the NT and BT groups, but not in the HT and BHT groups. CONCLUSIONS: These results collectively suggest that intrathecal bupivacaine does not provide neuroprotection during normothermic transient spinal cord ischemia in rats, but enhances the neuroprotective effects of hypothermia.     

Protection against ischemic spinal cord injury: One-shot perfusion cooling and percutaneous topical cooling

Purpose: We investigated the protective effect of two methods of hypothermia against ischemic spinal cord injury: one-shot perfusion cooling and percutaneous topical cooling.Methods: Twenty-five rabbits were divided into five equal groups. The abdominal aorta was isolated proximally by a vascular clamp and distally by an inflated balloon catheter for 60 minutes. Group I served as control. In groups II (2.5 ml/min) and III (5.0 ml/min), hypothermic lactated Ringer's solution was infused for 3 minutes from the distal end of the catheter. Ice blocks were placed behind the backs of rabbits 30 minutes before ischemia in group IV. Group V underwent the procedures combined with those in groups II and IV (infusion of hypothermic solution plus placement of ice blocks). Another 15 rabbits underwent laminectomy at the L₂ or L₃ level. A temperature probe was inserted into the spinal cord to monitor cord temperature continuously during the procedures in all five groups (three rabbits per group).Results: Neurologic status on the second postoperative day in groups IV and V was significantly superior to that in group I (p < 0.01), but the neurologic status of groups II and III did not differ significantly from the neurologic status of group I. The spinal cord temperature in groups II and III dropped rapidly with the infusion, but it rose again quickly. In contrast, the spinal cord was kept sufficiently hypothermic during ischemia in groups IV and V.Conclusions: We concluded that the percutaneous cooling method can keep the spinal cord sufficiently hypothermic during ischemia to lead to a significantly superior neurologic outcome. (J VASC SURG 1994;19:882-7.)     

Preconditioning with Hyperbaric Oxygen and Hyperoxia Induces Tolerance against Spinal Cord Ischemia in Rabbits

Background: The aim of this study was to determine if the ischemic tolerance could be induced in the spinal cord by pretreatment with hyperbaric oxygen (HBO) and what components of HBO (hyperoxia, hyperbaricity, and combination of these two) were critical in the induction of tolerance against ischemic injury.

Methods: In experiment 1, 21 rabbits were randomly assigned to one of three groups (n = 7 each): animals in the control group received no HBO before spinal cord ischemia; animals in the HBO-1 and HBO-2 groups received HBO (2.5 atmosphere absolute [ATA], 100% O2) pretreatment 1 h/day for 3 and 5 days before ischemia, respectively. In experiment 2, 48 rabbits were randomly assigned to one of four groups (n = 12 each): the control group received no HBO (21% O2, 1 ATA, 1 h/day, 5 days) before spinal cord ischemia; the HB group received 1-h treatment in 21% O2 at 2.5 ATA each day for 5 days; the HO group received 1-h treatment in 100% oxygen at 1 ATA each day for 5 days; and the HBO group received HBO (2.5 ATA, 100% O2) treatment 1 h/day for 5 days. Twenty-four hours after the last treatment, spinal cord ischemia was induced by an infrarenal aorta clamping for 20 min. Forty-eight hours after reperfusion, hind-limb motor function and histopathology of the spinal cord were examined in a blinded fashion.

Results: In experiment 1, the neurologic outcome in the HBO-2 group was better than that of the control group (P = 0.004). The number of normal neurons in the anterior spinal cord in the HBO-2 group was more than that of the control group (P = 0.021). In experiment 2, the neurologic and histopathologic outcomes in the HBO group were better than that of the control group (P < 0.01). The histopathologic outcome in the HO group was better than that in the control group (P < 0.05).     

Effect of post-ischemic hypothermia on spinal cord damage induced by transient ischemic insult in rabbits

OBJECTIVE: The effect of post-ischemic mild hypothermia applied immediately after induced transient ischemia on the extent of neuronal damage to the spinal cord was investigated in rabbit. SUBJECTS AND METHODS: A 15-minute period of transient abdominal aortic occlusion for spinal cord ischemia at a rectal temperature of 37.3 +/- 0.3 degrees C was performed just below the left renal vein via median laparotomy. Three groups of rabbits were investigated; Group 1 (n = 8) subjected to ischemia and reperfused at the same temperature for 7 hours, Group 2 (n = 8) also subjected to ischemia and then to 6 hours of systemic hypothermia (32.5 +/- 0.5 degrees C), and Group 3 (n = 8) non-ischemic controls. All the rabbits in Group 1 and Group 2 were sacrificed at 1 week after ischemic injury. Spinal cord sections were examined microscopically to determine the extent of ischemic neuronal damage. RESULTS: The mean modified Tarlov's score at 1 week after ischemic injury was 0.5 +/- 0.8 in Group 1, whereas it was 4.4 +/- 1.4 (p < .001) in Group 2. The mean total number of surviving neurons within examined sections of the spinal cord was significantly greater in Group 2 than in Group 1 (Group 1: 81 +/- 66.1 vs Group 2: 300.9 +/- 154.1, p < .001). CONCLUSION: Post-ischemic hypothermia induced immediately after reperfusion significantly reduced ischemia-induced neuronal damage in rabbit.     

Mild hypothermia protects the spinal cord from ischemic injury in a chronic porcine model.

OBJECTIVES: During thoracoabdominal aortic aneurysm repair, prolonged compromise of spinal cord blood supply can result in irreversible spinal cord injury. This study investigated the impact of mild hypothermia during aortic cross-clamping on postoperative paraplegia in a chronic porcine model. METHODS: The thoracic aorta was exposed and cross-clamped in 30 juvenile pigs (20-22 kg) for different intervals at normothermia (36.5 degrees C), and during mild hypothermia (32.0 degrees C). Three pigs were evaluated at each time and temperature. Myogenic motor-evoked potentials (MEPs) were monitored, and postoperative recovery evaluated using a modified Tarlov score. RESULTS: There were no significant hemodynamic or metabolic differences between individual animals, and the groups had equivalent arterial pressures (mean 64.3+/-3.6 mmHg). Time to recovery of MEPs correlated with severity of injury; all animals with irreversible MEP loss suffered postoperative paraplegia. At normothermia, animals with 20 min of aortic cross-clamping emerged with normal motor function, but those cross-clamped for 30 min suffered paraplegia. With mild hypothermia, animals tolerated 50 min of aortic cross-clamping without evidence of neurologic injury, but were all paraplegic after 70 min of ischemia. Animals appeared to recover normal motor function after 60 min of aortic cross-clamping at hypothermia initially, but exhibited delayed-onset paraplegia 36 h postoperatively. CONCLUSIONS: Our observations indicate that mild hypothermia dramatically increases the tolerance of the spinal cord to ischemia in the pig, and therefore suggests that cooling to 32.0 degrees C should be encouraged during surgery which may compromise spinal cord blood supply. An ischemic insult of borderline severity may result in delayed paraplegia.     

Preconditioning with hyperbaric oxygen and hyperoxia induces tolerance against spinal cord ischemia in rabbits

BACKGROUND: The aim of this study was to determine if the ischemic tolerance could be induced in the spinal cord by pretreatment with hyperbaric oxygen (HBO) and what components of HBO (hyperoxia, hyperbaricity, and combination of these two) were critical in the induction of tolerance against ischemic injury. METHODS: In experiment 1, 21 rabbits were randomly assigned to one of three groups (n = 7 each): animals in the control group received no HBO before spinal cord ischemia; animals in the HBO-1 and HBO-2 groups received HBO (2.5 atmosphere absolute [ATA], 100% O2) pretreatment 1 h/day for 3 and 5 days before ischemia, respectively. In experiment 2, 48 rabbits were randomly assigned to one of four groups (n = 12 each): the control group received no HBO (21% O2, 1 ATA, 1 h/day, 5 days) before spinal cord ischemia; the HB group received 1-h treatment in 21% O2 at 2.5 ATA each day for 5 days; the HO group received 1-h treatment in 100% oxygen at 1 ATA each day for 5 days; and the HBO group received HBO (2.5 ATA, 100% O2) treatment 1 h/day for 5 days. Twenty-four hours after the last treatment, spinal cord ischemia was induced by an infrarenal aorta clamping for 20 min. Forty-eight hours after reperfusion, hind-limb motor function and histopathology of the spinal cord were examined in a blinded fashion. RESULTS: In experiment 1, the neurologic outcome in the HBO-2 group was better than that of the control group (P = 0.004). The number of normal neurons in the anterior spinal cord in the HBO-2 group was more than that of the control group (P = 0.021). In experiment 2, the neurologic and histopathologic outcomes in the HBO group were better than that of the control group (P < 0.01). The histopathologic outcome in the HO group was better than that in the control group (P < 0.05). CONCLUSIONS: Serial exposure to high oxygen tension induced ischemic tolerance in spinal cord of rabbits. Simple hyperbaricity (2.5 ATA, 21% O2) did not induce ischemic tolerance.     

Motor Function Changes in the Rat Following Severe Spinal Cord Injury

Systemic hypothermia exerts neuroprotective effects following trauma and ischemia caused by vascular occlusion in the brain. In the spinal cord similar effects have been demonstrated following ischemia after aortic occlusion. We have previously presented protective effects on several morphological parameters in the early period after the injury, using an established spinal cord compression injury model and systemic hypothermia. In the present study we have evaluated the effects on motor function following severe spinal cord compression trauma and treatment with moderate systemic hypothermia. Thirty Sprague Dawley rats were randomized into three groups: In group 1 (n = 4), the animals underwent a hypothermic procedure, including a 2 h hypothermic period with a body temperature of 30 degrees C, following the initial laminectomy. In group 2 (n = 12) a 50 g compression was applied to the spinal cords for 5 min, after which the animals were kept under normothermic anesthesia for 3 h. In group 3 (n = 14), the animals underwent the same trauma procedure as in group 2 and the same hypothermic procedure as in group 1. The animals were allowed to survive for 14 days, during which the motor function was recorded. This degree of trauma results in a non-reversible paraplegia, and the addition of systemic hypothermia as described above did not alter the neurological recovery as measured by two different methods of recording the motor function up to two weeks after injury. All animals survived in group 1. However, the mortality rates in group 2 were 25% and in group 3, 50%, respectively, which mirrors the severity of the trauma. The application of systemic hypothermia and the lack of experimental therapeutic success highlight the difficulties of transferring experimental beneficial neuroprotective effects to a clinically useful treatment method. In this experimental set-up the effects of the severe primary injury may overshadow the effects of the secondary injury mechanisms, which limits the therapeutic possibilities of systemic hypothermic treatment.     

Effect of delayed induction of postischemic hypothermia on spinal cord damage induced by transient ischemic insult in rabbits

Objective: This study was performed to determine the effect of delayed induction of mild hypothermia after transient spinal cord ischemia in rabbits. Methods: Abdominal aortic occlusion was performed for 15 minutes to induce spinal cord ischemia at a rectal temperature of 37.3±0.3°C. Four groups of rabbits were investigated: Group 1 (n=8) was subjected to ischemia and reperfused at the same temperature for 7 hours; Group 2 (n=8) was subjected to ischemia and reperfused at the same temperature for 1 hour, followed by 6 hours of systemic hypothermia (32.5±0.5°C); Group 3 (n=8) was subjected to ischemia, reperfusion at the same temperature for 3 hours and then 6 hours of systemic hypothermia (32.5±0.5°C); and Group 4 (n=8) comprised non-ischemic controls. Neurological status of all rabbits in Groups 1– 3 was recorded and animals were sacrificed 1 week after ischemic injury. Spinal cord sections were examined microscopically to determine the extent of ischemic neuronal damage. Results: Mean modified Tarlov’s score at 1 week after ischemic insult was 0.5±0.8 in Group 1, compared to 4.3±1.5 in Group 2 and 2.9±1.8 in Group 3. Mean total number of surviving neurons within examined sections of spinal cord was significantly greater for Groups 2 and 3 compared with Group 1 (Group 1, 81±66.1; Group 2, 293.4±110.9; Group 3,227.1± 105.5; p<0.001). Conclusions: Delayed postischemic hypothermia induced within 3 hours after reperfusion significantly reduces ischemia-induced spinal cord neuronal damage in rabbits.     

Cyclosporin A reduces delayed motor neuron death after spinal cord ischemia in rabbits

BACKGROUND: Spinal cord ischemia has varied etiologies, and in some cases, may develop into paraplegia. This is attributable to the vulnerability of spinal motor neurons to ischemia. We evaluated the potential of the immunosuppressant cyclosporin A for treatment of spinal motor neuron damage caused by ischemia. METHODS: Twenty-eight rabbits were randomized into four groups of 7 animals each: group A (cyclosporin A not administered), group B (2.5 mg/kg cyclosporin A), group C (25 mg/kg cyclosporin A), and group S (sham-operated). The spinal cord ischemia model was created by a 15-minute occlusion of the aorta just caudal to a renal artery with a balloon catheter. Administration of cyclosporin A began 30 minutes after restoration of blood flow. The spinal cords were removed after 7-day monitoring of neurologic function. Pathology specimens were prepared, and after staining them with hematoxylin-eosin, viable motor neurons in the ventral spinal cord were counted under light microscopy. RESULTS: At 7 days after reperfusion, recovery of motor function was seen at varying degrees in groups B and C, whereas all animals in group A continued to exhibit paraplegia. In group C, most of the animals recovered to the baseline level, before creation of the ischemia model. A significant difference in numbers of viable neurons was found in group A (cell count, 10.1 +/- 4.7) and group C (cell count, 22.2 +/- 8.0) (p < 0.05). Higher numbers of viable motor neurons corresponded to a greater recovery of motor function. CONCLUSIONS: These results suggest that cyclosporin A administration is effective against neuronal damage caused by spinal cord ischemia.     

Peri-ischemic aminoguanidine fails to ameliorate neurologic and histopathologic outcome after transient spinal cord ischemia.

Inhibition of neurotoxic events that lead to delayed cellular damage may prevent motor function loss after transient spinal cord ischemia. An important effect of the neuroprotective substance aminoguanidine (AG) is the inhibition of inducible nitric oxide synthase (iNOS), a perpetrator of focal ischemic damage. The authors studied the protective effects of AG on hind limb motor function and histopathologic outcome in an experimental model for spinal cord ischemia, and related these findings to the protein content of iNOS in the spinal cord. Temporary spinal cord ischemia was induced by 28 minutes of infrarenal balloon occlusion of the aorta in 40 anesthetized New Zealand White rabbits. Animals were assigned randomly to two treatments: saline (n = 20) or AG (n = 20; 100 mg/kg intravenously before occlusion). Postoperatively, treatment was continued with subcutaneous injections twice daily (saline or 100 mg/kg AG). Normothermia (38 degrees C) was maintained during ischemia, and rectal temperature was assessed before and after subcutaneous injections. Animals were observed for 96 hours for neurologic evaluation (Tarlov score), and the lumbosacral spinal cord was examined for ischemic damage after perfusion and fixation. Lastly, iNOS protein content was determined using Western blot analysis 48 hours after ischemia in five animals from each group. Neurologic outcome at 96 hours after reperfusion was the same in both groups. The incidence of paraplegia was 67% in the saline-treated group versus 53% in the AG-treated group. No differences in infarction volume, total number of viable motoneurons, or total number of eosinophilic neurons were present between the groups. At 48 hours after reperfusion, iNOS protein content in the spinal cord was increased in one animal in the AG-treated group and in three animals in the control group. The data indicate that peri-ischemic treatment with high-dose AG in rabbits offers no protection against a period of normothermic spinal cord ischemia. There was no conclusive evidence of spinal cord iNOS inhibition after treatment with AG.     

Ischemic preconditioning reduces neurologic injury in a rat model of spinal cord ischemia.

BACKGROUND: Ischemic preconditioning (IPC) is an endogenous cellular protective mechanism whereby brief, noninjurious periods of ischemia render a tissue more resistant to a subsequent, more prolonged ischemic insult. We hypothesized that IPC of the spinal cord would reduce neurologic injury after experimental aortic occlusion in rats and that this improved neurologic benefit could be induced acutely after a short reperfusion interval separating the IPC and the ischemic insult. METHODS: Forty male Sprague-Dawley rats under general anesthesia were randomly assigned to one of two groups. The IPC group (n = 20) had 3 minutes of aortic occlusion to induce spinal cord ischemia 30 minutes of reperfusion, and 12 minutes of ischemia, whereas the controls (n = 20) had only 12 minutes of ischemia. Neurologic function was evaluated 24 and 48 hours later. Some animals from these groups were perfusion-fixed for hematoxylin and eosin staining of the spinal cord for histologic evaluation. RESULTS: Survival was significantly better at 48 hours in the IPC group. Sensory and motor neurologic function were significantly different between groups at 24 and 48 hours. Histologic evaluation at 48 hours showed severe neurologic damage in rats with poor neurologic test scores. CONCLUSIONS: Ischemic preconditioning reduces neurologic injury and improves survival in a rat model of spinal cord ischemia. The protective benefit of IPC is acutely invoked after a 30-minute reperfusion interval between the preconditioning and the ischemic event.     

Changes in Cerebrospinal Fluid Pressure and Lactate Concentrations during Thoracoabdominal Aortic Aneurysm Surgery

Background: Although ischemic injury to the spinal cord is a well-known complication of aortic surgery, no metabolic markers have been identified as predictors of an adverse outcome. This study evaluated the effect of cerebrospinal fluid (CSF) drainage, with and without distal femoral perfusion or moderate hypothermia on blood and CSF lactate concentrations and CSF pressure during thoracoabdominal aortic aneurysm surgery.

Methods: Three nonconcurrent groups of patients were studied prospectively: patients with normal body temperature (35 degrees Celsius) but without distal femoral bypass (n = 6), patients with normal body temperature with bypass (n = 7), and patients with hypothermia (30 degrees Celsius) and bypass (n = 8). In all patients, CSF pressure was recorded before, during, and after aortic cross-clamping. During the surgical repair, CSF drainage was performed using a 4-Fr intrathecal silicone catheter. Blood and CSF lactate concentrations were measured throughout the operation.

Results: Significant increases in blood (490%) and CSF (173%) lactate concentrations were observed during and after thoracic aortic occlusion in patients with normothermia and no bypass (P < 0.02 and 0.05, respectively). Distal perfusion attenuated the increase in both blood and CSF lactate (P < 0.01), and a further reduction was achieved with hypothermia of 30 degrees Celsius (P < 0.001). Patients who became paraplegic showed a greater increase in CSF lactate concentrations after aortic clamp release compared with those who suffered no neurological damage (275% vs. 123% of baseline; P < 0.05). Increased CSF pressure of 42-60% (P < 0.005) was noted soon after thoracic aortic occlusion, both with and without distal femoral bypass.     

Neuraxial morphine may trigger transient motor dysfunction after a noninjurious interval of spinal cord ischemia: a clinical and experimental study

BACKGROUND: A patient underwent repair of a thoracoabdominal aortic aneurysm. Epidural morphine, 4 mg, was given for pain relief. After anesthesia, the patient displayed lower extremity paraparesis. This effect was reversed by naloxone. The authors sought to confirm these observations using a rat spinal ischemia model to define the effects of intrathecal morphine administered at various times after reflow on behavior and spinal histopathology. METHODS: Spinal cord ischemia was induced for 6 min using an intraaortic balloon. Morphine or saline, 30 microg, was injected intrathecally at 0.5, 2, or 24 h after reflow. In a separate group, spinal cord temperature was decreased to 27 degrees C before ischemia. After ischemia, recovery of motor function was assessed periodically using the motor deficit index (0 = complete recovery; 6 = complete paraplegia). RESULTS: After ischemia, all rats showed near-complete recovery of function by 4-6 h. Intrathecal injection of morphine at 0.5 or 2 h of reflow (but not at 24 h) but not saline caused a development of hind limb dysfunction and lasted for 4.5 h (motor deficit index score = 4-6). This effect was reversed by intrathecal naloxone (30 microg). Intrathecal morphine administered after hypothermic ischemia was without effect. Histopathological analysis in animals that received intrathecal morphine at 0.5 or 2 h after ischemia (but not at 24 h) revealed dark-staining alpha motoneurons and interneurons. Intrathecal saline or spinal hypothermia plus morphine was without effect. CONCLUSIONS: These data indicate that during the immediate reflow following a noninjurious interval of spinal ischemia, intrathecal morphine potentiates motor dysfunction. Reversal by naloxone suggests that this effect results from an opioid receptor-mediated potentiation of a transient block of inhibitory neurons initiated by spinal ischemia.     

Neuroprotective effect of N-acetylcysteine and hypothermia on the spinal cord ischemia-reperfusion injury

The purpose of this study was to investigate the effect of N-acetylcysteine (NAC) on spinal cord ischemia-reperfusion (I-R) in rabbits. Thirty rabbits were divided into five equal groups, group I (sham-operated, no I-R), group II (control, only I-R), group III (I-R+NAC), group IV (I-R+hypothermia), group V (I-R+NAC+hypothermia). Spinal cord ischemia was induced by clamping the aorta both below the left renal artery and above the aortic bifurcation. Forty-eight hours postoperatively, the motor function of the lower limbs was evaluated in each animal according to Tarlov Score. Spinal cord samples were taken to evaluate the histopathological changes. The sham-operated rabbits (group I) showed no neurologic deficit (Score=4). Paraplegia (Score=0) developed in all rabbits in the control group (group II). Administration of 50 mg/kg of NAC (group III) resulted in significant reduction of motor dysfunction (Score=3.1+/-1.3, p=0.002). Application of hypothermia alone (group IV) showed significant recovery of motor functions (Score=3.0+/-1.1, p=0.002), and combination of hypothermia and 50 mg/kg of NAC (group V) showed complete recovery of lower limb motor function (Score=4, p=0.001). Histologic examination of the spinal cord in rabbits with paraplegia revealed several injured neurons. The cords of animals with no motor function deficits showed only minimal cellular infiltrates in the gray matter, and there was good preservation of nerve cells. NAC showed protective effects of the spinal cord. Moderate hypothermia alone also showed protective effects. Combined use of NAC and hypothermia resulted in highly significant recovery of spinal cord function.     

The role of transcranial motor evoked potentials in predicting neurologic and histopathologic outcome after experimental spinal cord ischemia

BACKGROUND: Monitoring of myogenic motor evoked potentials to transcranial stimulation (tcMEPs) is clinically used to assess motor pathway function during aortic and spinal procedures that carry a risk of spinal cord ischemia (SCI). Although tcMEPs presumably detect SCI before irreversible neuronal deficit occurs, and prolonged reduction of tcMEP signals is thought to be associated with impending spinal cord damage, experimental evidence to support this concept has not been provided. In this study, histopathologic and neurologic outcome was examined in a porcine model of SCI after different durations of intraoperative loss of tcMEP signals. METHODS: In 15 ketamine-sufentanil-anesthetized pigs (weight, 35-45 kg) the spinal cord feeding lumbar arteries were exposed. tcMEP were recorded from the upper and lower limbs. Under normothermic conditions, animals were randomly allocated to undergo short-term tcMEP reduction (group A, < 10 min, n = 5) or prolonged tcMEP reduction (group B, 60 min, n = 10), resulting from temporary or permanent clamping of lumbar segmental arteries. Neurologic function was evaluated every 24 h, and infarction volume and the number of eosinophilic neurons and viable motoneurons in the lumbosacral spinal cord was evaluated 72 h after induction of SCI. RESULTS: In all animals except one, segmental artery clamping reduced tcMEP to below 25% of baseline. All but one animal in group A had reduced tcMEP for less than 10 min and had normal motor function and no infarction at 72 h after the initial tcMEP reduction. Seven animals in group B (70%) had reduced tcMEP signals for more than 60 min and were paraplegic with massive spinal cord infarction at 72 h. Two animals (one in both groups) had tcMEP loss for 40 min, with moderate infarction and normal function. In general, histopathologic damage and neurologic dysfunction did not occur when tcMEP amplitude recovered within 10 and 40 min after the initial decline, respectively. CONCLUSION: Prolonged reduction of intraoperative tcMEP amplitude is predictive for postoperative neurologic dysfunction, while recovery of the tcMEP signal within 10 min after the initial decline corresponds with normal histopathology and motor function in this experimental model. This finding confirms that intraoperative tcMEPs have a good prognostic value for neurologic outcome during procedures in which the spinal cord is at risk for ischemia.     

Establishment of a local cooling model against spinal cord ischemia representing prolonged induction of heat shock protein

OBJECTIVES: Paraplegia is one of the serious complications of thoracoabdominal aortic operations. Regional hypothermia protects against spinal cord ischemia although the protective mechanism remains unknown. We attempted to create a simple model of local cooling under transient spinal cord ischemia and evaluated the effect using functional and histologic findings. METHODS: Male domesticated rabbits were divided into 3 groups: control, normothermic group (group N), and local hypothermic group (group H). A balloon catheter was used for spinal cord ischemia by abdominal aortic clamping. A cold pack attached to the lumbar region could lower the regional cord temperature initially. Neurologic function was evaluated by the Johnson score. Cell damage was analyzed by observing motor neurons with the use of hematoxylin and eosin staining, terminal deoxynucleotidyl transferase-mediated deoxy-uracil triphosphate biotin in situ nick end labeling (TUNEL), and immunoreactivity of heat shock protein. RESULTS: Physiologic estimation showed that local hypothermia improved the functional deficits (group N, 1.3 +/- 0.9; group H, 4.9 +/- 0.3; P =.0020). Seven days after reperfusion, there was a significant difference in the motor neuron numbers between groups N and H (group N, 7.2 +/- 1.9; group H, 20.4 +/- 3.2; P =.0090). The number of TUNEL-positive motor neurons was reduced significantly (group N, 7.2 +/- 2.4; group H, 1.0 +/- 0.7; P =.0082). Heat shock protein immunoreactivity was prolonged up to 2 days after reperfusion in the hypothermic group. CONCLUSIONS: These results suggest that local hypothermia extended the production of heat shock protein in spinal cord motor neurons after reperfusion and inhibited their apoptotic change.     

Is intrathecal magnesium sulfate safe and protective against ischemic spinal cord injury in rabbits?

We performed three sets of experiments to investigate the safety of intrathecal magnesium and to determine its optimal dose for protection, if any, against ischemic spinal cord injury in rabbits. First, we examined neurotoxicity of 0.3, 1, 2, or 3 mg/kg of magnesium sulfate (n = 6 each). Significant sensory dysfunction was observed in the 3-mg/kg group 7 days after administration. Motor dysfunction was found in two rabbits in both the 2- and 3-mg/kg groups. The area of destruction in laminae V-VII was observed in one, two, and one rabbit in the 1-, 2-, and 3-mg/kg groups, respectively. Second, we investigated the temporal profile (6 h, 48 h, and 96 h [n = 3 each]) of histopathologic changes after 3 mg/kg of magnesium sulfate and confirmed similar changes in the rabbits with motor dysfunction at 48 and 96 h. Third, we evaluated the effects of 0.3 mg/kg or 1 mg/kg of magnesium sulfate or saline (n = 6 each) administered before ischemia on hindlimb motor function and histopathology after spinal cord ischemia (15 min). Magnesium did not improve neurologic or histopathologic outcome 96 h after reperfusion. The results indicate that intrathecal magnesium has a risk of neurotoxicity and shows no evidence of protective effects against ischemic spinal cord injury.     

Ischemic spinal cord injury induced by aortic cross-clamping: prevention by riluzole.

OBJECTIVE: Recent studies confirmed the deleterious role of glutamate in the pathophysiology of spinal cord ischemia induced by aortic cross-clamping. We investigated the effect of riluzole, an anti-glutamate drug, in a rat model of spinal cord ischemia. MATERIALS AND METHODS: Spinal cord ischemia was induced in normothermia for 14 min in Sprague-Dawley rats using direct aortic arch plus left subclavian artery cross-clamping through a limited thoracotomy. Experimental groups were as follows: sham-operation (n=15), control (n=15) receiving only vehicle, riluzole (n=15) receiving riluzole (4 mg/kg) before clamping and at the onset of reperfusion. Separate animals were used for monitoring physiologic parameters in the sham-operation (n=3), control (n=5), and riluzole (n=5) groups. Neurologic status was assessed at 6, 24 h, and then daily up to 96 h. Rats were randomly killed at 24, 48, or 96 h (n=5 for each time). Spinal cords were harvested for histopathology, immunohistochemistry for microtubule-associated protein 2 (MAP-2), TUNEL staining, and analysis of DNA fragmentation by agarose gel electrophoresis. RESULTS: All sham-operated rats had a normal neurologic outcome, whereas all control rats suffered severe and definitive paraplegia. Riluzole-treated rats had significantly better neurologic function compared to the control. Histopathology disclosed severe neuronal necrosis in the lumbar gray matter of control rats, whereas riluzole-treated rats suffered usually mild to moderate injury. Riluzole particularly prevented motor neurons injury. MAP-2 immunoreactivity was completely lost in control rats, whereas it was preserved either completely or partly in riluzole-treated rats. TUNEL staining revealed numerous apoptotic neurons scattered within the whole gray matter of control rats. Riluzole prevented or dramatically attenuated apoptotic neuronal death in treated rats. DNA extracted from lumbar spinal cords of sham-operated and riluzole-treated rats exhibited no laddering, whereas spinal cords from control rats showed DNA laddering with fragmentation into approximately 180 multiples of base pairs. CONCLUSIONS: Riluzole may protect the spinal cord in a setting of severe ischemia by preventing neuronal necrosis and apoptosis. This drug may therefore be considered for clinical use during 'high risk' surgical procedures on the thoracoabdominal aorta.