Table 1.

Summary of the Characteristics and Results of the Pre-Clinical Studies on Timing of Surgical Decompression after Spinal Cord Injury

References	Sample features	Outcome measures	Injury model	Timing of decompression	Study conclusions
Brodkey et al. (1972)	• N = 5 • Cats • Weight: 2–4.5 kg • Level: low thoracic level	Mean arterial blood pressure, and CEP. No statistical analysis.	A weight-holding apparatus was positioned so that a predetermined weight would be delivered over the entire dorsal surface of the cord and intact dura.	Time since spinal cord compression and/or aortic clamping to CEP effects.	• In two experiments after the CEP had disappeared due to the combined influence of both the weight on the cord and blood pressure reduction, the weight was removed leaving the blood pressure low. • The CEP recordings in each animal returned within 5 min only to disappear again. On one occasion it disappeared 15 min later and on the other occasion 5 min later. • When the blood pressure finally rose to normal levels the CEP promptly returned and did not again disappear when the blood pressure subsequently dropped after about 30 min of normotension.
Croft et al. (1972)	• N = 15 • Cats • Weight: 2–4.5 kg • Level: T9–10	SSEP and behavioral assessment. No statistical analysis.	A weight holding apparatus delivered a predetermined amount of weight over the entire dorsal surface of the cord and intact dura.	18 g for 20 min; 28 g for 20 min; 38 g for 5 min; 38 g for 15 min; 38 g for 20 min; 48 g for 20 min; 58 g for 20 min	◦ Graded pressure (38 g for 5–20 min and 48 g for 20 min) on the spinal cord produced reversible blocking of SSEP. ◦ With this type of trauma, block of motor transmission through the cord paralleled the block of sensory transmission, and each seemed to be a sensitive indicator of spinal cord function. ◦ While a compression of 58 g for 20 min produced a profound clinical deficit, 48 g for 20 min produced a severe deficit with early signs of recovery, and 38 g for 20 min produced little clinical deficit.
Thienprasit et al. (1975)	• N = 28 • Cats • Weight: 2–5 kg • Level: 6 cm cranial from L2	CER at 5 min, 1 h, 3 h, and 6 h, and behavioral test (5-grade assessment). Statistical analysis was done, but the test used was not specified.	A Fogarty catheter (French n. 3) was passed through a L2 laminectomy extradurally in the cephalic direction for 6 cm. Then, its balloon was instantaneously inflated with 0.6–0.9 cm3 of air and immediately deflated.	Animals were divided into three groups: (i) no treatment after SCI; (ii) 2–4 level laminectomy at 6 h after SCI; and (iii) 2–4 level laminectomy at 6 h after SCI associated with cooling (saline at 15 ± 2°C) of spinal cord for 2 h.	• Animals were divided according to their CER. Group 1 included animals whose CER did not reappear until 6 h after SCI. Group 2 included animals whose CER disappeared at time of SCI but reappeared within 6 h. • Animals in the Group 1 did not recover the ability to walk. • There was no difference between the animals in the Group 1 that were treated with laminectomy and untreated animals in the Group 1 (p = 0.4). • In the Group 1, the animals treated with laminectomy and cooling significantly differed from the untreated animals (p < 0.01). • In the Group 2, animals had significant neurological recovery regardless of type of treatment. All animals were able to regain the ability to walk. • In the Group 2, there was no difference between the animals that were treated with laminectomy and cooling and untreated animals (p = 0.4).
Kobrine et al. (1978)	• N = 10 • Monkeys (macaque) • Weight: 3–4.5 kg • Level: T6	SER, blood flow, and adverse effects. No statistical analysis.	Spinal cord compression using Fogarty catheter in the epidural space lateral to the spinal cord on the right side.	Pumped infusion of 0.15–0.2 mL into the balloon in 1 h followed by immediate deflation of the balloon.	• SERs did not disappear until the blood flow in the compressed segment was zero. • In seven animals a post-ischemic hyperemia occurred. • Results suggested that mechanical forces of compression, rather than ischemia are mainly responsible for the loss of neural conduction in such a model.
Kobrine et al. (1979)	• N = 18 • Monkeys (macaque) • Weight = 3–4.5 kg • Level: T6	Spinal cord blood flow and SER. No statistical analysis.	Spinal cord compression using Fogarty catheter (French n. 3) in the epidural space lateral to the spinal cord on the right side.	The balloon was acutely inflated by hand to a volume of 0.25 cm3 and kept inflated for periods of 1, 3, 5, 7, or 15 min followed by immediate deflation of the balloon.	◦ The SER disappeared immediately in all groups upon acute balloon compression. ◦ Animals with compression for 3, 5, 7, and 15 min failed to demonstrate any return of SER during the 1-hour period following deflation. ◦ All animals in the 1-min compression group exhibited return of the SER by 1 h. ◦ The spinal cord blood flow in all animals was either normal or hyperemic by 5 min after deflation and remained so for the remainder of the experiment. ◦ No case of post-compression ischemia was demonstrated. ◦ No-reflow phenomenon was not demonstrated in any groups.
Bohlman et al. (1979)	• N = 14 • Dogs (purebred beagle hounds) • Sex: female • Weight: 14 kg • Level: C5–6	Behavioral test (climbing a 20° inclined plane and modified Tarlov grading), CEP, and histopathological examination. No statistical analysis.	• Compression model using a transducer. • Contusion model used Allen weight-drop device that produces 257–722 g-cm of energy on the spinal cord	In the compression group, pressure was maintained at a constant level for 4–8 weeks until neurologic recovery no longer occurred. If the animal had ceased to recover neurologic function at the 4-week post-operative interval, the transducer was retracted or removed and all subsequent recovery was observed and recorded (4–8 weeks).	◦ Central cord paralysis was noted in seven and anterior cord syndrome in one. ◦ The onset of paralysis was observed within 12–72 h of application of anterior cord pressure. ◦ Significant motor recovery occurred in all eight animals to some degree within 48 h after removing pressure from the spinal cord. ◦ All eight animals were able to walk a plane inclined up to 20°. ◦ Of the eight pressure-induced SCIs that recovered, microscopic examination was normal in two, central gray necrosis occurred in two, peripheral demyelinization in two, and lacerations occurred in three. ◦ Time from initial paralysis to recovery of grade 5 ranged from 2 days to 6 weeks. ◦ Pathological findings: mild anterior horn gray matter necrosis in two, laceration of the ventral white and gray matter in three, and no microscopic evidence of cord damage in one, even though significant paralysis occurred. ◦ In general, the cord conduction is abolished with severe injury and if electrical conduction does not return within hours, severe damage has occurred and the animal does not recover neurologic function. ◦ The CEP is also chronologically related to progression of the SCI. ◦ Improvement in neurologic function after injury was reflected by improvement in the CEP response. In this study the CEP response closely paralleled the degree of initial SCI either from contusion or compression as well as the neurologic recovery of the animals.
Dolan et al. (1980)	• N = 91 • Rats (white Wistar) • Sex: female • Weight: 280–300 g • Level: T1	Inclined plane test. Nonlinear regression analysis.	Spinal cord clip compression as developed by Rivlin and Tator (1978).	Laminectomy without SCI (myelectomy group). Ten rats received no anesthetic but had no surgery (control group). The other animals had compression of 16, 71, or 178 g for 3, 30, 60, 300, or 900 sec.	• In each group there was very little change in the angle achieved on the inclined plane from week to week. • The overall mean over the 8-week period for the control group was 81.4° and for the myelectomy group was 23°. • Functional recovery decreased as the duration of compression increased. • Functional recovery decreased as the force of compression increased. • Mathematical modeling produced a curve defining the relationship between force, duration, and functional recovery for each week after injury.
Aki and Toya (1984)	• N = 33 • Dogs • Level: thoracolumbar	SEP, blood flow, and histopathological examination. No statistical analysis.	Spinal cord device that delivers compressions at an area of 3.5 × 5 mm with weights of 6, 16, 36, and 60 g.	Spinal cord of dogs was compressed for periods of 30 or 60 min followed by removal of compression.	◦ With increasing compressive weights (6–60 g), SEP amplitudes were progressively more reduced and latencies more prolonged. ◦ Following release of compression, amplitudes and latencies recovered at the lower weights but were more likely to reflect greater conduction deficits with progressively greater weights. ◦ Amplitudes before compression ranged from 3.1 to 36 μV and latencies ranged from 5.0 to 6.5 msec. ◦ Poor arterial and venous filing was observed for 36- and 60-g weights but not for 6- and 16-g weights. ◦ No significant differences between 30 and 60 min of compression were observed with regard to circulatory disturbances. ◦ Pathologic findings: hemorrhage and necrosis were not found in the gray and white matter in the groups weighted with 6 and 16 g, whereas small petchial hemorrhages and tissue necrosis were observed in the center of the gray matter in the groups weighted with 36 and 60 g. ◦ However there were no distinct findings in the white matter with these higher weights.
Guha et al. (1987)	• N = 75 • Rats (Wistar) • Sex: female • Weight: 240–280 g. • Level: C7–T1	Inclined plane test. Univariate analysis, multiple comparisons using Student–Newman–Keuls test.	Spinal cord clip compression as developed by Rivlin and Tator (1978).	Animals had clip compression of 2.3, 16.9, or 53 g for 15, 60, 120, or 240 min in a 3 × 4 factorial design study.	◦ The major determinant of recovery was the intensity of compression applied to the spinal cord. ◦ The time until decompression also affected recovery, but only for the lighter compression forces (2.3 and 16.9 g).
Nystrom and Berglund (1988)	• N = 81 • Rats (Sprague-Dawley) • Sex: males • Weight: 231–319 g • Level: T7–8	Inclined plane test. Student's t test.	Thoracic spinal cord compression was created by loading a 2.2 × 5.0 mm plate with weights of 20, 35, or 50 g.	Three different weights were applied for 1, 5, and 10 min. For ethical reasons 50 g was not paired with 10 min.	• The 10-min compression rats were able to fully recover after 20 g compression, but not after 35 or 50 g during the first 21 days after SCI. • At 20 g, the duration of compression did not affect the animals' ability to recover completely. • During the initial 4–5 days, the 1-min compression group differed from the groups subjected to compression for 5 and 10 min (p < 0.01). • At 35 g, the 5-min compression group had more severe deterioration than the 1-min group, but animals were able to completely recover. • At 35 g, the 10-min compression group showed the same neurological deterioration as the 5-min compression group during the first 2 days, but the recovery was slower and incomplete in the 10-min group. • At 50 g, 1- and 5-min compression groups showed capacity angle values of about 22°, but recovery was slow and incomplete. Of note, control animals showed a mean capacity angle of 65.2 ± 0.6°.
Delamarter et al. (1991)	• N = 30 • Dogs (pure bred beagle hounds) • Sex: females • Weight: 10–12 kg • Level: cauda equina	Tarlov test, SSEP, and histopathological examination. Paired t test and ANOVA.	The entire caudal equina was constricted circumferentially with a nylon electrical cable, 2.8 mm wide.	Dogs in Group 1 were constricted and immediately decompressed (compression for 2–3 sec). The other groups of dogs had compression times of 1 h, 6 h, 24 h, and 1 week.	• All 30 dogs developed caudal equina syndrome after constriction. • All dogs recovered significant motor function 6 weeks after decompression. • All groups recovered to walking (Tarlov Grade 5) with bladder and tail control at 6 weeks after SCI. • Immediately after compression, all five groups demonstrated >50% deterioration of the posterior tibial nerve SSEP amplitudes. At 6 weeks after decompression, all five groups had a mean amplitude recovery of 20–30%. There was no difference in recovery of SSEPs among the groups. • All groups demonstrated scattered wallerian degeneration and axonal regeneration. There were no significant differences in the histological findings among the five groups.
Zhang et al. (1993)	• N = ? • Rats (Sprague-Dawley) • Weight: 350–450 g • Level: T7–8	Concentration of lactate, inosine, and hypo-xanthine, and an increase in the actate/pyruvate ratio in the extra-cellular fluid of the gray matter of the dorsal horn. One-way ANOVA and Tukey's test.	Spinal cord compression device that applied 9, 35, or 50 g over exposed spinal cord.	Group 1 included laminectomized animals (control). Group 2 included compression of 9 g for 5 min. Group 3 included compression of 35 g for 5 min. Group 4 had a compression of 50 g for 5 min.	• In Groups 2 and 3, lactate levels increased 6 to 7 times the basal levels in the first fraction. Group 2 levels normalized within about 30 min, while Group 3 levels were a lot slower in recovering. • Group 4 lactate levels increased 10-fold in the second fraction. Only partial recovery was seen in the 2-h period. • No significant change in pyruvate levels was seen in any of the groups. • Inosine levels rose 0.7–0.9 μM in Groups 2 and 3 and 1.4 μM in Group 4. • Inosine recovery was faster than lactate with the Group 4 recovering completely in about 40 min. • Recovery of hypozanthine was more delayed compared to other metabolites. Complete recovery took almost 80 min.
Delamarter et al. (1995)	• N = 30 • Dogs (pure bred beagle hounds) • Sex: female • Weight: 10–12 kg • Level: L4	SSEP, Tarlov test, histopathological examination, and electronic microscopy. Paired t test and ANOVA.	The caudal part of the spinal cord and dura was constricted circumferentially with a nylon electrical cable, 2.8 mm wide, to 50% of the diameter of the spinal canal.	Dogs in Group 1 were constricted and immediately decompressed (compression for 2–3 s). The other dogs were compressed for 1 h (Group 2), 6 h (Group 3), 24 h (Group 4), and 1 week (Group 5).	• The dogs with immediate decompression generally recovered neurological function within 2–5 days. • They recovered to walking by 1 week and Tarlov Grade 5 with bladder and tail control at 6 weeks after SCI. • Significant SSEP and motor recovery was observed among animals in Groups 1 and 2. • However, animals that were compressed for 6 h or more showed no significant motor recovery after decompression of spinal cord. • SSEP improved an average of 85% in Group 1, 72% in Group 2, 29% in Group 3, 26% in Group 4, and 10% in Group 5 (p < 0.0008). • Discrete areas of wallerian degeneration and demyelination were seen in the spinal cord of animals in Groups 1 and 2. In contrast, there was severe central necrosis in the spinal cord of animals that were decompressed at 6 h or later.
Carlson et al. (1997a)	• N = 21 • Dogs (beagles) • Weight: 11–14 kg • Level: T13	SEP, blood flow, and reperfusion flow. ANOVA and paired t tests	Dynamic cord compression was initiated through the loading device pre-calibrated to displace the spinal cord at a constant 0.17 mm/min.	Piston displacement was halted stopping dynamic compression when lower extremity SEP amplitudes were reduced by 50% of baseline (to). At this endpoint spinal cord displacement was maintained for 30 min (n = 7), 60 min (n = 8), or 180 min (n = 6).	• SEP recovery was seen in six of seven dogs in the 30-min group, five of eight dogs in the 60-min group, and zero of six dogs in the 180-min compression group. • Recovery in the 30-min and 60-min compression groups was significantly different from the 180-min compression group (p < 0.05). • Regional spinal cord blood flow at baseline, 21.4 ± 2.2 mL/100 g/min decreased to 4.1 ± 0.7 mL/100 g/min after stopping dynamic compression. • Reperfusion flows after decompression was inversely related to duration of compression. • Of the dogs in 30-min compression group, 5 min after decompression the blood flow was greater than 2 times baseline. • However, the early post-decompression blood flow was not significantly different from baseline in the 180-min compression group. • Of the eight dogs in the 60-min compression group, five that recovered SEP conduction revealed a lower spinal cord blood flow sampled immediately after stopping dynamic compression, compared to the three that did not recover (p < 0.05). • Reperfusion flows measured as the interval change in blood flow between the time dynamic compression was stopped to 5, 15, or 180 min after decompression, were significantly greater in those dogs that recovered SEP (p < 0.05). • 3 h after decompression, spinal cord blood flow in the three dogs in the 60-min compression group with no recovery was significantly less than the spinal cord blood flow of the recovered group. • Spinal cord decompression within 1 h of SEP loss resulted in significant electrophysiological recovery after 3 h of monitoring.
Carlson et al. (1997b)	• N = 12 • Dogs (beagles) • Weight: 10–12 kg • Level: T13	SSEP and regional spinal cord blood flow. Paired t test.	Constant velocity spinal cord compression was applied using a hydraulic loading piston with a subminiature pressure transducer rigidly attached to the spinal column. Spinal cord displacement was stopped when SSEP amplitudes, decreased by 50% (maximum compression).	Six animals were decompressed 5 min after maximum compression and were compared with six animals that had spinal cord displacement maintained for 3 h and were not decompressed.	• At maximum compression, regional spinal cord blood flow at the injury site fell from 19.0 ± 1.3 to 12.6 ± 1.0 mL/100 g/min, whereas piston-spinal cord interface pressure was 30.5 ± 1.8 kPa, and cord displacement measured 2.1 ± 0.1 mm. • 5 min after the piston translation was stopped the spinal cord interface pressure had dissipated 51%, whereas the SSEP amplitudes continued to decrease to 16% of baseline. • In the sustained compression group, cord interface pressure relaxed to 13% of maximum within 90 min. However, no recovery of SSEP occurred and blood flow remained significantly lower than baseline at 30 and 180 min after maximum compression. • In the six animals that underwent spinal cord decompression, SSEP and blood flow recovered to baseline 30 min after maximum compression. • Despite rapid cord relaxation of more than 50% within 5 min after maximum compression, SSEP recovered with early decompression. • Spinal cord decompression was associated with an early recovery of blood flow and SSEP recovery. • By 3 h, blood flow was similar in both the compressed and decompressed groups, even though SSEP recovery occurred only in the decompressed group.
Dimar et al. (1999)	• N = 42 • Rats (Sprague Dawley) • Age: 12 weeks • Weight: 298.7 g • Level: T9	tcMMEPs, BBB, and histopathological examination. Wilcoxon signed rank test, and ANCOVA.	A 12.5 g-cm spinal cord contusion was produced using an impactor (developed at New York University).	Rats were divided into five groups based on duration of spinal cord compression: 0 (the spacer was placed into the canal and immediately removed), 2, 6, 24, and 72 h.	• Shorter duration of spacer placement was associated with greater BBB scores over the 6-week recovery period (p < 0.05). • Statistical difference was found in the tcMMEPs response rates in the groups with 0-h and 2-h compression in comparison with the other groups (p < 0.05). There were no significant differences among the 6-, 24-, and 72-hour groups. • There was a progressively more severe central and dorsal cavitation as the time of spinal cord compression increased. • Midsagittal sections demonstrated progressive cephalad and caudal cord necrosis and cavitation, which worsened the longer the duration of compression. These changes were most severe in the 24- and 72-h specimens.
Carlson et al. (2003)	• N = 16 • Dogs (beagles) • Weight: 11–15 kg • Level: T13	SSEP, Tarlov motor test, balance test, stair-climbing test, inclined-plane test, and lesion volume (examined using MRI and histology). ANOVA, Mann–Whitney rank sum test, Friedman repeated measures ANOVA.	The spinal cord was compressed using a loading device with a hydraulic piston. A dynamic compression with a loading device precalibrated at a constant 0.17 mm/min.	When SSEP declined by 50%, dynamic compression loading was no longer increased but was sustained for 30 min in 8 dogs and for 180 min in 8 dogs. After designated time, the compression was discontinued.	• After decompression, SSEP returned in all dogs in the 30-min compression group, with recovery to 63% of the baseline value at 90 min after decompression. • At 28 days after the injury, the mean amplitude of the SSEP was 38% of the baseline in the 30-min compression group. • In contrast, in the 180-min compression group, decompression did not result in recovery of SSEP either early or late. • The mean modified Tarlov motor scores were significantly better for the 30-min compression group than for the 180-min compression group at all time points. • At 2 weeks after SCI the 30-min compression group did better than the 180-min compression group in balance (p < 0.01), cadence (p < 0.001), stair climbing (p < 0.01), and ability to walk up an inclined plane. • Lesion volumes as assessed using MRI were smaller in the 30-min compression group than the 180-min compression group (p = 0.04). • The 30-min compression group showed smaller lesion volume (p < 0.001) and greater percentage of residual white matter (p = 0.005) than the 180-min compression group.
Hejcl et al. (2008)	• N = 23 • Rats (Wistar) • Weight: 300–350 g • Age: 8 weeks • Sex: male • Level: T9	BBB scores, MRI, histopathological examination. Student's unpaired t test	Spinal cord transection	In 10 animals the dura was only sutured (Control). In seven animals a block of HEMA-MOETACl hydrogel was inserted right away after SCI (acute group). In six animals the block of hydrogel was implanted 1 week after SCI (delayed group).	• Both the early and delayed implantation group showed good hydrogel integration inside the lesion. • The control group differed significantly in the volume of pseudocyst compared to the acute (p < 0.001) and delayed (p < 0.05). • There was no significant difference in histopathological examination of spinal cord between the acute and delayed implantation groups. • There were no significant differences between the two treatment groups with regard to the BBB scores.
Rabinowitz et al. (2008)	• N = 18 • Dogs (beagle) • Adult (10–12 kg) • Sex: male • Level: L4 (thoracolumbar junction)	Modified Tarlov grading system, SSEPs, histopathology, exact Wilcoxon's rank sum tests—ordinal variables, Fisher exact test—nominal variables, Kruskal–Wallis tests—difference in medians for continuous non-Gaussian variables, Bonferroni adjustment for multiple comparisons.	Dura at the thoracolumbar junction was constricted circumferentially with a nylon band, 2.8 mm wide, to 60% of the diameter of the spinal canal.	Group 1: decompression at 6 h + methylprednisolone; Group 2: decompression at 6 h + sham; Group 3: methylprednisolone only.	◦ All animals were paraplegic (Tarlov Grade 1) after spinal cord compression. ◦ All animals lost SSEPs after spinal cord compression. ◦ Decompression within 6 h (Groups 1 and 2) showed significant neurological improvement when compared to no decompression (Group 3). ◦ Methylprednisolone did not significantly affect outcome. ◦ Groups 1 and 2 regained SSEPs at 2 weeks to 69% and 52%, respectively; in Group 3 only one animal regained SSEPs to 25%. None of these comparisons were statistically significant. ◦ There was no statistical difference in the percentage of cord involvement histologically between the three groups; Group 3 showed greater involvement below the level of the lesion.

SCI, spinal cord injury; CEP, cortical evoked potentials; SSEP, somatosensory evoked potentials; CER, cortical evoked response; SEP, spinal-evoked potentials; tcMMEPs, transcranial magnetic motor evoked potentials; ANOVA, Analysis of Variance; ANCOVA, Analysis of covariance; BBB, Basso, Beattie, Bresnahan Locomotor Rating Scale; MRI, magnetic resonance imaging; SER, spinal evoked response.