Difficulties Associated with Study Design

The difficulties in designing a prospective, randomized, clinical trial are many. Owing to statistical power, the study would need to be multicenter to generate adequate numbers of participants. Some of these patients would be transferred from other institutions to level 1 or appropriate trauma centers. Patients may or may not be given pharmacologic interventions such as the methylprednisolone protocol. They may already be 6 to 8 hours out from their time of injury when they arrive at the designated study institutions. The medical stability of acute SCI patients and their associated injuries, such as head trauma, blunt chest and/or abdominal trauma, and other orthopedic injuries necessitate a multidisciplinary approach. The coordination and orchestration of care of the polytrauma patient may delay the radiographic workup (CT and/or MRI) for SCI. Hypotension, surgery for other life-threatening injuries, and treatment of closed head injuries may further delay surgical intervention.

Basically, every SCI is unique. Controlling for age, sex, level, mechanism of injury, severity of injury, and extent of injury necessitates enrolling patients at different points in their disease.

Confounding the difficulty with study design are the real-life variables of ethics of randomization, potential for litigation, financial impact of both the injury and hospitalization, and the psychological devastation of the SCI itself.

Animal Studies in Timing of Surgery for Spinal Cord Injury

Animal studies have been easier to design and complete than have human studies. Multiple animal studies have shown the benefit of early surgical decompression. Typically, the studies have been performed with extradural balloon, static weight, clip, piston impactor, or circumferential cable models of SCI. The laboratory studies in various animal models have shown that neurologic recovery is improved by early decompression.

Carlson et al. studied 16 dogs undergoing a sustained spinal cord compression for 30 or 180 minutes using a hydraulic piston.³ Somatosensory-evoked potentials were monitored during a 60-minute recovery period and at 28 days after injury. Functional motor recovery was assessed at 26 days. MRI imaging and histologic analysis were performed to assess the volume of the lesion and tissue damage. Improved motor function and balance were noted in the 30-minute group compared to the 180-minute group. The longer duration of compression produced spinal cord lesions of greater volume, which corresponded to poorer long-term functional outcomes.

Dimar et al. studied the influence of spinal canal narrowing and timing of decompression on neurologic recovery after spinal cord contusion using a spacer model of injury in 40 adult rats.⁴ The results of this study concluded that there was strong evidence that the prognosis for neurologic recovery was adversely affected by both a higher percentage of canal narrowing and a longer duration of canal narrowing after an SCI. Dimar et al. concluded that the tolerance for spinal canal narrowing with a contused cord appears diminished, indicating that an injured spinal cord may benefit from early decompression. They also demonstrated that the longer the spinal cord compression exists after an incomplete cord injury, the worse the prognosis for neurologic recovery.

Carlson et al. also studied the early time-dependent decompression for SCI in 21 beagles and proposed vascular mechanisms of recovery.⁵ His results indicated that after precise dynamic spinal cord loading to a point of functional conduction deficit (50% decline in evoked potential amplitude), a critical time period exists during which intervention in the form of early spinal cord decompression can lead to effective recovery of electrophysiologic function in the 1- to 3-hour postdecompression period.

Delamarter et al. also studied spinal cord recovery after immediate and delayed decompression in dogs.⁶ They studied 30 dogs with a cable constriction SCI model with periods of compression ranging from 1 hour up to 1 week. Somatosensory evoked potentials, neurologic examination, and histologic and electron microscopy studies were performed. All dogs were paraplegic after the compression of the cord, but the dogs that underwent immediate decompression or decompression within 1 hour of compression recovered the ability to walk as well as bowel and bladder control and had improvement in somatosensory evoked potentials. When compression lasted 6 hours or more, there was no neurologic recovery, and progressive necrosis of the spinal cord was observed. Somatosensory evoked potential recovery by 6 weeks after the decompression was significantly related to the duration of the compression.

Delamarter et al. concluded that longer periods of displacement allowed propagation of the chronic axonal response, resulting in lack of recovery of somatosensory evoked potentials, limited functional recovery, and more extensive tissue damage.⁶

Multiple other animal models of SCI have shown the positive effect of early decompressive surgery to improve neurologic recovery.^7–10

Human Studies on Timing of Surgery for Spinal Cord Injury

Retrospective human studies have failed to provide convincing data to support the possibility that the neurologic outcome of early spinal surgery is superior to that of delayed spinal surgery. What has been shown is that earlier surgery can be done more safely than was previously thought. A paper in 1987 by Marshall et al. showed deterioration following SCI in 4.9% of 283 SCI patients in this prospective multicenter study.¹¹ They concluded that early surgery on the cervical spine when cord injury is present appears hazardous. No deteriorations were observed following surgery after the sixth day.

Multiple papers have since been published demonstrating that early spine surgery can be done safely. Mirza et al. studied the changes in neurologic status, length of hospitalization, and acute complications associated with surgery within 3 days of injury versus more than 3 days after the injury.¹² Forty-three patients were followed. Surgery within 72 hours of injury in patients with acute cervical cord injuries was found not to have a higher complication rate. Numbers were too small to conclude that there was definite neurologic improvement in the acute surgery group in comparison to the delayed surgery group, but trends indicated that early surgery may be beneficial. Decreased hospitalizations were observed in the early surgery group. The duration of stay in the ICU and on mechanical ventilation was not statistically different between the two groups. The neurologic status was maintained, and the change in Frankel grade from the preoperative level to the postoperative level was statistically significant in the groups of patients who underwent early surgery (P = .0026) but not in the group of patients who underwent late surgery (P = .30).

Croce et al. also studied early surgery (within 3 days) versus late surgery (after 3 days) in a mix of cervical (163: 83 early, 80 late), thoracic (79: 30 early, 49 late), and lumbar (49: 29 early, 20 late) fractures.¹³ Of the 291 patients, there were no differences in injury severity between the early and late groups for each fracture site. What was identified was that the thoracic fracture group showed that early fixation was associated with a lower incidence of pneumonia, a shorter ICU stay, a decreased number of days on a ventilator, and lower charges. Overall, high-risk patients were found to have had lower pneumonia rates and less hospital resource utilization with early fixation. The neurologic status was not an outcome variable in this study; however, the researchers concluded that early fixation resulted in significant resource reductions for patients with neurologic deficits. They concluded that early fixation resulted in a better outcome (not neurologic outcome) and less resource utilization regardless of neurologic deficit.

A retrospective study by Schlegel et al. of 138 patients with acute spine injuries also addressed the issue of timing of surgery.¹⁴ They found no statistically significant difference in the incidence of medical complications in patients with injury severity scores (ISSs) of less than 15 who were operated on within 72 hours or after 72 hours of injury. A separate group of patients with cervical spine injuries with neurologic deficit was analyzed, and it was determined that irrespective of associated injuries, all had fewer complications if they underwent surgery within 72 hours. Morbidity was found to be higher in the neurologic deficit group compared to the neurologically intact group. This study concluded that surgical decompression, reduction, and/or fixation of spine fractures within the first 72 hours are indicated in multiple trauma patients (ISS ≥18) and cervical injuries with neurologic deficits.

A retrospective study by Chipman et al. looked at early surgery for thoracolumbar spine injuries.¹⁵ One-hundred forty-six patients were identified (58 with ISS <15, 88 with ISS ≥15). Early surgery was determined to be within 72 hours or less, and late surgery was more than 72 hours following injury. Chipman was able to conclude that early surgery in severely injured patients with thoracolumbar spine trauma was associated with fewer complications and shorter hospital and ICU lengths of stay, required less ventilator support for noninfectious reasons, and did not increase neurologic deficits.

Schinkel et al. analyzed the German National Trauma Database (N = 8057).¹⁶ Clinical parameters and outcomes of patients with severe thoracic spine injuries (N = 298) were compared to patients undergoing early (<72 hours) versus late (>72 hours) spine stabilization. They were able to show further evidence that early stabilization of thoracic spine injuries in trauma patients reduces overall hospital and ICU stays and improves outcome. The outcome was, overall, not specific for neurologic function.