Laurance Johnston, Ph.D.

In a 2007 season-opening game, American football player Kevin Everett sustained a cervical C3-4 injury from tackling an opponent. While still in the ambulance, an ice-cold saline solution was injected into Everett putting him into a neuroprotective, hypothermic state and, later in the hospital, was systemically cooled for several days through a cooling catheter inserted in the femoral vein (see later discussion). In addition to this cooling, Everett was treated 15 minutes post injury with the commonly used drug methylprednisolone and had spinal decompressive surgery within seven hours of injury.  Although initially classified as having an ASIA-A motor and sensory complete injury, he  soon regained significant function, eventually transitioning to an ASIA-D incomplete injury classification with the ability to walk and normal bowel, bladder, and sexual functioning. Given the various interventions, the degree to which his recovery can be attributed to the cooling can not be determined.

As reviewed in a number of articles listed in the bibliography, studies dating back to the 1950s suggest that lowering central-nervous-system temperature can mitigate the harmful effects caused by restricted blood flow (ischemia) and associated oxygen deficiency (hypoxia) during operations that disrupt blood flow to the brain or spinal cord. Based on these observations and animal studies, cooling or hypothermic procedures were developed to preserve neurological function after spinal-cord trauma.

Such procedures supposedly protect the injured spinal cord by reducing the cord’s metabolic and energetic requirements after injury. So to speak, it is like putting the injured neurons on life support until they have a chance to recover. The cooled, spinal-cord tissue doesn’t need as much viable cellular processes to keep functioning and, as such, may survive longer after injury. Similar to an ice-pack placed on a sprain, the cooling reduces neuron-damaging swelling and bleeding at the injury site. The sometimes-used irrigating cooling solutions may also wash out harmful toxins that accumulate after injury and that promote secondary tissue damage.

Although studies cumulatively suggest that benefits may accrue, care must be taken in over-generalizing results because the studies 1) involved limited number of cases, 2) included no controls, 3) reported only generalized improvement during a post-injury phase in which some improvement is not unusual, 4) varied considerably in the time lapsing from injury when spinal-cord cooling was started, 5) were potentially confounded by the use of other drugs, and 6) weren’t always limited to cases with traumatic SCI.

Most of the human clinical experience using hypothermic procedures was acquired in the 1960-70s. By the 1980s, enthusiasm “cooled off” because of ambiguous results, technical complexity, and the decreased use of emergency laminectomy in acutely injured patients, which was needed to expose the cord to cooling. [A decompressive laminectomy is a surgical procedure in which various function-compromising tissue or bone fragments that compress the cord are removed]. Recently, with the development of more sophisticated technology, the protective potential of post-injury, spinal-cord cooling is being revisited.

Essentially, procedures can be categorized as either systemic (i.e., whole body) hypothermia or localized cooling:

LOCALIZED COOLING

Reported in 1970, Dr. GastonAcosta-Rua (USA) treated two men (17 and 21) with thoracic injuries from motor-vehicle accidents with spinal-cord cooling. After a decompressive laminectomy, the spinal-cord’s outer dura membrane was opened, and the cord cooled for three hours with a re-circulated saline solution (2^o C). The time lapsing from injury to cooling was two days in the first case and several hours in the second. Although both patients improved, the author only stated that the procedure “may contribute to the recovery of spinal cord function.”

In a 1971 article, Dr. Y. Demian et al described treating three individuals (age 15, 17, and 18) with acute cervical injuries. After a laminectomy surrounding the injury site, the spinal cord was cooled for 1.5 – 3 hours with an ice-cold, physiologically compatible, saline solution. In two cases, the time from injury to cooling was about five hours; in one case, it was over 12 hours. Recovery was noted in all.

Summarized in a 1971 article, Dr. Robert Selker (USA) used hypothermic cooling to treat four acutely injured patients within three hours of injury (Surg Forum 1971; 22). Two had cervical injuries and two thoracic; three injuries were from gunshot. Two patients died several months after the surgery, and the other two regained some function.

In 1972, Dr. Dexter Koons et al (USA) reported treating five patients with acute cervical (2) and thoracic (3) injuries with hypothermic procedures. Patients underwent a decompressive laminectomy 3-7 hours after injury. After the spinal-cord’s outer dura membrane was opened, the cord was cooled with a physiologically compatible saline slush for 30 minutes and the dura closed. The majority of patients did not regain function.

Reported in 1973, Drs. William Meacham and Warren McPherson (USA) treated 14 patients with spinal-cord cooling within eight hours of injury. Age ranged from 16 to 56; all but three were male; and 12 and 2 had cervical and thoracic injuries, respectively. Most patients were also treated with neuroprotective steroids. A decompressive laminectomy was carried out over three vertebral sections surrounding the injury site, and the cord cooled by cold saline (4^o C) for three hours. Four patients died, although the investigators believed that the deaths were not surgery associated. Of the 10 surviving patients, seven demonstrated some improvement, including improved sensation, motor control, and bladder functioning.

In a 1975 article, Dr. Juan Negrin (USA) described the treatment of three patients in the early to mid 1960s with delayed hypothermic cooling. After a cord-exposing, decompressive laminectomy, cooling was carried out after opening the cord’s covering membranes (called subarachnoid cooling) or leaving them intact. [As discussed in the appendix, the cord is covered by three membranes:  the outer dura mater, the middle arachnoid membrane, and the innermost pia mater.] Alternatively, procedures were developed to cool the spinal cord nonsurgically by routing the cooling solution in and out of the cord through catheters.

With the first patient, who sustained a thoracic injury five hours before laminectomy, the spinal cord was cooled without opening the membrane for three, 45-minute periods two, three, and four days after surgery. No improvement was reported.  With the second patient, who had a laminectomy a day after sustaining a SCI from a fall; the cord was cooled for one hour by subarachnoid cooling. Several weeks later when the spinal cord needed to be cut open again, cooling was carried out for a second time for another hour. Over time, the patient regained considerable function. Due to delayed complications, the third patient’s decompressive laminectomy was undertaken a year after acquiring a cervical injury by a car accident. At that time, subarachnoid cooling was carried out for 45 minutes. Improvement was noted.

In a 1979 article, Dr. Charles Tator (Canada) summarized his experience irrigating the acutely injured spinal cord of 11 patients treated over the 1968-77 period with either cooled or body-temperature solutions. He suggested that non-cooling irrigation may still provide benefits because the physiologically supportive irrigating solution would provide oxygen to the injured tissue, create a more biochemically supportive environment, and flush out injury-created noxious substances. Seven and four patients had sustained clinically complete cervical and thoracic injuries, respectively; and age ranged from 16 to 56. The time lapsing from injury to surgery varied from 3-8 hours. The irrigations were carried out with the spinal cord’s dura (outer) and arachnoid (middle) membranes widely opened. Six and five patients were irrigated with hypothermic (5^o C) and body-temperature (36^o C) solutions. Three patients recovered some sensation, one of whom recovered some motor function (toe wiggling). Of the three, two and one were irrigated with cooling and body-temperature solutions, respectively.

In 1976, Dr. Albino Bricola et al (Italy) described the hypothermic treatment of seven men and one woman with acute SCI (10). Age ranged from 18 to 61 (average 33) years; four patients each had cervical and thoracic injuries. The time from injury to initiating cooling ranged from seven to 26 hours. After a wide, three-level laminectomy, the cord’s covering dura-mater membrane was opened, and then the cord irrigated for 10-20 minutes - the time needed to inspect it for damage. Thereafter, the membrane was closed and catheter tubing put over the injury area, through which a cooling solution flowed for a duration ranging from 1.5 hours to eight days. Three patients died; four of the five survivors recovered some motor and sensory function. 

In 1984, Dr. Robert Hansebout and colleagues reported the results of treating seven male and three female patients (6 thoracic and 4 cervical) within 8.5 hours of injury with both spinal-cord cooling and neuroprotective steroids. After decompression, a cooling “saddle” (6^o C) was placed lightly against the cord’s outer dura membrane for four hours. Followed for at least six months, three of the patients accrued some motor or sensory recovery (one died).

SYSTEMIC COOLING

Due to a rise in body temperature after injury, Everett was systemically cooled, a procedure that has been more extensively used in traumatic brain injury (TBI). Even with TBI, however, the benefits of such cooling have been ambiguous. For example, a study completed in 1998 involving 392 patients with TBI did not demonstrate significant benefits, except in younger, quickly treated patients.

For SCI, medications used to prevent shivering interfere with monitoring neurological function and promote health complications. Addressing this issue, Dr. Jogi Inamasu and colleagues (Japan) stated “… patients with cervical SCI, who are most vulnerable to respiratory infection, hypotension, and bradycardia [slow heart rate] may be further compromised by induction of systemic hypothermia,” further noting that the prolonged use of sedatives and muscle relaxants essential during systemic hypothermia may worsen the respiratory function of these “fragile patients.”

Nevertheless, because animal studies suggest that post-injury elevated body temperatures are detrimental, Miami-Project investigators have started using state-of-the-art technology to treat acutely injured patients with mild hypothermia, producing a several degree drop in body temperature. Basically, a catheter is placed in the patient’s blood vessel, and a thermo-regulating device closely monitors and adjusts blood temperature as it passes by the catheter.  The study will follow long-term benefits by assessing improvements in motor and sensory function and acquisition of daily-living skills.

The cooling procedures were more thoroughly described in a 2009 article, which summarized the hypothermic treatment of 14 patients with complete cervical injuries. Patient age ranged from 16-62 years (average 39.4), and 10 were men and four females. The time elapsing from injury to initiation of treatment averaged 9.2 hours. After the cooling catheter was inserted into the femoral vein (see illustration), patients were cooled at a maximum rate 0.5^o C/hour until the target body temperature of 33^o C was reached, which usually took less than three hours. The target temperature was maintained for 48 hours, after which patients were warmed at a rate of 0.1^o C per hour. The duration of total cooling was nearly four days.

Patients were sedated and given medications to prevent shivering, although shivering with these cervical injuries was already greatly attenuated due to virtually complete body paralysis.  As expected, lowering the body temperatures slowed the heart rate. Respiratory complications were common and included atelectasis (collapse of lung tissue) (12 patients), pneumonia (8 patients), and acute respiratory distress syndrome (2 patients). The investigators noted, however, that a control group of patients who did not receive hypothermic treatment had comparable rate of respiratory complications. No functional outcomes were reported by the investigators in this article.

Clinical outcomes were reported in 2010 after the subjects had been followed for approximately a year (ref). Although all 14 subjects initially had ASIA-A complete cervical injuries, the injuries of six (43%) became incomplete after a year. Three improved to ASIA B with some sensory improvement, two to ASIA C with partial recovery of both sensory and motor function, and one improved to ASIA D with even greater improvement. These hypothermia-treated patients were compared to 14 untreated patients, who were matched with respect to injury level and completeness, and age. Although improvement in the cooled patients appeared greater than that observed in controls and that reported in the literature for the natural history of SCI neurological recovery, definitive conclusions could not be made because the study’s small sample size could not generate statistically significant results. The investigators concluded that the results, albeit lacking the needed statistical power, were encouraging enough to warrant the initiation of larger, more definitive studies.

In 2013, the investigators reported the results of cumulatively treating 35 patients with their cooling procedures. As before, all patients had Grade-A complete cervical injuries at the time of admission, although four improved within 24 hours to the Grade-B incomplete level. Of the 35 patients, 27 were males, and the majority became injured from motor vehicle accidents. Excluding several patients with delayed admission, the average time from injury to hypothermia treatment was 5.8 hours. All but four patients were followed for 12 months. Of the 35 patients, 15 improved at least one grade after the final follow-up assessment (only 11 if you exclude the four individuals who had improved a grade within the first day). The overall results compared favorably to what would be expected based on historical data. Once again, a high incidence of complications, especially respiratory, was observed, however, again noting that such complications are not uncommon with cervical injuries.

POTENTIAL MECHANISMS OF HYOPOTHERMIC COOLING

A recent article by Dr. W. Dalton Dietrich and colleagues (part of the aforementioned overall Miami Project group evaluating hypothermia) discussed several physiological mechanisms by which hypothermia may protect CNS tissue after injury (15):

1) Metabolic Influences: Hypothermia lowers cellular metabolic and energy requirements. It specifically lessens the depletion of ATP, an extremely important molecule that is consumed to drive most biochemical processes.

2) Blood Circulation: Hypothermic-induced changes in blood flow may be neuroprotective.

3) Excitotoxicity: Cooling reduces excitotoxicity. After injury, nerve cells lyse releasing excitatory amino acids, such as glutamate, which soon reach toxic concentrations. Through interactions with receptors on neighboring cells, excessive glutamate will initiate a neurotoxic biochemical cascade.

4) Blood-Brain Barrier: The BBB restricts the passage of various substances between the bloodstream and the CNS. Injury compromises this barrier allowing for the passage of water and neuron-damaging substances into the CNS. Hypothermia reduces this injury-associated permeability.  

5) Calcium: Calcium is an ion (i.e., electrically charged molecule) which is routinely present in extremely low concentrations within nerve cells. Injury disrupts the calcium equilibrium necessary for neuronal functioning; hypothermia lessens this disruption.  

6) Inflammation and Edema: Due to the preservation of the blood-brain barrier, hypothermia lessens 1) the infusion of inflammatory cells into the injury site and 2) edema swelling cause by the fluid accumulation.

7) Neuronal Cell Death: Hypothermia decreases post-injury apoptosis, a form of programmed cell death common after injury.

8) Global Molecular Changes: Hypothermia affects post-injury expression of genes and the substances they produce. These alterations may be neuroprotective.