Effects of local hypothermia–rewarming on physiology, metabolism and inflammation of acutely injured human spinal cord

Abstract

In five patients with acute, severe thoracic traumatic spinal cord injuries (TSCIs), American spinal injuries association Impairment Scale (AIS) grades A-C, we induced cord hypothermia (33 °C) then rewarming (37 °C). A pressure probe and a microdialysis catheter were placed intradurally at the injury site to monitor intraspinal pressure (ISP), spinal cord perfusion pressure (SCPP), tissue metabolism and inflammation. Cord hypothermia-rewarming, applied to awake patients, did not cause discomfort or neurological deterioration. Cooling did not affect cord physiology (ISP, SCPP), but markedly altered cord metabolism (increased glucose, lactate, lactate/pyruvate ratio (LPR), glutamate; decreased glycerol) and markedly reduced cord inflammation (reduced IL1β, IL8, MCP, MIP1α, MIP1β). Compared with pre-cooling baseline, rewarming was associated with significantly worse cord physiology (increased ICP, decreased SCPP), cord metabolism (increased lactate, LPR; decreased glucose, glycerol) and cord inflammation (increased IL1β, IL8, IL4, IL10, MCP, MIP1α). The study was terminated because three patients developed delayed wound infections. At 18-months, two patients improved and three stayed the same. We conclude that, after TSCI, hypothermia is potentially beneficial by reducing cord inflammation, though after rewarming these benefits are lost due to increases in cord swelling, ischemia and inflammation. We thus urge caution when using hypothermia-rewarming therapeutically in TSCI. Hypothermia is being investigated as a potential therapy for traumatic brain injury (TBI) 1 and traumatic spinal cord injury (TSCI) 2 based on compelling evidence from several laboratories and animal species that hypothermia is neuroprotective. In animal models of TBI, hypothermia has been shown to target many pathological processes including reducing the metabolic rate, inflammation, edema, oxidative stress, excitotoxicity, electrolyte imbalance as well as apoptotic and necrotic cell death in vulnerable tissue 3-8. Despite the encouraging findings of animal studies, randomized controlled human trials have failed to show functional benefit of hypothermia in TBI patients 1,9,10. Therapeutic hypothermia is also beneficial in animal models of TSCI: rodent models of TSCI show improved histological and functional outcomes after hypothermia 11,12. Small, non-randomized studies of TSCI patients also suggest improved functional outcomes after local 13,14 or systemic hypothermia 2,15. To date, there are no published randomized controlled trials of hypothermia for TSCI. Despite the wide interest in therapeutic hypothermia for CNS injuries, there is paucity of mechanistic data from humans regarding the effect of hypothermia on the injury site. In TSCI patients, the effect of cooling and rewarming on cord swelling, metabolism and inflammation are unknown. It is thus unclear if hypothermia and

Hypothermia Therapy for Traumatic Spinal Cord Injury: An Updated Review

“…In all respective cases, intravascular heat exchange catheters were used to induce systemic hypothermia and epidural cooling units were used for local hypothermia. All patients were intubated and sedated based on their clinical condition [ 43 , 44 , 45 , 46 ], and those receiving systemic hypothermia were given additional sedation as needed to control shivering [ 43 , 44 ].…”

“…Furthermore, Hansebout and Hansebout reported that 9 out of 14 (64%) patients from their study with cervical TSCI converted from AIS grade A to B or better [ 45 ]. None of the patients reported by Gallagher et al experienced a cervical injury [ 46 ]. All clinical studies reported that no neurologic deterioration occurred in any patient as a result of hypothermia treatment.…”

“…The authors also report that one case of ARDS was likely due to aspiration of salt water from drowning and another two were due to aspiration of orogastric fluid during resuscitation [ 43 ]. Gallagher et al decided to terminate their study after 3 out of 5 (60%) patients developed culture-positive wound infections [ 46 ]. In this trial, multiple catheters were implanted in the surgical incision site of patients for both local cooling and pathophysiologic monitoring of chemokines/cytokines.…”

“…However, when predicting AIS conversion, a logistic regression model of CSF biomarkers alone showed 91.2% accuracy and was not aided by the addition of MRI and/or baseline AIS data. Gallagher et al utilized these techniques in parallel with local hypothermia but stopped the trial due to high infection rates (60%) [ 46 ]. Hansebout and Hansebout reported only 1 infection in 20 patients (5%) but initiated treatment sooner than Gallagher and for a shorter duration [ 45 , 46 ].…”

Clinical guidelines for neurorestorative therapies in spinal cord injury (2021 China version)

“…The purpose of hypothermia treatment is to reduce the basic metabolic rate of the central nervous system, reduce energy consumption of the spinal cord, and alleviate the energy supply disorder caused by spinal cord ischemia and hypoxia [58]. Induction of systemic hypothermia to a temperature between 32 ℃ and 34 ℃ seems to be most effective [58][59][60][61][62][63][64][65][66]. Local hypothermia is also effective [64][65][66], which can be achieved using epidural or subdural coolant (6 ℃) [62] infused via an open or closed system.…”