Early management of spinal cord injury
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1) The document discusses the principles and evidence for early management of spinal cord injuries, including early surgery within 24 hours, maintaining mean arterial blood pressure between 85-90 mmHg, and the use of methylprednisolone. 2) Ongoing clinical trials are exploring optimal perfusion pressure targets as well as neuroprotective agents like riluzole. 3) Specialized spinal cord injury units allow for up-to-date management and access to clinical trials exploring new treatments.
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Early management of spinal cord injury
- 1. RNSH CONTEMPORARY EARLY MANAGEMENT OF SPINAL CORD INJURY CICM ASM 2019 Dr Jonathon R. Ball FRACS AMA(M) BMed BMedSc(Hons) GradDipBiomedE Neurosurgeon and Spinal Surgeon Royal North Shore and North Shore Private Hospitals www.spinesurgeon.sydn ey @DrJonathonBall #spinesurgsydney
- 2. RNSH "One having a dislocation in a vertebra of his neck, while he is unconscious of his two legs and his two arms, and his urine dribbles. An ailment not to be treated.” Case 31 Edwin Smith Papyrus c1600 BCE
- 3. RNSH
- 4. RNSHManagement Principles suspicion of injury protection of spine appropriate resuscitation detection of injury specific management
- 5. Injury seconds weeks Based on Fehlings (2013)
- 6. Guidelines
- 7. RNSHManagement Principles • perfusion – early surgery – MAP targets – perfusion pressure/pressure reactivity • protection – methylprednisolone – neuroprotective trials
- 8. Injury seconds weeks Based on Fehlings (2013)
- 9. RNSH Early Surgery ‘Conservative treatment is infinitely superior to any immediate surgical procedure … Incidents of tragic events … are high enough to make any surgeon very circumspect before indulging in any surgical procedure’ Sir Ludwig Guttman. 1973.
- 10. RNSH 2017 – “ early surgery be offered …. regardless of level” Early (<24 hr) Surgery Fehlings et al. Global Spine J. 2017. 7(3 Suppl):195S-202S.
- 11. RNSHSTASCIS (2012) • Non-randomised, multicentre, prospective cohort study • 313 patients with cervical SCI • ‘19.8% of patients undergoing early surgery showed a >2 grade improvement in AIS’ • ‘compared to 8.8% in the late decompression group’ • ‘complications occurred in 24.2% of early surgery patients and 30.5% of late surgery patients (p = 0.21)’
- 12. RNSH • 20 studies (11 RCTS, 9 observational) – 1162 pts (ASIA A <72 hrs) – 28.1% improved ≥1 AIS grade – early surgery : 46.1% improved – late surgery : 25% improved
- 13. RNSH • 13 studies – 422 pts (ASIA A) – outcome : ≥2 AIS grade – early surgery : 22.6% improved – late surgery : 10.4% improved
- 14. RNSHSCI-POEM • 309 patients with SCI • recruitment completed 2019 • 19 clinics in Europe • early surgery (< 12 hrs) vs late surgery (12 hrs – 14 days) • 1o endpoint – ISNCSCI motor score • results in 2020
- 15. RNSH Spinal Cord Perfusion SCPP = MAP - ISP
- 16. RNSH 2013 – “ maintenance of MAP between 85 and 90 mm Hg for the first 7 days” Ryken et al. Neurosurgery. 2013. 72(3S): 84-92. Spinal Cord Perfusion
- 19. RNSH • Retrospective analysis, prospectively collected data – 100 pts (994, 875 q1min ABP) – 74 of 100 pts – outcome recorded : ISNCSCI/ASIA exam – No improvement = 35 pts – 1 AIS improvement = 23 pts – ≥2 AIS improvement = 13pts
- 20. RNSH
- 21. RNSHOngoing Trial Mean Arterial Pressure in Spinal Cord Injury (MAPS) (ClinicalTrials.gov Identifier: NCT02232165) • University of Calgary/University of Texas • n = 100 • C0-T12/ASIA A, B, C • Group 1 – target MAP >65 mmHg • Group II – target MAP > 85 mmHg • Non-inferiority • Outcome – ISNCSCI motor score • Estimated Completion Date : June 2019
- 23. RNSH Spinal Cord Perfusion Phang & Papadopoulos. Neurocritical Care. (2015) 23:414–418
- 24. RNSH Spinal Cord Perfusion Phang & Papadopoulos. Neurocritical Care. (2015) 23:414–418
- 25. RNSH Spinal Cord Perfusion SCPP = MAP- ISP • Increasing SCPP – Improved blood flow – Improved MEPs – Improved biochemical parameters – Improved neurological status
- 26. RNSH Spinal Cord Perfusion Saadoun, Chen & Papadopoulos. J Neurol Neurosurg Psychiatry 2017;88:452–453.
- 27. RNSH Spinal Cord Perfusion • optimal perfusion pressure (SCPPopt) • pressure reactivity index (sPRx) – indicator of autoregulation – sPRx : -1 < 0 > +1 Saadoun, & Papadopoulos. Critical Care (2016) 20:308
- 28. RNSH Spinal Cord Perfusion pSCPPopt = 90 mmHg increase MAP decrease ISPiSCPPopt
- 29. RNSH Spinal Cord Perfusion pSCPPopt = 90 mmHg increase MAP decrease ISPiSCPPopt Saadoun, & Papadopoulos. Critical Care (2016) 20:308
- 30. RNSH Spinal Cord Perfusion pSCPPopt = 90 mmHg increase MAP decrease ISPiSCPPopt Phang et al. J Neurotrauma. (2015) 32:865-874.
- 32. RNSH 2013 – “ administration of methylprednisolone …. is not recommended” Hurlbert et al. Neurosurgery. 2013. 72(3S): 93-105. Methylprednisolone
- 33. RNSH 2017 – “ a 24-hour infusion of high- dose MPSS be offered .... within 8 hours … as a treatment option” Fehlings et al. Global Spine J. 2017. 7(3 Suppl):201S-137S. Methylprednisolone
- 34. RNSHAOSpine Guideline (2017) Fehlings et al. Global Spine J. 2017. 7(3 Suppl):116S-137S. NASCIS II – Issues 1. Subgroup analysis - ? a priori 2. Right sided motor scores – small effect
- 35. RNSHNeuroprotective Trials • RISCIS (Riluzole) • MASC (Minocycline) • SPRING (Cethrin/VX-210) • Phase I/II – Anti-Nogo-A (ATI-355) – G-CSF – Glibenclamide – Intravenous IgG (Brisbane, QLD)
- 36. RNSHRISCIS • international multi-centre • placebo controlled • double blind • randomised trial • target enrolment : 351 subjects • Adults – 18 to 75 years • Present to spinal unit within 12 hours injury • Cervical spine level – C4 to C8 • AIS A, B and C
- 37. RNSHRISCIS • international multi-centre • placebo controlled • double blind • randomised trial • target enrolment : 351 subjects • 24 centres open – 170 subjects to date • Australian sites & recruitment – Prince of Wales Hospital (19 subjects) – Royal North Shore Hospital (17 subjects) – Royal Adelaide Hospital (8 subjects) – John Hunter Hospital (0 subjects) – AUSTRALIAN TOTAL (43 subjects : 26% worldwide)
- 38. RNSHRiluzole • benzothiazole anti-convulsant • Na+ channel blocker • use in amyotrophic lateral sclerosis – Increases ventilator & tracheotomy free survival – Increases overall survival
- 39. Injury seconds weeks Based on Fehlings (2013)
- 45. RNSH Wu et al. J Neurotrauma 30:441–452 (2013) Rat Model Schwarz & Fehlings. J Neurosurg (Spine 2) 94:245–256 (2001)
- 46. RNSH Rat Model Wu et al. J Neurotrauma 30:441–452 (2013)
- 47. RNSH • 36 patients treated – 28 cervical injuries ASIA A, B, C • Riluzole – First dose 50mg by mouth within 12 hours injury – Continued twice a day for 14 days • 6 months follow-up • Historical controls from registry data Phase I Human Trial
- 48. RNSHPhase I Human Trial
- 49. RNSHSummary • Emerging evidence and new treatments in acute SCI – perfusion • early surgery • MAP targets • perfusion pressure & pressure reactivity – neuro-protection • methylprednisolone • neuroprotective trials • Specialised units offer access to up to date knowledge and clinical trials
- 50. RNSHComprehensive Care ‘Surgeons of whatever specialty who are engaged in the immediate treatment of spinal paraplegics and tetraplegics should take account of all aspects of the treatment and not merely the spine itself’ Sir Ludwig Guttman. 1973.
- 51. RNSH Thank you ‘The Injured Lioness’ from Lion Hunt of Ashurbanipal. Nineveh, Assyria c640 BCE. The British Museum
- 57. RNSH Thank you ‘The Injured Lioness’ from Lion Hunt of Ashurbanipal. Nineveh, Assyria c640 BCE. The British Museum
Editor's Notes
- Good afternoon. Before my substantive presentation, I would like to thank the organisers of this meeting for the honour and privilege of been asked to present on a topic that id both an area of passion and personal interest. Today I will be discussing key issues in the early management of acute spinal cord injury.
- The earliest evidence based recommendation regrading spinal cord injuries is found in the Edwin Smith Papyrus from c1600 BCE Egypt that concludes that spinal cord injury is an ailment “Not to be treated”. Spinal cord Injuries since, have long been considered a somewhat ‘hopeless’ case.
- And today SCI remains a devastating neurologic injury with significant consequences for the injured and their community. In pure financial terms the estimated cost of SCI in 2009 was $2 billion dollars annually. The lifetime care costs for an individual with SCI was almost $10 million. As opposed to brain injury, where ill advised treatment may produce a “devastated survivor”, a spinal cord injured patient is very likely to survive and anything we can do that may save neurologic function needs to be fairly considered. There are massive functional implications from small neurologic improvements – one level can make the difference between mechanical ventilation or spontaneous breathing, between a breath controlled or hand controlled wheelchair, between independent transfer or being hoist dependent.
- The general principles of management include the suspicion of injury, appropriate measures to protect the spine, adequate resuscitation of the patient, investigations to define the injury. It is this area of specific management, which I will concentrate on today.
- At a basic science level, we know that a spectrum of biochemical and cellular events progresses over the seconds, hours, days and weeks following the injury. The goal of early management is to interrupt, slow or ameliorate the events, preventing secondary injury and improving neurologic and functional outcome.
- The last 10 years have seen a number of evidence based guidelines published on various aspects of spinal cord injury, some of which provide conflicting recommendations regarding treatment. I will refer to these guidelines today especially the 2013 guidelines published in the journal Neurosurgery and the 2017 guidelines published in the Global Spine Journal by the AOSpine group.
- Today, I would like to discuss specific areas of recent controversy and progress and I have divided these into perfusion and protection strategies. In erm of perfusion, I will focus on early surgery, MAP targets and concepts of perfusion pressure and pressure reaciivty. In terms of neuroprotection, I will cover the ongoing controversy around methylprednisolone and trials of neuroprotective agents.
- The early stages of secondary spinal cord injury are characterized by ischaemia of neural tissue. It is thought that early surgery, by decompressing the cord, may prevent this secondary injury.
- Historically, prominent figures in spinal injury care have warned against surgery. Sir Ludwig Guttman was the founder of modern rehabilitation care and the Paralympic movement and, in his historic text on cord injury warned against the tragic events that ensue from surgical meddling.
- However, the latest 2017 guidelines provide the recommendation that early surgery be offered for adult patients with acute cord injury. The quality of evidence is low and the strength of the recommendation weak.
- The most convincing single study regarding decompression was the STASCIS study. This was a non-randomized multi-centre prospective cohort study of 313 patients with cervical SCI. Almost 20% of patients undergoing early (<24 hours) surgery had a >2 grade improvement in AIS, compared to 9% in the late decompression group. The argument that early surgery was attendant with a higher rate of complications was not demonstrated to be true.
- In the last 12 months, there have been 2 meta-analyses that have reported the results of surgery in SCI. The first compiled data on over one thousand patients with complete injuries from 20 studies and reported that early surgery was associated with a greater chance of neurologic improvement, as measured as a one or more grade improvement in AIS grade. A one grade improvement in AIS may not confer functional improvement, .........
- .............. so the second meta-analysis compiled data on over four hundred patients from 13 studies and again reported that early surgery was associated with a greater chance of neurologic improvement, as measured as a two or more grade improvement in AIS grade – which is more likely to confer functional improvement.
- Just completed enrolment is a European study that aims to look at ultra-early surgery within 12 hours using a more sensitive indicator of outcome, the ISNCSCI motor score. The results, expected next year, are eagerly awaited.
- When thinking about spinal cord perfusion, it is useful to consider the spinal cord perfusion pressure. Analogous to the cerebral perfusion pressure in brain injury, the spinal cord perfusion pressure is calculated as the MAP minus the intraspinal pressure. While decompressive surgery may reduce intraspinal pressure, elevating MAP may also improve spinal cord perfusion.
- The 2013 guidelines suggest maintaining a MAP between 85 and 90 mm Hg for the first 7 days following injury. However, the underlying evidence is of poor quality.
- This 2017 systematic review of relevant evidence shows the studies are all largely retrospective case series, often involve no comparison group and some didn’t define the MAP goals.
- One of the better studies (from Michigan in the US), published in 2015,
- Was a retrospective analysis of prospectively collected minutely ABP data on 100 patients. For 74, there was an outcome ISNCSCI recorded and three subgroups were defined according to the amount of improvement – no improvement, one grade, two grades.
- The group who had a 2 or more improvement in AIS grade had a higher average MAP and a lower proportion of MAP values below 85mmHg. These are just associations and an ongoing trial ....
- An ongoing trial in North America aims to examine the question whether elevated MAP will be associated with improved neurologic outcome.
- A parallel stream of research has looked at measuring the actual spinal cord perfusion pressure. Much of the research in this area has come out of St Georges Hospital in London, led by Professor Marios Papadopoulos. He has placed a subdural Codman microsensor catheter at the level of injury and measured the subdural pressure.
- It has been shown that the subdural pressure is maximal at the site of injury because the swollen cord is compressed against the dura.
- In one patient who consented to an intraparenchymal, as well as a subdural catheter, there was a very good correlation between the 2 measurements, showing the subdural measurement is an appropriate surrogate for intraspinal pressure.
- They have shown in various studies that increasing SCPP improves blood flow, improves the amplitude of motor evoked potentials, improves biochemical parameters as assessed by microdialysis and, in incomplete patients, improves neurologic examination findings.
- In terms of neurologic outcome, in these graphs, the black and white bars represent improvement in AIS grade by 1 or 2 grades respectively. It can be seen that with decreasing ISP or increasing SCPP, there is a increasing proportion of subjects improving. If we focus on the SCPP, it can be seen that the greatest improvement occurred with SCPP > 90 mmHg. If you think the average ISP in an injured cord is 20-30 mmHg, you can imagine what a significant task it is to achieve this perfusion pressure. So the investigators set about calculating the optimal SCPP.
- They did this using the pressure reactivity index. This has been used in brain injuries and is an indicator of autoregulaton. Pressure reactivity measures the smooth muscle response to to changing perfusion pressures and is calculated as a running correlation coefficient of the SCPP and the ISP. Where values around zero reflect intact autoregulation and numbers more than zero reflect deranged regulation – that is the ISP increases directly with increased perfusion. Plotting sPRx against SCPP yields a U-shaped relationship and the optimal SCPP is the SCPP associated with the lowest PRx. In this pooled analysis the SCPPopt was about 80 to 90 mmHg. As with the SCPP, there is a very good correlation of biochemical and clinical assessments of outcome with deviation away from the SCPPopt.
- So we are left with this very significant target that even the current BP recommendations will not achieve. So our strategies can be increase the MAP, but this can be difficult in a patient with neurogenic shock requiring high doses of inotropes and the consequent complications. Alternatively, we can try and decrease the ISP or calculate individualized SCPPopt targets.
- By that I mean calculated a SCPPopt for each patient. Previously, the PRx could only be calculated after treatment but software now allows real time calculation of these parameters. Here we can see the U curves for 2 patients and how they have differing SCPPopt. This is the main focus of research in this area at this time.
- In terms of decreasing ISP, it is not influenced by changes in pCO2, mannitol, anaesthetic agents. Interestingly, it can be increased with supine positioning after laminectomy (esp in thoracic injuries). The London group performed duroplasty on a group of patients. Duroplasty involved opening the dura, sewing in a patch of tissue to increase the dural volume – similar to a decompressive crani - and have demonstrated that it reduces ISP and leads to a downwards shift in the U curve and SCPPopt and this in been further investigated as a new therapeutic strategy.
- This brings me onto neuroprotective agents and starting with methylpredinisolone. The use of MPSS, as extensively studied in the NASCIS trials has long been a source of controversy.
- The 2013 guidelines made a Level 1 recommendation that “administration of methylprednisolone is not recommended”.
- The new 2017 guidelines have taken a polar opposite view stating “ a 24 hour infusion of high dose MPSS should be offered within 8 hours as a treatment option” – that is the NASCIS II protocol.
- This Forrest plot from the new guideline indicates that the treatment effect favours MPSS. However 49% of the effect is contributed by the NASCIS studies of which criticism abounds – issues regarding subgroup analysis and lack of stratification, post-hoc analysis amongst others – too great to go into now. Many reject the findings of these studies as a result. The AOSpine group accepts the study was valid and as such, they are willing to accept that data. I would caution that the magnitude of effect is small – only 3 ½ points on the motor scale – less than a motor level. The MCID on the ISNCSCI motor score is ~4.5. Whether MPSS should be used may be an insoluable problem however the existence of these published guidelines (which we may well be judged by) behoves us to consider MPSS and be able to justify our decision regarding its use.
- Finally I would like to talk about neuroprotective trials. I will focus on the RISCIS trial for which I am a principal investigator. I understand a trial of Minocycline has been halted and there is a trial of Cethrin about to start. VX-210 is applied epidurally at surgery and is an inhibitor of the enzyme Rho which itself prevents axonal regeneration. There are a number of other agents in Phase I & II such as AntiNogoA, G-CSF, Glibenclamide and pooled GammaGlobulin.
- RISCIS is an international, placebo controlled, double blind, randomised trial of Riluzole in acute traumatic spinal cord injury. Recruitment started in 2015
- RISCIS is an international, placebo controlled, double blind, randomised trial of Riluzole in acute traumatic spinal cord injury. Recruitment started in 2015
- Riluzole is a benzothiazole compound developed as an anti-convulsant. It has powerful Na channelblocking actions. It is used in amyotrophic lateral sclerosis where its neuroprotecitve effects have been shown to increase ventilator & tracheotomy free survival and provide a modest increase in overall survival
- The use of Riluzole in SCI is targeting the loss of Na gradient and excitotoxic neurotransmitter relase seen after SCI.
- This model demonstrates a synaptic junction. After spinal cord injury there is persistent activation of voltage dependent sodium channels.
- The increase in intracellular sodium leads to cellular oedema through osmotic effects. As a secondary effect, intracellular calcium and acidosis increases through the action of. Intracellular ATP is depleted through the activity of such homeostatic mechanisms.
- The increase in sodium also leads to glutamate release ……
- ...... That actyivates post-synaptic Ca and Na channels and leading to glutamate mediated exicitotoxicty
- Riluzole blocks the persistent activation of voltage dependent sodium channels and aims to prevent these downstream effects
- There are 2 main published studies that examine riluzole in a rat model. In the riluzole animals, tissue preservation was greater at the epicenter of the injury and for a region around the injury. The 2 images on the left are transverse section through the rat spinal cord at the level of injury. In the riluzole animals, the bottom picture, there is better preservation of tissue and this preservation was seen to extend around the region of injury. This preservation was greatest in the animals receiving Riluzole within 1 hour of injury …..
- In both studies, the riluzole animals demonstrated better motor assessment. In this graph, demonstrating the BBB scores from injury until sacrifice at 6 weeks, it can be seen that those animals receiving riluzole within one hour had improved outcomes compared to those who had administration after 3 hours.
- Of the 36 patients enrolled, there were 28 with cervical injuries. The Riluzole was given within 12 hours of injury and continued twice daily for 14 days. No significant toxicity was noted and outcomes were compared to historical controls from registry data ….
- Riluzole was given to 36 patients with cervical SCI and compared to historical controls from registry data …. No significant toxicity was noted and in all cervical patients combined there was improvement in mean motor score, in favour of Riluzole. This is not evidence of effect but was enough to prompt this next Phase in trial …..