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Three Part Question

In [adult patients with traumatic spinal cord injury] does [a high MAP target (90mmHg) during the early stage of injury] lead to any improvement in [morbidity and/or survival]

Clinical Scenario

A 55-year-old male presents to the Emergency Department following a fall down the stairs while intoxicated. He suffers immediate onset tetraplegia with a high sensory level to his upper chest. He remains alert and a CT confirms a fracture dislocation at the C5/C6 junction with retropulsed fragments into the spinal canal. You site an arterial line while he awaits spinal orthopaedic review, but at present there is no sign of neurogenic shock and his mean arterial pressure (MAP) sits at 60. A colleague asks if you are planning to start vasopressors and aim for a higher MAP target in order to reduce the ischaemic penumbra. You nod sagely, then sneak off to a computer to google the word penumbra which you have heard before but never remember exactly what it means. While at the computer, you wonder if there is any actual evidence to support the idea of induced hypertension to improve outcome in traumatic spinal cord injury.

Search Strategy

Medline (1946 to Jan 2018) and Embase (1980 to 2018 week 3) were both searched with the following string: [exp ("traumatic spinal cord injury").ti,ab/ OR ("acute spinal cord injury").ti,ab OR ("acute cervical cord trauma").ti,ab AND ("Mean Arterial Pressure").ti,ab OR ("MAP" ADJ1 target).ti,ab OR ("blood pressure management").ti,ab OR ("haemodynamic parameter*").ti,ab OR ("hemodynamic parameter*").ti,ab OR exp "ARTERIAL PRESSURE"/ AND (morbidity).ti,ab OR MORBIDITY/ OR SURVIVAL/ OR (survival).ti,ab OR (outcome).ti,ab. OR "CRITICAL CARE OUTCOMES"/ OR "TREATMENT OUTCOME”/ 
23 papers were identified as potentially relevant following abstract review. On full review, 12 of these papers were deemed to be directly relevant to the 3-part clinical question. All 12 relevant articles were identified and summarised within 2 recent systematic reviews.

Search Outcome

2 recent systematic reviews containing all relevant papers are described in the table below.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Sabit et al Jan 2018 Canada	Prospective and retrospective data from adult and paediatric human studies in traumatic spinal cord injury (SCI)	Systematic Review of 9 cohort studies (level 2a)	Relationship between neurological improvement and elevated target mean arterial pressure	4 studies of 9 showed positive neurological improvement associated with higher MAP targets. 2 studies found episodes of hypotension related to poor neurological recovery.	Small number of mainly retrospective studies with heterogeneous outcome measures, study designs, treatments and MAP documentation (4-7 days). Follow up varied considerably between studies- ranging from just the first 5 days in hospital to some studies continuing to review after neurorehabilitation. Complications of vasopressor use were not routinely documented. Lumbar injuries not considered. Most studies appear to use dopamine or phenylephrine as vasoactive agents of choice, which limits generalisability.
			Relationship between neurological improvement and duration of higher MAP target	Elevated MAP shown to associate with greatest impact on neurological recovery during the first 72h after injury.
			Subgroup comparison of complete and incomplete SCI	Complete cord injuries have reduced potential for motor score improvement compared to incomplete.
Saadeh et al. Nov 2017 USA	Prospective and retrospective data from adult and paediatric human studies in traumatic spinal cord injury	Systematic review of 11 cohort studies (level 2a).	Relationship between neurological improvement and elevated target mean arterial pressure.	2 Prospective cohort studies, including 127 patients in total, report stable or improved neurological function following management to elevated MAP target during the early phase of care.	Individual studies often had low numbers of patients, with heterogeneous protocols, MAP goals and outcome measures. 2 prospective studies and 9 retrospective cohorts; overall conclusions severely limited by design evidence. No quantitative analysis due to limitations in methodology. Poor recording of adverse events. Most studies appear to use dopamine or phenylephrine as vasoactive agents of choice, which limits generalisability.
			Relationship between neurological improvement and duration of higher MAP target.	Many studies aimed for a supra-physiological MAP for 5 days’ post injury. There was no association of overall worsening in neurological outcome with this approach.
			Adverse events with vasopressor use	Major complications occurring with vasopressor use were reported in 3-10% patients.

Comment(s)

Few conditions are as devastating as traumatic spinal cord injury (SCI). Approximately 1—2 SCI cases occur daily in the UK, with the patients averaging 43 years of age 3. The majority are incomplete injuries, meaning both patients and clinicians hope for potential neurological improvement. Any medical interventions that can support improvement require strong consideration; the difference between a permanent motor level of C4 or C5 can manifest as the ability to breathe without long term mechanical assistance, or to move an arm. Initial medical treatment of SCI is focussed on preventing secondary injury, which starts immediately and can lead to swelling and ischaemia at the site of primary insult. Normally, spinal cord perfusion is maintained over a wide variation in blood pressure via complex autoregulation; this ability is lost in the injured state and periods of limited perfusion to a compromised cord can result. There are often parallels drawn between traumatic brain injury (TBI) and SCI in this regard; optimising perfusion pressure and neuronal blood flow to the site of injury has modest supporting evidence in TBI care and as such there is validity to the concept in SCI. The target MAP in traumatic SCI and the duration of intervention remain controversial. Previous work has explored the concept of directly measured spinal perfusion pressure, and proposes this as a target rather than the surrogate of systemic BP 4-7. Such methods are impractical in the acute phase of injury. As such, current guidelines for the management of SCI recommend maintenance of MAP between 85—90mmHg for the first 7 days to optimise cord perfusion, aid clearance of inflammatory cytokines at the injury site and limit further secondary damage 8,9. These guidelines are principally based on weak evidence from observational studies 10,11. The arbitrary target MAP of 85—90mmHg seems to have been taken from early studies by Levi and Vale. In 1997, Vale et al. completed a non-randomised prospective study, elevating patient MAP in the early stage of SCI to over 85mmHg for 7 days 12. 3 of 10 complete cervical spinal cord injuries developed ambulatory capacity, while 23 of 25 incomplete cervical cord injuries managed to become ambulatory (only 4 had initial examination scores consistent with regaining the ability to walk). The conclusion followed that early and aggressive volume and blood pressure resuscitation was distinct from any benefit of surgery. However, iatrogenic augmentation of blood pressure does not come without risk. In 2014, Inoue et al. reviewed the risks associated with vasopressor use and supra-physiological MAP targets, demonstrating a 70% complication rate related to vasopressor use 13. Complications included arrhythmias such as bradycardia, atrial flutter and ventricular tachycardia, elevated troponins, skin necrosis, and ST changes on the ECG 14. In conclusion, the evidence to support augmented MAP targets in acute spinal cord injury is weak. In addition, use of vasopressor infusions and supraphysiological BP targets carry risk. As such, a decision to initiate therapy should be considered on a per patient basis, and a decision shared after full disclosure of relevant risks where possible. Further research is required to determine the efficacy, clinical benefit and cost effectiveness of therapy. Such research is currently underway 15. References 1. Sabit B, Zeiler FA, Berrington N. The Impact of Mean Arterial Pressure on Functional Outcome Post Trauma-Related Acute Spinal Cord Injury: A Scoping Systematic Review of the Human Literature. J Intensive Care Med 2018; 33(1): 3-15. 2. Saadeh YS, Smith BW, Joseph JR, et al. The impact of blood pressure management after spinal cord injury: a systematic review of the literature. Neurosurg Focus 2017; 43(5): E20. 3. Center. NSCIS. Spinal Cord Injury Facts and Figures at a Glance. 2018. https://www.nscisc.uab.edu/Public/Facts%20and%20Figures%20-%202018.pdf. 4. Saadoun S, Chen S, Papadopoulos MC. Intraspinal pressure and spinal cord perfusion pressure predict neurological outcome after traumatic spinal cord injury. J Neurol Neurosurg Psychiatry 2017; 88(5): 452-3. 5. Saadoun S, Papadopoulos MC. Spinal cord injury: is monitoring from the injury site the future? Crit Care 2016; 20(1): 308. 6. Varsos GV, Werndle MC, Czosnyka ZH, et al. Intraspinal pressure and spinal cord perfusion pressure after spinal cord injury: an observational study. J Neurosurg Spine 2015; 23(6): 763-71. 7. Werndle MC, Saadoun S, Phang I, et al. Measurement of Intraspinal Pressure After Spinal Cord Injury: Technical Note from the Injured Spinal Cord Pressure Evaluation Study. Acta Neurochir Suppl 2016; 122: 323-8. 8. Consortium for Spinal Cord M. Early acute management in adults with spinal cord injury: a clinical practice guideline for health-care professionals. J Spinal Cord Med 2008; 31(4): 403-79. 9. Ryken TC, Hurlbert RJ, Hadley MN, et al. The acute cardiopulmonary management of patients with cervical spinal cord injuries. Neurosurgery 2013; 72 Suppl 2: 84-92. 10. Hawryluk G, Whetstone W, Saigal R, et al. Mean Arterial Blood Pressure Correlates with Neurological Recovery after Human Spinal Cord Injury: Analysis of High Frequency Physiologic Data. J Neurotrauma 2015; 32(24): 1958-67. 11. Martin ND, Kepler C, Zubair M, Sayadipour A, Cohen M, Weinstein M. Increased mean arterial pressure goals after spinal cord injury and functional outcome. J Emerg Trauma Shock 2015; 8(2): 94-8. 12. Vale FL, Burns J, Jackson AB, Hadley MN. Combined medical and surgical treatment after acute spinal cord injury: results of a prospective pilot study to assess the merits of aggressive medical resuscitation and blood pressure management. J Neurosurg 1997; 87(2): 239-46. 13. Inoue T, Manley GT, Patel N, Whetstone WD. Medical and surgical management after spinal cord injury: vasopressor usage, early surgerys, and complications. J Neurotrauma 2014; 31(3): 284-91. 14. Readdy WJ, Whetstone WD, Ferguson AR, et al. Complications and outcomes of vasopressor usage in acute traumatic central cord syndrome. J Neurosurg Spine 2015: 1-7. 15. Bradley-Jacobs W. Mean Arterial Blood Pressure Treatment for Acute Spinal Cord Injury (MAPS). 2018. https://clinicaltrials.gov/ct2/show/NCT02232165.

Clinical Bottom Line

Current evidence from observational cohort studies suggests that avoiding hypotension and aiming for a higher MAP target (85 to 90mmHg) in the early phase of acute SCI has the potential to improve clinical outcome. There are no published randomised controlled trials on the topic. As such it cannot be considered established best practice, and the risks of such therapy need careful consideration on a case by case basis. Level of Evidence Level 2 – Evidence considered was neither level 1 or 3.

References

1. Behzad Sabit, Frederick Adam Zeiler, Neil Berrington The Impact of MAP on Functional Outcome Post Trauma-Related Acute Spinal Cord Injury: A Scoping Systematic Review of the Human Literature Journal Of Intensive Care 2018. Vol. 33(1) 3-15
2. Yamaan S. Saadeh, Brandon W. Smith, Jacob R. Joseph, MD, Sohaib Y. Jaffer, BA, Martin J. Buckingham, Mark E. Oppenlander, Nicholas J. Szerlip, and Paul Park The impact of blood pressure management after spinal cord injury: a systematic review of the literature Neurosurgical Focus November 2017. 43 (5):E20.