Skip to main content

Advertisement

SpringerLink
Log in

Remote Ischemic Pre-conditioning in Subarachnoid Hemorrhage: A Prospective Pilot Trial

  • Original work
  • Published:
Neurocritical Care Aims and scope Submit manuscript

Abstract

Background

Cerebral injury from aneurysmal subarachnoid hemorrhage (aSAH) is twofold. The initial hemorrhage causes much of the injury; secondary injury can occur from delayed cerebral ischemia (DCI). Remote ischemic preconditioning (RIPC) is a mechanism of organ protection in response to transient ischemia within a distant organ. This pilot trial sought to apply RIPC in patients with aSAH to evaluate its effect on secondary cerebral injury and resultant outcomes.

Methods

Patients were randomized to the high-pressure occlusion group (HPO) or the low-pressure occlusion group (LPO). Lower extremity RIPC treatment was initiated within 72 h of symptom onset and every other day for 14 days or until Intensive Care Unit (ICU) discharge. In HPO, each treatment consisted of 4 five-minute cycles of manual blood pressure cuff inflation with loss of distal pulses. LPO received cuff inflation with lower pressures while preserving distal pulses. Retrospectively matched controls were also analyzed. Efficacy of treatment was measured by total days spent in vasospasm out of study enrollment days, hospital and ICU length of stay (LOS), cerebral infarction, one and six month modified Rankin score, and mortality.

Results

The final analysis included 33 patients with 11 in each group. Patient demographics, aneurysm location, admission airway status, Glasgow Coma Scale (GCS), modified Rankin score, Hunt and Hess score, modified Fisher Score and aneurysm management were not significantly different between groups. Hospital and ICU LOS was shorter in LPO compared to the control (p = 0·0468 and p = 0·0409, respectively). Total vasospasm days/study enrollment days, cerebral infarction, one and six month modified Rankin score, and mortality were not significantly different between the groups.

Conclusions

This pilot trial did demonstrate feasibility and safety. The shortened LOS in the LPO may implicate a protective role of RIPC and warrants future study.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. van Gijn J, Kerr RS, Rinkel GJ. Subarachnoid haemorrhage. Lancet. 2007;369:306–18.

    Article  Google Scholar 

  2. Koch S, Gonzalez N. Preconditioning the human brain: proving the principle in subarachnoid hemorrhage. Stroke. 2013;44:1748–53.

    Article  Google Scholar 

  3. Vergouwen MDI, Vermeulen M, van Gijn J, et al. Definition of delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage as an outcome event in clinical trials and observational studies. Stroke. 2010;41:2391–5.

    Article  Google Scholar 

  4. Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation. 1986;74(5):1124–36.

    Article  CAS  Google Scholar 

  5. Kharbanda RK, Mortensen UM, White PA, et al. Transient limb ischemia induces remote ischemic preconditioning in vivo. Circulation. 2002;106(23):2881–3.

    Article  CAS  Google Scholar 

  6. Jones H, Hopkins N, Bailey TG, et al. Seven-day remote ischemic preconditioning improves local and systemic endothelial function and microcirculation in healthy humans. Am J Hypertens. 2014;27:918–25.

    Article  Google Scholar 

  7. Kimura M, Ueda K, Goto C, et al. Repetition of ischemic preconditioning augments endothelium-dependent vasodilation in humans: role of endothelium-derived nitric oxide and endothelial progenitor cells. ArteriosclerThrombVascBiol. 2007;27:1403–10.

    CAS  Google Scholar 

  8. Meng R, Asmaro K, Meng L, et al. Upper limb ischemic preconditioning prevents recurrent stroke in intracranial arterial stenosis. Neurology. 2012;79:1853–61.

    Article  Google Scholar 

  9. Gonzalez NR, Hamilton R, Bilgin-Freiert A, et al. Cerebral hemodynamic and metabolic effects of remote ischemic preconditioning in patients with subarachnoid hemorrhage. ActaNeurochirSuppl. 2013;115:193–8.

    Google Scholar 

  10. Bruno A, Akinwuntan AE, Lin C, et al. Simplified modified rankin scale questionnaire: reproducibility over the telephone and validation with quality of life. Stroke. 2011;42(8):2276–9.

    Article  Google Scholar 

  11. Birkett MA, Day SJ. Internal pilot studies for estimating sample size. Stat Med. 1994;13:2455–63.

    Article  CAS  Google Scholar 

  12. Kieser M, Wassmer G. On the use of the upper confidence limit for the variance from a pilot sample for sample size determination. Biometrical J. 1996;8:941–9.

    Article  Google Scholar 

  13. Connolly ES, Rabinstein AA, Carhuapoma JR, et al. Guidelines for the management of aneurysmal subarachnoid hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2012;43:1711–37.

    Article  Google Scholar 

  14. Diringer MN, Bleck TP, Claude Hemphill J, et al. Critical care management of patients following aneurysmal subarachnoid hemorrhage: recommendations from the neurocritical care society’s multidisciplinary consensus conference. Neurocrit Care. 2011;15(2):211–40.

    Article  Google Scholar 

  15. D'Souza S. Aneurysmal Subarachnoid Hemorrhage. J NeurosurgAnesthesiol. 2015;27(3):222–40.

    Google Scholar 

  16. Geraghty JR, Testai FD. Delayed cerebral ischemia after subarachnoid hemorrhage: beyond vasospasm and towards a multifactorial pathophysiology. CurrAtheroscler Rep. 2017;19(12):50.

    Google Scholar 

  17. Pickard JM, Davidson SM, Hausenloy DJ, Yellon DM. Co-dependence of the neural and humoral pathways in the mechanism of remote ischemic conditioning. Basic Res Cardiol. 2016;111:50.

    Article  Google Scholar 

  18. Billah M, Ridiandries A, Allahwala U, et al. Circulating mediators of remote ischemic preconditioning: search for the missing link between non-lethal ischemia and cardioprotection. Oncotarget. 2019;10(2):216–44.

    Article  Google Scholar 

  19. Hausenloy DJ, Yellon DM. Preconditioning and postconditioning: underlying mechanisms and clinical application. Atherosclerosis. 2009;204:334–41.

    Article  CAS  Google Scholar 

  20. Nikkola E, Laiwalla A, Ko A, et al. Remote ischemic conditioning alters methylation and expression of cell cycle genes in aneurysmal subarachnoid hemorrhage. Stroke. 2015;46:2445–51.

    Article  CAS  Google Scholar 

  21. Mayor F, Bilgin-Freiert A, Connolly M, et al. Effects of remote ischemic preconditioning on the coagulation profile of patients with aneurysmal subarachnoid hemorrhage: a case-control study. Neurosurgery. 2013;73(5):808–15.

    Article  Google Scholar 

  22. Vellimana AK, Milner E, Azad TD, et al. Endothelial nitric oxide synthase mediates endogenous protection against subarachnoid hemorrhage-induced cerebral vasospasm. Stroke. 2011;42:776–82.

    Article  CAS  Google Scholar 

  23. Smithason S, Moore SK, Provencio JJ. Low-dose lipopolysaccharide injection prior to subarachnoid hemorrhage modulates delayed deterioration associated with vasospasm in subarachnoid hemorrhage. ActaNeurochirSuppl. 2013;115:253.

    Google Scholar 

  24. Røpcke DM, Hjortdal VE, Toft GE, et al. Remote ischemic preconditioning reduces thrombus formation in the rat. J ThrombHaemost. 2012;10:2405–6.

    Article  Google Scholar 

  25. Karaoglan A, Akdemir O, Barut S, et al. The effects of resveratrol on vasospasm after experimental subarachnoidalhemorrhage in rats. SurgNeurol. 2008;70:337–43.

    Google Scholar 

  26. Zhao W, Li S, Ren C, Meng R, et al. Remote ischemic conditioning for stroke: clinical data, challenges, and future directions. Ann ClinTranslNeurol. 2018;6(1):186–96.

    Google Scholar 

  27. Dankbaar JW, Rijsdijk M, van der Schaaf IC, et al. Relationship between vasospasm, cerebral perfusion, and delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage. Neuroradiology. 2009;51(12):813–9.

    Article  Google Scholar 

  28. Dhar R, Diringer MN. Relationship between angiographic vasospasm, cerebral blood flow, and cerebral infarction after subarachnoid hemorrhage. ActaNeurochirSuppl. 2015;120:161–5.

    Google Scholar 

  29. Laiwalla AN, Ooi YC, Liou R, Gonzalez NR. Matched cohort analysis of effects of limb remote ischemic conditioning in patients with aneurysmal subarachnoid hemorrhage. Transl Stroke Res. 2016;7(1):42–8.

    Article  Google Scholar 

  30. Gonzalez NR, Connolly M, Dusick JR, et al. Phase I clinical trial for the feasibility and safety of remote ischemic conditioning for aneurysmal subarachnoid hemorrhage. Neurosurgery. 2014;75:590–8.

    Article  Google Scholar 

  31. Zhao W, Meng R, Ma C, et al. Safety and efficacy of remote ischemic preconditioning in patients with severe carotid artery stenosis before carotid artery stenting: a proof-of-concept, randomized controlled trial. Circulation. 2017;135(14):1325–35.

    Article  Google Scholar 

  32. Li S, Ma C, Shao G, et al. Safety and feasibility of remote limb ischemic preconditioning in patients with unilateral middle cerebral artery stenosis and healthy volunteers. Cell Transpl. 2015;24(9):1901–11.

    Article  Google Scholar 

  33. Ahmad AM, Ali GS, Tariq W. Remote ischemic preconditioning is a safe adjuvant technique to myocardial protection but adds no clinical benefit after on-pump coronary artery bypass grafting. Heart Surg Forum. 2014;17(4):E220–E22323.

    Article  Google Scholar 

  34. Koch S, Katsnelson M, Dong C, Perez-Pinzon M. Remote ischemic limb preconditioning after subarachnoid hemorrhage: a phase Ib study of safety and feasibility. Stroke. 2011;42(5):1387–91.

    Article  Google Scholar 

Download references

Acknowledegments

None.

Funding

This project was departmentally supported.

Author information

Authors and Affiliations

  1. Department of Anesthesiology and Critical Care Center, Loma Linda University Medical Center, 11234 Anderson Street, Loma Linda, CA, 92354, USA

    Ronak N. Raval, Kristel Magsino, Briahnna Austin & Ihab Dorotta

  2. Department of Anesthesiology, Swedish Medical Center, Seattle, USA

    Oliver Small

  3. Department of Surgery, VA Loma Linda Healthcare System, Loma Linda, USA

    Ronak N. Raval

  4. Department of Neurosurgery, Cleveland Clinic of Case Western Reserve School of Medicine, Cleveland, USA

    Vikram Chakravarthy

  5. Department of Anesthesiology, Davis Medical Center, University of California, Sacramento, USA

    Richard Applegate

Authors
  1. Ronak N. Raval
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Oliver Small
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kristel Magsino
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Vikram Chakravarthy
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Briahnna Austin
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Richard Applegate
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ihab Dorotta
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

RNR study design, acquisition of data, analysis of data, drafting the article and final approval of the version to be published. OS study design, acquisition of data, revising article critically for important intellectual content and final approval of the version to be published. KM and VC acquisition of data, revising article critically for important intellectual content and final approval of the version to be published. BA analysis of data, revising article critically for important intellectual content and final approval of the version to be published. RA substantial contributions to conception, analysis of data, revising article critically for important intellectual content and final approval of the version to be published. ID substantial contributions to conception and design, analysis of data, revising article critically for important intellectual content and final approval of the version to be published.

Corresponding author

Correspondence to Ronak N. Raval.

Ethics declarations

Conflicts of interest

All authors have no conflicts of interest.

Ethical Approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed Consent

Informed consent was obtained from all individual participants included in the study.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Raval, R.N., Small, O., Magsino, K. et al. Remote Ischemic Pre-conditioning in Subarachnoid Hemorrhage: A Prospective Pilot Trial. Neurocrit Care 34, 968–973 (2021). https://doi.org/10.1007/s12028-020-01122-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12028-020-01122-y

Keywords

Search

Navigation