Advertisement

Neurocritical Care

, Volume 27, Issue 3, pp 341–349 | Cite as

SANGUINATE™ (PEGylated Carboxyhemoglobin Bovine) Improves Cerebral Blood Flow to Vulnerable Brain Regions at Risk of Delayed Cerebral Ischemia After Subarachnoid Hemorrhage

  • Rajat Dhar
  • Hemant Misra
  • Michael N. Diringer
Original Article

Abstract

Background

Delayed cerebral ischemia (DCI) after subarachnoid hemorrhage (SAH) has been linked to focal reductions in cerebral blood flow (CBF) and microvascular impairments in oxygen delivery. Effective therapies that restore flow and oxygen transport to vulnerable brain regions are currently lacking. SANGUINATE is a dual-action carbon monoxide-releasing and hemoglobin-based oxygen transfer agent with efficacy in animal models of focal brain ischemia and tolerability in patients with sickle cell disease.

Methods

We performed a safety and proof-of-principle study in 12 SAH patients at risk of DCI across three escalating doses (160, 240, and 320 mg/kg). We used 15O-PET (performed at baseline, after SANGUINATE and at 24 h) to evaluate efficacy for improving CBF and restoring flow–metabolism balance (assessed by oxygen extraction fraction [OEF]) to vulnerable regions (defined as baseline OEF ≥ 0.50).

Results

SANGUINATE resulted in a transient rise in mean arterial pressure (116 ± 15–127 ± 13 mm Hg, p = 0.001) that normalized by 24 h and allowed three patients with DCI to be weaned off vasopressors. No adverse events were noted during infusion. Global CBF did not rise (43 ± 8–46 ± 9 ml/100 g/min) although a trend was seen at the highest dose (45 ± 7–51 ± 9, p = 0.044). However, a significant 16% rise in regional CBF associated with reduction in OEF was seen in vulnerable regions, but did not persist at 24 h.

Conclusions

We demonstrated that this novel agent can improve regional CBF and may improve oxygen supply–demand balance. Clinical studies (likely with repeat dosing) are required to evaluate whether this effect can prevent DCI or cerebral infarction.

Keywords

Cerebral blood flow Brain ischemia Subarachnoid hemorrhage Vasospasm 

Notes

Acknowledgements

We would like to thank Michelle Allen and Hussain Jafri for their instrumental assistance in performing this study.

Funding

This study was funded by Prolong Pharmaceuticals who provided the study drug and research assistance.

Compliance with Ethical Standards

Conflict of interest

Hemant Misra is an employee of Prolong Pharmaceuticals. All other authors declare that they have no related conflicts of interest.

Ethical Approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institution and with the 1964 Helsinki declaration and its later amendments.

References

  1. 1.
    Kak VK, Taylor AR. Cerebral blood flow in subarachnoid hemorrhage. Lancet. 1967;1:875–7.CrossRefPubMedGoogle Scholar
  2. 2.
    Grubb RL Jr, Raichle MEME, Eichling JOO, Gado MHH, Grubb RL. Effects of subarachnoid hemorrhage on cerebral blood volume, blood flow, and oxygen utilization in humans. J Neurosurg. 1977;46:446–53.CrossRefPubMedGoogle Scholar
  3. 3.
    Powers WJ, Grubb RL, Baker RP, Mintun MA, Raichle ME. Regional cerebral blood flow and metabolism in reversible ischemia due to vasospasm. Determination by positron emission tomography. J Neurosurg. 1985;62:539–46.CrossRefPubMedGoogle Scholar
  4. 4.
    Rabinstein AA, Weigand S, Atkinson JLD, Wijdicks EF. Patterns of cerebral infarction in aneurysmal subarachnoid hemorrhage. Stroke. 2005;36:992–7.CrossRefPubMedGoogle Scholar
  5. 5.
    Vergouwen MDI, Etminan N, Ilodigwe D, Macdonald RL. Lower incidence of cerebral infarction correlates with improved functional outcome after aneurysmal subarachnoid hemorrhage. J Cereb Blood Flow Metab. 2011;31:1545–53.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Etminan N, Vergouwen MDI, Ilodigwe D, Macdonald RL. Effect of pharmaceutical treatment on vasospasm, delayed cerebral ischemia, and clinical outcome in patients with aneurysmal subarachnoid hemorrhage: a systematic review and meta-analysis. J Cereb Blood Flow Metab. 2011;31:1443–51.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Dhar R, Scalfani MT, Blackburn S, Zazulia AR, Videen T, Diringer M. Relationship between angiographic vasospasm and regional hypoperfusion in aneurysmal subarachnoid hemorrhage. Stroke. 2012;43:1788–94.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Dhar R, Zazulia AR, Derdeyn CP, Diringer MN. RBC transfusion improves cerebral oxygen delivery in subarachnoid hemorrhage. Crit Care Med. 2017;45:653–9.CrossRefPubMedGoogle Scholar
  9. 9.
    Smith MJ, Le Roux PD, Elliott JP, Winn HR. Blood transfusion and increased risk for vasospasm and poor outcome after subarachnoid hemorrhage. J Neurosurg. 2004;101:1–7.CrossRefPubMedGoogle Scholar
  10. 10.
    Levine J, Kofke A, Cen L, et al. Red blood cell transfusion is associated with infection and extracerebral complications after subarachnoid hemorrhage. Neurosurgery. 2010;66:312–8 (discussion 8).CrossRefPubMedGoogle Scholar
  11. 11.
    Ryter SW, Otterbein LE. Carbon monoxide in biology and medicine. BioEssays. 2004;26:270–80.CrossRefPubMedGoogle Scholar
  12. 12.
    Klaus JA, Kibler KK, Abuchowski A, Koehler RC. Early treatment of transient focal cerebral ischemia with bovine PEGylated carboxy hemoglobin transfusion. Artif Cells Blood Substit Immobil Biotechnol. 2010;38:223–9.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Zhang J, Cao S, Kwansa H, Crafa D, Kibler KK, Koehler RC. Transfusion of hemoglobin-based oxygen carriers in the carboxy state is beneficial during transient focal cerebral ischemia. J Appl Physiol. 1985;2012(113):1709–17.Google Scholar
  14. 14.
    Misra H, Lickliter J, Kazo F, Abuchowski A. PEGylated carboxyhemoglobin bovine (SANGUINATE): results of a phase I clinical trial. Artif Organs. 2014;38:702–7.CrossRefPubMedGoogle Scholar
  15. 15.
    Misra H, Bainbridge J, Berryman J, et al. A phase Ib open label, randomized, safety study of SANGUINATE in patients with sickle cell anemia. Rev Bras Hematol Hemoter. 2017;39:20–7.CrossRefPubMedGoogle Scholar
  16. 16.
    Abuchowski A. PEGylated bovine carboxyhemoglobin (SANGUINATE): results of clinical safety testing and use in patients. Adv Exp Med Biol. 2016;876:461–7.CrossRefPubMedGoogle Scholar
  17. 17.
    Raichle ME, Martin WR, Herscovitch P, Mintun MA, Markham J. Brain blood flow measured with intravenous H2(15)O. II. Implementation and validation. J Nucl Med Off Publ Soc Nucl Med. 1983;24:790–8.Google Scholar
  18. 18.
    Videen TO, Perlmutter JS, Herscovitch P, Raichle ME. Brain blood volume, flow, and oxygen utilization measured with 15O radiotracers and positron emission tomography: revised metabolic computations. J Cereb Blood Flow Metab. 1987;7:513–6.CrossRefPubMedGoogle Scholar
  19. 19.
    Woodson RD, Fitzpatrick JH, Costello DJ, Gilboe DD. Increased blood oxygen affinity decreases canine brain oxygen consumption. J Lab Clin Med. 1982;100:411–24.PubMedGoogle Scholar
  20. 20.
    Kassell NF, Peerless SJ, Durward QJ, Beck DW, Drake CG, Adams HP. Treatment of ischemic deficits from vasospasm with intravascular volume expansion and induced arterial hypertension. Neurosurgery. 1982;11:337–43.CrossRefPubMedGoogle Scholar
  21. 21.
    Diringer MN, Dhar R, Scalfani M, et al. Effect of high-dose simvastatin on cerebral blood flow and static autoregulation in subarachnoid hemorrhage. Neurocrit Care. 2016;25:56–63.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Kumar A, Brown R, Dhar R, et al. Early versus delayed cerebral infarction after aneurysm repair after subarachnoid hemorrhage. Neurosurgery. 2013;73:617–23 (discussion 23).CrossRefPubMedGoogle Scholar
  23. 23.
    Ananthakrishnan R, Li Q, O’Shea KM, et al. Carbon monoxide form of PEGylated hemoglobin protects myocardium against ischemia/reperfusion injury in diabetic and normal mice. Artif Cells Nanomed Biotechnol. 2013;41:428–36.CrossRefPubMedGoogle Scholar
  24. 24.
    Ekelund A, Reinstrup P, Ryding E, et al. Effects of iso- and hypervolemic hemodilution on regional cerebral blood flow and oxygen delivery for patients with vasospasm after aneurysmal subarachnoid hemorrhage. Acta Neurochir. 2002;144:703–12.CrossRefPubMedGoogle Scholar
  25. 25.
    Astrup J, Siesjo BK, Symon L. Thresholds in cerebral ischemia—the ischemic penumbra. Stroke. 1981;12:723–5.CrossRefPubMedGoogle Scholar
  26. 26.
    Frykholm P, Andersson JLR, Långström B, Persson L, Enblad P. Haemodynamic and metabolic disturbances in the acute stage of subarachnoid haemorrhage demonstrated by PET. Acta Neurol Scand. 2004;109:25–32.CrossRefPubMedGoogle Scholar
  27. 27.
    Hayashi T, Watabe H, Kudomi N, et al. A theoretical model of oxygen delivery and metabolism for physiologic interpretation of quantitative cerebral blood flow and metabolic rate of oxygen. J Cereb Blood Flow Metab. 2003;23:1314–23.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  1. 1.Department of Neurology (Division of Neurocritical Care)Washington University School of Medicine in St. LouisSt. LouisUSA
  2. 2.Prolong PharmaceuticalsSouth PlainfieldUSA

Personalised recommendations