Remote ischaemic perconditioning as an adjunct therapy to thrombolysis in patients with acute ischaemic stroke a randomised trial

Hougaard KD, Niels H, Dora Z, Leif S, Anne N, Troels MH, et al. Remote ischaemic perconditioning as an adjunct therapy to thrombolysis in patients with acute ischaemic stroke a randomised trial. Stroke 2014:159-67.

Preconditioning is a procedure by which a noxious stimulus near to but below the threshold of damage is applied to the tissue through which the organ (and therefore the organism) develops resistance to, or tolerance of, the same, similar or even different noxious stimuli given beyond the threshold of damage thereby conferring protection. Ulrich Dirnagl et al., [1] in their review article published in Lancet Neurology dwells on the mechanisms of ischaemic preconditioning and its possible clinical uses. Basically sub-threshold ischaemia protects through four ways which are increased substrate delivery (via angiogenesis), metabolic downregulation through gene modulation, antagonism of damaging pathways (downregulation of NMDA and AMPA receptors) and improved recovery by stimulating progenitor cells in the subventricular zone of the lateral ventricles and the subgranular zone in the hippocampal dentate gyrus.

The current study by Hougaard et al., is an open-label blinded outcome proof-of-concept study of prehospital, paramedic-administered remote ischaemic preconditioning through (rPerC) intermittent upper arm ischaemia in patients with suspected acute stroke. Post-neurological examination and MRI, patients with verified stroke receiving alteplase treatment were included and had MRI at 24 hours and 1 month and clinical re-examination after 3 months. The primary end point was penumbral salvage, defined as the volume of the perfusion–diffusion mismatch not progressing to infarction after 1 month. Four hundred and forty-three patients were enrolled out of which 247 received rPerC while 196 had standard treatment. Transient ischaemic attack was more frequent (P = 0.006), and NIHSS on admission was lower (P = 0.016) in the intervention group compared with controls. Although penumbral salvage, infarct growth and size at 1 month, and clinical outcome after 3 months did not differ among groups but the authors concluded that prehospital rPerC may have immediate neuroprotective effects.

Hahn et al., [2] carried out the first study showing the effectiveness of preconditioning as a neuroprotective strategy. Thirty nine male P60 Sprague-Dawley rats were randomly allocated to three groups: a control group, which received no intervention, a preconditioning group through transient limb ischaemia 40 minutes before surgery and a per-conditioning group where it was initiated 40 minutes before reperfusion. Focal cerebral ischaemia was achieved using transient right middle cerebral artery occlusion, performed surgically under isoflurane anaesthesia. The resulting infarct size at 24 hours was quantified using computerised image analysis of 2–3-5-triphenyl tetrazolium chloride-stained brain sections. It was observed that compared with control, preconditioning significantly reduced brain infarct size with the more clinically relevant per-conditioning stimulus being superior to preconditioning. The authors concluded that remote per-conditioning by transient limb ischaemia provides potent neuroprotection in a model of regional brain ischaemia–reperfusion injury.

In 2012 Meng et al., [3] studied the protective effectiveness of brief repetitive bilateral arm ischaemic preconditioning (BAIPC) on stroke recurrence in patients with symptomatic atherosclerotic intracranial arterial stenosis (IAS). Sixty-eight patients were enrolled with symptomatic IAS, diagnosed by imaging in this prospective and randomised study. All patients received standard medical management. Patients in the BAIPC group (n = 38) underwent five brief cycles consisting of bilateral upper limb ischaemia followed by reperfusion. The BAIPC procedure was performed twice daily over 300 consecutive days. Incidence of recurrent stroke and cerebral perfusion status in BAIPC-treated patients were compared with the untreated control group (n = 30). In the control group, incidence of recurrent stroke at 90 and 300 days were 23.3% and 26.7%, respectively. In the BAIPC group, incidence of recurrent stroke was reduced to 5% and 7.9% at 90 and 300 days (P < 0.01), respectively. The average time to recovery (modified Rankin Scale score 0-1) was also shortened by BAIPC. Cerebral perfusion status, measured by SPECT and transcranial Doppler sonography, improved remarkably in BAIPC-treated brain than in control (P < 0.01). It was concluded that BAIPC may be an effective way to improve cerebral perfusion and reduce recurrent strokes in patients with IAS.

A Cochrane database review[4] in 2011 on remote ischaemic preconditioning versus no remote ischaemic preconditioning for vascular and endovascular surgical procedures conclude insufficient data at present to say whether remote ischaemic preconditioning has any beneficial or harmful effects. There is a need for further randomised trials on this technique to give shape to definite therapeutic guidelines.

• REFERENCES

• 1 Dirnagl U, Becker K, Meisel A. Preconditioning and tolerance against cerebral ischaemia: From experimental strategies to clinical use. Lancet Neurol 2009; 8: 398-412
• 2 Hahn CD, Manlhiot C, Schmidt MR, Nielsen TT, Redington AN. Remote ischemic per-conditioning a novel therapy for acute stroke?. Stroke 2011; 42: 2960-2
• 3 Meng R, Asmaro K, Meng L, Liu Y, Ma C, Xi C. Upper limb ischemic preconditioning prevents recurrent stroke in intracranial arterial stenosis. Neurology 2012; 79: 1853-61
• 4 Desai M, Gurusamy KS, Ghanbari H, Hamilton G, Seifalian AM. Remote ischaemic preconditioning versus no remote ischaemic preconditioning for vascular and endovascular surgical procedures. Cochrane Database Syst Rev 2011; 12 DOI: CD008472.