The cerebral `no-reflow' phenomenon after cardiac arrest in rats—influence of low-flow reperfusion

doi:10.1016/S0300-9572(96)01029-5

Resuscitation

Volume 34, Issue 1, February 1997, Pages 79-87

https://doi.org/10.1016/S0300-9572(96)01029-5 Get rights and content

Abstract

Objective: Experimental data indicate that early microcirculatory reperfusion is disturbed after cardiac arrest. We investigated the influence of prolonged cardiac arrest and basic life support (BLS) procedures on the quality of cerebral microcirculatory reperfusion.

Materials and methods: In mechanically ventilated male Wistar rats anesthetized with N₂O and halothane, cardiac arrest was induced by electrical fibrillation. Ten animals (group I) were subjected to 17 min of cardiac arrest (no-flow). Nine additional animals (group II) underwent only 12 min of cardiac arrest (no-flow), which was followed by a 5-min phase of BLS (i.e. mechanical ventilation and external cardiac compressions). In both groups, advanced resuscitation procedures including mechanical ventilation, external cardiac massage, 0.2 mg kg⁻¹ epinephrine, 0.5 mmol kg⁻¹ NaHCO₃, and defibrillation were started 17 min after induction of cardiac arrest. The perfusion of the cerebral microcirculation was visualized by injection of 0.3 g kg⁻¹ 15% fluorescein isothiocyanate (FITC)–albumin 5 min after restoration of spontaneous circulation (ROSC), and the animals were decapitated 2 min later. The left hemispheres were fixed in 4% formalin, and coronal sections of 200 μm thickness at three different standard levels of the rat brain were investigated using fluorescence microscopy. Areas without capillary filling (cerebral `no-reflow') were identified and calculated.

Results: ROSC could be achieved in five of 10 animals (50%) of group I, and in six of nine animals (67%) of group II (P=n.s.). The severity of cerebral `no-reflow' was higher in group II compared with group I (6.9±7.6 vs. 0.7±0.7% of total sectional areas; P≤0.05). Two sham-operated animals showed homogeneous reperfusion.

Conclusions: Wistar rats did not develop a marked cerebral `no-reflow' phenomenon after circulatory arrest. A relevant degree of cerebral `no-reflow' occurred, however, in animals subjected to a phase of BLS before circulatory stabilization. Therefore, low-flow states following prolonged cardiocirculatory arrest may aggravate early cerebral microcirculatory reperfusion disorders.

Introduction

Evidence from animal studies suggests that functional and biochemical recovery of the brain may occur even after 1 h of complete cerebrocirculatory arrest, if reperfusion is adequate [1]. In contrast, a safe recovery time for the brain of a maximum of 10 min was demonstrated in most experimental and clinical studies 2, 3. The reason for this discrepancy still remains unresolved. Growing experimental data suggest that the quality of early postischemic microcirculatory reperfusion is a relevant factor for postischemic brain recovery 4, 5, 6, 7, 8, 9, 10, 11, 12. Among the hemodynamic factors mediating postischemic brain alterations, the incompleteness of early microvascular filling, the cerebral `no-reflow' phenomenon, and the delayed postischemic hypoperfusion syndrome are of paramount interest [10]. The cerebral `no-reflow' phenomenon, first described by Ames and co-workers 4, 5, has been demonstrated to be a relevant pathogenic factor after complete cerebral ischemia and after cardiac arrest in gerbils, rabbits, primates, dogs, and cats 4, 5, 6, 7, 8, 9, 11, 12. In cats subjected to complete cardiocirculatory arrest, the severity of `no-reflow' increases significantly with the duration of cardiac arrest [6]. Following an arrest period of 15 min or more, spontaneous recirculation did not reduce the severity of `no-reflow' within 30 min of recirculation. The `no-reflow' phenomenon in early microvascular reperfusion has been shown to occur in a number of organs 13, 14. Although the precise underlying mechanisms of `no-reflow' are not well understood, endothelial cell swelling, extravascular compression due to an altered blood–brain barrier permeability 10, 11, 15, increased blood viscosity [10], adhesion and sticking of white blood cells [14], and activation of blood coagulation and platelet aggregation 16, 17, 18are most likely involved. In contrast to experimental data obtained after cardiac arrest, however, nearly homogeneous microcirculatory reperfusion was observed in rats subjected to prolonged four-vessel occlusion [19]and after selective forebrain ischemia 20, 21. Besides the animal species chosen for the experiments, cardiac arrest models and four-vessel occlusion or selective forebrain ischemia models may differ in their immediate postischemic level of reperfusion pressure [22]. Experimental data suggest that low-flow reperfusion in the early phase after complete cerebral ischemia increases cerebral damage 22, 23. It is not known, however, whether low-flow states, which occur frequently during CPR and in the early phase after cardiac arrest, may aggravate cerebral reperfusion disorders such as the `no-reflow' phenomenon. We therefore investigated the influence of prolonged cardiac arrest with or without a low-flow reperfusion phase before cardiocirculatory stabilization on the quality of early cerebral microcirculatory reperfusion in rats.

Section snippets

Animal preparation

After institutional approval by the Governmental Animal Care Committee, 21 male Wistar rats, two sham-operated and 19 experimental animals (body weight 410–500 g), were studied. All animals were handled according to the Guiding Principles published by the National Institutes of Health and the Council of the American Physiological Society [24]. The animals were anesthetized without premedication using halothane 0.8–1.5% and 70% nitrous oxide (N₂O) in oxygen (O₂). By local cut-down procedures,

Physiological variables

In the prearrest steady-state control period after animal preparation, all physiological variables were within the normal range Table 1Table 2). No differences were observed between groups regarding $P_{aO_{2}}$ , $P_{aCO_{2}}$ , pH, BE, Hb, Hct, Na⁺, and K⁺. Transesophageal electrical fibrillation with subsequent immediate circulatory arrest was achieved in all experimental animals within 10 s (see Fig. 1). No spontaneous defibrillations were observed during the period of circulatory arrest. During BLS

Discussion

Using a newly developed rodent model of cardiac arrest and reperfusion, the present study demonstrates for the fist time that male Wistar rats subjected to 17 min of complete circulatory arrest did not develop a relevant cerebral `no-reflow' phenomenon 7 min after hemodynamic stabilization (ROSC). We used 17 min of cardiac arrest in the present study, because cerebral `no-reflow' has been demonstrated to increase with the duration of cardiac arrest [6], and because 50% and more of all animals

Acknowledgements

This study was supported by a grant of the Medical Faculty of the University of Heidelberg, Heidelberg, Germany (No. 11/94; to Bernd W. Böttiger). The authors would like to thank Professor K.-A. Hossmann (Director of the Max-Planck-Institute for Neurological Research, Department of Experimental Neurology, Cologne, Germany) and M. Fischer (Department of Anesthesiology, University of Bonn, Bonn, Germany) for support and relevant discussions in developing the model and the technique of

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¹: Presented in part at the XVIIth International Symposium on Cerebral Blood Flow and Metabolism `BRAIN 95', Cologne, Germany, July 2–6, 1995; and at the American Society of Anesthesiologists Annual Meeting, Atlanta, USA, October 21–25, 1995.

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The cerebral `no-reflow' phenomenon after cardiac arrest in rats—influence of low-flow reperfusion1