Do different anesthesia regimes affect hippocampal apoptosis and neurologic deficits in a rodent cardiac arrest model?

Stepani Bendel, Dirk Springe, Adriano Pereira, Denis Grandgirard, Stephen L Leib, Alessandro Putzu, Jannis Schlickeiser, Stephan M Jakob, Jukka Takala, Matthias Haenggi, Stepani Bendel, Dirk Springe, Adriano Pereira, Denis Grandgirard, Stephen L Leib, Alessandro Putzu, Jannis Schlickeiser, Stephan M Jakob, Jukka Takala, Matthias Haenggi

Abstract

Background: Different anesthesia regimes are commonly used in experimental models of cardiac arrest, but the effects of various anesthetics on clinical outcome parameters are unknown. We conducted a study in which we subjected rats to cardiac arrest under medetomidine/ketamine or sevoflurane/fentanyl anesthesia.

Methods: Asystolic cardiac arrest for 8 minutes was induced in 73 rats with a mixture of potassium chloride and esmolol. Daily behavioral and neurological examination included the open field test (OFT), the tape removal test (TRT) and a neurodeficit score (NDS). Animals were randomized for sacrifice on day 2 or day 5 and brains were harvested for histology in the hippocampus cornus ammonis segment CA1. The inflammatory markers IL-6, TNF-α, MCP-1 and MIP-1α were assessed in cerebrospinal fluid (CSF). Proportions of survival were tested with the Fisher's exact test, repeated measurements were assessed with the Friedman's test; the baseline values were tested using Mann-Whitney U test and the difference of results of repeated measures were compared.

Results: In 31 animals that survived beyond 24 hours neither OFT, TRT nor NDS differed between the groups; histology was similar on day 2. On day 5, significantly more apoptosis in the CA1 segment of the hippocampus was found in the sevoflurane/fentanyl group. MCP-1 was higher on day 5 in the sevoflurane/fentanyl group (p = 0.04). All other cyto- and chemokines were below detection threshold.

Conclusion: In our cardiac arrest model neurological function was not influenced by different anesthetic regimes; in contrast, anesthesia with sevoflurane/fentanyl results in increased CSF inflammation and histologic damage at day 5 post cardiac arrest.

Figures

Figure 1
Figure 1
Flow chart of the number of animals assigned into the different groups.
Figure 2
Figure 2
Mean blood pressure at different time points. Variation of blood pressure is similar in both groups. Data are shown as means and [IQR].
Figure 3
Figure 3
Temperature at different time points. Friedmans’s test within each anesthesia group is significant (both p < 0.01), but at no time there is a significant difference between both groups. Data are shown as means and [IQR].
Figure 4
Figure 4
Example of injury to the hippocampus (cresyl violet staining). Left: sham animal, right: 8 minutes cardiac arrest. The 4 different slides of one hemisphere are showing the different sections of the CA1 segment of the hippocampus while moving from rostral to caudal (starting up-left, up-right, down-left and down-right). Delineating the border of the CA1 segments is difficult in the caudal sections because of the curvature of the hippocampus. The inlays demonstrate the shrunken and pyknotic neurons, resulting in a diminished cell layer of CA1 in the cardiac arrest animal (400x). Histomorphometric analysis of the CA1 segment was performed by 1. cell count and 2. automated surface area calculation (details see Methods). The sham animal was operated in the pilot phase, and received complete surgery under sev/fnt anesthesia, but was not subjected to cardiac arrest.

References

    1. Madl C, Holzer M. Brain function after resuscitation from cardiac arrest. Curr Opin Crit Care. 2004;10(3):213–7. doi: 10.1097/01.ccx.0000127542.32890.fa.
    1. Hossmann KA. Cerebral ischemia: models, methods and outcomes. Neuropharmacology. 2008;55(3):257–70. doi: 10.1016/j.neuropharm.2007.12.004.
    1. Bernard SA, Gray TW, Buist MD, Jones BM, Silvester W, Gutteridge G, et al. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med. 2002;346(8):557–63. doi: 10.1056/NEJMoa003289.
    1. TherapeuticHypothermiaGroup Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med. 2002;346(8):549–56. doi: 10.1056/NEJMoa012689.
    1. Nielsen N, Wetterslev J, Cronberg T, Erlinge D, Gasche Y, Hassager C, et al. Targeted temperature management at 33 degrees C versus 36 degrees C after cardiac arrest. N Engl J Med. 2013;369(23):2197–206. doi: 10.1056/NEJMoa1310519.
    1. von Planta I, Weil MH, von Planta M, Bisera J, Bruno S, Gazmuri RJ, et al. Cardiopulmonary resuscitation in the rat. J Appl Physiol. 1988;65(6):2641–7.
    1. Bottiger BW, Krumnikl JJ, Gass P, Schmitz B, Motsch J, Martin E. The cerebral ‘no-reflow’ phenomenon after cardiac arrest in rats–influence of low-flow reperfusion. Resuscitation. 1997;34(1):79–87. doi: 10.1016/S0300-9572(96)01029-5.
    1. Hendrickx HH, Rao GR, Safar P, Gisvold SE. Asphyxia, cardiac arrest and resuscitation in rats. I. Short term recovery. Resuscitation. 1984;12(2):97–116. doi: 10.1016/0300-9572(84)90062-5.
    1. Rogers P, Hillman H. Biochemical changes in the blood during hypothermic cardiac arrest and recovery of rats. Resuscitation. 1972;1(1):25–9. doi: 10.1016/0300-9572(72)90060-3.
    1. Blomqvist P, Wieloch T. Ischemic brain damage in rats following cardiac arrest using a long-term recovery model. J Cereb Blood Flow Metab. 1985;5(3):420–31. doi: 10.1038/jcbfm.1985.57.
    1. Head BP, Patel P. Anesthetics and brain protection. Curr Opin Anaesthesiol. 2007;20(5):395–9. doi: 10.1097/ACO.0b013e3282efa69d.
    1. Haenggi M. Anesthesia and analgesia protocol during therapeutic hypothermia after cardiac arrest: it is time to build evidence. Anesth Analg. 2010;110(5):1259–60. doi: 10.1213/ANE.0b013e3181d77357.
    1. Hellstrom J, Owall A, Martling CR, Sackey PV. Inhaled isoflurane sedation during therapeutic hypothermia after cardiac arrest: a case series. Crit Care Med. 2014;42(2):e161–6. doi: 10.1097/CCM.0b013e3182a643d7.
    1. Katz L, Ebmeyer U, Safar P, Radovsky A, Neumar R. Outcome model of asphyxial cardiac arrest in rats. J Cereb Blood Flow Metab. 1995;15(6):1032–9. doi: 10.1038/jcbfm.1995.129.
    1. Manwani B, Liu F, Xu Y, Persky R, Li J, McCullough LD. Functional recovery in aging mice after experimental stroke. Brain Behav Immun. 2011;25(8):1689–700. doi: 10.1016/j.bbi.2011.06.015.
    1. Albertsmeier M, Teschendorf P, Popp E, Galmbacher R, Vogel P, Bottiger BW. Evaluation of a tape removal test to assess neurological deficit after cardiac arrest in rats. Resuscitation. 2007;74(3):552–8. doi: 10.1016/j.resuscitation.2007.01.040.
    1. Walsh RN, Cummins RA. The open-field test: a critical review. Psychol Bull. 1976;83(3):482–504. doi: 10.1037/0033-2909.83.3.482.
    1. Grandgirard D, Oberson K, Buhlmann A, Gaumann R, Leib SL. Attenuation of cerebrospinal fluid inflammation by the nonbacteriolytic antibiotic daptomycin versus that by ceftriaxone in experimental pneumococcal meningitis. Antimicrob Agents Chemother. 2010;54(3):1323–6. doi: 10.1128/AAC.00812-09.
    1. Schmidt-Kastner R, Freund TF. Selective vulnerability of the hippocampus in brain ischemia. Neuroscience. 1991;40(3):599–636. doi: 10.1016/0306-4522(91)90001-5.
    1. Adamczyk S, Robin E, Simerabet M, Kipnis E, Tavernier B, Vallet B, et al. Sevoflurane pre- and post-conditioning protect the brain via the mitochondrial K ATP channel. Br J Anaesth. 2010;104(2):191–200. doi: 10.1093/bja/aep365.
    1. Zhu J, Jiang X, Shi E, Ma H, Wang J. Sevoflurane preconditioning reverses impairment of hippocampal long-term potentiation induced by myocardial ischaemia-reperfusion injury. Eur J Anaesthesiol. 2009;26(11):961–8. doi: 10.1097/EJA.0b013e328330e968.
    1. Landoni G, Greco T, Biondi-Zoccai G, Nigro Neto C, Febres D, Pintaudi M, et al. Anaesthetic drugs and survival: a Bayesian network meta-analysis of randomized trials in cardiac surgery. Br J Anaesth. 2013;111(6):886–96. doi: 10.1093/bja/aet231.
    1. Meybohm P, Gruenewald M, Albrecht M, Zacharowski KD, Lucius R, Zitta K, et al. Hypothermia and postconditioning after cardiopulmonary resuscitation reduce cardiac dysfunction by modulating inflammation, apoptosis and remodeling. PLoS One. 2009;4(10):e7588. doi: 10.1371/journal.pone.0007588.
    1. Zitta K, Meybohm P, Bein B, Ohnesorge H, Steinfath M, Scholz J, et al. Cytoprotective effects of the volatile anesthetic sevoflurane are highly dependent on timing and duration of sevoflurane conditioning: findings from a human, in-vitro hypoxia model. Eur J Pharmacol. 2010;645(1–3):39–46. doi: 10.1016/j.ejphar.2010.07.017.
    1. Maier C, Steinberg GK, Sun GH, Zhi GT, Maze M. Neuroprotection by the alpha 2-adrenoreceptor agonist dexmedetomidine in a focal model of cerebral ischemia. Anesthesiology. 1993;79(2):306–12. doi: 10.1097/00000542-199308000-00016.
    1. Jolkkonen J, Puurunen K, Koistinaho J, Kauppinen R, Haapalinna A, Nieminen L, et al. Neuroprotection by the alpha2-adrenoceptor agonist, dexmedetomidine, in rat focal cerebral ischemia. Eur J Pharmacol. 1999;372(1):31–6. doi: 10.1016/S0014-2999(99)00186-7.
    1. Hudetz JA, Pagel PS. Neuroprotection by ketamine: a review of the experimental and clinical evidence. J Cardiothorac Vasc Anesth. 2010;24(1):131–42. doi: 10.1053/j.jvca.2009.05.008.
    1. Teschendorf P, Padosch SA, Spohr F, Albertsmeier M, Schneider A, Vogel P, et al. Time course of caspase activation in selectively vulnerable brain areas following global cerebral ischemia due to cardiac arrest in rats. Neurosci Lett. 2008;448(2):194–9. doi: 10.1016/j.neulet.2008.10.030.
    1. Knapp J, Bergmann G, Bruckner T, Russ N, Bottiger BW, Popp E. Pre- and postconditioning effect of Sevoflurane on myocardial dysfunction after cardiopulmonary resuscitation in rats. Resuscitation. 2013;84(10):1450–5. doi: 10.1016/j.resuscitation.2013.04.012.
    1. Ivacko J, Szaflarski J, Malinak C, Flory C, Warren JS, Silverstein FS. Hypoxic-ischemic injury induces monocyte chemoattractant protein-1 expression in neonatal rat brain. J Cereb Blood Flow Metab. 1997;17(7):759–70. doi: 10.1097/00004647-199707000-00006.
    1. Liu H, Sarnaik SM, Manole MD, Chen Y, Shinde SN, Li W, et al. Increased cytochrome c in rat cerebrospinal fluid after cardiac arrest and its effects on hypoxic neuronal survival. Resuscitation. 2012;83(12):1491–6. doi: 10.1016/j.resuscitation.2012.04.009.
    1. Rosen C, Rosen H, Andreasson U, Bremell D, Bremler R, Hagberg L, et al. Cerebrospinal fluid biomarkers in cardiac arrest survivors. Resuscitation. 2014;85(2):227–32. doi: 10.1016/j.resuscitation.2013.10.032.
    1. Langdon KD, Granter-Button S, Corbett D. Persistent behavioral impairments and neuroinflammation following global ischemia in the rat. Eur J Neurosci. 2008;28(11):2310–8. doi: 10.1111/j.1460-9568.2008.06513.x.
    1. Hsu WH, Hummel SK. Xylazine-induced hyperglycemia in cattle: a possible involvement of alpha 2-adrenergic receptors regulating insulin release. Endocrinology. 1981;109(3):825–9. doi: 10.1210/endo-109-3-825.
    1. Nurmi J, Boyd J, Anttalainen N, Westerbacka J, Kuisma M. Early increase in blood glucose in patients resuscitated from out-of-hospital ventricular fibrillation predicts poor outcome. Diabetes Care. 2012;35(3):510–2. doi: 10.2337/dc11-1478.
    1. Becker DE, Rosenberg M. Nitrous oxide and the inhalation anesthetics. Anesth Prog. 2008;55(4):124–30. doi: 10.2344/0003-3006-55.4.124.
    1. Kiryk A, Pluta R, Figiel I, Mikosz M, Ulamek M, Niewiadomska G, et al. Transient brain ischemia due to cardiac arrest causes irreversible long-lasting cognitive injury. Behav Brain Res. 2011;219(1):1–7. doi: 10.1016/j.bbr.2010.12.004.
Pre-publication history
    1. The pre-publication history for this paper can be accessed here:

Source: PubMed

Спонсоры и соавторы

Заболевания

Медикаментозные вмешательства

Подписаться