Skip to main content
Top
Published in: Critical Care 1/2015

Open Access 01-12-2015 | Research

Inhaled nitric oxide improves transpulmonary blood flow and clinical outcomes after prolonged cardiac arrest: a large animal study

Authors: Matthias Derwall, Andreas Ebeling, Kay Wilhelm Nolte, Joachim Weis, Rolf Rossaint, Fumito Ichinose, Christoph Nix, Michael Fries, Anne Brücken

Published in: Critical Care | Issue 1/2015

Login to get access

Abstract

Introduction

The probability to achieve a return of spontaneous circulation (ROSC) after cardiac arrest can be improved by optimizing circulation during cardiopulomonary resuscitation using a percutaneous left ventricular assist device (iCPR). Inhaled nitric oxide may facilitate transpulmonary blood flow during iCPR and may therefore improve organ perfusion and outcome.

Methods

Ventricular fibrillation was electrically induced in 20 anesthetized male pigs. Animals were left untreated for 10 minutes before iCPR was attempted. Subjects received either 20 ppm of inhaled nitric oxide (iNO, n = 10) or 0 ppm iNO (Control, n = 10), simultaneously started with iCPR until 5 hours following ROSC. Animals were weaned from the respirator and followed up for five days using overall performance categories (OPC) and a spatial memory task. On day six, all animals were anesthetized again, and brains were harvested for neurohistopathologic evaluation.

Results

All animals in both groups achieved ROSC. Administration of iNO markedly increased iCPR flow during CPR (iNO: 1.81 ± 0.30 vs Control: 1.64 ± 0.51 L/min, p < 0.001), leading to significantly higher coronary perfusion pressure (CPP) during the 6 minutes of CPR (25 ± 13 vs 16 ± 6 mmHg, p = 0.002). iNO-treated animals showed significantly lower S-100 serum levels thirty minutes post ROSC (0.26 ± 0.09 vs 0.38 ± 0.15 ng/mL, p = 0.048), as well as lower blood glucose levels 120–360 minutes following ROSC. Lower S-100 serum levels were reflected by superior clinical outcome of iNO-treated animals as estimated with OPC (3 ± 2 vs. 5 ± 1, p = 0.036 on days 3 to 5). Three out of ten iNO-treated, but none of the Control animals were able to successfully participate in the spatial memory task. Neurohistopathological examination of vulnerable cerebral structures revealed a trend towards less cerebral lesions in neocortex, archicortex, and striatum in iNO-treated animals compared to Controls.

Conclusions

In pigs resuscitated with mechanically-assisted CPR from prolonged cardiac arrest, the administration of 20 ppm iNO during and following iCPR improved transpulmonary blood flow, leading to improved clinical neurological outcomes.
Literature
1.
go back to reference Field JM, Hazinski MF, Sayre MR, Chameides L, Schexnayder SM, Hemphill R, Samson RA, Kattwinkel J, Berg RA, Bhanji F, et al. Part 1: executive summary: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2010;122:S640–656 Field JM, Hazinski MF, Sayre MR, Chameides L, Schexnayder SM, Hemphill R, Samson RA, Kattwinkel J, Berg RA, Bhanji F, et al. Part 1: executive summary: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2010;122:S640–656
2.
go back to reference Derwall M, Brücken A, Bleilevens C, Ebeling A, Fohr P, Rossaint R, Kern KB, Nix C, Fries M. Doubling survival and improving clinical outcomes using a left ventricular assist device instead of chest compressions for resuscitation after prolonged cardiac arrest: a large animal study. Crit Care. 2015;19:123. Derwall M, Brücken A, Bleilevens C, Ebeling A, Fohr P, Rossaint R, Kern KB, Nix C, Fries M. Doubling survival and improving clinical outcomes using a left ventricular assist device instead of chest compressions for resuscitation after prolonged cardiac arrest: a large animal study. Crit Care. 2015;19:123.
3.
go back to reference Ichinose F, Roberts JD, Jr., Zapol WM. Inhaled nitric oxide: a selective pulmonary vasodilator: current uses and therapeutic potential. Circulation. 2004;109:3106–3111. Ichinose F, Roberts JD, Jr., Zapol WM. Inhaled nitric oxide: a selective pulmonary vasodilator: current uses and therapeutic potential. Circulation. 2004;109:3106–3111.
4.
go back to reference Zapol WM. Life at the frontier: the third annual John W. Severinghaus lecture on translational science. Anesthesiology. 2011; 114:771–781. Zapol WM. Life at the frontier: the third annual John W. Severinghaus lecture on translational science. Anesthesiology. 2011; 114:771–781.
5.
go back to reference Hataishi R, Rodrigues AC, Neilan TG, Morgan JG, Buys E, Shiva S, Tambouret R, Jassal DS, Raher MJ, Furutani E, et al. Inhaled nitric oxide decreases infarction size and improves left ventricular function in a murine model of myocardial ischemia-reperfusion injury. American Journal of Physiology - Heart and Circulatory Physiology. 2006;291:H379–H384. Hataishi R, Rodrigues AC, Neilan TG, Morgan JG, Buys E, Shiva S, Tambouret R, Jassal DS, Raher MJ, Furutani E, et al. Inhaled nitric oxide decreases infarction size and improves left ventricular function in a murine model of myocardial ischemia-reperfusion injury. American Journal of Physiology - Heart and Circulatory Physiology. 2006;291:H379–H384.
6.
go back to reference Liu X, Huang Y, Pokreisz P, Vermeersch P, Marsboom G, Swinnen M, Verbeken E, Santos J, Pellens M, Gillijns H, et al. Nitric oxide inhalation improves microvascular flow and decreases infarction size after myocardial ischemia and reperfusion. J Am CollCardiol. 2007;50:808–817. Liu X, Huang Y, Pokreisz P, Vermeersch P, Marsboom G, Swinnen M, Verbeken E, Santos J, Pellens M, Gillijns H, et al. Nitric oxide inhalation improves microvascular flow and decreases infarction size after myocardial ischemia and reperfusion. J Am CollCardiol. 2007;50:808–817.
7.
go back to reference Lang JD, Jr., Teng X, Chumley P, Crawford JH, Isbell TS, Chacko BK, Liu Y, Jhala N, Crowe DR, Smith AB, et al. Inhaled NO accelerates restoration of liver function in adults following orthotopic liver transplantation. J Clin Invest. 2007;117:2583–2591. Lang JD, Jr., Teng X, Chumley P, Crawford JH, Isbell TS, Chacko BK, Liu Y, Jhala N, Crowe DR, Smith AB, et al. Inhaled NO accelerates restoration of liver function in adults following orthotopic liver transplantation. J Clin Invest. 2007;117:2583–2591.
8.
go back to reference Lovich MA, Pezone MJ, Wakim MG, Denton RJ, Maslov MY, Murray MR, Tsukada H, Agnihotri AK, Roscigno RF, Gamero LG, et al. Inhaled Nitric Oxide Augments Left Ventricular Assist Device Capacity by Ameliorating Secondary Right Ventricular Failure. ASAIO journal. 2015; 61:379–385. Lovich MA, Pezone MJ, Wakim MG, Denton RJ, Maslov MY, Murray MR, Tsukada H, Agnihotri AK, Roscigno RF, Gamero LG, et al. Inhaled Nitric Oxide Augments Left Ventricular Assist Device Capacity by Ameliorating Secondary Right Ventricular Failure. ASAIO journal. 2015; 61:379–385.
9.
go back to reference Derwall M, Timper A, Kottmann K, Rossaint R, Fries M. Neuroprotective effects of the inhalational anesthetics isoflurane and xenon after cardiac arrest in pigs. Crit Care Med. 2008;36:S492–495. Derwall M, Timper A, Kottmann K, Rossaint R, Fries M. Neuroprotective effects of the inhalational anesthetics isoflurane and xenon after cardiac arrest in pigs. Crit Care Med. 2008;36:S492–495.
10.
go back to reference Fries M, Nolte K, Demir F, Kottmann K, Timper A, Coburn M, Weis J, Rossaint R. Neurocognitive performance after cardiopulmonary resuscitation in pigs. Crit Care Med. 2008;36:842–847. Fries M, Nolte K, Demir F, Kottmann K, Timper A, Coburn M, Weis J, Rossaint R. Neurocognitive performance after cardiopulmonary resuscitation in pigs. Crit Care Med. 2008;36:842–847.
11.
go back to reference Fries M, Nolte KW, Coburn M, Rex S, Timper A, Kottmann K, Siepmann K, Hausler M, Weis J, Rossaint R. Xenon reduces neurohistopathological damage and improves the early neurological deficit after cardiac arrest in pigs. Crit Care Med. 2008;36:2420–2426. Fries M, Nolte KW, Coburn M, Rex S, Timper A, Kottmann K, Siepmann K, Hausler M, Weis J, Rossaint R. Xenon reduces neurohistopathological damage and improves the early neurological deficit after cardiac arrest in pigs. Crit Care Med. 2008;36:2420–2426.
12.
go back to reference Fries M, Brücken A, Cizen A, Westerkamp M, Lower C, Deike-Glindemann J, Schnorrenberger NK, Rex S, Coburn M, Nolte KW et al. Combining xenon and mild therapeutic hypothermia preserves neurological function after prolonged cardiac arrest in pigs. Crit Care Med. 2012;40:1297–1303. Fries M, Brücken A, Cizen A, Westerkamp M, Lower C, Deike-Glindemann J, Schnorrenberger NK, Rex S, Coburn M, Nolte KW et al. Combining xenon and mild therapeutic hypothermia preserves neurological function after prolonged cardiac arrest in pigs. Crit Care Med. 2012;40:1297–1303.
13.
go back to reference Niemann JT, Rosborough JP, Ung S, Criley JM. Coronary perfusion pressure during experimental cardiopulmonary resuscitation. Ann Emerg Med. 1982;11:127–131. Niemann JT, Rosborough JP, Ung S, Criley JM. Coronary perfusion pressure during experimental cardiopulmonary resuscitation. Ann Emerg Med. 1982;11:127–131.
14.
go back to reference Baim DS, Grossman W: Grossman's cardiac catheterization, angiography, and intervention, 7th edn. Philadelphia: Lippincott Williams & Wilkins; 2006. Baim DS, Grossman W: Grossman's cardiac catheterization, angiography, and intervention, 7th edn. Philadelphia: Lippincott Williams & Wilkins; 2006.
15.
go back to reference Argenziano M, Choudhri AF, Moazami N, Rose EA, Smith CR, Levin HR, Smerling AJ, Oz MC. Randomized, double-blind trial of inhaled nitric oxide in LVAD recipients with pulmonary hypertension. The Annals of thoracic surgery. 1998;65:340–345. Argenziano M, Choudhri AF, Moazami N, Rose EA, Smith CR, Levin HR, Smerling AJ, Oz MC. Randomized, double-blind trial of inhaled nitric oxide in LVAD recipients with pulmonary hypertension. The Annals of thoracic surgery. 1998;65:340–345.
16.
go back to reference Chandra NC, Tsitlik JE, Halperin HR, Guerci AD, Weisfeldt ML. Observations of hemodynamics during human cardiopulmonary resuscitation. Crit Care Med. 1990;18:929–934. Chandra NC, Tsitlik JE, Halperin HR, Guerci AD, Weisfeldt ML. Observations of hemodynamics during human cardiopulmonary resuscitation. Crit Care Med. 1990;18:929–934.
17.
go back to reference Ornato JP, Ryschon TW, Gonzalez ER, Bredthauer JL. Rapid change in pulmonary vascular hemodynamics with pulmonary edema during cardiopulmonary resuscitation. Am J Emerg Med. 1985;3:137–142. Ornato JP, Ryschon TW, Gonzalez ER, Bredthauer JL. Rapid change in pulmonary vascular hemodynamics with pulmonary edema during cardiopulmonary resuscitation. Am J Emerg Med. 1985;3:137–142.
18.
go back to reference Einav S, Kaufman N, Algur N, Strauss-Liviatan N, Kark JD. Brain biomarkers and management of uncertainty in predicting outcome of cardiopulmonary resuscitation: a nomogram paints a thousand words. Resuscitation. 2013;84:1083–1088. Einav S, Kaufman N, Algur N, Strauss-Liviatan N, Kark JD. Brain biomarkers and management of uncertainty in predicting outcome of cardiopulmonary resuscitation: a nomogram paints a thousand words. Resuscitation. 2013;84:1083–1088.
19.
go back to reference Derwall M, Stoppe C, Brücken D, Rossaint R, Fries M. Changes in S-100 protein serum levels in survivors of out-of-hospital cardiac arrest treated with mild therapeutic hypothermia: a prospective, observational study. Crit Care. 2009;13:R58. Derwall M, Stoppe C, Brücken D, Rossaint R, Fries M. Changes in S-100 protein serum levels in survivors of out-of-hospital cardiac arrest treated with mild therapeutic hypothermia: a prospective, observational study. Crit Care. 2009;13:R58.
20.
go back to reference Minamishima S, Kida K, Tokuda K, Wang H, Sips PY, Kosugi S, Mandeville JB, Buys ES, Brouckaert P, Liu PK, et al. Inhaled nitric oxide improves outcomes after successful cardiopulmonary resuscitation in mice. Circulation. 2011; 124:1645–1653. Minamishima S, Kida K, Tokuda K, Wang H, Sips PY, Kosugi S, Mandeville JB, Buys ES, Brouckaert P, Liu PK, et al. Inhaled nitric oxide improves outcomes after successful cardiopulmonary resuscitation in mice. Circulation. 2011; 124:1645–1653.
21.
go back to reference Terpolilli NA, Kim S-W, Thal SC, Kataoka H, Zeisig V, Nitzsche B, Klaesner B, Zhu C, Schwarzmaier S, Meissner L, et al. Inhalation of Nitric Oxide Prevents Ischemic Brain Damage in Experimental Stroke by Selective Dilatation of Collateral Arterioles. Circulation Research. 2012;110:727–738. Terpolilli NA, Kim S-W, Thal SC, Kataoka H, Zeisig V, Nitzsche B, Klaesner B, Zhu C, Schwarzmaier S, Meissner L, et al. Inhalation of Nitric Oxide Prevents Ischemic Brain Damage in Experimental Stroke by Selective Dilatation of Collateral Arterioles. Circulation Research. 2012;110:727–738.
22.
go back to reference Li YS, Shemmer B, Stone E, M AN, Jonas S, Quartermain D. Neuroprotection by inhaled nitric oxide in a murine stroke model is concentration and duration dependent. Brain Res. 2013;1507:134–145. Li YS, Shemmer B, Stone E, M AN, Jonas S, Quartermain D. Neuroprotection by inhaled nitric oxide in a murine stroke model is concentration and duration dependent. Brain Res. 2013;1507:134–145.
23.
go back to reference Charriaut-Marlangue C, Bonnin P, Gharib A, Leger PL, Villapol S, Pocard M, Gressens P, Renolleau S, Baud O. Inhaled nitric oxide reduces brain damage by collateral recruitment in a neonatal stroke model. Stroke. 2012;43:3078–3084. Charriaut-Marlangue C, Bonnin P, Gharib A, Leger PL, Villapol S, Pocard M, Gressens P, Renolleau S, Baud O. Inhaled nitric oxide reduces brain damage by collateral recruitment in a neonatal stroke model. Stroke. 2012;43:3078–3084.
24.
go back to reference Nagasaka Y, Buys ES, Spagnolli E, Steinbicker AU, Hayton SR, Rauwerdink KM, Brouckaert P, Zapol WM, Bloch KD. Soluble guanylate cyclase-alpha1 is required for the cardioprotective effects of inhaled nitric oxide. Am J Physiol Heart Circ Physiol. 2011;300:H1477–1483. Nagasaka Y, Buys ES, Spagnolli E, Steinbicker AU, Hayton SR, Rauwerdink KM, Brouckaert P, Zapol WM, Bloch KD. Soluble guanylate cyclase-alpha1 is required for the cardioprotective effects of inhaled nitric oxide. Am J Physiol Heart Circ Physiol. 2011;300:H1477–1483.
25.
go back to reference Nagasaka Y, Fernandez BO, Garcia-Saura MF, Petersen B, Ichinose F, Bloch KD, Feelisch M, Zapol WM. Brief periods of nitric oxide inhalation protect against myocardial ischemia-reperfusion injury. Anesthesiology. 2008; 109:675–682.CrossRef Nagasaka Y, Fernandez BO, Garcia-Saura MF, Petersen B, Ichinose F, Bloch KD, Feelisch M, Zapol WM. Brief periods of nitric oxide inhalation protect against myocardial ischemia-reperfusion injury. Anesthesiology. 2008; 109:675–682.CrossRef
26.
go back to reference Mathru M, Huda R, Solanki DR, Hays S, Lang JD. Inhaled nitric oxide attenuates reperfusion inflammatory responses in humans. Anesthesiology. 2007; 106:275–282.CrossRef Mathru M, Huda R, Solanki DR, Hays S, Lang JD. Inhaled nitric oxide attenuates reperfusion inflammatory responses in humans. Anesthesiology. 2007; 106:275–282.CrossRef
27.
go back to reference Ng ES, Jourd'heuil D, McCord JM, Hernandez D, Yasui M, Knight D, Kubes P. Enhanced S-nitroso-albumin formation from inhaled NO during ischemia/reperfusion. Circ Res. 2004; 94:559–565.CrossRef Ng ES, Jourd'heuil D, McCord JM, Hernandez D, Yasui M, Knight D, Kubes P. Enhanced S-nitroso-albumin formation from inhaled NO during ischemia/reperfusion. Circ Res. 2004; 94:559–565.CrossRef
28.
go back to reference Cannon RO, 3rd, Schechter AN, Panza JA, Ognibene FP, Pease-Fye ME, Waclawiw MA, Shelhamer JH, Gladwin MT. Effects of inhaled nitric oxide on regional blood flow are consistent with intravascular nitric oxide delivery. J Clin Invest. 2001; 108:279–287.CrossRef Cannon RO, 3rd, Schechter AN, Panza JA, Ognibene FP, Pease-Fye ME, Waclawiw MA, Shelhamer JH, Gladwin MT. Effects of inhaled nitric oxide on regional blood flow are consistent with intravascular nitric oxide delivery. J Clin Invest. 2001; 108:279–287.CrossRef
29.
go back to reference Mullner M, Sterz F, Binder M, Schreiber W, Deimel A, Laggner AN. Blood glucose concentration after cardiopulmonary resuscitation influences functional neurological recovery in human cardiac arrest survivors. J Cereb Blood Flow Metab. 1997; 17:430–436.CrossRef Mullner M, Sterz F, Binder M, Schreiber W, Deimel A, Laggner AN. Blood glucose concentration after cardiopulmonary resuscitation influences functional neurological recovery in human cardiac arrest survivors. J Cereb Blood Flow Metab. 1997; 17:430–436.CrossRef
30.
go back to reference Kim SH, Choi SP, Park KN, Lee SJ, Lee KW, Jeong TO, Youn CS, Korean Hypothermia Network I. Association of blood glucose at admission with outcomes in patients treated with therapeutic hypothermia after cardiac arrest. Am J Emerg Med. 2014; 32:900–904.CrossRef Kim SH, Choi SP, Park KN, Lee SJ, Lee KW, Jeong TO, Youn CS, Korean Hypothermia Network I. Association of blood glucose at admission with outcomes in patients treated with therapeutic hypothermia after cardiac arrest. Am J Emerg Med. 2014; 32:900–904.CrossRef
31.
go back to reference Daviaud F, Dumas F, Demars N, Geri G, Bougle A, Morichau-Beauchant T, Nguyen YL, Bougouin W, Pene F, Charpentier J et al. Blood glucose level and outcome after cardiac arrest: insights from a large registry in the hypothermia era. Intensive Care Med. 2014; 40:855–862.CrossRef Daviaud F, Dumas F, Demars N, Geri G, Bougle A, Morichau-Beauchant T, Nguyen YL, Bougouin W, Pene F, Charpentier J et al. Blood glucose level and outcome after cardiac arrest: insights from a large registry in the hypothermia era. Intensive Care Med. 2014; 40:855–862.CrossRef
32.
go back to reference Losert H, Sterz F, Roine RO, Holzer M, Martens P, Cerchiari E, Tiainen M, Mullner M, Laggner AN, Herkner H et al. Strict normoglycaemic blood glucose levels in the therapeutic management of patients within 12h after cardiac arrest might not be necessary. Resuscitation. 2008; 76:214–220.CrossRef Losert H, Sterz F, Roine RO, Holzer M, Martens P, Cerchiari E, Tiainen M, Mullner M, Laggner AN, Herkner H et al. Strict normoglycaemic blood glucose levels in the therapeutic management of patients within 12h after cardiac arrest might not be necessary. Resuscitation. 2008; 76:214–220.CrossRef
33.
go back to reference 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; 35:510–512.CrossRef 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; 35:510–512.CrossRef
Metadata
Title
Inhaled nitric oxide improves transpulmonary blood flow and clinical outcomes after prolonged cardiac arrest: a large animal study
Authors
Matthias Derwall
Andreas Ebeling
Kay Wilhelm Nolte
Joachim Weis
Rolf Rossaint
Fumito Ichinose
Christoph Nix
Michael Fries
Anne Brücken
Publication date
01-12-2015
Publisher
BioMed Central
Published in
Critical Care / Issue 1/2015
Electronic ISSN: 1364-8535
DOI
https://doi.org/10.1186/s13054-015-1050-2

Other articles of this Issue 1/2015

Critical Care 1/2015 Go to the issue