European Journal of Pharmacology 734 (2014) 42–49

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European Journal of Pharmacology journal homepage: www.elsevier.com/locate/ejphar

Review

The effects of nitroglycerin during cardiopulmonary resuscitation Antonia Stefaniotou n, Giolanda Varvarousi, Dimitrios P. Varvarousis, Theodoros Xanthos MSc Program Cardiopulmonary Resuscitation, University of Athens, Medical School, Greece, 75 Mikras Asias Street, 11527 Athens, Greece

art ic l e i nf o

a b s t r a c t

Article history: Received 15 January 2014 Received in revised form 3 April 2014 Accepted 3 April 2014 Available online 13 April 2014

The outcome for both in-hospital and out-of hospital cardiac arrest remains dismal. Vasopressors are used to increase coronary perfusion pressure and thus facilitate return of spontaneous circulation during cardiopulmonary resuscitation. However, they are associated with a number of potential adverse effects and may decrease endocardial and cerebral organ blood flow. Nitroglycerin has a favourable haemodynamic profile which promotes forward blood flow. Several studies suggest that combined use of nitroglycerin with vasopressors during resuscitation, is associated with increased rates of resuscitation and improved post-resuscitation outcome. This article reviews the effects of nitroglycerin during cardiopulmonary resuscitation and postresuscitation period, as well as the beneficial outcomes of a combination regimen consisting of a vasopressor and a vasodilator, such as nitroglycerin. & 2014 Published by Elsevier B.V.

Keywords: Cardiac arrest Cardiopulmonary resuscitation Vasopressor Nitroglycerin Blood flow

Contents 1. 2. 3. 4.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Vasopressors during CPR. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Nitroglycerin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . NTG during cardiopulmonary resuscitation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Animal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Human studies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5. Pathophysiology of ischaemic reperfusion injury. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6. Cardioprotective role of NTG in ischaemic reperfusion injury. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7. NTG and neuroprotection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction Hospital discharge rates for both in-hospital and out-of hospital cardiac arrest (CA) remain dismal (Bobrow et al., 2008). Vasopressors are used to increase diastolic aortic pressure (DAP) and coronary perfusion pressure (CPP) and thus facilitate return of spontaneous circulation (ROSC) during cardiopulmonary resuscitation (CPR). However, they are associated with a number of potential adverse effects

n

Corresponding author. Tel.: þ 30 2110121756. E-mail addresses: [email protected], [email protected] (T. Xanthos).

http://dx.doi.org/10.1016/j.ejphar.2014.04.002 0014-2999/& 2014 Published by Elsevier B.V.

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and may decrease endocardial and cerebral organ blood flow (Mayr et al., 2001; Ristagno et al., 2007). The current CPR research is oriented toward possible drug combinations for enhancing forward organ blood flow and optimizing vital organ perfusion pressures. Therefore, the use of a vasodilator agent with potential beneficial effects in CA, such as nitroglycerin (NTG), is currently investigated in the literature since NTG has a favourable haemodynamic profile which promotes forward blood flow (Mehta, 1995). The purpose of this paper is to review the literature in order to assess the effects of NTG during cardiopulmonary resuscitation and postresuscitation period and to review the beneficial outcomes of a

A. Stefaniotou et al. / European Journal of Pharmacology 734 (2014) 42–49

combination regimen consisting of a vasopressor and a vasodilator, such as NTG.

2. Vasopressors during CPR Epinephrine is a naturally occurring catecholamine and a potent alpha- and beta-adrenergic agonist. Its alpha-adrenergic effects, cause peripheral arteriolar vasoconstriction (Varon et al., 1998) thus promoting coronary and cerebral pressures increase (Otto and Yakaitis, 1984). Through its beta-1 effects it increases myocardial contractility and heart rate which lead to increased myocardial oxygen consumption. Moreover its beta-2-agonist effects cause smooth muscle relaxation, peripheral vasodilatation, and bronchial dilatation (Xanthos et al., 2011). Epinephrine, however, also causes adverse effects. Its beta-1 agonist effect may result in a critically decreased endocardial blood flow and ischaemic injury. Moreover, epinephrine, through its alpha-1 adrenergic action, causes intramyocardial coronary arteriolar vasoconstriction with the potential of further reductions in myocardial blood flow. Although alpha-1-adrenergic stimulation mediates vasoconstriction and increases cerebral perfusion pressure (Gedeborg et al., 2000), it increases cerebral ischaemia severity through the reduction of cerebral microcirculatory flows (Mayr et al., 2001; Wenzel et al., 2000). It may induce dissociation between macrovascular and microvascular blood flow (Foreman et al., 1991) and adversely affect neurological function (Berecek and Brody, 1982). At high doses epinephrine may also exert direct effects on the brain independently of cerebral perfusion pressure increase. It may stimulate the increase of cerebral oxygen consumption during severe hypertension (Bryan, 1990). The aforementioned epinehrine disadvantages have led to the use of vasopressin. Arginine vasopressin is an endogenous hypothalamic hormone with osmoregulatory, vasoconstrictive, haemostatic, thermoregulatory and central nervous effects. Via the V1 receptors, it stimulates the contraction of vascular smooth muscles, resulting in peripheral vasoconstriction and increased blood pressure. It also causes coronary vasoconstriction (Cooke et al., 2001) and can reduce blood flow to the myocardial tissue, thus, causing myocardial ischaemia. Vasopressin may have a biphasic action on coronary and vertebrobasilar circulations (Martínez et al., 1994). It is characterized by an initial potent vasoconstriction, mediated by stimulation of V1 receptors which is then followed by vasodilation, which is mediated by V2 receptor stimulation (Cooke et al., 2001). Moreover, studies have shown that vasopressin dilates the cerebral vasculature via the release of nitric oxide (Oyama et al., 1993). Although laboratory investigations demonstrated that vasopressin caused an increase in vital organ blood flow when compared to epinephrine (Lindner et al., 1995; Wenzel et al., 1999), as well as improved neurological recovery (Miller and Wadsworth, 2009; Wenzel et al., 2000), other studies show controversial results. Animal studies in which vital organ blood flow has been evaluated, have indicated that vasopressin results in suboptimal endocardial perfusion during CPR (Cooke et al., 2001) and contributes to hypoperfusion of the myocardium (Foreman et al., 1991). Due to the V2 mediated vasodilatory effect of vasopressin it was hypothesized that the combination of epinephrine and vasopressin would improve the end-organ hypoperfusion caused by epinephrine. Experimental studies (Mayr et al., 2001) showed that the addition of vasopressin to epinephrine improves the impaired cerebral microcirculatory blood flow caused by epinephrine. Vasopressin's vasodilating effect counterbalanced the vasoconstriction induced by epinephrine. Moreover, experimental models indicated that an epinephrine–vasopressin combination increases survival (Stadlebauer et al., 2003) and improves the histopathologic outcomes when compared with epinephrine alone (Wenzel et al.,

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1998a, 1998b). However, other studies have shown different results. The combination of vasopressin plus epinephrine was associated with a decrease in cerebral and endocardial blood flow CPR when compared with vasopressin alone (Mulligan et al., 1997). In another study by Wenzel et al., epinephrine significantly diminished the vasodilating effect of vasopressin on the cerebral vasculature (Wenzel et al., 1998a, 1998b).

3. Nitroglycerin NTG as well as other nitrates function as prodrugs that, when bioactivated, release nitric oxide (NO) in the vascular smooth muscle and endothelial cells (Kleschyov et al., 2003). NO activates soluble guanylyl cyclase (sGC) (Munzel et al., 2003) in the vascular smooth muscle, an intracellular NO receptor, subsequently stimulating the synthesis of the intracellular second messenger cyclicguanosine monophosphate (cGMP). cGMP exerts its effects by interacting with cGMP-dependent protein kinases (PKC), leading to smooth muscle relaxation. It has been shown that PKC mediates vasorelaxation through phosphorylation of proteins that regulate intracellular calcium levels (Fullerton and McIntyre, 1996) (Fig. 1). NTG is a powerful venodilator and reduces venous return and cardiac preload (Hollenberg, 2007). The reduction in preload is manifested by a decrease in ventricular filling pressure, and wall stress (Brazzamono et al., 1988; Groszmann et al., 1982; Wenzel et al., 1998a, 1998b). The reduction in wall tension decreases the subendocardial resistance to blood flow (Mehta, 1995). At high plasma nitrate concentrations, it has a mild arteriolar vasodilatory effect, leading to increased arterial conductance and decreased peripheral vascular resistance with consequent reduction in the left ventricular afterload. The reduction in preload and afterload lowers myocardial oxygen requirements and provides unique therapeutic benefit in cardiac ischaemia (Abrams, 1996). NTG is known to increase cardiac output in animal models (Brazzamono et al., 1988) and in humans (Groszmann et al., 1982). Moreover, studies have shown that NTG has a positive inotropic effect. This NTG induced positive inotropic effect is based on the fact that elevated amounts of intracellular cGMP increase myocardial contractility (Kojda et al., 1996). NTG potently dilates the larger coronary arteries thus improving the subendocardial/subepicardial blood flow ratio (Klemenska and Beręsewicz, 2009). It also dilates coronary collateral vessels and improves collateral subendocardial blood flow (Mehta, 1995). For this reason, NTG has clear benefits for the treatment of angina pectoris, congestive heart failure, unstable angina, non-ST-segment myocardial infarction and acute myocardial infarction (Brunton et al., 2006). Due to the beneficial effects of NTG, its use in conjunction with vasopressors has been evaluated in several studies. Bache studied the effect of the combination of nitroglycerin with a vasopressor phenylephrine in a laboratory model with acute occlusion of the left circumflex coronary artery. The combination significantly improved myocardial blood flow in both injured and non-injured areas (Bache, 1978). The approach of combining a vasodilator with vasopressin has been used successfully for the management of patients with bleeding esophageal varices (D’Amico et al., 1994). Moreover, Spronk et al. (2002) showed that impaired microcirculatory perfusion from septic shock was treated with NTG.

4. NTG during cardiopulmonary resuscitation 4.1. Animal studies The combined use of NTG with vasopressors was also evaluated in critical conditions such as cardiac arrest. Wenzel et al.

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Fig. 1. Beneficial effects of nitroglycerin during cardiopulmonary resuscitation.

administered a combination of vasopressin (0.4 U/kg) with low dose NTG (5 μg/kg) during CPR in pigs and they observed an increase of CPP, regardless of the reported decrease in survival rate. When compared with vasopressin therapy alone, the combination of vasopressin and NTG significantly improved endocardial perfusion and the endocardial to epicardial blood flow ratio immediately after drug administration during CPR. This suggested a beneficial effect on myocardial function during CPR due to improved myocardial blood flow (Wenzel et al., 1998a, 1998b). In addition to the above, Lurie et al. assessed whether low dose NTG (7.5 μg/kg), when co-administered during resuscitation from CA in a porcine model of ventricular fibrillation, would attenuate the vasoconstrictive properties of vasopressors on organ blood flow. In this study, CPP remained considerably higher in the groups of animals that were treated with the vasopressor–NTG combination (Lurie et al., 2002). However, there was no significant difference in ROSC rates between the two groups of animals. Following 4 min of ventricular fibrillation (VF) and 4 min of standard CPR, left ventricular and global cerebral blood flow were significantly higher in animals who received NTG as part of the therapy. These data are consistent with a possible, low-dose NTGassociated, benefit in CA. Such potential benefit can be explained mainly by the vasodilatory effect, possibly attenuating the untoward effects of the vasopressors on organ blood flow. Kitsou et al. (2009) conducted a prospective randomized blinded controlled study, involving 20 animals with ventricular fibrillation, in which the efficacy of the epinephrine (0.02 mg/kg) and NTG (50 μg/kg) combination during CPR versus epinephrine (0.02 mg/kg) alone was studied. The authors reported a significant increase in CPP during the first 2 min of CPR in animals treated with the epinephrine–NTG combination. No significant difference was observed with regard to ROSC rates between the epinephrine treated animals and the animals treated with the drug combination. Despite the administration of a higher dose of NTG, hypotension did not occur, probably due to a concurrent increase in cardiac

output (Kitsou et al., 2009). A major limitation of the aforementioned studies is that they were conducted on healthy young pigs with no atherosclerotic disease that did not need additional myocardial blood flow enhancement in order to survive from CA. This could possibly explain the fact that there was no statistically significant difference in ROSC rate in animals that received the combination of NTG with vasopressors. Beneficial effects of NTG was shown not only in VF models of CA but also in asphyxia CA models. Kono et al. (2002) reported an asphyxia model where 14 rats were randomized to receive vasopressin (0.8 U/kg) or NTG (0.3 μg/kg) 45 s after the administration of vasopressin (0.8 U/kg). The authors addressed the optimal timing of NTG administration during CPR in order to avoid a decrease in MAP. They observed an increased survival rate after increasing the interval of NTG administration from vasopressin. The onset time of NTG is shorter than that of vasopressin, therefore delayed administration of NTG did no significant decrease of MAP during CPR. Although the number of the animals tested was relatively small to reach safe conclusions, it is clear that in this study the combination of NTG with vasopressin improved survival, thus justifying the need for further research in this area (Kono et al., 2002). Varvarousi et al. assessed whether NTG, when co-administered during resuscitation from asphyxial CA, would improve neurological outcome. Co-administration of epinephrine, vasopressin and NTG resulted in improved functional cerebral recovery. This improvement in neurological outcome can be best explained by the interactions between the vasopressors and the NTG/NO pathway (Varvarousi et al., 2012). However, due to the pharmacotherapy combination the authors could not separately assess NTG efficacy. Moreover, the aforementioned studies tested the efficacy on organ blood flow of a bolus dose of NTG combined with vasopressors during CPR. A continuous infusion of NTG after administration of a loading dose may have extended the beneficial effects of NTG on organ blood flow in the post-resuscitation

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period. Further studies must be conducted in order to determine the optimal way of NTG administration during CPR. Εbmeyer et al. initiated for the first time NTG at a very low infusion rate (1 μg kg  1 min  1) for 1 h after standard resuscitation with epinephrine instead of a bolus injection after ROSC. They reported a beneficial effect of the combination of NTG with epinephrine on neurological outcome after asphyxial CA. They demonstrated that animals receiving the drug combination developed a significantly higher initial mean arterial pressure (MAP) peak after ROSC. Moreover, despite the vasodilatory actions of NTG, initial MAP at post-resuscitation period was increased probably due to a NTG-induced positive inotropic effect. The increase in MAP in the early post-resuscitation period improved cerebral and functional outcomes (Ebmeyer et al., 2013) (Table 1). 4.2. Human studies Limited amount of evidence exists regarding the use of NTG in human victims of CA. Most of the literature consists of case reports. In fact only one clinical prospective human study tested the effect of the NTG–vasopressor combination in patients with cardiac arrest (Ducros et al., 2011). Interestingly, in 1984, a beneficial effect of intravenous NTG was described in a case report of refractory CA. Ward and Reid (1984) described a case in which a patient with coronary artery spasm, myocardial infarction, CA and pulseless electrical activity (PEA) was successfully resuscitated after intravenous administration of large doses of NTG alone. A case of a patient with cardiac arrest due to refractory PEA was also described by Osada

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et al. (2000). The patient had a myocardial infarction due to coronary artery spasm which caused myocardial contractile dysfunction. Administration of NTG released the coronary spasm and restored spontaneous circulation (Osada et al., 2000). Guglin and Postler (2009) also reported a case where a high dose of NTG caused beneficial effects on a patient with CA after a myocardial infarction. In all case reports, NTG was administered as a ‘last resort’ therapy, after failure of advanced life support protocols in refractory CA (Guglin and Postler, 2009; Ward and Reid, 1984; Osada et al., 2000). Vasodilatory therapy with NTG may be particularly effective in a clinical setting of coronary artery disease and acute myocardial infarction, which are usually present in patients suffering from CA. In the aforementioned case reports NTG potently dilated the coronary arteries and improved myocardial blood flow. Moreover, it decreased left ventricular filling pressure while increasing cardiac index. Therefore NTG may have a more advantageous haemodynamic profile than conventional therapy in patients with an already compromised myocardium before CA. The only prospective randomized study in the pre-hospital setting consisted of 44 patients receiving epinephrine alone or epinephrine plus vasopressin or epinephrine plus vasopressin plus NTG. It was noted that diastolic blood pressures were not statistically different between groups. Moreover, the rate of ROSC was 63% in the epinephrine group, 43% in the epinephrine plus vasopressin group and 36% in the triple therapy group (NS). Epinephrine administration alone induced higher, though non-significant, values of arterial blood pressure, ROSC and survival rates (Ducros et al., 2011) (Table 2). However this study exhibits

Table 1 Summary of animal studies which present data on the effectiveness of nitroglycerin in cardiopulmonary resuscitation. Study

Population

Outcomes

Wenzel et al. (1998a, 1998b) Lurie et al. (2002)

Experimental control study

14 Pigs. Vasopressin and vasopressin combined with nitroglycerin Combined vasopressin and nitroglycerin significantly improved were given in each group of 7 pigs while in ventricular fibrillation endocardial perfusion compared to vasopressin

Experimental control study

Kono et al. (2002) Kitsou et al. (2009) Varvarousi et al. (2012)

Experimental control study Experimental control study

24 Pigs. Epinephrine and epinephrine combined with vasopressin and nitroglycerin were given in each group of 12 pigs while in ventricular fibrillation 14 Pigs. Vasopressin and vasopressin combined with nitroglycerin were given in each group of 7 pigs while in asphyxial CA 20 Pigs. Epinephrine and epinephrine combined with nitroglycerin were given in each group of ten pigs while being in ventricular fibrillation 20 Pigs. Epinephrine and epinephrine combined with vasopressin and nitroglycerin were given in each group of 10 pigs while ashyxial CA

Ebmeyer et al. (2013)

Experimental control study

Experimental control study

The combination of both vasopressors with nitroglycerin significantly improved vital organ blood flow during CPR compared with epinephrine alone Vasopressin combined with delayed nitroglycerin resulted in higher ROSC rates compared with vasopressin alone Epinephrine combined with nitroglycerin increased coronary perfusion pressure

Nitroglycerin to epinephrine and vasopressin resulted in higher diastolic arterial pressure and coronary arterial pressure compared with epinephrine alone. Neurologic and histopathologic outcomes were significantly better in the epinephrine vasopressin nitroglycerin group compared with the epinephrine group 84 Rats were subjected to 8 min of asphyxial CA. Normal saline or Nitroglycerin group developed a significantly higher initial mean nitroglycerin was infused for 1 h starting immediately after ROSC arterial pressure and improved neurological outcome

Table 2 Summary of case reports and human studies which present data on the effectiveness of nitroglycerin in cardiopulmonary resuscitation. Study Ward and Reid (1984) Osada et al. (2000) Ducros et al. (2011)

Population

Outcomes

Case report

One patient

Successful resuscitation after refractory CA with nitroglycerin

Case report

One patient

Controlled prospective study

44 Pre-hospital patients developing CA. Epinephrine alone (16 patients) or epinephrine and vasopressin (14 patients) or epinephrine, vasopressin and nitroglycerin (14 patients) were given in each group One patient

Successful resuscitation after refractory pulseless electrical activity with 2.5 mg of nitroglycerin No benefit regarding perfusion blood pressure between groups

Guglin and Case report Postler (2009)

Successful resuscitation after CA with 4 mg of nitroglycerin

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limitations. There was no assessment of CPR quality and the sample size was small to draw safe conclusions. Moreover, the study protocol did not allow a precise determination of the relative contribution of vasopressin and NTG to the lower diastolic blood pressure and ROSC rate during CPR. Further clinical studies are needed on order to determine the efficacy and the appropriate dosage and timing of NTG administration. Maintenance of adequate DAP and CPP preserve vital organ perfusion and is important for survival (Spronk et al., 2002). The use of NTG in critical conditions is limited because of its ability to decrease arterial pressure. According to current recommendations, intravenous NTG is contraindicated when systolic blood pressure (BP) is below 90 mmHg. In the study by Ducros et al., NTG diminished the vasopressor effect of vasopressors during CPR by dilating smaller arterioles and resistance vessels, which, in turn, may have decreased blood pressure and made ROSC less possible. Moreover, Krismer et al. (2001) postulated that nitric oxide-mediated excessive vasodilation occurred during CA, a fact that may render successful resuscitation unlikely. Although experimental studies (Kitsou et al., 2009; Lurie et al., 2002; Varvarousi et al., 2012; Wenzel et al., 1998a, 1998b) demonstrate an increase in DAP and CPP after combined administration of NTG with vasopressors, the NTG potential, to decrease blood pressure during CPR has to be further investigated (Table 2).

5. Pathophysiology of ischaemic reperfusion injury CA results in global multi-organ ischaemic reperfusion (I/R) injury and is associated with significant morbidity and mortality (Nichol et al., 2008). I/R injury initiates its damage at a mitochondrial level and can be characterized by two stages. First is the ischaemic phase, which causes a decrease in oxygen delivery and malfunction of the respiratory chain complex leading to anaerobic metabolism and inadequate adenosine triphosphate ATP synthesis (Warner et al., 2004). Consequently, all energy-dependent processes gradually cease their activity, leading to a sudden loss of the mitochondrial membrane potential and to mitochondrial calcium overload. Second, during the reperfusion phase the changes of the mitochondrial membrane potential leads to opening of the mitochondrial permeability transition pore (mPTP) (Zorov et al., 2009). During reperfusion the sudden increase in oxygen delivery to the mitochondria and the opening of the mPTP leads to a dramatic increase in reactive oxygen species production, which overwhelms the endogenous scavenging mechanisms (Anderson et al., 2006). The main sites of reactive oxygen species generation are mitochondrial complexes I and III. This sudden increase in reactive oxygen species, along with calcium overloading, leads to the release of pro apoptotic proteins, which initiates apoptotic signalling and cell death (Di Lisa and Bernardi, 2006). Moreover, the oxygen radicals increase endothelial injury, which causes dysfunction in the microcirculation; principally at the capillary level (Lefer and Lefer, 1996).

6. Cardioprotective role of NTG in ischaemic reperfusion injury I/R injury results in post-cardiac arrest myocardial dysfunction, which contributes to low survival rates after in-hospital and out-ofhospital cardiac arrest (Hsu et al., 2009). Post-cardiac arrest myocardial dysfunction includes myocardial stunning, arrhythmias and cardiomyocyte death (Chalkias and Xanthos, 2012). Myocardial stunning refers to reversible ventricular contractile dysfunction that follows a period of non-lethal ischaemia despite restoration of normal blood flow (Chalkias and Xanthos, 2012). The acute generation of oxygen free radicals during reperfusion causes oxidative

injury resulting in myocardial stunning (Bolli, 1991). Moreover, strong evidence suggests that prolonged dysfunction after reperfusion in stunned myocardium is mediated by abnormalities of calcium homeostasis (Parent de Curzon et al., 2000). NTG through NO may attenuate the generation of reactive oxygen species during reperfusion and calcium uptake. NO has been shown to transiently inhibit complex I of the mitochondrial respiratory chain complex, which leads to a decreased electron flux through the respiratory chain (Anderson et al., 2006). Such interaction of NO with the respiration chain limits mitochondrial respiration, which in turn depolarizes the mitochondrial membrane and prevents generation of reactive oxygen species and calcium uptake (Luo et al., 2010). Studies have shown that NTG is a cardioprotective agent against myocardial stunning (Adams et al., 2007; Beiser et al., 2011; Iwamoto et al., 1993; Zhou et al., 2002). Enhancement of NO signalling within minutes of CPR can improve myocardial function and survival. In the cardiomyocyte NO-derived NTG binds to sGC to increase cGMP. The increase in cGMP improves the contractile response of cardiomyocytes and attenuates myocardial stunning (Dragoni et al., 2007; Minamishima et al., 2011; Rubanyi et al., 1991). Post-resuscitation myocardial dysfunction is accompanied by reperfusion arrhythmias. The mechanism underlying the functional and electrophysiologic derangements in reperfusion arrhythmias is altered calcium homeostasis (Chen and Rembold, 1996). NTG has a protective role against arrhythmias which are induced by I/R injury. NTG through NO reduces incidence and duration of ventricular arrhythmias by blocking the calcium channel (Gori et al., 2007). Flow through microvessels provides the ultimate source of tissue perfusion following resuscitation from CA. NTG improves microcirculation due to the beneficial effects of NO on the endothelium. It has been suggested that NO reaches microvessels directly and acts as an important vasodilatory factor in these vessels of small resistance (Fries et al., 2006a, 2006b). Furthermore, NO exerts potentially anti-inflammatory effects in the vascular wall (Luo et al., 2010). It inhibits platelet adhesion and aggregation and attenuates reperfusion induced leukocyte aggregation and adhesion to the endothelium (Cowled et al., 2007; Grisham et al., 1998). Moreover, NO modulates the permeability and integrity of the vascular endothelium which leads to reduction of vascular protein leakage (Kurose et al., 1994). In addition to the above, NO down regulates macrophage cytokine production and therefore attenuates reperfusion induced microvascular injury (Banick et al., 1997). Furthermore, NTG through NO plays a cardioprotective role by preconditioning tissues to I/R injury (Hill et al., 2001). Ischaemic preconditioning (IPC) is a powerful form of cardioprotection mediated by repetitive brief episodes of ischaemia before the actual ischaemic insult (Hill et al., 2001). I/R injury can be attenuated by preconditioning, which renders organ resistant to subsequent severe reperfusion injury. Studies have pointed out that NTG-derived NO could mimic the cardioprotective effect of IPC in myocardium and that effect is most likely mediated via activation of protein kinase C and mitochondrial ATP-sensitive K þ -channels (KATP) (Banerjee et al., 1999). KATP activation closes the mPTP, limiting the rise in intra-mitochondrial calcium and reducing mitochondrial swelling during the periods of preconditioning and therefore is able to protect cells against the subsequent lethal insults. NO-mediated protein S-nitrosylation has been proved to play an essential role in cardioprotection against ischaemia–reperfusion (I/R) injury (Murphy and Steenbergen, 2008). Studies have shown that preconditioning by NO results in S-nitrosylation and inhibition of L-type Ca channel which attenuates the rise in cytosolic Ca during I/R injury. Preconditioning has also been shown to lead to S-nitrosylation and inhibition of complex 1, (Burwell et al., 2006). This was associated with a decrease in

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reactive oxygen species production during I/R injury. Moreover, S-nitrosylation of proteins involved in regulation of mitochondrial energetics leads to conserving cytosolic ATP (Foster et al., 2009). Taken together, the increase of protein S-nitrosylation during PC would be expected to lead to preservation of ATP and reduced mitochondrial Ca2 þ and reactive oxygen species generation (Murphy and Steenbergen, 2008). This would be expected to prevent the MPTP opening and reduce cell death, as MPTP opening has been shown to be an important determinant of myocardial I/R death. However, NO is defined as a dual-faced molecule in I/R injury, which contributes to both cardioprotective and deleterious signalling pathways within the myocardium. Studies have shown that NO at high but unspecified concentrations, is a cytotoxic molecule which may exacerbate IR injury and compromise myocardial function (Liaudet et al., 2000; Yu et al., 2010). Due to these controversial results, human trials studying the cardiac effects of NTG administration in I/R injury after cardiac arrest are needed.

7. NTG and neuroprotection Long term survival after CA remains poor, at least in part, due to post-cardiac arrest neurologic failure (Warner et al., 2004). Neuronal tissue is especially vulnerable to ischaemia, given its high metabolic demand and studies have shown that there is correlation between reduction of cerebral blood flow and development of neuronal ischaemic injuries (Shaffner et al., 1999). Neurologically intact survival from CA largely depends on early restitution of blood flow to ischaemic tissues during CPR (Sanders et al., 1984). Improved CPP and cerebral blood flow during CPR is associated with better neurological outcome (Sanders et al., 1984). Epinephrine is the drug of choice because it increases CPP during CPR. However, its vasoconstrictive effect decreases cerebral blood flow and prolongs ischaemia in cerebral tissue beds (Fries et al., 2006a, 2006b). In a study, epinephrine constricted microvessels and reduced capillary blood flow with little or no perfusion of the swine brain despite increased pressure in the large arteries (Ristagno et al., 2008). Due to these adverse effects studies have pinpointed to the favourable effects of the combination of NTG with vasopressors. This drug combination, increased CPP and MAP during CPR which was accompanied by increased cerebral perfusion and improved neurological outcome (Kitsou et al., 2009; Lurie et al., 2002; Varvarousi et al., 2012). During the post-resuscitation period global and regional cerebral blood flow disturbances cause a cerebral oxygen delivery/ uptake mismatch. Under normal conditions, changes in arterial pressure influences cerebral blood flow only minimally due to reactive dilatation and constriction of cerebral resistance vessels in response to arterial hypotension and hypertension, that is, cerebral blood flow autoregulation (Paulson et al., 1990). In the early postresuscitation phase cerebrovascular autoregulation is impaired due to I/R injury and the lower limit of autoregulation is shifted to a higher blood pressure (Sundgreen et al., 2001). During I/R/ injury the generation of reactive oxygen species, the disrupted calcium homeostasis and the mitochondrial injury leads to nonhomogeneous reperfusion conditions and consequently to microcirculatory failure (Sundgreen et al., 2001). Moreover, I/R/injury results in the impaired regulation of endothelium derived NO which contributes to the disturbance of cerebral microcirculatory perfusion. The endothelium dysfunction results in impaired vasodilation, activation of platelets and neutrophils and extensive tissue injury (Gursoy-Ozdemir et al., 2004). One approach to overcoming regional and global perfusion disturbances is hypertensive reperfusion (Müllner et al., 1996). MAP in the post-resuscitation phase is a critical determinant of the

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degree of microcirculatory cerebral hypoperfusion. Studies have shown that MAP had to be maintained at a higher level than normal to ensure cerebral perfusion and that MAP during the first 2 h after ROSC was correlated with neurological outcome (Müllner et al., 1996). In a study by Εbmeyer et al., animals receiving NTG in combination with epinephrine in a porcine model of asphyxial CA (ACA) developed a significantly higher initial MAP peak and had better cerebral and functional outcomes after ACA (Ducros et al., 2011). Moreover, in another study NO improved cerebral perfusion post-resuscitation and reduced CA1 damage (Dezfulian et al., 2012). Improved peri-arrest haemodynamics attenuated cerebral ischaemia and contributed to neurological recovery. NTG is a lipid soluble substance that diffuses through all membranes, including the blood–brain barrier. It is a potent cerebrovasodilator and increases cerebral blood flow through the release of NO from the endothelium (Nishida et al., 2009). It improves blood flow in the ischaemic territory and ameliorates ischaemic damage (Radomski et al., 1991). Moreover, in a microcirculatory level NTG has the potential of balancing and optimizing the vascular tone of cerebral vessels and therefore improves the cerebrovascular autoregulatory function. In addition, NTG through NO can inhibit platelet aggregation and neutrophil adhesion simultaneously preventing microvascular occlusion in regions of stasis and therefore improving microvascular flow (Radomski et al., 1991). NTG improves the endothelium function by scavenging reactive free radicals, thus reducing the ischaemic injury and improving neuronal survival (Mohanakumar et al., 2002). In addition to the primarily vascular activity, NTG may also have antioxidant effects. Studies have shown that NTG therapy has been associated with antioxidant effects when given upon reperfusion. NO is a potent antioxidant and is capable of rendering neuroprotection against oxidative stress-induced neurotoxicity (Nicolescu et al., 2002).

8. Conclusion NTG is a potent vasodilator and has the potential to become an important adjunct to ameliorate organ perfusion during CPR and ultimately improve the CPR outcome. It has cardiocerebral protective properties and may outweigh the adverse effects observed after the use of vasopressors. There is a need for a CPR approach that is finally directed to really improving microvascular blood flow rather than only achieving potential benefits expressed by increases in CPP. Even though experimental animal studies and case reports point towards a beneficial effect from a NTG–vasopressor combination during CPR, high quality human trials are still lacking. Further human CA studies are required to determine the efficacy of NTG administration during resuscitation and in the post-resuscitation period.

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