13RC1 Gasco. Drugs in CPR: What do we need to know? M. Carmen Gasco Garcia. Introduction. Pathophysiological trends - 1 -

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1 13RC1 Gasco Drugs in CPR: What do we need to know? M. Carmen Gasco Garcia Anaesthesiology and Reanimation, Department of Pharmacology. Hospital Clinico San Carlos, School of Medicine, Universidad Complutense de Madrid, Spain Introduction Cardiac arrest is a major public health problem in the world. Recent data suggest that at least 166,000 people experience an out-ofhospital cardiac arrest each year in the United States. All survival rates remain low and in contrast to the decline in morbidity and mortality observed for most cardiovascular diseases, have not improved despite considerable attention and efforts to improve the treatment of cardiac arrest [1]. In Europe the most important cause of death is cardiac arrest which takes place out-of-hospital. This accounts for a figure as high as 40% of all deaths occurring under 75 years of age. At the same time, sudden cardiac arrest from coronary heart disease is responsible for more than 60% of adult health problems [2]. In 2008 the European Resuscitation Council (ERC) set up a group whose remit was to establish a uniform European Registry of Cardiac Arrests (EuReCa) based on the collective experiences of the constituent member countries. However, an up-to-date system is not yet available to provide an overview and monitor the outcomes of cardiac arrest and resuscitation throughout Europe. The ERC defines the European continent according to the definition adopted by the Council of Europe. This includes 47 countries and 823 million inhabitants. Custodians of five existing European registries based in Andalusia (Spain), Belgium, Germany, North-Holland (the Netherlands) and Sweden, representing a population of 34.9 million inhabitants have agreed to be included in the European registry. However, these individual registries show marked differences in terms of structure and complexity. Considerable variation is found between countries in the number of cardiopulmonary resuscitation (CPR) episodes recorded, the number of patients brought to hospital alive, and the extent of bystander s involvement in CPR [3]. Survival from out-of-hospital cardiac arrest depends on a sequence of therapeutic interventions according to the Chain of Survival, a concept adopted by the ERC, the American Heart Association (AHA) and the International Liaison Committee on Resuscitation (ILCOR). This sequence includes rapid access to emergency medical care, Basic life support (BLS), defibrillation and Advanced Life Support. The 2010 guidelines for CPR based on the recent International Consensus on CPR Science with treatment Recommendations (CoSTR) have shown that BLS and early defibrillation are of primary importance. A key point during delivery of CPR is the quality of the chest compressions; thus, to give effective chest compressions, it is essential that the rescuers or the automated devices designed to deliver chest compressions ensure they push sufficiently hard and fast [2]. If the chest compressions delivered are ineffective, blood flow will be compromised and the effects on survival rates could be dismal - between 5 and 14% Pathophysiological trends Once a cardiac arrest has occurred circulation stops completely and brain perfusion decreases rapidly. Therefore, cardiac arrest deprives the brain of oxygen, glucose and other substrates required to support brain metabolism. Removal of metabolites is also affected. Hence the brain is subjected to a state of hypoxia and ischaemia. This ischaemic state is characterised by failure to provide energy to support metabolism, membrane depolarization and brain oedema. The rise in release of neurotransmitters (particularly of the excitatory amino acid neurotransmitters) and inhibition of their uptake increases intracellular calcium, oxygen-free radicals, lipid peroxidation and disturbs autoregulation of cerebral blood flow at both micro and macroscopic levels. These molecular events contribute to modify the permeability of the blood-brain barrier (BBB). In addition, transient hypoxic-ischaemic states disrupt brain function, and, if they are sufficiently severe or prolonged, may provoke neuronal death and irreversible brain injury [4]. Recent advances in the understanding of the molecular and immunological consequences of ischaemia and reperfusion may make it possible to develop innovative therapeutic strategies for the treatment of patients with ischaemia and reperfusion-associated tissue inflammation and organ dysfunction [5] - 1 -

2 Drug therapy Drug therapy continues to be recommended as part of the management of cardiac arrest and the peri-arrest period. Three important groups of drugs were reviewed during the 2010 Consensus Conference: vasopressors, anti-arrhythmics and other drugs [2]. There has been increasing transparency about the lack of evidence to support such drug therapy. Only a few drugs are indicated during the immediate management of a cardiac arrest. These should be considered when chest compressions and ventilation have been commenced and after initial shocks have been delivered. Vasopressors Adrenaline (epinephrine) Adrenaline is a vasopressor that has been used for decades for CPR, but there is insufficient evidence to absolutely support or refute its routine use. Adrenaline increases short term survival in humans and it is still recommended, based on animal data and clinical experience. There are two subtypes of adrenergic receptors (α- and β). The α 1 -receptors mediate arteriolar vasoconstriction, they are positively inotropic and chronotropic and may induce coronary vasoconstriction. By comparison, the main effect of α 2 -receptors is venoconstriction, among other effects. With regard to the β-receptors, β 1 - and β 2 -receptors induce positive inotropy and chronotropy and can also vasodilate the coronaries [6]. Adrenaline activates all adrenergic receptors α 1, α 2, β 1, β 2, β 3. The potential therapeutic effects of adrenaline include positive inotropy and chronotropy and enhanced conduction in the heart (β 1 ); smooth muscle relaxation in the vasculature and bronchial tree (β 2 ) and vasoconstriction (α 1 ). The aortic diastolic pressure resulting from vasoconstriction is increased, promoting coronary flow during cardiac arrest, which may be the single most important determinant of survival. Higher coronary blood flow increases the frequency and amplitude of the VF waveform and should improve the chance of restoring circulation when defibrillation is attempted. The endocrine and metabolic effects of adrenaline include increased levels of glucose, lactate and free fatty acids [6]. Adrenaline may not be the ideal vasopressor to use during resuscitation following cardiac arrest, given that the α-effects of adrenaline are beneficial while its β-effects may be detrimental. Careful evaluation and monitoring of the effect of adrenaline on renal, cerebral and myocardial perfusion should be undertaken. Adrenaline is given intravenously by bolus or by infusion. Current recommendations are to give 1mg intravenously every 3 to 5 minutes to adults. If this dose seems ineffective or, alternatively, in the treatment of β-blocker or calcium channel blocker overdose, higher doses (3 to 8mg) may be considered. Adrenaline is a potent renal vasoconstrictor acting directly by α-receptor stimulation and indirectly by stimulation of rennin release. Although low dose adrenaline increases the heart rate by direct β 1 adrenergic stimulation, reflex bradycardia appears with higher doses due to a notable elevation of blood pressure through peripheral vasoconstriction [7]. Until recently, no randomized controlled human trail has specifically evaluated the early administration of adrenaline in cardiac arrest and CPR [8,9,10]. While several observational studies have reported the use of adrenaline in out-of-hospital cardiac arrest in the past, their design features and limitations have resulted in findings that cannot be applied to modern approaches associated with out-of-hospital cardiac arrest. Nowadays, definitive studies have been performed in human cardiac arrests. The most recent randomized controlled trial of the use of intravenous drug treatment, including adrenaline in out-of-hospital cardiac arrest was conducted by Olasveengen and co-workers in Norway. In this study patients were randomized to one of two groups: an advanced life support (ALS) group including intravenous cannulation and intravenous drugs (N = 418) or an ALS group without intravenous cannulation or drugs (N = 433). The patients in the intravenous group had a higher rate of return of spontaneous circulation, hospital admission and admission to the intensive care unit. No significant difference existed in survival at 1 month or 1 year after hospital discharge between the two groups. The study did not show any difference in survival to hospital discharge or survival with good neurological outcome. The authors concluded that giving drugs such as adrenaline, atropine or amiodarone at the time of cardiac arrest did not improve long term survival. Adrenaline is not harmful but the long term benefit associated with its use appears to be poor. They remarked that this study may have been too underpowered to prove a difference. Attention was drawn to the late administration of epinephrine during out-of-hospital cardiac arrest. The mean ambulance response time was ten minutes; time between ambulance arrival and intravenous administration was not provided. It seemed that the late administration of epinephrine was not helpful [11]. Different experts have carefully dissected this study and are in accord with the author s conclusion that more effective therapies should be sought [12]

3 The second study, a randomized double blind placebo-controlled trial (RCT) in out-of-hospital arrest was conducted by Jacobs and co-workers from Australia. Up to now this has been the only trial of adrenaline in out-of-hospital cardiac arrest. Patients were randomised to receive either intravenous preparation of adrenaline 1ml, 1:1000 (i.e. 1mg) in one group (N = 272 patients or placebo (sodium chloride 0.9%) in the second group (N = 262). This study demonstrated that the administration of adrenaline during out-of-hospital cardiac arrest was associated with improvements in short term survival. The authors concluded that the results established efficacy for the continued use of adrenaline in cardiac arrest as currently recommended however suggested that many questions governing its use remained unanswered. For example, the optimal dose of adrenaline is not known and there are insufficient data supporting the use of repeated doses. Adrenaline s use has been based on decades of efficacy based on animal models, despite a lack of definitive evidence in clinical trials [8,12,13,14,15,16]. Two major reasons explain the disparity between models. The first relates to the timing of its administration; in the experimental laboratory adrenaline is administered earlier; the second difference relates to the different aetiology of cardiac arrest in animal studies compared with clinical studies. Antiarrhythmics Amiodarone After vasopressors, the most important drugs used during CPR are those that help to suppress ectopic ventricular rhythms. Amiodarone is used during cardiac arrest to assist defibrillation when Ventricular fibrillation (VF) is refractory to electrical counter shock therapy alone or when VF recurs following successful conversion. According to the Vaughan Williams classification, Amiodarone is a Class III antiarrhythmic agent useful for the treatment of atrial and ventricular dysrhythmias. Amiodarone can cause hypotension and bradycardia when it is infused too fast in patients with an intact circulation. These reactions can usually be prevented by slowing the rate of the infusion or concurrent treatment with fluids, vasopressors, chronotropic agents or temporary pacing [6,7]. There are two randomized, blinded, placebo-controlled clinical trials in shock-resistant cardiac arrest victims that have demonstrated improved rates of admission to hospital with amiodarone treatment, although there was no difference in survival to discharge [18]. Although weak, there is more evidence of efficacy for amiodarone than exists for lidocaine. When VF or pulseless ventricular tachycardia is recognized, defibrillation should be attempted. No antiarrhythmic agent has been shown to be superior to electrical defibrillation or more effective than placebo in the treatment of VF. Consequently, defibrillation should not be withheld or delayed to establish intravenous access or to administer drugs. When ventricular tachycardia or VF has been unresponsive to or recurred following basic life support (BLS) or adrenaline, amiodarone should be administered [18]. In cardiac arrest, amiodarone at a dose of 300mg is initially administered as a rapid infusion. Supplementary infusions of 150mg can be repeated as necessary for recurrent or resistant dysrhythmias to a maximum total daily dose of 2g. For dysrhythmias in which the circulation is maintained, 150mg amiodarone is usually administered intravenously over 10 minutes, followed by an infusion of 1 mg/min for 6 hours, reduced to 0.5mg/min thereafter [7]. Lidocaine Lidocaine is primarily an antiectopic agent with relatively few hemodynamic effects, and tends to reverse the reduction in the VF threshold caused by ischaemia or infarction. It depresses automaticity by reducing the slope of phase 4 depolarization and reduces the heterogeneity of ventricular refractoriness. Lidocaine is indicated in VF or pulseless ventricular tachycardia (VT) which has proved refractory to defibrillation (up to three shocks), when first line treatment with amiodarone is unavailable [6,7,19]. An initial bolus of 1 to 1.5mg/ kg should be given and an additional bolus of 0.5 to 0.75mg/kg can be given every 5 to 10 minutes during CPR up to a total dose of 3mg/kg. In order to establish and maintain therapeutic blood levels rapidly during CPR, relatively large doses are necessary. Bolus dosing should be used during CPR, but an infusion of 2 to 4mg/min can be started after successful resuscitation. After 24 h of continuous infusion, the plasma half-life increases significantly and it is best is to reduce the dose and re-evaluate the indication. Two different clinical electrolyte deficiencies, hypomagnesaemia and hypokalaemia may decrease the efficiency of lidocaine [7]

4 Atropine Atropine is an anticholinergic drug that easily crosses the blood-brain barrier. Central nervous system effects have been seen when relatively large doses (1 to 2mg) are given to block the muscarinic effects of anticholinesterase drugs that reverse neuromuscular blockade. Muscarinic antagonists compete with neurally released acetylcholine for access to muscarinic cholinoreceptors and block its effects. Atropine has a short duration of effect; it has antisialagogue properties and an effect on the heart rate [6]. Atropine sulphate enhances sinus node automaticity and atrioventricular conduction by its vagolytic effects. Although atropine is frequently given during cardiac arrest associated with an electrocardiogram (ECG) recording either asystole or pulseless electrical activity (PEA), neither animal nor human studies provide evidence that it actually improves the outcome from either situation. The predominant cause of asystole and PEA is severe myocardial ischaemia. Excessive parasympathetic tone probably contributes little to these rhythms during cardiac arrest in adults. Therefore, the most important treatment is effective chest compressions, ventilation, and adrenaline to improve coronary perfusion and myocardial oxygenation. Irrespective of the treatment given, cardiac arrest associated with these rhythms has a poor prognosis. The administration of atropine had no long-term neurological benefit in adults with out-of-hospital cardiac arrest due to non-shockable rhythm. Atropine is not useful for adults with PEA [20]. Atropine is indicated in sinus, atrial or nodal bradycardia when the hemodynamic condition of the patient is unstable. The dose is 1.0mg intravenously, repeated every 3 to 5 minutes up to a total of 0.04mg/kg, which completely suppresses vagal activity. Fully vagolytic doses of atropine administered intravenously may be associated with mydriasis following successful resuscitation confounding neurologic examination [6]. Occasionally, a sinus tachycardia following resuscitation may be the result of the use of atropine during CPR. Sodium Bicarbonate Although the use of sodium bicarbonate was common during CPR in the past, there is little evidence to support its efficacy. This use of sodium bicarbonate during resuscitation has been based on the theoretical considerations that acidosis lowers the fibrillation threshold and impairs the physiological response to catecholamines [6]. However, most studies have failed to demonstrate improved success of defibrillation or resuscitation due to the use of bicarbonate. The lack of effect from the use of buffer therapy may be partially explained by the slow onset of metabolic acidosis during a cardiac arrest. When measured by blood lactate or base deficit, acidosis does not become severe for the first 15 or 20 minutes of cardiac arrest. In contrast to the lack of evidence that buffer therapy during CPR improves survival, the adverse effects of excessive sodium bicarbonate administration are well documented. In the past, metabolic alkalosis, hypernatraemia and hyperosmolarity were common after the administration of bicarbonate during resuscitation attempts. These abnormalities are also associated with low successful resuscitation rates and poor outcome [7]. However, if sodium bicarbonate is given according to standard recommendations, no significant metabolic abnormalities should occur. Tissue acidosis during CPR is caused primarily by low tissue perfusion and accumulation of CO 2.. Carbon dioxide readily diffuses across cell membranes and the blood-brain barrier, whereas bicarbonate diffuses much more slowly. Thus, it is possible that sodium bicarbonate administration could result in a paradoxical worsening of intracellular and cerebral acidosis. Routine administration of sodium bicarbonate during cardiac arrest and CPR, or after ROSC, is not recommended except in life-threatening hyperkalaemia, and in cardiac arrest associated with hypokalaemia and tricyclic overdose. In these cases, a dose of 50 mmol (50 ml of an 8.4% solution) of sodium bicarbonate is advisable and can be repeated according to the clinical condition and the results of serial blood gas analyses as a guide. Magnesium Magnesium is intrinsic to many enzyme systems, especially those involved in ATP generation in muscle. It plays an important role in neurochemical transmission and affects the sensitivity of the motor endplate. It also improves the contractile response of the myocardium and limits the size of an infarct by a mechanism which is not well-established [6]. The normal plasma concentration ranges from 0.8 to 1.0 mmol -1. Hypomagnesaemia is often associated with hypokalaemia and predisposes to arrhythmias and cardiac arrest

5 A decreased intracellular magnesium concentration promotes myocardial excitability but, even in the absence of a low magnesium level, a bolus of IV magnesium will suppress ventricular ectopic beats. The efficacy of the use of magnesium in cardiac arrest is unproven, but it may be useful when hypokalaemia may have contributed to the arrest. Ventricular or supraventricular tachycardia is associated with hypomagnesaemia, torsades de pointes and digoxin toxicity. When VF/ pulseless VT cardiac arrest is associated with torsades de pointes, magnesium sulphate may be administered in a dose of 1 to 2g diluted in 10 ml in 5% of dextrose as a slow intravenous bolus, typically over 5 to 20 minutes (Class IIa for torsades). When torsades are present in a patient in whom a cardiac output is retained, the same 1 to 2g is mixed in 50 to 100 ml of 5% of dextrose infusion and given more slowly (e.g. over 5 to 60 minutes IV) under these conditions [7] as a loading dose. Calcium Calcium has a specific indication as emergency protection against the effects of hyperkalaemia or the unusual condition of calcium channel blocker (e.g. verapamil) overdose. Despite its crucial role in the myocardial action potential and contraction, its administration for any other reason appears to be ineffective, or even detrimental, as high intracellular calcium concentration is damaging to injured myocardial and neuronal cells. However, if the serum potassium level is above 6 mmol/l, 10ml of 10% calcium chloride should be given. Some authors have reported that there are no studies evaluating the treatment of hypercalcaemia or hypocalcaemia during arrest. However, empirical use of calcium may be considered when hyperkaleamia or hypermagnesaemia is suspected as the cause of cardiac arrest [7]. When pulseless electrical activity is caused by hyperkalaemia, hypocalcaemia and overdose of calcium channel-blocking drugs, the initial dose is 10ml of 10% calcium chloride. Conclusions There is a mounting body of evidence to suggest that adrenaline, amiodarone, lidocaine and, atropine individually in cardiac arrest as well as together do not improve long-term survival but some of them are promising with regard to their effect on short-term survival. Research has to continue to incorporate drugs without negative effects. Quality of CPR and early defibrillation are more important than ALS drugs. Key learning points The 2010 CPR guidelines indicate basic life support and early defibrillation are of primary importance. The quality of chest compressions is essential as if they are ineffective their effect on survival is catastrophic. The molecular changes that occur during cardiac arrest contribute to modify the blood-brain barrier. The associated hypoxicischaemia states at the time of cardiac arrest may provoke neuronal death and irreversible brain injury. Recent advances in the study of molecular and immunological mechanisms that prevail during ischaemia and reperfusion may lead to develop new therapeutics strategies. The role of drugs during cardiac arrest is secondary to basic life support and early defibrillation. Nowadays, randomized controlled trials on the use of vasopressors such as epinephrine have been performed in human cardiac arrest. Antiarrhythmic drugs such as amiodarone suppress ectopic ventricular rhythms. Others drugs such as atropine, magnesium sulphate, calcium and sodium bicarbonate have specific indications for their use at cardiac arrests. There is no data to prove that any drugs used during cardiac arrest improve long term survival

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