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Epinephrine, Sodium Bicarbonate and Calcium
Alfredo Sierra Unzueta, MD
Unidad de Terapia Intensiva "Alberto
Villazón S", Hospital Español de México,
México Distrito Federal, México
During cardiac arrest, medication has a secondary role to other interventions like ventilation and effective cardiac compressions. CPR, defibrillation, and adequate management of airways constitute the most important treatment of a patient in cardiac arrest. Once that there interventions have been initiated, the team should install an IV line in order to administrate medication. Although the role of these medications remains controversial, due to very little evidence which supports its use, they are indicated in the treatment for cardiopulmonary resuscitation. Before referring to its precise use, I am going to refer to some physiological elements, and also to experimental and clinical studies on which its use is based upon.
Myocardial blood flow is determined by the presence of a gradient created between the pressures in the aorta and the right atrium, when diastole begins (coronary perfusion pressure). (1) The return of spontaneous circulation as well al the survival of cardiac arrest victims has been clearly related to the ability of achieving a coronary perfusion pressure above 15mmhg. When administering any alpha adrenérgica agonist during CPR, it has been demonstrated that this pressure gradient is increased. The mechanism by which these agents augment the coronary perfusion pressure is through producing systemic arterial vasoconstriction, augmenting vascular resistance and vascular tone as well as preventing arteriolar collapse. These effects are necessary to maintain blood flow to the brain and heart during the relaxation phase while giving cardiac compressions. (2)
Epinephrine Hydrochloride is an alpha and beta adrenergic agent with a beneficial effect on patients during cardiac arrest. This effect is fundamentally due to its properties as an alpha adrenergic receptor agonist. (3) The action resulting from the adrenergic stimulation of epinephrine is an increment in blood flow to the myocardium and brain during CPR. These actions are similar to those which are initiated as a result of contraction or loss of volume in which the adrenergic response produces peripheral vasoconstriction to preserve perfusion to vital organs, particularly the brain, heart and lungs. The value of the adrenergic agonists which share actions on beta receptors is still in controversy because they increase myocardial work and reduce subendocardial perfusion, which causes an imbalance between myocardial oxygen delivery and consumption. (4)
Although epinephrine has been used universally during resuscitation, it still remains to be seen that there is actually evidence of benefit in humans.
In retrospective studies, Van Walraven and cols. (5) demonstrated a significant association between unsuccessful resuscitation and the use of epinephrine (O.R. 0.8, atropine O.R. 0.24, bicarbonate 0.31, calcium O.R. 0.32 and lydocaine 0.48). These investigators demonstrated that medication with adrenergic actions which resulted significantly effective in bettering the recovery rate during resuscitation had a common denominator; their alpha adrenergic activity. Medication which had exclusively beta adrenergic activity (i.e. isoproterenol), either had no effect during resuscitation or there were fewer survivors. When used early on during resuscitation, medication like epinephrine and metoxamine, there was a much higher rate of recovery. Medication with adrenergic action which also increased arterial pressure during CPR and also selectively increase blood flow to the heart and brain should be used. The extent to which one individual agent may increase flow to these areas are critical determinants for successful resuscitation.
Although epinephrine has been recommended by the AHA since 1970, there is no scientific data which can demonstrate that this medication provides better results after cardiac arrest. In laboratory studies, epinephrine is associated to an increase in myocardial oxygen consumption, ventricular arrhythmias, severe intrapulmonary veno-arterial shunt and myocardial dysfunction after resuscitation.
These changes are greatly diminished when using a pure alpha adrenergic agonist or when it is combined with a adrenergic beta blocker (6). More so, when compared to vasopresin, the pressor effect of epinephrine is shorter, resulting in a lowering of the coronary perfusion pressure, with a marked attenuation after a certain amount of time as well as repeated doses of the medication. Epinephrine also increases myocardial oxygen consumption resulting in a sever disproportion between myocardial oxygen consumption and delivery during CPR. This experimental data is supported by clinical studies in which epinephrine did not result better when compared to placebo.
For many years clinician and investigators have questioned the optimum dosage of epinephrine. The "standard" dose of epinephrine (1,0 mg) is not based on weight. Historically, the standard dose of 1 mg of epinephrine has been used during surgery for intracardiac injection. Surgeons observed that 1 to 3 mg of intra cardiac epinephrine was effective for starting an arrested heart. When these and other experts proposed the first guidelines during the 70's, they assumed that 1 mg of epinephrine could work in a similar fashion as the intracardiac route. Adult patients vary greatly in body weight, height, body surface area etc, but clinicians continue to use 1 mg of epinephrine whether or not there is great variation in weight or body surface area, which makes one believe that this is incorrect.
The dose- response curve of epinephrine was investigated in a series of experimental studies in the dog during the 80's. These paper showed that epinephrine produced a response which was considered a optimal between 0.045 and 0.20 mg/kg (7). From these studies on, it was shown probable that higher doses would better hemodynamics as well as having successful resuscitation, particularly when there was a prolonged cardiac arrest. These studies made clinicians use higher doses in man, and studies where published with retrospective fundaments from the end of the 1980's to 1990 (8,9).
The results of 4 clinical studies in which high vs conventional doses where compared, will be mentioned hereafter (10,11,12). The general rate of recovery of spontaneous circulation (GRRSC) was increased as greater doses were used 0.07 to 0.20 mg/kg), but there was no significant statistical difference in terms of increasing the rate of survival or hospital discharge. On the positive side, it was shown that the studies failed to detect harm after using higher doses. Based on this information and on the guidelines and recommendations of the AHA of 1992, it was stipulated that the first dose be 1 mg I.V. these guidelines also recommended that intervals of 3 to 5 minutes between doses should be used instead of every 5 minutes. If this dose was shown to be ineffective, it was accepted that higher doses be used. This could be done by either of 3 ways; an escalating dose (1,3,5) , an intermediate dose (5 mg/dose instead of 1 mg/dose) or a dose based on body weight (0.1 mg/kg).
The administration of epinephrine during cardiac arrest, experimentally and clinically it has shown to have equally beneficial as well as harmful effects. Escalating or high doses, occasionally have demonstrated better GRRSC in short term survival and neurologic prognosis. Other 8 randomized clinical studies of more than 9000 patients in cardiac arrest did not show better survival rates nor a better neurological prognosis, including the subgroups where high doses where used from the beginning compared to standard doses (11,12).
These studies orient us, after the failure of the initial 1 mg dose, to use initially high doses and not escalating doses. These same studies did not show worse results using epinephrine with high doses.
Retrospective studies, however, have suggested that the accumulation of epinephrine used at high doses was associated with hemodynamic worsening and a worse neurologic prognosis, even though they did not show a proven cause.
Laboratory studies, have proven both favorable and unfavorable effects. High doses of epinephrine may improve coronary perfusion, vascular resistances as well as a better GRRSC during CPR, but these same effects may lead to a worsening of myocardial dysfunction and occasionally to a severe hyper-adrenergic intoxication during the post-resuscitation period. A target population has to be identified a high risk group or a group with potential benefit (refractory conditions to catecholamines to obtain more studies) (13,14,15,16).
In conclusion, initial high doses of epinephrine during cardiac arrest may increase coronary perfusion pressure and increase GRRSC, but may also worsen myocardial dysfunction after resuscitation. High doses epinephrine has not improved long term survival, nor the neurologic prognosis when being used as an initial therapy. Higher doses definitely does not cause more harm, therefore high dose epinephrine is not routinely recommended but may be considered when there is failure to respond to the 1 mg dose (Undetermined class: acceptable although not recommendable). There is evidence which creates certain conflict in favor and against high doses. (above 0.2 mg/kg) when the 1 mg dose has failed (Class IIb ; acceptable but not recommendable, lacking in evidence to support).
More recent studies with epinephrine show that the dose of 0.1 mg/kg had better results in 10 kg dogs with cardiac arrest. This dose is used in the clinical setting in humans, with no evidence of comparable clinical success. After 30 years of clinical use, studies in humans and in animals suggest that the standard doses of 1 mg is insufficient. These studies showed a dose dependent relationship between an increase in arterial pressure and cerebral and myocardial blood flow when epinephrine was used at doses between 0.45 and 0.2 mg/kg. Based the mg/kg dosage, an equivalent dose in humans for a 70 kg male would be from 3 to 14 mg. After these studies, a small number of them reported better survival in patients treated with high doses of epinephrine. In 4 large scale clinical studies referred to before, when comparing conventional doses versus high doses, there were no statistical differences in the rate of spontaneous recovery of the cardiorespiratory function. There was no improvement in short term survival or in hospital discharge, there was also no difference in the neurologic results in those patients who survived. In fact, a small group of patients who received a high dose of epinephrine after 10 minutes showed statistically less possibility of survival after the arrest in this study.
The recommended dose of epinephrine hydrochlorides 1.0 mg (10 ml of a solution 1:10 00) IV every 3 to 5 minutes during CPR. Each peripheral dose administrated should be followed by a bolus of 20 cc of solution to assure that the drug has made it to central circulation.
Epinephrine possesses good biodisponibility after being administered by the endotraqueal route, if administered appropriately. Although the optimal dose for this route is unknown, at least 2 to 2.5 times the intravenous dose should be administered. Direct intracardiac administration should be limited to the operating room during direct cardiac compressions or when there is no possibility of using the other routes. An intracardiac injection presents the risk of producing laceration of a coronary artery, cardiac tamponade and pneumothorax. There is also the problem of having to suspend cardiac compressions and ventilation during its administration.
Epinephrine may also be used as a vasopressor in patients who are not in cardiac arrest and have other indications for using vasopressors. For example, epinephrine is considered class IIb for symptomatic bradycardia (class IIb: acceptable but not recommended: poor clinical evidence), after using atropine and a pacemaker, and having failed.
Norepinephrine, like epinephrine shares alpha and beta adrenergic actions, it is effective in raising myocardial and brain blood flow, it also augments myocardial oxygen extraction in experimental studies done on animals and humans. This does not mean that norepinephrine has advantages over epinephrine in cardiac arrest. Phenilephrine and metoamine are pure alpha agonists. These drugs have been proven to be less effective in increasing hemodynamic indexes, the relationship of myocardial extraction and the rates of resuscitation during prolonged CPR, when they are compared to norepinephrine and epinephrine.
Recently vasopresin has become a potential drug that replaces epinephrine in cardiac arrest patients. In investigations of cardiac arrest, either secondary to ventricular fibrillation or pulseless electrical activity, vasopresin provides a higher level of coronary perfusion and maintained better oxygen delivery to the brain than did epinephrine. These studies showed that the recovery rate was significantly higher in animals treated with vasopresin than in those treated with epinephrine. More so, after prolonged arrest, the presor effect of catecholamines is lowered and with vasopresin it is maintained. The superiority of vasopresin over epinephrine is supported by recently published randomized clinical studies, where cardiac arrest patients (n-40) who received vasopresin had higher rates of return of spontaneous circulation as well as a higher hospital survival when compared to epinephrine. We currently recommend vasopresin in patients with ventricular fibrillation who do not respond to the standard dose of epinephrine after 5 minutes of continued CPR. Vasopresin may replace epinephrine as the presor of election during CPR.
The central part in the control of the acid base equilibrium during cardiac arrest and during to post resuscitation period is to maintain sufficient alveolar ventilation. Hyperventilation corrects respiratory acidosis by removing carbon dioxide, which is freely diffusible through cellular and organic membranes.(e.g. Brain). The resulting acidosis and acidemia during cardiac arrest and during resuscitation are dynamic processes which result in low blood flow. This process depends on the duration of the cardiac arrest as well as the existing blood flow during cardiopulmonary resuscitation. The understanding and knowledge of acid base pathophysiology during cardiac arrest and resuscitation indicate that carbon dioxide which is generated during low blood flow conditions is due to tissue hypoxia. The best indicator of individual organic perfusion is the CO2 level pressure, which has led to the development of PCO2 sensors, which is the basis of the principals of tonometry, which is used to study shock and other low flow states. During cardiac arrest carbon dioxide is liberated, which is a volatile acid and acids like lactic acid are not. Acidosis during arrest is of mixed origin, meaning respiratory and metabolic. To treat the respiratory component there must be adequate alveolar ventilation, to treat the metabolic component, adequate compressions and the return of spontaneous circulation to restore tissue perfusion must be achieved, treating both components is key in controlling this equilibrium. Both laboratory data as well as clinical data have not shown that low pH adversely affects the defibrillation umbral, the ability to restore spontaneous circulation or short term survival. Adrenergic response does not seem to be affected by tissue acidosis.
There is little data concerning benefits of therapy with buffers during cardiac arrest. On the contrary, there is certain laboratory and clinical evidence which indicates that bicarbonate does not improve results of defibrillation, and does not improve survival rates in animal experiments. There may be alterations in coronary perfusion pressure, there may be adverse effects due to a paradox intracellular acidosis including a shift of the oxyhemoglobin dissociation curve inhibiting oxygen delivery, it may also produce hyperosmolarity and hypernatremia; produce carbon dioxide which is highly diffusible through cellular membranes tissues of the heart and the brain producing a paradox intracellular acidosis, it may worsen central venous acidosis and may inactivate administered catecholamines.
In certain conditions like preexisting acidosis, hyperkalemia or overdoses of trycyclics or phenobarbital, bicarbonate may be of use. After an almost refractory cardiac arrest or with very prolonged resuscitation, it is possible that bicarbonate may be of some use. Therapy with bicarbonate should be considered only after there have been confirmed interventions which have failed, like defibrillation, cardiac compressions, intubation, ventilation and therapy with vasopressors.
Recommendations of bicarbonate use vary, depending on the clinical situation. Its indications can be found in the algorithms of the new guidelines of the American Heart Association and are basically 3, ventricular tachycardia and fibrillation, pulseless electrical activity and during asystole.
When using bicarbonate, it should be administered with an initial dose of 1 mEq/kg. Whenever possible therapy should be guided by measuring levels of seric bicarbonate and/or base excess. To avoid the risk of iatrogenic alkalosis complete correction of base deficit should be avoided.
Although calcium ions play a critical role in contractile performance and the generation of electrical impulse of the heart, prospective and retrospective studies during cardiac arrest have not been able to demonstrate any benefit with its use. There also exists certain concern, based on theoretical theories that high levels of seric calcium could have harmful effects. When there is existing hyperkalemia, hypocalcemia of beta blocker intoxication, then the administration of calcium could be of use (class IIb). Calcium should not be used in other situations (class III).
When indicated, it may be administered as a 10% solution of calcium chloride, 2 to 4 mg/kg with repeated doses used at 10 minute intervals.(the 10% solution contains 1.36 mEq of calcium for every 100 mg of sodium/ml) 5 to 7 ml of calcium gluceptate can be administered or 5 to 8 ml of calcium gluconate.
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