Can Resuscitation Jeopardize Survival?
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《新英格兰医药杂志》
Resuscitations are events that are often clouded by desperation and frenzy and directed by persons with limited experience, who may feel a great burden of responsibility for the circumstances precipitating the respiratory or cardiac arrest. The consequences of any delay in restoring ventilation and circulation are both sobering and frightening. Failure often assumes a personal tone, leaving the responders with feelings of inadequacy, especially when the patient is a child.
Anyone who witnessed the attempted resuscitation of an infant or child before the publication of the first Pediatric Advanced Life Support (PALS) guidelines in 19861 recognizes the value of an organized approach. Leon Chameides, his colleagues, and the American Heart Association are to be commended not only for their vision and tenacity in bringing order out of chaos but also for their willingness to revise the guidelines frequently as new knowledge develops. Adherence to the PALS guidelines provides the best opportunity for a wide range of caregivers with highly variable experience to maximize the chances of success. As is often the case, simplicity is the secret behind the effectiveness of the PALS guidelines. Simplicity is also their main vulnerability, however, because it is difficult for simple procedures to address all possible situations optimally.
Every resuscitation effort aims to fulfill two sequential objectives. The first is to restore ventilation and circulation. The second is to minimize tissue damage during and after the resuscitation, thereby maximizing the chances that the patient will survive relatively intact. These two objectives are inherently aligned, but as the findings reported by Perondi et al. in this issue of the Journal (pages 1722–1730) suggest, they may also be in competition with one another. The issue at hand is the use of high-dose epinephrine during attempted cardiovascular resuscitation in children. Epinephrine has been used for almost 100 years to increase cardiac automaticity and contractility and to redistribute the blood flow to vital organs such as the brain and the myocardium, which are relatively insensitive to the alpha-adrenergic or vasoconstrictor effects of this drug. The question of the appropriate dose (both individual doses and the cumulative dose) has been a matter of contention that is often resolved as much on the basis of mnemonic simplicity as it is through pharmacokinetic justification. Contrary to the conventional wisdom that if a little is good, more is better, evidence has been accumulating that high-dose epinephrine is not beneficial2 and may even impair organ function and survival after the arrest.3 Perondi et al. report that children who received one or more doses of 0.1 mg of epinephrine per kilogram of body weight had rates of recovery after an arrest that were similar to those among children treated with the customary dose, which is 1/10 of this amount, but the children who received the higher dose were more likely to die soon thereafter.
All statistical caveats aside, the most intriguing aspect of these results is the possibility that a change in dose that may appear to be trivial can have such a detectable influence on the dismal survival rates after cardiac arrest. The key may reside in the calorigenic effects of epinephrine on various tissues, including the myocardium. Epinephrine may increase myocardial and cerebral perfusion during resuscitation, but in the process, it also increases oxygen use for a given measure of mechanical work by the heart (a very well recognized effect) and for the delivery of a given amount of oxygen to many other organs (a poorly recognized effect). How the ensuing imbalance between oxygen supply and use affects survival is not well established. What is undeniable is that epinephrine does affect survival, at least under the controlled circumstances of the laboratory.
We have known for a long time that epinephrine shortens the survival of animals that are ventilated with a hypoxic gas, subjected to hemorrhagic shock, or resuscitated from cardiac arrest, whereas beta-adrenergic antagonists prolong survival under each of these circumstances.4 Elucidating the mechanisms by which epinephrine aggravates the imbalance between oxygen supply and demand may be key for understanding how individual tissue injuries are aggregated to initiate an irreversible course toward death after cardiac arrest. In more practical terms, the question is whether most deaths after cardiac arrest are caused by irreversible cerebral injury from sustained hypoxia or by other injuries that might be preventable. Collecting the information needed to answer this question with regard to adults presents problems that are more than logistic, because cardiac arrests do not happen in healthy adults; it is therefore difficult to differentiate the consequences of the arrest from those of the primary process that caused it.
Children, however, may offer a unique opportunity to explore these issues prospectively. Most cardiac arrests that occur during childhood result from respiratory failure, which not only is treatable and reversible in most cases, but also tends to spare other organs. It is precisely in the group of children with asphyxia that Perondi et al. found the negative effects of epinephrine to be most distinct. Because the first priority after respiratory arrest is to restore oxygenation and ventilation, the use of epinephrine or other inotropic medications is less likely to be beneficial in these circumstances than in others and is more likely to result in toxic effects. (One might question whether epinephrine should be used at all before ventilation has been fully reestablished or after cardiac contraction has been initiated.) In addition, children usually have a healthy cardiovascular system, which should be more tolerant of low perfusion pressures than that of an adult who has arteriosclerosis and obstructive coronary artery disease.
But before we write off epinephrine, it is essential that we evaluate its effects and advantages carefully. Studies like the one performed by Perondi et al. are exceptional, not only because of the infrequency of cardiac arrest in children, but also because of the formidable difficulties involved in forcing people to follow a protocol in desperate situations when few caregivers are present at the scene. For the time being, the standard intravenous dose of 0.01 mg per kilogram recommended in the PALS guidelines may be the safest bet. Limiting the use of epinephrine to this dose has the additional advantage of minimizing the number of formulations of epinephrine that must be stocked in resuscitation boxes and carts, which is likely to reduce the rate of error. Persons who are frequently involved in resuscitation attempts will do well, however, to remember that the effects of multiple doses of epinephrine (or, for that matter, of any medication) are cumulative and that the diminishing returns obtained with multiple doses may not compensate for the attendant epinephrine-mediated organ damage.
Source Information
From the Department of Pediatrics, University of Texas Southwestern Medical School, Dallas (G.L.); and the Department of Pediatrics, Washington University School of Medicine, St. Louis (J.J.P.F.).
References
Standards and guidelines for cardiopulmonary resuscitation (CPR) and emergency cardiac care (ECC). V. Pediatric advanced life support. JAMA 1986;255:2961-2969.
Gueugniaud P-Y, Mols P, Goldstein P, et al. A comparison of repeated high doses and repeated standard doses of epinephrine for cardiac arrest outside the hospital. N Engl J Med 1998;339:1595-1601.
Behringer W, Kittler H, Sterz F, et al. Cumulative epinephrine dose during cardiopulmonary resuscitation and neurologic outcome. Ann Intern Med 1998;129:450-456.
Cain SM. Survival time of hypoxic dogs given epinephrine or propranolol. Am J Physiol 1973;225:1405-1410.(George Lister, M.D., and )
Anyone who witnessed the attempted resuscitation of an infant or child before the publication of the first Pediatric Advanced Life Support (PALS) guidelines in 19861 recognizes the value of an organized approach. Leon Chameides, his colleagues, and the American Heart Association are to be commended not only for their vision and tenacity in bringing order out of chaos but also for their willingness to revise the guidelines frequently as new knowledge develops. Adherence to the PALS guidelines provides the best opportunity for a wide range of caregivers with highly variable experience to maximize the chances of success. As is often the case, simplicity is the secret behind the effectiveness of the PALS guidelines. Simplicity is also their main vulnerability, however, because it is difficult for simple procedures to address all possible situations optimally.
Every resuscitation effort aims to fulfill two sequential objectives. The first is to restore ventilation and circulation. The second is to minimize tissue damage during and after the resuscitation, thereby maximizing the chances that the patient will survive relatively intact. These two objectives are inherently aligned, but as the findings reported by Perondi et al. in this issue of the Journal (pages 1722–1730) suggest, they may also be in competition with one another. The issue at hand is the use of high-dose epinephrine during attempted cardiovascular resuscitation in children. Epinephrine has been used for almost 100 years to increase cardiac automaticity and contractility and to redistribute the blood flow to vital organs such as the brain and the myocardium, which are relatively insensitive to the alpha-adrenergic or vasoconstrictor effects of this drug. The question of the appropriate dose (both individual doses and the cumulative dose) has been a matter of contention that is often resolved as much on the basis of mnemonic simplicity as it is through pharmacokinetic justification. Contrary to the conventional wisdom that if a little is good, more is better, evidence has been accumulating that high-dose epinephrine is not beneficial2 and may even impair organ function and survival after the arrest.3 Perondi et al. report that children who received one or more doses of 0.1 mg of epinephrine per kilogram of body weight had rates of recovery after an arrest that were similar to those among children treated with the customary dose, which is 1/10 of this amount, but the children who received the higher dose were more likely to die soon thereafter.
All statistical caveats aside, the most intriguing aspect of these results is the possibility that a change in dose that may appear to be trivial can have such a detectable influence on the dismal survival rates after cardiac arrest. The key may reside in the calorigenic effects of epinephrine on various tissues, including the myocardium. Epinephrine may increase myocardial and cerebral perfusion during resuscitation, but in the process, it also increases oxygen use for a given measure of mechanical work by the heart (a very well recognized effect) and for the delivery of a given amount of oxygen to many other organs (a poorly recognized effect). How the ensuing imbalance between oxygen supply and use affects survival is not well established. What is undeniable is that epinephrine does affect survival, at least under the controlled circumstances of the laboratory.
We have known for a long time that epinephrine shortens the survival of animals that are ventilated with a hypoxic gas, subjected to hemorrhagic shock, or resuscitated from cardiac arrest, whereas beta-adrenergic antagonists prolong survival under each of these circumstances.4 Elucidating the mechanisms by which epinephrine aggravates the imbalance between oxygen supply and demand may be key for understanding how individual tissue injuries are aggregated to initiate an irreversible course toward death after cardiac arrest. In more practical terms, the question is whether most deaths after cardiac arrest are caused by irreversible cerebral injury from sustained hypoxia or by other injuries that might be preventable. Collecting the information needed to answer this question with regard to adults presents problems that are more than logistic, because cardiac arrests do not happen in healthy adults; it is therefore difficult to differentiate the consequences of the arrest from those of the primary process that caused it.
Children, however, may offer a unique opportunity to explore these issues prospectively. Most cardiac arrests that occur during childhood result from respiratory failure, which not only is treatable and reversible in most cases, but also tends to spare other organs. It is precisely in the group of children with asphyxia that Perondi et al. found the negative effects of epinephrine to be most distinct. Because the first priority after respiratory arrest is to restore oxygenation and ventilation, the use of epinephrine or other inotropic medications is less likely to be beneficial in these circumstances than in others and is more likely to result in toxic effects. (One might question whether epinephrine should be used at all before ventilation has been fully reestablished or after cardiac contraction has been initiated.) In addition, children usually have a healthy cardiovascular system, which should be more tolerant of low perfusion pressures than that of an adult who has arteriosclerosis and obstructive coronary artery disease.
But before we write off epinephrine, it is essential that we evaluate its effects and advantages carefully. Studies like the one performed by Perondi et al. are exceptional, not only because of the infrequency of cardiac arrest in children, but also because of the formidable difficulties involved in forcing people to follow a protocol in desperate situations when few caregivers are present at the scene. For the time being, the standard intravenous dose of 0.01 mg per kilogram recommended in the PALS guidelines may be the safest bet. Limiting the use of epinephrine to this dose has the additional advantage of minimizing the number of formulations of epinephrine that must be stocked in resuscitation boxes and carts, which is likely to reduce the rate of error. Persons who are frequently involved in resuscitation attempts will do well, however, to remember that the effects of multiple doses of epinephrine (or, for that matter, of any medication) are cumulative and that the diminishing returns obtained with multiple doses may not compensate for the attendant epinephrine-mediated organ damage.
Source Information
From the Department of Pediatrics, University of Texas Southwestern Medical School, Dallas (G.L.); and the Department of Pediatrics, Washington University School of Medicine, St. Louis (J.J.P.F.).
References
Standards and guidelines for cardiopulmonary resuscitation (CPR) and emergency cardiac care (ECC). V. Pediatric advanced life support. JAMA 1986;255:2961-2969.
Gueugniaud P-Y, Mols P, Goldstein P, et al. A comparison of repeated high doses and repeated standard doses of epinephrine for cardiac arrest outside the hospital. N Engl J Med 1998;339:1595-1601.
Behringer W, Kittler H, Sterz F, et al. Cumulative epinephrine dose during cardiopulmonary resuscitation and neurologic outcome. Ann Intern Med 1998;129:450-456.
Cain SM. Survival time of hypoxic dogs given epinephrine or propranolol. Am J Physiol 1973;225:1405-1410.(George Lister, M.D., and )