- Email: [email protected]
Aortic-Based Therapy for Cardiac Arrest
CPR PROCEEDINGS
Aortic-Based Therapy for Cardiac Arrest From the Department of Medicine, Columbia University College of Physicians and Surgeons, and the Department of Emergency Medicine, St Luke's-Roosevelt Hospital Center, New York, New York.
Norman A Paradis, MD
Received for publication March 17, 1995. Revision received June 25, 1995. Accepted for publication September 8, 1995. Supported in part by a development grant from Reperfusion @stems, Boston. Presented in part at the Second Chicago Symposium on Advances in CPR Research and Guidelines for Laboratory Research, Chicago, October 1994. The author holds US patent no. 5,334,142 covering the selective aortic per.fusion and oxygen system. The Biopure Corporation holds US patent no. 5,084,558 (BP86-OIAA) on ultrapurified polymerized bovine hemoglobin. Copyright © by the American College of Emergency Physicians.
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After the failure of electrical countershock, the successful treatment of cardiac arrest is a function of raising aortic pressure so as to improve vital organ perfusion. Pharmacologic pressor agents have until recently been the most direct means of increasing aortic pressure. We have now begun to reevaluate direct aortic techniques including occlusion, infusion, counterpulsation, and combinations of these. Clinical studies have demonstrated that the aorta can be accessed quickly and reliably even under emergency conditions. Initial laboratory studies indicate that some nonpharmacologic aortic therapies hold promise as adjuncts to external chest compression, or even as stand-alone therapies. Considerable research will be needed to identify the most effective approach before clinical trials can be considered. [Paradis NA: Aortic-based therapy for cardiac arrest. Ann Emerg Med May 1996;27:563-568.]
INTRODUCTION CPR has not fulfilled the expectations of its early proponents, and the prognosis for patients in cardiac arrest for more than 10 minutes remains poor. ~ Studies in animal models have shown that vital organ blood flow, and therefore oxygen delivery, during CPR is usually inadequate to achieve return of spontaneous circulation (Rose). 2'3 Coronary perfusion pressure, 4,5 a principal predictor of ROSC, is usually inadequate after the first few minutes of cardiac arrest. 6-9 Outcome studies in humans confirm the limited efficacy of standard advanced cardiac life support (ACLS).l°,ll The fact that standard therapy is rarely effective after the first minutes of cardiac arrest is now the central clinical problem in emergency cardiac care. Studies in patients and laboratory models of cardiac arrest demonstrate that ROSC is dependent on myocardial perfusion, and that myocardial perfusion is a function of the pressure gradient between the aorta and the right atrium. <7 During the
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relaxation phase of external chest compression, this gradient is considered the CPR coronary perfusion pressure (CPP). Therapies for cardiac arrest refractory to initial electrical countershock are principally intended to increase CPP and to improve the metabolic state of the myocardium so as to achieve ROSC. DISCUSSION
Resuscitative techniques that are based solely on external chest compression may be limited in their ability to generate adequate perfusion pressures. 12 Alternate therapies, such as open-chest CPR or cardiopulmonary bypass, can dramatically increase CPP 13,14 but require resources or expertise not generally available. Therapies that require special expertise or transport of the patient to a hospital may have only limited clinical applicability, because almost all patients will have irreversible central nervous system injury. 15 To significantly improve the outcome of patients in cardiac arrest, a relatively quick and simple procedure to improve CPP is needed. Two approaches may be taken: either increase the aortic pressure or lower the right atrial pressure. Methods to lower right atrial pressure have obvious limitations, forcing us to focus on techniques to raise aortic pressure. Because therapies that raise aortic pressure through modifications of chest compression or vasopressor drugs have been extensively reviewed, the focus in this discussion is on potential techniques to raise the pressure in the aorta by direct manipulation of this vital structure. Traditionally, aortic pressure was thought to be increased mechanically by improvement in cardiac output through modification of chest compression. This approach, however, has had only limited success. The aortic-based therapies discussed here are intended to raise perfusion pressure by direct physical manipulation of the aorta or its intravascular compartment. There are two broad approaches to raising aortic pressure by nonpharmacologic means: direct occlusion and fluid infusion. The thoracic pump model of CPR predicts that simple occlusion during external chest compression will be only minimally effective. 16 Most laboratory studies are consistent with this prediction and show only slight increases in aortic pressure with percutaneous balloon occlusion of the descending aorta during external chest compression. ~7,18 On the other hand, Tang et a119 found that CPP and the rate of ROSC were improved by prommal placement in the ascending aorta. However, it is difficult to access the ascending aorta safely and reliably under emergency conditions. If a subgroup of patients benefit
S 64
from perfusion generated by a cardiac pump model, there may be occasional benefit in simple occlusion of the thoracic aorta. 2° Occlusion or counterpulsation during open-chest cardiac compression appears to consistently improve hemodynamics 21,22, indicating that a significant stroke volume is needed for simple distal occlusion to be effective. Balloon occlusion during open-chest CPR is of only theoretic interest, however, because direct aortic cross-clamping can be performed. Aortic balloon counterpulsation may be effective even in dosed-chest models 23, and this technique may provide a means to apply mechanical aortic therapy with the use of available devices. Because existing counterpulsation catheters were designed for use during spontaneous circulation, development of systems optimized for the arrested state may increase efficacy. Our objective may not be simple augmentation of the relaxation phase pressure but the movement of fluid columns so as to augment cardiac output and vital organ blood flow. From the earliest days of modern resuscitation, there has been interest in arterial fluid infusions. 24 Negovsky et a125 are reported to have studied the effects of whole blood arterial infusions more than 40 years ago. Sanders et a126 found arterial autotransfusion of exsanguinated venous blood ineffective, and Gentile et al 2r found arterial and venous crystalloid infusions therapeutically ineffective as well. Arterial volume infusion may be unable to improve outcome because crystalloid solutions decrease the oxygen-carrying capacity of blood in direct proportion to the volume infused. This may create a situation in which the aortic pressure and CPP are not predictive of ROSC because they no longer are surrogate markers for oxygen delivery, r The oxygen content of the perfused fluid appears to be of central importance in preparing the myocardium for defibrillation and restoration of mechanical function. Infusion of oxygenated blood, as first envisioned by Negovsky~ has recently been found to be effective by Sun et al. 28 In their study, transient aortic infusion of oxygenated blood improved both CPP and ROSC. The failure of simple aortic occlusion or infusion of unoxygenated fluid to significantly improve outcome during external chest compression led investigators to consider combining these therapies. Aortic occlusion restricts the infusate to the important proximal portion of the aorta, maximizing vital organ perfusion pressures. The study of Sun et al 2s indicated that use of an oxygen-carVing material would be optimal. Manning et a129 compared infusions of saline solution, oxygenated lactated Ringer's solution, and perfluorochemical in a canine model of car-
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diac arrest. The latter two groups also received 2 mg/L and 4 mg/L of epinephrine, respectively, CPP increased in all groups and was highest in animals that had received epinephrine. However, there appeared to be no significant differences in the rate of ROSC, and animals that received larger-volume infusions had large increases in central venous pressure. Because neither the lactated Ringer's solution nor the perfIuorochemical caused large increases in aortic oxygen content, and because of the lack of equivalence among the subgroups with respect to pressor therapy, this study is difficult to interpret. The combination of aortic volume infusion with aortic administration of epinephrine increased perfusion pressures. In another study, Manning et aP ° found that the infusion of a poorly miscible perfluorocarbon was no more effective than intraaortic administration of epinephrine alone. In this model, improvements in CPP after proximal aortic infusions appeared insufficient to improve outcome. Larger Figure 1. An aortic occlusion-infusion catheter positioned in the proximal descending aorta.
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volumes or longer infusion times resulted in unacceptable increases in right atrial pressure. Increases in right atrial pressure reduce CPP and appear to limit the duration of infusion. Pulsing of the infusion during the relaxation phase may limit the total amount of fluid needed to achieve a given delivered oxygen content and decrease volume overload. Our laboratory has undertaken a series of studies intended to develop effective aortic therapies. Thus far, these studies have shown that certain aortic therapies can dramatically increase vital organ perfusion pressures and the rate of ROSC after prolonged periods of arrest. 17 Whether these results lead to improved intact long-term survival in laboratory models or patients remains to be determined. To achieve maximal efficacy, aortic therapy may require infusion of oxygen-carrying material. 31 The safest and most effective fluid to carry oxygen during ischemia and reperfusion is not known) 2 Whole blood, with its attendant costs and risk of hypersensitivity, is unsuitable for the treatment of an emergency condition. Studies using crystalloids and poorly miscible perfluorocarbons indicate that inadequate oxygen-carrying capacity is a major obstacle to efficacy Recently, stroma-free hemoglobins (SFH) have become available; they have oxygen-carrying capacities similar to that of whole blood and appear to be relatively nontoxic during spontaneous circulation) 3 The newer generations of perfluorocarbons have potentially attractive oxygen dissociation curves. The choice of agent is greatly affected by the toxicity profile during ischemia and reperfusion. Pilot studies in our laboratory indicated that aortic infusions alone were not as effective in restoring spontaneous circulation as a combination of external chest compression and aortic therapy. Therefore, our first laboratory study compared standard ACLS (including epinephrine and electrical countershock) with standard ACLS plus aortic occlusion and a 2-minute proximal infusion of oxygenated SFH. lr In a canine model of ventricular fibrillation, this selective aortic perfusion and oxygenation (SAPO) treatment increased the maximal CPP from 33_+21 mm Hg in ACLS-treated animals to 62___26mm Hg in animals receiving ACLS+SAPO. Only 2 of 10 dogs receiving ACLS had ROSC, compared with 6 of 7 dogs receiving ACLS+SAPO. This model incorporated both a prolonged period of untreated arrest and a force of compression adjusted to produce intravascular pressures comparable to those seen clinically. 9,34,35 This resulted in a success rate for standard ACLS that was comparable to that seen in humanbeings ~, whereas ACLS+SAPO dramatically
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improved the short-term outcome. In this study, the occluding balloon was placed at the proximal descending aorta, a position that can be readily and reliably cannulated even during external chest compression (Figure 1). 36 The presence of the occluding balloon allowed control of afterload during the critical period just after ROSC and assisted in preventing postreperfusion hypotension. This study confirmed the feasibility of aortic therapy and demonstrated its potential to improve the efficacy of ACLS in a clinically relevant model. In this setting, aortic therapy is an adjunct to external chest compression, not a replacement. Should aortic therapy become part of clinical treatment for cardiac arrest, its effect on other components of advanced life support will need additional study. Aortic infusions, for instance, may delay the appearance of intravenously administered medications in the arterial circulation. For this reason, we have theorized that adrenergic agents may be more effective if administered through the aortic catheter before the start of infusion. This is consistent with Manning et al, 3r who found that the pressor response was more rapid and of a greater magnitude when epinephrine was administered intraaortically. Almost all current data on resuscitation from cardiac arrest have been developed with the use of IV pharmaFigure 2.
The relation between volume of infused oxygenated stromafree hemoglobin and rate of return of spontaneous circulation in a canine model of ventricular fibrillation.
cotherapy. 38 It may not be appropriate to assume that this pharmacology is applicable to intraarterial therapy. Intravenously administered epinephrine can cause significant impairment in lung function during passage through the pulmonary vasculature. 39 This toxicity may be ameliorated by direct aortic administration, which may require lower dosages. First, however, the role of pressor agents during aortic therapy must be more clearly delineated. It was not known, for instance, whether SAPO, which increases perfusion pressure directly by volume expansion of the central arterial vascular compartment, requires augmented vasomotor tone to be effective. Using a standard model of ventricular fibrillation, we performed ACLSSAPO with and without exogenous epinephrine. 4°,41 Maximal aortic pressures were higher in animals treated with epinephrine, a result similar to that of Manning et al. 29,3° The characteristic dramatic rise in aortic pressure that accompanies the onset of aortic infusion occurred only in animals who had received epinephrine. Animals who had received saline placebo had only a gradual rise in aortic pressure which, because of the concomitant rise in right atrial pressure, resulted in only small increases in perfusion pressure. Epinephrine-treated animals had an increase in aortic relaxation phase pressure of 58+5 mm Hg with the onset of infusion, compared with only 20+11 in animals receiving saline placebo. Only 2 of 7 animals in the placebo group had ROSC, compared with 7 of 8 animals in the epinephrine group. Figure 3.
The "comb needle"for rapid placement of intravascular catheters.
% Resuscitation 00
Zz
bt
75
112-i
50
//
25
10 mL/kg
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20 mL/kg Volumeof oxygenatedfluid
11111
30 mL/kg a
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Apparently, after prolonged cardiac arrest, exogenous pressor is needed to reduce the compliance of the arterial compartment. Without the increased vasomotor tone, much of the infused material may run off into nonvital vascular beds. The importance of increased vasomotor tone during aortic infusion should not, however, be confused with the central role of increased flow. The large increases in perfusion pressure result from the interaction of flow, which is a combination of cardiac output and infused fluid, and compliance, which is vasopressor-mediated vasomotor tone. During standard ACLS, there is a significant decrease in serum epinephrine levels between the intravenous and intraarterial compartments, 8 possibly reflecting catabolism during the prolonged transit from the venous to the arterial circulations. Because this does not occur during ACLS+SAPO with intraarterial administration, dose-response data from models using IV administration may not be applicable during aortic therapy. We have completed a preliminary study which appears to confirm that there is a dose-response relation between intraaortic epinephrine and aortic pressure during ACLS+SAPO. 41 Although dosages that are usually ineffective when administered intravenously may be minimally effective when administered directly into the aorta, the optimal dosage is in the range of .01 mg/kg, which is equivalent to the standard 1-mg dose in human beings, r This may reflect the poor state of the vascular smooth muscle cell after prolonged arrest. Preliminary data indicate that the purely [3-adrenergic drug phenylephrine may be as effective as epinephrine, which is a mixed (z- and [3-adrenergic agonist. It is not known what volume or rate of infusion is optimal during aortic therapy. These parameters may be a function of ischemic time, with large volumes and higher rates needed later in arrest. In our laboratory, there appears to be a dose-response relation between the volume of oxygen-carrying fluid, the perfusion pressures, and the rate of ROSC. 31 It remains to be determined whether the relation between the volume of infused material and the rate of ROSC (Figure 2) reflects delivered oxygen, washout of carbon dioxide, or a combination of these two processes. 42 These relations do appear to change with time, but the specific interactions remain to be studied. Possibly, we should think of these agents not as bulk carriers of oxygen but as pharmacologic agents. The pharmacologic effects may be variable between agents and dynamic with respect to ischemic time. Eventually, it may be possible to adjust the "dose" of oxygen so as to balance the volume necessary for restoration of organ function against the t o x -
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icity of oxygen in reperfusion. SFHs, for instance, appear to cause a nonadrenergic-mediated postresuscitation hypertension that may help to ameliorate the "no-reflow" phenomenon. Therapies that incorporate infusion of material before ROSC may allow early administration of neuronal salvaging agents. Potentially, oxygen-carrying infusions may be combined with antioxidant drugs, ameliorating the negative aspects of reoxygenation. This is the ultimate promise of aortic therapies: improved vital organ perfusion and oxygen supply, combined with immediate therapy for reperfusion injury. Eventually, combinations of devices and agents may allow hemodynamic and biochemical control of the reperfusion event from the field to the emergency department. Possibly the greatest challenge faced by all of the aortic therapies is development of a rapid and reliable technique for placement during cardiac arrest. Our laboratory has made a significant effort toward developing techniques for rapid cannulation of the femoral artery and accurate placement of catheters in the aorta. We have begun to evaluate an introducer device, which we call a "comb needle" (Figure 3), which produces a series of punctures and increases the chance that the femoral artery will be cannulated. Preliminary work indicates that this device may allow rapid placement of large catheters by wire-guide technique with a high rate of success. Appropriate stiffening and sizing of the catheter can aid in correct placement within the thoracic aorta. Several investigators have demonstrated the feasibility of aortic therapies in laboratory models. ~s,~9,28,3o A subset of these may have demonstrated efficacy.19,28 The next step in the development process is to evaluate the effects of aortic therapies on the neurologic outcome and survival. These techniques cannot be considered ready for clinical use until this research is completed. Preliminary studies in our laboratory indicate that aortic therapies can have a salutary effect on neurologic outcome, but additional studies, possibly including models with coronary occlusion, are needed. Until clinical studies are undertaken, it will not be possible to predict the ultimate role of aortic therapy in the treatment of cardiac arrest. If found to be clinically effective, aortic therapy could reasonably be administered after failure of vasopressor therapy and before invasive techniques such as cardiopulmonary bypass and open-chest CPR. A therapy that falls between standard ACLS and cardiopulmonary bypass in efficacy and invasiveness is needed, and aortic therapies may fill this niche. Currently, these therapies are limited to balloon counterpulsation or aortic cross-clamping during open-chest CPR, but pub-
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lished studies indicate that newer modalities may improve perfusion pressure and short-term outcome. Only if these therapies can be demonstrated to increase the fraction of animals with neurologically intact survival after clinically relevant global ischemic insults should human clinical trials be considered. We have not yet reached that point.
22. Wesley RC Jr, Morgan DB: Effect of continuous intra-aortic balloon inflation in canine open chest cardiopulmonary resuscitation. Crit CareMed 1990;18:630-633. 23. EmermanCL, PinchakAC, HagenJE, et al: Hemodynamiceffects of the intra-aortic balloon pump during experimental cardiac arrest. Am J EmergMad 1989;7:378-383. 24. StephensonHE, Hinton JW: Use of intra-aortic and intracardiac transfusions in cardiac arrest. JAMA 1953;152:500-503. 25. NegovskyVA, GurvitchAM, Zolotokrylina ES: Postresuscitatiendisease. Amsterdam: Elsevier, 1983. 26. SandersAB, Kern KB, Ewy GA, et ah The effect of autotransfusion en the coronary perfusion pressureduring cardieputmonaryresuscitation (abstract). C/inRes1983;31:828A.
REFERENCES 1. EisenbergMS, Horwood BT, Cummins RO, et ah Cardiacarrest and resuscitation: A tale of 29 cities. Ann EmergMeal1990;19:179-188. 2, Ditchey RV, Winkler JV, RhodesCA: Relative lack of coronary blood flow during closed-chest resuscitation in dogs. Circulation1982;66:297-302. 3. Oitchey RV, Horwitz LD: Metabolic evidence of inadequate coronary blood flow during closedchest resuscitation in dogs. CardiovascRes 1985;19:419-425. 4. N;emann JT, RosboroughJP, Ung S, at al: Coronaryperfusion pressure during experimental cardiopulmonaryresuscitation. Ann EmergMad 1982;11:127-131. 5. SandersAB, Ogle M, Ewy GA: Coronaryperfusion pressureduring cardiopurmenaryresuscitation. Am J EmergMad 1985;3:11-14. 6. American Heart Association: Standards and guidelines for cardiopulmonaryresuscitation (CPR) and emergencycardiac care (ECC).JAMA 1986;255:2841-3044.
27. Gentile NT, Martin GB, Appleton TJ, et al: Effects of arterial and venous volume infusion en coronary perfusion pressuresduring canine CPR.Resuscitation1991;22:55-63. 28, Sun S, Well MH, Tang W, et ah Cardiacresuscitation by retroaortic infusion of blood. J Lab Clin Mefl 1994;123:81-88. 29. Manning JE, Murphy CA Jr, Hertz CM: Selective aortic arch perfusien during cardiac arrest: A new resuscitation technique. Ann EmergMad 1992;21:1058-1065. 30. Manning JE, Batson DN, Murphy CA, et al: Selective aortic arch perfusion with oxygenated fluorocarbons combined with aortic arch epinephrine (abstract).Ann EmergMad 1993;22:929930. 31. Paradis NA, OavisonC, Fuller J: What "dose" of oxygen is required in treating prolonged cardiac arrest? (abstract) Crit CareMad 1995;23:A177. 32. Sehgal LR, Gould SA, RosenAL, et ah Polymerizedpyridoxylated hemoglobin:A red cell substitute with normal oxygen capacity. Surgery1984;95:433-438.
7. Paradis NA, Martin GB, Rivers EP, et ah Coronaryperfusion pressureand return of spontaneous circulation in human cardiopulmonary resuscitation. JAMA 1990;263:1106-1113.
33. Vlahakes GJ, Lee R, Jacobs EEJr, et ah Hemodynamiceffects and oxygen transport properties of a new blood substitute in a model of massive blood replacement. J ThoracCardiovasc Surg1990;100:379-388.
8. Paradis NA, Martin GB, Rivers EP, et al: The effect of standard- and high-dose epinephrine on coronary perfusion pressureduring prolonged cardiopulmonary resuscitation. JAMA 1991;265:1139-1144.
34. Paradis NA, Martin GO, Goetting MG, et al: Aortic pressure during human cardiac arrest: Identification of pseudo-aleetromechanicaldissociation. Chest19£2;101:123-128.
9. Paradis NA, Martin GB, Goetting MG, et ah Simultaneousaortic, jugular bulb, and right atrial pressuresduring cardiopulmonaryresuscitation in humans: Insights into mechanisms. Circulation 1989;80:361-368. 10. BeckerLB, Ostrander MP, Barrett J, et ah Outcomeof CPR in a large metropolitan area: Where are the survivors?Ann EmergMed1991;20:355-361. 11. Eitel DR, Walton SL, Guerci AD, et ah Out-of-hospital cardiac arrest: A six-year experience in a suburban-ruralsystem. Ann EmergMad 1988;17:808-912. 12. Martin GB, CardenOL, Nowak RM, et ah Aortic and right atrial pressuresduring standard and simultaneous compressionand ventilation CPR in human beings. Ann EmergMed1986;15:125130. 13. Kern KB, SandersAB, 8adylak SF, et ah Long-termsurvival with open-chestcardiac massage after closed-chest compressionin a canine preparation. Circulation1987;75:498403. 14. Martin GB, Nowak RM, CardenDL, et al: Cardiopulmanarybypassvs CPRas treatment for prolonged cardiopulmonaryarrest. Ann EmergMed 1987;16:628-836. 15. Abramsen NS, Safar P, Detre KM, et al: Neurolegic recovery after cardiac arrest: Effect of duration of ischemia. Crit CareMad 1985;13:930-931. 16. Weisfeldt ML, ChandraNC, Tsitlik J: Increasedintrathoracic pressure--not direct heart campression--causes the rise in intrathoracic vascular pressuresduring CPRin dogs and pigs. Crit CareMad 1981;9:377-378. 17. Paradis NA, Rose MI, Gawryl M: Selective aortic perfusion and oxygenation: An effective adjunct to external chest compression-basedcardiepulmenary resuscitation. J Am Cell Carflio/ 1994;23:497-504. 18. SandersAB, Kern KB, Ewy GA, et al: The effect of balloon occlusion on the coronary perfusion pressure during cardiopulmonary resuscitation (abstract). CilnRes1983;31:829A.
35. Paradis NA, Martin GB, Rivers EP, et ah Coronaryperfusion pressureand the return of spontaneous circulation in human cardiopulmonary resuscitation. JAMA 1990;263:1106-1113. 36. Paradis NA, Nowak RM, Martin GB: Prospectiveresuscitation methodologies. TopEmerg Mad 1989;11:77-86. 37. Manning JE, Murphy CA Jr, Batsen ON, et ah Aortic arch versus central venous epinephrine during CPR.Ann EmergMad 1993;22:703-708. 38. Paradis NA, KoscoveEM: Epinephrinein cardiac arrest: A critical review. Ann EmergMad 1990;19:1288-1301. 39. Tang W, Well MH, GazmuriRJ, et ah Pulmonaryventilation/perfusion defects induced by epinephrine during cardiopulmenary resuscitation (see comments). Circulation1991;84:21012107. 40. Paradis NA, Davison C, Fuller J, et ah Intra-aortic epinephrine and perfusien pressuresduring ACLS and selective aortic perfusion and oxygenation. Crit CareMad 1994;22:A224. 41. Paradis NA, Davis C: The dose-responserelationship for epinephrine during CPR-selective aortic perfusion and oxygenation therapy of cardiac arrest. AcadEmergMad 1994;1:A81. 42. Johnson BA, Well MH: Redefining ischemia due to circulatory failure as dual defects of oxygen deficits and of carbon dioxide excesses. CritCareMad1991;19:1432-1438.
Reprint No. 47/1/71888 Address for reprints: Norman A Paradis, MD 48 Rernsen Street Brooklyn, New York 11201-4106
19. Tang W, Well MH, Noc M, et ah Augmented efficacy of external CPR by intermittent occlusion of the ascending aorta. Circulation1993;88:1916-1921.
212-523-2202
20. ChandraNC: Mechanisms of blood flow during CPR.Ann EmergMeal1993;22:281-288.
E-mail [email protected]
Fax 718-625-3005
21. Spance PA, Lust RM, Chitwood WR Jr, et ah Transfemoral balloon aortic occlusion during open cardiepulmonaryresuscitation improves myocardial and cerebral blood flow. J SurgRes 1990;49:217-221.
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Aortic-Based Therapy for Cardiac Arrest From the Department of Medicine, Columbia University College of Physicians and Surgeons, and the Department of Emergency Medicine, St Luke's-Roosevelt Hospital Center, New York, New York.
Norman A Paradis, MD
Received for publication March 17, 1995. Revision received June 25, 1995. Accepted for publication September 8, 1995. Supported in part by a development grant from Reperfusion @stems, Boston. Presented in part at the Second Chicago Symposium on Advances in CPR Research and Guidelines for Laboratory Research, Chicago, October 1994. The author holds US patent no. 5,334,142 covering the selective aortic per.fusion and oxygen system. The Biopure Corporation holds US patent no. 5,084,558 (BP86-OIAA) on ultrapurified polymerized bovine hemoglobin. Copyright © by the American College of Emergency Physicians.
MAY 1996 27:5
ANNALS OF EMERGENCY MEDFCINE
After the failure of electrical countershock, the successful treatment of cardiac arrest is a function of raising aortic pressure so as to improve vital organ perfusion. Pharmacologic pressor agents have until recently been the most direct means of increasing aortic pressure. We have now begun to reevaluate direct aortic techniques including occlusion, infusion, counterpulsation, and combinations of these. Clinical studies have demonstrated that the aorta can be accessed quickly and reliably even under emergency conditions. Initial laboratory studies indicate that some nonpharmacologic aortic therapies hold promise as adjuncts to external chest compression, or even as stand-alone therapies. Considerable research will be needed to identify the most effective approach before clinical trials can be considered. [Paradis NA: Aortic-based therapy for cardiac arrest. Ann Emerg Med May 1996;27:563-568.]
INTRODUCTION CPR has not fulfilled the expectations of its early proponents, and the prognosis for patients in cardiac arrest for more than 10 minutes remains poor. ~ Studies in animal models have shown that vital organ blood flow, and therefore oxygen delivery, during CPR is usually inadequate to achieve return of spontaneous circulation (Rose). 2'3 Coronary perfusion pressure, 4,5 a principal predictor of ROSC, is usually inadequate after the first few minutes of cardiac arrest. 6-9 Outcome studies in humans confirm the limited efficacy of standard advanced cardiac life support (ACLS).l°,ll The fact that standard therapy is rarely effective after the first minutes of cardiac arrest is now the central clinical problem in emergency cardiac care. Studies in patients and laboratory models of cardiac arrest demonstrate that ROSC is dependent on myocardial perfusion, and that myocardial perfusion is a function of the pressure gradient between the aorta and the right atrium. <7 During the
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relaxation phase of external chest compression, this gradient is considered the CPR coronary perfusion pressure (CPP). Therapies for cardiac arrest refractory to initial electrical countershock are principally intended to increase CPP and to improve the metabolic state of the myocardium so as to achieve ROSC. DISCUSSION
Resuscitative techniques that are based solely on external chest compression may be limited in their ability to generate adequate perfusion pressures. 12 Alternate therapies, such as open-chest CPR or cardiopulmonary bypass, can dramatically increase CPP 13,14 but require resources or expertise not generally available. Therapies that require special expertise or transport of the patient to a hospital may have only limited clinical applicability, because almost all patients will have irreversible central nervous system injury. 15 To significantly improve the outcome of patients in cardiac arrest, a relatively quick and simple procedure to improve CPP is needed. Two approaches may be taken: either increase the aortic pressure or lower the right atrial pressure. Methods to lower right atrial pressure have obvious limitations, forcing us to focus on techniques to raise aortic pressure. Because therapies that raise aortic pressure through modifications of chest compression or vasopressor drugs have been extensively reviewed, the focus in this discussion is on potential techniques to raise the pressure in the aorta by direct manipulation of this vital structure. Traditionally, aortic pressure was thought to be increased mechanically by improvement in cardiac output through modification of chest compression. This approach, however, has had only limited success. The aortic-based therapies discussed here are intended to raise perfusion pressure by direct physical manipulation of the aorta or its intravascular compartment. There are two broad approaches to raising aortic pressure by nonpharmacologic means: direct occlusion and fluid infusion. The thoracic pump model of CPR predicts that simple occlusion during external chest compression will be only minimally effective. 16 Most laboratory studies are consistent with this prediction and show only slight increases in aortic pressure with percutaneous balloon occlusion of the descending aorta during external chest compression. ~7,18 On the other hand, Tang et a119 found that CPP and the rate of ROSC were improved by prommal placement in the ascending aorta. However, it is difficult to access the ascending aorta safely and reliably under emergency conditions. If a subgroup of patients benefit
S 64
from perfusion generated by a cardiac pump model, there may be occasional benefit in simple occlusion of the thoracic aorta. 2° Occlusion or counterpulsation during open-chest cardiac compression appears to consistently improve hemodynamics 21,22, indicating that a significant stroke volume is needed for simple distal occlusion to be effective. Balloon occlusion during open-chest CPR is of only theoretic interest, however, because direct aortic cross-clamping can be performed. Aortic balloon counterpulsation may be effective even in dosed-chest models 23, and this technique may provide a means to apply mechanical aortic therapy with the use of available devices. Because existing counterpulsation catheters were designed for use during spontaneous circulation, development of systems optimized for the arrested state may increase efficacy. Our objective may not be simple augmentation of the relaxation phase pressure but the movement of fluid columns so as to augment cardiac output and vital organ blood flow. From the earliest days of modern resuscitation, there has been interest in arterial fluid infusions. 24 Negovsky et a125 are reported to have studied the effects of whole blood arterial infusions more than 40 years ago. Sanders et a126 found arterial autotransfusion of exsanguinated venous blood ineffective, and Gentile et al 2r found arterial and venous crystalloid infusions therapeutically ineffective as well. Arterial volume infusion may be unable to improve outcome because crystalloid solutions decrease the oxygen-carrying capacity of blood in direct proportion to the volume infused. This may create a situation in which the aortic pressure and CPP are not predictive of ROSC because they no longer are surrogate markers for oxygen delivery, r The oxygen content of the perfused fluid appears to be of central importance in preparing the myocardium for defibrillation and restoration of mechanical function. Infusion of oxygenated blood, as first envisioned by Negovsky~ has recently been found to be effective by Sun et al. 28 In their study, transient aortic infusion of oxygenated blood improved both CPP and ROSC. The failure of simple aortic occlusion or infusion of unoxygenated fluid to significantly improve outcome during external chest compression led investigators to consider combining these therapies. Aortic occlusion restricts the infusate to the important proximal portion of the aorta, maximizing vital organ perfusion pressures. The study of Sun et al 2s indicated that use of an oxygen-carVing material would be optimal. Manning et a129 compared infusions of saline solution, oxygenated lactated Ringer's solution, and perfluorochemical in a canine model of car-
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diac arrest. The latter two groups also received 2 mg/L and 4 mg/L of epinephrine, respectively, CPP increased in all groups and was highest in animals that had received epinephrine. However, there appeared to be no significant differences in the rate of ROSC, and animals that received larger-volume infusions had large increases in central venous pressure. Because neither the lactated Ringer's solution nor the perfIuorochemical caused large increases in aortic oxygen content, and because of the lack of equivalence among the subgroups with respect to pressor therapy, this study is difficult to interpret. The combination of aortic volume infusion with aortic administration of epinephrine increased perfusion pressures. In another study, Manning et aP ° found that the infusion of a poorly miscible perfluorocarbon was no more effective than intraaortic administration of epinephrine alone. In this model, improvements in CPP after proximal aortic infusions appeared insufficient to improve outcome. Larger Figure 1. An aortic occlusion-infusion catheter positioned in the proximal descending aorta.
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volumes or longer infusion times resulted in unacceptable increases in right atrial pressure. Increases in right atrial pressure reduce CPP and appear to limit the duration of infusion. Pulsing of the infusion during the relaxation phase may limit the total amount of fluid needed to achieve a given delivered oxygen content and decrease volume overload. Our laboratory has undertaken a series of studies intended to develop effective aortic therapies. Thus far, these studies have shown that certain aortic therapies can dramatically increase vital organ perfusion pressures and the rate of ROSC after prolonged periods of arrest. 17 Whether these results lead to improved intact long-term survival in laboratory models or patients remains to be determined. To achieve maximal efficacy, aortic therapy may require infusion of oxygen-carrying material. 31 The safest and most effective fluid to carry oxygen during ischemia and reperfusion is not known) 2 Whole blood, with its attendant costs and risk of hypersensitivity, is unsuitable for the treatment of an emergency condition. Studies using crystalloids and poorly miscible perfluorocarbons indicate that inadequate oxygen-carrying capacity is a major obstacle to efficacy Recently, stroma-free hemoglobins (SFH) have become available; they have oxygen-carrying capacities similar to that of whole blood and appear to be relatively nontoxic during spontaneous circulation) 3 The newer generations of perfluorocarbons have potentially attractive oxygen dissociation curves. The choice of agent is greatly affected by the toxicity profile during ischemia and reperfusion. Pilot studies in our laboratory indicated that aortic infusions alone were not as effective in restoring spontaneous circulation as a combination of external chest compression and aortic therapy. Therefore, our first laboratory study compared standard ACLS (including epinephrine and electrical countershock) with standard ACLS plus aortic occlusion and a 2-minute proximal infusion of oxygenated SFH. lr In a canine model of ventricular fibrillation, this selective aortic perfusion and oxygenation (SAPO) treatment increased the maximal CPP from 33_+21 mm Hg in ACLS-treated animals to 62___26mm Hg in animals receiving ACLS+SAPO. Only 2 of 10 dogs receiving ACLS had ROSC, compared with 6 of 7 dogs receiving ACLS+SAPO. This model incorporated both a prolonged period of untreated arrest and a force of compression adjusted to produce intravascular pressures comparable to those seen clinically. 9,34,35 This resulted in a success rate for standard ACLS that was comparable to that seen in humanbeings ~, whereas ACLS+SAPO dramatically
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improved the short-term outcome. In this study, the occluding balloon was placed at the proximal descending aorta, a position that can be readily and reliably cannulated even during external chest compression (Figure 1). 36 The presence of the occluding balloon allowed control of afterload during the critical period just after ROSC and assisted in preventing postreperfusion hypotension. This study confirmed the feasibility of aortic therapy and demonstrated its potential to improve the efficacy of ACLS in a clinically relevant model. In this setting, aortic therapy is an adjunct to external chest compression, not a replacement. Should aortic therapy become part of clinical treatment for cardiac arrest, its effect on other components of advanced life support will need additional study. Aortic infusions, for instance, may delay the appearance of intravenously administered medications in the arterial circulation. For this reason, we have theorized that adrenergic agents may be more effective if administered through the aortic catheter before the start of infusion. This is consistent with Manning et al, 3r who found that the pressor response was more rapid and of a greater magnitude when epinephrine was administered intraaortically. Almost all current data on resuscitation from cardiac arrest have been developed with the use of IV pharmaFigure 2.
The relation between volume of infused oxygenated stromafree hemoglobin and rate of return of spontaneous circulation in a canine model of ventricular fibrillation.
cotherapy. 38 It may not be appropriate to assume that this pharmacology is applicable to intraarterial therapy. Intravenously administered epinephrine can cause significant impairment in lung function during passage through the pulmonary vasculature. 39 This toxicity may be ameliorated by direct aortic administration, which may require lower dosages. First, however, the role of pressor agents during aortic therapy must be more clearly delineated. It was not known, for instance, whether SAPO, which increases perfusion pressure directly by volume expansion of the central arterial vascular compartment, requires augmented vasomotor tone to be effective. Using a standard model of ventricular fibrillation, we performed ACLSSAPO with and without exogenous epinephrine. 4°,41 Maximal aortic pressures were higher in animals treated with epinephrine, a result similar to that of Manning et al. 29,3° The characteristic dramatic rise in aortic pressure that accompanies the onset of aortic infusion occurred only in animals who had received epinephrine. Animals who had received saline placebo had only a gradual rise in aortic pressure which, because of the concomitant rise in right atrial pressure, resulted in only small increases in perfusion pressure. Epinephrine-treated animals had an increase in aortic relaxation phase pressure of 58+5 mm Hg with the onset of infusion, compared with only 20+11 in animals receiving saline placebo. Only 2 of 7 animals in the placebo group had ROSC, compared with 7 of 8 animals in the epinephrine group. Figure 3.
The "comb needle"for rapid placement of intravascular catheters.
% Resuscitation 00
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bt
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Apparently, after prolonged cardiac arrest, exogenous pressor is needed to reduce the compliance of the arterial compartment. Without the increased vasomotor tone, much of the infused material may run off into nonvital vascular beds. The importance of increased vasomotor tone during aortic infusion should not, however, be confused with the central role of increased flow. The large increases in perfusion pressure result from the interaction of flow, which is a combination of cardiac output and infused fluid, and compliance, which is vasopressor-mediated vasomotor tone. During standard ACLS, there is a significant decrease in serum epinephrine levels between the intravenous and intraarterial compartments, 8 possibly reflecting catabolism during the prolonged transit from the venous to the arterial circulations. Because this does not occur during ACLS+SAPO with intraarterial administration, dose-response data from models using IV administration may not be applicable during aortic therapy. We have completed a preliminary study which appears to confirm that there is a dose-response relation between intraaortic epinephrine and aortic pressure during ACLS+SAPO. 41 Although dosages that are usually ineffective when administered intravenously may be minimally effective when administered directly into the aorta, the optimal dosage is in the range of .01 mg/kg, which is equivalent to the standard 1-mg dose in human beings, r This may reflect the poor state of the vascular smooth muscle cell after prolonged arrest. Preliminary data indicate that the purely [3-adrenergic drug phenylephrine may be as effective as epinephrine, which is a mixed (z- and [3-adrenergic agonist. It is not known what volume or rate of infusion is optimal during aortic therapy. These parameters may be a function of ischemic time, with large volumes and higher rates needed later in arrest. In our laboratory, there appears to be a dose-response relation between the volume of oxygen-carrying fluid, the perfusion pressures, and the rate of ROSC. 31 It remains to be determined whether the relation between the volume of infused material and the rate of ROSC (Figure 2) reflects delivered oxygen, washout of carbon dioxide, or a combination of these two processes. 42 These relations do appear to change with time, but the specific interactions remain to be studied. Possibly, we should think of these agents not as bulk carriers of oxygen but as pharmacologic agents. The pharmacologic effects may be variable between agents and dynamic with respect to ischemic time. Eventually, it may be possible to adjust the "dose" of oxygen so as to balance the volume necessary for restoration of organ function against the t o x -
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icity of oxygen in reperfusion. SFHs, for instance, appear to cause a nonadrenergic-mediated postresuscitation hypertension that may help to ameliorate the "no-reflow" phenomenon. Therapies that incorporate infusion of material before ROSC may allow early administration of neuronal salvaging agents. Potentially, oxygen-carrying infusions may be combined with antioxidant drugs, ameliorating the negative aspects of reoxygenation. This is the ultimate promise of aortic therapies: improved vital organ perfusion and oxygen supply, combined with immediate therapy for reperfusion injury. Eventually, combinations of devices and agents may allow hemodynamic and biochemical control of the reperfusion event from the field to the emergency department. Possibly the greatest challenge faced by all of the aortic therapies is development of a rapid and reliable technique for placement during cardiac arrest. Our laboratory has made a significant effort toward developing techniques for rapid cannulation of the femoral artery and accurate placement of catheters in the aorta. We have begun to evaluate an introducer device, which we call a "comb needle" (Figure 3), which produces a series of punctures and increases the chance that the femoral artery will be cannulated. Preliminary work indicates that this device may allow rapid placement of large catheters by wire-guide technique with a high rate of success. Appropriate stiffening and sizing of the catheter can aid in correct placement within the thoracic aorta. Several investigators have demonstrated the feasibility of aortic therapies in laboratory models. ~s,~9,28,3o A subset of these may have demonstrated efficacy.19,28 The next step in the development process is to evaluate the effects of aortic therapies on the neurologic outcome and survival. These techniques cannot be considered ready for clinical use until this research is completed. Preliminary studies in our laboratory indicate that aortic therapies can have a salutary effect on neurologic outcome, but additional studies, possibly including models with coronary occlusion, are needed. Until clinical studies are undertaken, it will not be possible to predict the ultimate role of aortic therapy in the treatment of cardiac arrest. If found to be clinically effective, aortic therapy could reasonably be administered after failure of vasopressor therapy and before invasive techniques such as cardiopulmonary bypass and open-chest CPR. A therapy that falls between standard ACLS and cardiopulmonary bypass in efficacy and invasiveness is needed, and aortic therapies may fill this niche. Currently, these therapies are limited to balloon counterpulsation or aortic cross-clamping during open-chest CPR, but pub-
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lished studies indicate that newer modalities may improve perfusion pressure and short-term outcome. Only if these therapies can be demonstrated to increase the fraction of animals with neurologically intact survival after clinically relevant global ischemic insults should human clinical trials be considered. We have not yet reached that point.
22. Wesley RC Jr, Morgan DB: Effect of continuous intra-aortic balloon inflation in canine open chest cardiopulmonary resuscitation. Crit CareMed 1990;18:630-633. 23. EmermanCL, PinchakAC, HagenJE, et al: Hemodynamiceffects of the intra-aortic balloon pump during experimental cardiac arrest. Am J EmergMad 1989;7:378-383. 24. StephensonHE, Hinton JW: Use of intra-aortic and intracardiac transfusions in cardiac arrest. JAMA 1953;152:500-503. 25. NegovskyVA, GurvitchAM, Zolotokrylina ES: Postresuscitatiendisease. Amsterdam: Elsevier, 1983. 26. SandersAB, Kern KB, Ewy GA, et ah The effect of autotransfusion en the coronary perfusion pressureduring cardieputmonaryresuscitation (abstract). C/inRes1983;31:828A.
REFERENCES 1. EisenbergMS, Horwood BT, Cummins RO, et ah Cardiacarrest and resuscitation: A tale of 29 cities. Ann EmergMeal1990;19:179-188. 2, Ditchey RV, Winkler JV, RhodesCA: Relative lack of coronary blood flow during closed-chest resuscitation in dogs. Circulation1982;66:297-302. 3. Oitchey RV, Horwitz LD: Metabolic evidence of inadequate coronary blood flow during closedchest resuscitation in dogs. CardiovascRes 1985;19:419-425. 4. N;emann JT, RosboroughJP, Ung S, at al: Coronaryperfusion pressure during experimental cardiopulmonaryresuscitation. Ann EmergMad 1982;11:127-131. 5. SandersAB, Ogle M, Ewy GA: Coronaryperfusion pressureduring cardiopurmenaryresuscitation. Am J EmergMad 1985;3:11-14. 6. American Heart Association: Standards and guidelines for cardiopulmonaryresuscitation (CPR) and emergencycardiac care (ECC).JAMA 1986;255:2841-3044.
27. Gentile NT, Martin GB, Appleton TJ, et al: Effects of arterial and venous volume infusion en coronary perfusion pressuresduring canine CPR.Resuscitation1991;22:55-63. 28, Sun S, Well MH, Tang W, et ah Cardiacresuscitation by retroaortic infusion of blood. J Lab Clin Mefl 1994;123:81-88. 29. Manning JE, Murphy CA Jr, Hertz CM: Selective aortic arch perfusien during cardiac arrest: A new resuscitation technique. Ann EmergMad 1992;21:1058-1065. 30. Manning JE, Batson DN, Murphy CA, et al: Selective aortic arch perfusion with oxygenated fluorocarbons combined with aortic arch epinephrine (abstract).Ann EmergMad 1993;22:929930. 31. Paradis NA, OavisonC, Fuller J: What "dose" of oxygen is required in treating prolonged cardiac arrest? (abstract) Crit CareMad 1995;23:A177. 32. Sehgal LR, Gould SA, RosenAL, et ah Polymerizedpyridoxylated hemoglobin:A red cell substitute with normal oxygen capacity. Surgery1984;95:433-438.
7. Paradis NA, Martin GB, Rivers EP, et ah Coronaryperfusion pressureand return of spontaneous circulation in human cardiopulmonary resuscitation. JAMA 1990;263:1106-1113.
33. Vlahakes GJ, Lee R, Jacobs EEJr, et ah Hemodynamiceffects and oxygen transport properties of a new blood substitute in a model of massive blood replacement. J ThoracCardiovasc Surg1990;100:379-388.
8. Paradis NA, Martin GB, Rivers EP, et al: The effect of standard- and high-dose epinephrine on coronary perfusion pressureduring prolonged cardiopulmonary resuscitation. JAMA 1991;265:1139-1144.
34. Paradis NA, Martin GO, Goetting MG, et al: Aortic pressure during human cardiac arrest: Identification of pseudo-aleetromechanicaldissociation. Chest19£2;101:123-128.
9. Paradis NA, Martin GB, Goetting MG, et ah Simultaneousaortic, jugular bulb, and right atrial pressuresduring cardiopulmonaryresuscitation in humans: Insights into mechanisms. Circulation 1989;80:361-368. 10. BeckerLB, Ostrander MP, Barrett J, et ah Outcomeof CPR in a large metropolitan area: Where are the survivors?Ann EmergMed1991;20:355-361. 11. Eitel DR, Walton SL, Guerci AD, et ah Out-of-hospital cardiac arrest: A six-year experience in a suburban-ruralsystem. Ann EmergMad 1988;17:808-912. 12. Martin GB, CardenOL, Nowak RM, et ah Aortic and right atrial pressuresduring standard and simultaneous compressionand ventilation CPR in human beings. Ann EmergMed1986;15:125130. 13. Kern KB, SandersAB, 8adylak SF, et ah Long-termsurvival with open-chestcardiac massage after closed-chest compressionin a canine preparation. Circulation1987;75:498403. 14. Martin GB, Nowak RM, CardenDL, et al: Cardiopulmanarybypassvs CPRas treatment for prolonged cardiopulmonaryarrest. Ann EmergMed 1987;16:628-836. 15. Abramsen NS, Safar P, Detre KM, et al: Neurolegic recovery after cardiac arrest: Effect of duration of ischemia. Crit CareMad 1985;13:930-931. 16. Weisfeldt ML, ChandraNC, Tsitlik J: Increasedintrathoracic pressure--not direct heart campression--causes the rise in intrathoracic vascular pressuresduring CPRin dogs and pigs. Crit CareMad 1981;9:377-378. 17. Paradis NA, Rose MI, Gawryl M: Selective aortic perfusion and oxygenation: An effective adjunct to external chest compression-basedcardiepulmenary resuscitation. J Am Cell Carflio/ 1994;23:497-504. 18. SandersAB, Kern KB, Ewy GA, et al: The effect of balloon occlusion on the coronary perfusion pressure during cardiopulmonary resuscitation (abstract). CilnRes1983;31:829A.
35. Paradis NA, Martin GB, Rivers EP, et ah Coronaryperfusion pressureand the return of spontaneous circulation in human cardiopulmonary resuscitation. JAMA 1990;263:1106-1113. 36. Paradis NA, Nowak RM, Martin GB: Prospectiveresuscitation methodologies. TopEmerg Mad 1989;11:77-86. 37. Manning JE, Murphy CA Jr, Batsen ON, et ah Aortic arch versus central venous epinephrine during CPR.Ann EmergMad 1993;22:703-708. 38. Paradis NA, KoscoveEM: Epinephrinein cardiac arrest: A critical review. Ann EmergMad 1990;19:1288-1301. 39. Tang W, Well MH, GazmuriRJ, et ah Pulmonaryventilation/perfusion defects induced by epinephrine during cardiopulmenary resuscitation (see comments). Circulation1991;84:21012107. 40. Paradis NA, Davison C, Fuller J, et ah Intra-aortic epinephrine and perfusien pressuresduring ACLS and selective aortic perfusion and oxygenation. Crit CareMad 1994;22:A224. 41. Paradis NA, Davis C: The dose-responserelationship for epinephrine during CPR-selective aortic perfusion and oxygenation therapy of cardiac arrest. AcadEmergMad 1994;1:A81. 42. Johnson BA, Well MH: Redefining ischemia due to circulatory failure as dual defects of oxygen deficits and of carbon dioxide excesses. CritCareMad1991;19:1432-1438.
Reprint No. 47/1/71888 Address for reprints: Norman A Paradis, MD 48 Rernsen Street Brooklyn, New York 11201-4106
19. Tang W, Well MH, Noc M, et ah Augmented efficacy of external CPR by intermittent occlusion of the ascending aorta. Circulation1993;88:1916-1921.
212-523-2202
20. ChandraNC: Mechanisms of blood flow during CPR.Ann EmergMeal1993;22:281-288.
E-mail [email protected]
Fax 718-625-3005
21. Spance PA, Lust RM, Chitwood WR Jr, et ah Transfemoral balloon aortic occlusion during open cardiepulmonaryresuscitation improves myocardial and cerebral blood flow. J SurgRes 1990;49:217-221.
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