future directions for resuscitation research. iv. innovative advanced life support pharmacology

Resuscitation 33 (1996) 163-177

RESUSCITATION

Future directions for resuscitation research. IV. Innovative advanced life support pharmacology’ ,2

Charles Browna, Lars Wiklundb, Gad Bar-Joseph”, Brian Millerd, Nicholas Bircher”, Norman Paradisf, James Menegazzie, Martin von Plantag, George C. Kramer”,

Sven-Erik Gisvold’ “(Moderator), Columbus, OH, USA ‘(Co-moderator), Uppsala, Sweden

“Haifa. Israel ‘Denver, CO, USA

“Pittsburgh, PA, USA ‘New York, NY, USA

gBasel, Switzerland hGalveston, TX, USA ‘Trondheim, Norua)

Received 8 April 1996; revised 6 May 1996: accepted 6 May 1996

Abstract

The topics discussed in this session include a partial review of laboratory and clinical studies examining the effmts of adrenergic agonists on restoration of spontaneous circulation after cardiac arrest, the effects of varying doses of epiaephrine, and the effects of novel vasopressors, buffer agents (NaHCO,, THAM, ‘Carbicarb’) and anti-arrhythmics (lidocaine, bretylium, amiodarone) in refractory ventricular fibrillation. Novel therapeutic approaches include titrating electric countershocks against electrocardiographic power spectra and of preceding the first countershocks with single or multiple drug treatments. These approaches need to be investigated further in controlled animal and patient studies. Epidemiologic data from randomized clinical outcome studies can give clues, but cannot document pharmacologic mechanisms in the dynamically changing events during attempts to achieve restoration of spontaneous circulation from prolonged cardiac arrest. Also, rapid drug administration by the intraosseous route was compared with intratraoheal and intravenous (i.v.) drug administration.

Many studies on the above treatments have yielded conflicting results because of differences between healthy hearts of animals and sick hearts of patients, differences in arrest (no-flow) times and cardiopulmonary resuscitation (CPR) (Iow-flow) times, different pharmacokinetics, different dose/response requirements, and different timing of drug administration during low-flow CPR versus during spontaneous circulation. The need to stabilize normotension and prevent rearrest by titrated novel drug admiais;tration, once spontaneous circulation has been restored, requires research. Most of the above topics require some re-evaluation in clinically realistic animal models and in cardiac arrest patients, especially by titration of old and new drug treatments against variables that can be monitored continuously during resuscitation. Copyright 0 1996 Elsevier Science Ireland Ltd

Keywords: Adrenergic agonists; Anti-arrhythmia agents; Buffers; CarGopulmonary resuscitation; Clinical trials: Defibrillation; Electric countershock; Electrocardiography; Intraosseous medication; Ventricular fibrillation;

Edited by: Peter War, Uwe Ebmeyer and Laurence Katz, Safar Center for Resuscitation Research, University of Pittsburgh, PA, USA. ’ Address ali correspondence to: Peter Safar, M.D., Safar Center for Resuscitation Research, University of Pittsburgh. 3434 Fifth Avenue,

Pittsburgh, PA 15260, USA. Tel.: + 412 6246735; fax: + 412 6240943. ’ From a discussion at the International Resuscitation Research Conference of May 1994 at the University of Pittsburgh. For introduction and

other topics of this conference, see the journal Critical Care Medicine, supplement of February 1996.

0300-9572/96/$15.00 Copyright 0 1996 Elsevier Science Ireland Ltd. All rights reserved PrI SO3OO-9572~96)01017-9

164 C. Brown et al. /Resuscitation 33 (1996) 163-177

1. Perfusion pressures and blood flows

1.1. Brown

Crile and Dolley [l] and Redding and Pearson [2-51 demonstrated that epinephrine helps to maintain coronary and cerebral perfusion pressure during cardiopulmonary resuscitation (CPR). Subsequent investigators have tried to determine the minimal perfusion pressure and flow that is required during CPR to meet the metabolic demands of the heart and brain until the underlying cause(s) of the cardiac arrest can be resolved [6- 131. Data from these studies suggest that myocardial blood flow of at least 18 ml/min per 100 g, and cerebral blood flow (CBF) of at least 10 ml/min per 100 g, are required to meet these metabolic demands during ventricular fibrillation (VF). Myocardial blood flow and CBF in animal models of cardiac arrest and coronary perfusion pressure (CoPP) in humans are usually below these minimum levels during standard external CPR, especially after prolonged CPR and without the use of vasopressor agents [10,14- 161. An important, unre- solved issue is how to improve vital organ perfusion during external CPR.

1.2. Editor @afar)

A minimal CoPP of about 30 mmHg seems to be required for restoration of spontaneous circulation (ROSC). A brief period of hypertension following ROSC is beneficial to help overcome the cerebral no- reflow phenomenon [17,18]. However, the optimal CoPP and cerebral perfusion pressure (CPP) (mean arterial pressure [MAP] minus intracranial pressure [ICP]) during resuscitation remain to be determined.

1.3. Brown

Organ blood flow is determined by the driving pressure minus the back pressure divided by the vascular resistance of that organ. For myocardial blood flow, this is most commonly represented by the CoPP (i.e. aortic diastolic pressure minus the right atria1 diastolic pressure) divided by the myocardial vascular resistance [19]. Following prolonged cardiac arrest and resuscitation, aortic diastolic pressure becomes the main driving force for myocardial perfusion. Several studies in animals and humans have shown that right atria1 ‘thoracic diastolic’ pressure is low during external CPR [10,14]. In addition, vascular resistance is probably quite low as well. This may be in part due to the profound vasodilation that occurs secondary to generation of tissue acidosis. When right atria1 pressure and vascular resistance are low, aortic diastolic pressure becomes the main driving force (and limiting factor) for myocardial perfusion during external CPR. Because aortic diastolic

pressure is approximately equal to the volume of fluid in the aorta divided by its capacitance, these two com- ponents of the equation can be examined as a means to increase the aortic diastolic pressure, and thus CoPP, during CPR.

Several studies [10,20,21] have shown that volume infusions not only increase aortic diastolic pressure, but also increase right atria1 pressure as well. These studies have shown, for the most part, no significant improvement in myocardial perfusion after volume perfusion in this setting. Another approach to improve aortic diastolic pressure has been to decrease vascular capacitance or increase peripheral vascular resistance. This has been the rationale for the use of a-adrenergic agonists during resuscitation. Through their a-agonist effects, they promote peripheral vasoconstriction, and thus increase peripheral vascular resistance, decrease arterial capacitance, and enhance aortic diastolic pressure and myocardial perfusion [22].

2. Adrenergic agonists

2.1. Brown

The overall results of our studies in a swine model of cardiac arrest and resuscitation (Appendix A, 1A) suggest that after a prolonged duration of no-flow (cardiopulmonary arrest), standard external CPR, followed by 0.02 mg/kg of epinephrine i.v., improves brain and heart perfusion minimally. On the other hand, epinephrine, in doses of 0.20 mg/kg iv., significantly increases perfusion to the myocardium, cerebral cortex and brainstem. Similar improvements in blood flow occur with norepinephrine in doses ranging from 0.12 mg/kg to 0.16 mg/kg [23]. In addition, very high doses of phenylephrine (10 mg/kg) increase myocardial blood flow to levels seen with epinephrine and norepinephrine, but are not as effective in promoting CBF. Methoxamine, in doses up to 10 mg/kg, is not as effective as epinephrine or norepinephrine [23]. In these studies and others [24], all drugs were given by the peripheral i.v. route. It is interesting to explore why some adrenergic agonists, such as epinephrine and norepinephrine, improve perfusion to the myocardium and brain during CPR, while other drugs, such as phenylephrine and methoxamine, are less effective.

This difference in a-adrenergic effect may be due to the differences in the ai- versus azagonist properties of these adrenergic agonists. The site of action of these drugs is the peripheral vasculature, which may help to explain differences in the effects of these agents. In the peripheral vascular wall, there are at least two adrenergic receptors: the al-receptor located near the outer wall, and the a,-receptor which is located closer to the vascular lumen [23]. Stimulation of either c(,- or a,-re-

C. Brow et al. / Resuscitation 33 (I 996) 163- I77 I65

ceptors should cause peripheral vasoconstriction and an increase in aortic diastolic pressure. While n,-receptors respond primarily to norepinephrine released from adrenergic nerve terminals, a,-receptors respond primarily to circulating catecholamines released from the adrenal medulla. Under conditions of extreme ischemic hypoxia and acidosis, there may be a desensitization or down-regulation of x,-receptors. Post- synaptic r,-receptors may play a more important role in regulating vasomotor tone in the setting of prolonged cardiac arrest. Methoxamine and phenylephrine may be less effective in this setting because they exert primarily a,-receptor agonism. One must also note that methoxamine has some beta-blocking properties. In addition, it has been suggested that a fraction of the phenylephrine administered may be converted to epinephrine, accounting for its effects during CPR. Epinephrine and norepinephrine have both a,- and cr,-agonist properties. Epinephrine also has p-1 and P-2 agonist effects.

Theoretically, one could review the available clinical literature in which some of these adrenergic agonist agents have been compared (i.e. studies comparing ‘pure’ a,-agonists versus agents that con- tain both a,- and a,-agonist properties [25,26]) to ex- amine this hypothesis. Although these studies are difficult to interpret because of variable definitions for the outcome measures, ROSC rates appear to be better with the use of epinephrine, a mixed CI,- and CI~- agonist agent, compared with methoxamine [25]. This supports the notion that a2 agonism may be more important than x, activity, clinically.

The role of /I agonism is less well defined. Lindner 1371 compared the efficacy of I-mg doses of epinephrine versus a 1-mg dose of norepinephrine during cardiac arrest and external CPR on the ROSC and hospital discharge rate. In this study, there was a more than 2-fold increase in the ROSC rate in patients who received norepinephrine. These results suggest that the pz effects (vasodilation) of epinephrine may be counterproductive.

Optimal dosing oj’ x-adrenergic agonists has not been established for cardiac arrest and resuscitation. Several studies in animals have shown that increasing doses of epinephrine improve the aortic diastolic pressure along with myocardial perfusion and resuscitation rates [28-301. Two human studies have shown similar improvements in arterial diastolic pressure and CoPP with increasing doses of epinephrine [31,32]. Recent retrospective uncontrolled case series in chil- dren suggest that after failure of two standard doses of epinephrine, higher doses of epinephrine may improve short-term resuscitation and hospital discharge rates [33]. More recent prospective controlled clinical trials in adults with out-of-hospital and in-hospital cardiac arrest, although showing an improvement in

ROSC rates [34-361, found no improvement in hospital discharge rates with higher doses of epinephrine [34-381. Several studies suggest that epinephrine’s detrimental effect may stem from its /Y,-agonist properties, which increase myocardial oxygen consumption and may worsen myocardial ischemia [39,40]. This appears to be supported in at least one large-scale clinical study which found increased rates of complex ventricular arrhythmias and rearrest in patients treated with high doses of epinephrine compared with those treated with standard doses of epinephrine [38]. Other studies have shown that epinephrine may cause ventilation/perfusion defects in rats [41] as well as myocardial necrosis [42,43]. Therefore, there may be many reasons why large doses of epinephrine and norepinephrine fail to improve survival rates.

Research is underway to develop new compounds that have specific X- and B-agonist characteristics. One area of investigation concerns halogenated catecholamines. Selective halogenation of the catechol ring has been suggested as a means to separate out the a,-. x2- and p-agonist effects of catecholamines. A new class of compounds, imidazaiines. have also been shown to act as peripheral vasoconstrictors in the setting of cardiac arrest 1441. Another promising vasopressor agent is angiotensin [45]. More pre-clinical studies delineating the x and ,@ effects of these compounds, their comparative efficacy and most effective mode of administration, are needed.

Are casopressors needed at ail? A recent abstract reported on a study comparing no epinephrine to standard and high doses of epinephrine in cardiac arrest [46]. Although key confounding variables were not reported, it is interesting to note that the authors found no significant difference in the proportion of patients who achieved ROSC or hospital discharge among the three groups. This study raises questions about the use of vasopressors at all. and suggests that other factors, such as ‘metabolic’ issues. may have a significant role in resuscitation from cardiac arrest.

Endogenous Ienels of catecholamines attd metabolites. Plasma levels of epinephrine and norepinephrine during cardiac arrest and CPR may reach up to approximately 50 times baseline values [47-Z]. If this is the case, why are these high endogenous catecholamine levels not effective in augmenting perfusion pressures during cardiac arrest and CPR? While the answer to this question is unknown, it supports the concept that endogenous metabolites may suppress or inhibit the effect of catecholamines during profound ischemia.

One such metabolite that has been proposed is adenosine. It is known that adenosine can inhibit the vasopressor effect of catecholamines [53,54]. The effects of adenosine can be reversed by giving specific adenosine antagonists. A recent report examined the

166 C. Brown et al. 1 Resuscitation 33 (19%) 163-177

non-specific adenosine antagonist aminophylline during refractory bradyasystolic cardiac arrest. This case series suggests potential beneficial effects of aminophylline [55].

Route of drug administration. Intraarterial epinephrine [56-601 produces excellent hemodynamic responses during CPR. It is much less effective when given by the peripheral i.v. route [23]. This raises the question of whether the catecholamines are metabo- lized by catechol-o-methyl transferase as they circu- late through the lungs following peripheral i.v. administration.

Finally, the area of post-resuscitation pharmacology has not been explored adequately. Specifically, how should we treat the patient who is resuscitated for prolonged cardiac arrest and has profound hypotension? Few studies have addressed this issue.

2.2. Bar-Joseph

The American Heart Association [24,61] recom- mends administering epinephrine every 3-5 min. What is the scientific basis for this recommendation? Is it based on the fact that the half-life of epinephrine in a normal circulation is only l-2 min? In our dog model of VF 10 min and external CPR, we used 0.1 mg/kg epinephrine repeated every 5 min and found no substantial increase in blood pressure with additional doses, after a marked response to the initial epinephrine dose [62]. I would like to ask whether the recommendation to repeat epinephrine every 3-5 min during CPR is based on any hard data. I believe that more research is needed to determine the ideal interval between epinephrine doses during CPR, especially when higher doses are used.

2.3. Miller

We have data on catecholamine support during the post-resuscitation period from a study of magnesium sulfate given i.v. in patients with refractory cardiac arrest [63]. Some patients regained ROSC when they received MgSO,, but after ROSC they rapidly became hypotensive (systolic arterial pressure 45 mmHg) despite dopamine administration. When dopamine was replaced with norepinephrine, the resuscitation rate increased by 16%. Animal studies [64] have shown that the effect of magnesium to decrease aortic diastolic, aortic systolic, and coronary perfusion pressures during CPR lasts about 20 min. Simi- lar effects were observed in our clinical trials. Therefore, in future studies magnesium should be combined with a potent vasopressor, such as norepinephrine.

3. Anti-arrhythmic agents

3.1. Brown

Another class of compounds commonly used in cardiac arrest and resuscitation are anti-arrhythmic agents, including lidocaine and bretylium (Appendix A, 1A). One issue of discussion is the rationale be- hind the use of these drugs during VF cardiac arrest. One explanation that has been offered is that the drugs given during VF should make defibrillation easier and avoid refibrillation. In part, to understand this concept, an understanding of how electrical countershock may terminate VF is needed. While the definitive mechanism on how electrical countershock reverses VF has not been elucidated, it is interesting to hypothesize that electrical countershock, in part, converts VF by depolarizing the myocardial cells, thereby ‘opening up’ sodium channels 1651. Theoreti- cally, following electrical countershock, intracellular sodium concentration will increase, thus allowing spontaneous myocardial depolarization to occur. What we hope to achieve clinically through electrical countershock is complete myocardial depolarization followed by recovery of a single dominant pacemaker, thus restoring a normal heart rhythm. In this setting, what effect do agents like lidocaine and bretylium have on this process? Although lidocaine has many electrophysiological properties, one of its most promi- nent effects is that it is a sodium-channel blocker, which should make it more difficult for sodium to enter the myocardial cell during electrical countershock. On the other hand, bretylium, which increases the action potential duration, prevents potassium efflux from the myocardial cell. By preventing potassium from leaving the cell, the myocardium should require less energy for defibrillation.

The majority of animal studies to date have shown that lidocaine increases the defibrillation threshold and, as lidocaine concentrations increase, it becomes increasingly more difficult to successfully defibrillate [66-681. Although it is not known exactly how cur- rent i.v. dosing relates to myocardial tissue levels of lidocaine in this setting, it is possible that the administration of lidocaine during cardiac arrest may produce toxic levels [69]. It should also be noted that this explanation for the effect of lidocaine on the defibrillation threshold is not accepted universally. The interaction of anesthetic agents with the anti- arrhythmics has been suggested as an alternative explanation for the changes seen in defibrillation threshold [70]. Given these limitations, it is unclear why these anti-arrhythmics are used during CPR. In the only significant pre-clinical study, Redding [3], using a canine model of VF cardiac arrest and resuscitation, found no difference in outcome after

epinephrine alone versus epinephrine plus lidocaine. On the other hand, although bretylium seems to lower the energy requirements for defibrillation [71-731, an interesting factor that has been overlooked with bretylium in animal models of cardiac arrest is the high incidence of electromechanical dissociation and hypotension following its use [74]. The Brain Resuscitation Clinical Trial group has also shown that hypotension after ROSC clearly correlates with poor neurological outcome [75]. Thus, the hypotensive effects of bretylium may overshadow its potential beneficial effect on the defibrillation threshold.

Although animal data suggest that lidocaine may make it more difficult to defibrillate, bretylium, which lowers the defibrillation threshold, may lead to post-resuscitation hypotension. Limited clinical studies comparing lidocaine and bretylium in patients show no difference in outcome between these two agents 176,771. In addition, no credible prospective trials have been conducted to date comparing these anti-arrhythmic agents to placebo. There is no proof of efficacy of these drugs given during cardiac arrest and CPR. Clearly. future studies are needed to delineate the role of these agents before and after conversion of VF.

3.2. Puradis

In light of the animal data, could you justify a prospective human study on these anti-arrhythmics? Could you go to a committee and say this drug should be given in a systematic manner knowing that it raises the electric energy required for defibrillation?

Weaver et al. [78] examined the effects of epinephrine, lidocaine and bicarbonate in VF cardiac arrest. The results of this clinical study suggest an increased rate of ROSC with sodium bicarbonate alone.

3.4. Bur-Joseph

What is the inlluence of NaHCO, on sodium channels and defibrillation threshold? Paradis says that some people feel that it is beneficial. Are resuscitation rates decreasing now that less NaHCO, is being administered?

Is there experience with amiodarone as a potential anti-arrhythmic drug during cardiac arrest?

Amiodarone is a potassium-channel blocker like bretylium and, therefore, lowers the defibrillation threshold. There are only case reports of its use during CPR [79]. Patients who received amiodarone after

ROSC, when they rearrested, had apparently good results. Amiodarone also has potential peripheral va- sodilating effects that may counteract the vasoconstric- tive effect of epinephrine. Clearly, further study with amiodarone in refractory and recurrent VF is needed.

3.6. Gisvold

In our discussions, we should differentiate more clearly between the use of lidocaine during arrest and CPR versus its use after ROSC. It has been observed clinically that hypertrophic myocardium, which is difficult to defibrillate, is easier to convert to a supraventricular rhythm after administration of lidocaine. Experience has been similar during open heart surgery. Procaine may also be effective in this situation [80]. It would seem worthwhile also to test procaine in the post-arrest, post-ROSC setting.

3.7. Brown

Patients on cardiopulmonary bypass have continued coronary perfusion. These patients may more closely represent cardiac arrest patients following ROSC. If one gives judicious doses of norepinephrine or epinephrine after cardiac arrest to maintain arterial pressure, and NaHCO, and anti-arrhythmics to prevent rearrest, one is dealing with a situation quite different from the one we discussed before, namely cardiac arrest patients with no-flow or low-flow.

3.8. Wikhnd

We need more research on drug distribution during CPR.

4. VF signal analysis

4.1. Meneguzzi

I want to draw attention to a study from Milwaukee [81] concerning 1497 patients of witnessed arrest, pre- senting with VF. who first received the three routine countershocks recommended by the American Heart Association advanced cardiac life support (ACLS) algorithm [61]. After the first countershock, 12% had at least transient ROSC, while 34% achieved pulseless electric activity or asystole. After the second countershock, only an additional 4% achieved ROSC, while 16% more developed asystole. After the third countershock, the total ROSC rate had increased to 18% while 58% were in pulseless electric activity or asystole. One must question the rationale for routine administration of three shocks at first. Not all VF situations are the same.

168 C. Brown et al. / Resuscitation 33 (1996) 163-177

Because electric therapy is not innocuous, empiric shocking may not be as rational as shocking according to ECG power spectrum analysis [82-841. This area appears promising for research in the near future. The analogy of immediate countershock for all cases found in VF or pulseless VT is like trying to jumpstart a car that has no gasoline.

Our thinking is to first prime the myocardium, brain and other vital organs for countershock and reperfusion, using combination pharmacotherapy [85-871. We are exploring, in a pig model, the use of five drugs (epinephrine 0.2 mg/kg, aminosteroid U74389G 3 mg/ kg, lidocaine 1 mg/kg, bretylium 5 mg/kg, and propra- nolo1 1 mg/kg) given together i.v. at the start of CPR steps ABC, while delaying countershock by 2 min until these drugs are on board. We hypothesized that combination pharmacotherapy and delayed countershock would produce higher rates of ROSC and better l-h survival compared to standard CPR-ACLS. After elec- trically induced VF of 8 min no-flow (simulating a clinical scenario of 1 min for collapse recognition, 1 min for dispatch, and 6 min for the mobile ICU to arrive), we gave CPR-basic life support (BLS) for 1 min. Then, group 1 received delayed countershocks 2 min after the entire drug combination; group 2 received only high- dose epinephrine; group 3 received the two anti-arrhythmics only; group 4 received propranolol only; group 5 received the aminosteroid only; and group 6 received delayed countershocks without any drugs. After the first countershock (in all at 11 min of VF), ROSC was achieved in 8/8 pigs in group 1, 7/8 pigs in group 2, 318 pigs in group 3, 318 pigs in group 4, 5/8 pigs in group 5 and 4/X pigs in group 6. l-h survival was achieved by 8/S in group 1, 518 in group 2, 218 in group 3, 218 in group 4, 318 in group 5 and 218 in group 6. Standard ACLS achieved ROSC in 3/8 and l-h survival in only l/S. We conclude that a drug first approach may be superior following prolonged cardiac arrest or VF. High-dose epinephrine and delayed countershock was found to have certain benefit in dogs [88]. In our study, a combination of drugs and delay in countershock produced superior ROSC rates and l-h survival.

4:2. Editor (Safar)

Certain dog models since 1960 have routinely in- cluded reperfusion with brief CPR plus epinephrine first, to achieve a vigorous VF ECG signal and an increase in artificial diastolic arterial pressure before applying countershocks; this seems to increase the chance for prompt ROSC [18,58].

4.3. Brown

A number of investigators have hypothesized that delaying countershock may be beneficial following a

prolonged cardiopulmonary arrest [89-911. In this clinical setting, reversing myocardial ischemia prior to countershock enhances resuscitation rates [89-911 and may avoid countershock-induced myocardial injury PO1 .

Our research has focused on titrating therapy based on the duration of ischemia [83]. In these studies, we collected the ECG signal during VF cardiac arrest in swine. The ECG signal was analyzed using fast Fourier transform analysis following digitization of the analog VF ECG signal [83]. The resulting power spectrum was used to calculate single-valued parameters of VF amplitude and frequency. These preliminary studies demonstrated that certain frequency parameters that can be derived from the power spectrum follow a repeatable and predictable time course during VF cardiac arrest. One such parameter, median frequency, can be used to estimate the duration of VF [83]. We believed that titrating therapy based on the duration of ischemia might be possible.

From this initial study, we extended the technique as a non-invasive tool to help guide therapy during CPR. A non-invasive monitor was developed for use in our laboratory, which tracked median frequency in real time during experimental CPR studies. Our initial experience with this monitor suggested that not only did median frequency follow a repeatable pattern following the onset of VF, but that it responded in a characteristic fashion to therapeutic interventions. When blood flow to the myocardium increased following a pharmacolog ical intervention, median frequency increased as well [92]. In this initial study, there was a reasonable correlation between myocardial blood flow and median frequency [92]. We then examined the relationship between median frequency and the ability to successfully countershock VF into a perfusing rhythm. We found that a median frequency 2 9.14 Hz in swine had a sensitivity of 100% in predicting successful countershock with ROSC, and a median frequency below this value had a specificity of 92% in predicting unsuccessful countershocks. This form of non-invasive real-time ECG analysis during VF may provide a therapeutic modality for titrating therapy. Recent clinical studies suggest that this methodology may be applicable in the clinical setting of VF cardiac arrest [93].

4.4. von Planta

A high VF amplitude is known to predict successful defibrillation [94]. VF amplitude may be related to myocardial perfusion during CPR [95]. Methoxamine increases coronary perfusion pressure and survival after cardiac arrest in rats (Appendix A, 3A). Therefore, we proposed that methoxamine should increase VF amplitude during CPR. Surprisingly, in a rat model, CPR increased VF amplitude, but methoxamine had no ef-

C. Brown et al. / Resuscitation 33 (1996) 163 I77 169

feet, thus we were unable to use VF amplitude to monitor a response to therapy. These VF parameters should be examined vis-a-vis end-tidal CO,, which decreases after epinephrine administration during CPR as total flow decreases, while perfusion pressures through heart and brain increase [96].

3.5. Brown

When reviewing work on ECG signal analysis during cardiac arrest and resuscitation, it is important to dis- tinguish between the native or original ECG signal and those ECG signals that may be corrupted secondary to interference. One such source of interference is the ‘noise’ generated by external CPR. Clearly, this CPR noise is one of increased amplitude and usually of low frequency (which is dependent on CPR rate). In most clinical cases that we have reviewed, the amplitude of the noise generated from CPR is much greater than the amplitude normally seen during VF. Therefore, if one is to make the determination that changes in myocardial perfusion correlate with changes in VF amplitude, one must be assured that the ECG signal is free from this noise, because CPR interference can contribute to a large part of the amplitude of the VF signal. On the other hand, CPR interference tends to shift the power spectrum of the VF signal to the left (‘downward’ bias), because most VF appears to occur at a dominant frequency of approximately 3-7 Hz. Therefore, to ob- tain optimal signals, CPR should be terminated briefly just prior to acquisition of the ECG signal. We have found no predictive value of the VF amplitude measurement in our clinical studies of the VF waveform for determining the success or failure of countershock therapy t931.

While this technique holds promise for guiding therapy during cardiac arrest and resuscitation, the resuscitation community must come to some agreement on nomenclature and standardizing techniques, i.e. lead placement. in the acquisition and analysis of this data.

5. Buffer agents

5.1. Wiklund

Total blood flow generated by external CPR during cardiac arrest is approximately 5- 10% of normal [97]; organ blood flows generated are too low to guarantee the distribution of any drug to target organs. New and old methods should be re-examined to find the best method to promote blood flow during cardiac arrest (Appendix A, 4A). The old method of open-chest CPR generates at least 20% of normal blood flow [97]; its utility should be reconsidered.

When brain pH is monitored by rmclear magnetic resonance spectroscopy during cardiac arrest and external CPR, the decrease in pH can be to such low levels that it might cause coagulation within S-6 min. There is reason to believe that tissue pH is a crucial factor influencing recovery of brain and heart from cardiac arrest. When the heart stops beating in VF, there is rapid production of hydrogen ions, so that in myocardial venous blood sampks, the pH decreases from base line to 6.76 in about 10 min [98]. Tissue acidosis develops rapidly at the same time. During VF cardiac arrest and immediate external CPR, one sees signs of acidosis in peripheral blood by about 10 min [99]. Long before that there is tissue acidosis, at least in the heart and brain [ 1001.

Administration of NaHCO, during CPR increases arterial P,,, transiently. Because bicarbonate transport is limited a&oss cellular membranes, a transient worsening of acidemia is created. The opposite happens when we introduce Tris buffer (THAM), which binds hydrogen ions to the buffer and lowers CO,. In fact, CO, can be lowered so much that it can stop spontaneous breathing. In isolated rat myocardial cells, there is an immediate decrease in pH when sodium bicarbonate is introduced into the system. The decrease in pH is dependent on the dose of bicarbonate. Therefore, the dose of sodium bicarbonate should be as small as possible during CPR to avoid increasing acidosis transiently.

Other buffers like THAM and Carbicarb theoretically might be more beneficial during cardiac arrest since they do not induce this paradoxical (although transient) acidosis in the isolated cell system. MyOCdr-

dial contractility is reduced with use of bicarbonate [loll and improved by THAM [102]. A positive in- otropic effect of THAM is present even in the ischemic myocardium. Therefore, there are potentially beneficial effects of buffer therapy during cardiac arrest.

5.2. Bar-Joseph

I would like to critically review the animal models used in the experiments that have stirred up the bicarbonate controversy and to challenge its basic hypothesis. The hypothesis which was brought about by Dr Weil’s group states that during the very low-flow state of CPR, the limiting factor in CO, elimination is tissue perfusion rather than alveolar venriIation. When sodium bicarbonate is administered, CO, will be produced and, as it cannot be effectively eliminated, it accumulates in the tissues and penetrates the cells. This might aggravate intracehular ‘respiratory’ acidosis and therefore bicarbonate administration might worsen CPR outcome [ 103,104].

Let us review the experimental evidence of this hypothesis. The first issue is whether low tissue perfusion

170 C. Brown et al. 1 Resuscitation 33 (1996) 163-177

limits CO, elimination during CPR. The answer is probably yes, depending on the magnitude of perfusion reduction. In many animal models no epinephrine is used, the tissue perfusion pressures are extremely low, and as a result some increase in venous CO, is observed [101,103,105-1071. The veno-arterial PcO, gradient further increases due to arterial hypocarbia. Restoration of tissue perfusion is one of the mainstays of the control of acid-base balance during CPR, and failure to use epinephrine is an obvious deviation from AHA guidelines [6 11.

The second question is whether the administration of bicarbonate really increases venous CO, during CPR. The clinical reports are hard to interpret because they were not controlled [104,108]. We do not know when bicarbonate was given in the course of CPR. The amount of bicarbonate and timing of blood sampling were also not controlled. Results of animal studies depend heavily on the model used, including the duration of cardiac arrest, the timing and dosage of bicarbonate administration, and the timing of blood sampling. In a VF dog model using 0.1 mg/kg epinephrine during CPR, we have observed only a moderate increase in PVC0 after administration of I mmol/kg of sodium bicarbonate. PVC0 returned to pre-bicarbonate levels 5 min later [109f. If blood is sampled only 2 min after bicarbonate administration [101,105,106], the transitory nature of this increase in P vcoz can be missed.

The third issue is the hypothesized worsening of intracellular acidosis following bicarbonate administration during CPR. This hypothesis is supposedly supported by a single (often cited) in vivo study by Berenyi [llO]. The experimental protocol in dogs used in this study bears very little relevance to the clinical scenario. VF lasted only 4 min, by the end of which arterial pH was 7.37 and HCO, was 22 mmol/l. Bicarbonate administration was started immediately upon initiation of CPR as a continuous infusion of 0.5 mmol/kg per min (i.e. 5 mmol/kg per 10 min). Ventilation was maintained at baseline level. After 20 min of CPR and administration of this massive bicarbonate infusion, arterial P,, was 64 mmHg, arterial pH was 7.8 1 and arterial HC& was 120 mmol/l! Cerebrospinal fluid- reflecting intracellular acid-base status-had a Pco2 of 81 mmHg and a pH of 7.24. I believe this model examined bicarbonate overdosing rather than its therapeutic use in CPR. No other animal study, to the best of my knowledge, has shown a decrease in intracellular pH related to bicarbonate administration [105,1~7,111,112].

The final and most significant issue is whether bicarbonate administration has an adverse effect on the outcome of CPR. No controlled clinical trials have been performed. In retrospective, uncontrolled pub- lished clinical studies, the amount of bicarbonate ad-

ministered usually reflects the duration of CPR so that bicarbonate administration becomes an epiphenomenon of prolonged arrest and the CPR time interval [3,113- 1171. Animal experimental results again depend largely on the model, the CPR protocol, and the outcome parameters. Some have shown a clearcut benefit on outcome [3,109,116-l 191, whereas others have failed to show any benefit from bicarbonate administration [101,106,107,120,121]. A single study [105] found a lower ROSC rate in animals receiving bicarbonate, compared with controls. In our study comparing bicarbonate, Carbicarb, THAM and NaCl in a VF lo-min dog model [109], the dogs that received bicarbonate had the highest rate of ROSC, and ROSC was achieved twice as fast, compared with controls.

In summary, I believe that the bicarbonate issue in CPR is not yet resolved. It is true that low tissue perfusion may limit CO, elimination and that PVC02 may transiently increase after bicarbonate administration. However, venous and extracellular pH always increase. There is no evidence that intracellular acidosis worsens after bicarbonate administration during CPR. Several studies demonstrate a beneficial effect on outcome and I do not think there are any solid experimental data to support the notion that sodium bicarbonate administration during CPR is detrimental. We should await the results of well-designed clinical trials before we decide on the role of bicarbonate therapy during cardiac arrest and CPR.

5.3. von Planta

A recent prospective clinical trial in Norway compared 245 tribonate-treated patients with 257 saline placebo controls [ 1221. After tribonate administration, 10% of the patients were discharged alive; and after saline administration, 14% were discharged alive. A logistic regression demonstrated that buffering failed to correlate with improved patient outcome.

5.4. Bircher

Despite evidence that control of pH is essential to cellular life [123], the treatment of ischemic acidosis [ 1241 during CPR remains highly controversial [125]. Experimentally, sodium bicarbonate (NaHCO,) is nei- ther helpful nor harmful after brief cardiac arrests [ 12 1,126]. Unwitnessed arrests, prolonged arrest intervals, and prolonged periods of CPR, however, occur frequently both in and out of the hospital [127], and tend to be associated with severe tissue acidosis and consequent acidemia [ 128- 1331. Previous human studies have demonstrated that the immediate rate of resuscitation in persistent VF can be improved by NaHCO, 1781, as can the rate of hospital discharge [129]. Restor- ing an adequate spontaneous circulation is the best

C. Brown et al. Resuscitation 31 (I 9961 163 I77 ITI

means of correcting tissue acidosis, but whether or not NaHCO, facilitates this goal remains unclear [128].

Previously demonstrated beneficial effects of NaHCO, during experimental CPR include reduced energy required for defibrillation [116], reduced incidence of recurrent VF [ 1161, more frequent ROSC 131, increased 24-h survival [3] and improved neurological outcome [3,134]. No study has ever demonstrated wors- ened outcome with small doses of NaHCO, ( I 1 mmol/kg) when used along with epinephrine. When large doses of NaHCO, ( > 2 mmol/kg) are used after brief arrest times [ 1201, or epinephrine is omitted [ 1351, NaHCO, may impair resuscitation efforts.

Our hypothesis in our studies was that after 5, 10 or 15 min of untreated VF and with standardized CPR, titrated replenishment of bicarbonate ion with NaHCO, during and after CPR improves outcome as measured by ROSC, survival to 24 h, and neurological deficit scores (NDS) at 24 h, compared with a control group receiving no NaHCO, [ 118,119,136].

In our studies, epinephrine was administered into the right atrium in 0.1 mg/kg boluses [3,126,130] every 5 mitt, until ROSC or until 30 min had elapsed. In the NaHCO, groups, 1 mmol/kg (1 ml/kg) of 8.4% NaHCO, solution was given immediately after the first dose of epinephrine. NaHCO, proved a useful adjunct to defibrillation, CPR, and epinephrine in the treatment of VF after a prolonged arrest interval. This series of studies was designed to test the hypothesis that NaHCO, increases in efficacy with increasing arrest interval, and to define the therapeutic window [136] for NaHCO, with respect to arrest interval. Overall, ROSC was possible in 35/36 animals receiving NaHCO, compared with 24/36 in the control groups (P = 0.0013) [118,119]. With respect to the influence of arrest interval, ROSC was possible in 12/12 dogs after 5 min VF, 35140 dogs after 10 min VF, and in 12/20 dogs after 15 min VF arrest interval (P = 0.0125). Logistic regression on ROSC revealed significant effects of both NaHCO, (r = 0.3114, P = 0.0034) and arrest interval (Y = 0.3169, P = 0.0030) and a significant interaction (r = 0.4420, P = 0.0001). Logistic regression on 24-h survival also revealed significant effects of both NaHCO, (v = 0.3201. P = 0.0009) and arrest interval (u = 0.3315, P = 0.0006), and a significant interaction (r = 0.4100. P < 0.0005).

In the absence of epinephrine, hypertonic buffers limit resuscitability by reducing CoPP [135]. In our studies, NaHCO, improved CoPP by enhancing the pressor effect of epinephrine [3,116,128]. Consequently, both the proportion of dogs resuscitated as well as the speed with which this was accomplished were increased. In the ischemic acidosis of arrest and CPR, pH correc- tion alone would be expected to improve coupling of z,-adrenergic receptors [137,138].

Our data suggest that alveolar hypercarbia was resolved within minutes of NaHCO, administration, both during CPR and after ROE, as occurs in humans [139]. The calculated HCO; values after 5 min ACLS suggest that exogenously administered bicarbonate ions (HCO,~ ) serve largely to replete HCO, concentration rather than being converted entirely to CO?. A large part of the hypercarbia observed after ROSC in the NaHCO, group (and all of that observed in the control group) represents washout of CO? accumulated in tissues during ischemia rather than that generated from exogenously administered HCO, .

In both myocardial and cerebral &hernia, the most important mechanism of intracellular pH regulation is the Na + -dependent Cl -~ -HCO; antiporter [123]. which couples influx of Na + and HCO; to an eftlux of H c and Cl -, i.e., NaHCO, is brought into the cell and HCl is extruded. This mechanism is twice as efficient as Na + --H + antiport, Na + --HCO,- symport and Na + - independent Cl-HCO; exchanger, as it neutralizes two protons for each sodium ion brought into the cell. As three of the four mechanisms of intracellular pH regulation are HCO,--dependent. reduction of the HCO,- concentration accentuates the role of the Na + H - antiporter and worsens sodium-dependent calcium loading [140]. Proton transport by both the Na + H + and Cl -HCO, antiport mechanisms may be increased by replenishment of extracellular HCO, [ 141.1421. Given the several HCO; -dependent mechanisms above, further study will be necessary to identify precisely which HCO, effects are specific to that ion and which are related to general buffering effects. Al- though intracellular acidosis is a putative mechanism of necrosis [143], it may also induce apoptosis [144,145].

In 1985, the AHA recommended use of NaHCO, only as a last resort during resuscitation, based on limited evidence of benefit. Three of the four studies demonstrating benefit [3,116,129,134], however, were not cited in the rationale. Reported and theoretical risks of NaHCO, therapy include shifts in the axy- hemoglobin dissociation curve, hypernatremia (with consequent hyperosmolarity), exacerbation of preexist- ing hypoventilation and mixed venous hypercarbia [ 1281; iatrogenic alkalemia; hemodynamic compromise and increased lactate production if hypoxia is deliber- ately not corrected; and inactivation of catecholamines. None of these were seen in our studies, as Yaff CO, was titrated to correct base deficit and adequate alveolar ventilation was maintained. The present AHA position [61] reflects the ongoing controversy, as NaHCO, is variably classified between probably efficacious and inappropriate, depending on the indication.

In our studies, neurologic impairment at 24 h after resuscitation was much less extensive in the NaHCO, group [118,119]. Decreases in intracellular pH in the brain during CPR are prevented by administration of


NaHCO, and accelerated by infusion of lactic acid, compared with CPR alone [125]. Persistent ischemic acidosis of the brain delays mitochondrial recovery 11461 and produces free radical-mediated damage [147]. Severe depletion of intracellular HCO, also leads to failure of metabolic recovery in neurons [147]. Our results suggest faster return of neurological function and better long-term outcome with NaHCO, therapy. Our survival and neurological outcome data are consistent with those of others [3,109,116,134]. The most likely explanation for the absence of a histologic difference between groups at 24 h is that the histopathologic lesions did not have adequate time to develop so as to allow discrimination by light microscopy [148,149].

Further study will be needed to confirm improvements in long-term neurological outcome. Our data strongly suggest that NaHCO, therapy as used in these studies is safe at any arrest (no-flow) interval and efficacious at arrest intervals of 10 min or greater. Clinical trials of NaHGO, therapy in cardiac arrest are both needed and justified to clarify the indications for this agent in human resuscitation.

6. Route of drug administration

6. I. Kramer

Being cardiovascular physiologists, primarily work- ing on fluid resuscitation for hemorrhagic shock, our group studied intraosseous fluid infusion for treatment of hypovolemia [150]. Intraosseous vascular access is now recommended for emergency fluid and drug delivery in pediatric patients [151]. The intraosseous route should also be considered for vascular access in adults when standard access methods fail (Appendix A, 2A). Epinephrine and other drugs have been delivered successfully to adults by this route during CPR [152]. Because rapid treatment is critical to success in CPR and achieving vascular access can be difficult during cardiac arrest, the intraosseous route might be a more rapid means to deliver drugs into the circulation during CPR. There are commercially available intraosseous needles that can be used in adults for reaching the bone marrow in the sternum or tibia. However, the density and thickness of the adult tibia makes placement difficult and, in the sternum, there are concerns of hitting a great vessel or heart if the entire bone is pierced.

A better approach for intraosseous therapy could be an autoinjector to rapidly puncture tibia1 bone and automatically deliver drug into the marrow. Fig. 1 shows the positioning of a prototype intraosseous autoinjector, designed to deliver 2 ml of drugs into the tibia1 bone marrow. Tests in animals and cadavers show that it takes about 5-10 s to place the injector in

position on the tibia and about 2 s for drug delivery. The power of a compressed spring generates momen- tum for rapid bone puncture and placement of a 16- gauge needle in less than 0.1 s and drug infusion of 2 ml in 2 s. The needle is retracted automatically into the device after drug delivery.

We have tested a prototype intraosseous autoinjector and compared it with peripheral i.v. drug therapy during CPR in swine [153]. The intraosseous autoinjector delivered a 2 mg/2 ml epinephrine dose into the tibia and was compared with a standard 1 mg/ml i.v. dose administered via a leg vein. Epinephrine doses were tagged with tracer radioisotopes. Carotid arterial sampling and gamma camera imaging showed equivalent circulation times and arterial concentrations (Fig. 1). The larger intraosseous dose required during CPR is consistent with a depot of approximately 1 ml in the marrow as seen with the gamma camera and is most likely due to poor marrow perfusion in this CPR model.

In several studies, we and others have found intraosseous and i.v. drug delivery to be equivalent when the circulation is intact or an injection is followed by a flush [154,155]. The often used endotracheal route can only be used for some drugs and is problematic in that only a small and unpredictable portion of the dose is delivered to the circulation [156,157]. Direct compari- sons of the endotracheal route and the i.v. route should be performed with all the drugs used for ACLS. Clearly, there are many questions to keep researchers

B I 0.15, -O- IO (2 mL) Technetium

I :;;;;

tp” . 0 80 160240320400480560640~20~00

Number of Chest Compressions

Fig. 1. Top: A prototype intraosseous autoinjector designed to rapidly deliver 2 ml of drug into the vasculature via the bone marrow. Bottom: Representative experiment of CPR in swine. Intraosseous (IO) autoinjector delivery resulted in equivalent appearance times and arterial concentrations of tracers as did i.v. administration [153].

C. Brown et al. : Resuscitation 33 (1996) It‘d 177 173

busy in optimizing drug resuscitation protocols for CPR. The 1 ml deposited in the bone marrow during arrest would likely wash out after ROSC and have an impact similar to the multiple i.v. doses of epinephrine that are often infused during cardiac arrest.

The autoinjector is simple to use and can be applied by first responders, such as police and firemen. First responders are not trained to know when to deliver drugs. They currently only place automated external defibrillators on cardiac arrest victims for automatic diagnosis of VF and appropriate countershock treatment. However, automated external defibrillators could also be programmed to indicate when to administer drug therapy. A first responder equipped with such a computer-programmed defibrillator and pre-loaded intraosseous autoinjectors could administer both pharmacotherapy and countershocks properly. Intraosseous autoinjectors could become even more useful if initial treatment with a pharmacological cocktail is shown to be clinically efficacious during cardiac arrest [91]. Waveform EGG analyses could also be into an automated external defibrillator when drugs should be administered for come [92,93,158].

programmed to determine optimal out-

6.2. Editor (Sufiw)

The previous discussions on VF signal analysis [S 1~ 961 and the possibility of semi-automatic drug administration are strengthened by the results of a recent report from the University of Ulm [159]. This study in pigs shows that the median frequency of VF correlates with myocardial blood flow and the likelihood of successful defibrillation during standard external CPR with vasopressor treatment.

7. Conclusion

Based on these discussions and presentations, there are clearly several high-priority areas of research. These include the following: (1) It is necessary to delineate the role of adrenergic agonists (vasopressors) in CPR. Ad- ditional pre-clinical studies and clinical trials are needed to determine the efficacy and role of these agents in resuscitation. (2) If enhancement of perfusion pressure through regulation of vasomotor tone is required, can we isolate these effects and minimize toxicity through the development and use of newer vasoactive agents? (3) Optimum route, method and dosing of vasopressor agents should then follow. (4) The role of anti-arrhythmic agents needs to be re-evaluated. Pre-clinical studies determining their effects on defibrillation threshold, and their comparative efficacy in terminating VF and pre-

venting re-fibrillation need to be conducted. (5) The effects of tissue acidosis and buffer agents on resuscitability of heart and brain need clarification. (6) Non- invasive methods need to be developed to track the efficacy of therapeutic interventions in real-time. This will allow transition of therapeutic agents from pre-clinical studies to clinical investigation, as well as provide a guide to alternative therapeutic approaches during resuscitation, i.e. titration of therapy.

Acknowledgements

This publication was supported by the US Army (USAMRMC, grant # DAMD17-94-J-40 13), the Laerdal Foundation for Acute Medicine, and Baxter Laboratories. Francie Siegfried helped with editing. Fran Mistrick helped with preparation of the manuscript.

Appendix A

Abstracts of the International Resuscitation Re- search Conference in Pittsburgh, May 1994, available from P. Safar, SCRR, University of Pittsburgh, 3434 Fifth Avenue, Pittsburgh, PA 15260, USA.

1A. Brown CG. Pharmacology of cardiac arrest --. vasopressors and antiarrhythmics. Ohio State Univer- sity, Columbus, OH, USA.

2A. Kramer GC, Thomas B, Wilson J. Jenkinson J. An intraosseous auto-injector for vascular drug delivery. University of Texas Medical Branch, Galveston, TX and GVO. Palo Alto, CA, USA.

3A. Pan T, Zhou S, von Planta M, Studer W. Scheidegger D. Methoxamine effects on ventricular fibrillation (VF) amplitude during rodent resuscitation. Department of Anesthesia, University Hospital, Easel. Switzerland.

4A. Wiklund L. Rubertsson S, Gedeborg R. Improv- ing end-results after CPR: ACLS pharmaceuticals revis- ited. Back to basics? Department of Anesthesiology and Intensive Care, Uppsala University Hospital, Uppsala, Sweden.

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future directions for resuscitation research. iv. innovative advanced life support pharmacology

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