37 The Futureof Cardiopulmonary Resuscitation

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From: Contemporary Cardiology: Cardiopulmonary Resuscitation Edited by: J. P. Ornato and M. A. Peberdy © Humana Press Inc., Totowa, NJ

37 ^{The Future}

of Cardiopulmonary Resuscitation

Combination Therapy

Joseph P. Ornato, ^MD , ^FACP , ^FACC , ^FACEP

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INTRODUCTION

The physiology of cardiopulmonary resuscitation (CPR) is complex and changes over time. Becker and Weisfeldt defined three time-sensitive phases of resuscitation: electri- cal, circulatory, and metabolic (1). Each of these phases is characterized by multiple physiological abnormalities to become more profound and difficult to reverse over time.

Beyond the first phase, which can often be corrected by a single intervention (e.g., prompt defibrillation for ventricular fibrillation [VF] or pulseless ventricular tachycardia, and increasing host of challenges develop (e.g., maintaining coronary and cerebral blood flow and pressure, counteracting vasodilatation, cerebral protection, minimize and postresus- citation left ventricular dysfunction).

Attempts to improve resuscitation outcome have traditionally focused on improving one intervention (or variable) at a time. Experimental models and clinical trials have, thus, attempted to keep all variables constant (either by design or randomization) except for one intervention that could be divided into a control and experimental group. Although such a design is optimal from a scientific standpoint, it handicaps the process of finding dramatic enhancements in clinical resuscitation practice because solitary interventions can only address one of the many physiological derangements that are present at a time.

The situation is analogous to the search for cancer cures. Major breakthroughs, such as

have been seen in the treatment of childhood leukemia or certain forms of lymphoma,

have occurred because multiple intervention strategies were tested against conventional

therapy. Combination therapeutic techniques have been employed with equal success in

the management of patients with acquired immunodeficiency syndrome (AIDS).

The purpose of this chapter is to review a few examples of the combination resusci- tation strategies (both successful and unsuccessful) that have begun to appear in both the experimental and clinical trial literature.

DRUG COMBINATIONS Catecholamines and Buffer Therapy

There continues to be controversy regarding whether the use of buffer therapy during CPR enhances the actions of catecholamines (2). Recent evidence suggests that routine addition of buffer therapy to catecholamines early in resuscitation is not only unneces- sary, but may actually be harmful (3,4). Sun et al. induced VF in Sprague-Dawley rats.

Precordial compression and mechanical ventilation were initiated after 8 minutes of untreated VF. Animals were then randomized to receive either sodium bicarbonate, tromethamine, or saline placebo. Two minutes later, epinephrine was injected intrave- nously. In another subgroup, epinephrine was given first followed (2 minutes later) by either buffer or placebo. Electrical defibrillation was attempted after 8 minutes of precor- dial compression. Both bicarbonate and tromethamine significantly decreased coronary perfusion pressure (CPP) can reduce the magnitude of the vasopressor effect of the adrenergic agents. When the vasopressor preceded the buffer, the decline in CPP after buffer administration was prevented. These results may help to explain why a random- ized clinical trial involving 502 randomized, adult cardiac arrest (CA) victims had no better outcome when they received buffer therapy as opposed to placebo (4).

In contrast, one recent experimental study in a canine VF model suggests that, in a prolonged resuscitation, bicarbonate therapy and a period of perfusion prior to attempted defibrillation may increase survival (5). The experiment was designed to determine whether administration of sodium bicarbonate and/or epinephrine in combination with a brief period of CPR prior to defibrillation would improve the outcome of prolonged CA in dogs. After 10 minutes of VF, animals received either immediate defibrillation (fol- lowed by treatment with bicarbonate or control) or immediate treatment with bicarbonate or saline (followed by defibrillation). Treatment with bicarbonate was associated with increased rates of restoration of spontaneous circulation. This was achieved with fewer shocks and in a shorter time. CPP was significantly higher in bicarbonate-treated animals.

The best outcome in this study was achieved when defibrillation was delayed for approx 2 minutes, during which time sodium bicarbonate and epinephrine were administered with ongoing CPR.

Catecholamines and `-Blockers

Redding and Pearson were the first to show the importance of maintaining peripheral vascular resistance to maximize coronary and cerebral blood flow during resuscitation

than 30 years, primarily because of its _-adrenergic action, which increases CPP and favors an initial return of spontaneous circulation (ROSC). However, its `-adrenergic action may have detrimental effects on postresuscitation myocardial function by increas- ing myocardial oxygen consumption during and, immediately following, ROSC.

In experimental rodent model optimized to study postresuscitation cardiovascular

events, epinephrine increased the severity of postresuscitation myocardial dysfunction

and decreased duration of survival significantly (8). The researchers concluded that more

selective _-adrenergic agents or use of nonselective adrenergic agents (e.g., epinephrine)

with `-1 adrenergic blockade deserve further investigation. Even use of a relatively pure _-adrenergic vasoconstrictor such as phenylephrine in combination with a `-blocker (propanolol) appears to improve to balance between myocardial oxygen supply and demand during ongoing resuscitation compared to that which is seen when epinephrine is used (9).

Vasopressin and Epinephrine

Another approach to creating systemic vasoconstriction without `-adrenergic stimu- lation during resuscitation has been the use of arginine vasopressin (10–12). It was relatively easy to show that administration of vasopressin in a VF pig model leads to a significantly higher CPP and myocardial blood flow than epinephrine during closed- chest CPR (10). However, in a large, well-controlled, Canadian randomized clinical trial, survival-to-hospital discharge did not differ for patients receiving either epinephrine or vasopressin during resuscitation in the emergency department, intensive care unit, or hospital in-patient units (13).

This finding has been explained by some to possibly represent the lack of difference between the two vasoconstrictors early in resuscitation. This leaves open the possibility that vasopressin might be superior to epinephrine later in resuscitation when adrenergic agents typically become less effective as a result of down-regulation of receptors. Further study will be needed to determine whether vasopressin has advantages over epinephrine late in resuscitation.

In the meantime, a number of recent studies have focused on whether the combination of vasopressin and epinephrine offers advantages over the use of either agent alone (14–

18). The combination appears capable of maximizing both coronary and CPP. An even

more novel “cocktail” involves the combination of vasopressin, epinephrine, and nitro- glycerin during resuscitation. Nitroglycerin is added to offset the coronary vasoconstric- tion effects of vasopressin. This “cocktail” has been shown to improve survival in a rodent asphyxial CA model (19) and improved vital organ perfusion in a porcine model (20).

DEVICE COMBINATIONS

A variety of new closed-chest compression techniques and devices have been devel- oped and studied experimentally and clinically in the last two decades (21–44). Each of these methods are designed to exploit either or both of the cardiac or thoracic pump mechanisms of blood flow. Some of the new techniques and devices are being studied with each other in various combinations, attempting to create a syngeristic physiological effect.

Impedance Threshold Valve

One of the most promising techniques is the use of an impedance threshold valve

(ITV) to improve venous return in combination with other resuscitation techniques. For

example, Samniah et al. (45) tested the feasibility of transcutaneous phrenic nerve stimu-

lation used in conjunction with an inspiratory ITV on hemodynamic variables during

hemorrhagic shock. Anesthetized pigs were subjected to profound hemorrhagic shock

by withdrawal of 55% of estimated blood volume over 20 minutes. After a 10-minute

recovery period, the diaphragm was stimulated with a transcutaneous phrenic nerve

stimulator at 10 times per minute as the airway was occluded intermittently with the ITV

between positive pressure ventilations. Hemodynamic variables were monitored for 30

minutes. Phrenic nerve stimulation in combination with the ITV (p < 0.001) improved right and left ventricular diameter significantly compared with hypovolemic shock val- ues by 34 ± 2.5% and 20 ± 2.5%, respectively. Phrenic nerve stimulation together with the ITV also increased transaortic, transpulmonary, and transmitral valve blood flow by 48

group). Mean ± standard error of the mean (SEM) coronary perfusion and systolic aortic blood pressures were also significantly (p < 0.001) higher compared with values before stimulation (30 ± 2 vs 20 ± 2 mmHg, and 37 ± 2 vs 32 ± 3 mmHg, respectively). This feasibility study suggests that phrenic nerve stimulation with an ITV can improve car- diac preload and, subsequently, key hemodynamic variables in a porcine model of severe hemorrhagic shock.

The ITV is also synergistic with closed-chest compression (both standard CPR and several of the newer enhanced techniques. Voelckel et al. (44) evaluated the combination of active compression–decompression (ACD) CPR and ITV in a young porcine model of CA. After 10 minutes of VF, and 8 minutes of standard CPR, ACD + ITV CPR was performed in seven 4- to 6-week old pigs (8–12 kg); defibrillation was attempted 8 minutes later. Within 2 minutes after initiation of ACD + ITV CPR, mean (± SEM) CPP increased from 18 ± 2 to 24 ± 3 mmHg (p = 0.018). During standard vs ACD + ITV CPR, mean left ventricular myocardial and total cerebral blood flow was 59 ± 21 vs 126 ± 32 mL per minute per 100 g, and 36 ± 7 vs 60 ± 15 mL per minute per 100 g, respectively (p = 0.028). Six of seven animals were defibrillated successfully and survived longer than 15 minutes. Thus, the combination of ACD + ITV CPR increased both CPP and vital organ blood flow significantly after prolonged standard CPR in a young porcine VF model.

HYPOTHERMIA COMBINED

WITH OTHER RESUSCITATION TECHNIQUES

Dr. Peter Safar was the first to recognize the importance of cardiopulmonary cerebral resuscitation in effecting meaningful survival from CA. Although promising when given pre-arrest in animal models, a variety of single pharmaceutical agents have been admin- istered postresuscitation in humans without benefit (46). The most promising techniques appear to be the use of mild to moderate hypothermia begun early (within 3–4 hours) post- ROSC. Two recent multicenter, randomized clinical trials showed a clear survival advan- tage for comatose adult CA survivors whose core body temperature was maintained at mild hypothermic levels for 24 to 48 hours postresuscitation.

The ultimate combination will likely involve adding novel resuscitation devices to

new pharmacological interventions. One such example is a recent report from Raedler et

al. (47) who documented hemodynamic and vital organ flow benefit from the use of

ACD-CPR, ITV, vasopressin, and hypothermia during resuscitation in a porcine CA

model. Pigs were surface-cooled until their body core temperature was 26°C. After 10

minutes of untreated VF, 14 animals were assigned randomly to either ACD CPR with

the ITV (N = 7) or to standard (STD) CPR (N = 7). After 8 minutes of CPR, all animals

received 0.4 U/kg vasopressin intravenously, and CPR was maintained for an additional

10 minutes in each group; defibrillation was attempted after 28 minutes of CA, including

18 minutes of CPR. Before the administration of vasopressin, mean ± SEM common

carotid blood flow was significantly higher in the ACD + ITV group compared with STD

CPR (67 ± 13 vs 26 ± 5 mL per minute, respectively; p < 0.025). After vasopressin was

given at minute 8 during CPR, mean ± SEM CPP was significantly higher in the ACD + ITV group, but did not increase in the STD group (29 ± 3 vs 15 ± 2 mmHg, and 25 ± 1 vs 14 ± 1 mmHg at minutes 12 and 18, respectively; p < 0.001); mean ± SEM common carotid blood flow remained higher at respective time points (33 ± 8 vs 10 ± 3 mL per minute, and 31 ± 7 vs 7 ± 3 mL per minute, respectively; p < 0.01). Without active rewarming, spontaneous circulation was restored and maintained for 1 hour in three of seven animals in the ACD + ITV group vs none of seven animals in the STD CPR group (NS). During hypothermic CA, ACD-CPR with the ITV improved common carotid blood flow compared with STD CPR alone. After the administration of vasopressin, CPP was significantly higher during ACD + ITV CPR, but not during STD CPR. Thus, ACD-CPR with the ITV can improve carotid blood flow (and CPP with vasopressin) compared with STD CPR.

CONCLUSIONS

Resuscitation science is continuing to progress as new discoveries unlock the secrets of the human body during catastrophic medical and traumatic events. Improvement in the rate of neurologically intact survival following resuscitation will likely come from evo- lutionary steps rather than a single, major breakthrough. At present, the most promising hope seems to be a multifaceted approach targeting the many physiological derange- ments that are present during CA.

REFERENCES

1. Weisfeldt ML, Becker LB. Resuscitation after cardiac arrest: a 3-phase time-sensitive model. JAMA 2002; 288:3035–3038.

2. Vukmir RB, Bircher N, Safar P. Sodium bicarbonate in cardiac arrest: A reappraisal. Am J Emerg Med 1996; 14:192–206.

3. Sun S, Weil MH, Tang W, Povoas HP, Mason E. Combined effects of buffer and adrenergic agents on postresuscitation myocardial function. J Pharmacol Exp Ther 1999; 291:773–777.

4. Dybvik T, Strand T, Steen PA. Buffer therapy during out-of-hospital cardiopulmonary resuscitation Resuscitation 1995; 29:89–95.

5. Leong EC, Bendall JC, Boyd AC, Einstein R. Sodium bicarbonate improves the chance of resuscitation after 10 minutes of cardiac arrest in dogs. Resuscitation 2001; 51:309–315.

6. Pearson JW, Redding JS. Peripheral vascular tone in cardiac resuscitation. Anesth Analg 1965; 44:

746–762.

7. Pearson JW, Redding JS. Influence of peripheral vascular tone on cardiac resuscitation. Anesth Analg 1967; 46:746–752.

8. Tang W, Weil MH, Sun S, Noc M, Yang L, Gazmuri RJ. Epinephrine increases the severity of postresuscitation myocardial dysfunction. Circulation 1995; 92:3089–3093.

9. Ditchey RV, Rubio-Perez A, Slinker BK. Beta-adrenergic blockade reduces myocardial injury during experimental cardiopulmonary resuscitation. J Am Coll Cardiol 1994; 24:804–812.

10. Lindner KH, Prengel AW, Pfenninger EG, et al. Vasopressin improves vital organ blood flow during closed-chest cardiopulmonary resuscitation in pigs. Circulation 1995; 91:215–221.

11. Lindner KH, Prengel AW, Brinkmann A, Strohmenger HU, Lindner IM, Lurie KG. Vasopressin admin- istration in refractory cardiac arrest. Ann Intern Med 1996; 124:1061–1064.

12. Lindner KH, Haak T, Keller A, Bothner U, Lurie KG. Release of endogenous vasopressors during and after cardiopulmonary resuscitation. Heart 1996; 75:145–150.

13. Stiell IG, Hebert PC, Wells GA, et al. Vasopressin versus epinephrine for inhospital cardiac arrest: a randomised controlled trial. Lancet 2001; 358:105–109.

14. Mulligan KA, McKnite SH, Lindner KH, Lindstrom PJ, Detloff B, Lurie KG. Synergistic effects of vasopressin plus epinephrine during cardiopulmonary resuscitation. Resuscitation 1997; 35:265–271.

15. Wenzel V, Linder KH, Augenstein S, Prengel AW, Strohmenger HU. Vasopressin combined with epinephrine decreases cerebral perfusion compared with vasopressin alone during cardiopulmonary resuscitation in pigs. Stroke 1998; 29:1462–1467; discussion 7,8.

16. Voelckel WG, Lindner KH, Wenzel V, et al. Effects of vasopressin and epinephrine on splanchnic blood flow and renal function during and after cardiopulmonary resuscitation in pigs. Crit Care Med 2000;

28:1083–1088.

17. Mayr VD, Wenzel V, Voelckel WG, et al. Developing a vasopressor combination in a pig model of adult asphyxial cardiac arrest. Circulation 2001; 104:1651–1656.

18. Voelckel WG, Lurie KG, McKnite S, et al. Effects of epinephrine and vasopressin in a piglet model of prolonged ventricular fibrillation and cardiopulmonary resuscitation. Crit Care Med 2002; 30:957–962.

19. Kono S, Suzuki A, Obata Y, Igarashi H, Bito H, Sato S. Vasopressin with delayed combination of nitroglycerin increases survival rate in asphyxia rat model. Resuscitation 2002; 54:297–301.

20. Lurie KG, Voelckel WG, Iskos DN, et al. Combination drug therapy with vasopressin, adrenaline (epinephrine) and nitroglycerin improves vital organ blood flow in a porcine model of ventricular fibrillation. Resuscitation 2002; 54:187–194.

21. Schultz DD, Olivas GS. The use of cough cardiopulmonary resuscitation in clinical practice. Heart Lung 1986; 15:273–282.

22. Krischer JP, Fine EG, Weisfeldt ML, Guerci AD, Nagel E, Chandra N. Comparison of prehospital conventional and simultaneous compression-ventilation cardiopulmonary resuscitation. Crit Care Med 1989; 17:1263–1269.

23. Barranco F, Lesmes A, Irles JA, et al. Cardiopulmonary resuscitation with simultaneous chest and abdominal compression: comparative study in humans. Resuscitation 1990; 20:67–77.

24. Gazmuri RJ, Weil MH, von Planta M, Gazmuri RR, Shah DM, Rackow EC. Cardiac resuscitation by extracorporeal circulation after failure of conventional CPR. J Lab Clin Med 1991; 118:65–73.

25. Gazmuri RJ, Weil MH, Terwilliger K, Shah DM, Duggal C, Tang W. Extracorporeal circulation as an alternative to open-chest cardiac compression for cardiac resuscitation. Chest 1992; 102:1846–1852.

26. Cohen TJ, Tucker KJ, Redberg RF, et al. Active compression-decompression resuscitation: a novel method of cardiopulmonary resuscitation. Am Heart J 1992; 124:1145–1150.

27. Cohen TJ, Tucker KJ, Lurie KG, et al. Active compression-decompression. A new method of cardiop- ulmonary resuscitation. JAMA 1992; 267:2916–2923.

28. Cohen TJ, Goldner BG, Maccaro PC, et al. A comparison of active compression-decompression cardiop- ulmonary resuscitation with standard cardiopulmonary resuscitation for cardiac arrests occurring in the hospital. N Engl J Med 1993; 329:1918–1921.

29. Tucker KJ, Idris A. Clinical and laboratory investigations of active compression- decompression car- diopulmonary resuscitation [editorial]. Resuscitation 1994; 28:1–7.

30. Wik L, Naess PA, Ilebekk A, Steen PA. Simultaneous active compression-decompression and abdomi- nal binding increase carotid blood flow additively during cardiopulmonary resuscitation (CPR) in pigs.

Resuscitation 1994; 28:55–64.

31. Wik L, Mauer D, Robertson C. The first European pre-hospital active compression-decompression (ACD) cardiopulmonary resuscitation workshop: A report and a review of ACD-CPR. Resuscitation 1995; 30:191–202.

32. Wik L, Naess PA, Ilebekk A, Nicolaysen G, Steen PA. Effects of various degrees of compression and active decompression on haemodynamics, end-tidal CO2, and ventilation during cardiopulmonary resuscitation of pigs. Resuscitation 1996; 31:45–57.

33. Wik L, Schneider T, Baubin M, et al. Active compression-decompression cardiopulmonary resuscita- tion— instructor and student manual for teaching and training. Part II: A student and instructor manual.

Resuscitation 1996; 32:206–212.

34. Hoekstra OS, Van Lambalgen AA, Groeneveld ABJ, Van den Bos GC, Thijs LG. Abdominal compres- sions increase vital organ perfusion during CPR in dogs: Relation with efficacy of thoracic compres- sions. Ann Emerg Med 1995; 25:375–385.

35. Lurie KG, Coffeen P, Shultz J, McKnite S, Detloff B, Mulligan K. Improving active compression- decompression cardiopulmonary resuscitation with an inspiratory impedance valve. Circulation 1995;

91:1629–1632.

36. Lurie KG. Active compression-decompression CPR: a progress report. Resuscitation 1994; 28:115–22.

37. Lurie KG, Shultz JJ, Callaham ML, et al. Evaluation of active compression-decompression CPR in victims of out-of- hospital cardiac arrest. JAMA 1994; 271:1405–1411.

38. Lurie K, Voelckel W, Plaisance P, et al. Use of an inspiratory impedance threshold valve during cardiop- ulmonary resuscitation: a progress report. Resuscitation 2000; 44:219–230.

39. Lurie KG, Mulligan KA, McKnite S, Detloff B, Lindstrom P, Lindner KH. Optimizing standard cardiop- ulmonary resuscitation with an inspiratory impedance threshold valve. Chest 1998; 113:1084–1090.

40. Lurie KG. Recent advances in mechanical methods of cardiopulmonary resuscitation. Acta Anaesthesiol Scand Suppl 1997; 111:49–52.

41. Plaisance P, Lurie KG, Vicaut E, et al. A comparison of standard cardiopulmonary resuscitation and active compression-decompression resuscitation for out-of-hospital cardiac arrest. French Active Compression-Decompression Cardiopulmonary Resuscitation Study Group. N Engl J Med 1999; 341:

569–575.

42. Plaisance P, Lurie KG, Payen D. Inspiratory impedance during active compression-decompression cardiopulmonary resuscitation: a randomized evaluation in patients in cardiac arrest. Circulation 2000;

101:989–994.

43. Shultz JJ, Lurie KG. Variations in cardiopulmonary resuscitation techniques: Past, present and future.

Can J Cardiol 1995; 11:873–880.

44. Voelckel WG, Lurie KG, Sweeney M, et al. Effects of active compression-decompression cardiopulmo- nary resuscitation with the inspiratory threshold valve in a young porcine model of cardiac arrest. Pediatr Res 2002; 51:523–527.

45. Samniah N, Voelckel WG, Zielinski TM, et al. Feasibility and effects of transcutaneous phrenic nerve stimulation combined with an inspiratory impedance threshold in a pig model of hemorrhagic shock. Crit Care Med 2003; 31:1197–1202.

46. Gisvold SE, Sterz F, Abramson NS, et al. Cerebral resuscitation from cardiac arrest: Treatment poten- tials. Crit Care Med 1996; 24(Suppl):S69–S80.

47. Raedler C, Voelckel WG, Wenzel V, et al. Vasopressor response in a porcine model of hypothermic cardiac arrest is improved with active compression-decompression cardiopulmonary resuscitation using the inspiratory impedance threshold valve. Anesth Analg 2002; 95:1496–1502, table of contents.