- Email: [email protected]
Optimizing the duration of CPR prior to defibrillation improves the outcome of CPR in a rat model of prolonged cardiac arrest
Resuscitation 82S (2011) S3–S7
Optimizing the duration of CPR prior to defibrillation improves the outcome of CPR in a rat model of prolonged cardiac arrest Shijie Sun a,b , Yinlun Weng a , Xiaobo Wu a , Katherine Tang a , Sen Ye a , Wei Chen a , Max Harry Weil a,b , Wanchun Tang a,b, * a b
Weil Institute of Critical Care Medicine, Rancho Mirage, CA, USA Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA
A R T I C L E
I N F O
Keywords: Cardiopulmonary resuscitation Defibrillation Electrocardiography Survival
A B S T R A C T Aims: This study was to investigate whether optimal duration of CPR prior to defibrillation could be guided by Amplitude Spectrum Analysis (AMSA) in the setting of prolonged VF on outcome of CPR. Methods: VF was induced in thirty Sprague-Dawley rats and untreated for 8 minutes. Animals were then randomized into 3 groups prior to CPR: The duration of CPR prior to defibrillation was guided by AMSA (CC+AMSA); guidelines-based with delayed defibrillation that simulated the AED algorithm (GL+AED); and guidelines-based with immediate shock (GL+shock ready). Results: Regardless of groups, the majority of the animals (85%) required over 5 min of CPR to achieve restoration of spontaneous circulation (ROSC). Significantly greater rate of ROSC after first defibrillation (70% vs 0%, p < 0.01), lesser CPR interruptions and the number of defibrillations were observed in the CC+AMSA group when compared to both guidelines-based groups (p < 0.001). This was associated with a significantly better post-resuscitation myocardial and neurological function and longer durations of survival. Conclusions: After prolonged VF, optimal duration of CPR prior to defibrillation guided by AMSA improves the outcome of CPR. © 2011 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Immediate defibrillation following a short duration of ventricular fibrillation (VF) significantly improves the outcome of cardiac arrest. 1,2 However, the probability of successful defibrillation diminishes rapidly over time. For each minute that passes between sudden cardiac arrest and defibrillation, survival rates decrease 7% to 10% if no CPR is provided. 3,4 Clinical studies further demonstrated that when the duration of untreated VF is prolonged for more than 5 min, defibrillation immediately prior to CPR compromises the outcome of CPR. 5,6 Current AHA Guidelines therefore recommend to perform CPR for 1 1/2 to 3 minutes prior to defibrillation when the duration of VF is longer than 4 min. However, there is insufficient evidence to determine the optimal duration of CPR. 7 Also in most cases, the duration of VF is rarely known, especially in the outof-hospital setting. Since there is currently no objective feedback mechanism to indicate when the heart is ready to be resuscitated and specifically, when spontaneous circulation would be restored with a defibrillation, it is not reliable to determine the priority of CPR based on the duration of VF even the VF is witnessed.
* Address for correspondence: Wanchun Tang, MD, Weil Institute of Critical Care Medicine, 35100 Bob Hope Drive, Rancho Mirage, CA 92270, USA. Tel.: +1 760-778-4911; fax: +1 760-778-3468. E-mail address: [email protected] (W. Tang). 0300-9572/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved.
Clinical studies also demonstrated that the current rate of ROSC after defibrillation is low, and around 40% of the unsuccessful shocks could be avoided. 8,9 With current standard CPR procedure, there are multiple interruptions for defibrillations of chest compression. The interruption interval is even longer if automatic external defibrillators (AEDs) are used which require pauses for rhythm analysis and shock delivery. Studies have demonstrated that interruptions of chest compression significantly decrease the quality and worsen the outcome of CPR. 10,11 Our previous study further demonstrated that the multiple unsuccessful defibrillations significantly increase the severity of postresuscitation myocardial dysfunction. 12 Both experimental and clinical studies have showed that both myocardial blood flow generated during CPR and the defibrillation readiness of the fibrillating heart could be monitored by the dynamic changes of the VF waveforms. Increased VF waveform indicates a positive effect of CPR with an increased success of resuscitation. 9,13 –17 The amplitude spectrum analysis (AMSA) is one of the techniques for VF waveform analysis developed by us. 18,19 The changes in AMSA during CPR were highly correlated with coronary perfusion pressure (CPP), which provides a realtime indicator of successful defibrillation with no interruption of CPR. 18 – 20 In the present study, we investigated whether optimal duration of CPR prior to defibrillation and specifically when the heart is
S4
S. Sun et al. / Resuscitation 82S (2011) S3–S7
ready to be defibrillated could be guided by AMSA in the setting of prolonged VF. We hypothesized that optimizing the duration of CPR prior to defibrillation could be guided by AMSA, which will reduce the interruptions in CPR and the number of futile defibrillations. This will, in turn, improve the outcome of CPR. 2. Methods This study was approved by the Institutional Animal Care and Use Committee of the Weil Institute of Critical Care Medicine. All animals received humane care in compliance with the Guide for the Care and Use of Laboratory Animals. 21,22 Our established rodent model of cardiac arrest and resuscitation was utilized. Healthy male Sprague-Dawley rats, aged 6 to 8 months, weighing between 450 to 550 g, were supplied by a single source breeder (Harlan Sprague-Dawley Inc., Livermore, CA), which has consistently supplied healthy animals of relatively uniform age and weight. 2.1. Animal preparation All animals were fasted overnight except for free access to water. The detailed animal preparation has been published previously. 23 Briefly; the animals were anesthetized by intraperitoneal injection of pentobarbital (45 mg/kg). Additional doses (10 mg/kg) were administered at intervals of approximately 1 hour or when required to maintain anesthesia. The trachea was orally intubated with a 14-gauge cannula (Abbocath-T; Abbott Hospital, North Chicago, IL). A PE-50 catheter (Becton-Dickinson, Franklin Lakes, NJ) was advanced from the left femoral artery into the descending aorta for measurement of aortic pressure and sampling of arterial blood. Another PE-50 catheter was advanced through the left external jugular vein and into the right atrium for measurement of right atrial pressures. Aortic and right atrial pressures were measured with high-sensitivity transducers (model 42584-01, Abbott Critical Care Systems, North Chicago, IL). A thermocouple microprobe, 10 cm in length and 0.5 mm in diameter (9030-12-D-34, Columbus Instruments, Columbus, OH), was inserted into the right femoral artery and advanced into the descending aorta for measurement of blood temperature. A 3-French PE catheter (model C-PMS-301J, Cook Critical Care, Bloomington, IN) was advanced through the right external jugular vein into the right atrium. A pre-curved guide wire supplied with the catheter was then advanced through the catheter into the right ventricle to induce VF, as confirmed by an endocardial electrocardiogram. All catheters were flushed intermittently with saline containing 2.5 IU/mL of crystalline bovine heparin. A conventional lead II EKG was continuously monitored. The blood temperature for all animals was maintained between 36.5°C and 37.5°C during the whole experiment by a heating lamp. 2.2. Experimental procedure In preparation of the present study, AMSA value on 40 male Sprague-Dawley rats was calculated. 3-second strips prior to the defibrillation were selected to calculate the value of AMSA. The mean AMSA value of failed shocks is 7.85 ± 2.04 mV ·Hz, and that of successful shocks is 12.65 ± 2.92 mV ·Hz. The sensitivity and specificity over 10.00 mV ·Hz were 0.79 and 0.84, respectively. The value of 10 mV ·Hz was then utilized as an AMSA threshold of successful defibrillation. Baseline measurements were obtained 10 minutes before inducing VF. Mechanical ventilation was established with a tidal volume of 0.60 mL/100 grams of body weight and a frequency of 100 breaths/min. The inspired O2 fraction (FiO2 ) was maintained at 0.21. VF was electrically induced with progressive increase in 60 Hz current to a maximum of 3.5 mA delivered to the right ventric-
ular endocardium. The current flow was continued for 3 minutes to prevent spontaneous defibrillation. Mechanical ventilation was stopped after onset of VF. Precordial compression was begun 8 minutes after onset of untreated VF with a pneumatically driven mechanical chest compressor as previously described. 23 Depth of compression was initially adjusted such as to secure a CPP of 23 ± 2 mm Hg. Prior to CPR, animals were randomized into 3 groups. In animals randomized to the AMSA guided group, CPR was provided continuously and defibrillation was not attempted until the AMSA value reached 10 mV ·Hz (CC+AMSA). In animals randomized to the CPR procedure according to the guidelines with delayed defibrillation group (GL+AED), a single electrical shock was delivered 10 seconds after each 2 minutes of CPR. The 10 second delay was designed to simulate the algorithm of the currently available AEDs. In the third group, the CPR procedure was also based on guidelines with immediate shock (GL+shock ready); a single shock was delivered immediately after every 2 min of CPR, which was designed to simulate the manual defibrillation. A pre-programmed defibrillator was utilized for continuous analysis and monitoring of the AMSA value (E series, ZOLL, MA). If ROSC is not achieved after the first defibrillation, the same procedure was repeated for a maximum of 10 minutes. ROSC was defined as the return of supraventricular rhythm with a mean aortic pressure above 50 mm Hg for a minimum of 5 minutes. Following resuscitation, mechanical ventilation was continued with 100% oxygen for 15 minutes and then with 50% oxygen for another 15 minutes followed by 21% oxygen for half an hour. All catheters, except the endotracheal tube, were then removed. The animals were continuously observed by the investigators for an additional 3 hours. The endotracheal tube was removed whenever the animals were breathing spontaneously. All animals were then returned to their cages and closely monitored for 72 hours. 2.3. Measurements Aortic and right atrial pressures, electrocardiogram, and EtCO2 were continuously recorded for up to 1 hour after post-resuscitation on a PC-based data-acquisition system supported by WINDAQ software (DATAQ, Akron, OH). CPP was calculated as the difference between decompression diastolic aortic and time-coincident right atrial pressure measured at the end of each minute of precordial compression. During CPR, the real-time AMSA value was monitored and recorded continuously. After each experiment, the AMSA value was reanalyzed with the aid of MATLAB software (Mathworks Inc., Natick, MA), based on the VF waveform recorded during the experiment. Myocardial function was non-invasively measured at baseline and at hourly intervals after resuscitation with a Philips ultrasound system, utilizing a 12.5-Hz transducer (HD 11 XE, Philips Ultrasound, Bothell, WA). All the measurements, including cardiac output (CO), myocardial performance index (MPI) and ejection fraction (EF) were reviewed and confirmed separately by two of the investigators. MPI was obtained as both systolic and diastolic functions, it is the ratio of total time spent in isovolumic activity (isovolumic contraction and relaxation times) to the ejection time and was measured from the mitral inflow and left ventricular outflow time intervals. 24,25 EF served as an indicator of myocardial contractility. The post-resuscitation myocardial and neurologic functions were evaluated at 24-hour intervals for a total of 72 hours. Neurological deficit scores (NDS) were obtained according to the method of Hendrickx HL et al, ranging from 0 (no observed neurologic deficit) to 500 (death or brain death). 26 NDS was examined and confirmed by two investigators blinded to the treatment. After 72 hours of ROSC, animals were euthanized by intraperitoneal injection of
S. Sun et al. / Resuscitation 82S (2011) S3–S7
pentobarbital (150 mg/kg). Autopsy was routinely performed to identify adverse effects of the interventions. 2.4. Statistical analyses The correlation of AMSA between the real-time and the post experiment measurement in each group was performed with Pearson’s product–moment correlation coefficient (r) T test. For comparison of measurements among groups, analysis of variance and Scheffe’s multiple-comparison techniques were used. Comparisons between time-based measurements within each group were performed with analysis of variance repeated measurement. The outcome differences were analyzed with Fisher’s exact test. Measurements were reported as mean ± SD. A value of p < 0.05 was considered significant.
S5
Table 3 Number of defibrillation, duration and total interruptions of CPR.
Number of defibrillation Duration of CPR to ROSC, minutes Total interruptions, seconds
CC+AMSA
GL+shock ready
GL+AED
1.5 ± 0.8 5.4 ± 0.6 2.0 ± 3.3
3.4 ± 1.2** 7.1 ± 2.0* 8.4 ± 2.9**
2.9 ± 1.1** 7.3 ± 2.0** 26.0 ± 11**
*p < 0.05, **p < 0.01 vs CC+AMSA group. Values are presented as mean ± SD.
Table 4 AMSA value prior to the first DF and the rate of ROSC after the first DF.
AMSA prior to 1st DF, mV · Hz The rate of ROSC after 1st DF
CC+AMSA
GL+shock ready
GL+AED
10.7 ± 0.85 7/10
5.06 ± 1.2** 1/10**
3.84 ± 1.38**# 1/10**
1st DF: first defibrillation. **p < 0.01 vs CC+AMSA group. # p < 0.05 vs GL+shock ready group. Values are presented as mean ± SD.
3. Results Thirty-eight rats were utilized for this study and 30 were included and completed. Eight animals were excluded. One rat resuscitated spontaneously during VF and 7 with instrumentation or technical failure during the animal preparation. Baseline blood temperature, myocardial function, hemodynamics, and blood analytical measurements did not differ between the 3 groups (Table 1). There was no difference in AMSA values between groups during untreated VF and prior to randomization. There was also no significant difference in CPP prior to successful defibrillation between groups (Table 2). All the animals were resuscitated excepted 2 animals in GL+AED group and 1 animal in GL+shock ready group (p = NS). The duration of CPR was significantly shorter in CC+AMSA group compared with both of the guidelines-based groups (Table 3). This was associated with fewer interruptions of CPR and total number of defibrillations required for ROSC (Table 3). During CPR, the AMSA value was gradually increased in all the animals. There was no difference in the AMSA values between groups during the first 2 minutes of CPR. However, the AMSA value prior to the first defibrillation was significantly greater in the CC+AMSA group when compared with other two groups (p < 0.01, Table 4). The AMSA value in the GL+AED group was significantly decreased after a 10 second delay before defibrillation (5.3 ± 1.4
prior to the delay vs 3.84 ± 1.3 after 10 seconds delay, p = 0.03). This resulted in a higher rate of ROSC after the first defibrillation in the CC+AMSA group when compared with other two groups (p < 0.01, Table 4). The real-time AMSA value was highly correlated with post experiment analysis in each group (p < 0.01). The coefficient of correlation (r) was 0.97 with a sample size of 67 in CC+AMSA group, 0.91 with a sample size of 70 in GL+AED group and 0.93 with a sample size of 94 in GL+shock ready group. Regardless of the groups, ROSC was significantly greater when the duration of CPR was increased to 5 minutes or more compared to less than 5 minutes (p < 0.01, Fig. 1A). Twenty-three out of 27 resuscitated animals were successfully defibrillated after 5 minutes of CPR, including 9 animals in the CC+AMSA group, 6 animals in the GL+AED group and 8 animals in the GL+shock ready group, respectively. Four animals were resuscitated between 4 to 5 minutes of CPR and no ROSC was achieved in all groups before the 4 minutes of CPR (Fig. 1B). Postresuscitation arrhythmia duration including ventricular and supraventricular abnormal rhythms lasted much longer in both GL+AED and GL+shock ready groups when compared to the CC+AMSA group (21 ± 7 minutes, 15 ± 9 minutes vs 6 ± 7 minutes,
Table 1 Baseline characteristics.
Body weight, g Heart rate, bpm MAP, mm Hg RA, mm Hg End-tidal CO2 , mm Hg Temperature, °C Ejection fraction, % Cardiac output, L/min MPI Arterial pH Arterial lactate, mmol/L
CC+AMSA
GL+shock ready
GL+AED
513 ± 16 366 ± 21 138 ± 6 1.3 ± 0.2 39 ± 3 36.9 ± 0.1 70 ± 4 101 ± 6 0.66 ± 0.02 7.48 ± 0.03 0.61 ± 0.2
514 ± 13 362 ± 16 137 ± 4 1.3 ± 0.1 40 ± 2 37.1 ± 0.1 69 ± 4 102 ± 4 0.65 ± 0.06 7.46 ± 0.02 0.63 ± 0.2
518 ± 12 366 ± 22 140 ± 7 1.4 ± 0.2 39 ± 3 36.9 ± 0.1 71 ± 3 102 ± 9 0.65 ± 0.05 7.47 ± 0.0 0.66 ± 0.3
MAP: mean aortic pressure; RA: right atrial blood pressure; MPI: myocardial performance index. Values are presented as mean ± SD.
Table 2 AMSA value prior to randomization, CPP prior to defibrillation.
AMSA value in VF 8, mV · Hz CPP prior to successful DF, mm Hg
CC+AMSA
GL+shock ready
GL+AED
1.56 ± 0.4 23.1 ± 1.5
1.48 ± 0.2 23.6 ± 1.4
1.57 ± 0.3 23.0 ± 1.5
CPP: coronary perfusion pressure; VF 8: 8 minute after untreated ventricular fibrillation; DF: defibrillation. Values are presented as mean ± SD.
Fig. 1. Duration of CPR and the outcome of resuscitation. A. Percent of successfully defibrillated animal vs duration of CPR. # p < 0.05 vs the animals that were resuscitated after 4 minutes of CPR. **p < 0.01 vs the animals that were resuscitated after 5 minutes of CPR. B. Number of ROSC in each groups during CPR.
S6
S. Sun et al. / Resuscitation 82S (2011) S3–S7
Fig. 2. Myocardial function at baseline and post resuscitation. EF: ejection fraction; CO: cardiac output; MPI: myocardial performance index; BL: baseline; VF: ventricular fibrillation. Values are presented as mean ± SD. *p < 0.05, **p < 0.01 vs CC+AMSA group.
Table 5 24, 48 and 72 hour survival rate and neurological deficit score.
24 24 48 48 72 72
hrs hrs hrs hrs hrs hrs
survival rate NDS survival rate NDS survival rate NDS
CC+AMSA
GL+shock ready
GL+AED
10/10 115 ± 52 10/10 88 ± 71 9/10 72 ± 152
6/10* 328 ± 168** 5/10** 301 ± 212** 5/10* 282 ± 235*
3/10** 434 ± 106** 0/10** 500 ± 0**## 0/10** 500 ± 0**##
NDS: neurological deficit score. *p < 0.05, **p < 0.01 vs CC+AMSA group. 0.01 vs GL+shock ready group. Values are presented as mean ± SD.
##
p<
p = 0.02). Postresuscitation myocardial function, as measured by EF, CO and MPI, was significantly impaired in all animals following successful resuscitation when compared with baseline values (p < 0.01). However, significantly better postresuscitation myocardial function was observed in the CC+AMSA group within 4 hours and 24 hour recovery compared with both of guidelines-based groups (Fig. 2). Twenty-four, 48 and 72 hour survival and NDS following ROSC was significantly better in CC+AMSA group (Table 5). Survival time within 72 hours was inversely correlated with the total duration of CPR (r = −0.67471485, p < 0.001), the interruptions in CPR (r = −0.67483164, p < 0.001) and the number of defibrillations (r = −0.5617, p < 0.001) during CPR. In addition, one hour after ROSC, the arterial lactate returned to normal level in the CC+AMSA group when compared with other 2 groups (1.04 ± 0.44 mmol/L vs 2.46 ± 0.92 mmol/L, 2.23 ± 0.94 mmol/L, p = 0.01, respectively). 4. Discussion The present study demonstrated that in this rat model of cardiac arrest and resuscitation with a prolonged cardiac arrest, the optimal duration of CPR guided by AMSA significantly improved the success
of ROSC after the first defibrillation, and reduced the interruptions of CPR and the number of defibrillations. This was associated with significantly improved post resuscitation myocardial and neurologic function and the duration of survival. The rate of ROSC after the first defibrillation was significantly greater in the CC+AMSA group with continuous chest compression. Seven out of 10 animals were resuscitated after the first defibrillation compared with 0 out of 10 in each of guidelines-based group. AMSA guided resuscitation was associated with less interruptions of CPR and a lesser number of defibrillations to achieve ROSC. In contrast, there was an interruption interval after every 2 minutes of CPR in both guidelines-based groups, especially in the simulated AED group with a 10-second delay before defibrillation attempt. In both guidelines-based groups, defibrillation was attempted after every two minutes of CPR and frequent interruptions actually increased the total duration of CPR. These findings are in accordance with earlier studies indicating that any interruption during CPR would compromise the outcome. 10,11,27,28 However, current guidelines advise defibrillation after every 2 minutes during CPR. If the total interval of CPR is 10 minutes, the same as in our experimental setting, this would account for a total interruption time of up to one minute. We therefore believe this should be taken into account in the future guidelines. After prolonged VF, heart may not be in optimal condition for defibrillation after only 1½ to 3 minutes of CPR. In fact, the optimal duration of CPR before the defibrillation attempt may be difficult to define without an objective feedback measurement. It depends on the duration of VF and the quality of CPR. Our results indicate that regardless of the study group, following 8 minutes of untreated VF, ROSC was significantly greater when the duration of CPR exceeded 5 minutes. Eighty five percent of animals were resuscitated after 5 minutes of CPR and only 15% before 5 minutes. Most importantly, no single animal achieved ROSC before 4 minutes of CPR. This is probably related to prolonged VF; however, it is usually the case in the clinical settings. During CPR, the blood flow generated by chest compression usually below 30% of normal blood flow. 29,30 It may take longer than the currently recommended duration of CPR to improve the myocardial metabolic environment including restoration of high energy phosphates and mitigation of hypercarbic acidosis which may lead to ROSC after prolonged VF. 31,32 Studies have demonstrated that poor myocardial perfusion is associated with decreased VF frequency spectrum. On the other hand, the increased VF amplitude and frequency indicate a positive effect of CPR with improved myocardial perfusion resulting in increased ROSC. 9,13 –17 This study indicates that the optimal duration of CPR prior to defibrillation attempt could be guided by AMSA. The AMSA value of 10 mV ·Hz was utilized in this experimental study as a threshold of defibrillation attempt which is based on preliminary studies described in Methods. In the CC+AMSA group, the chest compression was delivered continuously without interruption. Nine out of 10 animals were successfully defibrillated after 5 minutes of CPR and 1 animal after 4 minutes when the AMSA value exceeded the threshold. However, the AMSA value was significantly below the threshold at 2 and 4 minutes of CPR when unsuccessful defibrillation was attempted in both of the guidelines-based groups. It is important to emphasize that AMSA significantly decreased after each of the 10 second delays in the GL+AED group. In addition to reducing the interruption of chest compression, the numbers of futile defibrillation attempts were significantly reduced in AMSA guided group. Our previous studies have demonstrated that the futile defibrillation attempt itself may increase the severity of postresuscitation myocardial dysfunction. 12 This may explain, at least in part, the better postresuscitation myocardial function in this group of animals. In conclusion, our study in a rat model of prolonged VF demonstrated that the heart may not be ready for defibrillation
S. Sun et al. / Resuscitation 82S (2011) S3–S7
before 5 minutes of CPR. Longer and uninterrupted CPR may significantly improve the rate of ROSC after the first defibrillation. We further demonstrated that the optimal duration of CPR prior to defibrillation after prolonged VF may be guided by AMSA which reduces the interruption of CPR and the number of futile defibrillation attempts. AMSA guided CPR decreases the severity of post-resuscitation myocardial and neurological dysfunction, and ultimately improves long term survival.
13. 14.
15.
16.
Acknowledgements The US patent (5,957,856) for AMSA measurements was awarded to the Weil Institute of Critical Care Medicine. All benefits of this invention are totally reserved for research support and none accrue to the personal benefit of any authors.
17.
18. 19.
Conflict of interest None of the authors has conflicts of interest. References 1. Valenzuela TD, Roe DJ, Nichol G, Clark LL, Spaite DW, Hardman RG. Outcomes of rapid defibrillation by security officers after cardiac arrest in casinos. N Engl J Med 2000;343:1206–9. 2. Caffrey SL, Willoughby PJ, Pepe PE, Becker LB. Public use of automated external defibrillators. N Engl J Med 2002;347:1242–7. 3. Valenzuela TD, Roe DJ, Cretin S, Spaite DW, Larsen MP. Estimating effectiveness of cardiac arrest interventions: a logistic regression survival model. Circulation 1997;96:3308–13. 4. Stiell IG, Wells GA, Field B, et al. Advanced cardiac life support in out-ofhospital cardiac arrest. N Engl J Med 2004;351:647–56. 5. Cobb LA, Fahrenbruch CE, Walsh TR, et al. Influence of cardiopulmonary resuscitation prior to defibrillation in patients with out-of-hospital ventricular fibrillation. JAMA 1999;28:1182–8. 6. Wik L, Hansen TB, Fylling F, et al. Delaying defibrillation to give basic cardiopulmonary resuscitation to patients with out-of-hospital ventricular fibrillation: a randomized trial. JAMA 2003;289:1389–95. 7. 2010 AHA Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Part 6: Electrical Therapies. Circulation 2010;122:S706– 19. 8. Sunde K, Eftestøl T, Askenberg C, Steen PA. Quality assessment of defibrillation and ALS using data from the medical control module of the defibrillator. Resuscitation 1999;41:237–47. 9. Eftestøl T, Sunde K, Ole Aase S, Husoy JH, Steen PA. Predicting outcome of defibrillation by spectral chaterization and nonparametric classification of ventricular fibrillation in patients with out-of-hospital cardiac arrest. Circulation 2000;102;1523–9. 10. Kern K, Hilwig RW, Berg RA, Sanders AB, Ewy GA. Importance of continuous chest compressions during cardiopulmonary resuscitation improved outcome during a simulated single lay-rescuer scenario. Circulation 2002;105:645–9. 11. Yu T, Weil MH, Tang W, et al. Adverse outcomes of interrupted precordial compression during automated defibrillation. Circulation 2002;106:368–72. 12. Tang W, Snyder D, Wang J, et al. 1-shock versus 3-shock defibrillation
20.
21. 22. 23.
24.
25.
26. 27.
28.
29.
30.
31.
32.
S7
protocol significantly improves outcome in a porcine model of prolonged cardiac arrest. Circulation 2006;113:2683–9. Brown CG, Griffith RF, Van Ligten P, et al. Median frequency: a new parameter for predicting defibrillation success rate. Ann Emerg Med 1991;20:787–9. Strohmenger HU, Lindner KH, Keller A, Lindner IM, Pfenninger EG. Spectral analysis of ventricular fibrillation and closed-chest cardiopulmonary resuscitation. Resuscitation 1996;33:155–61. Noc M, Weil MH, Tang W, Sun S, Pernat A, Bisera J. Electrocardiographic prediction of the success of cardiac resuscitation. Crit Care Med 1999;27:708– 14. Callaway CW, Sherman LD, Mosesso VN Jr, Dietrich TJ, Holt E, Clarkson MC. Scaling exponent predicts defibrillation success for out-of-hospital ventricular fibrillation cardiac arrest. Circulation 2001;103:1656–61. Menegazzi JJ, Callaway CW, Sherman LD, et al. Ventricular fibrillation scaling exponent can guide timing of defibrillation and other therapies. Circulation 2004;109:926–31. Marn-Pernat A, Weil MH, Tang W, Pernat A, Bisera J. Optimizing timing of ventricular defibrillation. Crit Care Med 2001;29:2360–5. Povoas HP, Weil MH, Tang W, Bisera J, Klouche K, Barbatsis A. Predicting the success of defibrillation by electrocardiographic analysis. Resuscitation 2002;53:77–82. Brown CG, Dzwonczyk R: Signal analysis of the human electrocardiogram during ventricular fibrillation: Frequency and amplitude parameters as predictors of successful countershock. Ann Emerg Med 1996;27:184–8. National Society for Medical Research Guide for the care and use of laboratory animals. Washington DC, National Academic Press, 1996. Institute of Laboratory Animal Resources Guide for the care and use of laboratory animals. National Institutes of Health, 1985;86-32. Sun S, Weil MH, Tang W, Kamohara T, Klouche K. Delta-opioid receptor agonist reduces severity of postresuscitation myocardial dysfunction. Am J Physiol Heart Circ Physiol 2004;287:H969–74. Jegger D, Jeanrenaud X, Nasratullah M, et al. Noninvasive Doppler-derived myocardial performance index in rats with myocardial infarction: validation and correlation by conductance catheter. Am J Physiol Heart Circ Physiol 2006;290:H1540–8. Xu T, Tang W, Ristagno G, Sun S, Weil MH. Myocardial performance index following electrically induced or ischemically induced cardiac arrest. Resuscitation 2008;76:103–7. Hendrickx HH, Rao GR, Safar P, Gisvold SE. Asphyxia cardiac arrest and resuscitation in rats. Resuscitation 1984;12:97–116. Eftestøl T, Sunde K, Steen PA. Effects of interrupting precordial compressions on the calculated probability of defibrillation success during out-of-hospital cardiac arrest. Circulation 2002;105:2270–3. Berg RA, Sanders AB, Kern KB, et al. Adverse hemodynamic effects of interrupting chest compressions for rescue breathing during cardiopulmonary resuscitation for ventricular fibrillation cardiac arrest. Circulation 2001;104:2465–70. Duggal C, Weil MH, Gazmuri RJ, Tang W, Sun S, O’Connell F, Ali M. Regional blood flow during closed-chest cardiac resuscitation in rats. J Appl Physiol 1993;74:147–52. Deshmukh HG, Weil MH, Gudipati CV, Trevino RP, Bisera J, Rackow EC. Mechanism of blood flow generated by precordial compression during CPR. I. Studies on closed chest precordial compression. Chest 1989;95:1092–9. Kern KB, Garewal HS, Sanders AB, et al. Depletion of myocardial adenosine triphate during prolonged untreated ventricular fibrillation: effect on defibrillation success. Resuscitation 1990; 20:221–9. Maldonado FA, Weil MH, Tang W, et al. Myocardial hypercarbic acidosis reduces cardiac resuscitability. Anaesthesiology 1993;78:343–52.
Optimizing the duration of CPR prior to defibrillation improves the outcome of CPR in a rat model of prolonged cardiac arrest Shijie Sun a,b , Yinlun Weng a , Xiaobo Wu a , Katherine Tang a , Sen Ye a , Wei Chen a , Max Harry Weil a,b , Wanchun Tang a,b, * a b
Weil Institute of Critical Care Medicine, Rancho Mirage, CA, USA Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA
A R T I C L E
I N F O
Keywords: Cardiopulmonary resuscitation Defibrillation Electrocardiography Survival
A B S T R A C T Aims: This study was to investigate whether optimal duration of CPR prior to defibrillation could be guided by Amplitude Spectrum Analysis (AMSA) in the setting of prolonged VF on outcome of CPR. Methods: VF was induced in thirty Sprague-Dawley rats and untreated for 8 minutes. Animals were then randomized into 3 groups prior to CPR: The duration of CPR prior to defibrillation was guided by AMSA (CC+AMSA); guidelines-based with delayed defibrillation that simulated the AED algorithm (GL+AED); and guidelines-based with immediate shock (GL+shock ready). Results: Regardless of groups, the majority of the animals (85%) required over 5 min of CPR to achieve restoration of spontaneous circulation (ROSC). Significantly greater rate of ROSC after first defibrillation (70% vs 0%, p < 0.01), lesser CPR interruptions and the number of defibrillations were observed in the CC+AMSA group when compared to both guidelines-based groups (p < 0.001). This was associated with a significantly better post-resuscitation myocardial and neurological function and longer durations of survival. Conclusions: After prolonged VF, optimal duration of CPR prior to defibrillation guided by AMSA improves the outcome of CPR. © 2011 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Immediate defibrillation following a short duration of ventricular fibrillation (VF) significantly improves the outcome of cardiac arrest. 1,2 However, the probability of successful defibrillation diminishes rapidly over time. For each minute that passes between sudden cardiac arrest and defibrillation, survival rates decrease 7% to 10% if no CPR is provided. 3,4 Clinical studies further demonstrated that when the duration of untreated VF is prolonged for more than 5 min, defibrillation immediately prior to CPR compromises the outcome of CPR. 5,6 Current AHA Guidelines therefore recommend to perform CPR for 1 1/2 to 3 minutes prior to defibrillation when the duration of VF is longer than 4 min. However, there is insufficient evidence to determine the optimal duration of CPR. 7 Also in most cases, the duration of VF is rarely known, especially in the outof-hospital setting. Since there is currently no objective feedback mechanism to indicate when the heart is ready to be resuscitated and specifically, when spontaneous circulation would be restored with a defibrillation, it is not reliable to determine the priority of CPR based on the duration of VF even the VF is witnessed.
* Address for correspondence: Wanchun Tang, MD, Weil Institute of Critical Care Medicine, 35100 Bob Hope Drive, Rancho Mirage, CA 92270, USA. Tel.: +1 760-778-4911; fax: +1 760-778-3468. E-mail address: [email protected] (W. Tang). 0300-9572/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved.
Clinical studies also demonstrated that the current rate of ROSC after defibrillation is low, and around 40% of the unsuccessful shocks could be avoided. 8,9 With current standard CPR procedure, there are multiple interruptions for defibrillations of chest compression. The interruption interval is even longer if automatic external defibrillators (AEDs) are used which require pauses for rhythm analysis and shock delivery. Studies have demonstrated that interruptions of chest compression significantly decrease the quality and worsen the outcome of CPR. 10,11 Our previous study further demonstrated that the multiple unsuccessful defibrillations significantly increase the severity of postresuscitation myocardial dysfunction. 12 Both experimental and clinical studies have showed that both myocardial blood flow generated during CPR and the defibrillation readiness of the fibrillating heart could be monitored by the dynamic changes of the VF waveforms. Increased VF waveform indicates a positive effect of CPR with an increased success of resuscitation. 9,13 –17 The amplitude spectrum analysis (AMSA) is one of the techniques for VF waveform analysis developed by us. 18,19 The changes in AMSA during CPR were highly correlated with coronary perfusion pressure (CPP), which provides a realtime indicator of successful defibrillation with no interruption of CPR. 18 – 20 In the present study, we investigated whether optimal duration of CPR prior to defibrillation and specifically when the heart is
S4
S. Sun et al. / Resuscitation 82S (2011) S3–S7
ready to be defibrillated could be guided by AMSA in the setting of prolonged VF. We hypothesized that optimizing the duration of CPR prior to defibrillation could be guided by AMSA, which will reduce the interruptions in CPR and the number of futile defibrillations. This will, in turn, improve the outcome of CPR. 2. Methods This study was approved by the Institutional Animal Care and Use Committee of the Weil Institute of Critical Care Medicine. All animals received humane care in compliance with the Guide for the Care and Use of Laboratory Animals. 21,22 Our established rodent model of cardiac arrest and resuscitation was utilized. Healthy male Sprague-Dawley rats, aged 6 to 8 months, weighing between 450 to 550 g, were supplied by a single source breeder (Harlan Sprague-Dawley Inc., Livermore, CA), which has consistently supplied healthy animals of relatively uniform age and weight. 2.1. Animal preparation All animals were fasted overnight except for free access to water. The detailed animal preparation has been published previously. 23 Briefly; the animals were anesthetized by intraperitoneal injection of pentobarbital (45 mg/kg). Additional doses (10 mg/kg) were administered at intervals of approximately 1 hour or when required to maintain anesthesia. The trachea was orally intubated with a 14-gauge cannula (Abbocath-T; Abbott Hospital, North Chicago, IL). A PE-50 catheter (Becton-Dickinson, Franklin Lakes, NJ) was advanced from the left femoral artery into the descending aorta for measurement of aortic pressure and sampling of arterial blood. Another PE-50 catheter was advanced through the left external jugular vein and into the right atrium for measurement of right atrial pressures. Aortic and right atrial pressures were measured with high-sensitivity transducers (model 42584-01, Abbott Critical Care Systems, North Chicago, IL). A thermocouple microprobe, 10 cm in length and 0.5 mm in diameter (9030-12-D-34, Columbus Instruments, Columbus, OH), was inserted into the right femoral artery and advanced into the descending aorta for measurement of blood temperature. A 3-French PE catheter (model C-PMS-301J, Cook Critical Care, Bloomington, IN) was advanced through the right external jugular vein into the right atrium. A pre-curved guide wire supplied with the catheter was then advanced through the catheter into the right ventricle to induce VF, as confirmed by an endocardial electrocardiogram. All catheters were flushed intermittently with saline containing 2.5 IU/mL of crystalline bovine heparin. A conventional lead II EKG was continuously monitored. The blood temperature for all animals was maintained between 36.5°C and 37.5°C during the whole experiment by a heating lamp. 2.2. Experimental procedure In preparation of the present study, AMSA value on 40 male Sprague-Dawley rats was calculated. 3-second strips prior to the defibrillation were selected to calculate the value of AMSA. The mean AMSA value of failed shocks is 7.85 ± 2.04 mV ·Hz, and that of successful shocks is 12.65 ± 2.92 mV ·Hz. The sensitivity and specificity over 10.00 mV ·Hz were 0.79 and 0.84, respectively. The value of 10 mV ·Hz was then utilized as an AMSA threshold of successful defibrillation. Baseline measurements were obtained 10 minutes before inducing VF. Mechanical ventilation was established with a tidal volume of 0.60 mL/100 grams of body weight and a frequency of 100 breaths/min. The inspired O2 fraction (FiO2 ) was maintained at 0.21. VF was electrically induced with progressive increase in 60 Hz current to a maximum of 3.5 mA delivered to the right ventric-
ular endocardium. The current flow was continued for 3 minutes to prevent spontaneous defibrillation. Mechanical ventilation was stopped after onset of VF. Precordial compression was begun 8 minutes after onset of untreated VF with a pneumatically driven mechanical chest compressor as previously described. 23 Depth of compression was initially adjusted such as to secure a CPP of 23 ± 2 mm Hg. Prior to CPR, animals were randomized into 3 groups. In animals randomized to the AMSA guided group, CPR was provided continuously and defibrillation was not attempted until the AMSA value reached 10 mV ·Hz (CC+AMSA). In animals randomized to the CPR procedure according to the guidelines with delayed defibrillation group (GL+AED), a single electrical shock was delivered 10 seconds after each 2 minutes of CPR. The 10 second delay was designed to simulate the algorithm of the currently available AEDs. In the third group, the CPR procedure was also based on guidelines with immediate shock (GL+shock ready); a single shock was delivered immediately after every 2 min of CPR, which was designed to simulate the manual defibrillation. A pre-programmed defibrillator was utilized for continuous analysis and monitoring of the AMSA value (E series, ZOLL, MA). If ROSC is not achieved after the first defibrillation, the same procedure was repeated for a maximum of 10 minutes. ROSC was defined as the return of supraventricular rhythm with a mean aortic pressure above 50 mm Hg for a minimum of 5 minutes. Following resuscitation, mechanical ventilation was continued with 100% oxygen for 15 minutes and then with 50% oxygen for another 15 minutes followed by 21% oxygen for half an hour. All catheters, except the endotracheal tube, were then removed. The animals were continuously observed by the investigators for an additional 3 hours. The endotracheal tube was removed whenever the animals were breathing spontaneously. All animals were then returned to their cages and closely monitored for 72 hours. 2.3. Measurements Aortic and right atrial pressures, electrocardiogram, and EtCO2 were continuously recorded for up to 1 hour after post-resuscitation on a PC-based data-acquisition system supported by WINDAQ software (DATAQ, Akron, OH). CPP was calculated as the difference between decompression diastolic aortic and time-coincident right atrial pressure measured at the end of each minute of precordial compression. During CPR, the real-time AMSA value was monitored and recorded continuously. After each experiment, the AMSA value was reanalyzed with the aid of MATLAB software (Mathworks Inc., Natick, MA), based on the VF waveform recorded during the experiment. Myocardial function was non-invasively measured at baseline and at hourly intervals after resuscitation with a Philips ultrasound system, utilizing a 12.5-Hz transducer (HD 11 XE, Philips Ultrasound, Bothell, WA). All the measurements, including cardiac output (CO), myocardial performance index (MPI) and ejection fraction (EF) were reviewed and confirmed separately by two of the investigators. MPI was obtained as both systolic and diastolic functions, it is the ratio of total time spent in isovolumic activity (isovolumic contraction and relaxation times) to the ejection time and was measured from the mitral inflow and left ventricular outflow time intervals. 24,25 EF served as an indicator of myocardial contractility. The post-resuscitation myocardial and neurologic functions were evaluated at 24-hour intervals for a total of 72 hours. Neurological deficit scores (NDS) were obtained according to the method of Hendrickx HL et al, ranging from 0 (no observed neurologic deficit) to 500 (death or brain death). 26 NDS was examined and confirmed by two investigators blinded to the treatment. After 72 hours of ROSC, animals were euthanized by intraperitoneal injection of
S. Sun et al. / Resuscitation 82S (2011) S3–S7
pentobarbital (150 mg/kg). Autopsy was routinely performed to identify adverse effects of the interventions. 2.4. Statistical analyses The correlation of AMSA between the real-time and the post experiment measurement in each group was performed with Pearson’s product–moment correlation coefficient (r) T test. For comparison of measurements among groups, analysis of variance and Scheffe’s multiple-comparison techniques were used. Comparisons between time-based measurements within each group were performed with analysis of variance repeated measurement. The outcome differences were analyzed with Fisher’s exact test. Measurements were reported as mean ± SD. A value of p < 0.05 was considered significant.
S5
Table 3 Number of defibrillation, duration and total interruptions of CPR.
Number of defibrillation Duration of CPR to ROSC, minutes Total interruptions, seconds
CC+AMSA
GL+shock ready
GL+AED
1.5 ± 0.8 5.4 ± 0.6 2.0 ± 3.3
3.4 ± 1.2** 7.1 ± 2.0* 8.4 ± 2.9**
2.9 ± 1.1** 7.3 ± 2.0** 26.0 ± 11**
*p < 0.05, **p < 0.01 vs CC+AMSA group. Values are presented as mean ± SD.
Table 4 AMSA value prior to the first DF and the rate of ROSC after the first DF.
AMSA prior to 1st DF, mV · Hz The rate of ROSC after 1st DF
CC+AMSA
GL+shock ready
GL+AED
10.7 ± 0.85 7/10
5.06 ± 1.2** 1/10**
3.84 ± 1.38**# 1/10**
1st DF: first defibrillation. **p < 0.01 vs CC+AMSA group. # p < 0.05 vs GL+shock ready group. Values are presented as mean ± SD.
3. Results Thirty-eight rats were utilized for this study and 30 were included and completed. Eight animals were excluded. One rat resuscitated spontaneously during VF and 7 with instrumentation or technical failure during the animal preparation. Baseline blood temperature, myocardial function, hemodynamics, and blood analytical measurements did not differ between the 3 groups (Table 1). There was no difference in AMSA values between groups during untreated VF and prior to randomization. There was also no significant difference in CPP prior to successful defibrillation between groups (Table 2). All the animals were resuscitated excepted 2 animals in GL+AED group and 1 animal in GL+shock ready group (p = NS). The duration of CPR was significantly shorter in CC+AMSA group compared with both of the guidelines-based groups (Table 3). This was associated with fewer interruptions of CPR and total number of defibrillations required for ROSC (Table 3). During CPR, the AMSA value was gradually increased in all the animals. There was no difference in the AMSA values between groups during the first 2 minutes of CPR. However, the AMSA value prior to the first defibrillation was significantly greater in the CC+AMSA group when compared with other two groups (p < 0.01, Table 4). The AMSA value in the GL+AED group was significantly decreased after a 10 second delay before defibrillation (5.3 ± 1.4
prior to the delay vs 3.84 ± 1.3 after 10 seconds delay, p = 0.03). This resulted in a higher rate of ROSC after the first defibrillation in the CC+AMSA group when compared with other two groups (p < 0.01, Table 4). The real-time AMSA value was highly correlated with post experiment analysis in each group (p < 0.01). The coefficient of correlation (r) was 0.97 with a sample size of 67 in CC+AMSA group, 0.91 with a sample size of 70 in GL+AED group and 0.93 with a sample size of 94 in GL+shock ready group. Regardless of the groups, ROSC was significantly greater when the duration of CPR was increased to 5 minutes or more compared to less than 5 minutes (p < 0.01, Fig. 1A). Twenty-three out of 27 resuscitated animals were successfully defibrillated after 5 minutes of CPR, including 9 animals in the CC+AMSA group, 6 animals in the GL+AED group and 8 animals in the GL+shock ready group, respectively. Four animals were resuscitated between 4 to 5 minutes of CPR and no ROSC was achieved in all groups before the 4 minutes of CPR (Fig. 1B). Postresuscitation arrhythmia duration including ventricular and supraventricular abnormal rhythms lasted much longer in both GL+AED and GL+shock ready groups when compared to the CC+AMSA group (21 ± 7 minutes, 15 ± 9 minutes vs 6 ± 7 minutes,
Table 1 Baseline characteristics.
Body weight, g Heart rate, bpm MAP, mm Hg RA, mm Hg End-tidal CO2 , mm Hg Temperature, °C Ejection fraction, % Cardiac output, L/min MPI Arterial pH Arterial lactate, mmol/L
CC+AMSA
GL+shock ready
GL+AED
513 ± 16 366 ± 21 138 ± 6 1.3 ± 0.2 39 ± 3 36.9 ± 0.1 70 ± 4 101 ± 6 0.66 ± 0.02 7.48 ± 0.03 0.61 ± 0.2
514 ± 13 362 ± 16 137 ± 4 1.3 ± 0.1 40 ± 2 37.1 ± 0.1 69 ± 4 102 ± 4 0.65 ± 0.06 7.46 ± 0.02 0.63 ± 0.2
518 ± 12 366 ± 22 140 ± 7 1.4 ± 0.2 39 ± 3 36.9 ± 0.1 71 ± 3 102 ± 9 0.65 ± 0.05 7.47 ± 0.0 0.66 ± 0.3
MAP: mean aortic pressure; RA: right atrial blood pressure; MPI: myocardial performance index. Values are presented as mean ± SD.
Table 2 AMSA value prior to randomization, CPP prior to defibrillation.
AMSA value in VF 8, mV · Hz CPP prior to successful DF, mm Hg
CC+AMSA
GL+shock ready
GL+AED
1.56 ± 0.4 23.1 ± 1.5
1.48 ± 0.2 23.6 ± 1.4
1.57 ± 0.3 23.0 ± 1.5
CPP: coronary perfusion pressure; VF 8: 8 minute after untreated ventricular fibrillation; DF: defibrillation. Values are presented as mean ± SD.
Fig. 1. Duration of CPR and the outcome of resuscitation. A. Percent of successfully defibrillated animal vs duration of CPR. # p < 0.05 vs the animals that were resuscitated after 4 minutes of CPR. **p < 0.01 vs the animals that were resuscitated after 5 minutes of CPR. B. Number of ROSC in each groups during CPR.
S6
S. Sun et al. / Resuscitation 82S (2011) S3–S7
Fig. 2. Myocardial function at baseline and post resuscitation. EF: ejection fraction; CO: cardiac output; MPI: myocardial performance index; BL: baseline; VF: ventricular fibrillation. Values are presented as mean ± SD. *p < 0.05, **p < 0.01 vs CC+AMSA group.
Table 5 24, 48 and 72 hour survival rate and neurological deficit score.
24 24 48 48 72 72
hrs hrs hrs hrs hrs hrs
survival rate NDS survival rate NDS survival rate NDS
CC+AMSA
GL+shock ready
GL+AED
10/10 115 ± 52 10/10 88 ± 71 9/10 72 ± 152
6/10* 328 ± 168** 5/10** 301 ± 212** 5/10* 282 ± 235*
3/10** 434 ± 106** 0/10** 500 ± 0**## 0/10** 500 ± 0**##
NDS: neurological deficit score. *p < 0.05, **p < 0.01 vs CC+AMSA group. 0.01 vs GL+shock ready group. Values are presented as mean ± SD.
##
p<
p = 0.02). Postresuscitation myocardial function, as measured by EF, CO and MPI, was significantly impaired in all animals following successful resuscitation when compared with baseline values (p < 0.01). However, significantly better postresuscitation myocardial function was observed in the CC+AMSA group within 4 hours and 24 hour recovery compared with both of guidelines-based groups (Fig. 2). Twenty-four, 48 and 72 hour survival and NDS following ROSC was significantly better in CC+AMSA group (Table 5). Survival time within 72 hours was inversely correlated with the total duration of CPR (r = −0.67471485, p < 0.001), the interruptions in CPR (r = −0.67483164, p < 0.001) and the number of defibrillations (r = −0.5617, p < 0.001) during CPR. In addition, one hour after ROSC, the arterial lactate returned to normal level in the CC+AMSA group when compared with other 2 groups (1.04 ± 0.44 mmol/L vs 2.46 ± 0.92 mmol/L, 2.23 ± 0.94 mmol/L, p = 0.01, respectively). 4. Discussion The present study demonstrated that in this rat model of cardiac arrest and resuscitation with a prolonged cardiac arrest, the optimal duration of CPR guided by AMSA significantly improved the success
of ROSC after the first defibrillation, and reduced the interruptions of CPR and the number of defibrillations. This was associated with significantly improved post resuscitation myocardial and neurologic function and the duration of survival. The rate of ROSC after the first defibrillation was significantly greater in the CC+AMSA group with continuous chest compression. Seven out of 10 animals were resuscitated after the first defibrillation compared with 0 out of 10 in each of guidelines-based group. AMSA guided resuscitation was associated with less interruptions of CPR and a lesser number of defibrillations to achieve ROSC. In contrast, there was an interruption interval after every 2 minutes of CPR in both guidelines-based groups, especially in the simulated AED group with a 10-second delay before defibrillation attempt. In both guidelines-based groups, defibrillation was attempted after every two minutes of CPR and frequent interruptions actually increased the total duration of CPR. These findings are in accordance with earlier studies indicating that any interruption during CPR would compromise the outcome. 10,11,27,28 However, current guidelines advise defibrillation after every 2 minutes during CPR. If the total interval of CPR is 10 minutes, the same as in our experimental setting, this would account for a total interruption time of up to one minute. We therefore believe this should be taken into account in the future guidelines. After prolonged VF, heart may not be in optimal condition for defibrillation after only 1½ to 3 minutes of CPR. In fact, the optimal duration of CPR before the defibrillation attempt may be difficult to define without an objective feedback measurement. It depends on the duration of VF and the quality of CPR. Our results indicate that regardless of the study group, following 8 minutes of untreated VF, ROSC was significantly greater when the duration of CPR exceeded 5 minutes. Eighty five percent of animals were resuscitated after 5 minutes of CPR and only 15% before 5 minutes. Most importantly, no single animal achieved ROSC before 4 minutes of CPR. This is probably related to prolonged VF; however, it is usually the case in the clinical settings. During CPR, the blood flow generated by chest compression usually below 30% of normal blood flow. 29,30 It may take longer than the currently recommended duration of CPR to improve the myocardial metabolic environment including restoration of high energy phosphates and mitigation of hypercarbic acidosis which may lead to ROSC after prolonged VF. 31,32 Studies have demonstrated that poor myocardial perfusion is associated with decreased VF frequency spectrum. On the other hand, the increased VF amplitude and frequency indicate a positive effect of CPR with improved myocardial perfusion resulting in increased ROSC. 9,13 –17 This study indicates that the optimal duration of CPR prior to defibrillation attempt could be guided by AMSA. The AMSA value of 10 mV ·Hz was utilized in this experimental study as a threshold of defibrillation attempt which is based on preliminary studies described in Methods. In the CC+AMSA group, the chest compression was delivered continuously without interruption. Nine out of 10 animals were successfully defibrillated after 5 minutes of CPR and 1 animal after 4 minutes when the AMSA value exceeded the threshold. However, the AMSA value was significantly below the threshold at 2 and 4 minutes of CPR when unsuccessful defibrillation was attempted in both of the guidelines-based groups. It is important to emphasize that AMSA significantly decreased after each of the 10 second delays in the GL+AED group. In addition to reducing the interruption of chest compression, the numbers of futile defibrillation attempts were significantly reduced in AMSA guided group. Our previous studies have demonstrated that the futile defibrillation attempt itself may increase the severity of postresuscitation myocardial dysfunction. 12 This may explain, at least in part, the better postresuscitation myocardial function in this group of animals. In conclusion, our study in a rat model of prolonged VF demonstrated that the heart may not be ready for defibrillation
S. Sun et al. / Resuscitation 82S (2011) S3–S7
before 5 minutes of CPR. Longer and uninterrupted CPR may significantly improve the rate of ROSC after the first defibrillation. We further demonstrated that the optimal duration of CPR prior to defibrillation after prolonged VF may be guided by AMSA which reduces the interruption of CPR and the number of futile defibrillation attempts. AMSA guided CPR decreases the severity of post-resuscitation myocardial and neurological dysfunction, and ultimately improves long term survival.
13. 14.
15.
16.
Acknowledgements The US patent (5,957,856) for AMSA measurements was awarded to the Weil Institute of Critical Care Medicine. All benefits of this invention are totally reserved for research support and none accrue to the personal benefit of any authors.
17.
18. 19.
Conflict of interest None of the authors has conflicts of interest. References 1. Valenzuela TD, Roe DJ, Nichol G, Clark LL, Spaite DW, Hardman RG. Outcomes of rapid defibrillation by security officers after cardiac arrest in casinos. N Engl J Med 2000;343:1206–9. 2. Caffrey SL, Willoughby PJ, Pepe PE, Becker LB. Public use of automated external defibrillators. N Engl J Med 2002;347:1242–7. 3. Valenzuela TD, Roe DJ, Cretin S, Spaite DW, Larsen MP. Estimating effectiveness of cardiac arrest interventions: a logistic regression survival model. Circulation 1997;96:3308–13. 4. Stiell IG, Wells GA, Field B, et al. Advanced cardiac life support in out-ofhospital cardiac arrest. N Engl J Med 2004;351:647–56. 5. Cobb LA, Fahrenbruch CE, Walsh TR, et al. Influence of cardiopulmonary resuscitation prior to defibrillation in patients with out-of-hospital ventricular fibrillation. JAMA 1999;28:1182–8. 6. Wik L, Hansen TB, Fylling F, et al. Delaying defibrillation to give basic cardiopulmonary resuscitation to patients with out-of-hospital ventricular fibrillation: a randomized trial. JAMA 2003;289:1389–95. 7. 2010 AHA Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Part 6: Electrical Therapies. Circulation 2010;122:S706– 19. 8. Sunde K, Eftestøl T, Askenberg C, Steen PA. Quality assessment of defibrillation and ALS using data from the medical control module of the defibrillator. Resuscitation 1999;41:237–47. 9. Eftestøl T, Sunde K, Ole Aase S, Husoy JH, Steen PA. Predicting outcome of defibrillation by spectral chaterization and nonparametric classification of ventricular fibrillation in patients with out-of-hospital cardiac arrest. Circulation 2000;102;1523–9. 10. Kern K, Hilwig RW, Berg RA, Sanders AB, Ewy GA. Importance of continuous chest compressions during cardiopulmonary resuscitation improved outcome during a simulated single lay-rescuer scenario. Circulation 2002;105:645–9. 11. Yu T, Weil MH, Tang W, et al. Adverse outcomes of interrupted precordial compression during automated defibrillation. Circulation 2002;106:368–72. 12. Tang W, Snyder D, Wang J, et al. 1-shock versus 3-shock defibrillation
20.
21. 22. 23.
24.
25.
26. 27.
28.
29.
30.
31.
32.
S7
protocol significantly improves outcome in a porcine model of prolonged cardiac arrest. Circulation 2006;113:2683–9. Brown CG, Griffith RF, Van Ligten P, et al. Median frequency: a new parameter for predicting defibrillation success rate. Ann Emerg Med 1991;20:787–9. Strohmenger HU, Lindner KH, Keller A, Lindner IM, Pfenninger EG. Spectral analysis of ventricular fibrillation and closed-chest cardiopulmonary resuscitation. Resuscitation 1996;33:155–61. Noc M, Weil MH, Tang W, Sun S, Pernat A, Bisera J. Electrocardiographic prediction of the success of cardiac resuscitation. Crit Care Med 1999;27:708– 14. Callaway CW, Sherman LD, Mosesso VN Jr, Dietrich TJ, Holt E, Clarkson MC. Scaling exponent predicts defibrillation success for out-of-hospital ventricular fibrillation cardiac arrest. Circulation 2001;103:1656–61. Menegazzi JJ, Callaway CW, Sherman LD, et al. Ventricular fibrillation scaling exponent can guide timing of defibrillation and other therapies. Circulation 2004;109:926–31. Marn-Pernat A, Weil MH, Tang W, Pernat A, Bisera J. Optimizing timing of ventricular defibrillation. Crit Care Med 2001;29:2360–5. Povoas HP, Weil MH, Tang W, Bisera J, Klouche K, Barbatsis A. Predicting the success of defibrillation by electrocardiographic analysis. Resuscitation 2002;53:77–82. Brown CG, Dzwonczyk R: Signal analysis of the human electrocardiogram during ventricular fibrillation: Frequency and amplitude parameters as predictors of successful countershock. Ann Emerg Med 1996;27:184–8. National Society for Medical Research Guide for the care and use of laboratory animals. Washington DC, National Academic Press, 1996. Institute of Laboratory Animal Resources Guide for the care and use of laboratory animals. National Institutes of Health, 1985;86-32. Sun S, Weil MH, Tang W, Kamohara T, Klouche K. Delta-opioid receptor agonist reduces severity of postresuscitation myocardial dysfunction. Am J Physiol Heart Circ Physiol 2004;287:H969–74. Jegger D, Jeanrenaud X, Nasratullah M, et al. Noninvasive Doppler-derived myocardial performance index in rats with myocardial infarction: validation and correlation by conductance catheter. Am J Physiol Heart Circ Physiol 2006;290:H1540–8. Xu T, Tang W, Ristagno G, Sun S, Weil MH. Myocardial performance index following electrically induced or ischemically induced cardiac arrest. Resuscitation 2008;76:103–7. Hendrickx HH, Rao GR, Safar P, Gisvold SE. Asphyxia cardiac arrest and resuscitation in rats. Resuscitation 1984;12:97–116. Eftestøl T, Sunde K, Steen PA. Effects of interrupting precordial compressions on the calculated probability of defibrillation success during out-of-hospital cardiac arrest. Circulation 2002;105:2270–3. Berg RA, Sanders AB, Kern KB, et al. Adverse hemodynamic effects of interrupting chest compressions for rescue breathing during cardiopulmonary resuscitation for ventricular fibrillation cardiac arrest. Circulation 2001;104:2465–70. Duggal C, Weil MH, Gazmuri RJ, Tang W, Sun S, O’Connell F, Ali M. Regional blood flow during closed-chest cardiac resuscitation in rats. J Appl Physiol 1993;74:147–52. Deshmukh HG, Weil MH, Gudipati CV, Trevino RP, Bisera J, Rackow EC. Mechanism of blood flow generated by precordial compression during CPR. I. Studies on closed chest precordial compression. Chest 1989;95:1092–9. Kern KB, Garewal HS, Sanders AB, et al. Depletion of myocardial adenosine triphate during prolonged untreated ventricular fibrillation: effect on defibrillation success. Resuscitation 1990; 20:221–9. Maldonado FA, Weil MH, Tang W, et al. Myocardial hypercarbic acidosis reduces cardiac resuscitability. Anaesthesiology 1993;78:343–52.