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CRITICAL CARE AND TRAUMA

Ventricular Fibrillation Median Frequency May Not Be Useful for Monitoring During Cardiac Arrest Treated with Endothelin-1 or Epinephrine

Michael Holzer, MD^*, Wilhelm Behringer, MD^*, Fritz Sterz, MD^*, Julia Kofler, MD^*, Elisabeth Oschatz, MD^*, Ernst Schuster, PhD, and Anton N. Laggner, MD^*

Departments of *Emergency Medicine and Medical Computer Sciences, University of Vienna, Vienna, Austria

Address correspondence and reprint requests to Prof. Dr. Fritz Sterz, Universitätsklinik für Notfallmedizin, Allgemeines Krankenhaus der Stadt Wien, 1090 Wien, Währinger Gürtel 18-20 (6/D), Austria. Address e-mail to fritz.sterz{at}meduniwien.ac.at

	Abstract

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In this study, we evaluated whether median fibrillation frequency (MF) and mean fibrillation amplitude (AMP) reflect coronary perfusion pressure (CoPP) and predict successful defibrillation. MF, AMP, and CoPP were measured during prolonged ventricular fibrillation (VF) cardiac arrest and resuscitation in pigs. After 5 min of VF, cardiopulmonary resuscitation was started. At 10 min, the pigs received randomly a single dose of endothelin-1 50 µg (n = 7), 100 µg (n = 7), or 200 µg (n = 5), or repeated doses of epinephrine 0.04 mg/kg (n = 6), or saline (n = 6) every 3 min. At 25 min, the pigs were defibrillated to achieve restoration of spontaneous circulation (ROSC). In a nonparametric spectral analysis of the individual MF versus CoPP and AMP versus CoPP curves, we found no link between the different curves in different animals or therapies. No difference was found in MF in pigs with ROSC (n = 8) compared with animals not achieving ROSC (n = 23) immediately before defibrillation (P = 0.85). Our data suggest that, in prolonged VF cardiac arrest, MF and AMP might not be useful tools to reflect myocardial perfusion.

IMPLICATIONS: Median fibrillation frequency (MF) has been suggested as an online monitoring tool during resuscitation. In a pig model, during prolonged resuscitation, we compared the individual curves of MF, mean fibrillation amplitude, and coronary perfusion pressure and found that MF was not useful for monitoring resuscitation efforts.

	Introduction

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Each year almost 375,000 people are victims of sudden cardiac arrest in Europe (1). In most of these cases, cardiac arrest is caused by ventricular fibrillation (VF) (2). During cardiac arrest, external cardiac massage and vasopressors have to be applied to maintain a threshold level of myocardial blood flow. In humans, a coronary perfusion pressure (CoPP) of 15 mm Hg seems to be necessary to achieve restoration of spontaneous circulation (ROSC) and may represent a therapeutic goal during resuscitative efforts (3). Cardiac arrest treatment in the field, however, is still highly unpredictable, because the effectiveness of resuscitation efforts can only be monitored by crude methods, and values for CoPP are not available. With the increasing number of interventions during resuscitation, such as defibrillation and administration of epinephrine, vasopressin, amiodarone, or buffers (4), it would be advantageous to have a tool to measure the effect of any individual intervention online during resuscitation to further adjust therapy and possibly improve outcome. Several studies have shown that real-time measurement of median fibrillation frequency (MF) or mean fibrillation amplitude (AMP) could provide a good estimate of CoPP (5,6). The MF especially showed correlation coefficients ranging from 0.61 to 0.91 (5–8) and it was concluded that it could be used for noninvasive monitoring of cardiac perfusion during cardiac arrest (9,10). However, in these studies, only very short segments (5–8) or only few time points (10) of VF were studied, and the usefulness of these methods to reflect myocardial perfusion during prolonged cardiac arrest remains unclear.

Therefore, in this study, a model of prolonged simulated shock refractory cardiac arrest was used, and varying conditions of coronary pressure were established with normal saline and two different vasopressors. MF, AMP, and CoPP were record-ed continuously and the curves obtained were compared using a nonparametric spectral analysis method.

The aim of this pig study was to evaluate whether MF and AMP reflect CoPP and predict successful defibrillation to return of spontaneous circulation in prolonged VF cardiac arrest.

	Methods

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The experimental protocol was approved by our institutional animal investigation committee. Retrospectively, MF, AMP, and CoPP were studied from previous prospective, randomized, double-blind experiments (11) investigating the effect of different vasopressors on tissue blood flow during prolonged VF cardiac arrest and resuscitation in pigs. The detailed experimental protocol is published elsewhere (11).

Experimental Protocol
Pigs of either sex were brought to the local animal care facility 7 days before the investigation and cared for according to National Institutes of Health guidelines. Anesthesia was started with 30 mg/kg ketamine IM followed by 10 mg/kg thiopental, 15 mg of piritramid, and 2 mg of pancuronium IV. To maintain anesthesia and relaxation during the experiment, 1.5 mg · kg^–1 · h^–1 piritramid IV and 0.2 mg · kg^–1 · h^–1 pancuronium IV were used. During preparation, instrumentation, and cardiopulmonary resuscitation, volume-controlled mechanical ventilation was performed with 21% oxygen and the ventilation rate was adjusted to maintain an end-tidal CO₂ of 35–45 mm Hg. An electrocardiogram (ECG) (lead II) was recorded via needle electrodes, and pressure tracings from the right atrium and aorta were recorded continuously in a data acquisition system (Deweport 2000^TM Dewetron GesmbH, Graz, Austria) which was used in combination with data analysis software (Dasylab^TM version 2; Dasytec, Amherst, NH) to analyze the data. At 5 min of untreated VF, cardiac massage was started with a mechanical precordial compression device (Thumper, Type 1000; MI Instruments, Grand Rapids, MI). Simultaneously, mechanical ventilation was started with a compression-ventilation rate of 5:1. At 10 min of VF, the animals were randomly assigned to 1 of 5 treatment groups. The control group (n = 6) received 10 mL of saline every 3 min, the endothelin-1 groups received 50 (n = 7), 100 (n = 7), or 200 (n = 5) µg of endothelin-1 (Sigma-Aldrich, Vienna, Austria) as a single dose, dissolved in 10 mL saline, followed by placebo injections every 3 min, and the epinephrine group (n = 6) received epinephrine 0.04 mg/kg every 3 min. At 25 min of VF, the animals were defibrillated to achieve return of spontaneous circulation. If defibrillation failed, the animals were resuscitated according to American Heart Association guidelines until 35 min after start of cardiac arrest.

ECG Analysis
After the ECG was digitized at a rate of 200 s^–1, it was analyzed by the Dasylab^TM program. MF of the power spectrum of VF was obtained by fast Fourier transformation of 4-s fragments. The MF is the frequency where equal amounts of the power spectrum lie below and above this value. The amplitude of VF was calculated as the mean of the difference of the peak and the next following minimum of the ECG signal within the 4-s segments. For analysis of MF and AMP, the frequency range was restricted by a band pass filter to 4.5–30 s^–1 to eliminate resuscitation artifacts.

CoPP
The CoPP was calculated with a computer-based algorithm using the Dasylab^TM data acquisition system. The aortic and right atrial pressure signals were examined and a window criterion that identified the relaxation (diastolic) interval was applied. The relaxation phase of the arterial and central venous pressure curves fitting the criterion was used to form an average CoPP by subtracting the area under the curves and averaging this difference over the selected time intervals automatically. Thus, a beat-by-beat CoPP was recorded over the entire experiment. A negative CoPP was defined as zero, because a retrograde flow was not expected to exist.

Myocardial Blood Flow
Regional blood flow was measured with the fluorescent microsphere method, as described elsewhere (11).

All values are given as median, 25th and 75th quartile. For comparison of continuous variables among groups, the Kruskal-Wallis test was used. MF and AMP values before drug administration versus before defibrillation were compared with the Wilcoxon test. The correlation of MF and AMP values with myocardial blood flow was performed by Pearson correlation at the time points in which blood flow was measured (8, 16, and 22 min after cardiac arrest). A P value < 0.05 was considered statistically significant. To detect interdependencies between the CoPP and the MF or AMP curves, nonparametric cross-spectral analysis for stationary time series was used (12). This method yields the possibility to correlate time series data over the whole experiment with regard to different therapies. The only assumption for this technique is that the underlying stochastic processes are stationary. The resulting squared coherency values indicate the validity of a linear prediction of one variable by the other variable. This method also takes into account temporal delays between the curves. We performed this analysis using the SAS statistical package, version 8 (SAS Institute Inc., Cary, NC) for the various groups of treatment as well as for individual pigs. We required that the value for the squared coherency function exceed 0.6 to ensure enough confidence that the linear model was appropriate (12).

	Results

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According to protocol, 6 animals were randomized to the control group (weight 22 ± 4 kg; 6 male), 7 to the 50-µg endothelin-1 group (weight 22 ± 4 kg; 7 male), 7 to the 100-µg endothelin-1 group (weight 20 ± 4 kg; 5 male), 5 to the 200-µg endothelin-1 group (weight 21 ± 5 kg; 4 male), and 6 to the epinephrine group (weight 18 ± 3 kg; 6 male). There were no differences in hemodynamic variables among groups at prearrest as well as immediately before drug administration (8 min after cardiac arrest) (11).

Course of MF, AMP, and CoPP
Figure 1A–C show the median VF frequency, AMP, and CoPP curves for each experimental group. Because there was no major difference in the response of MF and AMP to CoPP among the endothelin-1 groups, only data of the control, epinephrine, and endothelin-1 100-µg groups are presented (the figures of the endothelin-1 50- and 200-µg groups are available as an online supplement). During the no-flow period (0–5 min), the CoPP was virtually zero, the MF ranged from 6.9 to 10.1 s^–1, and the AMP ranged from 0.16 to 0.56 mV. After the start of chest compressions, and again after the start of medication, MF and AMP values briefly increased. Thereafter, MF uniformly decreased in all groups irrespective of further changes in CoPP.

View larger version (22K): [in this window] [in a new window]   Figure 1. Median fibrillation frequency, mean fibrillation amplitude, and coronary perfusion pressure (CoPP) in the treatment groups. Chest compressions and ventilation started at 5 min after cardiac arrest, drug application at 10 min after, and defibrillation at 25 min after. A, Control (n = 6, normal saline). B, Epinephrine (n = 6, 0.04 mg of epinephrine every 3 min). C, Endothelin-1 100 µg (n = 7, 100 µg of endothelin-1 at 10 min). Curves are presented as median and 25th and 75th quartiles. Figures of endothelin-1 50 and 200 µg are available as an online supplement.

View larger version (27K): [in this window] [in a new window]

View larger version (31K): [in this window] [in a new window]   Figure 1. Continued.

MF and AMP in Animals With and Without Return of Spontaneous Circulation
Return of spontaneous circulation was achieved only in the endothelin-1 50- and 100-µg groups (8 of 14 animals). When comparing these animals to the animals without return of spontaneous circulation (n = 23), no difference was found in MF immediately before defibrillation (Fig. 2), but AMP was significantly higher in animals with return of spontaneous circulation compared with animals without return of spontaneous circulation (Table 2, Fig. 2).

View larger version (33K): [in this window] [in a new window]   Figure 2. Median fibrillation frequency, mean fibrillation amplitude, and coronary perfusion pressure (CoPP) in animals with and without return of spontaneous circulation. Chest compressions and ventilation started at 5 min after cardiac arrest, drug application at 10 min after, and defibrillation at 25 min after. Animals with return of spontaneous circulation (n = 8, dotted line, median and 75th quartile), animals without return of spontaneous circulation (n = 23, straight line, median and 25th quartile).

Nonparametric Spectral Analysis
In the nonparametric spectral analysis for the various groups of treatment, the squared coherency values rarely exceeded the required minimum level of 0.6. Additionally, in the few cases in which the coherency values were >0.6, the results were very inconsistent over the various treatment groups. This indicates that neither the various types of treatment nor the measurements for individual pigs can be considered replicates for the interrelated mechanism of MF or AMP and CoPP.

	Discussion

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In this pig study of prolonged VF cardiac arrest under varying resuscitation conditions (normal saline, epinephrine, and endothelin-1), the pattern of VF in terms of MF and AMP seemed to be a poor surrogate for CoPP. MF and, to a lesser extent, AMP decreased over time, regardless of the present CoPP. In contrast to the AMP, MF could not be used to predict successful defibrillation to ROSC.

The amplitude of VF was described to correlate positively with coronary perfusion (5), higher mean amplitude was associated with higher defibrillation rates (13,14), and high amplitude was independently related to survival. However, there is great temporal and individual variability in amplitude values, partly because of different fibrillation vector orientation (15) and differences in thoracic impedance (16). Fewer artifacts were obtained when amplitude-independent variables such as MF were used (9,10). Correlation of this variable with myocardial perfusion and successful defibrillation was described for short segments (5) and a few time points (10) of VF, but not for the entire period of resuscitation.

In our model, using nonparametric spectral analysis of the individual MF versus CoPP and AMP versus CoPP, we could not find any link between the different curves in different animals or therapies during VF cardiac arrest of 25 minutes. MF and, to a lesser extent, AMP decreased over time, irrespective of the present CoPP (Fig. 1A–C). However, after the start of chest compressions, there was a short temporal concordant increase in CoPP and MF, but this was only transient and restricted to this time period. These findings might indicate the absence of a simple linear correlation between CoPP and MF or AMP. Other factors besides the CoPP, such as elapsed time of hypoperfusion and ischemia (17,18), seem to influence the MF and AMP. This is further supported by the fact that after the start of cardiac arrest and before the start of resuscitation efforts, MF and AMP were high, whereas coronary perfusion without chest compressions was virtually zero.

In our experiments, varying treatments resulted in different CoPPs, but led to similar median fibrillation frequencies. At 20 minutes of cardiac arrest, the MF was approximately 5 s^–1 in all groups, but the CoPPs at this time point ranged from 0 to 55 mm Hg, depending on the particular treatment. Even if it was feasible to find a nonlinear equation describing the dependence of MF on CoPP, it would not be possible to reverse this calculation. This might be explained in part by the pronounced coronary vasoconstriction of large-dose endothelin-1. Because this effect was not found in other studies with different vasopressors (7,10,19), this could be a treatment-specific effect of endothelin-1.

In contrast to studies without endothelin-1 treatment (10), we found no significant difference in MF in animals with and without return of spontaneous circulation immediately before defibrillation. The higher CoPP induced by endothelin-1 in our study did not increase MF, although more animals could be successfully resuscitated. This might indicate a treatment-specific power of MF to predict successful defibrillation to ROSC. However, increasing median VF frequency by a distinct drug treatment does not necessarily lead to increased resuscitation rates (20). AMP in our experiments was able to predict successful defibrillation, but showed great individual variation.

Other variables such as amplitude spectrum area, N(a) histograms, or principal component analysis extracted from VF signals (21) showed a higher sensitivity and specificity to predict successful defibrillation than MF and AMP (22–24). Further evaluation of these new variables in prolonged experimental resuscitation and clinical situations is warranted.

Our data suggest that in prolonged VF cardiac arrest, the MF and the AMP may not be a useful tool to reflect myocardial perfusion or to predict successful defibrillation to ROSC. Future studies are needed to find other methods that immediately reflect the quality of resuscitation efforts and that can possibly be used to guide specific therapy.

	Acknowledgments

 
This work was supported in part by Grant 6168 of the "Jubiläumsfond" of the Österreichische Nationalbank, Vienna, Austria.

	Footnotes

 
Supplemental material available at anesthesia-analgesia.org.

	References

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Web of Science (2) Citing Articles via Google Scholar Google Scholar Articles by Holzer, M. Articles by Laggner, A. N. Search for Related Content PubMed PubMed Citation Articles by Holzer, M. Articles by Laggner, A. N. Related Collections Critical Care Resuscitation