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Keywords:

  • antiarrhythmia agents;
  • arrhythmia;
  • cardiopulmonary resuscitation;
  • survival

Abstract

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Limitations
  7. Conclusions
  8. Acknowledgments
  9. References

Objectives:  Procainamide is an antiarrhythmic drug of unproven efficacy in cardiac arrest. The association between procainamide and survival from out-of-hospital cardiac arrest was investigated to better determine the drug’s potential role in resuscitation.

Methods:  The authors conducted a 10-year study of all witnessed, out-of-hospital, ventricular fibrillation (VF) or pulseless ventricular tachycardia (VT) cardiac arrests treated by emergency medical services (EMS) in King County, Washington. Patients were considered eligible for procainamide if they received more than three defibrillation shocks and intravenous (IV) bolus lidocaine. Four logistic regression models were used to calculate odds ratios (ORs) and 95% confidence intervals (CI) describing the relationship between procainamide and survival.

Results:  Of the 665 eligible patients, 176 received procainamide, and 489 did not. On average, procainamide recipients received more shocks and pharmacologic interventions and had lengthier resuscitations. Adjusted for their clinical and resuscitation characteristics, procainamide recipients had a lower likelihood of survival to hospital discharge (OR = 0.52; 95% CI = 0.36 to 0.75). Further adjustment for receipt of other cardiac medications during resuscitation negated this apparent adverse association (OR = 1.02; 95% CI = 0.66 to 1.57).

Conclusions:  In this observational study of out-of-hospital VF and pulseless VT arrest, procainamide as second-line antiarrhythmic treatment was not associated with survival in models attempting to best account for confounding. The results suggest that procainamide, as administered in this investigation, does not have a large impact on outcome, but cannot eliminate the possibility of a smaller, clinically relevant effect on survival.

ACADEMIC EMERGENCY MEDICINE 2010; 17:617–623 © 2010 by the Society for Academic Emergency Medicine

Antiarrhythmic medications are frequently during resuscitation from cardiac arrest, although research supporting their efficacy in this setting is scarce.1–4 Supporting evidence is stronger for their use in the treatment of hemodynamically stable arrhythmias,5 which, along with encouraging results from some animal studies,6 has spurred the extension of their use to the resuscitation of hemodynamically unstable cardiac arrest in humans. Antiarrhythmic agents currently recommended by the American Heart Association (AHA) for the treatment of cardiac arrest include amiodarone, lidocaine, and magnesium.4

Procainamide is a Vaughn Williams Class IA antiarrhythmic with conduction-slowing and vasodilatory properties. Currently, the AHA recommends procainamide for hemodynamically stable ventricular arrhythmias and atrial arrhythmias in patients with preserved ventricular function, but makes no recommendations about the use of the drug for the treatment of cardiac arrest.4 Indeed, the sum of the world’s published experience with intravenous (IV) procainamide in cardiac arrest is limited to the reporting of outcomes in a subgroup of only 20 patients from a larger observational study7 and no randomized clinical trials.

For patients with cardiac arrest in whom defibrillation or first-line cardiac medications are unsuccessful, alternative treatments are limited. A better understanding of alternative treatments such as procainamide may have important ramifications for determining the treatment of cardiac arrest. In the King County, Washington, emergency medical services (EMS) system, procainamide is a second-line treatment option, and its use is systematically tracked in a comprehensive out-of-hospital cardiac arrest surveillance system. Using this 10-year data set, we examined the association between procainamide and survival from out-of-hospital cardiac arrest due to shock- and lidocaine-refractory ventricular fibrillation (VF) or pulseless ventricular tachycardia (VT).

Methods

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Limitations
  7. Conclusions
  8. Acknowledgments
  9. References

Study Design

This was a retrospective cohort study of consecutive cardiac arrests meeting predefined eligibility criteria that occurred in King County, Washington (excluding Seattle), between January 1, 1998, and December 31, 2007. The study’s principal focus was on the association between procainamide and admission alive to hospital and survival to hospital discharge following witnessed, out-of-hospital cardiac arrest due to VF or pulseless VT.

This study was approved by the University of Washington Human Subjects Committee and the requirement for written informed consent to use these data was waived by this committee in accordance with applicable regulations.

Study Setting and Population

King County is a mixed urban, suburban, and rural region covering an area of about 2,000 square miles.8 Excluding Seattle, it has a population of approximately 1.2 million, with a median age of 35.7 years. Some 44% of the population is aged 18–44 years, 23% are 45–64 years, and 10.4% are 65 years and older. The entire region is served by a two-tiered EMS system that is activated by a single emergency dispatch telephone number. The first tier consists of firefighter-emergency medical technicians trained in basic life support (BLS) including defibrillation, while the second tier consists of paramedics trained in advanced life support (ALS), including endotracheal intubation and the administration of medications. Both tiers are dispatched simultaneously in cases of suspected cardiac arrest, with BLS arriving on scene an average of 5 minutes after dispatch and ALS arrival an average of 5 minutes after that.

The study population was identified from the surveillance database in accordance with Utstein guidelines9 and included all patients who were at least 18 years of age and had suffered a witnessed, nontraumatic, out-of-hospital cardiac arrest caused by heart disease, with VF or pulseless VT as the first documented rhythm on EMS arrival. To specifically identify those who did not respond to initial resuscitation measures, added requirements for inclusion in this study were the receipt of more than three defibrillation shocks and at least one IV bolus of lidocaine. Patients meeting these criteria were eligible to receive additional pharmacologic interventions, specifically procainamide, under local EMS treatment protocols. We excluded patients if the arrest occurred after the arrival of EMS personnel, if resuscitation was judged to be futile upon EMS arrival, or if a valid advance directive not to attempt resuscitation was present at the scene.

Study Protocol

Demographic and resuscitation data were obtained from the King County Cardiac Arrest Surveillance System, an ongoing comprehensive registry of all out-of-hospital cardiac arrests assessed by EMS that have occurred in King County since 1976. Data from each arrest are compiled from multiple sources, including dispatch records, defibrillator records, handwritten BLS and ALS incident reports, hospital records, and death certificates.10 In addition, we reviewed original written records to obtain specific information about the administration and doses of cardiac medications, hemodynamic parameters at the end of the resuscitation, and other chronological data about the resuscitation.

The total duration of EMS resuscitation efforts was calculated as the interval between first arrival of EMS personnel and the final time recorded in the prehospital resuscitation record at the time that resuscitation efforts ceased and/or the patient was readied for transport to hospital. In 51 cases in which the precise arrival time of EMS personnel was missing, times were imputed using the median value (4.9 minutes). Logistic regression models that specifically excluded these cases with missing data produced nearly identical results to those reported here.

At the time of this study, medications used in King County for the treatment of out-of-hospital cardiac arrest included epinephrine, norepinephrine, atropine, lidocaine, procainamide, magnesium, sodium bicarbonate, and calcium. Bretylium was also included in resuscitation protocols during a portion of the study, prior to its removal from guidelines in 2000. Amiodarone was not used clinically during the study period due to concerns over its unwieldy formulation and potential delays involved in its administration. Procainamide was reserved as a second-tier antiarrhythmic therapy, after failure of shock and lidocaine. It was typically administered to these patients with refractory VF or pulseless VT amid ongoing cardiopulmonary resuscitation (CPR) at a dose of 500 mg by rapid IV infusion, repeated if necessary, up to a total dose of 17 mg/kg.11

Measures

The primary outcome measures were admission alive to hospital and survival to hospital discharge. Hospital admission was defined as the patient being sufficiently stable to be formally transferred from the emergency department (ED) to an inpatient bed; patients who died in the ED were not considered to be admitted alive. Neurologic status of survivors at hospital discharge could not be uniformly determined from the medical record and was not included as an outcome measure.

Data Analysis

We calculated descriptive statistics for patient demographics and resuscitation characteristics, comparing procainamide recipients to nonrecipients. We used the two-tailed Pearson chi-square test for dichotomous variables and the nonparametric Mann-Whitney U-test (reporting the asymptotic two-tailed significance) for continuous variables. Statistical significance was defined as p ≤ 0.05.

We used logistic regression to obtain the adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs) for the association between procainamide and hospital admission rates and survival hospital discharge. To help address potential confounding, we first generated a propensity score that predicted the likelihood of receiving procainamide. The propensity score was calculated using patient age, sex, arrest location, bystander CPR status, paramedic agency, and time to first arrival of EMS care and was classified into quartiles. Balancing properties were satisfied. We then developed a parsimonious model with respect to the multivariable adjustment. The core multivariable model included only those covariates that altered the OR by more than 10% or were determined from descriptive analyses to differ significantly according to procainamide status. The final baseline model included sex, paramedic agency, bystander CPR status, and the propensity score.

We evaluated four multivariate models. These models differed with respect to the dose effect classification of procainamide and the inclusion of other cardiac medications coadministered with procainamide during resuscitation. Each model was applied to the entire study cohort. In Model 1, procainamide was entered as a dichotomous variable (none vs. any), whereas in Model 2, it was entered as a categorical variable stratified by total cumulative dose (none, <1000 mg, or ≥1000 mg). Neither Model 1 nor Model 2 controlled for other cardiac medications that may have been used during the resuscitation. In contrast, Models 3 and 4 adjusted for other coadministered cardiac medications (epinephrine, magnesium, and bretylium). In Model 3, procainamide, magnesium, and bretylium were entered as dichotomous variables (none vs. any) and epinephrine as a categorical variable stratified by total cumulative dose (none, 0.5–4.9 mg, and ≥5.0 mg). Model 4 was identical to Model 3, except that, like epinephrine, procainamide was also entered as a categorical variable stratified by total dose (none, <1000 mg, or ≥1000 mg).

Finally, we investigated potential interactions between procainamide and other medications and outcome by adding a multiplicative interaction term to each of these described models. Models were measured for goodness-of-fit using the Hosmer-Lemeshow test (goodness-of-fit defined as ≥0.05). All analyses were conducted with SAS version 9.2 (SAS Institute, Cary, NC, 2008).

Results

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Limitations
  7. Conclusions
  8. Acknowledgments
  9. References

During the 10-year study period, 8,092 patients were treated by EMS personnel in King County for out-of-hospital cardiac arrest, of whom 1,448 were at least 18 years of age and suffered a witnessed, nontraumatic VF or pulseless VT arrest caused by heart disease. Of this group, we excluded 196 patients whose arrests occurred after the arrival of EMS personnel and 587 patients who did not meet the minimum resuscitation criteria used in this study (more than 3 shocks and at least one IV bolus of lidocaine). The final study population consisted of 665 patients, 176 of whom received procainamide and 489 of whom did not (Figure 1).

image

Figure 1.  Overall composition of the study population. EMS = emergency medical services; VF = ventricular fibrillation; VT = ventricular tachycardia.

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Baseline demographics, event characteristics, and intervention characteristics of the final study population are presented in Table 1. On average, procainamide recipients were comparable to nonrecipients in age, but were more likely than nonrecipients to be male, to have received a greater numbers of shocks, and to have had a longer duration of resuscitation. They were also more likely to have received epinephrine, magnesium, and bretylium (all but one patient received at least one of these medications) and to have received higher total doses of epinephrine and lidocaine. Procainamide recipients did not significantly differ from nonrecipients in terms of the location of their arrests, the frequency of bystander CPR, or EMS response intervals.

Table 1.    Baseline Characteristics of the 665 Study Patients
CharacteristicAll Procainamide Recipients (n = 176)Patients Not Treated With Procainamide (n = 489)
  1. ALS = advanced life support; BLS = basic life support; CPR = cardiopulmonary resuscitation; EMS = emergency medical services.

  2. *Calculated as the interval between arrival of first EMS personnel and the final time recorded in the prehospital record when resuscitation efforts ceased and/or the patient was readied for transport to hospital.

  3. †Bretylium was removed from resuscitation guidelines beginning January 1, 2001; 56 patients were treated with bretylium prior to this date, 30 of whom also received procainamide and 26 of whom did not.

Age (yr), mean (±SD), median (n)63.0 (±12.5), 63.063.7 (±13.9), 64.0
Males62.7 (±12.7), 63.0 (152)63.5 (±13.8), 64.0 (388)
Females64.9 (±11.5), 64.0 (24)64.7 (±14.7), 65.0 (101)
Male sex, n (% of group)152 (86.4) 388 (79.3)
Arrest in public, n (% of group) 62 (35.2) 174 (35.6)
Bystander CPR, n (% of group)112 (63.6) 338 (69.1)
Continuous variables, mean (±SD), median
 Dispatch to arrival of first EMS unit (BLS or ALS) (minutes)4.9 (±2.2), 5.0 (valid n = 161)4.8 (±2.0), 4.8 (valid n = 453)
 Dispatch to ALS arrival (minutes)8.3 (±3.6), 8.0 (valid n = 176)8.5 (±3.7), 8.0 (valid n = 461)
 Total number of shocks (BLS and ALS)12.4 (±6.6), 10.07.0 (±3.2), 6.0
 Estimated length of resuscitation (minutes)*47.3 (±15.9), 46.9 (valid n = 149)38.5 (±13.3), 37.5 (valid n = 423)
EMS interventions, n (% of group)
 Epinephrine174 (98.9) 415 (84.9)
 Magnesium 58 (33.0)  49 (10.0)
 Bretylium 30 (17.0) 26 (5.3)
Medication dosages (mg), mean (±SD), median (n)
 Epinephrine (mg)6.8 (±4.2), 6.0 (174)4.4 (±3.2), 4.0 (414)
 Lidocaine (mg)266.5 (±67.5), 300.0 (175)189.0 (±79.0), 200.0 (488)
 Magnesium (g)2.6 (±1.4), 2.0 (58)2.7 (±1.9), 2.0 (49)
 Bretylium (mg)†870.0 (±481.5), 950.0 (30)692.3 (±376.2), 500.0 (26)
 Procainamide (mg)742.9 (±341.6), 500.0
Outcomes, number (% of group)
 Admitted alive to hospital 80 (45.5) 305 (62.4)
 Survived to hospital discharge 33 (18.8)1 56 (31.9)

Univariate (unadjusted) analysis showed that procainamide recipients, compared with nonrecipients, were less likely to be admitted alive to the hospital (45.5% vs. 62.4%, respectively, p < 0.001) or survive to hospital discharge (18.4% vs. 31.9%; p < 0.001; Table 1). This adverse association between procainamide and outcome persisted after adjusting for patient demographics and resuscitation characteristics (Table 2, Models 1 and 2). After adjusting for other cardiac medications used during the resuscitation (epinephrine, magnesium, and bretylium), we no longer observed a significant association between the receipt of procainamide and outcome (Table 3, Models 3 and 4). We also observed no significant interactions between procainamide and epinephrine, magnesium, or bretylium on outcome in any of the four models (data not shown).

Table 2.    Operating Rooms and 95% CIs for Associations Between Procainamide and Patient Outcome
 Model 1*Model 2*p-value†
  1. CPR = cardiopulmonary resuscitation. Model 1 depicts overall use versus nonuse of procainamide. Model 2 depicts use versus nonuse of procainamide at the cumulative doses shown.

  2. *Adjusted for sex, whether a citizen provided CPR, propensity score for receiving procainamide, and paramedic agency.

  3. †Hosmer-Lemeshow goodness-of-fit test.

  4. ‡Reference for comparison.

Hospital admission
 Procainamide (dichotomous)0.52 (0.36–0.75)0.76
 Procainamide (categorical)
  NoneReference‡0.44
  Total dose < 1000 mg0.66 (0.42–1.04) 
  Total dose ≥ 1000 mg0.39 (0.23–0.64) 
Survival to hospital discharge
 Procainamide (dichotomous)0.51 (0.32–0.79)0.90
 Procainamide (categorical)
  None Reference‡0.27
  Total dose < 1000 mg 0.60 (0.35–1.03) 
  Total dose ≥ 1000 mg 0.38 (0.19–0.76) 
Table 3.    Operating Rooms and 95% CIs for Associations Between Procainamide and Patient Outcomes, Adjusted for Other Cardiac Medications
 Model 3*Model 4*p-value†
Hospital admission
 Procainamide (dichotomous)1.02 (0.66–1.57)0.27
 Procainamide (categorical)   
  None Reference‡0.13
  Total dose < 1000 mg 1.29 (0.77–2.17) 
  Total dose ≥ 1000 mg 0.72 (0.40–1.32) 
 Epinephrine (categorical)   
  None Reference‡ 
  Total dose < 5.0 mg0.17 (0.06–0.49)0.17 (0.06–0.50) 
  Total dose ≥ 5.0 mg0.02 (0.01–0.06)0.02 (0.01–0.06) 
 Magnesium1.15 (0.65–2.01)1.21 (0.68–2.12) 
 Bretylium§1.14 (0.60–2.16)1.16 (0.61–2.21) 
Survival to hospital dischargeModel 1*Model 2*p-value†
  1. CPR = cardiopulmonary resuscitation. Model 3 depicts overall use versus nonuse of procainamide. Model 4 depicts use versus nonuse of procainamide at the cumulative doses shown.

  2. *Adjusted for sex, whether a citizen provided CPR, propensity score for receiving procainamide, and paramedic agency.

  3. †Hosmer-Lemeshow goodness-of-fit test.

  4. ‡Reference for comparison.

  5. §Bretylium was removed from resuscitation guidelines beginning January 1, 2001; 56 patients were treated with bretylium prior to this date, 30 of whom also received procainamide, and 26 of whom did not.

Procainamide (dichotomous)1.22 (0.72–2.05)0.40
Procainamide (categorical)   
            —Reference‡0.81
            —1.47 (0.80–2.70) 
            —0.90 (0.42–1.93) 
Epinephrine (categorical)   
 NoneReference‡Reference‡ 
 Total dose < 5.0 mg0.16 (0.09–0.30)0.17 (0.09–0.30) 
 Total dose ≥ 5.0 mg0.02 (0.01–0.05)0.02 (0.01–0.05) 
Magnesium1.23 (0.66–2.29)1.29 (0.69–2.41) 
Bretylium§0.73 (0.30–1.80)0.73 (0.29–1.80) 

Discussion

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Limitations
  7. Conclusions
  8. Acknowledgments
  9. References

In this retrospective investigation, we observed that procainamide administration for treatment of out-of-hospital cardiac arrest due to VF or pulseless VT was associated with a lower likelihood of survival in unadjusted analyses and analyses adjusted for common Utstein patient, circumstance, and treatment characteristics. However, inclusion of other medication treatments through multivariable modeling produced a null association between procainamide and survival. This latter model more rigorously accounted for issues of confounding and so likely represents a better assessment of potential clinical effect. Nonetheless, the change in association underscores the challenge of observational design when attempting to assess the clinical influence of treatments.

Previous Studies

The rationale for using procainamide in cardiac arrest resuscitation extends from its demonstrated ability to terminate hemodynamically stable ventricular arrhythmias, particularly in comparison with lidocaine.1,12,13 The sole clinical study to examine procainamide use specifically in the treatment of cardiac arrest described a favorable OR of 21.0 (95% CI = 5.2 to 84.0) for survival to 1 hour, among a small subset of patients (n = 20) who arrested in-hospital and in whom procainamide was administered during the course of resuscitation, with no further characterization.7 Because of such limited evidence, formal recommendations for using procainamide in cardiac arrest waned with the 2000 AHA guidelines, at which time procainamide was recommended for patients whose circulatory status permitted the drug’s administration as a controlled infusion.14 In the 2005 guidelines, procainamide no longer appeared in the cardiac arrest treatment algorithm.4 This inclusion and subsequent exclusion of procainamide from resuscitation guidelines illustrates the challenges of guideline formulation that attempts to incorporate new evidence on alternate treatments when such evidence (as illustrated by procainamide) is absent.

Current Study

We observed that the use of a second-line antiarrhythmic such as procainamide has a potentially important role in out-of-hospital VF resuscitation. Approximately 12% (176/1,448) of patients in this study were treated with procainamide following witnessed cardiac arrest due to VF or VT. This not infrequent use of second-line antiarrhythmic therapy highlights the challenges encountered during resuscitation from cardiac arrest, specifically the potential need for mixed antiarrhythmic medications in the important subset of patients with refractory VF or refibrillation.

Patients treated with procainamide experienced worse outcomes than those who were considered eligible but not so treated. One interpretation of this phenomenon, based on the unadjusted relationship, is that procainamide administration has an adverse effect on resuscitation outcome. This could be explained by procainamide’s possible aggravation of arrhythmias (proarrhythmia), elevation of the defibrillation threshold, hypotension after restoration of circulation, or other factors.2,3 Alternatively, because procainamide is in part a marker of refractory or recurrent arrhythmias, its use as such may have served as no more than a surrogate for worse outcome. Although the selection of an eligibility cohort attempted to restrict our analysis strictly to those who might be candidates for procainamide, descriptive statistics still revealed the potential for important confounding. Models that attempted to more fully account for this possibility resulted in a null association between procainamide and outcome. This suggests that there is not a large clinical survival effect, either positive or negative, associated with the use of procainamide, but rather one that is either negligible or more modest.

This study cannot fully assess the potential for an important association between procainamide and survival, even if its methods were more robust, included additional covariates, or afforded a more precise measure. For example, another model was developed that adjusted for the potentially important confounder of time to treatment with procainamide. This model identified a beneficial association between early administration of procainamide and survival outcome, but was eliminated from consideration because the relatively small number of survivors precluded making the necessary multivariate adjustments to assure its validity. Conversely, a larger overall sample size might have enabled detection of a smaller, yet clinically important association between procainamide and outcome. To this end, our study included 665 subjects, a cohort size that far exceeds any prior publication evaluating the potential clinical effects of procainamide in cardiac arrest. Despite this seemingly large size, a 40% or greater relative effect of procainamide on survival was required to be detected with 80% power at an alpha of 0.05.

Notably, even with efforts in analysis and design to address confounding and analytical power, the current study illustrates some of the challenges of observational studies in out-of-hospital resuscitation. Nonetheless, careful observational studies of medication treatment can provide a valuable method to assess community-based translation of clinical trial evidence and, as in this case, help gauge the potential effects of such therapies when randomized trial evidence is otherwise unavailable.15

Limitations

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Limitations
  7. Conclusions
  8. Acknowledgments
  9. References

This was a retrospective cohort study with a fixed sample size and was susceptible to bias, confounding, and incomplete power to detect more modest, yet still clinically important, survival associations. The study took place in a mature EMS system with relatively high survival rates. Whether the findings would be similar in other EMS systems and communities is not certain. Procainamide was used as a second-line antiarrhythmic given as a rapid infusion following unsuccessful administration of lidocaine. The results could vary were a different sequence, dose, or manner of antiarrhythmic administration used. Finally, since data regarding neurologic status at hospital discharge were not routinely collected throughout the period of this study, we were unable to assess how receipt of procainamide may have affected the long-term neurologic status of survivors of cardiac arrest.

Conclusions

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Limitations
  7. Conclusions
  8. Acknowledgments
  9. References

In this observational cohort study of out-of-hospital ventricular fibrillation and pulseless ventricular tachycardia arrest, treatment with procainamide was not associated with survival in models attempting to best account for confounding. The findings are useful, but cannot eliminate the possibility that procainamide may have more modest but still clinically relevant survival effects. Given the paucity of randomized trial results to guide the medication treatment of cardiac arrest, observational studies like this often serve as the sole vehicle from which to derive strategies for clinical care, but also exemplify the interpretive challenges and limitations that accompany such an approach.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Limitations
  7. Conclusions
  8. Acknowledgments
  9. References

The authors acknowledge the care provided by emergency dispatchers, emergency medical technicians, and paramedics in King County for their outstanding commitment to patient care. None of the authors have a potential conflict of interest to report with regard to this manuscript. This study received no external funding support.

References

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  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Limitations
  7. Conclusions
  8. Acknowledgments
  9. References
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