Effect of Out-of-Hospital Sodium Nitrite on Survival to Hospital Admission After Cardiac Arrest: A Randomized Clinical Trial.

Importance: Therapeutic delivery of sodium nitrite during resuscitation improved survival in animal models of cardiac arrest, but efficacy has not been evaluated in clinical trials in humans. Objective: To determine whether parenteral administration of sodium nitrite given by paramedics during resuscitation for out-of-hospital cardiac arrest improved survival to hospital admission. Design, Setting, and Participants: Double-blind, placebo-controlled, phase 2 randomized clinical trial including 1502 adults in King County, Washington, with out-of-hospital cardiac arrest from ventricular fibrillation or nonventricular fibrillation. Patients underwent resuscitation by paramedics and were enrolled between February 8, 2018, and August 19, 2019; follow-up and data abstraction were completed by December 31, 2019. Interventions: Eligible patients with out-of-hospital cardiac arrest were randomized (1:1:1) to receive 45 mg of sodium nitrite (n = 500), 60 mg of sodium nitrite (n = 498), or placebo (n = 499), which was given via bolus injection by the paramedics as soon as possible during active resuscitation. Main Outcomes and Measures: The primary outcome was survival to hospital admission and was evaluated with 1-sided hypothesis testing. The secondary outcomes included out-of-hospital variables (rate of return of spontaneous circulation, rate of rearrest, and use of norepinephrine to support blood pressure) and in-hospital variables (survival to hospital discharge; neurological outcomes at hospital discharge; cumulative survival to 24 hours, 48 hours, and 72 hours; and number of days in the intensive care unit). Results: Among 1502 patients with out-of-hospital cardiac arrest who were randomized (mean age, 64 years [SD, 17 years]; 34% were women), 99% completed the trial. Overall, 205 patients (41%) in the 45 mg of sodium nitrite group and 212 patients (43%) in the 60 mg of sodium nitrite group compared with 218 patients (44%) in the placebo group survived to hospital admission; the mean difference for the 45-mg dose vs placebo was -2.9% (1-sided 95% CI, -8.0% to ∞; P = .82) and the mean difference for the 60-mg dose vs placebo was -1.3% (1-sided 95% CI, -6.5% to ∞; P = .66). None of the 7 prespecified secondary outcomes were significantly different, including survival to hospital discharge for 66 patients (13.2%) in the 45 mg of sodium nitrite group and 72 patients (14.5%) in the 60 mg of sodium nitrite group compared with 74 patients (14.9%) in the placebo group; the mean difference for the 45-mg dose vs placebo was -1.7% (2-sided 95% CI, -6.0% to 2.6%; P = .44) and the mean difference for the 60-mg dose vs placebo was -0.4% (2-sided 95% CI, -4.9% to 4.0%; P = .85). Conclusions and Relevance: Among patients with out-of-hospital cardiac arrest, administration of sodium nitrite, compared with placebo, did not significantly improve survival to hospital admission. These findings do not support the use of sodium nitrite during resuscitation from out-of-hospital cardiac arrest. Trial Registration: ClinicalTrials.gov Identifier: NCT03452917.

Nitrite elicits divergent NO-dependent signaling that associates with outcome in out of hospital cardiac arrest.

Brain and heart injury cause most out-of-hospital cardiac arrest deaths but limited pharmacotherapy exists to protect these tissues. Nitrite is a nitric oxide precursor that is protective in pre-clinical models of ischemic injury and safe in Phase I testing. Protection may occur by cGMP generation via the sGC pathway or through S-nitrosothiol and nitrated conjugated linoleic acid (NO2-CLA) formation. We hypothesized that nitrite provided during CPR signals through multiple pathways and that activation of signals is associated with OHCA outcome. To this end, we performed a secondary analysis of a phase 1 study of intravenous nitrite administration during resuscitation in adult out-of-hospital cardiac arrest. Associations between whole blood nitrite and derived plasma signals (cGMP and NO2-CLA) with patient characteristics and outcomes were defined using Chi-square or t-tests and multiple logistic regression. Whole blood nitrite levels correlated inversely with plasma NO2-CLA (p = 0.039) but not with cGMP. Patients with shockable rhythms had higher cGMP (p = 0.027), NO2-CLA (p < 0.0001) and trended towards lower nitrite (p = 0.077). Importantly, plasma cGMP and NO2-CLA levels were higher in survivors (p = 0.033 and 0.019) and in those with good neurological outcome (p = 0.046 and 0.021). Nitrite was lower in patients with good neurologic outcome (p = 0.029). cGMP (OR 4.02; 95% CI 1.04-15.54; p = 0.044) and NO2-CLA (OR 3.74; 95% CI 1.11-12.65; p = 0.034) were associated with survival. Nitrite (OR 0.20; 95% CI 0.05-0.08; p = 0.026) and NO2-CLA (OR 3.96; 95% CI 1.01-15.60; p = 0.049) were associated with favorable neurologic outcome. In summary, nitrite administration was associated with increased plasma cGMP and NO2-CLA formation in selected OHCA patients. Furthermore, patients with the highest levels of cGMP and NO2-CLA were more likely to survive and experience better neurological outcomes.

Usefulness of Intravenous Sodium Nitrite During Resuscitation for the Treatment of Out-of-Hospital Cardiac Arrest.

It is hypothesized that intravenous (IV) sodium nitrite given during resuscitation of out-of-hospital cardiac arrest (OHCA) will improve survival. We performed a phase 1 open-label study of IV sodium nitrite given during resuscitation of 120 patents with OHCA from ventricular fibrillation or nonventricular fibrillation initial rhythms by Seattle Fire Department paramedics. A total of 59 patients received 25 mg (low) and 61 patients received 60 mg (high) of sodium nitrite during resuscitation from OHCA. Treatment effects were compared between high- and low-dose nitrite groups, and all patients in a concurrent local Emergency Medical Services registry of OHCA. Whole blood nitrite levels were measured in 97 patients. The rate of return of spontaneous circulation (48% vs 49%), rearrest in the field (15% vs 25%), use of norepinephrine (12% vs 12%), first systolic blood pressure (124 ± 32 vs 125 ± 38 mm Hg), survival to discharge (23.7% vs 16.4%), and neurologically favorable survival (18.6% vs 11.5%) were not significantly different in the low and high nitrite groups. There were no significant differences in these outcomes among patients who received IV nitrite compared with concurrent registry controls. We estimate that 60 mg achieves whole blood nitrite levels of 22 to 38 µM 10 minutes after administration, whereas 25 mg achieves a level of 9 to 16 µM 10 minutes after delivery. In conclusion, administration of IV nitrite is feasible and appears to be safe in patients with OHCA, permitting subsequent evaluation of the effectiveness of IV nitrite for the treatment of OHCA.

Lower-dose epinephrine administration and out-of-hospital cardiac arrest outcomes.

BACKGROUND: International guidelines recommend administration of 1 mg of intravenous epinephrine every 3-5 min during cardiac arrest. The optimal dose of epinephrine is not known. We evaluated the association of reduced frequency and dose of epinephrine with survival after out-of-hospital cardiac arrest (OHCA). METHODS: Included were patients with non-traumatic OHCA treated by advanced life support (ALS) providers from January 1, 2008 to June 30, 2016. During the before period, providers were instructed to give epinephrine 1 mg intravenously at 4 min followed by additional 1 mg doses every eight minutes to patients with OHCA with a shockable rhythm and 1 mg doses every two minutes to patients with a non-shockable rhythm (higher dose). On October 1, 2012, providers were instructed to reduce the dose of epinephrine treatment during out-of-hospital cardiac arrest (OHCA): 0.5 mg at 4 and 8 min followed by additional doses of 0.5 mg every 8 min for shockable rhythms and 0.5 mg every 2 min for non-shockable rhythms (lower dose). Patients with shockable initial rhythms were analyzed separately from those with non-shockable initial rhythms. The primary outcome was survival to hospital discharge with a secondary outcome of favorable neurological status (Cerebral Performance Category [CPC] 1 or 2) at hospital discharge. Multiple logistic regression modeling was used to adjust for age, sex, presence of a witness, bystander CPR, and response interval. RESULTS: 2255 patients with OHCA were eligible for analysis. Of these, 24.6% had an initially shockable rhythm. Total epinephrine dose per patient decreased from a mean ±â€¯standard deviation of 3.4 ±â€¯2.3 mg-2.6 ±â€¯1.9 mg (p < 0.001) in the shockable group and 3.5 ±â€¯1.9 mg-2.8 ±â€¯1.7 mg (p < 0.001) in the non-shockable group. Among those with a shockable rhythm, survival to hospital discharge was 35.0% in the higher dose group vs. 34.2% in the lower dose group. Among those with a non-shockable rhythm, survival was 4.2% in the higher dose group vs. 5.1% in the lower dose group. Lower dose vs. higher dose was not significantly associated with survival: adjusted odds ratio, aOR 0.91 (95% CI 0.62-1.32, p = 0.61) if shockable and aOR 1.26 (95% CI 0.79-2.01, p = 0.33) if non-shockable. Lower dose vs. higher dose was not significantly associated with favorable neurological status at discharge: aOR 0.84 (95% CI 0.57-1.24, p = 0.377) if shockable and aOR 1.17 (95% CI 0.68-2.02, p = 0.577) if non-shockable. CONCLUSION: Reducing the dose of epinephrine administered during out-of-hospital cardiac arrest was not associated with a change in survival to hospital discharge or favorable neurological outcomes after OHCA.

Hemodynamic effects of IV sodium nitrite in hospitalized comatose survivors of out of hospital cardiac arrest.

BACKGROUND: Patients resuscitated from cardiac arrest have brain and cardiac injury. Recent animal studies suggest that the administration of sodium nitrite after resuscitation from 12min of asystole limits acute cardiac dysfunction and improves survival and neurologic outcomes. It has been hypothesized that low doses of IV sodium nitrite given during resuscitation of out of hospital cardiac arrest (OHCA) will improve survival. Low doses of sodium nitrite (e.g., 9.6mg of sodium nitrite) are safe in healthy individuals, however the effect of nitrite on blood pressure in resuscitated cardiac arrest patients is unknown. METHODS: We performed a single-center, pilot trial of low dose sodium nitrite (1 or 9.6mg dose) vs. placebo in hospitalized out-of-hospital cardiac arrest patient to determine whether nitrite administration reduced blood pressure and whether whole blood nitrite levels increased in response to nitrite administration. RESULTS: This is the first reported study of sodium nitrite in cardiac arrest patients. Infusion of low doses of sodium nitrite in comatose survivors of OHCA (n=7) compared to placebo (n=4) had no significant effects on heart rate within 30min after infusion (70±20 vs. 78±3 beats per minute, p=0.18), systolic blood pressure (103±20 vs 108±15mmHg, p=0.3), or methemoglobin levels (0.92±0.33 vs. 0.70±0.26, p=0.45). Serum nitrite levels of 2-4µM were achieved within 15min of a 9.6mg nitrite infusion. CONCLUSIONS: Low dose sodium nitrite does not cause significant hemodynamic effect in patients with OHCA, which suggests that nitrite can be delivered safely in this critically ill patient population. Higher doses of sodium nitrite are necessary in order to achieve target serum level of 10µM.

The impact of first responder turnout and curb-to-care intervals on survival from out-of-hospital cardiac arrest.

PURPOSE: Patients with out-of-hospital cardiac arrest (OHCA) more likely survive when emergency medical services (EMS) arrive quickly. We studied time response elements in OHCA with attention to EMS intervals before wheels roll and after wheels stop to understand their contribution to total time response and clinical outcome. METHODS: We analyzed EMS responses to OHCA from 2009-2014 in an urban, fire department based system. The Call-to-Care Interval, from call receipt to hands-on EMS care, was comprised of four time intervals: 1) call received to EMS notification (Activation), 2) EMS notification to vehicle wheels rolling (Turnout), 3) wheels rolling to arrival at scene (Travel), and 4) arrival at scene to hands-on EMS care (Curb-to-Care). We created a new time interval (On-Feet) comprised of the turnout and curb-to-care intervals. Using logistic regression, we evaluated whether the total EMS response interval and discrete time intervals were related to survival to discharge. RESULTS: Of 1,831 cases, 1,806 (98.6%) had complete information. The mean lengths for the intervals were 7.2±3.6min. (call-to-care), 58±39s (activation), 63±29s (turnout), 2.5±1.3min (travel), 2.4±1.6min (curb-to-care), and 3.5±1.7min (on-feet). After adjustment, "On Feet" interval was associated with OHCA survival (OR=0.91 [95% CI=0.83-1.00] for each additional minute). CONCLUSIONS: Turnout and curb-to-care intervals were half of the total response interval in our EMS system. Measurement should incorporate these two intervals to accurately characterize and possibly reduce the professional response interval.

Briefer activation time is associated with better outcomes after out-of-hospital cardiac arrest.

BACKGROUND: Treatment of out-of-hospital cardiac arrest (OHCA) requires prompt intervention. Better outcomes are associated with briefer time from dispatch of emergency medical services (EMS) providers to arrival on scene, application of a defibrillator or insertion of an advanced airway. We assessed whether time from receipt of a call by a telecommunicator to dispatch of EMS providers was associated with outcomes. METHODS: This was a retrospective analysis of a prospective cohort study of persons who had OHCA treated by EMS providers in Seattle, WA. Activation interval was defined as time from call pick up by telecommunicator to notification of EMS providers to respond to the call. Response interval was defined as the time from notification of EMS providers to their arrival at patient side. We determined the association between time intervals and outcomes of sustained restoration of spontaneous circulation (ROSC), survival to hospital discharge and neurologically favorable survival using multiple logistic regression. Secondary analyses assessed the relative contribution of activation versus response interval, and adjusted for post-treatment patient and EMS characteristics. RESULTS: Among 2,687 patients, activation interval was mean 1.2±0.6min. Response interval was mean 6.1±2.4min. 1,232 (45.9%) achieved ROSC; 475 (17.7%) survived to discharge; and 428 (15.9%) had favorable neurologic status at discharge. Compared to an activation interval of at least 1.5min, patients with briefer intervals were more likely to survive to discharge (adjusted odds ratio (OR) for <1min, 1.69 (95% confidence interval (CI), 1.26, 2.28); adjusted odds ratio for 1 to 1.49min, 1.54 (95% CI, 1.14, 2.08); p value=0.002). With baseline survival of 10%, the absolute increase in survival associated with a 30s decrease in activation interval was 0.7% and for a 30s decrease in response interval was 0.4%. CONCLUSIONS: Briefer activation interval was independently associated with greater survival. Further research is needed to assess whether reduction of the activation interval improves outcome after OHCA.

Impact of Building Height and Volume on Cardiac Arrest Response Time.

Emergency medical services (EMS) care may be delayed when out-of-hospital cardiac arrest (OHCA) occurs in tall or large buildings. We hypothesized that larger building height and volume were related to a longer curb-to-defibrillator activation interval. We retrospectively evaluated 3,065 EMS responses to OHCA in a large city between 2003-13 that occurred indoors, prior to EMS arrival, and without prior deployment of a defibrillator. The two-tiered EMS system uses automated external defibrillator-equipped basic life support firefighters followed by paramedics dispatched from a single call center. We calculated three time intervals obtained from the computerized dispatch report and time-synchronized defibrillators: initial 911 call to address curb arrival by first unit (call-to-curb), curb arrival to defibrillator power on (curb-to-defib on), and the combined call-to-defib on interval. Building height and surface area were measured with a validated program based on aerial photography. Buildings were categorized by height as short (<25 ft), medium (26-64 ft) and tall (>64 ft). Volume was categorized as small (<60,000 ft(3)), midsize (60,000-1,202,600 ft(3)) and large (>1,202,600 ft(3)). Intervals were compared using the two-tailed Mann-Whitney test. EMS responded to 1,673 OHCA events in short, 1,134 in medium, and 258 in tall buildings. There was a 1.14 minute increase in median curb-to-defib on interval from 1.97 in short to 3.11 minutes in tall buildings (p < 0.01). Taller buildings, however, had a shorter call-to-curb interval (4.73 for short vs 3.96 minutes for tall, p < 0.01), such that the difference in call-to-defib on interval was only 0.27 minutes: 6.87 for short and 7.14 for tall buildings. A similar relationship was observed for small-volume compared to large-volume building: longer curb-to-AED (1.90 vs. 3.01 minutes, p < 0.01), but shorter call-to-curb (4.87 vs. 4.05, p < 0.01); the difference in call-to-defib on was 0.18 minutes. Both taller and larger-volume buildings had longer curb-to-AED intervals but shorter 911 call-to-curb arrival intervals. As a consequence, building height and volume had a modest overall relationship with interval from call to defibrillator application. These results do not support the hypothesis that either taller or larger-volume buildings need cause poorer outcomes in urban environments.

Effect of prehospital induction of mild hypothermia on 3-month neurological status and 1-year survival among adults with cardiac arrest: long-term follow-up of a randomized, clinical trial.

BACKGROUND: Randomized trials of prehospital cooling after cardiac arrest have shown that neither prehospital cooling nor targeted temperature management differentially affected short-term survival or neurological function. In this follow-up study, we assess the association of prehospital hypothermia with neurological function at least 3 months after cardiac arrest and survival 1 year after cardiac arrest. METHODS AND RESULTS: There were 508 individuals who were discharged alive from hospitals in King County, Washington; 373 (73%) were interviewed by telephone 123±43 days after the initial event. Overall, 59% of the treatment group and 58% of the control group had Cerebral Performance Category (CPC) 1 or 2 (P=0.70), and 50% of the treatment group and 49% of the control group had slight disability or better by the Modified Rankin Scale (MRS; (P=0.35). One-year survival was 87% in the treatment group and 84% in the control group (P=0.42). Of those with CPC 1 at hospital discharge, 68% had CPC 1 or 2 at follow-up, and 59% had MRS of slight disability or better. Of 41 patients with CPC 3 or 4 at discharge, only 12% had CPC 2 at follow-up, and just 5% had MRS of slight disability or better. One-year survival was 92% for CPC 1 at discharge, but only 40% for CPC 4. CONCLUSION: In addition to excellent survival, patients who had good neurological function at discharge continued to have good function at least 3 months after the event. CLINICAL TRIAL REGISTRATION: URL: Clinicaltrials.gov. Unique identifier: NCT00391469.

The relationship between chest compression fraction and outcome from ventricular fibrillation arrests in prolonged resuscitations.

BACKGROUND: Guidelines direct rescuers to minimize CPR interruptions during resuscitation. There is little evidence that evaluates the relationship of increasing CPR fraction among patients with relatively high fractions or prolonged resuscitation. METHODS: We conducted an observational study of persons who suffered out-of-hospital ventricular fibrillation arrest and required >5 min of emergency medical services (EMS) CPR for persistent pulselessness. We determined the association between hands-on CPR fraction and outcomes of spontaneous circulation, survival to hospital discharge, and neurologically favorable survival. Analyses were stratified by median hands-on CPR and were conducted for those who required 5, 10, and 20 min of EMS CPR for persistent pulselessness. RESULTS: Of 414 potentially eligible patients, 323 (78%) required >5 min of EMS CPR, 234 (56%) required >10 min of EMS CPR, and 153 (37%) required EMS CPR for >20 min. The median CPR fraction was 81%. We did not observe a significant association for the outcomes of hospital survival and neurologically favorable survival for the 5-min and 10-min groups. When restricted to patients who required >20 min of EMS CPR, the half who received a higher hands-on CPR fraction were more likely to achieve spontaneous circulation (40% versus 18%, p=0.004), survival to hospital discharge (20% versus 8%, p=0.03), and neurologically favorable survival (20% versus 7%, p=0.02). CONCLUSION: Over one-third required 20 min of persistent EMS CPR. The EMS was able to achieve a high hands-on CPR fraction in the context of advanced therapies. Those who required the most prolonged EMS CPR appeared to benefit from greater hands-on CPR fraction.

Effect of prehospital induction of mild hypothermia on survival and neurological status among adults with cardiac arrest: a randomized clinical trial.

IMPORTANCE: Hospital cooling improves outcome after cardiac arrest, but prehospital cooling immediately after return of spontaneous circulation may result in better outcomes. OBJECTIVE: To determine whether prehospital cooling improves outcomes after resuscitation from cardiac arrest in patients with ventricular fibrillation (VF) and without VF. DESIGN, SETTING, AND PARTICIPANTS: A randomized clinical trial that assigned adults with prehospital cardiac arrest to standard care with or without prehospital cooling, accomplished by infusing up to 2 L of 4°C normal saline as soon as possible following return of spontaneous circulation. Adults in King County, Washington, with prehospital cardiac arrest and resuscitated by paramedics were eligible and 1359 patients (583 with VF and 776 without VF) were randomized between December 15, 2007, and December 7, 2012. Patient follow-up was completed by May 1, 2013. Nearly all of the patients resuscitated from VF and admitted to the hospital received hospital cooling regardless of their randomization. MAIN OUTCOMES AND MEASURES: The primary outcomes were survival to hospital discharge and neurological status at discharge. RESULTS: The intervention decreased mean core temperature by 1.20°C (95% CI, -1.33°C to -1.07°C) in patients with VF and by 1.30°C (95% CI, -1.40°C to -1.20°C) in patients without VF by hospital arrival and reduced the time to achieve a temperature of less than 34°C by about 1 hour compared with the control group. However, survival to hospital discharge was similar among the intervention and control groups among patients with VF (62.7% [95% CI, 57.0%-68.0%] vs 64.3% [95% CI, 58.6%-69.5%], respectively; P = .69) and among patients without VF (19.2% [95% CI, 15.6%-23.4%] vs 16.3% [95% CI, 12.9%-20.4%], respectively; P = .30). The intervention was also not associated with improved neurological status of full recovery or mild impairment at discharge for either patients with VF (57.5% [95% CI, 51.8%-63.1%] of cases had full recovery or mild impairment vs 61.9% [95% CI, 56.2%-67.2%] of controls; P = .69) or those without VF (14.4% [95% CI, 11.3%-18.2%] of cases vs 13.4% [95% CI,10.4%-17.2%] of controls; P = .30). Overall, the intervention group experienced rearrest in the field more than the control group (26% [95% CI, 22%-29%] vs 21% [95% CI, 18%-24%], respectively; P = .008), as well as increased diuretic use and pulmonary edema on first chest x-ray, which resolved within 24 hours after admission. CONCLUSION AND RELEVANCE: Although use of prehospital cooling reduced core temperature by hospital arrival and reduced the time to reach a temperature of 34°C, it did not improve survival or neurological status among patients resuscitated from prehospital VF or those without VF. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00391469.

Comparison of role of early (less than six hours) to later (more than six hours) or no cardiac catheterization after resuscitation from out-of-hospital cardiac arrest.

Despite reports of patients with resuscitated sudden cardiac arrest (rSCA) receiving acute cardiac catheterization, the efficacy of this strategy is largely unknown. We hypothesized that acute cardiac catheterization of patients with rSCA would improve survival to hospital discharge. A retrospective cohort of 240 patients with out-of-hospital rSCA caused by ventricular tachycardia or fibrillation was identified from 11 institutions in Seattle, Washington from 1999 through 2002. Patients were grouped into those receiving acute catheterization within 6 hours (≤6-hour group, n = 61) and those with deferred catheterization at >6 hours or no catheterization during the index hospitalization (>6-hour group, n = 179). Attention was directed to survival to hospital discharge, neurologic status, extent of coronary artery disease, presenting electrocardiographic findings, and symptoms before arrest. Propensity-score methods were used to adjust for the likelihood of receiving acute catheterization. Survival was greater in patients who underwent acute catheterization (72% in the ≤6-hour group vs 49% in the >6-hour group, p = 0.001). Percutaneous coronary intervention was performed in 38 of 61 patients (62%) in the ≤6-hour group and 13 of 170 patients (7%) in the >6-hour group (p <0.0001). Neurologic status was similar in the 2 groups. A significantly larger percentage of patients in the acute catheterization group had symptoms before cardiac arrest and had ST-segment elevation on electrocardiogram after resuscitation. Age, bystander cardiopulmonary resuscitation, daytime presentation, history of percutaneous coronary intervention or stroke, and acute ST-segment elevation were positively associated with receiving cardiac catheterization. In conclusion, in this series of patients who sustained out-of-hospital cardiac arrest, acute catheterization (<6 hours of presentation) was associated with improved survival.

Perishock pause: an independent predictor of survival from out-of-hospital shockable cardiac arrest.

BACKGROUND: Perishock pauses are pauses in chest compressions before and after defibrillatory shock. We examined the relationship between perishock pauses and survival to hospital discharge. METHODS AND RESULTS: We included out-of-hospital cardiac arrest patients in the Resuscitation Outcomes Consortium Epistry-Cardiac Arrest who suffered arrest between December 2005 and June 2007, presented with a shockable rhythm (ventricular fibrillation or pulseless ventricular tachycardia), and had cardiopulmonary resuscitation process data for at least 1 shock (n=815). We used multivariable logistic regression to determine the association between survival and perishock pauses. In an analysis adjusted for Utstein predictors of survival, the odds of survival were significantly lower for patients with preshock pause ≥20 seconds (odds ratio, 0.47; 95% confidence interval, 0.27 to 0.82) and perishock pause ≥40 seconds (odds ratio, 0.54; 95% confidence interval, 0.31 to 0.97) compared with patients with preshock pause <10 seconds and perishock pause <20 seconds. Postshock pause was not independently associated with a significant change in the odds of survival. Log-linear modeling depicted a decrease in survival to hospital discharge of 18% and 14% for every 5-second increase in both preshock and perishock pause interval (up to 40 and 50 seconds, respectively), with no significant association noted with changes in the postshock pause interval. CONCLUSIONS: In patients with cardiac arrest presenting in a shockable rhythm, longer perishock and preshock pauses were independently associated with a decrease in survival to hospital discharge. The impact of preshock pause on survival suggests that refinement of automatic defibrillator software and paramedic education to minimize preshock pause delays may have a significant impact on survival.

A population-based investigation of public access defibrillation: role of emergency medical services care.

BACKGROUND: Although strategic use of public access defibrillation (PAD) can improve cardiac arrest survival, little is known about temporal trends in PAD deployment and use or how PAD affects the role of emergency medical services (EMS). We sought to determine the frequency, circumstances, and time trends of PAD AED and determine implications of PAD use for EMS providers. METHODS: The investigation was a population-based cohort study of treated out-of-hospital cardiac arrest from a heterogeneous metropolitan setting between January 1, 1999 and December 31, 2006. The study focused on cases where a PAD AED was applied. RESULTS: During the 8-year period, a PAD AED was applied in 1.5% (157/10,332) of all arrests and 4.4% (122/2759) of ventricular fibrillation arrests. PAD application increased over time overall (0.6% in 1999 to 2.4% in 2006) and among ventricular fibrillation arrests (1.8% in 1999 to 8.2% in 2006) (p<0.001 test for trend). Upon EMS arrival, over 90% (143/157) of PAD cases were unconscious and 73% (114/157) required CPR. EMS defibrillation occurred in 47% (73/157). Advanced life support included intubation in 85% (134/157), epinephrine treatment in 57% (90/157), and antiarrhythmic treatment in 64% (100/157). By the end of EMS care, spontaneous pulses were present in 76% (120/157) overall and 84% (102/122) of ventricular fibrillation arrests, a 50% absolute increase when compared to status upon EMS arrival. CONCLUSION: PAD AED increased over time. Most PAD patients were pulseless upon EMS arrival and required basic and advanced resuscitation care by EMS; yet most subsequently achieved spontaneous circulation.

Active surface cooling protocol to induce mild therapeutic hypothermia after out-of-hospital cardiac arrest: a retrospective before-and-after comparison in a single hospital.

OBJECTIVE: To evaluate whether implementation of a therapeutic hypothermia protocol on arrival in a community hospital improved survival and neurologic outcomes in patients initially found to have ventricular fibrillation, pulseless electrical activity, or asystole, and then successfully resuscitated from out-of-hospital cardiac arrest. DESIGN: A retrospective study of patients who presented after implementation of a therapeutic hypothermia protocol compared with those who presented before the protocol was implemented. SETTING: Harborview Medical Center, Seattle, WA. PATIENTS: A total of 491 consecutive adults with out-of-hospital, nontraumatic cardiac arrest who presented between January 1, 2000 and December 31, 2004. INTERVENTIONS: An active cooling therapeutic hypothermia protocol, using ice packs, cooling blankets, or cooling pads to achieve a temperature of 32 degrees C to 34 degrees C was initiated on November 18, 2002 for unconscious patients resuscitated from cardiac arrest. MEASUREMENTS AND MAIN RESULTS: Demographics and outcomes were obtained from medical records and an emergency medical database. The primary outcomes were survival and favorable neurologic outcome at discharge associated with the therapeutic hypothermia protocol. An adjusted analysis was performed, using a multivariate regression. During the therapeutic hypothermia period, 204 patients were brought to the emergency department; of these 204 patients, 132 (65%) ultimately achieved temperatures of <34 degrees C. Of the 72 patients who did not achieve goal temperatures: 40 (20%) died in the emergency department or shortly after being admitted to the hospital, 15 (7%) regained consciousness, four (2%) had contraindications, 13 (6%) had temperature increase or did not have documented use of the therapeutic hypothermia protocol. In the prior period, none of the 287 patients received active cooling. Patients admitted in the therapeutic hypothermia period had a mean esophageal temperature of 34.1 degrees C during the first 12 hrs compared with 35.2 degrees C in the pretherapeutic hypothermia period (p < .01). Survival to hospital discharge improved in the therapeutic hypothermia period in patients with an initial rhythm of ventricular fibrillation (odds ratio, 1.88, 95% confidence interval, 1.03-3.45), however not in patients with nonventricular fibrillation (odds ratio, 1.17, 95% confidence interval, 0.66-2.05). In adjusted analysis, ventricular fibrillation patients during the therapeutic hypothermia period trended toward improved survival (odds ratio, 1.71, 95% confidence interval, 0.85-3.46) and had favorable neurologic outcome (odds ratio, 2.62, 95% confidence interval, 1.1-6.27) compared with the earlier period. This benefit was not observed in patients whose initial rhythm was pulseless electrical activity or asystole. CONCLUSIONS: The therapeutic hypothermia period was associated with a significant improvement in neurologic outcomes in patients whose initial rhythm was ventricular fibrillation, but not in patients with other rhythms.

The use of pre-hospital mild hypothermia after resuscitation from out-of-hospital cardiac arrest.

Hypothermia has emerged as a potent neuroprotective modality following resuscitation from cardiac arrest. Although delayed hospital cooling has been demonstrated to improve outcome after cardiac arrest, in-field cooling begun immediately following the return of spontaneous circulation may be more beneficial. Cooling in the field following resuscitation, however, presents new challenges, in that the cooling method has to be portable, safe, and effective. Rapid infusion of intravenous fluid at 4 degrees C, the use of a cooling helmet, and cooling plates have all been proposed as methods for field cooling, and are all in various stages of clinical and animal testing. Whether field cooling will improve survival and neurologic outcome remains an important unanswered clinical question.

Pilot randomized clinical trial of prehospital induction of mild hypothermia in out-of-hospital cardiac arrest patients with a rapid infusion of 4 degrees C normal saline.

BACKGROUND: Although delayed hospital cooling has been demonstrated to improve outcome after cardiac arrest, in-field cooling started immediately after the return of spontaneous circulation may be more beneficial. The aims of the present pilot study were to assess the feasibility, safety, and effectiveness of in-field cooling. METHODS AND RESULTS: We determined the effect on esophageal temperature, before hospital arrival, of infusing up to 2 L of 4 degrees C normal saline as soon as possible after resuscitation from out-of-hospital cardiac arrest. A total of 125 such patients were randomized to receive standard care with or without intravenous cooling. Of the 63 patients randomized to cooling, 49 (78%) received an infusion of 500 to 2000 mL of 4 degrees C normal saline before hospital arrival. These 63 patients experienced a mean temperature decrease of 1.24+/-1 degrees C with a hospital arrival temperature of 34.7 degrees C, whereas the 62 patients not randomized to cooling experienced a mean temperature increase of 0.10+/-0.94 degrees C (P<0.0001) with a hospital arrival temperature of 35.7 degrees C. In-field cooling was not associated with adverse consequences in terms of blood pressure, heart rate, arterial oxygenation, evidence for pulmonary edema on initial chest x-ray, or rearrest. Secondary end points of awakening and discharged alive from hospital trended toward improvement in ventricular fibrillation patients randomized to in-field cooling. CONCLUSIONS: These pilot data suggest that infusion of up to 2 L of 4 degrees C normal saline in the field is feasible, safe, and effective in lowering temperature. We propose that the effect of this cooling method on neurological outcome after cardiac arrest be studied in larger numbers of patients, especially those whose initial rhythm is ventricular fibrillation.

Transthoracic incremental monophasic versus biphasic defibrillation by emergency responders (TIMBER): a randomized comparison of monophasic with biphasic waveform ascending energy defibrillation for the resuscitation of out-of-hospital cardiac arrest due to ventricular fibrillation.

BACKGROUND: Although biphasic, as compared with monophasic, waveform defibrillation for cardiac arrest is increasing in use and popularity, whether it is truly a more lifesaving waveform is unproven. METHODS AND RESULTS: Consecutive adults with nontraumatic out-of-hospital ventricular fibrillation cardiac arrest were randomly allocated to defibrillation according to the waveform from automated external defibrillators administered by prehospital medical providers. The primary event of interest was admission alive to the hospital. Secondary events included return of rhythm and circulation, survival, and neurological outcome. Providers were blinded to automated defibrillator waveform. Of 168 randomized patients, 80 (48%) and 68 (40%) consistently received only monophasic or biphasic waveform shocks, respectively, throughout resuscitation. The prevalence of ventricular fibrillation, asystole, or organized rhythms at 5, 10, or 20 seconds after each shock did not differ significantly between treatment groups. The proportion of patients admitted alive to the hospital was relatively high: 73% in monophasic and 76% in biphasic treatment groups (P=0.58). Several favorable trends were consistently associated with receipt of biphasic waveform shock, none of which reached statistical significance. Notably, 27 of 80 monophasic shock recipients (34%), compared with 28 of 68 biphasic shock recipients (41%), survived (P=0.35). Neurological outcome was similar in both treatment groups (P=0.4). Earlier administration of shock did not significantly alter the performance of one waveform relative to the other, nor did shock waveform predict any clinical outcome after multivariate adjustment. CONCLUSIONS: No statistically significant differences in outcome could be ascribed to use of one waveform over another when out-of-hospital ventricular fibrillation was treated.

Manual chest compression vs use of an automated chest compression device during resuscitation following out-of-hospital cardiac arrest: a randomized trial.

CONTEXT: High-quality cardiopulmonary resuscitation (CPR) may improve both cardiac and brain resuscitation following cardiac arrest. Compared with manual chest compression, an automated load-distributing band (LDB) chest compression device produces greater blood flow to vital organs and may improve resuscitation outcomes. OBJECTIVE: To compare resuscitation outcomes following out-of-hospital cardiac arrest when an automated LDB-CPR device was added to standard emergency medical services (EMS) care with manual CPR. DESIGN, SETTING, AND PATIENTS: Multicenter, randomized trial of patients experiencing out-of-hospital cardiac arrest in the United States and Canada. The a priori primary population was patients with cardiac arrest that was presumed to be of cardiac origin and that had occurred prior to the arrival of EMS personnel. Initial study enrollment varied by site, ranging from late July to mid November 2004; all sites halted study enrollment on March 31, 2005. INTERVENTION: Standard EMS care for cardiac arrest with an LDB-CPR device (n = 554) or manual CPR (n = 517). MAIN OUTCOME MEASURES: The primary end point was survival to 4 hours after the 911 call. Secondary end points were survival to hospital discharge and neurological status among survivors. RESULTS: Following the first planned interim monitoring conducted by an independent data and safety monitoring board, study enrollment was terminated. No difference existed in the primary end point of survival to 4 hours between the manual CPR group and the LDB-CPR group overall (N = 1071; 29.5% vs 28.5%; P = .74) or among the primary study population (n = 767; 24.7% vs 26.4%, respectively; P = .62). However, among the primary population, survival to hospital discharge was 9.9% in the manual CPR group and 5.8% in the LDB-CPR group (P = .06, adjusted for covariates and clustering). A cerebral performance category of 1 or 2 at hospital discharge was recorded in 7.5% of patients in the manual CPR group and in 3.1% of the LDB-CPR group (P = .006). CONCLUSIONS: Use of an automated LDB-CPR device as implemented in this study was associated with worse neurological outcomes and a trend toward worse survival than manual CPR. Device design or implementation strategies require further evaluation. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00120965.

Pilot study of rapid infusion of 2 L of 4 degrees C normal saline for induction of mild hypothermia in hospitalized, comatose survivors of out-of-hospital cardiac arrest.

BACKGROUND: Recent clinical studies have demonstrated that mild hypothermia (32 degrees C to 34 degrees C) induced by surface cooling improves neurological outcome after resuscitation from out-of-hospital cardiac arrest. Results from animal models suggest that the effectiveness of mild hypothermia could be improved if initiated as soon as possible after return of spontaneous circulation. Infusion of cold, intravenous fluid has been proposed as a safe, effective, and inexpensive technique to induce mild hypothermia after cardiac arrest. METHODS AND RESULTS: In 17 hospitalized survivors of out-of-hospital cardiac arrest, we determined the effect on temperature and hemodynamics of infusing 2 L of 4 degrees C cold, normal saline during 20 to 30 minutes into a peripheral vein with a high-pressure bag. Data on vital signs, electrolytes, arterial blood gases, and coagulation were collected before and after fluid infusion. Cardiac function was assessed by transthoracic echocardiography before fluid administration and 1 hour after infusion. Passive (fans, leaving patient uncovered) or active (cooling blankets, neuromuscular blockade) cooling measures were used to maintain mild hypothermia for 24 hours. Infusion of 2 L of 4 degrees C cold, normal saline resulted in a mean temperature drop of 1.4 degrees C 30 minutes after the initiation of infusion. Rapid infusion of fluid was not associated with clinically important changes in vital signs, electrolytes, arterial blood gases, or coagulation parameters. The initial mean ejection fraction was 34%, and fluid infusion did not affect ejection fraction or increase central venous pressure, pulmonary pressures, or left atrial filling pressures as assessed by echocardiography. Passive measures were ineffective in maintaining hypothermia compared with active measures. CONCLUSIONS: Infusion of 2 L of 4 degrees C cold, normal saline is safe and effective in rapidly lowering body temperature in survivors of out-of-hospital cardiac arrest.