Use of Sodium Nitrite in Out of Hospital Cardiac Arrest

Overview

Cardiac arrest is a medical problem with major adverse health impacts.  In the United States 225,000 people per year will die from cardiac arrest before reaching the hospital.  Many more may never leave the hospital, or will do so severely disabled.

Following cardiac arrest, the brain and other organs are often injured due to a lack of blood and oxygen.  Some patients will recover and wake up.  However, a majority of patients resuscitated from cardiac arrest never awaken, despite the excellent care they receive.  In other words, these patients never regain enough neurologic function to allow them to follow commands or to have comprehensible speech.

Effective treatments to protect the brain and other organs from the damage that accompanies cardiac arrest would allow more patients to awaken after cardiac arrest and survive to hospital discharge.  To date, studies using various drugs have failed to improve outcome after cardiac arrest.  Researchers continue to look for new therapies that may improve the patient’s chance of improved neurologic outcome and survival.

Based on studies on animals have shown that nitrite, given during cardiac arrest, may improve outcome.  Researchers at the University of Washington based at Harborview Medical Center are planning to conduct a large study of induced NITRITE in patients who have out of hospital cardiac arrest.  It is thought that giving NITRITE outside the hospital may improve neurologic outcome and survival in this group of patients. 

The “Use of Sodium NITRITE in Out of Hospital Cardiac Arrest” (NITRITE study) study is being conducted under the U.S. Food and Drug Administration (FDA) “emergency waiver of consent” guidelines.  This means patients are enrolled in the study without their prior consent.  Federal regulations do not allow patients to be enrolled in a study without their informed consent or without the consent of their next of kin.  However, in certain limited situations, such as emergency medicine research, the U.S. Food and Drug Administration (FDA) allow some studies to be conducted without prior consent.  In order to be able to do a study using “waiver of consent” requirements established by the FDA must be met.  These requirements are:

  • Patient cannot give consent
  • Patient may benefit from the research
  • Research project could not be done without this waiver of consent
  • Researcher agrees to inform patient or family at a later time
  • Researcher asks the community
  • UW Review Board approved study

Administration of NITRITE during cardiac arrest is considered experimental.  It is allowed by the United States Food and Drug Administration (FDA) in research studies only. 

The first part of this trial will enroll 100 patients who will receive nitrite.  This will be a dose finding trial to see if the amount of drug given during cardiac arrest produces therapeutic blood levels.  The larger study, to follow, will enroll 1000 patients treated for cardiac arrest by the Seattle Fire Department.  Half of these patients with receive nitrite and half will receive placebo. The potential risks involved in this trial include the risk of decreased blood pressure.  There are safety measures built into the plan to minimize any of these risks.  In the studies cited above there have not been any of these complications reported.  However there may be unknown or unexpected risks.

We have conducted community surveys to gauge interest and the community’s willingness to participate in this trial even though informed consent cannot be obtained.  There was strong support for the study:  1. Over 82% of those surveyed were in favor of this study to be carried out in Seattle 2. Nearly 66% of surveyed individuals would be willing to be a part of the study.  About 50% of non-white respondents would be willing to be part of the study.

Some of the information provided in this website might be difficult to understand.  If this is the case please view the consent form located under the "consent form" tab or contact us at 206-521-1588 where you will be able to get more information about the study.  If you leave a voice message your call will be returned. 

Opting out of this study.

Patients who do not want to participate in this study can request an opt-out bracelet to wear. The opt-out bracelets may be obtained by calling the research coordinator and this bracelet will need to be worn all the time.  If the patient suffers an out-of-hospital cardiac arrest and the arriving paramedics find that the patient is wearing this opt out bracelet, the patient WILL NOT BE enrolled.

Frequently Asked Questions

Cardiac arrest is a serious medical condition. During a cardiac arrest the heart stops beating effectively and is unable to pump oxygenated blood to the brain and the rest of the organs of the body. It usually occurs suddenly and unexpectedly. If untreated, death occurs within minutes.

Cardiac arrest can happen in any place. If the cardiac arrest occurs anywhere outside of the hospital it is referred to as an out-of-hospital cardiac arrest.

Cardiac arrest is the number one killer of Americans each year. It kills more than 450,000 people annually.

The most common underlying reason for patients to die suddenly from cardiac arrest is coronary heart disease. These people are at varying risks for cardiac arrest. In general, those with damaged hearts are at greater risk. Specific risk factors include a previous episode of cardiac arrest, a history of heart failure and a family history of sudden cardiac arrest. Other factors besides heart disease can cause cardiac arrest. They include respiratory arrest, electrocution, drowning, choking and drug overdoses. Cardiac arrest can also occur without any identifiable cause.

The first step in the treatment of an out-of-hospital cardiac arrest is quick identification of the problem. This can be done by checking for signs of life (consciousness, movement, normal breathing). Once a cardiac arrest is confirmed, quick access to the 911 system is essential. The standard treatment for cardiac arrest is immediate CPR, which can be started by citizens before emergency medical providers are on the scene. Once the emergency medical providers are on scene they continue CPR. Many times an electrical shock or shocks are given to the heart to try and restore a normal heartbeat. This is called defibrillation. Other procedures to treat patients in cardiac arrest are the placement of electrodes to monitor the heart’s electrical rhythm, the placement of an intravenous line (needle into the vein) to give fluids and medications and the placement of an endotracheal tube (tube into the lungs) to provide breathing.

During a cardiac arrest, while the heart is not pumping effectively, the brain and other organs are left without oxygen. This can lead to cell damage and even death. After a successful resuscitation, these organs, especially the brain, also face more damage from chemical reactions that occur when the blood starts to flow again.

Sodium nitrite is a common ingredient added to processed meats and fish that helps preserve the food and prevent bacterial growth that can cause botulism. This food additive also adds attractive color to meat and fish. Sodium nitrite is also naturally present in many fruits and vegetables (such as beets) and some investigators believe that nitrite is essential to maintain vascular health. Its use as a food preservative, however, has been linked to harmful health effects. However this is believed to occur when nitrite preserved meats are subjected to high temperatures (frying bacon), which may modify nitrite to a form, which may be more harmful.

Sodium nitrite (given at high doses- 300 mg) is also an approved medication that has been used for years to treat cyanide poisoning. Sodium nitrite is carried by Seattle paramedics and is also available in all of the emergency departments in Seattle.

Nitrite is given through an IV at a dose, which is almost 1/10th of dose given for cyanide poisoning. In this study it will be administered once the medics have established an IV and during resuscitation, It will be given as a onetime dose.

The benefits of nitrite have been shown in laboratory and animal experiments. These benefits include: a). anti-inflammatory effects; b) antithrombotic effects (prevents blood clots) c). scavenger of reactive oxygen species (these species have been linked to tissue damage) and d). protects cells from irreversible damage.

Yes. A small study was completed at Harborview Medical Center in 11 resuscitated cardiac arrest patients. Doses up to 10 mg were given to patients who were resuscitated by paramedics and admitted to the hospital. No significant side effects were noted in all of the patients who received sodium nitrite following cardiac arrest. Important information on the proper dose of sodium nitrite to achieve a therapeutic level was also obtained.

The full name of the larger NITRITE study is the “Use of Nitrite in Out of Hospital Cardiac Arrest” trial. The purpose of the study is to test the hypothesis that NITRITE given to patients in the field by paramedics will increase the number of patients who survive.

The first phase of this trial wills enroll 100 patients. All 100 of the patients will receive nitrite. This will be a dose finding trial to see if the amount of drug given during cardiac arrest produces therapeutic blood levels. The larger study, to follow, will enroll 1000 patients treated for cardiac arrest by the Seattle Fire Department. All patients will receive the regular medical treatment for cardiac arrest. In addition, half of these patients with receive nitrite and half will receive placebo. The potential risks involved in this trial include the risk of decreased blood pressure. There are safety measures built into the plan to minimize any of these risks. In patients who have received the drug there have not been any of these complications reported. However there may be unknown or unexpected risks.

In order to test whether NITRITE initiated before hospital arrival results in better outcome, hospital data will be collected. This data includes survival data and neurologic assessment at hospital discharge.

All subjects over the age of 18 years treated by the Seattle Fire Department for a cardiac arrest during the study period may be eligible for the study. The cardiac arrest cannot be due to trauma such as a gunshot wound, stabbing, severe motor vehicle accident, etc. NITRITE in this group of patients has not been studied.

If a subject is eligible for the trial he or she will have a 50% chance of receiving the NITRITE treatment. This is decided at random or by chance, like flipping a coin. We believe that this type of study, called a randomized trial, will enable the truest determination of the best approach for the treatment of cardiac arrest. This will be a double blinded trial. This means that neither the subjects of the experiment nor the persons administering the experiment know the treatment being administered. A double-blind procedure is used to guard against both experimenter bias and placebo effects".

The main potential risk involved in this trial included a decreased blood pressure. There may also be unknown or unexpected risks as a result of the study because giving nitrite during cardiac arrest is experimental. If this occurs, the paramedics will give medicines to correct this condition.

Obtaining an “informed consent” from victims of cardiac arrest is impossible as the participant is unconscious and the family is either not immediately available or extremely distraught.  To allow researchers to possibly improve the survival rate of individuals suffering from a life-threatening condition, the US Food and Drug Administration (FDA) has issued guidelines for the consent to be waived in emergency circumstances, as long as the research has the prospect of direct benefit to the patient.  In order to be able to do a study using an “emergency waiver of consent” the following requirements established by the FDA must be met.

  • A life-threatening situation with unproven or unsatisfactory treatment where research is necessary to improve outcome.
  • Obtaining informed consent is not feasible because the patient is unresponsive and treatment must begin immediately.
  • Participation in research has the prospect of direct benefit because the situation necessitates an intervention, science supports the potential of direct benefit and the risks of the research are reasonable compared to the medical condition.
  • The research could not practicably be done without waiver of informed consent.
  • The potential therapeutic window is short (in the case of cardiac arrest, treatment needs to be given within minutes)
  • The researchers must develop informed consent procedures they will implement when it is possible to obtain consent.
  • An Institutional Review Board (IRB) must approve the study.

This study meets these FDA requirements.

Participants or their legally authorized representative will be contacted as soon as possible after enrollment into the study. The purpose of this contact will be to provide information about the study and in some cases to ask permission for continued participation in the trial. Continuation in the trial means allowing access to medical records.

In an attempt to inform as many people as possible before the research begins, the researchers are required to disclose to the public the nature, risks and benefits of the study. The researchers want to provide the community with information about this study and an opportunity for people to ask questions about the potential risks and benefits involved. The researchers want to gather information from the community and inform as many people as possible about the study before, during, and after the research is conducted. This is being done through a variety of means:

  1. The information provided in this website
  2. Random digit telephone survey
    A random sample of 400 Seattle area households were called and asked their opinion of waiver of consent and whether or not they would want the NITRITE treatment given to them without their consent.
  3. Seattle event community survey
    A sample of 242 attendees at the Bite of Seattle completed a questionnaire asked their opinion of waiver of consent and whether or not they would want the NITRITE treatment given to them without their consent.

The subject or their legally authorized representative (LAR) will be notified soon after enrollment into the study. The subject or their LAR will be given written information about the trial and have an opportunity to ask questions.

By law, researchers must protect the privacy of health information about subjects. We make every effort to keep the information confidential. All subjects enrolled in the trial will be assigned a code number. This code number is used on any data we collect. A key linking the subject to the code number is kept locked in a secure location and will be available to the investigators. Once this study is completed this key will be destroyed.

Yes, it is possible to opt out of this study. Patients who do not want to participate in this study can request an opt-out bracelet to wear. This bracelet needs to be worn during the time the study is being conducted in order to be identified as someone not wishing to be included in it. The bracelet will advise those seeing it about your wishes. However there is no guarantee that wearing this bracelet will prevent you from being treated in this trial. If you do get treated as part of this research trial please realize that the special treatment provided in this trial is in addition to all standard treatments and not in place of them. In the unlikely event that you are treated in this trial we will not use any of the information collected about you. Opt-out bracelets may be obtained by contacting the research coordinator.

Investigators from the University of Washington based at Harborview Medical Center will conduct the study.

Principal Investigator:

Francis Kim, MD
Department of Medicine/Division of Cardiology
Harborview Medical Center

Co-investigators:

Michele Olsufka, RN
Research Nurse Coordinator
Department of Medicine/Division of Cardiology
Harborview Medical Center

Graham Nichol, MD
Department of Medicine
Harborview Medical Center

Michael Sayre, MD
Harborview Medical Center
Medical Director: Seattle Medic One

Peter Kudenchuk, MD
Department of Medicine/Division of Cardiology
Harborview Medical Center

We anticipate that the NITRITE study will contribute to a better understanding of how we can improve the treatment of patients that experience cardiac arrest. We hope that this study will improve outcomes from this very serious condition.  We are very interested in your comments. 

Please call or email Michele Olsufka, RN, Research Coordinator for Seattle at 206-521-1588 or olsufka@u.washington.edu with any questions or comments regarding the NITRITE study. 

Address

Harborview Medical Center
325 9th Ave
Box 359748
Seattle, WA 98104

Research Materials

  • Information Sheet
  • Consent Form
  • HIPPA Form

Community Consultation information

  • Press Release
  • Random Digit Dialing Survey
  • Bite of Seattle Community Event Survey
  • Union Gospel Mission Community Survey

Publications

Dezfulian C, Shiva S, Alekseyenko A, Pendyal A, Beiser DG, Munasinghe JP, et al. Nitrite therapy after cardiac arrest reduces reactive oxygen species generation, improves cardiac and neurological function, and enhances survival via reversible inhibition of mitochondrial complex I. Circulation. 2009;120(10):897-905.

Jung KH, Chu K, Ko SY, Lee ST, Sinn DI, Park DK, et al. Early intravenous infusion of sodium nitrite protects brain against in vivo ischemia-reperfusion injury. Stroke. 2006;37(11):2744-50.

Jung K-H, Chu K, Lee S-T, Park H-K, Kim J-H, Kang K-M, et al. Augmentation of nitrite therapy in cerebral ischemia by NMDA receptor inhibition. Biochemical and Biophysical Research Communications. 2009;378(3):507-12.

Dezfulian C, Alekseyenko A, Dave KR, Raval AP, Do R, Kim F, et al. Nitrite Therapy is Neuroprotective and Safe in Cardiac Arrest Survivors. Nitric Oxide. 2012;26(4):241-50.

Contact Us

Michele Olsufka RN, Research Coordinator – Seattle
Phone: 206-521-1588

Mailing address:
Harborview Medical Center
Department of Medicine/Division of Cardiology
325 9th Avenue
Box 359748
Seattle, WA 98104-2499