`doi:10.1093/jurban/jti053
` The Author 2005. Published by Oxford University Press on behalf of the New York Academy of Medicine. All rights
`reserved. For permissions, please e-mail: journals.permissions@oupjournals.org
`Advance Access publication May 4, 2005
`
`Naloxone Distribution and Cardiopulmonary
`Resuscitation Training for Injection Drug Users
`to Prevent Heroin Overdose Death: A Pilot
`Intervention Study
`
`Karen H. Seal, Robert Thawley, Lauren Gee,
`Joshua Bamberger, Alex H. Kral, Dan Ciccarone,
`Moher Downing, and Brian R. Edlin
`
`ABSTRACT Fatal heroin overdose has become a leading cause of death among injection
`drug users (IDUs). Several recent feasibility studies have concluded that naloxone distri-
`bution programs for heroin injectors should be implemented to decrease heroin over-
`dose deaths, but there have been no prospective trials of such programs in North
`America. This pilot study was undertaken to investigate the safety and feasibility of
`training injection drug using partners to perform cardiopulmonary resuscitation (CPR)
`and administer naloxone in the event of heroin overdose. During May and June 2001,
`24 IDUs (12 pairs of injection partners) were recruited from street settings in San
`Francisco. Participants took part in 8-hour training in heroin overdose prevention,
`CPR, and the use of naloxone. Following the intervention, participants were prospec-
`tively followed for 6 months to determine the number and outcomes of witnessed her-
`oin overdoses, outcomes of participant interventions, and changes in participants’
`knowledge of overdose and drug use behavior. Study participants witnessed 20 heroin
`overdose events during 6 months follow-up. They performed CPR in 16 (80%) events,
`administered naloxone in 15 (75%) and did one or the other in 19 (95%). All overdose
`victims survived. Knowledge about heroin overdose management increased, whereas
`heroin use decreased. IDUs can be trained to respond to heroin overdose emergencies
`by performing CPR and administering naloxone. Future research is needed to evaluate
`the effectiveness of this peer intervention to prevent fatal heroin overdose.
`
`KEYWORDS Heroin, Heroin-related deaths, Injection drug use, Overdose, Prevention.
`
`INTRODUCTION
`
`Dramatic increases in the incidence of fatal opiate overdose have shadowed bur-
`geoning heroin epidemics in several countries.1,2 In the United States, each year,
`more injection drug users (IDUs) die from heroin overdose than from any other
`cause, including AIDS, hepatitis, or homicide.3 In fact, heroin overdose was the single
`
`Dr. Seal is with the Department of Medicine, San Francisco VA Medical Center, University of California,
`San Francisco, California; Mr. Thawley, Ms. Gee, Dr. Kral, Dr. Ciccarone, Mr. Downing, and Dr. Edlin are
`with The Urban Health Study, University of California, San Francisco, California; Dr. Bamberger is with
`the San Francisco Department of Public Health, San Francisco, California; and Dr. Edlin is also with the
`Center for the Study of Hepatitis C, Weill Medical College of Cornell University, New York, New York.
`Correspondence: Karen H. Seal, Department of Medicine, San Francisco VA Medical Center, Univer-
`sity of California, San Francisco, 4150 Clement Street, Box 111-A1, San Francisco, CA 94121. (E-mail:
`karens@itsa.ucsf.edu)
`
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`largest cause of accidental death in San Francisco, California from 1997 to 2000.4
`Many of these deaths are preventable because heroin overdose can be readily
`reversed through the timely injection of naloxone, a legal, unscheduled opiate
`antagonist routinely used by emergency medical personnel to quickly and safely
`reverse opiate overdose.5 Peers witness most overdoses,6 but deaths occur because
`drug users are hesitant to summon emergency medical services for fear of police
`involvement7,8 and their attempts at resuscitation are often unsuccessful.8,9
`Naloxone effectively reverses opiate overdose. Naloxone precipitates acute
`withdrawal symptoms in opiate-dependent persons, but has no effect on nonopi-
`ate users; serious adverse effects are rare and naloxone has no abuse potential.9
`Several feasibility studies have concluded that if injection heroin users were pro-
`vided naloxone and resuscitation training, including training in CPR and rescue
`breathing, they might be able to intervene to prevent heroin overdose fatalities
`in their peers.8,10,11 Recently, through both underground and government-
`sponsored programs, naloxone has been made available to drug users in
`Germany, Italy,12,13 and in the United States, in Baltimore, Maryland, Chicago,
`Illinois14 and Rio Arriba County, New Mexico.15 There have been no formal
`evaluations of these programs however, and thus their effectiveness has not been
`established.14,16,17
`Although naloxone is not routinely prescribed to laypersons in the United
`States, naloxone distribution programs are being planned or considered in the
`United States—in other localities including New York City, New Haven, Connecti-
`cut, and several counties in Northern California. These programs have encountered
`political barriers, however, owing to concerns that naloxone will be viewed by drug
`users as a “safety net,” thus enabling more drug use, increasing the number of over-
`doses, and decreasing the use of emergency services.18 Moreover, while the legality
`of prescribing naloxone to laypersons for use in others who overdose has been
`called into question by politicians and physicians alike, a recent legal analysis pro-
`vides justification for the prescription of naloxone.5 To date, there have been no
`prospective trials of naloxone distribution in North America to investigate these
`specific concerns. In collaboration with the San Francisco Department of Public
`Health, the Urban Health Study at the University of California, San Francisco devel-
`oped and implemented a pilot overdose prevention and management program to
`train heroin injectors to perform cardiopulmonary resuscitation (CPR) and admin-
`ister naloxone to injection partners in the event of a heroin overdose emergency.
`Participants were followed for 6 months to investigate the safety and feasibility of
`this intervention.
`
`METHODS
`
`Study Participants
`During May and June 2001, 487 IDUs participating in the Urban Health Study, a
`semiannual cross-sectional serosurveillance study of injection drug users (IDUs),
`were recruited from street settings in San Francisco and screened for enrollment.
`IDUs were eligible if they injected heroin at least twice a week, reported one or
`more heroin overdoses in the past 5 years, and could enroll together with an eligible
`injection partner who met the same criteria. The study was approved by the University
`of California, San Francisco Committee on Human Research, and each participant
`provided written informed consent.
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`The Overdose Prevention and Management Program
`Twenty-four eligible, consenting IDUs enrolled in the study in pairs and underwent
`overdose prevention and management training in July and August 2001. The over-
`dose prevention and management program was modeled after existing community-
`based naloxone distribution programs in Chicago and San Francisco19 and consisted
`of four 2-hour interactive training sessions facilitated by experienced counselors.
`Sessions were held at convenient community-based field sites, and participants were
`reimbursed for their time at each session. Before beginning the training sessions,
`study staff met with local police to describe the program and to apprise them that
`participants would be carrying naloxone and using it in the event of an overdose.
`Moreover, police were educated about users’ reluctance to call 911 for an overdose
`because of the perception that arrests were made in conjunction with these emer-
`gency overdose calls.
`In Session 1 of the program, participants acknowledged the impact of heroin
`overdose on their lives by describing past experiences with heroin overdose including
`the loss of friends and family. Subsequently, participants were trained to recognize a
`life-threatening heroin overdose, defined as being unresponsive, with or without
`cyanosis, and/or as having slowed, shallow or absent respirations. Overdose preven-
`tion strategies were reviewed which included not using alcohol or sedatives together
`with heroin, not injecting alone, and starting with smaller doses after a period of
`abstinence or when using heroin from an unfamiliar source. Session 2 was hands-on;
`participants learned to perform rescue breathing and CPR and practiced emergency
`overdose resuscitation with their injection partners. (Fig. 1)
`Accessing emergency medical services (calling 911) after using naloxone for an
`overdose was the focus of Session 3. Staff reviewed the importance of definitive
`medical help to manage any complications of the overdose, including the victim’s
`withdrawal symptoms, after receiving naloxone. Participants listed barriers to calling
`911 for an overdose including lack of access to a telephone and fear of police arrest.
`Participants role-played calling 911 in such a way as to elicit a rapid medical
`response without necessarily triggering police involvement. In Session 4, partici-
`pants learned to safely and appropriately administer naloxone using the contents of
`the naloxone kit (see below). Participants were instructed to inject one 0.4 mg dose
`of naloxone intramuscularly and repeat in 5 minutes if the victim remained unre-
`sponsive. Finally, they developed and rehearsed individualized rescue plans to be
`used by their partner in the event the other overdosed.
`
`The Naloxone Kit
`Under the auspices of the San Francisco Department of Public Health, study physi-
`cians dispensed a labeled naloxone kit to each participant contingent on successful
`completion of the training program. Each kit included two 0.4 mg prefilled injection
`cartridges of naloxone with two injection devices, gloves, a rescue breathing mask,
`and detailed instructions all packaged inside a plastic case that also contained a safe
`compartment for used needles (Fitpacks, ASP Harm Reduction Systems, Australia).
`(Fig. 2) We chose to use 0.4 mg prefilled, single-dose, injection devices to minimize
`the likelihood of severe opiate withdrawal reactions from larger doses, eliminate the
`need to draw up the medication during an emergency, assure the availability of a
`sterile needle and injection device when it was needed, and reduce the likelihood of
`infectious disease transmission through a nonsterile syringe or multi-dose vial.20
`Participants were given a written prescription for naloxone in case they needed
`additional evidence that they were carrying a legally prescribed drug.
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`FIGURE 1. Participants practicing naloxone injection with their injection partner during the over-
`dose prevention and management program.
`
`Data Collection and Statistical Methods
`Participants were interviewed monthly for 6 months. Data were collected on over-
`dose-related knowledge, overdoses witnessed or experienced by study participants,
`and drug and alcohol use. Knowledge was assessed by asking participants to name
`identifying features of heroin overdose, risk factors for overdose, and overdose pre-
`vention and management strategies.
`Participants were asked to contact study staff as soon as possible after witness-
`ing or experiencing an overdose. Participants were interviewed in-depth after each
`overdose they witnessed or experienced, usually within 24–48 hours. Overdose
`events, including specific details, were confirmed by interviewing one or two witnesses.
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`FIGURE 2.
`
`The naloxone kit.
`
`To further verify the overdose event, when possible, records were obtained from
`San Francisco Emergency Medical Services, local hospital emergency departments,
`and the medical examiner. We excluded one death reported by a participant
`because it could not be confirmed by witnesses, paramedics, police, or hospital, or
`medical examiner records.
`Frequencies were calculated for categorical variables and medians with inter-
`quartile ranges (IQR) were calculated for continuous variables. Questions testing
`knowledge of overdose prevention and management were scored, and the scores
`were dichotomized and compared with baseline using a McNemar’s Q test.
`Number of overdoses, drug use frequency, and entry into drug treatment were
`compared at baseline and during 6 months of follow-up by using Wilcoxon
`signed-rank test for ordinal outcomes and a McNemar’s Q test for dichotomous
`outcomes.21
`
`RESULTS
`Twelve pairs of injection partners (n = 24 IDUs) enrolled and all completed the over-
`dose prevention and management program. Of the participants, 33% were female,
`46% African American, 54% white and 54% homeless. The median age was 41
`years (IQR = 34–49 years), and the median duration of injection drug use was 22
`years (IQR = 11–28 years). There were no statistically significant demographic dif-
`ferences between the 24 participants in the Overdose prevention and management
`program and the other 463 participants in the Urban Health Study.
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`From August 2001 through January 2002, participants reported witnessing 20
`heroin overdoses. (Table 1) In three (15%) cases, the victim was the participant’s
`study partner, in 12 (60%), an acquaintance, and in five (25%), a stranger. Study
`participants described the overdose victim as unresponsive in 87% of cases, cyan-
`otic in 70%, and not breathing in 57%; in all 20 cases, the victim was described as
`cyanotic or not breathing. Participants intervened in all 20 heroin overdose events.
`They performed CPR and rescue breathing in 16 (80%) overdose events, adminis-
`tered naloxone in 15 (75%), and did one or the other in 19 (95%). Emergency
`medical services were called by participants in two cases and by other witnesses in
`four cases. In one of these cases, a participant reported being harassed by police,
`but was not arrested. Reasons cited for not summoning emergency services were
`fear of police involvement and possible arrest in 10 (50%) cases, no nearby phone
`in five (25%), and a perceived lack of need in five (25%). All 20 overdose victims
`survived.
`After 6 months of follow-up, participants’ knowledge of heroin overdose pre-
`vention and management had increased. (Table 2) The frequency of heroin injection
`decreased (P = .003). The number of heroin overdoses experienced by participants
`was similar in the 6 months before and after the intervention (5 vs. 3, P = 0.83).
`Fourteen study participants entered drug treatment during the 6 months of follow-
`up. No arrests occurred and no participants were prosecuted for using naloxone
`prescribed for them for another overdose victim.
`
`DISCUSSION
`
`This pilot trial is the first in North America to prospectively evaluate a program of
`naloxone distribution to IDUs to prevent heroin overdose death. After an 8-hour
`training, our study participants’ knowledge of heroin overdose prevention and man-
`agement increased, and they reported successful resuscitations during 20 heroin
`overdose events. All victims were reported to have been unresponsive, cyanotic, or
`not breathing, but all survived. These findings suggest that IDUs can be trained to
`respond to heroin overdose by using CPR and naloxone, as others have reported.12,19
`Moreover, we found no evidence of increases in drug use or heroin overdose in
`study participants. These data corroborate the findings of several feasibility studies
`recommending the prescription and distribution of naloxone to drug users to pre-
`vent fatal heroin overdose.8,10,22
`
`Interventions performed by study participants in response to witnessed heroin
`TABLE 1.
`overdose events
`
`Interventions performed
`
`Naloxone used
`With CPR only
`With CPR and 911 call
`With rescue breathing only
`Without other intervention
`Naloxone not used
`CPR only
`CPR and 911 call
`Victim taken to emergency department
`911 call only
`
`Number of overdose events (N = 20)
`
`fifteen
`6
`3
`3
`3
`five
`2
`2
`1
`0
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`TABLE 2. Knowledge and behavior among study participants (N = 24) before and after the
`overdose prevention and management program
`
`
` Knowledge or behavior
`
`At baseline
`N (%)
`
`At 6 months follow-up
`N (%)
`
`
`
`
`
`Knowledge >50% correct responses
`Identifying a heroin overdose
`Risk factors for heroin overdose
`Heroin overdose prevention strategies
`Correct uses of naloxone
`Number heroin overdoses in past 6 months
`0
`1
`2
`Heroin injections during past 30 days.
`None
`1–29
`30–59
`60–89
`90+
`Drug treatment entry
`
`
`
`0 (0)
`2 (8)
`1 (6)
`21 (91)
`
`19 (83)
`3 (13)
`1 (4)
`
`3 (13)
`4 (17)
`2 (8)
`4 (17)
`11 (46)
`8 (35)
`
`13 (53)
`16 (68)
`8 (32)
`23 (95)
`
`21 (88)
`3 (12)
`0 (0)
`
`
`
`7 (37)
`7 (37)
`3 (16)
`2 (11)
`0 (0)
`14 (60)
`
` P-value
`
`
`<0.001
`0.003
`0.040
`1.000
`
`
`
`
`
`0.829
`—
`—
`
`0.003
`—
`—
`—
`—
`0.16
`
`Despite being trained to summon emergency medical services, participants
`called 911 in only two of the 20 overdose events, as other studies have found,
`largely because of fear of police intervention.7,18 In fact, we found that within the
`6-month follow-up period, no participant arrests occurred for possessing or using
`naloxone to resuscitate overdose victims. Our results indicate that more work needs
`to be done to ensure that drug users access emergency services when provided
`naloxone, yet until drug users’ perceptions change, they will likely resist calling for
`help. Thus, at present, putting life-saving interventions such as CPR, rescue breathing,
`and naloxone in the hands of drug users themselves may prevent unnecessary over-
`dose fatalities.23 Furthermore, forging a partnership with law enforcement and
`implementing policies that shield drug users from police harassment, arrest, or
`other legal consequences of accessing emergency services may be central to the suc-
`cess of a naloxone distribution program.
`Contrary to initial concerns about naloxone distribution, we found decreased
`heroin use among participants, even though the program did not advocate reduc-
`tion in drug use, abstinence, or drug treatment. The training program was interac-
`tive, capitalizing on participants’ prior overdose experiences and empowering them
`with additional knowledge and training. This may have increased self-efficacy and
`motivated participants to decrease drug use despite having the “safety net” of
`naloxone. Most of the overdose interventions occurred in nonstudy participants,
`confirming that IDUs are willing to intervene to resuscitate a peer in the event of
`overdose.18,24 These results suggest that limiting naloxone training and distribution
`to IDUs with stable injection partners may not be necessary.
`This pilot study was limited by the small sample, lack of a control group, possi-
`ble selection bias of motivated participants, and reliance on self-reported data. We
`were unable to quantify the number of lives saved because we had no way of know-
`ing how many of the 20 reported overdose victims would have died had our trained
`
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`study participant and naloxone not been available. Controlled trials of naloxone
`distribution may be problematic however as withholding naloxone, considered a
`life-saving intervention, from one group, raises ethical concerns. The overdose
`events were self-reported, but were corroborated by one or more witnesses and
`when possible, hospital, police, emergency medical services, and medical examiner
`records. Self-reported data from drug users recruited outside clinical settings have
`been shown to have high validity.25,26 Future studies should evaluate overdose pre-
`vention and management training and the prescription and distribution of naloxone
`to larger numbers of heroin users.
`Millions of dollars are spent annually to train lay people in CPR because
`bystander CPR can reduce mortality in sudden out-of-hospital cardiac arrest although
`no randomized study, to our knowledge, has ever shown a benefit from community
`CPR training programs.27 Few of those trained attain and retain competency in the
`technique, most rarely if ever perform it, and most people who receive bystander CPR
`do not survive.28,29 Heroin overdose, in contrast, can be quickly, easily, safely, and
`effectively reversed with naloxone, a medication that costs between $1 and $2 per
`dose. In a follow-up study of 891 laypersons, 6 months after CPR training, no one
`had performed CPR on a real victim.30 We trained 24 IDUs, and in 6 months they
`reported 20 resuscitations, with 100% survival and no evident adverse consequences.
`In the current political climate in the United States, drug policies that deviate
`from “zero tolerance” are considered a political liability, and the prescription of
`naloxone to heroin injectors has not been widely adopted. Nevertheless, on the
`basis of our study results, the San Francisco Department of Public Health recently
`began training IDUs and distributing naloxone as part of a comprehensive overdose
`prevention program. Our data suggest that providing drug users training in CPR
`and the use of naloxone may be a safe and feasible option for preventing heroin
`overdose fatalities and may be helpful for other localities considering the implemen-
`tation of naloxone distribution programs.
`
`ACKNOWLEDGEMENT
`
`The authors are grateful to Jon-Paul Hammond, Ro Giuliano, Matty Luv, Dan Bigg
`and the Harm Reduction Training Institute for their important contributions to the
`overdose prevention and management program. Photographs produced by Reid Thaler.
`
`REFERENCES
`
`1. Sporer KA. Strategies for preventing heroin overdose. BMJ. 2003;326:442–444.
`2. Drucker E, Garfield J. Overdose trends in five US cities: 1988–1997. Paper presented at:
`Preventing Heroin Overdose: pragmatic approaches; January 13–14, 2000; Seattle,
`Washington, DC.
`3. Latkin CA, Hua W, Tobin K. Social network correlates of self-reported non-fatal over-
`dose. Drug Alcohol Depend. 2004;73:61–67.
`4. Davidson PJ, McLean RL, Kral AH, Gleghorn AA, Edlin BR, Moss AR. Fatal heroin-
`related overdose in San Francisco, 1997–2000: a case for targeted intervention. J Urban
`Health. 2003;80:261–273.
`5. Burris S, Noreland J, Edlin B. Legal aspects of providing naloxone to heroin users in the
`United States. Int J Drug Policy. 2001;12:237–248.
`6. Darke S, Zador D. Fatal heroin “overdose”: a review. Addiction. 1996;91:1765–1772.
`7. Powis B, Strang J, Griffiths P, et al. Self-reported overdose among injecting drug users in
`London: extent and nature of the problem. Addiction. 1999;94:471–478.
`
`Opiant Exhibit 2192
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`
`
`NALOXONE DISTRIBUTION AND CARDIOPULMONARY RESUSCITATION TRAINING
`
`311
`
`8. Strang J, Best D, Man L, Noble A, Gossop M. Peer-initiated. Int J Drug Policy.
`2000;11:437–445.
`9. Sporer KA. Acute heroin overdose. Ann Intern Med. 1999;130:584–590.
`10. Strang J, Powis B, Best D, et al. Preventing opiate overdose fatalities with take-home
`naloxone: pre-launch study of possible
`impact and acceptability. Addiction.
`1999;94:199–204.
`11. Darke S, Hall W. The distribution of naloxone to heroin users. Addiction.
`1997;92:1195–1199.
`12. Dettmer K, Saunders B, Strang J. Take home naloxone and the prevention of deaths
`from opiate overdose: two pilot schemes. BMJ. 2001;322:895–896.
`13. Ronconi S. Prevention of overdoses among current heroin users in Torino Italy for the
`period 1995–1998. Paper presented at: Preventing Heroin Overdose: pragmatic
`approaches; January 13–14, 2000; Seattle, Washington, DC.
`14. Bigg D. Data on take home naloxone are unclear but not condemnatory (letter). BMJ.
`2002;324:678.
`15. Baca C, Richards M, Grant KJ. Take-home naloxone to prevent deaths from opiate over-
`dose [rapid response]. BMJ [serial online]. May 21, 2001. Available at: http://bmj.com/
`cgi/eletters/322/7291/895 14648.
`16. Mountain D. Take home naloxone for opiate addicts. Big conclusions are drawn from
`little evidence. BMJ. 2001;323:934.
`17. Ashworth AJ, Kidd A. Take home naloxone for opiate addicts. Apparent advantages
`may be balanced by hidden harms. BMJ. 2001;323:935.
`18. Seal KH, Downing M, Kral AH, et al. Attitudes about prescribing take-home naloxone
`to injection drug users for the management of heroin overdose. J Urban Health.
`2003;80:291–301.
`19. Chicago Recovery Alliance. CRA’s opiate overdose prevention program 2002 and opiate
`overdose prevention/intervention training slide show [on-line]. Available at: http://
`www.anypositivechange.org/res.html.
`20. Centers for Disease Control and Prevention. Transmission of hepatitis B and C viruses in
`outpatient settings—New York, Oklahoma, and Nebraska, 2000–2002. MMWR Morb
`Mortal Wkly Rep. 2003;52:901–906.
`21. SAS Release. Version 8.02. (1999–2001) by SAS Institute Inc., Cary, NC, USA.
`22. Lenton SR, Hargreaves KM. Should we conduct a trial of distributing naloxone to heroin
`users for peer administration to prevent fatal overdose? Med J Aust. 2000;173:260–263.
`23. Dietze P, Cantwell K, Burgess S. Bystander resuscitation attempts at heroin overdose:
`does it improve outcomes? Drug Alcohol Depend. 2002;67:213–218.
`24. Broadhead RS, Heckathorn DD, Weakliem DL, et al. Harnessing peer networks as an
`instrument for AIDS prevention: results from a peer-driven intervention. Public Health
`Rep. 1998;113:42–57.
`25. Watters JK, Needle R, Brown BS, Weatherby N, Booth R, Williams M. The self-reporting
`of cocaine use. JAMA. 1992;268:2374–2375.
`26. Dowling-Guyer S, Johnson ME, Fisher DG, et al. Reliability of drug users’ self-reported HIV
`risk behaviors and validity of self-reported recent drug use. Assessment. 1994;1:383–392.
`27. Cobb LA, Hallstrom AP. Community-based cardiopulmonary resuscitation. what have
`we learned? Ann N Y Acad Sci. 1982;382:330–342.
`28. Brennan RT, Braslow A. Skill mastery in public CPR classes. Am J Emerg Med.
`1998;16:653–657.
`29. Becker LB, Ostander MP, Barrett J, Kondos GT. Outcome of CPR in a large metropolitan
`area—where are the survivors? Ann Emerg Med. 1991;20:355–361.
`30. Pane GA, Salness KA. A survey of participants in a mass CPR training course. Ann
`Emerg Med. 1987;16:1112–1116.
`
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