Drug overdose poses a significant public health problem worldwide and accounts for thousands of deaths each year.1,2 Between 2004 and 2014, drug overdose caused nearly half a million deaths in the United States.1 In 2016, as many as 100,000 people older than 15 years died from drug overdose globally,1 and opioid overdose alone was responsible for about 70% of these deaths.2 Although the incidence of drug overdose has remained stable in the past few years, deaths from drug overdose have not reduced and continue to be a significant public health issue.1
Out-of-hospital cardiac arrest (OHCA) is a common pathophysiological mechanism of death following drug overdose and is relatively common among young adults.3-8 In a study conducted in London, United Kingdom, drug overdose accounted for 34% of OHCA cases and was concentrated among adults between the ages of 18 to 35 years.8 Similarly, drug overdose was the most common cause of OHCA (33.5%) in young adults aged 16 to 39 years in Melbourne, Australia.7
There is growing evidence that the incidence of OHCA precipitated by drug overdose is increasing in developed countries.5,6,9 In Ontario, Canada, the incidence of drug-overdose OHCA increased 9% between 2007 and 2013, and the number of deaths from drug overdose nearly tripled from 1.3 to 3.3 cases per 1000 people between 1992 and 2010.6 In 2011, approximately 8% of OHCAs in Pittsburgh, United States, were due to drug overdose, which is a three-fold increase from 1999.9 The widespread use of prescribed and recreational drugs is thought to be the key contributing factor to the increase in drug overdose OHCA.4-6
Emergency medical services (EMS) are often the first point of contact for most drug overdose-related events and can make a significant difference in reducing the burden of disease and illness from OHCA.3-6 A number of well-developed EMS systems have demonstrated that targeted improvements to the chain of survival, which focus on the early delivery of cardiopulmonary resuscitation (CPR) and defibrillation by members of the community, can yield substantial increases in the survival rate after OHCA.10-15 For example, in the United States, neurologically intact survival following OHCA of presumed cardiac etiology increased by 45% between 2005 and 2012.10 Similarly, there was a 53% increase in neurologically favorable survival in a nationwide study conducted in Japan between 2005 and 2009.11 However, much of the growth in survival following OHCA has occurred in populations with presumed cardiac etiology or initial shockable arrest rhythms, and these patients typically benefit from the early application of interventions such as bystander CPR and defibrillation.10-12,15
In comparison to OHCA of presumed cardiac etiology, cases of drug-overdose OHCA are usually unwitnessed and often present with asystole.3-6,16 As a result, it is unclear whether existing initiatives to tackle the low rate of survival from OHCA are useful in populations with non-cardiac etiologies, such as drug overdose. In addition, comparatively little is known about the global incidence and outcomes of drug-related OHCA. The lack of synthesized data can contribute to delays in the development of novel treatment interventions or preventive strategies, which can help minimize the burden of these events in the community.
A systematic review from 2010 examined the global incidence and outcomes of OHCA but focused mainly on cases with presumed cardiac etiologies.17 The review found that the global incidence of EMS-attended OHCA (i.e. all patients with OHCA attended by EMS irrespective of whether treatment was provided) was 83.7 cases per 100,000 person-years. The incidence of EMS-treated OHCA (i.e. patients receiving any attempt at resuscitation) was 34.7 per 100,000 person-years, and the rate of survival to hospital discharge was 7.1%. A preliminary literature search has been conducted through the Cochrane Database of Systematic Reviews, JBI Database of Systematic Reviews and Implementation Reports, and the databases of PROSPERO, MEDLINE and Embase, and found no systematic review, protocol or title published or underway on this topic. To date, studies investigating overdose OHCA have not been systematically assessed. Therefore, we aimed to systematically review the literature on the incidence and outcomes of adult OHCA precipitated by drug overdose. The findings of this review may help inform public health initiatives in the development of novel prevention and treatment strategies.
This review will consider studies, conducted worldwide, that include adult patients aged ≥ 15 years who are attended and/or treated by EMS for drug overdose. EMS-attended OHCA refers to all cases of OHCA attended by the EMS, irrespective of whether treatment has been provided. EMS-treated cases refer to the sub-group of EMS-attended OHCA who receive any attempt at resuscitation. Studies assessing only the pediatric population (aged <15 years) will be excluded.
Internationally agreed definitions for OHCA and drug-overdose OHCA have been reported.18 OHCA is defined as “the absence of signs of circulation irrespective of whether the assessment was made by EMS or bystander”.18(p.1288) OHCA precipitated by drug overdose is defined as “evidence that cardiac arrest was caused by deliberate or accidental overdose of prescribed medications, recreational drugs, or ethanol”.18(p.1290) This review will consider studies of drug overdose OHCA that are aligned with these definitions. Studies that have not clearly defined overdose but have used the terms “drug-related”, “overdose”, “poisoning” or “intoxication” as the cause of OHCA will be included. As the primary outcome of the study is to pool the global incidence and outcomes of an undifferentiated population of drug-related OHCA, we will exclude studies of selected or isolated cases of drug overdose (e.g. tricyclic antidepressant overdose or opioid overdose) or chemical poisoning (e.g. organophosphate or carbon monoxide poisoning), which could introduce heterogeneity.
We will include studies involving cardiac arrest populations in out-of-hospital settings. Studies of in-hospital cardiac arrest will be excluded.
The main outcome of this review is the pooled incidences rate of EMS-attended and EMS-treated OHCA cases per 100,000 people. Secondary outcomes include the pooled proportion of survivors to hospital discharge or 30 days, survivors with intact neurological function at hospital discharge, patients achieving return of spontaneous circulation, patients surviving to hospital, and patients surviving to 12 months.
Types of studies
This review will consider interventional studies including randomized controlled trials, non-randomized controlled trials, before and after studies, and interrupted time-series studies. In addition, both descriptive and analytical observational studies including retrospective and prospective cohort studies will be considered for inclusion. Studies published after January 1990 will be included; however, if a study collected data before 1990 but was published after 1990, it will be excluded. During 1990, the Utstein template for unified terms and definitions of OHCA was developed and implemented by many cardiac arrest registries.19 Our aim is to find studies with rigorous reporting and less heterogeneity so that we can have accurate estimates and summaries. Study designs that cannot be used to pool the incidence rates of EMS-attended and EMS-treated cases, including non-consecutive case series and case reports, will be excluded. Editorial letters will also be excluded.
We will use the Joanna Briggs Institute (JBI) methodology for systematic reviews of prevalence and incidence.20 The title of this review has been registered with JBI.
The search strategy aims to find published studies and unpublished studies written in English. We will use a three-step search strategy in this review. First, we will search MEDLINE and Embase using keywords specific for the topic (heart attack, cardiac arrest, cardiopulmonary resuscitation, drug overdose, substance abuse) (Appendix I). We will analyze text words contained in the titles and abstracts, and the index terms used to describe the topic. Second, we will search MEDLINE, Embase, Emcare, all EBM reviews (ACP Journal Club, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Cochrane Methodology Register, Database of Abstracts of Reviews of Effects, Health Technology Assessment, and National Health Service Economic Evaluation Database), and CINAHL using all relevant keywords and index terms. Third, we will identify relevant articles that are eligible for final inclusion and critical appraisal, and review their reference lists for potential studies that may have been missed in the initial search. The search for unpublished studies will include CORE, MedNar, Trove and the Resuscitation Outcomes Consortium.
Studies will be collated and uploaded using EndNote X7 (Clarivate Analytics, PA, USA), and duplicates will be removed. Two reviewers will independently review the titles and abstracts of all articles for relevant eligibility criteria. Discrepancies in included articles between reviewers will be resolved through mutual consensus. If not resolved, a third reviewer will make the final decision. A PRISMA flow chart will display the process of data search and inclusion.21
Assessment of methodological quality
Studies that will be considered for the review will be assessed by two independent reviewers. The JBI critical appraisal tools for studies reporting incidence data will be utilized and will be selected based on the type of study design.22 The reviewers will resolve any disagreements through consensus. If disagreements are not resolved, the consensus of a third reviewer will be sought. All studies, regardless of their methodological quality, will undergo data extraction and synthesis where possible.
We will develop a standardized data extraction form using Microsoft Excel (2013). This form is modified from the standardized data extraction tool for systematic reviews of prevalence and incidence developed by JBI.22 Main components of the form will include citation details, study details, demographics and clinical characteristics, and survival outcomes (Appendix II). The citation details include author(s) name, year of publication and aims. The study details include settings, study design and duration, total population and how overdose OHCA was defined. The patients’ demographics and clinical characteristics include the number of EMS-attended and EMS-treated cases, mean age, sex, and the percentage of cardiac arrest incidents that were witnessed by a bystander, received any attempt at CPR by a member of the public (i.e. bystander CPR), occurred in private residence and presented with shockable arrest rhythm. The survival outcomes include all outcomes that are described in the review questions. Two reviewers will extract data independently. Differences in data extraction will be resolved by discussion or a third opinion. If there are missing data, we will contact the main author for more clarification.
Quantitative data will be analyzed in STATA 15.0 (Stata Corp LLC, Texas, USA) for statistical meta-analysis using random-effects model because we assume that the true incidence and survival outcome estimates vary across studies. All results will undergo double data entry. First, the incidence rate for EMS-attended and EMS-treated drug-overdose OHCA will be calculated as the number of new cases divided by the average of the total population during that same period (person-years) multiplied by 100,000. The 95% confidence intervals (CI) will be calculated using the Poisson distribution.23 The DerSimonian and Laird method will be computed to pool incidence rates, with the estimate of heterogeneity taken from the inverse variance. Second, the proportions of survival outcomes will be calculated as the number of cases in each outcome divided by the EMS-treated cases. Because the proportions of survival outcomes in OHCA studies are below 0.5 and close to 0,24 we will enable the Freeman-Tuckey double arcsine transformation and use the score 95% CI for individual study.25
Third, subgroup analysis by study region and case definition (i.e. aligned with Utstein definition and not aligned with Utstein definition) will be conducted if sufficient data are available to explore sources of heterogeneity. Fourth, meta-regression will, where possible, be conducted using the random-effects model to assess if the rates of witnessed arrest status, bystander CPR and initial shockable arrest rhythm can explain any of the heterogeneity in survival proportions across studies. Heterogeneity will be assessed statistically using the standard Chi-square and I2 square tests. The I2 values of 25%, 50% and 75% will indicate low, moderate and high heterogeneity, respectively.26 The P value of < 0.10 will indicate significant heterogeneity. Where statistical pooling is not possible, the findings will be presented in narrative form including tables and figures to aid in data presentation where appropriate.
Appendix I: Search strategy
Appendix II Modified data extraction form
1. United Nations Office on Drug
and Crime. World drug
report [Internet]. New York: United Nations; 2016 [cited 15 October 2017]. Available from: https://www.unodc.org/wdr2016/
3. Paredes VL, Rea TD, Eisenberg MS, Cobb LA, Copass MK, Cagle A, et al. Out-of-hospital care of critical drug
overdoses involving cardiac arrest. Acad Emerg Med
2004; 11 1:71–74.
4. Koller AC, Salcido DD, Callaway CW, Menegazzi JJ. Resuscitation characteristics and outcomes in suspected drug overdose
-related out-of-hospital cardiac arrest
2014; 85 10:1375–1379.
5. Salcido DD, Torres C, Koller AC, Orkin AM, Schmicker RH, Morrison LJ, et al. Regional incidence and outcome of out-of-hospital cardiac arrest
associated with overdose
6. Orkin AM, Zhan C, Buick JE, Drennan IR, Klaiman M, Leece P, et al. Out-of-hospital cardiac arrest
survival in drug
-related versus cardiac causes in Ontario: a retrospective cohort study. PLoS ONE
7. Deasy C, Bray JE, Smith K, Harriss LR, Bernard SA, Cameron P. Out-of-hospital cardiac arrests in young adults in Melbourne, Australia. Resuscitation
2011; 82 7:830–834.
8. Donohoe RT, Innes J, Gadd S, Whitbread M, Moore F. Out-of-hospital cardiac arrest
in patients aged 35 years and under: a 4-year study of frequency and survival in London. Resuscitation
2010; 81 1:36–41.
9. Katz AZ, Grossestreuer AV, Gaieski DF, Abella BS, Kumar V, Perrone J. Outcomes of patients resuscitated from cardiac arrest in the setting of drug overdose
10. Chan PS, McNally B, Tang F, Kellermann A. Recent trends in survival from out-of-hospital cardiac arrest
in the United States. Circulation
2014; 130 21:1876–1882.
11. Kitamura T, Iwami T, Kawamura T, Nitta M, Nagao K, Nonogi H, et al. Nationwide improvements in survival from out-of-hospital cardiac arrest
in Japan. Circulation
2012; 126 24:2834–2843.
12. Nehme Z, Bernard S, Cameron P, Bray JE, Meredith IT, Lijovic M, et al. Using a cardiac arrest registry to measure the quality of emergency medical service care: decade of findings from the Victorian Ambulance Cardiac Arrest Registry. Circ Cardiovasc Qual Outcomes
2015; 8 1:56–66.
13. Perkins GD, Lockey AS, de Belder MA, Moore F, Weissberg P, Gray H. National initiatives to improve outcomes from out-of-hospital cardiac arrest
in England. Emerg Med J
2016; 33 7:448–451.
14. Wissenberg M, Lippert FK, Folke F, Weeke P, Hansen CM, Christensen EF, et al. Association of national initiatives to improve cardiac arrest management with rates of bystander intervention and patient survival after out-of-hospital cardiac arrest
2013; 310 13:1377–1384.
15. Stromsoe A, Svensson L, Axelsson AB, Claesson A, Goransson KE, Nordberg P, et al. Improved outcome in Sweden after out-of-hospital cardiac arrest
and possible association with improvements in every link in the chain of survival. Eur Heart J
2015; 36 14:863–871.
16. Claesson A, Djarv T, Nordberg P, Ringh M, Hollenberg J, Axelsson C, et al. Medical versus non medical etiology in out-of-hospital cardiac arrest
--changes in outcome in relation to the revised Utstein template. Resuscitation
17. Berdowski J, Berg RA, Tijssen JG, Koster RW. Global incidences of out-of-hospital cardiac arrest
and survival rates: systematic review of 67 prospective studies. Resuscitation
2010; 81 11:1479–1487.
18. Perkins GD, Jacobs IG, Nadkarni VM, Berg RA, Bhanji F, Biarent D, et al. Cardiac arrest and cardiopulmonary resuscitation
outcome reports: update of the Utstein Resuscitation Registry Templates for Out-of-Hospital Cardiac Arrest
: a statement for healthcare professionals from a task force of the International Liaison Committee on Resuscitation (American Heart Association, European Resuscitation Council, Australian and New Zealand Council on Resuscitation, Heart and Stroke Foundation of Canada, InterAmerican Heart Foundation, Resuscitation Council of Southern Africa, Resuscitation Council of Asia); and the American Heart Association Emergency Cardiovascular Care Committee and the Council on Cardiopulmonary, Critical Care, Perioperative and Resuscitation. Circulation
2015; 132 13:1286–1300.
19. Cummins RO, Chamberlain DA, Abramson NS, Allen M, Baskett PJ, Becker L, et al. Recommended guidelines for uniform reporting of data from out-of-hospital cardiac arrest
: the Utstein Style. A statement for health professionals from a task force of the American Heart Association, the European Resuscitation Council, the Heart and Stroke Foundation of Canada, and the Australian Resuscitation Council. Circulation
1991; 84 2:960–975.
20. Munn Z, Moola S, Lisy K, Riitano D, Tufanaru C. Methodological guidance for systematic reviews of observational epidemiological studies reporting prevalence and cumulative incidence data. Int J Evid Based Healthc
2015; 13 3:147–153.
21. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. J Clin Epidemiol
2009; 62 10:1006–1012.
22. Munn Z, Moola S, Lisy K, Riitano D, Tufanaru C. Chapter 5: Systematic reviews of prevalence and incidence. In: Aromataris E, Munn Z, eds. Joanna Briggs Institute Reviewer's Manual [Internet]. Adelaide (AU): The Joanna Briggs Institute; 2017 [cited 8 February 2018]. Available from: https://reviewersmanual.joannabriggs.org
23. Flanders WD, Kleinbaum DG. Basic models for disease occurrence in epidemiology. Int J Epidemiol
1995; 24 1:1–7.
24. Sasson C, Rogers MA, Dahl J, Kellermann AL. Predictors of survival from out-of-hospital cardiac arrest
: a systematic review and meta-analysis. Circ Cardiovasc Qual Outcomes
2014; 3 1:63–81.
25. Nyaga VN, Arbyn M, Aerts M. Metaprop: a Stata command to perform meta-analysis of binomial data. Arch Public Health
2014; 72 39:1–10.
26. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ
2003; 327 7414:557–560.