Hardly any other medical intervention is as directly relevant for life-and-death outcomes
as cardiopulmonary resuscitation (CPR). One would have expected, therefore, extensive
evidence from rigorous randomized controlled trials (RCTs) for fine-tuning best approaches
that maximize CPR effectiveness. However, this is not the case. Professional guidelines
reflect little tangible progress, and recommendations are not driven by strong effects
seen in RCTs.
To map the landscape of meta-analyses of RCTs on CPR, we searched PubMed (April 8,
2019) for “cardiopulmonary resuscitation AND meta-analysis AND (randomized OR randomised).”
We screened 114 retrieved items for meta-analyses of RCTs in real patients (not education
or simulation/manikins), addressing aspects pertaining to CPR per se rather than interventions
done afterwards (e.g., hypothermia) and using survival and/or neurologically intact
survival as outcomes. Whenever multiple overlapping meta-analyses existed, we kept
all of them if they were published after 2013, to examine consistency of results.
The available evidence (Table 1) suggests that we have a dearth of interventions that
improve survival rates at hospital discharge and, even less so, neurological outcomes
[1–12]. All benefits, if any, pertain to out-of-hospital cardiac arrest circumstances,
while no new technology or improvement seems to work for in-hospital arrests. For
out-of-hospital cardiac arrests, continuous (versus interrupted) chest compressions,
epinephrine, and use of endotracheal tube intubation (versus supraglottic airway devices)
may achieve modest increases in survival at hospital discharge. However, the lower
95% confidence intervals of the risk ratios in the most recent, inclusive meta-analyses
on these interventions reach down to 1.00–1.02. Therefore, we cannot exclude that
even these benefits are negligible or even non-existent. Survival with neurologically
intact outcome is not conclusively increased by any of the interventions listed in
the Table 1; epinephrine achieves a nominally statistically significant modest benefit
over pooled control treatments, but this is less clear in separate comparisons against
different control options. Epinephrine saves some patients who are admitted to the
hospital, but they are not discharged neurologically intact. Other interventions also
have disappointing results, e.g., no clear benefit is seen with mechanical devices
for chest compression (they are even harmful for in-hospital cardiac arrest) and the
order of chest compression versus defibrillation may not matter.
Table 1
Meta-analyses of randomized controlled trials with survival and neurologically intact
survival as outcomes
Comparison (setting)
N randomized
Outcome measures (timing) [N]
Relative risk (95% CI)
Heterogeneity
Chest compressions
Meier et al. [1]
Chest compression-first vs. defibrillation-first (OHCA)
1503
Survival (HD) [N = 1503]
OR 1.10 (0.70–1.70)
I
2 = 34%, p = 0.206
CPC 1–2 (HD) [N = 402]
OR 1.02 (0.31–3.38)
I
2 = 75%, p = 0.05
Long-term survival (1 year) [N = 1301]
OR 1.38 (0.95–2.02)
I
2 = 0.0%, p = 0.647#
Brooks et al. [2] and updated 2014 [3]
Mechanical vs. standard manual chest compressions (OHCA and IHCA)
868 and 1166¥
Survival (HA) [N = 164]
Not pooled
Studies not pooled
CPC 1–2 (HD) [N = 767]
RR 0.41 (0.21–0.79)
Single study
Survival (HD) [N = 1063]
Not pooled
Studies not pooled
Gates et al. [4]
Mechanical vs. standard manual chest compressions (OHCA)
12,206
Survival (HA) [N = 7208]
OR 0.95 (0.85–1.07)
I
2 = 0.0%, p = 0.78
Survival (HD or 30 days) [N = 12,206]
OR 0.89 (0.77–1.02)
I
2 = 0.0%, p = 0.49
CPC 1–2 or RS 0–3 (HD) [N = 12,206]
OR 0.76 (0.53–1.11)
I
2 = 68%, p = 0.02
Tang et al. [5]
Mechanical vs. manual chest compressions (OHCA)
12,510
Survival (HA) [N = 12,510]
RR 0.94 (0.89–1.00)
I
2 = 0.0%, p = 0.48
Survival (HD) [N = 12,510]
RR 0.88 (0.78–0.99)
I
2 = 27%, p = 0.24
CPC 1–2 or RS 0–3 (HD) [N = 12,058]
RR 0.80 (0.61–1.04)
I
2 = 65%, p = 0.04
Long-term survival (≥ 6 months) [N = 7060]
RR 0.96 (0.79–1.16)
I
2 = 16%, p = 0.28
Li et al. [6]
Mechanical vs. manual chest compression (OHCA and IHCA)
11,162
Survival (HA), OOH group [N = 9975]
RR 0.97 (0.91–1.04)
I
2 = 60%, p = 0.015
Survival (HD), OOH group [N = 4688]
RR 0.99 (0.82–1.18)
I
2 = 71%, p = 0.004
Survival (HD), IH group [N = 200]
RR 0.54 (0.29–0.98)
I
2 = 0.0%, p = 0.825
CPC 1–2 (HD), OOH group [N = 8885]
RR 1.11 (0.95–1.30)
I
2 = 59%, p = 0.032
Zhan et al. [7]
Continuous (+/− rescue breathing) vs. interrupted chest compression with pauses for
breaths (OHCA)
26,742¶
Survival (HA) [N = 520]
RR 1.18 (0.94–1.48)
Single study
Survival (HD) [N = 3031]
RR 1.21 (1.01–1.46)
I
2 = 0.0%, p = 0.68
CPC 1–2 (HD) [N = 1286]
RR 1.25 (0.94–1.66)
Single study
Adrenaline
Lin et al. [8]
SDA vs. placebo (OHCA)
12,246
Survival (HA) [N = 534]
RR 1.95 (1.34–2.84)
Single study
Survival (HD) [N = 534]
RR 2.12 (0.75–6.02)
Single study
CPC 1–2 (HD) [N = 534]
RR 1.73 (0.59–5.11)
Single study
SDA vs. HDA (OHCA)
Survival (HA) [N = 5699]
RR 0.87 (0.76–1.00)
I
2 = 34%, p = 0.21
Survival (HD) [N = 5638]
RR 1.04 (0.76–1.42)
I
2 = 0.0%, p = 0.66
CPC 1–2 (HD) [N = 3883]
RR 1.20 (0.74–1.96)
I
2 = 0.0%, p = 0.33
SDA vs. vasopressin (OHCA)
Survival (HA) [N = 336]
Not pooled
Single study
Survival (HD) [N = 336]
RR 0.68 (0.25–1.82)
Single study
CPC 1–2 (HD) [N = 336]
RR 0.68 (0.25–1.82)
Single study
SDA vs. vasopressin/adrenaline (OHCA)
Survival (HA) [N = 4877]
RR 0.88 (0.73–1.06)
I
2 = 56%, p = 0.06
Survival (HD) [N = 4877]
RR 1.00 (0.69–1.44)
I
2 = 25%, p = 0.26
CPC 1–2 (HD) [N = 4807]
RR 1.32 (0.88–1.98)
I
2 = 0.0%, p = 0.85
Kempton et al. [9]
Epinephrine vs. placebo (OHCA)
17,635
Survival (HA) [N = 9511]
OR 2.52 (1.63–3.88)
I
2 = 84%, p < 0.0001
Survival (HD) [N = 9805]
OR 1.09 (0.48–2.47)
I
2 = 77%, p = 0.0002
CPC 1–2 or RS 0–3 (HD) [N = 9383]
OR 0.81 (0.34–1.96)
I
2 = 83%, p = 0.0005
Finn et al. [10]
SDA vs. placebo (OHCA and IHCA)
21,704
Survival (HA) [N = 8489]
RR 2.51 (1.67–3.76)
I
2 = 77%, p = 0.04
Survival (HD) [N = 8538]
RR 1.44 (1.11–1.86)
I
2 = 0.0%, p = 0.45
Neurological outcome (HD) [N = 8535]
RR 1.21 (0.90–1.62)
I
2 = 0.0%, p = 0.49
SDA vs. HAD (OHCA and IHCA)
Survival (HA) [N = 5764]
RR 1.13 (1.03–1.24)
I
2 = 0.0%, p = 0.42
Survival (24 h) [N = 4179]
RR 1.04 (0.76–1.43)
I
2 = 39%, p = 0.16
Survival (HD) [N = 6274]
RR 1.10 (0.75–1.62)
I
2 = 24%, p = 0.23
Neurological outcome (HD) [N = 5803]
RR 0.91 (0.65–1.26)
I
2 = 0.0%, p = 0.42
SDA vs. vasopressin (OHCA and IHCA)
Survival (HA) [N = 1953]
RR 1.27 (1.04–1.54)
I
2 = 27%, p = 0.25
Survival (HD) [N = 2511]
RR 1.25 (0.84–1.85)
I
2 = 29%, p = 0.22
Neurological outcome (HD) [N = 2406]
RR 0.82 (0.54–1.25)
I
2 = 0.0%, p = 0.46
SDA vs. SDA + vasopressin (OHCA)
Survival (HA) [N = 3249]
RR 0.95 (0.83–1.08)
I
2 = 0.0%, p = 0.55
Survival (HD) [N = 3242]
RR 0.76 (0.47–1.22)
I
2 = 0.0%, p = 0.57
Neurological outcome (HD) [N = 2887]
RR 0.65 (0.33–1.31)
Single study
Vargas et al. [11]
Epinephrine vs. control (OHCA)
20,716
Survival (HA) [N = 20,306]
RR 1.02 (0.75–1.39)
I
2 = 96.21%, p < 0.01
Survival (HD) [N = 19,909]
RR 1.16 (1.00–1.35)
I
2 = 0.0%, p = 0.49
CPC 1–2 or similar (HD) [N = 18,458]£
RR 1.24 (1.05–1.48)
I
2 = 0.0%, p = 0.94
Airway management
White et al. [12]
Endotracheal tube intubation vs. supraglottic airway devices (OHCA)
539,146
Survival (HA) [N = 51,756]
OR 1.36 (1.12–1.66)
I
2 = 91%, p = 0.002
Survival (HD) [N = 440,564]
OR 1.28 (1.02–1.60)
I
2 = 96%, p = 0.03
CPC 1–2 or RS < 3 [HD] [N = 438,261]
OR 1.16 (0.94–1.41)
I
2 = 91%, p = 0.16
HA hospital admission, HD hospital discharge, RS Rankin score, OHCA out-of-hospital
cardiac arrest, IHCA in-hospital cardiac arrest, SDA standard dose adrenaline, HAD
high-dose adrenaline
¶Randomized and quasi-randomized studies
¥From randomized controlled trials, cluster-randomized controlled trials, and quasi-randomized
studies
£CPC 1–2, an overall performance category 1–2, a modified Rankin Scale score 1–2,
and a normal or moderate disability
This rather disheartening evidence pertains largely to short-time follow-up. Longer-term
outcomes are essential to make informed choices, but these data are rarely available
from RCTs. One can try to supplement the evidence gap with observational datasets,
and this is becoming increasingly convenient as large datasets become routinely available.
However, for what are likely to be modest or subtle differences, it is unlikely that
observational data will be sufficiently error-free to be conclusive. Many observational
studies in this field claim sizeable survival differences, but their credibility is
questionable—they need to be validated in carefully done RCTs [13]. For example, a
highly cited observational study has found that endotracheal intubation is harmful
for in-hospital arrest [14]. The availability of data on over 100,000 patients results
in a very tight 95% confidence interval for neurological outcome and an astronomically
low p value. However, this precision is misleading because potential bias may completely
invalidate this conclusion.
In contrast to massive observational datasets, the RCTs done to-date and even their
meta-analyses have usually had rather limited sample sizes. Clinically meaningful
differences between the tested interventions may still have been missed, e.g., 20%
relative risk differences in survival cannot be completely excluded for anything that
has been tested to-date. This suggests that we need much larger RCTs in this field.
Given that CPR is so commonly required, large simple trials should be feasible to
do in large enough health care structures. It is important to instill in the future
research agenda a strong element of pragmatism, so that the results would be more
directly applicable to real-life circumstances. CPR is a good example where “point
of care” randomization should be feasible without obtaining consent first given the
nature of the intervention. Randomization should be the default option for CPR encounters
if a protocol has been approved and set in place. RCTs with sample sizes in the tens
of thousands of participants should be the goal.
A challenge in conducting such large-scale pragmatic RCTs is to avoid diluting the
potential therapeutic effects by poor choices in the background management of the
resuscitated patients. For example, an intervention may be effective by itself, but
whatever benefit it produces may be lost if the patients undergo low-quality chest
compressions or if they are then sub-optimally managed in the intensive care setting,
e.g., improper choices are made for hypo- or hyper-ventilation. Meeting both pragmatism
and some essential quality standards needs careful design and proper background training
of the resuscitating and managing teams.
Another challenge is selecting the proper dose of various interventions to be tested.
Several standard choices in the CPR ritual have little evidence to support that the
dose, intensity, timing, or frequency used is optimized. For example, the standard
dose of adrenalin (1 mg) is largely based on an experiment done over a century ago
in 10-kg dogs, in which adrenaline was given at a dose of 0.1 mg/kg. While we have
some randomized evidence on higher doses, we have no evidence on lower than standard
doses. Timing may also be important. For example, another high-profile recent trial
[15] administered epinephrine in patients who were largely “dead” (at 20 min post-arrest)
and this may have affected its ability to be effective.
Finally, single interventions may have very limited efficacy and effectiveness, but
their combination may manage to achieve a breakthrough in success rates. Testing this
hypothesis would require running factorial trials, where two randomizations are performed
concurrently. Then, one can assess both interventions as well as their joint effect
in a statistically efficient manner.
CPR may save lives, and optimizing it should not be left to chance. A rigorous agenda
of large pragmatic RCTs is long due. With simple design, the cost of these trials
can be minimized, since data collection would pertain to only the most relevant information.
Health care systems, insurances, and public agencies could make excellent investments
in funding such trials.