Effect of Adrenaline on Survival in Out-of-Hospital Cardiac Arrests: A Randomized Double-Blind Placebo-Controlled Trial
- Hem Patel
The study shepherded by Jacobs et al juxtaposed the effect of adrenaline on survival in out-of-hospital cardiac arrests with a randomized double-blind placebo controlled trial. This study was the first of its kind to address the knowledge deficit of two majors goals: survival of the patient to a hospital discharge and return of spontaneous circulation (ROSC). Cardiac arrest occurring out of hospital is a significant public health issue causing fatality rates upwards of 90%, although improving in the recent decades.1 Thus, the researchers analytically examined the relationship between the uses of adrenaline in such patients through a randomized control led trial (RCT) in the region of Western Australia (WA), under government contract with St John Ambulance Western Australia (SJA-WA).
Being on top of the studies’ hierarchy, RCT studies like this one, quite evidently fortified the experiment’s internal validity. The creation of comparable groups in the study allowed the control of confounding variables enhancing the internal validity.
An investigation, such as RCT, decrease s the sampling bias by decreasing the likelihood of chance results occurring, enhancing the internal validity of the study which was evident in the Jacob study. The investigation was further augmented by logistic regression modeling which was undertaken to control for the effect of potential confounders (i.e. the patients’ initial cardiac rhythm, age and ambulance response time) on the relationship between study drug and patient outcome . 1 Although, as a result of a small sample size, often the case with RCTs, and specific geographical demographics, limited external validity was a given. This was evident in this study as four of the five hospitals requested to participate felt the ethi cality of the study superseded thei r own ethical board, negatively. Hence, the total number of patients being able to participate in this study had quite drastically decreased, in turn hampering the power of the study. However, two very crucial experimental qualities in high precision and internal validity were upheld consistently throughout the experiment, in spite of the very limited external validity.
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out-of-hospital cardiac arrests attended by SJA-WA paramedics between 11 August 2006 and 30th November 2009 were screened into the experiment for entry into the trial1 . 1 Patients suffering a cardiac arrest from any cause, aged 18 years or older with resuscitation commenced by paramedics were eligible for entry as well; indicating a moderately strict eligibility and inclusion criteria. Patients were excluded based on having no resuscitation commenced, were of an age less than 18 years, eligible patients’ personal declinatio n and randomization number of patient lost/As noticed, the external validity along with confounding bias of the study decreased due to the increased criterion required for a patient to take part in the trial. It may look as if few categories were used to determine the eligibility of the patient, though many factors such as patient age, male gender, bystander witnessed, response interval, and the study drug were accounted for through univariate analysis. The only confounding variable stated by the study is the factor of initial shockable rhythm (when a particular type of cardiac rhythm is treatable using a defibrillation) – one that is not very significant in changing the efficacy of adrenaline in out-of-hospital cardiac arrests. Being able to eliminate th ese potential confounding variable s and biases, internal validity increased showing that the lack of a causal relationship less likely to be an upshot of an uncontrolled confounding variable, rather than one accounted for.
In regards to a RCT stud y, a sample size of 534 patients, one that of a moderate size , out of which 272 were randomly assigned to the group being treated with adrenaline and 262 to that of the placebo group.1 . 1 As each of the patients had a completely equal chance to be presented with either of the treatments, this randomization of the participants controlled for a potentiality of a sampling bias – a chance yet again enhancing the internal validity. Additionally, although very diminutive confounding bias was associated with this study, it was unable to exclude the potential for selection bias as the participation in the study by the SJA-WA paramedics was voluntary, only 40% of eligible patients were recruited. However, trial patients were well matched on baseline characteristics .1 , . This ed
As mentioned above, as resuscitation commenced by paramedics, the patients were eligible for entry, where if they were administered adrenaline it would be at a rate of 1mL every 3 minutes, with no other drugs entering through tracheal administration. Prior to the commencement of each trial to be presented with an equal chance of the level of treatment for each of these patients specific training of the pharmacology of adrenaline, familiarization with the trial protocol, further practice in intravenous cannulation and cardiac simulation exercises along with testing was undertaken to ensure the prerequisite resuscitation competency standard had been achieved. This training was provided to all of the paramedics in the WA area regardless of their intention to participate in the study; being able to decline confounding bias from the patient-care givers’ aspect, enhancing the internal validity.Analyzed above are many aspects of the study that allow for a study to be very well received by majority of the readers, although there were a couple of limitations. Firstly, the researchers were unable to achieve full patient recruitment as planned (4103 patients who had cardiac arrests attended by an ambulance). This study was designed as a multicenter trial involving a five-ambulance service , despite having ethical approval four out of five hospitals opted otherwise. Thus giving the study a moderate sample size, increasing the chance of making a type two error ; essentially decreasing both the internal validity and the power of the study. The failure to achieve an adequate sample size left the trial underpowered to detect significant effects on survival to hospital discharge.1 The second was the ability to continue as the study drugs their expiry date and no additional funding was available. Grant ing blinding was well preserved in this study the researchers can consider the likelihood of these factors being differentially distributed between the two study arms (placebo vs. adrenaline) to be small.
Odds ratio (OR) were used to quantify how strongly the presence of the outcome was associated with the presence of the administered adrenaline versus the placebo saline solution 2 .
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Results indicated the OR for ROSC achieved pre-hospital patients at 3.4 (95% confidence interval [CI] 2.0-5.6; P<0.001) indicating a significant increase in the number of patients in comparison to those tested with saline placebo. The outcomes dictate an approximate 16% greater advantage of achieving ROSC pre-hospital with the administration of adrenaline than having the placebo. Statistical significance is generally considered at 20%, but in aspects dealing with topic as such, upwards of 5% could statistically mean more to the medical community; allowing to save more lives. 3 At an OR of 2.2 (95% confidence interval [CI] 0.7 – 6.3; P = 0.15) indicates no difference between the two testing groups with the p-value greater than that of the alpha value of 0.05. Results are further negatively supported by the CI including the value of 1, demonstrating statistical insignificance; decreasing the study’s precision in this aspect of the outcome, although balanced by the significance in the previous outcome.
The findings of this study are equivocal to several other clinical trials designed
the efficacy of adrenaline in cardiac arrest. The most dominant feature about this study is that it is the first ever-randomized placebo-controlled clinical trial of adrenaline in cardiac arrest, while others all have been non-randomized trials. Research conducted by Olasveengen et al a lso reported a doubling in the proportion of patients achieving ROSC with an OR of 1.99 (95% confidence interval [CI] 1.48-2.67), and achieving similar non-significant increasing results in the proportion surviving to hospital discharge . 4 Jacob’s study , although further expanded on the generality of the efficacy of drug to locations of arrests, ambulance response interval, cardiac arrest witnessed (bystander and paramedic) and airway management .1
Three sources of Mill’s Canons were evidently utilized to support the causality. The strength of association was statistically significant, as noted by the greater effect of adrenaline in ROSC being achieved pre-hospital transportation. An increase dosage of adrenaline would directly increase ROSC, and possibly an increase number of patients survive to hospital discharge.1, 5Adrenaline stimulates β-adrenergic receptors which stimulate the increase of blood flow indicates the final Mill’s Canon in biological plausibility. Thus, it can be noticed that a causal relationship can be agreed upon adrenaline and increased ROSC being achieved pre-hospital.
In my opinion, the study was
done extremely well, providing sufficient evidence for a relationship between the adrenaline and an increase ROSC in 18 and above out-of-hospital cardiac arrests. With the elimination of a majority of the biases, through the use of logistical regression and creating comparable groups internal validity and the precision of the study was enhanced. The findings of this study are clinically important in that it established efficacy for the continuous use of adrenaline in cardiac arrest as currently recommended . 5 With a study related to such a topic, the sample size should adequately be increased to allow for a greater power and external validity in the study; allowing a generalization to a greater portion of the public.
- Jacobs IG, Finn JC, Jelinek GA, Oxer HF, Thompson PL. Effects of adrenaline on survival in out-of-hospital cardiac arrest: a randomized double-blind placebo-controlled trial.resuscitation2011; 82: 1138-1143.
- Szumilas, M. Explaining odds ratios.National Center for Biotechnology Information2010; 19(3): 227-229. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2938757/ (accessed 28 October 2014).
- Pocock, SJ. Clinical trials with multiple outcomes: a statistical perspective on their design, analysis, and interpretation.Elsevier1997; 97.
- Olasveengen TM, Sunde K, Brunborg C, Thowsen K, Steen PA, Wik I. Intravenous drug administration during out-of-hospital cardiac arrest: a randomized trial.JAMA2009; 302: 2222-2229.
- Vandycke C, Martens P. High dose versus standard dose epinephrine in cardiac arrest – a meta-analysis.Resuscitation2000; 45: 161-166
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