Purpose

Sudden cardiac arrest (CA) is defined as the sudden interruption of spontaneous circulation and represents a major public health problem by annually affecting more than 420,000 patients in the USA and between 30,000 and 50,000 in France [1]. About 85% of CA occur in the out-of-hospital settings [1]. The survival rate from out of hospital cardiac arrest (OHCA) is poor, nearby of 5% at hospital discharge [2]. However, the survival rate from OHCA related to "shockable" rhythm (ventricular fibrillation (VF) and pulseless ventricular tachycardia (VT)) is better, around 30% at hospital discharge [3].

Advanced life support (ALS) for OHCA related to "shockable" rhythm is based on external electric shock (EES), and after 3 unsuccessful EES, on anti-arrhythmic drug administration. Two drugs are classically recommended in this indication known as CA by "refractory" shockable rhythm: amiodarone (300 mg intravenously (IV)) as first line, and lidocaine (1 mg/kg IV) as second line [2,4,5]. Nevertheless, according to studies published in the literature, whereas these two drugs may increase the rate of return of spontaneous circulation (ROSC) and/or the rate of patients admitted alive in hospital, it should be noted that the results are much more mixed regarding survival at 3 months and/or at hospital discharge, which is the “strong” criterion generally used to assess survival after OHCA [6]. These negative results in terms of survival can probably be explained by the pharmacokinetic and pharmacodynamic properties of the two antiarrhythmic molecules, amiodarone and lidocaine. Amiodarone, which is a class III antiarrhythmic agent according to the Vaughan-Williams classification, has many side effects and in particular a bradycardizing effect and a negative dromotropic effect (slowing down of conduction), both more pronounced during high-dose administration and intravenously, which is the case during refractory OHCA. Lidocaine, which is a class Ib antiarrhythmic agent according to the Vaughan-Williams classification, induces a myocardial depressant effect, characterized by hypotension, myocardial depression and bradycardia. It is therefore perfectly possible that the beneficial effects of these 2 molecules in terms of immediate ROSC would be counterbalanced by their negative cardiovascular side effects "persistent" after high dose IV administration, and thus ultimately do not allow any improvement in survival upon discharge from hospital. Consequently, it appears through the analysis of the literature that no molecule is more effective than a placebo in terms of survival at discharge from hospital in patients with OHCA due to VF or no-pulse VT, refractory to 3 EES. Other pharmacological research pathways are therefore necessary to try to improve the prognosis of these patients.

During surgical procedures performed under extracorporeal circulation (ECC), in particular cardiac valvular and/or coronary surgery, a cardioplegia solution is administered to interrupt the mechanical activity of the heart and thus facilitate the surgical procedure. Many cardioplegia solutions are available, varying in their chemical composition. Patho-physiologically, the essential element of these solutions is always represented by at a high concentration in potassium chloride, usually between 20 and 30 mmol/l [7]. The direct intravenous administration of this solution is then responsible for a transient hyperkalaemia, which has the immediate consequence of lowering the membrane resting potential of the myocytes, causing the cessation of their electrical and mechanical activity, and consequently inducing the immobility of the myocytes of the heart muscle. While these cardioplegia solutions are effective in stopping myocardial electrical activity during ECC implementation, some authors have by extension evaluated their effectiveness in interrupting VF. Since the first scientific publication by Weinstock and Clark in 1961 describing the administration of KCl in a 3-year-old child presenting with CA with refractory VF during an impossible intubation in the operating room, several cases series and human clinical studies have reported the efficacy and the safety of KCl injection to convert refractory VF or no-pulse VT [7–12]. However, most of these publications concerned patients during or after ECC for cardiac surgery requiring cardioplegia [8–12]. Elsewhere, we recently published the case of a resuscitation patient under ECC in intensive care unit, who presented with refractory VF after an OHCA: direct IV injection of 40 mmol of KCl allowed return to sinus rhythm within a few minutes, without subsequent recurrence of arrhythmias, and the patient was finally discharged alive from hospitalization with a good prognosis in terms of neurological function [13].

These various studies and clinical cases reporting the efficacy of a KCl injection are supported by experimental data. Indeed, it has been showed on an isolated endocardial fiber model that a concentration of 12 mM of KCl allows VF to give way, with a subsequent return to an organized electrical rhythm [14]. Elsewhere, a recent electrophysiological study on an isolated heart model has shown that hyperkalaemia acts mainly on the dynamic character and on the temporo-spatial organization of VF [15].

The question that obviously arises after an IV injection of KCl is the pharmacokinetics of the hyperkalaemia. Although studies are limited in this area, some data are nevertheless available in the literature. First, in their series of 100 patients who received an injection of 20 mmol of KCl, Øvrum et al. reported serum potassium values at the upper limit of normal values (5.5 ± 1.0 mmol/l) 10 minutes after injection, and returned within normal values (4.3 ± 0.4 mmol/l) after 20 minutes [9]. This therefore attests to the extremely transient nature of this hyperkalaemia following a direct IV injection of 20 mmol of KCl.

Finally, regarding the possible morbidity and mortality associated with an injection of potassium chloride, Almdahl et al. published reassuring data in a second article [16] using the same methodology as their first one [10]. In a series of 12,113 patients operated for cardiac surgery under ECC and cardioplegia, survival at D30 was not different between the 9,723 patients who did not present VF post-ECC and the 1,877 patients who presented VF successfully converted by an injection of 20 mmol of potassium chloride (1.2% vs 1.3%, p = 0.269). On the other hand, there was a tendency for an increase in long-term mortality in the 400 patients who presented VF resistant to “pharmacological defibrillation” and therefore required an internal electric shock (hazard ratio = 1.19; 95% CI [0, 99–1.4], p = 0.07). These results are therefore reassuring with respect to possible deleterious consequences that could have been linked to the injection of KCl. They also suggest (but with all the limit of non-statistically significant results) that this pharmacological defibrillation could improve survival by comparison with conventional defibrillation performed by electric shocks (internal electric shocks in this study since it included patients operated for cardiac surgery).

All those works therefore suggest that a direct intravenous injection of 20 mmol of KCl in an OHCA patient presenting with VF or no-pulse VT, refractory to 3 electric shocks, thanks to a transient hyperkalaemia, could give way to this arrhythmia and subsequently allow a return to an organized and hemodynamically efficient heart rate, without any immediate or long-term deleterious consequences.

Methods

Intervention

Fig 1 presents the management algorithm for a patient with OHCA by VF according to international recommendations (Fig 1A) and in the context of this research (Fig 1B).

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Fig 1.

Management algorithm for a patient with out of hospital cardiac arrest (OHCA) by VF according to international recommendations (Fig 1A) and in the context of this research (Fig 1B). Epinephrine injections are not shown in the figure for simplicity.

https://doi.org/10.1371/journal.pone.0284429.g001

According to international guidelines, a direct administration of 300 mg IV of amiodarone should be performed in case of refractory (or recurrent) VF after 3 EES. If VF persists, a second administration of amiodarone IV should be given at half dose (150 mg) after the 5th EES. If the VF still persists, it is then possible to start continuous IV administration by electric syringe at a dose of 900 mg/day, or to resort to direct IV administration of lidocaine (1 mg/kg).

During this research, the injection of KCl 20 mmol will be performed after the 3rd electric shock, instead of the 1st administration of amiodarone. If necessary, the 1st injection of amiodarone 300 mg IVD will be performed after the 5th electric shock, and the 2nd injection 150 mg IVD after the 7th electric shock, and the relay with continuous amiodarone or the use of lidocaine afterwards.

Results

No patient is currently included in the study.

Discussion

The direct IV injection of 20 mmol KCl in a patient presenting with VF, refractory to 3 EES, could result in a rapid return to a spontaneous hemodynamically efficient heart rate.

The effectiveness of KCl to interrupt refractory VF is indeed linked to the peak of hyperkalaemia, and it has been shown that the serum potassium measured 10 minutes after this injection is at the limit of normal (5.5 mmol/l) and normal after 20 minutes. There is therefore no risk of a persistent cardiovascular depressant effect once the peak of hyperkalaemia has subsided. In addition, the 2^nd study by Almdahl et al., admittedly in a post-operative context of cardiac surgery under ECC, clearly showed the absence of specific morbidity and mortality in the 1,877 patients who presented VF successfully converted by an injection of 20 mmol of KCl.

In contrast, amiodarone and lidocaine, reference molecules according to international recommendations for interrupting refractory VF, are characterized by cardiovascular depressant effects, which persist for a while after their direct intravenous administration.

The injection of potassium chloride IVD, instead of amiodarone or lidocaine, could therefore allow, like these last 2 molecules, to immediately interrupt refractory VF, but on the other hand without presenting the risk of a persistent cardiovascular depressant effect.

The possible risk of this direct IV injection of KCl can be considered as zero, since the patient is already in refractory cardiac arrest, under specialized cardiopulmonary resuscitation, therefore with an external cardiac massage making it possible to compensate for the absence of spontaneous cardiac activity, and manual or mechanical artificial ventilation to compensate for the lack of spontaneous ventilation.

The possible efficacy of KCl injection in the treatment of OHCA with refractory VF would therefore be likely to improve the prognosis of patients with refractory VF during OHCA. Logically, this should therefore result in a modification of international recommendations concerning this very bad prognosis pathology.

Supporting information

Acknowledgments

All members of prehospital emergency system and in-hospital team taking care of the patients included in the study.