Developing a new pharmacological therapy using different combinations of adenosine, lidocaine and magnesium for asphyxial cardiac arrest in rats

Djabir, Yulia Yusrini (2014) Developing a new pharmacological therapy using different combinations of adenosine, lidocaine and magnesium for asphyxial cardiac arrest in rats. PhD thesis, James Cook University.

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Background: Around 17 million people die from cardiac arrest worldwide every year, but no drug therapy has been shown to improve survival. Failure to adequately rescue the heart and brain leads to post-resuscitation syndrome, including coagulopathy imbalances, organ failure and death. Adenosine and lidocaine (AL) have been shown to elicit cardioprotection in cardiac surgery and haemorrhagic shock. In an effort to translate this protection to cardiopulmonary resuscitation, the effects of AL on cardiac and haemodynamic rescue were examined following asphyxial-induced cardiac arrest in the rat.

Methods: All studies employed asphyxial-induced cardiac arrest rat model. Cardiac arrest, defined as mean arterial pressure (MAP) <10 mmHg, was induced by stopping the ventilator and clamping the line for 8 minutes. Resuscitation attempt comprises of 0.5 mL intravenous drug injection, declamping ventilator line, and chest compressions (300 min⁻¹). The end points were return of spontaneous circulation (ROSC), haemodynamics during or following resuscitation, and ECG stability at different temperatures. When applicable, coagulopathy was assessed using plasmatic PT and aPTT tests and whole blood thromboelastometry. The level of statistical significance was p<0.05.

Experimental design: After obtaining the optimal AL dose, the first study is designed to assess the effect of adenosine (A 0.48 mg), lidocaine (L 1.0 mg), AL (0.48/1.0 mg) and saline (0.9% NaCl) on ROSC, haemodynamic rescue and ECG stability during compression phase every 5 min over 60 min. The animal’s temperature was allowed to drift (34-35°C). The second study examined the effect of intra arrest and post-resuscitation moderate hypothermia (28-32°C) versus normothermia (36-37°C) among the different treatment groups (AL, lidocaine or saline, n=8) during intermittent compression phase and following one 60 sec set of compressions. An adenosine group was not included due to high mortality in the first study. In the third study, the effect of Mg²⁺ addition was examined during post- ROSC moderate hypothermia (28-32°C) with 6 group treatments (n=8): 1) saline; 2) adenosine-Mg²⁺ (AM); 3) lidocaine-Mg²⁺ (LM), 4) AL-Mg²⁺ (ALM), 5) AL, and 6) Mg²⁺ alone (Mg). Post-arrest coagulopathy was also assessed. The fourth study investigated the effects of ALM (n=10) compared to saline (n=12) on ROSC, ECG rhythm, postresuscitation haemodynamics, coagulopathy and neurohistological changes following intra-arrest hypothermia and two-hour active rewarming post resuscitation. Lastly, ALM (n=12) was then compared with standard-of-care epinephrine (n=12) with the same resuscitation and temperature protocol as the fourth study.

Results: In the first study, AL led to consistently higher MAP during chest compressions (p<0.05; 35-45 and 55 minutes) followed by lidocaine, and was lowest with adenosine and saline. Improved ECG rhythm was apparent in AL-treated rats. No groups sustained ROSC after 5-10 min resuscitation at body temperature 34-35°C. Similarly, during normothermia, no rats achieved ROSC after 10 min. However, during induced hypothermia (28-32°C), ROSC was achieved in 75% controls and in 100% lidocaine and AL-treated rats. After 40 min, 37.5% of AL hypothermic rats achieved ROSC compared to 12.5% of lidocaine and none of saline rats (χ²=56.058 df (5) p<0.01). Arterial pressures were significantly higher in AL and lidocaine hypothermic rats than hypothermic controls or any normothermic groups (p<0.05 at 30-60 min). Saline controls (normothermic or hypothermic) experienced a large number of ventricular tachycardia (VT) and fibrillation (VF), whereas both AL groups had no VF over 60 min. With a single set of 60 sec compressions and induced hypothermia, 75% saline, 87.5% lidocaine and 100% AL-treated rats immediately achieved and maintained ROSC over the 60 min observation period. AL with Mg²⁺ (ALM) and AL only led to 100% ROSC without VF during two-hour post-ROSC hypothermia (28-32°C). Two out of eight animals in saline, three in Mg, four in AM and one in LM groups did not attain ROSC. Furthermore, ALM but not AL led to significantly higher arterial pressures from 30-120 min of ROSC compared to all other groups. After 90-120 min, ALM rats had MAP ranging from 70-76 mmHg; whereas, Mg rats had the lowest pressures, with MAPs ranging from 41-46 mmHg. Following intra-arrest hypothermia and post resuscitation rewarming, 100% ALM rats achieved ROSC compared to 67% controls (χ²=3.889, p<0.05), and generated higher MAP from 45-120 min post ROSC than controls (p<0.05 at 75-120 min). After 120 min, coagulation analysis from saline controls displayed hypocoagulopathy (prolonged EXTEM/INTEM clotting time, clot formation time, prothrombin time, activated partial thromboplastin time), decreased maximal clot firmness, lowered elasticity, and lowered clot amplitudes but no change in lysis index. These coagulation abnormalities were mostly prevented by ALM, but the presence of neurohistopathology changes was not significantly different from controls. Compared to epinephrine, ALM achieved 100% ROSC at significantly lower MAP (39 ± 3.3 mmHg vs 129 ± 7.0 mmHg) and heart rate (59 ± 5.5 bpm vs 151 ± 13.6 bpm), while three out of 12 epinephrine rats failed to achieve ROSC due to persistent VF. After 90-120 min, arterial pressures in ALM were significantly higher than epinephrine group (81 ± 2.9 mmHg compared to 62 ± 3.9 mmHg at 120 min). Similar to ALM, epinephrine treatment mostly prevented abnormal coagulation at 120 min post resuscitation.

Conclusion: A bolus of AL administered immediately prior to chest compressions resulted in higher developed arterial pressures during compressions compared to lidocaine, adenosine or saline treatment at body temperatures 34-35°C. However, ROSC was not sustained within 5-10 min in any group. Moderate hypothermia during and after resuscitation significantly improved ROSC sustainability and developed pressures during intermittent compressions, however, ROSC achievement was higher in AL than any other group. Mg²⁺ addition in AL solution (ALM) further improved post-resuscitation haemodynamics compared to saline, AM, LM, AL and Mg²⁺ alone during moderate hypothermia. ALM also improved ROSC and haemodynamics during post-resuscitation rewarming following intra-arrest hypothermia, and was superior when compared to epinephrine. Death of epinephrine-treated rats was from refractory VF, while ALM prevented fatal arrhythmias during induced hypothermia or active rewarming. Acute coagulopathy was apparent after 120 min ROSC following cardiac arrest, and both ALM and epinephrine mostly prevented the abnormalities. ALM with induced hypothermia may offer clinical benefits in cardiac arrest victims to rescue the heart and improve post cardiac arrest haemodynamics and coagulation status.

Item ID: 40707
Item Type: Thesis (PhD)
Keywords: adenosine; animal models; asphyxia hypoxia; asphyxia; cardiac arrest; cardiopulmonary resuscitation; cardiovascular disease; chest compressions; coagulation; ECG; electrocardiogram; epinephrine; haematology; haemodynamics; hematology; hypothermia; lidocaine; magnesium; rats; resuscitation; spontaneous circulation
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Publications arising from this thesis are available from the Related URLs field. The publications are:

Chapter 3: Djabir, Yulia, and Dobson, Geoffrey P. (2013) Hemodynamic rescue and ECG stability during chest compressions using adenosine and lidocaine after 8-minute asphyxial hypoxia in the rat. American Journal of Emergency Medicine, 31 (11). pp. 1539-1545.

Chapter 6: Djabir, Yulia, Letson, Hayley L., and Dobson, Geoffrey P. (2013) Adenosine, lidocaine, and Mg²⁺ (ALM™) increases survival and corrects coagulopathy after eight-minute asphyxial cardiac arrest in the rat. Shock, 40 (3). pp. 222-232.

Date Deposited: 14 Oct 2015 01:21
FoR Codes: 11 MEDICAL AND HEALTH SCIENCES > 1102 Cardiovascular Medicine and Haematology > 110299 Cardiovascular Medicine and Haematology not elsewhere classified @ 100%
SEO Codes: 92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920103 Cardiovascular System and Diseases @ 100%
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