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Intralipid™ administration attenuates the hypotensive effects of acute intravenous amiodarone overdose in a swine model
IntralipidTM administration attenuates the hypotensive effects of acute intravenous amiodarone overdose in a swine model Theodoros Xanthos PhD, Nikolaos Psichalakis RN, David Russell PhD, Apostolos Papalois PhD, Anastasios Koutsovasilis PhD, Dimitrios Athanasopoulos MSc, Georgios Gkiokas PhD, Athanasios Chalkias PhD, Nicoletta Iacovidou PhD PII: DOI: Reference:
S0735-6757(16)30020-1 doi: 10.1016/j.ajem.2016.04.001 YAJEM 55721
To appear in:
American Journal of Emergency Medicine
Received date: Revised date: Accepted date:
24 January 2016 31 March 2016 1 April 2016
Please cite this article as: Xanthos Theodoros, Psichalakis Nikolaos, Russell David, Papalois Apostolos, Koutsovasilis Anastasios, Athanasopoulos Dimitrios, Gkiokas Georgios, Chalkias Athanasios, Iacovidou Nicoletta, IntralipidTM administration attenuates the hypotensive effects of acute intravenous amiodarone overdose in a swine model, American Journal of Emergency Medicine (2016), doi: 10.1016/j.ajem.2016.04.001
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ACCEPTED MANUSCRIPT IntralipidTM administration attenuates the hypotensive effects of acute intravenous amiodarone overdose in a swine model
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Theodoros Xanthos PhD1,2, Nikolaos Psichalakis RN3, David Russell PhD4, Apostolos Papalois PhD3, Anastasios Koutsovasilis PhD5, Dimitrios Athanasopoulos
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MSc6, Georgios Gkiokas PhD7, Athanasios Chalkias PhD2,6, Nicoletta Iacovidou PhD2,6
European University Cyprus, School of Medicine, Nicosia, Cyprus
2
Hellenic Society of Cardiopulmonary Resuscitation, Athens, Greece
3
Experimental - Research Center ELPEN, Athens, Greece
4
Cardiff Metropolitan University, Cardiff, UK
5
General Hospital of Nikaia, 3rd Department of Internal Medicine, Athens, Greece
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National and Kapodistrian University of Athens, Medical School, Postgraduate
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6
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1
7
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Study Program (MSc) “Cardiopulmonary Resuscitation”, Athens, Greece National and Kapodistrian University of Athens, Medical School, Aretaieion
University Hospital, 2nd Department of Surgery Corresponding author: Dr. Athanasios Chalkias, National and Kapodistrian University
of
Athens,
Medical
School,
MSc
Program
“Cardiopulmonary
Resuscitation”, 89 Patision Av., 10434, Athens, Greece. Tel.: +30 2110121756; Fax: +30 2110121758, Email: [email protected] Source(s) of support: Experimental - Research Center ELPEN Pharmaceuticals (E.R.C.E.). Keywords: lipid emulsion; amiodarone overdose; survival Running head: IntralipidTM and amiodarone
ACCEPTED MANUSCRIPT Abstract Purpose: To investigate whether a lipid emulsion could counteract the hypotensive
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effects of amiodarone overdose after an acute intravenous administration and improve
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4h survival in an established model of swine cardiovascular research.
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Methods: Twenty pigs were intubated and instrumented to measure aortic pressures, central venous pressures (CVP). After allowing the animals to stabilize for 60
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minutes, amiodarone overdose (1 mg/kg/min) was initiated for a maximum of 20 minutes. Afterwards, the animals were randomized into 2 groups. Group A (n=10) received 0.9% Normal Saline (NS) and Group B (n=10) received 20% Intralipid® (ILE). A bolus dose of 2 ml/kg in over 2 min time was initially administered in both
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groups followed by a 45min infusion (0.2 ml/kg/min) of either NS or ILE.
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Results: All animals survived the overdose and all animals survived the monitoring period of 4 hours. Systolic aortic pressure (6.90 vs 14.10mmHg, p=0.006) and MAP
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(6.10 vs 14.90mmHg, p=0.001) were higher in the ILE group 2 min after the bolus
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ILE infusion. This difference was maintained for 15 min after ILE infusion for both SpthAorta (7.85 vs 13.15mmHg, p=0.044) and MAP (7.85 vs 13.15mmHg, p=0.042). Animals that received ILE had higher central venous pressure (11.6 vs 15.7 mmHg, p=0.046), an effect which was attenuated 2 and 4 hours post administration. Animals receiving ILE were more acidotic (7.21 vs 7.38, p=0.048) in the monitoring period compared to animals receiving NS. Conclusions: Intralipid attenuated the hypotensive effects of amiodarone toxicity for a period of 15 minutes compared to animals receiving NS.
ACCEPTED MANUSCRIPT Introduction Intralipid® (ILE) is well known for its binding effect on lipophilic drugs. The
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use of ILE as an antidote was first introduced into human medicine as a rescue
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treatment of local anesthetic toxicities [1]. Current literature strongly supports the administration of ILE in patients who develop cardiac arrest after receiving an
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overdose of a local anesthetic such as bupivacaine [2]. ILE has been shown to be
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efficacious in the emergency treatment of neurotoxicity and cardiotoxicity that results from a variety of cardiovascular and psychoactive drug classes. Animal studies have established benefit from ILE in various models of toxicity [1,3]. Moreover, amiodarone when administered intravenously has been shown to cause hypotension in
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humans and swine [4-6]. On the other hand, amiodarone can be overdosed in various
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situations including iatrogenic overdose. To date only one study [7], has reported that amiodarone was sequestered to a
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great extent by the intravenously administered lipids in plasma, which completely prevented the decrease in arterial blood pressure caused by amiodarone infusion. The
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authors of this study however, administered amiodarone simultaneously with either the lipid infusion or Ringer‟s solution. Despite the fact that their primary aim was to show that amiodarone sequesters in the animals receiving lipid emulsion, their animal model does not really mimic a model of acute toxicity, where a physician has to counteract the deleterious effect of an overdose after it had occurred. This experimental study aimed at exploring whether ILE administration would counteract the beta-blocking and calcium antagonist actions of amiodarone that are responsible for its hypotensive effects and to explore whether ILE administration
ACCEPTED MANUSCRIPT could improve 4 h survival in a swine model of acute intravenous amiodarone
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overdose.
Material and methods
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The subjects of the present study were female Landrace-Large/White swine. The species has significant similarities with the human cardiovascular system and
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responds to injuries in a similar way in anesthesia and cardiac arrest and resuscitation unlike rodents and rabbits. The experimental protocol has been described in detail elsewhere [8], but it has been modified to address the primary hypothesis stated
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above.
The protocol has been approved by the Protocol Evaluation Committee of the
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Experimental - Research Center ELPEN according to Greek legislation regarding
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ethical and experimental procedures. Twenty female Landrace/Large-White piglets aged 10-15 weeks with average weight 19±2 kg, all from the same breeder (Validakis,
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Athens, Greece) were studied. All animals were prepared in a standardized fashion in the research facility (ELPEN Experimental-Research Center, Pikermi, Greece) as previously described [8]. Initial sedation was achieved by intramuscular administration of ketamine hydrochloride (10 mg/kg), midazolam (0.5 mg/kg) and atropine (0.05 mg/kg). Anaesthesia was induced by an intravenous bolus dose of propofol (2mg/kg) via the marginal auricular vein. The pigs were intubated with a 4.5 mm cuffed endotracheal tube. Animals were mechanically ventilated with a volume-controlled ventilator with tidal volume 15ml/kg and FiO2 0.21. End-tidal CO2 (ETCO2) was monitored by in-line waveform
ACCEPTED MANUSCRIPT capnography (Tonocap TC-200-22-01, Engstrom Division Instrumentarium Corp., Helsinki, Finland), and the respiratory frequency was adjusted to maintain ETCO2
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between 35 and 40 mm Hg. A bolus dose of cis-atracurium (0.15 mg/kg) was
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administered to ascertain synchrony with the ventilator. Continuous infusion of propofol 150 μg/kg/min was used to maintain adequate anesthetic depth and fentanyl
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4μg/kg was administered to ensure satisfactory analgesia. Despite the fact that propofol is also a lipid emulsion, it has been administered to both groups and it has Cardiac rhythm and heart rate was
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been unlikely to alter the measured effects.
monitored by electrocardiography (ECG), using leads I, II, III, aVR, aVL and aVF. Pulse oximetry (SpO2) was monitored continuously. Arterial blood gases were
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measured on a blood-gas analyzer (IRMA SL Blood Analysis System, Part 436301, Diametrics Medical Inc., USA) (pH, pO2, pCO2, HCO3).
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Right carotid artery and right internal jugular vein were surgically prepared
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and catheterized under aseptic conditions. Aortic pressures were measured using a catheter (model 6523, USCI CR, Bart, Papapostolou, Athens, Greece) advanced via
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the right carotid artery into the thoracic aorta. Mean arterial pressure was determined by electronic integration of the aortic blood pressure waveform. A catheter was inserted into the right atrium via the right jugular vein for continuous measurement of central venous pressures (CVP). All catheters were calibrated before use and their correct position verified by the presence of the typical pressure waveform. Cardiac output was monitored using VigileoTM. The experimental protocol is shown in Figure 1. After allowing the animals to stabilize for 60 minutes amiodarone overdose (1 mg/kg/min) was initiated for a maximum of 20 minutes or until the MAP reached 50% of the baseline value, or the heart rate became less than 50 bpm. The animals
ACCEPTED MANUSCRIPT were then randomized into 2 groups. Group A (n=10) received 0.9% saline solution and Group B (n=10) received 20% Intralipid®. Intralipid® 20% is a sterile, non-
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pyrogenic fat emulsion prepared for intravenous administration as a source of calories
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and essential fatty acids. It is made up of 20% soybean oil, 1.2% egg yolk phospholipids, 2.25% glycerin, and water for injection. In addition, sodium hydroxide
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has been added to adjust the pH so that the final product pH is 8.
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A bolus dose of 2 ml/kg in over 2 min time was initially administered in both groups followed by a 45min infusion (0.2 ml/kg/min) in either arm of the study (Group A received the saline infusion and group B received ILE in the doses specified). All animals were monitored invasively for 4 hours and after the end of the
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experiment they were humanely euthanized with Dolethal® overdose as previously
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described [8].
The ECG, MAP and CVP were monitored and recorded for the duration of the
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amiodarone overdose and were also recorded in all resuscitation procedures in both groups. Since the aim of the present study is to record outcomes, no further
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resuscitation procedure, other than that specified in the protocol was initiated and the 4-hour survival was also recorded. Statistical Analysis Statistical analysis of the data was performed using Statistical Package for the Social Sciences version 15.0 (SPSS Inc, Chicago IL, USA) and Stata statistical software package version 9.2 (StataCorp LP, College Station, TX, USA). Due to small number of subjects, the non-parametric Wilcoxon-Mann-Whitney test for independent samples was utilized for comparisons of quantitative measurements between the two groups at baseline, and each distinct time-point, calculating
ACCEPTED MANUSCRIPT differences in absolute values. Fisher‟s exact test was used to investigate associations between groups and survival, all of which will be treated as categorical variables.
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Generalized linear regression analysis for longitudinal data was further utilized to
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examine overall group effect on repeated measurements, also adjusting for the effect of time. A cut-off point of p-value <0.05 was used to mark statistical significance.
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The study utilized 20 animals in total, as this was required to ascertain adequate power to counteract the hypotensive effect of amiodarone 2 minutes following
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administration of ILE.
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Results
All animals received the overdose of amiodarone for 20 minutes. All animals
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survived the overdose and all animals survived the monitoring period of 4 hours. Amiodarone overdose caused significant hypotension in all animals accompanied by a
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significant bradycardia. In our study, no statistically significant differences were
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observed in baseline hemodynamic parameters and during amiodarone infusion between the two groups, but significant statistical difference were recorded between baseline and amiodarone overdose in all recorded parameters. ILE infusion had varying effect on hemodynamic and metabolic parameters. The main action was evident at 2 min after ILE infusion (Table 1). The examined parameters were divided into two main categories. The first category includes all parameters on which ILE infusion had no effect [heart rate (F = 1.310, p = 0.267), diastolic aortic pressure (DpthAorta) (F = 0.656, p = 0.428), right atrial diastolic pressure (DPRAtr) (F = 2.012, p = 0.175), pO2 (F = 0.054, p = 0.820), and HCO3 (F = 0.139, p = 0.715)]. The second category includes parameters that were affected for a short period of time (<15
ACCEPTED MANUSCRIPT minutes) and were higher in the ILE group; a statistically significant difference was observed in systolic aortic pressure (SpthAorta) 2 min after the bolus ILE infusion
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(6.90mmHg vs 14.10 mmHg, p = 0.006), which was maintained for 15 min (7.85 vs
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13.15 mmHg, p = 0.044) (Fig. 2). A statistically significant difference was also observed in MAP 2 min after the bolus ILE infusion (6.10 vs 14.90 mmHg, p =
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0.001), which was maintained for 15 min after ILE infusion (7.85 vs 13.15 mmHg, p = 0.042). Moreover, animals that received ILE had higher central venous pressure
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(11.6 vs 15.7 mmHg, p=0.046), an effect which was attenuated 2 and 4 hours post administration. Animals receiving ILE were more acidotic (7.21 vs 7.38, p=0.048) in the monitoring period compared to animals receiving NS. This phenomenon was
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evident at 45 min of administration of ILE or N/S, when the haemodynamic benefits
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of ILE were no longer apparent.
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Discussion
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This is the first study investigating whether ILE has any effect after induced acute amiodarone toxicity. In this preliminary study, ILE infusion had varying effect on hemodynamic and metabolic parameters. The main pharmacological action was evident at 2 min after ILE infusion, although it was not constant during time as in 45 min all beneficial effects of ILE had disappeared and animals became more acidotic. This study has also failed to show any benefit of ILE administration on short term survival, as all animals eventually survived both the overdose and either treatment. Although amiodarone itself causes hypotension, with significant reductions in cardiac contractility, relaxation, and cardiac output, it has been demonstrated to be sequestered by intravenously administered lipid emulsion, completely preventing a
ACCEPTED MANUSCRIPT decrease in arterial blood pressure [7]. Considering that amiodarone infusion has been suggested for the treatment of local anesthetic-induced cardiac arrhythmias [9,10], our
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study shows that ILE administration can prevent amiodarone-induced hypotension
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and can be considered as a new therapeutic option in such patients. Moreover, studies have shown that the hypotensive side-effect of amiodarone can be eliminated by the
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binding of amiodarone to the lipoid plasma, thus leading to hemodynamic stability [11]. Nevertheless, this effect was maintained until 15 min after ILE infusion,
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indicating the need for further mechanistic research.
ILE infusion did not increase heart rate, but increased cardiac output in Group B. This finding supports one of the proposed mechanisms of action of intravenous
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lipid emulsion. Research so far has shown that lipid administration may increase intracellular Ca2+ concentrations in cardiac myocytes, while within the myocardium,
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free fatty acid levels rise in parallel with increasing ionized Ca2+ levels. A study by
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Huang et al. proved that long-chain fatty acids are responsible for an increase in ionized Ca2+ levels, most likely by activating the myocardial Ca2+ channels, which
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results in a dose-dependent increase in the Ca2+ current. Also, Stehr et al showed that in rats, intravenous lipid emulsion administration did not produce an elevated heart rate [12], but did increase systolic blood pressure, which may support the role of lipid emulsion as an inotropic agent [13,14]. Considering, however, the effect of amiodarone on the cardiac contacting contraction system, the sequestration of amiodarone by Intralipid may have allowed for the increase in inotropy in our study. Of note, although lipid it remains unknown whether lipid infusion can prevent the antiarrhythmic effects of amiodarone, we did not notice any rhythm disturbances during the experiment.
ACCEPTED MANUSCRIPT Another interesting finding was the difference in right atrial pressures, which could be explained by the difference in central venous pressure and inotropy after
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Intralipid administration. Moreover, intravenous lipid emulsion can reduce the
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cardiodepressant effect on cardiac myocytes [13,15-17], while a direct metabolic effect of lipid emulsions has been previously reported. Van de Velde et al have
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demonstrated improved recovery from myocardial stunning in conscious dogs following infusion of 20% Intralipid [18]. The same authors further report increased
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contractile function in isolated rabbit hearts following myocardial stunning when Intralipid was administered during reperfusion [19]. The beneficial observed effect correlated with increased high-energy phosphate content in the globally stunned
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myocardium and was attributed to augmentation of free fatty acid and phospholipid metabolism [20,21]. Myocardial substrate preference under conditions of increased
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lactate concentration is known to shift toward greater oxidation of free fatty acids,
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assuming that there is sufficient oxygen available for this to occur [22]. The difference in pH between the two groups may be related to the
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simultaneous decrease in pO2 and increase in pCO2, indicating an amiodaroneinduced acute pulmonary toxicity, which was not ameliorated with ILE administration, when the haemodynamic benefits of ILE were no longer evident. One can deduce that ILE has no long-term effect in the amiodarone-induced pulmonary toxicity and in reality the fact that ILE animals became more acidotic 45 min post ILE infusion suggests that ILE may have a largely unrecognized unwanted effect in pulmonary toxicity. Acute amiodarone-induced lung disease appears rarely and is reported in occasional case reports, although some authors suggest that amiodarone has a potentially important, but largely under recognized, role in inducing acute lung injury
ACCEPTED MANUSCRIPT or acute respiratory distress syndrome in some patients, especially those undergoing cardiac surgery [23,24]. Of note, reported adverse effects associated with chronic
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parenteral nutrition containing lipid supplementation in humans include effects on the
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pulmonary function [25] and this can partly explain the reason why, animals in the ILE group became more acidotic 45 min in the infusion phase.
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In adult human patients with acute respiratory distress syndrome or other
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severe inflammatory diseases, lipid emulsion administration has been associated with a transient decrease in the ratio of the arterial partial pressure of oxygen to the fraction of inspired oxygen [26,27], perhaps due to ventilation/perfusion inequalities. In another animal study, however, no evidence of pulmonary emboli were found at
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necropsy, suggesting that intravenous lipid emulsion may not typically cause pulmonary damage without pre-existing pulmonary compromise [28]. In our study,
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the deterioration of pulmonary function may be related to amiodarone toxicity and to
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a less extent to Intralipid administration. Nevertheless, considering that our animals were healthy with no pre-existing pulmonary disease, further studies evaluating short
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intervals of large volumes of lipid emulsion are necessary to identify potential adverse effects of Intralipid when used as an antidote in amiodarone toxicity. The exact mechanism of action of ILE in the treatment of drug intoxication is not completely understood. In general, three mechanisms of action that may benefit ILE have been suggested. The prevailing theory of ILE‟s mechanism of action is a phenomenon termed “lipid sink” [29]. Despite the fact that this phenomenon was not investigated in the present study, it is possible that the lipid-sink theory only partially explains the haemodynamic measurements, mostly because the hemodynamic benefits of ILE were not evident after 45 min of infusions and the 2 groups had no statistical differences in invasive measurements of aortic pressures.
ACCEPTED MANUSCRIPT An alternate theory for ILE‟s successful reversal of local anesthetic drug toxicity may be related to its ability to increase intracellular Ca2+ concentrations in
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cardiac myocytes. Stehr et al [12] showed that in live rats, ILE administration did not
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produce an elevated heart rate, but did increase systolic blood pressure, which may support the role of ILE as an inotropic agent [13]. Moreover, direct cardiotonic effects
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of ILE have been reported [14]. Partownavid et al [30] have additionally demonstrated the necessity for fatty-acid oxidation, and failure to resuscitate
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bupivacaine toxic rats with LE following administration of FFA oxidation inhibitors, providing compelling evidence for a metabolic mechanism for ILE in drug-induced cardiotoxicity. This theory can also explain partly the results of the present study.
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Cardiac output was increased in several phases of the experiment in the ILE group. Given the fact that amiodarone possesses calcium-antagonizing, it is possible that the
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observed measurements in CO could be partly attributed to direct inotropy.
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The present study has significant limitations. It was performed in a rather small number of animals and the results should be extrapolated into human medicine
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with caution. Despite the fact that ILE showed significant improvement in the first min of infusion, this study did not record any benefit in the monitoring period. This study also addressed a mechanistic question regarding the haemodynamic response following amiodarone overdose, but did not shed any light on the underlying mechanism of action. This study has also shown that 45 min in the ILE group the animals became more acidotic, but as no lung histology was performed, it is not possible to comment on the possible mechanism of this effect. Moreover, ILE causes hypertriglyceraemia and in this study no biochemical parameters were measured. Another limitation of the study is that the animals were not monitored for a longer period and as a result, we are unable to predict either the neurological outcome or
ACCEPTED MANUSCRIPT their long-term survival. Moreover, no measurements of amiodarone (or its
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metabolites) concentrations were performed.
Conclusion
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Infusion of Intralipid resulted in a short-term prevention of amiodaroneinduced hypotension. Further research is needed to evaluate the clinical usefulness of
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Intralipid as an antidote in amiodarone overdoses.
Acknowledgements: The authors would like to thank A. Zacharioudaki, E.
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Karampela, K. Tsarea, M. Karamperi, A. Karaiskos, S. Gerakis, and E. Gerakis, staff
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experiments.
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members of the Experimental-Research Center ELPEN, for their assistance during the
Conflicts of interest: The authors report no relationships that could be construed as a conflict of interest.
ACCEPTED MANUSCRIPT References
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ACCEPTED MANUSCRIPT Figure legends Figure 1. Flowchart of the experimental protocol with 13 distinct points 1: Baseline,
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2: 5΄ Amiodarone infusion; 3: 10΄ Amiodarone infusion; 4: 15΄ Amiodarone infusion;
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5: 20 Amiodarone infusion; 6: 2΄ Bolus infusion 7: 15΄ infusion; 8: 30΄ infusion; 9: 45΄ infusion; 10: 1 hour monitoring; 11: 2 hours monitoring; 12: 3 hours monitoring;
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13: 4 hours monitoring.
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Figure 2. Systolic aortic pressure versus time. The asterix indicates statistical significant difference between the two groups.
1: Baseline, 2: 5΄ Amiodarone infusion; 3: 10΄ Amiodarone infusion; 4: 15΄ Amiodarone infusion; 5: 20 Amiodarone infusion; 6: 2΄ Bolus infusion 7: 15΄
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infusion; 8: 30΄ infusion; 9: 45΄ infusion; 10: 1 hour monitoring; 11: 2 hours
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monitoring; 12: 3 hours monitoring; 13: 4 hours monitoring.
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3
4
5
6
7
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9
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13
0.93
0.7
0.7
0.8
0.7
0.0
0.0
0.11
0.0
0.08
0.0
0.0
0.1
orta
9
04
33
79
05
06
44
1
94
1
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57
19
97
DPth
0.36
0.4
0.6
0.4
0.7
0.0
0.0
0.19
0.1
0.94
0.9
0.0
0.9
Aorta
1
24
49
48
01
03
68
8
70
0
41
69
70
MAP
0.40
0.7
0.4
0.7
0.8
0.0
0.0
0.0
0.3
0.0
0.7
3
02
01
62
0.67
0.4
0.1
6
45
08
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Base
0.12
0.3
0.1
7
60
36
0.32
0.8
CVP
7 CO
pH
PO2
PCO2
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tr
01
42
9
93
4
23
33
04
0.0
0.1
0.0
0.0
0.00
0.1
0.00
0.0
0.3
0.4
47
58
77
03
1
70
4
03
82
93
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DPRA
79
0.1
0.1
0.2
0.0
0.00
0.0
0.61
0.0
0.1
0.2
43
36
83
08
5
54
6
05
53
67
0.2
0.2
0.3
0.0
<0.0
0.0
0.01
0.0
0.1
0.1
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tr
0.2
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SPRA
0.22
0.16
77
15
06
07
65
02
001
04
5
03
18
07
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SPthA
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line
0.76
0.5
0.7
0.1
0.1
0.8
0.7
0.05
0.1
<0.0
0.0
0.0
0.0
1
68
61
29
28
20
04
8
98
001
11
23
80
0.91
0.7
0.2
0.2
0.3
0.1
0.0
0.16
0.0
<0.0
0.0
0.0
0.0
6
59
86
85
61
47
79
5
04
001
34
20
21
0.40
0.0
0.1
0.0
0.1
0.4
0.6
0.54
0.9
0.00
0.2
0.3
0.2
3
58
11
69
30
95
23
4
28
4
09
59
46
0.94
0.8
0.7
0.9
0.7
0.8
0.9
0.32
0.2
0.26
0.1
0.3
0.2
ACCEPTED MANUSCRIPT 40
61
80
22
4
18
1
82
45
06
0.40
0.3
0.5
0.5
0.5
0.3
0.4
0.91
0.3
0.69
0.0
0.8
0.1
1
63
44
43
44
63
10
5
66
9
67
33
69
0.59
0.8
0.2
0.8
0.0
0.8
0.2
0.21
0.2
0.28
0.0
0.5
0.0
6
01
58
05
82
04
15
5
17
0
31
43
83
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04
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HCO3
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Table 1. Statistical difference (p-value) between the two groups in time: The various time points are explained below
1: Baseline, 2: 5΄ Amiodarone infusion; 3: 10΄ Amiodarone infusion; 4: 15΄
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Amiodarone infusion; 5: 20 Amiodarone infusion; 6: 2΄ Bolus infusion 7: 15΄
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infusion; 8: 30΄ infusion; 9: 45΄ infusion; 10: 1 hour monitoring; 11: 2 hours
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monitoring; 12: 3 hours monitoring; 13: 4 hours monitoring. SPthAorta = Systolic aortic pressure; DPthAorta = diastolic aortic pressure; MAP =
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mean arterial pressure; SPRAtr = right atrial systolic pressure; DPRAtr = right atrial diastolic pressure; CVP = central venous pressure; CO = cardiac output.
S0735-6757(16)30020-1 doi: 10.1016/j.ajem.2016.04.001 YAJEM 55721
To appear in:
American Journal of Emergency Medicine
Received date: Revised date: Accepted date:
24 January 2016 31 March 2016 1 April 2016
Please cite this article as: Xanthos Theodoros, Psichalakis Nikolaos, Russell David, Papalois Apostolos, Koutsovasilis Anastasios, Athanasopoulos Dimitrios, Gkiokas Georgios, Chalkias Athanasios, Iacovidou Nicoletta, IntralipidTM administration attenuates the hypotensive effects of acute intravenous amiodarone overdose in a swine model, American Journal of Emergency Medicine (2016), doi: 10.1016/j.ajem.2016.04.001
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT IntralipidTM administration attenuates the hypotensive effects of acute intravenous amiodarone overdose in a swine model
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Theodoros Xanthos PhD1,2, Nikolaos Psichalakis RN3, David Russell PhD4, Apostolos Papalois PhD3, Anastasios Koutsovasilis PhD5, Dimitrios Athanasopoulos
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MSc6, Georgios Gkiokas PhD7, Athanasios Chalkias PhD2,6, Nicoletta Iacovidou PhD2,6
European University Cyprus, School of Medicine, Nicosia, Cyprus
2
Hellenic Society of Cardiopulmonary Resuscitation, Athens, Greece
3
Experimental - Research Center ELPEN, Athens, Greece
4
Cardiff Metropolitan University, Cardiff, UK
5
General Hospital of Nikaia, 3rd Department of Internal Medicine, Athens, Greece
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National and Kapodistrian University of Athens, Medical School, Postgraduate
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6
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1
7
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Study Program (MSc) “Cardiopulmonary Resuscitation”, Athens, Greece National and Kapodistrian University of Athens, Medical School, Aretaieion
University Hospital, 2nd Department of Surgery Corresponding author: Dr. Athanasios Chalkias, National and Kapodistrian University
of
Athens,
Medical
School,
MSc
Program
“Cardiopulmonary
Resuscitation”, 89 Patision Av., 10434, Athens, Greece. Tel.: +30 2110121756; Fax: +30 2110121758, Email: [email protected] Source(s) of support: Experimental - Research Center ELPEN Pharmaceuticals (E.R.C.E.). Keywords: lipid emulsion; amiodarone overdose; survival Running head: IntralipidTM and amiodarone
ACCEPTED MANUSCRIPT Abstract Purpose: To investigate whether a lipid emulsion could counteract the hypotensive
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effects of amiodarone overdose after an acute intravenous administration and improve
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4h survival in an established model of swine cardiovascular research.
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Methods: Twenty pigs were intubated and instrumented to measure aortic pressures, central venous pressures (CVP). After allowing the animals to stabilize for 60
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minutes, amiodarone overdose (1 mg/kg/min) was initiated for a maximum of 20 minutes. Afterwards, the animals were randomized into 2 groups. Group A (n=10) received 0.9% Normal Saline (NS) and Group B (n=10) received 20% Intralipid® (ILE). A bolus dose of 2 ml/kg in over 2 min time was initially administered in both
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groups followed by a 45min infusion (0.2 ml/kg/min) of either NS or ILE.
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Results: All animals survived the overdose and all animals survived the monitoring period of 4 hours. Systolic aortic pressure (6.90 vs 14.10mmHg, p=0.006) and MAP
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(6.10 vs 14.90mmHg, p=0.001) were higher in the ILE group 2 min after the bolus
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ILE infusion. This difference was maintained for 15 min after ILE infusion for both SpthAorta (7.85 vs 13.15mmHg, p=0.044) and MAP (7.85 vs 13.15mmHg, p=0.042). Animals that received ILE had higher central venous pressure (11.6 vs 15.7 mmHg, p=0.046), an effect which was attenuated 2 and 4 hours post administration. Animals receiving ILE were more acidotic (7.21 vs 7.38, p=0.048) in the monitoring period compared to animals receiving NS. Conclusions: Intralipid attenuated the hypotensive effects of amiodarone toxicity for a period of 15 minutes compared to animals receiving NS.
ACCEPTED MANUSCRIPT Introduction Intralipid® (ILE) is well known for its binding effect on lipophilic drugs. The
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use of ILE as an antidote was first introduced into human medicine as a rescue
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treatment of local anesthetic toxicities [1]. Current literature strongly supports the administration of ILE in patients who develop cardiac arrest after receiving an
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overdose of a local anesthetic such as bupivacaine [2]. ILE has been shown to be
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efficacious in the emergency treatment of neurotoxicity and cardiotoxicity that results from a variety of cardiovascular and psychoactive drug classes. Animal studies have established benefit from ILE in various models of toxicity [1,3]. Moreover, amiodarone when administered intravenously has been shown to cause hypotension in
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humans and swine [4-6]. On the other hand, amiodarone can be overdosed in various
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situations including iatrogenic overdose. To date only one study [7], has reported that amiodarone was sequestered to a
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great extent by the intravenously administered lipids in plasma, which completely prevented the decrease in arterial blood pressure caused by amiodarone infusion. The
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authors of this study however, administered amiodarone simultaneously with either the lipid infusion or Ringer‟s solution. Despite the fact that their primary aim was to show that amiodarone sequesters in the animals receiving lipid emulsion, their animal model does not really mimic a model of acute toxicity, where a physician has to counteract the deleterious effect of an overdose after it had occurred. This experimental study aimed at exploring whether ILE administration would counteract the beta-blocking and calcium antagonist actions of amiodarone that are responsible for its hypotensive effects and to explore whether ILE administration
ACCEPTED MANUSCRIPT could improve 4 h survival in a swine model of acute intravenous amiodarone
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overdose.
Material and methods
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The subjects of the present study were female Landrace-Large/White swine. The species has significant similarities with the human cardiovascular system and
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responds to injuries in a similar way in anesthesia and cardiac arrest and resuscitation unlike rodents and rabbits. The experimental protocol has been described in detail elsewhere [8], but it has been modified to address the primary hypothesis stated
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above.
The protocol has been approved by the Protocol Evaluation Committee of the
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Experimental - Research Center ELPEN according to Greek legislation regarding
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ethical and experimental procedures. Twenty female Landrace/Large-White piglets aged 10-15 weeks with average weight 19±2 kg, all from the same breeder (Validakis,
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Athens, Greece) were studied. All animals were prepared in a standardized fashion in the research facility (ELPEN Experimental-Research Center, Pikermi, Greece) as previously described [8]. Initial sedation was achieved by intramuscular administration of ketamine hydrochloride (10 mg/kg), midazolam (0.5 mg/kg) and atropine (0.05 mg/kg). Anaesthesia was induced by an intravenous bolus dose of propofol (2mg/kg) via the marginal auricular vein. The pigs were intubated with a 4.5 mm cuffed endotracheal tube. Animals were mechanically ventilated with a volume-controlled ventilator with tidal volume 15ml/kg and FiO2 0.21. End-tidal CO2 (ETCO2) was monitored by in-line waveform
ACCEPTED MANUSCRIPT capnography (Tonocap TC-200-22-01, Engstrom Division Instrumentarium Corp., Helsinki, Finland), and the respiratory frequency was adjusted to maintain ETCO2
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between 35 and 40 mm Hg. A bolus dose of cis-atracurium (0.15 mg/kg) was
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administered to ascertain synchrony with the ventilator. Continuous infusion of propofol 150 μg/kg/min was used to maintain adequate anesthetic depth and fentanyl
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4μg/kg was administered to ensure satisfactory analgesia. Despite the fact that propofol is also a lipid emulsion, it has been administered to both groups and it has Cardiac rhythm and heart rate was
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been unlikely to alter the measured effects.
monitored by electrocardiography (ECG), using leads I, II, III, aVR, aVL and aVF. Pulse oximetry (SpO2) was monitored continuously. Arterial blood gases were
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measured on a blood-gas analyzer (IRMA SL Blood Analysis System, Part 436301, Diametrics Medical Inc., USA) (pH, pO2, pCO2, HCO3).
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Right carotid artery and right internal jugular vein were surgically prepared
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and catheterized under aseptic conditions. Aortic pressures were measured using a catheter (model 6523, USCI CR, Bart, Papapostolou, Athens, Greece) advanced via
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the right carotid artery into the thoracic aorta. Mean arterial pressure was determined by electronic integration of the aortic blood pressure waveform. A catheter was inserted into the right atrium via the right jugular vein for continuous measurement of central venous pressures (CVP). All catheters were calibrated before use and their correct position verified by the presence of the typical pressure waveform. Cardiac output was monitored using VigileoTM. The experimental protocol is shown in Figure 1. After allowing the animals to stabilize for 60 minutes amiodarone overdose (1 mg/kg/min) was initiated for a maximum of 20 minutes or until the MAP reached 50% of the baseline value, or the heart rate became less than 50 bpm. The animals
ACCEPTED MANUSCRIPT were then randomized into 2 groups. Group A (n=10) received 0.9% saline solution and Group B (n=10) received 20% Intralipid®. Intralipid® 20% is a sterile, non-
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pyrogenic fat emulsion prepared for intravenous administration as a source of calories
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and essential fatty acids. It is made up of 20% soybean oil, 1.2% egg yolk phospholipids, 2.25% glycerin, and water for injection. In addition, sodium hydroxide
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has been added to adjust the pH so that the final product pH is 8.
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A bolus dose of 2 ml/kg in over 2 min time was initially administered in both groups followed by a 45min infusion (0.2 ml/kg/min) in either arm of the study (Group A received the saline infusion and group B received ILE in the doses specified). All animals were monitored invasively for 4 hours and after the end of the
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experiment they were humanely euthanized with Dolethal® overdose as previously
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described [8].
The ECG, MAP and CVP were monitored and recorded for the duration of the
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amiodarone overdose and were also recorded in all resuscitation procedures in both groups. Since the aim of the present study is to record outcomes, no further
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resuscitation procedure, other than that specified in the protocol was initiated and the 4-hour survival was also recorded. Statistical Analysis Statistical analysis of the data was performed using Statistical Package for the Social Sciences version 15.0 (SPSS Inc, Chicago IL, USA) and Stata statistical software package version 9.2 (StataCorp LP, College Station, TX, USA). Due to small number of subjects, the non-parametric Wilcoxon-Mann-Whitney test for independent samples was utilized for comparisons of quantitative measurements between the two groups at baseline, and each distinct time-point, calculating
ACCEPTED MANUSCRIPT differences in absolute values. Fisher‟s exact test was used to investigate associations between groups and survival, all of which will be treated as categorical variables.
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Generalized linear regression analysis for longitudinal data was further utilized to
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examine overall group effect on repeated measurements, also adjusting for the effect of time. A cut-off point of p-value <0.05 was used to mark statistical significance.
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The study utilized 20 animals in total, as this was required to ascertain adequate power to counteract the hypotensive effect of amiodarone 2 minutes following
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administration of ILE.
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Results
All animals received the overdose of amiodarone for 20 minutes. All animals
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survived the overdose and all animals survived the monitoring period of 4 hours. Amiodarone overdose caused significant hypotension in all animals accompanied by a
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significant bradycardia. In our study, no statistically significant differences were
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observed in baseline hemodynamic parameters and during amiodarone infusion between the two groups, but significant statistical difference were recorded between baseline and amiodarone overdose in all recorded parameters. ILE infusion had varying effect on hemodynamic and metabolic parameters. The main action was evident at 2 min after ILE infusion (Table 1). The examined parameters were divided into two main categories. The first category includes all parameters on which ILE infusion had no effect [heart rate (F = 1.310, p = 0.267), diastolic aortic pressure (DpthAorta) (F = 0.656, p = 0.428), right atrial diastolic pressure (DPRAtr) (F = 2.012, p = 0.175), pO2 (F = 0.054, p = 0.820), and HCO3 (F = 0.139, p = 0.715)]. The second category includes parameters that were affected for a short period of time (<15
ACCEPTED MANUSCRIPT minutes) and were higher in the ILE group; a statistically significant difference was observed in systolic aortic pressure (SpthAorta) 2 min after the bolus ILE infusion
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(6.90mmHg vs 14.10 mmHg, p = 0.006), which was maintained for 15 min (7.85 vs
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13.15 mmHg, p = 0.044) (Fig. 2). A statistically significant difference was also observed in MAP 2 min after the bolus ILE infusion (6.10 vs 14.90 mmHg, p =
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0.001), which was maintained for 15 min after ILE infusion (7.85 vs 13.15 mmHg, p = 0.042). Moreover, animals that received ILE had higher central venous pressure
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(11.6 vs 15.7 mmHg, p=0.046), an effect which was attenuated 2 and 4 hours post administration. Animals receiving ILE were more acidotic (7.21 vs 7.38, p=0.048) in the monitoring period compared to animals receiving NS. This phenomenon was
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evident at 45 min of administration of ILE or N/S, when the haemodynamic benefits
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of ILE were no longer apparent.
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Discussion
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This is the first study investigating whether ILE has any effect after induced acute amiodarone toxicity. In this preliminary study, ILE infusion had varying effect on hemodynamic and metabolic parameters. The main pharmacological action was evident at 2 min after ILE infusion, although it was not constant during time as in 45 min all beneficial effects of ILE had disappeared and animals became more acidotic. This study has also failed to show any benefit of ILE administration on short term survival, as all animals eventually survived both the overdose and either treatment. Although amiodarone itself causes hypotension, with significant reductions in cardiac contractility, relaxation, and cardiac output, it has been demonstrated to be sequestered by intravenously administered lipid emulsion, completely preventing a
ACCEPTED MANUSCRIPT decrease in arterial blood pressure [7]. Considering that amiodarone infusion has been suggested for the treatment of local anesthetic-induced cardiac arrhythmias [9,10], our
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study shows that ILE administration can prevent amiodarone-induced hypotension
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and can be considered as a new therapeutic option in such patients. Moreover, studies have shown that the hypotensive side-effect of amiodarone can be eliminated by the
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binding of amiodarone to the lipoid plasma, thus leading to hemodynamic stability [11]. Nevertheless, this effect was maintained until 15 min after ILE infusion,
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indicating the need for further mechanistic research.
ILE infusion did not increase heart rate, but increased cardiac output in Group B. This finding supports one of the proposed mechanisms of action of intravenous
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lipid emulsion. Research so far has shown that lipid administration may increase intracellular Ca2+ concentrations in cardiac myocytes, while within the myocardium,
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free fatty acid levels rise in parallel with increasing ionized Ca2+ levels. A study by
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Huang et al. proved that long-chain fatty acids are responsible for an increase in ionized Ca2+ levels, most likely by activating the myocardial Ca2+ channels, which
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results in a dose-dependent increase in the Ca2+ current. Also, Stehr et al showed that in rats, intravenous lipid emulsion administration did not produce an elevated heart rate [12], but did increase systolic blood pressure, which may support the role of lipid emulsion as an inotropic agent [13,14]. Considering, however, the effect of amiodarone on the cardiac contacting contraction system, the sequestration of amiodarone by Intralipid may have allowed for the increase in inotropy in our study. Of note, although lipid it remains unknown whether lipid infusion can prevent the antiarrhythmic effects of amiodarone, we did not notice any rhythm disturbances during the experiment.
ACCEPTED MANUSCRIPT Another interesting finding was the difference in right atrial pressures, which could be explained by the difference in central venous pressure and inotropy after
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Intralipid administration. Moreover, intravenous lipid emulsion can reduce the
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cardiodepressant effect on cardiac myocytes [13,15-17], while a direct metabolic effect of lipid emulsions has been previously reported. Van de Velde et al have
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demonstrated improved recovery from myocardial stunning in conscious dogs following infusion of 20% Intralipid [18]. The same authors further report increased
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contractile function in isolated rabbit hearts following myocardial stunning when Intralipid was administered during reperfusion [19]. The beneficial observed effect correlated with increased high-energy phosphate content in the globally stunned
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myocardium and was attributed to augmentation of free fatty acid and phospholipid metabolism [20,21]. Myocardial substrate preference under conditions of increased
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lactate concentration is known to shift toward greater oxidation of free fatty acids,
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assuming that there is sufficient oxygen available for this to occur [22]. The difference in pH between the two groups may be related to the
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simultaneous decrease in pO2 and increase in pCO2, indicating an amiodaroneinduced acute pulmonary toxicity, which was not ameliorated with ILE administration, when the haemodynamic benefits of ILE were no longer evident. One can deduce that ILE has no long-term effect in the amiodarone-induced pulmonary toxicity and in reality the fact that ILE animals became more acidotic 45 min post ILE infusion suggests that ILE may have a largely unrecognized unwanted effect in pulmonary toxicity. Acute amiodarone-induced lung disease appears rarely and is reported in occasional case reports, although some authors suggest that amiodarone has a potentially important, but largely under recognized, role in inducing acute lung injury
ACCEPTED MANUSCRIPT or acute respiratory distress syndrome in some patients, especially those undergoing cardiac surgery [23,24]. Of note, reported adverse effects associated with chronic
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parenteral nutrition containing lipid supplementation in humans include effects on the
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pulmonary function [25] and this can partly explain the reason why, animals in the ILE group became more acidotic 45 min in the infusion phase.
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In adult human patients with acute respiratory distress syndrome or other
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severe inflammatory diseases, lipid emulsion administration has been associated with a transient decrease in the ratio of the arterial partial pressure of oxygen to the fraction of inspired oxygen [26,27], perhaps due to ventilation/perfusion inequalities. In another animal study, however, no evidence of pulmonary emboli were found at
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necropsy, suggesting that intravenous lipid emulsion may not typically cause pulmonary damage without pre-existing pulmonary compromise [28]. In our study,
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the deterioration of pulmonary function may be related to amiodarone toxicity and to
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a less extent to Intralipid administration. Nevertheless, considering that our animals were healthy with no pre-existing pulmonary disease, further studies evaluating short
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intervals of large volumes of lipid emulsion are necessary to identify potential adverse effects of Intralipid when used as an antidote in amiodarone toxicity. The exact mechanism of action of ILE in the treatment of drug intoxication is not completely understood. In general, three mechanisms of action that may benefit ILE have been suggested. The prevailing theory of ILE‟s mechanism of action is a phenomenon termed “lipid sink” [29]. Despite the fact that this phenomenon was not investigated in the present study, it is possible that the lipid-sink theory only partially explains the haemodynamic measurements, mostly because the hemodynamic benefits of ILE were not evident after 45 min of infusions and the 2 groups had no statistical differences in invasive measurements of aortic pressures.
ACCEPTED MANUSCRIPT An alternate theory for ILE‟s successful reversal of local anesthetic drug toxicity may be related to its ability to increase intracellular Ca2+ concentrations in
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cardiac myocytes. Stehr et al [12] showed that in live rats, ILE administration did not
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produce an elevated heart rate, but did increase systolic blood pressure, which may support the role of ILE as an inotropic agent [13]. Moreover, direct cardiotonic effects
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of ILE have been reported [14]. Partownavid et al [30] have additionally demonstrated the necessity for fatty-acid oxidation, and failure to resuscitate
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bupivacaine toxic rats with LE following administration of FFA oxidation inhibitors, providing compelling evidence for a metabolic mechanism for ILE in drug-induced cardiotoxicity. This theory can also explain partly the results of the present study.
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Cardiac output was increased in several phases of the experiment in the ILE group. Given the fact that amiodarone possesses calcium-antagonizing, it is possible that the
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observed measurements in CO could be partly attributed to direct inotropy.
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The present study has significant limitations. It was performed in a rather small number of animals and the results should be extrapolated into human medicine
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with caution. Despite the fact that ILE showed significant improvement in the first min of infusion, this study did not record any benefit in the monitoring period. This study also addressed a mechanistic question regarding the haemodynamic response following amiodarone overdose, but did not shed any light on the underlying mechanism of action. This study has also shown that 45 min in the ILE group the animals became more acidotic, but as no lung histology was performed, it is not possible to comment on the possible mechanism of this effect. Moreover, ILE causes hypertriglyceraemia and in this study no biochemical parameters were measured. Another limitation of the study is that the animals were not monitored for a longer period and as a result, we are unable to predict either the neurological outcome or
ACCEPTED MANUSCRIPT their long-term survival. Moreover, no measurements of amiodarone (or its
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metabolites) concentrations were performed.
Conclusion
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Infusion of Intralipid resulted in a short-term prevention of amiodaroneinduced hypotension. Further research is needed to evaluate the clinical usefulness of
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Intralipid as an antidote in amiodarone overdoses.
Acknowledgements: The authors would like to thank A. Zacharioudaki, E.
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Karampela, K. Tsarea, M. Karamperi, A. Karaiskos, S. Gerakis, and E. Gerakis, staff
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experiments.
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members of the Experimental-Research Center ELPEN, for their assistance during the
Conflicts of interest: The authors report no relationships that could be construed as a conflict of interest.
ACCEPTED MANUSCRIPT References
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[1] Jamaty C, Bailey B, Larocque A, Notebaert E, Sanogo K, Chauny JM. Lipid
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emulsions in the treatment of acute poisoning: a systematic review of human and animal studies. Clin Toxicol (Phil) 2010;481:1-27.
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[2] Picard J, Ward SC, Zumpe R, Meek T, Barlow J, Harrop-Griffiths W. Guidelines and the adoption of „lipid rescue‟ therapy for local anaesthetic
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toxicity. Anaesthesia 2009;64:122-5.
[3] Harvey M, Cave G. Lipid emulsion may augment early blood pressure recovery in a rabbit model of atenolol toxicity. J Med Toxicol 2009;51:50-1.
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[4] Xanthos T, Bassiakou E, Vlachos IS, Bassiakos S, Michalakis K, Moutzouris DA, et al. Intravenous and oral administration of amiodarone for the treatment
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of recent onset atrial fibrillation after digoxin administration. Int J Cardiol 2007;121:291-5.
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[5] Xanthos T, Prapa V, Papadimitriou D, Papadimitriou L. Comparative study of
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intravenous amiodarone and procainamide in the treatment of atrial fibrillation of recent onset. Minerva Cardioangiol 2007;55:433-41.
[6] Karlis G, Iacovidou N, Lelovas P, Niforopoulou P, Zacharioudaki A, Papalois A, et al. Effects of early amiodarone administration during and immediately after cardiopulmonary resuscitation in a swine model. Acta Anaesth Scand 2014;581:114-22. [7] Niiya T, Litonius E, Petäjä L, Neuvonen PJ, Rosenberg PH. Intravenous lipid emulsion sequesters amiodarone in plasma and eliminates its hypotensive action in pigs. Ann Emerg Med 2010;564:402-8.e2.
ACCEPTED MANUSCRIPT [8] Xanthos T, Lelovas P, Vlachos I, Tsirikos-Karapanos N, Kouskouni E, Perrea D, et al. Cardiopulmonary arrest and resuscitation in Landrace/Large White
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ACCEPTED MANUSCRIPT Figure legends Figure 1. Flowchart of the experimental protocol with 13 distinct points 1: Baseline,
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2: 5΄ Amiodarone infusion; 3: 10΄ Amiodarone infusion; 4: 15΄ Amiodarone infusion;
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5: 20 Amiodarone infusion; 6: 2΄ Bolus infusion 7: 15΄ infusion; 8: 30΄ infusion; 9: 45΄ infusion; 10: 1 hour monitoring; 11: 2 hours monitoring; 12: 3 hours monitoring;
SC
13: 4 hours monitoring.
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Figure 2. Systolic aortic pressure versus time. The asterix indicates statistical significant difference between the two groups.
1: Baseline, 2: 5΄ Amiodarone infusion; 3: 10΄ Amiodarone infusion; 4: 15΄ Amiodarone infusion; 5: 20 Amiodarone infusion; 6: 2΄ Bolus infusion 7: 15΄
ED
infusion; 8: 30΄ infusion; 9: 45΄ infusion; 10: 1 hour monitoring; 11: 2 hours
AC
CE
PT
monitoring; 12: 3 hours monitoring; 13: 4 hours monitoring.
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AC
CE
PT
ED
Fig. 1
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T
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AC
CE
PT
Fig. 2
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3
4
5
6
7
8
9
10
11
12
13
0.93
0.7
0.7
0.8
0.7
0.0
0.0
0.11
0.0
0.08
0.0
0.0
0.1
orta
9
04
33
79
05
06
44
1
94
1
T
57
19
97
DPth
0.36
0.4
0.6
0.4
0.7
0.0
0.0
0.19
0.1
0.94
0.9
0.0
0.9
Aorta
1
24
49
48
01
03
68
8
70
0
41
69
70
MAP
0.40
0.7
0.4
0.7
0.8
0.0
0.0
0.0
0.3
0.0
0.7
3
02
01
62
0.67
0.4
0.1
6
45
08
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Base
0.12
0.3
0.1
7
60
36
0.32
0.8
CVP
7 CO
pH
PO2
PCO2
SC
tr
01
42
9
93
4
23
33
04
0.0
0.1
0.0
0.0
0.00
0.1
0.00
0.0
0.3
0.4
47
58
77
03
1
70
4
03
82
93
ED
DPRA
79
0.1
0.1
0.2
0.0
0.00
0.0
0.61
0.0
0.1
0.2
43
36
83
08
5
54
6
05
53
67
0.2
0.2
0.3
0.0
<0.0
0.0
0.01
0.0
0.1
0.1
PT
tr
0.2
CE
SPRA
0.22
0.16
77
15
06
07
65
02
001
04
5
03
18
07
AC
SPthA
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line
0.76
0.5
0.7
0.1
0.1
0.8
0.7
0.05
0.1
<0.0
0.0
0.0
0.0
1
68
61
29
28
20
04
8
98
001
11
23
80
0.91
0.7
0.2
0.2
0.3
0.1
0.0
0.16
0.0
<0.0
0.0
0.0
0.0
6
59
86
85
61
47
79
5
04
001
34
20
21
0.40
0.0
0.1
0.0
0.1
0.4
0.6
0.54
0.9
0.00
0.2
0.3
0.2
3
58
11
69
30
95
23
4
28
4
09
59
46
0.94
0.8
0.7
0.9
0.7
0.8
0.9
0.32
0.2
0.26
0.1
0.3
0.2
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61
80
22
4
18
1
82
45
06
0.40
0.3
0.5
0.5
0.5
0.3
0.4
0.91
0.3
0.69
0.0
0.8
0.1
1
63
44
43
44
63
10
5
66
9
67
33
69
0.59
0.8
0.2
0.8
0.0
0.8
0.2
0.21
0.2
0.28
0.0
0.5
0.0
6
01
58
05
82
04
15
5
17
0
31
43
83
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04
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SC
LAC
20
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HCO3
0
Table 1. Statistical difference (p-value) between the two groups in time: The various time points are explained below
1: Baseline, 2: 5΄ Amiodarone infusion; 3: 10΄ Amiodarone infusion; 4: 15΄
ED
Amiodarone infusion; 5: 20 Amiodarone infusion; 6: 2΄ Bolus infusion 7: 15΄
PT
infusion; 8: 30΄ infusion; 9: 45΄ infusion; 10: 1 hour monitoring; 11: 2 hours
CE
monitoring; 12: 3 hours monitoring; 13: 4 hours monitoring. SPthAorta = Systolic aortic pressure; DPthAorta = diastolic aortic pressure; MAP =
AC
mean arterial pressure; SPRAtr = right atrial systolic pressure; DPRAtr = right atrial diastolic pressure; CVP = central venous pressure; CO = cardiac output.