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Original Article

Effects of calcium and magnesium pretreatment on hyperkalaemic cardiac arrest in rats

Hollmann, M. W.*,†; Strümper, D.¶,‡; Salmons, V. A.*,§; Washington, J. M.*; Durieux, M. E.*,¶

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European Journal of Anaesthesiology: August 2003 - Volume 20 - Issue 8 - p 606-611

Abstract

The use of succinylcholine as a muscle relaxant has been challenged because of its propensity to induce increases in serum potassium concentration in patients with muscle disorders [1]. The interest has focused primarily on children, but lethal increases in serum potassium concentration can also occur in adults with acute renal failure [2], burns [3] or spinal cord injury [4]. Nonetheless, there are clinical situations where succinylcholine would be considered the safest muscle relaxant for intubation because of its unmatched speed of onset and recovery.

In such cases, it might be beneficial to pretreat with drugs that would mitigate the detrimental cardiac effects of hyperkalaemia if they were to occur. Such drugs must be without significant side-effects, as they will of necessity be administered to many who will not become hyperkalaemic. Administration of calcium safely and effectively reverses many of the electrophysiological actions of hyperkalaemia [5], but this has not been studied for pretreatment. Based on cellular studies, magnesium has also been suggested to prevent the effects of potassium on the heart [6]. As their mechanisms of action differ, a combination of these drugs might have a synergistic protective action. Both compounds are inexpensive and can be administered safely in modest doses. Our hypothesis was that pretreatment with either of them, or with a combination of the two, would be beneficial in preventing cardiac electrophysiological abnormalities during hyperkalaemia. To test this hypothesis, we investigated the effects of magnesium and calcium pretreatment in an animal model of hyperkalaemic cardiac arrest.

Methods

The study was approved by the Animal Care and Use Committee of the University of Virginia. Thirty male Sprague-Dawley rats with a mean weight of 376 g (range 348-425 g) were used. The animals were housed in the institutional animal care facility and received food and water ad libitum. Twenty-four animals were randomized to one of four groups:

• Control: this group received NaCl 0.9% as pretreatment.

• Magnesium (Mg): this group received MgSO4, 30 mg kg−1 as pretreatment.

• Calcium (Ca): this group received CaCl2, 15 mg kg−1 as pretreatment.

• Calcium + magnesium (Ca + Mg): this group received one-half of each drug (CaCl2 7.5 mg kg−1 and MgSO4 15 mg kg−1) as pretreatment.

Six rats did not enter the study protocol because of unsuccessful cannulation or significant blood loss during cannulation. This was determined before the start of the experiment, and their randomization number was reused.

The study drug was diluted in NaCl 0.9% to a volume of 3 mL kg−1. The animals were anaesthetized with halothane in oxygen and breathed spontaneously through a nose cone. Anaesthesia was maintained with 1 vol.% halothane in 100% oxygen. After ascertaining an appropriate depth of anaesthesia (determined by lack of a response to skin incision), the femoral arterial and venous catheters were placed and arterial pressure transduced (Transpac® IV; Abbott Critical Care Systems, North Chicago, IL, USA). The arterial waveform, calculated heart rate (HR) and mean arterial pressure (MAP) were displayed continuously (Hewlett-Packard 78833A®; Hewlett-Packard, Boblingen, Germany). The electrocardiogram (ECG) and respiratory rate were recorded from electrodes placed subcutaneously in the four quadrants of the chest wall and displayed continuously. At 3 min intervals, as well as at the time of occurrence of one of the end-points of the study (see below), 10 s printouts of ECG and arterial pressure traces were recorded on paper for more precise analysis. Haemodynamic data presented here were determined by calculation from these hard copies. Temperature was measured by a rectal thermocouple (Mallinckrodt Critical Care, HiLo Temp® Model 8200; Sensortek, Inc., Clifton, NJ, USA) and maintained close to 38°C (normothermia for these animals) using a heating lamp.

After a stabilization period, baseline haemodynamic data and arterial blood (0.2 mL) for blood-gas analysis were obtained. Next, the pretreatment drug to be studied was administered intravenously by slow bolus injection. The drug was allowed to circulate for 3 min, and its haemodynamic and respiratory effects were recorded. An intravenous infusion of KCl (0.01 mmol kg−1 min−1) was then started, with the dose calculated to increase the serum potassium concentration from a baseline of 3 mmol L−1 to approximately 10 mmol L−1 in the first 10 min, and with an addition of approximately 10% of circulating volume for the animal. Vital signs were followed as described above and the time to the occurrence of several clinically relevant end-points was determined. The primary end-point was cardiovascular collapse, defined as the absence of measurable arterial pressure and ventricular fibrillation or asystole on the ECG. Secondary end-points were the first occurrence of ventricular dysrhythmia and a decrease in mean arterial pressure (MAP) to <35 mmHg (approximately 40% of the baseline value). If none of these end-points were reached within 20 min, the rate of KCl infusion was doubled (to 0.02 mmol kg−1 min−1) for the remainder of the protocol. An arterial blood sample was taken at the time of the first dysrhythmia via the femoral artery catheter. Immediately after the primary end-point of full arrest was reached, arterial blood was obtained by cardiac aspiration for blood-gas analysis.

The study was powered to detect a 40% change in means between the groups with α = 0.05 and β = 0.80 (a smaller difference between the group means would probably lack clinical significance). This required six animals per group. Data are presented as mean ± standard deviation (SD). Differences between study groups were determined by using one- or two-way ANOVAs with repeated measurements for time, followed by a least significant differences (LSD) post-hoc test for multiple comparisons. P < 0.05 was considered as statistically significant.

Results

Baseline haemodynamic and blood-gas data are presented in Tables 1 and 2. No statistically significant differences were observed between the groups. All animals were normothermic, normotensive, normoxic and normocapnic before administration of the test drugs.

Table 1
Table 1:
Blood-gases, acid-base status, haemoglobin and calcium concentrations at baseline, at the time of the first occurrence of dysrhythmias and at cardiovascular collapse.
Table 2
Table 2:
Heart rate, MAP, temperature and respiratory rate at three different time points in the study.

No significant haemodynamic effects occurred during the administration of the test drugs. There were no significant differences between the groups in HR, MAP or respiratory rate immediately before start of the KCl infusion (Table 2).

The potassium concentrations increased to similar degrees in all groups, from an average of 4.0 ± 0.1 mmol L−1 before infusion to an average of 12.0 ± 0.2 mmol L−1 at the time of cardiovascular collapse (Fig. 1). The response to KCl infusion followed a predictable pattern. The animals maintained normal haemodynamic status and respiratory rate for approximately 35 ± 0.3 min (Fig. 2, Table 2), corresponding to a potassium concentration of 8.8 ± 0.1 mmol L−1 (control 8.8 ± 0.8; Mg 8.7 ± 0.6; Ca 9.0 ± 0.7; Ca + Mg 8.6 ± 0.8 mmol L−1). Then the first ventricular dysrhythmia, MAP decrease to <40% of baseline, and cardiovascular collapse occurred in rapid succession. There were no significant differences among the groups in the time at which these events appeared (Fig. 2).

Figure 1
Figure 1:
Potassium concentrations in the control group and three treatment groups at baseline and at the time of cardiovascular collapse. Values are the mean ± SD. ▪: Control;JOURNAL/ejanet/04.02/00003643-200308000-00003/ENTITY_OV0071/v/2017-07-27T035934Z/r/image-png: Mg2+; □: Ca2+; ▥: Mg2+ + Ca2+.
Figure 2
Figure 2:
Time (min) to reach, respectively, the first dysrhythmia, a decrease in mean arterial pressure (MAP) to <40% of baseline and to cardiovascular collapse. Values are the mean ± SD. ▪: Control;JOURNAL/ejanet/04.02/00003643-200308000-00003/ENTITY_OV0071/v/2017-07-27T035934Z/r/image-png: Mg2+; □: Ca2+; ▥: Mg2+ + Ca2+.

Blood-gas analyses at the time of cardiovascular collapse demonstrated hypercapnia and acidaemia (Table 1). However, all animals were normoxic. No significant differences in blood-gas values were found among the groups (P > 0.05). There was a trend, although not significant (P > 0.05), for animals in the magnesium group to have lower PaCO2, greater pH and greater PaO2 at this point than animals in the other groups (Table 1). The animals in the magnesium group did not differ from controls or the other study groups in respiratory rate (Table 2).

Discussion

Our data indicate that clinically acceptable doses of calcium and magnesium, administered several minutes before initiation of hyperkalaemia, do not protect against the cardiovascular effects of high potassium concentrations in our model. The times to ventricular dysrhythmias, arterial pressure decrease and cardiovascular collapse were not different between control animals and those treated with calcium, magnesium or both. It should be realized that our study was powered to detect a 40% difference between group means, and that smaller changes therefore may have been missed. However, such smaller changes would likely not be clinically relevant.

We used halothane as the anaesthetic, as it has been for many years the standard agent for induction using paediatric masks. However, in some countries, sevoflurane has rapidly replaced halothane as the preferred drug. It is conceivable that our findings could have been different with sevoflurane anaesthesia, which lacks the catecholamine-sensitizing effects on the myocardium seen with halothane. A further study using sevoflurane would therefore be of value. Our study employed spontaneous ventilation of the lungs, whereas patients in the clinical setting might be intubated or ventilated with positive pressure by mask at the time that the hyperkalaemic symptoms become apparent. However, none of our groups was hypoxaemic at the time of cardiac arrest, so that hypoxia can be excluded as a cause of cardiovascular collapse. However, the animals were hypercarbic and acidaemic, which may have influenced myocardial and vascular behaviour. As haemodynamic status was normal until a few minutes before arrest, respiratory depression cannot be attributed to an overdose of anaesthetic. Therefore, hypercarbia was most likely a result of decreased cardiac output during cardiovascular collapse, although to settle this issue an additional control group (anaesthetized but not receiving potassium) would have been required. Artificial ventilation of the lungs, in the face of greatly decreased cardiac output and resulting increased dead space, is highly inefficient and would probably not have changed our findings significantly.

The doses of calcium and magnesium used were as high as one would routinely administer without a significant risk of side-effects. Unfortunately, this requirement limited the doses given. It is possible that significant preventive effects would have been observed if greater amounts of magnesium and calcium had been administered. Calcium has a long history as a treatment for hyperkalaemia [7-9]. Its duration of action, in terms of treatment of hyperkalaemia, has been shown to be 30-60 min [10], meaning that we could have expected an effect at the time of cardiac arrest. Its mechanism of action is a transient depression of the threshold potential of the cell membrane, which temporarily reverses the hyperexcitability induced by potassium [5,11,12]. Magnesium has also been suggested as a potential treatment, and indeed it prevented the electrophysiological actions of hyperkalaemia in cardiac myocytes [6]. In addition, magnesium has other beneficial effects, in particular protective effects on ischaemic brain [13] and myocardium [14], and it might be of interest as a treatment in hyperkalaemic circulatory arrest. It also has significant nicotinic receptor blocking properties [7]. Therefore, it is possible that magnesium might offer protection in the clinical setting of succinylcholine-induced hyperkalaemia by decreasing potassium release, a hypothesis not addressed here.

In addition to the primary end-point of cardiovascular collapse, we determined the time to several other end-points: first occurrence of ventricular dysrhythmia and a significant decrease in arterial pressure. This was done to investigate if any of these secondary end-points could serve as early warning signs for impending cardiac arrest. In our model, these events happened so closely together (approximately 35 min to dysrhythmia, 38 min to arterial pressure decrease, 39 min to cardiovascular collapse) that they are unlikely to be of significant benefit as warning signs. Of note is that this short period represented a rise in serum potassium concentration from an average of 9 mmol L−1 to an average of 12.0 mmol L−1. Since we delivered potassium by intravenous infusion, this very rapid rise may not be representative of every clinical situation. Regardless, the study groups did not demonstrate any variation in the onset of the potential early warning signs.

It is of interest that animals treated with magnesium 30 mg kg−1 showed a trend toward improved respiratory values (PaO2, pH, PaCO2). This was not observed after administration of magnesium 15 mg kg−1 (in combination with CaCl2 7.5 mg kg−1). We cannot provide a definitive explanation for this finding. Magnesium has been suggested to contribute to respiratory muscle fatigue and failure [15], probably due to its muscle relaxant properties at higher concentrations. On the other hand, a more recent study showed no effect of magnesium on respiratory muscle strength [16]. In addition, magnesium has been recommended as an alternative treatment option in asthmatic patients [17-21]. By competing with calcium for uptake into smooth muscle cells, leading to lower intracellular calcium, magnesium may cause smooth muscle relaxation and bronchodilation [21].

In summary, we showed that pretreatment with calcium, magnesium or a combination of the two was not effective in preventing the haemodynamic consequences of progressive hyperkalaemia in a rat model. The compounds appeared not to affect serum potassium concentrations. A trend towards better respiratory values was observed in animals receiving the highest magnesium dose. However, this did not translate in a longer time until cardiovascular collapse.

Acknowledgements

M. W. H. was supported in part by the Department of Anesthesiology, University of Heidelberg, Heidelberg, and by a grant from the German Research Society (DFG HO 2199/1-1), Bonn. He was also supported in part by the 2000 Ben Covino Research Award, sponsored by AstraZeneca Pain Control, Sweden, National Institutes of Health Grant GMS 52387, Bethesda, MD, USA, and an American Heart Association grant Mid-Atlantic Affiliation VHA 9920345U, Baltimore, MD. Our sincere thanks to Dr Jos Prickaerts for statistical analysis.

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Keywords:

CARDIOVASCULAR PHYSIOLOGY, ventricular function; HOMEOSTASIS, electrolyte balance; VERTEBRATES, rats, Sprague-Dawley

© 2003 European Academy of Anaesthesiology