THERAPEUTIC HYPOTHERMIA AND TEMPERATURE MANAGEMENT Volume 2, Number 1, 2012 ª Mary Ann Liebert, Inc. DOI: 10.1089/ther.2012.0004

Serum Potassium Changes During Therapeutic Hypothermia After Out-of-Hospital Cardiac Arrest— Should It Be Treated? Helle Soeholm, M.D.,1 and Hans Kirkegaard, M.D., Ph.D., D.MSc.2

Background: Therapeutic hypothermia (TH) after out-of-hospital cardiac arrest (OHCA) is associated with adverse events, for example hypokalemia and arrhythmias. In the present study, we report the impact of serum potassium changes related to the rate of cardiac arrhythmias, and the advantages and disadvantages of potassium supplementation are discussed. Methods: Fifty-four consecutive patients suffering from OHCA and treated with TH (32–34C) for 24 hours at one University Hospital were included and followed for 48 hours. Results: Serum potassium levels decreased during cooling from a median admission value of 4.0 mmol/L (quartiles 3.6–4.5 mmol/L) to a nadir of 3.6 mmol/L (3.5–3.9 mmol/L) 6 hours after target temperature ( p = 0.005), and 76% reached values of < 3.5 mmol/L. During rewarming, serum potassium increased, with 15% reaching values of > 5.5 mmol/L. Potassium supplementation was initiated at 3.5 mmol/L (quartiles 3.2– 3.6 mmol/L) and stopped at 4.5 mmol/L (4.1–4.8 mmol/L). A total of 11% of patients experienced ventricular fibrillation (VF) or ventricular tachycardia (VT). Potassium levels in patients experiencing VF or VT were lower, though not significantly ( p = 0.119) compared to the rest of the patients. Conclusion: Serum potassium decreases significantly during the induction of TH ( p = 0.005). Potassium levels were not found to be different in patients with and without VF/VT in this study, perhaps due to the low number of patients, as a difference has been seen in other studies. It is recommended that an infusion of supplementary potassium be initiated during the early cooling phase in order to avoid severe hypokalemia (serum potassium < 3.0 mmol/L) and terminated in due time before normothermia is reached during rewarming in order to avoid severe hyperkalemia (serum potassium > 5.5 mmol/L), as serum potassium increases during rewarming.

pokalemia), impaired coagulation cascade with risk of bleeding, and EKG changes that can lead to arrhythmia (e.g., VF, VT, and bradycardia; Polderman and Herold, 2009). The focus of this study is the impact of potassium changes on the risk of arrhythmia. A few studies have shown that serum potassium decreases during hypothermia and that subsequent rewarming causes a rebound increase in potassium (Koht et al., 1983; Sprung et al., 1992; Mirzoyev et al., 2010). Our current knowledge of the potassium changes during TH and its effects on physiology remain sparse. It is known that high or low levels of potassium increase the risk of adverse arrhythmia (Podrid 1990; Cohn et al., 2000; Mirzoyev et al., 2010). Patients with cardiac ischemia and heart failure are at greater risk of arrhythmias due to myocardial ischemia, increased endogenous level of catecholamines, and treatment with diuretics and arrhythmogenic drugs (Leier et al., 1994; Cohn et al., 2000). The normal laboratory value for serum

Introduction

D

espite major improvements in prehospital care in recent years, out-of-hospital cardiac arrest (OHCA) still has a dismal prognosis (Engdahl et al., 2000; Jacobs et al., 2004). The 2010 advanced life support guidelines focus on the importance of post-resuscitation care in an attempt to improve outcome further after OHCA. The recommendations are partly built on two randomized controlled clinical trials from 2002, which proved therapeutic hypothermia (TH) beneficial with regard to neurological outcome and survival after OHCA with ventricular fibrillation (VF) as initial arrhythmia (Bernard et al., 2002; HACA Study Group, 2002). Retrospective analysis has since proven that TH is also advantageous for nonshockable rhythms (Kim et al., 2011; Lundbye et al., 2011). Treatment with TH is associated with adverse events such as increased infection risk, electrolyte disturbances (e.g., hy-

1 2

Department of Cardiology 2142, Copenhagen University Hospital Rigshospitalet, Denmark. Department of Anesthesia and Intensive Care Medicine, Aarhus University Hospital, Skejby, Aarhus N, Denmark.

30

POTASSIUM AND THERAPEUTIC HYPOTHERMIA potassium is 3.5–5.0 mmol/L, but in patients with ischemic heart disease a value of 4.0–4.5 mmol/L is recommended (Leier et al., 1994; Cohn et al., 2000; Bernard et al., 2002). A recent study found a significant association between adverse arrhythmia during TH and the occurrence of hypokalemia and prolonged QTc (Mirzoyev et al., 2010). The aim of the current study is to present and discuss changes in potassium, occurrences of cardiac arrhythmias, and whether potassium correction during TH should be carried out. Furthermore, acid-base disturbances, blood-glucose, and administered inotropics are investigated, as they may also affect the potassium level. Materials and Methods The investigation, a cohort study, is based on comatose (Glasgow Coma Score < 8) survivors after OHCA. All patients treated with TH at a university hospital during a period of 26 months were included in the study. Exclusion criteria of the study are equivalent to the exclusion criteria for treatment with TH, as recommended by ILCOR (Nolan et al., 2003). The present study is a retrospective quality assurance study that analyzes the quality of the potassium correction in a group of patients treated with mild hypothermia. According to Danish law, no ethical committee has to approve such a study. Fifty-nine consecutive patients treated with TH for 24 hours after OHCA due to ventricular fibrillation (VF; 51 patients) or asystole (eight patients) were included in the study. Of these, five were excluded, one due to missing temperature registration, another due to TH of only 12 hours, and three because they died before the data collection period was completed. A fictional time scale was arranged to equate the patients’ 24-hour hypothermia period. Hour 0 is defined as the point in time when the patient’s core temperature reaches p34.0C. The patients are then followed for another 48 hours. Arterial

31 blood gasses were drawn every 2 hours, vital parameters were documented once every hour, and arrhythmias were observed and the diagnosis and treatment documented by intensive care staff. Continuous variables are presented as mean – standard deviation for normally distributed data and as median and quartiles for non-normal distributed data. Differences were analyzed with the non-parametric Mann–Whitney U-test. Categorical variables are presented as number and percent as appropriate. All statistical analysis was carried out in Microsoft Excel and SPSS with a level of significance defined as p < 0.05. Analyses of differences in potassium levels are carried out for the hypothermia period unless stated otherwise in the text. All data are displayed as median (25th and 75th quartiles) if not stated otherwise. Results Patient characteristics The study population consists of 54 patients, 80% men and 20% women, with a median age of 63 years (quartiles 56–70 years). The patients have an average weight of 80 kg – 7,3 kg. No significant difference in serum potassium levels from when the target temperature was obtained to when normal temperature was restored was found in patients with VF compared to those with asystole ( p > 0.132), or when analyzing independently on age ( p > 0.198). The data for all patients, independent of primary arrhythmia and age, are therefore analyzed together. Temperature Figure 1 shows potassium levels and temperature during and after TH. The median cooling period to obtaining the target temperature (p34C) is 2 hours (quartiles 1–3 hours) counted from admission to the intensive care unit. The

FIG. 1. Median temperature and potassium levels related to time in out-of-hospital cardiac arrest patients treated with therapeutic hypothermia. Hour 0 is when target temperature of mild hypothermia (p34C) is reached.

32

SOEHOLM AND KIRKEGAARD

FIG. 2. Number of patients treated with therapeutic hypothermia who suffered from hypokalemia with serum potassium levels < 3.5 mmol/L and hyperkalemia with serum potassium levels > 5.0 mmol/L illustrated with the median temperature curve related to time. median rewarming period is 8 hours (quartiles 6–10 hours). After rewarming, 68% suffer from hyperthermia (q38.0C), but no significant difference in serum potassium (from when the target temperature is obtained to when the normal temperature is restored) is found between the normothermic and the hyperthermic patients ( p > 0.113). The cerebral outcome was not analyzed in this study. Serum potassium Potassium levels decrease significantly during the cooling phase from a median admission value of 4.0 mmol/L (3.6–4.5 mmol/L) to a nadir of 3.6 mmol/L (3.5–3.9 mmol/L) 6 hours after hypothermia is reached ( p = 0.005). During the hypothermia period, all 54 patients had potassium values < 4.0 mmol/L, 76% had levels < 3.5 mmol/L at the median 5 hours (quartiles 2–13 hours), and 13% had severe hypokalemia < 3.0 mmol/L. The number of patients suffering from hypokalemia per hour is shown in Figure 2. It can be seen that the majority of patients suffer from hypokalemia during the period were the body temperature decreases and during the following hours after the target temperature is reached. The peak potassium value of 4.7 mmol/L (4.1–5.0 mmol/L) is reached at hour 34 (Fig. 1). Remarkably fewer patients suffered from hyperkalemia compared with hypokalemia (Fig. 2). Almost half of the patients had potassium levels > 5.0 mmol/L (46%), 15% of patients had potassium levels > 5.5 mmol/L, and only four patients reached values > 6.0 mmol/L.

Potassium correction All patients, except for one, were treated with supplementary potassium during TH. The primary potassium correction treatment was intravenous-infusion (IV), but eight patients were treated with oral administration only. Potassium correction is initiated 4 hours after target temperature is reached at a median potassium value of 3.4 mmol/L (3.2– 3.6 mmol/L) for IV and oral administration. IV-infusion is stopped at 4.5 mmol/L 1 hour before normothermia is restored (hour 31). Because the oral administration of potassium is not carried out continuously, the termination of the oral treatment cannot be analyzed. Median dose of IV potassium during the 24 hours of cooling is 129 mmol (quartiles 72–162 mmol) and for the eight patients only treated with oral supplementation the median dose is 115 mmol (86–121 mmol). No significant difference is found between the total amount of potassium given to the eight patients with hyperkalemia > 5.5 mmol/L compared with the rest of the patients ( p > 0.212). Arrhythmias One third of the patients suffered from arrhythmias during TH (VF, ventricular tachycardia (VT), atrial fibrillation (AF), and atrioventricular (AV) block). All patients, except for one, suffered from the arrhythmia during the TH period (Table 1). Potassium levels during the cooling phase of TH (hour 0 to 24) for patients with and without arrhythmias are not

Table 1. Arrhythmias: Ventricular Fibrillation, Ventricular Tachycardia, Atrial Fibrilliation, Atrioventricular Block All arrhythmias Number of patients S-K level at the time of the arrhythmia Time of the arrhythmia Temperature at the time of the arrhythmia

19/54 4.0 mmol/L Hour 10 33.1C

(35%) (3.7–4.6 mmol/L) (1–22) (32.2–33.2C)

Median values are given, with quartiles within parentheses. S-K, serum potassium; VT, ventricular fibrillation; VT, ventricular tachycardia.

VT/VF 7/54 3.6 mmol/L Hour 4 33.2C

(13%) (3.5–4.4 mmol/L) (0–8) (33.7–33.3C)

POTASSIUM AND THERAPEUTIC HYPOTHERMIA

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Table 2. Acid-Base Parameters During Therapeutic Hypothermia

pH pCO2 SBE Lactate

Admission

Hour 0 (p34C)

Hour 24

Hour 32 (normothermia)

Hour 48

7.29 (7.25; 7.35) 5.7 (5.2; 6.7) - 4.4 ( - 7.5; - 2.7) 2.2 (1.3; 3.5)

7.32 (7.27; 7.40) 5.4 (4.6; 6.3) - 5.0 ( - 6.8; - 2.9) 1.7 (1.1; 2.6)

7.36 (7.33; 7.39) 5.3 (4.8; 5.5) - 3.8 ( - 4.7; - 1.8) 1.7 (1.0; 2.0)

7.37 (7.34; 7.39) 5.1 (4.7; 5.5) - 3.4 ( - 4.9; - 1.8) 1.4 (1.1; 1.7)

7.42 (7.38; 7.45) 4.7 (4.2; 5.3) - 2.1 ( - 3.4; - 0.8) 1.1 (0.8; 2.1)

Median values are given, with quartiles within parentheses.

significantly different ( p = 0.119). Seven patients (13%) had adverse arrhythmia (VF or VT). Potassium levels at target temperature and at hour 24 (just before rewarming) in patients without arrhythmia compared with VF/VT are lower although not significant, phour 0 = 0.47, phour 24 = 1, in nonparametric tests. The potassium level at the time of the adverse arrhythmia is lower (median 3.6 mmol/L) compared with patients suffering from AF or AV-block (median 4.0 mmol/L), though not significantly lower ( p = 0.384; Table 1). Acid-base, insulin, and inotropics The level of pH at admission is low, but normalizes at the end of TH, as does the standard base excess and lactate (Table 2). Blood-glucose values (Fig. 3) are high at admission but decrease to a stable level of 6–8 mmol/L (108–144 mg/dL) when mild hypothermia is obtained. A total of 23 of 54 patients (43%) were treated with supplementary insulin on a sliding scale evenly throughout the hypothermia period (Fig. 3). A total of 88% of patients were treated with one (31 patients), two (11 patients), or three (six patients) types of inotropics. Dopamine alone was given to 25 patients, dobutamine to six patients, and the most common combination of the two was given to seven patients. Norepinephrine and epinephrine were used as the second or third add on for five and six patients respectively. The mean arterial pressure was stable during TH at 77.5 mmHg (quartiles 75.0 and 83.6 mmHg).

Sixteen patients (30%) were treated with Amiodarone, all with a loading dose of 300 mg and a maintenance dose of 50 mg/ hour. Discussion Therapeutic hypothermia has been used for nearly 9 years as a standardized treatment after successful resuscitation from OHCA due to VF and non-shockable rhythms, but the treatment is associated with a number of adverse events (Castren et al., 2009; Kim et al., 2011; Lundbye et al., 2011). The correlation between potassium abnormalities and the tendency to suffer from arrhythmia is well established (Podrid, 1990; Cohn et al., 2000). This study confirms the findings in previous studies that serum potassium decreases significantly during TH. Treatment guidelines for patients treated with TH recommend replacing potassium to maintain normal levels and avoid hypokalemia, but the recommendations are not based on a single clinical study (Castren et al., 2009). The serum potassium levels for the three patients that died during the data collection period were within normal levels and could therefore not explain the cause of death. Serum potassium levels are influenced by several factors during TH: the shift between the intra- and extracellulary space due to endogenous catecholamines during and after the cardiac arrest, the low body temperature leading to ‘cold’ diuresis, the kidney function and urinary excretion, serum

FIG. 3. Median blood-glucose, insulin treatment, and temperature related to time in patients treated with mild therapeutic hypothermia. Blood-glucose (measured in mmol/L) and insulin (IU) are shown on the left axis and temperature (C) is shown on the right axis.

34 pH, amount of supplementary insulin, administered catecholamines, as well as the amount of diuretics given (Curry and Curry, 1970; Boelhouwer et al., 1987; Sprung et al., 1992; Bernard and Buist, 2003; Polderman and Herold, 2009; Mirzoyev et al., 2010). In this study, it does not appear that the potassium changes are caused by either changes in bloodglucose or insulin treatment or by the minimal acid-base changes seen. In the study by Oddo et al, (2006), 36% of 55 patients treated with TH suffered from VF or AF, which is consistent with the number found in our study. Mirzoyev et al. (2010) found that 11% of their patients suffered from polymorphic VT, which is quite consistent with our finding of 13% suffering from VF or VT. But what is worth mentioning is that the two randomized studies by HACA and Bernard do not find any significant difference in arrhythmias in the hypothermic group compared with the normothermic patient group (Bernard et al., 2002; HACA Study Group, 2002). In a recent study, significant differences were found in potassium levels in patients suffering from polymorphic VT compared to patients without this arrhythmia (Mirzoyev et al., 2010). In this study, a tendency, although not statistically significant, toward lower potassium levels in patients with VF/VT was seen. All patients but one suffered from their arrhythmia during TH, which is consistent with other studies (Oddo et al., 2006; Mirzoyev et al., 2010). Overall it seems that the arrhythmias are related to the cold temperature during TH, the period with relative hypokalemia, or perhaps the close relation in time to the cardiac arrest, where circulation is affected and the myocardium is more sensitive to stress. An important issue is the correction with supplementary potassium during TH, and when and how this treatment should be initiated to reduce the risk of arrhythmias. No good evidence for treatment with supplementary potassium during TH is found in the literature, except for the recent study by Mirzoyev et al. (2010). In the study by Mirzoyev et al. (2010), 64% of the patients were treated with a mean dose of 57 mmol/L, which is lower that in this study, with treatment of 98% of patients and a median dose of 129 and 115 mmol/L for IV and oral supplementation respectively. Some studies argue that potassium correction with supplementary potassium should not be carried out, as hypokalemia during TH protects the heart from developing arrhythmias and the sensitivity to exogenous potassium is increased during TH (Sprung et al., 1992). Another view is that treating hypokalemia is not necessary during TH, as potassium fluctuations are physiological (a shift from extracellulary to intracellulary space during hypothermia and vice versa during rewarming; Sprung et al., 1992; Castren et al., 2009). Sprung et al. (1992) finds a significant decrease in serum potassium during mild hypothermia (31C) in rats. By ligating the rats’ urinary tract, the excretion of potassium is eliminated during rewarming. In the control group (no potassium supplementation), a normalization of serum potassium was seen after rewarming. But in rats receiving supplementary potassium a statistical significant hyperkalemia after rewarming was documented (Sprung et al., 1992). The study is performed over a short period of time, as the rewarming takes place over 30–40 minutes (Sprung et al., 1992). Other studies argue the opposite by saying that the kidneys will have time to excrete excess potassium only if rewarming is done slowly (Nolan et al., 2003; Castren et al., 2009).

SOEHOLM AND KIRKEGAARD In this study and that by Mirzoyev et al. (2010), arrhythmias are primarily seen during the cooling phase of TH when the lowest level of potassium is seen and not during the rewarming period. Mirzoyev et al. (2010) found a significant association between hypokalemia and the development of polymorphic VT, and the association was particularly strong in the cooling phase. They conclude that keeping the potassium level > 3.0 mmol/L may be critical to avoid the development of polymorphic VT during TH. It seems reasonable to keep serum potassium levels within the normal limits of 3.5–5.0 mmol/L during TH, or at least > 3.0 mmol/L. Recommendation for patients with ischemic heart disease have in older studies been defined as serum potassium levels of 4.0–4.5 mmol/L, and as many patients with OHCA have ischemic heart disease, this strict level can be reasonable as well (Cohn et al., 2000). A newly published observational study of 38,000 patients with ST-segment elevation myocardial infarction shows a U-shaped odds ratio for the rate of VF/cardiac arrest corresponding to high ( > 4.0 mmol/L) and low ( < 3.0 mmol/L) potassium levels with the lowest mortality rates for 3.5–4.0 mmol/L (Goyal et al., 2012). A significantly higher risk was seen when inhospital levels went below 3.0 mmol/L (odds ratio 2.31 (0.74– 7.24)) or above 5.0 mmol/L (odds ratio 1.62 (1.16–2.26)). The authors argue that guidelines for potassium levels of 3.5– 4.5 mmol/L are reasonable in patients with acute myocardial infarction (Goyal et al., 2012). Especially during the cooling phase, potassium levels should be closely monitored and cautious supplementation should be initiated, as this phase has been shown to be vulnerable to developing arrhythmia (Mirzoyev et al., 2010). The cooling phase is also closely related to the cardiac arrest, where the myocardium is even more susceptible to electrolyte changes and other arrhythmogenic factors that can destabilize the membranes in the cardiac myocytes. The potassium supplementation treatment in the present study was initiated at a median potassium level of 3.5 mmol/L 4 hours after the goal temperature was reached, and in five patients the serum potassium level dropped to < 3.0 mmol/L before the initiation. This indicates that potassium correction in general is initiated too late. To make sure potential excess potassium is excreted, rewarming should be done slowly over at least 8 hours or at a speed of 0.3–0.5C per hour (Nolan et al., 2003; Sterz et al., 2003; Castren et al., 2009). In this study, eight patients suffered from hyperkalemia with potassium levels > 5.5 mmol/L, but no clear association between hyperkalemia and the amount of potassium supplementation or the speed of rewarming could be found. The IV-infusions for these patients were terminated at serum potassium level of 4.9 mmol/L (median), which is a plausible reason for the hyperkalemia. In the study by Mirzoyev et al, (2010), the peak serum potassium was 4.19 – 0.7 (40 hours after initiation of cooling), and in this study the peak value is 4.7 mmol/L (4.1–5.0 mmol/L) 34 hours after the goal temperature is reached. This difference might be explained by the considerably lower amount of supplementary potassium given by Mirzoyev, as mentioned above. In this study, potassium supplementation is stopped 1 hour prior to reaching normothermia at a median serum potassium level of 4.5 mmol/L. This is in our opinion too late. Potassium depletion is primarily seen during the cooling phase and to avoid partly the rebound hyperkalemia and partly the increased mortality found in patients with serum potassium

POTASSIUM AND THERAPEUTIC HYPOTHERMIA levels > 5.0 mmol/L (odds ratio 1.62 (1.16–2.26; Goyal et al., 2012). Therefore potassium correction should be stopped in due time before normothermia is reached. IV potassium infusion is preferred, as uptake of oral mixture is affected by many factors, for example low body temperature (Bernard and Buist, 2003). The limitations of this study consist of the restricted number of patients and the fact that we did not have a control group (i.e., no supplementation of potassium or a normothermic group of patients). We did not have measurements of the kidney function or the urinary excretion of potassium. The latter would have helped to estimate and quantify the amount of potassium excreted and the amount shifting from the intrato the extracellulary compartment. These results would have contributed to a more precise estimation of the need for supplementary potassium. The arrhythmias were observed and documented by the intensive care staff, but it would have been more precise to study electrocardiograms or continuous telemetry recordings for the analysis of the arrhythmia. Conclusion Serum potassium decreases significantly during the induction of therapeutic hypothermia ( p = 0.005). Potassium levels were not found to be different in patients with and without VF/VT in this study, perhaps due to the low number of patients, as a difference has been seen in other studies. Infusion of supplementary potassium is recommended to be initiated during the early cooling phase in order to avoid severe hypokalemia (serum potassium < 3.0 mmol/L) and terminated in due time before normothermia is reached during rewarming in order to avoid severe hyperkalemia (serum potassium > 5.5 mmol/L), as serum potassium increases during rewarming. Acknowledgment The article was previously published as an abstract: Andersen HS, Kirkegaard H. Changes in serum potassium during mild therapeutic hypothermia after cardiac arrest. Acta Anaesth Scand 2009;53:44–61. Disclosure Statement No competing financial interests exist. References Bernard SA, Buist M. Induced hypothermia in critical care medicine: a review. Crit Care Med 2003;31:2041–2051. Bernard SA, Gray TW, Buist MD, Jones BM, Silvester W, Gutteridge G, Smith K. Treatment of comatose survivors of outof-hospital cardiac arrest with induced hypothermia. N Engl J Med 2002;346:557–563. Boelhouwer RU, Bruining HA, Ong GL. Correlations of serum potassium fluctuations with body temperature after major surgery. Crit Care Med 1987;15:310–312. Castren M, Silfvast T, Rubertsson S, Niskanen M, Valsson F, Wanscher M, Sunde K. Scandinavian clinical practice guidelines for therapeutic hypothermia and post-resuscitation care after cardiac arrest. Acta Anaesthesiol Scand 2009;53: 280–288. Cohn JN, Kowey PR, Whelton PK, Prisant LM. New guidelines for potassium replacement in clinical practice: a contemporary

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SOEHOLM AND KIRKEGAARD Address correspondence to: Professor Hans Kirkegaard, M.D., Ph.D., D.MSc. Department of Anesthesia and Intensive Care Medicine Aarhus University Hospital, Skejby Brendstrupgaardsvej 100 8200 Aarhus N Denmark E-mail: [email protected]