QT Interval Dispersion in Acute Alcohol Intoxication

International Journal of Advance in Medical Science (AMS) Volume 4, 2016 doi: 10.14355/ams.2016.04.001

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QT Interval Dispersion in Acute Alcohol Intoxication Willy Aasebø Medical Department, Section of Nephrology, Akershus University Hospital, 1478 Lørenskog, Norway wiaa@ahus.no Abstract Alcohol intoxication is probably the most common intoxication worldwide. Some studies have suggested an association between QT interval dispersion (QTd) and the risk of arrhythmias. The aim of this report is to assess how alcohol in potential lethal blood concentrations affects QTd. Eighty-four patients were included in analyses. QTd at admittance was compared with a control group (n = 27) and with QTd at discharge. Univariate and multivariate logistic regression analyses were performed in order to explore odds ratio for dispersion including several variables. Mean QTd was 48.6 msec (SD: 13.9) in alcohol intoxicated patients compared to 40.8 msec (SD: 16.5) in the controls (p = 0.019). QTd was larger at admission than at discharge in patients with alcohol intoxication (49.7 msec (13.3) vs. 41.9 (13.8). P = 0.032). Mean blood alcohol level was 2.9‰ in the study group.

High to very high blood alcohol concentration may increase QT interval dispersion.

Keywords Alcohol Intoxication; ECG; QTd; QTc Interval

Introduction Alcohol intoxication is probably the most common intoxication worldwide and may cause physical and psychological harm in different ways. Deaths may occur related to binge drinking. The mean serum ethanol concentration in deaths caused by alcohol intoxication, in one study, was 3.2‰ (range 2.3–5.0‰) [1]. The exact mechanism by which alcohol intoxication contributes to death is unknown, although ventricular tachyarrhythmias degenerating into fibrillation is a possible cause [2]. In alcoholics, cardiac arrhythmias may occur during a binge or shortly after [3-5], however arrhythmias have also been reported when non-alcoholics drink [6].

In general, no single variable in the ECG can predict cardiac arrhythmias, though some features have been associated with later development of arrhythmia. Thus, an association has been established between prolonged corrected QT interval (QTc) and sudden death [7-10]. Some previous studies have found that an increased QT interval dispersion (QTd) is a marker for arrhythmias [11-13]. However, in a number of studies, QTd did not have a prognostic value [11,12]. Finally some reports have stated that the larger the QTd the higher the risk of arrhythmias [13,14].

Alcohol in (very) high blood concentrations has been shown to prolong several ECG intervals: P-wave, PR interval, QRS complex and QTc interval as well as increased QRS voltage [15,16]. Moderate alcohol intake has been associated with increased QTd in a previous study [17]. In the present study of patients hospitalised with acute alcohol intoxications the effect of alcohol in (very) high blood concentrations on QTd was explored.

Methods Subjects and Study Design Thirty-two consecutive patients admitted to Akerhus Universtity hospital in Norway with acute alcohol intoxication had ECGs taken at admittance and at discharge. In addition, 86 patients were admitted for acute alcohol intoxication during the same year of whom 52 were retrospectively included (se exclusion criteria below).

To establish a control group of patients without alcohol intoxication, all patients who during a 2-week period were

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admitted to the hospital’s medical observation unit and had their ECG recorded both at admission and discharge (n = 27) were included.

Patients with incomplete data, those having consumed other toxic alcohols, patients living in nursing homes or other institutions and those presenting with cardiac arrhythmias, AV-blocks or bundle branch blocks, unstable coronary heart disease, heart failure, other severe symptoms than those of intoxication or daily use of >5 medications at hospital admission, were excluded.

During hospitalisation 10 patients (31%) in the alcohol-intoxicated group (n = 32) received specific medical treatment (4 N-acetylcystein, 5 carbamazepine, 1 naloxone and flumazenil and 6 miscellaneous neuroleptics), and 5 patients (19%) in the control group (n = 27) (1 antibiotics, 1 acetylsalicylic acid, 2 low molecular heparin, 1 esomeprazol, and 1 ketomidon).

Laboratory Examinations and ECGs At admission, serum osmolality (mOsm/Kg H2O) was measured, using freezing point depression technique, to estimate the approximate serum ethanol concentration. To obtain an estimate of serum ethanol concentration in ‰, adapted to our laboratory, a regression equation for conversion from a sample of consecutive patients who later were admitted to the hospital and had both serum ethanol and osmolality measured was performed (n = 62, adjusted R2 = 0.92): CEthanol = (Cosmolality – 295) / 2.8.

The ECGs were recorded on paper with the speed 50 mm/s, using a Marquette Mac 6 (Marquette Electronics Inc, Milwaukee, USA) or a Siemens Sicard 460 (Siemens Elena, Germany) apparatus. QTd was calculated as the difference between maximum and minimum QT interval in each ECG. One investigator, without any knowledge of the patient, examined all ECGs. In the alcohol-intoxicated group with two ECGs (n = 32) the mean time between ECG at admission and discharge was 20 hours (range 6-44), compared with 17 hours (range 4-31) in the control group (n = 27).

Patients were classified as alcoholics if they previously had been hospitalised with alcohol intoxications, if they considered themselves to be alcoholics (admitted daily or periodically uncontrolled consume of alcohol), if they had known complications related to long-term use of alcohol and/or if they had been in contact with the alcohol ward.

Statistical Analysis For group comparison t-tests or chi square tests were used. Univariate and multivariate logistic regression analyses were performed in order to further explore associations between QTd and several variables: blood alcohol concentration, comorbidity (no/yes), alcohol habits (alcoholics vs. occasional drinkers), age, sex, treatment during hospitalisation (n = 32 only), s-sodium, s-potassium, s-albumin and albumin corrected s-calcium.

Two multiple logistic regression analysis were performed. In the first, including all patients, QTd >40 msec vs. QTd =< 40 msec was selected as dependent variable. In the second analysis positive QTd difference between ECGs taken at admittance, influenced by high blood alcohol concentration, and discharge, after sobering up, vs. zero or negative difference was selected as dependent variable (n = 32).

We chose a 5% significance level using two-sided tests. The SPSS version 16.0 (SPSS Inc., Chicago, Ill.) or Statview version 5.0.1 (SAS Institute, Inc., Cary, NC) were used for statistical analysis.

Results Table 1 shows differences in characteristics between groups. Mean blood alcohol concentration was 2.9‰. QTd was larger in patients with acute alcohol intoxication than in the control group (Figure 1). QTd was larger at admittance than at discharge in patients admitted for acute alcohol intoxication (Figure 1). In the logistic regression analyses males had higher odds ratio for high QTd than females and alcoholics had lower odds ratio for positive QTd difference between ECGs taken at admittance and at discharge (Tables 2 and 3).

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TABLE 1 CHARACTERISTICS OF PATIENTS ADMITTED FOR ACUTE ALCOHOL INTOXICATION AND THE CONTROL GROUP. MEAN (SD) UNLESS OTHERWISE NOTED.

Study group (n = 84)

Control group (n = 27)

p

Age (years)

38.6 (15.7)

53.0 (20.2)

<0.001

Male sex

52 (62%)

16 (59%)

0.80

No comorbidity

48 (57%)

17 (63%)

0.92

No treatment

46 (55%)

18 (67%)

0.74

Alcoholics

38 (45%)

Heart rate (beats/min)

85.1 (15.4)

77.6 (16.6)

0.034

S-Sodium (mmol/l)

143.9 (3.2)

139.4 (3.3)

<0.001

S-Potassium (mmol/l)

4.1 (0.4)

3.9 (0.4)

0.042

S-Calcium (mmol/l)

2.31 (0.14)

2.24 (0.15)

0.11

Albumin adjusted Ca.

2.36 (0.12)

2.34 (0.14)

0.53

S-Albumin (g/l)

40.6 (4.3)

35.2 (6.8)

0.001

55 p = 0.032

p = 0.019

50

QTd

45

40

35

30 Admission

Discharge

Alcohol intoxication at admission vs. at discharge (n = 32).

Alcohol intox

Controls

Alcohol intoxication at admission vs. control group (n = 112).

FIGURE 1 QT INTERVAL DISPERSION (QTd) IN PATIENTS WITH ALCOHOL INTOXICATION COMPARED WITH THE SAME PATIENTS AT DISCHARGE AND COMPARED WITH SOBER CONTROLS. TABLE 2 QT INTERVAL DISPERSION (OTD) (>40 MSEC VS. <= 40 MSEC) EXPLORED BY LOGISTIC REGRESSION (N = 109)

Univariate

Multivariate

Odds Ratio

95% C.I.

P

Odds Ratio

95% C.I.

P

Age

0.97

0.95-1.00

0.022

0.97

0.95-1.00

0.046

Sex (Female to Male

1.98

0.90-4.32

0.088

2.52

1.06-5.97

0.036

Blood Alcohol Concentration

1.01

1.00-1.02

0.15

1.01

0.99-1.02

0.28

Alcohol Habits (OD to Alcoholics)

1.05

0.48-2.33

0.90

0.92

0.32-2.68

0.88

Comorbidity (None to Yes)

0.71

0.31-1.61

0.41

0.92

0.35-2.37

0.86

TABLE 3 DIFFERENCES IN QT INTERVAL DISPERSION (QTD) FROM ADMITTANCE TO DISCHANRGE EXPLORED BY LOGISTIC REGRESSION (N = 32).

DEPENDENT VARIABLE: POSITIVE DIFFERENCE VS. NONE AND NEGATIVE DIFFERENCE.

Univariate

Multivariate

Odds Ratio

95% C.I.

p

Odds Ratio

95% C.I.

p

Age

1.01

0.97-1.06

0.61

1.04

0.97-1.12

0.25

Sex (Female to Male)

4.68

1.04-21.04

0.044

10.66

1.44-68.72

0.020

Blood Alcohol Concentration

1.02

0.99-3.06

0.69

0.096

0.007-1.31

0.079

Alcohol Habits (OD til Alcoholics)

0.75

0.18-3.06

0.69

0.096

0.007-1.31

0.079

Treatment in hospital

2.33

0.48-11.44

0.30

3.95

0.43-36.23

0.22

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Discussion The main finding in this study is that QT interval dispersion (QTd) seemed to be affected by alcohol in (very) high blood concentrations. This is in line with one previous study that included healthy volunteers receiving a moderate amount of alcohol compared to the blood alcohol levels in patients in the present study [17]. No linear doseresponse relationship between alcohol concentration and QTd was found, but this may in part due to the fact that subjects with low to moderate blood alcohol concentrations were not included in the study.

Although deaths caused by alcohol intoxication have been reported at low serum ethanol concentrations, the majority of these deaths occur in persons with high concentrations [1]. The mechanisms are uncertain, but acute ethanol intoxication or abstinence/hangover influences many physiological mechanisms in the heart, for example the autonomic nervous system [18,19], ion channels involved in the action potentials [20,21], and modulation of receptor proteins [21]. Alterations in these physiological processes might also affect QTd. The finding that males had larger QTd than females is intriguing. Previously, QTd has not been considered to be gender dependant [14]. The small number of subjects included in the present study may have influenced the result.

The difference in QTd from admission to discharge (Table 3) between sexes is probably a result of the small QTd in females at admission. Surprisingly, alcoholics did not differ from occasional drinkers in QTd at admission.

However, alcoholics still had high QTd at discharge whereas occasional drinkers did not, indicating that the abstinence experienced by alcoholics might be different from the hangover in occasional drinkers, or that alcoholics may have chronic changes in the heart. A previous study has described that alcoholics in their abstinence phase have prolonged QTc [22], the present study indicated that QTd also may be affected.

QT interval dispersion (QTd) is the difference between the longest and shortest QT interval in the standard 12-lead ECG. Increased QTd has been related to inhomogeneity of ventricular depolarisation [11,12]. However, the meaning of QTd has been questioned, some papers argued that QTd is an artefact and should be discarded [11,12].

On the other hand one recent study described that successful cardiac reperfusion decreased QTd, indicating that QTd is not an artefact [23]. In the present study QTd was larger in conditions when the blood alcohol level was high compared to QTd in the same patient after most of the alcohol was metabolised. The dynamics of QTd is of interest, indicating that alcohol indeed affects QTd even though the magnitude of QTd is small. The magnitude of QTd may be relevant to risk of Arrhythmias [24]. In apparently healthy individuals, QTd >50 msec was considered abnormal and might indicate an increased risk of arrhythmias [25]. In the present study mean QTd was 48.5 msec.

The length of the QT interval, and thus QTd, depends on heart rate. Higher heart rate shortens the QT interval. In this study the differences in heart rate was small, but the heart rate was higher in the alcohol-intoxicated group than in the control group. This might contribute to lessen the QTd in the study group, compared to the controls, thus contradicting the results.

This study has several limitations, such as the difficulty in obtaining accurate information from intoxicated patients, both at admission and the following day. Some patients received medication that may have affected the results.

The ECGs obtained before hospital discharge do not represent a normal situation for the patients. Some of them were discharged before elimination of all the ethanol, or in a situation with symptoms of hangover or abstinence that also may have affected the ECGs. However, it is unethical to intoxicate humans with alcohol to the levels in this study in a laboratory setting. Therefore, it is not possible to control all confounding variables.

We used serum osmolality as an indicator of the level of ethanol influence. The use of an indirect measure is a weakness of the study because many osmotically active substances influence serum osmolality. On the other hand previous studies have found a close association between serum values of osmolality and ethanol [26]. In some patients with alcoholic acidosis the osmolal gap may not accurately reflect serum ethanol concentration [27].

Conclusion Despite some methodological difficulties this study suggests an association between high blood alcohol concentration and QT dispersion. Whether or not these findings indicate increased risk of arrhythmias related to alcohol intoxication is highly uncertain. However it may contribute to a better understanding of how alcohol in potential lethal concentrations affects the heart.

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REFERENCES

[1]

Aasebø, W., Erikssen, J. and Jonsbu J. Dødsfall i Norske Politiarrester. Tidsskr Nor Laegeforen 123 (2003): 1066-7.

[2]

Kupari, M. and Koskinen, P. Alcohol, cardiac arrhythmias and sudden death. Novartis Found Symp 216 (1998): 68-85.

[3]

Ettinger, P.O., Wu, C.F., De La Cruz C. Jr., Weisse, A.B. and Regan T.J. Arrhythmias and the “Holiday Heart”: Alcoholassociated cardiac rhythm disorders. Am Heart J 95 (1978): 555-62.

[4]

Fuenmayor, A.J. and, Fuenmayor, A.M. Cardiac arrest following holiday heart syndrome. Int J Cardiol 59 (1997): 101-3.

[5]

Greenspon, A.J., Stang, J.M., Lewis, R.P. and Schaal, S.F. Provocation of ventricular tachycardia after consumption of alcohol. N Engl J Med 301(1979): 1049-50.

[6]

Thornton, J.R. Atrial fibrillation in healthy non-alcoholic people after an alcoholic binge. Lancet 2 (1979): 1013-4.

[7]

Day, C.P., James, O.F., Butler, T.J. and Campbell, R.W. QT prolongation and sudden cardiac death in patients with alcoholics liver disease. Lancet 341 (1993): 1423-7.

[8]

Brooksby, P., Batin, P.D., Nolan, J. et al.(1999) The relationship between QT intervals and mortality in ambulant patients with chronic heart failure. Eur Heart J 20 (1999): 1335-41.

[9]

Rossinen, J., Sinisalo, J., Partanen, J., Nieminen, M.S. and Viitasalo, M. Effects of acute alcohol infusion on duration and dispersion of QT interval in male patients with coronary artery disease and in healthy controls. Clin Cardiol 22 (1999): 5914.

[10] Straus, S.M., Sturkenboom, M.C., Bleumink, G.S. et al. Non-cardiac QTc-prolonging drugs and the risk of sudden cardiac death. Eur Heart J 26 (2005): 2007-12.

[11] Molnar, J. and Somberg, J.C. QT dispersion: still a useful measurement. Cardiology 112 (2009): 165-7.

[12] Molnar, J. and Somberg, J.C. The dynamics of QT dispersion. Cardiology 113 (2009): 169-71.

[13] Cuddy, T.E., Halli, P.S. and Tate, R.B. QT dispersion and heart rate predict the risk of sudden unexpected cardiac death in men: the Manitoba follow-up study. Preventive Cardiology 12 (2009) 27-33.

[14] Macfarlane, P.W., McLauglin, S.C. and Rodger, J.C. Influence of lead selection and population on automated measurement of QT dispersion. Circulation 98 (1998): 2160-7.

[15] Aasebø, W., Erikssen, J. and Jonsbu, J. ECG changes in patients with acute ethanol intoxication. Scand Cardiovasc J 41 (2007): 79-84.

[16] Aasebø, W. ECG-voltage in alcoholics and non-alcoholics with acute alcohol intoxication. J Forensic Leg Med. 26 (2009): 381-4.

[17] Uyarel, H., Ozdol, C., Gencer, A.M., Okmen, E. and Cam, N. Acute alcohol intake and QT dispersion in healthy subjects. J Stud Alcohol 66 (2005): 555-8.

[18] Mäki, T., Toivonen, L., Koskinen, P., Näveri, H., Härkönen, M. and Leinonen, H. Effect of ethanol drinking, hangover, and exercise on adrenergic activity and heart rate variability in patients with a history of alcohol-induced atrial fibrillation. Am J Cardiol 82 (1998) :317-22.

[19] Reed, S.F., Porges, S.W. and Newlin, D.B. Effect of alcohol on vagal regulation of cardiovascular function: contributions of the polyvagal theory to the psychophysiology of alcohol. Exp Clin Psychopharmacol 7 (1999): 484-92.

[20] Deitrich RA, Dunviddie TV, Harris A et al. (1989) Mechanism of action of ethanol: Initial central nervous system actions.

Pharmacol Rev 41 (1989): 489-537.

[21] Narahashi, T., Kuriyama, K., Illes, P. et al. Neuroreceptors and ion channels as targets of alcohol. Alcohol Clin Exp Res 23 (2001): 182-8.

[22] Otero-Anton, E., Gonzalez-Quintela, A., Saborido, J. Torre, J.A., Virgos, A. and Barrio, E. Prolongation of the QTc interval during alcohol withdrawal Syndrome. Acta Cardiol 52 (1997): 285-94.

[23] Jimènez-Candil, J., Hernandez Hernandez, J., Agüero, V.L. et al. Early reduction of QT dispersion after primary percutaneous intervention in ST-segment elevation acute myocardial infartion: mechanisms and clinical implications.

Cardiology 113 (2009): 172-9.

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[24] Engel, G., Beckerman, J.G., Froelicher, V.F. et al. Electrocardiografic arrhythmia risk testing. Curr Probl Cardiol 29 (2005): 365-432.

[25] Zaidi, M., Robert, A., Fesler, R., Derwaal, R. and Brohet C7) Dispersion of ventricular repolarization: a marker of ventricular arrhythmias in patients with previous myocardial infarction. Heart 78 (1997): 371-5.

[26] Pappas AA, Gadsden RH, Taylor EH. (1985) Serum osmolality in acute intoxication: a prospective clinical study. Am J Clin Pat 84:74-9.

[27] Braden, G.L., Strayhorn, C.H., Germain, M.J., Mulhern, J.G. and Skutches, C.L. Increased osmolal gap in alcoholic acidosis.

Arch Int Med 153 (1993): 2377-80.

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