Alcohol and Alcoholism Advance Access originally published online on October 18, 2005
Alcohol and Alcoholism 2006 41(1):5-10; doi:10.1093/alcalc/agh221
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Published by Oxford University Press on behalf of the Medical Council on Alcohol.
HYPERTENSION IN EARLY ALCOHOL WITHDRAWAL IN CHRONIC ALCOHOLICS
1 Alcohol Unit, University La Sapienza, Rome, 2 Istituto Superiore di Sanità, Rome and 3 Emergency Dept., University La Sapienza, Rome, Italy
* Author to whom correspondence should be addressed at: Via G. Lanza 172, 00184, Rome. Fax: +390649972096; E-mail: mauro.ceccanti{at}uniroma1.it
(First received 4 May 2005; first review notified 11 July 2005; in final revised form 25 August 2005; accepted 20 September 2005)
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ABSTRACT |
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Aims: Hypertension is an established risk factor in chronic alcoholics, but little is known about the relationship between blood pressure (BP), severity of their alcohol abuse, and severity of alcohol withdrawal syndrome (AWS). Method: BP was assessed daily for 18 days in a series of chronic alcoholics on early alcohol withdrawal (AW), while also assessing the severity of their AWS on the CIWA-Ar scale. Results: A sharp and sustained decrease in BP was observed after AW; at T0, BP had increased in 55% of patients, and at T18 in 21%. The variation of BP is partially explained by years of at-risk drinking and AWS severity, but other factors may play a role in hypertension in alcoholics, as a large amount of BP variation was not explained by the alcohol-abuse-related parameters that we studied. BP values were not correlated with cigarette smoking, anxiety, or depression. Hypertension found in ‘detoxified’ alcoholics (
20%) may be related to alcohol-independent hypertension or to a long-lasting alcohol-induced derangement of the BP regulating mechanisms. Further research is needed in these patients to elucidate the mechanisms of persistent hypertension and to set up a treatment protocol. At present, careful monitoring is advisable, as well as pharmacological treatment for moderate or severe hypertension; often a modification of life-style is needed which includes physical activity and possibly sodium (Na) restriction, since hypertension in detoxified alcoholics seems to be Na sensitive. Conclusion: Complete alcohol abstinence must be recommended to all hypertensive alcoholics, as AW-induced transient hypertension was found to be harmless in all our subjects, and abstinence leads to a complete recovery from hypertension in most cases. |
INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSSTATISTICSRESULTSDISCUSSIONREFERENCES |
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Alcoholism is a worldwide social problem, with severe effects on public health. In Western countries,
10% of the general population aged over 14 years is affected by alcohol abuse or dependence (DSM-IV, 1994
) [In this paper, alcohol abuse is a maladaptative pattern of alcohol consumption, leading to poor job performance, hazardous use, legal problems, social, or interpersonal problems. Alcohol dependence or alcoholism is a chronic abuse leading to alcohol tolerance, withdrawal symptoms, and severe behaviour impairment (DSM-IV, 1994). A drink is a beverage containing 13 g of alcohol. At risk drinking, according to the WHO guidelines, is daily alcohol intake over 40 g (three drinks) for males and 25 (two drinks) for females.], and in the United States an estimated 63 718 deaths were attributable to harmful drinking in 2000 (Rivara et al., 2004).
Among alcohol-related health problems, hypertension is rather common, but it is under-evaluated in many clinical settings. As alcohol is considered to be a vasodilator (Heberden recommended the use of ethanol for the treatment of angina pectoris in 1786) (Heberden, 1786), alcohol-triggered hypertension seems unlikely; unfortunately, the vasodilator effect of alcohol, if any, is completely suppressed by the sympathetic reaction to excess alcohol intake (Randin et al., 1995), as discussed below.
A close relationship between alcohol abuse and hypertension has been established (Puddey et al., 1987; Chobanian et al., 2003); alcohol abuse is an independent variable that acts on BP with a magnitude similar to that observed for obesity (Klatsky, 1995). In a careful meta-analysis of randomized controlled trials, a dose—response relationship was observed between mean reduction in reported consumption of alcohol and net change in both systolic and diastolic blood pressure (SBP, DBP) (Xin et al., 2001).
According to some studies, three drinks a day (40 g alcohol) may trigger a 10 mm Hg BP increase per 10 g/day alcohol intake (Keil et al., 1993; Randin et al., 1995; Nakanishi et al., 2002). In Japanese studies, even light-to-moderate alcohol intake (
12 g/day) seems to have a noticeable influence on BP and on future hypertension in males (Nakanishi et al., 2002; Ohmori et al., 2002). The hypertensive effect of alcohol seems to be independent of age, as hypertension was observed in alcoholics aged between 18 and 30 years (MacMahon, 1987).
Alcohol abuse is a major risk factor in ‘holiday heart syndrome’ (an increased risk of supraventricular tachyarrhythmias), dilative cardiomyopathy, and stroke (Neaton et al., 1995). For haemorrhagic stroke, a relationship with heavy drinking has been reported (Gorelick et al., 1989; Gill et al., 1991; Beghi et al., 1995; Bots et al., 2002; Daniel and Bereczki, 2004; Iso et al., 2004)—while for cerebral infarction, conflicting results have been reported, namely, graded (Beghi et al., 1995), J-shaped (Gill et al., 1991; Iso et al., 2004), or bivariate association (Balow et al., 1966; Gill et al., 1991), or no association at all (Gorelick et al., 1989; Shinton et al., 1993). Controversy remains regarding the effect of mild-to-moderate alcohol consumption: while some studies have reported a protective effect, others have found a dose-dependent linear relationship between the amount of alcohol consumed and the risk of hemorrhagic stroke; in yet others no association was found (Daniel and Bereczki, 2004; Iso et al., 2004).
Increased sympathetic nervous activity, completely suppressing the vasodilator effect of alcohol, seems to be a major factor of hypertension in alcoholics: vasodilating activity is suppressed by the increased production of corticotropin-releasing hormone (CRH), leading to a direct sympathoexcitatory effect. This hypothesis is supported by the suppression of alcohol-induced hypertension by dexamethasone, a CRH-suppressor (Randin et al., 1995).
Other hypertensive mechanisms in alcoholics are alterations of vascular smooth-muscle contractility (triggered by intra- and extra-cellular Ca++ mobilization and activation of the contractile vascular apparatus) and alcohol-induced Mg deficit, influencing cellular Ca++ homeostasis, as well as endothelial vasorelaxation (Maiorano et al., 1999; Chakraborti et al., 2002). In addition, some vasoactive substances, such as catecholamines, prostacyclin, and endothelin, may be affected (Forstermann and Feuerstein, 1987; Grogan and Kochar, 1994). Activation of the renin–angiotensin–aldosterone system is associated with an increased BP sensitivity to sodium (Na) (Vannucchi et al., 1977; Di Gennaro et al., 2000). In chronic alcoholics, insulin resistance, leading to Na retention, vascular smooth-muscle hypertrophy, and increased cytosolic Ca++ levels, all of which trigger hypertension, has been reported (Angelico et al., 2003), as well as hyperdynamic circulation with high cardiac output (Aguilera et al., 1999).
Little is known about the relationship between alcohol withdrawal syndrome (AWS) and hypertension (Balster et al., 1993; Blaho et al., 1996; Ceccanti and Balducci, 1996; Williams and Mc Bride, 1998; Addolorato et al., 1999; Zullino et al., 2004). In chronic alcoholics AWS is fairly frequent and may lead to a sudden derangement of several functions, including BP control and heart rate (HR). After alcohol withdrawal (AW), the channels of N-metil-D-aspartate receptors are suddenly opened, with neuronal depolarization and increased firing. The hypothalamic–pituitary–adrenal system is activated, leading to increased levels of cortisol and catecholamines (Randin et al., 1995). Thus, a transient BP increase may be triggered by AWS, and in hypertensive subjects, such a further increase may be dangerous (Daniel and Bereczki, 2004).
The aims of this study were the assessment of
- BP in alcoholics during early AW, from day 0 (T0) to day 18 (T18)
- The relationship between BP values and the severity of AWS
- The relationship between BP values and severity of alcohol abuse, cigarette smoking, anxiety, and depression.
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MATERIALS AND METHODS |
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Subjects
The subjects enrolled in this study—147 chronic alcoholics (120 males, 27 females, aged 45.3 ± 11.2 years; patient characteristics are reported in Table 1)—entered consecutively in the Alcohol Liver Disease Unit (University "La Sapienza", Rome), where they were treated in the day-hospital (DH) for
20 days (8.00 AM–1.00 PM). The diagnosis of chronic alcoholism was established according to DSM IV criteria (DSM-IV, 1994). Patients affected by any disease (including addiction) other than alcoholism were excluded. Informed consent was obtained from each subject.
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All the patients under study drank alcoholic beverages until the day before admission to the DH (T0). Smoking was not restricted.
SBP and DBP were assessed daily at 9.30 AM, by trained observers using standard mercury sphygmomanometers on the right arm of seated patients after 5 min rest (WHO, 1999; Williams et al., 2004).
Blood alcohol concentration (BAC), BP, HR, and the previous day's alcohol consumption (if any) were recorded. Subjects with BAC values >100 mg/100 ml and/or with ascertained drinking relapse during the study were excluded. Symptoms of AWS (tremors of the hands, agitation, etc.) were carefully investigated, and AWS severity was assessed daily using the CIWA-Ar test (Sullivan et al., 1989), a structured questionnaire based on the semi-quantitative evaluation of the main symptoms of AWS. The highest CIWA-Ar value assessed during the hospitalization was taken into account for statistics. As severe AWS must be treated (Balster et al., 1993; Blaho et al., 1996; Ceccanti and Balducci, 1996; Williams and Mc Bride, 1998; Addolorato et al., 1999; Zullino et al., 2004) to prevent the onset of major AWS complications (seizures, delirium tremens), the patients were divided into two subsets according to their CIWA-Ar levels (Sullivan et al., 1989):
- CIWA-Ar 10 (low CIWA): no pharmacological treatment.
- CIWA-Ar >10 (high CIWA): administration of benzodiazepines: diazepam, 7.5–10 mg three times a day for 5 days; dosage progressively decreased, stopping at day 10.
No hypotensive drugs were administered.
The Severity of Alcohol Dependence Questionnaire (SADQ) test (Schaefer et al., 1987), the Italian version of the State-Trait Anxiety Inventory test (STAI-y2 test) (Spielberger, 1989), the self-rating depression scale (SDS) (Zung, 1965), and the mini mental state test (MMSE) (Folstein et al., 1975) were administered to each patient by a trained psychologist.
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STATISTICS |
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According to their BP values, the subjects were divided into normal, mild, moderate, and severe hypertension subsets, according to the WHO guidelines (WHO, 2000) slightly modified (Table 2). For each patient, if the SBP and DBP values fell into different categories, the highest value was taken for classification (WHO, 1999; Williams et al., 2004
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For each parameter studied, mean and standard deviation were calculated. The significance of differences between means was assessed using Student's t-test. The significance of correlation was assessed using Spearman's R. Non-parametric tests were employed for parameters with non-Gaussian distribution. For nominal parameters, frequency and significance were assessed using the
2 test. Regression analysis (stepwise method) was performed. The SSPS Windows 11.0 statistics package was employed.
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RESULTS |
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Descriptive statistics and alcohol intake parameters are reported in Table 1.
The number of subjects affected by hypertension decreased sharply (Table 3) from T0 (56.5%) to T3 (36.5%), with a slower decrease to T5 (29.9%), T10 (23.8%), and T18 (21.8%). Most patients were in the mild or moderate hypertension groups; severely hypertensive subjects made up only 6.3% at T0 and 0.7% at T18.
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The progressive decrease in BP values from T0 to T18 was significant (Friedman's test, P < 0.0005), as was the decrease in SBP values (P < 0.0005). HR decreased by 6.25 s/min (Willcoxon test, P < 0.0005).
As expected, CIWA-Ar values decreased sharply from T0 to T4 (Table 4). A further slower decrease to T18 was observed. About 31% (n = 41) of the subjects had severe AWS according to their CIWA-Ar values. None of them had major complications. Values of SBP and DBP in the low- and high-CIWA subsets are reported in Tables 5 and 6. At T0, a significant difference between the low-CIWA and high-CIWA subsets was found for SBP values (P < 0.03), for DBP (P < 0.0005), and for HR (P < 0.017).
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A weak but significant relationship (P < 0.002, R = 0.28) between CIWA-Ar values and SBP values (R = 0.28; P < 0.001) was obtained from calculating partial correlation, controlling for age, sex, smoking behaviour, and alcohol-related parameters.
Values of SBP were correlated to CIWA-Ar values at T0 (P < 0.002), T2 (P < 0.008), T3 (P < 0.001), T4 (P < 0.014), and T18 (P < 0.005). Values of DBP were correlated to CIWA-Ar values at T0 (P < 0.006), T2 (P < 10–5), T3 (P < 10–5), T4 (P < 0.006), T5 (P < 0.04), and T18 (P < 0.035).
As expected, CIWA-Ar values were correlated to HR values at T0 (P < 0.01), T3 (P < 0.02), T4 (P < 0.04), and T5 (P < 0.02). No correlation was found between BP values and the number of cigarettes smoked, alcohol intake in the previous month, SADQ test, STAI-y2 test, and SDS test, while a weak correlation between DBP and SADQ test (P < 0.026), SDS test (P < 0.02), and STAI-y2 test (P < 0.004) was found.
Values of CIWA-Ar at T0 were highly correlated to STAI-y2 (R = 0.453, P < 10–5), SDS (R = 0.415, P < 10–5) and SADQ values (R = 0.456, P < 10–5). A weak but significant correlation was found between alcohol intake in the previous month and CIWA-Ar values at T0 (R = 0.211, P < 0.010), age (R = –0.242, P < 0.003), STAI-y2 (R = 0.201, P < 0.015), and SADQ values (R = 0.289, P < 10–5). Years of at-risk drinking was highly correlated (P < 10–5) with age, as expected; a tendency towards correlation with MMSE results was found.
Finally, a multiple regression was assessed using the stepwise method, taking all the alcohol-related parameters (years of at-risk drinking, alcohol intake in the previous month, etc.) and psychological tests (STAI-y2, SDS, SADQ) under study as independent variables, and SBP and DBP as dependent variables at T0 and T18 (Table 6). At T0, 14% of the SBP and DBP was predicted by CIWA-Ar and years of at-risk drinking (P < 0.0005). At T18, 8% of SBP was predicted by CIWA-Ar and years of at-risk drinking (P < 0.004), while only 4% of DBP was predicted by CIWA-Ar alone (P < 0.025).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSSTATISTICSRESULTSDISCUSSIONREFERENCES |
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In our study, 56.5% of the alcoholics during the early stages of abstinence were hypertensive (mild and moderate hypertension in most cases) at T0, but only 21.8% were hypertensive at the end of the observation period. Three major factors could have led to increased BP values in our patients:
- at-risk drinking;
- AWS-related hypertension;
- age-related hypertension.
All these mechanisms may have been present in our patients. As reliable data about the BP values of our patients when they were drinking were not available, the hypertensive effect of alcohol abuse could not be firmly established in this study, but this hypothesis is sustained by some findings, such as the sharp decrease of hypertension after AW; the interval (days) between T0 and the observation time proved to be a good predictor of SBP values.
As expected, BP values were correlated with age, but the increase of BP values was not fully explained by age (30%).
Assessing the stepwise multiple regression, at T0 14% of SBP was predicted by the CIWA-Ar and by years of at-risk drinking, but with a weak correlation; 14% of DBP was predicted by the same parameters, with a strong correlation. At T18, 8% of SBP was predicted by CIWA-Ar and by years of at-risk drinking (strong correlation), while 4% of DBP was predicted by CIWA-Ar alone (weak correlation). Thus, since the variability of BP was only partially explained by the alcohol-related parameters under study, other alcohol-dependent factors, such as impaired endothelium-dependent vasorelaxation (Maiorano et al., 1999), persistent BP dysregulation following AW (King et al., 1994), and marked Na sensitivity of BP (Di Gennaro et al., 2000), could play a significant role.
About 20% of the patients were hypertensive after an 18 day AW, a result similar to the finding of (Aguilera et al., 1999) (28% after a 30 day AW). For these patients this could have been the effect of the long-lasting alcohol-dependent factors discussed below, or they could have been affected by alcohol-independent essential hypertension. In studies of the general Italian population (Capuano et al., 2001; La Torre et al., 2001; Sega et al., 2001; Angelico et al., 2003; Cricelli et al., 2003) the prevalence of hypertension (from 12 to 29%) results were similar to the prevalence found in this study despite bias with respect to BP assessment procedures and the chosen cut-off between normal and hypertensive subjects in the earliest studies.
In our study, one-third of the patients were affected by severe AWS, a possible cause of hypertension in alcoholics during early AW. However, the BP values (from T0 to T18) were not correlated with the CIWA-Ar values (assessing the severity of AWS), while a weak correlation was found between BP and CIWA-Ar values at some observation times. For both SBP and DBP, a significant difference between low- and high-CIWA-Ar subsets was found only at T0. Correlation between CIWA-Ar and BP values was significant only in the first day of AW; DBP seems more correlated to CIWA-Ar than to SBP.
The lack of correlation may be of interest: SBP values seemed not to be affected by cigarette smoking, anxiety, and depression, as suggested (Sjol et al., 2004). However, the finding about smoking may be biased, since self-reported cigarette intake may be underestimated—most alcoholics are uncooperative about reporting their habits, not only about their alcohol intake. Hypertension seems also to be unrelated to recent alcohol consumption.
A remarkable finding is the lack of major complications among the patients affected by severe AWS, in spite of AWS-induced platelet hyperaggregation (Hutton et al., 1981), increased levels of ß-thromboglobulin and platelet factor 4, and increased platelet number (Santini et al., 1986) reported as risk factors of cerebral thrombosis. A possible explanation is the increase of overall fibrinolytic activity in alcoholics during AW, mainly because of decreased tissue-type plasminogen activator inhibitor (PAI-1) levels (Delahousse et al., 2001), reducing the risk of stroke associated with elevated PAI-1 levels and probably also preventing the thrombogenic effects of platelet activation. No patient experienced hallucination or seizures. Thus, AW in a controlled setting proved safe for all the subjects, including severe AWS patients.
In conclusion, taking into account the aims of this study, BP during early AW was assessed and a sharp and sustained decrease of BP was observed after AW: at T0, a BP increase resulted in 56% of patients; at T18, in 21%.
BP value results correlated with CIWA-Ar values, but the significance of the correlation was not stable all through the study. A noticeable finding is that >50% of patients were affected by hypertension (mostly mild or moderate) in the first days after AW.
On assessing the relationship between BP values and severity of alcohol abuse, cigarette smoking, anxiety, and depression, only a correlation between BP and years of at-risk drinking and AWS severity was found. But other factors may play a role in hypertension in alcoholics, as a large part of the BP variation was not explained by the alcohol-abuse-related parameters under study.
An unexpected finding was hypertension in 20% of ‘detoxified’ subjects caused by alcohol-independent hypertension or sustained by some long-lasting alcohol-related hypertensive mechanisms. A long-lasting alcohol-induced derangement of the BP regulating mechanisms may be hypothesized, but long-term monitoring is needed, as well as further research. These patients need careful clinical assessment to exclude any underlying cause of secondary hypertension (independent of alcoholism) as well as hypertension-related complications. Pharmacological treatment is required in persistent hypertension, with a modification of life-style (food intake, physical activity, etc.); restriction of Na intake may be crucial, since marked sensitivity to Na seems to be a major factor in long-lasting alcohol-related hypertension. The need for treatment of hypertension in alcoholics must be stressed, at least in Italy, where alcoholics are treated mostly in specialized rehabilitation facilities, and where hypertension treatment may be sidestepped.
Complete alcohol abstinence must be recommended to all hypertensive alcoholics, as AW-induced transient hypertension is not dangerous, and abstinence leads to a complete recovery from hypertension in most cases.
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