A view from the acute hospital: managing patients with alcohol problems.

Regular heavy consumption of alcohol is associated with a wide range of physical, psychological and social problems. All health-care clinicians should be able to screen for and detect problematic levels of alcohol consumption in their patients, and deliver an effective brief intervention. When patients with alcohol dependence are admitted to hospital there must be an assessment of whether medication is required to prevent withdrawal symptoms and potential delirium tremens and withdrawal seizures. Medically assisted alcohol withdrawal using a long-acting benzodiazepine such as chlordiazepoxide should be carefully monitored and titrated to effect, and the clinician should be aware of the risk of Wernicke-Korsakoff syndrome and other complications. Abstinence from alcohol is usually only the first step in treatment, and effective linkage to community alcohol services is an important step.

Alcohol withdrawal syndrome: mechanisms, manifestations, and management.

The alcohol withdrawal syndrome is a well-known condition occurring after intentional or unintentional abrupt cessation of heavy/constant drinking in patients suffering from alcohol use disorders (AUDs). AUDs are common in neurological departments with patients admitted for coma, epileptic seizures, dementia, polyneuropathy, and gait disturbances. Nonetheless, diagnosis and treatment are often delayed until dramatic symptoms occur. The purpose of this review is to increase the awareness of the early clinical manifestations of AWS and the appropriate identification and management of this important condition in a neurological setting.

Effects of acute alcohol withdrawal on nest building in mice selectively bred for alcohol withdrawal severity.

Nest building has been used to assess thermoregulatory behavior and positive motivational states in mice. There are known genetic influences on ethanol withdrawal severity as well as individual/thermoregulatory nest building. Withdrawal Seizure-Prone (WSP-1, WSP-2) and Withdrawal Seizure-Resistant (WSR-1, WSR-2) mice were selectively bred for high vs low handling-induced convulsion (HIC) severity, respectively, during withdrawal from chronic ethanol vapor inhalation. They also differ in HIC severity during withdrawal from an acute, 4g/kg ethanol injection. In our initial study, withdrawal from an acute dose of ethanol dose-dependently impaired nest building over the initial 24h of withdrawal in genetically segregating Withdrawal Seizure Control (WSC) mice. In two further studies, acute ethanol withdrawal suppressed nest building for up to two days in WSP-1 females. Deficits in nest building from ethanol were limited to the initial 10h of withdrawal in WSR-1 females and to the initial 24h of withdrawal in WSP-1 and WSR-1 males. Effects of ethanol on nest building for up to two days were found in WSP-2 and WSR-2 mice of both sexes. Nest building deficits in female mice from the first replicate could not be explained by a general decrease in locomotor behavior. These results suggest that nest building is a novel behavioral phenotype for indexing the severity of acute ethanol withdrawal, and that genes contributing to this trait differ from those affecting acute withdrawal HIC severity.

Outcomes of Patients with Alcohol Withdrawal Syndrome Treated with High-Dose Sedatives and Deferred Intubation.

RATIONALE: High doses of sedating drugs are often used to manage critically ill patients with alcohol withdrawal syndrome. OBJECTIVES: To describe outcomes and risks for pneumonia and endotracheal intubation in patients with alcohol withdrawal syndrome treated with high-dose intravenous sedatives and deferred endotracheal intubation. METHODS: Observational cohort study of consecutive patients treated in the intensive care unit (ICU) of a university-affiliated, community hospital for alcohol withdrawal syndrome, where patients were not routinely intubated to receive high-dose or continuously infused sedating medications. MEASUREMENTS AND MAIN RESULTS: We studied 188 patients hospitalized with alcohol withdrawal syndrome from 2008 through 2012 at one medical center. The mean age (SD) of the subjects was 50.8 ± 9.0 years and their mean ICU admission APACHE (Acute Physiology and Chronic Health Evaluation) II score was 6.2 ± 3.4. Thirty subjects (16%) developed pneumonia, and 38 (20.2%) required intubation. All of the 188 patients received lorazepam (median total dose, 42.5 mg), and 170 of 188 received midazolam, all but 2 by continuous intravenous infusion (median total dose, 527 mg; all administered in ICU); 19 received propofol (median total dose, 6,000 mg); and 19 received dexmedetomidine (median total dose, 1,075 mg). Intubated patients received substantially more benzodiazepine (median total dose, 761 mg of lorazepam equivalent vs. 229 mg for subjects in the nonintubated group; P < 0.0001). Endotracheal intubation was associated with pneumonia and higher acuity of illness (APACHE II score, >10). Intubated patients had a longer duration of hospital stay (median, 15 d vs. 6 d; P ≤ 0.0001). One patient did not survive hospitalization. CONCLUSIONS: In this single-center, observational study, where endotracheal intubation was deferred until aspiration or cardiopulmonary decompensation, treatment of alcohol withdrawal syndrome with high-dose, continuously infused sedating medications was not associated with excess morbidity or mortality.

Novel MPDZ/MUPP1 transgenic and knockdown models confirm Mpdz's role in ethanol withdrawal and support its role in voluntary ethanol consumption.

Association studies implicate multiple PDZ domain protein (MPDZ/MUPP1) sequence and/or expression in risk for alcoholism in humans and ethanol withdrawal (EW) in mice, but confirmation has been hindered by the dearth of targeted genetic models. We report the creation of transgenic (MPDZ-TG) and knockout heterozygote (Mpdz(+/-) ) mice, with increased (2.9-fold) and decreased (53%) target expression, respectively. Both models differ in EW compared with wild-type littermates (P ≤ 0.03), providing compelling evidence for an inverse relationship between Mpdz expression and EW severity. Additionally, ethanol consumption is reduced up to 18% (P = 0.006) in Mpdz(+/-) , providing the first evidence implicating Mpdz in ethanol self-administration.

Safety and efficacy of flumazenil for reversal of iatrogenic benzodiazepine-associated delirium toxicity during treatment of alcohol withdrawal, a retrospective review at one center.

Both alcohol withdrawal syndrome (AWS) and benzodiazepines can cause delirium. Benzodiazepine-associated delirium can complicate AWS and prolong hospitalization. Benzodiazepine delirium can be diagnosed with flumazenil, a GABA-A receptor antagonist. By reversing the effects of benzodiazepines, flumazenil is theorized to exacerbate symptoms of AWS and precludes its use. For patients being treated for alcohol withdrawal, flumazenil can diagnose and treat benzodiazepine delirium without precipitating serious or life-threatening adverse events. Hospital admission records were retrospectively reviewed for patients with the diagnosis of AWS who received both benzodiazepines and flumazenil from December 2006 to June 2012 at a university-affiliated inpatient toxicology center. The day of last alcohol consumption was estimated from available blood alcohol content or subjective history. Corresponding benzodiazepine, flumazenil, and adjunctive sedative pharmacy records were reviewed, as were demographic, clinical course, and outcome data. Eighty-five patients were identified (average age 50.3 years). Alcohol concentrations were detectable for 42 patients with average 261 mg/dL (10-530 mg/dL). Eighty patients were treated with adjunctive agents for alcohol withdrawal including antipsychotics (n = 57), opioids (n = 27), clonidine (n = 35), and phenobarbital (n = 23). Average time of flumazenil administration was 4.7 days (1-11 days) after abstinence, and average dose was 0.5 mg (0.2-1 mg). At the time of flumazenil administration, delirium was described as hypoactive (n = 21), hyperactive (n = 15), mixed (n = 41), or not specified (n = 8). Response was not documented in 11 cases. Sixty-two (72.9 %) patients had significant objective improvement after receiving flumazenil. Fifty-six patients required more than one dose (average 5.6 doses). There were no major adverse events and minor adverse effects included transiently increased anxiety in two patients: 1 patient who received 0.5 mg on abstinence day 2 and another patient who received 0.2 mg flumazenil on abstinence day 11. This is the largest series diagnosing benzodiazepine delirium after AWS in patients receiving flumazenil. During the treatment of AWS, if delirium is present on day 5, a test dose of flumazenil may be considered to establish benzodiazepine delirium. With the limited data set often accompanying patients with AWS, flumazenil diagnosed benzodiazepine delirium during the treatment of AWS and improved impairments in cognition and behavior without serious or life-threatening adverse events in our patients.

Voluntary wheel running attenuates ethanol withdrawal-induced increases in seizure susceptibility in male and female rats.

We recently found that voluntary wheel running attenuated ethanol withdrawal-induced increased susceptibility to chemoconvulsant-induced seizures in male rats. Since female rats recover from ethanol withdrawal (EW) more quickly than male rats across several behavioral measures, this study was designed to determine whether the effects of exercise on EW seizures also exhibited sex differences. Animals were maintained under no-wheel, locked-wheel or free-wheel conditions and ethanol was administered by liquid diet for 14 days with control animals pair-fed an isocaloric diet, after which seizure thresholds were determined at 1 day or 3 days of EW. Consistent with previous reports, females ran significantly more than males, regardless of diet condition. Introduction of the ethanol-containing liquid diet dramatically increased running for females during the day (rest) phase, with little impact on night phase activity. Consistent with previous reports, EW increased seizure susceptibility at 1 day in non-exercising males and females and at 3 days in males. These effects were attenuated by access to running wheels in both sexes. We also assessed the effects of sex, ethanol diet and exercise on ethanol clearance following an acute ethanol administration at 1 day EW in a separate set of animals. Blood ethanol concentrations at 30 min post-injection were lower in males, ethanol-exposed animals, and runners, but no interactions among these factors were detected. Interestingly, females displayed more rapid ethanol clearance than males and there were no effects of either diet or wheel access on clearance rates. Taken together, these data suggest that voluntary wheel running during ethanol administration provides protective effects against EW seizures in both males and females. This effect may be mediated, in part, in male, but not in female rat, by effects of exercise on early pharmacokinetic contributions. This supports the idea that encouraging alcoholics to exercise may benefit their recovery.

Tako-tsubo cardiomyopathy precipitated by alcohol withdrawal.

A 57 year-old woman with no history of cardiac disease presented to the emergency department with confusion and seizures secondary to alcohol withdrawal. Elevated troponin levels and an electrocardiogram demonstrating global T-wave inversions prompted coronary angiography, which revealed coronary vessels free of significant disease. An echocardiogram showed both hypokinesis of the left-ventricular mid-segments with apical involvement and a hyperkinetic base consistent with tako-tsubo cardiomyopathy (TCM). Several clinical conditions have been reported as triggers of TCM. We report a case of TCM in a post-menopausal woman that was precipitated by alcohol withdrawal.

Development of ethanol withdrawal-related sensitization and relapse drinking in mice selected for high- or low-ethanol preference.

BACKGROUND: Previous studies have shown that high alcohol consumption is associated with low withdrawal susceptibility, while at the same time, other studies have shown that exposure to ethanol vapor increases alcohol drinking in rats and mice. In the present studies, we sought to shed light on this seeming contradiction using mice selectively bred for High- (HAP) and Low- (LAP) Alcohol Preference, first, assessing these lines for differences in signs of ethanol withdrawal and second, for differences in the efficacy of intermittent alcohol vapor exposure on elevating subsequent ethanol intake. METHODS: Experiment 1 examined whether these lines of mice differed in ethanol withdrawal-induced CNS hyperexcitability and the development of sensitization to this effect following intermittent ethanol vapor exposure. Adult HAP and LAP lines (replicates 1 and 2), and the C3H/HeNcr inbred strain (included as a control genotype for comparison purposes) received intermittent exposure to ethanol vapor and were evaluated for ethanol withdrawal-induced seizures assessed by scoring handling-induced convulsions (HIC). Experiment 2 examined the influence of chronic intermittent ethanol exposure on voluntary ethanol drinking. Adult male and female HAP-2 and LAP-2 mice, along with male C57BL/6J (included as comparative controls) were trained to drink 10% ethanol using a limited access (2 h/d) 2-bottle choice paradigm. After stable baseline daily intake was established, mice received chronic intermittent ethanol vapor exposure in inhalation chambers. Ethanol intake sessions resumed 72 hours after final ethanol (or air) exposure for 5 consecutive days. RESULTS: Following chronic ethanol treatment, LAP mice exhibited overall greater withdrawal seizure activity compared with HAP mice. In Experiment 2, chronic ethanol exposure/withdrawal resulted in a significant increase in ethanol intake in male C57BL/6J, and modestly elevated intake in HAP-2 male mice. Ethanol intake for male control mice did not change from baseline levels of intake. In contrast, HAP-2 female and LAP-2 mice of both sexes did not show changes in ethanol intake as a consequence of intermittent ethanol exposure. CONCLUSIONS: Overall, these results indicate that the magnitude of ethanol withdrawal-related seizures is inversely related to inherited ethanol intake preference. Additionally, intermittent ethanol vapor exposure appears more likely to affect high-drinking mice (C57BL/6J and HAP-2) than low drinkers, although these animals are less affected by ethanol withdrawal.

The influence of a chronic adolescent nicotine exposure on ethanol withdrawal severity during adulthood in C3H mice.

Animal and human studies have shown tolerance, consumption, relapse, and behavioral interactions between ethanol and nicotine, but little is understood about their interaction, especially as it relates to ethanol withdrawal in adulthood for subjects who have an adolescent history of using these drugs. This study investigated nicotine's influence on ethanol withdrawal seizures in two different age groups of male C3H mice. Adolescent and adult male C3H mice, beginning at postnatal day 28 or 70, respectively, were subjected to a 7-day chronic exposure to ethanol only, ethanol plus nicotine, nicotine only, or vehicle treatment. Six weeks later, all the groups were subjected to chronic exposure to ethanol vapors and the severity of their ethanol withdrawal seizures was assessed by handling-induced convulsions. An adolescent exposure to chronic nicotine resulted in an exacerbation of ethanol withdrawal seizures in adulthood. Given this, adolescence may contain a neurophysiological critical period that is sensitive to nicotine and which may result in an altered response to ethanol dependency in adulthood. These findings have serious implications for the long-term consequences following co-abuse of these drugs during adolescence.

Nursing assessment and management of alcohol-related brain damage in young people.

The long term consequences of chronic alcohol misuse are increasingly affecting young people. This one part unit outlines the main signs and symptoms of Wernicke's encephalopathy and Korsakoff's syndrome. It details nursing assessment and management of these conditions, as well as regimens for safe detoxification.

Role of the amygdala in ethanol withdrawal seizures.

Ethanol withdrawal (ETX) after induction of ethanol dependence results in a syndrome that includes enhanced seizure susceptibility. During ETX in rodents, generalized audiogenic seizures (AGS) can be triggered by intense acoustic stimulation. Previous studies have implicated specific brainstem nuclei in the neuronal network that initiates and propagates AGS during ETX. Although ethanol and ETX are known to affect amygdala neurons, involvement of the amygdala in the network subserving AGS is unclear. Since ethanol and ETX affect N-methyl-d-aspartate (NMDA) receptors in the amygdala, the present study evaluated the effect of focally microinjecting a NMDA antagonist into the amygdala of rats treated with a binge protocol (intragastric administration of ethanol 3 times daily for 4 days). Separate experiments examined extracellular neuronal firing in the amygdala. Cannulae or microwire electrodes were chronically implanted into the amygdala, and changes in seizure behaviors and/or extracellular action potentials were evaluated. Bilateral focal microinjection of a NMDA antagonist, 2-amino-7-phosphonoheptanoate (AP7), into either central nucleus or lateral nucleus of the amygdala (LAMG) significantly reduced AGS. The doses of AP7 and time course of effect were similar in each site, suggesting that both amygdala nuclei participate in the AGS network. Acoustic responses of LAMG neurons were significantly decreased 1 h after the first ethanol dose and also during ETX, as compared to pre-binge controls. However, LAMG neurons consistently exhibited rapid tonic firing during the generalized tonic convulsions of AGS. These findings suggest a critical role of the amygdala in the ETX seizure network in generating tonic convulsions during AGS.

Ionotropic glutamate receptor gene GRIK3 SER310ALA functional polymorphism is related to delirium tremens in alcoholics.

Upregulation of glutamatergic neurotransmission resulting from chronic ethanol intoxication may cause a hyperexcitable state during alcohol withdrawal, which may lead to seizures and delirium tremens. The aim of our study was to evaluate the association between a history of alcohol withdrawal-induced seizures and delirium tremens, and a functional polymorphism (Ser310Ala) of the GRIK3 gene coding for the glutamatergic kainate receptor subunit GlurR7 in a sample of well-characterized alcoholics compared to controls. In total, 233 patients meeting DSM-IV alcohol dependence criteria and 309 controls, all of German descent, were investigated. GRIK3 functional polymorphism was determined using PCR (polymerase chain reaction) of lymphocyte DNA. History of alcohol withdrawal-induced delirium tremens and seizures were obtained using the SSAGA (Semi-Structured Assessment for the Genetics of Alcoholism). Data were cross-checked with in-patients' clinical files. While a significant relationship between history of delirium tremens and the Ser310 allele was detected, no significant results were obtained for alcohol withdrawal-related seizures. Although this result is suggestive for a significant role of this polymorphism in the pathogenesis of delirium tremens in alcohol-dependent individuals, further investigation and confirmation are warranted.

Effects of finasteride on chronic and acute ethanol withdrawal severity in the WSP and WSR selected lines.

BACKGROUND: The neurosteroid allopregnanolone (ALLO) is a potent positive modulator of gamma-aminobutyric acidA (GABAA) receptors that can modulate ethanol (EtOH) withdrawal. The 5alpha-reductase inhibitor finasteride blocks the formation of ALLO from progesterone and was recently found to reduce certain effects of EtOH. Using the Withdrawal Seizure-Prone (WSP) and Withdrawal Seizure-Resistant (WSR) selected lines, in the present studies we examined the effect of finasteride on acute and chronic EtOH withdrawal severity. METHODS: In the first two studies, male WSP and WSR mice were exposed to 72-hr EtOH vapor or air and received four injections of finasteride (50 mg/kg intraperitoneal (IP) or vehicle 24 hr before and each day of the vapor exposure. After removal from the inhalation chamber, mice were scored for handling-induced convulsions (HICs) hourly for 12 hr and then again at 24 hr (study 1) or were tested on the elevated plus maze at 24 hr after removal from the inhalation chamber (study 2). In the third experiment, mice were pretreated with finasteride or vehicle 24 hr before an acute dose of EtOH (4 g/kg ip) or saline and then were tested for HICs as in the chronic study. RESULTS: In both chronic EtOH studies, finasteride pretreatment reduced EtOH withdrawal severity, measured by HICs, and anxiety-related behavior, but only in the WSP selected line. However, finasteride pretreatment also significantly decreased blood EtOH concentration on the initiation of withdrawal in both chronic EtOH studies in WSP and WSR mice. In contrast, pretreatment with finasteride slightly enhanced acute EtOH withdrawal severity in WSP mice, whereas there was no effect of finasteride or EtOH injection on HICs in WSR mice. CONCLUSIONS: Collectively, these findings indicate that the WSP line is more sensitive than the WSR line to the modulatory effects of finasteride in terms of both chronic and acute EtOH withdrawal severity. The differential effect of finasteride on acute versus chronic EtOH withdrawal severity may result from an indirect effect of finasteride on EtOH pharmacokinetics in the chronic paradigm.

GRIN1 locus may modify the susceptibility to seizures during alcohol withdrawal.

N-Methyl-D-aspartate (NMDA) receptors, members of the glutamate receptor channel superfamily, are generally inhibited by alcohol. The expression and alternative splicing of the obligatory NR1 subunit is altered by alcohol exposure, emphasizing the involvement of the NR1 subunit, which is coded by the GRIN1 gene, in alcohol-mediated effects. We performed an association study in patients with alcohol dependence with the GRIN1 locus. Two independent case control samples consisting of a total of 442 alcohol-dependent patients and 442 unrelated controls were included. There was no overall difference in allele or genotype frequency between patients and controls. However, the 2108A allele and A-containing genotypes were over-represented in the patients with a history of withdrawal-induced seizures when compared to healthy volunteers (allele: chi(2) = 5.412, df = 1, P = 0.020) or an independent sample of patients without a history of seizures (allele: chi(2) = 4.185, df = 1, P = 0.041). Age at onset, years of alcohol dependence, and a history of delirium tremens did not differ between genotype or allele groups. These findings support the hypothesis that the GRIN1 locus may modify the susceptibility to seizures during alcohol withdrawal. This novel finding warrants replication.

[Folate against hyperhomocysteinemia. A new approach for the prevention and therapy of alcoholism-associated disorders?]. / Folsäure gegen Hyperhomocysteinämie. Ein neuer Ansatz zur Prävention und Therapie Alkoholismus-bedingter Störungen?

There is growing evidence that chronic alcoholism is associated with a derangement in the sulfur amino acid metabolism. Excitatory aminoacids such as glutamate, aspartate, and homocysteine have been shown to be increased in patients with chronic alcoholism who underwent alcohol withdrawal. Furthermore, sustained hyperhomocysteinemia occurred in chronic alcoholics with active drinking pattern. Excitotoxicity can be induced by increased hormocysteine levels via rebound activation of NMDA receptor-mediated glutamatergic neurotransmission upon the removal of ethanol-evoked inhibition. Therefore, hyperhomocysteinemia may be responsible for the higher incidence of complications during alcohol withdrawal (e.g.stroke,convulsions). In addition, an association between brain atrophy and increased levels of homocysteine in chronic alcoholism was shown. This may have important implications for the pathogenesis of brain atrophy in alcoholics. Taking into account that high plasma homocysteine levels are helpful in the prediction of alcohol withdrawal seizures, early anti-convulsive therapy could prevent this severe complication. Supplementation of folate, a cofactor of the homocysteine metabolism, lowers raised homocysteine levels and therefore could be established as a new therapeutic strategy in alcohol withdrawal treatment. The results of various studies highlight the need for further research to prove whether alcoholics benefit from a reduced homocysteine level with respect to both, alcohol-related disorders and alcohol withdrawal symptoms.

The candidate gene approach in alcoholism: are there gender-specific differences?

It is well established that genetic factors play a major role in the development of alcoholism in both sexes. Several twin studies demonstrated a nearly equally high magnitude of genetic influence for men and women. However, the genetic sources of vulnerability are supposed to only partially overlap in men and women. Therefore, we evaluated the gender-specific effects of two single nucleotide polymorphisms affecting dopaminergic neurotransmission (dopamine D2 receptor: -141C Ins/Del polymorphism; Dopamine D3 receptor: Bal I) in our large sample of primary alcoholics. Only a gender-specific analysis of subgroups with a putatively high genetic load, e.g., family-history-positive or presence of severe withdrawal complications, revealed significant differences in allele-/genotype-frequency. Our results demonstrate that a varying sex distribution in the samples investigated might contribute to the heterogeneous results reported in association studies for candidate genes in alcoholism and, therefore, should be taken into account in future studies.