Caspase-cleaved keratin-18 fragments increase during alcohol withdrawal and predict liver-related death in patients with alcoholic liver disease.

Noninvasive assessment of disease activity in patients with nonalcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD) is still unsettled, but essential for the evaluation of disease progression. We here studied the association of total (M65) and caspase-cleaved (M30) serum keratin-18 fragments (n = 204) with histological parameters (n = 106) in heavy drinkers primarily admitted for alcohol withdrawal before and after alcohol detoxification. An age-, sex-, and fibrosis-stage matched NAFLD cohort (n = 30) was used for comparison. The prognostic value of M30 and M65 levels were assessed in an additional prospectively followed-up cohort of 230 patients with alcoholic cirrhosis (AC) using competing risk analyses. Among the histological parameters, both M30/65 correlated significantly and better than any other serum marker with apoptosis and liver damage, such as ballooning (r = 0.65; P < 0.001), followed by lobular inflammation (0.48; P < 0.001), steatosis (0.46; P < 0.001), but less with fibrosis (0.24; P < 0.001). Area under the receiver operating characteristics curves to detect ballooning, steatosis, or steatohepatitis (SH) were slightly better for M30 (P < 0.005). Optimal M30 cut-off values for mild and severe ballooning were 330 and 420 U/L, and 290 and 330 U/L for SH grades 1 and 2. No significant differences of M30/65 were found between the matched NAFLD and ALD cohort. In contrast to aspartate-amino-transferase and M65, M30 levels increased significantly from 391 to 518 U/L during alcohol detoxification. Moreover, levels of M30 and M65 predicted non-hepatocellular carcinoma liver-related mortality in patients with AC during a mean observation interval of 67.2 months. CONCLUSION: Our data suggest M30 as highly specific marker of liver apoptosis both in ALD and NAFLD. In addition, hepatocellular apoptosis, as determined by M30 levels, occurs during alcohol withdrawal, and survival data point toward a novel underestimated role of apoptosis in patients with ALD. (Hepatology 2017;66:96-107).

Occurrence, Predictors, and Prognosis of Alcohol Withdrawal Syndrome and Delirium Tremens Following Traumatic Injury.

OBJECTIVES: We sought to determine occurrence, predictors, and prognosis of alcohol withdrawal syndrome and delirium tremens in patients with traumatic injury. DESIGN: Retrospective multicenter cohort study. SETTING: Three U.S. trauma centers. PATIENTS: Twenty-eight thousand one hundred one trauma patients admitted from 2010-2014. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Measures included occurrence of alcohol withdrawal syndrome and delirium tremens, injury characteristics, risk factors for alcohol withdrawal syndrome, clinical outcomes, pharmacologic treatment for alcohol withdrawal syndrome, and Clinical Institute Withdrawal Assessment for Alcohol, Revised (CIWA-Ar) scores. Alcohol withdrawal syndrome severity was defined by CIWA-Ar score as minimal (< 10), moderate (10-20), and severe (> 20). Alcohol withdrawal syndrome developed in 0.88% (n = 246), including 12% minimal, 36% moderate, and 53% severe. Alcohol withdrawal syndrome progressed to delirium tremens in 11%. Before adjustment, alcohol withdrawal syndrome severity was associated with injury severity, hypokalemia, baseline CIWA-Ar score, and established alcohol withdrawal syndrome risk factors. Logistic regression identified the following predictors of delirium tremens: baseline CIWA-Ar score greater than or equal to 10 (odds ratio, 6.05; p = 0.02) and age greater than or equal to 55 (odds ratio, 3.24; p = 0.03). In patients with severe alcohol withdrawal syndrome, severe head injury also predicted progression to delirium tremens (odds ratio, 6.08; p = 0.01), and hypokalemia was borderline significant (odds ratio, 3.23; p = 0.07). Clinical outcomes of hospital length of stay, ICU length of stay, and alcohol withdrawal syndrome complications differed significantly by alcohol withdrawal syndrome severity and were worse with more severe manifestations of alcohol withdrawal syndrome. Mortality also significantly differed by alcohol withdrawal syndrome severity but was only greater in patients who progressed to delirium tremens (11.1%; p = 0.02); otherwise, there were no differences in mortality by severity (4%, 4%, and 0% by minimal, moderate, and severe alcohol withdrawal syndrome). CONCLUSIONS: Trauma patients with alcohol withdrawal syndrome experience a high occurrence of delirium tremens that is associated with significant mortality. These data demonstrate the predictive ability of baseline CIWA-Ar score, age, and severe head injury for developing delirium tremens.

[Dexmedetomidine in the treatment of acute alcohol withdrawal delirium]. / Dexmedetomidin in der Therapie des akuten Alkoholentzugsdelirs.

Alcohol withdrawal syndrome has a high clinical prevalence. Severe cases must be treated in an intensive care unit and are associated with a high mortality rate, depending on patient comorbidities. Clinical requirements include sedation, control of vegetative symptoms, treatment of hallucinations and, when necessary, anticonvulsive therapy. Currently, there is no single substance that fulfills these requirements. National and international guidelines recommend a combination of various substances. The central α2-adrenergic receptor agonist clonidine is used as a therapeutic adjuvant. In consideration of its pharmacological characteristics, dexmedetomidine is assumed to be more advantageous compared to clondine. Case studies with dexmedetomidine in alcohol withdrawal syndrome show the safety of its application and a benzodiazepine-sparing effect. Its incorporation in escalating intensive care therapy of severe cases could be appropriate.

[Alcohol withdrawal syndrome showing various progress: A case report].

We experienced a case showing various psychotic symptoms following cessation of alcohol consumption. The symptoms included depressive state, delusion, confusion, psychomotor excitement and delirium, all of which disappeared in about two months. At first, we regarded all the symptoms as alcoholic hallucinosis, by a clinical standpoint, in spite of no auditory hallucination in this case. However, taking the overall clinical course into consideration, withdrawal syndrome could have been affected by some factors. One of the possibilities is that delusion might have been induced by aripiprazole. There still may be some other unknown influential factors on withdrawal, which are indicated by previous papers.

[APPLICATION OF DEXMEDETOMIDIN FOR SEDATION OF PATIENTS IN ALCOHOL WITHDRAWAL STATE IN THE ICU].

The efficacy and safety of sedation on 44 patients in alcohol withdrawal state (AWS) for use of intravenous dexmedetomidine infusion. Dexmedetomidine increased the duration of target sedation level to 20%, decreased the duration of excessive/insufficient sedation to 10%, it was associated with AWS symptoms regression, better communication with the patient, reduced consumption of benzodiazepines (BZD) from 40 to 30 mg per day and antypsihotics for control AWS symptoms. The common complications of dexmedetomidine infusion were bradycardia and hypotension. Dexmedetomidine could be an alternative drug for sedation patients with mild or moderate AWS and applied in addition to BZD and antipsyhotics in patients with severe AWS.

Comparison of oxidative DNA damage between alcohol-dependent patients with and without delirium tremens.

BACKGROUND: Chronic and excessive alcohol consumption increases oxidative stress. We previously found that levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG), a marker of oxidative DNA damage, are elevated in alcohol-dependent patients without delirium tremens (DTs). The aim of this study was to compare serum 8-OHdG levels between alcohol-dependent patients with and without DTs. METHODS: We recruited 16 alcohol-dependent patients with DTs (DTs group) and 58 patients without DTs (non-DTs group). Alcohol withdrawal severity was evaluated using the Chinese version of the revised Clinical Institute Withdrawal Assessment for Alcohol Scale (CIWA-Ar-C) every 8 hours. Serum levels of 8-OHdG and other biological indices were assayed at baseline and after 1 week of detoxification. RESULTS: The mean 8-OHdG level in the DTs group was significantly higher than that in the non-DTs group (0.50 vs. 0.34 ng/ml, p < 0.001). A significant correlation was found between the highest CIWA-Ar-C scores and serum 8-OHdG levels (ß = 0.43, p = 0.001) in the non-DTs group, but not in the DTs group (ß = 0.34, p = 0.19). An area under receiver operating characteristic curve of 0.83 suggests that 8-OHdG levels potentially differentiate patients with DTs from those without DTs. After dividing the patients into quartiles by 8-OHdG level, we found that compared to the patients in the third and fourth quartiles, the patients in the highest quartile had an odds ratio of 24.1 (p < 0.001) to have DTs, while those in the second highest quartile had an odds ratio of 3.5 (p = 0.19). Serum 8-OHdG levels did not significantly change after 1 week of detoxification in either group. CONCLUSIONS: Alcohol-dependent patients with DTs have higher serum 8-OHdG levels than those without DTs, suggesting that higher oxidative stress carries a greater risk of the occurrence of DTs.

[Delirium in patients with neurological diseases: diagnosis, management and prognosis]. / Delir in der Neurologie : Diagnose, Behandlung und Prognose.

Delirium is a common acute neuropsychiatric syndrome. It is characterized by concurrent disturbances of consciousness and attention, perception, reasoning, memory, emotionality, the sleep-wake cycle as well as psychomotor symptoms. Delirium caused by alcohol or medication withdrawal is not the subject of the current review. Specific predisposing and precipitating factors have been identified in delirium which converge in a common final pathway of global brain dysfunction. The major predisposing factors are older age, cognitive impairment or dementia, sensory deficits, multimorbidity and polypharmacy. Delirium is always caused by one or more underlying pathologies which need to be identified. In neurology both primary triggers of delirium, such as stroke or epileptic seizures and also secondary triggers, such as metabolic factors or medication side effects play a major role. Nonpharmacological interventions are important in the prevention of delirium and lead to an improvement in prognosis. Delirium is associated with increased mortality and in the long term the development of cognitive deficits and functional impairment.

Agrypnia excitata.

Agrypnia (from the Greek: to chase sleep) excitata (AE) is a syndrome characterized by loss of sleep and permanent motor and autonomic hyperactivation (excitata). Disruption of the sleep-wake rhythm consists in the disappearance of spindle-delta activities, and the persistence of stage 1 non-rapid eye movement (NREM) sleep. Rapid eye movement (REM) sleep persists but fails to stabilize, appearing in short recurrent episodes, isolated, or mixed with stage 1 NREM sleep. Diurnal and nocturnal motor, autonomic and hormonal overactivity is the second hallmark of AE. Of particular interest is the finding that norepinephrine secretion is extremely elevated at all hours of the day and night whereas the nocturnal melatonin peak is lacking. Oneiric stupor is probably an exclusive sign of AE and consists in the recurrence of stereotyped gestures mimicking simple daily life activities. Agrypnia excitata aptly defines 3 different clinical conditions, fatal familial insomnia (FFI), an autosomal dominant prion disease, Morvan syndrome (MS), an autoimmune encephalitis, and delirium tremens (DT), the alcohol withdrawal syndrome. Agrypnia excitata is due to an intralimbic disconnection releasing the hypothalamus and brainstem reticular formation from cortico-limbic inhibitory control. This pathogenetic mechanism is visceral thalamus degeneration in FI, whereas it may depend on autoantibodies blocking voltage-gated potassium (VGK) channels within the limbic system in MS, and in the sudden changes in gabaergic synapses down-regulated by chronic alcohol abuse within the limbic system in DT.

Symptom profile and outcome of delirium associated with alcohol withdrawal syndrome: a study from India.

AIM: To study the profile of delirium associated with alcohol withdrawal syndrome (AWS) in a developing country in terms of symptomatology, associated risk factors/physical complications, and outcome. METHODOLOGY: Using a prospective design, 112 patients in whom delirium could be attributed to AWS as either the sole or a contributory cause were assessed by Delirium Rating Scale-Revised-98 and the associated etiological factors were assessed by using delirium etiology checklist. FINDINGS: In all patients, delirium was acute in onset and all patients had disturbance of sleep-wake cycle and inattention. Other common symptoms were: disorientation (99.1%), fluctuation in symptoms (97.3%), motor agitation (94.6%), and short-term memory disturbance (92.9%). In terms of delirium etiology checklist etiological categories, besides alcohol withdrawal, the most common factors were metabolic/endocrine abnormalities (76%), followed by organ insufficiency and infection (37% and 35%, respectively). Most patients (67%) improved or recovered completely from delirium during the short stay of 4 days. During the short stay of mean duration of 4 days 13.4% of the patients died during the hospital stay. CONCLUSION: Delirium associated with alcohol withdrawal is characterized by an acute onset of symptoms with high prevalence of disturbance of sleep-wake cycle, inattention, disorientation, fluctuation in symptoms, motor agitation, and disturbance in short-term memory. There are certain differences in the symptom profile of delirium associated with alcohol withdrawal and that associated with medical-surgical causes. About one-sixth of the patients developing delirium due to alcohol withdrawal die during the short hospital stay of 4 days.

Evolution of Wernicke-Korsakoff syndrome in self-neglecting alcoholics: preliminary results of relation with Wernicke-delirium and diabetes mellitus.

We present a descriptive, retrospective study of initial symptoms, comorbidity, and alcohol withdrawal in 73 alcoholic patients with subsequent Korsakoff syndrome. In 25/73 (35%) of the patients the classic triad of Wernicke's encephalopathy with ocular symptoms, ataxia and confusion, was found. In at least 6/35 (17%) of the initial deliria (95% confidence interval: 10-25%) we observed no other underlying causes, thus excluding other somatic causes, medication, (recent) alcohol withdrawal, or intoxication. We suggest that these deliria may have been representing Wernicke's encephalopathy. A high frequency (15%) of diabetics may reflect a contributing factor of diabetes mellitus in the evolution of the Wernicke-Korsakoff syndrome.

Pattern and risk factors of alcohol withdrawal delirium.

OBJECTIVE: To determine the incidence, prescribing risk factors of alcohol withdrawal delirium (AWD), and factors complicating AWD, in alcohol dependent patients hospitalized for alcohol detoxification. MATERIAL AND METHOD: Patients attending the detoxification program at Chiang Mai University Hospital and the Northern drug dependence treatment center between May and September 2005 were assessed. Patients with signs of AWD at baseline were excluded. Incidence, risk factors, and dosage of benzodiazepines of patients with and without subsequent AWD were compared Risk factors that prolonged the course of AWD were analyzed. RESULTS: Nineteen male patients were assessed. Ten patients (52.6%) developed AWD despite receiving benzodiazepine detoxification. Risk factors of age, previous history of AWD and epilepsy, alcohol use history, frequency and quantity of drinking, signs of simple withdrawal at first admission, and dosage of benzodiazepines were not significantly different between the groups. However, patients with systolic blood pressure at first admission (> 120 mmHg) had longer duration of AWD than those without abnormal blood pressure (72.0 +/- 53.7 hr versus 168.0 +/- 24.0 hr, respectively, p = 0.038). CONCLUSION: The incidence of AWD was relatively high despite treatment. Although the present study did not find any risk factor predicting AWD. AWD patients hypertensive at the first admission had significantly longer duration of delirium. Physicians should be aware of monitor and treat hypertensive state and give early treatment of alcohol withdrawal with adequate doses of benzodiazepines to decrease morbidity and mortality of AWD.

[Treatment of alcohol withdrawal symptoms]. / Alkoholivieroitusoireiden hoito.

In the summer, alcohol consumption increases and the number of those requiring rehabilitation peaks at the end of the holiday season. Treatment of alcohol withdrawal symptoms early enough helps the patient to break the drinking cycle. Treatment of alcohol withdrawal symptoms will also prevent complications, such as convulsions and alcoholic delirium. Untreated alcoholic delirium is a life-threatening condition. Treatment aims to calm down the hyperactivity state of the autonomous nervous system, and correct electrolyte and fluid balance disturbances. Initiation of rehabilitation is determined by the severity of the patient's withdrawal symptoms. Benzodiazepines are the first-line drugs.

Alcohol-use disorders.

Alcohol dependence and alcohol abuse or harmful use cause substantial morbidity and mortality. Alcohol-use disorders are associated with depressive episodes, severe anxiety, insomnia, suicide, and abuse of other drugs. Continued heavy alcohol use also shortens the onset of heart disease, stroke, cancers, and liver cirrhosis, by affecting the cardiovascular, gastrointestinal, and immune systems. Heavy drinking can also cause mild anterograde amnesias, temporary cognitive deficits, sleep problems, and peripheral neuropathy; cause gastrointestinal problems; decrease bone density and production of blood cells; and cause fetal alcohol syndrome. Alcohol-use disorders complicate assessment and treatment of other medical and psychiatric problems. Standard criteria for alcohol dependence-the more severe disorder-can be used to reliably identify people for whom drinking causes major physiological consequences and persistent impairment of quality of life and ability to function. Clinicians should routinely screen for alcohol disorders, using clinical interviews, questionnaires, blood tests, or a combination of these methods. Causes include environmental factors and specific genes that affect the risk of alcohol-use disorders, including genes for enzymes that metabolise alcohol, such as alcohol dehydrogenase and aldehyde dehydrogenase; those associated with disinhibition; and those that confer a low sensitivity to alcohol. Treatment can include motivational interviewing to help people to evaluate their situations, brief interventions to facilitate more healthy behaviours, detoxification to address withdrawal symptoms, cognitive-behavioural therapies to avoid relapses, and judicious use of drugs to diminish cravings or discourage relapses.

Interaction of SLC6A4 and DRD2 polymorphisms is associated with a history of delirium tremens.

Several genetic polymorphisms have been reported to be associated with alcohol withdrawal seizures (AWS) and delirium tremens (DT). To replicate and further explore these findings, we investigated the effects of 12 previously reported candidate genetic variations in two groups of alcohol-dependent European Americans with a history of withdrawal, which differed according to the presence (n = 112) or absence (n = 92) of AWS and/or DT. Associations of AWS and/or DT with the genomic and clinical characteristics and gene-gene interaction effects were investigated using logistic regression models. None of the polymorphisms were significantly associated with AWS/DT after correction for multiple testing. However, we found a significant interaction effect of the SLC6A4 promoter polymorphism (5-HTTLPR) and DRD2 exon 8 single nucleotide polymorphism rs6276 on AWS and/or DT history (P = 0.009), which became more significant after adjustment for lifetime maximum number of drinks consumed per 24 hours (P < 0.001). Subsequent analysis revealed an even stronger association of the SLC6A4-DRD2 interaction with DT (P < 0.0001), which remained significant after Bonferroni correction. Results reveal decreased likelihood of DT in alcoholics that carry the DRD2 rs6276 G allele and SLC6A4 LL genotype. This study provides the first evidence to implicate the interaction between serotonin and dopamine neurotransmission in the etiology of DT. Replication is necessary to verify this potentially important finding.

Alcohol withdrawal syndrome: diagnostic and therapeutic methods.

Alcohol withdrawal syndrome (AWS) is a medical emergency, rare in the general population, but very common among alcoholic individuals, which can lead to severe complications when unrecognized or late treated. It represents a clinical condition which can evolve in few hours or days following an abrupt cessation or reduction of alcohol intake and is characterized by hyperactivity of the autonomic nervous system resulting in the development of typical symptoms. According to DSM-5 criteria, the alcohol withdrawal syndrome is defined as such: if patients present at least two of typical signs and symptoms. The Clinical Institute Withdrawal Assessment of Alcohol Scale, revised version (CIWA-Ar), is the tool for assessing the severity of AWS. The support to patient with AWS includes pharmacological intervention as well as general support, restoration of biochemical imbalances and specific therapy. Regarding the pharmacological treatment, benzodiazepines represent the gold standard, in particular long-acting benzodiazepines, administered with a gradual reduction up to cessation.

Fatal familial insomnia and agrypnia excitata.

This review summarizes the pioneering steps culminating in the identification of a novel disease, fatal familial insomnia (FFI), a hereditary prion disease. Together with Morvan's chorea and delirium tremens, FFI is characterized by an inability to sleep associated with motor and autonomic overactivation. We named this pattern agrypnia excitata, a syndrome caused by a dysfunction in thalamolimbic circuits. This review highlights the strategic role of the limbic thalamus in the central autonomic network running from the limbic cortex to the lower brainstem and regulating sleep and wakefulness.

ECG changes amongst patients with alcohol withdrawal seizures and delirium tremens.

INTRODUCTION: Alcohol withdrawal seizures and delirium tremens (DT) are serious complications of alcohol dependence. The prevalence of arrhythmias and other electrocardiographic (ECG) changes occurring in these clinical situations is not well studied. METHODS: We performed a retrospective analysis of clinical data and ECG's from patients discharged between 1995 and 2005 with the diagnosis of DT (ICD-Code F10.4) or alcohol withdrawal seizures (F10.3). Measurement of the ECG intervals was done in lead II. The corrected QT interval (QTc) was obtained using Bazett's formula. RESULTS: 49 patients (38 males; 11 females) with a mean age of 48 years were included in the study. 23 patients with DT and 16 with convulsions were admitted to the hospitals. Ten patients developed DT while being hospitalised for other reasons. The QTc interval was prolonged (>440 ms and >460 ms in males and females, respectively) in 31 patients (63%). Five patients (10%) developed tachyarrhythmias (two torsade de pointes, one sustained ventricular tachycardia, two supraventricular tachycardia, one atrial fibrillation). All returned to sinus rhythm after appropriate treatment. CONCLUSIONS: Tachyarrhythmias are common amongst patients with severe alcohol withdrawal syndromes. The majority of the patients had an acquired long QT syndrome which led to a torsade de pointes in two cases. No patient died in the hospital and all were discharged in sinus rhythm. Clinicians should possibly avoid QT prolonging drugs and carefully monitor the rhythm in patients with severe alcohol withdrawal syndromes.

Alcohol withdrawal severity in inbred mouse (Mus musculus) strains.

Male mice (Mus musculus) from 15 standard inbred strains were exposed to a nearly constant concentration of ethanol (EtOH) vapor for 72 hr, averaging 1.59 +/- 0.03 mg EtOH/mL blood at withdrawal. EtOH- and air-exposed groups were tested hourly for handling-induced convulsions for 10 hr and at Hours 24 and 25. Strains differed markedly in the severity of withdrawal (after subtraction of control values), and by design these differences were independent of strain differences in EtOH metabolism. Correlation of strain mean withdrawal severity with other responses to EtOH supported previously reported genetic relationships of high EtOH withdrawal with low drinking, high conditioned taste aversion, low tolerance to EtOH-induced hypothermia, and high stimulated activity after low-dose EtOH. Also supported were the positive genetic correlations among EtOH, barbiturate, and benzodiazepine withdrawal. Sensitivity of naive mice to several chemical convulsant-induced seizures was also correlated with EtOH withdrawal.

Cardiorespiratory patterns in severe delirium tremens.

To define the hemodynamic and oxygen metabolism patterns associated with severe delirium tremens, we examined cardiorespiratory variables in five patients over the 24 hours before (control), at the time of (delirium tremens), and during the 24 hours after resolution of (postresolution) delirium tremens. In comparing the delirium tremens period with the control period, significant increases were found in mean +/- SD cardiac index (4.9 +/- 1.7 L/min X sq m vs 3.6 +/- 0.7 L/min X sq m), left cardiac work index (6.4 +/- 2.4 kg X m/sq m vs 5.0 +/- 1.7 kg X m/sq m), oxygen delivery (681 +/- 204 mL/min X sq m vs 546 +/- 176 mL/min X sq m), and oxygen consumption (204 +/- 38 mL/min X sq m vs 165 +/- 16 mL/min X sq m). Values for the control and postresolution periods were not significantly different. These results demonstrate that a hyperdynamic cardiorespiratory state is present during delirium tremens; this increased cardiac output may be a compensatory hemodynamic response to increased oxidative metabolism that requires additional therapeutic support.