MAILIS TÕNISSON. Clinical picture and biochemical changes in blood in children with acute alcohol intoxication - PDF

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DISSERTATIONES MEDICINAE UNIVERSITATIS TARTUENSIS 238 MAILIS TÕNISSON Clinical picture and biochemical changes in blood in children with acute alcohol intoxication DISSERTATIONES MEDICINAE UNVERSITATIS

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DISSERTATIONES MEDICINAE UNIVERSITATIS TARTUENSIS 238 MAILIS TÕNISSON Clinical picture and biochemical changes in blood in children with acute alcohol intoxication DISSERTATIONES MEDICINAE UNVERSITATIS TARTUENSIS 238 DISSERTATIONES MEDICINAE UNVERSITATIS TARTUENSIS 238 MAILIS TÕNISSON Clinical picture and biochemical changes in blood in children with acute alcohol intoxication Department of Pathological Anatomy and Forensic Medicine, Faculty of Medicine, University of Tartu, Estonia The dissertation is accepted for the commencement of the degree of Doctor of Philosophy in Medicine on August 26, 2015 by the Council of the Faculty of Medicine, University of Tartu, Estonia Supervisors: Professor Marika Väli, MD, PhD Department of Pathological Anatomy and Forensic Medicine University of Tartu, Estonia Professor Vallo Tillmann, MD, PhD Department of Pediatrics University of Tartu, Estonia Reviewers: Professor Aleksandr Žarkovski, MD, PhD Institute of Biomedicine and Translational Medicine Department of Farmacology University of Tartu, Estonia Associate Professor Katrin Lang, MD, PhD Department of Public Health University of Tartu, Estonia Opponent: Professor Henrik Druid, MD, PhD Department of Oncology-Pathology Karolinska Institute, Stockholm, Sweden Commencement: October 28, 2015 Publication of this dissertation is granted by the University of Tartu. Copyright: Mailis Tõnisson, 2015 ISSN X ISBN (print) ISBN (pdf) University of Tartu Press CONTENTS LIST OF ORIGINAL PUBLICATIONS... 7 ABBREVIATIONS INTRODUCTION REVIEW OF LITERATURE Alcohol consumption In the world In Estonia Among children and adolescents Alcohol pharmacokinetics and pharmacodynamics Clinical signs of alcohol intoxication Clinical features and symptoms of acute alcohol intoxication in adults Clinical features and symptoms of AAI in children Ratio of SAC/BAC Biochemical disturbances in serum of patients with AAI Glucose and lactate Electrolytes Hormones AIMS OF THE STUDY METHODS AND SUBJECTS Patients Reporting of clinical signs of acute alcohol intoxication Samples and laboratory tests Statistical analysis RESULTS Clinical signs in different AAI severity groups and comparison of AILCS with the SAC The prevalence of clinical signs in different AAI severity groups The distribution of subjects by the AILCS and by SAC or BAC The establishment of SAC/BAC ratio in children The prevalence of biochemical (glucose, lactate, potassium and sodium) changes in serum in children with AAI, and the impact of SAC on the biochemical changes in serum Glucose Lactate Potassium Sodium The impact of SAC on the biochemical changes 5.5 The hormonal changes (testosterone, estradiol, progesterone and cortisol) in AAI children and their relationship with plasma biochemical markers DISCUSSION Clinical signs in different AAI severity groups and comparison of AILCS with the SAC The diagnostic performance characteristics of clinical assessment in the diagnosis of AAI in children The establishment of SAC/BAC ratio in children The prevalence of biochemical changes in children with AAI, and the impact of SAC on the biochemical changes in plasma The hormonal changes in AAI children and their relationship with plasma biochemical markers CONCLUSIONS REFERENCES SUMMARY IN ESTONIAN ACKNOWLEDGEMENTS PUBLICATIONS CURRICULUM VITAE LIST OF ORIGINAL PUBLICATIONS I Tõnisson, M., Tillmann, V., Kuudeberg, A., Lepik, D., Väli, M. (2013). Acute alcohol intoxication characteristics in children. Alcohol & Alcoholism, 48(4): II Tõnisson, M., Tillmann, V., Kuudeberg, A., Väli, M. (2011). Plasma cortisol, testosterone, estradiol and progesterone levels in children with acute alcohol intoxication. Journal of Addiction Research and Therapy, 2(111): 1 5. III Tõnisson, M., Tillmann, V., Kuudeberg, A., Väli, M. (2010). Plasma glucose, lactate, sodium and potassium levels in children hospitalised with acute alcohol intoxication. Alcohol, 44(6): Applicant s contribution to these publications: Study design, collection of clinical and biological testing materials, participation in data analysis, writing the papers. 7 AAI ACCAL ACTH ADH AILCS BAC Cmax CNS CYP2E1 DHEAS DSM ICD k m NAD NADH PRL SAC T ABBREVIATIONS acute alcohol intoxication annual per capita consumption of pure alcohol (100%) in litres adrenocorticotropic hormone alcohol dehydrogenase acute alcohol intoxication level by clinical signs blood alcohol concentration maximal concentration central nervous system cytochrome P4502E1 dehydroepiandrosterone-sulphate Diagnostic and Statistical Manual of Mental Disorders International Statistical Classification of Diseases and Related Health Problems Michelis-Menten constant nicotinamide adenine dinucleotide oxidized form nicotinamide adenine dinucleotide reduced form prolactin serum alcohol concentration testosterone 8 1. INTRODUCTION Ethanol is the most frequently abused drug in the United States and Western countries, including in Estonia (U.S. Department of Health and Human Services, 2007; Falk et al., 2008). Increasing alcohol consumption is accompanied by the growing problem of alcohol consumption among children and adolescents (Madu et al., 2003; Meyer et al., 2003; Meyer et al., 2008; Schöberl et al., 2008; Sutherland et al., 1998; Woolfenden et al., 2002). The International Self- Reported Delinquency Study-2, or ISRD-2, showed that on average 53% of Estonian year-old adolescents had had at least one heavy drinking episode in the past 30 days (Markina et al., 2007). As per WHO, heavy episodic drinking is defined as the proportion of adults (15+ years) who have had at least 60 gram or more of pure alcohol on at least one occasion in the past 30 days (WHO, 2014). Drinking alcohol at a young age is a risk factor for alcohol addiction later in life (Patrick et al., 2013), and is connected with problems in school (Latvala et al., 2014), binge drinking (White et al., 2013), tobacco addiction (Hughes et al., 2015; Lee et al., 2014), illegal drug use (Harris et al., 2014), and risky sexual behaviours (de Looze et al., 2015; Monk et al., 2014; Hagemann et al., 2013). Alcohol is also linked to violent crimes (Archimi et al., 2014; Green et al., 2011), suicides (Lahti et al., 2014; Kaplan et al., 2013; Holmgren and Jones, 2010; Flensborg-Madsen et al., 2009), and accidental deaths (Weiss et al., 2014; Estonian Institute of Economic Research Yearbook, 2013; Mørland et al., 2011; Koski et al., 2007). As the frequency and amount of alcohol consumption by children and adolescents has gradually increased, medical personnel at hospitals have to be prepared for an increased workload due to the medical problems caused by acute alcohol intoxication (AAI). Biochemical tests, such as glucose, lactate and electrolytes levels in plasma or serum are a part of clinical practise to evaluate the clinical condition of patients with AAI. There have been very few studies about the relationships between biochemical and hormonal changes in the blood of children hospitalised with AAI. The aim of the current study was to describe clinical, mental and physical signs in children with different severity of AAI levels. In addition, to investigate the prevalence of changes in plasma levels of glucose, lactate, potassium and sodium in children hospitalized with AAI, and their relationships with plasma cortisol, testosterone, estradiol and progesterone levels. 9 2. REVIEW OF LITERATURE 2.1. Alcohol consumption In the world Alcoholic beverages are available throughout the world. The level of alcohol consumption is conventionally reported in terms of annual per capita consumption of pure alcohol (100%) in litres (ACCAL). The mean worldwide ACCAL in 2005 was 6.13 litres consumed by every person aged 15 years or older, ranging from more than 12.5 litres in the developed world (mostly the Northern Hemisphere, Argentina, Australia and New Zealand) to under 2.5 litres in North and sub-saharan Africa, the Eastern Mediterranean region, and South- East Asia regions, but worldwide, recorded consumption has been stable at litres of pure alcohol per capita since 1990 (WHO; 2011). There is a gender difference in ACCAL: from 2.3 to 62.1 litres in males and from 0.2 to 33.0 litres in females (WHO, 2011). According to the Summary Health Statistics for United States, 52% of adults aged 18 and over were regular drinkers, 13% were currently infrequent drinkers, 6% were formerly regular drinkers, and 8% were formerly infrequent drinkers (National Health Interview Survey, 2012). The same study reported that 60% of men and 44% of women were currently regular drinkers In Estonia The total (recorded and unrecorded) consumption of alcohol in Estonia in 2005 was litres per capita, 36.1 litres for men and 12.2 litres for women. The alcohol consumed was mostly in the form of spirits and beer in 2005 (WHO, 2011). Over the next eight years, the total consumption of alcohol in Estonia decreased to 11.9 litres per capita in The largest amount of alcohol consumed in 2013 was beer and light alcoholic drinks, whereas the consumption of strong alcoholic beverages decreased over the period of (Estonian Institute of Economic Research, 2014). Inhabitants assessments of their own alcohol consumption in showed that 15.3% of respondents did not use alcohol at all, 55.3% drank a little, 26.7% drank moderately and 2.7% drank a lot (Estonian Institute of Economic Research, 2013) Among children and adolescents In the European School Survey Project on Alcohol and Other Drugs, 41% of all males between 15 and 16 years of age and 38% of all females at the same age interviewed reported five drinks or more on the same occasion during the past 30 days (European School Survey Project on Alcohol and Other Drugs, 2011). Among a teenage population evaluated in Australia, 29% of the subjects reported drinking to the point of drunkenness (Williams et al., 2000). About 86% 10 of 13 to 16-year-old adolescents in Estonia had consumed alcohol in their lifetime and the average age at initial alcohol consumption was 11.3 years in girls, and 10.7 years in boys (Markina et al., 2007). Similar results have been reported in different European countries. For example, 78% of Polish children declared consumption of alcohol in the last 12 months (Kaminska et al., 2012). According to the Health Behaviour in School-aged Children (HBSC) study, the prevalence of drunkenness increased significantly between ages 11 and 15 for boys and girls in European countries. Totally, 2% of 11-year-old girls and 5% of boys (1% of girls and 2% of boys in Estonia) and 17% of 15-year-old girls and 25% boys (13% of girls and 20% of boys in Estonia) had drunk alcohol at least once a week. The same study reported that 1% of 11-year-old girls and 3% of boys (1% of girls and 1% of boys in Estonia) and 29% of 15-year-old girls and 34% of boys (42% of girls and 48% of boys in Estonia) had been drunk at least twice (Currie et al., 2012) Alcohol pharmacokinetics and pharmacodynamics Acute alcohol intoxication (AAI) is a clinically harmful condition that follows the ingestion of a large amount of ethanol. Ethanol (CH3CH2OH) is an easily water-divided compound that rapidly crosses cell membranes. Ethanol is rapidly absorbed in the stomach and in the duodenum, while only a small percentage occurs in the remaining intestinal tract. The consumption of alcohol together with or after a meal leads to a slower rate of absorption because stomach emptying is delayed and the maximal concentration (Cmax) is lower and occurs later compared with a drinking on an empty stomach (Jones et al., 1994; Klockhoff et al., 2002). Blood from the gastrointestinal tract goes to the portal vein, where the alcohol is transported through the liver, and then on to the heart and the systemic circulation. The metabolism of alcohol occurs mainly through the action of enzymes located in the liver, and small amounts are metabolized also in the mucosa of the stomach. After absorption, ethanol is distributed into the water compartment of the body. The concentration of alcohol in the organs and tissues after reaching equilibrium depends primarily on the water content in these tissues (Endres et al., 1994). Body fluids such as sweat, saliva and urine, which are almost 100% water, contain a higher concentration of ethanol than whole blood, which is 80% water (Jones, 2006; Jones, 1993). Plasma and serum with a water content of 92% hold a higher concentration of alcohol than blood (Iffland et al., 1999). The majority of bloodstream alcohol (95 98%) is eliminated from the body by oxidative metabolism (Lieber et al., 2000), primarily by the liver. Metabolism of ethanol occurs via two pathways. The first pathway comprises two steps. The first step is metabolism to acetaldehyde, catalysed by the enzyme alcohol dehydrogenase (ADH), which takes place in the cytosol of the liver. The second step to acetate, catalysed by the aldehyde dehydrogenase (ALDH), takes place in mitochondria. In ADH-mediated oxidation of alcohol, hydrogen is transferred 11 from the substrate to the cofactor nicotinamide adenine dinucleotide oxidized form (NAD), converting it to nicotinamide adenine dinucleotide reduced form (NADH), and acetaldehyde is produced. Thus, ethanol consumption leads to an accumulation of NADH. This high concentration of NADH inhibits gluconeogenesis by preventing the oxidation of lactate to pyruvate. The altered redox state, in turn, is responsible for a variety of biochemical and hormonal disturbances. About 3 5% of the alcohol is excreted unchanged in breath, urine, and sweat (Jones, 2006). Less than 1% of the amount of alcohol undergoes conjugation by ethyl glucuronide in the gastric mucosa or in the liver. Conjugation Ethyl glucuronide 1% 3 5% Ethanol Excretion breath, urine, sweat Chemically reactive CYP2E1 microsomes ~10% Acetaldehyde +NADH +NAD + ADH cytocol ~85% Toxic metabolite +NAD +H 2 O ALDH mitochondria H 2 O Acetate +NADH +H + CO 2 Figure 1. Diagram of alcohol metabolism. The second pathway for ethanol metabolism is called the ethanol-inducible microsomal ethanol-oxidizing system (MEOS), and about 10% of alcohol is metabolized by the enzyme cytochrome P4502E1 (CYP2E1). This pathway uses oxygen, and therefore generates free radicals that damage tissues (Berg et al., 2002). The CYP2E1 has a higher Michelis-Menten constant (k m ) for oxidation of ethanol, and therefore comes into play when blood alcohol concentration (BAC) reaches higher concentration, as in heavy drinkers and alcoholics (Figure 1). The other effect is that liver mitochondria can convert acetate into acetyl CoA in a reaction requiring adenosine triphosphate (ATP). Further processing of the acetyl CoA by the citric acid cycle is blocked, as NADH inhibits two regulatory enzymes isocitrate dehydrogenase and α-ketoglutarate dehydrogenase. The result of accumulation of acetyl CoA is forming and releasing of ketone bodies into the blood, exacerbating the acidic condition already resulting from the high lactate concentration. The processing of the acetate in the liver becomes 12 inefficient, leading to a build-up of acetaldehyde, which forms covalent bonds with many important proteins, impairing protein function (Berg et al., 2002) Clinical signs of alcohol intoxication Clinical features and symptoms of acute alcohol intoxication in adults The effects of alcohol on the individual depend on the amount of alcohol ingested, the speed of drinking, the rate of increase in BAC, and previous experience with drinking (tolerance). Clinical signs and symptoms of acute alcohol intoxication have been well studied in adults, and the Diagnostic and Statistical Manual of Mental Disorders IV (DSM-4) published by the American Psychiatric Association for the diagnosis of AAI is used in everyday work (Diagnostic and Statistical Manual of Mental Disorders 4 th edition, 1994). Disturbed consciousness or memory, slurred speech, imbalance, aggressiveness, or euphoria may be a sign of AAI. Somnolence, stupor, disorientation, and disturbance of balance are frequent and well-recognised CNS symptoms of alcohol intoxication. It has been found that the psychomotor disturbances in adults with AAI with similar drinking customs are similar at different age groups (Karch, 1998). Studied men who received ethanol, reliably detected its effects when plasma ethanol levels reached 32 mg/dl, but only the subjects who received the high dose reported episodes of intense well-being or euphoria (Morgan et al., 2001). Ethanol-induced euphoria occurred while plasma ethanol levels were rapidly rising (Di Chiara et al., 1996; Lukas et al., 1986). Measurements of the pulse, frequency of breath, blood pressure, and body temperature are part of the physical examination of a patient, but they are not specific to estimating the level of drunkenness. Some studies have found that the pulse of alcohol intoxicated people is often accelerated (Brunelle et al., 2004; Ryan et al., 2002), but can also occasionally be slower than normal (Brvar et al., 2009). Blood pressure can express a similar tendency from hypotension in rare cases (Wilson et al., 2007) to hypertension in common cases (Puddey and Beilin, 2006; Reims et al., 2004; Spencer et al., 1999). However, one study has reported the decrease of blood pressure after acute alcohol consumption and thereafter increase during 24 hours (Barden et al., 2013). The breathing frequency is related to the intoxication level and lactate level in plasma an increased lactate level leads to acidosis and this in turn to an increased breathing rate. Body temperature is often influenced by the outside temperature: the hazard to hypothermia is greater in cold weather (Bouthoorn et al., 2010; Kornfält and Johansson, 2010; Devaney et al., 2003). Many studies describe good correlations between CNS symptoms and the blood alcohol concentration (BAC) in adults (McKnight et al., 1997; Zoethout et al., 2011), but there is insufficient information about similar studies in children (Lamminpää, 1994). 13 2.3.2 Clinical features and symptoms of AAI in children Although there are a lot of studies related to different aspects of AAI in children, few have looked at the clinical signs and symptoms of AAI (Bouthoorn et al., 2011; Weinberg et al., 2006). Bouthoorn et al. retrospectively studied that reduced consciousness (45%) and hypothermia (43.1%) were the most common clinical findings of AAI children in the hospital (Bouthoorn et al., 2011). The psychomotor disturbances in children varies greatly between different age groups due to the variances in the maturation of the body. Acute alcohol intoxication is worse in younger children (Minera and Robinson, 2014; Fong and Muller, 2014; Palano et al., 2007), because of the faster rise in the blood alcohol concentration and the development of pronounced euphoria. Children s studies have usually described children with serious alcohol intoxication without the comparable groups of mildly or moderately intoxicated children. Alcohol is distributed throughout the water in the body without binding to plasma proteins. This property causes the gender difference i.e. as females with the same body mass have less water content than males, they develop higher blood alcohol concentration than men (Mirand and Welte, 1994). In younger children, the entire water content of the body exceeds or is similar to the adult man s water content, calculated with Mellits-Cheek formula (http://www.medcalc.com/tbw.html). At the same blood alcohol concentration, the child has much more alcohol per body weight than an adult has and therefore has much more severe alcohol intoxication. In the emergency department, the paediatrician on-call should diagnose and treat the AAI in the first instance to avoid complications. Assessment of the intoxication level by clinical signs can help to determine treatment tactics, but the clinical assessment of drunken children is not an easy task as there are no objective criteria to determine the alcoh
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