Delirium tremens (DTs), first described in 1813, is a severe disease characterized by altered mental status, global confusion, and sympathetic overdrive due to an autonomic hyperactivity, which can progress to cardiovascular collapse. DTs is a medical emergency with a high mortality rate, making early recognition and treatment essential.
Withdrawal from alcohol, sedative-hypnotics such as benzodiazepines, or barbiturates, may cause delirium tremens and death if not properly managed. When caused by alcohol, it occurs only in patients with a history of alcoholism. Occurrence of a similar syndrome due to benzodiazepines does not require as long a period of consistent intake of such drugs.
In a general population alcohol-dependent, less than 50% people develop any significant withdrawal symptoms that require pharmacologic treatment upon cessation of alcohol intake. Among alcoholists that suffer from alcohol withdrawal syndrome, only 5% of patients progress and develop delirium tremens and withdrawal seizures.
It has been observed that white patients have a higher risk of developing severe alcohol withdrawal, while black patients have a lower risk. Whether or not sex differences exist in the rates of development of severe alcohol withdrawal is not clear and the data collected are not statistically significant. In any particular alcohol-dependent person, symptoms of withdrawal can differ widely among different episodes.
Delirium tremens rarely occurs among pediatric patients, because the physiologic substrate for severe alcohol withdrawal takes time to develop: although they may suffer from severe neurological damage and seizure.
Racial variations in the incidence of severe alcohol withdrawal.
Delirium tremens primarily occurs following abrupt withdrawal of alcohol in heavy users.
Alcohol causes a widespread depression on the SNC and it provokes anxiolytic effects and serious behavior modifications, as other substances like barbiturics and benzodiazepines do.
Long-term alcohol abuse and alcoholism cause the body to become used to alcohol, otherwise known as pharmacodynamic tolerance. Pharmacodynamic Tolerance afflicts liver, but also causes changes in the central nervous system. Some research suggests that long-term alcohol use results in an increased action of many neurotransmitters in the brain. The body does this to compensate for alcohol's depressant effects on the brain.
Ethanol is rapidly absorbed in small intestine and, as soon as it reaches the SNC, it interacts with GABA receptors, enhancing their activity in the acute use.
receptors are a family of
chloride ion channels that mediate inhibitory neurotransmission.
They are pentameric complexes composed of several glycoprotein subunits.
Chronic ethanol abuse seems to modify the GABA
receptor trough several mechanisms, leading to a decrease in GABA
activity and a downregulation of the receptor. Chronic ethanol exposure has been found to alter gene expression and to increase cellular internalization of certain subunits, affecting the type of GABA
receptors that are available at the cell surface and the synapse. It has also been found that ethanol causes phosphorylation of GABA
receptors, which may alter receptor function.
When ethanol is withdrawn, a functional decrease in the inhibitory neurotransmitter GABA
is seen. This leads to a loss of the inhibitory control of excitatory neurotransmitters such as norepinephrine, glutamate, and dopamine, especially in the VTA
(Ventral Tegmental Area).
KEGG Pathway: Alcoholism
Ethanol also acts as an NMDA
receptor antagonist. In the acute consumption of ethanol, the activity of the glutamate on the NDMA
receptors is depressed.
In the chronic use, besides, gene expression is increased and more receptors are exposed on the cell surface, internalization and phosporilation of the receptors are decreased, leading to an overall increased activity of these excitatory neurotransmitters.
The role of Glutamatergic Neurotrasmission in the pathophysiology of alcoholism
When the level of alcohol in the body of an alcoholic drops suddenly, neurotransmitter levels are unable to adjust quickly to the change. Since neurotransmitters are in charge of signaling the body's functions, this can cause all types of problems in the body as seen in the symptoms of DTs.
Sign and Symptoms
- Diaphoresis (heavy sweating, often on the hands or face)
- Extreme shakiness, tremors
- Altered mental status, panic attacks
- Severe psychomotor agitation
- Global confusion, agitation, irritability and difficulty concentrating
Hallucinations in Delirium Tremens
Frequently, hallucinations caused by DTs have a common theme: these include unpleasant crawling creatures such as snakes, spiders, roaches and other bugs. People may also feel these creatures crawling all over their bodies.
GABA is the major inhibitory neurotransmitter and sudden down regulation of this neurochemical receptors may cause uncontrolled firing of the neural impulses along synapses causing the up-regulation in the production of excitatory neurotransmitters such as epinephrine, norepinephrine, serotonin and dopamine which plays a major role in the onset of hallucinations.
This unopposed sympathetic hyperactivation is also known as “adrenergic storm": this is the most probably cause of visual and tactile hallucinations in DTs patients because, as we know, the onset of such phenomena is directly correlated to the increased activity of the dopaminergic system that occurs in other pshychiatric diseases such schizophrenia.
This dopamine hypotesis is based on the discovery that chlorpromazine and other antipsychotic drugs of the phenothiazine class attach themselves to the postsynaptic dopamine D2 receptor, and in this way appear to reduce the neurotransmitter's excitatory effect upon the mesolimbic pathways and other parts of the CNS resulting in a remarkable reduce of the hallucinatory phenomena in these patients.
It is now generally held that other neurotransmitters like glutamate and serotonin may play a role in the onset of hallucinations as well.
An abstract on hallucinations in DTs
Principles of hallucinatory phenomenon
It is strongly recommended that medical personnel proceed with monitoring vital signs and blood chemistry as well as fluid and electrolyte levels to prevent seizures or cardiovascular fatal events in the patient experiencing this kind of symptoms. A toxicologic screening is advised to make a differential diagnosis.
Serum studies are important in the diagnosis and in the assessment of patients with alcohol withdrawal. These may include:
An EEG my be performed if the patient present seizure attack during delirium: it may shows, for very short period, abnormal waves caracterized by spikes and paroxysmal bursts that shows the hyperactivity of SNC; besides the patient always present photosensibility and increased responsiveness to light stimuli which may break out in generalized myoclonic attacks.
EEG in DTs
The Role of Creatine Phosphokinase
CPK is one of the enzymes found primarily in the heart, skeletal muscles and brain.
- CPK-1 (CPK-BB) found mostly in the brain and lungs
- CPK-2 (CPK-MB) found mostly in the heart
- CPK-3 (CPK-MM) found mostly in skeletal muscle
This enzyme's primary function is to convert the creatine into phosphate, which then gets consumed or burned up as a quick energy source by the cells of the body. The normal blood concentration of CPK is 21 to 232 IU/L (International Unit/Liters). When any kind of muscle damage or stress occurs, the levels of CPK enzyme rise significantly. Indeed some patients may develop Alcohol Myopathy that is the cause of CPK blood levels increasing.
In addition to those three cytosolic CK isoforms, there are two mitochondrial creatine kinase isoenzymes (MtCK), the ubiquitous (CKMT1A, CKMT1B) and sarcomeric form (CKMT2). The functional of these two mitochondrial CK isoforms is an octamer consisting of four dimers each.
While mitochondrial creatine kinase is directly involved in formation of phospho-creatine from mitochondrial ATP, cytosolic CK regenerates ATP from ADP, using PCr. This happens at intracellular sites where ATP is used in the cell, with CK acting as an in situ ATP regenerator.
It is known that alcohol reduces mitochondrial respiration in heart cells (Alcoholic depression of oxidative phosphorylation) and increases the levels of free radicals like *OH and H2O2 in the mitochondria leading to a serious damage of the cell and a remarkable reduced octamerization of dimeric MtCK and dose dependent dissociation of octamers into dimers. This cause the inactivation of these enzymes, the lack of ATP and the death of the cell.
Mitochondrial creatine kinase in human health and disease
- Injury from falls during seizures
- Injury to self or others caused by mental state (confusion/delirium)
- Irregular heartbeat, may be life threatening
Delirium tremens is most often treated with benzodiazepines. Since benzodiazepines are sedatives, they can control many of the symptoms of sudden alcohol withdrawal. In severe cases where hospitalization is needed, high doses of these drugs may be needed to relieve symptoms and prevent death.
- Chlordiazepoxide: very useful in controlling convulsion and tremors, usually 0 a 160 mg/die is given. It may be reduced if collateral effects manifest.
- Diazepam: equally effective as Chlordiazepoxide, the therapy begins with a single dose of 10 mg. e.v. with the possibility to increase the dose of 5 mg. or more (until 40 mg) every 1-4 hours.
- Oxazepam, Alprazolam, Flurazepam e Clorazepam: second choice drugs. Equally effective to Diazepam but with more collateral effects.
- Propofol: used recentely in controlled studies, it has given moderate results in controlling DTs in benzodiazepine-non responsive patients.
- Beta-blockers: useful in decreasing psychomotor agitation, anxiety, agitation and tachycardia, reducing also the need to use benzodiazepine and other sedatives. First choices of this class are propanolol and athenol.
Anticonvulsants can be given if a patient experiences seizures during DTs.
- Carbamazepine: useful in controlling seizures, but it must be somministrated only in patient under strict control for its strong interaction with ethanol in blood.
In the moment of visual and tactile hallucinations, a doctor may also give a patient an antipsychotic medication, like neurolectics.
It is necessary to administer intravenous fluids for rehydration. Most patients with severe alcohol withdrawal are significantly dehydrated, and their fluid requirements range from 4-10 L in the first 24 hours.
For hypoglycemia is common in these patients due to depleted glycogen stores, a 5% dextrose solution (in 0.90% or 0.45% saline) should be used to prevent hypoglycemia.
It is highly recommended to administer endovenous Thiamine for preventing Wernicke encephalopathy (confusion, ataxia, ophthalmoplegia) and Wernicke-Korsakoff syndrome. Although thiamine has no effect on the symptoms or signs of alcohol withdrawal or on the incidence of seizures or DTs.
People affected by alcoholism frequently have large total body deficits of magnesium.
For a 70-kg person with normal renal function, 4-6 g of magnesium sulfate (32-48 mEq of magnesium) is administered by continuous IV infusion on the first day, followed by half that amount daily for 4 days.
Finally, it is important to provide a calm, quiet, well-lit environment and medical personnel should be very reassuring and encouraging toward the patient.