Acute Poisonings English

Management of Patients with Acute Poisoning

Most poisonings are self-inflicted, but not all. Acute poisoning can be caused by medications and drugs, but also by gases, chemicals, mushrooms, and other types of biological toxins. An initial assessment should try to determine whether the poisoning is intentional or accidental and whether it is self-inflicted or caused by someone else; this should be documented in the medical record as it affects diagnostic classification. Here are general guidelines for the acute management of poisonings, but treatment can vary, and each case must be assessed based on the severity of the poisoning and the patient’s condition.

Patients with acute poisoning must be closely monitored, which is crucial for a good prognosis. In most cases, the main treatment is symptomatic. The most important factors are adequate monitoring of breathing, circulation, and consciousness. The acute management includes securing vital functions, ensuring an open airway, and optimizing breathing and circulation.

At the same time, a thorough medical history and identification of the ingested poison, alcohol, drugs, or medications in the case of drug poisoning are essential. What drugs have been taken, and when? Adequate antidote treatment is provided in severe poisonings when applicable. The most important points in most cases of poisoning are:

• Careful monitoring of consciousness and breathing
• Support breathing and circulation if necessary
• Manage acute confusion and motor agitation calmly and safely
• Identify the toxic agent
• Implement active elimination when indicated, such as gastric emptying, activated charcoal, or dialysis
• Antidote treatment when a clear indication exists and the benefits outweigh the risks
• Admit the patient to a ward with the appropriate level of care, avoiding a too-low level of care if consciousness is reduced or breathing is impaired
• Arrange for follow-up with psychiatry and social services

ACUTE MANAGEMENT

Open Airway

• Recovery position
• Nasopharyngeal or oropharyngeal airway if the airway is obstructed
• Endotracheal intubation if necessary; in emergencies, a laryngeal mask
• Assisted ventilation if necessary
• Liberal use of oxygen
• Pulse oximeter
• Prevent aspiration; consider gastric aspiration

Open Venous Access

• Peripheral venous catheter (PVC), preferably two if unconscious
• Arterial line if unconscious, metabolic acidosis, or circulatory impairment
• Central venous catheter (CVC) if unconscious or circulatory collapse

Gastric Emptying – see below under treatment

• Manually, only in young children initially
• Ipecac syrup, no longer recommended for treatment
• Gastric lavage via a large-bore tube through the mouth

Activated Charcoal – see below under treatment

• Manually, in a cup or sippy cup
• Administered into the stomach via a gastric tube, dissolved in water

Laboratory Tests

• Acute toxicity tests according to local protocols (ethanol, methanol, paracetamol, etc.)
• Biological alcohol markers if alcohol abuse is suspected (PEth, CDT)
• Drug screening of urine (on patients with a urinary catheter)
• Targeted toxicology tests (urine, serum, possibly hair, nails)
• Frequent electrolyte status checks (routine status)
• Arterial blood gases with acid-base status (including lactate and CO-Hb)
• SvO₂ and lactate if cyanide poisoning or severe heart failure is suspected
• Blood glucose
• Serum myoglobin (rhabdomyolysis)
• Cardiac enzyme markers in carbon monoxide poisoning or with ECG changes or myocardial ischemia plus CO-Hb
• Save and freeze an extra tube of venous blood (serum) from admission for supplementary diagnostics in unclear or severe cases

Antidote Treatment

Antidotes are given when the patient’s condition requires it and when there is an opportunity to significantly improve the prognosis. Some common and important antidotes include:

• Acetylcysteine for paracetamol and mushroom poisoning. Note that overdose with paracetamol 665 mg requires a specific acetylcysteine protocol with an extended phase-II dose.
• 4-methylpyrazole (Fomepizole^®) for methanol or ethylene glycol poisoning
• Hydroxocobalamin (Cyanokit^®) for cyanide poisoning (fire smoke) or other cyanide compounds
• Beclometasone (Becotide^®) for poisoning with irritating gases (steroids in inhalation)
• Desferoxamine (Desferal^®) for iron poisoning
• Digitalis antibodies (DigiFab^TM®) for digitalis poisoning (digoxin, digitoxin)
• Flumazenil (Lanexat^®) for benzodiazepine poisoning
• Naloxone (Naloxone^®) (Nexodal^®) for opioid poisoning
• Obidoxime (Toxogonin^®) for nerve gas poisoning (deregistered)
• Antivenom (Vipera Tab^®) for snake bites; for other snake bites, specific antivenom.

Important antidotes

Differential Diagnosis

Any patient under the age of 50 with unexplained unconsciousness should be considered as having poisoning or intoxication until proven otherwise! The diagnosis of intoxication or poisoning should always be considered with unexplained reduced consciousness, and it is often the correct diagnosis when, for example, stroke was the preliminary diagnosis! Conversely, intoxication has been incorrectly diagnosed when the correct diagnosis was, for example, hypoglycemic coma! Always consider a differential diagnosis in cases of unexplained unconsciousness! Consider alcohol and drugs when patients are agitated and restless. Smell their breath! Among patients with unexplained unconsciousness under 40 years of age, it has been reported that more than 80 percent are caused by poisoning, while among patients over 60 years, more than 90 percent are caused by something other than acute poisoning. In cases of unexplained unconsciousness, a CT scan of the brain should be performed with relatively wide indications. Trauma and poisoning are common parallel diagnoses.

MONITORING

Circulatory and respiratory monitoring

• ECG with arrhythmia monitoring, continuous and recorded in the medical record at admission. Determine rhythm, QT interval, and QRS duration.
• Invasive monitoring, continuous arterial pressure, and central venous pressure (CVP) in severe intensive care cases.
• Echocardiography (UCG) in cases of heart failure or severe hypotension.
• Pulse oximetry and respiratory rate.
• Spirometry on ventilated patients and in cases of exposure to irritating gases.
• Urinary catheter (KAD) with hourly urine output and temperature measurement.

Prolonged QT interval is relatively common in drug poisonings. In cases of repeated episodes of ventricular tachycardia or ventricular fibrillation, think of drug-induced prolonged QT interval.

Consciousness

Continuous assessment of the patient’s consciousness and level of consciousness should be carried out and documented. Consciousness grading should be done continuously (1-2 times per hour), and several different scales are available for this purpose. A common scale in the Nordic countries is the so-called RLS scale (Reaction Level Scale, 0-8 p), but internationally, the Glasgow Coma Scale (GCS) is more commonly used. Which scale is used is less important. The important thing is that the level of consciousness is graded and documented regularly. Neurological deficits must be documented and investigated promptly. A grading instrument that can be used clinically to assess the severity of poisoning is the Poisoning Severity Score (PSS).

A negative change in the patient’s level of consciousness must be observed, and appropriate countermeasures must be taken. Severe poisoning symptoms such as respiratory arrest or cardiac arrhythmias often occur suddenly after a decline in consciousness.

SAMPLING

Quantitative concentration determination should be monitored in cases of poisoning by the following substances:

• Paracetamol (4, 8, 12, and 24 hours after ingestion)
• Carbamazepine
• Acetylsalicylic acid
• Digoxin
• Ethanol
• Ethylene glycol
• Iron
• Isopropyl alcohol
• Lithium
• Methanol
• Theophyllamine

Measure serum concentrations of relevant drugs 1-4 times during the first day. On the following day or when concentrations have dropped below toxic levels, tests can be taken once per day.

Note that when a given elimination treatment, such as hemodialysis, is discontinued, serum concentrations may rise again (rebound), as in lithium poisoning.

For refined diagnostics, both arterial and venous samples can be taken to provide information about continued drug absorption from the intestine or redistribution in different body compartments. In most cases, it is sufficient to follow venous concentration determinations. Note that alcohol can be measured in blood, breath, and urine.

Drug Screening

Drug screening is performed on the patient’s urine to detect drug poisonings, which can often explain changes in consciousness in acute poisoning cases. This is especially true in cases of motor agitation and psychotic symptoms or seizures. Drug tests usually detect the presence of cocaine, cannabis, morphine, amphetamines, and benzodiazepines. New drug tests can detect more substances, typically between 8 and 14 different drugs. This screening should be liberally performed in cases of unexplained unconsciousness in younger patients with known substance abuse. A screening test usually provides results within 5-10 minutes, which facilitates the acute diagnosis of a poisoned patient. Additionally, send a urine sample to the chemistry lab for analysis with GC-MS (gas chromatography-mass spectrometry) for verification or if GHB poisoning is suspected. Note that GHB and LSD are not included in standard rapid drug tests. Newer tests can detect up to 14 different substances. There are now tests for Spice (synthetic cannabinoids), buprenorphine, methadone, ecstasy, and GHB.

Treatment for Acute Poisoning

The treatment of acute poisoning is mainly symptomatic, and antidotes are available in only a limited number of cases. Consciousness, breathing, and hemodynamics can change suddenly during the first six hours. Seizures, psychomotor agitation, reduced consciousness, nausea, and vomiting are common. Insufficient breathing is supported as needed by endotracheal intubation and ventilator treatment in an intensive care unit. Uncomplicated poisoning cases often require no more than four hours of monitoring; in complicated cases, longer monitoring is necessary as the condition varies.

Medical Charcoal (Activated Charcoal)

Activated charcoal is valuable if administered early in treatment, preferably within one hour of toxic substance ingestion. Administration of medical charcoal should be standard treatment for acute drug poisonings. Charcoal is of limited value if administered late in treatment, more than six hours after the poisoning event. The usual dosage is 50 g of medical charcoal for adults and 1 g/kg for children up to 12 years of age.
Charcoal adsorbs most drugs; however, not iron, lithium, ethanol, methanol, or cyanide. Medical charcoal can be given later than after one hour in life-threatening poisoning and should complement gastric lavage when performed. See specific guidelines for gastric lavage and medical charcoal.

Gastric Lavage

Gastric lavage is of limited value and should only be performed if the patient is admitted to the hospital early after the poisoning event, usually within one hour of ingestion (less than 25% of all cases). In very severe poisonings (life-threatening poisoning), after the ingestion of very large doses or drugs with anticholinergic effects, gastric lavage may be performed at a later stage or repeatedly, up to 24 hours after ingestion. See specific guidelines for gastric lavage. Examples of particularly toxic substances include chloroquine, potassium, and various heavy metals.

Sodium bicarbonate is an essential part of the treatment for many poisonings, especially in cases of pronounced metabolic acidosis, such as methanol, ethylene glycol, and other toxic alcohol poisonings. Sodium bicarbonate is also crucial after overdoses of tricyclic antidepressants and some other cardiotoxic drugs. Alkalinization reduces the free concentration of overdosed drugs in the bloodstream, limiting their transfer to myocardial cells. Toxicity from tricyclic antidepressants decreases with sodium bicarbonate treatment. In cases of severe poisoning, give an initial dose of approximately 200 ml sodium bicarbonate (120 mmol). Then titrate based on blood gas results. Aim for a pH above 7.45 and a positive Base Excess.

Treatment with Vasoactive Drugs

If it is difficult to maintain blood pressure after administering crystalloid and colloid fluids, vasoactive drugs can be used to increase blood pressure and cardiac output and improve oxygen delivery to vital organs and peripheral tissues. The same drugs used in cases of severe heart failure from other causes are typically used. The most common drugs are dopamine, dobutamine, noradrenaline, and adrenaline in continuous infusion. Additionally, isoprenaline can be used in severe heart failure and bradycardia, such as after poisoning with calcium channel blockers, beta-blockers, or tricyclic antidepressants. Inotropic drugs that strengthen the heart independently of beta-receptors can also be used, such as glucagon. Glucagon can be tried in cases of poisoning with beta-blockers or calcium channel blockers. High-dose glucose-insulin can also be tried.

In cases of severe bradycardia and heart failure, treatment with a transvenous pacemaker may also be beneficial.

Treatment with Fat Emulsion (ILE)

This treatment can be life-saving in cases of cardiovascular collapse after an overdose of local anesthetics, especially bupivacaine (Marcain^®) and several other drugs. In cases of overdose involving other fat-soluble drugs, such as verapamil (Isoptin^®), treatment with intravenous fat emulsion (Intralipid^®) has been effective in isolated cases. One theory is that intravenous lipid treatment creates a depot in the bloodstream that extracts toxic substances from heart cells, reducing cardiotoxicity (“sink theory – redistribution”). Initially, 100-200 ml of Intralipid 20% is given intravenously along with CPR. Please see treatment for overdose with local anesthetics. This treatment remains controversial and is recommended only as a last resort in cases of cardiovascular collapse after ingestion of fat-soluble drugs.

Treatment with Extracorporeal Circulatory Support (ECCS, ECMO, Aortic Balloon Pump)

In cases of cardiovascular collapse due to poisoning, mechanical circulatory support can often be life-saving. In cases of poisoning, severe heart failure is usually temporary, lasting a few hours or up to 2-3 days. Initially, a mechanical heart compression device, such as a LUCAS pump, can be life-saving. The patient can then be transported to a thoracic surgery department or intensive care unit, where an aortic balloon pump or other mechanical circulatory support (ECMO/ECCS) can be placed. If this can be done quickly without brain damage, survival is generally possible. ECMO may be needed for 2-3 days, after which the heart usually recovers. The method is invasive and resource-intensive but very effective. This treatment should be considered in the presence of very wide QRS complexes (> 140 msec), severe hypotension, severe bradycardia, or very low SvO₂ (< 45%). Examples of drug overdoses where ECMO may be appropriate include poisoning with:

• Tricyclic antidepressants (TCA)
• Neuroleptics
• Antipsychotic drugs
• Antiepileptic drugs
• Chloroquine
• Beta-blockers
• Antiarrhythmic heart medications (flecainide)
• Calcium channel blockers (calcium antagonists)

Many of these drugs are described as membrane-stabilizing drugs with a negative inotropic effect due to sodium channel blockade. In cases of overdose, a gradual widening of the QRS complex is often seen on the ECG, along with a drop in blood pressure and bradycardia leading to circulatory shock.

Agitated Patient

If the patient is agitated and psychomotorically restless, sedative medications such as benzodiazepines can be given. Sedative neuroleptics have also been used but should be avoided in cases of poisoning with other neuroleptics or in cases of unstable blood pressure; clomethiazole (Heminevrin^®) should be avoided entirely.

The following medications are suitable for sedation:

• Midazolam (Midazolam^®) 1-5 mg i.v., i.m., or in continuous infusion 1-5 mg/h (1 mg/ml). Can also be given orally.
• Diazepam (Stesolid^®) 2.5-5 mg i.v.
• Propofol (Propofol^®) 20-40 mg i.v. or in continuous infusion, 20 mg/ml with 3-10 ml/h.
• Olanzapine (Zyprexa^®) 5-20 mg i.m. x 2.
• Droperidol (Dridol^®) 5-10 mg i.m. (SIC)
• Ketamine 20-100 mg i.v.

Note that consciousness fluctuates and the patient may quickly become unconscious with insufficient breathing after administration of sedative medications.

If the patient is severely agitated and/or violent, it may be necessary to fully anesthetize the patient and place them on a ventilator with controlled ventilation. This should only be done when it benefits the patient. Midazolam (Midazolam^®) 5 mg i.v. plus propofol (Diprivan^®) 50-200 mg i.v. can be used until the patient is lightly sedated. Patients usually require continuous infusion of propofol for 3 to 8 hours. The infusion rate is adjusted based on the level of consciousness, with 200-400 mg propofol given per hour (5-10-20 ml/hour).
The patient should be monitored in an intensive care unit, and the airway must be secured by endotracheal intubation and mechanical ventilation. Sedation can usually be discontinued afterward, and the patient typically wakes up calmly and peacefully.

Anesthesia with intravenous propofol should only be performed by an anesthesiologist when the situation is untenable and poses an immediate danger to the patient’s life. This usually requires intubation and mechanical ventilation for at least 4-6 hours.

Agitated patients should not be discharged from the emergency department while still under the influence of drugs, restless, and lacking self-control. They may be violent toward themselves, relatives, or staff. Patients with agitation and an “anticholinergic syndrome” can significantly improve with intravenous physostigmine, for example, after poisoning with antidepressants or neuroleptics. However, there is a risk of lowering the seizure threshold; physostigmine has been reported to cause seizures and bradycardia, so caution should be exercised in the early phase of poisoning.

In severe poisonings, such as methanol poisoning or severe paracetamol poisoning with liver failure, the patient should be referred to a regional hospital.

INDICATIONS FOR ADMISSION TO AN INTENSIVE CARE UNIT (ICU)

• Life-threatening poisoning
• Ingestion of highly toxic substances
• Large quantities of drugs or other poisons have been ingested
• Severe airway irritation due to exposure to irritating gases
• Significant decrease in consciousness
  • RLS 3 or higher
  • GCS below 10
• Significantly agitated or confused patient
• Sudden loss of consciousness
• Inability to maintain a free airway in a supine position
• Cardiac arrhythmias
• Hypoxia with SaO₂ < 90% on room air or SaO₂ < 95% with oxygen
• Respiratory rate less than 10 or more than 30 breaths per minute
• Pulse below 40 or above 130 beats per minute
• Systolic blood pressure below 90 mm Hg despite fluids
• Seizures
• Severe metabolic acidosis or significant lactic acidosis (> 5 mmol/L)
• Hypothermia or hyperthermia
• Severe electrolyte disturbances
• Other significantly concerning conditions!

Sleeping Patient (Somnolence – Lethargy)

If the patient is deeply asleep and cannot be awakened, they should be monitored in an intensive care unit with readiness for intubation.

If vital signs are stable and the patient is breathing calmly and regularly, monitoring is usually sufficient, and the patient should be allowed to sleep until they wake up. Comatose patients should be placed in a stable lateral position and turned every two hours. Other causes of deep unconsciousness besides poisoning should, of course, be ruled out. Check electrolytes, toxicity tests, and an arterial blood gas, as well as blood alcohol concentration. Perform a CT brain scan in unclear cases of unconsciousness or in the presence of focal neurological symptoms.

In cases of drug poisoning, the patient usually sleeps deeply for 3-12 hours. Longer periods of unconsciousness than 12 hours are often due to other causes but can be associated with certain poisonings, such as antidepressants, barbiturates, or sustained-release preparations with a long half-life (Voxra^®, Propavan^®, Lithium^®). Awakening usually occurs calmly, and the patient feels quickly restored. The patient can generally be discharged home. If the patient is motorically agitated upon awakening, they should be sedated to provide additional sleep and a calmer awakening, for example, with midazolam (Midazolam^®) 1-2 mg i.v.

Serious incidents with poisoned patients usually occur within six hours of hospital admission, such as seizures, blood pressure drops, or cardiac arrhythmias.

An agitated patient may present with a clinical picture consistent with a so-called “toxidrome.” Various “toxidromes” (clinical syndromes) have been described in connection with poisonings, namely “anticholinergic syndrome,” “serotonin syndrome,” “malignant neuroleptic syndrome,” and “agitated delirium.” A patient with a toxidrome has a characteristic clinical presentation and may require specific treatment. These syndromes often share the common feature of hyperthermia and agitation, which can become life-threatening. The main treatment for these syndromes is sedation and cooling. The most important factor is recognizing hyperthermia and controlling temperature in the management of an agitated or drug-intoxicated patient. Note that patients who have ingested amphetamines usually present with hyperthermia but may also arrive with hypothermia.

FOLLOW-UP

Psychiatric and social follow-up of the patient is important when the intoxication occurs in connection with a suicide attempt or when the patient has active substance abuse with drugs, alcohol, or narcotics. A follow-up appointment with psychiatry, addiction care, or social services is desirable, and a referral should be written. In cases of life-threatening addiction (GHB, Opiates, Amphetamines), social services must always be contacted, either in writing or verbally.

Abuse of central stimulants (amphetamines, cocaine, ecstasy, party drugs) and cannabis is common among younger patients with drug intoxication, as is general social disorder in these cases. Cases involving minors under 18 years of age should be reported to social services and child and adolescent psychiatry (BUP). The school health service may also need to be involved.

In cases of repeated acute overdoses, a report to social services should be made, and consideration should be given to involuntary care under LVU (the Care of Young Persons Act – < 20 years) or LVM (the Care of Substance Abusers Act). The report to social services can be verbal or written.

Long-Term Effects

A drug overdose usually does not result in long-term effects unless serious complications such as apnea, aspiration pneumonia, acute liver failure, acute kidney failure, or severe generalized hypoxia occur. The risk of withdrawal symptoms from substance abuse, alcohol, or drugs must always be considered when discharging a patient. Transient sleep disturbances with severe insomnia for 3-4 weeks are not uncommon. Other side effects reported include stomach pain, difficulty concentrating, depression, anxiety, and impotence. Many patients experience low quality of life for a long time after being treated for acute poisoning. The risk of a new fatal poisoning within a week of the current treatment is very low.

ICD-10 Codes

• Poisoning by drugs, medications, and biological substances T36-T50
• Toxic effect of substances primarily used for non-medicinal purposes T51-T65
• Toxic effect of alcohol T51
• Toxic effect of other and unspecified substances T65
• Accidental poisoning and exposure to harmful substances X40-X49
• Intentional self-harm by poisoning X60-X69
• Assault by poisoning X85-X90
• Poisoning with unclear intent Y10-Y19
• Mental and behavioral disorders due to sedatives and hypnotics, acute intoxication F13.0

Acute poisonings references

Gastric Lavage and Medical Charcoal (Activated Charcoal)

Gastric emptying and gastric lavage have long been standard procedures in the management of acute poisoning patients who still have toxic substances in the gastrointestinal tract. Today, significantly fewer poisoned patients undergo gastric emptying compared to 10-20 years ago. This is because several studies have raised doubts about the usefulness of the procedure. However, it remains a method that can be life-saving in some cases, and how to perform it safely and simply should be known by all who work in a medical emergency department.

Gastric emptying was previously done through gastric lavage with water via a tube or through the induction of vomiting (manually or with the help of emetic drugs). There is no longer scientific support for gastric emptying with emetic drugs. Manual vomiting is only performed on small children immediately after ingesting toxic substances, such as at home or in preschools. Gastric emptying in adults can be performed when indicated through tubing and gastric lavage with tap water.

The benefit of gastric lavage is evidence-based in scientific animal studies and experimental human studies. However, in controlled randomized clinical trials, the benefit of gastric lavage has only been demonstrated when performed very early in the poisoning process, usually within one hour of ingesting a toxic substance. The same applies to the administration of medical charcoal (activated charcoal). Gastric emptying later than one hour after ingesting toxic drugs has not been shown to have any impact on the clinical course in controlled randomized scientific studies.

However, it is difficult in clinical studies to select patients who may benefit from the procedure. Experience suggests that some patients may still benefit from gastric lavage even at a later stage in cases of severe poisoning or poisoning with slow-release preparations (depot preparations). Each poisoning incident must therefore be evaluated and tested individually, taking into account what was ingested, the quantity, and the patient’s condition. The guidelines below are intended as general guidelines. The guidelines apply to both gastric emptying and gastric lavage.

Administering medical charcoal to reduce the absorption of toxic substances is a routine procedure after gastric emptying. Charcoal can also be administered without gastric lavage through a gastric tube or orally (oral suspension – charcoal suspension). Administering medical charcoal is considered the first-line treatment in the management of acute poisonings and should be much more common than gastric lavage. All patients who are admitted to the hospital with severe poisoning should be evaluated for gastric emptying and treatment with medical charcoal.

GUIDELINES FOR DECONTAMINATION IN ACUTE INTOXICATION

Gastric Lavage

Gastric emptying in adults should be performed when indicated through gastric lavage via a large-bore tube (28-32 Ch) inserted into the stomach through the mouth. The procedure includes both gastric emptying and gastric lavage, usually with tap water.

After gastric lavage is performed, medical charcoal should be administered to the patient through the same tube in most cases, typically 50 g of charcoal, sometimes more.

Gastric emptying should be performed within a reasonable time (< 1 hour) if severe poisoning is suspected based on information about the ingested substance’s toxicity, the quantity ingested, and the time of ingestion. Gastric emptying should be performed liberally in complicated and severe cases. Complicated and severe poisoning cases often occur after overdoses of the following medications:

• Beta-blockers
• Calcium channel blockers
• Digitalis
• Tricyclic antidepressants
• Antiepileptics
• Barbiturates
• Chloroquine
• Oral antidiabetics
• Potassium tablets
• Slow-release preparations

Gastric emptying should be performed in cases of acute intoxication:

• Within 1 hour after an overdose of tablets or liquid preparations (medication mixtures, suspensions).

Gastric lavage may be considered:

• Within 12 hours after an overdose of a very large amount of tablets, or after ingestion of highly toxic substances or slow-release preparations, such as Paracetamol 665 mg.
• Within 24 hours if toxic plants or toxic mushrooms have been ingested (
  
  mushrooms containing amatoxins).

If the ingested drugs are not highly toxic and more than 1 hour has passed since ingestion, gastric lavage can usually be avoided. In many of these cases, medical charcoal administration alone may suffice.

However, gastric lavage may be performed later than 1 hour after ingestion of poorly digestible material such as mushrooms and plant parts, drugs with anticholinergic effects (TCA), or in cases of conglomerate formation in the intestines (iron, lead, potassium) or otherwise delayed intestinal peristalsis. Deeply unconscious patients generally have no or severely reduced intestinal peristalsis. The presence of conglomerates can and should be demonstrated by imaging (abdominal X-ray, CT). Note that paracetamol in the 665 mg preparation contains a double layer of medication with delayed release, so gastric lavage and the administration of activated charcoal may be considered even later than 1 hour after ingestion. There is a risk that this preparation may form conglomerates in the intestines.

If circulation and respiration are stable, the patient’s alertness is adequate (the patient responds to verbal stimuli), and the ingested substance and time of ingestion are unknown, gastric emptying can generally be avoided.

Note that patients who have ingested certain highly toxic drugs may initially appear relatively unaffected. This applies to substances like chloroquine (Klorokinfosfat Recip^®), paracetamol (Alvedon^®, Reliv^®, Panodil^®), venlafaxine (Efexor Depot^®), or digoxin (Digoxin^®). Therefore, it is essential to document the ingested substance, quantity, time of ingestion, and to observe the patient’s alertness, respiration, and circulation. Note whether paracetamol is in an “immediate release” or “modified release” form.

Each patient’s clinical presentation must be assessed individually to weigh the benefits of gastric lavage against the risks. The amount of medication or toxin eliminated through gastric lavage must favorably influence the clinical course for the procedure to benefit the patient. This is naturally difficult to assess in advance, and some degree of overtreatment may be necessary.

Gastric lavage should not be performed if ingestion of corrosive acids, alkalis, lye, petroleum products like lighter fluid or lamp oil, or alcohols is suspected. In exceptional cases, gastric lavage may be justified after alcohol ingestion if the patient has ingested a large amount very recently (e.g., in the hospital). In most cases, however, it is pointless in cases of poisoning with ethanol, methanol, ethylene glycol, isopropyl alcohol, or GHB. The procedure only introduces additional risk to the patient.

In cases of isopropyl alcohol (2-propanol, hand sanitizer, windshield washer fluid) ingestion, gastric lavage may be warranted up to one hour after ingestion.

Gastric Lavage Procedure

A routinely performed gastric lavage by experienced hands is a relatively simple and safe procedure. If the airway is inadequate or uncertain, the patient should be intubated before gastric lavage. The assessment of whether the airway is clear and swallowing reflexes are intact is clinical and can be challenging. If there is significant doubt, the patient should be intubated first to secure the airway and avoid complications. An anesthesiologist should assist during the procedure.

• In gastric lavage, a large tube (28-32 Ch) is used, which allows tablets to be aspirated from the stomach.
• The patient is placed in a stable left lateral position during the procedure, and the tube is inserted into the stomach through the mouth. A tongue depressor can sometimes help guide the tube through the mouth. The tube should be lubricated. The tube is advanced as the patient swallows. The tube’s position may need to be adjusted a few times in the stomach during the procedure. A typical distance to the stomach is 35-50 cm. If the tube is not correctly placed in the stomach, there is an increased risk of airway aspiration (past the cardia). There is also a risk of gastric content leakage around the tube.
• Oxygen is supplied to the patient via a catheter or nasal cannula throughout the procedure (2-4 L/min O₂).
• Once the tube is placed in the stomach, gastric contents should be aspirated using suction (gastric aspiration) before flushing with water or saline through the tube. Tap water is most easily used to flush the stomach. No more than 200 ml should be used at a time to avoid flushing stomach contents into the intestines. The water is flushed in and aspirated out. Flushing continues until a clear return is obtained, but the procedure should not take more than 10 minutes.
• A closed irrigation system (similar to a bladder irrigation system) with two bags and large tubing clamps can be used to flush in and flush out without air mixture. It is essential to ensure no net fluid uptake by the patient.
• It is estimated that about 25% of the gastric contents will be flushed into the small intestine. There is a risk that tablet conglomerates will dissolve. Therefore, there is an increased risk of toxic reactions 20-30 minutes after lavage. During this period, the patient should not be transported between departments or be on a radiology ward!
• After the lavage, 50 g of medical charcoal dissolved in a suspension is usually administered through the tube.
• When removing the tube, it is advisable to clamp the tube proximally with a hemostat (clamping the tube). The tube is clamped to prevent its contents from draining into the pharynx at the level of the laryngeal inlet and into the trachea.
• It is not uncommon for the patient to gag at the moment the tube is removed; be prepared with a large suction device. Suction the pharynx clean.
• Careful observation of the patient is necessary immediately after the gastric lavage procedure.
• Intubated patients should not be extubated directly after gastric lavage but monitored on a ventilator for at least four hours after the procedure.

Whole Bowel Irrigation

Whole bowel irrigation may be indicated in cases of heavy metal poisoning, such as lead or arsenic poisoning, but it has also been used in potassium poisoning. One method of accelerating the elimination of toxic agents is to flush tablets through the intestines with the fastest possible intestinal transit, effectively a type of bowel irrigation. This method is more commonly used in certain countries, such as Canada and Australia. Large amounts of fluid are given by mouth or via a tube, with a laxative effect, such as Laxabon^®. A typical dose is 4 liters for adults and 25 ml/kg for children. 1-1.25 liters are initially administered via a tube. The first bowel movement occurs approximately one hour after Laxabon is administered, so the method is somewhat slow. The active ingredient is primarily macrogol, but note that Laxabon also contains potassium, so this preparation should be avoided in cases of potassium poisoning! An alternative to Laxabon is irrigation with a polyethylene glycol solution.

Medical Charcoal – Activated Charcoal

All patients admitted to the hospital with suspected poisoning (acute intoxication) should be evaluated for whether they should receive medical charcoal (activated charcoal). The effectiveness of medical charcoal is greatest within the first hour after ingesting a toxic agent. Its effect rapidly diminishes over time.

Medical charcoal should be routinely administered in cases of overdose with substances that adsorb to charcoal when a toxic reaction is feared. Almost all medications bind to medical charcoal except iron and lithium, but potassium also binds poorly to charcoal. Ethanol, methanol, and cyanides do not bind to medical charcoal either. Medical charcoal suspended in water can also be administered pre-hospitally if the patient is cooperative. However, it should not be administered if there is a significant risk of vomiting and lung aspiration of the charcoal.

Administration of medical charcoal without gastric lavage can be applied when poisoning is assessed as mild to moderate (unaffected vital parameters) or when the patient arrives relatively late after the poisoning incident, e.g., later than one hour after drug ingestion or in cases of mushroom poisoning, even at a late stage.

In such cases, medical charcoal can be administered to the patient as a suspension via a piped mug that the patient drinks from, or via a gastric tube. In these cases, a thinner tube (18 Ch) than that used for gastric lavage can be used and inserted through the nose. Administration of medical charcoal through a tube placed via the nose is best performed with the patient semi-sitting in a supine position. The nasal opening and the tube should be well lubricated, and the procedure is usually quick and painless when performed by experienced staff.

The amount of medical charcoal administered should exceed the ingested toxic dose by ten times in weight. Routinely, a single dose of 50 g of charcoal is administered in suspension. If the ingested toxic dose exceeds 5000 mg, more than 50 g of charcoal must be administered.

Children up to one year old should be given 1 g/kg body weight. Children between 1 and 12 years old should receive 25-50 g. Adolescents and adults should be given 25-100 g of charcoal in a single dose.

In certain cases of severe poisoning, the administration of medical charcoal should be repeated four to six times within the first 24 hours. This procedure is simply called “Repeated Medical Charcoal.” In these cases, gastric lavage has usually also been performed. A gastric tube can be left in the stomach after it has been rinsed with saline and secured with tape. Adults are given 25 g of medical charcoal via the tube every four hours during the first day (25 g x 6), and children are given 5-10 g of charcoal every four hours (5-10 g x 6).
Repeated medical charcoal should be administered in severe poisoning with:

• Barbiturates (Fenemal^®)
• Phenytoin (Epanutin^®, Fenantoin^®, Lehydan^®)
• Carbamazepine (Hermolepsin^®, Tegretol^®, Trimonil retard^®)
• Quinine (Quinine Recip^®)
• Chloroquine (Klorokinfosfat Recip^®)
• Salicylates (Albyl minor^®, Aspirin^®, Alka-Seltzer^®, Asasantin Retard^®, Bamyl^®, Magnecyl^®, Treo^®, Trombyl^®)
• Theophylline (Theo-Dur^®)
• Poisonous mushrooms (death cap, destroying angel, Cortinarius, funeral bell)

Diagnostic Codes According to ICD-10

V9227 Insertion of a gastric tube
V9229 Gastric lavage

References

Alcohol Intoxication

Acute alcohol poisoning is the most common of all poisonings in Sweden, with thousands of cases occurring every month. Ordinary alcohol intoxication gradually progresses into alcohol poisoning without a specific threshold. About 5% of all adult men and 2% of women in Sweden are alcohol-dependent. Approximately 300,000 people are estimated to have risky alcohol consumption, though some estimates suggest significantly higher numbers. About 20% of the population has occasional alcohol problems. These figures are approximate and relatively uncertain, as large variations exist across different estimates and scientific studies, including those from the Central Association for Alcohol and Narcotics Information (CAN), which publishes annual reports. Total alcohol consumption in Sweden has slightly decreased in recent years from a peak in 2004, when the average consumption was 10.5 liters of pure alcohol per person per year, to 9 liters of pure alcohol per person per year in 2016. Alcohol consumption is distributed as 42% wine, 37% strong beer, 21% spirits, 5% medium-strength beer, and 1% cider.

Risky alcohol consumption refers to the intake of alcohol that, over time, leads to medical and social complications. It is usually defined as the consumption of more than 14 standard drinks per week for men and 9 standard drinks per week for women. This corresponds to 56 cl of spirits or 2.2 bottles of wine for men, and 36 cl of spirits or 1.4 bottles of wine for women per week. One standard drink (or standard unit) corresponds to 12 g of alcohol, or one can of medium-strength beer (50 cl), one bottle of strong beer (33 cl), 12 cl of table wine, or 4 cl of spirits.

Binge drinking typically involves men consuming 5 standard drinks and women consuming 4 standard drinks or more at one time. One bottle of wine is considered to contain 6 standard units.

Mild and moderate alcohol intoxications (intoxication) are usually not subject to hospital care. Most patients who come to the hospital with alcohol poisoning also have injuries requiring medical treatment, such as abrasions, stab wounds, contusions, fractures, or lacerations. Other serious incidents, such as drowning, drug poisoning, smoke inhalation, assault, or hypothermia, are common in connection with acute alcohol poisoning. Hypothermia during mixed poisoning with drugs and alcohol can delay drug absorption, meaning that an intoxicated person may become increasingly drug-poisoned as they warm up. Vomiting and diarrhea are common with alcohol poisoning, sometimes leading to airway aspiration. Fluid and electrolyte disturbances are common during prolonged drinking. Hypokalemia, hyponatremia, and hypomagnesemia are relatively common in alcohol abuse. In acute care, these electrolyte imbalances should be monitored.

Pure alcohol poisoning may require hospital care if it is pronounced, is part of mixed intoxication, or affects young, debilitated, sick, or particularly sensitive individuals. Severe alcohol poisoning typically occurs with a blood alcohol content > 2.0 ‰, but there are significant individual differences depending on the degree of tolerance. It is generally possible to walk and stand steadily up to about 2 ‰. The most common cause of death due to alcohol poisoning is respiratory depression with hypoxia, lung atelectasis, and airway aspiration of stomach contents. Hypothermia is also common in fatal alcohol poisonings.

Approximately 150-200 people die each year from acute alcohol poisoning in Sweden, of which only 2-3 are under 30 years old. About 2,000 people die annually due to the effects of alcohol. The lethal dose of alcohol can be about 30-40 cl of pure alcohol (100%), which corresponds to 1-1.5 full bottles of spirits (75 cl, 40%) or 3.3-4.4 bottles of wine or 11-14 cans of strong beer consumed in a short time. At very high blood alcohol levels (> 3 ‰), it is usually spirits that have been consumed. Wine and beer take longer to drink, so the maximum concentration is rarely as high as after the consumption of spirits.

Moderate alcohol consumption has been described in several studies as having positive health effects. These positions are controversial and should be regarded as scientifically uncertain. Observational studies are limited by methodological problems, mainly confounding factors and misclassification. It is always difficult to prove causality, as opposed to correlations among groups with low alcohol consumption and stable social conditions.

Technical Alcohol

Various chemical alcohol solutions are used as fuel, cleaning agents, and solvents in technical alcohol. Common solutions of technical alcohol are T-red, T-blue, T-yellow, K-alcohol, and M-alcohol. Poisonings with these agents are not uncommon.

The alcohol content of technical alcohol varies between 70% and 95%. Technical alcohol generally contains denaturing additives to make the solution undrinkable, but some people, often degraded alcoholics or experimenting youths, still drink denatured alcohol.

In addition to ethanol, technical alcohol contains methyl ethyl ketone, acetone, ethyl acetate, propanol, paraffins, and in some cases, Bitrex. Denatured alcohol is also found in many hand sanitizers, disinfectants, aftershaves, perfumes, and some medicinal solutions. In Sweden, methanol is not used as a denaturing agent, but it is found abroad.

Pharmacokinetics of Alcohol

Swallowed alcoholic beverages are quickly absorbed into the bloodstream from the mucous membranes of the duodenum and small intestine. Alcohol does not bind to proteins and is distributed throughout the body’s tissues. The apparent volume of distribution for alcohol (Vd) is 0.7 L/kg. The effect on the brain (“target site”) occurs within a few minutes after ingestion (approximately 60-90 seconds), which is well known to most regular consumers. Blood alcohol concentration can continue to rise for about an hour after ingestion.

A normal-sized adult male who drinks 3-4 cans of strong beer or 4-6 glasses of wine (12 cl, 12%) will reach an approximate blood alcohol concentration of 1 g/L, equivalent to 1 ‰. An adult female will reach the same blood alcohol concentration after consuming about 3 cans of strong beer or 3-5 glasses of wine (12 cl). One ‰ corresponds to 27 mmol/L of ethanol in the blood.

Conversion factor from mmol to ‰: mmol/L x 0.0376. The achieved blood alcohol concentration varies with body size, how quickly the alcohol is consumed, and concurrent food intake.

Ninety percent of alcohol is broken down by oxidation, the majority of which occurs in the liver. Ethanol is broken down at a relatively constant rate in the human body with the help of the enzyme alcohol dehydrogenase. Ethanol is converted to acetaldehyde, which is then quickly broken down into acetic acid and subsequently into carbon dioxide and water. The breakdown into acetaldehyde begins in the stomach but primarily occurs in the liver. Acetaldehyde (ethanal) is an intermediate product in the breakdown of alcohol. There is some evidence that acetaldehyde causes some of the classic hangover symptoms such as nausea, dizziness, headache, instability, and fatigue. Acetaldehyde is further broken down into acetic acid by the enzyme acetaldehyde dehydrogenase during peripheral respiration. The acetic acid is then further broken down into carbon dioxide and water in several steps.

The enzyme alcohol dehydrogenase, which breaks down alcohol, becomes saturated at a blood alcohol concentration (BAC) over 0.1%. Beyond this threshold, the breakdown rate remains constant, following zero-order kinetics. Approximately 90% of alcohol is eliminated by liver metabolism, while 10% is eliminated through breath, sweat, and urine. The ratio of alcohol in blood to exhaled air is about 2100:1. The normal rate of alcohol metabolism is approximately 0.1 g/kg body weight per hour, which translates to 5-10g of alcohol per hour for most people. This corresponds to 2-3 cl of spirits, 6-12 cl of wine, or 12-25 cl of beer per hour, roughly one “unit of alcoholic beverage” per hour. In an adult, the BAC is estimated to decrease by about 0.15 per hour. Alcohol in a light beer is broken down in about 15-30 minutes, while a strong beer typically takes 60-90 minutes. There are relatively large individual variations.

Tolerance

Alcohol tolerance varies greatly depending on age and habituation. The more frequently a person drinks, the higher the level of tolerance developed over time. Most people without alcohol problems have difficulty reaching blood alcohol levels above 2% ethanol.

Life-threatening intoxication is typically seen at BAC levels over 4.5% in women and over 5% in men, though lower concentrations can also be fatal. It’s difficult to reach these levels by drinking only beer or wine; large quantities of spirits are usually required. It’s not uncommon for alcoholics admitted to hospitals for acute intoxication to have BAC levels over 5%, sometimes reaching 7-8%, and in rare cases, even higher. Serious alcohol poisoning among youth occurs at levels above 2.5%. Severe alcohol poisoning is often associated with memory loss, hangover symptoms, and anxiety in the aftermath.

SYMPTOMS

Mild intoxication is considered to occur at a BAC of 0.5-1% (see the table above). At BAC levels between 1-1.5%, most adults feel moderately intoxicated (after a few strong beers or a bottle of wine), and over 1.5%, most feel heavily intoxicated (one to two bottles of wine). Young girls in their early teens may feel intoxicated after just one strong beer and exhibit clear signs of intoxication after two strong beers.

Polydrug Intoxication

Simultaneous use of medications such as sleeping pills or painkillers (opioids) potentiates alcohol’s toxic effects. In particular, the combination of alcohol with opioids, benzodiazepines, neuroleptics, barbiturates, or certain antidepressants poses significant risks. A BAC over 2%, combined with flunitrazepam, opioids, or other respiratory depressants, is considered life-threatening. Moderate alcohol poisoning can become life-threatening when combined with moderate or high doses of sedatives or painkillers. The combination of alcohol and energy drinks makes people feel more alert and less aware of their intoxication, leading to a higher risk of overconsumption and increased intoxication, often accompanied by memory loss.

Technical Alcohol

The symptoms of poisoning with denatured alcohol are similar to those of intoxication with “regular” ethanol-based beverages: varying degrees of intoxication, altered consciousness, impaired balance, hyperventilation, nausea, and vomiting. A characteristic acetone-like odor from the breath is often present. There is a significant risk of metabolic acidosis, nausea, and vomiting.

INVESTIGATION

• S-Ethanol
• S-Methanol
• S-Acetone
• Pulse and blood pressure
• Oxygen saturation with pulse oximetry (SaO₂)
• Drug screening for illicit substances (urine test)
• Arterial blood gas (ABG) to assess acid-base status
• Calculate the anion gap
• Infection parameters (CRP, ESR, Procalcitonin)
• Hb, glucose, Na, K, Mg
• Optional: Alcohol markers such as B-PEth (phosphatidylethanol), S-CDT (carbohydrate-deficient transferrin)
• Optional: U-Ethylglucuronide (EtG), U-Ethylsulfate (EtS) (detects alcohol consumption in the last 3 days)
• Liver function tests
• ECG
• Temperature
• Assess neurological status, palpate the skull, rule out trauma. If unconscious or suspect trauma, perform a head CT scan to exclude epidural or subdural hematoma, as well as other intracranial bleeding or stroke.
• If airway aspiration is suspected, order a chest X-ray.
• In case of poisoning with illegal alcohol or moonshine, check for methanol and ethylene glycol in serum and calculate the anion and osmolal gaps.

Electrolyte Disorders

Beware of the risk of electrolyte imbalances. Hyponatremia, hypokalemia, and hypomagnesemia are common in alcohol intoxication and alcohol abuse.

• Severe hyponatremia increases the risk of cerebral edema and impaired consciousness. Acute hyponatremia usually results in significant somnolence. Severe hyponatremia (< 120 mmol/L) with mild cognitive impairment indicates chronic hyponatremia. Chronic hyponatremia must be corrected slowly over several days. Rapid correction can lead to myelin damage in brain cells (myelinolysis), causing serious neurological damage. Hyponatremia is most commonly seen
  
  in beer drinkers but also poses an increased risk in those taking SSRIs (antidepressants).
• Hypokalemia causes fatigue and increases the risk of cardiac arrhythmias.
• Hypomagnesemia increases the risk of cardiac arrhythmias (especially atrial fibrillation) and seizures.

Other abnormalities in routine tests

Note the presence of anemia and hypoglycemia.

Biological Alcohol Markers

U-Ethylglucuronide (EtG) and U-Ethylsulfate (EtS) detect alcohol consumption in the last 3 days. S-CDT (carbohydrate-deficient transferrin) increases after a few weeks of high alcohol consumption and can indicate chronic high alcohol consumption. CDT has high specificity for identifying heavy alcohol use.

Ethylglucuronide can also be measured in hair strands to determine alcohol intake over the past 6 months, for example, during a pre-transplant assessment.

B-PEth (phosphatidylethanol) is a group of phospholipids formed from phosphatidylcholine in the presence of alcohol. PEth reflects alcohol consumption over the past few weeks. S-GT (gamma-glutamyltransferase) is a membrane protein mainly found in the liver and increases with chronic alcohol use. Some medications can induce elevated GT levels in plasma. GT may also increase in diabetes, brain tumors, obesity, and biliary diseases. A good alcohol consumption control can include EtG, CDT, and PEth. EtG reflects high alcohol consumption over the last few days, PEth over the last few weeks, and CDT over the last few months. PEth typically rises after about a week of heavy drinking, but a high value strongly indicates high alcohol consumption, as it has high specificity.

• EtG (days)
• PEth (weeks)
• CDT (months)

Vitamin Deficiency

Be especially aware of the risk of acute B vitamin deficiency. Vitamin K and B often need to be substituted with intramuscular injections for three days.

Withdrawal

Be aware of the risk of severe withdrawal symptoms during the detoxification process, with the potential for delirium and generalized myoclonic seizures.

Acidosis

Metabolic acidosis is commonly seen in intoxication from both alcoholic beverages and technical alcohol. If the measured arterial blood gas pH is below 7.1, the poisoning is considered life-threatening. A base excess of less than -10 mmol/L indicates a cause other than standard ethanol intake.

TREATMENT of Alcohol Intoxication

All patients, including those intoxicated with alcohol, have the right to good general care and to be treated with respect. Interact calmly and confidently with the patient. General supervision to prevent traumatic injuries and disruptive behavior is the primary concern.

The treatment of acute alcohol poisoning is mainly symptomatic, as there is no specific antidote. Determine the appropriate level of care, but keep in mind that consciousness and breathing may fluctuate suddenly.

In uncomplicated alcohol poisoning, a sick bag, fluids, sleep under observation, and antacids may be sufficient. Avoid placing the patient in a high position on the bed or examination table to reduce the risk of falls. Resting on a mattress on the floor may be an alternative. In cases of agitation and anxiety, administer diazepam (Stesolid) 2.5-5 mg intravenously with caution or orally. Substitute B vitamins and vitamin K in alcoholics:

• Neurobion 3 ml x 1 IM for 3 days
• Konakion 1 ml x 1 IV (10 mg/ml)

In more severe cases of intoxication or when complicating factors are present, the situation is different:

• Closely monitor consciousness and breathing.
• Administer oxygen.
• Suction the mouth and throat if there is an increase in mucus.
• Support breathing and circulation as needed (ensure a clear airway, treat hypoxia/hypercapnia, fluids, and inotropic drugs if circulatory failure occurs, etc. See details below). If paradoxical breathing is present, better airway conditions are needed, and intubation is usually required.
• Monitor body temperature.
• Treat acute confusion and motor agitation.
• Administer fluids, either orally or intravenously. Poisoned patients typically need rehydration with IV fluids. Administer buffered glucose solutions. If necessary, correct electrolyte imbalances.
• In case of hypothermia, provide warming.
• If airway aspiration is suspected, order a chest X-ray and administer antibiotics for a respiratory infection (cefotaxim (Zinacef) 1.5 g x 3 IV). In cases of severe aspiration: intubation, suctioning, and mechanical ventilation with PEEP.
• Consider prophylaxis for delirium and generalized seizures (e.g., carbamazepine (Hermolepsin, Tegretol) 200 mg 1×3 PO). Rule out status epilepticus.
• Gastric lavage and activated charcoal are administered only in cases of mixed poisoning with medication when the patient arrives within 1 hour of ingestion.

Free Airway

The airway may be partially or fully obstructed in alcohol intoxication. Securing a free airway is the highest priority. Suction the mouth and throat if there is an increase in mucus. Nasal or oropharyngeal airways are the first-line devices. Be aware that nasal airways may cause severe nosebleeds, and the risk of nosebleeds is increased in alcohol poisoning (due to alcohol’s vasodilating effect). Therefore, use plenty of gel when inserting the nasal airway.

The patient’s position should be in the recovery position, with the tongue pulled forward through a firm jaw thrust. Patients who cannot maintain a free airway in the supine position or are unresponsive should be monitored in an intensive care unit.

Endotracheal intubation is necessary if the airway cannot be adequately maintained, if there is hypoxia, or if there is carbon dioxide retention.

Breathing

Avoid hypoxia and hypercapnia by administering liberal amounts of oxygen. If breathing is inadequate, consider endotracheal intubation and mechanical ventilation in the intensive care unit. Suction the airway of any mucus.

Circulation

Treat hypotension with intravenous fluids and, if necessary, with vasopressor drugs (e.g., ephedrine, phenylephrine, dopamine, or norepinephrine).

Confusion and Aggression

Agitated and aggressive patients may require sedation to prevent self-harm or harm to others.

This type of sedation is challenging and difficult to manage correctly. The treatment itself poses risks such as hypotension or sudden decreased consciousness, with difficulties in maintaining a free airway and respiratory depression. Sedatives must therefore be used with caution and under supervision. Treatment requires the ability to take over the patient’s breathing with controlled ventilation and mechanical ventilation if necessary.

Suitable agents include haloperidol (Haldol) 1-5 mg IV, midazolam (Dormicum) 1-5 mg IV, or propofol (Diprivan, Propofol) 20-100 mg IV. Propofol should only be used by an experienced anesthesiologist who can handle airway issues, as there is a significant risk of hypotension and apnea. Haldol should not be used in patients with seizures or a history of seizures.

Hangover

The hangover is characterized by nausea, dizziness, fatigue, instability, anxiety, and headache. It occurs when the BAC is near zero. The severity of the hangover is primarily determined by the amount of alcohol consumed, but also by the speed at which it was consumed and the type of alcoholic beverages ingested. Colored beverages such as whiskey are believed to cause worse hangovers compared to clear spirits. Red wine often causes more hangovers than white wine. Drinking alcohol during dehydration increases the risk of hangovers and headaches, so alcoholic beverages should not be used as thirst quenchers. The hangover is partly explained by acetaldehyde, though not entirely. New theories suggest an inflammatory component as a cause of the hangover. The sensitivity to hangovers is individual, but most people who reach a BAC of over 1.5% experience hangover symptoms. About 25% of the population experiences little to no hangover symptoms.

The symptoms are also due to relative dehydration and the intake of substances known as congeners. Congeners are by-products formed during the fermentation of alcohol and include furfural, tannins, and fusel oils. Whether drinking water after alcohol consumption can prevent hangovers is scientifically unclear, although many people report positive personal experiences with this practice.

The main cause of nausea and the general feeling of discomfort is due to acetaldehyde, which is produced during the breakdown of alcohol. Treatment for hangovers is symptomatic, focusing on rehydration, rest, sleep, simple analgesics, and antacids.

FOLLOW-UP

For severe alcohol misuse, patients should be followed up with psychiatry, addiction medicine, and social services. Any potential co-occurring mental health disorders (comorbidity) should be assessed and treated.

ICD-10 Diagnosis Codes

• Mental and behavioral disorders due to alcohol, acute intoxication F10.0
• Ethanol T51.0
• Mild alcohol intoxication Y91.0
• Moderate alcohol intoxication Y91.1
• Severe alcohol intoxication Y91.2
• Very severe alcohol intoxication Y91.3

Sick Leave

Links to the National Board of Health and Welfare’s insurance medical decision support:

F10 Mental and behavioral disorders caused by alcohol

References

1. Alcohol testing in hospitals is not straightforward for legal use Conversion of ethanol levels in plasma or serum to BAC. Jones AW, Läkartidningen No. 6 2008 Volume 105 Link to article
2. The National Public Health Survey – Health on Equal Terms. More about the survey
3. Andersson P, Moller L & Galea G (2012). Alcohol in the European Union: Consumption, harm, and policy approaches. WHO Regional Office for Europe. Link
4. Anderson P & Baumberg B (2006). Alcohol in Europe – A public health perspective. A report for the European Commission. London: Institute of Alcohol Studies. Link
5. CAN (2012). Drug Development in Sweden 2011. Report No. 130. Stockholm: Centralförbundet för alkohol- och narkotikaupplysning. Link to report
6. Hibell B et al. (2012). The ESPAD report 2011. Alcohol and Other Drug Use Among Students in 36 European Countries. Stockholm: Swedish Council for Information on Alcohol and Other Drugs (CAN), The European Monitoring Centre for Drugs and Drug Addiction (EMCDDA), and the Pompidou Group at the Council of Europe. Link
7. Ramstedt M, Lindell A & Raninen J (2013a). Talking about Alcohol – A Statistical Annual Report from the Monitor Project. SoRAD. Stockholm University.
8. Kühlhorn E, Ramstedt M, Hibell B, Larsson S & Zetterberg H (1999). Alcohol consumption in Sweden during the 1990s. Stockholm: Ministry of Health and Social Affairs.
9. Stockwell T, Zhao J, Panwar S, et al. Do “moderate” drinkers have reduced mortality risk? A systematic review and meta-analysis of alcohol consumption and all-cause mortality. J Stud Alcohol Drugs. 2016;77(2):185–198. Link to article

Published with permission from Internetmedicin AB

Benzodiazepines – Intoxication and Abuse

Benzodiazepines are a class of anxiolytic drugs that began to be used in Sweden during the 1960s as sedatives and hypnotics. Benzodiazepines are internationally accepted as standard drugs for the treatment of anxiety disorders and temporary sleep disturbances. They have also been used to treat milder forms of anxiety and nervousness to varying extents. Women are more often prescribed benzodiazepines, which may be related to the fact that anxiety disorders are more common in women than in men. The use of benzodiazepines is also related to age. People over the age of 65 account for more than half of the consumption. Benzodiazepines are commonly involved in medication-related overdoses and acute intoxications, often in combination with alcohol. Diazepam is metabolized in the body into various active metabolites, mainly nordiazepam and temazepam, but also oxazepam, which is excreted in the urine. Maximum blood concentrations of diazepam occur after 30-90 minutes, with a half-life that can vary between 20-40 hours for diazepam and 50-99 hours for nordiazepam (long half-life!).

All benzodiazepines carry some risk of dependence. Dependence means that the patient cannot stop using the drug due to withdrawal symptoms or psychological dependence. In Sweden, it is estimated that 65,000 people have a prescription drug addiction, and 315,000 have a risk of addiction. Being dependent means feeling a craving for the drug, having difficulty controlling its use, finding it hard to stop, and developing withdrawal symptoms when the drug is not used. Different benzodiazepines have varying risks of dependence, but they generally share similar pharmacological profiles with comparable risks of overdose and abuse. Diazepam is classified as a narcotic according to LVFS 2011:10, Schedule IV.

The benzodiazepines with the greatest risk of dependence are those with a rapid onset and high potency. These include flunitrazepam, alprazolam, oxazepam, and lorazepam. Today, alprazolam (Xanor^®, Alprazolam^®, Xanor Depot^®) is considered to pose the highest risk for dependence. Regular use of some of these benzodiazepines can lead to tolerance and withdrawal symptoms when attempting to stop.

Flunitrazepam (Flunitrazepam Mylan^® 0.5 mg/1 mg) is primarily used as a sleeping aid (sedative, hypnotic), but due to its significant abuse potential, it is also available illegally in Sweden. Flunitrazepam was previously available in several brands, such as Rohypnol, Flupam, and Fluscand, which have since been deregistered.

Benzodiazepines are primarily prescribed as sleeping aids for older patients, but they are also used as premedication before surgical operations. In recent years, benzodiazepines have played a lesser role in premedication and have been replaced by other pharmacological agents, such as clonidine.

As a sleeping pill, flunitrazepam has largely been replaced by the so-called Z-drugs, such as zopiclone (Imovane^®), zolpidem (Stilnoct^®), and zaleplon (Sonata^®). Zopiclone is recommended as a first-line treatment for sleep difficulties. As a drug of abuse, Rohypnol has to some extent been replaced by these medications as well as diazepam (Stesolid^®), oxazepam (Sobril^®), lorazepam (Temesta^®), and alprazolam (Xanor^®).

ABUSE

Benzodiazepines can be used recreationally due to their relaxing and euphoric effects, which carry some risk of abuse, often in combination with alcohol. The relaxing and intoxicating effects are enhanced by alcohol. The progression from regular use to overuse, risk-taking behavior, and abuse is commonly seen in cases of chronic pain conditions and prolonged anxiety and stress disorders.

In drug abuse, the recommended daily dose is often exceeded by more than double (from one to two tablets to four or five or more per day). Benzodiazepine abuse occurs as either pure drug abuse or as part of polysubstance abuse with alcohol, analgesics, or narcotics. A gradual transition can be seen from normal use to risky use and abuse. Flunitrazepam, alprazolam (Xanor^®), and oxazepam (Sobril^®) are the drugs with the highest potential for dependence, but all benzodiazepines carry some risk of dependence. That said, many patients manage well with stable dosages without developing tolerance or needing dose increases, especially older patients.

Alprazolam (Xanor^®) poses a significant risk of dependence and abuse. Doses higher than 1 mg of alprazolam or more than 10 mg of diazepam typically result in drowsiness and sedation, which can progress to sleep, deeper sleep, or coma. A person who has taken such a dose may appear intoxicated with symptoms such as dilated pupils, giddiness, talkativeness, slow reflexes, flaccid muscles, clumsiness, slurred speech, drowsiness, and eventually coma.

In some individuals, a paradoxical effect may occur with increased intake, leading to “increased alertness” (an “excitation state”) combined with a disinhibitory effect. The risk of an excitation state increases with the simultaneous use of amphetamines. It is not uncommon to see psychomotor agitation, including an inability to sit still, hyperactivity, increased aggressiveness, and impulsivity. This paradoxical effect has occurred during surgical premedication in both children and adults. In children, it is sometimes described as them “climbing the walls.”

The excitation stage involves an altered state of wakefulness that may progress to sleep or coma. However, regular abusers may maintain the “increased wakefulness” and avoid sleep by adjusting dosing intervals or combining benzodiazepines with central nervous system stimulants such as amphetamines, methamphetamines, cocaine, synthetic cathinones, or ecstasy. This is primarily seen in habitual abusers with increased tolerance to the drug. The excitation state can progress to acute confusion with agitation, often accompanied by aggressiveness, disorderly behavior, and hallucinations.

Several illegal benzodiazepine preparations are available in Sweden or can be purchased online. These include adinazolam, bromazepam, flubromazepam, diclazepam, flubromazolam, flunitrazolam, N-desmethylflunitrazepam, norfludiazepam, phenazepam, clonazolam, cloniprazepam, zapizolam, meclonazolam, pyrazolam, and etizolam.

Withdrawal

In cases of developed benzodiazepine dependence, withdrawal symptoms occur when the drug is abruptly discontinued. Symptoms include feelings of unreality, increased nervousness, nonspecific discomfort, intrusive anxiety, and worry. Physical symptoms such as palpitations, tremors, abdominal pain, cold sweats, and withdrawal seizures also occur. In cases of long-term abuse, a slow and gradual reduction in dosage is typically required, using, for example, diazepam (Stesolid^®), which can take several months to up to a year. Withdrawal symptoms begin a few days after stopping the medication. In some cases, tapering starts at doses much higher than the recommended daily doses. Starting doses can be as high as 60-100 mg diazepam per day, which is then gradually reduced. Alternative medications for treating withdrawal symptoms have not shown better results than using benzodiazepines in tapering doses. Medications tested include beta-blockers and buspirone (Buspiron).

Special Risks with Polydrug Abuse

There are particular risks associated with the abuse of benzodiazepines in combination with painkillers (opioids). The enhanced suppressive effects on the respiratory and circulatory centers in the brain can lead to overdose and death, especially in combination with opioids or alcohol. When the use of multiple drugs is abruptly stopped, different withdrawal symptoms can arise. Benzodiazepines enhance the respiratory-depressant effects of painkillers. Benzodiazepines also amplify the intoxicating effects of other drugs such as cannabis, amphetamines, and opiates.

Cross-Tolerance

When tolerance to a drug within a specific category develops, tolerance to other drugs within the same category also increases. For example, doctors preparing to anesthetize a patient for surgery may find that the patient does not respond to the normal dose of anesthetic. This is often due to the patient’s heavy use of a similar substance.

Cross-Sensitization

Certain drug effects become enhanced with long-term use, such as “craving” for the drug, as well as the psychosis-inducing effects. Sensitization to one drug can result in cross-sensitization to another drug. In practice, this means that a person dependent on one drug is more likely to become dependent on another.

OVERDOSE

Symptoms of Acute Overdose

• Somnolence, drowsiness
• Dizziness
• Hypotension
• Bradycardia
• Hypothermia
• Apnea episodes
• Mydriasis, dilated pupils (small miotic pupils are also seen, especially in unconsciousness)
• Ataxia
• Dysarthria, slurred speech
• Nausea
• Muscle weakness
• Respiratory depression
• Restlessness
• Excitation
• Tachycardia
• Hallucinations
• Coma

TREATMENT FOR ACUTE OVERDOSE

• General supervision to prevent falls and disruptive behavior
• Ensure a free airway. The patient should be placed in the recovery position. A so-called “kantarell nasal tube” or similar can be used
• Oxygen therapy
• If a significant amount of the drug has been ingested, gastric lavage should only be performed within 1 hour of ingestion
• Activated charcoal should only be given within 1 hour of ingestion
• Monitor respiration, circulation, and consciousness
• Intravenous fluids with isotonic crystalloid solutions, such as Ringer’s acetate
• Intubation and controlled ventilation in cases of deep unconsciousness
• Antidote treatment with flumazenil (Lanexat^®) in appropriate cases

25-50 mg of alprazolam combined with a blood alcohol level of 2% has resulted in fatal intoxication.

The specific antidote flumazenil (Lanexat 0.1 mg/ml, 5 ml in one ampoule = 0.5 mg) can be administered slowly intravenously to wake a comatose or semi-comatose patient in doses of 0.3-0.5 mg. The dose should be repeated after one minute if there is no effect. Usually, 2-3 doses are sufficient. The maximum dose for adults is 2-5 mg flumazenil. Be mindful of the number of ampoules. A new injection is sometimes necessary after 1-4 hours. In rare cases, flumazenil can be administered as a continuous infusion. Flumazenil can be combined with naloxone in cases of unclear unconsciousness when drug-induced unconsciousness is suspected.

Flumazenil (Lanexat^®) is unsuitable for use in mixed overdoses with drugs that can induce generalized seizures, such as antidepressants, as the antidote lowers the seizure threshold. In cases of uncertainty, the patient should instead be monitored for respiration and airway status in an intensive care unit. Treatment should be guided by what is best for the patient, not by the availability of beds in the ICU.

Gastric lavage should only be performed if a very large amount of benzodiazepines has been ingested or if the drug has been ingested in combination with other dangerous substances, up to one hour after ingestion. If there is doubt about whether the patient can protect their airway, an experienced anesthesiologist should be involved during the procedure.

Patients who are deeply unconscious or have inadequate breathing should be monitored and followed up in an intensive care unit. Generally, patients wake up after benzodiazepine overdose within 4-12 hours, depending on the dose and type of drug ingested. Note that several benzodiazepines have active metabolites with long half-lives, so prolonged deep unconsciousness beyond 12 hours can occur. The half-life is further prolonged in cases of impaired liver function. Once vital functions are stabilized and breathing and airway are secured, the prognosis is generally very good with only symptomatic treatment.

FOLLOW-UP

It is crucial to guide the patient during the acute phase to the appropriate level of care so that vital functions can be monitored and stabilized in a medical emergency ward or intensive care unit.

Following the acute phase, the drug abuse should be treated. A psychiatric assessment, referral to an addiction medicine clinic, and contact with social services are usually necessary. Inpatient withdrawal treatment should be planned, as severe withdrawal symptoms are expected.

A report to social services is mandatory in cases of life-threatening addiction, when treating children under 18, or when adults have children who are at risk of neglect.

Psychosocial support must be provided alongside medication management of any withdrawal symptoms. It is important to assess the patient’s personality, emotional state, and cognitive function to provide the right treatment. The assessment should determine whether psychotic symptoms, increased suicidality, or dependence are present. If depression and psychotic symptoms are observed, there is a significant risk of suicidal behavior.

Treatment in outpatient care is individualized, based on frequent contact with a psychiatrist or psychologist experienced in drug dependence, and regular urine tests to check for benzodiazepines, THC (tetrahydrocannabinol), and other drugs. After a period of abuse, short-term memory impairment and poor motivation for sobriety are common.

Social aspects should also be considered in the patient’s treatment, and a social worker should be involved. An evaluation of the risk factors and protective factors (family support) in the patient’s environment is important to provide the right interventions. One key question to investigate is the patient’s living situation. A personal collaboration between the addiction clinic and social services is often necessary in these cases. A referral to a psychologist or social worker with specialized competence in addiction disorders and benzodiazepine use is essential for the patient’s ongoing care. When treating school-aged patients, the school health services should also be informed. An assessment of the patient’s level of dependence and suicidality should be done using established psychological measurement tools such as the ASI interview, AUDIT, and tools to assess suicide risk.

ICD-10 Diagnosis Code

• T42.4 Benzodiazepines
• X60-X69 Intentional self-harm by poisoning
• Y10-Y19 Poisoning with unclear intent
• F13.0 Mental and behavioral disorders due to sedatives and hypnotics, acute intoxication

Contact the Poison Information Center at 08 – 736 03 84 or 08 – 517 747 42 if needed.

References

Tricyclic Antidepressants (TCA)

Tricyclic antidepressants (TCA) are second-generation antidepressants that became common in the treatment of depression in Sweden during the 1970s. These drugs are primarily prescribed for major depressive disorder but also for several other conditions such as severe pain, OCD, panic disorder, PTSD, narcolepsy, and nocturia. Several related pharmacological variants exist, including bicyclic and tetracyclic antidepressants.

Poisoning with tricyclic antidepressants (TCA) is still common, and fatalities occur regularly, although serious poisonings were much more frequent during the 1980s and 90s than they are today. Antidepressants are common in intentional self-poisonings and have significant morbidity and mortality. TCA poisonings have higher mortality than other antidepressants. The suicide risk in depressed patients persists during treatment until remission occurs and may even initially increase, as inhibition may decrease before mood improves. Amitriptyline is one of the most common drugs involved in fatal suicide poisonings worldwide. TCA poisoning is typically diagnosed using the ICD code T43.0. In 2014, 47 deaths were caused by these poisonings in Sweden, 24 women and 23 men (approximately 250 deaths per year occur in England).

Poisoning with TCA usually requires intensive care. In total, approximately 12 million daily doses of TCA are sold per year, compared to approximately 170 million DDD of SSRIs. Several tricyclic antidepressants have been deregistered in Sweden in recent years as they have been replaced by newer agents with fewer side effects. Classic TCA have relatively strong side effects that can be noticeable when starting treatment, such as orthostatic hypotension with dizziness and unsteadiness, palpitations, dry mouth, and constipation.

Acute TCA poisoning can cause an anticholinergic syndrome with large pupils, palpitations, agitation, and mental confusion. The anticholinergic syndrome should be distinguished from the serotonin syndrome, which can occur after SSRI overdose. Severe poisoning is characterized by coma, seizures, and cardiac arrhythmias. On the EKG, widened QRS complexes and irregular rhythms are usually seen. Significantly widened QRS complexes indicate severe poisoning, with the wider the complex, the more dangerous it is. A QRS width of over 140 ms indicates very severe poisoning.

Toxicity

The toxic effect in overdose is primarily due to:

1. Inhibition of norepinephrine reuptake presynaptically in nerve terminals
2. A direct alpha-receptor blockade
3. A membrane-stabilizing effect in the myocardium (quinidine-like)
4. An anticholinergic effect

Amitriptyline and dosulepin have the highest toxicity.

Degree of Poisoning

Ingestion of less than 10 mg/kg causes mild poisoning. Ingestion of more than 15-20 mg/kg likely results in severe poisoning. Ingestion of 1 to 2 g usually causes moderate poisoning, while over 2.5 g causes severe poisoning. Ingesting more than 5 g causes very severe poisoning.

Common Cyclic Antidepressants in Sweden

• Amitriptyline (Saroten)
• Clomipramine (Anafranil)
• Nortriptyline (Sensaval)
• Maprotiline (Ludiomil)
• Mianserin (Mianserin)

Some antidepressants that were previously available in Sweden but have since been deregistered include:

• Desipramine (Pertrofin)
• Imipramine (Tofranil)
• Lofepramine (Tymelyt)
• Protriptyline (Concordin)
• Trimipramine (Surmontil)

Other cyclic antidepressants available abroad that may be encountered in Sweden include:

• Opipramol
• Trimipramine
• Dothiepin
• Dibenzepin
• Protriptyline
• Doxepin
• Iprindole
• Melitracen
• Butriptyline
• Dosulepin
• Amoxapine
• Dimethacrine

SYMPTOMS

• Sedation and coma
  Decreased consciousness to unconsciousness, ranging from mild to deep unconsciousness lasting several days. The duration of the coma depends on the drugs ingested, the amount taken, and the drug’s half-life in plasma. In cases of severe poisoning, at least one day of unconsciousness is common.
• Agitation
  Confusion and agitation are common
• Large pupils
  Caused by an anticholinergic effect.
• Hypotension
  Blood pressure may initially be elevated but is more often slightly lowered, with systolic blood pressure around 80-90 mm Hg. Even lower blood pressure occurs in severe poisoning.
• Cardiac arrhythmias
  Tachycardia is common, as are ventricular arrhythmias. In severe cases, multiple PVCs with complete irregularity and ”Torsades de Pointes” arrhythmias occur. Arrhythmias are often accompanied by heart failure.
• Respiratory depression
  Slow, regular but inadequate breathing with a risk of hypoventilation and carbon dioxide retention.
• Seizures
  Increased agitation with limb jerking is common, as are convulsive seizures.
• Anticholinergic syndrome
  – Large pupils
  – Dry, warm skin
  – Tachycardia
  – Confusion
  – Hallucinations
• The English mnemonic for anticholinergic syndrome is helpful to remember
  – Mad as a hatter
  – Dry as a bone
  – Red as a beet
  – Blind as a bat
  – Hot as a desert

Severe Poisoning (ingestion of more than 2500 mg)

• Severe hypotension
• EKG changes
  Widened QRS complexes, AV block, prolonged QT interval, ST-T changes.
• Heart failure
  Cardiogenic shock is associated with bradycardia and marked QRS widening on the EKG, as well as ventricular arrhythmias.

Finally, bradycardia and asystole develop, along with a sinusoidal curve on the EKG. A QRS time over 100 ms increases the risk of seizures. A QRS time over 160 ms increases the risk of ventricular arrhythmias.

ACUTE CARE

History Taking

• What medication? Quantity? Time of ingestion? Mixed poisoning? Signs of intentional suicide attempt?

Examinations

• Clinical diagnostics
• Toxicology screening, including alcohol in serum
• EKG
• Pulse oximetry
• Blood pressure
• Check blood tests, including myoglobin if prolonged unconsciousness is suspected
• Drug screening

Treatment is mainly symptomatic, aiming to counteract hypotension, hypoxia, and metabolic acidosis. Most TCA are highly lipid-soluble with a large distribution volume, making elimination methods like hemodialysis ineffective in treatment. Tricyclic antidepressants have anticholinergic effects that are dose-dependent and decrease over time with treatment.

Preparation must be made for treating respiratory depression, seizures, cardiac arrhythmias, and hypotension, so patients with severe poisoning should always be treated in the ICU (for doses >2.5 g). In cases of pronounced hypotension, isotonic crystalloid fluids, hypertonic saline (RescueFlow), and sodium bicarbonate are administered.

One should also avoid giving membrane-stabilizing drugs such as quinidine, beta-blockers, calcium antagonists, and flecainide (Tambocor). Amiodarone (Cordarone) should likely be avoided in the treatment of arrhythmias as it may cause prolonged QT interval, hypotension, bradycardia, and possibly arrhythmias.

Treatment

• Gastric lavage
  Within one hour of ingestion – until clear output. In later arrivals, gastric lavage can be considered in life-threatening poisoning up to 24 hours after intoxication.
• Activated charcoal
  At least 50 g. Administer at least 10 times the ingested dose.
• Alkalinization
  Sodium bicarbonate is administered on broad indications – correct acidosis until the Base Excess (BE) becomes positive in the blood gas response. pH should be above 7.45. Alkalinization can reverse part of the conduction block in the heart and improve depolarization. Hypotension can also improve. Sodium bicarbonate reduces the free fraction of the drug in the bloodstream, resulting in less TCA binding to the heart, while plasma protein binding increases. One can often start with two bottles of 100 ml Sodium Bicarbonate (60 mmol/unit).
• Hypertonic saline
  For widened QRS complexes on ECG (> 160 ms). Administer 200 mmol sodium intravenously, rapidly.
• Oxygen
  Intubation and controlled ventilation in respiratory insufficiency
• Adequate fluid administration, sodium chloride, and possibly dextran (Macrodex)
• Physostigmine
  For pronounced anticholinergic symptoms with confusion, psychomotor agitation, and restlessness, physostigmine can be given intravenously, but not if circulatory compromise or bradycardia is present. There is a risk that physostigmine may induce seizures.
• Inotropic treatment with vasopressors
  Norepinephrine or epinephrine. Dopamine sometimes has insufficient effect. In experimental studies, epinephrine has caused fewer arrhythmias than norepinephrine and may be preferred. In severe bradycardia, isoprenaline can be given.
• Arrhythmia treatment if needed
  Magnesium sulfate (20-40 mmol intravenously), in ventricular tachyarrhythmias, or in rare cases, lidocaine. In the treatment of arrhythmias, polypharmacy should be avoided.
• Diazepam (Stesolid)
  For seizures
• In circulatory collapse, extracorporeal support such as arteriovenous ECMO may be connected.
• ILE (Intravenous Lipid Emulsion Therapy)
  May be considered in circulatory collapse. ILE has been shown to work primarily in overdoses with local anesthetics, especially bupivacaine. In TCA overdoses, many positive case reports have been published. However, a thorough review of the subject published in 2016 has raised significant doubts about the efficacy of this treatment in TCA poisoning. Controlled animal studies have shown minimal entrapment of amitriptyline but no beneficial hemodynamic effect or improved survival. Therefore, the evidence for this treatment is considered very low in TCA poisoning. In some animal studies, increased mortality has even been demonstrated with ILE, and there is a theoretical risk of ARDS and pancreatitis as a result of the treatment.

ICD-10

Tricyclic and tetracyclic antidepressants T43.0
Observation for suspected toxic effect of ingested substance Z03.6

References

1. Kerr GW, McGuffie AC, Wilkie S. Tricyclic antidepressant overdose: a review. Emerg Med J 2001;18:236–41. Link
2. Hawton K, Bergen H, Simkin S, Cooper J, Waters K, Gunnell D et al. Toxicity of antidepressants: rates of suicide relative to prescribing and non-fatal overdose. Br J Psychiatry 2010;196:354–8. Link
3. Body R, Bartram T, Azam F, Mackway-Jones K. Guidelines in Emergency Medicine Network (GEMNet): guideline for the management of tricyclic antidepressant overdose. Emerg Med J 2011;28:347–68. Link
4. Levine M, Hoffman RS, Lavergne V, Stork CM, Graudins A, Chuang R, et al. Systematic review of the effect of intravenous lipid emulsion therapy for non-local anesthetics toxicity. Clin Toxicol (Phila) 2016;epubl ahead of print. Link
5. Engels PT, Davidow JS. Intravenous fat emulsion to reverse haemodynamic instability from intentional amitriptyline overdose. Resuscitation 2010;81:1037–9. Link
6. Harvey MG, Cave G. Case report: successful lipid resuscitation in multi-drug overdose with predominant tricyclic antidepressant toxidrome. Int J Emerg Med 2012;5:8. Link
7. Kiberd MB, Minor SF. Lipid therapy for the treatment of a refractory amitriptyline overdose. CJEM 2012;14:193–7. Link
8. Litonius ES, Niiya T, Neuvonen PJ, Rosenberg PH. No antidotal effect of intravenous lipid emulsion in experimental amitriptyline intoxication despite significant entrapment of amitriptyline. Basic Clin Pharmacol Toxicol 2012;110:378–83. Link
9. Heinonen JA, Litonius E, Backman JT, Neuvonen PJ, Rosenberg PH. Intravenous lipid emulsion entraps amitriptyline into plasma and can lower its brain concentration – an experimental intoxication study in pigs. Basic Clin Pharmacol Toxicol 2013;113:193-200. Link
10. Forsberg M, Forsberg S, Höjer J. No support that lipid therapy is an effective antidote in acute poisoning. Lakartidningen 2015;112:1723-6. Link
11. Knudsen K, Abrahamsson J. Effects of magnesium sulfate and lidocaine in the treatment of ventricular arrhythmias in experimental amitriptyline poisoning in the rat. Crit Care Med 1994;22:494–8. Link
12. Knudsen K, Abrahamsson J. Magnesium sulfate in the treatment of ventricular fibrillation in amitriptyline. Eur Heart J;18:881–2. Link
13. Knudsen K, Heath A. Effects of self poisoning with maprotiline. BMJ 1984;288:601–3. Link
14. Knudsen K, Abrahamsson J. Effects of epinephrine and norepinephrine on haemodynamic parameters and arrhythmias during a continuous infusion of amitriptyline in rats. Clin Toxicol 1993;31:461–71. Link
15. Knudsen K, Abrahamsson J. Epinephrine and sodium bicarbonate independently and additively increase survival in experimental amitriptyline poisoning. Crit Care Med 1997;25:669–74. Link

SSRI preparations, SNRI preparations, NaSSA preparations, and Atypical Antidepressants

The prescription of antidepressants other than classical tricyclic agents (TCA) has increased dramatically over the past 20 years in Sweden. In 2015, it was estimated that approximately 600,000 patients were treated with antidepressants. The drugs can be divided into three groups: SSRI preparations – Selective Serotonin Reuptake Inhibitors, SNRI preparations – Selective Norepinephrine Reuptake Inhibitors, and NaSSA preparations – Noradrenergic and Specific Serotonergic Antidepressants. In general, SSRIs have taken over the majority of the antidepressant market. In 2015, SSRIs were sold at a rate of 82 daily doses per 1,000 inhabitants per day. SSRIs accounted for 413,000 of the total 600,000 patients (68%) treated with antidepressants.

Clinical cases of poisoning with SSRIs or other antidepressants have thus become common in an emergency room setting. SSRIs have significantly lower acute toxicity compared to classical TCAs, while SNRIs occupy an intermediate position in terms of toxicity. Approximately 7% of all poisonings with these drugs are reported as serious cases. Cardiotoxicity is lower for SSRIs, but severe heart failure can occur after ingestion of high doses, usually more than 5 g. Generalized seizures are relatively common and can be difficult to treat. Ingestion of SSRIs can also lead to a so-called ”Serotonin Syndrome.” This syndrome can occur after the ingestion of multiple drugs that inhibit the reuptake of serotonin in the CNS – for example, an SSRI and an analgesic (tramadol, fentanyl) – or various illegal drugs such as amphetamine and ecstasy, which increase the risk of seizures. Certain SSRI preparations require special attention in cases of acute poisoning, described below. In 2013, 49 people in Sweden died from poisoning with classical antidepressants, while 69 people died from other and unspecified antidepressants (Cause of Death Register – T43.2).

Some Common Antidepressants

SSRI Preparations

• citalopram (Cipramil^®, Citalopram^®)
• escitalopram (Cipralex^®, Escitalopram^®, Premalex^®)
• fluoxetine (Fluoxetine^®, Fontex^®),
• fluvoxamine (Fevarin^®)
• paroxetine (Paroxetine^®, Paroxiflex^®, Seroxat^®)
• sertraline (Zoloft^®, Sertralin^®, Oralin^®, Sertrone^®)

SNRI Preparations

• venlafaxine (Efexor^®) (Venlafaxine^®)
• duloxetine (Cymbalta^®, Yentreve^®)
• reboxetine (Edronax^®)
• atomoxetine (Strattera^®)

NaSSA Preparations

• venlafaxine (Efexor^®) (Venlafaxine^®)
• duloxetine (Cymbalta^®, Yentreve^®)
• reboxetine (Edronax^®)
• atomoxetine (Strattera^®)

NaSSA Preparations

• mianserin (Mianserin^®)
• mirtazapine (Remeron^®, Mirtazapin^®)

Venlafaxine (Efexor^®) is an antidepressant that works by inhibiting the reuptake of both norepinephrine and serotonin in the brain and is classified as an SNRI preparation. Dopamine reuptake is also inhibited to some extent.

Efexor is sold as tablets in strengths of 37.5 and 75 mg and in depot form in strengths of 75 or 150 mg. The high strength of the tablets means that the amount ingested in an overdose is often high. This medication thus deserves extra attention in cases of acute overdose.

Ingestion of up to 1 g venlafaxine in an adult constitutes mild poisoning, and ingestion of 1-1.5 g constitutes moderate poisoning. Ingestion of 1.5-2.5 g is considered severe poisoning, and over 2.5 g is considered very severe poisoning. Note that patients who have ingested Efexor Depot^® may deteriorate up to 24 hours after ingestion. Therefore, mild symptoms at the time of hospital arrival do not rule out a severe poisoning course.

Several cases of poisoning have been reported in Sweden in recent years with fatal outcomes. In one case, the amount ingested was approximately 4.8 g Efexor Depot, and in another case, 7.5 g Efexor and an unknown amount of oxazepam (Sobril^®) in a suicide attempt.

Similar Preparations

There are several antidepressants such as mianserin (Mianserin^®), mirtazapine (Remeron^®, Mirtazapin^®), bupropion (Zyban^®), reboxetine (Edronax^®), atomoxetine (Strattera^®) and duloxetine (Cymbalta^®, Yentreve^®) that are not classified as tricyclic preparations or SSRIs but as SNRIs or NaSSAs. Edronax^® and Strattera^® are selective norepinephrine reuptake inhibitors. Strattera is a relatively new drug used for concentration difficulties with the indication ADHD in children and adults. Bupropion (Zyban^®, Voxra^®, Bupropion^®) has a special indication for smoking cessation. Bupropion has been used as a drug of abuse and in these contexts may have some central stimulant effect. In overdose, bupropion has two metabolites with a long half-life (>30 h), which can cause patients to be comatose for a very long time, in some cases for several days.

Clinically, the effects of an overdose resemble those of SSRIs, but the pharmacological effect varies. Pay particular attention to the risk of prolonged QT interval and the risk of seizures during acute poisoning. Myoclonus or seizures may occur without other warning signs, for example after ingestion of venlafaxine (Efexor^®) or bupropion (Zyban^®, Voxra^®). In moderate or severe poisoning, special attention should be given to the presence of muscle twitches or generalized seizures. These may occur suddenly in an otherwise mildly symptomatic patient. Seizures can be prolonged and persistent and may recur even after administration of diazepam (Stesolid^®). ST-T changes on ECG and prolonged QT interval have been seen even in younger patients with healthy hearts. The absence of ECG changes does not rule out serious poisoning, unlike poisoning with classical antidepressants. Patients with moderate or large ingestion of these medications and initially mild symptoms should therefore be monitored in an intensive care unit with close observation for at least 12 hours in serious poisoning and for at least 24 hours in serious poisoning with depot preparations (Efexor depot^®). Pay attention to the QT interval on ECG as prolonged QT interval increases the risk of serious cardiac arrhythmias. Be cautious of prolonged QT interval especially in poisoning with venlafaxine (Efexor^®), citalopram (Cipramil^®) and mirtazapine (Remeron^®).

In unconscious elderly patients, the clinical picture can be relatively non-specific and other clinical recognition signs may be absent. The diagnosis can easily be missed, making a thorough history extremely important, as well as checking for empty packaging. Urine testing can be performed in unclear cases.

SYMPTOMS AND CLINICAL PRESENTATION

CNS Symptoms in Overdose

• Excitation with anxiety, agitation, confusion, dizziness, hallucinations
• Tremors, chills
• Ocular oscillations
• Dizziness
• CNS depression with coma or decreased alertness
• Seizures can occur suddenly, even in relatively unaffected patients
• Extrapyramidal side effects; rigidity, restlessness, tremor, akathisia (inability to stay still)
• Easily elicited deep tendon reflexes, clonus
• Hyperthermia

Circulatory Symptoms

• Hypotension, but blood pressure can also be elevated (autonomic instability)
• Tachycardia or bradycardia
• AV block, prolonged QT interval, ST-T changes, widened QRS complexes
• Ventricular arrhythmias and extrasystoles
• Circulatory collapse and ventricular fibrillation in severe cases. Ventricular fibrillation can occur suddenly without significant preceding ECG changes. Ventricular fibrillation is often preceded by seizures.

Other Symptoms

• Rigidity, tremor, hyperthermia, rhabdomyolysis, serotonin syndrome
• Respiratory insufficiency
• Myoclonus (muscle twitches)
• Mydriasis
• Sweating
• Gastrointestinal symptoms; diarrhea, nausea, and vomiting
• Liver and kidney impairment in rare cases
• Electrolyte imbalances – hyponatremia, hypokalemia, hypomagnesemia

Serotonin Syndrome

Overdose with SSRI preparations, SNRI preparations, and atypical antidepressants can all cause serotonin syndrome. The syndrome can occur after an acute overdose but also after taking therapeutic doses. Serotonin syndrome refers to a marked overactivity in serotonergic neurotransmission in the CNS and the resulting symptoms. The symptomatology is dominated by CNS symptoms such as akathisia, tremor, sweating, restlessness, agitation, confusion, diarrhea, hyperreflexia, clonus, tachycardia, rigidity, and hyperthermia. It is a serious condition that in the worst case can lead to death. The risk is particularly high when an antidepressant is combined with other agents that also release serotonin. Examples of other agents include various analgesics and central nervous system stimulants such as amphetamine, cocaine, and ecstasy. Even sumatriptan (Imigran^®), valproate (Absenor^®, Ergenyl^®, Orfiril^®), levodopa (< a href=”http://old.internetmedicin.se/fasslink.asp?s1=Madopark&t=p&pageid=1634″>Madopark^®, Sinemet^®), bromocriptine (Pravidel^®), lamotrigine (Lamictal^®), lithium (Lithionit^®) and certain health supplements can trigger serotonin syndrome. Among analgesics, tramadol (Dolatramyl^®, Gemadol^®, Nobligan^®, Tiparol^®, Tradolan^®, Tramadol^®), pethidine (Petidin^®) and fentanyl (Leptanal^®, Fentanyl^®) can be mentioned. Symptoms can appear suddenly, including fever, muscle rigidity, and excitation in general.

The syndrome is usually relatively mild and transient. In severe cases, rhabdomyolysis, generalized seizures, renal failure, respiratory failure, liver failure, and multiple organ failure may occur. The most important treatment for the syndrome is sedation and cooling. If necessary, specific medications can be administered with some “antidote effect” such as cyproheptadine (Periactin^® – licensed medication) and haloperidol (Haldol^®). Beta-blockers (Seloken^®, Tenormin^®), bromocriptine (Pravidel^®) or dantrolene (Dantrium^® – licensed medication) have no place in the treatment.

Treatment of serotonin syndrome can be tried with one of the following medications:

• Cyproheptadine (Periactin) – 8 mg x 3 (licensed medication) orally
• Olanzapine 10 mg x 3
• Risperidone (Risperdal^®) 1 mg x 2

MANAGEMENT AND TREATMENT

The treatment of acute poisoning with SSRI and SNRI preparations is mainly symptomatic and resembles the treatment of poisoning with classical antidepressants. Alertness, breathing, and hemodynamics can deteriorate suddenly without warning. Seizures, psychomotor agitation, decreased alertness, nausea, and vomiting are common. Insufficient breathing is supported as needed with the help of endotracheal intubation and ventilator treatment in an intensive care unit.

If vital parameters are stable and the patient is breathing calmly and regularly, monitoring is usually sufficient, and the patient is allowed to sleep until they wake up. Comatose patients are placed stably on their side and turned every two hours. Another cause of deep unconsciousness besides poisoning should of course be ruled out. Check electrolytes, intoxication tests, and an arterial blood gas as well as the blood alcohol concentration. Perform CT brain imaging in unclear cases of unconsciousness or in the presence of focal neurological symptoms.

Activated charcoal is valuable if administered early in treatment, especially within one hour after ingesting toxic substances. The administration of activated charcoal should be standard treatment in serious poisoning. Charcoal is of limited value if administered later than one hour after the poisoning incident. Early administration of charcoal is very effective and absorbs most antidepressants. Activated charcoal can also be given later than one hour in life-threatening poisoning and should complement gastric lavage when this is performed. See specific guidelines for gastric lavage and activated charcoal.

Gastric lavage (stomach pumping) is valuable but should only be performed if the patient arrives at the hospital early after the poisoning event, preferably within one hour. In very severe poisonings (life-threatening poisoning), after the ingestion of very large doses or depot preparations, gastric lavage may need to be performed even at a later stage. See specific guidelines for gastric lavage.

See the overview of Gastric Lavage

• Gastric lavage if indicated.
• Activated charcoal (Carbomix, Charcoal Suspension 150 mg/ml) 50 g orally, or more in cases of poisoning with more than 5 g of the drug. Insert a gastric tube if repeated doses of activated charcoal are to be given.
• Adequate fluid replacement with crystalloid infusion solutions, e.g., 2000-3000 ml Ringer’s Acetate, or possibly dextran (Macrodex^®) 500 ml.
• Monitoring of circulation, respiration, and urine output. Follow lactate levels.
• Diazepam (Stesolid^®) 5-10 mg i.v. for anxiety, hyperthermia, rigidity, or seizures. Treatment with diazepam has caused prolonged unconsciousness.
• Sodium bicarbonate for acidosis, arrhythmias, or widened QRS complexes. Initially administer 100-300 ml of sodium bicarbonate.
• Be liberal with intubation and controlled ventilation.
• Inotropic treatment, dopamine, norepinephrine, or adrenaline for refractory hypotension.
• In cases of severe circulatory failure, consider treatment with extracorporeal circulation (ECMO system).
• In the event of cardiac arrest, perform immediate cardiopulmonary resuscitation, and lipid therapy may be attempted:
  – Administer a bolus of 20% lipid emulsion (Intralipid^®), 1.5 ml/kg i.v. or 100 ml rapidly intravenously.
  – Start an infusion with a lipid emulsion of 0.25 ml/kg/min for 10 minutes while performing CPR, or give 100 ml intravenously – which may be repeated.
  – Bolus doses can be repeated every 5 minutes, two or three times if needed, 1 ml/kg Intralipid. More than 8 ml/kg lipid emulsion should not be given.
• Hypertonic saline (Rescueflow^®) can be tested for widened QRS complexes (200 mmol over 20 minutes).
• Potential arrhythmia treatment with magnesium sulfate. Twenty (20) mmol magnesium in 100 ml sodium chloride is administered intravenously over 20 minutes.
• For serotonin syndrome: sedation and cooling. Possible muscle relaxation.
• Specific treatment for serotonin syndrome can be given with:
  – Cyproheptadine (Periactin) 8 mg x 3 orally – licensed medication.
• Other symptomatic treatments, i.e., treating acidosis, hypovolemia, hypotension, arrhythmias, and electrolyte disturbances.
• For hyperthermia:
  – Remove the patient’s clothing.
  – Cool the patient with cold packs in the armpits, groin, and over the forehead.
  – Administer 1000 ml refrigerator-cold sodium chloride intravenously through a peripheral needle over 30 minutes. NOTE! Never administer cold solutions through a central venous catheter!
  – In severe, hard-to-treat hyperthermia: sedation, ventilator care, and muscle relaxation.
• Document in the medical record the time of tablet ingestion, type of drug, quantity (total in mg), any empty drug packaging, and the source of the information.
• Confirm or negate signs of external trauma, needle marks, etc.
• If needed, contact the Poison Information Center at 08-736 03 84 or 08-517 747 42 or 08-33 12 31.

FOLLOW-UP

Psychiatric and social follow-up of the patient is important when the intoxication occurs in connection with a suicide attempt or when the patient has an active addiction to medication, alcohol, or drugs. A follow-up visit to psychiatry or social services is desirable, and a referral should always be written. Assess the patient’s level of depression and the presence of psychotic symptoms.

If there is increased suicidal ideation with an active desire to die, treatment under the Compulsory Psychiatric Care Act (LPT) must be considered.

Permanent Damage

A drug overdose generally does not cause permanent damage unless serious complications arise such as apnea, aspiration pneumonia, acute liver failure, acute kidney failure, or severe general hypoxia. The risk of withdrawal after abuse of alcohol, drugs, or medication must always be considered at discharge. Temporary sleep disturbances with severe insomnia lasting 3-4 weeks are not uncommon, as well as fatigue and muscle pain. Other side effects that have been reported include stomach pain, difficulty concentrating, depression, anxiety, and impotence.

ICD-10

• T43 Poisoning by psychotropic drugs, not elsewhere classified
• T43.2 Other and unspecified antidepressants
• X60-X69 Intentional self-harm by poisoning
• Observation for suspected toxic effect of ingested substance Z03.6

Also see the treatment overview on Intoxication – SSRI

REFERENCES

1. Howell C, Wilson AD, Waring WS. Cardiovascular toxicity due to venlafaxine poisoning in adults: a review of 235 consecutive cases. Br J Clin Pharmacol. 2007;64(2):192-7.
2. Kelly CA, Dhaun N, Laing WJ, Strachan FE, Good AM, Bateman DN. Comparative toxicity of citalopram and the newer antidepressants after overdose. J Toxicol Clin Toxicol. 2004;42(1):67-71
   
   .
3. Colbridge MG, Volans GN. Venlafaxine in overdose – experience of the National Poisons Information Service (London centre) [abstract]. J Toxicol Clin Toxicol. 1999;37:383.
4. Blythe D, Hackett LP. Cardiovascular and neurological toxicity of venlafaxine. Hum Exp Toxicol. 1999;18(5):309-13.
5. Cumpston S, Chao M, Pallasch E. Massive venlafaxine overdose resulting in arrhythmogenic death [abstract]. J Toxicol Clin Toxicol. 2003;41:659.
6. Mazur JE, Doty J, Krygiel A. Fatality related to a 30-g venlafaxine overdose. Pharmacotherapy. 2003;23(12):1668-72.
7. Pascale P, Oddo M, Pacher P, Augsburger NM, Liaudet L. Severe rhabdomyolysis following venlafaxine overdose. Ther Drug Monit. 2005;27(5):562-4.
8. Daniels RJ. Serotonin syndrome due to venlafaxine overdose. J Accid Emerg Med. 1998;15:333-4.
9. Whyte I, Dawson A, Buckley N. Relative toxicity of venlafaxine and selective serotonin reuptake inhibitors in overdose compared to tricyclic antidepressants. QJM. 2003;96:369-74.
10. Hernández JL, Ramos F, Infante J, Rebello M, Gonzales-Macias J. Severe serotonin syndrome induced by mirtazapine monotherapy. Ann Pharmacother. 2002;36:641-3.
11. Personne M, Sjöberg G. Toxicity in overdose of newer antidepressants. Läkartidningen 2008; 105 (3):125-7.
12. Hanekamp, et al. Serotonin syndrome and rhabdomyolysis in venlafaxine poisoning. The Netherlands Journal of Medicine. 2005;63(8):316-318
13. Danescu IL, Macovei RA, Caragea G, Ionica M, Cioca G. Rhabdomyolysis in a venlafaxine poisoning case [abstract]. Toxicology Letters. 2008;180:S1, Page S129

Phenothiazine Derivative Poisoning

Phenothiazines are a group of older antipsychotic drugs that can cause serious poisoning. This group includes drugs such as levomepromazine (Nozinan), fluphenazine (Siqualone), perphenazine (Trilafon), and prochlorperazine (Stemetil). Previously, drugs such as Hibernal, Mallorol, and Esucos were also part of this group but are now deregistered. Phenothiazines are closely related to tricyclic antidepressants and can cause life-threatening conditions such as coma and severe cardiac arrhythmias in overdose.

Phenothiazine derivatives are a type of neuroleptic used systemically with sedative, anticholinergic, and antihistaminergic properties. Phenothiazine derivatives are commonly involved in drug poisoning, often in combination with other medications used for anxiety and agitation. The prescription of promethazine (Lergigan) has increased significantly in Sweden in recent years, as has the number of poisoning cases, despite this being an older drug. In 2017, more than 600 poisoning cases occurred. Most poisoning cases have mild or moderate symptoms, but fatalities do occur. Toxnet (Toxicology Data Network) reports cases of respiratory depression, sleep apnea, and sudden infant death in several infants or young children. Sudden and unexpected deaths have also occurred in patients receiving phenothiazines, particularly with long-term administration.

Phenothiazine derivatives are thus derivatives of phenothiazines, where some preparations lack actual antipsychotic effects, such as Theralen, Lergigan, and Propavan, while others have distinct antipsychotic effects (those with a piperazine ring). Phenothiazine derivatives are often used for anxiety, agitation, and insomnia, but also for seasickness, nausea, and allergic reactions. Chemically, they can be divided into substances with an aliphatic side chain such as chlorpromazine (Hibernal), levomepromazine (Nozinan), promazine, acepromazine, triflupromazine, or those with a piperazine ring such as fluphenazine (Siqualone) or perphenazine (Trilafon). Phenothiazine derivatives generally cause less severe poisoning compared to phenothiazines, but their numbers have increased. Thioxanthenes are other related preparations that cause similar symptomatology in poisoning, such as chlorprothixene (Truxal), zuclopenthixol (Cisordinol), and flupentixol (Fluanxol).

These drugs are available as tablets, oral drops, and oral solutions. Previously, promethazine was also available for injection use, but it has been deregistered. Abroad, phenothiazine derivatives are present in several other medications in different formulations that sometimes appear in Sweden in connection with poisoning incidents.

The most common phenothiazine derivatives are:

• Alimemazine (Theralen (tablets, drops), Alimemazine (capsules, drops))
• Promethazine (Lergigan (tablets, oral solution), Promethazine (tablets))
• Promethazine in combination preparations: Lergigan Comp (tablets)
• Propiomazine (Propavan)

Phenothiazines can cause prolonged QT intervals and serious cardiac arrhythmias after overdose. Palpitations, tachycardia, and irregular heart rhythms may occur but are not particularly common. However, it is important to be aware that prolonged QT intervals can occur, and malignant arrhythmias such as ventricular tachycardia and Torsades de Pointes may appear. In many cases, the QT prolongation is very limited and lacks clinical relevance. The absolute risk is probably very small, but it is difficult to assess the risk in an individual patient. Other risk factors such as cardiovascular disease, age (high or low), and family history of heart attack/stroke must be considered.

Combination preparations, in addition to promethazine, also contain caffeine and ephedrine, which can present a different poisoning picture. The main effects observed in overdose and poisoning with phenothiazine derivatives are fatigue, somnolence, and, to an increasing extent, decreased alertness and coma. The sedative effect is potentiated by other sedatives, hypnotics, or alcohol. Propiomazine (Propavan) is a centrally acting phenothiazine derivative where the poisoning picture is mainly characterized by reduced alertness or coma with respiratory failure in severe cases.

The diagnosis of phenothiazine derivative poisoning is based on history and the possible finding of tablet packs, packaging, or drugs. Usually, no drug determination is made in blood or urine. The diagnosis and treatment of anticholinergic syndrome are guided by the clinical picture. Treatment is mainly symptomatic. Antidote treatment with physostigmine may be effective in some cases, primarily for central nervous system symptoms. Phenothiazine derivatives can cause prolonged QT intervals, so an ECG must always be taken to determine the QT interval.

Toxicity

The toxicity of phenothiazine derivatives varies with the ingested dose, the patient’s age and condition, and concurrent intake of other substances. Most incidents result in only moderate symptoms.

Ingestion of 20-100 mg can cause toxicity in children under one year of age. Ingestion of 100-1000 mg can result in moderate intoxication in children aged one to ten years. In adults, ingestion of 1-2.5 g usually results in moderate intoxication unless other substances have been taken simultaneously. Ingestion of over 2.5 g should be considered serious, but symptomatology can vary greatly.

Common Symptoms of Poisoning

• Decreased level of consciousness
• Confusion
• Hallucinations
• Impaired vision
• Photophobia
• Restlessness
• Motor agitation, “jitteriness,” twitching
• Aggressiveness

Common Clinical Findings

• Hyperthermia
• Prolonged QT interval
• Dry mucous membranes
• Warm, dry skin
• Large, often light-insensitive pupils
• Sinus tachycardia
• Reduced bowel sounds
• Urinary retention
• Normal to elevated blood pressure
• Contractions in the extensor muscles
• Opisthotonos, positive Babinski reflex

Anticholinergic Syndrome

Phenothiazine derivatives have strong anticholinergic properties that can produce characteristic symptoms in overdose. Symptoms may include anxiety, confusion, large pupils, tachycardia, dry mouth, hallucinations, and sometimes full-blown delirium. Seizures are less common, but spastic muscle contractions can occur. The patient often appears “jittery” with involuntary muscle twitches. In rare cases, opisthotonos and strange twitches in the torso and large muscle groups are seen, making the symptomatology difficult to interpret. The English mnemonic for anticholinergic syndrome describes the symptoms well: “Blind as a bat, mad as a hatter, red as a beet, hot as Hades (or hot as a hare), dry as a bone, the bowel and bladder lose their tone, and the heart runs alone.”

The anticholinergic syndrome can be treated with intravenous physostigmine to address the central nervous effects, which manifest as delirium. When treated with physostigmine, an agitated and confused patient may suddenly wake up, become mentally clear and oriented, dramatically improving the clinical picture and calming those present.

Treatment

The most important measures in most cases of phenothiazine derivative poisoning are to:

• Identify the toxic agent
• Carefully monitor alertness and breathing
• Support breathing and circulation as needed
• Perform active elimination if indicated, e.g., gastric lavage, and instillation of activated charcoal
• Treat acute confusion and motor agitation calmly and safely
• Administer antidote treatment with physostigmine when clearly indicated and the benefits outweigh the risks, such as in anticholinergic syndrome
• Treat heart failure and hypotension with standard inotropic drugs such as norepinephrine or adrenaline
• Treat with intravenous lipid emulsion (ILE) as a last resort in cardiovascular collapse
• Admit the patient to an appropriate care level and avoid too low a level of care when consciousness is impaired or breathing is compromised
• Arrange follow-up with psychiatry and social services

Gastric lavage and administration of activated charcoal are indicated if a large dose has been taken and the patient presents within one to two hours of ingestion. Typically, 50 g of charcoal is administered suspended in water orally through a large-bore nasogastric tube.

If the patient is circulatorily and respiratorily stable but agitated and delirious, intravenous physostigmine may be tried, often with good effect. Contraindications include co-ingestion of other cardio-depressive drugs such as tricyclic antidepressants or drugs that lower the seizure threshold. Physostigmine should not be given if the patient has widened QRS complexes, bradycardia (pulse < 50 beats/min), or other cardiac arrhythmias. If anticholinergic syndrome is suspected, physostigmine should be tried before benzodiazepines, as the latter has only a moderate effect on anticholinergic syndrome. However, physostigmine lowers the seizure threshold, so there is a risk of seizures if drugs that can provoke seizures, such as TCAs, have been ingested.

Dosage of Physostigmine

Administer 1-2 mg slowly i.v. to adults and 0.02-0.04 mg/kg i.v. to children. In severe cases, an infusion with a dose of 1-3 mg/h may be tried. Effects can be expected within minutes, and the duration is about 90 minutes. The dose may need to be repeated at hourly intervals if pronounced symptoms recur, but clinical experience suggests that additional doses are rarely needed more than 8 hours after the first. The patient should be connected to a cardiac monitor during the physostigmine injection, and atropine should be available.

Physostigmine (Anticholium) is a licensed drug stocked at most emergency hospitals in Sweden as an injection solution of 0.4 mg/ml in packs of 5 × 5 ml.

In addition to the acute toxic effects of phenothiazines, it is also worth noting that these drugs can cause idiosyncratic agranulocytosis and jaundice.

Follow-up

Psychiatric and social follow-up of the patient is important when the intoxication occurs in connection with a suicide attempt or when the patient has an active addiction to medication, alcohol, or drugs. A follow-up visit to psychiatry, addiction services, or social services is desirable, and a referral should be written. In life-threatening addiction (alcohol, opioids, or illegal drugs), social services should always be contacted, either in writing or verbally.

Cases involving young people under 18 years of age must be reported to social authorities and child and adolescent psychiatric services (BUP). The school health service may also need to be involved.

In cases of repeated acute overdoses, a report to social services should be made, and consideration should be given to involuntary care under the Care of Young Persons (LVU) or the Care of Substance Abusers Act (LVM). Reports to social services can be made verbally or in writing.

Permanent Damage

Drug overdose with phenothiazine derivatives generally does not cause permanent damage unless serious complications arise such as apnea, aspiration pneumonia, severe arrhythmias, acute liver failure, acute kidney failure, or pronounced general hypoxia. The risk of withdrawal after abuse of alcohol, drugs, or medication must always be considered at discharge. Temporary sleep disturbances with severe insomnia lasting 3-4 weeks are not uncommon. Other side effects that have been described include stomach pain, difficulty concentrating, depression, anxiety, and impotence. Many patients experience a low quality of life for a long time after being treated for acute poisoning. There is always a risk of re-poisoning or overdose in the next year.

References

1. Höjer J, Tellerup M. Renässans för Lergigan med kraftig ökning av intoxikationsfall. Läkartidningen. 2018;115:E9EZ.
2. Owczuk R, Twardowski P, Dylczyk-Sommer A, Wujtewicz MA, Sawicka W, Drogoszewska B, Wujtewicz M. Influence of promethazine on cardiac repolarisation: a double-blind, midazolam-controlled study. Anaesthesia. 2009 Jun;64(6):609-14.
3. Nachimuthu S, Assar MD, Schussler JM. Drug-induced QT interval prolongation: mechanisms and clinical management. Ther Adv Drug Saf. 2012 Oct;3(5):241-53. doi: 10.1177/2042098612454283. Review.
4. van Noord C, Eijgelsheim M, Stricker BH. Drug- and non-drug-associated QT interval prolongation. Br J Clin Pharmacol. 2010 Jul;70(1):16-23.
5. Phenergan product summary FDA. https://www.accessdata.fda.gov/drugsatfda_docs/label/2004/07935s030lbl.pdf
6. Kondou N, Hiasa Y, Kishi K, Fujinaga H, Ohishi Y, Ohtani R, Wada T, Aihara T [A case of life-threatening ventricular arrhythmias probably due to psychotropic drugs]. Kokyu To Junkan. 1993 Nov;41(11):1117-20.

Antidotes

Antidotes should be stored in special antidote stores to ensure they are available for immediate use in treating acute poisonings. The Antidote List 2019-01 outlines the preparations suitable for healthcare facilities to keep in their antidote stores, along with recommended quantities, as shown below.

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Most hospitals around Sweden have their own antidote stores. In case of isolated accidents or mass casualty situations, antidotes can be requisitioned from other stores. An antidote register is available online where you can see which antidotes are provided by different hospitals. Go to the antidote register here!

In the antidote register, healthcare personnel can find current information on where and in what quantities antidotes for treating acute poisonings are stored at their hospital. This information can also be used to determine from which nearby hospital more antidotes can be requisitioned in case of a shortage. Quantities stored at the C.W. Scheele emergency pharmacy in Stockholm are also listed. Antidotes can be requisitioned from there 24/7. A list of available antidotes can be found here.

The register also helps healthcare facilities determine the appropriate size of their own antidote stockpiles. The Antidote List 2019-01 is a list of recommended antidotes intended for healthcare professionals and hospital pharmacy staff managing hospital antidote supplies. A copy of the antidote list should be available in antidote stores and in emergency kits for chemical accidents.

Antidotes are administered when the patient’s condition warrants and when there is a possibility of significantly improving the prognosis. Some common and important antidotes are:

• Acetylcysteine for poisoning with paracetamol and certain toxic mushrooms. Note: Paracetamol 665 mg overdose requires a specific acetylcysteine regimen with an extended phase II dose.
• 4-Methylpyrazole (Fomepizole^®) for methanol or ethylene glycol poisoning
• Hydroxocobalamin (Cyanokit^®) for cyanide poisoning (smoke inhalation) or other cyanide compounds
• Beclomethasone (Becotide^®) for poisoning with irritant gases (inhaled steroids)
• Desferrioxamine (Desferal^®) for iron poisoning
• Digitalis antibodies (DigiFab TM^®) for digitalis poisoning (digoxin, digitoxin)
• Flumazenil (Lanexat^®) for benzodiazepine poisoning
• Naloxone (Naloxone^®) (Nexodal^®) for opioid poisoning
• Obidoxime (Toxogonin^®) for nerve agent poisoning (deregistered)
• Immune serum (Vipera Tab^®) for viper bites; specific snake serum for other snake bites.

Important Antidotes

Physostigmine (Anticholium)

An antidote for central nervous effects of anticholinergic drugs. A reversible cholinesterase inhibitor, physostigmine crosses the blood-brain barrier unlike neostigmine, and can reverse central anticholinergic effects of drugs such as confusion and agitation. Other anticholinergic symptoms include tachycardia, high blood pressure, dilated pupils, red warm and dry skin, and urinary retention.

Physostigmine has a half-life of 30-60 minutes and may need to be administered multiple times.

Indications: Overdose or poisoning with anticholinergic drugs. Anticholinergic syndrome. Non-specific treatment for some effects of Baclofen.

Concentration: 5 ml ampoule containing 2 mg physostigmine (0.4 mg/ml).

Dosage: Adults: 1-2 mg intravenously, administered slowly at approximately 0.2 mg/min. Children: 0.02 mg/kg intravenously. Use with caution due to the risk of triggering seizures and bradycardia.