General Principles in the Management of Intoxications

Chapter 1

Abstract

exposure, and injection.

toxicology laboratory

1. Introduction

3

Patient

Ehab Said Aki and Jalal Alessai

General Approach to Poisoned

Poisoning is a serious worldwide public health problem. Based on the World Health Organization data in 2012, almost 190,000 people died worldwide and the number of deaths due to poisoning in 2008 exceeded the number of deaths due to motor vehicular crashes; also, poisoning death rate nearly tripled worldwide. The number of patients presenting to the emergency departments with overdose had been increased both intentionally and accidentally. All the previous facts make toxicology an important field in emergency medicine. According to the American Association of Poison Control Centers (AAPCC) in the United States, over 2.1 million human exposure calls are reported in 2016. Management of intoxicated patients has a unique approach because of the challenge in diagnosis and treatment of overdose cases. This chapter focuses on general approaches for intoxicated patients and initial management and on how the history and physical examinations could help physicians to have a clue about the drugs that have been abused. Patients are most commonly poisoned via oral ingestion, but other routes could also cause intoxication including inhalation, insufflation, cutaneous and mucous membrane

Keywords: initial approach, physical examination, toxidromes, decontamination,

Poisoning is a serious worldwide public health problem. Based on the World Health Organization (WHO) data in 2012, almost 190,000 people died worldwide and the number of deaths due to poisoning in 2008 exceeded the number of deaths due to motor vehicular crashes; also, the death rate due to poisoning nearly tripled worldwide. The number of patients presenting to the emergency departments with overdose had been increased both intentionally and accidentally. All the previous facts make toxicology an important field in emergency medicine [1, 2]. According to the American Association of Poison Control Centers (AAPCC) in the United

Management of intoxicated patients has a unique approach because of the challenge in diagnosis and treatment of overdose cases. This chapter focuses on general approaches for intoxicated patients and initial management, explaining how the history and physical examinations could help physicians to have a clue about the drugs that have been abused. Patients are most commonly poisoned via oral

States, over 2.1 million human exposure calls are reported in 2016.

#### Chapter 1

## General Approach to Poisoned Patient

Ehab Said Aki and Jalal Alessai

#### Abstract

Poisoning is a serious worldwide public health problem. Based on the World Health Organization data in 2012, almost 190,000 people died worldwide and the number of deaths due to poisoning in 2008 exceeded the number of deaths due to motor vehicular crashes; also, poisoning death rate nearly tripled worldwide. The number of patients presenting to the emergency departments with overdose had been increased both intentionally and accidentally. All the previous facts make toxicology an important field in emergency medicine. According to the American Association of Poison Control Centers (AAPCC) in the United States, over 2.1 million human exposure calls are reported in 2016. Management of intoxicated patients has a unique approach because of the challenge in diagnosis and treatment of overdose cases. This chapter focuses on general approaches for intoxicated patients and initial management and on how the history and physical examinations could help physicians to have a clue about the drugs that have been abused. Patients are most commonly poisoned via oral ingestion, but other routes could also cause intoxication including inhalation, insufflation, cutaneous and mucous membrane exposure, and injection.

Keywords: initial approach, physical examination, toxidromes, decontamination, toxicology laboratory

#### 1. Introduction

Poisoning is a serious worldwide public health problem. Based on the World Health Organization (WHO) data in 2012, almost 190,000 people died worldwide and the number of deaths due to poisoning in 2008 exceeded the number of deaths due to motor vehicular crashes; also, the death rate due to poisoning nearly tripled worldwide. The number of patients presenting to the emergency departments with overdose had been increased both intentionally and accidentally. All the previous facts make toxicology an important field in emergency medicine [1, 2]. According to the American Association of Poison Control Centers (AAPCC) in the United States, over 2.1 million human exposure calls are reported in 2016.

Management of intoxicated patients has a unique approach because of the challenge in diagnosis and treatment of overdose cases. This chapter focuses on general approaches for intoxicated patients and initial management, explaining how the history and physical examinations could help physicians to have a clue about the drugs that have been abused. Patients are most commonly poisoned via oral

ingestion, but other routes like inhalation, insufflation, cutaneous and mucous membrane exposure, and injection could also cause intoxication.

#### 2. General approach to toxicological cases in emergency medicine

The approach to poisoned patients must be systematic. The range of symptoms and clinical findings in the physical examination are wide in drug poisoning patients; initial management is focused on stabilization of life-threatening conditions. The approach for the poisoned patients in emergency includes: resuscitation, history, physical examination, and management.

Initial screening examination should be done on all patients to find out immediate abnormal measures which need to be stabilized starting with vital signs, conscious level and pupil size, skin temperature, pulse oximetry, and electrocardiogram. Patients who are hemodynamically unstable must be kept in continuous cardiac monitoring. Intravenous access should be done and the blood glucose must be checked especially if the patients have a decreased level of consciousness.

#### 3. Resuscitation

#### 3.1 Airway and ventilation

The initial priorities for a poisoned patient presented to the emergency department are: securing the airway and breathing and stabilizing the circulation. Adequate ventilation and intubation with mechanical ventilation must be done early in the intoxicated patients with depressed mental status, except in cases of easy reversible causes of coma like opioid intoxication or hypoglycemia to prevent complications of intubation like aspiration. Other indications for intubation include severe acid-base disturbances or acute respiratory failure. In intubated patients, development of a respiratory acidosis must be prevented by adequate ventilation; in some cases like high-grade physiologic stimulation, the patient may need sedation and paralysis to prevent complications such as hyperthermia, acidosis, and rhabdomyolysis.

#### 3.2 Hypotension

Drugs cause hypotension by four major mechanisms: decreased peripheral vascular resistance, decreased myocardial contractility, dysrhythmias, and depletion of intravascular volume. First-line treatment of hypotension is IV fluid bolus (10 to 20 mL/kg); if hypotension is not responding to fluid, it may be necessary to add vasopressors such norepinephrine. Norepinephrine is better than dopamine.

#### 3.3 Hypertension

Elevated blood pursues caused by CNS sympathetic overactivity, increased myocardial contractility or increased peripheral vascular resistance, or a combination.

The treatment of hypertension and agitated patients starts with sedatives such as benzodiazepines; if not responding for initial treatment and there is evidence of endorgan dysfunction, calcium-channel blocker is preferred treatment. The use of betablockers is not recommended in the case of sympathetic hyperactivity because it may cause unopposed alpha-adrenergic stimulation and intensified vasoconstriction.

Ventricular tachycardia occurs because of tricyclic antidepressant toxicity. Sodium bicarbonate is first line therapy. Types IA (e.g., procainamide), IC, and III

#### General Approach to Poisoned Patient DOI: http://dx.doi.org/10.5772/intechopen.84681

antiarrhythmic agents may worsen cardiac conduction; hence, they are not recommended; also, using these agents could be potentially dangerous.

Magnesium sulfate can also be used in the case of drug-induced torsade de pointes and prolonged QT intervals on ECG.

Digoxin toxicity with life-threatening tachyarrhythmias or bradyarrhythmias should be treated with specific Fab fragments (Digibind).

#### 3.4 Bradyarrhythmias

Treatment of bradyarrhythmias with hypotension starts with atropine and/or temporary pacing. Calcium, glucagon, or high-dose insulin are used in the case of calcium channel blocker or beta blocker intoxication.

#### 3.5 Seizures

The best treatment of intoxicated patients with seizures is benzodiazepines; we may add barbiturates if necessary. Phenytoin is not recommended to control seizures in poisoned patients.

#### 3.6 Severe hyperthermia

Elevated temperature (hyperthermia) due to drug toxicity (e.g., sympathomimetic overdose, serotonin syndrome, or neuroleptic malignant syndrome) must be treated aggressively to prevent complications like rhabdomyolysis, organ failure, and disseminated intravascular coagulation. Treatment of hyperthermia includes active cooling like ice water immersion; if active cooling is ineffective, the patient may need sedation, neuromuscular paralysis, and intubation.

Patients presenting with signs of opioid overdose (low Glasgow coma scale-GCS respiratory depression, meiosis) must be given naloxone (0.1–2.0 mg I.V) as soon as possible [3].

#### 4. History

History of the present illness is very important and can be obtained from the patients if they are alert and conscious; although the history following intentional ingestion is often unreliable, which makes history taking very challenging especially if the patients are comatose or cannot give their history, in such situations, history can be taken from collateral information from family, friends, ambulance crew, or medical records looking for past psychiatry illness, previous history of suicide or drug abuse, chronic medication, etc.

History must include time, route of entry, quantity, intentional or accidental exposure, availability of drugs at home, and if any member of the family has chronic diseases (hypertension, diabetic, etc.) and missing tablets or any empty pill bottles or other material was found around him [4]. It is very important to ask specifically about the use of traditional or herbal remedies and dietary supplements.

#### 5. Physical examination

Physical examination of poisoned patients may give clues regarding the substance which has been abused and toxidromes. Physical examination includes: general appearance,

• Mental status (agitated or confused)

Some drugs or substances affect the central nervous system either causing agitation or depression.

Central nervous system depression may be caused by the following:

Anticholinergics, antidepressants, antipsychotics, lithium, cholinergic beta blockers, clonidine, and sedative-hypnotics.

Central nervous system agitation

Sympathomimetics, anticholinergics, salicylates, central hallucinogens, drug withdrawal states, carbon monoxide, hypoglycemic agents, and heavy metals.

• Skin (cyanosis,flashing, and physicalsigns ofintravenous drug abuse (track marks)

Red and flushed skin occurs in the case of overdose of anticholinergic agents, antihistamines, TCAs, atropine, scopolamine, and phenothiazines.

Pale and diaphoretic skin occurs in the case of sympathomimetics (cocaine), cholinergic agents (organophosphates), central hallucinogens (lysergic acid diethylamide (LSD) and phencyclidine) and salicylate toxicities.

Cyanotic skin occurs in the case of methemoglobinemia and sulfhemoglobinemia.

• Eye examination: (pupil size reactivity lacrimation and nystagmus)

Common drugs causing miosis


Common drugs causing nystagmus Barbiturates, carbamazepine, phencyclidine, phenytoin, and lithium



#### Table 1.

Substances causing specific odor.


#### 5.1 Toxidromes

The term toxidrome was coined in 1970 by Mofenson and Greensher. Toxidromes are a group of abnormal physical examinations and abnormal vital signs known to be present with a specific group of medications or substances. The most common toxidromes are cholinergics, anticholinergics, sympathomimetics, opioids, and serotonin syndrome [4, 5].

#### 5.2 Cholinergic toxidrome

Patients with cholinergic toxidrome present with wet manifestation. SLUDGE+3 Killer B<sup>0</sup> s and DUMBELLS are simple mnemonics for the common clinical symptoms. Also, patients present with bradycardia, hypertension or hypotension, tachypnoea, or bradypnea.

SLUDGE: salivation, lacrimation, urination, defecation, GI cramping, Emesis + Killer B<sup>0</sup> s: bronchorrhea, bradycardia, and bronchospasm.

DUMBELLS: diarrhea, urination, miosis (small pupils), bradycardia, emesis, lacrimation, lethargy, and salivation.

Most common causes: organophosphate pesticides, carbamates, some types of mushrooms, and sarin (warfare agent) [4].

#### 5.3 Anticholinergic toxidrome

Patients present with anticholinergic toxidrome with dry manifestation, delirium, tachycardia, dry flushed skin, dilated pupils, hypertension, tachypnoea clonus, elevated temperature, decreased bowl sounds, and urinary retention. Simple mnemonics: "Hot as a Hare, Mad as a Hatter, Red as a Beet, Dry as a Bone, Blind as a Bat."

Most common causes: antihistamines, antiparkinsonians, atropine, scopolamine, amantadine, antipsychotics, antidepressants, muscle relaxants, and plants (jimsonweed) [4].

#### 5.4 Sympathomimetic toxidrome

Patients present with CNS stimulation and psychomotor agitation, elevated blood pressure, tachycardia, dilated pupils, hyperthermia, widened pulse pressure, tachypnoea, hyperpnea diaphoresis, and seizure in severe cases.

Most common causes: cocaine and amphetamine.

#### 5.5 Opioid toxidrome

The most common clinical presentation of opioid toxidrome are: coma, respiratory depression and meiosis, hypotension, hypothermia, bradycardia, and seizure that may occur in propoxyphene overdose, but small pupils not always present may present with normal size pupils such in meperidine and, propoxyphene toxicities [4].

#### 5.6 Serotonin syndrome

Patients present with altered mental status, hypertensive, and tachycardia, myoclonus, hyperreflexia, hyperthermia, and increase in muscle rigidity. Most common causes: SSRI interaction or overdose of SSRIs.

MAOIs, tricyclic antidepressants, amphetamines, and fentanyl [4].

#### 5.7 Neuromuscular malignant

Patients present with severe muscle rigidity, hyperpyrexia, altered mental status, autonomic instability, diaphoresis, mutism, incontinence. Most common causes: antipsychotic medication.

#### 5.8 Sedative/hypnotic

Patients present with central nervous system depression, ataxia, dysarthria, bradycardia, respiratory depression, hypothermia, hypotension, and bradypnea. Most common causes are benzodiazepines and barbiturates.

#### 5.9 Hallucinogenics

Patients present with hallucinations, perceptual distortions, depersonalization, synaesthesia, and agitation.

Mydriasis, hyperthermia, tachycardia, hypertension, tachypnoea, and nystagmus. Most common causes:

phencyclidine, LSD, mescaline, psilocybin, and MDMA ["Ecstasy"].

#### 5.10 Ethanolic

Patients present with central nervous system depression, ataxia, dysarthria, and odor of ethanol.

#### 5.11 Extrapyramidal

Patients present with dystonia, torticollis, muscle rigidity, choreoathetosis, hyperreflexia, and sometimes seizures. Most common causes: risperidone, haloperidol, and phenothiazines.

#### 5.12 Salicylate

Patients with salicylate toxidrome present with altered mental status, mix respiratory alkalosis, metabolic acidosis, tinnitus, tachypnoea, tachycardia, diaphoresis, nausea, vomiting, and hyperpyrexia.

Most common toxin: aspirin and oil of wintergreen (methyl salicylate).

#### 6. Management

#### 6.1 Electrocardiogram (ECG)

ECG should be done on all patients who are symptomatic or who have been exposed to cardiotoxic agents looking for the rate and conduction; ECG abnormalities may help in diagnosis or may help as prognostic information. Specific attention should be paid to QRS interval and QT interval; in the case of prolongation of QT or QRS sodium bicarbonate infusion should be strongly considered.

#### 6.2 Radiographic studies

Imaging examinations are not necessary in every poisoned patient but may be useful in some situations where the toxins are radiopaque [6]. The toxins which are radiopaque can be summarized by the mnemonic "CHIPES" (Table 2); also, "body packers" may be seen on plain films (Figure 1). Chest x-ray is useful in the case of noncardiogenic pulmonary edema and the acute respiratory distress syndrome due to exposure to certain toxins.

#### 6.3 Abdominal ultrasound

Ultrasound abdomen is not helpful in poisoned patient and the use of ultrasound is very limited and does not appear to be a reliable method of detecting ingested toxins [7].

#### 6.4 Laboratory test

Blood test must be done with all intoxicated patients; especially in the case of intentional overdose, the laboratory test should include basic lab (full cell count and kidney function liver function and electrolytes). Acetaminophen screening is very important in every patient presenting with altered mental status or intentional overdose [8].

For the patients with an acid-base abnormality, serum osmolarity needs to be checked, looking for increasing osmolar gap, which rolls out toxic alcohol ingestion.

In the case of presence of anion gap, metabolic acidosis may help and give to physician a clue of ingestion of certain toxins like (salicylates, ethylene glycol, and methanol or other drugs which may cause high anion gap metabolic acidosis; also serum creatinine, glucose, ketones, and lactate should be tested to detect other causes of the anion gap acidosis.


When serum creatinine is elevated with a normal BUN, this finding is seen in the case of isopropyl alcohol toxicity (or with diabetic ketoacidosis). Co-oximetry can be used for rapid diagnosis of carbon monoxide toxicity and methemoglobinemia.

#### 6.5 Toxicology screening

Toxicology screening is not necessary in case of nonintentional ingestion are asymptomatic patient or have clinical findings that are match with the medical history.

Drugs of abuse to opioids, benzodiazepines, cocaine metabolites, barbiturates, tricyclic antidepressants, tetrahydrocannabinol, and phencyclidine can be detected by using immunoassay screens in urine.

Positive and negative screens for drugs do not necessarily confirm diagnosis of acute poisoning but require further investigations.

#### 6.6 Limitations of toxicologic drug screening assays


#### 7. Decontaminations

Decontamination of poisoned patient means removing the patient from the toxin and removing the toxin from the patient, either outside the patient's body by gross washing or inside the body by gastrointestinal decontamination or enhanced elimination.

#### 7.1 Gross decontamination

Patient must be fully undressed and washed thoroughly with copious amount of water twice regardless of how much time has elapsed since the exposure. All the clothing must be removed and placed in plastic bags, and then the bags must be sealed; no need to neutralize an acid with a base or a base with an acid because that may lead to more tissue damage because the heat could be generated by this reaction. Using any greases or creams must be avoided because they will only keep the xenobiotic in close contact with the skin and ultimately make its removal more difficult.

Decontamination must be done in an isolated specific area. Gross decontamination is used in chemical, biological, and radiation exposure. Healthcare providers must wear universal precautions (gown, gloves, and eye protection) and sometimes may need personal protective equipment.

#### 7.2 Ocular decontamination

In the case of eye exposures to chemical substance, initially, application of a local anesthetic agent (e.g., 0.5% tetracaine) may be needed, then copious irrigation with crystalloid solution. Lid retraction facilitates the irrigation. Alkalis cause more injury than acids because of deep tissue penetration via liquefaction so may need prolonged irrigation (1 to 2 hours). pH of conjunctival sac should be tested and irrigation should be continued until pH is <7.4.

#### 7.3 Gastrointestinal decontamination

There are multiple methods used for gastrointestinal decontamination including:

• Emesis

Induced vomiting by ipecac syrup can decrease absorption and was used in the past but now is rarely indicated because there is no evidence supporting its effectiveness in reducing toxin absorption. It may also increase the risk of complications. Syrup ipecac may be considered in conscious, alert patients with ingestion of a potential number of toxic drugs and present in a very short time after ingestion (<1 hour).

Contradictions:


Gastric lavage is an intervention widely used to remove the ingested toxin drugs from the stomach by an orogastric tube. Because of the absence of published evidence that shows that orogastric lavage may change the outcome, now orogastric lavage is rarely indicated. It may be considered in the case of recent (<1 hour) ingestion of life-threatening amount of a toxin for which there is no effective treatment once absorbed.

Contraindications:


Complications:


Activated charcoal is a super-heating carbonaceous material. Activated charcoal works by reducing the absorption of a substance in the gastrointestinal lumen but it is not effective in metal, alcohols, corrosives, and lithium. The most effective action can be achieved when activated charcoal is given within the first hour of ingestion. In the case of intubated patients, activated charcoal may be administered via an orogastric or nasogastric tube.

Dose:


Contraindications: Substances not adsorbed by activated charcoal.


General Approach to Poisoned Patient DOI: http://dx.doi.org/10.5772/intechopen.84681

Complications:


Whole-bowel irrigation is a mechanical cleansing of the whole gastrointestinal track reducing toxin absorption. The whole-bowel irrigation can be done by Polyethylene glycol solution. Polyethylene glycol is an osmotically balanced electrolyte solution; polyethylene glycol can be given orally to cooperative, awake patients. Patient positioning (head up 30°) reduces the risk of pulmonary aspiration; during whole-bowel irrigation also bowel sounds must be present. Clear rectal effluent and imaging shows the absence of foreign bodies considered as endpoint of wholebowel irrigation treatment.

Indication:


Gastrointestinal obstruction absent bowel sound or perforation [11]. Recurrent, unstoppable vomiting. Complications:


#### 8. Enhanced elimination

Enhanced elimination is a method used to increase the rate of toxic removal from the body so as to reduce the severity and duration of clinical intoxication.

Enhanced elimination methods are not routinely used in poisoned patients. The indications for enhanced elimination include: [4].


There are different techniques to enhance elimination: Multiple dose activated charcoal (MDAC).

MDAC is defined as at least two sequential doses of activated charcoal [12]. Multidose activated charcoal can be given via orogastric or nasogastric tube to intubated patients.

Mechanism of action:


#### Indications:

Ingestion of a life-threatening amount of carbamazepine, dapsone, phenobarbital, quinine, salicylates, or theophylline. Ingestion of a life-threatening amount of another toxin that undergoes enterohepatic or enteroenteric recirculation and that is adsorbed to activated charcoal. Ingestion of a significant amount of any slowly released toxin.

Contraindications:


Complications:


Dose: no optimal dose of MDAC has been established. But the acceptable regimen of 50 g is administered every 4 hours, or 25 g every 2 hours. Study on volunteer found no difference in effectiveness of larger doses spread out over time compared to smaller, more frequent dose [13].

• Urinary alkalinization

#### General Approach to Poisoned Patient DOI: http://dx.doi.org/10.5772/intechopen.84681

Urine alkalinization is a treatment regimen which enhances the elimination of toxins by administration of intravenous sodium bicarbonate to produce urine with pH > or = 7.5.

Alkaline urine acts on ionization of acidotic toxins within renal tubules, stopping resorption of the ionized drug back across the renal tubular epithelium and enhancing elimination through the urine [14].

Characteristics of drugs which respond to urinary alkalinization are [15].


Urinary alkalinization for poisoned patients can be done by the following steps:


#### Indications:


#### Contraindications:


#### Complications:

• Hypokalaemia


Indications: Life-threatening toxicity of


Contraindications:


#### 9. Extracorporeal membrane oxygenation (ECMO)

ECMO: extracorporeal technique used when the patients are critically ill and they cannot provide an adequate amount of gas exchange or perfusion to sustain. This technique may be used in the case of severe and massive overdose especially cardiotoxic drugs (beta blockers, calcium channel blocker) [18].

### 10. Antidotes

Although supportive care is the main treatment of most poisoned patients, there are cases in which administration of a specific antidote is potentially life-saving. Antidote is a substance that can prevent further poisoning from specific substances. Table 3 shows the most common antidote used in the emergency department (see Table 1) [4].


Table 3. Antidote.

#### 11. Disposition

If the patient has persistent and toxic effects, the patient will require prolonged care course. Admission is indicated for completing his treatment and observation; in the case of severe toxicity, the patient may need admission to intensive care unit.

In the case of mild toxicity or asymptomatic patient, a 6-hour observation period is sufficient to exclude the development of serious toxicity.

A number of toxins have delayed onset clinical toxicity, for example (but not limited to): modified-release preparations of calcium channel antagonists, selective norepinephrine reuptake inhibitors (tramadol and venlafaxine), and newer antipsychotics (amisulpride); this means that the duration of observation should be longer than usual.

The decision to admit a patient with a toxic exposure to an intensive care setting should be based upon clinical criteria that relate to the stability of the airway, respiratory system, cardiovascular system, and the patient's level of consciousness.

A retrospective study which was done in more than 200 patients with drug overdoses shows that clinical assessment in the emergency department could reliably find out patients who are at high risk for complications and need intensive care unit admission [19].

Based on the following clinical criteria: if the patient has one of any of the following clinical criteria, the patient may need admission to intensive care unit:


#### 12. Conclusion

The first step in the approach to intoxicated patient should start with stabilization measures including protected airway and adequate ventilation and circulation and control of the convulsion.

History in poisoning cases could be difficult; especially in self-harm poisoning or comatose patients, the physician must use collateral information from friends, family, prehospital personal and medical records.

Always ask, especially about the use of over-the-counter drugs and traditional or herbal preparations.

Physical examination may help to find the toxidrome and complication of toxins; physical examination should include all systems.

Focused laboratory test helps physicians to understand the severity of toxicity and suspected toxin and guides in management, making sure the drug level is sent

#### General Approach to Poisoned Patient DOI: http://dx.doi.org/10.5772/intechopen.84681

at proper time not so early or late to avoid wrong interpretation; urine or blood toxicology screen assays have limited value in the case of acute over dose. Most of poisoned patients only supportive care with decontamination will be sufficient for them, but antidotes same times is the cornerstone of the treatment.

In the end, remember all the time "treat the patient, not the poison."

### Author details

Ehab Said Aki\* and Jalal Alessai Emergency Department, Hamad Medical Corporation, Doha, Qatar

\*Address all correspondence to: akiehab2004@gmail.com

© 2019 The Author(s). Licensee IntechOpen. This chapteris distributed underthe terms oftheCreative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

### References

[1] Warner M, Chen LH, Diane M, Makuc RN, Anderson AM. Miniño. Drug poisoning deaths in the United States, 1980–2008. NCHS Data Brief. 2011;81:1-8

[2] Liu Q, Zhou L, Zheng N, et al. Poisoning deaths in China: Type and prevalence detected at the Tongji Forensic Medical Center in Hubei. Forensic Science International. 2009; 193:88

[3] Erickson TB, Thompson TM, Lu JJ. The approach to the patient with an unknown overdose. Emergency Medicine Clinics of North America. 2007;25:249

[4] Shaun G. General management of poisoned patients. In: Tintinalli JE, et al., eds. Tintinalli's Emergency Medicine Comprehensive Study Guide. 8th ed. New York, NY: McGraw-Hill; 2016

[5] Mofenson HC, Greensher J. The nontoxic ingestion. Paediatric Clinics of North America. 1970;17(3):583-590

[6] Savitt DL, Hawkins HH, Roberts JR. The radiopacity of ingested medications. Annals of Emergency Medicine. 1987; 16(3):331-339

[7] Taftachi F, Sanaei-Zadeh H, Zamani N, Emamhadi M. The role of ultrasound in the visualization of the ingested medications in acute poisoning—A literature review. European Review for Medical and Pharmacological Sciences. 2012;16(15):2175-2177

[8] Sporer KA, Khayam-Bashi H. Acetaminophen andsalicylate serum levels in patients with suicidal ingestion or altered mental status. The American Journal of Emergency Medicine. 1996; 14(5):443-446

[9] Manoguerra AS, Cobaugh DJ. Guidelines for the Management of Poisoning Consensus Panel: Guideline on the use of ipecac syrup in the out-ofhospital management of ingested poisons. Clinical Toxicology (Philadelphia). 2005;43:1

[10] Adams BK, Mann MD, Aboo A, et al. Prolonged gastric emptying halftime and gastric hypomotility after drug overdose. The American Journal of Emergency Medicine. 2004;22:548

[11] Lheureux P, Tenenbein M. Position paper: Whole bowel irrigation. Journal of Toxicology. Clinical Toxicology. 2004;42(6):843

[12] Vale JA, Krenzelok EP, Barceloux GD. Position statement and practice guidelines on the use of multi-dose activated charcoal in the treatment of acute poisoning. American Academy of Clinical Toxicology: European Association of Poisons Centres and Clinical Toxicologists. Journal of Toxicology. Clinical Toxicology. 1999;37:731-751

[13] Ilkhanipour K, Yealy DM, Krenzelok EP. The comparative efficacy of various multiple-dose activated charcoal regimens. The American Journal of Emergency Medicine. 1992;10(4):298

[14] Proudfoot AT, Krenzelok EP, Vale JA. Position paper on urine alkalinization. Journal of Toxicology: Clinical Toxicology. 2004;42:1-26

[15] Garrettson LK, Geller RJ. Acid and alkaline diuresis. When are they of value in the treatment of poisoning? Drug Safety. 1990;5:220

[16] Bronstein AC, Spyker DA, Cantilena LR Jr, et al. Annual report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 28th annual report. Clinical Toxicology (Philadelphia). 2010, 2011; 49:910-941

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[17] Fertel BS, Nelson LS, Goldfarb DS. Extracorporeal removal techniques for the poisoned patient: A review for the intensivist. Journal of Intensive Care Medicine. 2010;25:139-148

[18] Rona R, Cortinovis B, Marcolin R, et al. Extra-corporeal life support for near-fatal multi-drug intoxication: A case report. Journal of Medical Case Reports. 2011;5:231. DOI: 10.1186/ 1752-1947-5-231

[19] Brett AS, Rothschild N, Gray R, et al. Predicting the clinical course in intentional drug overdose. Implications for use of the intensive care unit. Archives of Internal Medicine. 1987; 147(1):133-137

**23**

**Chapter 2**

**Abstract**

patients.

**1. Introduction**

Poisoning in the Pediatric

*Nicolai Nistor, Otilia Frăsinariu, Aniela Rugină,* 

Poisonings during childhood (both accidental and voluntary) are a common cause of presentation in the emergency departments (EDs) and the pediatric intensive care unit (PICU). The admission to PICU is warranted both for treatment and for continuous monitoring, as sometimes the evolution of a poisoning could be unpredictable. Sometimes, complications arise that may prolong the patients' hospitalization and may contribute to lowering the survival rate. The staff in these departments must be well trained to ensure patient monitoring, early detection of complications, and rapid intervention. Supporting vital functions is the main objective of the management of a poisoned patient admitted in PICU. In recent years, staff competence and advanced medical technology have helped to improve the prognosis of the patients admitted to these departments, including of the poisoned

Poisoning is a relatively common medical emergency worldwide and raises particular problems of diagnosis and treatment especially in children, regardless of the path the toxic enters the body (ingestion, inhalation, injection, or skin absorption). This age group is the most vulnerable population with the highest risk of accidental intoxications that can be partially prevented [1]. It is a common cause of presentation in the ED and the PICU. Early identification of the clinical characteristics of patients with acute intoxication and rapid initiation of therapy in these services can help reduce the mortality of intoxicated patients [2, 3]. These departments have the ability to continuously monitor vital parameters, use the most advanced medical technology and the most appropriate treatment. Usually, admission to PICU is by ED or by transfer from another hospital [4]. Often, a poisoned patient will be brought into intensive care not for treatment, but for continuous surveillance and monitoring in order to minimize mortality. On the other hand, care in these units has a very high cost. It is therefore recommended that the admission of poisoning cases in intensive care should take into account the efficient use of resources without compromising patient care [5]. The percentage of children with acute poisoning in PICU ranges from 8% [6] to 11.7% [2]. In the United States in 2014, 2336 intoxicated patients admitted to intensive care units needed ventilatory

support, 509 received vasopressors, and 127 needed hemodialysis [4].

*Irina Mihaela Ciomaga and Violeta Ștreangă*

Intensive Care Unit

**Keywords:** intensive care, poisoning, children

#### **Chapter 2**

## Poisoning in the Pediatric Intensive Care Unit

*Nicolai Nistor, Otilia Frăsinariu, Aniela Rugină, Irina Mihaela Ciomaga and Violeta Ștreangă*

#### **Abstract**

Poisonings during childhood (both accidental and voluntary) are a common cause of presentation in the emergency departments (EDs) and the pediatric intensive care unit (PICU). The admission to PICU is warranted both for treatment and for continuous monitoring, as sometimes the evolution of a poisoning could be unpredictable. Sometimes, complications arise that may prolong the patients' hospitalization and may contribute to lowering the survival rate. The staff in these departments must be well trained to ensure patient monitoring, early detection of complications, and rapid intervention. Supporting vital functions is the main objective of the management of a poisoned patient admitted in PICU. In recent years, staff competence and advanced medical technology have helped to improve the prognosis of the patients admitted to these departments, including of the poisoned patients.

**Keywords:** intensive care, poisoning, children

#### **1. Introduction**

 Poisoning is a relatively common medical emergency worldwide and raises particular problems of diagnosis and treatment especially in children, regardless of the path the toxic enters the body (ingestion, inhalation, injection, or skin absorption). This age group is the most vulnerable population with the highest risk of accidental intoxications that can be partially prevented [1]. It is a common cause of presentation in the ED and the PICU. Early identification of the clinical characteristics of patients with acute intoxication and rapid initiation of therapy in these services can help reduce the mortality of intoxicated patients [2, 3]. These departments have the ability to continuously monitor vital parameters, use the most advanced medical technology and the most appropriate treatment. Usually, admission to PICU is by ED or by transfer from another hospital [4]. Often, a poisoned patient will be brought into intensive care not for treatment, but for continuous surveillance and monitoring in order to minimize mortality. On the other hand, care in these units has a very high cost. It is therefore recommended that the admission of poisoning cases in intensive care should take into account the efficient use of resources without compromising patient care [5]. The percentage of children with acute poisoning in PICU ranges from 8% [6] to 11.7% [2]. In the United States in 2014, 2336 intoxicated patients admitted to intensive care units needed ventilatory support, 509 received vasopressors, and 127 needed hemodialysis [4].

### **2. Admission of intoxicated patients in PICU**

 There are several studies that attempt to establish criteria for admission to intensive care in patients based on severity scores (APACHE II/III, PRISM II/III, SAPS II, Glasgow etc.). These included patients with various medical and surgical conditions, but few can be validated using such scoring systems in poisoned patients [7–9]. Until more specific poisoning factors are established, it is thought that experience and proper clinical judgment can predict which patients will receive intensive care. The presence of certain abnormal symptoms or abnormal test results may require monitoring and/or treatment in PICU regardless of the suspected toxic. This approach is more consistent with the principle of "treating the patient and not the poison" [5]. It should be kept in mind that an initially asymptomatic poisoned patient may worsen later. Poisoned children and adolescents should be directed to the nearest intensive care unit that has pediatric critical care practitioners and equipment appropriate to pediatric age.

#### **2.1 Criteria for admission to intensive care of the poisoned patient**

	- • Need for ventilatory support or emergency tracheostomy.
	- Marked respiratory compromise as indicated by:
		- a. FR <20 or >60 for children <1 year and <12 or >60 for children >1 year.
		- b. SpO2 <92% when O2 is administrated by mask or tracheostomy.
		- c. PaO2 <80 mm Hg at 100% O2 administrated by mask.
	- Rapidly progressive deterioration in respiratory status.
	- Respiratory acidosis with PaCO2 > 60 mmHg and pH < 7.25.
	- Airway obstruction, apnea, anaphylaxis.
	- • Shock as indicated by capillary refill time >4 s, distal or proximal nonpalpable pulse, systolic TA < lower age limit or TA < mean 50 mmHg (<40 mmHg in newborn), metabolic acidosis with < pH 7.25, base deficit >10 or serum bicarbonate <10 mEq/l, need for invasive hemodynamic monitoring.
	- Cardiac instability and arrhythmia, necessity of continuous perfusion or vasoactive substances, ECG ischemic changes, congestive heart failure, and vascular volume instability.
	- Neurological damage with one or more of the following: Glasgow score <10, severe irritability, hallucinations, and change of posture.
	- Intracranial bleeding, increased intracranial pressure, seizures, or delirium.
	- Within a few hours, one of the above criteria is expected.
	- Suicide patient that cannot be monitored in other unit care.

#### **3. Specific monitoring and treatment in PICU**

The main concern in the management of a patient with acute intoxication in PICU is the support of the vital functions. The general measures in a poisoned patient do not differ significantly from those required in a patient admitted to PICU with similar symptoms and a comparable level of severity but with pathology [4]. These critically intoxicated patients should be rapidly recognized by the clinician and evaluated for appropriate therapy. Continuous follow-up of vital functions, neurological status, blood volume, and heart rate makes possible early detection of poisoning worsening signs requiring rapid intervention to prevent complications [5]. Advanced medical technology in PICU offers a number of invasive and noninvasive options that can trigger an early warning of rapid deterioration or provide feedback about the response to treatment. For example, monitoring hemodynamic parameters are valuable for managing poisoned patients with hypotension, volume depletion, or respiratory failure from acute lung injury (ALI). Most importantly, clinicians need to recognize that no monitoring device improves clinical outcome unless is completed by a treatment.

Some antidotes and specific therapies are initiated in ED and continued in PICU, which is the most appropriate place to administer or continue treatment. In addition to conventional therapies, PICU's medical practitioners also know how to deal with situations that do not look like treatment protocols. For example, high doses of atropine, like hundreds of milligrams, can be used to treat organophosphate insecticides [5, 10]. Sometimes the antidote has less effect than the toxin. For example, opioid-intoxicated coma patients responding to naloxone are rapidly recovering. But these patients should be closely monitored for rejoining their coma, and in this situation, the antidote should be repeated. A surveillance period of at least 2 h after the last dose of naloxone is required to assert that the risk of recurrence of toxicity has passed [11].

Pulse oximetry is the recommended method to detect the presence of hypoxemia and to guide the administration of oxygen. Gasometry is a more accurate method for highlighting hypoxemia [4].

#### **4. The poisoning effects on specific organ systems**

#### **4.1 Acute respiratory failure**

 Acute respiratory failure is a common condition for children with various intoxications to come into the PICU. Respiratory failure occurs due to central hypoventilation, central nervous system depression, by the poisoning of central nervous system

 depressants (barbiturates, opiates, alcohol, and tranquilizers), intoxication with organophosphate compounds, alkaloids, and atropine. Respiratory muscular paralysis is another mechanism encountered in hemlock poisoning (*Conium maculatum*) and organophosphate. Mechanical ventilation disorders may occur during toxic seizures [12, 13]. Airway obstruction through laryngeal edema is another mechanism of acute respiratory failure encountered in poisoning with corrosive or toxic acidic and toxic bases that cause anaphylactic shock, and obstruction through hypersecretion may occur in intoxication with sympathomimetic substances or organophosphate compounds. Acute toxic respiratory failure may also occur with acute pulmonary edema in alpha-naphthylthiourea (ANTU) intoxications, organophosphate compounds, chlorine, carbon monoxide, ammonia, or hydrogen sulfide. Decreasing oxygenation capacity is another mechanism that can be produced by hemolysis in poisoning with saponin-containing plants or by methemoglobinemia or carboxyhemoglobinemia in nitrite/nitrate intoxication and carbon monoxide intoxication, respectively. The last mechanism consists in altering the oxidative tissue metabolism by inhibiting oxidative systems (cytochromes, cytochromoxidase) that may occur in cyanide, hydrogen sulfide, opaque, or fluorine intoxications [14].

As for the diagnosis of acute toxic respiratory insufficiency, in the initial phase, the signs and symptoms of background intoxication are highlighted. Once the respiratory failure has occurred, its symptoms, which are generally circumscribed to the pathophysiological mechanisms involved, become evident. In acute respiratory failure (ARF) from CNS disorders, consciousness status can be abolished and respiratory movements diminished in amplitude and frequency. The symptoms of ARF by affecting the resilient muscles are dominated by generalized muscular asthenia and dyspnea, and in the ARF by pulmonary damage, the tachypnea is more common. The clinical signs associated with hypercapnia and hypoxia in comatose patients are psychomotor agitation, dyspnea, and cyanosis [4]. However, the severity of cyanosis does not adequately reflect the severity of respiratory insufficiency. Increased intracranial pressure due to cerebral vasodilatation may result in cerebral edema, causing headache, obtundation, and even coma.

Blood gas analysis may reveal respiratory acidosis (pH < 7.35 and PaCO2 > 45 mmHg), which can be partially compensated by lowering the alkaline reserve and, in the absence of oxygen therapy, decreasing PaCO₂. A serious form of acute respiratory failure is acute respiratory distress syndrome (ARDS) manifested by bilateral pulmonary infiltration on radiography, PaO2/FiO2 ratio (partial oxygen pressure in arterial blood/oxygen fraction in the inspired air) below 200 mmHg and hemodynamic parameters within normal limits [12].

Corticosteroids and antibiotics may be used for the prophylactic purposes. Corticosteroids have been used for many toxic inhalational injuries. The prophylactic treatment of patients with inhalation injury with antibiotics has a empirical support [14, 15]. Essential therapy aims to ensure adequate blood oxygenation. Ensuring the ventilatory support should be seen in dynamics. Thus, ventilatory support begins with the least invasive supportive methods and progresses to the most aggressive techniques; you must minimize risks such as pneumothorax [16]. Oxygen supplementation is indicated for patients with suspected or confirmed respiratory failure.

 Approximately 10% of children admitted to the PICU for poisoning may require endotracheal intubation [6]. After the decision for mechanical ventilation has been made, the route needs to be selected. Some experts prefer oral intubation because it allows the use of a larger endotracheal tube—usually 8 mm or more in adults—than nasal intubation [17]. A wide range of equipment is necessary to allow for a wide range of patient size. A selection of both straight and curved blades should be available. Capnography should be available to assist the endotracheal tube placement in the airway.

*Poisoning in the Pediatric Intensive Care Unit DOI: http://dx.doi.org/10.5772/intechopen.83573* 

The goal of mechanical ventilation is to provide a sufficient exchange of oxygen and carbon dioxide and the metabolic needs of a patient to be accomplished with minimum adverse effects [4]. The purpose of mechanical ventilation is not always to achieve the normal blood gas concentration. Given the predisposition to hypoventilation and the risk of acute pulmonary edema, the mechanical ventilation of patients intoxicated with salicylates requires a lot of attention [18, 19]. Highfrequency ventilation and ECMO should be considered to treat some severe intoxications, but there are limited reports on their use in pediatric toxicology [4, 20].

 Noninvasive ventilation refers to providing the ventilation support without an invasive artificial path (intubation or tracheostomy probe). Patient selection is made taking into account noninvasive ventilation indications and contraindications as well as predictive factors of success or failure. Before starting noninvasive ventilation, a plan should be established to be applied if therapy fails. Noninvasive ventilation can be done with either portable CPAP or BiPAP devices that can also be used for home ventilation with either intensive ventilation or portable ventilation. One of the common causes of failure of noninvasive ventilation is the large air loss around to the ventilation mask [21].

#### **4.2 Neurological complications**

These are often the most prevalent symptoms in accidental or voluntary poisonings. Acute voluntary poisonings often involve psychotropic drugs (anxiolytichypnotic, antidepressant, antipsychotic, etc.) or ethanol, whose central toxic target is the central nervous system. If the alteration of consciousness is a frequent complication of poisoning, mortality directly attributable to neurological impairment is small compared to other etiologies (traumatic, vascular, etc.). Alteration of consciousness is most often due to a functional and reversible nature. It results from an interaction with one or more essential neurotransmitters (gamma-acidobutyric acid, serotonin, dopamine, etc.). However, lesional damage remains possible in case of exposure to a toxicant that prevents oxygen cellular use (e.g., carbon monoxide), when late detection or cardiopulmonary resuscitation complications cause anoxic or ischemic brain injury and ultimately neurovascular lesions [4, 22].

#### *4.2.1 Acute alteration of consciousness*

This is one of the most common pediatric emergencies. Its most serious form, coma, is one of the most critical situations faced by a doctor. Child coma occurs on an immature and fragile brain. In all cases of coma under the age of 7 years (including accidental poisoning), there is a risk that child's natural development achievements process will be compromised because the damage to the nervous system occurs during the full development process [23, 24]. The central nervous system (CNS), due to its rich lipid content and abundant vascularization is frequently the target organ for many toxic and nontoxic drugs. In intoxications, coma may occur due to direct toxic effects, metabolic abnormalities, or toxic-induced anoxia [25, 26].

The frequency of toxic coma varies in different studies, from 5% [26] to 28.9% [27]. In a recent prospective observational study, they accounted for 11.5% of all nontraumatic coma [28].

#### *4.2.1.1 Anamnestic and clinical diagnosis of toxic comas*

The toxic etiology of a coma must be raised in any patient who presents a severe deterioration of consciousness, without another obvious cause. In the absence of seizures, the patient often progresses to coma passing through the stages of

lethargy, confusion, and stupor. A carefully conducted anamnesis, taken from the caregivers, can sometimes indicate a poisoning. The child's age can provide important information. Small children are prone to accidental poisoning, and in this situation, questioning the caregivers about toxic substances found in the house may be useful. Adolescents tend to experience alcohol, psychoactive substances, or recreational drugs. In the absence of an obvious history, toxicological exams need to be conducted in serum and urine [29, 30].

The physical examination can also provide clues about a possible intoxication. Thus, a careful examination of the teguments may reveal signs of venous punctures suggesting a drug self-injection, including heroin. Sclero-tegumentary jaundice may be highlighted, suggesting a hepatic failure of a toxic cause that has evolved into a coma. Epistaxis may exist in snorting cocaine. The presence of head lesions should alert the doctor about the possibility of a possible simultaneous cranial trauma [31]. The vital signs are also important for orientation toward a toxic etiology. For example, benzodiazepines and opiates often cause respiratory depression. Amphetamines and cocaine can cause hypertension and tachyarrhythmias. Drugs that affect the autonomic nervous system may induce hyperthermia, vasoconstriction or vasodilatation, and heart rhythm disorders [32].

Neurological examination is very important for the diagnosis (**Figure 1**). Evaluation of the coma is important in unconscious patients (**Table 1**). The general characteristics of toxic coma are the absence of meningeal signs and neurological focal signs, unless hypoglycemia is involved. During neurological examination, the plantar, deep tendon reflex, and muscle tone must be examined. Depending on the changes found, one of the following three syndromes can be outlined: pyramidal, extrapyramidal, or myorelaxation, which may indicate the toxins involved in inducing coma.

#### **Figure 1.**

*Neurological examination of the patient with toxic coma [33].* 


#### *Poisoning in the Pediatric Intensive Care Unit DOI: http://dx.doi.org/10.5772/intechopen.83573*

#### **Table 1.**

*Modified Glasgow coma scale for infants and children.* 

Eye exams are essential for the toxic etiology. The type of coma associated with pupillary response may also suggest the toxin responsible for the coma appearance [33–35] (**Figure 1**). Periodic movement type "ping-pong" has been described in poisoning with monoamine oxidase inhibitors [34]. Hyperthermia is part of the anticholinergic syndrome; when associated with neurological disorders and toxic ingestion is not evident, then it is necessary to search for a *cerebromeningeal* infectious cause [31]. A convulsive coma may occur in the evolution of a poisoning with tricyclic antidepressants, phenothiazines, antihistamines, lithium, theophylline, carbamazepine, dextropropoxyphene, amphetamines, cocaine, and hypoglycemic substances [35]. Coma associated with hemodynamic disorders can be found in meprobamate poisoning, membrane stabilizers, calcium inhibitors, or beta-blockers [4]. Detecting some breathing disorders associated with coma may be suggestive of some toxics. Decreased respiratory rate below 12 breaths/min, with regular breathing, indicates opioids or sedative hypnotics. Some sympathomimetic agents (salicylates, amphetamines, CO) on the contrary stimulate breathing, causing tachypnea. Kussmaul-type breathing (high frequency, regular) is usually associated with metabolic acidosis from poisonings with ethylene glycol, methanol, or salicylates [36, 37].

#### *4.2.1.2 Laboratory investigations*

Useful investigations into a toxic coma are mainly in serum determinations and much less often in neuroimaging investigations. Any metabolic acidosis in a toxic coma requires further investigation. The presence of low anionic gap suggests lithium or bromine intoxication. Highlighting an osmolar gap usually indicates a poisoning with ethanol, isopropanol, methanol, or ethylene glycol. Pure respiratory acidosis is consistent with hypoventilation, possibly a sign of poisoning with

hypnotic sedatives or opioids. Although urinary toxicological tests may sometimes be useful in a toxic coma, the results are often false positive or false negative [24, 25].

Dosage of serum concentrations of some drugs is of great help, if available. Other useful investigations are the dosage of serum cholinesterases and carboxyhemoglobin. Coma caused by tricyclic antidepressants poisoning may be accompanied by electrocardiographic abnormalities (dysrhythmia) and seizures [38].

#### *4.2.1.3 Treatment*

The main life threat in toxic coma is the alteration of respiratory function. Therefore, maintaining airway permeability and ensuring effective breathing are a priority, because providing the O2 requirement of the brain is essential. In any suspicion of hypoxia or CO intoxication, O2 should be administered [32]. Not every child in a toxic coma should be intubated. It is estimated that orotracheal intubation is required in about 20% of toxic coma. The main indications are coma with alteration of swallow reflexes, acute respiratory failure unresponsive to O2 administration, severe circulatory insufficiency or toxic comas associated with severe symptoms, refractory to pharmacological treatment (convulsions, hyperthermia) [33].

Glycemia should be measured as a matter of urgency, and if there is hypoglycemia, this must be quickly rectified. Activated charcoal gastrointestinal decontamination can sometimes provide benefits, if done early. Gastric lavage can be performed if the patient has the respiratory tract protected by endotracheal tube. If the toxic is adsorbed on the activated charcoal, it can be administered by nasogastric tube. There is a lot of attention needed when administered to non-intubated patients. Hemodynamic instability induced by toxic shock, which may be hypovolemic, distributive, or cardiogenic, requires vascular filling with saline or Ringer's solution, injected quickly and possibly vasopressor medication. Any detected heart rhythm disorders and hypertension or hypotension need to be corrected. Simultaneously with the stabilization measures, the antidote will be administered according to the protocols in toxic-induced coma [25].

In comas of unknown etiology, the concept of "coma cocktail" containing dextrose, oxygen, naloxone, and thiamine (vitamin B1) was proposed. But indications and efficiency were controversial.

Currently, in toxic comas, precise indications for flumazenil and naloxone are used. Flumazenil acts by a competitive mechanism at the benzodiazepine receptor level, canceling the sedation effects of benzodiazepines within 1–2 min of administration. In the case of children, we start with a dose of 0.01 mg/kg intravenously, which can be repeated 1–2 min to a total dose of 0.05 mg/kg maximum 1 mg. It is effective in toxic-induced coma by zolpidem and zopiclone. If in a calm coma of undetermined etiology, there is no patient awakening after the administration of flumazenil referred to dose, the diagnosis of intoxication with benzodiazepines is infirmed [39]. Naloxone is a pure opioid antagonist, which acts by competitive antagonism at μ receptors to determine the reversibility of respiratory depression, hypotension, and miotic within 2 min. For children >3 years, the indicated dose is 0.01–0.1 mg/kg. If the desired effect is obtained, it may be repeated two times at an interval of 5 min; the dose may reach 10 mg. Regardless of the way of administration (intravenous, subcutaneous, intramuscular, endotracheal intubation probe, or inhalation), the effect is similar. The lack of response within 15 min after administration requires looking for another coma cause [4, 5].

Extrarenal epuration may sometimes have indications in coma due to alcohol intoxications (ethylene glycol, isopropyl alcohol, and methanol), salicylates, theophylline, lithium, valproic acid, carbamazepine, or carbamates [40].

#### *4.2.1.4 Prognosis*

The prognosis of toxic coma is generally better than that of anoxic coma. For example, in sedative poisoning, mortality is below 1%. The following neurological signs provide a poor prognosis for recovery from toxic coma: absence of corneal reflexes after day 1, absence of eye opening response on day 3, loss of pupillary reflexes (up to 1 week), lack of oculovestibular response, abnormal skeletal muscle tonus, the absence of spontaneous eye movement, the isoelectric pathway on the electroencephalogram [25].

Some toxic may cause prolonged coma (>100 h) with intermittent agitation periods known as cyclic coma: barbiturates, carbamazepine, clonazepam, ethchlorvynol, glutethimide, meprobamate, olanzapine, quetiapine. Short-term memory alteration and postcoma amnesia are possible, secondary to neuron damage in the pyramidal system at the hippocampus level in CO intoxication [25, 38].

#### *4.2.2. Convulsions*

 Convulsions are common in situations when the toxic involved affects the central nervous system. In the context of poisoning, seizures are often a sign of severity [41]. From the clinical point of view, toxic-induced convulsions can occur with or without warning signs (e.g., aura) or mental state alteration. Most toxic-induced seizures are generalized, tonic–clonic ("grand mal"). Epileptic status is defined as a continuous convulsive activity lasting more than 30 min or more convulsive episodes between which consciousness is not completely regained [4, 5, 42]. Patients with preexisting epileptogenic focal conditions may experience focal seizures [42].

#### *4.2.2.1 Etiology of toxic seizures*

**Table 2** presents the etiology of toxic seizures.

#### *4.2.2.2 Treatment of toxic seizures*

Seizure control in PICU is a fundamental problem in the management of a poisoned child. Convulsions associated with toxic ingestion are sometimes difficult to control, being recurrent or persistent leading to status epileptics. This is associated with an increase in oxygen in the brain level. The imbalance between supply and demand can lead to cerebral ischemia. That is why an aggressive management of toxic seizures is critical to preventing brain damage. The first priority in managing seizure crises is to provide airway permeability and oxygen therapy to ensure delivery of oxygen to the brain. Evaluation and correction of electrolyte disturbances and hypoglycemia should also be promptly performed [4, 43]. The first therapeutic line for toxic-induced convulsions is represented by benzodiazepines (diazepam, lorazepam, or midazolam). Lorazepam and diazepam exhibit a similar clinical response time (until termination of seizure activity) [41, 42]. However, after treatment with lorazepam, the rate of seizure recurrence appears to be lower [44]. Also, according to some studies, lorazepam has been shown to have a longer duration of action of the anticonvulsant effect (12–24 h vs. 15–30 min) and is therefore the preferred choice of some clinicians [42]. The preferred route of administration of benzodiazepines is intravenous. **Table 3** lists the doses of benzodiazepines that can be used in toxic-induced convulsions in children and adolescents.

In the absence of response to benzodiazepines, phenobarbital or valproic acid may be effective for crises control. Phenytoin is less effective in the treatment of induced seizures [42]. If seizures do not stop at the referred medication, it is


#### **Table 2.**

*Proconvulsant agents (adapted after Hanson [44]).* 

necessary to induce coma with sodium thiopental or propofol. To induce a coma, sodium thiopental is administered as a bolus of 3 mg/kg, which is repeated after 2 min, followed by maintenance with 1–15 mg/kg/h. For propofol, the dose is 1–5 mg/kg bolus (repeatable) followed by continuous infusion up to a maximum


#### **Table 3.**

*Posology of benzodiazepines in seizures in childhood (adapted after Blais and Dubé [41]).* 

of 5 mg/kg/h [45]. A special category of seizure, which does not respond to traditional therapy, is that of isoniazid intoxication. In this case, the crises result from exhaustion of pyridoxine (vitamin B6) and respond only to its administration [4]. In case of intoxication with isoniazid, the vitamin B6 posology is 1 gram per gram of ingested isoniazid (maximum 5 grams). This dose will be given slowly within 10 min, or until seizures cease. If the seizures stop during administration, the remaining dose will be given within the next 4 h. If the dose of isoniazid is unknown, 70 mg/kg iv (maximum 5 g) should be administered in the same manner. The initial dose may be repeated once seizures relapse. Pyridoxine is also anticonvulsant therapy of choice in intoxication with gyromitra mushrooms in the dose of 25 mg/kg iv in 10 min and can be repeated in case of seizure recurrence [41].

#### **4.3 Cardiovascular disorders**

 These are a serious complication of some poisoning, requiring prompt monitoring and treatment. Assessing a poisoned child at risk of cardiovascular disease requires a detailed physical exam. In addition to cardiac volume and output evaluation, a series of laboratory tests must be performed: blood gases, electrolyte dosing, blood sugar, transaminases, and azote retention tests. In some cases, the serum level of the toxic substance can also be determined, which helps to assess the severity of intoxication and to support the therapeutic decision. Additional care management such as blood pressure measurement, electrocardiography, and echocardiography can also be useful to guide therapy in case of a poisoning accompanied by cardiovascular instability. Identification of a certain toxic can simplify the treatment through specific intervention. If the poison is unknown, the initial resuscitation consists in administration of intravenous fluids to maintain a proper intravascular volume [4, 5]. Rapid administration of 20 ml/kg bolus isotonic fluids, usually crystalloid (normal saline or Ringer's lactate) over 10–15 min, is used to restore intravascular volume. Additional fluid bolus may be required depending on the reassessment of intravascular volume [46]. However, the intravascular volume should be corrected cautiously, because too vigorous expansion may lead to fluid retention, liver enlargement, signs of pulmonary edema, jugular vein distension, or cardiomegaly, without improvement of vital signs and tissue perfusion. Positively inotropic agents are required in such patients. The cardiovascular disorders, which are present at the time, determine which inotropic agents and vasopressor drugs to choose.

Arrhythmia is a frequent complication in cardiovascular drug poisoning. Dysrhythmia may occur by direct affecting of the electrical conduction system of the heart, by changing the electrical membrane potential across the myocardial cell, or by indirect disturbance of the electrical conduction system through the nervous system or due to electrolytic and metabolic disorders, which affect the electrical activity of the heart.

#### *4.3.1 Bradyarrhythmias: etiology and treatment*

Bradyarrhythmias occur due to some toxic substances, which decrease the central nervous system influx or the chronotropic activity of the conduction system. Agents that can induce bradyarrhythmias are tricyclic antidepressants, α2-adrenergic agonists, β-adrenergic blockers, calcium channel blockers, cholinomimetics, digoxin, sedative hypnotics, organophosphorus and carbamates, plants containing cardiac glycosides, opioids, cocaine, organophosphorus, and carbamates [47].

Bradyarrhythmia due to ingestion of unknown toxic substance is managed with supportive treatment. Atropine or positive inotropic agents, such as epinephrine, are used to correct bradyarrhythmia. When the toxic agent is known, the aim of the therapy is to antagonize the toxic effects (e.g., calcium chloride is used to treat calcium channel blockers intoxication). Literature data showed that in poisoning with β-blocker, calcium channel blocker, and tricyclic antidepressant, glucagon may be used, given its positive inotropic and chronotropic effects. Glucagon dose in children is 0.03–0.15 mg/kg in 1–2 min bolus, followed by 0.07 mg/kg/h infusion or by repeated boluses in 5–10 min, as needed [48]. Other therapies that may be used in severe β-blocker and calcium channel blocker poisoning are hyperinsulinemia—euglycemia (HIE) and intravenous fat emulsion (IFE) [49]. In bradycardia mediated by vagal reflex, atropine is the treatment of choice. For unresponsive sinus bradycardia, as well as for junctional or ventricular bradyarrhythmias, isoproterenol may be used. Specific therapy should also be used (calcium in calcium channel blockers intoxication; digoxin antibodies in digoxin poisoning). Sodium bicarbonate is beneficial in tricyclic antidepressant poisoning. Concomitant correction of electrolyte disturbances, hypoxia, and acidosis is mandatory because they may contribute to failure of pacing stimulus to depolarize cardiac cells [47]. In severe cases of bradyarrhythmia or heart block unresponsive to pharmacological therapy, direct transthoracic pacing may be necessary.

#### *4.3.2 Tachyarrhythmias*

Tachyarrhythmias are common in poisonings. They are classified as widecomplex and narrow-complex rhythm (**Tables 4** and **5**).

Electrocardiogram (ECG) in narrow-complex tachyarrhythmias shows sinus tachycardia or supraventricular tachycardia (normal conduction).

Specific therapies include antidotes depending on xenobiotic. Treatment imposes corrections of hypotension, hypoxia, or electrolyte abnormalities and administration of esmolol or other short-acting beta-blocker for intractable tachycardia in the absence of hypotension or other signs of myocardial depression [4, 47].

ECG in wide-complex tachyarrhythmias may show ventricular tachycardia (VT) monomorphic or polymorphic, ventricular fibrillation (VF), ECG signs preceding

**Anticholinergic:** amantadine, antihistamines, atropine, belladonna, scopolamine, cyclic antidepressants, mushrooms (muscarine-containing, e.g., clitocybe dealbata), neuroleptics (thioridazines and mesoridazines also are membrane depressants), plants (e.g., Jimson weed)

**Sympathomimetic:** amphetamines and their congeners (e.g., ecstasy), caffeine, chloral hydrate, cocaine, ethanol, ephedrine and pseudoephedrine, lysergic acid diethylamide (LSD) and other hallucinogens, monoamine oxidase inhibitors, phencyclidine, scorpion or spider envenomation, sedative-hypnotic withdrawal, selective serotonin reuptake inhibitors, theophylline

**Cholinomimetic**: organophosphates

#### **Table 4.**

*Poisoning-induced narrow-complex tachyarrhythmias.* 

Antiarrhythmics (type Ia, Ic, III), antihistamines, arsenic, cardiac glycosides, cyclic antidepressants, carbamazepine, chloral hydrate

**Other toxic**: sodium fluoride, freon (and other fluorocarbon aerosols), hydrocarbon solvents, neuroleptics, propoxyphene, quinine, and related agents

#### **Table 5.**

*Poisoning-induced wide-complex tachyarrhythmias.* 

VF/VT, supraventricular tachyarrhythmias, prominent R wave lead AVR, rightward deviation of QRS axis, and QT prolongation [47].

Correction of possible hydroelectrolytic and acido-basic imbalance is required in treatment of toxic ventricular tachycardia. In monomorphic ventricular tachycardia, if the patient's condition is stable and there is no hemodynamic instability, chemical cardioversion with amiodarone 5 mg/kg iv, or procainamide 15 mg/kg iv or lidocaine 1 mg/kg bolus is first attempted. In wide QRS complex tachycardias, adenosine is not useful. If the chemical cardioversion has results, the drug will be administered by continuous intravenous infusion to avoid relapses. The IV infusion time will be decided along with the pediatric cardiologist. If the chemical cardioversion is ineffective, synchronized biphasic electrical cardioversion with 0.5–1 J/kg is needed [47, 50]. In polymorphic ventricular tachycardia with hemodynamic instability, the treatment is based on electrical cardioversion associated with magnesium. If magnesium sulfate is ineffective or bradyarrhythmias occur, isoproterenol IV may be useful. Hypokalemia can exacerbate ventricular tachycardia, and therefore, potassium supplementation is required even in patients with normal potassium at the time of determination.

Bidirectional ventricular tachycardia is a hallmark of severe digitalis toxicity, and immediate specific antidote treatment with FAB antibodies must be started. This type of ventricular tachycardia may occur in aconite poisoning too [51, 52].

 Torsades de pointes (TdP) is a specific type of polymorphic ventricular tachycardia exhibiting a characteristic morphology on the electrocardiogram, in which the QRS complexes "twist" around the isoelectric line. This is a major toxin-induced arrhythmia, which may degenerate into ventricular fibrillation and sudden death [53, 54]. In this situation, the corrections of electrolyte disorders, bradycardia, acidosis, low blood pressure, and hypoxia are needed. If poisoning involves a drug with Na+ channel blocking properties (e.g., tricyclic antiarrhythmic drugs, cocaine, class IA and IC antiarrhythmic drugs, or antipsychotic drugs), sodium bicarbonate may be used to reduce the degree of sodium channel blockade by increasing extracellular sodium [55]. The treatment of choice in torsade de pointes is magnesium sulfate. The pediatric dose is 25–50 mg/kg iv. If a poisoned patient does not respond to the abovementioned therapeutic measures, intravenous lipid emulsion therapy should be considered if the drug has lipophilic properties. A last therapeutic alternative is arteriovenous extracorporeal membrane oxygenation (ECMO) [47, 55].

#### **5. Techniques for extrarenal treatment in toxicology**

The Extracorporeal Treatments in Poisoning (EXTRIP) Workgroup is a group of international experts spanning disciplines of nephrology, toxicology, pediatrics, emergency medicine, critical care, and clinical pharmacologists that has been reviewing the evidence in the literature and provide recommendations for the use of extracorporeal treatments in poisonings. To date, EXTRIP has published systematic reviews on the role of extracorporeal treatment (ECTR) for poisoning from acetaminophen, barbiturates, carbamazepine, digoxin, lithium, metformin, methanol, salicylates, thallium, theophylline, tricyclic antidepressants, and valproic acid [56]. Waste treatment methods are

numerous, and techniques and/or equipment continuously evolve. It mainly involves hemodialysis, hemoperfusion, hemofiltration, and albumin dialysis [57].

#### **5.1 Hemodialysis**

Hemodialysis is the technique of removing toxins from the blood using a diffusion gradient through a semipermeable membrane. To be dialyzable, poisons must meet the following conditions: hydrosolubility, low molecular weight, apparent low volume of distribution, low protein binding, and low endogenous clearance [5]. It may be necessary in the following situations: severe poisoning with salicylates, accompanied by important mental disorders, in some phenobarbital intoxications, ethylene glycol, lithium, and theophylline [4, 6].

Possible complications of hemodialysis are hypotension, hypoxemia, bleeding, embolism, and cardiac rhythm disorders [4].

#### **5.2 Hemoperfusion**

 The hemoperfusion column can be considered as an extracorporeal clearance organ, increasing the overall clearance of the body. Its efficacy is superior to hemodialysis or hemofiltration. It has been proposed in serious poisonings with theophylline, carbamazepine, and cardiotoxic (membrane stabilizers, inhibitors calculation, and meprobamate) that do not quickly respond well to symptomatic treatment led. Its indication should be taken into account very early and in intoxications with some toxic lesions such as colchicine or paraquat [57]. Complications of hemoperfusion can be thrombocytopenia (30%), leukopenia (10%), hypocalcemia, hypoglycemia, reduction of fibrinogen, and hypothermia. The future lies in hemoperfusion devices coated with drug-specific antibodies or the antidote of the toxin instead of activated charcoal [58].

#### **5.3 Hemofiltration and hemodiafiltration**

Hemofiltration and hemodiafiltration have similar properties as hemodialysis regarding the distribution volume and protein-binding percentage. Water-like substances move out of the plasma through the membrane, and this fluid is replaced with isotonic fluids. The rate of removal of the toxin is influenced by the degree of protein binding and the ultrafiltration (UF) and the sieving coefficient, which is the ability of the solute to cross a membrane by convection. Although this makes high-efficiency convective techniques suitable for poisoning, reports of their use in poisoned patients remain limited due to their higher technical requirements and lesser availability [58, 59].

#### **5.4 Other purification techniques used in toxicology**

The most developed and most commonly used hepatic dialysis systems are the molecular adsorbent recirculation (MARS) and fractional plasma separation and absorption (Prometheus).

#### *5.4.1 MARS albumin dialysis*

MARS is a hemodialysis technique that combines the selective removal of albuminbound toxins with the removal of water-soluble toxins. The MARS system uses a 20% human albumin solution as a dialyzate and a semipermeable membrane as a dialyzer.

 The albumin acquires an increased ability to bind toxins through contact with membrane's polymers. Through the membrane, the patient's blood comes into

#### *Poisoning in the Pediatric Intensive Care Unit DOI: http://dx.doi.org/10.5772/intechopen.83573*

 contact with the albumin solution, and the albumin-related toxins cross the membrane and enter the dialyzate, the transfer being made in the sense of the existing concentration gradient between the blood compartment and the albumin solution. After detoxification, the albumin solution is recirculated, coming into contact with the patient's blood again [60–62]. Several small randomized controlled trials and case control studies in adults showed significant improvement, both in morbidity and mortality, in patients treated with MARS. However, there are little data on the use of MARS in the children [63].

#### *5.4.2 The Prometheus system*

It consists of a bloodstream where two filters perform a purification of watersoluble toxins and then a fractional separation of plasma, so that cellular components and macromolecules are separated by albumin and by low-molecular-weight solvents. Then, the autologous albumin solution crosses a neutral resin filter, which has an increased affinity for bile acids, aromatic amino acids, and phenols, and also an anion exchange resin filter that removes unconjugated bilirubin [64–66].

 These techniques were initially used in hepatology. Subsequently, they were also used for the treatment of acute poisonings with or without liver failure, especially the MARS technique. The aim is to remove albumin-related toxic substances. There are several reports regarding the use of these purification techniques in high liver toxicity mushrooms poisoning as *Amanita phalloides* [60, 62, 64] and also in paracetamol poisoning [56, 60]. These techniques were also used to treat phenytoin, theophylline, and diltiazem poisoning, and for calcium channel blockers poisoning too [57, 67].

#### *5.4.3 Arteriovenous extracorporeal membrane oxygenation (ECMO)*

ECMO is a special technique for maintaining pulmonary and cardiac function through an extracorporeal circulation pump. The purpose of this method is to provide a good oxygenation support and remove the excess of CO₂. It is an exceptional therapy proposed for serious poisonings, especially those that are complicated with respiratory distress syndrome or cardiogenic shock refractor on conventional therapy [68]. ECMO is difficult and should only be done in experienced centers as it carries significant risks. It is a method that requires systemic anticoagulation. The main possible complications are bleeding, systemic infection, and thromboembolic accidents [4, 68]. If the ECMO indication has been established, this therapy should be initiated as soon as possible, before irreversible cerebral or visceral anoxic lesions [68, 69].

#### **6. Organ donation**

Despite the best efforts of the care team, it is not possible to save every child with poisoning. Particularly, in cases where there was significant hypoxic–ischemic central nervous system injury, patient may progress to brain death [70]. Because poisoning is not a sign of organ donation, these patients can be a potential donor source [71]. Toxicological risk assessment should be rigorously conducted in the sense that the transmission of intoxication to the recipient should be avoided. Some toxic substances accumulate in the liver, heart, or lung and could theoretically be released from these grafts after transplantation. These risks, however, should not be exaggerated. They can be diminished by knowledge of kinetics and toxics in target organs. Taking risks is more important for heart or kidney transplantation, organs

that are more susceptible to anoxic-ischemic damage [4–6]. Since severe depression of the central nervous system induced by some toxic can mimic brain death, it is important to allow sufficient time, depending on the pharmacology of the toxic substance, until the plasma concentration decreases to an acceptable level. To declare cerebral death, the following are necessary [4, 72, 73]:

	- mandatory: flat track on the EEG, apnea test, atropine test;
	- optional: cerebral angiography (stroke), transcranial echo-Doppler, scintigraphy, etc.

The conditions for declaring brain death vary according to the country's legislation. Basically, the patient's examination should be performed by two physicians: neurologist or neurosurgeon and anesthetist. In children, the intervals between examinations must be 24 h for the child aged 2 months to 1 year and at least 12 h over 1 year [74].

#### **7. Conclusion**

Complications of poisonings during childhood may enforce hospitalization to PICU and may contribute to lowering the survival rate. Supporting vital functions is the main objective of the management of a poisoned patient admitted in PICU.

#### **Conflict of interest**

None.

#### **Author details**

 Nicolai Nistor, Otilia Frăsinariu\*, Aniela Rugină, Irina Mihaela Ciomaga and Violeta Ștreang<sup>ă</sup> Grigore T. Popa University of Medicine and Pharmacy, Iași, Romania

\*Address all correspondence to: otiliafrasinariu@gmail.com

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*Poisoning in the Pediatric Intensive Care Unit DOI: http://dx.doi.org/10.5772/intechopen.83573* 

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## **Chapter 3**  Forensic Toxicology

*Sahar Y. Issa* 

#### **Abstract**

 Forensic toxicology is a broad science that integrates principles and practices about toxicology and legal aspects, which occur in conjunction with medicolegal instances as with homicide, suicide, road traffic and other types of accident and/ or disasters. Nowadays, the practitioners of forensic toxicology science have to deal with three chief sections, namely: postmortem, drug testing, and human performance forensic toxicology. Postmortem forensic toxicology is dealing mostly with investigation of abnormal deaths, or when drug intoxication incidence is assumed as a cause of death and no abnormal findings were detected during autopsy.

**Keywords:** forensic toxicology, postmortem, workplace testing, drugs of abuse, adulteration

#### **1. Introduction**

Toxicology; is the study of the toxic effect of chemicals or xenobiotic on living organisms, particularly the humans, or animals. Toxicology involves studying the symptoms, mechanisms, detection and treatments of poisoning of a living body. Chemicals, or toxic agents, may be biological, physical, or chemical. As the toxicology and science are in a continuous evolving status, the familiarity to the effects of toxic agents on human body keeps progression and advancement [1].

 Toxicology is usually referred to as the "science of poisons," including the continuous study of all toxic effects of physical or chemicals compounds and the association between the causative defined dose and its effect on any exposed body [2].

Habitually, the toxicology is defined as the science representing the information, source, toxic or fatal effect, lethal dose determination, analysis of poisons and the curative methods used to treat any of such exposures [1].

#### **2. Some definitions**

 A poison is a chemical or substance that can induce damage or death when our bodies are exposed to, and it is only the optimum doses that can distinguish a poison from a therapeutic agent. All known chemicals can lead to cellular damage or death under certain circumstances and if they exceeded permissible or therapeutic ranges. Therefore, a poison can be defined as any substance capable of producing injurious effects in a living organism.

Toxicologists are the trained experts who can evaluate the role of toxic substances and their adverse effects on living organisms or environment [2, 3].

The broad spectrum of probable toxic adverse effects and the endless lists of chemicals existing in our environment, together make toxicology a very broad field of science. Consequently, many specialties of toxicology are needed to handle the numerous areas of toxicology science, including but not limited to; clinical, forensic, marine, and environmental toxicologists.

Forensics, by definition, is the use of science within the legal system to interpret a medical finding. The difference between clinical and forensic toxicology is not in the science or the methodologies used, but the difference lies in the end use of the attained results [4].

 In clinical toxicology, the end user is a physician using the findings to treat and care for an intoxicated or poisoned patient, while in forensic toxicology, the end user can be a physician, a non-medical professional such as a lawyer, an employee, or police officer using the results to interpret a cause of death, employment eligibility, or compliance with workforce laws and terms. Hence, based on such situation the toxicologist may be a Physician, pharmacist, scientist, laboratory specialist or technician [3].

#### **2.1 Main branches of toxicology**

 The professional activities of scientists and medical professionals within the field of toxicology fall into four main branches namely; forensic, industrial, clinical and environmental toxicology. Forensic toxicology is mainly concerned with the determination of the presence or absence and role of alcohol, drugs and their metabolites as well as other toxic substances in biological fluids, and/or tissues to solve a medico legal problem [5].

Based on that forensic toxicology is mainly referred to the science entailing the fusion of analytical forensic chemistry with toxicological principles and effects, dealing toxic substances, drugs of abuse, doping agents, chemical warfare agents, and their metabolisms and analyses, which are related to laws and ethics. Scientists responsible for testing bodily fluids and tissue samples during autopsies looking for the presence of chemicals, as well as laboratory specialists concerned with determination of presence or absence of any recreational drug or substance in samples collected from employees, or sportsmen are usually referred to as forensic toxicologists. Such toxicologists work mainly in laboratories to perform tests on samples collected by crime scene investigators, or workplace or sport officers [2–4].

Forensic toxicology laboratories handle the analytical procedures performed on both biological and sometimes non-biological samples to search for controlled substances. Following that, they generate analysis reports requested by the criminal justice system, or workforce departments. All Forensic Toxicology providers should exert sound efforts to guarantee that all their analytical results meet high ethical and moral standards and that all working personnel adhere to relevant legislation of the country [1].

The forensic toxicology laboratory should have standard operating procedures (SOPs) that are complete, updated, and accessible to all toxicologists carrying out forensic toxicology tests. SOPs should include detailed descriptions of all procedural processes starting from sample receiving, fulfillment of secured chain of custody, analysis, quality assurance and quality control (including validation of methods), reviewing of data, reporting and sample disposal as well as electronic program usage and security protocols of such programs if any. Their performance should be thoroughly and periodically assessed to accept the results released by their laboratories [3].

Forensic toxicology jobs most of the time involve testing for the presence of toxic gases (e.g., carbon monoxide, hydrogen sulfide, or phosphine); illegal or medicinal drugs; toxins; liquor; metals or elements; and other toxic substances when intoxication or drug poisoning are anticipated. Their scope of responsibility may include

#### *Forensic Toxicology DOI: http://dx.doi.org/10.5772/intechopen.82869*

analyzing samples from criminal cases, and once their analytical reports are ready, they might present their testimony about it in a court of law [4].

 Using highly specialized tests, methodologies and state-of-the-art equipment, chemical and biomedical instrumentation and chemical reagents, forensic toxicologists are requested to determine either the presence or the absence of chemicals while documenting each step of the process, and to determine the concentration of any detected substance to help finding out whether or not such xenobiotic was a cause of an unexplained death, accident or act [5].

The majority of forensic toxicologists are employed by law enforcement agencies, private drug testing facilities, and governmental bodies as Ministry of health in some countries. In forensic toxicology the main interest is the extent to which drugs and poisons may have contributed to impairment or death. In the field of forensic toxicology, the accreditation is important. It requires a great deal of energy and expense but does not, however, warranty all of the quality levels needed.

The conformity of a forensic toxicology laboratory with acknowledged quality and management structures is currently mandated in many countries, to be able to accept their analytical results and reports. As there are an essentially unlimited number of poisons that may be present in individual cases, therefore forensic toxicology is a scientific discipline in which everlasting efforts should be constantly exerted to complete and improve the methods of poison detection and show its close relation to raising quality [4–6].

Forensic toxicology can hence be generally divided into three main sectors [2–4]:


 Therefore, the work of forensic toxicologist is considered as highly complicated as small quantities of poisons and their metabolites are to be isolated, purified and quantified from a highly complex matrix. Individual Forensic Toxicology specimens should be handled in such a manner as to reduce the possibility of degradation, contamination, adulteration, and/or damage during all steps from collection to transport, analysis and finally result reporting. Conventional transportation of specimens to the toxicology laboratory might include manual delivery, postal shipments, or a private courier service. A chain-of-custody form should be designed that will accompany specimens from the place of collection to the laboratory [7].

#### **3. Workplace drug testing**

Workplace drug testing is divided into two divisions, regulated and nonregulated testing:


#### **3.1 Samples used for screening in workplace testing**

#### *3.1.1 Urine sample*

The specimen for regulated workplace testing is always urine, but in some countries, an additional sample is requested, which might be oral fluid sample, or blood sample. It must be collected under direct observation or with measures in place so that tampering with the collection are eliminated, as by using adulteration detection kits directly after sample collection by donor, where the samples proved to be adulterated are rejected before being received by the laboratory personnel.

Secured chain of custody is applied for all samples collected since their collection till the release of the final Analytical report [7].

#### *3.1.2 Blood sample*

Blood sample is of particularly useful to the forensic toxicologists since the drug or poison existence in blood shows that exposure followed by absorption has taken place, hence a recent exposure might be ascertained. Furthermore, significant associations exist between the blood levels of most chemicals, poisons or drugs and their pharmacological and/or behavioral effects exerted on living bodies. On the other hand, urine drug levels, only indicate a previous drug exposure without conclusive evidence about the exact time of possible exposure or its probable physiological effects [4].

#### *3.1.3 Oral fluid sample*

Oral fluid is getting recent credit as a standard matrix for rapid drugs or substances of abuse detection. When compared to blood and urine samples, the oral fluid collection is non-invasive, easy technique with negligible intrusion into personal privacy. Such a sample can be collected under direct observation, consequently excluding the likelihood of sample exchange or adulteration as seen with urine samples. Hence, oral fluid can be beneficial in numerous situations that necessitate drug testing, as workplace screening, drug monitoring follow up, or for definitive treatment [2–4].

 When compared to urine samples, oral fluid is a better reflection of blood concentrations of a drug. It specifies recent drug use and offers better association with pharmacological effects such as impaired driving performance. Hence, recently it is considered as the most appropriate biological matrix that enables roadside testing in

#### *Forensic Toxicology DOI: http://dx.doi.org/10.5772/intechopen.82869*

road traffic accidents or other situations mandating the diagnosis of driving under the influence of drugs or alcohol.

It is becoming a more accepted testing specimen, due to the ease of its collection. Being an ideal specimen to collect where a restroom is not available, such as at the scene of a traffic accident, popularity of using oral fluid sample is increasing by time. As oral fluid is a hyper filtrate of blood, parent compounds are detected opposed to metabolites. Detection lengths are thus shorter than in urine, being only 1–2 days compared with 2–5 days with urine [7].

#### *3.1.4 Hair samples*

Hair is an alternative sample type that can be used for drug testing. The main advantage over the other samples is the wider length of detection, as in hair it might reach up to 3 months. However, environmental contamination is a major concern with hair testing, so laboratories must take special precautions during specimen preparations to ensure removal of environmental contamination.

#### *3.1.5 Human breath testing*

 Lastly, another biological sample that has established recognition in many global areas in forensic toxicology testing is human breath. It is usually sampled for the detection and estimation of blood alcohol concentration in an individual and the detected level will be compared with the legal level of each country for driving under the effect of alcohol and other driving related offenses. It may also be sampled for the presence or absence of inhalants, most of which are volatile organic solvents that are not easily detected in blood, that are getting more abused among youths and adolescents [1–5].

#### **3.2 Urine sample adulteration**

Specific precautions are required to determine if the specimen has been tampered with or adulterated in any way. All urine samples should be tested for creatinine, specific gravity, pH, and oxidants (nitrites).

 When specimen adulteration testing falls out of the specified ranges of what is considered normal, it is termed as one of four classes, namely; diluted, substituted, adulterated, or invalid.

#### *3.2.1 Diluted sample*

A substituted specimen will be identified if [2–7]:


#### *3.2.2 Substituted sample*

Substituted sample is generally applied to non-human samples submitted by the donor during testing process. Any sample will be reported as substituted one if:


#### *3.2.3 Adulterated sample*

 If the donor has added any substance to the collected sample, this will be referred to as an adulterated sample. Such sample should be reported as adulterated when any of the following criteria is encountered:

• pH < 3


#### *3.2.4 Invalid sample*

A specimen will be reported as invalid when any of the following conditions is met:


#### **4. Postmortem testing**

 Analytical toxicology is a main procedure following the autopsy process. In postmortem setting and directly after death, metabolism of drugs and chemicals cease. If an autopsy is performed within a reasonable time frame, and the body was protected from harsh environmental conditions, the toxicology results will be as close as possible to what was in the body directly at the time of death. Quantitation of any drugs can indicate if an overdose occurred, a sub-therapeutic drug level was present, or a combination of multiple substances contributed to the cause of death [8].

In contrast to workplace drug testing, where urine samples are usually analyzed for a relatively fewer drugs and/or drug metabolites, the scope of work in postmortem forensic toxicology often encompasses search analysis for a larger number of

#### *Forensic Toxicology DOI: http://dx.doi.org/10.5772/intechopen.82869*

poisons and drugs in numerous altered samples including blood, gastric contents, vitreous, and tissues including; renal, liver, spleen, muscle and brain tissues [5].

In addition, analysis of blood is mostly noteworthy as lethal drug concentrations in blood are well known for most of the drugs. However, drug concentrations in blood are generally lower than in urine or in tissues, which make their detection much harder than in urine samples [3, 5].

In many occasions, the forensic pathologist is dependent on the toxicological results to offer aid in determination of the cause of death. This is usually the situation when either gross or microscopic examinations during the autopsy process do not interpret a cause of death [9].

The forensic pathologists' requests of the forensic toxicologist have transformed over the last years. Before, they mainly requested identifying and reporting any lethal drug and/or poison levels that eventually lead to death. Definitely, due to the obvious limitations in the methods available at that time, this was the only possible request [10].

Accordingly, many drug-related deaths before were probably pass unobserved. But in modern times, larger scope of results and interpretations were requested from forensic toxicologists to clarify, including reporting drugs given at therapeutic or even sub therapeutic doses.

Such contribution might help to determine whether the deceased was compliant in taking the prescribed medicine. Many questions can be easily answered by toxicologists in current years as finding out whether noncompliance contributed to the death occurrence or not, or did the simultaneous use of many groups of medication together at therapeutic doses lead to unwanted drug interactions.

Another common question encountered by forensic pathologists is to clarify whether or not the deceased was under the effect of drugs at the time of the fatal accident, or was the suspect of the homicide under the influence of illegal drugs. Nowadays, such queries can best be easily answered by forensic toxicology laboratories equipped with state-of-the-art chromatographic instruments attached to mass spectroscopic units [1–3, 5].

#### **4.1 Specimen**

 Postmortem testing is not limited to only urine. Specimens can be blood, urine, vitreous humor, gastric contents, liver tissue, hair, fingernails, or bile. This is not a comprehensive list. In postmortem investigations, the types of samples and tissue specimens and fluids needed for toxicological investigation are based often on the body condition and the type and/or number of analytes that must be identified and hence quantified. The toxicologist should also be informed about any putrefactive state of the body, injuries owing to the manner of death and other autopsy findings [3].

 Many deaths involve ingestion of multiple drugs, necessitating larger amounts of tissue and fluids to be collected at post-mortem examination for toxicological examination. Prior to tissue extraction and analysis, all analyzed tissues must be homogenized. Water or buffer solutions such as sodium phosphate, might be added to the tissue sample preceding homogenization. It is vital to record the tissue weight as well as the fluid volume used to homogenize tissues in, as such data is of utmost importance in correctly estimate the drug concentration per each tissue weight unit [10].

Effective sample extraction and non-contamination are additional analytical process challenges while dealing with postmortem samples collected from decomposed bodies. Decomposition Products, can diminish the efficacy of extraction and produce interfering peaks during the analytical processes using chromatography methods. Also, tissue homogenates containing fatty materials must be separated from the drug analytes prior to analysis [1–3].

 Basic drugs can be efficiently separated from lipid material by a process known as back-extraction, where the extracted drug from the tissue homogenate into a waterimmiscible organic solvent and then back-extracted into a dilute acid solution where the neutral lipid material remains in the immiscible organic solvent, and the dilute acid solution will be turned basic to re-extracted the drug again into an organic solvent [1–3, 5].

 All items collected from the death scene such as powders, pills, syringes, tools or liquids must be sent for analysis as well. A precise report including full description of the sample type and the site of collection should be prepared and sent to the laboratory with the samples needed to be analyzed. Blood samples can be collected from different body parts, as each area or collection compartment can have a varying drug concentration. Central blood samples can be collected from the heart, jugular, subclavian, and femoral veins, while blood collected from other sites is called peripheral compartment blood [2].

 Preferably, blood samples must be collected from central and at least one peripheral site, to overcome the probability that any of these sites might be contaminated owing to different death manners. Blood is usually collected into preservative treated tubes, to stop further blood sample decomposition. Another important factor is that most of collected specimens are often stored for extended time periods. Samples' states might be deteriorated by bacteria, which might give erroneous results' interpretation mainly for ethanol levels. Based on putrefactive state and manner of death, certain specimens may become contaminated with bacteria, either via exposure to the normal flora or through external contamination, as in case of a body with multiple open wounds or gunshots. The collection of specimens as well as the testing of these samples should always be performed under chain of custody. Postmortem blood is difficult to work with as a result of coagulation and/or degradation, and because of the state of the specimen at the time of testing [11].

#### **4.2 Specimen type, amount and site of collection**

The following is a suggested list of specimens and amounts to be collected at post-mortem in such cases [3–6, 9]:


#### **5. Human performance testing**

 How an individual acts when under the effect of a substance or drug of abuse is determined by human performance testing. This type of testing includes determination of blood alcohol level and drugs of abuse testing from a suspected driver. Blood testing for drugs from a potential drug assisted sexual assault, or testing of a worker exhibiting weird behavior while at work is another aspect of human performance testing. Criminal Toxicology is another aspect of human performance testing, where the determining factors or toxicological causes during the investigation of any criminal offenses have to be studied [12].

#### **5.1 Specimen**

The specimen of choice in human performance testing is blood, though oral fluid sample is another promising sample. Analyzing a blood sample is of utmost importance because upon confirming the presence of any abused substance, it is then probable to establish an estimated time frame of drug or substance exposure. Such finding is not likely to be estimated upon using a urine sample, where all drugs have a much longer detection window. Ability to conclusively verify the timeframe of drug consumption, is crucial in all human performance testing settings [3].

#### **6. Types of testing in the field of forensic toxicology**

#### **6.1 Screening or initial testing**

Initial testing of collected specimens, is known as screening or screen testing. It is done by immunoassay methods. The cutoffs to determine negative from nonnegative samples are established by Governmental regulatory bodies in each country. Any value greater than or equal to the cutoff is considered "nonnegative" (The term positive can only be used with confirmatory testing because of the possibility of false-positive screening test). Screening testing is done for a specific class of drugs; opiates, amphetamines, benzodiazepines, etc.

If all performed initial screening tests were negative, the results will be released as negative and there is no further testing to be requested. If any of the performed test results were equal to or above the cutoff value, a new aliquot from the main sample will be obtained and confirmatory testing will be started.

The initial identification or detection of drugs and other toxins by an immunoassay or enzymatic screening methods should be confirmed by a second procedure utilizing a different analytical principle. It is to be well stated that the use of a second immunoassay screening system (e.g. RIA—radioimmunoassay) to confirm another immunoassay result (e.g. FPIA—fluorescence polarization immunoassay), is not acceptable, even if it is supposed to be a more specific assay or testing procedure. Final results are not released until all confirmatory results are finalized [13].

#### **6.2 Confirmatory testing**

 The forensic toxicologist is usually confronted with the hard mission of screening a given sample for the "unknown". The toxicology laboratory consequently must be equipped with state-of-the-art instruments, capable enough to perform a wide range of toxicological tests with high specificity. This procedure is usually referred to as "systematic toxicological analysis" (STA), or "general unknown screening".

All chemical substances exposed to screening procedures, must be firstly separated from the liquidified biological matrix. The simplest sample preparation method is to use a water miscible solvent, as acetonitrile or acetone. Such solvents will be added to the biological fluid to precipitate protein and other unwanted constituents. A filtration or centrifugation step follows before the extraction processes that end up with a more concentrated extract than the original sample, followed by the final confirmatory analytical step.

Confirmation testing is performed by detector as mass spectrometry, coupled either to Chromatography technique that provides a chemical separation of analytes in a gaseous (GC) or liquid (LC) system namely; gas chromatography or liquid chromatography. The selected detector should be appropriate to the analytes among other factors. The testing occurs on a fresh aliquot from the original sample, to exclude likelihood of a possible erroneously mix up with the initial screening aliquot [11].

For each drug class to be screened, there is a group of specific confirmatory tests. Such analytical confirmatory testing result is conclusive, and indisputable, when the testing process is performed correctly. Such an assurance is partly based on the fact that the confirmed result was reached based on multiple parameters, e.g.; retention times, parent and daughter ions ratios. If confirmatory testing procedure is performed correctly and properly maintained through applying proficiency testing with similar laboratories, the confirmation test is considered to be definitive and undisputable [9].

#### **7. Result reporting**

Reporting of the results is done following a second review of all results by another laboratory personnel who was not a part of the testing process. On finding them acceptable, all results will be certified and released either to the medical review officer or to the requesting entity [1–3].

 A medical review officer is usually a physician acting as an intermediary between the Toxicology laboratory and the requestor or client who ordered for the test. The medical review officer should be well trained to communicate with the client, donor, and legal representative and/or forensic pathologist to help interpreting the testing results. They are responsible to deal with a donor whose samples proved to be positive, and determine if the detected drug was taken complying with a physician's instructions or were recreationally abused [5–7].

Following the release of a final report, it might turn out to be essential to correct an error that might be typographical or otherwise. A corrected report should be issued in this occasion comprising the same demographic data as in the original report(s) and be well labeled as a corrected report replacing the original faulty one.

Forwarding samples to another laboratory for analysis or result evaluation, should be well recorded and referred to on the final report/statement demonstrating this fact. Results of referred laboratory tests may be integrated into the original laboratory's final report/statement, but the name of the laboratory that truly carried out the test should be clearly stated [1–4].

#### **8. Accreditation**

Forensic toxicology laboratory accreditation is an important recommendation to standardize the results. Proficiency testing and comparing results to certified regional laboratories is an initial step during the journey to laboratory accreditation [3, 5–8].

### **Conflict of interest**

No conflict or competing of interests to declare.

### **Thanks**

 "I have to start by thanking my awesome husband, Mohammed. From reading early drafts of my chapter to giving me advice on the scientific content to taking care of Yasmin and Yousef our young daughter and son so I could edit, he was as important to this book chapter getting done as I was. Thank you so much, dear."

"Thanks to everyone on the IntechOpen team who helped me so much. Special thanks to Martina Josavac, the ever-patient Author Service Manager for her great help."

### **Acronyms and abbreviations**


### **Author details**

Sahar Y. Issa Faculty of Medicine, Alexandria University, Egypt

\*Address all correspondence to: sahar\_issa71@yahoo.com

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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[4] Drug Enforcement Administration, Department of Justice. Schedules of controlled substances: Extension of temporary placement of UR-144, XLR11, and AKB48 in schedule I of the Controlled Substances Act. Final order. Federal Register. 2015;**80**(94):27854-27856

[5] Jones JT. Advances in drug testing for substance abuse alternative programs. Journal of Nursing Regulation. 2016;**6**(4):62-67

[6] Elliott SP, Stephen DWS, Paterson S. The United Kingdom and Ireland association of forensic toxicologists forensic toxicology laboratory guidelines. Science & Justice. Sep 2018;**58**(5):335-345

[7] US Department of Health and Human Services, Substance Abuse and Mental Health Services Administration. Medical Review Officer Manual for Federal Agency Workplace Drug Testing Programs. Rockville (MD): Substance Abuse and Mental Health Services Administration; 2010

[8] Levine B. Postmortem forensic toxicology. In: Levine B, editor. Principles of Forensic Toxicology. 3rd ed. Washington, DC: AACC Press; 2009. pp. 3-13

[9] Committee on Identifying the Needs of the Forensic Sciences Community, National Research Council. Strengthening Forensic Science in the United States: A Path Forward. Washington (DC): National Academies Press; 2009

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## Section 2
