Ingestion
Patrick George Minges and Robert W. Shaffer
Introduction
Tricyclic antidepressant (TCA) overdoses have become less common over the last 20 years as their overall use has decreased with the advent of safer and more effective antidepressants. Despite their declining popularity in the management of depression, they continue to be used clinically for conditions including the management of neuro- pathic and chronic pain, cyclic vomiting, noctur- nal enuresis, OCD and ADHD. These medications continue to be a leading cause of mortality from intentional ingestions, and account for nearly half of all antidepressant-related deaths [1]. Common tricyclic antidepressants in use today include amitriptyline, nortriptyline, imipramine, desipra- mine and doxepin.
The management of tricyclic antidepressant poisonings can be quite challenging. Since they exert their toxicity through several different mechanisms an understanding of their pharmacol- ogy is imperative. TCAs all have inherent anti- cholinergic effects that may cause tachycardia,
altered mental status and seizures. They can cause profound hypotension through alpha- adrenergic blockade as well as catecholamine depletion through reuptake inhibition. Finally, they block fast sodium channels in the cardiac conduction system leading to myocardial depression and ven- tricular arrhythmias [2].
Successful treatment of patients poisoned by tricyclic antidepressants hinges on prompt diag- nosis and recognition of the classic EKG findings associated with their toxicity. GI decontamina- tion should be considered when patients present within the first 1–2 h following an overdose.
Serum alkalinization with sodium bicarbonate is considered the first-line treatment when signs of cardiotoxicity develop. Patients with refractory hypotension may require vasopressor support.
Case Presentation
A 32 year old female with a history notable for depression, migraine headaches, and chronic pel- vic pain arrived to the emergency department 90 min after ingesting approximately sixty 75 mg tablets of amitriptyline. On arrival, she was noted to be agitated and confused. Her presenting vital signs included the following: BP 96/62, P 122, RR18, T37.8, O2 sat (RA) 99 %, GCS 13. An EKG showed sinus tachycardia with normal intervals and normal axis. Blood glucose was normal, and serum lactate was 3.7. Serum and urine tox screening was negative. Shortly after
P.G. Minges
Department of Emergency Medicine, University of Michigan Hospitals, Ann Arbor, MI, USA R.W. Shaffer (*)
Department of Emergency Medicine, University of Michigan Health System, Ann Arbor, MI, USA e-mail: [email protected]
6
arrival, the patient had a generalized tonic-clonic seizure that was successfully aborted with 2 mg IV Ativan. She was subsequently intubated for airway protection, and 50 g of activated charcoal was administered through a nasogastric tube.
Upon arrival to the ICU, her blood pressure fell to 65/32 and a repeat EKG was obtained (Fig. 6.1).
Question How would you proceed in the man- agement of this patient?
Answer This patient now exhibits EKG findings that are consistent with fast sodium channel blockade due to tricyclic antidepressant toxicity (Table 6.1).
The patient was immediately given 2 meq/kg of IV sodium bicarbonate as a bolus and hydrated aggressively with 3 l of normal saline. A sodium bicarbonate drip was initiated to maintain a goal serum pH within the range of 7.45–7.55. Ventilator settings were managed accordingly to prevent hypercarbia. A repeat EKG was obtained once serum alkalinization was achieved and demon- strated improvement of the QRS duration to 90 ms, but the patient remained hypotensive. A norepi- nephrine drip was initiated and blood pressure improved. Over the ensuing 48 h, norepinephrine
and sodium bicarbonate were successfully weaned.
She was successfully extubated and transferred to the inpatient psychiatric service.
Principles of Management Diagnosis
Tricyclic antidepressants have a narrow therapeu- tic index, and significant CNS and cardiovascular toxicity may be seen with ingestions that exceed therapeutic doses by as little as three-fold.
Tricyclic Antidepressant Side Effects
• Anticholinergic
• Mucosal dryness
• Constipation
• Urinary retention
• Confusion
• Blurred vision
• Aggravation of narrow angle glaucoma
• Anti-alpha-adrenergic
• Orthostatic hypotension
• Antihistaminic
• Sedation
• Quinidine-like
• Cardiac arrhythmias and block
aVR
aVF aVL
V1 V4
V5 V2
V3 V6
Fig. 6.1 12-Lead Electrocardiogram obtained at time of patients presentation
Mental status on presentation has been shown to be predictive of patient outcomes, and most life-threatening arrhythmias occur within the first 24 h after ingestion [2]. Owing to rapid GI absorption, patients may initially appear well and then deteriorate rapidly. Serum drug assays that measure specific serum tricyclic antidepressant levels are not widely available and should not be relied on when managing suspected overdose.
Because these drugs are highly lipophilic and have high volumes of distribution, concentrations in brain and myocardium may exceed serum con- centrations by as much as 40 to 200-fold, and serum drug levels have not been shown to predict the clinical course [1, 3].
The single most useful test in identifying tri- cyclic antidepressant toxicity is the electrocar- diogram. The most common early EKG finding in overdoses is sinus tachycardia, due to anticho- linergic effects and initial transient catechol- amine excess. As toxicity progresses, tricyclic antidepressants block fast sodium channels in the cardiac conduction system thereby slowing depo- larization and decreasing contractility. This results in a widened QRS complex. Prolongation of the QRS complex >100 ms has been shown to
predict risk for seizures, and prolongation
>160 ms predicts a risk for ventricular arrhyth- mias [4]. Owing to the greater susceptibility of the right ventricular conduction system to the effects of sodium channel blockade, a rightward axis shift of the terminal 40 ms of the QRS axis in the frontal plane will develop; but this finding may be difficult to detect [3]. A more practical means for identifying this rightward axis shift is by noting the presence of a larger than expected R wave amplitude in aVR (Fig. 6.2). An ampli- tude of the R wave in this lead in excess of 3 mm has been shown to predict risk for seizures and arrhythmias [5].
Gastrointestinal Decontamination Activated charcoal has been shown to effectively bind tricyclic antidepressants. In a study of healthy volunteers activated charcoal given 5 min after oral administration of therapeutic doses of amitriptyline decreased GI absorption by 99 % [6]. Activated charcoal probably has the most benefit when administered within 1 h of a toxic ingestion, but may be considered for up to 2 h
Table 6.1 Clinical features associated with specific toxidromes
HR & BP RR Temp Pupils Bowel sounds Diaphoresis Anticholinergic
Low potency antipsychotics
Oxybutinin, Ipratropium Antihistamines
ACh receptor antagonists
↑ ⇔ ↑ ↑ ↓ ↓
Cholinergic
ACh receptor agonists AChEls i.e. Donepezil
⇔ ⇔ ⇔ ↓ ↑ ↑
Opioid Morphine Heroin Hydromorphone
↓ ↓ ↓ ↓ ↓ ↓
Sympathomimetic Epinephrine Cocaine Amphetamine &
Methylphenidate
↑ ↑ ↑ ↑ ↑ ↑
Sedative-Hypnotic Benzos & barbs
“Z-drugs” (i.e. Zopiclone)
↓ ↓ ↓ ⇔ ↓ ↓
since the anticholinergic effects of the drug may delay gastric emptying [7].
Gastric lavage carries risks such as aspiration, and is not routinely recommended following tri- cyclic antidepressant ingestion. One randomized study demonstrated no significant difference in patient outcomes when gastric lavage was com- bined with the use of activated charcoal [8].
Whole bowel irrigation is typically reserved for overdoses involving sustained-release prepa- rations or in cases where the drug binds poorly to activated charcoal. Therefore, its use is unlikely to provide any benefit [7].
Plasma Alkalinization
Although no randomized-controlled clinical tri- als exist in support of sodium bicarbonate ther- apy in the setting of tricyclic antidepressant poisoning, numerous animal studies and human case reports support its use as a first-line treat- ment [9–11]. Sodium bicarbonate has been shown to both prevent and terminate ventricular dysrhythmias. The benefits of serum alkaliniza- tion through the use of sodium bicarbonate are likely multifactorial. The fraction of drug that is protein-bound increases with alkalinity, and therefore the use of sodium bicarbonate would be expected to decrease the amount of free drug available for inhibition of sodium channels [2].
Additionally, increasing serum sodium concen- trations may overwhelm the sodium channel blockade by increasing the gradient between the intracellular and extracellular space [2]. The net
effect is improved myocardial contractility, nar- rowing of the QRS complex, and improved elec- trical stability.
Dosing and titration guidelines for sodium bicarbonate have not been well-studied, but most recommend initiating a bolus of 1–2 meq/kg fol- lowed by a continuous infusion to maintain a goal serum pH within 7.45–7.55 and titrating to a goal QRS duration of less than 100 ms [2, 10].
The prophylactic use of sodium bicarbonate is not supported when EKG abnormalities are absent [10]. Serum pH must be monitored closely, and while optimum pH has not been studied, it is reasonable to not exceed a pH of 7.6. Risks of marked alkalosis may include impaired tissue oxygenation due to shifts in the oxygen dissocia- tion curve, cerebral vasoconstriction, reduction in ionized calcium concentration, intracellular shift of potassium, and an increased myocardial sensitivity to catecholamines [10].
Management of Hypotension and Vasopressor Support
Hypotension is a common feature of tricyclic anti- depressant toxicity. These medications decrease systemic vascular resistance through alpha-adren- ergic blockade. Relative catecholamine depletion may occur through their effects on norepinephrine reuptake. Additionally, hypotension may occur as a direct result of decreased cardiac inotropy [2].
Profound hypotension may be refractory to fluid resuscitation and alkalinization therapy, and vaso- pressors may be indicated. There are very few
aVR Fig. 6.2 Prominent termi-
nal R wave (>3 mm ampli- tude) in lead aVR from e l e c t r o c a r d i o g r a m obtained from a patient experiencing TCA overdose
studies evaluating the benefit of one such agent over another [12]. One retrospective case series suggested norepinephrine may be superior to dopamine in these instances [13]. A single case report showed that vasopressin stabilized blood pressure in a patient with hypotension that failed to respond to high-dose norepinephrine [14].
Extracorporeal Elimination
Because tricyclic antidepressants are lipophilic and highly protein-bound, extracorporeal elimi- nation methods such as hemodialysis are ineffec- tive [1].
Seizure Management
Seizures are common in the setting of significant tricyclic antidepressant overdose and are a predic- tor of poor outcomes. Seizures may precipitate an undesired acidosis that increases TCA toxicity.
There is little high quality evidence describing first line anticonvulsant therapy for seizures sec- ondary to TCA overdose. Seizures associated with TCA overdose are often brief and resolve before abortive medications can be administered.
The use of benzodiazepines has been proposed as first line therapy. Barbiturates and propofol are second-line agents that have been noted to be effective in case reports. These therapies should be used in conjunction with the treatment strate- gies previously described [15, 16].
Evidence Contour
Intravenous Lipid Emulsion
The use of intravenous lipid emulsions were first reported in the 1990s as an antidote for systemic toxicity from local anesthetic agents. Since that time, the use of intravenous lipid emulsion therapy has been reported in the setting of overdoses of other lipophilic drugs including calcium channel blockers, beta blockers, and tricyclic antidepres- sants [17]. Several proposed mechanisms for the
benefit of lipid emulsion use in tricyclic antide- pressant poisonings have been described. Lipid emulsions may serve as a “lipid sink”, sequester- ing intravascular drug from the aqueous phase of plasma. Secondly, the lipids themselves may directly provide a supplemental fuel source to the stressed myocardium. Lastly, a positive inotropic effect might be seen from increased intracellular calcium shifts [17, 18]. A few animal studies have been conducted using intravenous lipid emulsions for the management of tricyclic antidepressant toxicity, and the reported benefits on hemody- namic stability and mortality were mixed [18–20].
There are, however, several human case reports of patients being successfully managed with lipid emulsions in the setting of refractory hemody- namic instability when the use of traditional thera- peutic modalities failed [21–24]. Dosing guidelines for intravenous lipid emulsion therapy for tricyclic antidepressant toxicity have not been established.
Recommended dosing in the setting of systemic toxicity from local anesthetics have been proposed where a 20 % emulsion is administered at a load- ing dose of 1.5 ml/kg based on lean body mass followed by a continuous infusion of 15 ml/kg/h until clinical response is achieved [17, 25]. It is unclear how to extrapolate dosing of lipid emul- sions for management of tricyclic antidepressant overdose given their different pharmacokinetics.
The use of lipid emulsion in the management of overdoses carry theoretical risks including infec- tion, but serious adverse events have not been reported [17]. Intravenous lipid therapy may be considered in cases of refractory cardiovascular collapse when more traditional treatments fail.
Hypertonic Saline
One animal study suggested that the use of hypertonic saline in the management of tricyclic antidepressant poisonings, when compared to sodium bicarbonate, produced a statistically sig- nificant improvement in systolic blood pressure and narrowing of the QRS complex [26]. One human case report exists for a patient with refractory ventricular ectopy and widened QRS complex despite sodium bicarbonate therapy
that stabilized upon administration of hypertonic saline [27]. Clinical studies supporting its use, however, do not exist [2].
Antiarrhythmic Drugs
Occasionally, ventricular dysrhythmias may not respond to serum alkalinization, and the use of antiarrhythmic medications may be necessary.
Class I antiarrhythmic medications are contrain- dicated in the setting of tricyclic antidepressant overdose since they act to inhibit cardiac sodium channels in a similar manner [9]. Other antiar- rhythmic drugs have negative inotropic effects, which may worsen hypotension in the setting of these overdoses. Lidocaine has traditionally been considered the most reasonable agent in these instances, but the efficacy is limited to case series [28]. Theoretically, lidocaine’s rapid binding to sodium channels may displace the effects of tricy- clic antidepressants and improve cardiac conduc- tion. Lidocaine has a stabilizing effect on the myocardium, but unfortunately may slow conduc- tion and depress contractility [29]. Furthermore, one must take into consideration the fact that lido- caine may lower the seizure threshold [30].
Magnesium is an alternative antiarrhythmic that has been investigated with some promise. A study in rats sought to evaluate magnesium sul- fate’s ability to terminate arrhythmias when com- pared with lidocaine and demonstrated favorable results [29]. One small randomized human trial suggested that use of magnesium in addition to traditional therapeutics decreased ICU length of stay and mortality, and several case reports describe the successful use of magnesium to abort ventricular arrhythmias [31–33].
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R.C. Hyzy (ed.), Evidence-Based Critical Care, DOI 10.1007/978-3-319-43341-7_7