Theophylline ToxicityTheophylline Toxicity: Does the diagnosis matter in

the management of acute toxicity?

A case report of survived undiagnosed patient presented to the Emergency Department, HUSM

Nasir M*, Nurkhairul NAH*, Kamarul AB*, Chew KS*Rashidi A*, Ismai R**

*Emergency Medicine Rsearch Group,Department of Emergency Medicine, School of Medical Sciences, USM Health Campus, Kelantan, Malaysia.** Pharmacogenetic

Research Group, Institute For Research In Molecular Medicine, USM Health Campus, Kelantan, Malaysia.

3rd Clinical Conference on Emergency MedicineKota Kinabalu, Sabah

23-25 April 2009

Outlines

Case study Overview: Theophylline

Related journals Pathophysiology Pharmacokinetics

Toxidromes Management: measures to be taken Conclusion References

We present a case of attempting suicide who sustained generalised tonic-clonic seizures and supraventricular tachycardia.

As this was our first experience encountering such a case, we recommend a few measures to be taken especially when managing patient with undiagnosed toxidrome in our emergency department.

Case discussion

A 22/ED/HUSM/10 H/ ? ingesting 30 tablets of antihistamine.

Intermittent nausea and non projectile vomiting.

complained of epigastric pain 2 hours post ingestion

Physical Examination

He was drowsy, tachypnoeic, tachycardic (120 bpm), borderline hyopotensive (90/64 mmHg) and normothermia with moist skin

The pupils sizes were 3mm EB and RTL.The lower abdomen was distended.Other systems were unremarkable. ECG showed sinus tachycardia RBS 6.7mmol/l.

iv metochlopramide 10 mg as well as iv ranitidine 50 mg was administrated

Activated charcoal was initiated.500 cc iv bolus crystalloid was

administered but the BP was still hypotensive.

iv noradrenalin was started to restore the blood pressure.

Initial ED Management

After 2 hours in ED, patient suddenly developed generalized tonic-clonic seizure twice. Each episode lasted 10 minutes

Fit was aborted after iv valium 5mg bolus was admistered.

He was prophylactically given iv phenytoin to prevent further fit

He was electively intubated for airway protection and cerebral resuscitation.

Initial blood gases noted to be metabolic alkalosis, and he was hypokalemic (refer Table 1).

Progress of patient in ED

Table 1: Serial ABG result

Day/time (Immediate) Post ET 2 3 4 5 6 7

pH 7.475 7.188 7.339 7.192 7.44 7.44 7.395 7.427

pCO2 (mmHg) 34.2 27.3 23.1 36.6 22.2 19.2 32.9 50.2

pO2 (mmHg) 291 56.5 187 181 195 63.4 165 84.3

Base excess 1.6 -16.6 -12.6 -13.1 -8.5 -10.5 -4.9 -8.0

HCO3 26.4 12.1 15.1 14.1 18.6 17.0 20.9 32.5

Serial pH results

7

7.05

7.1

7.15

7.2

7.25

7.3

7.35

7.4

7.45

7.5

0 1 2 3 4 5 6 7

Days of admission

pH

Patient was admitted into (ICU) for monitoring and supportive care.

In ICU, he developed supraventricular tachycardia (SVT) with unstable haemodynamics and synchronized cardioversion 50J was delivered

His rhythm was successfully reverted to sinus rhythm.

Patient was self extubated at day-2 of hospitalization

The BP was normotensive on inotrops and the PR remains tachycardic.

He sustained acute renal failure and was referred to nephro team for HD but he was treated consecutively.

Table 2: Serial Theophylline level

Time ( hours) Serum theophylline level

72 40. 4µg/ml

96 20.5µg/ml

120 2.83µg/ml

Serial Theophyline Level

0

5

10

15

20

25

30

35

40

45

72 96 120

Hours

Ser

um

Th

eop

hyl

ine

Day 1 2 3 4 5 6 7 8 9 10

Urea(mmol/l) 8.0 8.0 14.5 18.7 16.3 29.5 32.9 35.4 31.3 31

K (mmol/l) 2.6 3.0 4.8 5.7 5.1 4.9 5.0 4.4 4.3 4.0

Na (mmol/l) 132 137 145 147 152 151 154 153 148 148

Creat (mmol/l) 160 178 307 367 373 574 603 577 530 501

Table 3: Serial BUSE

Further history elicited from patient after he regained his consciousness, revealed that he took 30 tablets of neulin SR 250 mg.

Discharged well after 2 weeks hospitalization.

Teophylline: An Overview.

IntroductionIntroduction

Theophylline is a commonly used drug in the treatment of acute or chronic lung diseases.

Theophylline poisoning is a toxicological emergency It has a narrow therapeutic index with erratic absorption

and elimination contribute to toxicity with high morbidity and mortality.

Drugs included in this group: Aminophylline & Theophylline

Theophylline’s toxidrome may be overlapping with other drug toxicity especially in un-witnessed patient with altered higher mental functions.

Journals related to Theophylline toxicity:

Pub Med: 24

Drug screening of patients who deliberately harm themselves admitted to the emergency department .Ther Drug Monit. 1998 Feb;20(1):98-103.. Skelton H, Dann LM, Ong RT, Hamilton T, Ilett KF.

Treatment of acute asthma. Lack of therapeutic benefit and increase of the toxicity from aminophylline given in addition to high doses of salbutamol delivered by metered-dose inhaler with a spacer. Rodrigo C, Rodrigo G.Chest. 1994 Oct;106(4):1071-6.PMID: 7924475 [PubMed - indexed for MEDLINE]

The clinical implication of theophylline intoxication in the Emergency Department. Tsai J, Chern TL, Hu SC, Lee CH, Wang RB, Deng JF.Hum Exp Toxicol. 1994 Oct;13(10):651-7.PMID: 7826681 [PubMed - indexed for MEDLINE]

Theophylline toxicity.Cooling DS.J Emerg Med. 1993 Jul-Aug;11(4):415-25. Review.PMID: 8228104 [PubMed - indexed for MEDLINE

Severe theophylline toxicity in a pregnant asthmatic patient] .Nagahama H, Nagano K, Yamanaka I, Kasagawa J, Seki I, Suzuki Y.Masui. 1993 Jul;42(7):1076-80. Japanese. PMID: 8350478 [PubMed - indexed for MEDLINE]

Failure of gastric emptying and charcoal administration in fatal sustained-release theophylline overdose: pharmacobezoar formation.Bernstein G, Jehle D, Bernaski E, Braen GR.Ann Emerg Med. 1992 Nov;21(11):1388-90.PMID: 1416337 [PubMed - indexed for MEDLINE

Aminophylline in the emergency department. Maximizing safety and efficacy.Kino R, Day RO, Pearce GA, Fulde GW.Chest. 1991 Dec;100(6):1572-7.PMID: 1959397 [PubMed - indexed for MEDLINE]

Theophylline toxicity secondary to ciprofloxacin administration.Spivey JM, Laughlin PH, Goss TF, Nix DE.Ann Emerg Med. 1991 Oct;20(10):1131-4.PMID: 1928889 [PubMed - indexed for MEDLINE]

Severe lactic acidosis following theophylline overdose.Bernard S.Ann Emerg Med. 1991 Oct;20(10):1135-7.PMID: 1656819 [PubMed - indexed for MEDLINE

Theophylline intoxication, clinical features, treatment and outcome: a case report and a review of the literature.Stegeman CA, Jordans JG.Neth J Med. 1991 Aug;39(1-2):115-25. Review.PMID: 1961347 [PubMed - indexed for MEDLINE

Inpatient theophylline toxicity: preventable factors.Schiff GD, Hegde HK, LaCloche L, Hryhorczuk DO.Ann Intern Med. 1991 May 1;114(9):748-53.PMID: 1953845 [PubMed - indexed for MEDLINE

Risk of toxicity in patients with elevated theophylline levels.Emerman CL, Devlin C, Connors AF.Ann Emerg Med. 1990 Jun;19(6):643-8.PMID: 2344081 [PubMed - indexed for MEDLINE]

Theophylline toxicity: clinical features of 116 consecutive cases.Sessler CN.Am J Med. 1990 Jun;88(6):567-76. Review.PMID: 2189301 [PubMed - indexed for MEDLINE

Poor tolerance of oral activated charcoal with theophylline overdose.Sessler CN.Am J Emerg Med. 1987 Nov;5(6):492-5.PMID: 3663290 [PubMed - indexed for MEDLINE]

Rapid assay of serum theophylline levels.Reinecke T, Seger D, Wears R.Ann Emerg Med. 1986 Feb;15(2):147-51.PMID: 3946856 [PubMed - indexed for MEDLINE]

Treatment of theophylline toxicity with oral activated charcoal.Sessler CN, Glauser FL, Cooper KR.Chest. 1985 Mar;87(3):325-9.PMID: 3971756 [PubMed - indexed for MEDLINE]

Pathophysiology Pathophysiology

Excessive ß-adrenergic activity Phosphodiesterase Inhibitor causes increased intracellular cAMP (ß-adrenergic

mediators) and beta adrenergic activity Directly stimulates adrenal medulla to excrete catecholamine. Peripheral venodilatation, increase cardiac output, natriuresis, gastrin release

and H prroduction, gluconeogenesis, etc

Metabolic abnormalities Induced Intracellular shift of K hypoK, Metabolic Acidosis, Respiratory Alkalosis, Hyperglycaemia intracellular calcium translocation

The blockade of adenosine receptors Negative feedback to the heart in situations of sympathetic overstimulation.

CNS toxicity Overstimulation Mechanism is unclear- agitated, hyperreflexia, fit Increase cerebral vasoconstriction due to –ve inhibition Increase cAMP is an eliptogenic, it reduces the seizure threshold and increase

paroxysmal activity on EEG

Pharmacokinetics

Absorption Conventional preparations exhibit virtually complete and rapid

absorption (peak concentrations 0.5-2 H). Therapeutic doses of sustained release preparations vary in the total

extent of absorption and in the time to peak concentration (4-18 H). In acute poisoning with sustained release preparations the peak

concentration usually occurs between 2 and 18 H after admission but can occur up to 24 H.

Distribution Vd is 0.5 L/kg and in normal adults the clearance is 40-45 mL/kg/hr

giving a half-life of approximately 8 hours. Metabolism - Elimination

In overdose, hepatic metabolism of theophylline is frequently saturated & the apparent half-life can be as long as 30 hours.

The pharmacokinetics of theophylline may be further affected by intercurrent hepatic, cardiac or renal disease and numerous medications

Clinical PresentationClinical Presentation

2 types: Acute Intoxication Tolerate higher levels of the drug

Intentional Overdose Metabolic derangement Does not demonstrate adverse effects until the

Level >100mg/L

Chronic Intoxication: Manifest serious effect as low as 40mg/L

Discussion:Discussion:

10-hours post-ingestion:10-hours post-ingestion:

Abdominal pain, urinary retention, nausea, vomiting, normal body temperature and normal pupils sizes with altered mental

status, hypotension, sinus tachycardia and subsequently developed generalized tonic-clonic seizure and SVT

Possible diagnosis:

Sympathomemetic toxicity

Antidepressant toxicity

Anticholinergic toxicity the points that against it were hypotension, moist skin with normal body

temperature and the normal pupils’ sizes and hypokalaemia)

Other Toxidromes Potentially Toxic Drugs: by Type of Agent

Cardiopulmonary Signs* of Toxicity Therapy to Consider†

Stimulants (sympathomimetics)• Amphetamines• Methamphetamines• Cocaine• Phencyclidine (PCP)• Ephedrine

• Tachycardia• Supraventricular arrhythmias• Ventricular arrhythmias• Impaired conduction• Hypertensive crises• Acute coronary syndromes• Shock• Cardiac arrest

• Benzodiazepines• Lidocaine• Sodium bicarbonate (for cocaine-related ventricular arrhythmias)• Nitroglycerin• Nitroprusside• Reperfusion strategy based on cardiac catheterization data• Phentolamine (_1-adrenergic blocker)• _-Blockers relatively contraindicated (do not use propranolol forcocaine intoxication)

Calcium channel blockers• Verapamil• Nifedipine (and other dihydropyridines)• Diltiazem

• Bradycardia• Impaired conduction• Shock• Cardiac arrest

• NS boluses (0.5 to 1 L)• Epinephrine IV; or other _/_-agonists• Pacemakers• Circulatory assist devices?• Calcium infusions• Glucose/insulin infusion?• Glucagon

Adrenergic receptor antagonists• Propranolol• Atenolol• Sotalol• Metropolol

• Bradycardia• Impaired conduction• Shock• Cardiac arrest

• NS boluses (0.5 to 1 L)• Epinephrine IV; or other _/_-agonists• Pacemakers• Circulatory assist devices?• Calcium infusions?• Glucose/insulin infusion?• Glucagon

Tricyclic antidepressants• Amitriptyline• Desipramine• Nortriptyline• Imipramine

• Tachycardia• Bradycardia• Ventricular arrhythmias• Impaired conduction• Shock• Cardiac arrest

• Sodium bicarbonate• Hyperventilation• NS boluses (0.5 to 1 L)• Magnesium sulfate• Lidocaine• Epinephrine IV;

Cardiac glycosides• Digoxin• Digitoxin• Foxglove• Oleander

• Bradycardia• Supraventricular arrhythmias• Ventricular arrhythmias• Impaired conduction• Shock• Cardiac arrest

• Restore total body K_, Mg__• Restore intravascular volume• Digoxin-specific antibodies (Fab fragments: Digibind or DigiFab)• Atropine• Pacemakers (use caution and monitor for ventricular arrhythmias)• Lidocaine• Phenytoin?

Anticholinergics• Diphenhydramine• Doxylamine

• Tachycardia• Supraventricular arrhythmias• Ventricular arrhythmias• Impaired conduction• Shock, cardiac arrest

• Physostigmine

Cholinergics• Carbamates• Nerve agents• Organophosphates

• Bradycardia• Ventricular arrhythmias• Impaired conduction, shock• Pulmonary edema• Bronchospasm• Cardiac arrest

• Atropine• Decontamination• Pralidoxime• Obidoxime

Opioids• Heroin• Fentanyl• Methadone• Morphine

• Hypoventilation (slow and shallowrespirations, apnea)• Bradycardia• Hypotension• Miosis (pupil constriction)

• Assisted ventilation• Naloxone• Tracheal intubation• Nalmefene

Sodium channel blockers (Class IV antiarrhythmics)• Procainamide• Propafenone• Disopyramide• Flecainide• Lidocaine

• Bradycardia• Ventricular arrhythmias• Impaired conduction• Seizures• Shock, cardiac arrest

• Sodium bicarbonate• Pacemakers• Lidocaine (not for lidocaine overdose)• Hypertonic saline

Does the diagnosis matter in the acute management?

Important Questions…..Important Questions….. Does toxidrome identification affects the initial management at the ED What is our management strategy?

History does not compatible with clinical toxidromes. … Any role of gastric lavage in case of more than 1 hour post intoxication? Any role of activated charcoal or Multi-doses Activated Charcoal?

Any role of Metoclopramide ? Ranitidine ?

Is there any inter-variability of pharmacokinetics? In overdose, hepatic metabolism of theophylline is frequently saturated & the

apparent t½ can be as long as 30 H. CYP 450 polymorphisms affect the metabolisms It is further affected by

• intercurrent hepatic• cardiac • renal disease• numerous medications

Important Distinction

Which toxidrome the patient had? Rule out:

Alcohol, Bdz, Stimulants, PCM, TCA, Salicylate, etc If strongly suspected: Thophylline, Anticholinergic,

Cholinergic, etc.

Toxicity from an acute single ingestion or from chronic overmedication.

A sustained release preparation or not ?Gastric pharmacobenzoar formation?

Early Measures to be TakenEarly Measures to be Taken While Attempting While Attempting

Acute Intoxication…Acute Intoxication…

Management DecisionsManagement Decisions

Based on both Clinical Assessment Laboratory Information

(eg..theophylline concentrations).

Efforts toward achieving successful detoxification. Frequent observation Aggressive efforts

Determination of SeverityDetermination of Severity

Over treat versus under treat? All patients require frequent clinical assessment of their

severity. The history should establish

The time of ingestion The dose and type of preparation (sustained release or

conventional) Whether the poisoning is acute or chronic General history with emphasis on diseases which may

increase patient's susceptibility to major theophylline toxicity (e.g. cardiac or neurological disease) or alter theophylline pharmacokinetics (e.g. hepatic disease).

Concomitant drug therapy should be recorded

Clinical Features of SeverityClinical Features of Severity *The most serious category should be assumed.

Mild Moderate Severe

NauseaVomiting but tolerates decontamination

Vomiting & not tolerating decontamination

Pulse < 120 Pulse < 140 pulse >140

Systolic BP > 120 mmHg Systolic BP > 100 mmHg Systolic BP < 100 mmHg

No arrhythmias Atrial or ventricular ectopics SVT or Ventricular Tachycardia

. Agitation or hyperreflexia Seizures

. Potassium < 3.0 mmol/L Potassium < 3.0 mmol/L

. Glucose > 10 mmol/L Glucose > 10 mmol/L

.  Rising 2nd hourly theophylline concentrations in the presence of apparently effective decontamination

Potentially significant toxicity includes:1. All Chronic Overmedication, 2. Acute Ingestions of > 10 mg/kg, 3. Acute ingestions with more than mild toxicity regardless of stated amount ingested.

TreatmentTreatment

Supportive Control of vomiting GI decontamination Treatment of specific complications

Central nervous system Cardiac Metabolic effects

Elimination enhancement Multidose charcoal Charcoal haemoperfusion Haemodialysis

General MeasuresGeneral Measures

Basic Supportive: Airway Management Oxygen administration Haemodynamics monitoring Intra-venous access Symptomatic support

Correction of HypotensionCorrection of Hypotension

Peripheral ß2 ADR and venodilationBolus 250-500mls of crystalloidPharmacologic:

α-agonist: phenylepidrine or NA/ adrenalin Non-selective ß2 ADR blockade: propranolol

Antiarrhythmias Antiarrhythmias

Supraventricular dysrhythmias (ST, SVT,MFAT,AF)

ß-blocker: propranolol infusion Ca Channel Blocker: verapamil

Ventricular dysrhythmias K correction Lignocaine/Amiodarone

AnticonvulsantsAnticonvulsants

To stop seizures: Benzodiazepine Phenobarbitone Phenytoin

Role of general anaesthesia (GA) and muscle relaxant: to facilitate ventilation to protect the airway and cerebral resuscitation to prevent acidosis and rhabdomyolysis.

GI SymptomsGI Symptoms

Nausea and VomitingDyspepsiaAbdomen pain

Metoclopramide Ondansetron

GI DecontaminationGI Decontamination

Gastric Lavage controversiescontroversies 1 H : indicated 3-4 H : sustained release Theophylline toxicity: depends on preparation

Restricted to poisonings where benefits over oral activated charcoal are likely. should be considered in

Potentially life-threatening poisoning (or history is not available) and unconscious presentation √√

Potentially life-threatening poisoning and presentation within 1 hour Potentially life threatening poisoning with drug with anticholinergic effects

and presentation within 4 hours Ingestions of sustained release preparation of significantly toxic drug √√ Large salicylate poisonings presenting within 12 hours Iron or lithium poisoning

The Position Statement :The Position Statement :

1.American Academy of Clinical Toxicology 1.American Academy of Clinical Toxicology

2.European Association of Poisons Centres & Clinical Toxicologists.2.European Association of Poisons Centres & Clinical Toxicologists.

Gastric lavage should not be employed routinely in the management of poisoned patients.

In experimental studies, the amount of marker removed by gastric lavage was highly variable and diminished with time.

There is no certain evidence that its use improves clinical outcome and it may cause significant morbidity.

Gastric lavage should not be considered unless a patient has ingested a potentially life-threatening amount of a poison and the procedure can be undertaken within 60 minutes of ingestion.

Elimination EnhancementElimination Enhancement

1. Multiple Doses Activated Charcoal (MDAC) All patient to double the clearance of theophylline, being as effective

as a haemodialysis. 0.6-1g/kg or 10 g of charcoal for every gram of theophylline

ingested. 2 H charcoal administration will dramatically reduced the t½

2. Charcoal Hemoperfusion the most effective, increasing clearance 4- to 6-fold. Theophylline level of:

90-100 mg/L 60 mg/L

3. Hemodialysis/ Peritoneal Dialysis Med Toxicol Adverse Drug Exp. 1987 Jul-Aug;2(4):294-308

Take Home Messages……

ConclusionConclusion

To gain a better outcome requires :

Adequate history

Adequate Assessment: Thorough PE-identify toxidrome Rule out: Alcohol, Bdz, Stimulants, PCM, TCA, Salicylate, etc If strongly suspected: Thophylline, Anticholinergic, Cholinergic, etc.

Approach of management: Assess vital signs Identify pathophysiology changes To correct underlying pathological process: ABC Early serum toxicology screening based on high index of suspicion

Always have a 2nd opinion in case of doubt.

A good knowledge on toxicology Pharmacokinetics Pharmacidynamics

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