Theophylline toxicity

Critical care toxicology

1. Theopylline Toxicity Fadel kamal, md. ICU Registrar kauh A case study approach

2. Case History MALE PT. 24 YRS OLD NO MEDICAL ILLNESS , GASTRIC SLEEVE FROM 2 YRS BACK , ADMITTED TO OUR ED IN KAUH ON 24 TH OF DEC. 2018 ( 11:00 am) WITH HISTORY OF IBUPROFEN INGESTION (3200 mg) AS PER THE HISTORY FROM THE RELATIVES as suicidal attempt. ON EXAMINATION HE WAS DROWSY TACHYCARDIC sinus 120-130 bpm , HYPOTENSIVE WITH BP OF 82/55 mmHg , vesicular breathing with bilateral equal air entery , abdomen soft lax, U.O.P 1.5 ml/kg/hr , received 3 liters boluses of normal saline and potassium replacement (50 mEq) as his initial K+ was 2.5 , no fever & LACATE initially revealed 6.7 .

3. Case History Acetaminophen level was sent revealed results (below assay). Multiple doses of Ondansetron (8 mg). At 9:30 pm patient started to suffer from seizures attacks resolved with diazepam boluses & started on phenytoin loading dose , and ABG showed pH of 7.22 then the patient continued to suffer from seizures attacks until 2:30 am (25th of DEC.) when the medical team CONSULTED ICU for sever metabolic and respiratory acidosis with pH of 6.8-6.7 and pco2 120-130 mmHg & HCO3- of 6-3 mEq/l & ECG showing Sinus tachycardia of 140. Patient immediately sedated and intubated and CT-brain was done and admitted to the medical ICU.

4. Case History A detailed history was taken from the family members regarding the nature of the medication he received while committing his suicidal attempt, they found that the actual drug is not IBUPROFEN but ( QUIBRON SR 300 mg WITH 20 tab. Missed ).

5. Pharmacology Methylxanthines are so named because they are methylated derivatives of xanthine . ( purine base ) Are plant-derived alkaloids: Caffeine = Cola, Chocolate, Coffee , Tea. Theophylline = Tea Pentoxifylline = Trental

6. Pharmacology II- Theophylline is a bronchodilator and respiratory stimulant. Used to treat : Asthma, chronic obstructive pulmonary dis. Neonatal apnea syndrome. A weight-loss agent. Used, most commonly in beverages , for their stimulant, mood elevating , and fatigue abating effect s.

7. Pharmacokinetics Theophylline is 100% bioavailable by oral route. Theophylline is rapidly absorbed but may be delayed in sustained- release preparation or if bezoars. The VD is 0.6 L/kg , and 36% is protein bound. It is metabolized hepatically , undergoes entero -hepatic circulation after 6-8 hrs & up to 18 hrs in SR forms. Rapidly diffuses into the total body water and all tissues , readily crosses the blood-brain barrier .

8. Pathophysiology of Toxic Effects 1- Adenosine antagonist: Adenosine modulates histamine release and cause bronchoconstriction. Adenosine antag. results in nor- epinephrine release . IN therapeutic dose ------ Bronchodilator IN overdose ---------------- CNS manifestations 2- +++ release of endog. Catecholamines : CARDIAC & CNS symptoms.

9. Pathophysiology of Toxic Effects 3- Inhibit phosphodiesterase: Elevate cAMP . B, adrenergic stimulation. 4- Stomach: ↑↑ gastric acid secretion Smooth muscle relaxation Stimulation of CTZ .

10. Pathophysiology of Toxic Effects 5- Increase striated muscle contractility: ↑↑ intracellular calcium content. ↑↑ muscle O 2 consumption ↑↑ the BMR . These effects are sought by users of methylxanthines to enhance or improve athletic performance or lose weight .

11. Pathophysiology of Toxic Effects The specific catecholamine released vary depending on the type of intoxication . Acute intoxication associated with Epi. Concentrations ↑↑↑ fourfold - eightfold & NE. levels fourfold to tenfold normal. In chronic overdose , NE & dopamine levels were elevated compared with acute overdose.

12. Clinical Presentation and Life-Threatening Complications

13. Gastrointestinal Manifestations Nausea and vomiting are the predominant. Vomiting results from gastric acid hyperstimulation and central stimulation of the CTZ. Vomiting may be difficult to control and may make it impossible for the patient to tolerate activated charcoal.

14. Cardiovascular Manifestations Theophylline reduces VF threshold & ↑↑ cardiac conduction, favoring reentrant arrhythmias even at therapeutic serum concentrations. At toxic concentrations, tachyarrhythmias & hypotension are common findings, any type of atrial or ventricular tachyarrhythmias are seen after theophylline intoxication.

15. Cardiovascular Manifestations Coronary ischemia due to A2 receptor antagonism increases in circulating catecholamine, hypokalemia, and acidosis all causes arrhythmias. The hypotension is due to Vasodilatation due to theophylline beta2- adrenoceptor stimulation .   Tachyarrhythmias result in ↓↓ filling time & ↓↓ COP ; hypovolemia 2 ry to gastrointestinal losses & theophylline induced dieresis.

16. Central Nervous System Manifestations CNS manifestations of theophylline toxicity include agitation, tremor, & seizures either focal or generalized also, NCSE which are difficult to control. Theophylline- induced seizures may be associated with poor neurologic outcome ranging from profound memory deficit to persistent vegetative state.

17. Metabolic Manifestations Theophylline toxicity associated with hypokalemia , hyperglycemia , mild hypomagnesaemia & metabolic acidosis . Hypokalemia and hyperglycemia are more common in acute than in chronic . Hypokalemia is from intracellular shifting of potassium, Severe lactic acidosis has been reported with pH as low as 6.63 .

18. Metabolic Manifestations Hyperlactemia has been reported with therapeutic use of theophylline. Rhabdomyolysis & compartment syndrome have been reported after acute theophylline & caffeine intoxication. Caffeine poisoning has also been associated with hyponatremia and acute renal failure.

19. Diagnosis

20. Diagnosis History: Type of preparation. Underlying diseases. Clinical presentation Serum theophylline concentration: Correlates with the severity of acute toxicity as follows: - 10-20 ug /ml …… therapeutic level. (55-111 umol /l) - 20-40 ug /ml ….. mild toxicity. (111-222 umol /l) - 40-70 ug /ml ….. moderate toxicity. (222-400 umol /l) -  70 ug /ml …... severe toxicity. (400 umol /L) Blood gas analyses, serial electrolytes, blood glucose level, ECG .

21. Diagnosis In acute intoxication, serum theophylline concentrations correlate with the risk for major complications, although no serum concentration has been shown to have an acceptable degree of predictive sensitivity and specificity. For patients with chronic intoxication , age rather than serum theophylline concentration is the most important prognostic factor.

22. Diagnosis Using the criterion of age > 60 for predicting major toxicity had a sensitivity of 80% and specificity of 62%, LTEs were associated with infants younger than 1 year . There are reports of LTE occurring with serum concentrations in the therapeutic range of 10–20 μg / mL (55–111 μmol /L) , Most case series have not reported LTE, however, unless the serum theophylline concentration is greater than 30 μg /ml (167 μmol /L).

23. Case History Theophylline level was sent revealed 222 umol /l (Therapeutic range 55-111 umol /l), EEG was done in 25th of DEC. showed theta & delta waves suggesting metabolic or toxic encephalitis.

24. MANGEMENT

25. Supportive Care Patients with abnormal vital signs typical of methylxanthine intoxication should be cared for in a clinical setting with A,B,C,…. . Crystalloid should be given to replace losses from diuresis and emesis and that continuous ECG monitoring to assess for myocardial irritability should be instituted. A

26. Gastrointestinal Decontamination Methylxanthines are adsorbed by activated charcoal , & in one volunteer study, charcoal reduced the dose of ingested theophylline by 64% . For a patient who has ingested a large dose of methylxanthine, or who is showing signs of toxicity, administration of single-dose activated charcoal is indicated as long as there is an intact or protected airway. B

27. Gastrointestinal Decontamination Methylxanthine toxicity is often associated with nausea and vomiting which may limit activated charcoal use antiemetic may facilitate administration of activated charcoal. Toxicologists have recommended that whole-bowel irrigation ( WBI ) should be considered in an acute overdose with a sustained-release preparation . B

28. Gastrointestinal Decontamination A bezoars should be suspected in patients who continue to have rising serum concentrations despite tolerating activated charcoal, rarely, endoscopy has been used to remove a bezoars and whole tablets. B

29. Pharmacologic Management C

30. IV crystalloid boluses are the 1 st -line ttt for hypotension & any volume losses from diuresis. One case report the use of esmolol , to slow the heart rate & allow for greater ventricular filling time & SV to improve COP . (Grade III recommendation). Vasopressors 1

31. Hypokalemia should be treated cautiously because total body K+ is not depleted , Rather, results from intracellular shift. Hyperkalemia may occur as the serum theophylline concentration ↓↓ in a patient who is receiving K+ or propronalol . Administration of Mg & NaHCO3 indicated for clinically significant hypomagnesaemia and acidosis (Grade III recommendation). Electrolytes 2

32. Atrial tachyarrhythmias reversed by Nonspecific β-B, such as propranolol, should be administered cautiously to patients with asthma .   Esmolol , a selective β1- antagonistic safe to use in patients with asthma, thus, esmolol is reasonable choice for the treatment of xanthine-induced tachyarrhythmias (Grade III recommendation). Arrhythmias 3

33. Adenosine reverse theophylline-induced paroxysmal SVT at doses of 6 mg, although higher doses may be required.   Verapamil has been used to treat MAT but failed in SVT. Isolated premature ventricular contractions associated with no hemodynamic compromise require no treatment . More significant signs of myocardial irritability should be treated with lidocaine (Grade III recommendation), although the proconvulsant actions. Arrhythmias 3

34.   Hypotension that persists despite fluid resuscitation & arrhythmias Control treated with the α- agonist, phenylephrine (Grade III recommendation). Propranolol , antagonizes β2 - mediated vasodilatation . One case report describes the use of an IV lipid emulsion infusion (but not a bolus) + CVVHD to treat refractory VD & arrhythmias after caffeine overdose. Hypotension 4

35.   There is insufficient evidence to recommend the use of ILE for methylxanthine intoxication.   Vasopressin reported to increase blood pressure to facilitate HD in near-fatal caffeine poisoning. Hypotension 4

36.   Difficult to control , Phenobarbital or propofol may be used as adjunctive anticonvulsants. Phenytoin should be considered to be contraindicated as it is ineffective in the termination of theophylline-induced seizures, if anticonvulsants are ineffective, NMB is indicated . Seizures 5

37. Benzodiazepine or barbiturate considered in patients at high risk for theophylline-induced seizures (Grade III recommendation). High-risk patients: are those with acute overdose & serum theophylline concentration ≥ 80 μg /ml (444 μmol /L), chronic intoxication who are older than age 60 & serum theophylline concentration ≥ 30 μg / mL (167 μmol /L). Seizures 5

38. Emesis must be controlled to administer AC to prevent further fluid loss, antiemetic as phenothiazines are ineffective, also, phenothiazines lower seizure threshold . Ondansetron is the drug of choice as it reduce theophylline-associated vomiting through CTZ (Grade III recommendation). Ranitidine is important adjunct as it ↓↓ theophylline-induced gastric hypersecretion. 6 Emesis

39. Enhanced Elimination Three modalities for enhanced elimination of D MDAC Hemoperfusion HEMODILAYSIS

40. Enhanced Elimination MDAC reduce theophylline half-life from 25 h to ( 6.5 - 12.6 h ). The recommended regimen is 25 g of AC every 2 h until the serum theophylline concentration declined to a level associated with clinical improvement, AC should not be used if the patient has an ileus. D

41. Enhanced Elimination Peritoneal dialysis removes theophylline but too slowly to have a role in the treatment of theophylline intoxication. The molecular adsorbent recirculating system ( MARS reported in one case to be associated with increased clearance. D

42. Enhanced Elimination Although hemoperfusion is more efficient than HD at removing theophylline, it has not been shown to be better at improving clinical outcome. In acute caffeine overdose , caffeine is removed effectively by hemoperfusion with level ≥ to 120 μg / mL has been cited as a criterion for extracorporeal removal. D

43. Hemoperfusion Hemoperfusion

44. Enhanced Elimination Pentoxifylline overdose associated with hypokalemia, hyperglycemia, A-V block, & hypotension , in one case of massive pentoxifylline ingestion resulting in shock, dialysis clearance was calculated at 154 ml/min. D

45. Case History Patient received fluids in the form of normal saline , sodium bicarbonate until pH raised above 6.9 , U.O.P maintained on 1.5 ml/kg/hr. Continuous sedation with propfol & fentanyl without recurrent seizures attacks. No anti-epileptics was prescribed.

46. Case History patient extubated next day 26th of DEC. Patient discharged from the hospital DAMA as his father refused to admit him to a psychiatric hospital. 2 months forward in Feb. 2019 patient suffered from subglottic stenosis , bronchoscope balloon dilatation was done then after 1 week re-stenosis 30% again dilation done for the 2nd time and discharged from the hospital.