Critical care toxicology

2. • MALE PT. 24 YRS OLD NO MEDICAL ILLNESS , GASTRIC SLEEVE
FROM 2 YRS BACK , ADMITTED TO OUR ED IN KAUH ON 24TH 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. • 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. • 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).

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

8. II- Theophylline is a bronchodilator and respiratory
stimulant.
• Used to treat:
1. Asthma, chronic obstructive pulmonary dis.
2. Neonatal apnea syndrome.
3. A weight-loss agent.
 Used, most commonly in beverages, for their
stimulant, mood elevating, and fatigue abating
effects.

9. • 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 .

10. 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.

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

12. Pathophysiology of Toxic Effects
5- Increase striated muscle contractility:
• ↑↑ intracellular calcium content.
• ↑↑ muscle O2 consumption
• ↑↑ the BMR.
• These effects are sought by users of
methylxanthines to enhance or improve
athletic performance or lose weight.

13. 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.

15. Gastrointestinal Manifestations
Cardiovascular Manifestations
Central Nervous System Manifestations
Metabolic Manifestations

16. 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.

17. 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.

18. 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 2ry to gastrointestinal losses &
theophylline induced dieresis.

19. 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.

20. 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.

21. 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.

23. 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.

24. 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.

25. 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).

26. • 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.

28. Supportive
Care
Pharmacologic
Management
Gastrointestinal
Decontamination
Enhancement
of
Elimination

30. 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.

31. 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.

32. 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.

35. 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.

36. Arrhythmias
Vasopressors
Hypotension
Seizures
Electrolytes & emesis

37. • IV crystalloid boluses are the 1st -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).

38. • 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).

39. • 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).

40. • 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.

41. • 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.

42. • 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.

43. • 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.

44. • 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).

45. • 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.

47. Enhanced Elimination
Three modalities for enhanced elimination of

48. 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.

49. 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.

50. 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.

55. 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.

56. • 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.

57. • 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.