A concise pointer-laden info. about Salicylates and Paracetamol Poisoning in the context of TDM

1. TDM Pointers –
Salicylates Poisoning

2.  Salicylate poisoning is mainly due to ingestion of…
• Aspirin [10-20 g (adults); 3g (children)], or
• LMS (1 ml of 25% LMS = 300 mg salicylate)
 Pathophysiology:
SALICYLATES
Stimulate resp.
centre
Hyperpnoea
(hyperventilation)
Hypocarbia
(Hypocapnoea)
↓ed CO2;
↑ed HCO3
-
↑ed pH
Respiratory
Alkalosis
Body compensates:
Excretes HCO3
-, Na+,
Ca2+; BUT…
Retains Cl-
Hypokalemia and
dehydration

3.  Hypokalemia (mild toxicity); Hyperkalemia (severe toxicity);
 Stimulate metabolism (generally) causing Hyperthermia.
 Damage hepatocytes Renal dysfunction; ↑ed plasma
enzyme activity;
 ↑ed PT time; ↓ed platelet aggregation;
 Interferes w/ Carbohydrates metabolism
↑ed conc. of lactic acid, ketones and inorganic acids
HAGMA: Due to ↑ed conc. of acid in the body
Anion Gap;
High Anion
Gap;
Delta Ratio;
AG formula

4. Clinical Features
Mild Poisoning:
• Tachycardia; Hyperpnoea; Respiratory Alkalosis
• Tinnitus
• Alkaline Urine ( pH > 6)
Severe Poisoning:
• Convulsions; Coma;
• Respiratory and Cardiac Failure; Cerebral and pulmonary
oedema
• AKI; Acidosis;

5.  Salicylates are weak acids that cross cell membranes
relatively easily (they are more toxic when blood pH is
low).
 Dehydration, hyperthermia, and chronic ingestion
increase salicylate toxicity because they result in
greater distribution of salicylates to tissues.
 Excretion of salicylates increases when urine pH
increases.

6. Suspect Salicylate poisoning if patients present with
any of the following
H/o a single acute overdose
Repeated ingestions of therapeutic doses
Unexplained metabolic acidosis
Unexplained confusion and fever (in elderly
patients)
Other findings compatible with sepsis (fever,
hypoxia, non-cardiogenic pulmonary oedema,
dehydration, hypotension)

7.  The symptoms of acute salicylate poisoning may be minimal
initially with severe toxicity not evident until 6-12 hours.
 There is a poor correlation between salicylate concentration
and toxicity (Organs and systems deterioration may still occur
with falling serum concentrations due to rising CNS
concentration).
 In moderate to severe salicylate poisoning, consider
decontamination (activated charcoal) and the early
enhancement of elimination (urinary alkalization with or without
haemodialysis).

8. SALICYLATE DOSAGE CLINICAL EFFECTS
<150mg/kg Minimal symptoms
150-300mg/kg Mild-moderate symptoms:
Tinnitus, vomiting, hyperventilation
>300mg/kg Severe symptoms:
Acidosis, seizures, hyperthermia

9. Ix:
 Positive Ferric Chloride test (blood or urine sample)
 Blood salicylate levels:
• 50-110 mg/dl 6-hrs post-ingestion (mild-moderate intoxication);
• >110 mg/dl 6-hrs post-ingestion (severe intoxication; often fatal);
 Elevated Hct, WBC count, platelet count;
 Hypo- and Hyper- natremia; kalemia;
 Hypoglycemia
 Respiratory alkalosis; Metabolic acidosis;
 Respiratory alkalosis + Metabolic acidosis;
 Prolonged PT time
ABGs

10. Significant salicylate toxicity:
 Serum levels > therapeutic range (10 - 20 mg/dL),
particularly 6 hrs. post-ingestion (when absorption is
usually almost complete),
 Acidemia plus ABG results compatible with salicylate
poisoning.
• Serum levels are helpful in confirming the diagnosis
and may help guide therapy, but levels may be
misleading and should be clinically correlated.

11. ABGs result (usually):
 Primary respiratory alkalosis (during the first few hours
after ingestion);
 Later, they show compensated metabolic acidosis or
mixed metabolic acidosis/respiratory alkalosis.
 As salicylate levels decrease, poorly compensated or
uncompensated metabolic acidosis is the primary
finding.
 If respiratory failure occurs, ABGs suggest combined
metabolic and respiratory acidosis, and CXR shows
diffuse pulmonary infiltrates. Plasma glucose levels
may be normal, low, or high.
 Increased serum CK and urine myoglobin levels
suggest rhabdomyolysis.

12. Management:
 Gastric lavage performed for upto 12 – 24 hrs.
 Activated charcoal:
• Initial dose 1g/kg
• Subsequent doses 25 g Q2H for 3 doses, or
50 g Q4H for 2 doses;
 For dehydration: 0.9% NS and Potassium as indicated;
Correct electrolyte imbalance;
Oxygen and glucose may be required.
 For severe acidosis, treat with bicarbonate (pH < 7.15);

13.  Forced Alkaline Diuresis: Is indicated if/ in case of..
• Salicylate level > 50 mg/dl;
• Very symptomatic patient;
• Patient w/ increasing salicylate levels;
 Forced diuresis can be safely initiated if the urine flow rate is at
least 4 ml/min.
 If not, give IV Frusemide 20 – 40 mg.
 Even after this, if urine flow rate is still < 4 ml/min., abandon
the procedure as renal insufficiency is present.

14.  Regime of IV infusion:
• 500 ml D5% + 50 ml of 8.4% NaHCO3
• 500 ml D5% + 1 g KCl (if no hyperkalemia)
• 500 ml NS + 40 mg frusemide
• Given at a rate of 500 ml/hr.

15.  The above cycle can be repeated for 2-3 times for 24-
48 hrs.
 Monitor the following:
• Urine output (target > 4ml/min.);
• I/O chart
• Urine pH 7-8
• Potassium levels

16.  Monitor for fluid overload in pulmonary and cerebral
oedema cases (mostly among geriatric patients);
 Forced diuresis should be stopped in oliguric patients.
 Serum salicylate levels should be checked regularly
until a consistent downward trend is observed in 2
successive readings.

17. FYI:
 Alkaline diuresis is indicated for patients with any
symptoms of poisoning and should not be delayed until
salicylate levels are determined.
 This intervention is usually safe and exponentially
increases salicylate excretion.
 As hypokalemia may interfere with alkaline
diuresis, patients are given a solution consisting of 1 L
of 5% D/W, three 50-mEq ampules of NaHCO3, and 40
mEq of KCl at 1.5 to 2 times the maintenance IV fluid
rate. Serum K is monitored.
 As fluid overload can result in pulmonary edema,
patients are monitored for respiratory findings.

18. TDM Pointers -
Paracetamol Poisoning

19.  Paracetamol N-acetyl-p-benzoquinoneimine (toxic)
Inactivated
 This interaction is concentration-dependent.
 Large overdose:
• Glutathione is depleted.
• N-acetyl-p-benzoquinoneimine binds to hepatic cell membranes,
causing necrosis.
Glutathione Conjugation
Cyt.P-450

20. Clinical Features:
 1st 24 hrs.: Vomiting; diaphoresis; pts. are usually fully
conscious;
 After 24 hrs.: Hepatic enzymes’ conc. ↑es; peaks at 72-96 hrs.;
Rt. Upper quadrant pain, coagulopathy, jaundice, somnolence,
coma;
 Normally, recovery commences on 4th day post-ingestion, if
hepatic failure does not occur.

21.  Ix:
• If patient presents within 1-4 hrs. post-ingestion, plasma
paracetamol conc. should be estimated within 4 hrs. post-
ingestion.
• If it is ER product, one additional estimation should be done 4-
6 hrs. after the first estimation.
• AST, ALT, Sr. bilirubin, BU, PT time, and Sr. Creatinine levels
should be estimated daily for 3 days.
• Suspected fulminant liver failure cases: Additionally estimate
the Sr. glucose and ABG levels.

22. Management:
 For Pts. presenting within 1 hr.:
• Gastric lavage;
• Activated charcoal (one stat dose of 1 g/kg within 4 hrs. of
ingestion);
 Acetylcysteine (IV or oral) – if paracetamol concs. are above
toxic levels;
 Patients on enzyme-inducing drugs (CBZ, phenobarbitone,
phenytoin, rifampicin, etc.) can develop toxicity at lower
plasma paracetamol concs. They should be administered
acetylcysteine if plasma paracetamol concs. are > 50%
of the std. ref. values.
 For max. hepatoprotective effect, initiate Tx within 8-10
hrs. post-ingestion.

23.  Tx should be stopped if the conc. falls below the treatment line.
 Acetylcysteine IV: Continuous Infusion in D5%
1) 150 mg/kg in 200 ml over 15 mins., followed by
2) 50 mg/kg in 500 ml over 4 hrs., then followed by
3) 100 mg/kg in 1000 ml over 16 hrs.
 Acetylcysteine oral: 140 mg/kg stat, followed by 70 mg/kg Q4H
for 17 additional doses;
 Pts. w/ hepatic failure may require longer duration of admn.
( > 72 hrs.); Oral preparation may be more useful; End points
are clinical improvement and INR < 2.0

24.  Acetylcysteine should be used with caution in asthmatic
patients as it can induce bronchospasm.
Indications for acetylcysteine:
 Pt. ingested > 150 mg/kg paracetamol;
 Pt. has Hx of excessive ingestion of paracetamol.
 Sr. paracetamol cannot be done or is not available within 8 hrs.
 Pt. w/ unknown ingestion time, and Sr. paracetamol level > 10
mcg/ml;
 Lab evidence of hepatotoxicity (AST or ALT > 1000 IU/L);

25. Side effects:
If flushing: Can continue acetylcysteine infusion;
If urticaria: Stop the infusion;
Treat w/ IV antihistamine;
Restart infusion once symptoms resolve;
Hypotension or respiratory symptoms: Switch from
IV form to oral acetylcysteine;

26. Nomogram for paracetamol intoxication

27. THE END