Presentation

1. 1
ORGANOPHOSPHATE POISONING (OPP)
BY: W. M . CHEELO (ML)

2. 2
Background
 Organophosphates and carbamates are the most
frequently used insecticides world wide.
 Cause 80% of reported toxic exposure of
insecticides.
 Organophosphates were first discovered more
than 150 years ago.
 Widespread use began in German in the 1920s as
insecticides and chemical warfare agents.

3. 3
pathophysiology
 Organophosphates are absorbed through the
skin, respiratory and gastrointestinal tracks
 Some opp are very lipophilic and may be released
from fat depots over a period of many days
 Metabolism occurs by oxidation and hydrolysis by
esterases and by reaction with glutathione.

4. 4
Pathophysiology cont
 Elimination is mostly in the urine and
lesser amounts in he faeces and expired
air.
 OPP forms an irreversible bond with
cholinesterase.
 Effects of acetylcholine are then
pronounced.

5. 5
Patho cont
 Acetylcholine is found in;
 Parasympathetic and sympathetic ganglia
 Terminal postganglionic parasympathetic
nerves at the motor endplates of nerves in
the skeletal muscle
 Nicotinic stimulation leads to fasculations

6. 6
cont
 Muscarinic effects occur at the
postganglionic parasympathetic synapses.
 Acetylcholine receptors are widely
dispersed throughout the CNS

7. 7
Clinical features
 Most symptoms appear within 12-24 hours
of exposure.
 Muscarinic findings include;
 Salivation, lacrimation, urination, diarrhea
 Wheezing or broncoconstriction
 Pulmonary edema

8. 8
Muscarinic fetures con
 Increased pulmonary and oropharyngeal
secretions
 Sweating
 Bradycardia
 Abdominal cramping and intestinal
hypermotility
 miosis

9. 9
Nicotinic features
 Muscle fasculations
 Fatigue
 Paralysis
 Respiratory muscle weakness
 Diminished respiratory effort
 Tachycardia
 hypertension

10. 10
CNS findings
 Anxiety, seizures, coma
 Restlessness
 Confusion
 Headache
 Slurred speech
 Ataxia, hypotonia
 Central respiratory paralysis

11. 11
Clinical features cont
 Predominant s/s vary according to the age
of affected person
 Children present with altered level of
consciousness rather classic salivation,
urination, GI distress, emesis etc

12. 12
Lab studies
 FBC
 Chemistry tests to rule out electrolyte
disturbances.
 RBS and urinalysis
 Toxicology

13. 13
Other investigations
 CXR
 ECG

14. 14
DIAGNOSIS
 Based on clinical features: muscarinic &
nicotinic effects
 Confirmed by measuring plasma or preferably
RBC cholinesterase activity.
 Cholinesterase activities may be reduced to 30
– 50% in asymptomatic patients, 10 – 20% in
moderate poisoning and < 10% in severe
poisoning

15. 15
TREATMENTS LIKELY TO BE BENEFICIAL
ATROPINE
Considered mainstay of treatment
 Benefits: Reverses the early muscarinic effects of acute
OPP. Its effectiveness is beyond question.
 Harms: Excessive treatment results in toxicity -
confusion & tachycardia
 Dose: 2 mg IV every 10 - 30 mins till adequate
atropinisation (initial dose of 6 mg IVin life-threatening
cases) then every 1-4hrs for 24 hrs; not to exceed 50
mg in first 24 h (or 2 g over several days if intoxication
severe)

16. 16
TREATMENTS LIKELY TO BE BENEFICIAL
ATROPINE cont’d
 The endpoints for atropinization are heart rate >100
beats/min, midsized pupils, dryness of pulmonary
secretions & present bowel sounds
 Up to 3 days treatment may be needed

17. 17
BENZODIAZEPINES
Diazepam is considered standard treatment for OPP
induced seizures
 Benefits: controls seizures in acute OPP
 Harms: excessive treatment with diazepam may result in
respiratory depression requiring intubation and ventilation.
However, this is also a direct complication of OPP, and it is
difficult to distinguish between the two

18. 18
GLYCOPYRRONIUM BROMIDE
(GLYCOPYRROLATE)
 Glycopyrronium bromide has similar effects to atropine in
humans, but is more selective for peripheral cholinergic
synapses, resulting in less tachycardia and confusion than
occur with atropine
 It has been used instead of atropine because it is thought
to have fewer adverse effects on the central nervous
system.
 It is not widely used and is more expensive

19. 19
GLYCOPYRROLATE cont’d
 Comparison with atropine: A small RCT (39 people)
comparing glycopyrollate versus atropine found no
significant difference between atropine and
glycopyrronium bromide in death rates, need for
ventilation [Bardin PG, van Eeden SF. Organophosphate poisoning: grading the
severity and comparing treatment between atropine and glycopyrrolate. Crit Care
Med 1990;18:956–960]
 Animal studies have found that glycopyrronium
bromide is less effective than atropine at controlling
bradycardia and central nervous system complications
of OPP

20. 20
oximes
 Oximes (such as pralidoxime, obidoxime)
reactivate cholinesterases inhibited by OPP.
 Reactivation is limited by aging of the
acetylcholinesterases and high concentrations of
pesticides
 Should be given within 12 hrs for optimum effect
 May still be effective in the first 24 to 48 hrs after
exposure especially with highly lipophilic OPPs
(accumulate in fat and are gradually released.

21. 21
OXIMES cont’d
 Treatment may be beneficial if continued
for as long as the person is symptomatic
because it may take several days for the
pesticide concentration to drop below the
point at which the rate of reactivation
surpasses reinhibition
 Benefits: Studies in people with OPP have
not been able to prove clinical benefit with
oximes [Eddleston M, Szinicz L, Eyer P, et al. Oximes in acute
organophosphorus pesticide poisoning: a systematic review of
clinical trials. Q J Med 2002;95:275–283]

22. 22
OXIMES cont’d
Adverse effects
 Adverse effects of oximes include hypertension,
cardiac dysrhythmias (including cardiac arrest with
rapid administration), headache, blurred vision,
dizziness, and epigastric discomfort.
 Such adverse effects with pralidoxime have been
reported only with either rapid administration or doses
greater than 30 mg/kg bolus. It may be difficult to
distinguish these adverse effects from the effects of
organophosphorus [Bismuth C, Inns RH, Marrs TC. Efficacy, toxicity
and clinical uses of oximes in anticholinesterase poisoning. In: Ballantyne
B, Marrs TC, eds. Clinical and experimental toxicology of
organophosphates and carbamates. Oxford: Butterworth Heinemann,
1992:555–577]

23. 23
Activated charcoal
ACTIVATED CHARCOAL (SINGLE OR MULTIPLE DOSE)
 No human studies available on patients with OPP
 Benefits & harmful effects unknown
ALPHA2 ADRENERGIC RECEPTOR AGONISTS
(CLONIDINE)
 Clonidine inhibits the release of acetylcholine from
cholinergic neurones and has alpha2 adrenergic agonist
effects.

24. 24
ALPHA2 ADRENERGIC RECEPTOR AGONISTS
(CLONIDINE) cont’d
 Animal studies have found that treatment with clonidine
improves survival after organophosphorus poisoning;
combination with atropine was more than additive.
 This treatment has not yet been studied in OPP in humans.

25. 25
GASTRIC LAVAGE
GASTRIC LAVAGE
 Effective within 30 min. of ingestion (may still be
effective up to 4hrs)
MILK OR OTHER HOME REMEDY SOON AFTER ORAL
OPP EXPOSURE
 The lay practice of giving a “home remedy” soon after
ingestion, before bringing the poisoned person to
hospital, is common
 Problems may occur when large volumes of fluid are
given “to dilute the poison” or to make the person vomit.
 Gastric emptying of a fluid is proportional to volume

26. 26
Home remedies cont
 It is therefore believed that increasing the
volume of fluid in the stomach increases the rate
of emptying into the small bowel where the
pesticide is absorbed
 Giving fluids therefore risks speeding the onset of
poisoning and causing respiratory arrest before
the patient arrives at a healthcare facility.

27. 27
Organophospharus hydrolases
 Animal studies have found that organophosphorus
hydrolases (such as mammalian paraoxanase or the
bacterial hydrolase isolated from Pseudomonas
species) cleave organophosphorus compounds.
 These may prove beneficial for managing pts with
OPP
 However so far there are no human studies

28. 28
N-METHYL-D-ASPARTATE RECEPTOR ANTAGONISTS
Primate studies have found that treating OPP with NMDA
receptor antagonists, such as gacyclidine, improves
clinical recovery, reduces neural death, and improves
EEG activity
However no studies done in humans

29. 29
SODIUM BICARBONATE
 Animal studies suggest that increasing the pH with sodium
bicarbonate reduces mortality
 This effect is independent of correction of acidosis because
it is seen in animals that are not acidotic
 The mechanism of action of sodium bicarbonate in
organophosphorus poisoning is unknown

30. 30
Sodium bicarbonate
 Studies conducted in Brazil [Wong A, Sandron CA, Magalhaes AS, et al.
Comparative efficacy of pralidoxime vs sodium bicarbonate in rats and humans
severely poisoned with O-P pesticide. J Toxicol Clin Toxicol 2000;38:554–555] and
Iran [Balali-Mood M, Ayati MH, Ali-Akbarian H. Effects of high doses of sodium
bicarbonate in acute organophosphate pesticide poisoning. J Toxicol Clin Toxicol
2003;41:383] have claimed good results in uncontrolled
studies.

31. 31
COMPLICATIONS OF OPP
 Intermediate syndrome can develop 24-
96hrs.
 It comprises; weakness in motor cranial
nerves and proximal muscles
 Delayed peripheral neuropathy may
develop days to weeks after exposure.
 Persistent fatigue, lethargy and memory
loss

32. 32
conclusion
 Prognosis for patients treated early is
good. Most patients fully recover 7-10
days
 Patients not treated > 24hrs may have
prolonged and severe complications
 Death is related to respiratory failure and
may also be due to cardiac dysrhythmias

33. 33
THE END

34. 34
ACID & ALKALI INGESTION

35. 35
COMPLICATIONS
Acute
 Oephageal perforation
 Gastric and intestinal perforation
 Upper GI haemorrhage
 Airway obstruction

36. 36
Late
 Stricture formation (oesophageal strictures & pyloric
stenosis)
 Stricture formation is usually evident between 14-21 days
post ingestion and most manifest clinically within the first
two months

37. 37
MANAGEMENT
AVOID
 Gastric lavage & emesis: risk of further injury on re-
exposure of the oesophagus
 Neutralising chemicals: heat is produced during
neutralisation and this could exacerbate any injury

38. 38
GASTRO-OESOPHAGOSCOPY
 Should be done within 12 to 24 hours of the event to
assess the extent and severity of the injury
 Endoscopy is contraindicated in patients with 3rd degree
burns of the hypopharynx, burns involving the larynx or
those with respiratory distress
 If perforation is suspected or severe hypopharyngeal burns
are present, radiographic studies with water-soluble
contrast media may be used instead

39. 39
GENERAL PRINCIPLES
 Nil by mouth till extent of injury has been
determined
 Supportive treatment: treat shock, correct
acid/base balance, intubation & ventilation for pts
with resp distress
 Parental analgesics as needed for pain
 Pts with minor oesophageal injuries may be
discharged once they are able to take oral fluids.
 Pts with more extensive injuries should be given
parenteral nutrition and admitted to ICU

40. 40
LONG-TERM TREATMENT OBJECTIVE IN CAUSTIC
INGESTION
 Main objective is to reduce stricture formation
 Several authors have found that it is the depth of the
initial burn rather than the initial treatment which
determines the outcome [Anderson et al., 1990; Moazam et al., 1987;
Oakes et al., 1982; Webb et el., 1970]
 The difficulty here is determining the severity of the
injury from oesophagoscopy since it is difficult to
determine the depth of the burn and the endoscope is
sometimes not passed beyond the first identified burn
due to the risk of perforation

41. 41
THE USE OF STEROIDS IN CORROSIVE
INJURY
 Steroids have an anti-inflammatory effect and decrease
fibroblastic activity and scar tissue formation.
 Animal data has demonstrated that strictures formed in
subjects given steroids have been less well structured with
fewer inflammatory changes and less fibrin deposition.
 The use of steroids for corrosive injury in man is however
controversial

42. 42
THE USE OF STEROIDS IN CORROSIVE INJURY
cont’d
 Steroids are valuable in the management of laryngeal
oedema, a complication of alkali ingestion
 Steroids are probably most effective for 2nd degree or
moderately severe burns [Hawkins et al., 1980; Klein-Schwartz
and Oderda, 1983; Webb et al., 1970]
 They are not necessary for 1st degree burns since these
burns usually heal without stricture formation
 They appear to be ineffective in preventing stricture
formation following 3rd degree burns. Some burns are
so severe and extensive that strictures may develop
despite steroid therapy [Haller et al, 1971]

43. 43
THE USE OF STEROIDS IN CORROSIVE INJURY
cont’d
 There is no clinical evidence that steroid therapy is
more effective than non-steroid therapy in reducing
stricture in any patient, even those with 2nd degree
burns
 Some authors believe there is no place for steroid
therapy in the management of corrosive injury [Di
Costanzo et al., 1980; Wijburg et al., 1989].
 Oakes et al. (1982) stated that clinicians should not
feel compelled to institute steroid therapy for
caustic oesophagitis simply because it is considered
'standard therapy'.

44. 44
THE USE OF STEROIDS IN CORROSIVE INJURY
cont’d
CONTRAINDICATIONS TO STEROID THERAPY
 Active infection
 Perforation of the GIT or secondary mediastinitis
 Significant GI bleeding
 History of or active ulcer

45. 45
THE USE OF STEROIDS IN CORROSIVE INJURY
cont’d
PROBLEMS OF STEROID THERAPY
 Steroids depress the immune system and as a
result the patient is more susceptible to infection
 Steroids may mask the signs and symptoms of
infection as well as those of perforation and
peritonitis
 Steroid therapy may result in a thin-walled
oesophagus vulnerable to perforation due to
reduced wound healing and scar formation [Cardona
and Daly, 1971]

46. 46
THE USE OF STEROIDS IN CORROSIVE INJURY
cont’d
WHEN TO BEGIN STEROID THERAPY
 Should be started within 24 to 48 hours of the injury
because the major inflammatory insult occurs within the
first 48 hours and after this time steroids have little
antifibroblastic activity.
 Therapy started later may reduce scar formation but all
evidence indicates that the best results are obtained
with early institution of therapy [Haller et al., 1971].
 The short duration of steroid therapy (48 hrs) should not
produce a significant reduction in intrinsic steroid
production or alter the metabolic balance.

47. 47
USE OF ANTIBIOTICS IN CORROSIVE INJURY
 Antibiotics should be used in all patients with evidence of
infection.
 Some authors suggest that prophylactic antibiotics should
be given in patients on steroid therapy [Adam and Birck, 1982;
Howell et al., 1992], but others considered this unnecessary [Klein-
Schwartz and Oderda, 1983; Wijburg et al., 1989] since the risk of
infection is low [Knopp, 1979].

48. 48
ADJUNCTIVE TREATMENT
 The use of H2-blockers and metoclopramide may help to
prevent secondary acid injury to the esophagus [Haddad, 1998].
 H2-blockers reduce mucosa’s exposure to gastric acid, and
this may result in decreased stricture formation

49. 49
REFERENCES
 Adam JS and Birck HG. (1982) Pediatric caustic ingestion. Ann Otol
Rhinol Laryngol 91:656-658
 Anderson KD, Rouse TM and Randolph JGH. (1990) A controlled trial
of corticosteroids in children with corrosive injury of the oesophagus. N
Eng J Med 323 (10):637-640
 Cardona JC and Daly JF. (1971) Current mangement of corrosive
esophagitis. An evaluation of results of 239 cases. Ann Otol 80:521-527
 Di Costanzo J, Noirclerc M, Jouglard J, Escoffier JM, Cano N, Martin
J and Gauthier A. (1980) New therapeutic approach to corrosive burns
of the upper gastrointestinal tract. Gut 21:370-375

50. 50
REFERENCES cont’d
 Haller JA, Andrews HG, White JJ, Tamer MA and Cleveland
WW. (1971) Pathophysiology and management of acute
corrosive burns of the esophagus: results of treatment in 285
children. J Pediatr Surg 6 (5):578-584
 Howell JM, Dalsey WC, Hartsell FW and Butzin CA. (1992)
Steroids for the treatment of corrosive esophageal injury: a
statistical analysis of past studies. Am J Emerg Med 10:421-425
 Klein-Schwartz W and Oderda GM. (1983) Management of
corrosive ingestions. Clin Toxicol Consult 5 (2):39-5
 Knopp R. (1979) Caustic ingestions. JACEP 8:329-33
 Moazam F, Talbert JL, Miller D and Mollitt DL. (1987) Caustic
ingestion and its sequelae in children. South Med J 80:187-190

51. 51
REFERENCES cont’d
 Oakes DD, Sherck JP and Mark JBD. (1982) Lye ingestion. Clinical
patterns and therapeutic implications. J Thorac Cardiovasc Surg 83:194-
204
 Webb WR, Koutras P, Ecker RR and Sugg WL. (1970) An evaluation
of steroids and antibiotics in caustic burns of the esophagus. Ann Thorac
Surg 9:95-102
 Wijburg FA, Heymans HSA and Urbanus NAM. (1989) Caustic
esophageal lesions in childhood: prevention of stricture formation. J
Pediatr Surg 24 (2):171-173

52. 52
CHLOROQUINE POISONING
TOXICITY
 Chloroquine has a low margin of safety;
 The therapeutic, toxic & lethal doses are very
close
 20 mg/Kg is a toxic dose, 30 mg/Kg may be
lethal & 40 mg/Kg is usually lethal without early
intensive therapy
 In adults fatalities have been reported after
ingestion of 2.25 to 3 g chloroquine
 Without treatment, a dose of 4 g is usually lethal

53. 53
CHLOROQUINE POISONING
CLINICAL FEATURES OF TOXICITY
 Toxic manifestations appear rapidly within 1 to 3 hours after
ingestion
 CVS (CQ has quinidine-like [membrane stabilizing] actions on the
heart): conduction disturbances, hypotension, cardiogenic shock,
cardiac arrest. ECG - flatteming of T wave, widening of QRS,
ventricular tachycardia & fibrillation.
 Neurological symptoms: drowsiness, blurred vision, diplopia,
blindness, convulsions & coma
 RS: apnoea
 GIT: severe GI irritation; nausea, vomiting, cramps, diarrhoea.
 Hypokalaemia [< 3 mmol/L] (severe poisoning)

54. 54
CHLOROQUINE POISONING
Mild poisoning
 < 2g ingested, plasma conc < 2.5 mg/L
 Serum potassium 3.5 - 4 mmol/L
 Visual disturbances, vomiting
Moderate poisoning
 2 - 3.5 g ingested, plasma conc 2.5 - 5 mg/L
 Serum potassium 2.8 - 3.5 mmol/L
 ECG: increased QT, decreased T wave
 Visual disturbances, vomiting

55. 55
CHLOROQUINE POISONING
Severe poisoning
 > 3.5 - 4 g ingested, plasma conc > 5 mg/L
 Serum potassium < 2.8 mmol/L
 ECG: widening of QRS followed by sinus bradycardia,
ventricular tachycardia, ventricular fibrillation and finally
asystole.
 Cardiac failure, convulsions

56. 56
CHLOROQUINE POISONING
PROGNOSIS
 Criteria of severe intoxications are: dose ingested higher
than 3 to 4 g, hypotension, cardiogenic shock, QRS
widening, ventricular arrhythmias, hypokalaemia
 Severity of the intoxication is closely related to the
serum potassium concentration
CAUSE OF DEATH
 The cause of death is circulatory arrest which occurs
predominantly during the first few hours of the
intoxication & is related to cardiac insufficiency or
ventricular arrhythmia.

57. 57
CHLOROQUINE POISONING
MANAGEMENT
Admit to ICU
Decontamination
 Gastric lavage
 Activated charcoal 50 - 100 g (within 1 hr of ingestion)
[recommended at the end of gastric lavage and repeated
every 4 hours for 24 hours]
Severe hypotension
 Adrenaline is the drug of choice: 0.25 - 0.1 µg/kg/min. 5
mg adrenaline is diluted in 250 ml of 5% dextrose to
produce a conc of 20 µg/ml.
 Others: dopamine, isoprenaline

58. 58
CHLOROQUINE POISONING
Bradyarrhythmia, AV block
 Isoprenaline
Ventricular tachycardia, fibrillation
 Cardioversion
Hypokalaemia
 Initial hypokalaemia may be protective because potassium and
quinidine- like drugs have a synergistic cardiotoxic effect
 Persistent hypokalaemia beyond 8 hours after the ingestion favours
ventricular dysrhythmia & should be corrected.
 Administer potassium continuously with frequent control of plasma
potassium levels & ECG monitoring (every 4 hours)

59. 59
CHLOROQUINE POISONING
Respiratory depression
 Artificial ventilation
Protection against arrhythmias
Sodium hypertonic solutions: may be effective in conduction
disturbances due to quinidine-like membrane stabilizing effects.
 Molar sodium lactate: 100 to 250 ml over 15 to 45 min
 Molar sodium bicarbonate: administer 100 to 250 ml of molar
sodium bicarbonate solution (8.4 g per cent) over 15 to 45 min
Diazepam: has some protective effect against arrhythmias.
Experimental and clinical studies have shown that diazepam may
exert a protective effect against chloroquine cardiotoxicity

60. 60
CHLOROQUINE POISONING
Diazepam cont’d
 Dose: 2 mg/kg within 30 mins followed by IV infusion
of 2 - 4 mg/kg/24 hrs
 Chloroquine cardiotoxicity is rarely observed later
than 48 hours after ingestion. Diazepam
administration after the 48th hour is therefore not
justified.
MONITORING
 ECG
 BP
 Respiration
 Serum electrolytes esp potassium

61. 61
CHLOROQUINE POISONING
TREATMENTS INEFFECTIVE & NOT RECOMMENDED
Emesis
 Because coma, cardiac & respiratory arrests may occur 1
- 2 hours post-ingestion, emesis is contraindicated
unless done immediately after ingestion.
Cathartics
 The usefulness of cathartics has not been established.
 Cathartics should be used with caution because shock &
hypokalaemia are frequent.

62. 62
CHLOROQUINE POISONING
TREATMENTS INEFFECTIVE & NOT RECOMMENDED
cont’d
Forced diuresis
 Forced diuresis has no role coz the elimination of CQ in
urine is low
 Urine CQ elimination is more dependent on the
haemodynamic status than on infusion of osmotic
solutions or acidification of urine.
Dialysis
 Peritoneal dialysis and haemodialysis are ineffective in
removing CQ from the body (CQ has a large volume of
distribution therefore little remains in plasma)

63. 63
CHLOROQUINE POISONING
TREATMENTS INEFFECTIVE & NOT RECOMMENDED
cont’d
Haemoperfusion
 Haemoperfusion is not recommended
 The amount removed by haemoperfusion is insignificant
(only 5%)

64. 64
PARACETAMOL POISONING
 More common in Western countries
 Up to 40% of all admissions to hospital with self-poisoning
in the UK involve paracetamol
 Severity is dose related.
 An absorbed dose of >= 12g in adult is potentially serious
 Plasma concs > 250 mg/L at 4 hrs or 50 mg/L at 12 hrs are
usually associated with hepatic damage

65. 65
PARACETAMOL POISONING
MECHANISM OF PARACETAMOL TOXICITY
 At therapeutic doses 95% of paracetamol is metabolised by
glucuronidation + sulfation to conjugates & 5% is
metabolised thru oxidation via a cytochrome P450
dependent glutathione (GSH) conjugation pathway
 Oxidation gives N-acetyl-p-benzoquinone imine (NAPBQI),
which is conjugated with GSH and excreted as
mercaptopuric acid
 At high doses, the glucuronidation + sulfation pathways are
saturated and the Cyt P450 pathway becomes more
important
 When excessive amounts of NAPBQI are formed, GSH is
depleted

66. 66
PARACETAMOL POISONING
MECHANISM OF PARACETAMOL TOXICITY cont’d
 With depletion of GSH, NAPBQI forms conjugates with
tissue protein-bound SH groups. The covalent binding
results in destruction of cells & necrosis of the liver
 The antidotes N-acetylcysteine (NAC) & methionine (Met)
supplement endogenous SH groups & reduce conjugation
with protein.
 Synthesis of new GSH depends on the availability of
cysteine
 Cysteine is a precursor for GSH (methionine is a precursor
for cysteine): NAC & Met therefore increase GSH synthesis

67. 67
PARACETAMOL POISONING
High risk patients
 Pre-existing liver disease
 Malnutrition
 HIV related disease
 Pts taking enzyme-inducing drugs
 Chronic alcoholics
Clinical features
 Anorexia, nausea & vomiting
 Liver damage usually only detectable by routine
LFTs at least 18 hrs after drug ingestion

68. 68
PARACETAMOL POISONING
 Maximum liver damage as assessed by ALT/AST & PT
occurs 72 - 96 hrs after ingestion
 Hepatic failure may develop between 3rd and 5th day
 Renal failure due to acute tubular necrosis develops in
about 25% of pts with severe hepatic damage
 Hypophosphataemia (due to phosphaturia) indicates renal
tubular damage

69. 69
PARACETAMOL POISONING
FOUR STAGES OF PARACETAMOL TOXICITY
Stage I (0-24 hours)
 Anorexia, nausea, vomiting, malaise, diaphoresis or may
be asymptomatic.
Stage II (24-72 hours)
 RUQ pain or may be asymptomatic. Increase in
transaminases, bilirubin & PT may begin to occur.
Stage III (72-96 hours)
 Fuminant hepatic & multi-system failure may occur.
Significant increases in transaminases, bilirubin & PT
Stage IV (96 hours - 2 weeks)
 Hepatic recovery should occur in patients that survive
stage 3

70. 70
PARACETAMOL POISONING
MANAGEMENT
Decontamination
 Gastric lavage (if ingestion has occurred within 1 hr)
 Activated charcoal 50 - 100 g (prevents significant
absorption of paracetamol if administered less than 1 hr
after dosing)
ANTIDOTES
 Methionine & N-acetylcysteine (NAC). NAC is more
effective than methionine (fewer steps in conversion to
GSH)
 Administer within 8 - 10 hrs for opimum effect
 They act by replenishing cellular glutathione stores
 NAC also repairs oxidation damage caused by NAPBQI

71. 71
PARACETAMOL POISONING
 N-acetylcysteine (NAC) is the antidote of choice for
paracetamol toxicity.
 NAC acts as a glutathione substitute, increases glutathione
synthesis and increases sulphate conjugation of
paracetamol
DOSING REGIMENS
NAC (IV)
 150 mg/kg in 5% dextrose, 200 mls over 15 mins then
 50 mg/kg in 5% dextrose 500mls over the next 4 hrs and
 100 mg/kg in 5% dextrose 1000 mls over the next 16 hrs
 Total dose: 300 mg/kg over 20.25 hrs

72. 72
PARACETAMOL POISONING
NAC (PO)
 140 mg/kg initially, then 17 4-hrly doses of 60 mg/kg
 Total dose: 1330 mg/kg over 72 hrs
Side effects of NAC: rashes, anaphylaxis
METHIONINE (PO)
 2.5g initially, then three 4-hrly doses of 2.5g
 Total dose: 10g over 12 hrs
 Side effects: nausea, vomiting, drowsiness, irritability

73. 73
PARACETAMOL POISONING
PRESENTATION > 24 HRS AFTER OVERDOSE
 Treatment is aimed at preventing or supporting hepatic &/or renal
failure.
 An extended course of NAC has been recommended: 20.25 hrs
standard regimen + continued administration of the 16-hr infusion
until recovery or death

74. 74
PARACETAMOL POISONING
TREATMENTS OF UNKNOWN EFFECTIVENESS
Cimetidine
 Rationale: blocks the hepatic cytochrome P450 mixed
function oxidase system therefore would reduce the
production of NAPBQI, the toxic metabolite of paracetamol
 However there is insufficient clinical evidence supporting its
efficacy in paracetamol overdosage
TREATMENTS SHOWN TO BE INEFFECTIVE
 Haemodialysis & haemoperfusion have not been shown to
be effective in removing paracetamol.

75. 75
PARACETAMOL POISONING
POOR PROGNOSTIC FACTORS
 Peak PT > 180 secs
 Acidosis (pH < 7.3) developing > 24 hrs after overdose
 Serum creatinine > 300 micromol/L
LIVER TRANSPLANTATION
 Liver transplantation may be the only option in pts in whom
signs of hepatic failure occur despite NAC therapy
 Arterial blood lactate may distinguish those likely to require
liver transplantation (> 3.5 mmol/L) from those likely to
survive without it

76. 76
PARACETAMOL POISONING
CRITERIA FOR LIVER TRANSPLANT
When the patient has indications of irreversible hepatic
toxicity and potential multi-system failure:
 Evidence of acidosis
 Coagulopathy that does not respond to therapy or that
persists as transaminases decrease
 Hypoglycaemia
 Renal failure
 Hypotension (mean arterial pressure less than 60mmhg)
 Encephalopathy

77. 77
PARACETAMOL POISONING
KINGS COLLEGE HOSPITAL CRITERIA FOR HEPATIC
TRANSPLANTATION
(Oxford Handbook of clinical Medicine 5th Ed)
 Arterial ph < 7.3
Or all of the following
 PT > 100 sec
 Creatinine > 300 micromol/L
 Grade III encephalopathy

78. 78
ACETYLSALICYLIC ACID POISONING
PRIMARY EFFECTS OF SALYCYLATE OVERDOSE
 Stimulation of the respiratory centre
 Inhibition of citric acid cycle (carbohydrate metabolism)
 Stimulation of lipid metabolism
 Inhibition of amino acid metabolism
 Uncoupling of oxidative phosphorylation

79. 79
ACETYLSALICYLIC ACID POISONING
TOXIC DOSES
 Mild to moderate toxicity 150-300 mg/kg
 Serious toxicity 300-500 mg/kg
 Potentially lethal > 500 mg/kg
CLINICAL FEATURES
Mild to moderate intoxication (< 700 mg/L)
 Deafness, tinnitus
 Nausea, vomiting
 Hyperventilation
 Sweating

80. 80
ACETYLSALICYLIC ACID POISONING
Mild to moderate intoxication (< 700 mg/L) cont’d
 Vasodilatation
 Tachycardia
 Respiratory alkalosis
 Metabolic acidosis
Severe intoxication (> 700 mg/L)
 All symptoms of mild to moderate intoxication
 Confusion
 Delirium
 Hypotension
 Cardiac arrest

81. 81
ACETYLSALICYLIC ACID POISONING
Less common complications
 Non-cardiogenic pulmonary oedema
 Cerebral oedema
 Convulsions
 Coma
 Encephalopathy
 Renal failure
 Tetany
 Hyperpyrexia
 Hypoglycaemia
 Hyperglycaemia

82. 82
ACETYLSALICYLIC ACID POISONING
MANAGEMENT
Treatment of acute salicylate poisoning is directed primarily
towards:
 Prevention of absorption
 Correction of acid-base & fluid & electrolyte balance
 Enhancing elimination of the drug (in patients with features
of moderate to severe intoxication)

83. 83
ACETYLSALICYLIC ACID POISONING
DECONTAMINATION
 Induce emesis
 Gastric lavage
ASA is poorly soluble in an acid environment and may
coalesce to form a mass or coating in the stomach, from
which absorption may continue slowly over many hours.
Thus gastric lavage may be indicated >12 hours following
ingestion of the overdose
 Activated charcoal 50 - 100 mg

84. 84
ACETYLSALICYLIC ACID POISONING
ENHANCING ELIMINATION
 Forced diuresis by urine alkalinisation (to attain a pH of 7.5
- 8.5) with 225ml of 8.4% sodium bicarbonate
 Multi-dose activated charcoal (dose: 50 – 100 g start then
12.5 g/hr via NG tube) will increase the non-renal
elimination of salicylate and will greatly reduce the plasma
half-life
 Haemodialysis: in severely poisoned patients with features
of CNS toxicity, pulmonary oedema, renal failure, cerebral
oedema and in cases with plasma levels higher than > 700
mg/L (5.1 mmol/L) haemodialysis should be considered

85. 85
ACETYLSALICYLIC ACID POISONING
 Haemodialysis is preferred to haemoperfusion
because it more rapidly corrects acid-base &
electrolyte abnormalities & may avoid the need for
the administration of large amounts of sodium
bicarbonate
 Peritoneal dialysis is less effective than alkaline
diuresis, is 2 - 3 times less effective than
haemodialysis, and its use is not recommended
 Charcoal haemoperfusion is less effective than
haemodialysis & its use is not advocated

86. 86
ACETYLSALICYLIC ACID POISONING
SUPPORTIVE TREATMENT
 Correct metabolic acidosis (with IV sodium bicarbonate)
dehydration & electrolyte imbalance
 If non-cardiogenic pulmonary oedema is present, mechanical
ventilation with positive end-expiratory pressure (PEEP) may be
indicated

87. 87
ORAL ANTICOAGULANTS
Coumarin derivatives e.g. warfarin are used in most
rodenticides
Clinical features
 The target system is the haematological system,
with impairment of clotting
 The main risks are associated with potentially fatal
GI & intracerebral haemorrhage
 If toxic amounts have been ingested, coagulation
will be impaired, with gum bleeding, epistaxis,
ecchymosis, haematomata, haematemesis,
melenae, haematuria.

88. 88
ORAL ANTICOAGULANTS
DIAGNOSIS
The diagnosis is based on:
 H/o exposure (generally by ingestion of a rodenticide)
 Clinical evidence of bleeding, which may appear 1 to 2 days
post ingestion
 Abnormal prothrombin time (PT)
 Activated partial thromboplastin time (APTT) is also
abnormal

89. 89
ORAL ANTICOAGULANTS
PROTHROMBIN TIME
 PT monitoring is essential
 For the first 5 to 6 days it should be done at least daily, &
repeated even if results were normal upon admission
 PT may initially be normal, even in a severe poisoning
because vitamin K-dependent clotting factors have a long
half-life and are still circulating several hours after warfarin
starts its effect

90. 90
ORAL ANTICOAGULANTS
OTHER INVESTIGATIONS
 FBC
 Urinalysis (haematuria)
 Stool exam
 Toxicological analysis (although a sensitive HPLC technique
exists, it is not clinically useful)

91. 91
ORAL ANTICOAGULANTS
TREATMENT
Decontamination
 If <24 hours has elapsed: activated charcoal 50 - 100 mg
 Gastric lavage not necessary if activated charcoal can be
given promptly & should be avoided in patients who are
already anticoagulated
 If > 24 hours have elapsed: decontamination measures are
not effective & the pt should be monitored closely using PT
& APTT
Elimination
There is no role for enhanced elimination procedures

92. 92
ORAL ANTICOAGULANTS
ANTIDOTES
 Phytomenadione (vitamin K1) should be administered
 If PT is significantly reduced vitamin K1 should be
administered intravenously starting with 10mg each 6
hours (40 mg/day)
 The dosage should be adjusted according to the PT
LIFE SUPPORTIVE TREATMENT
Severe acute haemorrhage: whole blood, fresh frozen
plasma, prothrombin complex concentrate (factors II,
VII, IX & X) for correcting coagulopathy

93. 93
ORAL ANTICOAGULANTS
MANAGEMENT DISCUSSION
 There is no concensus on the appropriate administration schemes
for vitamin K. Some authors give oral vitamin K prophylactically in
cases where ingestion is uncertain.
 The usual route for treatment is intravenous, although in some
cases it has been given intramuscularly or subcutaneously.
 The use of phenobarbital as an hepatic microsomal enzyme
inducer is controversial.