1. VOLATILE POISONS

2. ETHANOL TOXICITY

3. Uses
1- Ingredient for many tinctures, elixirs, spirits 2- Cosmetic industry:perfumes, aftershaves,.. 3- Solvent 4- Antidote 5- Wide recreational (prohibited in Libya) use - Beers , Wines - Distilled beverages (Whisky, Vodka..)

4. Absorption: 20% stomach & 80% upper small intestine. GASTRIC EMPTYING
INCREASED
Tolerance to the alcohol.
Gastrectomy.
Type of beverage.
DECEASED
Presence of food in the stomach (milk & carbohydrates).
Drugs (e.g. atropine).
Emotional state.
Solutions with concentrations above 20% are absorbed slowly , inhibit gastric peristalsis and cause pylorospasm.

5. Blood Concentration Alcohol in blood can be detected after 5 min
Maximum concentration within min.
One unit alcohol increases blood level in females more than that in males because of:
Smaller body mass in women
Higher fats & lesser fluids in the body.
Diminished “first-pass” metabolism of alcohol in the gastric mucosa because of lesser alcohol dehydrogenase

6. Bioavailability Destroyed in gut Not absorbed Destroyed by gut wall
by liver
Dose to
systemic
circulation

7. Peak blood ethanol concentrations develop more slowly after rapid ingestion due to the irritant properties of ethanol.
Little difference in rate of absorption of the same dose of ethanol administered in the form of different alcoholic beverages.
This is important for forensic considerations, i.e., blood ethanol concentration is not significantly influenced by the type of alcoholic beverage consumed.

8. Distribution & Equilibrium
Alcohol enters various organs of the body as well as spinal fluid, urine, and pulmonary alveolar air, etc.
Alcohol is distributed in body water. Tissues rich in water take up more alcohol than those rich in fat do.
Equilibrium between tissues and blood takes place within 1-2 hours.
Elimination
About 10% of alcohol are excreted as such mainly through urine and breath and only negligible amount in sweat and faeces.

9. Metabolism in the liver
First Step
1- About 90% of the ingested alcohol are oxidized in the cytoplasm by alcohol dehydrogenase.
2- Catalase system: peroxisomes & mitochondria.
3- Microsomal ethanol-oxidizing system: smaller amount of alcohol is converted to acetaldehyde.
Second step
metabolism of acetaldehyde, which is converted to acetate by the effect of aldehyde dehydrogenase and the presence of NAD as cofactor.
Ethanol Acetaldehyde acetate
H2O + CO2

11. Acetaldehyde & Alcoholism:
Rule of acetaldehyde
Flushing syndrome caused by disulfiram & in Flushers (Chinese & some other Asians).
Acetaldehyde & Alcoholism:
Acetaldehyde activate dopaminergic neurons in dopaminergic neurons in ventral tagmental area which project to nucleus accumbens inducing reward pathway.
Stimulates release of beta endorphin.
Stimulates hypthamaic-pituitary access which release stress mediators which are involved in addiction set up.
Malta Medical Journal Volume 23 Issue

12. The reward pathway Ventral Tegmental Area(VTA),
Nucleus accumbens (NA) &
Prefrontal cortex (PFC).
VTA is connected to both NA & PFC via this pathway sending information via its dopaminergic neurons,
Dopamine released in NA & PFC

13. Metabolic adaptation (Tolerance)
Besides CNS adaptation, alcoholics (in the absence of liver disease) often have an increased rate of blood alcohol clearance.
This is called metabolic tolerance
Suggested mechanisms include:
Induction of ADH.
Increased reoxidation of NADH
Induction of CYP2E1 (the most active cytochrome P450 for oxidizing ethanol).
Clearance: rate of chemical elimination from the body per unit of time.

14. Blood Alcohol Curve
Alcohol concentration rises steeply to a distinct maximum (absorption phase). Peak concentration is reached after minutes (average 60 minutes).
Irregularly curved fall due to a period of diffusion within the tissues to equilibrium (15-30 minutes).
The BAC then falls progressively in linear fasion (elimination phase).

15. Blood Alcohol Curve
Fluctuations due to metabolism min min (Diffusion) Absorption Elimination

16. Factors that Affect Alcohol Absorption
Time of consumption
Type of alcoholic beverage
Presence of food in stomach

17. Alcohol is an example of Zero-order kinetics
Zero-order reaction
First-order reaction
The reaction proceeds at a constant rate and is independent of the concentration .
dA/dt = KA0
The reaction proceeds at a rate that is dependent on the concentration
dA/dt = KA1

18. Zero Order Elimination
10000
Zero Order Elimination
1000
Plasma Concentration
100 10 1 1 2 3 4 5 6
Time
logCt = logCo - Kel . t
2.303

19. Forensic Significance of Zero-order kinetics
The rate of elimination of ethanol is mg/dl/hour
At very high concentrations >200mg% over 12 hours are required to eliminate 200mg%.

20. Limits of blood alcohol content (BAC)
In Libya, alcohol is prohibited.
The alcohol level at which a person is considered to be legally impaired varies by country.
The list below gives limits by country. These are typically BAC limits for the operation of a vehicle.

21. Serum level 112 mg% = 100 mg% in whole blood.
Criminal Code of Canada reports legal limit for ethanol as 80 milligrams per 100 millilitres of blood (80 mg%).
Also expressed as 0.08 g/100 ml blood.
Serum/Plasma versus Whole Blood
Serum contains more alcohol than whole blood by a factor of 1.12:1.
Serum level 112 mg% = 100 mg% in whole blood.

22. Blood Alcohol legal lmits (g/dl)
ZERO
0.02
0.03
0.04
0.05
0.08
LIBYA
China
India
lituania
Australia
Canada
Islamic countries??
Estonia
Japan
Others
Malaysia
Slovakia
Poland
Russia
Malta
Romania
Norway
Urguay
Mexico
Brazil
Sweden
USA
Chech Rep
Puorto Rico
United kingdom
Hungary

23. Mode of Action
Direct effect by its lipid solubility, interacts with membrane lipoproteins.
It causes depression of CNS through several mechanisms:
Binds directly to GABA receptor in the CNS and causes sedative effects similar to those of BDZ.
Antagonist effect N -methyl-D-aspartate (NMDA) glutamate the CNS.
- Depression of CNS.
Releasing inhibition: euphoric effect.
Acts on the frontal lobe, psychic area, cerebellum, spinal cord, and finally the medulla.
Inhibits (1) higher nervous centers (control conduct & judgment), (2) motor centers (3) the vital organs.
The effect on the spinal cord leads to initial increase in deep tendon reflexes.

24. Movement: Slower, Inaccurate, Random Impairment of mental function:
interfering with the speed of perception
Interfering with the mental processing
slower learning, decreased focusing, concentration, judgment, discrimination, and thinking.
2- Acid-base disturbances: HIGH ANION GAP METABOLIC ACIDOSIS
3- Hypoglycemia (or hyperglycemia). Hypoglycemia most common.
4- Hypothermia

25. In young children, ethanol causes hypoglycemia and hypoglycemic seizures. Hypoglycemia occurs secondary to ethanol's inhibition of gluconeogenesis and secondary to the relatively smaller glycogen stores in the livers of young children.
In toddlers who have not eaten for several hours, even small quantities of ethanol can cause hypoglycemia.

26. CLINICAL MANIFESTATIONS
Phase I: Excitation ( mg/100ml)
Excitement, euphoria, and increased confidence
Talkative and argues on every point
Inhibition of self-control.
Face is flushed and the conjunctiva is injected
Pupils are dilated with sluggish light and accommodation reactions.
Judgment is impaired while mental alertness can be retained.

27. Phase II: Incoordination (Confusion)
BAC up to 300mg/100ml.
Important for medicolegal purposes
Incoordination of thought, speech, and action
Pupils are dilated and react sluggishly to light and accommodation
Sense of perceptions and skilled movements are affected
Ataxia.
There may be hangover due to brain edema, toxic effects of alcohol on the brain, GIT, and liver.

28. Phase III: Coma (Narcosis)
BAC is more than 300mg/100ml.
Motor and sensory cells are deeply affected.
Speech becomes thick and slurring
Incoordination is more marked the person staggers and falls
Gradually, he enters into coma and cannot be awakened by deep stimuli and reflexes are abolished.
Pupils may be constricted.

29. Serum level (mg/100ml) = Osmolar gap x 4.6
Clinical Diagnosis
Serum level (mg/100ml) = Osmolar gap x 4.6

30. Analysis of BAC
Breath Tests
Field Sobriety Tests
Blood Tests

31. The Breathalyzer

32. Other breath tests Infrared and Fuel Cell Breath Tests
Infrared Breath Test uses infrared wavelengths to test for alcohol or other interferences in the breath
Fuel Cell Test converts fuel (alcohol) and oxygen into a measurable electric current

33. Field Sobriety Tests Horizontal Gaze Nystagmus
Involuntary eye jerk as eye moves horizontally
Walk and Turn (divided attention tasks)
One-Leg Stand

34. Collection and preservation of blood
Use nonalcoholic disinfectant like
Povidone-iodine (Betadine)
Benzalkonium chloride (Zepiran)
Mercuric chloride
Stored in airtight container with anticoagulant and preservative under refrigeration

35. Pathological Alcohol intoxication (mania a potu)
Rare
Extraordinary severe response
Marked by apparently senseless violent behavior, usually followed by exhaustion, sleep and amnesia for the episode.
It is used by criminals to form legal defense against their criminal activities.

36. TREATMENT ABC: IV dextrose & 100 mg of thiamine.
Gastric lavage in noncomatose patients, if the patient comes early after the ingestion. The lavage should be done, at the beginning, with plain water, from which a sample should be sent for chemical analysis. The next wash will be done by NaHCO3. This will prevent further absorption and help for acidosis.

37. Maintain body temperature, especially in cold weather.
Others causes of coma should be excluded.
Treat acidosis if ABG results show low pH.
Hemodialysis or hemoperfusion may be considered in severe cases.

38. ALCOHOLISM
Alcoholism is a term used to mean compulsive & uncontrolled consumption of alcohol.
Several other terms are used, specifically "alcohol abuse" and "alcohol dependence" which have more specific definitions.
Alcohol dependence : an individual uses alcohol despite significant areas of dysfunction, evidence of physical dependence, and/or related hardship, and also may cause stress and bipolar disorder.
In 1979 an expert WHO committee discouraged the use of "alcoholism" in medicine, preferring the category of "alcohol dependence syndrome“.
The WHO estimates that there are 140 million people with alcoholism worldwide
In LIBYA, NO DATA
In USA, It costs annually billion dollars

39. CHRONIC ALCOHOLISM
Daily use of large amounts of alcohol for adequate functioning.
Regular heavy drinking limited to weekends.
Long periods of sobriety interspersed with binges of heavy alcohol intake lasting for weeks or months.

40. CHRONIC ALCOHOLISM Associated behaviors as:
Inability to stop drinking: Repeated efforts to control or reduce excessive drinking or restricting drinking to certain times
Binges (remaining intoxicated for at least 2 days).
The continuation of drinking despite a Binges.
Amnestic periods for events while intoxicated (blackouts).
The continuation of drinking despite a serious physical disorder that the person knows is exacerbated by alcohol use.
The drinking of nonbeverage alcohol such as fuel.
Impaired social and occupational functioning

41. Complications of Alcohol Withdrawal
1- Withdrawal Seizures
2- Impending delirium Tremens: common alcohol withdrawal syndrome. Mild to moderate agitation, tremor, insomnia, loss of blood pressure control. Acute alcoholic hallucinations, with auditory hallucinations.
Generalized tremor the most is the most obvious feature of the illness.
3- Delirium Tremens
Most severe form of withdrawal syndrome.
A medical emergency.
Due to severe cortical and brainstem hyperexcitability, cerebral edema, and increased pressure of CSF.
Onset follows 3-5 days after cessation of drinking.
Mortality is 20% if untreated, usually as a result of an intercurrent medical illness such as pneumonia, renal disease, hepatic insufficiency, pancreatitis, or heart failure.

42. Forensic Considerations
Time lag from consumption to peak level determined by factors affecting absorption.
Ethanol elimination rates; genetic, sex, age, Wt.
Partition ratio: differences between blood, breath, and urine ratios.
Fluctuations and anomalies: factors that change in blood levels of alcohol due to changes in absorption and elimination.

43. Postmortem appearance
External: congestion of conjunctiva, odor of alcohol around mouth and nose.
Internal: congestion of GIT, pulmonary and cerebral edema, congestion of other viscera.
In chronic alcoholism there may be additional features:
Fatty or cirrhotic liver
Degenerative changes in the brain.

44. METHANOL TOXICITY

45. Also called wood alcohol obtained by destructive distillation of wood.
Widely used as solvent and found in paint, varnish
Used as Antifreeze
Surgical spirit: Ethanol & Methanol.

46. Methanol Uses Gas Line Antifreeze 100% Windshield washer fluid 30%
Varnish removers
Fuel for food warming 3-70%
Industrial uses

47. Mechanism of toxicity
Methanol is slowly metabolized by ADH to formaldehyde and subsequently by aldehyde dehydrogenase to formic acid (formate).
Systemic acidosis is caused by the formic acid as well as by lactic acid, while blindness is caused primarily by formate.
Both ethanol and methanol compete for the enzyme alcohol dehydrogenase; the preference of this enzyme for metabolizing ethanol forms the basis for ethanol therapy in methanol poisonings

48. Toxicokinetics
Methanol is readily absorbed and quickly distributed to the body water . It is not protein bound.
It is metabolized slowly by alcohol dehydrogenase at a rate about one-tenth that of ethanol.
The reported “half-life” ranges from 2–24 hours.
Only about 3% is excreted unchanged by the kidneys and less than 10% through the breath.

49. METHANOL FORMALDEHYDE FORMATE
Formate is responsible for:
1- Ocular Toxicity
2- Acidosis
Mortality & Morbidity is related more to formate concentration (time between ingestion & initiation of therapy) rather than to initial methanol concentration).

50. Clinical Features Initially similar to ethanol toxicity
After a latent period (8-36 hours): nausea, vomiting, abdominal pain, severe metabolic acidosis, visual disturbances, cerebral edema, seizures, coma, & death.
Optic neuritis leads to blindness. The pupils are dilated and fixed.
In over dose, death is caused by respiratory paralysis.
Fatal Dose: approximately ml. Even as little as 10 ml may cause serious illness. Blindness has occurred even after a dose of 4 ml.
Toxicity, also, occur by inhalation and through skin.
Fatal Period: (6 – 30 hours).

51. Methanol Toxicity Delayed onset (8-36hrs) Anion gap acidosis Tachypnea
Visual complaints
Retinal metabolism
“Snow storm”
Optic atrophy with cupping 2 months after surviving
Pt with non-reactive pupils and min light perception
Yang CS et al Eye 2005;19:

52. University of Western Ontario:
Methanol Toxicity
CNS depression
Bilateral hemmorhage putamen
Abdominal pain
Multisystem organ failure
University of Western Ontario:
Neurology Collection

53. Diagnosis
Diagnosis is usually based on the history, symptoms, and laboratory findings because methanol levels are rarely available.
Methanol level = osmolal gap x 3.2
A large anion gap (not due to elevated lactate) suggests possible methanol (or ethylene glycol) poisoning.

54. Diagnosis Specific levels
Serum methanol levels higher than 20 mg/dL should be considered toxic, and levels higher than 40 mg/dL should be considered very serious. After the latent period, a low or nondetectable methanol level does not rule out serious intoxication in a symptomatic patient because all the methanol may already have been metabolized to formate.
2. Elevated serum formate concentrations may confirm the diagnosis and are a better measure of toxicity, but formate levels are not yet widely available.

55. Treatment Stabilization of the patient
Correction of metabolic acidosis by IV NaHCO3
Elimination
Induction of emesis or gastric lavage may be done.
Hemodialysis
Methanol level > 25 mg/dl
Formate level > 50mg/dl
Severe metabolic acidosis
Antidotes
Ethyl alcohol as the antidote.
The new antidote Fomepizole.
Folinic Acid it accelerates the conversion of formic acid to carbon dioxide and water

56. Postmortem appearance
Similar to ethanol
Toxic damage in liver and kidney
Lungs may reveal edema

57. ETHYLENE GLYCOL TOXICITY

58. Ethylene Glycol

59. Ethylene glycol is the primary ingredient (up to 95%) in antifreeze.
It is sometimes intentionally consumed as an alcohol substitute by alcoholics and is tempting to children because of its sweet taste. Intoxication

60. Mechanism of toxicity.
Metabolized by alcohol dehydrogenase to glycoaldehyde, which is then metabolized to glycolic, glyoxylic, and oxalic acids. These acids, along with excess lactic acid, are responsible for the anion gap metabolic acidosis.
Oxalate readily precipitates with calcium to form insoluble calcium oxalate crystals. Tissue injury is caused by widespread deposition of oxalate crystals and the toxic effects of glycolic and glyoxylic acids

61. ETHYLENE GLYCOL ETHYLENE GLYCOL GLYCOALDEHYDE GLYCOLIC ACID
Alcohol dehydrogenase
GLYOXYLIC ACID and OXALIC ACID cause toxicity
development of serious toxic effects is delayed while these acids are generated and accumulate in blood and tissues
OXALIC ACID combines with serum and tissue calcium, causing hypocalcemia and the formation of calcium oxalate crystals.
GLYCOALDEHYDE
Aldehyde dehydrogenase
GLYCOLIC ACID
metabolized by alcohol dehydrogenase in the liver to glycoaldehyde, which is further converted to glycolic acid by aldehyde dehydrogenase. Glycolic acid is metabolized to glyoxylic acid and oxalic acid, which cause toxicity. The development of serious toxic effects is delayed while these acids are generated and accumulate in blood and tissues. Oxalic acid combines with serum and tissue calcium, causing hypocalcemia and the formation of calcium oxalate crystals.
GLYCOXYLIC ACID AND
OXALIC ACID

62. Clinical Manifestations
Stage 1: Neurological (30 minutes to 12 hours after ingestion)
Within minutes to several hours, similar to ethanol symptoms of may be observed. Nausea and vomiting can also occur.
As metabolism progresses, metabolic acidosis and CNS depression can replace earlier symptoms.
Approximately 4-12 hours after ingestion, symptoms associated with toxic metabolites of EG predominate.
In severe cases, these symptoms can include coma associated with hypotonia, hyporeflexia, occasional seizures, and meningismus.
Cytotoxicity and the deposition of calcium oxalate can lead to cerebral damage and contribute to CNS depression.
Other neurological symptoms may include nystagmus, ataxia, opthalmoplegia, and myoclonic jerks. In most cases of ethylene glycol poisoning, the optic fundus is normal; however, in some situations, the presence of papilledema may confuse the clinical presentation with that of methanol poisoning.

63. Stage 2: Cardiopulmonary (12-24 hours after ingestion)
tachycardia and mild hypertension frequently occur.
In serious cases, severe metabolic acidosis with compensatory hyperventilation can develop accompanied by multiple organ failure.
Most deaths occur in this stage.

64. Stage 3: Renal (24-72 hours after ingestion)
The symptoms of the third stage can include oliguria, flank pain, acute tubular necrosis, renal failure and, in rare instances, bone marrow suppression.
In severe cases of ethylene glycol poisoning, renal failure may appear early and progress to anuria.
Recovery of renal function is often complete but may require several months of hemodialysis.
Serious damage to the liver is rare.

65. Estimation of serum level (mg/dl)= Osmolar gap x 6.2
Diagnosis
History of antifreeze ingestion, typical symptoms, and elevation of the osmolar and anion gaps.
Oxalate or hippurate crystals may be present in the urine (crystals may be cuboidal or elongate in form).
Because many antifreeze products contain fluorescein, the urine may fluoresce under Wood’s lamp, depending on the amount ingested, the time since ingestion, and the urine concentration.
Estimation of serum level (mg/dl)= Osmolar gap x 6.2

66. Calcium oxalate crystals
Folded envelope

67. Serum Level
Serum levels higher than 50 mg/dL are usually associated with serious intoxication, although lower levels do not rule out poisoning if the parent compound has already been metabolized (in such a case, the anion gap should be markedly elevated).
Calculation of the osmolar gap may be used to estimate the ethylene glycol level.
False-positive ethylene glycol levels can be caused by elevated triglycerides
In the absence of a serum ethylene glycol level, if the osmolar and anion gaps are both normal and the patient is asymptomatic, then serious ingestion is not likely to have occurred.

68. Treatment Stomach lavage with calcium salts.
Forced diuresis to eliminate the nonmetabolized part.
In the IV infusion 10% calcium gluconate will be added as an antidote to oxalic acid.
Ethyl alcohol to prevent further oxidation

69. Fomepizole is the newer antidote.
Pyridoxine, folate, and thiamine cofactors required for the metabolism of ethylene glycol that may decreasetoxicity by enhancing metabolism of glyoxylic acid to nontoxic metabolites.
Correction of metabolic acidosis.
Treatment of complications; pulmonary edema, shock, etc.

70. Fomepizole 4-methylpyrazole (4MP) Potent inhibitor of ADH
Has an affinity for ADH x of ethanol
Limited toxicity
Safely used in France since 1981(1)
2 US multi centre prospective trials confirmed efficacy(2,3)
Megarbane B, Borron SW, Trout H et al. treatment of acute methanol poisoning with fomepizole. Intensive Care Med :
Brent J, McMartin K, Phillips S et al. Fomepizole for the treatment of ethylene glycol poisoning. NEJM :
Brent J, McMartin K, Phillips S et al. Fomepizole for the treatment of methanol poisoning. NEJM :

71. Due to efficacy & safety profile
Current recommendations for treatment of severe toxic alcohol poisonings. Intensive care med. 2005
Fomepizole
Due to efficacy & safety profile
Recommended as 1st line antidote in confirmed ethylene glycol / methanol poisoning
Also recommend initial fomepizole dose
Suspicion of toxic alcohol ingestion
In presence of metabolic acidosis with elevated anion gap unexplained by equivalent increase in serum lactate

72. Peritoneal dialysis, hemodialysis or hemoperfusion.
Fatal Dose: ml. In children 3-4 ml/kg.

73. Postmortem appearance
cerebral edema
Toxic damage of liver and kidneys
Oxalate crystals in brain, spinal cord and kidneys

74. Alcohol dehydrogenase
Methanol
CH3OH
Ethylene Glycol
CH2OH-CHO
Alcohols
Alcohol dehydrogenase
Glyoxalate
CH2OH-CHO
Formaldehyde
HCHO
Aldehyde
dehydrogenase
Metabolic acidosis
Formate
HCOO-
Glycolate
CH2OH-COO-
Acids
Blindness
Coma & seizures
folate
Coma
Renal failure
Oxalate
COO--COO-
+ Ca2+
CO2 + H2O
Myocarditis
Hypocalcaemia

75. HYDROCARBONS Petrolium Distillates

76. Widely used in the petroleum, plastic, agricultural, and chemical industries as solvents, degreasers, fuels, and pesticides.
A hydrocarbon is any chemical containing hydrogen and carbon (essentially, any organic compound).
There are many subcategories of hydrocarbons, including aliphatic (saturated carbon structure), alicyclic (ring compounds), aromatic (containing one or more benzene ring structures), halogenated (containing chlorine, bromine, or fluoride atoms), alcohols and glycols, ethers, ketones, carboxylic acids, and many others.

77. Aliphatic form: includes kerosene, gasoline, furniture polish, petroleum ether, petroleum naphtha, lubricating oils
Aromatic hydrocarbons: benzene, xylenes,
etc.
The toxicity of hydrocarbons is generally indirectly proportional to the agent’s viscosity. Products with high viscosity (150 – 250), such as heavy greases and oils, considered to have limited toxicity.

78. Mechanism of Toxicity Pulmonary Aspiration: Chemical peumonitis.
Ingestion:
1- Aliphatic (kerosene) poorly absorbed by GIT giving less systemic toxicity.
2- Aromatic (benzene) are capable of causing systemic toxicity after ingestion such as convulsion, coma, cardiac arrhythmias.
Inhalation: vapors in an enclosed space may cause systemic intoxication.

79. Clinical Manifestations
After Inhalation:
Gasoline and kerosene produce symptoms resembling alcoholic intoxication.
The early effects of exposure are: headache, nausea, vomiting, dyspnea, and variety degrees of cyanosis and confusion.
Within few hours may progress to tachypnea, wheezing, chemical pneumonitis.
Muscular incoordination, convulsions, coma.
With more severe injury, pulmonary edema, hemoptysis.
Cardiorespiratory arrest.

80. After Ingestion Often causes- abrupt nausea, vomiting.
Irritation of upper GIT.
Occasionally hemorrhagic gastroenteritis.
Diarrhea (may be bloody), less common.
Some compounds may be absorbed and produce systemic toxicity:
There may be confusion, ataxia, lethargy, headache.
With severe exposure; syncope, coma, and respiratory arrest

81. Postmortem Appearance
1- characteristic odor
Froth at mouth and nostrils
Cyanosis of extremities
Congestion of GIT
Pulmonary edema, lung changes
Fatty change in liver
Cardiomyopathic changes