13 Poisoning

SECTION 13

Poisoning 112.

Approach to the Patient with Unknown Poisoning Biranchi Narayan Mohapatra, CBK Mohanty

529

113.

Management of Snake Bite in India Shibendu Ghosh, Prabuddha Mukhopadhyay

532

114.

Mushroom Poisoning Bhupen Barman, KG Lynrah, Iadarilang Tiewsoh

538

115.

Approach to Common Poisoning in Punjab Gursaran Kaur Sidhu

542

116.

Therapeutic Plasma Exchange and Continuous Renal Replacement Therapy as Rescue Therapy in Paracetamol Induced Fulminant Hepatic Failure Rajesh Mishra

547

C H A P T E R

112

Approach to the Patient with Unknown Poisoning

Poisoning is a common cause mortality and morbidity in India like many other countries in the world.

While pesticide poisoning is common in India many other poisoning are emerging like alcohol, sedatives, antipsychotics, anti-depression, cardiovascular drugs, analgesic, antimicrobial, herbal and plant products, household materials, homeopathic medicines and illicit drugs. The toxic agents can enter body by injection, inhalation and through skin. The number of possible causes of poisoning are large and that unless proper diagnosis is made in systematic way the diagnosis may be missed and the patient can be lost. Once diagnosed rational use of treatment will reduce the chance of deaths.

Suspecting possible poisoning are the cause of illness is most important in initating treatment. Factors that raises this suspicion of poinsoning include acute behavioural changes, concerns raised by family members and friends regarding possible poisoning and pills found in patients possession. The importance of taking the detailed history can not be over emphasised. However attempts to identify poison should not delay life saving supportive care.

Biranchi Narayan Mohapatra, CBK Mohanty

Table 1: Toxic Vital Signs and its Causes - Bradycardia: Oleander, organophosphorous poisoning and anticholinisterase drugs, betablockers, clonidine, calcium channel blocker, antiarrythmics alcohol, opioids.

- Tachycardia: Anticholinergic, antihistaminics, antipsychotic, sympathomimetics (Cocoine, Caffeine, Amphitamine) Theophilline, Thyroid hormone, trycyclic antidepressant (TCA) - Hypothermia: Alcohol, Sedatives and hypnotics, Hypoglcaemic agent, opioids, Carbon monoxide.

- Hyperthermia: Anticholinergics, antidepressants, antipsychotic, antihisteminics, salicylate, Alcohol withdrawal, Hypertension, Hypotension, Antihypertensive, Rodenticide, Antidepressants, Sedatives, Opiates, Heroin.

- Hypertension: Thyroid hormone, cocaine, sympathomyetics, Caffeine, Anticholiergic, Nicotine.

-

Rapid Respiration: OP Poisoning, Chemical pneumonitis, salicilate toxin included metabolic acidosis and nerve agents, paraquat.

-

Slow respiration: Sedatives, Alcohol, Opioids, Marijuna.

CLINICAL ASSESSMENT

Poisoning can be present with various clinical symptoms including abdominal pain, vomiting, tremor, altered mental status, seizure, cardiac dysrhythmias, respiratory depression. Some of the vital signs can give a clue to diagnosis.

Toxic Vital Signs

Toxic vital signs such as bradycardia, tachycardia, hypo & hyperthermia, hypo & hypertension, respiratory variability, seizure & coma, odour, cynosis, pupilary size can give clue to the diagnosis (Table 1).

Toxidromes

- Coma: Op poisoning, Alcohol, Ethyleneglycol, Tricyclinic Antidepressant, Anti-convulsant agents, anti-psychotics, anti-depressants, anti-histaminics, hypoglycaemic agents, isoniazid, heavy metals, hepatic encephalopathy.

-

Agents causing Seizure: Organo phosphorous poisoning (OP), Hypoglycaemic agent, isoniazid, salicylate, tricyclic antidepressant, Ethanol withdrawal.

A collection of symptoms associated with certain classes or poisoning is known as toxidrome which helps in making a diagnosis (Table 2).

- Miosis: Organophosphorous compound and other cholinergic agents, carbamates, opiates, clonidine, phenothiazine, sedatives.

Laboratory Test

- Mydriasis: Anticholinegic (Datura, Atropine), Sympathomimetics.

Routine Test: Measurement of electrolyte, blood urea nitrogen, creatinine, glucose, liver function test, bicarbonate and arterial blood gas analysis should be done in all cases. Blood gas analysis will demonstrate anion gap metabolic acidosis which is seen in methanol, ethelene glycol, acetaaminophen, salisylates, metformin, lacteacidosis. Metabolic acidosis with increasing osmolar gap may be present in poisoning due to methanol, ethanol, ethelene glycole.

- Diaphoresis: OP poisoning, salicylates, sympathomimetics.

-

Dry skin: Antihistamines, Anticholinergic

- Cyanosis: Dapsons, hypoxia, aniline dyes, nitrate, Ergotamine, Methhaemoglobinomia.

-

Odour : Garlic - OP Compound, Gasoline Petroleum products.

POISONING

530

Table 2: Toxidrome Syndromes

Symptoms

Common causes

Cholinergesic

Bradycardia, bronchorrhoea, miosis, salivation, wheezing, diarrhoea, diaphoresis

Organophosphorus, Physostigmine, Pyridostigmine

Cholinergic (Nicotinic)

Abdominal pain, fasciculation, Organ phosphorous compound, Nicotine hypertension, paresis, trachicardia, seizure.

Anticholinergic

Delirium, mydriasis, tachycardia, hyperthermia, dry skin, urinary retention

Antihistaminics, Atropine, Tricyclic antidepressants, Psychoactive drugs

Opioids

Miosis, sedation, hypotention, hypoventilation, coma, bradycardia

Opioids

Sympathomimetics

Mydriasis, Trachycardia, Hypertention, Seizure, Hyperthermia

Cocaine, Amphetamine, Ephedrine, Theophylline

gastric lavage in corossive poisoning, volatile hydrocarbon, combating patient, unconscious patients. Orogastric lavage can result in death.

Hence it is not recommended.

Serum cholinesterase estimation is a easier way of knowing organophosphorous poisoning.

ECG to be done in all cases particularly cases with dysrhythimias.

Toxicology Screening : The results are difficult to interpret.

It’s negative result will not exclude poisoning. Large no. of tests are available with high cost, time consuming and difficult to interpret. Therefore it should not be used routinely. Tests specifically related to suspected poisoning should be advised. Drugs whose concentration in blood is associated with treatment recommendations include acetaaminophen, Salicylate, theophiline, lithium, lead, Iron, carbon monoxide, methhaemoglobin, toxic alcohol, anticonvulsant and digoxin may be measured when suspected.

c.

Activated charcoal : Activated charcoal can be used within 1 hr of ingestion of potential toxin.

However it has not shown survival benefits. It is contraindicated in cases with unprotected airways.

Substances not absorbed by activated charcoal are pesticides, potassium hydrocarbon, acid, alcali, alcohol, iron, insecticide, lithium solvent.

Substances that are absorbed by activated charcol are antimalarial, barbiturate, carbamazepin, dapson.

d.

Cathertics : No definite indications for use. A single dose of sorbitol 1 ml/kg may be considered in poisoning due to sustained release/enteric coated drugs.

e.

Whole bowel irrigation : No conclusive evidence that it improved clinical outcome. However it may be considered in ingestion of large doses of enteric coated/sustained release drugs. It is given by infusion through nasogastric tube 1-2 litres of polyethelene glycol.

Gastric fluid analysis is helpful for forensic study but of no clinical use.

Urine testing is helpful in certain cases.

Treatment :Management of acute poisoning should start with basic supportive measures. Most patients do well with supportive care alone.

AIRWAY, BREATHING, CIRCULATION (ABC)

ABC has to be stabilized in every patient. Oxygen saturation can be measured using bed side pulse oxymetry. ABG analysis will further help in assessing the metabolic status which will guide the treatment.

Decontamination

Skin Decontaminations : Removal of dress and cleaning of skin with plain water will prevent poison from absorption from the skin. Hence recommended.

Gastrointestinal decontamination : Controversy exists concerning the role of induced emesis, gastric lavage, activated charchol and cathertics in decontaminating gastrointestinal tract. a.

Ipecac induced emesis is no longer recommended for use in the emergency department.

b.

Gastric lavage is no longer indicated for most ingestion. It may be considered when patients present within one hour of ingestion. No

Anticonvulsant

For toxin induced seizures and alcohol or sedative withdrawal phenytoin is not generally effective.

Benzodiazepins, barbiturates and valpoic acid are considered as 1st and 2nd line therapy.

Coma cocktail

In unknown poisoning with unconsciousness the following cocktail can be considered. a.

IV glucose can be given emperically to combat hypoglycaemia. However availability of urgent blood glucose monitoring will avoid emperical therapy. It will be indicated in hypoglycaemic state.

b.

Naloxone is an opoid antagonist which may be used in suspected cases of opioid overdose with caution. The usual initial dose is 0.4 to 2 mg in IV

Table 3 : Antidote and their Indication in Poisoning Poisoning where indicated

PAM

Organophosphorous

Calcium

Calcium Channel Blocker

n-acetylcysteine

Acetaminophen

Naloxine

Opioids

Physostigmine

Anticholinergics

Ethanol / Fomepizole

Methanol/ethylene glycol

Sodium bicarbonate

Tricyclic antidepressants

Fab fragments

Digoxin

Nitrites

Cyanide

Hyperbaric oxygen

Carbon monoxide

Dextrose, glucagon

Oral hypoglycemics

Methylene blue

Methemoglobinemia

Deferoxamine

Iron

Dimercaprol

Arsenic

Succimer

Lead, mercury

infusion. Flumazenil should not be emperically used as it can induce seizure. c.

Thiamine should be reserved for alcoholic patients.

Thiamine can produce anaphylaxis in certain cases.

ANTIDOTAL THERAPY (TABLE 3)

There should not be indiscriminate use of antidote. The no. of effective antidotes are few. With the exception of naloxone antidote therapy is limited in unknown poisoning. Most poisoning patients can have uneventful recovery with routine supportive care.

Hemodialysis Useful

Charcoal hemoperfusion useful

Salicylates

Theophylline

Alcohol

Barbiturates

Barbiturates

Carbamazepine

Lithium

Paraquat

Ethylene Glycol

Glutethimide

Extracorporeal elimination

Hemodialysis and charcoal hemoperfusion are helpful in certain poison elimination as mentioned in Table 4.

SUMMARY AND CONCLUSION

Treatment of patient with unknown poisoning is challenging. Careful history, clinical examination, routine test and useful supportive care can save life in many cases. Detecting or suspecting a offending poison helps in improving the survival of patients due to better management. It is not difficult. We can do it.

REFERENCES

1.

Erickson TB, Thompson TM, The approach to the patient with an unknown poisoning. Emerg Med Clin in AM 2007; 25:249-281.

2. Van Hoving DJ, Veala DGH, Muller GF. Emergency Management of Acute Poisoning. African Journal of Emergency Medicine 2011; 1:69-78.

3. Frithgen VL, William M, Simpson JR. Recognition and Management Acute Medication poisoning, Am. Fam Physician 2010; 81:316-223.

4.

Muller D, Degel H. Common Causes of Poisoning, Etiology, Diagnosis and Treatment. DTSCH Arztebl Int 2013; 110:690700.

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CHAPTER 112

Antidote

Table 4 : Toxins Accessible to Hemodialysis and Charcoal Hemoperfusion

C H A P T E R

113

Management of Snake Bite in India Shibendu Ghosh, Prabuddha Mukhopadhyay

INTRODUCTION

India is a country known to the western population as a country of snake charmers and snake over centuries.

Despite generation after generations some families in our country who play with snakes (snake charmers), we fail to protect the community from snake bite which requires at least education of the common people, how to protect themselves from snake bite as well as what to do after the bite has occurred.

The estimated death in India is 50,000/ yr, an underestimate because of lack of proper registration of snakebite. The real number of death in our country probably much higher. The persons or population at risk of snakebite in our country is around 50 million people which may occur any time in the life.

The infrastructure of the medical profession in India is mal-distributed in such a manner to protect this poor rural population against the snake bite. Scientifically and ethically we, the doctors can not treat the patients of snake bite properly. Moreover, ignorance of the people around the snake bite victims, the misbelieves about snake bite and ignorance of even the medical profession also play a large part to care this patients in a proper way. There are large number of conflicting protocols for dealing with first aid and treatment. In 2004,WHO established a snakebite Treatment Group, whose role was to develop recommendations to reduce mortality according to international norms. A primary recommendation was to establish a single protocol for both first-aid and treatment which contained evidence based procedures and was relevant to the Indian context. In July 2006, A National Snakebite Conference was convened, including Indian and International experts. Moreover publications issued by the WHO Regional Office for South-East Asia, written and edited by David A. Warrell in the year 2015 and enduring efforts of the scientist and doctors working in different regions of India is the back bone of this editorial.

We have treated about 10000 cases of snake bite patients in Medical College Hospitals, Kolkata, Tarakeswer Rural Hospitals and Seba Nursing Home, Tarakeswar, Hooghly, West Bengal, SRI Hospitals, Betai, Nadia, West Bengal since 1987.

FIRST AID TREATMENT PROTOCOL

Much of the first aid currently carried out is ineffective and dangerous.

Recommended Method for India

Modified by our team in West Bengal.

The first aid being currently recommended is based around the mnemonic.

“CARRY NO R.I.G.H.T.” It consists of the following:

CARRY = Do not allow victim to walk even for a short distance; just carry him in any form, specially when bite is at leg.

No - Tourniquate No - Electrotherapy No - Cutting No - Pressure immobilization Nitric oxide donor (Nitrogesic ointment/ Nitrate Spray) R = Reassure the patient. 70% of all snakebites are from non-venomous species. Only 50% of bites by venomous species actually envenomate the patient.

I = Immobilize in the same way as a fractured limb. Use bandages or cloth to hold the splints, not to block the blood supply or apply pressure. Do not apply any compression in the form of tight ligatures, they don’t work and can be dangerous!

G H = Get to Hospital Immediately. Traditional remedies have NO PROVEN benefit in treating snakebite.

T = Tell the Doctor of any systemic symptoms that manifest on the way of hospital.

Do not waste time for doing the first aid management.

This method will get the victim to the hospital quickly, without recourse to traditional medical approaches which can dangerously delay effective treatment, and will supply the doctor with the best possible information on arrival.

Traditional Methods to Be Discarded

TOURNIQUETS - TOURNIQUET USE IS CONTRAINDICATED IN INDIA

Risk of Ischemia and loss of-the limb.

Increased Risk of Necrosis with 4/5 of the medically significant snakes of India.

Increased risk of massive neurotoxic blockade when tourniquet is released.

Risk of embolism if used in viper bites. Pro-coagulant enzymes will cause clotting in distal blood. In addition, the effect of the venom in causing vasodilatation presents

533

Table 1: Clinical Features of Snakebite Feature

Cobra

Kraits

Russells Viper Saw scaled Viper Humped nose viper

Local Pain/ Tissue damage

Yes

No

Yes

Yes

Yes

Ptosis, Neurological sign

Yes

Yes

No*

No

No

Hemostatic abnormality

No

May Occour

Yes

Yes

Yes

Renal Complication

No

No

Yes

No

Yes

Response to neostigmine

Yes

±

No

No

No

Response to ASV

Yes

Yes

Yes

Yes

No

They do not work! Venom was not slowed by the tourniquet in several experimental studies, as well as in field conditions. Often this is because they are tied on the lower limb or are incorrectly tied.

They give patients a false sense of security, which encourages them to delay their journey to hospital.

SNAKEBITE PREVENTION & OCCUPATIONAL RISK

The normal perception is that rural agricultural workers are most at risk but a large population residing in rural India and semi-urban places are also at risk of snake bite.

• Lateralizing neurological symptoms and asymmetrical pupils may be indicative of intracranial bleeding.

•

Muscle pain indicating rhabdomyolysis.

General signs and symptoms of Elapid envenomation (Table 1) •

Swelling and local pain (Cobra), may be asymptomatic in case of krait patient often could not recognize the bite

•

Local necrosis and/or blistering (Cobra).

• Descending paralysis, initially of muscles innervated by the cranial nerves, commencing with ptosis, diplopia, or ophthalmoplegia.

Preventative Measures

•

Paralysis of jaw and tongue may lead to upper airway obstruction and aspiration of pooled secretions because of the patient’s inability to swallow.

Diagnosis Phase

•

In addition some of the krait bite (Shochoureki) does not respond to ASV of Indian origin. In our study none of the Russell’s Viper presented with neurotoxicity.

Hypoxia due to inadequate ventilation can cause cyanosis, altered sensoriun and coma. This is a life threatening situation and needs urgent intervention.

•

Paradoxical respiration, as a result of the intercostal muscles becoming paralyzed is a frequent sign.

Stomach pain which may suggest sub mucosal hemorrhages in the stomach (Krait).

•

Krait bites often present in the early morning with paralysis that can be mistaken for a stroke.

The areas, time of the day (night) and seasons of the year (monsoon), to be taken into account for preventative measure that usually the people of village adopt.

General assessment : Depending upon type of symptoms.

General signs and symptoms of Viperine envenomation •

Swelling and local pain.

•

Tender enlargement of local lymph nodes as large molecular weight Viper venom molecules enter the system via the lymphatics.

•

Bleeding from the different sites: 1.gingival sulci 2. Epistaxis 3. The skin and mucous membranes 4. sub-conjunctival hemorrhage 5. Acute abdominal tenderness which may suggest gastro-intestinal or retro peritoneal bleeding 6. The passing of reddish or dark-brown urine or declining or no urine output

• Vomiting.

•

Hypotension resulting from hypovolaemia or direct vasodilatation.

•

Low back pain, indicative of a early renal failure or retroperitoneal bleeding, although this must be carefully investigated as many rural workers involved in picking activities complain of back pain generally.

Late-onset envenoming

The patient should be kept under close observation for at feat 24 hours.

DIAGNOSIS PHASE: INVESTIGATIONS

20 Minute Whole Biood Clotting Test (20 WBCT)

Considered the most reliable test of coagulation and should be carried out at the bedside by treating physician.

It can also be carried out in the most basic settings.

A few mililiter of fresh venous blood is placed in a new, clean and dry, glass vessel and left at ambient temperature for 20 minutes. The vessel ideally should be a small glass test tube. The use of plastic bottles, tubes or syringes will give false, readings and should not be used.

The glass vessel should be left undisturbed for 20 minutes and then gently tilted, not shaken. If the blood is still liquid

CHAPTER 113

the danger of massive hypotension and neuroparalysis when the tourniquet is released.

534

then the patient has incoagulable blood. The must not be washed with detergent as this will inhibit the contact element of the clotting mechanism. The test should be carried out every. 30 minutes from admission for three hours and then hourly after that. If incoagulable blood is discovered, the 6 hourly cycle is then be adopted to test for the requirement for repeat doses of ASV.

MANAGEMENT OF SNAKE BITE IN GENERAL

ophthalmoplegia, muscle paralysis, inability to lift the head etc.

•

Cardiovascular abnormalities: hypotension, shock, cardiac arrhythmia, abnormal ECG.

•

Persistent and severe vomiting or abdominal pain.

Severe Current Local envenoming •

Severe current, local swelling involving more than half of the bitten limb (in the absence of a tourniquet). In the case of severe swelling after bites on the digits (toes and especially fingers) after a bite from a known necrotic species.

•

Rapid extension of swelling (for example beyond thewaist or ankle within a few hours of bites on the hands or feet). Swelling a number of hours old is not grounds for giving ASV.

•

Purely local swelling, even if accompanied by bite mark from an apparently venomous snake, is not grounds for administering ASV.

Pain

POISONING

Snakebite can often cause severe pain at the bite site; This can be treated with painkillers such as paracetamol.

Handling Tourniquets

Care must be taken when removing tight tourniquets which most of the time used. Sudden removal can lead to a massive surge of venom leading to neurological paralysis, hypotension due to vasodilatation etc.

•

•

Before removal of the tourniquet, test for the presence of a pulse distal to the tourniquet. If the pulse is absent ensure a doctor is present before removal.

Be prepared to handle the complications such as sudden respiratory distress or hypotension. If the tourniquet has occluded the distal pulse, then a blood pressure cuff can be applied to reduce the pressure slowly.

Anti Snake Venom (ASV)

After assessing patient whenever decision is taken for giving ASV, start ASV whatever dose is available in hand, do not wait for full dose to be available.

In India polyvalent ASV is only available, It is effective against all the four common species; Russells viper (Daboia russelii), Common Cobra (raja naja), Common Krait (Bungarus caeruleus) and Saw Scaled viper (Echis carinatus).

There are known species such as the Hump-nosed pitviper (Hypnale hypnale) where polyvalent ASV is known to be ineffective. In addition, there are regionally specific species such as Sochurek’s Saw Scaled Viper (Echis carinatus sochureki) in Rajasthan, and Kalach in West Bengal where the effectiveness of polyvalent ASV may be questionable. These species should be detected first and special measures to be taken for these bites.

ASV Administration Criteria

ASV is a scarce, costly commodity and should only be administered when there are definite signs of envenomation. Unbound, free flowing venom, can only be neutralised when it is in the bloodstream or tissue fluid. In addition, Anti-Snake Venom carries risks of anaphylactic reactions and should not therefore be used unnecessarily.

Systemic envenoming •

Evidence of coagulopathy: Primarily detected by 20WBCT or visible spontaneous systemic bleeding.

• Evidence

of

neurotoxicity:

ptosis,

external

Prevention of ASV Reactions – Prophylactic Regimes

There is no statistical, trial evidence of sufficient statistical power to show that prophylactic regimes are effective in the prevention of ASV Reactions in India. Recent trial in Sri lanka using low dose adrenalin (0.25 ml) on good number of patient showed benefit but a proper study to be undertaken in India before making it a routine procedure as a prophylactic manner. Moreover, Indian population are at high risk for premature atherosclerosis and coronary artery disease. Any adverse effect before ASV may be detrimental as a social issue also. However putting the adrenalin via three way cannula or by puncturing the latex tube may be undertaken and to be injected in emergency. Prophylactic regime should be reserved for children and young adult if at all needed.

Two regimen are normally recommended •

100mg of hydrocortisone and Hl antihistamine (10mg chlorpheniramine maleate IV) 5 minutes before ASV administration.

The conclusion in respect of prophylactic regimens to prevent anaphylactic reactions, is that there is no evidence from good quality randomized clinical trials to support their routine use. If they are used then the decision must rest on other grounds. But the regime have got an added advantage of decreasing the non-anaphylactic reaction such as febrile, allergic reaction, etc.

Adrenalin should not be used as premedication, when it will be required it should be given IV route without wasting time.

ASV Administration

Total required dose will be between 10 vials to 30 vials usually, as each vial neutralizes 6mg of Russells Viper venom. Not all victims will require 10 vials as some may be injected with less than 63mg. However, starting with 10 vials ensures that there is sufficient neutralizing power to neutralize the average amount of venom injected and

during the next 12 hours to neutralize any remaining free flowing venom, even in the large study from south India, the amount of ASV exceeded 50 vials in some patients. So decision of the treating physician is of utmost importance, because the guidelines may not be useful for all patients.

NO ASV TEST DOSE MUST BE ADMINISTERED

Test doses have been shown to have no predictive value in detecting anaphylactic or late serum reactions and should not be used. These reactions are not IgE mediated but Complement activated, They may also pre-sensitize the patient and thereby create greater risk.

occasion but in the vast majority of reactions, 2 doses of adrenaline will be sufficient in children.

•

If there is hypotension or hemodynamic instability, IV fluids should be given.

Once the patient has recovered, the ASV can be restarted slowly for 10-15 minutes, keeping the patient under close observation. Then the normal drip rate should be resumed.

Adrenalin should be given iv in case of anaphylactic reaction, because 1.

Faster action

2.

Predictable availability

Neurotoxic/ Anti Haemostatic 10 Vials

3.

Intra mascular haematoma coagulopathy can be avoided.

ASV can be administered in-two ways

• Infusion: liquid or reconstituted ASV in isotonic saline or glucose, may be started without any diluent fluid in volume overload patients.

All ASV to be administered over 1 hour at constant speed. Local administration of ASV, near the bite site, has been proven to be ineffective, painful and raises the intracompartmental pressure, particularly in the digits, it should not be used.

Snakebite in Pregnancy

Pregnant women are treated in exactly the same way as other victims. The same dosage of ASV is given. The victim should be referred to a gynecologist for assessment of any impact on the foetus.

ASV Reactions

Anaphylaxis can be rapid onset and can deteriorate into a life-threatening emergency very rapidly. Adrenaline should always be immediately available.

in

patient

with

Late serum sickness reactions can be easily treated with an oral steroid such as prednisolone, adults 5mg 6 hourly, paediatric dose 0.7mg/kg/day. Oral antihistaminic provide additional symptomatic relief.

Neurotoxic envenomation

Neostigmine is an anticholinesterase that prolongs the life of acetylcholine and can therefore reverse respiratory failure and neurotoxic symptoms. It is particularly effective for post synaptic neurotoxins such as those of the Cobra.

In the case of neurotoxic envenomation where edrophonium is not available Neostigmine Test can be done. The neostigmine dose is 0.04 mg/kg IV and atropine/ glycopyrolate may be given by continuous infusion.

The patient should be closely observed for l hour to determine if the neostigmine is effective.

The following measures are useful objective methods to assess this: a.

Single breath count

b.

Uncovered area of iris measured in mm

c.

Urticaria, itching, fever, chills, nausea, vomiting, diarrhea, abdominal cramps, tachycardia, hypotension, bronchospasm and angio-oedema

Inter incisor distance (Measured distance between the upper and lower incisors)

d.

Length of time upward gaze can be maintained

e.

FEV 1 or FVC (If available)

•

ASV to be discontinued

f.

•

Children are given 0.01mg/kg body weight of adrenaline iv.

Water column measurement. (length of water column that can be held with blowing through tubes)

•

In elderly noradrenalin and nitroglycerin infusion when hypotension is corrected can be given to avoid adrenalin induced arrhythmia which is common in elderly.

The patient should be monitored closely and at the first sign of any of the following:

If after 10 to 15 minutes the patient’s condition has not improved or is worsening, •

A second dose of 0.5 mg of adrenalin 1:1000 iv is given. This can be repeated for a third and final

For example, if single breath count or inter incisor distance is selected the breath count or distance between the upper and lower incisors, and more objective water level measurement that much patient can blow are measured and recorded. Every 10 minutes the measurement is repeated. The average blood plasma time for neostigmine is 20 minutes, so by T+30 minutes any improvement should be visible by an improvement in the measure.

CHAPTER 113

ASV is recommended to be administered in the following initial dose: N.B. Children and pregnant women receive the same ASV dosage as adults. The ASV is targeted at neutralizing the venom. Snakes inject the same amount of venom into adults and children.

535

536

Recovery Phase

POISONING

If an adequate dose of appropriate antivenom has been administered, the following responses may be seen: 1.

Spontaneous systemic bleeding such as gum bleeding usually stops within 15-30 minutes.

2.

Blood coagulability is usually restored in 6 hours.

Principal test is 20WBCT.

3.

Post synaptic neurotoxic envenoming such as the Cobra may begin to improve as early as 30 minutes after antivenom, but can take several hours.

4.

Presynaptic neurotoxic envenoming such as the Krait usually takes a considerable time to improve reflecting the need for the body to generate new acetylcholine emitters.

5.

Active haemolysis and rhabdomyolysis may cease within a few hours and the urine returns to its normal colour.

6.

In patients who were in shock, blood pressure may increase after 30 minutes.

Repeat Doses: Anti Haemostatic

90 hours and therefore is not required in a prophylactic dose to prevent re-envenomation. But if the patient comes even after few days reinstitute ASV therapy, because sometime absorption of snake venom depot under skin is erratic. If there is no improvement from the beginning of the whole blood clotting time, rather it goes on increasing then we are dealing with the snake bites which are not amenable to our usual polyvalent ASV.

ANTI HAEMOSTATIC MAXIMUM ASV DOSAGE GUIDANCE

Repeat Dose: Haematotoxic

The normal guidelines are to administer ASV every 6 hours until coagulation has been restored. However, what should the clinician do after say, 30 vials have been administered and the coagulation abnormality persists.

A large study recently done from south India (Kerala) showed that upto 50 vials (500 ml) has been given for Haemotoxic poisoning. •

It has been established that envenomation by the Hump-nosed Pitviper (Hypnale hypnale) does not respond to normal ASV. This may be a cause as, in the case of Hypnale, coagulopathy can continue for up to 3 weeks.

In case of anti haemostatic envenomation, the ASV strategy will be based around a six hour time period. When the initial blood test reveals a coagulation abnormality, the initial ASV amount will be given over 1 hour.

Surgical Intervention

No additional ASV will be given until the next Clotting Test is carried out. This is due to the inability of the liver to replace clotting factors in under 6 hrs.

Fasciotomy is required if the intracompartmental pressure is sufficiently high to cause blood vessels to collapse and lead to ischemia. Now a days we are using multiple puncture technique using large bore needle.

After 6 hours a further coagulation test should be performed and a further dose should be administered in the event of continued coagulation defect and in that case ASV to be given over 1 hr. CT tests and repeat doses of ASV should continue on a 6 hourly pattern until coagulation is restored or unless a species is identified as one against which polyvalent ASV is not effective.

The repeat dose should be 10 vials of ASV i.e. one full dose of the original amount. The most logical approach is to administer the same dose again, as was administered initially. Some Indian doctors however, argue that since the amount of unbound venom is declining, due to its continued binding to tissue, and due to the wish to conserve scarce supplies of ASV, there may be a case for administering a smaller second dose. In the absence of good trial evidence to determine the objective position, a range of vials in the second dose has been adopted.

Recurrent Envenomation

When coagulation has been restored no further ASV should be administered, unless a proven recurrence of a coagulation abnormality is established. If patient comes with features of coagulopathy ASV to be administered (10 Vials) There is no need to give prophylactic ASV to prevent recurrence (Srimannarayana et al, 2004). Recurrence has been a mainly U.S. phenomenon, due to the short half-life of Crofab ASV. Indian ASVis a F(ab)2, product and has a half-life of over

Whilst there is undoubtedly a place for a surgical debridement of necrotic tissue, the use of fasciotomy is highly questionable.

What is important is that the intracompartmental pressure should be measured objectively using saline manometers or newer specialised equipment such as the Stryker Intracompartmental Pressure Monitoring Equipment.

RENAL FAILURE IN SNAKEBITE

The acute renal failure which occurs due to snake bite are multifactorial 1) Severe and persistent hypotension leading to acute tubular necrosis, 2) Hb and other cellular parts of RBC and others (myoglobin and rhabdomylysis 3) part of DIC 4) vasculitis 5) acute diffuse intersticial nephritis 6) extra capillary proliferative glomerulonephritis.

Most of the patients of acute tubular necrosis recovers by few weeks, with the help of occational need of haemodialysis, but who develops cortical necrosis requires reanal replacement therapy on along term basis.

It is the hyperkalemia rather than elevated urea, creatinine requires dialysis. The hyperkalemia of snakebite AKI is a hypermetabolic hyperkalemia, which may kill the patient within few minutes and calcium gluconate and glucose insulin is mostly ineffective. Early urgent adequate treatment with ASV can reverse the whole process of deterioration of renal function which is far from our expectation in our country.

Renal failure is a common complication of Russells Viper and Hump-nosed Pitviper bites. The contributory factors

are intravascular haemolysis, DIC, direct nephrotoxicity and hypotension and rhabdomyolysis.

Renal damage can develop very early in cases of Russells Viper bite and even when the patient arrives at hospital soon after the bite, the damage may already have been done. Studies have shown that even when ASV is administered within 1-2 hours after the bite, it was incapable of preventing ARF.

NEUROLOGICAL MANIFESTATION IN SNAKEBITE

Heparin and Botropase – No role

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The primary consideration, in the case of neurotoxic bites, is respiratory failure. Capasity of neck lifting is good predictor of requirement of ventilator support. Refer such patient to the center equipped with invasive ventilation.

REFERENCES

1. Dr. Ian D Simpson. Management of Snakebite-The National,API WB branch, update in Medicine 2006; 88-93.

2. K Narvencar, Correlation Between Timing Of ASV Administration And Complication in Snake Bite, JAPI 2006; 54.

3.

Gudilines For the Clinical Management Of Snake Bites In South- East Asia Region Written and edited by David A Warrell published by WHO, 2005.

4.

J Srimannaryan, TK Dutta, A Sahai, S Badrinath. Rational Use of Anti-Snake Venom(ASV): Trial of Various Regimens in Hemotoxic snake Envenomation,JAPI 2004; 52:788- 792.

5. HS Bawaskar, Snake Venoms And Antivenoms: Critical Supply Issues. JAPI 2004; 52:11-13.

6. V paul, S pratibha, KA prahaald Jerry Earail, S Fracis, Francy Lewis, High-Dose Anti- Snake Venom Versus LowDose Anti Snake Venom in The treatment Of Poisonous Snake Bites- A Critical Study, JAPI 2004;52.

CHAPTER 113

Neurological manifestation of snake bite pose an important problem for transportation from the site of bite to the hospital. A well designed study from PGI Chandigarh shows that just putting an airway tube and an AMBU bag decrease the morbidity to a great extent. Mechanical ventilation to be avoided as far as possible, as because most of the death in ventilated snake bite patient is due to Ventilator associated pneumonia. Early initiation and early weaning from ventilator is the strategy, noninvasive ventilator with a patent upper air way is better option.

Referral Criteria

Mushroom Poisoning

C H A P T E R

114

Bhupen Barman, KG Lynrah, Iadarilang Tiewsoh

INTRODUCTION

Mushroom poisoning among other forms of poisoning contributes to high morbidity and mortality in the country. In certain ethnic populations of India, mushroom is an important constituent of their diet. The incidence of mushroom poisoning in India in the recent years has been recognized due to increasing awareness and the affected individuals seeking health care at the earliest. The tropical belt of the country with its biodiversity is a mother load of different fungal mushroom species. As per studies conducted in India, there are 1200 species with only 50 to 100 species known to be poisonous. Twelve groups of the identified mushroom toxins have been identified responsible for 14 described clinical syndromes.

Acute gastroenteritis – A wide variety of non eatable mushrooms when consumed causes nausea, vomiting, diarrhea and abdominal cramps within one to three hours of consumption. These symptoms are caused most commonly by the chlorophyllum molybdites species are also called “backyard mushrooms”.

NEUROTOXIC SYNDROMES

a.

The hallucinogenic effects are produced by the ingestion of mushroom containing psilocybin and psilocin. They are known to be abused for recreational purposes.

b.

CNS excitation and depression: This syndrome is caused by Amanita species containing toxins muscimol and ibotenic acid. Muscimol is a CNS depressant whereas ibotenic acid has excitatory effects at glutamic acid receptors in the CNS. Symptoms include somnolence, dizziness, hallucination, dysphoria, bizarre behavior and seizures.

c.

Cholinergic poisoning ocuurs when there is intake of inocybe and clitocybe species which contain muscarine toxin. Muscarine is structurally similar to acetylcholine and causes toxicity by binding to postganglionic cholinergic neurons in the autonomic nervous system. Symptoms usually appear 30 minutes post ingestion in the form of bradycardia, diaphoresis, salivation, lacrimation, bronchospasm, bronchorrhoea and incontinence.

EPIDEMIOLOGY

From the studies conducted the 50-100 toxic mushrooms produces the mycotoxins responsible for different clinical syndromes which are described below. In the United States the North American mycological association maintains a case registry where instances of mushroom poisoning are being reported. In India mushroom forms part of the diet especially in the ethnic populations. In most of the cases mushroom poisoning occurs from consumption of the wild mushrooms. However most of the cases are undiagnosed, unreported and epidemics of mushroom poisoning are reported in press which has been observed mostly in the monsoon season. Table 1 shows the different mushroom species with their toxins and mortality percentage.

From the case reports in India the reported cases are from the tribal areas of South India, the Eastern Ghats, Northern India and north eastern parts of the country. Most of the cases are being reported and documented in newspapers where mortality of such cases are being noticed. As per the clinical syndromes of most of the fatalities, they are very suggestive of Amanita phalloides poisoning (Table 2).

Disulfiram like reaction: The toxin coprine found in the coprinus atramentarius, the inky cap mushroom and its species are known to cause this syndrome. The symptoms occurs after 2 hours of ingestion in the form of headache, flushing of face, neck and trunk, nausea and vomiting, tachycardia, palpitations, chest pain, dyspnoea.

CLINICAL SYNDROMES

Gastroenteritis and delayed renal failure are encountered with the Amanita species particularly Amanita smithiana.

Onset of renal failure is observed 12-24 hours after ingestion. General supportive care is the management of choice with few patients requiring hemodialysis.

The 14 types of clinical syndromes caused by the 12 groups are described below. The syndromes are divided on the basis of their presentation as early onset (< 6 hours of ingestion) and late onset (> 6 hours of ingestion). The syndromic presentation and their identification help in making early diagnosis and empirical therapy.

Early onset syndromes are less toxic and life threatening, however does not exclude the possibility of consumption of lethal mushrooms.

Delayed onset syndrome (>6 hours) occurs mostly after ingestion of lethal mushrooms.

Delayed gastroenteritis and liver toxicity : Delayed onset of vomiting, diarrhoea, and hepatitis observed more than 6 hours post ingestion are known to be life threatening complications mostly observed with toxic mushrooms, Aminata, Galerina and Lepiota of which the Amanita

Table 1: Different types of mycotoxins Mycotoxins

Mushroom species

Cyclopeptides : Amanita phalloides Amatoxins, A.virosa Phallotoxins A.verna A.bisporigera Galerina marginata G.venenata Lepiota helveola

Mortality 2-30 percernt

The second phase begins 24-36 hours where there is laboratory evidence of hepatoxicity though clinical improvement is observed in patients.

In the third phase, seen after 48 hours is the onset of fulminant hepatitis progressing to hepatic coma, hemorrhage and renal failure, which becomes more evident within 4-7 days, resulting in death.

Gyromitra esculenta 0-10% G.infula Sarcosphaera coronaria Cyathipodia macropus

Orellanine, orelline, cortinarin

Cortinarius orellanus C.speciosissinus Mycena pura Omphalatus olearius

End stage renal failure 11% Renal transplant 13 %

Allenic norleucine

Amanita smithiana

Full recovery

Coprine

Coprinus atramentarius Clitocybe clavipes

Full recovery

Muscarine

Citocybe dealbata C.illudens Inocybe fastigiata Boletus calopus

Full recovery

Ibotenic acid, muscimol

Amanita muscaria A.pantherina A.gemmata

Full recovery

Psilocybin , psilocin

Psilocybe cubensis P.mexicana Conocybe cyanopus Gymnopilus aeruginosa

Full recovery

Delayed rhabdomyolysis is another clinical syndrome seen with Tricholoma equestre species. Onset of symptoms occurs within 24-72 hours after consumption, which results in myalgia, and progressive weakness. On laboratory evaluation there is hyperkalemia with raised creatinine phosphokinase.

Chlorophyllum molybdites Clitocybe nebularis Omphalates illudens

Full recovery

Rare manifestations: Other rare manifestations of mushroom poisoning which are less lethal are erythromelalgia, delayed encephalopathy, allergic bronchioalveolitis, and immune mediated hemolytic anemia.

Acromelic acid

Clitocybe acromelalga

Full recovery

Antibodies to Paxillus involutus

Paxillus involutus

Full recovery

Allergic to spores of Lycoperdon species

Lycoperdon species

Full recovery

Delayed renal failure: This is seen with the toxins orellanine, cortinarin A, cortinarin B causes interstitial nephritis and tubulointerstitial fibrosis found in mushroom species Cortinarius orellanus, Mycena pura and Omphalatus orarius. Treatment for Cortinarius ingestion requires supportive care for acute kidney injury and hemodialysis should be considered for few individuals.

Diagnosis

species are known to be the most fatal. This particular syndrome presents in three distinct clinical phases.

The first phase starts 6 hours after ingestion of the mushroom with cholera –like diarrhoea, vomiting, abdominal pain, and subsequent dehydration.

Any patient presenting to the ED with the delayed onset of vomiting and diarrhoea six hours or more​following consumption of foraged mushrooms must be presumed an amatoxin poisoning until proven otherwise. The key element in evaluating a patient with mushroom poisoning includes proper history, identification of the mushroom species, symptoms and signs that leads to a particular syndrome. The commonest wild mushrooms resulting in morbidity and mortality are the amanita species that grows in woodlands, on dead stumps and near pine trees in deciduous forests. Toxicity of most lethal mushrooms occurs 6 hours post ingestion affecting the gastrointestinal tract, liver and the kidneys.

The baseline investigations that can be a guide to the different clinical syndromes includes complete hemogram, renal and liver function tests, PT/INR,

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Seizures, delayed gastroenteritis and liver toxicity: Intake of gyromitra species are known to cause gastroenteritis with severe poisoning causing neurological and hepatic manifestations. The gyromitirn is present in most of the gyromitra mushrooms. The toxicity can be differentiated from that of the amanita species based on seasonal considerations as they grow more in spring and early summer compared to the Amanita species that are seen in the fall of the season. Apart from the seasonal consideration, the ‘brain like appearance’ of the gyromitra mushroom help in differentiating it from the Amanita species. The clinical manifestations of gyromitrin toxicity includes: delayed gastroenteritis, headache, seizures, hepatitis, hemolysis and methemoglobinemia.

Gyromitrin

GI irritants

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Table 2: Geographic distribution of mushroom poisoning in India Location

Clinical Syndrome

Possible mushrooms

South India (Eastern Ghats)

Acute gastroenteritis

Omphalotus olivascens, Mycena pura Chlorophyllum molybdites

Karnataka (Mangalore

Cholinergic excess

Clitocybe species

North India (Himachal Pradesh)

Acute gastroenteritis, liver failure

Amanita species

North east India (Assam, Meghalaya, Acute gastroenteritis ,liver failure Mizoram, Manipur)

Amanita species

POISONING

*As per case reports and media reports

creatinine kinase, serum lactate at presentation, followed by serial measurement of CMP, lactate, and PT/INR every 6 to 8 hours.

A medical toxicologist and professional mycologist are known to contribute in identification of the toxic mushrooms and their toxins. A rapid and specific diagnostic ELISA test for detection of amatoxin in serum and urine is there but ​is not ​available for clinical use.

Management

Supportive care is the mainstay of therapy of most patients with mushroom poisoning. Specific therapy is guided by the clinical presentation (clinical syndrome).

Gastrointestinal decontamination with activated charcoal benefits maximum when patients presents within one hour of the toxin mushroom ingestion. Gastric emptying by gastric lavage or ipecac syrup has shown minimal benefits, with increased risk of aspiration. Elimination enhancement with multiple activated charcoal has been shown to decrease circulation of the amatoxins after ingestion of the toxins. The recommended doses is 50 gm (0.5gm/kg) every four hourly for four days.

Hemodialysis or hemoperfusion do not remove significant amounts of mushroom toxins hence is not recommended for toxin removal unless patient s have signs of acute renal failure requiring hemodialysis in the form of hyperkalemia, metabolic acidosis, uremic signs and encephalopathy.

Biliary drainage ​ by interventional radiology (Simple/ Serial gallbladder aspiration, percutaneous cholecystostomy), general surgery (open cholecystostomy), or GI (Nasobiliary drainage with suction placed by ERCP) has been demonstrated to be effective in a growing number of case reports. Removing amatoxin laden bile from the gallbladder provides definitive protection to uninvolved hepatocytes by eliminating further enterohepatic exposure to the poison. Simple ultrasound guided gallbladder aspiration ​appears to be the fastest, safest, easiest, and most efficient means of permanently removing accumulated amatoxin from the biliary tract. It can be accomplished using a transhepatic approach early in the clinical course or via a transperitoneal approach if the INR is above 2. The collected bile sample should be labeled and frozen carefully for subsequent analysis of amatoxin content.

Intravenous Octreotide (200 mcg bolus followed by

50 mcg per hour) helps to keep amatoxin contained in the gallbladder and thus limiting further hepatocyte exposure. Octreotide effectively inhibits bile outflow from the common bile duct and gallbladder by raising pressure at the Sphincter of Oddi and enhances GB filling by reducing GB intraluminal pressure.

SPECIFIC ANTIDOTES IN DIFFERENT TOXINS INDUCED MUSHROOM POISONING

Amanita poisoning

Amatoxin uptake inhibitors like silibinin or intravenous penicillin G have been shown to be associated with higher levels of patients survival. This blockade or inhibition results in the diversion of amatoxin back into the general circulation for renal clearance, therefore maintaining renal function and a brisk urine output is crucial to the success of the drug. The recommended doses for silibinin is 5 mg/kg bolus then followed by 20 mg/kg/day for 6 days or till patient recovers. Intravenous Penicillin G is considered when silibinin is not available given at the dose of 300,000 -1,000,000 units /kg/day as continuous infusion for the same duration. Penicillin G probably acts by competitive inhibition of plasma protein binding of amatoxin and thus causing excess urinary excretion and also as uptake inhibitor. Other amatoxin uptake inhibitors which have been found to be effective include silymarin and ceftazidime. A dose of silymarin is given in high doses 150 -360 mg every 8 hourly upto 2 gm /day for 6 days or till recovers. Injection ceftazidime is also given in high dose of 4 gm every 2 hourly.

Antioxidants are also indicated in amatoxin poisoning as the toxins are known to enhance lipid peroxidation that contributes to membrane instability and cell death.

Antioxidant prevents lipid peroxidation. Among the antioxidants injectable N acetylcysteine (NAC) is preferred in the dose 150 mg/kg bolus over 1 hour, followed by 12.5 mg/kg over 4 hours, 6.25 mg /kg over 16 hours.

Gyromitrin toxicity with seizures should receive pyridoxine (70 mg/kg to 5 gm) per day along with anticonvulsant therapy. Pyridoxine acts by reversing pyridoxal 5 phosphate deficiency in the central nervous system mediated by toxic metabolite monomethylhydrazine. Methemoglobinemia also seen in gyromitrin poisoning when detected should receive intravenous methylene blue.

Cholinergic excess from muscarine toxins should receive

atropine or glycopyrrolate. Repeat anticholinergic agent as needed until bronchial secretions have dried.

REFERENCES

1.

Supportive care

Vomiting and diarrhoea are cause by most of the toxin containing mushrooms which can be treated with intravenous fluids and antiemetic.

Rhabdomyolysis caused by tricholoma equestra species characterized by raised creatinine phosphokinase with urine showing pigmented granular casts, a red or brown color of urine supernatant. The primary treatment is to give aggressive intravenous fluids preferable normal saline 20-40 ml/kg/hour upto 1 litre/hour.

Renal failure when present hemodialysis should be considered in candidates with fluid overload, refractory to diuretics, hyperkalemia, metabolic acidosis and signs of uremia (pericarditis, unexplained decline in mental status).

Fulminant hepatitis when present should prompt the physician for early transfer of patient to a liver transplant center and when patient with hepatotoxicity does not improved even after 4 days of supportive therapy.

CONCLUSION

More studies are required in mushroom poisoning in our country for proper judgment of the types of mushroom causing morbility and mortality. Awareness programs in the affected area should be carried out and early supportive therapy should be the goal in affected population.

Deshmukh SK, Natarajan K, Verekar SA. Poisonous and hallucinogenic mushrooms of India. Int J Med Mushr 2006; 8:251–62.

2. Goldfrank LR. Mushrooms. In: Nelson LS, Lewin NA, Howland MA, Hoffman RS, Goldfrank LR, Flomenbaum NE, editors. Goldfrank’s Toxicologic Emergencies. 9th ed.

New York: McGraw-Hill; 2011. pp. 1522–36.

3.

Brent J, Palmer RB. Mushrooms. Hadded and Winchester‘s Clinical Management of poisoning and Drug Overdose, 4th edition, Shannon MW, Borron SW, Burns MJ, Saunder Elsevier, Philadelphia, PA 2007. Pg 455.

4. George P, Hegde N. Muscarinic toxicity among family members after consumption of mushrooms. Toxicology International 2013; 20:113-115.

5. Kumar M, Kaviyarasan V. Few common poisonous mushrooms of Kolli Hills, South India. J Acad Indus Res 2012; 1:19-22 6.

Verma N, Bhalla A, Kumar S, Dhiman RK, Chawla YK. Wild mushroom poisoning in north India: case series with review of literature. J Clin Exp Hepatol 2014; 4:361-5.

7.

Sharma J,Malakar M, Sandiguria E, Das J. An expressive study of Mushroom poisoning cases in Lakhimpur district of Assam. International Journal of Advancements in Research & Technology 2013; 2:82-88.

8. Pond SM, Olson KR, Woo OF, Osterloh JD, Ward RE, Kaufman DA et al. Amatoxin poisoning in northern California, 1982-1983. West J Med 1986; 145:204-9.

9.

Vesconi S, Langer M, Iapichino G, Costantino D, Busi C, Fiume. Therapy of cytotoxic mushroom intoxication. Crit Care Med 1985; 13:402.

10. Köppel C. Clinical symptomatology and management of mushroom poisoning. Toxicon 1993; 31:1513-40.

CHAPTER 114

Agitation, delirium and hallucination are treated with benzodiazepines. Seizures caused by mushrooms containing muscimol, ibotenic acid and gyromitrin are treated with short acting benzodiazepines midazolam or lorazepam and if no responds phenytoin sodium is considered as per the epilepsy protocol management.

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C H A P T E R

115

Approach to Common Poisoning in Punjab Gursaran Kaur Sidhu

India is an agriculture based country with Punjab as one of the leading food grain producing states, with increasing burden to feed the growing population. This has led to over-usage of pesticides which on one hand has contributed significantly to increase the crop yield while on the other hand has led to sharp increase in the poisoning cases in the region.

Common poisoning in Punjab are related to most easily available agricultural based products i.e. pesticides, herbicides and preservatives. The nature of the poisoning is more often due to accidental and sprays related and suicidal. In parts of developing world pesticide poisoning causes more deaths than infectious diseases.

Organophosphate insecticides account for more than 50% of all acute poisoning in hospital practice; the majority of patients are younger than 30 yrs.1 In teenagers and adults the poisoning is generally due to suicidal intention although accidental poisoning during spraying can also occur.2 Mortality ranges from 4% to 38% in Indian studies.

ORGANOPHOSPHOROUS PIOSONING

Organophosphate poisoning results from exposure to organophosphates (OPs),which cause the inhibition of acetylcholinesterase (AChE), leading to the accumulation of acetylcholine (ACh) in the body. It inhibits AChE, causing OP poisoning by phosphorylating the serine hydroxyl residue on AChE, which inactivates AChE. AChE is critical for nerve function, so the irreversible blockage of this enzyme, which causes acetylcholine accumulation, results in muscle overstimulation. This causes disturbances across the cholinergic synapses.

Organophosphate compounds avidly bind to cholinesterase molecules as they share a similar chemical structure. In human beings, the two principal cholinesterases are RBC, or true cholinesterase (acetylcholinesterase), and serum cholinesterase.3 Intoxication by inhalation and absorption through skin may occur during spraying.

Poisoning as a mode of suicidal death is known from the antiquity. Poisoning among all the age groups and both sexes is seen everywhere and the incidence of Poisoning with reference to insecticides, pesticides and rodenticides has become more common than others in the modern times because of their easy availability, low cost, efficacy of action and rapid death. Also these days because of drug addiction, we see overdose of commonly abused addictions of herione and Smack etc.

Following absorption, OP compounds accumulate rapidly in fat, liver, kidneys and salivary glands. The phosphorothioates (P=S), for example diazonin, parathion, and bromophos, are more lipophilic than phosphates (P=O), for example dichlorvos, and are therefore stored extensively in fat which may account for the prolonged intoxication and clinical relapse after apparent recovery which has been observed in poisoning from these OP insecticides. OP compounds generally are lipophilic and therefore cross the blood / brain barrier in most cases.5

COMMONLY USED POISONS

Metabolism

1. Pesticides: Organophosphorous compounds i.e. Dichlorvos DDVD 76%, Chlorpyriphos, Deltamiethin 1% + Trizophos 35%, Monocrotophos 36%, Profenofos 40% + Cypermethrin 4% and Pretilavhlor 50%.

2. Herbicides: Imidachlopride, Propioconazone 25%.

Beldamycin

and

3. Endosulfan 4.

Aluminum Poisoning

5.

Corrosives & Others

HOW TO APPROACH

Poisoning is a medical emergency. The patient should be immediately brought to hospital and shifted to ICU or any other high intensity unit of facility. History of inhaled or suicidal intake of poisoning is of paramount importance and maintaining the airway patency is the top priority.

After absorption in skin, GI tract or inhalation, the insecticides and their metabolites gets distributed quickly especially in liver kidneys, adipose tissue and tissues rich in lipids. The plasma half life after a single administration is from few minutes to several hours which depend on type of compound and rate and amount of administration. Metabolism is mainly due to oxidation, by cytocrome-p-450 system and hydrolysis of ester bonds mediated by various esterases or paroxonases.

Elimination mainly occurs via urine and faeces. Some compounds remain longer in body like fenthion and Fenithrothion. The biological effects of OP compounds are a result of accumulation of endogenous acetyl choline at sites of cholinergic transmission. Ion binding by which enzyme AChE is inhibited, but eventually progressively phosphorelated by covalent bonding, a process normally takes 24-48 hrs. This process is called “Ageing” and this period is known as the “critical interval” because during this time administration of antidote is still effective in

reversing the process. Once ageing is completed the enzyme cannot be reactivated. Plasma AChE recovers quickly within 4 weeks. Red cell AChE takes longer and may not be restored. Affected AChE recovers at the rate of ~ 1% per day. Restoration of AChE activity occurs by slow denovo synthesis of free enzyme. Ageing has an important bearing on toxicity and treatment outcome.4

Three Clinical Phases

The muscarinic symptoms are diarrhea, lacrimation, salivation, bronchorrhoea, bronchospasm, bradycardia, urination and miosis. Patient may have hypertension and tachycardia occurring due to nicotinic actions rather than hypotension and bradycardia. The nicotinic receptors activated during acute intoxication lead to muscle paralysis. Fasciculations are seen and are a reliable sign of poisoning. Progression of paralysis may occur and the muscles of respiration may get affected. Severe intoxication may cause emotional irritability, mental obtundation, cognitive impairment, coma and convulsions because of CNS effects.

Intermediate Syndrome: Wadia et al first described this syndrome as type II paralysis.5 The term intermediate syndrome was coined by Senanayake and Karalliedde L. in 1987.6 This term is derived from the fact that it arises between the period of early cholinergic syndrome and the late onset peripheral neuropathy. This syndrome is commonly associated with OPs like diazinon, dimethoate, methylparathion, methamidaphos, monopcrotophos, fenthion and ethylparathion. It develops 12-96 hrs after exposure and reflects a prolonged action of acetylcholine on the nicotinic receptors and is characterized by muscular weakness in the ocular, neck, bulbar, proximal limb and respiratory muscles. The sensory functions characteristically remain normal and full recovery is evident in 4-18 days.

Organophosphate Induced Delayed Polyneuropathy (OPIDN): OPIDN is common following exposure to OPCs which have weak anticholinesterase activity. OPCs have been found to be neuropathic eg. Mipafox, merphos, leptophos, DEF, EPN, cyanophos and trichloronat.

Treatment

If the insecticide was in contact with skin or eyes, these should be thoroughly washed. Dirty clothes should be removed, patient cleaned and redressed in ICU gown.

On admission to ICU, maintaining respiratory airway clearance is a top priority. Oxygen, Endotracheal intubation and ventilation if required. A nasogastric tube inserted & Stomach Wash with 3-4L of saline needs to be done after securing clearance of respiratory passages.

PAM-Pralidoxime (1 ampoule -20ml contains 500mg):

543

Dosage: Adults: 30 mg/kg (1-2 g), administered by intravenous infusion therapy over 15–30 minutes. Dosage may be repeated 60 minutes later and then 500 mg at 6 hourly interval for next 3 days. It can also be given as a 500 mg/hr continuous IV infusion in severe cases.

Children: 20–50 mg/kg followed by a maintenance infusion at 5–10 mg/kg/hr. Intravenous infusions can lead to respiratory or cardiac arrest if given too quickly.

Atropine: Atropine was administered in the dose of 0.6mg/min infusion, till the patient is fully atropinised and signs of toxicity appear i.e. Tachycardia, dryness, dilated pupils, and urinary retention. Once atropinised, a maintenance dose of 1-3 mg was given hourly. The target end point of atropinisation was: dry and clear chest on auscultation with no wheeze, heart rate >80/min, dilated pupil, dry axilla and systolic blood pressure >80 mmHg. Atropinisation, once achieved, should be maintained for 3-4 days, with low dose of atropine. Atropinisation is evidenced by pupillary dilation, drying up of secretions and pulse rate >100. Tafuri and Roberts have shown beneficial effects of infusion of atropine 0.02-.08 mg/kg hourly. Sedation if required and analgesia was obtained administering midazolam and lorazepam.

Ventilatory support: Patients requiring ventilatory support were intubated and put on ventilator and managed accordingly.

Caution

Morphine, theophyline, aminophyline, succinycholine, reserpire and phenothiazine-type transquilizers should be avoided in patients with OP poisoning.

ENDOSULFAN POISONING

Endosulfan is a pesticide belonging to the organochlorine group of pesticides. It was introduced in the 1950’s as a leading broad spectrum pesticide. World Health Organisation (WHO) classifies endosulfan as a Highly Hazardous in category II. Endosulfan has now been banned in India, following the Supreme Court interim order on May 13, 2011, in a Writ Petition in the backdrop of the large no. of suicidal incidents reported in Kasargode, Kerala.

Acute Effects

Endosulfan is highly toxic and can be fatal if inhaled, swallowed or absorbed through the skin. It directly affects the central nervous system and recurrent epileptic seizures are reported. Symptoms of poisoning include hyperactivity, excitement, dyspnea (breathing difficulty), apnea, salivation, loss of consciousness, diarrhea, anemia, vomiting, insomnia, blurred vision, cyanosis, tremor, dry mouth, lack of appetite, irritability, headache, decreased

CHAPTER 115

Acute Cholinergic Crisis: OP’s lead to acute cholinergic crisis in the initial phase.The clinical findings are thereby a mixture of muscarinic effects, nicotinic effects resulting from accumulation of ACh at neuromuscular junctions and consequent depolarization and CNS effects causing initial excitation and subsequent inhibition of all CNS activity.

In the cholinergic phase, the use of oximes as rejunevators of the enzyme cholinesterase has found favour. The beneficial effects of oximes is exerted through the reactivation of enzyme cholinesterase by cleavage of the phosphorylated site and by a direct detoxifying effect on the unbounded organophosphorous compound.

544

respiration, loss of memory, haematuria, albuminuria, confusion, dizziness, imbalance and lack of coordination.7 Autopsy examination of an intentional ingestion (suicide) case has revealed damage to liver, lung and brain.

POISONING

Discussion & Treatment

Convulsions are a common and severe manifestation.

Endosulfan is also toxic to the liver, kidney and lung and can cause rhabdomyolysis in higher doses. Liver function tests are abnormal in the form of deranged AST or ALT. Severe poisoning results in death due to status epilepticus that can lead to asphyxia, and rhabdomyolysis leading to renal failure.

Treatment is symptomatic and supportive. Early termination of convulsive status epilepticus by aggressive treatment is the best way to prevent mortality. Refractory seizures requires more aggressive treatment as it is associated with higher mortality and morbidity.

ALUMINUM POISONING IN PUNJAB

Aluminium phosphide poisoning (ALP) is a large problem, particularly in the Indian subcontinent. It is readily available as a cheap solid fumigant for storing cereal grains. It is sold under various brand names such as QuickPhos and Celphos and is highly toxic, especially when consumed from a freshly opened container.

Unfortunately this has become the most common chemical agent used for the self poisoning.

Death results from profound shock, myocarditis and multiorgan failure.8 Aluminium phosphide has a fatal dose of between 0.15 and 0.5 grams (0.0053 and 0.0176 oz).9 It has been reported to be the most common cause of suicidal death in North India. Deaths have also been reported in Iran, Thailand and Southeast Asia.

Mortality Rate

The mortality rates 40 to 80 percent. The actual numbers of cases may be much larger, as less than five percent of those with AP eventually reach a tertiary care center. Since 1992, when aluminium phosphide became freely available in the market, it had, reportedly, overtaken all other forms of deliberate poisoning, such as organophosphorus and barbiturate poisoning, in North India. In a 25-year-long study on 5,933 unnatural deaths in northwest India, aluminium phosphide poisoning was found to be the major cause of death among all cases of poisonings.10

Mechanism of Toxicity

The toxicity of aluminium phosphide is attributed to the liberation of phosphine gas, a cytotoxic compound that causes free radical mediated injury, inhibits vital cellular enzymes and is directly corrosive to tissues. The following reaction releases phosphine when AlP reacts with water in the body: AlP + 3 H2O  Al(OH)3 + PH3 AlP + 3 HCl  AlCl3 + PH3 (stomach)

Signs, Symptoms & Diagnosis

After ingestion, toxic features usually develop within a few minutes. The major lethal consequence of aluminium

phosphide ingestion is profound circulatory collapse, is reportedly secondary to these toxins generated, which lead due to direct effects on cardiomyocytes, fluid loss, and adrenal gland damage. The signs and symptoms are non-specific, dose dependent and evolve with time. The dominant clinical feature is severe hypotension refractory to dopamine therapy. Other features may include dizziness, fatigue, tightness in the chest, headache, nausea, vomiting, diarrhoea, ataxia, numbness, paraesthesia, tremor, muscle weakness, diplopia and jaundice. If severe inhalation occurs, the patient may develop acute respiratory distress syndrome (ARDS), heart failure, arrhythmias, convulsion and coma.

Treatment & Management

Detailed history need to be taken regarding number of tablets, freshness of tablets, reason and mode of ingestionwhether dissolved in water/ liquid or ingested as such.

All patients of suicidal AlP intake needs to be shifted to ICU without any delay. Garlic odor in the breath is to be noticed and nasogastric tube put in and aspirate the contents. It is recommended not to do gastric lavage with water. Liquid paraffin/Coconut oil may be instilled through NG tube to give a protective coating over the mucosa and accelerate the excretion of aluminium phophide and phosphate.Some authors recommend gastric levage with potassium permagnate (1:10000) to reduce the absorption of phosphine. Permagnate oxidizes PH3 to form non-toxic phosphate.

On arrival in the ICU, the vital parameters are monitoredpulse, BP, SaO2 ,ABG, respiratory rate, and urine output.

Resuscitate the patient on the line of breathing and circulation. Order Immediate investigations of arterial blood gases, Na+ , K+ , and ionized Ca++. Establish I/V access and given normal saline guided by CVP (apprx.

12cm of water).

Low dose dopamine (4-6 ug/kg/min) to combat shock.

Oxygen is given for hypoxia. ARDS may require mechanical ventilation. All types of arrthymias esp. atrial fibrillation are seen in these patients,and the management has to be done accordingly. Magnesium sulphate used both high and low dose did not improve survival in controlled clinical trials. Hence Siwach et al do not recommend its use. Metabolic acidosis are corrected by intravenous sodium bicarbonate, requirement of which are guided by base excess.

NaHCO3 required (meq) = 0.6 x body weight (kg) x Base Excess Total requirement of sodium bicarbonate are given immediately (full correction) and arterial blood gases are estimated after one hour and sodium bicarbonate was given accordingly. After that, arterial blood gas analysis are done again at one-hour intervals till two consecutive readings of arterial blood pH above 7.4 are obtained.

Following which, ABG analysis is done at 2-, 4-, or 6hourly intervals, according to requirement. Associated electrolyte imbalances are treated accordingly.

OP poison

and oesophageal carcinoma may develop at such sites after 20-30 years. Gastric damage due to acids can be equally severe with haemorrhage, gangrene (which may involve the whole stomach) and peritonitis.

Celphos poison

Management of Ingestion

Percentile of Poisons Used

0% 1% 1% 0% 0% 2% 3% 1% 1%

15%

Belladonna

52%

24%

Herbicides(Paraquat, 2-4D)

Fig. 1: Percentile of Poisons used

All the patients are given injection hydrocortisone 200 IV on90% arrival and then 150 suicidal mg at 8 poisonings. â&#x20AC;&#x201C; hourly intervals. ing to themg study, of cases where In the Inotropic support is given with injections dopamine and ides are noradrenalin lying freely in the fields, in the motor pump sheds making them very Corticosteroids- no convincing evidence in limiting the available.The The outcome study has correlates shown an increased in males or preventing long term sequelae i.e oesophageal with the prevalence severity of of incidence the damage strictures. hypotension the patient develops.

The average time especially in the less than 35 years age group(52%), making them twice as likely interval between intake of poisoning and death is 3 Endoscopy ume poison compared females. hrsaswith rangeto o1-48hrs.Even with most aggressive Upper GI endoscopy in acute phase is hazardous the survival rate is 10 to 40%. ration of management the hospital stay on an average was less than 5 days (73%),but but ispatients necessary and should only be performed by an experienced endoscopist using a thinner instrument than Continuous Veno-Venous Hemofiltration (CVVH) ere more sick and needed ventilatory support stayed for more than 5 days. The Continuous veno-venous hemofiltration (CVVH) in the usual. It is done to establish the severity of oesophageal n of hospital stay in 248 (73%) patientsmay wasbe less than 5 days andthe 93(27%) and patients gastric burns. Circumferential burns have higher early stages of AP poisoning beneficial before development of multiple organ failure because AP causes chances for perforation and even causing mediastinitis. for more than 5 days. metabolic acidosis and hypotension resistant to medical Laporatomy treatment.

It including resection may be necessary if serious haemorrhage from the stomach. The chronic sequelae i.e CORROSIVES Many poisons other than the strong acids and alkalis the oesophageal and pyloric strictures can be managed listed below have corrosive effects on the gastrointestinal by repeated endoscopic dilatations and retrievable 40 tract. They include iron salts, paraquat, phenol, oxalic oesophageal stents. Accidental poisoning in children is most frequent and deliberate self-poisoning is common.

30 acid and mercuric chloride.

No. of Patients

Duration of Stay

20 Strong acids

Strong alkalies

10 Hydrochloric acid

Ammonia

0 Nitric acid 2010 2011 Sulphuric acid

Lye 2012

2013Potassium 2014 hydroxide 2015

Years

Male <5 Male >5

KEROSENE POISONING

Kerosene is an oil used as a fuel for lamps, as well as Female <5 heating and cooking.The harmful effects from swallowing or breathing in kerosene.

Female >5

Sodium hydroxide

Symptoms

Poisons ingredients like hydrocarbons lead to difficulty in breathing, throat swelling, pain in eyes and ears, abdominal pain with bloody stool, low BP - develops rapidly, unconsciousness, Drowsiness and skin burns.

Poisoning with strong alkalies and strong acids is uncommon. Ingestion of strong acids and alkalies immediate burning only pain 127 in the lips,patients needed the total produces 173 (51%)almost patients of OP poisoning, (73%) mouth, throat, substernal region and epigastrium. Data Collected at Sidhu Hospital, Doraha (Figure 1) or support.

Vomiting occurs very rapidly and may recur repeatedly. In a retrospective study done in a rural setting at Sidhu Hypersalivation is common. Shock and melena may Hospital Doraha Punjab, we analyzed the data of patients develop in severe poisoning. The patient may look pale from the past 6 years who were admitted with poisoning. and burns may be visible on the hands and face.

A total of 341 patients, 244 (72%) males and female 97 Development of oesophageal or gastric necrosis depends on whether acid or alkali is ingested. Alkalies commonly produce oesophageal burns but only 20% have gastric lesions. Oesophageal mucosa is relatively resistant to acids whereas gastric mucosa particularly in the antrum is vulneralble. Oesophageal necrosis may be present in about 15% without buccal abnormalities. Oesophagus may perforate leading to mediastinitis but this is more likely to be a complication of oesophagoscopy. The major long term complication is oesophageal stricture formation

(28%) were admitted to hospital from 2010 till November 2015. The most predominant poisonous agent used was Organophosphorus (52%)(Malathion, Parathion, Thimit, Baygon etc) followed by Celphos (aluminium phosphide 24%) and others like belladona, carbamates, rat poisons (zinc phosphide), herbicides (Diquat, Paraquat, 2-4d, Glyphosate- Roundup), acid poisoning, kerosine oil, phenyl tablets. Hospital has received appx. 20 cases of heroine & smack overdose with severe respiratory depression.

CHAPTER 115

Every case should be referred to hospital for assessment.

First aid management is given to help neutralize the corrosive but in severe cases the patient is unlikely to be able to retain it. Gastric emptying by any means is contraindicated. Analgesics and intravenous fluids or blood are often required and metabolic acidosis should be sought and treated appropriately. Oxygen and endotracheal rural area, the intubation may be required if the larynx is involved.

545

duration of hospital stay in 248 (73%) patients was less than 5 days and 93(27%) patients

546

40 No. of Patients

Deaths from Poisoning

Duration of Stay

30

Male <5

No. of patients

stayed for more than 5 days.

40

OP cases

30

Death of OP

20 Male >5 Out of the10total 173 (51%) patients of OP poisoning, only 127 (73%) patients needed 10 20

Female <5

ventilator support.

0

2010

2011

2012

2013

2014

2015

Female >5

Years

0

Celphos Cases Death of Celphos 2010 2011 2012 2013 2014 2015 Years

Requirement of Ventilation Fig. 2: Duration of Stay

Other Cases Death of Other

Fig. 4: Deaths from Poisoning

40

POISONING

No. of patient

REFERENCES Out of the total 30 173 (51%) patients of OP poisoning, only 127 (73%) patients needed 1. Karalliedde, Senanayake N. Organophosphorous Male: Yes ventilator support.

20 insecticide poisoning. Br J Anesthesia 1989; 63:739-750.

0

No. of patient

40 30

Male: No

10

Female: Yes 2010 2011 2012 2013 2014 Requirement of Ventilation

2009

2.

Franklin CA. Modi’s medical jurisprudence and toxicology.

22nd edn. Mumbai. N M Tripathi Private Limited 1991:p.8587.

3.

L Haddad, J Winchester. Clinical management of poisoning and overdose. Philedelphia, WB Saunders, 1983, 575-586.

4.

International Journal of Health Sciences & Research (www.

Female: No

Years

Fig. 3: Requirement of Ventilation

Male: Yes According to the study, 90% of cases where suicidal poisonings. In the rural area, the insecticides areMale: lying No 5. Wadia RS, SAdagopan C, Amin RB et al. Neurological 98% survival 10 freelyrate. in the fields, in the motor pump sheds making themYes Female: manifestations of organophosphorous insecticide very easily available. The study has shown an increased 0 poisoning. J Neurology, Neurosurgery and Psychiatry 1974; Female: No prevalence of incidence males 2013 (72%), 2014 especially in the 2009 2010 2011 in2012 137:841-47. less than 35 years age group(52%), making them twice as 6. Senanayake N, Karalliedde L. Neurotoxic effects of Years likely to consume poison as compared to females. organophosphorous insecticides - An Intermediate 20 OP poisoning had the least number of deaths as compared to Celphos poisoning having a ijhsr.org) 255 Vol.4; Issue: 8; August 2014.

The duration of the hospital stay on an average was less than 5 days (73%), but patients who were more sick and needed ventilatory support stayed for more than 5 days (Figure 2). The duration of hospital stay in 248 (73%) patients was less than 5 days and 93(27%) patients stayed for more than 5 days.

Out of the total 173 (51%) patients of OP poisoning, only 127 (73%) patients needed ventilator support (Figure 3).

OP poisoning had the least number of deaths as compared to Celphos poisoning having a 98% survival rate (Figure 4).

RECOMMENDATIONS

Prevention is better than cure. It is recommended that these insecticides should be rationed and not freely available and farmers using them should be made aware to dispose them completely after spraying in the fields, so that poisonings can be prevented.

syndrome. NEJM 1987; 316:761-63.

7.

Mirkin DB. Benzene and related aromatic hydrocarbons.

In: Shannon MW, Borron SW, Burns MJ, eds. Haddad and Winchester’s Clinical Management of Poisoning and Drug Overdose. 4th ed. Philadelphia, Pa: Saunders Elsevier; 2007:chap 94.

8. Mathai, Ashu; Bhanu, Madhuritasingh. “Acute aluminium phosphide poisoning: Can we predict mortality?”. Indian Journal of Anaesthesia 2010; 54:302–7.doi:10.4103/00195049.68372. PMC 2943698. PMID 20882171.

9. A Wahab; MS Zaheer; S Wahab; RA Khan. “Acute aluminium phosphide poisoning: an update” (PDF). Hong Kong Journal of Emergency Medicine: 152.

10. Singh, D; Dewan, I; Pandey, AN; Tyagi, S. “Spectrum of unnatural fatalities in the Chandigarh zone of northwest India—a 25 year autopsy study from a tertiary care hospital”. Journal of Clinical Forensic Medicine 2003; 10:145– 52. doi:10.1016/S1353-1131(03)00073-7. PMID 15275009.

C H A P T E R

116

Therapeutic Plasma Exchange and Continuous Renal Replacement Therapy as Rescue Therapy in Paracetamol Induced Fulminant Hepatic Failure Rajesh Mishra

INTRODUCTION

Patients still die from paracetamol poisoning because they are not recognized to be at risk of harm or present too late for effective treatment.

Patients who are malnourished, have been fasting, take enzyme inducing drugs, or regularly drink alcohol to excess are at higher risk of liver damage.

Patients who have ingested too much paracetamol should be treated within eight hours of ingestion whenever possible. If the time of ingestion is known, treatment can be based on blood tests taken after four hours. If the timing is uncertain or unknown, N- Acetylcysteine (NAC) should be started immediately in all patients who are at potential risk of dying due to toxic effect of paracetamol. All the patient should be considered as high risk unless factors that increase risk of harm are known to be absent.1 A flowchart for the management of patients with paracetamol poisoning can be found and can help clinicians in the emergency department.2 Once patient develops fulminant hepatic failure, only therapeutic option is liver transplantation.

Recently it is found that high-volume plasma exchange (HVPE)3 which removes plasma bound toxins and continuous renal replacement therapy (CRRT), which removes water soluble toxins like ammonia can be used as rescue therapy.

Treatment with high-volume plasma exchange (HVPE) improves outcome in patients with ALF by increasing liver transplant-free survival. Total plasma exchange

Fig. 1: This nomogram is not applicable for patient who present after 24 hours of injestion

(TPE) corrects coagulopathy in patients with liver disease and removes hepatotoxins /cytokines. This improvement is transient but can be used as a bridge until an organ is identified for liver transplantation (LTx) or the liver itself regenerates.4 This is attributable to attenuation of innate immune activation and amelioration of multi-organ dysfunction.

Specific conditions in which CRRT has been proposed as the preferred modality to maintain fluid electrolyte homeostasis, water soluble solute and ammonia removal, includes combined acute renal and hepatic failure (because of the beneficial impact of CRRT on cardiovascular stability and ICP) and acute brain injury (because of the ability of CRRT to prevent cerebral edema).5,6 Patients with acute liver failure who have suspected or proven cerebral edema should be treated with CRRT rather than intermittent renal replacement (IRRT) due to the risk for worsened cerebral edema with IRRT (even in hemodynamically stable patients).7,8 Both the therapy in combination can buy time and help in keeping the patient alive till hepatic failure phase (2-4 days post ingestion) is passed.9 Once this phase is passed liver start regenerating and patient can survive without liver transplant.9

CASE

A 54 year male was found unconscious after consuming unknown poison. He was shifted under our care in comatose state, intubated on ventilator after 30 hours of suspected poisoning. On, arrival his Glasgow Coma Scale (GCS) was 4, pupils pin point, corneal and cough reflex present. He was hemodynamically stable (BP 160/90 mmHg), & was passing urine. He came with normal Blood counts, PT (INR) aPTT, Renal function Test, MRI brain and CSF. His SGPT was 320 IU/L, Bilirubin 1.2 mg%, and ABG (pH-7.34, PCo2- 28, PaO2 130/ 0.4 O2, HCO3-18).

On admission his toxicology screen was sent. It was positive for paracetamol, 130 mg%; after 30 hours of ingestion (Paracetamol nomogram not applicable after 24 hours of arrival); Figure 1. Other significant positive reports -PLT-80,000. SGPT 550, SGOT 600, PT (INR)1.3, pH-7.30, optic nerve diameter (OND) was 5.4mm, is marker of raised intracranial pressure(ICP). Normal OND

POISONING

548

Adult acetylcysteine prescription (each ampoule = 200mg/mL acetylcysteine)

Please circle appropriate weight and volume

Regimen

First Infusion

Second Infusion

Third Infusion

Infusion fluid

200 rnLs 5% glucose or sodium chloride 0.9%

500 mLs 5% glucose or -odium chloride 0.9%

1000 mLs 5% glucose or sodium chloride 0.9%

Duration of infusion

1 hour

4 hours

16 hours

Drug dose

150 mg/kg acetylcysteine

50 mg/kg acetylcysteine

100 mg/kg acetylcysteine

Patient Weight’

Ampoule volume2

Infusion Rate

Ampoule volume2

Infusion Rate

Ampoule volume2

Infusion Rate

kg

mL

ml/h

mL

ml/h

mL

mL/h

40-49

34

234

12

128

23

64

SO-S9

42

242

14

129

28

64

60-69

49

249

17

129

33

65

70-79

57

257

19

130

38

65

80-89

64

264

22

131

43

65

90-99

72

272

24

131

48

66

100-109

79

279

27

132

53

66

≥110

83

283

28

132

55

66

Fig. 2: Protocol of NAC infusion in treatment of Paracetamol ACETAMINOPHEN-INDUCED ALF Arterial pH <7.3 (regardless of HE) OR all 3 of the following - INR>6.5 - Creatinine >300|imol/l - HE grade 3-4 NON-ACETAMINOPHEN-INDUCED ALF INR >6.5 (regardless of HE) OR 3 of 5 of the following (regardless of HE) - Age < 10 or >40 years - Etiology, indeterminate, drug-induced - Time interval icterus to encephalopathy > 7 days -INR>3.5 - Bilirubin >300µmol/l

Fig. 3: King’s college criteria for liver transplant alert in acute liver failure is 4.0-4.5 mm. N-Acetylcysteine infusion as per protocol was started, Figure 2.

In next 24 hour pupil became unequal, SGPT rose to 5800, pH dropped to 7.1, INR went up to 6.5, Platelets dropped to 40000, creatinine 1.30 mg%, arterial ammonia rose to 250 µmol/litre (on admission 65 µmol/litre). As per King’s college criteria he needed Immediate liver transplantation to avoid impending death (Figure 3).

As patient was non affording was not willing for liver transplant, rescue therapy in form of high volume plasma exchange (HVPE) and Continuous Veno-venous hemofilteration CVVHF (35 ml/kg/hr) was offered (Figure 4). We did three cycle of HVPE and 96 hours of CVVHF.

• In CVVH, solute clearance occurs by convection • No dialysate is used • Typically, hourly ultrafiltration rates of 1 to 2 L/h are used • Intravenous “replacement fluid” is provided to replace the excess volume that is being removed and Pump replenish desired solutes, can be administered either prefilter or postfilter.

Pump

To Patient Convection Across Pressure Gradient

• Effective method of solute removal and • Indicated for uremia or severe acidosis or electrolyte imbalance with or without fluid overload • Major advantages is that solutes can be removed in large quantities, maintaining a net zero or even a positive fluid balance

From Patient

Pump

Anticoagulant Continuous Veno-Venous HemoFiltration (CVVH)

Fig. 4: Continuous Veno-Venous Hemofiltration (CVVH) After 1st cycle of plasmapheresis & 24 Hours of CVVHF, his blood reports started improving, INR 1.5, pH 7.36, AND SGPT 860. GCS improved to 8, pupil constricted but reactive, OND dropped to 4.6 mm.

I stopped CVVHF after 48 hour and did 2nd HVPE. We again started 2nd cycle of CVVHF. After 72 hours patient woke up, but he was very irritable so we continued CVVHF for next 24 hours more (total 96 hours / 2 cycles) to control raised ICP. After this we did 3rd cycle of plasmapheresis and then monitored him for next 48 hours. He became alert and all the reports were normal after 48 hours of stopping CVVHF & Plasmapheresis. He got extubated on 6th day. He remained stable and got discharged on 11th day. So far he do not have any residual problem after 6 months.

CONCLUSIONS

PCM induced ALF has 90-95% mortality if liver transplantion is not offered immediately. Cause of death in these patients are cerebral edema, life threatening

bleeding and cardiovascular arrest. Rescue therapy (CVVHF & HVPE) was offered to keep the patient alive till hepatic failure phase of PCM induced ALF is passed.

As this combination has never been documented to save this kind of patient, but this combination has potential to rescue those patients where liver can regenerate. I believe that we may try this combination to rescue viral induced AFHF. We need to explore this combination in other AFHF.

4.

The effect of total plasma exchange on fulminant hepatic failure; Akdogan M1, Camci C, Gurakar A, Gilcher R, Alamian S, Wright H, Nour B, Sebastian A. J Clin Apher 2006; 21:96-9.

549

5. Davenport A, Bramley PN. Cerebral function analyzing monitor and visual evoked potentials as a noninvasive method of detecting cerebral dysfunction in patients with acute hepatic and renal failure treated with intermittent machine hemofiltration. Ren Fail 1993; 15:515–522.

[PubMed]

Clinical Review, Management of paracetamol poisoning.

BMJ 2011; 342.

Davenport A. Dialysate and substitution fluids for patients treated by continuous forms of renal replacement therapy.

Contrib Nephrol 2001; 132:313–322. [PubMed]

2.

Paracetamol overdose: an evidence based flowchart to guide management. CI Wallace, PI Dargan, A L Jones.

Emerg Med J 2002; 19:202–205.

7.

3.

High-volume plasma exchange in patients with acute liver failure: An open randomized controlled trial. Larsen FS1. J Hepatol 2016; 64:69-78... Epub 2015 Aug 29.

Davenport A, Will EJ, Davison AM. Effect of renal replacement therapy on patients with combined acute renal and fulminant hepatic failure. Kidney Int Suppl 1993; 41:S245–S251. [PubMed]

8.

Mehta RL. Continuous renal replacement therapy in the critically ill patient. Kidney Int 2005; 67:781–795. [PubMed]

9. Acetaminophen Toxicity: Susan E Farrell, MD; Chief Editor: AsimTarabar, medscape ; 18th May 2016. (PubMed).

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REFERENCES

6.

1.