substandard neostigmindr misal final

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Substandard Neostigmine: Acause of Postoperative Pulmonary

Complications. Case reportTo restore neuromuscular function postoperatively so that the patient can

maintain adequate spontaneous pulmonary ventilation and a patent airway, the

action of muscle relaxants is usually reversed with the anticholinesterases

(AChE) e.g. Edrophonium, Neostigmine, or pyridostigmine. Of which neostigmine

is the most commonly used agent.

Neostigmine inhibits the normal hydrolysis of acetylcholine and thus raises its

concentration at cholinergic nerve endings. The drug is more stable and effective

than physostigmine.

The drug increases both muscarinic and nicotinic effects of acetylcholine. The

muscarinic effects include brdycardia, hypotension, profuse salivary and

bronchial secretions, bronchospasm, and stimulation of smooth muscles

particularly of hollow viscera.

Neostigmine prolongs and increases local depolarization produced at the end

plate by acetylcholine. Thus, it reverses the action of non depolarizing muscle

relaxants. Neostigmine may potentiate the depolarizing muscle relaxants. It may

cause fasciculations.

In presence of respiratory acidosis the drug may cause severe dysrhythmias and

hypoventilation should always be avoided. It should be used with caution in

cases of asthma and heart disease.

Overdose of Neostigmine may cause restlessness, weakness, muscular twitching,

sweating, salivation, nausea, vomiting, pin point pupil, colic, bronchospasm, and

hypotension and so on. It may even cause cardiac arrest.

A series of pulmonary complications of more or less severity after reversal of

neuromuscular block with neostigmine occurred at Padmashree Vasantdada

Patil General Hospital, Sangli Government Medical College, Miraj during themonth of November and December 2007.

In this case report we are presenting four cases of frank pulmonary edema with

resultant morbidity and mortality (50 %). These patients were posted for various

surgical procedures viz. Cholecystectomy, modified radical mastectomy for

breast carcinoma (rt.side), radius-ulna plating of left hand, and

gastrojejunostomy for duodenal ulcer.


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Case

No

Diagnosis Operation planned Age

(years)

Sex Weight ASA

Statu

s

1 Chronic

cholelithiasis

Cholecystectomy 50 Female 40 kg II

2 Duodenal

ulcer

Gastrojejunostomy 45 Male 55 kg II

3 Carcinoma

breast (Rt)

Modified radical

mastectomy

42 Female 40 kg II

4 Fracture of

Lt. Radius-

Ulna

Open reduction &

internal fixation

(Plating)

53 Male 57 kg I

Case 1:

A 50 year female having cholelithiasis posted for cholecystectomy. Her

preoperative findings were: PR-86 beats/min; BP-110/70 mmHg; ECG-ST

depression with T wave inversion in leads II,III and aVF; suggestive of IHD; her

LFTs were WNL; and biochemical investigations were also normal. Her weight was

40kg.

Patient was induced with the drugs mentioned in table no 1.

Intraoperatively, her vitals were remained WNL throughout. After surgery, she

was reversed with inj neostigmine 2mg and inj glycopyrrolate 0.4mg and was

extubated in due course and was shifted to recovery room for observation

After 10 min, she complained of having difficulty in breathing and restlessness,

and was found to be having tachypnea, tachycardia and basal crepts were noted

on auscultation. Her BP was 86/50mmHg, and SpO2 was 86%.

She was given inj dexamethasone 8mg, hydrocortisone 100mg, deriphylline 2ml,

lasix 20mg, mephentine 10mg, propped up position and oxygen supplementation

by mask.

She improved symtomatically after 10 min with PR-116/min; BP-152/92 mmHg;

RR-26/min SpO2-93 %. Crepts decreased than before. With these findings she

was shifted to ward for further observation.

In ward, she again deteriorated after half an hour with similar findings of greater

severity where she was reintubated and ventilated for 8 hrs but then did notresponded to the treatment and succumbed.


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Case 2:

A middle aged male patient with a h/o duodenal ulcer was posted for

gastrojejunostomy. His preanesthesia findings were h/o vomiting on and off, pain

in abdomen, h/o repeated use of NSAIDs and chronic alcoholism. His biochemical

profile was normal and ECG and CXR show no abnormality. His PR was 88beats/min, and BP was 90/68 mmHg, and auscultation reveals no abnormality.


His vital parameters were stable throughout intraoperative period and his urine

output was 150 ml.

At the end of the surgery, his neuromuscular block was reversed with inj

Neostigmine 2.5 mg and inj Glycopyrrolate 0.4 mg IV. His trachea was extubated

after complete recovery and he was shifted to recovery room for observation.

While he was being observed there in recovery room, we noticed tachycardia

(PR-136/min), tachypnea (RR-32/min), mild to moderate cyanosis and air hunger

in the patient. His BP was 66/40 mmHg and SpO2 86 %. On auscultation there

were bilateral basal crepitations.

He was immediately reintubated and ventilated with Bain circuit with 100 %

oxygen supplementation. Inj mephentine 15 mg IV given along with inj

Dexamethasone (8mg) and Hydrocort (100mg), and when BP became normal

(106/60 mmHg), inj lasix 20+20 mg IV given. Inj deriphylline 2 ml IV given. He

was reparalysed with inj Vecuronium 4 mg and was shifted to ICCU where he was

put on ventilator for about next 12 hrs.

He improved symptomatically and clinically in due course of time and then

weaned off gradually from ventilator and extubated next day without any sequel.

Case 3:

A 42 year old female with carcinoma of right breast was posted for radical

mastectomy. Her preoperative findings were within normal limits except anaemia

(Hb-8.6 gm %). However, she was accepted for anaesthesia due to malignancy

with adequate reservation of blood.


Intraoperatively, vital parameters of the patient were more or less stable

throughout the procedure. After completion of the surgery, she was reversed

with inj Neostigmine 2.0 mg + inj Glycopyrrolate 0.4 mg IV and her trachea was

extubated. On extubation, her PR was 98/min, BP 110/68 mmHg, RR 16/min, and

SpO2 was 97 %.

When she was about to be shifted to recovery room for observation, she

complained respiratory discomfort. Her SpO2 was decreased from 97 % to 92 %.

She also had tachycardia and tachypnoea, and hypotension. On auscultation, airentry was reduced bilaterally at lung bases.


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Oxygen was supplemented immediately with mask and inj dexamethasone 8 mg,

hydrocort 100 mg given. She had no improvement. Mild cyanosis appeared with

SpO2 86 %. She was immediately reintubated and and her respiration was

assisted as she was having respiratory attempts and consciousness.

After 10 min, we noticed bilateral basal crepts and there were froathy secretionsin the endotracheal tube. The rebreathing bag was having resistance. PR-

130/min, BP-78/50 mmHg, RR-28/min and laboured, SpO2-86 %. Drugs given

were, inj mephentine 15 mg, inj lasix 40+40+20=100 mg total, inj aminophylline

250 mg, inj dopamine in drip, inj hydrocort 100 mg along with propped up

position. IV voluven 250 ml given fast.

During next 2 hrs her PR was: 130-144-160-154-146-140/min, BP was: 80-104-

100-92-84-96 mmHg systolic, SpO2 was 90-92 %, there were crepts at bases.

The patient was shifted to ICCU for further management where she was put on

ventilator with SIMV mode. She was never paralysed.

Various ups and downs were seen in due time and were managed

symptomatically, but she succumbed after 28 hrs.

Case 4:

A case of fracture left radius-ulna posted for plating. ASA-I fit middle aged male

initially received brachial plexus block which was inadequate for surgery so we

proceed for G A.


I/O: PR 80-104/min, BP 110-134 mmHg, RR 14-16/min controlled, SpO2 98-99 %.

P/O: Reversal with inj Neostigmine 2.5 mg, Glycopyrrolate 0.4 mg, extubation

after adequate recovery.

In recovery room- patient c/o dyspnoea, restlessness, nausea. There was mild

cyanosis, PR 126/min, BP 80/60 mmHg, SpO2 84 %, on auscultation there were

bilateral basal crepts and patient was tachypnoec.

Propped up position was given, 100 % oxygen supplementation with mask and

ventilation assisted on Magill circuit, inj dexamethasone and hydrocortisone weregiven along with aminophylline 250 mg bolus. IV voluven pushed fast (300 ml),

inj lasix 40+20+20=total 80 mg, dopamine drip in adequate dose to maintain BP

above 90 mmHg.

Patient subsequently improved symptomatically and clinically in next 3 hrs and

shifted to ICCU for observation. Next day he was shifted to ward without any

respiratory problem.

All these events compelled us to find out the cause of this morbidity andmortality. We have had a long discussion amongst the department staff and our


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colleagues from medicine and surgery departments. Consensus was reached that

the inj Neostigmine should be the most probable drug responsible for this.

Then we decided to stop the use of that particular batch of Neostigmine (batch

no 02288, supplied by Ciron pharma ltd) and reported to the authorities. Samples

were preserved and sent to the FDA department for analysis.

Similar cases were also reported from Sir JJ group of Hospitals, Mumbai from use

of the same batch with few mortalities and morbidities.

In the due course we received a letter from authorities that FDA had analysed

the drug from that particular batch and found that it was of a substandard

quality.

TABLE NO 1

Drugs used for Induction and Maintenance of G.A.

Drug Dose No of

Patients

In which

patients

Glycopyrrolate 0.2 mg 4 All 4 cases

Diazepam 0.1 mg/kg 1 Case 4

Midazolam 0.03 mg/kg 3 Case 1,2,3

Pentazocine 0.3 mg /kg 4 All 4 cases

Pentothal Sodium 5 mg/kg 3 Case 1,2,4

Propofol 2 mg/kg 1 Case 3

Suxamethonium 2 mg/kg 3 Case 1,2,4

Vecuronium Br. 0.08 0.1 mg/kg 1 Case 3

Atracurium 0.5 mg/kg 3 Case 1,2,4

Halothane 0.4-0.6 % 3 Case 1,3,4

Drugs used for Reversal of Neuromuscular Block

Drug Dose No of Patients

Neostigmine 0.05 mg/kg 4

Glycopyrrolate 0.004 mg/kg 4


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Discussion:

From the above description it is obvious that all these patients were of ASA

status I and II. There is nothing significant on their preanaesthetic record. Their

biochemical and serological investigations along with ECG and CXR P-A view

were within normal limits. All of them were induced more or less similarly for G A.They all were stable (vitals) throughout the operative procedure. All of them

became symptomatic 15-20 minutes after reversal of neuromuscular block.

This lead us to think that there is something related with the reversal agents that

is causing problem. Injection Glycopyrrolate was used at induction as

antisialogogue and vagolytic agent without any intraoperative sequel. So the

drug remained was Neostigmine. It should be the most probable agent behind all

of these happenings.

We again thought that this batch of the drug was in use from last one month or

so. Why only these patients suffered? We tried to find the answer and came toknow that this particular batch of Neostigmine though was in use since last 1

month; these were the only patients in whom all the ampoules used were of that

same batch. We were having previous batch stock remained with us and in other

patients mixed batch ampoules were taken for reversal. Because of this, the

reaction might have been mild and did not progressed to severe symptoms so

remained unnoticed in other patients.

Neostigmine is well known agent for its muscarinic side effects like bradycardia,

salivary and bronchial secretions, bronchospasm etc but in none of the patients

we got all these signs at one time. There were clear signs and symptoms ofpulmonary oedema.

It is known to cause various arrhythmias in patients with acidosis or in patients

with asthma or heart disease. But none of our patients were having asthma and

cardiac disease.

It is also the agent which may induce negative pressure pulmonary oedema. Our

patients were extubated after adequate recovery from their neuromuscular block

and there was a good air blast seen before we removed the tube. We usually

oxygenate the patients with face mask after extubation for not less than 10 min

or till they are shifted to recovery room.


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So we concluded that injection Neostigmine of that particular batch was the

agent which was of substandard quality and was responsible for all these

postoperative pulmonary symptoms.

Take Home Messages:

Observe the patients in the recovery room at least for 45-60 min post extubation

along with all monitors.

Do not hesitate to reintubate and paralyse the patient if there is respiratory

inadequacy. Elective ventilation will reduce the work of breathing and thereby

further complications.

Whenever there is a problem, call for help to your senior colleagues as well as

friends from other departments viz. Medicine etc.

Investigate the patient thoroughly.

Whenever you are using a drug from a new company, be alert and watchful for

some more time than usual.

Do not use substandard drugs or the drugs from unknown company, though they

are cheap.

Keep records in a proper way.

Inform to the authorities and FDA department if you are suspicious about any

drug.


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substandard neostigmindr misal final

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