CASE REPORT
SUBSTANDARD NEOSTIGMINE: A CAUSE OF POST-OPERATIVE
NON-CARDIOGENIC PULMONARY OEDEMA
Ullhas S. Misal1, Sudhir G. Chavan2, Vikas A. Kurhekar3
HOW TO CITE THIS ARTICLE:
Ullhas S. Misal, Sudhir G. Chavan, Vikas A. Kurhekar. “Substandard Neostigmine: A Cause of Post-Operative
Non-cardiogenic Pulmonary Oedema”. Journal of Evidence Based Medicine and Healthcare; Volume 1, Issue
9, October 31, 2014; Page: 1206-1211.
ABSTRACT: Cases of Non-cardiogenic pulmonary edema occurred at Government Medical
College, Miraj and PVP General Hospital, Sangli during the month of December 2007 after
reversal of neuromuscular block with Neostigmine resulting in morbidity. The drug was newly
supplied on a rate contract basis to Government hospitals. The incidence was reported to the
authorities. Further use of the drug stopped and the sample sent to Food and Drugs
Administration department (FDA) for analysis. FDA analyzed the drug and reported that it was of
a “Substandard Quality”. We are presenting 2 cases of Non-cardiogenic pulmonary edema
occurred after the use of this ‘Substandard Neostigmine’.
KEYWORDS: Neostigmine, Drug related pulmonary edema, reversal of neuromussular block.
INTRODUCTION: Neostigmine is the most commonly used anticholinesterase agent to reverse
residual neuromuscular block at the end of surgery. It inhibits the normal hydrolysis of
acetylcholine and thus raises its concentration at cholinergic nerve endings. The drug increases
both muscarinic and nicotinic effects of acetylcholine. The muscarinic effects include bradycardia,
hypotension, profuse salivary and bronchial secretions, bronchospasm, and stimulation of smooth
muscles particularly of hollow viscera.
In presence of respiratory acidosis the drug may cause severe dysrhythmias. It should be
used with caution in patients with asthma and heart disease. Neostigmine overdose may cause
restlessness, weakness, muscular twitching, sweating, salivation, nausea, vomiting, pin point
pupil, colic, bronchospasm, and hypotension etc.
Aspiration of stomach contents, trauma, septicaemia, drug allergies are well recognized
causes of Non-cardiogenic pulmonary edema after general anaesthesia. Non-cardiogenic
pulmonary edema occurred after reversal of neuromuscular block with neostigmine at
“Government Medical College and PVP General Hospital, Miraj-Sangli” during December 2007.
In this case report, we are presenting two cases of Non-cardiogenic pulmonary edema occurred
after reversal of neuromuscular block with neostigmine.
CASE 1: A middle aged male with h/o duodenal ulcer was posted for gastrojejunostomy.
Preanesthesia findings revealed h/o vomiting on and off, pain in abdomen, repeated use of
NSAIDs and chronic alcoholism. His biochemical profile, ECG and CXR show no abnormality. His
PR was 88 beats/min, and BP was 98/68 mmHg, and chest auscultation was normal. Patient’s
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
J of Evidence Based Med & Hlthcare, pISSN- 2349-2562, eISSN- 2349-2570/ Vol. 1/ Issue 9 / Oct. 31, 2014. Page 1206
CASE REPORT
was shifted to recovery room for observation. In recovery room, we noticed tachycardia (PR136/min), tachypnoea (RR-32/min), mild to moderate cyanosis and air hunger in the patient. His
BP was 66/40 mmHg and SpO2 84 %. Chest auscultation showed bilateral crepitation.
Immediate re intubation and ventilation with 100 % oxygen supplementation was carried
out. Inj mephentermine 15 mg IV given along with Inj Dexamethasone (8mg) and Hydrocortisone
(100mg), and when BP became normal (106/60 mmHg), Inj lasix 20+20 mg given IV. Inj
deriphylline 2 ml IV given. He was re paralyzed with Inj Vecuronium 4 mg and was shifted to ICU
where he was put on ventilator for next 12 hrs. In due course of time, he improved
symptomatically and clinically. Gradual weaning from ventilator done and he was extubated next
day without any sequel.
CASE 2: A middle aged female weighing 50 kg and ASA status I with fracture left radius-ulna
was posted for plating. 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, RR-32/min and SpO2 86 %. On auscultation there were bilateral basal
crepts. Patient re intubated and re-paralyzed by giving Inj Vecuronium 4 mg. Ventilated with 100
% oxygen.
Inj Dexamethasone and Hydrocortisone were given along with Aminophylline 250 mg
bolus. IV Hydroxyethyl starch pushed fast (300 ml), Inj Lasix 40+20+20=total 80 mg, Dopamine
drip started to maintain BP above 90 mmHg. Patient subsequently improved symptomatically and
clinically in next 3 hrs and shifted to ICU where he was put on mechanical ventilator. He was
weaned gradually from ventilator and extubated next day and shifted to the ward without any
respiratory problem.
Drug
Dose
Glycopyrrolate
0.2 mg
Midazolam
0.03 mg/kg
Pentazocine
0.3 mg /kg
Pentothal Sodium
5 mg/kg
Suxamethonium
2 mg/kg
Vecuronium Bromide
0.08 – 0.1 mg/kg
Halothane
0.4-0.6 %
Neostigmine
0.05 mg/kg
Glycopyrrolate
0.004 mg/kg
Table No. 1: Showing the drugs used for
Induction, Maintenance and Reversal of G.A.
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CASE REPORT
Fig. 1: CXR P-A view showing pulmonery oedema
These events compelled us to find out the cause of this morbidity. We have had a long
discussion amongst the departmental colleagues and surgeons and physician. Consensus was
reached that the inj Neostigmine should be the most probable drug responsible for this. We
stopped the use of that particular batch of Neostigmine (Batch No. 02288) and the incidence was
reported to the authorities. Samples were preserved and sent to the FDA department for analysis.
Fig. 2: Reporting of the complication to the authorities
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CASE REPORT
Similar cases were also reported from Sir JJ group of Hospitals, Mumbai from use of the
same batch. FDA analyzed the drug and reported that the drug supplied was of a substandard
quality.
Fig. 3: Analysis report received from FDA
DISCUSSION: According to literature, neostigmine overdose may cause acute cholinergic crisis
characterized by increased salivation, bronchial secretions, bronchospasm, tachy or bradycardia
and hypotension. Sometimes agitation, fear or restlessness may occur and death may result from
cardiac arrest or respiratory insufficiency and pulmonary edema. In our patients the dose of
neostigmine used was 0.05mg/kg body weight which rules out dose related complications.
Neostigmine 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 symptomatic
cardiac disease. Negative pressure pulmonary edema,(2,3,4) an uncommon problem of persistent
inspiratory efforts against an obstructed airway was ruled out in our patients as all of them were
extubated after adequate recovery from their residual neuromuscular block and there was a good
air blast seen before we removed the tube.
Raiger et al(1) reported two cases of non-cardiogenic pulmonary edema occurred after
reversal of neuromuscular block with neostigmine. This was questioned by Mukul Kapoor.(5) In
our case, it was the substandard quality of drug which caused post reversal non-cardiogenic
pulmonary edema.
Drug induced pulmonary edema (6,9,10,11,12) has also been documented with several agents
that have different pharmacological effects. To mention few are Salicylates, Naloxone, Tocolytics,
Protamine, Amiodarone, Insulins, Streptokinase, Hydrochlorothiazide etc. Non-cardiogenic
pulmonary edema has been reported after administration of Propofol and Ondansetron.
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CASE REPORT
The diagnosis of non-cardiogenic pulmonary edema is done by exclusion, as no specific
test is available. In our patients the incidence occurred just after reversal of residual
neuromuscular block with neostigmine and glycopyrrolate. Of these, glycopyrrolate was used at
induction hence the most probable agent should be neostigmine.
Another question was why only these patients suffered when the GA was given to many.
After detailed enquiries amongst staff and residents, we came to know that these were the only
patients in whom all the ampoules used were of the same batch. We were having old stock of
neostigmine and mixed batch ampoules were used for reversal in others due to which other
patients were not suffered.
Non-cardiogenic pulmonary edema can well be managed upon prompt recognition and
intense supportive therapy although mortality has been reported. Early ventilator support with or
without muscle paralysis reduces the work of breathing and is a key to success.
CONCLUSION: Whenever you are using a drug from an unfamiliar company, be alert and
watchful than usual. Substandard drugs may cause any complication. If you are suspicious about
any drug, stop using it. Inform immediately to the concerned authorities. Preserve samples and
send them to FDA department for analysis to avoid complications elsewhere.
Monitor the patients in the recovery room at least for 45-60 min after reversal. Do not
hesitate to re intubate and paralyze 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. Discuss the problem amongst fellow colleagues; some of them may
give helpful advice.
REFERENCES:
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after neostigmine given for reversal: A report of two cases; Indian J Anaesth 2010; 54: 33841.
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cause of non-cardiogenic pulmonary edema. J Ky Med Assoc. 2003; 101: 317-20.
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5. Mukul Kapoor. Could pulmonary oedema be attributed to the use of neostigmine? Indian J
Anaesth. 2010; 54 (6): 582.
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CASE REPORT
10. Gamboa PM, Achotegui V, Irigoyen J, Perez-Asenjo J, Merino J, Sanz ML.
Hydrochlorothiazide-induced acute non-cardiogenic pulmonary edema. J Investig Allergol
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AUTHORS:
1. Ullhas S. Misal
2. Sudhir G. Chavan
3. Vikas A. Kurhekar
PARTICULARS OF CONTRIBUTORS:
1. Professor, Department of Anaesthesia,
Government Medical College and Hospital,
CVTS Department, Aurangabad, Maharastra.
2. Professor, Department of Anaesthesia,
Government Medical College and Hospital,
CVTS Department, Aurangabad, Maharastra.
3. Associate Professor, Department of
Anaesthesia, Government Medical College
and Hospital, CVTS Department,
Aurangabad, Maharastra.
NAME ADDRESS EMAIL ID OF THE
CORRESPONDING AUTHOR:
Dr. Ullas S. Misal,
Flat No. S-1, Venkatesh Residency,
C. S. No. 246 A/B,
Behind Kelavkar Hospital,
Nagala Park, ‘E’-ward,
Kolhapur-416003.
E-mail: ullhasmisal@gmail.com
Date
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Submission: 08/09/2014.
Peer Review: 09/09/2014.
Acceptance: 06/10/2014.
Publishing: 23/10/2014.
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