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 Table of Contents  
CASE REPORT
Year : 2021  |  Volume : 8  |  Issue : 2  |  Page : 99-101

Diphenoxylate hydrochloride and atropine sulfate overdose in an infant presenting as respiratory failure


1 Department of Pediatrics, Pediatric Intensive Care Unit, Institute of Child Health, Kolkata, West Bengal, India
2 Department of Pediatric Medicine, Pediatric Intensive Care Unit, Institute of Child Health, Kolkata, West Bengal, India

Date of Submission28-Sep-2020
Date of Decision05-Dec-2020
Date of Acceptance11-Dec-2020
Date of Web Publication10-Mar-2021

Correspondence Address:
Dr. Sanchari Ghosh
Department of Pediatrics, Institute of Child Health, Kolkata, West Bengal
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jpcc.jpcc_156_20

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  Abstract 


A fixed-dose combination of diphenoxylate hydrochloride and atropine sulfate marketed widely as oral tablets, is one of the most frivolously used drugs to treat diarrhea in adults. Its safety and efficacy in children younger than 2 years are not known. In this case, we came across a 45-day-old infant being maltreated with adult dose of the drug, for diarrhea, by a local charlatan, which landed him in the emergency room with lethargy, altered sensorium, and type 2 respiratory failure and ultimately had to be salvaged by mechanical ventilation. This case describes the life-threatening adverse effects of an adult drug on the pediatric age group.

Keywords: Atropine sulfate, diarrhea, diphenoxylate hydrochloride, respiratory failure


How to cite this article:
Ghosh S, Sutradhar S, Giri PP. Diphenoxylate hydrochloride and atropine sulfate overdose in an infant presenting as respiratory failure. J Pediatr Crit Care 2021;8:99-101

How to cite this URL:
Ghosh S, Sutradhar S, Giri PP. Diphenoxylate hydrochloride and atropine sulfate overdose in an infant presenting as respiratory failure. J Pediatr Crit Care [serial online] 2021 [cited 2021 Apr 20];8:99-101. Available from: http://www.jpcc.org.in/text.asp?2021/8/2/99/311053




  Introduction Top


Diarrhea in the pediatric age group is mostly viral in origin and still the second leading cause of under 5 mortality worldwide. Pediatric diarrhea can mostly be managed by maintaining adequate hydration by oral rehydration solution and only a small number of patients need hospital admission for intravenous (IV) rehydration and antibiotics.[1] The role of anti-secretary medications is doubtful and mostly contraindicated in infancy. Diarrhea, even in its most nascent forms, raises a lot of anxiousness among parents and caregivers, causing them to resort to over the counter medicines or unqualified charlatans when the modern medicine practices do not yield swift results. The administration of these anti secretary medications such as the combination of diphenoxylate hydrochloride and atropine sulfate can have life-threatening adverse effects in infants like our index case.[2]


  Case Report Top


A 45-day-old baby boy, residing in a village of West Bengal, apparently well 3 days back, presented at the pediatric emergency in the month of April 2020 with a history of multiple episodes of loose watery stool for the past 3 days after the introduction of formula milk. The baby was in a state of altered sensorium, lethargic, and bradypneic. The evaluation of the vital parameters revealed tachycardia with a low oxygen saturation of 89% in room air and 97% with moist oxygen inhalation @ 2l/min through nasal prongs. The clinical presentation was highly suggestive of severe sepsis presenting as diarrhea and subsequent dehydration and lethargy due to associated dyselectrolytemia or central nervous system (CNS) infection. On further prodding, the parents gave the history of giving a medicine, after which the baby became increasingly drowsy and stopped feeding. The baby had been on fixed-dose combination (FDC) tablets of diphenoxylate hydrochloride 2.5 mg and atropine sulfate 25 mcg, one tablet twice a day for the past 2 days. Subsequently, pupil examination revealed pinpoint pupils. The baby was immediately shifted to the pediatric intensive care unit for further management.

The baby had been given gastric lavage with activated charcoal. An arterial blood gas was done which revealed mixed acidosis. The respiratory drive of the baby further declined with intermittent apneic spells and he had to be intubated and mechanically ventilated in pressure-regulated volume control mode after adequate fluid resuscitation. Empirical antibiotics were started. Routine blood investigations and chest X-ray were normal. Standard neuroprotective strategies had been taken. He had to be kept under control mode of ventilation for 36 h, during which he did not have any respiratory effort of his own, despite being on no sedation. A plan to give naloxone as an antidote was made. However, due to the nationwide lockdown and unavailability of naloxone at most medicine shops at that moment of time, it could not be given. The respiratory effort began improving after 36 h of mechanical ventilation and he started triggering few breaths. Subsequently, he was gradually shifted to pressure support modes and finally extubated after 60 h of ventilation. The baby regained good cry and activity by 72 h of admission. After this, he had an almost uneventful recovery and was discharged on day 6 of admission. The kid, therefore, followed up in the out-patient department for the next 3 months and he made an excellent neurological recovery without any sequelae.


  Discussion Top


A FDC of diphenoxylate hydrochloride 2.5 mg and atropine sulfate 25 mcg is used as an antisecretory medicine in diarrhea in adults patients. Diphenoxylate an opioid analog of meperidine, the main therapeutic ingredient of this combination, activates presynaptic opioid receptors in the enteric nervous system to block acetylcholine release and decrease peristalsis thus resulting in prolongation of gastrointestinal transit time. It can cross the blood-brain barrier and produce CNS effects. Difenoxin, its active metabolite has five times the antimotility action compared to diphenoxylate itself, with an elimination half-life of about 12–14 h.[3] A subtherapeutic amount of atropine sulfate is added to discourage abuse, owing to unwanted anticholinergic effects. Although effective in treating the symptoms of diarrhea, it is associated with serious adverse effects including severe constipation, bloating, flushing, paresthesia, hallucinations, tachypnea or hypopnea, tachycardia, and anuria. Dehydration and dyselectrolytemia can cause intensification of the adverse effects. Adult dosage in infants can cause severe to fatal adverse effects. Our patient had been given four tablets in a span of 40 h and landed in our emergency in respiratory failure at around 46 h from the ingestion of the first tablet. The exact lethal dose of the drug in children is not known as not too many cases of toxicity have been reported in recent literature. McCarron et al. reported eight pediatric accidental overdoses of diphenoxylate-atropine and reviewed 28 literature cases. They opined that overdose is primarily an opioid intoxication, occasionally associated with atropine toxicity. Contrary to popular belief, atropine effects occur before, during, or after opioid effects. Opioid overdose (CNS and respiratory depression with miosis) predominated or occurred without any signs of atropine toxicity in 33 cases (92%). Diphenoxylate-induced hypoxia was the major problem and was associated with tachypnea and/or bradypnea, hypotonia or rigidity, cardiac arrest, and in three cases cerebral edema and death. Interestingly, respiratory depression recurred in seven cases 13–24 h after the ingestion and was probably due to the accumulation of difenoxine, an active metabolite of diphenoxylate.[4] In our case, we fortunately did not face any recurrence of respiratory depression in spite of not giving naloxane.

Treatment should be instituted as soon as offending drug is identified. Because of its action in rendering the gut atonic, removal of diphenoxylate by gastric lavage is mandatory, even in patients admitted at least 24 h after drug ingestion. Repeated administration of activated charcoal should also be done.[5] Naloxone is the narcotic antagonist of choice and should be used in all cases where suspected diphenoxylate poisoning leads to respiratory depression or coma. In such cases of intoxication with impending respiratory failure, it is wise to intubate the baby and begin mechanical ventilation, and to start the patient on naloxone. The recommended dosing is about 0.005 mg/kg–0.1 mg/kg given IV, intramuscular, or subcutaneous sc, may be given multiple times maintaining a gap of 2–3 min, in accordance to the clinical response.[4],[5],[6],[7] Repeated dosing might be required because the elimination half-life of naloxone is far exceeded by diphenoxylate. Few experts also recommend continuous infusion of naloxone. Naloxone is much effective in reversing these opioid adverse effects of diphenoxylate and may even postpone intubation and mechanical ventilatory support. Khan et al. reported a similar case that had been salvaged by Naloxone administration.[2] In our case, naloxone remained unavailable as an effect of nationwide lockdown.

Our case exposes the danger of unauthorized use of adult medicines in improper doses in the pediatric population. Extreme caution should be maintained with respect to the adverse effects of the drugs used. It is also important to take a detailed history and have a high index of suspicion for early identification of such intoxication. A toxicology helpline is also a need of the hour to manage the rarely encountered intoxications. Few antidotes such as naloxone which are not frequently used should also be made available widely as they can be life-saving.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient (s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Ciccarelli S, Stolfi I, Caramia G. Management strategies in the treatment of neonatal and pediatric gastroenteritis. Infect Drug Resist 2013;6:133-61.  Back to cited text no. 1
    
2.
Khan HR, Ali Asghar S, Kanwal S, Qadar LT, Qadri KH, Khan HR, et al. Diphenoxylate-atropine (Lomotil) toxicity in infantile diarrhea: A case report of therapeutic failure. Cureus 2019;11:e5875.  Back to cited text no. 2
    
3.
Rumack BH, Temple AR. Lomotil® poisoning, pediatrics. American association of Pediatrics 1974;53:495-500.  Back to cited text no. 3
    
4.
McCarron MM, Challoner KR, Thompson GA. Diphenoxylate-atropine (Lomotil) overdose in children: An update (report of eight cases and review of the literature) Pediatrics 1991;87:694-700.  Back to cited text no. 4
    
5.
Curtis JA, Goel KM. Lomotil poisoning in children. Arch Dis Child 1979;54:222-5.  Back to cited text no. 5
    
6.
Farmer BM, Prosser JM, Hoffman RS. Re: “Are one or two dangerous? Diphenoxylate-atropine exposure in toddlers.” J Emerg Med 2010;38:384.  Back to cited text no. 6
    
7.
Nemlekar SS, Mehta RY, Shah ND. Diphenoxylate dependence treated with buprenorphine and naloxone combination. Ann Indian Psychiatry 2018;2:63-4.  Back to cited text no. 7
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