Introduction

Opioids are commonly used in the Pediatric Intensive Care Unit (PICU) especially during the postoperative period as analgesics and sedatives. Despite having well known side effects [1], in some multifactorial instances [2, 3], opioid metabolites can accumulate in the body leading to overdose, opioid induced neurotoxicity (OIN) or opioid withdrawal syndrome if improperly discontinued. While the constellation of symptoms for each complication might not all be present, its treatment or reversal is unique for each. We present the case of a 14-month-old girl who experienced severe hysteria and irritability after opioid use post operatively, findings that are similar to those seen in OIN, but who failed to respond to all known therapeutic measures and was fully reversed after the administration of naloxone.

Case presentation

Our patient is an 8.2 kg, 14-month-old girl with a ventricular septal defect (VSD) status post main pulmonary artery (MPA) banding, who was admitted to our hospital for VSD closure and MPA de-banding. Her operation was uncomplicated, and she was transferred to the PICU for post-operative management while intubated and sedated.

On post-op day 1, she had transient low cardiac output syndrome (LCOS), requiring inotropic and vasopressor support with milrinone, epinephrine and norepinephrine, and she had mild transient acute kidney injury (AKI) (creatinine increased from 0.3 to 0.6 mg/dl) without uremia. Her AKI and LCOS resolved on post operative day 2, and her inotropes weaned off on post operative day 3.

The patient’s initial sedation consisted of morphine (0.02 mg/kg/hour) and midazolam (0.05 mg/kg/hour) infusions, but since presentation, she was severely agitated, requiring multiple boluses of midazolam and morphine, as well as sedatives adjustment, first by gradual increase in the infusion rates reaching midazolam (0.2 mg/kg/hour) and morphine (0.1 mg/kg/hour), then by adding dexmedetomidine drip reaching gradually (0.4 mcg/kg/hour), using ketamine pushes as well, but to no avail. Decision taken to switch morphine to fentanyl drip (1 mcg/kg/hour), but no change in her status was noted. On post operative day 3, she was hemodynamically stable, the decision was to extubate her on Dexmedetomidine only, hoping to relieve her agitation as well. She was successfully extubated, but she continued to be inconsolable, agitated, hysteric and incapable of fixating nor tracking, a situation that distraught her parents so badly.

Pain was ruled out as pain killers and a fentanyl push did not relieve them. Additionally, low cardiac output was ruled out, as the patient was hemodynamically stable with good urine output, warm extremities and normal laboratory tests including serial lactate levels. Withdrawal was ruled out, as same symptoms were present since admission to PICU, she was maintained on opioids and midazolam for a short period of 3 days, and her symptoms did not resolve after low doses of fentanyl and midazolam pushes. Opioid toxicity was ruled out as she had normal size pupils on exam, no respiratory depression or change in her level of consciousness, no nausea or vomiting, and again these symptoms were present since post operative day 1. Opioid induced neurotoxicity syndrome was also ruled out, since symptoms were neither relieved after switching morphine to fentanyl, nor after stopping all the opioids nor after adding dexmedetomidine, and maintaining good fluid balance.

Prior to performing a computed tomography (CT) scan to rule out any bleeding post bypass surgery, she was given 0.1 mg/kg naloxone dose as a trial; after which she calmed down immediately, and was able to fixate her eyes, look at her mom, recognize her, point toward her milk, drink a little and slept. She woke up calmly the following morning with no signs of agitation. She could fixate, track and interact with her surroundings. The CT scan was within normal limits. She was followed closely and was back to her normal baseline within 2 days.

Discussion

Our patient underwent cardiac surgery, after which she was maintained on the usual opioid regimen for sedation and analgesia post operatively, but her severe agitation, irritability and hysteria were pertinent since admission to the PICU. Our possible differential diagnosis were pain or suboptimal sedation and analgesia, ventilator induced agitation, LCOS, opioid side effects, opioid overdose/intoxication, OIN, withdrawal syndrome and intracranial bleeding post bypass surgery. Although her symptoms shared some similarities with OIN, they did not fully fit any of the previously mentioned differential diagnosis. The serial physical examinations, the measures and management taken, helped us excluding the possible diagnosis progressively. Finally, the complete and immediate reversal of her symptoms after naloxone administration, pointed toward a possible unusual opioid side effect. To better understand opioid related signs and symptoms, we can divide them to: opioid side effects, overdose or intoxication, OIN and withdrawal syndrome. Please refer to (Table 1) to differentiate between each category and its specific treatment. The metabolism of morphine might be influenced by cardiac surgeries due to their effect on hepatic and renal blood flow, leading to delayed clearance and accumulation of metabolites [2]. Dagan et al. [3] found that clearance was prolonged in children who required inotropic support as well. Our patient underwent cardiac surgery, required inotropic support for 3 days and suffered a transient AKI, all of which may have contributed to an altered metabolism of opioids. Although unusual agitation and delirium are not sure to be a side effect of opioid or an association but it still needs to be considered. In conclusion, this case highlights a possible atypical side-effect of opioids, thus the need to bring awareness about these differential diagnoses in children receiving opioids and not following an expected course during their hospital stay.

Table 1 Differential diagnosis and treatment of different opioid related signs and symptoms
Full size table