Ranitidine-Induced Delirium in a 7-Year-Old Girl: A Case Report

Discussion

This is probably the first report of pediatric delirium associated with ranitidine infusion. Delirium is defined in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition as a disturbance of attention and awareness that can no longer be well explained by preexisting or evolving dementia. This disorder develops over a short period, with a tendency to fluctuate throughout the day, and is a direct physiologic consequence of another medical condition, substance intoxication or withdrawal, exposure to a toxin, or multiple etiologies.⁹ Thus, delirium may occur in different scenarios,¹⁰ and it is crucial to consider its diagnosis because it is associated with high morbidity and mortality.¹¹

We hypothesized that the ranitidine infusions triggered the episodes of delirium. However, one of the great challenges in health research is to attribute causality between 2 events. Classically, 9 conditions, known as “Hill Criteria,” are required to define a causal association: strength of association, consistency, specificity, temporality, biological gradient, plausibility, coherence, experimental evidence, and analogy.^12,13 Although no strength of association and no experimental evidence are provided in this case, some of the other Hill Criteria are present and can be used to support that hypothesis. Consistency is reinforced by similar reports in adults.⁷ Specificity is observed (the supposed causal factor of ranitidine was followed by the occurrence of the effect of delirium) more than once. After switching to omeprazole, the patient did not present further episodes. Temporality is a strong criterion because both delirium episodes began during ranitidine infusion, corroborating that the cause preceded the onset of effect. Concerning plausibility, coherence, and analogy, the current state of knowledge reveals that loss of cholinergic neuromodulation can lead to cognitive and attentional deficits.¹⁴ Several studies indicate anticholinergic drugs as risk factors for delirium and the role of anticholinergic burden in delirium pathophysiology.^5,14–17 Anticholinergic toxidrome is described after exposure to anticholinergic drugs, including H2 blockers,^16,17 which antagonize peripheral and central muscarinic receptors, producing anticholinergic toxoids. One CNS manifestation of these drugs is delirium.¹⁵ Unfortunately, the literature on anticholinergic toxidrome and its relationship to delirium is limited to adult populations, and, thus, the magnitude of its occurrence in childhood is still unknown.¹⁷ The fact that many risk factors described in the literature are lacking in this case gives further support to the hypothesis of a causal relationship between ranitidine and delirium. Important predisposing factors include the severity of the underlying disease, male sex, visual and hearing impairment, dehydration, malnutrition, low albumin, and past alcohol, substance, and/or cigarette abuse or multiple psychoactive drugs. In children, an age <2 years and preexisting developmental delay are quoted in the literature as relevant predisposing factors.^6,10,18 Precipitating factors include electrolyte imbalances, metabolic disturbances, hypoxia, shock, anemia, hypothermia or fever, severe acute illness, surgery, physical restraints, sedative hypnotics (such as benzodiazepines), opioids, and infections.^6,10

Patient blood tests revealed normal electrolytes, normal venous blood gases, and normal hepatic and renal function. At the time of the delirium episode, oxygen saturation was 98% in ambient air, and she did not return to oxygen therapy at any time until hospital discharge. The severity of the acute illness was low, and the patient did not require volumetric expansion or vasoactive drugs. No sedative or opioid drugs were prescribed, and the patient needed no physical restraint. Bacterial infection was excluded because the patient had no history of fever or hypothermia, presented normal leukogram, negative blood culture results, and no evidence of pneumonia on physical examination or on the chest radiograph. No clinical signals of CNS infection were detected, and a lumbar puncture was not indicated. The slight increase in CRP was attributed to the asthma exacerbation.¹⁹

One can argue that other precipitating factors, such as admission to the PICU, the presence of invasive devices, and multiple drug therapy,^6,10 were present and could have contributed to the delirium episodes. The patient had a peripheral venous access and received inhaled salbutamol and methylprednisolone. Salbutamol can stimulate the CNS, leading to anxiety, insomnia, motor restlessness, and delirium.^20,21 Corticosteroids induce both CNS side effects²² and stress responses, so clinicians are recommended to avoid steroids when a potential delirium mindset ocurrs.⁶ We believe that these factors may have contributed to elicit the delirium episodes, although the synchrony between both episodes and the ranitidine infusions was striking in this case.

Prevention is the most effective way to reduce delirium incidence. Understanding the risk factors is critical because they can, to some extent, be controlled and managed.⁶ Key strategies include modification of environmental, iatrogenic, and patient-related factors. Treatment relies on the prevention of risk factors, early diagnosis, clinical monitoring, and, if possible, resolution of the underlying disease.^23–25 Reserving pharmacological treatment for when nonpharmacological alternatives have been exhausted is recommended in the literature.^25–27 We used no drugs to treat the delirium episodes in this case.