Case Presentation: We present a 59-year-old male patient with a medical history significant for heart failure with a reduced ejection fraction who underwent aortic root replacement and transaortic valve replacement for severe aortic stenosis and an ascending aortic aneurysm. His postoperative course was complicated by cardiogenic shock requiring impella and inotropic support. He was transferred to the ICU for further hemodynamic monitoring via a Swan-Ganz catheter. During his ICU stay, he continued to have a complicated course of acute hypoxic respiratory failure, resulting in multiple reintubations and eventually requiring a tracheostomy. In the interim, he was started on Olanzapine for multiple episodes of agitation and restlessness. 2 days later, minute ventilation increased from 6.6 to 9.6 L/min (reaching max 20 L/min), with respiratory rate up to 40/min. An arterial blood gas revealed acute severe respiratory alkalosis. Chest x-ray and CTA chest did not show pulmonary embolism but demonstrated only mild pulmonary edema and small bilateral effusions, improving with hemodialysis, which did not explain subacute onset of hyperventilation. A decision was made to stop Olanzapine as the most likely culprit. Over the next 24 hours, the patient’s hyperventilation improved, minute ventilation decreased to 7 L/min, and respiratory rate to 20/min. ABG showed resolved respiratory alkalosis.

Discussion: Antipsychotic agents have been the primary treatment modality for schizophrenia, particularly demonstrating efficacy in the management of psychosis. Olanzapine belongs to the class of atypical antipsychotics and has demonstrated an enhanced efficacy and safety profile. It works via antagonism of different classes of receptors – dopamine (D1-4), serotonin (5HT1A, 2A, 2C, 3, 6,7) and α1, α2. Olanzapine also has been known to cause side effects of dystonia, tardive dyskinesia, insulin resistance, less commonly, seizures and neuroleptic malignant syndrome. However, only a handful of case reports have demonstrated a relationship between Olanzapine and hyperventilation. Although proving causality is difficult, an increased minute ventilation on the ventilator while on olanzapine therapy, lack of other causes of increased respiratory drive, and improvement after discontinuation suggest a causal association. Several medications, including adenosine, salicylates, progestin and quetiapine, have been shown to increase minute ventilation. However, the mechanism is still unclear. It is postulated due to its direct action on the respiratory center and indirect action, through serotonergic involvement, in central and peripheral chemoreceptors. Another explanation is respiratory dyskinesia, an akathisia-like extrapyramidal side effect involving respiratory muscles causing forceful breathing and hyperventilation.

Conclusions: Olanzapine is a commonly used medication for patients with agitation and delirium in the ICU. Compared to typical antipsychotics, atypical antipsychotics, like Olanzapine, are known for their better-tolerated side effect profile and decreased risk of extrapyramidal effects. This case report highlights that physicians should be cautious when using atypical antipsychotics – specifically Olanzapine- which can cause increased respiratory drive without other explainable causes.