To the editor:
Deliria in the setting of COVID infection are quite ubiquitous and mutifactorial in causation. Pneumonia, fever, dyselectrolitaemia, dehydration, pain, polypharmacy, and so on are all contributory. COVID-associated “cytokine storm” might account to the higher rates of deliria encountered particularly in these cases.Reference Ibrahim 1 Interestingly, data accrue speaking to the idea that COVID neurotropism might be responsible to a primary type of deliria—neurocovid. Reference De Berardis 2
COVID deliria have been specifically characterized by agitation (hyperactive delirium), requiring more sedation and poor lorazepam-responsive catatonic presentations. Multifocal myoclonus and frontal release signs are commonly seen too.Reference Ibrahim 3
Management follows general lines of addressing underlying infection (eg, antiviral remdesivir; but beware it is a substrate of CYP 3A4) and metabolic derangement, attention to hydration status, nutrition, ventilation, skin care, environmental accommodations, and reorientation.
A meta-analysis of four randomized controlled trial RCTs has demonstrated that melatonin supplementation at 9 pm had a significant preventive effect in decreasing the incidence of deliria in elderly patients in medical wards by 75%. This has also been demonstrated to melatonin analogue, ramelteon in another RCT.Reference Naguy, Alamiri and Shoukry 4 Given antioxidant, neuroprotective, and immunosuppressive actions (beneficial for the cytokine storm), melatonin 1 to 3 mg has been generally recommended for patients with COVID deliria.
Antipsychotics remain the mainstay of addressing hyperactive deliria with hallucinatory experiences, and delusional beliefs especially in the presence of safety concerns—it should be borne in mind, however, that the use of high-potency D2 blockers (typically haloperidol) in COVID-delirium with catatonic presentations or severe dehydration might significantly up the risk of neuroleptic malignant syndrome. Haloperidol, especially intravenous, is less neurotoxic and some evidence suggests a beneficial role beyond delirium, by virtue of actions on sigma receptors. If any, low-potency agents (eg, chlorpromazine different formulations) can be used instead. However, anticholinergic and adrenolytic actions of these latter agents should be carefully monitored. Close observation of QT interval corrected for heart rate QTc interval is warranted especially azithromycin and hydroxychloroquine, still being integral part of many COVID treatment protocols, can notoriously increase the risk of QTc prolongation and torsadogenecity. Contrariwise, subdued patients with hypoactive delirium might benefit from aripiprazole.
Because of these aforementioned risks, α2 agonists, like dexmedetomidine, have been strongly suggested in ICU setting to sedate patients with COVID deliria in lieu of antipsychotics. Risk of hypotension and bradycardia with these agents should be taken into consideration given the demonstrated systematic impact of COVID infection on cardiac conductivity (eg, high-grades atrio-ventricular AV block).
Benzodiazepines should be generally avoided as it can worsen and prolong deliria and meanwhile, may risk respiratory depression in COVID pneumonia.
Since multifocal myoclonus and seizures are fairly commonplace in COVID deliria, use of broad-spectrum antiepileptic drugs like valproate can be justified to target agitation as well. Valproate confers neuroprotection as a bonanza.Reference Naguy 5
It has been shown in COVID delirium-catatonia composite presentation is at times difficult to brush out, and given the differential response to antipsychotics-benzodiazepines, some authors have suggested deploying amantadine. Amantadine has dopaminomimetic, weak anticholinergic and antiglutamate actions that can be helpful in these complex clinical scenarios. Amantadine has antiviral actions that can be of potential use in COVID infection.
Vitamins C and D supplementation is highly advised in many COVID protocols currently.
Disclosure
The authors have no competing interests or financial affiliations.