key: cord-255435-mr239gai authors: Sher, Yelizaveta; Rabkin, Beatrice; Maldonado, Jose R.; Mohabir, Paul title: A CASE REPORT OF COVID-19 ASSOCIATED HYPERACTIVE ICU DELIRIUM WITH PROPOSED PATHOPHYSIOLOGY AND TREATMENT date: 2020-05-19 journal: Psychosomatics DOI: 10.1016/j.psym.2020.05.007 sha: doc_id: 255435 cord_uid: mr239gai There have been increasing reports of neuropsychiatric presentations and symptoms of COVID-19, more commonly seen in severely ill patients. Delirium, which is highly prevalent in general intensive care unit (ICU) populations, is expected to be frequent and prominent in COVID-19 patients hospitalized with acute respiratory distress syndrome (ARDS) in ICU. In this case report with associated review, we present a case of a critically ill patient with COVID-19 managed in ICU for ARDS. Psychiatry was consulted for management of her hyperactive delirium, likely complicated by environmental factors inherent in management of COVID-19 patients as well as the use of multiple sedatives. Patient was successfully managed by psychiatry with a combination of high-dose melatonin, suvorexant, guanfacine, intravenous haloperidol, and intravenous valproic acid. In addition to case presentation, we discuss a proposed delirium pathophysiology in COVID-19 associated delirium and a systematized approach to evaluation and management of such patients. There have been increasing reports of neuropsychiatric presentations and symptoms of COVID-19, more commonly seen in severely ill patients. Delirium, which is highly prevalent in general intensive care unit (ICU) populations, is expected to be frequent and prominent in COVID-19 patients hospitalized with acute respiratory distress syndrome (ARDS) in ICU. In this case report with associated review, we present a case of a critically ill patient with COVID-19 managed in ICU for ARDS. Psychiatry was consulted for management of her hyperactive delirium, likely complicated by environmental factors inherent in management of COVID-19 patients as well as the use of multiple sedatives. Patient was successfully managed by psychiatry with a combination of high-dose melatonin, suvorexant, guanfacine, intravenous haloperidol, and intravenous valproic acid. In addition to case presentation, we discuss a proposed delirium pathophysiology in COVID-19 associated delirium and a systematized approach to evaluation and management of such patients. Coronavirus disease 2019 (COVID-19) was first described in Wuhan, Hubei Province, China in December of 2019 (1). Worldwide, at the time of this publication, there have been over 4.2 million confirmed cases and over 287,000 deaths (2). Clinical manifestations vary from asymptomatic to an acute respiratory illness with progression to respiratory distress and failure (3) . Treatment challenges in the intensive care unit (ICU) include severe acute respiratory distress syndrome (ARDS) due to severe acute respiratory syndrome coronavirus (SARS-CoV-2), cardiac and other organ dysfunction, and superimposed infections (1,4). In addition, emerging data support a viral neuro-invasive component (5) . Mao and colleagues described numerous neurological symptoms imposing further challenges (6) . Delirium, not surprisingly, emerges, as an additional significant complication and burden in these patients. This case report details complexities in the management of hyperactive delirium associated with COVID-19 infection in the ICU. In general, delirium is associated with increased length of hospital stay, morbidity and mortality in mechanically ventilated ICU patients (7) . However, there is a paucity of literature discussing the management and impact of delirium on COVID-19 patients. We discuss the proposed pathophysiology of delirium associated with COVID-19 infection and provide a framework for the evaluation and management of delirium occurring in patients with SARS-CoV-2. A previously healthy 70 year old woman presented to an urgent care with 5 days of fever, malaise, headache, and dry cough. Chest radiography revealed right lung airspace opacities. She was prescribed azithromycin and amoxicillin/clavulanic acid. Over the next day, her shortness of breath worsened and her viral PCR for SARS-CoV-2 returned positive. She presented for a scheduled hospital admission, where she was febrile to 103.7F and tachypneic. Absolute lymphocyte count was 710, interleukin-6 31 pg/mL, ferritin 1,222 ng/mL, C-reactive protein (CRP) 3.4 mg/dL, and procalcitonin 0.53 ng/mL. Renal function demonstrated impairment above her baseline (estimated glomerular filtration rate 52mL/min/1.73m 2 .) Aspartate aminotransferase and alanine aminotransferase were mildly elevated at 112 and 139 units/L, respectively. Her initial QTc was 397 ms. She was treated with 5 days of ceftriaxone and azithromycin due to concern for bacterial coinfection and 10 days of remdesivir as a part of trial for treatment of COVID-19. She was transferred to the ICU for worsening hypoxic respiratory failure on admission day 3 and intubated on admission day 4. While she was briefly extubated on day 26, she required reintubation on the same day. To facilitate mechanical ventilation and combat significant agitation, patient received numerous sedative drips, including dexmedetomidine, hydromorphone, propofol, midazolam, and ketamine, as well oxycodone (up to 60 mg daily) and chlordiazepoxide (up to 30 mg daily). Other psychotropic agents used by her primary team included quetiapine (up to 175 mg daily) and melatonin 5 mg nightly. She remained restless and agitated. Psychiatry was consulted on admission day 29 to assist with management of agitation, one day prior to tracheostomy placement on hospital day 30. Due to strict COVID-19 infection control policies, patient was assessed virtually, by chart review, and via discussions with her nurses, ICU team, and family. The Under the psychiatry's recommendations, melatonin was increased to 15 mg nightly to regulate sleepwake cycle and for the antioxidant and anti-inflammatory effects and suvorexant, an orexin antagonist, was added at 20 mg, for sleep-wake cycle regulation. Guanfacine, an alpha-2 agonist, was started at 0.5 mg twice daily and titrated to 1 mg thrice daily to reduce sympathetic outflow, manage agitation, and assist in weaning intravenous sedatives. Intravenous valproic acid (VPA; titrated to 1250 mg per day) was also started for management of agitation and symptoms of hyperactive delirium and to facilitate tapering of multiple other sedative deliriogenic medications. Quetiapine was initially titrated to 250 mg distributed throughout the day, but due to its ineffectiveness, it was discontinued on day 3 of psychiatric consultation and instead intravenous haloperidol (titrated to 8 mg per day) was used to manage symptoms of hyperactive delirium. Of note, nursing staff was educated and asked to examine for extrapyramidal side effects of antipsychotics during their regular patient evaluation and care. Over the following five days, the patient tolerated discontinuation of all sedative drips with gradual tapering of chlordiazepoxide (discontinued on day 6 of psychiatric consultation) and oxycodone (discontinued on day 7 of psychiatric consultation). She had ongoing medical complications, including fevers and pneumothorax, during this phase of her treatment. Regardless, her mental status continued to improve. VPA was discontinued on day 5 of consultation, and haloperidol was discontinued on day 11 of consultation. On day 10 of psychiatric consultation, , the patient was fully cognizant, awake, alert, oriented, following simple and complex commands, communicative via the use of mouthing and writing (assessed virtually), and displayed no evidence of ongoing delirium on assessment by a psychiatry team and according to the DSM-5. She was discharged on day 52 after her initial hospitalization to a long-term acute care facility. The patient provided verbal consent for the case report, but was unable to physically sign associated documentation due to infection control measures. Neuropsychiatric presentations of COVID-19 are increasingly described in the literature. A retrospective case series of 214 hospitalized patients in China demonstrated that 24.8% had central nervous system (CNS) manifestations (e.g., dizziness, impaired consciousness, acute cerebrovascular disease, seizures), 8 .9% had peripheral nervous system manifestations (taste, smell, and/or vision impairment), and 10.7% -skeletal muscular injury manifestations (10.7%) (6) . Neurological abnormalities were observed in 45.5% of those severely ill with COVID-19 as compared to those less severely ill (P=0.02), including impaired consciousness (14.8% versus 2.4%, P < .001) (6). In general, delirium is present in up to 82% of ICU intubated patients (7). Not surprisingly, ICU patients with COVID-19 and ARDS are similarly expected to have a high delirium incidence. Helms and colleagues 12 reported on 58 severely ill COVID-19 patients with 69% agitated when weaning off sedation, and 65% of those able to participate in the CAM-ICU scoring positively, suggesting delirium. The differential diagnosis of neuropsychiatric symptoms, including delirium, in patients with COVID-19 is extensive. Cases of encephalitis and meningitis have been documented with specific SARS-CoV-2 RNA detected in cerebral spinal fluid (13) . In addition, patients with COVID-19 might have elevated D-dimer and impaired platelet functioning, thus placing them at risk for acute cerebrovascular accidents (14) . Non-convulsive seizures should also be entertained on the differential, based on the clinical picture. Various pathophysiological mechanisms for delirium development and propagation have been proposed (18) , many of which co-exist in patients with COVID-19. Some of these are unique to individual patients (i.e., substrates), some are related to the treatment environment (e.g., ICU, sedatives), and others are related to the acute effects of the virus and its comorbidities (i.e., precipitants). However, there are unique considerations in COVID-19 patients, including CNS viral effects, COVID-19 specific treatment side effects, and environmental factors. Evidence suggests that direct CNS invasion of the SARS-CoV-2 is possible, which might lead to deleterious neuropsychiatric effects. In fact, animal studies have demonstrated that SARS-CoV-2 is neuro-invasive, likely entering the brain parenchyma via ascending olfactory nerves, then spreading to the thalamus and brainstem (5) . Additionally, a subset of COVID-19 patients experience a cytokine storm (15) . While an immune response is important to fight the infection, an excessive and dysregulated immune overactivation is likely to contribute to the development of ARDS and multi-organ failure, including "brain failure" or delirium (16) . Many pro-inflammatory cytokines (e.g., interleukin-6, interleukin-8, interleukin-1 β) and chemokines (e.g., CCL2, CCL-5) have been linked to the development of ARDS, a frequent cause of mortality in patients with COVID-19 (15); the same have been associated with the development of delirium16. Specifically, Qin et al described extensive dysregulation of the immune response in patients with COVID-19 (17) . Moreover, cytokine storm is fueled by the release of catecholamines by immune cells via a self-amplifying circuit (18) . Catecholamines, such as norepinephrine, might also be elevated in hyperactive delirium contributing to its pathophysiology and symptomology (16) . Our patient's course was characterized by significant agitation, requiring use of multiple high-dose sedatives. This agitation, along with ARDS, might be one presentation of the cytokine storm and catecholamine release in this patient population. Among specific patient's characteristics, older age among COVID-19 patients is associated with higher morbidity and mortality rates (19) . Similarly, older age and associated medical comorbidities are recognized as major risk factors for delirium development (16) . In addition, patients with pneumonia and respiratory failure might experience CNS hypoxia and increasing anaerobic metabolism in the mitochondria of brain cells. This can then lead to cerebral vasodilation, brain cell and interstitial edema, and obstruction of cerebral blood flow (14) . These same mechanisms have been described as causative factors in delirium development (18) . Our patient was an older woman. Regarding treatment-related factors, patients with severe COVID-19 often require management in ICU settings and/or ventilatory support. Ventilated patients are frequently placed on combinations of CNS depressants to facilitate ventilatory compliance. Many of these sedatives are associated with an increased incidence of delirium (16) . In fact, due to significant agitation in many COVID-19 ICU patients and the risk to patients and staff associated with patients dislodging lines and endotracheal tubes in context of high viral infectivity, patients have anecdotally required combinations of multiple sedatives with very high doses. In our case, the patient had required propofol, opiods, and high-dose benzodiazepines, among other agents, which could have all further worsened her confusion and agitation. In addition, some medications that have been specifically used in the treatment of COVID-19 may themselves induce neuropsychiatric side effects. For example, hydroxychloroquine has been known to cause such side effects, including delirium (20) . These effects may be exacerbated by a cytokine storm-mediated increase in blood-brain permeability. While our patient was not treated with hydroxychloroquine, it might be an important consideration for others. Moreover, secondary complications, such as renal failure and secondary infections, can contribute to or worsen delirium. Environmental factors also increase the risk of delirium during these challenging times. Due to the high infectivity of this virus, shortage of personal protective equipment (PPE), and medical isolation to decrease virus transmission, COVID-19 patients might not have the benefit of conventional nonpharmacological prevention strategies or the support of loved ones (21) . The staff is unable to spend time and provide frequent re-orientation and cognitive stimulation for the patients, while family members are not allowed to visit and provide visual cues, reassurance, and practical support. In addition, unusual configuration of the rooms, inability to recognize faces due to staff's extensive PPE, and potentially even the use of the virtual modalities to communicate (e.g., remote telemedicine and virtual visits with family members) as opposed to live visits, all might worsen patients' perception of the reality and contribute to disorientation and confusion. The diagnosis of delirium in patients with COVID-19 is challenging due to limited interactions between staff and patients due to isolation protocols. A live neuropsychiatric evaluation (gold standard) might not be available and/or safe; thus screening tools, such as CAM-ICU (9) and the Intensive Care Delirium Screening Checklist (ICDSC) (22) might be especially useful. Yet, up to 30% of patients might not be able to complete screening tools that require patient participation (9) . Thus, a novel tool, the S-PTD, might be particularly helpful as it relies on nursing report of patients' cognition and behaviors, rather than on patient's participation (10, 11) . Our patient was initially evaluated remotely from outside of the room integrating review of the chart and descriptions of her behavior and mental status from her nursing and medical staff. CAM-ICU and S-PTD were also used in her evaluation and diagnosis. As patient improved and was able to engage in an evaluation, she was interviewed virtually with the use of telemedicine. In addition to usual infectious and metabolic work-up for delirium, pharmacological agents that can contribute to mental status alterations must be reviewed. Our patient received significant amounts of deliriogenic medications (e.g., propofol, hydromorphone, oxycodone, chlordiazepoxide). Based on the differential diagnosis, brain imaging, a lumbar puncture, and an electroencephalogram might be indicated. Since our patient did not display focal neurologic deficits, abnormal movements or consistently depressed mental status, these studies were not indicated or pursued. Renal and liver function as well as QTc on electrocardiogram should be established to safely choose an appropriate pharmacological regimen. Our patient had baseline elevated liver function tests (likely due to COVID-19 infection) and these were carefully monitored on daily basis while VPA was administered on short-term basis. LaHue and colleagues have suggested practical non-pharmacological interventions to prevent delirium in patients with COVID-19, given the unique challenges (21) . Some practical nonpharmacological interventions in this population include maintaining light-dark environment consistent with the diurnal cycle; minimization of nighttime disruptions; re-orientation and cognitive stimulation of the patient whenever possible; encouragement of family photos, phone calls, and virtual visits; provision of physical mobilization whenever possible; ensuring availability of glasses, hearing aids, and communication devices. Delirium-related agitation places the patient and healthcare providers at risk, thus medications should be available for acute management. While no studies have demonstrated pharmacological efficacy in the management of delirium among COVID-19 patients, we provide a framework for choosing psychotropic medications to assist in achieving behavioral control in ICU patients. Agents chosen to treat symptoms of delirium in our patient and included in Table 1 were specifically selected due to their own low deliriogenic potential and with the goal to minimize the use of conventional sedatives which are associated with worsening delirium, longer recovery, and impaired long-term cognition. At our center, the following medications have been used in management of agitation in patients with COVID-19 ICU-associated hyperactive delirium, including the described patient, with following considerations. High-dose melatonin is used for treatment of delirium and sleep-wake cycle regulation, and postulated to be useful in treatment of COVID-19 in general, given its anti-inflammatory and antioxidant effects (23) . We have maximized melatonin in this patient. Suvorexant regulates sleep-wake cycle and assists in treatment of delirium, especially in combination with melatonin or melatonin receptor agonist (24, 25) . Thus, it was added for management of sleep-wake cycle in this patient with hyperactive COVID-19 associated delirium. Alpha-2 agonists decrease noradrenergic upregulation secondary to cytokine storm. While dexmedetomidine can be used for acute agitation and cycling at night, guanfacine can help taper off dexmedetomidine and other sedatives. Our patient had already been managed with dexmedetomidine. Addition of guanfacine appears to have facilitated tapering off her other sedative drips, including dexmedetomidine. Antipsychotics can assist in delirium symptom control, while patients must be monitored for QTc prolongation and neurologic and sedative side effects. Specifically in this patient population, antipsychotic agents must be carefully monitored, given the potential use of COVID-19 specific medications that may prolong QTc (e.g., hydroxychloroquine, azithromycin), leading to a potentially increased risk of torsade's de pointes (26) , as well as rare cardiac manifestations of COVID-19. QTc was monitored on daily basis and did not demonstrate prolongation in our patient. While increasing doses of quetiapine did not seem helpful in our patient, switching to haloperidol in combination with other interventions, was correlated with improvement in patient's mental status. Haloperidol might have been more helpful due to its more potent dopamine blockade and minimal antihistaminic and anticholinergic activity as compared to quetiapine. In addition, haloperidol has been found to be an effective antagonist of Sigma-1 receptors, which, in theory, might potently protect against oxidative stress-related cell death (27) . Nursing staff was educated on assessing for extrapyramidal side effects associated with antipsychotics, integrating this into their regular patient assessment and care. VPA is used for management of hyperactive and/or mixed (i.e., fluctuating between agitation and hypoactivity) delirium, has potential anti-inflammatory and anti-oxidant effects, and might decrease transcription of interleukin-6 (28). Evidence also suggests potential neuroprotective effects of VPA (28) . VPA might assist to minimize or taper off sedative agents, however, liver function tests and platelets must be closely monitored. Addition of VPA seemed crucial in decreasing agitation of the patient and assisting in tapering off multiple sedating drips and as well as benzodiazepines and opiates. This case report discusses the proposed pathophysiology of COVID-19 associated ICU delirium. Derived from the clinical complexity of the patient described, we provide a framework to delirium evaluation and management in similar patients. As the number of cases of COVID-19 continues to increase, so will the hospital length of stay and inevitable incidence of delirium and agitation in these patients. Thus, a systematic approach to delirium prophylaxis, screening, diagnosis, and treatment are paramount to patients' management and improved outcomes. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. The authors report no conflict of interest. A Novel Coronavirus from Patients with Pneumonia in China Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72314 Cases From the Chinese Center for Disease Control and Prevention Intensive care management of coronavirus disease 2019 (COVID-19): challenges and recommendations. 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