Modafinil for wakefulness and disorders of consciousness in the critical care units: An updated narrative review and case series

Marwa Amer; Mouhamad Ghyath Jamil; Eiad Kseibi

doi:10.4103/sccj.sccj_15_22

REVIEW ARTICLE

Year : 2022 | Volume : 6 | Issue : 2 | Page : 23-35

Modafinil for wakefulness and disorders of consciousness in the critical care units: An updated narrative review and case series

Marwa Amer¹, Mouhamad Ghyath Jamil², Eiad Kseibi²
¹ Pharmaceutical Care Division, King Faisal Specialist Hospital and Research Center; College of Medicine and Pharmacy, Alfaisal University, Riyadh, Saudi Arabia
² Department of Critical Care Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia

Date of Submission	08-Jun-2022
Date of Decision	16-Jun-2022
Date of Acceptance	16-Jun-2022
Date of Web Publication	30-Sep-2022

Correspondence Address:
Marwa Amer
King Faisal Specialist Hospital and Research Center, Pharmaceutical Care Division (MBC # 11), PO Box 3354, Riyadh, 11211
Saudi Arabia

Source of Support: None, Conflict of Interest: None

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DOI: 10.4103/sccj.sccj_15_22

Abstract

Objective: Cognitive improvement after critical illness is complex. Neurostimulants are used to speed up physical and mental processes. Modafinil for wakefulness in the intensive care unit (ICU) holds the potential to facilitate recovery from cognitive impairment. We aim to provide an updated narrative review of the current evidence on modafinil use for wakefulness and disorders of consciousness (DoC) and describe modafinil effect for wakefulness in eight adults admitted to our ICUs at King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia. Methods: For the narrative review, we searched MEDLINE for modafinil studies as neurostimulant for wakefulness and DoC published from inception through May 30, 2022, with no language or study design restriction, focused on adults, and neurocritical care population (traumatic brain injury [TBI], poststroke). The case series included adult patients (age ≥18 years), admitted between January 2017 and June 2020 to coronavirus disease 2019 (COVID-19) and non-COVID ICUs with an ICU stay of at least 48 h, started on modafinil during ICU stay for at least 48 h and required ventilatory support. Results: For the narrative review, we identified five studies in TBI (n = 285; two RCTs and three retrospective cohort studies), one systematic review poststroke (n = 120), two studies on ICU population, and one case report describing modafinil use in post-COVID encephalopathy. We also identified additional three recent studies that were published after systematic review for modafinil use poststroke. A total of eight patients out of approximately 10,000–13,000 ICU admissions used modafinil over the 4 years' period and described in our case series; 3 admitted to COVID-19 ICU, 4 surgical ICU, and 1 transplant ICU. Modafinil 100–200 mg daily was started for median duration of 4 days and median initiation time in relation to ICU admission was 11 (IQR 9–17) days. Glasgow Coma Score improvement was noted in 5 (62.5%) patients. No significant adverse effects were documented. Conclusion: In this case series, modafinil as neurostimulant was infrequently prescribed in ICU over the 4 years and was associated with a low incidence of adverse effects. Based on our observations, modafinil might have a potential role when administered to certain patients. Our findings can be biased by confounders that influence cognitive function and recovery. Larger studies are warranted to evaluate its role in this indication fully.

Keywords: Coma, consciousness, COVID-19, critical care, modafinil, neurostimulants

How to cite this article:
Amer M, Jamil MG, Kseibi E. Modafinil for wakefulness and disorders of consciousness in the critical care units: An updated narrative review and case series. Saudi Crit Care J 2022;6:23-35

How to cite this URL:
Amer M, Jamil MG, Kseibi E. Modafinil for wakefulness and disorders of consciousness in the critical care units: An updated narrative review and case series. Saudi Crit Care J [serial online] 2022 [cited 2023 Jun 4];6:23-35. Available from: https://www.sccj-sa.org/text.asp?2022/6/2/23/357644

Introduction

Coma is widely encountered throughout health care settings and has a major impact on outcomes and goals of care decisions and is also known to complicate and prolong hospitalizations.^[1] Intensive care unit (ICU) patients are susceptible to neurocognitive, musculoskeletal complications, and disorders of consciousness (DoC). This is usually seen following disruption of the brainstem and/or cortical networks subserving arousal and awareness and may manifest as coma, the vegetative state/unresponsive wakefulness state (VS/UWS), or the minimally conscious state (MCS).^[1] The causative factors are multifactorial. It may occur in the context of a variety of different acute neurological disorders (cardiac arrest, traumatic brain injury [TBI], and stroke), hypoxia, nonconvulsive seizure, and metabolic abnormalities (acute renal failure, acute liver failure, and hypoglycemia). Moreover, impaired consciousness is commonly encountered in patients with systemic infections, such as sepsis.^[1] Beyond this, ongoing use of sedatives, analgesics, and neuromuscular blockade impact recovery from critical illness and may be a potential confounder for residual critical illness neuropathy/myopathy.^[1]

In addition, clinical experience from severe acute respiratory syndrome coronavirus 2 suggests its neuroinvasive potential.^[2] Approximately 36.4% of coronavirus disease 2019 (COVID-19) inpatients in Wuhan exhibited neurological symptoms.^[3] Manifestations included impairment and fluctuating states of consciousness, such as coma and delirium, executive dysfunction, anosmia, stroke, headache, Guillain–Barré syndrome (GBS), Miller Fisher syndrome, encephalitis, acute necrotizing encephalopathy, myelitis, and central nervous system (CNS) demyelinating lesions.^[2],[3]

Early detection of DoC is important to direct the diagnostic workup and medical support for these vulnerable patients. In response to this need, the Neurocritical Care Society established the Curing Coma Campaign, which intended to develop a framework for studying mechanisms of coma, promoting awareness, and developing evidence-based treatments for patients with acute illnesses who develop coma.^[1] Nonpharmacological modalities have been proposed as a potential treatment option, such as implementing an early neurorehabilitation protocol (occupational therapy [OT], physical therapy [PT], and speech-language therapy).^[4] Other therapeutic options include correcting underlying etiologies, sedation vacation/reversal, and neurostimulants to promote consciousness.^[1]

Neurostimulants are used to speed up physical and mental processes by increasing dopamine, serotonin, norepinephrine, and acetylcholine. This translates to improve neurocognition, enhanced arousal, wakefulness, and motor processing speed.^[5] Although prescribing trends of neurostimulants are yet to be fully elucidated, their use is increasing in TBI patients, especially those with coma, VS/UWS, or MCS. The clinical rationale is to facilitate the transition from VS and increase participation in PT and ambulation, thereby decreasing ICU-related complications such as deep vein thrombosis and ICU-acquired delirium while facilitating self-expression, accelerating recovery, hastening liberation from mechanical ventilation (MV), and decreasing ICU length of stay (LOS).

Modafinil is a neurostimulant with a distinct mechanism of action. Its cognition-enhancing properties are attributed to the modulation of glutamate, gamma-aminobutyric acid, and alpha-1B noradrenergic receptors while having minimal effect on serotonin, dopamine, and benzodiazepine receptors.^[5] Modafinil also offers several advantages over other conventional neurostimulants. It does not exhibit the same level of sympathomimetic effects, such as behavioral excitation or rebound hypersomnolence. It also has minimal potential for abuse and does not appear to disrupt normal sleep architecture. Side effects include insomnia, anxiety, agitation, and delirium. At our institution, modafinil is approved for improving wakefulness in adults with narcolepsy and idiopathic hypersomnia, shift work sleep disorder, and adjunctive therapy for obstructive sleep apnea (OSA)/hypopnea syndrome. In this updated narrative review and case series, we summarize the current evidence on modafinil use for wakefulness and DoC. We also described eight ICU cases to evaluate the safety and effectiveness of modafinil in those populations and provided additional data about the use of modafinil as a neurostimulant in COVID-19 patients.

Methods

Study design and participants

For the narrative review, we searched for modafinil studies as neurostimulant for wakefulness and DoC, focused on adults, and neurocritical care population (TBI, poststroke). We excluded studies that used modafinil for central disorders of hypersomnolence (narcolepsy, idiopathic hypersomnia, and Kleine–Levin syndrome), shift work sleep disorder, improve sleep in OSA, Parkinson's disease, amyotrophic lateral sclerosis, or cancer-related fatigue.

The case series included eight adults (age ≥18 years), admitted to COVID-19 and non-COVID ICUs with an ICU stay of at least 48 h, started on modafinil during ICU stay for at least 48 h and required ventilatory support. Those who did not receive modafinil or received modafinil for indications other than ICU wakefulness were excluded. Data were collected between January 2017 and June 2020.

Study setting

This study was conducted in a single tertiary care center, King Faisal Specialist Hospital and Research Centre (KFSHandRC), Riyadh, a primary referral center in Saudi Arabia with 1,589 beds. The study was approved by Research Ethics Committee and Clinical Research Committee at KFSHandRC (RAC # 2201230).

Data sources and data collection

For the narrative review, we searched MEDLINE for studies published from inception through May 30, 2022, with no language or study design restrictions. In addition, we reviewed reference lists of identified reports and searched medRxiv.org for pre-print articles. The results of the review were summarized qualitatively.

Data for the case series were collected and managed using Institutional Research Electronic Data Capture (REDCap). The access to REDCap data was limited to principal investigator and coinvestigators. We collected patients' demographics, comorbidities, ICU supports (tracheostomy, renal replacement therapy [RRT], steroids, COVID-19 treatment regimen, and vasopressors), modafinil initiation time in relation to ICU admission, dose, and duration of treatment. The severity of illness was evaluated using Sequential Organ Failure Assessment and Acute Physiology and Chronic Health Evaluation II scores.

Work-up for common etiologies of DoC was recorded including variables that potentially confound the neurologic examination, such as metabolic abnormalities, lumbar puncture, cerebrospinal fluid (CSF) analysis, electroencephalogram (EEG), CNS acute insult in neuroimaging (brain computed tomography [CT], and magnetic resonance imaging [MRI]). For EEG, we abstracted findings such as generalized and focal slowing, epileptiform discharges, seizures, generalized rhythmic delta activity, frontal intermittent rhythmic delta activity, lateralized rhythmic delta activity, and triphasic waves. We also recorded the daily presence of medications that are known to affect cognitive assessments including intravenous or oral sedatives (e.g., midazolam, propofol), opioid analgesics (e.g., fentanyl), and intermittent or continuous intravenous infusion neuromuscular blockers (e.g., atracurium, rocuronium) given for the management of acute respiratory distress syndrome and not in the context of intubation.

We identified coma with the following cardinal features: absence of wakefulness, Glasgow Coma Score (GCS) ≤8, failure to respond purposefully to visual, verbal, or tactile stimuli, inability to follow commands, and the above criteria are not due to use of paralytic agents, active use of sedatives, or another neurologic or psychiatric disorder (e.g., neuromuscular disorder, catatonia). These cardinal features were selected by review of the literature and expert consensus [Supplementary Table 1].^[1]

We opted to use the GCS as a clinical assessment tool for coma which was performed daily by the bedside nurse during sedation interruption (in the absence of contraindication) and was deferred if patients were on continuous sedation. We focused on the GCS assessments to define coma instead of other, more sophisticated assessments given the availability of these data collected as part of routine clinical care and the inability to obtain established measures, such as the Coma Recovery Scale Revise. The changes in GCS were examined graphically over time. We defined responders for modafinil as GCS change by 2 points increase from baseline post modafinil initiation up to 7 days or clinical improvement in wakefulness or responsiveness documented in caregiver notes or PT or OT notes.

The ICU LOS, hospital LOS, discharge disposition, duration of MV, mortality, findings of nerve conduction studies (NCS), electromyography (EMG), and other complications during ICU stay were documented. Documentation in EMR was reviewed to identify patients started on antipsychotics and possible adverse drug reactions (ADRs) related to modafinil including nervousness, insomnia, agitation, delirium, hypersensitivity, and drug rash. Naranjo scale was used to evaluate the association between ADRs and modafinil therapy.^[6]

Results

For the narrative review, we identified five studies in TBI (n = 285; 2 RCTs and 3 retrospective cohort studies),^{[7],[8],[9],[10],[11]} one systematic review poststroke which included 12 modafinil studies (n = 120),^{[12],[13],[14],[15],[16],[17],[18],[19],[20],[21],[22],[23],[24]} two studies in ICU population (one case series in nonventilated patients n = 3, and the another is a retrospective study in ventilated patients n = 60),^[25],[26] and one case report describing modafinil use in post-COVID encephalopathy.^[27] We also included additional three recent studies that were published after a systematic review for modafinil use poststroke.^{[28],[29],[30]} Study characteristics are summarized in [Table 1] and [Supplementary Table 2].

Table 1: Studies on modafinil use in neuro and intensive care unit population

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A total of 8 patients were described in this case series. Demographics, clinical characteristics, ICU complications, and patient disposition are summarized in [Table 2]. The median patient age was 76 (IQR 64.75–80.25) years, 7 (87.5%) were men, 3 (37.5%) admitted to COVID ICU, and 5 (62.5%) admitted to non-COVID ICU. The median time from ICU admission to modafinil administration was 11 (IQR 9-17) days. Seven patients (87.5%) started on modafinil 100 mg orally every morning, while one patient received 200 mg daily for a median duration of 4 days [IQR 3.25–5]. The main indication for modafinil initiation was DoC and altered mental status that precluded successful extubation or liberation from MV. All patients received vasopressors during their ICU stay, and 5 patients (62.5%) started on RRT for pre-existing chronic kidney disease or acute kidney injury (AKI). All COVID-19 patients were treated according to our institution's protocol for antivirals and immunomodulatory therapies. [Table 3] illustrates the workup for DoC during ICU stay. Two patients (25%) had initial neuroimaging that revealed hemorrhagic stroke, and one (12.5%) had ischemic stroke with hemorrhagic transformation. An EEG was performed for 7 patients, all of whom had nonspecific abnormalities, such as moderate to severe diffuse background slowing, triphasic waves, and generalized periodic discharges, but none revealed seizures or epileptic activity. Lumbar punctures and CSF analysis were done in 4 patients (50%), and 2 patients showed evidence of nosocomial meningitis that was treated with appropriate antimicrobials. All patients received multiple parenteral sedatives/narcotics during ICU stay. Median change of GCS (assessed during sedation interruption) 48 h before and 168 h after modafinil therapy is displayed in [Figure 1]. An improvement was noted in cases # 1, 3, 4, 5, 6. In case 8, the GCS slightly increased initially after modafinil administration and then remained unchanged after that. Patients # 2 and 7 noted no improvement in GCS after modafinil therapy. We used Naranjo scale for ADRs assessment, and a score of ≤0 indicated a doubtful association between ADRs and modafinil therapy. Notably, no ADR was determined to be of a probable or definite association with modafinil use for causality.

Figure 1: Trend of GCS over time before and after modafinil. The graphs present the median change of GCS 48 h before and 168 h (7 days) after modafinil therapy. The GCS ranges from 3 to 15, with higher scores indicating a higher level of consciousness. Time 0 was the time modafinil was first administered. Improvement was noted in patients # 1, 3, 4, 5, 6. No improvement was noted for patients # 2, 7. Patient # 8 received modafinil twice: the first trial was 100 mg oral every morning for 5 days (patient 8 a) and the second trial was of 100 mg oral every morning for 6 days (patient 8 b). In both scenarios, the GCS slightly increased initially after modafinil administration and then remained unchanged after that. GCS: Glasgow Coma Scale

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Table 2: Demographics, clinical characteristics, intensive care unit complications, and patients disposition

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Table 3: Workup for disorder of consciousness during intensive care unit stay

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Patient cases

Case 1

An 84-year-old male with a history of ischemic cardiomyopathy with an ejection fraction of 15–20, atrial fibrillation, hypertension, diabetes, ischemic stroke, provoked seizures, and dyslipidemia. He was admitted with COVID-19 infection. He was intubated and transferred to the ICU for acute hypoxemic respiratory failure, secondary to COVID-19 infection for further management. His ICU course was complicated by exaggerated cytokine release and he was given two doses of 400 mg anti-interleukin-6 tocilizumab. Despite diuresis to optimize his fluid status, the patient remained intubated for 20 d and required pressure-controlled ventilation, and the decision of tracheostomy was discussed. It was noted that he had decreased consciousness and was not awake. A non-contrast brain CT showed chronic ischemic changes without intracranial abnormalities. Multiple potential etiologies for change in acute mental status were ruled out, such as hypoxemia or hypercarbia due to respiratory failure, metabolic derangements, renal or hepatic dysfunction, nutritional deficiencies (thiamine was given), systemic infection leading to encephalopathy, and all sedatives agents were off for 1–3 days. An EEG and NCS were performed, to rule out the possibility of nonconvulsive seizures and any musculoskeletal complications with COVID-19 such as GBS or critical illness myopathy. Despite conservative nonpharmacologic measures to encourage a healthy sleep cycle, his level of consciousness remained the same (GCS around 7). Modafinil 100 mg orally each morning was administered to regulate his sleep–wake cycle and increase his consciousness level. On the second administration day, his ventilator setting transitioned to pressure support. Over the 5-day course of drug administration, he slowly improved in his level of consciousness and was eventually extubated on April 17, 2020. Within the following few days, he improved in rehabilitation and made a remarkable recovery. No adverse effects were noted. The patient was transferred from ICU to the floor and eventually discharged from the hospital.

Case 2

A 51-year-old male with a history of diabetes was admitted to a hospital with complaints of shortness of breath, fever, and cough and subsequently diagnosed with COVID pneumonitis causing acute lung injury leading to ARDS that required intubation. He was heavily sedated and paralyzed from severe acute hypoxic respiratory failure. He received treatment at the previous hospital for about 10–12 days before being transferred to our institution. On arrival at our institution's ICU, he was hemodynamically stable, and we were informed that he had been unconscious for 1 week and was off any sedation. His GCS with no sedation was 5. His brain CT scan showed no evidence of acute intracranial abnormality. An EEG was performed and did not show any seizure activity. He was administered 100 mg modafinil oral once daily for 4 d. His GCS minimally improved to 6/15. His ICU course was complicated by AKI, subsegmental pulmonary embolism, disseminated intravascular coagulation, and thrombocytopenia of unexplained etiology presumed to be heparin-induced thrombocytopenia for which his heparin infusion was switched to argatroban. Later, he developed gastrointestinal bleeding (GIB) requiring frequent transfusion and resuscitation for hemorrhagic shock. He was managed for severe COVID-19 infection according to our protocol but showed no signs of improvement. He remained in the same clinical condition with secondary multidrug-resistant bacterial infections that were treated with appropriate antimicrobial therapies with no clinical response. He was placed on do-not-resuscitate (DNR), and the patient died.

Case 3

A 67-year-old male with a history of diabetes, hypertension, end-stage renal disease (ESRD) on hemodialysis (HD), and status post right and left below-knee amputation. He was transferred from another hospital by Medivac for the management of septic shock and COVID-19 viral pneumonitis. He was initially kept on high-flow nasal cannula and his GCS was 9/15. He was drowsy and opened his eyes spontaneously. His ICU course was further complicated by stump infection and limb ischemia. He was intubated for OR and underwent above-knee amputation and surgical debridement. The sedation was weaned off, but his GCS remained 3/15 and we were unable to extubate him due to his altered mental status and encephalopathy. The RRT was continued, and brain CT showed microangiopathic changes with no acute intracranial insult. An EEG was performed, which showed no epileptic activity. Modafinil was administered for 5 days at 100 mg once daily. His GCS and level of consciousness improved to baseline and he was weaned off MV, extubated, and transferred to the ward. This was one-way extubation as he was assigned comfort care owing to his comorbidities and poor prognosis, and he passed away.

Case 4

A 77-year-old male with ESRD, on regular HD 3 times per week, heart failure with preserved ejection fraction, hepatitis C virus infection, diabetes, hypertension, dyslipidemia, OSA with pulmonary hypertension, osteoarthritis status post bilateral knee replacement. The patient presented to the Emergency Department (ED) complaining of vomiting and an associated decreased oral intake. CT scan of his abdomen showed evidence of proximal small bowel obstruction with transitional zone noted in the anterior abdominal hernia with no evidence of strangulation. The general surgery team was consulted and the patient was taken to the OR for exploratory laparotomy and small bowel resection. The patient was transferred to the ICU in an unstable condition with vasopressors. He underwent additional exploratory laparotomy twice. Subsequently, he was shifted back to the ICU. During this time, he was intubated, not sedated, GCS was 4/15, and equally reactive pupil bilaterally. Brain CT showed no acute intracranial insult or bleeding. In the ICU, he was started on RRT, feeding through jejunostomy tube, and had abnormal liver function likely due to underlying HCV, but his ammonia level was normal. Modafinil trial was started at a dose of 100 mg every 12 h for 3 d. He had fluctuating GCS (10-11/15), but an improved level of consciousness. His ICU course was complicated with upper GIB, infected surgical wound for which broad-spectrum antimicrobials were administered, and refractory septic shock secondary to intraabdominal infection. The patient remained in ICU and due to his overall general condition characterized by failure to thrive, inability to control the source of infections, and poor prognosis, he was placed on DNR and the patient died.

Case 5

A 75-year-old male with a history of hypertension, rectal polyp status post biopsy-adenoma with low-grade dysplasia, nonvalvular atrial fibrillation (on warfarin), an ischemic stroke 12 years before with no residual weakness, and OSA. He was transferred to our hospital for the management of intracranial bleeding (ICH) and intraventricular hemorrhage (IVH). Brain CT and CT angiography showed a large right frontoparietal hematoma extending to the motor cortex, with IVH into the lateral, 3^rd, and 4^th ventricles. His international normalized ratio (INR) was 2.3 and he was given 2000 units of prothrombin complex and Vitamin K. He underwent right frontoparietal craniotomy and evacuation of hematoma plus external ventricular drain (EVD) insertion. He was intubated and sedated which was discontinued to assess him neurologically. His GCS was 3/15 with positive cough and corneal reflex. Repeated brain CT showed improvement with minimal bleeding. An EEG was performed and no seizure activity was found. Modafinil 100 mg orally every morning was started for 5 days. His GCS improved slightly to 6–7/15 and sternal rub resulted in grimacing and movement of the torso and pressing the big toe produced flexion and slight withdrawal. His EVD was removed, GCS improved to 9/15; tube feeding was started and tolerated with good bowel movement. He was weaned off from MV, transferred to the ward, and eventually discharged.

Case 6

An 81-year-old male with a history of ESRD status post-renal transplant, atrial fibrillation, rheumatic heart disease, and hypertension. He presented to the ED with sudden onset weakness and aphasia and was found to have ischemic changes involving the left middle cerebral artery (MCA) territory. Brain CT revealed left internal carotid artery thrombosis, for which he underwent embolectomy. Post embolectomy, he was admitted to the ICU. His ICU course was complicated by hemorrhagic transformation (brain CT showed internal development of IVH within the left lateral ventricle and third ventricle with the progression of the left MCA territory acute infarction) that required decompressive craniotomy and evacuation of hematoma with EVD insertion. Post decompressive craniotomy, he remained intubated, unconscious, and unresponsive. His CSF was sent for analysis and results showed a red blood cell count of 8800, WBC count of 215, neutrophil count of 95, very high protein of 3000 mg/L, and glucose level of 6 mmol/L. The infectious diseases team was consulted and recommended to start him empirically on antimicrobial agents for nosocomial meningitis or ventriculitis. He remained intubated and on sedation which was interrupted for GCS assessment (GCS was 3-6/15). An EEG did not show any definite seizure activity. He was started on modafinil 100 mg every morning for 4 days and the neurologist noted that the patient was opening his eyes spontaneously with 4 mm pupils reactive to light, yawning, and coughing with positive cough and corneal reflexes. However, no significant improvement in GCS and response to command was noted. Care of the patient was continued in the form of feeding and MV and later switched to comfort care.

Case 7

A 75-year-old male is known to have hypertension, atrial fibrillation (on warfarin), and mechanical mitral valve replacement. He was presented to the ED with decreased level of consciousness post tonic–clonic seizure. His brain initial CT brain showed diffuse enlargement of the ventricle system with mild periventricular transependymal CSF permeation consistent with hydrocephalus associated with small dependent occipital intraventricular hemorrhage and his INR on admission was 3.5. He was admitted as a case of subarachnoid hemorrhage (SAH), IVH, and hydrocephalus. He underwent EVD insertion and started on 60 mg nimodipine PO every 4 h. His ICU stay was complicated with possible nosocomial meningitis or ventriculitis treated with antimicrobials and EVD removal, and AKI for which he was started on RRT. During this time, his GCS was 3/15 and he was off sedatives. EEG was done and did not reveal seizures or epileptic activity. Repeated brain CT did not show any evidence of increased bleeding or worsening of his hydrocephalus. Modafinil 100 mg once daily for 3 days was started. However, no significant improvement in GCS and response to command was noted. Later, his code status was changed to comfort care due to his comorbidities and the patient passed away.

Case 8

A 64-year-old woman with a history of diabetes, hypertension, and end-stage liver disease underwent living donor liver transplantation. Postoperatively, the patient was extubated on the second day, and then, she developed abdominal complications, bile leak and she underwent urgent abdominal exploration. Biliary reconstruction and drainage were done and the patient was transferred to ICU in a stable condition. Later, her condition deteriorated due to hypotension and decreased level of consciousness and she underwent another exploration and washout. Her ICU course was complicated with respiratory failure and it was difficult to wean her from MV. She developed an on and off chest and intra-abdominal infection for which she received antimicrobials and she ended up on tracheostomy. During this time, she was not obeying commands; GCS was 7/15 despite being off sedation for a week. Brain MRI was done and revealed small left frontal and right occipital acute/subacute infarcts with associated minimal punctate blood staining in the left frontal lobe, new small bilateral parietal microhemorrhage, and extensive nonspecific white matter diseases. An EEG was unremarkable and NCS/EMG was done and suggestive of critical illness myopathy/neuropathy. During her ICU stay, she received modafinil twice: First trial of 100 mg orally every morning for 5 days and the second trial was of 100 mg orally every morning for 6 days. The patient became more vigilant, oriented, and followed commands and had a GCS of 11/15. The patient was transferred to the floor.

Discussion

Early recovery of consciousness is a critical prognostic indicator of long-term functional recovery. Patients who remain unconscious on neurological examination are often believed to have a poor prognosis and are more likely to die in the ICU due to withdrawal of life-sustaining therapy.^[1]

The current case series provides additional knowledge on the usefulness and safety of modafinil as a neuro-stimulant for early recovery of consciousness in ICU patients during their acute hospitalization. The data supporting this practice are primarily limited to delayed treatment in rehabilitation or outpatient facilities. Very few reports and weaker evidence during the acute care hospitalization or acute DoC.^[29]

In this case series, we noticed modafinil as neuro-stimulant is infrequently prescribed in our patients during ICU admission over the 4 years' period and is associated with a low incidence of ADRs. This is similar to the study by Barra et al., on TBI population.^[9]

Persistent coma may have several causes including seizures, ischemic and hemorrhagic stroke, and leukoencephalopathy.^{[1],[2],[3],[4]} Many ICU patients are on deep sedation with continuous infusions of sedatives and analgesics and prolonged courses of neuromuscular blockade and have clinical courses complicated by AKI, leading to the possibility of delayed awakening. In the current case series, we addressed multiple potential etiologies for altered mental status before modafinil initiation including primary CNS process, metabolic derangements, hypoxemia or hypercarbia due to respiratory failure, renal or hepatic dysfunction, nutritional deficiencies (e.g., thiamine) in patients with poor nutritional status, infection- and sepsis-induced encephalopathy, sedatives use, EEG to rule out non-convulsive seizure, and lumbar puncture if above studies did not explain patient's neurological findings.

Moreover, mechanisms for coma in COVID-19 may differ from other conditions, especially given the direct pathogen invasion of the central nervous system.^[3] We are not the first to describe post-COVID encephalopathy responsive to modafinil. Roy et al. described the treatment of unexplained coma and hypokinetic-rigid syndrome in a patient with COVID-19 with cerebrovascular event. The patient was treated successfully with modafinil and carbidopa/levodopa and showed clinical improvement within 3–7 days and ultimately was able to be successfully discharged home.^[27] In the current case series, we described three cases of modafinil use in patients with COVID-19. We observed the GCS improved in two (out of 3 patients). The current role of modafinil in enhancing cognition in COVID-19 remains unclear given the limited data available. Thus, further prospective studies are needed to evaluate the safety, optimal dose range, and efficacy of modafinil in this population.

In this case series, we described modafinil use in three patients post-stroke (two patients with hemorrhagic stroke, and one patient with ischemic stroke and hemorrhagic transformation) and a favorable improvement was noted in GCS score in only one patient. The study by Leclerc et al. in nontraumatic ICH, ischemic stroke, or SAH showed that 55% of the patients were considered responders while receiving amantadine monotherapy (another neurostimulant), and 33% were responders while receiving both amantadine and modafinil.^[29] No patient was considered a responder in modafinil monotherapy. Modafinil appears to have limited dopaminergic effects, which may be of significance as post-stroke dopaminergic system dysfunction has been recently described.^[29] The lack of response to modafinil in our two post-stroke patients may have been the result of a mechanism of action separate from dopamine neurotransmission.^[5] Pre-clinical and clinical data suggest that dopamine activity is disturbed following acute stroke, and dopamine supplementation or augmentation may be of benefit, but this requires confirmation.^[31] Similarly, the common sequelae of stroke (e.g., vasospasm, hydrocephalus, and intracranial hypertension) also complicated our neurostimulant response assessments. For example, untreated hydrocephalus may blunt arousal, while CSF diversion or unclamping EVD may have induced wakening.^[29]

In addition, we observed analgesics and sedations concurrent use with modafinil in five patients of our series. Likewise, Barra ME et al. reported concurrent sedative use with stimulants in 14.6% of the patients and concurrent opioid use in 54.7% started on stimulants.^[9] In Mo et al., opioids and sedatives were used concurrently with modafinil and they found that modafinil administration was associated with a trend toward reduction in any sedatives exposure such as benzodiazepines, propofol, and/or dexmedetomidine over time 48 h after modafinil initiation.^[26] However, the evidence regarding this practice is scarce. Ideally, the use of modafinil concurrently with analgesics and sedation should be avoided due to the reduction in benefit of stimulant therapy which is most concerning in patients receiving longer-acting analgesics or sedations with active metabolite in a setting of AKI.

The strength of this study is the inclusion of expanded narrative review and providing pragmatic information on modafinil administration practices, clinical outcomes, potential ARDs, and included more inclusive list of recent publications. However, several limitations warrant comment. The small sample size, single-institution experience, observation nature, and lack of a control group will preclude causal interpretations. Similar to other observational studies, confounders can bias our findings from unmeasured factors that influence cognitive function and recovery. For example, we did not collect data on hyperosmolar therapy (mannitol or hypertonic saline), and the presence of an intracranial bolt, or ventriculoperitoneal shunt at the time of modafinil initiation which is also known to confound the neurologic examination. We also did not collect data on the confusion assessment method for the ICU (CAM-ICU) to assess delirium post modafinil use. Instead, the initiation of antipsychotics was used as a surrogate marker for ADRs attributed to modafinil therapy. In Barra ME et al., CAM-ICU was positive for delirium at least once during stimulant therapy in 18 (37.5%) patients.^[9] As such, potential ADRs associated with modafinil use might have been missed and larger prospective studies are needed to more comprehensively characterize modafinil safety in ICU. Moreover, modafinil dosing in our case series was limited and non-standardized, making it difficult to draw conclusions. Finally, we used a semi-structured approach to assess DoC through the GCS response. Although a GCS ≤ 8 has been considered a hallmark feature of coma, several limitations of the GCS have been identified, notably incomplete assessment of intubated patients, and failure to address brainstem reflexes.

Research priority and future research implication

The American Academy of Neurology suggested the use of neurostimulant medications, such as modafinil, carbidopa–levodopa (sinemet), and amantadine have all been shown to improve and accelerate functional recovery and sleep–wake cycles following an acute stroke or TBI patients.^[32]

In addition to the suggested research priority raised by Leclerc et al.,^[29] our updated narrative review and case series identified the following areas for future investigations:

Future controlled studies with a standardized administration protocol are needed to define the time of modafinil initiation, identify population that most likely benefit from therapy, define optimal drug dose and duration, and explore combination therapy role (e.g., amantadine and modafinil).
Larger prospective studies are needed to characterize stimulant safety in ICU patients more comprehensively.
Prospective RCT with adequate power should evaluate modafinil impact on overall patient-centered outcomes such as mortality, duration of MV, and ICU LOS.
Future studies should include more accurate behavioral assessments, such as the Coma Recovery Scale-Revised.
Future studies in the acute care setting should take into account potential confounders we encountered in this case series to properly evaluate the effectiveness and safety of modafinil.

Conclusion

Cognitive improvement after critical illness is complex. We reviewed the literature and described our center's experience with modafinil use for wakefulness in ICU, including additional data on COVID-19 patients. Based on our observations of these patients, known effects of modafinil, and its safety profile, we believe that modafinil might have a potential role when administered to certain critically ill patients, especially those who appear hypoactive and lethargic after a comprehensive assessment of potential etiologies for altered mental status. Although our observations are intriguing, they result from uncontrolled, retrospective chart review, and confounding bias is likely which precludes definitive statements. More data are essential to determine its role in wakefulness and DoC.

Acknowledgment

We would like to thank Talal Dahhan, Mohammed Bawazeer, Abid Butt for participation in patients care described in this series. We also thank the pharmacy automation team effort and their help to identify the ICU cases for our series [Maher Mominah, and Rania Al-Jaber]. We are thankful to Hala Khalil, PhD, Department of Biostatistics, Epidemiology and Scientific Computing for providing help in biostatistical part of manuscript.

Authors contribution

MA: Proposed the study, led the manuscript writing and did the data collection. MG: Proposed the idea, gave approval for modafinil as a sleep medicine consultant, reviewed and edited the manuscript. EK: Reviewed and edited the final version of the manuscript. All authors participated in the care of the patients, revised the manuscript for important intellectual content, and approved the final version to be published. We confirmed that the authorship followed the uniform requirements for manuscripts submitted to biomedical journals. Written informed consent was obtained from the patients for publication of this case series and available upon request.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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