Journal of Intensive Care Medicine 1-4 ª The Author(s) 2015 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0885066615571899 jic.sagepub.com
The Use of Modafinil in the Intensive Care Unit Michal Gajewski, DO1,2 and Gerald Weinhouse, MD3
Abstract As patients recover from their critical illness, the focus of intensive care unit (ICU) care becomes rehabilitation. Fatigue, excessive daytime somnolence (EDS), and depression can delay their recovery and potentially worsen outcomes. Psychostimulants, particularly modafinil (Provigil), have been shown to alleviate some of these symptoms in various patient populations, and as clinical trials are underway exploring this novel use of the drug, we present a case series of 3 patients in our institution’s Thoracic Surgery Intensive Care Unit. Our 3 patients were chosen as a result of their fatigue, EDS, and/or depression, which prolonged their ICU stay and precluded them from participating in physical therapy, an integral component of the rehabilitative process. The patients were given 200 mg of modafinil each morning to increase patient wakefulness, encourage their participation, and enable a more restful sleep during the night. Although the drug was undoubtedly not the sole reason why our patients became more active, the temporal relationship between starting the drug and our patients’ clinical improvement makes it likely that it contributed. Based on our observations with these patients, the known effects of modafinil, its safety profile, and the published experiences of others, we believe that modafinil has potential benefits when utilized in some critically ill patients and that the consequences of delayed patient recovery and a prolonged ICU stay may outweigh the risks of potential modafinil side effects. Keywords modafinil, Provigil, sleep cycle, rehabilitation, psychostimulants
Introduction It is well established that critically ill patients are at risk of neurological as well as musculoskeletal complications of critical care. Early mobilization of these patients has become the standard of care1-5; however those who are somnolent, fatigued, and depressed may not be able or willing to participate and, as a result, may have a delayed recovery. Although not studied in this context, psychostimulants, particularly modafinil (Provigil, Teva Pharmaceutical Industries Ltd.), have been shown to decrease fatigue and excessive daytime somnolence (EDS) in various patient populations, and additional trials are ongoing investigating the use of modafinil, and its enantiopure armodafinil, for such treatment in those with cancer, multiple sclerosis (MS), menopause, and hypoactive delirium.6-9 We present a case series of 3 patients admitted to our institution’s Thoracic Surgical Intensive Care Unit who, without a prior diagnosis of any sleep disorders and despite conservative, nonpharmacologic measures to encourage a healthy sleep cycle, were given modafinil ‘‘off-label’’ in order to expedite their recovery through early rehabilitation.
Clinical Cases Case 1. Mr G. was a 77-year-old male with a past medical history of nonsmall cell lung cancer, status post a left upper
lobectomy 1 month prior, who was readmitted from rehab for respiratory distress requiring intubation. After an initial diagnosis of fluid overload, he was quickly diuresed and extubated; however, over the next 3 days, the patient continued to require intermittent noninvasive positive pressure ventilation for dyspnea. Additionally, he felt ‘‘too tired’’ to participate with physical therapy or to get out of bed to the chair and therefore was bedbound for the majority of the time. One of the contributing factors was that the patient was not sleeping through the night and was therefore hypersomnolent throughout the day. Modafinil 200 mg each morning was administered in order to try to regulate his sleep–wake cycle and enable him to participate in his care. On the first day of administration, he continued to
1
Surgical Critical Care, Brigham and Women’s Hospital, Boston, MA, USA Department of Anesthesiology, New Jersey Medical School, Rutgers University, Newark, NJ, USA 3 Department of Medicine, Division of Pulmonary and Critical Care, Brigham and Women’s Hospital, Boston, MA, USA 2
Received September 16, 2014, and in revised form December 23, 2014. Accepted for publication January 8, 2015. Corresponding Author: Michal Gajewski, Department of Anesthesiology, New Jersey Medical School, Rutgers University, 185S. Orange Ave, MSB E-538, Newark, NJ 07103, USA. Email: [email protected]
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Journal of Intensive Care Medicine
require the same amount of respiratory support; however, he did ambulate for the first time since extubation and, as per the patient, rested well overnight. On day 2, physical therapy reported the patient saying ‘‘I’ll do exercises’’ and that same day he was also weaned to 3-L nasal cannula. Over the 13day course of drug administration, he slowly made advances in terms of his rehabilitation and was even noted to be ‘‘smiling and more interactive with staff,’’ despite his earlier ‘‘flat affect.’’ Within the following few days, the physical therapist reported that the patient was ‘‘making slow and steady progress.’’ No adverse effects were noted and no additional psychotropic medications were added to his regimen. Case 2. Mr M. was a 67-year-old male with a past medical history of esophageal cancer status post a minimally invasive esophagectomy 9 months earlier. His course was complicated by anastomotic dehiscence leading to numerous complications. After a prolonged treatment course, he was eventually transferred to our intensive care unit (ICU) for management of his pneumonia and sepsis. He subsequently was found to have a gastropleural fistula, which necessitated multiple trips to the operating room for resection as well as washouts. After his initial surgery, he improved from a rehabilitative standpoint, despite his continuous systemic inflammatory response and respiratory insufficiency. He ambulated and was even able to use the speaking valve on his tracheostomy. After returning from the operating room the second time, however, his mood was altered and he no longer was willing to participate in his care. Despite all his other conditions remaining stable in the perioperative period, he was now noted by physical therapy to be ‘‘extremely fatigued’’ and the nursing staff commented on his ‘‘angry affect, expressing wishes to withdraw care,’’ despite his continued home dose of venlafaxine. Modafinil was started at a dose of 200 mg and psychiatry was consulted to evaluate him. Per psychiatry, his Axis I diagnosis was delirium, adjustment disorder, and depression. Their recommendations consisted of pharmacologic treatment for his irregular sleep cycles as well as his fatigue, and modafinil was their agent of choice. On the first day of administration, the patient ‘‘promised to try physical therapy.’’ On follow-up by psychiatry 2 days later, ‘‘he did not appear demoralized, has been more engaged in his care, and participated in setting goals for himself.’’ Overall, the impression was that his ‘‘participation in care appears to have improved with the modafinil trial.’’ In another 2 days, physical therapy noted that ‘‘he was willing to participate in therapy session.’’ Further, ‘‘he was able to ambulate with assistance.’’ No side effects were noted throughout the 8-day course of this patient’s modafinil administration. Case 3. Mr. J. was a 70-year-old male with a past medical history of esophageal cancer who was transferred from the Veterans Administration Hospital (VA) for failure to thrive and a possible esophagectomy. He was initially stable; however, over the next few days he developed respiratory failure and was found to have bilateral pleural effusions, pneumonia, and pulmonary edema. He was intubated and transferred to the ICU for
further management. Upon drainage of his effusions, cytology revealed malignancy and he was therefore no longer being considered for surgical intervention of his cancer. Over the following few days, his respiratory status improved and he was extubated. His rehabilitative status was complicated by his malnourished state, his overall lack of energy, and his waxing and waning mental status. Psychiatry had already been consulted for this patient, and their initial recommendations were to treat acute changes with haloperidol as well as to continue his home regimen of clonazepam, paroxetine, as well as gabapentin. With time his delirium improved but his overall depressed and lethargic states persisted. The haloperidol was eventually discontinued as a result of the patient’s increase in QT interval, while the home regimen was continued. Modafinil was first started at a dose of 100 mg/d to try to improve his energy and mood. On the first day of administration, physical therapy noted that the patient ‘‘was in agreement with physical therapy goals.’’ Over the following few days, as a result of tolerating the medication well, the dose was increased to 200 mg/d. With the increase, he was transferred from bed to chair and was even wheeled outdoors. According to the patient, his sleep became more regular and he was not requiring his prior nightly dose of lorazepam for insomnia and agitation. Of note, Mr J would, on average, require 3 doses of 0.5 mg of lorazepam every night which, by the sixth day of modafinil administration, was not needed at all. Additionally, when the palliative care physician spoke with the patient, he communicated rationally with clear insight into his condition and was able to direct the course of his care. Modafinil was administered to this patient for a total of 7 days without any side effects.
Discussion Modafinil is a wakefulness-promoting drug that has been approved by the Food and Drug Administration for the treatment of narcolepsy, obstructive sleep apnea (OSA), and shift-work sleep disorder. The majority of its action has been attributed to its manipulation of the monoamine pathway although to date no clear pharmacodynamic profile has been established.10-13 In comparison to other stimulants, such as amphetamines, modafinil does not exhibit the same level of sympathomimetic effects, such as behavioral excitation or rebound hypersomnolence, suggesting that its mechanism of action is distinct.13-15 This could possibly explain why modafinil is not associated with interruption of normal nighttime sleep, as are amphetamines, and is also said to have a much lower abuse potential.13,16,17 The pharmacokinetics of single and multiple doses are similar.18-20 Of the oral dose, 90% is metabolized by the liver, partially by the 3A isoform subfamily of hepatic cytochrome P450 (CYP3A4).18 The products of metabolism are mostly 2 inactive metabolites, modafinil acid and modafinil sulfone, both of which are excreted in urine.18 Since the half-lives of the L- and D-isomers are 13 to 16 and 4 to 5 hours, respectively, the overall half-life of modafinil is due mainly to the pharmacokinetics of the L-enantiomer.19 Renal failure (creatinine clearance
The Use of Modafinil in the Intensive Care Unit Michal Gajewski, DO1,2 and Gerald Weinhouse, MD3
Abstract As patients recover from their critical illness, the focus of intensive care unit (ICU) care becomes rehabilitation. Fatigue, excessive daytime somnolence (EDS), and depression can delay their recovery and potentially worsen outcomes. Psychostimulants, particularly modafinil (Provigil), have been shown to alleviate some of these symptoms in various patient populations, and as clinical trials are underway exploring this novel use of the drug, we present a case series of 3 patients in our institution’s Thoracic Surgery Intensive Care Unit. Our 3 patients were chosen as a result of their fatigue, EDS, and/or depression, which prolonged their ICU stay and precluded them from participating in physical therapy, an integral component of the rehabilitative process. The patients were given 200 mg of modafinil each morning to increase patient wakefulness, encourage their participation, and enable a more restful sleep during the night. Although the drug was undoubtedly not the sole reason why our patients became more active, the temporal relationship between starting the drug and our patients’ clinical improvement makes it likely that it contributed. Based on our observations with these patients, the known effects of modafinil, its safety profile, and the published experiences of others, we believe that modafinil has potential benefits when utilized in some critically ill patients and that the consequences of delayed patient recovery and a prolonged ICU stay may outweigh the risks of potential modafinil side effects. Keywords modafinil, Provigil, sleep cycle, rehabilitation, psychostimulants
Introduction It is well established that critically ill patients are at risk of neurological as well as musculoskeletal complications of critical care. Early mobilization of these patients has become the standard of care1-5; however those who are somnolent, fatigued, and depressed may not be able or willing to participate and, as a result, may have a delayed recovery. Although not studied in this context, psychostimulants, particularly modafinil (Provigil, Teva Pharmaceutical Industries Ltd.), have been shown to decrease fatigue and excessive daytime somnolence (EDS) in various patient populations, and additional trials are ongoing investigating the use of modafinil, and its enantiopure armodafinil, for such treatment in those with cancer, multiple sclerosis (MS), menopause, and hypoactive delirium.6-9 We present a case series of 3 patients admitted to our institution’s Thoracic Surgical Intensive Care Unit who, without a prior diagnosis of any sleep disorders and despite conservative, nonpharmacologic measures to encourage a healthy sleep cycle, were given modafinil ‘‘off-label’’ in order to expedite their recovery through early rehabilitation.
Clinical Cases Case 1. Mr G. was a 77-year-old male with a past medical history of nonsmall cell lung cancer, status post a left upper
lobectomy 1 month prior, who was readmitted from rehab for respiratory distress requiring intubation. After an initial diagnosis of fluid overload, he was quickly diuresed and extubated; however, over the next 3 days, the patient continued to require intermittent noninvasive positive pressure ventilation for dyspnea. Additionally, he felt ‘‘too tired’’ to participate with physical therapy or to get out of bed to the chair and therefore was bedbound for the majority of the time. One of the contributing factors was that the patient was not sleeping through the night and was therefore hypersomnolent throughout the day. Modafinil 200 mg each morning was administered in order to try to regulate his sleep–wake cycle and enable him to participate in his care. On the first day of administration, he continued to
1
Surgical Critical Care, Brigham and Women’s Hospital, Boston, MA, USA Department of Anesthesiology, New Jersey Medical School, Rutgers University, Newark, NJ, USA 3 Department of Medicine, Division of Pulmonary and Critical Care, Brigham and Women’s Hospital, Boston, MA, USA 2
Received September 16, 2014, and in revised form December 23, 2014. Accepted for publication January 8, 2015. Corresponding Author: Michal Gajewski, Department of Anesthesiology, New Jersey Medical School, Rutgers University, 185S. Orange Ave, MSB E-538, Newark, NJ 07103, USA. Email: [email protected]
Downloaded from jic.sagepub.com at UNIV NEBRASKA LIBRARIES on April 9, 2015
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Journal of Intensive Care Medicine
require the same amount of respiratory support; however, he did ambulate for the first time since extubation and, as per the patient, rested well overnight. On day 2, physical therapy reported the patient saying ‘‘I’ll do exercises’’ and that same day he was also weaned to 3-L nasal cannula. Over the 13day course of drug administration, he slowly made advances in terms of his rehabilitation and was even noted to be ‘‘smiling and more interactive with staff,’’ despite his earlier ‘‘flat affect.’’ Within the following few days, the physical therapist reported that the patient was ‘‘making slow and steady progress.’’ No adverse effects were noted and no additional psychotropic medications were added to his regimen. Case 2. Mr M. was a 67-year-old male with a past medical history of esophageal cancer status post a minimally invasive esophagectomy 9 months earlier. His course was complicated by anastomotic dehiscence leading to numerous complications. After a prolonged treatment course, he was eventually transferred to our intensive care unit (ICU) for management of his pneumonia and sepsis. He subsequently was found to have a gastropleural fistula, which necessitated multiple trips to the operating room for resection as well as washouts. After his initial surgery, he improved from a rehabilitative standpoint, despite his continuous systemic inflammatory response and respiratory insufficiency. He ambulated and was even able to use the speaking valve on his tracheostomy. After returning from the operating room the second time, however, his mood was altered and he no longer was willing to participate in his care. Despite all his other conditions remaining stable in the perioperative period, he was now noted by physical therapy to be ‘‘extremely fatigued’’ and the nursing staff commented on his ‘‘angry affect, expressing wishes to withdraw care,’’ despite his continued home dose of venlafaxine. Modafinil was started at a dose of 200 mg and psychiatry was consulted to evaluate him. Per psychiatry, his Axis I diagnosis was delirium, adjustment disorder, and depression. Their recommendations consisted of pharmacologic treatment for his irregular sleep cycles as well as his fatigue, and modafinil was their agent of choice. On the first day of administration, the patient ‘‘promised to try physical therapy.’’ On follow-up by psychiatry 2 days later, ‘‘he did not appear demoralized, has been more engaged in his care, and participated in setting goals for himself.’’ Overall, the impression was that his ‘‘participation in care appears to have improved with the modafinil trial.’’ In another 2 days, physical therapy noted that ‘‘he was willing to participate in therapy session.’’ Further, ‘‘he was able to ambulate with assistance.’’ No side effects were noted throughout the 8-day course of this patient’s modafinil administration. Case 3. Mr. J. was a 70-year-old male with a past medical history of esophageal cancer who was transferred from the Veterans Administration Hospital (VA) for failure to thrive and a possible esophagectomy. He was initially stable; however, over the next few days he developed respiratory failure and was found to have bilateral pleural effusions, pneumonia, and pulmonary edema. He was intubated and transferred to the ICU for
further management. Upon drainage of his effusions, cytology revealed malignancy and he was therefore no longer being considered for surgical intervention of his cancer. Over the following few days, his respiratory status improved and he was extubated. His rehabilitative status was complicated by his malnourished state, his overall lack of energy, and his waxing and waning mental status. Psychiatry had already been consulted for this patient, and their initial recommendations were to treat acute changes with haloperidol as well as to continue his home regimen of clonazepam, paroxetine, as well as gabapentin. With time his delirium improved but his overall depressed and lethargic states persisted. The haloperidol was eventually discontinued as a result of the patient’s increase in QT interval, while the home regimen was continued. Modafinil was first started at a dose of 100 mg/d to try to improve his energy and mood. On the first day of administration, physical therapy noted that the patient ‘‘was in agreement with physical therapy goals.’’ Over the following few days, as a result of tolerating the medication well, the dose was increased to 200 mg/d. With the increase, he was transferred from bed to chair and was even wheeled outdoors. According to the patient, his sleep became more regular and he was not requiring his prior nightly dose of lorazepam for insomnia and agitation. Of note, Mr J would, on average, require 3 doses of 0.5 mg of lorazepam every night which, by the sixth day of modafinil administration, was not needed at all. Additionally, when the palliative care physician spoke with the patient, he communicated rationally with clear insight into his condition and was able to direct the course of his care. Modafinil was administered to this patient for a total of 7 days without any side effects.
Discussion Modafinil is a wakefulness-promoting drug that has been approved by the Food and Drug Administration for the treatment of narcolepsy, obstructive sleep apnea (OSA), and shift-work sleep disorder. The majority of its action has been attributed to its manipulation of the monoamine pathway although to date no clear pharmacodynamic profile has been established.10-13 In comparison to other stimulants, such as amphetamines, modafinil does not exhibit the same level of sympathomimetic effects, such as behavioral excitation or rebound hypersomnolence, suggesting that its mechanism of action is distinct.13-15 This could possibly explain why modafinil is not associated with interruption of normal nighttime sleep, as are amphetamines, and is also said to have a much lower abuse potential.13,16,17 The pharmacokinetics of single and multiple doses are similar.18-20 Of the oral dose, 90% is metabolized by the liver, partially by the 3A isoform subfamily of hepatic cytochrome P450 (CYP3A4).18 The products of metabolism are mostly 2 inactive metabolites, modafinil acid and modafinil sulfone, both of which are excreted in urine.18 Since the half-lives of the L- and D-isomers are 13 to 16 and 4 to 5 hours, respectively, the overall half-life of modafinil is due mainly to the pharmacokinetics of the L-enantiomer.19 Renal failure (creatinine clearance
