Federal Practitioner

The risk of melanoma was increased among patients taking biologics for immune-mediated inflammatory diseases, compared with biologic-naive patients on conventional systemic therapy, but the association was not statistically significant in a systematic review and meta-analysis published in JAMA Dermatology.

The studies included in the analysis, however, had limitations, including a lack of those comparing biologic and conventional systemic therapy in psoriasis and inflammatory bowel disease (IBD), according to Shamarke Esse, MRes, of the division of musculoskeletal and dermatological sciences at the University of Manchester (England) and colleagues. “We advocate for more large, well-designed studies of this issue to be performed to help improve certainty” regarding this association, they wrote.

Previous studies that have found an increased risk of melanoma in patients on biologics for psoriasis, rheumatoid arthritis, and IBD have “typically used the general population as the comparator,” they noted. There is a large amount of evidence that has established short-term efficacy and safety of biologics, compared with conventional systemic treatments, but concerns about longer-term cancer risk associated with biologics remains a concern. Moreover, they added, “melanoma is a highly immunogenic skin cancer and therefore of concern to patients treated with TNFIs [tumor necrosis factor inhibitors] because melanoma risk increases with suppression of the immune system and TNF-alpha plays an important role in the immune surveillance of tumors.12,13

In their review, the researchers identified seven cohort studies from MEDLINE, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) databases published between January 1995 and February 2019 that evaluated melanoma risk in about 34,000 patients receiving biologics and 135,370 patients who had never been treated with biologics, and were receiving conventional systemic therapy for psoriasis, RA, or IBD. Of these, four studies were in patients with RA, two studies were in patients with IBD, and a single study was in patients with psoriasis. Six studies examined patients taking TNF inhibitors, but only one of six studies had information on specific TNF inhibitors (adalimumab, etanercept, and infliximab) in patients with RA. One study evaluated abatacept and rituximab in RA patients.

The researchers analyzed the pooled relative risk across all studies. Compared with patients who received conventional systemic therapy, there was a nonsignificant association with risk of melanoma in patients with psoriasis (hazard ratio, 1.57; 95% confidence interval, 0.61-4.09), RA (pooled relative risk, 1.20; 95% CI, 0.83-1.74), and IBD (pRR, 1.20; 95% CI, 0.60-2.40).

Among RA patients who received TNF inhibitors only, there was a slightly elevated nonsignificant risk of melanoma (pRR, 1.08; 95% CI, 0.81-1.43). Patients receiving rituximab had a pRR of 0.73 (95% CI, 0.38-1.39), and patients taking abatacept had a pRR of 1.43 (95% CI, 0.66-3.09), compared with RA patients receiving conventional systemic therapy. When excluding two major studies in the RA subgroup of patients in a sensitivity analysis, pooled risk estimates varied from 0.91 (95% CI, 0.69-1.18) to 1.95 (95% CI, 1.16- 3.30). There were no significant between-study heterogeneity or publication bias among the IBD and RA studies.

Mr. Esse and colleagues acknowledged the small number of IBD and psoriasis studies in the meta-analysis, which could affect pooled risk estimates. “Any future update of our study through the inclusion of newly published studies may produce significantly different pooled risk estimates than those reported in our meta-analysis,” they said. In addition, the use of health insurance databases, lack of risk factors for melanoma, and inconsistent information about treatment duration for patients receiving conventional systemic therapy were also limitations.

“Prospective cohort studies using an active comparator, new-user study design providing detailed information on treatment history, concomitant treatments, biologic and conventional systemic treatment duration, recreational and treatment-related UV exposure, skin color, and date of melanoma diagnosis are required to help improve certainty. These studies would also need to account for key risk factors and the latency period of melanoma,” the researchers said.

Mr. Esse disclosed being funded by a PhD studentship from the Psoriasis Association. One author disclosed receiving personal fees from Janssen, LEO Pharma, Lilly, and Novartis outside the study; another disclosed receiving grants and personal fees from those and several other pharmaceutical companies during the study, and personal fees from several pharmaceutical companies outside of the submitted work; the fourth author had no disclosures.

SOURCE: Esse S et al. JAMA Dermatol. 2020 May 20;e201300.

The risk of melanoma was increased among patients taking biologics for immune-mediated inflammatory diseases, compared with biologic-naive patients on conventional systemic therapy, but the association was not statistically significant in a systematic review and meta-analysis published in JAMA Dermatology.

The studies included in the analysis, however, had limitations, including a lack of those comparing biologic and conventional systemic therapy in psoriasis and inflammatory bowel disease (IBD), according to Shamarke Esse, MRes, of the division of musculoskeletal and dermatological sciences at the University of Manchester (England) and colleagues. “We advocate for more large, well-designed studies of this issue to be performed to help improve certainty” regarding this association, they wrote.

Previous studies that have found an increased risk of melanoma in patients on biologics for psoriasis, rheumatoid arthritis, and IBD have “typically used the general population as the comparator,” they noted. There is a large amount of evidence that has established short-term efficacy and safety of biologics, compared with conventional systemic treatments, but concerns about longer-term cancer risk associated with biologics remains a concern. Moreover, they added, “melanoma is a highly immunogenic skin cancer and therefore of concern to patients treated with TNFIs [tumor necrosis factor inhibitors] because melanoma risk increases with suppression of the immune system and TNF-alpha plays an important role in the immune surveillance of tumors.12,13

In their review, the researchers identified seven cohort studies from MEDLINE, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) databases published between January 1995 and February 2019 that evaluated melanoma risk in about 34,000 patients receiving biologics and 135,370 patients who had never been treated with biologics, and were receiving conventional systemic therapy for psoriasis, RA, or IBD. Of these, four studies were in patients with RA, two studies were in patients with IBD, and a single study was in patients with psoriasis. Six studies examined patients taking TNF inhibitors, but only one of six studies had information on specific TNF inhibitors (adalimumab, etanercept, and infliximab) in patients with RA. One study evaluated abatacept and rituximab in RA patients.

The researchers analyzed the pooled relative risk across all studies. Compared with patients who received conventional systemic therapy, there was a nonsignificant association with risk of melanoma in patients with psoriasis (hazard ratio, 1.57; 95% confidence interval, 0.61-4.09), RA (pooled relative risk, 1.20; 95% CI, 0.83-1.74), and IBD (pRR, 1.20; 95% CI, 0.60-2.40).

Among RA patients who received TNF inhibitors only, there was a slightly elevated nonsignificant risk of melanoma (pRR, 1.08; 95% CI, 0.81-1.43). Patients receiving rituximab had a pRR of 0.73 (95% CI, 0.38-1.39), and patients taking abatacept had a pRR of 1.43 (95% CI, 0.66-3.09), compared with RA patients receiving conventional systemic therapy. When excluding two major studies in the RA subgroup of patients in a sensitivity analysis, pooled risk estimates varied from 0.91 (95% CI, 0.69-1.18) to 1.95 (95% CI, 1.16- 3.30). There were no significant between-study heterogeneity or publication bias among the IBD and RA studies.

Mr. Esse and colleagues acknowledged the small number of IBD and psoriasis studies in the meta-analysis, which could affect pooled risk estimates. “Any future update of our study through the inclusion of newly published studies may produce significantly different pooled risk estimates than those reported in our meta-analysis,” they said. In addition, the use of health insurance databases, lack of risk factors for melanoma, and inconsistent information about treatment duration for patients receiving conventional systemic therapy were also limitations.

“Prospective cohort studies using an active comparator, new-user study design providing detailed information on treatment history, concomitant treatments, biologic and conventional systemic treatment duration, recreational and treatment-related UV exposure, skin color, and date of melanoma diagnosis are required to help improve certainty. These studies would also need to account for key risk factors and the latency period of melanoma,” the researchers said.

Mr. Esse disclosed being funded by a PhD studentship from the Psoriasis Association. One author disclosed receiving personal fees from Janssen, LEO Pharma, Lilly, and Novartis outside the study; another disclosed receiving grants and personal fees from those and several other pharmaceutical companies during the study, and personal fees from several pharmaceutical companies outside of the submitted work; the fourth author had no disclosures.

SOURCE: Esse S et al. JAMA Dermatol. 2020 May 20;e201300.

The risk of melanoma was increased among patients taking biologics for immune-mediated inflammatory diseases, compared with biologic-naive patients on conventional systemic therapy, but the association was not statistically significant in a systematic review and meta-analysis published in JAMA Dermatology.

The studies included in the analysis, however, had limitations, including a lack of those comparing biologic and conventional systemic therapy in psoriasis and inflammatory bowel disease (IBD), according to Shamarke Esse, MRes, of the division of musculoskeletal and dermatological sciences at the University of Manchester (England) and colleagues. “We advocate for more large, well-designed studies of this issue to be performed to help improve certainty” regarding this association, they wrote.

Previous studies that have found an increased risk of melanoma in patients on biologics for psoriasis, rheumatoid arthritis, and IBD have “typically used the general population as the comparator,” they noted. There is a large amount of evidence that has established short-term efficacy and safety of biologics, compared with conventional systemic treatments, but concerns about longer-term cancer risk associated with biologics remains a concern. Moreover, they added, “melanoma is a highly immunogenic skin cancer and therefore of concern to patients treated with TNFIs [tumor necrosis factor inhibitors] because melanoma risk increases with suppression of the immune system and TNF-alpha plays an important role in the immune surveillance of tumors.12,13

In their review, the researchers identified seven cohort studies from MEDLINE, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) databases published between January 1995 and February 2019 that evaluated melanoma risk in about 34,000 patients receiving biologics and 135,370 patients who had never been treated with biologics, and were receiving conventional systemic therapy for psoriasis, RA, or IBD. Of these, four studies were in patients with RA, two studies were in patients with IBD, and a single study was in patients with psoriasis. Six studies examined patients taking TNF inhibitors, but only one of six studies had information on specific TNF inhibitors (adalimumab, etanercept, and infliximab) in patients with RA. One study evaluated abatacept and rituximab in RA patients.

The researchers analyzed the pooled relative risk across all studies. Compared with patients who received conventional systemic therapy, there was a nonsignificant association with risk of melanoma in patients with psoriasis (hazard ratio, 1.57; 95% confidence interval, 0.61-4.09), RA (pooled relative risk, 1.20; 95% CI, 0.83-1.74), and IBD (pRR, 1.20; 95% CI, 0.60-2.40).

Among RA patients who received TNF inhibitors only, there was a slightly elevated nonsignificant risk of melanoma (pRR, 1.08; 95% CI, 0.81-1.43). Patients receiving rituximab had a pRR of 0.73 (95% CI, 0.38-1.39), and patients taking abatacept had a pRR of 1.43 (95% CI, 0.66-3.09), compared with RA patients receiving conventional systemic therapy. When excluding two major studies in the RA subgroup of patients in a sensitivity analysis, pooled risk estimates varied from 0.91 (95% CI, 0.69-1.18) to 1.95 (95% CI, 1.16- 3.30). There were no significant between-study heterogeneity or publication bias among the IBD and RA studies.

Mr. Esse and colleagues acknowledged the small number of IBD and psoriasis studies in the meta-analysis, which could affect pooled risk estimates. “Any future update of our study through the inclusion of newly published studies may produce significantly different pooled risk estimates than those reported in our meta-analysis,” they said. In addition, the use of health insurance databases, lack of risk factors for melanoma, and inconsistent information about treatment duration for patients receiving conventional systemic therapy were also limitations.

“Prospective cohort studies using an active comparator, new-user study design providing detailed information on treatment history, concomitant treatments, biologic and conventional systemic treatment duration, recreational and treatment-related UV exposure, skin color, and date of melanoma diagnosis are required to help improve certainty. These studies would also need to account for key risk factors and the latency period of melanoma,” the researchers said.

Mr. Esse disclosed being funded by a PhD studentship from the Psoriasis Association. One author disclosed receiving personal fees from Janssen, LEO Pharma, Lilly, and Novartis outside the study; another disclosed receiving grants and personal fees from those and several other pharmaceutical companies during the study, and personal fees from several pharmaceutical companies outside of the submitted work; the fourth author had no disclosures.

SOURCE: Esse S et al. JAMA Dermatol. 2020 May 20;e201300.

Repetitive transcranial magnetic stimulation (rTMS) is an emerging therapy approved by the US Food and Drug Administration (FDA) for mental health indications but not widely available in the US Department of Veterans Affairs (VA). rTMS uses a device to create magnetic fields that cause electrical current to flow into targeted neurons in the brain.¹ The area of the brain targeted depends on the shape of the magnetic coil and dose of stimulation (Figures 1 and 2). The most common coil shape is the figure-8 coil, which is believed to stimulate about a 2- to 3-cm² area of the brain at a depth of about 2 cm from the coil surface. The stimulus is thought to activate certain nerve growth factors and ultimately relevant neurotransmitters in the stimulated areas and parts of the brain connected to where the stimulus occurs.²

The most common clinical use of rTMS is for the treatment of major depressive disorder (MDD). The FDA has approved rTMS for the treatment of MDD and for at least 4 device manufacturers. The treatment has been studied in multiple clinical trials.³ An overview of these trials, additional rTMS training and educational materials, and device information can be accessed at www.mirecc.va.gov/visn21/education/tms_education.asp. rTMS for MDD administers a personalized dose with stimulation delivered over the dorsolateral prefrontal cortex. A typical clinical course runs for 40 minutes a day for 20 to 30 sessions. In addition to studies of depression,^1,4-7 rTMS has been studied for the following diseases and conditions:

• Headache (especially migraine)⁸
• Alzheimer disease⁹
• Obsessive compulsive disorder (OCD)¹⁰
• Obesity¹¹
• Schizophrenia¹²
• Posttraumatic stress disorder (PTSD)¹³
• Alcohol and nicotine dependence¹⁴

The FDA also has approved the use of rTMS for OCD. In addition, some health care providers (HCPs) are treating depression with rTMS in conjunction with electroconvulsive therapy (ECT).

Treatment for Veterans

MDD is one of the most significant risk factors for suicide. Therefore, treating depression with rTMS would likely diminish suicide risk. The annual suicide rate among veterans has been higher than the national average.¹⁵ However, most of these veterans are not getting their care at the Veterans Health Administration (VHA). Major efforts at the VA have been made to address this problem, including modification and promotion of the Veterans Crisis Line, increased mental health clinic hours, mental health same-day appointment availability for veterans, as well as raising awareness of suicide and suicidal ideation.¹⁶ George and colleagues showed that it is safe and feasible to treat acutely suicidal inpatients at a VA or US Department of Defense hospital over an intensive 3 day, 3 treatments per day regimen. This regimen would be potentially useful in a suicidal inpatient population, a technically and ethically difficult group to study.¹⁷

MDD in many patients can be chronic and reoccurring with medication and psychotherapy providing inadequate relief.¹⁷ There clearly is a need for additional treatment options. MDD and OCD are the only indications that have received FDA approval for rTMS use. The initial FDA approval for MDD was based on a 2007 study of medication-free patients who had failed previous therapy and found a significant effect of rTMS compared with a sham procedure.⁷ MDD remains a common problem among veterans who have failed one or more antidepressant medications. Such patients might benefit from rTMS.^6,18

rTMS has several advantages over ECT, another significant FDA-approved, nonpharmacologic treatment alternative for medication-refractory MDD. rTMS is less invasive, requires fewer resources, does not require anesthesia or restrict activities, and does not cause memory loss. After an rTMS treatment, the patient can drive home.

Nationwide Pilot Program

The VA pilot program was created to supply rTMS machines nationwide to VHA sites and to offer a framework for establishing a clinical program. Preliminary program evaluation data suggest patients experienced a reduction in depression and suicidal ideation.

There were many challenges to implementation; for example, one VA site was eager to start using the device but could not secure space or personnel. An interdisciplinary team consisting of physicians, nurses, psychologists, suicide prevention coordinators, and others in the VA Palo Alto Health Care System (VAPAHCS) Precision Neurostimulation Clinic (PNC) has been instrumental in overcoming these challenges. VAPAHCS oversees the pilot and employs the national director.

Thirty-five sites nationwide were initially selected due to their ability to provide space for a rTMS machine and appropriate staffing to set up and run a Clinic (Figure 3). The pilot started with tertiary care VA medical centers then expanded to include community-based outpatient clinics as resources permitted. Sites that were unable to meet these standards were not included. Of these 35 original sites, 26 are treating patients and collecting data. Some early delays were due to unassigned relative value units (RVUs) to rTMS, which since have been revised as imputed RVU values. The American Medical Association established and defined RVUs to compare the value of different health care roles.¹⁹ The clinics have been established with smooth operations as the pilot program has provided the infrastructure.

REDCap (www.project-redcap.org), a data collection tool used primarily in academic research settings, was selected to gather program evaluation data through patient questionnaires informed by the VHA measurement-based care initiative. Standard psychometrics were readily available in the VHA application and REDCap Mental Health Assistant includes the Patient Health Questionnaire 9 (PHQ-9) Brief Symptom Inventory 18, Posttraumatic Checklist 5, Beck Scale for Suicidal Ideation, and Quality of Life Inventory. The Timberlawn Couple and Family Evaluation Scale (TCFES), which can be completed in 30 to 35 minutes and is a measure of overall function of relevant relationships, also may be added. Future studies are needed to confirm psychometrics of this scale in this setting, but the TCFES metric is widely used for similar purposes.

Nationwide, more than 950 patients have started treatment (ie, including active, completed, and discontinued treatment) and 412 veterans have completed the rTMS treatment. The goal of the program evaluation is to examine large scale rTMS efficacy in a large veteran population as well as determine predictors of individual patient response. Nationwide, PHQ-9 depression scores declined from a pretreatment average (SD) of 18.2 (5.5; range, 5-27) to a posttreatment average (SD) of 11.0 (7.1; range, 0-27). Patients also have indicated a high level of satisfaction with the treatment (Figure 4). Collecting data on a national level is a powerful way to examine rTMS efficacy and predictors of response that might be lost in a smaller subset of cases.

Implementation

It took 11 months for the VA contracting department to determine which machine to buy. However, the lengthy process assured that the equipment selected met all standards for clinical safety and efficacy. Furthermore, provision was made to allow for additional orders as new sites came online as well as upgrading the equipment for advances in technology.

The PNC set up several training programs to ensure proper use of this novel treatment. The education is ongoing and available as new sites are identified and initiated. The education includes, but is not limited to, in-person onsite and offsite training programs, online training modules that are available in the VA Electronic Educational Services (EES), and video telehealth consultations. Participants can view online lectures and then receive hands-on training as part of the educational program. Up to 3 HCPs for each site can receive funding to attend. Online programs also are available for new material to support continuing medical education. However, hands-on training is essential to understand how to obtain the motor threshold, which is used to determine the strength of the rTMS stimulus dose. Furthermore, hands-on training is essential for the proper localization of the stimulus, which is determined by certain anatomical landmarks. A phantom mannequin (ERIK [Evaluating Resting motor threshold and Insuring Kappa]) has been developed to assist in the hands-on learning.²⁰

Relative Value Units

The VHA uses RVUs to properly account for workload and clinician activities. As a result, RVUs play an essential role as a currency that denotes the relative value of one type of clinical activity when compared with other activities. Depending on the treating specialty, clinicians generally use procedure codes outlined in the Current Procedural Terminology (CPT) code set or the Healthcare Common Procedure Coding System (HCPCS) for medical billing. Most insurance carriers use RVUs set by the Centers for Medicare and Medicaid Services (CMS) system as a standard system to determine HCP reimbursement for medical procedures.

The CPT codes associated with rTMS currently are 90867 to 90869. CMS had initially assigned a zero RVU to these CPT codes due to wide variations in the cost of performing rTMS. When we began implementing rTMS in the VHA, the lack of RVUs for rTMS rendered it impossible to show clinical workload for this activity using established VHA clinical accounting methods. The lack of RVUs assigned to rTMS CPT codes made justification for this treatment to clinical management difficult, which limited its clinical use in the VHA. In addition, HCPs who were using rTMS to treat severely ill veterans appeared artificially unproductive despite a significant patient workload. As we and VHA leadership became aware the program could not be staffed locally without getting workload credit for work done, the value was raised to 1.37 for treatment (90868) and 2.12 and 1.93 for evaluations (90867) and reevaluations (90869), respectively, thus reducing a potential roadblock to implementation.

Challenges as the Program Expands

Future challenges include upgrading machines to do intermittent θ burst stimulation (iTBS), which decreases the standard treatment time from 37.5 minutes to 3 minutes. Both patients and HCPs find iTBS to have similar tolerability to standard rTMS but in much less time. iTBS mimics endogenous θ rhythms and has been shown to be noninferior to rTMS for depression.^21,22 Several devices have received FDA approval to treat MDD, including the Magstim and MagVenture TMS devices used in this program.

A major challenge for the VHA with rTMS will be to maintain a consistent level of competence and training. There is a need for continued maintenance of staff competence with ongoing training and training for new staff. Novel ways of training operators have been developed including ERIK.

Determining treatment interaction with other psychotherapies and pharmacotherapies is another challenge. Currently, rTMS is considered an adjunctive treatment added to the current patient treatment plan. We do not know yet how best to incorporate this somatic treatment with other approaches, and further research is necessary. A key issue is to determine which approach provides the best long-term results for a patient at risk for recurrence of depression. In addition, more research into maintaining healthy relationships for veterans with both MDD and PTSD is needed.

Many misconceptions exist about rTMS and HCPs need to be educated about the benefits of this modality. In addition, patients should understand the differences between rTMS and ECT. Even with newer approaches that streamline rTMS, the therapy remains costly in terms of direct costs as well as patient and HCP time.

Streamlining rTMS treatment remains an important concern. Compressing treatment schedules (ie, many treatments delivered to a patient in a single day) would allow the entire process to be delivered in days, not weeks. This would be especially advantageous to patients who live far from a treatment site. Performing multiple rTMS daily treatments is especially feasible with iTBS with its short treatment time.

Conclusions

rTMS is an emerging modality with both established and novel applications. The best studied application is treatment resistant MDD. Currently, rTMS has only been approved by the FDA for treatment of MDD. A pilot program was established by the VHA to distribute 30 rTMS machines sites nationwide. Results from data collected by these sites have shown patients improving on standard psychometric scales. Future changes include upgrading the machines to provide θ bursts, which has been shown to be faster and noninferior. Integrating rTMS with other pharmacotherapies and psychotherapies remains poorly understood and needs more research.

Repetitive transcranial magnetic stimulation (rTMS) is an emerging therapy approved by the US Food and Drug Administration (FDA) for mental health indications but not widely available in the US Department of Veterans Affairs (VA). rTMS uses a device to create magnetic fields that cause electrical current to flow into targeted neurons in the brain.¹ The area of the brain targeted depends on the shape of the magnetic coil and dose of stimulation (Figures 1 and 2). The most common coil shape is the figure-8 coil, which is believed to stimulate about a 2- to 3-cm² area of the brain at a depth of about 2 cm from the coil surface. The stimulus is thought to activate certain nerve growth factors and ultimately relevant neurotransmitters in the stimulated areas and parts of the brain connected to where the stimulus occurs.²

The most common clinical use of rTMS is for the treatment of major depressive disorder (MDD). The FDA has approved rTMS for the treatment of MDD and for at least 4 device manufacturers. The treatment has been studied in multiple clinical trials.³ An overview of these trials, additional rTMS training and educational materials, and device information can be accessed at www.mirecc.va.gov/visn21/education/tms_education.asp. rTMS for MDD administers a personalized dose with stimulation delivered over the dorsolateral prefrontal cortex. A typical clinical course runs for 40 minutes a day for 20 to 30 sessions. In addition to studies of depression,^1,4-7 rTMS has been studied for the following diseases and conditions:

• Headache (especially migraine)⁸
• Alzheimer disease⁹
• Obsessive compulsive disorder (OCD)¹⁰
• Obesity¹¹
• Schizophrenia¹²
• Posttraumatic stress disorder (PTSD)¹³
• Alcohol and nicotine dependence¹⁴

The FDA also has approved the use of rTMS for OCD. In addition, some health care providers (HCPs) are treating depression with rTMS in conjunction with electroconvulsive therapy (ECT).

Treatment for Veterans

MDD is one of the most significant risk factors for suicide. Therefore, treating depression with rTMS would likely diminish suicide risk. The annual suicide rate among veterans has been higher than the national average.¹⁵ However, most of these veterans are not getting their care at the Veterans Health Administration (VHA). Major efforts at the VA have been made to address this problem, including modification and promotion of the Veterans Crisis Line, increased mental health clinic hours, mental health same-day appointment availability for veterans, as well as raising awareness of suicide and suicidal ideation.¹⁶ George and colleagues showed that it is safe and feasible to treat acutely suicidal inpatients at a VA or US Department of Defense hospital over an intensive 3 day, 3 treatments per day regimen. This regimen would be potentially useful in a suicidal inpatient population, a technically and ethically difficult group to study.¹⁷

MDD in many patients can be chronic and reoccurring with medication and psychotherapy providing inadequate relief.¹⁷ There clearly is a need for additional treatment options. MDD and OCD are the only indications that have received FDA approval for rTMS use. The initial FDA approval for MDD was based on a 2007 study of medication-free patients who had failed previous therapy and found a significant effect of rTMS compared with a sham procedure.⁷ MDD remains a common problem among veterans who have failed one or more antidepressant medications. Such patients might benefit from rTMS.^6,18

rTMS has several advantages over ECT, another significant FDA-approved, nonpharmacologic treatment alternative for medication-refractory MDD. rTMS is less invasive, requires fewer resources, does not require anesthesia or restrict activities, and does not cause memory loss. After an rTMS treatment, the patient can drive home.

Nationwide Pilot Program

The VA pilot program was created to supply rTMS machines nationwide to VHA sites and to offer a framework for establishing a clinical program. Preliminary program evaluation data suggest patients experienced a reduction in depression and suicidal ideation.

There were many challenges to implementation; for example, one VA site was eager to start using the device but could not secure space or personnel. An interdisciplinary team consisting of physicians, nurses, psychologists, suicide prevention coordinators, and others in the VA Palo Alto Health Care System (VAPAHCS) Precision Neurostimulation Clinic (PNC) has been instrumental in overcoming these challenges. VAPAHCS oversees the pilot and employs the national director.

Thirty-five sites nationwide were initially selected due to their ability to provide space for a rTMS machine and appropriate staffing to set up and run a Clinic (Figure 3). The pilot started with tertiary care VA medical centers then expanded to include community-based outpatient clinics as resources permitted. Sites that were unable to meet these standards were not included. Of these 35 original sites, 26 are treating patients and collecting data. Some early delays were due to unassigned relative value units (RVUs) to rTMS, which since have been revised as imputed RVU values. The American Medical Association established and defined RVUs to compare the value of different health care roles.¹⁹ The clinics have been established with smooth operations as the pilot program has provided the infrastructure.

REDCap (www.project-redcap.org), a data collection tool used primarily in academic research settings, was selected to gather program evaluation data through patient questionnaires informed by the VHA measurement-based care initiative. Standard psychometrics were readily available in the VHA application and REDCap Mental Health Assistant includes the Patient Health Questionnaire 9 (PHQ-9) Brief Symptom Inventory 18, Posttraumatic Checklist 5, Beck Scale for Suicidal Ideation, and Quality of Life Inventory. The Timberlawn Couple and Family Evaluation Scale (TCFES), which can be completed in 30 to 35 minutes and is a measure of overall function of relevant relationships, also may be added. Future studies are needed to confirm psychometrics of this scale in this setting, but the TCFES metric is widely used for similar purposes.

Nationwide, more than 950 patients have started treatment (ie, including active, completed, and discontinued treatment) and 412 veterans have completed the rTMS treatment. The goal of the program evaluation is to examine large scale rTMS efficacy in a large veteran population as well as determine predictors of individual patient response. Nationwide, PHQ-9 depression scores declined from a pretreatment average (SD) of 18.2 (5.5; range, 5-27) to a posttreatment average (SD) of 11.0 (7.1; range, 0-27). Patients also have indicated a high level of satisfaction with the treatment (Figure 4). Collecting data on a national level is a powerful way to examine rTMS efficacy and predictors of response that might be lost in a smaller subset of cases.

Implementation

It took 11 months for the VA contracting department to determine which machine to buy. However, the lengthy process assured that the equipment selected met all standards for clinical safety and efficacy. Furthermore, provision was made to allow for additional orders as new sites came online as well as upgrading the equipment for advances in technology.

The PNC set up several training programs to ensure proper use of this novel treatment. The education is ongoing and available as new sites are identified and initiated. The education includes, but is not limited to, in-person onsite and offsite training programs, online training modules that are available in the VA Electronic Educational Services (EES), and video telehealth consultations. Participants can view online lectures and then receive hands-on training as part of the educational program. Up to 3 HCPs for each site can receive funding to attend. Online programs also are available for new material to support continuing medical education. However, hands-on training is essential to understand how to obtain the motor threshold, which is used to determine the strength of the rTMS stimulus dose. Furthermore, hands-on training is essential for the proper localization of the stimulus, which is determined by certain anatomical landmarks. A phantom mannequin (ERIK [Evaluating Resting motor threshold and Insuring Kappa]) has been developed to assist in the hands-on learning.²⁰

Relative Value Units

The VHA uses RVUs to properly account for workload and clinician activities. As a result, RVUs play an essential role as a currency that denotes the relative value of one type of clinical activity when compared with other activities. Depending on the treating specialty, clinicians generally use procedure codes outlined in the Current Procedural Terminology (CPT) code set or the Healthcare Common Procedure Coding System (HCPCS) for medical billing. Most insurance carriers use RVUs set by the Centers for Medicare and Medicaid Services (CMS) system as a standard system to determine HCP reimbursement for medical procedures.

The CPT codes associated with rTMS currently are 90867 to 90869. CMS had initially assigned a zero RVU to these CPT codes due to wide variations in the cost of performing rTMS. When we began implementing rTMS in the VHA, the lack of RVUs for rTMS rendered it impossible to show clinical workload for this activity using established VHA clinical accounting methods. The lack of RVUs assigned to rTMS CPT codes made justification for this treatment to clinical management difficult, which limited its clinical use in the VHA. In addition, HCPs who were using rTMS to treat severely ill veterans appeared artificially unproductive despite a significant patient workload. As we and VHA leadership became aware the program could not be staffed locally without getting workload credit for work done, the value was raised to 1.37 for treatment (90868) and 2.12 and 1.93 for evaluations (90867) and reevaluations (90869), respectively, thus reducing a potential roadblock to implementation.

Challenges as the Program Expands

Future challenges include upgrading machines to do intermittent θ burst stimulation (iTBS), which decreases the standard treatment time from 37.5 minutes to 3 minutes. Both patients and HCPs find iTBS to have similar tolerability to standard rTMS but in much less time. iTBS mimics endogenous θ rhythms and has been shown to be noninferior to rTMS for depression.^21,22 Several devices have received FDA approval to treat MDD, including the Magstim and MagVenture TMS devices used in this program.

A major challenge for the VHA with rTMS will be to maintain a consistent level of competence and training. There is a need for continued maintenance of staff competence with ongoing training and training for new staff. Novel ways of training operators have been developed including ERIK.

Determining treatment interaction with other psychotherapies and pharmacotherapies is another challenge. Currently, rTMS is considered an adjunctive treatment added to the current patient treatment plan. We do not know yet how best to incorporate this somatic treatment with other approaches, and further research is necessary. A key issue is to determine which approach provides the best long-term results for a patient at risk for recurrence of depression. In addition, more research into maintaining healthy relationships for veterans with both MDD and PTSD is needed.

Many misconceptions exist about rTMS and HCPs need to be educated about the benefits of this modality. In addition, patients should understand the differences between rTMS and ECT. Even with newer approaches that streamline rTMS, the therapy remains costly in terms of direct costs as well as patient and HCP time.

Streamlining rTMS treatment remains an important concern. Compressing treatment schedules (ie, many treatments delivered to a patient in a single day) would allow the entire process to be delivered in days, not weeks. This would be especially advantageous to patients who live far from a treatment site. Performing multiple rTMS daily treatments is especially feasible with iTBS with its short treatment time.

Conclusions

rTMS is an emerging modality with both established and novel applications. The best studied application is treatment resistant MDD. Currently, rTMS has only been approved by the FDA for treatment of MDD. A pilot program was established by the VHA to distribute 30 rTMS machines sites nationwide. Results from data collected by these sites have shown patients improving on standard psychometric scales. Future changes include upgrading the machines to provide θ bursts, which has been shown to be faster and noninferior. Integrating rTMS with other pharmacotherapies and psychotherapies remains poorly understood and needs more research.

Repetitive transcranial magnetic stimulation (rTMS) is an emerging therapy approved by the US Food and Drug Administration (FDA) for mental health indications but not widely available in the US Department of Veterans Affairs (VA). rTMS uses a device to create magnetic fields that cause electrical current to flow into targeted neurons in the brain.¹ The area of the brain targeted depends on the shape of the magnetic coil and dose of stimulation (Figures 1 and 2). The most common coil shape is the figure-8 coil, which is believed to stimulate about a 2- to 3-cm² area of the brain at a depth of about 2 cm from the coil surface. The stimulus is thought to activate certain nerve growth factors and ultimately relevant neurotransmitters in the stimulated areas and parts of the brain connected to where the stimulus occurs.²

The most common clinical use of rTMS is for the treatment of major depressive disorder (MDD). The FDA has approved rTMS for the treatment of MDD and for at least 4 device manufacturers. The treatment has been studied in multiple clinical trials.³ An overview of these trials, additional rTMS training and educational materials, and device information can be accessed at www.mirecc.va.gov/visn21/education/tms_education.asp. rTMS for MDD administers a personalized dose with stimulation delivered over the dorsolateral prefrontal cortex. A typical clinical course runs for 40 minutes a day for 20 to 30 sessions. In addition to studies of depression,^1,4-7 rTMS has been studied for the following diseases and conditions:

• Headache (especially migraine)⁸
• Alzheimer disease⁹
• Obsessive compulsive disorder (OCD)¹⁰
• Obesity¹¹
• Schizophrenia¹²
• Posttraumatic stress disorder (PTSD)¹³
• Alcohol and nicotine dependence¹⁴

The FDA also has approved the use of rTMS for OCD. In addition, some health care providers (HCPs) are treating depression with rTMS in conjunction with electroconvulsive therapy (ECT).

Treatment for Veterans

MDD is one of the most significant risk factors for suicide. Therefore, treating depression with rTMS would likely diminish suicide risk. The annual suicide rate among veterans has been higher than the national average.¹⁵ However, most of these veterans are not getting their care at the Veterans Health Administration (VHA). Major efforts at the VA have been made to address this problem, including modification and promotion of the Veterans Crisis Line, increased mental health clinic hours, mental health same-day appointment availability for veterans, as well as raising awareness of suicide and suicidal ideation.¹⁶ George and colleagues showed that it is safe and feasible to treat acutely suicidal inpatients at a VA or US Department of Defense hospital over an intensive 3 day, 3 treatments per day regimen. This regimen would be potentially useful in a suicidal inpatient population, a technically and ethically difficult group to study.¹⁷

MDD in many patients can be chronic and reoccurring with medication and psychotherapy providing inadequate relief.¹⁷ There clearly is a need for additional treatment options. MDD and OCD are the only indications that have received FDA approval for rTMS use. The initial FDA approval for MDD was based on a 2007 study of medication-free patients who had failed previous therapy and found a significant effect of rTMS compared with a sham procedure.⁷ MDD remains a common problem among veterans who have failed one or more antidepressant medications. Such patients might benefit from rTMS.^6,18

rTMS has several advantages over ECT, another significant FDA-approved, nonpharmacologic treatment alternative for medication-refractory MDD. rTMS is less invasive, requires fewer resources, does not require anesthesia or restrict activities, and does not cause memory loss. After an rTMS treatment, the patient can drive home.

Nationwide Pilot Program

The VA pilot program was created to supply rTMS machines nationwide to VHA sites and to offer a framework for establishing a clinical program. Preliminary program evaluation data suggest patients experienced a reduction in depression and suicidal ideation.

There were many challenges to implementation; for example, one VA site was eager to start using the device but could not secure space or personnel. An interdisciplinary team consisting of physicians, nurses, psychologists, suicide prevention coordinators, and others in the VA Palo Alto Health Care System (VAPAHCS) Precision Neurostimulation Clinic (PNC) has been instrumental in overcoming these challenges. VAPAHCS oversees the pilot and employs the national director.

Thirty-five sites nationwide were initially selected due to their ability to provide space for a rTMS machine and appropriate staffing to set up and run a Clinic (Figure 3). The pilot started with tertiary care VA medical centers then expanded to include community-based outpatient clinics as resources permitted. Sites that were unable to meet these standards were not included. Of these 35 original sites, 26 are treating patients and collecting data. Some early delays were due to unassigned relative value units (RVUs) to rTMS, which since have been revised as imputed RVU values. The American Medical Association established and defined RVUs to compare the value of different health care roles.¹⁹ The clinics have been established with smooth operations as the pilot program has provided the infrastructure.

REDCap (www.project-redcap.org), a data collection tool used primarily in academic research settings, was selected to gather program evaluation data through patient questionnaires informed by the VHA measurement-based care initiative. Standard psychometrics were readily available in the VHA application and REDCap Mental Health Assistant includes the Patient Health Questionnaire 9 (PHQ-9) Brief Symptom Inventory 18, Posttraumatic Checklist 5, Beck Scale for Suicidal Ideation, and Quality of Life Inventory. The Timberlawn Couple and Family Evaluation Scale (TCFES), which can be completed in 30 to 35 minutes and is a measure of overall function of relevant relationships, also may be added. Future studies are needed to confirm psychometrics of this scale in this setting, but the TCFES metric is widely used for similar purposes.

Nationwide, more than 950 patients have started treatment (ie, including active, completed, and discontinued treatment) and 412 veterans have completed the rTMS treatment. The goal of the program evaluation is to examine large scale rTMS efficacy in a large veteran population as well as determine predictors of individual patient response. Nationwide, PHQ-9 depression scores declined from a pretreatment average (SD) of 18.2 (5.5; range, 5-27) to a posttreatment average (SD) of 11.0 (7.1; range, 0-27). Patients also have indicated a high level of satisfaction with the treatment (Figure 4). Collecting data on a national level is a powerful way to examine rTMS efficacy and predictors of response that might be lost in a smaller subset of cases.

Implementation

It took 11 months for the VA contracting department to determine which machine to buy. However, the lengthy process assured that the equipment selected met all standards for clinical safety and efficacy. Furthermore, provision was made to allow for additional orders as new sites came online as well as upgrading the equipment for advances in technology.

The PNC set up several training programs to ensure proper use of this novel treatment. The education is ongoing and available as new sites are identified and initiated. The education includes, but is not limited to, in-person onsite and offsite training programs, online training modules that are available in the VA Electronic Educational Services (EES), and video telehealth consultations. Participants can view online lectures and then receive hands-on training as part of the educational program. Up to 3 HCPs for each site can receive funding to attend. Online programs also are available for new material to support continuing medical education. However, hands-on training is essential to understand how to obtain the motor threshold, which is used to determine the strength of the rTMS stimulus dose. Furthermore, hands-on training is essential for the proper localization of the stimulus, which is determined by certain anatomical landmarks. A phantom mannequin (ERIK [Evaluating Resting motor threshold and Insuring Kappa]) has been developed to assist in the hands-on learning.²⁰

Relative Value Units

The VHA uses RVUs to properly account for workload and clinician activities. As a result, RVUs play an essential role as a currency that denotes the relative value of one type of clinical activity when compared with other activities. Depending on the treating specialty, clinicians generally use procedure codes outlined in the Current Procedural Terminology (CPT) code set or the Healthcare Common Procedure Coding System (HCPCS) for medical billing. Most insurance carriers use RVUs set by the Centers for Medicare and Medicaid Services (CMS) system as a standard system to determine HCP reimbursement for medical procedures.

The CPT codes associated with rTMS currently are 90867 to 90869. CMS had initially assigned a zero RVU to these CPT codes due to wide variations in the cost of performing rTMS. When we began implementing rTMS in the VHA, the lack of RVUs for rTMS rendered it impossible to show clinical workload for this activity using established VHA clinical accounting methods. The lack of RVUs assigned to rTMS CPT codes made justification for this treatment to clinical management difficult, which limited its clinical use in the VHA. In addition, HCPs who were using rTMS to treat severely ill veterans appeared artificially unproductive despite a significant patient workload. As we and VHA leadership became aware the program could not be staffed locally without getting workload credit for work done, the value was raised to 1.37 for treatment (90868) and 2.12 and 1.93 for evaluations (90867) and reevaluations (90869), respectively, thus reducing a potential roadblock to implementation.

Challenges as the Program Expands

Future challenges include upgrading machines to do intermittent θ burst stimulation (iTBS), which decreases the standard treatment time from 37.5 minutes to 3 minutes. Both patients and HCPs find iTBS to have similar tolerability to standard rTMS but in much less time. iTBS mimics endogenous θ rhythms and has been shown to be noninferior to rTMS for depression.^21,22 Several devices have received FDA approval to treat MDD, including the Magstim and MagVenture TMS devices used in this program.

A major challenge for the VHA with rTMS will be to maintain a consistent level of competence and training. There is a need for continued maintenance of staff competence with ongoing training and training for new staff. Novel ways of training operators have been developed including ERIK.

Determining treatment interaction with other psychotherapies and pharmacotherapies is another challenge. Currently, rTMS is considered an adjunctive treatment added to the current patient treatment plan. We do not know yet how best to incorporate this somatic treatment with other approaches, and further research is necessary. A key issue is to determine which approach provides the best long-term results for a patient at risk for recurrence of depression. In addition, more research into maintaining healthy relationships for veterans with both MDD and PTSD is needed.

Many misconceptions exist about rTMS and HCPs need to be educated about the benefits of this modality. In addition, patients should understand the differences between rTMS and ECT. Even with newer approaches that streamline rTMS, the therapy remains costly in terms of direct costs as well as patient and HCP time.

Streamlining rTMS treatment remains an important concern. Compressing treatment schedules (ie, many treatments delivered to a patient in a single day) would allow the entire process to be delivered in days, not weeks. This would be especially advantageous to patients who live far from a treatment site. Performing multiple rTMS daily treatments is especially feasible with iTBS with its short treatment time.

Conclusions

rTMS is an emerging modality with both established and novel applications. The best studied application is treatment resistant MDD. Currently, rTMS has only been approved by the FDA for treatment of MDD. A pilot program was established by the VHA to distribute 30 rTMS machines sites nationwide. Results from data collected by these sites have shown patients improving on standard psychometric scales. Future changes include upgrading the machines to provide θ bursts, which has been shown to be faster and noninferior. Integrating rTMS with other pharmacotherapies and psychotherapies remains poorly understood and needs more research.

Sleep disturbance in the critically ill has received much attention over recent years as this is a common result of intensive care unit (ICU) admission. Disruptions in sleep not only can, at a minimum, cause distress and lower patient satisfaction, but also inhibit recovery from illness and increase morbidity.^1,2 Several studies have been conducted highlighting the altered sleep patterns of critically ill patients; although total sleep time may seem normal (7-9 hours), patients can experience multiple awakenings per hour, more time in light sleep (stages 1 and 2), and less time in restorative sleep (stages 3 and 4, [REM]rapid eye movement).^2-5

There are several hypothesized physiologic detriments that contribute to slower ICU recovery with sleep deprivation. Research in noncritically ill subjects suggests that sleep deprivation contributes to hypoventilation and potentially prolonged time on the ventilator.^6-9 Cardiovascular morbidity may be adversely affected by inflammatory cytokine release seen in sleep disruption.^10,11 Studies of noncritically ill patients also suggest that immune response is impaired, potentially protracting infection recovery.^12,13 Finally, although not directly investigated, sleep deprivation may contribute to ICU delirium, an independent adverse effect (AE) associated with increased mortality and worse long-term outcomes.^14-16

The Society of Critical Care Medicine (SCCM) recently updated its consensus guidelines for the management of pain, agitation/sedation, delirium, immobility, and sleep disruption (PADIS) in adult patients.¹⁷ These guidelines offer limited interventions to promote sleep in ICU patients based on available evidence and steer the clinician toward minimizing exacerbating factors. Although factors that affect sleep patterns are multifactorial, such as noise levels, pain, mechanical ventilation, and inflammatory mediators, medication therapy is a known modifiable risk factor for sleep disturbance in critically ill patients.² This focused review will specifically evaluate the effects of steroids on sleep deprivation, psychosis, delirium, and what is known about these effects in a critically ill population.

To include articles relevant to a critically ill population, a systematic search of MEDLINE and PubMed from 1966 to 2019 was performed using the following Medical Subject Headings (MeSH) terms: delirium/etiology, psychoses, substance-induced/etiology, sleep-wake disorders/chemically induced, neurocognitive disorders/chemically induced, dyssomnias/drug effects plus glucocorticoids/adverse effects, adrenal cortex hormones/adverse effects, prednisone/adverse effects, methylprednisolone/adverse effects, and hydrocortisone/adverse effects. The initial search produced 285 articles. Case reports, reviews, letters, and articles pertaining to primary care or palliative populations were excluded, leaving 8 relevant articles for inclusion (Table 1).^18-25

ICU Steroid Use

Steroids are commonly used in the ICU and affect nearly every critically ill population. Common indications for steroids in the ICU include anaphylaxis, airway edema, septic shock, asthma and COPD exacerbations, pneumocystis pneumonia, adrenal crisis, antiemetic treatment, elevated intracranial pressure from tumors, autoimmune disorders, and stress doses needed for chronic steroid users before invasive procedures.²⁶ Whether divided into glucocorticoid or mineralocorticoid subgroups, corticosteroids offer therapeutic benefit from their pharmacologic similarity to endogenously produced cortisol, which includes anti-inflammatory, immunosuppressive, antiproliferative, and vasoconstrictive effects.

Steroid receptors are present in most human tissue, and in varying degrees of binding affinity produce a wide variety of effects. After passive diffusion across cell membranes, steroid-receptor activation binds to various DNA sites, called glucocorticoid regulatory elements, which either stimulates or inhibits transcription of multiple nearby genes.

At the cellular level, corticosteroids inhibit the release of arachidonic acid through upstream production of lipocortin peptides and antagonism of phospholipase A₂. This action decreases subsequent inflammatory mediators, including kinins, histamine, liposomal enzymes, and prostaglandins. Steroids also inhibit NF-κB, which further decreases expression of proinflammatory genes while promoting interleukin-10 and its anti-inflammatory properties. Antiproliferative effects of steroids are seen by triggering cell apoptosis and inhibition of fibroblast proliferation.^27,28

By binding to mineralocorticoid receptors, steroids cause sodium retention coupled with hydrogen and potassium excretion in the distal renal tubule. Steroids also promote vasoconstriction by upregulating the production and sensitivity of β receptors in the endothelium while suppressing the production of vasodilators. Although rarely used for these physiologic effects, steroids also are involved in a number of metabolic pathways, including calcium regulation, gluconeogenesis, protein metabolism, and fat distribution. Given the similar structure to cortisol, exogenous steroids depress the hypothalamic-pituitary axis (HPA) and decrease the release of adrenocorticotropic hormone (ACTH). Tapering doses of steroid regimens is often required to allow natural androgen and cortisol synthesis and prevent steroid withdrawal.^27,28

The potency of various exogenous steroids closely parallels their ability to retain sodium (Table 2). Prolonged activation of steroid receptors can have numerous systemic AEs, including unwanted neurocognitive effects (Table 3). Insomnia and psychosis are commonly described in corticosteroid clinical trials, and in one meta-analysis, both are associated with high costs per episode per year.²⁹

Steroid-Induced Sleep Disruption and Psychosis

Sleep disruption caused by exogenous administration of steroids is thought to trigger other psychostimulant effects, such as mood swings, nervousness, psychoses, and delirium.³⁰ Similarly, the SCCM PADIS guidelines included an ungraded statement: “although an association between sleep quality and delirium occurrence exists in critically ill adults, a cause-effect relationship has not been established.”¹⁷ For this review, these AEs will be discussed as related events.

The medical literature proposes 3 pathways primarily responsible for neurocognitive AEs of steroids: behavior changes through modification of the HPA axis, changes in natural sleep-wake cycles, and hyperarousal caused by modification in neuroinhibitory pathways (Figure).

HPA Axis Modification

Under either physical or psychological stress, neural circuits in the brain release corticotropin-releasing hormone (CRH), dehydroepiandrosterone (DHEA), and arginine vasopressin, which go on to activate the sympathetic nervous system and the HPA axis. CRH from the hypothalamus goes on to stimulate ACTH release from the pituitary. ACTH then stimulates cortisol secretion from the adrenal glands. Circulating cortisol feeds into several structures of the brain, including the pituitary, hippocampus, and amygdala. Steroid-receptor complexes alter gene transcription in the central nervous system (CNS), affecting the production of neurotransmitters (eg, dopamine, serotonin) and neuropeptides (eg, somatostatin, β-endorphin). Feedback inhibition ensues, with downregulation of the HPA axis, which prevents depletion of endogenous production of steroids.³¹ DHEA has protective effects against excessive cortisol activity, but DHEA secretion declines with prolonged cortisol exposure. Exogenous steroids may have different effects than endogenous steroids, and neurocognitive sequelae stem from disruption and imbalance of these physiologic mechanisms.^32,33

Steroid receptors are densely located in behavior centers in the brain: the amygdala, septum, and hippocampus. Pharmacologic changes in gene expression alter norepinephrine and serotonin levels in the brain as well as their receptors.³² Prolonged exposure to exogenous steroids has been shown to decrease amygdala and hippocampal volumes.^34,35 Furthermore, prolonged corticosteroid exposure has been shown to decrease the number of steroid receptors in the hippocampus, pituitary gland, and amygdala.³⁶ In a somewhat paradoxical finding, the production of CNS proinflammatory cytokines like interleuken-1β and tumor necrosis factor α has been seen after steroid administration, suggesting alternate gene signaling in the CNS.³⁷ Although not proven conclusively, it is felt that these physiologic changes and hyperactivity of the HPA axis are predominantly responsible for changes in behavior, mood, memory, and eventually psychosis in steroid-treated patients.^33,38

Finally, alterations in cognition and behavior may be related to steroid-induced changes in CNS carbohydrate, protein, and lipid metabolism with subsequent cellular neurotoxicity.^32,38 Glucose uptake into the hippocampus is decreased with steroid exposure. Additionally, breakdown of metabolic compounds to produce energy can be destructive if left unchecked for prolonged periods. DHEA, growth hormone, and testosterone work to repair catabolic damage produced by cortisol, known as anabolic balance. A low anabolic balance (low DHEA levels to high cortisol levels) leads to a cascade of dysregulation in brain activity.³⁹

Changes in Natural Sleep-Wake Cycles

Natural sleep pathways are also affected by steroids. The sleep-wake cycle is primarily regulated in the hypothalamus with circadian release of melatonin from the pineal gland. Melatonin release is highest at night, where it promotes sleep onset and continuity. Upstream, tryptophan is an amino acid that serves as a precursor to serotonin and melatonin.⁴⁰ Both endogenous and exogenous corticosteroids decrease serum melatonin levels with a markedly diminished circadian rhythm secretion.^41,42Demish and colleagues found a significant decrease in mean (SD) nocturnal melatonin plasma levels after the evening administration of oral dexamethasone 1 mg in 11 healthy volunteers: 127 (42) pg/mL before vs 73 (38) pg/mL after; P < .01.⁴² This result is likely due to decreased cellular metabolism and melatonin synthesis in the pineal gland. Of note, melatonin has neuroprotective affects, and the administration of melatonin has been shown to reverse some steroid-induced neurotoxicities in animal models.⁴³

Steroids also reduce the uptake of tryptophan into the brain.³³ Additionally, in animal models, dexamethasone administration caused a significant decrease in the gene expression of tryptophan hydroxylase, which is part of the multistep pathway in synthesizing serotonin from L-tryptophan. These effects upstream could inhibit the biosynthetic capacity of both melatonin and serotonin.⁴⁴

A third pathway investigated in sleep regulation are the orexin neuropeptides. Orexins are produced in the hypothalamus and stimulate daytime wake activity in monoaminergic and cholinergic neurons. Subsequently, orexin receptor antagonists are a newer class of drugs aimed at mitigating nighttime hyperarousal and sleep disruption. Orexin overexpression may be a causal factor in steroid-induced sleep disturbance. However, this effect was specifically evaluated in a recent study in children with acute lymphoblastic leukemia, which showed that cerebral spinal fluid orexin levels (SD) were not significantly different from baseline after dexamethasone administration: 574 (26.6) pg/mL vs 580 (126.1) pg/mL; P = .8.⁴⁵

Hyperarousal State

Finally, a hyperarousal state is thought to be produced by nongenomic changes to natural neuroinhibitory regulation seen with nonclassical steroid production called neurosteroids. Animal studies revealed that high levels of steroids were found in the CNS long after adrenalectomy, suggesting CNS de novo synthesis.⁴⁶ In addition to altering gene expression at classic intercellular steroid receptors, neurosteroids can alter neurotransmission by direct interaction on ion-gated membranes and other receptors on the cell surface. Restlessness and insomnia could be due to γ-aminobutyric acid type A (GABA_A) receptor modulation in the CNS where neuroactive steroids slow the rate of recovery of GABA_A and potentially inhibit postsynaptic GABAergic transmission. It also is hypothesized that neuroactive steroids have excitatory action at nicotinic acetylcholine, 5HT₃ receptors, and through increasing the fractional open time of the N-methyl-D-aspartate -activated channels.⁴⁷ Allopregnanolone and DHEA are neurosteroids that act as GABA_A agonists and have neuroprotective effects with anxiolytic, antidepressant, and antiaggressive properties.

Neurosteroids are synthesized from cholesterol in the hippocampus. Neurosteroids are upregulated in response to stress by CNS cortisol effects on various enzyme expressions.⁴⁷ Whether exogenous steroid administration affects this biosynthesis vs the stress response in the HPA axis itself is not fully elucidated. Monteleone and colleagues found that dexamethasone 1 mg given orally significantly reduced cortisol and DHEA and allopregnanolone levels in both healthy volunteers and anorexia nervosa patients.⁴⁸ Similarly, Genazzani and colleagues demonstrated that oral dexamethasone administration (0.5 mg every 6 hours) caused significant reductions in both serum allopregnanolone and DHEA levels.⁴⁹

Outcomes Studies

The majority of reported data in steroid-induced insomnia and psychosis is in noncritically ill populations. In a randomized, prospective crossover study of healthy volunteers, dexamethasone administration (3 mg every 8 hours for 48 hours) resulted in significant changes in sleep patterns measured with polysomnography. Compared with placebo, steroid treatment showed significantly longer percentage (SD) of stage 0/awake times (11.7% [11.4] vs 2.9% [1.8]; P < .05); longer percentage (SD) of REM sleep latency (363.8 [74.5] minutes vs 202.8 [79.6] minutes; P < .01), and a reduced number (SD) of REM periods (3.8 [2.6] vs 9.7 [3.6]; P < .01).⁵⁰ Insomnia was one of the most commonly self-reported AEs (> 60%) in a survey of 2,446 chronic steroid users, and the incidence increased as steroid doses increased.⁵¹

A prospective, open-label study of 240 patients with cancer demonstrated significant sleep disruptions using the Pittsburgh Sleep Quality Index with the use of high-dose steroids in chemotherapy.⁵² Naber and colleagues evaluated 50 previously healthy patients taking methylprednisolone 119 mg (41 mg/d) for retinitis and uveitis.⁵³ They reported 26% to 34% of subjects experienced hypomanic syndrome based on a semistructured interview examination. Symptoms developed within 3 days and persisted for the 8-day course of therapy. Brown and colleagues prospectively evaluated 32 asthmatic patients prescribed bursts of prednisone > 40 mg daily. They observed significantly increased scores in the Young Mania Rating Scale within 3 to 7 days of starting therapy, which dissipated to baseline after stopping therapy.⁵⁴

Despite a high reported incidence of neurologic AEs, outcomes in critically ill populations are mixed. Study methods are varied, and many were largely observational. No prospective, randomized studies exist to date specifically aimed and powered to evaluate the effects of steroids on sleep disturbances or delirium in a critically ill population. Furthermore, sleep quality is difficult to measure in this population, and self-reporting often is not an option. In critical care trials, if AEs such as insomnia, delirium, or psychosis are recorded at all, there is heterogeneity in the definitions, and these AEs are generally poorly defined (eg, psychiatric or neurologic disorder not otherwise specified), making pooled analysis of this outcome difficult.⁵⁵

One of the largest observational studies in hospitalized patients was through the Boston Collaborative Drug Surveillance Program. A total of 718 consecutively enrolled inpatients who received prednisone were monitored for acute reactions. Psychiatric AEs were rare (1.3%) with low doses (< 40 mg/d), more prevalent (4.6%) with higher doses (41-80 mg/d), and most prevalent (18.4%) with the highest doses (> 80 mg/d), suggesting CNS AEs are dose dependent.¹⁸ A single-center, retrospective review of 755 psychiatric consults in hospitalized patients revealed that 54% of manic patients were due to corticosteroid administration.¹⁹ In a prospective observational study of 206 consecutive ICU admissions, steroid administration was an independent risk factor for development of ICU delirium, using the Confusion Assessment Method-ICU (CAM-ICU) at a single center (odds ratio [OR], 2.8; 95% CI, 1.05-7.28).²⁵

Two studies in hospitalized oncology patients found conflicting results using the Nursing Delirium Screening Scale (Nu-DESC). One did not find a significant association between delirium and dexamethasone equivalent doses > 15 mg, while the second found an increased hazard ratio (HR) for a positive Nu-DESC score (HR, 2.67; 95% CI, 1.18-6.03).^20,21 Similarly, conflicting results were found in 2 studies using first-order Markov models. In one prospective cohort study, 520 consecutive mechanically ventilated patients in 13 ICUs were monitored for the transition to delirium (CAM-ICU positive) from nondelirium states. Steroid administration was significantly associated with transitioning to delirium (OR, 1.52; 95% CI, 1.05-2.21).²² This conflicts with a similar study by Wolters and colleagues, which monitored 1,112 ICU patients who were given a median prednisone equivalent of 50 mg (interquartile range, 25-75 mg). Steroid administration was not significantly associated with the transition to delirium from an awake without delirium state (OR, 1.08; 95% CI, 0.89-1.32; adjusted OR, 1.00; 95% CI, 0.99-1.01 per 10-mg increase in prednisone equivalent).²³

Mitigating Effects

Although steroid therapy often cannot be altered in the critically ill population, research showed that steroid overuse is common in ICUs.^56,57 Minimizing dosage and duration are important ways clinicians can mitigate unwanted effects. CNS AEs seen with steroids often can be reversed once therapy is discontinued. Avoiding split-dose administration has been proposed given the natural diurnal production of cortisol.⁵⁸ A review by Flaherty discusses the importance of avoiding pharmacologic agents in hospitalized older patients if possible due to known risks (falls, dependency, hip fractures, rebound insomnia, and risk of delirium) and provides a HELP ME SLEEP nomogram for nonpharmacologic interventions in hospitalized patients (Table 4).⁵⁹

Historically, lithium has been recommended for steroid-induced mania with chronic steroid use; however, given the large volume and electrolyte shifts seen in critically ill patients, this may not be a viable option. Antidepressants, especially tricyclics, should generally be avoided in steroid-induced psychosis as these may exacerbate symptoms. If symptoms are severe, either typical (haloperidol) or atypical (olanzapine, quetiapine, risperidone) antipsychotics have been used with success.⁶⁰ Given the known depletion of serum melatonin levels, melatonin supplements are an attractive and relatively safe option for steroid-induced insomnia; however, there are no robust studies specifically aimed at this intervention for this population.

Conclusions

With known, multimodal foci driving sleep impairment in ICU patients, PADIS guidelines recommend myriad interventions for improvement. Recommendations include noise and light reduction with earplugs and/or eyeshades to improve sleep quality. Nocturnal assist-control ventilation may improve sleep quality in ventilated patients. Finally, the development of institutional protocols for promoting sleep quality in ICU patients is recommended.¹⁷

Sleep disturbance in the critically ill has received much attention over recent years as this is a common result of intensive care unit (ICU) admission. Disruptions in sleep not only can, at a minimum, cause distress and lower patient satisfaction, but also inhibit recovery from illness and increase morbidity.^1,2 Several studies have been conducted highlighting the altered sleep patterns of critically ill patients; although total sleep time may seem normal (7-9 hours), patients can experience multiple awakenings per hour, more time in light sleep (stages 1 and 2), and less time in restorative sleep (stages 3 and 4, [REM]rapid eye movement).^2-5

There are several hypothesized physiologic detriments that contribute to slower ICU recovery with sleep deprivation. Research in noncritically ill subjects suggests that sleep deprivation contributes to hypoventilation and potentially prolonged time on the ventilator.^6-9 Cardiovascular morbidity may be adversely affected by inflammatory cytokine release seen in sleep disruption.^10,11 Studies of noncritically ill patients also suggest that immune response is impaired, potentially protracting infection recovery.^12,13 Finally, although not directly investigated, sleep deprivation may contribute to ICU delirium, an independent adverse effect (AE) associated with increased mortality and worse long-term outcomes.^14-16

The Society of Critical Care Medicine (SCCM) recently updated its consensus guidelines for the management of pain, agitation/sedation, delirium, immobility, and sleep disruption (PADIS) in adult patients.¹⁷ These guidelines offer limited interventions to promote sleep in ICU patients based on available evidence and steer the clinician toward minimizing exacerbating factors. Although factors that affect sleep patterns are multifactorial, such as noise levels, pain, mechanical ventilation, and inflammatory mediators, medication therapy is a known modifiable risk factor for sleep disturbance in critically ill patients.² This focused review will specifically evaluate the effects of steroids on sleep deprivation, psychosis, delirium, and what is known about these effects in a critically ill population.

To include articles relevant to a critically ill population, a systematic search of MEDLINE and PubMed from 1966 to 2019 was performed using the following Medical Subject Headings (MeSH) terms: delirium/etiology, psychoses, substance-induced/etiology, sleep-wake disorders/chemically induced, neurocognitive disorders/chemically induced, dyssomnias/drug effects plus glucocorticoids/adverse effects, adrenal cortex hormones/adverse effects, prednisone/adverse effects, methylprednisolone/adverse effects, and hydrocortisone/adverse effects. The initial search produced 285 articles. Case reports, reviews, letters, and articles pertaining to primary care or palliative populations were excluded, leaving 8 relevant articles for inclusion (Table 1).^18-25

ICU Steroid Use

Steroids are commonly used in the ICU and affect nearly every critically ill population. Common indications for steroids in the ICU include anaphylaxis, airway edema, septic shock, asthma and COPD exacerbations, pneumocystis pneumonia, adrenal crisis, antiemetic treatment, elevated intracranial pressure from tumors, autoimmune disorders, and stress doses needed for chronic steroid users before invasive procedures.²⁶ Whether divided into glucocorticoid or mineralocorticoid subgroups, corticosteroids offer therapeutic benefit from their pharmacologic similarity to endogenously produced cortisol, which includes anti-inflammatory, immunosuppressive, antiproliferative, and vasoconstrictive effects.

Steroid receptors are present in most human tissue, and in varying degrees of binding affinity produce a wide variety of effects. After passive diffusion across cell membranes, steroid-receptor activation binds to various DNA sites, called glucocorticoid regulatory elements, which either stimulates or inhibits transcription of multiple nearby genes.

At the cellular level, corticosteroids inhibit the release of arachidonic acid through upstream production of lipocortin peptides and antagonism of phospholipase A₂. This action decreases subsequent inflammatory mediators, including kinins, histamine, liposomal enzymes, and prostaglandins. Steroids also inhibit NF-κB, which further decreases expression of proinflammatory genes while promoting interleukin-10 and its anti-inflammatory properties. Antiproliferative effects of steroids are seen by triggering cell apoptosis and inhibition of fibroblast proliferation.^27,28

By binding to mineralocorticoid receptors, steroids cause sodium retention coupled with hydrogen and potassium excretion in the distal renal tubule. Steroids also promote vasoconstriction by upregulating the production and sensitivity of β receptors in the endothelium while suppressing the production of vasodilators. Although rarely used for these physiologic effects, steroids also are involved in a number of metabolic pathways, including calcium regulation, gluconeogenesis, protein metabolism, and fat distribution. Given the similar structure to cortisol, exogenous steroids depress the hypothalamic-pituitary axis (HPA) and decrease the release of adrenocorticotropic hormone (ACTH). Tapering doses of steroid regimens is often required to allow natural androgen and cortisol synthesis and prevent steroid withdrawal.^27,28

The potency of various exogenous steroids closely parallels their ability to retain sodium (Table 2). Prolonged activation of steroid receptors can have numerous systemic AEs, including unwanted neurocognitive effects (Table 3). Insomnia and psychosis are commonly described in corticosteroid clinical trials, and in one meta-analysis, both are associated with high costs per episode per year.²⁹

Steroid-Induced Sleep Disruption and Psychosis

Sleep disruption caused by exogenous administration of steroids is thought to trigger other psychostimulant effects, such as mood swings, nervousness, psychoses, and delirium.³⁰ Similarly, the SCCM PADIS guidelines included an ungraded statement: “although an association between sleep quality and delirium occurrence exists in critically ill adults, a cause-effect relationship has not been established.”¹⁷ For this review, these AEs will be discussed as related events.

The medical literature proposes 3 pathways primarily responsible for neurocognitive AEs of steroids: behavior changes through modification of the HPA axis, changes in natural sleep-wake cycles, and hyperarousal caused by modification in neuroinhibitory pathways (Figure).

HPA Axis Modification

Under either physical or psychological stress, neural circuits in the brain release corticotropin-releasing hormone (CRH), dehydroepiandrosterone (DHEA), and arginine vasopressin, which go on to activate the sympathetic nervous system and the HPA axis. CRH from the hypothalamus goes on to stimulate ACTH release from the pituitary. ACTH then stimulates cortisol secretion from the adrenal glands. Circulating cortisol feeds into several structures of the brain, including the pituitary, hippocampus, and amygdala. Steroid-receptor complexes alter gene transcription in the central nervous system (CNS), affecting the production of neurotransmitters (eg, dopamine, serotonin) and neuropeptides (eg, somatostatin, β-endorphin). Feedback inhibition ensues, with downregulation of the HPA axis, which prevents depletion of endogenous production of steroids.³¹ DHEA has protective effects against excessive cortisol activity, but DHEA secretion declines with prolonged cortisol exposure. Exogenous steroids may have different effects than endogenous steroids, and neurocognitive sequelae stem from disruption and imbalance of these physiologic mechanisms.^32,33

Steroid receptors are densely located in behavior centers in the brain: the amygdala, septum, and hippocampus. Pharmacologic changes in gene expression alter norepinephrine and serotonin levels in the brain as well as their receptors.³² Prolonged exposure to exogenous steroids has been shown to decrease amygdala and hippocampal volumes.^34,35 Furthermore, prolonged corticosteroid exposure has been shown to decrease the number of steroid receptors in the hippocampus, pituitary gland, and amygdala.³⁶ In a somewhat paradoxical finding, the production of CNS proinflammatory cytokines like interleuken-1β and tumor necrosis factor α has been seen after steroid administration, suggesting alternate gene signaling in the CNS.³⁷ Although not proven conclusively, it is felt that these physiologic changes and hyperactivity of the HPA axis are predominantly responsible for changes in behavior, mood, memory, and eventually psychosis in steroid-treated patients.^33,38

Finally, alterations in cognition and behavior may be related to steroid-induced changes in CNS carbohydrate, protein, and lipid metabolism with subsequent cellular neurotoxicity.^32,38 Glucose uptake into the hippocampus is decreased with steroid exposure. Additionally, breakdown of metabolic compounds to produce energy can be destructive if left unchecked for prolonged periods. DHEA, growth hormone, and testosterone work to repair catabolic damage produced by cortisol, known as anabolic balance. A low anabolic balance (low DHEA levels to high cortisol levels) leads to a cascade of dysregulation in brain activity.³⁹

Changes in Natural Sleep-Wake Cycles

Natural sleep pathways are also affected by steroids. The sleep-wake cycle is primarily regulated in the hypothalamus with circadian release of melatonin from the pineal gland. Melatonin release is highest at night, where it promotes sleep onset and continuity. Upstream, tryptophan is an amino acid that serves as a precursor to serotonin and melatonin.⁴⁰ Both endogenous and exogenous corticosteroids decrease serum melatonin levels with a markedly diminished circadian rhythm secretion.^41,42Demish and colleagues found a significant decrease in mean (SD) nocturnal melatonin plasma levels after the evening administration of oral dexamethasone 1 mg in 11 healthy volunteers: 127 (42) pg/mL before vs 73 (38) pg/mL after; P < .01.⁴² This result is likely due to decreased cellular metabolism and melatonin synthesis in the pineal gland. Of note, melatonin has neuroprotective affects, and the administration of melatonin has been shown to reverse some steroid-induced neurotoxicities in animal models.⁴³

Steroids also reduce the uptake of tryptophan into the brain.³³ Additionally, in animal models, dexamethasone administration caused a significant decrease in the gene expression of tryptophan hydroxylase, which is part of the multistep pathway in synthesizing serotonin from L-tryptophan. These effects upstream could inhibit the biosynthetic capacity of both melatonin and serotonin.⁴⁴

A third pathway investigated in sleep regulation are the orexin neuropeptides. Orexins are produced in the hypothalamus and stimulate daytime wake activity in monoaminergic and cholinergic neurons. Subsequently, orexin receptor antagonists are a newer class of drugs aimed at mitigating nighttime hyperarousal and sleep disruption. Orexin overexpression may be a causal factor in steroid-induced sleep disturbance. However, this effect was specifically evaluated in a recent study in children with acute lymphoblastic leukemia, which showed that cerebral spinal fluid orexin levels (SD) were not significantly different from baseline after dexamethasone administration: 574 (26.6) pg/mL vs 580 (126.1) pg/mL; P = .8.⁴⁵

Hyperarousal State

Finally, a hyperarousal state is thought to be produced by nongenomic changes to natural neuroinhibitory regulation seen with nonclassical steroid production called neurosteroids. Animal studies revealed that high levels of steroids were found in the CNS long after adrenalectomy, suggesting CNS de novo synthesis.⁴⁶ In addition to altering gene expression at classic intercellular steroid receptors, neurosteroids can alter neurotransmission by direct interaction on ion-gated membranes and other receptors on the cell surface. Restlessness and insomnia could be due to γ-aminobutyric acid type A (GABA_A) receptor modulation in the CNS where neuroactive steroids slow the rate of recovery of GABA_A and potentially inhibit postsynaptic GABAergic transmission. It also is hypothesized that neuroactive steroids have excitatory action at nicotinic acetylcholine, 5HT₃ receptors, and through increasing the fractional open time of the N-methyl-D-aspartate -activated channels.⁴⁷ Allopregnanolone and DHEA are neurosteroids that act as GABA_A agonists and have neuroprotective effects with anxiolytic, antidepressant, and antiaggressive properties.

Neurosteroids are synthesized from cholesterol in the hippocampus. Neurosteroids are upregulated in response to stress by CNS cortisol effects on various enzyme expressions.⁴⁷ Whether exogenous steroid administration affects this biosynthesis vs the stress response in the HPA axis itself is not fully elucidated. Monteleone and colleagues found that dexamethasone 1 mg given orally significantly reduced cortisol and DHEA and allopregnanolone levels in both healthy volunteers and anorexia nervosa patients.⁴⁸ Similarly, Genazzani and colleagues demonstrated that oral dexamethasone administration (0.5 mg every 6 hours) caused significant reductions in both serum allopregnanolone and DHEA levels.⁴⁹

Outcomes Studies

The majority of reported data in steroid-induced insomnia and psychosis is in noncritically ill populations. In a randomized, prospective crossover study of healthy volunteers, dexamethasone administration (3 mg every 8 hours for 48 hours) resulted in significant changes in sleep patterns measured with polysomnography. Compared with placebo, steroid treatment showed significantly longer percentage (SD) of stage 0/awake times (11.7% [11.4] vs 2.9% [1.8]; P < .05); longer percentage (SD) of REM sleep latency (363.8 [74.5] minutes vs 202.8 [79.6] minutes; P < .01), and a reduced number (SD) of REM periods (3.8 [2.6] vs 9.7 [3.6]; P < .01).⁵⁰ Insomnia was one of the most commonly self-reported AEs (> 60%) in a survey of 2,446 chronic steroid users, and the incidence increased as steroid doses increased.⁵¹

A prospective, open-label study of 240 patients with cancer demonstrated significant sleep disruptions using the Pittsburgh Sleep Quality Index with the use of high-dose steroids in chemotherapy.⁵² Naber and colleagues evaluated 50 previously healthy patients taking methylprednisolone 119 mg (41 mg/d) for retinitis and uveitis.⁵³ They reported 26% to 34% of subjects experienced hypomanic syndrome based on a semistructured interview examination. Symptoms developed within 3 days and persisted for the 8-day course of therapy. Brown and colleagues prospectively evaluated 32 asthmatic patients prescribed bursts of prednisone > 40 mg daily. They observed significantly increased scores in the Young Mania Rating Scale within 3 to 7 days of starting therapy, which dissipated to baseline after stopping therapy.⁵⁴

Despite a high reported incidence of neurologic AEs, outcomes in critically ill populations are mixed. Study methods are varied, and many were largely observational. No prospective, randomized studies exist to date specifically aimed and powered to evaluate the effects of steroids on sleep disturbances or delirium in a critically ill population. Furthermore, sleep quality is difficult to measure in this population, and self-reporting often is not an option. In critical care trials, if AEs such as insomnia, delirium, or psychosis are recorded at all, there is heterogeneity in the definitions, and these AEs are generally poorly defined (eg, psychiatric or neurologic disorder not otherwise specified), making pooled analysis of this outcome difficult.⁵⁵

One of the largest observational studies in hospitalized patients was through the Boston Collaborative Drug Surveillance Program. A total of 718 consecutively enrolled inpatients who received prednisone were monitored for acute reactions. Psychiatric AEs were rare (1.3%) with low doses (< 40 mg/d), more prevalent (4.6%) with higher doses (41-80 mg/d), and most prevalent (18.4%) with the highest doses (> 80 mg/d), suggesting CNS AEs are dose dependent.¹⁸ A single-center, retrospective review of 755 psychiatric consults in hospitalized patients revealed that 54% of manic patients were due to corticosteroid administration.¹⁹ In a prospective observational study of 206 consecutive ICU admissions, steroid administration was an independent risk factor for development of ICU delirium, using the Confusion Assessment Method-ICU (CAM-ICU) at a single center (odds ratio [OR], 2.8; 95% CI, 1.05-7.28).²⁵

Two studies in hospitalized oncology patients found conflicting results using the Nursing Delirium Screening Scale (Nu-DESC). One did not find a significant association between delirium and dexamethasone equivalent doses > 15 mg, while the second found an increased hazard ratio (HR) for a positive Nu-DESC score (HR, 2.67; 95% CI, 1.18-6.03).^20,21 Similarly, conflicting results were found in 2 studies using first-order Markov models. In one prospective cohort study, 520 consecutive mechanically ventilated patients in 13 ICUs were monitored for the transition to delirium (CAM-ICU positive) from nondelirium states. Steroid administration was significantly associated with transitioning to delirium (OR, 1.52; 95% CI, 1.05-2.21).²² This conflicts with a similar study by Wolters and colleagues, which monitored 1,112 ICU patients who were given a median prednisone equivalent of 50 mg (interquartile range, 25-75 mg). Steroid administration was not significantly associated with the transition to delirium from an awake without delirium state (OR, 1.08; 95% CI, 0.89-1.32; adjusted OR, 1.00; 95% CI, 0.99-1.01 per 10-mg increase in prednisone equivalent).²³

Mitigating Effects

Although steroid therapy often cannot be altered in the critically ill population, research showed that steroid overuse is common in ICUs.^56,57 Minimizing dosage and duration are important ways clinicians can mitigate unwanted effects. CNS AEs seen with steroids often can be reversed once therapy is discontinued. Avoiding split-dose administration has been proposed given the natural diurnal production of cortisol.⁵⁸ A review by Flaherty discusses the importance of avoiding pharmacologic agents in hospitalized older patients if possible due to known risks (falls, dependency, hip fractures, rebound insomnia, and risk of delirium) and provides a HELP ME SLEEP nomogram for nonpharmacologic interventions in hospitalized patients (Table 4).⁵⁹

Historically, lithium has been recommended for steroid-induced mania with chronic steroid use; however, given the large volume and electrolyte shifts seen in critically ill patients, this may not be a viable option. Antidepressants, especially tricyclics, should generally be avoided in steroid-induced psychosis as these may exacerbate symptoms. If symptoms are severe, either typical (haloperidol) or atypical (olanzapine, quetiapine, risperidone) antipsychotics have been used with success.⁶⁰ Given the known depletion of serum melatonin levels, melatonin supplements are an attractive and relatively safe option for steroid-induced insomnia; however, there are no robust studies specifically aimed at this intervention for this population.

Conclusions

With known, multimodal foci driving sleep impairment in ICU patients, PADIS guidelines recommend myriad interventions for improvement. Recommendations include noise and light reduction with earplugs and/or eyeshades to improve sleep quality. Nocturnal assist-control ventilation may improve sleep quality in ventilated patients. Finally, the development of institutional protocols for promoting sleep quality in ICU patients is recommended.¹⁷

Sleep disturbance in the critically ill has received much attention over recent years as this is a common result of intensive care unit (ICU) admission. Disruptions in sleep not only can, at a minimum, cause distress and lower patient satisfaction, but also inhibit recovery from illness and increase morbidity.^1,2 Several studies have been conducted highlighting the altered sleep patterns of critically ill patients; although total sleep time may seem normal (7-9 hours), patients can experience multiple awakenings per hour, more time in light sleep (stages 1 and 2), and less time in restorative sleep (stages 3 and 4, [REM]rapid eye movement).^2-5

There are several hypothesized physiologic detriments that contribute to slower ICU recovery with sleep deprivation. Research in noncritically ill subjects suggests that sleep deprivation contributes to hypoventilation and potentially prolonged time on the ventilator.^6-9 Cardiovascular morbidity may be adversely affected by inflammatory cytokine release seen in sleep disruption.^10,11 Studies of noncritically ill patients also suggest that immune response is impaired, potentially protracting infection recovery.^12,13 Finally, although not directly investigated, sleep deprivation may contribute to ICU delirium, an independent adverse effect (AE) associated with increased mortality and worse long-term outcomes.^14-16

The Society of Critical Care Medicine (SCCM) recently updated its consensus guidelines for the management of pain, agitation/sedation, delirium, immobility, and sleep disruption (PADIS) in adult patients.¹⁷ These guidelines offer limited interventions to promote sleep in ICU patients based on available evidence and steer the clinician toward minimizing exacerbating factors. Although factors that affect sleep patterns are multifactorial, such as noise levels, pain, mechanical ventilation, and inflammatory mediators, medication therapy is a known modifiable risk factor for sleep disturbance in critically ill patients.² This focused review will specifically evaluate the effects of steroids on sleep deprivation, psychosis, delirium, and what is known about these effects in a critically ill population.

To include articles relevant to a critically ill population, a systematic search of MEDLINE and PubMed from 1966 to 2019 was performed using the following Medical Subject Headings (MeSH) terms: delirium/etiology, psychoses, substance-induced/etiology, sleep-wake disorders/chemically induced, neurocognitive disorders/chemically induced, dyssomnias/drug effects plus glucocorticoids/adverse effects, adrenal cortex hormones/adverse effects, prednisone/adverse effects, methylprednisolone/adverse effects, and hydrocortisone/adverse effects. The initial search produced 285 articles. Case reports, reviews, letters, and articles pertaining to primary care or palliative populations were excluded, leaving 8 relevant articles for inclusion (Table 1).^18-25

ICU Steroid Use

Steroids are commonly used in the ICU and affect nearly every critically ill population. Common indications for steroids in the ICU include anaphylaxis, airway edema, septic shock, asthma and COPD exacerbations, pneumocystis pneumonia, adrenal crisis, antiemetic treatment, elevated intracranial pressure from tumors, autoimmune disorders, and stress doses needed for chronic steroid users before invasive procedures.²⁶ Whether divided into glucocorticoid or mineralocorticoid subgroups, corticosteroids offer therapeutic benefit from their pharmacologic similarity to endogenously produced cortisol, which includes anti-inflammatory, immunosuppressive, antiproliferative, and vasoconstrictive effects.

Steroid receptors are present in most human tissue, and in varying degrees of binding affinity produce a wide variety of effects. After passive diffusion across cell membranes, steroid-receptor activation binds to various DNA sites, called glucocorticoid regulatory elements, which either stimulates or inhibits transcription of multiple nearby genes.

At the cellular level, corticosteroids inhibit the release of arachidonic acid through upstream production of lipocortin peptides and antagonism of phospholipase A₂. This action decreases subsequent inflammatory mediators, including kinins, histamine, liposomal enzymes, and prostaglandins. Steroids also inhibit NF-κB, which further decreases expression of proinflammatory genes while promoting interleukin-10 and its anti-inflammatory properties. Antiproliferative effects of steroids are seen by triggering cell apoptosis and inhibition of fibroblast proliferation.^27,28

By binding to mineralocorticoid receptors, steroids cause sodium retention coupled with hydrogen and potassium excretion in the distal renal tubule. Steroids also promote vasoconstriction by upregulating the production and sensitivity of β receptors in the endothelium while suppressing the production of vasodilators. Although rarely used for these physiologic effects, steroids also are involved in a number of metabolic pathways, including calcium regulation, gluconeogenesis, protein metabolism, and fat distribution. Given the similar structure to cortisol, exogenous steroids depress the hypothalamic-pituitary axis (HPA) and decrease the release of adrenocorticotropic hormone (ACTH). Tapering doses of steroid regimens is often required to allow natural androgen and cortisol synthesis and prevent steroid withdrawal.^27,28

The potency of various exogenous steroids closely parallels their ability to retain sodium (Table 2). Prolonged activation of steroid receptors can have numerous systemic AEs, including unwanted neurocognitive effects (Table 3). Insomnia and psychosis are commonly described in corticosteroid clinical trials, and in one meta-analysis, both are associated with high costs per episode per year.²⁹

Steroid-Induced Sleep Disruption and Psychosis

Sleep disruption caused by exogenous administration of steroids is thought to trigger other psychostimulant effects, such as mood swings, nervousness, psychoses, and delirium.³⁰ Similarly, the SCCM PADIS guidelines included an ungraded statement: “although an association between sleep quality and delirium occurrence exists in critically ill adults, a cause-effect relationship has not been established.”¹⁷ For this review, these AEs will be discussed as related events.

The medical literature proposes 3 pathways primarily responsible for neurocognitive AEs of steroids: behavior changes through modification of the HPA axis, changes in natural sleep-wake cycles, and hyperarousal caused by modification in neuroinhibitory pathways (Figure).

HPA Axis Modification

Under either physical or psychological stress, neural circuits in the brain release corticotropin-releasing hormone (CRH), dehydroepiandrosterone (DHEA), and arginine vasopressin, which go on to activate the sympathetic nervous system and the HPA axis. CRH from the hypothalamus goes on to stimulate ACTH release from the pituitary. ACTH then stimulates cortisol secretion from the adrenal glands. Circulating cortisol feeds into several structures of the brain, including the pituitary, hippocampus, and amygdala. Steroid-receptor complexes alter gene transcription in the central nervous system (CNS), affecting the production of neurotransmitters (eg, dopamine, serotonin) and neuropeptides (eg, somatostatin, β-endorphin). Feedback inhibition ensues, with downregulation of the HPA axis, which prevents depletion of endogenous production of steroids.³¹ DHEA has protective effects against excessive cortisol activity, but DHEA secretion declines with prolonged cortisol exposure. Exogenous steroids may have different effects than endogenous steroids, and neurocognitive sequelae stem from disruption and imbalance of these physiologic mechanisms.^32,33

Steroid receptors are densely located in behavior centers in the brain: the amygdala, septum, and hippocampus. Pharmacologic changes in gene expression alter norepinephrine and serotonin levels in the brain as well as their receptors.³² Prolonged exposure to exogenous steroids has been shown to decrease amygdala and hippocampal volumes.^34,35 Furthermore, prolonged corticosteroid exposure has been shown to decrease the number of steroid receptors in the hippocampus, pituitary gland, and amygdala.³⁶ In a somewhat paradoxical finding, the production of CNS proinflammatory cytokines like interleuken-1β and tumor necrosis factor α has been seen after steroid administration, suggesting alternate gene signaling in the CNS.³⁷ Although not proven conclusively, it is felt that these physiologic changes and hyperactivity of the HPA axis are predominantly responsible for changes in behavior, mood, memory, and eventually psychosis in steroid-treated patients.^33,38

Finally, alterations in cognition and behavior may be related to steroid-induced changes in CNS carbohydrate, protein, and lipid metabolism with subsequent cellular neurotoxicity.^32,38 Glucose uptake into the hippocampus is decreased with steroid exposure. Additionally, breakdown of metabolic compounds to produce energy can be destructive if left unchecked for prolonged periods. DHEA, growth hormone, and testosterone work to repair catabolic damage produced by cortisol, known as anabolic balance. A low anabolic balance (low DHEA levels to high cortisol levels) leads to a cascade of dysregulation in brain activity.³⁹

Changes in Natural Sleep-Wake Cycles

Natural sleep pathways are also affected by steroids. The sleep-wake cycle is primarily regulated in the hypothalamus with circadian release of melatonin from the pineal gland. Melatonin release is highest at night, where it promotes sleep onset and continuity. Upstream, tryptophan is an amino acid that serves as a precursor to serotonin and melatonin.⁴⁰ Both endogenous and exogenous corticosteroids decrease serum melatonin levels with a markedly diminished circadian rhythm secretion.^41,42Demish and colleagues found a significant decrease in mean (SD) nocturnal melatonin plasma levels after the evening administration of oral dexamethasone 1 mg in 11 healthy volunteers: 127 (42) pg/mL before vs 73 (38) pg/mL after; P < .01.⁴² This result is likely due to decreased cellular metabolism and melatonin synthesis in the pineal gland. Of note, melatonin has neuroprotective affects, and the administration of melatonin has been shown to reverse some steroid-induced neurotoxicities in animal models.⁴³

Steroids also reduce the uptake of tryptophan into the brain.³³ Additionally, in animal models, dexamethasone administration caused a significant decrease in the gene expression of tryptophan hydroxylase, which is part of the multistep pathway in synthesizing serotonin from L-tryptophan. These effects upstream could inhibit the biosynthetic capacity of both melatonin and serotonin.⁴⁴

A third pathway investigated in sleep regulation are the orexin neuropeptides. Orexins are produced in the hypothalamus and stimulate daytime wake activity in monoaminergic and cholinergic neurons. Subsequently, orexin receptor antagonists are a newer class of drugs aimed at mitigating nighttime hyperarousal and sleep disruption. Orexin overexpression may be a causal factor in steroid-induced sleep disturbance. However, this effect was specifically evaluated in a recent study in children with acute lymphoblastic leukemia, which showed that cerebral spinal fluid orexin levels (SD) were not significantly different from baseline after dexamethasone administration: 574 (26.6) pg/mL vs 580 (126.1) pg/mL; P = .8.⁴⁵

Hyperarousal State

Finally, a hyperarousal state is thought to be produced by nongenomic changes to natural neuroinhibitory regulation seen with nonclassical steroid production called neurosteroids. Animal studies revealed that high levels of steroids were found in the CNS long after adrenalectomy, suggesting CNS de novo synthesis.⁴⁶ In addition to altering gene expression at classic intercellular steroid receptors, neurosteroids can alter neurotransmission by direct interaction on ion-gated membranes and other receptors on the cell surface. Restlessness and insomnia could be due to γ-aminobutyric acid type A (GABA_A) receptor modulation in the CNS where neuroactive steroids slow the rate of recovery of GABA_A and potentially inhibit postsynaptic GABAergic transmission. It also is hypothesized that neuroactive steroids have excitatory action at nicotinic acetylcholine, 5HT₃ receptors, and through increasing the fractional open time of the N-methyl-D-aspartate -activated channels.⁴⁷ Allopregnanolone and DHEA are neurosteroids that act as GABA_A agonists and have neuroprotective effects with anxiolytic, antidepressant, and antiaggressive properties.

Neurosteroids are synthesized from cholesterol in the hippocampus. Neurosteroids are upregulated in response to stress by CNS cortisol effects on various enzyme expressions.⁴⁷ Whether exogenous steroid administration affects this biosynthesis vs the stress response in the HPA axis itself is not fully elucidated. Monteleone and colleagues found that dexamethasone 1 mg given orally significantly reduced cortisol and DHEA and allopregnanolone levels in both healthy volunteers and anorexia nervosa patients.⁴⁸ Similarly, Genazzani and colleagues demonstrated that oral dexamethasone administration (0.5 mg every 6 hours) caused significant reductions in both serum allopregnanolone and DHEA levels.⁴⁹

Outcomes Studies

The majority of reported data in steroid-induced insomnia and psychosis is in noncritically ill populations. In a randomized, prospective crossover study of healthy volunteers, dexamethasone administration (3 mg every 8 hours for 48 hours) resulted in significant changes in sleep patterns measured with polysomnography. Compared with placebo, steroid treatment showed significantly longer percentage (SD) of stage 0/awake times (11.7% [11.4] vs 2.9% [1.8]; P < .05); longer percentage (SD) of REM sleep latency (363.8 [74.5] minutes vs 202.8 [79.6] minutes; P < .01), and a reduced number (SD) of REM periods (3.8 [2.6] vs 9.7 [3.6]; P < .01).⁵⁰ Insomnia was one of the most commonly self-reported AEs (> 60%) in a survey of 2,446 chronic steroid users, and the incidence increased as steroid doses increased.⁵¹

A prospective, open-label study of 240 patients with cancer demonstrated significant sleep disruptions using the Pittsburgh Sleep Quality Index with the use of high-dose steroids in chemotherapy.⁵² Naber and colleagues evaluated 50 previously healthy patients taking methylprednisolone 119 mg (41 mg/d) for retinitis and uveitis.⁵³ They reported 26% to 34% of subjects experienced hypomanic syndrome based on a semistructured interview examination. Symptoms developed within 3 days and persisted for the 8-day course of therapy. Brown and colleagues prospectively evaluated 32 asthmatic patients prescribed bursts of prednisone > 40 mg daily. They observed significantly increased scores in the Young Mania Rating Scale within 3 to 7 days of starting therapy, which dissipated to baseline after stopping therapy.⁵⁴

Despite a high reported incidence of neurologic AEs, outcomes in critically ill populations are mixed. Study methods are varied, and many were largely observational. No prospective, randomized studies exist to date specifically aimed and powered to evaluate the effects of steroids on sleep disturbances or delirium in a critically ill population. Furthermore, sleep quality is difficult to measure in this population, and self-reporting often is not an option. In critical care trials, if AEs such as insomnia, delirium, or psychosis are recorded at all, there is heterogeneity in the definitions, and these AEs are generally poorly defined (eg, psychiatric or neurologic disorder not otherwise specified), making pooled analysis of this outcome difficult.⁵⁵

One of the largest observational studies in hospitalized patients was through the Boston Collaborative Drug Surveillance Program. A total of 718 consecutively enrolled inpatients who received prednisone were monitored for acute reactions. Psychiatric AEs were rare (1.3%) with low doses (< 40 mg/d), more prevalent (4.6%) with higher doses (41-80 mg/d), and most prevalent (18.4%) with the highest doses (> 80 mg/d), suggesting CNS AEs are dose dependent.¹⁸ A single-center, retrospective review of 755 psychiatric consults in hospitalized patients revealed that 54% of manic patients were due to corticosteroid administration.¹⁹ In a prospective observational study of 206 consecutive ICU admissions, steroid administration was an independent risk factor for development of ICU delirium, using the Confusion Assessment Method-ICU (CAM-ICU) at a single center (odds ratio [OR], 2.8; 95% CI, 1.05-7.28).²⁵

Two studies in hospitalized oncology patients found conflicting results using the Nursing Delirium Screening Scale (Nu-DESC). One did not find a significant association between delirium and dexamethasone equivalent doses > 15 mg, while the second found an increased hazard ratio (HR) for a positive Nu-DESC score (HR, 2.67; 95% CI, 1.18-6.03).^20,21 Similarly, conflicting results were found in 2 studies using first-order Markov models. In one prospective cohort study, 520 consecutive mechanically ventilated patients in 13 ICUs were monitored for the transition to delirium (CAM-ICU positive) from nondelirium states. Steroid administration was significantly associated with transitioning to delirium (OR, 1.52; 95% CI, 1.05-2.21).²² This conflicts with a similar study by Wolters and colleagues, which monitored 1,112 ICU patients who were given a median prednisone equivalent of 50 mg (interquartile range, 25-75 mg). Steroid administration was not significantly associated with the transition to delirium from an awake without delirium state (OR, 1.08; 95% CI, 0.89-1.32; adjusted OR, 1.00; 95% CI, 0.99-1.01 per 10-mg increase in prednisone equivalent).²³

Mitigating Effects

Although steroid therapy often cannot be altered in the critically ill population, research showed that steroid overuse is common in ICUs.^56,57 Minimizing dosage and duration are important ways clinicians can mitigate unwanted effects. CNS AEs seen with steroids often can be reversed once therapy is discontinued. Avoiding split-dose administration has been proposed given the natural diurnal production of cortisol.⁵⁸ A review by Flaherty discusses the importance of avoiding pharmacologic agents in hospitalized older patients if possible due to known risks (falls, dependency, hip fractures, rebound insomnia, and risk of delirium) and provides a HELP ME SLEEP nomogram for nonpharmacologic interventions in hospitalized patients (Table 4).⁵⁹

Historically, lithium has been recommended for steroid-induced mania with chronic steroid use; however, given the large volume and electrolyte shifts seen in critically ill patients, this may not be a viable option. Antidepressants, especially tricyclics, should generally be avoided in steroid-induced psychosis as these may exacerbate symptoms. If symptoms are severe, either typical (haloperidol) or atypical (olanzapine, quetiapine, risperidone) antipsychotics have been used with success.⁶⁰ Given the known depletion of serum melatonin levels, melatonin supplements are an attractive and relatively safe option for steroid-induced insomnia; however, there are no robust studies specifically aimed at this intervention for this population.

Conclusions

With known, multimodal foci driving sleep impairment in ICU patients, PADIS guidelines recommend myriad interventions for improvement. Recommendations include noise and light reduction with earplugs and/or eyeshades to improve sleep quality. Nocturnal assist-control ventilation may improve sleep quality in ventilated patients. Finally, the development of institutional protocols for promoting sleep quality in ICU patients is recommended.¹⁷

To the Editor: COVID-19 is a pandemic caused by the virus SARS-CoV-2. Serious complications of COVID-19 are characterized by acute respiratory distress syndrome (ARDS), pneumonia and rapidly progressing to multiorgan dysfunction syndrome (MODS).

The pathophysiology of COVID-19 is not fully understood yet and neither vaccine nor clearly effective antiviral treatment is available at this time. Based on the endothelial pathogenesis of viral sepsis, which includes ARDS as seen in severe acute respiratory syndrome (SARS) due to SARS-CoV and Middle East respiratory syndrome due to MERS-CoV,^1,2 we believe COVID-19-associated ARDS is also caused by endotheliopathy-associated vascular microthrombotic disease (EA-VMTD), which also involves multiorgan dysfunction syndrome (MODS) that has been reported as the cause of death.³ We suspect these complications are secondary to disequilibrium state (for various reasons^4,5) between insufficient ADAMTS13 and excessive exocytosis of ultra large von Willebrand factor multimers (ULVWF) from Weibel-Palade bodies present in endothelial cells due to COVID-19-induced endotheliopathy.

Endothelial-derived ULVWF multimers anchored to the endothelial surface of the vascular wall recruit platelets and initiate microthrombogenesis within the microvasculature, leading to large microthrombi strings composed of platelet and eULVWF complexes like “beads-on-a-string structures”⁶ where platelets firmly adhere to eULVWF, instead of roll on eULVWF strings.⁴ Platelets, once adhered to eULVWF strings, are rapidly activated causing platelet aggregation and also recruit leukocytes in a P-selectin dependent manner.⁴ These aggregates grow until they become sufficiently large and can no longer be held onto the eULVWF strings against the force of blood flow and released from endothelial cells into the circulation.⁴ It appears to us that in COVID-19 microthrombotic disease, large amounts of circulating complexes of endothelial-derived ULVWF decorated-platelet microthrombi strings are filtered in the microvasculature (embolism) or develops in the microvasculature in situ causing microthrombotic occlusion. During our data search, we have come across several articles published by Chang, including on endotheliopathy causing vascular microthrombotic disease based on a novel concept of “TTP-like syndrome”⁷

The genesis of EA-VMTD in TTP like syndrome is suspected to be triggered by complement activation and terminal complement complex (C5b-9, membrane attack complex, MAC) may play a key role in producing endotheliopathy.⁷ Magro and colleagues reported that COVID-19 patients have demonstrated generalized thrombotic microvascular injury involving the lungs and skin showing intense complement activation and C5b-9 deposition in the tissue.⁸ Also, recent pathology reports of COVID-19 diseased lungs showed extensive platelet-rich clotting with adherent mononuclear cells and extensive fibrin clotting,⁹ which appear consistent with involvement of NETosis.¹⁰ In another case report from Switzerland, a patient with severe COVID-19 had massive elevation of VWF antigen and activity (555% and 520%, respectively) and increased Factor VIII clotting activity (369%).¹¹ These findings support vascular endotheliopathy causing exocytosis of ULVWF and associated increase in Factor VIII causing microthrombotic disease/embolism.

COVID-19 clinical syndrome appears very much consistent with EA-VMTD presenting with ARDS and MODS as well as micro-macro-thrombotic complications, including peripheral ischemia/gangrene involving fingers and toes and skin necrosis.^8,12

We believe that an appropriate therapy may not be anticoagulation but should include antimicrothrombotic therapy targeting endotheliopathy and primary hemostasis in the early stages of the disease (platelet adhesion, activation, and aggregation; especially eULVWF) like recombinant CD59 (membrane attack complex inhibition factor [MACIF]), recombinant ADAMTS13, glycoprotein IIb/IIIa receptor blocker, therapeutic plasma exchange, and perhaps anticomplement therapy (in selected cases) and others; these need to be validated in clinical trials prior to clinical application.

Of note, ADAMTS13 is a zinc containing protease. We noted that zinc and calcium concentrations play a significant role (in vitro) in ADAMTS13 activity in citrated plasma and recombinant ADAMTS13 activity with no added chelators (recombinant ADAMTS13 activity can enhance up to 200-fold); whereas in high zinc concentrations, ADAMTS13 gets deactivated.¹³ We suggest this finding merits an urgent clinical trial since it appears to us as the best possible cost-effective treatment for COVID-19 microthrombotic complications.

In this view of clinical pathophysiology of sepsis in COVID-19, we would like to enlighten the relationship between endothelial pathogenesis of coronaviral sepsis and vascular microthrombotic disease and would urge the medical community to immediately explore appropriate therapeutic options.

N. Varatharajah, MD

Suganthi Rajah, MD

Virginia, US

To the Editor: COVID-19 is a pandemic caused by the virus SARS-CoV-2. Serious complications of COVID-19 are characterized by acute respiratory distress syndrome (ARDS), pneumonia and rapidly progressing to multiorgan dysfunction syndrome (MODS).

The pathophysiology of COVID-19 is not fully understood yet and neither vaccine nor clearly effective antiviral treatment is available at this time. Based on the endothelial pathogenesis of viral sepsis, which includes ARDS as seen in severe acute respiratory syndrome (SARS) due to SARS-CoV and Middle East respiratory syndrome due to MERS-CoV,^1,2 we believe COVID-19-associated ARDS is also caused by endotheliopathy-associated vascular microthrombotic disease (EA-VMTD), which also involves multiorgan dysfunction syndrome (MODS) that has been reported as the cause of death.³ We suspect these complications are secondary to disequilibrium state (for various reasons^4,5) between insufficient ADAMTS13 and excessive exocytosis of ultra large von Willebrand factor multimers (ULVWF) from Weibel-Palade bodies present in endothelial cells due to COVID-19-induced endotheliopathy.

Endothelial-derived ULVWF multimers anchored to the endothelial surface of the vascular wall recruit platelets and initiate microthrombogenesis within the microvasculature, leading to large microthrombi strings composed of platelet and eULVWF complexes like “beads-on-a-string structures”⁶ where platelets firmly adhere to eULVWF, instead of roll on eULVWF strings.⁴ Platelets, once adhered to eULVWF strings, are rapidly activated causing platelet aggregation and also recruit leukocytes in a P-selectin dependent manner.⁴ These aggregates grow until they become sufficiently large and can no longer be held onto the eULVWF strings against the force of blood flow and released from endothelial cells into the circulation.⁴ It appears to us that in COVID-19 microthrombotic disease, large amounts of circulating complexes of endothelial-derived ULVWF decorated-platelet microthrombi strings are filtered in the microvasculature (embolism) or develops in the microvasculature in situ causing microthrombotic occlusion. During our data search, we have come across several articles published by Chang, including on endotheliopathy causing vascular microthrombotic disease based on a novel concept of “TTP-like syndrome”⁷

The genesis of EA-VMTD in TTP like syndrome is suspected to be triggered by complement activation and terminal complement complex (C5b-9, membrane attack complex, MAC) may play a key role in producing endotheliopathy.⁷ Magro and colleagues reported that COVID-19 patients have demonstrated generalized thrombotic microvascular injury involving the lungs and skin showing intense complement activation and C5b-9 deposition in the tissue.⁸ Also, recent pathology reports of COVID-19 diseased lungs showed extensive platelet-rich clotting with adherent mononuclear cells and extensive fibrin clotting,⁹ which appear consistent with involvement of NETosis.¹⁰ In another case report from Switzerland, a patient with severe COVID-19 had massive elevation of VWF antigen and activity (555% and 520%, respectively) and increased Factor VIII clotting activity (369%).¹¹ These findings support vascular endotheliopathy causing exocytosis of ULVWF and associated increase in Factor VIII causing microthrombotic disease/embolism.

COVID-19 clinical syndrome appears very much consistent with EA-VMTD presenting with ARDS and MODS as well as micro-macro-thrombotic complications, including peripheral ischemia/gangrene involving fingers and toes and skin necrosis.^8,12

We believe that an appropriate therapy may not be anticoagulation but should include antimicrothrombotic therapy targeting endotheliopathy and primary hemostasis in the early stages of the disease (platelet adhesion, activation, and aggregation; especially eULVWF) like recombinant CD59 (membrane attack complex inhibition factor [MACIF]), recombinant ADAMTS13, glycoprotein IIb/IIIa receptor blocker, therapeutic plasma exchange, and perhaps anticomplement therapy (in selected cases) and others; these need to be validated in clinical trials prior to clinical application.

Of note, ADAMTS13 is a zinc containing protease. We noted that zinc and calcium concentrations play a significant role (in vitro) in ADAMTS13 activity in citrated plasma and recombinant ADAMTS13 activity with no added chelators (recombinant ADAMTS13 activity can enhance up to 200-fold); whereas in high zinc concentrations, ADAMTS13 gets deactivated.¹³ We suggest this finding merits an urgent clinical trial since it appears to us as the best possible cost-effective treatment for COVID-19 microthrombotic complications.

In this view of clinical pathophysiology of sepsis in COVID-19, we would like to enlighten the relationship between endothelial pathogenesis of coronaviral sepsis and vascular microthrombotic disease and would urge the medical community to immediately explore appropriate therapeutic options.

N. Varatharajah, MD

Suganthi Rajah, MD

Virginia, US

To the Editor: COVID-19 is a pandemic caused by the virus SARS-CoV-2. Serious complications of COVID-19 are characterized by acute respiratory distress syndrome (ARDS), pneumonia and rapidly progressing to multiorgan dysfunction syndrome (MODS).

The pathophysiology of COVID-19 is not fully understood yet and neither vaccine nor clearly effective antiviral treatment is available at this time. Based on the endothelial pathogenesis of viral sepsis, which includes ARDS as seen in severe acute respiratory syndrome (SARS) due to SARS-CoV and Middle East respiratory syndrome due to MERS-CoV,^1,2 we believe COVID-19-associated ARDS is also caused by endotheliopathy-associated vascular microthrombotic disease (EA-VMTD), which also involves multiorgan dysfunction syndrome (MODS) that has been reported as the cause of death.³ We suspect these complications are secondary to disequilibrium state (for various reasons^4,5) between insufficient ADAMTS13 and excessive exocytosis of ultra large von Willebrand factor multimers (ULVWF) from Weibel-Palade bodies present in endothelial cells due to COVID-19-induced endotheliopathy.

Endothelial-derived ULVWF multimers anchored to the endothelial surface of the vascular wall recruit platelets and initiate microthrombogenesis within the microvasculature, leading to large microthrombi strings composed of platelet and eULVWF complexes like “beads-on-a-string structures”⁶ where platelets firmly adhere to eULVWF, instead of roll on eULVWF strings.⁴ Platelets, once adhered to eULVWF strings, are rapidly activated causing platelet aggregation and also recruit leukocytes in a P-selectin dependent manner.⁴ These aggregates grow until they become sufficiently large and can no longer be held onto the eULVWF strings against the force of blood flow and released from endothelial cells into the circulation.⁴ It appears to us that in COVID-19 microthrombotic disease, large amounts of circulating complexes of endothelial-derived ULVWF decorated-platelet microthrombi strings are filtered in the microvasculature (embolism) or develops in the microvasculature in situ causing microthrombotic occlusion. During our data search, we have come across several articles published by Chang, including on endotheliopathy causing vascular microthrombotic disease based on a novel concept of “TTP-like syndrome”⁷

The genesis of EA-VMTD in TTP like syndrome is suspected to be triggered by complement activation and terminal complement complex (C5b-9, membrane attack complex, MAC) may play a key role in producing endotheliopathy.⁷ Magro and colleagues reported that COVID-19 patients have demonstrated generalized thrombotic microvascular injury involving the lungs and skin showing intense complement activation and C5b-9 deposition in the tissue.⁸ Also, recent pathology reports of COVID-19 diseased lungs showed extensive platelet-rich clotting with adherent mononuclear cells and extensive fibrin clotting,⁹ which appear consistent with involvement of NETosis.¹⁰ In another case report from Switzerland, a patient with severe COVID-19 had massive elevation of VWF antigen and activity (555% and 520%, respectively) and increased Factor VIII clotting activity (369%).¹¹ These findings support vascular endotheliopathy causing exocytosis of ULVWF and associated increase in Factor VIII causing microthrombotic disease/embolism.

COVID-19 clinical syndrome appears very much consistent with EA-VMTD presenting with ARDS and MODS as well as micro-macro-thrombotic complications, including peripheral ischemia/gangrene involving fingers and toes and skin necrosis.^8,12

We believe that an appropriate therapy may not be anticoagulation but should include antimicrothrombotic therapy targeting endotheliopathy and primary hemostasis in the early stages of the disease (platelet adhesion, activation, and aggregation; especially eULVWF) like recombinant CD59 (membrane attack complex inhibition factor [MACIF]), recombinant ADAMTS13, glycoprotein IIb/IIIa receptor blocker, therapeutic plasma exchange, and perhaps anticomplement therapy (in selected cases) and others; these need to be validated in clinical trials prior to clinical application.

Of note, ADAMTS13 is a zinc containing protease. We noted that zinc and calcium concentrations play a significant role (in vitro) in ADAMTS13 activity in citrated plasma and recombinant ADAMTS13 activity with no added chelators (recombinant ADAMTS13 activity can enhance up to 200-fold); whereas in high zinc concentrations, ADAMTS13 gets deactivated.¹³ We suggest this finding merits an urgent clinical trial since it appears to us as the best possible cost-effective treatment for COVID-19 microthrombotic complications.

In this view of clinical pathophysiology of sepsis in COVID-19, we would like to enlighten the relationship between endothelial pathogenesis of coronaviral sepsis and vascular microthrombotic disease and would urge the medical community to immediately explore appropriate therapeutic options.

N. Varatharajah, MD

Suganthi Rajah, MD

Virginia, US

For health care professionals, especially those in the epicenters of the pandemic, among the most distressing aspects of this first wave of COVID-19 has been the absence of any drug to treat the virus. The practitioners on the frontlines have confronted repeated surges of critically ill and dying patients without any effective treatment to offer, resulting in feelings of hopelessness, guilt, moral distress, depression, and in some tragic cases, suicide.²

On May 12th, the Centers of Disease Control and Prevention (CDC) released additional guidance on the antiviral medications that are the subject of this essay. The CDC may have updated its treatment guidelines in part to try and bring a measure of clinical reasoning and scientific order into the impassioned and politicized chaos that surrounded hydrocloroquine and remdesivir in the media.³

In this fourth installment of my series on pandemic ethics, we examine the desperate race for hope in the form of drug treatments for COVID-19. The race has been run faster than any in history thanks to biotechnology, genetic engineering, and artificial intelligence, although many experts believe it will still be a marathon rather than a sprint to a vaccine.⁴

The first editorial in this series provided a primer of the key differences between public health ethics and clinical ethics. Another crucial distinction is the far more pervasive and powerful influence of nonmedical factors in decision making, including political agendas, economic motives, journalistic hyperbole, and cultural biases and orientations. These competing interests make it even more challenging for scientists of integrity and health care institutions that are trying to uphold core values to make principled judgments about what is best for critically ill patients and the demoralized staff caring for them. In the remainder of this column, I will trace the dynamics of these forces as they impact the use of 2 drugs in federal practice: hydroxychloroquine and remdesivir.

The trajectory of hydroxychloroquine has been a political and medical roller-coaster since the pandemic hit, as is evident in its US Department of Veterans Affairs (VA) ride. Various media outlets have reported that beginning about March 26, 2020, VA placed orders for up to $400,000 of the antimalarial drug hydroxychloroquine to be given to veterans hospitalized with COVID-19.⁵ The same day the VA Office of Inspector General (OIG) issued a report critical of VA pandemic readiness and its availability of hydroxychloroquine.⁶

The VA strongly refuted the report, objecting to the premise of the OIG investigation, which was to determine whether VA facilities had on hand a 14-day supply of chloroquine or hydroxychloroquine. “This is both inaccurate and irresponsible.” Noting that the drugs were still under investigation, the VA insisted that “No conclusions have been made on their effectiveness. To insist that a 14 days’ supply of these drugs is appropriate or not appropriate displays this dangerous lack of expertise on COVID-19 and Pandemic response.”⁶

In April, National Institutes of Health-sponsored researchers released data that hydroxychloroquine actually increased mortality among VA patients with COVID-19,⁷ leading veterans’ groups and the Senate minority leader to demand that VA cease to use hydroxychloroquine for COVID-19.⁸ As recently as May 15, the Associated Press reported that top VA officials have defended their use of the medication and stated they will not stop administering the medication for this indication.⁹ And VA is not alone, many other health care institutions are still prescribing hydroxychloroquine even amid scientific controversy about its putative benefits. In response to the growing awareness of the potential harms of the drug, the World Health Organization on May 25 announced it was halting all hydroxychloroquine trials.¹⁰ Why then do some physicians and health care providers continue to prescribe it? Because when nothing else stands between the patient and certain death even if there are known risks and uncertain benefits, some in health care feel morally obliged to use their best clinical judgment to help a patient.

Remdesivir’s fortunes both scientific and monetary also rose and fell on the tide of mixed results from studies. Military Times reported on March 10, 2020, that the US Army Medical Research and Development Command had made an agreement with Gilead Sciences, the manufacturer of remdesivir, to provide the medication to COVID-19-positive service members.¹¹ The antiviral had failed against Ebola and hepatitis but showed some efficacy for Middle East respiratory syndrome (MERS) and severe acute respiratory syndrome (SARS). On April 15, the Secretary of the Army announced that 2 COVID-19-positive soldiers had recovered after being given remdesivir.¹² In late April, the National Institute of Allergy and Infectious Diseases reported that in the scientific gold standard randomized placebo-controlled trial, remdesivir did speed the recovery of patients with advanced COVID-19. With the publication of the study in the prestigious New England Journal of Medicine on May 22, 2020, clearly the Army had bet on the right horse.¹³

This column has not been about quack cures and patent medicines that greed and ignorance breed in almost every American public health crisis—although these are by no means absent in this pandemic. This is about the serious endeavor of the top scientists and physicians in the country and, indeed, the world to discover a new medication or to repurpose an older pharmaceutical that is effective in the battle against COVID-19. The pressure on scientists and physicians to find a magic bullet in the battle against such an implacable enemy is unprecedented and unimaginable and can easily lead to sloppy science and ethical erosion.

In a utopia, pharmaceutical and vaccine research would be a matter of the discoveries of basic science trialed in the proof of concept of clinical care on a methodical, deliberate, and exacting timetable that balanced burdens and benefits.

In our current dystopia, science and medicine are only one of the many considerations affecting drug and vaccine development. As scientists and health care practitioners, we all experience a therapeutic imperative that we must heed with both caution and courage. Without caution we risk causing more harm than the disease we are fighting. Without courage we lose hope, the most potent antidote of all.

For health care professionals, especially those in the epicenters of the pandemic, among the most distressing aspects of this first wave of COVID-19 has been the absence of any drug to treat the virus. The practitioners on the frontlines have confronted repeated surges of critically ill and dying patients without any effective treatment to offer, resulting in feelings of hopelessness, guilt, moral distress, depression, and in some tragic cases, suicide.²

On May 12th, the Centers of Disease Control and Prevention (CDC) released additional guidance on the antiviral medications that are the subject of this essay. The CDC may have updated its treatment guidelines in part to try and bring a measure of clinical reasoning and scientific order into the impassioned and politicized chaos that surrounded hydrocloroquine and remdesivir in the media.³

In this fourth installment of my series on pandemic ethics, we examine the desperate race for hope in the form of drug treatments for COVID-19. The race has been run faster than any in history thanks to biotechnology, genetic engineering, and artificial intelligence, although many experts believe it will still be a marathon rather than a sprint to a vaccine.⁴

The first editorial in this series provided a primer of the key differences between public health ethics and clinical ethics. Another crucial distinction is the far more pervasive and powerful influence of nonmedical factors in decision making, including political agendas, economic motives, journalistic hyperbole, and cultural biases and orientations. These competing interests make it even more challenging for scientists of integrity and health care institutions that are trying to uphold core values to make principled judgments about what is best for critically ill patients and the demoralized staff caring for them. In the remainder of this column, I will trace the dynamics of these forces as they impact the use of 2 drugs in federal practice: hydroxychloroquine and remdesivir.

The trajectory of hydroxychloroquine has been a political and medical roller-coaster since the pandemic hit, as is evident in its US Department of Veterans Affairs (VA) ride. Various media outlets have reported that beginning about March 26, 2020, VA placed orders for up to $400,000 of the antimalarial drug hydroxychloroquine to be given to veterans hospitalized with COVID-19.⁵ The same day the VA Office of Inspector General (OIG) issued a report critical of VA pandemic readiness and its availability of hydroxychloroquine.⁶

The VA strongly refuted the report, objecting to the premise of the OIG investigation, which was to determine whether VA facilities had on hand a 14-day supply of chloroquine or hydroxychloroquine. “This is both inaccurate and irresponsible.” Noting that the drugs were still under investigation, the VA insisted that “No conclusions have been made on their effectiveness. To insist that a 14 days’ supply of these drugs is appropriate or not appropriate displays this dangerous lack of expertise on COVID-19 and Pandemic response.”⁶

In April, National Institutes of Health-sponsored researchers released data that hydroxychloroquine actually increased mortality among VA patients with COVID-19,⁷ leading veterans’ groups and the Senate minority leader to demand that VA cease to use hydroxychloroquine for COVID-19.⁸ As recently as May 15, the Associated Press reported that top VA officials have defended their use of the medication and stated they will not stop administering the medication for this indication.⁹ And VA is not alone, many other health care institutions are still prescribing hydroxychloroquine even amid scientific controversy about its putative benefits. In response to the growing awareness of the potential harms of the drug, the World Health Organization on May 25 announced it was halting all hydroxychloroquine trials.¹⁰ Why then do some physicians and health care providers continue to prescribe it? Because when nothing else stands between the patient and certain death even if there are known risks and uncertain benefits, some in health care feel morally obliged to use their best clinical judgment to help a patient.

Remdesivir’s fortunes both scientific and monetary also rose and fell on the tide of mixed results from studies. Military Times reported on March 10, 2020, that the US Army Medical Research and Development Command had made an agreement with Gilead Sciences, the manufacturer of remdesivir, to provide the medication to COVID-19-positive service members.¹¹ The antiviral had failed against Ebola and hepatitis but showed some efficacy for Middle East respiratory syndrome (MERS) and severe acute respiratory syndrome (SARS). On April 15, the Secretary of the Army announced that 2 COVID-19-positive soldiers had recovered after being given remdesivir.¹² In late April, the National Institute of Allergy and Infectious Diseases reported that in the scientific gold standard randomized placebo-controlled trial, remdesivir did speed the recovery of patients with advanced COVID-19. With the publication of the study in the prestigious New England Journal of Medicine on May 22, 2020, clearly the Army had bet on the right horse.¹³

This column has not been about quack cures and patent medicines that greed and ignorance breed in almost every American public health crisis—although these are by no means absent in this pandemic. This is about the serious endeavor of the top scientists and physicians in the country and, indeed, the world to discover a new medication or to repurpose an older pharmaceutical that is effective in the battle against COVID-19. The pressure on scientists and physicians to find a magic bullet in the battle against such an implacable enemy is unprecedented and unimaginable and can easily lead to sloppy science and ethical erosion.

In a utopia, pharmaceutical and vaccine research would be a matter of the discoveries of basic science trialed in the proof of concept of clinical care on a methodical, deliberate, and exacting timetable that balanced burdens and benefits.

In our current dystopia, science and medicine are only one of the many considerations affecting drug and vaccine development. As scientists and health care practitioners, we all experience a therapeutic imperative that we must heed with both caution and courage. Without caution we risk causing more harm than the disease we are fighting. Without courage we lose hope, the most potent antidote of all.

For health care professionals, especially those in the epicenters of the pandemic, among the most distressing aspects of this first wave of COVID-19 has been the absence of any drug to treat the virus. The practitioners on the frontlines have confronted repeated surges of critically ill and dying patients without any effective treatment to offer, resulting in feelings of hopelessness, guilt, moral distress, depression, and in some tragic cases, suicide.²

On May 12th, the Centers of Disease Control and Prevention (CDC) released additional guidance on the antiviral medications that are the subject of this essay. The CDC may have updated its treatment guidelines in part to try and bring a measure of clinical reasoning and scientific order into the impassioned and politicized chaos that surrounded hydrocloroquine and remdesivir in the media.³

In this fourth installment of my series on pandemic ethics, we examine the desperate race for hope in the form of drug treatments for COVID-19. The race has been run faster than any in history thanks to biotechnology, genetic engineering, and artificial intelligence, although many experts believe it will still be a marathon rather than a sprint to a vaccine.⁴

The first editorial in this series provided a primer of the key differences between public health ethics and clinical ethics. Another crucial distinction is the far more pervasive and powerful influence of nonmedical factors in decision making, including political agendas, economic motives, journalistic hyperbole, and cultural biases and orientations. These competing interests make it even more challenging for scientists of integrity and health care institutions that are trying to uphold core values to make principled judgments about what is best for critically ill patients and the demoralized staff caring for them. In the remainder of this column, I will trace the dynamics of these forces as they impact the use of 2 drugs in federal practice: hydroxychloroquine and remdesivir.

The trajectory of hydroxychloroquine has been a political and medical roller-coaster since the pandemic hit, as is evident in its US Department of Veterans Affairs (VA) ride. Various media outlets have reported that beginning about March 26, 2020, VA placed orders for up to $400,000 of the antimalarial drug hydroxychloroquine to be given to veterans hospitalized with COVID-19.⁵ The same day the VA Office of Inspector General (OIG) issued a report critical of VA pandemic readiness and its availability of hydroxychloroquine.⁶

The VA strongly refuted the report, objecting to the premise of the OIG investigation, which was to determine whether VA facilities had on hand a 14-day supply of chloroquine or hydroxychloroquine. “This is both inaccurate and irresponsible.” Noting that the drugs were still under investigation, the VA insisted that “No conclusions have been made on their effectiveness. To insist that a 14 days’ supply of these drugs is appropriate or not appropriate displays this dangerous lack of expertise on COVID-19 and Pandemic response.”⁶

In April, National Institutes of Health-sponsored researchers released data that hydroxychloroquine actually increased mortality among VA patients with COVID-19,⁷ leading veterans’ groups and the Senate minority leader to demand that VA cease to use hydroxychloroquine for COVID-19.⁸ As recently as May 15, the Associated Press reported that top VA officials have defended their use of the medication and stated they will not stop administering the medication for this indication.⁹ And VA is not alone, many other health care institutions are still prescribing hydroxychloroquine even amid scientific controversy about its putative benefits. In response to the growing awareness of the potential harms of the drug, the World Health Organization on May 25 announced it was halting all hydroxychloroquine trials.¹⁰ Why then do some physicians and health care providers continue to prescribe it? Because when nothing else stands between the patient and certain death even if there are known risks and uncertain benefits, some in health care feel morally obliged to use their best clinical judgment to help a patient.

Remdesivir’s fortunes both scientific and monetary also rose and fell on the tide of mixed results from studies. Military Times reported on March 10, 2020, that the US Army Medical Research and Development Command had made an agreement with Gilead Sciences, the manufacturer of remdesivir, to provide the medication to COVID-19-positive service members.¹¹ The antiviral had failed against Ebola and hepatitis but showed some efficacy for Middle East respiratory syndrome (MERS) and severe acute respiratory syndrome (SARS). On April 15, the Secretary of the Army announced that 2 COVID-19-positive soldiers had recovered after being given remdesivir.¹² In late April, the National Institute of Allergy and Infectious Diseases reported that in the scientific gold standard randomized placebo-controlled trial, remdesivir did speed the recovery of patients with advanced COVID-19. With the publication of the study in the prestigious New England Journal of Medicine on May 22, 2020, clearly the Army had bet on the right horse.¹³

This column has not been about quack cures and patent medicines that greed and ignorance breed in almost every American public health crisis—although these are by no means absent in this pandemic. This is about the serious endeavor of the top scientists and physicians in the country and, indeed, the world to discover a new medication or to repurpose an older pharmaceutical that is effective in the battle against COVID-19. The pressure on scientists and physicians to find a magic bullet in the battle against such an implacable enemy is unprecedented and unimaginable and can easily lead to sloppy science and ethical erosion.

In a utopia, pharmaceutical and vaccine research would be a matter of the discoveries of basic science trialed in the proof of concept of clinical care on a methodical, deliberate, and exacting timetable that balanced burdens and benefits.

In our current dystopia, science and medicine are only one of the many considerations affecting drug and vaccine development. As scientists and health care practitioners, we all experience a therapeutic imperative that we must heed with both caution and courage. Without caution we risk causing more harm than the disease we are fighting. Without courage we lose hope, the most potent antidote of all.

A disease risk index is now available for pediatric patients with acute myeloid leukemia or acute lymphoblastic leukemia who undergo allogeneic hematopoietic stem cell transplantation.

The model, which was developed and validated using data from more than 2,000 patients, stratifies probabilities of leukemia-free survival (LFS) into four risk groups for acute myeloid leukemia (AML) and three risk groups for acute lymphoblastic leukemia (ALL), reported lead author Muna Qayed, MD, of Emory University, Atlanta, who presented findings as part of the American Society of Clinical Oncology virtual scientific program.

“The outcome of stem cell transplantation for hematologic malignancy is influenced by disease type, cytogenetics, and disease status at transplantation,” Dr. Qayed said. “In adults, these attributes were used to develop the disease risk index, or DRI, that can stratify patients for overall survival for purposes such as prognostication or clinical trial entry.”

But no such model exists for pediatric patients, Dr. Qayed said, noting that the adult DRI was found to be inaccurate when applied to children.

“[T]he [adult] DRI did not differentiate [pediatric] patients by overall survival,” Dr. Qayed said. “Therefore, knowing that pediatric AML and ALL differ biologically from adult leukemia, and further, treatment strategies differ between adults and children, we aimed to develop a pediatric-specific DRI.”

This involved analysis of data from 1,135 children with AML and 1,228 children with ALL who underwent transplantation between 2008 and 2017. All patients had myeloablative conditioning, and 75% received an unrelated donor graft. Haploidentical transplants were excluded because of small sample size.

Analyses were conducted in AML and ALL cohorts, with patients in each population randomized to training and validation subgroups in a 1:1 ratio. The primary outcome was LFS. Cox regression models were used to identify significant characteristics, which were then integrated into a prognostic scoring system for the training groups. These scoring systems were then tested in the validation subgroups. Maximum likelihood was used to identify age cutoffs, which were 3 years for AML and 2 years for ALL.

In both cohorts, disease status at transplantation was characterized by complete remission and minimal residual disease status.

In the AML cohort, approximately one-third of patients were in first complete remission with negative minimal residual disease. Risk was stratified into four groups, including good, intermediate, high, and very high risk, with respective 5-year LFS probabilities of 81%, 56%, 44%, and 21%. Independent predictors of poorer outcome included unfavorable cytogenetics, first or second complete remission with minimal residual disease positivity, relapse at transplantation, and age less than 3 years.

In the ALL cohort, risk was stratified into three risk tiers: good, intermediate, and high, with 5-year LFS probabilities of 68%, 50%, and 15%, respectively. Independent predictors of poorer outcome included age less than 2 years, relapse at transplantation, and second complete remission regardless of minimal residual disease status.

The models for each disease also predicted overall survival.

For AML, hazard ratios, ascending from good to very-high-risk tiers, were 1.00, 3.52, 4.67, and 8.62. For ALL risk tiers, ascending hazard ratios were 1.00, 2.16, and 3.86.

“In summary, the pediatric disease risk index validated for leukemia-free survival and overall survival successfully stratifies children with acute leukemia at the time of transplantation,” Dr. Qayed said.

She concluded her presentation by highlighting the practicality and relevance of the new scoring system.

“The components included in the scoring system used information that is readily available pretransplantation, lending support to the deliverability of the prognostic scoring system,” Dr. Qayed said. “It can further be used for improved interpretation of multicenter data and in clinical trials for risk stratification.”

In a virtual presentation, invited discussant Nirali N. Shah, MD, of the National Cancer Institute, Bethesda, Md., first emphasized the clinical importance of an accurate disease risk index for pediatric patients.

“When going into transplant, the No. 1 question that all parents will ask is: ‘Will my child be cured?’ ” she said.

According to Dr. Shah, the risk model developed by Dr. Qayed and colleagues is built on a strong foundation, including adequate sample size, comprehensive disease characterization, exclusion of patients that did not undergo myeloablative conditioning, and use of minimal residual disease status.

Still, more work is needed, Dr. Shah said.

“This DRI will need to be prospectively tested and compared to other established risk factors. For instance, minimal residual disease alone can be further stratified and has a significant role in establishing risk for posttransplant relapse. And the development of acute graft-versus-host disease also plays an important role in posttransplant relapse.”

Dr. Shah went on to outline potential areas of improvement.

“[F]uture directions for this study could include incorporation of early posttransplant events like graft-versus-host disease, potential stratification of the minimal residual disease results among those patients in complete remission, and potential application of this DRI to the adolescent and young adult population, which may have slight variation even from the adult DRI.”The study was funded by the National Institutes of Health. The investigators disclosed no conflicts of interest

SOURCE: Qayed M et al. ASCO 2020, Abstract 7503.

A disease risk index is now available for pediatric patients with acute myeloid leukemia or acute lymphoblastic leukemia who undergo allogeneic hematopoietic stem cell transplantation.

The model, which was developed and validated using data from more than 2,000 patients, stratifies probabilities of leukemia-free survival (LFS) into four risk groups for acute myeloid leukemia (AML) and three risk groups for acute lymphoblastic leukemia (ALL), reported lead author Muna Qayed, MD, of Emory University, Atlanta, who presented findings as part of the American Society of Clinical Oncology virtual scientific program.

“The outcome of stem cell transplantation for hematologic malignancy is influenced by disease type, cytogenetics, and disease status at transplantation,” Dr. Qayed said. “In adults, these attributes were used to develop the disease risk index, or DRI, that can stratify patients for overall survival for purposes such as prognostication or clinical trial entry.”

But no such model exists for pediatric patients, Dr. Qayed said, noting that the adult DRI was found to be inaccurate when applied to children.

“[T]he [adult] DRI did not differentiate [pediatric] patients by overall survival,” Dr. Qayed said. “Therefore, knowing that pediatric AML and ALL differ biologically from adult leukemia, and further, treatment strategies differ between adults and children, we aimed to develop a pediatric-specific DRI.”

This involved analysis of data from 1,135 children with AML and 1,228 children with ALL who underwent transplantation between 2008 and 2017. All patients had myeloablative conditioning, and 75% received an unrelated donor graft. Haploidentical transplants were excluded because of small sample size.

Analyses were conducted in AML and ALL cohorts, with patients in each population randomized to training and validation subgroups in a 1:1 ratio. The primary outcome was LFS. Cox regression models were used to identify significant characteristics, which were then integrated into a prognostic scoring system for the training groups. These scoring systems were then tested in the validation subgroups. Maximum likelihood was used to identify age cutoffs, which were 3 years for AML and 2 years for ALL.

In both cohorts, disease status at transplantation was characterized by complete remission and minimal residual disease status.

In the AML cohort, approximately one-third of patients were in first complete remission with negative minimal residual disease. Risk was stratified into four groups, including good, intermediate, high, and very high risk, with respective 5-year LFS probabilities of 81%, 56%, 44%, and 21%. Independent predictors of poorer outcome included unfavorable cytogenetics, first or second complete remission with minimal residual disease positivity, relapse at transplantation, and age less than 3 years.

In the ALL cohort, risk was stratified into three risk tiers: good, intermediate, and high, with 5-year LFS probabilities of 68%, 50%, and 15%, respectively. Independent predictors of poorer outcome included age less than 2 years, relapse at transplantation, and second complete remission regardless of minimal residual disease status.

The models for each disease also predicted overall survival.

For AML, hazard ratios, ascending from good to very-high-risk tiers, were 1.00, 3.52, 4.67, and 8.62. For ALL risk tiers, ascending hazard ratios were 1.00, 2.16, and 3.86.

“In summary, the pediatric disease risk index validated for leukemia-free survival and overall survival successfully stratifies children with acute leukemia at the time of transplantation,” Dr. Qayed said.

She concluded her presentation by highlighting the practicality and relevance of the new scoring system.

“The components included in the scoring system used information that is readily available pretransplantation, lending support to the deliverability of the prognostic scoring system,” Dr. Qayed said. “It can further be used for improved interpretation of multicenter data and in clinical trials for risk stratification.”

In a virtual presentation, invited discussant Nirali N. Shah, MD, of the National Cancer Institute, Bethesda, Md., first emphasized the clinical importance of an accurate disease risk index for pediatric patients.

“When going into transplant, the No. 1 question that all parents will ask is: ‘Will my child be cured?’ ” she said.

According to Dr. Shah, the risk model developed by Dr. Qayed and colleagues is built on a strong foundation, including adequate sample size, comprehensive disease characterization, exclusion of patients that did not undergo myeloablative conditioning, and use of minimal residual disease status.

Still, more work is needed, Dr. Shah said.

“This DRI will need to be prospectively tested and compared to other established risk factors. For instance, minimal residual disease alone can be further stratified and has a significant role in establishing risk for posttransplant relapse. And the development of acute graft-versus-host disease also plays an important role in posttransplant relapse.”

Dr. Shah went on to outline potential areas of improvement.

“[F]uture directions for this study could include incorporation of early posttransplant events like graft-versus-host disease, potential stratification of the minimal residual disease results among those patients in complete remission, and potential application of this DRI to the adolescent and young adult population, which may have slight variation even from the adult DRI.”The study was funded by the National Institutes of Health. The investigators disclosed no conflicts of interest

SOURCE: Qayed M et al. ASCO 2020, Abstract 7503.

A disease risk index is now available for pediatric patients with acute myeloid leukemia or acute lymphoblastic leukemia who undergo allogeneic hematopoietic stem cell transplantation.

The model, which was developed and validated using data from more than 2,000 patients, stratifies probabilities of leukemia-free survival (LFS) into four risk groups for acute myeloid leukemia (AML) and three risk groups for acute lymphoblastic leukemia (ALL), reported lead author Muna Qayed, MD, of Emory University, Atlanta, who presented findings as part of the American Society of Clinical Oncology virtual scientific program.

“The outcome of stem cell transplantation for hematologic malignancy is influenced by disease type, cytogenetics, and disease status at transplantation,” Dr. Qayed said. “In adults, these attributes were used to develop the disease risk index, or DRI, that can stratify patients for overall survival for purposes such as prognostication or clinical trial entry.”

But no such model exists for pediatric patients, Dr. Qayed said, noting that the adult DRI was found to be inaccurate when applied to children.

“[T]he [adult] DRI did not differentiate [pediatric] patients by overall survival,” Dr. Qayed said. “Therefore, knowing that pediatric AML and ALL differ biologically from adult leukemia, and further, treatment strategies differ between adults and children, we aimed to develop a pediatric-specific DRI.”

This involved analysis of data from 1,135 children with AML and 1,228 children with ALL who underwent transplantation between 2008 and 2017. All patients had myeloablative conditioning, and 75% received an unrelated donor graft. Haploidentical transplants were excluded because of small sample size.

Analyses were conducted in AML and ALL cohorts, with patients in each population randomized to training and validation subgroups in a 1:1 ratio. The primary outcome was LFS. Cox regression models were used to identify significant characteristics, which were then integrated into a prognostic scoring system for the training groups. These scoring systems were then tested in the validation subgroups. Maximum likelihood was used to identify age cutoffs, which were 3 years for AML and 2 years for ALL.

In both cohorts, disease status at transplantation was characterized by complete remission and minimal residual disease status.

In the AML cohort, approximately one-third of patients were in first complete remission with negative minimal residual disease. Risk was stratified into four groups, including good, intermediate, high, and very high risk, with respective 5-year LFS probabilities of 81%, 56%, 44%, and 21%. Independent predictors of poorer outcome included unfavorable cytogenetics, first or second complete remission with minimal residual disease positivity, relapse at transplantation, and age less than 3 years.

In the ALL cohort, risk was stratified into three risk tiers: good, intermediate, and high, with 5-year LFS probabilities of 68%, 50%, and 15%, respectively. Independent predictors of poorer outcome included age less than 2 years, relapse at transplantation, and second complete remission regardless of minimal residual disease status.

The models for each disease also predicted overall survival.

For AML, hazard ratios, ascending from good to very-high-risk tiers, were 1.00, 3.52, 4.67, and 8.62. For ALL risk tiers, ascending hazard ratios were 1.00, 2.16, and 3.86.

“In summary, the pediatric disease risk index validated for leukemia-free survival and overall survival successfully stratifies children with acute leukemia at the time of transplantation,” Dr. Qayed said.

She concluded her presentation by highlighting the practicality and relevance of the new scoring system.

“The components included in the scoring system used information that is readily available pretransplantation, lending support to the deliverability of the prognostic scoring system,” Dr. Qayed said. “It can further be used for improved interpretation of multicenter data and in clinical trials for risk stratification.”

In a virtual presentation, invited discussant Nirali N. Shah, MD, of the National Cancer Institute, Bethesda, Md., first emphasized the clinical importance of an accurate disease risk index for pediatric patients.

“When going into transplant, the No. 1 question that all parents will ask is: ‘Will my child be cured?’ ” she said.

According to Dr. Shah, the risk model developed by Dr. Qayed and colleagues is built on a strong foundation, including adequate sample size, comprehensive disease characterization, exclusion of patients that did not undergo myeloablative conditioning, and use of minimal residual disease status.

Still, more work is needed, Dr. Shah said.

“This DRI will need to be prospectively tested and compared to other established risk factors. For instance, minimal residual disease alone can be further stratified and has a significant role in establishing risk for posttransplant relapse. And the development of acute graft-versus-host disease also plays an important role in posttransplant relapse.”

Dr. Shah went on to outline potential areas of improvement.

“[F]uture directions for this study could include incorporation of early posttransplant events like graft-versus-host disease, potential stratification of the minimal residual disease results among those patients in complete remission, and potential application of this DRI to the adolescent and young adult population, which may have slight variation even from the adult DRI.”The study was funded by the National Institutes of Health. The investigators disclosed no conflicts of interest