From the Editor

Is there a role for haloperidol in the treatment of delirium in ICU settings? That may seem like an unusual question since many patients receive this medication, perhaps half. But evidence is light.

In the first selection, Dr. Nina C. Andersen-Ranberg (of the University of Southern Denmark) and her co-authors consider ICU delirium with a new RCT, published in The New England Journal of Medicine. In this elegant study, half of the patients were randomized to receive haloperidol (in the IV form) and the other half received a placebo. They find: “Among patients in the ICU with delirium, treatment with haloperidol did not lead to a significantly greater number of days alive and out of the hospital at 90 days than placebo.” We consider the paper.

In the second selection, Dr. Scott B. Patten (of the University of Calgary) and his co-authors analyze hospital admissions and psychiatric diagnoses before and after the start of the pandemic. In this Canadian Journal of Psychiatry paper, they draw on Alberta data. Noting an existing literature on eating disorders, they also find an increase in patients with personality disorders being admitted. “[T]he increase was more pronounced than the widely reported increase in admissions for eating disorders.”

And, in the third selection, Dr. Richard M. Boulay (of St. Luke’s University Health Network) weighs in on physician mental health. In this highly personal New England Journal of Medicine paper, the gynecologic oncologist describes the problems of a second-year surgery resident who almost dies by suicide. He feels that she was failed by her program and medical culture itself. He writes: “[S]olutions are available. It’s time we began looking after our own.”

DG

Selection 1: “Haloperidol for the Treatment of Delirium in ICU Patients”

Nina C. Andersen-Ranberg, Lone M. Poulsen, Anders Perner, et al.

The New England Journal of Medicine, 29 December 2022

Delirium is defined as an acute disturbance in attention and awareness and is the most common sign of acute brain dysfunction among critically ill patients. The condition is estimated to affect 30 to 50% of patients being treated in the intensive care unit (ICU) and is associated with increased morbidity and mortality.

Haloperidol, a typical antipsychotic compound, continues to be the most frequently used agent to treat delirium in ICU patients. Results of an international inception-cohort study that were published in 2018 showed that approximately half the ICU patients with delirium received haloperidol. The use of haloperidol is not supported by clinical practice guidelines because evidence of its effect is limited. A recent systematic review of trials comparing haloperidol with other pharmacologic interventions for the treatment of delirium in ICU patients identified only one placebo-controlled trial and concluded that the evidence for the use of haloperidol to treat delirium in ICU patients was sparse and inconclusive.

So begins a paper by Andersen-Ranberg et al.

Here’s what they did:

“In this multicenter, blinded, placebo-controlled trial, we randomly assigned adult patients with delirium who had been admitted to the ICU for an acute condition to receive intravenous haloperidol (2.5 mg 3 times daily plus 2.5 mg as needed up to a total maximum daily dose of 20 mg) or placebo. Haloperidol or placebo was administered in the ICU for as long as delirium continued and as needed for recurrences. The primary outcome was the number of days alive and out of the hospital at 90 days after randomization.”

Here’s what they found:

  • 510 were randomly assigned to the haloperidol group and 490 to the placebo group. 13 patients were excluded after randomization.
  • Demographics. Most were older (mean age of 70 in the haloperidol group; 71 in the placebo group), male (64.7% and 66.9%), and some used tobacco (31.2% and 30.2%).
  • Delirium. “At the time of randomization, 447 patients had hyperactive delirium and 540 patients had hypoactive delirium.”
  • Days alive. “At 90 days, the mean number of days alive and out of the hospital was 35.8… in the haloperidol group and 32.9… in the placebo group, with an adjusted mean difference of 2.9 days… (P=0.22).”
  • Mortality. “Mortality at 90 days was 36.3% in the haloperidol group and 43.3% in the placebo group (adjusted absolute difference, −6.9 percentage points…).”
  • Adverse reactions. “The number of patients with one or more serious adverse reactions was similar in the two groups.”

A few thoughts:

1. This is an impressive study with much to like: multicenter, randomized, blinded, placebo-controlled trial, and published in a big journal.

2. The finding in a sentence: at 90 days, haloperidol didn’t best placebo for days alive or out of hospital. (!)

3. In other words, by this measure, haloperidol didn’t do much – despite the incredible clinical use.

4. But is the study narrow in its consideration of haloperidol? In an accompanying Editorial, Dr. Edward R. Marcantonio (of Harvard University) puts the results in a larger context.

Edward R. Marcantonio

He writes: “They remind us that our current knowledge base does not exclude that treatment of delirium with antipsychotics, even haloperidol, may be relatively safe and beneficial in a subgroup of patients in the ICU. This trial highlights the need for future studies that will fully characterize the subgroup of patients who are most likely to benefit and that will provide a better understanding of the mechanisms underlying any such positive outcomes. In the meantime, clinicians will have to continue to individualize treatment on the basis of patient characteristics and target symptoms, administering the lowest dose of the least toxic drug for the shortest time possible and carefully monitoring for adverse events.”

5. Like all papers, there are limitations. The authors note several including: “The low number of patients from international sites may limit the generalizability of the findings.”

The full NEJM paper can be found here:

https://www.nejm.org/doi/full/10.1056/NEJMoa2211868

Selection 2: “Hospital Admissions for Personality Disorders Increased During the COVID-19 Pandemic”

Scott B. Patten, Gina Dimitropoulos, Jeanne V.A. Williams, et al.

The Canadian Journal of Psychiatry, 14 February 2023  Online First

In Canada, the COVID-19 pandemic was associated with more negative self-perceived mental health in the general population, with a greater impact in younger age groups. A study of Ontarians aged 10+ found a decrease in emergency department visits and hospital admissions soon after the onset of the pandemic, followed by a subsequent return to prepandemic levels. In distinction, increased hospital admissions for eating disorders have been reported globally and in Canada.

So begins a paper by Patten et al.

Here’s what they did:

  • “We sought to explore whether increased admissions occurred in diagnostic categories other than eating disorders by obtaining Alberta hospital discharge data for all hospital admissions having a most responsible diagnosis of a mental disorder.”
  • They focused on the 10-26 age range.
  • They looked at 3-month intervals around the WHO declaration of the pandemic.
  • Admission rates were stratified by diagnostic groups and diagnoses with the authors doing regression analyses.

Here’s what they found:

“[F]or eating disorders an increase starting at about 6 months was followed by a gradual reduction in admission rates, trending back towards prepandemic levels. Confidence intervals (95%) for the 6- to 9-month postpandemic interval were distinct from those of prepandemic levels indicating that the difference was unlikely to arise by chance, consistent with prior literature. Upon stratification, this increase was found to be exclusively due to AN (F50.0) and Atypical AN (F50.1), which is unsurprising since Bulimia Nervosa rarely leads to hospitalization. Stratification by age and sex was unsuccessful due to imprecision in the stratum-specific estimates.”

“Only one other diagnostic category showed a substantial increase during the pandemic, which was the Personality Disorders category… which showed a distinct increase after about 9 months. Of admissions in this category, 77% fell within the ICD F60.3 category of Emotionally Unstable Personality Disorders, a code most often used for the DSM-5 category of Borderline Personality Disorder, the category of personality disorder most likely to lead to hospitalization…There is no clear reduction in the months following the declaration, but there is a subsequent increase that peaks at 12–15 months postpandemic onset, with confidence intervals distinct from those of prepandemic rates.”

A few thoughts:

1. This is a short paper with important findings.

2. Others have noted the rise in admissions for those with eating disorders. For American data, see this JAMA Pediatrics paper:

https://jamanetwork.com/journals/jamapediatrics/fullarticle/2798255

3. The implications? The authors note several: “This observation has implications for pandemic preparedness of generic psychiatric inpatient resources, and not merely for the specialized inpatient resources often used by eating disorder patients. For example, in areas where personality disorder admissions are managed in short-stay or crisis support units, these may need increased resources during public health emergencies.”

The full CJP paper can be found here:

https://journals.sagepub.com/doi/10.1177/07067437231155999

Selection 3: “Looking After Our Own”

Richard M. Boulay

The New England Journal of Medicine, 16 February 2023

‘If you follow me, Dr. Boulay, she’s in ICU-10,’ the intensivist began, walking me down the labyrinthine corridors. ‘She remains delirious, but her rigidity is improving. Her head CT, bloodwork, and tox screen are normal. We just sent an LP. She’s still tachy to 180, but her pressure is holding. She’s not any worse in the few hours she’s been here, but she’s no better. Her husband brought in her empty antidepressant bottles. Our working diagnosis is serotonin syndrome.’

‘A suicide attempt?’ I ventured.

‘Just a hypothesis, sir. Any thoughts?’

My mind was a whirlwind. Although I’ve cared for countless ICU patients, this case was personal: she was one of our own — a second-year surgical resident.

And my firstborn daughter.

So begins a paper by Dr. Boulay.

He describes the gravity of the situation. “I steeled myself to confront a medical challenge and a parental hell. My doctor-self surveyed the patient. She appeared younger than her 27 years, thin and frail, restless and delirious. Brownian motion contained by a Posey. She spoke in gibberish and medical jargon. She performed a daily exam on an invisible patient, reassuring him that she heard his concerns and would return with the ‘Big Guy’ to develop a plan. Her head, wrapped in gauze channeling EEG leads, tossed on her pillow.”

Needless to say, the moment sparks many memories, including when she was young child. “At 3, when she fell and scraped her knee, I held her as her prolonged inhalation gave way to an unending wail.”

He notes that she has struggled, including with suicidal thoughts, in her senior year of university, but was able to recover. “She learned and practiced the tenets of self-care. Her sleeping and eating patterns normalized. And after a 2-month absence, the music of her spontaneous giggle returned.” Fortunately, she graduated on time.

But life in residency was different. “Work hours, often exceeding 90 per week, left no time to establish care in a new state. A 5:00 a.m.-to-7:30 p.m. schedule precluded online appointments. Prescriptions lapsed. The stressors of caring for the gravely ill during a pandemic turned an already-impossible job into one saturated in toxicity and hopelessness.” She relapsed into a depressive episode – and then attempted.

Physically, she shows improvement in the ICU – but he writes about an unsympathetic program. “Late on day 4, she finally awoke, recognized us, spoke clearly, and confirmed the working hypothesis. A suicide attempt. Relief, terror, joy, and apprehension comingled… On day 5, her program director called me, asking when she planned to return: she hadn’t answered his calls or emails, and he had a schedule to finalize. His concern ended there.” Indeed, he goes on to describe a general lack of support from her program.

Dr. Boulay comments on physician suicide:

  • “I lost a medical school classmate in 1989, shortly before graduation; he’s been followed by 12,000 U.S. physicians, at a rate of one per day — twice the suicide rate of the general population.”
  • “A 2015 meta-analysis found that as many as 43% of residents reported depressive symptoms.”
  • “Studies identify risk factors: untreated mental illness, substance abuse, sleep deprivation, stress, burnout.”

A few thoughts:

1. This is a moving and deeply personal essay.

2. Dr. Boulay makes good points, including a criticism of residency training – and of medical culture itself. “Practitioners in other fields pride themselves on protecting one another. Firefighters race into burning buildings to rescue trapped comrades. Soldiers brave enemy fire to retrieve the wounded from the battlefield. Yet we purported healers tolerate stacks of body bags filled with our dead colleagues, after people like me have failed to understand the depth of their suffering.” Ouch.

3. The New England Journal of Medicine has published important papers and correspondence on physician burnout and mental health in recent years. The Fang et al. letter – tying resident work hours to depression symptoms – was particularly strong. (This wasn’t considered in a past Reading, but we’ve recently interviewed Dr. Srijan Sen, a co-author, for a podcast.) The letter can be found here: https://www.nejm.org/doi/full/10.1056/NEJMc2210365

The full NEJM can be found here:

https://www.nejm.org/doi/full/10.1056/NEJMp2214345

Reading of the Week. Every week I pick articles and papers from the world of Psychiatry.