Olanzapine + Benzodiazepines

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Today, I’m going to touch on the co-administration of olanzapine with benzodiazepines.

Data is controversial regarding this, but the co-administration has not been studied in depth, which is why it is not currently recommended to give both. 

What’s the FDA’s stance?

“Concomitant administration of intramuscular olanzapine along with benzodiazepines is not recommended due to the potential for excessive sedation and cardiorespiratory depression.”

This advisory came about after there were 160 adverse events and 29 fatalities associated with IM olanzapine in 2005. 


Possible side effects of co-administration: Severe hypotension, respiratory depression

Why the FDA warning?

There was a study (n=29) looking at patient fatalities involving the administration of olanzapine.

3/29 fatalities involved olanzapine monotherapy.

1/29 fatalities involved IM olanzapine + benzodiazepine dual therapy

25/29 fatalities involved IM olanzapine + PO/IM/IV benzodiazepines + many other medications

The interesting thing about the study is that 12 patients died over 24 hours after administration of the medications. So it’s difficult to determine causality. 

Some olanzapine quick facts:

  • Olanzapine is an atypical antipsychotic

  • Side effect profile includes: neuroleptic malignant syndrome, hyperglycemia, constipation, dry mouth, tachycardia, orthostatic hypotension

    • Mortalities and increased risk of cerebrovascular accidents have been linked to elderly patients with dementia

  • IM olanzapine is 5 times more potent than PO olanzapine. 

  • ½ life: 21-54 hours

  • Peak: within 15-45 minutes

Why is this conversation controversial?

Well, if you look at the data regarding co-administration < 60 minutes apart studied in 41 patients, you see that their vitals are actually fine.

**** 4 Key takeaways ****

  1. According to the European Medicines Agency, it’s likely safe to administer olanzapine and a BZD at least 60 minutes apart. 

  2. It’s safer to use PO agents over IM agents. Our ED pharmacy team does not recommend administering IM of both. 

  3. Avoid co-administration particularly in high risk groups: elderly, dementia, acute alcohol intoxication, or patients requiring polypharmacy.

  4. If you’ve already used olanzapine, and you’re looking for an additional agent, ketamine is likely a safer option.

References: 

https://www.aliem.com/combination-parenteral-olanzapine-benzodiazepines-agitation-adverse-events/ 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6125121/ 

https://foamcast.org/2019/10/29/black-boxed-medications-in-the-ed-acep-2019/ 

https://meridian.allenpress.com/mhc/article/8/5/208/37281/Coadministration-of-intramuscular-olanzapine-and 

Why is dialysis free?

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Today, I’ll be touching on kidney failure and the reimbursement structure in the United States. As we all know, there’s been decades of debate regarding universal healthcare in the US. However, dialysis is different – lucky for you, your kidneys are completely covered under Medicare.

What part of kidney disease is covered under Medicare?

In 1972, President Nixon and Congress signed a bill ensuring free dialysis and renal transplants for US citizens. On average, Medicare covers 80% of dialysis costs. Medicare covers most of the costs for kidney transplants, and Medicare B covers 80% of immunosuppressant medication costs.

Quick stats:

  • Roughly 750,000 people in the US have kidney failure. 

  • ~550K patients get dialysis each year, and the numbers each year keep rising.

  • ~200K patients have kidney transplants in the US.

  • Over 100,000 patients are on the kidney transplant list. ~20-22K patients get kidney transplants each year.

What’s the cost to Medicare?

On average, each dialysis patient costs Medicare about $90,000/year. This totals $28 billion/ year, and composes roughly 7% of Medicare spending. 

The racial disparities:

African Americans represent 35% of dialysis patients, despite making up only 13% of the US population. Hispanics/Latinos, Native Americans, and Pacific Islanders are also much more likely to have kidney disease.

Types of dialysis:

There are two types of dialysis: hemodialysis and peritoneal dialysis. About 90% of US patients get hemodialysis in the US.

~12% of ESRD patients receive HD at home in the US, while the remainder receive it at dialysis centers. Not all countries work like this. Some countries favor peritoneal dialysis at home. For reference, over 80% of ESRD patients get peritoneal dialysis at home in Hong Kong.

The controversies:

I’m not going into the controversies too much about in-center dialysis. You can quickly Google it, or ask John Oliver about it. Just a few things to note: the US has some of the highest mortality rates for ESRD patients in the world, despite the highest spending. Shocking, I know. There are some theories about this: 

  • Per federal guidelines, a doctor does not need to present at the HD center. 

  • Only one nurse must be present at the facility. Many for-profit dialysis centers have minimal staffing.

  • Quick patient turnover leading to poor sanitation practices and higher infection rates.

Morbidity & mortality:

Not surprisingly, kidney failure portends a bad prognosis. There’s a 20% mortality rate within 1 year of starting HD, with a large fraction falling into the initial 90 day period. The 5 year survival rate is about 50%. 

On the other hand, kidney transplant receivers have a survival rate > 80% over 5 years.

The 2 most common causes of death for dialysis patients are:

#1 Cardiovascular disease and sudden cardiac death

#2 bacteremia (26x higher risk than the general population)

  • ¾ are from gram+ bacteria. Most commonly from Staph Aureus, MRSA, Staph epidermidis. 

  • Also gram- ¼ of the time: E Coli, Klebsiella.

Tell me more about home hemodialysis?

There are three types of *home* hemodialysis (not peritoneal dialysis.) It takes a bit of legwork for a patient to arrange this, but it is possible.

  1. Conventional home HD: Q2D, 3-4 hours long; just like the center

  2. Short daily home HD: 5-7 times per week, lasting about 2-3 hours

  3. Nocturnal home HD: QD or Q2D, lasting roughly 6-8 hours

****If there is ANYTHING to take away from this post, please remember this:****

Some patients are never informed about kidney transplants. I recommend quickly having a conversation with your dialysis patients to ensure they are educated about it. As you can see from above, there’s a huge survival benefit. Patients have to contact a transplant center to get added to the waitlist: https://optn.transplant.hrsa.gov/about/search-membership/ 

References:

https://www.washingtonpost.com/news/powerpost/paloma/the-health-202/2019/07/11/the-health-202-the-government-funds-kidney-dialysis-for-all-who-need-it-but-the-program-needs-fixing/5d25f517a7a0a47d87c570ac/ 

https://www.kidney.org/atoz/content/homehemo 

https://pharm.ucsf.edu/kidney/need/statistics#:~:text=Hemodialysis%20care%20costs%20the%20Medicare,patient%20care%20is%20%243.4%20billion

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5099594/

Posterior Reversible Leukoencephalopathy Syndrome (PRES)

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PRES: Posterior reversible leukoencephalopathy syndrome. 

It usually consists of a constellation of features, including:

  • AMS or encephalopathy** – in ~¾ of patients

  • Seizures** – in ~⅔ of patients

    • Often the presenting symptom

  • Headache – in ~½ of patients; global, gradual, refractory to meds

  • Visual changes - in ⅓ of patients

  • Hypertension - may precede the neurologic syndrome by ~24 hours

    • Most common key contributing fracture is a rapid increase in blood pressure

      • In the context of hypertension, PRES is equivalent to hypertensive encephalopathy 

      • BP can related to pre/eclampsia

    • The BP can be normal in ~20% of patients

  • Nausea / vomiting

The symptoms typically progress rapidly over hours or days.

Risk factors:

  • Hypertension – Pre/eclampsia 

  • Renal disease

  • Immunosuppressive meds, e.g.: tacrolimus and cyclosporine, high dose corticosteroids

  • Low magnesium

  • Transplant patient 

Pathophysiology:

  • Usually affects the posterior circulation of the brain

  • Cerebral endothelial dysfunction

  • Failure of autoregulation – usually the cerebral arterioles constrict with HTN

    • If autoregulation fails, the brain experiences high blood pressures

  • Vasogenic cerebral edema due to decreased integrity of the blood brain barrier 

Dx: 

  • MRI will show cerebral edema on the T2-weighted image in the posterior white matter

    • The edema is typically bilateral 

  • PRES is a diagnosis of exclusion

  • Ddx: 

    • R/o stroke, ICH, malignancy, eclampsia, meningoencephalitis, metabolic encephalopathy

Tx:

  • Remove causative factors like immunosuppressive meds

  • Replete magnesium if hypoMg or pre/eclampsia

  • Antiepileptics – benzos are firstline; keppra second line

  • Antihypertensives

    • Options: nicardipine, clevidipine, labetalol

    • Goal to reduce BP by 20-30% within 1 hour

Prognosis:

  • Proper treatment can reduce long term sequelae. 

  • 10-44% can have persistent neurologic deficits 

  • Overall mortality: 3-6%

  • Recovery takes a several days typically 


References:

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