Climate Change in Medicine (Murphy, 4/24/2024)

Thanks so much for a wonderful Grand Rounds this week -- a somber and thought provoking and hopeful presentation-- from SRFMR Alumnus Dr. Sarah Murphy on Climate Change in Medicine. A recording of the presentation can be found HERE. 

My notes:

Dr. Murphy began her presentation with the concept of Planetary Health and the question What if the planet were our patient? As family doctors, we can definitely all understand this question because anyone, really anyone, can be our patient, and the interconnectedness of the health of families and communities and our world are central to the work we do every day. 

Consider these thought-provoking statements about the relationship between human health, our planet's health, and health professionals' role:

• “Human health and the health of our planet are inextricably linked, and our civilization depends on human health, flourishing natural systems, and the wise stewardship of natural resources.” (2015 Rockefeller Foundation-Lancet Commission on Planetary Health)
• “Health professionals have an essential role in the achievement of planetary health: working across sectors to integrate policies that advance health and environmental sustainability, tackling health inequities, reducing the environmental impacts of health systems, and increasing the resilience of health systems and populations to environmental change.”

Climate change in 10 words, From Yale Program on Climate Change

Scientists agree.

It's real.

It's us.

It's bad.

. . . There's hope.

Climate change has a direct impact on human health across many different domains. Here are just a few concrete examples:

1. Extreme heat>>dehydration, heat stress (particularly children, elders), MI/CVA, altered mental status, food insecurity, higher food costs, etc.
2. Outdoor air quality>>smoke, high pollen counts, short and long-term health effects (including small and large particles that can cause acute disease, but also smaller particles that cross alveoli and can lead to long-term impacts on IQ, heart disease, obesity, etc. And then there's indoor air quality. . .
3. Flooding>>rising sea levels, more intense precipitation, hurricanes, leading to displacement, water-borne diseases, drowning, etc.
4. Vector born infection>>rising temperatures change the range of vectors, increasing Lyme disease distribution, mosquito-born illness (e.g. dengue) and increasing risk particularly for children, who are outside playing close to the earth often at dawn and dusk
5. Food born infection>> toxic algae blooms, increase rates of campylobacter, cholera crypto. Increased diarrheal disease
6. Mental health. Dr. Murphy introduced the idea of "eco-anxiety" or "eco-grief" that has three components: 1) acute or past physical ecological loss, 2) the loss of environmental knowledge and 3) anticipated future loss.

Ecological grief and anxiety

What kind of ecological grief do you see around you? What kind of climate change (aka eco-anxiety) do you personally experience or see in your clinical practice? How do we support patients in dealing with this kind of grief?

Participants at Grand Rounds shared their own grief and anxiety after the 2017 Tubb's wildfire, concerns about family lands destroyed by flooding in India, loss of salmon runs in Alaska. And more. We all have stories.

Graphic from paper: Ecological grief and anxiety: the start of a healthy response to climate change?

Dr. Murphy urged us rather than think about these responses as pathological, perhaps we reframe them as reasonable and functional responses. The key is what do we do with these feelings? Do we acknowledge them in ourselves? Do we ask patients about them? Do we have outlets to build community and affect change driving by the need to respond to these emotions? 

Climate change, health disparities and inequities

Unsurprising to those of us who practice in the safety net, there is intersection between social determinants of health and social vulnerability. Our most vulnerable populations suffer the greatest health impacts of climate change. 

For more information, check out the CDC+UCSF Pediatric Environmental Toolkit available at:  https://www.atsdr.cdc.gov/emes/health_professionals/pediatrics.html

https://peht.ucsf.edu/index.php

There is a subset of the toolkit that focuses on environmental exposures linked to climate change and gives providers key information and good tips on anticipatory guidance in well-child checks

The healthcare system's direct impact on Planetary Health Don't forget that the healthcare industry, in general, and hospitals, specifically, contribute a tremendous amount of waste and greenhouse gases that only compound climate change. 8.5% of US total waste is healthcare sector waste. If healthcare were our own nation, we would rank 13th in greenhouse gas emissions. This also doesn't take into account supply chain waste, single use waste, water and sanitation issues.

And yet, even still there is hope.

Hope you say?

Yes.

Yet among this crisis we have an opportunity: Our best science tells us that the The severity of climate-related health risks is highly dependent on how well health systems can protect people.

With timely, proactive and effective adaptation many risks for human health and wellbeing can be reduced and some potentially avoided (very high confidence) 

Read this article from UW: Hope Health and the Climate Crisis (Frumkin, 2022). Frumkin tells s that hopeful people feel better, hope leads to action, and hope is empirically justified.

What can healthcare providers do?

• We can vote with our wallet (spend money where it matters and buy things that are good for the planet)
• OR Buy LESS (se second hand, repurporse)
• Talk with patients about the health impact, their actions, and their eco-grief
• Enjoy the outdoors -- having a relationship with our planet will help us protect our planet
• Join a group that is doing advocacy

Take the examples of Dr. Plastic Picker (a Kaiser pediatrician in southern CA who is modeling beach cleanup and climate change action), Climate Health Now (Drs. McLure and Millstein, CA advocacy group) or anesthesiologists who are advocating to decresae their use of gases.

Looking for more resources. Here are a TON!!

Global Consortium on Climate and Health Education:
https://www.publichealth.columbia.edu/research/global-consortium-climate-and-health-education

Medical Society Consortium on Climate and Health
https://medsocietiesforclimatehealth.org/

Healthcare Without Harm Physician & Nurse Network
https://noharm-uscanada.org/HealthyClimate

Practice Greenhealth
https://practicegreenhealth.org/topics/climate-and-health/climate-and-health

Health Care Climate Challenge – for hospitals & health systems

Climate Resources for Health Educ - https://climatehealthed.org/

U of CO Climate & Health Program – diplomat/fellowship
https://medschool.cuanschutz.edu/climateandhealth

Citizens’ Climate Lobby
Project Drawdown: The World’s Leading Resource for Climate Solutions

Films/videos/books
Solving for Zero
Braiding Sweetgrass – Robin Wall Kimmerer
This Changes Everything - Documentary
Talking about Climate Change: https://ourclimateourfuture.org/video/secret-talking-climate-change/
Katharine Hayhoe TED Talk: The Most Important thing you can do about Climate Change? Talk about it!

Thyroid Hormonal Disease (Magnotti, 4/17/2024)

 A recording of this presentation is available HERE.

***

Thanks to Dr. Mike Magnotti, SMGR Endocrinologist, for an excellent presentation on Hypo and Hyperthyroid. This was a jam-packed presentation. Check out the link above or my notes below.

Hypothyroidism

Hypothyroidism is characterized by non-specific and relatively common constellation of symptoms, including fatigue, weight gain, mental cloudiness, cold intolerance, etc. Plenty of people with these symptoms believe they have thyroid disease (and will even feel better on thyroid replacement), but this doesn't mean they actually have thyroid disease. 

Of note, weight gain is a known symptom of hypothyroidism, but obesity is not generally caused by hypothyroidism. Treating a patient's hypothyroidism can help mood, mental acuity, and focus but likely little (if any) weight loss.

Also of note, alopecia 2/2 hypothyroid takes a very LONG time to get better -- 6 months to 1 year, even with normalization thyroid hormone. Patients need to either be patient or use another med (e.g. Rogaine) in the meantime.

The only test you need to diagnose hypothyroidism is TSH. A normal TSH range is 0.5 to about 5 and excludes thyroid disease (except in very rare cases). Always want to check twice (there are lots of transient highs that can self-resolve), on repeat TSH, also check FT4, consider thyroid antibodies (not recommended in guidelines). Ft4 distinguishes between subclinical and clinical hypothyroidism. Antibody results do NOT change treatment, but can be helpful to patients to know WHY they have hypothyroid. No need to monitor antibodies -- levels change due to immune system activity and do not indicate illness state. 

High TSH, low FT4--> overt hypothyroidism, treat with levothyroxine

High TSH, normal FT4--> subclinical hypothyroidism, consider treatment**

If thyroid antibodies are elevated, dx is most likely Hashimoto's thyroiditis

TSH increases with age. A TSH of 6-8 may be normal in patients >70 years old; TSH can also be low in younger people (0.3-0.5 can be normal in young).

**Treat patients with subclinical hypothyroidism if they have symptoms, if TSH>10 (even no symptoms because of reduced risk CAD), TSH 7-10 if under 65. Only treat elderly patient <7 if you really believe they are symptomatic. 

Note: Biotin supplements alter the ability of the assay to detect thyroid hormones (it doesn't change actual thyroid hormone). Must be high dose biotin-- e.g. those in hair and nail formulations. Should avoid products with biotin 3 days before the assay. Biotin generally makes people look hyperthyroid (Low TSH, high FT4)

Treatment of hypothyroidism

Treatment of hypothyroidism is Levothyroxine (T4)

1.6 mcg/kg/day is the FULL replacement dose of thyroid hormone (patients with NO thyroid will need this full dose)

• If older patient, start slow to avoid cardiac issues, arrhythmia
• Younger person with a very HIGH TSH probably needs most of the high replacement dose right up front. If they have a lower TSH, can start with 1/2 the dose
• take 30 minutes before food, 4 hours before calcium/iron/vitamin (absorption). 
• brand does NOT matter unless someone has intolerance to fillers/dyes in a certain brand
• Tirosint brand is a gel cap formulation with no filler, also liquid version, theoretically has least likelihood of having adverse reaction, but very expensive
• For rare patients who are super sensitive to batch variations, use the same brand to maintain consistent
• Only use TSH to monitor (goal is anywhere in the normal range), titrate to patient's feeling about how they feel
• no need to monitor T3 levels, which vary more with stress and illness (helpful in hyperthyroidism)
• Never use T3 alone! Our system has no way to regulate T3 levels in our body. T3 is the more active form. There is internal regulation of conversion T4>T3 (e.g. hospitalized patients have inhibition of conversion, normal stress response), but T3 is unregulated.
  

T3/T4 combination not generally recommended as first line treatment because most people feel fine on T4 alone. T3 is converted to T4 via deiiodinase. There are some (rare) patients with reduced ability to convert T4 to T3 (no ability is not compatible with life). Most people feel better on T3 because it gives them more energy. T3 makes people feel better like caffeine makes people feel better. 

• Most trials adding T3 to T4 show no benefit, though a few studies show some benefit. Hard to quantify symptoms energy, focus, sleep. Some people feel a rush when they take T3. 
• Consider adding T3 if patients are not better on T4 (but not an excessive amount)
• T3 has a very short half-life (needs to be taken am/pm, e.g. 7am, 3pm)
• Armour thyroid formulation (pig and cow thyroid) contains more T3 than normal human (4:1 ratio T4:T3 in Armour, humans generally have T4: T3, 13-16:1)
• if you check T3 levels, you will see relatively high T3, low T4 and normal TSH
• more variability from batch to batch (higher risk over-replacement)
• Dr. Magnotti generally does not recommend Armour, unless a patient is stable on it and you are just continuing it
• If you want to give T3, should dose separately
• T4 is 4x potent as T3
• Goal is maintain ratio T4/T3 13-16:1, e.g. 5mcg T3, 75mcg T4
• T3 only comes as 5mcg and 25 mcg. Generally don't use 25mcg pills
• Do NOT use T3 in pregnancy (doesn't cross placenta, so mom can be euthyroid and baby can be hypothyroid)
• Only monitor via TSH, symptoms

Secondary hypothyroidism is VERY rare. Unlikely to be de novo or surprising diagnosis. Patients with known pituitary tumor, history of pituitary or sella radiation, other pituitary hormone deficits (prolactin, LH, FSH). In these rare patients, TSH is useless. You treat using FT4 to monitor, goal mid normal.

Hypothyroid in pregnancy

• As soon as woman is pregnant, increase the dose up front 20-30% (right away) because risk of hypothyroidism on the fetus is WAY higher than hyperthyroidism 
• Check TSH q4 weeks (up through the second trimester)
• No T3 alone in pregnancy 
• Current goal in pregnancy is TSH<2.5
• Immediately after delivery, back to usual delivery
• Recheck TSH 8-12 weeks post partum (not too soon) because lots of women have post partum thyroiditis, which can confuse things and make you worried they have levothyroxine too high
• Let patient symptom guide 

If patient diagnosed with hypothyroidism during pregnancy. Guidelines vary about screening. 

BUT . . .

If TSH>4, treat

If TSH <2.5, no treatment

If between 2.5-4, check TPO, especially if recurrent miscarriage.

Starting dose based on level of TSH. If above 15-20, be more aggressive

Recheck 4 weeks even though not fully equilibrated.

***

Hyperthyroidism can definitely be more complex than hypothyroidism; there are more causes to consider, and the treatment is more nuanced.

Best first test for hyperthyroidism is TSH.

• If TSH is LOW, check BOTH FT4 and FT3 (elevations in either can cause overt disease),
• Also check TSI and/or TRAB (same test, different assay). 
• If Ab positive, your patient almost certainly has Grave's disease.
• If TSH is LOW, but BOTH FT4 and FT3 are normal>> this is by definition, subclinical hyperthyroid. 
• Treat subclinical hyperthyroidism if TSH<0.1 (or <0.3 if older, atrial fibrillation).
• CV risks of hyperthyroidism are definitely increased when TSH<0.1.
• If TSH is NORMAL with elevations in FT4 or FT3, this either secondary hyperthyroidism (VERY very very rare) OR T4 resistance (genetic)
• Refer to endocrine.

Additional lab findings: isolated elevation in alk phos is common with significant hyperthyroidism, will go down when treated. Transaminitis can be caused by methimazole but sometimes is also seen in hyperthyroidism.

Causes of hyperthyroidism

Grave's disease is by far the main cause of hyperthyroidism (75-80%, especially in younger patients), toxic multinodular goiter relatively more common in older population, also single functional nodule. Knowing the cause of hyperthyroidism doesn't impact who needs to be treated but can influence treatment decisions. 

• +TSI and no palpable nodules on exam (usually sizeable on exam, 2-4 cm) >> patient almost certainly has Grave's disease (no scan needed)
• -TSI and/or no nodules on exam >> need uptake scan (to r/o functional nodule)
• If palpable nodule>> need both ultrasound and uptake scan
• Toxic multinodular goiter usually is HUGE, nodular on exam

NOTE: If TSH is NOT close zero, the radioactive uptake scan is not reliable (even at 0.2 or 0.3, scan will generally be normal). If you cannot get uptake scan, ultrasound can be helpful (even without nodules). they evaluate blood flow. If blood flow is low, likely thyroiditis. High blood flow, likely Grave's. 

If no uptake>> likely dx thyroiditis (unless people taking iodine supplements, kelp, seaweed, or recent contrast in last 3 months. Amiodarone can also cause no uptake, even 3 months after taking it.

If normal or increased uptake>> dx Grave's

If uptake in single nodule>> dx toxic solitary nodule

Patchy uptake all around >> toxic multinodular goiter

Treatment of hyperthyroidism

3 options: methimazole, iodine (I-131), thyroidectomy. Beta blocker for symptom management

Methimazole is first line for most causes. 

Methimazole 10 mg/day, 20 mg/day, 40 mg/day for mild (<2x ULN), mod (2x ULN), severe (>2x ULN) disease, respectively. Taper down to 5-15mg (usual maintenance dose). Leave people on methimazole for 1-2 years before stopping. Want to be sure to have negative TSI (antibody) if they have positive to begin with. Don't stop methimazole in anyone who still has antibody at the receptor (+TSI is causing the hyperthyroidism).

There are some exceptions.

• Iodine should be considered for young women who desire pregnancy and people without eye disease
• Younger women who desire pregnancy may benefit from treatment with iodine treatment because methimazole can take years to get into remission. 
• Can get pregnant 6-9 months, need normal TSH (with levothyroxine). 
• Even after 3-4 years, with methimazole may not be in remission. Delays childbearing.
• Iodine is also great for single toxic nodule because people will come out euthyroid. Likely curative. Normal gland not affected. 
• Very severe hyperthyroidism in a younger person, especially with a large gland, they are very unlikely to have long-term remission at all with methimazole. Consider iodine vs. surgery.
• Surgery may be best option if need to get thyroid hormone levels down quickly. It will still take weeks (body has to metabolize FT4 already floating around)
• Consider surgery in case of: 1) very large goiter,  2) need for rapid correction, 3) concern for malignancy, 4) combo hyperthyroid+ hyperparathyroidism

Hyperthyroid eye disease: Send to neuro-ophtho if thyroid eye disease. Iodine can worsen thyroid eye disease. (if mild, can do Iodine with 3-4 months of prednisone to protect against progression). 

Hyperthyroid in pregnancy: 

Do NOT treat subclinical disease. 

Use PTU in first trimester, change to methimazole in 2nd and 3rd trimesters.

Target Total T4 and Total T3 in the high normal range, which is 1.5x ULN for pregnancy range due to higher estrogen, binding globulin. 

Prenatal Genetic Screening (Mullin, 4/10/2024)

 A recording of this presentation is available HERE. 

***

Many thanks to Dr. Briga Mullin for an excellent presentation this week on Prenatal Genetic Testing. Dr. Mullin reminded us from the get go -- that all patients have the right to accept or decline testing after counseling. Then she proceeded to update us on current prenatal genetic screening recommendations available to prenatal care providers and to pregnant patients. 

This topic is ever-changing, as genetic screening tools become increasingly sophisticated. If you want to watch the entire presentation, please see the link above. Here are my notes.

It is important to make the distinction for patients and ourselves between SCREENING and DIAGNOSTIC tests. As we know, screening tests are those designed to "pick up" disease in patients who are otherwise well-appearing; in the case of prenatal genetic screening, they are designed to assess a pregnancy for the risk of certain congenital conditions. Diagnostic tests are designed to confirm a specific diagnosis. 

In the world of prenatal genetic testing, current screening tests available to pregnant patients include: carriers testing, cell free DNA (cfDNA), AFP, early 1st tri and 2nd trimester ultrasound. The two currently available prenatal diagnostic tests are chorionic villous sampling -- CVS-- (10-13 weeks) and amniocentesis (>15 weeks).

Carrier Screening

Carrier screening looks for autosomal recessive and x-linked conditions in maternal DNA.  There is a huge range of options for carrier testing -- patients can be tested for up to 400 conditions, depending on the assay. ACOG currently recommends universal carrier screening for three conditions: 1) spinal muscular atrophy (SMA), 2) cystic fibrosis (CF), and 3) hemoglobinopathies. ACOG additionally recommends carrier screening for specific populations: Fragile X if a family history of intellectual disabilities and Tay Sachs disease for people who identify as Ashkenazi Jews, French Canadians and people of Cajun descent.

Sutter/CPMC currently offers a 112 gene expanded carrier screening panel (called "Horizon" by Natera). In contrast, SRCH -- via Quest labs -- offers a 3-condition carrier panel, which includes CF, Fragile X and SMA. 

Of note, it is only necessary to screen maternal serum once in a lifetime, ideally before pregnancy. If a patient screens positive for any of these conditions, the partner should be offered carrier testing as a follow-up. If BOTH parents screen positive, diagnostic testing via CVS, amniocentesis or even IVF with embryo testing are options.

Cell Free DNA (cfDNA)

cfDNA tests look for placental DNA in maternal serum. Typically, cfDNA screens for three trisomies - Trisomy 18 (Edwards Syndrome), 21 (Down Syndrome) and 13 (Patau Syndrome).  cfDNA is 98% sensitive in detecting these three trisomies. The gender of the fetus can also be identified with cfDNA. Testing is ideally done after 9-10 weeks gestational age because enough placental DNA is present at this time in the maternal serum to reliably detect and test. Of note, placental mosaicism does exist and can lead to a false positive screening test with cfDNA.

The California Genetic Disease Screening Program (GDSP) currently offers statewide cfDNA through their prenatal screen program to all patients with Medi-Cal. Their test detects Trisomy 18, 21, and 13 and gives gender  as well. As of 4/1/2024, the GDSP program will also test for chromosomal aneuploidies.   

Natera's Panorama screen, available to some privately insured patients, screens for for additional conditions. These tests cost between $170 and $300 out of pocket if not covered by insurance.

Early Anatomy Ultrasound (previously called nuchal translucency or NT ultrasound)

This ultrasound is generally performed at 10-13 weeks and is offered to detect severe structural anomalies (e.g. anencephaly). Given that it is only 70% sensitive for Down Syndrome, NT should no longer be used for screening over cfDNA. Arguments for doing an early anatomy ultrasound is to allow women to be able to terminate a pregnancy with severe structural anomalies as early as possible. 

Maternal Serum Alpha Feto Protein (MSAFP)

For many of us in practice, this OG of prenatal genetic screening tests. It is a maternal serum test done between 15-20 weeks EGA and still has utility in the detection of neural tube defects (e.g. spina bifida) and abdominal wall defects (e.g. omphalocele and gastroschisis). Recommendations are evolving but it does screen for defects that are not otherwise picked up on cfDNA and can be done prior to a second trimester ultrasound, and so some guidelines encourage using it in addition to cfDNA for this reason, particularly for higher risk patients (e.g. family history, maternal age, etc).

Second Trimester Ultrasound (Anatomy survey)

This is another screening tool that has a decently long history -- usually an ultrasound performed between 17-21 weeks EGA to look at the fetal anatomy. In actuality, there are two versions of this ultrasound: the original Level 1 ultrasound, performed by a radiology tech with static images interpreted by a radiologist and Level 2 ultrasound, performed by a maternal-fetal-medicine (MFM) physician. Level 1 ultrasounds have historically been considered adequate for "low risk" pregnancies, but local practice has evolved such that most pregnant women in Santa Rosa are offered a Level 2 ultrasound as the screening test of choice. This is, of note, not a current ACOG recommendation. Some argue that Level 2 ultrasounds have less false positive findings because of the skill of the technician performing the study. 

***

Regardless of which modality of prenatal genetic screening you are discussing with patients, the concept of shared decision-making is absolutely central to the practice of prenatal care. Shared decision making with pregnant patients should be 1) clear 2) objective and 3) non-directive. This can be challenging at times and take time to elicit a patient's values and goals as part of this discussion. 

There are patients for whom knowledge will absolutely change the way they experience their pregnancy. Some who might terminate or choose to deliver in a different setting based on the findings. There are others for whom the anxiety of choosing a screening modality that could return a false positive result is not worth it. See the slide image below to consider ways in which shared decision making can be considered for different types of patients. 

Remember that a positive screening test is not the same as a positive diagnostic test. The follow-up for most positive prenatal screens is either a CVS or amniocentesis. 

Positive Predictive Value

Also remember that positive predictive value of any test depends on the prevalence of that disease in the population, and in pregnancy, this is extremely dependent on maternal age. So, a positive cfDNA in a 40 year pregnant patient has very different implications than a positive cfDNA in a 20 year old patient. Dr. Mullin recommends the use of the prenatal screen calculator to help you help your patients understand their positive screening test.

That calculator is available here: NIPT Predictive Value Calculator      (https://ppv.geneticsupportfoundation.org/). See the images below to understand how a very highly sensitive screening test still gives very different PPV based on baseline risk. For example, note that a positive screen for Trisomy 21 in a 20 year old woman is still only going to turn out to be a true Trisomy 21 50% of the time. In contrast, a positive screen in a 39 year old woman will be true 91% of the time.

There is local help!

If you have a patient with a positive prenatal genetic screening test, our local MFM consultants are available to help you. Here's how to contact them: CPMC Sonoma Ave number: 707-569-7366 to reach on call Genetic Counselor and or MFM 

Phenobarbital for inpatient alcohol withdrawal (Bowen, 4/3/2024)

 A recording of this presentation can be found HERE.

***

Thanks to Dr. Anna Bowen, our future addiction medicine fellow (2024-2025), who gave an excellent talk this week on the use of Phenobarbital for Inpatient Alcohol Withdrawal. Dr. Bowen compiled the evidence for phenobarbital as well as a variety of phenobarbital protocols from different health systems. She urged us to create/modify one of our own at SSRRH, which seems like an excellent idea. 

My notes on her presentation:

• Alcohol use disorder is very common in the US! 10.5% of the US population (+29 million people) over age 12 quality has having an AUD
• In 2021, there were an estimated 178K deaths related to excessive alcohol use in the US. Alcohol is one of the leading causes of preventable deaths in our country
• Complicated alcohol withdrawal syndrome (AWS) occurs in 5-20% of hospitalized patients
• Alcohol use is responsible for nearly double the number of deaths per year as opiates

Most of us are well aware of the time course for AWS. See image below for a reminder. Remember that alcoholic hallucinosis, which often occurs early in the course, is a distinct entity from the more life-threatening delirium tremens (DTs). 

Our standard treatments for AWS include: 1) Benzodiazepines (the historic gold standard), 2) anti-epileptic drugs (including valproic acid, gabapentin, carbamazepine), and 3)Alpha-adrenergic blockers (clonidine, precedex and guanfacine).

Phenobarbital is a new old drug! It has recent (and growing) evidence for non-inferiority to the historic goal standards -- benzodiazepines-- as treatment for AWS. And in several studies, it is superior. It acts at both the GABA and NMDS receptors.

Studies of phenobarbital in AWS demonstrate:

• shorter ICU stays, decreased ICU admissions
• shorter hospital length of stay (LOS)
• lower rates of mechanical ventilation
• lower rates of adjuncts (including precedex, benzos)

Granted these studies, most recent -- between 2017 and 2023-- are all small (~100 patients each) and there are variable comparisons between different protocols, BUT in taken in totality, phenobarbital seems to have similar and/or better evidence for treatment of AWS compared to traditional treatment. If the goal is to decrease ICU admits and/or use of benzodiazepines in at-risk populations, phenobarbital is probably the tool of choice. 

So, how should it be used?

Dr. Bowen showed us 5 protocols from 5 different healthcare systems: Swedish (WA), BMC (MA), Yale (Connecticut), Contra Costa (CA) and ZSFGH (CA). While they have their own unique differences, there are three main steps to using phenobarbital in AWS:

1) Assessing risk for AWS (i.e. risk stratifying patients who screen positive for AUD for high risk AWS)

2) Understanding the risks/benefits of phenobarbital in different populations

3) Dosing protocols

Assessing for risk of Severe AWS

The benzo-sparing protocol that we currently use in the hospital -- often referred to as the Stanford Protocol --  uses the PAWSS score to risk-stratify for high risk AWS. Alternate protocols use other criteria to designate patients as high risk. These high risk characteristics include 1) a history of intubation or prior ICU stay for AWS 2) BAL>200 with signs of withdrawal despite high BAL, and/or 3) a personal history of seizures or DTs.

Whatever the methodology, the first step in treating AWS is the determination of this risk stratification. This will lead you to either treat or not treat prophylactically for AWS.

Understanding Risks/Benefits and Contraindications of Phenobarbital

Those of us who didn't "grow up" using phenobarbital may be less familiar with the pharmacology and/or risks and contraindications for phenobarbital. Here are a few important ones:

• Concomitant high dose administration of benzodiazepines. Several protocols use <8mg lorazepam as an acceptable cut-off for liberal admin of phenobarbital. If a patient has received >20mg of lorazepam, phenobarbital is contraindicated
• Respiratory depression (as a result of benzos or otherwise) makes patients high risk
• Advanced cirrhosis WITH active hepatic encephalopathy and/or AMS is considered a contra-indication. But a prior history of HE or well controlled HE is not. Of note, cirrhosis itself is NOT a contraindication to use of phenobarbital
• Patients on chronic seizure meds (including phenobarbital) is a relative contraindication
• Pregnancy
• Renal dysfunction (CrCl<30)
• History of allergy and/or Steven's Johnson syndrome

It is important to check for drug-drug interactions with phenobarbital (warfarin, OCPs, furosemide). 

Also important to know that the half-life of phenobarbital is 40-140 hours, this is VERY long, which is a big reason it is desirable to use in AWS (which can go on for days), but also to know it will stay in a patient's system and can have an impact over several days time. 

Patients with cirrhosis will clear phenobarbital more slowly, so a PO taper and/or repeated doses are less needed

AND that if administered slowly (either via slow IV or IM), the risks of respiratory depression as a negative side effect are decreased. 

Phenobarbital Protocols

Actual administration and dosing protocols vary widely across systems. Variations include: 

• Weight based vs. standard dosing
• 5 to 10 to 15mg/kg IDEAL BODY WEIGHT loading doses vs. 130mg vs. 260mg doses
• Single dose vs. subsequent 
• as often as q30-60 minutes dosing with respiratory effects noted prior to additional dosing
• IV vs. IM administration (vs. PO)
• +/- PO taper after initial admin
• Location of administration
• ED vs. ICU vs. step-down units vs. medical floor patients

See images below for some of the protocols. Note variations in dosing, admin, etc. The final image is a table comparing the main components of the protocols:

summary Table comparing different phenobarb protocols in AWS

Here's what I took home from Dr. Bowen's talk:

• Phenobarbital is a safe tool in our toolbox for management of AWS in many of our high risk patients
• We should risk assess all patients for AWS and consider phenobarbital for patients who we deem "high risk"
• Phenobarbital should ideally be administered early -- within the first 24 hours of that risk assessment
• We should be careful about the use of all adjuncts -- including benzos, as well as benzo-sparing protocols -- when using phenobarbital due to its long half-life and risks for respiratory issues
• We need a system for monitoring respiratory depression in patients who receive phenobarbital
• We can give a large loading dose (10-15mg/kg IBW) in a highly monitored environment (e.g. ED or ICU) or lower amounts (e.g. 130-260mg x 1) with frequent rechecks for respiratory depression
• Phenobarbital is safe in cirrhotic patients (except those with active HE) but with the understanding that it probably stays around even longer for these patients. No need for PO taper. 

I look forward to collaborating with Dr. Bowen and our ED in the coming months so that we can use phenobarbital more systematically for our high risk patients for AWS.