Nick Mark MD Profile picture
Jun 13, 2022 17 tweets 8 min read Read on X
Yet another large trial of ivermectin is now complete & the results are negative.

ACTIV-6 found no difference in mortality or hospitalization when people with COVID were randomized to ivermectin.

Yet another nail in the ivermectin ⚰️

Preprint medrxiv.org/content/10.110…

1/
ACTIV6 is a large placebo controlled RCT performed at 93 sites in the 🇺🇸 by @DCRINews

It enrolled adults >30yo w symptomatic COVID. They were randomized to either ivermectin or placebo.

The primary endpoints were death, Hospitalization, & symptoms
clinicaltrials.gov/ct2/show/NCT04…
2/
It was a “fully decentralized study”, meaning patients could be enrolled remotely & medication shipped to their home (via next day mail). Follow up was either remote or in person.

Theoretically this is a great pragmatic way to enroll a large number of people in a trial.
3/
The trial has multiple arms & tested multiple doses of ivermectin:
- Low dose was 400 mcg/kg x 3 days (this is what was just published as a pre-print)

- High dose was 600 mcg/kg x 6 days (this is definitely a high dose; it is still ongoing)
4/
The study enrolled n=1559, and n=817 were assigned to ivermectin and n=774 to placebo.

The patients had a median age of 47 yo, with the typical comorbidities.

~1/2 were unvaccinated & 1/2 had received 2 or more vaccine doses.

Median time from symptom onset to tx was 6 days
5/
The results were stone cold negative.

People treated with ivermectin had no decrease in hospitalization or mortality. The event rate was very low however; only one death occurred in the study, which was in the ivermectin arm.
6/
What’s with the low event rates?

3-4% rates of hospitalization or ED visit certainly are lower than we’ve seen in most studies. (Compare to the EPIC-HR study of paxlovid)

But recall that ACTIV6 didn’t enroll only high risk patients & and it did enroll vaccinated people.
7/
Time to symptom resolution (or conversely mean time unwell) was not clinically or statistically different: 10.96 days vs 11.45 days.

Even with the most optimistic priors the likelihood that ivermectin shortens symptoms by even one day is <1%.

8/
Fortunately at this dose (400 mcg/kg x3 days) there were few adverse effects. So while ivermectin does not appear to be doing anything beneficial at least it isn’t harmful.

(It will be interesting to see what the AEs look like at a higher dose given for longer).
9/
So what can we conclude from this?
In a large randomized double blind placebo controlled study performed in the US, ivermectin failed to demonstrate *any* significant clinical benefit.

Like *every* high quality RCT (I-TECH, EPIC, IVERCORCOVID, TOGETHER) this was negative.
10/
I’m sure the usual crowd of ivermectin zealots will opine, so let’s try to anticipate & respond to their criticisms:

11/
“ThE dOsE wAs ToOoO Low!”
This was the same dose proponents claimed was effective back in 2020 & 2021.
RCTs using a higher dose have also been negative (see I-TECH). Another arm of ACTIV6 is looking at 600 mcg/kg x 6 days. I’m not holding my breath that it will be different
12/
“ThEy StArTeD tReAtMeNt ToOoO late”
The median was 6 days after symptom onset. This seems like a long time to wait for “early therapy.” However if we look at the subgroup who got treatment earlier (within 3 days of onset) they did… no better than those at 5, 7, or 9 days.
13/
“WhAt aBoUt UTTAR PRADESH!?”

The UP narrative has been pretty thoroughly debunked. The COVID stats from UP are dubious; entire districts show no deaths from *ANY* cause for months. Either IVM literally prevents death from EVERYTHING or the data is 🗑
onepagericu.com/blog/debunking…
14/
“ThIs StUdY iS fAaAke!”

I see no evidence of any glaring errors but I’m curious to see what peer reviewers find.

Notably the #CultOfIvermectin accuses any negative study of being fake but still haven’t admitted that Elegazzar & others actually were. It’s been a year…

15/
“Why are we still talking about this?”

Good question!

Most of the US is vaxxed; ~90% adults have had ≥1 shot. Most peoples interest in ivermectin is waning

But with many cults, as more is disproved, the more zealously the #CultOfIvermectin believes

16/
I started debunking ivermectin because I was tired of watching people taking it die of COVID in my ICU.

No amount of high quality studies will ever convince the high priests & priestesses of ivermectin. But perhaps a few more of their vulnerable followers can be saved.
17/17

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More from @nickmmark

Oct 13
#HurricaneHelene damaged the factory responsible for manufacturing over 60% of all IV fluids used in the US, leading to a major national shortage.

As clinicians what can we do to about the #IVFluidShortage and how can we prevent this crisis from happening again?

A thread 🧵
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There are many things we can do as clinicians to improve ICU care & reduce IVF use.

1️⃣Don't order Maintenance IV Fluid!
Almost no patient actually needs continuous IV fluids.
Most either need resuscitation (e.g. boluses) or can take fluid other ways (PO, feeding tube, TPN).
2/
Frequently if someone is NPO overnight for a procedure, MIVF are ordered.
This is wrong for two reasons.
We are all NPO while asleep & don't need salt water infusions!
We should be letting people drink clears up to TWO HOURS before surgery, per ASA.

3/ pubs.asahq.org/anesthesiology…Image
Read 16 tweets
Oct 1
New favorite physiology paper: Central Venous Pressure in Space.

So much space & cardio physiology to unpack here including:
- effects of posture, 3g shuttle launch, & microgravity on CVP
- change in the relationship between filling pressure (CVP) & LV size
- Guyton curves!
1/

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To measure CVP in space they needed two things:
📼 an instrument/recorder that could accurately measure pressure despite g-force, vibration, & changes in pressure. They built & tested one!
🧑‍🚀👩‍🚀👨‍🚀 an astronaut willing to fly into space with a central line! 3 volunteered!
2/
Image
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The night before launch they placed a 4Fr central line in the median cubital vein & advanced under fluoro.

🚀The astronauts wore the data recorder under their flight suit during launch.

🌍The collected data from launch up to 48 hrs in orbit.
3/
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Read 16 tweets
Jul 16
The media silence on this is deafening.

Did he have a head CT? What did it show?
Did he have stitches? Tetanus shot?

The NYT ran nonstop stories about Biden’s health after the debate but can’t be bothered to report on the health of someone who was literally shot in the head?
To the people in the replies who say it’s impossible because of “HIPPA”
1. I assume you mean HIPAA
2. A normal presidential candidate would allow his doctors to release the info. This is exactly what happened when Reagan survived an assassination attempt.
washingtonpost.com/obituaries/202…
My advice to journalists is to lookup tangential gunshot wounds (TGSW).

Ask questions like:
- what imaging has he had?
- what cognitive assessments?
- has he seen a neurosurgeon or neurologist?
- he’s previously had symptoms like slurred speech, abnormal gait - are these worse?
Read 4 tweets
Jun 30
You've probably heard "don't give lactated ringers because it raises lactate"

This statement is ~98% false, but there's one crucial practice-changing fact that you need to know.

A 🧵 all about lactic acid and lactated ringers!
1/
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First off, we should ackowledge the obvious: Lactated ringers does in fact contain lactate... 28 mEq/L in fact

BUT there's one little detail to remember:
Lactate ≠ Lactic acid

When we measure "lactate" we care about the ACID (H+) which lowers pH & causes organ dysfunction
2/ Image
But the correlation between pH & lactate is really bad!

Look at this analysis of lactate vs pH in 171 ICU patients.

There is a *weak* correlation in people with arterial lactate > 5, but even w/ lactate =10, pH ranged from 7.5 to 7.05. Quite a spread!

3/ ncbi.nlm.nih.gov/pmc/articles/P…
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Read 10 tweets
Jun 13
If you intubate you need to read the #PREOXI trial!
-n=1301 people requiring intubation in ED/ ICU were randomized to preoxygenation with oxygen mask vs non-invasive ventilation (NIV)
-NIV HALVED the risk of hypoxemia: 9 vs 18%
-NIV reduced mortality: 0.2% vs 1.1%

#CCR24
🧵
1/

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Hypoxemia (SpO2 <85%) occurs in 10-20% of ED & ICU intubations.

1-2% of intubations performed in ED/ICU result in cardiac arrest!

This is an exceptionally dangerous procedure and preoxygenation is essential to keep patients safe.

But what’s the *BEST* way to preoxygenate?
2/
Most people use a non-rebreather oxygen mask, but because of its loose fit it often delivers much less than 100% FiO2.

NIV (“BiPAP”) delivers a higher FiO2 because of its tight fit. It also delivers PEEP & achieves a higher mean airway pressure which is theoretically helpful!
3/
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Read 15 tweets
Jun 12
Results from #PROTECTION presented #CCR24 & published @NEJM.
- DB RCT of amino acid infusion vs placebo in n=3511 people undergoing cardiac surgery w/ bypass.
- Reduced incidence of AKI (26.9% vs 31.7% NNT=20) & need for RRT (1.4% vs 1.9% NNT=200)

Potential game changer!

🧵
1/
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I work in a busy CVICU & I often see AKI following cardiac surgery.

Despite risk stratification & hemodynamic optimization, AKI remains one of the most common complications after cardiac surgery with bypass.

Even a modest reduction in AKI/CRRT would be great for my patients.
2/ From Nature reviews nephrology  https://www.nature.com/articles/nrneph.2017.119
During cardiac surgery w/ bypass, renal blood flow (RBF) is reduced dramatically. This causes injury, especially in susceptible individuals.

But what if we could use physiology to protect the kidneys?

Renal blood vessels dilate after a high protein meal increasing RBF & GFR!
3/ https://www.jtcvs.org/article/S0022-5223(18)33243-4/fulltext
Read 11 tweets

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