Tony Breu Profile picture
14 Sep, 14 tweets, 5 min read
1/14
Why do we feel cold (i.e., experience "chills") when we have a fever? Shouldn't we feel hot?

And what are rigors?

Answers to these questions will help us better understand when we should obtain blood cultures.

When do you think is the best time to draw them?
2/
Bacteremia exposes us to exogenous pyrogens. For example, the cell wall of gram-negative rods contains lipopolysaccharide (LPS; endotoxin).

When injected into humans LPS induces fever. But, there is a 3-5 hour delay between exposure and peak fever.

pubmed.ncbi.nlm.nih.gov/4897836/
3/
The delay between clinical bacteremia and fever was demonstrated in 1932 by Weiss and Ottenberg.

Their conclusion: Obtain blood cultures BEFORE fever. If only it were easy to predict future fevers!

[Maybe we can as you'll see in tweet 10 below.]

academic.oup.com/jid/article-ab…
4/
Why is there a delay between bacteremia and fever?

There's a lot to be done!

◾️LPS induces endogenous pyrogens (e.g., IL-6) which...
◾️Increase the hypothalamic set-point, resulting in...
◾️Thermogenesis, vasoconstriction, etc., and...
◾️Fever

pubmed.ncbi.nlm.nih.gov/9759682/
5/
During this period between bacteremia and fever we may feel cold (i.e., we experience chills).

Why? There are at least two possible explanations.

1⃣Peripheral vasoconstriction → fall in skin temperature → "I'm cold!"
2⃣Direct central signal → "I'm cold!"

Which is it?
6/
In one study, subjects were placed in water at a stable temperature and injected with a pyrogen.

Before fever, they felt cold. This was despite a stable skin temperature.

🔑chills must therefore arise from some central action of pyrogens

pubmed.ncbi.nlm.nih.gov/7189863/
7/
Why would an "I'm cold!" signal be sent?

This signal drives behavioral changes that aid with heat retention as our body aims to raise core temperature.

"I'm cold!" propels us to put on a blanket, seek shelter, etc.

🔑We ARE cold compared with what our body wants us to be!
8/
If we require a rapid increase in temperature we might also experience violent shivering.

aka shaking chills
aka RIGORS

The muscle contractions of rigors result in rapid heat production (thermogenesis) aiding fever onset.

pubmed.ncbi.nlm.nih.gov/14405791/
9/
We don't always require the rapid-onset fever that rigors produce. But bacteremia is a scenario where it might make sense.

So, is there an association between rigors and bacteremia?

Yes!

In fact, rigors predictor bacteremia better than fever.

pubmed.ncbi.nlm.nih.gov/22851117/
10/
Should we say "culture if shakes" instead of "culture if spikes"?

Maybe. Remember the order of events:

1⃣Bacteremia
2⃣Increased temperature set-point
3⃣"I'm cold" and4⃣Rigors
5⃣Fever

Chills and rigors should appear before a fever. And closer to the bacteremia.
11/
While rigors occur closer to bacteremia than fever (and therefore better predict positive cultures), there is still a delay. They're not perfect.

But, if you obtain blood cultures within 2 hours of rigors there is increased likelihood of positivity.

pubmed.ncbi.nlm.nih.gov/30059771/
12/
Before concluding, let me re-ask a version of the original question.

If you could obtain blood cultures at any of the following periods, which would you choose?
13/ - SUMMARY - Part 1
🔳The order of events: bacteremia and exogenous pyrogen exposure → increase temperature set-point → chills/rigors → fever
🔳We may feel cold chills as a cue to drive behavioral change (e.g., put on a sweater)
🔳Rigors promote rapid heat production
14/14 - SUMMARY - Part 2
🔳By the time fever occurs, bacteremia may have already cleared
🔳Because rigors occur before fever (i.e., temporally closer to bacteremia), they are better predictors of positive blood cultures
🔳Neither is perfect

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More from @tony_breu

20 Sep
1/5
Why is meperidine (Demerol) particularly good at treating rigors?

This is another association I learned early in training without hearing a potential mechanism.

For the second installment in my fevers, chills, and rigors tweetorial follow-up, let's have a brief look.
2/
The ability of meperidine to treat fevers and rigors associated with amphotericin B was demonstrated in 1980 in a SMALL randomized, placebo-controlled trial.

Percent with cessation of side effects with 30 minutes:
☞ Meperidine: 100%
☞ Placebo: 30%

pubmed.ncbi.nlm.nih.gov/7362377/ Image
3/
Meperidine is able to treat rigors (and post-anesthesia shivering) by lowering the shivering threshold.

The same temperature that would typically result in rigors isn't low enough after the use of meperidine.

pubmed.ncbi.nlm.nih.gov/9158353/ Image
Read 7 tweets
17 Sep
1/4
Why does amphotericin B lead to rigors and fever?

I learned about his side effect by the moniker "shake and bake" (thank you First Aid).

Let's have a brief look at this commonly tested side-effect.
2/
Amphotericin B was introduced in the 1950s.

It was clear early on that fevers and chills were common side effects.

More contemporary data show lower - though still relevant - rates of both side effects.

pubmed.ncbi.nlm.nih.gov/13749466/ - 1960
pubmed.ncbi.nlm.nih.gov/10072411/ - 1999
3/
When thinking back to the mechanism of fever, recall that PGE₂ is a key mediator.

Amphotericin B leads to an increase in PGE₂. This is likely the mechanism of chills and fever.

As this study shows, amphotericin B acts in a similar way to LPS!

pubmed.ncbi.nlm.nih.gov/3309074/
Read 5 tweets
1 Sep
1/6
Does hemochromatosis (HH) protect against Mycobacterium tuberculosis (MTB) infection?

If so, how could that be?

◾️MTB needs iron and HH is associated with overload
◾️MTB resides within macrophages, a site of iron storage

It seems that MTB should thrive in HH. Does it?
2/
It turns out that the distribution of iron overload in HH is not uniform. It preferentially accumulates within parenchymal (e.g., heart, liver, pancreas) cells.

One place it remarkably spares?

Macrophages of the reticuloendothelial system!

pubmed.ncbi.nlm.nih.gov/1115031/
3/
How is this discrepancy explained?

Monocytes from patients with HH release twice as much iron as normal human monocytes after RBC phagocytosis.

pubmed.ncbi.nlm.nih.gov/9746792/
Read 7 tweets
29 Aug
1/13
Why is ferritin elevated in anemia of chronic inflammation?

If the evolutionary point was/is to keep iron away from bacteria, why is our main maker of iron stores elevated?
2/
Let's start by reviewing a few key features of iron. First, recall that it has high redox potential. As a result, it is:

🔳Beneficial: Utilized for myriad cellular functions

And

🔳Potentially harmful: Creates damaging reactive hydroxide radicals

pubmed.ncbi.nlm.nih.gov/10787336/
3/
Based on its role in cellular functions and its ability to cause cell and tissue damage, it is unsurprising that >99% of iron is intracellular.

And the iron that's extracellular is bound to proteins (e.g., transferrin).

pubmed.ncbi.nlm.nih.gov/10787336/
Read 14 tweets
15 Aug
1/
Why is our thirst immediately quenched after the ingestion of water?

As we'll note, it takes ~10 minutes for serum osmolarity to change. And yet thirst drops far more rapidly.

Something must be bypassing the blood...
2/
Though I suspect we all agree that thirst is quenched rapidly after a sip of water, some of you will demand data.

If you infusion 5% saline, thereby increasing osmolarity, thirst shoots up. But, as soon as drinking is allowed, thirst drops.

pubmed.ncbi.nlm.nih.gov/19523569/ Image
3/
Notice that in the experiment in tweet 2, the serum osmolarity had NOT dropped when thirst plummeted.

This is because it takes 10+ minutes for ingested water to be fully absorbed into the bloodstream, decreasing osmolarity.

link.springer.com/article/10.375… Image
Read 8 tweets
15 Aug
1/16
Why do patients with primary polydipsia continue to drink, sometimes to the point of severe hyponatremia?

To answer this question, we'll have to explore what makes us thirsty.

Grab a beverage and read on! Image
2/
Cases of primary polydipsia in patients with psychiatric illnesses have been reported for decades.

While thirst isn't always mentioned as the primary driver, it is present often enough to suspect it has a role.

pubmed.ncbi.nlm.nih.gov/14185641/
pubmed.ncbi.nlm.nih.gov/1551044/ Image
3/
One driver of thirst is osmolarity.

As osmolarity increases, the subfornical organ (SFO) and the organum vasculosum of the lamina terminalis (OVLT) sense these changes and send projections to other brain structures.

The result: thirst

pubmed.ncbi.nlm.nih.gov/30699320/ Image
Read 16 tweets

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