The Pyramid Scheme - Adrenal Emergency

A young pediatric patient is having nausea and vomiting at school and is said to not be 'staying awake very well.' You discover assessment findings such as hypotension, hypoglycemia, and maybe even peaked T waves on the ECG. You receive information indicating that the child has something called "CAH". Or, perhaps...

An older patient is having dizziness upon standing, and persistent hypotension. You note a somewhat jaundiced appearance. They become unconscious in their kitchen while searching for a salty snack, and they appear rather sick. Or...

A middle-aged patient has suddenly stopped taking their high-dose prednisone for their asthma and is now feeling very weak and cannot stand.

We already know what this episode is about - adrenal insufficiency. However, what if those scenarios up above were in the form of a test question? Or worse yet, a real patient? Would we be aware of what's causing the signs and symptoms, and what the appropriate treatment is? Endocrinology does not get the respect it deserves in EMS, probably due to its low volume - we just do not see that many patients with endocrine emergencies outside of diabetes. Or do we, and we just don't notice?

The adrenal glands are pyramid-shaped glands that sit on top of the kidneys.

The outer cortex has three parts:

The outermost - Zona Glomerulosa (Aldosterone)

The middle - Zona Fasciculata (Cortisol)

The innermost - Zona Reticularis (Androgens)

The medulla is under the cortex - it secretes epinephrine and norepinephrine.

Image version of the above video:

The Adrenals are Cool

The very first thing I ever learned about the adrenal glands was that there was an ABSOLUTE CONTRAINDICATION TO GIVING EPINEPHRINE :) which was called pheochromocytoma (a very difficult word to teach EMT student Sam). This thought of an epinephrine secreting tumor ran through my mind every time that I looked over the med bag during rig check. Disease states such as Addison's, Cushing's Myxedema Coma, Graves Disease, Diabetes Mellitus and Insipitus, etc., were also covered, but I found these diseases very difficult to understand and remember, maybe with the exception of type 1 and 2 DM.

We'll just hit one of these processes today, which is what happens when the adrenal cortex stops producing sufficient amounts of a couple of hormones - cortisol and aldosterone (and how to fix it). The pathways that the adrenal glands use to maintain homeostasis are super cool, and I think you'll find them easier to understand than you thought they were in school.

Normal Function

We'll stick to the middle and outer areas of the cortex since those are the areas that aldosterone and cortisol are secreted.

The outermost layer of the cortex is the zona glomerulosa, and it secretes aldosterone. This is obviously an important part of the RAAS (renin-angiotensin-aldosterone system) (Fountain, 2021). Remember how that goes?

RAAS

1. Renin (from the kidneys) + Angiotensinogen (from the liver) = Angiotensin I.

2. Angiotensin I converted to angiotensin II by ACE (angiotensin-converting enzyme) (from the lungs).

3. Angiotensin II in and of itself causes some sodium and water retention, but it also travels to other locations:

• Vascular system - causes vasoconstriction

• Hypothalamus - causes thirst

• Pituitary - maintains baroreceptor function, ADH secretion

And of special note...

• Adrenal Cortex - sodium and water retention

It turns out that through such diseases as primary adrenal hyperplasia / Addison's disease, or congenital adrenal hyperplasia (CAH), you can have a lack of this aldosterone all on its own (New, 2017). You can probably guess from the function it has in the RAAS system, that a lack of aldosterone would cause a lack of sodium retention, and therefore a lack of water retention - nice! This can cause hypotension from hypovolemia since we're losing too much volume into our urine. In the nephrons, aldosterone pumps potassium into the urine and pumps sodium back into the blood (which water follows). Aldosterone also helps pump hydrogen ions out into the urine and helps reabsorb bicarbonate into the blood.

Low sodium (hyponatremia) is one of the symptoms that we're looking for, and now we know why it occurs. The diseased portion of the adrenal cortex that is responsible for aldosterone secretion isn't working, so we see low sodium, and low blood volume which may be causing hypotension.

What about the other layer, the zona fasciculata? This layer is for cortisol production. Normally when we hear about cortisol, we think of the bad stuff. We've all heard that cortisol is the 'stress hormone', and that it makes you gain abdominal weight, and 'shuts down' your immune system, and so on. However, cortisol is an essential hormone in the body, and its list of functions is not short. Just for reference, here are some of the things that cortisol does:

• Liver: Gluconeogenesis, glycogen storage.

• Pancreas: Decreased insulin secretion

• Cardiovascular: Increased sensitivity to catecholamines

• Renal: Sodium reabsorption, potassium excretion

If we had a lack of cortisol, can you see how some of that stuff on the list would get pretty messed up?

Liver: The liver isn't making much sugar out of protein or fat (gluconeogenesis), and it's also not storing any glycogen for later use. This sounds like a recipe for possible hypoglycemia...

Pancreas: The pancreas is no longer being appropriately regulated as regards its insulin secretion, so it will likely secrete too much insulin. This sounds like more problems that will cause hypoglycemia...

Cardiovascular: The cardiovascular system isn't responding very well to catecholamines (especially in the vasculature), so this could cause some hypotension all on its own.

Renal: The renal system is becoming even worse at retaining sodium, and therefore water. This is (again) causing the patient to lose too much volume (causing hypotension), just like the issue with aldosterone above. However, in addition to this, the patient is also not secreting enough potassium, which leads to hyperkalemia. This hyperkalemia could also be exacerbated by hemoconcentration due to low circulating intravascular volume.

Let's make sure we have our list complete:

1. Hypoglycemia

2. Hyperkalemia

3. Hyponatremia

4. Hypotension due to hypovolemia

Clearly, we need aldosterone and cortisol for homeostasis. Any type of disease that interferes with adequate amounts of aldosterone and cortisol being secreted into the system can cause the above clinical findings.

As a quick side note, I put some references below that link to articles about sodium correction and osmotic demyelination syndrome information. And this is an interesting case report. As a quick reminder, leaving sodium low (especially in the presence of hypoglycemia) can cause increased ICP from cerebral edema (due to low serum OS). Correcting the sodium too quickly can cause osmotic demyelination syndrome. A middle ground must be met to prevent either one from occurring.

Getting back on track... Is there anything else that would lead us towards a diagnosis of adrenal insufficiency?

In Addison's disease, it's often reported that a patient will have hyperpigmentation (typically a bronze appearance to the skin), which can be especially noticeable over joints.

Image retrieved from: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)31680-9/fulltext

Just to round out a little of the pathophysiology, I'll present an awful, evil graph that's used all over the place.

Was that hard to look at? We won't focus a ton on this, but it is worth breaking down these pathways briefly. Just for reference, solid white arrows are working pathways, and dotted red arrows are broken pathways (Nicolaides, 2017).

In primary adrenal insufficiency, you get low cortisol and aldosterone because the adrenal gland itself is not functioning normally. This means that no matter how much ACTH tries to get the adrenal gland to work, it's just beating a dead horse. Since cortisol is never made (because the gland doesn't work), a signal is never sent to the hypothalamus or the pituitary to stop the production of their signaling hormones (so CRH and ACTH are high because they're never turned off by cortisol).

In secondary, we have a pituitary problem. The pituitary cannot send ACTH to the adrenal glands, so they never make any cortisol. Without cortisol, a message is never sent back to the hypothalamus or the pituitary to turn them off (even though the hypothalamus is the only thing working in this state). In this state, we have high CRH, but low ACTH and cortisol.

In tertiary, the hypothalamus is broken. This means it never sends CRH to the pituitary, the pituitary therefore never made any ACTH, which means the adrenals never got any messages to release cortisol. The communication is broken at the very beginning.

All of this makes sense why we would have low cortisol - either a gland is not functioning or it never got a message telling it to secrete cortisol. However, why is it that in secondary and tertiary adrenal insufficiency the aldosterone is normal? This is because of what we covered above - the aldosterone is primarily regulated by the RAAS. Therefore, if cortisol and aldosterone are low, there is likely something wrong with the adrenal glands themselves.

One other quick thing I'll mention is adrenal suppression from steroids. The body is full of mechanisms in which we add something exogenous, and the body reacts by relying on that exogenous hormone. Think of someone who takes testosterone and causes their body to stop making it due to the body recognizing these high levels - it's the same thing with steroids. The patient's body becomes reliant on the steroids, and if they're stopped suddenly, the patient could have adrenal suppression due to the pathways above not kicking in quickly enough. This article from Adrenal Suppression United has an infographic that expresses the dangers of stopping steroids prematurely for asthmatics (but this could happen to anyone taking steroids).

Here is an interesting snippet from the Adrenal Suppression United page:

Did you notice which type of adrenal suppression/insufficiency is the most common? Secondary adrenal insufficiency from steroid complications! This gives us some important interview questions for our patients:

• "Do you take steroids?"

• "What do you take them for?"

• "Have you stopped taking them recently or adjusted your dose?"

Whew... endocrinology is hard. There are a lot of signaling pathways that those of us interested in emergency medicine rarely think about at all (and I don't just mean EMS). What are the important things for us to know about? Comprehension, recognition, and appropriate treatment. So far we've comprehended how and why these patients get sick, as well as how to recognize the set of signs and symptoms that do along with adrenal insufficiency. What about treatment?

Treatment

Dr. Antevy made a great video about CAH and even interviewed the patient as part of his Hantevy Minute series. It's a really good video - you should check it out here:

Depending on what you find during the assessment, don't forget about the glucose, sodium, potassium, and blood pressure issues! For the most part, the following problems are usually treated as:

• Sodium? 0.9% NS is usually administered (this is actually a good use case for 0.9% NS and not LR because you want the sodium in 0.9% NS).

• Glucose? D10.

• Potassium? Calcium is very important, and other hyperkalemic treatments.

• Blood pressure? Fluid should help, as well as norepinephrine if needed.

With that being said, steroids are a cornerstone treatment in this patient population (Nicolaides, 2017). Why? These patients have a lack of glucocorticoids - so we have to 'replace' them. Methylprednisolone, for example, is a systemic synthetic corticosteroid, which plays the role of cortisol in the body, dexamethasone is also an option. The patient may also have a form of hydrocortisone injection called solu-cortef in emergency kits, such as was demonstrated in the Handtevy Minute video. This CAH website also has some really good graphics to share. Sometimes patients will also be prescribed a medication called fludrocortisone link to help with aldosterone and therefore sodium/water balance.

An example of what would be found in the Solu-Cortef kit

While steroids are incredibly important, so is actively treating other problems while waiting for steroids to work. Here's a graph of how long each might take to reach its peak. Note the Solu-Cortef is IM, not IV on this graph. Doses will vary depending on guidelines / medical control, so I have not included them on the graph. Always use a reference for dosing.

And, of course, a meme -@Nursetany helping us understand how it feels to wait for the Solu-Cortef to kick in...

This is why it's important to understand the glucose, sodium, and volume status issues while waiting for steroids to kick in. (Check out Brittany's peer review below as well!)

Conclusion

Endocrine emergencies are a little daunting to think about - there are a lot of hormones and signaling pathways that we need to recognize in order to treat the condition properly. These diseases (much like DKA and HHS) are multifaceted, so I hope this blog and podcast help to put these pathways into perspective!

For more discussion on this topic, be sure to check out the live classes / EMS refresher (link below) that covers these adrenal topics as well!

Peer Review

Well guys, Sam said it best, “endocrinology is hard”. While it could be a new onset, more often than not, the patient is very familiar with their diagnosis of adrenal insufficiency whether it be from primary, secondary, or tertiary. As pre-hospital providers I know that endocrine emergencies are not always at the top of our radar, but they should be a close second and on your list of differentials.

Like Sam mentioned, oftentimes we are presented with Endocrine emergencies unknowingly. Adrenal insufficiencies can present with dehydration, hypoglycemia and even hypotension. After addressing critical signs and symptoms, we need to address the elephant in the room which is a good thorough medical history. Asking about past medical history, current signs and symptoms, and how long they have been going on are super important as well as any medications they may be taking.

While Sam talked about primary, secondary, and tertiary adrenal insufficiency, he also mentions that they have one thing in common. Low cortisol, leading me to my favorite part of Adrenal insufficiency treatment. Treatment of low cortisol or lack thereof is steroids. Solu-Cortef is the main drug that comes to mind when treating an adrenal crisis. Really, the best treatment you can offer your patient in an adrenal crisis is the replacement of glucocorticoids. In the ideal world, our patients present with hypoglycemia, hypotension, peaked T waves, and symptoms of hyponatremia, we recognize that they are in an adrenal crisis and give them a dose of Solu Cortef. Boom, magically cured. BUT, one thing that always stuck out to me was the onset of Solu Cortef and many other synthetic glucocorticoids. The onset is typically 1-2 hours. We can’t let our patient remain hypotensive or have an altered mental status due to hypoglycemia, can we? No. So we address the presenting problem with interventions of fluids, levophed, or D10. After these time-critical interventions are performed, the administration of Solu-Medrol is of utmost importance. Getting the initial dose of glucocorticoids as soon as possible will be key to improving patient outcomes.

-Brittany Grandfield, Flight Nurse.

References

Nicolaides NC, Chrousos GP, Charmandari E. Adrenal Insufficiency. [Updated 2017 Oct 14]. In: Feingold KR, Anawalt B, Boyce A, et al., editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK279083/

Fountain JH, Lappin SL. Physiology, Renin Angiotensin System. [Updated 2021 Jul 22]. In: StatPearls [Internet]: StatPearls Publishing; 2021 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK470410/

New M, Yau M, Lekarev O, et al. Congenital Adrenal Hyperplasia. [Updated 2017 Mar 15]. In: Feingold KR, Anawalt B, Boyce A, et al., editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK278953/

Andersen, S. E., Stausbøl-Grøn, B., & Rasmussen, T. B. (2008). Osmotisk demyeliniseringssyndrom ved Addisonkrise og svaer hyponatriaemi [Osmotic demyelination syndrome in Addison crisis and severe hyponatremia]. Ugeskrift for laeger, 170(50), 4142.

Yoshioka, K., Minami, M., Fujimoto, S., Yamaguchi, S., Adachi, K., & Yamagami, K. (2012). Incremental increases in glucocorticoid doses may reduce the risk of osmotic demyelination syndrome in a patient with hyponatremia due to central adrenal insufficiency. Internal medicine (Tokyo, Japan), 51(9), 1069–1072. https://doi.org/10.2169/internalmedicine.51.6507