Notes from the Video

What you're going to learn from this video

Three things that I am confident you're going to know, after this talk today:

1. Understand the three major stimulants to the body's response to injury.
2. Know the hormones that are critical and what they do following injury
3. Identify the most important cytokines involved in the injury response and what they do.

Cytokines, it's like a bad word, but after today, you're gonna know it, and you're gonna know it confidently.

We start by asking ourselves, what are the three major stimulants or major factors involved in the body's response to injury?

After injury, there are three things that initiate this cascade, and they are:

• Pain
• Hypovolemia
• Circulating stuff

Just put all the hormones and cytokines into circulating stuff, it'll be easier to remember.

Pain

When we talk about pain, we must think about pain, fear, and anxiety,

These are potent stimulators of the paraventricular nucleus in the hypothalamus.

And when you stimulate that, you stimulate the release of CRH, or corticotropin-releasing hormone, and that's gonna act on the anterior pituitary to secrete ACTH, and this is really the mother of the injury response.

In addition to pain, other things that can stimulate CRH release from the hypothalamus are angiotensin II, IL-1, IL-6, serotonin.

What are things that lessen CRH release?

Glucocorticoids, they're anti-inflammatory, or GABA is also a down regulator of CRH release, a down regulator of the inflammatory response.

Once released from the anterior pituitary, ACTH travels to the adrenal cortex to stimulate the release of cortisol and aldosterone which leads to tachycardia and preservation of intravascular volume, respectively.  These increase cardiac output.

Keep in mind that this is biochemistry for surgeons, so it is simplified!

Another thing to keep in mind with the pain pathway is that as you continue to secrete ACTH, and your patient has more pain, more fear, more anxiety, you get more cortisol release from the adrenal cortex, and eventually you'll get adrenal exhaustion.

That's why it's really important that we think about controlling pain in our patients.

It's not just to make them comfortable, it's to decrease the inflammatory response.

Hypovolemia

I want to have you picture that patient that is in the trauma bay and is bleeding out.

Or picture that baby with pyloric stenosis.

What do they look like?

What's going on?

What happens to the body when it's low on fluid, when it's hypovolemic?

One of the first thing that happens is that you have baroreceptors or pressure receptors, and those are located in the carotid body,

as well as the arch of the aorta.

So at normal blood volume in the normal patient, the vagus nerve, the parasympathetic system is firing, and it's keeping things status quo.  Remember acetylcholine slows things down when it comes to cardiac output.

And so that's the resting state of the parasympathetic system.

When hypovolemia sets in, those baroreceptors are activated and what do they do?

Well, they decrease the inhibitory input from the parasympathetic system, and they increase the sympathetic output via norepinephrine.

The way this happens is that the baroreceptors give a feedback loop into the brainstem, and to the medulla oblongata, and that inhibits the vagal tone.

In addition, the vasomotor center increase sympathetic output, and that's going to lead to increased norepinephrine secretion and that leads to your inotropy, your chronotropy, and of course your increase in cardiac output.

In addition to the baroreceptors, there are stretch receptors in the right atrium, and when they are stretched, they stimulate ADH or vasopressin release, as well as renal vasodilation to increase blood flow through the kidneys.

This will lead to increase preservation of volume, and something to keep in mind, that other receptors that are activated as a consequence of hypovolemia are your chemoreceptors.

Chemoreceptors can be peripheral and central, and these are activated by low pH, hypoxia and hypercarbia,

These are the consequences of being low on volume, either that baby with pyloric stenosis that is vomiting everything they take in or that patient at trauma bay who's tachycardic because they've been bleeding out.

Pain and hypovolemia are two factors that cause the body to respond to preserve volume and increase cardiac output.

Now they do this through the autonomic nervous system, the parasympathetic and sympathetic systems, they do this through baroreceptors, they also do this through the stimulation or the secretion of circulating stuff.

Circulating stuff

Now there is a lot of circulating stuff, but here I wanted do include the most important things for both the ward, the operating room, the trauma bay, and of course your exams.

When I think of hormones, it's easier for me to remember it if I try to think of the thing where it's from, what it acts on, and what it does.

It's that simple, right?

So here I wanna include the four major players, and those are CRH, ACTH, cortisol, and vasopressin.

Corticotropin Releasing Hormone

When we think of CRH, this is at the top of the food chain.

• It's stimulated by pain.
• It's stimulated by fear and anxiety.
• It's stimulated by angiotensin II, IL-1, IL-6.

It's really important in the inflammatory response, and the response to pain.

It stimulates the anterior pituitary to produce ACTH which travels from the anterior pituitary, and that acts on the zona fasciculata of the adrenal gland.

Now remember that this is the middle layer of the adrenal cortex, between the zona glomerulosa, and the zona reticularis, and it's responsible for glucocorticoid production.

The major glucocorticoid is cortisol, and it's called a glucocorticoid, because it's responsible for the metabolism of glucose.

This will be a common theme moving forward, when the body's injured, it needs glucose.

And you'll see this here for cortisol.

Cortisol

When released it acts on a number of end organs, including the liver to stimulate gluconeogenesis, peripherally, to decrease glucose uptake in binding, in the muscle to induce proteolysis,and it certainly has immune suppressive function.

But the main point I want you to take away is that the stimulation of cortisol is to make glucose readily available.

Vasopressin

Vasopressin produced in the anterior hypothalamus travels down the axon to the posterior pituitary, which where it's released after stimulation by a huge variety of things.

Most importantly, increased plasma osmolarity, the consequence of hypovolemia, as well as pain, anesthesia, and angiotensin II.

It acts on the distal convoluted tubule and the collecting system of the kidney for water reabsorption, and of course it acts peripherally as a vasoconstrictor.

More Hormones in the Body's Response to Injury

In addition, there are a few other hormones that are integral to understanding the body's response to injury.

Macrophage inhibitory factor is also secreted by the anterior pituitary gland, it acts on T-lymphocytes and is a glucocorticoid antagonist, in that it antagonizes cortisol's immunosuppressive function so that the leukocytes can act.

TSH or thyroid stimulating hormone is a really interesting hormone when it comes to injury.

• TSH is stimulated by TRH or thyroid releasing hormone in response to low thyroid hormone.
• In injury, despite having low T3 and low thyroid hormone, there is not a concomitant rise in thyroid stimulating hormone.
• Cortisol inhibits the peripheral conversion of T4 to T3, T3 being the more active compound, and instead, converts T4 to RT3, which is basically inactive.

The end result is that patients following injury have low thyroid hormone, and they're characterized as having euthyroid sick syndrome, where they have high RT3 and low thyroid hormone levels.

Growth hormone, and IGF-1, they come in a pair.

• Growth hormone is also released from the anterior pituitary
• Stimulated by GHRH or growth hormone releasing hormone, and there are a lot of reasons for its release (autonomic nervous system, thyroxin, vasopressin, but also ACTH and fear and anxiety.)
• During stress, growth hormone stimulates protein synthesis as well as mobilization of fat stores, it reduces glucose oxidation, and inhibits insulin release.
• Insulin like growth factor one is responsible for protein synthesis, and most of that protein synthesis takes place in the liver.
• During injury, IL-1, IL-6, TNF alpha, they all inhibit IGF-1's actions and because of inflammatory cytokines protein synthesis is attenuated.
• With respect to the immune system, IGF-1 and growth hormone are immunostimulatory, they lead to T-cell proliferation, as well as increase activity of T-killer cells or CDA-positive cells.

Autonomic Nervous System

The two effectors of the sympathetic system:

• Epinephrin from the adrenal medulla
• Norepinephrine from both the sympathetic nervous system consisting of the sympathetic chains, and the prevertebral ganglia.

Epinephrin comes mainly from the adrenal medulla, and has several effects on the immune system, the periphery and the muscle.

In the immune system, we get demargination of leukocytes, which would lead to the lymphocytosis you're gonna see in trauma and injured patients.

In addition, there is a push in the periphery to increase the availability of glucose and in muscle to inhibit glucose uptake.

Norepinephrine has many similar effects through the sympathetic nervous system, and the best way to think about norepinephrine's effect on end organs is that norepinephrin affects each organ and makes it more conducive to active body movement.  This is opposed to acetylcholine in the parasympathetic system which acts in a way to make the body rest and recover.

Aldosterone

In discussion of aldosterone, it is created from the renin angiotensin aldosterone system.

Aldosterone comes from the zona glomerulosa of the adrenal cortex, and its release is stimulated by ACTH, angiotensin II, and hyperkalemia.

It acts on the DCT or the district convoluted tubule of the kidney to absorb sodium and eliminate potassium, in an effort to maintain intravascular volume.

The other autonomic players include the whole renin angiotensin aldosterone system, as well as glucagon and insulin.

Now the RAAS, or the renin angiotensin aldosterone system begins with pro-renin in the juxtaglomerular apparatus.

The release of renin comes after stimulation by ACTH, vasopressin, electrolytes, such as potassium, but also the JG cells or baroreceptors.

And so when you get activation of those baroreceptors through hypovolemia, you also get renin release.

When you get renin release, you get local conversion of angiotensinogen to angiotensin I.

And remember that angiotensin I is inactive, it travels to the lungs peripherally, where angiotensin converting enzyme or ACE converts it from angiotensin I to angiotensin II.

And angiotensin II is a very powerful mediator.

Angiotensin II has powerful stimulation both inotrophy and chronotrophy in the heart.

But it's also important for the stimulation of both aldosterone and vasopressin release, for volume preservation.

Insulin

Insulin, which is normally stimulated by glucose and is released from the beta cells of the pancreas, has typical actions including gluconeogenesis, glycolysis, and lipogenesis.  These are all anabolic actions.

In injury, all of these things are inhibited.

Initially after injury, there is suppressed insulin release, but after injury, there are super normal levels of insulin.

However, that insulin doesn't work, because there's peripheral resistance.

Importantly, T-cells and B-cells both have receptors for insulin, and this means that insulin has an important effect on immune activity.

Glucagon

Glucagon is released from the alpha cells of the pancreas, and has opposite effects of insulin.

This is a catabolic hormone.

This is responsible for glycogenolysis, lipolysis, and ketogenesis.

Glucagon is responsible for the majority of glucose production from the liver.

Cytokines

And now we come to the cytokines, and this is usually a long list of molecules, which can be really painful to remember.

We start with TNF alpha, a pro-inflammatory cytokine that is one of the earliest mediators of inflammation.  A half-life of only 20 minutes, and produced from mainly macrophages and T-cells, it has profound catabolic effects,

Interleukin-1 release from activated macrophages works synergistically with TNF alpha and is critical in stimulating prostaglandin activity in the anterior hypothalamus, for the febrile response.  There is an alpha and a beta form of IL-1, and beta is the most potent.  Also it increases endogenous opioids, beta endorphins, from the pituitary.

Interleukin-2 is immune stimulatory. It promotes T-cell proliferation, and immunoglobulin production.

Interleukin-4 is another immune stimulator, is an important for class switching, for B-lymphocytes, from IgM production to mainly IgG and IgE.  This is an anti-inflammatory interleukin.

Interleukin-6 is pro-inflammatory and really important in the hepatic acute phase response.  One important thing about IL-6 is that its levels are proportional to the amount of injury.

Interleukin-8 is known as a chemokine, and that's what you wanna remember about this one.  And it works to attract leukocytes to an area of injury.

Interleukin-12 is pro-inflammatory, and promotes the differentiation of TH-1 cells.

Interferon gamma is pro-inflammatory and it is an activator of macrophages, specifically alveolar macrophages.  These macrophages are stimulated by interferon gamma, and they are responsible for acute lung injury in ARDS during trauma.

Cytokines: Good and Bad

Looking at cytokines, remember that they have beneficial effects after injury.  These include wound formation, immune stimulation, the febrile response, as well as increase in acute phase proteins.

In addition, there are negative effects of cytokines following injury, and this can be that prolonged pro-inflammatory response, can lead to end organ damage, as well as the development of pain.

Another important thing to remember about the cytokine response is that they can be divided into pro-inflammatory or TH-1 cells, as well as anti-inflammatory or TH-2 cells.

Summary

The metabolic response to injury is a really dense topic, but here's what I want you to remember.

Remember that there are three major factors involved in the body's response to injury, and these are pain, hypovolemia, and circulating factors.

Pain initiates a cascade of events beginning with ACTH released from the pituitary and thinking clinically, this is why it's so important to control pain.

Controlling pain is one important aspect of controlling inflammation.

It's not just to make the patient more comfortable, it's to make them better.

Hypovolemia stimulates an increased cardiac output, by decreasing the inhibitory inputs from acetylcholine mediated parasympathetic system.

Increasing the sympathetic norepinephrine-mediated system, and increasing the production and release of ADH, or antidiuretic hormone.

All of that circulating stuff works synergistically to promote glucose production, proteolysis, and lipolysis for energy, as well as volume retention.

And finally, cytokines promote the inflammatory response including fever, immune cell proliferation, and wound development.