Our next speaker, as I was telling some people, we're trying very hard to get different topics at the APP plenary session that are very important in our practice, that are not only neurosurgery, but in other subspecialties that work closely with neurosurgery. And Christina and I were talking in planning the session, and we felt that we probably don't get enough instruction. We don't get enough information in our patients that have endocrinological problems. And so we thought we would have someone speak to us on neurosurgery and endocrinology. Dr. Donegan, who's our next speaker, completed her residency and fellowship at the Mayo Clinic, during which time she also completed a master's in clinical and translational science. She is currently an assistant professor in endocrinology at Indiana University with a joint appointment in neurosurgery. She has a special interest in neuroendocrinology and is a member of the Irish Royal College of Physicians. Please welcome Dr. Donegan. Well, I have to commend all of you for being here when it's so nice outside. And maybe you're not jazz fans, but thanks for going through a long day anyway. So I want to thank the American Association of Neurological Surgeons for inviting me to talk about endocrinology in a neurosurgical patient. So this is my obligatory slide, nothing to disclose. So when I was asked to talk about endocrinology in a neurosurgical patient, I really was kind of perplexed how I was going to fit in the entire specialty into 30 minutes with room for questions. Because really, endocrine permeates every part of neurosurgery that there is. But there was one way of doing it, but I didn't think that that would be very helpful to all of you. So I thought I would pay attention or condense it down to those that you may see on a day-to-day basis and things that may be relevant to your practice. So I thought perhaps anterior pituitary deficiencies in those patients you're more likely to see on a day-to-day basis would be relevant. But also those posterior pituitary abnormalities, such as SIADH or diabetes insipidus, which often pose a lot of clinical problems in the hospital, may be of relevance. So technically, hypopituitarism is defined as one or more anterior pituitary hormone deficiencies. But this really doesn't give you an idea of which may be important at the time. Because really, having growth hormone deficiency in an acute setting is not really as relevant as having cortisol deficiency. But nevertheless, we use it as a term. And there are many, many causes of hypopituitarism, some of which affect the hypothalamus, but some of which also affect the pituitary. And they can be mass lesions, be it benign or malignant, can be radiation-induced, can be trauma, which may be intentional or unintentional, could be vascular, they could be infiltrative, infectious, genetic, and then the bucket term, idiopathic. But really, I think the ones that you're more likely to see usually would be these top four. So my objectives, as I described previously, but first of all, we'll talk about anterior pituitary hormone deficiencies as it's relevant to traumatic brain injury. So I don't need to tell this audience that traumatic brain injury, the rates are increasing. But thankfully, the rates of death as a result of traumatic brain injury are on the decline, in part due to neurosurgical techniques and in part due to advancements in medical care. But that means that individuals are living now with a chronic sequelae of traumatic brain injury. And part of that are neuroendocrine problems that do need to be recognized so that you can optimally treat the individual and allow their rehabilitation to progress as best as can be, and also to improve their quality of life. Now, damage can either be mechanical, unfortunately, as we were discussing earlier, shearing or tearing forces. That can affect either the hypothalamus or the pituitary itself. It can also be vascular. It can be, again, tearing or shearing forces to the blood vessels. Because as you can see, the pituitary or the anterior pituitary is supplied by long hypophysial blood vessels. And they traverse the diaphragmacellae, which makes them prone to damage or even compression. And that can be from increased intracranial pressure. Now, acute hypopituitarism in TBI has been looked at by a variety of different groups. And the prevalence is between about 50 to 80%. And the wide variation is due to the different cohorts that are looked at, the timing of the assessment, and the variety of different ways that they assess the individual for deficiencies. In this group, one of the largest studies, you can see that gonadotropin deficiency was the most common. And that was followed by growth hormone deficiency. But really, in the acute setting, whether somebody has growth hormone deficiency or gonadotropin deficiency is not really relevant clinically. And it's the cortisol deficiency that should be most sought after or something to be aware of. Because that can lead to the symptoms you often see in the intensive care unit, hypotension, hypoglycemia, and hyponatremia. And the treatment can be improved by replacing the hormone that's deficient. As you can see, many people have looked at chronic hypopituitarism or following TBI. And again, there is a variety of different methods that have been used, a variety of numbers of patients, methodologies were also different. And that gives rise to the huge variation in prevalence that you see from 15 to 69%. But really what I want you to take home from this is that on average, about one in three individuals will have evidence of hypopituitarism following traumatic brain injury in the long run. And that the most common deficiency that's seen is growth hormone deficiency. So what about subarachnoid hemorrhage? Well, as you know, it's most often due to aneurysms. And it's not a surprise that the pituitary would be affected due to its intimate relationship to the circle of Willis. And again, the mechanisms that have been proposed include increased intracranial pressure, infarction or ischemia, hydrocephalus, or direct compression from the aneurysm itself. Again, some groups have looked at this, but in terms of a systematic review and a meta-analysis in the acute setting, hypopituitarism is actually quite common. And you can see that it affects up to about 50% of individuals. But again, the most common deficiency are gonadotrophin deficiencies followed by growth hormone deficiency, then ACTH and then thyroid. And if you look in the subacute setting in this more recent systematic review and meta-analysis, you can see that about a third of individuals will have evidence of hypopituitarism. If we look in the chronic aspect, so six months following subarachnoid hemorrhage, in this same systematic review and meta-analysis, you can see that 25% of individuals are gonna have evidence of hypopituitarism. But again, unfortunately, due to the types of studies, the evidence or the data is very heterogeneous. But in actual fact, what we really see if you take it all together is that it is very common in the acute setting, but that the vast majority of them resolve such that by six months or greater following subarachnoid hemorrhage, only about one in four will have evidence of hypopituitarism. But that's still one in four, so not a negligible number. But the real question is here is, you know, what do we do about it? A lot of the symptoms that occur in individuals that have hypopituitarism overlap with those that have subarachnoid hemorrhage or traumatic brain injury. So if somebody says rely on clinical symptoms to guide your investigations, well, that's kind of hard. Also, is the deficiencies that we're seeing really just representative of normal adaptation? So I'm sure everybody's heard of sick u-thyroid or non-thyroidal illness that can happen in the intensive care unit. So gonadotropin deficiency, growth hormone deficiency, those kind, are they just adaptive mechanisms as a mean of conserving energy in a state that's usually catabolic from a critical illness? And the cortisol deficiency, is that real cortisol deficiency or not? The serum cortisol that we measure is total cortisol, and it's really the free cortisol that has the effect, like testosterone. And so we don't measure free cortisol, although the assay is being developed and looking at standardizing that. But a lot of the times in the intensive care unit, as I mentioned, they're catabolic, proteins go down, so is it really just a low total and not necessarily a low free cortisol? Also, a lot of what we do also has an impact on cortisol levels. If you give etomidate in anesthesia, that's gonna cause low cortisol. If you give opioids, which a lot of patients will receive in the setting of subarachnoid hemorrhage or traumatic brain injury, well, that can cause low cortisol levels. So is it truly as a result of the injury that the individual had? It's hard to know. So much happens at the same time. But I suppose trying to put that all together and trying to make it practical for what you see on a day-to-day basis, well, what do you do about it? So in an individual that has traumatic brain injury or subarachnoid hemorrhage, really looking at gonadotrophin, thyroid, or growth hormone deficiency is not really gonna be relevant in that acute setting. But what is important is thinking about the adrenal glands. And although the actual serum cutoff that's used varies between different institutions in papers that you read, I think we would all agree that a level less than 11, in the US, that is, would be consistent with cortisol deficiency in the acute setting, and they should receive stress dose steroids. In levels between 11 to 18, if they are symptomatic, so if they have evidence of hypotension, hypoglycemia, or hyponatremia, well, that may give you more evidence that adrenal insufficiency is likely to be occurring, consider stress dose steroids in that setting. If their levels are greater than 18, well, then that's a pretty robust response. And so it would be hard to convince somebody that adrenal insufficiency is contributing to their symptoms at the time. By stress dose steroids, typically we refer to 200 milligrams in 24 hours, so you can do that in divided doses. Now, in the chronic setting, what would you do? So really, we know that endocrine-related issues tend to occur more in individuals that have moderate to severe traumatic brain injury. So in those ones, you could consider assessment three to six months following their injury. And typically, dynamic testing is what is recommended. However, it really depends on your center. What are they used to doing? What kind of assessments are available? The insulin tolerance test is the gold standard for testing growth hormone and cortisol deficiency, but it's not always available in institutions, and plus may be contraindicated in this cohort, as it shouldn't be done in individuals with a history of seizures or cardiovascular disease. So there are a variety of other tests that can be done, and to consider retesting in a year. As we had mentioned, a lot of these tend to be fairly common in the acute setting, but seem to improve as time goes on, so you wouldn't want them to have treatment if it was unnecessary. So what about following surgery? So as I mentioned before, there are many hormones that are produced by the pituitary, as you all know. But really, in the acute setting, the one that's going to be of interest is going to be cortisol deficiency. And unfortunately, the assessment is really dependent on several factors, and it depends on the length of stay for the individual. As we're moving towards trying to get people out as soon as possible, the time for observation is shorter and shorter and shorter, and so it's hard to really be able to assess these individuals accurately. It also depends on intraoperative glucocorticoids. If you give them high-dose hydrocortisone, that cross-reacts with the assay, so are you measuring what they make or what you gave? If you're using dexamethasone and you're using a high dose, that can lead to endogenous suppression of your own ability to make cortisol. So is it low because of the dex that you gave them, or is it low because they're actually not making any? The other thing would be, well, who's going to follow them up? Do they have an endocrinologist? Are they seeing their primary? Can they see them in a timely fashion so that they're not on long-term steroids before they're seen? So you have one of two options. You can do where you assume the worst, which I'm not saying is better or worse than any other, but maybe a safe option, and assume that they are unable to make their own glucocorticoids and discharge them on hydrocortisone on a low dose until they're seen by an endocrinologist or a primary care physician. Or if they don't receive intraoperative glucocorticoids, you could do a day one postoperative 8 a.m. cortisol, and if it's at a good level, they don't require home-going glucocorticoids, but if it's low, then discharge them like option number one above. And institutions really do a variety of one or the other depending on, as I mentioned above, the factors that affect your assessment. So radiation. So these are people that you do see as well, because radiotherapy is an appropriate form of treatment for a variety of different reasons, including nasopharyngeal tumors. And unfortunately, it's often very hard to avoid the pituitary. And so radiation therapy can lead to damage to the hypothalamus or directly to the pituitary as well. And typically, we see primarily growth hormone deficiency, followed by gonadotropin deficiency, followed by ACTH, and then thyroid. And sometimes, you can see hyperprolactinemia. And that's thought to be as a result of damage to the dopaminergic pathways, which usually lead to tonic inhibition of prolactin. In a large study where they looked at 107 adults with brain tumors that received radiotherapy, they found after a median follow-up of eight years, 88% of individuals had evidence of hypopituitarism. I usually, for pituitary-related radiation treatment, I'd usually say about 50% five years is the kind of quote that I would use. It's easy for people to remember that. So who to test in this setting? Well, looking at the literature, there's really insufficient evidence to support routine screening. And so what they do say is rely on clinical signs and symptoms. And unfortunately, again, as I mentioned previously, that's kind of a little hard, especially when one of the signs is fatigue. I'm sure I would require testing in that setting. But usually, I would say a year after they receive their treatment is when you would most likely start seeing any deficiencies. But there's a slight caveat to that. I would only test, for example, growth hormone deficiency if your aim is to replace it. And if the reason that somebody received radiation therapy was as a result of an intracranial tumor, remember growth hormone is a growth factor. And so if you don't want to give it to somebody with a tumor, then don't test for it. So what about posterior pituitary abnormalities? So we know that the posterior pituitary does more than release ADH, but that's the one that causes us an awful lot of grief. And so in traumatic brain injury patients, dysnetremias are one of the most common biochemical abnormality that is seen. And in the acute setting, diabetes insipidus can occur in about a third of individuals. And SIADH can occur in about 15% of individuals, typically by day three. Thankfully, the vast majority of these are transient. And when they looked at individuals in the chronic setting six months following their injury and they did a formal water deprivation test, they found that the vast majority of DI had resolved. And in fact, they found only about 7% had DI at that time, only 2% of which required treatment. So again, the vast majority were still partial DI. In subarachnoid hemorrhage, hyponatremia is very common. And in one study, they found up to 50% of individuals that had a subarachnoid hemorrhage had hyponatremia. Again, peaked at around day three, but can occur anywhere from day one to day nine. And this is multifactorial. So this group from Dublin looked at Dublin, Ireland, looked at a group of individuals following subarachnoid hemorrhage. And they found that the vast majority was attributed to SIADH. Coming in second place was inappropriate IV fluids or diuretics and dehydration. Third was glucocorticoid deficiency, which is 8.2%, which isn't negligible, really. But they didn't find any cases of cerebral salt wasting. And I know that in neurosurgery, it is something that is often mentioned, frequently looked for, but is never truly or is very rarely seen, let's say. And it is important to differentiate between the two because the treatments are very different. In terms of subarachnoid hemorrhage, there was no predictive identifier. So they couldn't find a risk factor which could predict the individual who's going to develop hyponatremia. Diabetes insipidus occurs in subarachnoid hemorrhage as well, again, up to about 15%. It is an accurate predictor of mortality. So it's a negative predictive indicator. So people have worse outcome if they have diabetes insipidus. An adipsic DI is something that is, thankfully, uncommon, but has been reported in association with clipping of the anterior cerebral aneurysm, anterior communicating artery aneurysm, sorry. And the problem with this is that adipsic means that they don't have a thirst drive. So one of your main ways of compensating in DI is your thirst. And that's why people, an outpatient can survive with DI. But in these individuals, they have no thirst drive. And so it really becomes a challenge to manage. And they often require prescriptive fluid recommendations. So where you say, in a day, you must drink two liters. And then they have to have scheduled DDAVP or desmopressin. And then it becomes a balance between what's their urine output, what are their daily weights to make up for things. And unfortunately, this typically does not recover. But again, fortunately, is rare. So diabetes insipidus is deficiency or a reduction in ADH. And so this results in hypotonic polyuria. So you need to see polyuria. In the outpatient setting, greater than three liters per day. In the intensive care unit, typically greater than 250 mLs per hour in two consecutive hours or greater than 500 mLs in one hour. You need to prove that they have hypotonic urine. The specific gravity should be low or their uranosmalality should be low. And there should be an absence of other causes that may give rise to a similar picture. And so that should trigger the following. You must have accurate ins and outs. I don't know why it is so hard to obtain ins and outs. But it seems like I'm moving a mountain sometimes. But ins and outs are essential for you to be able to determine if somebody has polyuria in the first place. And then that should prompt a whole bunch of lab tests as well. The glucose is to ensure that it's not osmotic diuresis that's giving rise to the polyuria. And hypercalcemia or hypokalemia can give rise to a nephrogenic type of DI. So if somebody has possible diabetes insipidus, what do you do? All right. So you see that they have polyuria. It's going to prompt you to do those tests that we discussed. You want to prove that they have hypotonic urine. And then you're going to assess the patient. Do they have intact thirst or not? Are they awake? Are they reaching for their glass of water and they're downing it as needed? And if they are, then usually that's when I've heard people say to me, they have compensated DI. And so usually that means their sodium's normal, they're drinking, yes, they're peeing. But at the end of the day, the polyuria itself is not fatal. So what really can be is if you schedule the DD-AVP and it resolves, then you can have hyponatremia and all of the consequences that happen with that. So what I would say is, yes, you can give DD-AVP, but don't schedule it. As we'd seen in the studies previously, diabetes insipidus is often transient. And so you're not going to see that recovery if you schedule the DD-AVP. And if they're not conscious or they have an altered mental status or they have lack of thirst, then in those settings is when you're most commonly going to see the hypernatremia that ensues from the diabetes insipidus. You need to correct that with 5% dextrose initially, and you need to then give DD-AVP as well. And you can always give more once they've had breakthrough, but it's important not to schedule it. And just like hyponatremia, overcorrection of hypernatremia is also relevant. One pattern that is interesting but rare is something called triphasic diabetes insipidus. And this is uncommon, occurring in about 3%. You can see the first phase, which is diabetes insipidus, when you have trauma leading to a reduction in ADH production. This is followed by a second phase when you have degeneration of the neurons leading to uncontrolled release of ADH. And this is then followed by a third phase where you have diabetes insipidus again. And this occurs when 80% to 90% of the neurons are destroyed, and that diabetes insipidus is then permanent thereafter. So what about SIADH? Well, this is defined as euvolemic hyponatremia. So hyponatremia is less than 135 millimoles per liter in a euvolemic patient. And this results in hypotonic plasma, and you have inappropriately concentrated urine. So you shouldn't be concentrating your urine if you already have low sodium and low tonicity in your plasma. So that's why it's inappropriate. So your urine osmolality is elevated, and urine sodium is also elevated. And you need to exclude other causes as well. Glucocorticoid deficiency can give rise to a similar picture. Hypothyroidism can also give rise to a similar picture, but it would want to be marked hypothyroidism. So that should lead these following tests. Measure their plasma osmolality. Is it true hyponatremia, or is it as a result of hyperglycemia, which can alter your measurements? You want to measure their plasma sodium. You want to confirm that it wasn't taken from an arm that's receiving hypotonic fluids, for example. You also want to determine, well, what is the rate of change? Is this happening rapidly, I need to do something right now, or is this very slow? You want to measure their urinary sodium. Is it elevated inappropriately? Is it really low? Then that's from dehydration. And you can use the fractional excretion of urate if somebody is on diuretics to help you differentiate. You are going to measure their thyroid tests, a cortisol or a cosyntropin test to rule out glucocorticoid or thyroid deficiency as a cause. So if somebody has hyponatremia and you don't know the etiology as of yet, there's a couple of steps that you should follow. The first would be you need to assess the chronicity. Did it happen in less than 48 hours or greater than 48 hours? If you don't really know, but you know, if you know a sodium for sure within the 48-grade, but if you don't assume that it's chronic, you need to assess the cause. Do those lab tests that we discussed. And you want to determine the severity. And that can be either from symptoms or how low the sodium is, a combination of both. And if it's severe, for example, the individual has seizures or is abundant, they're in a coma, respiratory arrest. Well, in that case, irrespective of what the cause is, you want to elevate their sodium by about four to six millimoles per liter. So you give 100 mils of 3% saline and repeat as needed. And you want to monitor their sodium. It's not a one, give it and gone. If it's mild to moderate, so they have nausea, headaches, confusion, gait abnormalities. If it's acute and symptomatic, then you could consider giving them hypertonic saline. But if it's chronic and mild, assessing what the cause is and treating it as per the cause is the recommended thing to do. So for example, if it's SIADH, fluid restriction, salt tablets, all that kind of other good stuff that ensues is what you would do for chronic mild hyponatremia. So essentially, hypopitreousism, as I mentioned, is common following traumatic brain injury, subarachnoid hemorrhage, radiotherapy, or surgery. But usually, it's cortisol deficiency is the one that you should be most concerned about as opposed to the other ones. In the long run, yes, they are important, but they're not something in the acute setting that you need to worry about. Cortisol deficiency is going to be the most important. These are extremely common. And thankfully, they're often transient. But if you look at the patient, perform the labs, then that will help direct the most appropriate treatment. Any questions? Any questions? I have a question. In SIADH, in head trauma, when you want to replace the fluid, you said give DHT. But in head injury, you should not give D5. What fluid would you recommend? Well, it depends. I mean, it really depends on the circumstance of the individuals. If they're in head trauma, sometimes, depending on where it is, they may have an NG tube or that kind of thing. Giving free water flushes is another way of doing that. So that would be one way to do it. And that can be prescriptive as well. So there are other ways of getting around the same scenario. Okay. Thank you. Yeah? In the setting of TBI, do you recommend serum cortisol testing? So it really depends. I mean, if there is concerns about, for example, hypotension, and this comes to the intensive care unit, and that is a whole other lecture in of itself. But if there is ever a concern, then yes, I would say in that setting, measure it. Now, you'll have different schools of thoughts, and it can be a random. It depends on how far out from their trauma and how stable they are. If somebody has a cortisol even at 4 a.m. in the morning, that's 4, and they're in the intensive care unit and are hypotensive, that is not an appropriate level. And so in that circumstance, I would say absolutely, stressed-steroids would be beneficial. Yeah. Any other questions? No. All right. Thank you, Dr. King. All right. No problem. Thanks. Thank you.

endocrinology

neurosurgical patients

cortisol deficiency

diabetes insipidus

SIADH

hormone deficiencies