This is a presentation on hypertonic sodium solutions and how they can be used to treat elevated intracranial pressure and the impact on the cardiovascular and renal systems. My name is Joshua Meadow. I'm from the University of Wisconsin and I'm presenting this along with Dr. Christopher Zacco from Penn State University in this production by the American Association of Neurological Surgeons. In 1919, Weta McKibbin wrote a paper where they showed that they could reduce intracranial pressure using hypertonic sodium solutions. It didn't become mainstream though until Dr. Deed and Dr. Gilbo did significant research on the use of urea to control intracranial pressure. Not only did they publish that and use that original paper to show the advantages of treating intracranial pressure, but they also wrote a subsequent paper in 1964 showing that there is a rebound effect after bolus doses of urea to treat elevated intracranial pressure as well. When we think of the different fluid compartments, it's important to put them into the perspective of how we can use these compartments to best treat intracranial pressure. The three compartments that we typically describe are the intracellular compartment, which makes up two thirds of the body's water, the extracellular compartment, which makes up the other third of the body's water. If you divide the extracellular compartment, you will find that it's divided into the plasma and the interstitial fluid or interstitial spaces. We think of sodium as a predominantly extracellular ion and potassium as a predominantly intracellular ion. This is because there are sodium potassium ATPases that are constantly running to keep sodium on the outside and use that sodium gradient to selectively allow certain molecules to enter the cell. The sodium can also be used for muscle contractions, action potentials, etc., but this one little pump works very, very hard and it's in multiple, sorry, and it's in different cells for the purposes of setting up this gradient. This is a mode of active transport, but the gradient itself sets up the ability for passive transport. When we think of the passive transport and that gradient, we think of, we oftentimes could think of the example of glucose, so that in the presence of insulin, the glucose sodium co-transporter runs, allowing glucose to enter the cells, and then the sodium potassium ATPase has to kick up, which then results in expelling that sodium that entered the cell back into the interstitial fluid, and it also then causes the potassium that was in the interstitial fluid to enter the cell. We calculate serum osmols using a simple formula. It's two times the sodium plus the BUN over 2.8 and the glucose over 18. Normal serum osmolality is between 280 and 290 milli osmols. The reality is that simple complication does not necessarily entirely hold true, and as a result, if we were to measure the serum osmolality, we may find that there is a gap between the measured and the calculated serum osmols. This is known as the osmolar gap. If we were to give somebody a load of mannitol, we would find that they would have a elevated serum osmolality on the lab, but if we were to look at their other values, we might not find that those those values add up in the gap. The gap is made up in that case mostly by mannitol. There are other things that could add to that osmolar gap, toxins, other things that are not otherwise measured, but by far and away, the gap should not be substantial unless we're using things like osmotically active agents to try to decrease intracranial pressure. The brain has tight junctions that are normally intact. They are not water impermeable, but they are solute impermeable, and specific solutes are those that that are either charged or that are large particles. Non-charged small molecules can cross the blood-brain barrier, as can certain lipophilic agents. The effect of cellular dehydration is seen principally in the central nervous system, whereby stretching of the the shrunken neurons and endothelium, there is an alteration of the membrane potentials and a flux leading to ineffective functioning of the blood-brain barrier, and this basically makes the blood-brain barrier weaker and allows certain other things to cross that normally wouldn't be able to cross. As a consequence, there have been people that have used hypertonic agents to assist with other chemotherapies so that the hypertonic agent would shrink the the cells opening up the blood-brain barrier and then allowing the agent to cross the barrier. If we look at red cells, we can see in specific that isotonic fluids keep the biconcave look of the of the red cell. If we were to add hypotonic fluid, such as free water, or for example, if we were to give a patient D5W, which is initially isotonic, but then when the glucose is absorbed, basically leads them to free water, we would find the cells would swell. If we were to give somebody a hypertonic solution, say a load of mannitol or a bolus of hypertonic sodium, we'd find the cells would shrink. The sodium ion is an extracellular ion because of the sodium potassium ATPases that are running. If the ATPases in the cell fail to run, the sodium then no longer stays outside of the cell. The cell begins to swell. This is commonly what we see in cytotoxic edema. The issue that occurs with elevated intracranial pressure is variable, and we will discuss the different sorts of reasons why patients can develop elevated intracranial pressure. If we think about means by which we try to shrink swelling, you'll find that the hypertonic agents have a very limited scope, but they can do an exceedingly good job in what they do. People have reported that within an hour of hypernatremia that there are ideogenic osmoles that develop, or these intracellular organic solutes that are made to restore cell volume. It's important to note that there are probably levels of sodium or other solute that would be high enough that could overcome the ideogenic osmoles developing, and the associated risk of an increase in intracellular volume. Specifically, a lot of people talk about serum sodiums anecdotally above 155, resulting in significant reductions in intracranial pressure that do not seem to be phased by the production of ideogenic osmoles. Again, however, this is anecdotal. As in the human, the ideogenic osmoles themselves are probably not entirely understood, and we surely are not measuring them. So when we think of causes of elevated intracranial pressure, we think of mass lesions, we think of things such as blood or neoplastic process, we think of edema for elevated intracranial pressure that could be related to a neoplastic process, but we think of the edema being as either extracellular, meaning vasogenic or non-vasogenic, depending on the location of the fluid, and then we think of intracellular, such as cytotoxic edema, things that we might expect to see in a stroke. We also think about hydrocephalus as a cause of elevated intracranial pressure, where the ventricular volume is unable to be effectively drained, and the patient builds up fluid pressure that way. These different causes for intracranial pressure are very important. As you can imagine, if you had a small hemorrhage that was enough to increase intracranial pressure and cause distortion, you might be able to control that intracranial pressure with the use of an osmotic agent. It does not remove the mass lesion at all. Should the mass lesion grow, it would be very conceivable that the use of a hypertonic agent would no longer be able to control that mass lesion and the associated vasogenic edema that might go along with that mass lesion, or be it a hemorrhage or a tumor. When we think of cytotoxic edema or stroke-related edema, we should very clearly be thinking in the same realm. When we think of an MCA syndrome, where more than half of the middle cerebral artery distribution has a stroke in a patient that is relatively young, say under the age of 65, we get very concerned that the amount of edema that will develop as a consequence of the enormous amount of cell death from the stroke may be easily overcome by the use of osmotic agents alone, and many times these patients do need surgical decompression early on before they reach the point of herniation symptoms. But understanding the limitations of osmotic therapies, we can use the physiology that we understand to our advantage. There are two real ways to decrease intracranial pressure using osmotic therapies. The first one is with diuresis, and when we give people in the old days that used to give urea, it was a diuretic of sorts. The kidneys would spill it out quickly into the urine, and free water inside the human would go along with that. If we give somebody mannitol, by gosh, we have the same sort of effect. And we could also do other things like give patients Lasix or hydrochlorothiazide, etc. The other way that we can try to go ahead and increase serum osmolality is to increase the extracellular volume directly, again with mannitol, or with hypertonic sodium, or with hydroxyethyl starch, or with colloid. We do not recommend the use of colloids such as albumin routinely in neurosurgical patients, and especially do not recommend the use of albumin in patients with a traumatic brain injury, as outcomes may be worsened with the use of albumin. This is provided, of course, if the patients don't have critically low albumin levels that are as a consequence of liver dysfunction, profound malnutrition, etc. The use of hydroxyethyl starch has some benefits as a colloid. However, remember that the starches are dextrans. Other dextrans, such as heparin, can have similar effects on antithrombin 3, and so the excessive use of hydroxyethyl starch or similar compounds may lead to increased risk of bleeding. These direct increases in extracellular osmolarity happen as a consequence of the dose of the agent livered, and if that is mannitol or urea, that dose will typically be excreted from the body in short order, and result in diuresis without the presence of the urea or the mannitol at that time. The dose of hypertonic sodium, however, will do the same thing only in kidneys that clear the sodium quickly. Young patients with otherwise healthy kidneys will do so. The older we get, our kidneys will typically retain sodium as an evolutionary change because sodium wasn't as readily available in the human diet thousands of years ago as it is right now. When you think of diuresis, we think about decreasing the free water volume. The result is that any retained solutes that do not come out via excretion or otherwise through the kidneys remain in the plasma volume, and as a consequence of remaining in the plasma volume in the interstitium, they draw fluid out of the cells continuously. If we use mannitol, we will find that we can get to about 320 osms before the kidneys start to fail. Mannitol can also have direct toxicity to the kidneys, but as of recently, membranes for dialysis units can go ahead and decrease the mannitol load in patients that no longer have functioning kidneys. When we think about direct increases in plasmaticity, in addition to thinking about mannitol, we think about other things that would hang around longer, and in that circumstance, we could think about things like albumin, hypertonic sodium, etc. Again, we do not recommend the use of albumin for the use of intracranial pressure. We feel that most of the intracranial pressure control happens because of the incredible salt load that the albumin is bathed in, and that there is the hypertonic sodium that comes from the albumin infusion itself. The benefit of having persistent increases in vascular volume, however, are that you continue to get good blood flow to the kidneys, and by increasing GFR, we feel, as do many others that use hypertonic sodium solutions, that it is less likely that the kidneys will fail as quickly. In the presence of significant diuresis, the kidneys will not receive the blood flow that they otherwise would need because the body shunts blood to those areas that are most important, and when the kidneys do not get the blood flow they need, they eventually fail. The other thing that's important about kidneys is that they typically will tend to dump sodium, so especially in young patients, it may be hard to keep up with the amount of sodium that ends up in the urine. This is because the kidneys do not have to work to pump the sodium out so much as they don't have to work to retain the sodium that they would need to retain in the patient in the presence of significant hypovolemia. The hypervolemic-hypernatremic, where the vascular volume is actually elevated, can significantly improve the patient's renal function. And again, because the kidneys are not actively trying to reabsorb sodium to retain volume, as with mannitol diuresis or LASIKs, etc., they do not have the same sort of metabolic demand. With hypervolemia, if the kidneys are so inclined they can, and with the appropriate signaling, just spill the sodium out instead of working hard with their ATPases to reabsorb that sodium back into the blood supply. The benefits of hypervolemic-hypernatremia are improved cerebral blood flow, decreased intracranial pressure, and increased mean arterial pressure. This may benefit patients that have ischemia or vasospasm. Unlike mannitol or colloid solutions, sodium is dialyzable in it. I shouldn't say that mannitol is not dialyzable because, again, recent CVVHD machines or CVVH machines are capable of dialyzing off mannitol. Earlier units were not. So it depends on your institution and what they are currently running. If you have one of the machines and filter systems that was created in the last five or six years, you should probably have no problem dialyzing off mannitol. I do want to get on one particular issue with the use of dialysis, since I've mentioned it multiple times. If a patient that does have a significant head injury needs dialysis, we strongly discourage the use of intermittent hemodialysis because of dialysis disequilibrium syndrome. This is specific in that patients who have elevated blood urea nitrogen who undergo hemodialysis in rapid fashion will have the blood urea nitrogen pulled off very quickly. The consequence of that is that the blood urea nitrogen drops substantially plasma, and even though BUN is something that is freely permeable, urea is freely permeable, it is not instantly equilibratable. And because it is not instantly equilibratable, the concern is that the blood urea nitrogen or urea that is left in the cells will then quickly take on water from the interstitial plasma and cause the cells to swell, and they can do so substantially. Patients undergoing CVVHD three times, I'm sorry, patients that are undergoing regular hemodialysis three times a week oftentimes complain of headache during the dialysis process, and sometimes will drop their pressures as well for this reason. If you take a patient that has a significant head injury, the amount of swelling can be massive and can lead to herniation. So we strongly discourage rapid forms of hemodialysis. Instead, we would strongly encourage the use of CVVH, CVVHD, or CRRT so that you can slowly remove the blood urea nitrogen without forcing a fluid shift into the cells. Along those lines, any rapid changes in tonicity can lead to other sorts of brain damage, including central pontine myelinolysis. This particular group of patients that get CPM are typically those that are thiamine deficient, and that's why it's more common in your liver failure patients, your alcoholics, etc. A rapid correction of sodium is only an issue, up or down, if that rapid correction happens without knowing how long before the sodium became abnormal. So for example, if a patient goes into diabetes insipidus and takes a serum sodium of 140 and quickly rises to 160 or 170, and you correct them right back down to 140 again, within a 24 hour period, you should have no trouble. On the other hand, if an alcoholic presents to the emergency department with a close head injury and a sodium of 120, if you were to use hypertonic sodium and got their sodium up too quickly and left it in a sustained fashion, they could develop CPM. So it's important not to go ahead and let their sodium change by more than 12 points over a 24 hour period. Now there are rebound effects with osmotic therapies, but these rebound effects can be mitigated by how the osmotic therapy is used. When we think about osmotic therapies, such as mannitol, we typically think of them as being bolused every 2 hours, every 4 hours, whenever needed, that sort of thing. In doing so, we are counting on the fact that the load of mannitol will go into the human. As a consequence of doing that, the volume will end up in the vascular space, and the mannitol and water will then be excreted by the kidneys, and during that period of time, the ICP should drop pretty substantially. Then as volume builds back up though in the human, the ICP will go up along with it. When running hypertonic sodium or any other osmotic agent, these same things will happen because the bolus will cause a substantial decrease in intracranial pressure and substantial changes in tonicity in the plasma, which will then activate the kidneys if they are working accordingly to get rid of that extra tonicity. On the other hand, if you use a bolus infusion of hypertonic sodium followed by a sustained infusion to keep the sodium at a particular level, you will find that the rebound effects are not that substantial at all, and that for the most part, they will have a lowered sodium that will only very slowly creep up, and as needed, the hypertonic sodium can be increased to account for any elevations in intracranial pressure. The rebound effects, if you just use bolus hypertonic sodium, may be higher than with other agents such as mannitol or urea, but this is based on published data from 1964, and there are potentials for bias in the study. Some of the other benefits of using hypertonic sodium are improved gas exchange, improved cardiac output, and improved mean arterial pressure, all of which happen because the heart is working better. If the heart is not working better, in fact if the patient is volume overloaded or if the patient is CHF and then by giving them a hypertonic load brings more volume into the patient and their pump can't handle that, then they can go into fluorid failure, and in doing so, the map in cardiac output and gas exchange can actually get worse. With the use of hemodilution, there are some reostatic benefits, and consequent to the use of hypertonic sodium and shrinking of red cells, you might be able to improve blood flow through vessels that are otherwise narrowed for reasons such as vasospasm, etc. And then in the lab, there have been people that have looked at immunomodulation. The impact on the human is not really quite yet understood. The effects of hypertonic sodium on electrolytes can really be reasonably substantial. There is a mild acidosis that is often clinically found and is insignificant. This acidosis occurs as a consequence of hypertonic sodium being a mixture of sodium and chloride. The result is that the delivery of this substantial amount of chloride results in a hyperchloramic metabolic acidosis because the chloride is exchanged for bicarbonate. People have tried to mitigate this by adding acetate or other buffers in place of some of the chloride in the hypertonic sodium solution. Other things that can happen as well, there have been reports of bleeding diatheses. Many of us believe that the vast majority of these are more common when the hypertonic sodium is given in concert with hydroxyethyl starch or other dextrans, again because they can activate antithrombin 3 and make the patient more prone to being coagulopathic. The other thing is phlebitis. Because the load is hypertonic and does change the shape of blood vessels and does cause other alterations, there is a chance that clot can develop in superficial veins. We typically use lower dose agents such as 3% hypertonic sodium solutions to control intracranial pressure. We also make sure that we do not run greater than 1.8% hypertonic sodium through a peripheral IV at our institution. Some people say it's okay to run 3% through a peripheral IV. In an emergency circumstance with a large IV and good access with solid veins, we might do that, but we would switch to a central line as soon as possible. There have been numerous studies comparing mannitol versus hypertonic sodium solutions. I think the key thing to remember is that both will obtain results needed to control ICP. It is my personal opinion that hypertonic sodium allows you to more safely get to higher levels of tenacity in the blood without any significant problems with the kidneys as compared to mannitol, but it is more anecdotal. Some of the research that is presented here will show that there is improvement or benefit in using hypertonic sodium for that reason in the control of intracranial pressure in head injured patients, but there are other patients such as those with stroke or a type of stroke like subarachnoid hemorrhage that may benefit from hypertonic sodium because of the relative increase in vascular volume which helps with perfusion. A small patient study showed that hypertonic sodium does increase your blood flow and subarachnoid hemorrhage. The problem with the ten patient study was that patient outcomes remained bad despite the use of the hypertonic sodium, but it did increase cerebral blood flow and it may be something used to augment the issues that patients with elevated cranial pressure and subarachnoid hemorrhage need addressed. In patients with stroke, the use of hypertonic sodium was able to control ICP crisis where mannitol was ineffective. Again, there are some important things that you can get to a higher osmotic level with hypertonic sodium solutions, but you are not able to necessarily do so and save the patient without needing a surgical decompression. I do not want people listening to this talk to think that osmotic agents alone will be effective in young patients with greater than 50% of the MCA distribution having undergone a cerebrovascular event or stroke. If that should happen, surgical decompression early is probably going to be important because the malignant intracranial hypertension that develops may develop quickly and a proactive decompression may be the only way to prevent additional complications. In severe pediatric head injury, there was insufficient data to support a standard, but what they did find was that the minimum dose needed to keep ICP less than 20 was better with sodium than with mannitol and that 320 osms was safe with mannitol where 360 osms was safe with sodium. Now, I put in parentheses the sodium, that would be about 175 to 180 millimoles. That would mean, however, that there were no other osmols. In other words, the glucose would have to be in the low normal range and the BUN would have to be very low as well. We do not want to see a very low glucose under any circumstances and we do realize that patients, as they become a bit dry or that are catabolic, may have an elevation in their blood urea nitrogen. So, your general rule of thumb is try to keep the sodium less than 160 if possible. If you have no choice but to run the sodium higher in the mid to upper 160s range or even higher than that, you do so at peril with risking the kidneys and your patient may need a CVVHD, CVVH, or CRRT means by which to dialyze them continuously. In those circumstances, you may find that the use of a trisodium citrate buffer, which is used to anticoagulate the system but not the patient, so to prevent clotting within the system but not prevent clotting within the patient, that trisodium citrate buffer can be used to help control the intravascular sodium levels or plasma sodium levels, which can then be used to help control intracranial pressure. You will have to speak with your nephrologist when they are running the dialysis machine to titrate this accordingly. Fisher used hypertonic sodium versus saline and this is class 2 evidence. It was done in children. It was double blinded in perspective and 3% sodium solutions required less of a need of hyperventilation and thiopental. This is basically a placebo-controlled study. It did not compare hypertonic sodium to mannitol and although it showed effective hypertonic sodium in controlling intracranial pressure, we don't agree with the use of hyperventilation for management of elevated intracranial pressure except as a means to treat the patient en route to an emergent surgical decompression. Qureshi looked at a sodium acetate buffer solution in 27 consecutive patients and he found that it reduced midline shift by approximately 3 millimeters except in stroke. We should be clear that the use of hypertonic sodium does not shrink the bad brain. It does not shrink the cells where the ATPases don't work like they're supposed to that are either failing or have died along with the cell. It shrinks the good brain or it shrinks the cells that have ATPases that are functioning that can actively pump out the sodium and keep sodium out of the cells and prevent them from leaking in substantially. So for patients that have trauma where they have patchy areas of damage in the cerebrum along with areas that are not damaged, for example your diffuse axonal injury patients, etc., the use of hypertonic sodium may help prevent shift. In your patients that have malignant MCA syndromes because of stroke, you may actually find the shift increases and that's because you're shrinking the good brain at the expense of the bad brain, allowing the bad brain to swell more and shift the anatomy further. There has been a small review of hypertonic sodium versus mannitol and barbiturate coma and they found that seven and a half percent sodium, given when everything else failed, brought ICP down substantially by about 14 millimeters of mercury on average within the first hour or bolus dose and so this showed an improvement in ICP control. In liver failure patients, maintaining elevated sodiums significantly decreased intracranial pressure and improved mean arterial pressure resulting in less need for presser agents. In your patients that have significant liver failure and a coagulopathy and are unable to have an ICP device placed, you may find that this is the one group of patients where hypertonic sodium may be very useful to try to keep intracranial pressure down. We do not recommend the use of hypertonic sodium without the placement of an ICP device unless it is to correct sodium into normal range, but this is the one group, the coagulopathic patient group, where you have a high clinical suspicion that their intracranial pressure could be elevated and as a consequence of that elevated intracranial pressure but a coagulopathy that might preclude placement of a device safely running the sodium at the high end of safe, provided their kidneys are working fine, say with a sodium of 155 to 160, may end up being useful or potentially life-sparing in this patient population. That is anecdotal evidence, however, and everybody should be very aware that there is no clear evidence on the management of patients with liver failure and coagulopathy. Gajar and Hartle published a paper in 1997 using hypertonic sodium solutions to treat six patients with TBI, and they were able to lower ICP by 44% and improve CPP substantially. There is a prospective randomized control trial of mannitol versus seven and a half percent hypertonic sodium. Again, a very small study. It was a crossover study, however, and they did find that they were able to bring down ICP on average 13 millimeters of mercury further with hypertonic sodium and with longer duration than with mannitol alone. The prospective randomized control trial of 20% mannitol versus seven and a half percent mannitol by VLA in 20 consecutive patients showed the number of ICP crises decreased and the duration of these crises decreased as well. If we look at trauma specific to the human but not specific to the head alone, meaning penetrating trauma to the abdomen, chest, etc., there have been studies that have showed that hypertonic sodium solution is an excellent resuscitative fluid or resuscitation fluid for treating TBI. It's a very simple solution. It's a very simple solution to treat TBI. Hypertonic sodium solution is an excellent resuscitative fluid or resuscitation fluid and can improve outcome. The flip side of it is that patients that have significant burns often require substantial amounts of intravascular volume, and if that is not maintained well enough and patients that are given hypertonic sodium are not able to maintain that vascular volume in a means that is necessary, you can actually have worse outcomes in those patients. Recognizing the limitations of how you resuscitate a burn patient in the presence of a head injury, recognizing that it is very easy for burn patients, because of the significant weeping of fluid out through their burns, can lead to substantial decreases in intravascular volume and realizing that hypertonic sodium, although able to expand that intravascular volume, can also push the kidneys further than they ought to be pushed because of elevations of seromasomalality that can be quite substantial, may result in a greater use of dialysis in this patient population. Again, it's a matter of putting it all together. It's a matter of realizing all the different things that are going wrong in your patient and knowing how to mitigate many of those complications so that the outcome for the patient overall is the best possible outcome that you can have. So in conclusion, hypertonic sodium solutions do have promising data with respect to safety, with respect to improved ICP control. They work well with all forms of dialysis. Again, we are not recommending intermittent hemodialysis for patients. It turns out mannitol nowadays through newer systems and better filters can be filtered out, whereas in older systems or with older filters that was not the case. You'll have to defer to your institution's dialysis systems and the nephrologists that you work with to figure out if mannitol is a dializable osmolar agent, if your patient should require dialysis. We know that hypertonic sodium can generate a higher osmolar load safer, 360 osms with hypertonic sodium versus 320 osms with mannitol, but we desperately do need a randomized prospective large patient number trial to prove efficacy. Again, at the University of Wisconsin, our approach is to use bolus hypertonic sodium in patients with normal sodium levels to start, and then we run an infusion to keep the sodium level at a place that will keep intracranial pressure controlled. With bolus, additional hypertonic sodium is needed to control intracranial pressure if the infusion is not enough to do so. More than anything, we don't recommend that you listen to one webinar and change your practice entirely. If you are not used to using hypertonic sodium, this may be a good foundation or starting block for you to try to learn the basics, but we would recommend that you consult with peers in the neurosurgical or neurocritical care profession who do routinely use hypertonic sodium prior to embarking on changing your practice, because we would want you to keep safety first. Thank you for listening to this webinar.

hypertonic sodium solutions

intracranial pressure

cardiovascular system

renal system

sodium-potassium ATPase pumps

serum osmolality

blood-brain barrier

biconcave shape of red blood cells