I'm going to talk about fluids this morning. My name is Marty Shriver. I'm the Chief of Trauma at Oregon Health and Science University, and I'm on the Board of Directors for the TCAA. My goal is to keep you awake and not looking at your telephones this morning. Okay, I have no disclosures. The objectives of this lecture are to discuss the history of fluid resuscitation, describe the negative physiologic effects associated with giving fluids, and to outline the effects of plasma on the endothelial pathy of trauma, a process that I'll describe to you. Basically I'm going to try to convince you that you should stop giving fluids. So let's start with a typical scenario which you may face in your trauma center frequently. A 24-year-old male with very bad judgment gets in a fight at the bar, gets in his car drunk, smashes his car, comes into the trauma center drunk, disobedient, and bleeding. So in the field, EMS starts IVs, they give the most commonly given fluid in the world which is normal saline. How many people in the room give primarily normal saline for fluid resuscitation? Tell the truth. Everybody. Almost everybody. Primarily giving normal saline. So it will be very interesting to see where normal saline came from. So at this point in time, the only fluid that most EMS agencies have is room temperature fluid. That's 25 degrees Celsius fluid. Patient arrives in the trauma bay, you take off all their clothes which makes them get colder, they're hypotensive, the fast is positive, and you send off some labs to see if you want to give any blood products. In the meantime, you give more room temperature normal saline. Take the patient to the operating room, lots of red cells available. Patients have a four degree Celsius temperature. Now you're infusing four degrees Celsius into your patient. Their operation started, there's blood everywhere. The labs come back, it's an hour later. The INR is elevated, the PTT is 54, fibrinogen 120. Now you order some plasma cryoprecipitate and the patient gets that an hour later. So the first one hour of that patient's care, all they're getting is cold fluids and nothing to correct their cryogallopathy, nothing to stop the bleeding. Remember the entire goal here is to stop the bleeding. Okay, so let's talk about the importance of cryogallopathy, the etiology of cryogallopathy. We'll talk about the various effects of fluid on hypothermia, acidosis, as well as popping the clot as you raise the blood pressure. So this is a scene from World War I. World War I, a hundred years ago, this statement was made. What is wanted is a fluid that will have the advantages of salt solutions together with antagonism to the state of acidosis. A hundred years ago, that's Captain Walter B. Cannon in World War I, published in JAMA in 1918, almost exactly a hundred years ago. Walter B. Cannon, Captain U.S. Army, says normal saline is bad, but we're still using it a hundred years later. Okay, so let's talk about the history of fluids. These are the witch's brew of various fluids that were used prior to normal saline lactated ringers. You can see all these different kinds of things and what they were kind of masquerading are. Very interesting names like aqua kalide, that's hot water, sulfate of potash. Guess how all of these fluids were given? Any guesses? They were given in two ways. Either rectally, primarily to people with cholera, so they're having diarrhea and they're shoving this fluid up their butt, or subcutaneously. Very interesting, that's the history of fluids. Now in comes Sidney Ringer. This is the ringer's lactate guy. Okay, Sidney Ringer, here he is. He lived primarily in the 20th century, he was a British physiologist, a very good scientist. He was fanatically punctual. In fact, one time he was trying to get to a meeting on time, the door was locked, so he scaled the building. This old guy, look at him, scaled the building, broke the window, broke into the building and got there on time. This guy was a researcher, he was a very, very good researcher, and he said first and foremost you have to be honest and open eyed. His primary model was an isolated frog heart model. He took these frog hearts and he would put them in various solutions and he saw how long the frog heart beat. One day his assistant brought him a fluid and the heart beat for two days. All the other fluids would kill the heart, but this one day he had this fluid and it beat for two days. So he tried the experiment again the next day, it didn't work, tried it again the next day, it didn't work, so he grabs his assistant by the throat and he says, what did you give me two days ago? The guy turns bright red, he says, sir, we ran out of distilled water so I got the fluid out of the Thames River, which was right in the back of their trauma center. So then he goes, okay, the magic fluid is this fluid in the Thames River, and he looks at it and he finds that there's calcium and potassium in it, and because of the stupid assistant, that's where we got lactated ringers from. It was an accident, a scientific accident. Is that interesting? Now here's where the normal sanity comes in. This is a guy, Jacob Hartog Hamburger, last name Hamburger, and this guy said that the ideal fluid is going to be the fluid that has the same freezing point as human serum. So he looked at different concentrations of salt solutions and he found out that the same freezing point occurred at .9% saline, and that's where that came from. Now this poor guy, whose fluid we're still using as our primary fluid, he died as a poor popper in an unmarked grave. Very interesting. Okay, so what about coagulopathy? What this slide shows you is, regardless of your injury severity, if you're coagulopathic, you're more likely to die. And you can see this, regardless of ISS, those in the red bars who come in coagulopathic, initial blood test, elevation of the INR, no matter what your injury severity is, you're more likely to die. So coagulopathy is an independent predictor of death, okay? So here's your first question. I guess I threw in a few questions here to keep you awake and not looking at your phone. ATC and TIC, acute traumatic coagulopathy and trauma-induced coagulopathy, and I'll define these for you, result in all of the following except, and you can see the answer there, initial hypercoagulability. All the other things are bad, but they do not cause you to be hypercoagulable, they cause you to be hypocoagulant. So this is a very nice slide. This slide was made by one of my residents who kind of put the whole picture together. So what is acute traumatic coagulopathy? If you're hit by a train and you become hypotensive in the field, you will be hypocoagulable within minutes of being hit by the train. Train hits you, your blood pressure drops, you will become hypocoagulable. Okay, and I'll show you this data from the field, blood test measured in the field, you're hypocoagulable. Now, you're already hypocoagulable, now the meds come, what do the meds do? First thing they do is put some IVs in you, and they start infusing that normal saline. Did you know that the normal saline has a pH between 4 and 6, it's a moderately strong acid? Remember, one of the three things you want to avoid is acidosis, but you're pouring an acid into your patient, okay? And not only is it an acid, but it has a very high chloride content that causes hypochloric acidosis. So now in your coagulopathic patients, you're making them acidotic. You're also making them hypothermic, because it's room temperature normal saline, and you're hemodiluting them. So your bleeding coagulopathic patient is now becoming more coagulopathic. Now look at all those things on the bottom, a bunch of other things are happening as well, okay? Now that fluid causes an inflammatory response, a dysfunctional inflammation, and causes ARDS, we learned this in the Vietnam War. It causes your clots to dissolve, hyperfibroanalysis, it causes endothelial dysfunction, I'll show you this data, it causes the endothelium, the vascular endothelium, to leak. So that fluid that you're giving intravenously ends up in the patient's lungs, causing inflammatory response and leakage. It causes your fibrinogen that you do have not to work, and it causes platelet dysfunction. That's what that fluid does. Okay, this is what it looks like, this is a patient I took care of in Afghanistan. It was election day, we had eight gunshot wounds at once, this guy was shot in the abdomen and both legs, his whole left upper quadrant was blown up, we had to take out his spleen, his kidney, and half his pancreas, he had a popliteal artery injury, and this guy, you can see this is what coagulopathy looks like, there's blood all over the table and all over the doctors. Okay, now what about this hypothermia effect? Let's talk about the hypothermia. What does giving that one bag of normal saline do to you in terms of heat loss? Okay, now don't get bored with me, there's the equation for heat loss, Q, that's heat loss. Very simple equation, what's the mass of one liter of normal saline? It's one, okay? What's the specific heat of water? It's one, so so far I've got one times one. A patient's temperature is 37, and room temperature is 25. That means every time you give a bag of room temperature normal saline, you cost your patient 12 kilocalories of energy. Every single bag, 12 kilocalories of energy, okay? So I have listed here all these things we do to keep people warm, airway re-warming, overhead radiant, heating blankets, confective warmers. If you give a couple of liters of normal saline, you've overcome your ability to warm patients from all of those standard mechanisms. It's only the more radical mechanisms that gives you more heat, like continuous arterial venous re-warming. That means you put a catheter in the femoral artery, run the blood through a level one and put it back into the femoral vein. Now you can give over 100 kilocalories doing that, or cardiopulmonary bypass, but nobody does those things. So with a few liters of room temperature fluid, you are going to make your patient very cold. You'll make them hypothermic. Now unfortunately, some of these slides were changed and they don't show up very well, but this slide shows you what happens to patients with dilution and also with hypothermia. So what it shows you is, now remember, whenever you draw a coagulation assay on your patient, the first thing the lab does is they raise the temperature of that blood to 37 degrees. So if your patient has a temperature of 32 degrees, you will not see the effect of hypothermia on their coagulation assays because the lab is warming it to 37. Now what this slide shows is that when the temperature drops less than 35, the PT will go up rapidly. It's like anti-coagulating the patient. Now if you also give fluids that don't contain any coagulation factors, those two effects are additive and essentially you have an anti-coagulated patient. So if you give a lot of normal saline, you'll make the patient cold and you'll dilute them and it's like giving them a bolus of heparin, very severe coagulopathy. Now this slide shows you the effects of hypothermia and outcome. What you see is, again, when the temperature drops less than 35 degrees Celsius, the patient's mortality increases dramatically. And when you get to 32 degrees Celsius, the mortality is about 50%. So this hypothermia that we're inducing iatrogenically with fluids is actually resulting in an increased mortality. Very, very impressive. Now these results are actually better. If you looked at some of the data from the 1980s, that data showed 100% mortality in patients with a temperature of 32, so we've gotten a little bit better in that area. Now this is the most important study ever published, I think, in trauma. This is a paper published in the New England Journal of Medicine, 1994. This was a study done in Houston, Texas, and what they did was they got community consent and they looked at patients who had penetrating torso trauma, gunshot wounds or stab wounds to the chest or abdomen, who had a systolic blood pressure less than 90. On even days, they put two IVs in those patients and they aggressively resuscitate them. On odd days, they put the IVs in but they didn't give any fluid until hemorrhage was controlled. Hypotensive patients, gunshots and stab wounds, no fluid until hemorrhage was controlled. Okay? Houston, Texas, published in 1994. Okay? And what this shows was they were successful in their randomization. The patients who were randomized to aggressive resuscitation got about 3,500 cc's of fluid in the pre-hospital setting and in the hospital before bleeding was controlled. The patients randomized to delayed resuscitation only got about 350 cc's of fluid. Alright? So big difference in the fluid. So they then looked at survival. What they found was that if you didn't give fluid until hemorrhage was controlled, you were more likely to be alive. You're more likely to survive and you had less complications. So simply by not giving fluid, the patients were more likely to survive. Okay? Now, these are the lab tests on arrival. This is on arrival at the hospital. So what you see here is in the delayed resuscitation group, the hemoglobin is higher, so less diluted. The platelet count is higher. The PT and the PTT are lower. So by not giving fluid, you avoid hemodilution, anemia and coagulopathy. Very very nicely shown in this trial. Now the other very important thing that you avoid by not giving fluid is by not raising the blood pressure, you don't pop the clot and make the patient bleed. So think about how we evolve. So if you're a caveman and a woolly man that spears you in the aorta, you'll bleed until your blood pressure gets low and you'll stop bleeding. And you'll form a clot in your aorta and you'll either live or die. But if the medic comes around with his normal saline, infuses it in your veins, raises your blood pressure, you pop those clots and now you bleed. And you have a higher mortality. Very very interesting. Now this is a study I promised to show you. This is a study that actually looked at coagulation in patients in the field. Okay, so you see on scene, medics putting IVs in, drawing these lab tests and then they're run in the hospital. And what you see here is in the field, the mean INR is 1.3. The patient's already coagulopathic in the field. Very interesting. They get a median of 500 cc's of fluid and then when they get to the hospital, just with 500 cc's of fluid, the PTT is higher, the INR is higher and the fibrinogen is lower just with a 500 cc bolus. Very nicely showing the effects of fluid on coagulopathy. So why do we give all this fluid? What happened? The primary fluid given in World War I was whole blood. Wouldn't you like to have whole blood which we had 100 years ago instead of the normal saline? In World War II, whole blood. Now in the Vietnam War we started giving lots of lactated ringers and that's when we started seeing ARDS. So very, very interesting. What happened is in the late 70's there was a series of experiments that were done by Carrico and Shires. Now the studies were all done in dogs with controlled resuscitation. We don't bleed with controlled resuscitation. We bleed with uncontrolled resuscitation. The conclusion of the studies were to start giving lactated ringers until you replace the interstitial fluid loss and then give the whole blood. The problem is we forgot about the whole blood part and all we gave was the lactated ringers. Now in the 80's the whole blood went away and we started getting components and what we have now are all the various components. So believe it or not in 2017 we're starting to go back to using whole blood again. So this theory came around that we're going to use super normal resuscitation. The more fluid we give the better. Now some of you that have some gray hair like me remember the 80's and the 90's when we would just flood patients with fluid and our goal was to increase their cardiac output until it won't increase anymore. We would just give liters upon liters, 20 liters of fluid, 30 liters of fluid, not uncommon. They don't get well until they swell. I trained at Harborview. I had a t-shirt. It had all these equations on it, front and back, 50 different equations, and it said, Harborview, where the answer is always fluids. So, what did that do for us? We had ICUs full of these swollen patients with organ failure. And what we found was, over time, when you studied it carefully, that actually giving all this fluid resulted in increased abdominal compartments, and in fact, the abdominal compartments in the secondary abdominal compartment syndrome was described in this area. We gave so much fluid that we're giving people abdominal compartment syndrome. We had increased multiple organ failure, increased death, and ICUs full of Michelin people. Now, remember all this stuff? You see that on the top left there? We call that brain bowel. When's the last time you saw that? All the bowel was so swollen, you couldn't even close the abdomen. And we came up with all these various techniques. The Whitman patch, that's a Velcro patch, and you pull the Velcro together, and you have one person on one side, one on the other, and you pull it together, and you Velcro the human being, just like they were like a piece of meat or something, until you get the fascia together. And then you had all these fistulas, people walk around with these OBAMs. It was a nightmare. Thank God that went away. Now, this is a very nice study. This was done at Shock Trauma, and what they did was they looked at resuscitating in-house patients to either a goal systolic blood pressure of 70 or 100. And these were bleeding patients, very seriously injured patients that either need to go to the operating room or to the IR suite, 70 or 100. So, if your blood pressure was in the range, they simply monitored you. If your blood pressure was too low, you got a small 250 cc bowls. If your blood pressure was too high, then they gave you sedation to get your blood pressure down. Okay? Now, that top graph there, that is the best example I've ever seen published of what I call cyclical hyper-resuscitation. Okay? Remember, we're talking about popping the cloths. What's happening? The patient's blood pressure gets up to 100. They pop the cloth, they bleed. We give more fluid. Blood pressure comes up. Pop the cloth, they bleed. Blood pressure drops. More fluid. And you see the cyclical response? Until you get to about 17 on that graph, you put the stitches in the holes, you get control of the bleeding, and it stabilizes out. Now, when I was a resident, I'd be in the operating room, and I noticed this really weird series of events. We would put a bunch of stitches in the stuff, and the bleeding would stop. And we'd sort of high-five each other, and all of a sudden, the bleeding would start again. And I'm like, what's going on? We put some more stitches, the bleeding would stop, and the bleeding would start again. What was happening was, as we were controlling the bleeding, the anesthesiologists were giving fluid to catch up, and they were making the patient bleed again. And I'd go home, and my underwear would be full of blood, and my socks would be full of blood. My wife's like, what's up with this? And what was happening was, all this fluid was causing a lot of bleed. One line in this study, though, was survival was 92% whether you gave a lot of fluid or a little fluid. Very interesting. Okay, this is my favorite study. I call it EMS versus your mother. Okay? This is a study done in Los Angeles. And what they did was, they looked at patients who were brought to the hospital either by EMS, or by anybody else but EMS. So the gang guy that shoots them, throws them in the car, takes them to the hospital. Or your mother who loves you very much, or maybe your sister, whoever. What they found was, in the severely injured patients with an ISS greater than 15, you are more likely to live if somebody besides EMS brought you to the hospital. Twice as likely to live if somebody besides EMS brought you to the hospital. Okay? Now why would that be? Well, there's several possible reasons. Reason number one, the gang guy can get you to the hospital a lot faster than EMS. He just throws you in the car, takes you out. So you get to the hospital faster. If you have a hole in a blood vessel, you get the hole sewn in the blood vessel faster. Other possibilities, the things that EMS is doing to you actually may be hurting you. For instance, they're intubating you. If they intubate you in the field, maybe giving 100% oxygen isn't good for you. Maybe blowing down your CO2 too much isn't good for you. And then finally, if they're putting IVs in you and giving you a lot of fluid, that also may be harmful. But you're twice as likely to live if you're brought to the hospital by EMS. Now this has been repeated in multiple other places, like Philadelphia. About half the patients who come to the hospital in Philadelphia are gunshot wounds that are brought to the hospital by the police. Those patients are more likely to live than the ones brought to the hospital by EMS. Very, very interesting. Okay, here's a Canadian study. They wanted to look at patients who got IVs versus those that didn't. They randomized patients to either getting IVs or no IVs. It was actually the medics that were randomized. If you're a paramedic, A, you put in IVs. If you're a paramedic, B, you didn't put in IVs. Okay, they were matched for pre-hospital criteria and had to get to a hospital alive to be included in the study. Okay, what did this show? What it showed was if you didn't get an IV placed, you got to the hospital faster. Okay? By not getting an IV, you got to the hospital statistically sooner than if you got an IV. Very, very important. Okay, what else did it show? It showed that also that if you got to the hospital faster, you were more likely to be alive. Again, if you're bleeding and you need holes closed by sutures, the faster you get to the hospital, the better you do. Okay? Now what about this pop the clot phenomenon? Let's talk about that a little bit. So this is a study done by the same guy who published the Houston trial in People. Before he did a study in People, he did a study in animals. So he took pigs, he put a wire into their aorta, and he would pull that wire and make a hole in the aorta. Okay? And then he randomized the pigs either to aggressive resuscitation or no fluid. So he's actually studying this pop the clot phenomenon. And what he found was that if you're giving aggressive resuscitation, the pigs bled by over 2 liters. Then if you didn't give fluid, they bled about 800 cc. So three times the blood loss simply by giving aggressive resuscitation. Now interestingly, if you got resuscitation, all the animals died. If they didn't get resuscitation, they all survived. 100% mortality with resuscitation, 0% with no resuscitation. That's what caused them to go on to the human trial. And all the deaths were by 100 minutes. Okay? So Jill Sandin from the U.S. Army Institute of Surgical Research said, what exactly is the blood pressure that this re-bleeding occurs? So she repeated this experiment, took pigs, again with a wire in the aorta, tore the aorta, waited for the pigs to get hypotensive, they stopped bleeding. And then she resuscitated them, had catheters in the abdomen, and measured the time point at which the bleeding restarted. Really, really nice study. What you see here on the bottom left is at about a systolic blood pressure of about 90 millimeters mercury, the pigs re-bled. So if you resuscitate to over 90, that's the point at which the pigs re-bled. If they stayed below 90, they didn't bleed. And this really nicely shows this pop-to-clot phenomenon. So out of all this research came the Military Tactical Combat Casualty Care Guidelines. So the Committee on Tactical Combat Casualty Care governs how the military resuscitates patients in the field. So number one, the goal is organ perfusion. So the dictum is, if the patient is alert, with normal mental status, and has a normal radial pulse, you give no fluids. If they lose their radial pulse, or the radial pulse weakens, or they start to lose their mental status, then you give a small bolus, and the bolus used in the field is 500 cc of hexane. It's a colloid. You give smaller volumes and get a greater effect. Now, the other thing is they grade the triage of which fluid should be given. The number one fluid that should be given in the field is whole blood. Number two is one to one to one, plasma to platelets to red cells. Number three is plasma, number four is red cells. And then when you get to the end of all of that, the last fluids given should be lactate and ringers, at the very bottom of the list. Not the first fluids, the last fluids. Number one is whole blood in the field, and literally thousands of units of whole blood have been given in theater. Now, the other thing is that they looked at a bunch of criteria that predicts who gets a massive transfusion. And if the patient is hypotensive, tachycardic, anemic, and their pH is low, all things that you can measure within five minutes, there's an 85% chance that patient's going to need a massive transfusion, and a massive transfusion protocol is immediately initiated within five minutes of arrival of the patient. But look at the top of this slide. What is the primary goal? The primary goal is hemorrhage control. It's not resuscitation. The primary goal is hemorrhage control, not resuscitation. And the second thing that says there is avoid the lethal triad, that means do not give crystalloid. Okay, that is the dictum from the military. Okay, so we wanted to recreate this same thing in a civilian setting. Something called the Resuscitation Outcomes Consortium. It's a consortium of trauma centers in the United States and Canada that does pre-hospital trials. And we wanted to test this TCCC dictum in the United States in standard civilian centers with standard civilian traumas. So we want to look at the safety and efficacy of what we call controlled resuscitation. I'll tell you about that. So 19 EMS units, 10 hospitals in 6 regions all around the United States and Canada. The ones in the big blue there are the ones that participated in the trial. Okay, so the inclusion criteria was systolic blood pressure less than 90 with either blunt or penetrating trauma. Okay, we excluded prisoners, pregnant women, and the usual series of types of patients that are excluded. So how did we do this? You see those blue boxes? Those blue boxes were placed on EMS agency rigs and they either contained a 1 liter bag of normal saline or 2 250 cc bags of normal saline and a 500 cc bottle of water for the thirsty medic. So all the blue boxes weighed a kilogram and the medic couldn't tell what was in the box until they opened it. Alright? So when they opened the box, if there was a big bag of normal saline in there, a liter bag of normal saline, the patient got an aggressive resuscitation. They got a 2 liter bolus per ATLS and the goal systolic blood pressure was 110 millimeters mercury. If they opened the box and there's 250 cc bags of fluid in there, the patient didn't get any fluid until they lost the radial pulse just like the military or the systolic blood pressure was less than 70 and then all they got was a 250 cc bolus of fluid. Okay, that was the study done pre-hospital, continued into the hospital for 2 hours until bleeding was controlled. Alright? That's how the study was done. Now we also used standardized guidelines for how to manage the patients, the glue gland guidelines, and we did not dictate to the physicians how they would use blood products. They could use blood products in the study whenever they wanted to. Okay? So these are the two groups, standard resuscitation and controlled resuscitation, and if you look at a bunch of criteria, severity of injury, gender, age, how sick they were, all of these things, the two groups were very much equivalent. Okay, so this is the amount of fluid that was given, fluid and blood products. You can see that in the field, the standard resuscitation group got about twice as much fluid as the controlled resuscitation group. Now about 2 hours into the hospital stay, if you look at this, the overall volume of fluid given was the same, but most of the fluid given in the standard group was actually crystalloid, while most of the fluid given in the controlled group was blood. So this turns into a study comparing crystalloid and blood. So how do the patients do if you compare crystalloid and blood? So for all patients, in the standard group the mortality was 15% versus 5% in the controlled resuscitation group. You were three times more likely to die if you got a standard resuscitation with crystalloid. If you look at the blood trauma group, mortality 18% versus 3%. Six percent, six times more likely to die with crystalloid versus blood resuscitation. So this is how important this is. Okay, so I talked about crystalloid versus blood. What if you take this now to the pre-hospital setting? Several cities now have the ability to give blood pre-hospital. How many in the group here have the ability to give blood pre-hospital? I see one, two hands. Two hands. Blood, red cells only? Flights. So okay, helicopter agents only. So that's typical. So if you look at places like Mayo Clinic, Pittsburgh, Houston, Portland, Oregon, all of these are having blood products on the helicopter. So this is a study done in Pittsburgh, and they looked at helicopter transports, and they compared patients who received blood in the field versus those that don't. And in Pittsburgh at the time of this study, all they had was red cells. So patients receiving red cells pre-hospital versus those that didn't. Okay, this is a Pittsburgh study. Bottom line is for all helicopter transports, if you got red cells, you are five times more likely to survive, just like our study. Now if you look specifically at the same helicopter transports, look at patients who got red cells versus those that don't, six times more likely to survive if you got blood in the field versus just crystalloid. Very, very impressive. Now this is a very interesting trial. This is actually from Afghanistan, and this used three different types of agencies. The UK MERT, the MERT was a helicopter transport that was done by the British, had doctors, nurses, as well as medics on it. And they had both red cells and plasma. Also this had, this is also data from the US that also carried red cells and plasma. And in this study, they compared patients who got red cells and plasma versus those that didn't in Afghanistan, in war casualties. And the bottom line is you can't see what this says, but what it says is if you were on a helicopter that had blood, you got more blood, you got a higher ratio of plasma to red cells, and you were more likely to survive. So all of these studies are showing that if you can give pre-hospital blood, patients are more likely to survive. And this also shows that with pre-hospital blood, you give more red cells and more plasma. Very interesting. So let's skip that. So let's move on now to some of these trials comparing ratios of blood products. So the idea is in the theater, we can give whole blood. Most parts of civilian settings, we don't give whole blood, so what do we do? We give component therapy with high ratios. High ratios of plasma to platelets to red cells. So I'm going to tell you now about the proper trial. It was a prospective randomized trial we did a couple of years ago, and we compared ratios of 1 to 1 to 1 plasma to platelets to red cells versus 1 to 1 to 2. Okay, 1 to 1 to 1 versus 1 to 1 to 2. All right? Now the way this was done is in the participating centers, and there were 10 of them, if you had a patient who was predicted to get a massive transfusion, they activated the massive transfusion protocol, and boxes of blood with the correct ratios were brought to the patient's bedside. So the boxes contained the correct ratios, so you had to give the right ratio. All right? So it was either 1 to 1 to 1 versus 1 to 1 to 2. Now these graphs show the survival of the patients. And what do you see here? What you see here is an early separation in survival with a 1 to 1 to 1 group having a higher survival. And if indeed you measure survival at three hours, it was statistically higher in the 1 to 1 to 1 group. Now interestingly in this study, the randomization was only continued until the bleeding was stopped. And that occurred at about three hours. After three hours, again, the physicians could do whatever they want in terms of blood product resuscitation. And I'll show you the results of that. So what happens is in the first three hours, survival is higher in the 1 to 1 to 1 group, but after three hours, survival is the same in both groups, and at 24 hours and 30 days, there was no statistical difference in overall survival. The survival benefit was diluted out at 24 hours and 30 days. So look what happens. This is very interesting. This is the product ratios over time. Okay? So what you see here is the pre-randomization, during randomization and the post-randomization ratios. Okay, so in the pre-randomization period, the ratios with both groups were about one to two. During the randomization, the patients got exactly what they were supposed to get, one to one to one in that group and one to one to two in the other group. Look what happens post-randomization, both for plasma and platelets. The patients in the one to one to two groups got a lot more plasma and a lot more platelets and the two groups start to converge. So when the physicians could do whatever they wanted, they started to make up the difference and they gave all the plasma and the platelets. And that's probably why we didn't see any difference in mortality after the three hour period. Now these are the causes of death. Very interesting, by far and away, the leading causes of death in this study, no surprise, exsanguination number one, traumatic brain injury number two. Now look at all the other causes of death, things like sepsis, multiple organ failure, ARDS, those were very rare causes of death. In this bleeding study, the patients primarily bled to death. So that's the cause of death in exsanguination study. Okay, I wanna talk a little bit about, looks like I have a little bit of time left, I wanna talk a little bit about plasma. All plasma is not created equal. Okay, and you need to think about this when you go back to your trauma center, about various types of plasma. Now what I've shown you so far is that there appears to be a benefit to giving high amounts of plasma. Now there's a couple of reasons why that may be. One reason is because plasma corrects coagulopathy, but I'm gonna tell you about some other effects of plasma. Okay, so first of all, what are the types of plasma? First of all, thawed plasma, what is that? So you take whole blood, you separate into its components, and then the plasma that you take is frozen. That's frozen plasma. Once you thaw that frozen plasma, you can store it for five days. That's called thawed plasma, okay? Thawed plasma, so it's FFP that's been thawed and it's maintained between one and 60 degrees Celsius for up to five days. What does that allow you to do? If you have a lot of thawed plasma available, that allows you to maintain a one-to-one ratio of plasma to red cells. If it's all frozen, you can't maintain a high ratio because you have to thaw the plasma first, okay? And what happens is there's really minimal change in the quality of that plasma. This slide shows the degradation that occurs primarily in factors five, eight, and protein S. Now, protein S is an anticoagulant. Bottom line is the plasma has the same thrombogenic potential at one day and five day, and that's why you can store it for up to five days. So that's thawed plasma. Now, what about liquid plasma? This is what we use in our trauma center. Liquid plasma has never been frozen. If you're in a high-volume center and use lots of plasma, there's no reason to freeze it. Freezing and thawing actually degrades the clotting factor activity. So if you just take the plasma that's been separated from the whole blood and you never thawed, you store it at one to six degrees Celsius, you can store it for 26 days. If you work in a high-volume center, that's plenty long to keep the plasma. You don't have to freeze it. Okay, so that's liquid plasma. That's what we use at our center. Do any of you use liquid plasma in your center? So a couple, anybody else? So this is something, when you go home, say I want the liquid plasma, because this stuff has better factor activity, never been frozen, not degraded, and you store it for 26 days. Okay, so here's the actual data on the factor degradation. Once again, factors five and eight are the ones that degrade the most. They do not affect the thrombogenic potential. Essentially, that plasma's equivalent to 26 days as it is at one day. So that's liquid plasma. Now what about dried plasma? So this is plasma where you take the fluid out, you turn it into a powder, and then you can restore that powder at any time, okay? This is being used all around the world except for the United States. There's a French product, a German product, there's a South African product. Now think about this, if you have the plasma as a powder, you could literally put it in your medicine basket, and if you cut yourself shaving, put a little water in the plasma, you can inject it to stop the bleeding. Now literally, you could have this on any U.S. agency, any austere condition. You can have rural locations that don't use much plasma. All you have to do is put some fluid in there, you've got plasma. Okay, dried plasma, okay? U.S. products are currently in phase one trials. We don't have a product. There are several different products I mentioned. So the German Lioplas is one of the products. You can see it here below the written stuff there. It's a single donor plasma, so it has to be blood type compatible. It's stored for up to 15 months. They've given over 500,000 transfusions of this stuff, and it's very, very safe, as safe as regular plasma. Readily used throughout the German civilian and military uses. Okay, now there's something called the French Flip P. This is a little bit different product, very interesting. This has up to 11 donors, so it's a universally available product. You don't have to worry about blood type compatibility. Very nice product, stored up to 24 months. The United States Special Forces uses this product on IRB protocol in theater, but not in the United States. They've given over 1,000 transfusions with no major complications. Okay, here's another solution. This is a very interesting solution. This is from a study that just completed in Denver. So what do they do there? What they do is they store plasma in large, really thin bags. So special bags that are very thin, has very, very high surface area. So on the actual EMS ground rigs, they have these units of plasma frozen, and they have something called a plasmatherm. When they come upon an injured patient, they take one of these bags out of the freezer, on the rig, and they put in the plasmatherm, and in three minutes, it thaws. Because the surface area is so big, you can warm it in three minutes. Okay, so this is a technique where you can take plasma, put it in the field, and actually give it to patients in the field. And they gave it to over 100 patients in their study, and we'll see what the results of their study is. Okay, so I talked about some other potential benefits of plasma, right? We know it has coagulation benefits, but what else is going on? It turns out there's over 1,000 proteins in plasma. Over 1,000 proteins in plasma. Many of them, we don't even know what they do, but we know that they're biologically active, they have unknown functions, they suppress dysfunctional information, we know that they seal the endothelium, I'll talk about more of that, and they rebuild the glycocalyx. I'll show you these things. Okay, so I mentioned earlier the endotheliopathy of trauma. What's that? Here's a blood vessel and a capillary, okay? This is a normal blood vessel, normal capillary, no leakage is occurring, they are sealed. The endothelium is sealed in these normal vessels. All right? Now, as soon as you subject a human being or an animal to trauma, the endothelial cells contract, and they now start to leak fluid out of the endothelium. This is what causes edema. This is what causes ARDS, these leaky capillaries, okay? Now, if you give fluid, a crystalloid, normal stenolaxated ringers, the cells contract further and there's more leakage, more edema, Michelin people, abdominal compartment syndrome, ARDS. That's what causes these leaky capillaries, all right? But if you give plasma, you actually see the endothelium seals and the leakage stops. Another benefit of plasma, okay? That's the endotheliopathy of trauma. Now, it turns out if you take human endothelial cells and you cover a dish and you measure the conductivity of electricity, you can actually measure the degree of permeability of the cells. All right, so these are studies that I've done. They're very, very interesting studies. Here you see a study where they looked at plasma and what you see is in these chambers with endothelial cells, if you put plasma in there, there's absolutely no leakage. As you reduce the concentration of the plasma, there gets to be more and more leakage and then when you get to LR, they are fully permeable, 100% permeable, completely leaking, okay? That's plasma versus crystalloid. So this is the glycocalyx. The glycocalyx is in the inner portion of the endothelium. On your very left, you see a normal glycocalyx. It's very robust. You see hemorrhagic shock alone. You see injury to the glycocalyx. If you give lactated ringers, you basically get rid of the glycocalyx altogether, but if you give plasma, you start to recreate the glycocalyx and here's some studies in mice. These are hemorrhagic shock studies in mice. Once again, if you look at the lungs of these mice, if you look at injury plus lactated ringers, you see severe cellular inflammatory infiltrate into the cells which are mitigated and made better by plasma. So crystalloid cause endothelial permeability, lung injury, plasma makes it better. Very interesting. See the same thing here, the red and the green and the shock mice there is permeability which is treated with plasma. In all of these studies, you see benefits of plasma, decreasing permeability, decreasing leakage. Okay, now this is some very interesting stuff here. So these are some studies that were done where they took the circulations of two mice and they combined them. And they took an old mouse and a young mouse. Okay, and they combined their circulations. All right, so what did they see if they combined the circulations of an old mouse and a young mouse? Now this is the equivalent of giving blood, right? So donors, you don't know the age of your donor's blood. What if you get blood from a young donor versus an old donor? Well, this is what they're recreating in mice. What they found was that when they combined the circulations of these two mice, the old mice starts to become young again. They see axonal regeneration and robust muscular redevelopment and regeneration. And there's reversal of aging in the older mouse. What happens to the young mouse? That mouse gets old. So really, Bram Stoker was right. If you combine the circulation, you take blood from a young person, you can actually become young again. And it's even possible if you use fetal blood, you could reverse your scarring. Because fetuses don't scar. So this is very interesting, pure biosis. And this has major implications about not only the age of the blood that's donated, but the age of the donor and the qualities of the donor. So there's a whole area now of investigation looking at the ages of the donor and the qualities of the donor. Maybe there's good donors, maybe there's bad donors. And we can find those good and bad donors. Very interesting. Okay, a few more minutes. I wanna talk about the number one thing in that TCCC thing, stop the bleeding. Now y'all know about tourniquets, right? I'm gonna show you new and novel ways to stop bleeding. Okay, first one. This is the CROC, the Combat Ready Clamp, developed by the military. It's a little C-clamp. You see it has a screw device. You can put it over the inguinal area or the femoral region and you screw that thing down and you can stop bleeding from the femoral artery. Now, how many of you saw a Blackhawk down? So most of you saw it. Remember that soldier who bled to death? They had a gunshot wound, a fragment injury to the groin and the medic couldn't stop it. If he had this C-clamp, he could have put it approximately injury, screwed it down and stopped the bleeding. Okay, and this is available. This can be, EMS has this available. Now, this is a pig study. What you see here is a central complete occlusion of the iliac and femoral artery with this device in that graph on the side there. Now, here's another device created by the military. This is the Junctional Emergency Treatment Tool. Okay, this wraps around the pelvis. You can actually occlude either the right or left inguinal region by screwing this thing down. All right, so now you start to get control of junctional bleeding, which you couldn't with a regular tourniquet. So this is a junctional hemorrhage control. This is the SAM device, does the same thing. Now, some of you may use this as the pelvic binder, the SAM pelvic binder. This company's actually in Portland. Guy's a really nice guy. I don't have any financial interest, but he is a nice guy, makes these tourniquets. And basically, this is a pelvic binder that has these blottable balloons, and you can, again, you can put this on the pelvis, close down the pelvis, and then blow up these balloons and occlude flow in the iliac arteries and beyond. Very interesting. Last one is the abdominal aortic tourniquet. So this wraps around the abdomen, and it has a balloon that blows up. You can see there in the upper left, and you can occlude the aorta externally and distal blood flow. And the reason why I know this, because they did this in normal volunteers, which of course are medical students. And you can see here on the left, the flow in the femoral artery with this tourniquet raised. And what you see is, essentially, all blood flow in these medical students goes away when you blow up this tourniquet. You can actually occlude blood flow in the aorta with this tourniquet. Now, on the right is the pain scale. So these medical students were screaming in pain. It is painful. All right, here's another device. Again, this one was developed in Portland, Oregon. It's called X-STAT. What is this stuff? So think about a junctional injury. You've got a gunshot wound near the clavicle. There's a hole there, and blood is pouring out. So this is a syringe that has little pellets in it. And these little pellets, when they're put in the wound, increase in size by four times. So you can actually fill a cavity and compress it with these pellets that blow up in size. And this has been used down range. It's been used also by civilians. This is carried by medics in Portland. Another device, junctional hemorrhage. You might have a gunshot wound either to the shoulder, maybe, or groin. You put the syringe in the hole, fill it, fill these pellets. They blow up, and they compress the bleeding. Very, very interesting. Okay, how about the, this is another device. This is called, this is an arsenal phone. So what's this all about? Okay, this is a phone. Actually, the way this works is, you make a small hole in the abdomen, okay? And you have this gun, okay? And the gun contains two fluids. And what you're gonna see here is, through the small hole in the abdomen, the gun is injected, the two fluids are placed into the abdomen, and the two fluids combine. Those fluids then polymerize, fill the abdomen with a phone, which then compresses the abdomen, okay? So this could be done in the field, this could be done, to me, the ideal use for this is, I live in Portland, Oregon. 100 miles away is the Oregon coast. There are not very many surgeons on the Oregon coast. You got a guy with a spleen injury and a blood pressure of 50, they're not gonna make it to Portland. But if you have this phone, they could put the foam in the abdomen, blow up the phone, and the patient can survive till they get back to the hospital, 100 miles away. And this has now been studied in pigs, it's been studied in dead people, to get the dosing correct for human beings, and trials are getting ready to be started in humans, in living humans, and this could be available in the next five to 10 years. Very, very exciting explosion of device. So the focus, really, what I'm telling you is the focus is getting away from resuscitation, and the focus is on stopping the bleeding, and that's where it needs to be. Okay, so what can we conclude from all this? Number one, fluids are bad. They delay transport, they cause coagulopathy, they pop the clot, and they increase mortality. Prehospital blood is now becoming increasingly available, and you can expect a few people that raise their hands, the rest of you can expect that your agencies are going to have prehospital blood, both red cells and plasma, in the next five years or so. Okay, the benefits of plasma exceed coagulation. It's all about the endotheliopathy of trauma, sealing the vasculature, avoiding leak, and stopping the bleeding is the number one goal, and something that you're going to be hearing about, how many of you have heard of the Stop the Bleed campaign? That's great, everybody's heard about it, the idea being that every US citizen's going to be able to stop the bleed in the field, we've got lots of techniques to do it, the future is very exciting, and I think we're going to see a lot better outcomes with changing our focus on stopping the bleed. And that's all I have, I'm happy to take questions if we have time. So let me repeat the question. I don't know if all of you could hear it. So the question is about what if patients are being transported long distances from rural settings, takes maybe four to six hours. What's the recommendation with respect to hypotensive resuscitation? Okay, so I think that this is a very important, so there's a very important distinction here, right? So there's lots of different terminology. The delayed resuscitation, which was done in the Texas study, the Houston, Texas study, that means giving no fluid. So giving no fluid for four to six hours probably isn't gonna work in a patient who's in shock, okay? So that's why we use the term controlled resuscitation. So controlled resuscitation ensures that the patient is adequately perfused, but to the minimal level that restores adequate perfusion. So I think, and I think it's very well documented based on the military literature, a lot of those military transports were for long periods of time, like four to six hours, eight hours, 12 hours. Patients that are trapped in tactical scenarios end up with really prolonged resuscitations. Now, if controlled resuscitation is utilized and perfusion is maintained at the minimal level, those patients do well. So I think the recommendation at this point is to maintain adequate perfusion at the minimal level using minimal fluids possible, but maintaining adequate perfusion as evidenced by a good strong radial pulse and adequate normal mental status. I think that's the goal. Any other questions? Yes. Yes, a really good question. So the question was how are they doing this study in the field, this plasma study in the field? Is that a single donor plasma and what about blood type compatibility? So great question. The answer is that is single donor plasma. It's the same plasmas that you would use in your hospital except it's in this little thin bag. That's the only difference. So they use universal donor plasma for the study and there's two universal donor plasmas. It's either AB or it turns out that low titer A plasma is a universal donor. So you can use AB or A as a universal donor low titer A. So that's what's utilized and that's the same thing you're going to get in your hospital when you have a massive transfusion they bring you a box of blood and they don't know the patient's blood type. Use universal donor products. So for red cells that's type O. For women O negative, males O positive. For plasma it's either AB or A plasma. Universal donor. Good question. Any other questions? Yes. Schweitzer from Canton, Ohio. The question I have is on the ROCK study and on almost all these studies especially from the military it's young relatively healthy people. We have significant amount of data showing that in elderly people which is in our institution about 60% of our of our trauma registry is over 60. There's significant amount of data that shows that hyperperfusion of the brain is terrible. They have strokes, they have all kinds of neurological problems, deficits, worsening dementia, etc. So how do you how do you correlate the two? You have older people that fall that have bleeding you know that ruptured spleen or whatever and you know and then you're you're trying to do you know selective resuscitation. What's the target? So the great question I think y'all heard it because you had a microphone. So what about older patients? So older patients are a different ballgame and the reason for that is because older patients have normal blood pressures that are much higher than younger patients. So my you know normal blood pressure for a young person might be 120 but if a 70 year old person comes in with a blood pressure of 120 they may be in profound shock. So I think that you know it's very difficult but I think that the principles are the same. Restore adequate perfusion in those patients the same way that you would in a young patient but your goals may be a little bit different. Their blood pressure goal may be 160 or 150. I think mental status does help. Another important point which I think you alluded to is that these these techniques of hypotensive resuscitation controlled resuscitation do not apply to patients with traumatic brain injury. Most of the elderly patients are presenting as falls they have traumatic brain injuries. These types of resuscitations do not are actually contraindicated in patients of traumatic brain injury because adequate perfusion of the brain is the number one most important thing in those patients. So controlled resuscitation hypotensive resuscitation does not apply in patients with traumatic brain injury. Very very important point. Yes. Yeah so the question is what about albumin and starch? Very interesting. Those products do absolutely nothing for for coagulopathy. Actually starch after several units of starch it actually makes you coagulopathic. It's worse than crystalloid with coagulopathy. Those products actually more effectively raise the blood pressure which will more effectively pop the clot and there have been literally hundreds of studies tens of thousands of patients studied that showed no benefits of those solutions for resuscitation. So we do not use any starch we do not use any albumin in our center for resuscitation. We have to so we have time for another question or should we stop? One more question one more question. So the question is you have to give a fluid. Would you prefer to give LR or NS? Okay so remember what I said. Those are at the bottom of the list. Number one whole blood. Number two one to one to one. Number three plasma. Number four red cells. You don't have any of that stuff and you got to give one versus the other. My recommendation to you is to give lactated ringers and the reason why I would give lactated ringers over over NS is number one it has a more normal pH. The pH of lactated ringers is more in the 6.5 range as opposed to 4 to 6 for normal saline and number two lactated ringers is a balanced salt solution. It has a much lower chloride concentration so lactated ringers is actually a buffer and is much less likely to cause acidosis and coagulopathy. So between those two which are at the bottom of the list I emphasize I would give lactated ringers over normal saline. All right I better stop. Thank you all very much.

video

Dr. Martin S. Schreiber

trauma patients

fluid resuscitation

plasma

hemorrhage

endothelial pathology

Combat Ready Clamp

Junctional Emergency Treatment Tool