Okay, this morning so far we have heard about one aspect of keeping kids out of trouble and that's keeping an eye on avoiding respiratory failure, paying attention to what happens in the lungs. The second part of this, according to PALS, is keeping an eye, avoiding monitoring for shock, avoiding it completely or resuscitating it quickly. I have no disclosures that impact on this presentation. So for me, when you talk about respiration, Robbie would talk about the lungs, I talk about the mitochondria. So ultimately, oxygen turns out to be very important for what we want to do in life. In all shock states have this one of two things going on, either there is inadequate delivery of oxygen to the tissues or alternatively, delivery is fine but for some reason that oxygen isn't being utilized by the tissues. So a kind of a comprehensive view of shock is impaired or inadequate oxygen consumption relative to the needs of the tissue. It's not just delivery, it's also once the oxygen gets there, it needs to be utilized. So just to take this point home further, this is a typical substrate for generating ATP. And in cells, you can take this glucose molecule, split it in half, generate two pyruvate molecules and out of this total sequence of reactions generate two moles of ATP. Alternatively, if you have oxygen available to really metabolize this molecule to carbon dioxide and water, you can see that the ATP production, the efficiency of energy production is almost 20-fold higher. So if you're running a 100-yard dash and your calf muscles are sore, anaerobic metabolism is sort of okay for a while. But for your head and your heart and your renal collecting system, respiration has to be intact or you will get organ dysfunction very quickly. So there is this indispensable need for mitochondria for the way we live our lives as eukaryotic cells. And just as a side note, we made this deal, we, a collection of eukaryotic cells, I don't know, a million years ago or more with some bacteria that was very good at utilizing oxygen to generate ATP efficiently. So it turns out that in shock states, if you have damage to these mitochondria, what they really are are foreign bacteria. So the proteins that are inside of a mitochondria look like bacterial proteins. They don't look like eukaryotic proteins. The DNA that's inside of a mitochondria looks like bacterial DNA, not eukaryotic DNA. So if these mitochondria are broken up because the cell is disintegrating, it is just like getting a second hit damage associated molecular patterns that whatever shock state you're in can be amplified. So just taking this all the way to its logical conclusion, the mitochondrial electron transport chain ultimately is where this oxygen is utilized. There's really four steps to all of this. The first is generation of reducing equivalents. This happens during glycolysis in the cell cytoplasm with generation of NADH. That pyruvate goes into the Krebs cycle. You generate more reducing equivalents, FADH, in case you care. But these reducing equivalents are important. First of all, the hydrogen cation is what is used to set up this electrochemical gradient and drives this really neat molecule, the ATPA synthetase, and that's where ATP is generated. And all of this ultimately happens because at the end of all of this is this oxygen molecule that is a terminal electron acceptor for the whole process. So this is what is required for efficient energy production. This is ultimately what we're trying to maintain with our shock resuscitation. Now this mitochondrial electron transport chain can be manipulated. It can be damaged. For example, in septic shock, various components along the way can be altered by reactive oxygen species, and this system can then work ineffectively in what it's supposed to do. And we'll talk more about this in just a few seconds, a few minutes. So the major causes of lactic acidosis, lactate is the molecule that we utilize to measure our resuscitative efforts. It's not perfect. For example, in sepsis there's a number of reasons why lactate is produced, but in general it has withstood the test of time. And typically lactate is increased with impaired oxygen delivery because that pyruvate can't go into the Krebs cycle, can't utilize the mitochondrial electron transport chain, and that pyruvate is reduced to lactate to regenerate NADs so glycolysis can occur. Impaired oxygen delivery, people usually think of the heart and how that functions in delivery. They also think of heterogeneous perfusion, diffuse microvascular thrombosis at the tissue level because it can have the same effect. Aerobic glycolysis is production of energy with oxygen but utilizing glycolysis, in this case lipid fatty acids provide the energy source to make this work. This is not pathological. This is just a very fast way to make lots of ATP and where you see this typically is like somebody with acute myelogenous leukemia and a high burden of white cells that are doing this and generating lactate in the process. This aerobic glycolysis is augmented by beta 2 agonists, especially epinephrine, but also for example albuterol. And when you put somebody, a patient, initiate an infusion of epinephrine and you're measuring lactate frequently, you'll actually typically see a rise in lactate with that intervention. Again, that is driving this aerobic glycolysis. It is not pathologic. These poor kids who have these unrelenting seizure disorders that we all take care of and they're on four anticonvulsants and on top of that they still have seizures. These kids typically have a mitochondrial defect and can't metabolize energy efficient, generate energy efficiently, particularly in their brains where they need it most. Aerobic can also acquire damage without being congenital and sepsis is the best example of that. When this lactic acid is persistent and you just can't figure out what the hell is going on here, think about thiamine deficiency, particularly in a child who is on chronic total parenteral nutrition support. Is that recipe really right for this child? It's easy enough to give. It has a high benefit-risk ratio. And what it is doing is it's serving as an essential cofactor for pyruvate decarboxylase. That's the entry to the Krebs cycle and everything that happens after that. Then there are a number of drugs that are cytotoxic and generate lactate. For example, cyanide binds on cytochrome oxidase. Remember that diagram with oxygen at the very end. Cyanide sits at the active site and shuts the whole thing down. Finally, nitric oxide also does the same thing, but it is a competitive inhibitor there. Nitric oxide is one way of regulating the mitochondrial electron transport chain. In the larger lecture, I think the statement was made that this shock classification, there's lots of overlap and there's nothing magical about this, but it's just a good way of talking about a few issues. The most common type of shock around the world, vomiting, diarrhea, loss of fluid, is hypovolemic shock and it is appropriately corrected with volume replacement. Similarly, in trauma, the trauma surgeon who's running the code is going to scold you if you want to reach for norepinephrine quickly. These patients typically need fluid and as you now know, there is a shift towards using blood products earlier as compared to later. Obstructive causes of shock are all these things that can be happening during your resuscitation, which you think is going well, you're doing everything right and this patient's just not getting better. This is one set of the H's and T's in PALS. Pneumothorax, pericardial effusion, pulmonary embolism, even aortic dissection. We take care of kids with Marfan so that can actually happen in children as well as adults. Then there's this big cause of obstructive shock and that's abdominal compartment syndrome. We see this frequently in our sickest patients. It could be a post-surgical patient with an abdominal infection, but in my experience, it occurs more commonly in the hemock kids who have a transplant. Now they have vena occlusive disease or SOS, whatever you want to call it nowadays. They have a taut abdomen and now their urinary output is falling off. If you took the time to put in a Foley catheter and transduce it and find that the abdominal pressure exceeds 20, that's a pink flag that you better pay attention to the pressure in the abdomen. This is a big starling resistor that is first of all putting some pressure on the venous outflow from the kidney. It's probably pushing up on the diaphragms and restricting diaphragmatic motion. So now you have abdominal pressure and organ dysfunction and if this pressure exceeds 30 for sure, you need to get your surgical colleagues involved. Typically you could put a catheter in the abdomen to drain any acidic fluid that might be contributing to that. Frequently in the hemock patients, everything is swollen, the intestines, the liver and sticking a needle in that mess is probably dangerous and they just need to have a surgical decompression. Okay, that's obstructive shock. And cardiogenic shock, I'm sure we'll hear more about this in the lectures related to the heart. The thing about cardiogenic shock in general for resuscitating children is you should be thinking about it. You may think, oh, this is hypovolemic. This is septic. But when you're doing your resuscitation and you're listening to the patient and you hear this, when you auscultate the patient, that is the patient has developed a gallop or the liver is now big or in a teenager if the jugular distension has elevated or there are new rolls, you should think about is there something else going on here besides sepsis, for example. Is there something wrong with the heart? Is there a myocarditis that is actually affecting the pump and more volume is actually going to be a bad thing rather than a good thing for this patient? So that's just something to keep in mind. And then lastly, distributive or kinetic shock, the example that typically is utilized is sepsis. There's other important causes, cervical spine injury. The teenage patient who's jumped into a stream comes in with a C cholera on, maybe struggling to breathe, has no sensation. The blood pressure is 80 over 30 and the heart rate is only 80. That's the red flag. This patient probably has a broken neck, disrupted sympathetic chain and they need that catecholamine back so the patient needs volume to fill up the vascular space and then probably some norepinephrine. Anaphylaxis is yet another cause of distributive shock. So the treatment of shock is a couple of things. Treatment of normal bulimia, this may sound simplistic and it sort of is, but I would say this is the most important unanswered question in critical care medicine. How do you actually do this? Because now there's good evidence that too much is dangerous just as is too little. We'll talk more about that. And then optimizing cardiac performance. This is the other part of the H's and T's for a PEA rhythm in PALS. So establishing an effective circulatory volume, trying to hit that sweet spot without going overboard and optimizing oxygen delivery with appropriate cardiac output are the keys to resuscitating all shock states. So this is just a schematic of the same thing that kind of illustrates the four dysoxias. I'll close with that idea again. But this is an old concept, but I think worthwhile just in terms of discussing what can happen. Hypoxic dysoxia occurs in the lungs. We've already heard about in the face of hypoxemia, what's important there is recruiting that lung, opening up the alveoli in the setting of injury to the alveolar capillary membrane where there is probably plasma contents coming into the alveoli. from the environment through the alveolar capillary membrane on to a red cell. Red cells in the vascular space need to be adequate, number one. And I would say, you know, typically in the ICU we talk about a crit, hematocrit of 20 or hemoglobin of 7 being adequate. If you're resuscitating somebody, don't use 20, move to 30 of hematocrit or hemoglobin of 8 for the purposes of resuscitation. Then those red cells need to be pushed around the vascular space. They need a pump to do that, so you have to have adequate cardiac performance, and if you don't, that's known as stagnant dysoxia. And then the oxygen needs to transfer from the hemoglobin through the red cell, across the plasma, across the interstitial space, into the cellular membrane, across the cytoplasm, and finally get into the mitochondria, and this transport may be facilitated by myoglobin in skeletal muscle and cardiac muscle. Cytochrome AA3 is the end of the diagram where oxygen binds to facilitate aerobic metabolism. You've already seen this a couple of times, so you probably should know by now that you need to know this equation cold. So for shock resuscitation, what we're concerned about is ensuring adequate oxygen delivery. And when you think about what we do as intensivists, this is what we do. Most of it involves getting oxygen from the environment, atmosphere, into the lungs. That's the most frequent place where this is disturbed, and we use the ventilator and oxygen to do this. But as I said, the dysoxias also can involve the blood, the pump, and the mitochondria as well. So content is mostly hemoglobin. There's a small amount of oxygen dissolved in the blood, water space. This may be important in cyanotic disease, but most oxygen is carried on the hemoglobin. The objectives of administering fluid are to restore the effective circulating volume. Sometimes blood is the best fluid to give because it will stay in the vascular space, and particularly if the hematocrit is not adequate. And then lastly, to correct metabolic imbalances. The idea here with volume resuscitation is to get to the inflection point of this Frank Starling curve, provide adequate volume that has with it an improvement in cardiac output without overdoing it. So there's this Bellamy curve in critical illness, inadequate volume resuscitation associated with hypoperfusion, poor outcomes. But now there's lots of population studies that also demonstrate that hypervigilemia is also associated with all kinds of adverse outcomes. The principles of fluid resuscitation are shown here. The point nowadays is dynamic measures of fluid responsiveness are what we should be looking at, some version of the leg raising maneuver, and measures that actually monitor cardiac output with our volume challenge. The cardiac environment optimization are these things here. Again, the H's and T's in the PALS course don't give bicarbonate unless you can assure yourself that you'll be able to blow off the CO2. Terms of the drugs, if you need augmentation of inotropy, epinephrine is typically the first drug, afterload reduction, milrinone, but other things can be used as well, and afterload augmentation, norepinephrine, vasopressin, and now angiotensin 2. If the lactate is rising and the central venous oxygen saturation are rising simultaneously, that oxygen is being delivered but not being utilized, that's a mitochondrial problem. And lastly, here are the four dysoxias. We have treatments for three of them. If the patient does have this mitochondriopathy, for whatever reason, we currently do not have a resuscitation for that form of shock. Thanks for your attention.

respiratory failure

shock resuscitation

oxygen delivery

mitochondria

fluid resuscitation

shock states