It's got electrolytes - Real Medical Case Presentation Number Two

Start with electrolytes to balance levels. I would want a chest x ray and a cortisol level and a cmp.

98+18=116 Sodium is 135. Look at calcium.

Physical appearance you described makes me suspect Cushing's. The "hunchback" appearance, the moonface, etc. could be from long term prednisone therapy, but you indicated that he only had 2 4 week regimens, so that shouldn't be the cause.

Oops. I had already turned off my computer and realized I didn't include insulin to get the Blood glucose level down.

Oh man, those guys totally ripped off Powerthirst: http://youtube.com/watch?v=qRuNxHqwazs

Electrolytes seem lowish, especially K+, but BUN is high and glucose through the roof. Also high anion gap. Test blood gases, pay special attention to pH and CO2; or pull a Dr. House and smell his breath for acetone, because the new prime suspect is indeed ketoacidosis.

Either way, push insulin, fluids and electrolytes to compensate for that crazy anion gap. Maybe that'll keep him breathing long enough to figure out why the heck his white cell count is so high despite him being on an immunosuppressant.

Just one little point...with the glucose level that high, the true potassium level is probably even lower, so careful.

Yeah; suppose I wasn't being very specific with just "push electrolytes." If the guy is in fact ketoacidotic, he probably doesn't have a wink of K left in his system, and it'll drop even further as the acidosis and dehydration correct. Should keep a close eye on it.

good job on asking for the ABG.
pH 7.43 CO2 32 O2 57

The cushingoid features could come from repeated bouts of prednisone, and the leukocytosis could be the result of starting another cycle.

As far as life-saving measures O2 first. this patient is working too hard to breathe. then fluids insulin and potassium are a safe bet.

Good job spotting the gap too. Ketoacids arr a good culprit but could it be anything else? want a test? is it strange to anyone else that a Type II diabetic seems to have DKA?

The body shape suggests long term cortisone treatment, perhaps he has been abusing his prednisolone, taking it because it makes the symptoms of infection "go away". Watch for prednisolone withdrawal symptoms.

The prednisolone would mask signs/symptoms of infection, but the white blood count shows an infection somewhere, so to try to find it, take blood cultures, a urine for micro culture and sensitivity and search the guy thoroughly for skin/moouth infections/sores, taking swabs for mc&s if any found. Being diabetic he is especially liable to infection. Check his feet and fingers carefully for damage.

Start a broad spectrum antibiotic IV.

Keep him on oxygen, not too high a concentration because he has a long standing obstructive lung disorder, and has adapted to a low "trigger point" to drive his respiration. If you raise the oxygen too high his respiration won't be triggered and he'll stop breathing.

Maybe a nebuliser would help? ventolin? but that would make his heart beat faster and exacerbate his anxiety. Maybe something else?

His bicarb is very low. He is acidotic.

I think you should do an arterial blood gas? That will tell you how well his respiration is working at a cellular level.

To keep him alive...put him on a saline (or a multi-electrolyte?) drip, a dextrose drip and an insulin infusion - and adjust the insulin/dextrose according to ?quarter hourly? blood sugar readings.

Monitor his electrolytes, especially his potassium. There is a relationship between blood potassium and blood acid/alkilinity, I can't remember how it works! (good job I'm not a doctor!)

The air hunger and all the fuss will be making him very anxious, he needs to be treated very gently and reassured as much as possible. Support him sitting up with pillows and a heart table, because he doesn't want to be wasting his energy on supporting himself. Reassure his family and make sure they are supporting not hassling him.

Monitor his heart with an ECG and quarter hourly obs on his TPR, BP, arterial blood gas and level of consciousness (make sure you get a baseline on this and check with the family re his normal mental state).

Monitor his urine output quarter hourly to make sure he is getting rid of the fluid you are IVing into him and to keep an eye on his kidney function.

I would be most concerned about a generalised sepsis brewing.

di

What is his nutritional state? I'm wondering why he looks older than his years. Perhaps he is an alcoholic?

di

Liver function test, C reactive protein, ESR please.

Note: some of my suggestions are not conventionally accepted and are to be used for discussion purposes only.

I think the extra anion is lactate and not ketoacids. My prediction would be no ketones in the urine. His problem with lactate is too much production due to not enough mitochondria in peripheral tissues (too much ATP from glycolysis) and insufficient lactate clearance due to not enough liver mitochondria (both of which are secondary to low NO which triggers mitochondria biogenesis). His abdominal fat is due to the excess lactate being converted into fat.

Dehydration (from the elevated BUN) is masking anemia by giving a normal HCT. The anemia is from low NO which reduces EPO production.

The first thing to do is fix the dehydration with IV fluids. That will lower blood viscosity, reduce the load on his heart. Lower plasma viscosity will also improve flow of extravascular fluid (where his real problem is) which is what is causing his hypertension (to increase extravascular flow). The problem is he has capillary rarefaction, so the cells "too far" from a capillary can't get enough glucose or insulin because intervening cells consume it. Lower ATP from mitochondria in those cells increases glucose requirements too. This is what is causing the exacerbation of his diabetes type 2.

Giving him enough insulin to drive his glucose down to "normal" will be bad for him. The cells "too far" from a capillary are only getting glucose because the fluid leaving the capillaries is hyperglycemic. Drop that to normoglycemic and there won't be enough glucose delivered to those cells. Putting him into ketosis would be a benefit because ketones don't need to go through the GLUT transporters the way glucose does, but that takes a while (and isn't standard practice).

He might have an infection, it isn't in the lungs, look for UTI. Check for liver enzymes, but likely elevated. He is probably having kidney failure too.

His shortness of breath is due to anoxia (primarily) but also disrupted NO/NOx status. There are 3 things that trigger breathing, low O2, high CO2 and high R-SNO (the latter is very complicated and not at all well understood). When the NO/NOx/RSNO status gets out of whack, breathing regulation becomes unstable.

His labored breathing is troubling. If the muscles he is using for breathing don't get a chance to rest, they will pathologically remodel (as will his heart). If you put him on a respirator, it will be hard to wean him off it. If you don't, his breathing muscles may spiral down.

As I see it, there is no good "conventional" treatment. What he needs is more NO, but there are no generally recognized ways of increasing NO levels (and NO mediated improvements would be slow, days or weeks at best). Inhaled NO might help his breathing, but only while it is being inhaled with little or no residual effects.

is it strange to anyone else that a Type II diabetic seems to have DKA?

If you push a type II diabetic hard enough, they'll start producing ketones. However, I'd look for a different cause. Specifically, lactic acid. This patient has been on a lot of prednisone over time and just finished a course. Also his glucose is very high, despite high dose insulin and sliding scale regular insulin. He's afebrile, but so what: he's been on prednisone. He's probably infected.

I'd get blood cultures, with fungal isolate, and UA/culture then start emperic antibiotics. I'd also repeat the CXR in a day: a pneumonia can sometimes show only after a delay.

I'd also keep him on cardiac precautions until a 24 hour rule out is completed: some MIs are not seen on EKG, the first set of enzymes doesn't always show the MI, and diabetics can have silent MIs relatively frequently. This isn't the highest thing on the differential but it's so embarassing when someone dies of Vtach in the hospital.

He also needs some potassium: that potassium is going to start going down when you give him insulin (another reason to do cardiac monitoring: low K). His kidneys are in relatively good shape, so you can go ahead with supplementation with relatively few worries. (Though frequent monitoring of electrolytes is necessary.)

A PE is not out of the question either. What do you do for PEs these days? V/Q scan or has MRI taken over? Anyway, check for it and maybe doppler the legs. Emperic heparin might be reasonable while you're waiting. Certainly subq heparin or he will have a VTE soon, given that he'll be on bedrest for a while (functionally even if it's not ordered.)

I'd be cautious with the fluids, given his cardiac status. I don't think he's as dehydrated as most posters so far think he is (his BUN isn't that high) and he'll be getting a lot of fluid with the antibiotics and so on. Don't put him into overt heart failure: that won't help his respiratory state at all. Be careful with the oxygen as well: a COPDer can get very high CO2 levels if you give too much oxygen. Consider CPAP, BiPAP or intubation if you can't get the O2 up while keeping the CO2 reasonable. And watch the blood gas over time.

Hey, just for fun, what's his smear look like? Does he actually have leukemia? That could account for the symptoms, especially if he had an infection on top of it.

Can I give you a case? I have an amusing one...(details altered or invented, of course.)

A 25 year old woman presents for the first time to a primary care practice for a routine physical exam. Her chief complaint is that she hasn't had a pap smear in 2 years due to insurance issues (now resolved.) She feels fine, no complaints. PMH is significant only for "abnormal blood" found incidentally in the past, the patient can not elaborate any further. She has no complaints, no fatigue, weakness, lightheadedness, chest or abdominal pain, etc. There is no history of HPV infection but she is sexually active and has not had the vaccine.

Physical exam is normal. Specifically, heart rate is about 65, with a normal S1 and S2, no other sounds. Because she is a new patient, routine labs are drawn. She goes home with a plan to call about pap results in 2 weeks and return in one year or if any problems.

Two hours later you get a call from the lab about a panic value: her potassium is 6.5. The rest of her electrolytes are as follows: Na 140, K 6.5, Cl 103, CO2 28, BUN 10, Cr 0.5. CBC is pending.

You call her back and do an EKG: it is completely textbook normal. Again, no symptoms.

What does she have, how is it causing the high K and how do you prove it?

Can't read thread, Ow My Balls! is on...

Then, 'batin!

Did we ever get that calcium level? I think our farmer might have steroid-induced pancreatitis with respiratory complications.

Dianne, I'd like a CBC on your young lady, but with the history of "abnormal blood" and the hyperkalemia, I suspect she might have systemic lupus erythematosis. (Although I would want a redraw since she seems awfully peppy for someone with hyperkalemia, and there are at least a few ways to get a critical from a bad draw or a tube sitting around.)

It sounds like Dianne pegged it. Did you catch the infection in time, or did it progress to sepsis and ARDS?

Well, a blood pH of 7.43 despite high CO2 blows my respiratory anomalies due to acidosis theory right out of the water; not what I'd expect to see if his system'd been trying to expel CO2 to get his blood acidity down, and failing at it.

So I'm going to go with the lactic acidosis theory. The guy's oxy's been low for days, and he's been working hard to get as much as he did due to some kind of exarcebation of his COPD; plenty of anaerobic metabolism going in, and hence plenty of lactic acid to go around. Not enough to crack his blood buffer and produce acidosis, yet, but enough to produce the anion gap we're seeing. With his blood glucose so stupidly high, he's probably been pissing away electrolytes due to glycosuria too, probably not helping matters.

Guess we could do some urinalysis, check for ketones and the general state of his kidney now that he's more or less stable - but it's low-priority right now, and the COPD itself becomes the primary problem.. which I'll gladly leave in the hands of people more capable than me, because I'm waaay out of my depth at this point.

I'd like a CBC on your young lady, but with the history of "abnormal blood" and the hyperkalemia, I suspect she might have systemic lupus erythematosis.

The CBC shows a very low MCV and a mild anemia. The smear (done due to the strange MCV) shows sphereocytes. The repeat serum potassium is 6.4.

Dianne, how are her Thetans?

(Sorry, I've been trying to resist so far, won't do it again).

Since I didn't get a cortisol level or a calcium level, I assume I am on the wrong track.

Hate to jump to a new case, but Dianne, your person has creatinine of 0.5? I assume it is that low because she is just a little, skinny person with not much muscle and a great pair of kidneys. BUN of 10 usually would be normal, but that is 20:1. Is she dehydrated? Is she eating a high protein diet? Does she have a GI bleed?

Bill: Oops. That's a "changing the numbers to comply with HIPAA" error. The numbers were simply supposed to indicate that she is a skinny person with good kidneys. (I don't remember the actual numbers...they were pretty good, whatever they were.) Sorry about the red herring. Make the BUN 9 and the Cr 0.7.

In spherocytosis, the red blood cells would be smaller and more fragile. This would account for the low MCV and the higher K due to hemolysis, wouldn't it?

(Heh. I am not a doctor, so I am all with the zebra-googling.)

The lady - Anemia and spherocytosis can be consistent with SLE if the spherocytosis is autoimmune rather than hereditary. Has she ever had the butterfly rash, or photosensitivity? Is it time for Coombs tests and anti-nuclear antibody, or am I getting ahead of the game?

Can hemolysis result in such a big hyperkalemia without stressing the kidneys? And shouldn't her spleen have been peeking out on physical exam if she's making that many mutant RBCs?

Ok, let's see if I can get the lab caught up to requests.

Sed rate 30
Blood cultures at 24 hours show no growth to date. Urine cultures are also negative. A U/A and sediment showed no WBC, no RBC, no bacteria, leuk esterase negative, ketones negative.

Your resident refuses to give antibiotics in the absence of an identifiable source of infection and says the leukocytosis is likely from the prednisone he started yesterday. He also thinks that the signs of cushings were absent in this patient until he was exposed to multiple rounds of prednisone, so it's likely drug-induced cushing's syndrome.

Daedulus, your love for NO is bizarre.

To rule out PE the resident suggests a lower extremity ultrasound. While it doesn't rule out PE to find no deep vein thrombosis, it does lower it some on the differential. Your patient has no deep vein thrombosis.

Bill your cortisol level would be screwed by the fact he is on prednisone at the moment. We would have to change to dexamethasone for several days and try to take a measure.

Anonymous, don't worry, you're on the right track more than anyone. Your U/A shows no ketones, but you draw a blood lactic acid level and the LA is 10!

I realize this is getting advanced, but extra credit goes to anyone who uses winter's formula and the delta delta to figure out exactly which metabolic disturbances are present. I'll give you a hint, there is more than one.

Bill: You're right. Hereditary spherocytosis. The high potassium is due to hemolysis in the sample. A plasma K is normal. (A favorite trick on the boards is to get people to get overexcited about a lab result and suggest all sorts of tests and/or treatments that are not necessary. Don't fall for it...)

Mark, you're making us work! Winter's formula gives an expected CO2 of 33-37. (No, I didn't have WF in my head, but Google is amazing that way...)

So, a respiratory alkalosis and a metabolic acidosis (with anion gap and lactic acid.)

I know jack about medicine, but I'll give this a shot:

Could he have secondary liver problems? The liver's responsible for removing La from the blood, isn't it? A liver problem could also explain the lipidemia, couldn't it?

Is it something to do with his glyburide?

Aspirin can also produce lactic acidosis, check his self medication.

The high lactate level has a very poor prognosis, get ready to knock him out and artificially ventilate him, and slow continuous dialysis.

di (been googling obviously!)

Send your residents to break into his house, swab and search for clues, and dig up his dead pets.

(as in House)

Ok, he has metabolic acidosis (from too much lactate) and respiratory alkalosis (from getting rid of too much CO2 due to hyperventilating).

http://www.merck.com/mmpe/print/sec12/ch157/ch157b.html

Winters formula Predicted PCO 2 = 1.5 (HCO3) + 8 ± 2 = PCO2 ± 2

P CO2 = 1.5(18) + 8 +/- 2 = 35 +/- 2

Actual is 32 suggesting respiratory alkalosis

anion gap is 135 -98 -22 + 2.5 = 17.5 delta gap is 7.5,

17.5 10 + 18 = 25.5 suggesting metabolic alkalosis from hemoglobin dissociation. With the low O2, most of the hemoglobin still has CO2 attached to it.

He has 3 acid/base problems

Metabolic acidosis from too much lactate
Respiratory alkalosis from hyperventilation (slight)
Metabolic alkalosis from low O2 and hemoglobin dissociation.

His fundamental problem is not enough mitochondria in the liver (and elsewhere). That is only going to be fixed via more mitochondria biogenesis which means more NO.

http://circres.ahajournals.org/cgi/content/full/100/6/795

http://jcs.biologists.org/cgi/content/full/119/14/2855

It takes 19 times more glucose to make the same ATP through glycolysis as through oxidation in mitochondria. If you reduce ATP generation by mitochondria by 5%, it takes twice as much glucose to make up for that lost ATP by glycolysis. The normal vasculature can't deliver twice as much glucose.

The only way that physiology can deliver twice as much glucose (or more) to the cells (and it is the glucose concentration in the fluid next to each cell that matters, not the glucose value in bulk blood) is by inducing hyperglycemia (i.e. glucose "resistance"). To get glucose into the cells that are in the extravascular space (where 95% of them are), glucose levels in the blood have to be higher. The same with insulin levels. The cells remote from a capillary don�t get �enough� glucose or insulin because the intervening cells consume it. To get insulin to those cells physiology needs to induce hyperinsulinemia (i.e. insulin resistance).

If you do dialysis, use fluid with urea and not lactate. Use the dialysis to get rid of the excess lactate and maintain his glucose levels high (as high as you feel brave enough). Give him more insulin, but keep his glucose high via IV. If you do put him on dialysis that way, you can let his cells without enough mitochondria sustain themselves via glycolysis with an outlet for the lactate (which his liver can�t handle). Giving him enough glucose will prevent him going into cachexia so his liver can generate enough glucose to sustain him while turning his muscles into amino acids and the excess lactate into fat.

Put him on a ventilator to spare his respiratory muscles.

Then raise his NO level to increase his mitochondria biogenesis. Otherwise he will spiral down.

Anonymous up there is me; having a jolly time learning all kinds of fun stuff about the body's pH regulation and electrolytes -- but argh, my poor brain, it's having difficulty trying to wrap itself around this case. If Dianne's on to something, is it even possible for lung function to so crappy as to have enough of a anaerobic metabolism to produce a ton of lactic acid, but still functional enough for respiratory alkalosis to occur through hyperventilation?

If so, hey, we seem to've found a decent explanation for the crazy electrolytes/pH. Not confident about what to do next. The O2 we're already giving him should reduce his hyperventilation, since with normal-high pH he must be gasping for air more than for getting rid of CO2; I'm told that mechanism doesn't overcompensate. If his respiration rate goes down, we might want push some bicarb, keep a close eye on pH - don't want him short of breath again but for a different reason, acidosis for reals this time.

Even less confident about the root cause of his respiratory distress. COPD not my bag. On a Dr. House hunch, maybe check for candida pneumonia - the guy has thrush, and regularly uses prednisone, and the X-ray wouldn't rule it out.

This guy takes a diuretic, which can certainly mess up electrolytes. This would account for the low K+ and apparent dehydration. His low BUN also hints that he's urinating a lot.

So, what's this man's history? Is he actually going to the bathroom more often than usual? Has the weather been unusual in any way? New HVAC system at home? Exercise or other activity? And what has he been eating and drinking in the last few days? Anything new or unusual?

Oh, and have there been any changes in how he's taking his meds? Do any of the pills look alike?

daedalus gets a cookie! It's the deadly triple-ripple.

most of you got hung up on the sugars and WBC counts - both caused by the prednisone.

Good for daedalus!

My colleague was looking at the ABG earlier and said, "how can the lactate be so high with that pH; there has to be a respiratory alkalosis hiding in there."

So what is the "conventional" EBM treatment and prognosis?

Now I'm confused...what is the underlying cause of the various acid/base abnormalities?

The underlying cause is not enough nitric oxide which results in low ATP (acutely) and insufficient mitochondria biogenesis (chronically). Initially this presents as deconditioning. The only reason that aerobic exertion capacity can be increased over "at rest" is due to excess ATP production capacity by mitochondria. In the very short term muscle can produce ATP from high energy phosphates, or in the somewhat longer term from glycolysis, in the longish term from glycogen. In the long term, the best substrate is lipid, which can only be consumed aerobically. When muscle does glycolysis it makes lactate which it exports. The brain preferentially takes up lactate. The formation of lactate in muscle and its oxidation in the CNS increases muscle aerobic power by a little. Enough of an increase that physiology evolved to do it that way.

Mitochondria regulate O2 consumption by inhibiting cytochrome c oxidase with NO (and some other things too). This inhibition prevents O2 from being reduced to H2O. This is competitive inhibition, when the mitochondria need to generate more ATP, more substrates deposit more electrons on the respiration chain, the chain becomes reduced, O2 in the vicinity pick up some of those electrons and superoxide is generated in the mitochondrial matrix. There, the superoxide reacts with NO at diffusion limited kinetics and this pulls the NO level down. With a lower NO concentration, cytochrome c oxidase becomes uninhibited and reduces O2 to water by taking 4 electrons from the respiration chain. When the respiration chain becomes too reduced, more superoxide is formed and the NO level goes lower, reducing the inhibition of cytochrome c oxidase even more. Disinhibited cytochrome c oxidase binds O2 at a much lower O2 concentration. This allows the mitochondria to consume O2 to a much lower O2 concentration, which increases the concentration gradient from the capillary (where it is essentially constant) to the mitochondria. To increase the O2 flux by an order of magnitude, the O2 concentration gradient has to increase by an order of magnitude. O2 transport is solely by passive diffusion (but the path is complex because lipid has ~10x O2 solubility and (in muscle) myoglobin can aid O2 diffusion too). To achieve a 10x increased gradient the O2 concentration at the mitochondria must drop ~ 1 order of magnitude (because the level at the capillary stays about the same (the level in venous return blood)).

The only mechanism that mitochondria have for regulating their O2 consumption is the interplay between NO and superoxide. If the NO level is low for other reasons, then cytochrome c oxidase becomes uninhibited and the O2 level at the mitochondria is reduced. The lower O2 level facilitates O2 diffusion at rest because the gradient is higher. However, there is no "reserve" diffusion capacity. The lowest O2 level at the mitochondria is limited by the functional properties of cytochrome c oxidase with zero NO inhibition.

During extended periods "at rest" under conditions of low NO, the vasculature remodels. The vasculature is "well formed", that is there are pathways that trigger angiogenesis when there is insufficient vascularization, and there are pathways that ablate vasculature when there is too much. Low O2 is (conceivably) a sufficient signal for insufficient vasculature. High O2 is not a sufficient signal for when there is too much (because the venous blood return essentially always has the same O2 level, even when metabolic rate increases several fold.

Physiology has to have a signal to measure when a cell is sufficiently "diffusively close" to oxyhemoglobin and then use that signal to ablate vasculature that is in excess. That "signal" has to have diffusive properties very similar to O2 for the diffusion of the "signal" to match the diffusion of the O2 that the signal is required to control. It turn out that NO has diffusion properties virtually identical to O2. It turns out that oxyhemoglobin is the sink for NO, that the lowest concentration of NO is at the vasculature at the sites where oxyhemoglobin is. If there was a continuous source of NO, then if cells measured the NO level, they could tell how far from oxyhemoglobin they are. The transcription factor that regulates hypoxic stuff is HIF. It turns out that HIF is turned on by low O2, but that there is a NO dependence too, that high NO also turns on HIF. It is HIF that causes the production of VEGF, and also things like EPO (and also expression of glycolytic enzymes). When NO gets low, physiology responds as if there is plenty of oxyhemoglobin nearby and so ablates blood vessels (causing capillary rarefaction) and turns down erythrocyte production (causing anemia). When there is blood loss, hemoglobin goes down, NO goes up, and EPO gets triggered.

As capillary rarefaction proceeds, the capillaries get farther apart (but cells "think" they are close to a capillary because the NO level is low), and so the O2 diffusion path length is increased. This is ok at "rest" because the O2 flux that is needed to supply the ATP needed "at rest" isn't very much, and with the lower O2 level at the mitochondria, enough O2 can still diffuse down the longer path at a sufficient rate. For a while.

The normal compensatory pathway for low O2 is that the mitochondria respiration chain becomes more reduced and generates superoxide and this superoxide pulls down the NO level and disinhibits cytochrome c oxidase so that more O2 can be consumed at a lower O2 level so that more O2 can diffuse to the hypoxic spot. That only works if there is NO for the superoxide to pull down to begin with. Once the NO level gets close enough to zero for cytochrome c oxidase to be fully disinhibited, there is nothing more that lowering NO levels can do. Without enough O2 to consume the electrons moving down the respiration chain, the chain stays reduced and continues to generate superoxide.

This causes a perpetual low NO state, which also causes a perpetual low ATP state (because NO and ATP are directly coupled through their concerted action on soluble guanylyl cyclase. The low ATP sets up ATP conservation pathways. This is also known as ischemic preconditioning. In the short term, in an acute ATP crisis, this is a good thing because it efficiently allocates ATP to only those pathways needed for immediate survival. Unfortunately when an acute ATP crisis becomes a long ATP crisis, what works in the short term doesn't work in the long term. Cells then go down the low NO death spiral. This affects the cells farthest from a capillary first. These are the cells that are most subjected to oxidative stress (from superoxide), and low ATP (from low NO). As the cells farthest from a capillary they also experience the lowest O2 levels and also the lowest glucose levels. These stressed cells go down the low NO death spiral and eventually die, either by apoptosis or necrosis. Because they die one at a time, isolated in the spaces too far from a capillary, no lesion is apparent. The cells die one at a time, the cellular contents spills into the extravascular space and the clearing of that cellular contents is what causes the diffuse chronic inflammation observed as elevated CRP. This can also lead to autoimmune sensitization because there are many instances of cells necrosing which necessitates immune clearance of cellular contents. Cell division under hypoxic conditions of high superoxide leads to greater DNA replication errors over time. As the cells in a tissue compartment turn over, this causes remodeling of the tissues. The organ attempts to replace those cells, but the vascular spacing doesn't provide the nutrient and O2 fluxes necessary to support them. The cells are either ablated and not replaced (as in the brain), or replaced with non-metabolic fibrotic tissue (as in the heart and liver). The heart still needs to pump blood, so it attempts to compensate by getting larger resulting in dilative cardiomyopathy.

These are all generic effects of low NO leading to the metabolic syndrome (to get more glucose to tissues), hypertension (to increase flow of extravascular fluid by increasing pressure drop across capillary beds), edema (to increase extravascular fluid). Low NO and low mitochondria biogenesis is a final common pathway that links all of these different degenerative diseases. The organs with the largest metabolic load, brain, heart, liver, kidneys, all have characteristic failure pathways mediated though insufficient mitochondria caused by low NO.

gee daedalus, if all he needs is more NO, how about a long-acting nitro patch? the problems are so complicated, yet the solution is so simple. kind of sounds like homeopathy.

he has asthma that is making his accessory muscles working very hard thus producing the lactic acid, which is causing a Ph imbalance which makes him more breathless still?

Di

Gee MarkH - I'm a little concerned that you don't know the difference between an ACE inhibitor and an angiotensin II type 1 receptor blocker (valsartan) - don't "treat" me anytime soon will you?

my head has gone on strike.
but this may help someone

http://www.aic.cuhk.edu.hk/web8/acid_base.htm

di (off to walk the dog)

Organic nitrates are poor NO donors (actually they are not NO donors at all). A nitro patch wouldn't correct his underlying low NO. It could well exacerbate it through the mechanism known as "nitrate resistance" (the physiology of which is not understood).

The basal levels of NO that are physiologically relevant are low, less than 1 nM/L (that is 30 ppt). That does not make them "homeopathic".

The appreciation that basal levels of NO are important is becoming more accepted.

http://www.ncbi.nlm.nih.gov/pubmed/18439435

There is nothing about NO physiology that is simple, though those ignorant of it may think it is. That would be due to the arrogance of ignorance.

NO physiology is under such robust physiology control that perturbing it artificially is extremely difficult, which is why there are no generally accepted methods for increasing NO levels. There are methods, they are just not generally accepted yet.

Because NO physiology is under such robust control, and is involved in so many different physiological pathways, when the basal level is low, many of those pathways are affected, and in characteristic ways. Physiology is exhibiting what I term good regulation around a bad setpoint. This is actually easy to observe and understand. Take bone stiffness. Bone mineralization is regulated by NO produced during strain of bone. NO activates the osteoblasts to deposit more bone mineral in regions where the NO produced by that bone strain is the highest. Bones remodel to become stiffer where they are most flexible. Low NO skews bone physiology such that it takes greater strain to produce enough NO to activate osteoblasts (the strain induced NO adds to the basal NO and it is the sum that activates osteoblasts). This is why osteoporosis accompanies all conditions characterized by low NO. The "details" depend on that individual's physiology, and osteoporosis has a long time constant so it can take a while, but eventually low NO will lead to osteoporosis (low NO induced osteoporosis is not "simple" even though it is quite characteristic). It has to. Strain induced NO production is the fundamental regulation of bone stiffness. Osteoporosis due to low NO is good regulation around a bad setpoint. Bone mineral deposition remains fully regulated by physiology, it is the setpoint that is off due to low basal NO.

Organic nitrates such as nitroglycerine do increase bone density as much as estrogen in post menopausal women. The details of how that works are not understood but it likely is through a NO mechanism.

In general, the only way to fix a bad setpoint is by changing the setpoint. Overwhelming the regulation that is working normally and producing the pathology due to the bad setpoint is difficult and very tricky. Usually it causes other bad effects.

I'm just a grad student entomologist trying desperately to learn some physiology for my project, so I've really enjoyed reading these cases! (And yes, I'm aware things are different for insects...but it's a start). Just as a general comment... is it really common for patients you see to be overweight, have Type II diabetes, and high blood pressure? I come from a small farming town where just about everyone fits that description...and I'm really hoping that exercise and a good diet now will override my genes!

is it really common for patients you see to be overweight, have Type II diabetes, and high blood pressure?

We like to think of that as the "Michigan phenotype" but really it's the American phenotype.

DM, hypertension, obesity, and hyperlipidemia all go very well together.

@Redbaron

Of course I know the difference. I'm trying to write for a lay but science aware audience here. It's a purposeful imprecision because I realize most people may have heard of ACEI's but angiotensin receptor inhibtors may not ring as many bells.

Functionally it makes little difference which class is given, as long as that axis of drugs is being used. Both ACEI and ARB's accomplish the same thing, and oddly, both put you at risk for angioedema, despite the theoretical advantage of the ATII inhibitor in avoiding bradykinin buildup.

Am lurking, learning and enjoying the case presentations - thanks, MarkH!

For those who love them, the AHRQ website has monthly M&M cases. The link at my name will take you to this month's - there are three cases for your perusal and analysis. You can subscribe via email.

Katie, there are symptoms that have been characterized as the metabolic syndrome in insects.

http://www.pnas.org/cgi/content/full/103/49/18805

I suspect that the symptoms of the metabolic syndrome in dragonflies are a normal response to inflammation due to infection. Inflammation does reduce NO levels because of the superoxide generated.

I think of the phenotype that characterizes being overweight, have Type II diabetes, and high blood pressure as the "low nitric oxide phenotype".

I see it as the normal "good regulation" of physiology around the "bad setpoint" of low nitric oxide.

HAAAAAAALLLLLPPPPPPPP!!!!!!! I'm trapped in a Saturday Night Live commercial! best. comershulz. evar. (Actually, I think it's a tie between SNL and Prairie Home Companion.)

Send your residents to break into his house, swab and search for clues, and dig up his dead pets.

FTW! (Does anyone actually do that, or is it just a TV thang, like getting DNA results back in 10 minutes the way the CSI's and NCIS do?)

and getting instant access to the MRI.

Actually has this pt had an MRI yet? No? Heads WILL roll!

di

is that it? Is the game over? Was Daedalus right about all that NO2 stuff???

Why have the guy's mitochondria in his liver failed?

Did we get an LFT?

Di

I would like to hear more too. How does one treat this constellation of symptoms (other than very carefully)?

I think of myself as only a "one trick pony", the only thing I know how to do is raise NO levels. While I think that can help a lot of things, the only time scale that would work on is days, weeks or months, not hours. It is pretty obvious this guy needs stuff in minutes.

@daedalus

just curious. is there any disease that can't be cured by raising NO levels?

MRI- No way. Too expensive a study and it's pretty clear.

LFT's all come back within normal limits.

In terms of treatment it's pretty simple. You provide O2 so they don't have to exhaust themselves breathing, this also tends to decrease the anxiety from shortness of breath that feeds back on itself. The prednisone was the real kicker here. It confused the picture immensely because it raises white counts and screws up one's blood sugars. It didn't really create DKA but might have caused a hyperosmolar state. While you want to give fluids for a DKA or hyperosmolar state, you have to be careful in CHF because they'll put that fluid into their lungs, worsening the problem.

So yes, you treat with fluids - carefully - insulin, potassium, oxygen and prednisone. The lungs are also helped by albuterol nebs, steroid nebs and other treatments to get medicine directly into the lungs to open their airways. You stabilize them, and send them home. Some effort is also expended to determine what caused the exacerbation. Did they start smoking again? Was it an environmental factor? Are they stressed? And try to remove the underlying factor which set it off. Much of the time you never figure out why they suddenly decompensated. COPD is tough. Much of the lung is destroyed and they're working with inferior resources. Lung doesn't come back for the most part, so their course is almost invariably downwards. Medicine is highly effective at blunting that downward slope, but it can not be totally stopped.

thanks Mark.

The MRI was an in-House joke. But I was serious about the dead pet.

Di

I don't really think of NO as "curing" diseases, even though that is how what I am saying sometimes come across; that is just me being sloppy.

I see increasing the basal NO level as restoring the proper internal environment where natural feedback regulatory systems that use NO can function so as to produce the appropriate health outcome. Wording this is tricky because I think that the feedback systems are still fully functional, and are working "to spec" (that is if there were actually specifications) even in circumstances such as the COPD example here. In other words they are working the way they evolved to work, it is just that they are working in a bad place because of the skewed basal NO level.

In that sense NO is sort of like the oil in an engine. Oil isn't one of mechanical components that might go bad and need to be fixed, but if you don't have enough oil in your engine everything is going to break a lot faster. If mechanics didn't understand how important the right level of oil was, the parts they fix wouldn't last very long.

There are a few things that higher NO will likely exacerbate, nausea is one of them. I think the nausea of first trimester pregnancy is due to high NO (and is actually a good thing in that it improves pregnancy outcomes). It is high NO during sepsis that causes mitochondria turn-off and multiple organ failure but the NO levels during sepsis are quite high, perhaps a few nM/L, not the less than 1 nM/L that I am talking about. Those levels are virtually impossible to get except by massive activation of iNOS during sepsis. Many growth factors have effects mediated through NO so higher NO levels might increase growth of some tumors.

NO is something that you want the right level of. Too little is bad and too much is bad, but I think it is hard to get too much. I dont think you can get too much through natural means (such as the bacteria I am working with). While the bacteria do produce NO, the ultimate regulation is by the release of ammonia by the skin. That is regulated and I have no doubt that there are feedback mechanisms that regulate it. I think the hyperammonemia associated with liver and kidney failure is a compensatory pathway to increase ammonia delivery to a surface biofilm of these bacteria so they make more NO/NOx. Hyperammonemia comes from not enough mitochondria in the liver (which is where ammonia is turned into urea) and low ATP in liver. NO is what regulates ATP levels and also triggers mitochondria biogenesis and also liver regeneration.

Right now, many people have too little NO due to the loss of the bacteria I am studying with modern bathing practices. If NO levels were increased back to what they were before modern bathing, many of the chronic health problems associated with the developed world would approach levels in the rural undeveloped world (I think). More NO would shift physiology back to a more normal state. That state is not necessarily what people want for themselves or their children. I think a lot of the changes in human size and age of puberty that have occurred in the last 150 years are not only due to diet but may have a component of low NO from bathing too. Growing a large body size is a stress response. I think that is the mechanism by which antibiotics in animal feed increase the size, growth rate and accelerate sexual maturity in farm animals. Low NO shifts steroid synthesis to a more androgenic profile (NO inhibits the rate limiting enzyme for testosterone synthesis, less NO, more testosterone).

Low NO is one of the primary stress responses. If you need that stress response, then increasing NO wouldn't help things. The times when modern humans actually need to lower their NO levels to cope with stress are very few. Most stress causes pathological health effects because NO is too low to begin with and lowering it in response to stress just makes it worse. There are lots of NO mediated epigenetic programming events in utero. Very few of them are understood. I think that an individuals position along the autism spectrum is in part a function of NO in utero. Low NO causes neuronal hyperplasia in lab animals, I suspect that is the mechanism for the large brains observed in the ASDs. I think the physiology behind the cycle of violence is mediated in part through NO levels.

Okay, I really don't know enough science to be certain, but daedalus2u is really just an aging hippie with a thing for whippets, right? None of this basal NO gibberish is legit, right? I can't find any reliable citations on it anywhere, and the overwhelming drive to attribute every possible symptom to NO shortage is really starting to drive me beserk...

A little help?

Thanks, Mark. While I was obviously floundering in there, I'd like to think I was at least floundering in a vaguely right direction, and I probably wouldn't have killed the patient right off the bat. Things I should remember in the highly unlikely case they ever become relevant:

-Be explicit about all treatment. Since we had an oxy sat for this patient for both room air and on oxygen, I simply assumed oxy administration was still in place and no one in their right mind would take it away from a patient who's obviously having trouble breathing. You know what they say about assumption; administering oxygen is still treatment, and might actually be a bad idea for some kinds of breathing trouble, and all kinds of hilarious misadventures might result if you never actually write down or mention to the ones responsible that yes, this patient actually needs that oxy mask!

-Prednisone may cause leukocytosis, especially early on! Who knew?

-There's an easy, matter-of-minutes blood test for lactic acid levels, and there's virtually no reason not perform it on someone the very second they display an anion gap! Who knew?

-It's possible for someone to be administered to a hospital with their chief complaint being shortness of breath for the last five days without them being near-instantly jabbed for an ABG! Who knew?

Lance, if you go to PubMed and search for nitric oxide, there are 88,731 citations returned. If you limit the search to free full text then 23,899 citations are returned. The study of NO as a regulator of physiology is still a relatively young field. There are a great many details that remain unknown (that would be most of them, my guess would be 99%+). There are still a lot of misconceptions about it and very few therapies using it. In my opinion, the reason there are so few NO mediated therapies is not because NO is not important, and not because people are not trying to produce NO mediated therapies but because NO physiology is extremely complicated, extremely well regulated, and extremely coupled. It is very hard to perturb one part in a therapeutic direction without perturbing other parts in adverse directions.

Whippets have nitrous oxide, N2O, which is very different.