However, it is imperative to calculate solute balances for each combination of blood, citrate, and ultrafiltration flow and to adhere carefully to written protocols before implementing the method in the ICU. Anyway, close monitoring of ionized calcium should already allow sufficient control under those circumstances.
In the predilution CVVH system of Pallson and Thoenen Table 1 , [ 5 ] citrate is added to the replacement fluid and calcium is infused by a separate line. Citrate infusion is matched by the loss of buffer in the ultrafiltrate unless a larger amount of fluid is withdrawn. Although striking by its simplicity, a major drawback of the system is that the buffer cannot be titrated separately.
This might be detrimental when buffer needs are increased e. Separate infusion of bicarbonate is not a valuable option. Indeed, this could induce major side effects, as the concentration of such bicarbonate infusion is roughly fold greater than the concentration in solutions.
As mentioned earlier, the plasma citrate concentration depends on the balance between the rate of infusion and the loss by filtration and its metabolic degradation plus any losses through dialysis if CVVDF is used.
Plasma citrate is mainly bound to calcium and, to a lesser extent, to other cations such as magnesium. Therefore, any accumulation of citrate may be associated with metabolic acidosis or metabolic alkalosis, depending on the metabolism and infusion rate. In case of metabolic acidosis, citrate may accumulate if liver and muscle fail to metabolize citric acid, a situation occurs in decompensated liver cirrhosis, severe shock, or after a prolonged cardiac arrest.
Acid accumulates under these circumstances or—according to the Stewart approach—strong anions increase with subsequent metabolic acidosis. However, lactate will mostly accumulate at the same time, which complicates this interpretation of events.
With citrate binding to calcium, systemic ionized calcium concentration falls and the bound fraction of calcium rises. Total calcium remains constant or more often rises, depending on the amount of calcium infused to correct hypocalcemia. If calcium infusion is increased to correct low-ionized calcium levels, most of the calcium is captured by citrate. As a consequence, a disproportional rise in total calcium concentration occurs while ionized calcium remains low. Once again, the use of a lower e.
CVVH can generally be continued without anticoagulation and bicarbonate-buffered replacement, because patients with liver failure usually have coagulation disorders. Metabolic acidosis due to failure to metabolize citric acid can be diagnosed early by routine metabolic monitoring. It is corrected by discontinuing or tapering the dose of citrate and by adjusting the replacement fluid.
In case of metabolic alkalosis, large amounts of citrate may enter the systemic circulation. If ultrafiltration flow gradually declines as a result of decreased filter performance induced by increased clogging, while blood flow is constant and also citrate infusion rate remains constant, less citrate and bicarbonate are lost by filtration and more citrate enters the systemic circulation. If liver function is normal, citrate is metabolized and metabolic alkalosis ensues as a result of an imbalance between loss and supply of citrate.
Ionized calcium concentration may subsequently fall and the calcium ratio may rise proportionally because of alkalosis and not because of accumulation of citrate. A normal liver has a large reserve for citrate metabolism. Metabolic alkalosis at reduced ultrafiltration flow is better controlled by changing the filter instead of reducing the citrate dose, because this may cause filter clotting.
Depending on blood and citrate flow, a definite lower limit of UF flow has to be protocolized, e. The TMP threshold above mm Hg is probably much better than the ultrafiltration flow as with the computerized system; it may not reflect a decline in filter porosity.
In fact, the slope of the TMP curve will determine the membrane change, which implies that mm Hg is not a cut-off value per se. Monitoring of acid—base balance remains pivotal. Nonetheless, accumulation of citrate with metabolic alkalosis and hypocalcemia may also occur if too much citrate is infused accidentally or if the patient has received a large volume of transfusion blood and UF flow is low.
Hypocalcemia is observed when citrate accumulates and also when calcium is bound to citrate in the ultrafiltrate.
In this case, hypocalcemia is not accompanied by a rising anion gap and calcium must be adjusted by infusion via a separate line. The required amount depends on the ultrafiltration flow and the calcium content of the replacement fluid.
However, this scenario is very rare and a calcium infusion through a central line must always be provided and adapted according to the ionized calcium blood levels. In conventional hemofiltration, the replacement fluid bears resemblance to the electrolyte composition of plasma and extracellular fluid, except for a lower potassium content and a higher buffer content.
At a lower UF flow, less bicarbonate and citrate are filtered, resulting in increased uptake in the systemic circulation. At a higher filtration flow, more citrate and bicarbonate are filtered. Thus, part of the replacement fluid should contain buffer. This obviates the need for a separate bicarbonate infusion, which should be discouraged because of side effects. Patients with severe acidosis and a high metabolic rate usually need full bicarbonate replacement from onset and the use of a high filtration flow.
The ratio between citrate and citric acid as well as the mode are probably key issues in this context. Guided by plasma acid—base state, replacement is then further adjusted to the needs. However, the lifespan of a good filter can be expected under higher filtration fraction rates when citrate is used. Citrate indeed has the capacity to dramatically reduce protein deposit and associated clogging processes at the inner side of the membrane.
Changing blood flow at a constant citrate flow may lead to changes in sodium and citrate concentration in the filter and subsequently in the ultrafiltrate. Until recently, many commercially available fluids contained calcium. As the calcium in the replacement fluid counteracts the anticoagulant effect of citrate in the venous chamber, coagulation may be induced at this site.
Therefore, the increasing popularity of introducing calcium-free replacement solutions is expected to benefit circuit survival time. Such solutions are already available in some European countries and await worldwide breakthrough. In the predilution, as opposed to postdilution, CVVH circuit initially described by Pallson Table 1 , [ 5 ] citrate is added to a usually homemade calcium-free replacement fluid with normal sodium concentration. Calcium is supplied through a separate venous line.
The system is simple except for the inconvenience that buffer and anticoagulant cannot be dosed separately, making it less flexible and intermingling dose and anticoagulation adaptation. In severely acidotic patients, the amount of buffer may be insufficient and a replacement solution containing both citrate and bicarbonate may be more appropriate. In that case, simplicity is lost. Potassium is added to the replacement fluid, and calcium and magnesium are infused via a separate line.
Additional supplementation of calcium is often necessary because more citrate-bound calcium is lost in the ultrafiltrate than during heparin-CVVH. The amount of supplementation depends on whether the replacement fluid contains calcium or not.
Magnesium is probably lost as well. However, low concentrations of magnesium are seldom seen supposedly because of a compensatory shift from the intracellular compartment as has been observed in patients with severe burns.
For supplementation, a standard calcium gluconate solution may be used and, eventually, a calcium—magnesium solution in case of magnesium deficit. It is not known which serum calcium concentration must be targeted because hypocalcemia is an inherent sign of critical illness and is possibly protective. The infused calcium might penetrate into the cells and enhance cytotoxicity.
Aiming at an ionized Ca of 1. Values as low as 0. However, Mitchell uses a calcium-containing dialysate as used in intermittent HD. As calcium will chelate part of the citrate in this condition, the citrate infusion rate is high relative to blood flow. However, this implies that treatment dose has to be changed if pH changes e. In the predilution circuits with dialysis, citrate is generally infused separately and the composition of the replacement fluid is adjusted as good as possible.
Anticoagulation regimen running with citrate in predilution as established in our unit. Reprint by permission of Blood Purif [17]. Therefore, the CRRT is seen as an alkalinizing therapy transferring bicarbonate from the replacement liquid into the blood to replenish the consumed bicarbonate. This results in an increase in pH and bicarbonate concentration and base excess.
According to the Stewart—Fencl physicochemical approach, the measured strong ion difference SIDm , i. As such, metabolic acidosis and alkalosis are reflected by, respectively, a decrease and increase in strong ion difference SID.
CRRT acts to increase this reduced SID by enabling accumulation of other strong anions, such as sulfate and hippurate. Nevertheless, recent studies have shown that CRRT-induced alkalosis, at least to a certain level, is not harmful. As only independent variables can modify acid—base status in the Stewart—Fencl approach, CRRT would not cause bicarbonate flux from replacement liquid into blood but rather eliminate the accumulated strong anions.
Serum chloride is normalized and SID restored, which translates into a secondary bicarbonate increase. Hence, bicarbonate stops being the main factor in the regeneration of acid—base status. In , Fencl and colleagues developed a mathematical model to calculate SID and pH when the other independent variables pCO 2 , albumin, and phosphate are known. The simplified equation, composed of CO 2 , anion charge of albumin, and anion charge of phosphate, is mostly used.
On the other hand, other studies demonstrated a slight but significant decrease in SIDm from This is in apparent contradiction to the expected increase in pH and bicarbonate concentration and base excess due to the alkalinizing effect of CRRT or HD. How can this apparent contradiction between two variables that essentially measure the same effect be explained: because stable patients on periodic HD or CRRT usually have normal chloride levels, the unmeasured strong anions sulfate, hippurate, etc.
However, these anions are not taken into account in the measured SID formula, so that, apparently, this variable does not change. Some studies found only a significant correlation between base excess and SID gap or strong ion gap , but not between base excess and chloride and albumin and phosphates, and thus support the evidence that SID gap or strong ion gap is the only parameter associated with base excess regeneration.
Other studies in critically ill ICU patients show similar results. However, when classifying patients in the high- and low-chloride groups, relating to this anion level in the dialysis fluid or the replacement solution, acid—base status correction by means of variation of base excess was significantly higher in the group with high chloride values.
Furthermore, some studies claimed a correlation between base excess and SID gap or strong ion gap and chloride, while others emphasized the importance of chloride levels as an acidosis component in patients on HD or CRRT. This corroborates the hypothesis that correction of acid—base status during CRRT is not only due to the elimination of non-measured strong anions but also due to a normalization of serum chloride levels.
Hyperchloremic acidosis can easily be confounded with sepsis-associated metabolic acidosis e. Measured SID, however, only allows to detect the increments in case of sodium increase without accompanying rise in chloride or a decrease in chloride. Another important aspect is the albumin and phosphate anion charges included in the expression of total weak anions ATot. A number of studies showed that ATot as a whole was not modified throughout the session or the CRRT because the increment in albumin charge after the session was compensated by the decrease in the phosphate charge.
The Stewart—Fencl approach allows to evaluate non-measured anions much more precisely than the anion gap. The latter, extensively used in the classic approach, presents remarkable interferences on the part of serum albumin and phosphate. As a consequence, correct evaluation of the type of metabolic acidosis becomes cumbersome, particularly in the presence of significant alterations in the ATot components, such as nephrotic syndrome, malnutrition, negative protein catabolism, and phosphorus intoxications and in ICU patients under citrate anticoagulation.
In fact, the difference between SIDm and SIDe provides a quantity of non-measured anions strong ion gap free from the interference of weak acids. Studies by Kellum et al. Therefore, the anion gap remains a valuable marker of non-measured anions in stable chronic HD patients and also in acutely treated CRRT patients, although less reliable in certain cases of AKI. Still, the strong ion gap is the parameter that best reflects non-measured anion accumulation during the interdialysis period or before CRRT.
This parameter decreases significantly and, logically, includes anions from protein catabolism mainly sulfate , which are adequately eliminated by HDF or CRRT. As opposed to anion gap, strong ion gap will not change either with pH or with changes in albumin and phosphate.
In conclusion, it can be stated that the Stewart—Fencl approach does improve the evaluation of acid—base status in patients with AKI receiving citrate anticoagulation. In these circumstances, the HD session or the CRRT treatment are perceived as non-metabolizable inorganic anion withdrawal especially sulfate techniques.
The only advantage would be the evaluation of anions not measured by the strong ion gap, without the effects of albumin and phosphate. The fact that citrate can be considered as a weak acid citric acid or an unmeasured anion underscores the advantages of measuring the anion gap, the calcium gap, and the strong ion gap for adequate detection of its accumulation in ICU patients with citrate-treated AKI. The Stewart approach proves useful to detect a citrate intoxication in ICU patients with complex or mixed forms of acidosis and alkalosis.
It stands to reason that when the direct measurement of citrate in the blood becomes routinely available, the detection of citrate accumulation will become much easier. Correction: reduce or stop citrate, continue CVVH without anticoagulation or with low dose heparin, supply calcium target ionized calcium should be 1.
Correction: infusion of calcium. Classical cause: declining filtration flow while citrate infusion is fixed or adjusted to blood flow. Treatment: change filter if filtration flow remains less than — mL depending on blood and citrate flow.
If the cause is accidental or over-infusion of citrate: stop the citrate infusion, replace it with buffer-free solution, and increase filtration flow as necessary. There was no increase in adverse events with the higher dose. Conclusions: Sildenafil at 50 mg or mg significantly improved erection quality, treatment satisfaction, anxiety levels, and the sexual experience compared with placebo during DBPC.
Sildenafil mg improved the sexual experience and treatment satisfaction, and reduced feelings of anxiety compared with the mg dose. The conversion of pyruvate to acetyl CoA is a three-step process. Breakdown of Pyruvate : Each pyruvate molecule loses a carboxylic group in the form of carbon dioxide. Step 1. A carboxyl group is removed from pyruvate, releasing a molecule of carbon dioxide into the surrounding medium. Note: carbon dioxide is one carbon attached to two oxygen atoms and is one of the major end products of cellular respiration.
The result of this step is a two-carbon hydroxyethyl group bound to the enzyme pyruvate dehydrogenase; the lost carbon dioxide is the first of the six carbons from the original glucose molecule to be removed. This step proceeds twice for every molecule of glucose metabolized remember: there are two pyruvate molecules produced at the end of glycolysis ; thus, two of the six carbons will have been removed at the end of both of these steps.
Step 2. Step 3. The enzyme-bound acetyl group is transferred to CoA, producing a molecule of acetyl CoA. This molecule of acetyl CoA is then further converted to be used in the next pathway of metabolism, the citric acid cycle.
Acetyl CoA links glycolysis and pyruvate oxidation with the citric acid cycle. In the presence of oxygen, acetyl CoA delivers its acetyl group to a four-carbon molecule, oxaloacetate, to form citrate, a six-carbon molecule with three carboxyl groups. During this first step of the citric acid cycle, the CoA enzyme, which contains a sulfhydryl group -SH , is recycled and becomes available to attach another acetyl group.
The citrate will then harvest the remainder of the extractable energy from what began as a glucose molecule and continue through the citric acid cycle. In the citric acid cycle, the two carbons that were originally the acetyl group of acetyl CoA are released as carbon dioxide, one of the major products of cellular respiration, through a series of enzymatic reactions.
Acetyl CoA and the Citric Acid Cycle : For each molecule of acetyl CoA that enters the citric acid cycle, two carbon dioxide molecules are released, removing the carbons from the acetyl group. In addition to the citric acid cycle, named for the first intermediate formed, citric acid, or citrate, when acetate joins to the oxaloacetate, the cycle is also known by two other names.
The TCA cycle is named for tricarboxylic acids TCA because citric acid or citrate and isocitrate, the first two intermediates that are formed, are tricarboxylic acids.
Additionally, the cycle is known as the Krebs cycle, named after Hans Krebs, who first identified the steps in the pathway in the s in pigeon flight muscle. Like the conversion of pyruvate to acetyl CoA, the citric acid cycle takes place in the matrix of the mitochondria. Almost all of the enzymes of the citric acid cycle are soluble, with the single exception of the enzyme succinate dehydrogenase, which is embedded in the inner membrane of the mitochondrion.
Unlike glycolysis, the citric acid cycle is a closed loop: the last part of the pathway regenerates the compound used in the first step. This is considered an aerobic pathway because the NADH and FADH2 produced must transfer their electrons to the next pathway in the system, which will use oxygen. If this transfer does not occur, the oxidation steps of the citric acid cycle also do not occur.
Note that the citric acid cycle produces very little ATP directly and does not directly consume oxygen.
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