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After gaining sufficient experience, monitoring circuit anticoagulation can subsequently be limited to particular cases (e.g., unexplained early filter clotting). Some centers still prefer intensive monitoring of anticoagulation in the extracorporeal circuit and repeatedly titrate citrate dose because this, although unproven, tends to increase FLS. The anticoagulation effect is evaluated by measuring post-filter ionized calcium concentration (level below 0.35 mmol/L [0.8 and 1.3 mg/dL]), activated clotting time, or activated partial thromboplastin time [15, 17, 18]. Several algorithms for adjusting the citrate infusion rate are described in the literature. Yet, continuous monitoring of ionized calcium in the circuit remains the gold standard.

      Side Effects and Complications of RCA

Plasma citrate concentration depends on the balance between citrate input (infusion rate) and loss (filtration, metabolic degradation, additional loss through dialysis in continuous veno-venous hemodiafiltration). Plasma citrate is mainly bound to calcium and, to a lesser extent, to other cations such as magnesium. Dependent on metabolism and infusion rate, the accumulation of citrate may be associated with metabolic acidosis or metabolic alkalosis. Citrate may accumulate when liver and muscle fail to metabolize citric acid, as seen in decompensated liver cirrhosis, severe shock, or following a prolonged cardiac arrest. According to the Stewart acid-base approach, strong anions increase and metabolic acidosis develops. In a majority of cases, an increase in citrate is also reflected by a rising anion gap. Simultaneous increase of lactate is often observed. When citrate binds to calcium, systemic ionized calcium concentrations fall and the bound fraction of calcium rises. Total calcium concentration remains constant but mostly increases in the function of the amount of calcium infused. If calcium infusion is increased to correct low ionized calcium levels, most of the calcium is captured by citrate. Consequently, a disproportional rise in total calcium concentration occurs, while ionized calcium remains low. Thus, the calcium gap (total calcium minus ionized calcium) or the calcium ratio (total calcium/ionized calcium) will increase. A calcium gap >2.5 in the absence of any obvious cause of metabolic acidosis, is a valuable indicator of citrate accumulation. Using a lower (e.g., 0.5%) concentration of citrate should minimalize metabolic alterations [18–20]. Therapy includes tapering or discontinuation of citrate infusion and replacement with normal sodium and/or bicarbonate-buffered substitution fluids. In liver failure, continuous veno-venous hemofiltration (CVVH) can generally be continued without or at a 50% reduced anticoagulation dose because of pathology-bound coexisting coagulation disorders.

A gradually declining UF flow due to increased filter clogging [9] at constant blood flow and citrate infusion rate will result in less citrate and bicarbonate loss and more citrate entering the systemic circulation. A normally functioning liver will metabolize the excess citrate and metabolic alkalosis ensues. Ionized calcium concentration subsequently falls and, as a result of alkalosis, calcium ratio may rise proportionally. Metabolic alkalosis at reduced UF flow can be controlled by changing the filter and not by reducing citrate dose since this may precipitate filter clotting. A lower limit of UF flow has to be determined in function of blood and citrate flow. For instance, at a blood and citrate flow of respectively 200 mL/min and 35 mmol/h, a filter change is envisaged when the UF flow remains lower than 2,000 mL/h or when the trans-membrane pressure (TMP) exceeds 250 mm Hg [15, 21]. This threshold TMP better reflects a decline in filter porosity than monitoring UF flow. Since a higher renal replacement dose may improve mortality in patients with acute kidney injury, continuing CVVH at lower UF flows is not advised. Importantly, the need for filter change is not determined by a solitary TMP value but by the evolution of the slope of the TMP curve over time. Timely filter change also is the best way to prevent metabolic alkalosis. Citrate accumulation accompanied by metabolic alkalosis and hypocalcemia may also occur if too much citrate is accidentally infused in an occasional patient who received a high transfusion load at low UF flow. More calcium is lost in the ultrafiltrate during CVVH under RCA than under heparin. In this case, hypocalcemia is not accompanied by an increase in anion gap and adjustment necessitates calcium infusion via a separate line. The required amount depends on both UF flow and calcium content of the replacement fluid. At a sufficiently high UF flow (2,000 mL/h), additional calcium infusion is not needed if the replacement fluid contains calcium [22]. However, this scenario rarely occurs and calcium infusion through a dedicated central venous line must always be provided.

      A Practical Bedside Approach. How to Handle…

      Citrate Accumulation?

      –Cause: liver failure, poor muscle perfusion.

      –Metabolic alterations: metabolic acidosis, increased anion gap, decreased ionized calcium, rising calcium ratio and calcium gap, increased lactate.

–Therapy: reduce or stop citrate, continue CVVH without anticoagulation or under low dose heparin, supply calcium (target a ionized calcium of 1.0 mmol/L [between 4 and 5 mg/dL] [15, 23]).

      Citrate Intoxication?

      –Cause: accidental over-infusion of citrate or decrease of UF flow below the lower limit at constant citrate infusion rate.

      –Metabolic alterations: metabolic alkalosis, low ionized calcium, and proportional rise of calcium ratio as a result of alkalosis.

      –Treatment: withdraw citrate infusion.

      Hypocalcemia?

      –Cause: citrate accumulation.

      –Therapy: calcium infusion. Since most critically ill patients have some degree of hypocalcemia, the targeted ionized calcium level should be approximately 1.0 mmol/L (4 mg/dL).

      Metabolic Alkalosis?

      –Cause: excessive bicarbonate substitution relative to UF flow.

–Treatment: substitution of more buffer-free and less bicarbonate-buffered solution. The use of normal saline (400–800 mL/h) instead of bicarbonate, as substitution liquid was recently shown to effectively correct metabolic alkalosis [24].

      –Specific situations:

      a. Declining UF flow while citrate infusion remains fixed adjusted to blood flow. Treatment: filter change if UF flow is less than 1,500–2,000 mL/h (depending on blood and citrate flow).

      b. Metabolic conversion of accumulated citrate with recovering liver function. Treatment: replacement with buffer-free solution or halving citrate dose in pre-dilution.

      c. Accidental over-infusion of citrate. Treatment: withdraw citrate infusion, replacement with buffer-free solution, increase UF flow as needed.

      Hypomagnesemia?

      –Cause: increased loss of citrate-bound magnesium by ultrafiltration.

–Treatment: infusion of magnesium together with calcium. Magnesium levels must be maintained between 2 and 4 mmol/dL [15, 25].

      Hypokalemia?

      Potassium levels must be kept strictly between 4 and 5 meq/dL.

      Steadily Increasing Calcium Infusion Rate?

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