score
2 points
1 point
zero
Thrombocytopenia
×10 9 l
20–100 or
Fall > 50 %
10 – 19 or
Fall 30–50 %
<10 or
Fall <30 %
Timing of onset in
fall plateletsa
5–10 days
heparin Rx
>10 days or
timing not evident
<1 day heparin
exposure
Thrombosis or
Acute systemic
symptoms
Proven thrombosis
Skin necrosis or
Acute systemic
reaction
Progressive, recurrent, silent thrombosis or erythematous skin lesions
none
Other aetiology for thrombocytopenia
None evident
possible
probable
The lower the peripheral platelet count reflects greater platelet activation and platelet adhesion to the endothelium, with greater risk of thrombosis. HIT can lead to both major venous and arterial thrombosis and platelet activation in the lung can lead to acute lung injury, so-called “pseudo-pulmonary” embolus. The management of HIT centers on both withdrawal of all heparins (including heparin flushes, catheter locks and subcutaneous administration) and also systemic anticoagulation to prevent thrombosis. The lower the platelets count the greater the risk of thrombosis and need for systemic anticoagulation. Typically thrombocytopenia starts to recover within 72 h following heparin withdrawal, and if there is no response to heparin withdrawal, then an alternative explanation for thrombocytopenia should be considered. Currently systemic anticoagulation options include the direct thrombin inhibitor argatroban, and the heparinoids, danaparoid and fondaparinux [25, 26]. Although danaparoid may cause cross reactivity with ELISA assays for HIT, this has not been reported to have adverse clinical consequences. Argatroban is a reversible thrombin inhibitor and requires a continuous infusion, with the infusion adjusted to maintain an activated partial thromboplastin ratio (aPPTr) of 2.0–2.5, and as it is hepatically metabolised then much lower dosages are required for patients with liver disease. Both danaparoid and fondaparinux are renally excreted and accumulate in patients with acute kidney injury and chronic kidney disease. As they have minimal effect on the aPPTr, monitoring requires measurement of anti-Xa activity, aiming for a therapeutic window of 0.4–0.6 IU/ml. Given the procoagulant nature of HIT, regional anticoagulants such as citrate for CRRT do not provide the systemic anticoagulation required to prevent systemic thrombosis, and as such additional systemic anticoagulation should be considered.
Once the platelet count has recovered to >150,000 × 106/l, then warfarin therapy can be considered, as there is a risk of precipitating skin gangrene if warfarin therapy is started before the platelet count has recovered. Argatroban prolongs the prothrombin time, and therefore caution is required when converting patients from intravenous argatroban to oral warfarin therapy. For the majority of patients HIT antibodies are a temporary phenomenon and disappear over time. However before considering rechallenging patients with heparin, then both ELISA and platelet agglutination assays should be negative on at least two occasions (Table 15.1).
Key Messages Heparin Induced Thrombocytopenia
Consider heparin induced thrombocytopenia in any patient with a 50 % fall in peripheral platelet count after starting heparin within the previous 10 days.
Heparin induced thrombocytopenia remains a clinical diagnosis. Use the “4 Ts” scoring system to estimate probability.
With a score ≥6, withdraw all heparins immediately whilst awaiting confirmation with ELISA and platelet agglutination assays, and start alternative systemic anticoagulation with argatroban as first choice and consider additional citrate anticoagulation for the circuit.
With a score between 3 and 6, order ELISA testing, while continuation of heparins awaiting results seems to be justified.
The lower the platelet count the greater the risk of thrombosis and systemic anticoagulation is required.
For a definite diagnosis of HIT, positive ELISA testing should be confirmed with a platelet agglutination assay.
15.3 Prostacyclin
(7)
Division of Critical Care Medicine, 3C1.16 University of Alberta Hospital, Edmonton, AB, Canada
Prostacyclin is an anti-hemostatic prostaglandin that inhibits platelet function, activation and adhesion by diminishing the expression of platelet fibrinogen receptors and P-selectin and reduces heterotypic platelet-leukocyte aggregation. At higher infusion doses it is also a potent smooth muscle relaxant and vasodilator. It is available for clinical therapy as a synthetic analogue, epoprostenol. It is produced primarily in the endothelial and smooth muscle cells of blood vessels. Prostacyclin has a short half-life of 2–3 min with a clinical effect on end-organs and platelets of approximately 30 min [27, 28]. It has been used in combination with low dose heparin infusions and on its own as an adjunct to prolong hemofilter life during intermittent dialysis and CRRT [29–31].
15.3.1 Indication
Prostacyclin has primarily been used as an anti-hemostatic to enhance hemofilter life in patients with acute kidney injury and acute liver failure and concern to avoid hemorrhage. Although many such patients have severe coagulopathy, some continually thrombosehemofilters during CRRT, even while suffering from ongoing hemorrhage, usually gastrointestinal. This is likely due to deficiencies in the synthesis of anti-thrombotic substances such as anti-thrombin III, protein C and protein S [32]. Since prostacyclin exerts its effect on platelet function, it unlikely to be of significant value in patients with severe thrombocytopenia.
Although regional citrate anticoagulation has been shown to be more effective in maintaining hemofilter patency, its use is often not possible as these patients are at risk of citrate accumulation as citrate is primarily metabolized in the liver [33]. In this difficult clinical situation, the use of prostacyclin may be valuable in prolonging hemofilter life without adding extra risk of bleeding [34].
15.3.2 Practical Considerations
Prostacyclin is available clinically as epoprostenol in a freeze dried powder which must be reconstituted as directed, only using the supplied diluent containing a glycine buffer to maintain a pH of 10–11. It must be infused via a separate infusion line to avoid inactivation by acidic drugs such as catecholamine vasopressor agents. It is important that only syringe infusion pumps with noncompliant intravenous tubing external to the pumps on the CRRT machine are used for infusion when using prostacyclin with CRRT. The infusion pumps on some CRRT machines, although ostensibly syringe pumps, operate by using “micro boluses” of drug rather than a smooth continuous infusion and may be associated with the development of intermittent episodes of hypotension. A similar issue may be seen using other infusion pumps that use peristaltic mechanisms. Since prostacyclin does not interfere with the coagulation systems, there is no simple clinical means of readily monitoring and titrating the infusion dose although thromboelastography could be used for this purpose [27].
15.3.3 Alone or Incombination with Heparin
Prostacyclin has been used both as a sole anti-hemostatic agent and in combination with unfractionated heparin. It has been shown to extend hemofilter survival, particularly when used in combination with low dose heparin [22–24].
The use of prostacyclin combined with regional anticoagulation with prefilter heparin and postfilter protamine has been studied in a prospective randomized trial and provided excellent filter survival and minimal bleeding when compared with conventional heparin [11].
15.3.4 Dose and Side Effects
Because of its vasodilator properties, prostacyclin can cause hypotension, although, the typical infusion doses used to enhance hemofilter life by antagonism of platelet activation and aggregation is in the range of 3–5 ng/kg/min and, generally does not impact on blood pressure significantly in most patients, although occasionally the dose of vasopressor infusions needs to be increased. (The typical dose required to achieve pulmonary vasodilatation is up to 35 ng/kg/min).
The main side effect of prostacyclin is hypotension caused by vasodilatation which may be managed by ensuring adequate fluid volume status, by reducing the rate of infusion or by titrating a vasopressor infusion. Theoretically, the risk of bleeding increases with platelet inhibition. However, in an observational study of 51 critically ill patients undergoing CRRT with prostacyclin as sole anti-hemostatic agent there was minimal bleeding (one episode per 1,000 h treatment) although 15 % required either fluids or vasopressor therapy either for the first time or an increase in dose following initiation of prostacyclin [34]. Prostacyclin is relatively expensive, but at the low doses used for CRRT the cost is similar to citrate regional anticoagulation.
15.4 Citrate Anticoagulation for Continuous Renal Replacement Therapy
(8)
Department of Intensive Care, VU University Medical Center, Amsterdam, The Netherlands
15.4.1 Summary
Citrate acts as anticoagulant by chelating ionized calcium (iCa) and thereby causing hypocalcemia in the filter. At an iCa concentration of 0.25 mmol/L, anticoagulation is maximal. Part of the citrate is removed by dialysis or filtration, the remains enter the systemic circulation. Citrate is rapidly metabolized in the mitochondria, the chelated calcium is released and the lost calcium is replaced. Citrate therefore provides regional anticoagulation and does not increase the risk of bleeding.
Sodium citrate is a buffer as well provided that citrate is metabolized. The buffer strength is equivalent to 3 mmol bicarbonate per mmol citrate if all cations are sodium (trisodium citrate) and less so if part of the cations are hydrogen (citric acid).
Citrate anticoagulation is better tolerated than heparin, and is associated with less bleeding and generally longer circuit survival. Its main risk is accumulation due to decreased metabolism as a result of liver failure or systemic hypoperfusion. Accumulation is characterized by a decrease in iCa, a rise in total Ca and metabolic acidosis. It is monitored by measuring systemic iCa (to adjust calcium replacement) and acid–base balance. A rise in total/iCa is the most sensitive marker of accumulation.
15.4.2 Introduction
Sodium citrate has become the first choice anticoagulant for continuous renal replacement therapy (CRRT). It provides regional anticoagulation of the circuit, without increasing the patient’s risk of bleeding. Its anticoagulant properties are due to the chelation of ionized calcium (iCa) thereby causing hypocalcemia in the circuit. Calcium is a necessary cofactor in the formation of thrombin. Coagulation is inhibited as soon as ionCa falls below 0.50 mmol/L, and is maximal at an iCa concentration of 0.25 mmol/l [35].
15.4.3 Regional Anticoagulation
Within the CRRT circuit, sodium citrate is administered before the filter. Citrate dose is titrated to blood flow. Postfilter iCa can be monitored to fine-tune anticagulation by adjusting citrate dose to iCa targets (0.25–0.35 mmol/L),but many protocols use a fixed citrate to blood flow proportion. Part of the calcium citrate complexes are removed by dialysis or filtration. The remains enter the patient’s circulation to be metabolized in the Krebs cycle of liver, kidney and muscle. The chelated calcium is released, while the calcium lost by dialysis or filtration is replaced. Regional anticoagulation is the result, and this is the main benefit of citrate [8, 36].
15.4.4 Citrate Is a Buffer
Sodium citrate is a buffer base as well. According to the classical concept, each mole of trisodium citrate provides a buffer equivalent of three moles of bicarbonate, if and when citrate is metabolized. According to the Stewart concept of acid–base [30], sodium citrate increases the strong ion difference (SID = (Na+ + K+ + Ca2+ + Mg2+) – (Cl− + lactate−)) provided that citrate is metabolized. This concept explains why the buffer strength of the citrate solution depends on the accompanying cation [31]. The buffer strength is higher when using a trisodium citrate solution and lower when part of the cations are hydrogen, as is the case in the acid dextrose citrate (ACD-A) solution, as used in some protocols, in which 30 % of the cations consist of hydrogen [37–39].
15.4.5 Principles of the Citrate Circuit
Citrate is administered before the filter, either as a separate more or less concentrated trisodium citrate solution [18, 40–43] or as part of an isotonic balanced calcium-free predilution hemofiltration solution. In the latter, the bicarbonate is replaced by citrate and the solution is calcium-free [44–46]. When a separate sodium citrate solution is used, the associated dialysate or postdilution hemofiltration solution contains no or less bicarbonate and less sodium to compensate for the citrate buffer and the sodium content of the citrate solution. In most protocols, calcium is replaced separately. It should be noted that citrate additionally chelates magnesium and that citrate CRRT can lead to a negative magnesium balance because the magnesium content of most CRRT solutions is too low [47].
15.4.6 Modalities
Different modalities for citrate are in use: Hemodialysis [41],predilution hemofiltration [44–46], postdilution hemofiltration [18, 43] or hemodiafiltration [42]. Modern CRRT devices have a strict citrate protocol incorporated in the software, allowing for choices to determine the desired citrate concentration in the filter (2.5–4.5 mmol/L blood flow), to adjust acid–base derangements (more or less buffer supply) and to adjust calcium infusion rate to compensate for calcium loss (zero calcium balance). Each protocol has strict rules for citrate dosing, acid base compensation and calcium replacement. These rules depend on the composition of the fluids in use and cannot be generalized. The use of a strict protocol, adherence to the protocol and training are crucial for safety of the method.
15.4.7 Monitoring of Citrate Anticoagulation
Citrate anticoagulation is monitored by measuring ion- and total calcium concentration and blood gas analysis (for acid–base) in systemic blood at 6–8 h interval. Chloride and lactate can be measured to monitor anion gap and tissue perfusion, but this is not obligatory. Postfilter iCa can be measured to fine-tune anticoagulation.
15.4.8 Citrate Accumulation
Metabolism of citrate is conditional for its safe use. Citrate is metabolized in the mitochondria of liver, kidney and muscle and is decreased in patients with liver cirrhosis [43] and systemic hypoperfusion. Although a high lactate concentration at the start of CRRT should raise awareness of the risk of citrate accumulation, septic patients with a high lactate level and other shock patients generally tolerate citrate remarkably well if circulation improves. Citrate anticoagulation is even feasible in patients severe lactate acidosis due to metformine intoxication (personal experience). Citrate is likely to accumulate in patients with persistent severe cardiogenic shock, ischemic hepatitis and poor muscle perfusion [44], because the Krebs cycle only operates under aerobic conditions. However, most critically ill patients tolerate citrate better than heparin [18, 48]. Even in patients with liver failure, the use of citrate is feasible with intensified monitoring [49].
When citrate accumulates, iCa concentration in the patient’s blood falls, while total calcium rises due to chelation with citrate and replacement of calcium according to the protocol. A rise of total/iCa ratio is the most sensitive sign of citrate accumulation [50]. A rise above 2.25–2.5 indicates citrate accumulation. Second, if citrate is not metabolized, acidosis will ensue and anion gap will rise, because the alkalizing effect of citrate depends on its metabolism. Due to liver failure or severe hypoperfusion, citrate accumulation is associated with a rise in lactate as well. Citrate accumulation is seen in the most severely ill patients and seems a predictor of mortality [51].
Thus iCa, total calcium, total/iCa ratio, blood gas analysis (for acid base) and lactate are used to monitor citrate accumulation. In patients at risk, intensified monitoring is recommended, initially at 2-h interval. If the total/iCa ratio rises, the risks of continuing citrate should be weighed against the use of alternative anticoagulation (heparin) with risk of bleeding or CRRT without anticoagulation (early circuit clotting). In general, citrate is not toxic. If acid–base is in balance and ionized calcium can be controlled with additional calcium supplementation, the continuation of citrate seem safer than the alternatives [49]. If calcium ratio plateaus, monitoring interval can be prolonged.
15.4.9 Benefits of Citrate Anticoagulation
Clinical benefits of citrate are primarily related to less bleeding, a better circuit survival and lower requirement for blood products. The use of citrate does not increase the patient’s risk of bleeding. In addition, anticoagulation with citrate seems more effective than with heparin, especially when higher doses are used, and the calcium is replaced outside the CRRT circuit. Three meta-analyses, one including up to six randomized controlled trials (comparing citrate to unfractionated heparin) [52, 53], to low molecular weight heparin [18] or to heparin/protamine [54] with a total of 417 patients and one including four studies (comparing citrate to unfractionated heparin) found less bleeding and a longer circuit survival time with citrate [55–57]. After this meta-analysis, a large multicenter trial has appeared, showing that citrate was superior in terms of safety, efficacy and costs [58]. The largest randomized controlled trial (200 patients) found an unexpected survival benefit for citrate. This benefit could not be fully explained by less bleeding and not to less circuit clotting. It was especially seen in younger patient, surgical patients, and patients with sepsis or those with a high degree of organ failure, suggesting a role of citrate limiting inflammation or oxidative stress [18]. Compared to heparin, citrate confers less complement activation and neutrophil degranulation in the filter and less endothelial activation [58]. Up to now, this survival benefit had not been confirmed by other studies.
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