Continuous Renal Replacement Therapy (CRRT) is a form of blood purification for critically ill patients, often those with acute kidney injury. This therapy works around the clock to slowly remove waste products and excess fluid, mimicking the function of healthy kidneys. To prevent blood from clotting in the machine’s tubing and filter, a process called anticoagulation is required.
A common method is regional citrate anticoagulation (RCA), where a citrate solution is infused into the blood as it enters the CRRT circuit. Citrate is often chosen because its effects are confined to the machine, reducing patient bleeding risks compared to anticoagulants like heparin. While this approach is beneficial, the use of citrate can lead to a complication known as citrate toxicity.
The Mechanism of Citrate Toxicity
Citrate’s function as an anticoagulant is based on its ability to bind with calcium. As blood enters the CRRT circuit, a citrate solution is added, which attaches to ionized calcium, a mineral necessary for blood clot formation. By binding this calcium, citrate prevents the blood from clotting inside the filter and tubing.
Under normal circumstances, the body can process the infused citrate. A significant portion of the citrate-calcium complexes are removed by the CRRT filter. Any citrate returned to the patient’s bloodstream is rapidly metabolized by the liver, muscles, and kidneys, which converts each citrate molecule into three molecules of bicarbonate.
Citrate toxicity arises when the amount of citrate infused outpaces the body’s ability to metabolize it. This imbalance leads to an accumulation of citrate in the patient’s systemic circulation. The excess citrate then binds with the body’s own supply of ionized calcium, causing a drop in this active calcium, a condition called hypocalcemia.
This accumulation leads to two primary metabolic disturbances. The first is systemic hypocalcemia, where low levels of active calcium interfere with muscle and nerve function. The second is metabolic alkalosis, a state where the blood becomes too alkaline because the ongoing metabolism of citrate produces excess bicarbonate.
Identifying Citrate Toxicity
The clinical signs of citrate toxicity are the result of systemic hypocalcemia. Early symptoms can be subtle, including sensory disturbances like numbness or a tingling sensation around the mouth or in the fingertips. As the condition progresses, patients may experience muscle twitching, cramping, or sustained muscle contractions known as tetany. These symptoms are difficult to recognize in critically ill patients, many of whom are sedated.
Due to the unreliability of physical symptoms, laboratory tests are the main tool for identification. It is important to understand the difference between total calcium and ionized calcium measurements. Total calcium measures all calcium in the blood, including that bound to citrate, while ionized calcium measures only the free, biologically active form.
In cases of citrate toxicity, the ionized calcium level will be low, while the total calcium level may appear normal or elevated. This is because the test is also measuring the calcium bound to the accumulating citrate. This discrepancy is the key to diagnosis, and clinicians use the total-to-ionized calcium ratio to detect it. A ratio greater than 2.5 is the indicator of significant citrate accumulation.
Patient Risk Factors
Certain conditions can make a patient more susceptible to developing citrate toxicity. The most significant risk factor is impaired liver function, as the liver is the primary site for citrate metabolism. Patients with pre-existing liver diseases, such as cirrhosis or acute liver failure, have a diminished capacity to clear citrate from their blood.
Any medical state that reduces blood flow to the liver also increases the risk. Conditions like septic shock or cardiogenic shock compromise organ perfusion, meaning less citrate-rich blood reaches the liver to be metabolized. This reduction in clearance can lead to citrate buildup even in patients with a previously healthy liver.
Other factors can contribute to toxicity. Hypothermia, or a low body temperature, can slow the enzymatic processes responsible for breaking down citrate. Additionally, clinical situations requiring very high citrate infusion rates can overwhelm the metabolic capacity of a patient even if their liver function is normal.
Management and Prevention Strategies
The approach to citrate toxicity begins with prevention through routine laboratory monitoring. For any patient undergoing CRRT with citrate anticoagulation, frequent blood tests are performed, every 6 to 12 hours, to measure systemic ionized calcium and calculate the total-to-ionized calcium ratio. This monitoring allows the clinical team to detect rising citrate levels before symptoms appear.
When the total-to-ionized calcium ratio begins to climb, several interventions are made. The first step is to reduce the rate of the citrate infusion. Decreasing the amount of citrate entering the circuit gives the body’s metabolic systems an opportunity to process the existing excess and restore balance.
Further management may involve directly addressing the calcium imbalance. This can be done by increasing the calcium concentration within the dialysate or replacement fluids. For patients who show symptoms of hypocalcemia or have a low ionized calcium level, a separate intravenous (IV) infusion of calcium is administered to restore active calcium levels.
If these adjustments do not resolve the issue and the ratio continues to rise, citrate anticoagulation is discontinued entirely. The patient is then switched to an alternative anticoagulant, like systemic heparin, to ensure the CRRT circuit remains functional while eliminating further citrate-related complications.