Continuous Renal Replacement Therapy (CRRT) is a sophisticated form of life support used to manage acute kidney failure in critically ill patients. This therapy continuously filters the blood, removing excess fluid, waste products, and toxins. Blood must be circulated outside the body through a filter and tubing, which creates a high risk of clotting within the circuit. To keep the blood flowing and prevent the filter from prematurely failing, an anticoagulant is required, and citrate has become the preferred choice. While effective for preventing circuit clotting, citrate carries a specific risk of toxicity that requires constant management.
The Purpose of Citrate in CRRT
Anticoagulation is necessary during CRRT because contact between blood and the artificial surfaces of the tubing and filter initiates the natural clotting cascade. Failure to prevent clotting leads to frequent interruptions in therapy and necessitates circuit replacements. Citrate is favored over older systemic anticoagulants, such as heparin, because it provides a localized effect that avoids increasing the patient’s risk of bleeding.
Citrate, a small organic acid molecule, acts by binding to ionized calcium in the blood, a process known as chelation. Ionized calcium is a required co-factor in the coagulation cascade, so removing it effectively stops the clotting process. The citrate solution is infused directly into the blood line just before the filter, creating a high concentration of the citrate-calcium complex within the circuit.
The goal is to reduce the ionized calcium level within the filter, typically below 0.35 mmol/L, to prevent clotting while passing through the device. Most of the citrate-calcium complex is removed by the filter and carried away in the waste fluid, so only a fraction returns to the patient. Systemic calcium is replaced through a separate infusion line near the end of the circuit to ensure the patient’s blood calcium levels remain stable.
How Citrate Toxicity Develops
The mechanism of citrate toxicity begins when the citrate-calcium complex leaves the CRRT circuit and enters the patient’s circulation. Citrate is a natural intermediate in the Krebs cycle and is metabolized primarily by the liver and, to a lesser extent, by muscle tissue. Metabolism converts citrate into bicarbonate, a buffer that helps regulate the body’s acid-base balance.
Toxicity develops when the rate of citrate infusion exceeds the body’s metabolic capacity, causing the citrate-calcium complex to accumulate systemically. This metabolic impairment is commonly seen in patients with severe liver dysfunction, the main organ responsible for processing the compound. Conditions causing poor blood flow to the liver, such as shock or low blood pressure, can also slow the metabolic rate and lead to accumulation.
When the accumulated citrate complex is not metabolized, it continues to bind to the patient’s free ionized calcium. Failure to metabolize citrate also prevents its conversion into bicarbonate, leading to severe metabolic acidosis and an increased anion gap. This combination of systemic ionized hypocalcemia and severe acidosis forms the hallmark of true citrate toxicity.
Identifying the Signs of Toxicity
The physical signs of citrate toxicity result from the systemic reduction in ionized calcium. As ionized calcium levels fall, patients may experience symptoms related to increased neuromuscular excitability, such as muscle twitching, cramping, or numbness around the mouth. The heart muscle also becomes unstable, which can lead to sudden hypotension, a prolonged QT interval on an electrocardiogram, and life-threatening cardiac arrhythmias.
The definitive diagnostic tool for identifying citrate accumulation is the ratio of total calcium to ionized calcium (T/I Ca ratio). Total calcium measures all calcium in the blood, including the calcium bound to proteins and citrate. Ionized calcium measures only the free, active form. In a patient with citrate accumulation, the total calcium level rises due to the increasing amount of non-metabolized citrate-calcium complex, while the free ionized calcium level falls.
This disparity causes the T/I Ca ratio to increase significantly; a ratio greater than 2.5 suggests ongoing citrate accumulation and toxicity. Monitoring this ratio is more reliable than observing hypocalcemia symptoms alone, as it directly reflects the presence of the non-metabolized citrate complex. An escalating need for calcium replacement infusion without a corresponding rise in systemic ionized calcium is also an early warning sign.
Treatment and Prevention Strategies
Preventing citrate toxicity relies on frequent monitoring and adherence to protocol. The T/I Ca ratio and systemic ionized calcium levels are checked frequently, often every few hours, especially in high-risk patients with liver impairment. Integrated CRRT machines that automatically link the citrate infusion rate to the blood flow rate help maintain consistency and reduce the risk of over-dosing.
If citrate accumulation is detected, immediate management involves reducing the amount of citrate delivered. This is achieved by decreasing the citrate infusion rate or increasing the effluent flow rate of the CRRT machine, which enhances removal of the citrate-calcium complex. Simultaneously, the infusion rate of the systemic calcium replacement must be increased to counteract the effects of the accumulated citrate on ionized calcium levels.
In cases of severe toxicity, the citrate infusion must be temporarily stopped, and the CRRT session may be paused until the patient’s metabolism stabilizes. Alternatively, the medical team may switch to a different method of anticoagulation, such as low-dose heparin, if the patient’s bleeding risk allows. This decision is made when the risk of systemic citrate accumulation outweighs the benefits of regional anticoagulation.