Chapter 99: Continuous Venovenous Hemofiltration

CVVH is a form of CRRT that has a slower rate of solute or fluid removal per unit of time. It is generally better tolerated than conventional intermittent hemodialysis as many of the complications of hemodialysis are related to the rapid rate of solute and fluid loss as well as complement-induced hypotension. Acute kidney injury (AKI) occurs in up to 70% of patients admitted to the ICU and is associated with an increased mortality rate.¹ CRRT is the treatment of choice in critically ill septic patients in the ICU.^2,3 Sepsis leads to renal hypoperfusion and subsequent volume resuscitation that cannot be autoregulated by the already insufficient kidney. This is further compounded by the numerous nephrotoxic medications and contrast agents used in diagnosis and treatment. Mortality from AKI is commonly the result of multiorgan system failure (MOSF). Growing evidence suggests that AKI may also damage the lungs, brain, heart, or liver. Some forms of renal replacement therapy (RRT) may prevent MOSF.⁴ There is also evidence that fluid overload increases mortality and that volume control can improve outcomes.^5,6,7 This has shifted the trend toward more aggressive and earlier RRT.

The acute dialysis quality initiative (ADQI) developed the following classification of AKI to foster uniformity in both research and clinical practice (Tables 99–1 and 99–2).

The acute kidney injury network (AKIN) classification is based on the risk, injury, failure, loss, end-stage renal disease (RIFLE) system with a few relevant modifications.⁸ First, it uses smaller increments in serum creatinine for the diagnosis of AKI. Second, it introduces a 48-hour time for diagnosis. Last, it eliminates the “loss” and “failure” categories as these represent outcomes, and should not be listed as part of the diagnosis. Recent evidence indicates that even minor declines in glomerular filtration rate are associated with increased mortality in different populations of hospitalized patients. A meta-analysis of 8 studies observed a graded relationship between the amount of elevation of serum creatinine and mortality in AKI.⁹ Regardless of ICU type or clinical scenario, creatinine elevations of 10% to 24% above baseline resulted in a relative risk of 1.8 (1.3-2.5) for short-term mortality (30 days or less); patients with a rise of 25% to 49% had a relative risk of 3 (1.6-5.8), and those with greater than 50% increase had a risk of 6.9 (2-24.5). These data justify the “tighter” criteria proposed in the AKIN classification. Neutrophil gelatinase–associated lipocalin (NGAL) is a protein expressed in multiple tissues that is upregulated in proximal tubular cells immediately following ischemic injury has been studied as a biomarker of early kidney injury.¹⁰ Likewise, interleukin 18 (IL-18), cystatin C, and kidney injury molecule 1 (KIM-1) have all been studied and demonstrated the usefulness in early detection of acute renal injury.

Intermittent hemodialysis has long been the preferred method of RRT in the United States. However, CRRT is gaining in popularity and is now reported to account for 36% of prescribed RRT treatments.¹¹ Internationally, continuous therapies had become the norm for AKI support.¹² “Beginning and Ending Supportive Therapy for the Kidney” (BEST Kidney), a multinational, prospective study reported that CRRT with RRT support was used in 80% of treatments in the ICU, distantly followed by intermittent hemodialysis (17%).¹³ No evidence currently supports the superiority of one continuous modality over another or continuous over intermittent treatment. Choice of RRT modality should be based on clinical judgment and experience of the prescribing physician as well as the technologic, fiscal, and nursing resources available to deliver RRT.

Dialysis therapies involve the movement of solute and plasma water across a semipermeable membrane separating a blood compartment and a dialysate compartment. This process occurs within a cartridge called a hemofilter or hemodialyzer. Characteristics such as membrane thickness and pore dimensions determine the size and transfer rate of molecules that move between the blood and dialysate. Removal of solute and water in RRT may occur by diffusion or convection (Figure 99–1). Diffusion involves movement of solute down a concentration gradient, from areas of high concentration to low concentration. Conversely, water will move from an area of low osmolality to an area of high osmolality. Solvent drag is a phenomenon by which large shifts of water pull some solute through the membrane. In a static system, net transfer (dialysis) ceases when solute concentrations equilibrate in the compartments. For RRT, blood and dialysate are continuously replenished to maintain the high concentration gradients favoring maximum transfer of solute and water. Convection involves the transfer of solute across a semipermeable membrane driven by a hydrostatic pressure gradient. Those solutes small enough to pass through pores are swept along with water by solvent drag; substitution fluid is required to prevent excessive fluid removal. The membrane acts as a sieve, retaining molecules that exceed the pore size. All filtered solutes below the membrane pore size are removed at rates proportionate to their concentration. The convective removal of fluid in this manner is termed hemofiltration or ultrafiltration. This technique does not change the plasma concentration of small solutes (blood urea nitrogen [BUN], creatinine, electrolytes, glucose), as water is removed in proportion to solute. In contrast, the concentration of larger molecules, such as albumin, increase as they are sieved off by the smaller membrane pores. Thus, the chemical composition of the filtrate (ultrafiltrate) is almost identical to that of the plasma except for the absence of large molecules such as albumin. The administration of substitution fluid will dilute the plasma concentrations of those solutes (such as urea, creatinine, or potassium) not present in the substitution fluid.

In summary, whether or not a solute is diffused is inversely proportional to its molecular weight. The higher the molecular weight the more inefficient the diffusion.

The modern paradigm recognizes that AKI is an independent risk factor for death^14,15,16 and that the aggressive management of RRT may affect outcomes and reduce mortality.^17,18,19 However, there is no consensus on the optimal time to initiate RRT. This has led to a wide variation in clinical practice. Traditionally the indication for RRT²⁰ has been based on or a combination of the following: volume overload, such as pulmonary edema that is not controlled with diuretic use, hyperkalemia-induced arrhythmias, uncontrolled metabolic acidosis, intoxication with a dialyzable drug or toxin, and overt uremic signs such as encephalopathy, pericarditis, or even uremic bleeding diathesis.

Access for RRT

The optimal access for hemodialysis are arteriovenous fistulas (AVFs) that provide high blood flow (> 500 mL/min), durable long-term vascular access, relatively low thrombosis rates, and low infection rates. AVFs require months to mature and be functional, making them unsuitable for patients with AKI. AVFs cannot withstand prolonged cannulation associated with CCRT. Therefore with CVVH a temporary central venous catheter is needed. These catheters are generally noncuffed, nontunneled, double lumen with a large diameter of 12 to 15 Fr, providing a flow between 200 and 500 mL/min. They contain a venous and an “arterial” lumen although both lumens are in the same vein. The arterial lumen (typically red) withdraws blood from the patient and carries it to the CVVH machine, while the venous lumen (typically blue) returns blood to the patient from the machine. These catheters are typically constructed of materials such as polyurethane and are relatively stiff at room temperature, but become pliable at body temperature. They are inserted at the bedside. The internal jugular or femoral veins are preferred, over the subclavian vein due to the risk of developing venous stenosis after placement precluding future placement of an AVF in the ipsilateral arm.

Dosing

Despite the widespread use of CRRT, there is little consensus regarding the optimum delivery of RRT, resulting in wide variations in clinical practice.²¹ Some studies have suggested survival benefit from delivery of higher-intensity CRRT to patients with AKI, whereas other studies have been inconsistent in their results. CRRT is most often prescribed based on the body weight to effluent flow rate target of 20 to 25 mL/kg/h. Recent studies have shown that effluent flow rate higher than 25 mL/kg/h does not improve outcomes in ICU patients.²² In our institution, the typical rates used for CVVH are a blood flow rate of 200 mL/min and RF rate of 2 L/h with ultrafiltration rate based on the individual need for fluid balance. This rate is variable and changes every hour depending on the total input and output of the previous hour. For example, if the desired fluid balance is –50 mL/h with a total input of 200 mL and output of 100 mL from the previous hour, the balance is +100 mL, therefore the ultrafiltration rate will be set at 150 mL/h.

Anticoagulation

Although CRRT can be run without anticoagulation, filters last much longer if some form of anticoagulation is used. Their fibers are prone to thrombosis, as removal of fluid through ultrafiltration leads to hemoconcentration at the distal end. Anticoagulation is generally recommended, as the clotting cascades are activated when the blood touches the nonendothelial surfaces of the tubing and filter. Multiple options exist for anticoagulation including heparin, prostacyclin, citrate, and even direct thrombin inhibitors. Unfractionated heparin is most commonly used, but can result in systemic anticoagulation and may be contraindicated in patients with active hemorrhage or heparin-induced thrombocytopenia (HIT). Any dose less than 5 units/kg/h is considered low-dose prefilter unfractionated heparin. This dose is reported to have minimal effect on the activated partial thromboplastin time (aPTT). A dose between 8 and 10 units/kg/h is considered medium-dose prefilter unfractionated heparin. This dose mildly elevates the aPTT and is recommended for patients with minimal risk of bleeding. Heparin may be administered using a pump integrated into the CRRT machine, or via a separate volumetric pump. Systemic unfractionated heparin is reserved for patients with other indications for systemic anticoagulation and is administered intravenously and titrated to achieve a target aPTT of about 1.5 to 2.5 times above the patient’s baseline. For patients with high risk of bleeding regional unfractionated heparin to the CVVH blood circuit may be used. In this technique, a prefilter dose of 1500 units/h of heparin combined with administration of protamine postfilter at a dose of 10 to 12 mg/h is used. This approach is monitored with the aPTT to keep it as close to normal as possible. Another option for these patients is the use of citrate. Citrate regional anticoagulation is widely used and has become the primary mode of anticoagulation in many centers. Citrate infused in the arterial limb of the CRRT circuit prevents hemofilter thrombosis by chelating calcium, a critical component of the clotting cascade. Calcium chloride infused into the venous line of the system restores normal systemic calcium levels. This approach appears to reduce the risk of hemorrhage and extend hemofilter patency.²³ In addition, citrate can be used for patients with HIT. Serum and ionized calcium levels should be carefully monitored, especially in patients with significant liver dysfunction, and the calcium infusion appropriately adjusted. Citrate is hepatically metabolized into bicarbonate and can cause metabolic alkalosis. In the setting of hepatic failure, citrate accumulation results in elevated serum but low ionized calcium levels, reflecting increased circulating calcium bound to citrate.

Filters

Semipermeable membranes are the basis of all blood purification therapies. The surface area of the membrane depends on the number and length of these fibers. Membrane surface area affects solute clearance and ultrafiltration. Membrane size or surface area varies with the specific model of hemodialyzer or hemofilter. Larger dialysis cartridges are used for patients with a larger surface area or those needing high solute clearances. They allow water and some solutes to pass through the membrane, while cellular components and other solutes remain behind. The water and solutes that pass through the membrane are called the ultrafiltrate. Pore dimensions determine the size selectivity of molecular flux across the membrane, typically pore size membranes are 30,000 Da. Low-flux (< 500 Da) membranes clear small molecules (urea, potassium, and creatinine), but do not clear the larger “middle molecules” that may act as toxins. High-flux membranes (< 20,000 Da) clear middle molecules, such as β₂-microglobulin and perhaps inflammatory cytokines generated by AKI and MOSF. There are 2 types of membranes used in RRT: cellulose and synthetic. Synthetic membranes are biocompatible, high flux, which allow clearance of larger molecules causing less trauma to platelets and white blood cells (WBCs), and are thus primarily used in CRRT. Filters are changed when they become contaminated, clogged, or according to individual hospital protocols.

RFs are used to increase the amount of convective solute clearance in CVVH by replacing large volumes of ultrafiltrate with fluids that do not contain the solutes targeted for removal. Solute clearance and volume removal are adjusted by altering the ultrafiltration rate and the rate of infusion of RF. They can be replaced before or after the filter depending on individual needs (Figure 99–2). As the filtration fraction (FF), that is, the proportion of plasma flow that is filtered, increases, the risk of filter thrombosis also rises. Higher rates of ultrafiltration, especially if coupled with low blood flows, predispose to hemofilter thrombosis. Poor filter performance and filter clotting increase sharply at FF greater than 20%. Higher blood flow rates permit greater rates of fluid removal, as hemoconcentration within the filter is limited by the short transit time of blood through the dialysis cartridge. In CVVH, blood flow rates are typically low and ultrafiltration rates are high, which is a significant barrier to effective implementation of these therapies. One approach called predilutional hemofiltration, which is preferred by the authors, involves infusion of RF into the CRRT circuit at a point before the filter, thus lowering the hematocrit through dilution. As a result, a higher ultrafiltration rate may be achieved without compromising filter life. Prefilter RF also dilutes the solute concentration of blood entering the filter and reduces effective clearance. The administration of RF maintains fluid balance and lowers the plasma concentration of solute by dilution. Typical RF rates are 1000 to 2000 mL/h. Rates slower than this are not effective for convective solute removal, but should not exceed one-third of the blood flow rate per hour. There are a number of variable RFs available including normal saline, plasmalyte, or specific commercial products for CVVH with variable electrolyte concentration depending on the clinical condition of the patient as well as the patient’s fluid, electrolyte, acid-base, and glucose balance.

Local bleeding can occur at the vascular access site or might be subcutaneous and not obvious. The access site should be closely monitored for bleeding, hematoma, or ecchymosis. Femoral lines in particular may cause internal bleeding that is not immediately apparent. Monitor the hemoglobin or hematocrit and vital signs closely as they may indicate occult bleeding. Inadvertent disconnection of the CRRT blood circuit could lead to significant blood loss. Modern CRRT machines are equipped with alarms and cutoff switches to minimize this risk. Watch for low access pressure alarms and low return pressure alarms, as they could indicate a disconnection. Generalized bleeding complications can occur as a side effect of anticoagulation or as a result of critical illness itself. It is vital to monitor the platelet count for thrombocytopenia, coagulation factors, and fibrinogen for signs of disseminated intravascular coagulation (DIC). Care should be taken when priming the tubing as to prevent air bubbles from entering the systemic circulation and causing an air embolism. Hypothermia is another potential complication because of the extracorporeal circulation during CVVH and exposure of RFs to room temperature. Patient’s body temperature should be kept above 36°C to maintain adequate hemodynamics and effective hemostasis. Newer CVVH machines have blood warmers integrated into them. Inline fluid and blood warmers are also available so that fluids can be warmed prior to administration. Most CRRT protocols require monitoring of electrolytes and pH every 4 to 6 hours during the first 24 hours of therapy and whenever RFs are changed. CRRT is an invasive process that increases the risk of infection in a patient that is already vulnerable due to renal failure, critical illness, and other invasive lines and procedures. These patients must be monitored closely for signs and symptoms of infection so treatment can be initiated as rapidly as possible. Infections caused by CVVH may be local to the vascular access site or systemic. It is important to remember that when CVVH is in progress fever may be masked due to the cooling effect of extracorporeal circulation. Monitor for other signs of infection such as elevated white blood cell count, increased numbers of immature WBCs, and local symptoms like redness, swelling, and purulent drainage. All connections and vascular access sites must be handled with meticulous aseptic technique to minimize the risk of infection. As patients receiving CVVH will clear renally excreted drugs efficiently, dosing of these drugs should not be reduced for renal function while on CVVH unless clinically indicated. After initiation of CRRT drug levels may need to be drawn to ensure adequate plasma concentrations especially for antibiotics and anticonvulsants. Drips of renally cleared drugs may need to be titrated up while on CVVH and likewise may need to be decreased once CVVH is stopped. Special care must be taken when discontinuing CVVH as certain drugs may build up to toxic levels.

Troubleshooting

Although there are many different types of CVVH machines and each one has its own individual characteristics, we will review some general issues. The access pressure is normally negative; however, excessive negative pressure usually indicates an occlusion somewhere in the access limb of the blood circuit. The complete tubing system should be inspected in search of kinks and stopcocks should be confirmed for proper position. Vascular access should also be evaluated for poor position or swelling at the site. The patient should be positioned properly to minimize flexion near the insertion site and the access port should be aspirated and manually flushed. The return pressure is normally positive and low return pressures could indicate a disconnection at some point, return tubing should be checked for proper connections. Low return pressures can also be encountered when patients are laterally rotated due to orthostatic changes in venous pressure. Alarms that occur due to position changes will usually resolve within a couple of minutes. High return pressures can occur because of occlusions. Filter pressure alarms usually only sound when the filter is clogged or clotted. Initial filter pressures should be measured each time a new filter is placed. Filter pressure usually remains stable throughout therapy. The filter pressure can be trended to help for predict clotting. CVVH machines can detect blood leaks indicating broken filaments in the filter by looking for the presence of blood in the effluent. The sensors will alarm if myoglobin or large amounts of bilirubin are detected in the effluent. A sample should be sent to the laboratory to confirm their presence. The bubble detector is designed to stop the blood pump if air is detected within the line. If it alarms, inspect all tubing carefully for the presence of air bubbles and either reprime or change the filter set. Make sure that all air is cleared from the system during priming, keep all connections tightly joined, and use Luer-lock type connectors. The fluid pump alarms when the bag is empty while the effluent pump alarms when full. Alarms will also sound if a clamp is left closed or a bag is improperly spiked.