Current ultrafiltration techniques before,during and after pediatric cardiopulmonary bypass procedures

Abstract

Ultrafiltration, which is currently considered as a standard method to remove excess water administered during pediatric cardiopulmonary bypass (CPB), aims to minimize the adverse effects of hemodilution, such as tissue edema and blood transfusion. Three ultrafiltration techniques can be used before, during and after CPB procedures, including conventional ultrafiltration (CUF), modified ultrafiltration (MUF) and zero-balance ultrafiltration (Z-BUF). These methods are widely different, but they have common benefits on hemoconcentration, less requirement for blood products, and reduction of the systemic inflammatory responses (SIRS). The present review attempts to restate these ultrafiltration circuitries, application methods, end-points, and clinical impacts.

Keywords

ultrafiltration MUF Z-BUF cardiopulmonary bypass pediatrics

Introduction

Ultrafiltration (UF) has been widely used during pediatric cardiopulmonary bypass (CPB). It was originally adapted from a renal dialysis technique which is used to provide an artificial replacement for kidney dysfunction in patients with renal failure by removing waste and excess water from blood. Ultrafiltration can reverse hemodilution during CPB by removing plasma water directly across a semipermeable membrane using hydrostatic forces. Although hemodilution is usually utilized during CPB and facilitates tissue-perfusion, hemodilution has been shown to contribute to some adverse effects, such as a decreased plasma colloidal oncotic pressure, increased total body water and interstitial edema in vital organs, hypoxia, hypotension, hypocoagulation, renal dysfunction, myocardial and cerebral ischemia, and even increased mortality.¹ Therefore, the application of ultrafiltration at the end of CPB primarily aims to concentrate the perfusate and then re-infuse it back to the patient. This method made wide use of hemodilution techniques and multidose cardioplegia for myocardial preservation during CPB.

To date, there are three types of ultrafiltration techniques used during CPB procedures. Conventional ultrafiltration (CUF) is a common method to maintain moderate hemodilution during CPB and a minimal venous reservoir blood after CPB. This technique can be used at any time during CPB prior to weaning from CPB. Modified ultrafiltration (MUF) developed by Naik et al.,² in contrast, is performed after CPB in order to concentrate circulating blood by removing excess water from the patient, and also to salvage blood from the bypass circuit. The technique of MUF has become widely adopted for use with hemodilution CPB in pediatric populations. In addition, zero-balance ultrafiltration (Z-BUF), first reported by Journois et al.,³ has a similar circuit to CUF and is performed during CPB with ultrafiltrate and replacement fluid with balanced electrolyte solution in a ratio of 1:1 so as to keep constant the blood volume during the Z-BUF procedure. It is usually performed after rewarming and aims to adjust electrolyte and acid-base balance and remove inflammatory mediators. Each one of these methods has its own advantages and disadvantages. Therefore, the combined application of different ultrafiltration styles may reach its maximal effect in the patient undergoing the CPB procedure.

Ultrafiltration circuitries

There are two main circuit connection methods during ultrafiltration – arterio-venous UF and veno-venous UF.

Arterio-venous ultrafiltration

From the purge line of the arterial filter to the venous reservoir (Figure 1.A) - This is the most commonly used method of CUF and plays an essential role in removing gaseous microemboli from the arterial filter.

From the arterial line to the venous line (Figure 1.B) - A classical connection method for MUF. The blood pump should be used as the power to control the blood flow rate.

From the recirculation line to the venous reservoir (Figure 1.C) - An alternative method for CUF.

From the arterial line to the cardioplegia deliver line (Figure 1.D) - Blood flow can be kept warm during the MUF procedure, using a heat exchanger of a cardioplegic system, especially for neonates and infants.

Veno-venous ultrafiltration

From the venous line to the venous reservoir (Figure 2.A) – The blood pump was inserted into the circuit.

From pump boot (pump loop) after the main blood pump to the venous reservoir (Figure 2.B).

From the vent line to the venous reservoir (Figure 2.C) - This method can be used after the release of the aortic cross-clamp and after cessation of CPB.

d. Other alternative methods - An ultrafilter was inserted between the femoral vein and contralateral femoral vein,⁴ or the venous reservoir and the cardiotomy reservoir.⁵ A dual-lumen catheter located in right atrium was used for veno-venous MUF.⁶ The blood pump should be used for power.

Type of ultrafilters (Hemoconcentrators)

Several ultrafilters are available for clinic use (see Table 1).

Table 1.

Ultrafilters: different characteristics.

Ultrafilter system	Minntech HPH	Jostra	Dideco	Fresenius	Terumo
	Jr.-Mini-400-700-1000-1400	BC20-60-140	DHF02-06-SH1.4	HF3000-5000	HC05-11
Fiber material	Polysulfone	Polyarylsulfone	Polyethersulfone	Polysulfone	Polysulfone
Prime volume (ml)	8-14-27-58-70-86	17-65-98	30-60-80	30-72	35-70
Membrane surface area (m²)	0.09-0.07-0.3-0.71-1.06-1.31	0.2-0.7-1.35	0.25-0.68-1.4	0.4-1.2	0.5-1.1
Pore size (Dalton)	65000	/	/	/	/
MTP (mmHg)	500	600	500	600	500
Pressure drop (mmHg)	55-30-61-142-85-78	/	50-150	144-65	/
Fiber internal diameter (μm)	200-620-200-200-200-200	215	200	200	/
Membrane thickness (μm)	/	50	30	/	/

MTP: maximum transmembrane pressure

Application methods

Currently, there are three methods for the application of ultrafiltration.

Conventional ultrafiltration

The most commonly used method is placing an ultrafilter between the arterial filter purge line and the venous reservoir. No pump is used. CUF can be performed by opening the arterial filter purge line of the arterial filter with blood flow from the high pressure of the arterial line to the low pressure of the venous reservoir at any time during the CPB procedure. In order to increase the transmembrane pressure, the ultrafilter outlet tubing can be partly clamped and the “stolen” blood flow from the purge line can decrease. A proper negative pressure in the dialysate compartment can be used to favor further ultrafiltration.

Modified ultrafiltration

The ultrafilter is placed with the inlet connected to the arterial line and the outlet connected to the venous line. The blood pump must be used before the ultrafilter. The ultrafilter should be primed for de-airing before CPB and kept isolated during CPB by clamping the inlet of the ultrafilter. After CPB ceases, the venous line between the venous reservoir and the outlet of the ultrafilter is clamped. The inlet of the ultrafilter is unclamped. Then MUF is conducted, with blood flowing from the arterial line through the ultrafilter and back through the venous line to patient. At the same time, the arterial pump is simultaneously activated to deliver the blood in the venous reservoir to the patient for compensating the volume of ultrafiltrate.

Zero-balance ultrafiltration

An identical circuit is used with CUF. Z-BUF is usually performed after the rewarming phase by administering a replacement fluid equal to the ultrafiltrate volume into the venous reservoir. The most commonly used replacement fluid is Plasmalyte, an isotonic electrolyte solution. Other crystalloid solutions, such as Duosol,⁷ or PrismaSATE® BK0/3.5⁸ are also used by clinical perfusionists. A single pump can be used for ultrafiltrate tubing and substitute tubing to ensure volume balance. High-volume Z-BUF allows one to control blood potassium and glucose levels throughout the conduct of CPB.

UF end-points

Before CPB

Z-BUF can be performed before CPB; aim to “wash” perfusate (containing packed red blood cells or fresh plasma) to reach normal electrolyte concentration and acid base balance. A replacement fluid should be administered during Z-BUF to maintain a constant blood level in the venous reservoir and blood gas analysis for the priming solution is needed to decide the Z-BUF end-point. CUF may also be used to concentrate the perfusate to a proper blood level in the venous reservoir when more priming solution is added by mistake. The ultrafilter is left in the CPB circuit, so it can be used for CUF or MUF.

During CPB

CUF can be performed at any time during the CPB procedure, especially when more crystalloid solution enters into the CPB circuit, resulting in a lower hematocrit. Circulating blood is concentrated by CUF and then the hematocrit increased when more packed red blood cells are added into circuit, if need be. The blood reservoir level can be kept at an acceptably minimal and safe operating level and the hematocrit reach a maximum before the termination of CPB. CUF’s effectiveness is limited by the need to maintain a minimum blood level in the venous reservoir, especially in pediatric patients. Z-BUF usually is performed after the rewarming phase. The blood level in the venous reservoir is maintained constant by administering replacement solution during the Z-BUF procedure. A time-based criterion or a filtrate-volume end-point may be adopted, depending on one’s own clinical guideline.

After CPB

MUF is usually performed for a period of 10 - 20 minutes, with 5 - 10 minutes after the cessation of CPB if the patient is hemodynamically stable. Reducing the amount of body water accumulation and concentrating circulating blood elements are its final aims. MUF is completed, either when the CPB circuit empties, or when the hematocrit reaches a reasonable level. Fresh plasma or packed red blood cells may be administered to further enhance the effects of MUF.

During ECMO

An ultrafilter can be placed in-line with an ECMO circuit from the high pressure arterial line to the low pressure venous line. Both CUF and Z-BUF can be adopted during ECMO. The goal is to remove excess body water and increase blood osmolarity or normalize fluid-electrolyte and acid-base balance by administering fluid replacement solutions. Blood gas analysis and the clinical situation are regarded as essential tools in determining its end-point.

Clinical impacts

Hemoconcentration

The CPB circuit must be primed with fluid and all air expunged before connection to the patient. Transfusion of large volumes of crystalloid solution during CPB can result in excessive hemodilution. Normal saline as “maintenance” fluid may cause increasing hemodilution. Most of all, there is a high ratio of prime volume to patient blood volume during a pediatric CPB procedure. However, these clear fluids cannot be totally removed by the kidneys after CPB ceases. Long duration of bypass, hypothermia and low body weight increase the risk of the accumulation of water in the body. Therefore, the primary goal of the introduction of CUF is the removal of the crystalloid priming fluid, and MUF can remove more body water from patients than CUF. This is the most direct and visual effect of ultrafiltration. Almost all published articles about ultrafiltration have demonstrated this effect and significant clinical benefit. Ultrafiltration can remove water from the circulation and, meanwhile, lead to increases in hematocrit and hemoglobin levels. Administering fresh plasma, packed red blood cells and human albumin into the CPB circuit may further increase the hematocrit (Hct) and plasma osmolarity. It is well known that blood concentration can increase the oxygen-carrying capacity of the blood to avoid end-organ ischemia and dysfunction after CPB procedures.

Blood product requirements

Excess water removal and blood salvage from the residual volume of the CPB circuit by MUF result in higher hematocrit and platelet levels after CPB, and then lead to a reduction in blood transfusion,⁹ although some clinical researches did not show this clinical effect.^10,11 A clinical study reported a significant reduction in blood loss in the first 48 hours after CUF plus MUF.¹² This effect may be related to the concentration of clotting factors (fibrinogen, prothrombin and factor VII) and platelets by ultrafiltration.¹³ In an animal experiment, lower thrombin antithrombin complex levels after MUF indicated less thrombin formation and might have been associated with better preserved coagulation function in neonatal piglets.¹⁴

Cardiac function

A clinical study demonstrated that MUF could improve intrinsic left ventricular systolic function, improves diastolic compliance, increases blood pressure, and decreases inotropic drug use in the early postoperative period in infants.¹⁵ Chaturvedi et al. showed that MUF improves global left ventricular systolic function in terms of the slope of the end-systolic pressure volume (median increase 57.8%, p=0.005) in infants and children following open-heart surgery.¹⁶ Honjo et al.¹⁷ demonstrated that MUF ameliorated the myocardial performance index of the systemic ventricles and may be particularly useful for restoring the global ventricular performance of pediatric patients undergoing longer CPB. Aggarwal et al.¹² also reported significant improvements in ejection fraction (EF) and fractional area change (FAC) and a decrease in posterior wall thickness after CPB with CUF plus MUF. The mechanism that accounts for the improvement in cardiac function by MUF may be MUF-induced hemoconcentration and reduction of myocardial edema. The increases in heart rate and diastolic blood pressure after MUF may have a beneficial effect on coronary arterial flow in neonates undergoing the first stage of the Norwood reconstruction.¹⁸

Pulmonary function

A clinical study showed that continuous ultrafiltration (Z-BUF+MUF) reduced the inflammatory response as well as helped pulmonary function. Pulmonary air exchange and pulmonary ventilation function were improved after CPB, which was associated with the concentration of blood and the removal of inflammatory mediators.¹⁹ Ultrafiltration could shorten time on mechanical ventilation and improve the postoperative alveolar-arterial oxygen gradient.³ Mahmoud et al.²⁰ found a temporary improvement in lung compliance and gas exchange capacity after MUF in infants. Hiramatsu et al.⁴ reported that Z-BUF and MUF suppressed the increase in plasma endothlin-1 (ET-1) concentration and maintained lower pulmonary vascular resistance after the Fontan procedure. In another study, Lou et al.²¹ found decreases in plasma procalcitonin level, PaCO₂ and mechanical ventilation time, and an increase in pulmonary compliance. They concluded that improved respiratory function might be due to a lower plasma procalcitonin level in patients with congenital heart disease. An animal experiment confirmed the clinical finding. Lower pulmonary vascular resistance, lower IL-8 levels in airway lavage fluid, higher static pulmonary compliance and lower lung water content were observed after MUF in 2-h bypass neonatal piglets.¹⁴

Intensive care unit (ICU) stay

Kotani retrospectively analyzed clinical data and reported that MUF could shorten ICU stay, but did not change the duration of ventilator support in neonates who underwent the arterial Switch operation.²² Sever et al.⁹ also reported a shortened length of ICU stay by MUF. Z-BUF of the blood prime combined with CUF significantly reduced inotropic support and shortened the duration of ventilator support and ICU stay.²³

Electrolytes

The semipermeable membrane ultrafilter allows water and some small molecules to pass through the membrane. Increasing the transmembrane pressure forces more fluid and solutes to be ‘‘pulled’’ through the membrane. During CPB, hyperkalemia may be caused by the administration of high-volume, high-potassium cardioplegia for myocardial protection, hemolysis, or packed red blood cells. In this situation, high-volume Z-BUF with no potassium replacement fluid can maintain the plasma potassium level in the normal range before the release of the aortic cross-clamp so as to contribute to the recovery of normal sinus rhythm. López et al.²⁴ reported that, after separation from CPB, the plasma potassium level was reduced by 13.7% after 10 minutes of MUF in pediatric patients; however, the reduction in magnesium at the same period of time was not significant. Pre-treatment of the priming solution can also minimize electrolyte and acid-base disturbances after the initiation of CPB. A clinical prospective study demonstrated that Z-BUF of pediatric priming blood before CPB could significantly increase pH, actual bicarbonate (HCO₃), base excess, sodium and calcium concentrations, decrease glucose, lactate and potassium concentrations and maintain the electrolyte and acid-base levels within normal ranges after approximately 1000ml of ultrafiltrate was hemofiltrated using a bicarbonate-buffered hemofiltration solution (Duosol, B.Braun, Melsungen, German) as a replacement solution.²⁵ An animal study showed that the “washing” of priming blood could reduce levels of potassium, serotonin, lactate and IL-8. As a result, pre-treatment of priming solution could adjust concentrations of electrolytes and metabolites and attenuate inflammatory mediators.¹⁴ A recent study reported that Z-BUF of the blood prime reduced metabolic load, resulting in low lactate and potassium before and after CPB.²³

Systemic inflammatory response syndrome

Exposure of blood to non-physiologic surfaces induces a systemic inflammatory response syndrome (SIRS), characterized by the systemic release of inflammatory cytokines. The ultrafiltration technique utilizes a hemoconcentrator to remove excess body water; at the same time, low– molecular-weight substances will be removed from plasma, such as TNF-α, IL-1, IL-6, IL-8, IL-10, and complements C3a, C5a, and C5b-9. The ultrafiltration efficiency of ultrafilters depends on the port size of the ultrafiltration membrane, flow across the membrane surface, ultrafiltrate volume, transmembrane pressure and operating temperature. So, different ultrafiltration membranes and different clinical situations may have different ultrafiltration efficiency. Ultrafiltration of priming blood could reduce the initial attack of inflammatory mediators after the onset of CPB and prohibit the increase of cytokine following CPB.²⁶ MUF decreased levels of IL-8 during the early postoperative hours in pediatric cardiac surgery, but there was no significant difference at 24h after CPB when compared with CUF.⁹ Berdat et al.²⁷ found that polyamide ultrafilter was more effective in lowering IL-10 and the terminal soluble C5b-9 complement complex (TCC) plasma levels, whereas the polyarylethersulfon ultrafilter was more effective in lowering IL-6, and CUF with the polyarylethersulfon ultrafilter could remove more IL-6 than MUF.

Drugs

Children undergoing cardiac surgery usually need the support of drugs after surgery. Certain drugs could be removed by ultrafiltration, and those highly protein-bound drugs were concentrated, dependent on the pore size of the ultrafiltration membrane used. Sieving coefficients for selected drugs are critical parameters in decreasing the plasma concentrations of drugs.²⁸ Bivalirudin is a direct thrombin inhibitor for heparin-induced thrombocytopenia (HIT); there is no known antidote to it. In a case report,²⁹ the activated clotting time (ACT) could rapidly fall with the discontinuation of bivalirudin infusion during MUF after CPB. Because bivalirudin can be removed by ultrafiltration, MUF could help to maintain good hemostasis after CPB. Masuda et al. found that almost one-fourth of the given dose of Flomoxef (a second generation cephalosporin antibiotic with a broad spectrum) was removed by MUF in children undergoing cardiac surgery.³⁰

Ultrafiltration disadvantages

Hypertension

The increase in blood pressure during MUF may come from the improvement of myocardial contractility associated with a reduction in myocardial water content.³¹ No correlation was detected between the increases in blood pressure and hematocrit.³² In addition, one study demonstrated that the removal of prostaglandin E₂ (PGE₂ - a major intrinsic vasodilator) is one reason for increased blood pressure during MUF in pediatric patients, with no change in the central venous pressure and dopamine dosage and with the effect more marked in low-weight patients.³³

Hypokalemia

Since plasma potassium, as a small ion, can pass freely through the ultrafiltration membrane, plasma potassium levels may decrease after MUF in children undergoing CPB procedures;²⁴ high volume Z-BUF with potassium-poor replacement fluid may result in abnormally low plasma potassium concentrations. Attention must be paid in this situation. López and colleagues suggested that supplementation with potassium in patients with low plasma potassium levels before MUF could prevent even lower plasma potassium levels after MUF.²⁴

Hemolysis

Long periods of ultrafiltration, high transmembrane pressures, and high flow rates through the ultrafilter can result in hemolysis. Early perfusate hemoconcentration during CPB may also induce hemolysis. The ultrafilter cannot remove free hemoglobin, but concentrates it.

Air delivery

The aortic cannula may entrain air during MUF.¹¹ When the tip of the aortic cannula touches the back wall of the aorta during MUF, the arterial tubing may collapse, resulting in injury to the aorta. During ECMO, if the outlet of the ultrafilter connects with the inlet side of a centrifugal pump, clamping the inlet of the ultrafilter may induce air entrainment from the hollow-fiber membrane pores in the ultrafilter. So, the ultrafiltration circuit keeps open continuously or both sides of the ultrafilter are clamped completely and not re-used.

Patient cooling

A long period of ultrafiltration without a heat exchanger may induce cooling of the patients and affect the coagulation system and the hemodynamic response to drug therapy, especially in neonates and infants. The application of heat exchangers during MUF will prevent patient cooling.

Hemodynamic instability

Ultrafiltration may result in hemodynamic instability or may impair aortic pulmonary shunt flow.¹¹ There are various reasons for this, including rapid decrease in blood volume, more aortic shunt by MUF, low body temperature, or cardiac dysfunction. In this situation, the best advice is to delay or stop MUF.

Cerebral ischemia

Medlin et al.³⁴ reported the trends in cerebral tissue oxygenation changes during MUF. Cerebral oxygen saturation (rSO₂) has positive correlations with pCO₂ and mean arterial pressure, and negative correlation with ultrafiltration pump flow rate. Rodriguez et al.³⁵ found decreases in middle cerebral artery blood flow velocities and cerebral mixed venous oxygen saturations during MUF, despite mild increases in systemic blood pressures and hematocrit, especially when high blood flow rates through the MUF circuit were used. This is possibly a result of “stolen” blood flow from the carotid circulation during MUF in small infants. Much attention should be given to performing any ultrafiltration during or after CPB in neonates or infants to prevent hypoperfusion, because of shunting flow through the ultrafiltration line. Controlling proper ultrafiltration speed is very important.

Others

There is an extra cost to the use of ultrafiltration. Exposure of blood to the non-endothelial surfaces of the ultrafilter may induce more immunologic reactivity. MUF extends the duration of cardiac surgery and delays protamine administration.

Penn State Hershey Children’s Hospital Approach

There is a concerted effort by most pediatric cardiac surgery centers to reduce the amount of hemodilution on CPB. That has been accomplished by reducing the length of the circuit, reducing the diameter of the tubing, assisted venous return, etc. Reducing the exposure of the patient to blood transfusions is important, but anything to excess can be detrimental. Reducing the size and length of the CPB circuit can increase the pressure of the circuit, which has been demonstrated to be detrimental, not to mention the increased risk of gaseous microemboli (GME). Our philosophy at Penn State Hershey Children’s Hospital is to have matched components (packed red blood cells (PRBC), fresh frozen plasma (FFP), and platelets) from the same donor, thus, reducing exposure. Our desired hematocrit on CPB is 26% or greater, so we usually prime with 250 ml of PRBC on our smaller patients. This affords us the ability to reach our goal of the desired Hct level while supplying enough volume to the MUF at the end of our case. We feel that it is important to remove 400-600 ml of effluent during MUF in order to raise the hematocrit to at least 40% and remove significant levels of circulating pro-inflammatory mediators. Better postoperative outcomes may be more than a result of higher hemoglobin levels.

Conclusion

Removal of excess water from the patient’s body is the main reason for using ultrafiltration during CPB procedures, regardless of CUF, Z-BUF or MUF before, during and after CPB. Removing larger amounts of water may lead to more clinical effects, including a reduction in the need for blood products, an increase in postoperative hematocrit, improvements of heart and lung function, and shorter periods of mechanical ventilation time and ICU stay, especially in neonates and infants. Apart from these clinical benefits, greater removal of systemic inflammatory mediators is another targeted purpose, and has benefits for early postoperative recovery in cardiac surgery patients. If possible, monitoring the inflammatory response in a continuous, real-time fashion will allow perfusionists to recognize variable trends in the inflammatory response during CPB, and to reach maximum effects by ultrafiltration.

Footnotes

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Conflict of Interest Statement

None declared.

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