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Eur J Cardiothorac Surg 2003;24:243-248
© 2003 Elsevier Science NL

Modified ultrafiltration may not improve neurologic outcome following deep hypothermic circulatory arrest

Richard J. Myunga, Paul M. Kirshboma, Matus Petkoa, Jeffrey A. Goldenb, Alexander R. Judkinsb, Richard F. Ittenbachc, Thomas L. Spraya, J. William Gaynora*

a Division of Cardiothoracic Surgery, The Children's Hospital of Philadelphia, 34th Street and Civic Center Boulevard, Suite 8527, Philadelphia, PA 19104, USA
b Department of Pathology, The Children's Hospital of Philadelphia, 34th Street and Civic Center Boulevard, Suite 8527, Philadelphia, PA 19104, USA
c Department of Biostatistics and Epidemiology, The Children's Hospital of Philadelphia, 34th Street and Civic Center Boulevard, Suite 8527, Philadelphia, PA 19104, USA

Received 23 September 2002; received in revised form 21 April 2003; accepted 26 April 2003.

* Corresponding author. Tel.: +1-215-590-2708; fax: +1-215-590-2715
e-mail: gaynor{at}email.chop.edu


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Objective: Modified ultrafiltration (MUF) improves systolic blood pressure and left ventricular performance, as well as lowering transfusion requirements, after cardiopulmonary bypass (CPB). MUF has also been shown to enhance acute cerebral metabolic recovery after deep hypothermic circulatory arrest (DHCA), but whether this improves neurologic outcome is unknown. Methods: Sixteen neonatal piglets underwent CPB and 90 min of DHCA. The hematocrit was maintained between 25 and 30%. Alpha-stat blood gas management was used. After separation from CPB, animals were randomized to 15 min of MUF (n=8) or no intervention (n=8). Neurologic injury was assessed with behavior scores and histologic examination. Standardized behavior scores were obtained on post-operative days 1, 3, and 6 (0=no deficit to 95=brain death). The percentage of injured neurons by hematoxylin and eosin staining and the degree of reactive astrocytosis by glial filbrillary acidic protein (GFAP) immunohistochemistry were assessed to determine histologic scores in the neocortex and hippocampus (0=no injury to 4=diffuse injury). Results: There were no statistically significant differences between groups during CPB. After MUF, the hematocrit was significantly higher (40%±5.7 vs. 28%±3.9, P<0.001). There were no significant differences in behavior scores between groups (p>0.1). There was resolution of deficits by day 6 in all animals. Neuronal injury was present in 81% (13/16) of the animals with no statistically significant differences between groups in incidence or severity. Conclusions: Use of MUF after DHCA does not prevent neuronal injury or improve neurologic outcome in this neonatal swine model.

Key Words: Modified ultrafiltration • Cardiopulmonary bypass • Deep hypothermic circulatory arrest • Neurologic injury


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
In the past two decades, there has been a dramatic reduction in surgical mortality following repair of congenital heart defects, which has been accompanied by increasing recognition of central nervous system (CNS) injury and adverse neurodevelopmental sequelae in some children. Adverse neurodevelopmental outcomes include cognitive impairment, expressive speech and language abnormalities, impaired visual-spatial and visual-motor skills, attention deficit/hyperactivity disorder, as well as learning disabilities [1]. The requirements for early intervention, rehabilitative services, and special education significantly reduce the quality of life for these children and their families. Cerebral ischemia before, during, and after surgical repair of congenital heart defects has been proposed to be a primary mechanism of CNS injury. In particular, perioperative events at the time of reconstructive surgery have been implicated as important factors in post-operative neurologic dysfunction. Factors which possibly contribute to intraoperative neurologic injury include the type of support during surgery (deep hypothermic circulatory arrest (DHCA) or continuous cardiopulmonary bypass (CPB)), use of hemodilution, degree of cooling and type of blood gas management [2]. The most common pathologic lesions identified in the CNS following repair of congenital heart defects are periventricular leukomalacia, selective neuronal necrosis, and focal ischemic changes. Unfortunately the available therapeutic options to prevent neurologic injury are limited and of uncertain efficacy.

Modified ultrafiltration (MUF) is a technique, which uses ultrafiltration of the patient and hemofiltration of the bypass circuit after separation from CPB to reverse hemodilution. MUF has been shown to ameliorate the increase in total body water (TBW) after CPB and to remove inflammatory mediators. Use of MUF after cardiac surgery in children has been demonstrated to have beneficial effects including increased systolic blood pressure, improved left ventricular function, increased pulmonary compliance, decreased post-operative bleeding, and decreased need for blood transfusion [3,4]. In experimental animals and children, cerebral oxygen consumption is impaired following DHCA. A study in our laboratory investigated the effects of MUF on acute cerebral metabolic recovery following DHCA using a neonatal swine model [5]. MUF was shown to increase both cerebral oxygen delivery and cerebral oxygen consumption, indicating that the brain could recover from acute metabolic dysfunction after DHCA. Unfortunately, this study did not assess the effects of MUF on functional recovery from DHCA or neuronal injury. The current study was undertaken to test the hypothesis that use of MUF following DHCA will decrease neurologic injury and improve neurologic outcome following DHCA.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
2.1. Surgical preparation
Twenty-five 3–10-day-old Yorkshire piglets (1.8–3.1 kg) were studied according to a protocol approved by the Institutional Animal Care and Use Committee of the Joseph Stokes, Jr. Research Institute at The Children's Hospital of Philadelphia. All piglets were studied in compliance with the ‘Guide for the Care and Use of Laboratory Animals’ prepared by the National Academy of Sciences and published by the National Institutes of Health (NIH publication no. 96-03, revised 1996). Animals were sedated with an intramuscular injection of ketamine (30 mg/kg) and acepromazine (1.2 mg/kg). Following mask ventilation with 2% isoflorane and endotracheal intubation, the animals were ventilated with a mechanical ventilator (Servoventilator 900C, Siemens, Iselin, NJ). Anesthesia was maintained with 1–2% isoflorane. Body temperature was maintained using a circulating warm water blanket. An intravenous catheter was placed in an ear vein. Lorazepam (0.1 mg/kg) and cephazolin (20 mg/kg) were administered. An epidural temperature probe (Type K, Fisher Scientific, Pittsburgh, PA) was placed through a 2 mm burr hole in the temporal region of the skull. An arterial catheter was placed into the superficial femoral artery for monitoring arterial pressure and obtaining samples for blood gas measurement. After heparinization (400 U/kg), the right carotid artery and external jugular vein were ligated distally and cannulated with a 14 gauge arterial angiocatheter and 10 French venous cannula, respectively.

2.2. CPB and MUF circuit
The CPB circuit consisted of a membrane oxygenator (Lilliput I, Cobe Cardiovascular, Arvada, CO), cardiotomy reservoir, and arterial filter (Capiox, Terumo, Ann Arbor, MI) with a roller pump (Sarns, Ann Arbor, MI). Perfusion temperature was controlled with a heater/cooler unit (Hemotherm, Cincinnati Subzero, Cincinnati, OH). A bridge of tubing connected to a hemofilter (Hemocor HPH, Minntech, Minneapolis, MN) and a second roller pump was placed between the arterial and venous line. The hemofilter was connected to vacuum suction. The circuit was primed with normal saline, donor porcine blood (500 cc whole blood), furosemide (1 mg/kg), pancuronium (0.2 mcg/kg), heparin (1000 U), sodium bicarbonate (20 mEq), 25% human albumin (60 cc), calcium chloride, and dexamethasone (30 mg/kg).

2.3. Management of CPB and DHCA
Following cannulation, the animals were placed on CPB at 150 cc/kg/min and mechanical ventilation was discontinued. Conventional ultrafiltration during CPB was used to maintain a pre-arrest hematocrit between 25 and 30%. {alpha}-Stat blood gas management was utilized. The animals were cooled to a brain temperature of 18 °C over 20 min. Topical hypothermia with ice bags placed around the head and chest was also utilized. Each animal underwent 90 min of DHCA. After reinstitution of CPB, the animals were warmed to at least 33 °C over 30 min. Mannitol (125 mg/kg) was administered during rewarming and the heart was defibrillated as necessary. After complete rewarming, the animals were weaned from CPB. Following 15 min of separation from CPB for stabilization, the animals were randomized to 15 min of MUF n=8 or no intervention n=8. MUF was performed by opening the bridge, clamping the venous return line to the cardiotomy reservoir and turning on the MUF pump with a flow rate of 100 cc/min. The vacuum line to the hemofilter was set at -150 mmHg. As ultrafiltrate was removed, intravascular volume was maintained by infusing blood from the cardiotomy reservoir through the hemofilter to maintain a mean arterial blood pressure of 40–50 mmHg. Crystalloid solution was added to the cardiotomy reservoir as needed. Following completion of the MUF period or no intervention, the animals were decannulated and all skin incisions were closed. The animals were extubated following the return of spontaneous breathing, adequate strength, and purposeful movements.

2.4. Neurologic injury assessment
The severity of neurologic injury was evaluated on post-operative days 1, 3, and 6 by a veterinarian blinded to treatment group assignment and a neuro-behavior score assigned. This score is based on both behavioral and neurologic examination comprised of categories relating to level of consciousness, respiration, cranial nerve deficits, motor, and sensory function, gait, and behavior [6] (Table 1). The score is calculated by summing the scores for each category with 0 representing no deficits and 95 indicating severe injury or brain death. Following the last examination on post-operative day 6, the animal was anesthetized with ketamine (30 mg/kg) and acepromazine (1.2 mg/kg) intramuscularly and mask ventilated with isoflorane 2%. Heparin 400 U/kg was given intravenously and the animal was euthanized with intravenous KCl. The left carotid artery was cannulated with a 14-gauge angiocatheter for cortical perfusion and the superior vena cava was incised to allow for venous drainage. The brain was perfused with 1 l of saline followed by 1 l of 4% paraformaldehyde. The brain was removed in toto and placed in 10% formalin.


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  		Table 1. Neuro-behavior score

 
2.5. Assessment of neuronal injury
The brain was cut into 5 mm coronal sections, which were then processed and embedded in paraffin blocks. Four-millimeter sections were cut and placed on poly-lysine coated slides for routine and immunohistochemical staining. One section from each brain containing both hemispheres including cortex and hippocampus was used for histologic examination. These two regions have been shown to be prone to hypoxic–ischemic neuronal injury following DHCA in neonatal piglets [6]. Routine staining with hematoxylin and eosin was used to characterize neuronal damage. White matter injury and reactive astrocytosis was assessed by immunohistochemical staining for GFAP as described [7]. Slides were incubated with mouse anti-GFAP primary antibody (Sigma, St Louis, MO) then stained according to a biotin/avidin immunoperoxidase technique (Vector ABC Kit, Vector Laboratories, Burlingame, CA) with 3,3'-diaminobenzidine used as the substrate.

Histopathologic analysis consisted of examination of the hippocampus and neocortex by a neuropathologist blinded to treatment group assignment. Changes indicative of neuronal injury included one or more of the following: hyperchromatic and shrunken nuclei, cytoplasmic eosinophilia, and karyorrhectic nuclei. A semiquantitative histopathologic score was used to determined the relative percentage of damaged neurons, 0=no damage to 4=diffuse damage (Table 2). Each section received a separate score for the cortex and hippocampus.


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  		Table 2. Histopathologic scoring criteria for hematoxylin and eosin and GFAP staining

 
2.6. Statistical analysis
Descriptive statistics were calculated for all relevant variables in the dataset. Due to the non-parametric nature of the data, measures of central tendency included both means and medians while measures of variability included both standard deviations and ranges. Data are presented as median and range. Differences between treatment (DHCA and MUF) and control groups (DHCA only) were tested using the Mann–Whitney U test. The experiment-wise error rate was held constant at the {alpha}=0.05 level across all six analyses, with each of the six tests conducted at the {alpha}=0.02 level using Tukey, Ciminera, and Heyse's adjustment for multiple, correlated comparisons [8].


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
Twenty-five piglets entered the study and underwent CPB. Five piglets died perioperatively due to complications associated with CPB prior to randomization. Two piglets, one from each group, died of unknown causes after extubation. Two more piglets, one from each group, were excluded due to the presence of an intracranial hemorrhage or abscess around the epidural temperature probe site during brain removal on post-operative day 6. The remaining 16 piglets completed the protocol as described. The perioperative hemodynamics and blood glucose levels were not significantly different between groups (Table 3). No significant differences in hematocrit existed between groups during CPB or prior to randomization. Following MUF, the hematocrit for the MUF group was 40% (35–53) which was significantly increased compared to the control group, 28% (21–34), P<0.001. A median of 463 ml (300–600) of ultrafiltrate was removed during the 15-min period of MUF.


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  		Table 3. Experimental conditions for MUF and control groups

 
Both groups showed neuro-behavioral deficits on post-operative days 1 and 3 (Table 4). In the MUF group, one piglet did not show any evidence of neuro-behavioral deficits on day 1. The majority of deficits were ataxia and failure to drink or explore. Deficits resolved quickly over the next 24 h and by post-operative day 3, only two animals remained minimally ataxic. By day 6, deficits had resolved in all animals. In the control group, all piglets showed neuro-behavioral deficits on day 1. In this group as well, the predominant deficits were ataxia and failure to drink or explore. Deficits resolved quickly over the next 24 h. Three animals remained minimally ataxic by post-operative day 3 and all deficits resolved by day 6. Major deficits of consciousness or cranial nerve impairment were not present in either group. Although the control group scored higher in neuro-behavioral score on post-operative days 1 and 3, the differences were not statistically significant between treatment groups (post-operative day 1, P=0.73 and post-operative day 3, P=0.60).


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  		Table 4. Statistics for neuro-behavior and histopathologic scores

 
Neuronal injury characterized by hematoxylin and eosin staining was present in both groups. Injured neurons appeared either with karyorrhexic nuclei, as an intensely eosinophilic ‘dead red neuron’, or with necrosis. In general, damaged neurons in the neocortex appeared in isolated clusters of cells in the deep layers of the grey matter (layers 4 and 5), interspersed between normal cells equally distributed throughout the hemispheres. Neuronal injury in the hippocampus was seen in all sectors to a variable degree and consisted mostly of dead red neurons. In the MUF group, cortical injury by hematoxylin and eosin staining was present in 62.5% of animals. Histopathologic scores in the cortex ranged from 0 to 2 with one cortex showing evidence of infarction. Cortical injury in the control group was present in 87.5% of animals with scores ranging between 0 and 3. Hippocampal injury in the MUF group was present in 75% of animals with scores ranging between 0 and 3. The hippocampus was most severely injured in the animal with cortical infarction. Hippocampal injury in the control group was present in 87.5% of animals with scores ranging between 0 and 3. Although the cortical and hippocampal injuries were most severe in the control group, there were no significant differences between treatment groups (cortex P=0.38, hippocampus P=0.32).

GFAP immunohistochemistry demonstrated areas of injury in animals in both groups. GFAP staining appeared in discrete clusters of reactive astrocytes in the grey matter. These clusters were present in areas generally corresponding to neuronal injury on hematoxylin and eosin staining. No significant pathologic changes were identified in the white matter of either group. Cortices with injury characterized by GFAP staining occurred in 50% of animals in the MUF group with scores ranging between 0 and 1. In the control group, only 25% of animals were involved, with scores between 0 and 3. There was minimal reactive astrocytosis in the hippocampus with injury in only one animal of the MUF group (score=3) and two animals in the control group (scores=1). There were no significant differences between treatment groups in either cortex or hippocampus (cortex P=0.46, hippocampus P=0.64).


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
CNS injury in children following cardiac surgery is the result of a complex interaction of patient-specific factors and environmental influences. Cerebral ischemia before, during, and after surgical repair has been proposed to be a primary mechanism of CNS injury. Many factors, however, contribute to neurologic dysfunction including congenital or acquired structural CNS abnormalities, hypoxia, and acidosis secondary to uncorrected congenital heart defects, as well as associated anomalies or genetic syndromes. Immaturity of the developing CNS may also be a factor. Nevertheless, perioperative events at the time of reconstructive surgery have been implicated as important factors in post-operative neurologic injury including the type of support used during surgery (DHCA or continuous CPB), use of hemodilution, degree and duration of cooling, and type of blood gas management. Several studies have suggested that use of DHCA may increase the risk of post-operative CNS dysfunction. Hemodynamic instability with impaired cerebral perfusion in the immediate post-operative period or hyperthermia with increased oxygen consumption may exacerbate cerebral injury. Many therapeutic interventions have been proposed to prevent or minimize neurologic injury during CPB, however, the results have been generally disappointing.

Use of CPB exposes blood to the foreign surfaces of the bypass circuit initiating a systemic inflammatory response characterized by neutrophil activation, compliment activation, and increased expression of inflammatory cytokines [9]. This inflammatory response may result in increased capillary permeability, tissue edema, and organ dysfunction. If continuous CPB is utilized, perfusion to the body and brain are maintained; however, when DHCA is utilized, there is a period of obligate global cerebral ischemia followed by reperfusion. Use of DHCA provides a bloodless surgical field facilitating meticulous completion of the repair and decreasing the duration of blood exposure to the bypass circuit, but at the cost of a period of global cerebral ischemia. Continuous CPB increases the duration of blood exposure to the bypass circuit and may increase the severity of the inflammatory response.

Ultrafiltration is a technique, which removes plasma proteins, water, and low molecular weight solutes by a convective process using hydrostatic forces across a semi-permeable membrane. The composition of the ultrafiltrate is dependent upon the pore size of the hemofilter. MUF was introduced by Naik et al. [10] from the Hospital for Sick Children in London. In previous studies, use of MUF has been shown to significantly reduce the post-operative increase in TBW and to increase blood pressure, as well as improve left ventricular function in the early post-operative period. The mechanisms by which MUF produces beneficial effects have not been fully elucidated. MUF was hypothesized to improve organ function by simply reducing excess TBW and tissue edema. Evaluation of the ultrafiltrate, however, demonstrated substantial amounts of inflammatory mediators and vasoactive substances including interleukins 6, 8, and 10, tumor necrosis factor {alpha}, and endothelin-1 [11,12]. It is tempting to speculate that removal of these mediators by MUF diminishes the inflammatory response to CPB, thus ameliorating some of the adverse sequelae.

Skaryak et al. [5] evaluated the effects of MUF on cerebral metabolic recovery following DHCA using a neonatal swine model. Animals underwent 90 min of DHCA followed by rewarming and separation from CPB. Cerebral oxygen consumption was decreased following separation from CPB, consistent with previous experimental and clinical studies [13]. After separation from CPB, animals were divided into three groups: control, MUF, and transfusion. Transfusion was used to mimic the increase in hematocrit seen following MUF to determine if MUF provided benefits in addition to hemoconcentration. In both the transfusion and MUF groups, there was a significant increase in cerebral oxygen delivery, consistent with the increase in oxygen carrying capacity secondary to the increased hematocrit. After MUF cerebral oxygen consumption was significantly increased, but continued to decline in both the control or transfusion groups. This study demonstrated that use of MUF could reverse the decrease in cerebral metabolism seen following DHCA. However, in this acute non-survival study, it was not possible to delineate if the improved cerebral metabolic recovery actually resulted in decreased neuronal injury and improved neurologic outcome.

The current study was designed to test the hypothesis that use of MUF will prevent or diminish neuronal injury thus improving neurologic outcome. A previously described neonatal swine survival model of CPB and DHCA was utilized allowing assessment of neurologic recovery [6]. The pattern of early neurologic deficits with rapid recovery is consistent with previous studies [6]. Unfortunately even though the behavior scores and histologic injury score tended to be slightly lower in animals undergoing MUF, no significant improvement could be demonstrated for either the behavior score or histologic evidence of CNS injury.

The reasons for the failure of MUF to decrease CNS injury are unclear. The mechanisms of CNS injury following DHCA are not fully understood. MUF does increase cerebral oxygen delivery by increasing the hematocrit and in our previous study, increased cerebral oxygen utilization. Increasing cerebral metabolism immediately following an injury could be disadvantageous, however, the MUF animals did not demonstrate increased injury compared to the control animals. Neurons may be irreversibly injured and unable to be salvaged by a technique such as MUF performed after separation from CPB. MUF has been shown to reverse hemodilution and remove inflammatory mediators. If the mechanism of CNS injury is cerebral ischemia during DHCA or CPB, reversal of hemodilution and removal of inflammatory mediators following bypass may not have a therapeutic benefit. The neonatal swine model does not perfectly imitate a child with congenital heart disease undergoing surgical repair. The 90-min period of DHCA is significantly greater than is commonly utilized clinically but was chosen to create severe injury. Previous studies in neonatal swine have shown that shorter periods of DHCA do not result in reproducible CNS injury [6,14]. In addition, neurologic assessment of pigs is non-specific and does not assess subtle deficits and defects. With more sensitive testing, it might be possible to detect a difference between groups. However, the findings of similar severity of neuronal injury on histologic examination suggests that there is no improvement with MUF.

Use of MUF following the repair of congenital heart defects is associated with many beneficial effects including improved blood pressure and ventricular function. In contrast to a prior experimental study, the current study demonstrates that use of MUF does not decrease CNS injury after DHCA. In spite of this finding, use of MUF may have beneficial effects on CNS function in children undergoing cardiac surgery. Exacerbation of CNS injury may occur secondary to post-operative hypoxia, hypotension, low cardiac output, and hyperthermia. MUF is known to improve post-operative hemodynamic performance and could minimize the occurrence of adverse post-operative events.


   Footnotes
 
Presented at the 16th Annual Meeting of the European Association for Cardio-thoracic Surgery, Monte Carlo, Monaco, September 22–25, 2002.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 

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  6. Kurth C.D., Priestley M., Golden J., McCann J., Raghupathi R. Regional patterns of neuronal death after deep hypothermic circulatory arrest in newborn pigs. J Thorac Cardiovasc Surg 1999;118(6):1068-1077.[Abstract/Free Full Text]
  7. Hsu S.M., Raine L., Fanger H. A comparative study of the peroxidase–antiperoxidase method and an avidin–biotin complex method for studying polypeptide hormones with radioimmunoassay antibodies. Am J Clin Pathol 1981;75(5):734-738.[Medline]
  8. Zhang J., Quan H., Ng J., Stepanavage M.E. Some statistical methods for multiple endpoints in clinical trials. Control Clin Trials 1997;18:204-221.[CrossRef][Medline]
  9. duPlessis A.J. Mechanisms of brain injury during infant cardiac surgery. Semin Pediatr Neurol 1999;6:32-47.[CrossRef][Medline]
  10. Naik S.K., Knight A., Elliott M. A successful modification of ultrafiltration for cardiopulmonary bypass in children. Perfusion 1991;6(1):41-50.[Abstract/Free Full Text]
  11. Wang M.J., Chiu I.S., Hsu C.M., Wang C.M., Lin P.L., Chang C.I., Huang C.H., Chu S.H. Efficacy of ultrafiltration in removing inflammatory mediators during pediatric cardiac operations. Ann Thorac Surg 1996;61(2):651-656.[Abstract/Free Full Text]
  12. Millar A.B., Armstrong L., van der Linden J., Moat N., Ekroth R., Westwick J., Scallan M., Lincoln C. Cytokine production and hemofiltration in children undergoing cardiopulmonary bypass. Ann Thorac Surg 1993;56(6):1499-1502.[Abstract]
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  14. Priestley M.A., Golden J.A., O'Hara I.B., McCann J., Kurth C.D. Comparison of neurologic outcome after deep hypothermic circulatory arrest with alpha-stat and pH-stat cardiopulmonary bypass in newborn pigs. J Thorac Cardiovasc Surg 2001;121(2):336-343.



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