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Ann Thorac Surg 1999;67:1765-1770
© 1999 The Society of Thoracic Surgeons

Original Articles

Delayed impairment of cerebral oxygenation after deep hypothermic circulatory arrest in children

Eero J. Pesonen, MDa, Kaija I. Peltola, MDa, Reijo E. Korpela, MDa, Heikki I. Sairanen, MDa, Mauri A. Leijala, MDa, Kari O. Raivio, MDa, Sture H.M. Andersson, MDa,b

a Hospital for Children and Adolescents, University of Helsinki, Helsinki, Finland
b Department of Obstetrics and Gynecology, University of Helsinki, Helsinki, Finland

Accepted for publication December 24, 1998.

Address reprint requests to Dr Pesonen, Hospital for Children and Adolescents, Stenbäckinkatu 11, 00290 Helsinki, Finland
e-mail: epesonen{at}helsinki.fi


   Abstract
Top
 Footnotes
 Abstract
Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 
Background. Clinical studies of deep hypothermic circulatory arrest (DHCA) have focused only on the immediate postoperative period. However, experimental findings suggest impairment of cerebral oxygenation at 2 to 8 hours after reperfusion.

Methods. In 10 children who had DHCA for heart operations, transcerebral differences of hemoglobin oxygen saturation and plasma hypoxanthine, xanthine, and lactoferrin concentrations were measured in concurrently obtained cerebral venous, arterial, and mixed venous samples up to 10 hours postoperatively.

Results. Compared with preoperative levels (57% ± 7%), cerebral venous oxygen saturation was not significantly reduced until 2 hours (44% ± 6%) and 6 hours (42% ± 5%) after DHCA (p < 0.05). A statistically significant transcerebral (ie, cerebral vein versus artery) concentration difference of hypoxanthine was observed at 30 minutes (3.6 ± 0.9 µmol/L), 1 hour (3.4 ± 1.1 µmol/L), and 2 hours (3.1 ± 0.8 µmol/L) after DHCA but not preoperatively (0.4 ± 0.2 µmol/L). A transcerebral concentration difference of lactoferrin occurred 30 minutes after DHCA (196 ± 70 µg/mL) but not preoperatively (16 ± 20 µg/mL).

Conclusions. Cerebral venous oxygen saturation of hemoglobin decreased as late as 2 to 6 hours after DHCA, in association with impaired cerebral energy status. Neutrophil activation in the cerebral circulation occurred 30 minutes after reperfusion.


   Introduction
Top
 Footnotes
 Abstract
 Introduction
Material and methods
 Results
 Comment
 Acknowledgments
 References
 
Deep hypothermic circulatory arrest (DHCA) is used to enhance surgical repair of complex congenital heart defects. For the brain, the safe period of DHCA at 18°C is considered to be 39 to 65 minutes [1]. However, heart operations done with DHCA are associated with increased risk of delayed motor development and neurologic abnormalities [2]. In children, despite hypothermia of 15° to 20°C, cerebral metabolism of oxygen still occurs immediately before DHCA [1, 3], and cerebral oxygenation of hemoglobin decreases during DHCA [4, 5]. Likewise, cerebral acidosis and impaired energy status have been reported during experimental DHCA [6, 7].

Neutrophils are activated during cardiopulmonary bypass (CPB) and are sequestered in the heart and the lungs during reperfusion [8, 9]. Activated neutrophils, as a potent source of oxygen free radicals and many proteolytic enzymes, have pathophysiologic significance in reperfusion injury [8, 9]. Because neutrophils accumulate in the brain after experimental cerebral ischemia [10], activated neutrophils could significantly affect cerebral complications after DHCA.

Cardiac function decreases at 4 to 8 hours after openheart operations in children [11, 12]. We previously detected increased plasma purine concentrations, lipid peroxidation, and neutrophil degranulation at 6 to 10 hours after CPB in children [13]. However, previous clinical studies of children who had DHCA focused exclusively on the perioperative and immediate postoperative periods. In the only experimental study in an animal model with extended follow-up period, Mezrow and colleagues [14] observed decreased cerebral oxygenation only after 2 to 8 hours after DHCA.

In the present study we evaluated cerebral oxygenation, purine metabolism, and neutrophil activation up to 10 hours after DHCA in children who had elective repair of congenital heart defects.


   Material and methods
Top
 Footnotes
 Abstract
 Introduction
 Material and methods
Results
 Comment
 Acknowledgments
 References
 
Patients
We studied 10 patients (eight boys and two girls) who had cardiopulmonary bypass (CPB) with DHCA for elective repair of congenital heart defects. The age of the patients was 0.30 (range, 0.02 to 1.17) years, perfusion time 52 (range, 38 to 79) minutes cross-clamp time 52 (range, 21 to 103) minutes, and arrest time 26 (range 7 to 49) minutes. Individual patient data are given in Tables 1 and 2. Three patients (3, 4, and 5 in Tables 1 and 2) had a cyanotic heart defect.


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  		Table 1. Patient and Operative Data

 

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  		Table 2. Diagnoses of the Patients

 
Anesthesia and operation
Patients were premedicated with flunitrazepam (0.1 mg/10 kg). Anesthesia was induced with fentanyl, thiopentone sodium, and pancuronium and maintained with a high dose of fentanyl (50 to 100 µg/kg). Isoflurane was administered if needed. Steroids or barbiturates to protect the brain were not used. Cardiopulmonary bypass was established with the use of a Masterflo 34 hollowfiber membrane oxygenator and a Midicard 20-µ cardiotomy reservoir (Dideco S.p.A., Mirandola, Italy). A roller pump (Gambro, Lund, Sweden) was used with a standard flow of 2.4 L/minute per m2 (at 37°C), which was then reduced to match the requirements of 15°C of hypothermia as previously described [15]. Alpha-stat management of acid-base status was used. Cooling time was at least 20 minutes before DHCA.

A prime solution comprising albumin and fresh whole blood was used to adjust the hematocrit value to 25%. During rewarming, hemofiltration (Ultraflux 400 filter, Fresenius, Germany) was used to increase the hematocrit value to at least 30%. To achieve this, fresh whole blood was added if needed. Mannitol (15%) was administered as an infusion of 1 mL/kg per hour from the beginning of perfusion. The protein inhibitor aprotinin (30,000 IU/kg) was added in the priming solution, and the same amount also was infused for 1 hour after induction of anesthesia. Infusion of aprotinin (8,000 IU/kg per hour) was continued throughout CPB. For myocardial preservation, cold (4°C) blood cardioplegic solution (30 mL/kg) was used initially and repeated (10 mL/kg) every 20 minutes.

Sample collection
For the collection of cerebral venous samples, a catheter to the jugular venous bulb was inserted via the internal jugular vein with a cranially directed puncture. The tip of the catheter was placed at the level of the mastoid process. Blood samples were collected at the following time points: after induction of anesthesia but before the operation (designated as 0); immediately before beginning DHCA (designated as 0b); 2, 7, 15, 30, and 60 minutes, and 2, 6, and 10 hours after cerebral reperfusion, ie, cessation of DHCA. Before and after CPB, parallel blood samples were taken from the jugular venous bulb (ie, cerebral venous blood), the radial artery, and the central venous catheter. During CPB, the respective samples were drawn from the jugular venous bulb and from the arterial and venous lines of the oxygenator. The samples were collected into tubes containing ethylenediaminetetraacetic acid and were immediately centrifuged for 5 minutes at 1,000 g. The samples were stored at -70°C.

Hypoxanthine was quantified with high-pressure liquid chromatography [16] and lactoferrin with an ELISA method as previously described [17].

Statistical analysis
Plasma concentrations were calculated both corrected and uncorrected for the hematocrit value. Hemodilution did not have a significant effect on the results. Therefore, results are presented uncorrected for hemodilution. In statistical analysis, the two-tailed Wilcoxon test and simple regression test were used. A p value less than 0.05 was considered significant. Patient data are present as median and range. Results are presented as mean ± standard error of the mean.

The study was approved by the local ethics committee. Informed consent was obtained from the parents before the operation.


   Results
Top
 Footnotes
 Abstract
 Introduction
 Material and methods
 Results
Comment
 Acknowledgments
 References
 
In one patient (patient 10 in Tables 1 and 2) cardiac function deteriorated suddenly approximately 90 minutes postoperatively, requiring resuscitation and open heart massage. The patient survived, but the samples after resuscitation were omitted from the study. Patient 2 had seizures postoperatively. Hyperkinesia was observed in patient 7 at age 3 years, and patient 9 had developmental delay of approximately 1 year in age 2.5 years.

Oxygen saturation of hemoglobin
Throughout the study, oxygen saturation of hemoglobin in arterial blood was at least 92% in every patient. Oxygen saturation in the cerebral venous samples (ie, jugular venous bulb) was 57% ± 7% preoperatively and 73% ± 5% immediately before the beginning of DHCA (p < 0.05, Fig 1). At 2 and 7 minutes after DHCA, cerebral venous oxygen saturation remained virtually unchanged compared with the level immediately before DHCA. From 15 minutes on, the saturation steadily declined, reaching the nadir at 6 hours postoperatively. Consequently, at 2 hours (44% ± 6%) and 6 hours (42% ± 5%) after DHCA, cerebral venous hemoglobin oxygen saturation was significantly lower than preoperative levels (both p < 0.05, Fig 1). Saturation at 6 hours ranged from 16.8% to 59.3%, with all under 50% except in 1 patient. At 2 to 6 hours after DHCA, values less than 37% were observed in 5 patients.



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  		Fig 1. Oxygen saturation of hemoglobin in arterial (closed triangles), mixed venous (open squares), and cerebral venous (closed squares) blood. 0 = preoperative level; 0b = before deep hypothermic circulatory arrest; and 2 minutes to 10 hours after deep hypothermic circulatory arrest. *p < 0.05 and **p < 0.01 versus 0.

 
Immediately before DHCA, mixed venous oxygen saturation of hemoglobin increased to 93% ± 2%, compared with preoperative saturation (68% ± 5%, p < 0.01, Fig 1). At 2 minutes after DHCA, mixed venous oxygen saturation of hemoglobin transiently decreased, but at 7 to 30 minutes after DHCA it returned almost to the level immediately before DHCA (Fig 1). Thereafter, mixed venous saturation also decreased, in parallel with cerebral venous saturation, to the nadir at 6 hours (60% ± 3%). The decrease in mixed venous oxygen saturation was not as marked as that in the cerebral venous samples (p > 0.05 versus preoperative values).

Hypoxanthine and xanthine
Preoperatively, plasma concentration of hypoxanthine in arterial samples was 2.1 ± 0.4 µmol/L and that of xanthine 1.3 ± 0.5 µmol/L (Fig 2). At 2 minutes after DHCA, hypoxanthine concentration increased to 15.2 ± 2.1 µmol/L (p < 0.01) and xanthine concentration to 5.0 ± 1.4 µmol/L (p < 0.01). Highly increased concentrations were observed throughout the study period. In xanthine, the highest concentrations did not occur until 6 hours (6.6 ± 3.5 µmol/L) after DHCA (Fig 2).



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  		Fig 2. Arterial plasma concentrations of hypoxanthine (white bars) and xanthine (black bars). 0 = preoperative level; 0b = before deep hypothermic circulatory arrest, and 2 minutes to 10 hours after deep hypothermic circulatory arrest. **p < 0.01 versus 0.

 
At 30 minutes, 1 hour, and 2 hours after DHCA, hypoxanthine concentration was significantly higher in cerebral venous samples than in arterial samples, resulting in a transcerebral concentration difference (ie, cerebral vein minus artery) of 3.6 ± 0.9 µmol/L at 30 minutes, 3.4 ± 1.1 µmol/L at 1 hour, and 3.1 ± 0.8 µmol/L at 2 hours (all p < 0.05, Fig 3A). A significant transcerebral concentration difference of xanthine was also observed at 1 hour (1.8 ± 0.4 µmol/L) and 2 hours (1.0 ± 0.5 µmol/L) after DHCA (both p < 0.05) but not preoperatively (-0.2 ± 0.6 µmol/L, p > 0.05, data not shown). At 1 hour after DHCA, mixed venous hypoxanthine concentration was significantly higher than the respective arterial concentration (p < 0.05, Fig 3B).



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  		Fig 3. (A) Cerebral (ie, cerebral venous concentration - arterial concentration) and (B) whole body (ie, central venous concentration - arterial concentration) production of hypoxanthine. 0 = preoperative level; 0b = before deep hypothermic circulatory arrest, and 2 minutes to 10 hours after deep hypothermic circulatory arrest. *p < 0.05 and **p < 0.01, venous concentration versus arterial concentration.

 
During rewarming (specified here as time on CPB after DHCA), transcerebral difference in hypoxanthine correlated with nasopharyngeal temperature (R = 0.51, p = 0.004) and mixed venous blood temperature (R = 0.50, p = 0.005). The respective correlations for xanthine were weaker: R = 0.37 and p = 0.04 for nasopharyngeal temperature, and R = 0.36 and p = 0.054 for mixed venous blood temperature. During the initial 2 hours after DHCA (ie, the time period of steadily decreasing oxygen saturation of hemoglobin in cerebral venous samples), an inverse correlation between transcerebral hypoxanthine difference and cerebral venous oxygen saturation was observed (R = 0.37, p = 0.015).

Lactoferrin
Plasma lactoferrin concentration was significantly higher immediately before DHCA (539 ± 87 µg/mL) than preoperatively (175 ± 28 µg/mL, p < 0.05, Fig 4). Postoperatively, highly elevated concentrations were observed throughout the study period (Fig 4). Lactoferrin concentration peaked at 30 minutes after DHCA. The concentration was significantly higher at 15 minutes (783 ± 106 µg/mL) and 30 minutes (1084 ± 228 µg/mL) after DHCA, compared with the level immediately before DHCA. At 30 minutes after DHCA, a significant concentration difference of lactoferrin (196 ± 70 µg/mL) was observed across the cerebral circulation (p < 0.05, Fig 5).



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  		Fig 4. Arterial plasma concentrations of lactoferrin. 0 = preoperative level; 0b = before deep hypothermic circulatory arrest, and 2 minutes to 10 hours after deep hypothermic circulatory arrest. **p < 0.01 versus 0.

 


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  		Fig 5. Cerebral (ie, cerebral venous concentration - arterial concentration) production of lactoferrin. 0 = preoperative level; 0b = before deep hypothermic circulatory arrest, and 2 minutes to 10 hours after deep hypothermic circulatory arrest. *p < 0.05, venous concentration versus arterial concentration.

 

   Comment
Top
 Footnotes
 Abstract
 Introduction
 Material and methods
 Results
 Comment
Acknowledgments
 References
 
In the present study, we noticed that cerebral venous oxygen saturation of hemoglobin did not decrease significantly until 2 to 6 hours after DHCA. At the nadir at 6 hours, the saturation ranged from 16.2% to 59.3% and was less than 50% in 9 of 10 patients. At 2 to 6 hours after DHCA, saturation levels less than 37% were observed in half of the patients. Based on central nervous system dysfunction, cerebral desaturation has been defined as cerebral venous oxygen saturation less than 60% [18]. Accordingly, at 6 hours after DHCA all patients suffered from cerebral desaturation. Cerebral hypoxia was further evidenced by significant cerebral hypoxanthine and xanthine production at 0.5 to 2 hours after DHCA. These two degradation compounds of the catabolic pathway of adenosine monophosphate are sensitive indicators of tissue hypoxia [19]. Previous clinical studies of children who had DHCA have focused exclusively on the perioperative and immediate postoperative period. In weaning beagles, Mezrow and colleagues [14] observed, in accordance with our present results, increased cerebral extraction of oxygen at 2 to 8 hours, decreased cerebral venous saturation of oxygen at 2 to 8 hours, increased cerebral vascular resistance at 2 to 4 hours, and increased cerebral metabolic rate of oxygen at 8 hours after DHCA of 45 to 60 minutes.

Poor cerebral oxygenation was unlikely a result of pulmonary dysfunction, because arterial oxygen saturation of hemoglobin was over 92% in each patient throughout the study period. Two factors suggest decreased cardiac performance at 2 to 6 hours after DHCA. First, mixed venous hemoglobin oxygen saturation decreased in parallel with cerebral venous saturation. Second, from 1 hour on, whole body production of hypoxanthine (ie, the difference between mixed venous and arterial concentrations) varied in parallel with cerebral hypoxanthine production (ie, transcerebral concentration difference). Consequently, high plasma concentrations of hypoxanthine and xanthine were detected up to 10 hours after DHCA. The present results are in accordance with our previous observations of increased plasma concentrations of hypoxanthine and xanthine at 6 to 10 hours after pediatric cardiac operations without DHCA [13]. In intensive care patients, plasma concentrations of hypoxanthine indicate impaired oxygenation [19]. As cardiac function was not measured, cardiac dysfunction in our patients remains speculative. However, cardiac function has been reported to decrease at 4 to 8 hours after pediatric open heart operations [11, 12]. Irrespective of the cause, the present results reflect generally decreased tissue oxygenation. When the brain, a sensitive organ that is already metabolically compromised, suffers from hypoxia, cerebral hypoxanthine and xanthine production and decreased oxygen saturation result.

Despite cooling the patient to a nasopharyngeal temperature of 15°C, cerebral venous oxygen saturation of hemoglobin immediately before DHCA was 73% ± 5%, indicating ongoing cerebral metabolism. This level is substantially less than those previously reported [20]. Insufficient brain cooling in our patients might have influenced our results. Indeed, during brain cooling before DHCA, cerebral venous oxygen saturation increases less in children with postoperative neurologic abnormalities than in children without neurologic complications [5]. However, despite sufficient brain cooling at hypothermia of 18 to 20°C, oxygen metabolism still occurs in the brain at the beginning of DHCA [1, 3]. As a result, hemoglobin oxygen saturation decreases in infants during DHCA at 15°C [4, 5]. Likewise, brain tissue pH, oxygen tension, and concentration of high-energy phosphates decrease during experimental DHCA at 15 to 20°C [6, 7]. Alpha-stat management of acid-base status was used in this study as well as in the studies referred to above. In experimental settings, pH-stat management results in enhanced and more uniform cooling of the brain [21, 22]. Compared with the alpha-stat strategy, pH-stat strategy lowers postoperative morbidity in infants [23]. The deleterious effect of cerebral acidosis during pH-stat management can be avoided by using pH-stat management only during cooling and alpha-stat management during rewarming [21].

After DHCA, cerebral metabolic rate of oxygen and oxygen extraction remain low despite reperfusion and rewarming [1, 3]. Cerebral oxidation of cytochrome c oxidase is also low despite high cerebral oxygen saturation of hemoglobin, suggesting reduced cerebral oxygen utilization [3]. Consequently, reduced energy status after DHCA is paradoxically combined with reduced oxygen utilization, resulting in prolonged hypoxia, reflected in our patients as cerebral production of hypoxanthine and xanthine up to 2 hours after DHCA. Similarly, after experimental DHCA, brain tissue pH continues to decrease even during reperfusion, irrespective of increased partial pressure of oxygen in brain tissue [6]. In beagles, cerebral metabolic rate of oxygen did not increase until 8 hours after DHCA with concomitantly decreased cerebral venous oxygen saturation as a result of increased cerebral extraction of oxygen [14]. Likewise in our patients, we speculate that cerebral metabolic rate of oxygen might not be increased until 2 to 6 hours after reperfusion, ie, when there is decreased cerebral venous oxygen saturation with gradually declining cerebral production of hypoxanthine and xanthine.

In this study we assessed neutrophil activation by measuring neutrophil degranulation as plasma lactoferrin concentration. Several neutrophilic granule protein levels increase during CPB, and local neutrophil activation in the heart has been detected by measuring arteriovenous difference of elastase across the coronary circulation [24]. In the present study, cerebral neutrophil activation was documented as a transcerebral concentration difference of lactoferrin at 30 minutes after DHCA. Our results are in accordance with those of experimental models of cerebral ischemia, where neutrophils accumulated in the reperfused brain [10]. The results also suggest the pathophysiologic significance of neutrophil activation in the no-reflow phenomenon after cerebral ischemia [10].

In conclusion, marked decrease in cerebral venous oxygen saturation of hemoglobin was not observed until 2 to 6 hours after deep hypothermic circulatory arrest in children. The findings emphasize the importance of routine monitoring of cerebral venous oxygenation. Extended therapeutic interventions to reduce this late postoperative cerebral deoxygenation are needed.


   Acknowledgments
Top
 Footnotes
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
References
 
Supported by the Foundation for Pediatric Research, Helsinki, Finland.


   Footnotes
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 Footnotes
Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 
This article has been selected for the open discussion on the STS Web site: http://www.sts.org/section/atsdiscussion/


   References
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 Footnotes
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 

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  10. Hudome S., Palmer C., Roberts R.L., Mauger D., Housman C., Towfighi J. The role of neutrophils in the production of hypoxic-ischemic brain injury in the neonatal rat. Pediatr Res 1997;41:607-616.[Medline]
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