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Ann Thorac Surg 2003;76:523-527
© 2003 The Society of Thoracic Surgeons

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Original article: cardiovascular

Impaired oxygenation and increased hemolysis after cardiopulmonary bypass in patients with glucose-6-phosphate dehydrogenase deficiency

^a Department of Cardiothoracic Surgery, Hebrew University, Hadassah Medical School, Jerusalem, Israel

Accepted for publication February 14, 2003.

^* Address reprint requests to Dr Gerrah, Department of Cardiothoracic Surgery, Hadassah University Hospital, P.O. 12000, Jerusalem 91120, Israel
e-mail: rgerrah{at}yahoo.com

	Abstract

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BACKGROUND: The purpose of this study was to determine whether the damaging effects of cardiopulmonary bypass, ischemia, and reperfusion would be more pronounced in patients with glucose-6-phosphate dehydrogenase deficiency undergoing cardiac surgery.

METHODS: Forty-two patients with glucose-6-phosphate dehydrogenase deficiency underwent open heart procedures using cardiopulmonary bypass. This group was matched with a control group of identical size for comparison of operative course and postoperative outcome. The perioperative variables were compared between the two groups using univariate and multivariate analysis.

RESULTS: The duration of ventilation after the operation was significantly longer in the glucose-6-phosphate dehydrogenase–deficient group (13.7 ± 7.6 hours versus 7.7 ± 2.8 hours; p < 0.0001). Minimal value of arterial oxygen tension was lower in patients with glucose-6-phosphate dehydrogenase deficiency (66 ± 12 mm Hg versus 85 ± 14 mm Hg; p < 0.0001), and more cases of hypoxia (arterial oxygen tension < 60 mm Hg) were found in this group (11 versus 1; p = 0.001). Compared with the control group, patients with glucose-6-phosphate dehydrogenase deficiency had significantly elevated hemolytic indices expressed by bilirubin levels (26 ± 10 mmol/L versus 17 ± 6.7 mmol/L; p < 0.0001) and lactic dehydrogenase levels (970 ± 496 U/L versus 505 ± 195 U/L; p < 0.0001). They also required significantly more blood transfusion perioperatively (1.9 ± 1.4 packed cell units/patient versus 0.8 ± 1.0 packed cell units/patient; p = 0.0001).

CONCLUSIONS: Patients with glucose-6-phosphate dehydrogenase deficiency who are undergoing cardiac surgery may have a more complicated course with a longer ventilation time, more hypoxia, increased hemolysis, and a need for more blood transfusion. Because this difference may be caused by subnormal free radical deactivation, strategies that minimize bypass in general and free radicals specifically may be beneficial.

	Introduction

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Deficiency of a nicotinamide adenine dinucleotide phosphate–dependent enzyme, glucose-6-phosphate dehydrogenase (G6PD), is responsible for a myriad of pathologic mechanisms in the human body. The enzyme plays an important role in the hexose monophosphate/pentose phosphate shunt, and its deficiency is the most important defect in this pathway. Glucose-6-phosphate dehydrogenase deficiency is an X-linked disorder, which occurs in approximately 10% of African-American men, fewer African-American women, and in low frequency among people from the Mediterranean basin (ie, Italians, Greeks, Arabs, and Sephardic Jews) [1, 2]. The usual clinical expression of this disorder includes anemia, jaundice, and reticulocytosis, all consequences of hemolysis. Hemolysis usually occurs after exposure to drugs or to other substances that produce peroxide, resulting in oxidation of hemoglobin and red blood cell membranes. In clinical practice, fever, infections, and diabetic acidosis are the most common precipitating events.

The main end product of the hexose monophosphate pathway is reduced nicotinamide dinucleotide diphosphate, a key metabolite that plays a major role in minimizing the devastating effects of oxidative injury to cells (mainly red blood cells) by free radicals [3]. An important metabolite that inhibits oxidative injury is glutathione in its sulfhydryl reduced form (G-SH). A prototype reaction between reduced glutathione and a free radical (H₂O₂) is 2 G-SH + H₂O₂ G-S-S-G + 2H₂O.

Reduced nicotinamide dinucleotide diphosphate, the end product of the hexose monophosphate pathway mediated by G6PD, reduces the oxidized glutathione to its effective form. Shifting the balance between the protective antioxidant mechanisms and the production of free radicals, with consequent accumulation of radicals, will damage membranes, resulting in hemolysis of red blood cells.

Cardiac surgery in its conventional form involves many processes in which cell damage is likely to occur. Perioperative ischemia and reperfusion, circulation of whole body blood through the cardiopulmonary bypass (CPB) circuit, hypothermia, acidosis, and hypoperfuassion and hyperperfusion are all events that commonly occur during cardiac operations [4, 5]. These events lead to increased production of free radicals, resulting in damage to almost every organ [6–8]. Preoperative administration of free radical scavengers reduced postoperative hemolysis and inflammatory response after open heart procedures [9–11]. Lung injury as a result of free radicals is known to occur in mechanically ventilated patients. Depletion of leukocytes, a major source of free radicals, has ameliorated free radical–mediated lung injury after CPB [12]. In most cases, however, protective mechanisms are initiated, and they neutralize most of the potentially damaging substances. Whether deficiency in G6PD potentiates the harmful effect of free radicals in such patients undergoing cardiac surgery has never been investigated.

In the present study we examined whether G6PD-deficient patients undergoing a cardiac operation showed evidence of greater hemolysis and need for blood transfusions and whether G6PD deficiency increased the perioperative and postoperative pulmonary-related morbidity.

	Material and methods

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Eighty-four patients undergoing cardiac surgery were enrolled in the study. The study group consisted of 42 patients with Mediterranean variant of G6PD deficiency. During the same period, 42 patients who underwent cardiac surgery and did not have G6PD deficiency or favism were selected as control subjects. All patients were diagnosed as having G6PD deficiency by previous laboratory investigations during prior hospitalizations or by a positive history of favism [13].

The selection of patients in the control group was based on a 1:1 case-control study. For each case in the study group, a control patient was randomly matched using our computerized database as follows: same age, same sex, same type of operation, and presence of chronic obstructive pulmonary disease, diabetes mellitus, hypertension, and duration of CPB (Table 1).

Postoperative fluid and transfusion management was according to standard protocols, identical for all patients in the study and the control groups. Blood was transfused for hemodynamic instability in patients with significant chest drainage or when the hemoglobin value was less than 8 g/dL, or less than 10 g/dL concomitant with symptoms related to anemia. Plasma was transfused to correct coagulation disorders in bleeding patients.

The postoperative complications and outcome, including ICU stay and total hospitalization time, were also recorded.

Statistical analysis
Data were analyzed both at the univariate and multivariate levels. The univariate analyses included the Student’s t test for comparison of the two groups for quantitative variables, the ² test for the assessment of association between two categorical variables, and the Pearson correlation coefficient for the calculation of correlation between two quantitative variables. The multivariate analysis that was applied was analysis of covariance (ANCOVA). This model was used for almost all of the clinical outcome variables, which were regarded as dependent variables in this study, when quantitative. Analysis of covariance was applied twice on each of the dependent variables. Stage one included all of the potential explanatory variables (defined in the Results), and the second time included only the independent variables that were found to be statistically significant (p 0.05) at the first stage of the ANCOVA analysis. Data are presented as mean ± standard deviation. The p value of less than 0.05 is considered statistically significant.

	Results

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Both groups were similar with regard to preoperative variables (Table 1). The mean age of patients in the study group was 66.9 ± 9.4 years. The male to female ratio was 30 to 12. Of 42 patients, 31 underwent coronary artery bypass grafting, 8 had a valve replacement procedure, and 3 underwent combined valve replacement and coronary artery bypass grafting. Not one of the procedures was reoperation in either group. No patient in the study group was exposed to medications contraindicated in G6PD deficiency. All blood samples drawn for typing and crossmatch are routinely examined for the presence of cold agglutinin antibodies, and they were negative for all patients in either group. The operative data are presented in Table 2.

Of the 31 patients who underwent coronary artery bypass grafting in each group, one internal thoracic artery was used for bypass in 29 patients of the study group and in 30 of the control group. The mean number of grafts in coronary artery bypass grafting operations was similar in the study and the control group. An insignificant difference was also found between the G6PD-deficient group and the control group in the duration of aortic cross-clamping (58 ± 29 minutes versus 60 ± 17 minutes, respectively). The volume of cardioplegic solution and the lowest core temperature did not differ significantly between the groups. Operation time was longer in the study group (4.3 ± 0.7 hours versus 3.8 ± 0.4 hours in control group, p = 0.004). The postoperative data are summarized in Table 3. Each one of the clinical outcomes that was found to be significantly different between the study and the control groups was regarded as a dependent variable, and the ANCOVA model was applied to it. The following variables were always initially entered into the model as independent variables (some were considered to be confounders and others to be risk factors): disease state (G6PD deficiency or normal subject), chronic obstructive pulmonary disease, urgency of operation, platelet count, operation time, CPB time, aortic cross-clamp time, degree of hypothermia, chest drainage, amount of crystalloid fluid administration and urine output during the first 24 postoperative hours, and the difference between them (fluid balance).

Postoperative hemolysis and transfusion requirements
The lowest hemoglobin value, recorded immediately after the operation, was 9.1 ± 0.9 g/dL in the study group, compared with 10.4 ± 1.1 in the control group (p < 0.0001). Of the 42 patients in each group, 31 in the G6PD-deficient group (73%) and 16 in the control group (38%) received blood transfusions (p = 0.001). The G6PD-deficient patients required a significantly larger number of blood transfusions (1.9 ± 1.4 U/patient) than did the control group patients (0.8 ± 1.0 U/patient; p = 0.0001). The hemoglobin values on discharge were still lower in the study group (10.9 ± 1.0 g/dL) than in the control group (12.1 ± 1.0 mg/dL; p = 0.0001). A significant correlation was found between operative temperature and hemoglobin at discharge in the study group (r = 0.6; p < 0.05), but not in the control group (r = 0.1).

Both groups had significantly higher levels of total bilirubin and lactate dehydrogenase on the first day after the operation compared with preoperative values. Postoperative bilirubin was 26 ± 10 µmol/L in the study group and 17 ± 6.7 µmol/L in the control group (p < 0.0001). Postoperative lactate dehydrogenase levels were 970 ± 496 U/L in the study group versus 505 ± 195 U/L in the control group (p < 0.0001).

Mean urine output during the first 24 hours after operation was 1,840 ± 550 mL in the G6PD-deficient group, and this was significantly lower than that in the control group (2,400 ± 890 mL; p = 0.001). In the study group there was a mild but significant increase (p < 0.05) in the creatinine level measured 24 hours after surgery (Table 3). The volume of mediastinal drainage was 590 ± 260 mL (study) versus 490 ± 280 mL (control), but the difference did not reach statistical significance (p = 0.09).

When the ANCOVA model was applied it was found that hemoglobin values (minimal, at discharge from the ICU, and on discharge from the hospital) were unrelated to chest drainage or to hemodilution (positive fluid balance) and were predicted strongly by the group (p < 0.0001, p < 0.0001, and p = 0.04, respectively). The need for blood transfusion was also highly dependent on the group (p = 0.001).

Intensive care unit and hospital stay
The patients with G6PD deficiency had a similar ICU stay to the control group: 2.7 ± 1.3 days versus 2.3 ± 1.4 days (p = 0.1), and no difference was found in the duration of hospital stay (p = 0.2). According to the ANCOVA model, hospital stay in both groups was dependent on the degree of hypothermia (p = 0.01) and on CPB time (p = 0.01). Interestingly, CPB time correlated very well with the duration of hospital stay in the G6PD-deficient group (r = 0.6, p < 0.05), although the correlation between the same variables was not significant in the control group (r = 0.2).

Postoperative complications, which prolonged hospitalization in the study group, included atrial fibrillation in 6 patients, chest wound infection in 3 patients (requiring surgical reconstruction in one of them), stroke with hemiparesis (n = 1), renal failure (n = 1), low cardiac output (n = 1), complete atrioventricular block (n = 1), and pneumonia (n = 1). In the control group 10 patients had postoperative complications: atrial fibrillation (n = 5), superficial wound infection (n = 2), adult respiratory distress syndrome (n = 1), low cardiac output necessitating intraaortic balloon counterpulsation (n = 1), and urinary tract infection (n = 1).

Thirty-seven of the 42 patients (88%) in the group with G6PD deficiency and 40 of the 42 patients (95%) in the control group were discharged to their homes. Four of the 42 (9.5%) in the study group and 2 of 42 (4.7%) in the control group were transferred to another ward for treatment of postoperative complications or because of the need for rehabilitation after a neurologic event.

	Comment

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Patients with G6PD deficiency require special attention when admitted to the hospital for an operative procedure, exercising caution to prevent the use of contraindicated medications. Most heart operations are performed using extracorporeal circulation, and many postoperative complications are attributed to the harmful effects of CPB. Activation of the inflammatory response during CPB with production of oxygen free radicals is one of the many processes of injury resulting from CPB [4, 5]. One of the end results of this process is endothelial injury, which is expressed clinically as capillary leak during the postbypass period. Apparently the lungs are the main organ affected by and sustaining this damage. Consequently, these patients lose pulmonary oxygenation reserve as seen in lower minimal PaO₂ compared with normal individuals. There are a few compensatory mechanisms that act to neutralize the damaging effect of free radicals. Among these mechanisms is the free radical deactivating system. Hypoxemia after heart surgery may result from imbalance between these injurious stimuli and the compensatory mechanisms. The significant difference in duration of ventilation between the G6PD-deficient patients and the control group may be explained by the limited compensation in patients with G6PD deficiency. Lung injury is more likely to occur in these patients than in those with normal levels of G6PD, probably because of a weaker free radical deactivating system in the deficient patients. We are not aware of a study showing increased susceptibility of pulmonary endothelial cells (or other nonerythrocytes) to oxidative stress in G6PD-deficient patients. However, in the presence of a weaker deactivation system, even normal endothelium may not be able to withstand an overwhelming burden of free radicals generated after CPB. This free radical–mediated stress might lead to a degradation in pulmonary function in these patients compared with controls. Our finding of direct correlation between the duration of CPB and the degree of hypoxia in the study group supports the hypothesis that CPB is a causative factor for hypoxia in these patients. Although the mechanical effect of venting and suction on red blood cell destruction should have been similar for both groups, the significantly increased need for blood among the patients with G6PD deficiency and the higher levels of indirect markers of hemolysis in this group are in agreement with the theory that hemolysis is exaggerated when an inborn error such as G6PD deficiency exists. We found a correlation between the cold temperature during operation and postoperative hemolysis. Search of the literature has not revealed an association between cold temperature and increased hemolysis among patients with G6PD deficiency. The postoperative increase in creatinine levels may be secondary to increased hemolysis among these patients. Although no direct complication of blood transfusion has been observed in any of these patients, the risk of transmitting viral infection with blood products is not negligible and increases in direct relation to the number of units of blood given to each of them. There have been no reports whether administration of antifibrinolytic or antiproteolytic agents or steroids could have a beneficial effect on hemolysis and cell injury in G6PD-deficient patients. These effects must be evaluated in a large patient series.

Operation time was longer in the study group. Transfusion of blood after conclusion of the operation but before transfer to the ICU, with observation for immediate reactions, and stabilization of blood gases before transport may have been responsible for the prolongation of operative time in this group. Intensive care unit and total hospital stays were equal for both groups. Yet, although the knowledge that patients had enzyme deficiency might have influenced the postoperative care of these patients, they were more prone to complications secondary to hypoxemia and longer ventilation time on the one hand, and excessive hemolysis and need for more blood on the other hand. Hence, one could consider the deficiency of G6PD to be a risk factor in cardiac surgery incorporating cardiopulmonary bypass.

In recent years an increasing number of coronary artery bypass grafting operations are performed without CPB and with good results. Taking into account that CPB is more deleterious to G6PD-deficient patients, off-pump bypass operations could not only reduce oxidative stress and inflammation [14], but could also reduce the risk of blood loss caused by hemolysis and the need for foreign blood transfusion. Further study is necessary to show whether this approach will be of greater benefit for patients with G6PD deficiency.

In conclusion, patients deficient in G6PD demonstrated impaired oxygenation, prolonged ventilation, increased hemolysis, and increased need for blood transfusion after open heart procedures compared with control patients. On reperfusion after a period of ischemia, the antioxidant system recruits all of its components in an attempt to neutralize the overwhelming oxidative stress of free radicals. A defect in any one of the components of the antioxidant system will shift the balance toward excessive oxidative damage. Minimizing reperfusion injury is an important goal after surgery as it may improve outcome. Every effort should be made to reduce the formation of free radicals and to increase their deactivation in G6PD-deficient patients. Successful approaches in these vulnerable patients may affect favorably all patients exposed to CPB, ischemia, and reperfusion.

	References

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