The effect of anaesthesia technique on maternal and cord blood ischaemia-modified albumin levels during caesarean section: A randomized controlled study

Abstract

Objective

Ischaemia-modified albumin (IMA) is an early marker for various ischaemic events, including cardiac ischaemia. This study determined variations in IMA levels during caesarean section, performed under general anaesthesia or with combined spinal epidural anaesthesia.

Methods

Full-term, healthy pregnant women were allocated to undergo caesarean section, using either general anaesthesia or combined spinal epidural anaesthesia. IMA and albumin levels were measured in maternal serum samples taken immediately prior to caesarean section and 30 min into the procedure, as well as from serum taken from cord blood after double clamping.

Results

At total of 51 healthy pregnant women underwent either general anaesthesia (n = 28) or combined spinal epidural anaesthesia (n = 23). Within-group analysis of the general anaesthesia group showed that both IMA levels and IMA/albumin ratios were significantly higher at 30 min of surgery compared with the immediate preoperative period.

Conclusions

Lower IMA levels in the combined spinal epidural anaesthesia group may have been due to improved balancing of oxidative stress during caesarean section. Further research on IMA levels during caesarean section should take into account the method of anaesthesia used.

Keywords

Albumin caesarean section combined spinal epidural anaesthesia cord blood general anaesthesia ischaemia-modified albumin

Introduction

Ischaemia-modified albumin (IMA), a metabolic variant of albumin, has been used as a predictor of coronary artery disease.^1–4 In patients with acute coronary syndrome, there is a decrease in exogenous cobalt binding to human serum albumin due to the presence of IMA; levels of this variant protein can be measured using an albumin cobalt binding test.^5–7

Ischaemia-modified albumin has been shown to be a sensitive and early biochemical marker of ischaemia. IMA is known to be an important indicator of several pathogenic processes including myocardial ischaemia,^1,2 musculoskeletal ischaemia,⁸ mesenteric ischaemia,^9,10 pulmonary embolism,¹¹ stroke¹² and cerebrovascular events.¹³ In addition to being an indicator of hypoxia and ischaemia, IMA is also indicative of oxidative stress responses.^14–16 Research into anaesthetic techniques has shown that oxidative stress responses can be affected by the method of anaesthesia used.^14,16

In normal pregnancies, maternal IMA levels are known to be elevated^17,18 and cord levels of IMA have been shown to increase during caesarean sections compared with vaginal deliveries.¹⁶ Despite research on changes in IMA levels after vaginal birth and caesarean section, no information is available on maternal and cord IMA levels during caesarean deliveries where different anaesthesia techniques have been used.

The present study investigated the hypothesis that regional anaesthesia will result in lower IMA levels than general anaesthesia, by comparing IMA levels in women who underwent caesarean section with either general anaesthesia or combined spinal epidural anaesthesia.

Subjects and methods

Study population

This case–control study was conducted at the Department of Anaesthesiology and Reanimation, Teaching and Medical Research Hospital, Çanakkale Onsekiz Mart University, Çanakkale, Turkey, between March and August 2011. The study protocol was approved by the Çanakkale Onsekiz Mart University Human Ethics Committee (approval number 45, 20 June 2011) and all participants provided written informed consent prior to entry into the study.

Inclusion criteria for the study were as follows: women met traditional indications for Caeserean section; women had an American Society of Anesthesiology physical classification status of I–II (http://www.asahq.org/Home/For-Members/Clinical-Information/ASA-Physical-Status-Classification-System); there was an expectation of a normal pregnancy outcome, defined as the delivery of a term baby whose weight was above the 10th percentile; the mother did not have gestational hypertension or diabetes (throughout the pregnancy). Gestational age was calculated from the date of the last menstrual period and was confirmed by ultrasound.

Exclusion criteria were as follows: women with any known medical condition including diabetes mellitus, connective tissue disorders, renal disease, essential hypertension and cardiac disease; women with multiple pregnancies, major or minor fetal anomalies, known history of ischaemia in the fetus or mother, history of and/or current smoking; parturients with any contraindication to central neuraxial block.

Subjects were randomized into two groups using a random sampling table. The doctors (F.K.T. and C.D.) who examined the biochemical samples were blinded to the study conditions. The general anaesthesia group included women who were scheduled for elective caesarean section under general anaesthesia. In the combined spinal epidural anaesthesia group, combined spinal epidural anaesthesia was used prior to elective caesarean section.

Anaesthesia induction

None of the subjects was premedicated. On arrival in the operating room, each subject was monitored using standard 12-lead digital electrocardiogram (ECG), pulse oximetry, capnography, respiratory rate and noninvasive arterial pressure measurements (all measurements taken using equipment from Datex-Ohmeda, Madison, WI, USA). Immediately prior to anaesthesia, all subjects received 7 ml/kg of 0.9% NaCl solution administered via intravenous (i.v.) infusion.

General anaesthesia group

Prior to anaesthesia, subjects were oxygenated for 3–5 min with 100% O₂. Induction of anaesthesia was performed using 2 mg/kg propofol i.v. and 0.6 mg/kg rocuronium i.v. as a muscle relaxant. Oral intubation was achieved using a no. 7.5 endotracheal tube. Anaesthesia was administered with 1 minimum alveolar concentration sevoflurane in 50% O₂/air. Caesarean section was performed in a standardized way for all participants. End-tidal carbon dioxide volume and frequency were altered to keep values between 35 and 40 mmHg. All subjects received a 7 ml/kg/h i.v. infusion of 0.9% NaCl solution during the operation.

Combined spinal epidural anaesthesia group

Following administration of 7 ml/kg 0.9% NaCl solution, a 16-gauge Tuohy needle was inserted into the L3–4 interval. The epidural space was found using the loss of resistance method. A 27-gauge spinal needle (B Braun Medical, Melsungen, Germany) was then inserted into the subarachnoid space, and 2 ml of 0.5% bupivacaine and 0.01 mg of fentanyl were administered intrathecally. After this spinal injection, an epidural catheter was placed so that 3 cm of the catheter remained in the space. None of the subjects was medicated using the catheter, however. The sensory block was tested using the pinprick test along the bilateral midclavicular line; when sensory loss was achieved at the T6 level, surgery was started. Nasal oxygen was supplied at 3 l/min. Following the delivery of the infant, all subjects were administered 15 units of oxytocin as an i.v. bolus and 15 units of oxytocin as an i.v. infusion, in addition to 1 mg midazolam.

Study assessments

For all subjects, hypotension was defined as a > 20% decrease in the basal systolic blood pressure or a systolic blood pressure < 90 mmHg and was treated with 10 mg of ephedrine as an i.v. bolus.

The results of standard monitoring (ECG, heart rate, blood pressure, transdermal oxygen saturation), degree of sensorial and motor block, sedation and demographics (including maternal age, body mass index [BMI], gestational age, gravidity and parity) were recorded for all subjects. Apgar scores at 1 and 5 min after delivery, neonate birth weight and sex, and the caesarean operating time were recorded perioperatively.

Venous blood sampling and laboratory analysis

In all cases, at the start of the procedure, 5 ml of maternal blood was drawn into a nonheparinized tube, using an 18-gauge catheter inserted into a forearm vein. Blood was taken to measure preoperative IMA and albumin levels; the catheter was then used for fluid and drug administration. To measure intraoperative IMA and albumin levels at 30 min following the start of the operation, 5 ml of venous blood was taken from the back of the hand of the noncatheterized arm into a nonheparinized tube. Following delivery, 5 ml of cord blood was taken from the doubly clamped umbilical cord to measure IMA and albumin levels.

Blood samples were sent to the laboratory within 1 h of collection. Samples were allowed to clot for ∼30 min at room temperature and in the same way centrifuged for 10 min at 1200 g at room temperature. Serum was collected for assessment of biochemical parameters and stored at –80℃ until analysis. Analyses were carried out only once pregnancy outcomes were available. All laboratory staff were blinded to the anaesthesia techniques used.

Serum albumin was measured by the bromocresol green albumin method.¹⁹ Analysis was carried out using the fully automated Dimension® RxL Max biochemical analyser (Siemens Healthcare Diagnostic, Tarrytown, NY, USA). Albumin cobalt binding was analysed according to the method described by Bar-Or et al.⁷ Briefly, 200 μl of serum was added to 50 μl 0.1% (w/v) cobalt chloride (CoCl2·6H2O [Sigma-Aldrich, St Louis, MO, USA]) and mixed gently, then allowed to sit for 10 min at room temperature for sufficient cobalt–albumin binding to occur. Next, 50 μl of dithiothreitol (DTT) (1.5 mg/ml in H2O [Sigma-Aldrich]) was added as a colouring agent. After 2 min at room temperature, 1 ml of 0.9% NaCl was added to stop the cobalt–albumin binding process. Absorbance was measured using a spectrophotometer at 470 nm. A blank sample without DTT was used as the control. The results were reported in absorbance units.

The IMA/Alb ratio was calculated for each individual subject and the mean value was calculated for the whole study population.

Sample size calculation

The primary endpoint was the change in IMA levels measured preoperatively and 30 min into the operation. Sample size estimation was based on the study performed by Aran et al.¹⁴ To detect a 25% change in IMA levels, with an α-error of 0.05 and a power of 80%, it was calculated that the sample size should be ≥ 21 subjects per group. The sample size estimation was performed using the power calculator available at http://www.dssresearch.com/KnowledgeCenter/toolkitcalculators/samplesizecalculators.aspx.

Statistical analyses

Data were analysed using the SPSS® software package, version 16.0 (SPSS Inc., Chicago, IL, USA) for Windows®. Results were presented as median (minimum–maximum) and number and percentage of subjects. An analysis of distribution was performed using the Kolmogorov–Smirnov test. The Mann–Whitney U-test was used for between-group comparisons of independent variables and the Wilcoxon signed–rank test was used for within-group comparisons of dependent variables. The χ²-test was used for the analysis of categorical variables. Correlations between quantitative variables were estimated using Pearson’s correlation coefficient. A P-value < 0.05 was considered to be statistically significant.

Results

Out of 90 preoperative subjects interviewed, 26 did not meet the inclusion criteria and four declined to participate in the study. A total of 60 consecutive pregnant women between 22 and 38 years of age, who were scheduled for elective caesarean section, were recruited. Of 30 subjects assigned to the general anaesthesia group, blood samples from two subjects were not useable, therefore, 28 subject samples were analysed. Of 30 women assigned to the combined spinal epidural anaesthesia group, three required extra medication and four blood samples clotted prior to the start of analysis, leaving 23 samples available for final analysis.

There were no significant between-group differences in maternal age, BMI, gestational age, parity, gravidity or physical status, or in Apgar scores at 1 and 5 min, birth weight and sex of the neonates, and total caesarean operation time (Table 1).

Table 1.

Demographic and neonatal data for women scheduled to receive elective caesarean section under general anesthesia (GA) or combined spinal epidural anesthesia (CSEA).

Demographic	Anaesthesia group
	GA	CSEA
	n = 28	n = 23
Maternal age, years	27.5 (22–35)	31.0 (24–38)
Body mass index, kg/m²	29.39 (22.8–40.6)	27.34 (24.2–39.3)
Gestational age, weeks	38.0 (37–40)	38.0 (36–40)
Parity, n	0 (0–2)	1.0 (0–2)
Gravidity, n	2.0 (1–4)	1.0 (1–3)
Apgar score
1 min	8.5 (6–9)	9.0 (7–9)
5 min	10.0 (8–10)	10.0 (9–10)
Birth weight, g	3325 (2300–4050)	3200 (2720–3970)
Operation time, min	30.0 (19–45)	37.0 (22–70)
Neonate sex
Male	15 (53.6)	13 (56.5)
Female	13 (46.4)	10 (43.5)
ASA physical status
I	24 (85.7)	21 (91.3)
II	4 (14.3)	2 (8.7)

Data presented as median (minimum–maximum), n of subjects or n (%) of subjects.

No statistically significant between-group differences (P ≥ 0.05); Mann–Whitney U-test for continuous data; χ²-test for categorical data.

ASA, American Society of Anesthesiologists (www.asahq.org).

There were no statistically significant between-group differences with respect to preoperative and 30-min maternal serum IMA and albumin levels, or cord serum IMA and albumin levels. There were also no statistically significant between-group differences in IMA/albumin ratios in preoperative and 30-min maternal serum, and in cord serum samples (Table 2). Within-group analysis of the general anaesthesia group revealed that both IMA levels and IMA/albumin ratios were significantly higher at 30 min into surgery compared with in the immediate preoperative period (P = 0.0001, Table 2), the increases being 11.2% (IMA levels) and 38.2% (IMA/albumin ratio). No statistically significant increases in IMA levels or IMA/albumin ratios were observed in the combined spinal epidural anaesthesia group (Table 2). Albumin levels in maternal serum at 30 min into surgery were significantly lower than those in the immediate preoperative period, in both groups (P = 0.0001).

Table 2.

Ischaemia-modified albumin (IMA) levels, albumin levels and IMA/albumin ratios in serum samples from women scheduled for caesarean section under general anaesthesia (GA) or combined spinal epidural anaesthesia (CSEA), taken preoperatively or 30 min into surgery, and from cord serum samples.

Variable	Anaesthesia group
Variable	GA n = 28	CSEA n = 23
IMA-0, ABSU	0.374 (0.226–0.548)^a	0.423 (0.270–0.700)
IMA-1, ABSU	0.416 (0.305–0.591)	0.459 (0.232–0.627)
IMA-C, ABSU	0.324 (0.138–0.692)	0.384 (0.264–0.863)
Albumin-0, g/dl	2.9 (2.0–3.7)^b	2.7 (2.2–3.9)^d
Albumin-1, g/dl	2.4 (2.0–3.3)	2.5 (1.4–3.4)
Albumin-C, g/dl	2.9 (2.4–3.7)	3.1 (2.5–4.0)
IMA-0/albumin-0 ratio	0.129 (0.06–0.23)^c	0.157 (0.07–0.25)
IMA-1/albumin-1 ratio	0,173 (0.11–0.25)	0.184 (0.7–0.42)
IMA-C/albumin-C ratio	0.112 (0.06–0.25)	0.124 (0.06–0.32)

Data presented as median (minimum–maximum).

P = 0.0001 compared with IMA-1 in GA group; ^bP = 0.0001 compared with albumin-1 in GA group; ^cP = 0.0001 compared with IMA-1/albumin-1 ratio in GA group; ^dP = 0.0001 compared with Albumin-1 in CSEA group; Mann–Whitney U-test was used for between-group comparisons of independent variables and Wilcoxon signed–rank test for within-group comparisons of dependent variables.

IMA-0, preoperative maternal IMA; ABSU, absorbance units; IMA-1, maternal IMA 30 min after start of surgery; IMA-C, cord serum IMA; Albumin-0, preoperative maternal albumin; albumin-1, maternal albumin 30 min after start of surgery; albumin-C, cord serum albumin.

A significant positive correlation was observed between maternal preoperative maternal IMA levels and cord serum IMA levels (r = 0.70, P = 0.0001). A significant inverse correlation between serum IMA and albumin levels was also found (r = –0.36, P = 0.017).

Discussion

In our study, women undergoing caesarean section using general anaesthesia displayed a significant increase in maternal serum IMA and IMA normalized to albumin, after 30 min of surgery compared with the immediate preoperative period. No such statistically significant increase in IMA was observed in women undergoing caesarean section using combined spinal epidural anaesthesia. In both study groups, there were significant decreases in serum albumin levels during caesarean section. There were no statistically significant between-group differences in umbilical cord IMA levels.

Under normal circumstances metals such as cobalt, copper and nickel are primers for the N-terminus region of albumin and can directly bind to it. Under hypoxic conditions, the first four amino acids of the N-terminus region (i.e. N-Asp-Ala-His-Lys) undergo various alterations that reduce the metal binding capability.⁵ Levels of this protein variant, IMA, can increase in a matter of minutes and remain high for 6–12 h.³ The diagnostic albumin cobalt binding test for IMA used in the present study was based on the observation that the affinity of serum albumin for cobalt is reduced after N-terminus modifications.⁵

Ischaemia-modified albumin is an early indicator of hypoxia in cardiac ischaemia,^1–4,20 general hypoxia, ischaemia^1,8–10 and oxidative stress.^14–16 IMA has been shown to increase during several pathogenic processes,^1,8–13 as well as during the first trimester of a healthy pregnancy (possibly as a result of physiological oxidative stress).¹⁷ Data regarding IMA in pregnancy and the delivery period, however, are sparse. Maternal serum IMA has been found to be elevated to supraphysiological levels in early pregnancy compared with nonpregnant controls, due to normal trophoblast development in the hypoxic intrauterine environment.¹⁷ Another study in pregnant and nonpregnant women showed that cross-sectional mean IMA levels in pregnant women were significantly increased, while mean serum albumin levels were significantly decreased, throughout pregnancy.¹⁸ This inverse correlation between IMA and albumin is consistent with findings of the present study and other published reports.^21–23

A 1% change in albumin concentration in a healthy person with normal albumin levels could result in a 2.6% inverse change in IMA levels.²¹ A study into IMA and albumin levels in vaginally delivered babies compared with healthy adults (15 male and 15 female, aged 25–45 years) revealed a 45% increase in cord blood IMA and a 9% decrease in cord blood albumin levels from vaginally delivered babies,²³ with the investigators concluding that changes in neonatal IMA levels could not be completely attributed to the lower cord blood albumin levels and were, in part, due to transient localized tissue ischaemia of the fetus during labour. The presence of an inverse relationship between albumin and IMA levels results in increased IMA levels due to lower albumin concentrations in the blood. To counteract this effect, in the present study, a normalized IMA to albumin ratio was used.

Maternal serum albumin levels decreased during surgery in both groups, while IMA levels significantly increased in the general anaesthesia group. There was a slight increase in serum IMA in the combined spinal epidural anaesthesia group, but this was not statistically significant. The decrease in albumin levels could have been related to perioperative blood loss and fluid administration, the volume of which was similar between the groups.

Umbilical cord blood IMA levels have been reported to be elevated during elective caesarean section compared with vaginal delivery, though the type of anaesthesia used for the caesarean sections was not reported in this particular study.¹⁶ A number of investigations have suggested that different anaesthesia techniques may have different effects on the oxidative stress response. Research conducted in 36 patients undergoing the Lichtenstein operation for hernia repair revealed that local and spinal anaesthesia resulted in lower oxidative stress responses, compared with general anaesthesia, under which levels of C-reactive protein (as an acute phase marker) increased by the lowest amount in the SA group within 24 h after the procedure.²⁴ In addition, levels of proinflammatory cytokines (interleukin [IL]-1β, IL-6 and tumour necrosis factor-α) and oxidative stress markers have been shown to increase under general anaestheisa for laparoscopic cholecystectomy, compared with local anaesthesia.²⁵

Under surgical conditions, IMA increases with systemic oxidative stress.¹⁴ An investigation into levels of oxidative stress markers, following elective laparoscopic unilateral cystectomy, showed significantly increased IMA levels in blood samples taken 30 min into surgery.¹⁴ No increases in malondialdehyde, total oxidant status, total antioxidant status and oxidative stress index levels were observed, suggesting that IMA is more sensitive than these other parameters as an early marker of oxidative stress, and that levels increase before ischaemic injury or reperfusion damage occur.¹⁴ The present study found a significant increase in maternal blood IMA levels at 30 min into caesarean section under general anaesthesia; this was not observed in the combined spinal epidural anaesthesia group.

In clinical studies, IMA has been shown to rise within minutes of the start of surgery, remain elevated for 6–12 h, then return to baseline values after 24 h.^1,26 While the duration of caesarean section is variable, the mean duration in the Department of Anesthesiology and Reanimation, Teaching and Medical Research Hospital, Çanakkale Onsekiz Mart University is 33.5 min. In order to examine the maximum effect of the applied anaesthetic technique, blood samples were taken at 30 min following the start of surgery.

The present study appears to have been the first to compare the effects of different anaesthesia techniques on maternal and cord serum IMA and albumin levels during caesarean section delivery. Although reports indicate that IMA is an effective marker for oxidative stress, the present study was limited by the lack of measurements of maternal blood pH levels and other markers of oxidative stress.

In conclusion, maternal serum IMA levels and IMA/albumin ratios were increased during caesarean section under general anaesthesia, whereas no significant increase was observed under combined spinal epidural anaesthesia. In contrast, albumin levels were significantly lower at 30 min compared with the immediate preoperative period for both anaesthesia groups. Cord serum IMA levels did not differ between the two groups. Reduced IMA levels under local anaesthesia may be due to better suppression of oxidative stress by local anaesthesia. Research on IMA levels should consider the fact that the anaesthetic technique used may affect the results. These preliminary findings require confirmation with a study involving a larger sample of subjects.

Footnotes

These data were presented as an oral presentation at the 31st Annual ESRA Congress, Bordeaux, France, 5–8 September 2012. Abstract number: A-472-0003-00146.

Declaration of conflicting interest

The authors declare that there are no conflicts of interest.

Funding

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

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