Secretory phospholipase A(2) in newborn infants with sepsis.

OBJECTIVE: To investigate secretory phospholipase A(2) (sPLA(2)) activity in neonatal sepsis. STUDY DESIGN: Plasma sPLA(2) activity, C-reactive protein (CRP) concentration, leukocyte count and immature/total neutrophil (I/T) ratio were assessed in a group of 156 infants admitted for neonatal intensive care, who were classified as documented sepsis (n=24), suspected infection (n=77) and controls (n=55). Interleukin-6 (IL-6) concentrations were assessed in a subgroup (n=29). RESULT: sPLA(2) activity, CRP concentration and I/T ratio were higher in sepsis than in suspected infection or control groups. sPLA(2) activity advanced with increasing CRP, I/T ratio and IL-6 was highest in infants with respiratory distress syndrome (RDS). Compared to CRP, sPLA(2) had equal sensitivity and lower specificity. Compared to I/T ratio, sensitivity and specificity of sPLA(2) were higher. CONCLUSION: Plasma sPLA(2) activity is increased in neonatal sepsis and highest in infants with RDS. Further studies should assess the potential of sPLA(2) inhibition in neonatal sepsis.

Non-protein-bound iron and free radical damage in fetuses with rhesus haemolytic disease: influence of intrauterine transfusions.

OBJECTIVE: To determine iron-induced free radical damage in fetal rhesus haemolytic disease (RHD) before and after repeated intrauterine red blood cell transfusions and its relation to hydrops fetalis. DESIGN: Prospective, observational study. SETTING: Department of Obstetrics, Leiden University Medical Centre, the Netherlands. POPULATION: Fifty anaemic fetuses, including 13 hydropic ones, 9 preterm and 12 term neonates and 8 female non-pregnant adults. METHODS: Venous blood plasma samples were collected from 50 fetuses suffering from RHD preliminary to the first, and if appropriate, subsequent intrauterine red blood cell transfusions for determination of iron status including non-protein-bound iron (NPBI) and iron-binding primary antioxidant proteins, total plasma anti-oxidant capacity and its contributing secondary antioxidants (e.g. vitamin C, uric acid, sulphydryl groups and peroxidation products). Results were compared with values of healthy preterm and term neonates directly at birth and adult controls. Within the fetal haemolytic group, 13 hydropic fetuses were analysed as a separate group. MAIN OUTCOME MEASURES: Non-protein-bound iron, antioxidants, total antioxidant capacity and peroxidation products. Sub analysis of the outcome measures of the hydropic fetuses. RESULTS: RHD fetuses had at initial cordocentesis a significantly higher NPBI level and a significantly lower total plasma antioxidant capacity than control babies and adults. Their vitamin C tended to be more oxidised but lipid peroxidation had not increased, when compared with preterm babies. The repeated intrauterine red blood cell transfusions had a positive effect on the total antioxidant capacity of plasma and did not increase the concentration of NPBI. The hydropic fetuses, who had higher NPBI concentrations and lower plasma protein concentrations and total antioxidant capacity, did not show more peroxidation products in plasma than the non-hydropic fetuses. Fetuses without reversal of hydrops despite intrauterine transfusions showed decreasing levels of proteins with subsequent transfusions but peroxidation products remained constant. CONCLUSION: Repeated intrauterine red blood cell transfusions do not lead to free radical damage in the fetus in utero. Iron-induced free radical activity does not appear to play a causative role in the proceeding of hydrops fetalis in RHD.

Non-protein bound iron release during chemotherapy in cancer patients.

Non-protein bound iron (NPBI) is able to catalyse oxidative reactions, causing damage to vital structures. Adverse effects induced by cisplatin seem, in part, to be mediated by free radicals. In the present study, we have measured plasma NPBI, various other iron parameters and antioxidants in 28 cancer patients undergoing cisplatin-based chemotherapy at various time points before and during chemotherapy. No NPBI was present prior to therapy, but within 1-4 days following the first administration of chemotherapy, mean NPBI rose significantly to 10.6+/-6.6 micromol/l (range, 0.6-21.3 micromol/l) in 18 (64.3%) of the 28 patients measured. The rise in NPBI was accompanied by a significant rise in total plasma iron and ferritin and a marked decrease in the latent iron-binding capacity. Concomitantly, plasma vitamins C and E decreased significantly, indicating consumption of antioxidants. Similar observations were also made during the fourth chemotherapy cycle. The increase in NPBI preceded and correlated significantly with chemotherapy toxicity, such as a decrease in leucocyte count and haemoglobin, with a transient rise in various liver enzymes and with known cisplatin-related toxicity, i.e. the loss of renal and hearing function. In conclusion, cisplatin chemotherapy induces oxidative damage which rapidly leads to release of iron from intracellular proteins and the appearance of NPBI. Bone marrow, red blood cells, liver and kidney seem to be a likely source of NPBI. The observed high levels of NPBI may be a major causative determinant in chemotherapy-induced toxicity.

Prime solutions for cardiopulmonary bypass in neonates: antioxidant capacity of prime based on albumin or fresh frozen plasma.

OBJECTIVE: Oxidative damage and inflammation are believed to play an important role in postoperative complications after cardiopulmonary bypass. During bypass, a prime solution with a high antioxidant capacity may reduce the oxidative damage and inflammation. We investigated total antioxidant capacity and individual scavengers during the preparation of 2 different prime solutions. METHODS: The prime solutions were prepared with either pasteurized human albumin or fresh frozen plasma. The total antioxidant capacity was measured with the total radical antioxidant parameter assay and with the ferric-reducing ability of plasma assay. The individual scavengers vitamin C, sulfhydryl groups, uric acid, and total protein were measured before, during, and after the prime preparation. Malondialdehyde was measured as a parameter for lipid peroxidation. RESULTS: Neither prime solution showed a total radical antioxidant parameter value. The ferric-reducing ability of plasma value of prime solutions was lower than that of undiluted human albumin or fresh frozen plasma. Addition of mannitol did not increase the ferric-reducing ability of plasma value. Vitamin C was only found in the fresh frozen plasma prime. Both prime solutions contained sulfhydryl groups and uric acid in low concentrations. During ultrafiltration, low-molecular-weight antioxidants were lost into the ultrafiltrate. CONCLUSIONS: We showed that prime solutions based on either albumin or fresh frozen plasma had very low antioxidant capacity and that ultrafiltration of the prime solution further lowers this capacity. A prime solution with a low antioxidant capacity may increase oxidative stress in neonates undergoing cardiopulmonary bypass.

Phospholipase A2 is present in meconium and inhibits the activity of pulmonary surfactant: an in vitro study.

UNLABELLED: Atelectasis, a major contributor to pulmonary dysfunction in meconium aspiration syndrome (MAS), is produced by bronchiolar obstruction and surfactant inactivation. It has been shown that substances in meconium, e.g. fatty acids, inhibit surfactant activity. However, the role of the enzyme phospholipase A2 (PLA2), which hydrolyses surfactant in adult respiratory distress syndrome (ARDS), has not yet been studied. Our objective was to investigate whether PLA2 is present in meconium and inhibits pulmonary surfactant activity in vitro. Therefore, the presence of PLA2 activity in meconium, collected from 10 newborns, was measured by the formation of lysophosphatidylcholine after incubation of meconium with radioactively labelled dipalmitoylphosphatidylcholine. Meconium was fractionated by Sephadex G-100 column chromatography and the fractions were assayed for PLA2 activity. Also, their effect on the surface tension of surfactant (Curosurf) was measured using a pulsating bubble surfactometer (PBS). PLA2 activity was present in all meconium samples. Addition of meconium to surfactant significantly increased surface tension (mean +/- SD: 1.7 +/- 1.6 mN/m to 24.3 +/- 6.7 mN/m, p = 0.0001) and only the addition of the PLA2 containing fraction from meconium to surfactant also significantly increased surface tension (mean 1.7 +/- 1.6 mN/m to 19.0 +/- 3.58 mN/m, p < 0.0001). CONCLUSION: PLA2 is present in meconium and inhibits the activity of pulmonary surfactant in vitro. Therefore, PLA2 in meconium may contribute to surfactant inactivation and alveolar atelectasis in MAS.

The capacity of different infusion fluids to lower the prooxidant activity of plasma iron: an important factor in resuscitation?

BACKGROUND: Prooxidant activity of non-protein-bound iron (NPBI) is an important contributor to reactive oxygen species-induced injury after the resuscitation of critically ill patients. Plasma NPBI occurs in critically ill adults, children, and newborn babies, who often require resuscitation. The ability of the resuscitation fluids to bind iron and lower the patients' NPBI levels in vitro has not previously been studied. STUDY DESIGN AND METHODS: In an in vitro model, highly iron-saturated cord blood plasma from 10 preterm and 10 term babies was mixed with FFP, pasteurized plasma protein solution, and 0.9-percent saline. Plasma from 10 healthy adult volunteers was used as a control. Before and after the mixing with any resuscitation fluid, NPBI levels and ceruloplasmin iron-oxidizing and transferrin iron-binding antioxidant capacities were measured. RESULTS: After the in vitro mixing with FFP, the incidence and concentration of NPBI were markedly decreased and the iron-binding antioxidant capacity was increased in the plasma of the preterm and term babies. Being mixed with pasteurized plasma protein solution and 0.9-percent saline did not influence the iron-binding antioxidant capacity of newborn babies' plasma. In the control plasma, results were not changed after the mixing with any resuscitation fluid. In every group, the iron-oxidizing antioxidant capacity was not changed after the mixing with any fluid. CONCLUSION: Iron-induced oxidative tissue damage may be influenced by resuscitation fluids. In the ongoing debate over the choice of crystalloid or colloid resuscitation fluids, the influence of each fluid on the patient's antioxidant capacity warrants more attention.

Postnatal changes in plasma ceruloplasmin and transferrin antioxidant activities in preterm babies.

Postnatal changes in plasma ceruloplasmin ferroxidase and transferrin iron-binding antioxidant activity were studied in 10 healthy preterm babies during the first 6 weeks of life. Ceruloplasmin levels and ceruloplasmin ferroxidase activity were low at birth, remained stable for the first 3 weeks, and increased between 3 and 6 weeks. The transferrin levels were also low at birth, and this finding persisted throughout the 6-week study period. However, although the plasma iron-binding antioxidant activity was correspondingly low at birth, it thereafter rose and remained high. In four cord blood samples, but not in subsequent postnatal samples, peroxidation was actually stimulated in the assay measuring plasma iron-binding antioxidant activity. We have previously shown that this phenomenon is probably due to the presence of non-protein-bound iron.

Influence of inhibition of nitric oxide synthesis on cardiac function in the newborn lamb after hypoxic-ischemic injury.

The aim of the present study was to investigate the effect of immediate post-hypoxic-ischemic (HI) inhibition of nitric oxide synthesis by N(omega)-nitro-L-arginine (NLA) on cardiac function and reactive oxygen species production. Fifteen newborn lambs were subjected to severe HI. Upon resuscitation 5 received 10 mg NLA/kg, 4 40 mg NLA/kg and 6 a placebo. Left ventricular (LV) contractility, cardiac output (CO), non-protein-bound iron (NPBI), ratio of reduced/oxidized ascorbic acid, alpha-tocopherol, sulfhydryl groups and malondialdehyde were measured before and 15, 60 and 120 min after resuscitation. There was a significant decrease in CO in all 3 groups at 60 min post-HI (p < 0.05). Reactive oxygen species production was also highest at 60 min post-HI (significantly increased NPBI and decrease in sulfhydryl groups in control lambs; p < 0.05). These results suggest neither a positive nor a negative effect of nitric oxide synthesis inhibition on post-HI myocardial performance but may suggest a positive effect of NLA on reactive oxygen species-mediated post-HI damage.

Impaired plasma antioxidative defense and increased nontransferrin-bound iron during high-dose chemotherapy and radiochemotherapy preceding bone marrow transplantation.

To analyze the effects of radiochemotherapy on the pro-oxidative/antioxidative balance in plasma, we measured the total radical antioxidant parameter of plasma (TRAP) and single plasma antioxidants (uric acid, sulfhydryl groups, alpha-tocopherol, ubiquinone-10/total coenzyme-Q10 ratio, ascorbate, and bilirubin) every 12 h during high-dose chemotherapy and radiochemotherapy preceding bone marrow transplantation (BMT). Nontransferrin-bound iron (NTBI) was monitored as a potential pro-oxidant. Plasma levels of polyunsaturated fatty acids (PUFA) were measured as substrates, and thiobarbituric acid-reactive substances (TBARS) were measured as products of lipid peroxidation. Allantoin was analyzed as the product of uric acid oxidation. Patients receiving busulfan, VP-16, and cyclophosphamide (BU/VP/CY) (n = 8) were compared with those receiving total body irradiation in addition to VP-16 and cyclophosphamide (TBI/VP/CY) (n = 8). TRAP values were within the normal range before therapy and decreased after BU/VP/CY by 37% (p <. 02) and after TBI/VP/CY by 39% (p <.02). During TBI and after VP-16, a temporary increase in TRAP values occurred, which was not related to changes in individual antioxidants. In vitro experiments confirmed that VP-16 had an antioxidative effect. The concentration of uric acid declined in both groups and correlated with TRAP (BU/VP/CY: r =.80, p <.001; TBI/VP/CY: r =.84, p <.001). Levels of NTBI, which is normally not found in plasma, increased rapidly during conditioning therapy (p <.02 in both groups) and correlated inversely with TRAP (weighted intraindividual Spearman rank correlation coefficient for both groups: NTBI and TRAP: r = -.59, p <.001) and PUFA (in the radiochemotherapy group: r = -.67, p <.001). Whereas PUFA declined (p <.02 in both groups), TBARS increased (p <. 05 in both groups). Furthermore, an increase of allantoin and ubiquinone-10/total coenzyme-Q10 ratio in the BU/VP/CY group was found (allantoin: p <.02; ubiquinone-10/total coenzyme-Q10 ratio: p <.05). Antioxidants only partially recovered to baseline values until day 14 after BMT. Our findings indicate oxidative stress after high-dose radiochemotherapy and suggest a contribution of NTBI therein.

[Metabolic acidosis in children: the usefulness of 'anion gap']. / Metabole acidose bij kinderen: het nut van de 'anion gap'.

Metabolic acidosis occurs frequently in small children. The most common causes are hypoxia, sepsis, gastroenteritis and hypovolaemia. Calculation of the anion gap is useful in establishing the cause. An increased anion gap represents unmeasured anions, e.g. lactate in lactic acidosis. Metabolic acidosis was diagnosed in two boys aged one year and six weeks respectively. The first patient had a normal, the second an increased anion gap in blood. By determining the pH and the anion gap in urine it is possible to distinguish between a proximal and a distal tubular disease. The first patient had distal renal tubular acidosis; he recovered after correction of the acidosis. The second patient had a defect in the mitochondrial respiratory chain; he died at the age of seven months.

Plasma proteins in acute and chronic lung disease of the newborn.

This study compared plasma levels of albumin, transferrin, and ceruloplasmin in well preterm babies (n = 21) with those with respiratory distress syndrome (RDS, n = 13) and chronic lung disease (CLD, n = 13) over the first 28 postnatal days. Plasma lipid peroxidation, total radical trapping capacity (TRAP assay), and iron binding antioxidant capacity were also measured. In RDS and CLD albumin levels were decreased on days 1, 4 and 10; on day 10 albumin was lower in CLD compared to RDS (p < .05). After day 10 the levels were similar in all groups. The transferrin levels showed a similar trend. Ceruloplasmin levels did not differ, except for a higher day 28 level in CLD (p < .05). Albumin levels significantly decreased with increasing FiO2 and duration of oxygen therapy (within patient r = -0.30, p < .05 and r = -0.51, p < .005, respectively). On day 10, increasing oxygen therapy increased plasma lipid peroxidation (r = +0.49, p < .01), which was also significantly related to lower plasma protein levels (r = -0.42, p < .01). Lower plasma albumin and transferrin lowered the TRAP and iron binding antioxidant capacity, respectively (r = +0.36, p < .05, and r = +0.41, p < .005). Prediction of CLD using day 10 albumin levels had a specificity of 94%, but a sensitivity of only 50%. The interaction between oxygen toxicity and high ventilation pressures in immature babies appears to lower plasma proteins by increasing pulmonary permeability. The lower plasma albumin level was not useful in predicting the development of CLD; however, the fall in plasma transferrin and albumin will further decrease the preventive and chain-breaking antioxidant capacity of plasma of these ill babies.

Effect of interleukin 8 in meconium on in-vitro neutrophil chemotaxis.

BACKGROUND: Pneumonitis, characterised by large numbers of neutrophils in the lung, is an important feature of the meconium aspiration syndrome. The mechanism underlying the neutrophil influx is not known. We have investigated whether meconium has chemotactic activity and whether such activity is related to the presence of interleukin 8. METHODS: The chemotactic activity of meconium on neutrophils from newborn infants was assessed in a Boyden-chamber assay. Interleukin 8 and formyl-methionyl-leucyl-phenylalanine (f-MLP) served as positive controls. Inhibition of chemotaxis was assessed with monoclonal antibody to interleukin 8. The interleukin-8 concentration was measured by ELISA. FINDINGS: Sterile meconium suspension from seven unrelated newborn babies increased migration of neutrophils from neonates in comparison with random migration (79, 72, 70, 50, 58, 88 microm vs 46 microm; p<0.001). This effect was greatest at a meconium concentration of 5 g/L, although differences between samples from individual babies were observed. Interleukin 8 was present in all meconium suspensions (480-3980 ng/L). Anti-interleukin-8 inhibited neutrophil migration. INTERPRETATION: Interleukin 8 is present in meconium and it induces chemotaxis of neutrophils in vitro. This mechanism may have a role in the pathogenesis of pneumonitis in meconium aspiration syndrome.

The effect of antioxidative combination therapy on post hypoxic-ischemic perfusion, metabolism, and electrical activity of the newborn brain.

Reoxygenation and reperfusion after severe hypoxia and ischemia (HI) contribute substantially to birth asphyxia-related brain injury. Excess production of free radicals via metabolization of arachidonic acid, xanthine oxidase, and non-protein-bound iron play an important role. Cerebral reperfusion injury is characterized by a decrease in perfusion, oxygen consumption, and electrical activity of the brain. Reduction of free radical production may attenuate these features. We therefore induced severe HI in 35 newborn lambs, and upon reperfusion the lambs received a placebo [control (CONT), n = 7], the cyclooxygenase inhibitor indomethacin (INDO, 0.3 mg/kg/i.v., n = 7), the xanthine oxidase inhibitor allopurinol (ALLO, 20 mg/kg/i.v., n = 7), the iron chelator deferoxamine (DFO, 2.5 mg/kg/i.v., n = 7), or a combination of these drugs (COMB, n = 7). In each group changes (%) from pre-HI values were investigated for brain perfusion [measured by carotid artery flow (Qcar, mL/min)], (relative) cerebral O2 metabolism (CMR(O2)), and electrocortical brain activity (ECBA, microV) at 15, 60, 120, and 180 min post-HI. Qcar decreased significantly at 120 and 180 min post-HI in CONT (p < 0.05), but not in INDO, ALLO, DFO, and COMB groups. CMR(O2) decreased significantly in CONT at 60 min post-HI (p < 0.05), remained stable in DFO and INDO, and was significantly higher in ALLO and COMB (p < 0.05) at 120 and 180 min post-HI. ECBA was significantly lower in CONT during the whole post-HI period (p < 0.05), ECBA in INDO and COMB were significantly decreased at 60 and 120 min post-HI (p < 0.05), but recovered afterward, whereas DFO and ALLO remained stable during the post-HI period. In conclusion preservation of Qcar and CMR(O2), and recovery of ECBA occurred after treatment with INDO, ALLO, and DFO; combination of these drugs did not have an additional positive effect.

Effect of deferoxamine and allopurinol on non-protein-bound iron concentrations in plasma and cortical brain tissue of newborn lambs following hypoxia-ischemia.

Reduction of non-protein-bound iron (NPBI) using iron chelators may attenuate hypoxia-ischemia-induced reperfusion injury of the brain. This study investigated whether administration of low-dose deferoxamine and allopurinol, both having NPBI-chelating properties, reduced hypoxia-ischemia-induced NPBI formation in plasma effluent from the brain and in cerebral cortical tissue. Twenty-one newborn lambs underwent severe hypoxia-ischemia. Upon reperfusion and reoxygenation the lambs received either a placebo (n = 7), or deferoxamine 2.5 mg/kg (n = 7) or allopurinol 20 mg/kg (n = 7). The post-hypoxic-ischemic NPBI levels in plasma were significantly lower after deferoxamine but not after allopurinol as compared to placebo-treated lambs. Cortical NPBI levels in both deferoxamine and allopurinol-treated lambs were significantly lower than NPBI levels in placebo-treated lambs. We conclude that deferoxamine effectively lowers NPBI in plasma effluent from the brain, and that both, deferoxamine and allopurinol, lower NPBI in cortical brain tissue.

Vitamin E status in preterm infants: assessment by plasma and erythrocyte vitamin E-lipid ratios and hemolysis tests.

BACKGROUND: Vitamin E is an essential component of the antioxidant defenses, but supplementation can have side effects in the preterm infant. Careful monitoring of vitamin E status is thus essential, however no consensus has been reached on the best clinical method. METHODS: In 47 healthy preterm infants, several methods for assessment of vitamin E status were evaluated: plasma and erythrocyte vitamin E levels were measured, vitamin E lipid ratios were calculated, and two variations of the hydrogen peroxide hemolysis test were conducted. RESULTS: At birth, the plasma and erythrocyte vitamin E levels were low. After birth, the plasma levels rose gradually, whereas the erythrocyte levels remained low. In contrast, the vitamin E-total-lipid ratio was in the low normal range from birth onwards. Vitamin E-lipid ratios using two lipid components (cholesterol with triglycerides, or cholesterol with phospholipids) or one lipid component (cholesterol) correlated with the vitamin E-total-lipid ratio with a good sensitivity and specificity. The susceptibility of erythrocytes to hydrogen peroxide-induced damage (measured as potassium release or malondialdehyde production) was high at birth and declined after birth. However, this susceptibility did not correlate with plasma or erythrocyte vitamin E levels or vitamin E-total-lipid ratio, and the hydrogen peroxide hemolysis test is not a reliable indicator of vitamin E status in preterm infants. CONCLUSIONS: Our study indicated that a gold standard for clinical assessment of vitamin E status in preterm infants is yet to be found.

Effect of allopurinol on postasphyxial free radical formation, cerebral hemodynamics, and electrical brain activity.

OBJECTIVE: Free radical-induced postasphyxial reperfusion injury has been recognized as an important cause of brain tissue damage. We investigated the effect of high-dose allopurinol (ALLO; 40 mg/kg), a xanthine-oxidase inhibitor and free radical scavenger, on free radical status in severely asphyxiated newborns and on postasphyxial cerebral perfusion and electrical brain activity. METHODS: Free radical status was assessed by serial plasma determination of nonprotein-bound iron (microM), antioxidative capacity, and malondialdehyde (MDA; microM). Cerebral perfusion was investigated by monitoring changes in cerebral blood volume (delta CBV; mL/100 g brain tissue) with near infrared spectroscopy; electrocortical brain activity (ECBA) was assessed in microvolts by cerebral function monitor. Eleven infants received 40 mg/kg ALLO intravenously, and 11 infants served as controls (CONT). Plasma nonprotein-bound iron, antioxidative capacity, and MDA were measured before 4 hours, between 16 and 20 hours, and at the second and third days of age. Changes in CBV and ECBA were monitored between 4 and 8, 16 and 20, 58 and 62, and 104 and 110 hours of age. RESULTS: Six CONT and two ALLO infants died after neurologic deterioration. No toxic side effects of ALLO were detected. Nonprotein-bound iron (mean +/- SEM) in the CONT group showed an initial rise (18.7 +/- 4.6 microM to 21.3 +/- 3.4 microM) but dropped to 7.4 +/- 3.5 microM at day 3; in the ALLO group it dropped from 15.5 +/- 4.6 microM to 0 microM at day 3. Uric acid was significantly lower in ALLO-treated infants from 16 hours of life on. MDA remained stable in the ALLO group, but increased in the CONT group at 8 to 16 hours versus < 4 hours (mean +/- SEM; 0.83 +/- 0.31 microM vs 0.50 +/- 0.14 microM). During 4 to 8 hours, delta CBV-CONT showed a larger drop than delta CBV-ALLO from baseline. During the subsequent registrations CBV remained stable in both groups. ECBA-CONT decreased, but ECBA-ALLO remained stable during 4 to 8 hours of age. Neonates who died had the largest drops in CBV and ECBA. CONCLUSION: This study suggests a beneficial effect of ALLO treatment on free radical formation, CBV, and electrical brain activity, without toxic side effects.

Cisplatin combination chemotherapy induces a fall in plasma antioxidants of cancer patients.

BACKGROUND: Antioxidants protect the body against cellular oxidative damage and thus some of the adverse effects induced by cisplatin and other cytostatic drugs. PATIENTS AND METHODS: The effect of cisplatin-combination chemotherapy on concentrations of plasma antioxidants was studied in 36 cancer patients, including osteosarcoma and testicular carcinoma patients. RESULTS: Eight to 15 days after the start of each cytostatic drug infusion concentrations of various plasma antioxidants were measured and compared to pretreatment values: vitamin C and E, uric acid and ceruloplasmin levels fell significantly (P < 0.01-0.005) and returned to baseline levels before the start of the next chemotherapy cycle. Levels of the antioxidants bilirubin albumin and the ratio vitamin E/cholesterol + triglycerides measured three weeks after the start of chemotherapy significantly decreased compared to pretreatment levels and remained low thereafter (P < 0.001-0.002). Dietary intake of antioxidants and anthropometric measurements, evaluated in 14 patients did not change during the whole treatment period. CONCLUSIONS: Cisplatin-combination chemotherapy induces a fall in plasma antioxidant levels, that may reflect a failure of the antioxidant defense mechanism against oxidative damage induced by commonly used anticancer drugs. This probably results from consumption of antioxidants caused by chemotherapy induced-oxidative stress as well as renal loss of water-soluble, small molecular weight antioxidants such as uric acid.

Allopurinol dosage and effect on ischemia-reperfusion damage in elective and acute aortic surgery.

To study the effect of a safe dosage of allopurinol on ischemia-reperfusion damage following aortic surgery, 24 patients undergoing either elective or acute aortic reconstruction, were randomized to receive allopurinol or placebo, yielding four groups: elective/placebo (EP), elective/allopurinol (EA), acute/placebo (AP) and acute/allopurinol (AA). Blood concentrations of allopurinol, oxypurinol, uric acid, malondialdehyde, ascorbic acid, and 99mTc-albumin were determined perioperatively. Adequate concentrations and biochemical activity of allopurinol and oxypurinol were obtained, without side-effects. Malondialdehyde did not increase perioperatively, but was significantly higher in acute surgery than in elective surgery intraoperatively. Yet, ascorbic acid levels and 99mTc-albumin disappearance were not different from groups EP and EA. No influence of allopurinol was found on malondialdehyde, ascorbic acid and 99mTc-albumin. An influence of allopurinol may have been obscured, as patients in group AA were more hypotensive than in group AP. In conclusion, adequate allopurinol concentration can be obtained with a safe dosage in abdominal aortic surgery. Signs of ischemia-reperfusion injury were found in acute surgery, not in elective surgery. Therefore, further investigation on the clinical effect of allopurinol is only useful in acute aortic surgery.