Effect of Indomethacin on Cerebral Oxidized Cytochrome Oxidase in Preterm Infants

McCormick, David; Edwards, A. David; Brown, Guy C.; Wyatt, John; Potter, A.; Cope, M; Delpy, DT; Reynolds, E. O. R.

doi:10.1203/00006450-199306000-00015

Cited by 56 publications

(21 citation statements)

References 32 publications

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Section: Articles Arora Et Almentioning

confidence: 79%

“…Earlier NIRS studies reported significant reductions in the concentration of oxidized cytochrome oxidase after indomethacin infusion (16)(17)(18). The study by McCormick et al used a 30-min infusion protocol similar to the one in the current study (17). However, it was concluded that the observed effects were more likely a result of a reduction in oxygen delivery (i.e., CBF), rather than a direct effect on mitochondrial respiration because the concentration of oxidized cytochrome oxidase depends on the balance between oxygen delivery and utilization.…”

Section: Articles Arora Et Almentioning

confidence: 99%

“…Interpreting cerebral oxygenation in terms of energy metabolism is difficult because cerebral blood oxygenation depends on the balance between oxygen delivery and consumption. Earlier studies investigating the effects of indomethacin on cerebral cytochrome oxidase reported reduction in the oxidized state (16)(17)(18). However, no study has directly measured the effects of indomethacin on the cerebral metabolic rate of oxygen (CMRO 2 ), despite the ability of NIRS to determine CMRO 2 by combining cerebral flow and oxygenation measurements (19)(20)(21).…”

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confidence: 99%

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Preservation of the metabolic rate of oxygen in preterm infants during indomethacin therapy for closure of the ductus arteriosus

et al. 2013

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Background:The aim of this study was to assess and quantify the effects of indomethacin on cerebral blood flow (CBF), oxygen extraction fraction (OEF), and cerebral metabolic rate of oxygen (CMRO 2 ) in preterm infants undergoing treatment for a patent ductus arteriosus (PDA). Methods: CBF and CMRO 2 were measured before and after the first dose of a 3-d course of indomethacin to close hemodynamically significant PDA in preterm neonates. Indocyaninegreen (ICG) concentration curves were acquired before and after indomethacin injection to quantify CBF and CMRO 2 . results: Eight preterm neonates (gestational age, 27.6 ± 0.5 wk; birth weight, 992 ± 109 g; 6 males:2 females) were treated at a median age of 4.5 d (range, 4-21 d). Indomethacin resulted in an average CBF decrease of 18% (pre-and post-CBF = 12.9 ± 1.3 and 10.6 ± 0.8 ml/100 g/min, respectively) and an OEF increase of 11% (pre-and post-OEF = 0.38 ± 0.02 and 0.42 ± 0.02, respectively) but no significant change in CMRO 2 (pre-and post-CMRO 2 = 0.83 ± 0.07 and 0.76 ± 0.07 ml O 2 /100 g/min, respectively). Corresponding mean blood pressure (BP), arterial oxygen saturation (S a O 2 ), heart rate, and endtidal carbon dioxide tension levels remained unchanged. conclusion: Indomethacin resulted in significant reduction in CBF but did not alter CMRO 2 because of a compensatory increase in OEF.

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Section: Articles Arora Et Almentioning

confidence: 79%

Section: Articles Arora Et Almentioning

confidence: 99%

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confidence: 99%

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Preservation of the metabolic rate of oxygen in preterm infants during indomethacin therapy for closure of the ductus arteriosus

et al. 2013

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“…One (Nollert et al 1995) measured a number of parameters, including NIRS, during cardiac surgery and found that the only parameter correlating with subsequent neurological dysfunction was the reduction of cytochrome oxidase Cu A . Another study on neonates (McCormick et al 1993) showed that the standard treatment of patent ductus arteriosus, indomethacin, caused a significant unwanted side-effect, namely a drop in the Cu A redox state. Alternative treatments with ibuprofen appear not to have this problem (Patel et al 1995) and this, to our knowledge, is likely to become the first example of clinical practice being altered, at least in part due to a cytochrome oxidase NIRS measurement.…”

Section: Oxygen Dependence Of the Cu A Nirs Signalmentioning

confidence: 99%

Measurement of cytochrome oxidase and mitochondrial energetics by near–infrared spectroscopy

Cooper

Springett

1997

Phil. Trans. R. Soc. Lond. B

139

111

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SUMMARYCytochrome oxidase is the terminal electron acceptor of the mitochondrial respiratory chain. It is responsible for the vast majority of oxygen consumption in the body and essential for the efficient generation of cellular ATP. The enzyme contains four redox active metal centres ; one of these, the binuclear Cu A centre, has a strong absorbance in the near-infrared that enables it to be detectable in i o by near-infrared spectroscopy. However, the fact that the concentration of this centre is less than 10 % of that of haemoglobin means that its detection is not a trivial matter.Unlike the case with deoxyhaemoglobin and oxyhaemoglobin, concentration changes of the total cytochrome oxidase protein occur very slowly (over days) and are therefore not easily detectable by nearinfrared spectroscopy. However, the copper centre rapidly accepts and donates an electron, and can thus change its redox state quickly ; this redox change is detectable by near-infrared spectroscopy. Many factors can affect the Cu A redox state in i o , but the most significant is likely to be the molecular oxygen concentration (at low oxygen tensions, electrons build up on Cu A as reduction of oxygen by the enzyme starts to limit the steady-state rate of electron transfer).The factors underlying haemoglobin oxygenation, deoxygenation and blood volume changes are, in general, well understood by the clinicians and physiologists who perform near-infrared spectroscopy measurements. In contrast, the factors that control the steady-state redox level of Cu A in cytochrome oxidase are still a matter of active debate, even amongst biochemists studying the isolated enzyme and mitochondria. Coupled with the difficulties of accurate in i o measurements it is perhaps not surprising that the field of cytochrome oxidase near-infrared spectroscopy has a somewhat chequered past. Too often papers have been written with insufficient information to enable the measurements to be repeated and few attempts have been made to test the algorithms in i o.In recent years a number of research groups and commercial spectrometer manufacturers have made a concerted attempt to not only say how they are attempting to measure cytochrome oxidase by nearinfrared spectroscopy but also to demonstrate that they are really doing so. We applaud these attempts, which in general fall into three areas : first, modelling of data can be performed to determine what problems are likely to derail cytochrome oxidase detection algorithms (Matcher et al. 1995) ; secondly haemoglobin concentration changes can be made by haemodilution (using saline or artificial blood substitutes) in animals (Tamura 1993) or patients (Skov & Greisen 1994) ; and thirdly, the cytochrome oxidase redox state can be fixed by the use of mitochondrial inhibitors and then attempts made to cause spurious cytochrome changes by dramatically varying haemoglobin oxygenation, haemoglobin concentration and light scattering (Cooper et al. 1997).We have previously written reviews covering the difficulties of measuring the cyt...

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“…Indomethacin decreases cerebral blood flow and oxygen consumption to a greater degree than ibuprofen lysine. 16,17 This is associated with a preventative effect in the occurrence of IVH when given prophylactically in low-birthweight infants, whereas ibuprofen lysine has no such protective effect. 18,19 Indomethacin more profoundly decreases renal blood flow compared to ibuprofen lysine, resulting in significant oliguria and an increase in serum creatinine levels.…”

Section: Treatment Options For Pdamentioning

confidence: 99%

Treatment of patent ductus arteriosus: indomethacin or ibuprofen?

Sekar

Corff

2008

J Perinatol

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Persistent patent ductus arteriosus (PDA) in preterm infants can result in serious hemodynamic changes causing respiratory, gastrointestinal and renal morbidities if not treated within the first week of life. The treatment options available are a conservative approach, pharmacological treatment with cyclo-oxygenase (COX) inhibitors and surgical ligation. The COX inhibitors approved for use in the United States are indomethacin and ibuprofen lysine. Both of these drugs are equally effective in closing the PDA. Subtle differences exist between these two preparations. Indomethacin has a protective effect on the incidence of intraventricular hemorrhage (IVH) but reduces the blood flow to the kidneys and the brain. Ibuprofen is less toxic but has no effect on IVH. Efficacy of pharmacological treatment is influenced by timing of initiation of therapy. Surgical treatment is the only option when pharmacological treatment fails to close the PDA in symptomatic infants. Long-term neurological and respiratory morbidities are associated with surgical ligation. This paper reviews these medical considerations in the treatment options for PDA in premature infants.

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Effect of Indomethacin on Cerebral Oxidized Cytochrome Oxidase in Preterm Infants

Cited by 56 publications

References 32 publications

Preservation of the metabolic rate of oxygen in preterm infants during indomethacin therapy for closure of the ductus arteriosus

Preservation of the metabolic rate of oxygen in preterm infants during indomethacin therapy for closure of the ductus arteriosus

Measurement of cytochrome oxidase and mitochondrial energetics by near–infrared spectroscopy

Treatment of patent ductus arteriosus: indomethacin or ibuprofen?

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