Organ-protective effects on the liver and kidney by minocycline in small piglets undergoing cardiopulonary bypass.

Cardiopulmonary bypass (CPB) often is required for the operative correction of congenital heart defects in small infants. Unfortunately, CPB is associated with injury of inner organs such as the brain, kidney, lung, and liver. Renal failure and increase in liver enzymes are typical side effects observed after CPB. Here, we investigate whether organ protection of the kidney and liver can be achieved with the application of minocycline, which is known-besides its anti-infective effects-to act as a poly-ADP-ribose-polymerase inhibitor. Twenty-nine 4-week-old Angler Sattelschwein-piglets (8-15 kg) were divided into four groups: control group (n = 8), CPB group (n = 9), minocycline-control group (n = 6), and the minocycline-CPB group (n = 6). CPB groups were thoracotomized and underwent CPB for 120 min (cross-clamp, 90 min; reperfusion, 30 min) followed by a 90-min recovery time. The control groups also were thoracotomized but not connected to CPB. The minocycline group received 4 mg/kg minocycline before and 2 mg/kg after CPB. In the kidneys, CPB histologically resulted in widening of Bowman's capsule, and-mainly in tubules-formation of poly-ADP-ribose, nitrosylation of tyrosine-residues, nuclear translocation of hypoxia-induced factor HIF-1α, and of apoptosis-inducing factor (AIF). In addition, we found significantly less ATP in the kidney and significantly increased plasma urea and creatinine. Similar but gradually attenuated changes were found in the liver together with significantly elevated de-Ritis coefficient. These changes in the kidney and liver were significantly diminished by minocycline (except AIF in the liver which was similar in all groups). In conclusion, CPB causes damage in the kidney and-to a lower degree-in the liver, which can be attenuated by minocycline.

Hippocampal Neuroprotection by Minocycline and Epigallo-Catechin-3-Gallate Against Cardiopulmonary Bypass-Associated Injury.

Surgical correction of congenital cardiac malformations mostly implies the use of cardiopulmonary bypass (CPB). However, a possible negative impact of CPB on cerebral structures like the hippocampus cannot be neglected. Therefore, we investigated the effect of CPB on hippocampus CA1 and CA3 regions without or with the addition of epigallocatechin-3-gallate (EGCG) or minocycline. We studied 42 piglets and divided them into six experimental groups: control without or with EGCG or minocycline, CPB without or with EGCG or minocycline. The piglets underwent 90 minutes CPB and subsequently, a 120-minute recovery and reperfusion phase. Thereafter, histology of the hippocampus was performed and the adenosine triphosphate (ATP) content was measured. Histologic evaluation revealed that CPB produced a significant peri-cellular edema in both CA regions. Moreover, we found an increased number of cells stained with markers for hypoxia, apoptosis and nitrosative stress. Most of these alterations were significantly reduced to or near to control levels by application of EGCG or minocycline. ATP content was significantly reduced within the hippocampus after CPB. This reduction could not be antagonized by EGCG or minocycline. In conclusion, CPB had a significant negative impact on the integrity of hippocampal neural cells. This cellular damage could be significantly attenuated by addition of EGCG or minocycline.

Protective effects of pulsatile flow during cardiopulmonary bypass.

BACKGROUND: Children with congenital heart disease are often operated at a very young age. Cardiopulmonary bypass (CPB) has become indispensable for these sometimes very complex operations, but one cannot neglect a possible negative impact of CPB on organ function. Traditionally, CPB was developed with non-pulsatile flow but there are clinical observations that pulsatile flow might be superior with improved patient outcomes. Therefore, we attempted to elucidate whether CPB with pulsatile flow preserves organ integrity compared with nonpulsatile flow. METHODS: We studied 27 piglets of 4 weeks age and divided them into 3 experimental groups: control group (no CPB); non-pulsatile and pulsatile-CBP with 90-minutes CPB and 120-minutes recovery and reperfusion. Thereafter, histology of kidney, liver, and hippocampus was performed. Moreover, we measured adenosine triphosphate (ATP) content in these organs. RESULTS: Histologic evaluation revealed that laminar flow produced significant cellular edema in the kidney and hippocampus. Additionally, markers for hypoxia, apoptosis, and nitrosative stress were elevated but predominately in the hippocampus and proximal tubules of the kidney. Most of these alterations were reduced to or near control levels with pulsatile CPB. Moreover, ATP content of all 3 organs examined was higher and kidney and liver enzymes were lower in the pulsatile group compared with the non-pulsatile CPB. With regard to histologic changes, the liver seemed to be a less sensitive organ. CONCLUSIONS: In our study during pulsatile CPB, organ damage was significantly attenuated as compared with non-pulsatile CPB. Therefore, in pediatric patients pulsatile CPB may improve clinical outcomes.