G. von Bernuth

Influence of temperature during cardiopulmonary bypass on leukocyte activation, cytokine balance, and post-operative organ damage

This study examined the hypothesis that core temperature (T(o)) during cardiopulmonary bypass (CPB) influences the perioperative systemic inflammatory response and post-operative organ damage. Twenty-four pigs were assigned to a T(o) regimen during CPB: normothermia (T(o) 37 degrees C; n = 8), moderate hypothermia (T(o) 28 degrees C; n = 8), or deep hypothermia (T(o) 20 degrees C; n = 8). Perioperative leukocyte activation, endotoxin release, and production of tumor necrosis factor-alpha (TNFalpha) and interleukin-10 (IL10) were examined with regard to post-operative organ damage, which was scored at histological examination of tissue probes of heart, lungs, liver, kidney, and ileum, taken 6 h after CPB. Total blood leukocyte count and TNFalpha plasma levels during CPB were significantly lower and IL10 levels were significantly higher in the moderate hypothermic group than in both other groups. Elastase activity, leukotriene B4-, and endotoxin levels were not affected by T(o) regimen. Moderate hypothermia was associated with the lowest histological organ damage score and normothermia with the highest. In all animals organ damage score for heart, lungs, and kidneys correlated significantly with TNFalpha levels at the end of CPB. Our data demonstrate a clear relationship between TNFalpha production during cardiac operations and post-operative multiple-organ damage. Moderate hypothermia, by stimulating IL10 synthesis and suppressing TNFalpha production during CPB, might provide organ protection.

Cardiac involvement in tuberous sclerosis.

OBJECTIVE--To assess the incidence, importance, and history of cardiac involvement in infants and children with tuberous sclerosis. DESIGN--Prospective study; clinical examination, sector and Doppler echocardiography, standard and ambulatory electrocardiography. SETTING--A tertiary referral centre. PATIENTS--21 patients with tuberous sclerosis aged 1 day to 16 years (mean 6.3 years); follow up investigations were available in 14 cases (10 retrospective, 4 prospective; mean follow up 4.3 years). RESULTS--Multiple cardiac rhabdomyomas in the right ventricle (11) and left ventricle (14) as well as in the right atrium (1) were present in 14/21 patients. Two of them had obstruction of the left ventricular inflow and outflow tract related to a tumour. In the remaining 7 patients, echocardiography was normal in 4 and equivocal in 3 cases. The standard electrocardiogram (n = 20) showed ventricular hypertrophy (2), ventricular pre-excitation (1), arrhythmias (2), and repolarisation disturbances (4) in 7/13 patients with rhabdomyomas but was normal in all patients with a normal or equivocal echocardiogram. The ambulatory electrocardiogram (n = 19) showed frequent premature atrial (2) and polymorphous ventricular (2) contractions. The polymorphous ventricular contractions coexisted with rhabdomyomas. No arrhythmias that needed medical treatment were found. Follow up investigations showed return to a normal standard electrocardiogram in 3 patients. Definite regression or complete disappearance of the tumour occurred in 6 infants. CONCLUSIONS--Cardiac rhabdomyomas, although often present in these patients with tuberous sclerosis, caused neither major arrhythmias nor haemodynamic obstruction except in the neonatal period. The indication for operation is limited to cases with life threatening obstruction or arrhythmias refractory to medical treatment.

Evaluation of aortic coarctation after surgical repair: role of magnetic resonance imaging and Doppler ultrasound.

OBJECTIVE--To compare the usefulness of magnetic resonance imaging (MRI) and Doppler ultrasound with that of cross sectional echocardiography and oscillometric blood pressure measurement for the evaluation of aortic coarctation after surgical repair. DESIGN--Prospective study. Aortic diameters measured by cross sectional echocardiography, MRI, and angiography (selected cases) and functional data determined by physical examination, oscillometric blood pressure measurement, and continuous wave Doppler. SETTING--Tertiary referral centre. PATIENTS--40 patients aged 2-28 years (mean 10.6 years) who had had surgical correction of aortic coarctation (mean follow up 5.7 years). RESULTS--In all patients MRI gave diameter measurements of the aortic arch and the thoracic aorta whereas in half of them cross sectional echocardiographic measurement of the isthmic region failed. The correlation coefficient for aortic diameters measured by MRI and angiography was 0.97 and that between MRI and echocardiography was 0.89. Peak velocities in the descending aorta correlated better with residual narrowing of the aortic isthmus or distal aortic arch or both than systolic blood pressure gradients between the upper and lower limbs. A peak velocity of < 2 m/s in the descending aorta during systole excluded important restenosis. Prolongation of anterograde blood flow during diastole always indicated a morphological abnormality--either important restenosis or aneurysmal dilatation. CONCLUSIONS--MRI was better than cross sectional echocardiography for imaging the aortic arch after coarctation repair and measuring its diameter. Peak velocity in the descending aorta correlated better with residual stenosis than did the systolic blood pressure gradient between the upper and lower limbs and this index could be used to indicate a need for MRI.

The Production of Pro- and Anti- Inflammatory Cytokines in Neonates Assessed by Stimulated Whole Cord Blood Culture and by Plasma Levels at Birth

The capability of neonates to achieve cytokine balance was evaluated. Production of the pro-inflammatory cytokines TNFα and IL-8, of the natural anti-inflammatory cytokine IL10 and of the regulator of the acute phase response IL6 was assessed after whole blood stimulation by lipopolysaccharide in cord blood (n = 10), adult volunteers serving as control (n = 17). Additionally, circulating cytokines were determined in cord and in maternal blood immediately after delivery (n = 27, respectively). Significant production of TNFα, IL8, IL10 and IL6 was observed in cord blood after lipopolysaccharide stimulation and was similar to cytokine production in adult blood. The plasma concentrations of TNFα were significantly higher in cord than in maternal blood, while plasma concentrations of IL10 and IL6 were significantly lower. Our results demonstrate fully developed capability of whole cord blood to synthesize pro- and anti-inflammatory cytokines in response to a pro-inflammatory stimulation in vitro. In vivo, however, higher circulating TNFα and lower IL10 and IL6 levels in cord blood suggest that the inflammatory stress associated with normal delivery does not induce detectable anti-inflammatory response in neonates at birth.

Effect of biologically active coating on biocompatibility of Nitinol devices designed for the closure of intra-atrial communications

Anti-thrombogenicity and rapid endothelialisation are prerequisites for the use of closure devices of intra-atrial communications in order to reduce the risk of cerebral embolism. The purpose of this study was therefore to assess the effect of bioactive coatings on biocompatibility of Nitinol coils designed for the closure of intra-atrial communications. Nitinol coils (n = 10, each) and flat Nitinol bands (n = 3, each) were treated by basic coating with poly(amino-p-xylylene-co-p-xylylene) and then coated with either heparin, r-hirudin or fibronectin. Anti-thrombogenicity was studied in vitro in a dynamic model with whole blood by partial thromboplastin time (PTT), platelet binding and thrombin generation, respectively, and cytotoxicity by hemolysis. Endothelialisation was studied on Nitinol bands with human umbilical venous endothelial cells (HUVEC) by 3-(4,5-dimethylthiazole-2yl)-2,5-triphenyl tetrazolium (MTT) assay and immnuofluorescence analysis of Ki67, vinculin, fibronectin and von Willebrand Factor. Uncoated or coated devices did not influence hemolysis and PTT. r-Hirudin (but not heparin) and fibronectin coating showed lower platelet binding than uncoated Nitinol (p < 0.005, respectively). Heparin and r-hirudin coating reduced thrombin formation (p < 0.05 versus Nitinol, respectively). HUVEC adhesion, proliferation, and matrix formation decreased in the order: fibronectin coating > uncoated Nitinol > r-hirudin coating > heparin coating > basic coating. MTT assay corroborated these findings. In conclusion, r-hirudin and fibronectin coating, by causing no acute cytotoxicity, decreasing thrombogenicity and increasing endothelialisation improve in vitro biocompatibility of Nitinol devices designed for the closure of intra-atrial communications.

Thoracic sequelae after surgical closure of the patent ductus arteriosus in premature infants

Thirty‐six children (median chronological age 6 years 1 month) who had undergone surgical closure of a patent ductus arteriosus through a left posterolateral thoracotomy in the neonatal period (median gestational age 32 weeks) were investigated prospectively with respect to anatomical and functional changes of the chest. At follow‐up examination, residual or recurrent patent ductus arteriosus was not observed. Three patients had chronic bronchial obstruction. Two patients showed pathological musculoskeletal thoracic sequelae that did not require any treatment at the time of follow‐up: persistence of immediate postoperative left phrenic palsy (n= 1) and thoracic scoliosis (n= 1). Twenty of the 27 patients in whom chest X‐ray was performed had minor radiological skeletal anomalies in the form of rib deformation or fusion related to die thoracotomy, lesions which have a potential to induce thoracic scoliosis. Left shoulder elevation at chest X‐ray and isolated left arm dysfunction at clinical examination were not observed. Despite the low incidence of scoliosis and the absence of left arm dysfunction observed at mid‐term follow‐up in our series, the incidence of minor rib deformations with a potential to induce severe anomalies such as scoliosis should motivate late follow‐up examination at adolescence to definitively assess the prevalence of thoracic sequelae after surgical closure of the patent ductus arteriosus in premature infants.

Detection of abnormal aortic elastic properties in asymptomatic patients with Marfan syndrome by combined transoesophageal echocardiography and acoustic quantification.

OBJECTIVE: To evaluate the potential value of transoesophageal echocardiography combined with automated border detection and acoustic quantification for the assessment of elastic properties of the thoracic aorta in patients with Marfan syndrome. SUBJECTS: 16 patients with Marfan syndrome and 12 age matched normal controls. METHODS: Transoesophageal echocardiography was performed in all subjects. Minimum and maximum diameters of the descending thoracic aorta were obtained from M mode images and acoustic quantification was used for the on-line evaluation of cross sectional aortic area and peak positive area changes over time. Compliance, distensibility, and stiffness index were calculated using M mode data and non-invasively measured blood pressure and were compared with the indices derived from acoustic quantification. RESULTS: Aortic dimensions normalised for body surface area were not statistically different between patients and normal controls, but there were significant differences for all elasticity indices except compliance. Marfan patients had a lower distensibility [4.2 (SD 1.8) v 5.8 (2.1) cm2/dyn, P < 0.05] and a higher stiffness index [9.7 (3.0) v 7.1 (1.8), P < 0.05]. The dynamic indices derived from the acoustic quantification were significantly smaller in Marfan patients [peak positive area change: 5.1 (1.0) v 7.7 (1.7) cm2/s; P < 0.001; and normalised peak positive area change: 2.5 (1.2) v 4.0 (0.8) cm2/s respectively, P < 0.001] and were suitable to discriminate between normal and abnormal elastic properties. CONCLUSIONS: In Marfan syndrome elastic properties of the descending aorta are significantly different from normal controls, even in the absence of vessel dilatation. In addition to established static indices, indices derived from acoustic quantification reflect dynamic changes of the cross sectional area for the evaluation of regional vessel mechanics. The on-line assessment of peak positive area change allows differentiation from normal individuals and may be more accurate than standard M mode measurements.

Evaluation of in vivo biocompatibility of different devices for interventional closure of the patent ductus arteriosus in an animal model

OBJECTIVE To evaluate the in vivo biocompatibility of three different devices following interventional closure of a patent ductus arteriosus (PDA) in an animal model. MATERIALS AND METHODS A medical grade stainless steel coil (n = 8), a nickel/titanium coil (n = 10), and a polyvinylalcohol foam plug knitted on a titanium wire frame (n = 11) were used for interventional closure of PDA in a neonatal lamb model. The PDA had been maintained by repetitive angioplasty. Between one and 278 days after implantation the animals were killed and the ductal block removed. In addition to standard histology and scanning electron microscopy, immunohistochemical staining for biocompatibility screening was also undertaken. RESULTS Electron microscopy revealed the growth of a cellular layer in a cobblestone pattern on the implant surfaces with blood contact, which was completed as early as five weeks after implantation of all devices. Immunohistochemical staining of these superficial cells showed an endothelial cell phenotype. After initial thrombus formation causing occlusion of the PDA after implantation there was ingrowth of fibromuscular cells resembling smooth muscle cells. Transformation of thrombotic material was completed within six weeks in the polyvinylalcohol plug and around the nickel/titanium coil, and within six months after implantation of the stainless steel coil. An implant related foreign body reaction was seen in only one of the stainless steel coil specimens and in two of the nickel/titanium coil specimens. CONCLUSION After implantation, organisation of thrombotic material with ingrowth of fibromuscular cells was demonstrated in a material dependent time pattern. The time it took for endothelium to cover the implants was independent of the type of implant. Little or no inflammatory reaction of the surrounding tissue was seen nine months after implantation.

Results of exercise testing at a mean age of 10 years after neonatal arterial switch operation.

Aim: This prospective follow‐up study investigated long‐term exercise capacity at a mean age of 10 y after neonatal arterial switch operation for transposition of the great arteries in a large group of homogeneous unselected children. Methods: 56 asymptomatic children, aged 7.9–14.3 y (10.5 ± 1.6, mean ± SD), were examined with respect to exercise tolerance, electrocardiographic (ECG) response and activity of biochemical markers for myocardial injury. The protocol included standard electrocardiography, M‐mode and two‐dimensional echocardiography at rest, a Bruce walking treadmill test to voluntary exhaustion, and determination of cardiac troponin I and T, creatine kinase and myoglobin from venous blood samples at rest and 4 h after exercise. Heart rate, blood‐pressure response to exercise stress and endurance time were compared with published results of age‐matched normal children. Results: 54 patients (96.4%) had normal exercise capacity; a reduction in 2 patients was not due to cardiac disease. Heart rate and systolic blood pressure rose significantly between rest and peak exercise and did not differ from normal controls, whereas diastolic blood pressure was lower. ECG remained normal at rest and on exercise in 54 children (96.4%). Serum values of cardiac troponin I and T, creatine kinase and myoglobin were normal at rest and after exercise in all patients.

Retrievable patent ductus arteriosus plug for interventional, transvenous occlusion of the patent ductus arteriosus. Evaluation in lambs and preliminary clinical results.

RATIONALE AND OBJECTIVES The clinically most widely used devices (Porstmann-plug, Rashkind-umbrella, Botallooccluder) have inherent specific limitations (eg, transarterial approach, residual shunts, limited retrieval). The authors assess practicability, efficacy, and tissue reaction of the new retrievable transvenous plug device for the occlusion of the persistent patent ductus arteriosus (PDA). METHODS A foam plug (polyvinyl alcohol) is mounted on a titanium core pin where, at both ends, small legs (titanium nickel alloy) with titanium heads are anchored, to ensure safe fixation in the ductus. The device is introduced transvenously through a long sheath (Mullins sheath) and held by a modified biopsy forceps allowing complete retrieval until final release. A common lamb model of large PDAs (n = 11) was used to test for practicability and the histomorphologic outcome. Clinical results were obtained from a consecutive series of 16 patients (aged 13 to 71 years). RESULTS In all lambs, placement of the plug within the PDA was possible. Histopathology (follow-up 10 to 215 days; mean 112 days) revealed an adequate ingrowing of the device and no pathologic foreign body reaction. The diameter of the human PDAs ranged from 3 to 7 mm (mean 5 mm). The size of the sheath used for introducing the plug (diameter 8 to 16 mm) ranged from 8 to 16 French. Fourteen of 16 PDAs were closed immediately after or on day 1 after implantation, 1 was closed after the 12-month follow-up, and 1 needed an additional plug after 30 months for definitive closure. CONCLUSIONS The device demonstrated practicability and biocompatibility in our experimental lamb model and effectively closed the PDA in a consecutive series of 16 patients. A greater number of patients and a longer follow-up period are necessary for the definitive clinical assessment of the new device.