Lars Göran Friberg

Nitric oxide in the oxygenator sweep gas reduces platelet activation during experimental perfusion

BACKGROUND Hemorrhage is a major complication experienced in 10% to 35% of neonates treated with extracorporeal life support (ECLS). The increased bleeding tendency is partly due to an ECLS-induced thrombocytopenia and impaired platelet function. In the present study, we evaluated the effect of nitric oxide on the ECLS-induced platelet consumption and activation. METHODS Two identical in vitro ECLS circuits were primed with fresh, heparin-treated human blood and circulated for 24 hours. Nitric oxide (15, 40, or 77 ppm) was added to one of the oxygenators in each pair. Eight paired experiments were performed. Platelet count, plasma beta-thromboglobulin, platelet serotonin content, plasma nitrate, plasma cyclic guanosine monophosphate, and platelet membrane glycoprotein Ib were assayed before the start and at 0.5, 1, 3, 12, and 24 hours of perfusion. RESULTS Plasma nitrate and plasma cyclic guanosine monophosphate levels were significantly higher in the nitric oxide circuits than in the control circuits (p < 0.01). Higher platelet counts (p < 0.01) and lower beta-thromboglobulin levels (p < 0.01) were observed in the nitric oxide circuits compared with the control circuits. However, no significant differences in platelet serotonin content or platelet membrane glycoprotein Ib density were noted between the circuits. CONCLUSIONS Nitric oxide probably reduces platelet consumption and platelet activation during ECLS.

The effect of albumin priming solution on platelet activation during experimental long-term perfusion.

The objective of this study was to evaluate the effect of albumin priming on platelet consumption and activation during long-term perfusion. Two identical in vitro extracorporeal membrane oxygenation circuits were used; one was primed with Ringer’s solution containing human serum albumin, the other with Ringer’s solution only. Fresh heparinized human blood was pooled, divided between the two systems and circulated for 24 h at 37°C. Platelet count, plasma concentration of betathromboglobulin (BTG), platelet membrane density of glycoprotein (GP) Ib and of GPIIb/IIIa were assayed before the start and at 0.5, 1, 3, 12 and 24 h of perfusion. In total, seven experiments were performed. We found that during the first hour of perfusion, slightly higher platelet counts (p = 0.058) and lower BTG values (p = 0.0005) were observed in the circuits primed with albumin, compared to the control circuits. No statistically significant differences were observed for the platelet membrane expression of GPIb and GPIIb/IIIa. We conclude that albumin priming appears to transiently prevent platelet consumption and activation during long-term perfusion.

Piglet model for studying esophageal regrowth after resection and interposition of a silicone stented small intestinal submucosa tube.

Purpose: To investigate the use and subsequent healing of a silicone stented small intestinal submucosa (SIS) tube as a full-circumference replacement following surgical resection of the esophagus in piglets. Material and Methods: Three centimeters of the intrathoracic esophagus was replaced with a silicone stented SIS tube (Cook Medical) in 6 growing piglets. The esophageal stent was retained for 4 weeks. Esophageal dilations were performed, if needed, after stent removal. Results: The piglets were sacrificed 1–17 weeks after surgery. Recurrent dilations were needed after stent removal. Histology showed that the gap between the resection margins was filled with new loose connective tissue consisting of fibroblasts and few inflammatory cells. In this tissue, intense angiogenesis was seen at the early time points, which then gave way to the proliferation of immature-looking smooth-muscle-like cells in the submucosa, which appeared to stem from the pericytes of the ingrowing capillaries. Conclusions: Through using a stented SIS tube as a circumferential esophageal replacement in a piglet model, this study suggests that pericytes from ingrowing capillaries may play a role in the remodeling of the SIS mesh. It remains to be seen if this process gives a favorable end result because stricture formation after stent removal remains a problem.

Dysphagia in adults operated on for esophageal atresia--use of a symptom score to evaluate correlated factors.

INTRODUCTION Dysphagia is not unusual following repair of esophageal atresia (EA). The lack of a uniform definition has led to a variance when it comes to reporting the prevalence of dysphagia among patients operated on for EA. Our aim is to estimate the occurrence and degree of dysphagia, using a numerical score with its statistical versatility independent of a specific definition. The results are used to find early risk factors of dysphagia within this patient group. The results are also used to see whether we can find a correlation between dysphagia and symptoms of gastroesophageal reflux (GER) and quality of life (QoL). METHODS 79 consecutive survivors operated on for EA in Gothenburg between 1968 and 1983 were located. Hospital charts were reviewed and patients received questionnaires on dysphagia, symptoms of GER and QoL. Dysphagia was measured by a numerical score, symptoms of GER were extracted using a predetermined questionnaire (GerdQ), and QoL was determined using the generic questionnaire SF-36. RESULTS 73 patients (92.4%) returned the questionnaires. In order to make the study group as homogeneous as possible with regard to the malformation we choose to study the 63 patients representing the vast majority: those with Gross type C. 36 patients (57%) had symptoms of dysphagia to varying degrees. We did not find any aggravating factors in their hospital charts nor did we find any correlation to the most recent demographics. There was a significant difference in dysphagia scores when we compared Gross type C to the often more complex type A (p<0.05). We did not find any correlation to heartburn but a strong correlation to regurgitation with an OR of 2.8 (95% CI: 1.2-6.6). The QoL was good for this patient group, and we did not find any correlation between QoL and the dysphagia score. CONCLUSIONS The dysphagia score provides easy-to-use results when it comes to evaluating the potential influence of dysphagia. Dysphagia is common within this patient group. Patients operated on for EA Gross type A seem to do worse when it comes to dysphagia. Regurgitation is associated with dysphagia, which could imply that GER is an aggravating factor. Further studies to support this finding will show whether there is a correlation between the dysphagia score and the results of 24-h pH-monitoring. If so, this could mean that treating GER might decrease dysphagia, at least in this patient group.

Subclavian flap angioplasty with absorbable suture polydioxanone (PDS): an experimental study in growing piglets

The fate of the subclavian flap in aortoplasty was studied and a new synthetic monofilament, absorbable vascular suture (polydioxanone, PDS) was evaluated. In 11 piglets submitted to the aortic repair, the diameter of the aortic arch and descending aorta and the length and width of the subclavian flap were measured. The aortoplasty was performed with a continuous running suture of 6/0 PDS. All the animals survived and grew normally. They were sacrificed 6-26 weeks postoperatively, when the mentioned variables were reestimated. No aortic narrowing was found and no suture material was detectable in the lumen. The subclavian flap had grown uniformly in length and width. Histologic examination showed evening of the inner surface by intimal proliferation and healing of the anastomoses. There was no sign of flap destruction and tissue reaction to PDS suture was minimal, indicating normal growth and viability in all parts of the flap. The suture material was absorbed 26 weeks postoperatively. Continuous suture with absorbable PDS seems to be a good alternative for repair of aortic coarctation in early infancy.

Physiological Studies at 7 Years of Age in Children Born with Esophageal Atresia.

OBJECTIVE For many years, esophageal atresia (EA) has been curable by surgery. However, severe respiratory morbidity and gastroesophageal reflux (GER) symptoms remain a problem in many patients. The purpose of this study was to describe respiratory and esophageal morbidity, esophageal function, and lung function, including the small airways, in patients with the most common type of the malformation (EA with a distal fistula). METHODS The study comprised 26 children undergoing surgery for EA, who had performed respiratory and esophageal function studies at the age of 7 years in a follow-up program. The study design was retrospective analysis of both these 7-year functional investigations and esophageal and respiratory morbidity from birth to the age of 7 years, as documented in medical records. Pulmonary function was evaluated mainly by spirometry and multiple breath washout (MBW), whereas esophageal function was evaluated by 24-hour pH studies. RESULTS We found a high prevalence of both respiratory (69%) and esophageal (62%) morbidity between birth and 7 years among the EA children. Examination with MBW (peripheral airway function) revealed few abnormal results, whereas spirometry revealed high airway obstruction in half the children, which also correlated well with overall respiratory symptoms (p = 0.047), as well as recurrent pneumonias (p = 0.035). However, no association with GER symptoms was found. In addition, 46% of the children had GER according to pH measurements, which were correlated to clinical GER symptoms but not to respiratory symptoms. CONCLUSION This study confirms a high prevalence of respiratory and esophageal morbidity. In terms of respiratory function, the high proportion with a spirometric abnormality indicated an associated developmental delay/dysfunction in the central airways, whereas the peripheral airways appeared to have normal function at this age. Tracheomalacia may explain the spirometric abnormalities, but this need to be studied in more detail.

Treatment and Follow-Up of Patients with Long-Gap Esophageal Atresia: 15 Years' of Experience from the Western Region of Sweden.

OBJECTIVE This retrospective study aims to report treatment results in patients with long-gap esophageal atresia (LGEA), gross A + B type, and discuss the value of different clinical findings and physiological tests in the follow-up. METHODS This retrospective observational study comprises all patients with LGEA admitted to our department between 1995 and 2010. RESULTS A total of 16 patients were included. Their mean gestational age was 35(+2) weeks and their mean birth weight was 1,945 g (-2.5 standard deviation scores). No catch-up growth in height could be seen and they remained smaller than the average population during the study period. Gastrostomy was performed as the first surgical procedure. Overall, 11 of the 16 patients had a delayed primary anastomosis. Elongation of the distal esophageal segment was required in 3 of the 16 patients and a colonic interposition in 2 of the 16 patients. The median age at definitive surgery was 150 days. All the patients had gastroesophageal reflux after their definitive surgery. Three of the 16 patients required surgery due to aspiration and all 3 had a pathological lung clearance index (LCI) at multiple-breath washout (MBW). At the age of 1 or 7 years, the LCI was pathological in 4 of the 14 patients, and spirometry showed an obstruction in 9 of the 14 patients. CONCLUSION LGEA is a severe congenital malformation, with severe morbidity. No mortality was seen. MBW could be a useful tool for the early detection of progressive pulmonary damage.

RESECTION + CAROTID FLAP PLASTY A New Surgical Technique for Newborn Children with Coarctation of the Aorta and Critical Hypoplasia of the Aortic Arch

Coarctation of the aorta with critical hypoplasia of the aortic arch is a ductus dependent malformation-complex often combined with severe intracardiac malformations with a common denominator: there is a predominance of the pulmonary circulation and a flow restriction through the ascending aorta. Coarctation of the aorta with critical hypoplasia of the aortic arch may be looked upon as a malformation bordering on hypoplastic left heart syndrome. The degree of aortic arch hypoplasia seems to mirror the severity of the intracardiac malformation. The first objective in reconstructing these hearts is to create an unobstructed flow through the aortic arch. Resection of the coarcted segment combined with carotid flap plasty is a surgical alternative which fulfils this objective. We have used the technique in premature-born and severely ill neonates where one-step total correction was considered contraindicated. Thirteen neonates were operated upon, there were no cerebral consequences referable to the carotid artery ligation and no recoarctations.

The effect of prolonged perfusion with a membrane oxygenator (PPMO) on white blood cells

Preserving the rheological properties of whole blood cells is vital for their smooth passage in the capillaries without causing blockage and disturbances in the microcirculation. To evaluate the effect of mechanical trauma on the rheology of white blood cells during prolonged perfusion with membrane oxygenation (PPMO), 16 in vitro experiments were conducted for 72 hours. The St George Carrimed Filtrometer was used to estimate the plasma white cell filtration rates (P-WFR). Also an in vitro estimation of the ability of individual cells to pass through capillaries, the white blood cell clogging rate (WBC-CR), the number of clogging particles (WBC-CP), the total white blood cell count (T-WBC) and two in vitro estimations to assess the effect of aggregates and stiff cells in blocking the microcirculation were performed. The traumatized white cells reduced their mean P-WFR by 37% ± 9, 72% ± 2 and 76% ± 2 at 24, 48 and 72 hours respectively (p < 0.001). The mean WBC-CR was increased to 15.2 ± 1.5, 32.6 ± 2.2 and 40.3 ± 8.3 x 102%/ml at 24, 48 and 72 hours respectively (p < 0.001). The mean WBC-CP was increased to 6.6 ± 1.5, 9.7 ± 1.2 and 13.9 ± 2.1 x 106/ml at 24 hours (p < 0.05), 48 and 72 hours respectively (p < 0.001). The T-WBC was decreased to 55% ± 0.3, 23% ± 0.2 and 14% ± 0.1 at 24,48 and 72 hours respectively (p < 0.001). This study showed a serious loss in white cell rheology during PPMO, which may contribute to the plugging effect of the microvessels in clinical use and may explain the organ dysfunction seen during ECMO on the basis of inadequate tissue oxygenation and nutrition due to areas of reduced perfusion, which results in increased frequency of morbidity.

Macrophage Phenotype Is Associated With the Regenerative Response in Experimental Replacement of the Porcine Esophagus

A porcine model for bridging circumferential defects in the intrathoracic esophagus has been developed in order to improve the treatment of children born with long-gap esophageal atresia. The aim of this study was to identify factors beneficial for tissue regeneration in the bridging area in this model and to describe the histological progression 20 days after replacement with a silicone-stented Biodesign mesh. Resection of 3 cm of intrathoracic esophagus and replacement with a bridging graft was performed in six newly weaned piglets. They were fed through a gastrostomy for 10 days, and then had probe formula orally for another 10 days prior to sacrifice. Two out of six piglets had stent loss prior to sacrifice. In the four piglets with the stent in place, a tissue tube, with visible muscle in the wall, was seen at sacrifice. Histology showed that the wall of the healing area was well organized with layers of inflammatory cells, in-growing vessels, and smooth muscle cells. CD163+ macrophages was seen toward the esophageal lumen. In the animals where the stent was lost, the bridging area was narrow, and histology showed a less organized structure in the bridging area without the presence of CD163+ macrophages. This study indicates that regenerative healing was seen in the porcine esophagus 20 days after replacement of a part of the intrathoracic esophagus with a silicone-stented Biodesign mesh, if the bridging graft is retained. If the graft is lost, the inflammatory pattern changes with invasion of proinflammatory, M1 macrophages in the entire wall, which seems to redirect the healing process toward scar formation.