Dietrich E. Birnbaum

A new pumpless extracorporeal interventional lung assist in critical hypoxemia/hypercapnia*

Objective:Pump-driven extracorporeal gas exchange systems have been advocated in patients suffering from severe acute respiratory distress syndrome who are at risk for life-threatening hypoxemia and/or hypercapnia. This requires extended technical and staff support. Design:We report retrospectively our experience with a new pumpless extracorporeal interventional lung assist (iLA) establishing an arteriovenous shunt as the driving pressure. Setting:University hospital. Patients:Ninety patients with acute respiratory distress syndrome. Interventions:Interventional lung assist was inserted in 90 patients with acute respiratory distress syndrome. Measurements and Main Results:Oxygenation improvement, carbon dioxide elimination, hemodynamic variables, and the amount of vasopressor substitution were reported before, 2 hrs after, and 24 hrs after implementation of the system. Interventional lung assist led to an acute and moderate increase in arterial oxygenation (Pao2/Fio2 ratio 2 hrs after initiation of iLA [median and interquartile range], 82 mm Hg [64–103]) compared with pre-iLA (58 mm Hg [47–78], p < .05). Oxygenation continued to improve for 24 hrs after implementation (101 mm Hg [74–142], p < .05). Hypercapnia was promptly and markedly reversed by iLA within 2 hrs (Paco2, 36 mm Hg [30–44]) in comparison with before (60 mm Hg [48–80], p < .05], which allowed a less aggressive ventilation. For hemodynamic stability, all patients received continuous norepinephrine infusion. The incidence of complications was 24.4%, mostly due to ischemia in a lower limb. Thirty-seven of 90 patients survived, creating a lower mortality rate than expected from the Sequential Organ Failure Assessment score. Conclusions:Interventional lung assist might provide a sufficient rescue measure with easy handling properties and low cost in patients with severe acute respiratory distress syndrome and persistent hypoxia/hypercapnia.

Role of apoptosis in myocardial stunning after open heart surgery

BACKGROUND Myocardial preservation during open heart surgery is a subject of intense investigation. A prerequisite for further improvement is a better understanding of the underlying pathophysiologic mechanisms responsible for postoperative myocardial stunning. In this report, we analyzed the role of apoptosis in myocardial stunning. METHODS Myocardial samples were obtained from 11 patients undergoing elective coronary artery bypass grafting before (control) and after cardioplegic arrest and reperfusion. Specimens were examined for apoptosis by electron microscopy, in situ end-labeling of DNA fragments, and biochemically for mitochondrial cytochrome c release. RESULTS Electron microscopy revealed condensation and margination of nuclear chromatin after surgery, as well as swelling and membrane rupture in mitochondria of single myocytes surrounded by healthy cells. TUNEL-positive cells were also found. Cytochrome c release, an initial step in apoptosis, revealed a 3.4 +/- 0.4-fold increase during surgery (p < 0.0001). Furthermore, cytochrome c release from otherwise intact mitochondria showed a negative correlation with left ventricular function and a positive correlation with the duration of cardioplegic arrest and reperfusion (p < 0.05). CONCLUSIONS Our data demonstrate that programmed cell death is evident early after open heart surgery and correlates with declining cardiac contractility. We conclude that apoptosis may be an important mechanism in postoperative myocardial stunning.

Pumpless extracorporeal lung assist – experience with the first 20 cases

OBJECTIVE Long-term extracorporeal lung assist is limited by a significant mechanical blood trauma resulting in bleeding and hemolysis. To reduce the drawbacks of extracorporeal lung assist a new technique has been developed, by which the driving force for the extracorporeal circuit derives from the patients arterio-venous pressure gradient (pumpless extracorporeal lung assist). The aim of this clinical study was to test the feasibilty and effectiveness of pumpless extracorporeal lung assist in patients with acute respiratory distress syndrome. METHODS Twenty patients (41+/-16 years) with acute respiratory distress syndrome of various causes and failing respirator therapy were enrolled. The minimum hemodynamic requirements included a cardiac output (CO) >6 l/min and mean arterial pressure (MAP) >70 mmHg. Pumpless extracorporeal lung assist was established using a short circuit arterio-venous shunt including a special designed low-resistance membrane oxygenator which was placed between the patients legs. RESULTS At the time of inclusion FiO(2) in all patients was 1.0 (paO(2) 45.9+/-7 mmHg, paCO(2) 58.9+/-17 mmHg). After 24 h of pumpless extracorporeal lung assist FiO(2) was reduced to 0.8+/-0.1. A significant improvement in oxygenation (paO(2) 84.1+/-21 mmHg, P<0.05) and CO(2) removal (paCO(2) 32.7+/-5 mmHg, P<0.05) was notable. The mean extracorporeal flow was 2.6+/-0.6 l/min, which represented approximately 25% of the patients mean CO (10.8+/-2 l/min). The median assist time was 12+/-8 (1-32) days. Fifteen out of twenty patients were weaned off pumpless extracorporeal lung assist. Five out of twenty patients died while on the system (four sepsis, one ventricular fibrillation). Three out of twenty patients died after successful weaning on day 8, 30, and 50, respectively. Twelve out of twenty patients were discharged in a healthy state (overall survival 60%). Technical problems included thrombosis of the venous cannula (n=5), thrombus formation within the membrane oxygenator (n=2), membrane oxygenator plasma leakage (n=2), and membrane oxygenator contamination with Candida albicans. No bleeding complication was observed. CONCLUSION Pumpless extracorporeal lung assist is feasible and effective in a selected group of patients with acute respiratory distress syndrome but preserved hemodynamic function. By eliminating the pump and reducing the tubing length blood trauma can be minimized. Being very simple the system entails fewer risks of technical complications and also facilitates nursing care.

Ascending aortic aneurysm associated with bicuspid and tricuspid aortic valve: involvement and clinical relevance of smooth muscle cell apoptosis and expression of cell death-initiating proteins

OBJECTIVE There is relationship between a dilated ascending aorta and a bicuspid aortic valve. Controversy exists concerning techniques available for surgical restoration of the functional and anatomical integrity of the aortic root. The present study was undertaken to define the histopathologic and molecular biologic condition of ascending aortic aneurysms associated with bicuspid (BAV) or tricuspid aortic valve (TAV) and the relationship to valve sparing or pulmonary autograft procedures. METHODS Aortic aneurysm wall specimens from 20 patients (10 BAV; 10 TAV) undergoing elective repair and normal aortic tissues from organ donors (n=5) were analysed for patterns of smooth muscle cells (SMCs) and infiltrating leukocytes (immunohistochemistry), apoptosis (in situ end-labelling of DNA-fragments (TUNEL)), and expression of the death-promoting proteins perforin, Fas, and FasLigand (Immunoblotting). RESULTS Segments from aneurysms exhibited a distinct pattern of medial destruction, elastic fragmentation, and disorientation with rarefication of SMCs. BAV wall segments contained more cells bearing markers of apoptosis than TAV specimens whereas normal aorta displayed only few apoptotic cells (P<0.05). TUNEL showed higher levels of DNA fragmentation in BAV than in TAV, and double immunostaining identified SMCs as the principal cell type displaying fragmented DNA. Immunohistochemistry confirmed expression of death-promoting mediators by infiltrating lymphocytes, and Western blotting documented their presence in BAV and TAV aneurysmal tissue, with the greatest increases seen in specimens from aneurysms associated with BAV. CONCLUSIONS There is evidence for a molecular link between SMC apoptosis initiated by infiltration and local signal expression of immune cells and weakening of the aortic wall being more prevalent in patients with BAV. Our findings may suggest a mechanism responsible for aneurysm formation of the aorta and aortic dilatation after autograft root or sinus remodelling procedures.

The heart produces but the lungs consume proinflammatory cytokines following cardiopulmonary bypass

OBJECTIVE Proinflammatory cytokines, such as interleukin-6 (IL-6), and soluble adhesion molecules, such as E-selectin, may play an important role in patient response to cardiopulmonary bypass (CPB). We sought to define whether the heart and the lungs serve as important sources of these inflammatory mediators under clinical conditions of myocardial revascularization using CPB and cardioplegic arrest. METHODS Plasma levels of IL-6 and E-selectin were measured in coronary sinus (CS), arterial, pulmonary arterial (PA) and left atrial (LA) blood samples taken from 12 consecutive patients (68.3 +/- 11 years; five females) undergoing coronary artery bypass grafting (CABG). Blood samples were collected preoperatively, after reperfusion, and 1, 6, 12 and 18 h following surgery. CS and LA blood was drawn using transcutaneous catheters. PA artery blood was obtained through a Swan-Ganz catheter. Cytokine levels were determined by standard enzyme linked immunosorbent assay (ELISA) technique. RESULTS A mean of 3.8 +/- 1 coronary anastomoses were performed. The CPB time and aortic X-clamp time were 91 +/- 15 and 45 +/- 10 min, respectively. IL-6 levels increased significantly after CPB and peaked 6 h postoperatively. There was also a significant increase of E-selectin levels with an onset at 1 h and a peak at 12 h postoperatively. At all time points the IL-6 and E-selectin concentrations were significantly higher in the CS than in arterial blood. In contrast, the levels of both mediators measured in the LA were significantly lower than those in the PA. CONCLUSION The reperfusion of ischemic myocardium during CABG results in a significant increase in plasma levels of IL-6 and E-selectin. Our data indicate that the myocardium, but not the lungs, is a predominant source of IL-6 and E-selectin release following CPB. The lungs may consume rather than release those mediators during reperfusion. Not the CPB per se, but the myocardial ischemia seems to be crucial in the pathogenesis of the inflammatory response observed following open heart surgery.

Endothelial apoptosis is induced by serum of patients after cardiopulmonary bypass.

OBJECTIVE Increased serum levels of a multitude of mediators like interleukins, tumor necrosis factor, elastase, adhesion molecules, and endotoxin have been described following cardiopulmonary bypass (CPB). The biological consequences of this complex response are unclear. METHODS Serum samples of nine patients scheduled for elective coronary artery bypass grafting were obtained preoperatively and 1, 6, and 12 h after weaning from CPB. Additional serum samples were obtained perioperatively from four patients undergoing major lung resection and from four healthy volunteers. The apoptosis-inducing activity of serum samples on endothelial cells was examined using a tissue culture assay system. Endothelial cells were derived from human umbilical cords and incubated for 48 h with serum samples in various dilutions during their second passage. The culture plates were fixed with methanol/acetone and stained with the DNA dye diamidinophenylindole. Apoptotic and normal cells were identified and counted using phase contrast and fluorescence microscopy. RESULTS The proportion of apoptotic endothelial cells was 5.6-fold higher in culture plates incubated with diluted (30%) serum samples obtained at 6 h after weaning from CPB when compared to plates incubated with preoperative samples (P=0.0077). A smaller effect occurred already at 1 h in some patients, whereas at 12 h after weaning from CPB no increased endothelial apoptosis was observed. No proapoptotic activity was found in preoperative as well as in control samples from patients undergoing lung resection or from healthy volunteers. CONCLUSIONS Serum of patients after CPB exerts a strong apoptosis inducing activity on human endothelial cells. Apoptotic death of endothelial cells following CPB may be responsible for postoperative vascular and bypass dysfunction including phenomena like increased capillary permeability.

Influence of Inflow Cannula Length in Axial-flow Pumps on Neurologic Adverse Event Rate: Results From a Multi-center Analysis

BACKGROUND The application of axial-flow pumps in patients with end-stage heart failure reveals a significantly reduced infectious complication rate as compared with rates observed with pulsatile devices. The remaining adverse event rate relates mainly to thromboembolic complications with neurologic consequences. We investigated the dependence of the neurologic adverse event rate on the length of the inflow cannula. METHODS A total of 216 consecutive patients with an axial-flow pump (INCOR; Berlin Heart GmbH, Berlin, Germany) were included in a retrospective multi-center analysis. In 138 patients, a short inflow cannula (24-mm tip length into the left ventricle), and in 78 patients a long inflow cannula (tip length 34 mm) was applied. RESULTS Patients with a long inflow cannula (LC) demonstrated a better survival rate than those with a short inflow cannula (SC) at the end of the observation period (LC, 63.4%; SC, 52.9%; p = 0.05). The thromboembolic adverse event rate was also significantly lower. Only 3 of the 78 patients (3.8%) with an LC had a thromboembolic adverse event (thromboembolic events per patient-year = 0.11) as compared with 32 (23.2%) of SC patients (thromboembolic events per patient-year = 0.50, p < 0.001). CONCLUSIONS Patients with a long inflow cannula had a better survival rate and a lower incidence of cerebrovascular adverse events than patients with a short inflow cannula.

Deep hypothermia and circulatory arrest for surgery of complex intracranial aneurysms.

OBJECTIVE Some intracranial aneurysms may not be operable by conventional neurosurgery due to their location or morphology. Cardiopulmonary bypass (CPB) and deep hypothermic circulatory arrest renders surgery of these complex aneurysms possible. Brain temperatures can be measured directly in this setting. METHODS Eight patients with complex intracranial aneurysms were operated on with the aid of CPB. Femoro-femoral bypass with heparin-coated circuit components was used in all cases. Venous drainage was augmented by a centrifugal pump in six patients and by a newly developed vacuum technique in two patients. Temperatures were monitored by probes in brain, tympanum, nasopharynx, bladder, rectum, arterial and venous blood. These measurements were recorded on-line together with those of cerebral oxygen saturation, AP, CVP and PAP. Blood gas analyses and an EEG were also performed continuously. RESULTS Outcome was excellent in seven patients, in one patient moderate neurological disability occurred. Mean time on cardiopulmonary bypass was 160 (117-215) min, for cooling to a brain temperature of 18 degrees C 33 (20-47) min, and for total circulatory arrest 27 (15-45) min. Additionally, terminal brain arteries were clamped for up to 68 min in four patients. No cardiac complications were observed. Actual brain temperatures were best reflected by the tympanum probes (max. deviation 2 degrees C), whereas temperatures measured in bladder or rectum exhibited deviations of up to 10 degrees C. EEG activities were arrested between brain temperatures of 19 and 26 degrees C. CONCLUSIONS Complex intracranial aneurysms can be treated successfully using deep hypothermic circulatory arrest. Extensive monitoring adds to the speed and safety of the procedure. The resulting comparative measurements of temperatures at different body sites including brain, EEG, and other variables may be of general relevance for operations employing deep hypothermia and circulatory arrest.

Induction of early immediate genes and programmed cell death following cardioplegic arrest in human hearts

OBJECTIVE Under experimental conditions cardiac stress may induce early immediate genes. Of these, heat shock proteins like hsp 70 have been linked to preconditioning and cellular salvage. Protooncogenes like c-fos and c-jun act as transcription factors for other genes and may be involved in the regulation of programmed cell death. METHODS Patients, 30, undergoing elective coronary artery bypass grafting, received either cold antegrade St. Thomas II or Bretschneider or Hamburg cardioplegic solutions with ten patients in each group. Tissue from right atria was removed before cardiopulmonary bypass and following cardioplegic arrest and reperfusion. Tissues were examined by Northern blots, immunohistochemistry, and in situ nick-end labeling of fragmented DNA as evidence for programmed cell death. RESULTS There were no significant preoperative or operative differences between groups. Following cardioplegia and reperfusion, a significant induction of both protooncogene and heat shock protein 70 mRNA was observed. Whereas levels of hsp 70 were increased about two-fold in all groups (P < 0.05), induction of c-fos and c-jun was most pronounced following the Hamburg cardioplegic solution (P < 0.05 versus baseline and for differences to other groups). Induction on the protein level was confirmed using immunohistochemistry that furthermore, identified cardiac myocytes and endothelial cells being the cell types that expressed these genes. In contrast to prebypass samples, in situ nick-end labeling of fragmented DNA following cardioplegic arrest and reperfusion was positive, preponderately in subendocardial myocytes and endothelial cells. CONCLUSIONS Cold cardioplegia is a potent stimulus for induction of the early immediate genes examined in human hearts. Increased expression of protooncogenes may be deleterious to cardiac myocytes as indicated by in situ nick-end labeling of DNA fragments. Differences in gene induction may add additional information for the evaluation of different cardioplegic strategies.

Outcome of Cardiopulmonary Resuscitation Following Open Heart Surgery

The outcome of cardiopulmonary resuscitation (CPR) following cardiac surgery is not known to date. A retrospective analysis of all patients subjected to CPR during their hospital stay following heart surgery was conducted; 1.4% of patients required CPR 0.5-192 h following surgery. The mean duration of CPR was 42 +/- 29 min. Twenty-nine patients were subjected to emergency rethoractomy and 14 patients received coronary artery bypass grafting. The hospital mortality was 46%. There was a significant correlation of duration of CPR and death (r = 0.44, p = 0.004). The commonest cause of death was consecutive multiorgan failure in 12 patients. Twenty-one patients were long-term survivors without neurological sequelae. Twenty patients were in NYHA class I or II. Ventricular fibrillation and myocardial ischaemia are the commonest conditions leading to CPR in an average population of patients immediately after cardiac surgery. Aggressive treatment and emergency rethoracotomy in most cases results in long-term survival in 50%.