Trygve Sjöberg

Transplantation of lungs from a non-heart-beating donor

BACKGROUND In animals, we have previously done successful lung transplantations using organs from non-heart-beating donors. We have also developed an ex-vivo system of assessing the function of such organs before transplantation. The next stage was to try the technique in human beings. Bearing in mind the sensitive ethical issues involved, our first aim was to find out what procedures would be acceptable, and to use the results to guide a clinical lung transplantation from a non-heart-beating donor. METHODS The ethical acceptability of the study was gauged from the results of a broad information programme directed at the general public in Sweden, and from discussions with professionals including doctors, nurses, hospital chaplains, and judges. The donor was a patient dying of acute myocardial infarction in a cardiac intensive-care unit after failed cardiopulmonary resuscitation. The next of kin gave permission to cool the lungs within the intact body, and intrapleural cooling was started 65 min after death. Blood samples were sent for virological testing and cross matching. The next of kin then had time to be alone with the deceased. After 3 h, the body was transported to the operating theatre and the heart-lung block removed. The lungs were assessed ex vivo, and the body was transported to the pathology department for necropsy. RESULTS No contraindications to transplantation were found, and the right lung was transplanted successfully into a 54-year-old woman with chronic obstructive pulmonary disease. The donor lung showed excellent function only 5 min after reperfusion and ventilation, and during the first 5 months of follow-up, the function of the transplanted lung has been good. INTERPRETATION About half the deaths in Sweden are caused by cardiac and cerebrovascular disease. This group could be a potential source of lung donors. When all hospitals and ambulance personnel in Sweden have received training in non-heart-beating lung donation, we hope that there will be enough donor lungs of good quality for all patients needing a lung transplant.

The critical importance of minimal delay between chest compressions and subsequent defibrillation: a haemodynamic explanation

Outcome after prehospital defibrillation remains dire. The aim of the present study was to elucidate the pathophysiology of cardiac arrest and to suggest ways to improve outcome. Ventricular fibrillation (VF) was induced in air-ventilated pigs, after which ventilation was withdrawn. After 6.5 min of VF, ventilation with 100% oxygen was initiated. In six pigs (group I), defibrillation was the only treatment carried out. In another six pigs (group II), mechanical chest compression-decompression CPR (mCPR) was carried out for 3.5 min followed by a 40-s hands-off period before defibrillation. If unsuccessful, mCPR was resumed for a further 30 s before a second or a third, 40-s delayed, shock was given. In a final six pigs (group III) mCPR was applied for 3.5 min after which up to three shocks (if needed) were given during on-going mCPR. Return of spontaneous circulation (ROSC) occurred in none of the pigs in group I (0%), in 1 of six pigs in group II (17%) and in five of six pigs in group III (83%). During the first 3 min of VF arterial blood was transported to the venous circulation, with the consequence that the left ventricle emptied and the right ventricle became greatly distended. It took 2 min of mCPR to establish an adequate coronary perfusion pressure, which was lost when the mCPR was interrupted. During 30 s of mCPR coronary perfusion pressure was negative, but a carotid flow of about 25% of basal value was obtained. In this pig model, VF caused venous congestion, an empty left heart, and a greatly distended right heart within 3 min. Adequate heart massage before and during defibrillation greatly improved the likelihood of return of spontaneous circulation (ROSC).

Evaluation of LUCAS, a new device for automatic mechanical compression and active decompression resuscitation.

LUCAS is a new gas-driven CPR device providing automatic chest compression and active decompression. In an artificial thorax model, superior pressure and flow were obtained with LUCAS compared with manual CPR. In a randomized study on pigs with induced ventricular fibrillation significantly higher cardiac output, carotid artery blood flow, end-tidal CO(2), intrathoracic decompression-phase aortic- and coronary perfusion pressures were obtained with LUCAS-CPR (83% ROSC) compared to manual CPR (0% ROSC). In normothermic fibrillating pigs, the ROSC rate was 100% after 15 min and 38% after 60 min of LUCAS-CPR (no drug treatment). The ROSC rate increased to 75% if surface cooling to 34 degrees C was applied during the first 30 min of the 1-h resuscitation period. Experience with the first 20 patients has shown that LUCAS is light (6.5 kg), easy to handle, quick to apply (10-20 s), maintains a correct position, and works optimally during transport both on stretchers and in ambulances. In one hospital patient with a witnessed asystole where manual CPR failed, LUCAS-CPR achieved ROSC within 3 min. One year later the patients mental capacity was fully intact. To conclude, LUCAS-CPR gives significantly better circulation during ventricular fibrillation than manual CPR.

Transplantation of lungs from non–heart-beating donors after functional assessment ex vivo

BACKGROUND If lungs from patients dying of heart attacks are to serve as donor organs in a safe way, their function should be properly assessed before transplantation. The aim of this study was to investigate donor lung function evaluation in a realistic large animal model. METHODS Twelve 60-kg pigs were used. Five minutes after ventricular fibrillation was induced, cardiopulmonary resuscitation was initiated and maintained for 20 minutes. After a 10-min hands-off period, heparin was administered through a central venous catheter followed by 20 chest compressions. Intrapleural cooling was initiated after 65 minutes of warm ischemia. Cooling proceeded for 6 hours within the cadaver, after which lung function was assessed ex vivo. Recipient pigs underwent left lung transplantation followed by right pneumonectomy, thus making these animals 100% dependent for their survival on the function of the donor lungs. RESULTS The assessment showed that all lungs had adequate function to serve as donor lungs. All recipient animals were in good condition during the 24-hour observation period after the operation. The blood gas function did not differ significantly from that in the healthy donor animals before induction of ventricular fibrillation; pulmonary vascular resistance was within normal range. CONCLUSIONS Lungs from non-heart-beating donors topically cooled in situ for 6 hours after 65 minutes of warm ischemia were assessed ex vivo and found to have normal function. They were then transplanted and retained normal function during a 24-hour observation period.

Clinical transplantation of initially rejected donor lungs after reconditioning ex vivo.

BACKGROUND A major problem in clinical lung transplantation is the shortage of donor lungs. Only about 20% of donor lungs are accepted for transplantation. A method to evaluate and recondition lungs ex vivo has been tested on donor lungs that have been rejected for transplantation. METHODS The donor lungs were reconditioned ex vivo in an extracorporeal membrane oxygenation (ECMO) circuit with STEEN solution (Vitrolife AB, Kungsbacka, Sweden) mixed with erythrocytes. The hyperoncotic solution dehydrates edematous lung tissue. Functional evaluations were performed with deoxygenated perfusate by varying the inspired fraction of oxygen. After the reconditioning, the lungs were kept immersed at 8 degrees C in extracorporeal membrane oxygenation until transplantation was performed. RESULTS Six of nine initially rejected donor lungs were reconditioned to acceptable function, and in six recipients, double lung transplantation was performed. Three-month survival was 100%. One patient has since died due to sepsis after 95 days, and one due to rejection after 9 months. Four recipients are alive and well without any sign of bronchiolitis obliterans syndrome 24 months after the transplantation. CONCLUSIONS The result from the present study is promising, and we continue to transplant reconditioned lungs.

Safe lung preservation for twenty-four hours with perfadex

The function of six porcine left lung allografts was studied after pulmonary (140 mL/kg) and bronchial (50 mL/kg) artery perfusion with Perfadex (Kabi Pharmacia, Uppsala, Sweden) at room temperature, followed by 24-hour storage of the lungs in an atelectatic state in 6 degrees to 8 degrees C Perfadex, which is a low-potassium-dextran solution. Left lung transplantation was done followed by right pneumonectomy, thereby making all the animals 100% dependent for their survival on the transplanted lungs. The pigs (mean weight = 56 kg, range = 51 to 58 kg, n = 18; 6 donors, 6 recipients, and 6 sham operated) were ventilated with a volume-controlled ventilator (20 breaths/min, 500 mL tidal volume, 8 cm H2O positive end-expiratory pressure, inspired oxygen fraction = 0.5). All the transplanted animals were in good condition throughout the 24-hour observation period with arterial oxygen tensions around 25 kPa (188 mm Hg) and arterial carbon dioxide tensions around 5 kPa (38 mm Hg). The mean pulmonary arterial pressure was around 30 mm Hg, and the pulmonary vascular resistance around 500 dyn.s.cm-5; neither showed any tendency to change with time. After 24 hours the inspired oxygen fraction was increased to 1.0 and the arterial oxygen tension increased to 43.3 +/- 5 kPa (325 +/- 38 mm Hg) (mean +/- standard error of the mean; n = 6). A sham operation (bilateral thoracotomy, right pneumonectomy) was done in 6 pigs, which were followed up for 24 hours.(ABSTRACT TRUNCATED AT 250 WORDS)

Successful Transplantation of Lungs Topically Cooled in the Non–Heart-Beating Donor for 6 Hours

BACKGROUND The aim of this study was to transplant lungs that had been topically cooled in the non-heart-beating donor for 6 hours, using the most challenging evaluation method possible, namely single-lung transplantation followed by immediate contralateral pneumonectomy. METHODS Domestic pigs were used (6 donors and 6 recipients) with a mean body weight of 59 +/- 3 kg. Ventricular fibrillation was induced, and after 1 minute, cardiac massage was started and heparin (5 mg/kg body weight) was given via a central venous catheter. Cardiac massage was continued for 10 minutes, during which the pig was ventilated with 50% oxygen. The pleural cavities were opened and the tracheal tube disconnected from the ventilator, with the result that both lungs deflated. Saline slush was placed in both pleural cavities so that it completely covered the lungs. Within 40 minutes the lung core temperature was less than 10 degrees C, and it was kept around 8 degrees C for 6 hours by adjusting the amounts of ice slush. The left lung was then harvested and transplanted into a prepared recipient, followed by right pneumonectomy within 46 +/- 4 minutes, thus making the recipient pig 100% dependent on the transplanted cadaver lung. RESULTS The mean ischemic time for the cadaver lungs was 8 hours and 2 minutes (range, 7 hours and 25 minutes to 8 hours and 59 minutes). All animals remained in excellent condition throughout the 24-hour observation period, with arterial oxygen tensions of approximately 225 mm Hg, or 30 kPa (inspired oxygen fraction, 0.5). CONCLUSIONS Lungs from non-heart-beating donors may be used for transplantation if heparinization and topical cooling can be initiated within minutes of irreversible cardiac arrest.

High potassium contents in organ preservation solutions cause strong pulmonary vasocontraction

Euro-Collins (ECS) and UCLA-formula organ preservation solutions induced strong vasocontraction in porcine pulmonary arteries when studied in organ baths at temperatures of 37 degrees C and 30 degrees C. At 20 degrees C ECS induced a 30% contraction, but at 6 degrees C no contraction (n = 5) or a weak contraction (n = 1) was elicited. Neither prostaglandin E1 nor nifedipine caused any significant reduction of the vasocontraction elicited by ECS and UCLA. Krebs solution, enriched with potassium in amounts corresponding to those in ECS (115 mmol/L) or UCLA (30 mmol/L), induced vasocontraction comparing well with those induced by ECS or UCLA, indicating that it is the high potassium content that causes the vasocontraction. In a second experiment lung segments were stored at 4 degrees C for 9 hours in ECS, UCLA, or Krebs solution. Pulmonary arterial segments were then studied in organ baths at 37 degrees C. The choice of preservation solution did not significantly affect the contractile properties of potassium, noradrenaline, or the thromboxane mimic U-46619. To conclude, high potassium contents in organ preservation solutions induce strong pulmonary vasocontraction in lung temperatures greater than 20 degrees C but not in temperatures less than 10 degrees C. These vasocontractions are not significantly reduced by prostaglandin E1 or nifedipine. We suggest that the initial preservation solution used to cool down the lungs should contain 4 mmol/L or no potassium. When the lung temperature is less than 10 degrees C, a second perfusion might be done, and then a high potassium content (if thought to be essential) will not cause vasocontraction.

A Paleolithic diet confers higher insulin sensitivity, lower C-reactive protein and lower blood pressure than a cereal-based diet in domestic pigs

BackgroundA Paleolithic diet has been suggested to be more in concordance with human evolutionary legacy than a cereal based diet. This might explain the lower incidence among hunter-gatherers of diseases of affluence such as type 2 diabetes, obesity and cardiovascular disease. The aim of this study was to experimentally study the long-term effect of a Paleolithic diet on risk factors for these diseases in domestic pigs. We examined glucose tolerance, post-challenge insulin response, plasma C-reactive protein and blood pressure after 15 months on Paleolithic diet in comparison with a cereal based swine feed.MethodsUpon weaning twenty-four piglets were randomly allocated either to cereal based swine feed (Cereal group) or cereal free Paleolithic diet consisting of vegetables, fruit, meat and a small amount of tubers (Paleolithic group). At 17 months of age an intravenous glucose tolerance test was performed and pancreas specimens were collected for immunohistochemistry. Group comparisons of continuous variables were made by use of the t-test. P < 0.05 was chosen for statistical significance. Simple and multivariate correlations were evaluated by use of linear regression analysis.ResultsAt the end of the study the Paleolithic group weighed 22% less and had 43% lower subcutaneous fat thickness at mid sternum. No significant difference was seen in fasting glucose between groups. Dynamic insulin sensitivity was significantly higher (p = 0.004) and the insulin response was significantly lower in the Paleolithic group (p = 0.001). The geometric mean of C-reactive protein was 82% lower (p = 0.0007) and intra-arterial diastolic blood pressure was 13% lower in the Paleolithic group (p = 0.007). In evaluations of multivariate correlations, diet emerged as the strongest explanatory variable for the variations in dynamic insulin sensitivity, insulin response, C-reactive protein and diastolic blood pressure when compared to other relevant variables such as weight and subcutaneous fat thickness at mid sternum. There was no obvious immunohistochemical difference in pancreatic islets between the groups, but leukocytes were clearly more frequent in sampled pancreas from the Cereal group.ConclusionThis study in domestic pigs suggests that a Paleolithic diet conferred higher insulin sensitivity, lower C-reactive protein and lower blood pressure when compared to a cereal based diet.

Efficacy of topical cooling in lung preservation: is a reappraisal due?

The aim of the present study was to test the efficacy of topical cooling as the only viable lung preservation method using the most challenging evaluation method, namely single-lung transplantation followed by immediate contralateral pneumonectomy. Ten domestic pigs (5 donors and 5 recipients) with a mean body weight of 57 kg (range, 53 to 59 kg) were used. After we administered systemic heparin (4 mg/kg), the lungs were harvested and placed in an atelectatic state under cold (8 degrees to 9 degrees C) low-potassium-dextran solution for 12 hours. Left lung transplantation was then done in the recipient pig followed by right pneumonectomy, thus making the recipient 100% dependent on the transplanted donor lung. No operative mortality or morbidity occurred. All animals were in excellent condition throughout the 24-hour observation period. They had normal blood gases which did not differ significantly from the preoperative blood gases obtained from the 5 recipients before transplantation (ie, when they had their own two lungs). A moderate increase (p < 0.05) in pulmonary vascular resistance was seen as compared with sham-operated animals. To conclude, topical cooling to 8 degrees C provides excellent lung preservation for 12 hours in pigs. If similar results can be obtained with other species, the currently accepted 6-hour limit for safe clinical lung preservation may be extended to 12 hours. It seems also warranted to critically reconsider which factors, apart from cooling alone, actually contribute favorably to 12-hour lung preservation.