Lars Algotsson

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.

Effects of vacuum‐assisted closure therapy on inguinal wound edge microvascular blood flow

Vacuum‐assisted closure (VAC) therapy has been shown to facilitate wound healing. Data on the mechanisms are scarce, although beneficial effects on blood flow and granulation tissue formation have been presented. In the current study, laser Doppler was used to measure microvascular blood flow to an inguinal wound in pigs during VAC therapy (− 50 to − 200 mmHg), including consideration of the different tissue types and the distance from the wound edge. VAC treatment induced an increase in microvascular blood flow a few centimeters from the wound edge. The increase in blood flow occurred closer to the wound edge in muscular as compared to subcutaneous tissue (1.5 cm and 3 cm, at − 75 mmHg). In the immediate proximity to the wound edge, blood flow was decreased. This hypoperfused zone was increased with decreasing pressure and was especially prominent in subcutaneous as compared to muscular tissue (0–1.9 cm vs. 0–1.0 cm, at − 100 mmHg). When VAC therapy was terminated, blood flow increased multifold, which may be due to reactive hyperemia. In conclusion, VAC therapy affects microvascular blood flow to the wound edge and may thereby promote wound healing. A low negative pressure during treatment may be beneficial, especially in soft tissue, to minimize possible ischemic effects. Intermittent VAC therapy may further increase blood flow.

Acute right ventricular failure—from pathophysiology to new treatments

The right ventricle (RV) provides sustained low-pressure perfusion of the pulmonary vasculature, but is sensitive to changes in loading conditions and intrinsic contractility. Factors that affect right ventricular preload, afterload or left ventricular function can adversely influence the functioning of the RV, causing ischaemia and right ventricular failure (RVF). As RVF progresses, a pronounced tricuspid regurgitation further decreases cardiac output and worsens organ congestion. This can degenerate into an irreversible vicious cycle.The effective diagnosis of RVF is optimally performed by a combination of techniques including echocardiography and catheterisation, which can also be used to monitor treatment efficacy. Treatment of RVF focuses on alleviating congestion, improving right ventricular contractility and right coronary artery perfusion and reducing right ventricular afterload. As part of the treatment, inhaled nitric oxide or prostacyclin effectively reduces afterload by vasodilating the pulmonary vasculature. Traditional positive inotropic drugs enhance contractility by increasing the intracellular calcium concentration and oxygen consumption of cardiac myocytes, while vasopressors such as norepinephrine increase arterial blood pressure, which improves cardiac perfusion but increases afterload. A new treatment, the calcium sensitiser, levosimendan, increases cardiac contractility without increasing myocardial oxygen demand, while preserving myocardial relaxation. Furthermore, it increases coronary perfusion and decreases afterload. Conversely, traditional treatments of circulatory failure, such as mechanical ventilation and volume loading, could be harmful in the case of RVF. This review outlines the pathophysiology, diagnosis and treatment of RVF, illustrated with clinical case studies.

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.

A Pilot Study of Rapid Cooling by Cold Saline and Endovascular Cooling Before Reperfusion in Patients With ST-Elevation Myocardial Infarction

Background—Experimental studies have shown that induction of hypothermia before reperfusion of acute coronary occlusion reduces infarct size. Previous clinical studies, however, have not been able to show this effect, which is believed to be mainly because therapeutic temperature was not reached before reperfusion in the majority of the patients. We aimed to evaluate the safety and feasibility of rapidly induced hypothermia by infusion of cold saline and endovascular cooling catheter before reperfusion in patients with acute myocardial infarction. Methods and Results—Twenty patients with acute myocardial infarction scheduled to undergo primary percutaneous coronary intervention were enrolled in this prospective, randomized study. After 4±2 days, myocardium at risk and infarct size were assessed by cardiac magnetic resonance using T2-weighted imaging and late gadolinium enhancement imaging, respectively. A core body temperature of <35°C (34.7±0.3°C) was achieved before reperfusion without significant delay in door-to-balloon time (43±7 minutes versus 40±6 minutes, hypothermia versus control, P=0.12). Despite similar duration of ischemia (174±51 minutes versus 174±62 minutes, hypothermia versus control, P=1.00), infarct size normalized to myocardium at risk was reduced by 38% in the hypothermia group compared with the control group (29.8±12.6% versus 48.0±21.6%, P=0.041). This was supported by a significant decrease in both peak and cumulative release of Troponin T in the hypothermia group (P=0.01 and P=0.03, respectively). Conclusions—The protocol demonstrates the ability to reach a core body temperature of <35°C before reperfusion in all patients without delaying primary percutaneous coronary intervention and that combination hypothermia as an adjunct therapy in acute myocardial infarction may reduce infarct size at 3 days as measured by MRI. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00417638.

Levosimendan : molecular mechanisms and clinical implications: consensus of experts on the mechanisms of action of levosimendan

The molecular background of the Ca(2+)-sensitizing effect of levosimendan relates to its specific interaction with the Ca(2+)-sensor troponin C molecule in the cardiac myofilaments. Over the years, significant preclinical and clinical evidence has accumulated and revealed a variety of beneficial pleiotropic effects of levosimendan and of its long-lived metabolite, OR-1896. First of all, activation of ATP-sensitive sarcolemmal K(+) channels of smooth muscle cells appears as a powerful vasodilator mechanism. Additionally, activation of ATP-sensitive K(+) channels in the mitochondria potentially extends the range of cellular actions towards the modulation of mitochondrial ATP production and implicates a pharmacological mechanism for cardioprotection. Finally, it has become evident, that levosimendan possesses an isoform-selective phosphodiesterase-inhibitory effect. Interpretation of the complex mechanism of levosimendan action requires that all potential pharmacological interactions are analyzed carefully in the framework of the currently available evidence. These data indicate that the cardiovascular effects of levosimendan are exerted via more than an isolated drug-receptor interaction, and involve favorable energetic and neurohormonal changes that are unique in comparison to other types of inodilators.

Effects of nitrous oxide on human regional cerebral blood flow and isolated pial arteries.

BackgroundResults from previous studies on the effect of nitrous oxide (N2O) on the cerebral circulation are conflicting. Early reports claim N2O to have no effect whereas recent findings demonstrate a cerebral cortical vasodilatation during N2O inhalation, but the regional cerebral blood flow (CBF) in the subcortical structures is unknown. MethodsRegional CBF was measured three-dimensionally with single photon emission computer-aided tomography after injection of xenon 133 in 8 spontaneously breathing men (mean age 29.6 yr) during normocapnia and hypocapnia with and without inhalation of 50% N2O. 8 isolated human pial arterial segments were mounted in organ baths. The segments were contracted with prostaglandin F2α and subjected to 30% oxygen and 5.6% carbon dioxide in nitrogen or N2O. ResultsNormocapnic young men had a global CBF of 55 ± 4 ml · 100 g−1. min−1. Decreasing end-tidal CO2 tension by 1.3 kPa (9.3 mmHg) reduced CBF uniformly, with a decrease in global CBF to 45 ± 2 ml · 100 g−1. min−1 (P < 0.0001). During normocapnia, inhalation of 50% N2O increased mean CBF to 67 ± 7 ml · 100 g−1. min−1 (P < 0.0001). Inhalation of 50% N2O during hypocapnia increased mean CBF to 63 ± 5 ml · 100 g−1. min−1 (P < 0.0001). During N2O inhalation there was no significant difference in mean CBF between normo- and hypocapnia. However, during hypocapnia, but not during normocapnia, N2O inhalation significantly changed the distribution of regional CBF (P < 0.0001). Compared with hypocapnia without N2O, flow increased through the frontal (143%), parietal (140%) and temporal (133%) regions as well as through insula (151%), basal ganglia (145%) and thalamus (133%). In isolated human pial arteries, addition of N2O changed neither basal tension, nor the contraction elicited by prostaglandin F2α. ConclusionsInhalation of 50% N2O increased global CBF mainly by augmenting flow in frontal brain structures. In contrast, changes in carbon dioxide without N2O affected CBF uniformly in the brain. The uneven change in distribution of the CBF when N2O was added during hypocapnia, the reduced carbon dioxide response, and the lack of effect of N2O on isolated human pial arteries suggest that N2O may increase metabolism in selected brain areas.

The effect of vacuum-assisted closure therapy on the pig femoral artery vasomotor responses.

Vacuum‐assisted closure (VAC) is frequently used to treat wound infections. The aim of the present study was to evaluate the effect of VAC therapy on blood vessels. Vasodilatation and vasoconstriction were studied in isolated ring segments of the pig femoral artery after continuous VAC therapy of an inguinal wound for 12 hours. Vasoconstriction induced by endothelin‐1 (ET‐1), which is mainly an endothelin type A receptor agonist (Emax = 181 ± 2% of potassium), and the endothelin type B receptor agonist, sarafotoxin 6c (Emax = 30 ± 1%), were significantly increased after VAC therapy (ET‐1; 325 ± 3% and sarafotoxin 6c; 69 ± 1%). The norepinephrine‐, phenylephrine‐, and angiotensin II‐induced vasoconstrictions were not affected by VAC therapy. Acetylcholine induced an endothelium‐dependent dilatation that was enhanced after VAC therapy (Rmax = 38 ± 1% of norepinephrine‐preconstriction after sham and 47 ± 1% after VAC therapy, p < 0.05). The dilatory response was mediated by nitric oxide (Rmax = 39 ± 1%), prostaglandins (5 ± 1%) and endothelium‐derived hyperpolarizing factor (16 ± 1%), which were all significantly increased after VAC therapy. In conclusion, VAC therapy for 12  hours enhances an endothelin type A and type B receptor‐mediated vasoconstriction. This may be compensated for by a more efficacious endothelium‐dependent vasodilatation. No spontaneous bleeding, perforation, dissection, or other macroscopic change could be observed in the arteries exposed to VAC therapy.

Simultaneous transcranial Doppler sonography and cerebral blood flow measurements of cerebrovascular CO2-reactivity in patients with aneurysmal subarachnoid haemorrhage

Transcranial Doppler sonography (TCD) flow velocities and cerebral blood flow (CBF) measurements were evaluated in 14 patients who had suffered a major aneurysmal subarachnoid hemorrhage (SAH). Cerebrovascular reactivity to hypocapnia was evaluated simultaneously by the two methods. The measurements were performed under general anaesthesia preoperatively, within 72 hours after the bleed, during normocapnia and hypocapnia. There was poor correlation between absolute values of hemispheric CBF and corresponding TCD mean flow velocity. Controlled hyperventilation was associated with a significant decrease in CBF as well as TCD flow velocity (p less than 0.001). In terms of reactivity indices the correlation between the two methods was poor and not significant (r = 0.33, p = 0.09). The principal differences between the methods are discussed as well as the application of TCD in the evaluation of cerebrovascular reactivity.

Preoperative and perioperative use of levosimendan in cardiac surgery: European expert opinion

In cardiac surgery, postoperative low cardiac output has been shown to correlate with increased rates of organ failure and mortality. Catecholamines have been the standard therapy for many years, although they carry substantial risk for adverse cardiac and systemic effects, and have been reported to be associated with increased mortality. On the other hand, the calcium sensitiser and potassium channel opener levosimendan has been shown to improve cardiac function with no imbalance in oxygen consumption, and to have protective effects in other organs. Numerous clinical trials have indicated favourable cardiac and non-cardiac effects of preoperative and perioperative administration of levosimendan. A panel of 27 experts from 18 countries has now reviewed the literature on the use of levosimendan in on-pump and off-pump coronary artery bypass grafting and in heart valve surgery. This panel discussed the published evidence in these various settings, and agreed to vote on a set of questions related to the cardioprotective effects of levosimendan when administered preoperatively, with the purpose of reaching a consensus on which patients could benefit from the preoperative use of levosimendan and in which kind of procedures, and at which doses and timing should levosimendan be administered. Here, we present a systematic review of the literature to report on the completed and ongoing studies on levosimendan, including the newly commenced LEVO-CTS phase III study (NCT02025621), and on the consensus reached on the recommendations proposed for the use of preoperative levosimendan.