Armin Sablotzki

Clinical pharmacology of tramadol.

Tramadol, a centrally acting analgesic structurally related to codeine and morphine, consists of two enantiomers, both of which contribute to analgesic activity via different mechanisms. (+)-Tramadol and the metabolite (+)-O-desmethyl-tramadol (M1) are agonists of the μ. opioid receptor. (+)-Tramadol inhibits serotonin reuptake and (−)-tramadol inhibits norepinephrine reuptake, enhancing inhibitory effects on pain transmission in the spinal cord. The complementary and synergistic actions of the two enantiomers improve the analgesic efficacy and tolerability profile of the racemate.Tramadol is available as drops, capsules and sustained-release formulations for oral use, suppositories for rectal use and solution for intramuscular, intravenous and subcutaneous injection. After oral administration, tramadol is rapidly and almost completely absorbed. Sustained-release tablets release the active ingredient over a period of 12 hours, reach peak concentrations after 4.9 hours and have a bioavailability of 87–95% compared with capsules. Tramadol is rapidly distributed in the body; plasma protein binding is about 20%.Tramadol is mainly metabolised by O- and N-demethylation and by conjugation reactions forming glucuronides and sulfates. Tramadol and its metabolites are mainly excreted via the kidneys. The mean elimination half-life is about 6 hours.The O-demethylation of tramadol to M1, the main analgesic effective metabolite, is catalysed by cytochrome P450 (CYP) 2D6, whereas N-demethylation to M2 is catalysed by CYP2B6 and CYP3A4. The wide variability in the pharmacokinetic properties of tramadol can partly be ascribed to CYP polymorphism. O-and N-demethylation of tramadol as well as renal elimination are stereoselective. Pharmacokinetic-pharmacodynamic characterisation of tramadol is difficult because of differences between tramadol concentrations in plasma and at the site of action, and because of pharmacodynamic interactions between the two enantiomers of tramadol and its active metabolites.The analgesic potency of tramadol is about 10% of that of morphine following parenteral administration. Tramadol provides postoperative pain relief comparable with that of pethidine, and the analgesic efficacy of tramadol can further be improved by combination with a non-opioid analgesic. Tramadol may prove particularly useful in patients with a risk of poor cardiopulmonary function, after surgery of the thorax or upper abdomen and when non-opioid analgesics are contraindicated.Tramadol is an effective and well tolerated agent to reduce pain resulting from trauma, renal or biliary colic and labour, and also for the management of chronic pain of malignant or nonmalignant origin, particularly neuropathic pain. Tramadol appears to produce less constipation and dependence than equianalgesic doses of strong opioids.

Alterations of acute phase reaction and cytokine production in patients following severe burn injury

To determine the acute immunologic reaction, mediated by cytokines, interleukines (ILs) and growth factors and the susceptibility to infections and sepsis after severe burn injury a prospective, single unit, longitudinal study of acute phase reactants and mediators who performed. After approval by the ethics committee of our hospital, we investigated the plasma concentrations of IL-2, -6, -8, -10, and -13, the soluble IL-2 receptor (sIL-2R), and the acute phase proteins procalcitonin (PCT) and C-reactive protein (CRP) at admission and every 3 days in 24 patients over a time course of 28 days after thermal injury and categorized by percent burn: < or =30% (group 1; n=12) and >30% (group 2; n=12). Shortly after burn injury we found higher concentrations of IL-2, -6, -10 and PCT in those patients >30% TBSA. During the study period, we found significant higher levels of acute phase proteins, IL-6 and -8 in patients >30% TBSA. The incidence of SIRS and MODS was three times increased in patients >30% TBSA. Our results show different patterns of cytokines and acute phase proteins in patients with different burned surface areas over a long time and continuous monitoring of a more distinct inflammatory response in these patients.

The systemic inflammatory response syndrome following cardiac surgery: different expression of proinflammatory cytokines and procalcitonin in patients with and without multiorgan dysfunctions

Cardiopulmonary bypass is associated with an injury that may cause pathophysiological changes in the form of systemic inflammatory response syndrome (SIRS) or multiple organ dysfunction syndrome (MODS). In the present study, we investigated the inflammatory response of patients with multiple organ dysfunctions following open-heart surgery. Plasma levels of cytokines (IL-1β, IL-6, IL-8, IL-18) and procalcitonin (PCT) were measured on the first four postoperative days in 12 adult male patients with SIRS and two or more organ dysfunctions after myocar-dial revascularization (MODS group), and 15 patients without organ dysfunctions (SIRS group). All cytokines (except IL-1β) and PCT were significantly elevated in MODS patients, with peak values at the first two postoperative days. The results of our study show a different expression of members of the IL-1 family following extracorporeal circulation. For the first time, we can document that IL-18 is involved in the inflammatory response and the initiation of the MODS following cardiopulmonary bypass. In addition to APACHE-II score, PCT, IL-8, and IL-18 may be used as parameters for the prognosis of patients with organ dysfunctions after cardiac surgery. Furthermore, it must be noted that the duration of the surgical procedure is one of the most important factors for the initiation of the inflammatory response.

Pulmonary hypertension due to chronic lung disease: Updated Recommendations of the Cologne Consensus Conference 2011

The 2009 European Guidelines on Pulmonary Hypertension did not cover only pulmonary arterial hypertension (PAH) but also some aspects of pulmonary hypertension (PH) in chronic lung disease. These guidelines point out that the drugs currently used to treat patients with PAH (prostanoids, endothelin receptor antagonists and phosphodiesterase type-5 inhibitors) have not been sufficiently investigated in other forms of PH. Therefore, the use of these drugs in patients with chronic lung disease and PH is not recommended. This recommendation, however, is not always in agreement with medical needs as physicians feel sometimes inclined to also treat other forms of pulmonary hypertension which may affect the quality of life and survival of these patients in a similar manner as in PAH. In June 2010, a consensus conference was held in Cologne, Germany, to discuss open and controversial issues surrounding the practical implementation of the European Guidelines. The conference was sponsored by the German Society of Cardiology, the German Society of Respiratory Medicine and the German Society of Pediatric Cardiology (DGK, DGP and DGPK). To this end, a number of working groups were initiated, one of which was specifically dedicated to the diagnosis and treatment of PH due to chronic lung disease. This manuscript describes in detail the results and recommendations of this working group which were last updated in October 2011.

Hydroxyethyl starch (HES) does not directly affect renal function in patients with no prior renal impairment

STUDY OBJECTIVES To examine the effects of hydroxyethyl starch (HES) on renal function. DESIGN Randomized, controlled trial. SETTING Operating theatre of a university hospital. PATIENTS 60 ASA physical status I and II male patients undergoing middle ear surgery. INTERVENTIONS Patients received either lactated Ringers solution (LRS) or one of three HES solutions. The HES solutions were administered in a dose of 15 mL/kg bodyweight (bw), the Ringers solution in a dose of 60 mL/kg bw, after induction of anesthesia over a period of one hour. MEASUREMENTS Blood and urine samples for hormone and enzyme tests were obtained at defined times before, during, and after surgery. Urine excretion, glomerular filtration rate (GFR), renal plasma flow, and routine hemodynamic parameters were measured simultaneously. MAIN RESULTS There were no significant intergroup differences regarding GFR, renal plasma flow, or tubular and glomerular integrity as measured by specific proteins and enzymes (alpha-1-microglobulin, Tamm-Horsfall-protein, immunoglobulin G, and N-acetyl-beta-D-glucosaminidase). Arginine vasopressin decreased in all groups during and following anesthesia, aldosterone and plasma renin activity decreased only in the HES groups, and angiotensin II decreased only in the HES 200/0.5 group. Central venous pressure increased during fluid administration in the LRS group and returned to baseline sooner in the HES groups. CONCLUSIONS Hydroxyethyl starch administration appears to be risk-free with regard to renal function in patients without preexisting renal dysfunction who undergo general anesthesia. The relevance of the decrease in aldosterone following HES therapy needs further investigation.

Hemodynamic effects of inhaled aerosolized iloprost and inhaled nitric oxide in heart transplant candidates with elevated pulmonary vascular resistance

OBJECTIVE An elevated pulmonary vascular resistance (PVR) is described as a predictor of postoperative right heart failure and increased mortality in patients undergoing orthotopic heart transplantation. The use of intravenous vasodilators is limited by their systemic effects. We evaluated the pulmonary and systemic hemodynamic effects of inhaled nitric oxide (NO) and inhaled aerosolized iloprost (IP) in heart transplant candidates with elevated PVR. METHODS Fourteen male heart transplant candidates due to dilative or ischemic cardiomyopathia with elevated PVR (> or = 180 dyn s cm(-5)) were included in the study. Increasing concentrations of NO (5, 10 and 30 ppm) and 50 microg aerosolized IP were administered by inhalation. Hemodynamic measurements preceded and followed administration of each agent. RESULTS Inhalation of IP, 10, and 30 ppm NO reduced PVR and mean pulmonary artery pressure (MPAP), but did not affect blood pressure or systemic vascular resistance. Comparing the effectiveness of 10 ppm NO and IP, we found a significant higher reduction of MPAP in patients treated with IP. An increase of cardiac index and stroke index could only be shown with IP-inhalation. CONCLUSIONS Inhaled iloprost induces pulmonary vasodilation which is significantly greater than the effects of 10 and 30 ppm NO. The results of our study show, that inhaled iloprost induces a reliable hemodynamic response in the evaluation of heart transplant candidates. Further advantages of iloprost inhalation are the lack of adverse reactions and toxic side effects and an easier administration. Due to this facts we recommend iloprost as a routine screening drug for vascular reactivity in HTx-candidates. Based on our results it would be of great interest to investigate the role of iloprost in management of postoperative right heart insufficiency following cardiac transplantation.

Selective pulmonary vasodilation with inhaled aerosolized milrinone in heart transplant candidates

PurposeSelective pulmonary vasodilation is an advantageous method for testing the responsiveness of the pulmonary vasculature of heart transplant candidates. A pilot study was undertaken to test the hypothesis that inhaled aerosolized milrinone may cause selective pulmonary vasodilation.Methods18 consecutive male heart transplant candidates with either dilated or ischemic cardiomyopathy were included in this open clinical study. Nine of the patients had significant pulmonary hypertension with a mean pulmonary arterial pressure > 30 mmHg. After baseline measurements, 2 mg of milrinone was administered by ultrasonic nebulization. Pulmonary and systemic hemodynamics were measured ten, 30, and 60 min after inhalation.ResultsAfter inhalation for ten minutes, milrinone induced a significant reduction of mean pulmonary arterial pressure (32.7 ± 9.1vs 37.7 ± 7.5 mmHg,P = 0.01), pulmonary vascular resistance index (296 ± 150vs 396 ± 151 dyn·sec-1·cm-5·m2,P = 0.02) and transpulmonary gradient (10.6 ± 5.5vs 15 ± 4.9,P = 0.01) only in patients with significant pulmonary hypertension. There was no significant effect on mean arterial pressure or systemic vascular resistance at any time after inhalation in either group. Furthermore, there was no influence on extravascular lung water or intrathoracic blood volume.ConclusionsWe conclude that inhaled aerosolized milrinone for a short period selectively dilates the pulmonary vasculature in heart transplant candidates with elevated pulmonary arterial pressure, without producing systemic side effects. Further comparative studies are necessary to evaluate possible advantages of milrinone compared to other inhaled vasodilators.RésuméObjectifLa vasodilatation pulmonaire sélective permet de vérifier avantageusement la réactivité du système vasculaire pulmonaire des candidats à la greffe cardiaque. Nous avons vérifié si ľinhalation de milrinone en aérosol pouvait causer une vasodilatation pulmonaire sélective.MéthodeOnt été inclus dans notre étude clinique ouverte 18 hommes, candidats à la greffe cardiaque, atteints de cardiomyopathie de dilatation ou ischémique. Neuf ďentre eux présentaient une hypertension artérielle pulmonaire moyenne > 30 mmHg. Après les mesures de base, nous avons administré 2 mg de milrinone avec une nébulisation par ultrasons. Ľhémodynamique pulmonaire et générale ont été mesurées à 10, 30 et 60 min après ľinhalation.RésultatsAprès avoir été inhalée pendant 10 min, la milrinone a réduit significativement la tension artérielle pulmonaire moyenne (32,7 ± 9,1 vs 37,7 ± 7,5 mmHg, P = 0,01), ľindex de résistance vasculaire pulmonaire (296 ± 15 vs 396 ± 151 dyn·s-1·cm-5·m2,P = 0,02) et le gradient transpulmonaire (10,6 ± 5,5 vs 15 ± 4,9,P = 0,01) dans les cas ďhypertension artérielle pulmonaire significative. Après ľinhalation, il n’y a pas eu ďeffet significatif sur la tension artérielle moyenne ou la résistance vasculaire générale pour tous les temps de mesure chez les patients des deux groupes. Et, il n’y a pas eu ďinfluence sur le liquide pulmonaire extravasculaire ou le volume sanguin intrathoracique.ConclusionĽinhalation de milrinone en aérosol pendant une courte période produit une dilatation sélective du système vasculaire pulmonaire chez des candidats à la greffe cardiaque qui présentent une tension artérielle pulmonaire élevée, sans produire ďeffets secondaires généralisés. Il reste à évaluer les avantages possibles de la milrinone comparée à ďautres vasodilatateurs inhalés.

Iloprost improves hemodynamics in patients with severe chronic cardiac failure and secondary pulmonary hypertension

PurposeSignificant pulmonary hypertension is a predictor of postoperative right heart insufficiency and increased mortality in patients undergoing orthotopic heart transplantation. Since the use of iv vasodilators is limited by their systemic effects, we evaluated the pulmonary and systemic hemodynamic effects of inhaled aerosolized iloprost (IP) in heart transplant candidates with elevated pulmonary vascular resistance (PVR).MethodsTwenty-nine male heart transplant candidates because of dilated or ischemic cardiomyopathy with elevated PVR were included in the study. After assessing baseline hemodynamics, 50 μg aerosolized IP were administered by inhalation.ResultsInhalation of iloprost reduced PVR index (PVRI; 416 ± 180 vs 349 ± 173 dyn·sec−1·m−2·cm−5;P < 0.01) and mean pulmonary artery pressure (MPAP; 28.6 ± 9 vs 24.2 ± 9.1 mmHg;P < 0.01), but did not affect blood pressure or systemic vascular resistance. An additional improvement of ventricular performance with an increase of cardiac index (CI; 2.8 ± 0.7 vs 2.6 ± 0.7 L·min−1m−2;P < 0.05) and a decrease of pulmonary capillary wedge pressure (PCWP; 15.6 ± 6.8 vs 12.8 ± 7.1 mmHg;P < 0.01) was observed after inhalation of IPConclusionsInhaled aerosolized iloprost effectively reduces MPAP and is accompanied by an increase in CI and stroke index. Further advantages of iloprost inhalation are the lack of adverse reactions and ease of administration. Iloprost may be a useful drug to screen for vascular reactivity in cardiac transplantation patients.RésuméObjectifL’hypertension artérielle pulmonaire élevée est un prédicteur d’insuffisance postopératoire du cœur droit et elle accroît la mortalité des candidats à la transplantation cardiaque. L’usage des vasodilatateurs iv étant limité par leurs effets généraux, nous avons évalué les effets pulmonaires et généraux de l’iloprost (IP) en inhalation aérosol chez des candidats à la transplantation cardiaque présentant une résistance vasculaire pulmonaire élevée (RVP).MéthodeVingt-neuf hommes, candidats à une transplantation cardiaque à cause d’une cardiomyopathie dilatée ou ischémique et d’une RVP élevée, ont participé à l’étude. À la suite de l’évaluation hémodynamique de base, 50 μg d’IP en aérosol ont été administrés par inhalation.RésultatsL’inhalation d’iloprost a réduit l’index de RVP (IRVP; 416 ± 180 vs 349 ± 173 dyn·sec−1·m−2·cm−5; P < 0,01) et la pression artérielle pulmonaire moyenne (PAPM; 28,6 ± 9 vs 24,2 ± 9,1 mmHg; P < 0,01), mais n’a pas affecté la tension artérielle ou la résistance vasculaire générale. Une amélioration supplémentaire de la performance ventriculaire accompagnée d’une hausse de l’index cardiaque (IC; 2,8 ± 0,1 vs 2,6 ± 0,7 L·min−1·m−2; P < 0,05) ainsi qu’une baisse de la pression capillaire pulmonaire bloquée (PCPB; 15,6 ± 6,8 vs 12,8 ± 7,1 mmHg; P < 0,01) ont été observées après l’inhalation d’IPConclusionL’iloprost en aérosol administré par inhalation réduit efficacement la PAPM. Cet effet est accompagné d’une hausse de l’IC et de l’index systolique. Les autres avantages de l’inhalation d’iloprost sont l’absence de réactions indésirables et la facilité d’administration. L’iloprost pourrait servir au dépistage de la réactivité vasculaire chez les candidats à la transplantation cardiaque.

Alterations of the cytokine network in patients undergoing cardiopulmonary bypass.

Cardiovascular surgery using extracorporeal circulation causes a systemic inflammatory response which often results in severe organ dysfunction and increased postoperative mortality. Advances in knowledge about the interactions of cytokines involved in the response to cardiopulmonary bypass (CPB) may improve the outcome of patients undergoing cardiac surgery. The purpose of our study was to investigate the fluctuations in cytokine production, during and after CPB. In 24 patients undergoing elective coronary artery bypass grafting, plasma levels of interleukins IL-2, IL-6, IL-10 and IL-12, soluble IL-2-receptor (sIL-2R), and transforming growth factor-beta (TGF-β) were measured at eight time points before, during and after CPB, using a standardized enzyme-linked immunosorbant assay technique. There was a significant increase in plasma levels of IL-10, IL-6 and TGF-β after weaning off CPB. The IL-2 plasma levels decreased after the onset of CPB until 24 h postoperatively (p < 0.05). Concentrations of sIL-2R decreased 20 min after the start of CPB until the end of the operation (p < 0.05). In the postoperative course, sIL-2R levels increased, with peak values 48 h after the end of the surgical procedure. The IL-12 levels decreased after weaning off CPB (p < 0.05) until 6 h postoperatively. The results of our study demonstrate an intraoperative-predominant immunosuppression, followed by an early postoperative immunological activation, combined with a distinct acute phase response.

Ischemic pre-conditioning of 5 minutes but not of 10 minutes improves lung function after warm ischemia in a canine model☆

BACKGROUND Protection from reperfusion injury by ischemic pre-conditioning (IPC) before prolonged ischemia has been proven for the heart and the liver. We now assess the efficacy of IPC to protect lungs from reperfusion injury. METHODS Eighteen foxhounds (25 to 30 kg) were anesthetized, intubated, and ventilated with a fraction of inspired oxygen of 0.3 at a volume-controlled mode to maintain arterial pCO2 of 30 to 40 mm Hg. After left thoracotomy, we performed warm ischemia for 3 hours by clamping the left hilus, and followed with 8 hours of reperfusion (control, n = 6). In the treated groups, IPC was performed either for 5 minutes followed by 15-minute reperfusion (n = 6, IPC-5), or by 2 successive cycles of 10-minute ischemia, followed by 10-minute reperfusion (n = 6, IPC-10) before prior to the 3-hours warm-ischemia period. Pulmonary compliance and gas exchange were determined separately for each lung, and we recorded pulmonary and systemic hemodynamics. We performed bronchoalveolar lavage (BAL) at the end of the experiment and determined total protein concentration as well as tumor necrosis factor alpha (TNF-alpha) mRNA expression in cell-free supernatant and in BAL cells, respectively. We also assessed the wet/dry ratio of the lung. RESULTS In the controls, on reperfusion, we encountered a progressive deterioration of gas exchange, especially of the reperfused left lung, which we could largely avoid using the IPC-5 protocol. Similarly, pulmonary compliance steadily declined but was much better in the ICP-5 group. Parallel to the improvement of gas exchange and lung mechanics, we found less total alveolar protein content and TNF-alpha mRNA expression in BAL cells in the IPC-5 than in the controls. However, we did not find IPC-10 to be paralleled by a significant improvement of lung function. Neither IPC-5 nor IPC-10 influenced the pulmonary vascular resistance index or the fluid accumulation in the lung. CONCLUSION The major finding of the present study was that 5 minutes of IPC improved lung function after 3 hours of warm ischemia of the lung.