Thomas Hachenberg

Induction of P‐glycoprotein by rifampin increases intestinal secretion of talinolol in human beings: A new type of drug/drug interaction

P‐Glycoprotein is an efflux pump in many epithelial cells with excretory function. It has been demonstrated that rifampin (INN, rifampicin) induces P‐glycoprotein, particularly in the gut wall. We therefore hypothesized that rifampin affects pharmacokinetics of the P‐glycoprotein substrate talinolol, a β1‐blocker without appreciable metabolic disposition but intense intestinal secretion in human beings.

The Pulmonary Immune Effects of Mechanical Ventilation in Patients Undergoing Thoracic Surgery

Mechanical ventilation (MV) may induce an inflammatory alveolar response. One-lung ventilation (OLV) with tidal volumes (Vt) as used during two-lung ventilation is a suggested algorithm but may impose mechanical stress of the dependent lung and potentially aggravate alveolar mediator release. We studied whether ventilation with different Vt modifies pulmonary immune function, hemodynamics, and gas exchange. Thirty-two patients undergoing open thoracic surgery were randomized to receive either MV with Vt = 10 mL/kg (n = 16) or Vt = 5 mL/kg (n = 16) adjusted to normal Paco2 during and after OLV. Fiberoptic bronchoalveolar lavage of the ventilated lung was performed, and cells, protein, tumor necrosis factor (TNF)-&agr;, interleukin (IL)-8, soluble intercellular adhesion molecule (sICAM)-1, IL-10, and elastase were determined in the bronchoalveolar lavage. Data were analyzed by parametric or nonparametric tests, as indicated. In all patients, an increase of proinflammatory variables was found. The time courses of intra-alveolar cells, protein, albumin, IL-8, elastase, and IL-10 did not differ between the groups after OLV and postoperatively. TNF-&agr; (8.4 versus 5.0 &mgr;g/mL) and sICAM-1 (52.7 versus 27.5 &mgr;g/mL) concentrations were significantly smaller after OLV with Vt = 5 mL/kg. These results indicate that MV may induce epithelial damage and a proinflammatory response in the ventilated lung. Reduction of tidal volume during OLV may reduce alveolar concentrations of TNF-&agr; and of sICAM-1.

Atelectasis and gas exchange after cardiac surgery.

Background Sometimes a high intrapulmonary shunt occurs after cardiac surgery, and impairment of lung function and oxygenation can persist for 1 week after operation. Animal studies have shown that postoperative shunt can be explained by atelectasis. In this study the authors tried to determine if atelectasis can explain shunt in patients who have had cardiac surgery. Methods Nine patients having coronary artery bypass graft surgery and nine patients having mitral valve surgery were examined using the multiple inert gas elimination technique before and after operation. On the first postoperative day, computed tomography scans were made at three levels of the thorax. Results Before anesthesia, the average shunt was low (2 +/‐ 3%; range, 0–13%), but on the first postoperative day shunt had increased to 12 +/‐ 6% (range, 3–28%). The computed tomography scans showed bilateral dependent densities in all patients but one. The mean area of the densities was 8 +/‐ 8% (range, 0–37%) of total lung area, corresponding to a calculated fraction of collapsed lung tissue of 20 +/‐ 14% (range, 0–59%). In the basal region, the calculated amount of collapsed tissue was 28 +/‐ 19% (range, 0–73%). One mitral valve patient was an outlier and had a large shunt both before and after the operation. Conclusions Large atelectasis in the dorsal part of the lungs was found on the first postoperative day after cardiac surgery. However, there was no clear correlation between atelectasis and measured shunt fraction.

Ventilation-perfusion inequality in patients undergoing cardiac surgery.

BackgroundImpaired gas exchange is a major complication after cardiac surgery with the use of extracorporeal circulation. Blood gas analysis gives little information on underlying mechanisms, in particular if the impairment is multifactorial. In the current study we used the multiple inert gas technique with recordings of hemodynamics to analyze the separate effects of intrapulmonary shunt (&OV0422;s/&OV0422;r), ventilation-perfusion (&OV0312;A/&OV0422;) mismatch, and low mixed venous oxygen tension on arterial oxygenation during cardiac surgery. Methods&OV0312;A/&OV0422; distribution was studied in nine patients undergoing coronary artery revascularization surgery. The obtained data related to &OV0312;A/&OV0422; distribution were perfusion of lung regions with &OV0312;A/&OV0422; < 0.005 (&OV0422;s/&OV0422;r), perfusion of lung regions with 0.005 < &OV0312;A/&OV0422; < 0.1 (“low”-&OV0312;A/&OV0422; regions), ventilation of lung regions with 10 < &OV0312;A/&OV0422; < 100 (“high”-&OV0312;A/&OV0422; regions), and ventilation of lung regions with &OV0312;A/&OV0422; > 100 (dead space [&OV0312;D/&OV0312;T]). In addition, arterial and mixed venous oxygen and carbon dioxide tensions and systemic and pulmonary hemodynamics were analyzed. Recordings were made before and after induction of anesthesia, after sternotomy, 45 min after separation from extracorporeal circulation, 4 h postoperatively during mechanical ventilation, and on the 1st postoperative day during spontaneous breathing. ResultsIn the awake state, &OV0422;s/&OV0422;r was 4 ± 4%, and perfusion of low-&OV0312;A/&OV0422; regions was 3 ± 5%. The sum of &OV0422;s/&OV0422;r and low-&OV0312;A/&OV0422; units correlated with the alveolar-arterial oxygen tension gradient (PA-ao2) (r = 0.63, P < 0.05). After induction of anesthesia, &OV0422;s/&OV0422;r increased to 10 ± 9% (P = 0.069). Sternotomy had little effect on shunt, but &OV0422;s/&OV0422;r increased to 22 ± 8% (P < 0.01) after separation from extracorporeal circulation, which was correlated with a significantly higher PA-ao2 (r = 0.77, P < 0.05). Postoperatively, gas exchange improved rapidly, as assessed by a decrease of PA-ao2 from 341 ± 77 to 97 ± 36 mmHg (P < 0.01) and a reduced &OV0422;s/&OV0422;r (5 ± 4%, P < 0.05). On the 1st postoperative day, arterial oxygen tension was significantly lower than preanesthesia values (58 ± 6 vs. 68 ± 8 mmHg, P < 0.05). &OV0422;s/&OV0422;r had increased to 11 ± 6% (P < 0.05), but little perfusion of low-&OV0312;A/&OV0422; units was observed. A correlation was found between PA-ao2 and &OV0422;s/&OV0422;r (r = 0.82, P < 0.03). Conclusions&OV0422;s/&OV0422;r is a major component of impaired gas exchange before, during, and after cardiac surgery. &OV0422;s/&OV0422;r increases after induction of general anesthesia, probably because of development of atelectasis. After separation from extracorporeal circulation, accumulation of extravascular lung water or further collapse of lung tissue may aggravate &OV0422;s/&OV0422;r-Postoperatively, oxygenation improves, possibly because of recruitment of previously nonventilated alveoli or resolution of extravascular lung water. During spontaneous breathing, additional mechanisms such as altered mechanics of the chest, perfusion of low-&OV0312;A/&OV0422; regions, and decreased mixed venous oxygen tension may contribute to impaired gas exchange.

Effects of volatile and intravenous anesthesia on the alveolar and systemic inflammatory response in thoracic surgical patients.

Background:One-lung ventilation (OLV) results in alveolar proinflammatory effects, whereas their extent may depend on administration of anesthetic drugs. The current study evaluates the effects of different volatile anesthetics compared with an intravenous anesthetic and the relationship between pulmonary and systemic inflammation in patients undergoing open thoracic surgery. Methods:Sixty-three patients scheduled for elective open thoracic surgery were randomized to receive anesthesia with 4 mg · kg−1 · h−1 propofol (n = 21), 1 minimum alveolar concentration desflurane (n = 21), or 1 minimum alveolar concentration sevoflurane (n = 21). Analgesia was provided by remifentanil (0.25 &mgr;g · kg−1 · min−1). After intubation, all patients received pressure-controlled mechanical ventilation with a tidal volume of approximately 7 ml · kg−1 ideal body weight, a peak airway pressure lower than 30 cm H2O, a respiratory rate adjusted to a Paco2 of 40 mmHg, and a fraction of inspired oxygen lower than 0.8 during OLV. Fiberoptic bronchoalveolar lavage of the ventilated lung was performed immediately after intubation and after surgery. The expression of inflammatory cytokines was determined in the lavage fluids and serum samples by multiplexed bead-based immunoassays. Results:Proinflammatory cytokines increased in the ventilated lung after OLV. Mediator release was more enhanced during propofol anesthesia compared with desflurane or sevoflurane administration. For tumor necrosis factor-&agr;, the values were as follows: propofol, 5.7 (8.6); desflurane, 1.6 (0.6); and sevoflurane, 1.6 (0.7). For interleukin-8, the values were as follows: propofol, 924 (1680); desflurane, 390 (813); and sevoflurane, 412 (410). (Values are given as median [interquartile range] pg · ml−1). Interleukin-1&bgr; was similarly reduced during volatile anesthesia. The postoperative serum interleukin-6 concentration was increased in all patients, whereas the systemic proinflammatory response was negligible. Conclusions:OLV increases the alveolar concentrations of proinflammatory mediators in the ventilated lung. Both desflurane and sevoflurane suppress the local alveolar, but not the systemic, inflammatory responses to OLV and thoracic surgery.

Thoracic Intravascular and Extravascular Fluid Volumes in Cardiac Surgical Patients

BackgroundOne possible mechanism of impaired oxygenation in cardiac surgery with extracorporeal circulation (ECC) is the accumulation of extravascular lung water (EVLW). Intrathoracic blood volume (ITBV) and pulmonary blood volume (PBV) also may increase after separation from ECC, which can influence both cardiac performance and pulmonary capillary fluid filtration. This study tested whether there were any relationships between lung fluid accumulation and pulmonary gas exchange during the perioperative period of cardiac surgery and ECC. MethodsTen patients undergoing myocardial revascularization were studied. ITBV, PBV, and EVLW were determined from the mean transit times and decay times of the dye and thermal indicator curves obtained simultaneously in the descending aorta. Gas exchange was assessed by arterial and mixed venous partial pressure of oxygen (Po2) and carbon dioxide (Pco2), and calculation of alveolo-arterial Po2 gradient (Pa-ao2) and venous admixture (Qva/Qt). Recordings were made after Induction of anesthesia, after sternotomy, 15 min after separation from ECC, and 4 and 20 h postoperatively. ResultsAfter induction of anesthesia, EVLW (6.0 ± 1.0 ml/kg, ± ± SD), PBV (3.6 ± 1.3 ml/kg), and ITBV (18.4 ± 2.7 ml/kg) were within normal ranges. Oxygenation was moderately impaired, as indicated by an increased Pa-ao2 (144 ± 46 mmHg) and Qva/Qt (11 ± 4%). After separation from ECC, EVLW had increased to 9.1 ± 2.6 ml/kg, which was accompanied by an increase of ITBV (26.0 ± 4.4 ml/kg) and PBV (5.6 ± 1.9 ml/kg). Paa-02 (396 ± 116 mmHg) and Qva/Qt (29 ± 7%) also were increased. ITBV and PBV remained increased 4 and 20 h post-operatively, but EVLW decreased to presurgery values. No correlations were found between thoracic intravascular and extravascular fluid volumes and gas exchange. ConclusionsCardiac surgery with the use of ECC induces alterations of thoracic intravascular and extravascular fluid volumes. Postoperatively, increased ITBV and PBV need not be associated with higher EVLW. Thus, sufficient mechanisms protecting against lung edema formation or providing resolution of EVLW probably are maintained after ECC. Since oxygenation is impaired during and after cardiac surgery, it is concluded that mechanisms other than or in addition to changes of ITBV, PBV, and EVLW predominantly influence gas exchange.

One-lung ventilation induces hyperperfusion and alveolar damage in the ventilated lung: an experimental study

BACKGROUND One-lung ventilation (OLV) increases mechanical stress in the lung and affects ventilation and perfusion (V, Q). There are no data on the effects of OLV on postoperative V/Q matching. Thus, this controlled study evaluates the influence of OLV on V/Q distribution in a pig model using a gamma camera technique [single-photon emission computed tomography (SPECT)] and relates these findings to lung histopathology after OLV. METHODS Eleven anaesthetized and ventilated pigs (V(T)=10 ml kg(-1), Fio2=0.40, PEEP=5 cm H2O) were studied. After lung separation, OLV and thoracotomy were performed in seven pigs (OLV group). During OLV and in a two-lung ventilation (TLV), control group (n=4) ventilation settings remained unchanged. SPECT with (81m)Kr (ventilation) and (99m)Tc-labelled macro-aggregated albumin (perfusion) was performed before, during, and 90 min after OLV/TLV. Finally, lung tissue samples were harvested and examined for alveolar damage. RESULTS OLV affected ventilation and haemodynamic variables, but there were no differences between the OLV group and the control group before and after OLV/TLV. SPECT revealed an increase of perfusion in the dependent lung compared with baseline (49-56%), and a corresponding reduction of perfusion (51-44%) in non-dependent lungs after OLV. No perfusion changes were observed in the control group. This resulted in increased low V/Q regions and a shift of V/Q areas to 0.3-0.5 (10(-0.5)-10(-0.3)) in dependent lungs of OLV pigs and was associated with an increased diffuse alveolar damage score. CONCLUSIONS OLV in pigs results in a substantial V/Q mismatch, hyperperfusion, and alveolar damage in the dependent lung and may thus contribute to gas exchange impairment after thoracic surgery.

Effects of different anaesthetic agents on immune cell function in vitro

Background and objective: Anaesthesia may affect the regulatory balance of postoperative immune response. The aim of this study was to investigate the effects of different volatile and non‐volatile anaesthetic agents and particularly of clinically used agent combinations on the proliferation capacity and cytokine production of immune cells. Methods: Peripheral blood mononuclear cells from healthy donors were PHA‐activated in the presence or absence of various concentrations of thiopental, propofol, fentanyl, sufentanil, sevoflurane, nitrous oxide and combinations of these anaesthetics. Cell proliferation was assessed by tritiated thymidine uptake. Interleukin‐2 production and release of the soluble IL‐2 receptor were determined by enzyme immunoassays and used as measures of lymphocyte activation. Results: Thiopental inhibited cell proliferation in a dose dependent manner (P < 0.001) and reduced sIL‐2R release (2090‐970 pg mL−1; P < 0.05). Propofol reduced sIL‐2R release at the high concentration of 10 μg mL−1 (2220 pg mL−1‐1780 μg mL−1; P < 0.05). Fentanyl and sufentanil did not compensate for or enhance the inhibitory effects of thiopental. Nitrous oxide, but not sevoflurane, reduced the proliferation of human peripheral blood mononuclear cells (P < 0.05). In combinations with thiopental or nitrous oxide, sevoflurane compensated the inhibitory effects of these two agents. Fentanyl, sufentanil, sevoflurane and nitrous oxide did not affect PHA‐induced IL‐2 and sIL‐2 receptor release by human peripheral blood mononuclear cells. Conclusion: Thiopental and nitrous oxide have immunosuppressive activity. In contrast, sevoflurane may have a beneficial effect by alleviating the immunosuppressive effects of both substances.

Non-analgetic effects of thoracic epidural anaesthesia.

Purpose of review This review presents a brief overview of the non-analgetic effects of thoracic epidural anaesthesia. It covers the cardiac, pulmonary and gastrointestinal effects of thoracic epidural anaesthesia. The results of newer studies are of particular importance regarding mortality and major morbidity after thoracic epidural anaesthesia. Recent findings The clinical effects of thoracic epidural anaesthesia are mainly attributed to a transient thoracic sympathetic block affecting different organs. Furthermore, local anaesthetic itself reabsorbed from the epidural space may contribute to the non-analgetic effects of thoracic epidural anaesthesia. Experimental studies have suggested that thoracic epidural anaesthesia may attenuate the perioperative stress response after major surgery. The possible beneficial mechanisms of action include an improvement of left ventricular function by direct anti-ischaemic effects, a reduction in cardiovascular complications, an advance on gastrointestinal function, and a reduction in pulmonary complications, as well as a positive impact on the coagulation system and the postoperative inflammatory response. However, it is questionable whether these effects of thoracic epidural anaesthesia may lead to an improved perioperative outcome after major surgery. Recent studies have suggested that, despite the superior quality of pain relief and better quality of life, thoracic epidural anaesthesia does not reduce mortality and major morbidity, especially after major abdominal and cardiac surgery. Summary Despite this controversy, the numerous positive effects and advantages of thoracic epidural anaesthesia are the reasons for its increasing popularity. However, the advantages of thoracic epidural anaesthesia must be incorporated into a multimodal treatment management aimed at improving outcomes after surgery. Abbreviations CABG: coronary artery bypass grafting; HPV: hypoxic pulmonary vasoconstriction; TEA: thoracic epidural anaesthesia.

Mechanical ventilation in the prone position for acute respiratory failure after cardiac surgery

Ten patients with acute respiratory failure (ARF) after coronary artery bypass grafting were studied during conventional mechanical ventilation in the supine and in the prone position. Impaired gas exchange was defined as an inspired oxygen fraction (FIO2) greater than 0.5 to maintain an arterial oxygen tension (PaO2) > or = 70 mmHg, an alveolar-arterial PaO2 gradient (PA-aO2) > 200 mmHg and a venous admixture (QVA/QT) > 15% during mechanical ventilation with a tidal volume (VT) = 10 to 12 mL/kg, frequency (f) = 10 to 15 VT/min, inspiratory-expiratory (I:E) ratio = 0.5, and positive end-expiratory pressure (PEEP) of 5 to 7.5 cm H2O. In the supine position, systemic and pulmonary hemodynamics were in the normal range, but oxygenation was severely impaired. In all patients thoracic computed tomography scans were obtained and revealed crest-shaped bilateral densities in the dependent lung regions. FIO2 of 0.67 +/- 0.22 was required to maintain a PaO2 greater than 70 mmHg during mechanical ventilation in the supine position. Under these conditions PA-aO2 and QVA/QT were 362 +/- 153 mmHg and 32.5 +/- 8.3%, respectively. CO2 elimination was not severely affected. The patients were turned into the prone position after an average of 30.6 +/- 5.4 hours postoperatively and ventilated with unchanged VT, f, PEEP, and inspiratory-expiratory ratio for 26.7 +/- 11.7 hours (range, 10 to 42 hours). A second cardiopulmonary status was obtained within 2 to 5 hours of ventilation in the prone position.(ABSTRACT TRUNCATED AT 250 WORDS)