[Intraocular Lens as a Drug Delivery Device: State of the Art and Future Perspective]. / Die Intraokularlinse als Arzneimittelträger: Stand der Forschung und Ausblick.

Development of an intraocular lens (IOL) as a drug delivery device has been pursued for many years and is a promising concept in modern cataract surgery. Common postoperative conditions such as posterior capsule opacification (PCO), intraocular inflammation or the rare but severe complications of cataract surgery like endophthalmitis are potential therapeutic targets for a drug-eluting IOL. There are three techniques of pharmacological IOL modification: Firstly, surface modification of the IOL ("coating"); secondly, IOL optic modification ("soaking") and lastly, loading the IOL haptics with a slow release system. The last option does not interfere with the IOL optics at all. Therefore, a broad spectrum of pharmacological agents needs to be assessed in preclinical and clinical studies to determine which agent/IOL combination is safe and efficient. For pharmacological PCO prophylaxis, erufosine-loaded IOLs are of great clinical interest. Heparin-coated IOLs might become clinically relevant for attenuation of intraocular inflammation after cataract surgery and cefuroxime-loaded IOLs for endophthalmitis prophylaxis.

Anesthesia in swine : optimizing a laboratory model to optimize translational research.

In order to extrapolate novel therapies from the bench to the bedside (translational research), animal experiments are scientifically necessary. Swine are popular laboratory animals as their cardiorespiratory physiology is very similar to humans. Every study has to be approved by the local and/or national animal ethical committees. As swine are extremely sensitive to stress the primary goal is therefore to provide a calm, stress-free environment in both housing and experimental facilities. Swine should be properly sedated for transport and normothermia needs to be ensured. It is recommended to commence anesthesia by injecting ketamine and propofol followed by endotracheal intubation during spontaneous breathing. After intubation, anesthesia maintenance is performed with morphine or piritramide, propofol and rocuronium and routine monitoring is applied analogue to a clinical operating theater for humans. Normothermia (38.5 °C) needs to be ensured. While surgical procedures can be readily extrapolated from a human operating theater to swine, non-anesthesiologist scientists may lose the animal rapidly due to airway management problems. Vascular access can be secured by cut-downs or ultrasound-guided techniques in the inguinal and the neck region. For humane euthanasia of pigs, morphine, followed by propofol, rocuronium and potassium chloride are recommended. As radical animal right groups may threaten scientists, it is prudent that animal laboratories have unmarked entrance doors, are located in buildings that are not accessible to the public and strictly controlled access of laboratory staff is enforced. In conclusion, swine are an excellent laboratory animal for bench to bedside research and can be managed properly when basic knowledge and adequate skills on careful handling, anesthesia and surgical considerations are present.

Attenuation of human lens epithelial cell spreading, migration and contraction via downregulation of the PI3K/Akt pathway.

BACKGROUND: Posterior capsule opacification (PCO) represents a major challenge in the postoperative management of cataract patients. Spreading, migration and contraction of residual human lens epithelial cells play a pivotal role in the pathogenesis of PCO. Therefore, we analyzed the effect of the alkylphosphocholine (APC) erufosine on these cellular features as well as on PI3K/Akt, a crucial pathway in PCO pathogenesis. METHODS: Human lens epithelial cells were cultured under standard cell culture conditions. Cell spreading was analyzed on fibronectin-coated wells and chemokinetic migration was assessed by time-lapse microscopy. For evaluation of cell-mediated collagen matrix contraction, the cells were seeded into collagen gels and incubated with an APC in different non-toxic concentrations before the surface area was measured on day 6. The activity of PI3K/Akt was assessed by an ELISA kit after incubation of the cells with different APC concentrations. RESULTS: Human lens epithelial cell spreading and migration were attenuated by APCs as follows: 7 % spreading, 48 % migration (0.1 µM APC), and 32 % spreading, 68 % migration (1.0 µM APC). APC concentrations of 0.1 µM reduced collagen gel diameter by 5 %, and 1.0 µM by less than 1 %, compared to untreated, cell-populated gels that resulted in a cell diameter contraction of 36 %. PI3K was downregulated in a concentration-dependent manner. CONCLUSIONS: The crucial cellular features of PCO pathogenesis are attenuated by the APC erufosine via downregulation of the PI3K pathway. Thus, erufosine might become a valuable tool for pharmacologic PCO prophylaxis in the future.

[Out-of-hospital emergency medicine in Germany, Austria and Switzerland : randomized prospective studies from 1990 to 2012]. / Außerklinische Notfallmedizin in Deutschland, Österreich und der Schweiz : Randomisierte, prospektive Studien von 1990 bis 2012.

BACKGROUND: Only randomized clinical trials can improve the outcome of life-threatening injuries or diseases but observations from England and North America suggest that the number of such randomized clinical trials is decreasing. In this study contributions from German speaking countries with regards to randomized clinical trials in emergency medicine over the last 22 years were investigated. METHODS: The Medline database was searched from January 1990 to December 2012 for prospective randomized clinical trials in the prehospital setting using the criteria "cardiac arrest", "cardiopulmonary resuscitation", "multiple trauma", "hemorrhagic shock", "head trauma", "stroke" as well as myocardial infarction and emergency medical service. Only studies originating from Germany, Austria or Switzerland were included. RESULTS: A total of 474 studies were found and 25 studies (5.3 %) fulfilled the inclusion criteria. In the last 22 years German speaking countries have published approximately one prospective, randomized, clinical trial per year on prehospital emergency medicine. The median number of patients included in the trials was 159 (minimum 16, maximum 1,219). Most (80 %) studies originated from Germany and most (64 %) studies were conducted by anesthesiology departments. Cardiac arrest was the most frequent subject of the investigated studies. Approximately 50 % of the studies had financial support from industrial companies. CONCLUSION: A significant increase or decrease in the number of prospective randomized clinical trials in the out-of-hospital setting could not be found in German speaking countries despite the fact that the absolute numbers of studies had increased. Only about one prospective, randomized clinical trial with an emergency medicine core tracer diagnosis originated from Germany, Austria and Switzerland per year.

EGF receptor inhibitor erlotinib as a potential pharmacological prophylaxis for posterior capsule opacification.

BACKGROUND: Posterior capsule opacification (PCO) is the most frequent complication after cataract surgery, leading to a loss of sight if untreated. Erlotinib might be of therapeutic interest as an effective target agent (selective EGF-tyrosin-kinase-1 inhibitor). In this in-vitro study, erlotinib was evaluated for ocular biocompatibility and its effect on cell proliferation, migration, 3D matrix contraction and spreading of human lens epithelial cells. METHODS: To exclude toxic concentrations, erlotinib was assessed for its biocompatibility on five different human ocular cell types in vitro by the tetrazolium dye-reduction assay (MTT) and the Live-Dead assay. To determine its effect on human lens epithelial cell (HLE-B3) proliferation, the MTT test was performed after incubation with different concentrations of erlotinib. Chemotactic migration was analyzed with the Boyden chamber assay and chemokinetic migration was assessed by time lapse microscopy. Contraction was measured by a 3D collagen type 1 matrix contraction assay, and cell spreading was determined by measuring the cell diameter on a fibronectin coated surface. RESULTS: The maximum non-toxic concentration of erlotinib was determined to be 100 µM in cell culture. Erlotinib potently inhibits human lens epithelial cell proliferation, with an IC50 of about 10 µM (8.8 µM ± 0.9 µM SD; r (2) =0.94). Chemotactic migration (p=0.004) and chemokinetic migration (p=0.001) were reduced significantly in a concentration-based manner. Erlotinib prevented human lens epithelial cells from matrix contraction (p=0.001) and cell-spreading (p=0.001). CONCLUSIONS: Erlotinib might become of clinical relevance for PCO prophylaxis in the future since it displayed good biocompatibility on ocular cells and mitigated human lens epithelial cell proliferation, migration, contraction, and spreading in vitro. Further studies are warranted to evaluate its potential for clinical application.

Effect of decreased inspiratory times on tidal volume. Bench model simulating cardiopulmonary resuscitation.

BACKGROUND: During cardiopulmonary resuscitation (CPR) with a chest compression rate of 60-100/min the time for secure undisturbed ventilation in the chest decompression phase is only 0.3-0.5 s and it is unclear which tidal volumes could be delivered in such a short time. OBJECTIVES: Attempts were made to assess the tidal volumes that can be insufflated in such a short time window. METHODS: In a bench model tidal volumes were compared in simulated non-intubated and intubated patients employing an adult self-inflating bag-valve with inspiratory times of 0.25, 0.3, and 0.5 s. Respiratory system compliance values were 60 mL/cmH(2)O being representative for respiratory system conditions shortly after onset of cardiac arrest and 20 mL/cmH(2)O being representative for conditions after prolonged cardiac arrest. RESULTS: With a respiratory system compliance of 60 mL/cmH(2)O, tidal volumes (mean+/-SD) in non-intubated versus intubated patients were 144+/-13 mL versus 196+/-23 mL in 0.25 s (p<0.01), 178+/-10 versus 270+/-14 mL in 0.3 s (p<0.01), and 310+/-12 mL versus 466+/-20 mL in 0.5 s (p<0.01). With a respiratory system compliance of 20 mL/cmH(2)O, tidal volumes in non-intubated patient versus intubated patients were 128+/-10 mL versus 186+/-20 mL in 0.25 s (p<0.01), 158+/-17 versus 250+/-14 mL in 0.3 s (p<0.01) and 230+/-21 mL versus 395+/-20 mL in 0.5 s (p<0.01). CONCLUSIONS: Ventilation windows of 0.25, 0.3, and 0.5 s were too short to provide adequate tidal volumes in a simulated non-intubated cardiac arrest patient. In a simulated intubated cardiac arrest patient, ventilation windows of at least 0.5 s were necessary to provide adequate tidal volumes.

[Fatalities due to nitrous oxide. Complications from mistakes in nitrous oxide supply]. / Lachgasbedingte Todesfälle. Komplikationen durch Verwechslungen in der Lachgaszufuhr.

Despite inspiratory oxygen fraction measurement being regulated by law in the European norm EN 740, fatal errors in nitrous oxide delivery still occur more frequently than expected, especially after construction or repair of gas connection tubes. Therefore, if nitrous oxide is to be used further in a hospital, all technical measures and system procedures should be employed to avoid future catastrophes. Among these are measurement of the inspiratory oxygen fraction (F(I)O(2)) and an automatic limitation of nitrous oxide. Also all anaesthetists involved should be informed about repair or construction of central gas supply tubes. Additionally, more awareness of this problem in daily routine is necessary. Furthermore, a system of detecting and analysing errors in anaesthesia has to be improved in each hospital as well as in the anaesthesia community as a whole. Measures for a better "error culture" could include data exchange between different critical incident reporting systems, analysis of closed claims, and integration of medical experts in examination of recent catastrophes.

Fatal errors in nitrous oxide delivery.

Nitrous oxide continues to be used frequently and the possibility of inadvertent fatal hypoxaemia resulting from technical errors with its administration still exists. A Medline analysis revealed only a few case reports over the last 30 years, and a closed claim analysis only reported 'claims involving oxygen supply lines' predating 1990. The aim of this study was to assess the frequency of nitrous oxide-related catastrophes during general anaesthesia in Germany, Austria, and Switzerland. As nitrous oxide-related anaesthesia casualties are rare but generally prosecuted, they almost invariably attract significant media attention. We scanned mass media archives from April 2004 until October 2006 for nitrous oxide-related disasters during general anaesthesia. This approach detected six incidents which were almost certainly nitrous oxide ventilation-related deaths. Searching non-scientific data bases demonstrates that severe incidents involving oxygen supply lines occurred after 1990, and may be much more frequent than previously thought.

Developing a vasopressor combination in a pig model of adult asphyxial cardiac arrest.

BACKGROUND: The purpose of this study was to investigate the effects of vasopressin versus epinephrine, and both drugs combined, in a porcine model of simulated adult asphyxial cardiac arrest. METHODS AND RESULTS: At approximately 7 minutes after the endotracheal tube had been clamped, cardiac arrest was present in 24 pigs and remained untreated for another 8 minutes. After 4 minutes of basic life support cardiopulmonary resuscitation, pigs were randomly assigned to receive, every 5 minutes, either epinephrine (45, 200, or 200 microgram/kg; n=6); vasopressin (0.4, 0.8, or 0.8 U/kg; n=6); or epinephrine combined with vasopressin (high-dose epinephrine/vasopressin combination, microgram/kg and U/kg: 45/0.4, 200/0.8, or 200/0.8; n=6; optimal-dose epinephrine/vasopressin combination, 45/0.4, 45/0.8, or 45/0.8; n=6). Mean+/-SEM coronary perfusion pressure was significantly (P<0.05) higher 90 seconds after high- or optimal-dose epinephrine/vasopressin combinations versus vasopressin alone and versus epinephrine alone (37+/-10 versus 25+/-7 versus 19+/-8 versus 6+/-3 mm Hg; 42+/-6 versus 40+/-5 versus 21+/-5 versus 14+/-6 mm Hg; and 39+/-6 versus 37+/-4 versus 9+/-3 versus 12+/-4 mm Hg, respectively). Six of 6 high-dose, 6 of 6 optimal-dose vasopressin/epinephrine combination, 0 of 6 vasopressin, and 1 of 6 epinephrine pigs had return of spontaneous circulation (P<0.05). CONCLUSIONS: Epinephrine combined with vasopressin, but not epinephrine or vasopressin alone, maintained elevated coronary perfusion pressure during cardiopulmonary resuscitation and resulted in significantly higher survival rates in this adult porcine asphyxial model.

Survival with full neurologic recovery and no cerebral pathology after prolonged cardiopulmonary resuscitation with vasopressin in pigs.

OBJECTIVES: We sought to determine the effects of vasopressin and saline placebo in comparison with epinephrine on neurologic recovery and possible cerebral pathology in an established porcine model of prolonged cardiopulmonary resuscitation (CPR). BACKGROUND: It is unknown whether increased cerebral blood flow during CPR with vasopressin is beneficial with regard to neurologic recovery or detrimental owing to complications such as cerebral edema after return of spontaneous circulation. METHODS: After 4 min of cardiac arrest, followed by 3 min of basic life support CPR, 17 animals were randomly assigned to receive every 5 min either vasopressin (0.4, 0.4 and 0.8 U/kg; n = 6), epinephrine (45, 45 and 200 microg/kg; n = 6) or saline placebo (n = 5). The mean value +/- SEM of aortic diastolic pressure was significantly (p < 0.05) higher 90 s after each of three vasopressin versus epinephrine versus saline placebo injections (60 +/- 3 vs. 45 +/- 3 vs. 29 +/- 2 mm Hg; 49 +/- 5 vs. 27 +/- 3 vs. 23 +/- 1 mm Hg; and 50 +/- 6 vs. 21 +/- 3 vs. 16 +/- 3 mm Hg, respectively). After 22 min of cardiac arrest, including 18 min of CPR, defibrillation was attempted to achieve return of spontaneous circulation. RESULTS: All the pigs that received epinephrine and saline placebo died, whereas all pigs on vasopressin survived (p < 0.05). Neurologic evaluation 24 h after successful resuscitation revealed only an unsteady gait in all vasopressin-treated animals; after 96 h, magnetic resonance imaging revealed no cerebral pathology. CONCLUSIONS: During prolonged CPR, repeated vasopressin administration, but not epinephrine or saline placebo, ensured long-term survival with full neurologic recovery and no cerebral pathology in this porcine CPR model.

Employing vasopressin during cardiopulmonary resuscitation and vasodilatory shock as a lifesaving vasopressor.

Epinephrine during cardiopulmonary resuscitation (CPR) is being discussed controversially due to its beta-receptor mediated adverse effects such as increased myocardial oxygen consumption, ventricular arrhythmias, ventilation-perfusion defect, postresuscitation myocardial dysfunction, ventricular arrhythmias and cardiac failure. In the CPR laboratory simulating adult pigs with ventricular fibrillation or postcountershock pulseless electrical activity, vasopressin improved vital organ blood flow, cerebral oxygen delivery, resuscitability, and neurological recovery better than did epinephrine. In paediatric preparations with asphyxia, epinephrine was superior to vasopressin, whereas in both paediatric pigs with ventricular fibrillation, and adult porcine models with asphyxia, combinations of vasopressin and epinephrine proved to be highly effective. This may suggest that a different efficiency of vasopressors in paediatric vs. adult preparations; and different effects of dysrhythmic vs. asphyxial cardiac arrest on vasopressor efficiency may be of significant importance. Whether these theories can be extrapolated to humans is unknown at this point in time. In patients with out-of-hospital ventricular fibrillation, a larger proportion of patients treated with vasopressin survived 24 h compared with patients treated with epinephrine; during in-hospital CPR, comparable short-term survival was found in groups treated with either vasopressin or epinephrine. Currently, a large trial of out-of-hospital cardiac arrest patients being treated with vasopressin vs. epinephrine is ongoing in Germany, Austria and Switzerland. The new CPR guidelines of both the American Heart Association, and European Resuscitation Council recommend 40 U vasopressin intravenously, and 1 mg epinephrine intravenously as equally effective for the treatment of adult patients in ventricular fibrillation; however, no recommendation for vasopressin was made to date for adult patients with asystole and pulseless electrical activity, and paediatrics due to lack of clinical data. When adrenergic vasopressors were unable to maintain arterial blood pressure in patients with vasodilatory shock, continuous infusions of vasopressin ( approximately 0.04 to approximately 0.1 U/min) stabilised cardiocirculatory parameters, and even ensured weaning from catecholamines.

Continuous positive airway pressure effect on functional residual capacity, vital capacity and its subdivisions.

Thirty-four otherwise healthy patients having to undergo elective upper abdominal surgery were randomly assigned to two equal groups. In the treatment group, constant positive airway pressure (CPAP) with an expiratory pressure of 12 cm H2O was applied at one hour following extubation, and at daily intervals for the first five days following surgery for a continuous period of three hours. The control group received no CPAP treatment. All patients were given postoperative physiotherapy. In patients who received postoperative CPAP with an end-expiratory pressure of 12 cm H2O, marked normalization of pulmonary function was noted.

Right ventricular function during weaning from respirator after coronary artery bypass grafting. Comparison of two different weaning techniques.

The purpose of this investigation was to determine right ventricular function during weaning from controlled ventilation comparing a biphasic positive airway pressure ventilatory support system (BiPAP [Respironics]) with pressure support ventilation (PSV). In 22 patients following coronary artery bypass grafting, both weaning techniques were used in randomized chronological order for 60 min each. Right ventricular end-systolic (RVESV) and end-diastolic volume (RVEDV) and ejection fraction (RVEF) were evaluated using the fast-response Swan-Ganz catheter. In comparison to PSV, the BiPAP system resulted in a significantly higher mean pulmonary artery pressure (20.6 +/- 5.0 vs 19.3 +/- 4.2 mm Hg, p = 0.0158), pulmonary vascular resistance index (206 +/- 55 vs 181 +/- 61 dyn.s.cm-5.m2, p = 0.0355), RVESV (92.2 +/- 36.3 vs 77.2 +/- 30.4 ml, p = 0.0017), and RVEDV (176.4 +/- 48.5 vs 161.8 +/- 43.3 ml, p = 0.0061), while the RVEF was significantly lower (46.0 +/- 11.9 vs 51.8 +/- 12.4 percent, p = 0.0012). No differences in left ventricular function or arterial blood gas analyses were measured during both study periods. In summary, the RV afterload was higher with the BiPAP system compared with PSV which suggested that this was due to differences in the respiratory support between both weaning modes. Because of the Frank-Starling mechanism, this higher afterload did cause a small but significant increase in RV volumes and a significant decrease in RV ejection fraction with the BiPAP system.

Analysis of the ventricular fibrillation ECG signal amplitude and frequency parameters as predictors of countershock success in humans.

OBJECTIVE: The purpose of this study was to assess from the ventricular fibrillation ECG signal whether certain amplitude parameters, or frequency parameters derived using fast Fourier transform analysis, are predictive of countershock success (defined as a stable supraventricular rhythm following countershock). DESIGN: Retrospective, descriptive study. SETTING: Emergency medical service at a university hospital. PATIENTS: Twenty-six patients with out-of-hospital cardiac arrest, whose initial ECG rhythm was identified as ventricular fibrillation. METHODS AND RESULTS: In all patients, advanced cardiac life support was performed in the out-of-hospital setting and a semiautomatic defibrillator was used for countershock therapy and simultaneous on-line ECG recording. For each patient, ECG data were stored in modules in digitized form over a period of 20 min and analyzed retrospectively. Using fast Fourier transform analysis of the ventricular fibrillation ECG signal in the frequency range of 0.3 to 30 Hz (mean +/- SD), median frequency, dominant frequency, edge frequency, and amplitude were as follows: 5.17 +/- 1.05 Hz, 4.56 +/- 0.99 Hz, 10.74 +/- 3.46 Hz, and 1.33 +/- 0.44 mV before successful countershock (n = 20); and 4.21 +/- 1.17 Hz (p = 0.0034), 3.31 +/- 1.57 Hz (p = 0.0004), 9.46 +/- 2.93 Hz (p = 0.5390), and 1.15 +/- 0.69 mV (p = 0.0134) before unsuccessful countershock (n = 134). Using software filters to completely eliminate interference due to manual cardiopulmonary resuscitation from the ventricular fibrillation power spectrum, only amplitude remained statistically different (p < or = 0.03) in predicting countershock success. CONCLUSIONS: We conclude that in patients, median frequency, dominant frequency, and amplitude are predictive of countershock success in humans.

Epinephrine and norepinephrine in cardiopulmonary resuscitation. Effects on myocardial oxygen delivery and consumption.

Norepinephrine, an alpha 1,2-beta 1,2-adrenergic agonist, seems to be an alternative to epinephrine, an alpha 1,2-beta 1,2-agonist, for restoration of spontaneous circulation in VF. We therefore studied the effect of epinephrine and norepinephrine on MDO2 and MVO2 using OCCM after five minutes of cardiopulmonary arrest in 21 pigs. After OCCM of three minutes, seven animals each received placebo (controls) or epinephrine (45 micrograms/kg) or norepinephrine (45 micrograms/kg). All drugs were given blindly. At 90 seconds after epinephrine or norepinephrine, mean arterial blood pressure was significantly higher than in the control group. Prior to cardiac arrest, MBF, measured with radioactive microspheres, was 193 +/- 30 ml/min/100 g. During CPR but before drug administration, MBF was 51 +/- 23 in the control group, 71 +/- 10 in the group with epinephrine, and 74 +/- 11 ml/min/100 g in the group with norepinephrine. At 90 seconds after epinephrine, MBF increased to 126 +/- 18 and after norepinephrine to 107 +/- 30 ml/min/100 g (p less than 0.05). Compared to OCCM alone, MDO2 increased from 9.6 +/- 1.7 to 17.1 +/- 3.2 ml/min/100 g after epinephrine and from 9.4 +/- 1.8 to 13.6 +/- 4.2 ml/min/100 g after norepinephrine (p less than 0.05). There was an increase in MVO2 from 4.0 +/- 1.5 to 9.4 +/- 3.0 ml/min/100 g after epinephrine (p less than 0.05), whereas MVO2 increased only from 4.2 +/- 0.8 to 5.1 +/- 2.0 ml/min/100 g after norepinephrine. Because epinephrine led to a greater increase in MVO2 than norepinephrine, the myocardial oxygen ER remained unchanged. The oxygen requirements of the fibrillating heart seemed to be increased via beta 2-adrenergic stimulation. In both the control and epinephrine-treated groups, only three of the seven animals could be successfully resuscitated, whereas all of the animals in the group with norepinephrine survived the 15-minute period of observation. In this model, norepinephrine, in contrast to epinephrine, improves the balance between MDO2 and MVO2 and eases restoration of spontaneous circulation.

Median fibrillation frequency in cardiac surgery: influence of temperature and guide to countershock therapy.

OBJECTIVE: This study was designed (1) to investigate the effects of normothermic and hypothermic perfusion on the median frequency of the fibrillating myocardium, and (2) to elucidate whether frequency-guided countershock therapy improves countershock success during the reperfusion phase of cardiac surgery. DESIGN: Prospective, randomized study. SETTING: University hospital cardiac surgery room. PATIENTS: Thirty patients (first part of the study) and 38 patients (second part of the study) scheduled for elective coronary artery bypass surgery. METHODS AND RESULTS: During cardiopulmonary bypass, ventricular fibrillation (VF) was induced at a core body temperature of 34.1+/-0.2 degrees C (normothermia) (n=15) or at a core body temperature of 29.8+/-0.2 degrees C (hypothermia) (n=15). Using fast Fourier transformation of the ECG signal, median fibrillation frequency was recorded continuously for a period of 120 s. At the end of surgery, countershock was performed as soon as VF was recognized on the ECG monitor (X Hz group; n=19) or countershock was not performed until median fibrillation frequency had increased to the threshold of at least 5 Hz (5 Hz group; n=19). Median fibrillation frequency in the normothermic fibrillation group was statistically higher than in the hypothermic group. In the X Hz and 5 Hz countershock group, median fibrillation frequency before the first countershock attempt was 3.6+/-0.2 Hz and 5.4+/-0.1 Hz (p<0.0001), respectively. In the X Hz group, six countershocks resulted in supraventricular rhythm, 10 in VF, two in electromechanical dissociation, and one in asystole. In the 5 Hz group, 16 countershocks resulted in supraventricular rhythm, two in VF, and one in asystole (p=0.008). CONCLUSIONS: During normothermia, median fibrillation frequency is significantly higher than during hypothermic perfusion conditions. During the reperfusion phase of cardiac surgery, countershock success rate is significantly higher when a threshold of at least 5 Hz had been reached before the first countershock attempt.

Optimizing standard cardiopulmonary resuscitation with an inspiratory impedance threshold valve.

OBJECTIVES: This study was designed to assess whether intermittent impedance of inspiratory gas exchange improves the efficiency of standard cardiopulmonary resuscitation (CPR). BACKGROUND: Standard CPR relies on the natural elastic recoil of the chest to transiently decrease intrathoracic pressures and thereby promote venous blood return to the heart. To further enhance the negative intrathoracic pressures during the "relaxation" phase of CPR, we tested the hypothesis that intermittent impedance to inspiratory gases during standard CPR increases coronary perfusion pressures and vital organ perfusion. METHODS: CPR was performed with a pneumatically driven automated device in a porcine model of ventricular fibrillation. Eight pigs were randomized to initially receive standard CPR alone, while seven pigs initially received standard CPR plus intermittent impedance to inspiratory gas exchange with a threshold valve set to -40 cm H2O. The compression:ventilation ratio was 5:1 and the compression rate was 80/min. At 7-min intervals the impedance threshold valve (ITV) was either added or removed from the ventilation circuit such that during the 28 min of CPR, each animal received two 7-min periods of CPR with the ITV and two 7-min periods without the valve. RESULTS: Vital organ blood flow was significantly higher during CPR performed with the ITV than during CPR performed without the valve. Total left ventricular blood flow (mean+/-SEM) (mL/min/g) was 0.32+/-0.04 vs 0.23+/-0.03 without the ITV (p<0.05). Cerebral blood flow (mL/min/g) was 20% higher with the ITV (+ITV, 0.23+/-0.02; -ITV, 0.19+/-0.02; p<0.05). Each time the ITV was removed, there was a statistically significant decrease in the vital organ blood flow and coronary perfusion pressure. CONCLUSIONS: Intermittent impedance to inspiratory flow of respiratory gases during standard CPR significantly improves CPR efficiency during ventricular fibrillation. These studies underscore the importance of lowering intrathoracic pressures during the relaxation phase of CPR.

Are the effects of noradrenaline, adrenaline and dopamine infusions on VO2 and metabolism transient?

OBJECTIVE: To determine whether noradrenaline, adrenaline and dopamine have persistent actions on VO2 and metabolism. DESIGN: Descriptive laboratory investigation. SETTING: Laboratory of the Department of Anaesthesiology at a University Hospital. SUBJECTS: 9 volunteers. INTERVENTION: VO2 and the plasma concentration of glucose and free fatty acids were measured prior to and during a 4 h infusion of saline (control), noradrenaline (0.14 microgram/kg min) adrenaline (0.08 microgram/kg min) or dopamine (7 micrograms/kg min), n = 9 each. VO2 was measured using an open circuit gas exchange system. MEASUREMENTS AND MAIN RESULTS: VO2 increased from 250 +/- 22 ml/min to 280 +/- 38 ml/min during noradrenaline, to 298 +/- 30 ml/min during adrenaline and to 292 +/- 39 ml/min during dopamine infusion. The plasma glucose concentration increased from 6.2 +/- 0.6 mmol/l to 8.8 +/- 0.8 mmol/l, 13.2 +/- 1.4 and 7.3 +/- 0.4 mmol/l during infusion of noradrenaline, adrenaline or dopamine, respectively. The plasma free fatty acid concentration increased from 0.28 +/- 0.10 mmol/l to 0.79 +/- 0.21 mmol/l during noradrenaline and to 0.52 +/- 0.09 mmol/l during dopamine. In contrast, free fatty acid values averaged baseline values at the end of the adrenaline infusion after an initial increase to 0.72 +/- 0.31 mmol/l. CONCLUSIONS: Administration of noradrenaline, adrenaline or dopamine resulted in persistent increases in VO2 in volunteers. With the exception of the transient adrenaline effect on fatty acids the metabolic actions were steady during 4 h of adrenergic stimulation. Since the adrenergic effect on VO2 is persistent over time a similar action in patients (e.g. septic shock) during treatment with adrenoceptor agonists may be important. Thus, an increase in VO2 during therapy may not only reflect an oxygen debt but also a pharmacodynamic action of adrenoceptor mediated calorigenic and metabolic induction.

Comparison of epinephrine and dopamine during cardiopulmonary resuscitation.

The effectiveness of epinephrine and dopamine for restoring spontaneous circulation after asphyxial or fibrillatory cardiac arrest was compared using a porcine model. Asphyxial arrest: 7 animals received 45 micrograms/kg epinephrine, 7 animals 2.5 mg/kg dopamine, the remaining 7 animals received no drug treatment. All 7 animals given epinephrine could be resuscitated after 174 +/- 53 s, spontaneous circulation could be restored in only 3 of 7 animals given dopamine after 487 +/- 63 s and in none of the control animals could spontaneous circulation be established. Ventricular fibrillation: 7 animals were defibrillated without either mechanical measures or drug therapy. The following doses were given before defibrillation and after starting mechanical measures to separate groups of 7 animals each: 45 micrograms/kg epinephrine, 2.5 mg/kg dopamine, or no drug therapy. In the absence of either drug or mechanical measures and with mechanical measures only, spontaneous circulation could not be established in any of the cases. After administration of epinephrine, defibrillation and restoration of spontaneous circulation was achieved in 6 of 7 animals in 667 +/- 216 s, with dopamine, all the animals could be successfully resuscitated in the shorter time of 174 +/- 85 s. Epinephrine was found to be superior to dopamine in the treatment of asphyxial arrest whereas dopamine was found to be better in the management of ventricular fibrillation, probably by improving the balance between myocardial oxygen supply and demand.

Work of breathing, inspiratory flow response, and expiratory resistance during continuous positive airway pressure with the ventilators EVITA-2, EVITA-4 and SV 300.

OBJECTIVE: To analyze work of breathing (WOB) imposed by the respirators EVITA-2, EVITA-4 (Drägerwerk, Lübeck, Germany) and SV 300 (Siemens-Elema, Sweden) as well as inspiratory flow response and expiratory flow resistance during continuous positive airway pressure (CPAP). DESIGN: Five study conditions on a lung model (CPAP at 0, 5, and 10 mbar, CPAP 5 mbar plus pressure support 2 mbar with both EVITA models, and CPAP 5 mbar with decreasing levels of flow and pressure trigger sensitivity with the SV 300) and three randomized study conditions in nine patients recovering from open heart surgery (condition A: EVITA-2, CPAP 5 mbar; condition B: SV 300, CPAP 5 mbar, flow trigger; condition C: SV 300, pressure trigger-4 mbar). SETTING: University hospital intensive care unit and laboratory of pulmonary physiology. MEASUREMENTS AND RESULTS: At each study condition we measured WOB, pressure-time product (PTP), WOB and PTP imposed (WOBimposed and PTPimposed), tidal volume, minute ventilation, respiratory rate, inspiratory trigger time, trigger pressure, trigger PTP, duration of inspiration, mean and peak inspiratory flow, and the delay from the onset of inspiration to peak inspiratory flow. Since the SV 300 automatically generates an additional pressure support of 2 cm H2O PTP, WOB, WOBimposed, and PTPimposed were higher with the EVITA-2 and EVITA-4 regardless of the trigger sensitivity set on the SV 300. The difference was neutralized with both types of EVITA ventilator by adding 2 mbar of pressure support during CPAP in order to achieve comparable conditions. Inspiratory flow response was faster with both EVITA models, expiratory flow resistance was higher with the SV 300. Decrements of trigger sensitivity with the SV 300 accelerated the flow response. CONCLUSIONS: Under similar conditions, no difference in WOBimposed was observed, although inspiratory flow response and expiratory flow resistance differed substantially between the three ventilators tested. Trigger sensitivity plays a minor role in determining PTP and WOB but has major influence on flow.