Danja Strümper

Perioperative Blood Transfusions and Delayed Wound Healing After Hip Replacement Surgery: Effects on Duration of Hospitalization

Patients who receive allogeneic blood transfusions after orthopedic surgery have a longer duration of hospitalization, and this cannot be explained by a more frequent incidence of infections in transfused patients. To determine whether transfusion of allogeneic blood interferes with wound healing and therefore increases the duration of hospitalization, we performed an observational study in 444 consecutive patients scheduled for elective primary hip surgery. Transfusion, wound, and infection variables were collected at five time points during treatment. Of the 444 consecutive patients studied, 92 received blood transfusions during their perioperative course. Thirty-one percent of transfused patients developed wound-healing disturbances versus 18% of the nontransfused group (P < 0.05); allogeneic blood transfusion was the only significant predictor for development of minor wound-healing disturbances. Duration of hospitalization was prolonged in transfused patients (12.3 versus 9.8 days) and could be predicted by 4 significant variables: requirement for blood transfusion (adds 2.7 ± 0.5 days), presence of wound-healing disturbances (adds 1.3 ± 0.5 days), duration of surgery (adds 0.2 ± 0.1 days/10 min), and patients age (adds 0.9 ± 0.2 days/10 yr). These data suggest that allogeneic blood transfusion is associated with an increased incidence of wound-healing disturbances and that prevention of allogeneic blood transfusion may be relevant in limiting the duration of admission after elective orthopedic surgery.

Remifentanil Directly Activates Human N-methyl-D- aspartate Receptors Expressed in Xenopus laevis Oocytes

Background: Clinical studies suggest that intraoperative administration of the clinical remifentanil formulation Ultiva® (GlaxoWellcome GmbH & Co, Bad Oldesloe, Germany) increases postoperative pain and postoperative analgesic requirements, but mechanisms remain unclear. N-methyl-d-aspartate (NMDA) receptors are thought to play a major role in development of postoperative pain and opiate tolerance. The authors hypothesized that Ultiva® directly stimulates human NMDA receptors. Methods: To test this hypothesis, the authors expressed human NR1A/NR2A and NR1A/NR2B NMDA receptors in Xenopus laevis oocytes by injection of messenger RNA prepared in vitro. After protein expression, they used a two-electrode voltage clamp to measure currents induced by NMDA receptor agonists and opioids. Results: Noninjected cells were unresponsive to all compounds tested. Glutamate/glycine (1 nm–1 mm each) or Ultiva® (0.01 pm–0.1 mm) stimulated NMDA receptors concentration dependently. NR1A/2A EC50 values were 8.0 μM/12 μM for glutamate/glycine and 3.5 nM for Ultiva®, and NR1A/2B EC50 values were 3.9 μM/1.9 μM for glutamate/glycine and 0.82 μM for Ultiva®. Glycine in combination with Ultiva® showed no additive effect compared with Ultiva® alone. Ultiva®-induced currents were inhibited by MK-801 (pore blocker) but not by 7-CK (glycine antagonist), D-AP5 (glutamate antagonist), or naloxone. Fentanyl (10 μM) did not stimulate NMDA receptors. Conclusion: These data indicate that Ultiva® but not fentanyl stimulates NMDA receptors of different subunit combinations (NR1A/2A, NR1A/2B). The mechanism seems to be allosteric activation of the NMDA receptor.

Fetoscopic Direct Fetal Cardiac Access in Sheep An Important Experimental Milestone Along the Route to Human Fetal Cardiac Intervention

BackgroundFetal cardiac interventions by direct ultrasound-guided approaches or open fetal cardiac surgery have been fraught with technical difficulties, as well as with significant maternal and fetal morbidity in humans. Therefore, the purpose of our study in sheep was to assess the feasibility and potential of fetoscopic direct fetal cardiac access. Methods and ResultsIn 15 anesthetized pregnant ewes (88 to 109 days of gestation; term, 145 days), 3 to 4 trocars were percutaneously placed in the uterus. Using videofetoscopic equipment, we assessed the feasibility of achieving direct fetal cardiac access. Minimally invasive direct fetal cardiac access by operative fetoscopy was achieved in 10 of the 15 fetal sheep. In 7 fetuses, the approach was successfully tested for fetal cardiac pacing (n=5) or antegrade fetal cardiac catheterization (n=2). Access was not achieved in 5 fetuses because of bleeding complications (n=2) or because the fetoscopic setup could not be established (n=3). All but 2 fetal sheep were alive at the end of the procedure. Acute fetal demise resulted from maternal hypotension or kinking of the fetal inferior caval vein by sternal suspension. Six ewes continued gestation; 3 of these went to term, with a normal fetal outcome. Two ewes died from septicemia 3 and 7 days after the procedure, and 1 ewe aborted 1 month after the procedure. ConclusionsMinimally invasive direct fetal cardiac access by operative fetoscopy is feasible in fetal sheep. The fetoscopic approach carries important potential for fetal cardiac pacing, antegrade fetal valvuloplasties, and resection of fetal intrapericardial teratomas in human fetuses.

Receptors, G proteins, and their interactions

Membrane receptors coupling to intracellular G proteins (G protein–coupled receptors) form one of the major classes of membrane signaling proteins. They are of great importance to the practice of anesthesiology because they are involved in many systems of relevance to the specialty (cardiovascular and respiratory control, pain transmission, and others) and many drugs target these systems. In recent years, understanding of these signaling systems has grown. The structure of receptors and G proteins has been elucidated in more detail, their regulation is better understood, and the complexity of interactions between the various parts of the system (receptors, G proteins, effectors, and regulatory molecules) has become clear. These findings may help explain both actions and side effects of drugs. In addition, these newly discovered targets are likely to play important roles in disease states of relevance to anesthesiologists.

Operative techniques and strategies for minimally invasive fetoscopic fetal cardiac interventions in sheep.

AbstractBackground: Recent efforts to develop procedures for fetoscopic fetal cardiac interventions have been prompted by the development of severe secondary damage to the fetal heart due to semilunar valvar obstructions and the poor outcome of therapy-refractory fetal arrhythmias. The purpose of our manuscript is to analyze and share our experience with the creation of an operative setup for these procedures in sheep. Methods: We studied a total of 48 fetal sheep between 81 and 106 days of gestation (term, 145 days). After entering the amniotic cavity by a percutaneous approach, we performed various fetoscopic fetal cardiac procedures. We analyzed the success of percutaneous fetal access, methods of trocar support, the incidence and management of trocar dislodgement or accidental insertion into the chorioamniotic space, problems related to amniotic insufflation and trocar placement, as well as techniques for fetal posturing and uterine closure. Results: Percutaneous fetal access was achieved in all sheep. The use of resterilizable trocars substantially decreased the costs of our procedures. Utilizing a percutaneous transuterine purse-string suture for trocar support helped to minimize the number of nonabsorbable T-fasteners remaining inside the uterus postoperatively. As complications such as trocar dislodgement, insertion of the trocar into the chorioamniotic space, and problems with intraamniotic insufflation and gas loss were mastered, conversion to an open operative approach was never required. A novel strategy that we devised for percutaneous fetal posturing permitted adequate fetal posturing with ease and minimal trauma to the fetal skin. Conclusion: As operative techniques have become more refined, the feasibility of performing fetoscopic fetal cardiac interventions in human fetuses now depends mainly on technical improvements in imaging and interventional catheters, as well as advances in pacemaker equipment.

Antidepressants as long-acting local anesthetics

t o m c g r t s i p w or a variety of reasons, ever more operations are being performed as outpatient surgery. As he envelope of the feasible is gradually stretched, it as become clear that postoperative pain is one of he major factors necessitating admission to the ospital. Conversely, the ability to provide proonged, effective pain relief at home would allow ignificantly more procedures to be performed on n outpatient basis. A major research effort is thereore underway to develop approaches for prolonged ain relief in this setting. Much of this effort focuses n regional and local anesthesia: prolonged (prefrably differential) nerve blockades using catheter echniques are being investigated, slow-release reparations of local anesthetics have been develped, and new, very-long-acting compounds are eing studied. Within the latter group, the antideressants occupy a prominent place. Their analgesic roperties have been known for some time,1,2 both n the setting of neuropathic pain3 and inflammaory pain.4 However, the observation that these ompounds block neuronal Na channels5 stimuated further developments in the field, since they ould now rightfully be considered as local aneshetics. In a variety of models, these compounds ave indeed been shown to have local anesthetic ctions and frequently exhibit duration of action hat is many times greater than that of classical local nesthetics. Thus, they might potentially be useful o provide long-lasting analgesia when used for erve blockade for outpatient surgery. A variety of compounds are being investigated, ncluding such classic tricyclic antidepressants as mitriptyline, imipramine, and doxepin, as well as ore recently synthesized derivatives, such as -phenylethyl-amitriptyline, and N-methyl-ami-

Fetal Plasma Concentrations after Intraamniotic Sufentanil in Chronically Instrumented Pregnant Sheep

Background Rapid progress is being made in fetal surgery. Because the fetus is capable of pain perception after the 26th week of gestation, adequate postoperative fetal pain management is essential. The preferred approach would provide fetal analgesia without affecting the mother. Intraamniotically administered sufentanil may be an interesting option if it achieves therapeutic plasma concentrations (PCs) in the fetus but not the mother. Methods After approval of the study, 25 or 50 &mgr;g sufentanil was administered intraamniotically in 10 chronically instrumented pregnant ewes. Maternal and fetal vital signs, arterial blood gases, and uterine blood flow were recorded over 120 min. Sufentanil PCs were determined before and 1, 3, 5, 10, 15, 30, 45, 60, 90, and 120 min after injection. Statistical analysis was performed using one- or two-way analysis of variance followed by Dunnett or Tukey test, as appropriate (P < 0.05; data presented as median [95% confidence interval]). Results After 25 &mgr;g sufentanil, fetal PC stabilized at 134 ± 89 pg/ml (after 10 min), and maternal PCs stabilized at 44 ± 11 pg/ml (after 15 min). After 50 &mgr;g sufentanil, fetal PCs stabilized at 134 ± 35 pg/ml (after 15 min), and maternal PCs reached 80 ± 25 pg/ml (at 30 min). Injection of 25 &mgr;g sufentanil intraamniotically did not affect maternal or fetal hemodynamics, uterine blood flow, or arterial blood gases. Fetal heart rate increased after administration of 50 &mgr;g sufentanil (maximum change at 10 min: +16 ± 12%). Conclusion The sheep fetus absorbs sufentanil after intraamniotic instillation. Significantly greater PCs were obtained in the fetal lamb as compared with the ewe. This suggests that investigation of intraamniotic opioids for fetal analgesia might be worthwhile.

Effects of Cafedrine/Theodrenaline, Etilefrine and Ephedrine on Uterine Blood Flow during Epidural-Induced Hypotension in Pregnant Sheep

Introduction:Maternal hypotension is a major concern in obstetric anesthesia, and concerns have been raised about standard vasopressor therapy with ephedrine. Therefore, we evaluated the maternal and fetal hemodynamic effects of two potential alternatives to ephedrine. Methods: Hypotension was induced by epidural administration of lidocaine in 6 chronically instrumented pregnant ewes (at 118–122 days of gestation, term 145 days). Three treatments were studied: 25 mg ephedrine, 5 mg etilefrine and 100 mg cafedrine/5 mg theodrenaline (C/T) intravenously. Mean fetal and maternal blood pressure and heart rate, uterine blood flow, as well as fetal and maternal arterial blood gases were recorded for 60 min. Results:All three vasopressors increased maternal blood pressure, accompanied by a significant increase in uterine blood flow. C/T caused marked maternal tachycardia, whereas ephedrine decreased maternal heart rate. Maternal and fetal blood gases did not change during any of the three treatment regimens. Conclusion:All three vasopressors restored maternal blood pressure and uterine blood flow after epidurally induced maternal hypotension. However, restoration of uterine perfusion was delayed and less pronounced with C/T.

Effects of calcium and magnesium pretreatment on hyperkalaemic cardiac arrest in rats.

Background and objective: Administration of calcium safely and effectively reverses many of the electrophysiological actions of hyperkalaemia, but it has not been studied for pretreatment. Based on cellular studies, magnesium also has been suggested to prevent the effects of potassium on the heart. As their mechanisms of action differ, a combination of these drugs might have a synergistic protective action. Both compounds are inexpensive and can be administered safely in modest doses. We investigated whether magnesium, calcium or their combination could protect against hyperkalaemic cardiac arrest. Methods: Twenty-four adult rats were anaesthetized with halothane and randomly pretreated with CaCl2 15 mg kg−1, MgSO4 30 mg kg−1, CaCl2 7.5 mg kg−1 + MgSO4 15 mg kg−1 or physiological saline. Potassium (0.01 mmol kg−1 h−1) was infused. The times to the first dysrhythmia, mean arterial pressure decrease to <40% of baseline and cardiovascular collapse were measured. Results: Serum potassium concentrations increased to similar values in all groups (to 12.0 ± 0.2 mmol L−1 at the time of collapse). No differences in survival times were observed between groups. There was a trend for respiratory values to be better in the group receiving magnesium. Conclusions: Pretreatment with magnesium, calcium or a combination of both did not influence the time to cardiovascular collapse, and is therefore - at least in our model - not of any benefit in preventing hyperkalaemic cardiac arrest.

Local anesthetics inhibit thromboxane A2 signaling in Xenopus oocytes and human k562 cells.

ThromboxaneA2 (TXA2)has been proposed as a mediator of perioperative myocardial ischemia, vasoconstriction, and thrombosis. As these adverse events are minimized with epidural anesthesia, rather than general anesthesia, we hypothesized that local anesthetics would inhibit TXA2-receptor signaling. We used fluorometric determination of intracellular [Ca2+] in human K562 cells and 2-electrode voltage clamp measurements in Xenopus laevis oocytes expressing TXA2 receptors. After 10-min incubation, lidocaine (IC50: 1.02 ± 0.2 × 10−3 M), ropivacaine (IC50: ropivacaine 6.3 ± 0.9 × 10−5 M), or bupivacaine (IC50: 1.42 ± 0.08 × 10−7 M) inhibited TXA2-induced [Ca2+]i in K562 cells. These data were confirmed in Xenopus oocytes recombinantly expressing TXA2 receptors, with IC50s of bupivacaine 1.2 ± 0.2 × 10−5 M, R(+) ropivacaine 4.9 ± 1.7 × 10−4 M, S(−) ropivacaine 5.3 ± 0.9 × 10−5 M, and lidocaine 6.4 ± 2.8 × 10−4 M. Intracellular pathways activated by IP3 and GTPγS were not significantly affected by the local anesthetics tested. QX314, a positively charged lidocaine analog, inhibited only if injected intracellularly (IC50: 5.3 ± 1.7 × 10−4 M), indicating one local anesthetic target is most likely inside the cell. Benzocaine (largely uncharged) inhibited with an IC50 of 8.7 ± 1.8 × 10−4 M. This suggests that some of the beneficial effects of regional anesthesia techniques might be due to direct interaction of local anesthetics with the functioning of membrane proteins.