Treatment of intraoperative hypotension with cafedrine/theodrenaline versus ephedrine : A prospective, national, multicenter, non-interventional study-the HYPOTENS trial.

BACKGROUND: Sympathomimetic drugs are a therapeutic cornerstone for the management of hypotensive states like intraoperative hypotension (IOH). While cafedrine/theodrenaline (C/T) is widely used in Germany to restore blood pressure in patients with IOH, more research is required to compare its effectiveness with alternatives such as ephedrine (E) that are more commonly available internationally. METHODS: HYPOTENS (NCT02893241, DRKS00010740) was a prospective, national, multicenter, open-label, two-armed, non-interventional study that compared C/T with E for treatment of IOH. We describe a prospectively defined cohort of patients ≥50 years old with comorbidities undergoing general anesthesia induced with propofol and fentanyl. Primary objectives were to examine treatment precision, rapidity of onset and the ability to restore blood pressure without relevant increases in heart rate. Secondary endpoints were treatment satisfaction and the number of required additional boluses or other accompanying measures. RESULTS: A total of 1496 patients were included in the per protocol analysis. Overall, effective stabilization of blood pressure was achieved with both C/T and E. Post-hoc analysis showed that blood pressure increase from baseline was more pronounced with C/T. Fewer additional boluses or other accompanying measures were required in the C/T arm. The incidence of tachycardia was comparable between groups. Post-hoc analysis showed that E produced dose-dependent elevated heart rate values. By contrast, heart rate remained stable in patients treated with C/T. Physicians reported a higher level of treatment satisfaction with C/T, with a higher proportion of anesthetists rating treatment precision and rapidity of onset as good or very good when compared with E. CONCLUSION: Neither drug was superior in restoring blood pressure levels; however, post-hoc analyses suggested that treatment is more goal-orientated and easier to control with C/T. Heart rate was shown to be more stable with C/T and fewer additional interventions were required to restore blood pressure, which could have contributed to the increased treatment satisfaction reported by anesthetists using C/T.

The effectiveness of an oral opioid rescue medication algorithm for postoperative pain management compared to PCIA : A cohort analysis.

BACKGROUND: Standard protocols or algorithms are considered essential to ensure adequate analgesia. Germany has widely adopted postoperative protocols for pain management including oral opioids for rescue medication, but the effectiveness of such protocols has only been evaluated longitudinally in a before and after setting. The aim of this cohort analysis was to compare the effectiveness of an oral opioid rescue medication algorithm for postoperative management of pain to the gold standard of patient-controlled intravenous analgesia (PCIA). MATERIAL AND METHODS: This study compared cohorts of patients of two prospective observational studies undergoing elective total hip replacement. After surgery patients received piritramide to achieve a pain score of ≤3 on the numeric rating scale (NRS 0-10). A protocol was started consisting of oral long-acting oxycodone and ibuprofen (basic analgesia). Cohort 1 (C1, 126 patients) additionally received an oral opioid rescue medication (hydromorphone) when reporting pain >3 on the NRS. Cohort 2 (C2, 88 patients) was provided with an opioid by PCIA (piritramide) for opioid rescue medication. Primary endpoints were pain intensity at rest, during movement, and maximum pain intensity within the first 24 h postoperative. Secondary endpoints were opioid consumption, functional outcome and patient satisfaction with pain management. RESULTS: Pain during movement and maximum pain intensity were higher in C1 compared to C2: pain on movement median 1st-3rd quartile: 6 (3.75-8) vs. 5 (3-7), p = 0.023; maximum pain intensity: 7 (5-9) vs. 5 (3-8), p = 0.008. There were no differences in pain intensity at rest or between women and men in either group. The mean opioid consumption in all patients (combined PACU, baseline, and rescue medication; mean ± SD mg ME) was 126.6 ± 51.8 mg oral ME (median 120 (87.47-154.25) mg ME). Total opioid consumption was lower in C1 than C2 (117 ± 46 mg vs 140 ± 56 mg, p = 0.002) due to differences in rescue opioids (C1: 57 ± 37 mg ME, C2: 73 ± 43 mg ME, p = 0.006, Z = -2.730). Basic analgesia opioid use was comparable (C1: 54 ± 31 mg ME, C2: 60 ± 36 mg ME, p = 0.288, Z = -1.063). There were no differences in respect to the addition of non-opioids and reported quality of mobilization, sleep, frequency of nausea and vomiting, or general satisfaction with pain management. CONCLUSION: In this study PCIA provided a better reduction of pain intensity, when compared to a standardized protocol with oral opioid rescue medication. This effect was associated with increased opioid consumption. There were no differences in frequencies of opioid side effects. This study was a retrospective analysis of two cohorts of a major project. As with all retrospective studies, our analysis has several limitations to consider. Data can only represent the observation of clinical practice. It cannot reflect the quality of a statement of a randomized controlled trial. Observational studies do not permit conclusions on causal relationships.

Prediction of postoperative opioid analgesia using clinical-experimental parameters and electroencephalography.

BACKGROUND: Opioids are often used for pain treatment, but the response is often insufficient and dependent on e.g. the pain condition, genetic factors and drug class. Thus, there is an urgent need to identify biomarkers to enable selection of the appropriate drug for the individual patient, a concept known as personalized medicine. Quantitative sensory testing (QST) and clinical parameters can provide some guidance for response, but better and more objective biomarkers are urgently warranted. Electroencephalography (EEG) may be suitable since it assesses the central nervous system where opioids mediate their effects. METHODS: Clinical parameters, QST and EEG (during rest and tonic pain) was recorded from patients the day prior to total hip replacement surgery. Postoperative pain treatment was performed using oxycodone and piritramide as patient-controlled analgesia. Patients were stratified into responders and non-responders based on pain ratings 24 h post-surgery. Parameters were analysed using conventional group-wise statistical methods. Furthermore, EEG was analysed by machine learning to predict individual response. RESULTS: Eighty-one patients were included, of which 51 responded to postoperative opioid treatment (30 non-responders). Conventional statistics showed that more severe pre-existing chronic pain was prevalent among non-responders to opioid treatment (p = 0.04). Preoperative EEG analysis was able to predict responders with an accuracy of 65% (p = 0.009), but only during tonic pain. CONCLUSIONS: Chronic pain grade before surgery is associated with the outcome of postoperative pain treatment. Furthermore, EEG shows potential as an objective biomarker and might be used to predict postoperative opioid analgesia. SIGNIFICANCE: The current clinical study demonstrates the viability of EEG as a biomarker and with results consistent with previous experimental results. The combined method of machine learning and electroencephalography offers promising results for future developments of personalized pain treatment.

[Process control in acute pain management. An analysis of the degree of organization of applied standard protocols]. / Prozesssteuerung in der Akutschmerztherapie. Eine Analyse des Organisationsgrades angewandter Behandlungsstandards.

BACKGROUND: The aim of this study was to analyze the degree of organization of different standard protocols for acute pain management, as well as the derivation and definition of typical but structurally different models. METHODS: A total of 85 hospitals provided their written standardized protocols for analysis. Protocols for defined target processes from 76 hospitals and another protocol used by more than one hospital were included into the analysis. The suggested courses of action were theoretically simulated to identify and characterize process types in a multistage evaluation process. RESULTS: The analysis included 148 standards. Four differentiated process types were defined ("standardized order", "analgesic ladder", "algorithm", "therapy path"), each with an increasing level of organization. These four types had the following distribution: 27 % (n = 40) "standardized order", 47 % (n = 70) "analgesic ladder", 22 % (n = 33) "algorithm", 4 % (n = 5) "therapy path". Models with a higher degree of organization included more control elements, such as action and intervention triggers or safety and supervisory elements, and were also associated with a formally better access to medication. For models with a lower degree of organization, immediate courses of action were more dependent on individual decisions. Although not quantifiable, this was particularly evident when simulating downstream courses of action. Interfaces between areas of hospital activity and a cross-departmental-boundary validity were only considered in a fraction of the protocols. Concepts from clinics with a certificate in (acute) pain management were more strongly process-oriented. For children, there were proportionately more simple concepts with a lower degree of organization and less controlling elements. CONCLUSION: This is the first analysis of a large sample of standardized protocols for acute pain management focusing on the degree of organization and the possible influence on courses of action. The analysis shows how different the structures and presumably the practical objectives of the various concepts are. The analyzed protocols with a lower degree of organization can manage only the assignment of a particular medication to the corresponding patient group, with a presumably high requirement for considerable implicit knowledge of the responsible employees. Accordingly, a requirement for such protocols should be that they not only describe the preferred standard therapy, but also define the interactions between the staff members involved. It remains questionable whether a protocol with a low level of organization and a comparably high requirement for implicit knowledge and individual action--also from nonmedical personnel--is able to ensure efficient pain therapy, particularly in view changing staff and dynamic responses to changing pain situations.

[Process optimization by central control of acute pain therapy: implementation of standardized treatment concepts and central pain management in hospitals]. / Prozessoptimierung durch zentrale Steuerung der Akutschmerztherapie : Implementierung von standardisierten Behandlungskonzepten und zentralem Schmerzmanagement im Krankenhaus.

BACKGROUND: The aim of this investigation was to describe the effects of standardization and central control of the processes involved in postoperative pain management from patient and employee perspectives. MATERIALS AND METHODS: Patients (n = 282/307) and respective hospital staff (n = 149/119) evaluated the processes, the quality of postoperative pain management and result parameters 3 months before and 12 months after the introduction of standardization of the postoperative pain therapy process using a set of standardized questionnaires. RESULTS: Pain level and the waiting period for an analgesic partially decreased and a higher subjective effectiveness of medication was achieved in patients after the standardization. Patients felt that the pain was taken more seriously and contacted the staff for additional medication more frequently. From an employee viewpoint the quality of care and individual competence and ability to treat pain increased after the introduction of standardization. Pain assessment was improved and employees rated their knowledge and education level as higher than before the intervention. Patients with pre-existing chronic pain and patients with special regional therapy benefited only partially after the introduction and an increase in pain intensity was even observed. CONCLUSIONS: The quality of care was improved by standardization of the postoperative pain management. The legal and practical ability of the nursing stuff to administer pain medication within well-defined margins reduced the dependence on the ward doctor and at the same time patient pain levels. Patients received analgesics more quickly and experienced increased effectiveness. These results should be an incentive to reconsider the importance of the organization of postoperative pain management, because the quality of care with all potential medical and economic advantages, can be easily optimized by such simple mechanisms. They also show that the quality assessment of acute pain and the selection of appropriate indicators need further development.

Reliability of continuous cardiac output determination by pulse-contour analysis in porcine septic shock.

BACKGROUND: Pulse-contour analysis represents a technique for cardiac output (CO)-measurement and allows continuously monitoring trends in CO. We evaluated reliability of pulse-contour CO (COpc) in septic shock. METHODS: Seventeen anaesthetized and mechanically ventilated pigs were investigated. After baseline measurements, 14 animals received 0.75 g/kg body weight faeces into the abdominal cavity to induce sepsis and were observed over 9 h, three animals served as controls. A central venous catheter was inserted into the jugular vein and an arterial catheter for thermodilution was inserted into the femoral artery. Two bedside computers were used for COpc. After induction of sepsis, COpc-computer No. 1 (COpcCAL) was recalibrated hourly. No further calibrations were performed in computer No. 2 (COpcNoCAL). We directly compared COpcCAL hourly before recalibration with COpcNoCAL. One hundred and seventy parallel triplicate determinations of CO were analysed using the method of Bland-Altman. RESULTS: Three hours after sepsis induction, correlation between recalibrated and non-recalibrated CO was r = 0.74, P < 0.01, at 5 h r = 0.59, P < 0.05 and 9 h r = 0.02, NS. Three hours after sepsis induction, bias +/- SD (limits of agreement) between both groups was 1.6 +/- 15.5 (-29.4-32.6) ml/kg/min, at 5 h -15.0 +/- 24.3 (-63.6-33.7) ml/kg/min and at 9 h -87.0 +/- 90.8 (-268.5-94.6) ml/kg/min. CONCLUSION: Continuous CO determination using pulse-contour analysis is a reliable method of assessing CO up to 5 h without recalibration in porcine septic shock. Thus, COpc may be a useful tool for assessment of unpredictable haemodynamic changes in sepsis.

[Aseptic central venous catheter exchange with a guide wire]. / Aseptischer Wechsel des zentralen Venenkatheters über einen Führungsdraht.

Central venous catheters are exchanged in cases of malfunction, suspected infections, or when another catheter type is required. It can be replaced by new venipuncture or using a guide wire. The guide wire technique should be used with a defective catheter or when the catheter type is to be changed. It is contraindicated at exit site infections or proven or suspected catheter infections. Due to possible cross contamination of new by old catheter material meticulous aseptic technique is required. A detailed description of the process of catheter exchange using a guide wire with special regard to the aseptic technique is given.

HLA-B*4431: a new HLA-B variant with a complex ancestral history involving HLA-B*44, B*40 and B*07 alleles.

We here describe the identification of the new allele HLA-B*4431, which was found in three members of a Turkish family. Sequencing of the new allele following haplotype-specific PCR amplification revealed that exon 2 is identical to HLA-B*4402, whereas exon 3 resembles a HLA-B*40 variant with the exception of position 572, where a single nucleotide transversion (C > G) leads to an amino acid exchange (Trp162Ser). The generation of the 3' part of B*4431 may be best explained by a separate recombination between B*40 and B*07. Although B*4431 consists of B44 in its alpha1 domain and of B60(40) in its alpha2 domain; the new allele only displayed B44 seroreactivity, which demonstrates that epitopes crucial for B60(40) specificity must be located in the alpha1 domain.

C1-Inhibitor for treatment of acute vascular xenograft rejection in cynomolgus recipients of h-DAF transgenic porcine kidneys.

At present, the major barrier to successful discordant xenotransplantation of unmodified or complement regulator transgenic porcine xenografts is acute vascular xenograft rejection (AVR). AVR is associated with the intragraft deposition of induced recipient xenoreactive antibodies and subsequent complement activation. In a life-supporting pig to primate kidney xenotransplantation setting using h-DAF transgenic donor organs and postoperative immunosuppression, episodes of AVR were either treated with boluses of cyclophosphamide and steroids or with the same regimen supplemented by a three-day course of C1-Inhibitor, a multifunctional complement regulator. In 8 out of 10 animals stable initial graft function was achieved; in all animals one or more episodes of AVR were observed. When, in 4 animals, C1-Inhibitor was added to the standard anti-rejection treatment regimen, AVR was successfully reversed in 6 out of 7 episodes, while in another group of 4 animals receiving the standard anti-rejection treatment 0 out of 4 episodes of AVR responded to treatment. Response to anti-rejection treatment was associated with a significant increase in recipient survival time. We conclude that AVR of h-DAF transgenic porcine kidneys can be successfully treated by additional short-term fluid phase complement inhibition.

Hemodynamic consequences of porcine kidney xenograft reperfusion in cynomolgus monkeys.

BACKGROUND: After xenograft reperfusion, complement activation may lead to generation of anaphylatoxins and cardiocirculatory instability of the recipient. METHODS: In 13 cynomolgus recipients of either unmodified or human decay accelerating factor transgenic porcine kidneys cardiocirculatory parameters were measured by single indicator transpulmonary thermodilution. RESULTS: After graft reperfusion, recipient cardiac output decreased by 25.4% (P<0.05), intrathoracic blood volume by 22.8% (P<0.05), extravascular lung water increased slightly (P=n.s.). The impairment in cardiac output was neither influenced by the graft's weight or human decay accelerating factor transgenicity. sC3a and sC5b-9 complement levels in the recipient monkeys showed a sharp peak upon reperfusion. CONCLUSIONS: After reperfusion a marked and significant cardiodepression accompanied by relative volume depletion were observed. Analysis of volume status ruled out a mere volume shift as the underlying reason for the observed drop in cardiac output. These data may be relevant for the perioperative management of human recipients of discordant xenografts in the future.

A primate model for discordant pig to primate kidney xenotransplantation without hyperacute graft rejection.

Organs transplanted between phylogenetically disparate species, such as from the pig into the primate, are subject to intragraft deposition of preformed recipient immunoglobulin M (IgM) antibodies with subsequent complement activation finally leading to complete and rapid destruction of the xenograft (hyperacute graft rejection, HAR). Current therapeutic strategies for abrogation of HAR include pretransplant antibody absorption by specific or nonspecific extracorporeal column perfusion, ex vivo donor organ perfusion, the administration of substances interfering with complement activation, or even the genetic alteration of the donor. Here, in the pig to cynomolgus monkey species combination, we are describing an experimental model for abrogation of HAR by using large, relative to the recipient weight, oversized donor kidneys as xenotransplants. Porcine kidney xenotransplantation (n = 15) was performed using large white pigs of different weights and ages as organ donors and cynomolgus monkeys as recipients. In grafts with an organ weight below 50 g (20 to 48 g, median 25 g), primary nonfunction (PNF) of the porcine kidney was observed in 11 out of 12 cases and complete HAR in 5 out of 12 experiments. In contrast, none of three grafts with a donor organ weight >70 g showed signs of HAR or PNF. In one animal, a second porcine kidney from the same donor (23 g) was successfully transplanted immediately after HAR and subsequent removal of a first porcine kidney (20 g). By using appropriate immunohistochemistry stainings of reperfusion biopsies, profound deposition of recipient natural antibodies in both small and large xenografts was shown, with only scarce deposition of C3 and C5b-9 in the latter, indicating only incomplete intragraft activation of the complement cascade in these organs. Intraoperative cardiac output (CO) measurements performed in 7 experiments demonstrated a 20 to 50% decrease in CO following reperfusion in 6 out of 7 grafts irrespective of the donor organ weight. The intraoperative decrease in CO was not associated with perioperative morbidity or mortality. The use of oversized doner kidneys can enable the study of a variety of immunologic and physiologic sequela beyond HAR associated with life-supporting discordant primate kidney transplantation.

Analysis of potential porcine endogenous retrovirus (PERV) transmission in a whole-organ xenotransplantation model without interfering microchimerism.

The question whether porcine xenografts can lead to porcine endogenous retrovirus (PERV) infection of recipients is critical for the evaluation of the safety of pig-to-man xenotransplantation. Unfortunately, polymerase chain reaction (PCR)-based analysis of potential PERV infections in nonhuman-primate whole-organ xenotransplantation models is hampered by false positive results due to chimeric porcine cells. To avoid the inherent analytical problem of xenomicrochimerism, we developed a non-life-supporting pig-to-primate kidney xenotransplantation model: porcine kidneys were transplanted, whereas the functioning recipient kidneys remained in situ. Subsequent to rejection (after 2 hours to 15 days), xenografts were removed, and recipients remained alive for up to 287 days. Immunosuppressive therapy based on cyclophosphamide, cyclosporine, and steroids was maintained for 28 days after transplantation. Using appropriate PCR assays, xenochimerism was found in tissue samples and partly even in peripheral blood leukocytes (PBLs) while the porcine kidneys were in situ. After graft removal, xenochimerism was no longer detectable, thus allowing analysis for possible PERV transmission.

Acute vascular rejection is associated with systemic complement activation in a pig-to-primate kidney xenograft model.

The introduction of h-DAF transgenic porcine organs into pre-clinical pig-to-primate discordant xenotransplantation has led to complete and reliable abrogation of hyperacute xenograft rejection (HAR). Despite additional heavy immunosuppression however, most xenografts are still lost due to acute vascular rejection (AVR), with current treatment protocols being of only limited value. In a life-supporting model of pig-to-primate kidney transplantation, unmodified (n=8) or h-DAF-transgenic (n=9) porcine kidneys were transplanted into cynomolgus monkeys under cyclophosphamide (CyP), cyclosporine and low-dose steroid immunosuppression. Longest recipient survival was 11 days in the control group and 68 days in the h-DAF transgenic group. Stable initial graft function with recipient survival >4 days was generated in eight animals (two controls and six transgenics). In these animals, plasma complement levels were analyzed during ongoing AVR. Compared with baseline levels, a two-fold increase in C3a levels and a four-fold increase in sC5b-9 levels were measured. In parallel to systemic complement activation, increased deposition of C3 and C5b-9 along with massive staining for recipient IgM immunoglobulins was detected in the xenografts on immunohistochemistry. We conclude that acute vascular xenograft rejection of porcine kidneys in cynomolgus monkeys is associated with classical pathway complement activation following binding of induced recipient anti-porcine antibodies. This complement activation can be observed despite membrane bound expression of human complement regulators in the porcine xenografts. Therefore, additional short-term fluid phase complement inhibition seems necessary for the future development of protocols designed for treatment of AVR in the pig-to-primate combination.