Non-opioid analgesic modes of pain management are associated with reduced postoperative complications and resource utilisation: a retrospective study of obstructive sleep apnoea patients undergoing elective joint arthroplasty.

BACKGROUND: Studies on the effectiveness of multimodal analgesia, particularly in patients at higher perioperative risk from obstructive sleep apnoea (OSA), are lacking. We aimed to assess the impact of multimodal analgesia on opioid use and complications in this high-risk cohort. METHODS: We conducted a population-based retrospective cohort study of OSA patients undergoing elective lower extremity joint arthroplasty (2006-16, Premier Healthcare database). Multimodal analgesia was defined as opioid use with the addition of one, two, or more non-opioid analgesic modes including, nonsteroidal anti-inflammatory drugs (NSAIDs), cyclooxygenase-2 inhibitors, paracetamol/acetaminophen, peripheral nerve blocks, steroids, gabapentin/pregabalin, or ketamine. Multilevel multivariable regression models measured associations between multimodal analgesia and opioid prescription (primary outcome; oral morphine equivalents). Secondary outcomes included opioid- and OSA-related complications, and resource utilisation. Odds ratios (OR) or % change and 95% confidence intervals (CI) are reported. RESULTS: Among 181 182 OSA patients included, 88.5% (n = 160 299) received multimodal analgesia with increasing utilisation trends. Multivariable models showed stepwise beneficial postoperative outcome effects with increasing additional analgesic modes compared with opioid-only analgesia. In patients who received more than two additional analgesia modes (n = 64 174), opioid dose prescription decreased by 14.9% (CI -17.0%; -12.7%), while odds were significantly decreased for gastrointestinal complications (OR 0.65, CI 0.53; 0.78), mechanical ventilation (OR 0.23, CI 0.16; 0.32), and critical care admission (OR 0.60, CI 0.48; 0.75), all P<0.0001. CONCLUSIONS: In a population at high risk for perioperative complications from OSA, multimodal analgesia was associated with a stepwise reduction in opioid use and complications, including critical respiratory failure.

Child-Pugh versus MELD score in predicting survival in patients undergoing transjugular intrahepatic portosystemic shunt.

BACKGROUND: In patients undergoing transjugular intrahepatic portosystemic shunt (TIPS), prognostic scores may identify those with a poor prognosis or even those with a clear survival benefit. The Child-Pugh score (CPS) is well established but several drawbacks have led to development of the model of end stage liver disease (MELD). AIM: The aim of the study was to compare the predictive power of CPS and MELD, to validate the original MELD formula, and to assess the predictive value of the determinants used in the two prognostic scores outside of a study setting. PATIENTS: A total of 501 patients underwent elective TIPS placement and 475 patients fulfilled the inclusion criteria. METHODS: Data of all patients undergoing elective TIPS in one university hospital and four community hospitals in Vienna, Austria, between 1991 and 2001, were analysed retrospectively. The main statistical tests were Cox proportional hazards regression model, the log rank test, Kaplan-Meier analysis, and concordance c statistics. RESULTS: Median follow up was 5.2 years and median survival was 4.6 years. During follow up, 230 patients died, 75 within three months after TIPS placement. In stepwise proportional hazards analyses, independent predictors of death were creatinine level, bilirubin level, age, and refractory ascites. MELD was better in predicting survival in a stepwise Cox model but both scores were equally predictive in c statistics for one month, three month, and one year survival. Renal function was the strongest independent predictor of survival. CONCLUSIONS: Although MELD was the primary predictor of overall survival in multivariate analysis, c statistics showed that both scores can be used for patients undergoing TIPS with equal accuracy. For assessing prognosis in patients undergoing TIPS implantation, there seems little reason to replace the well established Child-Pugh score.

[Radiofrequency-thermoablation in malignant liver disease]. / Radiofrequenz-Thermoablation maligner Raumforderungen der Leber.

The clinical application of radiofrequency tumor ablation in primary liver tumors and metastatic liver disease is rapidly growing because this technique has proven to be simple, safe, and effective in first clinical studies. Most of the patients with malignant liver disease are not candidates for surgical resection due to localisation or comorbidity, so radiofrequency therapy offers a good alternative for inoperable patients. With this method, high frequency alternating current is delivered to tissue via a needle electrode, the produced heat leads to coagulation necrosis. The largest focus of necrosis that can be induced with the currently available systems is approximately 4 - 5 cm with a single application. The radiofrequency needle is usually placed with US or CT guidance. For follow up examinations CT and MRI can be used, they proved to be equally accurate in the assessment of treatment response.

Recombinant von Willebrand factor: preclinical development.

Von Willebrand factor (vWF) is a multimeric glycoprotein (GP) that attracts platelets to the site of vascular injury, mediates platelet-platelet interaction, and stabilizes factor VIII (FVIII) in the circulation. Quantitative and qualitative defects of vWF result in von Willebrand disease (vWD), manifested by modest to severe bleeding episodes. Substitution therapy, with plasma-derived FVIII/vWF complex concentrates, is used for patients suffering the more severe forms of vWD. Efficacy of these preparations is often unsatisfactory because inadvertent proteolytic degradation during the manufacturing process causes them to lack the hemostatically most active high-molecular-weight multimers. In contrast, recombinant vWF (r-vWF), which is constitutively expressed at high yields in Chinese hamster ovary (CHO) cells and secreted into the conditioned medium under perfusion fermentation in "protein-free" medium, has high-molecular-weight multimers of extraordinary structural integrity. Functional analysis has shown that r-vWF promotes ristocetin cofactor-mediated platelet aggregation, collagen interaction and FVIII binding, and platelet-collagen adhesion under shear stress. Infusing vWF-deficient animals with r-vWF corrected vWF concentration and reduced blood loss, subsequently stabilizing endogenous FVIII associated with the reduction of bleeding time. Compared with plasma-derived vWF preparations, r-vWF was found to have a prolonged half-life, further enhancing the potential value of r-vWF as a therapeutic agent for treating patients suffering from vWD.

Effects of alpha 1-acid glycoprotein on acute pancreatitis and acute lung injury in rats.

alpha 1-Acid glycoprotein (AAG), a highly negatively charged glycoprotein, well known for its capillary stabilizing effect, was tested in rat models of acute edematous pancreatitis, acute hemorrhagic-necrotizing pancreatitis, and acute respiratory distress syndrome (ARDS). In cerulein-elicited edematous pancreatitis AAG improved histological alterations at 200 mg/kg i.v. and plasma amylase activity at 1800 or 4200 mg/kg i.v. All other parameters (edema, plasma lipase) were not affected in a biologically relevant manner. In glycodeoxycholic acid-induced hemorrhagic-necrotizing pancreatitis AAG was without effect on parameters measured (plasma amylase, plasma lipase activity, histological scores) at 1800 or 4200 mg/kg i.v. At the extremely high dose of 1500 mg/kg i.v. plasma amylase and lipase levels were decreased. In lipopolysaccharide-mediated ARDS, AAG was tested at 50, 200 or 600 mg/kg i.v. AAG, but also the placebo formulation decreased the myeloperoxidase content in the bronchoalveolar lavage fluid. Histological alterations were improved by AAG, however, not by the placebo formulation. Lung water content was not significantly influenced by AAG, whereas Evans blue extravasation was significantly diminished by all three doses of AAG. It is concluded that the edematous pancreatitis is the first in vivo condition with increased extravascular fluid accumulation, in which AAG is not effective. Based on data presented here and literature data, there is evidence for a beneficial effect of AAG in acute lung injury.

Factor Xa and prothrombin: mechanism of action of FEIBA.

A complex consisting of activated factor X (FX) (enzyme) and prothrombin (substrate), both highly purified from human plasma and virus inactivated, was formulated, characterised biochemically as well as in animal studies, and given the name Partial Prothrombinase (PPT). In vitro, PPT shortened the clotting time of a high-titre human factor VIII (FVIII) inhibitor plasma in a manner similar to that of the activated prothrombin complex concentrate FEIBA and triggered coagulation in plasma samples in which factor V (FV) is present. In vivo, the ability of PPT to activate coagulation in both chimpanzees and baboons was equivalent to that of FEIBA. PPT also triggered coagulation in a von Willebrand factor(vWF)-deficient dog and controlled bleeding in rabbits with antibody-induced haemophilia A. Thus, studying the mechanism of action of PPT also explains the therapeutic principle of FEIBA.

Evidence for extracellular processing of pro-von Willebrand factor after infusion in animals with and without severe von Willebrand disease.

Although proteolytic processing of pro-von Willebrand factor (pro-vWF) resulting in free propeptide and mature vWF is known to be initiated intracellularly, vWF released from endothelial cells may contain a high proportion of incompletely processed pro-vWF. Because pro-vWF is only rarely detectable in normal human plasma, we investigated whether extracellular processing of pro-vWF is possible. A recombinant preparation (rpvWF) containing both pro-vWF and mature vWF subunits was infused into 2 pigs and 1 dog with severe von Willebrand disease, 2 mice with a targeted disruption of the vWF gene, and 2 healthy baboons. Total vWF antigen (vWF:Ag), free propeptide, and pro-vWF were measured using enzyme-linked immunosorbent assay techniques in blood samples drawn before and after infusion. vWF:Ag increased promptly. No pro-vWF could be detected when the first postinfusion sample was drawn after 30 minutes (pigs) or 60 minutes (mice), but pro-vWF was detectable for short periods when postinfusion samples were drawn after 15 minutes (dog) or 5 minutes (baboons). In contrast, free propeptide was increased at the first timepoint measured, suggesting that it was generated from the pro-vWF in the rpvWF preparation. vWF multimers were analyzed in the rpvWF preparation and in plasma samples drawn before and after infusion of rpvWF using ultra-high resolution 3% agarose gels to allow separation of homo- and hetero-forms of the vWF polymers. Within 30 minutes after infusion in the pigs, 1 hour in the dog and the mice, and within 2 hours in the baboons, the multimer pattern had changed to that typically seen in mature vWF. These data indicate that propeptide cleavage from unprocessed vWF can occur extracellularly in the circulation. The enzyme or enzymes responsible for this cleavage in plasma remain to be identified.

Preclinical evaluation of recombinant von Willebrand factor in a canine model of von Willebrand disease.

Dutch Kooiker dogs with hereditary von Willebrand disease (vWD) have undetectable levels of von Willebrand factor (vWF), resulting in spontaneous hemorrhage of mucosal surfaces similar to the clinical picture of vWD in humans. We used this canine model of vWD to study the in vivo effects of a new recombinant von Willebrand factor (rvWF) preparation that contained all species of vWF multimers compared with an rvWF fraction containing only low molecular weight multimers (LMW-rvWF) and with a plasma-derived factor VIII/vWF concentrate (pdvWF). Administration of rvWF in these vWF-deficient dogs resulted in a vWF:Ag half-life of 21.6 hours in one dog and 22.1 hours in a second dog. Administration of pdvWF resulted in a half-life for vWF:Ag of 7.7 hours, and LMW-rvWF, 9 hours. The in vivo recovery of vWF:Ag after administration of rvWF was 59, 64 and 70% in three dogs, respectively; 33% after pdvWF, and 92% after LMW-rvWF. The in vivo recovery of ristocetin cofactor (RCoF) was 78, 110 and 120% for rvWF, and 25% for pdvWF. Both rvWF and pdvWF caused increases in factor VIII. Although no effect was seen on bleeding time at the dosages used, the rate of blood flow from cuticle wounds was reduced after a single bolus administration of rvWF. The rvWF was able to control a severe nose bleed in one dog.

[Preclinical investigation of alpha 1-acid glycoprotein (orosomucoid)]. / Präklinische Untersuchung von alpha 1-saurem Glykoprotein (Orosomucoid).

The molecular properties of alpha 1-acid glycoprotein are briefly discussed. This molecule has been shown in in vitro experiments to have both a stabilizing effect on vascular permeability and antiinflammatory properties. We were able to demonstrate these two effects in vivo in guinea pigs (skin, Evan's Blue extravasation) and in rats (paw, carrageenan induced inflammation). Further experiments were performed in rats relating to possible therapeutic indications for alpha 1-acid glycoprotein: (1) inhibitory effect on brain edema formation after experimental stroke, (2) therapeutic effect in the puromycin aminonucleoside-induced minimal change nephrosis, (3) improvement of vital parameters in hemorrhagic-hypovolemic shock, (4) increase in survival rate in septic peritonitis, and (5) promising effects in burn-induced remote lung injury. The high content of sialic acid and the high negative charge of alpha 1-acid glycoprotein are believed to be major contributors to its stabilizing effect on vascular permeability. The protein is bound to the glycocalyx of the endothelial cells (and presumably to structures of the glomerular basement membrane), thereby hindering the passage of other polyanionic molecules through the vascular wall. The antiinflammatory/immunomodulatory effect of alpha 1-acid glycoprotein appears mainly due to suppression of polymorphonuclear neutrophils. This action is dependent on the glycan part of the molecule, which is highly variable (microheterogeneity). It is obvious that there are differences between the different glycan forms as far as the antiinflammatory property of the protein is concerned. Together with data in the literature, the results presented here suggest a variety of potential indications for therapeutic use of alpha 1-acid glycoprotein in humans.

[Endovascular brachytherapy for the prevention of recurrence after PTA]. / Endovasculäre Brachytherapie zur Rezidivprophylaxe nach PTA.

PURPOSE: Recurrent stenosis after PTA is caused by intimal hyperplasia and constrictive arterial remodeling. In experimental and first clinical studies, ionizing radiation has demonstrated its potential to control excessive intimal proliferation. We wanted to evaluate the safety, feasibility and efficacy of endoluminal irradiation after PTA and/or stent implantation. MATERIAL AND METHODS: From September 1996, 24 patients (24 lesions) who had a stenosis or occlusion measuring more than 5 cm in length in the superficial femoral artery or a restenosis after PTA underwent endoluminal irradiation. An isodose of 14 Gy was applied to the vessel wall using an Ir-192-HDR afterloading unit. The radiation was tolerated well; the additional time needed for the procedure was 30-45 min. RESULTS: In a mean follow-up time of 15 months we found a cumulative patency rate of 60%. No side effects were observed. CONCLUSION: Endovascular brachytherapy is a safe and brief procedure. In our selection of patients, a patency rate of approx. 40% after 1 year has to be expected. Thus, these first results are promising, although first published studies of endoluminal irradiation in peripheral vessels with stent implantation showed higher patency rates. No randomized data are currently available. We conclude that endovascular irradiation should be performed together with stent implantation in long lesions or recurrent stenosis after PTA, in order to control not only excessive intimal proliferation but also constrictive arterial remodeling.

Effects of human alpha-1-acid glycoprotein on aminonucleoside-induced minimal change nephrosis in rats.

A minimal change nephrosis was induced in rats by a single intraperitoneal injection of puromycin aminonucleoside (100 mg/kg). This resulted in increased urine protein output, plasma creatinine, blood urine nitrogen, and relative kidney weight. Electronoptically, there was a retraction of the glomerular podocytic foot processes. When human alpha1-acid glycoprotein was injected at 600 mg/kg intravenously on experimental days 6, 7, 8, and 9 into these animals, urine protein output decreased significantly, and the number of podocytic foot processes increased significantly. alpha1-Acid glycoprotein is rich in sialic acid and largely negatively charged. Its therapeutic role in nephrosis, which is characterized by a loss of sialic acid and a loss of negative charge, thereby leading to a loss of permselectivity, is discussed.

Effects of alpha 1-acid glycoprotein in different rodent models of shock.

It was the aim of the present study to investigate the effects of the acute phase protein alpha 1-acid glycoprotein in different models of shock. The human plasma preparation used was without effect on mortality in lipopolysaccharide-injected mice when administered in two different doses (1 or 0.33 g/kg i.v.) and according to different treatment schedules. The same preparation significantly increased survival rate (48 h) in rats with septic peritonitis. This effect was seen when alpha 1-acid glycoprotein (200 mg/kg i.v.) was given 15 min prior to and 24 h after cecal puncture. All other dose regimes tested were without significant effect on survival rate. A hemorrhagic/hypovolemic shock model (including a defined trauma) in rats resuscitated with 200 mg/kg alpha 1-acid glycoprotein resulted in significantly higher values of mean arterial blood pressure, cardiac output and stroke volume when compared to corresponding values obtained after resuscitation with Ringer's solution or 200 mg/kg albumin i.v. (free of alpha 1-acid glycoprotein; placebo formulation). Taking all other possible mechanisms of alpha 1-acid glycoprotein into consideration, the partially protective effects of the preparation are explained by enhancing the capillary barrier function and thereby maintaining perfusion of vital organs.

Evaluation of recombinant von Willebrand factor in a canine model of von Willebrand disease.

Dutch Kooiker dogs with hereditary von Willebrand disease have undetectable levels of von Willebrand factor (vWF), resulting in spontaneous haemorrhage of mucosal surfaces similar to the clinical picture of von Willebrand disease in humans. We used this canine model of von Willebrand disease to study the in vivo effects of a new recombinant von Willebrand factor (rvWF) preparation that contained all species of vWF multimers compared with a rvWF fraction containing only low molecular weight multimers (LMW-rvWF) and with a plasma-derived factor VIII/vWF concentrate (pdvWF). Administration of rvWF in these vWF-deficient dogs resulted in a vWF:Ag half-life of 21.6 h in one dog and 22.1 h in a second dog. Administration of pdvWF resulted in a half-life for vWF:Ag of 7.7 h, and LMW-rvWF, 9 h. The in vivo recovery of vWF:Ag after administration of rvWF was 59%, 64% and 70% in three dogs, respectively; 33% after pdvWF, and 92% after LMW-rvWF. The in vivo recovery of ristocetin cofactor (RCoF) was 78%, 110% and 120% for rvWF, and 25% for pdvWF. Both rvWF and pdvWF caused increases in FVIII. Although no effect was seen on bleeding time at the dosages used, the rate of blood flow from cuticle wounds was reduced after a single bolus administration of rvWF. The rvWF was able to control a severe nose bleed in one dog.

In vivo characterization of recombinant von Willebrand factor in dogs with von Willebrand disease.

Hereditary von Willebrand factor (vWF ) deficiency in Dutch Kooiker dogs, which have undetectable levels of vWF, causes spontaneous hemorrhage of mucosal surfaces similar to the clinical picture of von Willebrand disease in humans. Therefore, we used this canine model to study the in vivo effects of a new recombinant von Willebrand factor (rvWF ) preparation containing all species of vWF multimers compared with a rvWF fraction containing only low molecular weight multimers (LMW-rvWF ) and with a plasma-derived factor VIII/vWF concentrate (pdvWF ). In the vWF-deficient dogs, the half-life of vWF:Ag was 21.6 and 22.1 hours for rvWF, 7.7 hours for pdvWF, and 9 hours for LMW-rvWF; in vivo recovery of vWF:Ag was 59%, 64%, and 70% for rvWF, 33% for pdvWF and 92% for LMW-rvWF; in vivo recovery of RCoF was 78%, 110%, and 120% for rvWF, and 25% for pdvWF. Both rvWF and pdvWF caused increases in factor VIII, which were sustained even when vWF:Ag had decreased to nearly undetectable levels and only monomeric or dimeric species were detectable on agarose gels. At the dosages used, no effect was seen on bleeding time, but the rate of blood flow from cuticle wounds was reduced after a single bolus administration of rvWF. The rvWF was able to control a severe nose bleed in one dog.

Assessment of bleeding for the evaluation of therapeutic preparations in small animal models of antibody-induced hemophilia and von Willebrand disease.

Three small animal models of bleeding are described and used to evaluate the effects of preparations intended for therapy of human bleeding disorders. We modified techniques for the assessment of bleeding to be able to reproducibly quantify blood loss and rate of blood flow in addition to the measurement of bleeding time. Temporary hemophilia was induced in a rabbit model by injection of high titer human inhibitor plasma [> or = 1000 Bethesda units (BU)/ml]. A decrease in rabbit FVIII from normal values to below the limit of detection was observed within 30 min, cuticle bleeding time changed from normal (approx. 10 min) to steady state bleeding (> 30 min), and the rate of blood flow increased from 4 to > 30 microliters blood/min. Infusion of an activated prothrombin complex concentrate, (FEIBA STIM4, Immuno) at doses between 75 and 150 U/kg normalized the rate of blood flow, while infusion of FVIII/vWF concentrate resulted in partial correction. Administration of FVIIa, both recombinant and plasma-derived, failed to correct bleeding, however. In an analogous murine model, FVIII/ vWF inhibitor plasma was obtained by immunizing goats with a purified human FVIII/vWF complex. This plasma cross-reacted with mouse vWF in vitro. Injection of the anti-FVIII/vWF inhibitor plasma into mice caused a decrease in vWF antigen, in some animals with a complete loss of vWF multimers comparable to severe von Willebrand disease. A specific anti-vWF inhibitor plasma obtained by immunization of goats with recombinant vWF was used in a further murine model, resulting in a gradual but substantial decrease in FVIII as well as in intensive bleeding. The infusion of a FVIII/vWF concentrate (IMMUNATE, IMMUNO) normalized the rate of blood flow in both murine models. The same assessment methods were used to characterize bleeding in a natural mouse model of von Willebrand disease (strain RIIIS/J). The use of quantitative techniques of assessment of blood loss and rate of blood flow appears to be a helpful tool for characterizing hemorrhagic situations and evaluating the capacity of therapeutic preparations to correct hemostatic defects.

Studies on the effect of human lys-plasminogen in a rat model of global cerebral ischemia.

Human lys-plasminogen and the corresponding formulation buffer were tested in a rat model of global cerebral ischemia (clamping of both carotid arteries, withdrawal of 5 ml blood for 30 min). The two main parameters, tested in different experimental set-ups, were 1. brain edema (water content) 23.5 h after reperfusion and 2. assessment of neurological deficits 24, 48 and 72 h after reperfusion. In some groups of animals of the first set-up, brains were examined histologically for microvascular fibrin deposits. In a separate group of animals the fibrinolytic plasma activity of rats treated with 500 CU/kg lys-plasminogen was studied. Concerning brain water content lys-plasminogen completely antagonized the formation of brain edema when given with 500 caseolytic Units (CU)/kg i.v. with blood reperfusion and was still effective when given 30 min later. 200 CU/kg i.v. given with blood reperfusion as well as 500 CU/kg i.v. given 60 min after blood reperfusion proved ineffective. In none of the brains investigated microvascular fibrin deposits were found. In experiments with assessment of neurological deficits, animals treated with 500 CU/kg lys-plasminogen i.v. showed almost no disabilities (like sham operated animals) when compared to ischemic (positive) controls which were rather severely handicapped. The formulation buffer of lys-plasminogen, tested in an equivalent volume, was without any effect in both set-ups. No fibrinolytic activity was found in plasma samples of rats up to 240 min after treatment with 500 CU/kg lys-plasminogen i.v. It is concluded from these experiments that human lys-plasminogen has a protective effect in rats against the sequelae of global cerebral ischemia which is not related to the well-known fibrinolytic potential but might be a separate quality.

In vivo effect of alpha 1-acid glycoprotein on experimentally enhanced capillary permeability in guinea-pig skin.

Anesthetized guinea-pigs were intravenously injected with Evans blue. After intracutaneous injection of agonists (lys-plasminogen, histamine, platelet-activating factor, thrombin, bradykinin), the resulting wheals appeared blue in a dose-dependent manner, due to an enhanced capillary permeability, alpha 1-Acid glycoprotein, given i.v. in different doses (3.125-50 mg/kg) and at different times (30-180 min) before Evans blue administration, antagonized the effects of all agonists listed above. This was shown by a parallel shift of the agonist dose-response curves to the right. The effect was time-dependent (tmax: mainly 120 min) and dose-dependent. alpha 1-Acid glycoprotein antagonized the agonists in the following order: lys-plasminogen > histamine = platelet-activating factor > thrombin > bradykinin. As all agonist mentioned are suggested to play a major role in the shock-related increase in vascular permeability, a putatively beneficial role of alpha1-acid glycoprotein in shock is discussed.