A macroscopic approach for stress-driven anisotropic growth in bioengineered soft tissues.

The simulation of growth processes within soft biological tissues is of utmost importance for many applications in the medical sector. Within this contribution, we propose a new macroscopic approach for modelling stress-driven volumetric growth occurring in soft tissues. Instead of using the standard approach of a-priori defining the structure of the growth tensor, we postulate the existence of a general growth potential. Such a potential describes all eligible homeostatic stress states that can ultimately be reached as a result of the growth process. Making use of well-established methods from visco-plasticity, the evolution of the growth-related right Cauchy-Green tensor is subsequently defined as a time-dependent associative evolution law with respect to the introduced potential. This approach naturally leads to a formulation that is able to cover both, isotropic and anisotropic growth-related changes in geometry. It furthermore allows the model to flexibly adapt to changing boundary and loading conditions. Besides the theoretical development, we also describe the algorithmic implementation and furthermore compare the newly derived model with a standard formulation of isotropic growth.

[Kirschner wire migration in the contralateral lung after osteosynthesis of a clavicular fracture]. / Kirschner-Draht-Migration in die kontralaterale Lunge nach Klavikulafraktur-Osteosynthese.

A 59-year-old patient was admitted complaining breathing-dependent pain in the lower right chest and increasing dyspnoea. Diminished breath sounds in the right lung and dullness in the lower right chest were found. Chest x-ray and complementary CT scan showed an intrapulmonary Kirschner wire and a large haematothorax but no pneumothorax. At 6 weeks before admission, the patient suffered a fracture of the medial left clavicle which was treated by closed reduction and percutaneous osteosynthesis with two Kirschner wires. The migrated K-wire and the haematoma were removed by video-assisted thoracoscopy without complications. Migration of Kirschner wires after clavicle fracture osteosynthesis is rare but dangerous. Migrations into the heart, lung, pulmonary vein or the cervical spinal cord have been recorded. Patients with K-wire osteosynthesis should be informed of the risk of wire migration and should undergo regular postoperative follow-ups including radiography every 2-4 weeks.

Tetrodotoxin-induced conduction blockade is prolonged by hyaluronic acid with and without bupivacaine.

BACKGROUND: In isolated nerves, tetrodotoxin (TTX) blocks nerve conduction longer than bupivacaine. In vivo, however, both substances block nerve conduction to an equal duration, presumably because the hydrophilic TTX binds only weakly to the perineural tissue. High molecular weight hyaluronic acid (HA) prolongs the action of local anaesthetics several-fold. We tested whether admixture of HA enhances the binding of TTX to the perineural tissue and thus induces an ultra-long conduction block after a single application. METHODS: In 12 anaesthetized rabbits, the minimal blocking concentrations of TTX, TTX and HA (TTX/HA) and bupivacaine with HA (bupivacaine/HA) were determined by blocking the natural spike activity of the aortic nerve. In 18 other animals, equipotent concentrations of either TTX, TTX/HA or TTX/bupivacaine/HA were applied topically to the aortic nerve. After disappearance of the spike activity, the wound was closed to simulate the clinical situation of a single shot nerve block. The time until recovery of spike activity was determined. The nerves were examined for signs of neurotoxicity 24 h after the application of the drugs. Data are presented as means +/- SD and compared by ANOVA and Student's t-test for unpaired data. RESULTS: The conduction block by TTX/bupivacaine/HA (10.1 +/- 1.9 h) or TTX/HA (9.3 +/- 1.0 h) was significantly longer than that of plain TTX (7.9 +/- 1.0 h). Neurotoxicity was not observed. CONCLUSIONS: Both HA and HA/bupivacaine prolong the TTX-induced conduction blockade of the aortic nerve of rabbits in vivo. No signs of neurotoxicity were observed.

Tetrodotoxin-induced conduction blockade is prolonged by hyaluronic acid with and without bupivacaine.

BACKGROUND: In isolated nerves, tetrodotoxin (TTX) blocks nerve conduction longer than bupivacaine. In vivo, however, both substances block nerve conduction to an equal duration, presumably because the hydrophilic TTX binds only weakly to the perineural tissue. High molecular weight hyaluronic acid (HA) prolongs the action of local anaesthetics several-fold. We tested whether admixture of HA enhances the binding of TTX to the perineural tissue and thus induces an ultra-long conduction block after a single application. METHODS: In 12 anaesthetized rabbits, the minimal blocking concentrations of TTX, TTX and HA (TTX/HA) and bupivacaine with HA (bupivacaine/HA) were determined by blocking the natural spike activity of the aortic nerve. In 18 other animals, equipotent concentrations of either TTX, TTX/HA or TTX/bupivacaine/HA were applied topically to the aortic nerve. After disappearance of the spike activity, the wound was closed to simulate the clinical situation of a single shot nerve block. The time until recovery of spike activity was determined. The nerves were examined for signs of neurotoxicity 24 h after the application of the drugs. Data are presented as means +/- SD and compared by ANOVA and Student's t-test for unpaired data. RESULTS: The conduction block by TTX/bupivacaine/HA (10.1 +/- 1.9 h) or TTX/HA (9.3 +/- 1.0 h) was significantly longer than that of plain TTX (7.9 +/- 1.0 h). Neurotoxicity was not observed. CONCLUSIONS: Both HA and HA/bupivacaine prolong the TTX-induced conduction blockade of the aortic nerve of rabbits in vivo. No signs of neurotoxicity were observed.

[The significance of nitric oxide in nociception and spinal pain processing]. / Die Bedeutung von Stickstoffmonoxid (NO) für Nozizeption und spinale Schmerzverarbeitung.

Nitric oxide (NO) has been shown to be involved in the generation and processing of pain signals. Most experimental studies on animals and also the few observations in humans point to an involvement of the NO-system in inflammatory pain, whereas acute pain and chronic pain without inflammatory component seem to be independent of NO. It is yet unknown whether specific inhibition of the NO pathway is useful for treatment or prevention of inflammatory pain in humans.

Subjective ratings of pain correlate with subcortical-limbic blood flow: an fMRI study.

Studies investigating the cerebral representations of pain using functional imaging techniques failed to elucidate the affective aspects of pain. This investigation used functional magnetic resonance imaging to measure pain-related changes in cerebral activity during painful stimulation with a strong affective component. Vascular pain was induced via balloon dilatation of a dorsal foot vein of healthy volunteers. The subjects rated their perceived pain uninterruptedly during imaging, allowing cerebral activity to be correlated with both stimulus function (boxcar) and, more importantly, subjective ratings reflecting individual pain experience. The findings indicated signal increases in subcortical-limbic regions, particularly in the amygdala. This region is suggested to be involved in the affective dimension of pain.

Minimal blocking concentrations of bupivacaine and procaine in an exclusively nociceptive system in humans.

BACKGROUND AND OBJECTIVES: Prior to this investigation, there was no approach to compare both the potency of local anesthetics and their time course of action in a reproducible nociceptive system in humans. We tested whether the vascularly isolated vein segment is appropriate for such an approach. METHODS: In six healthy men, a hand vein segment was vascularly isolated and intraluminally stimulated with electropulses of constant current intensity. The subjects rated pain between threshold and maximally tolerable pain on a visual analogue scale. For determining minimal blocking concentrations (a measure of potency), the vein segment was continuously perfused with Tyrode's solution with increasing concentrations of bupivacaine or procaine for at least 10 minutes each until pain was completely blocked. Subsequently, the respective local anesthetic was rinsed off with Tyrode's solution to determine the time course of recovery. RESULTS: Both bupivacaine and procaine blocked pain in a concentration-related fashion, the minimal blocking concentrations being 1.6 (0.6-1.9; median and range) mmol/L for bupivacaine and 15.0 (7.5-22.5) mmol/L for procaine. Whereas the onset of block (time of 50% block) did not differ significantly between bupivacaine and procaine [43 s (range, 3-80) vs 53 s (range, 30-115)], local anesthesia lasted significantly longer after application of bupivacaine [278 s (range, 215-325)] than after procaine [183 s (range, 125-225)]. CONCLUSIONS: The vascularly isolated vein segment is well suited to compare in vivo the properties of local anesthetics with a minimally invasive approach at a reproducible nociceptive system in humans.

Substance P is not involved in vascular nociception in humans.

Blood vessels are similar to skin invested with substance P-containing nerves and the binding sites for substance P, which has been shown to be involved in nociception from skin. No attempts have been made so far to see whether substance P is also involved in vascular nociception. We therefore tested substance P for its algesic properties in human veins because their innervation exclusively subserves nociception. Substance P never evoked pain from veins at concentrations of 10(-8)-10(-4) M but did so in a concentration-related fashion from skin. Therefore, substance P is not involved in the generation of acute vascular pain.

[Chronopharmacology. Time of day variations in the action of bupivacaine are not manifested in nerves]. / Chronopharmakologie. Tageszeitabhängige Schwankungen in der Wirksamkeit von Bupivacain manifestieren sich nicht am Nerven.

UNLABELLED: To test the hypothesis that the efficacy of local anaesthetics to block nerve conduction is related the time of day (TOD) of drug application, we retrospectively analysed data from previous experiments on tachyphylaxis. During the course of these experiments, as a measure of drug efficacy we determined the minimal blocking concentration (c(m)) of bupivacaine in rabbit aortic nerves at several TODs. The special in situ preparation used permitted study of local anaesthetic pharmacodynamics without the influence of pharmacokinetics, making it possible to investigate the chronopharmacodynamics of these drugs by relating c(m)s to the respective TODs of their measurement. METHODS: In 43 New Zealand rabbits anaesthetised with urethane, the aortic nerve was dissected and partly placed in a double-lumen perfusion chamber (Fig. 1A), which was continuously perfused with tyrode solution or bupivacaine. Spike activity was continuously recorded by bipolar platinum-iridium electrodes caudad to the chamber for control and cephalad for registration of blocking effects. As a measure of drug efficacy, by increasing the bupivacaine concentration stepwise we determined the smallest concentration that blocks spike activity i.e., c(m). After each determination bupivacaine was rinsed off to confirm intact nerve function (Fig. 18). RESULTS: Forty-nine determinations of bupivacaine c(m) were performed between 12:25 p.m. and 2:35 a.m. Data were pooled into groups of 2 h (Fig. 2). There was no significant difference between groups (ANOVA). In particular, c(m) at 3:00 p.m. was not lower than at 11:00 p.m., times at which local anaesthetics have been found to be most and least effective, respectively. CONCLUSIONS: The c(m) of bupivacaine, and thus its efficacy to block nerve conduction, does not depend on TOD of drug application. Therefore, it is suggested that chronopharmacodynamics does not play an important role in the well-known circadian rhythm of the action of bupivacaine and probably of local anaesthetics in general.

Nociception from blood vessels is independent of the sympathetic nervous system under physiological conditions in humans.

To test the hypothesis that vascular pain depends on sympathetic drive under physiological conditions we studied the effects of both alpha-adrenoceptor stimulation by noradrenaline and alpha-adrenoceptor blockade by phentolamine on the intensity of physicochemically evoked pain from veins in humans. In seven healthy volunteers, a vascularly isolated hand vein segment was perfused continuously with noradrenaline (6 x 10(-9)-6 x 10(-6) M), or phentolamine (1.24 x 10(-4) M). Pain was evoked by intraluminal electrostimulation or by injection of hyperosmolar saline during control perfusion of isoosmolar saline and after each noradrenaline concentration, as well as after perfusion of phentolamine. Subjects rated pain intensity continuously on an electronically controlled visual analogue scale (VAS) between 0% VAS (no pain) and 100% VAS (tolerance maximum). Intravenous electrostimulation as well as hyperosmolar solutions evoked pain in each subject. The intensity of pain was neither influenced by noradrenaline, nor by phentolamine, so that nociception from blood vessels is unlikely to be modulated by the sympathetic nervous system under physiological conditions in humans.

Nitric oxide is not involved in vascular nociception of noxious physical stimuli in humans.

We tested the hypothesis that nitric oxide (NO) is involved in vascular nociception of physical stimuli in humans. Vascularly isolated hand vein segments of six healthy volunteers were pretreated with the NO synthase inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME; 10(-7)-10(-4) M) and repeatedly subjected to noxious thermal (2 degrees C, 52 degrees C) or mechanical stimuli (balloon distention) and, for control, to the endogenous algetic bradykinin (10(-6) M). L-NAME prevented in a concentration-related manner the algesic action of bradykinin, but had no effect on pain evoked by heat, cold, or stretch. NO is therefore not a general chemical link in nociception.

Involvement of the NO/cyclic GMP pathway in bradykinin-evoked pain from veins in humans.

Cyclic GMP is probably a second messenger in vascular nociceptors that are excited by nitric oxide (NO), because NO is known to activate the guanylate cyclase. If so, inhibition of this enzyme should render nociceptors insensitive to algesics that act via NO. To test this hypothesis, the effect of the specific guanylate cyclase inhibitor methylene blue was studied on bradykinin-evoked, i.e. NO-mediated pain and, for control, on mechanically-evoked pain, which is probably not mediated by NO. In eight subjects, pain was evoked from isolated hand vein segments by either injection of bradykinin (1 x 10(-6) M) or noxious balloon distention. Pretreatment of the vein segments with methylene blue inhibited bradykinin-evoked pain in a concentration-dependent manner and abolished pain at a concentration of 1 x 10(-3) M. Methylene blue had no effect on mechanically evoked pain. Tachyphylaxis to intravenously applied bradykinin was not observed. These results are consistent with the hypothesis that cyclic GMP plays a role in the transduction of NO-mediated noxious stimuli in vascular nociceptors in humans.

The role of pain from veins for the formation of perivenous edema in humans.

To test the hypothesis that nociception from veins plays a role in the formation of perivenous edema, we looked at edema along hand veins of humans during painful noxious stimulation in the presence and absence of nerve conduction block. Pain from vascularly isolated hand vein segments was evoked by perfusion with hyperosmolar saline and rated with the help of an electronically controlled visual analogue scale. Perivenous edema measured as changes in skin altitude was continuously recorded by means of infrared reflection. To alternately block the innervation of skin and vein segment we used a perivenous block (vein but not skin numbed), a distal ulnar nerve block (skin but not vein numbed), and a proximal ulnar nerve block (both vein and skin numbed). Without nerve block, hyperosmolar saline always evoked both pain and a continuous increase in perivenous edema to a maximum of 2.0-3.2 mm after 30 min. On painless control perfusions with isoosmolar saline, edema increased slightly (0.2-0.8 mm) to a plateau which was maintained until the end of perfusion. When the vein was denervated by perivenous or proximal ulnar nerve block, hyperosmolar saline evoked a slight increase in edema which resembled that of control perfusions in both extent and time course. On distal ulnar nerve block, which numbed the skin but not the vein, both pain and substantial edema were evoked. These observations show that nociception from veins is a prerequisite for perivenous edema to occur.

Nitric oxide evokes pain at nociceptors of the paravascular tissue and veins in humans.

1. Nitric oxide (NO) evokes pain on intracutaneous application, apparently by exciting cutaneous nociceptors. To look for similarities in the responsiveness and sensitivity of other nociceptive systems to NO we determined pain intensity-concentration relations for NO applied to paravascular tissue and veins in humans. 2. NO solutions (0.4-2.0 mM) were either injected paravascularly or perfused through a vascularly isolated hand vein segment. The subjects rated pain continuously with the help of an electronically controlled visual analog scale, which made it possible to determine both the time course (latency, duration) and the intensity of NO-evoked pain. 3. Regardless of where it was applied, at concentrations above 0.7 mM NO always evoked pain of similar time course and concentration dependence. Pain increased proportionally to the concentration of applied NO, reaching subjects' tolerance maximum at four to five times the threshold concentration. 4. Pain intensity-NO concentration relations were congruent, indicating that the respective nociceptive systems are equally sensitive to NO. 5. Our observations are consistent with the hypothesis that NO is a chemical link in peripheral nociception.

Pre-emptive analgesia: comparison of preoperative with postoperative caudal block on postoperative pain in children.

We have compared in 25 children the effect of preoperative with postoperative caudal block on pain after circumcision in a double-blind, randomized study. After induction of anaesthesia, patients were allocated randomly to receive a caudal block either before (n = 14) or immediately after (n = 11) surgery. Postoperative pain was rated on a paediatric pain scale. If pain occurred, children received paracetamol in a dose related to body weight. Using the Mann-Whitney U test (significance < or = 0.05) there was no significant difference in cumulative postoperative analgesic requirements within the first 48 h and in times to first analgesic administration between the groups. Cumulative pain score, assessed every 30 min for the first 8 h after operation, was significantly lower for those patients who received caudal anaesthesia after operation. Thus we could not demonstrate any advantage in performing caudal block before compared with after surgery.

Nitric oxide evokes pain in humans on intracutaneous injection.

To test the hypothesis that nitric oxide (NO) acts algetically in humans, we determined pain intensity/dose relations for intracutaneously applied NO solutions. NO, dissolved in isoosmolar phosphate buffer, was injected in the forearm of six volunteers and the subjects rated NO-evoked pain continuously with the help of an electronically controlled visual analogue scale. Pain always occurred at a NO dose of 12 nmol, increased with dose and reached the tolerance maximum at 50 nmol. This shows for the first time the genuine pain evoking properties of NO.

Tachyphylaxis to local anesthetics does not result from reduced drug effectiveness at the nerve itself.

Possible development of tachyphylaxis to local anesthetics in the nerve itself (time-dependent change in axonal conduction properties) was studied in the aortic nerve of eight rabbits anesthetized with urethane. The nerve was immersed in Tyrode solution with or without bupivacaine at pH 7.4 and 38 degrees C in a trough molded from the surrounding tissues. After control measurements the nerve was exposed to increasing bupivacaine concentrations until complete nerve block at minimal blocking concentration. Subsequently, bupivacaine concentrations were reduced and kept constant for 4 h (partial block). Finally, intact nerve function was confirmed after bupivacaine washout with Tyrode solution. For quantification total nerve activity was recorded continuously and related to drug concentrations. Two findings argue against the occurrence of tachyphylaxis at the nerve itself: 1) nerve activity decreased rather than increased over time in the presence of constant bupivacaine concentrations during partial block; and 2) for the same bupivacaine concentration, nerve activity during partial block was always lower than during the initial blocking experiments. Thus, drug effectiveness increased rather than decreased over time, which cannot be reconciled with the theory that tachyphylaxis might be mediated by changes in axonal conduction properties.