Inflammation and activity augment brain-derived neurotrophic factor peripheral release.

Brain-derived neurotrophic factor (BDNF) release to nerve terminals in the central nervous system is crucial in synaptic transmission and neuronal plasticity. However, BDNF release peripherally from primary afferent neurons has not been investigated. In the present study, we show that BDNF is synthesized by primary afferent neurons located in the dorsal root ganglia (DRG) in rat, and releases to spinal nerve terminals in response to depolarization or visceral inflammation. In two-compartmented culture that separates DRG neuronal cell bodies and spinal nerve terminals, application of 50mM K(+) to either the nerve terminal or the cell body evokes BDNF release to the terminal compartment. Inflammatory stimulation of the visceral organ (e.g. the urinary bladder) also facilitates an increase in spontaneous BDNF release from the primary afferent neurons to the axonal terminals. In the inflamed viscera, we show that BDNF immunoreactivity is increased in nerve fibers that are immuno-positive to the neuronal marker PGP9.5. Both BDNF and pro-BDNF levels are increased, however, pro-BDNF immunoreactivity is not expressed in PGP9.5-positive nerve-fiber-like structures. Determination of receptor profiles in the inflamed bladder demonstrates that BDNF high affinity receptor TrkB and general receptor p75 expression levels are elevated, with an increased level of TrkB tyrosine phosphorylation/activity. These results suggest a possibility of pro-proliferative effect in the inflamed bladder. Consistently we show that the proliferation marker Ki67 expression levels are enhanced in the inflamed organ. Our results imply that in vivo BDNF release to the peripheral organ is an important event in neurogenic inflammatory state.

Glutamatergic transmission in hydra: NMDA/D-serine affects the electrical activity of the body and tentacles of Hydra vulgaris (Cnidaria, Hydrozoa).

Previous electrophysiological studies on the early-evolved metazoan Hydra vulgaris provided evidence that glutamate, acting through alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainate receptors, affects hydra's pacemaker systems; immunocytochemical studies showed that N-methyl-d-aspartate (NMDA) receptors were present in hydra tentacles; behavioral studies demonstrated that NMDA/d-serine affected mouth opening induced by reduced glutathione, and with AMPA/kainate, discharge of nematocysts. In this study, extracellular recordings were made from the tentacle and peduncle of hydra during bath application of NMDA and d-serine (both at 1 x 10(-5) mol l(-1) to 1 x 10(-9) mol l(-1)) in the presence of 1 x 10(-7) mol l(-1) AMPA or kainate. NMDA/d-serine produced a significant increase in tentacle activity, increasing the rate of tentacle pacemaker pulses (TPs) at 1 x 10(-7) mol l(-1), and small, behaviorally uncorrelated tentacle pulses (SUTPs) at 1 x 10(-5) mol l(-1). The NMDA antagonist, d-2-amino-5-phosphonopentanoic acid (D-AP5), counteracted the effects. NMDA/d-serine (1 x 10(-7) mol l(-1)) also caused a potentially significant (trend) decrease in the rate of small, behaviorally uncorrelated electrical body pulses (SUBPs) and rhythmic potentials (RPs). The effect was counteracted by D-AP5. The ectodermal contraction burst (CB) pacemaker system was unaffected by NMDA/d-serine. Our results indicate that glutamate, acting on NMDA/AMPA-kainate receptors, may cause opposing effects on the coordinating systems of tentacle and body-exciting the tentacle effectors and potentially causing an inhibition in the body column.

Inhaled nitric oxide does not alter pulmonary or cardiac effects of fat embolism in dogs after cemented arthroplasty.

PURPOSE: We examined the effect of inhaled nitric oxide (NO) on the acute pulmonary hypertension and right ventricular (RV) dilation after fat embolism. METHODS: A bilateral cemented arthroplasty (BCA), created fat embolism in 20 dogs. In Part A, 12 dogs were randomized to an NO group (n=6, inhaled NO 40 ppm before BCA and throughout the study) or a control group (n=6). In Part B, a third group of dogs (n=8) were given NO 20-40 ppm 2-3 min after BCA when pulmonary artery pressure (PAP) increased. Transesophageal echocardiography (TEE) and invasive hemodynamic monitoring evaluated the hemodynamic response to BCA. Postmortem, quantitative morphometry was used to estimate the number of fat emboli and diameter of lung vessel occluded by fat. RESULTS: Part A: The increase in PAP in the NO group (16 +/- 1 to 34 +/- 9 mmHg) within three minutes of BCA was not different from that in the control group (14 +/- 4 to 35 +/- 9 mmHg). Within three minutes of BCA, TEE demonstrated RV dilation in all groups (P < 0.05) but there was no difference in the change in RV area in the NO and control groups. When NO was given after BCA, no difference in PAP or RV dilation was noted from that in the control group. There were no differences, at post mortem, between the groups in the diameter of lung vessel occluded by fat CONCLUSION: Whether given before the embolic insult or two to three minutes after the onset of pulmonary hypertension, inhaled NO did not attenuate the acute pulmonary hypertension or RV dilation after cemented arthroplasty.

Relationship of fat embolism to haemodynamic and echocardiographic changes during cemented arthroplasty.

PURPOSE: Pressurisation of the medullary cavity during cemented arthroplasty causes "intravasation" of marrow fat. The purpose of this study was to examine the relationship between the amount of pulmonary intravascular fat and the haemodynamic and echocardiographic changes. METHODS: Anaesthetised mongrel dogs (n = 16) underwent bilateral cemented arthroplasty (BCA) to create a large embolic load. Haemodynamic measurements included blood pressure (BP), pulmonary artery pressure (PAP), right atrial pressure and cardiac output as well as transoesophageal echocardiographic (TEE) assessment of right ventricular (RV) and left ventricular (LV) areas. Using quantitative morphometry on postmortem lung specimens, the proportion of lung tissue occluded by fat was measured. RESULTS: Mean BP decreased within one minute of BCA, coinciding with the appearance of echogenic material in the RV. The RV area increased by 56% (P < 0.05) and LV area decreased by 34% (P < 0.05) while PAP increased from 15 +/- 3 mmHg to 39 +/- 10 mmHg within one minute (P < 0.001). The PAP remained elevated throughout the study (30 min). Stroke volume decreased in 14/15 dogs, yet cardiac output was maintained by increased heart rate. There was a curvilinear relationship (r = 0.87) between the maximum increase in PAP and the proportion of lung occupied by fat. CONCLUSION: In this model, stroke volume decreased within one minute of BCA when fat embolism accompanied prosthesis insertion. The TEE detected an increased RV area and reduced LV area associated with decreased stroke volume. The maintenance of cardiac output after intraoperative fat embolism depends primarily on the ability to increase heart rate.

Hypotension during cemented arthroplasty. Relationship to cardiac output and fat embolism.

An episode of hypotension is common during cemented joint replacement, and has been associated with circulatory collapse and sudden death. We studied the mechanism of hypotension in two groups of six dogs after simulated bilateral cemented arthroplasty. In one group, with no lavage, the insertion of cement and prosthesis was followed by severe hypotension, elevated pulmonary artery pressure, decreased systemic vascular resistance and a 21% reduction in cardiac output. In the other group, pulsatile intramedullary lavage was performed before the simulated arthroplasties. Hypotension was less, and although systemic vascular resistance decreased, the cardiac output did not change. The severity of the hypotension, the decrease in cardiac output and an increase in prostaglandin metabolites were related to the magnitude of pulmonary fat embolism. Pulsatile lavage prevents much of this fat embolism, and hence the decrease in cardiac output. The relatively mild hypotension after lavage was secondary to transient vasodilation, which may accentuate the hypotension caused by the decreased cardiac output due to a large embolic fat load. We make recommendations for the prevention and management of hypotension during cemented arthroplasty.

Prostanoid production and pulmonary hypertension after fat embolism are not modified by methylprednisolone.

Bilateral cemented arthroplasty (BCA) in anaesthetized mongrel dogs produces particulate fat and marrow embolism of the lung. Methylprednisolone sodium succinate (MPSS) has been advocated for post-traumatic fat embolism to prevent acute lung injury. We used the BCA procedure to produce acute fat and marrow embolism, and tested the efficacy of MPSS (30 mg.kg-1) in preventing physiological and pathological markers of acute lung injury. Dogs (n = 6) pre-treated with MPSS demonstrated similar acute increases in pulmonary artery pressure (PAP) within one minute of BCA (17.8 +/- 7.3 mmHg) as the untreated (control n = 7) dogs (18.6 +/- 12.6). Pulmonary vascular resistance (PVR) increased to the same degree in both groups (455 +/- 323 and 319 +/- 137 dyne.sec.cm-5) and PaO2 decreased by 18.3 +/- 6.4 mmHg in the control group as opposed to 12.4 +/- 7.7 mmHg in the MPSS group within five minutes of BCA. Circulating arterial and mixed venous plasma concentrations of thromboxane B2 (TxB2) increased within one minute of BCA in both groups with no increase in the transpulmonary gradient. Arterial plasma 6-keto prostaglandin F1 alpha (6-keto PGF1 alpha) increased (0.91 +/- 0.29 ng.ml-1 and 0.87 +/- 0.43 ng.ml-1) in both groups one minute after BCA. Mixed venous 6-keto PGF1 alpha plasma concentration also increased, but a significant transpulmonary 6-keto PGF1 alpha gradient was found.(ABSTRACT TRUNCATED AT 250 WORDS)

High-volume, high-pressure pulsatile lavage during cemented arthroplasty.

To determine the efficacy of high-volume, high-pressure pulsatile lavage in the prevention of cardiopulmonary dysfunction and fat embolism during cemented arthroplasty, we studied twenty-eight mongrel dogs that had had a bilateral cemented arthroplasty. Significant increases in pulmonary-artery pressure and pulmonary vascular resistance, accompanied by decreases in arterial oxygen tension and increases in intrapulmonary shunt fraction (Qs/Qt), characterized cardiopulmonary dysfunction after bilateral cemented arthroplasty when no lavage was used. Low-volume, low-pressure manual lavage did not significantly alter these physiological changes, but there was a significant reduction in the number of fat emboli that were demonstrated in the lungs as compared with the no-lavage group. High-volume, high-pressure pulsatile lavage of the intramedullary cavity after reaming significantly reduced the changes in pulmonary-artery pressure, pulmonary vascular resistance, arterial oxygen tension, and intrapulmonary shunt fraction (Qs/Qt). In the pulsatile-lavage group, the number of fat microemboli that were found in the lungs was reduced to 25.7 per cent of those found in the no-lavage group. We concluded that meticulous high-volume, high-pressure pulsatile lavage reduces both pulmonary physiological derangements and fat emboli during bilateral cemented arthroplasty in dogs.

Capnography is not as sensitive as pulmonary artery pressure monitoring in detecting marrow microembolism. Studies in a canine model.

We studied several methods for detecting pulmonary embolic events in a model of fat and marrow microembolism during canine cemented arthroplasty procedures. The cardiopulmonary effects of bilateral cemented arthroplasty in this model include increased pulmonary artery pressure and pulmonary vascular resistance accompanying a decrease in arterial oxygen tension. We documented significant fat and marrow microembolism by postmortem quantitative morphometry of lung sections. Vessels occluded ranged in diameter from 0.5 to 190 microns. The acute increases in pulmonary artery pressure (PAP) (to 26.8 +/- 4.4 mm Hg from 15.3 +/- 3.3 mm Hg) after cemented arthroplasty were not detected by changes in continuously monitored end-tidal CO2 or in right atrial or arterial blood pressures. Although capnography is a useful intra-operative monitor, in this model it is less sensitive than PAP monitoring in detection of fat and marrow microemboli.

Effects of emboli, positive-pressure ventilation, and airway water on lung water measurements.

We tested the effects of microemboli, continuous positive-pressure ventilation (CPPV), and aspirated airway water on measurements of extravascular lung water by use of the technique of thermal indicator dilution (ETVL). A control group of dogs and a group of dogs in which dextran was infused created all levels of pulmonary edema. In an emboli group 0.125 g/kg of starch microemboli (63-74 micron diam) were infused. In groups with emboli and CPPV, starch emboli were infused and CPPV was then applied at 15 cmH2O. In an airway saline group measured amounts of saline were poured into the airway. In all groups postmortem pulmonary extravascular tissue weight (PETW) was determined and compared with the last ETVL. Emboli created an increased scatter when the last ETVL is compared with PETW because 1) blood trapped distal to emboli was included in the ETVL measurement, and/or 2) diffusion limitations for the thermal indicator were exceeded. Emboli and CPPV decreased ETVL/PETW. Airway saline (80 +/- 5%) was measured by ETVL. In conclusion, the ETVL technique is reliable in well-perfused lungs but loses accuracy in measuring lung water after emboli of any size or with large amounts of airway fluid.

Cardiopulmonary function and pulmonary microemboli during arthroplasty using cemented or non-cemented components. The role of intramedullary pressure.

An experimental model was designed to investigate the role of intramedullary pressure on cardiopulmonary function and pulmonary pathology during arthroplasty using cemented and non-cemented components. Twenty-four dogs were divided randomly into three groups: a group that received a non-cemented implant in which low intramedullary pressure was generated, a group that received a cemented implant, and one that received bone wax and an implant; high intramedullary pressures were generated in the latter two groups. Bone wax was used to generate high intramedullary pressures without the use of bone cement. In the group with the non-cemented implant, few pulmonary microemboli and no significant cardiorespiratory changes were found. In the groups that received bone wax and an implant or the cemented implant, there were many pulmonary microemboli and significant cardiorespiratory changes, including decreased arterial oxygen tension, increased pulmonary arterial pressure, and increased intrapulmonary shunt fraction. There was no evidence that methylmethacrylate monomer was responsible for the cardiorespiratory changes in the group with the cemented implant.

Pulmonary marrow embolism: a dog model simulating dual component cemented arthroplasty.

The cardiopulmonary changes resulting from cemented arthroplasty procedures were monitored in 11 dogs with a single prosthesis implanted and nine dogs with a dual arthroplasty procedure. These changes were characterized by decreased BP, elevated PPA, and elevated PVR, associated with decreases in PaO2, cardiac output and mixed venous oxygen tension. All changes were more pronounced and prolonged in the dual component arthroplasty group. Histologic lung examination and morphometry demonstrated significant degrees of marrow (fat) microembolism in the dual arthroplasty model. Cardiopulmonary collapse has been associated with Guepar dual component arthroplasties clinically and these patients are at increased risk and should be monitored continuously. Prophylactic measures include meticulous lavage of the intramedullary cavity, increased FIO2, and maintenance of intravascular volume and cardiac output. The bilateral arthroplasty model is useful in investigating therapeutic interventions which may detect and prevent the marrow microembolism syndrome intraoperatively.

Effect of cardiac output on extravascular lung water measurements made with the thermoconductivity method.

The authors tested the effects of injectate temperature and of changing cardiac output on the measurement of lung water by the thermoconductivity technique (ETVL). Cardiac output in dogs was increased and decreased with isoproterenol and halothane, respectively. Post mortem extravascular lung water (pulmonary extravascular tissue weight [PETW] was determined using a weighing technique. Cardiac output varied between 0.7 and 8.8 l/min and did not influence the ETVL measurement. The authors conclude ETVL measured by the thermoconductivity technique is not influenced by large changes in cardiac output.

The effects of dobutamine, nitroprusside, or volume expansion on cardiac output and lung water after CPPV.

Pulmonary microemboli can create an ARDS-like state in dogs (high pulmonary vascular resistance, pulmonary oedema and arterial hypoxemia). CPPV can correct the hypoxemia of pulmonary microemboli but reduces cardiac output (Q) and tissue oxygenation. This paper compares the effect of improving Q by infusing volume, reducing afterload, or increasing myocardial contractility. Four groups of seven dogs were studied. All had 0.125 g . kg-1 of starch microemboli (63-74 microns) infused and then CPPV at 15 cm H2O applied. The control group had no further treatment applied. In three other groups volume (dextran) or dobutamine or nitroprusside (NTP) was infused to return Q to the level before CPPV was applied. All treatments (volume, dobutamine and NTP) improved Q and O2 transport. Only the volume group had a significant increase in pulmonary microvascular pressure, Pmv = PLA + 0.4 (PPA - PLA) from 2.53 +/- 0.27 to 3.35 +/- 0.13 kPa, p less than 0.05. Only the volume group demonstrated a significant increase in lung water above (double) the control group as measured by a double indicator dilution technique (ETVL) and post mortem lung weights. We conclude volume infusions to improve a CPPV depressed Q may increase lung water and that better treatment would be to infuse NTP or dobutamine, thus maintaining a lower Pmv and therefore lung water. As a corollary the least CPPV should be applied to maintain adequate oxygenation and create the least need for interventions to improve Q.

Effect of continuous positive-pressure ventilation on oxygenation after pulmonary microemboli in dogs.

We infused starch microemboli (63 to 74-mu diameter) into the external jugular vein of 28 dogs, to observe the effects of continuous positive-pressure ventilation (CPPV) on gas exchange and hemodynamics during hypoxemia (PaO2 53 +/- 3 torr). CPPV at both 10 and 15 cm H2O end-tidal pressure improved PaO2. CPPV 15 returned PaO2 and pulmonary shunt to control values but reduced cardiac output, O2 transport, and O2 consumption. In spite of these changes suggesting inadequate tissue oxygenation with CPPV 15, mixed venous oxygenation was not reduced. We conclude that: (a) hypoxemia after microemboli infusion is improved by CPPV and therefore likely caused by ventilation/perfusion abnormalities; (b) the improvement in PaO2 produced by CPPV after microemboli is not beneficial if CPPV reduces perfusion and O2 transport; and (c) mixed venous oxygenation does not appear to be an adequate measure of oxygen transport to tissues when CPPV is applied in this high pulmonary vascular resistance setting.

Lung water increases with fluid administration during CPPV after pulmonary microembolization.

Hypoxemia created by pulmonary microemboli is improved by continuous positive-pressure ventilation (CPPV) but at a cost of reducing cardiac output (Q). In this high pulmonary vascular resistance (PVR), pulmonary edema setting, the authors attempted to increase the Q, which had been reduced by CPPV, with an infusion of dextran. In 14 dogs, 0.125 g/kg of starch microemboli (63-74 microns in diameter) were infused. CPPV at 15 cm H2O then was applied and PaO2 increased from 53 +/- 4 to 69 +/- 3 mmHg, but Q decreased from 2.9 +/- 0.2 to 1.7 +/- 0.2 1/min. Seven of these dogs (control group) were monitored for 3 h. In the remaining seven dogs (volume group), dextran 40 was infused until Q returned to pre-CPPV values, and monitoring was continued for 3 h. With return of Q to pre-CPPV levels, indices of tissue oxygenation (O2 transport, PVO2, O2 consumption and metabolic acidosis) were significantly improved. However lung water was increased significantly by the volume infusion, so that at 3 h lung water in the volume group was double the value in the control group. The authors conclude that volume infusion in the face of a high PVR may correct the reduced Q of CPPV and improve tissue oxygenation, but it also may increase pulmonary edema.

Large airway response to cemented arthroplasty: relationship to hypoxaemia. An experimental study in dogs.

Alteration in airway smooth muscle tone has been implicated in the mechanism of hypoxemia, pulmonary hypertension and changes in dynamic thoracic compliance after total hip arthroplasty (THA). We used the pressure within a water-filled cuff of an endotracheal tube as a continuous measure of changes in tracheomotor tone during THA in mongrel dogs, while intermittently assessing gas exchange abnormalities. In all 16 dogs the instillation of polymethylmethacrylate (PMMA) into the femoral medullary shaft resulted in tracheal dilation. In ten dogs we demonstrated simultaneous hypotension, hypoxemia and increase in shunt fraction (Qs/Qt) after THA. In six dogs the medullary canal was thoroughly lavaged prior to PMMA injection, and no hypoxemia, hypotension or increased Qs/Qt was found in spite of persisting tracheomotor relaxation. We conclude that these well-documented gas-exchange abnormalities are not mediated by changes in large airway tone. Since the hypoxemia was abolished by medullary lavage in our animal model, we suggest that this syndrome is mediated by alterations in lung perfusion and associated small airway constriction and not by changes in large airway smooth muscle tone.

The role of lavage in preventing hemodynamic and blood-gas changes during cemented arthroplasty.

UNLABELLED: An experimental model was designed to investigate the role of meticulous intramedullary lavage in the prevention of the blood-gas and hemodynamic changes that have been documented to occur during cemented arthroplasty. Twenty-one adult mongrel dogs were divided into two groups. One group had the medullary canal thoroughly lavaged prior to insertion of the cement and prosthesis and the other group had no lavage. The results clearly showed that careful lavage can eliminate the significant decreases in arterial PO2 and increases in intrapulmonary shunt fraction and pulmonary artery pressure that were evident in the group that did not have lavage. Femoral medullary reaming was investigated and was shown not to compromise the dogs' cardiopulmonary status. CLINICAL RELEVANCE: During cemented arthroplasty, thorough lavage of a plugged medullary canal prior to insertion of the cement and prosthesis is a highly effective prophylactic measure in the elimination of gas-exchange and hemodynamic complications.

Extrathoracic cuff pressure reflects changes of intrathoracic large airway circumference.

The pressure measured in water-filled cuffs of endotracheal tubes has been used to evaluate the effect of drugs and physiologic stimuli on large airway tone. In six mongrel dogs, extrathoracic cuff pressure was monitored while simultaneously monitoring intrathoracic tracheal circumference measured by an implanted mercury strain gauge. The airways of each animal were alternately dilated with intravenous aminophylline (10 mg/kg) and constricted with edrophonium (10 mg). In each animal a significant linear relationship was found between cuff pressure and intrathoracic tracheal circumference. The slopes of these linear relationships were consistent for each animal, but varied between animals. In a second group of 11 dogs, cuff pressure was measured at extrathoracic and intrathoracic tracheal sites, as well as in the left main stem bronchus. Similar directional changes in cuff pressure were found at each site. This suggests that a water-filled system monitoring cuff pressure in the extrathoracic trachea reflects the direction of circumference change in the intrathoracic trachea and major bronchi.