Reamed locked intramedullary nailing for studying femur fracture and its complications.

Morbidity associated with femur fractures in polytrauma patients is known to be high. The many unsolved clinical questions include the immunological effect of the fracture and its fixation, timing of fracture fixation, management of fracture non-union, effect of infection and critical size of bone defects. The aim of this study was to establish a clinically-relevant and reproducible animal model with regards to histological, biomechanical and radiological changes during bone healing. A custom-designed intramedullary nail with interlocking system (RabbitNail, RISystem AG, Davos Platz, Switzerland) was used for fixation, following femur fracture. New Zealand White rabbits were assigned to two groups: 1. closed fracture model (CF; non-survival model: n = 6, survival model: n = 3) with unilateral mid-shaft femur fracture created by blunt force; 2. osteotomy model (OT; survival model: n = 14) with unilateral transverse osteotomy creating femur fracture. There were no intraoperative complications and full-weight bearing was achieved in all survival rabbits. Significant periosteal reaction and callus formation were confirmed from 2 weeks postoperatively, with a significant volume formation (739.59 ± 62.14 mm3) at 8 weeks confirmed by micro-computed tomography (µ-CT). 2 months after fixation, there was no difference between the osteotomised and contralateral control femora in respect to the maximum torque (3.47 ± 0.35 N m vs. 3.26 ± 0.37 N m) and total energy (21.11 ± 3.09 N m × degree vs. 20.89 ± 2.63 N m × degree) required to break the femur. The data confirmed that a standardised internal fixation technique with an intramedullary nail for closed fracture or osteotomy produced satisfactory bone healing. It was concluded that important clinically-relevant studies can be conducted using this rabbit model.

The effect of haemorrhagic shock and resuscitation on fracture healing in a rabbit model: an animal study.

Aims: Little is known about the effect of haemorrhagic shock and resuscitation on fracture healing. This study used a rabbit model with a femoral osteotomy and fixation to examine this relationship. Materials and Methods: A total of 18 male New Zealand white rabbits underwent femoral osteotomy with intramedullary fixation with 'shock' (n = 9) and control (n = 9) groups. Shock was induced in the study group by removal of 35% of the total blood volume 45 minutes before resuscitation with blood and crystalloid. Fracture healing was monitored for eight weeks using serum markers of healing and radiographs. Results: Four animals were excluded due to postoperative complications. The serum concentration of osteocalcin was significantly elevated in the shock group postoperatively (p < 0.0001). There were otherwise no differences with regard to serum markers of bone healing. The callus index was consistently increased in the shock group on anteroposterior (p = 0.0069) and lateral (p = 0.0165) radiographs from three weeks postoperatively. The control group showed an earlier decrease of callus index. Radiographic scores were significantly greater in the control group (p = 0.0025). Conclusion: In a rabbit femoral osteotomy model with intramedullary fixation, haemorrhagic shock and resuscitation produced larger callus but with evidence of delayed remodelling. Cite this article: Bone Joint J 2018;100-B:1234-40.

Limitations of a pulsed Doppler velocimeter for blood flow measurement in small vessels.

The performance of a new and simplified flow probe construction and the Iowa 545C-4 pulsed Doppler velocimeter was evaluated for measurement of blood flow over several months in small arteries of awake animals. Calibrations were performed over a wide range of intraluminal pressures and physiological flow velocities. Pressure-dependent differences in slope of the Doppler shift-volume flow relationship were detected in some probes. Signal strength was maintained at hematocrits > 10%. Distortion of pulsed Doppler signal peaks occurred in the conscious rabbit at peak aortic velocities, at which Reynold's number for turbulence was exceeded and the Doppler shift surpassed the Nyquist limit of 31.25 kHz for the velocimeter. Although the Doppler shift-volume flow relationship is linear at < 5 kHz, in some cases at higher Doppler shifts and blood flow velocities the relationship may become nonlinear, thus causing the volume flow rate to be underestimated by up to 38%. The cause of this phenomenon may be "aliasing" and/or the consequence of the range control capability of the velocimeter selectively sampling changing velocity profiles and flow disturbances in the central stream at higher velocities.

Venous hydrostatic indifference point as a marker of postnatal adaptation to orthostasis in swine.

The postulate that venous adaptation assists postural baroreflex regulation by shifting the hydrostatic indifference point (HIP) toward the heart was investigated in eight midazolam-sedated newborn piglets. Whole body head-up (+15, +30, and +45 degrees ) and head-down (-15 and -30 degrees ) tilt provided a physiological range of orthostatic strain. HIP for all positive tilts shifted toward the heart (P < 0.05), +45 degrees HIP shifted most [6.7 +/- 0.3, 5.9 +/- 0.5, and 3.6 +/- 0.3 (SE) cm caudal to right atrium on days 1, 3, and 6, respectively]. HIP for negative tilts (3.0 +/- 0.2 cm caudal to right atrium) did not shift with postnatal age. Euthanasia on day 6 caused 2.1 +/- 0.3-cm caudal displacement of HIP for positive and negative tilts (P < 0.05). HIP proximity to right atrium was not altered by alpha-, beta-adrenoceptor and cholinoceptor blockade on day 5. It is concluded that early HIP migration reflects enhancement of venous pressure control to head-up orthostatic strain. The effect is independent of baroreflex-mediated adrenoceptor and cholinoceptor mechanisms.

Analysis of bronchovascular downstream blood pressure changes in exercising sheep.

The relative roles of neural and pressure gradient factors, causing a fall or maintenance of bronchial blood flow in exercising sheep, are unknown. These were examined in sheep prepared under thiopentone/isoflurane general anaesthesia with a pulsed Doppler probe mounted on the bronchial artery, and aortic pressure (Pa) catheter in superficial cervical artery. After recovery, Swan-Ganz catheters were inserted under local anaesthesia into the pulmonary artery. Bronchial flow and conductance (Qbr, Cbr), and pressure gradients (Pg; i.e. aortic minus right atrial, Pg_RAP; pulmonary artery, Pg_Ppa; and, left atrial (wedge) Pg_LAP) were derived from continuous records, after switching between downstream sites during and after moderately severe treadmill exercise (3.8 km.h(-1), for 1.7 min, 6 min recovery). The protocol was repeated after combined alpha1,alpha2-adrenoceptor/cholinoceptor blockade using phentolamine methanesulfonate and methscopolamine bromide. Bronchial flow fell in both receptor intact (INT) and (BL) blocked state. Pa rose in INT, but downstream pressures rose only 3.7 (RAP), 2.8 (Ppa) and 2.0 (LAP) mmHg (P for each < 0.05) in both INT and BL. Pg_RAP and Pg_Ppa did not rise, but Pg_LAP rose 4.0 mmHg (P < 0.05). In BL, Pa fell, as did Pg_RAP (7.0 mmHg, P < 0.05), Pg_Ppa (8.9 mmHg, P < 0.001), but Pg_LAP did not change. Thus, downstream pressures change by small amounts, and pressure gradients to RAP and Ppa sites do not change during moderately severe exercise in normal sheep. The fall in Qbr in INT is due to neural factors, but in BL is due to a fall in Pg. The relative rise in Pg_LAP in both INT and BL favours redistribution within total Qbr to the pulmonary capillary/vein/left atrium site.

Integration of baroreflex and autoregulation control of bronchial blood flow in awake dogs.

AIM: Baroreflex control of the bronchial circulation is unresolved. Early studies suggested that baroreflexes dilate or have no effect, but recent studies in awake dogs suggested baroreflexes did not normally engage tonic vasoconstrictor efferents but during excitement systemic pressure rises may also trigger local sensory-motor dilator reflexes. We examined the postulate that bronchial flow is normally regulated at rest during controlled changes in pressure gradient (Pg) by integration of tonic autonomic activity with autoregulation. METHODS: Twelve greyhounds were instrumented under general anaesthesia by surgical implantation of pulsed Doppler flow transducers on the right bronchial artery (BA). After recovery baroreflex effects were evoked by raising and lowering aortic pressure using a lower thoracic aortic balloon in 11 animals, and in six of these after cholinoceptor plus adrenoceptor blockade. RESULTS: The right BA bed showed pressure-passive responses and the time-dependent bronchial bed effects in the autonomically intact state (INT) were largely similar to those in the blocked state (TAB). When results were replotted as pressure-flow relationships and analysed using covariance, the regression line over the pressure range 70-135 mmHg for TAB demonstrated a significant slope (P < 0.05), a linear regression elevated 120% (P = 0.006) above and parallel to INT (Y(Q) = 0.034 + 0.00033(X(Pg) - 104.6). The regression fell on the line of equal proportional change. CONCLUSION: Baroreflexes do not functionally engage the autonomic outflow to the bronchial circulation. Under controlled conditions of systemic Pg change, the bronchial circulation is normally controlled by the integration of resting autonomic tone, myogenic autoregulation and pressure-passive effects.

Effects of graded exercise on bronchial blood flow and airway dimensions in sheep.

Exercise stimulus-response relationships for airway blood supply and dimensions have not been described in mammalian species. These relationships are vital for postulates concerning integrated reflex factors normally controlling the airways and which may underlie the asthma syndromes of exercise. This study defines airways stimulus-response relationships in exercising sheep. Ewes between 35 and 40kg were instrumented at left thoracotomy under thiopentone/isoflurane general anaesthesia. Pulsed Doppler ultrasonic transducers were mounted on the bronchial artery, and transit-time plus single-crystal sonomicrometers on the left main bronchus. These recorded simultaneously and continuously bronchial blood flow (Q(br)) and conductance (C(br)), bronchial circumference (Circ(br)) and wall thickness (Th(br)). In Protocol 1 (P1), four sheep ran duplicate 5min protocols on a horizontal treadmill at continuous step-up-and-down speeds of 1min duration, namely, 0.8, 1.6, 2.2, 1.6 and 0.8mph (moderate exercise), followed by 10min recovery. In P2, four sheep ran duplicate 2min protocols at constant 4mph (strenuous exercise), and in P3, one sheep ran duplicate protocols each of 3min at 2.2, 4.4 and 6mph (severe exercise). Regression analysis and repeated measures ANOVA were used to assess differences between times, runs and exercise intensity. In P1, airway effects were directly related to graded exercise effort sustained over 5min. Peak effects occurred at 2.2mph, except for Th(br). Heart rate and P(a) rose (to 156% and 111% of resting, respectively), and Q(br) and C(br) fell (to 83% and 75%; both P<0.001). Circ(br) fell to 96% (P=0.02), and Th(br) rose at low speeds early and late, and thinned at the highest speed. In P2 and P3 for all variables the steady-state effects were systematically greater than for P1 (4.4mph: C(br) to 43%, Circ(br) to 93%; 6.6mph: C(br) to 25%, Circ(br) to 82%). There was no significant recovery hyperaemia, but there was residual post-exercise bronchoconstriction. The exercise stimulus-response relationships from rest to a maximal 6mph for sheep airway circumference and its bronchial circulation are inverse and functionally constrictor.

Autonomic control of bronchial blood flow and airway dimensions during strenuous exercise in sheep.

BACKGROUND: During exercise and recovery the transient and steady-state changes in autonomic activity regulating lower airway blood flow and dimensions are unknown. The aim of this study was to define changes in bronchial blood flow (Q(br)) and dimensions during moderate and strenuous exercise, and to analyse the role of vagal and sympathetic nerves. METHODS: Nine ewes (34-44kg) underwent left thoracotomy during general anaesthesia (thiopentone/isoflurane) and either (5 sheep=Group 1) a pulsed Doppler transducer was placed on the bronchial artery, or (4 sheep=Group 2) a pulsed Doppler transducer was placed on the bronchial artery, and transit-time and single crystal sonomicrometers were mounted on the left main bronchus. These measured continuously Q(br), bronchial circumference (Circ(br)) and wall thickness (Th(br)). Aortic pressure (P(a)) and central venous pressure catheters were placed in the superficial cervical artery and vein. Trained sheep exercised on a horizontal treadmill, i.e. Group 1, moderate exercise 2.2mph over 1.6, 6min recovery, for analysis of changes in Q(br) before and after cholinoceptor blockade; Group 2, strenuous exercise 4.4mph over 2, 10min recovery for analysis of changes in Q(br) and airway dimensions, before and after cholinoceptor plus alpha(1)-, alpha(2)-adrenoceptor blockade. beta-adrenoceptor systems were intact. RESULTS: In Group 1 during moderate exercise P(a) and heart rate (HR) rose. Q(br) and blood flow conductance (C(br)) fell immediately to 83% (P<0.001) before returning toward resting levels, but fell when exercise ceased to 89% (P<0.01) before recovering. Prior cholinoceptor blockade abolished the immediate fall in Q(br) and C(br), but not the recovery vasoconstriction. Later in recovery the bronchial bed dilated progressively over 6min (P<0.05). In Group 2 during strenuous exercise P(a) and HR rose substantially. Q(br) and C(br) fell to 68% and 54% (P<0.001), respectively, and there was early vasoconstriction in recovery. Circ(br) fell immediately and remained at 93% (P<0.01), and did not recover fully when exercise ceased. Th(br) did not change during or after exercise. Prior cholinoceptor plus alpha-adrenoceptor block caused P(a) and Q(br) to fall slightly during exercise, but the bronchovascular constriction during and after exercise was abolished, as was circumferential shortening in the airway. CONCLUSIONS: At exercise onset and steady-state, resetting the arterial baroreflex upward in sheep increases parasympathetic cholinergic vasoconstrictor activity and causes bronchial wall and bronchovascular smooth muscle contraction in concert with sympathetic adrenergic constriction of systemic vascular beds. Whether the known sigmoid baroreflex control of tracheal smooth muscle tension at rest is extended to tracheobronchial smooth muscle and its circulation during exercise is yet to be determined.

Modern inhalational anaesthetic agents. A review of halothane, isoflurane and enflurane.

The intelligent use of modern inhalational anaesthetic agents requires a detailed knowledge of their pharmacology. Currently, the volatile agents in most-common use in Australia are halothane, isoflurane and enflurane. This brief review analyses the similarities and differences in the pharmacological properties of these three drugs in order to provide practitioners with the necessary background knowledge to assist in the selection of an appropriate anaesthetic agent for a given clinical problem.

Halothane attenuates myogenicity in the rabbit ear artery.

UNLABELLED: The aim of this study was to test the hypothesis that halothane interferes with the myogenic response to an increase in intraluminal pressure. Myogenic responsiveness refers to the intrinsic property of vascular smooth muscle to dilate and then constrict in response to an increase in intraluminal pressure, in an attempt to maintain vessel diameter. Vessel segments taken from the rabbit central ear artery were cannulated, pressurized to 60 mm Hg, and perfused with and suspended in Krebs solution. After exposure to extraluminal l-norepinephrine, vessels contracted to an initial diameter (Di) and were subjected to intraluminal pressure increases to 100 mm Hg. Myogenic reactivity was assessed by measurement of the extent of dilatation after the pressure increase from Di to a maximal diameter (Dm) and then the constriction and recovery (against the pressure increase) to a final (Df) diameter. Myogenicity was further assessed by determining the rate of return of the vessel diameter (angle of recovery) and vessel recovery (defined as Dm - Df/Dm - Di) and expressed as a percentage. Myogenicity was determined before and after exposure to halothane in concentrations of between 1-5%. Halothane significantly attenuated the myogenic response at all concentrations studied. The effect of halothane was maximal at a concentration of 5% where there was virtual abolition of the myogenic response with recovery assessed at 6+/-2.7% (SEM), compared with control (98+/-2.5%, P < 0.05). The angle of recovery was likewise attenuated. These data suggest that halothane, in a dose-dependent manner, attenuates myogenicity in the isolated rabbit ear artery preparation. IMPLICATIONS: Blood pressure is controlled partially by the myogenic response. This refers to the capacity of arteries to dilate and then constrict in response to pressure increase. Using arteries from rabbits, we have shown that administration of halothane reduces or abolishes this response. This observation may be a contributing factor to hypotension caused by halothane.

Effects of changing haematocrit, ventricular rate and myocardial inotropy on the accuracy of impedance cardiography.

1. The accuracy and limitations of the non-invasive impedance cardiograph technique were examined in dogs with electromagnetic flow-transducers mounted on the aortic root over a wide range of physiological conditions of anaemia, heart rate, stroke volume and myocardial inotropy. 2. The in vivo blood resistivity (rho-haematocrit relationship is linear and slightly inverse, and is thus opposite to the curvilinear, direct relationship of the bench-derived rho-haematocrit relationship. At haematocrit 41%, in vivo rho is 135 ohm.cm (s.e.m. = 1.0, n = 134) and rises only to 143 ohm.cm (s.e.m. = 1.6, n = 134) as haematocrit falls to 26%. 3. When in vivo rho is used in the Kubicek formula for stroke volume (SV) calculation, the instrument is linear and accurate for heart rates over 38-156 min-1. Thus 82% of all points fall within +/- 20% of the line of equal value over stroke volumes ranging from 8-46 ml (N = 3, n = 105). The standard error of the estimate for pooled data is +/- 2% of the mean impedance stroke volume value of 22.2 ml. The instrument tends to overread at heart rates lower than 60 min-1.

Lesions of A1 noradrenergic cells affect AVP release and heart rate during hemorrhage.

The role of A1 noradrenergic cells of the ventrolateral medulla in the changes in mean arterial pressure (MAP), heart rate (HR), and plasma arginine vasopressin (AVP) after slow continuous hemorrhage (2% blood vol/min up to 35%) was examined by comparing responses in conscious rabbits before and 3 wk after a sham operation or A1 lesions. In the control experiments, MAP fell minimally up to the withdrawal of 20% of blood volume after which it fell abruptly to 20-30 mmHg below control by the 35% level. Plasma AVP increased nonlinearly during progressive hemorrhage with significant increases occurring only after 25% of blood volume was removed. In contrast, HR increased linearly after the onset of bleeding. After A1 lesions, which destroyed 84% (range 80-94%) of the noradrenergic cells, the amount of AVP released and the tachycardia during hemorrhage were reduced by 83 and 61%, respectively (P less than 0.005), but the fall in MAP was minimally affected. Basal values of MAP, HR, or plasma AVP were not affected by the lesions. These results suggest that during hemorrhage in conscious rabbits A1 noradrenergic neurons are important for the secretion of AVP and the reflex tachycardia but play little role in the maintenance of blood pressure.

Central nervous system 5-hydroxytryptamine and noradrenaline specificity of ear vascular and ventilation reflexes in thermoregulating rabbits.

Contrasting hypotheses of mammalian thermoregulation were tested in unanesthetized rabbits in relation to the role of the central nervous (CNS) monoamines 5-hydroxytryptamine (5-HT) and noradrenaline (NA) in regulating lung function and ear skin blood flow (Doppler flowmeter). Normal rabbits and rabbits with CNS depletion of 5-HT and NA (caused by the neurotoxins 5,7-dihydroxytryptamine and 6-hydroxydopamine) were studied in an airconditioned chamber at ambient temperatures of 12 degrees, 22 degrees and 35 degrees C. The results suggest that CNS 5-HT plays an excitatory role in the heat conservation mechanism of cold-induced ear skin vasoconstriction, and that this effect is inhibited by CNS NA to cause heat dissipation during heat stress. Both CNS 5-HT and NA appear to exert a mild inhibitory restraint on ventilation even during heat stress. The data support the theory that CNS 5-HT is concerned with heat conservation and CNS NA with heat loss mechanisms in the cutaneous circulation, and that both monoamines moderate heat loss through panting. CNS monoamine-dependent thermoregulation in the rabbit thus resembles the model postulated for the cat, dog and monkey rather than, as previously proposed, for the sheep and goat.

Suprabulbar and bulbar integration of ventilation and ear vascular control during thermoregulation in the rabbit.

Suprabulbar and bulbospinal integration of cardiorespiratory responses to cold and heat stress was studied in groups of normal, thalamic and pontine rabbits. The animals sat in an airconditioned environmental chamber in which ambient temperature (TA) was maintained sequentially at 22 degrees C, 12 degrees C, 22 degrees C and 35 degrees C, with an accuracy of +/- 1 degree C. Neither thalamic nor pontine rabbits could maintain core temperature in cold or heat. At TA 35 degrees C, thalamic and pontine animals did not pant, indicating that telencephalic responses were necessary for the integration of mechanisms promoting respiratory heat loss. Thalamic animals, however, could inhibit ear vascular sympathetic tone in the heat, but the response was absent in pontine animals, suggesting diencephalic responses were essential for the integration of mechanisms promoting ear skin heat loss. Thus, the neural adjustments to thermal stress depend on mechanisms of integration distributed longitudinally throughout the central nervous system, and different components of the reflex cardiorespiratory response depend on different sites in the central nervous system for their full expression.

Cardiac and arterial baroreceptor influences in release of vasopressin and renin during hemorrhage.

We studied the role of arterial and cardiac baroreceptors on mean arterial pressure (MAP) and release of arginine vasopressin (AVP) and plasma renin activity (PRA) during hemorrhage in conscious rabbits. Each rabbit was bled at 2% of its blood volume (BV) per minute until 35% had been removed, after which the blood was reinfused. Each rabbit was studied on three occasions, 7 days apart, and in each experiment, BV-MAP and BV-hormone response curves were constructed. The response to hemorrhage was examined when the input from arterial and cardiac baroreceptors were both intact; arterial baroreceptors only were intact (cardiac receptors were blocked with intrapericardial procaine); cardiac receptors only were intact (after sinoaortic denervation); neither receptor was intact. Resting AVP and PRA levels were unaffected by the various deafferentation procedures. AVP steeply increased only after more than 25% BV had been removed; this response was entirely mediated by cardiac baroreceptors. Increases in PRA occurred at BV loss greater than 15% and were largely independent of baroreceptor input. Maintenance of MAP during hemorrhage was mostly due to drive from the arterial baroreceptors. Thus AVP secretion during hemorrhage contributes little to the maintenance of MAP, and the hypovolemic stimulus to AVP release comes entirely from the cardiac baroreceptors.

Polyamines in bacteriophage phi W-14 and in phi W-14-infected Pseudomonas acidovorans.

Bacteriophage phi W-14 is sensitive to osmotic shock. It contain sufficient free putrescine, 2-hydroxyputrescine and spermidine to neutralize about 15% of the DNA phosphates. The alpha-putrescinylthymine residues of the DNA could neutralize a further 25% of the phosphates. Label is transferred from ornithine to the alpha-putrescinyl residues of phi W-14 DNA. The rates of polyamine synthesis in Pseudomonas acidovorans are increased by phi W-14 infection.

Role of central nervous system monoamines in cardiopulmonary effects of Althesin in rabbit and man.

The steroid induction agent, Althesin, infused intravenously in light anesthetic doses in otherwise unsedated man (84 micrograms kg-1 min-1) and rabbit (140 micrograms kg-1 min-1) causes similar autonomic and somatic effects. In the rabbit, the rise in heart rate (mainly due to central vagal blockade) and the selective depressant effects on respiratory rate are independent of CNS 5-hydroxytryptamine and noradrenaline. The rise in arterial pressure and the fall in hindlimb conductance is dependent on CNS 5-hydroxytryptamine and noradrenaline synthesizing neurons, which are probably arranged in series. These findings provide a working hypothesis for the mechanisms of action of Althesin on central cardiopulmonary controls in man.