In this area the previously described structures are visible with reverse and attenuate patterns cheap 40mg lasix with visa. Its conchae) 100 mg lasix amex, surrounded by a depression corresponding to the role as a fixing structure is undeniable and its section anthelix; which outlines a cavity buy lasix 40mg on-line, the anthelix fossa order genuine lasix online. Posteriorly the since they are joining expansions deriving from the peri- skin is thick, firm and slides on the cartilage through a layer chondrium. On the contrary, the skin notches or exert some traction on certain portions of the covering the anterior surface is very thin; it is quite adher- cartilage, thus contributing to its shape. The following Lobule: it constitutes the lower one third of the ear pavil- muscles are found: the superior auricular muscle, from the ion. It hangs from the concha, while its inferior extremity temporal aponeurosis upward and the internal portion of the forms a free semicircular edge. The lobule is made up with ear pavilion where it is inserted at the level of the little anthe- two thick skin layers, separated from one another by an lix fossa; the anterior auricular muscle, running from the epi- abundant cellular adipose tissue lacking any cartilaginous cranial aponeurosis to the spine of the helix and to the anterior support. The fol- veins drain into the temporal vein (upward) and into the lowing muscles should be mentioned: the great and the small deep veins of the posterior parotid gland (downward). Blood supply: the arterial blood supply comes from the inter- Nerve supply: the sensorial innervation is provided by nal carotid artery and is characterized by two systems three nerves: (Fig. An anterior peduncle formed by three anterior auric- ular arteries, branches of the superficial temporal artery, that • The auriculo-temporal nerve, branch of the trigeminal are in detail an anterosuperior branch for the anterosuperior nerve, that supplies the ascending portion of the anthelix, quadrant of the ear pavilion, an anteromedial branch for the and the tragus; concha and the root of the helix, and an anteroinferior branch • The great auricular nerve, a posterior branch of the super- for the tragus and the lobule. A posterior peduncle arising ficial cervical plexus, that supplies the internal aspect of from the posterior auricular artery is more important than the ear pavilion, the lobule, the antitragus, the posterosu- that previously mentioned, inasmuch as it gives origin to two perior portion of the helix, the anthelix, the scapha, the different branches supplying the entire posterior aspect and a external acoustic meatus, the retro-auricular groove, and portion of the anterior aspect of the ear pavilion through the concha; and some perforating vessels that encircle the helix. Such a rich • The sensory branch of the facial nerve, that supplies the blood supply explains the relatively hemorrhagic pattern of area formed by the concha and the external acoustic 826 C. Multiple techniques as well as numerous variants exist in order to solve the different phenotypic expressions of loop ears. It is impossible to outline all of them in this article; therefore, only those more commonly used at present are 5 Anatomic Variations and Associated hereinafter described, inasmuch as their knowledge appears Aesthetic Deformities to be necessary for completing the technical education of every plastic surgeon. Certain angles between the ear and the skull are expressed by well-codified values. The knowledge of such values as well as the analysis of their prospective deviation may facilitate 6. It is • Cephalo-conchal angle: it is between two planes, one of which indicated in instances of mild to moderate defects particu- runs through the mastoid bone and the other is tangential to the larly in children, in whom the cartilage is mobile and can be concha. The causes may be an altered junction between external gers on the helix in order to recreate the missing folds. Then meatus and concha, or a change in the cartilage elasticity at the several pairs of dots are drawn on the concha and on the anterior level of the inferior arm of the antihelical bifurcation. By using several 25-gauge needles dipped • Scapho-conchal angle: it is responsible for helix angula- in ink, the dots are reproduced on the posterior aspect of the ear tion over the anthelix. Such dots indicate the position in which the conchal- the angle is delimited by scaphal and conchal tangential scaphal mattress sutures are going to be applied. Its value must be maintained when either recon- rior aspect of the pavilion, immediately internally to the two structing or repositioning the anthelix. In fact, one of the rows of drawn dots, a lozenge-shaped skin area is selected and typical deformities of loop ears consists of a widening of then removed deeply down to the cartilage; all the soft tissues this angle up to approximately 175°. The skin surrounding sis of such a variation is easily achieved by pressing with the removed lozenge-shaped skin flap is then going to be the examining fingers on the patient’s helix, thus forcing detached enough to expose the dots where the mattress sutures the scapho-conchal angle within normal values. In applying such sutures the full toid bone and the posterior edge of the ear pavilion; its thickness of the cartilage is passed through, being careful to apex lies in the retro-auricular groove, and its value oscil- include the external perichondrium at a strictly subcutaneous lates between 20° and 30°. Usually two to three sutures are adequate; they must be enced by changes occurring in the two angles previously tied in a progressive order, starting from the medial one, then described; in addition it is in relationship with the concha. Then the skin is closed between the ear pavilion and mastoid bone; this is typical with a continuous intradermal suture or with an overcasting 4-0 of flap ears. This technique corrects the upper two thirds of an accurate diagnosis of the different malformations in order the ear pavilion when a well-defined fold of anthelix is pres- to plan surgical therapy to correct of the defect without per- ent; otherwise it may be associated with Mustardè technique forming any secondary procedures. The muscles and the posterior auricular liga- enclose the perichondrium anteriorly underneath the skin. At be tied in a progressive fashion, namely the middle one at this stage it is necessary to pay special attention to preserving first, then the superior one, and finally the inferior one. The technique antici- skin is approximated with a continuous intradermal suture or pates the excision of a portion of the fascia covering the mas- with an overcasting 4-0 nylon suture. In such a way the concha, in its new location, has a monly used variants, such as the variant suggested by Gibson, greater space posteriorly in the absence of soft tissues. The contemplate weakening the cartilage of the anterior aspect of conchal cartilage is sutured to the portion of fascia which had the anthelix; such a weakening is done by means of specific been left in place. Two or three 4-0 polyester mattress sutures surgical instruments (otoabrader, diamond drills, surgical are enough; they must pass through the full thickness of the forceps, etc). The In 1971, Converse and Wood-Smith described a technique drawing identifying the new anthelix fold is a line that encir- contemplating the section of the conchal cartilage followed cles the superior crus on three sides and includes the upper by its tubularization. Such a technique is indicated in the edge of the superior crus, the upper edge of the triangular treatment of severe loop ears at any age, being satisfactorily fossa, and the line indicating the junction between scapha suitable for poorly elastic cartilages, such as in adults pre- and helix. The lines drawn on the anterior aspect its posterior aspect by means of either a rotating brush or a must be replicated on the posterior aspect. The sutures should be tied use straight needles that are passed through the full thickness concomitantly; enough tension should be exerted to ensure a of the ear pavilion. We are able, therefore, to identify posteri- satisfactory bending of the anthelix. The concha is remod- orly the skin area to be removed, together with the underlying eled by removing a crescent portion of it; it is then attached soft tissues, including both cartilage and perichondrium. The limit of thickness cartilage incisions are carried out along the edges of this technique consists in obtaining an excessively elevated the prospective anthelix; attention is paid to preserve the skin antihelical ring together with a reduction in the scapha; at of the anterior surface. The upper horizontal incision should times an un-natural shape of the ear may be the outcome. When the cartilage is particularly thick or refractory reconstructing the antihelical fold by incising the cartilage; 830 C. We continue to apply Keith’s method of trans- the needles; subsequently, the cartilage is dissected from the fixion stitches in order to position the anthelix backward; anterior aspect of the skin. The incision is then prolonged we are able to discover its position by manipulating the ear horizontally, towards the base of implant of the ear in order pavilion. On the anterior rior surface; soft tissues are removed until the underlying aspect of the cartilaginous flap a scoring is carried out by cartilage is exposed. Then a full-thickness incision is made using partial thickness parallel incisions that follow the a b c d e Fig. As a result of such anterior chondroto- mies, the weakened cartilage tends to bend spontaneously, thus recreating the anthelix fold. Similarly to the previously described techniques, even in this procedure the skin is approximated by a few 4-0 nylon sutures, applied either as a continuous intradermal suture or as an overcasting suture. The Chongchet tech- nique provides a natural curve for the anthelix but exposes to the risk of recurrences at the level of the upper one third of the ear. The muscle is then isolated; special atten- tion should be paid at its insertion to the conchal ponticulus. A lozenge-shaped partial resection of the concha is carried out, inclusive of the quadrangular segment to which the muscle is inserted. A chondromuscular flap is then prepared which is moved forward and sutured laterally with 4-0 nylon sutures in order to create the cephalo-auricular angle. At this stage the correction of any possible deviation of the main axis can be carried out by repositioning the muscle in a more caudal or cranial location, so that the entire ear is rotated in a sagittal plane. Then the ear cartilage; the strip of rectangular cartilage adherent to the line along which the anthelix shall be created is obtained by anterior perichondrium is isolated by undermining the lateral pressing the ear pavilion against the skull. Such a procedure mobilizes The patient lies down with the head turned towards one the cartilage flaps, that are then sutured in order to recreate side. The hair, surrounding the ear pavilion is held in place by transparent sterile strips of adhesive tape, that 6. A wisp the Chongchet Technique of cotton wool is inserted into the external meatus so that no disinfectant shall penetrate the tympanic chamber; then Granted that no technique exists which is suitable for all loop disinfection of the operative field is carried out. The authors describe in helix and the hairline, at the level of the anterior auricular detail the technique that they perform and from which they muscle, in order to block auriculo-temporal nerve pathways; obtain the most satisfactory and long-lasting results. Such a the anesthetic infiltration continues along the cutaneous area Otoplasty 833 incised in its full thickness along the broken line, so that a cartilage flap is obtained.

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A confidence interval is obtained by the general formula estimator Æ reliability coefficient standard error of the estimator In the previous chapter we saw that when both np and n 1 À p are greater than 5 discount lasix 40 mg on-line, we may consider the sampling distribution of ^p to be quite close to the normal distribution order lasix 100mg online. When this condition is met purchase lasix 100 mg with mastercard, our reliability coefficient is some value of z from the standard pffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi normal distribution generic 100 mg lasix amex. Since p, the parameter we are trying to estimate, is unknown, we must use ^p as an estimate. The sample consisted of 1220 adult Internet users, and information was collected from telephone interviews. We wish to construct a 95 percent confidence interval for the proportion of Internet users in the sampled population who have searched for information on experimental treatments or medicines. Thesizeofthesampleandourestimateofp are of sufficient magnitude to justify use of the standard normal distribution in constructing a confidence interval. The 95 percent confidence interval for p, based on these data, is :18 Æ 1:96 :0110 :18 Æ :022 :158;:202 We are 95 percent confident that the population proportion p is between. On the basis of these results we would expect, with 95 percent confidence, to find somewherebetween 15. Identify each component of the interval: point estimate, reliability coefficient, and standard error. These researchers assert, however, that there are some indications that residual viable tissue may be present in Q-wave-infarcted regions. Their study of 150 patients with chronic electrocardiographic Q-wave infarction found 202 dysfunctional Q-wave regions. Construct a 90 percent confidence interval for the proportion of viable regions that one might expect to find a population of dysfunctional Q-wave regions. Syncope is the temporary loss of consciousness due to a sudden decline in blood flow to the brain. Construct a 99 percent confidence interval for the population proportion of subjects with syncope or near syncope who also have cardiovascular disease. In a simple random sample of 125 unemployed male high-school dropouts between the ages of 16 and 21, inclusive, 88 stated that they were regular consumers of alcoholic beverages. We may want to compare, for example, men and women, two age groups, two socioeconomic groups, or two diagnostic groups with respect to the proportion possessing some characteris- tic of interest. An unbiased point estimator of the difference between two population proportions is provided by the difference between sample proportions, ^p1 À p^2. Aswe have seen, when n1and n2are large and the population proportions are not too close to 0 or 1, the central limit theorem applies and normal distribution theory may be employed to obtain confidence intervals. The standard error of the estimate usually must be estimated by sffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi p^1 1 À p^1 ^p2 1 À p^2 s^^p1À^p2 ¼ þ n1 n2 because, as a rule, the population proportions are unknown. A 100 1 À a percent confidence interval for p1 À p2 is given by sffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi p^1 1 À p^1 ^p2 1 À p^2 ð p^1 À ^p2 z1Àa=2 þ (6. The subjects were from unsolicited consecutive referrals to a residential treatment center and a pediatric psychopharmacology clinic serving a tertiary hospital and medical school. We wish to construct a 99 percent confidence interval for the difference between the proportions of sexual abuse in the two sampled populations. Solution: The sample proportions for the females and males are, respectively, ^pF ¼ 31=68 ¼ :4559 and ^pM ¼ 53=255 ¼ :2078. The estimated standard error of the difference between sample proportions is rffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi ð :4559 :5441 :2078 :7922 s^^pFÀ^pM ¼ þ 68 255 ¼ :0655 The reliability factor from Appendix Table D is 2. Since the interval does not include zero, we conclude that the two population proportions are not equal. Identify each component of the interval: point estimate, reliability coefficient, and standard error. For a control group, they located 510 subjects who as children attended the same elementary school and lived within a five-block radius of those in the abused/neglected group. In the abused/neglected group, and control group, 114 and 57 subjects, respectively, had developed antisocial personality disorders over their lifetimes. Construct a 95 percent confidence interval for the difference between the proportions of subjects developing antisocial personality disorders one might expect to find in the populations of subjects from which the subjects of this study may be presumed to have been drawn. A treatment group of 138 women received a leaflet on screening that contained more information (average individual risk for cervical cancer, likelihood of positive finding, the possibility of false positive/negative results, etc. Inthetreatmentgroup,109women indicated they wanted to have the screening test for cervical cancer while in the control group, 120 indicated they wanted the screening test. Construct a 95percent confidence interval for thedifference in proportions for the two populations represented by these samples. The first group had current angina medications optimized, and the second group was tapered off existing medications and then started on long-acting diltiazem at 180 mg/day. The researchers performed several tests to determine if there were significant differences in the two treatment groups at baseline. One of the characteristics of interest was the difference in the percentages of subjects who had reported a history of congestive heart failure. In the group where current medications were optimized, 16 of 49 subjects reported a history of congestive heart failure. In the subjects placed on the diltiazem, 12 of the 51 subjects reported a history of congestive heart failure. State the assumptions that you think are necessary and construct a 95 percent confidence interval for the difference between the proportions of those reporting congestive heart failure within the two populations from which we presume these treatment groups to have been selected. To study the difference in drug therapy adherence among subjects with depression who received usual care and those who received care in a collaborative care model was the goal of a study conducted by Finley et al. The collaborative care model emphasized the role of clinical pharmacists in providing drug therapy management and treatment follow-up. Of the 50 subjects receiving usual care, 24 adhered to the prescribed drug regimen, while 50 out of 75 subjects in the collaborative care model 6. Construct a 90 percent confidence interval for the difference in adherence proportions for the populations of subjects represented by these two samples. To take a larger sample than is needed to achieve the desired results is wasteful of resources, whereas very small samples often lead to results that are of no practical use. Let us consider, then, how one may go about determining the sample size that is needed in a given situation. In this section, we present a method for determining the sample size required for estimating a population mean, and in the next section we apply this method to the case of sample size determination when the parameter to be estimated is a population proportion. By straightforward extensions of these methods, sample sizes required for more complicated situations can be determined. Objectives The objectives in interval estimation are to obtain narrow intervals with high reliability. If we look at the components of a confidence interval, we see that the width of the interval is determined by the magnitude of the quantity ð reliability coefficient standard error of the estimator since the total width of the interval is twice this amount. We have learned that this quantity is usually called the precision of the estimate or the margin of error. For a given standard error, increasing reliability means a larger reliability coefficient. But a larger reliability coefficient for a fixed standard error makes for a wider interval. On the other hand, if we fix the reliability coefficient, the only way to reduce the width of the interval is to reduce the standard error. Since the standard error is equal to pffiffiffi s= n; and since s is a constant, the only way to obtain a small standard error is to take a large sample. That depends on the size of s, the population standard deviation, the desired degree of reliability, and the desired interval width. Let us suppose we want an interval that extends d units on either side of the estimator. Estimating s2 The formulas for sample size require knowledge of s2 but, as has been pointed out, the population variance is, as a rule, unknown. A pilot or preliminary sample may be drawn from the population, and the variance computed from this sample may be used as an estimate of s2. Observations used in the pilot sample may be counted as part of the final sample, so that n (the computed sample size) Àn1 (the pilot sample size) ¼ n2 (the number of observations needed to satisfy the total sample size requirement).

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It is important to note that in each of the mentioned studies lasix 100 mg mastercard, mesh was simply sutured to the vagina and not tensioned as is done for prolapse and incontinence surgeries utilizing mesh buy generic lasix pills. As such cheap lasix line, these studies ignore the impact of mechanics on mesh outcomes and highlight that the biological response to a material is vastly different in the vagina relative to the abdominal wall buy genuine lasix. Overall, the vagina is a harsher biologic environment for mesh implantation compared to the abdomen. Surgical entry for transvaginal procedures may potentially contaminate the mesh via vaginal microflora, resulting in subclinical infection, and intensifying the host response. The failure to acknowledge the biologic environment in the development of urogynecologic meshes has likely resulted in high complication rates of polypropylene mesh; however, the mechanical demands place on synthetic meshes used for prolapse repair is another significant factor that must be considered. Mechanical Environment Mechanical Demands of Mesh Pelvic organ support is a complex mechanical system in which support to the vagina is provided by the levator ani muscles and connective tissue attachments to the pelvic sidewall. The vagina, in turn, orchestrates support to the pelvic organs by maintaining static equilibrium and resisting transient changes in abdominal pressure. Given the interactions between these components, imbalance or degradation of any tissue may lead to dysfunction or conditions such as prolapse. Current synthetic graft repair attempts to restore support, mimicking the mechanical role of connective tissue, as current meshes have no active properties. While it may seem inconceivable to truly recreate native pelvic organ support, understanding nonpathological support and the mechanical behavior of both grafts and healthy native tissues would greatly improve outcomes of reconstructive surgery in the soft tissues of the pelvis. During prolapse repair, synthetic meshes are typically attached to the vagina and then secured to the sacrum (sacrocolpopexy) or to structures along the pelvic sidewall (transvaginal procedure). Under these conditions, mesh devices assume the role of suspension cables, maintaining the position of the vagina while resisting the downward forces of abdominal pressure and the weight of other pelvic floor viscera. This function results in a predominately uniaxial tensile loading condition, which is quite dissimilar from in vivo loading for hernia repair. During a hernia repair, the mesh is often fixed along 1387 its perimeter in the abdominal wall, over the defect. This scenario, analogous to the wall of a pressure vessel, places hernia mesh in tension along all axes simultaneously, much like the surface of a balloon upon inflation. The omniaxial loading in the abdomen helps maintain geometric features of mesh, such as geometry and pore size. While stable graft geometries are expected in the abdominal wall, tensile loading conditions of the vagina provides an increased likelihood of mesh deformation highlighted by reports of significant mesh contraction (Figure 90. Thus, for urogynecological meshes to function as intended, it is necessary to understand how mesh products deform under loading conditions similar to those in the pelvic floor. Many studies have evaluated the mechanical behavior of mesh in response to uniaxial loading, often reporting structural properties such as ultimate elongation, ultimate load, and stiffness [32–34]. While these studies are useful for comparing mesh behavior, often the focus is placed on the failure criteria for grafts, with loads typically exceeding 30 N. Rather, focus should be placed on mesh behavior at loads that are experienced in vivo [53,54]. Perhaps the greatest impact of mechanical loads on mesh behavior is on the mesh porosity and pore size, properties that dictate the host response. Indeed, uniaxial loads dramatically decrease the maximum pore size and porosity of nearly all current synthetic meshes [32,34,42]. Uniaxial loading of composite, porous materials results in elongation of the graft in the direction of applied force and causes individual filaments to rotate and reorganize to resist the applied force. The degree of reorganization is largely governed by the geometry of a mesh and contributes to the nonlinear behavior observed for mesh products. Meshes whose filaments are highly aligned with the loading axis exhibit little nonlinear load–elongation behavior, while the same mesh tested with filaments offset 45° from the loading axis have elongated toe regions and significant pore deformation before resisting applied forces. For most materials, elongation along one axis results in narrowing of the axis perpendicular to the applied force. This phenomenon is known as Poisson’s effect for continuous materials, though a similar occurrence is observed for porous materials. Typically for porous structures, this narrowing results from a reduction in pore size as pores collapse during filament reorganization. Uniaxial tension dramatically reduces pore size for most mesh products, as pores in a tensioned mesh are often less than 1 mm in diameter even at low levels of force (Figure 90. Given the importance of pore size on the host response, one would anticipate a diminished potential for tissue ingrowth and a high likelihood of bridging fibrosis for meshes implanted under tension. Though mesh shrinkage may also involve contraction of fibrotic tissue or other biological mechanisms, tensile forces have the potential to cause large alterations in mesh dimensions and induce fibrosis. Factors including tissue ingrowth and the boundaries imposed by the vagina may help to limit pore size reduction in vivo to some extent. Nonetheless, mesh deformation must be considered when “tensioning” or placing a mesh surgically, as well as during in vivo loading conditions both before and after host tissue integration occurs, as this dictates the initial host response following implantation. For hernia repair, mesh is placed in the abdominal wall and loaded along all axes simultaneously to resist expansion of the abdominal cavity resulting from internal pressure. Vaginally, mesh arms are placed in tension, acting as support cables to hold the vagina in place. This disparity in mechanical loading leads to notably different deformation of mesh products in vivo. Explanted hernia mesh is typically flat and pore geometries appear similar to the preimplanted state (c), while prolapse mesh is often bunched with dramatic alterations in pore geometry and decreased pore size (d). As shown here, Gynemesh, representative of current wide-pore, low-weight polypropylene synthetic meshes, experiences significant deformation at forces well below its ultimate load. Macroscopically (top), the mesh undergoes lateral contraction, similar to that shown in Figure 90. Microscopically (bottom), pore dimensions are drastically reduced bringing filaments closer together. Uniaxial biomechanical properties of seven di erent vaginally implanted meshes for pelvic organ prolapse. To date, nearly all ex vivo structural testing of prolapse mesh have utilized clamps to applied forces to mesh, forcing mesh deformations to occur in plane only. Though the assumption of planar deformation is necessary for measurement of structural properties such as stiffness, clamped restraints at the boundary are not representative of mesh fixation in vivo. Recently, discrete suture fixation of mesh products was found to significantly increase the amount of folding and wrinkling that occurs upon application of tensile forces. Inclusion of suture attachments resulted in a 15-fold increase in surface curvature for tested mesh devices at just 10 N of force, relative to traditional mechanical testing boundary conditions (Figure 90. Increased folding of the mesh provides an additional mechanism by which filaments can be brought closer (increasing mesh burden), increasing the likelihood of bridging fibrosis. Given these results, it is clear that the number and placement of sutures used to fix mesh in vivo greatly impacts the manner in which forces are transferred throughout a graft, creating regions that are at increased risk of complication. When considering the interface between two materials, such as the vagina and implanted mesh, the properties of the each material must be considered. Mechanically, material interfaces are subject to stress concentrations, with the magnitude of stress proportional to the difference in stiffness between the materials [57,58]. Examination of tendons, tissues that transfer force from the compliant muscle to the stiff bone, reveals a variable stiffness along their length. Tendons have increased stiffness at the boney insertions, relative to the muscular attachments, which are quite compliant (low stiffness). Such a distribution of stiffness is created by variable tissue composition and functions to minimize stress concentrations at the respective boundaries [58,59]. The importance of this interface has also been demonstrated in other medical implants, as increased implant stiffness was found to induce a maladaptive remodeling response through a phenomenon known as “stress shielding” [60–62]. When prothesis bear are the primary load bearing structure, biological tissues, which respond to mechanical stimuli, may atrophy. Stress shielding was detrimental to soft tissues following hip arthroplasty, resulting in increased periprosthetic breakdown of both collagen and elastin upon implantation of implants of increasing stiffness [63–66]. When examining the surface curvature of synthetic mesh (top), discrete placement of sutures (yellow circles) results in significant curvature or bunching of mesh upon application of tensile loads. Bunching of mesh brings mesh fibers closer together, including fibers that have deformed out of plane (bottom).

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Thus purchase lasix no prescription, lB agents will demonstrate minimal effects at relatively slow rates purchase discount lasix online, while lC agents will demonstrate significant effects at comparable or even slower rates buy lasix with visa. This is one of the causes of postrepolarization refractoriness noted in such fibers discount lasix 40 mg overnight delivery. These interactions are voltage and time dependent and appear operative for both sodium and calcium channels. Use- dependence and the modulated receptor hypothesis are interactive and may lead to totally different conclusions about the electrophysiologic effects of a given agent than if the agent was evaluated on a normal isolated Purkinje fiber at a slow rate. Changes in extracellular potassium, intracellular calcium, and pH can affect active membrane currents through ionic channels and may induce nonspecific ionic channels. The inhibition of the sodium/potassium pump by digitalis and the sodium/calcium pump during ischemia may also affect the action of antiarrhythmic agents. Many of the effects on sodium, potassium, and calcium channels can be reversed by enhanced sympathetic tone or circulating catecholamines. The effects on passive membrane properties may differ among agents of the same class. The developing field of pharmacogenomics will no doubt revolutionize our understanding of antiarrhythmic drug effects. The Vaughan Williams classification has no contingencies to take this sort of specificity into account. The “classic” mechanism of action of these antiarrhythmic agents is shown in Table 12-1. One must remember that these “actions,” which are based on data from single-cell microelectrode recordings, whole-cell voltage clamping, and patch clamping, simply reveal how these drugs modify ionic conductance in normal tissues. Evaluation of Electrophysiologic Effects of Drugs in Humans Using standard intracardiac recording and stimulation techniques, one can determine the effects of individual drugs on specific cardiac tissue. As noted in Chapters 2 and 3, measurements of sinoatrial conduction time and automaticity, as well as conduction and refractoriness in the atrium, A-V node, His–Purkinje system, and ventricle during sinus and paced rhythms are readily obtainable and generally reproducible. A summary of the electrophysiologic properties of various currently available and some promising experimental antiarrhythmic agents in humans is shown in Tables 12-2 and P. Limitations of such measurements and suggestions for other parameters to be studied are discussed in subsequent paragraphs. Besides evaluating the effect of antiarrhythmic agents on conduction (intra-atrial, A-V nodal, His–Purkinje, and intraventricular) and refractoriness, measurements of threshold of excitability and strength-interval curves114 115, should also be performed. The frequency-dependent effects of these drugs should be evaluated by assessing the effects of different drive cycle lengths on these parameters. Several investigators have demonstrated use-dependent effects in vivo using canine models as well as in humans. For example, the blunting or reversal of cycle length–dependent shortening of refractoriness by an antiarrhythmic agent may signify an important electrophysiologic response that predicts clinical efficacy. Results presented may vary according to tissue type, experimental conditions, and drug concentration. Verapamil ↔↓ ↑ ↔ ↔ ↑ ↔ Ranolazine ↔ ↔ ↔ ↑ ↔ ↔ Results presented may vary according to tissue type, experimental conditions, and drug concentration. As noted previously, the presence of disease states can markedly influence the effect of a drug on conduction or refractoriness. An example is shown in Figure 12-3, in which lidocaine, a drug that is supposed to have no significant effect on A-V nodal or His-Purkinje conduction, produces ventricular asystole in a patient with left bundle branch block and prolonged H-V conduction. Block is produced in the A-V node, as is marked depression of conduction in the His–Purkinje system (H-V increased from 50 to 95 msec on conducted beats). Thus, the presence of abnormal A-V nodal function and His–Purkinje function (manifested by left bundle branch block) can provide a substrate in which lidocaine is able to markedly impair conduction. One must be cognizant of such potential responses when using drugs in patients with diseased conducting systems. Following procainamide the curve is shifted somewhat upward and to the right compared to the control. Conduction and refractory period measurements (both of which are based on the ability to record propagated impulses) are generally reproducible (±10 msec) over a period of several hours for the atria, His–Purkinje system, and ventricles. However, they are not nearly as consistent for measurements of electrophysiologic characteristics of the sinus and A-V nodes. Such changes in autonomic tone can alter sinoatrial conduction and recovery times, A-H intervals, and A-V nodal refractory periods by as much as 20% during a single study. While there is an influence of the autonomic nervous system on the atrium, His–Purkinje system, and ventricle,67 in most cases it is not significant enough to affect the reproducibility of measurements. However, unless the patient is in a truly basal state throughout the study, the effects of drugs on the sinus and A-V nodes, in particular, must be interpreted with caution. Refractory period measurements should be performed at comparable stimulus strengths before and after administration of an antiarrhythmic agent. Generally, refractory period measurements are performed using stimuli at twice the diastolic threshold. The current needs to be checked before and after drug administration to ensure that stimulation is carried out at comparable current strengths P. In the performance of strength-interval curves, as the current used is increased from threshold to 10 mA, we have observed a decrease in the measured refractory period of 20 to 100 msec (mean ≈40 msec) in the atrium and ventricle. Thus, while most laboratories use twice diastolic threshold to measure refractoriness, strength-interval curves, or the use of 10 mA routinely may provide more reliable information since the steep portion of the strength-interval curve appears to always be reached by 10 mA. Whether use of this measurement has clinical significance is uncertain; it would, however, ensure that local tissue refractoriness is not the limiting factor in induction of arrhythmias. However, it is important that investigators use comparable current strengths before and after an antiarrhythmic agent. Before lidocaine administration, left bundle branch block with prolonged (A-V) conduction is observed. Following lidocaine complete A- V block is produced with failure of conduction localized to the A-V node. Conduction resumes in 3 seconds, at which time the H-V is markedly increased to 95 msec. Assessment of refractory periods of the A-V node or His–Purkinje system is impossible if the functional and/or effective refractory period of the atrium exceeds the refractory period of these subatrial structures. Similarly, if the functional refractory period of the A-V node exceeds the relative and effective refractory period of the His–Purkinje system, the latter measurement cannot be determined. Difficulties may be encountered during the control study, or they may be produced following antiarrhythmic drug administration. Therefore, it may not be possible to determine the effect of a drug on A-V nodal or His–Purkinje refractoriness if atrial refractoriness is prolonged beyond the A-V nodal refractory period. The effect of an antiarrhythmic agent administered intravenously may not be the same as the effect of a drug given orally, even when blood levels are comparable. Moreover, if the diluent in which the drug is prepared has vasodilatory properties, or if the drug itself induces alterations in systemic blood pressure, this may result in enhanced sympathetic tone, producing a different electrophysiologic effect than when the drug is administered orally. Whereas intravenous verapamil produces hypotension, and secondarily enhances sympathetic tone producing a decrease in the refractory period of the bypass tract, oral administration of that agent does not significantly affect the refractory period of the bypass tract. In our experience, electrophysiologic effects of intravenously administered Group lA drugs (procainamide and quinidine) are similar to the effects ascertained following oral administration. Nonetheless, we have demonstrated that the clinical efficacy of these agents can be predicted if administered acutely, as long as hypotension and myocardial depression do not take place. In view of the fact that the rate of administration can markedly influence the hemodynamic response, we recommend that Class 3 studies always be determined on chronic oral doses of various agents. This observation suggests limited clinical antiarrhythmic efficacy of n-acetyl procainamide. A single dose of a given agent may be inadequate to assess its range of effects; therefore, multiple incremental doses should be evaluated, particularly if no effects are noted initially. For example, minimal effects on His–Purkinje function may be noted in response to Group lA drugs at one plasma level, whereas at a slightly higher level, marked and potentially dangerous depression of conduction can be observed. This is especially true if the use-dependent effects of the antiarrhythmic agents are assessed. One should not neglect the use-dependent effects of antiarrhythmic agents at any dose. This is important in assessing their clinical efficacy and toxicity since these agents are usually used to treat tachyarrhythmias; thus, the effect of a single dose of an agent at baseline heart rate may not yield information relative to its action during a tachycardia.