Jonathan Abrams, MD

• Department of Medicine
• Division of Cardiology
• University of New Mexico Health Sciences Center
• Albuquerque, NM

Autologous tissue grafts possess several advantages such as low immunogenicity and a structural support that promotes cell adhesion and migration [10] hair loss in men 2 piece order generic propecia canada. Obtaining a natural graft could lead to loss of function and potential neuroma formation at the donor site hair loss in men 07 1 mg propecia visa, multiple small grafts may be needed in case of a long nerve gap hair loss treatment using onion buy propecia 1 mg amex, and there could be a size mismatch between the donor nerve graft and the injured nerve hair loss patterns buy discount propecia on-line. More important curezone hair loss buy 5 mg propecia with mastercard, complete functional recovery is seldom obtained with autografts [11]. Therefore, there is interest in developing treatments and biomaterials that match or exceed the functional performance of autografts. In addition, scaffolds contain multiple properties or elements inside the tubular structure that promote and guide nerve regeneration, reduce scar tissue formation, and reduce inflammation, among others. In general, scaffolds for nerve repair should support axonal proliferation, have low antigenicity, support vascularization, be porous for oxygen diffusion, and avoid long-term compression. In this article, the grafts are classified as isotropic or anisotropic based on the distribution of these four central components. In isotropic grafts, the components are distributed uniformly within the graft with no directional cues. In anisotropic grafts, one or more of these components is distributed nonuniformly to create a gradient that may provide a directional cue, usually to direct the axonal growth toward the distal target. Although these materials support nerve regeneration, they do not provide directional cues to the axons. Autologous vein grafts have been shown to provide a good environment for axonal regeneration in short nerve gaps [13,14]. However, the use of vein grafts for long nerve gaps has been less successful because of the collapse of veins caused by their thin walls and constriction owing to the surrounding scar tissue [15]. Collagen-filled vein grafts were found to promote better axonal growth than empty vein grafts for a 15-mm nerve gap in rabbits [16,17]. Muscleevein combined grafts, in which the muscle fibers are inserted in veins, were used in 10-mm-long nerve gaps in rats and were found to promote axonal regeneration comparable to that of syngeneic nerve grafts [20]. Although the muscleevein grafts were able to promote nerve regeneration in 55-mm-long nerve defects in rabbits, they were not comparable to nerve autografts [20]. Autologous muscleevein combined grafts have been used clinically in humans to bridge nerve gaps ranging from 5 to 60 mm. The results were scored as "poor," "satisfactory," "good," and "very good," based on the recovery of sensory and motor functions. Of the 21 lesions repaired (in 20 patients), 10 were of the sensory nerves and 11 were mixed nerve lesions. Research in this field has encompassed multiple strategies, each targeting a unique aspect of the healing process after nerve injury. Future iterations in the design of scaffolds could combine these strategies and possibly evoke a synergistic response in nerve repair and regeneration. All lesions in the mixed nerves showed "satisfactory" to "good" recovery of motor and sensory functions [21]. Although autogenous/natural materials have shown encouraging results when used for nerve repair, they have certain drawbacks. In the case of autogenous grafts, drawbacks include the need for a second surgery, loss of function at the donor site, and neuropathic pain at the donor site. To circumvent these problems, researchers have developed artificial or synthetic scaffolds for peripheral nerve. This fluid contains neurotrophic factors as well as several cytokines and inflammatory cells such as macrophages. Within days, the fibrin coalesces and forms a longitudinally oriented fibrin cable bridging the two nerve ends. Without the formation of the fibrin cable, axonal regeneration cannot occur, which makes the fibrin cable formation a critical step. These strategies augment nerve regeneration by affecting the sequence of events that lead to bridging of the nerve gap. Nerves regenerated in semipermeable tubes featured more myelinated axons and less connective tissue [24,25]. The use of bioresorbable tubes negates the need for a second surgery to remove the implant and prevents long-term compression of the nerve. However, it is critical that degradation of the tube not allow fibroblasts to invade the lumen space before regeneration occurs, because this may prevent axons from regenerating. Agarose is a polysaccharide derived from red agar and is widely used in gel electrophoresis and gel chromatography. SeaPrep agarose hydrogel has been shown to support neurite extension from a variety of neurons in a nonimmunogenic manner [26e28]. Agarose gels also allow molecules to be covalently linked to the gels through functional groups on their polysaccharide chains. For example, laminin protein or fragments of laminin can be covalently coupled to SeaPrep agarose gels to enhance their ability to support neurite extension [29]. Collagen can be used to fill the intraluminal space of a vein graft to prevent it from collapsing and improve its nerve repair efficiency. In collagen-filled vein grafts, the number and diameter of myelinated axons were significantly increased compared with vein grafts without collagen gel [16,17]. Nerve repair with silicone tubes has also been significantly improved by filling them with collagen gel. Additionally, Collagen tubes filled with collagen gel have promoted more rapid nerve sprouting and better morphology than saline-filled collagen tubes [30]. This negative effect, which presumably results from gel remnants blocking diffusion and axonal elongation, might be overcome by reducing the concentration of the collagen gel [32]. Hyaluronan-based tubular conduits, which are used for peripheral nerve regeneration, resulted in more myelinated axons and higher nerve conduction velocities than silicone tubes filled with saline with little cytotoxicity upon degradation [34,35]. Other gels used in vivo to promote nerve regeneration include Matrigel, alginate gels, fibrin gels, and heparin sulfate gels (Tables 69. Anisotropic grafts: have directional distribution of one or more of the four components A: Scaffolds Aligned filaments Magnetically aligned gels B: Neurotrophic factors C: Extracellular matrix proteins D: Support cells 3. Similarly, a gel mixture containing laminin, collagen, and fibronectin significantly improved nerve regeneration compared with saline-filled silicone channels [40]. Therefore, peptides and proteins that facilitate cell adhesion and migration within the scaffolds have an important role in cellescaffold interactions and could be used to enhance nerve regeneration. A nerve injury usually results in disruption of communication between the target organs and the neuronal cell body and leads to Wallerian degeneration (the breakdown of myelin sheath and axons). Neurotrophic factors are likely an important part of future clinical therapies for peripheral nerve injuries and diseases. Various studies have developed scaffolds for the sustained delivery of neurotrophic factors to enhance nerve regeneration. Hubble and Sakiyama-Elbert developed a fibrin matrix that immobilizes heparin molecules by electrostatic interactions, which in turn immobilizes heparin-binding growth factors. When implanted in vivo, the fibrin matrix releases the bound growth factor as a result of fibrin degradation [48]. Future research in this field may focus on developing biomaterials for the sequential delivery of neurotrophic factor and cytokines after peripheral nerve injury. In addition to neurotrophic factors, other cytokines can be delivered to modulate aspects of the regenerative process after peripheral nerve injury. Scientists have focused on the effect of inflammatory and immune responses in the healing mechanisms of multiple tissues. In the context of peripheral nerve injury, scientists have found that macrophage polarization has an important role in nerve regeneration [51]. Macrophages can be classified across a spectrum in which the two ends represent inflammatory (M1) and antiinflammatory macrophages (M2). Another approach to creating an antiinflammatory environment within the injury site is the selective recruitment of M2 macrophages. For nerve gaps less than a critical length (10 mm), these processes occur spontaneously, leading to axonal regeneration. However, for nerve gaps ¨ greater than 10 mm, spontaneous nerve regeneration does not occur, because a fibrin cable and bands of Bungner fail to form [9]. All of these components have been suggested to have roles in supporting neuronal survival and axonal regeneration. This could decrease the time required by the axons to reconnect to the target organ and may increase the distance over which regeneration occurs. Olfactory ensheathing cells have been shown to promote the regeneration of cut nerves in the adult rat spinal cord [58]. Similarly, pluripotent stem cells derived from hair follicles have shown improvements in rats [59]. However, the difficulties of isolating and culturing these cells from the patient before surgery could limit this approach for some surgical procedures. Electroconductive Scaffolds for Nerve Regeneration Electrical stimulation is another technique that has been used to promote nerve regeneration. Previous work showed that electrical stimulation of the soleus nerve of rabbits after a crush injury promoted twitch force, tetanic tension, and muscle action potential in soleus muscle, indicating enhanced nerve growth [60]. To elucidate how electrical stimulation accelerated nerve growth, various groups evaluated its effects on growth factors expression as well as other cellular responses. Another group observed increased neurotrophin expression after electrical stimulation following nerve repair using a nerve allograft [62]. In addition to an increase in growth factor expression, it was found that stimulating motor neurons at 20 Hz for 1 h accelerated the sprouting of axons after nerve injury [61,63]. These results have motivated research groups to develop electroconductive scaffolds that create an electrical environment within large nerve gaps [64]. The mechanism by which electrical stimulation enhances peripheral nerve regeneration still needs to be fully elucidated. However, future strategies could combine electrical stimulation with other scaffold components discussed throughout this chapter to accelerate successful nerve repair after a peripheral nerve injury. Neuronal as well as glial cells respond to the underlying topographical cues in a particular manner. Distinct cellular processes, including migration, polarization, and gene expression, have been shown to be affected by the isotropy of tissue engineered scaffolds [67]. Although the exact mechanisms of how topographical cues affect cell behavior have yet to be elucidated, they have been hypothesized to affect protein attachment, orient cell cytoskeleton, and affect downstream gene regulation [68,69]. In this section, studies involving nerve grafts that provide directional guidance are discussed. Aligned Anisotropic Scaffolds We hypothesize that the superior performance of autologous nerve grafts is the result of its cellular components and its longitudinally aligned structure. The longitudinally aligned structure of the degenerating nerves in the autografts provides contact guidance and direction to the regenerating nerves. It has been shown that a poly(acrylonitrile-co-methylacrylate) nanofilament-based scaffold alone can facilitate regeneration across a 17-mm nerve gap in rats [70]. All have been found to improve regeneration significantly compared with saline-filled tubes. In addition to synthetic filaments, magnetically aligned fibrin and collagen type I gels have been used to provide directional guidance to neurites in vitro and axons in vivo [36,76,77]. Neurotrophic Factors Neurotrophic factors have been delivered mostly in an isotropic manner in vivo. However, in vitro studies suggested that gradients of neurotrophic factors can direct growth cones toward the source of neurotrophic factor [78]. Other graft sources include the anterior branch of the medial antebrachial cutaneous nerve, the lateral femoral cutaneous nerve, and the superficial radial sensory nerve [90]. Similarly, a mixed nerve shows superior regeneration with either a mixed nerve or a motor nerve graft compared with a sensory nerve graft [91]. Therefore, clinical outcomes might be improved by using alternatives to sensory nerve grafts in reconstructing a mixed nerve. However, there are relatively few expendable motor or mixed nerves in the human body that could be used as graft materials. Therefore, a more feasible alternative would be to use nerve allografts or biosynthetic graft materials. Cadavers are an abundant source of graft materials and avoid the complications of harvesting autografts. However, cadaveric nerve allografts require maintenance and can be used only with immunosuppressive therapy. Withdrawal of the immunosuppressant leads to profound loss of axons in the allografts. The axonal loss is most profound in mixed nerve allografts compared with motor nerve allografts, followed by sensory nerve allografts [92]. Allografts, cold-preserved and/or freeze-thawed to prevent immune rejection by the host body, perform better than fresh allografts in terms of axon density, fiber diameter, and nerve conduction velocity [93]. However, it has been shown that if autografts or allografts are preserved for too long, their ability to support regeneration supporting is compromised [94]. Although nerve autografts are used as the reference standard, the lack of functional recovery even with autografts remains an important clinical problem. Autografts treated with a combination of all four enzymes showed the most significant neurite growth into the graft. However, combination treatment was not significantly different from the arithmetic sum of the individual treatments. These techniques, used in clinical applications, could lead to better results with autografts or allografts. Acellular grafts have been developed to address the problem of host response to allografts as well as the shortage of autografts. It has been show that acellular cadaveric nerves from rats are able to bridge a 10-mm nerve injury [100]. Functionality of acellular grafts depends on the structural integrity of the graft after it has been processed for the removal of cells and immunogenic components.

Comparing preincisional with postincisional bupivacaine infiltration in the management of postoperative pain hair loss in horses order propecia online now. The effect of preemptive analgesia in postoperative pain relief-a prospective double-blind randomized study hair loss cure quikrete 5 mg propecia. Intraoperative injection of bupivacaine-adrenaline close to the fascia reduces morphine requirements after cesarean section: a randomized controlled trial hair loss joint pain fatigue propecia 1 mg purchase. A comparison between preincisional and postincisional lidocaine infiltration and postoperative pain hair loss dermatologist 5 mg propecia with amex. Ultrasound-guided transversus abdominal plane block with multimodal analgesia for pain management after total abdominal hysterectomy hair loss in men quotes buy propecia 5 mg on-line. Transversus abdominal plane block for postoperative analgesia: a systematic review and meta-analysis of randomized-controlled trials. Comparison between ultrasound-guided transversus abdominis plane and conventional ilioinguinal/iliohypogastric nerve blocks for day-case open inguinal hernia repair. Comparison of the analgesic effect between continuous wound infiltration and single-injection transversus abdominis plane block after gynecologic laparotomy. Surgical site infection and analytic morphometric assessment of body composition in patients undergoing midline laparotomy. Comparing surgical outcomes in obese women undergoing laparotomy, laparoscopy, or laparotomy with panniculectomy for the staging of uterine malignancy. The safety of pelvic surgery in the morbidly obese with and without combined panniculectomy: a comparison of results. Long-term outcome of women who undergo panniculectomy at the time of gynecologic surgery. A systematic review on the effectiveness of slowlyabsorbable versus non-absorbable sutures for abdominal fascial closure following laparotomy. Subcutaneous tissue reapproximation, alone or in combination with drain, in obese women undergoing cesarean delivery. Prophylactic subcutaneous drainage for prevention of wound complications after cesarean delivery-a metaanalysis. A combination of subcuticular sutures and a drain for skin closure reduces wound complications in obese women undergoing surgery using vertical incisions. Closed incision negative-pressure therapy is associated with decreased surgical-site infections: a meta-analysis. Reducing surgical site infection with negative-pressure wound therapy after open abdominal surgery: a prospective randomized controlled study. Sutures versus staples for the management of surgical wounds: a metaanalysis of randomized controlled trials. Wound complication rates after staples or suture for midline vertical skin closure in obese women: a randomized controlled trial. Superficial incisional surgical site infection rate after cesarean section in obese women: a randomized controlled trial of subcuticular versus interrupted skin suturing. Wound complications in obese women after cesarean: a comparison of staples versus subcuticular suture. A randomized controlled trial of early versus delayed skin staple removal following caesarean section in the obese patient. Effect of desiccation and temperature during laparoscopy on adhesion formation in mice. Intraoperative humidification and cooling of the peritoneal cavity can reduce adhesions. Comparison of ultrasonic energy, bipolar thermal energy, and vascular clips for the hemostasis of small-, medium-, and large-sized arteries. Vaginal hysterectomy and multimodal anaesthesia with bipolar vessel sailing (Biclamp((R)) 101. Efficacy of electrosurgical bipolar vessel sealing for abdominal hysterectomy with uterine myomas more than 14 weeks in size: a randomized controlled trial. Experience and efficacy of a bipolar vessel sealing system for radical abdominal hysterectomy. Efficacy of tranexamic acid on myomectomyassociated blood loss in patients with multiple myomas: a randomized controlled clinical trial. Anti-hemorrhagic effect of prophylactic tranexamic acid in benign hysterectomya double-blinded randomized placebo-controlled trial. The role of knotless barbed suture in gynecologic surgery: systematic review and meta-analysis. Mechanical performance of square knots and sliding knots in surgery: comparative study. Peritoneal closure versus no peritoneal closure for patients undergoing non-obstetric abdominal operations. Effect of stitch length on wound complications after closure of midline incisions: a randomized controlled trial. Mechanical performance of knots using braided and monofilament absorbable sutures. Pressurized pulse irrigation with saline reduces surgical-site infections following major hepatobiliary and pancreatic surgery: randomized controlled trial. Intra-operative wound irrigation to reduce surgical site infections after abdominal surgery: a systematic review and meta-analysis. Subcutaneous closure versus no subcutaneous closure after noncaesarean surgical procedures. Subcuticular sutures versus staples for skin closure after open gastrointestinal surgery: a phase 3, multicentre, openlabel, randomised controlled trial. Randomized clinical trial of skin closure by subcuticular suture or skin stapling after elective colorectal cancer surgery. Randomized comparison of subcuticular sutures versus staples for skin closure after open abdominal surgery: a multicenter open-label randomized controlled trial. Indeed, when the authors of this chapter began their gynecological careers more than 40 years ago, the most available opportunity to look inside the uterus in vivo was at cesarean section. However, advances in endoscopic technology now allow real-time visualization of the endometrial cavity by the surgeon, assistants, and, when performed with no local or regional anesthesia, the patient as well. For example, metroplasty for the treatment of a uterine septum formerly required a laparotomy, hysterotomy, uterine repair, and significant post-procedure recovery time measured in weeks to months. Now, hysteroscopic metroplasty can be performed in an office procedure room under local anesthesia, providing the patient the opportunity to return to normal activity as soon as the day of surgery. When such structural abnormalities are identified, the clinician can assess the feasibility of surgical therapy, anticipate and plan for the technical requirements, and determine the need for adjunctive measures necessary for full evaluation. Indeed, hysteroscopy can be performed in conjunction with contrast hysterosonography to provide a more global view of the uterus, as sonography offers detail regarding the myometrium, and, for example, the myometrial extent of submucous leiomyomas not visible with hysteroscopy. There is also high-quality evidence that contrast hysterosonography is as sensitive as hysteroscopy for the detection of structural abnormalities in the endometrial cavity (Chapter 8). Of course, the countervailing argument is that, given adequate equipment and patient comfort, diagnostic hysteroscopy can be seamlessly converted to operative hysteroscopy, at least for selected disorders such as endometrial polyps, adhesions, and small leiomyomas. This saves the patient and the medical system the time and costs associated with another procedure. Indeed, newer technologies have facilitated the addition of even larger leiomyomas to the list of procedures that can be completed successfully in an office procedure room. Regardless of the location of care, safe and effective hysteroscopic surgery requires that the surgeon possess both appropriate equipment and supplies, and a number of core competencies that, together, will be the subject of this chapter. Endoscopes and sheaths Standard hysteroscopes comprise an eyepiece, a distally located lens, and an intervening shaft, typically about 30 cm in length. Included in the construction are a mechanism for transmitting the image from the distal lens to the eyepiece and a set of fiber-optic bundles designed to transmit light from an external source along the inside of the shaft through the distal end and into the endometrial cavity. Flexible hysteroscopes are self-contained, do not require a sheath for distending media, and are generally of smaller diameter than rigid systems. They integrate one set of fiber-optic bundles for light transmission and another linked to the distal objective lens for visualization. Also included is a channel to transmit distension media, which may double as a portal for the insertion of operating instruments. In addition, they are designed to be "steerable" with a deflectable tip that facilitates insertion into and through a curvilinear cervical canal and angled viewing of lateral aspects of the endometrial cavity. However, the fiber-optic bundles of a flexible hysteroscope generally have lower resolution than that of rigid instruments with rod lenses. The rod lens-based construction of a rigid hysteroscope provides both a more durable instrument and a superior image. Whereas the viewing angle of flexible hysteroscopes can be varied or steered, that of rigid hysteroscopes is fixed. However, by varying the angle of the distal lens of a rigid hysteroscope, a foreoblique view can be obtained. The angle of the distal lens of the hysteroscope is, by convention, directed away from the location of the proximally located light post used to attach the endoscope to the light cable. The 0° endoscopes provide easy orientation to the image, since it is similar to that of normal vision. However, the flat terminal end of the 0° hysteroscope neither lends itself to atraumatic passage through the curvilinear cervical canal nor does it allow for any angled viewing within the endometrial cavity. Sheaths are critical to hysteroscopy with rigid endoscopes, as they include the conduits necessary for delivery of distension media and operative instruments into the endometrial cavity. Such continuous flow systems are essential for any complex operative hysteroscopic procedure. Light sources and cables Adequate illumination of the endometrial cavity is a critical component for effective hysteroscopy. Light is delivered from a remote source via a specially designed fluid or fiberoptic cable to the "light post" on the hysteroscope that also serves to identify the direction of the viewing angle of a foreoblique lens. Field of view with 0°, 12°, and 30° foreoblique Light post adaptors for various light cords. Inset, a cable is attached to the Olympus light post adapter after the other two (Wolf and Storz) have been removed. For most cameras and endoscopes, the element must have at least 150 W of power for direct viewing and preferably 250 W or more for video and operative procedures. Video imaging Although diagnostic hysteroscopy may be performed with direct visualization, it is best to use video guidance for prolonged operations. The surgical team can view and anticipate the needs of the surgeon, and in the office environment, video imaging allows the patient to share the view of the operative field with the surgeon. In teaching centers, video monitoring allows trainees to see procedures and, once familiarity has been gained, allows the supervising surgeon the opportunity to provide guidance to the trainee in the performance of surgical procedures. Video imaging also allows for recording of findings and procedures that can be edited for training purposes or for the use of the patient and her other providers. The sensor must be extremely light sensitive because of the narrow diameter of the endoscope and the frequently dark background of the endometrial cavity, particularly when it is enlarged or when it contains blood. The output of the controller is transmitted to a video monitor and can also be connected to image storage or output devices, such as hard drives and color printers. The shaft of these endoscopes serves only to contain the wiring connecting the distal elements to electrical sources or image acquisition units leaving the opportunity to use that shaft for media infusion, allowing a reduction in the overall diameter of the hysteroscopic system. Systems for uterine distension Distension of the endometrial cavity is necessary to create the viewing space required for all hysteroscopic procedures. The most common high-viscosity fluid media, 32% Dextran-70 (Hyskon), is useful in the presence of bleeding but creates problems for the instruments that require extensive cleaning after each use to prevent interference with mechanical function due to the high sugar content. The low-viscosity fluids either contain electrolytes, such as normal saline, or are electrolyte-free, including dextrose in water and those with a sugar molecule to increase osmolality such as 3% glycine, 1. There are essentially three components of fluid management: infusion into the endometrial cavity, removal from the endometrial cavity, and estimation or quantification of the amount of fluid that might be transferred to the systemic circulation, intravasation, or through breaches in endometrial or myometrial vascular integrity. Simple pressure infusion may be accomplished with a syringe filled with fluid media and tubing to connect the syringe to the hysteroscope or, for rigid systems, to a suitable port on the sheath. Pressure may also be added using any of a variety of infusion pumps that range from simple devices that continue Equipment and supplies for hysteroscopy 109 to pump fluid into the uterine cavity regardless of resistance to pressure-sensitive pumps that maintain a preset intrauterine pressure and reduce the flow rate when the preset level is reached. For simple diagnostic systems, there is no dedicated outflow port, so fluid may egress from the endometrial cavity through an overdilated cervix by disconnecting the infusion tubing or by completely removing the hysteroscopic system. However, for systems with a dedicated outflow port (continuous flow systems), tubing can be connected and directed either passively into a receptacle or bucket or attached to low-pressure suction to facilitate removal. The passage of significant volumes of distending media into the systemic circulation can pose a hazard to electrolyte balance with electrolyte-free media and to cardiac overload with any type of media. Consequently, a number of fluid management systems are available to continuously monitor inflow and outflow of distension fluid and provide real-time monitoring of fluid balance. Most systems measure the discrepancy by the weight of infused versus collected fluid or, alternatively, the volume of the infused fluid compared to the weight of the outflow fluid. Most systems provide a user-adjustable alarm that sounds off when a preset discrepancy has occurred. Instruments for intrauterine transection and hemostasis Hysteroscopic surgery utilizes incision, excision, or destruction of intrauterine tissue under direct visual guidance. While their narrow diameter permits surgery in a restricted operative field (the endometrial cavity or cervical canal), their small size and delicate construction also limit their capabilities. Hysteroscopic electromechanical morcellators allow intrauterine morcellation and excision of endometrial polyps and selected submucous fibroids. The distending media bags are hung on hangers (A) and empty canisters for collecting outflow are positioned on the base of the unit (B). The media bags are connected to the pump (C) that transmits the fluid to the uterus via the hysteroscopic sheath (D). The outflow port is connected to tubing (E) and other escaped fluid collected in a buttocks drape (F,G) and from a suction floor mat (H).

Patients may become extremely dyspneic and tachypneic hair loss treatment video order propecia 1 mg online, and rales may be heard on chest auscultation hair loss 9 months after pregnancy buy propecia 5 mg overnight delivery. Chest radiographic findings become highly abnormal hereditary hair loss cure order propecia 5 mg on line, revealing interstitial and alveolar edema that can be extensive hair loss cure latest 5 mg propecia mastercard. Our improved ability over the past 40 years to provide respiratory support for these patients has now made death directly due to respiratory failure relatively uncommon hair loss in men menopause discount propecia 1 mg buy online. Patients fortunate enough to recover may have surprisingly few respiratory sequelae that are both serious and permanent. Pulmonary function may essentially return to normal, although sophisticated assessment frequently shows persistent subtle abnormalities. However, there is increasing recognition that a significant portion of survivors may suffer from impaired neurocognitive function, depression, anxiety, weakness, and posttraumatic stress disorder related to critical care. However, within a short period of time, evidence of interstitial and alveolar edema generally develops, the latter being the most prominent finding on chest radiograph. As an indication that fluid is filling alveolar spaces, air bronchograms often appear within the diffuse infiltrates. Unless the patient has prior heart disease and cardiac enlargement unrelated to the present problem, heart size remains normal. Calculation of AaDo2 clearly shows that gas exchange is actually worse than it may appear at first glance, with alveolar Po2 elevated as a result of hyperventilation. As the amount of interstitial and alveolar edema increases, oxygenation becomes progressively more abnormal, and severe hypoxemia results. Because true shunting of blood across unventilated alveoli is important in the pathogenesis of hypoxemia, Po2 may be relatively unresponsive to administration of supplemental O2. This measurement is facilitated by use of either a central venous catheter (a catheter inserted into a systemic vein and then advanced to the superior vena cava) or a pulmonary artery catheter, which is advanced further and passed through the right atrium and right ventricle into the pulmonary artery. The relatively easy passage of the pulmonary artery catheter (commonly known as a Swan-Ganz catheter) results from a balloon at the tip, which can be inflated with air and then carried along with blood flow through the tricuspid and pulmonic valves into the pulmonary artery. The catheter is positioned at a point in the pulmonary artery where inflation of the balloon occludes the lumen and prevents forward flow. Consequently, if pressure is measured at the tip of the catheter when forward flow has been prevented, a static column of blood is created between the catheter and the left atrium, with the measured pressure theoretically reflecting pressure in the left atrium, which in turn corresponds to left ventricular preload. In recent years, central venous catheters are used more commonly than pulmonary artery catheters because they can be placed more quickly and easily, have fewer complications, and have been shown in large trials to produce similar patient outcomes to pulmonary artery catheters by using measurements of central venous pressure as a surrogate marker for left ventricular preload (see Chapter 12, section on Pulmonary Vascular Resistance). These measurements can help distinguish whether the observed pulmonary edema is cardiogenic or noncardiogenic in origin. In cardiogenic pulmonary edema, the hydrostatic pressure within the pulmonary capillaries is high as a result of "back-pressure" from the pulmonary veins and left atrium. In addition, the catheters may provide helpful information during the course of the complicated management of these cases, even though their use has not been unequivocally demonstrated to improve mortality. Measurements from a central venous or pulmonary artery (Swan-Ganz) catheter can estimate left ventricular preload. Although treatment of the precipitating disorder is not always possible or successful, the principle is relatively simple: as long as the underlying problem persists, the pulmonary capillary leak may remain. In the case of a disorder such as sepsis, management of the infection with appropriate antibiotics (and drainage if necessary) is crucial to allowing the pulmonary vasculature to reestablish the normal permeability barrier for protein and fluid. Failure of other organ systems besides the respiratory system is common, and patients often present some of the most complex and challenging management problems handled in intensive care units. This so-called lung-protective ventilation has a significant mortality benefit that has been documented in a large, well-designed randomized trial. However, the exact reasons why this approach is beneficial remain somewhat speculative. It is hypothesized that ventilating the lungs at lower lung volumes avoids overdistention of alveoli and a consequent deleterious release of inflammatory mediators. The mechanisms by which gas exchange improves with prone ventilation are complicated, but include more even distribution of ventilation and perfusion. However, to date, this approach has been unsuccessful, and no agents blocking the effect of a particular mediator have been useful. A more nonspecific approach has been use of corticosteroids in an attempt to block a variety of mediators and control or reverse the capillary permeability defect allowing fluid and protein to leak into the interstitium and alveolar spaces. This approach is based in part on experimental evidence suggesting that corticosteroids inhibit aggregation of neutrophils induced by activated complement. By producing preferential vasodilation in areas of the lungs that are well ventilated (because these are the areas to which the inhaled medications are delivered), inhaled nitric oxide or epoprostenol can facilitate better perfusion of well-ventilated areas, leading to better ventilation-perfusion matching and improved oxygenation. Unfortunately, however, beneficial physiologic effects on gas exchange have not been accompanied by documentation of improved survival in clinical trials conducted to date. Epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in 50 countries. The fibroproliferative response in acute respiratory distress syndrome: mechanisms and clinical significance. The pulmonary endothelium in acute respiratory distress syndrome: insights and therapeutic opportunities. The role of stretch-activated ion channels in acute respiratory distress syndrome: finally a new target Extracorporeal gas exchange: the expanding role of extracorporeal support in respiratory failure. The effect of inhaled nitric oxide in acute respiratory distress syndrome in children and adults: a Cochrane Systematic Review with trial sequential analysis. Physiology in Medicine: Understanding dynamic alveolar physiology to minimize ventilator-induced lung injury. Effect of noninvasive ventilation delivered by helmet vs face mask on the rate of endotracheal intubation in patients with acute respiratory distress syndrome: a randomized clinical trial. Endothelial cell signaling and ventilator-induced lung injury: molecular mechanisms, genomic analyses, and therapeutic targets. In acute respiratory failure, survival depends on the ability to provide supportive therapy until the patient recovers from the acute illness that precipitated the need to support the respiratory system. This article outlines the goals and methods of supportive therapy, focusing on various aspects of mechanical ventilation and strategies for maintaining adequate gas exchange. Because the principles for supportive management differ in hypoxemic respiratory failure. The chapter concludes with a consideration of two specific topics applicable to patients with chronic respiratory insufficiency: chronic ventilatory assistance and lung transplantation. Abstract Chapter 29 describes the management of the two broad classes of respiratory failure ­ hypoxemic respiratory failure and hypercapnic respiratory failure. The goals of each are described in terms of the principles of support and the desired targets for gas exchange. The available types of mechanical ventilation are presented, focusing on pressure support ventilation and pressure-controlled ventilation as the major modes of pressure-limited ventilation, and assist-control ventilation and synchronized intermittent mandatory ventilation as the major modes of volume-cycled ventilation. Positive end-expiratory pressure is explained as a technique to avoid alveolar closure during expiration, increase functional residual capacity, reduce the amount of shunting, and improve oxygenation. The technique of noninvasive ventilation as an alternative to intubation and ventilation through an endotracheal tube is described, along with the clinical scenarios where it may be most applicable. Complications associated with intubation, with endotracheal or tracheostomy tubes, and with use of a mechanical ventilator are described as the major categories of complications associated with intubation and mechanical ventilation. Options for chronic ventilatory support in the home setting are presented, focusing primarily on home noninvasive ventilation. In selected patients with severe lung disease of various etiologies, lung transplantation may be an option, although it does replace the underlying disease with the potential complications of infection and rejection following transplantation. In terms of O2 uptake by the blood, almost all of the O2 carried by blood is bound to hemoglobin, and only a small portion is dissolved in plasma. It is apparent from the oxyhemoglobin dissociation curve that elevating Po2 beyond the point at which hemoglobin is almost completely saturated does not significantly increase the O2 content of blood (see Chapter 1). On average, assuming that the oxyhemoglobin dissociation curve is not shifted, hemoglobin is approximately 90% saturated at a Po2 of 60 mm Hg. Increasing Po2 to this level is important for tissue oxygen delivery, but a Po2 much beyond this level does not provide that much incremental benefit. In practice, patients with respiratory failure often are maintained at a Po2 slightly higher than 60 mm Hg (or an O2 saturation slightly >90%) to allow a "margin of safety" for fluctuations in oxygenation. Oxygen delivery to the tissues, however, depends not only on arterial Po2 but also on hemoglobin concentration and cardiac output. In patients who are anemic, O2 content and thus O2 transport can be compromised as much by the low hemoglobin level as by hypoxemia (see Eq. In selected circumstances, blood transfusion may be useful in raising the hemoglobin and O2 content to more desirable levels. Similarly, when cardiac output is impaired, tissue O2 delivery also decreases, and measures to augment cardiac output may improve overall O2 transport. Unfortunately, some of the measures used to improve arterial Po2 may have a detrimental effect on cardiac output. As a result, tissue O2 delivery may not improve (and even may worsen) despite an increase in Po2. In patients with chronic hypercapnia (and metabolic compensation), abruptly restoring Pco2 to normal (40 mm Hg) may cause significant alkalosis and thus risk precipitating either arrhythmias or seizures. When a large fraction of the cardiac output is being shunted through areas of unventilated lung and therefore not oxygenated during passage through the lungs, supplemental O2 is relatively ineffective at raising Po2 to an acceptable level. In these cases, patients may require inspired O2 concentrations in the range of 60% to 100% and still may have difficulty maintaining Po2 greater than 60 mm Hg. For patients with hypoxemic respiratory failure, inability to achieve a Po2 of 60 mm Hg or greater on supplemental O2 readily administered by face mask (generally in the fractional concentration of inspired oxygen [FiO2] range of 40% to 80%) is often considered a justification for intubation. A mechanical ventilator is then connected to the endotracheal tube to provide the desired Goals of optimizing O2 transport to tissues are: 1. Delivery of more reliable tidal volumes than those achieved spontaneously by the patient 3. Other factors taken into consideration include the nature of the underlying problem and the likelihood of a rapid response to therapy. First, higher concentrations of O2 can be administered much more reliably through a tube inserted into the trachea than through a mask placed over the face. Finally, when a tube is in place in the trachea, positive pressure can be maintained in the airway throughout the respiratory cycle and not just during the inspiratory phase. The concentration of inspired O2 then can be lowered, and the patient is less likely to experience O2 toxicity from extremely high concentrations of O2. Patients with chronic obstructive lung disease, chest wall disease, and neuromuscular disease are all subject to the development of hypercapnia. Hypercapnia may be purely acute in certain other groups of patients-individuals who have suppressed respiratory drive resulting from ingestion of certain drugs, especially narcotics, or occasional patients with severe asthma and status asthmaticus. Traditionally, ventilator support has been initiated following endotracheal intubation. Most cases of hypercapnic respiratory failure are also associated with some degree of hypoxemia, due to hypoventilation as well as to ventilation-perfusion mismatch that accompanies the underlying disease. For these mechanisms of hypoxemia, Mechanical ventilation for patients with hypercapnic respiratory failure is often provided initially with noninvasive positive pressure ventilation. Management of Respiratory Failure n 373 administration of supplemental O2 is quite effective in improving Po2, and high concentrations of inspired O2 are usually not necessary. As previously noted in Chapter 18, patients with chronic hypercapnia may be subject to further increases in Pco2 when they receive supplemental O2. Fortunately, this complication of significant hypercapnia is infrequent with judicious use of supplemental O2. Reducing Work of Breathing One pathophysiologic feature shared by most patients with respiratory failure is an imbalance in the work of breathing relative to the ability of the respiratory muscles to perform that work. In the case of acute-on-chronic respiratory failure in the patient with chronic obstructive lung disease, the diaphragm is flattened and mechanically disadvantaged at the same time the work of breathing may be increased. In neuromuscular disease in either the purely acute or the acute-on-chronic setting, respiratory muscle strength may be insufficient to handle even a relatively normal work of breathing. Consequently, ventilatory assistance in the patient with respiratory failure is important not only for temporary support of gas exchange but also for mechanical support of inspiration, allowing the respiratory muscles to rest. Dyspnea is often alleviated when such support is provided and the patient no longer must expend so much energy on the act of breathing. Fatigued respiratory muscles are allowed to recover, and the relatively large amount of blood flow required by overworking respiratory muscles can be shifted to perfusion of other organ systems. Reducing the work of breathing is a benefit of mechanical ventilation in all forms of acute respiratory failure. By supporting gas exchange and assisting with the work of ventilation for as long a period as necessary, mechanical ventilators can keep a patient alive while the acute process precipitating respiratory failure is treated or allowed to resolve spontaneously. This section briefly describes the operation of mechanical ventilators, the available modes of ventilation, and the complications that can ensue from their use. Ventilators currently used for management of acute respiratory failure are positivepressure devices: they deliver gas under positive pressure during inspiration. However, the ventilator settings are often quite different, depending upon the type of respiratory failure. Pressure-Limited Ventilation Two types of pressure-limited ventilation are used commonly in certain clinical settings. This level of pressure support is reached rapidly and maintained throughout most of inspiration. The volume 374 n Principles of Pulmonary Medicine With volume-cycled ventilation, inspiration terminates after a specified tidal volume has been delivered by the ventilator. With pressure-limited ventilation, inspiration terminates after the targeted airway pressure has been achieved.

Because the peripheral airways contribute only about 10% to 20% of overall airways resistance hair loss in men burning discount propecia online, total resistance is preserved unless small airways disease is considerable hair loss cure quiberon safe propecia 1 mg, or additional disease affects the larger airways hair loss chemo propecia 1 mg overnight delivery. The use of inhaled bronchodilators may or may not result in significantly improved flow rates hair loss in men explain purchase 5 mg propecia otc. However hair loss cure 360 order propecia 5 mg overnight delivery, if expiration is prolonged and the respiratory rate is high, the patient may not have sufficient time during expiration to reach the normal resting end-expiratory point. One consequence of decreased elastic recoil is a decreased driving pressure that expels air from the alveoli during expiration. A simple analogy is a balloon filled with air, in which the elastic recoil is the "stiffness" of the balloon. With a given volume of air inside an unsealed balloon, a stiffer balloon will expel air more rapidly than a less stiff balloon. An emphysematous lung is like a less stiff balloon: a smaller than normal force drives air out of the lungs during expiration. Normally, the walls of airways are pulled radially outward by a supporting structure of tissue from the adjacent lung parenchyma. During a forced expiration, the strongly positive pleural pressure promotes collapse. Airways lacking an adequate supporting structure are more likely to collapse (and have diminished flow rates and air trapping) than normally supported airways. The decrease in elastic recoil in emphysema also alters the compliance curve of the lung and measured lung volumes. The compliance curve relates transpulmonary pressure and the associated volume of gas within the lung (see Chapter 1). Mechanisms of Abnormal Gas Exchange In obstructive lung disease, many of the observed pathologic changes affecting airflow are not uniformly distributed. For example, in chronic bronchitis, some airways are extensively affected by secretions and plugging, but others remain relatively uninvolved, so ventilation is not uniformly distributed throughout the lung. Schematic diagram of radial traction exerted by alveolar walls (represented as springs), acting to keep the airways open. In addition to shift of curve upward and to left, total lung capacity in emphysema (point B on volume axis) is greater than normal total lung capacity (point A). Although there may be a compensatory decrease in blood flow to underventilated alveoli, the compensation is not totally effective, and inequalities and mismatching of ventilation and perfusion result. This type of ventilation-perfusion disturbance, with some areas of lung having low ventilationperfusion ratios and contributing desaturated blood, leads to arterial hypoxemia. Carbon dioxide elimination is impaired in some patients with obstructive lung disease. Several factors probably contribute, including increased work of breathing (due to impaired airflow), abnormalities of central ventilatory drive, and ventilation-perfusion mismatch creating some areas with high ventilationperfusion ratios that effectively act as dead space. The importance of diaphragmatic fatigue in the stable patient with chronic hypercapnia is less certain. However, it is clear that contraction of the diaphragm, the major muscle of inspiration, is less efficient and less effective in patients with obstructive lung disease. A shortened, flattened diaphragm is at a mechanical disadvantage compared with a longer, curved diaphragm and is less effective as an inspiratory muscle. Long-standing pulmonary hypertension places an added workload onto the right ventricle, which hypertrophies and eventually may fail. A decrease in Po2 is a strong stimulus to the constriction of pulmonary arterioles (see Chapter 12). If hypoxia is corrected, the element of pulmonary vasoconstriction may be reversible, but vascular remodeling from chronic hypoxia may not fully reverse. Several other, but less important, factors that may contribute to elevated pulmonary artery pressure are hypercapnia, polycythemia, and reduction in the area of the pulmonary vascular bed. To a large extent, this effect may be mediated by the change in pH resulting from an increase in Pco2. Finally, in emphysema, destruction of the alveoli is accompanied by a loss of pulmonary capillaries. Therefore, in extensive disease, the limited pulmonary vascular bed may result in a high resistance to blood flow and, consequently, an increase in pulmonary artery pressure. As originally conceived, type A (so-called pink puffer) physiology was associated with underlying emphysema, high minute ventilation, and relatively normal arterial Po2. Type B (so-called blue bloater) physiology was equated with chronic bronchitis, hypoxemia, and hypercapnia. Additional factors include hypercapnia, polycythemia, and destruction of the pulmonary vascular bed. Frequently, patients have a certain level of chronic symptoms, but their disease course is punctuated by periods of exacerbation. An exacerbation is defined as an acute event characterized by worsening of symptoms that requires a change in medication. The precipitating factor producing an exacerbation is often a respiratory tract infection of either viral or bacterial origin. Other factors that cause acute deterioration in patients include exposure to air pollutants, bronchospasm (particularly if patients have a superimposed asthmatic component to their disease), and heart failure. However, in up to one-third of cases, the cause of an exacerbation cannot be identified. When exacerbations are severe, patients may go into frank respiratory failure, a complication discussed in Chapter 27. In addition to chronic symptoms of dyspnea, cough, or both, which may worsen during periods of acute exacerbation, patients may experience secondary cardiovascular complications of their lung disease. Patients with chronic hypoxemia and hypercarbia are particularly at an increased risk for cor pulmonale. Early in the course of the disease, physical examination may be normal or show only a prolonged expiratory time. Some patients do not wheeze during normal tidal breathing, but do so when asked to give a forced exhalation. In patients with profuse airway secretions, coarse gurgling sounds labeled as rhonchi are frequently appreciated. Examination of the chest often discloses an increased anteroposterior diameter, indicating hyperinflation of the lungs. When diaphragmatic excursion is assessed by percussion of the lung bases during inspiration and expiration, diminished movement is noted. When cor pulmonale is present, with or without frank right ventricular failure, patients have the cardiac findings described in Chapter 14. Patients who continue to smoke appear to have the greatest further deterioration of pulmonary function over time. Exacerbations and respiratory tract infections frequently cause acute deterioration in lung function, but their effect on the long-term rate at which pulmonary function is lost is not well established. Patients with mild disease are able to continue their usual work and lifestyle with minimal, if any, changes. Patients with severe disease are quite limited in their capacity for any exertion, are subject to frequent hospitalizations, and may have a life expectancy of less than 5 years. Chronic bronchitis is actually a clinical diagnosis, and the history is particularly crucial. Although emphysema is formally a pathologic diagnosis, a lung biopsy is not performed to make the diagnosis. Pathologic confirmation is generally obtained only at postmortem examination, if one is performed. In patients with 1-antitrypsin deficiency and early onset of emphysema, the arterial deficiency pattern is quite striking in the lower lobes, where there may be almost a complete loss of vascular markings. These include enlargement of the proximal pulmonary arteries, pronounced tapering of the distal vessels, and cardiomegaly indicative of right ventricular hypertrophy or dilation. Chest radiographs of a patient with severe chronic obstructive pulmonary disease, showing the arterial deficiency pattern of emphysema. The lungs are hyperinflated, the diaphragms are low and flat (in this case they are actually inverted on lateral film), and there is a paucity of vascular markings. Whether emphysema is present can be indirectly assessed by measuring the diffusing capacity for carbon monoxide. In patients with emphysema, in whom the surface area for gas exchange is lost, the diffusing capacity typically is decreased. With chronic elevation in Pco2, the kidneys retain bicarbonate in an attempt to compensate and return the pH toward normal. Surgery (selected cases) to those discussed in Chapter 5, including sympathomimetic agents (2 agonists), anticholinergic drugs, and methylxanthines. For patients with more severe disease who require regular therapy, either a long-acting 2 agonist. The methylxanthine theophylline is another option, but concern for systemic side effects often relegates it to a secondary role in comparison with the inhaled bronchodilators. A 5-day course of systemic corticosteroids is frequently administered at the time of an acute exacerbation, and most studies suggest the benefit of improved pulmonary function and reduced treatment failure in this setting. On the other hand, only a minority of patients with chronic, stable, but severe disease show improved pulmonary function after a regimen of oral corticosteroids. In patients with frequent exacerbations, an alternative to combination therapy with a long-acting 2agonist and an inhaled corticosteroid that may be even more effective is combination therapy with a long-acting 2-agonist and a long-acting anticholinergic (antimuscarinic) agent. Phosphodiesterase-4 inhibitors decrease inflammation and promote airway smooth muscle relaxation and bronchodilation. Roflumilast is typically used in patients with more severe disease, particularly those with chronic bronchitis and frequent exacerbations. However, a bacterial cause is difficult to document with certainty, and many exacerbations are thought to be either noninfectious or triggered by viral respiratory infections. In practice, patients are frequently treated with antibiotics when a change in quantity, color, and/or thickness of sputum is noted in comparison with the usual pattern of sputum production, regardless of whether a bacterial infection is documented. Of the potential bacterial pathogens, those most frequently implicated are Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis. As a result, the choice of an empiric antibiotic should provide coverage for these organisms. More recently, there has also been interest in the chronic use of a macrolide antibiotic. However, as with chronic use of virtually any antibiotic, there is an associated risk of selecting out more resistant bacterial strains. A low flow rate of O2 (1 to 2 L/min) given by nasal prongs is an effective, well-tolerated method for achieving these concentrations of inspired O2. Oxygen is particularly important in patients with pulmonary hypertension and in those with secondary polycythemia, because each of these complications is largely due to hypoxemia and is Chronic Obstructive Pulmonary Disease n 109 responsive to treatment for it. For significantly hypoxemic patients, as defined earlier, administering supplemental O2 has been shown to alter the natural history of the disease and improve long-term survival. However, no such benefit appears to accrue in patients with less severe or episodic hypoxemia. The goal of O2 therapy is to shift Po2 into the range where hemoglobin is almost fully saturated. Ideally, O2 saturation should be well maintained on a continuous basis throughout the day and night. In these patients, nocturnal O2 theoretically may be of benefit, although this has not been proven. For patients in whom airway secretions cause significant symptoms, chest physiotherapy and postural drainage are sometimes used to help mobilize and clear secretions. These techniques use percussion of the chest wall to loosen secretions and induce cough, followed by positional changes to allow gravity to aid in the drainage of secretions. To use these devices, the patient exhales into the apparatus, which applies oscillatory positive end-expiratory pressure, allowing more efficient clearance of secretions. However, the usefulness of chest physiotherapy and postural drainage or mucus-clearing devices is not generally accepted because outcome studies have not clearly supported their benefit. The rationale for this therapy is to replace the deficient protease inhibitor and attempt to inhibit or prevent unchecked proteolytic destruction of alveolar tissue. Although intravenous infusions of 1-antitrypsin have been shown to increase concentrations of this antiprotease in alveolar epithelial lining fluid, whether such replacement therapy alters the accelerated decline in pulmonary function is not definitively known. Most patients participating in such a program report an improved sense of well-being at the same time they experience an improvement in exercise tolerance. Smoking cessation education and assistance are absolutely critical parts of any comprehensive therapeutic program. Pharmacologic assistance to ameliorate the effects of nicotine withdrawal- nicotine replacement therapy, bupropion, or varenicline-is often a valuable component of smoking cessation efforts. Vaccination against influenza and pneumococcus is indicated for all patients as a preventive strategy and a component of the overall therapeutic regimen. One approach, lung volume reduction surgery, initially seems counterintuitive because it involves removing portions of both lungs from patients whose pulmonary reserve is marginal at best. First, removal of some lung tissue diminishes overall intrathoracic volume, allowing the flattened and foreshortened diaphragm to return toward its normal position and resume its usual curved configuration. A flattened, foreshortened diaphragm is an inefficient respiratory muscle, and the changes in its position and shape following surgery facilitate its effectiveness during inspiration. Lung elastic recoil is an important determinant of expiratory flow and airway collapse, and improving elastic recoil has secondary benefits on airway patency and expiratory flow. Although lung volume reduction surgery is a novel and potentially attractive approach, it appears to be beneficial only in well-selected patients. Critical aspects of patient selection include the severity of disease and the anatomic distribution of emphysematous changes. Patients whose emphysema is due to 1-antitrypsin deficiency, in whom the disease occurs at an early age, may be a particularly appropriate subgroup to consider for lung transplantation. Such ventilatory assistance with intermittent positive pressure may be delivered via either a mask (noninvasive positive-pressure ventilation) or an endotracheal tube, but the former noninvasive method is preferred. More detailed information about the treatment of acute respiratory failure superimposed on chronic disease of the obstructive variety is covered in Chapter 27. Global strategy for the diagnosis, management, and prevention of chronic obstructive lung disease 2017 report.

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