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In one common conﬁguration 60mg dapoxetine, a well- collimated line source is mounted that is translated across the plane parallel to the detector face to collect transmission data 90 mg dapoxetine. Then a transmission scan is obtained with the patient in the scanner before the emission scan is acquired dapoxetine 90 mg. The ratio of counts of each pixel between the blank scan and the transmission scan is the attenuation correction factor for the pixel dapoxetine 30 mg, which is applied to the emission pixel data obtained next 60 mg dapoxetine. Because the patient is positioned separately in the two scans dapoxetine 60mg, error may result in the attenuation correction dapoxetine 30mg. However dapoxetine 90mg, one should keep in mind that there is spillover of scattered high- energy photons (i dapoxetine 60 mg. The transmission data are used to calculate the attenuation factors 30mg dapoxetine, which are then applied to the emission data. Factors from the map are then applied to the corresponding pixels in the patient’s emission scan for attenuation correc- tion. This factor is assumed to be the same for all tissues except bone, which has a slightly higher mass attenuation coefﬁcient. Single Photon Emission Computed Tomography 175 factors because contrast-enhanced pixels overestimate attenuation. Some investigators advocate not using contrast agents and others suggest the use of water-based contrast agents to mitigate this effect. Partial-Volume Effect Partial-volume effects are inherent ﬂaws of all imaging devices, because no imaging device has perfect spatial resolution. When a “hot” spot relative to a “cold” background is smaller than twice the spatial resolution of the imaging device, the activity around the object is smeared over a larger area than it occupies in the reconstructed image. Although the total counts are preserved, the object appears to be larger and to have a lower activity concentration than it actually has. Similarly, a small cold spot relative to a hot background would appear smaller as if with higher activity concentra- tion. Such underestimation and overestimation of activities around smaller objects result from what is called the partial-volume effect. The partial-volume effect is a serious problem for smaller structures in images, and correction needs to be applied for the overestimation or under- estimation of the activities in them. A correction factor, called the recovery coefﬁcient, is the ratio of the reconstructed count density to the true count density of the region of interest that is smaller than twice the spatial reso- lution of the system. The recovery coefﬁcient can be determined by mea- suring the count densities of different objects containing the same activity but with sizes larger as well as smaller than the spatial resolution of the system. Recovery coefﬁcients are usually measured using phantoms which may not truly be representative of the human body. The measured recov- ery coefﬁcients are then applied to the image data of the patient to correct for partial volume effect. Ideally, for accurate reconstruction, the number of angular projections should be at least equal to the size of the acquisition matrix (e. How many angular projections should be taken over 180° or 360° to reconstruct the images accurately depends on the spatial resolution of the camera. As a general rule, 120 to 128 projections (using a 128 × 128 matrix) are needed for large organs such as lungs and liver, whereas 60 to 64 projec- tions (using a 64 × 64 matrix) are sufﬁcient for smaller organs such as head and heart. Scattering Radiations are scattered in patients, and the scattered photons, depending on the energy and angle of scattering, may strike the detector. Nor- mally, most of these scattered photons fall outside the photopeak window and are rejected. However, a fraction whose photon energy falls within the photopeak window will be counted, but their (X, Y) positions remain uncer- tain causing degradation of the image resolution. There are a few methods of scatter correction, of which the most common method is the use of two windows: a scatter window and a photopeak window. The scatter window is set at a lower energy than the photopeak window, and it is assumed that scatter in the photopeak window is the same as that in the scatter window. The scatter counts in the scatter window are subtracted from the photopeak counts for each projection to obtain the scatter-corrected projections, which are then used for reconstruction. The scatter spectrum is variable in energy; therefore, to have more accu- rate scatter corrections, multiple scatter windows can be used. Scatter cor- rections are made prior to attenuation correction, because the former are ampliﬁed during the latter operation. Typically, it consists of intrinsic resolution, collimator reso- lution, and scatter resolution. Spatial resolution deterio- rates but sensitivity increases with increasing slice thickness. As a trade-off between spatial resolution and sensitivity, an optimum slice thickness should be chosen. Sensitivity The sensitivity of an imaging system is always desired to be higher for better image contrast. For con- ventional two-dimensional planar images of good contrast, about 500,000 counts are required. Total counts may be increased by either counting for a longer period or by administering more activity. However, long counting is inconvenient for the patient and administering a larger amount of activ- ity increases the radiation dose to the patient. Other Parameters Other important parameters to evaluate include effects of high-count rates, uniformity, and contrast of images. Ideally this can be achieved by acquiring at least 30 million counts for 64 × 64 images or 120 million counts for 128 × 128 images. For Siemens e-Cam cameras, acquisition of 5 million counts in a 1024 × 1024 matrix is recommended. In determining spatial resolution by the intrinsic method, the two detectors must be kept apart at maximum radius, and a 99mTc point source is placed in a source holder on the rear bed mechanism provided by the manufacturer. The bar phantom is placed on the detector, and the bed is raised to a maximum height. Nowadays, many manufacturers provide a phantom using 5-point sources for low-energy high-resolution collimators or 3-point sources for medium- and high-energy collimators. In the case of 90° conﬁgurations, the default radius is applied as given by the manufacturer. This method is also used to check the head alignment and noncircular orbit conﬁguration in multihead camera systems with the computer software. The next daily test is the quality control test that is performed by using a quality phantom provided by the manufacturer. With a multihead camera, does the sensitivity of an imaging device increase or decrease? Which of the following acquisition matrices would give better spatial resolution: a 64 × 64 matrix or a 128 × 128 matrix? In the ﬁltered backprojection method, the Fourier method is preferred to the convolution method. A ﬁlter with a low cut-off frequency should be used for noisy data and low count density studies in order not to curtail image detail. Single-photon emission computed tomography in the year 2001: Instrumentation and quality control. Positrons are annihilated in body tissue and produce two 511-keV annihi- lation photons that are emitted in opposite directions (180°). Two photons are detected in an electronic time interval, called “coincidence time window,” by two detectors connected in coincidence. Detectors are arranged in the array of several rings to have the organ of interest in the ﬁeld of view. Data collected over 360° simultaneously around the body axis of the patient are used to recon- struct the image of the activity distribution in the slice of interest. Because the two opposite photons are detected in a straight line, no collimator is needed to limit the ﬁeld of view, and the technique is called the electronic collimation. Of these, 82Rb-RbCl is 18 commonly used for myocardial perfusion imaging and F-ﬂuorodeoxyglu- cose for metabolic imaging of the heart, brain, and various types of can- cers. The number of rings in current scanners (18–32), and the number of detectors per ring vary with the manufacturer. The number of rings and, hence, the width of the array of rings deﬁne the axial ﬁeld of view. Typically, each block is about 3-cm deep and grooved into 6 × 8, 7 × 8, or 8 × 8 elements by partial cuts through the crystal with a saw. The cuts are made at varying depths, with the deepest cut at the edge of the block. The cuts are ﬁlled with opaque reﬂective mate- rials to prevent spillover of light between elements. The block detectors are arranged in an array of full or partial rings with a diameter of 80 to 90cm. Different arrangements of block detectors adopted by manufacturers are shown in Figure 13. In the case of partial ring conﬁgurations, the blocks have to be rotated around the patient to obtain 360° acquisition of data. This uncertainty in detection time is called the timing resolution or coincidence timing window. The timing resolution results from the difference in pulse formation in the detector primarily due to statisti- cal variations in gain and scintillation decay time of the detector. Further- more, there is a time delay in the arrival of one photon relative to the other, because of the difference in distances traveled by the two photons, partic- 186 13. Because the velocity of light is 3 × 10 m/s, the difference between the arrival times of the two photons is about 3 to 4ns (time to travel 1m). After annihilation, two timing signals A and B are formed with timing width, say t, depending on the scanner system. Both A and B indicate that the timing window of the coincidence circuit must be at least 2t to detect all events in coincidence. Each detector is connected in coincidence with as many as half the total number of detectors in a ring and the data for each detec- tor are acquired in a “fan beam” projection. Thus the timing resolution or coincidence timing window has to be a minimum of 2t. The number of opposite detectors can vary from one to a maximum of half the total number of detectors present in a ring. Each detector element can be connected in coincidence to a maximum of half the total number N of opposite detector elements (N/2). The horizontal travel range of the scanning table varies with the designs of the scanners. The actual scan ﬁeld is the maximum travel range of the scanning table minus the displacement distance. The mobile unit moves to different clients’ facilities on different days depending on the schedule. The van must meet the Department of Transportation’s over- load regulations, and the rules and regulations of ﬁre safety and security of local authorities. Data Acquisition 191 Hybrid Gamma Cameras Conventional dual-head and triple-head gamma cameras (Fig. The hybrid cameras suffer from a disadvantage of low sensitivity due to low detection efﬁciency of NaI(Tl) crystal for 511-keV photons. In a full ring system, data are collected in 360° simulta- neously, whereas in the partial ring system, the rings are rotated around the patient for 360° data acquisition. First, the location of the detector pair in the ring is determined for each coincident event. Because each detector is connected to many opposite detectors in coin- cidence, which detector pair detected a coincidence event must be deter- mined. As in gamma cameras, the position X, Y of each detector in the ring is determined by ( + X = (13. If it is outside the window, it is rejected; otherwise, it is accepted for storage. It is not known where along the line of travel of the two photons the event occurred, because they are accepted within the set time window (say, 12ns) and their exact times of arrival are not compared. Data can be collected in both static and dynamic imaging using either the frame mode or the list mode, described in Chapter 11. The whole-body scan of the patient is obtained at dif- ferent axial positions of the bed. Positron Emission Tomography Two-Dimensional Versus Three-Dimensional Data Acquisition Coincident counts detected by a detector pair are called the prompts which include true, random, and scatter events described later (Fig. They mostly allow direct coincidence events to be recorded from a given ring and prevent random and scatter from other rings. The use of septa reduces the contribution of scattered photons from 30–40% without septa to 10–15%. To improve sensitivity, detector pairs in two adjacent or nearby rings are also connected in coincidence. Coincidence events detected by the detectors connected in the same ring are called the direct plane events, whereas those detected by detectors interconnected between different rings are called the cross plane events. Data Acquisition 195 2-D 3-D Septa Cross plane Direct plane Block detectors A B Fig. However, detectors are connected in adjacent rings and cross plane data are obtained as shown. In this mode, all events detected by detectors in coincidence in all rings are counted including random and scatter events, and the sensitivity in the 3-D mode increases four- to eight- fold over 2-D acquisition. The incidences of random and scatter can be reduced by having a smaller angle of acceptance; that is, a detector is con- nected to a smaller number of opposite detectors. The reconstruction of images from 3-D data is complicated by a very large volume of data, especially in a multiring scanner. After rebinning of 3-D data into 2-D data, either the ﬁltered backprojection or iterative method is applied. The observed count Ci in the ith pixel from the patient is then nor- malized by Cnorm,i = Ci × Fi (13.
Shock dapoxetine 60 mg, injury dapoxetine 30 mg, and altered tissue perfusion have been associated with the loss of membrane polarization dapoxetine 60mg, and the shift of sodium and water into the intracellular space 60 mg dapoxetine. At a theoretical level 30mg dapoxetine, there is abundant reason to anticipate that the conventional dosing of antibiotics may be inadequate in these circumstances (Fig 90 mg dapoxetine. The vascular changes in activation of the inflammatory cascade also result in the relaxation of arteriolar smooth muscle and a reduction in systemic vascular resistance 60mg dapoxetine. The reduction in systemic vascular resistance becomes a functional reduction in left ventricular afterload 90mg dapoxetine, which combined with an appropriate preload resuscitation of the severely injured patient leads to an increase in cardiac index dapoxetine 30mg. The hyperdynamic circulation of the multiple- trauma patients leads to the “flow” phase of the postresuscitative patient dapoxetine 90 mg. Increased perfusion of the kidney and liver results in acceleration of excretory functions and potential enhancement Antibiotic Kinetics in the Multiple-System Trauma Patient 525 Figure 2 Illustrates the influence upon the clearance curve of the theoretical antibiotic in Figure 1 of an increase in extracellular and/or intracellular water in a trauma patient that has fever secondary to invasive infec- tion. The peak concentration [A ]* and the equilibrated peak concentration [B ] are less* than those concentrations observed under normal circumstances. Subsequent organ failure from the ravages of sustained sepsis results in impairment of drug elimination and prolongation of T1/2. Severe injury results in the infiltration of the soft tissues with neutrophils and monocytes as part of the phagocytic phase of the inflammatory response. Proinflammatory cytokine signals are released from the phagocytic cells, from activated mast cells, and from other cell populations. The circulation of these proinflammatory signals leads to a febrile response with or without infection. The febrile response is associated with systemic hypermetabolism and autonomic and neuroendocrine changes that further amplify the systemic dyshomeostasis. Pro-inflammatory signaling up-regulates the synthesis of acute-phase reactants and down- regulates the synthesis of albumen, which further impacts the restoration of oncotic pressure and predictable drug pharmacokinetics. The summed effects of injury, fever, and the sequela of systemic inflammation result in pathophysiologic alterations (Table 1) that compromise the effectiveness of antibiotic therapy because of suboptimal dosing. A review of the literature identifies a paucity of clinical studies in the 526 Fry multiple-injury patient, despite the fact that antibiotics are used for a wide array of indications in these patients. The effects of pathophysiologic changes upon antibiotic therapy will be cited among studies of critically ill and severely septic patients in the intensive care unit, and not exclusively in multiple-trauma patients. Preventive Antibiotics in the Injured Patient Preventive antibiotics have been used for over 30 years in trauma patients (1). The recognized principals of preoperative administration of an antibiotic with activity against the likely pathogens to be encountered have been the hallmark of utilization in this setting. However, trauma patients have blood loss and large volumes of resuscitation in the period of time leading up to, and during, the operative intervention. The sequestration of the resuscitation volume into injured tissue results and the obligatory expansion of the extracellular water volume all contribute to a vastly expanded Vd. In a limited number of preliminary-study patients, they noted that conventional doses of 7. The explanation for the lower antibiotic concentrations in the conventional dosing regimen was found in the larger Vd and short T1/2 that were seen in the trauma patients compared to normal controls. In a study of eight patients that averaged 37 years of age and had normal creatinine, each received between 6. Subsequent studies of an additional 28 trauma patients confirmed the impact of the increased Vd and the increased elimination rates of the drug in adversely affecting preventive antibiotic concentrations (3). A prospective study examined the wound and intra-abdominal infection rates of penetrating abdominal trauma patients who received different doses of amikacin (2). Significantly, higher doses of amikacin resulted in statistically reduced infection rates in all patients studied. Subgroup analysis indicated that lower infection rates were identified in patients with high-volume blood loss and in patients with injury severity scores >20. No improvement in rates infections was seen in patients when colon injury was present, indicating that high inocula of surgical site contamination cannot likely be overcome by preventive antibiotics. This observed uncertainty about antibiotic pharmacoki- netics in the setting of blood loss and injury has led to some experimental investigation in the use of continuous infusion of antibiotics as a means to overcome the problem. Another strategy has been to simply not use potentially toxic agents like the aminoglycosides, but rather choose Table 2 Differences in Clinical Outcomes of Infection when 7. Antibiotic Kinetics in the Multiple-System Trauma Patient 527 b-lactam alternatives where toxicity concerns are minimized and larger doses can be safely utilized. The data that evaluate other antibiotics in preventive indications in trauma patients is very limited. They identified lower antibiotic concentrations in selected patients in the recovery room, and found that lower postoperative antibiotic concentrations were predictive of postoperative infections. They identified blood loss, extensive intraoperative resuscitation, and expanded Vd as likely causes for reduced postoperative antibiotic concentrations and recommended consideration for increased preop- erative dose of preventive antibiotics. They recommended re-dosing or continuous infusion as a requirement for effective use of preventive antibiotics in this population. Aminoglycosides The aminoglycosides more than any antibiotic group have been studied most extensively in the setting of critical illness. Nephro- and ototoxicity have been the driving issues that have stimulated pharmacokinetic studies of the aminoglycosides. However, the data indicate that perhaps more patients have been underdosed than have received toxic levels of these antibiotics. Given that gentamicin and the other aminoglycosides have been demonstrated to have highly variable pharmacokinetics even with patients that appear to have normal kidney function (6), it is not surprising that physiologic changes of trauma and clinical fever will further compound an already difficult situation. All study patients received at least one aminoglycoside with the majority receiving gentamicin or tobramycin. The Vd increased approximately 50% greater than normal for this population with one patient demonstrating a threefold increase. Using individual patient pharmacokinetic parameters, adjustments in gentamicin doses ranged from 1. In this latter study, drug elimination rates were strongly influenced by the patient’s serum creatinine as a marker of clinical renal function. Despite larger doses that were required, doses of the aminoglycosides were given less frequently with patients having a creatinine above 1 mg/dL. They identified 59% of patients that had blood concentration of the antibiotic that was significantly below expected concentrations. The expanded Vd was considered to be responsible for the low blood concentrations. Dasta and Armstrong (10) studied aminoglycoside pharmacokinetics in 181 critically ill patients in a surgical intensive care unit. Additional studies have validated that the observations of increased Vd and highly variable T1/2 are applicable to all of the aminoglycosides in trauma (11) and intensive care unit patients (12). Understanding these changes of aminoglycosides under circumstances of trauma, fever, and critical illness should lead to pharmacokinetic dosing and changes in the management of these patients. Once-daily dosing of aminoglycosides has become very common at present, but again the pharmacokinetic observations have demonstrated that conventional doses will be inadequate, especially for the younger trauma patient with normal renal function. Vancomycin Like the aminoglycosides, the pharmacokinetics of vancomycin is highly variable among patients with normal renal function (14). They assumed and documented that the Vd of vancomycin was essentially that of total body water, or 0. In selected cases, the Vd was so high that it actually exceed the theoretical maximum of 1. Pharmacokinetic dosing required a 20% increase in the predicted dose of vancomycin, but a 50% increase in the interval between doses reflected a longer T1/2 than expected. Vancomycin clearance was 143 mL/min in the burn patient which was more than twice as great as that seen in control patients (68 mL/min). Vancomycin patients required larger and more frequent doses of the drug to achieve satisfactory peaks and troughs during therapy. The hyperdynamic circulation of the burn patient with normal kidney function was thought to be the basis for accelerated drug clearance. Garrelts and Peterie (17) made similar observations with respect to a reduced T1/2 in burn patients receiving vancomycin. Van Dalen and Vree (18) studied Vd and T1/2 in critically ill patients after the administration of ceftriaxone, the most commonly employed third-generation cephalosporin. They identified that the pharmacokinetics patterns were very similar to the aminoglycosides with an expanded Vd and wide inter-patient variability with T1/2. They concluded that unique nomograms needed to be developed to permit dosing of ceftriaxone that was consistent with each patient’s unique severity of disease profile. Yet another study demonstrated similar findings with a 90% increase in Vd and that drug clearance was increased in patients with normal renal function (19). Patients with diminished renal function demonstrated a very prolonged T1/2 and posed a serious problem of potential drug accumulation. They suggested that the expanded Vd could serve as a reservoir for the drug and result in slow return to the circulation, which would explain the reduced clearance. They concluded that continuous infusion would prove to use less total drug and would ensure reliable therapeutic drug concentrations. Cefepime is a commonly used antibiotic especially later in the trauma patient’s course when fever and nosocomial infection are significant issues. The pharmacokinetics of aztreonam were studied in 28 critically ill, mostly trauma patients, with gram-negative infections (27). The patients were a relatively young group (age ¼ 35 years) and received 2 g of aztreonam every six hours. The larger dose of aztreonam was the likely reason that adverse effects were not seen from the increase in Vd. Carbapenems The carbapenem antibiotics are a subgroup of the b-lactams that are commonly used to treat the most difficult of infected trauma patients, especially with hospital-acquired bacteria. Vd and T1/2 tended to be similar to normal adult measurements in surgical patients with intraabdominal infection and other surgical infections. Profound changes in ertapenem pharmacokinetics have been reported in critically ill patients. They found that the Vd of ertapenem nearly doubled, and that peak concentration– and the area- under-the-serum concentration–time curve were dramatically reduced. Ertapenem is a highly protein-bound drug (85% to 95%) and they associated these changes with the decline in the serum albumin of the patients. However, acute declines in serum proteins are certainly markers of the severity of infection, and the changes in ertapenem pharmacokinetics are still likely to be consequences of the systemic manifestations of severe infection. Quinolones While specific data in the trauma patient are not available, the quinolone group of antibiotics appear to follow a different pattern of pharmacokinetic change in the critically ill patient and can be anticipated to have a different pattern in the injured patient as well. Peak and trough concentrations did not appear to be influenced by the septic state. These observations with ciprofloxacin were confirmed in patients with intraabdominal infection (37). Studies with levofloxacin in patients with critical illness (39) and with ventilator- associated pneumonia (40) have similarly demonstrated no adverse changes in pharmacoki- netic profiles. The observation that the quinolone group of antibiotics have very large Vd that exceeds total body water means that increases in extracellular water volume have little impact. This potentially constitutes an advantage for this group of antibiotics in the febrile, critically ill patient, and perhaps in the trauma patient as well. This has led to considerable interest in the identification of alternative antibiotic treatment for both community-associated and hospital-acquired staph- ylococcal infections. The combined observations of the quinolones and linezolid suggest that antibiotics with Vd that exceed total body water are less likely to be adversely affected by physiologic changes of injury, critical illness, and sepsis. Traditional pharmacokinetic dosing could be employed, where peak and trough measurements permit the clinician to adjust the total dose, the dosing interval, or both. This becomes a biological titration where doses are empirically modified and remeasurement is undertaken to assess favorable changes in subsequent peak/trough concentrations. This has been a traditional way of managing aminoglycosides and in some cases vancomycin use. Most clinical pharmacokinetic dosing has been geared to avoid toxicity and only secondarily to the maintenance of therapeutic concentrations. Measurement of these nontoxic agents will be an expense that most will not be willing to accept. Increase the Dose/Frequency of the Drug One strategy to overcome the reduction in antibiotic concentrations in the febrile, trauma patient is to either increase the dose or shorten the dosing interval. It does give a high peak concentration, which may be of value for antibiotics like the aminoglycosides that are concentration-dependent and have a sustained post-antibiotic effect (47). For example, a q6h drug might be shortened to give the same dose to q4h to reduce the interval of subtherapeutic concentration. Increasing the dose or shortening the dosing interval can only be entertained when the antibiotic being used has a favorable therapeutic ratio. The rate of clearance of the drug and the Vd are dynamic processes, and very high concentrations of the antibiotic can be the result when dosing is increased in a patient with rapidly resolving pathophysiological hemody- namics of the systemic inflammatory response. Continuous Antibiotic Infusion Antibiotic infusions are commonly given as 30 to 60 minute infusions. This results in the rapid spike in antibiotic concentration in serum that is identified in Figure 1. A very large amount of Antibiotic Kinetics in the Multiple-System Trauma Patient 531 Figure 3 Illustrates the enhanced serum concentration of antibiotics that are achieved when the dose is doubled of a hypothetical drug with a normal dosing interval of six hours and a T1/2 of 1. Figure 4 Illustrates the effects of con- tinuous infusion and prolonged infusion upon the serum concentrations of the theoretical antibiotic model. Continuous infusion is begun after the initial inter- mittent full dose has been administered. The pro- longed infusion results in an area under the curve that is similar to the same dose given normally, but the slower increase in the peak concentration results in slower total drug elimination. If the antibiotic is given by a continuous infusion, it is possible to sustain the antibiotic concentration above the desired concentration target, but without the peaks and troughs that characterize the normal rapid administration.
New medication for severe malaria available under an investigational new drug protocol 60mg dapoxetine. Exchange transfusion as an adjunct to the treatment of severe falciparum malaria: case report and review 30mg dapoxetine. Exchange transfusion as an adjunct therapy in severe Plasmodium falciparum malaria: a meta-analysis dapoxetine 90mg. Hemofiltration and peritoneal dialysis in infection-associated acute renal failure in Vietnam 90 mg dapoxetine. The clinical spectrum of severe imported falciparum malaria in the intensive care unit: report of 188 cases in adults 30 mg dapoxetine. Respiratory tract infections in travelers: a review of the GeoSentinel Surveillance Network dapoxetine 90 mg. Risk of infection with Mycobacterium tuberculosis in travelers to areas of high tuberculosis endemicity dapoxetine 30 mg. Miliary tuberculosis: epidemiology dapoxetine 30mg, clinical manifestations dapoxetine 60 mg, diagnosis 60 mg dapoxetine, and outcome. Miliary tuberculosis: rapid diagnosis, hematologic abnormalities, and outcome in 109 treated adults. Guidelines for preventing the transmission of Mycobacterium tuberculosis in health-care facilities. Retreatment tuberculosis cases* factors associated with drug resistance and adverse outcomes. Outbreak of Legionnaires’ disease among cruise ship passengers exposed to a contaminated whirlpool spa. Prevalence and diagnosis of Legionella pneumonia: a 3-year prospective study with emphasis on application of urinary antigen detection. Clinical features that differentiate hantavirus pulmonary syndrome from three other acute respiratory illnesses. Discriminators between hantavirus-infected and -uninfected persons enrolled in a trial of intravenous ribavirin for presumptive hantavirus pulmonary syndrome. Prospective, double-blind, concurrent, placebo- controlled clinical trial of intravenous ribavirin therapy of hemorrhagic fever with renal syndrome. Placebo-controlled, double-blind trial of intravenous ribavirin for the treatment of hantavirus cardiopulmonary syndrome in North America. Multicenter prospective randomized trial comparing ceftazidime plus co-trimoxazole with chloramphenicol plus doxycycline and cotrimoxazole for treatment of severe melioidosis. A large outbreak of histoplasmosis among American travelers associated with a hotel in Acapulco, Mexico, spring 2001. A clinical prediction rule for diagnosing severe acute respiratory syndrome in the emergency department. Who rapid advice guidelines for pharmacological management of sporadic human infection with avian influenza A (H5N1) virus. Eosinophilic meningitis caused by Angiostrongylus cantonensis: a case report and literature review. Salmonella typhi infections in the United States, 1975–1984: increasing role of foreign travel. Relative efficacy of blood, urine, rectal swab, bone- marrow, and rose-spot cultures for recovery of Salmonella typhi in typhoid fever. Multidrug-resistant typhoid fever in children: epidemiology and therapeutic approach. Reduction of mortality in chloramphenicol-treated severe typhoid fever by high-dose dexamethasone. Global burden of Shigella infections: implications for vaccine development and implementation of control strategies. Acute liver failure: established and putative hepatitis viruses and therapeutic implications. Lamivudine therapy for severe acute hepatitis B virus infection after renal transplantation: case report and literature review. Leptospirosis—an emerging pathogen in travel medicine: a review of its clinical manifestations and management. Acute lung injury in leptospirosis: clinical and laboratory features, outcome, and factors associated with mortality. Leptospirosis as a cause of acute respiratory failure: clinical features and outcome in 35 critical care patients. Ceftriaxone compared with sodium penicillin g for treatment of severe leptospirosis. Acute pulmonary schistosomiasis in travelers returning from Lake Malawi, sub-Saharan Africa. African tick-bite fever: four cases among Swiss travelers returning from South Africa. Update: management of patients with suspected viral hemorrhagic fever—United States. Preheim Departments of Medicine, Medical Microbiology and Immunology, Creighton University School of Medicine, University of Nebraska College of Medicine, and V. The clinical manifestations vary widely from asymptomatic disease (up to 40% of patients) to fulminant liver failure. In the United States cirrhosis has an estimated prevalence of 360 per 100,000 population and accounts for approximately 30,000 deaths annually. The majority of cases in the United States are a result of alcoholic liver disease or chronic infection with hepatitis B or C viruses. A Danish death registry study (5) examined long-term survival and cause-specific mortality in 10,154 patients with cirrhosis between 1982 and 1993. The results revealed an increased risk of dying from respiratory infection (fivefold), from tuberculosis (15-fold) and other infectious diseases (22-fold) when compared to the general population. In a prospective study (6) 20% of cirrhotic patients admitted to the hospital developed an infection while hospitalized. The mortality among patients with infection was 20% compared with 4% mortality in those who remained uninfected. The most common bacterial infections seen in cirrhotic patients are urinary tract infections (12% to 29%), spontaneous bacterial peritonitis (7% to 23%), respiratory tract infections (6% to 10%), and primary bacteremia (4% to 11%) (7). The increased susceptibility to bacterial infections among cirrhotic patients is related to impaired hepatocyte and phagocytic cell function as well as the consequences of parenchymal destruction (portal hypertension, ascites, and gastroesophageal varices). It should be noted that the usual signs and symptoms of infection may be subtle or absent in individuals who have advanced liver disease. Thus a high index of suspicion is required to ensure that infections are not overlooked in this patient population, especially in those who are hospitalized. Occasionally fever may be due to cirrhosis itself (8), but this must be a diagnosis of exclusion made only when appropriate diagnostic tests, including cultures, have been unrevealing. The incidence of infection is highest for patients with the most severe liver disease (6,21–23). Accurate assessment for risk of infection is dependent upon proper classification of the extent of liver disease. The Child–Pugh scoring system of liver disease severity (24) is based upon five parameters: (i) serum bilirubin, (ii) serum albumin, (iii) prothrombin time, (iv) ascites, and (v) encephalopathy. A total score is 342 Preheim Table 1 Modified Child–Pugh Classification of Liver Disease Severity Points Assigned Parameter 1 2 3 Ascites None Slight Moderate/severe Encephalopathy None Grade 1–2 Grade 3–4 Bilirubin (mg/dL) <2. Patients with chronic liver disease are placed in one of three classes (A, B, or C). Despite having some limitations the modified Child–Pugh scoring system continues to be used by many clinicians to assess the risk of mortality in patients with cirrhosis (Table 1). Several mechanisms have been proposed to explain the movement of organisms from the intestinal lumen to the systemic circulation (reviewed in Ref. Cirrhosis-induced depression of the hepatic reticuloendothelial system impairs the liver’s filtering function, allowing bacteria to pass from the bowel lumen to the bloodstream via the portal vein. Cirrhosis also is associated with a relative increase in aerobic gram-negative bacilli in the jejunum. A decrease in mucosal blood flow due to acute hypovolemia or drug-induced splanchnic vasoconstriction may compromise the intestinal barrier to enteric flora, thereby increasing the risk of bacteremia. Finally, bacterial translocation may occur with movement of enteric organisms from the gut lumen through the mucosa to the intestinal lymphatics. From there bacteria can travel through the lymphatic system and enter the bloodstream via the thoracic duct. An elevated bilirubin level also is correlated with a high risk of peritonitis in patient with cirrhosis (28). Infections in Cirrhosis in Critical Care 343 Figure 1 Pathogenic mechanisms underlying spontaneous bacterial perito- nitis. Therefore a high index of suspicion must be maintained in all cases of cirrhotic patients who have ascites and are acutely ill. Gram-stain of centrifuged ascitic fluid will reveal organisms in approximately 30% of cases. Inoculating some fluid directly into blood culture bottles increases the yield of positive cultures. But this nonquantitative culture technique also increases the risk of false-positives if any skin flora contaminant is introduced into the blood culture bottle at the bedside. If ascitic fluid cultures yield polymicrobial flora, Candida albicans (or other yeast), or Bacteroides fragilis one should suspect a secondary peritonitis caused by an acute abdominal infection. Earlier detection and treatment and the use of non- nephrotoxic antibiotics has contributed to the increased short-term survival. However the risk of aminoglycoside nephrotoxicity in cirrhotic patients has limited the usefulness of this class of agents (30). Cefotaxime has been shown effective in a number of trials with regimens of 2 g administered every 8 hours for five days (26) or 2 g every 12 hours for a mean of nine days (31). These included intravenous followed by oral therapy with amoxicillin–clavulanic acid (36) or ciprofloxacin (37) and oral ofloxacin (38). While some experts recommend that patients with moderate symptoms and a positive response to a short course of intravenous antibiotics could benefit from therapy with oral fluoroquinolones (39), others have found the supporting evidence to be inconclusive (40). A major concern regarding repeated or prolonged courses of antibiotic prophylaxis is selection for resistant bacterial pathogens. The majority of these patients have asymptomatic bacteriuria, but approximately one-third have symptomatic infections (23). The incidence of significant bacteriuria 5 (>10 colony-forming units/mL) is higher in women than in men and does not correlate with the severity of the underlying liver disease or with the age of the patient (50). Asymptomatic bacteriuria does not require treatment, particularly in patients with an indwelling urinary catheter. A urine culture should be obtained on any cirrhotic patient suspected to have a urinary tract infection. Antibiotic therapy, when indicated, should be guided by microbiologic susceptibility testing of the urinary isolate. Antibiotic options for empiric therapy of symptomatic infections include fluoroquinolones or expanded-spectrum penicillins or cephalosporins. Indwelling urinary catheters should be removed as soon as possible to reduce the risk of infection. Bacteremia has been reported to occur in approximately 9% of hospitalized cirrhotic patients (51) and accounts for 20% of the infections diagnosed during their hospital stay (23). The incidence of bacteremia increases with Infections in Cirrhosis in Critical Care 345 the severity of liver disease, and individuals with cirrhosis are more likely to have a diagnosis of sepsis when compared with patients without a diagnosis of cirrhosis (52). The most commonly identified sources of bacteremia have been spontaneous bacterial peritonitis, urinary tract infections, pneumonia, soft tissue infections, and biliary tract infections (51,53). The pathogens identified in blood cultures from bacteremic patients mirror those responsible for the primary source infections. Bloodstream infection is associated with a poor prognosis despite appropriate antibiotic therapy. Poor outcome is independent of the type of bacteremia (54), but in-hospital mortality has been correlated with the absence of fever, an elevated serum creatinine, and marked leukocytosis (53). Cirrhotic patients with suspected bacteremia should receive empiric therapy directed against the most common gram-negative and gram-positive pathogens in this setting. Antibiotic selection should take into consideration local microbial susceptibility patterns. Usual therapeutic options would include expanded- spectrum cephalosporins, piperacillin/tazobactam, or a fluoroquinolone such as levofloxacin or moxifloxacin. Cirrhotic patients who undergo endoscopic procedures for gastrointestinal hemorrhage or transhepatic procedures are at increased risk of bacteremia. Endoscopic variceal sclerotherapy or band ligation for bleeding esophageal varices is associated with a reported risk of bacteremia ranging from 5% to 30% (55–57). Although the bacteremia associated with these procedures may be brief, cirrhotic patients are susceptible to infections from transient bacteremia. Gastrointestinal hemorrhage itself is an independent risk factor for bacteremia and other infections in cirrhotic patients. Antibiotic administration has been shown to reduce infectious complications and mortality in cirrhotic patients who are hospitalized for gastrointestinal hemorrhage (58–61). Antibiotic prophylaxis is recommended for all cirrhotic inpatients with gastrointestinal bleeding (62,63). Fluoroquinolone antibiotics were used in most trials with a median treatment duration of seven days. Chronic liver disease has long been recognized as a risk factor for bacteremic pneumococcal pneumonia (66). The mortality rate for pneumococcal bacteremia in cirrhotic patients may exceed 50% despite appropriate antibiotic therapy (67). Sputum and blood samples should be obtained for appropriate diagnostic studies, including gram-stain (sputum) and cultures (sputum and blood). Appropriate empiric therapy while awaiting the results of cultures and other tests would include an expanded-spectrum cephalosporin plus a macrolide or a beta-lactam/betalactamase- inhibitor plus a macrolide or a fluoroquinolone (69).
The remaining three comparisons do not cross the zero line of no difference and are statistically signiﬁcant as indicated by the P values in the Multiple Comparisons table 90mg dapoxetine. Therefore dapoxetine 90 mg, each P level obtained from a Bonferroni test in the Multiple Comparisons table should be evaluated at the critical level of 0 dapoxetine 60mg. The mean values are identical but the conﬁdence intervals are adjusted so that they are wider as shown in Figure 5 60mg dapoxetine. Under this test dapoxetine 30mg, there is a progressive comparison between the largest and smallest mean values until a difference that is not signiﬁcant at the P < 0 dapoxetine 90mg. The output from this test is presented as subsets of groups that are not signiﬁcantly different from one another dapoxetine 60 mg. Thus in the table 60 mg dapoxetine, the mean values for groups of singletons and babies with one sibling are not signiﬁcantly different from one another with a P value of 0 30mg dapoxetine. Similarly 90 mg dapoxetine, the mean values of groups with one sibling, two siblings, or three or more siblings are not Homogeneous Subsets Weight (kg) Subset for alpha = 0. Singletons do not appear in the same subset as babies with two siblings or with three or more siblings which indicates that the mean weight of singletons is signiﬁcantly different from these two groups at the P < 0. Means plot A means plot provides a visual presentation of the mean value for each group. It also provides visual evidence as to why the group with one sibling is not signiﬁcantly different from singletons or babies with two siblings or with three or more siblings, and why singletons are signiﬁcantly different from the groups with two siblings or with three or more siblings. Also, the line connecting the mean value of each group should be removed because the four groups are independent of one another. However, the cell sizes are unequal and therefore the weighted linear term is used. The table shows that the weighted linear term sum of squares is signiﬁcant at the P = 0. The P value for the linear term-weighted indicates that the slope of the line through the plot is signiﬁ- cantly different from zero. The descriptive statistics show that the mean weight increases as parity increases. When reporting the table, it is important to include details stating that weight was approxi- mately normally distributed in each group and that the group sizes were all large (min- imum 62) with a cell size ratio of 1:3 and a variance ratio of 1:1. The signiﬁcant difference in weight at 1 month between children with different parities can be described as F = 3. The degrees of freedom are conventionally shown as the between-group and within-group degrees of freedom separated with a comma. If the Bonferroni post-hoc test had been conducted, it could be reported that the only signiﬁcant difference in mean weights was between singletons and babies with two siblings (P = 0. If Duncan’s post-hoc test had been conducted, it could be reported that babies with two siblings and babies with three or more siblings were signiﬁcantly different from singletons (P < 0. However, babies with one sibling did not have a mean weight that was signiﬁcantly different from either singletons (P = 0. The term ‘uni- variate’ may seem confusing in this context but in this case refers to the fact that there is only one outcome variable rather than only one explanatory variable. The more explana- tory variables that are included in a model, the greater the likelihood of creating small or empty cells. The number of cells in a model is calculated by multiplying the number of groups in each factor. For a model with three factors that have three, two and four groups, respectively, as shown in Table 5. However, the between-group differences are again calculated as the difference of each participant from the grand mean, that is, the mean of the entire data set. When both random and ﬁxed effect factors are included, this is referred to as a mixed model. A ﬁxed factor is a factor in which all possible groups or all levels of the factor are included, for example, males and females or number of siblings. Usually, treatment effects such as a treatment group and a control group are ﬁxed. With ﬁxed factors, inferences can be made only to the levels of the factor used in the study. When using ﬁxed factors, the differences between the speciﬁed groups are the statistics of interest. Factors are considered to be random when only a sample of a wider range of groups or all possible levels is included. For example, factors may be classiﬁed as having random effects when only three or four ethnic groups are represented in the sample but the results will be generalized to all ethnic groups in the community. In this case, only general differences between the groups are of interest because the results will be used to make inferences to all possible ethnic groups rather than to only the groups in the sample. That is, inferences from the data are for all levels of the factor in the population from which the levels were selected. It is important to classify groups as random factors if the study sample was selected by recruiting, for example, speciﬁc sports teams, schools or doctors’ practices and the results will be generalized to all sports teams, schools or doctors’ practices or if different sports teams, schools or doctors’ practices would be selected in the future. In these types of study designs, there is a cluster sampling effect and the group is entered into the model as a random factor. In random effect models, any unequal variance between cells is less important when the numbers in each cell are equal. However, when there is increasing inequality between the numbers in each cell, then differences in variance become more problematic. The use of ﬁxed or random effects can give very different P values because the F statistic is computed differently. For ﬁxed effects, the F value is calculated as the between-group mean square divided by the error mean square whereas for random effects, the F value is calculated as the between-group mean square divided by the interaction mean square. That is, there is an interaction between factors since the effects of one factor depend on the level of another factor. When there is a signiﬁcant interaction, the main effects are not interpreted in isolation since this may lead to erroneous conclusions and the interaction is the most important effect. To interpret the results in more detail, the interaction can be explored further by exam- ining the effect of one explanatory variable at a ﬁxed level of the other explanatory variable, referred to as simple main effects. However, depending on the number of lev- els of a factor, it is recommended that not all possible simple effects conducted as this will increase the probability of a Type I error occurring. Question: Are the weights of babies related to their gender, parity or maternal level of education? First, the summary statistics need to be obtained to verify that there are an adequate number of babies in each cell. This can be achieved by splitting the ﬁle by gender which has the smallest number of groups and then generating two tables of parity by maternal education as shown in Box 5. For males, the cell size ratio is 4:55, or 1:14, and for females the cell size ratio is 2:45, or 1:23. Without maternal education included, all cell sizes as indicated by the Total row and Total column totals are quite large. To increase the small cell sizes, it would make sense to combine the groups of two siblings 138 Chapter 5 and three or more siblings. This combining of cells is possible because the theory is valid and because the post-hoc tests indicated that the means of these two groups are not signiﬁcantly different from one another. By combining these groups, the smallest cells will be larger at 8 + 4 or 12 for males and 13 + 2 or 15 for females. The ratio for males is close to the assumption of 1:4 and within this assumption for females. Gender = 1male Maternal education * parity crosstabulationa Count Parity One Two Three or more Singleton sibling siblings siblings Total Maternal Year 10 15 40 26 17 98 education Year 12 22 16 8 4 50 Tertiary 55 42 22 8 127 Total 92 98 56 29 275 aGender = male. Gender = 2 female Maternal education * parity crosstabulationa Count Parity One Two Three or more Singleton sibling siblings siblings Total Maternal Year 10 24 36 21 19 100 education Year 12 19 15 13 2 49 Tertiary 45 43 26 12 126 Total 88 94 60 33 275 aGender = female. These val- ues are not effect sizes in units of the standard deviations, so the differences cannot be directly compared. The effect of maternal education is so small that it is unlikely to be a signiﬁcant predictor in a multivariate model. The cell size ratio when parity is recoded into three cells has been found to be adequate. The variance ratio for each factor, for example for parity, can be calculated by squaring the standard deviations from the Means table. The largest difference between mean values is between genders; therefore, it is important to examine the distribution for each gender to identify any outlying values or outliers. In fact, the distribution of each group for each factor should be checked for the presence of any outlying values or univariate outliers. The ﬁrst two rows show tests for the corrected model and intercept which usually are not of interest and can be ignored. The corrected model sum of squares divided by the corrected total sum of squares, that is, 32. This value indicates that gender, maternal education and parity together explain 0. The F values for the three factors show that both gender and parity are signiﬁcant predic- tors of weight at 1 month with P < 0. After combining two of the parity groups and adjusting for gender differences in the parity groups, the signiﬁ- cance of parity in predicting weight has increased to P = 0. The sums of squares for the model, intercept, factors and the error term when added up manually equal 9244. The polynomial linear contrast in the Contrast Results table again shows that there is a signiﬁcant linear trend for weight to change with parity at the P < 0. Examination of mean weight by parity indicates that there is an increasing linear trend, with weight increasing as parity increases. The subscript to this Custom Hypothesis Tests table indicates that the outcome is being assessed over the three parity groups, that is, the groups labelled 1, 2 and 3. The quadratic term is not relevant because there is no evidence to suggest that the relationship between weight and parity is curved rather than linear, and consistent with this, the quadratic contrast is not signiﬁcant. Custom Hypothesis Tests Contrast results (K matrix) Parity recoded (three levels) Dependent variable polynomial contrasta Weight (kg) Linear Contrast estimate 0. Analysis of variance 143 Marginal means The Estimated Marginal Means table shows mean values adjusted for the other factors in the model, that is, the predicted mean values. Marginal means that are similar to the unadjusted mean values provide evidence that the model is robust. If the marginal means change by a considerable amount after adding an additional factor to the model, then the added factor is an important confounder or covariate. Estimated Marginal Means Estimates Dependent variable: weight (kg) 95% conﬁdence interval Gender Mean Std. Univariate Tests Dependent variable: weight (kg) Sum of squares df Mean square F Sig. This test is based on the linearly independent pairwise comparisons among the estimated marginal means. The estimated marginal mean is the mean value of a factor averaged across other levels of the factors, that is, averaged over all cell means. In this model, the marginal means are averaged over parity and maternal education. The standard errors are identical in the two groups because the pooled data for all cases are used to compute a single estimate of the standard error. For this reason, it is important that the assumptions of equal variance and similar cell sizes in all groups are met. Pairwise comparisons for maternal education and parity were also requested although they have not been included here. In the plot, if the lines cross one another this would indicate an interaction between factors. The cell size was within the assumption of 1:4 for females and close to this assumption for males and the variance ratio was less than 1:2. There was a signiﬁcant difference in weight between males and females and between groups deﬁned according to parity, but not between groups deﬁned according to maternal education status. A polynomial contrast indicated that there was a signiﬁcant linear trend between weight and levels of parity (P < 0. Pairwise contrasts showed that the difference in marginal means between males and females was 0. In addition, the difference in marginal means between singletons and babies with one sibling was statistically signiﬁcant at −0. Regression which provides a line of best ﬁt through the data is discussed in detail in Chapter 7. Adjusting for a covariate has the effect of reducing the residual (error) term by reducing the amount of noise in the model. As in regression, it is important that the association between the outcome and the covariate is linear. Few covariates are measured without any error but unreliable covariates lead to a loss of statistical power. Covariates such as age and height can be measured reliably but other covariates such as reported hours of sleep or time spent exercising may be subject to signiﬁcant reporting bias. It is also important to limit the number of covariates to variables that are not signif- icantly related to one another. As in all multivariate models, multicollinearity, that is a signiﬁcant association or correlation between explanatory variables, can result in an unstable model and unreliable estimates of effect, which can be difﬁcult to interpret. Ideally, the correlation between covariates (which is discussed in Chapter 7) should be low with an r value of less than 0. For partial eta squared, the variances for other factors are partialled out, that is, removed from the total non-error variation. Eta squared values sometimes over-estimate effect because the values add to over 1.
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