Judgment order levitra super active on line erectile dysfunction treatment herbal remedy, reasoning order levitra super active in united states online erectile dysfunction treatment injection cost, and applying one’s values under conditions of uncertainty must also play a role in decision making. Users of an evidence report must also keep in mind that not proven does not mean proven not; that is, if the evidence supporting an assertion is insufficient, it does not mean the assertion is untrue. The quality of the evidence on effectiveness is a key component, but not the only component, in making decisions about clinical policy. Additional criteria include acceptability to physicians and patients, potential for unrecognized harm, applicability of the evidence to practice, and consideration of equity and justice. Scope and Key Questions The purpose of this review is to compare the benefits and harms of different pharmacologic treatments for nausea and vomiting. The Oregon Evidence-based Practice Center wrote preliminary key questions, identifying the populations, interventions, and outcomes of interest, and based on these, the eligibility criteria for studies. These were reviewed and revised by representatives of organizations participating in the Drug Effectiveness Review Project. The participating organizations of Drug Effectiveness Review Project are responsible for ensuring that the scope of the review reflects the populations, drugs, and outcome measures of interest to both clinicians and patients. The participating organizations approved the following key questions to guide this review: 1. What is the comparative effectiveness of newer antiemetics in treating or preventing nausea and/or vomiting? Antiemetics Page 8 of 136 Final Report Update 1 Drug Effectiveness Review Project 2. What are the comparative tolerability and safety of newer antiemetics when used to treat or prevent nausea and/or vomiting? Are there subgroups of patients based on demographics (age, race, gender), pregnancy, other medications, or comorbidities for which 1 newer antiemetic is more effective or associated with fewer adverse events? Inclusion Criteria Populations Adults or children at risk for or with nausea, vomiting (including retching), or both related to the following therapies and conditions: • Chemotherapy of various emetogenicity • Radiation therapy • Surgical procedure • Pregnancy In this report, we use the emetogenicity classification scale that Hesketh defined in 1997 and 12, 13 modified in 1999 to clarify the level of emetogenicity of the chemotherapeutic regimen with which the cancer population of the study is being treated. This scale rates the emetic potential of the chemotherapeutic agent (or combination of agents) given to a cancer patient as if the patient would not be receiving any antiemetic drugs; that is, it classifies the chemotherapeutic agents by the likelihood that the patient will experience emesis. Chemotherapeutic agents rated as “1” on this scale have a low emetic potential, while agents rated as “5” are considered to be severely emetic (a >90% chance of emesis in patients). Interventions Included interventions are listed in Table 2. Included interventions Drug Trade name Formulations a Aprepitant/fosaprepitant Emend injectable, oral Dolasetron Anzemet injectable, oral Granisetron Kytril injectable, oral Ondansetron Zofran , generics injectable, oral, orally disintegrating tablet a a Palonosetron Aloxi injectable, oral a Not available in Canada Effectiveness outcomes Treatment of established postoperative nausea and/or vomiting • Success: Absence of vomiting and/or retching in a nauseated or vomiting and/or retching patient o Early: Within or close to 6 hours after surgical procedure o Late: Within or close to 24 hours after surgical procedure • Success: Absence of any emetic event (nausea, vomiting, retching) o Early: Within or close to 6 hours after surgical procedure o Late: Within or close to 24 hours after surgical procedure Antiemetics Page 9 of 136 Final Report Update 1 Drug Effectiveness Review Project • Other: Patients’ satisfaction or quality of life, number of vomiting and/or retching episodes, degree of nausea, need for rescue medications, serious emetic sequelae, delay until first emetic episode, number of emesis-free days Prevention of postoperative nausea and/or vomiting • Success: Absence of vomiting and/or retching in the postoperative period o Acute: Within or close to 6 hours after surgical procedure o Late: Within or close to 24 hours after surgical procedure • Success: Absence of any emetic event (nausea, vomiting and/or retching, or nausea and vomiting and/or retching) in the postoperative period o Acute: Within or close to 6 hours after surgical procedure o Late: Within or close to 24 hours after surgical procedure • Other: Patients’ satisfaction or quality of life, number of vomiting and/or retching episodes, degree of nausea, need for rescue medications, serious emetic sequelae, delay until first emetic episode, number of emesis-free days Prevention of nausea and/or vomiting related to chemotherapy • Success: Absence of vomiting and/or retching o Acute: During the first 24 hours of chemotherapy administration Vomiting and/or retching induced by highly emetic chemotherapy Vomiting and/or retching induced by moderately emetic chemotherapy o Late: After the first 24 hours of chemotherapy administration Vomiting and/or retching induced by highly emetic chemotherapy Vomiting and/or retching induced by moderately emetic chemotherapy • Success: Absence of any emetic event (nausea, vomiting, retching) o Acute: During the first 24 hours of chemotherapy administration Emetic event induced by highly emetic chemotherapy Emetic event induced by moderately emetic chemotherapy o Late: After the first 24 hours of chemotherapy administration Emetic event induced by highly emetic chemotherapy Emetic event induced by moderately emetic chemotherapy • Other: Patients’ satisfaction or quality of life, number of vomiting and/or retching episodes, degree of nausea, need for rescue medications, serious emetic sequelae, worst day nausea/vomiting and/or retching, delay until first emetic episode, number of emesis- free days Prevention of radiation-induced nausea and/or vomiting • Success: Absence of vomiting and/or retching o Acute: During the first 24 hours of onset of radiation therapy o Delayed: After the first 24 hours of onset of radiation therapy or after consecutive radiation therapy doses given during several days • Success: Absence of any emetic event (nausea, vomiting, retching) o Acute: During the first 24 hours of onset of radiation therapy o Delayed: After the first 24 hours of onset of radiation therapy or after consecutive radiation therapy doses given during several days Antiemetics Page 10 of 136 Final Report Update 1 Drug Effectiveness Review Project • Other: Patients’ satisfaction or quality of life, number of vomiting and/or retching episodes, degree of nausea, or need for rescue medications, serious emetic sequelae, worst day nausea/vomiting and/or retching, delay until first emetic episode, number of emesis-free days Treatment of nausea and/or vomiting associated with pregnancy (including hyperemesis gravidarum) • Success: Absence of vomiting and/or retching in a nauseated or vomiting and/or retching pregnant woman • Success: Absence of any emetic event (nausea, vomiting, retching) • Change in Rhodes index or visual analog scale assessments of symptom severity • Fetal outcome • Other: Patients’ satisfaction or quality of life, number of vomiting and/or retching episodes per period of time, need for rescue medications, serious emetic sequelae, number of emesis-free days, number of episodes and duration of hospitalization Wherever possible, data on effective dose range, dose response, and duration of therapy (time to success) will be evaluated within the context of comparative effectiveness. Harms • Overall adverse events • Specific adverse events (headache, constipation, dizziness, sedation, etc) • Withdrawals due to adverse events • Serious adverse events reported Study designs • For effectiveness, controlled clinical trials and good-quality systematic reviews. The benefit of the randomized controlled trial design is the ability to obtain a reliably unbiased estimate of treatment effects in a controlled setting. This is accomplished by using randomization 14, to produce groups that are comparable based on both known and unknown prognostic factors. Observational studies are thought to have greater risk of introducing bias, although they typically reflect effects in a broader section of the overall patient population. While some observational studies and randomized controlled trials of the same treatments have similar findings, there are also multiple examples of situations where this 16, 17 has not been true; the question of what type of evidence is best has not been resolved. While randomized controlled trials also provide good evidence on short-term adverse events, observational designs are useful in identifying rare, serious adverse events, which often require large numbers of patients exposed to a treatment over longer periods of time to be identified. Antiemetics Page 11 of 136 Final Report Update 1 Drug Effectiveness Review Project METHODS Literature Search To identify relevant citations for the original report, we searched the Cochrane Central Register th of Controlled Trials (4 Quarter 2004), Cochrane Database of Systematic Reviews, MEDLINE nd (1966 to week 1 of February 2005), EMBASE (2 Quarter 2005), and CancerLit (1974 to March 2005) using terms for included drugs, indications, and study designs (see Appendix D for complete search strategies). For update 1, we searched Medline (1996 to week 2 of 2008), nd Cochrane Central Register of Controlled Trials (2 Quarter 2008), Cochrane Database of st Systematic Reviews (1 Quarter 2008), and Database of Abstracts of Reviews of Effects (DARE) nd rd (2 Quarter 2008). These searches were repeated in October 2008 in Medline and 3 Quarter 2008 in Cochrane and DARE Databases to identify any additional publications published before the draft report was finalized. We have attempted to identify additional studies through searches of reference lists of included studies and reviews, the Food and Drug Administration website, and dossiers submitted by pharmaceutical companies for the current review. All citations were imported into an electronic database (EndNote XI). Study Selection Using the criteria listed above, two reviewers independently assessed abstracts of citations identified from literature searches for inclusion, Full-text articles of potentially relevant abstracts were retrieved, and a second review for inclusion was conducted by reapplying the inclusion criteria. Data Abstraction The following data were abstracted from included trials: study design; setting; population characteristics (including sex, age, ethnicity, diagnosis); eligibility and exclusion criteria; interventions (dose and duration); comparisons; numbers screened, eligible, enrolled, and lost to follow-up; method of outcome ascertainment; and results for each outcome. We recorded intention-to-treat results when reported. In cases where only per protocol results were reported, we calculated intention-to-treat results if the data for these calculations were available. In trials with crossover, outcomes for the first intervention were recorded if available. This approach controlled for the potential for biased results caused by differential withdrawal before crossover and for the possibility of either a “carryover effect” (from the first treatment) in studies without a washout period or a “rebound effect” from withdrawal of the first intervention. Data abstracted from observational studies included design; eligibility criteria; duration; interventions; concomitant medication; assessment techniques; age, gender, and ethnicity; number of patients screened, eligible, enrolled, withdrawn, or lost to follow-up; number of patients analyzed; and results. Validity Assessment We assessed the internal validity (quality) of trials with the predefined criteria listed in Appendix E. These criteria are based on the US Preventive Services Task Force and the National Health 18, 19 Service Centre for Reviews and Dissemination (United Kingdom) criteria. We rated the Antiemetics Page 12 of 136 Final Report Update 1 Drug Effectiveness Review Project internal validity of each trial based on the methods used for randomization, allocation concealment, and blinding; the similarity of compared groups at baseline; maintenance of comparable groups; adequate reporting of dropouts, attrition, crossover, adherence, and contamination; loss to follow-up; and the use of intention-to-treat analysis. Trials that had a fatal flaw were rated “poor-quality”; trials that met all criteria were rated “good-quality”; the remainder were rated “fair-quality. A poor-quality trial is not valid—the results are at least as likely to reflect flaws in the study design as the true difference between the compared drugs. A fatal flaw is reflected by failure to meet combinations of items of the quality assessment checklist. External validity of trials was based on whether the publication adequately described the study population, how similar patients were to the target population in whom the intervention would be applied, and whether the treatment received by the control group was reasonably representative of standard practice. Overall quality ratings for an individual study were based on internal and external validity ratings for that trial. A particular randomized trial might receive 2 different ratings: 1 for effectiveness and another for adverse events. The overall strength of evidence for a particular key question reflects the quality, consistency, and power of the set of studies relevant to the question. Included systematic reviews were also rated for quality based on predefined criteria (see Appendix E) based on clear statement of the questions(s) and inclusion criteria, adequacy of search strategy, validity assessment and adequacy of detail provided for included studies, and appropriateness of the methods of synthesis. Data Synthesis We constructed evidence tables showing the study characteristics, quality ratings, and results for all included studies. Trials that evaluated 1 newer antiemetic against another provided direct evidence of comparative effectiveness and adverse event rates. In theory, trials that compare newer antiemetic to other drug classes or placebos can also provide evidence about effectiveness. This is known as an indirect comparison and must be interpreted with caution for a number of reasons, mainly issues related to heterogeneity between trial populations, interventions, and assessment of outcomes.
The culling of variation depends on the intensity of nat- ural selection acting on the particular regulatory step buy levitra super active 40mg amex erectile dysfunction drugs at walgreens. Steps that aﬀect ﬁtness relatively weakly will accumulate relatively more variation purchase cheap levitra super active on line impotence natural food, un- til a balance of mutation and selection occurs. Steps that aﬀect ﬁtness strongly will accumulate relatively less variation. In each case, the vari- ation in ﬁtness will be roughly the same. The major polymorphisms likely arise by processes in addition to mutation-selection balance. In those cases, various trade-oﬀs between immune control of parasites and collateral damage probably balance the ﬁtnesses of diﬀerent variants. The collateral damage may be inﬂam- matory or other negative eﬀects of a hyperimmune response, as in the gastric tissue damage promoted by IL6. Or more rarely, the damage may arise from reducing the proliferation of immune cells that normally con- trol pathogens but also can be the target of parasitic attack. This latter trade-oﬀ appears to occur in IL10 control of macrophages in the context of HIV-1 infection. Regulatory variability may sometimes alter immunodominance be- cause cytokines modulate positive and negative stimulation of T and Bcell clones. In their study, normal levels of interferon-γ were associated with about a 5-fold ratio of immunodominant to subdominant T cell clones for two Listeria monocytogenes epitopes. By contrast, reduced interferon-γ was associated with roughly equivalent clonal expansion of CTLs speciﬁc for these two epitopes. Im- munodominance, in turn, aﬀects the intensity of selection on particular GENETIC VARIABILITY OF HOSTS 121 pathogen epitopes. Thus, variations in immune regulation may inﬂu- ence patterns of antigenic variation. Parasites may fa- vor change in the frequencies of host MHC alleles. For example, the human class I MHC molecule B35 binds to common epitopes of Plasmo- dium falciparum’s circumsporozoite protein (Gilbert et al. The B35 allele occurs in higher frequency in The Gambia, a region with en- demic malaria, than in parts of the world with less severe mortality from malaria. It would be interesting to know if variant epitopes inﬂuence the fre- quency of matching MHC alleles. For example, one epitope variant may be common in one location and another variant common in another lo- cation. Do those variants aﬀect the local frequencies of MHC alleles in the host population? This questionfocuses attention on the kind of selection pressure parasites impose on MHC alleles. Each MHC allele may have a qualitative relationship with each par- ticular epitope, in that one amino acid substitution in the epitope can have a large eﬀect on binding. But over the lifetime of an individual, each MHC type meets many potential epitopes from diverse parasites. Thus, MHC alleles vary quantitatively in the net beneﬁt they provide by their diﬀerent matches to the aggregate of potential epitopes. It may be rather rare for a single parasite to impose strong, sustained pressure on a particular MHC allele. Perhaps only major killers of young hosts can cause such strong selection. Mathematical models could clarify the nature of aggregate selection imposed on MHC alleles. Does the distri- bution of MHC alleles in the host population shape the distribution of antigenic variants? It would be interesting to compare parasites in two locations, each location with hosts that have diﬀerent frequencies of MHC alleles. In principle, diﬀering host MHC proﬁles could inﬂuence antigenic varia- tion. Each epitope could potentially interact with several MHC alleles. The net eﬀect depends on the balance of ﬁtness gains by an escapesubstitution against one MHC allele and the potential costs of that substitution in terms of functional 122 CHAPTER 8 performance and the possibility of creating enhanced binding to other MHC alleles. It would also be interesting to compare parasites that attack only a single host species with those that attack multiple vertebrate species. The generalist parasites face variable selective pressures in the diﬀerent hosts. Idescribed a few major polymorphisms in immune regulatory promoters. I also listed several hypotheses to explain those polymorphisms: linkage with synergistic coding regions, mutation-selection balance, and heterozygote advan- tage. These explanations lack empirical support, and the case of het- erozygote advantage may also have logical ﬂaws. Ireviewedtwo cases in which the costs and beneﬁts of a more potent regulatory stimulus may favor polymorphism. In one example, host genotypes withstrongerIL1β responses probably clear infection by He- licobacter pylori more eﬀectively, but also suﬀer greater gastric tissue damage and a higher risk of gastric cancer. In another example, humans with a more active promoter of IL10 had asigniﬁcantlydelayed onset of AIDS. IL10 inhibits macrophage prolifer- ation, possibly reducing the number of activated macrophages available for HIV-1 replication. Against other pathogens that do not replicate in macrophages, reduced macrophage proliferation may favor the patho- gen against the immune system. Mathematical analysis could establish the necessary conditions to maintain polymorphism for controls of the immune response by trade- oﬀs between high and low expression. Such models would clarify the kinds of experiments needed to understand these polymorphisms. Eﬀects of regulatory variability on antigenic diversity. First, diﬀerent patterns of immune regulation may aﬀect immunodominance (Badovinac et al. Second, immune regulation may aﬀect theintensityandduration of memory. Immuno- logical memory shapes antigenic diversity because a parasite often can- not succeed in hosts previously infected by a similar antigenic proﬁle. Regulatory variability as model for quantitative variability. The widespread genetic variability of quantitative traits forms a classical un- solved puzzle of genetics. To solve this puzzle, one must understand the links between nucleotide variants, the regulatory control of trait de- GENETIC VARIABILITY OF HOSTS 123 velopment and expression, and ﬁtness. The immune system is perhaps the most intensively studied complex regulatory system in biology.
Ex- cessive weight gain will also give anovulatory cycles and PCOS (see section on causes of subfertility) levitra super active 20 mg without prescription erectile dysfunction treatment himalaya. HIV with chronic infec- tions could lead to anovulation and amenorrhea (read about special considerations for HIV- positive infertility patients in Chapter 18) levitra super active 20mg low price erectile dysfunction doctors los angeles. When women have already changed partners frequently because of sub- Figure 5 An example of a post-coital test under the fertility it will be more likely that the cause of microscope. Use the 40 × ocular and look if progressive infertility is either anovulation or blocked tubes motile sperm cells are present and not poor sperm quality. Production only around period of insertion of cervical mucus is stimulated by hormones (estro- N Depo-Provera: it could take up to 1 year gen produced in growing follicle). Examine cervical mucus for progressive motile • Stress: both mental and physical stress reduce spermatozoa using a microscope with the ocular on ovulation. You can remove some mucus from • History of abdominal operations or hydrocele/ the cervix by using a tuberculin syringe (without a herniography in men. In women abdominal needle, suck some mucus into your syringe) or use operations can cause adhesions. Unfortunately, a sponge-holding forceps (just grasp some mucus in many doctors still perform curettages because your forceps). Put the mucus on a microscope slide they think this will cure subfertility. INVESTIGATIONS IN SUBFERTILITY • The PCT is positive if one or more progressive PATIENTS motile sperm is seen per high-power field (40×). In all these cases you should repeat Post-coital test the PCT later in this cycle and when still not The post-coital test (PCT) is a test you should per- positive, in the next cycle. For women with a sound machine you could check if a follicle is regular cycle of 28 days this is on cycle day 12–14 present and measure the size of the follicle. Just before ovulation, cervical mucus is cells are seen or no progressive motile sperm 174 Subfertility cells are present. This could be a sperm problem: repeat the PCT in the next cycle or do a sperm analysis (see later). Please note: no research has been done on the PCT in low-resource settings and many gynecologists prefer to perform a sperm count. However, a sperm count is more difficult to perform and you need a well-equipped laboratory to have reliable results. The UK Royal College of Gynaecologists (RCOG) guidelines do not mention anything about PCT and it is largely because the practice in the UK, and the West for that matter, relies very heavily on the Figure 6 An example of a hydrosalpinx seen on support network of the laboratories and in vitro ultrasound. Courtesy Esther Westen fertilization (IVF) units which can give far better prognostic information about the pregnancy out- come results of the tests. There has however been a steep decline in the enthusiasm for this test because of lack of validity9,10. In low-resource countries a case could be made for this test on the basis that it would be easier to set Figure 7 An ultrasound of a woman with polycystic it up with very low overheads than say a fully ovary syndrome: you can see the follicles looking like a equipped laboratory, which will also require addi- necklace of small follicles of the same size. A PCT could be done by van Ham any clinical staff already available and will require very little by way of training and equipment. So you could Ultrasound in subfertility predict when ovulation will take place and plan You can use the ultrasound to help you to make a the date of a PCT. It is very nice if you have a You can use the ultrasound for: good ultrasonographer in your health facility or if you are one or become one yourself! What can you • Detection of follicle (Figure 2) see on a (vaginal) ultrasound in subfertility? For sub- • Abnormal ovarian cysts fertility ultrasound please have a look at the following: • Hydrosalpinx detection • Fibroid detection • Endometrium: • Timing of PCT: follicle at least 16–18mm and N Triple line endometrium (Figure 3): sign of triple line endometrium follicular phase of the cycle (before ovulation) • PCOS (see Figure 7) N Dense white endometrium (Figure 4) with- out the triple line phenomenon: after ovula- Semen analysis tion, or no ovulation occurred. It is important 175 GYNECOLOGY FOR LESS-RESOURCED LOCATIONS to collect the entire sperm sample, so please realize it is very difficult to collect an entire sperm sample in a test tube, please advise use of, for example, a urine collection bottle. If no containers are avail- able at the hospital the clients could boil any glass container in water at home and use this. The speci- men should be collected <1 h before analysis. Speak to your lab technician about whether he/she is able to perform a semen analysis and if not try to arrange training. It is not necessary to perform semen analysis in every subfertile couple: only when the PCT re- mains negative should you perform a semen analy- Figure 8 Diagram illustrating a hysterosalpingography sis. The quality of semen fluctuates a lot: after a period of fever it takes 3 months for semen to nor- syringe with X-ray contrast solution to it and malize. Only when no sperm at all are found in slowly inject 20 ml of the solution into the uterus. Make an X-ray during the is there absolute infertility. When the sperm count 5 injection, just after the injection and 1 min after is abnormal you should repeat it after 3 months. Then remove all the Table 2 shows normal semen analysis according equipment in the order – last in first out (Figure 8). When the semen is a bit less If you do not have HSG facilities but you have/ than the WHO criteria it does not mean that this is are a good ultrasonographer, try to visualize the the direct cause of subfertility – as already men- tubes and check their patency by using normal tioned, the quality of semen fluctuates a lot and saline: insert a small intrauterine cannula or catheter many times more than one factor makes a couple and slowly rinse the catheter with maximum 50ml subfertile! You should only • Uterine cavity do this method under aseptic conditions, and one • Tubes night before and 1h before the procedure you • Adhesions should administer 200mg doxycycline and 50– 100mg diclofenac. Both HSG and hydrotubation Disadvantages of HSG are that it often gives false- are reported to be successful in achieving pregnan- negative or false-positive results and it needs some cies in selective patients: thin peritubal adhesions specialized X-ray equipment that might not be 11 might be opened (level of evidence 3). In addition it should be noted that the X-ray contrast solution is rather expensive. Schistosomiasis and infections To prevent infections and reduce pain: one night before and 1h before HSG give 200mg In some areas in the world schistosomiasis could be doxycycline and 50–100 mg diclofenac. Detect schistosomiasis in urine dure is as follows: on the X-ray table you do a or cervix biopsy (see Chapter 9) and if positive, speculum examination and grab the cervix with a give appropriate treatment. Clean the cervix with antiseptic and If you suspect gonorrhea or a Trichomonas infec- introduce a hysterophore or a small catheter. The tion: do a high vaginal swab to exclude pathogenic big advantage if you have a hysterophore is that microorganisms and treat accordingly (see Chapter this instrument will close the cervix and no fluid 17 about STI). After the In some countries tuberculosis is endemic and instrument has passed the internal cervix, attach the causes infertility. It is very difficult to detect 176 Subfertility endometrial tuberculosis. This could be done after Table 3 Overview of possible treatments for various endometrium sampling using the smallest cannula infertility disorders; conditions in bold cannot be treated from manual vacuum aspiration and special patho- In woman logy staining. No ovulation PCOS: ovulation induction with clomiphene citrate DIAGNOSIS OF SUBFERTILITY Hyperprolactinemia: bromocriptine Early menopause After you have done the history taking and specific Hypophysis abnormalities examination you can diagnose the cause of the Tubes are not patent subfertility.
Middelburg RA generic levitra super active 40mg mastercard erectile dysfunction 38 years old, van de Watering LM purchase levitra super active 20mg overnight delivery erectile dysfunction caused by spinal stenosis, Briet E, van der Bom same recipient is transfused with fresh RBCs and then old RBCs JG. Storage time of red blood cells and mortality of transfusion (through different tail veins), the presence of the fresh RBCs recipients. Clinical studies of the effect of blood ity of the stored RBCs. However, should such biology exist in human transfusion, 8. Effects of red blood cell storage in it further complicates trials in which groups receive an age range of heavily transfused patients. For ethical concerns, groups are often established that 204-207. Relationship between red cell storage whether purposefully giving a group uniform older blood is duration and outcomes in adults receiving red cell transfusions: ethically appropriate. The age of red blood Summary cells in premature infants (ARIPI) randomized controlled trial: The answer to the question of whether there is a difference between study design. The Age of Blood lesion is a clear process by which RBCs degrade over time. On the Evaluation (ABLE) randomized controlled trial: study design. Ongoing prospective trials have the potential to question of the effect of RBC storage on clinical outcomes: the shed great light on this issue and represent an excellent step forward Red Cell Storage Duration Study (RECESS) (Section 7). However, many confounding problems are unavoid- Transfus Apher Sci. Will clinical studies elucidate the connection be- negative ﬁnding will not resolve the issue. Due to the sheer tween the length of storage of transfused red blood cells and magnitude of transfusions given each year (1/70 Americans), even clinical outcomes? An analysis based on the simulation of small effects on outcome may have widespread medical signiﬁcance randomized controlled trials. Harmful effects of transfusion of older blood cell transfusions on clinical outcomes in premature, very stored red blood cells: iron and inﬂammation. Nitric oxide scavenging by inﬂammation, immunity, and infection. Blood content of canines with experimental pneumonia. Silliman CC, Moore EE, Kelher MR, Khan SY, Gellar L, Elzi Vox Sang. Identiﬁcation of lipids that accumulate during the routine 32. Platelet-white storage of prestorage leukoreduced red blood cells and cause blood cell (WBC) interaction, WBC apoptosis, and procoagu- acute lung injury. Procoagulant activity of in nitric oxide-mediated vasodilation. Published long-term stored red blood cells due to phosphatidylserine online ahead of print March 11, 2013. Advanced tion precipitated by transfusion of storage-aged but not fresh glycation end products on stored red blood cells increase red blood cells. American College of Cardiology Annual endothelial reactive oxygen species generation through interac- Meeting 2013. Strain-speciﬁc RBC day-old leukoreduced or non-leukoreduced red blood cells storage, metabolism, and eicosanoid generation in a mouse induces an inﬂammatory response in healthy dogs [AABB model. Published online ahead of print May 30, meeting abstract]. Female red cell cells after prolonged storage produces harmful effects that are donor units have reduced hemolysis during routine storage mediated by iron and inﬂammation. Gender human volunteers with older, stored red blood cells produces differences in the hemolytic propensity of human and mouse extravascular hemolysis and circulating non-transferrin-bound red blood cells Transfusion. Hendrickson JE, Hod EA, Spitalnik SL, Hillyer CD, Zimring 24. Storage of murine red blood cells enhances alloantibody trauma and transfusion in induction of immune modulation responses to an erythroid-speciﬁc model antigen. Hendrickson JE, Hod EA, Hudson KE, Spitalnik SL, Zimring cytokines and markers of endothelial activation increase after JC. Transfusion of fresh murine red blood cells reverses packed red blood cell transfusion in the preterm infant. Pediatr adverse effects of older stored red blood cells. Transfusion requirements in critical care (TRICC): blood cells and platelets transfused in cardiac surgery reduces a multicentre, randomized, controlled clinical study. Transfu- postoperative inﬂammation and number of transfusions: results sion Requirements in Critical Care Investigators and the of a prospective, randomized, controlled clinical trial. Hess1 1University of Maryland School of Medicine, Baltimore, MD For 30 years, the Advanced Trauma Life Support course of the American College of Surgeons taught that coagulopathy was a late consequence of resuscitation of injury. The recognition of trauma-induced coagulopathy overturns that medical myth and creates a rationale for procoagulant resuscitation. Analysis of the composition of currently available blood components allows prediction of the upper limits of achievable coagulation activity, keeping in mind that oxygen transport must be maintained simultaneously. RBCs, plasma, and platelets given in a 1:1:1 unit ratio results in a hematocrit of 29%, plasma concentration of 62%, and platelet count of 90 000 in the administered resuscitation ﬂuid. Additional amounts of any 1 component dilute the other 2 and any other ﬂuids given dilute all 3. In vivo recovery of stored RBCs is 90% and that of platelets 60% at the mean age at which such products are given to trauma patients. This means that useful concentrations of the administered products are a hematocrit of 26%, a plasma coagulation factor activity of 62% equivalent to an international normalized ratio of 1. This means there is essentially no good way to give blood products for resuscitation of trauma-induced coagulopathy other than 1:1:1. Because 50% of trauma patients admitted alive to an academic-level 1 trauma center who will die of uncontrolled hemorrhage will be dead in 2 hours, the trauma system must be prepared to deliver plasma- and platelet-based resuscitation at all times. Who needs resuscitation of trauma-induced reaching the hospital. Among soldiers who The fraction of injured patients exhibiting trauma-induced coagulopa- die of battleﬁeld injuries, the fraction dying before they reach surgical care is even greater, approaching 85%. Among 68 000 patients who arrived inhibition of ﬁbrinolysis. As injury Resuscitation is one of the goals trauma teams try to accomplish severity increases, coagulopathy becomes more common, rising from within that golden hour. The objectives of resuscitation are to several percent in the moderately injured with injury severity scores restore cardiac output, oxygen delivery, and blood coagulation.