The OPTN Deceased Donor Potential Study: Implications for Policy and Practice.

The Organ Procurement and Transplantation Network (OPTN) Deceased Donor Potential Study, funded by the Health Resources and Services Administration, characterized the current pool of potential deceased donors and estimated changes through 2020. The goal was to inform policy development and suggest practice changes designed to increase the number of donors and organ transplants. Donor estimates used filtering methodologies applied to datasets from the OPTN, the National Center for Health Statistics, and the Agency for Healthcare Research and Quality and used these estimates with the number of actual donors to estimate the potential donor pool through 2020. Projected growth of the donor pool was 0.5% per year through 2020. Potential donor estimates suggested unrealized donor potential across all demographic groups, with the most significant unrealized potential (70%) in the 50-75-year-old age group and potential Donation after Circulatory Death (DCD) donors. Actual transplants that may be realized from potential donors in these categories are constrained by confounding medical comorbidities not identified in administrative databases and by limiting utilization practices for organs from DCD donors. Policy, regulatory, and practice changes encouraging organ procurement and transplantation of a broader population of potential donors may be required to increase transplant numbers in the United States.

Solid organ transplantation from hepatitis B virus-positive donors: consensus guidelines for recipient management.

Use of organs from donors testing positive for hepatitis B virus (HBV) may safely expand the donor pool. The American Society of Transplantation convened a multidisciplinary expert panel that reviewed the existing literature and developed consensus recommendations for recipient management following the use of organs from HBV positive donors. Transmission risk is highest with liver donors and significantly lower with non-liver (kidney and thoracic) donors. Antiviral prophylaxis significantly reduces the rate of transmission to liver recipients from isolated HBV core antibody positive (anti-HBc+) donors. Organs from anti-HBc+ donors should be considered for all adult transplant candidates after an individualized assessment of the risks and benefits and appropriate patient consent. Indefinite antiviral prophylaxis is recommended in liver recipients with no immunity or vaccine immunity but not in liver recipients with natural immunity. Antiviral prophylaxis may be considered for up to 1 year in susceptible non-liver recipients but is not recommended in immune non-liver recipients. Although no longer the treatment of choice in patients with chronic HBV, lamivudine remains the most cost-effective choice for prophylaxis in this setting. Hepatitis B immunoglobulin is not recommended.

Impact of catastrophic brain injury guidelines on donor management goals at a level I trauma center.

BACKGROUND: An organ procurement organization (OPO) and a level I trauma center developed catastrophic brain injury guidelines (CBIGs) to assist in the care of severely brain-injured adult patients before brain death. The CBIGs provided a set of clinical guidelines to maintain patient stability and optimize opportunity for organ donation. OBJECTIVE: The aim of this study was to determine if the use of the CBIGs affected the OPO's ability to achieve donor management goals (DMGs) before organ recovery. METHODS: We conducted a retrospective analysis comparing the number of DMGs met in the hospital's donors before and after the CBIGs were used. The analysis included 133 cases; 67 donors in the pre-CBIG data and 66 donors in the post-CBIG review. Donor management goals measured included: systolic blood pressure >100 mm Hg; 1 pressor ≤10 µg/kg/min; urine output 1-2 mL/kg/h; pO(2) >100 mm Hg; Na <160 meq/L; pH within normal limits (7.35-7.45); temperature 36.5-37.5°C; arterial line in place and central line in place with monitor. RESULTS: After the introduction of the CBIGs, 78% of DMGs were met more often, with 1 goal (Na) remaining equivalent and 2 goals (pO(2) and pH) met less often. Increase in achievement of individual DMGs ranged from 4% to 33%. The pre-CBIG cases averaged 2.90 missed goals per donor compared with an average of 1.79 in the post-CBIG data. Only 5 pre-CBIG donors (7%) achieved all of the DMGs. That figure rose to 12 donors (18%) in the post-CBIG data. CONCLUSIONS: While other factors may have contributed to our results, we think that there is a positive relationship between the CBIGs and the increase in meeting most DMGs. As we refine our donor management, we will focus on the factors we met less successfully. Ultimately, the use of the CBIGs before brain death led to more stable donors, maximizing transplantable organs.

Diagnosis and management of tuberculosis in transplant donors: a donor-derived infections consensus conference report.

Mycobacterium tuberculosis is a ubiquitous organism that infects one-third of the world's population. In previous decades, access to organ transplantation was restricted to academic medical centers in more developed, low tuberculosis (TB) incidence countries. Globalization, changing immigration patterns, and the expansion of sophisticated medical procedures to medium and high TB incidence countries have made tuberculosis an increasingly important posttransplant infectious disease. Tuberculosis is now one of the most common bacterial causes of solid-organ transplant donor-derived infection reported in transplant recipients in the United States. Recognition of latent or undiagnosed active TB in the potential organ donor is critical to prevent emergence of disease in the recipient posttransplant. Donor-derived tuberculosis after transplantation is associated with significant morbidity and mortality, which can best be prevented through careful screening and targeted treatment. To address this growing challenge and provide recommendations, an expert international working group was assembled including specialists in transplant infectious diseases, transplant surgery, organ procurement and TB epidemiology, diagnostics and management. This working group reviewed the currently available data to formulate consensus recommendations for screening and management of TB in organ donors.

Current practices and evaluation of screening solid organ donors for West Nile virus.

The first cases of West Nile virus (WNV) transmitted through solid organ transplantation (SOT) were identified in 2002. Subsequently, 5 additional clusters have been reported to public health officials in the United States. Based upon a limited number of known cases, patients who acquire WNV from infected donor organs might be at higher risk for severe neurologic disease and death, compared with patients infected through mosquito bites. In response, some organ procurement organizations (OPOs) have instituted pre-transplant screening of organ donors for WNV infection. We evaluated the current practices, concerns, and challenges related to screening organ donors for WNV in the United States by reviewing the relevant medical literature and interviewing key stakeholders. Screening organ donors for WNV is not required by national policy. In 2008, 11 (19%) of 58 OPOs performed WNV screening using nucleic acid amplification testing (NAT). These OPOs differ in their screening strategies, NAT performed, and logistical challenges. Concerns of delays in receiving NAT results before transplant and potential false-positive results leading to organ wasting are limitations to more widespread screening. Furthermore, it is unknown if WNV screening practices decrease SOT-related morbidity and mortality, or if screening is cost-effective. Additional data are needed to assess and improve transplant outcomes related to WNV.

Development of donor yield models.

Increasing donor yield, or the number of organs transplanted per donor, has been a focus of the transplant community in recent years. However, an exclusive focus on observed yield, unadjusted for the donor characteristics, ignores important differences between donors and donor case mixes in donation service areas (DSAs). We analyzed deceased donor registry data from the Organ Procurement and Transplantation Network/Scientific Registry of Transplant Recipients from January 2006 to December 2009 (N = 32 116 donors). Overall yields and kidney yields were modeled using ordinal logistic regression, and logistic regression was used to model heart, lung, pancreas and liver yields. Donor characteristics, including demographics, historical information and positive serology were related to overall and organ-specific yield. This study shows the potential value of the yield models as evaluation metrics and as tools that can inform DSA-wide practices in donor management and can improve organ utilization.

Nucleic acid testing (NAT) of organ donors: is the 'best' test the right test? A consensus conference report.

Nucleic acid testing (NAT) for HIV, HBV and HCV shortens the time between infection and detection by available testing. A group of experts was selected to develop recommendations for the use of NAT in the HIV/HBV/HCV screening of potential organ donors. The rapid turnaround times needed for donor testing and the risk of death while awaiting transplantation make organ donor screening different from screening blood-or tissue donors. In donors with no identified risk factors, there is insufficient evidence to recommend routine NAT, as the benefits of NAT may not outweigh the disadvantages of NAT especially when false-positive results can lead to loss of donor organs. For donors with identified behavioral risk factors, NAT should be considered to reduce the risk of transmission and increase organ utilization. Informed consent balancing the risks of donor-derived infection against the risk of remaining on the waiting list should be obtained at the time of candidate listing and again at the time of organ offer. In conclusion, there is insufficient evidence to recommend universal prospective screening of organ donors for HIV, HCV and HBV using current NAT platforms. Further study of viral screening modalities may reduce disease transmission risk without excessive donor loss.

Donor screening for human T-cell lymphotrophic virus 1/2: changing paradigms for changing testing capacity.

Organ Procurement and Transplant Network (OPTN) policy currently requires the testing of all potential organ donors for human T-cell lymphotrophic virus (HTLV)-1/2. Most Organ Procurement Organizations (OPO) use the Abbott HTLV-I/HTLV-II Enzyme Immunoassay (EIA). This assay will no longer be manufactured after December 31, 2009; the only commercially available FDA-licensed assay will be the Abbott PRISM HTLV-I/II assay which poses many challenges to OPO use for organ donor screening. As a result, screening donors for HTLV-1/2 in a timely manner pretransplant after December 31, 2009 will be challenging. The true incidence of HTLV-1 in United States (U.S.) organ donors is not well described but appears to be low ( approximately 0.03-0.5%). HTLV-1 is associated with malignancy and neurological disease; HTLV-2 has not been convincingly associated with disease in humans. Donors that are HTLV-1/2 seropositive are infrequently used despite most results being either false positive or resulting from HTLV-2 infection. There is urgent need to encourage the development of assays, instruments and platforms optimized for organ donors that can be used to screen for transmissible disease in donors; these must have appropriate sensitivity and specificity to identify all infections while minimizing organ loss through false positive testing.

Organ donation and utilization in the United States: 1998-2007.

Organ transplantation remains the only life-saving therapy for many patients with organ failure. Despite the work of the Organ Donation and Transplant Collaboratives, and the marked increases in deceased donors early in the effort, deceased donors only rose by 67 from 2006 and the number of living donors declined during the same time period. There continue to be increases in the use of organs from donors after cardiac death (DCD) and expanded criteria donors (ECD). This year has seen a major change in the way organs are offered with increased patient safety measures in those organ offers made by OPOs using DonorNet. Unfortunately, the goals of 75% conversion rates, 3.75 organs transplanted per donor, 10% of all donors from DCD sources and 20% growth of transplant center volume have yet to be reached across all donation service areas (DSAs) and transplant centers; however, there are DSAs that have not only met, but exceeded, these goals. Changes in organ preservation techniques took place this year, partly due to expanding organ acceptance criteria and increasing numbers of ECDs and DCDs. Finally, the national transplant environment has changed in response to increased regulatory oversight and new requirements for donation and transplant provider organizations.

Why doctors use or do not use ethics consultation.

BACKGROUND: Ethics consultation is used regularly by some doctors, whereas others are reluctant to use these services. AIM: To determine factors that may influence doctors to request or not request ethics consultation. METHODS: A survey questionnaire was distributed to doctors on staff at the University Community Hospital in Tampa, Florida, USA. The responses to the questions on the survey were arranged in a Likert Scale, from strongly disagree, somewhat disagree, neither agree nor disagree, somewhat agree to strongly agree. Data were analysed with the Wilcoxon test for group comparisons, the chi2 test to compare proportions and a logistic regression analysis. RESULTS: Of the 186 surveys distributed, 121 were returned, giving a 65% response rate. Demographic data were similar between the groups saying yes (I do/would use ethics consultation when indicated) and no (I do not/would not use ethics consultation when indicated). No statistically significant differences were observed between the user and non-user groups in terms of opinions about ethics consultants having extensive training in ethics or participating in ethics educational opportunities. On the issue "Ethics committee members or consultants cannot grasp the full picture from the outside", the non-users were neutral, whereas the users somewhat disagreed (p=0.012). Even more significant was the difference between surgeons and non-surgeons, where, by logistic regression analysis, surgeons who believed that ethics consultants could not grasp the full picture from the outside were highly likely to not use (p=0.0004). Non-users of ethics consultations thought that it was their responsibility to resolve issues with the patient or family (72.2% agree, p<0.05). Users of ethics consultation believed in shared decision making or the importance of alternate points of view (90.8% agree, p<0.05). IMPLICATIONS: Ethics consultations are used by doctors who believe in shared decision making. Doctors who did not use ethics consultation tended to think that it was their responsibility to resolve issues with patients and families and that they were already proficient in ethics.

Organ donation and utilization, 1995-2004: entering the collaborative era.

Continued progress in organ donation will help enable transplantation to alleviate the increasing incidence of end-stage organ disease. This article discusses the implementation and effect of the federally initiated Organ Donation Breakthrough Collaborative; it then reviews organ donation data, living and deceased, from 1995 to 2004. It is the first annual report of the Scientific Registry of Transplant Recipients to include national data following initiation of the collaborative in 2003. Prior to that, annual growth in deceased donation was 2%-4%; in 2004, after initiation of the collaborative, deceased donation increased 11%. Identification and dissemination of best practices for organ donation have emphasized new strategies for improved consent, including revised approaches to minority participation, timing of requests and team design. The number of organs recovered from donation after cardiac death (DCD) grew from 64 in 1995 to 391 in 2004. While efforts are ongoing to develop methodologies for identifying expanded criteria donors (ECD) for organs other than kidney, it is clear DCD and ECD raise questions regarding cost and recovery. The number of living donor organs increased from 3493 in 1995 to 7002 in 2004; data show trends toward more living unrelated donors and those providing non-directed donations.

Diffusion-weighted imaging and status epilepticus during vagus nerve stimulation.

PURPOSE: Transient abnormalities have been reported on diffusion-weighted imaging (DWI) during status epilepticus. Vagus nerve stimulation (VNS) is a therapy for epilepsy that has previously demonstrated alteration in regional cerebral blood flow on functional neuroimaging. We describe the peri-ictal DWI abnormalities in a patient with status epilepticus. METHODS: A 21-year-old woman with pharmacoresistant localization-related epilepsy was treated with VNS and underwent brain magnetic resonance imaging (MRI) with DWI for clinical purposes. RESULTS: Transient and reversible hyperintense signal abnormalities were noted on DWI at the site of seizure onset, in addition to the thalamus and midbrain bilaterally. A concomitant decrease in the apparent diffusion coefficient mimicked ischemia, yet complete clinical, and electrographic resolution occurred following successful termination of status. CONCLUSIONS: High-energy brain MRI sequences using DWI were safely performed in our epilepsy patient with a vagus nerve stimulator who experienced status epilepticus. This case highlights the bilateral and robust involvement of subcortical structures present immediately following status epilepticus. Additionally, bilateral abnormalities in the thalamus and midbrain in addition to the region of seizure origin, were observed in our patient implanted with a vagus nerve stimulator. Modulation of regional cerebral blood flow is one potential mechanism of action for VNS in humans; therefore, these regions of involvement could reflect the effects of status epilepticus, activation or facilitation by VNS, or both.

Identification of sites in the second exomembrane loop and ninth transmembrane helix of the mammalian Na+/H+ exchanger important for drug recognition and cation translocation.

Mammalian Na(+)/H(+) exchanger (NHE) isoforms are differentially sensitive to inhibition by several distinct classes of pharmacological agents, including amiloride- and benzoyl guanidinium-based derivatives. The determinants of drug sensitivity, however, are only partially understood. Earlier studies of the drug-sensitive NHE1 isoform have shown that residues within the fourth membrane-spanning helix (M4) (Phe(165), Phe(166), Leu(167), and Gly(178)) and a 66-amino acid segment encompassing M9 contribute significantly to drug recognition. In this report, we have identified two residues within M9, one highly conserved (Glu(350)) and the other non-conserved (Gly(356)), that are major determinants of drug sensitivity. In addition, residues in the second exomembrane loop between M3 and M4 (Gly(152), Phe(157), and Pro(158)) were also found to modestly influence drug sensitivity. A double substitution of crucial sites within M4 and M9 of NHE1 with the corresponding residues present in the drug-resistant NHE3 isoform (i.e. L167F/G356A) greatly reduced drug sensitivity in a cooperative manner to levels nearing that of wild type NHE3. The above mutations did not appreciably affect Na(o)(+) affinity but did markedly decrease the catalytic turnover of the transporter. These data suggest that specific sites encompassing M4 and M9 are critical determinants of both drug recognition and cation translocation.

Role of the cytoskeleton in mediating cAMP-dependent protein kinase inhibition of the epithelial Na+/H+ exchanger NHE3.

The Na(+)/H(+) exchanger NHE3 isoform mediates the entry of Na(+) into epithelial cells of the kidney and gastrointestinal tract. Hormones and pharmacological agents that activate cAMP-dependent protein kinase A (PKA) are potent inhibitors of native and ectopically expressed NHE3 in epithelial and Chinese hamster ovary AP-1 cells, respectively. Previous studies have shown that acute inhibition is coupled to direct phosphorylation of the exchanger, but this only partly accounts for the observed effects. In this report, we show that inhibition of NHE3 activity by forskolin, an activator of adenylate cyclase, occurs without changes in surface expression of the exchanger but is associated with altered cytoskeletal structure. This effect resembles that obtained with cytochalasin D or latrunculin B, actin disrupting agents that also inhibit NHE3. Such similarities prompted us to further investigate the relationship between PKA-induced inhibition of the exchanger and changes in the actin cytoskeleton. Inhibition of NHE3 by cytochalasin D does not require PKA, because the inhibitory effect is preserved in a mutant NHE3 that is not phosphorylated by PKA and in cells pretreated with the PKA inhibitor H89. In contrast, involvement of actin in the effect of cAMP on the exchanger is supported by the following observations: (i) jasplakinolide, an F-actin stabilizer, prevents the inhibition caused by forskolin, and (ii) constitutively active forms of RhoA and Rho kinase interfere with actin disruption by forskolin and also decrease inhibition of the transporter. These results suggest that reorganization of the cytoskeleton by PKA is involved in mediating inhibition of NHE3.

Modulation of Na+/H+ exchange activity by Cl-.

Na+/H+ exchanger (NHE) activity is exquisitely dependent on the intra- and extracellular concentrations of Na+ and H+. In addition, Cl- ions have been suggested to modulate NHE activity, but little is known about the underlying mechanism, and the Cl- sensitivity of the individual isoforms has not been established. To explore their Cl- sensitivity, types 1, 2, and 3 Na+/H+ exchangers (NHE1, NHE2, and NHE3) were heterologously expressed in antiport-deficient cells. Bilateral replacement of Cl- with nitrate or thiocyanate inhibited the activity of all isoforms. Cl- depletion did not affect cell volume or the cellular ATP content, which could have indirectly altered NHE activity. The number of plasmalemmal exchangers was unaffected by Cl- removal, implying that inhibition was due to a decrease in the intrinsic activity of individual exchangers. Analysis of truncated mutants of NHE1 revealed that the anion sensitivity resides, at least in part, in the COOH-terminal domain of the exchanger. Moreover, readdition of Cl- into the extracellular medium failed to restore normal transport, suggesting that intracellular Cl- is critical for activity. Thus interaction of intracellular Cl- with the COOH terminus of NHE1 or with an associated protein is essential for optimal activity.

Point-of-care testing.

Point-of-care testing technology rapidly is changing the way physicians practice medicine by facilitating the availability of biochemical parameters immediately or almost immediately. The constant evolution and developments in [figure: see text] microchemistry and computer technology will make this area a dynamic part of medicine with the constant emergence of improved and newer technologies. Clinicians must not forget, however, that the best analyzer and monitor is the physician, nurse, or other health care worker in direct contact with the patient, constantly reassessing, re-examining, and integrating all of the physiologic and biochemical data in the context of the history and physical examination. If POC testing is implemented, its goal should be to improve and assist in patient care.

Drowning. Rescue, resuscitation, and reanimation.

Several myths about drowning have developed over the years. This article has attempted to dispel some of these myths, as follows: 1. Drowning victims are unable to call or wave for help. 2. "Dry drownings" probably do not exist; if there is no water in the lungs at autopsy, the victim probably was not alive when he or she entered the water. 3. Do not use furosemide to treat the pulmonary edema of drowning; victims may need volume. 4. Seawater drowning does not cause hypovolemia, and freshwater drowning does not cause hypervolemia, hemolysis, or hyperkalemia. 5. Drowning victims swallow much more water than they inhale, resulting in a high risk for vomiting spontaneously or on resuscitation. No discussion of drowning would be complete without mentioning the importance of prevention. Proper pool fencing and water safety training at a young age are instrumental in reducing the risk for drowning. Not leaving an infant or young child unattended in or near water can prevent many of these deaths, especially bathtub drownings. Also crucial is the use of personal flotation devices whenever boating. Proper training in water safety is crucial for participation in water recreation and sporting activities, including SCUBA diving. The incidence of pediatric drowning deaths in the United States has decreased steadily over the past decade, perhaps as a result of increased awareness and attention to drowning-prevention measures (Box 1).

Status epilepticus.

Status epilepticus is a serious medical emergency that requires prompt and appropriate intervention. Maintenance of adequate vital function with attention to airway, breathing, and circulation; prevention of systemic complications; and rapid termination of seizures must be coupled with investigating and treating any underlying cause. In most patients with SE, the use of adequate dosages of first-line antiepileptic agents allows for the successful and rapid termination of SE and avoidance of potential neurologic complications. Refractory SE requires more aggressive treatment, often the use of intravenous anesthetic agents and intense monitoring, and therefore must be managed in a pediatric intensive care unit with a multidisciplinary approach. Large, controlled, multicenter, comparative studies are needed urgently to clarify better the optimal management of these patients.

Molecular cloning and characterization of a novel (Na+,K+)/H+ exchanger localized to the trans-Golgi network.

The luminal pH of organelles along the secretory and endocytic pathways of mammalian cells is acidic and tightly regulated, with the [H+] varying up to 100-fold between compartments. Steady-state organellar pH is thought to reflect a balance between the rates of H+ pumping by the vacuolar-type H+-ATPase and H+ efflux through ill-defined pathways. Here, we describe the cloning of a novel gene (NHE7) in humans that is homologous to Na+/H+ exchangers, is ubiquitously expressed, and localizes predominantly to the trans-Golgi network. Significantly, NHE7 mediates the influx of Na+ or K+ in exchange for H+. The activity of NHE7 was also found to be relatively insensitive to inhibition by amiloride but could be antagonized by the analogue benzamil and the unrelated compound quinine. Thus, NHE7 displays unique functional and pharmacological properties and may play an important role in maintaining cation homeostasis of this important organelle.

Regulation of the epithelial Na(+) /H(+) exchanger isoform by the cytoskeleton.

Members of the Na(+)/H(+) exchanger (NHE) family mediate electroneutral countertransport of H(+) for Na(+) across cellular membranes. The six known isoforms mediate transepithelial Na(+) transport processes and housekeeping functions such as the regulation of cellular and organellar pH and volume. NHE3 is found primarily in the apical membrane of epithelial cells of the kidney and gastrointestinal tract, where it mediates Na(+) (re)absorption. Its fine regulation, whether by hormones that utilize cAMP as a signalling mechanism, or by physical parameters such as the cell volume, provides the adjustments necessary for the maintenance of systemic salt and fluid balance. Although the exact molecular mechanism of this control is unknown, two major modes of regulation have been invoked: 1) alteration of the number of cell surface transporters by changes in the rate of endocytosis and/or exocytosis and 2) regulation of the intrinsic activity of the individual exchangers. NHE3 requires an intact cytoskeleton for its optimal function. Pharmacological interference with actin polymerization or myosin phosphorylation markedly inhibits the exchanger, without altering the number of transporters exposed at the surface. This effect is isoform specific and is mediated by the cytoplasmic tail of the transporter. The small GTP-binding protein, RhoA and its downstream effector, Rho kinase regulate NHE3, possibly by controlling the level of myosin phosphorylation, that in turn determines the organization of actin. The cytoskeleton may not only be involved in the maintenance of the basal rate of transport, but is also likely to sense physical alterations and transmit signals to modulate NHE3 activity, thus providing fast and effective control of the exchanger.