Diabetes is a disease of increasing worldwide prevalence and is the main cause of chronic renal failure. Type 1 diabetic patients with chronic renal failure have the following therapy options: kidney transplant from a living donor, pancreas after kidney transplant, simultaneous pancreas-kidney transplant, or awaiting a deceased donor kidney transplant. For type 2 diabetic patients, only kidney transplant from deceased or living donors are recommended. Patient survival after kidney transplant has been improving for all age ranges in comparison to the dialysis therapy. The main causes of mortality after transplant are cardiovascular and cerebrovascular events, infections and neoplasias. Five-year patient survival for type 2 diabetic patients is lower than the non-diabetics' because they are older and have higher body mass index on the occasion of the transplant and both pre- and posttransplant cardiovascular diseases prevalences. The increased postransplant cardiovascular mortality in these patients is attributed to the presence of well-known risk factors, such as insulin resistance, higher triglycerides values, lower HDL-cholesterol values, abnormalities in fibrinolysis and coagulation and endothelial dysfunction. In type 1 diabetic patients, simultaneous pancreas-kidney transplant is associated with lower prevalence of vascular diseases, including acute myocardial infarction, stroke and amputation in comparison to isolated kidney transplant and dialysis therapy.Type 1 and 2 diabetic patients present higher survival rates after transplant in comparison to the dialysis therapy, although the prevalence of cardiovascular events and infectious complications remain higher than in the general population. Diabetes is a disease of increasing worldwide prevalence, with a perspective of 330 million people affected by 2030. In the United States of America, diabetes is the main cause of chronic kidney failure, corresponding to approximately 40% of the patients undergoing renal replacement therapy and outgrowing the number of cases of nephritis and systemic arterial hypertension . Throughout the last four decades, it has been observed a change in the time interval from the diabetes diagnosis to the development of chronic kidney failure, which was shown to increase from 20 to 30 years . In BrazPatients with type 1 diabetes and chronic kidney failure have the following therapy options, besides the dialysis treatment: kidney transplant from a living donor, pancreas transplant after kidney transplant, simultaneous pancreas-kidney transplant, or awaiting a deceased donor kidney transplant . On the The awaiting time is shorter in this transplant modiality than in other ones because it takes just the time to prepare the living donor. Imunossuppressive regimen may be tailored according to the Human Leucocytes Antigens (HLA) compatibility. If there is is an identical donor, the dose of the immunosuppressors will be lower, which minimizes their side effects. This is the transplant modality that has the greatest life expectancy rate, around 18.3 years .In Brazil, the organ allocation for kidney transplant from a deceased donor is determined by the HLA compatibility, resulting in a waiting time that may be over five or six years, which increases the secondary clinical complication events, either related to the diabetes or to the chronic kidney failure. The patient survival rate, although longer than in dialysis, is around 11.4 years [vs 81.9%, respectively), whereas the kidney graft survival of the kidney alone from non-pancreas donors was significantly lower than the other two groups (64.3%). When controlling for recipient and transplant differences, it was observed a reduction of 50% in the risk of kidney graft loss in the group of kidney alone from pancreas donors in comparison to simultaneous pancreas-kidney transplant [On the other hand, it has recently been discussed if the comparison of the kidney survival can be done without a bias between simultaneous pancreas-kidney transplant and deceased donor kidney alone, inasmuch as there are donor, recipient and transplant differences that may interfere with the outcomes . In thisPancreas after kidney transplant (PAKT) modality has the shortest waiting time for pancreas transplant in Brazil, since many teams capture the pancreas, but do not perform the pancreas transplant surgical procedure, which results in a shorter waiting time in comparison to simultaneous pancreas-kidney transplant. The life expectancy rate is reported to be 17.2 years . HoweverFurthermore, PAKT indications are still controversial in the literature, but they may be certainly indicated for cases of severe asymptomatic hypoglycemia and ketoacidosis of difficult control . Therefovs 95%, respectively), as well as the 1-year pancreas graft survival  [In addition, it was recently demonstrated that the 1-year patient survival after PAKT was similar to the simultaneous pancreas-kidney transplant (98% ctively) . The immIn type 1 diabetic patients under dialysis, the 5-year patient survival, even for young patients, ranges from 25 to 35%, increasing to 80% after the transplant . In thisConfirming the transplant benefits with regards to the life expectancy of type 1 diabetic patients in comparison to the dialysis therapy, it was demonstrated that patients that are awaiting a deceased donor kidney transplant have an 8-year life expectancy as opposed to the patients that have 12.9-year, 21-year and 23-year life expectancies after the kidney transplant from deceased donors, the kidney transplant from living donors and the SPKT, respectively [However, other authors reported a shorter life expectancy after the SPKT in comparison to the kidney transplant from living donors in type 1 diabetic patients . It coulNowadays, the pancreas graft survival tends to be longer after the SPKT. There was shown an increase from 75% to 85% in the pancreas graft survival rates in the first year as compared to the other modalities of pancreas transplants, such as pancreas transplant alone and PAKT, which showed pancreas graft survival rates around 75% at 1-year . After tUnited States Renal Data System) from 1988 through 1996 indicated a 23% decrease in the mortality rates of the patients awaiting a deceased donor kidney transplant, which was also associated with a 30% decrease in the mortality rates of the patients submitted to kidney transplant [Regarding patients with chronic kidney failure that are under renal replacement therapy, data collected from the USRDS  [vs 17.2%, respectively). In other study conducted with type 2 diabetic and non-diabetic patients, the patient survival rates regarding kidney grafts from deceased donors were 68% vs 80% and from living donors were 81% vs 90%, which suggests that the great differential seems to be the recipients' age, which has affected both the diabetic and the non-diabetic patients' survival rates [vs 82% and 77% vs 77%, repsctively) [After the kidney transplant, the type 2 diabetic patients have 8 to 19 additional years in their life expectancy . In addictively) . Howeveral rates . Boucek ctively) .The causes of kidney graft loss after the first year of transplant include chronic graft injury in 50% of the cases , and the other 50% represent the death with a functioning kidney graft . The phyThe main cause of mortality after the kidney transplant is cardiovascular diseases (37%), followed by the cerebrovascular diseases (7%), infections (20%), neoplasias (13%) and other causes (23%). The yearly cardiovascular mortality rate after the kidney transplant is 0.54% and for patients undergoing dialytic treatment it is over 9%, which is much higher in comparison to the general population (0.28%).The risk factors for cardiovascular disease in diabetic patients are associated with insulin resistance, higher values of triglycerides and lower values of HDL-cholesterol, abnormalities in coagulation and fibrinolysis and endothelial dysfunction, so that the time of type 2 diabetes history has direct correlation to the mortality . In thisvs 93%) [vs 16%), and higher incidence of posttransplant cardiovascular events (37% vs 9%). In addition, the main cause of death after the transplant in type 2 diabetic patients included cardiovascular disease (61% vs 26% for non-diabetics) [More recent data demonstrated that the 5-year patient survival rate for type 2 diabetic patients was lower than the non-diabetics' (70 vs 93%) . When boabetics) . Anotherabetics) .vs preemptive transplant , while in the diabetic patients, the background of dialysis and cardiovascular disease have also influenced the patients' survival rates after the transplant [Thus, in the non-diabetics, the 5-year patient survival rates after the transplant were mainly affected by the following factors: recipients' age and dialysis background ansplant .Additionally, the incidence of cardiovascular events after the transplant in non-diabetic patients had a correlation to the traditional factors, while for the diabetic patients these cardiovascular events were associated with the presence of cardiovascular disease background .preemptive pancreas-kidney transplant is associated with the longer survival rates, either for the patient or for the kidney graft [For type 1 diabetic patients, it was demonstrated that 2-year patient survival rate after kidney transplant in comparison to the dialysis therapy was not different, though after the kidney transplant the lipid profile has improved , but the average carotid intima-media thickness was not different, as opposed to the stabilization of the diabetic retinopathy in over 90% of the cases . These fey graft .In the longer follow-up, 5-year patient and kidney graft survival rates in type 1 diabetic patients that were submitted to SPKT and in the non-diabetics submitted to kidney transplant were 96% and 90%, and 85% and 75%, respectively . Such diAfter the SPKT, type 1 diabetic patients present a reduction in the left ventricular mass in the first year of the transplant, the glycated hemoglobin values also improve, as well as the BMI, the triglycerides values and either the systolic or the diastolic blood pressure control in comparison to the patients submitted to the isolated kidney transplant -17,36.vs 70%) [In addition, after 10 years the type 1 diabetic patients submitted to the SPKT in comparison to the isolated kidney transplant present lower prevalence of vascular diseases, including acute myocardial infarction, cerebrovascular events and peripheral arterial disease associated with amputation . The 10-vs 70%) , probablvs 70%) . These fvs 70%) . Regardivs 70%) , probablvs 70%) ,40. In tvs 70%) . So, in vs 20%, respectively [Regarding autonomic neuropathy, after the SPKT, there is an improvement that starts after two years, which may justify the difference observed in the 10-year survival rates of the SPKT patients in comparison to the isolated kidney transplant patients, i.e., 80% ectively . Howeverectively .Another discussed topic is if there is a room for glucose improvement after pancreas transplant in type 2 diabetic patients. In one study, the 5-year and 10-year survival rates for type 2 diabetic patients who were submitted to the SPKT were not different in comparison to the type 1 diabetic patients that were also submitted to the SPKT . Yet, thvs PAKT and pancreas transplant alone), with type 2 diabetes vs type 1 diabetes history, with the pretansplant insulin dose and BMI, and with the acute rejection episodes occurrence [2 and daily insulin dose greater than 70 U, regardless of the diabetes type (1 or 2), were the ones that had hyperglycemia in 80 to 90% of the times [Another study has recently shown that 17% of the type 1 diabetic patients had hyperglycemia after the pancreas transplant, which has also occurred in 45% of the type 2 diabetic patients . The riscurrence . By analhe times . Thus, the times .After the transplant, the approach to the diabetic patients must be aggressive in relation to the systemic blood pressure control, weight control through diet and exercise, discontinuing smoking, proteinuria control, dyslipidemia control and hyperglycemia treatment, so that all the goals established prior to the transplant should be pursued in the posttransplant period . OptimizGlitazones are also associated with the reduction of insulin resistance and with the preservation of the beta cells mass. Besides, they have impact on the reduction of the cardiovascular risks and death rates of the patients with chronic kidney failure , furtherType 1 and 2 diabetic patients show higher survival rates after transplant in comparison to the dialysis therapy, although the prevalence of cardiovascular events and infectious complications remain higher posttransplant than in the general population.The authors declare that they have no competing interests.EBR designed and wrote the paper, JRSA participated in the design of the study and read the paper, CSM participated in the design of the study, AMG participated in the design of the study, MML participated in the design of the study, AS participated in the design of the study, JOMP participated in the design of the study and coordination. All authors read and approved the final manuscript.


Previous studies have examined the spectrum of diseases identified with a kidney biopsy and the complications of the procedure. However, few studies have examined the utility of the test to clarify the diagnosis and guide treatment of pediatric patients. This retrospective, single-center chart review was performed to test the hypothesis that at least 80% of native kidney biopsies provide clinically valuable information that rationally guides diagnosis and patient management.200 biopsies performed between January 1, 2000 and June 30, 2008 were reviewed. A scheme composed of six categories was devised to classify the utility of each kidney biopsy.196 complete case files were available for review. Twenty-four (12.2%) biopsies did not shed light on the diagnosis and were unhelpful in patient management – 21 biopsies (10.7%) were non-diagnostic and 3 (1.5%) failed to yield enough tissue for examination. The number of unhelpful biopsies did not cluster in any specific disease entity.Our findings provide guidance to nephrologists about the total risk of a kidney biopsy, including uninformative results, when seeking informed consent for the procedure. The results suggest an appropriate balance has been reached which maximizes the use of kidney biopsies while minimizing the risk of this invasive procedure (word count: 202). A kidney biopsy is an important diagnostic procedure in nephrology and can aid in determining the appropriate diagnosis, treatment, and prognosis for specific patients. Based upon physical examination, urinalysis and blood tests, physicians attempt to make a clinical diagnosis which is used to guide treatment. This is not always feasible using non-invasive tools, and in such cases a kidney biopsy may need to be performed to confirm or determine the diagnosis, severity, and urgency of therapy.A kidney biopsy may not always provide information that is needed or pertinent to the clinical scenario. Sometimes an adequate tissue sample of the kidneys cannot be obtained or the information provided from the biopsy fails to shed any light on the patients' symptoms or clinical data. Due to the invasiveness of the procedure, it is important, when recommending a biopsy for an individual patient, to bear in mind not only the risks of the procedure itself but the distinct possibility that it might prove unhelpful in the patient's management.There are a number of recent studies that have detailed the array of diagnoses obtained from kidney biopsies in adults -8 and chA database of biopsy procedures was obtained from the Department of Pathology that contained information on all native kidney biopsies completed at Schneider Children's Hospital between January 1, 2000 and June 31, 2008. The database included the patient's name, date of biopsy, date of birth, and final diagnosis.The medical records of patients were retrieved from active clinical files or from off-site storage. The following data were extracted from each available chart: age, gender, blood pressure, dipstick urinalysis results, height (cm), serum creatinine, estimated glomerular filtration rate (GFRe), and urine protein/creatinine ratio in an early morning specimen at the last evaluation prior to the biopsy. In addition, the reason for biopsy, physician's predicted diagnosis, the biopsy-confirmed diagnosis, and treatment outcome were recorded. The predicted diagnosis was based on the correspondence from the nephrologist who performed the biopsy to the patient's primary physician or was based on the clinical diagnosis recorded on the biopsy report at the time of submission of the tissue sample.Classification of diagnostic outcomes of the biopsy: A six-point scheme was designed to determine whether the biopsy served as a useful tool in establishing treatment. If the physician conclusively predicted a particular diagnosis which the biopsy confirmed, the patient was categorized as type 1. A type 2 categorization denoted a biopsy that confirmed one of multiple possible diagnoses. A type 3 categorization accounted for an incorrect pre-biopsy prediction but in which the biopsy finding was conclusive and sufficient to determine appropriate treatment. If the biopsy was used to determine the severity of an established disease, category 4 was assigned to that patient. Failures were identified as either content based or technical and were separated accordingly. Thus, patients in whom the biopsy was insufficient on its own to define prognosis and treatment were categorized as type 5. Technical failures, namely an inability to obtain tissue, were categorized as type 6.Each case was independently reviewed by one of the four primary authors . Clinical and biopsy reports were recorded and categorized according to the scheme outlined above. Agreement between all pairs of primary reviewers was reached in over 85% of all cases. When there was a discrepancy between the primary reviewers, an independent observer (RF), who did not perform the biopsy, reviewed the case. This reviewer also checked randomly selected charts for accuracy and agreed with the primary reviewers in all cases. A nurse was chosen to adjudicate conflicts among the primary reviewers and to confirm accuracy of the chart reviews because this person would be less likely to be biased in interpreting the utility of the kidney biopsy procedures. The nephrologist who did the kidney biopsy did not participate in the categorization of the informational outcome of the procedure to avoid potential bias.Data are reported as mean ± SD. Differences in proportion were assessed by the chi square or Fisher exact test as appropriate. Differences were considered statistically significant if the P value was <0.05. All information was gathered on a pre-approved form.Data were de-identified and coded by study number in accordance with the Health Insurance Portability and Accountability Act guidelines (HIPAA). This chart review was approved by the Institutional Review Board of North Shore-LIJ Health System.A total of 200 biopsies were identified in the pathology database. All charts were retrieved. 4 charts were excluded because the biopsy was done at a different center and the diagnostic assessment and its impact on management by the attending physician could not be directly assessed. Thus, this report is based on the outcomes of 196 kidney biopsies.P/C >1 and 30 (15%) had GFRe <90 mL/min/1.73 m2.The number of biopsies per year is illustrated in Figure Eleven of the patients who had biopsies underwent repeat biopsies. Nine patients had a second biopsy, one had three, and another underwent four procedures. In the last case, of the four biopsies performed, one of the biopsies was a technical failure. In two of these patients, the first biopsies were normal or non-diagnostic and subsequent biopsies showed FSGS and MPGN, respectively. In two other patients, neither the original nor follow up biopsies resulted in a definitive diagnosis. In the remaining 6 patients, the repeat kidney biopsy was done to assess response to treatment, 4 in patients with SLE and 2 in patients with MPGN.Fifty-eight 29%) patients were classified as type 1, 28 (15%) were type 2, 27 (14%) were type 3, 59 (30%) were type 4  were useful as defined above. In particular, of the 113 kidney biopsies that were done for diagnostic purposes  85% were helpful, and all of the procedures done to assess severity were also deemed helpful. From a clinical perspective, categories 1–4 were all considered useful and could have been combined into one group. We divided them into four distinct subcategories to better characterize how nephrologists utilize the information content of a kidney biopsy in a productive manner.In most circumstances, a renal biopsy is a semi-elective procedure, and technical failures can occur when the procedure fails to obtain adequate tissue. Of all the biopsies analyzed in this study, only 3 were technical failures. The fact that renal biopsies were not useful in 12.2% of cases needs to be considered in assessing the benefit of performing biopsies. In those cases, further testing is needed after the biopsy, and treatment has to be guided by clinical factors rather than the histopathological findings. In our study, we found the overall yield of uninformative biopsies was 12.2%, which is below the 20% threshold that we defined as an acceptable rate. This constitutes an acceptable risk/benefit ratio. Despite the potential risks involved, families can be reassured that a renal biopsy will be helpful in the great majority of patients who must undergo the procedure.In judging this study, it is worth noting that there has been general uniformity in practice and staffing over the study period. One physician (HT) has been one of the primary nephrologists over the past 20 years and active throughout the 8-year study period and one pathologist (EV) interpreted all the biopsies from 2000 to 2007. It is reasonable to conclude that there was consistency in the use of kidney biopsies to predict, diagnose, and treat patients suspected of having kidney disease. The number of biopsies performed per year Figure  showed nIt is important to acknowledge that the study cannot definitively assess the utility of kidney biopsies performed to determine severity (type 4) in SLE patients. We assumed the results to be useful, excluding those in which a technical failure occurred, because the biopsies identified the WHO class of the disease in all cases and presumably guided treatment by the rheumatologists. This reflects the approach to patient management at Schneider Children's Hospital in which the care of children with SLE nephritis is delivered primarily by the rheumatologists unless the patients have specific issues such as hypertension, edema, or progress to end stage kidney disease. The utility of the biopsy may vary in those centers where nephrologists directly supervise the full care of patients with SLE. In addition, this study was limited to native kidney biopsies and did not address the value of transplant biopsies. Finally, we have not commented on complications of the procedure because we have reviewed our experience in a previous publication which confirms the overall safety of kidney biopsies performed using ultrasound localization .Based upon clinical experience and perennial difficulties distinguishing between FSGS and MCNS clinically, we anticipated that kidney biopsies performed on these patients would have the highest non-diagnostic rate. Table It is likely that nephrologists will always have to grapple with the fact that there will be a percentage of biopsies that fail to yield a diagnosis. Too small a percentage suggests too stringent requirements for performing a kidney biopsy. Conversely, a high percentage suggests that kidney biopsies are being performed for inadequate indications. The issue of an acceptable value will vary depending upon the urgency of the patient's clinical situation, the spectrum of clinical outcomes that might occur, and the availability of treatments that can materially alter the outcome of an anticipated disease entity. For example, pediatric surgeons recognize that not every child with abdominal pain who undergoes a laparotomy should have appendicitis because they realize it is better to occasionally find a normal abdomen rather than manage a ruptured appendix. Interestingly, a recent report in the surgical literature suggests that an acceptable negative appendectomy rate is 10–20%, in the range of our rate of negative kidney biopsies . In viewIn summary, we present our findings about the diagnostic value of a kidney biopsy in a varied group of pediatric patients. The overall rate of 12% seems to strike an appropriate balance between maximizing the application and minimizing the risk of this invasive procedure. Our findings may need to be reassessed as clinical information regarding specific disease changes and technical innovations are introduced in the performance of kidney biopsies and handling renal tissue specimens.P/C: Urine protein:creatinine ratio; WHO: World Health OrganizationAIN: Acute interstitial nephritis; FSGS: Focal segmental glomerulosclerosis; GFRe: Estimated glomerular filtration rate; HSP: Henoch-Schonlein purpura; MCNS: Minimal change nephrotic syndrome; MPGN: Membranoproliferative glomerulonephritis; SLE: Systemic lupus erythematosus; UThe authors declare that they have no competing interests.BS, AP, JR and FT retrieved patient data, collated the information and performed data analyses. RF, SV, CH, and BG assisted in patient identification, reviewed biopsy reports. EV and DC performed review of pathology data. BS, AP, and HT wrote the manuscript. HT conceived of the study and designed the retrospective review. All authors read and approved the final version of the manuscriptThe pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2369/10/11/prepub


In Korea, many stroke patients receive oriental medical care, in which pattern-identification plays a major role. Pattern-identification is Oriental Medicine's unique diagnostic system. This study attempted to standardize oriental medical pattern-identification for stroke patients. This was a community-based multicenter study that enrolled stroke patients within 30 days after their ictus. We assessed the patients' general characteristics and symptoms related to pattern-identification. Each patient's pattern was determined when two doctors had the same opinion. To determine which variables affect the pattern-identification, binary logistic regression analysis was used with the backward method. A total of 806 stroke patients were enrolled. Among 480 patients who were identified as having a certain pattern, 100 patients exhibited the Fire Heat Pattern, 210 patients the Phlegm Dampness Pattern, nine patients the Blood Stasis Pattern, 110 patients the Qi Deficiency Pattern, and 51 patients the Yin Deficiency Pattern. After the regression analysis, the predictive logistic equations for the Fire Heat, Phlegm Dampness, Qi Deficiency, and Yin Deficiency patterns were determined. The Blood Stasis Pattern was omitted because the sample size was too small. Predictive logistic equations were suggested for four of the patterns. These criteria would be useful in determining each stroke patient's pattern in clinics. However, further studies with large samples are necessary to validate and confirm these criteria. The prevalence rate of stroke has been rising recently, as the average life span has become longer. Since stroke can be fatal at acute stages and may leave irreversible neurological deficits, it has generated a great deal of social concern. In modern Western medicine, thrombolysis and anticoagulants are conventionally used. However, these are insufficient and are known to pose some adverse effects including a hemorrhagic tendency –3. ThereOKETSU made by Terasawa et al. [There has been little progress, however, in the standardization of oriental medical pattern-identification. In Japan, several standardized questionnaires have been suggested and used in the literature. All these questionnaires, except for the diagnostic criteria for a et al. , do not a et al. . The auta et al. –10. TheyThis study was a community-based multi-center trial. We enrolled stroke patients within 30 days after their ictus from the oriental medical university hospitals in the National Capital Region, including Seoul and Kyunggi-do. Kyung Hee Oriental Medical Center (Seoul), Kyung Hee East-West Neo Medical Center (Seoul), Dong Guk International Hospital (Kyunggi-do), and Kyung Won Oriental Medical Hospitals (Seoul and Incheon) were the involved hospitals. We excluded traumatic stroke such as subarachnoid, subdural, and epidural hemorrhage. Informed consent of all the study patients was obtained after a thorough explanation of the details. This study was approved by the Institutional Review Board (IRB) of Kyung Hee Oriental Medical Center (KOMC IRB 2007-07).In this study, we used the Case Report Form (CRF) and the Standard Operation Procedures (SOPs) developed by the Experts Committee organized by the Korean Institute of Oriental Medicine –14. ThesTwo oriental internal medical doctors from each hospital and who had at least more than three years of clinical experience with stroke identified the pattern of each patient as follows the Fire Heat Pattern, the Phlegm Dampness Pattern, the Blood Stasis Pattern, the Qi Deficiency Pattern, and the Yin Deficiency Pattern, as suggested by the Korean Institute of Oriental Medicine –13. In tP/1 − P) = β0 + β1X1 + β2X2 + ⋯ +βnXn, where the Xs are independent variables, the βs are regression coefficients, and P is the probability of the pattern-identification. The entire analysis was performed using SPSS for Windows, version 12.0 .To determine which variables affect the pattern-identification, binary logistic regression was used. We removed the variables without statistical significance step by step using the backward method until a combination composed of purely significant variables was reached and considered each retained variable as an independent factor for the predictive model. The derived logistic equation was log  found, afternoon tidal fever, white fur, and slow pulse were less statistically significant and were removed earlier. Nausea, floating pulse, and deep pulse were found to have been relatively very significant in the first analysis. They were removed, however, because their significance decreased while the backward method progressed. Aversion to heat, pale tongue, and strong pulse had low statistical significance at first, but these increased as the backward method progressed. Reddened complexion, thin pulse, slippery pulse, eyeball congestion, thick fur, and teeth marked tongue had high significance levels and, thus, were retained.A total of 100 patients  were identified as having the Fire Heat Pattern. All of the assessed variables were included in the first logistic regression analysis. Among the statistically significant variables (P < .1) in the first analysis. The significance levels of spotted tongue, rapid pulse, deep pulse, eyeball dryness, and night sweating were relatively high at first, but the levels decreased as the backward method progressed Fatigue and pale tongue had higher significance levels after the other variables were removed. Overweight, pale complexion, reddened complexion, flushed cheeks, and slippery pulse had high significance levels and, thus, were retained.Phlegm Dampness Pattern was identified in 210 patients . Thick fur and slow pulse had lower significance and were removed earlier from among the significant variables (P < .1), variables with lower significance levels such as profuse sweating and afternoon tidal fever were removed earlier. Faint low voice, borborigmus, and thin pulse had high significance levels in the first analysis, but were removed as the backward method progressed. The significance levels of vacuous pulse and nausea were low at first, but strengthened and were retained. Overweight, pale complexion, reddened complexion, flushed cheeks, eyeball dryness, night sweating, reversal cold in the extremities, thick fur, deep pulse, rapid pulse, and slippery pulse had high significance levels and, thus, were retained.A total of 110 patients  were identified as having the Qi Deficiency Pattern. Among the statistically significant variables (P < .1), night sweating, heat in the palms and soles, mirror tongue, white fur, and rough pulse were removed earlier as the backward method progressed. Flushed cheeks, thirst, afternoon tidal fever, dry fur, rapid pulse, and strong pulse had high significance levels and, thus, were retained. So that the characteristics of each pattern may be seen as a whole, a figure of β regression coefficients is presented here.There were 51 patients, or 10.6% of all the patients, with the Yin Deficiency Pattern. Among the statistically significant variables (P/1 − P) = β0 + β1X1 + β2X2 + ⋯ +βnXn, where the Xs are independent variables, the βs are regression coefficients, and P is the probability of the Pattern-Identification. It is a popular method of building a predictive model that has a familiar interpretation. According to the β coefficient, there would be positively quantified or negatively quantified variables. This means that if a patient has more positives, the probability of the pattern-identification being correct would increase, while if a patient has more negatives, the probability of the pattern-identification being incorrect would increase.This is the first study to standardize oriental medical diagnostic pattern-identification of stroke patients in Korea. The following predictive logistic equation was set log (P/1 − P) = 3.021*(Reddened complexion) + 1.052* + 0.682*(Aversion to heat) − 1.388* + 0.727*(Thick fur) − 1.134*(Teeth marked tongue) + 1.295*(Strong pulse) − 1.122 (Thin pulse) − 0.972*(Slippery pulse) − 2.865. Among the positively quantified variables, reddened complexion, eyeball congestion, and aversion to heat are traditionally considered the indicators for Fire or Heat in oriental medicine. Thick fur and strong pulse are the indicators of the excessive patterns to which the Fire Heat Pattern belongs. Thus, the above mentioned positive variables seem reasonable. With the negatively quantified variables, the Fire Heat Pattern could be distinguished from the Phlegm Dampness Pattern by teeth marked tongue, and from the deficiency patterns by pale tongue and thin pulse. Some other variables considered as factors of the Fire Heat Pattern such as tongue sore, thirst, vexing heat in the extremities, reddish yellow urine, yellow fur, constipation, rapid pulse, and flooding pulse did not register statistical significance. These results might be because those variables could be related to more than two patterns at once. For example, constipation can be seen in both the Fire Heat Pattern and the Qi Deficiency Pattern.The Fire Heat Pattern is by pathogenic Fire characterized by intense heat that is apt to injure fluid, consume Qi, engender wind, induce bleeding, and disturb mental activities . In thisP/1 − P) = 0.578*(Overweight) − 0.754*(Fatigue) − 1.754* − 2.189*(Reddened complexion) − 2.719*(Flushed cheeks) + 1.496* + 2.365*(Slippery pulse) − 1.136. Slippery pulse was the most potent factor for determining the Phelgm Dampness Pattern, followed by pale tongue and overweight with the negatively quantified variables, the Phlegm Dampness Pattern could be distinguished from the Yin Deficiency Pattern by flushed cheeks, and from the Qi Deficiency Pattern by fatigue and pale complexion.In the Phlegm Dampness Pattern, which is characterized by its impediment to Qi movement and its turbidity, heaviness, stickiness, and downward flowing properties , the folP/1 − P) = −0.882*(Overweight) + 2.417* − 2.869*(Reddened complexion) − 2.252*(Flushed cheeks) + 1.451* − 1.577*(Night sweating) − 1.474*(Nausea) + 1.165* + 0.783*(Deep pulse) − 2.214*(Rapid pulse) + 0.993*(Vacuous pulse) − 2.572*(Slippery pulse) − 0.907. In this pattern, there were more negatively quantified variables than positively quantified variables. Thus, the exclusion of the other patterns was important. Overweight, thick fur, and slippery pulse were for the Phlegm Dampness Pattern, while reddened complexion and rapid pulse were for the Fire Heat Pattern.Qi is the basic element that constitutes the cosmos and, through its movement, changes and transformations. In the field of medicine, Qi refers both to the refined nutritive substance that flows within the human body as well as to its functional activities. Qi Deficiency generally leads to decreased visceral functions and lowered body resistance . The preP/1 − P) = 3.552*(Flushed cheeks) + 1.024*(Thirst) + 1.740* + 0.963*(Dry fur) + 0.982*(Rapid pulse) − 1.932*(Strong pulse) − 3.705. The variables, which are traditionally believed to be the indicators of the Yin Deficiency Pattern, were included in the equation, and these include flush cheeks, thirst, afternoon tidal fever, dry fur, and rapid pulse. However, thin pulse and heat in the palms and soles were not included, which might have been due to the relatively low frequency of such variables in the study data.Yin Deficiency indicates a pathologic change marked by deficiency of Yin with diminished moistening, calming, downbearing, and Yang-inhibiting function, leading to relative hyperactivity of Yang Qi . The equThe finding that Korean OM doctors take tongue and pulse diagnosis seriously into their consideration is notable because all the patterns in this study basically included tongue and pulse diagnosis in their final equations. The Fire Heat Pattern and the Yin Deficiency Pattern have more positively quantified variables than negatively quantified variables. Thus, if some symptoms or signs reflect heat, the pattern could be determined easily. The Phlegm Dampness Pattern has two simple criteria overweight and slippery pulse. The Qi Deficiency Pattern is an exclusive pattern composed of many negatively quantified variables. This pattern could be identified merely on the condition that the other patterns were excluded. Delphi method from OM doctors. They set the variables by asking OM doctors what factors they think of most in identifying pattern. Thus, their variables were mere repetitions of theories, without practicality. The questionnaires did not offer anything new. Recently, Kim et al. suggested a questionnaire for the Heat Pattern . Among tWith the results of this study, predictive logistic equations were suggested for four patterns the Fire Heat Pattern, the Phlegm Dampness Pattern, the Qi Deficiency Pattern, and the Yin Deficiency Pattern. These criteria would be helpful in determining the pattern of each stroke patient in clinics. However, further studies using large samples are necessary to validate and confirm these criteria.


Isolated systolic hypertension is a highly prevalent disease among the elderly. The little available evidence on the efficacy of nitrates for treating the disease is based on small experimental studies.We performed a multicenter, randomized, double-blind, phase III, placebo-controlled trial in 154 patients aged over 65 years with refractory isolated systolic hypertension. Patients were randomized to placebo or 40 mg/day of extended-release isosorbide mononitrate added to standard therapy and titrated to 60 mg/day at week 6 if blood pressure exceeded 140/90 mmHg.The primary objective was to assess the effect on clinical pulse pressure of extended-release isosorbide mononitrate added to standard therapy in patients aged over 65 years with refractory isolated systolic hypertension after 3 months of treatment.The secondary objectives were as follows: to quantify the effect of adding the study drug on central blood pressure and vascular compliance using the augmentation index and pulse wave velocity; to evaluate the safety profile by recording adverse effects  and the percentage of patients who had to withdraw from the trial because of adverse events; to quantify the percentage of patients who reach a clinical systolic blood pressure <140 mmHg or <130 mmHg measured by ambulatory blood pressure monitoring; and to quantify the change in pulse pressure measured by ambulatory blood pressure monitoring.Few clinical trials have been carried out to test the effect of oral nitrates on isolated systolic hypertension, even though these agents seem to be effective. Treatment with extended-release isosorbide mononitrate could improve control of systolic blood pressure without severe side effects, thus helping to reduce the morbidity and mortality of the disease.Number: 2012-002988-10EUDRACT  Hypertension is responsible for many deaths worldwide ,2. It isTreating ISH is beneficial, as it can reduce both cardiovascular morbidity and total mortality , even inNitrates have been used for many years to treat patients with angina pectoris, acute coronary syndrome, and acute lung edema. These agents are not generally used to treat hypertension, except in emergency cases, in which case they are used intravenously to produce a rapid decrease in blood pressure, although tachyphylaxis occurs within a few days of treatment. All nitrates, as donors of nitric oxide (NO), produce intense arterial vasodilation associated with direct effects on smooth muscle cells, by activating guanylyl cyclase to form cGMP, which inhibits calcium entry into the cell. The most common adverse events are headache and hypotension, although dizziness, nausea, fatigue, weakness, and tachycardia can also be observed.Currently available tools enable us to evaluate vascular function and central hemodynamics non-invasively. Central blood pressure (CBP) can be measured in larger arteries using pulse wave analysis, and available data suggest a closer relationship between CBP and cardiovascular morbidity and mortality . AdditioOur literature review revealed only five mini-trials assessing the effect of nitrates on blood pressure (BP) and control of ISH. Sample sizes were small and the studies were not performed in the context of refractory ISH -20. The Therefore, we designed a study to evaluate the effect on PP and vascular function  of the addition of extended-release isosorbide mononitrate to standard treatment in older patients with refractory ISH. Refractory hypertension is defined as uncontrolled hypertension in patients using three or more antihypertensive drugs (one of which is a diuretic) at the maximum dosage; we changed our protocol to include patients receiving low doses of diuretic and maintaining at least two more drugs, since most patients never use diuretics at the maximum dosage .If a beneficial effect is demonstrated, a study of morbidity and mortality would be justified.The addition of extended-release isosorbide mononitrate to standard antihypertensive treatment in patients with refractory ISH produces a positive effect on vascular function, resulting in reduced PP and improved CBP, AI, and PWV.The primary objective of our study was to compare the effect of extended-release isosorbide mononitrate on clinical PP with that of a placebo, in addition to the standard treatment, in patients over 65 with refractory ISH after 3 months of treatment.The secondary goals were as follows:1. To quantify the effect of extended-release isosorbide mononitrate on vascular function .2. To evaluate the safety profile by estimating the frequency, type, and severity of adverse events and the percentage of patients who had to withdraw from the study because of adverse events, in particular headache and orthostatic hypotension.3. To determine the percentage of patients who reach clinical SBP <140 mmHg in both treatments groups.4. To determine the percentage of patients who reach a 24-hour mean SBP <130 mmHg (measured using ambulatory blood pressure monitoring (ABPM)) in both treatment groups.5. To measure the change in PP using ABPM.Ours is a phase III, multicenter, randomized, double-blind, placebo-controlled trial performed in several primary care centers in the Regional Community of Madrid and in Hospital La Princesa, Madrid. The trial is registered in the EU Clinical Trials Register (EUDRACT Number: 2012-002988-10), and the protocol was approved by the Clinical Research Ethics Committee of the Regional Community of Madrid.The study was designed to evaluate the efficacy and safety of a marketed drug in a therapeutic indication different from that for which it is approved. The objective of the study was to evaluate, after 3 months of appropriate treatment, the effect of adding extended-release isosorbide mononitrate to standard treatment in patients with resistant ISH. No recommendations have been made on the treatment of these patients; therefore, we designed a study to compare the net effect of the study drug with that of placebo.The study population comprises patients aged ≥65 years of both genders attended at primary care centers or at the Hypertension Unit of Hospital La Princesa. All patients give their written informed consent to participate in the study. Patients are included if they meet all the inclusion criteria and none of the exclusion criteria. Table Variables reported for trial participants include the following:1. Demographic characteristics: sex, age, height, weight, body mass index, waist circumference, and smoking and drinking habits, at screening.2. Antihypertensive treatment and concomitant treatments, at screening.3. Medical history: presence of macrovascular or microvascular disease and diabetes mellitus or dyslipidemia.4. Laboratory tests: hematology and biochemistry with kidney and liver function markers to assess that the patient meets all the inclusion criteria (screening visit).5. BP measurement at baseline, 6 weeks, and completion  while seated and 1 minute after standing). Monitoring is performed between 8 am and 10 am, before patients take their medication.http://www.spacelabshealthcare.com/): mean of SBP, DBP, heart rate, and PP during activity and at rest (baseline and completion). Patients take their antihypertensive medication as usual.6. 24-hour ABPM .7. CBP, PWV, and AI at visits 1 and 3  at screening and at visits two and four.9. Side effects: any adverse event during administration of the study drug, in particular headache and orthostatic hypotension.Subject numbers are assigned sequentially as each patient enters the study. Subjects are assigned to the study drug through a randomization schedule based on the randomization plan. The study drug is stored under the conditions specified on the label in a locked, safe area of the pharmacy department to prevent unauthorized access.Both the study drug and the placebo are indistinguishable; they are manufactured by the same company and are similar in appearance, organoleptic characteristics, and presentation.In the event of an emergency, the investigator decides whether it is necessary to unblind the subject’s treatment assignment using the unblinding envelopes provided to the hospital and/or pharmacy. If unblinding is necessary, the investigator or study pharmacist must record the reason for unblinding, as well as the date and time of the event.During the study, the events considered sufficient reason for unblinding are as follows: admission to hospital or visit to the emergency department related to the study drug. The patients can be removed from the study without unblinding in the following circumstances: withdrawal of consent, major adverse event(s), ineligibility (arising either during the study or retrospectively after having been overlooked at screening), significant protocol deviation, disease progression requiring discontinuation of the study medication or inability to continue to comply with study procedures, loss to follow-up, or death. Each participant has the right to withdraw from the study at any time, for any reason, and with no repercussions for his/her medical care.In the case of unblinding, the analyses are based on an intent-to-treat population, which includes all randomized subjects. Because the percentage of lost participants was predicted in the calculation of sample size, lost patients need not be replaced during follow-up. The person analyzing the results remains blind to the patient’s group.When all of the procedures at the inclusion visit are performed, the patients are sent to the investigator responsible for assessing vascular function , randomization, and delivery of the study medication (12-week supply). Vascular function parameters are measured by the same trained investigator to ensure consistency and homogeneity.Before administration of the drug, the investigator explains the most common adverse events (headache and orthostatic hypotension) to the patient.After randomization, a single 40-mg dose of extended-release isosorbide mononitrate is administered between 9:30 and 10:30 am during the first 6 weeks. Study patients attend three visits after randomization. The first is at 6 weeks from baseline, when clinical parameters are assessed. These include BP (seated and standing), resting pulse, and the Morisky-Green test. All adverse events are recorded, regardless of their relationship to the study medication. If the objective (SBP <140 mmHg) is not reached, the dose is titrated to 60 mg/d (single dose); otherwise, the 40-mg dose is maintained.After 12 weeks of treatment, the study is considered to have finished, except in the case of patients who withdraw prematurely. At the final visit, the parameters recorded are PP, SBP, DBP, heart rate and ambulatory BP. Compliance is also evaluated using the Morisky-Green test, and the investigator questions the patient about adverse events, orthostatic hypotension, and other treatments taken during the study. Vascular function parameters  are measured between 2 and 5 days before the final visit while the patient is still taking the medication.Figure The study drug is considered effective if PP decreases significantly with respect to placebo according to the primary objective.Secondary efficacy is assessed based on the improvement in vascular function parameters, the percentage of patients achieving control of BP at the clinic and with ABPM, and the change in PP measured by ABPM. All objectives are measured based on the comparison of values from the baseline and final visits.The planning and conduct of this trial are subject to national legislation. The trial is performed in accordance with the Guidelines of the World Medical Association (WMA), the Declaration of Helsinki (1996), the Guidelines of GCP (CPMP/ICH/135/95), and the stipulations of national drug and data protection laws and other applicable regulatory requirements.The investigator is responsible for ensuring that no patient undergoes any study-related examination or activity before either the patient or the legal guardian has signed an informed consent document. Detailed information is provided to the patient/legal guardian before consent is given.The investigator must inform the patient of the aims, methods, anticipated benefits, and potential hazards of the study, including any discomfort it may entail. The investigator must inform patients that in providing informed consent, they are giving permission for representatives of the trial site coordinating investigator or regulatory authorities to inspect their medical records to verify the information collected. The patient must be given every opportunity to clarify any points he/she does not understand. Patients or legal guardians must sign and date the informed consent form. Patients who refuse to give or withdraw their written informed consent are either not included or do not continue to participate in the study.In accordance with Spanish legislation (RD 223/2004 of 6 February), a civil liability insurance policy has been taken out to cover possible adverse events arising from the study medication that could affect the trial subjects.The most common adverse events are headache, orthostatic hypotension, somnolence, dizziness, and asthenia. These generally disappear with continued treatment. Less common or rare adverse events include bradycardia, angina pectoris, acute hypotension and syncope, nausea, vomiting, exfoliative dermatitis, allergic reactions, and flushing. Overdose can produce hypotension, tachycardia, cyanosis, shock, seizures, vomiting, agitation, respiratory failure, bradycardia, and methemoglobinemia.The period for reporting an adverse event starts when the study drug is administered and ends with the last follow-up visit. The association between an adverse event and the trial medication must be classed as related or not related to the study drug by a study physician.Adverse events considered related to the study medication are monitored until resolution or until the event is considered stable. All related adverse events that result in a participant’s withdrawal from the study or are present at the end of the study should be monitored until resolution. It is left to the investigator’s clinical judgment whether or not an adverse event is of sufficient severity to warrant the participant’s withdrawal from treatment.This study is performed without an external sponsor under the coordination of the scientific committee and under the supervision of a safety committee, which is blind to the intervention. The safety committee is composed of three physicians, each of whom is an expert in hypertension. The committee also includes a biostatistician and expert in bioethics.t test for independent samples, with an α risk of 5%, the sample size for each group must be 64 patients. Considering losses of 20% of recruited individuals, which could weaken the sample for some secondary objectives, we decided to increase the sample size by this percentage, although all the tests are performed by intent to treat. For this reason, the final sample size for each group is 77 patients.Sample size is predetermined based on the effect the variable PP, which is the primary objective. According to the results of the Starmans-Kool trial , the PP The statistical analysis will comprise the following parts:1. In descriptive analysis of the sample, quantitative variables will be expressed as measures of central tendency (mean or median) and dispersion (standard deviation or interquartile range) for symmetrical distributions; normality will be tested using Kolmogorov-Smirnov test. Appropriate transformations will be applied in cases of a non-normal distribution. Qualitative variables will be expressed as proportions with their standard error.t test or Mann–Whitney test for quantitative variables and the Pearson chi-squared or Fisher exact test for qualitative variables. The main variables that could influence the result of this study at initiation are age, PP, SBP, and DBP. In the case of inequality, these factors will be treated as confounding variables in the final efficacy analysis.2. Baseline characteristics, especially those that could influence the results, will be compared using the 3. The differences between the means and their confidence interval (CI), or the median ratio and their CI, will be used as the main measure of the effect. The relative risk, absolute risk reduction, and relative risk reduction will be used as a measure of the effect for the qualitative variables. A 95% CI will be calculated for all estimations.4. To control for possible confounding variables, linear models or linear regression will be applied for dependent quantitative variables and logistic regression models for dependent qualitative variables.5. In all the analyses, the null hypothesis tested will be the lack of effect  between the experimental and the control groups. Missing data will be processed using a sensitivity analysis.6. As this is a two-arm, placebo-controlled, parallel study, no subgroups will be analyzed to measure secondary endpoints and no interim analysis will be performed.ISH remains difficult to control in many cases, despite the availability of various types of appropriate medication; however, most are able to reduce SBP, albeit with a considerable associated reduction in DBP. The consequent severe side effects, such as reduced coronary perfusion and orthostatic hypotension, limit treatment options.Hypertension continues to be the most important cardiovascular risk factor today, and cardiovascular illnesses are the main cause of death in developed countries, especially among people over 65.The results of our trial should demonstrate whether treatment with isosorbide mononitrate improves not only control of arterial pressure, but also vascular function in patients with refractory ISH. If our hypotheses are proved, a clinical trial with morbidity and mortality as the main end-points would be justified. Such a trial could also be used to investigate the long-term effects of this drug.Few clinical trials have been carried out to test oral nitrates in patients with ISH, even though these agents seem to be effective and have been used over long periods in the treatment of other illnesses, such as ischemic heart disease, hypertensive emergency, or acute lung edema.Our trial is performed on a collaborative basis between the hospital (center for recruitment and vascular function tests) and the primary care center, because most of these patients have their main contact with the health service through their primary care physicians. A collaboration of this type makes it easier to reach patients and provides more robust results with greater external validity.Our study is subject to three limitations. First, potentially high loss to follow-up because of non-fatal side effects; however, this is compensated for, as it was taken into account in the sample size calculation. Second, in the long term, patients could develop tolerance to nitrates, although this was not demonstrated in any of the trials we reviewed. Finally, our trial was not designed to demonstrate reductions in morbidity and mortality; rather, our main objective was to evaluate tolerance and effects on some intermediate variables.In conclusion, treatment of ISH with extended-release isosorbide mononitrate could improve control of SBP with minimal side effects, thus helping to reduce the morbidity and mortality of the disease.The trial is in the recruitment phase.AE: Adverse event; AI: Augmentation index; AR: Adverse reaction; BP: Blood pressure; CBP: Central blood pressure; CI: Confidence interval; CRF: Case report form; DBP: Diastolic blood pressure; ISH: Isolated systolic hypertension; NO: Nitric oxide; PP: Pulse pressure; PWV: Pulse wave velocity; SBP: Systolic blood pressure.All the authors declare that they have no competing interests.DAP participated in the design and coordination of the study, performed the vascular function measurements, and drafted the manuscript. BNA participated in the design and coordination of the study and helped to draft the manuscript. FJRS participated in the design of the study, performed the sample size calculations, and designed the statistical analysis. IGP participated in the design and coordination of the study and helped to draft the manuscript. As Principal Investigator, she also recruited patients. LMSG participated in the design and coordination of the study, performed the sample size calculations, and designed the statistical analysis. CVG participated in the design and coordination of the study. CSF conceived the study, participated in its design and coordination, and helped to draft the protocol and manuscript. She also recruited patients. All the authors read and approved the final version of the manuscript. The NISH group is composed of: Daniel Abad Pérez, María Jesús Fernández Luque, Ángela Gallego Arenas, Iluminada García Polo, Gema Gil Juberias, Amelia González Gamarra, Pilar Loeches Belinchón, Javier López González, Soledad Mayayo Vicente, Blanca Novella Arribas, Francisco José Rodríguez Salvanés, Lourdes Ruíz Díaz, Félix Mata Benjumea, Milagros González Béjar, Francisco López Corral, Marta Ruíz López, Rosa Sánchez Alcalde, Luis María Sánchez Gómez, Belén Sierra García, Carmen Suárez Fernández and Carmen Verge González. .EUDRACT Number: 2012-002988-10.


Ingestion of a meal increases the blood flow to the gastrointestinal organs and affects the heart rate (HR), blood pressure and cardiac output (CO), although the mechanisms are not known. The aim of this study was to evaluate the effect of endogenously released glucose, insulin, glucagon-like peptide 1 (GLP-1), ghrelin on CO, HR, stroke volume (SV), and blood pressure.2)) were included in this study. The CO, HR, SV, systolic and diastolic blood pressure, antral area, gastric emptying rate, and glucose, insulin, GLP-1 and ghrelin levels were measured.Eleven healthy men and twelve healthy women ((mean ± SEM) aged: 26 ± 0.2 y; body mass index: 21.8 ± 0.1 kg/mP < 0.05). In men, significant correlations were found between GLP-1 level at 30 min and SV at 30 min , and between ghrelin levels and HR  at 110 min. Significant correlations were also found between the change in glucose level at 30 min and the change in systolic blood pressure , and the change in SV  relative to the fasting in men. The insulin 0-30 min AUC was significantly correlated to the CO 0-30 min AUC  in men. Significant correlations were also found between the 0-120 min ghrelin and HR AUCs  in men. No statistically significant correlations were seen in women.The CO and SV at 30 min were significantly higher, and the diastolic blood pressure was significantly lower, than the fasting in both men and women (Physiological changes in the levels of glucose, insulin, GLP-1 and ghrelin may influence the activity of the heart and the blood pressure. There may also be gender-related differences in the haemodynamic responses to postprandial changes in hormone levels. The results of this study show that subjects should not eat immediately prior to, or during, the evaluation of cardiovascular interventions as postprandial affects may affect the results, leading to erroneous interpretation of the cardiovascular effects of the primary intervention.NCT01027507 Several kinds of postprandial cardiovascular changes have been reported in the literature. The postprandial blood flow in the superior mesenteric artery (SMA) seems to be approximately double the fasting value, and initiates an increase in cardiac output (CO) . PostpraThe autonomic innervation of the stomach and the heart is divided into the parasympathetic and sympathetic systems. The parasympathetic innervation is controlled by the vagus nerve, whose cell bodies are found in the brainstem. The vagus nerve consists of 20% efferent fibres and 80% afferent sensory fibres, which transmit information to the brain . The vag2 (range: 17.0-25.9 kg/m2)) without symptoms or a history of gastrointestinal disease, abdominal surgery or diabetes mellitus, were included in this observational study. The mean waist:hip ratio of the women was 0.74 ± 0.02 and of the men 0.87 ± 0.01. The subjects had no connective tissue disease or cerebrovascular or endocrine disease, and none was taking any medication, except four women who were taking oral contraceptives. Three men were snuff users and one was a smoker, while two of the women were snuff users. All subjects were recruited from the population of southern Sweden.Twenty-three healthy subjects  aged: 26 ± 0.2 y (range: 18-33 y); body mass index: 21.8 ± 0.1 kg/mNCT01027507.All subjects gave their written informed consent. The study was approved by the Ethics Committee of Lund University, and performed according to the Helsinki Declaration. The study started on 13 January 2009 and ended on 18 September 2009. The trial is registered in the US National Library of Medicine with the trial registration number The subjects were examined between 7.30 and 11.00 a.m. after an 8-h fast. Smoking and snuff-taking were prohibited 8 h prior to and during the examination. The fasting blood glucose concentration of each subject was measured on the day of the examination to ensure that it was normal (≤ 7.0 mmol/L). If the subjects reported gastrointestinal symptoms (diarrhoea or constipation) on the day of the study, the examination was postponed.The test meal consisted of 300 g rice pudding . The total caloric value of the meal was 330 kcal: 10% from protein (9 g), 58% from carbohydrates (48 g) and 32% from fat (12 g). The meal was ingested within 5 minutes. The gastric emptying rate (GER) was estimated using an ultrasound method described previously . The sonMeasurements of the gastric antrum were performed by the same radiologist. The abdominal aorta and the left lobe of the liver were used as internal landmarks in the measurements on the gastric antrum. The subjects were examined in the supine position, and were not allowed to sit up between examinations.2 × 0.785 × VTI, where VTI = left ventricular outflow tract velocity-time integral and D = left ventricular outflow tract diameter. CO was calculated as SV × Heart rate. A separate intra-observer variability study concluded low variability for CO and SV measurement (< 5%). Figure Blood pressure was measured in the supine position using a conventional  sphygmomanometer with an aneroid manometer and a stethoscope. Systolic pressure (first phase) was identified by the first of the continuous Korotkoff sounds. Diastolic pressure was identified as the moment the Korotkoff sounds disappeared (fifth phase). Transthoracic echocardiography examinations were performed with a Sonos 5500 ultrasound system  in the left lateral position, after 15 minutes' rest. A single observer performed all the echocardiography measurements. The left ventricular SV was measured, and the left ventricular CO was calculated according to current guidelines . The DopVenous blood samples were taken before and 15, 30, 45, 60, 90, and 120 after the start of the meal to measure glucose, insulin, GLP-1 and ghrelin levels. Dipeptidyl peptidase-IV inhibitor was added to the low pressure blood test bottles before collection of blood for GLP-1. We were not able to collect venous blood samples for the measurement of GLP-1 and ghrelin levels in 6 men and 3 women for technical reasons'. Blood glucose concentrations were measured with the HemoCue glucose system . The precision of this system is better than 0.3 SD between 0 mmol/L and 22.2 mmol/L. Insulin concentrations were measured using an immunoassay with an alkaline phosphatase conjugate . The sensitivity of the insulin immunoassay is 0.03 mUnit/L (mU/L), and the intra-assay coefficient of variation was below 10% between 0.03 mU min/L and 300 mU/L.Plasma ghrelin concentrations were determined using a radioimmunoassay kit (GHRT-89k) manufactured by Linco Research , which measures total ghrelin (intact as well as desoctanoylated). The sensitivity obtained was 100 pg/mL, and the intra-assay coefficients of variation were below 10%. Quality controls were always within acceptable limits. GLP-1 concentration in plasma was measured after extraction of plasma with 70% ethanol . The plasma concentrations of GLP-1 were measured against standards of synthetic GLP-1 7-36 amide using antiserum code no. 89390 , which iP < 0.025 after Bonferroni correction.All analyses were performed for men and women separately. Results are given as mean values and SEM, unless otherwise stated. The total areas under the curves (AUCs) were calculated for blood glucose, insulin, GLP-1, ghrelin, CO, HR, SV, and systolic and diastolic blood pressure in each subject using GraphPad Prism software . All other statistical calculations were performed in SPSS for Windows . Changes in the values of blood glucose, insulin, GLP-1 and ghrelin levels were calculated as the difference between the levels before the meal  and 30 and 120 min after the end of the meal. Changes in CO, HR, SV, and systolic and diastolic blood pressure were calculated as the difference between levels before the meal  and 30 and 110 min after the end of the meal. To determine whether the meal affected a given parameter, the fasting value was compared with the values 30 min and 120 min after the meal, using the Wilcoxon t-test. The values at 30 min and 120 min postprandially were also compared using the Wilcoxon t-test. The significance in differences between a given parameter in women and men was determined using the Mann-Whitney U test. Possible correlations between blood pressure, CO, HR, SV and levels of blood glucose, plasma insulin, GLP-1, ghrelin, or antral area were analysed with the Pearson correlation. The level of statistical significance was set at P = 0.023) and at 120 min in men (P = 0.004)  and women . The insulin level at 30 min was significantly higher than at 120 min in both men (P = 0.003) and women (P = 0.006). The insulin level at 120 min (P = 0.019) and insulin AUC 0-120 min (P = 0.019) were significantly higher in the women than men  were significantly higher in men than women. The ghrelin levels at 30 min and 120 min were significantly lower than the fasting in women (both P = 0.008)  and men (P = 0.003). The CO at 30 min was also significantly higher than at 110 min in both women and men (both P = 0.003). The CO at fasting and at 30 min was significantly higher in men than in women  . The HR at 110 min was significantly lower in men than women (P = 0.019)  and men (P = 0.003). The SV at 110 min was significantly higher than the fasting in women (P = 0.016). The SV at 30 min was significantly higher than at 110 min in both women (P = 0.008) and men (P = 0.005). The SV at fasting, at 30 min and at 110 min was significantly higher in men than women (P = 0.000) . The AUCs for HR 0-30 min were 1771 ± 59 in men, and 979 ± 39 beats in women. The AUCs for HR 0-120 min were 6408 ± 202 in men, and 7237 ± 313 beats in women. The AUCs for HR 0-30 min (P = 0.000) and HR 0-110 min (P = 0.000) were significantly lower in men than women.The CO at 30 min was significantly higher than the fasting in both women  Figure . The HR ) Figure . The SV ) Figure . The AUCP = 0.004, P = 0.013, respectively)  and men (P = 0.012). The diastolic blood pressure at 30 min was significantly lower than at 110 min in the women (P = 0.006). The diastolic blood pressure at fasting was significantly lower in the women than in the men (P = 0.001) , and diastolic blood pressure: 0-30 min (P = 0.002) were significantly higher in the men than the women.The systolic blood pressure at fasting, and at 110 min was significantly higher in the men than the women  Figure . The dia) Figure . The AUCP = 0.015, r = 0.946). There were also significant correlations between ghrelin levels and HR  at 110 min.Statistically significant correlations were only found in men. Significant correlations were found between GLP-1 level at 30 min and SV at 30 min , and the change in SV  relative to the fasting. The insulin 0-30 min AUC was significantly correlated to the CO 0-30 min AUC . Significant correlations were also found between the 0-120 min ghrelin and HR AUCs Significant correlations were also found between the change in glucose level at 30 min and the change in systolic blood pressure (The aim of this study was to evaluate the effect of endogenously released glucose, insulin, glucagon-like peptide 1, ghrelin on CO, HR, SV, and blood pressure. Our hypothesis was that the intake of food would change the activity of the heart due to postprandial changes in the antral area, and levels of glucose, insulin, GLP-1 and ghrelin. We were able to partly verify this hypothesis. The results of the study show that postprandial CO and SV increased in both men and women. The ingestion of food decreased the diastolic blood pressure, without affecting the systolic blood pressure. In men, the postprandial changes in glucose levels were positively correlated to systolic blood pressure, the GLP-1 levels to SV, the insulin levels to CO and the ghrelin level to HR. To our best knowledge, this is the first study to examine at the effect of, endogenously released insulin, glucagon-like peptide 1, ghrelin levels on CO, SV, HR, systolic and diastolic blood pressure in both men and women.In our study, the ingestion of food led to a decrease in the diastolic blood pressure, without affecting the systolic blood pressure. Previous studies have shown that gastric distension influences blood pressure, probably due to activation of the gastrovascular reflex in patients with autonomic failure -24, and In a previous study on two men and two women, Waaler reported postprandial increases in CO and SV, which were explained by an increase in HR . In a slIn the present study, it was found that postprandial changes in glucose and GLP-1 levels were positively correlated to SV, and that insulin levels were positively correlated to CO in men. Intravenous insulin administration has previously been reported to increase the CO before any significant decrease in glucose levels was seen, in six healthy male subjects . A dose-We observed significantly greater changes in GLP-1 levels, compared with fasting values, in the men than in the women in this study. The reason for these differences is not known, but could be related to the fact that we did not observe any correlations between postprandial GLP levels and haemodynamic responses in women. We observed no differences in ghrelin levels between the genders, but the ghrelin levels were correlated to the HR in the men in this study. It has been suggested that ghrelin suppresses sympathetic activity . IntravePostprandial haemodynamic responses in men and women were analysed separately in this study as there are known gender differences in heart function -45. TherThe present study had some limitations: the small sample size of healthy young subjects and the fact that it was not possible to perform the echocardiography or gastric ultrasound examinations at the same time. However, the measurements of the gastric antrum and the heart were performed by the same radiologist. The results of the echocardiography examinations were stored digitally and analysed at a later date in an attempt to avoid bias.This study shows that postprandial CO and SV increase in both men and women. Ingestion of food decreased the diastolic blood pressure without affecting the systolic blood pressure or heart rate in healthy subjects. Physiological changes in the levels of glucose, insulin, GLP-1 and ghrelin may influence the activity of the heart and the blood pressure. There may also be gender-related differences in the haemodynamic responses to postprandial changes in hormone levels. Subjects undergoing evaluation of cardiovascular interventions should therefore refrain from eating before or during such examinations, as postprandial affects may affect the results, leading to erroneous interpretation of the cardiovascular effects of the primary intervention.AUCs: areas under the curves; CO: in cardiac output; GER: gastric emptying rate; GLP-1: glucagon-like peptide 1; HR: heart rate; HRV: heart rate variability; LVEF: left ventricular ejection fraction; SMA: superior mesenteric artery; SV: stroke volume.The authors declare that they have no competing interests.The authors' contributions were as follows: JH and MD designed the study; JH was responsible for recruiting the subjects. OB performed the ultrasound examinations; MD performed the echocardiographic examinations; JH, SL, and MD carried out the statistical calculations. JH and MD wrote the first draft of the manuscript, and SL and OB made critical revisions of the manuscript. All authors read and approved the final manuscript.


Both end-tidal carbon dioxide pressure (ETCO2) is used routinely as an indicator of arterial partial pressure of carbon dioxide (PaCO2) and thus adequacy of ventilation. Accurate determination of the PaCO2 level in neuroanesthesia is quite important because of its effect on cerebral blood flow and also hyperventilation is often used to reduce intracranial pressure in neurosurgical patients. This study was aimed to evaluate the relationship between ETCO2 and arterial PaCO2 in neurosurgical patients undergoing craniotomy to assess the predictive value of ETCO2 as an indicator of PaCO2 level.Forty-five consecutive adult patients with inclusion criteria, scheduled to undergo elective craniotomy surgery were enrolled in this prospective study. Measurements of PaCO2 and ETCO2 were performed at three different intervals: Time 1: 10 min after induction of general anesthesia; time 2: after cranium opening prior to dural incision; and at time 3: start of dural closure. All patients received the same anesthetic agent . Data were initially analyzed using Pearson’s Correlation to assess the relationship between PaCO2 and ETCO2 at different stages of the operation. A p-value (P) of less than 0.05 was considered significant. The agreement between the measures of CO2 was assessed using Bland-Altman method, where mean difference and average between PaCO2 and ETCO2 were calculated. The 95% confidence intervals for the lower and upper limits of agreement were presented.A total of 44 patients, aged 18 to 65 years, ASA grades 1 and 2 were participated in the study. Mean difference, standard deviation and correlation coefficient of the parameters were calculated for three time periods. The values for PaCO2, ETCO2, (PaCO2- ETCO2), and correlation coefficient for 10 min after anesthetic induction, prior to dural incision, and start of dural closure were 35.4 ± 3.2, 32.1 ± 3.2, 3.8 ± 2.1, and 0.565, 36.2 ± 3.1, 32.6 ± 3.2,4.8 ± 3.1, and 0.574, and 36.7 ± 2.4, 33 ± 3.2,3.8 ± 2.3, and 0.627, respectively . The greatest mean difference occurred just prior to dural incision. The lowest mean difference was observed at 10 min post-anesthetic induction. To the present study was aimed to correlate between End-tidal and arterial carbon dioxide partial pressure in neurosurgical patients undergoing craniotomy. Findings of this study showed that ETCO2 consistently underestimates the value of PaCO2 during craniotomy indicating that ETCO2 value can be used instead of PaCO2.End-tidal carbon dioxide pressure, Arterial partial pressure of carbon dioxide, Craniotomy


Furthermore, these measures can be made increasingly more sensitive and specific if coupled to other "traditional" measures of organ perfusion, such as blood lactate levels.Recent interest in functional hemodynamic monitoring for the bedside assessment of cardiovascular insufficiency has heightened. Functional hemodynamic monitoring is the assessment of the dynamic interactions of hemodynamic variables in response to a defined perturbation. Accordingly, fluid responsiveness can be predicted in a quantities fashion by measuring as arterial pulse pressure variation and left ventricular stroke volume variation during positive pressure breathing or the change in cardiac output response to a passive leg raising maneuver. However, volume responsiveness, though important, reflects only part of the overall spectrum of functional physiological variables that can be measured to define physiologic state and monitor response to therapy. Dynamic tissue O Recently, increased interest in a more proactive use of monitoring technologies has emerged, using the response to the measured variables to a defined stress to unveil the physiological state of the subject. This entire field when applied to the assessment of cardiovascular state is referred to as functional hemodynamic monitoring. Within this context, we can define functional hemodynamic monitoring as the assessment of the dynamic interactions of hemodynamic variables in response to a defined perturbation . Such dyA primary resuscitation question is whether the patient will increase their cardiac output in response to intravascular volume infusion. Volume responsiveness has been arbitrarily defined as ≥15% in cardiac output in response to a 500-ml bolus fluid challenge. Although the presence of fluid responsiveness in a subject does not equate for the need to give fluids, it does define that if fluids are infused cardiac output will increase. Many studies have validated, during recent years, the usefulness of some methods that give the clinician the ability to predict whether a patient is going to respond to the volume infusion as a primary step of the hemodynamic resuscitation. Some of the most commonly used methods are those based in changes in left ventricular output during positive pressure ventilation, such pulse pressure variation (PPV) and stroke volume variation (SVV). During the inspiratory phase of positive pressure ventilation, intrathoracic pressure increases passively, increasing right atrial pressure and causing venous return to decrease, decreasing right ventricular output, and after two or three heart beats, left ventricular output if both ventricles are volume responsive . Thus, iAlthough powerful diagnostic tools, these parameters are highly dependent on the cyclic changes in intrathoracic pressure being regular and great enough to alter central venous pressure. Thus, tidal volumes of ≤6 ml/kg or the imposition of variable spontaneous inspiratory efforts often result in false-negative PPV and SVV values. Moreover, all of these techniques assume a fixed heart rate, so in the setting of atrial fibrillation or frequent premature ventricular contractions, these measures become inaccurate. In these settings, one can always perform a passive leg raising maneuver .Fluid therapy is one of the first steps in the goal-directed therapy in clinical guidelines of hemodynamic resuscitation of patients in shock ,7. Thus,2 delivery relative to the metabolic demands. Shock can be, in the early stages, compensated by autonomic mechanisms, such regional vasoconstriction, in an attempt to maintain central blood pressure and vital organ perfusion above an anaerobic threshold. In this stage of compensated shock, microcirculatory measures, such as arterial pressure or cardiac output often are inside the range of values defined as normal and, therefore, insensitive as early predictors of subsequent decompensation due to the increased risk of tissue ischemia and subsequent development of multiorgan failure and death. However, microcirculation alterations in muscle and skin blood flow already occur during these early stages and measures of tissue cardiovascular reserve should be a sensitive early warning measure of impending cardiovascular collapse. Thus, a valid method to assess the microcirculatory status, such as the noninvasive measurement of tissue oxygen saturation (StO2) when coupled with a functional hemodynamic monitoring test, such as the vascular occlusion test (VOT), may allow early identification of compensated circulatory shock and thus guide initial resuscitation efforts.Cardiovascular insufficiency is characterized by an inadequate O2 using near-infrared spectroscopy has been shown as a valid method to assess the microcirculation status, especially in septic and trauma patients. The absolute StO2 value has a limited discriminating capacity because StO2 remains within the normal range until shock is quite advanced. But the addition of a dynamic ischemic challenge, such as the VOT, improves and expands the predictive ability of StO2 to identify tissue hypoperfusion , could be useful to identify those patients who still were inadequately resuscitated. Patients with [P(cv-a)CO2] higher than 6 mmHg had a lower cardiac index, a larger clearance of lactate, and a slower decrease of SOFA score in the first 24 h than patients with a [P(cv-a)CO2] lower than 6 mmHg [These studies show that microcirculation status, measured by a dynamic test, such the StOe et al.  proved tn 6 mmHg .2 >70% and lactate concentration ≤2 mmol/L by improving the oxygen delivery in postsurgical patients whose lactate levels were high or did not decrease showed a shorter hospital stay and lower morbidity [2 as a goal, as well as CVP and MAP, showed no difference for in-hospital mortality.The presence of cardiovascular insufficiency in patients with shock also can be assessed by metabolic products, such as lactate or strong ion difference (SID). The early presence of high levels of plasma lactate is associated with higher in-hospital mortality in patients presenting with circulatory shock ,17. Moreorbidity . A more orbidity  focused 2) that independently determine the pH. It has been proven that the SID is useful to identify patients with major acid-base disturbances even when the standard base excess is normal [In addition to the creation of lactate, tissue hypoperfusion due to cardiovascular insufficiency induces formation of anions as results of anaerobic metabolism and, finally, acidosis. The anion gap and, especially, the SID calculated as the difference between fully dissociated anions and cations, may help to evaluate those cases of metabolic disorders with acidosis adding the possibility to quantify the contribution of each metabolic disorder and to know the source of the acidosis. The approach, based on the principles described by Stewart , proposes normal . Neverths normal ,22.Functional hemodynamic monitoring is the pluripotential approach to interpolation of physiological data in a proactive form. It has acquired a strong foothold in assessment of volume responsiveness for the management of the critically ill patient, showing a high applicability in shock resuscitation, but needs to be considered within the broader aspects of risk stratification to reach its full potential. Because early goal-directed therapy algorithms need to resuscitate to circulatory sufficiency, defining endpoints become as important as defining treatments to initiate. This field is rapidly expanding and has potential application for assessment of regional perfusion and function and across all acute care disciplines.Xiame Garcia declares that he has no competing interests. Michael R. Pinsky is a consultant for Edwards LifeScieince, LiDCO Ltd, Cheetah Medical, Inc., has stock options with LiDCO Ltd., and has been paid to present a lecture by Edwards LifeScieinces, LiDCO Ltd and Hutchinson, Industries.XG wrote the original version of the manuscript after consultation with MRP. MRP defined the scope of the manuscript and wrote all the revisions of the manuscript to final form.


Background. The aim of the present study was to assess the value of electromagnetic programmable shunt valves for the treatment of subdural collections. Methods. Adult patients with hydrocephalus of various causes that were treated with programmable shunt valves during the last ten years were retrospectively studied. In 127 patients, 139 electromagnetic programmable shunt valves were implanted. Results. A nontraumatic subdural fluid collection was detected in 12 patients. The treatment of these patients consisted of reprogramming of the valve's opening pressure. In 5 patients small subdural hematomas were detected; 4 of these patients were treated by raising the opening pressure alone and one patient required surgical drainage and change of the pressure setting. Traumatic chronic subdural hematomas were detected in 6 patients. These patients were treated by surgical drainage and readjustment of the valve's opening pressure. Conclusion. The ability to treat a shunt-related complication, such as a subdural fluid collection, by reprogramming the valve's opening pressure to a higher setting is an advantage over nonprogrammable valves, and it enables the opening pressure to be slowly lowered once the fluid collection is reabsorbed. Based on our results, we believe that programmable shunt valves should be preferred. Programmable shunt valves have been used for the treatment of hydrocephalus of various causes . Theses Over a 7-year period, 139 electromagnetic programmable shunt valves were implanted in 127 adult patients. There were 68 (53.5%) males and 59 (46.5%) females, mean age 56.7 ± 17.8 years, ranging from 18 to 89 years. In all patients the distal catheter of the shunt was placed in the peritoneal cavity. The opening pressure settings at the time of implantation were selected on the basis of patient's age, diagnosis, and duration of the underlying disease. The initial setting was adjusted while the valve was in its sterile blister package. The underlying conditions that prompted the placement of a shunt valve system are summarized in All patients had a minimum 2-year follow-up. During this period, in twelve cases (8.6%) the shunt system was replaced. The replacement was due to shunt infection (25%), blockage by protein clots (25%), proximal catheter obstruction (16.67%), proximal catheter suboptimum position (16.67%), and shunt malfunction, due to difficulty in adjusting the opening pressure (16.67%). Possible causes of adjustment failure were early removal of the programming unit's transmitter and difficulty in accurately positioning the transmitter.2O in steps of 10 mm H2O. This spares the patient from undergoing reoperation to achieve pressure adjustments.Adjustments of the valve's opening pressure were made in accordance with clinical or radiological findings obtained during the postoperative period. Changing the polarity of the magnetic field surrounding the valve allows transcutaneous adjustment of the opening pressure, of a programmable valve, in a range from 30 to 200 mm HA nontraumatic subdural fluid collection (hygroma) was detected in 12 (9.4%) patients. The treatment in these cases consisted of reprogramming the valve's opening pressure. No surgery was required in all cases. In 5 patients small subdural hematomas were detected; 4 of these patients were treated by raising the opening pressure alone and one patient required surgical drainage and change of the pressure setting. Traumatic chronic subdural hematomas were detected in 6 patients. These patients were treated by surgical drainage and readjustment of the valve's opening pressure.2O. Four weeks later a subdural hygroma was detected on follow-up CT (2O. Six weeks after the adjustment the hygroma was resolved (A 65-year-old patient developed hydrocephalus after treatment of a right cerebelopontine angle tumor . The patow-up CT . The valresolved .2O was placed. Twenty-three months later and 3 months after a minor head injury the patient presented with headache. CT scan was performed and revealed bilateral traumatic chronic subdural hematomas (2O. Two days after the operation a CT was performed (2O.A 73-year-old patient presented with symptoms suggestive of normal pressure hydrocephalus. Brain CT revealed enlarged ventricular system . A progrematomas . Bilatererformed . Two weeerformed . The valThe present study showed that when electromagnetic programmable valves are implanted and a shunt-related complication occurs, the surgeon has the option for a noninvasive reprogramming of the valve's opening pressure. This may be sufficient for the treatment of a subdural collection.The valve's opening pressure is the most important factor in determining CSF drainage. Subdural effusions occurred in 71% of patients with a low pressure shunt and in 34% of patients with a medium pressure shunt . It is dNevertheless, programmable valves are more expensive compared to nonadjustable valves. However, the expenses of CSF shunt valves comprise only a small part when compared with the total cost of treatment and care of patient with hydrocephalus . The lifIn conclusion, subdural fluid collections, such as hygromas and hematomas, are common complications in hydrocephalic patients treated with shunt valve systems. When electromagnetic programmable valves are used, the surgeon may noninvasively readjust the valve's opening pressure to a higher setting, if a shunt-related complication occurs. This is an advantage compared to fixed-pressure valves and enables the opening pressure to be slowly lowered once the subdural fluid collection is reabsorbed. Because we cannot predict which patient will need an adjustment later in his lifelong treatment, therefore our suggestion is the usage of programmable shunt valves in all conditions that require CSF drainage.