Guidelines recommend that a mean arterial pressure (MAP) value greater than 65 mm Hg should be the initial blood pressure target in septic shock, but what evidence is there to support this statement? We searched Pubmed and Google Scholar by using the key words ‘arterial pressure’, ‘septic shock’, and ‘norepinephrine’ and retrieved human studies published between 1 January 2000 and 31 July 2014. We identified seven comparative studies: two randomized clinical trials and five observational studies. The results of the literature review suggest that a MAP target of 65 mm Hg is usually sufficient in patients with septic shock. However, a MAP of around 75 to 85 mm Hg may reduce the development of acute kidney injury in patients with chronic arterial hypertension. Because of the high prevalence of chronic arterial hypertension in patients who develop septic shock, this finding is of considerable importance. Future studies should assess interactions between time, fluid volumes administered, and doses of vasopressors. The blood pressure value that should be targeted during the management of septic shock is an important clinical issue. The mean arterial pressure (MAP) is one of the first variables that is monitored in these patients, and manipulation with vasopressor agents is relatively easy. Prolonged hypotension, defined as a MAP of less than 60 to 65 mm Hg, is associated with poor outcome ,2.per se. We reviewed the published data related to MAP targets in septic shock and discuss the clinical implications.The Surviving Sepsis Guidelines recommend that vasopressor therapy initially target a MAP of 65 mm Hg (grade 1C recommendation)  but thatSeptic shock is characterized by both vasodilation and cardiac dysfunction, leading to a decrease in blood pressure. Hypotension generates organ failure due to hypoperfusion, with the MAP reflecting the driving pressure at the organ level. The goal of resuscitation is to restore adequate organ perfusion . In healthy individuals, blood flow remains constant over a large range of blood pressures, at least in the brain and the kidney. For many years, researchers have hypothesized that this autoregulatory mechanism is impaired in septic shock -7, so thThe microcirculation is markedly altered in septic shock ,11. AlteThese concepts are based on the theoretically linear relationship between pressure and flow in septic states Figure . To reacExperimentally, increasing arterial pressure excessively has harmful effects. In an ovine model of septic shock, Corrêa and colleagues  showed tPubmed and Google Scholar were searched by using the key words ‘arterial pressure’, ‘septic shock’, and ‘norepinephrine’. The search was limited to studies published between 1 January 2000 and 31 July 2014. Only randomized clinical trials, comparative studies, and observational studies were analyzed; reviews and editorials were excluded as were animal studies and studies published in languages other than English.We identified 12 studies; seven were comparative studies determining the effect of different goals of blood pressure on outcome  imaging, Dubin and colleagues  increasepost hoc analysis, Dünser and colleagues [In two of the observational studies, MAP levels of less than 60 to 70 mm Hg were independent determinants of mortality ,2. Howevlleagues  found node novo atrial fibrillation in the high-target group . Chronic arterial hypertension was reported in 44% of patients, and in a predefined stratum analysis of these patients, targeting a MAP of 80 to 85 mm Hg was associated with better renal function . However, as also reported in one of the observational studies [In a large randomized clinical trial of 776 patients, Asfar and colleagues  compared studies , there w studies  was thatper se may have impacted outcomes in that not only was the level of MAP altered but also the dosages of vasopressors. One of the observational studies analyzed the interactions between MAP, norepinephrine load, and outcome [per se, was associated with impaired outcomes. This limitation, which is related to the design of these studies, makes it difficult to differentiate between the effects of blood pressure and those of norepinephrine.In the comparative studies, the doses of norepinephrine were increased by about 63% in order to increase MAP from 65 to 85 mm Hg -24. Henc outcome . The norMAP may be a relevant goal for improving outcomes in septic shock but, although in general a low-MAP target strategy seems to be similar to a high-target strategy in terms of outcomes , a singlA 1-day audit of intensive care practice showed that a MAP goal was pre-fixed in only 70% of patients with septic shock . In mostCentral venous pressure (CVP) is often inaccurate for predicting the need for volume expansion -35. HoweIt has been suggested that the microcirculation could be a critical end-point for resuscitation of septic shock. Microcirculatory assessment has been facilitated by the development of non-invasive devices, such as SDF imaging or near-infrared spectroscopy -39. SeveThe results of the SEPSISPAM  study  suggest Our results encourage the development of monitoring at the bedside to help determine the optimal level for each individual, although whether an individual-based approach will result in better outcomes than a protocol-based approach targeting a pre-determined level of MAP in all patients remains to be demonstrated . ImportaIn heterogeneous populations of patients with septic shock, there is no difference in survival rates for target mean arterial pressure levels of between 65 and 85 mm Hg.In patients with a history of arterial hypertension, a mean arterial pressure level of greater than 75 mm Hg may protect against progression to acute kidney injury.


Current therapy directed at delaying the progression of diabetic nephropathy includes intensive glycemic and optimal blood pressure control, renin angiotensin-aldosterone system blockade and multifactorial intervention. However, the renal protection provided by these therapeutic modalities is incomplete. There is a scarcity of studies analysing the nephroprotective effect of antihyperglycaemic drugs beyond their glucose lowering effect and improved glycaemic control on the prevention and progression of diabetic nephropathy. This article analyzes the exisiting data about older and newer drugs as well as the mechanisms associated with hypoglycemic drugs, apart from their well known blood glucose lowering effect, in the prevention and progression of diabetic nephropathy. Most of them have been tested in humans, but with varying degrees of success. Although experimental data about most of antihyperglycemic drugs has shown a beneficial effect in kidney parameters, there is a lack of clinical trials that clearly prove these beneficial effects. The key question, however, is whether antihyperglycemic drugs are able to improve renal end-points beyond their antihyperglycemic effect. Existing experimental data are post hoc studies from clinical trials, and supportive of the potential renal-protective role of some of them, especially in the cases of dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter 2 inhibitors. Dedicated and adequately powered renal trials with renal outcomes are neccessary to assess the nephrotection of antihyperglycaemic drugs beyond the control of hyperglycaemia. Diabetes mellitus (DM) is the leading cause of end stage renal disease in the world. According to the latest figures from the International Diabetes Federation, 382 million people live with diabetes around the world  and apprCurrent therapy directed at delaying the progression of diabetic nephropathy includes intensive glycemic and optimal blood pressure control, proteinuria and albuminuria reduction, interruption of the renin angiotensin-aldosterone system through the use of angiotensin converting enzyme inhibitors and angiotensin type-1 receptor blockers, along with dietary modification and cholesterol-lowering agents , includiThe exact pathogenesis of diabetic nephropathy (DN) is multifactorial, complex and not completely understood. Evidence of that is that an increasing number of studies have indicated that certain diabetic patients do not present the same evolution as was then defined: for example, some often have significant initial deterioration of glomerular filtration rate whereas, in others, microalbuminuria is reduced spontaneously. Chronic kidney disease may be accompanied, rather than preceded, by macroalbuminuria, or it may develop in patients with microalbuminuria or even in those with albuminuria levels that revert to normal. In fact diabetic kidney disease without proteinuria is increasingly recognized .The classic term “diabetic nephropathy” has shifted to a new one “diabetic chronic kidney disease” (DCKD) . From heIntensive control of glycemia and of blood pressure are effective in both preventing the onset and reducing the progression of albuminuria and DN. Antihypertensive agents differ significantly in their albuminuria-lowering capacity despite having similar blood pressure lowering potency. Renin-angiotensin-aldosterone system (RAAS) inhibitors have been shown to be more effective than other drugs. Multifactorial intervention has also been shown to be effective and intensive treatment has demonstrated a 61% reduction in the risk of developing macroalbuminuria and a 55% reduction in the cardiovascular composite end point when the intensive treatment group is compared to the conventional care group . HoweverThis article analyzes the exisiting data about older and newer drugs as well as the mechanisms associated with hypoglycemic drugs, apart from their well-known blood glucose lowering effect, in the prevention and progression of diabetic nephropathy. Most of them have been tested in humans, but with varying degrees of success. Although some of them have shown promising results, in most cases clinical trials in humans are lacking or have resulted in failure  was a milestone in delaying the onset and slowing up the progression of DN in patients with type 1 DM . The Uniet al. [Pilz et al.  analyzinTo sum up, intensive glycemic treatment in both type 1 and type 2 DM reduces the risk and progression of early DCKD, but no data exists as to the specific nephroprotective properties of insulin therapy apart from the benefits derived from blood glucose control.Metformin is a biguanide drug that improves sensitivity to insulin, increases insulin-stimulated uptake and utilization of glucose, reduces basal hepatic glucose production, causes weight reduction and decreases hunger. It is a well-established drug for the treatment of type 2 DM and there are more than 40 million patient years of experience in the past 50 years . EvidencIn addition to the cardiovascular benefit, some experimental studies have also suggested that metformin has nephroprotective properties. Metformin, in rats, reduces vascular dysfunction and protects against tubular injury induced by gentamicin , by moduDespite these cardiovascular benefits of metformin and the experimental data about nephroprotection, no study has shown any benefit with the use of metformin for renal end points in patients with diabetes mellitus.There is a lack of studies about the renal effects of sulphonylureas on DCKD. Very recently, an experimental study has investigated the effect of implanting micro-osmotic pumps containing gliquidone into the abdominal cavities of rats with DN . When coA great limitation of the study is the fact that administration of gliquidone via a micro-osmotic pump probably differs from oral administration in terms of therapeutic efficacy. A higher plasma concentration might be obtained with the use of a micro-osmotic pump. If this is the case, the renal excretion of gliquidone will be higher and the glomerular and tubular effects might be more apparent. As a result, it may be difficult to control diabetic nephropathy and lower urinary protein through oral administration of gliquidone.Another study compared the effect of rosiglitazone, metformin, or glyburide in 4351 recently diagnosed type 2 diabetic patients followed up over 5 years . Only roWhether these effects would have translated into microvascular and, perhaps more importantly, macrovascular protection is unknown, since the study was not designed to assess these long-term outcomes.In the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) study, a combined approach of routine blood pressure lowering and intensive glucose control resulted in substantial reductions in major renal events and all-cause death . The absNo other studies have analyzed the effect of sulphonylureas on the development or progression of DN.Alpha-glucosidase inhibitors such as acarbose slow down carbohydrate digestion and primarily reduce postprandial hyperglycemia, thereby offering an additional therapeutic approach in the long-term treatment of type 2 diabetes.Although there have been no reported direct effects on DN associated with acarbose treatment, extrapolating data from experimental animal studies suggests that this drug can favourably influence cardiovascular risk factors. Acarbose treatment up-regulates glucagon-like peptide-1 (GLP-1) production, insulin-like growth factor-I (IGF-I) and modulates fibroblast growth factor . Neverthvs. placebo. After three years, acarbose significantly improved glycemic control irrespective of concomitant therapy for diabetes, with a high percentage of flatulence, 30% vs. 12% reported in the placebo group. Urine albumin and insulin sensitivity were not significantly different at any time during the study [An analysis from UKPDS studied 1946 type 2 diabetes mellitus patients comparing acarbose he study .Although two glinides are available, nateglinide and repaglinide, this latter has a more extended use and may be prescribed in patients with differing degrees of renal insufficiency since it is mainly metabolised by the liver. There is a lack of studies analyzing the effect of glinides on albuminuria or the progression of DN.In order to analyze the effect on hyperfiltration and nitric oxide bioavailability, nine patients newly diagnosed with type 2 DM without microalbuminuria were randomized to a treatment with rosiglitazone or nateglinide, each for 12 weeks . Ten heaRosiglitazone ameliorated glomerular hyperfiltration in early type 2 diabetes and improved nitric oxide bioavailability. No other renal parameters were analized when nateglinide and rosiglitazone were compared. No other studies have tested the effect of glinides on DN.Thiazolidinediones are oral antidiabetic compounds that decrease insulin resistance and stimulate the peroxisome proliferator-activated receptor (PPAR-γ), a nuclear receptor present in various tissues. Apart from improving glycemic control, many background and clinical studies have shown that thiazolidinediones have beneficial effects on other components of metabolic syndrome and cardiovascular risk factors. Moreover, accumulating evidence suggests that these agents may have renal benefits.Animal studies show that thiazolidinediones decrease urine protein excretion and prevent glomerulosclerosis and tubulointerstitial fibrosis ,30 and rA number of human studies have also examined the renal effects of thiazolidinediones on patients with diabetes. Some of them reported significant decreases in urine albumin excretion ,34,35, wA meta-analysis that includes 15 studies (five with rosiglitazone and 10 with pioglitazone) involving 2860 patients showed that treatment with thiazolidinediones significantly decreases urinary albumin and protein excretion in patients with diabetes .Nevertheless, the discrepancy between the conflicting results in clinical studies could perhaps be explained by the fact that the risk of albuminuria among patients with type 2 DM, seems to be modulated by, among other factors, the presence of the PPARG-γ2 P12A polymorphism variant. A reduced risk of albuminuria is significantly associated with this phenomenon ,38. ThisSeveral mechanisms have been described to explain the association of thiazolidinediones with renal benefit including improving insulin sensitivity by inhibiting the release of free fatty acids, inhibition of tumor necrosis factor-α, stimulating the production of several insulin-sensitizing adipokines, including adiponectin and visfatin ,35,37,38The favorable renal effect of thiazolidinediones on type 2 DM is not completely dependent on their insulin-sensitizing action. Metformin produces similar glycemic control but has practically no effect on urinary albumin excretion ,38.Finally, it is also worth mentioning that rosiglitazone treatment has been shown to cause severe side effects, such as weight gain, fluid retention, and increased cardiovascular risk and it has been withdawn from the market . PioglitDespite the possible benefits of thiazolidinediones in delaying the progression of DCKD, it is important to determine whether the benefit of using pioglitazone outweighs the risks, especially in patients with chronic kidney disease.Incretin-based therapies in the treatment of patients with type 2 DM include the orally active dipeptidyl peptidase-4 (DPP-4) inhibitors (gliptins) and the injectable glucagon-like peptide-1 (GLP-1) receptor agonists. Both share the same mechanism of action, stimulating insulin secretion and inhibiting glucagon secretion. While gliptins act by inhibiting the enzyme that breaks down GLP-1, thus increasing the level of GLP-1 in the blood stream, GLP-1 receptor (GLP-1R) agonists act directly on the beta cell to stimulate insulin secretion by activating signal transduction when glucose is present. When glucose is not present, this receptor no longer couples to stimulate insulin secretion in order to prevent hypoglycemia. Active GLP-1 is responsible for glucose-dependent insulin secretion, suppression of glucagon secretion and delayed gastric emptying.The antidiabetic action of DPP-4 inhibitors is mediated by slowing the degradation of endogenous GLP-1. DPP-4 inhibitors are, however, not able to raise the GLP-1 to levels achieved after injection of GLP-1R agonists and, therefore, their hypoglycaemic efficacy is less than that of GLP-1R agonists . HoweverGLP-1R agonists also have effects beyond glucose control that may be of indirect help for nephroprotection: they reduce body weight, induce satiety and influence the gastrointestinal system  and the cardiovascular system . GLP-1R agonists reduce body weight, whereas DPP-4 inhibitors do not affect body weight . In geneEvidence from animal and human studies indicates that incretin-based therapies might prevent the onset and progression of DCKD, as measured by clinical and histological improvements. Incretin-based therapies may positively influence haemodynamic variables , metabolic factors  and inflammatory pathways in the pathogenesis of DCKD .In addition, there is some evidence that GLP-1R agonists and DPP-4 inhibitors mediate sodium excretion and diuresis to lower blood pressure. The pleiotropic actions of DPP-4 inhibitors are ascribed primarily to their effects on GLP-1 signalling, but other substrates of DPP-4, such as brain natriuretic peptide and stromal-derived factor-1a, may play other roles . Collectin situ hybridization, and GLP-1R expression was detected using 125I-labelled GLP-1 [In the human kidney, expression of GLP‑1R mRNA was demonstrated by ed GLP-1  but the DPP-4 inhibitors (gliptins) are emerging as second line treatment ahead of sulphonylureas or metformin due to a possible beneficial effect on the beta cell and their weight neutrality. They are effective, well tolerated and have been shown to be safe in general. All of them, except for linaglitin, require dose adjustment based on glomerular filtration rate in order to avoid plasma accumulation and side effects.The main action of DPP-4 inhibitors is to increase the levels of endogenous incretin hormones, especially GLP-1. But DPP-4 inhibitors are also bound to the surface of many cell types including kidney proximal tubular cells and endothelial cells . Microveet al. [Sun et al.  also deset al. .Renal effects of DPP-4 inhibitors appear to be, at least in part, mediated by increased GLP-1 levels . In addiIn the kidney, DPP-4 is expressed on the brush border of proximal tubules and glomerular podocytes . DPP-4 iPreclinical data suggesting the nephroprotective effects of DPP- 4 inhibitors can de attributed to sitagliptin , vildaglHowever, since the discovery of DPP-4 as an adenosine deaminase binding protein , the expet al. [Liu et al. , using aIn streptozotocin treated rats, when compared to vehicle, treatment with linagliptin has shown reduced glomerulosclerosis after treatment with linagliptin alone or in combination with angiotensin receptor blockade .Sitagliptin ameliorated renal lesions, including glomerular, tubulointerstitial, and vascular lesions ,59,60,61et al. [A more recent study by Vavrinec et al.  showed tWhether these effects are direct or partially mediated by changing glucose concentration warrants further scrutiny, even though results obtained in models of Type 1 DM seem to support a direct effect.Besides GLP-1 and GIP, DPP-4 cleaves multiple substrates, such as brain natriuretic peptide (BNP), ANP, substance P, among others, many of which are vasoactive . On the Few studies have been devoted to directly assessing the effects of DPP4 inhibitors on renal functional measures and the key question is whether DPP4 inhibitors are able to improve renal end-points beyond their antihyperglycemic effect.In some uncontrolled studies with small number of patients, six months of treatment with sitagliptin  for 12 oA similar inhibitory trend against the development and progression of microalbuminuria was observed in another study using saxagliptin in patients with type 2 diabetes and cardiovascular complications , althoughttps://clinicaltrials.gov/ct2/show/NCT01792518 Identifier: NCT01792518). It is currently ongoing.Another phase IIIb, multicenter, randomized, double-blind, placebo-controlled, parallel-group study, evaluating the glycemic and renal efficacy of linagliptin in subjects with type 2 diabetes and renal impairment, is the MARLINA study   and medium long-term (CAROLINA: Cardiovascular Outcome Study of Linagliptin Versus Glimepiride in Patients with Type 2 Diabetes) and CARMELINA  and also MARLINA trial, studying the effects of linagliptin on microalbuminuria in type-2 DM patients, that will help us to completely assess cardiovascular and renal safety.Two such trials for DPP-4 inhibitors have been published ,72. ThesApart from the several effects described above, the effects of GLP-1R agonists and DPP-4 inhibitors on kidney disease have been extensively studied in diabetic kidney disease models, where they may have protective roles in reducing proteinuria and glomerular sclerosis, which are associated with protection from endothelial injury and reduction in oxidative stress and inflammation ,73. Of nExperimental studies using various diabetic models suggest that incretins protect the vascular endothelium from injury by binding to GLP-1 receptors, thereby ameliorating oxidative stress and the local inflammatory response, which reduces albuminuria and inhibits glomerular sclerosis .Initial studies in hypertension-prone rats showed that GLP-1 prevented the development of hypertension, ameliorated histologically verified renal damage and reduced albuminuria .There is evidence to suggest that long-term treatment with the GLP-1R agonist exendin-4 ameliorates DN in both type 1 and type 2 DM animal models, most probably through its action on the glomerular endothelial and infiltrating inflammatory cells .In humans, GLP-1 promotes natriuresis by acting on the proximal tubule, thereby also increasing the fractional excretion of lithium  . GLP-1 aet al. [p < 0.01), while glycemic control showed no statistical difference between the two groups. These results suggest that exenatide reduces urinary TGF-β1 and type IV collagen excretion in patients with type 2 diabetes and microalbuminuria, which may be partly contributory to its directly renoprotective role [In the study of Zangh et al. , 31 typeive role .In phase III trials included in meta-analyses, GLP-1R agonists decreased systolic blood pressure by 2–5 mmHg, having a modest effect on diastolic blood pressure (0.5–2 mmHg), although not achieving statistical significance . The antGLP-1, GLP-1R agonists and DPP-4 inhibitors also affect renal haemodynamics . The GLPAs occurs with DPP4 inhibitors, cardiovascular safety is a key point with GLP1-R analogues. Large-scale clinical studies with cardiovascular end points are underway, although much needed studies with renal end points are still required.DPP4 inhibitors have shown neutral effect in cardiovascular outcomes ,72. NeveThe effects of GLP-1 or its analogues on cardiovascular outcomes may be related to a direct effect on cardiomyocytes mediated both by GLP-1-increased myocardial insulin sensitivity and subsequent glucose uptake, endothelial function, endothelial cells and vascular smooth muscle cells and pro-inflammatory markers .To date, mechanistic investigation of their effects on microvascular or large-vessel diabetic vascular disease is lacking. LIRA-RENAL Study is ongoing (The Effect of Liraglutide in Patients With Prediabetes and Kidney Failure). Regardless of the mechanisms involved, ongoing cardiovascular outcome trials including EXSCEL , LEADER (Liraglutide Effect and Action in Diabetes), and also HARMONY  may help to dissipate doubts about cardiovascular safety.Sodium-glucose cotransporter-2 (SGLT2) inhibitors are emerging as new therapies with complementary mechanisms of action that are independent of insulin secretion or action. They have acceptable safety profiles and may provide additional therapeutic options to achieve glycaemic control and renoprotection. This renoprotection may be derived from direct effects, such as attenuating diabetes-associated hyperfiltration and tubular hypertrophy, as well as reducing the tubular toxicity of glucose and indirect effects such as improving glycaemic control, reducing insulin levels and improving insulin sensitivity, improving weight control due to modest reductions in body weight, improving blood pressure control due to the natriuretic effect and weight loss and lowering uric acid levels .Like agents that block the renin–angiotensin system, SGLT2 inhibitors also reduce single-nephron glomerular filtration rate in the chronically diseased kidney, though by quite different mechanisms. In case of SGLT2 inhibitors these drugs reduce sodium reabsorption in the proximal tubule, so increasing delivery to the macula densa, augmenting the tubuloglomerular feedback and reducing single-nephron glomerular filtration rate ,88. ThisThese beneficial effects may not be present in patients with established renal impairment. This may be due to the fact that the magnitude of glucose excretion and haemoglobin A1c reduction induced by SGLT2 inhibitors is dependent upon the filtered glucose load and is maximal in diabetic subjects with normal glomerular filtration rate (GFR). However, a high filtered glucose load is associated with only modest glucose reduction in patients with renal impairment, where the filtered glucose load is reduced. As a consequence, in this context, SGLT2 inhibitors show a decrease of glucose lowering efficacy.Moreover, DCKD is associated with impaired autoregulation of renal blood flow, meaning that drops in blood pressure will be more likely to be associated with reduction in renal perfusion in the diabetic kidney. This is particularly the case in patients with established renal impairment. In some cases, volume depletion and blood pressure lowering associated with SGLT2 inhibitors has been associated with acute-on-chronic renal impairment . This faMonitoring of renal function is currently justified when using RAAS blockade in patients with diabetes and similar considerations may also be appropriate in selected (volume sensitive or patients with increased hypertensive response to sodium depletion stimuli) patients receiving SGLT2 inhibitors, especially as nearly all diabetic patients receive RAAS blockade.Experimental evidence has been collected to determine whether SGLT2 inhibitors act in a nephroprotective manner in diabetes. Some experimental studies have shown beneficial effects via the different mechanisms by which SGLT2 inhibitors may be associated with nephroprotection. For this purpose experimental models have been set up in rodents. These studies have shown a reduction in the inflammatory response in the kidney, such as less macrophage infiltrates, lower cytokine levels (TGF-β and MCP-1) as well as lower apoptosis rates, and indicate anti-oxidative effects through SGLT2 inhibition. These effects are independent of its effects on blood pressure or glucose control .On the other hand, SGLT2 inhibitors are able to attenuate the hyperfiltration associated with experimental diabetes ,94. ThisRenal angiotensin aldosterone blockade is one of the keys to nephroprotection in diabetic kidney disease. Indeed in one experimental study, the combination of RAAS blockade with SGLT2 inhibition was associated with additive renoprotective effects compared to either drug alone .Finally, the use of SGLT2 inhibitor empaglifozin has demosntrated that inhibition of glucose reabsorption was able to attenuate the renal hypertrophy associated with experimental diabetes ,97, reduDedicated renal protection studies have not yet been completed on humans, although such studies are currently underway  trial-NCT02065791).Clinical data on nephroprotection of SGLT2 inhibitors come only from clinical trials, conducted with end points of efficacy and safety, not with renal end points. Few clinical studies examined the effects of SGLT2 inhibition on renoprotection and glycaemic control in CKD ,103,104.In these studies the urinary albumin/creatinine ratio fell in treatment groups and increased or decreased at a lesser extent in controls. These studies show results at short and medium term, and glomerular filtration rate showed a slight decrease in eGFR that was observed due to the haemodynamic effect of SGLT2 inhibitors. Nevertheless, after a follow-up greater than 80 weeks, a reverse pattern was observed in a small number of participants. This finding should be confirmed in a larger population using renal measurements as primary end-points. Unfortunately, these large trials do not offer insights into the potential nephroprotective effect of these agents due to the short-term follow-up.One of the major issues still under debate is the cardiovascular risk profile of SGLT2 inhibition. The incidence of cardiovascular events was observed to increased in the first 30 days post-initiation of treatment probably due to volume depletion and hypotensive episodes . SimilarVery recently the US Food and Drug Administration (FDA) and the the European Medicines Agency (EMA) have begun a review of SGLT2 inhibitors used to treat type 2 DM to evaluate the risk for diabetic ketoacidosis. This is as a consequence of the appearance of 121 cases of euglycemic asymptomatic diabetic ketoacidosis with blood sugar levels only moderately increased. During the review review, healthcare professionals will be informed about the risk of diabetic ketoacidosis and how to manage it in those patients. More information is needed about this complication as well as its possible relation with the drug. To date there is no data to suggest that this complication can directly affect renal function.Taken together, these findings suggest that SGLT2 inhibitors may have a renoprotective effect with a decline in albuminuria and a long-term maintenance of glomerular filtration rate. However at present, it is not possible to determine if the above-mentioned effects have a long-term advantageous impact on the progression of diabetic nephropathy. It is also not posible to determine whether the decline in albuminuria is related to indirect effects , changes in intraglomerular hemodynamic and pressure, as demonstrated for ACEi and sartans, or whether it may be ascribed to other actions of SGLT2 inhibitors on renal function. Interestingly, the pattern of an acute reduction followed by a stabilization in GFR reported in these studies on SGLT2 inhibitor groups is similar to those reported with angiotensin converting enzyme inhibitor in subjects with CKD but with different underlying mechanisms for the changes in GFR ,100,107.In conclusion, SGLT2 inhibitors are a new class of antidiabetic drugs that induce a moderate effect on blood glucose, in chronic kidney disease patients. Existing data are supportive of a potential renal-protective role for SGLT2 inhibition in patients with diabetes. Further studies are needed to investigate whether SGLT2 inhibitors have renoprotective effects beyond the control of hyperglycaemia in diabetic patients as well as subjects with established DCKD. Nevertheless, they may represent a significant additional therapeutic tool to the current trreatments in the clinical prevention and management of diabetic nephropathy. Dedicated, adequately powered, renal outcome trials are eagerly awaited to assess the clinical utility of SGLT2 inhibition as a renal-protective therapy.Although experimental data about most antihyperglycemic drugs has shown a beneficial effect in kidney parameters, there is a lack of clinical trial results that clearly prove these beneficial effects. The key question, however, is whether antihyperglycemic drugs are able to improve renal end-points beyond their antihyperglycemic effect. Existing experimental data comes from post hoc studies from clinical trials, and are supportive of the potential renal-protective role of some of them, especially dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter 2 inhibitors. Dedicated and adequately powered renal trials with renal outcomes are neccessary to assess the nephroprotection of antihyperglycaemic drugs beyond the control of hyperglycaemia.


Opioid analgesics are used in most trauma systems, and only a few studies report on the use of ketamine for prehospital analgesia. In a low-cost rural trauma system in Iraq paramedics have been using prehospital ketamine analgesia for ten years. This study aims to evaluate the effects of prehospital analgesia on physiologic trauma severity indicators and compare the effect of ketamine and pentazocine on those indicators.n = 275), pentazocine analgesia (n = 888), and ketamine analgesia (n = 713). Physiologic severity scores were calculated based on rated values for respiratory rate, blood pressure, and consciousness. The associations between outcomes and explanatory variables were assessed using a generalized linear model.The investigation was conducted as a retrospective cohort study with parallel group design. Three subsamples of trauma patients were compared: no analgesia (p = 0.01). In the two subsamples receiving analgesia significantly better outcomes were observed for respiration (p < 0.0001) and systolic blood pressure (p < 0.0001). In patients with Injury Severity Score >8 ketamine was associated with a significantly better effect on the systolic blood pressure compared to opioid analgesia (p = 0.03).Paramedic administration of analgesia was associated with a better physiologic severity score (PSS) outcome (Prehospital analgesia for trauma victims improves physiologic severity indicators in a low-resource trauma system. Compared to pentazocine, ketamine was associated with improved blood pressure for patients with serious injuries. In a low-resource setting, ketamine seems to be a good choice for prehospital analgesia in trauma patients. In addition to the humane reasons for providing optimal pain relief, pain relief is required because the systemic response to pain affects nearly all organ systems. Recent changes in trauma care include an emphasis on pain treatment to decrease the potent inflammatory response that results in hyper-coagulability, organ dysfunction, systemic inflammatory response, lung injury, brain injury, depression, and post-traumatic stress disorder .In most prehospital trauma systems, opioid analgesics have been the preferred choice over the last decades. However, the therapeutic range is narrow in opioids; there is the risk of accidental overdose that can cause respiratory depression, hypotension and the loss of protective airway reflexes.Ketamine hydrochloride is a non-opioid potent analgesic used for anesthesia for decades. Ketamine stimulates the sympathetic nervous system and moderately increases heart rate and systolic blood pressure; these side effects might benefit trauma victims. Ketamine does not affect respiration or laryngeal reflexes; under ketamine analgesia and anesthesia, patients breathe spontaneously and maintain airway control .Hence, the drug does not have the same dangerous side effects as opioids, even if accidentally administered in excessive doses , 4. SideThe London helicopter emergency medical service has reported on their use of ketamine for analgesia and procedural sedation and concluded that ketamine is safe when used by physicians in prehospital trauma care . To the Some studies have looked into the addition of ketamine to morphine analgesia. In a study including 135 patients receiving either morphine alone or with addition of ketamine, the combination were shown to be superior. However, there were more adverse effects reported, most commonly disorientation reported for 11 % of the patients . A similIn a low-cost rural prehospital trauma system, we aimed to assess the effects of the paramedic administration of prehospital analgesia on physiologic trauma severity indicators and compare the effect of prehospital ketamine and pentazocine analgesia on physiologic severity indicators.The study was conducted as a non-randomized retrospective cohort study with a parallel group design. The patients were analysed in three subset based on prehospital analgesia: no analgesia, pentazocine analgesia or ketamine analgesia. The reference population for the study are trauma patients managed by rural, low-cost trauma systems.The intervention was conducted in the warzones and minefields of North and Central Iraq. The trauma system was initiated in 1997 to rescue land mine victims from the vast mine fields in the mountainous areas along the Iran-Iraq border, and it was later expanded to the Central Iraq war zone. The prehospital trauma system under study is a three-tiered system that consists of lay first responders (“first helpers”), trained paramedics at local clinics and district hospitals, and emergency room staff at the surgical hospitals.Evacuations are often rough and difficult for both rural trauma scenarios and urban mass casualties; patients may be carried off-road without ambulances, and the first helpers may not be able to provide continuous close care and monitoring of vital signs.The training began in 1997 when 20 paramedics were trained at rural health centres and equipped for advanced trauma life support by two of the authors . The training consisted of three 150-h courses over a 3-year period . DetailsThe study population comprised adult trauma patients who were consecutively managed by the trauma system from January 1997 to December 2006. The physiological responses to trauma differ between children and adults; therefore, trauma patients aged <15 years were not included in the study but will be reported in a separate study.n = 228) was co-administered to the ketamine patients in one single IV dose of 5 mg. During protracted evacuations with repeated ketamine injections, 1 mg atropine (n = 63) was also administered IV to prevent excessive salivation. For both analgesics, repeated doses were given for clinical indications during assisted evacuations. Unfortunately, the trauma registry does not contain information on the dosage or frequency of drug administration.The first dose of analgesics was administered at the scene as soon as the initial assessment of vital functions was assessed and intravenous access was established. Due to local medical traditions and the lack of evidence-based studies of ketamine analgesia, pentazocine was mainly used in blunt injuries and all cases of eye and/or traumatic brain injury. The drug was administered IV with an initial dosage of 20–30 mg for adults (0.4 mg/kg). Ketamine was used in all other cases of penetrating injuries and burns, with an initial IV dose of 0.2 mg/kg as a separate injection. In cases of agitation and unrest, diazepam (The main outcome variable was the change in the physiologic severity score (PSS) . The PSSThe Revised Trauma Score (RTS) uses standard vectors for the three physiological indicators . A ReceiThe data were collected at two time points. The first point was the first in-field encounter with a paramedic, and the end point was admission to the referral hospital. If data were missing from the hospital admission, the final in-field ratings by the paramedic prior to hospital admission were used as the end point.The paramedics gathered time factors, tentative clinical diagnoses, PSS scores and life support measures on injury charts in Kurdish and Arabic. Similar vital data were also registered at the endpoints by the emergency room staff. All the data were audited at monthly meetings with the paramedics by the author supervising the program (MKM).The Injury Severity Score (ISS) was estimated by the senior trauma supervisor (MKM) using the Abbreviated Injury Scale-90 (1998 update), based on the case injury form, as well as hospital information from the surgical reports and X-ray findings. Because of local traditions, autopsy on prehospital fatalities was not performed; in such cases, the ISS values were set conservatively.n = 113); endpoint data were unavailable for this patient subsample, and the ISS and PSS were estimated from the prehospital clinical files.A total of 2983 adult patients were registered in the trauma database from January 1997 to December 2006 and assessed for eligibility  were performed in JMP  ver. 8 for Mac. Continuous variables are presented as means with 95 % confidence intervals (95 % CI), while the categorical data are expressed as proportions with 95 % CI. Dispersion is shown as median followed by 25–75 % interquartile range. For comparison of means across groups ANOVA was done. If significance was shown in the ANOVA, post hoc Tukey HSD comparison of means were done. Associations between the main outcome variables and potential explanatory factors were analyzed using a GLM linear regression model. The models were fit by forcing the following variables into each model: analgesia , analgesia (ketamine vs. pentazocine), gender , age, the time from the injury to the first medical assistance (hours), the time from the injury to the hospital arrival (hours) and the ISS. Standard statistical procedures and normality plots were used to assess the model fit.The Directorate of Health Suleimaniah, Ministry of Health, Kurdistan region, provided ethical approval for the study (Ref. no. 22082). There is no other authorized committee for medical research ethics in North Iraq. The data were stored in de-identified form and processed according to the Norwegian Social Science Data Service standards (ref. no. 2006/13702).There were more severe injuries in the no analgesia group, as demonstrated by both the anatomic (ISS) and physiologic (PSS) severity scores. Both the in-field response time and total prehospital transit time were longer in the ketamine group. Table The endpoint scores for each physiological variable as related to the initial physiological score and analgesia are shown in Table The GLM analysis showed that analgesia was associated with a positive effect on respiratory rate score, while no difference was found between pentazocine and ketamine Table . IncreasReceiving analgesia was associated with a better blood pressure score. In the subset of patients with serious injuries, ketamine analgesia was associated with a significant positive change in systolic blood pressure.Analgesia had a negative impact on the level of consciousness. No significant difference between the drugs was observed.The study shows that prehospital analgesia was associated with an improvement of physiological severity indicators. For patients with an ISS >8, ketamine analgesia was associated with a better treatment effect than opioid analgesia. Better treatment effects on respiration and blood pressure contributed to the better physiologic outcome.First, the study was strictly observational, and treatment was decided by paramedic preference; therefore, some baseline characteristics varied between the three subsets. The patients not receiving analgesia were more severely injured. Further, the in-field response times and total transit times were higher in the ketamine cohort. Ketamine was regularly used in penetrating injuries, most of which were land mine injuries that occurred in remote rural areas, while pentazocine often was the analgesic of choice in blunt trauma cases, which were predominantly caused by road traffic accidents. The confounder effects of these variables were adjusted for in the GLM model.n = 228), particularly when the evacuations were risky and agitation might have caused security problems. Diazepam may have affected the outcome indicators by depressing the respiratory rates, blood pressure, and consciousness.Second, a small subset of patients was given diazepam  systematically audited the treatments and outcomes for all of the study patients at monthly meetings.The study indicates that prehospital analgesia has a positive effect on systolic blood pressure. Although it may appear that this effect was confounded by volume replacement, the fluid protocol was similar for all three cohorts. In patients with severe injuries, ketamine had a significantly better effect on blood pressure compared to opioid analgesia. This finding corresponds well with a small Swedish randomized study that demonstrated that the addition of ketamine to opioid analgesia increases blood pressure after trauma .The increased blood pressure for seriously injured patients in the ketamine group is a clinically important finding. The optimal blood pressure target for trauma victims is controversial, and it is not possible to determine a general blood pressure target in the current literature . In thisAnother clinically important finding in this study was the improved respiratory rates in patients receiving analgesia. Pain relief may normalize the respiratory rate, increase the ventilated parts of the lungs and assist in oxygenation.Airway control is crucial, particularly with mass casualties in chaotic settings in which trauma victims cannot be monitored closely on-scene and during evacuation. The London helicopter emergency medical service has reported emergency physicians administering ketamine to 1030 adult patients, and no significant airway complications were observed. Ketamine has been used in this service by a physician-paramedic team to provide analgesia, sedation and (rarely) the induction of anesthesia .Another study described ketamine use in 40 patients in a physician-equipped regional aeromedical critical care service. The patients maintained airway responsiveness and adequate oxygen saturations . This stWe have limited adverse event data in our study population, as only major side effects would affect physiologic variables. There is a free text field in the injury chart, and one of the authors (MKM) conducted monthly meetings with the paramedics in an attempt to collect this information.This study was performed in a low-resource setting, but even in high-income countries the close monitoring of patients in the prehospital setting is challenging. In the study setting, it is of utmost importance that the drugs given are safe and do not cause cardiorespiratory trouble.Adverse events associated with ketamine administration were studied in a narrative review of 88 studies. These studies reported adverse events for more than 70,000 patients; a cardiorespiratory event of lasting significance reported (hypoxic cardiac arrest) was recorded in one patient .Another concern is the respiratory depression caused by opioids , while kIn our study, we could observe that receiving analgesia was associated with decreased consciousness. It is expected that analgesics with a central mechanism of action might influence consciousness. Similar findings have been used as an argument for not providing pain relief to patients with suspected brain injuries. It is proposed that pain relief creates problems in assessing consciousness and the neurologic findings in traumatic brain injury cases.Current recommendations for the prehospital care of patients with head injuries emphasize preventing secondary brain injuries by avoiding hypoxemia and hypotension . Our stuKetamine administration has been controversial in traumatic brain injuries, also because some early studies have reported increased intracranial pressure (ICP) in patients receiving ketamine , 19. ForPrehospital analgesia for trauma victims improves physiologic severity indicators in a low-resource trauma system. Compared to pentazocine, ketamine was associated with improved blood pressure for patients with serious injuries. Ketamine seems to be a good choice for prehospital analgesia in trauma victims, particularly in a low-resource setting.


The extent of lung hypoplasia in neonates with congenital diaphragmatic hernia (CDH) can be assessed from gas exchange. We examined the role of preductal capillary blood gases in prognosticating outcome in patients with CDH.We retrospectively reviewed demographic data, disease characteristics, and preductal capillary blood gases on admission and within 24 h following admission for 44 high-risk outborn neonates. All neonates were intubated after delivery due to acute respiratory distress, and were emergently transferred via ground ambulance to our unit between 1/2000 and 12/2014. The main outcome measure was survival to hospital discharge and explanatory variables of interest were preductal capillary blood gases obtained on admission and during the first 24 h following admission.2/FIO2) on admission predicted survival . However, some neonates substantially improve PcO2/FIO2 following initiation of treatment. Among neonates who survived at least 24 h, the highest preductal PcO2/FIO2 achieved in the initial 24 h was the strongest predictor of survival . Nonsurvivors had a mean admission preductal PcCO2 higher than survivors , and their PcCO2 remained high during the first 24 h of treatment.Higher ratio of preductal partial pressure of oxygen to fraction of inspired oxygen (PcOThe inability to achieve adequate gas exchange within 24 h of initiation of intensive care treatment is an ominous sign in high-risk outborn neonates with CDH.We suggest that improvement of oxygenation during the first 24 h, along with other relevant clinical signs, should be used when making decisions regarding treatment options in these critically ill neonates. The presence of respiratory distress in neonates with congenital diaphragmatic hernia (CDH) may indicate severe pulmonary hypoplasia, which is a major contributor to morbidity and mortality. In neonates with CDH , an early presentation of respiratory distress is related to an increased degree of pulmonary hypoplasia , 2. Accuadmission preductal hemoglobin saturation predicts survival ½. In all cases, 2-tailed P values <0.05 were considered statistically significant. Data were analyzed with SAS version 9.3 software .The main outcome measure was survival to hospital discharge and the explanatory variables of interest were preductal capillary blood gas values from the first 24 h. Data are presented as mean ± standard deviation for continuous variables and frequency (percentage of sample) for categorical variables. Differences between survivors and nonsurvivors were compared with the independent samples n = 25) and nonsurvivors (n = 19) , and 53 high-risk CDH neonates presented with early respiratory distress after delivery. We excluded 9 of the 53 patients: 1 with lethal trisomy 18 (Edward’s syndrome), 1 with missing medical records, 1 with surgery performed in a remote hospital transferred to our unit for further treatment, and 6 moribund neonates who were briefly resuscitated but died during admission. Demographic data, disease characteristics, and therapeutic interventions for the remaining 44 high-risk neonates were summarized for survivors (9) Table .Table 1D2/FIO2 ratio, higher PcCO2, and lower pH. At 24 h predictors of mortality were lower PcO2/FIO2 ratio and higher PcCO2 . For survivors, PcCO2 remained similar after admission while among nonsurvivors, the PcCO2 increased , and a cutoff of 81.8 mmHg for admission PcCO2 had a sensitivity of 63 %, specificity of 80 %, PPV of 71 %, and NPV of 74 % for predicting hospital mortality.High PcCOP = 0.03; Table Low pH on admission was also a predictor of mortality. Among survivors, mean pH on admission was higher than among nonsurvivors . Among hospital survivors, PcO2/FIO2 increased during the first 24 h of treatment . Of those who died after 24 h, PcO2/FIO2 did not change significantly over the first 24 h . The predictive value of highest PcO2/FIO2 ratio over 24 h determined from ROC analysis found the AUC was 0.87 , and a cutoff of 100 mmHg for PcO2/FIO2 had a sensitivity of 92 %, specificity of 75 %, PPV of 65 %, and NPV of 95 % for predicting hospital mortality .We also examined the predictive role of other vital signs. The lowest body temperature and lowest mean blood pressure over the first 12 h following admission were significantly lower in patients who died than in those who did not  had AUC of 0.87 with a PPV of 82 % and an NPV of 88 % [For our neonates who survived the first 24 h, the highest PcO2/FIO2 achieved over 24 h of treatment represents a better approach in predicting outcome. Furthermore, inefficient ventilation, as inferred from inability to reduce PcCO2, was a good prognosticating indicator for mortality.All our neonates were transferred from either local or remote hospitals. The most typical ventilatory support during travel was a self-inflating bag and, less frequently, transport ventilators. Because of this, a proportion of neonates in this cohort probably received suboptimal ventilation. This was the basis for our hypothesis that the institution of proper mechanical ventilation upon admission may separate “responders” (those with recruitable lung units) from “non-responders” (those with more severe pulmonary hypoplasia). Based on that premise, one would expect to find the admission blood gas values to be less predictive of outcome than the blood gases following treatment. Indeed, we found that the highest PcO2, PCO2, and pH. A recent meta-analysis showed that blood sampled from the fingertip accurately reflects PaCO2 and arterial pH over a wide range of values [2 and pH between capillary and arterial samples, our findings of association between capillary PcCO2 and pH and survival likely indicate that obtaining arterial blood gases would have similar association. In contrast, PcO2 less accurately approximates PaO2, but the accuracy improves in hypoxic conditions [2 in our neonates was lower than normal. While we do not know how accurately PcO2 in our study approximated PaO2, it is likely that the increase in PcO2/FIO2 represents an improvement in oxygenation. We have shown that an increase in this ratio per se prognosticates outcome comparably to WHSRPF prediction formula [2apply only to blood gases from capillary samples. Furthermore, because contemporary ventilatory strategies for children with CDH allow for mild hypercapnia, values of PaCO2 less than 60–65 mmHg have little meaning for outcome prognostication ; however, high PaCO2 values (>80 mmHg) are universally undesirable and are undoubtedly markers of severe lung hypoplasia and increased mortality. Furthermore, the long study period used in our investigation may encompass therapeutic advances which could have changed outcomes in neonates over time. We did not detect a significant temporal change in survival and we do not believe any substantial improvements in practice occurred in our institution during the study period . Finally, our results may lack generalizability to settings with more sophisticated transport management capabilities and institutions with ECMO availability.The limitation of this study is related to its retrospective design, and evaluation of a relatively small number of patients admitted to a single large academic center. Proper interpretation of blood gas analyses may be complex when blood gases are not obtained in a standardized fashion . Instead of using arterial blood, UHC used capillary blood to obtain measurements of POf values . Given tnditions , and the formula . HoweverUsing a unique population of high-risk CDH outborns with early respiratory distress, we found that the inability to improve gas exchange within 24 h of the initiation of treatment is an ominous sign. Of all the blood gas parameters considered, the magnitude of increase in oxygenation in response to treatments was the best predictor of survival. Therefore, we suggest that improvement of oxygenation during the first 24 h, along with other relevant clinical signs, may help when making decisions regarding survivability or the use of ECMO when available.2, fraction of inspired oxygen; NICU, neonatal intensive care unit; NPV, negative predictive value; PcCO2, partial pressure of carbon dioxide in the capillary blood; PcO2, partial pressure of oxygen in the capillary preductal blood; POS, probability of survival; PPV, positive predictive value; ROC, receiver operating characteristic; UHC, University Hospital Centre; WHSRPF, Wilford Hall/Santa Rosa clinical prediction formulaAUC, area under the curve; CDH, congenital diaphragmatic hernia; CDHSG, Congenital Diaphragmatic Hernia Study Group; ECMO, Extracorporeal membrane oxygenation; FIO


Purpose: Glaucomatous neuropathy can be a consequence of insufficient blood supply, increase in intraocular pressure (IOP), or other risk factors that diminish the ocular blood flow. To determine the ocular perfusion pressure (OPP) in normal and systemic hypertensive patients.Materials and methods: One hundred and twenty-one patients were enrolled in this prospective and comparative study and underwent a complete ophthalmologic examination including slit lamp examination, Goldmann applanation tonometry, stereoscopic fundus examination, and pulsatile ocular blood flow (POBF) measurements. The OPP was calculated as being the medium systemic arterial pressure (MAP) less the IOP. Only right eye values were considered for calculations using Student’s t-test.Results: The mean age of the patients was 57.5 years (36-78), and 68.5% were women. There was a statistically significant difference in the OPP of the normal and systemic hypertensive patients (p < 0.05). The difference in the OPP between these groups varied between 8.84 and 17.9 mm Hg.Conclusion: The results of this study suggest that although the systemic hypertensive patients have a higher OPP in comparison to normal patients, this increase does not mean that they also have a higher OBF (as measured by POBF tonograph). This may be caused by chronic changes in the vascular network and in the blood hemodynamics in patients with systemic hypertension.How to cite this article: Kanadani FN, Figueiredo CR, Miranda RM, Cunha PLT, Kanadani TCM, Dorairaj S. Ocular Perfusion Pressure and Pulsatile Ocular Blood Flow in Normal and Systemic Hypertensive Patients. J Curr Glaucoma Pract 2015;9(1):16-19. Both have been defended by research groups over the last 150 years. In accordance with the mechanical theory, the increase in intraocular pressure (IOP) stretches the laminar beam and causes damage to the axons of the ganglion retinal cells, while the vascular theory considers the GON a consequence of insufficient blood supply, increase in IOP, or other risk factors that diminish the ocular blood flow (OBF). In congenital, acute angle close, secondary glaucoma, clearly the increase in IOP is enough to cause GON. However, innumerable findings of normal tension glaucoma (NTG) cannot satisfactorily be explained only by this theory. The fact is that the reduction of OBF frequently precedes the structural damage. It also occurs in other parts of the body of these glaucomatous patients, indicating that hemodynamic alterations can at least partially be primary. The biggest cause of this reduction is not atherosclerosis, but a vascular disequilibrium that leads to the reduction of the ocular perfusion pressure (OPP) and insufficient autoregulation.2 Using the angiofluoresceinography, Hayreh et al3 demonstrated a zone of the short posterior ciliary’s arterioles that supply the posterior portion of the optic nerve. This area can be vulnerable to the ischemia when the OPP is reduced. The OPP is defined as median arterial pressure (MAP) less IOP (OPP = MAP - IOP).4 In agreement with the vascular theory, low systemic arterial pressure (AP) relative to IOP can lead to a low OPP, consequently, decreasing the perfusion of the optic nerve and leading to a glaucomatous loss of the visual field. On the other hand, systemic hypertension can increase the risk of damage to the small vessels of the optic disk.5 A reduction in MAP or an increase in IOP can diminish the ocular perfusion. The accurate mechanism of the regulation of IOP is unknown. If the autoregulation mechanisms are continuous, the sanguineous flow will remain steady with a substantial fall of the ocular perfusion.4The reduction in OBF can have a decisive implication in the pathophysiology of many ocular illnesses like diabetic retinopathy, age-related retinopathy, pigmentary retinosis, myopia, and glaucoma. Abnormalities of the blood flow in glaucoma have been evaluated with diverse techniques, including angiofluoresceinography, colored Doppler, Doppler laser fluxometry, and pulsatile ocular blood flow (POBF) tonograph.9 This method measures mainly the OBF in the choroids and anterior portion of the head of the optic nerve supplied by the posterior ciliary’s vessels, which provides 80 to 90% of the OBF.2The pulse of the cardiovascular system is also expressed in the eye to each systolic-diastolic cycle. The blood flows in the vessels of the ocular globe during systole and continues to flow more slowly during diastole. This phenomenon, according to a relationship between volume and pressure, implies a maximum IOP during systole and a minimum IOP during diastole. In this way, this transitory changes of the IOP allow us to calculate changes in ocular volume. POBF tonograph is capable of catching minimum changes in the IOP pulse and to correlate them with the volume. However, it cannot determine the OBF of isolated parts of the intrinsic vascular net of the eye. Therefore, its principle is based on the total influx of blood in each cardiac systole.The aim of this study is to determine the OPP and OBF in normal and systemic hypertensive patients.The study was performed in adherence to the guidelines of the declaration of Helsinki. The study protocols were approved by the Ethics Committee of Santa Casa of Belo Horizonte, and all patients have signed the informed consent.One hundred and twenty-one patients were enrolled in this prospective and comparative study and underwent a complete ophthalmologic examination including history of previous ocular diseases, trauma or surgery, slit lamp examination, Goldmann applanation tonometry, stereoscopic fundus examination, and POBF measurements.Two measurements of IOP and AP were taken with Goldmann applanation tonometer in a seated position, with a 2-minute interval between the measurements. The patients were divided into two groups: normal and systemic hypertensive. After 5 minutes in a seated position, OBF measurements were taken with the POBF tonograph.The same examiner (FK) took all the measurements of the POBF in the patients after the topic instillation of cloridrate of proximetacain 5 mg. The POBF tonograph has one pneumotonometer with disposable tips that, in contact with the previously anesthetized cornea, measures the pulses of the IOP. During the examination, the POBF tonograph produces a sound that helps the examiner to capture five representative pulses of the IOP. If after 20 seconds, the equipment is not able to detect five complete pulses of the IOP, the examination is automatically interrupted. The POBF tonograph is capable of detecting initial tensional levels from 5 to 127 mm Hg. The data supplied after the detection of the five pulses of the IOP are: IOP, minimum IOP (in mm Hg), pulse amplitude, pulse volume [(PV) in micro liters], pulse rate [(PR) in beats per minute] and, POBF (micro liters per second).Normal patients were ≥ 35 years old with an absence of ocular or systemic diseases, no ocular surgeries, and no use of any systemic medications. Refraction could not be greater than + 6 diopters (D) spheric and 3 cylindric. They had to have a best corrected visual acuity of 20/40 or better, IOP ≤ 21 mm Hg and cup/disk ratio < 0.4, and an absence of asymmetry.Systemic hypertensive patients were ≥ 35 years old with an absence of ocular pathologies and surgeries, and systolic systemic AP ≥ 140 mm Hg and diastolic ≥ 90 mm Hg or normal levels of systemic AP with use of antihypertensive medications. Refraction could not be greater than + 6D spheric and 3 cylindric. They had to have a best corrected visual acuity of 20/40 or better, IOP ≥ 21 mm Hg and cup/disk ratio < 0.4, and absence of asymmetry.The OPP was calculated as being the MAP less the IOP. Only right eye values were considered for calculations using Student’s t-test.The patients stayed in the sitting position for 10 minutes before all measurements. Systolic and diastolic blood pressures were measured on the upper arm by a calibrated tycos sphygmomanometer.The mean age of the patients was 57.5 years (36 to 78), and 68.5% were women . There w1011 In this study, the median IOP was 14.5 mm Hg (SD 3.5), with 14.1 mm Hg (SD 3.8) in the normal and 14.7 mm Hg (SD 3.18) in the systemic hypertensive patients with no statistically significant difference. The MAP in normal patients was 94.2 mm Hg (SD 11.2) while that of the systemic hypertensive patients was 108.4 mm Hg (SD 14.78). This statistically significant difference (p = 0.000) confirms the good division of the groups. Leske et al5 investigated the relationship between the OPP and the incidence of open angle glaucoma (OAG) and found a relative risk of 3.1 for patients with OPP < 41.0 mm Hg. Fuchsjager-Mayrl et al11 concluded that the hemodynamics of ocular parameters are lower in patients with OAG in comparison with normal patients. Sehi et al12 described that the diurnal changes of the IOP were similar in normal and primary OAG patients; however, the OPP was significantly different between these groups with significant reductions at 7:00 am and after lunch, times when the IOP was in its maximum value. Our results demonstrated an OPP of 80.1 mm Hg (SD 10.6) in the normal patients and 93.5 mm Hg (SD 14.6) in the systemic hypertensive patients. The difference was statistically significant (p = 0) and confirmed a higher OPP in the systemic hypertensive patients.Previous studies consider the normal IOP to be between 10 and 20 mm Hg.13There is evidence of an abnormal association between ocular perfusion parameters and systemic blood pressure in patients with glaucoma. However, these data do refer to long-term adaptations of perfusion to the eye with blood pressure rather than a short-term increase in blood pressure.Despite this, we cannot quantify with any current diagnostic method, the real amount of blood in the anterior portion of the optic nerve or the level of existing gaseous exchange in this place. It is important to highlight that although was found that the systemic arterial hypertensive patients had a better ocular OPP in comparison to the normal population, they not necessarily have a better ocular nutrition. Usually in these chronic systemic arterial hypertensive patients coexist some microvascular changes, as the thickening of the intima vascular layer.14 in the first study of its kind with a large sample size (n = 163), indicated normal average POBF of 11.16 ul/s for men and 14.03 ul/s for women, a statistically significant difference influenced by the greater cardiac frequency in women. In another study with a larger normal population (n = 664), Massey and Crowhurst obtained average POBF of 13.46 ul/s. Women had greater POBF (p = 0.001). Myopia, increase of the IOP, and older patients are related to reduced POBF value.15 Our study showed POBF values higher than described in the literature, 20.31 ul/s (SD 0.98) in normal patients and 20.15 ul/s (SD 0.75) in systemic hypertensive patients. This difference was not statistically significant (p = 0.895). None of the other parameters measured for the OBF were statistically significant.Yang et al,2 In this study, in many patients, the device was not able to take five complete cycles for the POBF calculation. While we observed a statistically significant difference in systemic AP among normal and hypertensive patients, a difference in the POBF between the groups was not seen, suggesting the existence of intrinsic factors related to the ocular hemodynamics or extrinsic factors related to the device or its software that regulates the OBF or makes its measuring difficult.The great variability of the measure of the POBF has been attributed to its relation with a great number of variables, including age, sex, cardiac frequency, pregnancy, corporal position, and ocular axial diameter.The results of this study suggest that although systemic hypertensive patients have a higher OPP in comparison to normal patients, this increase does not imply that they also have a higher OBF (as measured by the POBF tonograph). The higher OPP may be caused by chronic changes in the vascular net by the hemodynamics.There is a statistically significant difference in the OPP between normal and systemic hypertensive patients. More studies are required to evaluate the role of the OPP in ocular pathologies, especially in normal tension glaucoma. The results of this study suggest that although the systemic hypertensive patients have a higher OPP in comparison to a normal patient, this increase does not mean that they also have a higher OBF (as measured by POBF tonograph). This may be caused by chronic changes in the vascular net and in the blood hemodynamics in patients with systemic hypertension.


During robot-assisted laparoscopic prostatectomy, specific physiological conditions such as carbon dioxide insufflation and the steep Trendelenburg position can alter the cardiac workload and cerebral hemodynamics. Inadequate arterial blood pressure is associated with hypoperfusion, organ damage, and poor outcomes. Dynamic arterial elastance (Ea) has been proposed to be a useful index of fluid management in hypotensive patients. We therefore evaluated whether dynamic Ea can predict a mean arterial pressure (MAP) increase ≥ 15% after fluid challenge during pneumoperitoneum and the steep Trendelenburg position.We enrolled 39 patients receiving robot-assisted laparoscopic prostatectomy. Fluid challenge was performed with 500 mL colloids in the presence of preload-dependent conditions and arterial hypotension. Patients were classified as arterial pressure responders or arterial pressure nonresponders according to whether they showed an MAP increase ≥15% after fluid challenge. Dynamic Ea was defined as the ratio between the pulse pressure variation and stroke volume variation. Receiver operating characteristic curve analysis was performed to assess the arterial pressure responsiveness after fluid challenge during robot-assisted laparoscopic prostatectomy.P < 0.001). In receiver operating characteristic curve analysis, dynamic Ea showed an area under the curve of 0.810. The optimal cut-off value of dynamic Ea for predicting an MAP increase of ≥ 15% after fluid challenge was 0.74.Of the 39 patients, 17 were arterial pressure responders and 22 were arterial pressure nonresponders. The mean dynamic Ea before fluid challenge was significantly higher in arterial pressure responders than in arterial pressure nonresponders (0.79 vs 0.61, Dynamic Ea can predict an MAP increase ≥ 15% after fluid challenge during robot-assisted laparoscopic prostatectomy. This result suggests that evaluation of arterial pressure responsiveness using dynamic Ea helps to maintain an adequate arterial blood pressure and to improve perioperative outcomes in preload-dependent patients receiving robot-assisted laparoscopic prostatectomy under pneumoperitoneum and in the steep Trendelenburg position. Previous reports have shown that pneumoperitoneum and the Trendelenburg position can affect the cardiac workload3 and cerebral hemodynamics.5 Additionally, the upper age limit of patients receiving robotic prostatectomy is increasing,6 and patients with prostate cancer have increased cardiovascular risks.7 Therefore, further consideration of hemodynamic management, including fluid therapy, is needed during the perioperative period for patients undergoing robotic prostatectomy.Robot-assisted laparoscopic prostatectomy is widely performed due to its many advantages, including a reduced need for blood transfusion and fewer surgical complications compared with conventional open prostatectomy.10 When the mean arterial pressure (MAP) decreases in preload-dependent conditions, fluid administration is generally regarded as an initial therapy. Interestingly, dynamic arterial elastance (Ea), which is defined as the ratio between the pulse pressure variation (PPV) and stroke volume variation (SVV), has been proposed to be a useful index of fluid management in hypotensive patients.12 However, there are no reports on the ability of dynamic Ea to predict arterial pressure responsiveness under the special surgical conditions generated by the steep Trendelenburg position and carbon dioxide pneumoperitoneum.Maintenance of adequate arterial blood pressure is essential to avoid tissue hypoperfusion, organ damage, and subsequent poor outcomes in noncardiac surgery.13 in preload-dependent conditions (SVV > 10%)14 and with arterial hypotension 8 in patients receiving robot-assisted laparoscopic prostatectomy under carbon dioxide pneumoperitoneum and in the steep Trendelenburg position.In our present study, we hypothesized that dynamic Ea could be a useful predictor of arterial pressure responsiveness in robot-assisted laparoscopic prostatectomy. To test our hypothesis, we evaluated whether dynamic Ea could predict an MAP increase ≥ 15%http://cris.nih.go.kr, KCT0001131). A total of 42 male patients who were scheduled for robot-assisted laparoscopic prostatectomy due to prostate cancer were enrolled and written informed consent was obtained from all patients. The exclusion criteria were as follows: < 20 or > 80 years of age; medical history of arrhythmia, valvular heart disease, ischemic heart disease, or left ventricular ejection fraction < 40%; any pulmonary disease or abnormal preoperative chest radiography; renal disease ; new-onset arrhythmia after anesthesia induction; failure of arterial catheterization; or an unexpected severe intraoperative hemodynamic change.This prospective observational clinical study was conducted between June 2014 and September 2014. The study protocol was approved by the Asan Medical Center Institutional Review Board  and registered on an international clinical trials registry platform . The PPV was automatically calculated and averaged >4 consecutive cycles of 8 s.where PPA specialized hemodynamic monitoring system  was connected to the arterial line via FloTrac™ sensors (Edwards Lifesciences Corp). Cardiac output and stroke volume were calculated by real-time arterial waveform analysis. The SVV was computed every 20 s according to the following formula: max, SVmin, and SVmean indicate the maximal, minimal, and mean stoke volume in a respiratory cycle, respectively.After zeroing to atmosphere, cardiac output, stroke volume, and SVV values were obtained continually by arterial waveform analysis. SV12 the PPV measured by the IntelliVue MP90 and the SVV measured by the EV1000 were used to evaluate fluid responsiveness in robotic prostatectomy.Dynamic Ea was defined as the PPV/SVV ratio and was calculated from the average of 3 consecutive measurements of the SVV and PPV at a specific time point. In a previous report,® Base Primea; Fresenius Kabi, Bad Homburg, Germany) with an effect site concentration of 3 ng/mL. Rocuronium bromide 0.6 mg/kg was given to facilitate tracheal intubation. Anesthesia was maintained with 1vol% to 2vol% sevoflurane and 50% oxygen in medical air. The effect site concentration of remifentanil target-controlled infusion was adjusted to between 3 and 8 ng/mL. The depth of anesthesia was monitored using the bispectral index , which was maintained between 40 and 60. Sevoflurane administration and remifentanil target-controlled infusion were intermittently adjusted during surgery according to the bispectral index or hemodynamic parameters but were not changed during fluid challenge or hemodynamic measurements. Mechanical ventilation using an anesthetic machine  was performed using a fixed tidal volume of 8 mL/kg  and a respiratory rate of 10 to 16/min to maintain an end-tidal carbon dioxide concentration of between 35 and 40 mm Hg. A positive end-expiratory pressure of 8 cm H2O was applied equally in all patients. During surgery, all patients were placed in the Trendelenburg position at 35° and pneumoperitoneum was achieved by continuous carbon dioxide insufflation maintaining an intra-abdominal pressure of 12 cm H2O.General anesthesia and patient monitoring were performed according to our institutional standards. Intraoperative monitoring included electrocardiography, intra-arterial blood pressure, end-tidal carbon dioxide concentration, and peripheral oxygen saturation. Anesthesia was induced with thiopental sodium 5 mg/kg and target-controlled infusion of remifentanil .8After the induction of anesthesia, intra-arterial pressure was continuously monitored using radial arterial catheterization, and an additional intravenous route for fluid challenge was secured with a 16-gauge catheter. After zeroing to atmosphere, an indwelling radial artery catheter was simultaneously connected to the Philips IntelliVue MP90 monitoring system and the EV1000. Intraoperative basal fluid was restricted with continuous infusion of 2 mL/kg/h of crystalloid solution. Hemodynamic parameters were measured at 4 time points: 10 min after the Trendelenburg position was adopted and carbon dioxide insufflation (T1), just before fluid challenge (T2), 3 min after fluid challenge (T3), and at the time of skin closure (T4). T1 was regarded as the baseline for the hemodynamic parameters. T2 was determined by the presence of the preload-dependent condition, which is defined as the maintenance of SVV > 10% for >10 min,®; Fresenius Kabi, Bad Homburg, Germany) >20 min via an infusion pump. During fluid challenge (between T2 and T3), the respiratory rate or anesthetic concentration was not altered. When MAP was not maintained at 65 mm Hg or higher despite fluid challenge, 5 to 10 mg intravenous ephedrine was administered after evaluating the dynamic Ea.Fluid challenge was carried out with 500 mL 6% hydroxyethyl starch , and abnormal findings in laboratory tests were evaluated until postoperative day 7.13 At each time point, the cardiac index, MAP, heart rate, stroke volume index, PPV, and SVV were measured. All variables are recorded directly from the hemodynamic monitoring system, except for dynamic Ea, which was derived and calculated from the PPV and SVV.Patients were classified as arterial pressure responders or arterial pressure nonresponders according to whether they achieved an MAP increase ≥ 15% after fluid challenge.t test or the Mann–Whitney rank sum test. Categorical data between the 2 groups were compared using the chi-square test or Fisher's exact test. To simultaneously compare the change in hemodynamic variables after fluid challenge and the difference between arterial responders and arterial nonresponders, 2-way repeated measure analysis of variance was used. Receiver operating characteristic curve analysis was performed to assess the arterial pressure responsiveness after fluid challenge for each hemodynamic variable . The optimal cut-off value was determined using a value based on the Youden index, which was calculated as a maximum (sensitivity + specificity – 1). An area under the curve of > 0.75 was considered to show good prediction.15 All results are expressed as mean ± SD or number (proportion). P < 0.05 was considered statistically significant. Statistical analysis was performed using MedCalc® version 13.2.0  or SigmaPlot 10.0 .Sample size was determined using the difference between the area under the curve of 0.75  and 0.5 (null hypothesis). Assuming a type I error of 0.05 and a desired power of 0.80, 38 patients were required for the analysis. Expecting a dropout rate of 10%, 42 patients were enrolled. Normality of data was tested using the Shapiro–Wilk test. Differences in patient characteristics, preoperative laboratory values, and intraoperative and postoperative data between arterial pressure responders and arterial pressure nonresponders were compared using an unpaired A total of 42 patients were initially eligible for this study. However, 3 patients were excluded: 1 developed paroxysmal atrial fibrillation during surgery, another had arterial catheterization failure, and the remaining patient had sudden surgical bleeding and a subsequent severe intraoperative hemodynamic change. Finally, 39 patients were enrolled . Various cut-off values are listed in Table The area under the curve of each hemodynamic variable for the prediction of arterial pressure responsiveness after fluid challenge is provided in Table In our present study, we have shown that dynamic Ea can predict an increase in the MAP of ≥ 15% after fluid challenge in preload-dependent patients receiving robot-assisted laparoscopic prostatectomy under carbon dioxide pneumoperitoneum and in the steep Trendelenburg position. In addition, we found that a dynamic Ea value of > 0.74 was associated with an MAP increase of ≥ 15% during robot-assisted laparoscopic prostatectomy.16 Significant changes in the MAP, stroke volume, and systemic vascular resistance are associated with carbon dioxide insufflation and/or the head-down position.16 These earlier findings suggest that special surgical conditions during robotic prostatectomy can increase cardiac workload. In addition, cerebral perfusion pressure can be affected by increased intracranial pressure and intrathoracic pressure in patients receiving robotic prostatectomy under carbon dioxide pneumoperitoneum and in the steep Trendelenburg position.17 Furthermore, in elderly patients undergoing robotic prostatectomy, cardiovascular function can be compromised.18 Importantly, inadequate arterial blood pressure is associated with tissue hypoperfusion, organ damage, and poor outcomes.10 Thus, adequate maintenance of intraoperative arterial blood pressure is important in patients receiving robotic prostatectomy under carbon dioxide pneumoperitoneum and in the steep Trendelenburg position.The steep Trendelenburg position and pneumoperitoneum increase right- and left-side cardiac filling pressure.20 During positive pressure ventilation, cyclic changes in intrathoracic pressure can induce changes in stroke volume and arterial pulse pressure, and such variation can consequently be used as a dynamic volume index. However, clinical situations causing intrathoracic pressure changes can induce variations in right atrial pressure, thereby changing intrathoracic blood volume during positive pressure ventilation.21 In robot-assisted laparoscopic prostatectomy, for a good surgical field, the patient must be placed in a steep Trendelenburg position (25°–45° head down).21 In this specific position, the abdominal organs are pulled away from the operative field by gravity, causing an intrathoracic pressure increase. Moreover, additional carbon dioxide insufflation may affect venous return to the right atrium and exaggerate intrathoracic pressure changes. Therefore, fluid responsiveness assessed by the SVV or PPV may be influenced by the increased intrathoracic pressure and be less accurate during robotic prostatectomy.23 In addition, to evaluate the stroke volume index after a fluid challenge , a relatively constant arterial vascular tone would be required.25 Specific surgical conditions such as carbon dioxide insufflation and the steep Trendelenburg position can decrease venous return and predispose the patient to a decreased cardiac afterload,26 possibly reducing the predictability of the fluid responsiveness of both the SVV and PPV. Based on these considerations, the predictability of the arterial pressure responsiveness of the SVV and PPV can also be influenced, at least in part, by the increased intrathoracic pressure and decreased cardiac afterload during robotic prostatectomy.The SVV and PPV are widely used as fluid responsiveness indexes.27 In addition, dynamic Ea reflects the arterial vascular tone.28 Taken together, dynamic Ea is thought to be minimally influenced by changes in intrathoracic pressure and cardiac afterload. In previous studies, dynamic Ea was used to detect the need for vasopressor administration in preload-dependent patients.29 In our present study, we found that dynamic Ea can predict an increase in the MAP of ≥ 15% after a fluid challenge in preload-dependent patients receiving robotic prostatectomy under carbon dioxide pneumoperitoneum and in the steep Trendelenburg position. We considered that evaluation of the arterial pressure responsiveness using dynamic Ea could help to maintain adequate arterial blood pressure and to improve perioperative outcomes in patients receiving robotic prostatectomy.However, dynamic Ea, which is not an absolute value but a ratio between the PPV and SVV, is a useful index of fluid management in hypotensive patients under spontaneous breathing.27 The dynamic Ea cut-off value during robotic prostatectomy in our current analyses was measured as 0.74, which was lower than that of previous reports.27 Although it would be difficult to compare our results with those of previous studies, the SVV is thought to be more affected by intrathoracic pressure changes than the PPV in patients under carbon dioxide pneumoperitoneum and in the steep Trendelenburg position.22 Increased intrathoracic pressure could consequently increase both the SVV and PPV.23 However, the SVV is reported to be more influenced by increased intra-abdominal pressure than the PPV.22We obtained various cut-off values from 0.52 to 0.85 and found that the optimal cut-off value of dynamic Ea to predict an MAP increase of ≥ 15% after fluid challenge was 0.74. The optimal cut-off value of 0.74 can be used clinically as a good guide for predicting arterial pressure responsiveness after volume loading during robotic prostatectomy. The optimal cut-off value of dynamic Ea for predicting an MAP increase after fluid challenge has been reported to be 0.9 to 1.25 in several clinical situations.30 Also, use of intraoperative transesophageal echocardiography requires a trained physician and is expensive and invasive.32 Compared with cardiac output measurement using pulmonary arterial catheterization or transesophageal echocardiography, dynamic Ea can be measured more simply and less invasively. Second, SVV and PPV values were obtained at different times by their respective measurement devices. The SVV was calculated from the FloTrac® sensor/EV1000 device every 20 s, whereas the PPV was obtained from the Philips MP90 monitor every 8 s. However, to decrease the time difference, we recorded all SVV or PPV values for 3 consecutive measurements at specific time points and used an average value. Therefore, we consider that the effect of the time difference on dynamic Ea is minimal.There were several possible limitations to our present study. First, we evaluated fluid responsiveness using the MAP increase. Although cardiac output can be more important in preventing tissue hypoperfusion than MAP, measurement of cardiac output using pulmonary arterial catheterization or transesophageal echocardiography is clinically invasive and difficult in routine daily practice. The insertion of a pulmonary arterial catheter is associated with fatal complications.In conclusion, the dynamic Ea, which is simply calculated from the SVV and PPV, can be predictive of arterial pressure responsiveness to fluid challenge in robot-assisted laparoscopic prostatectomy. The optimal cut-off value of dynamic Ea for predicting an MAP increase of ≥ 15% after fluid challenge is 0.74. Our present findings provide useful information for future fluid management protocols in patients with preload-dependent condition and arterial hypotension during carbon dioxide pneumoperitoneum and the steep Trendelenburg position.