Angiotensin-II Use for Refractory Hypotension in an Infant With Bilateral Renal Agenesis.

Infants with congenital bilateral renal agenesis are at significant risk for morbidity and mortality, despite substantial and continuing advances in fetal and neonatal therapeutics. Infants with bilateral renal agenesis may episodically develop severe hypotension that can be refractory to traditional vasopressors. Synthetic angiotensin-II has been successfully used in adult and a few pediatric patients with refractory hypotension but has not been extensively studied in infants. We describe the use of angiotensin-II in treating refractory hypotension in a premature infant with congenital bilateral renal agenesis admitted to the NICU. Within 48 hours, he no longer required other vasopressors. Subsequently, angiotensin-II was gradually weaned and discontinued over 10 days and the patient was ultimately discharged from the hospital. This case demonstrates that angiotensin-II may be a helpful agent to treat refractory hypotension in infants with bilateral renal agenesis.

Renin and Survival in Patients Given Angiotensin II for Catecholamine-Resistant Vasodilatory Shock. A Clinical Trial.

Rationale: Exogenous angiotensin II increases mean arterial pressure in patients with catecholamine-resistant vasodilatory shock (CRVS). We hypothesized that renin concentrations may identify patients most likely to benefit from such therapy.Objectives: To test the kinetic changes in renin concentrations and their prognostic value in patients with CRVS.Methods: We analyzed serum samples from patients enrolled in the ATHOS-3 (Angiotensin II for the Treatment of High-Output Shock) trial for renin, angiotensin I, and angiotensin II concentrations before the start of administration of angiotensin II or placebo and after 3 hours.Measurements and Main Results: Baseline serum renin concentration (normal range, 2.13-58.78 pg/ml) was above the upper limits of normal in 194 of 255 (76%) study patients with a median renin concentration of 172.7 pg/ml (interquartile range [IQR], 60.7 to 440.6 pg/ml), approximately threefold higher than the upper limit of normal. Renin concentrations correlated positively with angiotensin I/II ratios (r = 0.39; P < 0.001). At 3 hours after initiation of angiotensin II therapy, there was a 54.3% reduction (IQR, 37.9% to 66.5% reduction) in renin concentration compared with a 14.1% reduction (IQR, 37.6% reduction to 5.1% increase) with placebo (P < 0.0001). In patients with renin concentrations above the study population median, angiotensin II significantly reduced 28-day mortality to 28 of 55 (50.9%) patients compared with 51 of 73 patients (69.9%) treated with placebo (unstratified hazard ratio, 0.56; 95% confidence interval, 0.35 to 0.88; P = 0.012) (P = 0.048 for the interaction).Conclusions: The serum renin concentration is markedly elevated in CRVS and may identify patients for whom treatment with angiotensin II has a beneficial effect on clinical outcomes.Clinical trial registered with www.clinicaltrials.gov (NCT02338843).

Angiotensin I and angiotensin II concentrations and their ratio in catecholamine-resistant vasodilatory shock.

BACKGROUND: In patients with vasodilatory shock, plasma concentrations of angiotensin I (ANG I) and II (ANG II) and their ratio may reflect differences in the response to severe vasodilation, provide novel insights into its biology, and predict clinical outcomes. The objective of these protocol prespecified and subsequent post hoc analyses was to assess the epidemiology and outcome associations of plasma ANG I and ANG II levels and their ratio in patients with catecholamine-resistant vasodilatory shock (CRVS) enrolled in the Angiotensin II for the Treatment of High-Output Shock (ATHOS-3) study. METHODS: We measured ANG I and ANG II levels at baseline, calculated their ratio, and compared these results to values from healthy volunteers (controls). We dichotomized patients according to the median ANG I/II ratio (1.63) and compared demographics, clinical characteristics, and clinical outcomes. We constructed a Cox proportional hazards model to test the independent association of ANG I, ANG II, and their ratio with clinical outcomes. RESULTS: Median baseline ANG I level (253 pg/mL [interquartile range (IQR) 72.30-676.00 pg/mL] vs 42 pg/mL [IQR 30.46-87.34 pg/mL] in controls; P <  0.0001) and median ANG I/II ratio (1.63 [IQR 0.98-5.25] vs 0.4 [IQR 0.28-0.64] in controls; P <  0.0001) were elevated, whereas median ANG II levels were similar (84 pg/mL [IQR 23.85-299.50 pg/mL] vs 97 pg/mL [IQR 35.27-181.01 pg/mL] in controls; P = 0.9895). At baseline, patients with a ratio above the median (≥1.63) had higher ANG I levels (P <  0.0001), lower ANG II levels (P <  0.0001), higher albumin concentrations (P = 0.007), and greater incidence of recent (within 1 week) exposure to angiotensin-converting enzyme inhibitors (P <  0.00001), and they received a higher norepinephrine-equivalent dose (P = 0.003). In the placebo group, a baseline ANG I/II ratio <1.63 was associated with improved survival (hazard ratio 0.56; 95% confidence interval 0.36-0.88; P = 0.01) on unadjusted analyses. CONCLUSIONS: Patients with CRVS have elevated ANG I levels and ANG I/II ratios compared with healthy controls. In such patients, a high ANG I/II ratio is associated with greater norepinephrine requirements and is an independent predictor of mortality, thus providing a biological rationale for interventions aimed at its correction. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT02338843. Registered 14 January 2015.

Sensitivity to angiotensin II dose in patients with vasodilatory shock: a prespecified analysis of the ATHOS-3 trial.

BACKGROUND: Early clinical data showed that some patients with vasodilatory shock are responsive to low doses of angiotensin II. The objective of this analysis was to compare clinical outcomes in patients requiring ≤ 5 ng kg-1 min-1 angiotensin II at 30 min (≤ 5 ng kg-1 min-1 subgroup) to maintain mean arterial pressure (MAP) ≥ 75 mmHg versus patients receiving > 5 ng kg-1 min-1 angiotensin II at 30 min (> 5 ng kg-1 min-1 subgroup). Data from angiotensin II-treated patients enrolled in the ATHOS-3 trial were used. RESULTS: The subgroup of patients whose angiotensin II dose was down-titrated from 20 ng kg-1 min-1 at treatment initiation to ≤ 5 ng kg-1 min-1 at 30 min (79/163) had significantly lower endogenous serum angiotensin II levels and norepinephrine-equivalent doses and significantly higher MAP versus the > 5 ng kg-1 min-1 subgroup (84/163). Patients in the ≤ 5 ng kg-1 min-1 subgroup were more likely to have a MAP response at 3 h versus those in the > 5 ng kg-1 min-1 subgroup (90% vs. 51%, respectively; odds ratio, 8.46 [95% CI 3.63-19.7], P < 0.001). Day 28 survival was also higher in the ≤ 5 ng kg-1 min-1 subgroup versus the > 5 ng kg-1 min-1 subgroup (59% vs. 33%, respectively; hazard ratio, 0.48 [95% CI 0.28-0.72], P = 0.0007); multivariate analyses supported the survival benefit in patients with lower angiotensin II levels. The ≤ 5 ng kg-1 min-1 subgroup had a more favorable safety profile and lower treatment discontinuation rate than the > 5 ng kg-1 min-1 subgroup. CONCLUSIONS: This prespecified analysis showed that down-titration to ≤ 5 ng kg-1 min-1 angiotensin II at 30 min is an early predictor of favorable clinical outcomes which may be related to relative angiotensin II insufficiency.

Broad spectrum vasopressors: a new approach to the initial management of septic shock?

The mainstay of hemodynamic treatment of septic shock is fluid resuscitation followed by vasopressors where fluids alone are insufficient to achieve target blood pressure. Norepinephrine, a catecholamine, is the first-line vasopressor used worldwide but given that all routinely used catecholamines target the same adrenergic receptors, many clinicians may add a non-catecholamine vasopressor where refractory hypotension due to septic shock is present. However, the timing of this additional intervention is variable. This decision is based on three key factors: availability, familiarity, and safety profile. In our opinion, further consideration should be potential vasopressor response because following appropriate volume resuscitation, the response to different vasopressor classes is neither uniform nor predictable. Critically ill patients who are non-responders to high-dose catecholamines have a dismal outcome. Similarly, patients have a variable response to non-catecholamine agents including vasopressin and angiotensin II: but where patients exhibit a blood pressure response the outcomes are improved over non-responders. This variable responsiveness to vasopressors is similar to the clinical approach of anti-microbial sensitivity. In this commentary, the authors propose the concept of "broad spectrum vasopressors" wherein patients with septic shock are started on multiple vasopressors with a different mechanism of action simultaneously while the vasopressor sensitivity is assessed. Once the vasopressor sensitivities are assessed, then the vasopressors are 'de-escalated' accordingly. We believe that this concept may offer a new approach to the treatment of septic shock.

Therapeutic Opportunities for Hepcidin in Acute Care Medicine.

Iron homeostasis is often disrupted in acute disease with an increase in catalytic free iron leading to the formation of reactive oxygen species and subsequent tissue-specific oxidative damage. This article highlights the potential therapeutic benefit of exogenous hepcidin to prevent and treat iron-induced injury, specifically in the management of infection from enteric gram-negative bacilli or fungi, malaria, sepsis, acute kidney injury, trauma, transfusion, cardiopulmonary bypass surgery, and liver disease.

Synthetic Human Angiotensin II in Pediatric Patients With Vasodilatory Shock: A Report on Two Patients.

Severe sepsis and septic shock continue to be an important problem in children, with hospital mortality rates for pediatric severe sepsis as high as 25%. CASE SUMMARY: Two pediatric patients with septic shock requiring high dose vasopressors, who were treated with angiotensin II as part of an open-label study. Both patients had a significant increase in mean arterial pressure shortly after initiation of angiotensin II, with a reduction of the dose of catecholamines and vasopressin infusions. Serious adverse events reported were not attributable to angiotensin II by investigators. One patient survived, and one died related to progressive cerebral edema. CONCLUSIONS: Angiotensin II may represent another therapeutic option for pediatric patients who remain hypotensive despite receiving fluids and standard vasopressor therapy and deserves further study.

Outcomes in Patients with Vasodilatory Shock and Renal Replacement Therapy Treated with Intravenous Angiotensin II.

OBJECTIVE: Acute kidney injury requiring renal replacement therapy in severe vasodilatory shock is associated with an unfavorable prognosis. Angiotensin II treatment may help these patients by potentially restoring renal function without decreasing intrarenal oxygenation. We analyzed the impact of angiotensin II on the outcomes of acute kidney injury requiring renal replacement therapy. DESIGN: Post hoc analysis of the Angiotensin II for the Treatment of High-Output Shock 3 trial. SETTING: ICUs. PATIENTS: Patients with acute kidney injury treated with renal replacement therapy at initiation of angiotensin II or placebo (n = 45 and n = 60, respectively). INTERVENTIONS: IV angiotensin II or placebo. MEASUREMENTS AND MAIN RESULTS: Primary end point: survival through day 28; secondary outcomes included renal recovery through day 7 and increase in mean arterial pressure from baseline of ≥ 10 mm Hg or increase to ≥ 75 mm Hg at hour 3. Survival rates through day 28 were 53% (95% CI, 38%-67%) and 30% (95% CI, 19%-41%) in patients treated with angiotensin II and placebo (p = 0.012), respectively. By day 7, 38% (95% CI, 25%-54%) of angiotensin II patients discontinued RRT versus 15% (95% CI, 8%-27%) placebo (p = 0.007). Mean arterial pressure response was achieved in 53% (95% CI, 38%-68%) and 22% (95% CI, 12%-34%) of patients treated with angiotensin II and placebo (p = 0.001), respectively. CONCLUSIONS: In patients with acute kidney injury requiring renal replacement therapy at study drug initiation, 28-day survival and mean arterial pressure response were higher, and rate of renal replacement therapy liberation was greater in the angiotensin II group versus the placebo group. These findings suggest that patients with vasodilatory shock and acute kidney injury requiring renal replacement therapy may preferentially benefit from angiotensin II.

Angiotensin II for the Treatment of Vasodilatory Shock.

BACKGROUND: Vasodilatory shock that does not respond to high-dose vasopressors is associated with high mortality. We investigated the effectiveness of angiotensin II for the treatment of patients with this condition. METHODS: We randomly assigned patients with vasodilatory shock who were receiving more than 0.2 µg of norepinephrine per kilogram of body weight per minute or the equivalent dose of another vasopressor to receive infusions of either angiotensin II or placebo. The primary end point was a response with respect to mean arterial pressure at hour 3 after the start of infusion, with response defined as an increase from baseline of at least 10 mm Hg or an increase to at least 75 mm Hg, without an increase in the dose of background vasopressors. RESULTS: A total of 344 patients were assigned to one of the two regimens; 321 received a study intervention (163 received angiotensin II, and 158 received placebo) and were included in the analysis. The primary end point was reached by more patients in the angiotensin II group (114 of 163 patients, 69.9%) than in the placebo group (37 of 158 patients, 23.4%) (odds ratio, 7.95; 95% confidence interval [CI], 4.76 to 13.3; P<0.001). At 48 hours, the mean improvement in the cardiovascular Sequential Organ Failure Assessment (SOFA) score (scores range from 0 to 4, with higher scores indicating more severe dysfunction) was greater in the angiotensin II group than in the placebo group (-1.75 vs. -1.28, P=0.01). Serious adverse events were reported in 60.7% of the patients in the angiotensin II group and in 67.1% in the placebo group. Death by day 28 occurred in 75 of 163 patients (46%) in the angiotensin II group and in 85 of 158 patients (54%) in the placebo group (hazard ratio, 0.78; 95% CI, 0.57 to 1.07; P=0.12). CONCLUSIONS: Angiotensin II effectively increased blood pressure in patients with vasodilatory shock that did not respond to high doses of conventional vasopressors. (Funded by La Jolla Pharmaceutical Company; ATHOS-3 ClinicalTrials.gov number, NCT02338843 .).

Angiotensin II for the Treatment of High-Output Shock 3 (ATHOS-3): protocol for a phase III, double-blind, randomised controlled trial.

OBJECTIVE: Catecholamine-resistant hypotension (CRH) is characterised by inadequate response to standard doses of vasopressors, and increased mortality. Our Angiotensin II for the Treatment of High-Output Shock 3 (ATHOS-3) trial compares the efficacy and safety of angiotensin II (ANGII) versus placebo in CRH. DESIGN, SETTING AND PARTICIPANTS: A phase III, multicentre, randomised, placebo-controlled trial of LJPC-501 (synthetic ANGII) for CRH in up to 120 intensive care units. We have set a target of 300 critically ill patients with CRH receiving standard-of-care (SOC) vasopressor therapy (ie, catecholamine dose > 0.2 µg/kg/min for 6-48 hours to maintain a mean arterial pressure [MAP] of 55-70 mmHg). Calculation of a norepinephrine-equivalent vasopressor dose is critical to determining patient eligibility, as ANGII will supplement ongoing vasopressor therapy. INTERVENTIONS: Stable patients will be randomised 1:1 to SOC vasopressor plus continuous intravenous infusion of ANGII or placebo for 48 hours, with an aim of achieving MAP of 75 mmHg for the first 3 hours. ANGII (initiated at 20 ng/ kg/min) will be titrated according to pre-specified guidelines until 48 hours, with patients followed until Day 7. Frequent vital sign and haemodynamic monitoring will support ANGII titration, safety monitoring and efficacy assessments. MAIN OUTCOME MEASURES: The primary efficacy endpoint is MAP ≥ 75 mmHg or an increase of ≥ 10 mmHg at treatment Hour 3. Secondary endpoints include change in total and cardiovascular Sequential Organ Failure Assessment scores over 48 hours, and safety data. CONCLUSION: Our study will investigate the utility of adding ANGII to current SOC vasopressor options to increase the efficacy and safety of CRH therapy.

Combination of galectin inhibitor GCS-100 and BH3 mimetics eliminates both p53 wild type and p53 null AML cells.

Galectin 3 (LGALS3) expression is prognostic for poor survival in acute myeloid leukemia (AML) patients. GCS-100 is a novel galectin inhibitor that may prove useful for AML therapy. In this study, we found that GCS-100 induced apoptosis in AML cells. The agent reduced MCL-1 expression suggesting that GCS-100 could be more effective when combined with a BH3 mimetic. Indeed, potent synergistic cytotoxicity was achieved when GCS-100 was combined with ABT-737 or ABT-199. Furthermore, the GCS-100/ABT-199 combination was effective against primary AML blast cells from patients with FLT3 ITD mutations, which is another prognostic factor for poor outcome in AML. This activity may involve wild-type p53 as shRNA knockdown of LGALS3 or galectin 1 (LGALS1) sensitized wild-type p53 OCI-AML3 cells to GCS-100/ABT-737-induced apoptosis to a much greater extent than p53 null THP-1 cells. Suppression of LGALS3 by shRNA inhibited MCL-1 expression in OCI-AML3 cells, but not THP-1 cells, suggesting the induced sensitivity to ABT-737 may involve a MCL-1 mediated mechanism. OCI-AML3 cells with LGALS1 shRNA were also sensitized to ABT-737. However, these cells exhibited increased MCL-1 expression, so MCL-1 reduction is apparently not required in this process. A role for p53 appears important as GCS-100 induces p53 expression and shRNA knockdown of p53 protected OCI-AML3 cells from the cytotoxic effects of the GCS-100/ABT-737 treatment combination. Our results suggest that galectins regulate a survival axis in AML cells, which may be targeted via combined inhibition with drugs such as GCS-100 and ABT-199.

Pharmacodynamic evaluation of intragastric pH and implications for famotidine dosing in the prophylaxis of non-steroidal anti-inflammatory drug induced gastropathy-a proof of concept analysis.

OBJECTIVE: Famotidine given at a dose of 80 mg/day is effective in preventing NSAID-induced gastropathy. The aim of this proof of concept study was to compare twice a day (BID) vs 3-times a day (TID) administration of this total dose of famotidine on intragastric pH in healthy volunteers. RESEARCH DESIGN AND METHODS: Two analyses were undertaken: (1) a 13 subject controlled cross-over 24-h intragastric pH evaluation of the BID and TID administration of 80 mg/day of famotidine, as well as measures for drug accumulation over 5 days (EudraCT, number 2006-002930-39); and (2) a pharmacokinetic (PK)/pharmacodynamic (PD) model which predicted steady-state famotidine plasma concentrations and pH of the two regimens. RESULTS: For the cross-over study, gastric pH was above 3.5 for a mean of 20 min longer for TID dosing compared to BID dosing on Day 1. On Day 5, the mean time above this threshold was higher with the BID regimen by ∼25 min. For pH 4, subjects' gastric pH was above this pH value for a mean of 25 min longer for TID dosing compared to BID dosing on Day 1. For Day 5, the pH was above 4 for ∼45 min longer with the TID regimen as compared with the BID regimen. The mean 24-h gastric pH values when taken in the upright position trended higher for the TID dosing period compared to the BID regimen on Day 1. The steady-state simulation model indicated that, following TID dosing, intragastric pH will be above 3 for 24 h vs 16 h for the BID regimen. There was no evidence for plasma accumulation of famotidine with TID dosing as compared to BID dosing from either analysis. CONCLUSION: The data indicate that overall more time is spent above the acidic threshold pH values when 80 mg/day of famotidine is administered TID vs BID. Key limitations included small study size with a short duration and lack of a baseline examination, but was compensated for by the cross-over and PK/PD modeling design. Although most of the comparisons in this proof of concept study were not statistically significant these results have important implications for future research on gastric acid lowering agents used for the prevention of NSAID-induced gastropathy.

Bridging the gap between basic and applied biology: towards preclinical translation.

To better translate basic research findings into the clinic, we are moving away from the traditional one-gene-one-phenotype model towards the discovery of complex mechanisms. In this Editorial, the new Editor-in-Chief and Senior Editors of Disease Models & Mechanisms (DMM) discuss the role that the journal will play in this transition. DMM will continue to provide a platform for studies that bridge basic and applied science, and, by demanding the rigorous assessment of animal models of disease, will help drive the establishment of robust standards of preclinical testing for drug development.

A phase 2 trial of glufosfamide in combination with gemcitabine in chemotherapy-naive pancreatic adenocarcinoma.

OBJECTIVES: A dose-escalation study of glufosfamide plus gemcitabine showed that the combination could be administered safely at full doses. The purpose of this phase II study was to evaluate the safety and efficacy of this combination in chemotherapy-naive pancreatic adenocarcinoma. METHODS: Eligible patients had metastatic and/or locally advanced pancreatic adenocarcinoma, Karnofsky performance status >or=70, creatinine clearance (CrCL) >or=60 mL/min, and acceptable organ function. Patients received glufosfamide 4500 mg/m intravenous on day 1 and gemcitabine 1000 mg/m intravenous on Days 1, 8, and 15 of every 28-day cycle. The primary end point was response rate. RESULTS: Twenty-nine patients were enrolled; 14 male, median age 58 years. Twenty-three (79%) patients had distant metastases. Median cycles on treatment was 4 (range: 1-18+). Of 28, 5 (18%; 95% CI: 6%-37%) patients had a confirmed partial response (median duration: 8.4 months) and 1 had an unconfirmed partial response. Eleven patients (39%) had stable disease. Median progression-free survival was 3.7 months, median overall survival was 6 months, and 1-year survival was 32%. Grade 3/4 neutropenia occurred in 23 (79%) patients and grade 3/4 thrombocytopenia in 10 (34%) patients. The CrCL fell below 60 mL/min in 10 of 27 (37%) patients. Renal failure occurred in 4 patients. Decrease in CrCL was correlated with glufosfamide and isophosphoramide mustard pharmacokinetic area under the curve. CONCLUSIONS: The combination of glufosfamide plus gemcitabine is active in pancreatic cancer; however, hematologic and renal toxicity were pronounced. Alternative dosing of glufosfamide plus gemcitabine should be explored.

A randomised Phase III trial of glufosfamide compared with best supportive care in metastatic pancreatic adenocarcinoma previously treated with gemcitabine.

PURPOSE: There are currently no approved therapies for patients with metastatic pancreatic adenocarcinoma previously treated with gemcitabine. This Phase III trial evaluated the efficacy and safety of glufosfamide as compared with best supportive care (BSC) in this patient population. METHODS: Patients were randomised to glufosfamide plus BSC or to BSC alone with baseline performance status as a stratification factor. The primary end-point was overall survival. RESULTS: Three hundred and three patients were randomised: 148 to glufosfamide plus BSC and 155 to BSC alone. There was an 18% increase in overall survival for glufosfamide that was not statistically significant: hazard ratio (HR) 0.85 (95% confidence interval (CI) 0.66-1.08, p=0.19). Median survival was 105 (range 5-875) days for glufosfamide and 84 (range 2+ to 761) days for BSC. Grade 3/4 creatinine increase occurred in 6 patients on glufosfamide, including 4 with dosing errors. CONCLUSION: These results suggest low activity of glufosfamide in this very refractory patient population.