Efficacy and Safety of Ceftazidime-Avibactam Plus Metronidazole Versus Meropenem in the Treatment of Complicated Intra-abdominal Infection: Results From a Randomized, Controlled, Double-Blind, Phase 3 Program.

BACKGROUND: When combined with ceftazidime, the novel non-ß-lactam ß-lactamase inhibitor avibactam provides a carbapenem alternative against multidrug-resistant infections. Efficacy and safety of ceftazidime-avibactam plus metronidazole were compared with meropenem in 1066 men and women with complicated intra-abdominal infections from 2 identical, randomized, double-blind phase 3 studies (NCT01499290 and NCT01500239). METHODS: The primary end point was clinical cure at test-of-cure visit 28-35 days after randomization, assessed by noninferiority of ceftazidime-avibactam plus metronidazole to meropenem in the microbiologically modified intention-to-treat (mMITT) population (in accordance with US Food and Drug Administration guidance), and the modified intention-to-treat and clinically evaluable populations (European Medicines Agency guidance). Noninferiority was considered met if the lower limit of the 95% confidence interval for between-group difference was greater than the prespecified noninferiority margin of -12.5%. RESULTS: Ceftazidime-avibactam plus metronidazole was noninferior to meropenem across all primary analysis populations. Clinical cure rates with ceftazidime-avibactam plus metronidazole and meropenem, respectively, were as follows: mMITT population, 81.6% and 85.1% (between-group difference, -3.5%; 95% confidence interval -8.64 to 1.58); modified intention-to-treat, 82.5% and 84.9% (-2.4%; -6.90 to 2.10); and clinically evaluable, 91.7% and 92.5% (-0.8%; -4.61 to 2.89). The clinical cure rate with ceftazidime-avibactam plus metronidazole for ceftazidime-resistant infections was comparable to that with meropenem (mMITT population, 83.0% and 85.9%, respectively) and similar to the regimen's own efficacy against ceftazidime-susceptible infections (82.0%). Adverse events were similar between groups. CONCLUSIONS: Ceftazidime-avibactam plus metronidazole was noninferior to meropenem in the treatment of complicated intra-abdominal infections. Efficacy was similar against infections caused by ceftazidime-susceptible and ceftazidime-resistant pathogens. The safety profile of ceftazidime-avibactam plus metronidazole was consistent with that previously observed with ceftazidime alone. CLINICAL TRIALS REGISTRATION: NCT01499290 and NCT01500239.

A randomized, double-blind, placebo-controlled, Phase 2b study to evaluate the safety and efficacy of recombinant human soluble thrombomodulin, ART-123, in patients with sepsis and suspected disseminated intravascular coagulation.

OBJECTIVES: To determine the safety and efficacy of recombinant thrombomodulin (ART-123) in patients with suspected sepsis-associated disseminated intravascular coagulation. DESIGN: Phase 2b, international, multicenter, double-blind, randomized, placebo-controlled, parallel group, screening trial. SETTING: Two hundred and thirty-three ICUs in 17 countries. PATIENTS: All adult patients admitted with sepsis and suspected disseminated intravascular coagulation as assessed using a modified International Society on Thrombosis and Hemostasis score. INTERVENTIONS: Patients were randomized to receive IV ART-123 (0.06 mg/kg/d) for 6 days or placebo, in addition to standard of care. The primary endpoint was reduction in mortality. Secondary endpoints included reversal of overt disseminated intravascular coagulation and reduction in disease severity. MEASUREMENTS AND MAIN RESULTS: A total of 750 patients were randomized, nine of whom did not receive the allocated treatment so that 371 patients received ART-123 and 370 received placebo. There were no meaningful differences between the two groups in any of the baseline variables. Twenty-eight-day mortality was 17.8% in the ART-123 group and 21.6% in the placebo group (Cochran-Mantel-Haenszel two-sided p value of 0.273 in favor of ART-123, which met the predefined statistical test for evidence suggestive of efficacy). There were no statistically significant differences in event-free and alive days between the two groups. d-dimer, prothrombin fragment F1.2 and TATc concentrations were lower in the ART-123 group than in the placebo group. There were no differences between the two groups in organ function, inflammatory markers, bleeding or thrombotic events or in the development of new infections. In post hoc analyses, greatest benefit from ART-123 was seen in patients with at least one organ system dysfunction and an international normalized ratio greater than 1.4 at baseline. CONCLUSIONS: ART-123 is a safe intervention in critically ill patients with sepsis and suspected disseminated intravascular coagulation. The study provided evidence suggestive of efficacy supporting further development of this drug in sepsis-associated coagulopathy including disseminated intravascular coagulation. Future study should focus on using ART-123 in the subgroup of patients most likely to respond to this agent.

Effect of eritoran, an antagonist of MD2-TLR4, on mortality in patients with severe sepsis: the ACCESS randomized trial.

IMPORTANCE: Eritoran is a synthetic lipid A antagonist that blocks lipopolysaccharide (LPS) from binding at the cell surface MD2-TLR4 receptor. LPS is a major component of the outer membrane of gram-negative bacteria and is a potent activator of the acute inflammatory response. OBJECTIVE: To determine if eritoran, a TLR4 antagonist, would significantly reduce sepsis-induced mortality. DESIGN, SETTING, AND PARTICIPANTS: We performed a randomized, double-blind, placebo-controlled, multinational phase 3 trial in 197 intensive care units. Patients were enrolled from June 2006 to September 2010 and final follow-up was completed in September 2011. INTERVENTIONS: Patients with severe sepsis (n = 1961) were randomized and treated within 12 hours of onset of first organ dysfunction in a 2:1 ratio with a 6-day course of either eritoran tetrasodium (105 mg total) or placebo, with n = 1304 and n = 657 patients, respectively. MAIN OUTCOME MEASURES: The primary end point was 28-day all-cause mortality. The secondary end points were all-cause mortality at 3, 6, and 12 months after beginning treatment. RESULTS: Baseline characteristics of the 2 study groups were similar. In the modified intent-to-treat analysis (randomized patients who received at least 1 dose) there was no significant difference in the primary end point of 28-day all-cause mortality with 28.1% (366/1304) in the eritoran group vs 26.9% (177/657) in the placebo group (P = .59; hazard ratio, 1.05; 95% CI, 0.88-1.26; difference in mortality rate, -1.1; 95% CI, -5.3 to 3.1) or in the key secondary end point of 1-year all-cause mortality with 44.1% (290/657) in the eritoran group vs 43.3% (565/1304) in the placebo group, Kaplan-Meier analysis of time to death by 1 year, P = .79 (hazard ratio, 0.98; 0.85-1.13). No significant differences were observed in any of the prespecified subgroups. Adverse events, including secondary infection rates, did not differ between study groups. CONCLUSIONS AND RELEVANCE: Among patients with severe sepsis, the use of eritoran, compared with placebo, did not result in reduced 28-day mortality. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00334828.

Intra-arrest transnasal evaporative cooling: a randomized, prehospital, multicenter study (PRINCE: Pre-ROSC IntraNasal Cooling Effectiveness).

BACKGROUND: Transnasal evaporative cooling has sufficient heat transfer capacity for effective intra-arrest cooling and improves survival in swine. The aim of this study was to determine the safety, feasibility, and cooling efficacy of prehospital transnasal cooling in humans and to explore its effects on neurologically intact survival to hospital discharge. METHODS AND RESULTS: Witnessed cardiac arrest patients with a treatment interval

Frequent intravenous pulses of growth hormone together with glutamine supplementation in prolonged critical illness after multiple trauma: effects on nitrogen balance, insulin resistance, and substrate oxidation.

OBJECTIVES: To estimate the efficacy and metabolic effects of growth hormone substitution as intravenous pulses together with alanyl-glutamine supplementation and tight blood glucose control in prolonged critical illness. DESIGN: Prospective double-blind, randomized trial with open-label control arm. SETTING: Intensive care unit of tertiary level hospital. PATIENTS: Thirty multiple trauma patients (median Injury Severity Score 34). INTERVENTIONS: Patients were randomized, at day 4 after trauma, to receive intravenous alanyl-glutamine supplementation (0.3 g/kg x day(-1) from day 4 until day 17) and intravenous growth hormone (administered days 7-17, full dose 50 microg/kg x day(-1) from day 10 onward) (group 1, n = 10) or alanyl-glutamine and placebo (group 2, n = 10). Group 3 (n = 10) received isocaloric isonitrogenous nutrition (proteins 1.5 g/kg x day(-1)) without alanyl-glutamine. MEASUREMENTS AND MAIN RESULTS: Cumulative nitrogen balance for the whole study period was -97 +/- 38 g of nitrogen for group 1, -193 +/- 50 g of nitrogen for group 2, and -198 +/- 77 g of nitrogen for group 3 (p < .001). This represents a daily saving of 300 g of lean body mass in group 1. Insulin-mediated glucose disposal, during euglycemic clamp, as a measure of insulin sensitivity, significantly worsened between days 4 and 17 in group 1 but improved in groups 2 and 3. Group 1 required significantly more insulin to control blood glucose, resulting in higher insulinemia (approximately 70 mIU in group 1 vs. approximately 25 mIU in groups 2 and 3). Despite this, growth hormone treatment caused an increase in plasma nonesterified fatty acid (approximately 0.5-0.6 mM in group 1 in comparison with approximately 0.2-0.3 mM in groups 2 and 3) but did not influence lipid oxidation. There were no differences in morbidity, mortality, or 6-month outcome among the groups. CONCLUSIONS: Treatment with frequent intravenous pulses of low-dose growth hormone together with alanyl-glutamine supplementation improves nitrogen economy in patients with prolonged critical illness after multiple trauma but worsens insulin sensitivity. Tight blood glucose control is possible but requires higher doses of insulin.

Frequent intravenous pulses of growth hormone together with alanylglutamine supplementation in prolonged critical illness after multiple trauma: effects on glucose control, plasma IGF-I and glutamine.

OBJECTIVE: We aim to demonstrate that low dose growth hormone (GH) administered in i.v. pulses every 3h is able to normalize IGF-I levels in subjects with prolonged critical illness, after multiple trauma. We also ask whether it is possible to control glycaemia during such a treatment and how alanylglutamine (AG) supplementation influences plasma glutamine concentration. METHODS: We used a prospective double-blind (group 1 vs. 2), randomized trial with an open-label control arm (group 3). Thirty multiple trauma patients (median age: 36, 42, 46 years) were randomized on day 4 after trauma to receive (group 1, n=10) i.v. AG supplementation (0.3 g/kg day from day 4 till 17) and i.v. GH (0.05 mg/kg day divided into 8 boluses, maximum dose at 3 AM, administered on days 7-17) or AG and placebo (group 2, n=10). Group 3 (n=10) received isocaloric isonitrogenous (proteins 1.5 g/kg day) nutrition without AG. Glycaemia was controlled by i.v. insulin infusion according to a routine protocol. RESULTS: GH treatment caused an increase of IGF-I (from median 169 on day 4 to 493 ng/ml on day 17), IGFBP-3 (from 2.4 to 3.2 microg/ml) and a fall in IGFBP-1 (from 11.5 to 3.1 microg/ml), whilst in both groups 2 and 3 these indices remained unchanged. At the end of the study (day 17) IGF-I and IGFBP-1 differed significantly among groups (p=0.008 resp. p=0.010, Kruskal-Wallis). Plasma glutamine remained below the normal range through the study in all groups (median: 0.18-0.30 mM), but had a tendency to rise in group 2 in contrast with a fall in groups 1 and 3 (NS). Group 1 required more insulin (p<0.01) than did the control group but median glycaemia was only 0.4-0.5 mM higher in group 1 (6.5 mM) than in groups 2 and 3 (6.1 resp. 6.0 mM). CONCLUSIONS: GH (0.05 g/kg day) administered in i.v. pulses is able to normalize IGF-I levels in subjects with prolonged critical illness after trauma. During this treatment, the standard dose of AG prevents worsening of plasma glutamine deficiency and glucose control is possible using routine algorithms, but it requires higher insulin doses.

Dymanics of matrix-metalloproteinase 9 after brain trauma--results of a pilot study.

BACKGROUND: Secondary brain injury contributes to poor outcome for patients sustaining brain trauma. Matrix metalloproteinase-9 (MMP-9) is a potential marker, as well as effector of secondary brain injury. This enzyme degrades components of extracellular matrix, and thus it can contribute to blood-brain barrier disruption. METHODS: We studied dynamics of MMP-9 in jugular venous blood of 15 patients sustaining either an isolated head injury or a head injury as a part of major trauma, and requiring intensive care (Glasgow Coma Scale <8 at the time of admission). Blood samples were taken at the 1st, 3rd and 5th day, levels of MMP-9 in plasma were assessed using ELISA. Outcome quality was assessed at the time of discharge from our hospital. FINDINGS: Our results show an increase of MMP-9 levels on the 1st day after the brain trauma, followed by a drop on the 3rd day and a rise on day 5. This biphasic time-course was observed in all patients, but no statistically significant differences between each group (major trauma vs. isolated brain trauma, good outcome vs. poor outcome) were found. CONCLUSIONS: Initially increased MMP-9 levels in the 1st posttraumatic day is probably related to transient blood-brain barrier dysruption. The decrease of MMP-9 levels observed on the 3rd day can be explained by restoration of blood-brain barrier integrity and its reduced permeability. The second rise of MMP-9 levels observed in the 5th day probably indicates a developing secondary brain injury during which MMP-9 is produced in the brain as a part of an inflammatory response. RESULTS: of our study suggest that MMP-9 could play an important role in pathogenesis of secondary brain injury.

Ceftazidime-avibactam versus meropenem in nosocomial pneumonia, including ventilator-associated pneumonia (REPROVE): a randomised, double-blind, phase 3 non-inferiority trial.

BACKGROUND: Nosocomial pneumonia is commonly associated with antimicrobial-resistant Gram-negative pathogens. We aimed to assess the efficacy and safety of ceftazidime-avibactam in patients with nosocomial pneumonia, including ventilator-associated pneumonia, compared with meropenem in a multinational, phase 3, double-blind, non-inferiority trial (REPROVE). METHODS: Adults with nosocomial pneumonia (including ventilator-associated pneumonia), enrolled at 136 centres in 23 countries, were randomly assigned (1:1) to 2000 mg ceftazidime and 500 mg avibactam (by 2 h intravenous infusion every 8 h) or 1000 mg meropenem (by 30-min intravenous infusion every 8 h) for 7-14 days; regimens were adjusted for renal function. Computer-generated randomisation codes were stratified by infection type and geographical region with a block size of four. Participants and investigators were masked to treatment assignment. The primary endpoint was clinical cure at the test-of-cure visit (21-25 days after randomisation). Non-inferiority was concluded if the lower limit of the two-sided 95% CI for the treatment difference was greater than -12·5% in the coprimary clinically modified intention-to-treat and clinically evaluable populations. This trial is registered with ClinicalTrials.gov (NCT01808092) and EudraCT (2012-004006-96). FINDINGS: Between April 13, 2013, and Dec 11, 2015, 879 patients were randomly assigned. 808 patients were included in the safety population, 726 were included in the clinically modified intention-to-treat population, and 527 were included in the clinically evaluable population. Predominant Gram-negative baseline pathogens in the microbiologically modified intention-to-treat population (n=355) were Klebsiella pneumoniae (37%) and Pseudomonas aeruginosa (30%); 28% were ceftazidime-non-susceptible. In the clinically modified intention-to-treat population, 245 (68·8%) of 356 patients in the ceftazidime-avibactam group were clinically cured, compared with 270 (73·0%) of 370 patients in the meropenem group (difference -4·2% [95% CI -10·8 to 2·5]). In the clinically evaluable population, 199 (77·4%) of 257 participants were clinically cured in the ceftazidime-avibactam group, compared with 211 (78·1%) of 270 in the meropenem group (difference -0·7% [95% CI -7·9 to 6·4]). Adverse events occurred in 302 (75%) of 405 patients in the ceftazidime-avibactam group versus 299 (74%) of 403 in the meropenem group (safety population), and were mostly mild or moderate in intensity and unrelated to study treatment. Serious adverse events occurred in 75 (19%) patients in the ceftazidime-avibactam group and 54 (13%) patients in the meropenem group. Four serious adverse events (all in the ceftazidime-avibactam group) were judged to be treatment related. INTERPRETATION: Ceftazidime-avibactam was non-inferior to meropenem in the treatment of nosocomial pneumonia. These results support a role for ceftazidime-avibactam as a potential alternative to carbapenems in patients with nosocomial pneumonia (including ventilator-associated pneumonia) caused by Gram-negative pathogens. FUNDING: AstraZeneca.

A randomized, blinded, multicenter trial of lipid-associated amphotericin B alone versus in combination with an antibody-based inhibitor of heat shock protein 90 in patients with invasive candidiasis.

BACKGROUND: Mycograb (NeuTec Pharma) is a human recombinant monoclonal antibody against heat shock protein 90 that, in laboratory studies, was revealed to have synergy with amphotericin B against a broad spectrum of Candida species. METHODS: A double-blind, randomized study was conducted to determine whether lipid-associated amphotericin B plus Mycograb was superior to amphotericin B plus placebo in patients with culture-confirmed invasive candidiasis. Patients received a lipid-associated formulation of amphotericin B plus a 5-day course of Mycograb or placebo, having been stratified on the basis of Candida species (Candida albicans vs. non-albicans species of Candida). Inclusion criteria included clinical evidence of active infection at trial entry plus growth of Candida species on culture of a specimen from a clinically significant site within 3 days after initiation of study treatment. The primary efficacy variable was overall response to treatment (clinical and mycological resolution) by day 10. RESULTS: Of the 139 patients enrolled from Europe and the United States, 117 were included in the modified intention-to-treat population. A complete overall response by day 10 was obtained for 29 (48%) of 61 patients in the amphotericin B group, compared with 47 (84%) of 56 patients in the Mycograb combination therapy group (odds ratio [OR], 5.8; 95% confidence interval [CI], 2.41-13.79; P<.001). The following efficacy criteria were also met: clinical response (52% vs. 86%; OR, 5.4; 95% CI, 2.21-13.39; P<.001), mycological response (54% vs. 89%; OR, 7.1; 95% CI, 2.64-18.94; P<.001), Candida-attributable mortality (18% vs. 4%; OR, 0.2; 95% CI, 0.04-0.80; P = .025), and rate of culture-confirmed clearance of the infection (hazard ratio, 2.3; 95% CI, 1.4-3.8; P = .001). Mycograb was well tolerated. CONCLUSIONS: Mycograb plus lipid-associated amphotericin B produced significant clinical and culture-confirmed improvement in outcome for patients with invasive candidiasis.

Effect of the degree of tricuspid regurgitation on cardiac output measurements by thermodilution.

OBJECTIVE: To determine the relationship between the degree of tricuspid regurgitation (TR) and accuracy of cardiac output measurement by thermodilution in mechanically ventilated patients. DESIGN AND SETTING. Prospective observational study in a 20-bed general intensive care unit in the university hospital. PATIENTS: We examined 27 patients (not undergoing cardiac surgery): 8 with no or 1st degree TR, 9 with 2nd degree, and 10 with 3rd degree TR. INTERVENTIONS: All patients were measured twice using simultaneously transesophageal echocardiography and pulmonary artery catheter for cardiac output. MEASUREMENTS AND RESULTS: Continuous Doppler measurements were taken in the left ventricular outflow tract at the level of the aortic valve. Cardiac output was calculated by multiplying the velocity-time integral by aortic valve area and heart rate. Simultaneous pulmonary artery catheter measurements were taken averaging the results of the three 10-cc boluses of iced saline. The difference between the methods was 0.5+/-1.1 l/min (mean +/-2 SD) in patients with no or 1st degree TR (r=0.96), 0.8+/-2.0 l/min in those with 2nd degree TR (r=0.92), and 1.9+/-2.3 l/min in those with 3rd degree TR (r=0.69). CONCLUSIONS: A high degree of TR is associated with underestimation of cardiac output measured by thermodilution.

Changes in cholesterol and its precursors during the first days after major trauma.

BACKGROUND: The causes of hypocholesterolemia in the critically ill, including major trauma patients, have not yet been fully elucidated. OBJECTIVE: We tested the hypothesis that hypocholesterolemia is caused by decreased production of cholesterol precursors. DESIGN: Serum concentrations of squalene, lanosterol, and lathosterol were measured on admission, and then at 24 and 48 hours after injury using gas chromatography coupled with mass spectrometry. Serum concentrations of total low-density and high-density lipoprotein cholesterol were measured on admission and every day in the first week after injury. RESULTS: 83 consecutive patients with multiple trauma were examined. Significant drops in concentrations of lanosterol and lathosterol were found in the patients in comparison with the control group. The most profound drop was in lathosterol. CONCLUSION: Decreased synthesis of cholesterol precursors is the major cause of hypocholesterolemia in patients with multiple trauma. Lathosterol concentration is proposed as a marker of cholesterol synthesis.

Efficacy and safety of anidulafungin in elderly, critically ill patients with invasive Candida infections: a post hoc analysis.

Post hoc analysis of a non-comparative, prospective, multicentre, phase IIIb study was performed to compare efficacy and safety of anidulafungin in elderly (≥65 years) versus non-elderly (<65 years) Intensive Care Unit (ICU) patients with candidaemia/invasive candidiasis (C/IC). Adult ICU patients with confirmed C/IC meeting ≥1 of the following criteria were enrolled: post-abdominal surgery; solid tumour; renal/hepatic insufficiency; solid organ transplantation; neutropenia; age ≥65 years. Patients received anidulafungin (200 mg on Day 1, 100 mg/day thereafter) for ≥10 days followed by optional azole step-down therapy for a total treatment duration of 14-56 days. The primary efficacy endpoint was global (clinical and microbiological) response at the end of all therapy (EOT). Primary efficacy analysis was performed in the modified intent-to-treat (mITT) population (n=170), excluding unknown and missing responses. In total, 80 patients (47.1%) were aged ≥65 years and 90 (52.9%) were aged <65 years; the mean age difference between the two groups was 21.9 years. Global success at EOT in mITT patients was similar in elderly (68.1%) and non-elderly (70.7%) patients (P=0.719). However, global success rates were significantly lower in elderly versus non-elderly patients at 2 and 6 weeks after EOT (P=0.045 and P=0.016, respectively). Ninety-day survival was significantly lower (P=0.006) for elderly (42.8%) versus non-elderly patients (63.3%). The incidence and profile of adverse events were similar in elderly and non-elderly patients. Anidulafungin was effective and safe for treatment of C/IC in elderly ICU patients, despite higher baseline severity of illness scores.

The BRAIN TRIAL: a randomised, placebo controlled trial of a Bradykinin B2 receptor antagonist (Anatibant) in patients with traumatic brain injury.

BACKGROUND: Cerebral oedema is associated with significant neurological damage in patients with traumatic brain injury. Bradykinin is an inflammatory mediator that may contribute to cerebral oedema by increasing the permeability of the blood-brain barrier. We evaluated the safety and effectiveness of the non-peptide bradykinin B2 receptor antagonist Anatibant in the treatment of patients with traumatic brain injury. During the course of the trial, funding was withdrawn by the sponsor. METHODS: Adults with traumatic brain injury and a Glasgow Coma Scale score of 12 or less, who had a CT scan showing an intracranial abnormality consistent with trauma, and were within eight hours of their injury were randomly allocated to low, medium or high dose Anatibant or to placebo. Outcomes were Serious Adverse Events (SAE), mortality 15 days following injury and in-hospital morbidity assessed by the Glasgow Coma Scale (GCS), the Disability Rating Scale (DRS) and a modified version of the Oxford Handicap Scale (HIREOS). RESULTS: 228 patients out of a planned sample size of 400 patients were randomised. The risk of experiencing one or more SAEs was 26.4% (43/163) in the combined Anatibant treated group, compared to 19.3% (11/57) in the placebo group (relative risk = 1.37; 95% CI 0.76 to 2.46). All cause mortality in the Anatibant treated group was 19% and in the placebo group 15.8% (relative risk 1.20, 95% CI 0.61 to 2.36). The mean GCS at discharge was 12.48 in the Anatibant treated group and 13.0 in the placebo group. Mean DRS was 11.18 Anatibant versus 9.73 placebo, and mean HIREOS was 3.94 Anatibant versus 3.54 placebo. The differences between the mean levels for GCS, DRS and HIREOS in the Anatibant and placebo groups, when adjusted for baseline GCS, showed a non-significant trend for worse outcomes in all three measures. CONCLUSION: This trial did not reach the planned sample size of 400 patients and consequently, the study power to detect an increase in the risk of serious adverse events was reduced. This trial provides no reliable evidence of benefit or harm and a larger trial would be needed to establish safety and effectiveness. TRIAL REGISTRATION: This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN23625128.

Parenterally administered dipeptide alanyl-glutamine prevents worsening of insulin sensitivity in multiple-trauma patients.

BACKGROUND: Dipeptide alanyl-glutamine is a commonly used substrate in major trauma patients. Its importance and effects are widely discussed; as yet, it has not been elucidated whether its administration influences glucose homeostasis. OBJECTIVE: We studied the effect of alanyl-glutamine administration on insulin resistance. DESIGN: Prospective, randomized, controlled trial. SETTING: Intensive care unit of a tertiary level hospital. PATIENTS: Multiple-trauma patients. INTERVENTIONS: Patients were randomized into two groups and assigned to receive parenterally an equal dose of amino acids either with alanyl-glutamine in the dose of 0.4 g x kg body weight(-1) x 24 hrs(-1) (group AG) or without alanyl-glutamine (control group C). This regimen started 24 hrs after injury and continued for 7 days. To assess insulin sensitivity, we performed an euglycemic clamp on day 4 and day 8 after injury. MEASUREMENTS AND MAIN RESULTS: We randomized 40 patients, 20 into each group. At day 4, insulin-mediated glucose disposal was higher in group AG (2.4 +/- 0.7 mg x kg(-1) x min(-1) glucose), with significant difference from group C (1.9 +/- 0.6 mg x kg(-1) x min(-1), p = .044). At day 8, glucose disposal was higher in group AG (2.2 +/- 0.7 mg x kg(-1) x min(-1) glucose), with significant difference in comparison with group C (1.2 +/- 0.6, p < .001). Diminution of the main glucose homeostasis variables in group C between days 4 and 8 of the study was statistically significant (p < .001); however, differences in these variables in group AG were without statistical significance. CONCLUSIONS: Parenteral supplementation of alanyl-glutamine dipeptide was associated with better insulin sensitivity in multiple-trauma patients.

Relationship between natriuretic peptides and residual diuresis during continuous hemodiafiltration.

BACKGROUND: The reasons for the decrease or increase of urine output following the start of continuous venovenous hemodiafiltration (CVVHDF) have not yet been explained sufficiently. The renoprotective properties of natriuretic peptides were described. METHODS: The levels of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) were measured in 23 mechanically ventilated patients before and during the first 48 h of CVVHDF. Samples were drawn both from the ports proximal and distal to the filter. The results were compared between the group where daily diuresis (Vu) remained low or decreased and the group where diuresis increased to the level of 1.5 ml x kg(-1) x h(-1) or higher after 48 h of treatment. Left ventricular dysfunction (LVD) was defined as LV ejection fraction below 40%. A control group consisted of 10 patients exposed to abdominal surgery. RESULTS: The average AVdiff (%) of ANP and BNP on filter were insignificant. Patients with increasing diuresis (n = 12) had significantly lower levels of both ANP (p < 0.001) and BNP (p < 0.005) than the patients with decreasing diuresis (n = 11). Significant correlations were revealed for ANP and Vu (p < 0.01) and for BNP and Vu (p < 0.05). The levels of both peptides were grossly elevated in comparison to controls and were predictive of survival. The differences between cardiac and non-cardiac patients were significant both for ANP and for BNP. CONCLUSIONS: The elimination of ANP and BNP by the CVVHDF is negligible. The levels of natriuretic peptides are inversely related to Vu and predict survival. ANP and BNP levels correlate with left ventricular function even during acute renal failure and CVVHDF.