Intravenous vitamin C administration to patients with septic shock: a pilot randomised controlled trial.

BACKGROUND: Intravenous vitamin C administration in septic shock may have a sparing effect on vasopressor requirements, and vitamin C's enzyme cofactor functions provide a mechanistic rationale. Our study aimed to determine the effect of intravenous vitamin C administration on vasopressor requirements and other outcomes in patients with septic shock. METHODS: This was a double-blind, randomised placebo-controlled trial in 40 patients with septic shock who were randomised (1:1) to receive intravenous vitamin C (at a dose of 25 mg/kg of body weight every 6 h) or placebo (intravenous 5% dextrose) for up to 96 h, or until death or discharge. The primary outcome was intravenous vasopressor requirements (dose and duration), and secondary outcomes included Sequential Organ Failure Assessment (SOFA) scores, intensive care unit (ICU) and hospital length of stay, and mortality. In addition, blood samples were collected to determine vitamin C kinetics and inflammatory marker concentrations. RESULTS: Median plasma vitamin C concentrations were deficient at baseline (9.2 [4.4, 12] µmol/L) and increased to 408 (227, 560) µmol/L following 72 h of intervention. The mean duration of intravenous vasopressor infusion in the vitamin C group was 48 (95% CI 35-62) hours and in the placebo group was 54 (95% CI 41-62) hours (p = 0.52). The dose of vasopressor delivered over time was comparable between the two groups, as were SOFA scores (p > 0.05). The median ICU length of stay in the intervention group was 3.8 (2.2, 9.8) days versus 7.1 (3.1, 20) days in the placebo group (p = 0.12). The median hospital length of stay for the vitamin C group was 18 (11, 35) days versus 22 (10, 52) days for the placebo group (p = 0.65). Mortality was comparable between the two groups (p > 0.05). Of the inflammatory markers, neutrophil counts were elevated in the vitamin C group relative to placebo by 72 h (p = 0.01). C-reactive protein and myeloperoxidase concentrations were elevated at baseline, however, the two groups were comparable over time (p > 0.05). CONCLUSIONS: Our pilot study indicated that intravenous vitamin C did not provide significant decreases in the mean dose or duration of vasopressor infusion. Further research that takes into account the potential impact of intervention timing, dose and duration, and location of trial, may provide more definitive evidence. TRIAL REGISTRATION: ACTRN12617001184369 (11/8/2017).

The effect of conservative oxygen therapy on systemic biomarkers of oxidative stress in critically ill patients.

BACKGROUND: Supplemental oxygen is delivered to critically ill patients who require mechanical ventilation. Oxidative stress is a potential complication of oxygen therapy, resulting in damage to essential biomolecules such as proteins, lipids, and nucleic acids. Whether plasma levels of oxidative stress biomarkers vary based on how liberally oxygen therapy is applied during mechanical ventilation is unknown. METHODS: We carried out an oxidative stress substudy nested within a large multi-centre randomized controlled trial in which critically ill adults were randomized to receive either conservative oxygen therapy or standard oxygen therapy. Blood samples were collected at enrolment, and daily thereafter for up to three days. The antioxidant ascorbate (vitamin C) was assessed using HPLC with electrochemical detection and protein oxidation using a sensitive protein carbonyl ELISA. We also assessed whether critically ill patients with different disease states exhibited varying levels of oxidative stress biomarkers. RESULTS: A total of 125 patients were included. Mean ascorbate concentrations decreased over time (from 25 ± 9 µmol/L to 14 ± 2 µmol/L, p < 0.001), however, there was no significant difference between the conservative oxygen group and standard care (p = 0.2), despite a significantly lower partial pressure of oxygen (PaO2) in the conservative oxygen group (p = 0.03). Protein carbonyl concentrations increased over time (from 208 ± 30 µmol/L to 249 ± 29 µmol/L; p = 0.016), however, there was no significant difference between the conservative and standard oxygen groups (p = 0.3). Patients with sepsis had significantly higher protein carbonyl concentrations than the other critically ill patients (293 ± 92 µmol/L vs 184 ± 24 µmol/L, p = 0.03). Within the septic subgroup, there were no significant differences in protein carbonyl concentrations between the two interventions (p = 0.4). CONCLUSIONS: Conservative oxygen therapy does not alter systemic markers of oxidative stress in critically ill ventilated patients compared with standard oxygen therapy. Patients with sepsis exhibited elevated protein carbonyls compared with the other critically ill patients implying increased oxidative stress in this patient subgroup.

Hypovitaminosis C and vitamin C deficiency in critically ill patients despite recommended enteral and parenteral intakes.

BACKGROUND: Vitamin C is an essential water-soluble nutrient which cannot be synthesised or stored by humans. It is a potent antioxidant with anti-inflammatory and immune-supportive roles. Previous research has indicated that vitamin C levels are depleted in critically ill patients. In this study we have assessed plasma vitamin C concentrations in critically ill patients relative to infection status (septic shock or non-septic) and level of inflammation (C-reactive protein concentrations). Vitamin C status was also assessed relative to daily enteral and parenteral intakes to determine if standard intensive care unit (ICU) nutritional support is adequate to meet the vitamin C needs of critically ill patients. METHODS: Forty-four critically ill patients (24 with septic shock, 17 non-septic, 3 uncategorised) were recruited from the Christchurch Hospital Intensive Care Unit. We measured concentrations of plasma vitamin C and a pro-inflammatory biomarker (C-reactive protein) daily over 4 days and calculated patients' daily vitamin C intake from the enteral or total parenteral nutrition they received. We compared plasma vitamin C and C-reactive protein concentrations between septic shock and non-septic patients over 4 days using a mixed effects statistical model, and we compared the vitamin C status of the critically ill patients with known vitamin C bioavailability data using a four-parameter log-logistic response model. RESULTS: Overall, the critically ill patients exhibited hypovitaminosis C (i.e., < 23 µmol/L), with a mean plasma vitamin C concentration of 17.8 ± 8.7 µmol/L; of these, one-third had vitamin C deficiency (i.e., < 11 µmol/L). Patients with hypovitaminosis C had elevated inflammation (C-reactive protein levels; P < 0.05). The patients with septic shock had lower vitamin C concentrations and higher C-reactive protein concentrations than the non-septic patients (P < 0.05). Nearly 40% of the septic shock patients were deficient in vitamin C, compared with 25% of the non-septic patients. These low vitamin C levels were apparent despite receiving recommended intakes via enteral and/or parenteral nutritional therapy (mean 125 mg/d). CONCLUSIONS: Critically ill patients have low vitamin C concentrations despite receiving standard ICU nutrition. Septic shock patients have significantly depleted vitamin C levels compared with non-septic patients, likely resulting from increased metabolism due to the enhanced inflammatory response observed in septic shock.

Effect of a Buffered Crystalloid Solution vs Saline on Acute Kidney Injury Among Patients in the Intensive Care Unit: The SPLIT Randomized Clinical Trial.

IMPORTANCE: Saline (0.9% sodium chloride) is the most commonly administered intravenous fluid; however, its use may be associated with acute kidney injury (AKI) and increased mortality. OBJECTIVE: To determine the effect of a buffered crystalloid compared with saline on renal complications in patients admitted to the intensive care unit (ICU). DESIGN AND SETTING: Double-blind, cluster randomized, double-crossover trial conducted in 4 ICUs in New Zealand from April 2014 through October 2014. Three ICUs were general medical and surgical ICUs; 1 ICU had a predominance of cardiothoracic and vascular surgical patients. PARTICIPANTS: All patients admitted to the ICU requiring crystalloid fluid therapy were eligible for inclusion. Patients with established AKI requiring renal replacement therapy (RRT) were excluded. All 2278 eligible patients were enrolled; 1152 of 1162 patients (99.1%) receiving buffered crystalloid and 1110 of 1116 patients (99.5%) receiving saline were analyzed. INTERVENTIONS: Participating ICUs were assigned a masked study fluid, either saline or a buffered crystalloid, for alternating 7-week treatment blocks. Two ICUs commenced using 1 fluid and the other 2 commenced using the alternative fluid. Two crossovers occurred so that each ICU used each fluid twice over the 28 weeks of the study. The treating clinician determined the rate and frequency of fluid administration. MAIN OUTCOMES AND MEASURES: The primary outcome was proportion of patients with AKI (defined as a rise in serum creatinine level of at least 2-fold or a serum creatinine level of ≥3.96 mg/dL with an increase of ≥0.5 mg/dL); main secondary outcomes were incidence of RRT use and in-hospital mortality. RESULTS: In the buffered crystalloid group, 102 of 1067 patients (9.6%) developed AKI within 90 days after enrollment compared with 94 of 1025 patients (9.2%) in the saline group (absolute difference, 0.4% [95% CI, -2.1% to 2.9%]; relative risk [RR], 1.04 [95% CI, 0.80 to 1.36]; P = .77). In the buffered crystalloid group, RRT was used in 38 of 1152 patients (3.3%) compared with 38 of 1110 patients (3.4%) in the saline group (absolute difference, -0.1% [95% CI, -1.6% to 1.4%]; RR, 0.96 [95% CI, 0.62 to 1.50]; P = .91). Overall, 87 of 1152 patients (7.6%) in the buffered crystalloid group and 95 of 1110 patients (8.6%) in the saline group died in the hospital (absolute difference, -1.0% [95% CI, -3.3% to 1.2%]; RR, 0.88 [95% CI, 0.67 to 1.17]; P = .40). CONCLUSIONS AND RELEVANCE: Among patients receiving crystalloid fluid therapy in the ICU, use of a buffered crystalloid compared with saline did not reduce the risk of AKI. Further large randomized clinical trials are needed to assess efficacy in higher-risk populations and to measure clinical outcomes such as mortality. TRIAL REGISTRATION: clinicaltrials.gov Identifier: ACTRN12613001370796.

A protocol for the 0.9% saline versus Plasma-Lyte 148 for intensive care fluid therapy (SPLIT) study.

BACKGROUND: 0.9% saline is the most commonly used intravenous (IV) fluid in the world. However, recent data raise the possibility that, compared with buffered crystalloid fluids such as Plasma-Lyte 148, the administration of 0.9% saline to intensive care unit patients might increase their risk of acute kidney injury (AKI). OBJECTIVE: To describe the protocol for the 0.9% Saline v Plasma-Lyte 148 for ICU Fluid Therapy (SPLIT) study. METHODS: This is a multicentre, cluster-randomised, double crossover feasibility study to be conducted in four New Zealand tertiary ICUs over a 28-week period and will enroll about 2300 participants. All ICU patients who need crystalloid IV fluid therapy (except those with established renal failure needing dialysis and those admitted to the ICU for palliative care) will be enrolled. Participating ICUs will be randomly assigned to 0.9% saline or Plasma-Lyte 148 as the routine crystalloid IV fluid, in a blinded fashion, in four alternating 7-week blocks. MAIN OUTCOME MEASURES: The primary outcome will be the proportion of patients who develop AKI in the ICU. Secondary outcomes will include the difference between the most recent serum creatinine level measured before study enrollment and the peak serum creatinine level in the ICU; use of renal replacement therapy; and ICU and in hospital mortality. All analyses will be conducted on an intention-to-treat basis. RESULTS AND CONCLUSION: The SPLIT study started on 1 April 2014 and will provide preliminary data on the comparative effectiveness of using 0.9% saline v Plasma- Lyte 148 as the routine IV fluid therapy in ICU patients.

Verified clinical failure with cefotaxime 1g for treatment of gonorrhoea in the Netherlands: a case report.

We describe the first case of treatment failure of gonorrhoea with a third generation cephalosporin, cefotaxime 1g intramuscularly, in the Netherlands. The case was from a high-frequency transmitting population (men having sex with men) and was caused by the internationally spreading multidrug-resistant gonococcal NG-MAST ST1407 clone. The patient was clinically cured after treatment with ceftriaxone 500 mg intramuscularly and this is the only third generation cephalosporin that should be used for first-line empiric treatment of gonorrhoea. Increased awareness of failures with third generation cephalosporins, enhanced monitoring and appropriate verification of treatment failures including more frequent test-of-cures, and strict adherence to regularly updated treatment guidelines are essential globally.

Early intervention with erythropoietin does not affect the outcome of acute kidney injury (the EARLYARF trial).

We performed a double-blind placebo-controlled trial to study whether early treatment with erythropoietin could prevent the development of acute kidney injury in patients in two general intensive care units. As a guide for choosing the patients for treatment we measured urinary levels of two biomarkers, the proximal tubular brush border enzymes gamma-glutamyl transpeptidase and alkaline phosphatase. Randomization to either placebo or two doses of erythropoietin was triggered by an increase in the biomarker concentration product to levels above 46.3, with a primary outcome of relative average plasma creatinine increase from baseline over 4 to 7 days. Of 529 patients, 162 were randomized within an average of 3.5 h of a positive sample. There was no difference in the incidence of erythropoietin-specific adverse events or in the primary outcome between the placebo and treatment groups. The triggering biomarker concentration product selected patients with more severe illness and at greater risk of acute kidney injury, dialysis, or death; however, the marker elevations were transient. Early intervention with high-dose erythropoietin was safe but did not alter the outcome. Although these two urine biomarkers facilitated our early intervention, their transient increase compromised effective triaging. Further, our study showed that a composite of these two biomarkers was insufficient for risk stratification in a patient population with a heterogeneous onset of injury.