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1.  Paracetamol therapy and outcome of critically ill patients: a multicenter retrospective observational study 
Critical Care  2015;19(1):162.
Introduction
In this study, we aimed to examine the association between paracetamol administration in the intensive care unit (ICU) and mortality in critically ill patients.
Methods
We conducted a multicenter retrospective observational study in four ICUs. We obtained information on paracetamol use, body temperature, demographic, clinical and outcome data from each hospital’s clinical information system and admissions and discharges database. We performed statistical analysis to assess the association between paracetamol administration and hospital mortality.
Results
We studied 15,818 patients with 691,348 temperature measurements at 4 ICUs. Of these patients, 10,046 (64%) received at least 1 g of paracetamol. Patients who received paracetamol had lower in-hospital mortality (10% vs. 20%, P <0.001), and survivors were more likely to have received paracetamol (66% vs. 46%; P <0.001). However, patients treated with paracetamol were also more likely to be admitted to the ICU after surgery (70% vs. 51%; P <0.001) and/or after elective surgery (55% vs. 37%; P <0.001). In multivariate logistic regression analysis including a propensity score for paracetamol treatment, we found a significant and independent association between the use of paracetamol and reduced in-hospital mortality (adjusted odds ratio =0.60 (95% confidence interval (CI), 0.53 to 0.68), P <0.001). Cox proportional hazards analysis showed that patients who received paracetamol also had a significantly longer time to death (adjusted hazard ratio =0.51 (95% CI, 0.46 to 0.56), P <0.001). The association between paracetamol and decreased mortality and/or time to death was broadly consistent across surgical and medical patients. It remained present after adjusting for paracetamol administration as a time-dependent variable. However, when such time-dependent analysis was performed, the association of paracetamol with outcome lost statistical significance in the presence of fever and suspected infection and in patients in the lower tertiles of Acute Physiology and Chronic Health Evaluation II scores.
Conclusions
Paracetamol administration is common in the ICU and appears to be independently associated with reduced in-hospital mortality and time to death after adjustment for multiple potential confounders and propensity score. This association, however, was modified by the presence of fever, suspected infection and lesser illness severity and may represent the effect of indication bias.
Electronic supplementary material
The online version of this article (doi:10.1186/s13054-015-0865-1) contains supplementary material, which is available to authorized users.
doi:10.1186/s13054-015-0865-1
PMCID: PMC4411740  PMID: 25879463
2.  A pilot feasibility, safety and biological efficacy multicentre trial of therapeutic hypercapnia after cardiac arrest: study protocol for a randomized controlled trial 
Trials  2015;16:135.
Background
Cardiac arrest causes ischaemic brain injury. Arterial carbon dioxide tension (PaCO2) is a major determinant of cerebral blood flow. Thus, mild hypercapnia in the 24 h following cardiac arrest may increase cerebral blood flow and attenuate such injury. We describe the Carbon Control and Cardiac Arrest (CCC) trial.
Methods/Design
The CCC trial is a pilot multicentre feasibility, safety and biological efficacy randomized controlled trial recruiting adult cardiac arrest patients admitted to the intensive care unit after return of spontaneous circulation. At admission, using concealed allocation, participants are randomized to 24 h of either normocapnia (PaCO2 35 to 45 mmHg) or mild hypercapnia (PaCO2 50 to 55 mmHg). Key feasibility outcomes are recruitment rate and protocol compliance rate. The primary biological efficacy and biological safety measures are the between-groups difference in serum neuron-specific enolase and S100b protein levels at 24 h, 48 h and 72 h. Secondary outcome measure include adverse events, in-hospital mortality, and neurological assessment at 6 months.
Discussion
The trial commenced in December 2012 and, when completed, will provide clinical evidence as to whether targeting mild hypercapnia for 24 h following intensive care unit admission for cardiac arrest patients is feasible and safe and whether it results in decreased concentrations of neurological injury biomarkers compared with normocapnia. Trial results will also be used to determine whether a phase IIb study powered for survival at 90 days is feasible and justified.
Trial registration
Australian New Zealand Clinical Trials Registry ACTRN12612000690853.
doi:10.1186/s13063-015-0676-3
PMCID: PMC4393877  PMID: 25872502
cardiac arrest; hypercapnia; intensive care; normocapnia; randomized trial; resuscitation
3.  Renal replacement therapy in acute kidney injury: controversy and consensus 
Critical Care  2015;19(1):146.
Renal replacement therapies (RRTs) represent a cornerstone in the management of severe acute kidney injury. This area of intensive care and nephrology has undergone significant improvement and evolution in recent years. Continuous RRTs have been a major focus of new technological and treatment strategies. RRT is being used increasingly in the intensive care unit, not only for renal indications but also for other organ-supportive strategies. Several aspects related to RRT are now well established, but others remain controversial. In this review, we review the available RRT modalities, covering technical and clinical aspects. We discuss several controversial issues, provide some practical recommendations, and where possible suggest a research agenda for the future.
doi:10.1186/s13054-015-0850-8
PMCID: PMC4386097  PMID: 25887923
4.  Assessment of Cell-Cycle Arrest Biomarkers to Predict Early and Delayed Acute Kidney Injury 
Disease Markers  2015;2015:158658.
Purpose. To assess urinary tissue inhibitor of metalloproteinases-2 and insulin-like growth factor binding protein 7 ([TIMP-2]·[IGFBP7]), urinary neutrophil gelatinase-associated lipocalin (NGAL), and urinary cystatin-C as acute kidney injury predictors (AKI) exploring the association of nonrenal factors with elevated biomarker levels. Methods. We studied 94 patients with urine collected within 48 hours of ICU admission and no AKI at sampling. AKI was defined by the Kidney Disease: Improving Global Outcomes criteria. Predictive performance was assessed by the area under the receiver operating characteristics (ROC) curve. Associations between biomarkers and clinical factors were assessed by multivariate linear regression. Results. Overall, 19 patients (20%) developed AKI within 48 hours. [TIMP-2]·[IGFBP7], NGAL, or cystatin-C admission levels did not differ between patients without AKI and patients developing AKI. [TIMP-2]·[IGFBP7], NGAL, and cystatin-C were poor AKI predictors (ROC areas 0.34–0.51). Diabetes was independently associated with higher [TIMP-2]·[IGFBP7] levels (P = 0.02) but AKI was not (P = 0.24). Sepsis was independently associated with higher NGAL (P < 0.001) and cystatin-C (P = 0.003) levels. Conclusions. Urinary [TIMP-2]·[IGFBP7], NGAL, and cystatin-C should be used cautiously as AKI predictors in general ICU patients since urine levels of these biomarkers are affected by factors other than AKI and their performance can be poor.
doi:10.1155/2015/158658
PMCID: PMC4381987  PMID: 25866432
5.  A multicenter study on the effect of continuous hemodiafiltration intensity on antibiotic pharmacokinetics 
Critical Care  2015;19(1):84.
Introduction
Continuous renal replacement therapy (CRRT) may alter antibiotic pharmacokinetics and increase the risk of incorrect dosing. In a nested cohort within a large randomized controlled trial, we assessed the effect of higher (40 mL/kg per hour) and lower (25 mL/kg per hour) intensity CRRT on antibiotic pharmacokinetics.
Methods
We collected serial blood samples to measure ciprofloxacin, meropenem, piperacillin-tazobactam, and vancomycin levels. We calculated extracorporeal clearance (CL), systemic CL, and volume of distribution (Vd) by non-linear mixed-effects modelling. We assessed the influence of CRRT intensity and other patient factors on antibiotic pharmacokinetics.
Results
We studied 24 patients who provided 179 pairs of samples. Extracorporeal CL increased with higher-intensity CRRT but the increase was significant for vancomycin only (mean 28 versus 22 mL/minute; P = 0.0003). At any given prescribed CRRT effluent rate, extracorporeal CL of individual antibiotics varied widely, and the effluent-to-plasma concentration ratio decreased with increasing effluent flow. Overall, systemic CL varied to a greater extent than Vd, particularly for meropenem, piperacillin, and tazobactam, and large intra-individual differences were also observed. CRRT dose did not influence overall (systemic) CL, Vd, or half-life. The proportion of systemic CL due to CRRT varied widely and was high in some cases.
Conclusions
In patients receiving CRRT, there is great variability in antibiotic pharmacokinetics, which complicates an empiric approach to dosing and suggests the need for therapeutic drug monitoring. More research is required to investigate the apparent relative decrease in clearance at higher CRRT effluent rates.
Trial registration
ClinicalTrials.gov NCT00221013. Registered 14 September 2005.
Electronic supplementary material
The online version of this article (doi:10.1186/s13054-015-0818-8) contains supplementary material, which is available to authorized users.
doi:10.1186/s13054-015-0818-8
PMCID: PMC4404619  PMID: 25881576
6.  Fever in sepsis: is it cool to be hot? 
Critical Care  2014;18(1):109.
Changes in body temperature are a characteristic feature of sepsis. The study by Kushimoto and colleagues in a recent issue of Critical Care demonstrates that hypothermia is a very important manifestation of infection associated with very high mortality. Combined with recent data suggesting that febrile patients with infections have the lowest mortality risk, the study raises the question of whether inducing therapeutic hyperthermia might be beneficial in this patient group. Body temperature is easily measured and manipulated in the ICU, and interventional trials defining the most appropriate temperature targets in ICU patients with infections are urgently needed. One such study is in progress.
doi:10.1186/cc13726
PMCID: PMC4056432  PMID: 24521542
7.  Erythropoietin in traumatic brain injury: study protocol for a randomised controlled trial 
Trials  2015;16:39.
Background
Traumatic brain injury is a leading cause of death and disability worldwide. Laboratory and clinical studies demonstrate a possible beneficial effect of erythropoietin in improving outcomes in the traumatic brain injury cohort. However, there are concerns regarding the association of erythropoietin and thrombosis in the critically ill. A large-scale, multi-centre, blinded, parallel-group, placebo-controlled, randomised trial is currently underway to address this hypothesis.
Methods/design
The erythropoietin in traumatic brain injury trial is a stratified prospective, multi-centre, randomised, blinded, parallel-group, placebo-controlled phase III trial. It aims to determine whether the administration of erythropoietin compared to placebo improves neurological outcome in patients with moderate or severe traumatic brain injury at six months after injury. The trial is designed to recruit 606 patients between 15 and 65 years of age with severe (Glasgow Coma Score: 3 to 8) or moderate (Glasgow Coma Score: 9 to 12) traumatic brain injury in Australia, New Zealand, Kingdom of Saudi Arabia, France, Finland, Germany and Ireland.
Trial patients will receive either subcutaneous erythropoietin or placebo within 24 hours of injury, and weekly thereafter for up to three doses during the intensive care unit admission. The primary outcome will be the combined proportion of unfavourable neurological outcomes at six months: severe disability or death. Secondary outcomes will include the rate of proximal deep venous thrombosis detected by compression Doppler ultrasound, six-month mortality, the proportion of patients with composite vascular events (deep venous thrombosis, pulmonary embolism, myocardial infarction, cardiac arrest and cerebrovascular events) at six months and quality of life with health economic evaluations.
Discussion
When completed, the trial aims to provide evidence on the efficacy and safety of erythropoietin in traumatic brain injury patients, and to provide clear guidance for clinicians in their management of this devastating condition.
Trial registration
Australian New Zealand Clinical Trials registry: ACTRN12609000827235 (registered on 22 September 2009).
Clinicaltrials.gov: NCT00987454 (registered on 29 September 2009). European Drug Regulatory Authorities Clinical Trials: 2011-005235-22 (registered on 18 January 2012).
Electronic supplementary material
The online version of this article (doi:10.1186/s13063-014-0528-6) contains supplementary material, which is available to authorized users.
doi:10.1186/s13063-014-0528-6
PMCID: PMC4326467  PMID: 25884605
Traumatic brain injury; Erythropoietin; Outcome; Critical care; Randomised controlled trials
8.  Early temperature and mortality in critically ill patients with acute neurological diseases: trauma and stroke differ from infection 
Intensive Care Medicine  2015;41(5):823-832.
Background
Fever suppression may be beneficial for patients with traumatic brain injury (TBI) and stroke, but for patients with meningitis or encephalitis [central nervous system (CNS) infection], the febrile response may be advantageous.
Objective
To evaluate the relationship between peak temperature in the first 24 h of intensive care unit (ICU) admission and all-cause hospital mortality for acute neurological diseases.
Design, setting and participants
Retrospective cohort design from 2005 to 2013, including 934,159 admissions to 148 ICUs in Australia and New Zealand (ANZ) and 908,775 admissions to 236 ICUs in the UK.
Results
There were 53,942 (5.8 %) patients in ANZ and 56,696 (6.2 %) patients in the UK with a diagnosis of TBI, stroke or CNS infection. For both the ANZ (P = 0.02) and UK (P < 0.0001) cohorts there was a significant interaction between early peak temperature and CNS infection, indicating that the nature of the relationship between in-hospital mortality and peak temperature differed between TBI/stroke and CNS infection. For patients with CNS infection, elevated peak temperature was not associated with an increased risk of death, relative to the risk at 37–37.4 °C (normothermia). For patients with stroke and TBI, peak temperature below 37 °C and above 39 °C was associated with an increased risk of death, compared to normothermia.
Conclusions
The relationship between peak temperature in the first 24 h after ICU admission and in-hospital mortality differs for TBI/stroke compared to CNS infection. For CNS infection, increased temperature is not associated with increased risk of death.
Electronic supplementary material
The online version of this article (doi:10.1007/s00134-015-3676-6) contains supplementary material, which is available to authorized users.
doi:10.1007/s00134-015-3676-6
PMCID: PMC4414938  PMID: 25643903
Temperature; Mortality; Stroke; Traumatic brain injury; Meningitis; Encephalitis
9.  Paracetamol: a review with specific focus on the haemodynamic effects of intravenous administration 
Heart, Lung and Vessels  2015;7(2):121-132.
Paracetamol is one of the most commonly used drugs worldwide with non-prescription sales exceeding 25 thousand million doses per year in the United States of America. The haemodynamic effects of the intravenous paracetamol formulations are largely understudied. There is an emerging body of evidence suggesting that intravenous paracetamol may cause iatrogenic hypotension. Little is known as to the mechanisms of this phenomenon or if intravenous paracetamol indeed does cause hypotension. As paracetamol has negligible solubility in aqueous solutions, many of the commercially available intravenous formulations contain mannitol (up to 3.91 g/100 mL paracetamol) as a stabilising ingredient. It is unknown if mannitol is a contributing factor in the observed hypotension. In this review, we outline the development of paracetamol’s current intravenous formulations, describe the composition of these formulations, and overview the literature pertaining to the proposed phenomenon of paracetamol-induced altered hypotension. Understanding the pharmacokinetic and pharmacodymanic properties of intravenous paracetamol may have important clinical implications for vulnerable patients in subgroups where haemodynamic stability is at risk such as those undergoing elective and emergency surgery.
PMCID: PMC4476766  PMID: 26157738
Intravenous; paracetamol; acetaminophen; haemodynamic; blood pressure
10.  Physiological changes after fluid bolus therapy in sepsis: a systematic review of contemporary data 
Critical Care  2014;18(6):696.
Fluid bolus therapy (FBT) is a standard of care in the management of the septic, hypotensive, tachycardic and/or oliguric patient. However, contemporary evidence for FBT improving patient-centred outcomes is scant. Moreover, its physiological effects in contemporary ICU environments and populations are poorly understood. Using three electronic databases, we identified all studies describing FBT between January 2010 and December 2013. We found 33 studies describing 41 boluses. No randomised controlled trials compared FBT with alternative interventions, such as vasopressors. The median fluid bolus was 500 ml (range 100 to 1,000 ml) administered over 30 minutes (range 10 to 60 minutes) and the most commonly administered fluid was 0.9% sodium chloride solution. In 19 studies, a predetermined physiological trigger initiated FBT. Although 17 studies describe the temporal course of physiological changes after FBT in 31 patient groups, only three studies describe the physiological changes at 60 minutes, and only one study beyond this point. No studies related the physiological changes after FBT with clinically relevant outcomes. There is a clear need for at least obtaining randomised controlled evidence for the physiological effects of FBT in patients with severe sepsis and septic shock beyond the period immediately after its administration.
‘Just as water retains no shape, so in warfare there are no constant conditions’
Sun Tzu (‘The Art of War’)
Electronic supplementary material
The online version of this article (doi:10.1186/s13054-014-0696-5) contains supplementary material, which is available to authorized users.
doi:10.1186/s13054-014-0696-5
PMCID: PMC4331149  PMID: 25673138
11.  Statistical analysis plan for the Erythropoietin in Traumatic Brain Injury trial: a randomised controlled trial of erythropoietin versus placebo in moderate and severe traumatic brain injury 
Trials  2014;15:501.
Background
The Erythropoietin in Traumatic Brain Injury (EPO-TBI) trial aims to determine whether the administration of erythropoietin to patients with moderate or severe traumatic brain injury improves patient-centred outcomes.
Methods
EPO-TBI is a multicentre, blinded, randomised, parallel groups, placebo-controlled, phase III superiority trial of erythropoietin in ICU patients with traumatic brain injury conducted in Australia and New Zealand, Saudi Arabia and Europe; 606 critically ill patients aged 15 to 65 years with moderate or severe acute traumatic brain injury will be enrolled.
Trial patients will receive either 40,000 IU erythropoietin or placebo by subcutaneous injection administered weekly for up to three doses during their ICU admission.
The primary outcome measure is the proportion of unfavourable neurological outcomes, comprising death or severe disability, observed at 6 months following randomisation utilizing the Extended Glasgow Outcome Scale. Secondary outcomes, also assessed at 6 months following randomisation, include the probability of an equal or greater Extended Glasgow Outcome Scale level, mortality, the proportions of patients with proximal deep venous thrombosis or with composite thrombotic vascular events, as well as assessment of quality of life and cost-effectiveness. The planned sample size will allow 90% power to detect a reduction from 50% to 36% in unfavourable neurological outcomes at a two-sided alpha of 0.05.
Discussion
A detailed analysis plan has been developed for EPO-TBI that is consistent with international guidelines. This plan specifies the statistical models for evaluation of primary and secondary outcomes, as well as defining covariates for adjusted analyses.
Application of this statistical analysis plan to the forthcoming EPO-TBI trial will facilitate unbiased analyses of these important clinical data.
Trial registration
Australian New Zealand Clinical Trials Registry: ACTRN12609000827235 (22 September 2009). ClinicalTrials.gov: NCT00987454 (29 September 2009). European Drug Regulatory Authorities Clinical Trials: 2011-005235-22 (18 January 2012).
Electronic supplementary material
The online version of this article (doi:10.1186/1745-6215-15-501) contains supplementary material, which is available to authorized users.
doi:10.1186/1745-6215-15-501
PMCID: PMC4414377  PMID: 25528574
Traumatic brain injury; Erythropoietin; Outcome; Critical care; Randomised controlled trials
12.  Systemic and renal hemodynamic effects of intra-arterial radiocontrast 
Background
Decreased renal blood flow (RBF) and vasoconstriction are considered major mechanisms of contrast-induced acute kidney injury (CIAKI). To understand the severity and duration of such putative effects, we measured systemic and renal hemodynamics after intra-arterial radiocontrast administration. The subjects were six Merino ewes. The setting was a university-affiliated research institute. This is a randomized cross-over experimental study.
Methods
Transit-time flow probes were implanted on the pulmonary and left renal arteries 2 weeks before experimentation. We simulated percutaneous coronary intervention by administering five intra-arterial boluses of 0.5 mL/kg saline (control) or radiocontrast (iodixanol) to a total of 2.5 mL/kg over 1 h. Cardiac output (CO), heart rate, mean arterial pressure (MAP), RBF, renal vascular conductance (RVC), urine output (UO), creatinine clearance (CrCl), and fractional excretion of sodium (FENa) were measured.
Results
In the first 8 h after intra-arterial administration of radiocontrast, CO, total peripheral conductance (TPC), and heart rate (HR) increased compared with those after normal saline administration. Thereafter, CO and TPC were similar between the two groups, but HR remained higher with radiocontrast (p < 0.001). After a short (30 min) period of renal vasoconstriction with preserved RBF secondary to an associated increase in MAP, RBF and RVC showed an earlier and greater increase (vasodilatation) with radiocontrast (p < 0.001) and remained higher during the first 2 days. Radiocontrast initially increased urine output (p < 0.001) and FENa (p = 0.003). However, the overall daily urine output decreased in the radiocontrast-treated animals at 2 days (p < 0.001) and 3 days (p = 0.006). Creatinine clearance was not affected.
Conclusions
In healthy animals, intra-arterial radiocontrast increased RBF, induced renal vasodilatation, and caused a delayed period of oliguria. Our findings suggest that sustained reduction in RBF and renal vasoconstriction may not occur in normal large mammals after intra-arterial radiocontrast administration.
doi:10.1186/s40635-014-0032-z
PMCID: PMC4513043
Radiocontrast agent; Angiography; Contrast-induced acute kidney injury; Renal vascular resistance; Vasoconstriction; Renal blood flow; Iodixanol
13.  Contrast-enhanced ultrasonography to evaluate changes in renal cortical microcirculation induced by noradrenaline: a pilot study 
Critical Care  2014;18(6):653.
Introduction
We used contrast-enhanced ultrasound (CEUS) to estimate the effect of an increase in mean arterial pressure (MAP) induced by noradrenaline infusion on renal microvascular cortical perfusion in critically ill patients.
Methods
Twelve patients requiring a noradrenaline infusion to maintain a MAP more than 60 mmHg within 48 hours of intensive care unit admission were included in the study. Renal CEUS scans with destruction-replenishment sequences and Sonovue® (Bracco, Milano Italy) as a contrast agent, were performed at baseline (MAP 60 to 65 mmHg) and after a noradrenaline-induced increase in MAP to 80 to 85 mmHg.
Results
There was no adverse effect associated with ultrasound contrast agent administration or increase in noradrenaline infusion rate. Adequate images were obtained in all patients at all study times. To reach the higher MAP target, median noradrenaline infusion rate was increased from 10 to 14 μg/min.
Noradrenaline-induced increases in MAP were not associated with a significant change in overall CEUS derived mean perfusion indices (median perfusion index 3056 (interquartile range: 2438 to 6771) arbitrary units (a.u.) at baseline versus 4101 (3067 to 5981) a.u. after MAP increase, P = 0.38). At individual level, however, we observed important heterogeneity in responses (range -51% to +97% changes from baseline).
Conclusions
A noradrenaline-induced increase in MAP was not associated with an overall increase in renal cortical perfusion as estimated by CEUS. However, at individual level, such response was heterogeneous and unpredictable suggesting great variability in pressure responsiveness within a cohort with a similar clinical phenotype.
Electronic supplementary material
The online version of this article (doi:10.1186/s13054-014-0653-3) contains supplementary material, which is available to authorized users.
doi:10.1186/s13054-014-0653-3
PMCID: PMC4262130  PMID: 25439317
14.  Contrast-enhanced ultrasound evaluation of renal microcirculation in sheep 
Background
Contrast-enhanced ultrasonography (CEUS) is a novel imaging modality to estimate microvascular perfusion. We aimed to assess renal cortical microcirculatory changes by CEUS during pharmacologically or mechanically induced modifications of renal blood flow (RBF) in experimental animals.
Methods
We implanted invasive transit-time Doppler flow probes and a vascular occluder around the renal artery in six Merino sheep. After induction of general anaesthesia, renal CEUS studies with destruction-replenishment sequences were performed at baseline and after different interventions aimed at modifying RBF. First, we administered angiotensin II (AngII) to achieve a 25% (AngII 25%) and 50% (AngII 50%) decrease in RBF. Then, we applied mechanical occlusion of the renal artery until RBF decreased by 25% (Occl 25%) and 50% (Occl 50%) of the baseline. Finally, a single dose of 25 mg of captopril was administered. CEUS sequences were analysed offline with dedicated software and perfusion indices (PI) calculated.
Results
Pharmacological reduction of RBF with AngII was associated with a 62% (range: 68 decrease to 167 increase) increase (AngII 25%) and a 5% increase in PI (range: 92% decrease to 53% increase) (AngII 50%) in PI. Mechanical occlusion of the renal artery was associated with a 2% (range: 43% decrease to 2% increase) decrease (Occl 25%) and a 67% (range: 63% decrease to a 120% increase) increase (Occl 50%) in PI. The administration of captopril was associated with a 8% (range: 25% decrease to a 101% increase) decrease in PI. Pooled changes in PI failed to reach statistical significance. The study was limited by the difficulty to obtain high quality images.
Conclusions
CEUS-derived parameters were highly heterogeneous in this sheep model. The current protocol and model did not allow the evaluation of the correlation between macro and microcirculation assessment by CEUS.
doi:10.1186/s40635-014-0033-y
PMCID: PMC4513025
Renal perfusion; Microcirculation; Contrast-enhanced ultrasonography
15.  Effects of selective β1-adrenoceptor blockade on cardiovascular and renal function and circulating cytokines in ovine hyperdynamic sepsis 
Critical Care  2014;18(6):610.
Introduction
Activation of the sympathetic nervous system has beneficial cardiovascular effects in sepsis, but there is also evidence that sympatholytics have beneficial actions in sepsis. We therefore determined the effect of selective β1-adrenoceptor blockade on cardiac and renal function and cytokine release in ovine hyperdynamic sepsis.
Methods
Hyperdynamic sepsis was induced by infusion of live E. coli for 24 hours in nine conscious sheep instrumented with flow probes on the pulmonary and left renal artery. Cardiovascular and renal function and levels of plasma cytokines were determined in a control group and during selective β1-adrenoceptor blockade with atenolol (10 mg intravenous bolus then 0.125 mg/kg/h) from 8 to 24 hours of sepsis.
Results
Hyperdynamic sepsis was characterized by hypotension with increases in cardiac output (CO), heart rate (HR) and renal blood flow (RBF), and acute kidney injury. Atenolol caused sustained reductions in HR (P <0.001) and CO (P <0.001). Despite the lower CO the sepsis-induced fall in mean arterial pressure (MAP) was similar in both groups. The sepsis-induced increase in RBF, decrease in renal function and increase in arterial lactate were unaffected by atenolol. Sepsis increased plasma levels of tumour necrosis factor alpha (TNF-α), interleukin 6 (IL-6) and IL-10. Atenolol caused a further increase in IL-10, but did not affect levels of TNF-α or IL-6.
Conclusions
In sepsis, selective β1-adrenoceptor blockade reduced CO, but not MAP. During sepsis, atenolol did not alter the development of acute kidney injury or the levels of pro-inflammatory cytokines, but enhanced the release of IL-10. Atenolol appears safe in sepsis, has no deleterious cardiovascular or renal effects, and has an anti-inflammatory effect.
doi:10.1186/s13054-014-0610-1
PMCID: PMC4262191  PMID: 25413250
16.  Economics of dialysis dependence following renal replacement therapy for critically ill acute kidney injury patients 
Background
The obective of this study was to perform a cost-effectiveness analysis comparing intermittent with continuous renal replacement therapy (IRRT versus CRRT) as initial therapy for acute kidney injury (AKI) in the intensive care unit (ICU).
Methods
Assuming some patients would potentially be eligible for either modality, we modeled life year gained, the quality-adjusted life years (QALYs) and healthcare costs for a cohort of 1000 IRRT patients and a cohort of 1000 CRRT patients. We used a 1-year, 5-year and a lifetime horizon. A Markov model with two health states for AKI survivors was designed: dialysis dependence and dialysis independence. We applied Weibull regression from published estimates to fit survival curves for CRRT and IRRT patients and to fit the proportion of dialysis dependence among CRRT and IRRT survivors. We then applied a risk ratio reported in a large retrospective cohort study to the fitted CRRT estimates in order to determine the proportion of dialysis dependence for IRRT survivors. We conducted sensitivity analyses based on a range of differences for daily implementation cost between CRRT and IRRT (base case: CRRT day $632 more expensive than IRRT day; range from $200 to $1000) and a range of risk ratios for dialysis dependence for CRRT as compared with IRRT (from 0.65 to 0.95; base case: 0.80).
Results
Continuous renal replacement therapy was associated with a marginally greater gain in QALY as compared with IRRT (1.093 versus 1.078). Despite higher upfront costs for CRRT in the ICU ($4046 for CRRT versus $1423 for IRRT in average), the 5-year total cost including the cost of dialysis dependence was lower for CRRT ($37 780 for CRRT versus $39 448 for IRRT on average). The base case incremental cost-effectiveness analysis showed that CRRT dominated IRRT. This dominance was confirmed by extensive sensitivity analysis.
Conclusions
Initial CRRT is cost-effective compared with initial IRRT by reducing the rate of long-term dialysis dependence among critically ill AKI survivors.
doi:10.1093/ndt/gfu314
PMCID: PMC4286762  PMID: 25326472
acute kidney injury; dialysis dependence; economic analysis
17.  Haemostatic management for aortic valve replacement in a patient with advanced liver disease 
Redo-sternotomy and aortic valve replacement in patients with advanced liver disease is rare and associated with a prohibitive morbidity and mortality. Refractory coagulopathy is common and a consequence of intense activation of the coagulation system that can be triggered by contact of blood with the cardiopulmonary bypass circuitry, bypass-induced fibrinolysis, platelet activation and dysfunction, haemodilution, surgical trauma, hepatic decompensation and hypothermia. Management can be further complicated by right heart dysfunction, porto-pulmonary hypertension, poor myocardial protection, and hepato-renal syndrome. Complex interactions between coagulation/fibrinolysis and systemic inflammatory response syndrome reactions like “post-perfusion-syndrome” also compound haemostatic failure. Given the limited information available for the specific management and prevention of cardiopulmonary bypass-induced haemostatic failure, this report serves to guide the anaesthesia and medical management of future cases of a similar kind. We discuss our multimodal management of haemostatic failure using pharmacological strategies, thromboelastography, continuous cerebral and liver oximetry, and continuous cardiac output monitoring.
doi:10.12998/wjcc.v2.i10.596
PMCID: PMC4198416  PMID: 25325074
Cardiac surgery; Liver failure; Coagulopathy; Cardiopulmonary bypass
18.  Re-thinking resuscitation goals: an alternative point of view! 
Critical Care  2013;17(5):458.
doi:10.1186/cc12775
PMCID: PMC4057104  PMID: 24103536
19.  Current ventilation practice during general anaesthesia: a prospective audit in Melbourne, Australia 
BMC Anesthesiology  2014;14:85.
Background
Recent evidence suggests that the use of low tidal volume ventilation with the application of positive end-expiratory pressure (PEEP) may benefit patients at risk of respiratory complications during general anaesthesia. However current Australian practice in this area is unknown.
Methods
To describe current practice of intraoperative ventilation with regard to tidal volume and application of PEEP, we performed a multicentre audit in patients undergoing general anaesthesia across eight teaching hospitals in Melbourne, Australia.
Results
We obtained information including demographic characteristics, type of surgery, tidal volume and the use of PEEP in a consecutive cohort of 272 patients. The median age was 56 (IQR 42–69) years; 150 (55%) were male. Most common diagnostic groups were general surgery (31%), orthopaedic surgery (20%) and neurosurgery (9.6%). Mean FiO2 was 0.6 (IQR 0.5-0.7). Median tidal volume was 500 ml (IQR 450-550). PEEP was used in 54% of patients with a median value of 5.0 cmH2O (IQR 4.0-5.0) and median tidal volume corrected for predicted body weight was 9.5 ml/kg (IQR 8.5-10.4). Median peak inspiratory pressure was 18 cmH2O (IQR 15–22). In a cohort of patients considered at risk for respiratory complications, the median tidal volume was still 9.8 ml/kg (IQR 8.6-10.7) and PEEP was applied in 66% of patients with a median value of 5 cmH20 (IQR 4–5). On multivariate analyses positive predictors of tidal volume size included male sex (p < 0.01), height (p = 0.04) and weight (p < 0.001). Positive predictors of the use of PEEP included surgery in a tertiary hospital (OR = 3.11; 95% CI: 1.05 to 9.23) and expected prolonged duration of surgery (OR = 2.47; 95% CI: 1.04 to 5.84).
Conclusion
In mechanically ventilated patients under general anaesthesia, tidal volume was high and PEEP was applied to the majority of patients, but at modest levels. The findings of our study suggest that the control groups of previous randomized controlled trials do not closely reflect the practice of mechanical ventilation in Australia.
doi:10.1186/1471-2253-14-85
PMCID: PMC4190393  PMID: 25302048
Tidal volume; PEEP; Intraoperative ventilation; Anaesthesia
20.  Sepsis-associated hyperlactatemia 
Critical Care  2014;18(5):503.
There is overwhelming evidence that sepsis and septic shock are associated with hyperlactatemia (sepsis-associated hyperlactatemia (SAHL)). SAHL is a strong independent predictor of mortality and its presence and progression are widely appreciated by clinicians to define a very high-risk population. Until recently, the dominant paradigm has been that SAHL is a marker of tissue hypoxia. Accordingly, SAHL has been interpreted to indicate the presence of an ‘oxygen debt’ or ‘hypoperfusion’, which leads to increased lactate generation via anaerobic glycolysis. In light of such interpretation of the meaning of SAHL, maneuvers to increase oxygen delivery have been proposed as its treatment. Moreover, lactate levels have been proposed as a method to evaluate the adequacy of resuscitation and the nature of the response to the initial treatment for sepsis. However, a large body of evidence has accumulated that strongly challenges such notions. Much evidence now supports the view that SAHL is not due only to tissue hypoxia or anaerobic glycolysis. Experimental and human studies all consistently support the view that SAHL is more logically explained by increased aerobic glycolysis secondary to activation of the stress response (adrenergic stimulation). More importantly, new evidence suggests that SAHL may actually serve to facilitate bioenergetic efficiency through an increase in lactate oxidation. In this sense, the characteristics of lactate production best fit the notion of an adaptive survival response that grows in intensity as disease severity increases. Clinicians need to be aware of these developments in our understanding of SAHL in order to approach patient management according to biological principles and to interpret lactate concentrations during sepsis resuscitation according to current best knowledge.
doi:10.1186/s13054-014-0503-3
PMCID: PMC4421917  PMID: 25394679
21.  Urine biochemistry in septic and non-septic acute kidney injury: a prospective observational study✩,✩✩ 
Journal of critical care  2012;28(4):371-378.
Purpose
Determine whether there are unique patterns to the urine biochemistry profile in septic compared with non-septic acute kidney injury (AKI) and whether urinary biochemistry predicts worsening AKI, need for renal replacement therapy and mortality.
Materials and Methods
Prospective cohort study of critically ill patients with septic and non-septic AKI, defined by the RIFLE (Risk, Injury, Failure, Loss, End-Stage) criteria. Urine biochemistry parameters were compared between septic and non-septic AKI and were correlated with neutrophil gelatinase-associated lipocalin (NGAL), worsening AKI, renal replacement therapy (RRT), and mortality.
Results
Eighty-three patients were enrolled, 43 (51.8%) with sepsis. RIFLE class was not different between groups (P = .43). Urine sodium (UNa) <20 mmol/L, fractional excretion of sodium (FeNa) <1%, and fractional excretion of urea (FeU) < 35% were observed in 25.3%, 57.8%, and 33.7%, respectively. Septic AKI had lower UNa compared with non-septic AKI (P = .04). There were no differences in FeNa or FeU between groups. Urine NGAL was higher for FeNa≥1% compared to FeNa<1% (177.4 ng/mL [31.9-956.5] vs 48.0 ng/mL [21.1-232.4], P = .04). FeNa showed low correlation with urine NGAL (P = .05) and plasma NGAL (P = .14). There was poor correlation between FeU and urine NGAL (P = .70) or plasma NGAL (P = .41). UNa, FeNa, and FeU showed poor discrimination for worsening AKI, RRT and mortality.
Conclusion
Urine biochemical profiles do not discriminate septic and non-septic AKI. UNa, FeNa, and FeU do not reliably predict biomarker release, worsening AKI, RRT or mortality. These data imply limited utility for these measures in clinical practice in critically ill patients with AKI.
doi:10.1016/j.jcrc.2012.10.007
PMCID: PMC4145696  PMID: 23159144
Acute kidney injury; Fractional excretion of sodium; Fractional excretion of urea; Neutrophil gelatinase-associated lipocalin; Sepsis; Renal replacement therapy
22.  Extended Renal Outcomes with Use of Iodixanol versus Iohexol after Coronary Angiography 
BioMed Research International  2014;2014:506479.
The impact of isoosmolar versus low-osmolar contrast media (CM) administration on contrast-induced acute kidney injury (CI-AKI) and extended renal dysfunction (ERD) is unclear. We retrospectively examined incidences of CI-AKI and ERD in patients who received iodixanol (isoosmolar) versus iohexol (low-osmolar) during angiography for cardiac indications. Of 713 patients, 560 (cohort A), 190 (cohort B), and 172 (cohort C) had serum creatinine monitored at 3 days, 30 days, and 6 months after angiography, respectively. 18% of cohort A developed CI-AKI, which was more common with iodixanol than iohexol (22% versus 13%, P = 0.006). However, patients given iodixanol were older with lower baseline estimated glomerular filtration rates (eGFR). On multivariate analysis, independent associations with higher CI-AKI risk include age >65 years, female gender, cardiac failure, ST-elevation myocardial infarction, intra-aortic balloon pump, and critical illness, but not CM type, higher CM load, or eGFR < 45 mL/min/1.73 m2. 32% of cohort B and 34% of cohort C had ERD at 30 days and 6 months, while 44% and 41% of subcohorts had ERD at 90 days and 1 year, respectively. CI-AKI, but not CM type, was associated with medium- and longer-term ERD, with 3-fold higher risk. Advanced age, emergent cardiac conditions, and critical illness are stronger predictors of CI-AKI, compared with CM-related factors. CI-AKI predicts longer-term ERD.
doi:10.1155/2014/506479
PMCID: PMC4142278  PMID: 25180184
23.  Intensive care sedation: the past, present and the future 
Critical Care  2013;17(3):322.
Despite the universal prescription of sedative drugs in the intensive care unit (ICU), current practice is not guided by high-level evidence. Landmark sedation trials have made significant contributions to our understanding of the problems associated with ICU sedation and have promoted changes to current practice. We identified challenges and limitations of clinical trials which reduced the generalizability and the universal adoption of key interventions. We present an international perspective regarding current sedation practice and a blueprint for future research, which seeks to avoid known limitations and generate much-needed high-level evidence to better guide clinicians' management and therapeutic choices of sedative agents.
doi:10.1186/cc12679
PMCID: PMC3706847  PMID: 23758942
24.  Urinalysis and pre-renal acute kidney injury: time to move on 
Critical Care  2013;17(3):141.
Urinary indices are classically believed to allow differentiation of transient (or pre-renal) acute kidney injury (AKI) from persistent (or acute tubular necrosis) AKI. However, the data validating urinalysis in critically ill patients are weak. In the previous issue of Critical Care, Pons and colleagues demonstrate in a multicenter observational study that sodium and urea excretion fractions as well as urinary over plasma ratios performed poorly as diagnostic tests to separate such entities. This study confirms the limited diagnostic and prognostic ability of urine testing. Together with other studies, this study raises more fundamental questions about the value, meaning and pathophysiologic validity of the pre-renal AKI paradigm and suggests that AKI (like all other forms of organ injury) is a continuum of injury that cannot be neatly divided into functional (pre-renal or transient) or structural (acute tubular necrosis or persistent).
doi:10.1186/cc12676
PMCID: PMC3672654  PMID: 23659200
25.  Clinical review: The role of the intensivist and the rapid response team in nosocomial end-of-life care 
Critical Care  2013;17(2):224.
In-hospital end-of-life care outside the ICU is a new and increasing aspect of practice for intensive care physicians in countries where rapid response teams have been introduced. As more of these patients die from withdrawal or withholding of artificial life support, determining whether a patient is dying or not has become as important to intensivists as the management of organ support therapy itself. Intensivists have now moved to making such decisions in hospital wards outside the boundaries of their usual closely monitored environment. This strategic change may cause concern to some intensivists; however, as custodians of the highest technology area in the hospital, intensivists are by necessity involved in such processes. Now, more than ever before, intensive care clinicians must consider the usefulness of key concepts surrounding nosocomial death and dying and the importance and value of making a formal diagnosis of dying in the wards. In this article, we assess the conceptual background, reference points, challenges and implications of these emerging aspects of intensive care medicine.
doi:10.1186/cc11856
PMCID: PMC3672544  PMID: 23672813

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