Predictors of New Onset Atrial Fibrillation Burden in the Critically Ill.

INTRODUCTION: Atrial fibrillation (AF) is common in the intensive care unit (ICU) setting and has been associated with adverse outcomes. In this context, there is increasing research interest in AF burden as a predictor of subsequent adverse events. However, the pathophysiology and drivers of AF burden in the ICU are poorly understood. This study sought to evaluate the predictors of AF burden in critical illness-associated new-onset AF (CI-NOAF). METHODS: Out of 7,030 admissions in a tertiary general ICU between December 2015 and September 2018, 309 patients developed CI-NOAF. AF burden was defined as the percentage of monitored time in AF, as extracted from hourly interpretations of continuous ECG monitoring. Low and high AF burden groups were defined relative to the median AF burden. Clinical, laboratory, and echocardiographic parameters were extracted, and multivariable modelling with binary logistic regression was performed to evaluate for independent associations with AF burden. RESULTS: The median AF burden was 7.0%. Factors associated with increased AF burden were age, dyslipidaemia, chronic kidney disease, increased creatinine, CHA2DS2-VASc score, ICU admission diagnosis category, amiodarone administration, and left atrial area (LAA). Factors associated with lower AF burden were previous alcohol excess, burden of ventilation, the use of inotropes/vasopressors, and beta blockers. On multivariate analysis, increased LAA, chronic kidney disease, and amiodarone use were independently associated with increased AF burden, whereas beta blocker use was associated with lower AF burden. CONCLUSION: Left atrial size and chronic cardiovascular comorbidities appear to be the primary drivers of CI-NOAF burden, whereas factors related to acute illness and critical care intervention paradoxically did not appear to be a substantial driver of arrhythmia burden. Further research is needed regarding drivers of AF and the efficacy of rhythm control intervention in this unique setting.

Critical illness associated new onset atrial fibrillation: subsequent atrial fibrillation diagnoses and other adverse outcomes.

AIMS: Amongst patients with critical illness associated new onset AF (CI-NOAF), the risk of subsequent atrial fibrillation (AF) diagnoses and other adverse outcomes is unknown, and the role for long-term anticoagulation is unclear. This study sought to determine the factors associated with subsequent AF diagnoses and other adverse outcomes in this cohort. METHODS AND RESULTS: Admissions to a tertiary general intensive care unit (ICU) between December 2015 and September 2018 were screened for AF episodes through hourly analysis of continuous ECG monitoring. Patients with a prior history of AF were excluded. AF burden was defined as the percentage of monitored ICU hours in AF. The primary endpoint was subsequent AF diagnoses, as collated from the statewide electronic medical records. Secondary endpoints included mortality, embolic events, MACE and subsequent anticoagulation. RESULTS: Of 7030 admissions with 509 303 h of monitoring data, 309 patients with CI-NOAF were identified, and 235 survived to discharge. Subsequent AF diagnoses were identified in 75 (31.9%) patients after a median of 413 days. Increased AF burden had the strongest independent association with AF recurrence (OR = 15.03, P = 0.002), followed by increased left atrial area (OR = 1.12, P = 0.01). Only 128 (54.5%) patients had their AF diagnosis acknowledged at ICU discharge, and 50 (21.3%) received anticoagulation at hospital discharge. CONCLUSION: CI-NOAF is often under-recognized, and subsequent AF diagnoses are common post-discharge. AF burden during ICU admission has a strong independent association with subsequent AF diagnoses. Left atrial size is also independently associated with subsequent AF.

Does mechanical threshold inspiratory muscle training promote recovery and improve outcomes in patients who are ventilator-dependent in the intensive care unit? The IMPROVE randomised trial.

BACKGROUND: In patients who are ventilator-dependent in the intensive care unit, inspiratory muscle training may improve inspiratory muscle strength and accelerate liberation from the ventilator, but optimal training parameters are yet to be established, and little is known about the impact of inspiratory muscle training on quality of life or dyspnoea. Thus, we sought to ascertain whether inspiratory muscle training, commenced while ventilator-dependent, would improve outcomes for patients invasively ventilated for 7 days or longer. METHODS: In this randomised trial with assessor blinding and intention-to-treat analysis, 70 participants (mechanically ventilated ≥7 days) were randomised to receive once-daily supervised high-intensity inspiratory muscle training with a mechanical threshold device in addition to usual care or to receive usual care (control). Primary outcomes were inspiratory muscle strength (maximum inspiratory pressure % predicted) and endurance (fatigue resistance index) at ventilator liberation and 1 week later. Secondary outcomes included quality of life (SF-36v2, EQ-5D), dyspnoea, physical function, duration of ventilation, and in-hospital mortality. RESULTS: Thirty-three participants were randomly allocated to the training group, and 37 to the control group. There were no statistically significant differences in strength (maximum inspiratory pressure) (95% confidence interval [CI]: -7.4 to 14.0) or endurance (fatigue resistance index) (95% CI: -0.003 to 0.436). Quality of life improved significantly more in the training group than in the control group (EQ-5D: 17.2; 95% CI: 1.3-33.0) (SF-36-PCS: 6.97; 95% CI: 1.96-12.00). Only the training group demonstrated significant reductions in dyspnoea (-1.5 at rest, -1.9 during exercise). There were no between-group differences in duration of ventilation or other measures. In-hospital mortality was higher in the control group than in the training group (9 vs 4, 24% vs 12%, p = 0.23). CONCLUSIONS: In patients who are ventilator-dependent, mechanical threshold loading inspiratory muscle training improves quality of life and dyspnoea, even in the absence of strength improvements or acceleration of ventilator liberation.

Early Sequential Microcirculation Assessment In Shocked Patients as a Predictor of Outcome: A Prospective Observational Cohort Study.

OBJECTIVES: A dysfunctional microcirculation is universal in shock and is often dissociated from global hemodynamic parameters. Persistent microcirculatory derangements reflect ongoing tissue hypoperfusion and organ injury. The initial microcirculatory dysfunction and subsequent resolution could potentially guide therapy and predict outcomes. We evaluated the microcirculation early in a heterogenous shocked population. Microcirculatory resolution was correlated with measures of tissue perfusion and global hemodynamics. The relationship between the microcirculation over 24 h and outcome were evaluated. DESIGN: We prospectively recruited patients with all forms of shock, based on global hemodynamics and evidence of organ hypoperfusion. SETTING: A 30-bed adult intensive care unit (ICU). PATIENTS: Eighty-two shocked patients. MEASUREMENTS AND MAIN RESULTS: Following the diagnosis of shock, patients underwent a sublingual microcirculation examination using Sidestream Dark Field Imaging. The median age of patients was 66 years old (interquartile range [IQR] 54-71), with an Acute Physiology and Chronic Health Evaluation II of 27 (IQR 20-32). Microcirculatory parameters included Percentage Perfused Vessels (PPV), De Backer Score, and a heterogeneity index in patients with septic shock, according to the second consensus guidelines Additional parameters collected: temperature, heart rate and arterial pressure, cumulative fluid balance, and vasopressor use. Arterial blood samples were taken at the time of microcirculatory assessments, providing HCO3, lactate concentrations, PaO2, and PaCO2 measurements. A statistically significant improvement in PPV and the heterogeneity index was demonstrated. This improvement was mirrored by biomarkers of perfusion; however, the global hemodynamic parameter changes were not significantly different over the 24-h period. The early microcirculatory improvement was not predictive of an improvement in acute kidney injury, length of stay, ICU, or hospital mortality. CONCLUSIONS: Early sequential evaluation of the microcirculation in shocked patients, demonstrated statistically significant improvement in the PPV and microvascular heterogeneity with standard care. These improvements were mirrored by biomarkers of organ perfusion; however, the changes in global hemodynamics were not as pronounced in this early phase. Early improvement in the microcirculation did not predict clinical outcome.

Which ICU patients benefit most from inspiratory muscle training? Retrospective analysis of a randomized trial.

Background: Inspiratory muscle training (IMT) increases inspiratory muscle strength and improves quality of life in intensive care unit (ICU) patients who have been invasively mechanically ventilated for ≥7 days. The purpose of this study was to identify which patients benefit most from IMT following weaning from mechanical ventilation. Methods: Secondary analysis of a randomized trial of supervised daily IMT in 70 patients (mean age 59 years) in a 31-bed ICU was carried out. Changes in inspiratory muscle strength (maximum inspiratory pressure, MIP) between enrolment and 2 weeks (ΔMIP) were analyzed to compare the IMT group (71% male) and the control group (58% male). Linear regression models explored which factors at baseline were associated with ΔMIP. Results: Thirty-four participants were allocated to the IMT group where baseline MIP was associated with an increase in ΔMIP, significantly different from the control group (p = 0.025). The highest ΔMIP was associated with baseline MIP ≥ 28 cmH2O. In the IMT group, higher baseline quality of life (EQ5D) scores were associated with positive ΔMIP, significantly different from the control group (p = 0.029), with largest ΔMIP for those with EQ5D ≥ 40. Conclusions: Physiotherapists should target ICU patients with moderate inspiratory muscle weakness (MIP ≥28 cmH2O) and moderate to high quality of life (EQ5D>40) within 48 h of ventilatory weaning as ideal candidates for IMT following prolonged mechanical ventilation.

Augmented Renal Clearance in Traumatic Brain Injury: A Single-Center Observational Study of Atrial Natriuretic Peptide, Cardiac Output, and Creatinine Clearance.

Augmented renal clearance (ARC) is being increasingly described in neurocritical care practice. The mechanisms driving this phenomenon are largely unknown. The aim of this project was therefore to explore changes in renal function, cardiac output (CO), and atrial natriuretic peptide (ANP) concentrations in patients with isolated traumatic brain injury (TBI). This prospective observational cohort study was conducted in a tertiary-level, university-affiliated intensive care unit (ICU). Patients with normal plasma creatinine concentrations (<120 µmol/L) at admission and no history of chronic kidney disease, admitted with isolated TBI, were eligible for enrollment. Continuous CO measures were obtained using arterial pulse waveform analysis. Eight-hour urinary creatinine clearances (CLCR) were used to quantify renal function. ANP concentrations in plasma were measured on alternate days. Data were collected from study enrollment until ICU discharge, death, or day 15, which ever came first. Eleven patients, contributing 100 ICU days of physiological data, were enrolled into the study. Most participants were young men, requiring mechanical ventilation. Median ICU length of stay was 9.6 [7.8-13.0] days. Elevated CLCR measures (>150 mL/min) were frequent and appeared to parallel changes in CO. Plasma ANP concentrations were also significantly elevated over the study period (minimum value = 243 pg/mL). These data suggest that ARC is likely to complicate the care of TBI patients with normal plasma creatinine concentrations, and may be driven by associated cardiovascular changes and/or elevated plasma ANP concentrations. However, significant additional research is required to further understand these findings.

Inspiratory muscle training to enhance recovery from mechanical ventilation: a randomised trial.

BACKGROUND: In patients who have been mechanically ventilated, inspiratory muscles remain weak and fatigable following ventilatory weaning, which may contribute to dyspnoea and limited functional recovery. Inspiratory muscle training may improve inspiratory muscle strength and endurance following weaning, potentially improving dyspnoea and quality of life in this patient group. METHODS: We conducted a randomised trial with assessor-blinding and intention-to-treat analysis. Following 48 hours of successful weaning, 70 participants (mechanically ventilated ≥7 days) were randomised to receive inspiratory muscle training once daily 5 days/week for 2 weeks in addition to usual care, or usual care (control). Primary endpoints were inspiratory muscle strength and fatigue resistance index (FRI) 2 weeks following enrolment. Secondary endpoints included dyspnoea, physical function and quality of life, post-intensive care length of stay and in-hospital mortality. RESULTS: 34 participants were randomly allocated to the training group and 36 to control. The training group demonstrated greater improvements in inspiratory strength (training: 17%, control: 6%, mean difference: 11%, p=0.02). There were no statistically significant differences in FRI (0.03 vs 0.02, p=0.81), physical function (0.25 vs 0.25, p=0.97) or dyspnoea (-0.5 vs 0.2, p=0.22). Improvement in quality of life was greater in the training group (14% vs 2%, mean difference 12%, p=0.03). In-hospital mortality was higher in the training group (4 vs 0, 12% vs 0%, p=0.051). CONCLUSIONS: Inspiratory muscle training following successful weaning increases inspiratory muscle strength and quality of life, but we cannot confidently rule out an associated increased risk of in-hospital mortality. TRIAL REGISTRATION NUMBER: ACTRN12610001089022, results.

Reliability and utility of the Acute Care Index of Function in intensive care patients: An observational study.

OBJECTIVES: To establish the inter-rater reliability of the Acute Care Index of Function (ACIF) in intensive care unit (ICU) patients and determine whether ACIF scores have predictive utility beyond ICU discharge. BACKGROUND: Accurate and reliable measures of physical function are required to describe the recovery trajectory of ICU survivors. The clinimetric properties of the ACIF are yet to be established in ICU patients. METHODS: Prospective observational study in a single tertiary ICU. ACIF scores were recorded independently by 2 physiotherapists across a convenience sample of 100 physiotherapy assessments, and at ICU discharge. RESULTS: Inter-rater reliability of total ACIF scores was very strong (ICC = 0.94). ACIF <0.40 at ICU discharge predicted hospital discharge to a destination other than home (area under ROC = 0.79, 95% CI 0.64-0.89) (sensitivity 0.78). CONCLUSION: The ACIF has excellent inter-rater reliability in ICU patients and scores at ICU discharge predict the likelihood of discharge home. TRIAL REGISTRATION: ACTRN12614001008617 (September 18 2014).

Pharmacokinetics of a novel dosing regimen of oral melatonin in critically ill patients.

BACKGROUND: Loss of circadian rhythms and reduced concentrations of endogenous melatonin are common in critically ill patients. After exogenous administration, supra-physiological concentrations in serum are only ephemeral, which may explain the absence of significant therapeutic effect on sleep. The aim of this study is to describe the pharmacokinetics of enteral melatonin in critically ill patients administered in a novel regimen aiming to simulate endogenous release. METHODS: Thirteen patients in the recovery phase of critical illness were randomised to receive enteral melatonin or placebo. In the melatonin group, a total of 6 mg was administered as solution through their feeding tube, commencing with a 3 mg loading dose at 9 pm and six subsequent 0.5 mg doses hourly. The placebo was administered using a similar regimen. Serial blood samples were taken and measured using a validated chromatographic method. The concentration-time data for serum melatonin concentrations were described using non-linear mixed-effects modelling. RESULTS: The observed concentrations in the melatonin patients were significantly higher than that observed in the placebo patients. The concentrations in the patients administered melatonin were also higher than endogenous melatonin concentrations previously reported in non-critically ill patients. The patients administered melatonin had a mean clearance, volume of distribution and absorption rate constant of melatonin was 55.2 L/h, 767 L and 0.76 h-1, respectively. CONCLUSIONS: Exogenous administration of melatonin with a loading dose of 3 mg followed by an hourly dose of 0.5 mg demonstrates good oral bioavailability and results in supra-physiological and sustained concentrations of serum melatonin during 12 h overnight.

Early physical rehabilitation in intensive care patients with sepsis syndromes: a pilot randomised controlled trial.

RATIONALE: Survivors of sepsis syndromes have poor outcomes for physical and cognitive function. No investigations of early physical rehabilitation in the intensive care unit have specifically targeted patients with sepsis syndromes. OBJECTIVE: To determine whether early physical rehabilitation improves physical function and associated outcomes in patients with sepsis syndromes. METHODS: Fifty critically ill adults admitted to a general intensive care unit with sepsis syndromes were recruited into a prospective double-blinded randomised controlled trial investigating early physical rehabilitation. MEASUREMENTS: Primary outcomes of physical function (acute care index of function) and self-reported health-related quality of life were recorded at ICU discharge and 6 months post-hospital discharge, respectively. Secondary measures included inflammatory biomarkers; Interleukin-6, Interleukin-10 and tumour necrosis factor-α, blood lactate, fat-free muscle mass, exercise capacity, muscle strength and anxiety. MAIN RESULTS: A significant increase in patient self-reported physical function (81.8 ± 22.2 vs. 60.0 ± 29.4), p = 0.04) and physical role (61.4 ± 43.8 vs. 17.1 ± 34.4, p = 0.005) for the SF-36 at 6 months was found in the exercise group. Physical function scores were not significantly different between groups. Muscle strength scores were (51.9 ± 10.5 vs. 47.3 ± 13.6, p = 0.24) with the standard care mean Medical Research Council Muscle Score (MRC) <48/60. The mean change of Interleukin-10 increased and was significantly higher in the exercise group (1.8 pg/ml, 180 % vs. 0.9 pg/ml, 90 %, p = 0.04). There was no significant difference between groups for lactate, Interleukin-6, tumour necrosis factor-α, muscle strength, exercise capacity, fat-free mass or hospital anxiety. CONCLUSION: Implementation of early physical rehabilitation can improve self-reported physical function and induce systemic anti-inflammatory effects.

Are interstitial fluid concentrations of meropenem equivalent to plasma concentrations in critically ill patients receiving continuous renal replacement therapy?

OBJECTIVES: To describe the interstitial fluid (ISF) and plasma pharmacokinetics of meropenem in patients on continuous venovenous haemodiafiltration (CVVHDF). PATIENTS AND METHODS: This was a prospective observational pharmacokinetic study. Meropenem (500 mg) was administered every 8 h. CVVHDF was targeted as a 2-3 L/h exchange using a polyacrylonitrile filter with a surface area of 1.05 m2 and a blood flow rate of 200 mL/min. Serial blood (pre- and post-filter), filtrate/dialysate and ISF concentrations were measured on 2 days of treatment (Profiles A and B). Subcutaneous tissue ISF concentrations were determined using microdialysis. RESULTS: A total of 384 samples were collected. During Profile A, the comparative median (IQR) ISF and plasma peak concentrations were 13.6 (12.0-16.8) and 40.7 (36.6-45.6) mg/L and the trough concentrations were 2.6 (2.4-3.4) and 4.9 (3.5-5.0) mg/L, respectively. During Profile B, the ISF trough concentrations increased by ∼40%. Meropenem ISF penetration was estimated at 63% (60%-69%) and 69% (65%-74%) for Profiles A and B, respectively, using comparative plasma and ISF AUCs. For Profile A, the plasma elimination t1/2 was 3.7 (3.3-4.0) h, the volume of distribution was 0.35 (0.25-0.46) L/kg, the total clearance was 4.1 (4.1-4.8) L/h and the CVVHDF clearance was 2.9 (2.7-3.1) L/h. CONCLUSIONS: This is the first known report of concurrent plasma and ISF concentrations of a meropenem antibiotic during CVVHDF. We observed that the ISF concentrations of meropenem were significantly lower than the plasma concentrations, although the present dose was appropriate for infections caused by intermediately susceptible pathogens (MIC≤4 mg/L).

Weaned but weary: one third of adult intensive care patients mechanically ventilated for 7 days or more have impaired inspiratory muscle endurance after successful weaning.

OBJECTIVES: The purpose of this study was to establish whether intensive care unit (ICU) patients have impaired inspiratory muscle (IM) endurance immediately following weaning from prolonged mechanical ventilation (MV), and whether IM weakness is related to function or perceived exertion. BACKGROUND: Impaired IM endurance may hinder recovery from MV, however it is unknown whether this affects patients' function or perceived exertion. METHODS: Prospective observational study of 43 adult ICU patients following weaning from MV (>7 days duration). IM endurance was measured using the fatigue resistance index (FRI). RESULTS: IM endurance was impaired (FRI = mean 0.90, SD 0.31), with 37% scoring below 0.80. IM strength did not significantly correlate with function (r = 0.24, p = 0.12) or perceived exertion during exercise (r = -0.146, p = 0.37). CONCLUSIONS: IM endurance is reduced in one third of patients, while IM weakness does not appear closely associated with function or perceived exertion immediately following successful weaning.

Burn resuscitation--hourly urine output versus alternative endpoints: a systematic review.

Controversy remains over appropriate endpoints of resuscitation during fluid resuscitation in early burns management. We reviewed the evidence as to whether utilizing alternative endpoints to hourly urine output produces improved outcomes. MEDLINE, CINAHL, EMBASE, Cochrane Library, Web of Science, and full-text clinicians' health journals at OVID, from 1990 to January 2014, were searched with no language restrictions. The keywords burns AND fluid resuscitation AND monitoring and related synonyms were used. Outcomes of interest included all-cause mortality, organ dysfunction, length of stay (hospital, intensive care), time on mechanical ventilation, and complications such as incidence of pulmonary edema, compartment syndromes, and infection. From 482 screened, eight empirical articles, 11 descriptive studies, and one systematic review met the criteria. Utilization of hemodynamic monitoring compared with hourly urine output as an endpoint to guide resuscitation found an increased survival (risk ratio [RR], 0.58; 95% confidence interval, 0.42-0.85; P < 0.004), with no effect on renal failure (RR, 0.77; 95% confidence interval, 0.39-1.43; P = 0.38). However, inclusion of the randomized controlled trials only found no survival advantage of hemodynamic monitoring over hourly urine output (RR, 0.72; 95% confidence interval, 0.43-1.19; P = 0.19) for mortality. There were conflicting findings between studies for the volume of resuscitation fluid, incidence of sepsis, and length of stay. There is limited evidence of increased benefit with utilization of hemodynamic monitoring, however, all studies lacked assessor blinding. A large multicenter study with a priori-determined subgroup analysis investigating alternative endpoints of resuscitation is warranted.

A new marker of sepsis post burn injury?*.

OBJECTIVES: Accurate diagnosis of sepsis is difficult in patients post burn due to the large inflammatory response produced by the major insult. We aimed to estimate the values of serum N-terminal pro-B-type natriuretic peptide and procalcitonin and the changes in hemodynamic variables as markers of sepsis in critically ill burn patients. DESIGN: Prospective, observational study. SETTING: A quaternary-level university-affiliated ICU. PATIENTS: Fifty-four patients with burns to total body surface area of greater than or equal to 15%, intubated with no previous cardiovascular comorbidities, were enrolled. INTERVENTIONS: At admission, a FloTrac/Vigileo system was attached and daily blood samples taken from the arterial catheter. Infection surveillance was carried out daily with patients classified as septic/nonseptic according to American Burns Consensus criteria. MEASUREMENTS AND MAIN RESULTS: N-terminal pro-B-type natriuretic peptide, procalcitonin, and waveform analysis of changes in stroke volume index and systemic vascular resistance index were measured within the first 24 hours after burn and daily thereafter for the length of the ICU stay or until their first episode of sepsis. Prevalences of stroke volume variation less than 12% (normovolemia) with hypotension (systolic blood pressure < 90 mm Hg) were recorded. Patients with sepsis differed significantly from "no sepsis" for N-terminal pro-B-type natriuretic peptide, systemic vascular resistance index, and stroke volume index on days 3-7. Procalcitonin did not differ between sepsis and "no sepsis" except for day 3. Area under the receiver operating characteristic curves showed excellent discriminative power for B-type natriuretic peptide (p = 0.001; 95% CI, 0.99-1.00), systemic vascular resistance index (p < 0.001; 95% CI, 0.97-0.99), and stroke volume index (p < 0.01; 95% CI, 0.96-0.99) in predicting sepsis but not for procalcitonin (not significant; 95% CI, 0.29-0.46). A chi-square crosstab found that there was no relationship between hypotension with normovolemia (stroke volume variation < 12%) and sepsis. CONCLUSIONS: Serum N-terminal pro-B-type natriuretic peptide levels and certain hemodynamic changes can be used as an early indicator of sepsis in patients with burn injury. Procalcitonin did not assist in the early diagnosis of sepsis.

IMPOSE (IMProving Outcomes after Sepsis)-the effect of a multidisciplinary follow-up service on health-related quality of life in patients postsepsis syndromes-a double-blinded randomised controlled trial: protocol.

INTRODUCTION: Patients post sepsis syndromes have a poor quality of life and a high rate of recurring illness or mortality. Follow-up clinics have been instituted for patients postgeneral intensive care but evidence is sparse, and there has been no clinic specifically for survivors of sepsis. The aim of this trial is to investigate if targeted screening and appropriate intervention to these patients can result in an improved quality of life (Short Form 36 health survey (SF36V.2)), decreased mortality in the first 12 months, decreased readmission to hospital and/or decreased use of health resources. METHODS AND ANALYSIS: 204 patients postsepsis syndromes will be randomised to one of the two groups. The intervention group will attend an outpatient clinic two monthly for 6 months and receive screening and targeted intervention. The usual care group will remain under the care of their physician. To analyse the results, a baseline comparison will be carried out between each group. Generalised estimating equations will compare the SF36 domain scores between groups and across time points. Mortality will be compared between groups using a Cox proportional hazards (time until death) analysis. Time to first readmission will be compared between groups by a survival analysis. Healthcare costs will be compared between groups using a generalised linear model. Economic (health resource) evaluation will be a within-trial incremental cost utility analysis with a societal perspective. ETHICS AND DISSEMINATION: Ethical approval has been granted by the Royal Brisbane and Women's Hospital Human Research Ethics Committee (HREC; HREC/13/QRBW/17), The University of Queensland HREC (2013000543), Griffith University (RHS/08/14/HREC) and the Australian Government Department of Health (26/2013). The results of this study will be submitted to peer-reviewed intensive care journals and presented at national and international intensive care and/or rehabilitation conferences. TRIAL REGISTRATION NUMBER: Australian and New Zealand Clinical Trials Registry ACTRN12613000528752.

Pharmacokinetics of piperacillin and tazobactam in plasma and subcutaneous interstitial fluid in critically ill patients receiving continuous venovenous haemodiafiltration.

This prospective pharmacokinetic study aimed to describe plasma and interstitial fluid (ISF) pharmacokinetics of piperacillin and tazobactam in critically ill patients on continuous venovenous haemodiafiltration (CVVHDF). Piperacillin/tazobactam (4g/0.5g) was administered every 8h and CVVHDF was performed as a 3-3.5L/h exchange using a polyacrylonitrile filter with a surface area of 1.05m(2). Serial blood (pre- and post-filter), filtrate/dialysate, urine and ISF concentrations were measured. Subcutaneous tissue ISF concentrations were determined using microdialysis. A total of 407 samples were collected. Median peak plasma concentrations were 210.5 (interquartile range=161.5-229.0) and 29.4 (27.9-32.0) mg/L and median trough plasma concentrations were 64.3 (49.0-68.9) and 12.3 (7.7-13.7) mg/L for piperacillin and tazobactam, respectively. The plasma elimination half-life was 6.4 (4.6-8.7) and 7.3 (4.6-11.8) h, volume of distribution 0.42 (0.29-0.49) and 0.32 (0.24-0.36) L/kg, total clearance 5.1 (4.2-6.2) and 3.8 (3.3-4.2) L/h and CVVHDF clearance 2.5 (2.3-3.1) and 2.5 (2.3-3.2) L/h for piperacillin and tazobactam, respectively. The tissue penetration ratio or ratio of area under the concentration-time curve of the unbound drug in ISF to plasma (unbound AUCISF/AUCplasma) was ca. 1 for both piperacillin and tazobactam. This is the first report of concurrent plasma and ISF concentrations of piperacillin and tazobactam during CVVHDF. For the CVVHDF settings used in this study, a dose of 4.5g piperacillin/tazobactam administered evry 8h resulted in piperacillin concentrations in plasma and ISF >32mg/L throughout most of the dosing interval.

Augmented renal clearance in the ICU: results of a multicenter observational study of renal function in critically ill patients with normal plasma creatinine concentrations*.

OBJECTIVE: To describe the prevalence and natural history of augmented renal clearance in a cohort of recently admitted critically ill patients with normal plasma creatinine concentrations. DESIGN: Multicenter, prospective, observational study. SETTING: Four, tertiary-level, university-affiliated, ICUs in Australia, Singapore, Hong Kong, and Portugal. PATIENTS: Study participants had to have an expected ICU length of stay more than 24 hours, no evidence of absolute renal impairment (admission plasma creatinine < 120 µmol/L), and no history of prior renal replacement therapy or chronic kidney disease. Convenience sampling was used at each participating site. INTERVENTIONS: Eight-hour urinary creatinine clearances were collected daily, as the primary method of measuring renal function. Augmented renal clearance was defined by a creatinine clearance more than or equal to 130 mL/min/1.73 m. Additional demographic, physiological, therapeutic, and outcome data were recorded prospectively. MEASUREMENTS AND MAIN RESULTS: Nine hundred thirty-two patients were admitted to the participating ICUs over the study period, and 281 of which were recruited into the study, contributing 1,660 individual creatinine clearance measures. The mean age (95% CI) was 54.4 years (52.5-56.4 yr), Acute Physiology and Chronic Health Evaluation II score was 16 (15.2-16.7), and ICU mortality was 8.5%. Overall, 65.1% manifested augmented renal clearance on at least one occasion during the first seven study days; the majority (74%) of whom did so on more than or equal to 50% of their creatinine clearance measures. Using a mixed-effects model, the presence of augmented renal clearance on study day 1 strongly predicted (p = 0.019) sustained elevation of creatinine clearance in these patients over the first week in ICU. CONCLUSIONS: Augmented renal clearance appears to be a common finding in this patient group, with sustained elevation of creatinine clearance throughout the first week in ICU. Future studies should focus on the implications for accurate dosing of renally eliminated pharmaceuticals in patients with augmented renal clearance, in addition to the potential impact on individual clinical outcomes.