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).

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.

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.

Augmented renal clearance in septic and traumatized patients with normal plasma creatinine concentrations: identifying at-risk patients.

INTRODUCTION: Improved methods to optimize drug dosing in the critically ill are urgently needed. Traditional prescribing culture involves recognition of factors that mandate dose reduction (such as renal impairment), although optimizing drug exposure, through more frequent or augmented dosing, represents an evolving strategy. Elevated creatinine clearance (CLCR) has been associated with sub-therapeutic antibacterial concentrations in the critically ill, a concept termed augmented renal clearance (ARC). We aimed to determine the prevalence of ARC in a cohort of septic and traumatized critically ill patients, while also examining demographic, physiological and illness severity characteristics that may help identify this phenomenon. METHODS: This prospective observational study was performed in a 30-bed tertiary level, university affiliated, adult intensive care unit. Consecutive traumatized and septic critically ill patients, receiving antibacterial therapy, with a plasma creatinine concentration ≤110 µmol/L, were eligible for enrolment. Pulse contour analysis (Vigileo / Flo Trac system, Edwards Lifesciences, Irvine, CA, USA), was used to provide continuous cardiac index (CI) assessment over a single six-hour dosing interval. Urinary CLCR measures were obtained concurrently. RESULTS: Seventy-one patients contributed data (sepsis n = 43, multi-trauma n = 28). Overall, 57.7% of the cohort manifested ARC, although there was a greater prevalence in trauma (85.7% versus 39.5%, P <0.001). In all patients, a weak correlation was noted between CI and CLCR (r = 0.346, P = 0.003). This was mostly driven by septic patients (r = 0.508, P = 0.001), as no correlation (r = -0.012, P = 0.951) was identified in trauma. Those manifesting ARC were younger (P <0.001), male (P = 0.012), with lower acute physiology and chronic health evaluation (APACHE) II (P= 0.008) and modified sequential organ failure assessment (SOFA) scores (P = 0.013), and higher cardiac indices (P = 0.013). In multivariate analysis, age ≤50 years, trauma, and a modified SOFA score ≤4, were identified as significant risk factors. These had greater utility in predicting ARC, compared with CI assessment alone. CONCLUSIONS: Diagnosis, illness severity and age, are likely to significantly influence renal drug elimination in the critically ill, and must be regularly considered in future study design and daily prescribing practice.

A comparison of CKD-EPI estimated glomerular filtration rate and measured creatinine clearance in recently admitted critically ill patients with normal plasma creatinine concentrations.

BACKGROUND: The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) estimated glomerular filtration rate (eGFR) has been widely integrated into clinical practice. Although useful in screening for CKD, its' application in critically ill patients with normal plasma creatinine concentrations remains uncertain. The aim of this study was to assess the performance of CKD-EPI eGFR in comparison to creatinine clearance (CLCR) in this setting. METHODS: This prospective observational study was performed in a tertiary level, university affiliated intensive care unit (ICU). Study participants had to have an expected ICU length of stay > 24 hours, a plasma creatinine concentration < 121 µmol/L, and no history of prior renal replacement therapy or CKD. CKD-EPI eGFR was compared against 8-hour measured urinary CLCR. Data capture occurred within 48 hours of admission. RESULTS: One hundred and ten patients (n = 110) were enrolled in the study. 63.6% were male, the mean age was 50.9 (16.9) years, 57.3% received invasive mechanical ventilation, and 30% required vasopressor support. The mean CLCR was 125 (45.1) ml/min/1.73 m(2), compared to a CKD-EPI eGFR of 101 (23.7) ml/min/1.73 m(2) (P < 0.001). Moderate correlation was evident (r = 0.72), although there was significant bias and imprecision (24.4 +/- 32.5 ml/min/1.73 m(2)). In those patients with a CKD-EPI eGFR between 60-119 ml/min/1.73 m(2) (n = 77), 41.6% displayed augmented renal clearance (CLCR ≥ 130 ml/min/1.73 m(2)), while 7.8% had a CLCR < 60 ml/min/1.73 m(2). CONCLUSIONS: These data suggest CKD-EPI eGFR and measured CLCR produce significantly disparate results when estimating renal function in this population. Clinicians should consider carefully which value they employ in clinical practice, particularly drug dose modification.

Early rehabilitation in sepsis: a prospective randomised controlled trial investigating functional and physiological outcomes The i-PERFORM Trial (Protocol Article).

BACKGROUND: Patients with sepsis syndromes in comparison to general intensive care patients can have worse outcomes for physical function, quality of life and survival. Early intensive care rehabilitation can improve the outcome in general Intensive Care Unit (ICU) patients, however no investigations have specifically looked at patients with sepsis syndromes. The 'i-PERFORM Trial' will investigate if early targeted rehabilitation is both safe and effective in patients with sepsis syndromes admitted to ICU. METHODS/DESIGN: A single-centred blinded randomized controlled trial will be conducted in Brisbane, Australia. Participants (n = 252) will include those ≥ 18 years, mechanically ventilated for ≥ 48 hours and diagnosed with a sepsis syndrome. Participants will be randomised to an intervention arm which will undergo an early targeted rehabilitation program according to the level of arousal, strength and cardiovascular stability and a control group which will receive normal care.The primary outcome measures will be physical function tests on discharge from ICU (The Acute Care Index of Function and The Physical Function ICU Test). Health-related quality of life will be measured using the Short Form-36 and the psychological component will be tested using The Hospital Anxiety and Depression Scale. Secondary measures will include inflammatory biomarkers; Interleukin-6, Interleukin-10 and Tumour Necrosis Factor-α, peripheral blood mitochondrial DNA content and lactate, fat free muscle mass, tissue oxygenation and microcirculatory flow. DISCUSSION: The 'i-PERFORM Trial' will determine whether early rehabilitation for patients with sepsis is effective at improving patient outcomes with functional and physiological parameters reflecting long and short-term effects of early exercise and the safety in its application in critical illness. TRIAL REGISTRATION: Australia and New Zealand Clinical Trials Register (ANZCTR): ACTRN12610000808044.

Surveillance culture utility and safety using low-volume blind bronchoalveolar lavage in the diagnosis of ventilator-associated pneumonia.

BACKGROUND AND OBJECTIVES: Surveillance cultures may improve the prediction of ventilator-associated pneumonia (VAP) and empirical antibiotic selection. This study examined the utility and patient safety of blind, non-protected, low-volume mini-bronchial lavage (BM-BAL) surveillance cultures in predicting VAP. METHODOLOGY: A prospective, cohort study was performed in a large general intensive care unit. BM-BALs were collected within 12 h of admission then thrice weekly. Each BM-BAL was screened by Gram staining for intracellular organisms and then quantitatively cultured. VAP was diagnosed using the Clinical Pulmonary Infection Score. The concordance for isolates from the BM-BAL was assessed against concurrently collected endotracheal aspirates (EA). RESULTS: Four hundred and twelve patients requiring a minimum of 48 h of mechanical ventilation were enrolled. Fifty patients developed 58 episodes of VAP. Concordant pathogens were found in 85% of BM-BAL specimens collected 2 days prior to VAP onset. Their antibiograms were stable over the preceding 4 days. The isolation of pathogens with colony counts >or=10(4) cfu/mL from BM-BAL performed 2 days prior to the clinical onset of VAP had a sensitivity of 84%, specificity of 50%, positive predictive value of 31% and a negative predictive value of 93% for predicting the development of VAP. BM-BAL WCC, quantification of bacterial growth and the percentage of intracellular organisms were not helpful in predicting VAP diagnosis. CONCLUSIONS: BM-BAL surveillance cultures are well tolerated and useful in predicting the pathogens and their antibiograms causing VAP. Diagnostic specimen collection at the time of VAP onset is still required as surveillance cultures may be negative even one day prior to VAP onset.

Reduced inspiratory muscle endurance following successful weaning from prolonged mechanical ventilation.

STUDY OBJECTIVES: Respiratory muscle weakness and decreased endurance have been demonstrated following mechanical ventilation. However, its relationship to the duration of mechanical ventilation is not known. The aim of this study was to assess respiratory muscle endurance and its relationship to the duration of mechanical ventilation. DESIGN: Prospective study. SETTING: Tertiary teaching hospital ICU. PATIENTS: Twenty subjects were recruited for the study who had received mechanical ventilation for > or = 48 h and had been discharged from the ICU. MEASUREMENTS: FEV1, FVC, and maximal inspiratory pressure (P(I(max)) at functional residual capacity were recorded. The P(I(max)) attained following resisted inspiration at 30% of the initial P(I(max)) for 2 min was recorded, and the fatigue resistance index (FRI) [P(I(max)) final/P(I(max))initial] was calculated. The duration of ICU length of stay (ICULOS), duration of mechanical ventilation (MVD), duration of weaning (WD), and Charlson comorbidities score (CCS) were also recorded. Relationships between fatigue and other parameters were analyzed using the Spearman correlations (rho). RESULTS: Subjects were admitted to the ICU for a mean duration of 7.7 days (SD, 3.7 days) and required mechanical ventilation for a mean duration of 4.6 days (SD, 2.5 days). The mean FRI was 0.88 (SD, 0.13), indicating a 12% fall in P(I(max)), and was negatively correlated with MVD (r = -0.65; p = 0.007). No correlations were found between the FRI and FEV1, FVC, ICULOS, WD, or CCS. CONCLUSIONS: Patients who had received mechanical ventilation for > 48 h have reduced inspiratory muscle endurance that worsens with the duration of mechanical ventilation and is present following successful weaning. These data suggest that patients needing prolonged mechanical ventilation are at risk of respiratory muscle fatigue and may benefit from respiratory muscle training.

Case report: inspiratory muscle training in chronic critically ill patients--a report of two cases.

BACKGROUND AND PURPOSE: Inspiratory muscle weakness and fatigue has been documented following prolonged mechanical ventilation despite successful weaning from mechanical ventilation. This report describes the application of inspiratory muscle training in two patients following successful discharge from an intensive care unit (ICU) after prolonged mechanical ventilation. METHODS: Both patients undertook inspiratory muscle training in conjunction with standard physiotherapy rehabilitation. RESULTS: Improvements in inspiratory muscle strength and endurance, exercise tolerance and functional performance following twice-daily inspiratory muscle training were recorded. In both cases, an improvement in maximal inspiratory pressure (MIP) and maximal tolerated inspiratory load (MIP(load)) was found following training. CONCLUSION: These positive results indicate further research is needed to investigate the effect of inspiratory muscle training on respiratory function, exercise tolerance and functional performance, for the possible inclusion of inspiratory muscle training into the physiotherapy management of patients following prolonged mechanical ventilation.

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.

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.

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.

Protocol: inspiratory muscle training for promoting recovery and outcomes in ventilated patients (IMPROVe): a randomised controlled trial.

INTRODUCTION: Inspiratory muscle weakness is a known consequence of mechanical ventilation and a potential contributor to difficulty in weaning from ventilatory support. Inspiratory muscle training (IMT) reduces the weaning period and increases the likelihood of successful weaning in some patients. However, it is not known how this training affects the residual inspiratory muscle fatigability following successful weaning nor patients' quality of life or functional outcomes. METHODS AND ANALYSIS: This dual centre study includes two concurrent randomised controlled trials of IMT in adult patients who are either currently ventilator-dependent (>7 days) (n=70) or have been recently weaned from mechanical ventilation (>7 days) in the past week (n=70). Subjects will be stable, alert and able to actively participate and provide consent. There will be concealed allocation to either treatment (IMT) or usual physiotherapy (including deep breathing exercises without a resistance device). Primary outcomes are inspiratory muscle fatigue resistance and maximum inspiratory pressures. Secondary outcomes are quality of life (Short Form-36v2, EQ-5D), functional status (Acute Care Index of Function), rate of perceived exertion (Borg Scale), intensive care length of stay (days), post intensive care length of stay (days), rate of reintubation (%) and duration of ventilation (days). ETHICS AND DISSEMINATION: Ethics approval has been obtained from relevant institutions, and results will be published with a view to influencing physiotherapy practice in the management of long-term ventilator-dependent patients to accelerate weaning and optimise rehabilitation outcomes. TRIAL REGISTRATION NUMBER: ACTRN12610001089022.

Intensive exercise after thermal injury improves physical, functional, and psychological outcomes.

BACKGROUND: Although exercise programs after burns are considered a standard of care, there is limited evidence for efficacy in adult patients. This study aimed to investigate the effects of an exercise program on physical, functional, and quality of life measures. METHODS: A quasi-experimental controlled trial was instituted after final grafting. Both groups completed stretching, and the intervention group underwent a supervised high-intensity (80% maximal heart rate and 70% three repetition maximum) combined aerobic or resisted exercise program for 6 weeks, with outcome measures at baseline, 6 weeks, and 3 months by a blinded assessor. Analysis was by intention to treat. RESULTS: Thirty patients (24 men) with a mean age of 34.3 years (± 13.1 years) and mean total body surface area 42.9% (± 13.3%) were enrolled. Inequalities at baseline (age and total body surface area %) were adjusted statistically. A between within repeated measures analysis of variance found significant group × time effects between the groups. Mean change scores from baseline to 12 weeks between control and intervention groups, respectively, were strength (kg): quadriceps (17.5 vs. 66.87), latissimus dorsi (6.07 vs. 27.82), right (4.86 vs. 14.86) and left (7.26 vs. 16.83) hand grip; fitness: peak oxygen consumption (L/min; 0.11 vs. 0.93) and shuttle walk distance (m; 168.93 vs. 459); function: lower extremity function score (8.87 vs. 27.31) and QuickDash (-5.7 vs. -23.98); and health-related quality of life: Burns-Specific Health Scale-Abbreviated (-7.64 vs. 35.13). There were no adverse events during either testing or training. CONCLUSION: A high-intensity cardiovascular or resisted exercise program resulted in significant improvements in functional, physical, and psychologic measures and should be mandatory for all burns patients. Larger multicenter trials with longer follow-up periods are required. LEVEL OF EVIDENCE: Therapeutic study, level III.

Pharmacokinetics of intraperitoneal gentamicin in peritoneal dialysis patients with peritonitis (GIPD study).

BACKGROUND AND OBJECTIVES: Peritonitis is a major infectious complication in peritoneal dialysis patients, and intraperitoneal antibiotic administration is preferred to ensure maximal antibiotic concentrations at the site of infection. This study aimed to describe the plasma and infection site pharmacokinetics of intraperitoneal gentamicin in patients with peritonitis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This prospective pharmacokinetic study of intraperitoneal gentamicin was conducted in peritoneal dialysis patients presenting to hospital with clinically defined signs and symptoms of peritonitis. Twenty-four patients were administered a 0.6-mg/kg dose of intraperitoneal gentamicin, which was allowed to dwell for 6 hours. Serial blood and dialysate samples were collected for 24 hours after the first dose. Gentamicin concentrations in plasma and dialysate were measured using a validated assay. RESULTS: The median percentage of the dose absorbed into the systemic circulation was 76% (interquartile range=69%-82%) and significantly different between patients with low average, high average, and high peritoneal membrane transporter status (P=0.03). The calculated pharmacokinetic parameters were plasma terminal elimination half-life of 24.7 (20.4-29.9) hours, terminal volume of distribution of 0.30 (0.20-0.36) L/kg, observed peak plasma concentration of 3.1 (2.4-3.4) mg/L, and observed trough plasma concentration of 1.9 (1.4-2.2) mg/L. The peak gentamicin concentration in dialysate was at least eight times the minimum inhibitory concentration of the likely pathogens. CONCLUSIONS: The high systemic absorption of gentamicin in patients with peritonitis and prolonged plasma elimination half-life may lead to drug accumulation in the systemic circulation, increasing the risk of toxicity.