Jeffrey Lipman

International Study of the Prevalence and Outcomes of Infection in Intensive Care Units

CONTEXT Infection is a major cause of morbidity and mortality in intensive care units (ICUs) worldwide. However, relatively little information is available about the global epidemiology of such infections. OBJECTIVE To provide an up-to-date, international picture of the extent and patterns of infection in ICUs. DESIGN, SETTING, AND PATIENTS The Extended Prevalence of Infection in Intensive Care (EPIC II) study, a 1-day, prospective, point prevalence study with follow-up conducted on May 8, 2007. Demographic, physiological, bacteriological, therapeutic, and outcome data were collected for 14,414 patients in 1265 participating ICUs from 75 countries on the study day. Analyses focused on the data from the 13,796 adult (>18 years) patients. RESULTS On the day of the study, 7087 of 13,796 patients (51%) were considered infected; 9084 (71%) were receiving antibiotics. The infection was of respiratory origin in 4503 (64%), and microbiological culture results were positive in 4947 (70%) of the infected patients; 62% of the positive isolates were gram-negative organisms, 47% were gram-positive, and 19% were fungi. Patients who had longer ICU stays prior to the study day had higher rates of infection, especially infections due to resistant staphylococci, Acinetobacter, Pseudomonas species, and Candida species. The ICU mortality rate of infected patients was more than twice that of noninfected patients (25% [1688/6659] vs 11% [ 682/6352], respectively; P < .001), as was the hospital mortality rate (33% [2201/6659] vs 15% [ 942/6352], respectively; P < .001) (adjusted odds ratio for risk of hospital mortality, 1.51; 95% confidence interval, 1.36-1.68; P < .001). CONCLUSIONS Infections are common in patients in contemporary ICUs, and risk of infection increases with duration of ICU stay. In this large cohort, infection was independently associated with an increased risk of hospital death.

Hydroxyethyl Starch or Saline for Fluid Resuscitation in Intensive Care

BACKGROUND The safety and efficacy of hydroxyethyl starch (HES) for fluid resuscitation have not been fully evaluated, and adverse effects of HES on survival and renal function have been reported. METHODS We randomly assigned 7000 patients who had been admitted to an intensive care unit (ICU) in a 1:1 ratio to receive either 6% HES with a molecular weight of 130 kD and a molar substitution ratio of 0.4 (130/0.4, Voluven) in 0.9% sodium chloride or 0.9% sodium chloride (saline) for all fluid resuscitation until ICU discharge, death, or 90 days after randomization. The primary outcome was death within 90 days. Secondary outcomes included acute kidney injury and failure and treatment with renal-replacement therapy. RESULTS A total of 597 of 3315 patients (18.0%) in the HES group and 566 of 3336 (17.0%) in the saline group died (relative risk in the HES group, 1.06; 95% confidence interval [CI], 0.96 to 1.18; P=0.26). There was no significant difference in mortality in six predefined subgroups. Renal-replacement therapy was used in 235 of 3352 patients (7.0%) in the HES group and 196 of 3375 (5.8%) in the saline group (relative risk, 1.21; 95% CI, 1.00 to 1.45; P=0.04). In the HES and saline groups, renal injury occurred in 34.6% and 38.0% of patients, respectively (P=0.005), and renal failure occurred in 10.4% and 9.2% of patients, respectively (P=0.12). HES was associated with significantly more adverse events (5.3% vs. 2.8%, P<0.001). CONCLUSIONS In patients in the ICU, there was no significant difference in 90-day mortality between patients resuscitated with 6% HES (130/0.4) or saline. However, more patients who received resuscitation with HES were treated with renal-replacement therapy. (Funded by the National Health and Medical Research Council of Australia and others; CHEST ClinicalTrials.gov number, NCT00935168.).

Pharmacokinetic issues for antibiotics in the critically ill patient.

Objective:To discuss the altered pharmacokinetic properties of selected antibiotics in critically ill patients and to develop basic dose adjustment principles for this patient population. Data Sources:PubMed, EMBASE, and the Cochrane-Controlled Trial Register. Study Selection:Relevant papers that reported pharmacokinetics of selected antibiotic classes in critically ill patients and antibiotic pharmacodynamic properties were reviewed. Antibiotics and/or antibiotic classes reviewed included aminoglycosides, &bgr;-lactams (including carbapenems), glycopeptides, fluoroquinolones, tigecycline, linezolid, lincosamides, and colistin. Data Synthesis:Antibiotics can be broadly categorized according to their solubility characteristics which can, in turn, help describe possible altered pharmacokinetics that can be caused by the pathophysiological changes common to critical illness. Hydrophilic antibiotics (e.g., aminoglycosides, &bgr;-lactams, glycopeptides, and colistin) are mostly affected with the pathphysiological changes observed in critically ill patients with increased volumes of distribution and altered drug clearance (related to changes in creatinine clearance). Lipophilic antibiotics (e.g., fluoroquinolones, macrolides, tigecycline, and lincosamides) have lesser volume of distribution alterations, but may develop altered drug clearances. Using antibiotic pharmacodynamic bacterial kill characteristics, altered dosing regimens can be devised that also account for such pharmacokinetic changes. Conclusions:Knowledge of antibiotic pharmacodynamic properties and the potential altered antibiotic pharmacokinetics in critically ill patients can allow the intensivist to develop individualized dosing regimens. Specifically, for renally cleared drugs, measured creatinine clearance can be used to drive many dose adjustments. Maximizing clinical outcomes and minimizing antibiotic resistance using individualized doses may be best achieved with therapeutic drug monitoring.

Individualised antibiotic dosing for patients who are critically ill: challenges and potential solutions

Infections in critically ill patients are associated with persistently poor clinical outcomes. These patients have severely altered and variable antibiotic pharmacokinetics and are infected by less susceptible pathogens. Antibiotic dosing that does not account for these features is likely to result in suboptimum outcomes. In this Review, we explore the challenges related to patients and pathogens that contribute to inadequate antibiotic dosing and discuss how to implement a process for individualised antibiotic therapy that increases the accuracy of dosing and optimises care for critically ill patients. To improve antibiotic dosing, any physiological changes in patients that could alter antibiotic concentrations should first be established; such changes include altered fluid status, changes in serum albumin concentrations and renal and hepatic function, and microvascular failure. Second, antibiotic susceptibility of pathogens should be confirmed with microbiological techniques. Data for bacterial susceptibility could then be combined with measured data for antibiotic concentrations (when available) in clinical dosing software, which uses pharmacokinetic/pharmacodynamic derived models from critically ill patients to predict accurately the dosing needs for individual patients. Individualisation of dosing could optimise antibiotic exposure and maximise effectiveness.

Assessment of the worldwide burden of critical illness: the Intensive Care Over Nations (ICON) audit

BACKGROUND Global epidemiological data regarding outcomes for patients in intensive care units (ICUs) are scarce, but are important in understanding the worldwide burden of critical illness. We, therefore, did an international audit of ICU patients worldwide and assessed variations between hospitals and countries in terms of ICU mortality. METHODS 730 participating centres in 84 countries prospectively collected data on all adult (>16 years) patients admitted to their ICU between May 8 and May 18, 2012, except those admitted for fewer than 24 h for routine postoperative monitoring. Participation was voluntary. Data were collected daily for a maximum of 28 days in the ICU and patients were followed up for outcome data until death or hospital discharge. In-hospital death was analysed using multilevel logistic regression with three levels: patient, hospital, and country. FINDINGS 10,069 patients were included from ICUs in Europe (5445 patients; 54·1%), Asia (1928; 19·2%), the Americas (1723; 17·1%), Oceania (439; 4·4%), the Middle East (393; 3·9%), and Africa (141; 1·4%). Overall, 2973 patients (29·5%) had sepsis on admission or during the ICU stay. ICU mortality rates were 16·2% (95% CI 15·5-16·9) across the whole population and 25·8% (24·2-27·4) in patients with sepsis. Hospital mortality rates were 22·4% (21·6-23·2) in the whole population and 35·3% (33·5-37·1) in patients with sepsis. Using a multilevel analysis, the unconditional model suggested significant between-country variations (var=0·19, p=0·002) and between-hospital variations (var=0·43, p<0·0001) in the individual risk of in-hospital death. There was a stepwise increase in the adjusted risk of in-hospital death according to decrease in global national income. INTERPRETATION This large database highlights that sepsis remains a major health problem worldwide, associated with high mortality rates in all countries. Our findings also show a significant association between the risk of death and the global national income and suggest that ICU organisation has an important effect on risk of death. FUNDING None.

Meropenem dosing in critically ill patients with sepsis and without renal dysfunction: intermittent bolus versus continuous administration? Monte Carlo dosing simulations and subcutaneous tissue distribution

OBJECTIVES To compare the plasma and subcutaneous tissue concentration-time profiles of meropenem administered by intermittent bolus dosing or continuous infusion to critically ill patients with sepsis and without renal dysfunction, and to use population pharmacokinetic modelling and Monte Carlo simulations to assess the cumulative fraction of response (CFR) against Gram-negative pathogens likely to be encountered in critical care units. PATIENTS AND METHODS We randomized 10 patients with sepsis to receive meropenem by intermittent bolus administration (n = 5; 1 g 8 hourly) or an equal dose administered by continuous infusion (n = 5). Serial subcutaneous tissue concentrations were determined using microdialysis and compared with plasma data for first-dose and steady-state pharmacokinetics. Population pharmacokinetic modelling of plasma data and Monte Carlo simulations were then undertaken with NONMEM. RESULTS It was found that continuous infusion maintains higher median trough concentrations, in both plasma (intermittent bolus 0 versus infusion 7 mg/L) and subcutaneous tissue (0 versus 4 mg/L). All simulated intermittent bolus, extended and continuous infusion dosing achieved 100% of pharmacodynamic targets against most Gram-negative pathogens. Superior obtainment of pharmacodynamic targets was achieved using administration by extended or continuous infusion against less susceptible Pseudomonas aeruginosa and Acinetobacter species. CONCLUSIONS This is the first study to compare the relative concentration-time data of bolus and continuous administration of meropenem at the subcutaneous tissue and plasma levels. We found that the administration of meropenem by continuous infusion maintains higher concentrations in subcutaneous tissue and plasma than by intermittent bolus dosing. Administration by extended or continuous infusion will achieve superior CFR against less-susceptible organisms in patients without renal dysfunction.

Antibacterial dosing in intensive care : Pharmacokinetics, degree of disease and pharmacodynamics of sepsis

Treatment of sepsis remains a significant challenge with persisting high mortality and morbidity. Early and appropriate antibacterial therapy remains an important intervention for such patients. To optimise antibacterial therapy, the clinician must possess knowledge of the pharmacokinetic and pharmacodynamic properties of commonly used antibacterials and how these parameters may be affected by the constellation of pathophysiological changes occurring during sepsis.Sepsis, and the treatment thereof, increases renal preload and, via capillary permeability, leads to ‘third-spacing’, both resulting in higher antibacterial clearances. Alternatively, sepsis can induce multiple organ dysfunction, including renal and/or hepatic dysfunction, causing a decrease in antibacterial clearance.Aminoglycosides are concentration-dependent antibacterials and they display an increased volume of distribution (Vd) in sepsis, resulting in decreased peak serum concentrations. Reduced clearance from renal dysfunction would increase the likelihood of toxicity. Individualised dosing using extended interval dosing, which maximises the peak serum drug concentration (Cmax)/minimum inhibitory concentration ratio is recommended.β-Lactams and carbapenems are time-dependent antibacterials. An increase in Vd and renal clearance will require increased dosing or administration by continuous infusion. If renal impairment occurs a corresponding dose reduction may be required.Vancomycin displays predominantly time-dependent pharmacodynamic properties and probably requires higher than conventionally recommended doses because of an increased Vd and clearance during sepsis without organ dysfunction. However, optimal dosing regimens remain unresolved. The poor penetration of vancomycin into solid organs may require alternative therapies when sepsis involves solid organs (e.g. lung).Ciprofloxacin displays largely concentration-dependent kill characteristics, but also exerts some time-dependent effects. The Vd of ciprofloxacin is not altered with fluid shifts or over time, and thus no alterations of standard doses are required unless renal dysfunction occurs.In order to optimise antibacterial regimens in patients with sepsis, the pathophysiological effects of systemic inflammatory response syndrome need consideration, in conjunction with knowledge of the different kill characteristics of the various antibacterial classes.In conclusion, certain antibacterials can have a very high Vd, therefore leading to a low Cmax and if a high peak is needed, then this would lead to underdosing. The Vd of certain antibacterials, namely aminoglycosides and vancomycin, changes over time, which means dosing may need to be altered over time. Some patients with serum creatinine values within the normal range can have very high drug clearances, thereby producing low serum drug levels and again leading to underdosing.

Continuous Infusion of Beta-Lactam Antibiotics in Severe Sepsis: A Multicenter Double-Blind, Randomized Controlled Trial

BACKGROUND Beta-lactam antibiotics are a commonly used treatment for severe sepsis, with intermittent bolus dosing standard therapy, despite a strong theoretical rationale for continuous administration. The aim of this trial was to determine the clinical and pharmacokinetic differences between continuous and intermittent dosing in patients with severe sepsis. METHODS This was a prospective, double-blind, randomized controlled trial of continuous infusion versus intermittent bolus dosing of piperacillin-tazobactam, meropenem, and ticarcillin-clavulanate conducted in 5 intensive care units across Australia and Hong Kong. The primary pharmacokinetic outcome on treatment analysis was plasma antibiotic concentration above the minimum inhibitory concentration (MIC) on days 3 and 4. The assessed clinical outcomes were clinical response 7-14 days after study drug cessation, ICU-free days at day 28 and hospital survival. RESULTS Sixty patients were enrolled with 30 patients each allocated to the intervention and control groups. Plasma antibiotic concentrations exceeded the MIC in 82% of patients (18 of 22) in the continuous arm versus 29% (6 of 21) in the intermittent arm (P = .001). Clinical cure was higher in the continuous group (70% vs 43%; P = .037), but ICU-free days (19.5 vs 17 days; P = .14) did not significantly differ between groups. Survival to hospital discharge was 90% in the continuous group versus 80% in the intermittent group (P = .47). CONCLUSIONS Continuous administration of beta-lactam antibiotics achieved higher plasma antibiotic concentrations than intermittent administration with improvement in clinical cure. This study provides a strong rationale for further multicenter trials with sufficient power to identify differences in patient-centered endpoints.

Subtherapeutic initial β-lactam concentrations in select critically ill patients: association between augmented renal clearance and low trough drug concentrations.

BACKGROUND β-Lactams are routinely used as empirical therapy in critical illness, with extended concentrations above the minimum inhibitory concentration (MIC) of the infecting organism required for effective treatment. Changes in renal function in this setting can significantly impact the probability of achieving such targets. METHODS Analysis was made of trough plasma drug concentrations obtained via therapeutic drug monitoring, compared with renal function, in critically ill patients receiving empirical β-lactam therapy. Drug concentrations were measured by means of high-performance liquid chromatography and corrected for protein binding. Therapeutic levels were defined as greater than or equal to MIC and greater than or equal to four times MIC (maximum bacterial eradication), respectively. Renal function was assessed by means of an 8-h creatinine clearance (CLCR). RESULTS Fifty-two concurrent trough concentrations and CLCR measures were used in analysis. Piperacillin was the most frequent β-lactam prescribed (48%), whereas empirical cover and Staphylococcus species were the most common indications for therapy (62%). Most patients were mechanically ventilated on the day of study (85%), although only 25% were receiving vasopressors. In only 58% (n = 30) was the trough drug concentration greater than or equal to MIC, falling to 31% (n = 16) when using four times MIC as the target. CLCR values ≥ 130 mL/min/1.73 m2 were associated with trough concentrations less than MIC in 82% (P < .001) and less than four times MIC in 72% (P < .001). CLCR remained a significant predictor of subtherapeutic concentrations in multivariate analysis. CONCLUSION Elevated CLCR appears to be an important predictor of subtherapeutic β-lactam concentrations and suggests an important role in identifying such patients in the ICU.

Augmented renal clearance: implications for antibacterial dosing in the critically ill.

The prescription of pharmaceuticals in the critically ill is complicated by a paucity of knowledge concerning the pharmacokinetic implications of the underlying disease state. Changes in organ function can be dramatic in this population, both as a consequence of the primary pathophysiology and in response to clinical interventions provided. Vascular tone, fluid status, cardiac output and major organ blood flow can be significantly altered from baseline, influencing the volume of distribution and clearance of many commonly prescribed agents.Although measurable endpoints can be used to titrate doses for many drugs in this setting (such as sedatives), for those agents with silent pharmacodynamic indices, enhanced excretory organ function can result in unexpectedly low plasma concentrations, leading to treatment failure. This is particularly relevant to the use of antibacterials in the critically ill, where inadequate, inappropriate and/or delayed prescription can have significant effects on morbidity and mortality.Augmented renal clearance (ARC) refers to enhanced renal elimination of circulating solute and is being described with increasing regularity in the critically ill. However, defining this process in terms of current measures of renal function is problematic, as although the glomerular filtration rate (GFR) is largely considered the best index of renal function, there is no consensus on an upper limit of normal. In addition, the most readily available and accurate estimate of the GFR at the bedside is still widely debated. From a pharmacokinetic point of view, ARC can result in elevated renal elimination and subtherapeutic plasma concentrations of pharmaceuticals, although whether this process solely involves augmented filtration (as opposed to enhanced tubular secretion and/or reabsorption) remains uncertain.The primary contributors to this process are likely to be the innate immune response to infection and inflammation (with its associated systemic and haemodynamic consequences), fluid loading and use of vasoactive medications. The resultant increase in cardiac output and renal blood flow prompts enhanced glomerular filtration and drug elimination. Current evidence suggests that young patients without preexisting co-morbidity or organ dysfunction who present with trauma are most likely to manifest ARC. As this phenomenon has received little attention in the literature, dose modification has rarely been considered.However, with increasing data supporting the concept, and many investigators demonstrating subtherapeutic concentrations of drugs in the critically ill, consideration of ARC and alternative dosing regimens is now mandatory, both to improve the likelihood of treatment success and to reduce the rate of development of antibacterial resistance.