Population pharmacokinetics of four β-lactams in critically ill septic patients comedicated with amikacin

ObjectivesThe study aimed to characterize the pharmacokinetics (PK) of four β-lactams (piperacillin, ceftazidime, cefepime, and meropenem) in patients comedicated with amikacin (AMK), and to confirm the predictive performance of AMK data, obtained from therapeutic drug monitoring (TDM), on these PK, using a population modeling approach.Design and methodsSerum samples were collected in 88 critically ill septic patients. For each β-lactam, the covariate model was optimized using renal function. Furthermore, predictive performance of AMK concentrations and PK parameters was assessed on β-lactam PK.ResultsA two-compartment model with first-order elimination best fitted the β-lactam data. Results supported the superiority of AMK concentrations, over renal function and AMK PK parameters, to assess the β-lactam PK.ConclusionThe study confirmed the significant link between the exposure to AMK and to β-lactams, and presented population models able to guide β-lactam dosage adjustments using renal biomarkers or TDM-related aminoglycoside data.     

Duration of adrenal inhibition following a single dose of etomidate in critically ill patients

Objective To determine the incidence and duration of adrenal inhibition induced by a single dose of etomidate in critically ill patients. Design Prospective, observational cohort study. Setting Three intensive care units in a university hospital. Patients Forty critically ill patients without sepsis who received a single dose of etomidate for facilitating endotracheal intubation. Measurements and main results Serial serum cortisol and 11β-deoxycortisol samples were taken at baseline and 60 min after corticotropin stimulation test (250 μg 1–24 ACTH) at 12, 24, 48, and 72 h after etomidate administration. Etomidate-related adrenal inhibition was defined by the combination of a rise in cortisol less than 250 nmol/l (9 μg/dl) after ACTH stimulation and an excessive accumulation of serum 11β-deoxycortisol concentrations at baseline. At 12 h after etomidate administration, 32/40 (80%) patients fulfilled the diagnosis criteria for etomidate-related adrenal insufficiency. This incidence was significantly lower at 48 h (9%) and 72 h (7%). The cortisol to 11β-deoxycortisol ratio (F/S ratio), reflecting the intensity of the 11β-hydroxylase enzyme blockade, improved significantly over time. Conclusions A single bolus infusion of etomidate resulted in wide adrenal inhibition in critically ill patients. However, this alteration was reversible by 48 h following the drug administration. The empirical use of steroid supplementation for 48 h following a single dose of etomidate in ICU patients without septic shock should thus be considered. Concomitant serum cortisol and 11β-deoxycortisol dosages are needed to provide evidence for adrenal insufficiency induced by etomidate in critically ill patients. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. Financial support: All of the authors have disclosed that they have no financial relationship with or interest in any commercial companies.     

Evidence of altered cortisol metabolism in critically ill patients: a prospective study

Context Changes in cortisol metabolism due to altered activity of the enzyme 11β-hydroxysteroid dehydrogenase (11β-HSD) have been implicated in the pathogenesis of hypertension, obesity and the metabolic syndrome. No published data exist on the activity of this enzyme in critical illness. Objective To investigate cortisol metabolism in critically ill patients utilising plasma cortisol: cortisone ratio as an index of 11β-HSD activity. Setting Tertiary level intensive care unit. Patients Three cohorts of critically ill patients: sepsis (n = 13); multitrauma (n = 20); and burns (n = 19). Main outcome measures Serial plasma cortisol: cortisone ratios. Measurements and main results Plasma total cortisol cortisone ratios were determined serially after admission to the intensive care unit. As compared with controls, the plasma cortisol:cortisone ratio was significantly elevated in the sepsis and trauma cohorts on day 1 (22 ± 9, p = 0.01, and 23 ± 19, p = 0.0003, respectively) and remained elevated over the study period. Such a relationship was not demonstrable in burns. The ratio was significantly correlated with APACHE II (r = 0.77, p = 0.0008) and Simplified Acute Physiology Score (r = 0.7, p = 0.003) only on day 7 and only in the burns cohort. There were no significant correlations observed between total plasma cortisol or cortisone and sickness severity in the sepsis and trauma cohorts. Conclusions In critically ill patients, there is evidence of altered cortisol metabolism due to an increase in 11β-HSD activity as demonstrated by an elevation of plasma cortisol: cortisone ratios. Further studies with larger sample sizes specifically designed to examine altered tissue 11β-HSD activity and its clinical significance and correlation with outcome are warranted.     

Reporting the methodology of height and weight acquisition in studies of body mass index–based prognosis in critically ill patients

Purpose

Conflicting findings were reported on the body mass index (BMI)–based prognosis of critically patients. Errors in source weight and height data can confound BMI group allocation. The aim of the present work was to examine investigators' reporting on the methods of height and weight acquisition (HWA).

Materials and Methods

PubMed and Embase databases were searched for studies describing BMI group–based risk of death in critically ill patients. Eligible studies were examined for reporting on (1) the use of measured and/or estimated HWA, (2) details of measuring devices, (3) device accuracy, and (4) methods of adjustment for acute and chronic fluid-related weight changes.

Results

Thirty studies met the eligibility criteria, including 159?565 patients. No data were provided in 13 studies (52% of reported patients) on whether estimates or measurements were used for HWA. Measured HWA was used exclusively in 6 studies (3% of patients), and an unspecified combination of estimated and/or measured HWA was reported for the remainder. Only 1 study reported the specific devices used. None of the studies provided data on the bias and precision of measuring devices. Adjustment for chronic and/or acute fluid-related weight changes was addressed in 2 studies for each.

Conclusions

These findings demonstrate the prevalent risk for BMI group misallocation in the reviewed studies, which may confound BMI-based prognosis, raising concerns about the validity of reported BMI-related prognostic impact.     

Erythromycin dose of 70 mg accelerates gastric emptying as effectively as 200 mg in the critically ill

Objective To compare the effectiveness of 70-mg and 200-mg doses of intravenous erythromycin in improving gastric emptying in critically ill patients.Design Gastric emptying was measured on consecutive days; day 1 (pre-treatment), day 2 (post-treatment) after an intravenous infusion of either 70 or 200 mg erythromycin or saline placebo (0.9%), in a randomized double-blind fashion.Setting Mixed medical/surgical intensive care unit, tertiary referral.Patients and participants Thirty-five randomly selected, mechanically ventilated, enterally fed critically ill patients (median APACHE II score 19 on admission).Interventions On day 2 either 70 or 200 mg erythromycin or saline was administered intravenously over 20 min.Measurements and results Gastric emptying was measured using the [¹³C]octanoic acid breath test. The gastric emptying coefficient (GEC) and half-emptying time (t_1/2) were calculated from the area under the ¹³CO₂-recovery curve. Pre-treatment gastric emptying measurements were similar in all three patient groups. Treatment with both doses of erythromycin significantly reduced the gastric t_1/2: 70 mg, 98 min (IQR 88–112); 200 mg, 86 min (75–104); vs. placebo, 122 min (102–190) (p<0.05). The GEC was higher with both doses of erythromycin: 70 mg, 3.8 (3.3–4.0); 200 mg, 4.0 (3.6–4.2); vs. placebo, 2.9 (2.5–3.7) (p<0.05). There was no difference in gastric emptying post-treatment between the two doses of erythromycin. The effect of erythromycin was greatest in patients with delayed gastric emptying.Conclusions Treatment with 70 and 200 mg intravenous erythromycin are equally effective in accelerating gastric emptying in the critically ill     

A comparison of early gastric and post-pyloric feeding in critically ill patients: a meta-analysis

Objective To investigate the potential beneficial and adverse effects of early post-pyloric feeding compared with gastric feeding in critically ill adult patients with no evidence of impaired gastric emptying.Design Randomised controlled studies comparing gastric and post-pyloric feeding in critically ill adult patients from Cochrane Controlled Trial Register (2005 issue 3), EMBASE and MEDLINE databases (1966 to 1 October 2005) without any language restriction were included. Two reviewers reviewed the quality of the studies and performed data extraction independently.Measurements and results Eleven randomised controlled studies with a total of 637 critically ill adult patients were considered. The mortality (relative risk [RR] 1.01, 95% CI 0.76–1.36, p = 0.93; I ² = 0%) and risk of aspiration or pneumonia (RR 1.28, 95% CI 0.91–1.80, p = 0.15; I ² = 0%) were not significantly different between patients treated with gastric or post-pyloric feeding. The effect of post-pyloric feeding on the risk of pneumonia or aspiration was similar when studies were stratified intothose with and those without the use of concurrent gastric decompression (RR ratio 0.95, 95% CI 0.48–1.91, p = 0.89). The risk of diarrhoea and the length of intensive care unit stay (weighted mean difference in days –1.46, 95% CI –3.74 to 0.82,p = 0.21; I ² = 24.6%) were not statistically different. The gastric feeding group had a much lower risk of experiencing feeding tube placement difficulties or blockage (0 vs 9.6%, RR 0.13, 95% CI 0.04–0.44, p = 0.001; I ² = 0%).Conclusions Early use of post-pyloric feeding instead of gastric feeding in critically ill adult patients with no evidence of impaired gastric emptying was not associated with significant clinical benefits.This study was solely funded by the Department of Intensive Care, Royal Perth Hospital. No financial support was received for this study from pharmaceutical companies or other private companies in the form of grants and awards.     

Fish oil supplementation in the parenteral nutrition of critically ill medical patients: a randomised controlled trial

OBJECTIVE: To test whether supplementation of parenteral nutrition with fish oil - aimed at increasing the n-3:n-6 ratio of polyunsaturated fatty acids (PUFA) to 1:2 - affects systemic inflammation and clinical outcome compared to standard parenteral nutrition with an n-3/n-6 ratio of 1:7 in medical intensive care unit (ICU) patients. DESIGN: Single-centre, placebo-controlled, double-blind, randomised clinical trial. SETTING: Twelve-bed medical ICU of a university hospital. PATIENTS: A total of 166 consecutive patients anticipated to need parenteral nutrition for more than 6 days. Patients were stratified for the presence of systemic inflammatory response syndrome (SIRS) at baseline (115 SIRS, 51 non-SIRS). INTERVENTION: Patients were randomly assigned to receive either a 1:1-mixture of medium-chain triglycerides (MCT) and long-chain triglycerides (LCT) with an n-3/n-6 PUFA ratio of 1:7, or the same MCT/LCT emulsion supplemented with fish oil (resulting in an n-3/n-6 ratio of 1:2). MEASUREMENTS AND RESULTS: Primary endpoints were changes in interleukin 6 (IL-6) and monocyte HLA-DR expression relative to baseline. Secondary endpoints were incidence of nosocomial infections, duration of mechanical ventilation, length of ICU stay, and 28-day mortality. Bleeding complications were recorded as a possible side effect of fish oil. Between standard and intervention groups, overall as well as stratified for SIRS or non-SIRS, no significant difference was detected in any of the endpoints or frequency and severity of bleeding events. CONCLUSIONS: In unselected critically ill medical patients, fish oil supplementation that increased the n-3/n-6 PUFA ratio to 1:2 did not affect inflammation or clinical outcome, compared to parenteral lipid nutrition with an MCT/LCT emulsion.     

Antibiotics in critically ill patients: a systematic review of the pharmacokinetics of β-lactams

Introduction  

Several reports have shown marked heterogeneity of antibiotic pharmacokinetics (PK) in patients admitted to ICUs, which might potentially affect outcomes. Therefore, the pharmacodynamic (PD) parameter of the efficacy of β-lactam antibiotics, that is, the time that its concentration is above the bacteria minimal inhibitory concentration (T > MIC), cannot be safely extrapolated from data derived from the PK of healthy volunteers.     

Modulation of asymmetric dimethylarginine in critically ill patients receiving intensive insulin treatment: a possible explanation of reduced morbidity and mortality?

OBJECTIVE: Asymmetric dimethylarginine, which inhibits production of nitric oxide, has been shown to be a strong and independent predictor of mortality in critically ill patients with clinical evidence of organ dysfunction. Interestingly, intensive insulin therapy in critically ill patients improved morbidity and mortality, but the exact mechanisms by which these beneficial effects are brought about remain unknown. Therefore, we aimed to investigate whether modulation of asymmetric dimethylarginine concentrations by intensive insulin therapy is involved in these effects. DESIGN: A prospective, randomized, controlled trial. SETTING: A 56-bed predominantly surgical intensive care unit in a tertiary teaching hospital. PATIENTS: From a study of 1,548 critically ill patients who were randomized to receive either conventional or intensive insulin therapy, we included 79 patients who were admitted to the intensive care unit after complicated pulmonary and esophageal surgery and required prolonged (>/=7 days) intensive care. INTERVENTIONS: Determination of asymmetric dimethylarginine concentrations. MEASUREMENTS AND MAIN RESULTS: Asymmetric dimethylarginine concentrations were determined with high-performance liquid chromatography on the day of admission, on day 2, on day 7, and on the last day at the intensive care unit. Although the asymmetric dimethylarginine levels did not change between day 0 and day 2 in patients receiving intensive insulin treatment, there was a significant increase during this period in the conventionally treated patients (p = .043). Interestingly, the mean daily insulin dose was inversely associated with the asymmetric dimethylarginine concentration on the last day (r = -.23, p = .042), and the asymmetric dimethylarginine concentration on the last day at the intensive care unit was significantly lower in the intensive insulin treatment group (p = .048). Furthermore, asymmetric dimethylarginine was positively associated with duration of intensive care unit stay, duration of ventilatory support, duration of inotropic and vasopressor treatment, number of red cell transfusions, duration of antibiotic treatment, presence of critical illness polyneuropathy, mean Acute Physiology and Chronic Health Evaluation II score, and cumulative Therapeutic Intervention Scoring System-28 score. In addition, asymmetric dimethylarginine levels in patients who died were significantly higher compared with survivors, and changes in the course of asymmetric dimethylarginine plasma concentrations were predictive for adverse intensive care unit outcome. CONCLUSIONS: Modulation of asymmetric dimethylarginine concentration by insulin at least partly explains the beneficial effects found in critically ill patients receiving intensive insulin therapy.     

Empirical models for dosage optimization of four β-lactams in critically ill septic patients based on therapeutic drug monitoring of amikacin

ObjectivesThe study aims to develop empirical models able to predict the pharmacokinetics (PK) of four β-lactams using the amikacin (AMK) therapeutic drug monitoring (TDM), in order to optimize their dosage regimens.Design and methods69 critically ill septic patients were included. All received a first dose of AMK combined with piperacillin/tazobactam, ceftazidime, cefepime or meropenem. A multivariate analysis was performed to predict the β-lactam PK using AMK PK parameters estimated from TDM and using pathophysiological variables.ResultsAn optimal prediction model was identified for each PK parameter of each β-lactam. The best predictor of each model was one of the AMK PK parameters estimated from TDM. Other variables included colloid solution, renal and hepatic biomarkers, age and body weight.ConclusionPK of the four β-lactams could be easily and rapidly predicted in critically ill septic patients using the AMK TDM. These predictions could improve the β-lactam dosages in clinical practice.     

Estimation of fluid status changes in critically ill patients: Fluid balance chart or electronic bed weight?

Purpose

Monitoring of fluid balance (FB) can be achieved by subtracting recorded fluid output from input or by measuring changes in body weight (BW). The latter approach is difficult in the critically ill. Recently, hospital beds have become available with the ability to directly weigh patients in the intensive care unit (ICU) patients directly. We sought to compare FB estimates obtained by these 2 methods in a cohort of critically ill patients.

Materials and Methods

Between November 2010 and May 2011, all patients admitted in our ICU for more than 2 consecutive days and nursed on a Hill-Rom (Batesville, Ind) Total Care bed were weighed daily at midnight hours. Fluids charting was done by electronic spreadsheet with automated 24 hours calculation. Differences in BW and FB between 2 consecutive days were compared using correlation and Bland-Altman analysis. Corrections for unmeasured fluids losses were performed using a predetermined formula based on peak temperature and intubation status.

Results

We obtained complete data in 160 (31%) of 504 admissions exceeding 2 days (153 patients) resulting in 435 data points. The change in BW over 24 hours and FB for the same period was only weakly correlated before (r = 0.34; P < .001; Fig. 1) or after correction for insensible fluid losses (r = 0.34; P < .001). On Bland-Altman plot, the mean bias was small (0.07 kg), but the 95% limits of agreement, very large (−5.8 and 6.0 kg). The lack of agreement increased with the magnitude of the changes.

Conclusion

Obtaining daily weights in ICU patients proved difficult. Compliance was poor. The correlation between changes in BWs and FB was weak. Further studies are required to establish if accurate and reproducible daily weighing of ICU patients is feasible.     

Changing use of noninvasive ventilation in critically ill patients: trends over 15 years in francophone countries

Purpose

Over the last two decades, noninvasive ventilation (NIV) has been proposed in various causes of acute respiratory failure (ARF) but some indications are debated. Current trends in NIV use are unknown.

Methods

Comparison of three multicenter prospective audits including all patients receiving mechanical ventilation and conducted in 1997, 2002, and 2011 in francophone countries.

Results

Among the 4132 patients enrolled, 2094 (51 %) required ventilatory support for ARF and 2038 (49 %) for non-respiratory conditions. Overall NIV use was markedly increased in 2010/11 compared to 1997 and 2002 (37 % of mechanically ventilated patients vs. 16 % and 28 %, P < 0.05). In 2010/11, the use of first-line NIV for ARF had reached a plateau (24 % vs. 16 % and 23 %, P < 0.05) whereas pre-ICU and post-extubation NIV had substantially increased (11 % vs. 4 % and 11 % vs. 7 %, respectively, P < 0.05). First-line NIV remained stable in acute-on-chronic RF, continued to increase in cardiogenic pulmonary edema, but decreased in de novo ARF (16 % in 2010/11 vs. 23 % in 2002, P < 0.05). The NIV success rate increased from 56 % in 2002 to 70 % in 2010/11 and remained the lowest in de novo ARF. NIV failure in de novo ARF was associated with increased mortality in 2002 but not in 2010/11. Mortality decreased over time, and overall, NIV use was associated with a lower mortality.

Conclusion

Increases in NIV use and success rate, an overall decrease in mortality, and a decrease of the adverse impact NIV failure has in de novo ARF suggest better patient selection and greater proficiency of staff in administering NIV.

Trial registration

Clinicaltrials.gov Identifier NCT01449331.

     

An assessment of the validity of spectral entropy as a measure of sedation statein mechanically ventilated critically ill patients

Objective To assess whether the Entropy Module (GE Healthcare, Helsinki, Finland), a device to measure hypnosis in anesthesia, is a valid measure of sedation state in critically ill patients by comparing clinically assessed sedation state with Spectral Entropy Design Prospective observational study. Setting Teaching hospital general ICU. Patients and participants 30 intubated, mechanically ventilated patients without primary neurological diagnoses or drug overdose receiving continuous sedation. Interventions Monitoring of EEG and fEMG activity via forehead electrodes for up to 72 h and assessments of conscious level using a modified Ramsay Sedation Scale. Measurements and results 475 trained observer assessments were made and compared with concurrent Entropy numbers. Median State (SE) and Response (RE) Entropy values decreased as Ramsay score increased, but wide variation occurred, especially in Ramsay 4–6 categories. Discrimination between different sedation scores [mean (SEM) P_K value: RE 0.713 (0.019); SE 0.710 (0.019)] and between lighter (Ramsay 1–3) vs.deeper (Ramsay 4–6) sedation ranges was inadequate [P_K: RE 0.750 (0.025); SE 0.748 (0.025)]. fEMG power decreased with increasing Ramsay score but was often significant even at Ramsay 4–6 states. Frequent “on–off” effects occurred for both RE and SE, which were associated with fEMG activity.Values switched from low to high values even in deeply sedated patients. High Entropy values during deeper sedation were strongly associated with simultaneous high relative fEMG powers. Conclusions Entropy of the frontal EEG does not discriminate sedation state adequately for clinical use in ICU patients. Facial EMG is a major confounder in clinical sedation ranges.     

Implementation of a combo videolaryngoscope for intubation in critically ill patients: a before–after comparative study

Purpose

Airway management in intensive care unit (ICU) patients is challenging. The main objective of this study was to compare the incidence of difficult laryngoscopy and/or difficult intubation between a combo videolaryngoscope and the standard Macintosh laryngoscope in critically ill patients.

Methods

In the context of the implementation of a quality-improvement process for airway management, we performed a prospective interventional monocenter before–after study which evaluated a new combo videolaryngoscope. The primary outcome was the incidence of difficult laryngoscopy (defined by Cormack grade 3–4) and/or difficult intubation (more than two attempts). The secondary outcomes were the severe life-threatening complications related to intubation in ICU and the rate of difficult intubation in cases of predicted difficult intubation evaluated by a specific score (MACOCHA score ≥3).

Results

Two hundred and ten non-selected consecutive intubation procedures were included, 140 in the standard laryngoscope group and 70 in the combo videolaryngoscope group. The incidence of difficult laryngoscopy and/or difficult intubation was 16 % in the laryngoscope group vs. 4 % in the combo videolaryngoscope group (p = 0.01). The severe life-threatening complications related to intubation did not differ between groups (16 vs. 14 %, p = 0.79). Among the 32 patients with a MACOCHA score ≥3, there were significantly more patients with difficult intubation in the standard laryngoscope group in comparison to the combo videolaryngoscope group [12/23 (57 %) vs. 0/9 (0 %), p < 0.01].

Conclusions

The systematic use of a combo videolaryngoscope in ICU was associated with a decreased incidence of difficult laryngoscopy and/or difficult intubation.     

The repeatability of Stewart’s parameters and anion gap in a cohort of critically ill adult patients

Purpose

To examine the repeatability of Stewart’s parameters and anion gap in a cohort of critically ill patients and to determine the smallest detectable changes in individual patients.

Methods

A total of 161 patients were included prospectively. They underwent two subsequent blood samplings within 10?min of each other and samples were analyzed using the same central laboratory analyzer. Measured and calculated parameters from the two samples were compared. The repeatability was expressed as the smallest detectable difference (SDD), coefficient of variation (CV) and intraclass correlation coefficient (ICC).

Results

The mean differences?±?SD (mEq/L) for the repeated measurements were 0.1?±?0.76, 0.12?±?0.68, ?0.02?±?1.02, and ?0.08?±?1.05 for the apparent strong ion difference (SID_app), effective strong ion difference (SID_eff), strong ion gap (SIG), and albumin-corrected anion gap (AG_corr), respectively. The SDDs (mEq/L) for SID_app, SID_eff, SIG, and AG_corr, were ±1.49, ±1.33, ±2, and ±2.06, respectively. The CVs (%) for these variables were 1.4, 1.45, 13.3, and 4.15, respectively. The ICCs for all these variables were high, largely above 0.75.

Conclusions

The repeatability of all these calculated variables was good. In repeated measurements, a change in value of these parameters exceeding 1.96√2 CV (%), the least significant change (LSC) or the SDD should be regarded as significant. Use of SDD is preferable to CV and LSC (%) because of its independence from the levels of variables and its expression in absolute units. Expressed as SDD, a SIG change value, e.g., of at least ±2?mEq/L should be significant.     

Association of prophylactic synbiotics with reduction in diarrhea and pneumonia in mechanically ventilated critically ill patients: A propensity score analysis

Introduction

The preventive association of synbiotics therapy has not been thoroughly clarified in mechanically ventilated patients. The purpose of this study was to evaluate whether synbiotics therapy has preventive association against septic complications in ventilated critically ill patients.