Augmented renal clearance: a retrospective,cohort study of urinary creatinine clearance in critically ill patients in the United Kingdom

ObjectiveAugmented renal clearance (ARC) is associated with sub-therapeutic antibiotic, anti-epileptic, and anticoagulant serum concentrations leading to adverse patient outcomes. We aimed to describe the prevalence and associated risk factors for ARC development in a large, single-centre cohort in the United Kingdom.MethodsWe conducted a retrospective observational study of critically unwell patients admitted to intensive care between 2014 and 2016. Urinary creatinine clearance was used to determine the ARC prevalence during the first 7 days of admission. Repeated measures logistic regression was used to determine risk factors for ARC development.ResultsThe ARC prevalence was 47.0% (95% confidence interval [95%CI]: 44.3%–49.7%). Age, sex, Acute Physiology and Chronic Health Evaluation (APACHE) II score, and sepsis diagnosis were significantly associated with ARC. ARC was more prevalent in younger vs. older (odds ratio [OR] 0.95 [95%CI: 0.94–0.96]), male vs. female (OR 0.32 [95%CI: 0.26–0.40]) patients with lower vs. higher APACHE II scores (OR 0.94 [95%CI: 0.92–0.96]).ConclusionsThis patient group probably remains unknown to many clinicians because measuring urinary creatinine clearance is not usually indicated in this group. Clinicians should be aware of the ARC risk in this group and consider measurement of urinary creatinine clearance.     

连续性血液净化治疗对危重患者药物清除率影响的研究进展

本文通过查阅文献,了解药物本身药理学及连续性血液净化治疗（ CBP）的滤过膜材料、面积、孔径大小,透析液／超滤液流速,过滤器使用时间,血液滤过模式及滤过原理等对药物清除率的影响,总结连续性血液滤过治疗对各类药物清除率的研究进展。为临床医师调整治疗方案,更好地进行个体化治疗提供参考,同时为药物清除率的进一步研究开拓思路。     

万古霉素在成人危重症患者中的应用进展

万古霉素是糖肽类杀菌剂,主要用于治疗耐药金黄色葡萄球菌和肠球菌等革兰氏阳性菌引起的严重感染。重症患者由于生理屏障被破坏,感染发生率高,而且常常合并耐药菌感染,但危重症患者因为毛细血管渗漏和器官功能障碍等使得药物在体内的药动学发生极大的改变,因此万古霉素在重症患者中的使用还需要结合具体实际情况。现就在重症患者中正确合理使用万古霉素作一综述,为优化特殊人群给药提供新思路。     

1例危重型新型冠状病毒感染患儿气道廓清护理

<正>新型冠状病毒(简称“新冠”)感染以发热、干咳、乏力为主要表现,部分患者出现咽痛、鼻塞及流涕等上呼吸道感染症状,儿童症状相对成人较轻^[1]。研究^[2-3]显示,儿童肥胖、合并有基础性疾病是儿童感染危重型新冠的高危因素,其中合并神经系统及呼吸系统疾病是最为常见的影响因素。重型及危重型患儿通常需要行呼吸支持,在此过程中气道廓清技术(airway clearance therapy,ACT)有着举足轻重的作用。     

Clinical applicability of urinary creatinine clearance for determining the initial dose of vancomycin in critically ill patients

IntroductionThe purpose of this study was to evaluate the clinical applicability of urinary creatinine clearance (CrCl) for determining the initial dose of vancomycin (VCM) in critically ill patients and to assess VCM trough plasma concentration/maintenance daily dose (C/D) ratio in patients with augmented renal clearance (ARC).MethodsAs the primary outcome measure, correlations between estimated renal function and the VCM C/D ratio were compared using the following formulas: CrCl, Cockcroft-Gault equation (eCrCl_C-G) and KineticGFR equation (KeGFR). Patients were divided into those with or without changes in renal function. The patients were further classified based on the presence or absence of ARC. The secondary outcome was the comparison of VCM C/D ratio between ARC and Non-ARC patients.ResultsA total of 65 patients were enrolled for analysis. In all groups, CrCl tended to correlate better with the VCM C/D ratio than eCrCl_C-G and KeGFR. A significantly lower VCM C/D ratio was observed in patients with persistent ARC than in the Non-ARC group (0.24 versus 0.52 kg/L).ConclusionsThe clinical applicability of CrCl for the initial dosing design of VCM in critically ill patients was shown. Furthermore, the results indicated that patients with persistent ARC required a higher VCM dose than Non-ARC patients. Although our findings are limited, they have a value for further verification.     

Vancomycin clearance during continuous venovenous haemofiltration in critically ill patients

Objective: To study the pharmacokinetics of vancoymcin in critically ill patients with acute renal failure treated with continuous venovenous haemofiltration (CVVHF).¶Design: Open-label study.¶Setting: Hospital pharmacy centre and medical intensive care unit of the University Medical Centre Utrecht.¶Materials and methods: In a laboratory setting, the sieving coefficient (s) of vancomycin by polyacrilonitrile (PAN) haemofilters of different surface areas was studied. In one patient, the pharmacokinetics of vancomycin were studied following a single dose of vancomycin. Another patient was treated with a vancomycin dosing regimen based on data from the literature, but high trough concentrations made dose reduction necessary after 24 h of withholding therapy. After two doses of 250 mg, serum and ultrafiltrate samples were collected for pharmacokinetic evaluation.¶Intervention: CVVHF with the following operational characteristics: blood flow 200 ml/min, ultrafiltrate flow 25 ml/min, postdilution, PAN 06 hollow fibre haemofilter.¶Measurements and results: The average sieving coefficient in vitro was 0.73 ± 0.06, 0.86 ± 0.11, and 0.80 ± 0.06 for the PAN 03, 06, and 10 haemofilters, respectively. Changes in the sieving coefficient by increasing the ultrafiltration rate were not clinically significant. The first patient was given a single dose of vancomycin, 1000 mg by intravenous infusion. The following pharmacokinetic data were obtained: apparent volume of distribution (Vd) 55.8 l, terminal half-life time (t_{1/2 term}) 15.4 h, total clearance (Cl_tot) 2.5 l/h, CVVHF clearance (CL_{CVVHF, form 1}) 1.4 l/h, and body clearance (Cl_body) 1.1 l/h. The average sieving coefficient during the study period was 0.89 ± 0.03. In the second patient, the pharmacokinetics of vancomycin were studied following dose reduction: Vd 41.7 l, ¶t_{1/2 term} 20.3 h, Cl_tot 1.4 l/h, Cl_{CVVHF, form 1} 1.4 l/h, and Cl_body < 0.1 l/h. The average sieving coefficient during the study period was 0.88 ± 0.03. The cumulative amount of vancomycin removed by means of CVVHF during the 12-h study period was 245 mg in patient 1 and 228 mg in patient 2.¶Conclusion: CVVHF with a PAN 06 haemofilter effectively removed vancomycin in two critically ill patients. The amount of vancomycin removed with CVVHF was about 250 mg per 12 h. A clear difference in body clearance in the two patients was observed. Our dosage recommendation for vancomycin in critically ill patients receiving CVVHF is a loading dose of 15–20 mg/kg followed after 24 h by 250 to 500 mg twice daily with close monitoring of the serum and ultrafiltrate vancomycin concentration.     

Dalteparin thromboprophylaxis for critically ill medical-surgical patients with renal insufficiency

PURPOSE: Thromboprophylaxis with low-molecular-weight heparin (LMWH) may be more effective than unfractionated heparin but also more likely to bioaccumulate and potentially cause bleeding in patients with renal insufficiency. The objectives of this study were to assess, among medical-surgical patients in the intensive care unit receiving dalteparin 5,000 IU daily for thromboprophylaxis, (1) the relationship between renal dysfunction and LMWH bioaccumulation as measured by trough anti-Xa levels, (2) the relationship between renal dysfunction and risk of bleeding as measured by a surrogate marker (peak anti-Xa levels), and (3) the relationship between anti-Xa levels, bleeding events, and thrombotic events. MATERIALS AND METHODS: In this prospective single-center cohort study, we enrolled patients 18 years or older, expected to stay 72 hours or longer, and with a creatinine clearance 30 mL/min or higher at intensive care unit admission. We administered 5,000 IU dalteparin subcutaneously each day. The main phase 1 objective was to detect bioaccumulation of dalteparin by measuring trough anti-Xa levels (22-23 hours post dalteparin). The main phase 2 objective was to examine the relationship between renal dysfunction and peak anti-Xa levels (4 hours post dalteparin). We recorded creatinine clearance daily and bleeding and thrombotic events, blinded to anti-Xa levels. RESULTS: We enrolled 19 patients aged 62.7 (13.2) years with an APACHE II score of 23.5 (9.4). We measured trough anti-Xa levels on 185 occasions in 19 patients; we measured peak anti-Xa levels on 113 occasions in 11 patients. We identified no bioaccumulation of LMWH in this study, as detected by trough anti-Xa levels. Most peak anti-Xa levels were in the conventional prophylactic range. CONCLUSIONS: When administered in prophylactic doses to critically ill patients with a wide range of calculated creatinine clearances, we found no evidence of bioaccumulation of dalteparin. If dalteparin does not bioaccumulate, it may be an attractive alternative agent for thromboprophylaxis.     

Dopamine clearance in critically ill infants and children: effect of age and organ system dysfunction

To learn if there are age-related differences in the pharmacokinetic behavior of dopamine, plasma dopamine clearance was determined in 27 acutely ill infants and children who were receiving a continuous intravenous infusion of the drug. Steady-state clearance was calculated from dopamine concentration in arterial blood. Dopamine clearance was 60.7 +/- 28.1 ml/kg/min. The age of the patient exerted an effect on clearance of dopamine (r = -0.63; p less than 0.05), and dopamine clearance was nearly twice as rapid in children younger than 2 years as it was in older children (82.3 +/- 27.7 ml/kg/min versus 45.9 +/- 17.0 mg/kg/min). Conjugated bilirubin exerted an age-independent effect on clearance of dopamine; clearance was 44.8 +/- 28.6 ml/kg/min in children with abnormal conjugated bilirubin (greater than or equal to 0.9 mg/dl) and 70.1 +/- 2.56 ml/kg/min in children with normal conjugated bilirubin (less than 0.9 mg/dl). Clearance was lowest (29.8 +/- 5.7 ml/kg/min) in the four children who had both hepatic and renal dysfunction. Age is an important determinant of dopamine clearance, explaining in part the clinical observation that infants and young children require higher infusion rates.     

血乳酸水平及清除率和升高时间与重症监护病房危重患者预后的关系

目的 探讨乳酸动态监测指标与重症监护病房(ICU)危重患者预后的相关关系,并对这种关系进行量化评价.方法 收集101例乳酸升高的危重患者,分为死亡组(50例)和存活组(51例),比较两组的乳酸监测指标(乳酸水平、乳酸升高时间、乳酸清除率)、急性生理学与慢性健康状况评分系统Ⅰ(APACHE Ⅰ)评分及其他反映器官功能的指标,使用logistic回归分析找出与预后显著相关的指标.以相应的乳酸指标进行量化分组,分别比较各组休克和多器官功能障碍综合征(MODS)发生率、APACHE Ⅰ评分和病死率.结果 死亡组入ICU乳酸值、乳酸峰值、APACHE Ⅰ评分高于存活组,12 h和24 h乳酸清除率、pH值低于存活组(P<0.05或P<0.01).乳酸峰值、12 h乳酸清除率、APACHE Ⅰ评分和pH值与患者的预后明显相关,相对比值比(OR)分别为1.466、0.922、1.208、0.032.乳酸峰值≥10 mmol/L、12 h乳酸清除率≤10%的患者病死率明显升高,分别为77.8%和70.6%(P<0.05和P<0.01),乳酸升高时间>24 h时病死率虽升高,但无统计学意义.结论 乳酸峰值、12 h乳酸清除率、APACHE Ⅰ评分和pH值是评价患者预后的良好指标.乳酸峰值≥10 mmol/L、12 h乳酸清除率≤10%时应警惕患者较差的预后,而乳酸升高时间评价预后的价值有限.     

Augmented renal clearance is a common finding with worse clinical outcome in critically ill patients receiving antimicrobial therapy

Introduction

We describe incidence and patient factors associated with augmented renal clearance (ARC) in adult intensive care unit (ICU) patients.

Materials and Methods

A prospective observational study in a mixed cohort of surgical and medical ICU patients receiving antimicrobial therapy at the Ghent University Hospital, Belgium. Kidney function was assessed by the 24-hour creatinine clearance (Ccr); ARC defined as at least one Ccr of > 130 mL/min per 1.73 m². Multivariate logistic regression analysis: to assess variables associated with ARC occurrence. Therapeutic failure (TF): an impaired clinical response and need for alternate antimicrobial therapy.

Results

Of the 128 patients and 599 studied treatment days, ARC was present in 51.6% of the patients. Twelve percent permanently expressed ARC. ARC patients had a median Ccr of 144 mL/min per 1.73 m² (IQR 98-196). Median serum creatinine concentration on the first day of ARC was 0.54 mg/dL (IQR 0.48-0.69). Patients with ARC were significantly younger (P < .001). Age and male gender were independently associated with ARC whereas the APACHE II score was not. ARC patients had more TF (18 (27.3%) vs. 8 (12.9%); P = .04).

Conclusion

ARC was documented in approximately 52% of a mixed ICU patient population receiving antibiotic treatment with worse clinical outcome. Young age and male gender were independently associated with ARC presence.     

Severe hyperlactatemia,lactate clearance and mortality in unselected critically ill patients

Purpose

Hyperlactatemia may occur for a variety of reasons and is a predictor of poor clinical outcome. However, only limited data are available on the underlying causes of hyperlactatemia and the mortality rates associated with severe hyperlactatemia in critically ill patients. We therefore aimed to evaluate the etiology of severe hyperlactatemia (defined as a lactate level >10 mmol/L) in a large cohort of unselected ICU patients. We also aimed to evaluate the association between severe hyperlactatemia and lactate clearance with ICU mortality.

Methods

In this retrospective, observational study at an University hospital department with 11 ICUs during the study period between 1 April 2011 and 28 February 2013, we screened 14,040 ICU patients for severe hyperlactatemia (lactate >10 mmol/L).

Results

Overall mortality in the 14,040 ICU patients was 9.8 %. Of these, 400 patients had severe hyperlactatemia and ICU mortality in this group was 78.2 %. Hyperlactatemia was associated with death in the ICU [odds ratio 1.35 (95 % CI 1.23; 1.49; p < 0.001)]. The main etiology for severe hyperlactatemia was sepsis (34.0 %), followed by cardiogenic shock (19.3 %), and cardiopulmonary resuscitation (13.8 %). Patients developing severe hyperlactatemia >24 h of ICU treatment had a significantly higher ICU mortality (89.1 %, 155 of 174 patients) than patients developing severe hyperlactatemia ≤24 h of ICU treatment (69.9 %, 158 of 226 patients; p < 0.0001). Lactate clearance after 12 h showed a receiver-operating-characteristics area under the curve (ROC-AUC) value of 0.91 to predict ICU mortality (cut-off showing highest sensitivity and specifity was a 12 h lactate clearance of 32.8 %, Youden Index 0.72). In 268 patients having a 12-h lactate clearance <32.8 % ICU mortality was 96.6 %.

Conclusions

Severe hyperlactatemia (>10 mmol/L) is associated with extremely high ICU mortality especially when there is no marked lactate clearance within 12 h. In such situations, the benefit of continued ICU therapy should be evaluated.

     

Treatment implications of augmented renal clearance in a critically ill COVID-19 patient: A case report

Augmented renal clearance (ARC) is a pathophysiological phenomenon that can occur in critically ill patients, leading to enhanced renal function. It is defined as a creatinine clearance of >130 mL/min/1.73 m². ARC can lead to subtherapeutic levels of renally cleared drugs and subsequent treatment failure. In COVID-19, it has only been described in the literature in a few cases. We present the case of a 38-year-old critically ill patient with COVID-19 who developed ARC with an initial clearance of 226 mL/min/1.73 m², persisting for 30 days. He required high doses of sedatives and neuromuscular blocking agents, as well as increased doses of vancomycin and dalteparin, to reach adequate serum levels. This case emphasizes the importance for clinicians to consider ARC in the dosing of all renally cleared drugs, including antibiotics, low molecular weight heparins, and sedatives, to prevent subtherapeutic drug levels and treatment failure.     

Pharmacokinetics and pharmacodynamics of dopamine and norepinephrine in critically ill head-injured patients

Objective To explore the pharmacokinetics and pharmacodynamics of dopamine and norepinephrine.Design Prospective, controlled, trial.Setting Neurosciences critical care unit.Patients Eight patients with a head injury, requiring dopamine or norepinephrine infusions to support cerebral perfusion pressure (CPP).Intervention Patients received in randomised order, either dopamine or norepinephrine to achieve and maintain a CPP of 70 mmHg, and then, following a 30-min period of stable haemodynamics, a CPP of 90 mmHg. Data were then acquired using the second agent. Haemodynamic measurements were made during each period and a blood sample was obtained at the end of each study period for analysis of plasma catecholamine concentrationsMeasurements and results Plasma levels of norepinephrine and dopamine were significantly related to infusion rates but did not have a simple linear relationship to haemodynamic parameters. However, there was a significant quadratic relationship between the infusion rate of dopamine and cardiac index (r ²=0.431), and systemic vascular resistance index (r ²=0.605), with a breakpoint (at which cardiac index reduced and SVRI increased) at a dopamine plasma level of ~ 50 nM/l (corresponding to an infusion rate of ~ 15 g·kg^-1·min^-1).Conclusions Norepinephrine and dopamine have predictable pharmacokinetics; however, those of dopamine do not fit a simple first-order kinetic model. The pharmacodynamic effects of dopamine and norepinephrine show much inter-individual variability and unpredictability. Plasma levels of dopamine appear to relate to variations in adrenergic receptor effects with break points that reflect expectations from infusion-rate related pharmacodynamics.     

Immediate intralipid clearance from plasma in critically ill patients after a single-dose injection

Plasma fractional removal rates (k2) of Intralipid injected in parallel with 125I albumin were analyzed in five healthy males and nine critically ill patients. The k2 values of critically ill patients were similar to those of healthy subjects. However, the initial plasma concentrations of Intralipid calculated by extrapolation to zero-time (y0) were markedly different. The mean y0 value in the critically ill patients was 43% that of healthy subjects. No plasma loss of 125I albumin occurred throughout the test. Intralipid to 125I albumin plasma concentration ratios during the removal phase paralleled the curves obtained from the iv fat tolerance test. This suggests that these ratios depend on Intralipid clearance rather than leakage from the circulation. The immediate loss of Intralipid suggests that the pulmonary vasculature, the first capillary bed through which the emulsion passes, could be the site where a substantial uptake of the emulsion occurs in critically ill patients.     

Steady-state dopamine clearance in critically ill infants and children

Little is known about dopamine pharmacokinetics in pediatric patients, especially in critically ill infants and children who often receive treatment with dopamine. Arterial plasma concentrations of dopamine were measured in 27 patients who were hemodynamically stable and received dopamine for at least one hour. The dopamine levels were measured using liquid chromatography with electrochemical detection. Dopamine clearance averaged 96.2 +/- 55.4 ml/kg.min in 13 patients in the neonatal ICU, and 58.8 +/- 51 ml/kg.min in 14 patients in the pediatric ICU. Six patients had renal (BUN greater than 25 mg/dl, or creatinine greater than 1.2 mg/dl) or hepatic (liver enzymes greater than 3 times normal) dysfunction. Dopamine clearance in these patients (25.1 +/- 17.2 ml/kg.min) was substantially lower than in the other patients (p less than .01). Neither postnatal nor gestational age correlated with dopamine clearance. Substantial interindividual variation was observed in steady-state dopamine clearance in critically ill infants and children, and plasma dopamine could not be predicted accurately from the dopamine infusion rate. Because of the more than three-fold prolongation of dopamine clearances in patients with hepatic or renal dysfunction, these patients may be more likely to suffer toxic effects of dopamine at the usual drug infusion rates.     

Pharmacokinetics of single-dose intravenous amikacin in critically ill patients undergoing slow hemodialysis

Objective The pharmacokinetics of amikacin were studied in patients undergoing slow hemodialysis (HD).Design Slow HD was performed at the dialysate flow rate of 30 ml/min. After a single intravenous dose of amikacin 5 mg/kg, pharmacokinetic variables were calculated by fitting indivdual concentration-time curves to a two-compartment open model.Patients 6 critically ill patients with renal failure were entered into the study.Results The volume of distribution was 0.35±0.03 l/kg. Total body clearance was 35.1±2.3 ml/min with an elimination half-life of 10.5 h. During a 10.5 h session of slow HD, the serum amikacin concentration decreased from the peak level of 21.3±1.2 mg/l to 7.2±0.9 mg/l.Conclusion Slow HD eliminate amikacin more efficiently than other types of slowly performed renal replacement therapy and had profound effects on the pharmacokinetics. Amikacin elimination by this approach should be taken into consideration for designing a dosage schedule during the treatment.     

The use of propofol for sedation of critically ill patients undergoing haemodiafiltration

Objective To assess the requirement for propofol to provide sedation in critically ill patients in established renal failure during the commencement of haemodiafiltration.Design Prospective clinical study.Setting ICU, University Hospital.Patients 10 adult patients. All were mechanically ventilated, had acute oliguric renal failure which necessitated continuous veno-venous haemodiafiltration and were receiving a continuous intravenous infusion of propofol for sedation. Sedation was assessed using a scoring system.Intervention Veno-venous haemodiafiltration.Measurements and results Connection of the extracorporeal circuit produced a reduction in plasma propofol concentration in 7 out of 9 patients (one sample misplaced) with subsequent awakening in 3 of these 7 patients. The commencement of haemodiafiltration itself did not significantly influence the requirement for propofol (8 out of 10 patients).Conclusion Haemodiafiltration does not substantially influence the requirement for propofol but the initial introduction of the extracorporeal circuit will reduce plasma concentrations in the majority of patients. This may be due to haemodilution alone or absorption of plasma albumin (with propofol) onto the membrane.