Sedation, analgesia, and delirium in the critically ill patient

Most critically ill patients receive a myriad of psychoactive medications during their hospital stay. An understanding of the pharmacology of the more commonly used sedative and analgesic therapies enables the clinician to aptly utilize these medications and limit toxicity. A key to the appropriate provision of sedative and analgesic pharmacotherapy is a thorough patient assessment, use of validated monitoring tools, and defined therapeutic goals. Limiting these therapies while optimizing patient comfort has been shown to reduce the duration of mechanical ventilation and reduce intensive care unit (ICU) and hospital length of stay and should be the aim of the multidisciplinary medical team. This review is intended to provide the reader with a fundamental understanding of how to facilitate comfort of the mechanically ventilated critically ill adult patients and how to minimize medication-related toxicities.     

Sedation and analgesia

Sedation is a process of soothing. The concept of the ideal level of sedation is controversial and has changed over the last decade. A shift from deep sedation, often enhanced by muscle relaxants that completely detaches the patient from their environment, to light sedation rendering the patient sleepy but easily arousable has been widely accepted. This change in attitude has been brought about by sophisticated modes of ventilation allowing the ventilator to synchronize with the patient's own breathing pattern. In addition, the increasingly recognised adverse effects of over-sedation have contributed to the reduction in the depth of sedation.     

危重患者液体治疗

液体治疗是重症患者常用的治疗手段,其治疗方案的合理与否对患者预后起着决定性作用。本文对液体治疗的途径、液体种类的优缺点以及液体治疗的并发症及监测进行了论述。     

阿米卡星在严重败血症患者体内的药代动力学研究

目的：初步探讨25 mg·kg －1的阿米卡星在重症监护室（ICU）患者体内的药代动力学。方法纳入符合条件的30例革兰阴性（G －）败血症患者进行阿米卡星药物治疗研究,通过非房室模型计算每名患者的阿米卡星的药代动力学。结果阿米卡星在 G －败血症患者体内平均药物分布为（0．36±0．07）L·kg －1,平均血液清除率为（3．88±0．97）mL·min －1·kg －1。肌酐清除率与血清肌酸酐（SCr）相关性具有统计学意义。结论对 ICU 患者应用高剂量阿米卡星（≥25 mg·kg －1）需要考虑败血症对血液动力学的影响,需要密切监测败血症血液药物浓度变化,关键要考虑到重症患者体内药代动力学与普通人群是不同的。     

Pharmacokinetics of linezolid in critically ill patients

Introduction: Linezolid is an oxazolidinone antibiotic active against Gram-positive bacteria, and is most commonly used to treat life-threatening infections in critically ill patients. The pharmacokinetics of linezolid are profoundly altered in critically ill patients, partly due to decreased function of vital organs, and partly because life-sustaining drugs and devices may change the extent of its excretion.

Areas covered: This article is summarizes key changes in the pharmacokinetics of linezolid in critically ill patients. The changes summarized are clinically relevant and may serve as rationale for dosing recommendations in this particular population.

Expert opinion: While absorption and penetration of linezolid to tissues are not significantly changed in critically ill patients, protein binding of linezolid is decreased, volume of distribution increased, and metabolism may be inhibited leading to non-linear kinetics of elimination; these changes are responsible for high inter-individual variability of linezolid plasma concentrations, which requires therapeutic plasma monitoring and choice of continuous venous infusion as the administration method. Acute renal or liver failure decrease clearance of linezolid, but renal replacement therapy is capable of restoring clearance back to normal, obviating the need for dosage adjustment. More population pharmacokinetic studies are necessary which will identify and quantify the influence of various factors on clearance and plasma concentrations of linezolid in critically ill patients.     

Combination antibiotic therapy in critically ill patients

Combination antibiotic therapy may be used for a number of reasons in critically ill patients. The potential benefits of combination therapy include prevention of resistance, treatment of polymicrobial infections, to decrease toxicity, or for synergy. Selected literature is reviewed which examines the use of combination therapy in critically ill patients. Research reports have not uniformly demonstrated the benefits of combination therapy. The situations where combination therapy has been beneficial are discussed.     

Pharmacokinetics of cimetidine in critically ill patients

Summary Cimetidine disposition was studied after rapid (1 min) intravenous infusion in eight critically ill patients aged between 20 years and 77 years; one patient was studied on two occasions. Cimetidine dose was 300 mg in seven patients and 400 mg in the remaining patient. Arterial plasma cimetidine concentrations at the end of the infusion were very high and ranged from approximately 15–35 mg/l. Pharmacokinetic parameters displayed wide interpatient variability (coefficients of variation of 30–50%) and significant relationships emerged between some of these parameters and certain patient characteristics. Most notable, total systemic plasma clearance of cimetidine was directly related to estimated creatinine clearance (p<0.01). This relationship might prove to be a useful method of individualizing cimetidine dosage in critically ill patients.     

Intravenous esomeprazole pharmacodynamics in critically ill patients

Abstract

Objective:

A widely held belief contends that food-induced proton pump activation is important for optimal proton pump inhibitor–induced inhibition of gastric acid secretion. This study was undertaken to assess intragastric acid control with intravenous (IV) esomeprazole in critically ill patients.     

利奈唑胺在重症感染患者中的药动学

目的:研究重症感染患者静脉滴注和鼻饲2种不同给药途经下利奈唑胺的药动学特点。方法:本研究为前瞻性研究,2013年8月-2014年3月使用利奈唑胺治疗的6例ICU患者,根据给药途径不同,分为静脉滴注组4例,鼻饲管给药组2例,2组均给予利奈唑胺600 mg/q12h,于给药后第5天的0,0.5,1,2,3,4,6,8,12 h采取静脉血1 mL,监测利奈唑胺的血药浓度。结果:6例患者的C_min变化范围为3.59~19.82 μg·mL^-1,其中2例超过了安全临界值10 μg·mL^-1,AUC_{0-12 h}变化范围为116.7~305.5 μg·h^-1·mL^-1,C_min与AUC_{0-12 h}具有很强的相关性(r=0.997,P=0.001)。结论:重症感染患者利奈唑胺药动学参数个体差异较大,应根据PK/PD相关参数制定合理的给药方案,预防细菌耐药,保证临床治疗效果,减少不良反应。     

Infectious diseases in the critically ill patients

Infection is common in the critically ill and often results due to the severity of the patient's illness. Recent data suggest 51% of intensive care unit (ICU) patients are infected, and 71% receive antimicrobial therapy. Bacterial infection is the primary concern, although some fungal infections are opportunistic. Infection more than doubles the ICU mortality rate, and the costs associated with infection may be as high as 40% of total ICU expenditures. There are many contemporary antimicrobial resistance concerns that the critical care clinician must consider in managing the pharmacotherapy of infection. Methicillin resistance in Staphylococcus aureus, vancomycin resistance in Enterococci, beta-lactamase resistance in Enterobacteriaceae, multidrug resistance in Pseudomonas aeruginosa and Acinetobacter species, fluoroquinolone resistance in Escherichia coli, and fungal resistance are among the most common issues ICU clinician's must face in managing infection. Critical illness causes changes in pharmacokinetics that influence drug and dosing considerations. Absorption, distribution, metabolism, and excretion may all be affected by the various disease states that define critical illness. Several specific diseases are discussed, including ventilator-associated pneumonia, various fungal infections, gastrointestinal infections due to Clostridium difficile, urinary tract infections, and bloodstream infections. Within each disease section, discussion includes causes and prevention strategies, microbiology, evidence-based guidelines, and important caveats.     

Pharmacokinetics and pharmacodynamics of meropenem in critically ill patients

The pharmacokinetics and pharmacodynamics of meropenem were investigated in 14 critically ill patients with sepsis. Patients with creatinine clearance (CrCl) higher than 50 ml/min received 1 g meropenem three times daily (Group I) and patients with CrCl lower than 50 ml/min received 1 g meropenem twice daily (Group II). Meropenum concentrations in plasma were determined by high performance liquid chromatography with UV detection. The pharmacokinetic parameters differed between the two groups as follows, Group I, maximal concentration 56.3 +/- 19.1 microg/ml; trough concentration 3.3 +/- 2.5 microg/ml; elimination half life 2.5 +/- 1.2 h; clearance (Cl) 155.8 +/- 40.6 ml/min; MRT 2.2 +/- 0.4 h; steady state volume of distribution (V(ss)) 21.7 +/- 5.7 l, and AUC(-8) 119.4 +/- 32.6 microg/ml h. Group II, maximal concentration 71.1 +/- 5.1 microg/ml; trough concentration 3.4 +/- 1.8 microg/ml; elimination half life 3.9 +/- 1.6 h; Cl 77.7 +/- 15.8 ml/min; MRT 3.5 +/- 0.6 h; V(ss), 17.1 +/- 2.1 l, and AUC(0-12) 230.2 +/- 43.3 microg/ml h. The most frequently isolated bacteria from blood and wound infections were Acinetobacter baumanii, Pseudomonas aeruginosa, Klebsiella pneumoniae and Escherichia coli; their meropenem minimal inhibitory concentrations (MICs) ranged from 0.064 to 3.0 mg/l. In most cases the pharmacodynamic parameters, measured as T>MIC index, were higher than 75%. In both groups, patients with susceptible pathogens (MIC<1 mg/l) had meropenem plasma levels which exceeded the MIC for the whole dosing interval. When pathogens were highly resistant (A. baumanii or P. aeruginosa) the T>MIC indices were lower.     

Potential roles for statins in critically ill patients

The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) are the most commonly prescribed agents for hypercholesterolemia and have revolutionized the management of hyperlipidemia and the area of cardiovascular risk reduction. However, recent data suggest that their effects go well beyond the lipid lowering seen with long-term use and may include acute antiinflammatory activity, anticoagulation, immunomodulation, as well as promotion of changes in smooth-muscle tone. Because of these data, promising research has begun into the use of these agents in various critical care areas such as the early phases of sepsis, bacteremia, and ischemic stroke. Recent data also show a decrease in cerebral vasospasm after subarachnoid hemorrhage, an area deficient in therapeutic options. More research is necessary to ascertain the true role of statins in the treatment of these various disorders. Nevertheless, the concept of a statin's role as being only a routine preventive therapy with benefits limited to patients undergoing extended treatment is rapidly becoming inaccurate.     

危重症患者替加环素的群体药动学

目的: 建立替加环素在危重症患者中的群体药动学模型,探究该类人群中影响替加环素药动学的因素。方法: 收集静脉使用替加环素的危重症患者的血样,使用高效液相色谱-质谱联用技术测定替加环素的血药浓度。利用NONMEM软件估算替加环素的药动学参数,通过向前纳入法和逆向剔除法建立替加环素群体药动学模型,并对该模型进行验证和评价。结果: 收集54名患者的143个血药浓度建立替加环素的群体药动学模型,静脉给药的一室模型较好地描述替加环素的药动学特征,替加环素的清除率(CL)、表观分布容积(V_d)的群体典型值分别为11.3 L·h^-1和105 L,患者的APACHE Ⅱ评分和年龄对模型有显著影响。结论: 建立的替加环素群体药动学模型预测性能稳定良好,APACHE Ⅱ评分影响替加环素CL,年龄影响替加环素V_d,可为临床替加环素在危重症患者中的个体化给药提供参考。     

Relationship between hyperglycemia and infection in critically ill patients

Hyperglycemia is a common problem encountered in hospitalized patients, especially in critically ill patients and those with diabetes mellitus. Uncontrolled hyperglycemia may be associated with complications such as fluid and electrolyte disturbances and increased infection risk. Studies have demonstrated impairment of host defenses, including decreased polymorphonuclear leukocyte mobilization, chemotaxis, and phagocytic activity related to hyperglycemia. Until 2001, hyperglycemia (blood glucose concentrations up to 220 mg/dl) had been tolerated in critically ill patients not only because high blood glucose concentrations were believed to be a normal physiologic reaction in stressed patients and excess glucose is necessary to support the energy needs of glucose-dependent organs, but also because the true significance of short-term hyperglycemia was not known. Recent clinical data show that the use of intensive insulin therapy to maintain tight blood glucose concentrations between 80 and 110 mg/dl decreases morbidity and mortality in critically ill surgical patients. Intensive insulin therapy minimizes derangements in normal host defense mechanisms and modulates release of inflammatory mediators. The principal benefit of intensive insulin therapy is a decrease in infection-related complications and mortality. Further research will define which patient populations will benefit most from intensive insulin therapy and firmly establish the blood glucose concentration at which benefits will be realized.     

药理营养素在重症患者中的应用

随着重病医学与临床营养的不断发展,越来越多的具有免疫药理作用的营养素应用于临床,如,谷氨酰胺,n-3多不饱和脂肪酸,n-9单不饱和脂肪酸,精氨酸等。本文主要对近年来研究较多的几种药理营养素的应用和进展进行综述。     

Pharmacokinetic evaluation of fluconazole in critically ill patients

INTRODUCTION: Invasive candidiasis has emerged over the last few decades as an increasingly important nosocomial problem for the critically ill, affecting around 2% of intensive care unit patients. Although poor outcomes associated with invasive candidiasis among critically ill patients may relate to severe underlying disease processes and delayed institution of antifungal therapy, inadequate dosing of antifungal agents may also contribute. AREAS COVERED: This drug evaluation provides a critical appraisal of the published literature pertaining to the pharmacokinetics of fluconazole in critically ill, obese or severely burned patients, including those receiving acute renal replacement therapy. The pharmacodynamics of fluconazole is also covered, as well as the likely clinical implications for optimal dosing and the toxicity of fluconazole. Last, variations in fluconazole susceptibility patterns of Candida spp. are also discussed. EXPERT OPINION: Recently, there has been an increased but geographically variable prevalence of non-albicans Candida spp., causing invasive candidiasis and an overall trend towards reduced fluconazole susceptibility. The pathophysiological changes of critical illness, coupled with a lack of dose finding studies, support the use of local susceptibility patterns to guide fluconazole dosing until such time as pharmacokinetic-pharmacodynamic information to guide optimal fluconazole dosing strategies and pharmacodynamic targets becomes available.     

The pharmacokinetics of ketobemidone in critically ill patients

AIMS: To study the pharmacokinetics of orally and intravenously administered ketobemidone in critically ill patients. METHODS: Seventeen patients were studied during their stay in the intensive care unit at Huddinge University Hospital. Nine patients received a single intravenous dose of ketobemidone (0.04 mg kg-1) and eight patients received a single oral dose of 5 mg. Plasma concentrations of ketobemidone were measured using liquid chromatography-mass spectrometry. The pharmacokinetic analysis was performed using WinNonlin trade mark software. RESULTS: There was a wide variation in the different pharmacokinetic parameters among patients. Mean clearance in patients treated intravenously was 74.5 (95% CI 43.2, 128.3) and mean Vd was 2.4 l kg-1 (95% CI 2.0, 2.8). t1/2,z also varied widely with a mean value of 4.41 h (95% CI 2.7, 7.0). The corresponding values for MRT were 5.4 and 3.3, 8.8. Mean oral clearance (CL/F) was 102 l h-1 (95% CI 82.7, 125.8), mean Vz/F was 11.2 l kg-1 (95% CI 9.7, 13.1) and mean t1/2,z was 6.0 (95% CI 4.9, 7.3) in orally treated patients. Cmax showed a mean of 38 nmol l-1 (95% CI of 31, 47). A significant correlation was observed between the glomerular filtration rate (GFR) and the half-life of ketobemidone (r = -0.72, P < 0.05). t1/2,z was generally longer and the variation larger in critically ill patients compared with healthy individuals. However, there was no correlation between the elimination of ketobemidone in critically ill patients and plasma C-reactive protein, white blood count or plasma albumin concentrations. CONCLUSIONS: The disposition of ketobemidone is highly variable in critically ill patients. In order to ensure sufficient analgesia and avoid toxicity, therapeutic monitoring should be employed when using ketobemidone in this group of patients.