Cation Metabolism During Propofol Sedation With and Without EDTA in Patients With Impaired Renal Function

Objective: To compare the effects of propofol with and without disodium edetate (EDTA) on cation metabolism in intensive care unit (ICU) patients with renal insufficiency who received propofol or propofol plus EDTA (propofol EDTA) for sedation and mechanical ventilation. Design: Double-blind, randomised, multicentre study. Setting: Medical and surgical ICUs from 5 hospitals. Patients: Thirty-nine ICU patients with acute and chronic renal impairment expected to require at least 24 hours of continuous sedation and respiratory failure necessitating mechanical ventilation. Interventions: Propofol or propofol EDTA administered for sedation by continuous intravenous infusion. Measurements and Results: The depth of sedation, as measured by the Modified Ramsay Sedation Scale, was similar in the 2 groups, when adjusted for dosing differences. The amount of propofol required to maintain adequate sedation was decreased in both groups compared to propofol requirements in ICU patients with normal renal function. EDTA levels were elevated at baseline in both groups. In the propofol EDTA group, the EDTA levels increased further by 20 % but decreased to below baseline EDTA levels at 48 hours after sedation. In the propofol group, EDTA levels decreased during sedation and remained below baseline levels at 48 hours after sedation. Patients in both groups were hypocalcaemic and hyperphosphataemic at baseline with low levels of 1,25-dihydroxyvitamin D and elevated parathyroid hormone (PTH) levels. Other than a slight difference in ionised serum calcium levels at 4 h after the start of sedation, there were no significant differences observed in serum calcium levels between the two groups. There were no significant differences in 1,25-dihydroxyvitamin D or PTH levels over time between the two groups. There was no significant effect on renal function in either group. Conclusions: The results of this study suggest that adding EDTA to propofol does not adversely affect cation homeostasis or renal function when used for sedation of ICU patients with renal insufficiency. Although EDTA levels increased over time from baseline levels in patients with renal insufficiency who receive propofol EDTA, this increase does not appear to be clinically significant, and EDTA levels return to below baseline levels within 48 hours of discontinuing the propofol EDTA infusion. The efficacy of propofol with and without EDTA also appears comparable in these patients.     

Cation Metabolism During Propofol Sedation With and Without EDTA in Patients With Impaired Renal Function

Objective: To compare the effects of propofol with and without disodium edetate (EDTA) on cation metabolism in intensive care unit (ICU) patients with renal insufficiency who received propofol or propofol plus EDTA (propofol EDTA) for sedation and mechanical ventilation. Design: Double-blind, randomised, multicentre study. Setting: Medical and surgical ICUs from 5 hospitals. Patients: Thirty-nine ICU patients with acute and chronic renal impairment expected to require at least 24 hours of continuous sedation and respiratory failure necessitating mechanical ventilation. Interventions: Propofol or propofol EDTA administered for sedation by continuous intravenous infusion. Measurements and Results: The depth of sedation, as measured by the Modified Ramsay Sedation Scale, was similar in the 2 groups, when adjusted for dosing differences. The amount of propofol required to maintain adequate sedation was decreased in both groups compared to propofol requirements in ICU patients with normal renal function. EDTA levels were elevated at baseline in both groups. In the propofol EDTA group, the EDTA levels increased further by 20 % but decreased to below baseline EDTA levels at 48 hours after sedation. In the propofol group, EDTA levels decreased during sedation and remained below baseline levels at 48 hours after sedation. Patients in both groups were hypocalcaemic and hyperphosphataemic at baseline with low levels of 1,25-dihydroxyvitamin D and elevated parathyroid hormone (PTH) levels. Other than a slight difference in ionised serum calcium levels at 4 h after the start of sedation, there were no significant differences observed in serum calcium levels between the two groups. There were no significant differences in 1,25-dihydroxyvitamin D or PTH levels over time between the two groups. There was no significant effect on renal function in either group. Conclusions: The results of this study suggest that adding EDTA to propofol does not adversely affect cation homeostasis or renal function when used for sedation of ICU patients with renal insufficiency. Although EDTA levels increased over time from baseline levels in patients with renal insufficiency who receive propofol EDTA, this increase does not appear to be clinically significant, and EDTA levels return to below baseline levels within 48 hours of discontinuing the propofol EDTA infusion. The efficacy of propofol with and without EDTA also appears comparable in these patients.     

Procedural Sedation of Critically Ill Patients in the Emergency Department

Objectives: Procedural sedation is routinely performed in the emergency department (ED). However, some authors believe it is unsafe in nonintubated, critically ill patients. The objective of this study was to determine the safety of ED procedural sedation in the American Society of Anesthesiologists (ASA) physical status classification P3 and P4 patients. Methods: This was a prospective observational study of patients undergoing procedural sedation in the ED between August 2002 and December 2003 who were classified as ASA physical status score P3 or P4. Patients received either propofol or etomidate at the discretion of the treating physician before their painful procedure. Doses, vital signs, end‐tidal CO₂ (ETCO₂) by nasal cannulae, and pulse oximetry were recorded. Respiratory depression (RD) was defined as a change from baseline ETCO₂ >10 mm Hg, an oxygen saturation of < 90%, or an absent ETCO₂ waveform at any time. Results: Sixty‐two critically ill, nonintubated patients were enrolled. Thirty‐one patients received propofol, and 31 patients received etomidate. No cardiac rhythm abnormalities were detected. RD was seen in 37 of 62 patients (59.7%): 19 of the 31 (61.3%) who received propofol and 18 of the 31 (58.1%) who received etomidate. The mean decrease from baseline systolic blood pressure was 11.3% (95% confidence interval [CI] = 7.3% to 15.5%): 5.0% (95% CI = 3.0% to 8.1%) for those receiving etomidate and 17.1% (95% CI = 9.9% to 24.3%) for those receiving propofol. No adverse events were reported. Conclusions: The rate of subclinical RD detected by these criteria was similar to previous reports for noncritically ill patients. Procedural sedation of nonintubated ASA physical status score P3 and P4 patients in the ED with either propofol or etomidate appears to be safe.     

Effects of Propofol Containing EDTA on Mineral Metabolism in Medical ICU Patients With Pulmonary Dysfunction

Objective: To determine whether the addition of disodium edetate (EDTA) to propofol significantly alters mineral metabolism, adverse events, and outcome in critically ill medical patients with acute pulmonary dysfunction. Design: Multicentre, double-randomised, double-blind, comparative trial. Setting: Medical intensive care units of 5 health centres. Patients: A total of 85 haemodynamically stable men and women aged 18–81 years who had pulmonary dysfunction or adult respiratory distress syndrome as a primary diagnosis or complication and who were expected to require at least 48 hours of sedation and mechanical ventilation. Interventions: Patients were randomised to receive propofol with or without EDTA and then to 1 of 2 sedation levels: light (Modified Ramsay Sedation Scale [MRSS] score of 2 to 3) or deep (MRSS score of 4 to 5). Propofol was administered by continuous infusion at an initial rate of 5 μg/kg per min and titrated as needed. Measurements and Results: Approximately 63 % of patients had a high severity of illness as indicated by an Acute Physiology and Chronic Health Evaluation II score ≥ 19. As expected, these patients had a higher mortality rate but did not require a higher dose of propofol or propofol with EDTA. Extensive evaluation of cation homeostasis showed that ionised calcium and magnesium concentrations remained remarkably stable during treatment. Total calcium concentration was low as a result of hypoalbuminemia. Parathyroid hormone (PTH) concentration was elevated in both study groups at baseline, on day 4, and at the end of sedation. There were no significant differences in electrolyte levels and no progression to renal dysfunction. There were also no significant differences in haemodynamic or adverse-event profiles. Treatment-related adverse events occurred in 5 patients in each group; 4 of these (in 3 patients receiving propofol and 1 patient receiving propofol with EDTA) were considered serious. Because a large percentage of patients experienced a change in sedation level, no analyses were performed using sedation level. Conclusions: The addition of EDTA to propofol does not alter calcium and magnesium homeostasis in critically ill patients with acute pulmonary dysfunction. The reason for the elevation in PTH concentrations in such patients is not known.     

Effects of Propofol Containing EDTA on Mineral Metabolism in Medical ICU Patients With Pulmonary Dysfunction

Objective: To determine whether the addition of disodium edetate (EDTA) to propofol significantly alters mineral metabolism, adverse events, and outcome in critically ill medical patients with acute pulmonary dysfunction. Design: Multicentre, double-randomised, double-blind, comparative trial. Setting: Medical intensive care units of 5 health centres. Patients: A total of 85 haemodynamically stable men and women aged 18-81 years who had pulmonary dysfunction or adult respiratory distress syndrome as a primary diagnosis or complication and who were expected to require at least 48 hours of sedation and mechanical ventilation. Interventions: Patients were randomised to receive propofol with or without EDTA and then to 1 of 2 sedation levels: light (Modified Ramsay Sedation Scale [MRSS] score of 2 to 3) or deep (MRSS score of 4 to 5). Propofol was administered by continuous infusion at an initial rate of 5 wg/kg per min and titrated as needed. Measurements and Results: Approximately 63 % of patients had a high severity of illness as indicated by an Acute Physiology and Chronic Health Evaluation II score S 19. As expected, these patients had a higher mortality rate but did not require a higher dose of propofol or propofol with EDTA. Extensive evaluation of cation homeostasis showed that ionised calcium and magnesium concentrations remained remarkably stable during treatment. Total calcium concentration was low as a result of hypoalbuminemia. Parathyroid hormone (PTH) concentration was elevated in both study groups at baseline, on day 4, and at the end of sedation. There were no significant differences in electrolyte levels and no progression to renal dysfunction. There were also no significant differences in haemodynamic or adverse-event profiles. Treatment-related adverse events occurred in 5 patients in each group; 4 of these (in 3 patients receiving propofol and 1 patient receiving propofol with EDTA) were considered serious. Because a large percentage of patients experienced a change in sedation level, no analyses were performed using sedation level. Conclusions: The addition of EDTA to propofol does not alter calcium and magnesium homeostasis in critically ill patients with acute pulmonary dysfunction. The reason for the elevation in PTH concentrations in such patients is not known.     

Safety and Efficacy of Propofol With EDTA When Used for Sedation of Surgical Intensive Care Unit Patients

Objective: To compare propofol with disodium edetate (EDTA) and propofol without EDTA when used for the sedation of critically ill surgical intensive care unit (ICU) patients. Design: Prospective, randomised, multicentre trial. Patients: A total of 122 surgical ICU patients who required intubation and mechanical ventilation. Interventions: Patients were randomised to receive either propofol or propofol plus EDTA (propofol EDTA) by continuous infusion for sedation. Measurements and Results: The addition of EDTA to propofol had no effect on calcium or magnesium homeostasis, renal function, haemodynamic function, or efficacy when used for the sedation of surgical patients in the ICU. The most common adverse events were hypotension, atrial fibrillation, and hypocalcaemia. In this trial, a greater number of serious adverse events and adverse events leading to withdrawal occurred in the propofol group relative to the propofol EDTA group. There was a significantly lower crude mortality rate at 7 and 28 days for the propofol EDTA group compared with the propofol group. There were no statistically significant differences between groups with respect to depth of sedation. Conclusion: The propofol EDTA formulation had no effect on calcium or magnesium homeostasis, renal function, or sedation efficacy compared with propofol alone when used for sedation in critically ill surgical ICU patients. There was a significant decrease in mortality in the propofol EDTA group compared with the propofol group. Further investigations are needed to validate this survival benefit and elucidate a possible mechanism.     

Safety and Efficacy of Propofol With EDTA When Used for Sedation of Surgical Intensive Care Unit Patients

Objective: To compare propofol with disodium edetate (EDTA) and propofol without EDTA when used for the sedation of critically ill surgical intensive care unit (ICU) patients. Design: Prospective, randomised, multicentre trial. Patients: A total of 122 surgical ICU patients who required intubation and mechanical ventilation. Interventions: Patients were randomised to receive either propofol or propofol plus EDTA (propofol EDTA) by continuous infusion for sedation. Measurements and Results: The addition of EDTA to propofol had no effect on calcium or magnesium homeostasis, renal function, haemodynamic function, or efficacy when used for the sedation of surgical patients in the ICU. The most common adverse events were hypotension, atrial fibrillation, and hypocalcaemia. In this trial, a greater number of serious adverse events and adverse events leading to withdrawal occurred in the propofol group relative to the propofol EDTA group. There was a significantly lower crude mortality rate at 7 and 28 days for the propofol EDTA group compared with the propofol group. There were no statistically significant differences between groups with respect to depth of sedation. Conclusion: The propofol EDTA formulation had no effect on calcium or magnesium homeostasis, renal function, or sedation efficacy compared with propofol alone when used for sedation in critically ill surgical ICU patients. There was a significant decrease in mortality in the propofol EDTA group compared with the propofol group. Further investigations are needed to validate this survival benefit and elucidate a possible mechanism.     

Continuous Renal Replacement Therapy Liberation and Outcomes of Critically Ill Patients With Acute Kidney Injury

ObjectiveTo examine the association between continuous renal replacement therapy (CRRT) liberation and clinical outcomes among patients with acute kidney injury (AKI) requiring CRRT.MethodsThis single-center, retrospective cohort study included adult patients admitted to intensive care units with AKI and treated with CRRT from January 1, 2007, to May 4, 2018. Based on the survival and renal replacement therapy (RRT) status at 72 hours after the first CRRT liberation, we classified patients into liberated, reinstituted, and those who died. We observed patients for 90 days after CRRT initiation to compare the major adverse kidney events (MAKE₉₀).ResultsOf 1135 patients with AKI, 228 (20%), 437 (39%), and 470 (41%) were assigned to liberated, reinstituted, and nonsurvival groups, respectively. The MAKE₉₀, mortality, and RRT independence rates of the cohort were 62% (707 cases), 59% (674 cases), and 40% (453 cases), respectively. Compared with reinstituted patients, the liberated group had a lower MAKE₉₀ (29% vs 39%; P=.009) and higher RRT independence rate (73% vs 65%; P=.04) on day 90, but without significant difference in 90-day mortality (26% vs 33%; P=.05). After adjustments for confounders, successful CRRT liberation was not associated with lower MAKE₉₀ (odds ratio, 0.71; 95% CI, 0.48 to 1.04; P=.08) but was independently associated with improved kidney recovery at 90-day follow-up (hazard ratio, 1.81; 95% CI, 1.41 to 2.32; P<.001).ConclusionOur study demonstrated a high occurrence of CRRT liberation failure and poor 90-day outcomes in a cohort of AKI patients treated with CRRT.     

Pharmacokinetic and Pharmacodynamic Analysis of Critically Ill Patients Undergoing Continuous Renal Replacement Therapy With Imipenem

PurposeThis study explores factors that affect behavior in critically ill patients receiving continuous renal replacement therapy (CRRT) with imipenem and provides dosing regimens for these patients.MethodsA prospective, open-label study was conducted in a clinical setting. Both blood and effluent samples were collected pairwise at the scheduled time points. Plasma and effluent imipenem concentrations were determined by HPLC-UV. A population pharmacokinetic model was developed using a nonlinear mixed-effects modeling method. The final model was evaluated by a bootstrap and visual predictive check. A population pharmacokinetic and pharmacodynamic analysis using Monte Carlo simulations was performed to explore the effects of empirically used dosing regimens (0.5 g q6h, 0.5 g q8h, 0.5 g q12h, 1 g q6h, 1 g q8h, and 1 g q12h) on the probability of target attainment.FindingsThirty patients were included in the population model analysis. Imipenem concentration data were best described by a 3-compartment model (central, peripheral, and dialysis compartments). The clearance of the dialysis compartment (CL_d) was used to characterize drug elimination from the dialyzer. Creatinine clearance (CrCl) was the covariate that influenced the central clearance (CLc), and the effects of dialysate flow (Qd) was significant for CLd. Model validation revealed that the final model had qualified stability and acceptable predictive properties. A pharmacokinetic and pharmacodynamic analysis was conducted by Monte Carlo simulation, and patients were categorized into 12 subgroups based on different CrCl values (<30, 31–60, 61–90, and >90 mL/min) and Qd values (300, 500, and 1000 mL/h). Under the same MIC value and administration regimen, probability of target attainment values decreased with an increase of CrCl and Qd.ImplicationsCrCl and Qd had significant effects on CL_c and CL_d, respectively. The proposed final model may be used to guide practitioners in imipenem dosing in this specific patient population.     

Pharmacokinetics of Ganciclovir during Continuous Venovenous Hemodiafiltration in Critically Ill Patients

Ganciclovir is an antiviral agent that is frequently used in critically ill patients with cytomegalovirus (CMV) infections. Continuous venovenous hemodiafiltration (CVVHDF) is a common extracorporeal renal replacement therapy in intensive care unit patients. The aim of this study was to investigate the pharmacokinetics of ganciclovir in anuric patients undergoing CVVHDF. Population pharmacokinetic analysis was performed for nine critically ill patients with proven or suspected CMV infection who were undergoing CVVHDF. All patients received a single dose of ganciclovir at 5 mg/kg of body weight intravenously. Serum and ultradiafiltrate concentrations were assessed by high-performance liquid chromatography, and these data were used for pharmacokinetic analysis. Mean peak and trough prefilter ganciclovir concentrations were 11.8 ± 3.5 mg/liter and 2.4 ± 0.7 mg/liter, respectively. The pharmacokinetic parameters elimination half-life (24.2 ± 7.6 h), volume of distribution (81.2 ± 38.3 liters), sieving coefficient (0.76 ± 0.1), total clearance (2.7 ± 1.2 liters/h), and clearance of CVVHDF (1.5 ± 0.2 liters/h) were determined. Based on population pharmacokinetic simulations with respect to a target area under the curve (AUC) of 50 mg · h/liter and a trough level of 2 mg/liter, a ganciclovir dose of 2.5 mg/kg once daily seems to be adequate for anuric critically ill patients during CVVHDF.     

危重患者肠内营养期间腹泻原因探讨

目的探讨危重症患者肠内营养治疗期间发生腹泻的相关因素及预防对策。方法调查我院2012年期间进行肠内营养治疗的危重症成年患者240例,收集其临床资料,并按是否发生腹泻分为腹泻组和对照组,分析两组之间相关因素差异。结果腹泻组69例,对照组171例,共筛选出APACHEⅡ评分〉15分、禁食时间≥7d、血清白蛋白〈28g/L、抗生素使用时间〉14d、使用促胃肠动力药等5个因素为肠内营养患者腹泻的危险因素（P〈0.05）,及使用益生菌等1个因素为肠内营养患者腹泻的保护因素（P〈0.05）。结论患者APACHEⅡ评分〉15分、禁食时间≥7d、血清白蛋白低〈28g/L、抗生素使用时间〉14d及使用促胃肠动力药可以导致肠内营养期间腹泻率增加,而给予患者微生物制剂可减少腹泻的发生。     

Effect of Propofol With and Without EDTA on Haemodynamics and Calcium and Magnesium Homeostasis During and After Cardiac Surgery

Objective: To determine the effect of the addition of disodium edetate (EDTA) to propofol on haemodynamics, ionised calcium and magnesium serum concentrations, and adverse events during cardiac surgery. Design: Double-blind, randomised, multicenter trial. Setting: Operating room and intensive care unit of 5 academic health centres. Patients: A total of 102 evaluable patients, aged 34 to 85 years, undergoing first-time, elective coronary artery bypass graft surgery. Interventions: Comparison of propofol with EDTA and propofol without EDTA, each in conjunction with the opioid sufentanil, for intraoperative anaesthesia and postoperative sedation. Measurements and Results: There were no significant differences at any time between the two formulations in any clinical chemistry measurements, including ionised calcium, ionised magnesium, total calcium, parathyroid hormone, blood urea nitrogen, creatinine, sodium, potassium, and phosphate. During bypass, the mean concentration of ionised calcium decreased to below the normal range, but the decrease was similar in both groups (propofol with EDTA, 0.98 - 0.07 mmol/L [N = 51]; propofol, 0.99 - 0.10 mmol/L [N = 51]; p = NS). Calcium concentration returned to normal after rewarming. Mean ionised magnesium concentrations remained within normal limits in both groups. Similarly, there were no clinically meaningful differences between treatments with respect to haemodynamic variables, efficacy variables, or incidence of adverse events. Conclusions: The inclusion of EDTA in the current formulation of propofol appears to have no significant effects on calcium and magnesium profiles, renal function, haemodynamic variables, or other indicators of safety and efficacy during intraoperative anaesthesia and postoperative sedation in patients undergoing cardiac surgery.     

Effect of Propofol With and Without EDTA on Haemodynamics and Calcium and Magnesium Homeostasis During and After Cardiac Surgery

Objective: To determine the effect of the addition of disodium edetate (EDTA) to propofol on haemodynamics, ionised calcium and magnesium serum concentrations, and adverse events during cardiac surgery. Design: Double-blind, randomised, multicenter trial. Setting: Operating room and intensive care unit of 5 academic health centres. Patients: A total of 102 evaluable patients, aged 34 to 85 years, undergoing first-time, elective coronary artery bypass graft surgery. Interventions: Comparison of propofol with EDTA and propofol without EDTA, each in conjunction with the opioid sufentanil, for intraoperative anaesthesia and postoperative sedation. Measurements and Results: There were no significant differences at any time between the two formulations in any clinical chemistry measurements, including ionised calcium, ionised magnesium, total calcium, parathyroid hormone, blood urea nitrogen, creatinine, sodium, potassium, and phosphate. During bypass, the mean concentration of ionised calcium decreased to below the normal range, but the decrease was similar in both groups (propofol with EDTA, 0.98 ± 0.07 mmol/L [N = 51]; propofol, 0.99 ± 0.10 mmol/L [N = 51]; p = NS). Calcium concentration returned to normal after rewarming. Mean ionised magnesium concentrations remained within normal limits in both groups. Similarly, there were no clinically meaningful differences between treatments with respect to haemodynamic variables, efficacy variables, or incidence of adverse events. Conclusions: The inclusion of EDTA in the current formulation of propofol appears to have no significant effects on calcium and magnesium profiles, renal function, haemodynamic variables, or other indicators of safety and efficacy during intraoperative anaesthesia and postoperative sedation in patients undergoing cardiac surgery.     

Pharmacokinetics of Caspofungin in Critically Ill Patients on Continuous Renal Replacement Therapy

Caspofungin pharmacokinetics was assessed in 27 critically ill patients, including 7 on continuous venovenous hemofiltration (CVVH), 8 on continuous venovenous hemodialysis (CVVHD), and 13 not requiring continuous renal replacement therapy (CRRT). Caspofungin exposure during CRRT was very similar to that of the control group and comparable to that in healthy volunteers. Caspofungin clearance by CRRT was very low. Therefore, the standard dosage of caspofungin is probably adequate for critically ill patients undergoing CVVH or CVVHD.     

Altered Pharmacokinetics in Prolonged Infusions of Sedatives and Analgesics Among Adult Critically Ill Patients: A Systematic Review

Purpose

The pharmacokinetic (PK) parameters of many drugs are altered as a consequence of the pathophysiological changes associated with critical illness. The critically ill population presents challenges when titrating infusions of sedatives and analgesics to maintain optimal sedation and pain levels. This systematic review examined the PK data in critically ill adult patients with prolonged infusions (>24 hours) of commonly used sedatives and analgesics to highlight possible altered PK parameters compared with noncritically ill patients.