A prospective evaluation of propylene glycol clearance and accumulation during continuous-infusion lorazepam in critically ill patients

Propylene glycol is a commonly used diluent in several pharmaceutical preparations, including the sedative lorazepam. Fifty critically ill patients receiving continuous-infusion lorazepam for a minimum of 36 hours were prospectively evaluated to determine the extent of propylene glycol accumulation over time, characterize propylene glycol clearance in the presence of critical illness, and develop a pharmacokinetic model that would predict clearance based on patient-specific clinical, laboratory, and demographic factors. In this cohort, the median lorazepam infusion rate was 2.1 mg/h (0.5-18). Propylene glycol concentration correlated poorly with osmolality, osmol gap, and lactate. In all, 8 patients (16%) had significant propylene glycol accumulation (>25mg/dL). When propylene glycol concentrations were >25 mg/dL, the median lorazepam infusion rate before sample collection was higher, 6.4 (1.9-11.3) versus 2.0 (0.5-7.4) mg/h (P =.0003). A linear first-order model with interoccasion variability on clearance adjusted for total body weight and Acute Physiology and Chronic Health Evaluation II score predicted propylene glycol concentration.     

Withdrawal from lorazepam in critically ill children

BACKGROUND: Sedatives are used in critically ill children to facilitate mechanical ventilation. Although tolerance and withdrawal are associated with use of sedatives, information about withdrawal from benzodiazepines in children is limited. OBJECTIVE: To document the occurrence of lorazepam withdrawal in critically ill children and identify predictors for the development of withdrawal. METHODS: This prospective, investigational, open-label study enrolled pediatric patients receiving a continuous infusion of lorazepam for at least 72 hours. The lorazepam dosage was tapered in a uniform fashion over 6 days by decreasing the total daily dose by 50% every other day on 3 occasions; it was then discontinued. The occurrence of withdrawal from lorazepam was determined by pediatric intensive care unit attending physicians based on clinical judgment. Patients were assessed for withdrawal twice daily beginning 48 hours after the initiation of the lorazepam taper. Assessments were continued for 72 hours after lorazepam discontinuation or until the patient experienced withdrawal, whichever came first. Patient demographic, sedative dosing, and lorazepam serum concentration data were collected to identify risk factors for withdrawal. RESULTS: Twenty-nine patients completed the study. They received lorazepam for a median duration of about 21 days, and withdrawal occurred in 7 patients. There were no significant differences in demographic variables, lorazepam dosage or other sedative therapy, or lorazepam serum concentrations between patients with withdrawal and those without withdrawal. No predictors of withdrawal were identified. CONCLUSIONS: Withdrawal occurred in 24% of critically ill children receiving long-term sedation from lorazepam. Risk factors for withdrawal are unknown.     

Propylene glycol accumulation associated with continuous infusion of lorazepam in pediatric intensive care patients

OBJECTIVE: To determine if propylene glycol accumulates in children receiving continuous lorazepam infusion and, if accumulation occurs, to determine if it is associated with significant laboratory abnormalities. DESIGN: Prospective study. SETTING: A tertiary care pediatric intensive care unit. PATIENTS: Eleven intubated pediatric intensive care patients receiving continuous lorazepam infusion for sedation. INTERVENTIONS: Propylene glycol accumulation was determined by comparing concentrations at baseline, after 48 hrs, and at end of therapy. Laboratory abnormalities were determined by comparing serum lactate and osmolar gap at baseline, after 48 hrs, and at end of therapy. Correlation between the cumulative dose of lorazepam received and the propylene glycol concentration measured at the end of therapy was determined. MEASUREMENTS AND MAIN RESULTS: Patients aged 1-15 months were studied. Lorazepam infusion rates ranged from 0.1 to 0.33 mg.kg.hr and lasted 3-14 days. Propylene glycol accumulated significantly in patients receiving continuous infusion of lorazepam. The propylene glycol concentration increased during the study from 86 +/- 93 microg/mL at baseline to 763 +/- 660 microg/mL at the end of the study ( p=.038). A statistically significant correlation between the cumulative dose of lorazepam received and propylene glycol concentration at the end of therapy was demonstrated ( r(2)=.65, p<.005). However, the propylene glycol accumulation was not associated with significant laboratory abnormalities. Neither serum lactate concentrations nor osmolar gap were significantly elevated over baseline. CONCLUSION: Propylene glycol accumulated significantly in pediatric intensive care patients receiving continuous lorazepam infusion, and propylene glycol concentration correlated with the cumulative lorazepam dose the patient received. However, significant laboratory abnormalities due to propylene glycol accumulation were not observed.     

Failure of lorazepam to treat alprazolam withdrawal in a critically ill patient

Management of sedation in the critical care unit is an ongoing challenge. Benzodiazepines have been commonly used as sedatives in critically ill patients. The pharmacokinetic and pharmacodynamic properties that make benzodiazepines effective and safe in critical care sedation include rapid onset of action and decreased respiratory depression. Alprazolam is a commonly used benzodiazepine that is prescribed for anxiety and panic disorders. It is frequently prescribed in the outpatient setting. Its use has been reported to result in a relatively high rate of dependence and subsequent withdrawal symptoms. Symptoms of alprazolam withdrawal can be difficult to recognize and treat in the critical care setting. In addition, other benzodiazepines may also be ineffective in treating alprazolam withdrawal. We present a case of alprazolam withdrawal in a critically ill trauma patient who failed treatment with lorazepam and haloperidol. Subsequent replacement with alprazolam resulted in significant improvement in the patient’s medication use and clinical status.     

Albumin bolus administration versus continuous infusion in critically ill hypoalbuminemic pediatric patients

Objective To test the hypothesis that the rate of degradation of exogenously administered albumin is fater with bolus administration that with continuous infusion and thus that a bolus administration is less efficacious in restoring blood albumin concentration (BAC) in the hypoalbuminemic critically ill pediatric patient.Design A prospective, controlled study of two groups of patients.Setting Pediatric intensive care unit (PICU) of a children's hospital.Patients 37 cirtically ill hypoalbuminemic patients. (BAC2.8 g/dl), in whom no overt protein-losing disease was identified, were divided into two treatment groups and included in a 60-h study.Interventions 18 patients were given an i.v. bolus of 1 g/kg of 25% albumin over 4 h. This treatment was repeated after 24 and 48 h. Nineteen other patients were given the same dose of 1 g/kg of 25% albumin as a continuous 24-h infusion throughout the 60-h study period. BAC along with sodium, potassium, and total and ionized calcium were measured in the serum of blood samples obtained at predetermined intervals.Measurement and main results A 4 h bolus of albumin resulted in an acute rise in BAC, which declined to baseline within 24 h. A continuous infusion resulted in a steady rise in BAC with 24-h levels significantly higher than baseline. The percent change in mean BAC from baseline, calculated at 12-h intervals during the 60-h study period, showed a steady increase in the continuous infusion group with a 34% increase after the first 24 h. In contrast, the 4-h bolus method resulted in major fluctuations in the BAC values with only a 14% increase (p<0.05) after 24 h. Albumin's volume of distribution, half-life and elimination constant, calculated based on blood albumin values during the first 24 h after the bolus administration, were 0.12±0.03 1/kg, 4.6±1.8 h and 0.17±0.06 h^–1, respectively. This half-life did not apply to the continuous infusion group as a steady state was not achieved after 30 h (6 half-lives), and BAC continued to rise throughout the 60-h study period. No significant changes in blood electrolytes were observed with either method.Conclusions The half-life of exogenous albumin in the critically ill hypoalbuminemic pediatric patient is short if given as a bolus. Continuous infusion therapy appears to be more efficacious in increasing BAC over time, as the half-life with this method appears to be longer.An abstract of this paper was presented at the SCCM meeting in Orlando, Florida in February 1994.     

Paralysis in the critically ill: intermittent bolus pancuronium compared with continuous infusion

OBJECTIVES: To compare recovery times from neuromuscular blockade between two groups of critically ill patients in whom pancuronium was administered by continuous infusion or intermittent bolus injection. To compare the mean pancuronium requirements (milligrams per kilogram per hour) and to assess the incidence of prolonged recovery times (>12 hrs) and residual muscle weakness. DESIGN: Prospective, observational cohort. SETTING: Intensive care unit in a university-affiliated hospital. PATIENTS: A total of 30 mechanically ventilated patients who required pharmacologic paralysis. Patients were excluded if they had renal failure (creatinine clearance <30 mL/min), heart rate >130 beats/min, hepatic failure, peripheral nerve disease or myopathy, stroke, spinal cord damage, or myasthenia gravis. INTERVENTIONS: Patients were assigned to receive pancuronium either by continuous infusion (n = 14) or intermittent bolus (n = 16). Depth of paralysis was titrated to maintain one or two responses to Train-of-Four stimulation with an accelerograph and desired clinical goals. Recovery time was defined as time from discontinuation of muscle relaxant until the amplitude of the fourth twitch, measured every 15-30 min using an accelerograph, was 70% the amplitude of the first twitch (Train-of-Four > or = 0.7). MEASUREMENTS AND MAIN RESULTS: These patients included the only three patients with status asthmaticus in our study. The groups were similar with respect to age, sex, weight, Acute Physiology and Chronic Health Evaluation II score, mode of ventilation, creatinine clearance, indications for paralysis, and duration of pancuronium administration. The median time for patients to recover from paralysis was 3.5 hrs (95% confidence interval, 1.82-5.18) in the infusion group vs. 6.3 hrs (95% confidence interval, 3.40-9.19) in the intermittent bolus group (p = .10). Less drug was administered in the intermittent group (mean, 0.02+/-0.01 mg/kg/hr) than by infusion (mean, 0.04+/-0.01 mg/kg/hr; p < .001). Six patients (five in the infusion group and one in the intermittent group) developed persistent severe muscle weakness. In addition, six different patients (three from each group) had prolonged recovery >12 hrs. CONCLUSIONS: Our study suggests that recovery time after paralysis with continuous infusion is faster than that after intermittent bolus injection. Although more pancuronium was administered in the continuous-infusion group, recovery time was not prolonged as a consequence. It is uncertain whether pancuronium given by infusion increases the risk of persistent muscle weakness.     

Transport of critically ill adults

Interhospital transport can be hazardous because of rapid changes in a patient's physiologic status and the use of monitoring systems. A retrospective study evaluated the first 204 critically ill adult patients transported from community hospitals to Stanford Medical Center by a special transport team. To relate the risk of transport to severity of illness, a retrospective scoring system was devised. Sixty-one percent (n = 125) of the patients were at high risk for transport. The patients were stabilized at the referring hospital, and invasive monitoring was used as mandated by the patient's condition. The average transport distance was 133 km, and the average duration of transport was 4.38 h. One hundred and five patients (51.5%) were transported by air, and the remaining patients were transported by surface ambulance. All patients survived the transport, and 71.6% were eventually discharged from the hospital. Hospital mortality correlated with the risk-scoring system (p less than .01) and increased five-fold as severity of illness increased. This study demonstrates that, with appropriate hemodynamic stabilization and monitoring, severely ill patients can be transported safely.     

Propofol infusion syndrome in critically ill patients

OBJECTIVE: To describe the clinical presentation of propofol infusion syndrome in critically ill adults. DATA SOURCES: Clinical literature was accessed through MEDLINE (1966 - March 2001). Key search terms included Diprivan, propofol, and propofol infusion syndrome. Case reports and small case series evaluating the use and toxicity of propofol in sedating critically ill adults were reviewed. DATA SYNTHESIS: The association between propofol infusion syndrome and death in children secondary to myocardial failure is well documented. However, few data are available regarding the syndrome in critically ill adults. Based on a review of those data, it appears that propofol infusion syndrome can occur in both children and adults. Common clinical features of propofol infusion syndrome may include hyperkalemia, hepatomegaly, lipemia, metabolic acidosis, myocardial failure, and rhabdomyolysis. Although the premise has not been proven, recent published cases appear to demonstrate an association between propofol infusion and death secondary to myocardial failure. CONCLUSIONS: Until further safety data become available, caution should be exercised when using high-dose (>5 mg/kg/h) and long-term (>48 h) propofol infusion in sedating critically ill adults.     

Physical antipyresis in critically ill adults

Nurses use a variety of methods to cool critically ill patients, even though there are no guidelines for the treatment of temperature elevation in this population. In order to determine whether physical methods of antipyresis, such as the application of cooling blankets, are appropriate for use in the ICU, and if so which methods are best, the authors conducted a literature review. Their findings raise concerns about whether external cooling methods should be used at all in the absence of hyperthermia or cerebral damage. In addition, the authors give an overview of the causes and effects of temperature elevation, focusing mostly on fever.A literature review examines external cooling methods for use in the ICU. The findings raise some doubts.     

Benzodiazepine-associated delirium in critically ill adults

Purpose

The association between benzodiazepine use and delirium risk in the ICU remains unclear. Prior investigations have failed to account for disease severity prior to delirium onset, competing events that may preclude delirium detection, other important delirium risk factors, and an adequate number of patients receiving continuous midazolam. The aim of this study was to address these limitations and evaluate the association between benzodiazepine exposure and ICU delirium occurrence.

Methods

In a cohort of consecutive critically ill adults, daily mental status was classified as either awake without delirium, delirium, or coma. In a first-order Markov model, multinomial logistic regression analysis was used, which considered five possible outcomes the next day (i.e., awake without delirium, delirium, coma, ICU discharge, and death) and 16 delirium-related covariables, to quantify the association between benzodiazepine use and delirium occurrence the following day.

Results

Among 1112 patients, 9867 daily transitions occurred. Benzodiazepine administration in an awake patient without delirium was associated with increased risk of delirium the next day [OR 1.04 (per 5 mg of midazolam equivalent administered) 95 % CI 1.02–1.05). When the method of benzodiazepine administration was incorporated in the model, the odds of transitioning to delirium was higher with benzodiazepines given continuously (OR 1.04, 95 % CI 1.03–1.06) compared to benzodiazepines given intermittently (OR 0.97, 95 % CI 0.88–1.05).

Conclusions

After addressing potential methodological limitations of prior studies, we confirm that benzodiazepine administration increases the risk for delirium in critically ill adults but this association seems to be limited to continuous infusion use only.

     

危重症患者血清胰岛素、C肽及血浆皮质醇与血镁关系的临床研究

对ＩＣＵ８０例患者血清镁与血清胰岛素、Ｃ肽和血浆皮质醇之间关系进行研究。发现血镁与胰岛素呈正相关（ｒ＝０．４０７，Ｐ＜０．０１）；而与血清Ｃ肽和血浆皮质醇无关。低血镁组血清胰岛素浓度低于正常血镁组（Ｐ＜０．０１）；两组间血Ｃ肽及皮质醇浓度无显著差异。高血糖组患者血胰岛素浓度较正常血糖组低（Ｐ＜０．０５）。作者认为：危重症患者血镁浓度受血清胰岛素影响较大，胰岛素与Ｃ肽均为胰岛素原的分解产物，而本结果血镁仅与血清胰岛素有关，故危重症患者体内可能存在胰岛素抗体或胰岛素拮抗物，干扰血清胰岛素测定，也影响了胰岛素的正常生物活性，而这些胰岛素抗体或拮抗物并不影响Ｃ肽的测定     

Plasma and lung concentrations of ceftazidime administered in continuous infusion to critically ill patients with severe nosocomial pneumonia

Objective To determine the steady-state plasma and epithelial lining fluid (ELF) concentrations of ceftazidime administered in continuous infusion to critically ill patients with severe nosocomial pneumonia.Design Prospective, open-label study.Setting An intensive care unit and research ward in a university hospital.Patients A total of 15 adult patients with severe nosocomial bacterial pneumonia on mechanical ventilation were enrolled.Interventions All subjects received a 30 min intravenous infusion of 2 g ceftazidime followed by a continuous infusion of 4 g over 24 h. The concentrations of ceftazidime in plasma and ELF were determined at steady-state after 2 days of therapy by high performance liquid chromatography.Measurements and main results The mean ±SD steady-state plasma and ELF concentrations of 4 g ceftazidime in continuous infusion were 39.6±15.2 µg/mL and 8.2±4.8 µg/mL, respectively, showing a mean ±SD percentage penetration of ceftazidime into ELF of 20.6±8.9%.Conclusion The administration of 4 g ceftazidime in continuous infusion in critically ill patients with severe nosocomial pneumonia provides concentrations in excess of the minimal inhibitory concentration of many susceptible organisms over the course of therapy both in serum and ELF. However, for some pathogens such as P. aeruginosa, higher doses of ceftazidime should be administered, or another agent should be used in combination.     

Removal of propylene glycol and correction of increased osmolar gap by hemodialysis in a patient on high dose lorazepam infusion therapy

We report a case of successful treatment of propylene glycol toxicity by discontinuation of propylene glycol administration and hemodialysis therapy. A critically ill woman receiving high dose intravenous lorazepam therapy is described. Although propylene glycol toxicity often resolves promptly after discontinuation of the causative parenteral source, renal or liver dysfunction may prolong the sequelae of propylene glycol infusion. Hemodialysis efficiently lowers propylene glycol serum concentrations in a manner analogous to extracorporeal therapy for other small molecular weight alcohol intoxications. Therefore, hemodialysis may be a useful component of therapy for critically ill patients exhibiting propylene glycol toxicity in the context of multiple organ dysfunction.     

Incidence of propofol-related infusion syndrome in critically ill adults: a prospective, multicenter study

Introduction

While propofol is associated with an infusion syndrome (PRIS) that may cause death, the incidence of PRIS is unknown. Determining the incidence of PRIS and the frequency of PRIS-related clinical manifestations are key steps prior to the completion of any controlled studies investigating PRIS. This prospective, multicenter study sought to determine the incidence of PRIS and PRIS-related clinical manifestations in a large cohort of critically ill adults prescribed propofol.

Methods

Critically ill adults from 11 academic medical centers administered an infusion of propofol for [>/=] 24 hours were monitored at baseline and then on a daily basis until propofol was discontinued for the presence of 11 different PRIS-associated clinical manifestations and risk factors derived from 83 published case reports of PRIS.

Results

Among 1017 patients [medical (35%), neurosurgical (25%)], PRIS (defined as metabolic acidosis plus cardiac dysfunction and [>/=] 1 of: rhabdomyolysis, hypertriglyceridemia or renal failure occurring after the start of propofol therapy) developed in 11 (1.1%) patients an average of 3 (1-6) [median (range)] days after the start of propofol. While most (91%) of the patients who developed PRIS were receiving a vasopressor (80% initiated after the start of propofol therapy), few received a propofol dose >83 mcg/kg/min (18%) or died (18%). Compared to the 1006 patients who did not develop PRIS, the APACHE II score (25 +/- 6 vs 20 +/- 7, P = 0.01) was greater in patients with PRIS but both the duration of propofol use (P = 0.43) and ICU length of stay (P = 0.82) were similar.

Conclusions

Despite using a conservative definition for PRIS, and only considering new-onset PRIS clinical manifestations, the incidence of PRIS slightly exceeds 1%. Future controlled studies focusing on evaluating whether propofol manifests the derangements of critical illness more frequently than other sedatives will need to be large. These studies should also investigate the mechanism(s) and risk factors for PRIS.