Clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit

OBJECTIVE: To revise the "Clinical Practice Guidelines for the Sustained Use of Sedatives and Analgesics in the Critically Ill Adult" published in Critical Care Medicine in 2002. METHODS: The American College of Critical Care Medicine assembled a 20-person, multidisciplinary, multi-institutional task force with expertise in guideline development, pain, agitation and sedation, delirium management, and associated outcomes in adult critically ill patients. The task force, divided into four subcommittees, collaborated over 6 yr in person, via teleconferences, and via electronic communication. Subcommittees were responsible for developing relevant clinical questions, using the Grading of Recommendations Assessment, Development and Evaluation method (http://www.gradeworkinggroup.org) to review, evaluate, and summarize the literature, and to develop clinical statements (descriptive) and recommendations (actionable). With the help of a professional librarian and Refworks database software, they developed a Web-based electronic database of over 19,000 references extracted from eight clinical search engines, related to pain and analgesia, agitation and sedation, delirium, and related clinical outcomes in adult ICU patients. The group also used psychometric analyses to evaluate and compare pain, agitation/sedation, and delirium assessment tools. All task force members were allowed to review the literature supporting each statement and recommendation and provided feedback to the subcommittees. Group consensus was achieved for all statements and recommendations using the nominal group technique and the modified Delphi method, with anonymous voting by all task force members using E-Survey (http://www.esurvey.com). All voting was completed in December 2010. Relevant studies published after this date and prior to publication of these guidelines were referenced in the text. The quality of evidence for each statement and recommendation was ranked as high (A), moderate (B), or low/very low (C). The strength of recommendations was ranked as strong (1) or weak (2), and either in favor of (+) or against (-) an intervention. A strong recommendation (either for or against) indicated that the intervention's desirable effects either clearly outweighed its undesirable effects (risks, burdens, and costs) or it did not. For all strong recommendations, the phrase "We recommend …" is used throughout. A weak recommendation, either for or against an intervention, indicated that the trade-off between desirable and undesirable effects was less clear. For all weak recommendations, the phrase "We suggest …" is used throughout. In the absence of sufficient evidence, or when group consensus could not be achieved, no recommendation (0) was made. Consensus based on expert opinion was not used as a substitute for a lack of evidence. A consistent method for addressing potential conflict of interest was followed if task force members were coauthors of related research. The development of this guideline was independent of any industry funding. CONCLUSION: These guidelines provide a roadmap for developing integrated, evidence-based, and patient-centered protocols for preventing and treating pain, agitation, and delirium in critically ill patients.

Clinical measurement, statistical analysis, and risk-benefit: controversies from trials of spinal injury.

BACKGROUND: The National Acute Spinal Cord Injury Studies have been a series of trials assessing the role of pharmacologic agents in the prevention of secondary neuronal damage after acute spinal cord injury. METHODS: The trials were multicenter randomized, controlled studies. RESULTS: Two trials have demonstrated the efficacy of high-dose methylprednisolone in improving neurologic and functional recovery and have shown a reassuring safety profile. CONCLUSION: This study responds to a recent commentary on these trials and examines in particular the roles of clinical measurement, statistical analysis, and risk benefit in assembling evidence for or against innovative therapies.

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 EDTAwhen 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.

Propofol in the treatment of moderate and severe head injury: a randomized, prospective double-blinded pilot trial.

OBJECT: Sedation regimens for head-injured patients are quite variable. The short-acting sedative-anesthetic agent propofol is being increasingly used in such patients, yet little is known regarding its safety and efficacy. In this multicenter double-blind trial, a titratable infusion of 2% propofol accompanied by low-dose morphine for analgesia was compared with a regimen of morphine sulfate in intubated head-injured patients. In both groups, other standard measures of controlling intracranial pressure (ICP) were also used. METHODS: Forty-two patients from 11 centers were evaluated to assess both the safety and efficacy of propofol: 23 patients in the propofol group (mean time of propofol usage 95+/-87 hours) and 19 patients in the morphine group (mean time of morphine usage 70+/-54 hours). There was a higher incidence of poor prognostic indicators in the propofol group than in the morphine group: patient age older than 55 years (30.4% compared with 10.5%, p < 0.05), initial Glasgow Coma Scale scores of 3 to 5 (39.1% compared with 15.8%, p < 0.05), compressed or absent cisterns on initial computerized tomography scanning (78.3% compared with 57.9%, p < 0.05), early hypotension and/or hypoxia (26.1% compared with 10.5%, p = 0.07). During treatment there was a trend toward greater use of vasopressors in the propofol group. However, the mean daily ICP and cerebral perfusion pressure were generally similar between groups and, on therapy Day 3, ICP was lower in the propofol group compared with the morphine group (p < 0.05). Additionally, there was less use of neuromuscular blocking agents, benzodiazepines, pentobarbital, and cerebrospinal fluid drainage in the propofol group (p < 0.05). At 6 months postinjury, a favorable outcome (good recovery or moderate disability) was observed in 52.1% of patients receiving propofol and in 47.4% receiving morphine; the mortality rates were 17.4% and 21.1%, respectively. Patients who received the highest doses of propofol for the longest duration tended to have the best outcomes. There were no significant differences between groups in terms of adverse events. CONCLUSIONS: Despite a higher incidence of poor prognostic indicators in the propofol group, ICP therapy was less intensive, ICP was lower on therapy Day 3, and long-term outcome was similar to that of the morphine group. These results suggest that a propofol-based sedation and an ICP control regimen is a safe, acceptable, and, possibly, desirable alternative to an opiate-based sedation regimen in intubated head-injured patients.

Methylprednisolone or tirilazad mesylate administration after acute spinal cord injury: 1-year follow up. Results of the third National Acute Spinal Cord Injury randomized controlled trial.

OBJECT: A randomized double-blind clinical trial was conducted to compare neurological and functional recovery and morbidity and mortality rates 1 year after acute spinal cord injury in patients who had received a standard 24-hour methylprednisolone regimen (24MP) with those in whom an identical MP regimen had been delivered for 48 hours (48MP) or those who had received a 48-hour tirilazad mesylate (48TM) regimen. METHODS: Patients for whom treatment was initiated within 3 hours of injury showed equal neurological and functional recovery in all three treatment groups. Patients for whom treatment was delayed more than 3 hours experienced diminished motor function recovery in the 24MP group, but those in the 48MP group showed greater 1-year motor recovery (recovery scores of 13.7 and 19, respectively, p=0.053). A greater percentage of patients improving three or more neurological grades was also observed in the 48MP group (p=0.073). In general, patients treated with 48TM recovered equally when compared with those who received 24MP treatments. A corresponding recovery in self care and sphincter control was seen but was not statistically significant. Mortality and morbidity rates at 1 year were similar in all groups. CONCLUSIONS: For patients in whom MP therapy is initiated within 3 hours of injury, 24-hour maintenance is appropriate. Patients starting therapy 3 to 8 hours after injury should be maintained on the regimen for 48 hours unless there are complicating medical factors.

Administration of methylprednisolone for 24 or 48 hours or tirilazad mesylate for 48 hours in the treatment of acute spinal cord injury. Results of the Third National Acute Spinal Cord Injury Randomized Controlled Trial. National Acute Spinal Cord Injury Study.

OBJECTIVE: To compare the efficacy of methylprednisolone administered for 24 hours with methyprednisolone administered for 48 hours or tirilazad mesylate administered for 48 hours in patients with acute spinal cord injury. DESIGN: Double-blind, randomized clinical trial. SETTING: Sixteen acute spinal cord injury centers in North America. PATIENTS: A total of 499 patients with acute spinal cord injury diagnosed in National Acute Spinal Cord Injury Study (NASCIS) centers within 8 hours of injury. INTERVENTION: All patients received an intravenous bolus of methylprednisolone (30 mg/kg) before randomization. Patients in the 24-hour regimen group (n=166) received a methylprednisolone infusion of 5.4 mg/kg per hour for 24 hours, those in the 48-hour regimen group (n=167) received a methylprednisolone infusion of 5.4 mg/kg per hour for 48 hours, and those in the tirilazad group (n=166) received a 2.5 mg/kg bolus infusion of tirilazad mesylate every 6 hours for 48 hours. MAIN OUTCOME MEASURES: Motor function change between initial presentation and at 6 weeks and 6 months after injury, and change in Functional Independence Measure (FIM) assessed at 6 weeks and 6 months. RESULTS: Compared with patients treated with methylprednisolone for 24 hours, those treated with methylprednisolone for 48 hours showed improved motor recovery at 6 weeks (P=.09) and 6 months (P=.07) after injury. The effect of the 48-hour methylprednisolone regimen was significant at 6 weeks (P=.04) and 6 months (P=.01) among patients whose therapy was initiated 3 to 8 hours after injury. Patients who received the 48-hour regimen and who started treatment at 3 to 8 hours were more likely to improve 1 full neurologic grade (P=.03) at 6 months, to show more improvement in 6-month FIM (P=.08), and to have more severe sepsis and severe pneumonia than patients in the 24-hour methylprednisolone group and the tirilazad group, but other complications and mortality (P=.97) were similar. Patients treated with tirilazad for 48 hours showed motor recovery rates equivalent to patients who received methylprednisolone for 24 hours. CONCLUSIONS: Patients with acute spinal cord injury who receive methylprednisolone within 3 hours of injury should be maintained on the treatment regimen for 24 hours. When methylprednisolone is initiated 3 to 8 hours after injury, patients should be maintained on steroid therapy for 48 hours.

Effect of interferon gamma on infection-related death in patients with severe injuries. A randomized, double-blind, placebo-controlled trial.

OBJECTIVE: To assess the efficacy of interferon gamma in reducing infection and death in patients sustaining severe injury. DESIGN: Multicenter, randomized, double-blind, placebo-controlled trial with observation for 60 days and until discharge for patients with major infection on day 60. SETTING: Nine university-affiliated level 1 trauma centers. PATIENTS: Four hundred sixteen patients with severe injuries, assessed by Injury Severity Score and degree of contamination. INTERVENTION: Recombinant human interferon gamma, 100 micrograms, was administered subcutaneously once daily for 21 days (or until patient discharge if prior to 21 days) as an adjunct to standard antibiotic and supportive therapy. MAIN OUTCOME MEASURES: Incidence of major infection, death related to infection, and death. RESULTS: Infection rates were similar in both treatment groups; however, patients treated with interferon gamma experienced fewer deaths related to infection (seven [3%] vs 18 [9%]; P = .008) and fewer overall deaths (21 [10%] vs 30 [14%]; P = .17). While 12 early deaths (days 1 through 7) occurred in each treatment group, late death occurred in 18 placebo-treated patients and nine in interferon gamma-treated patients. The results were dominated by findings at one center, which had the highest enrollment and higher infection and death rates. Statistical analysis did not eliminate the possibility of an unidentified imbalance between arms as an explanation for the results. CONCLUSION: Further evaluation is required to determine the validity of the observed reduction in infection-related deaths in patients treated with interferon gamma.

Effect of the insecticides toxaphene and carbaryl on induction of lung tumors by benzo[a]pyrene in the mouse.

The insecticides toxaphene and carbaryl, when fed in the diet alone for 20 wk, were not tumorigenic to female A/J mice. Dietary levels of these insecticides were investigated for their effects on the incidence of lung tumors induced by oral administration of benzo[a]pyrene (BP). A significant reduction in BP-induced lung tumors was found after feeding 100 ppm toxaphene for 12 wk or 200 ppm for 20 wk. In contrast, 1000 ppm carbaryl fed for 20 wk caused a significant enhancement of BP-induced lung tumors. Mice that received toxaphene in the diet alone, or toxaphene and BP, showed an increase in BP hydroxylase activity in the liver and a decrease in enzyme activity in the lung. Carbaryl and BP increased BP hydroxylase activity in the lung without altering enzyme activity in the liver. Inhibition of lung BP hydroxylase activity was paralleled by a reduction in BP-induced lung tumors in mice fed toxaphene. Conversely, increased lung BP hydroxylase activity was associated with an enhancement of BP-induced lung tumors in animals fed carbaryl. The metabolism of BP by organs susceptible to BP-induced tumors and possible mechanisms for interactions with the insecticides are discussed.

Induction of aryl hydrocarbon hydroxylase and forestomach tumors ben benzo(a)pyrene.

While papillomatous tumors developed in the forestomach of female Ha/ICR mice after a 12-week chronic feeding period of benzo(a)pyrene (BP), no tumors developed in the glandular portion of stomach or in the lung or liver. Among all tissues examined, the forestomach showed the greatest increase of aryl hydrocarbon hydroxylase (AHH) activity following acute or chronic administration of BP. Single acute doses of BP induced AHH activity in forestomach, glandular stomach, lung, and small intestine, but not in the kidney and liver of these animals. Similarly, after chronic administration of BP, AHH activity was inducible in the forestomach, glandular stomach, and lung, but again not in the liver. Although the formation of tumors is associated with greater inducibility of AHH activity in the forestomach after BP administration, the relationship between tissue inducibility of AHH activity and susceptibility to BP carcinogenesis is still not clear. Further studies regarding the formation of specific carcinogenic epoxides of BP in itssues both susceptible (e.g., forestomach) and resistant to BP carcinogenesis would more clearly define the relationship between AHH inducibility and BP carcinogenesis.