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.

Seasonal changes in testicular size and serum LH, prolactin and testosterone concentrations in male polar bears (Ursus maritimus).

Little is known about the reproductive endocrinology of the male polar bear, Ursus maritimus, except that serum testosterone concentrations are high in April and May during the mating season and are low from August to November during the non-mating season. The objective of this study was to describe the relationship between seasonal changes in testicular size and serum concentrations of testosterone, LH and prolactin. Blood samples and testicular measurements were obtained from free-ranging male polar bears in Canada in April (n = 5) and May (n = 15) near Resolute Bay, Northwest Territories and near Churchill, Manitoba in July (n = 15) and October (n = 22). Testis size was greater in May (39.4 +/- 3.5 cm(2)) than in October (27.3 +/- 2.0 cm(2)) (P = 0.002). Serum testosterone concentrations were approximately three-fold higher in April (5.8 +/- 0.8 ng ml(-1)) than in May (1.7 +/- 0.5 ng ml(-1)), July (0.6 +/- 0.2 ng ml(-1)) and October (1.1 +/- 0.2 ng ml(-1)). Similarly, serum LH concentrations were high in April (0.14 +/- 0.04 ng ml(-1)) and low in May (0.09 +/- 0.01 ng ml(-1)), July (0.10 +/- 0.02 ng ml(-1)) and October (0.08 +/- 0.00 ng ml(-1)). Serum prolactin concentrations were high in April (1.9 +/- 0.3 ng ml(-1)), highest in May (2.5 +/- 0.2 ng ml(-1)), lower in July (1.3 +/- 0.1 ng ml(-1)) and lowest in October (0.8 +/- 0.07 ng ml(-1)). The present study demonstrates a positive relationship between testicular size and serum concentrations of LH, prolactin and testosterone in the male polar bear and confirms the previously reported seasonal changes in serum testosterone concentrations. Data from the present study provide important baseline and comparative endocrine information that can be used to aid captive breeding programmes in zoos and to further ecological-behavioural studies of polar bears.

Body burdens and tissue concentrations of organochlorines in polar bears (Ursus maritimus) vary during seasonal fasts.

Lipophilic organochlorines (OCs) are ingested by mammals through their foods and are generally stored in adipose tissue depots. For some species, such as polar bears, the size of these depots can fluctuate seasonally by several-fold. However, the effect of these fluctuations on the fate of stored OCs in an animal with such labile lipid depots is unknown. We determined the whole body burden and tissue concentrations of OCs in free-ranging polar bears categorized by age (cubs-of-the-year, yearlings and adults) and sex before and after a fast averaging 56 days. Adipose tissue, plasma, and milk samples were analysed for sum of chlorobenzenes (sigma-ClBzs), hexachlorocyclohexanes (sigma-HCHs), chlordanes (sigma-CHLORs), dichlorodiphenyltrichloroethane compounds (sigma-DDTs) and polychlorinated biphenyls (sigma-PCBs). Decline in body mass during fasting ranged from 0.2 kg/day for cubs-of-the-year to 0.9 kg/day for sub-adult and adult males. Although all bears showed a decline in both lipid and lean mass during fasting, patterns of OC whole body burden changes were not consistent among compounds and bear classes. The burdens of sigma-DDTs declined by 11-50% for most bears during fasting, those of sigma-CHLORs declined by 67% during fasting in sub-adult and adult males but remained constant for all females, indicating male-specific metabolism of sigma-CHLORs. As fat depots became depleted, OC concentrations in the remaining adipose tissue varied; sigma-DDTs and sigma-HCHs declined while those of sigma-CHLORs and sigma-PCBs generally increased. Thus. within a 3-4 month fast, most polar bears were able to significantly rid their adipose tissue of sigma-DDTs and sigma-HCHs. Burdens of sigma-CHLORs (except males), sigma-ClBzs and sigma-PCBs remained constant for all classes of bears, therefore there was no significant excretion or metabolism during the fast of the specific congeners in these compound classes typically found in polar bears. The ratio of plasma/adipose tissue and milk/adipose tissue OC concentrations was the same for before and after the fast indicating that OC concentrations in polar bears are probably at a steady state among various body compartments. Concentrations of sigma-CHLORs and sigma-PCBs in milk almost doubled during the fast. As a consequence of this rise in milk OC concentrations, the whole body concentrations of these compounds increased in nursing cubs. Since developing young may be susceptible to the effects of environmental contaminants, the increased exposure of nursing cubs to OCs during a fast by their mothers is noteworthy.

Readmission to the intensive care unit after liver transplantation.

OBJECTIVE: We undertook this study to understand the factors at our transplant center that contribute to patients' return to the ICU after their liver transplant and their initial discharge from that unit. Patients who, after liver transplantation, fail discharge from the Intensive Care Unit (ICU) and must be readmitted to that unit may well utilize many more resources than those patients who are well enough to stay out of the ICU. DESIGN: A retrospective review of a prospectively maintained liver transplant research database followed by a retrospective review of (a subgroup) patient charts and contemporaneous controls. SETTING: A large metropolitan tertiary care center and adult liver transplant center. PATIENTS: A total of 1,197 consecutive adult patients who underwent their initial liver transplantation from 1984 to 1996. INTERVENTION: Readmission to the intensive care unit after adult liver transplantation and discharge from that unit. MAIN RESULTS: Only recipient age, pretransplant synthetic function labs (protime and albumin), bilirubin levels, and intraoperative blood product requirements could be statistically linked to the group requiring ICU readmission. The primary etiology for ICU readmission was cardiopulmonary deterioration. Readmission was associated with significantly lower patient and graft survivals. A detailed review of 23 patients transplanted from October 1994 to June 1996 was made, with special emphasis on cardiopulmonary status (hemodynamics, respiratory variables, and chest radiograph findings). This subgroup was compared with 30 temporally matched controls who were not readmitted to the ICU. Intravascular fluid overload and lower inspiratory capacity were significant factors related to ICU readmission. Readmitted patients had a longer hospitalization with higher hospital charges than the control group. CONCLUSIONS: We conclude that the most important means of preventing ICU readmission in liver transplantation patients is to optimize cardiopulmonary function and status. Close monitoring of fluid balance to avoid hypervolemia is essential. Readmitted patients have a greater resource utilization and have lower survival rates.

Pharmacokinetics and tissue residues of Telazol in free-ranging polar bears.

A pharmacokinetic and tissue residue study was conducted to assess the risks associated with human consumption of polar bears in arctic Canada that have been exposed to the immobilizing drug Telazol, a mixture of tiletamine hydrochloride and zolazepam hydrochloride. Twenty-two bears were remotely injected with about 10 mg/kg of Telazol. Following immobilization, serum samples were collected serially at regular intervals until the bears awakened. Sixteen of the bears were relocated and killed under permit by local hunters at various times from 0.5 to 11 days after dosing. Serum, kidney, muscle and adipose tissue samples were collected immediately after death. All samples were stored at -70 C until analysis by HPLC. The concentration-time data of tiletamine and zolazepam in serum during the immobilization period were fitted to curves by computer and the pharmacokinetic parameters assessed. In addition, the serum and tissue samples collected at the time of death were analyzed for both parent drugs, for one metabolite of tiletamine (CI-398), and for three metabolites of zolazepam (metabolites 1, 2 and 4). A one-compartment model with first-order absorption and elimination best fit the time-series data for the drugs in serum during the immobilization period. This model gave half-lives (mean +/- SE) for tiletamine and zolazepam of 1.8+/-0.2 h and 1.2+/-0.08 h, respectively, clearance values of 2.1+/-0.3 l x h(-1) x kg(-1) and 1.1+/-0.1 l x h(-1) x kg(-1), and volumes of distribution of 5.2+/-0.6 l/kg and 1.8+/-0.2 l/kg. The concentrations of both drugs and their metabolites declined rapidly to trace levels by 24 h post-dosing, although extremely low concentrations of some metabolites were encountered sporadically over the entire sampling period. In particular, zolazepam metabolite 2, remained detectable in fat and muscle tissue at the end of the study, 11 days after dosing. It was concluded that during immobilization, both tiletamine and zolazepam levels decline rapidly in a monoexponential fashion, and their pharmacokinetic parameters in polar bears are similar to those observed in other species. Tissue levels of the drugs and their metabolites declined sufficiently rapidly that individuals eating meat from exposed bears would be unlikely to experience pharmacological effects from the drugs. Nevertheless, slight exposure to the drugs and/or their metabolites might be possible for an indeterminate time after dosing.

Anesthesia of polar bears (Ursus maritimus) with zolazepam-tiletamine, medetomidine-ketamine, and medetomidine-zolazepam-tiletamine.

A 1:1 combination (by weight) of zolazepam and tiletamine is the drug of choice for anesthetizing polar bears (Ursus maritimus), but recovery time is prolonged when additional doses are administered. Recoveries may last 24 hr and may threaten the health of the bears. We compared the anesthetic effects of zolazepam-tiletamine (ZT) with those of medetomidine-ketamine (MK) and medetomidine-zolazepam-tiletamine (MZT) in 93 free-ranging polar bears. The MZT combination was administered in smaller dose and volume, resulted in more rapid, safer, and more predictable induction, provided more reliable anesthesia, and was safely reversed with atipamezole. Frequent occurrence of sudden recoveries during anesthesia with MK limited our use of this combination. MK and MZT sometimes caused apnea and bradycardia initially and hyperthermia at increased ambient temperatures. Hypoxemia occurred transiently with all combinations. When anesthesia with ZT and MK exceeded 1 hr, frequent necessary top-up doses caused irregular physiologic function. ZT is recommended for short duration anesthesia (< or = 1 hr), but MZT is better for anesthesia of longer duration and under circumstances where reversibility is desirable.

Cardiopulmonary response of anesthetized polar bears to suspension by net and sling.

Since 1995, at least three polar bears (Ursus maritimus) have died in the area of Churchill (Manitoba, Canada) as a direct result of being suspended in a net during helicopter-assisted translocations. To assess and improve methods of suspending anesthetized polar bears, we conducted a study during November 1997 to determine the cardiopulmonary responses of eight captive polar bears to suspension by net and by sling. Each bear was anesthetized on two occasions in which the sequence of activities followed and the type of data collected was identical, with only the method of suspension differing. Control data obtained from 11 captive polar bears during 1995-96 was included in the statistical analyses of cardiopulmonary data to help clearly differentiate the cardiopulmonary effects of suspension from those of drug metabolism. Suspending polar bears above the ground by net caused acute hypertension (e.g., 17 to 49% increase in mean arterial pressure), possibly as a result of increased venous return due to body compression. Increased arousal (e.g., head, tongue, and limb movement) also occurred consistently during net-suspension and suggested a stress response. Surprisingly, most suspended bears showed little change in blood gas values, but at least one bear became hypoxemic (i.e., PaO2 < 60 mm Hg) with each method of suspension. Because of the potential health risks of hypertension and hypoxemia, we recommend modifying the method by which polar bears are suspended with the goal of reducing body compression.