Michael O'Connor

Urinary cystatin C as an early biomarker of acute kidney injury following adult cardiothoracic surgery

There is a need to develop early biomarkers of acute kidney injury following cardiac surgery, where morbidity and mortality are increased by its presence. Plasma cystatin C (CyC) and plasma and urine Neutrophil Gelatinase Associated Lipocalin (NGAL) have been shown to detect kidney injury earlier than changes in plasma creatinine in critically ill patients. In order to determine the utility of urinary CyC levels as a measure of kidney injury, we prospectively collected plasma and urine from 72 adults undergoing elective cardiac surgery for analysis. Acute kidney injury was defined as a 25% or greater increase in plasma creatinine or renal replacement therapy within the first 72 hours following surgery. Plasma CyC and NGAL were not useful predictors of acute kidney injury within the first 6 hours following surgery. In contrast, both urinary CyC and NGAL were elevated in the 34 patients who later developed acute kidney injury, compared to those with no injury. The urinary NGAL at the time of ICU arrival and the urinary CyC level 6 hours after ICU admission were most useful for predicting acute kidney injury. A composite time point consisting of the maximum urinary CyC achieved in the first 6 hours following surgery outperformed all individual time points. Our study suggests that urinary CyC and NGAL are superior to conventional and novel plasma markers in the early diagnosis of acute kidney injury following adult cardiac surgery.

Methylnaltrexone prevents morphine-induced delay in oral-cecal transit time without affecting analgesia: a double-blind randomized placebo-controlled trial.

Methylnaltrexone is a quaternary opioid antagonist with limited ability to cross the blood‐brain barrier and the potential to antagonize the peripherally mediated effects of opioids. The effectiveness of methylnaltrexone in preventing morphine‐induced changes in gastrointestinal motility and transit without affecting analgesia was evaluated in humans. Twelve healthy volunteers were given intravenous placebo, placebo plus 0.05 mg/kg morphine, or 0.45 mg/kg methylnaltrexone plus 0.05 mg/kg morphine. Oral‐cecal transit time was assessed by the pulmonary hydrogen measurement technique, and analgesia was measured with use of the cold‐pressor test. Morphine significantly increased oral‐cecal transit time from 104.6 ± 31.1 minutes (mean ± SD) to 163.3 ± 39.8 minutes (p < 0.01). Methylnaltrexone prevented 97% of morphine‐induced increase in oral‐cecal transit time (106.3 ± 39.8 minutes; not significant compared with baseline; p < 0.01 compared with morphine alone). Methylnaltrexone did not affect the analgesic effect of morphine on both pain intensity and pain bothersomeness ratings. At a higher dose of morphine (0.1 mg/kg), our preliminary results indicated that 0.45 mg/kg methylnaltrexone also prevented the morphine‐induced delay in oral‐cecal transit time, with no effect on analgesia. Methylnaltrexone may be a useful adjunct to opioids for the relief of opioid‐induced constipation.

Effects of intravenous methylnaltrexone on opioid-induced gut motility and transit time changes in subjects receiving chronic methadone therapy: a pilot study.

In this preliminary study, we evaluated the effects of methylnaltrexone, a peripheral opioid-receptor antagonist, on chronic opioid-induced gut motility and transit changes in four subjects with chronic methadone-induced constipation. Subjects participated in this single blind, placebo controlled study for up to 8 days. We gave placebo the first day; for the remainder of the study, we gave intravenous methylnaltrexone (0.05-0.45 mg/kg) twice daily. During the study period, we recorded oral-cecal transit time and opioid withdrawal symptoms, as well as laxation response based on the frequency and consistency of the stools. Subjects 1 and 2 who were administered methylnaltrexone 0.45 mg/kg, a dose previously administered in normal volunteers, showed immediate positive laxation. Subject 2, after positive laxation response, had severe abdominal cramping, but showed no opioid systemic signs of withdrawal. The subject was discontinued due to the cramping. In Subjects 3 and 4, we reduced the methylnaltrexone dose to 0.05-0.15 mg/kg. The latter two subjects also had an immediate laxation response during and after intravenous medication without significant side effects. The stool frequency of these four subjects increased from 1-2 times per week before the study to approximately 1.5 stool per day during the treatment period. Oral-cecal transit times of Subjects 1, 3, and 4 were reduced from 150, 150 and 150 min (after placebo) to 90, 60 and 60 min (with methylnaltrexone), respectively. Our preliminary results demonstrate that low dose intravenous methylnaltrexone effectively reversed chronic methadone-induced constipation and delay in gut transit time. Thus, we anticipate that cancer patients receiving chronic opioids may also have increased sensitivity to methylnaltrexone, and that low dose methylnaltrexone may have clinical utility in managing opioid-induced constipation in chronic-pain patients.

Tolerability, Gut Effects, and Pharmacokinetics of Methylnaltrexone Following Repeated Intravenous Administration in Humans

Previous studies have shown that a single dose of methylnaltrexone, a unique peripheral opioid antagonist, reverses opioid‐induced gut hypomotility in humans. Because repeated drug doses are likely to be needed to treat patients with opioid‐induced or postsurgical bowel dysfunction, the authors have now examined the safety, pharmacological activity, and pharmacokinetics of a multiple‐dose regimen of methylnaltrexone, administered as 12 consecutive intravenous doses (0.3 mg/kg every 6 hours) in 12 healthy subjects. Steady state was achieved rapidly, and after repeated dosing for 3 days, methylnaltrexone decreased oral‐cecal transit time from a pretreatment baseline value of 101.3 ± 29.4 min (mean ± SD) to 82.5 ± 20.7 min. Maximum observed plasma concentrations, measured 5 minutes postdose, were 538 ± 237 and 675 ± 180 ng/mL after doses 1 and 2, respectively. Based on 6‐hour sampling periods, the plasma half‐life, 2.5 ± 0.5 and 2.9 ± 0.9 hours following the 1st and 12th doses, respectively, was unchanged at steady state. There was essentially no accumulation of methylnaltrexone, based on the ratio of AUC values after doses 12 and 1. This study showed that repeated administration of intravenous methylnaltrexone is well tolerated in humans, with no significant adverse events or changes in opioid subjective ratings and no clinically noteworthy alterations in pharmacokinetics. The observation of a significant reduction in the gut transit time after repeated administration of methylnaltrexone to these opioid‐naive volunteers suggests that endogenous opioids modulate human gut motility.

Effects of enteric‐coated methylnaltrexone in preventing opioid‐induced delay in oral‐cecal transit time

Methylnaltrexone is the first peripheral opioid receptor antagonist. It has the potential to prevent or reverse the peripherally mediated gastrointestinal effects of opioids. In previous human volunteer trials, we demonstrated that oral uncoated methylnaltrexone prevented morphine‐induced delay in gastrointestinal transit time.

Effects of Low‐Dose Morphine on Gastric Emptying in Healthy Volunteers

Appropriate preoperative pain therapy for patients undergoing surgery may be withheld due to the fear that opioids will inhibit gastric emptying and increase the risk of aspiration. Previously, doses of 5 to 10 mg of morphine have been shown to delay gastric emptying time. However, the effect of lower doses of morphine on gastric emptying in humans has not been reported. In this study, the effects of intravenous morphine 0.05 mg/kg—3.5 mg for 70‐kg body weight, a dose that can cause analgesia—on gastric emptying were evaluated in a double‐blind, randomized, placebo‐controlled study in 15 healthy human volunteers using the acetaminophen test. Our data indicated that this low dose of morphine significantly prolonged the gastric emptying time. Thus, even small doses of morphine inhibit gastric emptying. This effect may be important in patients undergoing surgery, in patients receiving other oral medications after surgery in ambulatory settings, and in instances of patient‐controlled analgesia.

Propofol in an Emulsion of Long- and Medium-chain Triglycerides: The Effect on Pain

IMPLICATIONS In a test of two formulations of propofol for induction, patients experienced less pain with the formulation in Intralipid (Propofol-Lipuro 1%) than with Diprivan 1%.

Safety and Tolerance of Methylnaltrexone in Healthy Humans: A Randomized, Placebo‐Controlled, Intravenous, Ascending‐Dose, Pharmacokinetic Study

N‐methylnaltrexone bromide (methylnaltrexone) is a quaternary opioid antagonist with a limited ability to cross the blood—brain barrier. In animal models it reverses at peripheral receptors such side effects of opioids as decreased gastrointestinal motility, emesis, and cough suppression without affecting the desired analgesic effect mediated by central nervous system receptors. Methylnaltrexone thus may be a clinically useful compound for the prevention and treatment of opioid‐induced side effects. This study was designed to examine the safety and tolerance of methylnaltrexone in healthy human participants over a range of doses and to identify any adverse effects or toxicity associated with methylnaltrexone and the doses at which these adverse effects occur. Healthy male volunteers received intravenous methylnaltrexone in six ascending doses with a placebo randomly inserted into the sequence. Each participant was observed for subjective and hemodynamic changes. Electrocardiogram and laboratory studies were also performed. The dose‐limiting adverse effect of methylnaltrexone was orthostatic hypotension at 0.64 mg/kg (n = 3) or 1.25 mg/kg (n = 5), which was transient and self‐limiting. Plasma levels of methylnaltrexone in excess of 1,400 ng/mL were observed to be associated with orthostatic hypotension. There were no significant subjective changes, no release of histamine, and no changes in physical examination or laboratory studies during the course of the study. Pharmacokinetic analysis revealed an elimination half‐life of 117.5 minutes (±53.2), and a clearance of 38.8 L/hr (±17.4) with a methylnaltrexone dose of 0.64 mg/kg. Our results indicate that methylnaltrexone is well tolerated at doses of 0.32 mg/kg in healthy humans.

The Accreditation Council for Graduate Medical Education resident duty hour new standards: history, changes, and impact on staffing of intensive care units.

Objectives:The Accreditation Council for Graduate Medical Education recently released new standards for supervision and duty hours for residency programs. These new standards, which will affect over 100,000 residents, take effect in July 2011. In response to these new guidelines, the Society of Critical Care Medicine convened a task force to develop a white paper on the impact of changes in resident duty hours on the critical care workforce and staffing of intensive care units. Participants:A multidisciplinary group of professionals with expertise in critical care education and clinical practice. Data Sources and Synthesis:Relevant medical literature was accessed through a systematic MEDLINE search and by requesting references from all task force members. Material published by the Accreditation Council for Graduate Medical Education and other specialty organizations was also reviewed. Collaboratively and iteratively, the task force corresponded by electronic mail and held several conference calls to finalize this report. Main Results:The new rules mandate that all first-year residents work no more than 16 hrs continuously, preserving the 80-hr limit on the resident workweek and 10-hr period between duty periods. More senior trainees may work a maximum of 24 hrs continuously, with an additional 4 hrs permitted for handoffs. Strategic napping is strongly suggested for trainees working longer shifts. Conclusions:Compliance with the new Accreditation Council for Graduate Medical Education duty-hour standards will compel workflow restructuring in intensive care units, which depend on residents to provide a substantial portion of care. Potential solutions include expanded utilization of nurse practitioners and physician assistants, telemedicine, offering critical care training positions to emergency medicine residents, and partnerships with hospitalists. Additional research will be necessary to evaluate the impact of the new standards on patient safety, continuity of care, resident learning, and staffing in the intensive care unit.

Cardiopulmonary bypass produces greater pulmonary than systemic proinflammatory cytokines.

Cardiopulmonary bypass (CPB) impairs pulmonary endothelial injury in part by increasing expression of adhesion molecules that results in neutrophil influx. Although numerous proinflammatory cytokines up-regulate these responses, the extent to which systemic and pulmonary proinflammatory cytokines increase remains unknown. We therefore examined systemic and pulmonary gene expression and production of proinflammatory cytokines during CPB. Bronchoalveolar lavage and peripheral blood sampling were performed just after the induction of anesthesia and at the end of surgery in 80 patients undergoing CPB. RNA was extracted from harvested cells and cDNA was synthesized by reverse transcription. The expression of interleukin (IL)-6, IL-8, and tumor necrosis factor-&agr; (TNF-&agr;) was measured by semiquantitative polymerase chain reaction using &bgr;-actin as an internal standard. We also measured these cytokines in cultured alveolar macrophages and plasma monocytes in standard medium alone, or in the presence of lipopolysaccharide. We found 2- to 20-fold increases in gene expression for these cytokines in both plasma and alveolar leukocytes at the end of surgery. However, the increases were 4–8 times greater in alveolar than plasma leukocytes. Alveolar macrophages obtained at the end of surgery produced 1.5–3 times more IL-6, IL-8, and TNF-&agr; than those obtained at the beginning (P < 0.0001). Although plasma monocytes produced more IL-8 at the end of surgery (P < 0.001), TNF-&agr; and IL-6 did not increase. The production of all cytokines was 1.5–3 times greater in alveolar macrophages obtained at the end of surgery than in plasma monocytes obtained simultaneously (P < 0.005). Our data thus suggest that CPB provokes a greater pulmonary than systemic inflammatory response. Implications Both gene expression and production of proinflammatory cytokines were greater in alveolar than plasma leukocytes after cardiopulmonary bypass. These results suggest that cardiopulmonary bypass provokes more serious pulmonary than systemic inflammatory responses.