Naloxegol to Prevent Constipation in ICU Adults Receiving Opioids: A Randomized Double-Blind Placebo-Controlled Pilot Trial.

Background: Constipation is frequent in critically ill adults receiving opioids. Naloxegol (N), a peripherally acting mu-receptor antagonist (PAMORA), may reduce constipation. The objective of this trial was to evaluate the efficacy and safety of N to prevent constipation in ICU adults receiving opioids. Methods and Patients. In this single-center, double-blind, randomized trial, adults admitted to a medical ICU receiving IV opioids (≥100 mcg fentanyl/day), and not having any of 17 exclusion criteria, were randomized to N (25 mg) or placebo (P) daily randomized to receive N (25mg) or placebo (P) and docusate 100 mg twice daily until ICU discharge, 10 days, or diarrhea (≥3 spontaneous bowel movement (SBM)/24 hours) or a serious adverse event related to study medication. A 4-step laxative protocol was initiated when there was no SBM ≥3 days. Results: Only 318 (20.6%) of the 1542 screened adults during the 1/17-10/19 enrolment period met all inclusion criteria. Of these, only 19/381 (4.9%) met all eligibility criteria. After 7 consent refusals, 12 patients were randomized. The study was stopped early due to enrolment futility. The N (n = 6) and P (n = 6) groups were similar. The time to first SBM (N 41.4 ± 31.7 vs. P 32.5 ± 25.4 hours, P = 0.56) was similar. The maximal daily abdominal pressure was significantly lower in the N group (N 10 ± 4 vs. P 13 ± 5, P = 0.002). The median (IQR) daily SOFA scores were higher in N (N 7 (4, 8) vs. P 4 (3, 5), P < 0.001). Laxative protocol use was similar (N 83.3% vs. P 66.6%; P = 0.51). Diarrhea prevalence was high but similar (N 66.6% vs. P 66.6%; P = 1.0). No patient experienced opioid withdrawal. Conclusions: Important recruitment challenges exist for ICU trials evaluating the use of PAMORAs for constipation prevention. Despite being underpowered, our results suggest time to first SBM with naloxegol, if different than P, may be small. The effect of naloxegol on abdominal pressure, SOFA, and the interaction between the two requires further research.

Noninvasive Ventilatory Support for Acute Hypercapnic Respiratory Failure.

Noninvasive ventilation is well established as the ventilatory modality of first choice to treat acute or acute-on-chronic hypercapnic respiratory failure in patients with COPD by improving dyspnea and gas exchange, avoiding the need for intubation, and reducing morbidity and mortality rates. Noninvasive ventilation also offers benefit for patients with COPD and with accompanying pneumonia or with hypercapnic respiratory failure in postextubation, postoperative, and do not intubate settings. Noninvasive ventilation, in addition, offers benefit in other forms of acute hypercapnic respiratory failure, including those caused by asthma, cystic fibrosis, and obesity hypoventilation. A newer form of noninvasive ventilatory assistance, high-flow nasal cannula, has emerged in recent years as a technique to not only oxygenate effectively but also to improve ventilatory efficiency and reduce the work of breathing in patients with severe COPD. Results of recent studies indicate that high-flow nasal cannula therapy can benefit some patients with acute hypercapnic respiratory failure, either instead of or in combination with noninvasive ventilation, but more study is needed.

Polypharmacy and Delirium in Critically Ill Older Adults: Recognition and Prevention.

Among older adults, polypharmacy is a sequelae of admission to the intensive care unit and is associated with increased medication-associated adverse events, drug interactions, and health care costs. Delirium is prevalent in critically ill geriatric patients and medications remain an underappreciated modifiable risk for delirium in this setting. This article reviews the literature on polypharmacy and delirium, with a focus on highlighting the relationships between polypharmacy and delirium in critically ill, older adults. Discussed are clinician strategies on how to recognize and reduce medication-associated delirium and recommendations that help prevent polypharmacy when interventions to reduce the burden of delirium in this vulnerable population are being formulated.

A survey of critical care nurses' practices and perceptions surrounding early intravenous antibiotic initiation during septic shock.

BACKGROUND: Delays in antibiotic administration after severe sepsis recognition increases mortality. While physician and pharmacy-related barriers to early antibiotic initiation have been well evaluated, those factors that affect the speed by which critical care nurses working in either the emergency department or the intensive care unit setting initiate antibiotic therapy remains poorly characterized. AIM: To evaluate the knowledge, practices and perceptions of critical care nurses regarding antibiotic initiation in patients with newly recognised septic shock. METHODS: A validated survey was distributed to 122 critical care nurses at one 320-bed academic institution with a sepsis protocol advocating intravenous(IV) antibiotic initiation within 1hour of shock recognition. RESULTS: Among 100 (82%) critical care nurses responding, nearly all (98%) knew of the existence of the sepsis protocol. However, many critical care nurses stated they would optimise blood pressure [with either fluid (38%) or both fluid and a vasopressor (23%)] before antibiotic initiation. Communicated barriers to rapid antibiotic initiation included: excessive patient workload (74%), lack of awareness IV antibiotic(s) ordered (57%) or delivered (69%), need for administration of multiple non-antibiotic IV medications (54%) and no IV access (51%). CONCLUSIONS: Multiple nurse-related factors influence IV antibiotic(s) initiation speed and should be incorporated into sepsis quality improvement efforts.

Efficacy and safety of early dexmedetomidine during noninvasive ventilation for patients with acute respiratory failure: a randomized, double-blind, placebo-controlled pilot study.

BACKGROUND: Successful application of noninvasive ventilation (NIV) for acute respiratory failure (ARF) requires patient cooperation and comfort. The efficacy and safety of early IV dexmedetomidine when added to protocolized, as-needed IV midazolam and fentanyl remain unclear. METHODS: Adults with ARF and within 8 h of starting NIV were randomized to receive IV dexmedetomidine (0.2 µg/kg/h titrated every 30 min to 0.7 µg/kg/h to maintain a Sedation-Agitation Scale [SAS] score of 3 to 4) or placebo in a double-blind fashion up to 72 h, until NIV was stopped for ≥ 2 h, or until intubation. Patients with agitation (SAS ≥ 5) or pain (visual analog scale ≥ 5 of 10 cm) 15 min after each dexmedetomidine and placebo increase could receive IV midazolam 0.5 to 1.0 mg or IV fentanyl 25 to 50 µg, respectively, at a minimum interval of every 3 h. RESULTS: The dexmedetomidine (n = 16) and placebo (n = 17) groups were similar at baseline. Use of early dexmedetomidine did not improve NIV tolerance (score, 1 of 4; OR, 1.44; 95% CI, 0.44-4.70; P = .54) nor, vs. placebo, led to a greater median (interquartile range) percent time either tolerating NIV (99% [61%-100%] vs. 67% [40%-100%], P = .56) or remaining at the desired sedation level (SAS score = 3 or 4, 100% [86%-100%] vs. 100% [100%-100%], P = .28], or fewer intubations (P = .79). Although use of dexmedetomidine was associated with a greater duration of NIV vs placebo (37 [16-72] vs. 12 [4-22] h, P = .03), the total ventilation duration (NIV + invasive) was similar (3.3 [2-4] days vs. 3.8 [2-5] days, P = .52). More patients receiving dexmedetomidine had one or more episodes of deep sedation vs placebo (SAS ≤ 2, 25% vs. 0%, P = .04). Use of midazolam (P = .40) and episodes of either severe bradycardia (heart rate ≤ 50 beats/min, P = .18) or hypotension (systolic BP ≤ 90 mm Hg, P = .64) were similar. CONCLUSIONS: Initiating dexmedetomidine soon after NIV initiation in patients with ARF neither improves NIV tolerance nor helps to maintain sedation at a desired goal. Randomized, multicenter trials targeting patients with initial intolerance are needed to further elucidate the role for dexmedetomidine in this population.

Perceptions of nurses and physicians of their communication at night about intensive care patients' pain, agitation, and delirium.

BACKGROUND: Ineffective daytime nurse-physician communication in intensive care adversely affects patients' outcomes. Nurses' and physicians' communications and perceptions of this communication at night are unknown. OBJECTIVES: To determine perceptions of nurses and physicians of their communication with each other at night in the intensive care unit about patients' pain, agitation, and delirium and to develop a qualitative survey instrument to investigate this topic. Methods A validated survey was distributed to nighttime nurses and physicians in 2 medical intensive care units. RESULTS: Most nurses (30/45; 67%) and physicians (56/75; 75%) responded. Nurses (35%) and physicians (31%) thought that a similar proportion of communications was related to pain, agitation, and delirium. Most nurses (70%) and physicians (80%) agreed that nurses used good judgment when paging physicians at night because of patients' pain, agitation, and delirium, but physicians (72%) were more likely than nurses (48%) to think that these pages did not portray the situation accurately (P = .004). For many text pages, physicians attributed a heightened level of urgency more often than did the nurses who sent the texts. Nurses often thought that physicians did not appreciate the urgency (33%) or complexity (33%) of the situations the nurses communicated via pages. More physicians (41%) than nurses (14%) agreed that nurses exceeded medication orders for pain, agitation, and delirium before contacting a physician (P = .008). CONCLUSIONS: Perceptual differences between physicians and nurses about nurse-physician communications at night regarding pain, agitation, and delirium were numerous and should be studied further.

Development, implementation, and evaluation of an institutional daily awakening and spontaneous breathing trial protocol: a quality improvement project.

INTRODUCTION: While one controlled trial found that a daily awakening and spontaneous breathing trial (DA-SBT) decreases time on mechanical ventilation (MV), there is a paucity of real-world data surrounding the development, implementation, and impact of DA-SBT protocols. We describe a multidisciplinary process improvement effort in 2, 10-bed medical intensive care units (MICUs) at a 330-bed academic medical center that focused on the development, implementation, and evaluation of a new DA-SBT protocol. METHODS: A DA-SBT protocol, developed using results from a nursing survey literature and available institutional resources, was implemented after extensive clinician education and institution of quality reminders to boost use. Postprotocol compliance was evaluated. Use of sedation, DA and SBT practices, and clinical outcomes were retrospectively compared between the before and after DA-SBT protocol groups (ie, consecutive MICU patients requiring a continuously infused sedative [CIS] ≥24 hours). RESULTS: In the after group (n = 32), the DA and SBT compliances were 44% and 84%, respectively. Compared with the before group (n = 33), after group patients received CIS on fewer days of MV (100% vs 67%, P = .003) and had their CIS down-titrated by ≥25% on more days of CIS (40% vs 71%, P = .006). Neither total CIS dose (P = .49), total MV days (P = .75), days of MV where a SBT occurred (P = .38), nor episodes of self-extubation (15% vs 6%, P = .43) differed between the 2 groups. CONCLUSION: Despite the implementation of a DA-SBT protocol that was individualized to clinician preferences and institutional resources and accompanied by substantial education and reminders for use, compliance to the DA component of this protocol was low and duration of MV remained unchanged. Additional quality improvement strategies are needed to overcome barriers to DA-SBT protocol use that may not exist in controlled clinical trials.

Impact of enteral methadone on the ability to wean off continuously infused opioids in critically ill, mechanically ventilated adults: a case-control study.

BACKGROUND: Continuously infused opioids are frequently used to optimize patient comfort in the intensive care unit (ICU). However, concerns about rebound pain and opioid withdrawal may delay efforts to discontinue this therapy. OBJECTIVE: To measure the association between use of scheduled enteral methadone according to a protocol in mechanically ventilated, medical critically ill adults receiving prolonged continuously infused fentanyl and the time to discontinue continuously infused fentanyl therapy. METHODS: This case-control study included 20 consecutive mechanically ventilated adults in a medical ICU, without a history of chronic opioid use, who received 72 or more hours of continuously infused fentanyl and were prescribed scheduled enteral methadone as part of a protocol medical ICU strategy to wean off continuously infused fentanyl. Patients were matched in a 1:2 fashion, by duration of mechanical ventilation, to 40 consecutive preprotocol medical ICU patients meeting the same criteria but who were never given methadone. Duration of continuously infused fentanyl was compared between the 2 groups by constructing Kaplan-Meier plots and estimating the likelihood that methadone use was associated with a decrease in continuously infused fentanyl requirements over time, using a Cox proportional hazards model. RESULTS: The groups were well matched except the methadone patients were older (p = 0.04). Time (median [interquartile range]) to continuously infused fentanyl discontinuation was shorter in the methadone group (4.5 [3.9-5.8] vs 7.0 [4.9-11.5] days; p = 0.002). Continuously infused fentanyl was more likely to be discontinued 2 days after methadone was first initiated (hazard ratio 9.1; p = 0.0004). The proportion of patients who experienced 1 or more episodes of either QTc interval prolongation (p = 0.79) or unarousability (p = 0.47) was similar between the groups. CONCLUSIONS: Enterally administered methadone is associated with earlier cessation of continuously infused fentanyl in mechanically ventilated adults without a history of opioid dependence admitted to a medical ICU. Prospective, controlled studies are needed to further evaluate the safety and efficacy of methadone as a strategy to wean off continuously infused fentanyl in different ICU populations.

Impact of a national propofol shortage on duration of mechanical ventilation at an academic medical center.

OBJECTIVE: To measure the impact of a national propofol shortage on the duration of mechanical ventilation. DESIGN: Before-after study. SETTING: Three, noncardiac surgery, adult intensive care units at a 320-bed academic medical center. PATIENTS: Consecutive patients requiring mechanical ventilation ≥48 hrs, administered a continuously infused sedative ≥24 hrs, extubated, and successfully discharged from the intensive care unit were compared between before (December 1, 2008 to May 31, 2009) and after (December 1, 2009, to May 31, 2010) a propofol shortage. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: Sedation drug use and common factors affecting time on mechanical ventilation were collected and if found either to differ significantly (p ≤ .10) between the two groups or to have an unadjusted significant association (p ≤ .10) with time on mechanical ventilation were included in a multivariable model. The unadjusted analyses revealed that the median (interquartile range) duration of mechanical ventilation increased from 6.7 (9.8; n = 153) to 9.6 (9.5; n = 128) days (p = .02). Fewer after-group patients received ≥24 hrs of continuously infused propofol (94% vs. 15%, p < .0001); more received ≥24 hrs of continuously infused lorazepam (7% vs. 15%, p = .037) and midazolam (30% vs. 81%, p < .0001). Compared with the before group, the after group was younger, had a higher admission Acute Physiology and Chronic Health Evaluation II score, was more likely to be admitted by a surgical service, have acute alcohol withdrawal, and be managed with pressure-controlled ventilation as the primary mode of mechanical ventilation. Of these five factors, only the Acute Physiology and Chronic Health Evaluation II score, admission service, and use of a pressure-controlled ventilation affected duration of mechanical ventilation across both groups. Although a regression model revealed that Acute Physiology and Chronic Health Evaluation II score (p < .0001), admission by a medical service (p = .009), and use of pressure-controlled ventilation (p = .02) each affected duration of mechanical ventilation in both groups, inclusion in either the before- or after-propofol shortage groups (i.e., high vs. low use of propofol) did not affect duration of mechanical ventilation (p = .35). CONCLUSIONS: An 84% decrease in propofol use in the adult intensive care units at our academic institution as a result of a national shortage did not affect duration of mechanical ventilation.

Impact of quetiapine on resolution of individual delirium symptoms in critically ill patients with delirium: a post-hoc analysis of a double-blind, randomized, placebo-controlled study.

INTRODUCTION: We hypothesized that delirium symptoms may respond differently to antipsychotic therapy. The purpose of this paper was to retrospectively compare duration and time to first resolution of individual delirium symptoms from the database of a randomized, double-blind, placebo-controlled study comparing quetiapine (Q) or placebo (P), both with haloperidol rescue, for critically ill patients with delirium. METHODS: Data for 10 delirium symptoms from the eight-domain, intensive care delirium screening checklist (ICDSC) previously collected every 12 hours were extracted for 29 study patients. Data between the Q and P groups were compared using a cut-off P-value of ≤ 0.10 for this exploratory study. RESULTS: Baseline ICDSC scores (5 (4 to 7) (Q) vs 5 (4 to 6)) (median, interquartile range (IQR)) and % of patients with each ICDSC symptom were similar in the two groups (all P > 0.10). Among patients with the delirium symptom at baseline, use of Q may lead to a shorter time (days) to first resolution of symptom fluctuation (4 (Q) vs. 14, P = 0.004), inattention (3 vs. 8, P = .10) and disorientation (2 vs. 10, P = 0.10) but a longer time to first resolution of agitation (3 vs. 1, P = 0.04) and hyperactivity (5 vs. 1, P = 0.07). Among all patients, Q-treated patients tended to spend a smaller percent of time with inattention (47 (0 to 67) vs. 78 (43 to 100), P = 0.025), hallucinations (0 (0 to 17) vs. 28 (0 to 43), P = 0.10) and symptom fluctuation (47 (19 to 67) vs. 89 (33 to 00), P = 0.04] and there was a trend for Q-treated patients to spend a greater percent of time at an appropriate level of consciousness (26% (13 to 63%) vs. 14% (0 to 33%), P = 0.17]. CONCLUSIONS: Our exploratory analysis suggests that quetiapine may resolve several intensive care unit (ICU) delirium symptoms faster than the placebo. Individual symptom resolution appears to differ in association with the pharmacologic intervention (that is, P vs Q, both with as needed haloperidol). Future studies evaluating antipsychotics in ICU patients with delirium should measure duration and resolution of individual delirium symptoms and their relation to long-term outcomes.

Efficacy and safety of quetiapine in critically ill patients with delirium: a prospective, multicenter, randomized, double-blind, placebo-controlled pilot study.

OBJECTIVE: To compare the efficacy and safety of scheduled quetiapine to placebo for the treatment of delirium in critically ill patients requiring as-needed haloperidol. DESIGN: Prospective, randomized, double-blind, placebo-controlled study. SETTING: Three academic medical centers. PATIENTS: Thirty-six adult intensive care unit patients with delirium (Intensive Care Delirium Screening Checklist score > or = 4), tolerating enteral nutrition, and without a complicating neurologic condition. INTERVENTIONS: Patients were randomized to receive quetiapine 50 mg every 12 hrs or placebo. Quetiapine was increased every 24 hrs (50 to 100 to 150 to 200 mg every 12 hrs) if more than one dose of haloperidol was given in the previous 24 hrs. Study drug was continued until the intensive care unit team discontinued it because of delirium resolution, therapy > or = 10 days, or intensive care unit discharge. MEASUREMENTS AND MAIN RESULTS: Baseline characteristics were similar between the quetiapine (n = 18) and placebo (n = 18) groups. Quetiapine was associated with a shorter time to first resolution of delirium [1.0 (interquartile range [IQR], 0.5-3.0) vs. 4.5 days (IQR, 2.0-7.0; p =.001)], a reduced duration of delirium [36 (IQR, 12-87) vs. 120 hrs (IQR, 60-195; p =.006)], and less agitation (Sedation-Agitation Scale score > or = 5) [6 (IQR, 0-38) vs. 36 hrs (IQR, 11-66; p =.02)]. Whereas mortality (11% quetiapine vs. 17%) and intensive care unit length of stay (16 quetiapine vs. 16 days) were similar, subjects treated with quetiapine were more likely to be discharged home or to rehabilitation (89% quetiapine vs. 56%; p =.06). Subjects treated with quetiapine required fewer days of as-needed haloperidol [3 [(IQR, 2-4)] vs. 4 days (IQR, 3-8; p = .05)]. Whereas the incidence of QTc prolongation and extrapyramidal symptoms was similar between groups, more somnolence was observed with quetiapine (22% vs. 11%; p = .66). CONCLUSIONS: Quetiapine added to as-needed haloperidol results in faster delirium resolution, less agitation, and a greater rate of transfer to home or rehabilitation. Future studies should evaluate the effect of quetiapine on mortality, resource utilization, post-intensive care unit cognition, and dependency after discharge in a broader group of patients.