Ryan M. Rivosecchi

An evidence based systematic review of remifentanil associated opioid-induced hyperalgesia.

Introduction: Therapeutic opioid use continues to grow, with greater than a fivefold increase in usage of fentanyl-based products over a 10-year period. Opioids are known for their side-effect profile, including bradycardia and respiratory depression; questions remain, however, regarding lesser known side effects such as opioid-induced hyperalgesia (OIH). Areas covered: A systematic review of published literature addressing remifentanil OIH in the surgical setting was completed. A search was conducted of PubMed, Embase and Ovid from 1946 until June 2013. Inclusion criteria consisted of age ≥ 18 years, humans, full-text articles and English language. A total of 35 unique articles were included. Sixteen articles reported outcomes that supported remifentanil OIH and 6 that refuted and 22 were focused on prevention. Expert opinion: There is conflicting evidence regarding the existence of remifentanil OIH. Outcomes evaluating measures of hyperalgesia frequently conclude that remifentanil OIH exists, while those evaluating opioid consumption do not. Therefore, remifentanil does induce a degree of hyperalgesia, but we do not believe that it reaches a level of clinical significance that requires prevention. If a significant concern for the development of remifentanil OIH is suspected, we suggest using the least possible effective dose of remifentanil as the primary prevention strategy.

Nonpharmacological Interventions to Prevent Delirium: An Evidence-Based Systematic Review

Development of delirium in critical care patients is associated with increased length of stay, hospital costs, and mortality. Delirium occurs across all inpatient settings, although critically ill patients who require mechanical ventilation are at the highest risk. Overall, evidence to support the use of antipsychotics to either prevent or treat delirium is lacking, and these medications can have adverse effects. The pain, agitation, and delirium guidelines of the American College of Critical Care Medicine provide the strongest level of recommendation for the use of nonpharmacological approaches to prevent delirium, but questions remain about which nonpharmacological interventions are beneficial.

The implementation of a nonpharmacologic protocol to prevent intensive care delirium.

PURPOSE The purpose was to determine if the implementation of an evidence-based nonpharmacologic protocol reduced the percentage of time patients spent delirious in a medical intensive care unit (MICU) that already uses a sedation and mobility protocol. MATERIALS AND METHODS This was a prospective, pre-post quality improvement project of MICU patients conducted from September 2013 to April 2014. Evidence-based effective nonpharmacologic interventions with nursing education were bundled into the project protocol: music, opening/closing of blinds, reorientation/cognitive stimulation, and eye/ear care. RESULTS Patients were evaluated between September 2013 and April 2014, with 230 and 253 patients being included in the each phase. There was a 50.6% reduction (16.1% vs 9.6%, P < .001) in time spent delirious in the MICU. Incidence of delirium developed was decreased (15.7% vs 9.4%, P = .04). The protocol reduced the odds of developing delirium by 57% (odds ratio, 0.43; P = .005) after controlling for age, Acute Physiology and Chronic Health Evaluation II, mechanical ventilation, and dementia. CONCLUSIONS The implementation of a nonpharmacologic delirium prevention protocol resulted in a significant decrease in the percentage of time spent delirious in the MICU while reducing the risk of delirium development. Additional studies with more rigorous study designs need to be completed to further the research of nonpharmacologic interventions with appropriate sedation and mobility protocols.

Effects of Isavuconazole on the Plasma Concentrations of Tacrolimus among Solid Organ Transplant Patients

ABSTRACT We evaluated the interaction between isavuconazole and tacrolimus among 55 organ transplant recipients. After isavuconazole discontinuation, the tacrolimus concentration/dose ratio normalized by weight (C/D) was reduced by 16%. Liver transplant recipients experienced the largest C/D reduction. A 1.3-fold decrease in tacrolimus daily dose was required to maintain desired tacrolimus levels. There was considerable interpatient variability in the magnitude of the drug interaction. Tacrolimus doses should not be adjusted uniformly but, rather, be guided by therapeutic drug monitoring.

Fentanyl-induced hyperalgesia in acute pain management.

ABSTRACT There are safety concerns with the use of fentanyl, including respiratory depression, nausea, constipation, and possibly opioid-induced hyperalgesia (OIH). The purpose of this review is to evaluate the occurrence and significance of opioid-induced hyperalgesia (OIH) after acute fentanyl exposure. A literature search was conducted from October 1995 through January 2015 using MEDLINE, Embase, and Scopus with the terms hyperalgesia, fentanyl, pronociceptive, acute tolerance, and acute. Published articles evaluating the adverse effects of fentanyl during acute pain management (≤96 hours) in humans were included. Opioid-induced hyperalgesia is a phenomenon defined by increasing pain after opioid exposure with the worsening of pain occurring when opioid doses are increased. Hyperalgesia has been described following remifentanil and morphine use, but the question remains about the associated risk with acute fentanyl exposure. Six randomized, controlled trials evaluating the effect of fentanyl on pain in the acute setting have been conducted. Two trials oppose whereas four trials support the occurrence of fentanyl-induced hyperalgesia. The data on OIH after acute fentanyl exposure are limited and conflicting. Hyperalgesia should be considered in patients with uncontrolled pain despite escalating fentanyl doses, since the possibility of fentanyl-induced OIH exists in the acute setting. Well-designed trials are needed to determine the clinical significance of this phenomenon.

Pharmacokinetics of Azole Antifungals in Cystic Fibrosis

Defects in mucociliary clearance predispose cystic fibrosis (CF) patients to airway colonization and infection by various fungi, especially Aspergillus fumigatus. Although the clinical significance of airway fungal colonization is not clear, several studies have suggested its association with worsening lung function and increased risk of CF exacerbations. Antifungal triazole agents have been used in CF patients with airway fungal colonization or infections with varying results. Limited pharmacokinetic studies to date have demonstrated high inter-subject variability of triazole levels among CF patients. This review discusses the basic principles of pharmacokinetics, the pharmacokinetic changes associated with CF and the effect of CF on the pharmacokinetic principles of azole antifungals. The inconsistent azole serum levels in CF patients may be associated with sub-therapeutic (thus risk of therapeutic failure and/or emergence of azole-resistant fungi) or supratherapeutic exposures (thus potential risk of azole toxicity), suggesting that therapeutic dose monitoring is necessary in CF patients.

Trigger alerts associated with laboratory abnormalities on identifying potentially preventable adverse drug events in the intensive care unit and general ward

Background Medication safety strategies involving trigger alerts have demonstrated potential in identifying drug-related hazardous conditions (DRHCs) and preventing adverse drug events in hospitalized patients. However, trigger alert effectiveness between intensive care unit (ICU) and general ward patients remains unknown. The objective was to investigate trigger alert performance in accurately identifying DRHCs associated with laboratory abnormalities in ICU and non-ICU settings. Methods This retrospective, observational study was conducted at a university hospital over a 1-year period involving 20 unique trigger alerts aimed at identifying possible drug-induced laboratory abnormalities. The primary outcome was to determine the positive predictive value (PPV) in distinguishing drug-induced abnormal laboratory values using trigger alerts in critically ill and general ward patients. Aberrant lab values attributed to medications without resulting in an actual adverse event ensuing were categorized as a DRHC. Results A total of 634 patients involving 870 trigger alerts were included. The distribution of trigger alerts generated occurred more commonly in general ward patients (59.8%) than those in the ICU (40.2%). The overall PPV in detecting a DRHC in all hospitalized patients was 0.29, while the PPV in non-ICU patients (0.31) was significantly higher than the critically ill (0.25) (p = 0.03). However, the rate of DRHCs was significantly higher in the ICU than the general ward (7.49 versus 0.87 events per 1000 patient days, respectively, p < 0.0001). Although most DRHCs were considered mild or moderate in severity, more serious and life-threatening DRHCs occurred in the ICU compared with the general ward (39.8% versus 12.4%, respectively, p < 0.001). Conclusions Overall, most trigger alerts performed poorly in detecting DRHCs irrespective of patient care setting. Continuous process improvement practices should be applied to trigger alert performance to improve clinician time efficiency and minimize alert fatigue.

Ketamine Infusion for Adjunct Sedation in Mechanically Ventilated Adults

Many critically ill patients receive ketamine for adjunct sedation despite a paucity of evidence on its use, dosing, and monitoring in this setting.

Apixaban or Rivaroxaban Versus Warfarin for Treatment of Submassive Pulmonary Embolism After Catheter-Directed Thrombolysis:

Background: Little data exist on the use of direct oral anticoagulant (DOAC) factor Xa inhibitors for submassive pulmonary embolism (PE) after catheter-directed thrombolysis (CDT). The objective of this evaluation was to determine whether the transition from parenteral anticoagulation to DOACs for submassive PE after CDT would decrease hospital length of stay (LOS) compared to warfarin. Methods: A retrospective review of patients diagnosed with submassive PE who underwent CDT was conducted from January 1, 2012, to February 28, 2017. Hospital LOS and major and minor bleeding events were recorded during hospitalization and at 90 days. Results: Sixty-two patients met the inclusion criteria, 36 in warfarin group and 26 in the DOAC group. Overall, patients receiving rivaroxaban or apixaban had a shorter median hospital LOS compared to warfarin (4.0 vs 6.1 days, P = .002). In the multivariate regression analysis, administration of DOAC was an independent predictor of decreased hospital LOS, β: −2.1, 95% confidence interval (−3.5 to −0.7). Conclusion: Among patients with submassive PE, initiation of a DOAC shortly after CDT may result in a decreased hospital LOS compared to parenterally bridged warfarin.

Association Between Train-of-Four Values and Gas Exchange Indices in Moderate to Severe Acute Respiratory Distress Syndrome:

Background: Acute respiratory distress syndrome (ARDS) is associated with a mortality rate of approximately 40%. Neuromuscular blockade is associated with an improvement in oxygenation and a reduction in mortality in ARDS. Objective: The goal of this evaluation was to determine if the depth of paralysis, determined by train-of-four (TOF) monitoring, correlates with gas exchange in moderate to severe ARDS. Methods: This was a retrospective review of moderate to severe ARDS patients who were prescribed >12 hours of continuous infusion cisatracurium between January 1, 2013, and December 31, 2014, with a PaO2:FiO2 ratio <150 and documented TOF and arterial blood gases. Patients were evaluated for inclusion at 12, 24, and 48 hours after initiation of neuromuscular blockade. Results: A total of 378 patients were screened for inclusion, with 107 evaluable patients meeting criteria at baseline. Poor correlation existed between TOF and oxygenation index (OI) at 12 (τ = 0.03), 24 (τ = 0.15) and 48 hours (τ = 0.08). When controlling for proning and baseline OI, the depth of paralysis did not have a significant effect on OI at 12, 24, or 48 hours. Conclusions: This evaluation demonstrates that the use of TOF monitoring for neuromuscular blockade does not correlate with gas exchange markers in moderate to severe ARDS.