High-versus low-dose clonidine for sedation and analgesia in critically ill adults: A retrospective cohort study.

WHAT IS KNOWN AND OBJECTIVE: Limited data suggest clonidine may be useful for sedation and analgesia in critically ill patients. Our objectives were to describe clonidine dosing regimens used for sedation and analgesia in critically ill adults, the associated adverse effects (i.e., hypotension), and whether clonidine dose was associated with dosage reductions of traditional sedatives and analgesics. METHODS: We conducted a retrospective cohort study of all critically ill adults who received enteral clonidine for sedation and analgesia during a five-year study period (2011-2016). We categorized patients as low-dose (LD ≤0.4 mg/day) or high-dose (HD >0.4 mg/day) based on the maximum total daily clonidine dose. RESULTS AND DISCUSSION: In total, 166 patients received clonidine for sedation analgesia; the median age was 56 years, 36% were female, and 96% were mechanically ventilated (median 10 days). Eighty-eight patients (53%) received HD clonidine. There were no significant differences in hypotension, bradycardia, rebound hypertension or tachycardia between groups. The HD group had a greater reduction in mean daily opioid requirements throughout clonidine use compared with the LD group (-218.8 mcg vs. -42.5 mcg fentanyl equivalents, p = 0.049), while antipsychotic doses increased (5.7 mg vs. 0 mg olanzapine equivalents, p = 0.04) and sedative doses did not differ. WHAT IS NEW AND CONCLUSIONS: Clonidine doses >0.4 mg/day were associated with a decrease in patients' opioid but not sedative requirements without causing significant adverse effects. Antipsychotic doses increased in conjunction with HD clonidine use.

The critical role of the inferior frontal cortex in establishing a prediction model for generating subsequent mismatch negativity (MMN): A TMS-EEG study.

BACKGROUND: The prediction violation account of automatic or pre-attentive change detection assumed that the inferior frontal cortex (IFC) is involved in establishing a prediction model for detecting unexpected changes. Evidence supporting the IFC's contribution to prediction model is mainly based on the Mismatch Negativity (MMN) to deviants violating predictions that are established based on the frequently presented standard events. However, deviant detection involves processes, such as events comparison, other than prediction model establishment. OBJECTIVE: The current study investigated the critical role of the IFC in establishing a prediction model during standards processing for subsequent deviant detection. METHODS: Transcranial Magnetic Stimulation (TMS) was applied at the IFC to disrupt the processing of the initial 2 or 5 standards of a 3-, 6-, or 9-standard train, while the MMN responses to pitch deviant presented after the standard trains were recorded and compared. RESULTS: An abolishment of MMN was only observed when TMS was delivered to the IFC at the initial 2 standards of the 3-standard train, but not at the initial 5 standards, or when TMS at the vertex or TMS sound recording was applied. The MMNs were also preserved when IFC TMS, vertex TMS, or TMS sound recording was applied at the initial 2 or 5 standards of longer trains. CONCLUSION: The IFC plays a critical role in processing the initial standards of a short standard train for subsequent deviant detection. This result is consistent with the prediction violation account that the IFC is important for establishing the prediction model.

Functional connectivity of the frontotemporal network in preattentive detection of abstract changes: Perturbs and observes with transcranial magnetic stimulation and event-related optical signal.

Current theories of automatic or preattentive change detection suggest a regularity or prediction violation mechanism involving functional connectivity between the inferior frontal cortex (IFC) and the superior temporal cortex (STC). By disrupting the IFC function with transcranial magnetic stimulation (TMS) and recording the later STC mismatch response with event-related optical signal (EROS), previous study demonstrated a causal IFC-to-STC functional connection in detecting a pitch or physical change. However, physical change detection can be achieved by memory comparison of the physical features and may not necessarily involve regularity/rule extraction and prediction. The current study investigated the IFC-STC functional connectivity in detecting rule violation (i.e., an abstract change). Frequent standard tone pairs with a constant relative pitch difference, but varying pitches, were presented to establish a pitch interval rule. This abstract rule was violated by deviants with reduced relative pitch intervals. The EROS STC mismatch response to the deviants was abolished by the TMS applied at the IFC 80 ms after deviance onset, but preserved in the spatial (TMS on vertex), auditory (TMS sound), and temporal (200 ms after deviance onset) control conditions. These results demonstrate the IFC-STC connection in preattentive abstract change detection and support the regularity or prediction violation account.

Clinical Interventions to Prevent Tumour Lysis Syndrome in Hematologic Malignancy: A Multisite Retrospective Chart Review.

BACKGROUND: Tumour lysis syndrome (TLS) occurs when lysis of malignant cells causes electrolyte disturbances and potentially organ dysfunction. Guidelines recommending preventive therapy according to TLS risk are based on low-quality evidence. OBJECTIVES: The primary objective was to characterize utilization of TLS preventive strategies through comprehensive description of current practice. Secondary objectives were to determine TLS incidence, to compare use of preventive strategies among intermediate- and high-risk patients, and to describe TLS treatment strategies. METHODS: This retrospective chart review examined data for patients with newly diagnosed hematologic malignancy who were admitted to an oncology centre and/or affiliated intensive care unit between October 2015 and September 2016 in Toronto, Ontario, Canada. RESULTS: Fifty-eight patients (29 at intermediate risk, 29 at high risk) were eligible for inclusion. Use of preventive allopurinol, IV bicarbonate, and furosemide was similar between groups. Rasburicase was more frequently used for high-risk patients (3% [1/29] of intermediate-risk patients versus 36% [9/25] of high-risk patients; p = 0.003). In 4 (14%) of the intermediate-risk patients and 2 (8%) of the high-risk patients, TLS developed during the admission. TLS was observed in 10% (1/10) of patients who received preventive rasburicase and 11% (5/44) of those who did not (p > 0.99), and in 9% (4/45) of patients who received preventive IV bicarbonate and 25% (2/8) of those who did not (p = 0.22). Treatment strategies included rasburicase, IV bicarbonate, furosemide, and renal replacement therapy. CONCLUSIONS: In this retrospective chart review, rasburicase was more commonly used for high-risk patients, whereas the use of other agents was similar between risk groups. This pattern of use is inconsistent with guidelines, which recommend that all high-risk patients receive rasburicase. There was no difference in TLS incidence between patients who did and did not receive preventive rasburicase or IV bicarbonate. Further prospective studies are needed to inform management of patients with malignancies who are at intermediate or high risk of TLS.

CONTEXTE: Le syndrome de lyse tumorale (SLT) se produit lorsque la lyse de cellules malignes provoque des perturbations électrolytiques et la dysfonction potentielle d'un organe. Les lignes directrices préconisant une thérapie préventive basée sur le risque de SLT se fondent sur des éléments de preuve de piètre qualité. OBJECTIFS: L'objectif principal consistait à décrire l'adoption des stratégies de prévention du SLT en décrivant précisément la pratique actuelle. Les objectifs secondaires consistaient, quant à eux, à déterminer l'incidence du SLT, à comparer l'utilisation des stratégies de prévention pour les patients présentant un risque élevé et moyen et à décrire les stratégies de traitement du SLT. MÉTHODES: Cet examen rétrospectif a permis d'examiner les données de patients ayant récemment reçu un diagnostic d'hémopathie maligne et ayant été admis dans un centre d'oncologie ou une unité de soins intensifs affiliée, entre octobre 2015 et septembre 2016 à Toronto (Ontario), au Canada. RÉSULTATS: Cinquante-huit patients (29 présentant un risque moyen et 29 un risque élevé) étaient admissibles. L'utilisation d'allopurinol à titre préventif, de bicarbonate par voie intraveineuse et de furosémide était similaire d'un groupe à l'autre. Le rasburicase était plus fréquemment utilisé pour les patients présentant un risque élevé (3 % [1/29] de patients présentant un risque moyen contre 36 % [9/25] de patients présentant un risque élevé; p = 0.003). Quatre (14 %) patients présentant un risque moyen et deux (8 %) présentant un risque élevé ont développé un SLT pendant l'admission. Le SLT a été observé chez 10 % (1/10) des patients ayant reçu du rasburicase à titre préventif et chez 11 % (5/44) des patients qui n'en avaient pas reçu (p > 0,99); il a aussi été observé chez 9 % (4/45) des patients ayant reçu du bicarbonate par voie intraveineuse à titre préventif et chez 25 % (2/8) des patients qui n'en avaient pas reçu (p = 0.22). Les stratégies de traitement comprenaient le rasburicase, le bicarbonate par voie intraveineuse, le furosémide et la thérapie de remplacement rénal. CONCLUSIONS: Dans cet examen rétrospectif des dossiers, l'usage du rasburicase était plus fréquent pour les patients présentant un risque élevé, tandis que celui d'autres agents était similaire entre les groupes à risque. Ce schéma d'utilisation n'est pas conforme aux lignes directrices, qui recommandent que tous les patients présentant un risque élevé reçoivent du rasburicase. Aucune différence n'est apparue dans l'incidence du SLT parmi les patients ayant reçu du rasburicase ou du bicarbonate par voie intraveineuse à titre préventif et parmi ceux qui n'en avaient pas reçu. Davantage d'études prospectives sont nécessaires pour mieux connaitre la gestion des patients à haut risque ou ceux qui présentent des risques moyens de SLT, mais qui ont des malignités.

Psychotropic Drug Use in Physically Restrained, Critically Ill Adults Receiving Mechanical Ventilation.

BACKGROUND: Restraining therapies (physical or pharmacological) are used to promote the safety of both patients and health care workers. Some guidelines recommend nonpharmacological or pharmacological interventions be used before physical restraints in critically ill patients. OBJECTIVES: To characterize psychotropic drug interventions before and after use of physical restraints in critically ill adults receiving mechanical ventilation. METHODS: A single-center, prospective, observational study documenting psychotropic drug use and Sedation-Agitation Scale (SAS) scores in the 2 hours before and the 6 hours after application of physical restraints. RESULTS: Ninety-three patients were restrained for a median of 21 hours (interquartile range, 9-70 hours). Thirty percent of patients did not receive a psychotropic drug or had a drug stopped or decreased before physical restraints were applied. More patients received a psychotropic drug intervention after use of physical restraints than before (86% vs 56%, P = .001). Administration of opioids was more common after the use of physical restraints (54% vs 20% of patients, P = .001) and accounted for more drug interventions (45% vs 29%, P = .001). Fifty patients had SAS scores from both time periods; 16% remained oversedated, 24% were appropriately sedated, and 16% remained agitated in both time periods. Patients became oversedated (20%), more agitated (10%), less agitated (8%), and less sedated (6%) after restraint use. CONCLUSIONS: Psychotropic drug interventions (mostly using opioids) were more common after use of physical restraints. Some patients may be physically restrained for anticipated treatment interference without consideration of pharmacological options and without documented agitation.

Melatonin and melatonin agonists to prevent and treat delirium in critical illness: a systematic review protocol.

BACKGROUND: Delirium is a syndrome characterized by acute fluctuations and alterations in attention and arousal. Critically ill patients are at particularly high risk, and those that develop delirium are more likely to experience poor clinical outcomes such as prolonged duration of ICU and hospital length of stay, and increased mortality. Melatonin and melatonin agonists (MMA) have the potential to decrease the incidence and severity of delirium through their hypnotic and sedative-sparing effects, thus improving health-related outcomes. The objective of this review is to synthesize the available evidence pertaining to the efficacy and safety of MMA for the prevention and treatment of ICU delirium. METHODS: We will search Ovid MEDLINE, Web of Science, EMBASE, PsycINFO, the Cochrane Central Register of Controlled Trials (CENTRAL), and CINAHL to identify studies evaluating MMA in critically ill populations. We will also search http://apps.who.int/trialsearch for ongoing and unpublished studies and PROSPERO for registered reviews. We will not impose restrictions on language, date, or journal of publication. Authors will independently screen for eligible studies using pre-defined criteria; data extraction from eligible studies will be performed in duplicate. The Cochrane Risk of Bias Scale and the Newcastle-Ottawa Scale will be used to assess the risk of bias and quality of randomized and non-randomized studies, respectively. Our primary outcome of interest is delirium incidence, and secondary outcomes include duration of delirium, number of delirium- and coma-free days, use of physical and chemical (e.g., antipsychotics or benzodiazepines) restraints, duration of mechanical ventilation, ICU and hospital length of stay, mortality, long-term neurocognitive outcomes, hospital discharge disposition, and adverse events. We will use Review Manager (RevMan) to pool effect estimates from included studies. We will present results as relative risks with 95% confidence intervals for dichotomous outcomes and as mean differences, or standardized mean differences, for continuous outcomes. DISCUSSION: Current guidelines make no pharmacological recommendations for either the prevention or treatment of ICU delirium. This systematic review will synthesize the available evidence on the efficacy and safety of MMA for this purpose, thus potentially informing clinical decision-making and improving patient outcomes. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42015024713.

Thiamine prescribing practices within university-affiliated hospitals: a multicenter retrospective review.

BACKGROUND: Patients with suspected thiamine deficiency should receive treatment with parenteral thiamine to achieve the high serum thiamine levels necessary to reverse the effects of deficiency and to circumvent problems with absorption common in the medically ill. OBJECTIVE: To quantify rates of parenteral administration of thiamine across university-affiliated hospitals and to identify factors associated with higher rates of parenteral prescribing. DESIGN: Multicenter, retrospective observational study of thiamine prescriptions. METHODS: Prescriptions for thiamine were captured from computerized pharmacy information systems across participating centers, providing information concerning dose, route, frequency, and duration of thiamine prescribed from January 2010 to December 2011. SETTING: Fourteen university-affiliated tertiary care hospitals geographically distributed across Canada, including 48,806 prescriptions for thiamine provided to 32,213 hospitalized patients. RESULTS: Parenteral thiamine accounted for a statistically significant majority of thiamine prescriptions (57.6%, P < 0.001); however, oral thiamine constituted a significant majority of the total doses prescribed (68.4%, z = 168.9; P < 0.001). Protocols prioritizing parenteral administration were associated with higher rates of parenteral prescribing (61.3% with protocol, 45.8% without protocol; P < 0.001). Patients admitted under psychiatry services were significantly more likely to be prescribed oral thiamine (P < 0.001). CONCLUSIONS: Although parenteral thiamine accounted for a statistically significant majority of prescriptions, oral thiamine was commonly prescribed within academic hospitals. Additional strategies are needed to promote parenteral thiamine prescribing to patients with suspected thiamine deficiency.