David J. Gagnon

Prophylactic antibiotics are associated with a lower incidence of pneumonia in cardiac arrest survivors treated with targeted temperature management

INTRODUCTIONnProphylactic antibiotics (PRO) reduce the incidence of early-onset pneumonia in comatose patients with structural brain injury, but have not been examined in cardiac arrest survivors undergoing targeted temperature management (TTM). We investigated the effect of PRO on the development of pneumonia in that population.nnnMETHODSnWe conducted a retrospective cohort study comparing patients treated with PRO to those not receiving PRO (no-PRO) using Northern Hypothermia Network registry data. Cardiac arrest survivors ≥ 18 years of age with a GCS<8 at hospital admission and treated with TTM at 32-34 °C were enrolled in the registry. Differences were analyzed in univariate analyses and with logistic regression models to evaluate independent associations of clinical factors with incidence of pneumonia and good functional outcome.nnnRESULTSn416 of 1240 patients (33.5%) received PRO. Groups were similar in age, gender, arrest location, initial rhythm, and time from collapse to return of spontaneous circulation. PRO patients had less pneumonia (12.6% vs. 54.9%, p < 0.001) and less sepsis (1.2 vs. 5.7%, p < 0.001) compared to no-PRO patients. ICU length of stay (98 vs. 100 h, p = 0.2) and incidence of a good functional outcome (41.1 vs. 36.6%, p = 0.19) were similar between groups. Backwards stepwise logistic regression demonstrated PRO were independently associated with a lower incidence of pneumonia (OR 0.09, 95% 0.06-0.14, p < 0.001) and a similar incidence of good functional outcome.nnnCONCLUSIONSnProphylactic antibiotics were associated with a reduced incidence of pneumonia but a similar rate of good functional outcome.

Transition from dexmedetomidine to enteral clonidine for ICU sedation: an observational pilot study.

Enteral clonidine represents a potentially less costly alternative to dexmedetomidine for sedation in intensive care unit (ICU) patients. This study describes our practice of transitioning selected adult ICU patients from dexmedetomidine to clonidine with a focus on efficacy, safety, and drug acquisition costs.

Serotonin Syndrome Following Methylene Blue Administration During Cardiothoracic Surgery

Introduction: Despite its favorable safety profile, there have been reports of methylene blue-induced encephalopathy and serotonin syndrome in patients undergoing parathyroidectomy. We report a case of serotonin syndrome following methylene blue administration in a cardiothoracic surgery patient. Case Report: A 59-year-old woman taking preoperative venlafaxine and trazodone was given a single dose of 2 mg/kg methylene blue (167 mg) during a planned coronary artery bypass and mitral valve repair. Postoperatively, she was febrile to 38.7°C and developed full-body tremors, rhythmic twitching of the perioral muscles, slow conjugate roving eye movements, and spontaneous movements of the upper extremities. Electroencephalography revealed generalized diffuse slowing consistent with toxic encephalopathy, and a computed tomography scan showed no acute process. The patient’s symptoms were most consistent with a methylene blue-induced serotonin syndrome. Her motor symptoms resolved within 48 hours and she was eventually discharged home. Discussion: Only 2 cases of methylene blue-induced serotonin syndrome during cardiothoracic surgery have been described in the literature, with this report representing the third case. Methylene blue and its metabolite, azure B, are potent, reversible inhibitors of monoamine oxidase A which is responsible for serotonin metabolism. Concomitant administration of methylene blue with serotonin-modulating agents may precipitate serotonin syndrome.

Analgesia, sedation, and neuromuscular blockade during targeted temperature management after cardiac arrest

The approach to sedation, analgesia, and neuromuscular blockade during targeted temperature management (TTM) remains largely unstudied, forcing clinicians to adapt previous research from other patient environments. During TTM, very little data guide drug selection, doses, and specific therapeutic goals. Sedation should be deep enough to prevent awareness during neuromuscular blockade, but titration is complex as metabolism and clearance are delayed for almost all drugs during hypothermia. Deeper sedation is associated with prolonged intensive care unit (ICU) and ventilator therapy, increased delirium and infection, and delayed wakening which can confound early critical neurological assessments, potentially resulting in erroneous prognostication and inappropriate withdrawal of life support. We review the potential therapeutic goals for sedation, analgesia, and neuromuscular blockade during TTM; the adverse events associated with that treatment; data suggesting that TTM and organ dysfunction impair drug metabolism; and controversies and potential benefits of specific monitoring. We also highlight the areas needing better research to guide our therapy.

Cefepime-induced neurotoxicity: a systematic review

BackgroundCefepime is a widely used antibiotic with neurotoxicity attributed to its ability to cross the blood–brain barrier and exhibit concentration-dependent ϒ-aminobutyric acid (GABA) antagonism. Neurotoxic symptoms include depressed consciousness, encephalopathy, aphasia, myoclonus, seizures, and coma. Data suggest that up to 15% of ICU patients treated with cefepime may experience these adverse effects. Risk factors include renal dysfunction, excessive dosing, preexisting brain injury, and elevated serum cefepime concentrations. We aimed to characterize the clinical course of cefepime neurotoxicity and response to interventions.MethodsA librarian-assisted search identified publications describing cefepime-associated neurotoxicity from January 1980 to February 2016 using the CINAHL and MEDLINE databases. Search terms included cefepime, neurotoxicity, encephalopathy, seizures, delirium, coma, non-convulsive status epilepticus, myoclonus, confusion, aphasia, agitation, and death. Two reviewers independently assessed identified articles for eligibility and used the Preferred Reporting Items for Systematic review and Meta-Analysis Protocols (PRISMA-P) for data reporting.ResultsOf the 123 citations identified, 37 (representing 135 patient cases) were included. Patients had a median age of 69xa0years, commonly had renal dysfunction (80%) and required intensive care (81% of patients with a reported location). All patients exhibited altered mental status, with reduced consciousness (47%), myoclonus (42%), and confusion (42%) being the most common symptoms. All 98 patients (73% of cohort) with electroencephalography had abnormalities, including non-convulsive status epilepticus (25%), myoclonic status epilepticus (7%), triphasic waves (40%), and focal sharp waves (39%). As per Food and Drug Administration (FDA)-approved dosing guidance, 48% of patients were overdosed; however, 26% experienced neurotoxicity despite appropriate dosing. Median cefepime serum and cerebrospinal fluid (CSF) concentrations were 45xa0mg/L (nu2009=u200921) and 13xa0mg/L (nu2009=u20094), respectively. Symptom improvement occurred in 89% of patients, and 87% survived to hospital discharge. The median delay from starting the drug to symptom onset was 4xa0days, and resolution occurred a median of 2xa0days after the intervention, which included cefepime discontinuation, antiepileptic administration, or hemodialysis.ConclusionsCefepime-induced neurotoxicity is challenging to recognize in the critically ill due to widely varying symptoms that are common in ICU patients. This adverse reaction can occur despite appropriate dosing, usually resolves with drug interruption, but may require additional interventions such as antiepileptic drug administration or dialysis.

Valproate for agitation in critically ill patients: A retrospective study

Purpose: The purpose was to describe the use of valproate therapy for agitation in critically ill patients, examine its safety, and describe its relationship with agitation and delirium. Materials and methods: This retrospective cohort study evaluated critically ill adults treated with valproate for agitation from December 2012 through February 2015. Information on valproate prescribing practices and safety was collected. Incidence of agitation, delirium, and concomitant psychoactive medication use was compared between valproate day 1 and valproate day 3. Concomitant psychoactive medication use was analyzed using mixed models. Results: Fifty‐three patients were evaluated. The median day of valproate therapy initiation was ICU day 7, and it was continued for a median of 7 days. The median maintenance dose was 1500 mg/d (23 mg/kg/d). The incidence of agitation (96% vs 61%, P < .0001) and delirium (68% vs 49%, P = .012) significantly decreased by valproate day 3. Treatment with opioids (77% vs 65%, P = .02) and dexmedetomidine (47% vs 24%, P = .004) also decreased. In mixed models analyses, valproate therapy was associated with reduced fentanyl equivalents (−185 &mgr;g/d, P = .0003) and lorazepam equivalents (−2.1 mg/d, P = .0004). Hyperammonemia (19%) and thrombocytopenia (13%) were the most commonly observed adverse effects. Conclusions: Valproate therapy was associated with a reduction in agitation, delirium, and concomitant psychoactive medication use within 48 hours of initiation.

Valproate Protein Binding Is Highly Variable in ICU Patients and Not Predicted by Total Serum Concentrations: A Case Series and Literature Review

The free fraction of valproate (the pharmacologically active moiety, normally 5–10%) may vary significantly in critically ill patients, but this topic is understudied, with only four prior intensive care unit (ICU) case reports. The objective of this study was to evaluate the range of valproate plasma protein binding in ICU patients.

Repurposing valproate, enteral clonidine, and phenobarbital for comfort in adult ICU patients: a literature review with practical considerations

Provision of adequate sedation is a fundamental part of caring for critically ill patients. Propofol, dexmedetomidine, and benzodiazepines are the most commonly administered sedative medications for adult patients in the intensive care unit (ICU). These agents are limited by adverse effects, need for a monitored environment for safe administration, and lack of universal effectiveness. Increased interest has recently been expressed about repurposing older pharmacologic agents for patient comfort in the ICU. Valproate, enteral clonidine, and phenobarbital are three agents with increasing evidence supporting their use. Potential benefits associated with their utilization are cost minimization and safe administration after transition out of the ICU. This literature review describes the historical context, pharmacologic characteristics, supportive data, and practical considerations associated with the administration of these agents for comfort in critically ill adult patients.

Etomidate in sepsis: understanding the dilemma.

Etomidate is the most commonly utilized induction agent for rapid sequence intubation in emergency departments in the United States (1). Favorable characteristics include reliably good intubating conditions, a rapid onset and offset of activity, non-renal elimination, and maintenance of the cardiorespiratory drive (2). Unfortunately, etomidate causes relative adrenal insufficiency in up to 90% of patients after a single dose (3). Serious safety concerns first surfaced in the early 1980’s when continuous infusions were associated with increased mortality in trauma patients (4,5). Since then, there has been considerable uncertainty regarding its role for rapid sequence intubation, especially in septic patients who may depend on their adrenal reserves for survival during the acute phase of illness (6,7). Understanding the history of this controversy, and reviewing the most recent research into etomidate use in sepsis may help clinicians decide whether or not to use the drug in routine clinical practice.

Continuous surface EMG power reflects the metabolic cost of shivering during targeted temperature management after cardiac arrest

AIMnShivering may interfere with targeted temperature management (TTM) after cardiac arrest, contributing to secondary brain injury. Early identification of shivering is challenging with existing tools. We hypothesized that shivering detected by continuous surface sEMG monitoring would be validated with calorimetry and detected earlier than by intermittent clinical observation.nnnMETHODSnThis prospective observational study enrolled a convenience sample of comatose adult cardiac arrest patients treated with TTM at 33u2009°C. Clinical shivering was monitored hourly using the Bedside Shivering Assessment Scale (BSAS) by bedside nurses who administered intermittent neuromuscular blockade (NMB) when BSASu2009≥u20091. The research team monitored independently for shivering with BSAS every 15u2009min during continuous blinded monitoring of oxygen consumption (VO2) via indirect calorimetry and sEMG power during the maintenance phase of TTM. A sustained 20% increase in the 5-min rolling average of VO2 above baseline identified the Gold Standard shivering threshold (VO2-20).nnnRESULTSnAmong 18 patients, clinical shivering was detected 23 times in 14 patients. Hierarchical models to predict a shiver event determined by the VO2-20 for sEMG power and BSAS revealed an AUC for sEMG power of 0.92 (95%CIu2009=u20090.88-0.95), and 0.90 (CIu2009=u20090.87-0.94) for BSAS. The optimal threshold of sEMG to predict VO2-20 was 32 decibels (dB), and this was exceeded 38 (29-56) min before nurse-detected shivering.nnnCONCLUSIONSnShivering was detected by sEMG power earlier than by clinical assessment with BSAS, with similar accuracy compared to the indirect calorimetry gold standard. Continuous sEMG monitoring appears useful for clinical assessment and research for shivering during TTM.