Scott W. Mueller

Early Administration of Infliximab for Severe Ipilimumab-Related Diarrhea in a Critically Ill Patient

Objective: To report a case of ipilimumab-associated life-threatening diarrhea responding quickly to a single dose of infliximab. Case Summary: A 67-year-old man presented 3 weeks after his second dose of ipilimumab with severe diarrhea, acute kidney injury, and hypotension. After 2 days of high-dose corticosteroids and supportive care, he continued to have 2.8 L of stool output per day (grade 4 National Cancer Institute Common Terminology Criteria for Adverse Events). The patient was transferred to the medical intensive care unit requiring endotracheal intubation because of concerns of worsening mental status, metabolic acidosis, and increased work of breathing, with a serum bicarbonate concentration of <5 mmol/L. Despite aggressive fluid resuscitation and a sodium bicarbonate infusion, he remained hypotensive and hyponatremic with persistent premature ventricular contractions. On the evening of day 3, infliximab (5 mg/kg) was given, resulting in a rapid decrease in diarrhea. After 48 hours, the acidosis was corrected and electrolytes, renal function, and fluid status were improving. At discharge, diarrhea, acute kidney injury, and acidosis had resolved, and he was discharged on a slow steroid taper. Discussion: Autoimmune colitis is a described immune-related adverse event of ipilimumab. Prompt recognition, initiation of steroids, and supportive therapy are key to the management of diarrhea. Infliximab should be considered early in steroid-nonresponsive or life-threatening diarrhea. Conclusion: Infliximab is a life-saving intervention in patients with ipilimumab-induced diarrhea.

Management of Extravasation Injuries: A Focused Evaluation of Noncytotoxic Medications

Extravasations are common manifestations of iatrogenic injury that occur in patients requiring intravenous delivery of known vesicants. These injuries can contribute substantially to patient morbidity, cost of therapy, and length of stay. Many different mechanisms are behind the tissue damage during extravasation injuries. In general, extravasations consist of four different subtypes of tissue injury: vasoconstriction, osmotic, pH related, and cytotoxic. Recognition of high‐risk patients, appropriate cannulation technique, and monitoring of higher risk materials remain the standard of care for the prevention of extravasation injury. Prompt interdisciplinary action is often necessary for the treatment of extravasation injuries. Knowledge of the mechanism of extravasation‐induced tissue injury, agents for reversal, and appropriate nonpharmacologic treatment methods is essential. The best therapeutic agent for treatment of vasopressor extravasation is intradermal phentolamine. Topical vasodilators and intradermal terbutaline may provide relief. Intradermal hyaluronidase has been effective for hyperosmotic extravasations, although its use largely depends on the risk of tissue injury and the severity of extravasation. Among the hyperosmotic agents, calcium extravasation is distinctive because it may present as an acute tissue injury or may possess delayed clinical manifestations. Extravasation of acidic or basic materials can produce significant tissue damage. Phenytoin is the prototypical basic drug that causes a clinical manifestation known as purple glove syndrome (PGS). This syndrome is largely managed through preventive and conservative treatment measures. Promethazine is acidic and can cause a devastating extravasation, particularly if administered inadvertently through the arteriolar route. Systemic heparin therapy remains the accepted treatment option for intraarteriolar administration of promethazine. Overall, the evidence for managing extravasations due to noncytotoxic medications is nonexistent or limited to case reports. More research is needed to improve knowledge of patient risk, prompt recognition of the extravasation, and time course for tissue injury, and to develop prevention and treatment strategies for extravasation injuries.

A randomized, double-blind pilot study of dexmedetomidine versus midazolam for intensive care unit sedation: patient recall of their experiences and short-term psychological outcomes.

Introduction: Sedation with dexmedetomidine may facilitate ventilator liberation and limit the occurrence of delirium. No trial has assessed patient recall or the development of psychological outcomes after dexmedetomidine sedation. This pilot study evaluated whether transitioning benzodiazepine sedation to dexmedetomidine alters patient recall and the incidence of anxiety, depression, or acute stress disorder (ASD). Methods: This investigation was a randomized, double-blind, single-center study. Existing continuous benzodiazepine sedation was converted to dexmedetomidine or midazolam when patients qualified for daily awakenings. Sedation was titrated to achieve Riker sedation agitation scores of 3 to 4. The intensive care unit (ICU) Stressful Experiences Questionnaire, hospital anxiety and depression scale, and the impact of event scale-revised were administered before hospital discharge to assess recall, anxiety, depression, and manifestations of ASD. Results: A total of 11 patients received dexmedetomidine, and 12 patients received midazolam. Median dosing was 0.61 µg/kg/h for 3.5 days for dexmedetomidine and 3.7 mg/h for 3 days for midazolam. Attainment of goal sedation and analgesia was similar; however, more dexmedetomidine patients experienced agitation and pain. The median duration of mechanical ventilation from study drug initiation to extubation was 3.4 days in dexmedetomidine patients and 2.9 days in midazolam patients. Dexmedetomidine patients remembered 18.5 experiences compared with 8.5 in midazolam patients (P = .015). Rates of anxiety and depression were similar. In all, 5 (62.5%) dexmedetomidine patients and 1 (12.5%) midazolam patient manifested ASD (P = .063), and 1 dexmedetomidine patient and 5 midazolam patients developed new-onset delirium (P = .07). Hypotension occurred in 10 (90.9%) dexmedotomidine patients and 6 (50%) midazolam patients (P = .069). Conclusions: Transitioning benzodiazepine sedation to dexmedetomidine when patients qualify for daily awakenings may reduce the development of delirium and facilitate remembrance of ICU experiences but may lead to manifestations of ASD. Monitoring hypotension is required for both the sedatives. Additional comparative studies focusing on the long-term impact of ICU recall and psychological outcomes are needed.

Evaluation of Early Dexmedetomidine Addition to the Standard of Care for Severe Alcohol Withdrawal in the ICU: A Retrospective Controlled Cohort Study

Purpose: This study evaluated the impact of dexmedetomidine (DEX) administration on benzodiazepine (BZD) requirements in intensive care unit (ICU) patients experiencing alcohol withdrawal syndrome (AWS). Methods: This trial included adults admitted to the ICU for >24 hours for AWS. Early DEX was defined as receiving DEX within 60 hours of hospital admission. The primary outcome was 12-hour BZD requirement from the inflection point or DEX initiation. Secondary outcomes included 24-hour BZD requirements, symptom control, ICU and hospital length of stay, and incidence and duration of mechanical ventilation. Safety outcomes included incidence of bradycardia and hypotension. Results: Twenty patients receiving DEX were matched to 22 control patients. The mean 12-hour change in BZD requirement was significantly different for DEX versus control (−20 vs −8.3 mg, P = .0455) with a trend toward significance at 24 hours (−29.6 vs −11 mg, P = .06). No significant differences were noted in other secondary outcomes. Patients receiving DEX experienced significantly more bradycardia than controls (35% vs 0%, P < .01) but not hypotension. Conclusions: This study suggests DEX is associated with a reduction in BZD requirement when utilized as adjunctive therapy for AWS. A larger prospective trial is needed to evaluate the clinical impact of DEX for AWS.

A Case-Based Approach to the Practical Application of Dexmedetomidine in Critically Ill Adults

Dexmedetomidine is a selective α2‐adrenoceptor agonist that offers unique sedation because patients are readily awakened while administration continues and the drug does not suppress the respiratory center. Limitations of use include higher acquisition cost, inability to produce deep sedation, and bradycardia and hypotension. Using a case‐based approach, the purpose of this review was to qualitatively assess the role of dexmedetomidine in the care of the critically ill and in the management of alcohol withdrawal, and to formulate recommendations regarding its clinical application. Sixty‐six studies were identified that investigated dexmedetomidine for the provision of sedation. These studies were heterogeneous in design and patient populations; most investigated patients did not require heavy sedation, and few used propofol as the comparator. In general, though, the aggregate results of all studies demonstrate that dexmedetomidine provides comfort, possibly shortens the duration of mechanical ventilation to facilitate extubation, reduces the occurrence of acute brain dysfunction, and facilitates communication, but the drug is associated with hemodynamic instability and requires the supplemental use of traditional sedative and analgesic agents. These outcomes need to be substantiated in additional studies that include assessments of cost‐effectiveness. Dexmedetomidine should be considered when patients require mild to moderate levels of sedation of short to intermediate time frames, and they qualify for daily awakenings with traditional sedative therapies. The data for dexmedetomidine in relation to alcohol withdrawal are limited to 12 retrospective reports representing a total of 127 patients. Its role for this indication requires further study, but it may be considered as adjunctive therapy when clinicians are concerned about respiratory suppression associated with escalating doses of γ‐aminobutyric acid agonists. Regardless of the indication for dexmedetomidine, the practitioner must closely monitor patient comfort and the occurrence of hemodynamic deviations with the realization that as‐needed administration of traditional sedatives and analgesics will be required and some degree of bradycardia and hypotension expected but intervention rarely required.

Intraventricular Daptomycin and Intravenous Linezolid for the Treatment of External Ventricular-Drain—Associated Ventriculitis Due to Vancomycin-Resistant Enterococcus faecium

Objective: To report the successful treatment of external ventricular-drain (EVD)– associated infection due to vancomycin-resistant Enterococcus faecium (VRE) with intraventricular daptomycin and intravenous linezolid. Case Summary: A 64-year-old white male with a complicated medical history was admitted to the neurosurgical unit with Scedosporium apiospermum meningitis and hydrocephalus requiring management with a right and left EVD. On day 28, cerebrospinal fluid cultures from the right EVD grew VRE. Despite initiation of intravenous linezolid, cultures from the right EVD remained positive. Intraventricular daptomycin 5 mg daily was initiated and administered into the right EVD for 7 days. Cerebrospinal fluid was collected from EVD outputs and analyzed for daptomycin concentrations. VRE in cultures from the EVD cleared after 1 day of therapy and no adverse effects were noted. Right and left EVD daptomycin concentrations were discordant throughout therapy by at least a 3-fold difference. First-dose peak and trough daptomycin concentrations in the cerebrospinal fluid were 112.2 and 1.34 μg/mL, respectively, for the right EVD and 37.4 and 0.37 μg/mL, respectively, for the left EVD. Daptomycin accumulation was evident after 3 days of therapy. Discussion: Varying doses and frequencies of intraventricular daptomycin have been reported effective for VRE ventriculitis. Intraventricular drug distribution may not be homogeneous throughout the central nervous system. Therefore, daptomycin minimum inhibitory concentration for VRE, cerebrospinal fluid communication throughout the central nervous system, EVD output, and the potential for drug accumulation should be considered when selecting a dose and frequency. Conclusions: Intraventricular daptomycin may be an option for EVD-associated VRE infections that do not respond to conventional therapy. Intraventricular daptomycin 5 mg is a reasonable initial dose in adults with VRE ventriculitis, based on our experience in this patient.

A comparison of dexmedetomidine and placebo on the plasma concentrations of NGF, BDNF, GDNF, and epinephrine during severe alcohol withdrawal

Alcohol withdrawal and therapies may affect nerve growth factor (NGF), brain-derived neurotrophic growth factor (BDNF), glial-derived neurotrophic growth factor (GDNF), and epinephrine (EPI). This study evaluated dexmedetomidine (DEX) on NGF, BDNF, GDNF, and EPI in severe alcohol withdrawal and related their plasma concentrations to DEX concentrations. Twenty-four subjects were randomized to DEX 1.2 mcg/kg/hour (high dose [HD]), 0.4 mcg/kg/hour (low dose [LD]), or placebo. Blood was collected at 0 (T0), 48 (T48), and 96-120 (T96) hours after starting the study drug, and concentrations of these transmitters and DEX were determined. Similar NGF suppression occurred at T48 and T96 across all groups. BDNF and GDNF levels increased insignificantly at T48 in the placebo group but steadily declined in both DEX groups, with a trend toward significance in the HD group at T48. EPI concentrations declined significantly in the HD group at T48, only to increase at T96. Median DEX concentrations during the study were insignificantly higher in HD than LD. T0 values of BDNF (r = -0.47, p = 0.02) and GDNF (r = -0.37, p = 0.05) were inversely associated with the need for mechanical ventilation before study enrollment. No other clinical parameter was associated with the plasma concentrations of these transmitters. Daily lorazepam requirements were associated with the severity of withdrawal (r = 0.7, p < 0.0001) and DEX concentrations were inversely related to daily lorazepam requirements (r = -0.33, p = 0.008). DEX utilization suppressed EPI (r = -0.57, p = 0.004). EPI concentrations were associated with BDNF values at T0 (r = 0.55, p = 0.04) and throughout the study (r = 0.25, p = 0.04). In summary, the plasma concentrations of NGF, BDNF, GDNF, and EPI during alcohol withdrawal are variable and the effects of DEX were marginal. DEX administration and higher DEX concentrations attenuated lorazepam administration in the short-term and suppressed EPI.

A survey of prescriber perceptions about the prevention of stress‐related mucosal bleeding in the intensive care unit

Practices vary between institutions and amongst prescribers regarding when to initiate stress ulcer prophylaxis (SUP), which agent to choose (including doses and frequencies) and rationale, and decisions about escalation or discontinuation of therapy. The purpose of this survey is to evaluate the perceptions of prescribers about risk assessment of stress‐related mucosal bleeding (SRMB) and practice patterns of SUP.

Evaluation of Sulfobutylether-β-Cyclodextrin Exposure in a Critically Ill Patient Receiving Intravenous Posaconazole While Undergoing Continuous Venovenous Hemofiltration

ABSTRACT We present a 31-year-old female who had undergone an allogeneic bone marrow transplantation and who was started on intravenous posaconazole for pulmonary mycosis while undergoing continuous venovenous hemofiltration (CVVH). We performed steady-state pharmacokinetic evaluations for both posaconazole and sulfobutylether-β-cyclodextrin (SBECD). SBECD was effectively removed by CVVH, with observed exposure similar to that for patients with moderate renal impairment. Intravenous posaconazole at standard doses may be utilized in critically ill patients undergoing CVVH without significant risk of SBECD accumulation.

A Retrospective Cohort Analysis of Pharmacologic VTE Prophylaxis and Padua Prediction Score in Hospitalized Patients With Chronic Liver Disease

Purpose: Coagulopathy resulting from chronic liver disease (CLD) creates uncertainty regarding the risks and efficacy of pharmacologic venous thromboembolism (VTE) prophylaxis (ppx). We aim to describe patient characteristics associated with VTE ppx and the clinical impact of ppx in hospitalized patients with CLD. Methods: This retrospective study included patients with CLD, an international normalized ratio (INR) of ≥1.3, and hospital stay of ≥72 hours. Baseline characteristics, incidence of VTE, and major bleeding were compared between patients given ppx and those not given ppx. Results: Of 300 patients with CLD included, 157 (52%) received VTE ppx. Characteristics associated with VTE ppx were lower activated partial thromboplastin time, INR, bilirubin, and Model for End-Stage Liver Disease (MELD) score as well as a higher Padua Prediction Score, hemoglobin, platelet count, and antiplatelet use. VTE occurred in 12 (7.6%) ppx versus 4 (2.8%) non-ppx patients (P = .07). Major bleeding occurred in 47 (30%) ppx versus 49 (34.3%) non-ppx patients (P = .46). Ppx was not associated with VTE or bleeding outcomes by multivariate regression. Conclusion: The use of VTE ppx in hospitalized patients with CLD was not associated with a lower risk of VTE nor did it increase the risk of bleeding. Further studies examining the risks and benefits of VTE ppx in this population are needed.