Physical and Chemical Compatibility of Medications Commonly Used in Critically Ill Patients With Balanced Crystalloids: A Systematic Review.

OBJECTIVE: Evaluate available evidence of physical and/or chemical compatibility of commonly used medications in critically ill patients with balanced crystalloids. DATA SOURCES: Ovid MEDLINE, Embase, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews were queried from inception to September 2022. STUDY SELECTION AND DATA EXTRACTION: This review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. English-language studies reporting physical and/or chemical compatibility data between 50 selected medications and balanced crystalloids were included. A previously designed tool to assess risk of bias was adapted for use. DATA SYNTHESIS: Twenty-nine studies encompassing 39 (78%) medications and 188 unique combinations with balanced crystalloids were included. Combinations included 35 (70%) medications with lactated Ringer's, 26 (52%) medications with Plasma-Lyte, 10 (20%) medications with Normosol, and one (2%) medication with Isolyte. Studies commonly evaluated physical and chemical compatibility (55.2%). More medications were evaluated via Y-site than admixture. Incompatibilities were identified in 18% of combinations comprising 13 individual drugs. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: This systematic review evaluates the compatibility of select critical care medications with balanced crystalloid solutions. Results may be used as a tool to guide clinicians on balanced crystalloid compatibility, potentially increasing ubiquitous use and reducing patient exposure to normal saline. CONCLUSION AND RELEVANCE: Data are limited regarding chemical/physical compatibility of commonly used medications in critically ill patients with balanced crystalloids. Additional compatibility studies are warranted, particularly methodologically rigorous studies assessing Plasma-Lyte, Normosol, and Isolyte. Of the evaluated medications, there was a low frequency of incompatibilities with balanced crystalloids.

Enteral feeding tolerance during pharmacologic neuromuscular blockade.

A common misperception is that critically ill patients who receive paralytic therapy will not tolerate enteral nutrition. As a result, some clinicians empirically withhold enteral feedings for critically ill patients who receive neuromuscular blocker pharmacotherapy (NMB). The intent of this review is to examine the evidence regarding enteral feeding tolerance for critically ill patients given NMB. Studies evaluating enteral feeding during paralytic therapy are provided and critiqued. Evidence examining enteral feeding tolerance during NMB is limited. Enteral feeding intolerance is more likely attributable to the underlying illnesses and concurrent opioid analgesia, sedation, and vasopressor therapies. Most critically ill patients can be successfully fed during NMB. Prokinetic pharmacotherapy may be warranted in some patients.

Carboxylesterase-2 plays a critical role in dabigatran etexilate active metabolite formation.

Dabigatran etexilate (DABE), an oral anticoagulant prodrug, is nearly completely metabolized to the dabigatran (DAB) active metabolite by carboxylesterase-1 (CES1) and carboxylesterase-2 (CES2). The high interpatient variation in DAB plasma concentrations, coupled with its low therapeutic index, emphasizes the need to understand how CES1 and CES2 impact active metabolite formation. Previous work focused on CES1 enzyme activity but the contributions of CES2 remain unclear. The purpose of this study was to determine how CES2 activity influences DAB active metabolite formation. We compared the efficiency of DAB formation from DABE when exposed sequentially to human intestinal and then human hepatic microsomes (mimicking the normal metabolic sequence) with the reverse metabolic sequence in which DABE is exposed to hepatic and then intestinal microsomes. The poor efficiency of DAB formation with reverse sequential hydrolysis indicates that CES2 activity is crucial for active metabolite formation. Thus, the decrease in DAB formation with normal sequential hydrolysis was more sensitive to CES2 inhibition by verapamil (CES2 IC50 = 3.4 µM) than CES1 inhibition by diltiazem (CES2 IC50 = 9.1 µM). These results show CES2 activity plays a crucial role in DAB formation and that variability in its activity is an important determinant of therapeutic response.

Correlation of antimicrobial fraction unbound and sieving coefficient in critically ill patients on continuous renal replacement therapy: a systematic review.

BACKGROUND: Fraction unbound has been used as a surrogate for antimicrobial sieving coefficient (SC) to predict extracorporeal clearance in critically ill patients on continuous renal replacement therapy (CRRT), but this is based largely on expert opinion. OBJECTIVES: To examine relationships between package insert-derived fraction unbound (Fu-P), study-specific fraction unbound (Fu-S), and SC in critically ill patients receiving CRRT. METHODS: English-language studies containing patient-specific in vivo pharmacokinetic parameters for antimicrobials in critically ill patients requiring CRRT were included. The primary outcome included correlations between Fu-S, Fu-P, and SC. Secondary outcomes included correlations across protein binding quartiles, serum albumin, and predicted in-hospital mortality, and identification of predictors for SC through multivariable analysis. RESULTS: Eighty-nine studies including 32 antimicrobials were included for analysis. SC was moderately correlated to Fu-S (R2 = 0.55, P < 0.001) and Fu-P (R2 = 0.41, P < 0.001). SC was best correlated to Fu-S in first (<69%) and fourth (>92%) quartiles of fraction unbound and above median albumin concentrations of 24.5 g/L (R2 = 0.71, P = 0.07). Conversely, correlation was weaker in patients with mortality estimates greater than the median of 55% (R2 = 0.06, P = 0.84). SC and Fu-P were also best correlated in the first quartile of antimicrobial fraction unbound (R2 = 0.66, P < 0.001). Increasing Fu-P, flow rate, membrane surface area, and serum albumin, and decreasing physiologic charge significantly predicted increasing SC. CONCLUSIONS: Fu-S and Fu-P were both reasonably correlated to SC. Caution should be taken when using Fu-S to calculate extracorporeal clearance in antimicrobials with 69%-92% fraction unbound or with >55% estimated in-hospital patient mortality. Fu-P may serve as a rudimentary surrogate for SC when Fu-S is unavailable.

Evaluation of a patient specific, targeted-intensity pharmacologic thromboprophylaxis protocol in hospitalized patients with COVID-19.

Patients with COVID-19 are at higher risk of thrombosis due to the inflammatory nature of their disease. A higher-intensity approach to pharmacologic thromboprophylaxis may be warranted. The objective of this retrospective cohort study was to determine if a patient specific, targeted-intensity pharmacologic thromboprophylaxis protocol incorporating severity of illness, weight, and biomarkers decreased incidence of thrombosis in hospitalized patients with COVID-19. Included patients were hospitalized with COVID-19 and received thromboprophylaxis within 48 h of admission. Exclusion criteria included receipt of therapeutic anticoagulation prior to or within 24 h of admission, history of heparin-induced thrombocytopenia, extracorporeal membrane oxygenation, pregnancy, or incarceration. Per-protocol patients received thromboprophylaxis according to institutional protocol involving escalated doses of anticoagulants based upon severity of illness, total body weight, and biomarker thresholds. The primary outcome was thrombosis. Secondary outcomes included major bleeding, mortality, and identification of risk factors for thrombosis. Of 1189 patients screened, 803 were included in the final analysis. The median age was 54 (42-65) and 446 (55.5%) were male. Patients in the per-protocol group experienced significantly fewer thrombotic events (4.4% vs. 10.7%, p = 0.002), less major bleeding (3.1% vs. 9.6%, p < 0.001), and lower mortality (6.3% vs. 11.8%, p = 0.02) when compared to patients treated off-protocol. Significant predictors of thrombosis included mechanical ventilation and male sex. Post-hoc regression analysis identified mechanical ventilation, major bleeding, and D-dimer ≥ 1500 ng/mL FEU as significant predictors of mortality. A targeted pharmacologic thromboprophylaxis protocol incorporating severity of illness, body weight, and biomarkers appears effective and safe for preventing thrombosis in patients with COVID-19.

Tigecycline to treat Stenotrophomonas maltophilia ventilator-associated pneumonia in a trauma intensive care unit as a result of a drug shortage: A case series.

WHAT IS KNOWN AND OBJECTIVE: Stenotrophomonas maltophilia is an intrinsically multidrug-resistant (MDR) organism which commonly presents as a respiratory tract infection. S. maltophilia is typically treated with high-dose sulfamethoxazole/trimethoprim (SMX/TMP). However, SMX/TMP and other treatment options for S. maltophilia can be limited because of resistance, allergy, adverse events or unavailability of the drug; use of novel agents may be necessary to adequately treat this MDR infection and overcome these limitations. CASE DESCRIPTION: This small case series describes two patients who underwent treatment with tigecycline for ventilator-associated pneumonia (VAP) caused by S. maltophilia after admission to a trauma intensive care unit. At the time of admission for the two reported patients, a national drug shortage of intravenous (IV) SMX/TMP prevented its use. Tigecycline was chosen as a novel agent to treat S. maltophilia VAP based on culture and susceptibility data, and it was used successfully. Both patients showed clinical signs of improvement with eventual cure and discharge from the hospital after treatment with tigecycline, and one patient demonstrated confirmed microbiological cure with a negative repeat bronchoscopic bronchoalveolar lavage (BAL). WHAT IS NEW AND CONCLUSION: To our knowledge, this small case series is the first documentation of utilizing tigecycline to treat S. maltophilia VAP in the United States. Although it likely should not be considered as a first-line agent, tigecycline proved to be an effective treatment option in the two cases described in the setting of a national drug shortage of the drug of choice.