Pierre Voirol

Impact of the introduction of real-time therapeutic drug monitoring on empirical doses of carbapenems in critically ill burn patients

PURPOSE Adequate empirical antibiotic dose selection for critically ill burn patients is difficult due to extreme variability in drug pharmacokinetics. Therapeutic drug monitoring (TDM) may aid antibiotic prescription and implementation of initial empirical antimicrobial dosage recommendations. This study evaluated how gradual TDM introduction altered empirical dosages of meropenem and imipenem/cilastatin in our burn ICU. METHODS Imipenem/cilastatin and meropenem use and daily empirical dosage at a five-bed burn ICU were analyzed retrospectively. Data for all burn admissions between 2001 and 2011 were extracted from the hospitals computerized information system. For each patient receiving a carbapenem, episodes of infection were reviewed and scored according to predefined criteria. Carbapenem trough serum levels were characterized. Prior to May 2007, TDM was available only by special request. Real-time carbapenem TDM was introduced in June 2007; it was initially available weekly and has been available 4 days a week since 2010. RESULTS Of 365 patients, 229 (63%) received antibiotics (109 received carbapenems). Of 23 TDM determinations for imipenem/cilastatin, none exceeded the predefined upper limit and 11 (47.8%) were insufficient; the number of TDM requests was correlated with daily dose (r=0.7). Similar numbers of inappropriate meropenem trough levels (30.4%) were below and above the upper limit. Real-time TDM introduction increased the empirical dose of imipenem/cilastatin, but not meropenem. CONCLUSIONS Real-time carbapenem TDM availability significantly altered the empirical daily dosage of imipenem/cilastatin at our burn ICU. Further studies are needed to evaluate the individual impact of TDM-based antibiotic adjustment on infection outcomes in these patients.

Massive copper and selenium losses cause life-threatening deficiencies during prolonged continuous renal replacement

OBJECTIVE Several trace elements are essential for immunity and wound healing, particularly after major burns. Continuous renal replacement therapy (CRRT), which is used to treat renal failure, causes significant trace elements losses. The aim of the present review is to update the current literature and draw attention to this type of complication, as copper deficiency is rarely suspected and diagnosed in clinical conditions and may occur in chronic critically ill patients. METHODS This is an emblematic case report and review of literature. RESULTS Major copper and selenium deficiencies were documented in a patient with major burns complicated by renal failure. The main cause was effluent loss during prolonged CRRT. The copper deficit resulted in life-threatening bradycardia and the alteration of lipid metabolism with severe hypertriglyceridemia. The published data are scarce, but trace element losses with effluent have been previously documented, as has the affect of copper deficiency on cardiac rhythm. CONCLUSION The literature regarding the specific requirements for chronically critically ill patients is limited. During prolonged CRRT, copper and selenium levels decrease and probably should be monitored during prolonged therapy. Research in this area is required.

Effective Treatment of Invasive Aspergillus fumigatus Infection Using Combinations of Topical and Systemic Antifungals in a Severely Burned Patient.

The authors describe an invasive Aspergillus fumigatus deep-burn wound infection in a severely burned patient that was successfully treated with a combination of topical terbinafine and systemic voriconazole antifungal therapy. To our knowledge, this is the first case report describing the effective control of an invasive deep-burn wound infection using this combination.

In vitro compatibility of remifentanil hydrochloride and sufentanil citrate with selected drugs

Objectives Physicochemical incompatibilities between intravenous drugs are a recurrent problem in intensive care units. The present study was aimed at investigating the physical compatibility of remifentanil and sufentanil with other drugs (insulin, midazolam, propofol, potassium chloride, magnesium sulfate, furosemide, heparin, monobasic potassium phosphate) that are frequently administered together intravenously. In addition, the physicochemical compatibility of three common associations of drugs was evaluated in glass tube tests and during dynamic simulated Y site administrations (remifentanil–insulin–midazolam; remifentanil–insulin–propofol; sufentanil–insulin–midazolam). Methods Physical compatibility was verified by visual inspection of the various mixtures (two, three or four drugs) in glass tubes and by pH determination of the mixtures collected during simulated Y site administrations. Solutions were considered as compatible in the absence of any visual change in the solution and of any significant variation in pH value. In addition, chemical stability was checked during in vitro dynamic simulations. The solutions were prepared in 50 ml syringes, placed on syringe pumps and connected to a Swan-Ganz catheter; the liquid collected at the tip was assayed by high performance liquid chromatography. Results In the visual examinations, only the associations of remifentanil and furosemide were incompatible. The three assayed associations were compatible in the tested proportion range over 24 h. Conclusions Remifentanil was physically compatible with the tested drugs, except for furosemide (Lasix; Sanofi-Aventis, 250 mg/25 ml) and physicochemically compatible with insulin and midazolam and insulin and propofol. Sufentanil was physically compatible with all tested drugs and physicochemically compatible with insulin and midazolam.

Recombinant factor VIIa for intractable life-threatening bleeding in patients with circulatory assist devices.

Dear Editor, Circulatory assist devices require tight anticoagulation therapy and may be complicated by severe bleeding. Despite warnings related to potential lethal thrombotic complications, offlabel use of recombinant factor VIIa (rFVIIa) is increasingly reported for refractory hemorrhage, including after cardiac surgery [1, 2]. However, its use in patients with circulatory assist devices has seldom been reported and its safety remains to be established [3–5]. We reviewed 12 consecutive patients with surgically implanted devices who received rFVIIa as rescue treatment for intractable lifethreatening bleeding between March 2004 and November 2009 (Table 1). According to strict and constringent local consensus guidelines, a systematic cross-check for aggressive correction of hypothermia, acidosis, and coagulation factors with parallel surgical control for bleeding or embolization was obtained before rFVIIa administration in all cases. The median age of patients was 45 years. The rFVIIa was administered in the operating room (3/12), in the intensive care unit (7/12), or both (2/12). Underlying conditions were cardiovascular surgery (11/12, including 4 heart transplantations) and bipulmonary transplantation (1/12). The device was an extracorporal membrane oxygenator (9/12) and a left ventricular assist device (3/12). Median dose of rFVIIa was 95 lg/kg (45–180), administered in one (3/12) or several doses (9/12). In these otherwise terminal patients, the bleeding assessed by the number of ml/kg of packed red blood cells and fresh frozen plasma requirement within 12 h before and after rFVIIa administration was significantly reduced. Six patients (50%) died within 30 days, including 2 (18%) from persistent bleeding. A careful analysis of coagulation and other physiological parameters did not reveal significant difference between responders and non-responders.

Impact of Real-Time Therapeutic Drug Monitoring on the Prescription of Antibiotics in Burn Patients Requiring Admission to the Intensive Care Unit

ABSTRACT As pharmacokinetics after burn trauma are difficult to predict, we conducted a 3-year prospective, monocentric, randomized, controlled trial to determine the extent of under- and overdosing of antibiotics and further evaluate the impact of systematic therapeutic drug monitoring (TDM) with same-day real-time dose adaptation to reach and maintain antibiotic concentrations within the therapeutic range. Forty-five consecutive burn patients treated with antibiotics were prospectively screened. Forty fulfilled the inclusion criteria; after one patient refused to participate and one withdrew consent, 19 were randomly assigned to an intervention group (patients with real-time antibiotic concentration determination and subsequent adaptations) and 19 were randomly assigned to a standard-of-care group (patients with antibiotic administration at the physicians discretion without real-time TDM). Seventy-three infection episodes were analyzed. Before the intervention, only 46/82 (56%) initial trough concentrations fell within the range. There was no difference between groups in the initial trough concentrations (adjusted hazard ratio = 1.39 [95% confidence interval {CI}, 0.81 to 2.39], P = 0.227) or the time to reach the target. However, thanks to real-time dose adjustments, the trough concentrations of the intervention group remained more within the predefined range (57/77 [74.0%] versus 48/85 [56.5%]; adjusted odd ratio [OR] = 2.34 [95% CI, 1.17 to 4.81], P = 0.018), more days were spent within the target range (193 days/297 days on antibiotics [65.0%] versus 171 days/311 days in antibiotics [55.0%]; adjusted OR = 1.64 [95% CI, 1.16 to 2.32], P = 0.005), and fewer results were below the target trough concentrations (25/118 [21.2%] versus 44/126 [34.9%]; adjusted OR = 0.47 [95% CI, 0.26 to 0.87], P = 0.015). No difference in infection outcomes was observed between the study groups. Systematic TDM with same-day real-time dose adaptation was effective in reaching and maintaining therapeutic antibiotic concentrations in infected burn patients, which prevented both over- and underdosing. A larger multicentric study is needed to further evaluate the impact of this strategy on infection outcomes and the emergence of antibiotic resistance during long-term burn treatment. (This study was registered with the ClinicalTrials.gov platform under registration no. NCT01965340 on 27 September 2013.)

In vitro compatibility of various cardioactive drugs during simulated Y-site administration

Objectives Physicochemical incompatibilities between intravenous drugs are a recurrent problem in ICUs. A study was undertaken to evaluate the physicochemical compatibility of five common associations of cardioactive drugs: dopamine (DA)–norepinephrine (NE); dobutamine (DU)–NE; amiodarone (AM)–DU–NE; DU–sodium nitroprusside (NI)±sodium thiosulfate (THIO); and NI–THIO. Methods The drugs were diluted in the usual manner performed in the ICU. Their compatibility was verified by visual inspection of the different mixtures in glass tubes and by chemical assays and pH determination of the mixtures collected during in vitro simulated Y-site administration (solutions prepared in syringes placed on syringe pumps and connected to a Swan–Ganz catheter). Solutions were considered to be compatible in the absence of any visual change in the solution and of any significant variation in pH value and drug concentration at each time of the study. Results DA–NE, DU–NE, DU–NI (±THIO) and NI–THIO associations were compatible over 24 h in the tested proportion ranges, with the proviso that NI was protected from light. In addition, it was observed that AM, DU and NE were compatible but, in the dynamic simulation, AM reached the expected concentration only after 4 h. Conclusions When combined, the cardioactive amines were stable over 24 h. AM was compatible with DU and NE, but with a latency period owing to its adsorption on the heparin-coated Swan–Ganz catheter. Mixtures involving NI were compatible provided that NI was supplied in amber syringes or protected with aluminum foil.

Medication reconciliation in a Swiss hospital: methods, benefits and pitfalls

Objectives To assess the feasibility and main obstacles to the implementation of a medication reconciliation (MR) process in a Swiss hospital and to develop a standardised method which can be used in similar healthcare systems. Methods For this prospective, observational single-centre and single-ward study, a best possible medication history (BPMH) was established by a clinical pharmacist for 147 patients with heart failure based on two sources and a patient interview for each case. Identified discrepancies with medication histories established during emergency service were conveyed to the ward physician. At the end of each hospital stay, the planned discharge treatments were compared with the BPMHs to identify discrepancies and to propose modifications. After a final validation, the comparative treatment plans were distributed. Results MR was conducted for 120 (82%) patients and the mean time needed was 74 min/patient. At least one discrepancy was identified among 94% of the patients on admission, with 4.1 discrepancies found per patient (mainly omissions). At discharge, 83% of the patients had at least one discrepancy, with 2.3 discrepancies found per patient (mainly unintentional substitutions). The majority (86%) of pharmaceutical interventions to adjust the discharge prescriptions were accepted by the physician. Conclusions A standardised method of MR which offers precise definitions of discrepancies and key tools for the process was developed. This method was applicable to most of our cohort and it effectively identified medication discrepancies. Two potential obstacles for its implementation are the time needed for MR and the questionable impact of pharmaceutical interventions on discrepancies.

4CPS-173 Cancer pain assessment and associated analgesics prescriptions

Background The ultimate objective of cancer pain management is the elimination or reduction to bearable levels. Evaluating pain should use validated instruments. Our institution’s strategy involves asking patients to self-report pain intensity using a 10-level Numerical Rating Scale (NRS) (mild (1–3) moderate (4–6), severe (7–10)) correlating with the WHO pain ladder and recommended dosing guidelines.1 Purpose To determine how pain was evaluated, its intensity and prevalence, and whether guidelines were applied. This will be a starting point for comparisons when implementing and evaluating future strategies to improve oncological pain management. Material and methods Retrospective study of data from all patients hospitalised in our university hospital oncology unit from 15 March to 15 June 2017 who gave informed consent. Data retrieved from patients’ medical records included means of pain intensity evaluation, intensity, prescribed analgesic doses and administration routes. Results One hundred and sixteen patients were included, representing 153 hospitalisations and 1701 evaluations, of which 940 were positive for pain. 693 evaluations used non-validated qualitative-scale criteria; 356 evaluations used the NRS; and 109 were mixed evaluations. NRS-evaluated pain levels and analgesics for treatment were: mild pain=37% (WHO ladder 1=38%, ladder 2=3%, ladder 3=55%, other adjuvant=4%); moderate pain=44%, (WHO ladder 1=30%, ladder 2=4%, ladder 3=58%); and severe pain=19% (WHO ladder 1=34%, ladder 2=4%, ladder 3=52%, other adjuvant=9%). Concerning good dosing practices, independently of pain level, the most used WHO ladder 3 analgesic was morphine (52% parenteral (38% subcutaneous, 14% intravenous), 48% PO (33% sirup)), involving single 4-hourly morphine doses: subcutaneous (2–8 mg) of which 59%<5 mg; intravenous (2–6 mg) of which 24%<5 mg; sirup (1–15 mg): of which 89%<10 mg. Conclusion Because most pain intensity evaluations are made without using a validated ladder, drawing conclusions about whether good dosing-practice guidelines are being followed is impossible, and reliable prevelance rates cannot be calculated. We must understand whether pain assessment is inadequately done or whether the problem involves documentation. Considering our NRS results, it seems that both the presence of pain and its intensity remain highly problematic within our unit. Another concern is why prescribers favour seemingly weak subcutaneous morphine doses. Oral morphine doses also seem affected by under-dosage. Further research is needed. Reference and/or Acknowledgements 1. Ripamonti C. Annals of Oncology2012:23(7). No conflict of interest

Screening for physicochemical incompatibilities of intravenous drugs in intensive care units: the case of monobasic potassium phosphate and furosemide

Objectives Physicochemical incompatibilities between intravenous drugs are a recurrent problem in hospital settings. Having observed a drug precipitation during Y-site administration in our intensive care units, we undertook an investigation to find out its cause. Methods We conducted a literature search on the injectable drugs involved in the observed precipitates and undertook laboratory physicochemical incompatibility testing of potentially incompatible drug combinations not reported in the literature. Results Among the drugs tested, only furosemide with midazolam or with monobasic potassium phosphate was physically incompatible. The pH-dependent solubility of furosemide was the origin of the observed incompatibilities. Conclusions Monobasic potassium phosphate is not compatible with furosemide in the concentration range used in our intensive care unit and should not be administered together in the same intravenous line. Other drug formulations buffered to a low pH should not be administered with furosemide solutions either.