Catching the Culprit: Benzylpenicillin Neurotoxicity Confirmed by Therapeutic Drug Monitoring in a Critically Ill Patient With Continuous Venovenous Hemofiltration.

ABSTRACT: We present the case of a 65-year-old patient who was treated with high-dose benzylpenicillin for severe invasive pneumococcal pneumonia, complicated by acute renal failure managed with continuous venovenous hemofiltration. After cessation of continuous venovenous hemofiltration, the patient experienced multiple tonic-clonic seizures. Therapeutic drug monitoring revealed high total serum concentrations of benzylpenicillin, identifying it as the likely cause of the neurotoxicity. This case study presents the first documented total serum benzylpenicillin concentration associated with neurotoxicity.

Tacrolimus Variability and Clinical Outcomes in the Early Post-lung Transplantation Period: Oral Versus Continuous Intravenous Administration.

BACKGROUND AND OBJECTIVE: High variability in tacrolimus pharmacokinetics directly after lung transplantation (LuTx) may increase the risk for acute kidney injury (AKI) and transplant rejection. The primary objective was to compare pharmacokinetic variability in patients receiving tacrolimus orally versus intravenously early after LuTx. METHODS: Pharmacokinetic and clinical data from 522 LuTx patients transplanted between 2010 and 2020 in two university hospitals were collected to compare orally administered tacrolimus to intravenous tacrolimus early post-transplantation. Tacrolimus blood concentration variability, measured as intrapatient variability (IPV%) and  percentage of time within the therapeutic range (TTR%), was analyzed within the first 14 days after LuTx. Secondary outcomes were AKI, acute rejection, length of stay in the intensive care unit (ICU), and mortality in the ICU and during hospital admission. RESULTS: We included 224 patients in the oral and 298 in the intravenous group. The mean adjusted IPV% was 10.8% (95% confidence interval [CI] 6.9-14.6; p < 0.001) higher in the oral group (27.2%) than the intravenous group (16.4%). The mean TTR% was 7.3% (95% CI - 11.3 to - 3.4; p < 0.001) lower in the oral group (39.6%) than in the intravenous group (46.9%). The incidence of AKI was 46.0% for oral and 42.6% for intravenous administration (adjusted odds ratio [OR] 1.2; 95% CI 0.8-1.8; p = 0.451). The frequencies of clinically diagnosed acute rejection in the oral and intravenous groups were nonsignificant (24.6% vs 17.8%; OR 1.5 [95% CI 1.0-2.3; p = 0.059]). ICU and hospital mortality rate and ICU length of stay were similar. CONCLUSIONS: Administering tacrolimus orally directly after LuTx leads to a higher variability in blood concentrations compared to intravenous administration. There was no difference in the occurrence of AKI or transplant rejection.

Continuous infusion of cefiderocol in a critically ill patient with continuous venovenous haemofiltration.

Cefiderocol is a broad-spectrum cephalosporin antibiotic and is indicated in patients with difficult-to-treat Gram-negative bacterial infections. Cefiderocol is applied as a 2-4-times daily prolonged 3-h infusion. The therapeutic target of cefiderocol suggests that continuous infusion (CI) may be advantageous, since it is more likely to achieve 100% of time of the unbound concentration above the minimal inhibitory concentration (MIC). However, limited information on cefiderocol as CI has been assessed. We present a case of a critically ill 37-year-old woman with continuous venovenous haemofiltration (CVVH) treated with a CI of cefiderocol for multidrug-resistant Pseudomonas aeruginosa. She received 4 g per 24 h, in accordance with the recommendations for the total daily dose during CVVH with an effluent flow rate of 2.1-3 L/h. We evaluated intraperitoneal, plasma arterial pre- and postfilter and ultrafiltrate (urine) total cefiderocol concentrations and discussed the pharmacokinetics in respect to the CVVH settings. The predicted unbound plasma concentrations during CI resulted in 6.8-9.5-fold higher concentrations than the adopted MIC of 2 mg/L for cefiderocol against P. aeruginosa. The optimal time of the unbound concentration >MIC target of cefiderocol was met during the sampling period, suggesting adequate exposure during the total treatment period. The obtained intraperitoneal concentration indicated adequate cefiderocol exposure at the site of infection. Continuous infusion of 4 g cefiderocol per 24 h led to sufficient plasma concentrations in our anuric critically ill patient treated with CVVH. This case is supportive to the use of cefiderocol as continuous infusion.

Drug waste of ready-to-administer syringes in the intensive care unit: Aseptically prepared syringes versus prefilled sterilized syringes.

BACKGROUND: The availability of ready-to-administer (RTA) syringes for intravenous (IV) drugs facilitates rapid and safe administration in emergency and intensive care situations. Hospital pharmacies can prepare RTA syringes through aseptic batchwise filling. Due to excess production of these RTA syringes for sufficient availability for patient care and their limited (microbiological) shelf-life, waste is unavoidable, which contributes to environmental pollution. RTA prefilled sterilized syringes (PFSSs) have much longer shelf-lives than aseptically prepared RTA syringes and might contribute to reducing drug waste. AIM: This study aimed to evaluate the difference in drug waste between RTA syringes that were prepared through aseptic batchwise filling and RTA PFSSs in the Intensive Care Unit (ICU). METHODS: We measured drug waste of RTA syringes over an 8-year time period from August 2015 to May 2023 in the 32-bed ICU of the University Medical Center Utrecht. We distinguished between RTA syringes prepared through aseptic batchwise filling by our hospital pharmacy ("RTA aseptic syringes", shelf-life of 31 days) and RTA PFSSs (shelf-life of 18 months). An intervention group of three drug products that were replaced by PFSSs was compared to a control group of five drug products that were not replaced by PFSSs during the study period. We then defined four different periods within the total study period, based on quarantine time of the RTA aseptic syringes and time of PFSS introduction: 1) no quarantine, 2) 3-day quarantine, 3) 7-day quarantine and 4) PFSS introduction. Our primary endpoint was the number of RTA syringes that was wasted, expressed as the percentage of the total number of syringes dispensed to the ICU in each of these four periods. We used a Kruskall-Wallis test to test if waste percentages differed between time periods in the control and intervention groups, with a post-hoc Dunn's test for pairwise comparisons. Furthermore, we applied two interrupted time series (ITS) analyses to visualize and test the effect of introducing different quarantine times and the PFSSs on waste percentage. RESULTS: Introduction of PFSSs significantly decreased drug waste of RTA syringes irrespective of drug type in the intervention group, from 31% during the 7-day quarantine period to 5% after introduction of the PFSS (p<0.001). The control group showed no significant decrease in drug waste over the same time periods (from 20% to 16%; p=0.726). We observed a significant difference in the total drug waste of RTA aseptic syringes between time periods, which may be attributed to the implementation of different quality control quarantine procedures. The ITS model of the intervention group showed a direct decrease of 17.7% in waste percentage after the introduction of PFSSs (p=0.083). CONCLUSION: Drug waste of RTA syringes for the ICU can be significantly decreased by introducing PFSSs, supporting hospitals to enhance environmental sustainability. Furthermore, the waste percentage of RTA syringes prepared through aseptic batchwise filling is significantly impacted by duration of quarantine time.

Influence of a strict glucose protocol on serum potassium and glucose concentrations and their association with mortality in intensive care patients.

INTRODUCTION: Tight glucose control therapy (TGC) has been implemented to control hyperglycemia in ICU patients. TGC may also influence serum potassium concentrations. We therefore investigated the influence of TGC on both serum glucose and serum potassium concentrations and associated mortality. METHOD: We performed a retrospective analysis including all patients admitted to the ICU of a tertiary hospital for 24 hours or more and with at least three serum glucose and serum potassium concentrations between 1999-2001 (conventional period), 2002-2006 (implementation period) or 2007-2009 (TGC period). Segmented regression analysis was used to estimate changes in outcomes that occurred after the intervention controlling for pre-intervention trends. Means and standard deviations (SDs) of serum glucose and serum potassium concentrations, and rate of severe hypoglycemia (≤ 2.2 mmol/L) and hypokalemia (≤ 3 mmol/L), were compared between the TGC and conventional period. RESULTS: Although mean serum glucose concentrations dropped 2.1 mmol/L (95% CI =-1.8 to -2.3 mmol/L, p<0.002), mean serum potassium concentrations did not change (absolute increase 0.02 mmol/L; 95% CI = -0.06 to 0.09 mmol/L, p=0.64). The rate of severe hypoglycemia increased with 5.9% (95% CI=-3.0 to -8.9, p<0.002), but the rate of hypokalemia remained equal (absolute reduction 4.8%; 95% CI = -11.1% to 1.5%, p=0.13). The SD of serum glucose concentrations within a patient did not change, while the SD of serum potassium concentrations even decreased 0.04 mmol/L (95% CI = -0.01 to -0.07, p = 0.01). ICU mortality decreased but this decrease was not significant (absolute difference -3.63%; 95% CI = -9.33 to 2.09, p = 0.20). Mean serum glucose concentrations, mean serum potassium concentrations and SDs of both serum glucose and serum potassium concentrations were all independently associated with ICU mortality. Highest mortality rates were seen at both the lowest and highest mean values (U/J-shaped association) and mortality rates increased with increasing variability (SDs) for both serum glucose and serum potassium concentrations. CONCLUSION: Our study shows that a TGC was not associated with an increased risk of serum potassium related events. Low and high mean values and high variability of both serum glucose and serum potassium concentrations are predictors for high ICU mortality.

Analysis of potential drug-drug interactions in medical intensive care unit patients.

OBJECTIVE: To describe the frequency and type of potential drug-drug interactions (pDDIs) in a general intensive care unit (ICU) and to make recommendations to improve the management of these pDDIs. DESIGN: Retrospective observational study. SETTING: General ICU of a tertiary care hospital. SUBJECTS: All patients admitted for more than 24 hours between May 2009 and December 2010 who were prescribed at least one medication. MEASUREMENT AND MAIN RESULTS: Based on the G-Standaard, the Dutch national drug database, pDDIs were identified and classified into categories of potential clinical outcome and management advice. In total, 35,784 medication episodes were identified, resulting in 2887 pDDIs (8.1%). These 2887 pDDIs occurred in 1659 patients for a mean frequency of 1.7 (95% confidence interval [CI] 1.6-1.9) pDDIs per patient. Overall, 54% of the patients experienced at least one pDDI with pDDIs present during 27% of all ICU admission days. All pDDIs could be reconstructed using 81 of the 358 (23%) relevant unique pDDI pairs described in the G-Standaard. The most frequently occurring potential clinical consequence was an increased risk of side effects or toxicity (91% of the pDDIs) such as electrolyte disturbances and masking of hypoglycemia. The most important advised management strategy was monitoring (81%), consisting of monitoring of laboratory values (52%), clinical monitoring of toxicity or effectiveness (48%), or monitoring of physical parameters such as electrocardiogram and blood pressure (11%). CONCLUSION: Potential drug-drug interactions occur in 54% of all ICU patients, which is two times more than the rate seen in patients on general wards. A limited set of 20 pDDI pairs is responsible for more than 90% of all pDDIs. Therefore, it is worthwhile to develop guidelines for the management of these specific pDDIs. As the vast majority of the interactions can be managed by monitoring, advanced clinical decision support systems linking laboratory data to prescription data may be an effective risk management strategy.

Lithium lacks effect on survival in amyotrophic lateral sclerosis: a phase IIb randomised sequential trial.

OBJECTIVES: To determine the safety and efficacy of lithium for the treatment of amyotrophic lateral sclerosis (ALS) in a randomised, placebo controlled, double blind, sequential trial. METHODS: Between November 2008 and June 2011, 133 patients were randomised to receive lithium carbonate (target blood level 0.4-0.8 mEq/l) or placebo as add-on treatment with riluzole. The primary endpoint was survival, defined as death, tracheostomal ventilation or non-invasive ventilation for more than 16 h/day. Secondary outcome measures consisted of the revised ALS Functional Rating Scale and forced vital capacity. Analysis was by intention to treat and according to a sequential trial design. RESULTS: 61 patients reached a primary endpoint, 33 of 66 in the lithium group and 28 of 67 patients in the placebo group. Lithium did not significantly affect survival (cumulative survival probability of 0.73 in the lithium group (95% CI 0.63 to 0.86) vs 0.75 in the placebo group (95% CI 0.65 to 0.87) at 12 months and 0.62 in the lithium group (95% CI 0.50 to 0.76) vs 0.67 in the placebo group (95% CI 0.56 to 0.81) at 16 months). Secondary outcome measures did not differ between treatment groups. No major safety concerns were encountered. CONCLUSIONS: This trial, designed to detect a modest effect of lithium, did not demonstrate any beneficial effect on either survival or functional decline in patients with ALS. TRIAL REGISTRATION NUMBER: NTR1448. Name of trial registry: Lithium trial in ALS.

Serum potassium influencing interacting drugs: risk-modifying strategies also needed at discontinuation.

BACKGROUND: Although the discontinuation of a medication may have important clinical consequences, there is generally much less attention given to medication surveillance when a drug is stopped than when it is started. OBJECTIVE: To investigate the consequences on serum potassium levels of discontinuing a drug that increases the serum potassium level (PID↑) and a drug that decreases the serum potassium level (PLD↓) in patients taking both. METHODS: Patients who were hospitalized in the University Medical Centre Utrecht in 2004-2009 and were using both a PID↑ and a PLD↓ were included when one of these drugs was discontinued during hospitalization. Serum potassium levels measured before (potassium(1)) and after (potassium(2)) discontinuation were compared in patients who stopped the PLD↓ and in patients who stopped the PID↑. RESULTS: In the group of patients who stopped the PLD↓ (ie, continued the PID↑), mean serum potassium levels increased 0.19 mEq/L (range -0.9 to 1.8 mEq/L). After discontinuation of the PLD↓, serum potassium levels increased in 91 (59%) patients. Five patients (3.2%) developed hyperkalemia (potassium(2) >5.5 mEq/L). In the group of patients who stopped the PID↑ (ie, continued the PLD↓), mean serum potassium levels decreased 0.40 mEq/L (range -2.6 to 0.7 mEq/L). Serum potassium levels decreased in 61 (70%) patients after discontinuation of the PID↑. Fifteen patients (17%) developed hypokalemia (potassium(2) <3.5 mEq/L). Results were not influenced by length of stay, age, sex, renal function, and type of medication discontinued. CONCLUSIONS: The effects of serum potassium-influencing drugs need to be monitored not only after starting but also after stopping the medication. The same may hold true for the effects of other drugs. Clinical risk management should therefore focus on the risks not only when new medication is prescribed, but also when medication is stopped.

Frequency of laboratory measurement and hyperkalaemia in hospitalised patients using serum potassium concentration increasing drugs.

PURPOSE: Although, drug-drug interactions (DDIs) between potassium-increasing drugs (PIDs) are known risk factors for developing hyperkalaemia, not much is known about their risk and management strategies during hospitalisation. This study examines the frequency of serum potassium measurements and hyperkalaemia in hospitalised patients, based on the use of one or more PIDs, and the determinants thereof. METHODS: Adult patients hospitalised in the University Medical Centre Utrecht between 2006 and 2008 were included in this cross-sectional study. The frequency of serum potassium measurements and of hyperkalaemia were compared between patients using only one PID at a time (monotherapy group) and patients using two or more PIDs concomitantly (interaction group). The determinants studied were renal failure, diabetes mellitus, use of diuretics, type of DDI, start of the PIDs within the hospital versus continued home medication and medical speciality. RESULTS: Serum potassium was measured more frequently in the interaction group than in the monotherapy group [67 vs. 56%; relative risk (RR) 1.19, 95% confidence interval (CI) 1.14-1.24] and the risk of hyperkalaemia was also increased in the interaction group (9.9 vs. 5.9%, RR 1.7, 95% CI 1.3-2.1). The combination of potassium-sparing diuretics plus a potassium supplement, start of the PID within the hospital and hospitalisation in non-internal medicine departments was associated with higher relative risk estimates for hyperkalaemia. CONCLUSIONS: Among our patient cohort, even when physicians received a direct pop-up to monitor serum potassium levels when prescribing two PIDs concomitantly, serum potassium levels were not measured in 33% of patients, and 10% of patients developed hyperkalaemia. Improved management strategies and/or clinical decision-support systems are needed to decrease the frequency of hyperkalaemia following DDIs.

Randomized sequential trial of valproic acid in amyotrophic lateral sclerosis.

OBJECTIVE: To determine whether valproic acid (VPA), a histone deacetylase inhibitor that showed antioxidative and antiapoptotic properties and reduced glutamate toxicity in preclinical studies, is safe and effective in amyotrophic lateral sclerosis (ALS) using a sequential trial design. METHODS: Between April 2005 and January 2007, 163 ALS patients received VPA 1,500mg or placebo daily. Primary end point was survival. Secondary outcome measure was decline of functional status measured by the revised ALS Functional Rating Scale. Analysis was by intention to treat and according to a sequential trial design. This trial was registered with ClinicalTrials.gov (number NCT00136110). RESULTS: VPA did not affect survival (cumulative survival probability of 0.72 in the VPA group [standard error (SE), 0.06] vs 0.88 in the placebo group [SE, 0.04] at 12 months, and 0.59 in the VPA group [SE, 0.07] vs 0.68 in the placebo group [SE, 0.08] at 16 months) or the rate of decline of functional status. VPA intake did not cause serious adverse reactions. INTERPRETATION: Our finding that VPA, at a dose used in epilepsy, does not show a beneficial effect on survival or disease progression in patients with ALS has implications for future trials with histone deacetylase inhibitors in ALS and other neurodegenerative diseases. The use of a sequential trial design allowed inclusion of only half the number of patients required for a classic trial design and prevented patients from unnecessarily continuing potentially harmful study medication.

Frequency and nature of drug-drug interactions in a Dutch university hospital.

AIM: Drug-drug interactions (DDIs) may lead to often preventable adverse drug events and health damage. Especially within hospitals, this might be an important factor, as patients are severely ill and multiple medications may be prescribed simultaneously. The objective of this study was to measure the frequency and nature of DDI alerts in a Dutch university hospital. METHODS: All patients hospitalized in the University Medical Centre Utrecht in 2006 who were prescribed at least one medication were included. The frequency of DDIs was calculated as: (i) the percentage of patients experiencing at least one DDI, and (ii) the percentage of prescriptions generating a DDI alert. Based on the national professional guideline, DDIs were classified into categories of potential clinical outcome, management advice, clinical relevance (A-F) and available evidence (0-4). RESULTS: Of the 21 277 admissions included, 5909 (27.8%) encountered at least one DDI. Overall, the prescribing physician received a DDI alert in 9.6% of all prescriptions. The most frequently occurring potential clinical consequence of the DDIs was an increased risk of side-effects such as increased bleeding risk (22.0%), hypotension (14.9%), nephrotoxicity (12.6%) and electrolyte disturbances (10.5%). Almost half (48.6%) of the DDIs could be managed by monitoring laboratory values. CONCLUSIONS: Computerized DDI alerts may be a useful tool to prevent adverse drug events within hospitals, but they may also result in 'alert fatigue'. The specificity of alerts could significantly improve by the use of more sophisticated clinical decision support systems taking into account, for example, laboratory values.