Are Antibiotics Appropriately Dosed in Critically Ill Patients with Augmented Renal Clearance? A Narrative Review.

Aims: Augmented renal clearance (ARC), which is commonly defined as increased renal clearance above 130 ml/min/1.73 m2, is a common phenomenon among critically ill patients. The increased elimination rate of drugs through the kidneys in patients with ARC can increase the risk of treatment failure due to the exposure to subtherapeutic serum concentrations of medications and affect the optimal management of infections, length of hospital stay, and outcomes. The main goal of this review article is to summarize the recommendations for appropriate dosing of antibiotics in patients with ARC. Methods: This article is a narrative review of the articles that evaluated different dosing regimens of antibiotics in patients with ARC. The keywords "Augmented Renal Clearance," "Critically ill patients," "Drug dosing," "Serum concentration," "Beta-lactams," "Meropenem," "Imipenem," "Glycopeptide," "Vancomycin," "Teicoplanin," "Linezolid," "Colistin," "Aminoglycosides," "Amikacin," "Gentamycin," "Fluoroquinolones," "Ciprofloxacin," and "Levofloxacin" were searched in Scopus, Medline, PubMed, and Google Scholar databases, and pediatric, nonhuman, and non-English studies were excluded. Results: PK properties of antibiotics including lipophilicity or hydrophilicity, protein binding, the volume of distribution, and elimination rate that affect drug concentration should be considered along with PD parameters for drug dosing in critically ill patients with ARC. Conclusion: This review recommends a dosing protocol for some antibiotics to help the appropriate dosing of antibiotics in ARC and decrease the risk of subtherapeutic exposure that may be observed while receiving conventional dosing regimens in critically ill patients with ARC.

Decreased in-hospital mortality associated with aspirin administration in hospitalized patients due to severe COVID-19.

Hypercoagulability and thrombosis caused by coronavirus disease 2019 (COVID-19) are related to the higher mortality rate. Because of limited data on the antiplatelet effect, we aimed to evaluate the impact of aspirin add-on therapy on the outcome of the patients hospitalized due to severe COVID-19. In this cohort study, patients with a confirmed diagnosis of severe COVID-19 admitted to Imam Hossein Medical Center, Tehran, Iran from March 2019 to July 2020 were included. Demographics and related clinical data during their hospitalization were recorded. The mortality rate of the patients was considered as the primary outcome and its association with aspirin use was assessed. Nine hundred and ninety-one patients were included, of that 336 patients (34%) received aspirin during their hospitalization and 655 ones (66%) did not. Comorbidities were more prevalent in the patients who were receiving aspirin. Results from the multivariate COX proportional model demonstrated a significant independent association between aspirin use and reduction in the risk of in-hospital mortality (0.746 [0.560-0.994], p = 0.046). Aspirin use in hospitalized patients with COVID-19 is associated with a significant decrease in mortality rate. Further prospective randomized controlled trials are needed to assess the efficacy and adverse effects of aspirin administration in this population.

Evaluation of pharmacokinetic and pharmacodynamic parameters of meropenem in critically ill patients with acute kidney disease.

PURPOSE: No study has been evaluated pharmacokinetic (PK) and pharmacodynamic (PD) properties of ß-lactam antibiotics in patients with acute kidney injury (AKI), not requiring renal replacement therapy (RRT). We evaluated the time that plasma concentrations remain above four times the MIC (ft > 4MIC) and PK parameters of meropenem in this population. METHODS: In this prospective, randomized clinical trial (RCT), all patients received standard dose (3 g daily) of meropenem for 48 h, then randomly allocated in standard or adjusted groups. The standard group received meropenem without dose adjustment. In the adjusted group, the meropenem dose was adjusted based on the Cockcroft-Gault(C-G) equation. Meropenem concentrations were measured at the peak and trough times on the 2nd and 5th days of the study. RESULTS: On the 2nd day of the study, 3 out of 10 (30%) of patients attained the PD target (≥ 80%ft > 4MIC). In the 5th day of the study, the PD target was attained in 2 out of 10 (20%) and 1 out of 5 (20%) of patients who received standard and adjusted doses of meropenem, respectively (p = 1). In all samples, increased volume of distribution (Vd) (median; IQR) (46.04; 23.06-103.18 L), terminal half-life (T1/2) (4.51; 2.67-8.88 h) and decreased clearance (6.52; 4.43-10.16 L/h) have been shown. CONCLUSION: In critically ill patients with AKI, who not receive RRT, standard doses, and adjusted according to renal function of meropenem failed to achieve PD target of ≥ 80%ft > 4MIC. Higher doses are required for this target. RETROSPECTIVELY REGISTERED: The study protocol with registered retrospectively and approved on January 19, 2019, with the number of IRCT20160412027346N5.

Promising effects of atorvastatin on mortality and need for mechanical ventilation in patients with severe COVID-19; a retrospective cohort study.

PURPOSE: Considering the anti-inflammatory effect of atorvastatin and the role of medical comorbidities such as hypertension and coronary artery disease on the prognosis of the COVID-19 patients, we aimed to assess the effect of atorvastatin add-on therapy on mortality caused by COVID-19. METHODS: We conducted a retrospective cohort study, including patients who were hospitalised with confirmed diagnosis of severe COVID-19. Baseline characteristics and related clinical data of patients were recorded. Clinical outcomes consist of in-hospital mortality, need for invasive mechanical ventilation and hospital length of stay. COX regression analysis models were used to assess the association of independent factors to outcomes. RESULTS: Atorvastatin was administered for 421 of 991 patients. The mean age was 61.640 ± 17.003 years. Older age, higher prevalence of hypertension and coronary artery disease reported in patients who received atorvastatin. These patients have shorter hospital length of stay (P = .001). Based on COX proportional hazard model, in-hospital use of atorvastatin was associated with decrease in mortality (HR = 0.679, P = .005) and lower need for invasive mechanical ventilation (HR = 0.602, P = .014). CONCLUSIONS: Atorvastatin add-on therapy in patient with severe COVID-19 was associated with lower in-hospital mortality and reduced the risk of need for invasive mechanical ventilation which supports to continue the prescription of the medication.

Intragastric Botulinum Toxin Injection and Botulism: An Alarm for Clinicians.

Clostridium botulinum produces the most potent bacterial toxin, botulinum toxin A (BTXA), which has various therapeutic and cosmetic indications. Intragastric BTXA injection is a new obesity treatment method that was argued to be safe due to the inactivation of BTXA through the liver or metabolization within the gastric wall. However, a 36-year-old woman was admitted to the intensive care unit (ICU) due to developing botulism as a result of an intragastric injection of BTXA. The diplopia, headaches, ptosis, decreased muscle force, and respiratory distress two days after injection were her first chief complaints, and also, she experienced significant dysphagia, hoarse voice, thick tongue, constipation, hyposmia, and hypogeusia after two weeks. This case report highlights the necessity for physicians to have sufficient information about this method and consider possible life-threatening adverse effects including botulism.

Linalool attenuated ischemic injury in PC12 cells through inhibition of caspase-3 and caspase-9 during apoptosis.

Numerous studies have indicated the pharmacological properties of linalool, a volatile terpene alcohol found in many flowers and spice plants, including anti-nociceptive, anti-inflammatory, and neuroprotective activities. The aim of this study was to explore the mechanisms of neuroprotection provided by (±) linalool and its enantiomer, (R)-(-) linalool against oxygen, and glucose deprivation/reoxygenation (OGD/R) in PC12 cells. PC12 cells were treated with (±) linalool and (R)-(-) linalool before exposure to OGD/R condition. Cell viability, reactive oxygen species (ROS) production, malondialdehyde (MDA) level, DNA damage, and the levels of proteins related to apoptosis were evaluated using MTT, comet assay, and western blot analysis, respectively. IC50 values for the PC12 cells incubated with (±) linalool and (R)-(-) linalool were 2700 and 2600 µM after 14 h, as well as 5440 and 3040 µM after 18 h, respectively. Survival of the ischemic cells pre-incubated with (±) linalool and (R)-(-) linalool (100 µM of both) increased compared to the cells subjected to the OGD/R alone (p < .001). ROS and MDA formation were also decreased following incubation with (±) linalool and (R)-(-) linalool compared to the OGD/R group (p < .01). In the same way, pre-treatment with (±) linalool and (R)-(-) linalool significantly reduced OGD/R-induced DNA injury compared to that seen in OGD/R group (p < .001). (±) Linalool and (R)-(-) linalool also restored Bax/Bcl-2 ratio and cleaved caspase-3 and caspase-9 (p < .001, p < .01) following ischemic injury. The neuroprotective effect of linalool against ischemic insult might be mediated by alleviation of oxidative stress and apoptosis.

A spontaneous dissecting posterior cerebral artery aneurysm in a 10-month-old female infant: a case report.

Introduction: Posterior cerebral artery (PCA) aneurysms are a rare group of intracranial aneurysms. Pediatric aneurysms account for approximately 4% of all aneurysms and are commonly associated with an underlying predisposing disorder, such as trauma. In contrast to traumatic aneurysms, spontaneous dissecting cases are pointed out as a rare cause of pediatric aneurysms. The current paper presented a spontaneous dissecting aneurysm in a 10-month-old female infant. Case Report: The case was a 10-month-old female infant admitted to the Neurology Ward of Imam Hossein Hospital, Tehran, Iran, with a ruptured dissecting PCA aneurysm for a diagnostic brain angiography. Brain computerized tomography scan and magnetic resonance imaging showed left occipital subarachnoidal and intraventricular hemorrhage, left periventricular intracranial hemorrhage, and PCA infarct. The endovascular embolization was performed for her, and the aneurysm and parent artery were obliterated with two coils. No clinical deficits and complications happened during and after the procedure. Discussion: Dissecting PCA aneurysm is a rare condition, particularly in infants. Endovascular coiling and surgical clipping are two treatment options for cerebral aneurysms, one of which might be preferred according to the symptoms and age of the patient.

The Evaluation of the Neuroprotective Effect of a Single High-Dose Vitamin D3 in Patients with Moderate Ischemic Stroke.

INTRODUCTION: Vitamin D insufficiency is highly prevalent and is a negative predictor for survival in ischemic stroke patients. We evaluated the effect of a high dose of vitamin D3 on the Neuron-Specific Enolase (NSE) level, National Institute of Health Stroke Scale (NIHSS), and Barthel Index (BI) scoring system in moderate ischemic stroke patients. METHODS: This prospective, double-blind, randomized clinical trial (RCT) study was conducted from April 2020 to March 2021. Patients with moderate ischemic stroke (NIHSS 5 to 15) who had vitamin D deficiency (serum 25-OH vitamin D ≤30 ng/mL) were recruited and randomized into intervention and control groups. Subjects in the intervention group received a single dose, intramuscular (IM) injection of 600000 international unit (IU) vitamin D3, in addition to the standard treatment. NSE level and NIHSS were evaluated at baseline and 48 hours after the intervention. The BI was monitored three months after discharge. RESULTS: During the study period, 570 patients were assessed; finally, forty-one patients completed the study. Except for the age which was higher in the control group (p = 0.04), there were no statistically significant differences in other baseline characteristics between the two groups. After 48 hours, the NIHSS score was significantly lower in the intervention group (median 8 vs. 6.5, p = 0.008 in the control and intervention groups, respectively), but there was no significant difference in the NSE level (p = 0.80). Three months after discharge, the BI was significantly higher in the intervention group (median 8 vs. 9, p = 0.03 in the control and intervention groups, respectively). CONCLUSIONS: Administration of a single 600000 IU of vitamin D3 could have neuroprotective effects in patients with moderate ischemic stroke, according to its significantly positive effects on functional clinical outcomes (NIHSS and BI), but this effect on the biomarker related to neural damage (NSE) was not significant.

Using Two Predictor Scoring Systems Together to Increase the Chance of Identifying the Augmented Renal Clearance Phenomenon: A Cross-sectional Study.

INTRODUCTION: Augmented Renal Clearance (ARC) reflects a measured creatinine clearance (CrCl) of more than 130 ml/min. Also, there are two scoring systems for the prediction of the ARC phenomenon i.e., the ARC score (ARCS) and the Augmented Renal Clearance in Trauma Intensive Care score (ARCTICs). The objectives of the current study were the evaluation the effect of using both scoring systems, on the chance of identifying this phenomenon and evaluating the accuracy of the three commonly used formulas for estimating glomerular filtration rate (eGFR) in ICU patients. METHODS: In this prospective cross-sectional study, the CrCls of all patients admitted to the ICU were evaluated by using ARCS and ARCTICS, and for high-risk subjects based on scoring systems, a 12-hour urine sample was collected to measure CrCl. Besides, daily serum creatinine was recorded to estimate the daily eGFR. RESULTS: During the study period, 810 subjects were evaluated and 145 were categorized as high-risk using scoring systems. The ARC phenomenon was confirmed in 79 patients on the recruitment day and 81.01 and 18.98% of them were recruited by ARCS and ARCTICS, respectively. The ROC curves showed AUCs > 0.5 for CockcroftGault (C-G) and CKD-EPI with the cut-off of 100.48 and 107.05 mL/min/ 1.73m2, respectively; to detect the ARC phenomenon. CONCLUSION: We recommend using ARCS and ARCTICS simultaneously to assess critically ill patients regarding the possibility of the ARC phenomenon which should be confirmed by using urinary CrCl, as none of the formulas could accurately detect the ARC phenomenon, neither the 12-hour CrCl.  DOI: 10.52547/ijkd.6695.

The effects of memantine on the serum concentrations of matrix metalloproteinases and neurologic function of patients with ischemic stroke.

Memantine was suggested as a promising treatment for stroke due to its neuroprotective property and efficacy in reducing ischemic brain injury and improving post-ischemic neurological recovery. This pilot, open-label, randomized clinical trial was conducted to investigate the impact of memantine on serum concentrations of matrix metalloproteinases (MMP)-2 and MMP-9, as neuronal damage biomarkers, and neurologic function evaluated by the National Institute of Health Stroke Scale(NIHSS) and Barthelindex(BI) in patients with ischemic stroke. Admitted patients with mild to moderate ischemic stroke were assessed for eligibility, and eligible patients were randomized to the intervention or control group. Enrolled patients in the intervention group received 20 mg memantine every 8 h for five days and then 20 mg daily for three months. Both groups managed with the standard treatments. From 77 randomized patients, 29 participants in the control group and 24 patients in the intervention group completed the study. Data showed that the increase in the serum concentrations of MMP-9 within the first 5 days of the study was significantly lower in the intervention group (P = 0.005). This effect of memantine on the MMP-2 was not significant (P = 0.448). memantine also could significantly improve the neurologic function of the patients according to NIHSS (P < 0.0001) and BI (P = 0.002) during hospitalization and after that. In conclusion, memantine could be considered as a neuroprotective agent in patients with mild to moderate ischemic stroke, based on its significant effects on reducing brain damage and improving neurologic function of the patients.

Comparison of Intravenous Ampicillin-sulbactam Plus Nebulized Colistin with Intravenous Colistin Plus Nebulized Colistin in Treatment of Ventilator Associated Pneumonia Caused by Multi Drug Resistant Acinetobacter Baumannii: Randomized Open Label Trial.

The purpose of this study was evaluating the efficacy and safety of intravenous (IV) ampicillin-sulbactam plus nebulized colistin in the treatment of Ventilator-Associated Pneumonia (VAP) caused by MDR Acinetobacter (MDRA) in ICU patients as an alternative to IV plus nebulized colistin. In this single-blinded RCT, one group received IV colistin and another group IV ampicillin-sulbactam (16 and 12 patients from total 28 patients, respectively) for 14 days or since clinical response. Both groups received nebulized colistin by mesh nebulizer. There were no statistically significant differences between the 2 groups in baseline characteristics and previous antibiotic therapy. In follow up period, no significant difference was observed between 2 groups in rate of microbiological eradication, clinical signs of VAP improvement, survival rate and length of hospital as well as ICU stays. Although we have found no significant differences in Acute Kidney Injury (AKI) incidence between two groups, comparison of cumulative patient-days with stages 2 and 3 AKI with days with no or stage 1 AKI, according to AKIN criteria, revealed significant difference in IV colistin versus IV ampicillin-sulbactam group (p = 0.013). The results demonstrated that the high dose IV ampicillin-sulbactam plus nebulized colistin regimen has comparable efficacy with IV plus nebulized colistin in the treatment of VAP caused by MDRA, with sensitivity to colistin only, with probably lower incidence of kidney injury.