Recommended β-lactam regimens are inadequate in septic patients treated with continuous renal replacement therapy

Introduction  

Sepsis is responsible for important alterations in the pharmacokinetics of antibiotics. Continuous renal replacement therapy (CRRT), which is commonly used in septic patients, may further contribute to pharmacokinetic changes. Current recommendations for antibiotic doses during CRRT combine data obtained from heterogeneous patient populations in which different CRRT devices and techniques have been used. We studied whether these recommendations met optimal pharmacokinetic criteria for broad-spectrum antibiotic levels in septic shock patients undergoing CRRT.     

Complications of continuous renal replacement therapy in children: are all created equal?

Continuous renal replacement therapy (CRRT) in pediatric acute kidney dysfunction has evolved in recent decades; however, little objective data exist for complications associated with CRRT. Santiago and colleagues are among the first to document four complications of acute kidney dysfunction in critically ill children: catheterization-related insertion complications, hypotension, hemorrhage, and electrolyte disturbances. They reported that hypotension at connection (41.3%) and electrolyte disturbance (50.6%) were the leading complications. Although this study is limited by small sample size and the outcome variables measured, it is an important first step in assessing outcomes of CRRT in children. A prospective multicenter randomized trial will be needed to fully delineate the complications and define the risk/benefit ratio of CRRT in children.     

Evaluation of sulfobutylether-β-cyclodextrin (SBECD) accumulation and voriconazole pharmacokinetics in critically ill patients undergoing continuous renal replacement therapy

IntroductionIntravenous (IV) voriconazole is not recommended in patients with creatinine clearance <50 ml/min to avoid potentially toxic accumulation of sulfobutylether-β-cyclodextrin (SBECD). The purpose of this study was to evaluate the pharmacokinetics of SBECD, voriconazole, and voriconazole N-oxide in critically ill patients undergoing continuous renal replacement therapy (CRRT) and to determine if CRRT removes SBECD sufficiently to allow for the use of IV voriconazole without significant risk of SBECD accumulation.MethodsThis prospective, open-label pharmacokinetic study enrolled patients >18 years old receiving IV voriconazole for a known or suspected invasive fungal infection while undergoing CRRT. Serial blood and effluent samples were collected on days 1, 3, 5, 7, and every 3 to 5 days thereafter. SBECD, voriconazole, and voriconazole N-oxide plasma and effluent concentrations were measured by liquid chromatography-tandem mass spectrometry. Pharmacokinetic, pharmacodynamic, and pharmacogenetic analyses were conducted.ResultsTen patients (mean ± standard deviation (SD)) 53 ± 11 years old, 50% male, 81 ± 14 kg, with Acute Physiologic and Chronic Health Evaluation II (APACHE II) scores of 31.5 ± 3.8 were evaluated. All patients underwent continuous venovenous hemofiltration (CVVH) with a median predilution replacement fluid rate of 36 (interquartile range (IQR) 32 to 37) ml/kg/hr and total ultrafiltration rate of 38 (IQR 34 to 39) ml/kg/hr. Mean ± SD voriconazole and SBECD dosages administered were 8.1 ± 2.1 mg/kg/day and 129 ± 33 mg/kg/day, respectively. Voriconazole plasma trough concentrations were >1 mg/L in all patients with CVVH accounting for only 15% of the total body clearance. CVVH accounted for 86% of the total body clearance of SBECD with the majority of the dose being recovered in the effluent. Minimal increases in dose normalized SBECD area under the concentration-time curve from 0 to 12 hours (AUC0-12) (4,484 ± 4,368 to 4,553 ± 2,880 mg*hr/L; P = 0.97) were observed after study day 1.ConclusionsCVVH effectively removed SBECD at a rate similar to the ultrafiltration rate. Voriconazole clearance by CVVH was not clinically significant. Standard dosages of IV voriconazole can be utilized in patients undergoing CVVH without significant risk of SBECD accumulation.

Trial registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01101386","term_id":"NCT01101386"}}NCT01101386. Registered 6 April 2010.

Electronic supplementary material

The online version of this article (doi:10.1186/s13054-015-0753-8) contains supplementary material, which is available to authorized users.     

Can nasal continuous positive airway pressure decrease clinic blood pressure in patients with obstructive sleep apnea?

Obstructive sleep apnea (OSA) is commonly associated with systemic hypertension and now recognized as an independent risk factor for daytime hypertension. We aimed to study the short- and long-term effect of nasal continuous positive airway pressure (CPAP) in hypertensive and normotensive patients with OSA. Forty-six patients with moderated to severe OSA were treated with nasal CPAP and followed after one year of treatment. Clinic blood pressure, heart rate, and body weight were taken before and followed up for one year after beginning nasal CPAP. In this study 25 patients with OSA were found to have hypertension (54.3%). The hypertensive group showed a significant reduction in clinic blood pressure after nasal CPAP, whereas the normotensive group showed no changes. The subgroup of hypertensive patients with OSA who had no anti-hypertensive medication revealed a decrease in clinic blood pressure comparable to those with anti-hypertensive drugs. The heart rate was not significantly changed in any patients. There was no significant correlation between the decrease in body weight and the reduction in blood pressure. These results suggest that nasal CPAP alone might have a substantial blood pressure lowering effect in hypertensive patients with OSA. This effect could decrease the morbidity and mortality related to cardiovascular complications in patients with OSA.     

Can early initiation of continuous renal replacement therapy improve patient survival with septic acute kidney injury when enrolled in early goal-directed therapy?

PurposeThe purpose of our study was to investigate the timing of continuous renal replacement therapy (CRRT) application, based on the interval between the start of early goal-directed therapy (EGDT) and CRRT initiation, to ascertain whether the timing was an independent predictor of mortality in patients with septic acute kidney injury (AKI).Materials and methodsAn observational retrospective cohort study was conducted of 60 patients (> 18 years old) who had been admitted to the emergency department and received resuscitation according to the standard EGDT algorithm for severe sepsis and septic shock, and who were treated with CRRT due to septic AKI, between June 2008 and February 2013 at a tertiary hospital in Seoul, Korea. The patients were divided into 2 groups based on the median interval between the start of EGDT and the commencement of CRRT. The main outcome was 28-day all-cause mortality, and a multivariate Cox analysis for mortality was used to evaluate the independent impact of the early CRRT treatment.ResultsThe mean patient age was 66.3 years, and 52 (86.7%) were male. The most common comorbid disease was diabetes mellitus (35.0%) followed by malignancy (26.7%). The median interval between the start of EGDT and commencement of CRRT was 26.4 hours. During the study period, 28-day mortality was 43.3% (26 of 60 patients). The 28-day all-cause mortality rate was significantly higher in the late CRRT group than in the early CRRT group (56.7 vs 30.0%, P= .037). Furthermore, the higher mortality risk in the late group remained significant even after adjusting for diabetes mellitus, liver failure, and Acute Physiology and Chronic Health Evaluation II scores (hazard ratio, 2.461; 95% confidence interval, 1.044-5.800; P= .026).ConclusionEarly initiation of CRRT may be of benefit. Given the complex nature of this intervention and the ongoing controversy regarding early vs late initiation of therapy in acute and chronic situations, it is vital to develop accurate clinical trials to find definitive answers.     

Renal effects of sodium–glucose cotransporter-2 inhibitors in patients with type 2 diabetes and renal impairment

In patients with type 2 diabetes (T2D), microvascular changes in the kidney often result in diabetic kidney disease (DKD), the progression of which is associated with an increased risk of cardiovascular (CV) and all-cause mortality. Sodium-glucose cotransporter-2 inhibitors (SGLT-2is) are a newer class of oral glucose-lowering therapies that were associated with significant reductions in the risk of major adverse CV events, CV death, and hospitalization for heart failure compared with placebo in CV outcomes trials (CVOTs) of patients with T2D and established CV disease or varying levels of CV risk. In addition, SGLT-2is reduced the risks of clinically relevant renal outcomes in these large randomized studies, indicating the potential for renoprotective effects in patients with T2D and DKD. This review discussed the non-glycemic effects of SGLT-2is in patients with T2D and renal impairment, including reductions in systolic and diastolic blood pressure, decreases in albuminuria and plasma uric acid, changes in estimated glomerular filtration rate, and minimal changes in electrolytes. Potential mechanisms for the renoprotective effects of SGLT-2is observed in CVOTs were considered, including the likely incremental benefits of SGLT-2is when added to renin-aldosterone-angiotensin system inhibitors (RAASis). The possibility of extending the use of SGLT-2is to patients with non-DKD was also discussed. Although the exact mechanisms by which SGLT-2is improve renal outcomes are not fully understood, they are likely to be multifactorial and additive when these drugs are used in combination with RAASis in patients with DKD.     

Does yoga therapy reduce blood pressure in patients with hypertension?: an integrative review

The aim of this article was to present a evidence-based integrative research review that validates yoga therapy as an effective complementary treatment in the management of high blood pressure (BP). The article also uses the theoretical framework of Dr Hans Selye's general adaptation syndrome. Yoga researchers demonstrate that yoga works because it modulates the physiological system of the body, specifically its effect on the heart rate. This review is significant because yoga presents an effective method of treating hypertension that is nonpharmacologic and therefore there are no adverse effects and there are other valuable health benefits. Research suggests that stress is a contributing factor to high BP; hence, the use of the general adaptation syndrome and the most important attribute of yoga, that is, it is a physical and mental exercise program, that is in sync with the philosophy of holistic nursing care where one treats the whole individual and not just the disease. The review was conducted with a search of computerized databases such as OVID, Academic Search Premier, CINAHL, MEDLINE, and Health Source: Nursing/Academic edition, PsychINFO, as well as reliable Web sites such as the cdc.gov, among others. An integrative review search was conducted, and 10 studies met the inclusion criteria. They include a combination of randomized controlled trials, quasi-experimental studies, and pilot studies. Yoga therapy is a multifunctional exercise modality with numerous benefits. Not only does yoga reduce high BP but it has also been demonstrated to effectively reduce blood glucose level, cholesterol level, and body weight, major problems affecting the American society. The completed integrative review provides guidelines for nursing implementation as a complementary treatment of high BP.     

Anticoagulation strategies in continuous renal replacement therapy: can the choice be evidence based?

Objectives Critical illness increases the tendency to both coagulation and bleeding, complicating anticoagulation for continuous renal replacement therapy (CRRT). We analyzed strategies for anticoagulation in CRRT concerning implementation, efficacy and safety to provide evidence-based recommendations for clinical practice. Methods We carried out a systematic review of the literature published before June 2005. Studies were rated at five levels to create recommendation grades from A to E, A being the highest. Grades are labeled with minus if the study design was limited by size or comparability of groups. Data extracted were those on implementation, efficacy (circuit survival), safety (bleeding) and monitoring of anticoagulation. Results Due to the quality of the studies recommendation grades are low. If bleeding risk is not increased, unfractionated heparin (activated partial thromboplastin time, APTT, 1–1.4 times normal) or low molecular weight heparin (anti-Xa 0.25–0.35 IU/l) are recommended (grade E). If facilities are adequate, regional anticoagulation with citrate may be preferred (grade C). If bleeding risk is increased, anticoagulation with citrate is recommended (grade D⁻). CRRT without anticoagulation can be considered when coagulopathy is present (grade D⁻). If clotting tendency is increased predilution or the addition of prostaglandins to heparin may be helpful (grade C⁻). Conclusion Anticoagulation for CRRT must be tailored to patient characteristics and local facilities. The implementation of regional anticoagulation with citrate is worthwhile to reduce bleeding risk. Future trials should be randomized and should have sufficient power and well defined endpoints to compensate for the complexity of critical illness-related pro- and anticoagulant forces. An international consensus to define clinical endpoints is advocated. Electronic supplementary material Electronic supplementary material to this contribution can be obtained by using the Springer Link server located at and is accessible for authorized users.     

Fluid resuscitation with 6 % hydroxyethyl starch (130/0.4 and 130/0.42) in acutely ill patients: systematic review of effects on mortality and treatment with renal replacement therapy

Purpose

To determine whether fluid resuscitation of acutely ill adults with 6 % hydroxyethyl starch (6 % HES 130) with a molecular weight of 130 kD and a molar substitution ratio of approximately 0.4 (6 % HES 130) compared with other resuscitation fluids results in a difference in the relative risk of death or treatment with renal replacement therapy (RRT).

Methods

Systematic review and meta-analysis of randomized controlled trials comparing intravascular fluids for resuscitation of hospitalised adults that reported mortality or treatment with RRT. The risk of bias was assessed independently by two reviewers and meta-analysis was performed using random effects.

Results

Thirty-five trials enrolling 10,391 participants were included. The three largest trials had the lowest risk of bias, were published (or completed) in 2012, and together enrolled 77 % of all participants. Death occurred in 928 of 4,691 patients (19.8 %) in the 6 % HES 130 group versus 871 of 4,720 (18.5 %) in the control fluid groups relative risk (RR) in the 6 % HES 130 group 1.08, 95 % confidence interval (CI) 1.00 to 1.17, I ² = 0 %). Treatment with RRT occurred in 378 of 4,236 patients (8.9 %) in the 6 % HES 130 group versus 306 of 4,260 (7.2 %) in the control fluid group (RR in the 6 % HES 130 group 1.25, 95 % CI 1.08 to 1.44, I ² = 0 %).

Conclusions

The quality and quantity of data evaluating 6 % hydroxyethyl starch (130/0.4 and 130/0.42) as a resuscitation fluid has increased in the last 12 months. Patients randomly assigned to resuscitation with 6 %HES 130 are at significantly increased risk of being treated with RRT.     

Home-based zoledronic acid infusion therapy in patients with solid tumours: compliance and patient–nurse satisfaction

Purpose

This study aimed to explore patient and nurse satisfaction, compliance with best practice, technical feasibility and safety of home infusion of the bisphosphonate zoledronic acid (ZOL).

Methods

This was a prospective 1-year survey of home ZOL therapy (4 mg Zometa®, 15-min i.v., every 3–4 weeks) in patients with bone metastases secondary to a solid malignancy. A physician questionnaire, nurse satisfaction/feasibility questionnaire and patient satisfaction questionnaire were administered at several time-points.

Results

Physician participation rate was 56.5 % (87/154). Physicians enrolled 818 patients visited by 381 predominantly community nurses. Of the 788 case report forms received, 763 met inclusion criteria. Patient characteristics were as follows: median age, 68 years (30–95); M/F, 40/60; ECOG-PS 0 or 1, 78.6 %;and primary tumour site, breast (55.2 %), prostate (28.4 %), lung (7.2 %) or other (9.4 %). Nurse satisfaction rates were high: organisation of home ZOL therapy, 90.9 %; ease of infusion, 96.7 %; patient–nurse relationship, 97.5 %; and relationship with hospital staff, 73 %. Patient satisfaction was also very high (95.3 %). The main reasons were quality of the nurse–patient relationship (57.6 %), less travel/waiting (68.8 %), home environment (52.9 %) and less disruption to daily routine (36.6 %). ZOL therapy was well tolerated, the discontinuation rate due to adverse events (including deaths whether related to diseases progression or not) was 33.6 %. The incidence of osteonecrosis of the jaw was 0.6 % and of fractures, 0.2 %. Practitioner compliance with best practice was 76.7–83.7 % for recommended and/or tolerated dosage, 73 % for dental hygiene checks at inclusion and 48–56 % thereafter, 66 % for pre-infusion hydration, and often undocumented for calcium/vitamin D supplementation.

Conclusions

Home ZOL therapy was well tolerated. Both patient and nurse satisfaction were very high. However, better compliance with best practice should be encouraged.     

Relationship of red-cell 2,3-diphosphoglycerate with anaemia,hypoxaemia and acid—base status in patients with cirrhosis of the liver

The red-cell 2,3-diphosphoglycerate (DPG) concentration is determined in 60 patients with hepatic cirrhosis, in 33 with ferropenic anaemia and in 86 healthy subjects. In all cases, the erythrocyte volume fraction and the haemoglobin concentration are simultaneously measured, while the cirrhotic patients undergo, at the same time, analyses of the arterial pH, po₂ and pco₂ and of the levels of inorganic phosphate, bicarbonate and lactate in their venous blood. In the 60 cirrhotic patients the red-cell DPG concentration (7.40 ± 1.23 mmol/1) is significantly higher (P<0.001) than in the 86 control subjects (4.58 ± 0.59 mmol/1) and the 33 patients with ferropenic anaemia (5.86 ± 1.06 mmol/1), although the level of anaemia in the latter is greater (P<0.001) than in the patients with liver cirrhosis. The DPG concentration found in the cirrhotic patients was far higher (P<0.001) than the theoretical value attributable to them by virtue of their grade of anaemia (5.21 ± 0.95 mmol/1), which value is deduced mathematically from the equation of the regression line between haemoglobin and DPG normal in patients with ferropenic anaemia. Anaemia, hypoxaemia and acid-base disturbances are disorders frequently associated with cirrhosis of the liver. In the present study we deduce that alkalosis, and therefore the plasma pH level, is the most important factor causing the increased DPG concentration in patients with liver cirrhosis for any level of haemoglobin, with respect to other subjects with anaemia.