Acetazolamide Therapy for Metabolic Alkalosis in Pediatric Intensive Care Patients.

OBJECTIVE: Patients in PICUs frequently present hypochloremic metabolic alkalosis secondary to loop diuretic treatment, especially those undergoing cardiac surgery. This study evaluates the effectiveness of acetazolamide therapy for metabolic alkalosis in PICU patients. DESIGN: Retrospective, observational study. SETTING: A tertiary care children's hospital PICU. PATIENTS: Children receiving at least a 2-day course of enteral acetazolamide. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Demographic variables, diuretic treatment and doses of acetazolamide, urine output, serum electrolytes, urea and creatinine, acid-base excess, pH, and use of mechanical ventilation during treatment were collected. Patients were studied according to their pathology (postoperative cardiac surgery, decompensated heart failure, or respiratory disease). A total of 78 episodes in 58 patients were identified: 48 were carried out in cardiac postoperative patients, 22 in decompensated heart failure, and eight in respiratory patients. All patients received loop diuretics. A decrease in pH and PCO2 in the first 72 hours, a decrease in serum HCO3 (mean, 4.65 ± 4.83; p < 0.001), and an increase in anion gap values were observed. Urine output increased in cardiac postoperative patients (4.5 ± 2.2 vs 5.1 ± 2.0; p = 0.020), whereas diuretic treatment was reduced in cardiac patients. There was no significant difference in serum electrolytes, blood urea, creatinine, nor chloride after the administration of acetazolamide from baseline. Acetazolamide treatment was well tolerated in all patients. CONCLUSIONS: Acetazolamide decreases serum HCO3 and PCO2 in PICU cardiac patients with metabolic alkalosis secondary to diuretic therapy. Cardiac postoperative patients present a significant increase in urine output after acetazolamide treatment.

Acyclovir and hyponatremia: a case report.

A 61-year-old man attended the emergency department with decreased level of consciousness, repetitive language, and memory loss. Clinical history included type II diabetes and hypertension. Domiciliary treatment included oral metformin 850 mg every 24 hours and oral indapamide 2.5 mg every 24 hours. Laboratory tests disclosed high glycemia (198 mg/dL), increased C-reactive protein (7.4 mg/dL), and normal renal function. Intravenous acyclovir of 800 mg every 8 hours was started on admission due to suspicion of viral encephalitis. Blood analysis on 10th day displayed hyponatremia (123 mmol/L) that was at first explained by the high water intake in the 3 preceding days; therefore, water restriction was decided. Nuclear magnetic resonance on day 14 identified an ictus and treatment with acyclovir was withdrawn. Three days after the withdrawal, plasmatic sodium levels began to increase (128 mmol/L) and returned to normal after 6 days (133 mmol/L). Although hyponatremia is not mentioned in the acyclovir summary of product characteristics, 2 reports in literature suggest that this drug could be a causative agent of hyponatremia. We believe that there is a relationship between acyclovir and hyponatremia. Application of the Karch and Lasagna algorithm to assess the causality of the reaction induced by acyclovir revealed the relationship to be possible.

Antiangiogenic drugs and cardiogenic shock: a case report.

A 56-year-old man attended the emergency room with respiratory failure, deteriorated general status, fatigue, and diarrhea. His clinical history included a liver transplant because of alcoholic cirrhosis, which developed to hepatocellular carcinoma. Initial immunosuppression consisted of corticosteroids, tacrolimus, and mycophenolate mofetil. Examination of the explant revealed vascular invasion, and tacrolimus was replaced with everolimus. The patient presented recurrence of the carcinoma with peritoneal implants, and treatment with sorafenib was started. He was admitted to the gastroenterology department and, after withdrawal of sorafenib, the patient improved clinically. However, 6 days later, he was admitted to the intensive care unit with acute respiratory failure and metabolic acidosis. The final diagnosis was cardiogenic shock. Although cardiogenic shock is not mentioned in the summaries of product characteristics of sorafenib or everolimus, there are reports of a relationship between cardiotoxicity and antiangiogenic therapy that inhibits the proliferation of vascular smooth muscle cells, as is the case with these drugs. We believe that there is a relationship between sorafenib (especially when combined with everolimus) and cardiogenic shock. Application of the Karch and Lasagna algorithm to assess the causality of the reaction induced by the combination of sorafenib and everolimus revealed the relationship to be probable.

Cardiovascular toxicity and sorafenib: a case report.

We report a case of a 55-year-old male with chronic hepatitis C virus infection and compensated liver disease treated with sorafenib for advanced hepatocarcinoma (Barcelona Clinic Liver Cancer stage C). At follow-up, the patient developed hypertension, which was well controlled with beta-blocker medication, and an aortic dilation detected by abdominal computerized tomography and echocardiography. There are some reports of the side effects of sorafenib on the cardiovascular system. The patient had no cardiac or aortic pathology before the start of this palliative chemotherapy. There is an article that describes the development of an aortic aneurysm in a patient with uncontrolled hypertension, who received treatment with sorafenib for renal carcinoma. However, our patient had a good control of blood pressure. The adverse vascular effects of Sorafenib may be due to the inhibition of the proliferation of vascular endothelial muscle cells. We believe that this case illustrates a probable relationship between sorafenib and aortic dilatation according to the Karch and Lasagna causality algorithm.

Prevention and treatment of intraluminal catheter thrombosis in children hospitalised in a paediatric intensive care unit.

AIM: The aim of the study was to develop and implement a protocol for the prevention and treatment of catheter related intraluminal thrombosis in a paediatric intensive care unit METHODS: A computerised search was carried out on MEDLINE, through PubMed, using the medical subject heading 'central venous catheter', 'central venous access device', 'central venous line' associated with 'occlusion', 'obstruction', 'catheter-related thrombosis', 'critically ill patients' and 'thrombolytic therapy'. References of reviewed articles were also searched for relevant titles as well as non-randomised controlled trials and series of cases when no information of higher level of evidence was available. RESULTS: With the information gathered, a protocol for the prevention and treatment of catheter related intraluminal thrombosis was elaborated and those recommendations that best suit our environment were included. They were agreed upon by a broad panel of professionals working in the Pediatric Intensive Care Unit and the Pharmacy Department. CONCLUSIONS: Due to the variety of options available for the pharmacotherapeutic management of intraluminal catheter thrombosis, one measure to improve the quality of the therapy and to diminish the variability in the prescription could be the implementation of a protocol as described in this paper.

Treatment and prophylaxis of catheter-related thromboembolic events in children.

PURPOSE: The therapeutic management of catheter-related thromboembolic events in children is still a challenge due to the large number of potentially effective pharmacological alternatives and the insufficient scientific evidence available. A bibliographic review was performed in order to identify the available pharmacological alternatives for the prophylaxis and therapeutic management of catheter-related thrombosis in children. METHODS: A literature search was carried out on MEDLINE using the medical subject heading (MeSH) central venous catheter thrombosis and on Google Scholar. The search was limited to review papers, meta-analyses, clinical practice guidelines, and randomized controlled trials performed on pediatric populations until November 2011. RESULTS: The different options for anticoagulation include unfractionated heparin, low molecular weight heparin and vitamin K antagonists. Thrombus resolution is stimulated more rapidly with thrombolytic agents than with anticoagulants, but the risk-benefit ratio must be considered. Streptokinase is not considered an optimal alternative due to the risk of anaphylactic reactions and has been replaced by urokinase, alteplase or the newer reteplase. Preventive strategies have been considered and most centers have protocols for routine flushing of the catheter with heparin or normal saline. Intraluminal application of urokinase and alteplase has also been studied. CONCLUSIONS: The wide range of options available for the pharmacotherapeutic management of catheter-related thromboembolism in children and the lack of strong evidence on the comparative efficacy and safety of the different therapeutic options, make its positioning rather difficult. Randomized controlled trials and national plans should be set up urgently.

Cost-effectiveness of screening for DPYD polymorphisms to prevent neutropenia in cancer patients treated with fluoropyrimidines.

AIM: To compare the cost of screening for three mutations in the dihydropyrimidine dehydrogenase gene and the costs of treating severe fluoropyrimidine-induced neutropenia. MATERIALS & METHODS: The polymorphisms rs3918290 (DPYD*2A), rs67376798 (DPYD 2846A>T) and rs55886062 (1679T>G, DPYD*13) were genotyped using real-time PCR, TaqMan probes and a rapid cell lysis to provide PCR-ready DNA. RESULTS: We found that genotyping 1000 patients in our center cost €6400 and that the mean cost of treating severe neutropenia was €3044. Therefore, if severe fluoropyrimidine-induced neutropenia is reduced by genotyping the three DPYD variations in at least 2.21 cases per 1000 treated patients, then DPYD genotyping will prove cost effective. CONCLUSION: We demonstrated that real-time DPYD genotyping using TaqMan probes is cost effective in all fluoropyrimidine-based treatments.

Variants in CDA and ABCB1 are predictors of capecitabine-related adverse reactions in colorectal cancer.

Adverse reactions to capecitabine-based chemotherapy limit full administration of cytotoxic agents. Likewise, genetic variations associated with capecitabine-related adverse reactions are associated with controversial results and a low predictive value. Thus, more evidence on the role of these variations is needed. We evaluated the association between nine polymorphisms in MTHFR, CDA, TYMS, ABCB1, and ENOSF1 and adverse reactions, dose reductions, treatment delays, and overall toxicity in 239 colorectal cancer patients treated with capecitabine-based regimens. The ABCB1*1 haplotype was associated with a high risk of delay in administration or reduction in the dose of capecitabine, diarrhea, and overall toxicity. CDA rs2072671 A was associated with a high risk of overall toxicity. TYMS rs45445694 was associated with a high risk of delay in administration or reduction in the dose of capecitabine, HFS >1 and HFS >2. Finally, ENOSF1 rs2612091 was associated with HFS >1, but was a poorer predictor than TYMS rs45445694. A score based on ABCB1-CDA polymorphisms efficiently predicts patients at high risk of severe overall toxicity (PPV, 54%; sensitivity, 43%) in colorectal cancer patients treated with regimens containing capecitabine. Polymorphisms in ABCB1, CDA, ENOSF1,and TYMS could help to predict specific and overall severe adverse reactions to capecitabine.

Differential toxicity biomarkers for irinotecan- and oxaliplatin-containing chemotherapy in colorectal cancer.

PURPOSE: Oxaliplatin or irinotecan is usually administered jointly with fluoropyrimidines in colorectal cancer patients treated with chemotherapy. Both drugs have different toxicity patterns. Biomarkers for predicting high-risk severe adverse reactions can help select the best treatment. METHODS: A retrospective analysis of 106 colorectal cancer patients receiving an oxaliplatin-based treatment and 56 receiving an irinotecan-based treatment was performed. One copy number variant (GSTT1) and nine polymorphisms in irinotecan and oxaliplatin metabolism, transport or DNA repair genes (ABCB1, UGT1A1, XRCC1, ERCC1, ERCC2, GSTP1) were genotyped by SNaPshot, polymerase chain reactions' length fragments, or copy number assays. RESULTS: In irinotecan-treated patients, T allele of ABCB1C1236T SNP was associated with a lower risk of asthenia(OR = 0.047; 95 % CI = 0.004­0.493; P = 0.011) and Tallele of ABCB1 C3435T SNP was associated with a lower risk of diarrhea (OR = 0.177; 95 % CI = 0.034­0.919;P = 0.039), and individuals with two copies of GSTT1 gene had a lower risk for asthenia (OR = 0.093; 95 %CI = 0.011­0.794; P = 0.030). In oxaliplatin-treated patients, carriers of one or two T variants of Asn118Asn ERCC1 SNP had a lower risk for neutropenia(OR = 0.205; 95 % CI = 0.061­0.690; P = 0.01) [corrected]. CONCLUSIONS: These biomarkers could help oncologists select the best treatment by reducing toxicity associated with irinotecan or oxaliplatin in colorectal cancer patients, thus increasing their quality of life.

Pharmacogenetic markers of toxicity for chemotherapy in colorectal cancer patients.

Chemotherapeutic agents used in colorectal cancer are frequently associated with severe adverse reactions that compromise the efficacy of treatment. Predicting toxicity could enable therapy to be tailored. Genetic variations have been associated with toxicity in patients treated with fluoropyrimidines (5-fluorouracil, capecitabine and tegafur), oxaliplatin, irinotecan and cetuximab. Complexity of treatment and variability in toxicity classifications make it difficult to compare studies. This article analyzes the association between toxicity and polymorphisms in DPYD, TYMS, MTHFR, ABCB1, UGT1A1, ERCC1, ERCC2, XRCC1, GSTT1 and GSTM1. In addition, the state-of-the-art and future perspectives are discussed.

ABCB1 gene polymorphisms are associated with adverse reactions in fluoropyrimidine-treated colorectal cancer patients.

AIM: To find out whether SNPs in the transporter gene ATP-binding casette B1 (ABCB1) were related to adverse effects in colorectal cancer patients treated with 5-fluorouracil (5-FU) or capecitabine. MATERIALS & METHODS: Patients treated with a 5-FU-based therapy (n = 67) or a capecitabine-based therapy (n = 74) were recruited and genotyped for the ABCB1 SNPs rs1128503 (C1236T), rs2032592 (G2677T/A) and rs1045642 (C3435T). Clinical data and adverse reactions were recorded. ABCB1 genotypes of patients were statistically analyzed for association with the most frequent adverse reactions. RESULTS: Statistical associations were observed, suggesting a lower risk of neutropenia (p = 0.013) and hand-foot syndrome (HFS; p = 0.027) for the carriers of T variation for rs1128503 in capecitabine-treated patients, carriers of T variation for rs1045642 treated with capecitabine had a lower risk of HFS (p = 0.033), while those treated with 5-FU had a higher risk of diarrhea (p = 0.035), and carriers of T variation for rs2032592 treated with capecitabine were at less risk of developing HFS (p = 0.033). CONCLUSION: This is the first time evidence has been found of differing pharmacogenetic markers for capecitabine and 5-FU treatments. Genotyping of SNPs in the ABCB1 gene prior to chemotherapy administration could help reduce adverse reactions in colorectal cancer patients.