Increase In Creatinine Concentration Research Articles

Clinical Pharmacology of Dronedarone: Implications for the Therapy of Atrial Fibrillation

Dronedarone, a recently approved antiarrhythmic agent, is a chemical analog of amiodarone. It has an approximately 15% bioavailability, with plasma concentrations markedly increasing after a high-fat meal; it is recommended to be taken with food. The primary metabolic clearance pathway for dronedarone is via the hepatic enzyme system (primarily cytochrome P450 3A4 [CYP3A4]); the half-life of dronedarone is 27 to 31 hours. Strong CYP3A4 inhibitors, such as ketoconazole, are associated with a marked increase in dronedarone maximum concentration and are thus contraindicated; inducers of CYP3A4 will conversely decrease dronedarone exposure. Dronedarone is a substrate for P-glycoprotein (P-gp) and will lead to an increase in concentration of P-gp substrates such as digoxin. Dronedarone will cause a small increase in creatinine concentrations, without a change in glomerular filtration rate (GFR). Gender, renal dysfunction, weight, and age have little effect on the pharmacokinetics of dronedarone, and dose adjustment for these variables is not required.

Association of Immunosuppressant-Induced Protein Changes in the Rat Kidney with Changes in Urine Metabolite Patterns: A Proteo-Metabonomic Study

The basic mechanisms underlying calcineurin inhibitor (CI) nephrotoxicity and its enhancement by sirolimus are still largely unknown. We investigated the effects of CIs alone and in combination with sirolimus on the renal proteome and correlated these effects with urine metabolite pattern changes. Thirty-six male Wistar rats were assigned to six treatment groups (n = 4/group for proteome analysis and n = 6/group for urine (1)H NMR metabolite pattern analysis): vehicle controls, sirolimus 1 mg/kg/day, cyclosporine 10 mg/kg/day, cyclosporine 10 mg/kg/day + sirolimus 1 mg/kg/day, tacrolimus 1 mg/kg/day, tacrolimus 1 mg/kg/day + sirolimus 1 mg/kg/day. After 28 days, 24 h-urine was collected for (1)H NMR-based metabolic analysis and kidneys were harvested for 2D-gel electrophoresis and histology. Cyclosporine affected the following groups of proteins: calcium homeostasis (regucalcin, calbindin), cytoskeleton (vimentin, caldesmon), response to hypoxia and mitochondrial function (prolyl 4-hydroxylase, proteasome, NADH dehydrogenase), and cell metabolism (kidney aminoacylase, pyruvate dehydrogenase, fructose-1,6-bis phosphate). Several of the changes in protein expression, confirmed by Western blot, were associated with and explained changes in metabolite concentrations in urine. Representative examples are an increase in kidney aminoacylase expression (decrease of hippurate concentrations in urine), up regulation of pyruvate dehydrogenase and fructose-1,6-bisphosphatase, (increased glucose metabolism), and down regulation of arginine/glycine-amidino transferase (most likely due to an increase in creatinine concentrations). Protein changes explained and qualified immunosuppressant-induced metabolite pattern changes in urine.

Acute kidney injury in children

Acute kidney injury (AKI) (previously called acute renal failure) is characterized by a reversible increase in the blood concentration of creatinine and nitrogenous waste products and by the inability of the kidney to regulate fluid and electrolyte homeostasis appropriately. The incidence of AKI in children appears to be increasing, and the etiology of AKI over the past decades has shifted from primary renal disease to multifactorial causes, particularly in hospitalized children. Genetic factors may predispose some children to AKI. Renal injury can be divided into pre-renal failure, intrinsic renal disease including vascular insults, and obstructive uropathies. The pathophysiology of hypoxia/ischemia-induced AKI is not well understood, but significant progress in elucidating the cellular, biochemical and molecular events has been made over the past several years. The history, physical examination, and laboratory studies, including urinalysis and radiographic studies, can establish the likely cause(s) of AKI. Many interventions such as ‘renal-dose dopamine’ and diuretic therapy have been shown not to alter the course of AKI. The prognosis of AKI is highly dependent on the underlying etiology of the AKI. Children who have suffered AKI from any cause are at risk for late development of kidney disease several years after the initial insult. Therapeutic interventions in AKI have been largely disappointing, likely due to the complex nature of the pathophysiology of AKI, the fact that the serum creatinine concentration is an insensitive measure of kidney function, and because of co-morbid factors in treated patients. Improved understanding of the pathophysiology of AKI, early biomarkers of AKI, and better classification of AKI are needed for the development of successful therapeutic strategies for the treatment of AKI.

What Should the Physician Do When Creatinine Increases After Starting an Angiotensin‐Converting Enzyme Inhibitor or an Angiotensin Receptor Blocker?

Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) are generally well tolerated and are used extensively in the treatment of hypertension and heart failure and in patients with renal disease for the reduction of proteinuria.1–3 A common clinical problem arises when these renin-angiotensin system–blocking drugs are started and the serum creatinine becomes elevated above the patient’s baseline level. This may cause concern and may lead to stopping the ACE inhibitor or ARB. Here, we offer our clinical approach to this problem. ACE inhibitors prevent the conversion of angiotensin I to angiotensin II by inhibiting the ACE inhibitor enzyme complex, while ARBs inhibit the binding of angiotensin to its AT1 receptor. Angiotensin II constricts both the afferent and efferent arterioles, but it preferentially increases efferent arteriole resistance. When an ACE inhibitor or ARB is used, there is a decrease in resistance at the efferent (postglomerular) arteriole; this lowers intraglomerular pressure and reduces the glomerular filtration rate (GFR).4 In patients with chronic kidney disease (CKD) and heart failure, the GFR is often even more dependent on an angiotensin II–induced increases in resistance at the efferent arteriole. Patients with heart failure and CKD and patients who are volume-depleted often due to over enthusiastic diuresis may be more susceptible to these hemodynamic effects.5 Both the serum creatinine and potassium levels should be checked from 3 days to a 1 week after an ACE inhibitor is started, particularly in patients who might be considered susceptible to the hemodynamic effects of an ACE inhibitor or an ARB. The rise in serum creatinine values usually begins a few days after beginning therapy with an ACE inhibitor or an ARB, as angiotensin II levels are rapidly reduced or blocked from binding.6 This results in efferent arteriolar dilatation and decreased effective GFR. So what is an acceptable increase in creatinine level? An increase in creatinine concentration of about 25%–30% above baseline is acceptable (eg, creatinine level of 1.2 mg/dL increasing to 1.5 mg/dL). Frequently, creatinine levels will return to baseline or below if blood pressure is lowered, despite the continued use of a renin-angiotensin-aldosterone system inhibitor. A larger rise in creatinine level is likely to occur in patients with bilateral renovascular disease, CKD, and heart failure. What should be done when a creatinine increase exceeds this threshold after a recent medication adjustment? If a decrease in systolic pressure >20 mm Hg has occurred and the ACE inhibitor or ARB was recently added to a diuretic or the dose of ACE inhibitor ARB was increased, the ACE inhibitor or ARB dosage should be reduced or stopped and therapy restarted at a lower dosage later. If the diuretic dosage was recently changed, particularly if the patient lost weight as a result, it may be prudent to temporarily withhold the diuretic and restart at a lesser dose. These are empiric approaches, but the key is to distinguish a large pharmacodynamic effect due to renin-angiotensin system blockade from subtle or overt volume depletion from the diuretic. In our experience, the volume depletion may be so subtle that neither orthostasis in blood pressure nor a detectable increase in heart rate is evident. The important issue in patients with marginally or overtly impaired renal function is to check the creatinine level. In a minority of cases in our experience, substantial increases in creatinine values may be from bilateral renal artery stenosis. Like blood pressure, the biochemical changes induced with medication may be substantial while patients remain clinically asymptomatic.

Measurement of Creatinine in Whole Blood Samples Supplemented to Achieve Increased Creatinine Concentrations

During clinical trials of a new biosensor for measurement of whole blood creatinine, we were unable to obtain sufficient quantities of samples with naturally occurring high creatinine concentrations to validate performance of the sensor across the proposed reportable concentration range for the device [18–1326 μmol/L (0.2–15.0 mg/dL)]. Addition of creatinine to whole blood samples was required to validate performance of the sensor at the high end of the range. We noticed irreproducible results for samples that were supplemented with creatinine to increase the concentration. Like other direct-reading electrochemical biosensors (1), creatinine sensors respond to the molality of creatinine in the sample (amount of creatinine per unit mass of water). It is known that molality of creatinine in erythrocyte fluid is equal to molality in plasma (2) and that creatinine is transported by passive diffusion through the lipid bilayer of the erythrocyte membrane (3). Heparinized blood from a healthy volunteer was centrifuged and the separated plasma supplemented with creatinine to target concentrations of …

Delay in separating blood samples affects creatinine measurement using the Roche kinetic Jaffe method

We have examined the effect of delayed sample separation on serum creatinine measurement using the kinetic Jaffe method and estimated glomerular filtration rate (eGFR), and the impact this can have on chronic kidney disease (CKD) staging. In a preliminary study clotted samples were left at room temperature for up to 48 h prior to centrifugation and serum creatinine measurement on a Roche modular analyser. A larger study then used paired clotted samples separated at baseline (30 min) and after 24 h at room temperature. To determine the effect on CKD staging, eGFR was calculated using the simplified [4-v] Modification of Diet in Renal Disease formula. Preliminary study. A significant increase in creatinine concentration (P < or = 0.001) occurred after a 16 h delay in sample separation. By 48 h the mean increase in creatinine was 29% (range 21-63%). Twenty-four hour delay study. The mean increase in creatinine for 113 outpatient samples after delaying sample separation by 24 h was 11%, and exhibited considerable individual variation (range 2-87%). CKD staging for 32% of the group changed, 26% from stage 1 to 2 and 6% from stage 2 to 3. Delay in sample separation affects the creatinine measurement using the Roche kinetic Jaffe reaction, and can result in the misclassification of CKD staging. Laboratories using the kinetic Jaffe method should not report creatinine results where there has been a delay in separation. This advice should also be reflected in practice guidelines.

Management of Acute Kidney Injury in Children

Acute kidney injury (AKI; previously called acute renal failure) is characterized by a usually reversible increase in the blood concentration of creatinine and nitrogenous waste products and by the inability of the kidney to appropriately regulate fluid and electrolyte homeostasis. The incidence of AKI in children appears to be increasing and the etiology of AKI over the past decades has shifted from primary renal disease to multifactorial causes, particularly in hospitalized children. Renal failure can be divided into prerenal failure, intrinsic renal disease including vascular insults, and obstructive uropathies. The history, physical examination, and laboratory studies including a urinalysis and radiographic studies can establish the likely cause(s) of AKI. Once intrinsic renal failure has become established, management of the metabolic complications of AKI requires meticulous attention to fluid balance, electrolyte status, acid-base balance, and nutrition. Many children with AKI will need renal replacement therapy to remove endogenous and exogenous toxins and to maintain fluid, electrolyte, and acid-base balance until renal function improves. Renal replacement therapy may be provided by peritoneal dialysis (PD), intermittent hemodialysis (HD), or hemofiltration with or without a dialysis circuit. Many factors--including the age and size of the child, the cause of renal failure, the degree of metabolic derangements, blood pressure, and nutritional needs--are considered in deciding when to initiate renal replacement therapy and which modality of therapy to use. The prognosis of AKI is highly dependent on the underlying etiology of the AKI. Children who have AKI as a component of multisystem failure have a much higher mortality rate than children with intrinsic renal disease. Recovery from intrinsic renal disease is also highly dependent on the underlying etiology of the AKI. Children who have experienced AKI from any cause are at risk for late development of renal failure long after the initial insult. Such children need life-long monitoring of their renal function, blood pressure, and urinalysis.

The diagnostic accuracy of different natriuretic peptides in the investigation of canine cardiac disease

We aimed to validate and determine the accuracy of a new sandwich ELISA for canine N-terminal pro-B-type natriuretic peptide (NT-proBNP) in the discrimination of canine patients with cardiac disease from those with respiratory disease and to determine the effect of confounding variables on NT-proBNP concentrations. Validation studies for the new assay were undertaken. Concentrations of N-terminal atrial natriuretic peptide (NT-proANP) and NT-proBNP in both ethylenediaminetetraacetic acid (EDTA) plasma and serum were estimated in samples from 77 dogs at a laboratory blinded to the clinical status of the patient. The diagnostic accuracy of the each sample type and test was evaluated using receiver operating characteristic curves. The effect of age, gender and indicators of renal function was evaluated using a multivariate regression analysis. Concentrations of NT-proBNP in both serum and plasma accurately discriminated dogs with respiratory disease from those with cardiac disease, with an optimum cut-off concentration of 210 pmol/l. NT-proBNP concentrations were unaffected by sample type. Increasing creatinine concentration is associated with increasing concentration of NT-proBNP. Age and gender were not found to have significant effects on natriuretic peptide concentrations in this population. Canine NT-proBNP appears to be a useful marker of the presence of cardiac disease, although concentrations must be interpreted in the light of the patient's renal function.

The RIFLE criteria: Are the foundations robust?

We read with interest the article by Drs. Ostermann and Chang (1) about the RIFLE criteria as a classification of renal failure and as a prognostic factor in intensive care. We would like to make some comments, also valid for the other articles published on this topic. One important criterion in the RIFLE classification is the glomerular filtration rate (GFR). It is even the sole criterion used in this study because urine data were not available. In all studies published on the RIFLE criteria, GFR is not measured but estimated by the of diet in renal disease (MDRD) equation. This equation is based on four variables: gender, age, ethnicity, and serum creatinine. Among these variables, only serum creatinine can change abruptly. Therefore, using MDRD (or any other creatinine-based formula) in the intensive care setting is very questionable. The MDRD equation has been poorly validated in intensive care patients. Hoste et al. (2) showed that the MDRD equation was not adequate to estimate GFR, even if this study included few patients and used a questionable reference method for the GFR measurement (1-hr creatinine clearance). Once again, serum creatinine concentration, the most important variable of the MDRD equation, is also dependent on muscular mass, and patients hospitalized in intensive care units are prone to present decreased muscular mass. Consequently, serum creatinine may remain low or not increase as much as expected even if renal failure occurs. As a consequence, the MDRD equation may potentially overestimate true GFR. Such an overestimation has been clearly demonstrated in other patients with decreased muscular mass like heart transplant patients or patients with low body weight (3, 4). In the same way, even an increase in creatinine concentration of only 0.3 mg/dL could correspond to a large decrease in GFR in patients with loss of muscular mass and explain why such a limited modification of serum creatinine is linked to mortality (1). The inability of creatinine and MDRD to correctly estimate GFR in patients with decreasing muscular mass may also partially explain differences observed in the incidence of renal failure between studies with different populations and between studies using the GFR or the urine criteria.

Issue Highlights

HomeCirculationVol. 115, No. 10Issue Highlights Free AccessIn BriefPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessIn BriefPDF/EPUBIssue Highlights Originally published13 Mar 2007https://doi.org/10.1161/circ.115.10.1177Circulation. 2007;115:1177REMOTE MAGNETIC NAVIGATION TO GUIDE ENDOCARDIAL AND EPICARDIAL CATHETER MAPPING OF SCAR-RELATED VENTRICULAR TACHYCARDIA, by Aryana et al.Catheter mapping of ventricular tachycardia is challenging because of tissue heterogeneity in diverse scar-related disease substrates as well as limitations in maneuverability and accessibility to critical regions of the ventricular endocardium and epicardium. In this issue of Circulation, Aryana and colleagues report their clinical results obtained by using a remote magnetic navigation system combined with electroanatomic mapping to identify areas of interest related to ventricular tachycardia, while using a limited amount of fluoroscopy exposure. Although the majority of epicardial and endocardial ventricular sites could be safely and effectively mapped remotely, because of current limitations of the magnetic navigation catheter, most patients required additional manual ablation using an irrigated catheter to ablate fully the ventricular tachycardia substrates. See p 1191.RENAL INSUFFICIENCY FOLLOWING CONTRAST MEDIA ADMINISTRATION TRIAL (REMEDIAL): A RANDOMIZED COMPARISON OF 3 PREVENTIVE STRATEGIES, by Briguori et al.Exposure to radiocontrast media can lead to transient and permanent renal failure in high-risk patients such as those with preexisting moderate or severe renal failure. Current methods to prevent contrast-induced nephrotoxicity include volume expansion with saline and limitation of contrast volume. Other strategies have been proposed, including N-acetylcysteine (NAC), sodium bicarbonate infusion, and ascorbic acid. The study by Briguori et al was a 2-center, randomized, double-blind study of 3 strategies to prevent contrast-induced nephrotoxicity in 326 patients with moderate chronic renal disease undergoing coronary or peripheral angiography. Moderate renal failure was defined as a creatinine concentration of 2 to 8 mg/dL. Patients were randomized to saline plus NAC, sodium bicarbonate infusion plus NAC, or saline plus ascorbic acid plus NAC. Contrast-induced nephropathy defined as an increase in creatinine concentration by 25% occurred in 9.9%, 1.9%, and 10.3%, respectively. The sodium bicarbonate infusion plus NAC produced significantly better results than the other regimens (P=0.019). Other measures of contrast-induced nephrotoxicity showed similar results. In addition, similar results were seen in high-risk subgroups such as those with diabetes. These findings support the use of volume expansion with sodium bicarbonate plus NAC as a more effective strategy in preventing contrast-induced nephrotoxicity than saline plus NAC or saline plus ascorbic acid and NAC. See p 1211.USE OF A CONSTITUTIVELY ACTIVE HYPOXIA-INDUCIBLE FACTOR-1α TRANSGENE AS A THERAPEUTIC STRATEGY IN NO-OPTION CRITICAL LIMB ISCHEMIA PATIENTS: PHASE I DOSE-ESCALATION EXPERIENCE, by Rajagopalan et al.Critical limb ischemia is a serious manifestation of peripheral atherosclerosis associated with limb loss in a considerable number of patients. Although surgery and percutaneous transluminal angioplasty may provide improvement in some patients, in others, amputation is the only option. Several systems in the body sense hypoxia, among them the hypoxia-inducible factor-1α. Such ischemia-sensing systems activate protective pathways in the body to limit tissue damage. In the study by Rajagolpalan et al, therefore, the authors tested whether a constitutively active transcription factor of hypoxia-inducible factor-1α transfected with an adenovirus would be safe and potentially ameliorate symptoms and improve outcome in patients with critical limb ischemia and no other options. No serious adverse events of this treatment were noted, but peripheral edema disease progression and ischemia were still common. In approximately half of the hypoxia-inducible factor-1α treated patients, however, complete pain resolution was noted at 1 year and ulcer healing in almost one third. Although very preliminary, this study suggests that this novel gene therapy approach in critical limb ischemia should be pursued further and may, if confirmed in larger studies, offer a treatment for those patients with no other options. See p 1234.Visit http://circ.ahajournals.org:Images in Cardiovascular MedicineHuge Pericardial Hemangioma Imaging. See p e315. Download figureDownload PowerPointCardiovocal Syndrome Associated With Huge Left Atrium. See p e318.Infarction-Like Electrocardiographic Changes Due to a Myocardial Metastasis From a Primary Lung Cancer. See p e320.CorrespondenceSee p e322. Previous Back to top Next FiguresReferencesRelatedDetails March 13, 2007Vol 115, Issue 10 Advertisement Article InformationMetrics https://doi.org/10.1161/circ.115.10.1177 Originally publishedMarch 13, 2007 PDF download Advertisement

A randomized controlled trial comparing hydration therapy to additional hemodialysis or N-acetylcysteine for the prevention of contrast medium-induced nephropathy

Contrast medium-induced nephropathy (CIN) is a serious complication with increasing frequency and an unfavorable prognosis. Previous analyses of surrogate parameters have suggested beneficial effects of hemodialysis that are assessed in this randomized clinical trial. We performed a prospective single-center trial in 424 consecutive patients with serum creatinine concentrations between 1.3- 3.5 mg/dl who underwent elective coronary angiography. Patients were randomized to one of three treatment strategies with all patients receiving pre- and postprocedural hydration: One group received no additional therapy, patients in the second group were hemodialyzed once, and the third group received oral N-acetylcysteine. The frequency of CIN (defined as an increase in serum creatinine>or=0.5 mg/dl) from 48 to 72 h after catheterization was 6.1% in the hydration-only group, 15.9% with hemodialysis treatment, and 5.3% in the N-ACC group (intention-to-treat analysis; P=0.008). There were no differences between the treatment groups with regard to increased (>or=0.5 mg/dl) serum creatinine concentrations after 30-60 days (4.8%, 5.1%, and 3.1%, respectively; P=0.700). Analyses of long-term follow-up (range 63 to 1316 days) by Cox regressions models of the study groups found quite similar survival rates (P=0.500). In contrast to other (retrospective) studies, long-term survival of patients with vs those without CIN within 72 h was not different, but patients who still had elevated creatinine concentrations at 30-60 days suffered from a markedly higher 2-year mortality (46% vs 17%, P=0.002). In conclusion, hemodialysis in addition to hydration therapy for the prevention of CIN provided no evidence for any outcome benefit but evidence for probable harm. Increased creatinine concentrations at 30-60 days, but not within 72 h, were associated with markedly reduced long-term survival.

Contrast-induced nephropathy: Pharmacological prophylaxis

Contrast media-associated acute renal failure represents the third most common cause of in-hospital renal function deterioration after decreased renal perfusion and post-operative renal insufficiency. Although generally benign, this complication is associated with a mortality rate ranging from 3.8 to 64%, depending on the increase of creatinine concentration. Multiple drugs have been tested in an attempt to prevent this complication. Central to the pathophysiology of contrast-induced nephrotoxicity (CIN) is an alteration in renal hemodynamics. In an effort to reverse these hemodynamic changes, vasodilators and diuretics have been tested as prophylactic drugs. However, their effectiveness has not been confirmed. Recently, considerable interest has resulted from the initial positive data on the effectiveness of prophylactic administration of antioxidant compounds, such as acetylcysteine and ascorbic acid. In this review, we focus on the effectiveness of pharmacologic therapies for preventing CIN.

A propensity score case‐control comparison of aprotinin and tranexamic acid in high‐transfusion‐risk cardiac surgery

Cardiac surgery with cardiopulmonary bypass may result in excessive fibrinolysis and platelet (PLT) dysfunction, resulting in impaired hemostasis and excessive blood loss. Prophylactic use of the antifibrinolytic drugs aprotinin and tranexamic acid is thought to prevent these hemostatic defects. Their relative clinical utility and safety in high-transfusion-risk cardiac surgery, however, is not known. Using propensity scores, 449 patients who received aprotinin for high-transfusion-risk cardiac surgery were matched to 449 patients who received tranexamic acid from a pool of 10,870 consecutive patients who underwent cardiac surgery at a single center, 586 of whom received aprotinin and the remainder of whom received tranexamic acid. The two matched groups were well balanced in terms of measured perioperative variables. Blood product transfusion rates were similar in the aprotinin and tranexamic acid groups: red blood cells, 79 percent versus 76 percent (p = 0.3); PLTs, 56 percent versus 50 percent (p = 0.06); and plasma, 66 percent versus 61 percent (p = 0.1). Adverse events rates were comparable in the two groups, except for renal dysfunction (defined as a greater than 50% increase in creatinine concentration during the first postoperative week to >100 micromol/L in women and >110 micromol/L in men or a new requirement for dialysis support), which occurred in 24 percent (107/449) of aprotinin patients and 17 percent (75/449) of tranexamic acid patients (p = 0.01). Aprotinin and tranexamic acid have similar hemostatic effectiveness in high-transfusion-risk cardiac surgery. Within the confines of propensity score matching, our results suggest that aprotinin may be associated with renal dysfunction.

Poor prognosis indicated by nucleated red blood cells in peripheral blood is not associated with organ failure of the liver or kidney

The appearance of nucleated red blood cells (NRBCs) in peripheral blood is associated with a variety of severe diseases. When NRBCs are detected in blood, this is generally associated with increased mortality. In a prospective study, NRBCs and other laboratory parameters were measured daily in the peripheral blood of surgical intensive care patients. The appearance of NRBCs was analyzed in relation to laboratory indicators of organ injury. A total of 284 surgical intensive care patients were included in this study. The mortality of NRBC-positive patients was 44.0% (40/91). This was significantly higher (p<0.001) than the mortality of NRBC-negative patients (4.2%, 8/193). Mortality increased with the NRBC concentration and the length of the NRBC-positive period. Multiple logistic regression analysis of several other clinical and laboratory risk indicators revealed a significant association between NRBCs and increased mortality, with an odds ratio of 1.95 (95% CI 1.35-2.82; p<0.001) for each increment in NRBC category (0, 1-40, 41-80, 81-240 and >240 NRBC/microL). After the initial detection of NRBCs in blood, there were no significant increases in creatinine concentrations or alanine aminotransferase activity. However, the appearance of NRBCs coincided with increasing C-reactive protein and thrombocyte concentrations. The detection of NRBCs in blood of surgical intensive care patients is of prognostic power with regard to patient mortality. This prognostic significance of NRBCs was independent of some clinical and other laboratory risk parameters. The appearance of NRBCs in blood was not associated with kidney failure or lesion of the liver.

Prophylactic fenoldopam for renal protection in sepsis: A randomized, double-blind, placebo-controlled pilot trial*

Acute renal failure is common in septic patients. Fenoldopam, a dopamine-1 receptor agonist, increases renal blood flow and may, therefore, reduce the risk of acute renal failure in such patients. Accordingly, we sought to determine the safety and efficacy of fenoldopam for the prevention of acute renal failure in septic patients. Prospective, double-blind, placebo-controlled trial. Three multidisciplinary intensive care units at a university hospital. Three hundred septic patients with baseline serum creatinine concentrations <150 micromol/L. We randomized patients to a continuous infusion of either fenoldopam (n = 150) at 0.09 microg x kg x min or placebo (n = 150) while in the intensive care unit. The primary outcome measure was the incidence of acute renal failure, defined as a serum creatinine concentration increase to >150 micromol/L, during study drug infusion. The incidence of acute renal failure was significantly lower in the fenoldopam group compared with the control group (29 vs. 51 patients; p = .006). The odds ratio of developing acute renal failure for patients treated with fenoldopam was estimated to be 0.47 (p = .005). The difference in the incidence of severe acute renal failure (creatinine >300 mumol/L), however, failed to achieve statistical significance (10 vs. 21; p = .056). The length of intensive care unit stay in surviving patients was significantly lower in the fenoldopam group compared with the control group (10.64 +/- 9.3 vs. 13.4 +/- 14.0; p < .001). There were no complications of fenoldopam infusion. A direct effect of treatment on the probability of death, beyond its effect on acute renal failure, was not significant (odds ratio = 0.68, p = .1). Compared with placebo, low-dose fenoldopam resulted in a smaller increase in serum creatinine in septic patients. The clinical significance of this finding is uncertain. A large multiple-center trial is now needed to confirm these findings.

Elevated plasma homocysteine: cause or consequence of myocardial infarction?

To determine whether a first myocardial infarction leads to increased plasma homocysteine concentrations and whether the association between homocysteine and myocardial infarction was greater at follow-up compared with baseline. A population-based, prospective, nested case-referent study. Screening took place at the nearest health survey centre in northern Sweden. Of more than 36,000 persons screened, 78 developed a first myocardial infarction (average 18 months after sampling). Fifty of these had participated in a follow-up health survey (average 8(1/2) years between surveys) and were sex- and age-matched with 56 referents. Comparison of plasma homocysteine levels in case and referent subjects before and after development of a first myocardial infarction. No statistically significant difference was found between cases and referents regarding homocysteine at baseline or follow-up. Plasma homocysteine and plasma creatinine increased significantly, and plasma albumin decreased significantly over time. Conditional univariate logistic regression indicated that high homocysteine at follow-up but not baseline was associated with first myocardial infarction (OR 2.49; 95% CI: 1.03-6.02), but the relation disappeared in multivariate analyses including plasma creatinine and plasma albumin. High plasma creatinine remained associated with first myocardial infarction at both baseline (OR 2.94; 95% CI: 1.05-8.21) and follow-up (OR 3.38; 95% CI: 1.21-9.48). In this study, first myocardial infarction did not cause increased plasma homocysteine concentration.

Use of Once-Daily Netilmicin to Treat Infants with Suspected Sepsis in a Neonatal Intensive Care Unit

Once-daily administration of aminoglycoside antibiotics has become the most acceptable dosing schedule for the majority of patients. There are few published data on the impact of post-natal age on aminoglycoside concentrations in preterm infants receiving once-daily dosage regimens. Netilmicin was administered as a once-daily dose of 4 mg/kg. In 141 episodes of suspected sepsis in 123 babies, trough netilmicin concentrations ranged from undetectable to 4.0 mg/l. Netilmicin concentrations were above a level of 2 mg/l in 10.6% of episodes. Netilmicin concentrations decreased with increasing post-natal age and weight. Levels were higher in males compared to females. Increased creatinine concentrations were associated with higher netilmicin concentrations. This study emphasises the importance of post-natal age as a determinant of aminoglycoside concentrations with a once-daily dosing regimen in a neonatal intensive care population. Trough levels should be carefully monitored and consideration given to extending dosage intervals particularly when netilmicin is administered once daily to preterm infants in the first week of life.

Hyperhomocysteinemia, Pregnancy Complications, and the Timing of Investigation

To assess associations between vitamin-dependent homocysteine metabolism and vascular-related pregnancy complications by considering interval between delivery and postpartum investigation and maternal age. Case-control study performed at the University Medical Center Nijmegen in the Netherlands. Patients had experienced pregnancy-induced hypertension (n = 37), preeclampsia (n = 144), hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome (n = 104), recurrent early pregnancy loss (n = 544), abruptio placentae (n = 135), intrauterine growth restriction (n = 144), or intrauterine fetal death (n = 104). Controls comprised 176 women with uncomplicated obstetric histories. Oral methionine loading tests and fasting vitamin profiles were performed more than 6 weeks after delivery. Odds ratios and 95% confidence intervals were calculated after logistic regression analysis. Hyperhomocysteinemia was associated with an approximately 2-fold to 3-fold increased risk for pregnancy-induced hypertension, abruptio placentae, and intrauterine growth restriction. Cobalamin deficiency was associated with HELLP syndrome, abruptio placentae, intrauterine growth restriction, and intrauterine fetal death. Pyridoxal 5-phosphate deficiency increased the risk for pregnancy-induced hypertension 4-fold. These associations lost their significance after adjustment for time interval and maternal age. High red cell folate was associated with a decreased risk for abruptio placentae and intrauterine growth restriction. An increased creatinine concentration was associated with pregnancy-induced hypertension, preeclampsia, HELLP syndrome, and abruptio placentae. Hyperhomocysteinemia and vitamin deficiencies are largely determined by the interval between delivery and postpartum investigation and by maternal age. Time interval and maternal age should be considered in the risk estimation for vascular-related pregnancy complications.

High-dosage continuous amiodarone therapy to treat new-onset supraventricular tachyarrhythmias in surgical intensive care patients: an observational study.

New-onset supraventricular tachyarrhythmias (SVTA) are a complication contributing significantly to morbidity and mortality in surgical intensive care unit (SICU) patients. Although only few data on efficiency can be found in the literature, class III antiarrhythmics have become popular in the treatment of SVTA in critically ill patients. 12-bed general and surgical ICU in a university teaching hospital. Observational, retrospective study. 131 SICU patients with SVTA (narrow-complex non-sinus tachyarrhythmias with heart rates > or = 100 bpm). High-dosage amiodarone infusion according to an institutional protocol. Hemodynamic data, acid-base status, and single organ functions were obtained in all patients before amiodarone infusion and at 12, 24, and 48 hours afterwards. Patients were divided into responders and nonresponders. Amiodarone infusion (mean dosage 24 h: 1625+/-528 mg; 48 h: 2708+/-895 mg) restored sinus rhythm in 54% of study patients within 12 h, in 64% within 24 h, and in 75% within 48 h. Heart rate, central venous pressure, and milrinone requirements significantly decreased in all patients; this was accompanied by a significant increase in stroke-volume index and mean arterial pressure. Serum concentrations of creatinine and bilirubin increased in all patients. High-dosage continuous amiodarone infusion during a period of 48 hours resulted in restoration of SR in 75% of SICU patients with new-onset SVTA and moderate to severe multiple-organ dysfunction syndrome. A significant improvement in cardiocirculatory function was more pronounced in responders but could be demonstrated irrespective of restoration of sinus rhythm in all patients. Apart from a possibly amiodarone-mediated increase in concentrations of creatinine and bilirubin, no major drug-related adverse effects occurred during the observation period.

Transient Remnant Removal Disease in Acute Fatty Liver of Pregnancy

Objective: To elucidate the potential role of an altered lipid metabolism in the pathophysiology of acute fatty liver of pregnancy (AFLP). Case Report: We report on two otherwise healthy women in the 34th gestational week who presented with symptoms of AFLP. Besides characteristic symptoms like nausea, abdominal pain, highly elevated serum amino transferase levels, and increased creatinine concentrations, the patients' clotting system showed consumption and/or decreased synthesis of coagulation factors. Pregnancies were terminated by elective cesarean section because of worsening symptoms. Blood tests normalized quickly and both the mothers and their baby boys could be dismissed in healthy condition. Study Design: Blood samples were collected shortly before delivery and 5, 15, 70, and 110 days afterwards. Lipids and apolipoproteins (apo) were analyzed in whole plasma as well as in very low density, intermediate density, low density (LDL), and high density lipoprotein. Total LDL was further separated into 6 LDL subfractions by equilibrium density ultracentrifugation. Results: Before delivery, the LDL subfraction pattern was characterized by the virtual absence of intermediate and most dense LDL. Lipoprotein electrophoresis showed the presence of β‐migrating VLDL. Within days after delivery, the distribution of apoB‐containing lipoproteins returned to normal. Genetic variations of apoE, lipoprotein lipases, and the long‐chain 3‐hydroxyacyl‐coenzyme A dehydrogenase were not detected in any of the patients. Conclusions: The lipoprotein metabolism in the acute phase of AFLP was reminiscent of hepatic lipase deficiency, a disorder characterized by impaired removal of lipoprotein remnants. As these triglyceride‐rich particles cause endothelial dysfunction, they may contribute to the pathophysiology of AFLP.