A prospective feasibility trial exploring novel biomarkers for neurotoxicity after isolated limb perfusion.

BACKGROUND: Isolated limb perfusion (ILP) is a regional cancer treatment in which high-dose chemotherapy is administered in an isolated extremity. The main side effect is regional toxicity, which occasionally leads to nerve damage. Measuring neuroaxonal biomarkers, might be a method predicting such complications. Therefore, the primary aim of the study is to investigate if neuronal biomarkers are measurable and alters in an isolated extremity during ILP. Secondly, if postoperative regional toxicity, alterations in sensitivity, and/or muscle strength are correlated to the biomarker levels. METHODS: Eighteen scheduled ILP-patients were included in the study. Glial fibrillary acidic protein (GFAP), neurofilament light (NfL), and tau concentrations were measured in plasma sampled preoperatively, at the start and end of the ILP, on days 3 and 30, using ultrasensitive Single molecule array (Simoa) technology. The patients were assessed by a physiotherapist pre- and postoperatively. RESULTS: At ILP end, significantly higher NfL and tau levels were measured in the extremity than in the corresponding systemic circulation (NfL; 17 vs 6 ng/L, p < .01, tau; 1.8 vs 0.6 ng/L, p < .01), and the extremity levels were significantly increased at ILP end (NfL; 66 ± 37%, p < .001, tau; 75 ± 45%, p = .001). On days 3 and 30, significantly increased NfL and GFAP levels were measured systemically (NfL day 3: 69 ± 30%, p < .001; day 30: 76 ± 26%, p < .001; GFAP day 3: 33 ± 22%, p < .002; day 30: 33 ± 23%, p ≤ .004). Finally, no significant correlations were found between regional toxicity or between postoperative muscle or sensitivity decrease and biomarker release. CONCLUSION: During ILP, NfL and tau levels increased significantly. No obvious correlations were observed between biomarker release and regional toxicity or decreased muscle strength or sensitivity, although large-scale studies are warranted.

Non-invasive and invasive measurement of skeletal muscular oxygenation during isolated limb perfusion.

BACKGROUND: Isolated limb perfusion (ILP) is a regional surgical treatment for localized metastatic disease. High doses of chemotherapeutic agents are administered within an extracorporeal circulated isolated extremity, treating the metastasis, while systemic toxicity is avoided. To our knowledge, indexed oxygen supply/demand relationship during ILP has not previously been described. Our aim was to measure and describe oxygen metabolism, specifically oxygen delivery, consumption, and extraction, in an isolated leg/arm during ILP. Also investigate whether invasive oxygenation measurement during ILP correlates and can be used interchangeable with the non-invasive method, near infrared spectroscopy (NIRS). METHODS: Data from 40 patients scheduled for ILP were included. At six time points blood samples were drawn during the procedure. DO2, VO2, and O2ER were calculated according to standard formulas. NIRS and hemodynamics were recorded every 10 min. RESULTS: For all observations, the mean of DO2 was 190±59 ml/min/m2, VO2 was 35±8 ml/min/m2, and O2ER was 21±8%. VO2 was significantly higher in legs compared to arms (38±8 vs. 29±7 ml/min/m2, p=0.02). Repeated measures showed a significant decrease in DO2 in legs (209±65 to 180±66 ml/min/m2, p=<0.01) and in arms (252±72 to 150±57 ml/min/m2, p=<0.01). Significant increase in O2ER in arms was also found (p=0.03). Significant correlation was detected between NIRS and venous extremity oxygen saturation (SveO2) (rrm=0.568, p=<. 001, 95% CI 0.397-0.701). When comparing SveO2 and NIRS using a Bland-Altman analysis, the mean difference (bias) was 8.26±13.03 (p=<. 001) and the limit of agreement was - 17.28-33.09, with an error of 32.5%. CONCLUSION: DO2 above 170 ml/min/m2 during ILP kept O2ER below 30% for all observations. NIRS correlates significant to SveO2; however, the two methods do not agree sufficiently to work interchangeable. Clinical Trial Registration URL: https://www.clinicaltrials.gov. Unique identifier: NCT04460053 and NCT03073304.

Renal Hemodynamics, Function, and Oxygenation in Critically Ill Patients and after Major Surgery.

This review outlines the available data from the work of our group on renal hemodynamics, function, and oxygenation in patients who are critically ill with acute renal dysfunction, such as those with postoperative AKI, those in early clinical septic shock, in patients undergoing cardiac surgery with cardiopulmonary bypass, or in patients undergoing liver transplantation. We also provide information on renal hemodynamics, function, and oxygenation in patients with chronic renal impairment due to congestive heart failure. This review will argue that, for all of these groups of patients, the common denominator is that renal oxygenation is impaired due to a lower renal oxygen delivery or a pronounced increase in renal oxygen consumption.

Effects of milrinone on renal perfusion, filtration and oxygenation in patients with acute heart failure and low cardiac output early after cardiac surgery.

PURPOSE: Early postoperative heart failure is common after cardiac surgery, and inotrope treatment may impact renal perfusion and oxygenation. We aimed to study the renal effects of the inodilator milrinone when used for the treatment of heart failure after weaning from cardiopulmonary bypass (CPB). MATERIAL AND METHODS: In 26 patients undergoing cardiac surgery with CPB, we used renal vein catheterization to prospectively measure renal blood flow (RBF), glomerular filtration rate (GFR), and renal oxygenation. Patients who developed acute heart failure and low cardiac output (cardiac index <2.1 L/min/m2) at 30 min after weaning from CPB (n = 7) were given milrinone, and the remaining patients (n = 19) served as controls. Additional measurements were made at 60 min after CPB. RESULTS: In patients with acute postoperative heart failure, before receiving milrinone, renal blood flow was lower (-33%, p < .05) while renal oxygen extraction was higher (41%, p < .05) compared to the control group. Milrinone increased cardiac index (21%, p < .001), RBF (36%, p < .01) and renal oxygen delivery (35%, p < .01), with no significant change in GFR and oxygen consumption compared to the control group. CONCLUSIONS: In patients with acute heart failure after weaning from CPB, the milrinone-induced increase in cardiac output was accompanied by improved renal oxygenation. TRIAL REGISTRATION: ClinicalTrials.gov; identifier NCT02405195, date of registration; March 27, 2015, and NCT02549066, date of registration; 9 September 2015.

Impact of Cardiopulmonary Bypass Flow on Renal Oxygenation in Patients Undergoing Cardiac Operations.

BACKGROUND: Cardiac surgery with cardiopulmonary bypass (CPB) is associated with acute kidney injury, and the risk increases with low oxygen delivery during CPB. We hypothesized that renal oxygenation could be improved at higher than normal CPB flow rates. METHODS: After ethical approval and informed consent, 17 patients with normal serum creatinine undergoing normothermic CPB were included and received pulmonary artery and renal vein catheters after anesthesia induction for measurements of systemic and renal variables. Renal oxygen extraction, a direct measure of the renal oxygen delivery/renal oxygen consumption ratio, and renal filtration fraction were measured, the latter by renal extraction of 51chromium-ethylenediaminetetraacetic acid. After start of CPB and aortic cross-clamp, the pump flow rate was randomly varied between 2.4, 2.7, and 3.0 L · min-1 · m-2, and measurements were made after 10 minutes at each flow rate. RESULTS: Renal oxygen extraction increased by 30% at a flow rate of 2.4 L · min-1 · m-2 versus pre-CPB (p < 0.05). At a flow rate of 2.7 and 3.0 L · min-1 · m-2, Renal oxygen extraction was 12% (p < 0.05) and 23% (p < 0.01) lower, respectively, compared with 2.4 L · min-1 · m-2. This corresponds to a 14% and 30% improvement, respectively, of the renal oxygen supply/demand relationship. Filtration fraction was not affected by changes in flow rate, indicating that the glomerular filtration rate increased in proportion to the increase in renal perfusion. CONCLUSIONS: The impaired renal oxygenation seen during CPB is ameliorated by an increase in CPB flow rate. Thus, one way to protect the kidneys during CPB could be to use a higher flow rate than the one traditionally used.

Renal Blood Flow, Glomerular Filtration Rate, and Renal Oxygenation in Early Clinical Septic Shock.

OBJECTIVE: Data on renal hemodynamics, function, and oxygenation in early clinical septic shock are lacking. We therefore measured renal blood flow, glomerular filtration rate, renal oxygen consumption, and oxygenation in patients with early septic shock. DESIGN: Prospective comparative study. SETTING: General and cardiothoracic ICUs. PATIENTS: Patients with norepinephrine-dependent early septic shock (n = 8) were studied within 24 hours after arrival in the ICU and compared with postcardiac surgery patients without acute kidney injury (comparator group, n = 58). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Data on systemic hemodynamics and renal variables were obtained during two 30-minute periods. Renal blood flow was measured by the infusion clearance of para-aminohippuric acid, corrected for renal extraction of para-aminohippuric acid. Renal filtration fraction was measured by renal extraction of chromium-51 labeled EDTA. Renal oxygenation was estimated from renal oxygen extraction. Renal oxygen delivery (-24%; p = 0.037) and the renal blood flow-to-cardiac index ratio (-21%; p = 0.018) were lower, renal vascular resistance was higher (26%; p = 0.027), whereas renal blood flow tended to be lower (-19%; p = 0.068) in the septic group. Glomerular filtration rate (-32%; p = 0.006) and renal sodium reabsorption (-29%; p = 0.014) were both lower in the septic group. Neither renal filtration fraction nor renal oxygen consumption differed significantly between groups. Renal oxygen extraction was significantly higher in the septic group (28%; p = 0.022). In the septic group, markers of tubular injury were elevated. CONCLUSIONS: In early clinical septic shock, renal function was lower, which was accompanied by renal vasoconstriction, a lower renal oxygen delivery, impaired renal oxygenation, and tubular sodium reabsorption at a high oxygen cost compared with controls.

Patients and families realising their future with chronic obstructive pulmonary disease-A qualitative study.

AIMS AND OBJECTIVES: To gain insight into the lived experience of learning about having chronic obstructive pulmonary disease for patients and their families. BACKGROUND: Chronic obstructive pulmonary disease often progresses for years. Adjustment to declining health is gradual, and the disease may have developed considerably when health care is sought and people are diagnosed. Reaching patients at early stages is necessary to delay progression of the disease. DESIGN: Interpretive phenomenology. METHODS: Data were collected in four family focus group interviews (N = 37) and a subsample of eight family-dyad interviews. Patients were eight men, and 14 women aged 51-68 years. Majority of the patients (n = 19) were at GOLD grades II and III, with three at grade IV. The family members were eight men, and seven women aged 29-73 years. Data were collected between June-November 2012. RESULTS: Five, not mutually exclusive themes, revealed a long and arduous process of learning about and becoming diagnosed with chronic obstructive pulmonary disease and how unaware participants were of the imminent threat that the disease imposes on life. The themes were as follows: burden of shame and self-blame, enclosed in addiction, living in parallel worlds, realising the existence of the disease and a cry for empathy. CONCLUSIONS: Learning about and realising the existence of chronic obstructive pulmonary disease and what it entails at present time and in the future was bleak for the participants. The patients tended to put aside the thought of being a person with chronic obstructive pulmonary disease and defer actions that might halter progression of the disease, particularly to quit smoking. RELEVANCE TO CLINICAL PRACTICE: Individuals and families need support early in the disease process to realise and accept the existence of chronic obstructive pulmonary disease and particularly to deal with the challenges that nicotine addiction, shame and self-blame present. Increased public awareness about this enormous, but hidden, health problem is necessary.

Renal function and oxygenation are impaired early after liver transplantation despite hyperdynamic systemic circulation.

BACKGROUND: Acute kidney injury (AKI) occurs frequently after liver transplantation and is associated with the development of chronic kidney disease and increased mortality. There is a lack of data on renal blood flow (RBF), oxygen consumption, glomerular filtration rate (GFR) and renal oxygenation, i.e. the renal oxygen supply/demand relationship, early after liver transplantation. Increased insight into the renal pathophysiology after liver transplantation is needed to improve the prevention and treatment of postoperative AKI. We have therefore studied renal hemodynamics, function and oxygenation early after liver transplantation in humans. METHODS: Systemic hemodynamic and renal variables were measured during two 30-min periods in liver transplant recipients (n = 12) and post-cardiac surgery patients (controls, n = 73). RBF and GFR were measured by the renal vein retrograde thermodilution technique and by renal extraction of Cr-EDTA (= filtration fraction), respectively. Renal oxygenation was estimated from the renal oxygen extraction. RESULTS: In the liver transplant group, GFR decreased by 40% (p < 0.05), compared to the preoperative value. Cardiac index and systemic vascular resistance index were 65% higher (p < 0.001) and 36% lower (p < 0.001), respectively, in the liver transplant recipients compared to the control group. GFR was 27% (p < 0.05) and filtration fraction 40% (p < 0.01) lower in the liver transplant group. Renal vascular resistance was 15% lower (p < 0.05) and RBF was 18% higher (p < 0.05) in liver transplant recipients, but the ratio between RBF and cardiac index was 27% lower (p < 0.001) among the liver-transplanted patients compared to the control group. Renal oxygen consumption and extraction were both higher in the liver transplants, 44% (p < 0.01) and 24% (p < 0.05) respectively. CONCLUSIONS: Despite the hyperdynamic systemic circulation and renal vasodilation, there is a severe decline in renal function directly after liver transplantation. This decline is accompanied by an impaired renal oxygenation, as the pronounced elevation of renal oxygen consumption is not met by a proportional increase in renal oxygen delivery. This information may provide new insights into renal pathophysiology as a basis for future strategies to prevent/treat AKI after liver transplantation. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02455115 . Registered on 23 April 2015.

Effects of Cardiopulmonary Bypass on Renal Perfusion, Filtration, and Oxygenation in Patients Undergoing Cardiac Surgery.

BACKGROUND: Acute kidney injury is a common complication after cardiac surgery with cardiopulmonary bypass. The authors evaluated the effects of normothermic cardiopulmonary bypass on renal blood flow, glomerular filtration rate, renal oxygen consumption, and renal oxygen supply/demand relationship, i.e., renal oxygenation (primary outcome) in patients undergoing cardiac surgery. METHODS: Eighteen patients with a normal preoperative serum creatinine undergoing cardiac surgery procedures with normothermic cardiopulmonary bypass (2.5 l · min · m) were included after informed consent. Systemic and renal hemodynamic variables were measured by pulmonary artery and renal vein catheters before, during, and after cardiopulmonary bypass. Arterial and renal vein blood samples were taken for measurements of renal oxygen delivery and consumption. Renal oxygenation was estimated from the renal oxygen extraction. Urinary N-acetyl-ß-D-glucosaminidase was measured before, during, and after cardiopulmonary bypass. RESULTS: Cardiopulmonary bypass induced a renal vasoconstriction and redistribution of blood flow away from the kidneys, which in combination with hemodilution decreased renal oxygen delivery by 20%, while glomerular filtration rate and renal oxygen consumption were unchanged. Thus, renal oxygen extraction increased by 39 to 45%, indicating a renal oxygen supply/demand mismatch during cardiopulmonary bypass. After weaning from cardiopulmonary bypass, renal oxygenation was further impaired due to hemodilution and an increase in renal oxygen consumption, accompanied by a seven-fold increase in the urinary N-acetyl-ß-D-glucosaminidase/creatinine ratio. CONCLUSIONS: Cardiopulmonary bypass impairs renal oxygenation due to renal vasoconstriction and hemodilution during and after cardiopulmonary bypass, accompanied by increased release of a tubular injury marker.

Predictors of dropout and bariatric surgery in Icelandic morbidly obese female patients.

BACKGROUND: Little is known on how morbidly obese individuals who participate in different treatments differ in relation to anthropometrical measurements and psychological characteristics. In the present study we investigated attrition and treatment choice, i.e., bariatric surgery and conservative treatment, of morbidly obese subjects. METHODS: Data was collected during screening from 292 morbidly obese women who participated in a weight loss program at an Icelandic rehabilitation center. Information were available on body composition, fasting blood samples, psychological characteristics, medication use, drop-out and whether patients underwent bariatric surgery after the weight loss program at the rehabilitation center. Inclusion criteria were age between 18 and 65 years and BMI>35 kg/m(2), exclusion criteria were alcohol- or drug addiction. RESULTS: Of the 292 women who finished screening, 113 (39%) dropped out, 100 (34%) finished the weight loss program and 79 (27%) finished the weight loss program and consecutively underwent surgery. According to multivariate models individuals with BMI ≥50 kg/m(2) were 4.5 times more likely (P=0.003) to undergo bariatric surgery than individuals with BMI <40 kg/m(2). Individuals with severe depression were 2.4 times more likely (P=0.01) to drop out than individuals with no depression. Serum glucose (+36% for an increase by 1 mmol/L, P=0.036) and use of psychotropic medication (+73%, P=0.05) were also associated with higher odds of dropout. CONCLUSION: A large proportion of morbidly obese individuals dropped out of a weight loss program at an Icelandic rehabilitation center and severe depression symptoms more than doubles this risk.

Clinical phenotype in heterozygote and biallelic Bernard-Soulier syndrome--a case control study.

Bernard-Soulier syndrome (BSS) is a rare severe autosomal recessive bleeding disorder. To date heterozygous carriers of BSS mutations have not been shown to have bleeding symptoms. We assessed bleeding using a semi-quantitative questionnaire, platelet parameters, PFA-100 closure times, ristocetin response, GP Ib/IX expression and VWF antigen in 14 BSS patients, 30 heterozygote carriers for related mutations and 29 controls. Eight mutations in GP1BA, GP1BB or GP9 were identified including four previously unknown pathogenic mutations. Subjects with BSS reported markedly more mucocutaneous bleeding than controls. Increased bleeding was also observed in heterozygotes. Compared to controls, patients with BSS had lower optical platelet counts (P < 0.001), CD61-platelet counts (P < 0.001) and higher mean platelet volume (17.7 vs. 7.8 fL, P < 0.001) and ristocetin response and closure times were unmeasurable. Heterozygotes had higher MPV (9.7 fL, P < 0.001) and lower platelet counts (P < 0.001) than controls but response to ristocetin and closure times were normal. The VWF was elevated in both BSS and in heterozygotes (P = 0.005). We conclude that heterozygotes for BSS mutations have lower platelet counts than controls and show a bleeding phenotype albeit much milder than in BSS. Both patients with BSS and heterozygote carriers of pathogenic mutations have raised VWF.

Effects of levosimendan on glomerular filtration rate, renal blood flow, and renal oxygenation after cardiac surgery with cardiopulmonary bypass: a randomized placebo-controlled study.

OBJECTIVES: Acute kidney injury develops in a large proportion of patients after cardiac surgery because of the low cardiac output syndrome. The inodilator levosimendan increases cardiac output after cardiac surgery with cardiopulmonary bypass, but a detailed analysis of its effects on renal perfusion, glomerular filtration, and renal oxygenation in this group of patients is lacking. We therefore evaluated the effects of levosimendan on renal blood flow, glomerular filtration rate, renal oxygen consumption, and renal oxygen demand/supply relationship, i.e., renal oxygen extraction, early after cardiac surgery with cardiopulmonary bypass. DESIGN: Prospective, placebo-controlled, and randomized trial. SETTING: Cardiothoracic ICU of a tertiary center. PATIENTS: Postcardiac surgery patients (n=30). INTERVENTIONS: The patients were randomized to receive levosimendan, 0.1 µg/kg/min after a loading dose of 12 µg/kg (n=15), or placebo (n=15). MEASUREMENTS AND MAIN RESULTS: The experimental procedure started 4-6 hours after surgery in the ICU during propofol sedation and mechanical ventilation. Systemic hemodynamic were evaluated by a pulmonary artery thermodilution catheter. Renal blood flow and glomerular filtration rate were measured by the renal vein retrograde thermodilution technique and by renal extraction of Cr-EDTA, respectively. Central venous pressure was kept constant by colloid/crystalloid infusion. Compared to placebo, levosimendan increased cardiac index (22%), stroke volume index (15%), and heart rate (7%) and decreased systemic vascular resistance index (21%), whereas mean arterial pressure was not affected. Levosimendan induced significant increases in renal blood flow (12%, p<0.05) and glomerular filtration rate (21%, p<0.05), decreased renal vascular resistance (18%, p<0.05) but caused no significant changes in filtration fraction, renal oxygen consumption, or renal oxygen extraction, compared to placebo. CONCLUSIONS: After cardiac surgery with cardiopulmonary bypass, levosimendan induces a vasodilation, preferentially of preglomerular resistance vessels, increasing both renal blood flow and glomerular filtration rate without jeopardizing renal oxygenation. Due to its pharmacodynamic profile, levosimendan might be an interesting alternative for treatment of postoperative heart failure complicated by acute kidney injury in postcardiac surgery patients.

Assessing glomerular filtration rate (GFR) in critically ill patients with acute kidney injury--true GFR versus urinary creatinine clearance and estimating equations.

INTRODUCTION: Estimation of kidney function in critically ill patients with acute kidney injury (AKI), is important for appropriate dosing of drugs and adjustment of therapeutic strategies, but challenging due to fluctuations in kidney function, creatinine metabolism and fluid balance. Data on the agreement between estimating and gold standard methods to assess glomerular filtration rate (GFR) in early AKI are lacking. We evaluated the agreement of urinary creatinine clearance (CrCl) and three commonly used estimating equations, the Cockcroft Gault (CG), the Modification of Diet in Renal Disease (MDRD) and the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations, in comparison to GFR measured by the infusion clearance of chromium-ethylenediaminetetraacetic acid (51Cr-EDTA), in critically ill patients with early AKI after complicated cardiac surgery. METHODS: Thirty patients with early AKI were studied in the intensive care unit, 2 to 12 days after complicated cardiac surgery. The infusion clearance for 51Cr-EDTA obtained as a measure of GFR (GFR51Cr-EDTA) was calculated from the formula: GFR (mL/min/1.73m2)=(51Cr-EDTA infusion rate×1.73)/(arterial 51Cr-EDTA×body surface area) and compared with the urinary CrCl and the estimated GFR (eGFR) from the three estimating equations. Urine was collected in two 30-minute periods to measure urine flow and urine creatinine. Urinary CrCl was calculated from the formula: CrCl (mL/min/1.73m2)=(urine volume×urine creatinine×1.73)/(serum creatinine×30 min×body surface area). RESULTS: The within-group error was lower for GFR51Cr-EDTA than the urinary CrCl method, 7.2% versus 55.0%. The between-method bias was 2.6, 11.6, 11.1 and 7.39 ml/min for eGFRCrCl, eGFRMDRD, eGFRCKD-EPI and eGFRCG, respectively, when compared to GFR51Cr-EDTA. The error was 103%, 68.7%, 67.7% and 68.0% for eGFRCrCl, eGFRMDRD, eGFRCKD-EPI and eGFRCG, respectively, when compared to GFR51Cr-EDTA. CONCLUSIONS: The study demonstrated poor precision of the commonly utilized urinary CrCl method for assessment of GFR in critically ill patients with early AKI, suggesting that this should not be used as a reference method when validating new methods for assessing kidney function in this patient population. The commonly used estimating equations perform poorly when estimating GFR, with high biases and unacceptably high errors.

Renal oxygenation and haemodynamics in acute kidney injury and chronic kidney disease.

Acute kidney injury (AKI) is a major burden on health systems and may arise from multiple initiating insults, including ischaemia-reperfusion injury, cardiovascular surgery, radiocontrast administration and sepsis. Similarly, the incidence and prevalence of chronic kidney disease (CKD) continues to increase, with significant morbidity and mortality. Moreover, an increasing number of AKI patients survive to develop CKD and end-stage renal disease. Although the mechanisms for the development of AKI and progression to CKD remain poorly understood, initial impairment of oxygen balance likely constitutes a common pathway, causing renal tissue hypoxia and ATP starvation that, in turn, induce extracellular matrix production, collagen deposition and fibrosis. Thus, possible future strategies for one or both conditions may involve dopamine, loop diuretics, atrial natriuretic peptide and inhibitors of inducible nitric oxide synthase, substances that target kidney oxygen consumption and regulators of renal oxygenation, such as nitric oxide and heme oxygenase-1.

Mannitol increases renal blood flow and maintains filtration fraction and oxygenation in postoperative acute kidney injury: a prospective interventional study.

INTRODUCTION: Acute kidney injury (AKI), which is a major complication after cardiovascular surgery, is associated with significant morbidity and mortality. Diuretic agents are frequently used to improve urine output and to facilitate fluid management in these patients. Mannitol, an osmotic diuretic, is used in the perioperative setting in the belief that it exerts reno-protective properties. In a recent study on uncomplicated postcardiac-surgery patients with normal renal function, mannitol increased glomerular filtration rate (GFR), possibly by a deswelling effect on tubular cells. Furthermore, experimental studies have previously shown that renal ischemia causes an endothelial cell injury and dysfunction followed by endothelial cell edema. We studied the effects of mannitol on renal blood flow (RBF), glomerular filtration rate (GFR), renal oxygen consumption (RVO2), and extraction (RO2Ex) in early, ischemic AKI after cardiac surgery. METHODS: Eleven patients with AKI were studied during propofol sedation and mechanical ventilation 2 to 6 days after complicated cardiac surgery. All patients had severe heart failure treated with one (100%) or two (73%) inotropic agents and intraaortic balloon pump (36%). Systemic hemodynamics were measured with a pulmonary artery catheter. RBF and renal filtration fraction (FF) were measured by the renal vein thermo-dilution technique and by renal extraction of chromium-51-ethylenediaminetetraacetic acid (51Cr-EDTA), respectively. GFR was calculated as the product of FF and renal plasma flow RBF × (1-hematocrit). RVO2 and RO2Ex were calculated from arterial and renal vein blood samples according to standard formulae. After control measurements, a bolus dose of mannitol, 225 mg/kg, was given, followed by an infusion at a rate of 75 mg/kg/h for two 30-minute periods. RESULTS: Mannitol did not affect cardiac index or cardiac filling pressures. Mannitol increased urine flow by 61% (P < 0.001). This was accompanied by a 12% increase in RBF (P < 0.05) and a 13% decrease in renal vascular resistance (P < 0.05). Mannitol increased the RBF/cardiac output (CO) relation (P = 0.040). Mannitol caused no significant changes in RO2Ext or renal FF. CONCLUSIONS: Mannitol treatment of postoperative AKI induces a renal vasodilation and redistributes systemic blood flow to the kidneys. Mannitol does not affect filtration fraction or renal oxygenation, suggestive of balanced increases in perfusion/filtration and oxygen demand/supply.

Effects of norepinephrine on renal perfusion, filtration and oxygenation in vasodilatory shock and acute kidney injury.

PURPOSE: The use of norepinephrine (NE) in patients with volume-resuscitated vasodilatory shock and acute kidney injury (AKI) remains the subject of much debate and controversy. The effects of NE-induced variations in mean arterial blood pressure (MAP) on renal blood flow (RBF), oxygen delivery (RDO(2)), glomerular filtration rate (GFR) and the renal oxygen supply/demand relationship (renal oxygenation) in vasodilatory shock with AKI have not been previously studied. METHODS: Twelve post-cardiac surgery patients with NE-dependent vasodilatory shock and AKI were studied 2-6 days after surgery. NE infusion rate was randomly and sequentially titrated to target MAPs of 60, 75 and 90 mmHg. At each target MAP, data on systemic haemodynamics, RBF, GFR and renal oxygen extraction were obtained by pulmonary artery catheter, by the renal vein thermodilution technique and by renal extraction of (51)Cr-ethylenediamine tetraacetic acid ((51)Cr-EDTA), respectively. RESULTS: At target MAP of 75 mmHg, RDO(2) (13%), GFR (27%) and urine flow were higher and renal oxygen extraction was lower (-7.4%) compared with at target MAP of 60 mmHg. However, the renal variables did not differ when compared at target MAPs of 75 and 90 mmHg. Cardiac index increased dose-dependently with NE. CONCLUSIONS: Restoration of MAP from 60 to 75 mmHg improves renal oxygen delivery, GFR and the renal oxygen supply/demand relationship in post-cardiac surgery patients with vasodilatory shock and AKI. This pressure-dependent renal perfusion, filtration and oxygenation at levels of MAP below 75 mmHg reflect a more or less exhausted renal autoregulatory reserve.

Acute renal failure is NOT an "acute renal success"--a clinical study on the renal oxygen supply/demand relationship in acute kidney injury.

OBJECTIVES: Acute kidney injury occurs frequently after cardiac or major vascular surgery and is believed to be predominantly a consequence of impaired renal oxygenation. However, in patients with acute kidney injury, data on renal oxygen consumption (RVO2), renal blood flow, glomerular filtration, and renal oxygenation, i.e., the renal oxygen supply/demand relationship, are lacking and current views on renal oxygenation in the clinical situation of acute kidney injury are presumptive and largely based on experimental studies. DESIGN: Prospective, two-group comparative study. SETTING: Cardiothoracic intensive care unit of a tertiary center. PATIENTS: Postcardiac surgery patients with (n = 12) and without (n = 37) acute kidney injury were compared with respect to renal blood flow, glomerular filtration, RVO2, and renal oxygenation. INTERVENTIONS: None MEASUREMENTS AND MAIN RESULTS: Data on systemic hemodynamics (pulmonary artery catheter) and renal variables were obtained during two 30-min periods. Renal blood flow was measured using two independent techniques: the renal vein thermodilution technique and the infusion clearance of paraaminohippuric acid, corrected for renal extraction of paraaminohippuric acid. The filtration fraction was measured by the renal extraction of Cr-EDTA and the renal sodium resorption was measured as the difference between filtered and excreted sodium. Renal oxygenation was estimated from the renal oxygen extraction. Cardiac index and mean arterial pressure did not differ between the two groups. In the acute kidney injury group, glomerular filtration (-57%), renal blood flow (-40%), filtration fraction (-26%), and sodium resorption (-59%) were lower, renal vascular resistance (52%) and renal oxygen extraction (68%) were higher, whereas there was no difference in renal oxygen consumption between groups. Renal oxygen consumption for one unit of reabsorbed sodium was 2.4 times higher in acute kidney injury. CONCLUSIONS: Renal oxygenation is severely impaired in acute kidney injury after cardiac surgery, despite the decrease in glomerular filtration and tubular workload. This was caused by a combination of renal vasoconstriction and tubular sodium resorption at a high oxygen demand.

Dopamine increases renal oxygenation: a clinical study in post-cardiac surgery patients.

BACKGROUND: Imbalance of the renal medullary oxygen supply/demand relationship can cause ischaemic acute renal failure (ARF). The use of dopamine for prevention/treatment of ischaemic ARF has been questioned. It has been suggested that dopamine may increase renal oxygen consumption (RVO(2)) due to increased solute delivery to tubular cells, which may jeopardize renal oxygenation. Information on the effects of dopamine on renal perfusion, filtration and oxygenation in man is, however, lacking. We evaluated the effects of dopamine on renal blood flow (RBF), glomerular filtration rate (GFR), RVO(2) and renal O(2) demand/supply relationship, i.e. renal oxygen extraction (RO(2)Ex). METHODS: Twelve uncomplicated, mechanically ventilated and sedated post-cardiac surgery patients with pre-operatively normal renal function were studied. Dopamine was sequentially infused at 2 and 4 ug/kg/min. Systemic haemodynamics were evaluated by a pulmonary artery catheter. Absolute RBF was measured using two independent techniques: by the renal vein thermodilution technique and by infusion clearance of paraaminohippuric acid (PAH), with a correction for renal extraction of PAH. The filtration fraction (FF) was measured by the renal extraction of (51)Cr-EDTA. RESULTS: Neither GFR, tubular sodium reabsorption nor RVO(2) was affected by dopamine, which increased RBF (45-55%) with both methods, decreased renal vascular resistance (30-35%), FF (21-26%) and RO(2)Ex (28-34%). The RBF/CI ratio increased with dopamine. Dopamine decreased renal PAH extraction, suggestive of a flow distribution to the medulla. CONCLUSIONS: In post-cardiac surgery patients, dopamine increases the renal oxygenation by a pronounced renal pre-and post-glomerular vasodilation with no increases in GFR, tubular sodium reabsorption or renal oxygen consumption.

Quantification of menstrual flow by weighing protective pads in women with normal, decreased or increased menstruation.

OBJECTIVE: To investigate the association between menstrual flow weight measured from modern sanitary pads (converting liquid to non-evaporating gel) and clinically assessed normal, increased or decreased menstrual flow. DESIGN: Objective method development study. SETTING: Outpatient clinic, University Hospital, Reykjavik. POPULATION: One hundred and thirteen volunteers included 26 normally menstruating adult women and 52 normally menstruating teenagers not using oral or intrauterine contraception, seven normally menstruating women using oral contraception, 17 women with clinically diagnosed menorrhagia, five women using oral contraception for clinical menorrhagia, and six teenage girls claiming heavy menstrual flow. METHODS: Menstruation length, menstrual flow weight and history of iron deficiency were assessed. During the menstruation following recruitment, all women collected their used protective pads in a hygienic manner and returned them to the laboratory for accurate weighing. MAIN OUTCOME MEASURES: Menstrual flow total weight measured in grams. RESULTS: Mean menstrual flow total weight in the 78 asymptomatic women was 51 g (median 44, range 5-144). The mean flow in 17 women clinically diagnosed with menorrhagia was 217 g (median 207, range 63-402) (p<0.0001 compared to healthy women). The seven healthy women using oral contraceptives discharged 13 g (13-19) (p=0.0004 compared with normals). Menstruation lasted < eight days in 77/78 healthy women and in 12 of 17 clinically diagnosed menorrhagic women. CONCLUSIONS: Measurement of menstrual flow total weight accurately reflects clinically assessed normal, increased and decreased flow. The method is an easy and accurate way of objectively estimating menstrual flow.