Lipid Infusion Research Articles

Treatment of Local Anesthetic Systemic Toxicity (LAST)

Severe, systemic local anesthetic toxicity is arguably the most feared complication of regional anesthesia. A combination of old and new therapies is recommended to reduce the morbidity and mortality of symptomatic local anesthetic overdose. Prevention remains the criterion standard for improving patient safety during regional anesthesia. However, when local anesthetic toxicity occurs, considering the diagnosis is the doctor's first step to successful treatment. Preparing a plan of action ahead of time and having the necessary tools readily at hand will likewise contribute to saving the patient's life. Airway management, oxygenation, ventilation, and good basic life support are the sine qua non of successful resuscitation. Seizure suppression is key, and we recommend communicating with a perfusion team for possible cardiopulmonary bypass. Lipid infusion should be considered early, and the treating physician should be familiar with the method. We also recommend avoiding vasopressin and using epinephrine only in small doses. Vigilance, preparedness, and quick action will improve outcomes of this dreaded complication.

Elevated plasma free fatty acids increase cardiovascular risk by inducing plasma biomarkers of endothelial activation, myeloperoxidase and PAI-1 in healthy subjects

BackgroundCVD in obesity and T2DM are associated with endothelial activation, elevated plasma vascular inflammation markers and a prothrombotic state. We examined the contribution of FFA to these abnormalities following a 48-hour physiological increase in plasma FFA to levels of obesity and diabetes in a group of healthy subjects.Methods40 non-diabetic subjects (age = 38 ± 3 yr, BMI = 28 ± 1 kg/m2, FPG = 95 ± 1 mg/dl, HbA1c = 5.3 ± 0.1%) were admitted twice and received a 48-hour infusion of normal saline or low-dose lipid. Plasma was drawn for intracellular (ICAM-1) and vascular (VCAM-1) adhesion molecules-1, E-selectin (sE-S), myeloperoxidase (MPO) and total plasminogen inhibitor-1 (tPAI-1). Insulin sensitivity was measured by a hyperglycemic clamp (M/I).ResultsLipid infusion increased plasma FFA to levels observed in obesity and T2DM and reduced insulin sensitivity by 27% (p = 0.01). Elevated plasma FFA increased plasma markers of endothelial activation ICAM-1 (138 ± 10 vs. 186 ± 25 ng/ml), VCAM-1 (1066 ± 67 vs. 1204 ± 65 ng/ml) and sE-S (20 ± 1 vs. 24 ± 1 ng/ml) between 13-35% and by ≥ 2-fold plasma levels of myeloperoxidase (7.5 ± 0.9 to 15 ± 25 ng/ml), an inflammatory marker of future CVD, and tPAI-1 (9.7 ± 0.6 to 22.5 ± 1.5 ng/ml), an indicator of a prothrombotic state (all p ≤ 0.01). The FFA-induced increase was independent from the degree of adiposity, being of similar magnitude in lean, overweight and obese subjects.ConclusionsAn increase in plasma FFA within the physiological range observed in obesity and T2DM induces markers of endothelial activation, vascular inflammation and thrombosis in healthy subjects. This suggests that even transient (48-hour) and modest increases in plasma FFA may initiate early vascular abnormalities that promote atherosclerosis and CVD.

Inducible Nitric Oxide Synthase Induction Underlies Lipid-Induced Hepatic Insulin Resistance in Mice

OBJECTIVEThe present study was undertaken to assess the contribution of inducible nitric oxide (NO) synthase (iNOS) to lipid-induced insulin resistance in vivo.RESEARCH DESIGN AND METHODSWild-type and iNOS−/− mice were infused for 6 h with a 20% intralipid emulsion, during which a hyperinsulinemic-euglycemic clamp was performed.RESULTSIn wild-type mice, lipid infusion led to elevated basal hepatic glucose production and marked insulin resistance as revealed by impaired suppression of liver glucose production and reduced peripheral glucose disposal (Rd) during insulin infusion. Liver insulin resistance was associated with a robust induction of hepatic iNOS, reduced tyrosine phosphorylation of insulin receptor (IR) β, insulin receptor substrate (IRS)-1, and IRS-2 but elevated serine phosphorylation of IRS proteins as well as decreased Akt activation. The expression of gluconeogenic enzymes Pepck and G6Pc was also increased in the liver of wild-type mice. In contrast to their wild-type counterparts, iNOS−/− mice were protected from lipid-induced hepatic and peripheral insulin resistance. Moreover, neither the phosphorylation of insulin signaling intermediates nor expression of gluconeogenic enzymes were altered in the lipid-infused iNOS−/− mice compared with their saline-infused controls. Importantly, lipid infusion induced tyrosine nitration of IRβ, IRS-1, IRS-2, and Akt in wild-type mice but not in iNOS−/− animals. Furthermore, tyrosine nitration of hepatic Akt by the NO derivative peroxynitrite blunted insulin-induced Akt tyrosine phosphorylation and kinase activity.CONCLUSIONSThese findings demonstrate that iNOS induction is a novel mechanism by which circulating lipids inhibit hepatic insulin action. Our results further suggest that iNOS may cause hepatic insulin resistance through tyrosine nitration of key insulin signaling proteins.

Evaluation of the use of the FAS endoluminal brush and 20% ethanol flushes to unblock central venous catheters used for long-term parenteral nutrition

Catheter occlusion is the second most common problem associated with vascular access devices. In patients receiving parenteral nutrition (PN), lipid deposits can form a waxy substance along the lumen of the line which gradually occludes the central venous catheter (CVC). The use of 70% ethanol locks has been reported to unblock lipid occlusions; while a 20% ethanol flush after lipid infusions has been reported to help prevent the build-up of lipid deposits that occlude the CVC. Endoluminal brushing of CVC’s is more widely known for improving flow rates in catheters used for haemodialysis. The FAS endoluminal brush has been used successfully to diagnose CVC related sepsis, while the line remains in situ. In this study, the FAS endoluminal brush is used to salvage occluded CVC’s used for long-term PN. A retrospective audit was done on all the patients receiving long-term PN over the preceding 4 years. Seventy six FAS endoluminal brushes were performed on 40 patient episodes of line occlusions over a 4-year period.

Selected Adipokines - Plasma Concentrations and Adipose Tissue Expressions during 24-Hour Lipid Infusion in Healthy Men

Our aim was to assess the reaction of TNFalpha, resistin, leptin and adiponectin to lipid infusion. Eight healthy subjects underwent a 24-hour lasting infusion of lipid emulsion. Plasma concentrations and expressions of selected cytokines in subcutaneous fat were measured. TNFalpha plasma concentration did not change during the first 4 hours of hypertriglyceridemia, but a significant increase after 24 hours was detected (p<0.001 for 0; 30; 240 min vs. 24 h). Plasma concentration of resistin significantly increased at 30 min of infusion and remained elevated (p<0.01 for 0 min vs. 30; 240 min; p<0.001 for 0 min vs. 24 h). Plasma concentrations of leptin and adiponectin did not show any significant changes. Although the expression of resistin in the subcutaneous adipose tissue tended to increase, the change was not significant. Expressions of TNFalpha, leptin and adiponectin were unaffected. In conclusions, our results indicate that acutely induced hyperlipidemia could influence the secretion of TNFalpha and resistin.

Transfusion-related acute lung injury

Sir, Transfusion-related acute lung injury (TRALI) is an uncommon, probably underrecognized complication of transfusion of plasma-containing blood components, which is characterized by acute respiratory distress. It is a clinical diagnosis and may be diagnosed when acute lung injury (ALI) occurs during or within six hours of transfusion in a patient without pre-existing ALI, in the absence of temporally related alternative risk factors for ALI (e.g., sepsis, shock, cardiac failure, etc.).[1] This communication discusses a case of TRALI in a middle-aged woman. A 52-year-old female patient with a diagnosis of inoperable carcinoma of the uterine cervix, received whole blood transfusion, in view of severe anemia. Before blood transfusion, she was alert, oriented, with no cardiorespiratory abnormality on clinicoradiological evaluation. Her vital parameters were normal and total leukocyte count was 8700/mm3 with normal blood biochemistry. After receiving approximately 200 ml of blood for over two hours, she complained of breathlessness, which progressively increased over the next 20 minutes. On examination she was febrile, tachypneic (respiratory rate 32/minute), slightly cyanotic, with a pulse rate of 120/minute, blood pressure 90/60 mmHg, and SpO2 68%. The jugular venous pressure (JVP) was normal and chest auscultation revealed bilateral basal fine inspiratory crackles with normal breath sounds. Sinus tachycardia was noted on an electrocardiogram (ECG). An urgent X-ray chest showed bilateral patchy infiltrates in the mid- and lower zones with normal heart size, suggestive of noncardiogenic pulmonary edema. Echocardiography also ruled out cardiogenic dysfunction. Hematological investigations at this stage showed a total leukocyte count of 3200/mm3, with no evidence of any hemolytic process. In the absence of other mechanisms to explain ALI, a diagnosis of TRALI was made. The blood transfusion was stopped immediately and she was managed with oxygen therapy and intravenous fluids that resulted in a gradual improvement of dyspnea and oxygen saturation. She became completely chest asymptomatic after three days, with a normal chest X-ray. The reported incidence of TRALI in medical literature is one in 5000 transfusions and this may actually be much higher as TRALI is usually an underrecognized and underreported entity.[2] TRALI has been associated with antibodies to WBCs in transfused blood components. Less frequently, it has been associated with leukocyte antibodies in the transfusion recipient. It has also been linked to the infusion of biologically-active lipids in stored cellular blood components.[3] A mild form of TRALI can present with dyspnea and fever, while more severe forms can have severe respiratory distress that can quickly progress to respiratory failure. Other features include hypotension, frothy endotracheal secretions, and so on. Transient leucopenia, as noted in our patient, is occasionally observed and is believed to be due to the sequestration of leukocytes in pulmonary circulation. It is important to distinguish TRALI from volume overload, as the treatment of the two conditions is markedly different. Diuretics are contraindicated in TRALI and there is no role for steroids also. Severe forms of TRALI may require mechanical ventilation.[3] Suspected cases of TRALI should be reported to the blood bank, to permit evaluation and deferral of high-risk donors, especially multiparous females. TRALI can be best prevented by avoiding unnecessary blood-product transfusions in selected populations.

Insulin sensitivity during acute elevation of NEFA: influence of fat composition and gender

Conditions associated with impairments in insulin sensitivity (SI), such as obesity and type-II diabetes (T2D), often present with elevated NEFA. While lipid infusion studies have shown that increasing NEFA can impair glucose metabolism (1) , there are relatively few studies investigating the effect of NEFA elevation following fat loads of differing composition. Sixty healthy volunteers participated in a single-blind crossover trial. Subjects were randomly assigned to either 0.75 g/kg bodyweight (bw) of palm stearin (SFA) or 0.65 g/kg bw of palm stearin and 0.1 g/kg bw of DHA-rich fish oil (n-3 PUFA) on separate occasions; study visits for females were conducted at 4-week intervals to control for the menstrual cycle. The oils were emulsified into chocolate drinks and given as a bolus at baseline (0 min), followed by smaller drinks every 30 min. At 60 min, an infusion of heparin (500 IU bolus + 0.4 IU/ kg bw/min) was administered to activate lipoprotein lipase (2) . At 240 min, a hyperinsulinaemic (HI)–euglycaemic clamp (1 mU/kg/min) was initiated. SI was calculated as the mean glucose infusion rate for the last 30 min of the 150 min clamp, either adjusted for bw or fat-free mass (ffm).

Reversal of intestinal failure–associated liver disease in infants and children on parenteral nutrition: experience with 93 patients at a referral center for intestinal rehabilitation

Purpose Intestinal failure (IF)–associated liver disease (IFALD) complicates the treatment of children with IF receiving parenteral nutrition (PN). We hypothesized that prevention or resolution of IFALD was possible in most children and that this would result in improved outcomes. Methods We reviewed prospectively gathered data on all children referred to the intestinal rehabilitation and transplantation center at our institution. Total bilirubin level (TB) was used as the marker for IFALD. Patients were grouped based on TB at referral and at subsequent inpatient stays and outpatient visits. Standard treatment consisted of cycling of PN, limiting lipid infusion, enteral stimulation, use of ursodeoxycholic acid, and surgical intervention when necessary. Outcomes such as mortality, dependence on PN, and need for transplantation were assessed. Statistical analyses were performed using Fisher's exact, Mann-Whitney U, and Wilcoxon signed rank tests. Results Ninety-three patients with intestinal failure and on PN were treated at our center from 2003 to 2009. Median age at referral was 5 months (0.5-264 months). Prematurity was a complicating factor in 63 patients and necrotizing enterocolitis was the most common diagnosis. Eighty-two children had short bowel syndrome, whereas the remaining 11 had extensive motility disorders. 97% of children required significant alteration of their PN administration. At referral, 76 of 93 children had TB 2.0 mg/dL or higher, and 17 had TB below 2.0 mg/dL. TB normalized in 57 of 76 children with elevated TB at referral, and TB remained elevated in 19. Normalization of TB was associated with a mortality of 5.2%, and transplantation was needed in 5.2%. Conversely, when TB remained elevated, mortality was 58% ( P = .0002 vs TB normalized), and transplantation occurred in 58% owing to failure of surgical and medical rehabilitation. Conclusions Most children referred for treatment of IF have IFALD. A dedicated IF rehabilitation program can reverse IFALD in many children, and this is associated with improved outcome.

Lack of Lipotoxicity Effect on β-Cell Dysfunction in Ketosis-Prone Type 2 Diabetes

OBJECTIVEOver half of newly diagnosed obese African Americans with diabetic ketoacidosis (DKA) discontinue insulin therapy and go through a period of near-normoglycemia remission. This subtype of diabetes is known as ketosis-prone type 2 diabetes (KPDM).RESEARCH DESIGN AND METHODSTo investigate the role of lipotoxicity on β-cell function, eight obese African Americans with KPDM, eight obese subjects with type 2 diabetes with severe hyperglycemia without ketosis (ketosis-resistant type 2 diabetes), and nine nondiabetic obese control subjects underwent intravenous infusion of 20% intralipid at 40 ml/h for 48 h. β-Cell function was assessed by changes in insulin and C-peptide concentration during infusions and by changes in acute insulin response to arginine stimulation (AIRarg) before and after lipid infusion.RESULTSThe mean time to discontinue insulin therapy was 11.0 ± 8.0 weeks in KPDM and 9.6 ± 2.2 weeks in ketosis-resistant type 2 diabetes (P = NS). At remission, KPDM and ketosis-resistant type 2 diabetes had similar glucose (94 ± 14 vs. 109 ± 20 mg/dl), A1C (5.7 ± 0.4 vs. 6.3 ± 1.1%), and baseline AIRarg response (34.8 ± 30 vs. 64 ± 69 μU/ml). P = NS despite a fourfold increase in free fatty acid (FFA) levels (0.4 ± 0.3 to 1.8 ± 1.1 mmol/l, P < 0.01) during the 48-h intralipid infusion; the response to AIRarg stimulation, as well as changes in insulin and C-peptide levels, were similar among obese patients with KPDM, patients with ketosis-resistant type 2 diabetes, and nondiabetic control subjects.CONCLUSIONSNear-normoglycemia remission in obese African American patients with KPDM and ketosis-resistant type 2 diabetes is associated with a remarkable recovery in basal and stimulated insulin secretion. A high FFA level by intralipid infusion for 48 h was not associated with β-cell decompensation (lipotoxicity) in KPDM patients.

Diet-Induced Obesity Prevents Interstitial Dispersion of Insulin in Skeletal Muscle

OBJECTIVEObesity causes insulin resistance, which has been interpreted as reduced downstream insulin signaling. However, changes in access of insulin to sensitive tissues such as skeletal muscle may also play a role. Insulin injected directly into skeletal muscle diffuses rapidly through the interstitial space to cause glucose uptake. When insulin resistance is induced by exogenous lipid infusion, this interstitial diffusion process is curtailed. Thus, the possibility exists that hyperlipidemia, such as that seen during obesity, may inhibit insulin action to muscle cells and exacerbate insulin resistance. Here we asked whether interstitial insulin diffusion is reduced in physiological obesity induced by a high-fat diet (HFD).RESEARCH DESIGN AND METHODSDogs were fed a regular diet (lean) or one supplemented with bacon grease for 9–12 weeks (HFD). Basal insulin (0.2 mU · min−1 · kg−1) euglycemic clamps were performed on fat-fed animals (n = 6). During clamps performed under anesthesia, five sequential doses of insulin were injected into the vastus medialis of one hind limb (INJ); the contralateral limb (NINJ) served as a control.RESULTSINJ lymph insulin showed an increase above NINJ in lean animals, but no change in HFD-fed animals. Muscle glucose uptake observed in lean animals did not occur in HFD-fed animals.CONCLUSIONSInsulin resistance induced by HFD caused a failure of intramuscularly injected insulin to diffuse through the interstitial space and failure to cause glucose uptake, compared with normal animals. High-fat feeding prevents the appearance of injected insulin in the interstitial space, thus reducing binding to skeletal muscle cells and glucose uptake.

Triglyceride Metabolism in the Neonate

Lipid infusion is an integral part of neonatal parenteral nutrition. In its absence, essential fatty acid deficiency can result as early as 3 days after birth. Triglyceride values are followed to monitor lipid tolerance. Acceptable values range between 150 and 200 mg/dL (1.7 and 2.3 mmol/L). This case of hypertriglyceridemia resulting from rapid lipid infusion in an extremely low-birthweight infant demonstrates a rapid decrease in the triglyceride concentration with no intervention. None of the common adverse effects of hypertriglyceridemia were noted. The case also highlights the importance of correctly positioning and regularly evaluating infusion pump tubing to assure the correct rate of lipid infusion.

Lipid-induced insulin resistance is associated with increased monocyte expression of scavenger receptor CD36 and internalization of oxidized LDL.

Elevated free fatty acids (FFAs) contribute to the development of insulin resistance, type 2 diabetes mellitus (T2DM), and may be atherogenic. We tested the relationship among lipid-induced insulin resistance, endothelial dysfunction, and monocyte capacity to form foam cells through scavenger receptor A (SRA) and CD36. Ten healthy subjects underwent 24-h infusion of Intralipid/heparin and saline (0.5 ml/min) on two separate occasions followed by brachial artery reactivity testing and a euglycemic hyperinsulinemic (80 mU/(kg.min)) clamp study to determine insulin sensitivity. Isolation of blood monocytes was performed 24 h after infusion. Surface expression and function of CD36 and SRA to take up oxidized low-density lipoprotein (oxLDL) was determined by flow cytometry and quantitative confocal imaging. Lipid infusion resulted in a twofold increase in serum FFA levels, reduced whole-body glucose disposal by approximately 20% (P < 0.05), and possibly impaired endothelial-dependent vasodilation (P = 0.1). Blood monocytes obtained during lipid infusion demonstrated a approximately 25% increase in cell surface expression of CD36 (P < 0.05) but no change in SRA expression. Enhanced CD36 expression was associated with a 50% increase in internalization of oxLDL (P < 0.05). The increase in CD36 surface expression during lipid infusion correlated inversely with glucose disposal (P < 0.05) and not with FFA levels or brachial artery dilation. These data support a role for FFAs in induction of insulin resistance and provide a link to atherogenic mechanisms mediated by expression of scavenger receptor CD36.

Circulating vaspin is unrelated to insulin sensitivity in a cohort of nondiabetic humans

To study the association of vaspin with glucose metabolism. Cross-sectional and intervention study. The association of serum vaspin with metabolic and anthropometric characteristics was investigated in 108 volunteers. Euglycemic-hyperinsulinemic clamps (EHC) were performed in 83 of the participants. Changes of circulating vaspin levels were additionally studied in a crossover study using 300 min EHC with lipid versus saline infusion (n=10). Neither glucose tolerance status nor insulin sensitivity, both as measured using EHCs and using homeostasis model assessment for insulin resistance (HOMA-IR), was significantly associated with serum vaspin in the cross-sectional study. Furthermore, there was no effect of short-term lipid-induced insulin resistance due to a 300 min intravenous lipid challenge on circulating vaspin. However, circulating vaspin levels were significantly elevated in women using oral contraceptives (OC), both compared to women without OC intake (1.17+/-0.26 vs 0.52+/-0.09 ng/ml, P=0.02) and males (1.17+/-0.26 vs 0.29+/-0.04 ng/ml, P=0.01). After exclusion of OC using females and stratification according to body mass index (BMI), a significant sexual dimorphism in subjects with a BMI <25 kg/m(2) was observed (males 0.21+/-0.04 ng/ml versus females 0.70+/-0.16 ng/ml, P=0.009). Our results support the existence of a sexual dimorphism regarding circulating vaspin. The lack of an association of serum vaspin with HOMA-IR and M value indicates, however, no major role for vaspin concerning insulin sensitivity in nondiabetic humans.

Complications and monitoring - Guidelines on Parenteral Nutrition, Chapter 11.

Compared to enteral or hypocaloric oral nutrition, the use of PN (parenteral nutrition) is not associated with increased mortality, overall frequency of complications, or longer length of hospital stay (LOS). The risk of PN complications (e.g. refeeding-syndrome, hyperglycaemia, bone demineralisation, catheter infections) can be minimised by carefully monitoring patients and the use of nutrition support teams particularly during long-term PN. Occuring complications are e.g. the refeeding-syndrome in patients suffering from severe malnutrition with the initiation of refeeding or metabolic, hypertriglyceridemia, hyperglycaemia, osteomalacia and osteoporosis, and hepatic complications including fatty liver, non-alcoholic fatty liver disease, cholestasis, cholecystitis, and cholelithiasis. Efficient monitoring in all types of PN can result in reduced PN-associated complications and reduced costs. Water and electrolyte balance, blood sugar, and cardiovascular function should regularly be monitored during PN. Regular checks of serum electrolytes and triglycerides as well as additional monitoring measures are necessary in patients with altered renal function, electrolyte-free substrate intake, lipid infusions, and in intensive care patients. The metabolic monitoring of patients under long-term PN should be carried out according to standardised procedures. Monitoring metabolic determinants of bone metabolism is particularly important in patients receiving long-term PN. Markers of intermediary, electrolyte and trace element metabolism require regular checks.

Lipid emulsions - Guidelines on Parenteral Nutrition, Chapter 6.

The infusion of lipid emulsions allows a high energy supply, facilitates the prevention of high glucose infusion rates and is indispensable for the supply with essential fatty acids. The administration of lipid emulsions is recommended within ≤7 days after starting PN (parenteral nutrition) to avoid deficiency of essential fatty acids. Low-fat PN with a high glucose intake increases the risk of hyperglycaemia. In parenterally fed patients with a tendency to hyperglycaemia, an increase in the lipid-glucose ratio should be considered. In critically ill patients the glucose infusion should not exceed 50% of energy intake. The use of lipid emulsions with a low phospholipid/triglyceride ratio is recommended and should be provided with the usual PN to prevent depletion of essential fatty acids, lower the risk of hyperglycaemia, and prevent hepatic steatosis. Biologically active vitamin E (α-tocopherol) should continuously be administered along with lipid emulsions to reduce lipid peroxidation. Parenteral lipids should provide about 25–40% of the parenteral non-protein energy supply. In certain situations (i.e. critically ill, respiratory insufficiency) a lipid intake of up to 50 or 60% of non-protein energy may be reasonable. The recommended daily dose for parenteral lipids in adults is 0.7–1.3 g triglycerides/kg body weight. Serum triglyceride concentrations should be monitored regularly with dosage reduction at levels >400 mg/dl (>4.6 mmol/l) and interruption of lipid infusion at levels >1000 mg/dl (>11.4 mmol/l). There is little evidence at this time that the choice of different available lipid emulsions affects clinical endpoints.

Effect of Short-Term Free Fatty Acids Elevation on Mitochondrial Function in Skeletal Muscle of Healthy Individuals

Mitochondrial dysfunction has been proposed as an underlying mechanism in the pathogenesis of insulin resistance and type 2 diabetes mellitus. To determine whether mitochondrial dysfunction plays a role in the free fatty acid (FFA)-induced impairment in insulin action in skeletal muscle of healthy subjects. Eleven lean normal glucose tolerant individuals received 8 h lipid and saline infusion on separate days with a euglycemic insulin clamp during the last 2 h. Vastus lateralis muscle biopsies were performed at baseline and after 6 h lipid or saline infusion. Inner mitochondrial membrane potential (Psi(m)) and mitochondrial mass were determined ex vivo by confocal microscopy. Compared with saline infusion, lipid infusion reduced whole-body glucose uptake by 22% (P < 0.05). Psi(m) decreased by 33% (P < 0.005) after lipid infusion and the decrement in Psi(m) correlated with change in plasma FFA after lipid infusion (r = 0.753; P < 0.005). Mitochondrial content and morphology did not change after lipid infusion. No significant changes in genes expression, citrate synthase activity, and total ATP content were observed after either lipid or saline infusion. Short-term physiological increase in plasma FFA concentration in lean normal glucose tolerant subjects induces insulin resistance and impairs mitochondrial membrane potential but has no significant effects on mitochondrial content, gene expression, ATP content, or citrate synthase activity.

Transfusion‐related acute lung injury (TRALI): a clinical review with emphasis on the critically ill

Transfusion-related acute lung injury (TRALI) is the leading cause of transfusion-related morbidity and mortality world-wide. Although first described in 1983, it took two decades to develop consensus definitions, which remain controversial. The pathogenesis of TRALI is related to the infusion of donor antibodies that recognize leucocyte antigens in the transfused host or the infusion of lipids and other biological response modifiers that accumulate during the storage or processing of blood components. TRALI appears to be the result of at least two sequential events and treatment is supportive. This review demonstrates that critically ill patients are more susceptible to TRALI and require special attention by critical care specialists, haematologists and transfusion medicine experts. Further research is required into TRALI and its pathogenesis so that transfusions are safer and administered appropriately. Avoidance including male-only transfusion practises, the use of leucoreduced components, fresher blood/blood components and solvent detergent plasma are also discussed.

Adequacy of Nutritional Support in Pediatric Blood and Marrow Transplantation

The use of nutrition support has become standard practice in blood and marrow transplantation, but what remains unclear is whether patients receive adequate nutrition supplementation during this time. This study is a retrospective audit of the nutritional supplementation of 34 pediatric patients admitted to a pediatric oncology unit for a blood and marrow transplantation. All patients received parenteral nutrition (PN) as their standard nutritional therapy with an average of 79 +/- 10.6% of their estimated requirements given over the transplant period. The glucose/amino acid infusion was inadequate on 40% of PN days mainly because of fluid overload causing a reduction in infusion rates. The lipid infusion was inadequate on 60% of PN days mainly because of stoppages when drugs and/or blood were infused. The mean percentage weight change on discharge was +0.3 +/- 4.7%. This had a large range of between -9.9% and +7.9% of body weight and did not seem to be related to adequacy of nutrition during transplant. This study showed that although frequent rate reductions in nutrition infusions did occur, most patients still received the majority of their nutritional requirements.

Improved insulin sensitivity after weight loss and exercise training is mediated by a reduction in plasma fatty acid mobilization, not enhanced oxidative capacity

Obesity is characterized by excessive rates of plasma fatty acid mobilization and uptake, which play a key role in mediating insulin resistance. While weight loss via diet-only or a diet + exercise program clearly improves insulin sensitivity, the precise mechanisms modulating this improvement are not completely understood. The purpose of the present study was to determine the role of the reduced fatty acid mobilization and uptake after weight loss in obese women who were randomly assigned to lifestyle interventions of either weight loss without exercise (WL) (n = 7) or a weight loss + exercise program (WL + EX) (n = 10). Before and after losing 12% of their body weight, we measured insulin sensitivity (S(I)), systemic fatty acid rate of appearance (Ra) and disappearance (Rd), oxidative capacity, and markers for pro-inflammatory pathways in skeletal muscle. Fatty acid Ra and Rd were reduced by 30% after both interventions (P < 0.05). While oxidative capacity increased 25% in WL + EX (compared with no increase after WL), the improvement in S(I) was identical in both groups (60%; P < 0.05), and skeletal muscle pro-inflammatory pathways were reduced (P < 0.05) similarly in both groups. When we artificially increased fatty acid mobilization after weight loss to pre-weight-loss levels via an overnight lipid infusion, the improvement in S(I) was almost completely reversed. Importantly, WL + EX did not protect against this lipid-induced reversal in S(I) despite a significant increase in resting whole-body fat oxidation and a marked increase in skeletal muscle oxidative capacity. In conclusion, reduced fatty acid mobilization and uptake appears to be a primary mediator of improved insulin sensitivity after weight loss. Moreover, enhancing fatty acid oxidative capacity via exercise training is not sufficient to prevent the insulin resistance caused by high fatty acid mobilization, such as that found in obesity.

Non-esterified fatty acids increase arterial pressure via central sympathetic activation in humans

Previous studies have shown that acute increases in plasma NEFAs (non-esterified fatty acids) raise SVR (systemic vascular resistance) and BP (blood pressure). However, these studies have failed to distinguish between CNS (central nervous system) mechanisms that raise sympathetic activity and paracrine mechanisms that increase SVR directly, independent of CNS involvement. The aim of the present study was to directly determine whether the sympathetic nervous system contributes to the pressor response to NEFAs. On 2 days separated by at least 2 weeks, 17 lean healthy volunteers (ten male/seven female; age, 22+/-1 years; body mass index, 23+/-1 kg/m2; values are means+/-S.E.M.) received a 4-h intravenous infusion of 20% Intralipid or placebo (in a single-blind randomized balanced order). MSNA (muscle sympathetic nerve activity), HR (heart rate), BP (oscillometric brachial measurement) and Q (cardiac output; acetylene rebreathing) were measured before and throughout infusion. The change in HR (+8.2+/-1.0 and +2.4+/-1.2 beats/min), systolic BP (+14.0+/-1.6 and +3.2+/-2.5 mmHg) and diastolic BP (+8.2+/-1.0 and -0.1+/-1.7 mmHg) were significantly greater after the 4-h infusion of Intralipid compared with placebo (P<0.001). The change in BP with Intralipid resulted from an increase in SVR (Q/mean arterial pressure; P<0.001) compared with baseline, without a change in Q. MSNA burst frequency increased during Intralipid infusion compared with baseline (+4.9+/-1.3 bursts/min; P<0.05), and total MSNA (frequencyxamplitude) was augmented 65% (P<0.001), with no change during placebo infusion. Lipid infusion increased insulin, aldosterone and F2-isoprostane, but not leptin, concentrations. On the basis of the concomitant increase in BP, MSNA and SVR, we conclude that central sympathetic activation contributes to the pressor response to NEFAs.