Position of draining venous cannula in extracorporeal membrane oxygenation for respiratory and respiratory/circulatory support in adult patients.

Extracorporeal membrane oxygenation (ECMO) is used in critically ill patients with severe pulmonary and/or cardiac failure. Blood is drained from the venous system and pumped through a membrane oxygenator where it is oxygenated. For pulmonary support, the blood is returned to the patient via a vein (veno-venous ECMO) and for pulmonary/circulatory support it is returned via an artery (veno-arterial ECMO).Veno-venous ECMO can be performed either with a single dual-lumen cannula or with two separate single-lumen cannulas. If the latter is chosen, flow direction can either be from the inferior caval vein (IVC) to the right atrium or the opposite. Earlier research has shown that drainage from the IVC yields less recirculation and therefore the IVC to right atrium route has become the standard in most centers for veno-venous ECMO with two cannulas. However, recent research has shown that recirculation can be minimized using a multistage draining cannula in the optimal position inserted via the right internal jugular vein and with blood return to the femoral vein. The clinical results with this route are excellent.In veno-arterial ECMO the most common site for blood infusion is the femoral artery. If venous blood is drained from the IVC, the patient is at risk of developing a dual circulation (Harlequin syndrome, North-South syndrome, differential oxygenation) meaning a poor oxygenation of the upper part of the body, while the lower part has excellent oxygenation. By instead draining from the superior caval vein (SVC) via a multistage cannula inserted in the right internal jugular vein this risk is neutralized.In conclusion, the authors argue that draining blood from the SVC and right atrium via a multistage cannula inserted in the right internal jugular vein is equal or better than IVC drainage both in veno-venous two cannula ECMO and in veno-arterial ECMO with blood return to the femoral artery.

Analysis of hypo- and hypermagnesemia in an intensive care unit cohort.

INTRODUCTION: The aim of this study was to evaluate if magnesium deviations correlate with higher 180 day overall mortality or increased morbidity, compared to controls. METHODS: We conducted a retrospective study on 5369 patients with 22,003 magnesium values treated at the Adult Intensive Care Unit at Skåne University Hospital, Lund, Sweden during 2006-2014. The patients were retrospectively divided into a control group with only normal magnesium values 0.7-1.0 mmol/l, and three study groups; hypomagnesemic; Mg2+ < 0.7 mmol/l, hypermagnesemic; Mg2+ > 1.0 mmol/l and an unstable mixed group showing both hypo/hypermagnesemia. Gender, age, disease severity represented by maximum organ system SOFA score, renal SOFA score, lowest potassium value and diagnoses classes were included in a Cox hazard model in order to adjust for confounding factors, with time to death in the first 180 days from the ICU admission as outcome. RESULTS: The hypermagnesemic study group and the mixed group showed increased hazard ratios for mortality; 1.4 (CI 98.3% 1.2, 1.6, P < 0.0001) and 2.1 (CI 98.3% 1.2, 2.8, P < 0.0001) respectively, compared to controls, while the hypomagnesemic group did not reach significance. In addition, patients in the hypermagnesemic and the mixed groups are older, more ill with significantly higher EMR and SOFA scores and show significantly longer ventilator times and ICU stays, compared to controls. CONCLUSIONS: Patients with magnesium deviations are more ill compared to patients with explicitly normal magnesium values throughout the ICU stay. Cox analysis suggests that the magnesium deviation itself might have an impact on mortality.

Low serum selenium is associated with the severity of organ failure in critically ill children.

BACKGROUND & AIMS: Low concentration of serum selenium is associated with the inflammatory response and multiple organ failure in adult ICU-patients. Critically ill children are less well characterized. In this study, serum selenium concentration and its possible relation to multiple organ failure as well as glutathione status was investigated in pediatric intensive care (PICU) patients. METHODS: A prospective consecutive cohort of critically ill children (n = 100) admitted to the PICU of a tertiary university hospital, and in addition an age stratified reference group of healthy children (n = 60) were studied. The concentrations of serum selenium and reduced and total glutathione were determined at admission and at day 5 for patients still in the PICU. RESULTS: Low concentration of serum selenium as well as a high-reduced fraction of glutathione (GSH/tGSH) was associated with multiple organ failure (p < 0.001 and p < 0.01) respectively. A correlation between low serum selenium concentration and high-reduced fraction of glutathione (GSH/tGSH) was also seen (r = -0.19 and p = 0.03). The serum selenium concentrations in the pediatric reference group in a selenium poor area were age dependent with lower concentrations in infants as compared to older children (p < 0.001). CONCLUSIONS: Both low serum selenium concentration and high reduced fraction of glutathione (GSH/tGSH) were associated with the development of multiple organ failure. The association between low serum selenium concentration and high fraction of reduced glutathione in whole blood favour the hypothesis that selenium is of critical importance for the scavenge capacity of glutathione peroxidase (GPX).

Trace elements in patients on continuous renal replacement therapy.

PURPOSE: Intensive care patients with acute kidney injury (AKI), treated with continuous renal replacement therapy (CRRT) are at great risk for disturbances in plasma levels of trace elements due to the underlying illness, AKI, and dialysis. This study was performed to increase our knowledge regarding eight different trace elements during CRRT. METHODS: Thirty one stable patients with AKI, treated with CRRT, were included in the study. Blood, plasma and effluent samples were taken at the start of the study and 36 ± 12 h later. A group of 48 healthy volunteers were included as controls and exposed to one fasting blood sample. Samples were analysed for trace elements (Cr, Cu, Mn, Co, Zn, Rb, Mo, Se) and standard blood chemistry. RESULTS: Blood and plasma levels of selenium and rubidium were significantly reduced while the levels of chromium, cobalt, and molybdenum were significantly increased in the study group vs. healthy volunteers. There was an uptake of chromium, manganese, and zinc. Molybdenum mass balance was around zero. For selenium, copper, and rubidium there were a marked loss. CONCLUSIONS: The low levels of selenium and rubidium in blood and plasma from CRRT patients, together with the loss via CRRT effluent, raises the possibility of the need for selenium supplementation in this group of patients, despite the unchanged levels during the short study period. Further investigations on the effect of additional administration of trace elements to CRRT patients would be of interest.

Malignant hyperthermia, a Scandinavian update.

BACKGROUND: Malignant Hyperthermia (MH) is a rare pharmacogenetic disorder, triggered by halogenated anesthetics and/or succinylcholine. In susceptible individuals, these drugs can activate an explosive life threatening clinical reaction. Leading symptoms are hypercarbia, muscle rigidity, and metabolic acidosis. MH is inherited in an autosomal-dominant manner and linked to mutations in the large ryanodine 1 gene (RYR1) gene in the majority of cases. Very few MH patients have been found to carry mutations in the CACNA1S gene. METHODS: For this review a large litterature search was carried out and the Swedish MH database consisting of 436 probands who have undergone in vitro muscle contraction test (IVCT) during 1984-2014 was analyzed. RESULTS: Twelve different MH causative mutations have been found in Swedish patients so far. These mutations lead to a disturbed calcium balance in striated muscle tissue. A muscle biopsy for the IVCT or finding of an approved causative mutation are required for the diagnosis. CONCLUSION: A Malignant Hyperthermia susceptible (MHS) patient should be anesthetized with trigger-free anesthesia. There are a few reports of MH-like reactions in patients unrelated to anesthesia. The outcome is dependent on early recognizing of the reaction and fast disconnection of the trigger agents and administration of dantrolene.

Next-generation DNA sequencing of a Swedish malignant hyperthermia cohort.

Malignant hyperthermia (MH)-related mutations have been identified in the ryanodine receptor type 1 gene (RYR1) and in the dihydropyridine gene (CACNA1S), but about half of the patients do not have causative mutations in these genes. We wanted to study the contribution of other muscle genes to the RYR1 phenotypes. We designed a gene panel for sequence enrichment targeting 64 genes of proteins involved in the homeostasis of the striated muscle cell. Next-generation sequencing (NGS) resulted in >50,000 sequence variants which were further analyzed by software filtering criteria to identify causative variants. In four of five patients we identified previously reported RYR1 mutations while the fifth patient did not show any candidate variant in any of the genes investigated. In two patients pathogenic variants were found in other genes known to cause a muscle disorders. All but one patient carried likely benign rare polymorphisms. The NGS technique proved convenient in identifying variants in the RYR1. However, with a clinically variable phenotype-like MH, the pre-selection of genes poses problems in variant interpretation.

Phosphate-containing dialysis solution prevents hypophosphatemia during continuous renal replacement therapy.

BACKGROUND: hypophosphatemia occurs in up to 80% of the patients during continuous renal replacement therapy (CRRT). Phosphate supplementation is time-consuming and the phosphate level might be dangerously low before normophosphatemia is re-established. This study evaluated the possibility to prevent hypophosphatemia during CRRT treatment by using a new commercially available phosphate-containing dialysis fluid. METHODS: forty-two heterogeneous intensive care unit patients, admitted between January 2007 and July 2008, undergoing hemodiafiltration, were treated with a new Gambro dialysis solution with 1.2 mM phosphate (Phoxilium) or with standard medical treatment (Hemosol B0). The patients were divided into three groups: group 1 (n=14) receiving standard medical treatment and intravenous phosphate supplementation as required, group 2 (n=14) receiving the phosphate solution as dialysate solution and Hemosol B0 as replacement solution and group 3 (n=14) receiving the phosphate-containing solution as both dialysate and replacement solutions. RESULTS: standard medical treatment resulted in hypophosphatemia in 11 of 14 of the patients (group 1) compared with five of 14 in the patients receiving phosphate solution as the dialysate solution and Hemosol B0 as the replacement solution (group 2). Patients treated with the phosphate-containing dialysis solution (group 3) experienced stable serum phosphate levels throughout the study. Potassium, ionized calcium, magnesium, pH, pCO(2) and bicarbonate remained unchanged throughout the study. CONCLUSION: the new phosphate-containing replacement and dialysis solution reduces the variability of serum phosphate levels during CRRT and eliminates the incidence of hypophosphatemia.

High frequency of cross-reacting antibodies against 2009 pandemic influenza A(H1N1) virus among the elderly in Finland.

Since May 2009, the pandemic influenza A(H1N1) virus has been spreading throughout the world. Epidemiological data indicate that the elderly are underrepresented among the ill individuals. Approximately 1,000 serum specimens collected in Finland in 2004 and 2005 from individuals born between 1909 and 2005, were analysed by haemagglutination-inhibition test for the presence of antibodies against the 2009 pandemic influenza A(H1N1) and recently circulating seasonal influenza A viruses. Ninety-six per cent of individuals born between 1909 and 1919 had antibodies against the 2009 pandemic influenza virus, while in age groups born between 1920 and 1944, the prevalence varied from 77% to 14%. Most individuals born after 1944 lacked antibodies to the pandemic virus. In sequence comparisons the haemagglutinin (HA) gene of the 2009 pandemic influenza A(H1N1) virus was closely related to that of the Spanish influenza and 1976 swine influenza viruses. Based on the three-dimensional structure of the HA molecule, the antigenic epitopes of the pandemic virus HA are more closely related to those of the Spanish influenza HA than to those of recent seasonal influenza A(H1N1) viruses. Among the elderly, cross-reactive antibodies against the 2009 pandemic influenza virus, which likely originate from infections caused by the Spanish influenza virus and its immediate descendants, may provide protective immunity against the present pandemic virus.

Mutation screening of the RYR1-cDNA from peripheral B-lymphocytes in 15 Swedish malignant hyperthermia index cases.

BACKGROUND: Malignant hyperthermia (MH), linked to the ryanodine receptor 1 gene (RYR1) on chromosome 19, is a potentially lethal pharmacogenetic disorder which may lead to a disturbance of intracellular calcium homeostasis when susceptible individuals are exposed to halogenated anaesthetics, suxamethonium, or both. Central core disease (CCD) is a rare dominantly inherited congenital myopathy allelic to MH-susceptibility. METHODS: In this study, 14 unrelated MH-susceptible probands and one CCD patient from Sweden were screened for mutations in the RYR1. Since the RYR1 is also expressed in B-lymphocytes, RYR1-cDNA was transcribed from total RNA extracted from white blood cells. RESULTS: We detected two known RYR1 mutations and two previously described unclassified sequence variants. In addition, six novel sequence variants were detected. All mutations or sequence variants were verified on genomic DNA. Seven of the probands did not show any candidate mutation, although the total coding region of RYR1 was sequenced. Segregation data in in vitro contracture tested family members of three probands support a causative role of three of the novel sequence variants. CONCLUSIONS: Our study contributes to the genetic aetiology of MH in Sweden, but also raises questions about the involvement of genes other than RYR1 since nearly half of the probands did not show any sequence variants in the total coding region of the RYR1.

[Molecular-epidemiologic characteristic of hepatitis A outbreak among workers of food stores network].

Investigation of hepatitis A (HA) outbreak developed in 2005 among workers of food stores networkwas performed using conventional epidemiologic diagnostics as well as methods of molecular epidemiology. In 14 of 15 ill persons, using polymerase chain reaction, HAV RNA was detected by PCR in serum obtained on 2 - 25 day of illness (mean - 9.3 days). In 10 cases it was possible to determine nucleotide sequence of VP1/VP2 region of HAV genome and perform phylogenetic analysis of obtained isolates. It was determined that all isolates belonged to subgenotype IA, had high degree of homology and grouped in one cluster. These findings demonstrate their descendance from one source of infection, which, with high degree of probability, was the cook who made salads from fresh vegetables. HAV strain, which caused this epidemic outbreak circulates in Saint Petersburg for a long time and was already detected in 2004. Importance of vaccination against HA for persons working in manufacturing and distribution of food and use of molecular epidemiologic methods of surveillance for this infection is underlined.

Parvovirus B19 infection in five European countries: seroepidemiology, force of infection and maternal risk of infection.

We conducted a seroprevalence survey in Belgium, Finland, England & Wales, Italy and Poland on 13 449 serum samples broadly representative in terms of geography and age. Samples were tested for the presence of immunoglobulin G antibody using an enzyme immunoassay. The age-specific risk of infection was estimated using parametric and non-parametric statistical modelling. The age-specific risk in all five countries was highest in children aged 7-9 years and lower in adults. The average proportion of women of child-bearing age susceptible to parvovirus B19 infection and the risk of a pregnant women acquiring B19 infection during pregnancy was estimated to be 26% and 0.61% in Belgium, 38% and 0.69% in England & Wales, 43.5% and 1.24% in Finland, 39.9% and 0.92% in Italy and 36.8% and 1.58% in Poland, respectively. Our study indicates substantial epidemiological differences in Europe regarding parvovirus B19 infection.

Malignant hyperthermia and central core disease causative mutations in Swedish patients.

BACKGROUND: Malignant hyperthermia (MH) susceptibility is a pharmacogenetic disorder of intracellular calcium homeostasis. In susceptible individuals, halogenated anaesthetics and/or suxamethonium may trigger an MH reaction. The diagnosis of MH susceptibility is made by an in vitro contracture test of biopsied muscle strips. METHODS: In 27 MH susceptible (MHS) probands and four MH negative (MHN) probands, exons 17, 39, 40, 45 and 46 of the RYR1 gene were screened for MH causative mutations. In addition, in three patients with established central core disease (CCD), exons 17, 39, 40, 45 and 46 and exons 95, 100, 101 and 102 were screened for MH and CCD causative mutations. All screenings were performed by direct sequencing of the entire exons. RESULTS: MH causative mutations were found in five of the 27 MHS probands (19%). CCD causative mutations were found in two of three CCD patients in the C-terminal exons. None of the CCD patients showed a mutation in N-terminal exon 17 or in the central exons. CONCLUSIONS: In a Swedish population, screening of N-terminal exon 17 and the central exons for MH causative mutations in the RYR1 gene covers 19% of families. Thus, other mutations must also be responsible for MH susceptibility in Sweden. Although the number of CCD patients in this study was small, screening of the C-terminal exons for CCD causative mutations seems to be a promising tool in the process of making a diagnosis.

Expression of AP-2 alpha in SV40 immortalized human lung fibroblasts is associated with a distinct pattern of cytosine methylation in the AP-2 alpha promoter.

Activator protein-2 alpha (AP-2 alpha) is a cell type-specific, developmentally regulated, transcription factor that has been implicated as a critical regulator of gene expression during vertebrate development and carcinogenesis. We found that AP-2 alpha was differentially expressed in the normal human lung fibroblast cell strains WI38, MRC-5 and their respective SV40-transformed cell counterparts WI38-VA, MRC-5VA. Since CpG methylation within genetic regulatory regions has been implicated as a mechanism of gene regulation, we investigated the CpG methylation status of the AP-2 alpha gene promoter in these cells. High resolution mapping of methylated cytosines revealed that differential expression of the AP-2 alpha gene in normal human lung fibroblasts and their SV40-transformed counterparts was associated with distinct patterns of cytosine methylation in the AP-2 alpha promoter just 5' to the transcription initiation site. Site-specific methylation was positively correlated with increased AP-2 alpha gene expression in both transformed cell lines investigated. Interestingly, one of the two major centers of hypermethylation in the transformed cells encompassed the cis-element for the AP-2 repressing transcription factor AP-2rep (KLF12). Finally, a sequence variation in human lung fibroblasts relative to the published sequence revealed a previously unidentified AP-2 binding site at position -528 with respect to the transcription initiation site that overlapped the AP-2rep site. Our results suggest that transcriptional activation of AP-2 alpha in the SV40-transformed cells is mediated, at least in part, by site-specific methylation of a negative regulatory cis-element in the AP-2 alpha promoter.

The assessment of cognitive procedural learning in amnesia: why the tower of Hanoi has fallen down.

The Tower of Hanoi has been widely accepted as an evaluation of cognitive procedural learning in amnesia but inconsistent findings have raised questions about the nature of the learning process involved in this task. This article presents the performance of a hippocampal amnesic, MS, who, showing poor learning across daily sessions of a formal evaluation, subsequently solved the puzzle through spontaneous use of a declarative-level strategy (the odd-even rule), suggesting that his primary approach to the task was the deployment of declarative solution-searching strategies. The presented data suggest normal learning within daily sessions, but subnormal learning across daily sessions due to the forgetting of acquired declarative information. It is suggested that tasks that are potentially solvable by an algorithm or rule, as is the Tower of Hanoi, be regarded as inappropriate for use in cognitive procedural assessments.

Influence of the sympathetic nervous system on renal function during hypothermia.

Hypothermia increases preglomerular vasoconstriction leading to decreases in renal blood flow (RBF) and glomerular filtration rate (GFR). Since plasma catecholamine concentrations are increased during hypothermia, the present study was performed to determine the role of the renal sympathetic nervous system in the cold-induced renal vasoconstriction. In Inactin anaesthetized rats, hypothermia at 28 degrees C decreased GFR by 50% but failed to alter efferent renal sympathetic nerve activity (ERSNA). Since hypothermia causes shivering which could have influenced the ERSNA recording, Inactin anaesthetized rats were treated with pethidine or rats were anaesthetized with pentobarbital sodium or Saffan to eliminate cold-induced shivering. In these non-shivering rats, hypothermia produced a reversible decrease in ERSNA in association with a fall in GFR that was of a similar magnitude as in shivering rats. Further studies in Inactin anaesthetized rats showed that the fall in GFR was unaltered by renal denervation, bilateral adrenalectomy or intrarenal administration of the alpha 1-adrenoceptor antagonist prazosin. We conclude that cold-induced renal vasoconstriction is not due to an increase in ERSNA or adrenaline/noradrenaline-mediated activation of renal alpha 1-adrenoceptors.

The role of antidiuretic hormone in cold-induced diuresis in the anaesthetized rat.

The aim of this study was to investigate whether the increased diuresis in consequence of hypothermia is due to a depression of the hypothalamic release of antidiuretic hormone (ADH). The plasma concentration of antidiuretic hormone and the effect of intravenous (i.v.) administration of 65 ng kg-1 desmopressin (selective V2-receptor agonist) were determined in the anaesthetized rat. In spite of a 50% (P < 0.001) decrease in glomerular filtration rate, urine flow increased sixfold (P < 0.01) and urine sodium excretion increased sevenfold (P < 0.05), whereas urine osmolality decreased (P < 0.001). At the same time plasma antidiuretic hormone decreased from 7.5 +/- 1.1 to 3.8 +/- 0.4 pg mL-1 (P = 0.01). After injection of desmopressin urine flow was completely restored, whereas urine osmolality and sodium excretion were only partially normalized. Since tubular conservation of water and fractional water reabsorption decreased during hypothermia, the diuresis must have resulted from an augmented loss of water. This is further supported by the fact that osmolal excretion was not influenced either by hypothermia or by desmopressin. It is concluded that the diuresis in consequence to hypothermia is due both to a decrease in the release of ADH and to a reduction of renal medullary hypertonicity.

Severe anterograde amnesia with onset in childhood as a result of anoxic encephalopathy.

Our patient (M.S.) had an abrupt onset of amnesia due to a respiratory arrest at the age of 8 years and has been followed by one of us (A.L.R.) for 19 years. A specially designed MRI study indicated that the neuroanatomical localization of his lesion is restricted to the hippocampal formation bilaterally. Comparison of M.S.'s present IQ and academic scores with earlier scores revealed that his literacy skills, certain basic language functions and vocabulary development were arrested by his memory disorder. In contrast, development of mathematical skill was less curtailed, and verbal and nonverbal logical abilities developed to adult levels. Neuropsychological examination at the age of 27 years elicited a pattern of memory deficits similar to those found in a case (H.M.) of known mesial temporal lobe damage in adulthood. The neuropsychological pattern revealed those aspects of cognitive development that do, and those that do not, require intact memory. The limitations to intellectual development imposed by severe amnesia in childhood are not pervasive, but rather, are limited to specific types of abilities.

The effects of hypothermia on renal function and haemodynamics in the rat.

The effects of 1-2 h of hypothermia at 28 degrees C and rewarming on renal function were investigated in anaesthetized rats, using conventional clearance methods and the micropuncture technique. Renal blood flow (RBF) decreased from 7.3 +/- 0.51 mL min-1 at 37.5 degrees C (control) to 4.0 +/- 0.47 at 28 degrees C, with almost complete restoration to 6.9 +/- 0.59 mL min-1 after rewarming. Systemic blood pressure remained essentially unaltered. The RBF reduction seen during hypothermia was due to a 75% increase in vascular resistance, mainly attributable to constriction of the afferent arteriole and increased blood viscosity. This was accompanied by a decline in glomerular capillary pressure from 56.7 +/- 0.6 to 46.4 +/- 1.3 mmHg, overshooting to 59.0 +/- 0.7 mmHg. The glomerular filtration rate (GFR) decreased from 1.1 +/- 0.08 to 0.6 +/- 0.04 mL min-1, returning to 1.0 +/- 0.07 after rewarming, a pattern also observed for single nephron GFR. This resulted from a decrease in net driving force for glomerular filtration, whereas the filtration coefficient was not affected. Both proximal and distal tubular fluid flow decreased, but fractional reabsorption remained unchanged. In contrast, urine flow increased from 1.8 +/- 0.16 to 5.7 +/- 1.08 microL min-1, returning to 2.1 +/- 0.18, the increase during hypothermia mainly resulting from a disproportionately reduced fluid reabsorption beyond the mid-distal tubule.

Comparison between transesophageal Doppler echocardiography and nuclear cardioangiography for the evaluation of left ventricular filling during coronary artery bypass grafting.

This study examines the relative contribution of early (E) and atrial (A) filling of the left ventricle. Ten patients were studied under anesthesia before and after coronary artery bypass grafting (CABG) using measurements of the mitral velocity-time integral (VTI) with transesophageal pulsed Doppler echocardiography and nuclear angiocardiography simultaneously. Thermodilution cardiac output measurements were made simultaneously in order to express the E and A filling in quantitative terms. The mean difference between methods in estimating E filling was -1.0 mL and the figures for the mean +/- 2 SD were 5.7 and -7.8 mL, r = 0.98 using regression analysis. The mean difference during A filling was 0.9 mL and the corresponding figures for the mean +/- 2 SD were 7.9 and -6.1 mL, r = 0.88. There was a reduction in the volume entering the left ventricle during the E filling (42-26 mL) and in the A phase (27-22 mL) from before surgery in comparison to after CABG. There was good agreement between transesophageal Doppler echocardiographic and nuclear angiocardiographic methods concerning the volume contribution during E and A phases of left ventricular filling.