Adherence to All Steps of a Pain Management Protocol in Intensive Care Patients after Cardiac Surgery Is Hard to Achieve.

Purpose. To investigate adherence to our pain protocol considering analgesics administration, number and timing of pain assessments, and adjustment of analgesics upon unacceptably high (NRS ≥ 4) and low (NRS ≤ 1) pain scores. Material and Methods. The pain protocol for patients in the intensive care unit (ICU) after cardiac surgery consisted of automated prescriptions for paracetamol and morphine, automated reminders for pain assessments, a flowchart to guide interventions upon high and low pain scores, and reassessments after unacceptable pain. Results. Paracetamol and morphine were prescribed in all 124 patients. Morphine infusion was stopped earlier than protocolized in 40 patients (32%). During the median stay of 47 hours [IQR 26 to 74 hours], 702/706 (99%) scheduled pain assessments and 218 extra pain scores were recorded. Unacceptably high pain scores accounted for 96/920 (10%) and low pain scores for 546/920 (59%) of all assessments. Upon unacceptable pain additional morphine was administered in 65% (62/96) and reassessment took place in 15% (14/96). Morphine was not tapered in 273 of 303 (90%) eligible cases of low pain scores. Conclusions. Adherence to automated prescribed analgesics and pain assessments was good. Adherence to nonscheduled, flowchart-guided interventions was poor. Improving adherence may refine pain management and reduce side effects.

Peripheral blood gene expression profiles linked to monoamine metabolite levels in cerebrospinal fluid.

The blood-brain barrier separates circulating blood from the central nervous system (CNS). The scope of this barrier is not fully understood which limits our ability to relate biological measurements from peripheral to central phenotypes. For example, it is unknown to what extent gene expression levels in peripheral blood are reflective of CNS metabolism. In this study, we examine links between central monoamine metabolite levels and whole-blood gene expression to better understand the connection between peripheral systems and the CNS. To that end, we correlated the prime monoamine metabolites in cerebrospinal fluid (CSF) with whole-genome gene expression microarray data from blood (N=240 human subjects). We additionally applied gene-enrichment analysis and weighted gene co-expression network analyses (WGCNA) to identify modules of co-expressed genes in blood that may be involved with monoamine metabolite levels in CSF. Transcript levels of two genes were significantly associated with CSF serotonin metabolite levels after Bonferroni correction for multiple testing: THAP7 (P=2.8 × 10-8, ß=0.08) and DDX6 (P=2.9 × 10-7, ß=0.07). Differentially expressed genes were significantly enriched for genes expressed in the brain tissue (P=6.0 × 10-52). WGCNA revealed significant correlations between serotonin metabolism and hub genes with known functions in serotonin metabolism, for example, HTR2A and COMT. We conclude that gene expression levels in whole blood are associated with monoamine metabolite levels in the human CSF. Our results, including the strong enrichment of brain-expressed genes, illustrate that gene expression profiles in peripheral blood can be relevant for quantitative metabolic phenotypes in the CNS.

Procedural pain does not raise plasma levels of cortisol or catecholamines in adult intensive care patients after cardiac surgery.

The gold standard for quantification of pain is a person's self-report. However, we need objective parameters for pain measurement when intensive care patients, for example, are not able to report pain themselves. An increase in pain is currently thought to coincide with an increase in stress hormones. This observational study investigated whether procedure-related pain is associated with an increase of plasma cortisol, adrenaline, and noradrenaline. In 59 patients receiving intensive care after cardiac surgery, cortisol, adrenaline, and noradrenaline plasma levels were measured immediately before and immediately after patients were turned for washing, either combined with the removal of chest tubes or not. Numeric rating scale scores were obtained before, during, and after the procedure. Unacceptably severe pain (numeric rating scale ≥ 4) was reported by seven (12%), 26 (44%), and nine (15%) patients, before, during and after the procedure, respectively. There was no statistically significant association between numeric rating scale scores and change in cortisol, adrenaline, and noradrenaline plasma levels during the procedure. Despite current convictions that pain coincides with an increase in stress hormones, procedural pain was not associated with a significant increase in plasma stress hormone levels in patients who had undergone cardiac surgery. Thus, plasma levels of cortisol, adrenaline, and noradrenaline seem unsuitable for further research on the measurement of procedural pain.

Genome-wide association study of NMDA receptor coagonists in human cerebrospinal fluid and plasma.

The N-methyl-D-aspartate receptor (NMDAR) coagonists glycine, D-serine and L-proline play crucial roles in NMDAR-dependent neurotransmission and are associated with a range of neuropsychiatric disorders. We conducted the first genome-wide association study of concentrations of these coagonists and their enantiomers in plasma and cerebrospinal fluid (CSF) of human subjects from the general population (N=414). Genetic variants at chromosome 22q11.2, located in and near PRODH (proline dehydrogenase), were associated with L-proline in plasma (ß=0.29; P=6.38 × 10(-10)). The missense variant rs17279437 in the proline transporter SLC6A20 was associated with L-proline in CSF (ß=0.28; P=9.68 × 10(-9)). Suggestive evidence of association was found for the D-serine plasma-CSF ratio at the D-amino-acid oxidase (DAO) gene (ß=-0.28; P=9.08 × 10(-8)), whereas a variant in SRR (that encodes serine racemase and is associated with schizophrenia) constituted the most strongly associated locus for the L-serine to D-serine ratio in CSF. All these genes are highly expressed in rodent meninges and choroid plexus, anatomical regions relevant to CSF physiology. The enzymes and transporters they encode may be targeted to further construe the nature of NMDAR coagonist involvement in NMDAR gating. Furthermore, the highlighted genetic variants may be followed up in clinical populations, for example, schizophrenia and 22q11 deletion syndrome. Overall, this targeted metabolomics approach furthers the understanding of NMDAR coagonist concentration variability and sets the stage for non-targeted CSF metabolomics projects.

Genome-wide association study of monoamine metabolite levels in human cerebrospinal fluid.

Studying genetic determinants of intermediate phenotypes is a powerful tool to increase our understanding of genotype-phenotype correlations. Metabolic traits pertinent to the central nervous system (CNS) constitute a potentially informative target for genetic studies of intermediate phenotypes as their genetic underpinnings may elucidate etiological mechanisms. We therefore conducted a genome-wide association study (GWAS) of monoamine metabolite (MM) levels in cerebrospinal fluid (CSF) of 414 human subjects from the general population. In a linear model correcting for covariates, we identified one locus associated with MMs at a genome-wide significant level (standardized ß=0.32, P=4.92 × 10(-8)), located 20 kb from SSTR1, a gene involved with brain signal transduction and glutamate receptor signaling. By subsequent whole-genome expression quantitative trait locus (eQTL) analysis, we provide evidence that this variant controls expression of PDE9A (ß=0.21; P unadjusted=5.6 × 10(-7); P corrected=0.014), a gene previously implicated in monoaminergic transmission, major depressive disorder and antidepressant response. A post hoc analysis of loci significantly associated with psychiatric disorders suggested that genetic variation at CSMD1, a schizophrenia susceptibility locus, plays a role in the ratio between dopamine and serotonin metabolites in CSF. The presented DNA and mRNA analyses yielded genome-wide and suggestive associations in biologically plausible genes, two of which encode proteins involved with glutamate receptor functionality. These findings will hopefully contribute to an exploration of the functional impact of the highlighted genes on monoaminergic transmission and neuropsychiatric phenotypes.

Seasonal variation of serotonin turnover in human cerebrospinal fluid, depressive symptoms and the role of the 5-HTTLPR.

Studying monoaminergic seasonality is likely to improve our understanding of neurobiological mechanisms underlying season-associated physiological and pathophysiological behavior. Studies of monoaminergic seasonality and the influence of the serotonin-transporter-linked polymorphic region (5-HTTLPR) on serotonin seasonality have yielded conflicting results, possibly due to lack of power and absence of multi-year analyses. We aimed to assess the extent of seasonal monoamine turnover and examined the possible involvement of the 5-HTTLPR. To determine the influence of seasonality on monoamine turnover, 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) were measured in the cerebrospinal fluid of 479 human subjects collected during a 3-year period. Cosine and non-parametric seasonal modeling were applied to both metabolites. We computed serotonin (5-HT) seasonality values and performed an association analysis with the s/l alleles of the 5-HTTLPR. Depressive symptomatology was assessed using the Beck Depression Inventory-II. Circannual variation in 5-HIAA fitted a spring-peak cosine model that was significantly associated with sampling month (P=0.0074). Season of sampling explained 5.4% (P=1.57 × 10(-7)) of the variance in 5-HIAA concentrations. The 5-HTTLPR s-allele was associated with increased 5-HIAA seasonality (standardized regression coefficient=0.12, P=0.020, N=393). 5-HIAA seasonality correlated with depressive symptoms (Spearman's rho=0.13, P=0.018, N=345). In conclusion, we highlight a dose-dependent association of the 5-HTTLPR with 5-HIAA seasonality and a positive correlation between 5-HIAA seasonality and depressive symptomatology. The presented data set the stage for follow-up in clinical populations with a role for seasonality, such as affective disorders.

Remifentanil during cardiac surgery is associated with chronic thoracic pain 1 yr after sternotomy.

BACKGROUND: Chronic thoracic pain after cardiac surgery is a serious condition affecting many patients. The aim of this study was to identify predictors for chronic thoracic pain after sternotomy in cardiac surgery patients by analysing patient and perioperative characteristics. METHODS: A follow-up study was performed in 120 patients who participated in a clinical trial on pain levels in the early postoperative period after cardiac surgery. The presence of chronic thoracic pain was evaluated by a questionnaire 1 yr after surgery. Patients with and without chronic thoracic pain were compared. Associations were studied using multivariable logistic regression analysis. RESULTS: Questionnaires of 90 patients were analysed. Chronic thoracic pain was reported by 18 patients (20%). In the multivariable regression model, remifentanil during cardiac surgery, age below 69 yr, and a body mass index above 28 kg m(-2) were independent predictors for chronic thoracic pain {odds ratios 8.9 [95% confidence interval (CI) 1.6-49.0], 7.0 (95% CI 1.6-31.7), 9.1 (95% CI 2.1-39.1), respectively}. No differences were observed in patient and perioperative characteristics between patients receiving remifentanil (58%, n=52) compared with patients not receiving remifentanil (42%, n=38). The association between remifentanil and chronic thoracic pain appeared dose-dependent, both for total dose and for dose corrected for kilogram lean body mass and duration of surgery (P-value for trend: <0.01 and <0.005, respectively). CONCLUSIONS: In this follow-up study in cardiac surgery patients, intraoperative remifentanil was predictive for chronic thoracic pain in a dose-dependent manner. Randomized studies designed to evaluate the influence of intraoperative remifentanil on chronic thoracic pain are needed to confirm these results.

Efficacy of an intravenous bolus of morphine 2.5 versus morphine 7.5 mg for procedural pain relief in postoperative cardiothoracic patients in the intensive care unit: a randomised double-blind controlled trial.

As pain in the intensive care unit (ICU) is still common despite important progress in pain management, we studied the efficacy of an intravenous bolus of morphine 2.5 vs 7.5 mg for procedural pain relief in patients after cardiothoracic surgery in the ICU. In a prospective double-blind randomised study, 117 ICU patients after cardiothoracic surgery were included. All patients were treated according a pain titration protocol for pain at rest, consisting of continuous morphine infusions and paracetamol, applied during the entire ICU stay. On the first postoperative day, patients were randomised to intravenous morphine 2.5 (n=59) or 7.5 mg (n=58) 30 minutes before a painful intervention (turning of patient and/or chest drain removal). Pain scores using the numeric rating scale (Numeric Rating Scale, range 0 to 10) were rated at rest (baseline) and around the painful procedure. At rest (baseline), overall incidence of unacceptable pain (Numeric Rating Scale ≥4) was low (Numeric Rating Scale >4; 14 vs 17%, P=0.81) for patients allocated to morphine 2.5 and 7.5 mg respectively. For procedure-related pain, there was no difference in incidence of unacceptable pain (28 vs 22%, P=0.53) mean pain scores (2.6 [95% confidence interval 2.0 to 3.2] vs 2.7 [95% confidence interval 2.0 to 3.4]) between patients receiving morphine 2.5 and 7.5 mg respectively. In intensive care patients after cardiothoracic surgery with low pain levels for pain at rest, there was no difference in efficacy between intravenous morphine 2.5 mg or morphine 7.5 mg for pain relief during a painful intervention.

Aminotransferase levels in relation to short-term use of acetaminophen four grams daily in postoperative cardiothoracic patients in the intensive care unit.

A volunteer study suggested that taking paracetamol 4 g daily could result in elevated alanine aminotransferase plasma levels in a substantial proportion of healthy volunteers. The safety of this dose of paracetamol for acute postoperative pain remains controversial. This study aimed to examine the incidence of alanine aminotransferase elevations after short-term use of paracetamol 4 g daily, as part of the standard pain management protocol, for 93 consecutive patients after cardiothoracic surgery. Alanine aminotransferase levels and other liver function tests were measured preoperatively as baseline and once daily after surgery during the intensive care unit stay. Preoperative alanine aminotransferase levels of more than one time the upper limit of normal (ULN >40 U/l) was observed in 11% (n=10) of the patients but none of these baseline alanine aminotransferase levels exceeded three times the ULN (>3 x ULN). The average daily dose of paracetamol administered was 50 mg/kg (SD=16) after surgery. Postoperative alanine aminotransferase levels of >1 x ULN was observed in 17% (n=16), and 4% (n=4) exceeded >3 x ULN The other liver function tests of the latter four patients, including aspartate aminotransferase (range 173 to 5590 U/l), gamma-glutamyltransferase (range 56 to 103 U/l), lactate dehydrogenase (range 376 to 3518 U/l) and the International Normalised Ratio (range 2.0 to 6.6), were all abnormal. These four patients all had right ventricular failure or cardiogenic shock during the postoperative period which could explain the significant rises in alanine aminotransferase after surgery. In conclusion, the incidence of significant alanine aminotransferase elevations after using daily paracetamol as an analgesic agent for cardiac surgery, at a dose of 4 g per day, was low and mostly due to complications after surgery. Our results, albeit still very limited, provided some reassurance about the safety of paracetamol 4 g daily, as a supplementary analgesic agent for adult patients undergoing cardiac surgery.

Using NMR to study full intact wine bottles.

A nuclear magnetic resonance (NMR) probe and spectrometer capable of investigating full intact wine bottles is described and used to study a series of Cabernet Sauvignons with high resolution 1H NMR spectroscopy. Selected examples of full bottle 13C NMR spectra are also provided. The application of this full bottle NMR method to the measurement of acetic acid content, the detection of complex sugars, phenols, and trace elements in wine is discussed.

Heparin-protamine complexes and C-reactive protein induce activation of the classical complement pathway: studies in patients undergoing cardiac surgery and in vitro.

The administration of protamine to patients undergoing cardiopulmonary bypass (CPB) to neutralize heparin and to reduce the risk of bleeding, induces activation of the classical complement pathway mainly by heparin-protamine complexes. We investigated whether C-reactive protein (CRP) contributes to protamine-induced complement activation. In 24 patients during myocardial revascularization, we measured complement, CRP, and complement-CRP complexes, reflecting CRP-mediated complement activation in vivo. We also incubated plasma from healthy volunteers and patients with heparin and protamine in vitro to study CRP-mediated complement activation. During CPB, CRP levels remained unchanged while C3 activation products increased. C4 activation occurred after protamine administration. CRP-complement complexes increased at the end of CPB and upon protamine administration. Incubation of plasma with heparin and protamine in vitro generated complement-CRP complexes, which was blocked by phosphorylcholine and stimulated by exogenous CRP. C4d-CRP complex formation after protamine administration correlated clinically with the incidence of postoperative arrhythmia. Protamine administration during cardiac surgery induces complement activation which in part is CRP-dependent, and correlates with postoperative arrhythmia.

Activation of the complement system during and after cardiopulmonary bypass surgery: postsurgery activation involves C-reactive protein and is associated with postoperative arrhythmia.

BACKGROUND: Complement activation during cardiopulmonary bypass (CPB) surgery is considered to result from interaction of blood with the extracorporeal circuit. We investigated whether additional mechanisms may contribute to complement activation during and after CPB and, in particular, focused on a possible role of the acute-phase protein C-reactive protein (CRP). METHODS AND RESULTS: In 19 patients enrolled for myocardial revascularization, perioperative and postoperative levels of complement activation products, interleukin-6 (IL-6), CRP, and complement-CRP complexes, reflecting CRP-mediated complement activation in vivo, were measured and related to clinical symptoms. A biphasic activation of complement was observed. The ratio between the areas under the curve of perioperative and postoperative C3b/c and C4b/c were 3:2 and 1:46, respectively. IL-6 levels reached a maximum at 6 hours post-surgery. CRP levels peaked on the second postoperative day. Each complement-CRP complex had peak levels on the second or third postoperative day. By multivariate analysis, maximum levels of CRP on the second postoperative day were mainly explained by C4b/c levels after protamine administration, leukocyte count on the second postoperative day, and preoperative levels of CRP. Peak levels of C4b/c after protamine administration (P=.0073) and on the second postoperative day correlated with the occurrence of arrhythmia on the same day (P=.0065). CONCLUSIONS: Cardiac surgery with CPB causes a biphasic complement activation. The first phase occurs during CPB and results from the interaction of blood with the extracorporeal circuit. The second phase, which occurs during the first 5 days after surgery, involves CRP, is related to baseline CRP levels, and is associated with clinical symptoms such as arrhythmia.

Clinical evaluation of Duraflo II heparin treated extracorporeal circulation circuits (2nd version). The European Working Group on heparin coated extracorporeal circulation circuits.

OBJECTIVES: To evaluate whether the application of heparin treated circuits for elective coronary artery surgery improves postoperative recovery, a European multicenter randomised clinical trial was carried out. METHODS: In 11 European heart centers, 805 low-risk patients underwent cardiopulmonary bypass (CPB) with either an untreated circuit (n = 407) or an identical but heparin treated circuit (n = 398, Duraflo II). RESULTS: Significant differences were found among participating centers with respect to patient characteristics, blood handling procedures and postoperative care. The use of heparin treated circuits revealed no overall changes in blood loss, blood use, time on ventilator, occurrence of adverse events, morbidity, mortality, and intensive care stay. These results did not change after adjustment for centers and (other) prognostic factors as analysed with logistic regression. In both groups no clinical or technical (patient or device related) side effects were reported. Because female gender and aortic cross clamp time appeared as prognostic factors in the logistic regression analysis, a subgroup analysis with these variables was performed. In a subpopulation of females (n = 99), those receiving heparin treated circuits needed less blood products, had a lower incidence of rhythm disturbances and were extubated earlier than controls. In another subgroup of patients with aortic cross clamp time exceeding 60 min (n = 197), the amount of patients requiring prolonged intensive care treatment (> 24 h) was significantly lower when they received heparin treated circuits versus controls. CONCLUSION: These findings suggest that improved recovery can be expected with heparin treated circuits in specific higher risk patient populations (e.g. females) and when prolonged aortic cross clamp time is anticipated. Further investigations are recommended to analyses the clinical benefit of heparin treated circuits in studies with patients in different well defined risk categories and under better standardised circumstances.

Conformer interconversion in the LC analysis of triostin A and its under-N-methylated synthetic analogue.

Multiple peak formation and interconversion in the liquid chromatographic (LC) analysis of triostin A and its under-N-methylated synthetic analogue, [N-MeCys3,N-MeCys7]-TANDEM (MCTANDEM), are investigated as a function of column temperature. Slow interconversion between chromatographic peaks, ascribed to the presence of the n- and p-solution conformers of the peptides, is exhibited in the normal-phase elution profiles of triostin A and in the reversed-phase elution profiles of MCTANDEM. A chromatographic model is developed to estimate the kinetics of conformer interconversion. Reversed-phase LC analysis of the n- and p-conformers of MCTANDEM yields a value of 0.01/s for the apparent interconversion rate constant (kn-p) at 25 degrees C, with a corresponding activation energy of 16 kcal/mol. Normal-phase LC analysis of the n- and p-conformer interconversion of triostin A dissolved in chloroform results in a value of 0.04/s for kn-p at 25 degrees C, with a corresponding activation energy of 18 kcal/mol. For triostin A, normal-phase LC findings as a function of column temperature are compared with 1H nuclear magnetic resonance (NMR) line-width measurements between 80 degrees C and 140 degrees C for the n- and p-conformers, which yield an activation energy of 19 kcal/mol and an extrapolated value of 0.02/s at 25 degrees C for kn-p in deuteriochloroform.