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1.  The estimation of cardiac output by the Nexfin device is of poor reliability for tracking the effects of a fluid challenge 
Critical Care  2012;16(5):R212.
The Nexfin device estimates arterial pressure by the volume clamp method through a finger pneumatic cuff. It also allows to estimate cardiac index (CInoninv) by pulse contour analysis of the non-invasive arterial pressure curve. We evaluated the ability of the device to track changes in cardiac index induced by a fluid challenge.
We included 45 patients for whom a volume expansion (500 mL of saline infused over 30 min) was planned. The volume expansion-induced changes in cardiac index measured by transpulmonary thermodilution (CIinv, PiCCO device) and in CInoninv were recorded.
In seven patients, the Nexfin could not record the arterial curve due to finger hypoperfusion. Considering both the values obtained before and after volume expansion (n = 76 pairs of measurements), the bias (lower and upper limits of agreement) between CIinv and CInoninv was 0.2 (-1.8 to 2.2) L/min/m2. The mean change in CInoninv was 10 ± 11%. The percentage error of CInoninv was 57%. The correlation between the changes in CIinv and CInoninv observed during volume expansion was significant (P = 0.0002) with an r2 = 0.31.
The estimation of CI by the Nexfin device in critically ill patients is not reliable, neither for estimating absolute values of CI nor for tracking its changes during volume expansion.
PMCID: PMC3682316  PMID: 23107227
2.  Meal pattern analysis in neural-specific proopiomelanocortin-deficient mice 
European journal of pharmacology  2011;660(1):131-138.
The central melanocortin system, consisting of melanocortin peptides, agouti gene related peptide and their receptors plays a critical role in the homeostatic control of energy balance. Loss of function mutations in the genes encoding proopiomelanocortin or melanocortin MC4 receptors cause profound obesity and hyperphagia. However, little is known about the functional relationship of melanocortin neurocircuits to the temporal organization of meal-taking behavior. We used an operant paradigm that combined lever pressing for food pellet deliveries with free water intake monitored by lickometers to quantify meal patterns in mutant mice that selectively lack proopiomelanocortin expression in hypothalamic neurons (nPOMCKO). Compared to wildtype siblings, nPOMCKO mice consumed 50% more food and water daily and exhibited a more stereotyped feeding pattern characterized by reduced inter-meal and inter-mouse variations. Average meals were larger in size but shorter in duration, with no change in meal number. Consequently, intermeal intervals were prolonged in nPOMCKO mice. Similar patterns were observed in pre-obese juvenile and frankly obese adult mice suggesting that neither age nor degree of obesity was responsible for the altered phenotypes. Spontaneous locomotion and wheel running were decreased in nPOMCKO mice, but circadian variations in locomotor and feeding activity were conserved. These data show that hyperphagia in male nPOMCKO mice is due to increased meal size but not meal number, and this pattern is established by age 5 wk. The combination of larger, more rapidly consumed meals and prolonged intermeal intervals suggests that proopiomelanocortin peptides are necessary for normal meal termination, but not the maintenance of satiety.
PMCID: PMC3096011  PMID: 21211523
Operant behavior; Obesity; Satiety; Hyperphagia; Circadian; Locomotor activity
3.  Stress-related cardiomyopathies 
Stress-related cardiomyopathies can be observed in the four following situations: Takotsubo cardiomyopathy or apical ballooning syndrome; acute left ventricular dysfunction associated with subarachnoid hemorrhage; acute left ventricular dysfunction associated with pheochromocytoma and exogenous catecholamine administration; acute left ventricular dysfunction in the critically ill. Cardiac toxicity was mediated more by catecholamines released directly into the heart via neural connection than by those reaching the heart via the bloodstream. The mechanisms underlying the association between this generalized autonomic storm secondary to a life-threatening stress and myocardial toxicity are widely discussed. Takotsubo cardiomyopathy has been reported all over the world and has been acknowledged by the American Heart Association as a form of reversible cardiomyopathy. Four "Mayo Clinic" diagnostic criteria are required for the diagnosis of Takotsubo cardiomyopathy: 1) transient left ventricular wall motion abnormalities involving the apical and/or midventricular myocardial segments with wall motion abnormalities extending beyond a single epicardial coronary artery distribution; 2) absence of obstructive epicardial coronary artery disease that could be responsible for the observed wall motion abnormality; 3) ECG abnormalities, such as transient ST-segment elevation and/or diffuse T wave inversion associated with a slight troponin elevation; and 4) the lack of proven pheochromocytoma and myocarditis. ECG changes and LV dysfunction occur frequently following subarachnoid hemorrhage and ischemic stroke. This entity, referred as neurocardiogenic stunning, was called neurogenic stress-related cardiomyopathy. Stress-related cardiomyopathy has been reported in patients with pheochromocytoma and in patients receiving intravenous exogenous catecholamine administration. The role of a huge increase in endogenous and/or exogenous catecholamine level in critically ill patients (severe sepsis, post cardiac resuscitation, post tachycardia) to explain the onset of myocardial dysfunction was discussed. Further research is needed to understand this complex interaction between heart and brain and to identify risk factors and therapeutic and preventive strategies.
PMCID: PMC3224539  PMID: 21933374
4.  Precision of the transpulmonary thermodilution measurements 
Critical Care  2011;15(4):R204.
We wanted to determine the number of cold bolus injections that are necessary for achieving an acceptable level of precision for measuring cardiac index (CI), indexed global end-diastolic volume (GEDVi) and indexed extravascular lung water (EVLWi) by transpulmonary thermodilution.
We included 91 hemodynamically stable patients (age 59 (25% to 75% interquartile range: 39 to 79) years, simplified acute physiologic score (SAPS)II 59 (53 to 65), 56% under norepinephrine) who were monitored by a PiCCO2 device. We performed five successive cold saline (15 mL, 6°C) injections and recorded the measurements of CI, GEDVi and EVLWi.
Considering five boluses, the coefficient of variation (CV, calculated as standard deviation divided by the mean of the five measurements) was 7 (5 to 11)%, 7 (5 to 12)% and 7 (6 to 12)% for CI, GEDVi and EVLWi, respectively. If the results of two bolus injections were averaged, the precision (2 × CV/√ number of boluses) was 10 (7 to 15)%, 10 (7 to 17)% and 8 (7 to 14)% for CI, GEDVi and EVLWi, respectively. If the results of three bolus injections were averaged, the precision dropped below 10%, that is, the cut-off that is generally considered as acceptable (8 (6 to 12)%, 8 (6 to 14)% and 8 (7 to 14)% for CI, GEDVi and EVLWi, respectively). If two injections were performed, the least significant change, that is, the minimal change in value that could be trusted to be significant, was 14 (10 to 21)%, 14 (10 to 24)% and 14 (11 to 23)% for CI, GEDVi and EVLWi, respectively. If three injections were performed, the least significant change was 12 (8 to 17)%, 12 (8 to 19)% and 12 (9 to 19)% for CI, GEDVi and EVLWi, respectively, that is, below the 15% cut-off that is usually considered as clinically relevant.
These results support the injection of at least three cold boluses for obtaining an acceptable precision when transpulmonary thermodilution is used for measuring CI, GEDVi and EVLWi.
PMCID: PMC3387646  PMID: 21871112
5.  Evaluation of a Susceptibility Gene for Schizophrenia: Genotype Based Meta-Analysis of RGS4 Polymorphisms from Thirteen Independent Samples 
Biological psychiatry  2006;60(2):152-162.
Associations between schizophrenia (SCZ) and polymorphisms at the regulator of G-protein signaling 4 (RGS4) gene have been reported (single nucleotide polymorphisms [SNPs] 1, 4, 7, and 18). Yet, similar to other SCZ candidate genes, studies have been inconsistent with respect to the associated alleles.
In an effort to resolve the role for RGS4 in SCZ susceptibility, we undertook a genotype-based meta-analysis using both published and unpublished family-based and case-control samples (total n = 13,807).
The family-based dataset consisted of 10 samples (2160 families). Significant associations with individual SNPs/haplotypes were not observed. In contrast, global analysis revealed significant transmission distortion (p = .0009). Specifically, analyses suggested overtransmission of two common haplotypes that account for the vast majority of all haplotypes. Separate analyses of 3486 cases and 3755 control samples (eight samples) detected a significant association with SNP 4 (p = .01). Individual haplotype analyses were not significant, but evaluation of test statistics from individual samples suggested significant associations.
Our collaborative meta-analysis represents one of the largest SCZ association studies to date. No individual risk factor arose from our analyses, but interpretation of these results is not straightforward. Our analyses suggest risk due to at least two common haplotypes in the presence of heterogeneity. Similar analysis for other putative susceptibility genes is warranted.
PMCID: PMC3133764  PMID: 16631129 CAMSID: cams1794
RGS4; schizophrenia; meta-analysis; association; polymorphism; linkage
6.  Weaning failure of cardiac origin: recent advances 
Critical Care  2010;14(2):211.
This article is one of ten reviews selected from the Yearbook of Intensive Care and Emergency Medicine 2010 (Springer Verlag) and co-published as a series in Critical Care. Other articles in the series can be found online at Further information about the Yearbook of Intensive Care and Emergency Medicine is available from
PMCID: PMC2887104  PMID: 20236455
7.  Early administration of norepinephrine increases cardiac preload and cardiac output in septic patients with life-threatening hypotension 
Critical Care  2010;14(4):R142.
We sought to examine the cardiac consequences of early administration of norepinephrine in severely hypotensive sepsis patients hospitalized in a medical intensive care unit of a university hospital.
We included 105 septic-shock patients who already had received volume resuscitation. All received norepinephrine early because of life-threatening hypotension and the need to achieve a sufficient perfusion pressure rapidly and to maintain adequate flow. We analyzed the changes in transpulmonary thermodilution variables associated with the increase in mean arterial pressure (MAP) induced by norepinephrine when the achieved MAP was ≥65 mm Hg.
Norepinephrine significantly increased MAP from 54 ± 8 to 76 ± 9 mm Hg, cardiac index (CI) from 3.2 ± 1.0 to 3.6 ± 1.1 L/min/m2, stroke volume index (SVI) from 34 ± 12 to 39 ± 13 ml/m2, global end-diastolic volume index (GEDVI) from 694 ± 148 to 742 ± 168 ml/m2, and cardiac function index (CFI) from 4.7 ± 1.5 to 5.0 ± 1.6 per min. Beneficial hemodynamic effects on CI, SVI, GEDVI, and CFI were observed in the group of 71 patients with a baseline echocardiographic left ventricular ejection fraction (LVEF) >45%, as well as in the group of 34 patients with a baseline LVEF ≤45%. No change in CI, SVI, GEDVI, or CFI was observed in the 17 patients with baseline LVEF ≤45% for whom values of MAP ≥75 mm Hg were achieved with norepinephrine.
Early administration of norepinephrine aimed at rapidly achieving a sufficient perfusion pressure in severely hypotensive septic-shock patients is able to increase cardiac output through an increase in cardiac preload and cardiac contractility. This effect remained in patients with poor cardiac contractility except when values of MAP ≥75 mm Hg were achieved.
PMCID: PMC2945123  PMID: 20670424
8.  Arterial pressure-based cardiac output in septic patients: different accuracy of pulse contour and uncalibrated pressure waveform devices 
Critical Care  2010;14(3):R109.
We compared the ability of two devices estimating cardiac output from arterial pressure-curve analysis to track the changes in cardiac output measured with transpulmonary thermodilution induced by volume expansion and norepinephrine in sepsis patients.
In 80 patients with septic circulatory failure, we administered volume expansion (40 patients) or introduced/increased norepinephrine (40 patients). We measured the pulse contour-derived cardiac index (CI) provided by the PiCCO device (CIpc), the arterial pressure waveform-derived CI provided by the Vigileo device (CIpw), and the transpulmonary thermodilution CI (CItd) before and after therapeutic interventions.
The changes in CIpc accurately tracked the changes in CItd induced by volume expansion (bias, -0.20 ± 0.63 L/min/m2) as well as by norepinephrine (bias, -0.05 ± 0.74 L/min/m2). The changes in CIpc accurately detected an increase in CItd ≥ 15% induced by volume expansion and norepinephrine introduction/increase (area under ROC curves, 0.878 (0.736 to 0.960) and 0.924 (0.795 to 0.983), respectively; P < 0.05 versus 0.500 for both). The changes in CIpw were less reliable for tracking the volume-induced changes in CItd (bias, -0.23 ± 0.95 L/min/m2) and norepinephrine-induced changes in CItd (bias, -0.01 ± 1.75 L/min/m2). The changes in CIpw were unable to detect an increase in CItd ≥ 15% induced by volume expansion and norepinephrine introduction/increase (area under ROC curves, 0.564 (0.398 to 0.720) and 0.541 (0.377 to 0.700, respectively, both not significantly different from versus 0.500).
The CIpc was reliable and accurate for assessing the CI changes induced by volume expansion and norepinephrine. By contrast, the CIpw poorly tracked the trends in CI induced by those therapeutic interventions.
PMCID: PMC2911755  PMID: 20537159
10.  Critical care management and outcome of severe Pneumocystis pneumonia in patients with and without HIV infection 
Critical Care  2008;12(1):R28.
Little is known about the most severe forms of Pneumocystis jiroveci pneumonia (PCP) in HIV-negative as compared with HIV-positive patients. Improved knowledge about the differential characteristics and management modalities could guide treatment based on HIV status.
We retrospectively compared 72 patients (73 cases, 46 HIV-positive) admitted for PCP from 1993 to 2006 in the intensive care unit (ICU) of a university hospital.
The yearly incidence of ICU admissions for PCP in HIV-negative patients increased from 1993 (0%) to 2006 (6.5%). At admission, all but one non-HIV patient were receiving corticosteroids. Twenty-three (85%) HIV-negative patients were receiving an additional immunosuppressive treatment. At admission, HIV-negative patients were significantly older than HIV-positive patients (64 [18 to 82] versus 37 [28 to 56] years old) and had a significantly higher Simplified Acute Physiology Score (SAPS) II (38 [13 to 90] versus 27 [11 to 112]) but had a similar PaO2/FiO2 (arterial partial pressure of oxygen/fraction of inspired oxygen) ratio (160 [61 to 322] versus 183 [38 to 380] mm Hg). Ventilatory support was required in a similar proportion of HIV-negative and HIV-positive cases (78% versus 61%), with a similar proportion of first-line non-invasive ventilation (NIV) (67% versus 54%). NIV failed in 71% of HIV-negative and in 13% of HIV-positive patients (p < 0.01). Mortality was significantly higher in HIV-negative than HIV-positive cases (48% versus 17%). The HIV-negative status (odds ratio 3.73, 95% confidence interval 1.10 to 12.60) and SAPS II (odds ratio 1.07, 95% confidence interval 1.02 to 1.12) were independently associated with mortality at multivariate analysis.
The yearly incidence of ICU admissions for PCP in HIV-negative patients in our unit increased from 1993 to 2006. The course of the disease and the outcome were worse in HIV-negative patients. NIV often failed in HIV-negative cases, suggesting that NIV must be watched closely in this population.
PMCID: PMC2374632  PMID: 18304356
11.  Clinical review: Interpretation of arterial pressure wave in shock states 
Critical Care  2005;9(6):601-606.
In critically ill patients monitored with an arterial catheter, the arterial pressure signal provides two types of information that may help the clinician to interpret haemodynamic status better: the mean values of systolic, diastolic, mean and pulse pressures; and the magnitude of the respiratory variation in arterial pressure in patients undergoing mechanical ventilation. In this review we briefly discuss the physiological mechanisms responsible for arterial pressure generation, with special focus on resistance, compliance and pulse wave amplification phenomena. We also emphasize the utility of taking into consideration the overall arterial pressure set (systolic, diastolic, mean and pulse pressures) in order to define haemodynamic status better. Finally, we review recent studies showing that quantification of respiratory variation in pulse and systolic arterial pressures can allow one to identify the mechanically ventilated patients who may benefit from volume resuscitation.
PMCID: PMC1414028  PMID: 16356245

Results 1-11 (11)