The effect of fluid bolus administration on cerebral tissue oxygenation in post-cardiac arrest patients.

PURPOSE: Fluid boluses (FB) are often used in post-cardiac arrest (CA) patients with haemodynamic instability. Although FB may improve cardiac output (CO) and mean arterial pressure (MAP), FB may also increase central venous pressure (CVP), reduce arterial PaO2, dilute haemoglobin and cause interstitial oedema. The aim of the present study was to investigate the net effect of FB administration on cerebral tissue oxygenation saturation (SctO2) in post-CA patients. METHODS: Pre-planned sub-study of the Neuroprotect post-CA trial (NCT02541591). Patients with anticipated fluid responsiveness based on stroke volume variation (SVV) or passive leg raising test were administered a FB of 500 ml plasma-lyte A (Baxter Healthcare) and underwent pre- and post-FB assessments of stroke volume, CO, MAP, CVP, haemoglobin, PaO2 and SctO2. RESULTS: 52 patients (mean age 64 ±â€¯12 years, 75% male) received a total of 115 FB. Although administration of a FB resulted in a significant increase of stroke volume (63 ±â€¯22 vs 67 ±â€¯23 mL, p = 0.001), CO (4,2 ±â€¯1,6 vs 4,4 ±â€¯1,7 L/min, p = 0.001) and MAP (74,8 ±â€¯13,2 vs 79,2 ±â€¯12,9 mmHg, p = 0.004), it did not improve SctO2 (68.54 ±â€¯6.99 vs 68.70 ±â€¯6.80%, p = 0.49). Fluid bolus administration also resulted in a significant increase of CVP (10,0 ±â€¯4,5 vs 10,7 ±â€¯4,9 mmHg, p = 0.02), but did not affect PaO2 (99 ±â€¯31 vs 94 ±â€¯31 mmHg, p = 0.15) or haemoglobin concentrations (12,9 ±â€¯2,1 vs 12,8 ±â€¯2,2 g/dL, p = 0.10). In a multivariate model, FB-induced changes in CO (beta 0,77; p = 0.004) and in CVP (beta -0,23; p = 0.02) but not in MAP (beta 0,02; p = 0.18) predicted post-FB ΔSctO2. CONCLUSIONS: Despite improvements in CO and MAP, FB administration did not improve SctO2 in post-cardiac arrest patients.

The impact of global hemodynamics, oxygen and carbon dioxide on epileptiform EEG activity in comatose survivors of out-of-hospital cardiac arrest.

AIM: To study the association between global hemodynamics, blood gases, epileptiform EEG activity and survival after out-of-hospital CA (0HCA). METHODS: We retrospectively analyzed 195 comatose post-CA patients. At least one EEG recording per patient was evaluated to diagnose epileptiform EEG activity. Refractory epileptiform EEG activity was defined as persisting epileptic activity on EEG despite the use of 2 or more anti-epileptics. The time weighted average mean arterial pressure 48h (TWA-MAP48), the percentage of time with a MAP below 65 and above 85mmHg and the percentage of time with normoxia, hypoxia (<70mmHg), hyperoxia (>150mmHg), normocapnia, hypocapnia (<35mmHg) and hypercapnia (>45mmHg) were calculated. RESULTS: We observed epileptiform EEG activity in 57 patients (29%). A shockable rhythm was associated with a decreased likelihood of epileptic activity on the EEG (OR: 0.41, 95%CI 0.22-0.79). We did not identify an association between the TWA-MAP48, the percentage of time with MAP below 65mmHg or above 85mmHg, blood gas variables and the risk of post-CA epileptiform EEG activity. The presence of epileptiform activity decreased the likelihood of survival independently (OR: 0.10, 95% CI: 0.04-0.24). Interestingly, survival rates of patients in whom the epileptiform EEG resolved (n=20), were similar compared to patients without epileptiform activity on EEG (60% vs 67%,p=0.617). Other independent predictors of survival were presence of basic life support (BLS) (OR:5.08, 95% CI 1.98-13.98), presence of a shockable rhythm (OR: 7.03, 95% CI: 3.18-16.55), average PaO2 (OR=0.93, CI 95% 0.90-0.96) and% time MAP<65mmHg (OR: 0.96, CI 95% 0.94-0.98). CONCLUSION: Epileptiform EEG activity in post-CA patients is independently and inversely associated with survival and this effect is mainly driven by patients in whom this pattern is refractory over time despite treatment with anti-epileptic drugs. We did not identify an association between hemodynamic factors, blood gas variables and epileptiform EEG activity after CA, although both hypotension, hypoxia and epileptic EEG activity were predictors of survival.

Low hemoglobin levels are associated with lower cerebral saturations and poor outcome after cardiac arrest.

PURPOSE: Post-cardiac arrest (CA) patients have a large cerebral penumbra at risk for secondary ischemic damage in case of suboptimal brain oxygenation during ICU stay. The aims of this study were to investigate the association between hemoglobin, cerebral oxygenation (SctO2) and outcome in post-CA patients. METHODS: Prospective observational study in 82 post-CA patients. Hemoglobin, a corresponding SctO2 measured by NIRS and SVO2 in patients with a pulmonary artery catheter (n=62) were determined hourly during hypothermia in the first 24h of ICU stay. RESULTS: We found a strong linear relationship between hemoglobin and mean SctO2 (SctO2=0.70×hemoglobin+56 (R(2) 0.84, p=10(-6))). Hemoglobin levels below 10g/dl generally resulted in lower brain oxygenation. There was a significant association between good neurological outcome (43/82 patients in CPC 1-2 at 180 days post-CA) and admission hemoglobin above 13g/dl (OR 2.76, 95% CI 1.09:7.00, p=0.03) or mean hemoglobin above 12.3g/dl (OR 2.88, 95%CI 1.02:8.16, p=0.04). This association was entirely driven by results obtained in patients with a mean SVO2 below 70% (OR 6.25, 95%CI 1.33:29.43, p=0.01) and a mean SctO2 below 62.5% (OR 5.87, 95%CI 1.08:32.00, p=0.03). CONCLUSION: Hemoglobin levels below 10g/dl generally resulted in lower cerebral oxygenation. Average hemoglobin levels below 12.3g/dl were associated with worse outcome in patients with suboptimal SVO2 or SctO2. The safety of a universal restrictive transfusion threshold of 7g/dl can be questioned in post-CA patients.

Hemodynamic targets during therapeutic hypothermia after cardiac arrest: A prospective observational study.

AIM: In analogy with sepsis, current post-cardiac arrest (CA) guidelines recommend to target mean arterial pressure (MAP) above 65 mmHg and SVO2 above 70%. This is unsupported by mortality or cerebral perfusion data. The aim of this study was to explore the associations between MAP, SVO2, cerebral oxygenation and survival. METHODS: Prospective, observational study during therapeutic hypothermia (24h - 33 °C) in 82 post-CA patients monitored with near-infrared spectroscopy. RESULTS: Forty-three patients (52%) survived in CPC 1-2 until 180 days post-CA. The mean MAP range associated with maximal survival was 76-86 mmHg (OR 2.63, 95%CI [1.01; 6.88], p = 0.04). The mean SVO2 range associated with maximal survival was 67-72% (OR 8.23, 95%CI [2.07; 32.68], p = 0.001). In two separate multivariate models, a mean MAP (OR 3.72, 95% CI [1.11; 12.50], p=0.03) and a mean SVO2 (OR 10.32, 95% CI [2.03; 52.60], p = 0.001) in the optimal range persisted as independently associated with increased survival. Based on more than 1625000 data points, we found a strong linear relation between SVO2 (range 40-90%) and average cerebral saturation (R(2) 0.86) and between MAP and average cerebral saturation for MAP's between 45 and 101 mmHg (R(2) 0.83). Based on our hemodynamic model, the MAP and SVO2 ranges associated with optimal cerebral oxygenation were determined to be 87-101 mmHg and 70-75%. CONCLUSION: we showed that a MAP range between 76-86 mmHg and SVO2 range between 67% and 72% were associated with maximal survival. Optimal cerebral saturation was achieved with a MAP between 87-101 mmHg and a SVO2 between 70% and 75%. Prospective interventional studies are needed to investigate whether forcing MAP and SVO2 in the suggested range with additional pharmacological support would improve outcome.

An observational near-infrared spectroscopy study on cerebral autoregulation in post-cardiac arrest patients: time to drop 'one-size-fits-all' hemodynamic targets?

AIMS: A subgroup of patients with ROSC after cardiac arrest (CA) with disturbed cerebral autoregulation might benefit from higher mean arterial pressures (MAP). We aimed to (1) phenotype patients with disturbed autoregulation, (2) investigate whether these patients have a worse prognosis, (3) define an individual optimal MAP per patient and (4) investigate whether time under this individual optimal MAP is associated with outcome. METHODS: Prospective observational study in 51 post-CA patients monitored with near infrared spectroscopy. RESULTS: (1) 18/51 patients (35%) had disturbed autoregulation. Phenotypically, a higher proportion of patients with disturbed autoregulation had pre-CA hypertension (31±47 vs. 65±49%, p=0.02) suggesting that right shifting of autoregulation is caused by chronic adaptation of cerebral blood flow to higher blood pressures. (2) In multivariate analysis, patients with preserved autoregulation (n=33, 65%) had a significant higher 180-days survival rate (OR 4.62, 95% CI [1.06:20.06], p=0.04]. Based on an index of autoregulation (COX), the average COX-predicted optimal MAP was 85 mmHg in patients with preserved and 100 mmHg in patients with disturbed autoregulation. (3) An individual optimal MAP could be determined in 33/51 patients. (4) The time under the individual optimal MAP was negatively associated with survival (OR 0.97, 95% CI [0.96:0.99], p=0.02). The time under previously proposed fixed targets (65, 70, 75, 80 mmHg) was not associated with a differential survival rate. CONCLUSION: Cerebral autoregulation showed to be disturbed in 35% of post-CA patients of which a majority had pre-CA hypertension. Disturbed cerebral autoregulation within the first 24h after CA is associated with a worse outcome. In contrast to uniform MAP goals, the time spent under a patient tailored optimal MAP, based on an index of autoregulation, was negatively associated with survival.

Accuracy of continuous thermodilution cardiac output monitoring by pulmonary artery catheter during therapeutic hypothermia in post-cardiac arrest patients.

PURPOSE: Thermodilution continuous cardiac output measurements (TDCCO) by pulmonary artery catheter (PAC) have not been validated during therapeutic hypothermia in post-cardiac arrest patients. The calculated cardiac output based on the indirect Fick principle (FCO) using pulmonary artery blood gas mixed venous oxygen saturation (FCO-BG-SvO2) is considered as the gold standard. Continuous SvO2 by PAC (PAC-SvO2) has also not been validated previously during hypothermia. The aims of this study were (1) to compare FCO-BG-SvO2 with TDCCO, (2) to compare PAC-SvO2 with BG-SvO2 and finally (3) to compare FCO with SvO2 obtained via PAC or blood gas. METHODS: We analyzed 102 paired TDCCO/FCO-BG-SvO2 and 88 paired BG-SvO2/PAC-SvO2 measurements in 32 post-cardiac arrest patients during therapeutic hypothermia. RESULTS: TDCCO was significantly although poorly correlated with FCO-BG-SvO2 (R2 0.21, p<0.01) without systematic bias (-0.15±1.76 l/min). Analysis according to Bland and Altman however showed broad limits of agreement ([-3.61; 3.45] l/min) and an unacceptable high percentage error (105%). None of the criteria for clinical interchangeability were met. Concordance analysis showed that TDCCO had limited trending ability (R2 0.03). FCO based on PAC-SvO2 was highly correlated with FCO-BG-SvO2 (R2 0.72) with a small bias (-0.08±0.72 l/min) and slightly too high percentage error (44%). CONCLUSION: Our results show an extreme inaccuracy of TDCCO by PAC in post-cardiac arrest patients during therapeutic hypothermia. We found a reasonable correlation between BG-SvO2 and PAC-SvO2 and subsequently between FCO calculated with SvO2 obtained either via blood gas or PAC. The decision to start or titrate inotropics should therefore not be guided by TDCCO in this setting.

Validation study of Nexfin® continuous non-invasive blood pressure monitoring in critically ill adult patients.

BACKGROUND: Nexfin® (BMEYE, Amsterdam, The Netherlands) is a totally non-invasive blood pressure and cardiac output (CO) monitor based on finger arterial pulse contour analysis. METHODS: We performed an open observational study in a mix of medical-surgical-burns critically ill patients (N.=45) to validate Nexfin obtained blood pressures (MAPnex) against PiCCO (MAPfem) derived blood pressure measurements. MAPnex, MAPfem and corresponding systolic (SBP) and diastolic (DBP) blood pressures were measured continuously and registered with a 2 hour interval during the 8-hour study period. Statistical analysis was performed by Pearson regression, Bland and Altman, Concordance plot and Polar plot analysis. RESULTS: MAPnex shows excellent correlation with MAPfem (R² 0.88, mean bias ± LA -2.3±12.4 mmHg, 14.7% error) and may be used interchangeably with invasive monitoring. The excellent MAPnex -MAPfem correlation was preserved in subgroup analysis for patients with severe hypotension, high systemic vascular resistance, low CO, hypothermia and in patients supported by inotropic/vasopressive agents. MAPnex is able to follow changes in MAPfem during the same time interval (level of concordance 85.5%). Nexfin SBP and DBP show significant correlation with PiCCO but the criteria for interchangeability were not met. Finally, polar plot analysis showed that trending capabilities were excellent when changes in MAPnex (ΔMAPnex) were compared to ΔMAPfem (96.1% of changes were within the level of 10% limits of agreement). CONCLUSION: In this sample of critically ill patients we found a good correlation between MAPnex and invasive blood pressures obtained by PiCCO.

Liver transplantation in a patient with an intraabdominally located left ventricular assist device: surgical aspects--case report.

The presence of a cardiac assist device in a liver transplantation candidate should not be considered to be an absolute contraindication to transplantation. In this first case report of liver transplantation in a patient with an intraabdominally located left ventricular assist device, we have described the surgical aspects and discussed the timing of the liver transplantation and the removal of the left ventricular assist device.

Endocannabinoid control of gastric sensorimotor function in man.

BACKGROUND: Little is known about the physiological role of the endocannabinoid system in the regulation of the motility and the sensitivity of the stomach. Endocannabinoid system dysfunction has been hypothesized to contribute to the control of food intake and the pathogenesis of functional dyspepsia. AIM: To study the influence of rimonabant, the endocannabinoid 1 (CB1) receptor antagonist, on gastric sensorimotor function in healthy controls. METHODS: After 4 days of pre-treatment with rimonabant 20 mg/day or placebo, 12 healthy volunteers (mean age 34 +/- 12 years, six men) participated in a placebo-controlled, double-blind, randomized, crossover study with a gastric barostat assessment of gastric sensitivity to distension, gastric compliance, gastric accommodation and phasic motility on day 3 and a liquid nutrient challenge test on day 4. RESULTS: Rimonabant did not influence gastric compliance and sensitivity to distension. The meal-induced gastric accommodation reflex was significantly inhibited by rimonabant (154.3 +/- 30.9 vs. 64.3 +/- 32.4 mL, P = 0.02). Rimonabant did not affect maximal nutrient tolerance or meal-related symptoms during the satiety drinking test. CONCLUSION: Endocannabinoids acting on the CB1 receptor are involved in the control of gastric accommodation in man.

Cannabinoid receptor 1 signalling dampens activity and mitochondrial transport in networks of enteric neurones.

Cannabinoid (CB) receptors are expressed in the enteric nervous system (ENS) and CB(1) receptor activity slows down motility and delays gastric emptying. This receptor system has become an important target for GI-related drug development such as in obesity treatment. The aim of the study was to investigate how CB(1) ligands and antagonists affect ongoing activity in enteric neurone networks, modulate synaptic vesicle cycling and influence mitochondrial transport in nerve processes. Primary cultures of guinea-pig myenteric neurones were loaded with different fluorescent markers: Fluo-4 to measure network activity, FM1-43 to image synaptic vesicles and Mitotracker green to label mitochondria. Synaptic vesicle cluster density was assessed by immunohistochemistry and expression of CB(1) receptors was confirmed by RT-PCR. Spontaneous network activity, displayed by both excitatory and inhibitory neurones, was significantly increased by CB(1) receptor antagonists (AM-251 and SR141716), abolished by CB(1) activation (methanandamide, mAEA) and reduced by two different inhibitors (arachidonylamide serotonin, AA-5HT and URB597) of fatty acid amide hydrolase. Antagonists reduced the number of synaptic vesicles that were recycled during an electrical stimulus. CB(1) agonists (mAEA and WIN55,212) reduced and antagonists enhanced the fraction of transported mitochondria in enteric nerve fibres. We found immunohistochemical evidence for an enhancement of synaptophysin-positive release sites with SR141716, while WIN55,212 caused a reduction. The opposite effects of agonists and antagonists suggest that enteric nerve signalling is under the permanent control of CB(1) receptor activity. Using inhibitors of the endocannabinoid degrading enzyme, we were able to show there is endogenous production of a CB ligand in the ENS.