Alpha-2-adrenergic receptor agonists for the prevention of delirium and cognitive decline after open heart surgery (ALPHA2PREVENT): protocol for a multicentre randomised controlled trial.

INTRODUCTION: Postoperative delirium is common in older cardiac surgery patients and associated with negative short-term and long-term outcomes. The alpha-2-adrenergic receptor agonist dexmedetomidine shows promise as prophylaxis and treatment for delirium in intensive care units (ICU) and postoperative settings. Clonidine has similar pharmacological properties and can be administered both parenterally and orally. We aim to study whether repurposing of clonidine can represent a novel treatment option for delirium, and the possible effects of dexmedetomidine and clonidine on long-term cognitive trajectories, motor activity patterns and biomarkers of neuronal injury, and whether these effects are associated with frailty status. METHODS AND ANALYSIS: This five-centre, double-blind randomised controlled trial will include 900 cardiac surgery patients aged 70+ years. Participants will be randomised 1:1:1 to dexmedetomidine or clonidine or placebo. The study drug will be given as a continuous intravenous infusion from the start of cardiopulmonary bypass, at a rate of 0.4 µg/kg/hour. The infusion rate will be decreased to 0.2 µg/kg/hour postoperatively and be continued until discharge from the ICU or 24 hours postoperatively, whichever happens first.Primary end point is the 7-day cumulative incidence of postoperative delirium (Diagnostic and Statistical Manual of Mental Disorders, fifth edition). Secondary end points include the composite end point of coma, delirium or death, in addition to delirium severity and motor activity patterns, levels of circulating biomarkers of neuronal injury, cognitive function and frailty status 1 and 6 months after surgery. ETHICS AND DISSEMINATION: This trial is approved by the Regional Committee for Ethics in Medical Research in Norway (South-East Norway) and by the Norwegian Medicines Agency. Dissemination plans include publication in peer-reviewed medical journals and presentation at scientific meetings. TRIAL REGISTRATION NUMBER: NCT05029050.

Effects of experimental hypovolemia and pain on pre-ejection period and pulse transit time in healthy volunteers.

Trauma patients may suffer significant blood loss, and noninvasive methods to diagnose hypovolemia in these patients are needed. Physiologic effects of hypovolemia, aiming to maintain blood pressure, are largely mediated by increased sympathetic nervous activity. Trauma patients may however experience pain, which also increases sympathetic nervous activity, potentially confounding measures of hypovolemia. Elucidating the common and separate effects of the two stimuli on diagnostic methods is therefore important. Lower body negative pressure (LBNP) and cold pressor test (CPT) are experimental models of central hypovolemia and pain, respectively. In the present analysis, we explored the effects of LBNP and CPT on pre-ejection period and pulse transit time, aiming to further elucidate the potential use of these variables in diagnosing hypovolemia in trauma patients. We exposed healthy volunteers to four experimental sequences with hypovolemia (LBNP 60 mmHg) or normovolemia (LBNP 0 mmHg) and pain (CPT) or no pain (sham) in a 2 × 2 fashion. We calculated pre-ejection period and pulse transit time from ECG and ascending aortic blood velocity (suprasternal Doppler) and continuous noninvasive arterial pressure waveform (volume-clamp method). Fourteen subjects were available for the current analyses. This experimental study found that pre-ejection period increased with hypovolemia and remained unaltered with pain. Pulse transit time was reduced by pain and increased with hypovolemia. Thus, the direction of change in pulse transit time has the potential to distinguish hypovolemia and pain.

Respiratory variations in pulse pressure and photoplethysmographic waveform amplitude during positive expiratory pressure and continuous positive airway pressure in a model of progressive hypovolemia.

PURPOSE: Respiratory variations in pulse pressure (dPP) and photoplethysmographic waveform amplitude (dPOP) are used for evaluation of volume status in mechanically ventilated patients. Amplification of intrathoracic pressure changes may enable their use also during spontaneous breathing. We investigated the association between the degree of hypovolemia and dPP and dPOP at different levels of two commonly applied clinical interventions; positive expiratory pressure (PEP) and continuous positive airway pressure (CPAP). METHODS: 20 healthy volunteers were exposed to progressive hypovolemia by lower body negative pressure (LBNP). PEP of 0 (baseline), 5 and 10 cmH2O was applied by an expiratory resistor and CPAP of 0 (baseline), 5 and 10 cmH2O by a facemask. dPP was obtained non-invasively with the volume clamp method and dPOP from a pulse oximeter. Central venous pressure was measured in 10 subjects. Associations between changes were examined using linear mixed-effects regression models. RESULTS: dPP increased with progressive LBNP at all levels of PEP and CPAP. The LBNP-induced increase in dPP was amplified by PEP 10 cmH20. dPOP increased with progressive LBNP during PEP 5 and PEP 10, and during all levels of CPAP. There was no additional effect of the level of PEP or CPAP on dPOP. Progressive hypovolemia and increasing levels of PEP were reflected by increasing respiratory variations in CVP. CONCLUSION: dPP and dPOP reflected progressive hypovolemia in spontaneously breathing healthy volunteers during PEP and CPAP. An increase in PEP from baseline to 10 cmH2O augmented the increase in dPP, but not in dPOP.

Correction: Associations between changes in precerebral blood flow and cerebral oximetry in the lower body negative pressure model of hypovolemia in healthy volunteers.

[This corrects the article DOI: 10.1371/journal.pone.0219154.].

Volumetric and End-Tidal Capnography for the Detection of Cardiac Output Changes in Mechanically Ventilated Patients Early after Open Heart Surgery.

BACKGROUND: Exhaled carbon dioxide (CO2) reflects cardiac output (CO) provided stable ventilation and metabolism. Detecting CO changes may help distinguish hypovolemia or cardiac dysfunction from other causes of haemodynamic instability. We investigated whether CO2 measured as end-tidal concentration (EtCO2) and eliminated volume per breath (VtCO2) reflect sudden changes in cardiac output (CO). METHODS: We measured changes in CO, VtCO2, and EtCO2 during right ventricular pacing and passive leg raise in 33 ventilated patients after open heart surgery. CO was measured with oesophageal Doppler. RESULTS: During right ventricular pacing, CO was reduced by 21% (CI 18-24; p < 0.001), VtCO2 by 11% (CI 7.9-13; p < 0.001), and EtCO2 by 4.9% (CI 3.6-6.1; p < 0.001). During passive leg raise, CO increased by 21% (CI 17-24; p < 0.001), VtCO2 by 10% (CI 7.8-12; p < 0.001), and EtCO2 by 4.2% (CI 3.2-5.1; p < 0.001). Changes in VtCO2 were significantly larger than changes in EtCO2 (ventricular pacing: 11% vs. 4.9% (p < 0.001); passive leg raise: 10% vs. 4.2% (p < 0.001)). Relative changes in CO correlated with changes in VtCO2 (ρ=0.53; p=0.002) and EtCO2 (ρ=0.47; p=0.006) only during reductions in CO. When dichotomising CO changes at 15%, only EtCO2 detected a CO change as judged by area under the receiver operating characteristic curve. CONCLUSION: VtCO2 and EtCO2 reflected reductions in cardiac output, although correlations were modest. The changes in VtCO2 were larger than the changes in EtCO2, but only EtCO2 detected CO reduction as judged by receiver operating characteristic curves. The predictive ability of EtCO2 in this setting was fair. This trial is registered with NCT02070861.

Associations between changes in precerebral blood flow and cerebral oximetry in the lower body negative pressure model of hypovolemia in healthy volunteers.

Reductions in cerebral oxygen saturation (ScO2) measured by near infra-red spectroscopy have been found during compensated hypovolemia in the lower body negative pressure (LBNP)-model, which may reflect reduced cerebral blood flow. However, ScO2 may also be contaminated from extracranial (scalp) tissues, mainly supplied by the external carotid artery (ECA), and it is possible that a ScO2 reduction during hypovolemia is caused by reduced scalp, and not cerebral, blood flow. The aim of the present study was to explore the associations between blood flow in precerebral arteries and ScO2 during LBNP-induced hypovolemia. Twenty healthy volunteers were exposed to LBNP 20, 40, 60 and 80 mmHg. Blood flow in the internal carotid artery (ICA), ECA and vertebral artery (VA) was measured by Doppler ultrasound. Stroke volume for calculating cardiac output was measured by suprasternal Doppler. Associations of changes within subjects were examined using linear mixed-effects regression models. LBNP reduced cardiac output, ScO2 and ICA and ECA blood flow. Changes in flow in both ICA and ECA were associated with changes in ScO2 and cardiac output. Flow in the VA did not change during LBNP and changes in VA flow were not associated with changes in ScO2 or cardiac output. During experimental compensated hypovolemia in healthy, conscious subjects, a reduced ScO2 may thus reflect a reduction in both cerebral and extracranial blood flow.

Impact of Norepinephrine on Regional Cerebral Oxygenation During Cardiopulmonary Bypass.

OBJECTIVES: Norepinephrine is used to increase mean arterial pressure during cardiopulmonary bypass. However, it has been suggested that norepinephrine could constrict cerebral arteries, reducing cerebral blood flow. The aim of this study, therefore, was to explore whether there was an association between doses of norepinephrine to maintain mean arterial pressure at ≈80 mmHg during cardiopulmonary bypass and cerebral oxygen saturation measured using near-infrared spectroscopy. DESIGN: Observational study. SETTING: University hospital. PARTICIPANTS: Patients undergoing cardiac surgery (n = 45) using cardiopulmonary bypass. INTERVENTIONS: Norepinephrine was administered to maintain mean arterial pressure ≈80 mmHg during cardiopulmonary bypass. MEASUREMENTS AND MAIN RESULTS: From initiation of cardiopulmonary bypass to removal of the aortic cross-clamp, norepinephrine dose, mean arterial pressure, partial pressure of arterial carbon dioxide, partial pressure of arterial oxygen, hemoglobin, and pump flow values were averaged over 1 minute, giving a total of 3,460 data points entered as covariates in a linear mixed model for repeated measurements, with cerebral oxygen saturation measured using near-infrared spectroscopy as outcome. There was no statistically significant association between norepinephrine dose to maintain mean arterial pressure and cerebral oxygen saturation (p = 0.46) in this model. CONCLUSIONS: Administration of norepinephrine to maintain mean arterial pressure ≈80 mmHg during cardiopulmonary bypass was not associated with statistically significant changes in cerebral oxygen saturation. These results indicated that norepinephrine could be used to increase mean arterial pressure during cardiopulmonary bypass without reducing cerebral oxygen saturation.

Respiratory variations in the photoplethysmographic waveform amplitude depend on type of pulse oximetry device.

Respiratory variations in the photoplethysmographic waveform amplitude predict fluid responsiveness under certain conditions. Processing of the photoplethysmographic signal may vary between different devices, and may affect respiratory amplitude variations calculated by the standard formula. The aim of the present analysis was to explore agreement between respiratory amplitude variations calculated using photoplethysmographic waveforms available from two different pulse oximeters. Analysis of registrations before and after fluid loads performed before and after open-heart surgery (aortic valve replacement and/or coronary artery bypass grafting) with patients on controlled mechanical ventilation. Photoplethysmographic (Nellcor and Masimo pulse oximeters) and arterial pressure waveforms were recorded. Amplitude variations induced by ventilation were calculated and averaged over ten respiratory cycles. Agreements for absolute values are presented in scatterplots (with least median square regression through the origin, LMSO) and Bland-Altman plots. Agreement for trending presented in a four-quadrant plot. Agreement between respiratory photoplethysmographic amplitude variations from the two pulse oximeters was poor with LMSO ΔPOPNellc = 1.5 × ΔPOPMas and bias ± limits of agreement 7.4 ± 23 %. Concordance rate with a fluid load was 91 %. Agreement between respiratory variations in the photoplethysmographic waveform amplitude calculated from the available signals output by two different pulse oximeters was poor, both evaluated by LMSO and Bland-Altman plot. Respiratory amplitude variations from the available signals output by these two pulse oximeters are not interchangeable.

Agreement between stroke volume measured by oesophageal Doppler and uncalibrated pulse contour analysis during fluid loads in severe aortic stenosis.

The purpose of this analysis was to study agreement and trending of stroke volume measured by oesophageal Doppler and 3rd generation Vigileo during fluid loads in patients with severe aortic stenosis. Observational study in 32 patients (30 analyzed) scheduled for aortic valve replacement due to severe aortic stenosis. After induction of anesthesia and before start of surgery, hemodynamic registrations for 1 min were obtained before and after a fluid load. Agreement between stroke volume measured by oesophageal Doppler (SVOD) and Vigileo (SVVig) was evaluated in Bland-Altman plot and trending in four-quadrant and polar plots. Bias ± limits of agreement (LOA) between SVOD and SVVig was 24 ± 37 ml (percentage error 45%). Concordance of the two methods from before to after a fluid load was 100%. Angular bias ± LOA was 12° ± 28°. Absolute values of SVOD and SVVig agreed poorly, but changes were highly concordant during fluid loads in aortic stenosis patients. The angular agreement indicated acceptable trending. The two measurement methods are not interchangeable in patients with aortic stenosis.

Respiratory Variations in Pulse Pressure Reflect Central Hypovolemia during Noninvasive Positive Pressure Ventilation.

Background. Correct volume management is essential in patients with respiratory failure. We investigated the ability of respiratory variations in noninvasive pulse pressure (ΔPP), photoplethysmographic waveform amplitude (ΔPOP), and pleth variability index (PVI) to reflect hypovolemia during noninvasive positive pressure ventilation by inducing hypovolemia with progressive lower body negative pressure (LBNP). Methods. Fourteen volunteers underwent LBNP of 0, -20, -40, -60, and -80 mmHg for 4.5 min at each level or until presyncope. The procedure was repeated with noninvasive positive pressure ventilation. We measured stroke volume (suprasternal Doppler), ΔPP (Finapres), ΔPOP, and PVI and assessed their association with LBNP-level using linear mixed model regression analyses. Results. Stroke volume decreased with each pressure level (-11.2 mL, 95% CI -11.8, -9.6, P < 0.001), with an additional effect of noninvasive positive pressure ventilation (-3.0 mL, 95% CI -8.5, -1.3, P = 0.009). ΔPP increased for each LBNP-level (1.2%, 95% CI 0.5, 1.8, P < 0.001) and almost doubled during noninvasive positive pressure ventilation (additional increase 1.0%, 95% CI 0.1, 1.9, P = 0.003). Neither ΔPOP nor PVI was significantly associated with LBNP-level. Conclusions. During noninvasive positive pressure ventilation, preload changes were reflected by ΔPP but not by ΔPOP or PVI. This implies that ΔPP may be used to assess volume status during noninvasive positive pressure ventilation.

Poor agreement between respiratory variations in pulse oximetry photoplethysmographic waveform amplitude and pulse pressure in intensive care unit patients.

BACKGROUND: To identify fluid responsiveness, a correlation between respiratory variations in pulse pressure (DeltaPP) and respiratory variations in pulse oximetry photoplethysmographic waveform amplitude (DeltaPOP) in mechanically ventilated patients has been demonstrated. To evaluate the agreement between the two methods, knowledge about the repeatability of the methods is imperative. However, no such data exist. Based on knowledge of slow oscillation in skin blood flow, the authors hypothesized that the variability of DeltaPOP would be larger than that of DeltaPP when calculations were performed continuously over a long recording period. METHODS: Respiration, continuous invasive blood pressure, pulse oximetry, and skin microcirculation were recorded in 14 mechanically ventilated intensive care unit patients. No intravenous fluid challenges were given, and no other interventions were performed during the measurements. Seventy consecutive comparisons between DeltaPP and DeltaPOP were calculated for each of the 14 patients. RESULTS: For all patients, DeltaPOP was 13.7 +/- 5.8% and DeltaPP was 5.8 +/- 2.6% (P < 0.001). There was a larger intraindividual (8.94 vs. 1.29; P < 0.001) and interindividual (26.01 vs. 5.57; P < 0.001) variance of DeltaPOP than of DeltaPP. In six patients, there was no significant correlation between DeltaPP and DeltaPOP. A Bland-Altman plot showed poor agreement between the two methods. CONCLUSION: A large variability of DeltaPOP and a poor agreement between DeltaPP and DeltaPOP limits DeltaPOP as a tool for evaluation of fluid responsiveness in intensive care unit patients. This is in contrast to DeltaPP, which shows a small variability.

The effects of general anesthesia on human skin microcirculation evaluated by wavelet transform.

BACKGROUND: Time-frequency analysis of the laser Doppler flowmetry signal, using wavelet transform, shows periodic oscillations at five characteristic frequencies related to the heart (0.6-2 Hz), respiration (0.15-0.6 Hz), myogenic activity in the vessel wall (0.052-0.15 Hz), sympathetic activity (0.021-0.052 Hz), and very slow oscillations (0.0095-0.021), which can be modulated by the endothelium-dependent vasodilator acetylcholine. We hypothesized that wavelet transform of laser Doppler flowmetry signals could detect changes in the microcirculation induced by general anesthesia, such as alterations in vasomotion and sympathetic activity. METHODS: Eleven patients undergoing faciomaxillary surgery were included. Skin microcirculation was measured on the lower forearm with laser Doppler flowmetry and iontophoresis with acetylcholine and sodium nitroprusside before and during general anesthesia with propofol, fentanyl, and midazolam. The laser Doppler flowmetry signals were analyzed using wavelet transform. RESULTS: There were significant reductions in spectral amplitudes in the 0.0095-0.021 (P < 0.01), the 0.021-0.052 (P < 0.001), and the 0.052-0.15 Hz frequency interval (P < 0.01) and a significant increase in the 0.15-0.6 Hz frequency interval. General anesthesia had no effect on the difference between acetylcholine and sodium nitroprusside on relative amplitudes in the 0.0095-0.021 Hz frequency interval (P < 0.001). CONCLUSION: General anesthesia reduces the oscillatory components of the perfusion signal related to sympathetic, myogenic activity and the component modulated by the endothelium. However, the iontophoretic data did not reveal a specific effect on the endothelium. The increase in the 0.15-0.6 Hz interval is related to the effect of mechanical ventilation.

Low-frequency oscillations of the laser Doppler perfusion signal in human skin.

Spectral analysis of the laser Doppler flow (LDF) signal in the frequency interval from 0.0095-2.0 Hz reveals blood flow oscillations with frequencies around 1.0, 0.3, 0.1, 0.04 and 0.01 Hz. The heartbeat, the respiration, the intrinsic myogenic activity of vascular smooth muscle, the neurogenic activity of the vessel wall and the vascular endothelium influence these oscillations, respectively. The first aim of this study was to investigate if a slow oscillatory component could be detected in the frequency area below 0.0095 Hz of the human cutaneous blood perfusion signal. Unstimulated basal blood skin perfusion and enhanced perfusion during iontophoresis with the endothelium-dependent vasodilator acetylcholine (ACh) and the endothelium-independent vasodilator sodium nitroprusside (SNP) were measured in healthy male volunteers and the wavelet transform was computed. A low-frequency oscillation between 0.005 and 0.0095 Hz was found both during basal conditions and during iontophoresis with ACh and SNP. Iontophoresis with ACh increased the normalized amplitude to a greater extent than SNP (P = 0.001) indicating modulation by the vascular endothelium. To gain further insight into the mechanisms for this endothelium dependency, we inhibited nitric oxide (NO) synthesis with N(G)-monomethyl-L-arginine (L-NMMA) and prostaglandin (PG) synthesis by aspirin. L-NMMA did not affect the increased response to ACh vs. SNP iontophoresis in the 0.005-0.0095-Hz interval (P = 0.006) but abolished the difference in the 0.0095-0.021-Hz interval (P = 0.97). Aspirin did not affect the difference in response to ACh and SNP in either of the two frequency intervals. Thus, other endothelial mechanisms, such as endothelium-derived hyperpolarizing factor (EDHF), might be involved in the regulation of this sixth frequency interval (0.005-0.0095 Hz).

[Heroin-induced pulmonary oedema]. / Heroinindusert lungeødem.

BACKGROUND: Heroin-induced pulmonary oedema is an infrequent complication to a heroin overdose; the incidence in Norway is unknown. MATERIAL AND METHODS: One case is presented and pathophysiology, diagnosis and treatment are discussed. RESULTS: Pulmonary oedema caused by the use of heroin may develop immediately or usually up to 1-2 hours after exposure. The symptoms usually resolve with supportive treatment within 1 or 2 days. Some patients require mechanical ventilation. The pathophysiology includes a rapid capillary leakage of unknown aetiology. INTERPRETATION: Heroin use is widespread in Norway, and users are found all over the country. There are important differences between cardiogenic and heroin-induced pulmonary oedema regarding pathophysiology and treatment.