New Hemodynamic Parameters in Peri-Operative and Critical Care-Challenges in Translation.

Hemodynamic monitoring technologies are evolving continuously-a large number of bedside monitoring options are becoming available in the clinic. Methods such as echocardiography, electrical bioimpedance, and calibrated/uncalibrated analysis of pulse contours are becoming increasingly common. This is leading to a decline in the use of highly invasive monitoring and allowing for safer, more accurate, and continuous measurements. The new devices mainly aim to monitor the well-known hemodynamic variables (e.g., novel pulse contour, bioreactance methods are aimed at measuring widely-used variables such as blood pressure, cardiac output). Even though hemodynamic monitoring is now safer and more accurate, a number of issues remain due to the limited amount of information available for diagnosis and treatment. Extensive work is being carried out in order to allow for more hemodynamic parameters to be measured in the clinic. In this review, we identify and discuss the main sensing strategies aimed at obtaining a more complete picture of the hemodynamic status of a patient, namely: (i) measurement of the circulatory system response to a defined stimulus; (ii) measurement of the microcirculation; (iii) technologies for assessing dynamic vascular mechanisms; and (iv) machine learning methods. By analyzing these four main research strategies, we aim to convey the key aspects, challenges, and clinical value of measuring novel hemodynamic parameters in critical care.

Implementation of an automated early warning scoring system in a surgical ward: Practical use and effects on patient outcomes.

INTRODUCTION: Early warning scores (EWS) are being increasingly embedded in hospitals over the world due to their promise to reduce adverse events and improve the outcomes of clinical patients. The aim of this study was to evaluate the clinical use of an automated modified EWS (MEWS) for patients after surgery. METHODS: This study conducted retrospective before-and-after comparative analysis of non-automated and automated MEWS for patients admitted to the surgical high-dependency unit in a tertiary hospital. Operational outcomes included number of recorded assessments of the individual MEWS elements, number of complete MEWS assessments, as well as adherence rate to related protocols. Clinical outcomes included hospital length of stay, in-hospital and 28-day mortality, and ICU readmission rate. RESULTS: Recordings in the electronic medical record from the control period contained 7929 assessments of MEWS elements and were performed in 320 patients. Recordings from the intervention period contained 8781 assessments of MEWS elements in 273 patients, of which 3418 were performed with the automated EWS system. During the control period, 199 (2.5%) complete MEWS were recorded versus 3991 (45.5%) during intervention period. With the automated MEWS systems, the percentage of missing assessments and the time until the next assessment for patients with a MEWS of ≥2 decreased significantly. The protocol adherence improved from 1.1% during the control period to 25.4% when the automated MEWS system was involved. There were no significant differences in clinical outcomes. CONCLUSION: Implementation of an automated EWS system on a surgical high dependency unit improves the number of complete MEWS assessments, registered vital signs, and adherence to the EWS hospital protocol. However, this positive effect did not translate into a significant decrease in mortality, hospital length of stay, or ICU readmissions. Future research and development on automated EWS systems should focus on data management and technology interoperability.

Finger and forehead photoplethysmography-derived pulse-pressure variation and the benefits of baseline correction.

To non-invasively predict fluid responsiveness, respiration-induced pulse amplitude variation (PAV) in the photoplethysmographic (PPG) signal has been proposed as an alternative to pulse pressure variation (PPV) in the arterial blood pressure (ABP) signal. However, it is still unclear how the performance of the PPG-derived PAV is site-dependent during surgery. The aim of this study is to compare finger- and forehead-PPG derived PAV in their ability to approach the value and trend of ABP-derived PPV. Furthermore, this study investigates four potential confounding factors, (1) baseline variation, (2) PPV, (3) ratio of respiration and heart rate, and (4) perfusion index, which might affect the agreement between PPV and PAV. In this work, ABP, finger PPG, and forehead PPG were continuously recorded in 29 patients undergoing major surgery in the operating room. A total of 91.2 h data were used for analysis, from which PAV and PPV were calculated and compared. We analyzed the impact of the four factors using a multiple linear regression (MLR) analysis. The results show that compared with the ABP-derived PPV, finger-derived PAV had an agreement of 3.2 ± 5.1%, whereas forehead-PAV had an agreement of 12.0 ± 9.1%. From the MLR analysis, we found that baseline variation was a factor significantly affecting the agreement between PPV and PAV. After correcting for respiration-induced baseline variation, the agreements for finger- and forehead-derived PAV were improved to reach an agreement of - 1.2 ± 3.8% and 3.3 ± 4.8%, respectively. To conclude, finger-derived PAV showed better agreement with ABP-derived PPV compared to forehead-derived PAV. Baseline variation was a factor that significantly affected the agreement between PPV and PAV. By correcting for the baseline variation, improved agreements were obtained for both the finger and forehead, and the difference between these two agreements was diminished. The tracking abilities for both finger- and forehead-derived PAV still warrant improvement for wide use in clinical practice. Overall, our results show that baseline-corrected finger- and forehead-derived PAV may provide a non-invasive alternative for PPV.

Exogenous hydrogen sulfide gas does not induce hypothermia in normoxic mice.

Hydrogen sulfide (H2S, 80 ppm) gas in an atmosphere of 17.5% oxygen reportedly induces suspended animation in mice; a state analogous to hibernation that entails hypothermia and hypometabolism. However, exogenous H2S in combination with 17.5% oxygen is able to induce hypoxia, which in itself is a trigger of hypometabolism/hypothermia. Using non-invasive thermographic imaging, we demonstrated that mice exposed to hypoxia (5% oxygen) reduce their body temperature to ambient temperature. In contrast, animals exposed to 80 ppm H2S under normoxic conditions did not exhibit a reduction in body temperature compared to normoxic controls. In conclusion, mice induce hypothermia in response to hypoxia but not H2S gas, which contradicts the reported findings and putative contentions.

A review of recent advances in data analytics for post-operative patient deterioration detection.

Most deaths occurring due to a surgical intervention happen postoperatively rather than during surgery. The current standard of care in many hospitals cannot fully cope with detecting and addressing post-surgical deterioration in time. For millions of patients, this deterioration is left unnoticed, leading to increased mortality and morbidity. Postoperative deterioration detection currently relies on general scores that are not fully able to cater for the complex post-operative physiology of surgical patients. In the last decade however, advanced risk and warning scoring techniques have started to show encouraging results in terms of using the large amount of data available peri-operatively to improve postoperative deterioration detection. Relevant literature has been carefully surveyed to provide a summary of the most promising approaches as well as how they have been deployed in the perioperative domain. This work also aims to highlight the opportunities that lie in personalizing the models developed for patient deterioration for these particular post-surgical patients and make the output more actionable. The integration of pre- and intra-operative data, e.g. comorbidities, vitals, lab data, and information about the procedure performed, in post-operative early warning algorithms would lead to more contextualized, personalized, and adaptive patient modelling. This, combined with careful integration in the clinical workflow, would result in improved clinical decision support and better post-surgical care outcomes.

On algorithms for calculating arterial pulse pressure variation during major surgery.

OBJECTIVE: Arterial pulse pressure variation (PPV) is widely used for predicting fluid responsiveness and supporting fluid management in the operating room and intensive care unit. Available PPV algorithms have been typically validated for fluid responsiveness during episodes of hemodynamic stability. Yet, little is known about the performance of PPV algorithms during surgery, where fast changes of the blood pressure may affect the robustness of the presented PPV value. This work provides a comprehensive understanding of how various existing algorithmic designs affect the robustness of the presented PPV value during surgery, and proposes additional processing for the pulse pressure signal before calculating PPV. APPROACH: We recorded arterial blood pressure waveforms from 23 patients undergoing major abdominal surgery. To evaluate the performance, we designed three clinically relevant metrics. Main results and Significance: The results show that all algorithms performed well during episodes of hemodynamic stability. Moreover, it is demonstrated that the proposed processing helps improve the robustness of PPV during the entire course of surgery.

Scavenging reactive oxygen species using tempol in the acute phase of renal ischemia/reperfusion and its effects on kidney oxygenation and nitric oxide levels.

BACKGROUND: Renal ischemia/reperfusion (I/R) injury is commonly seen in kidney transplantation and affects the allograft survival rates. We aimed to test our hypothesis that scavenging reactive oxygen species (ROS) with tempol would protect renal oxygenation and nitric oxide (NO) levels in the acute phase of renal I/R. METHODS: Rats were randomly divided: (1) no I/R, no tempol; (2) no I/R, but with tempol; (3) I/R without tempol; and (4) I/R with tempol. I/R was induced by 30-min clamping of the renal artery. Tempol (200 µmol/kg/h/i.v) was administered 15 min prior to I/R. RESULTS: I/R without tempol led to a significant decrease in renal oxygen delivery and microvascular oxygenation. Tempol, however, protected renal oxygenation after I/R. At R90, the creatinine clearance rate was lower in the I/R-subjected group that did not receive tempol compared to that in the other groups. I/R injury without tempol treatment led to a significant increase in tissue malondialdehyde levels and a significant decrease in tissue NO levels. Tempol administration before I/R could prevent oxidative stress and altered tissue NO levels. CONCLUSIONS: This underscores that unbalance between oxygen, NO, and ROS forms an important component of the pathogenesis of I/R-induced AKI and should therefore be taken into account when designing a prevention/treatment strategy for renal I/R injury in transplantation.

Photoplethysmography-based algorithm for detection of cardiogenic output during cardiopulmonary resuscitation.

Detecting return of spontaneous circulation (ROSC) during cardiopulmonary resuscitation (CPR) is challenging, time consuming, and requires interrupting chest compressions. Based on automated-CPR porcine data, we have developed an algorithm to support ROSC detection, which detects cardiogenic output during chest compressions via a photoplethysmography (PPG) signal. The algorithm can detect palpable and impalpable spontaneous pulses. A compression-free PPG signal which estimates the spontaneous pulse waveform, was obtained by subtracting the compression component, modeled by a harmonic series. The fundamental frequency of this series was the compression rate derived from the transthoracic impedance signal measured between the defibrillation pads. The amplitudes of the harmonic components were obtained via a least mean-square algorithm. The frequency spectrum of the compression-free PPG signal was estimated via an autoregressive model, and the relationship between the spectral peaks was analyzed to identify the pulse rate (PR). Resumed cardiogenic output could also be detected from a decrease in the baseline of the PPG signal, presumably caused by a redistribution of blood volume to the periphery. The algorithm indicated cardiogenic output when a PR or a redistribution of blood volume was detected. The algorithm indicated cardiogenic output with 94% specificity and 69% sensitivity compared to the retrospective ROSC detection of nine clinicians. Results showed that ROSC detection can be supported by combining the compression-free PPG signal with an indicator based on the detected PR and redistribution of blood volume.

Ascorbic acid improves renal microcirculatory oxygenation in a rat model of renal I/R injury.

BACKGROUND AND OBJECTIVES: Acute kidney injury (AKI) is a clinical condition associated with a degree of morbidity and mortality despite supportive care, and ischemia/reperfusion injury (I/R) is one of the main causes of AKI. The pathophysiology of I/R injury is a complex cascade of events including the release of free oxygen radicals followed by damage to proteins, lipids, mitochondria, and deranged tissue oxygenation. In this study, we investigated whether the antioxidant ascorbic acid would be able to largely prevent oxidative stress and consequently, reduce I/R-related injury to the kidneys in terms of oxygenation, inflammation, and renal failure. MATERIALS AND METHODS: Rats were divided into three groups (n = 6/group): (1) a time control group; (2) a group subjected to renal ischemia for 60 min by high aortic occlusion followed by 2 h of reperfusion (I/R); and (3) a group subjected to I/R and treated with an i.v. 100 mg/kg bolus ascorbic acid 15 min before ischemia and continuous infusion of 50 mg/kg/hour for 2 h during reperfusion (I/R + AA). We measured renal tissue oxidative stress, microvascular oxygenation, renal oxygen delivery and consumption, and renal expression of inflammatory and injury markers. RESULTS: We demonstrated that aortic clamping and release resulted in increased oxidative stress and inflammation that was associated with a significant fall in systemic and renal hemodynamics and oxygenation parameters. The treatment of ascorbic acid completely abrogated oxidative stress and inflammatory parameters. However, it only partly improved microcirculatory oxygenation and was without any effect on anuria. CONCLUSION: The ascorbic acid treatment partly improves microcirculatory oxygenation and prevents oxidative stress without restoring urine output in a severe I/R model of AKI.

TEMPOL has limited protective effects on renal oxygenation and hemodynamics but reduces kidney damage and inflammation in a rat model of renal ischemia/reperfusion by aortic clamping.

BACKGROUND: Renal ischemia-reperfusion (I/R) is a common clinical complication in critically ill patients that is associated with considerable morbidity and mortality. Renal I/R is a major cause of acute kidney injury (AKI) resulting from I/R-induced oxidative stress, sterile inflammation, and microcirculatory perfusion defects, which can be ameliorated with the superoxide scavenger TEMPOL. The most common cause of AKI in the clinical setting is aortic surgery with suprarenal aortic clamping. The protective effect of TEMPOL in aortic clamping-induced renal I/R has not been studied before. AIM: To evaluate the protective effects of TEMPOL on oxidative stress, inflammation, tissue injury, and renal hemodynamics and oxygenation in a clinically representative rat model of I/R using aortic cross-clamping. METHODS: Animals (N = 24) were either sham-operated or subjected to ischemia (30 min) and 90-min reperfusion, with or without TEMPOL treatment (15 min before ischemia and during entire reperfusion phase, 200 µmol/kg/h). Systemic and renal hemodynamics, renal oxygenation, and blood gas values were determined at 15 min and 90 min of reperfusion. At 90-min reperfusion, iNOS, inflammation (IL-6, MPO), oxidative stress (MDA), and tissue damage (NGAL, L-FABP) were determined in tissue biopsies. RESULTS: TEMPOL administration at a cumulative dose of 400 µmol/kg conferred a protective effect on AKI in terms of reducing renal damage, inflammation, and iNOS activation. With respect to renal hemodynamics and oxygenation, TEMPOL only reduced renal vascular resistance to near-baseline levels at both reperfusion time points and partially ameliorated the I/R-induced drop microvascular partial tension of oxygen at 90 min reperfusion. Also, TEMPOL alleviated the I/R-induced metabolic acidosis. However, TEMPOL exerted no restorative effect in terms of the severely reduced mean arterial pressure, renal blood flow, and renal oxygen delivery and consumption. The renal oxygen extraction ratio remained unchanged during the 90-min reperfusion phase. Kidneys in all groups were anuric throughout the experiment. CONCLUSIONS: This clinically representative renal I/R model, which entails both renal I/R and hind limb I/R as opposed to the standardly used renal I/R model that employs renal artery clamping, resulted in relatively moderate direct AKI. The damage was exacerbated by the perturbed systemic hemodynamics and metabolic acidosis as a result of the hind limb I/R. TEMPOL partially intervened in the factors that led to AKI as well as renal microvascular partial tension of oxygen and metabolic acidosis. However, more effective interventions should be devised for the mean arterial pressure drop (i.e., anuria) associated with aortic clamping and for restoring other critical renal hemodynamic and oxygenation parameters in order to improve post-I/R renal function. RELEVANCE FOR PATIENTS: TEMPOL is a promising compound that has been shown to protect kidneys from I/R damage, which is relevant in kidney transplantation, pancreas transplantation, and aortic aneurysm repair in kidney transplant patients. This study suggests that intervening with TEMPOL is not sufficient to ensure optimal clinical outcome in patients that have undergone aortic clamping and that more effective interventions should be investigated.

Red blood cell storage increases hypoxia-induced nitric oxide bioavailability and methemoglobin formation in vitro and in vivo.

BACKGROUND: In this study we investigated whether storage of red blood cells (RBCs) leads to alterations in nitrite reductase activity, hence in altered hypoxia-induced nitric oxide (NO) bioavailability and methemoglobin formation. STUDY DESIGN AND METHODS: Hypoxia-induced NO bioavailability and methemoglobin formation were measured in vitro after nitrite administration to fresh (<1 week of storage) and aged (5-6 weeks of storage) human RBC units and in blood samples of hemodiluted rats subjected to hypoxic ventilation after transfusion with fresh or aged human RBCs. RESULTS: In vitro, NO and methemoglobin levels 10 minutes after nitrite administration were lower in the fresh RBC samples compared to the aged RBC samples (p = 0.026 and p = 0.022, respectively). In vivo, NO bioavailability was also significantly lower in the rats receiving fresh RBCs compared to the group receiving aged RBCs (p = 0.003). In line with NO bioavailability, methemoglobin levels were higher, albeit not significantly, in the group receiving aged RBCs compared to in the group receiving fresh RBCs (p = 0.154). The difference in methemoglobin formation after nitrite administration between fresh and aged RBCs was only present under deoxygenated conditions and not under oxygenated conditions. There were no differences in methemoglobin reductase activity between fresh and aged RBCs. CONCLUSIONS: Storage of RBCs leads to an increased rate of hypoxia-induced nitrite reduction to NO and this is associated with increased methemoglobin formation. The increased methemoglobin formation and consequent decrease in oxygen delivery capacity might contribute to the storage-related impairment of aged RBCs to oxygenate the microcirculation.

Bis maltolato oxovanadium (BMOV) and ischemia/reperfusion-induced acute kidney injury in rats.

BACKGROUND: The aim of the present study was to test the potential protective effects of the organic vanadium salt bis (maltolato) oxovanadium (BMOV; 15 mg/kg) in the context of renal ischemia/reperfusion (30 min of ischemia) and its effects on renal oxygenation and renal function in the acute phase of reperfusion (up to 90 min post-ischemia). METHODS: Ischemia was established in anesthetized and mechanically ventilated male Wistar rats by renal artery clamping. Renal microvascular and venous oxygenation were measured using phosphorimetry. Creatinine clearance rate, sodium reabsorption, and renal oxygen handling efficiency were considered markers for renal function. RESULTS: The main findings were that BMOV did not affect the systemic and renal hemodynamic and oxygenation variables and partially protected renal sodium reabsorption. CONCLUSIONS: Pretreatment with the organic vanadium compound BMOV did not protect the kidney from I/R injury.

The use of skeletal muscle near infrared spectroscopy and a vascular occlusion test at high altitude.

Microcirculatory function, central to tissue regulation of oxygen flux, may be altered by the chronic hypoxemia experienced at high altitude. We hypothesized that at high altitude, adaptations within skeletal muscle would result in reduced oxygen consumption and reduced microcirculatory responsiveness, detectable by near infrared spectroscopy (NIRS) during a vascular occlusion test (VOT). The VOT comprised 3 min of noninvasive arterial occlusion; thenar eminence tissue oxygenation (Sto2) was measured by NIRS during the VOT at sea level, 4900 m and 5600 m (after 7 and 17 days at altitude, respectively) in 12 healthy volunteers. Data were derived from Sto2 time-curves using specifically designed computer software. Mean (±SD) resting Sto2 was reduced at 4900 m and 5600 m (69.3 (± 8.2)% (p=0.001) and 64.2 (± 6.1)% (p<0.001) respectively) when compared to sea level (84.4 (± 6.0)%. The rate of Sto2 recovery after vascular occlusion (Sto2 upslope) was significantly reduced at 4900 m (2.4 (± 0.4)%/sec) and 5600 m (2.4 (± 0.8)%/sec) compared to sea level (3.7 (± 1.3)%/sec) (p=0.021 and p=0.032, respectively). There was no change from sea level in the rate of desaturation during occlusion (Sto2 downslope) at either altitude. The findings suggest that in resting skeletal muscle of acclimatizing healthy volunteers at high altitude, microvascular reactivity is reduced (Sto2 upslope after a short period of ischemia) but that oxygen consumption remains unchanged (Sto2 downslope).

Detection of a spontaneous pulse in photoplethysmograms during automated cardiopulmonary resuscitation in a porcine model.

INTRODUCTION: Reliable, non-invasive detection of return of spontaneous circulation (ROSC) with minimal interruptions to chest compressions would be valuable for high-quality cardiopulmonary resuscitation (CPR). We investigated the potential of photoplethysmography (PPG) to detect the presence of a spontaneous pulse during automated CPR in an animal study. METHODS: Twelve anesthetized pigs were instrumented to monitor circulatory and respiratory parameters. Here we present the simultaneously recorded PPG and arterial blood pressure (ABP) signals. Ventricular fibrillation was induced, followed by 20 min of automated CPR and subsequent defibrillation. After defibrillation, pediatric-guidelines-style life support was given in cycles of 2 min. PPG and ABP waveforms were recorded during all stages of the protocol. Raw PPG waveforms were acquired with a custom-built photoplethysmograph controlling a commercial reflectance pulse oximetry probe attached to the nose. ABP was measured in the aorta. RESULTS: In nine animals ROSC was achieved. Throughout the protocol, PPG and ABP frequency content showed strong resemblance. We demonstrate that (1) the PPG waveform allows for the detection of a spontaneous pulse during ventilation pauses, and that (2) frequency analysis of the PPG waveform allows for the detection of a spontaneous pulse and the determination of the pulse rate, even during ongoing chest compressions, if the pulse and compression rates are sufficiently distinct. CONCLUSIONS: These results demonstrate the potential of PPG as a non-invasive means to detect pulse presence or absence, as well as pulse rate during CPR.

Peripheral perfusion index as an early predictor for central hypovolemia in awake healthy volunteers.

BACKGROUND: In healthy volunteers, we investigated the ability of the pulse oximeter-derived peripheral perfusion index (PPI) to detect progressive reductions in central blood volume. METHODS: Twenty-five awake, spontaneously breathing, healthy male volunteers were subjected to progressive reductions in central blood volume by inducing stepwise lower body negative pressure (LBNP) with 20 mm Hg for 5 minutes per step, from 0 to -20, -40, -60, and back to 0 mm Hg. Throughout the procedure, stroke volume (SV), heart rate (HR), and mean arterial blood pressure were recorded using volume-clamp finger plethysmography. Assessment of the PPI was done by pulse oximetry. Additionally, the forearm-to-fingertip skin-temperature gradient was measured. Data are presented as mean±SE. PPI underwent log transformation and is presented as median (25th-75th). RESULTS: Of the 25 subjects, one did not complete the study because of cardiovascular collapse. After the first LBNP step (-20 mm Hg), PPI decreased from 2.2 (1.6-3.3) to 1.2 (0.8-1.6) (P=0.007) and SV decreased from 116±3.0 mL to 104±2.6 mL (P=0.02). The magnitude of the PPI decrease (41%±6.0%) was statistically different from that observed for SV (9%±1.3%) and HR (3%±1.9%). During progression of LBNP, SV decreased and HR increased progressively with the increased applied negative pressure, whereas the PPI remained low throughout the remainder of the protocol and returned to baseline values when LBNP was released. At -60 mm Hg LBNP, SV decreased and HR increased by 36%±0.9% and 33%±2.4% from baseline, respectively. Mean arterial blood pressure remained in the same range throughout the experiment. CONCLUSIONS: These results indicate that the pulse oximeter-derived PPI may be a valuable adjunct diagnostic tool to detect early clinically significant central hypovolemia, before the onset of cardiovascular decompensation in healthy volunteers.

Activated protein C ameliorates impaired renal microvascular oxygenation and sodium reabsorption in endotoxemic rats.

INTRODUCTION: We aimed to test whether continuous recombinant human activated protein C (APC) administration would be able to protect renal oxygenation and function during endotoxemia in order to provide more insight into the role of coagulation and inflammation in the development of septic acute kidney injury. METHODS: In anesthetized, mechanically ventilated Wistar rats, endotoxemia was induced by lipopolysaccharide administration (10 mg/kg i.v. over 30 min). One hour later, the rats received fluid resuscitation with 0 (LPS + FR group; n = 8), 10 (APC10 group; n = 8), or 100 (APC100 group; n = 8) µg/kg/h APC for 2 h. Renal microvascular oxygenation in the cortex and medulla were measured using phosphorimetry, and renal creatinine clearance rate and sodium reabsorption were measured as indicators of renal function. Statistical significance of differences between groups was tested using two-way ANOVA with Bonferroni post hoc tests. RESULTS: APC did not have notable effects on systemic and renal hemodynamic and oxygenation variables or creatinine clearance. The changes in renal microvascular oxygenation in both the cortex (r = 0.66; p < 0.001) and medulla (r = 0.80; p < 0.001) were correlated to renal sodium reabsorption. CONCLUSION: Renal sodium reabsorption is closely correlated to renal microvascular oxygenation during endotoxemia. In this study, fluid resuscitation and APC supplementation were not significantly effective in protecting renal microvascular oxygenation and renal function. The specific mechanisms responsible for these effects of APC warrant further study.

Transfusion of banked red blood cells and the effects on hemorrheology and microvascular hemodynamics in anemic hematology outpatients.

BACKGROUND: The aim of this study was to investigate the effects of red blood cell (RBC) transfusion on the hemorrheologic properties and microcirculatory hemodynamics in anemic hematology outpatients receiving 2 to 4 RBC units of either "fresh" (leukoreduced storage for less than 1 week) or "aged" (leukoreduced storage for 3-4 weeks) RBCs. STUDY DESIGN AND METHODS: Measurements were performed before and 30 minutes after RBC transfusion in hematology outpatients. Leukoreduced RBC suspensions were stored in saline-adenine-glucose-mannitol (SAGM) additive solution. Whole blood viscosity was measured using Couette low-shear viscometry, RBC deformability and aggregability were measured using laser-assisted optical rotational cell analysis, and microcirculatory density and perfusion were assessed using sidestream dark field imaging. RESULTS: One group of patients (n = 10) received a median (interquartile range) of 3 (2-3) RBC bags that were stored for 7 (5-7) days (fresh) and the other group of patients (n = 10) received 3 (3-3) RBC bags that were stored for 23 (22-28) days (aged). After transfusion of fresh versus aged RBCs, hematocrit increased to 32 ± 3% versus 31 ± 2% (p < 0.363), whole blood viscosity increased to 4.2 ± 0.4 Pa/sec versus 4.2 ± 0.6 Pa/sec (p < 0.912), RBC deformability index remained unaffected, RBC aggregability index increased to 55 ± 10 versus 55 ± 13 (p = 0.967), microcirculatory flow remained unaffected, and microcirculatory density increased to 19.3 ± 2.5 mm/mm(2) versus 18.7 ± 1.9 mm/mm(2) (p = 0.595), respectively. CONCLUSION: Storing leukoreduced SAGM-suspended RBCs for 3 to 4 weeks did not affect their ability to improve hemorrheologic properties and microcirculatory hemodynamics in our small group of anemic hematology outpatients. Larger studies are needed to confirm this finding.

Reduced hexokinase II impairs muscle function 2 wk after ischemia-reperfusion through increased cell necrosis and fibrosis.

We previously demonstrated that hexokinase (HK) II plays a key role in the pathophysiology of ischemia-reperfusion (I/R) injury of the heart (Smeele et al. Circ Res 108: 1165-1169, 2011; Wu et al. Circ Res 108: 60-69, 2011). However, it is unknown whether HKII also plays a key role in I/R injury and healing thereafter in skeletal muscle, and if so, through which mechanisms. We used male wild-type (WT) and heterozygous HKII knockout mice (HKII(+/-)) and performed in vivo unilateral skeletal muscle I/R, executed by 90 min hindlimb occlusion using orthodontic rubber bands followed by 1 h, 1 day, or 14 days reperfusion. The contralateral (CON) limb was used as internal control. No difference was observed in muscle glycogen turnover between genotypes at 1 h reperfusion. At 1 day reperfusion, the model resulted in 36% initial cell necrosis in WT gastrocnemius medialis (GM) muscle that was doubled (76% cell necrosis) in the HKII(+/-) mice. I/R-induced apoptosis (29%) was similar between genotypes. HKII reduction eliminated I/R-induced mitochondrial Bax translocation and oxidative stress at 1 day reperfusion. At 14 days recovery, the tetanic force deficit of the reperfused GM (relative to control GM) was 35% for WT, which was doubled (70%) in HKII(+/-) mice, mirroring the initial damage observed for these muscles. I/R increased muscle fatigue resistance equally in GM of both genotypes. The number of regenerating fibers in WT muscle (17%) was also approximately doubled in HKII(+/-) I/R muscle (44%), thus again mirroring the increased cell death in HKII(+/-) mice at day 1 and suggesting that HKII does not significantly affect muscle regeneration capacity. Reduced HKII was also associated with doubling of I/R-induced fibrosis. In conclusion, reduced muscle HKII protein content results in impaired muscle functionality during recovery from I/R. The impaired recovery seems to be mainly a result of a greater susceptibility of HKII(+/-) mice to the initial I/R-induced necrosis (not apoptosis), and not a HKII-related deficiency in muscle regeneration.

The effects of conventional extracorporeal circulation versus miniaturized extracorporeal circulation on microcirculation during cardiopulmonary bypass-assisted coronary artery bypass graft surgery.

OBJECTIVES To reduce the complications associated with cardiopulmonary bypass (CPB) during cardiac surgery, many modifications have been made to conventional extracorporeal circulation systems. This trend has led to the development of miniaturized extracorporeal circulation systems. Cardiac surgery using conventional extracorporeal circulation systems has been associated with significantly reduced microcirculatory perfusion, but it remains unknown whether this could be prevented by an mECC system. Here, we aimed to test the hypothesis that microcirculatory perfusion decreases with the use of a conventional extracorporeal circulation system and would be preserved with the use of an miniaturized extracorporeal circulation system. METHODS Microcirculatory density and perfusion were assessed using sublingual side stream dark-field imaging in patients undergoing on-pump coronary artery bypass graft (CABG) surgery before, during and after the use of either a conventional extracorporeal circulation system (n = 10) or a miniaturized extracorporeal circulation system (n = 10). In addition, plasma neutrophil gelatinase-associated lipocalin and creatinine levels and creatinine clearance were assessed up to 5 days post-surgery to monitor renal function. RESULTS At the end of the CPB, one patient in the miniaturized extracorporeal circulation-treated group and five patients in the conventional extracorporeal circulation-treated group received one bag of packed red blood cells (300 ml). During the CPB, the haematocrit and haemoglobin levels were slightly higher in the miniaturized extracorporeal circulation-treated patients compared with the conventional extracorporeal circulation-treated patients (27.7 ± 3.3 vs 24.7 ± 2.0%; P = 0.03; and 6.42 ± 0.75 vs 5.41 ± 0.64 mmol/l; P < 0.01). The density of perfused vessels with a diameter <25 µm (i.e. perfused vessel density) decreased slightly in the conventional extracorporeal circulation-treated group from 16.4 ± 3.8 to 12.8 ± 3.3 mm/mm(2) (P < 0.01) and remained stable in the miniaturized extracorporeal circulation-treated group (16.3 ± 2.7 and 15.2 ± 2.9 mm/mm(2) before and during the pump, respectively). Plasma neutrophil gelatinase-associated lipocalin levels were increased following the use of extracorporeal circulation in both groups, and no differences were observed between the groups. Plasma creatinine levels and creatinine clearance were not affected by CABG surgery or CPB. CONCLUSIONS The results from this relatively small study suggest that the use of the miniaturized extracorporeal circulation system is associated with a statistically significant (but clinically insignificant) reduction in haemodilution and microcirculatory hypoperfusion compared with the use of the conventional extracorporeal circulation system.

Optimal flow and pressure management in machine perfusion systems for organ preservation.

Intra-organ flow is the most critical parameter in machine-perfused organ preservation systems (MPS). Ultrasonic flow sensors (UFS) are commonly employed in MPS. However, UFS are sensitive to changes in fluid composition and temperature and require recalibration. Novel Coriolis-type mass flow sensors (CFS) may be more suitable for MPS because the measurement technique is not amenable to these factors. The effect of viscosity, colloids, temperature, pressure, and preservation solution on flow measurement accuracy of UFS and CFS was therefore investigated. A CFS-based MPS was built and validated for setpoint stability using porcine kidneys and the ability to reproduce different pressure and flow waveforms. The UFS exhibited a temperature- and preservation solution-dependent overestimation of flow rate compared to the CFS. The CFS deviated minimally from the actual flow rate and did not require recalibration. The CFS-based MPS conformed to the preprogrammed temperature, flow, pressure, and vascular resistance settings during 6-h kidney preservation. The system was also able to accurately reproduce different pressure and flow waveforms. Conclusively, CFS-based MPS are more suitable for organ preservation than UFS-based MPS. Our CFS-based MPS provides a versatile yet robust experimental platform for testing and validating different types of clinical and experimental MPS.