Anesthesia-induced Lymphatic Dysfunction.

General anesthetics adversely alters the distribution of infused fluid between the plasma compartment and the extravascular space. This maldistribution occurs largely from the effects of anesthetic agents on lymphatic pumping, which can be demonstrated by macroscopic fluid kinetics studies in awake versus anesthetized patients. The magnitude of this effect can be appreciated as follows: a 30% reduction in lymph flow may result in a fivefold increase of fluid-induced volume expansion of the interstitial space relative to plasma volume. Anesthesia-induced lymphatic dysfunction is a key factor why anesthetized patients require greater than expected fluid administration than can be accounted for by blood loss, urine output, and insensible losses. Anesthesia also blunts the transvascular refill response to bleeding, an important compensatory mechanism during hemorrhagic hypovolemia, in part through lymphatic inhibition. Last, this study addresses how catecholamines and hypertonic and hyperoncotic fluids may mobilize interstitial fluid to mitigate anesthesia-induced lymphatic dysfunction.

Fluid distribution during surgery in the flat recumbent, Trendelenburg, and the reverse Trendelenburg body positions.

BACKGROUND: The distribution and elimination of infused crystalloid fluid is known to be affected by general anesthesia, but it is unclear whether changes differ depending on whether the patient is operated in the flat recumbent position, the Trendelenburg ("legs up") position, or the reverse Trendelenburg ("head up") position. METHODS: Retrospective data on hemodilution and urine output obtained during and after infusion of 1-2 L of Ringer's solution over 30-60 min were collected from 61 patients undergoing surgery under general anesthesia and 106 volunteers matched with respect to the infusion volume and infusion time. Parameters describing fluid distribution in the anesthetized and awake subjects were compared by population volume kinetic analysis. RESULTS: General anesthesia decreased the rate constant for urine output by 79% (flat recumbent), 91% (legs up) and 91% (head up), suggesting that laparoscopic surgery per se intensified the already strong anesthesia-induced fluid retention. General anesthesia also decreased the rate constant governing the return of the distributed fluid to the plasma by 32%, 15%, and 70%, respectively. These results agree with laboratory data showing a depressive effect of anesthetic drugs on lymphatic pumping, and further suggest that the "legs up" position facilitates lymphatic flow, whereas the "head up" position slows this flow. Both Trendelenburg positions increased swelling of the "third fluid space". CONCLUSIONS: General anesthesia caused retention of infused fluid with preferential distribution to the extravascular space. Both Trendelenburg positions had a modifying influence on the kinetic adaptations that agreed with the gravitational forces inflicted by tilting to body.

Accelerated lymph flow from infusion of crystalloid fluid during general anesthesia.

BACKGROUND: Kinetic analysis of crystalloid fluid yields a central distribution volume (Vc) of the same size as the expected plasma volume (approximately 3 L) except during general anesthesia during which Vc might be only half as large. The present study examined whether this difference is due to influence of the intravascular albumin balance. METHODS: A population volume kinetic analysis according to a three-compartment model was performed based on retrospective data from 160 infusion experiments during which 1-2.5 L of crystalloid fluid had been infused intravenously over 20-30 min. The plasma dilution based on blood hemoglobin (Hb) and plasma albumin (Alb) was measured on 2,408 occasions and the urine output on 454 occasions. One-third of the infusions were performed on anesthetized patients while two-thirds were given to awake healthy volunteers. RESULTS: The Hb-Alb dilution difference was four times greater during general anesthesia than in the awake state (+ 0.024 ± 0.060 versus - 0.008 ± 0.050; mean ± SD; P < 0.001) which shows that more albumin entered the plasma than was lost by capillary leakage. The Hb-Alb dilution difference correlated strongly and positively with the kinetic parameters governing the rate of fluid transfer through the fast-exchange interstitial fluid compartment (k12 and k21) and inversely with the size of Vc. Simulations suggest that approximately 200 mL of fluid might be translocated from the interstitial space to the plasma despite ongoing fluid administration. CONCLUSIONS: Pronounced plasma volume expansion early during general anesthesia is associated with a positive intravascular albumin balance that is due to accelerated lymphatic flow. This phenomenon probably represents adjustment of the body fluid volumes to anesthesia-induced vasodilatation.

Blood volume and hemodynamics during treatment of major hemorrhage with Ringer solution, 5% albumin, and 20% albumin: a single-center randomized controlled trial.

BACKGROUND: Volume replacement with crystalloid fluid is the conventional treatment of hemorrhage. We challenged whether a standardized amount of 5% or 20% albumin could be a viable option to maintain the blood volume during surgery associated with major hemorrhage. Therefore, the aim of this study was to quantify and compare the plasma volume expansion properties of 5% albumin, 20% albumin, and Ringer-lactate, when infused during major surgery. METHODS: In this single-center randomized controlled trial, fluid replacement therapy to combat hypovolemia during the hemorrhagic phase of cystectomy was randomly allocated in 42 patients to receive either 5% albumin (12 mL/kg) or 20% albumin (3 mL/kg) over 30 min at the beginning of the hemorrhagic phase, both completed by a Ringer-lactate replacing blood loss in a 1:1 ratio, or Ringer-lactate alone to replace blood loss in a 3:1 ratio. Measurements of blood hemoglobin over 5 h were used to estimate the effectiveness of each fluid to expand the blood volume using the following regression equation: blood loss plus blood volume expansion = factor + volume of infused albumin + volume of infused Ringer-lactate. RESULTS: The median hemorrhage was 848 mL [IQR: 615-1145]. The regression equation showed that the Ringer-lactate solution expanded the plasma volume by 0.18 times the infused volume while the corresponding power of 5% and 20% albumin was 0.74 and 2.09, respectively. The Ringer-lactate only fluid program resulted in slight hypovolemia (mean, - 313 mL). The 5% and 20% albumin programs were more effective in filling the vascular system; this was evidenced by blood volume changes of only + 63 mL and - 44 mL, respectively, by long-lasting plasma volume expansion with median half time of 5.5 h and 4.8 h, respectively, and by an increase in the central venous pressure. CONCLUSION: The power to expand the plasma volume was 4 and almost 12 times greater for 5% albumin and 20% albumin than for Ringer-lactate, and the effect was sustained over 5 h. The clinical efficacy of albumin during major hemorrhage was quite similar to previous studies with no hemorrhage. TRIAL REGISTRATION: ClinicalTrials.gov NCT05391607, date of registration May 26, 2022.

Detection of low urine output by measuring urinary biomarkers.

BACKGROUND: Urine output < 1 L per 24 h is a clinical warning sign that requires attention from hospital staff, who should determine whether the low flow is due to low habitual intake of water or disease-induced dehydration. The incidence of this condition is unclear. METHODS: A cohort of 20 healthy volunteers (mean age 42 years, range 23-62 years) recorded their food and water intakes daily for 8 days. They also collected and measured all urine and delivered first morning urine samples for analysis of osmolality and creatinine. Optimal cutoffs for these biomarkers to indicate urine output of < 1 L or 15 mL/kg during the preceding 24 h were applied with and without correction for age to cross-sectional data from 1,316 subjects in various clinical settings, including healthy volunteers, preoperative patients, patients seeking acute care at a hospital, and patients receiving institutional geriatric care. RESULTS: The urine output amounted to < 1 L during 22 of the 159 evaluable study days and was indicated by urine osmolality > 760 mosmol/kg or urine creatinine > 13 mmol/L, which had sensitivity and specificity of approximately 80%. Days with urine output < 1 L were associated with significantly less intake of both water (-41%) and calories (-22%) compared to other days. Application of age-corrected biomarker cutoffs to the 1,316 subjects showed a stronger dependency of low urine output on age than the clinical setting, occurring in 44% of the 72 participants aged 15-30 years and 18% of the 62 patients aged 90-104 years. CONCLUSION: Biomarkers measured in morning urine of young and middle-aged volunteers indicated urine output of < 1 L with good precision, but the cutoffs should be validated in older age groups to yield reliable results. TRIAL REGISTRATIONS: ISRCTN12215472 at http://www.isrctn.com ; NCT01458678 at ClinicalTrials.gov, and ChiCTR-TNRC-14,004,479 at the chictr.org/en.

A Slow-Exchange Interstitial Fluid Compartment in Volunteers and Anesthetized Patients: Kinetic Analysis and Physiology.

BACKGROUND: Physiological studies suggest that the interstitial space contains 2 fluid compartments, but no analysis has been performed to quantify their sizes and turnover rates. METHODS: Retrospective data were retrieved from 270 experiments where Ringer's solution of between 238 and 2750 mL (mean, 1487 mL) had been administered by intravenous infusion to awake and anesthetized humans (mean age 39 years, 47% females). Urinary excretion and hemoglobin-derived plasma dilution served as input variables in a volume kinetic analysis using mixed-models software. RESULTS: The kinetic analysis successfully separated 2 interstitial fluid compartments. One equilibrated rapidly with the plasma and the other equilibrated slowly. General anesthesia doubled the rate constants for fluid entering these 2 compartments (from 0.072 to 0.155 and from 0.026 to 0.080 min -1 , respectively). The return flows to the plasma were impeded by intensive fluid therapy; the rate constant for the fast-exchange compartment decreased from 0.251 to 0.050 when the infusion time increased from 15 to 60 minutes, and the rate constant for the slow-exchange compartment decreased from 0.019 to 0.005 when the infused volume increased from 500 to 1500 mL. The slow-exchange compartment became disproportionately expanded when larger fluid volumes were infused and even attained an unphysiologically large size when general anesthesia was added, suggesting that the flow of fluid was restrained and not solely determined by hydrostatic and oncotic forces. The dependence of the slow-exchange compartment on general anesthesia, crystalloid infusion rate, and infusion volume all suggest a causal physiological process. CONCLUSIONS: Kinetic analysis supported that Ringer's solution distributes in 2 interstitial compartments with different turnover times. The slow compartment became dominant when large amounts of fluid were infused and during general anesthesia. These findings may explain why fluid accumulates in peripheral tissues during surgery and why infused fluid can remain in the body for several days after general anesthesia.

Study of the f-cell ratio using plasma dilution and albumin mass kinetics.

BACKGROUND: The f-cell ratio of 0.91 is a conversion factor between the hematocrit measured in peripheral blood and the hematocrit obtained by separate measurements of the red blood cell mass and plasma volume. The physiological background of the f-cell ratio is unclear. METHODS: Data were retrieved from 155 intravenous infusion experiments where 15-25 mL/kg of crystalloid fluid diluted the blood hemoglobin and plasma albumin concentrations. The hemodilution was converted to plasma dilution using the peripheral hematocrit, and the volume of distribution of exogenous albumin was calculated in 41 volunteers who received 20 % or 5 % albumin by intravenous infusion. Finally, the kinetics of plasma albumin was studied during 98 infusion experiments with 20 % albumin. RESULTS: Plasma dilution based on hemoglobin and albumin showed a median difference of -0.001 and a mean difference of 0.000 (N = 2184), which demonstrates that these biomarkers indicate the same expandable vascular space. In contrast, exogenous albumin occupied a volume that was 10 % larger than the plasma volume indicated by the anthropometric equations of Nadler et al. and Retzlaff et al. The kinetic analysis identified a secondary compartment that was 450 mL in size and rapidly exchanged albumin with the circulating plasma. CONCLUSIONS: The results suggest that the f-cell ratio is due to rapid exchange of albumin between the plasma and a non-expandable compartment located outside the circulating blood (possibly the liver sinusoids). This means that the hematocrit measured in peripheral blood correctly represents the ratio between the red cell volume and the circulating plasma volume.

Evidence of serial connection between the plasma volume and two interstitial fluid compartments.

BACKGROUND: Kinetic analysis of fluid volume shifts can identify two interstitial fluid compartments with different turnover rates, but how they are connected to the bloodstream is unknown. METHODS: Retrospective data were retrieved from 217 experiments where 1.5 L of Ringer's solution (mean) had been administered by intravenous infusion over 30 min to awake and anesthetized humans (mean age 40 years). Urinary excretion and hemoglobin-derived plasma dilution served as input variables in a volume kinetic analysis using mixed models software. Possible modes of connection between the two interstitial fluid compartments and the bloodstream were judged by covariance analysis between kinetic rate constants, physiological variables, and time factors. RESULTS: The return flow of already distributed fluid to the plasma via a fast-exchange interstitial compartment was inhibited ongoing infusion of fluid (-38 %), which was probably due to increase of the venous pressure during volume loading. Ongoing infusion also greatly retarded the entrance of fluid to the slow-exchange compartment (-85 %), which suggests that infused Ringer's first had to enter the fast-exchange compartment. A high mean arterial pressure markedly increased the urine output and, to a lesser degree, also the rate of entrance of fluid to the fast-exchange compartment. Moreover, a high blood hemoglobin concentration retarded the rate of entrance of fluid to the fast-exchange compartment. CONCLUSIONS: The fast-exchange but not the slow-exchange interstitial fluid compartment was affected by intravascular events, which suggests that only the fast-exchange compartment is directly connected to the circulating blood.

Plasma Volume Oscillations during Fluid Therapy in Humans.

INTRODUCTION: Oscillations are frequently observed on plasma dilution curves during intravenous fluid therapy. This study aimed to examine how common these oscillations are and what they represent. METHODS: Fourier transforms were used to analyze the residuals obtained during fitting of a volume kinetic model to 269 plasma dilution curves. Oscillating patterns were identified in two-thirds of the fluid infusion experiments. RESULTS: The wave frequency usually had a dominating frequency of 1 h or multiples thereof. The wave amplitudes varied between 1% and 4% of the plasma volume. The "peak-to-peak" amplitudes were then twice as large, which corresponded to blood volume changes of 60-240 mL. A population kinetic analysis of the distribution of infused fluid between body fluid compartments was then applied to search for clues that could explain the oscillations. This analysis showed that amplitudes >1.5% were associated with doubled turnover of fluid in a fast-exchange interstitial fluid compartment and, together with data on plasma albumin, suggested that oscillations might represent bursts of efferent lymph. CONCLUSIONS: Oscillations with very low frequency were often observed on plasma dilution-time curves obtained during fluid therapy. They were associated with fast turnover of interstitial fluid and can possibly have resulted from accelerated lymphatic flow.

Modulation of the capillary leakage by exogenous albumin in a rat model of endothelial glycocalyx damage.

BACKGROUND: Endothelial glycocalyx (EG) plays a crucial role in maintaining the plasma proteins within the intravascular space. OBJECTIVE: We studied whether exogenous albumin protects the EG in an experimental model of EG enzymatic damage in rats. METHODS: Rats were divided into three groups of 10 animals that received (1) Evans blue (2) Evans blue + hyaluronidase, or (3) Evans blue + hyaluronidase + 20% human albumin via the tail vein. Spectrophotometric analysis was performed 2 h later to quantify the leakage of Evans blue-labeled albumin into the heart, lungs, brain, kidneys, liver, small intestine, spleen, and skeletal muscle. RESULTS: Administration of hyaluronidase numerically increased the capillary leakage of Evans blue in all examined tissues. Co-administration of albumin decreased the leakage of albumin in all tissues except the heart. In the lungs, the ratio between the absorbance and dry organ weight decreased from 5.3 ± 2.4 to 1.7 ± 0.5 (mean ± SD) (P <  0.002), and in the liver, the absorbance decreased from 2.2 ± 0.7 to 1.5 ± 0.4 (P <  0.011). CONCLUSION: Exogenous albumin decreased the capillary leakage of albumin which was interpreted as a sign of maintained EG integrity.

Role of Crystalloids in the Perioperative Setting: From Basics to Clinical Applications and Enhanced Recovery Protocols.

Perioperative fluid management, a critical aspect of major surgeries, is characterized by pronounced stress responses, altered capillary permeability, and significant fluid shifts. Recognized as a cornerstone of enhanced recovery protocols, effective perioperative fluid management is crucial for optimizing patient recovery and preventing postoperative complications, especially in high-risk patients. The scientific literature has extensively investigated various fluid infusion regimens, but recent publications indicate that not only the volume but also the type of fluid infused significantly influences surgical outcomes. Adequate fluid therapy prescription requires a thorough understanding of the physiological and biochemical principles that govern the body's internal environment and the potential perioperative alterations that may arise. Recently published clinical trials have questioned the safety of synthetic colloids, widely used in the surgical field. A new clinical scenario has arisen in which crystalloids could play a pivotal role in perioperative fluid therapy. This review aims to offer evidence-based clinical principles for prescribing fluid therapy tailored to the patient's physiology during the perioperative period. The approach combines these principles with current recommendations for enhanced recovery programs for surgical patients, grounded in physiological and biochemical principles.

Protection of the endothelium and endothelial glycocalyx by hydrogen against ischaemia-reperfusion injury in a porcine model of cardiac arrest.

BACKGROUND: Hydrogen is a potent antioxidant agent that can easily be administered by inhalation. The aim of the study was to evaluate whether hydrogen protects the endothelial glycocalyx layer after successful cardiopulmonary resuscitation (CPR). METHODS: Fourteen anesthetized pigs underwent CPR after induced ventricular fibrillation. During CPR and return of spontaneous circulation, 2% hydrogen gas was administered to seven pigs (hydrogen group) and seven constituted a control group. Biochemistry and sublingual microcirculation were assessed at baseline, during CPR, at the 15th, 30th, 60th, 120th minute. RESULTS: All seven subjects from the hydrogen group and six subjects in the control group were successfully resuscitated after 6-10 minutes. At baseline, there were no statistically significant differences in examined variables. After the CPR, blood pH, base excess, and lactate showed significantly smaller deterioration in the hydrogen group than in the control group. By contrast, plasma syndecan-1 and the measured variables obtained via sublingual microcirculation did not change after the CPR; and were virtually identical between the two groups. CONCLUSION: In pigs, hydrogen gas inhalation during CPR and post-resuscitation care was associated with less pronounced metabolic acidosis compared to controls. However, we could not find evidence of injury to the endothelium or glycocalyx in any studied groups.

Multidisciplinary expert panel report on fluid stewardship: perspectives and practice.

Although effective and appropriate fluid management is a critical aspect of quality care during hospitalization, the widespread adoption of consistent policies that ensure adequate fluid stewardship has been slow and heterogenous. Despite evidence-based guidelines on fluid management being available, clinical opinions continue to diverge on important aspects of care in this setting, and the consistency of guideline implementation is far from ideal. A multidisciplinary panel of leading practitioners and experts convened to discuss best practices for ongoing staff education, intravenous fluid therapy, new training technologies, and strategies to track the success of institutional fluid stewardship efforts. Fluid leads should be identified in every hospital to ensure consistency in fluid administration and monitoring. In this article, strategies to communicate the importance of effective fluid stewardship for the purposes of education, training, institutional support, and improvement of patient outcomes are reviewed and recommendations are summarized.

Concentrated urine, low urine flow, and postoperative elevation of plasma creatinine: A retrospective analysis of pooled data.

Elevations of plasma creatinine are common after major surgery, but their pathophysiology is poorly understood. To identify possible contributing mechanisms, we pooled data from eight prospective studies performed in four different countries to study circumstances during which elevation of plasma creatinine occurs. We included 642 patients undergoing mixed major surgeries, mostly open gastrointestinal. Plasma and urinary creatinine and a composite index for renal fluid conservation (Fluid Retention Index, FRI) were measured just before surgery and on the first postoperative morning. Urine flow was measured during the surgery. The results show that patients with a postoperative increase in plasma creatinine by >25% had a high urinary creatinine concentration (11.0±5.9 vs. 8.3±5.6 mmol/L; P< 0001) and higher FRI value (3.2±1.0 vs. 2.9±1.1; P< 0.04) already before surgery was initiated. Progressive increase of plasma creatinine was associated with a gradually lower urine flow and larger blood loss during the surgery (Kruskal-Wallis test, P< 0.001). The patients with an elevation > 25% also showed higher creatinine and a higher FRI value on the first postoperative morning (P< 0.001). Elevations to > 50% of baseline were associated with slightly lower mean arterial pressure (73 ± 10 vs. 80 ± 12 mmHg; P< 0.005). We conclude that elevation of plasma creatinine in the perioperative period was associated with low urine flow and greater blood loss during surgery and with concentrated urine both before and after the surgery. Renal water conservation-related mechanisms seem to contribute to the development of increased plasma creatinine after surgery.

The kinetics of isotonic and hypertonic resuscitation fluids is dependent on the sizes of the body fluid volumes.

Background and Aims: The extracellular and intracellular fluid volumes (ECV and ICV) vary not only with age, gender, and body weight but also with the habitual intake of water. The present study examines whether the baseline variations in the ECV and ICV change the distribution and elimination of subsequently given infusion fluids. Material and Methods: Twenty healthy male volunteers underwent 50 infusion experiments with crystalloid fluid for which the fluid volume kinetics was calculated based on frequent measurements of the hemodilution using mixed-effects modeling software. The results were compared with the ECV and ICV measured with multifrequency bioimpedance analysis before each infusion started. The fluids were given over 30 minutes and comprised 25 mL/kg Ringer's acetate (N = 20), Ringer's lactate, 5 mL/kg 7.5% saline, and 3 mL/kg 7.5% saline in 6% dextran 70 (these fluids, N = 10). Results: A large ICV was associated with a small extravascular accumulation of infused fluid, which increased the plasma volume expansion and the urinary excretion. With hypertonic fluid, a large ECV greatly accelerated urinary excretion. The body weight did not serve as a covariate in the kinetic models. Albumin was recruited to the plasma during infusion of both types of fluid. The hypertonic fluids served as diuretics. The infused excess sodium and osmolality were distributed over a 35% larger space than the sum of the ECV and ICV. Conclusion: A large ICV reduced the rate of distribution of Ringer's solution, whereas a large ECV accelerated the excretion of hypertonic saline.

Hypovolemia with peripheral edema: What is wrong?

Fluid normally exchanges freely between the plasma and interstitial space and is returned primarily via the lymphatic system. This balance can be disturbed by diseases and medications. In inflammatory disease states, such as sepsis, the return flow of fluid from the interstitial space to the plasma seems to be very slow, which promotes the well-known triad of hypovolemia, hypoalbuminemia, and peripheral edema. Similarly, general anesthesia, for example, even without mechanical ventilation, increases accumulation of infused crystalloid fluid in a slowly equilibrating fraction of the extravascular compartment. Herein, we have combined data from fluid kinetic trials with previously unconnected mechanisms of inflammation, interstitial fluid physiology and lymphatic pathology to synthesize a novel explanation for common and clinically relevant examples of circulatory dysregulation. Experimental studies suggest that two key mechanisms contribute to the combination of hypovolemia, hypoalbuminemia and edema; (1) acute lowering of the interstitial pressure by inflammatory mediators such as TNFα, IL-1ß, and IL-6 and, (2) nitric oxide-induced inhibition of intrinsic lymphatic pumping.

Recruitment of efferent lymph during infusion of 20 % albumin.

BACKGROUND: Intravenous infusion of hyper-oncotic 20 % albumin expands the plasma volume by approximately twice the infused volume. We investigated whether the recruited fluid stems from accelerated flow of efferent lymph, which would add protein to the plasma, or from reversed transcapillary solvent filtration, where the solvent is expected to be low in protein. METHODS: We analyzed data from 27 intravenous infusions of 20 % albumin (3 mL/kg; approximately 200 mL) over 30 min given to 27 volunteers and patients. Twelve of the volunteers were also given a 5 % solution and served as controls. The pattern of blood hemoglobin, colloid osmotic pressure, and the plasma concentrations of two immunoglobulins (IgG and IgM) were studied over 5 h. RESULTS: A decrease of the difference between the plasma colloid osmotic pressure and plasma albumin occurred during the infusions and was almost four times greater for 5 % albumin than for 20 % albumin at 40 min (P < 0.0036), which indicates that non-albumin protein enriched the plasma when 20 % was infused. Moreover, the difference between the infusion-derived dilution of the blood plasma based on hemoglobin and the two immunoglobulins amounted to -1.9 % (-6 to +0.2) for 20 % albumin and to -4.4 % (25th-75th percentile range - 8.5 to +0.2) during experiments with 5 % albumin (P < 0.001). This supports that the plasma was enriched by immunoglobulins, probably via the lymph, when 20 % was infused. CONCLUSIONS: Between half and two-thirds of the extravascular fluid that was recruited during infusion of 20 % albumin in humans consisted of protein-containing fluid consistent with efferent lymph.

Predicting fluid responsiveness using esophagus Doppler monitoring and pulse oximetry derived pleth variability index; retrospective analysis of a hemodynamic study.

BACKGROUND: Fluid therapy during major surgery can be managed by providing repeated bolus infusions until stroke volume no longer increases by ≥ 10%. However, the final bolus in an optimization round increases stroke volume by < 10% and is not necessary. We studied how different cut-off values for the hemodynamic indications given by esophagus Doppler monitoring, as well as augmentation by pulse oximetry, are associated with a higher or smaller chance that stroke volume increases by ≥ 10% (fluid responsiveness) before fluid is infused. METHODS: An esophagus Doppler and a pulse oximeter that displayed the pleth variability index were used to monitor the effects of a bolus infusion in 108 patients undergoing goal-directed fluid therapy during major open abdominal surgery. RESULTS: The analyzed data set comprised 266 bolus infusions. The overall incidence of fluid responsiveness was 44%, but this varied greatly depending on pre-infusion hemodynamics. The likelihood of being fluid-responsive was 30%-38% in the presence of stroke volume > 80 mL, corrected flow time > 360 ms, or pleth variability index < 10%. The likelihood was 21% if stroke volume had decreased by <8% since the previous optimization, which decreased to 0% if combined with stroke volume > 100 mL. By contrast, the likelihood of fluid responsiveness increased to 50%-55% when stroke volume ≤ 50 mL, corrected flow time ≤ 360 ms, or pleth variability index ≥ 10. A decrease in stroke volume by > 8% since the previous optimization was followed by a 58% likelihood of fluid responsiveness that, in combination with any of the other hemodynamic variables, increased to 66%-76%. CONCLUSIONS: Single or combined hemodynamic variables provided by esophagus Doppler monitoring and pulse oximetry derived pleth variability index could help clinicians avoid unnecessary fluid bolus infusions.

Co-morbidity associated with development of severe COVID-19 before vaccine availability: a retrospective cohort study in the first pandemic year among the middle-aged and elderly in Jönköping county, Sweden.

BACKGROUND: In preparation of future pandemics, it is important to recognise population-level determinants associated with development of severe illness before efficient vaccines and evidence-based therapeutic measures are available. The aim of this study was to identify pre-pandemic diagnoses recorded in a middle-aged and elderly population that were associated with development of severe COVID-19 during the first pandemic year. METHODS: A cohort study design was used. Severe COVID-19 was defined as a course of illness that resulted in hospital admission or death. A retrospective analysis was performed that comprised all individuals aged 39 years and older (N = 189,951) living in Jönköping County, Sweden. All diagnosed morbidity recorded in contacts with health care during the pre-pandemic year 2019 was used to identify which diagnoses that were associated with development of severe COVID-19 in the first pandemic year 2020. The analyses were performed separately for each diagnosis using binary logistic regression with adjustment for sex and age. RESULTS: Severe COVID-19 was suffered by 0.67% (N = 1,280) of the middle-aged and elderly population in the first pandemic year. Individuals previously diagnosed with dementia, cerebral palsy, kidney failure, type 2 diabetes mellitus, hypertension, and obesity were at higher risk of developing severe COVID-19. For patients with Type 2 diabetes mellitus, the odds ratio (OR) was 2.18 (95% confidence interval, 1.92-2.48). Type 1 diabetes mellitus was not associated with increased risk. CONCLUSION: Diagnoses suggesting service provision at long-term healthcare facilities and co-morbidity with components of the metabolic syndrome were associated with an increased risk of developing severe COVID-19 in a middle-aged and elderly population before vaccines were available.

Population Pharmacokinetics as a Tool to Reevaluate the Complex Disposition of Ethanol in the Fed and Fasted States.

The pharmacokinetics (PK) of ethanol are important in pharmacology and therapeutics because of potential drug-alcohol interactions as well as in forensic science when alcohol-related crimes are investigated. The PK of ethanol have been extensively studied since the 1930s, although some issues remain unresolved, such as the significance of first-pass metabolism, whether zero-order kinetics apply, and the effects of food on bioavailability. We took advantage of nonlinear mixed-effects modeling to describe blood-alcohol concentration (BAC) profiles derived from 3 published clinical studies involving oral, intraduodenal, and intravenous administration of ethanol with and without food. The overall data set included 1510 BACs derived from 72 healthy subjects (60 men, 12 women) aged between 20 and 60 years. Two-compartment models with first-order absorption and Michaelis-Menten elimination kinetics adequately described the BAC profiles. Food intake had 2 separate effects: It reduced the absorption rate constant and accelerated the maximum elimination rate. Estimates of the maximum elimination rate (fasted) and the food effect (as a factor) were 6.31 g/h (95%CI, 6.04-6.59 g/h) and 1.39-fold (95%CI, 1.33-1.46-fold), respectively. Simulations showed that the area under the BAC-time curve (AUC) was smaller with lower input rate of ethanol, irrespective of any first-pass metabolism. The AUC from time 0 to 10 hours for a 75-kg subject was 2.34 g â€¢ h/L (fed) and 3.83 g â€¢ h/L (fasted) after an oral dose of 45 g ethanol. This difference was mainly attributable to the food effect on ethanol elimination and depended less on the absorption rate. Our new approach to explain the complex human PK of ethanol may help when BAC predictions are made in clinical pharmacology and forensic medicine.