Population Kinetics of 0.9% Saline Distribution in Hemorrhaged Awake and Isoflurane-anesthetized Volunteers.

BACKGROUND: Population-based, pharmacokinetic modeling can be used to describe variability in fluid distribution and dilution between individuals and across populations. The authors hypothesized that dilution produced by crystalloid infusion after hemorrhage would be larger in anesthetized than in awake subjects and that population kinetic modeling would identify differences in covariates. METHODS: Twelve healthy volunteers, seven females and five males, mean age 28 ± 4.3 yr, underwent a randomized crossover study. Each subject participated in two separate sessions, separated by four weeks, in which they were assigned to an awake or an anesthetized arm. After a baseline period, hemorrhage (7 ml/kg during 20 min) was induced, immediately followed by a 25 ml/kg infusion during 20 min of 0.9% saline. Hemoglobin concentrations, sampled every 5 min for 60 min then every 10 min for an additional 120 min, were used for population kinetic modeling. Covariates, including body weight, sex, and study arm (awake or anesthetized), were tested in the model building. The change in dilution was studied by analyzing area under the curve and maximum plasma dilution. RESULTS: Anesthetized subjects had larger plasma dilution than awake subjects. The analysis showed that females increased area under the curve and maximum plasma dilution by 17% (with 95% CI, 1.08 to 1.38 and 1.07 to 1.39) compared with men, and study arm (anesthetized increased area under the curve by 99% [0.88 to 2.45] and maximum plasma dilution by 35% [0.71 to 1.63]) impacted the plasma dilution whereas a 10-kg increase of body weight resulted in a small change (less than1% [0.93 to 1.20]) in area under the curve and maximum plasma dilution. Mean arterial pressure was lower in subjects while anesthetized (P < 0.001). CONCLUSIONS: In awake and anesthetized subjects subjected to controlled hemorrhage, plasma dilution increased with anesthesia, female sex, and lower body weight. Neither study arm nor body weight impact on area under the curve or maximum plasma dilution were statistically significant and therefore no effect can be established.

Can noninvasive hemoglobin measurement reduce the need for preoperative venipuncture in pediatric outpatient surgery?

BACKGROUND: Noninvasive measurements of hemoglobin in the pediatric perioperative setting could be helpful to avoid venipunctures in children. The present study aims to evaluate this by using a noninvasive device for hemoglobin determination. We compared noninvasively obtained hemoglobin with laboratory hemoglobin concentrations in children during their preoperative assessment. METHODS: In an observational study, 122 nonanemic children (age 4.2 ± 1.6 years) who were scheduled to undergo different surgical procedures under general anesthesia were included. In their preoperative preparations, single invasive blood samples for laboratory hemoglobin concentrations were routinely taken following hospital policy and compared to simultaneous noninvasive determinations of hemoglobin. A preoperative invasive value ≤9 g/dL would have caused cancelation of surgery and implied further investigations. RESULTS: A Bland-Altman plot showed that the average difference between noninvasively obtained hemoglobin and laboratory hemoglobin concentration was -0.44 g/dL (bias) with a standard deviation of the mean bias of 1.04 g/dL. A hemoglobin error grid showed that the noninvasive device could identify almost all invasive hemoglobin values >9 g/dL. In total, there were 4 false-positive values where noninvasively obtained hemoglobin observations were below while the paired invasive values were above 9 g/dL. CONCLUSION: The data in this pediatric setting suggest that the device may eliminate the need for venipuncture in nonanemic children.

A mini volume loading test (mVLT) using 2.5-mLkg-1 boluses of crystalloid for indication of perioperative changes in hydration status.

BACKGROUND AND OBJECTIVE: A mini volume loading test (mVLT) evaluating hemodilution during step-wise crystalloid infusion has established that the arterio-capillary plasma dilution difference is inversely correlated to the body hydration level of subjects. This observational study aimed to test whether this can be replicated in a perioperative setting using a 2.5-mLkg-1 boluses. MATERIALS AND METHODS: The mVLT was performed before induction of regional anesthesia and 24h later. Step-wise infusion implied six mini fluid challenges. These consisted of 2.5-mLkg-1 boluses of Ringer's acetate infused during 2-3min and followed by 5-min periods with no fluids. Invasive (arterial) and noninvasive (capillary) measurements of hemoglobin were performed before and after each mini fluid challenge, as well as after a 20-min period without fluid following the last bolus. Hemoglobins were used to calculate the arterio-capillary plasma dilution difference which is used as an indication of changes in body hydration level. The 24-h fluid balance was calculated. RESULTS: Subjects were 69.5 (6.0) years old, their height was 1.62m (1.56-1.65), weight was 87.0kg (75.5-97.5) and body mass index (BMI) was 33.5kg/m2 (31.0-35.1). Preoperative arterio-capillary plasma dilution difference was significantly higher than postoperative (0.085 [0.012-0.141] vs. 0.006 [-0.059 to 0.101], P=0.000). The perioperative 24-h fluid balance was 1976mL (870-2545). CONCLUSIONS: The mVLT using 2.5-mLkg-1 boluses of crystalloid was able to detect the higher postoperative body hydration level in total knee arthroplasty patients.

A mini volume loading test for indication of preoperative dehydration in surgical patients.

BACKGROUND AND OBJECTIVE: Previously, a mini volume loading test (mVLT) detected signs of dehydration in healthy volunteers after an overnight fast. Our objective was to investigate whether mVLT could indicate preoperative dehydration in patients after an overnight fast. MATERIALS AND METHODS: The mVLT was performed in 36 elective primary total knee arthroplasty patients. Each subject received three fluid challenges before anesthesia induction. These consisted of 5 mL/kg boluses of Ringer's acetate infused over 3-5 min and followed by a 5-min period without fluids. Invasive (arterial, venous) and noninvasive (capillary) measurements of hemoglobin concentration were performed before and after each fluid challenge, as well as after a 20-min period without fluids which followed the last bolus. Arterial, venous and capillary plasma dilutions were calculated in every data point. Dilution values were used to calculate the plasma dilution efficacy of each fluid challenge. RESULTS: Venous dilution was higher than capillary after the first fluid challenge (P=0.030), but lower than capillary after 20 min period following the last bolus (P=0.009). Arterial dilution was lower than capillary (P=0.005) after 20 min following the last bolus. Veno-capillary and arterio-capillary plasma dilution efficacy differences decreased (P=0.004 and P=0.033, respectively) from positive to negative during mVLT. These are signs of re-hydration from pre-existing dehydration according to a transcapillary reflux model. CONCLUSIONS: Signs of dehydration were observed during mVLT in patients after pre-operative overnight fast. A revised transcapillary reflux model was proposed to explain the results.

The use of a noninvasive hemoglobin monitor for determining fluid distribution and elimination in pediatric patients undergoing minor surgery.

In pediatric fluid therapy it would be preferable to describe distribution and elimination a fluid bolus based on repetitive hemoglobin (Hb) according to kinetic principles. Pulse CO-Oximetry is a recent advancement in patient monitoring that allows for the continuous noninvasive measurement of Hb (SpHb). The aim of this study was to describe the distribution and elimination of hydroxyethylstarch (HES) 130/0.4 in combination with crystalloids using a noninvasive Hb monitor in two cohorts of young children undergoing minor surgeries under general anesthesia. Two cohorts, 16 children aged 1-3 years and 12 aged 4-6 years, were investigated during anesthesia and minor surgical procedures. They were given a maintenance solution of lactated Ringer's and a fluid bolus of HES 130/0.4, 6 mL/kg over a period of 20 min. The whole procedure lasted 120 min, and SpHb values were measured every 10 min. The SpHb values were used to calculate plasma dilution, net volume, and mean residence time (MRT) of the infused fluid. A total of 377 measured SpHbs generated individual dilution plots that showed variability, particularly for the older cohort. Distribution and elimination rates of the infused fluid were calculated. Mean dilution plots were generated. There were no significant differences in dilution, net volume or MRT between groups. A non invasive Hb analyzer could be used to calculate fluid distribution. The variability in the data can probably be explained by reactions to anesthetic drugs, variability in measurement technique, variability in generating the complex capillary signals, and individual variability in baseline fluid status. The latter finding is important because this is a prerequisite for perioperative fluid planning for each individual.

Evaluation of hydration status calculated from differences in venous and capillary plasma dilution during stepwise crystalloid infusions: A randomized crossover study in healthy volunteers.

BACKGROUND AND OBJECTIVE: A mini volume loading test (mVLT) was proposed for estimating hydration status and interstitial fluid accumulation during stepwise infusion of crystalloids. The method is based on both the transcapillary reflux model and the hypothesis that when subjects are dehydrated, venous plasma dilution induced by a fluid challenge is higher than in the capillaries, and that difference is diminished when the fluid challenge is given to more hydrated individuals. Our objective was to test that hypothesis by evaluating the veno-capillary dilution difference during mVLT in subjects with different hydration status. MATERIALS AND METHODS: In a prospective randomized crossover study, three mini fluid challenges were given to 12 healthy volunteers on two occasions. The subjects were either dehydrated or hydrated before the experiments. RESULTS: In dehydrated subjects only, capillary plasma dilution was significantly lower than venous (P=0.015, 0.005 and 0.006) after each mini fluid challenge. CONCLUSIONS: Veno-capillary dilution difference during mVLT depends on the hydration status. The mVLT method could possibly discriminate between the different states of hydration.

Use of the Airtraq® device for airway management in the prehospital setting--a retrospective study.

BACKGROUND: Difficulties with prehospital intubations have encouraged the development of indirect laryngoscopy techniques, facilitating laryngeal visualization. Airtraq® is a relatively new single-use indirect laryngoscope. The Airtraq® has been evaluated in several prehospital mannequin intubation trials. However, prehospital clinical experience with the device is limited. METHODS: A retrospective medical chart review was performed for patients who underwent prehospital endotracheal intubation in the Stockholm County between January 2008 and December 2012. Both anaesthesiologists and nurse anaesthetists performed prehospital intubations during the study period. All Airtraq® intubations during this period were included in the analysis. The objective was to estimate the success rate of Airtraq® used in a prehospital setting. RESULTS: During the 5-year period (January 2008- December 2012), 2453 tracheal intubations were performed. Airtraq® was used in 28 cases (1%). The overall Airtraq® intubation success rate was 68%. Among patients with anticipated or unexpected difficult airway (23/28) the Airtraq® success rate was 61% (14/23). Among patients who underwent drug facilitated or rapid-sequence intubation protocols 4/5 (80%) were successfully intubated with Airtraq®. CONCLUSION: In conclusion, this retrospective study showed a higher Airtraq® success rate than previous prospective prehospital trials. However, compared to other prehospital direct and indirect intubation methods the Airtraq success rate is low. Further clinical trials are necessary to evaluate the role of Airtraq® in the prehospital airway management.

A randomized double-blind clinical trial of tourniquet application strategies for total knee arthroplasty.

PURPOSE: The optimal timing of pneumatic lower limb tourniquet application during primary elective total knee arthroplasty surgery (TKA) is a matter of debate. Most previous reports have failed to show significant differences between different tourniquet timings. The aim of the work was to determine how three strategies of lower limb pneumatic tourniquet application affect the outcome for TKA patients. METHODS: Forty-three patients who undergo TKA were randomized into one of the three groups, and 36 of these patients completed the study. The tourniquet was inflated just before incision and deflated after the hardening of the cement for twelve patients (Group 1), it was inflated just before cement application and deflated after its hardening for another twelve patients (Group 2), and it was inflated before incision and deflated after the last suture of the skin for a further twelve patients (Group 3). Fit-to-discharge criteria and six methods for calculating estimated blood loss were used. RESULTS: The estimated blood loss in Group 1 was lower than in Group 2, as determined by six methods of calculation (p < 0.05). Estimated blood loss in Group 3 was lower than in Group 2, as determined by one method (p = 0.050). The mobilization performance in Group 1 was better than in Group 2 (p = 0.023) and in Group 3 (p = 0.033). Group 1 was better fit to discharge than Group 3 (p = 0.030). CONCLUSIONS: Inflation of an automatic pneumatic lower limb tourniquet before skin incision and its deflation after hardening of cement tends to give better outcomes in TKA patients during six postoperative days. The estimated blood loss was highest when the tourniquet was inflated just before cement application and deflated after its hardening.

The maintenance and monitoring of perioperative blood volume.

The assessment and maintenance of perioperative blood volume is important because fluid therapy is a routine part of intraoperative care. In the past, patients undergoing major surgery were given large amounts of fluids because health-care providers were concerned about preoperative dehydration and intraoperative losses to a third space. In the last decade it has become clear that fluid therapy has to be more individualized. Because the exact determination of blood volume is not clinically possible at every timepoint, there have been different approaches to assess fluid requirements, such as goal-directed protocols guided by invasive and less invasive devices.This article focuses on laboratory volume determination, capillary dynamics, aspects of different fluids and how to clinically assess and monitor perioperative blood volume.

Modelling of peripheral fluid accumulation after a crystalloid bolus in female volunteers - a mathematical study.

OBJECTIVE: To simultaneously model plasma dilution and urinary output in female volunteers. METHODS: Ten healthy female non-pregnant volunteers, aged 21-39 years (mean 29), with a bodyweight of 58-67 kg (mean 62.5 kg) participated. No oral fluid or food was allowed between midnight and completion of the experiment. The protocol included an infusion of acetated Ringer's solution, 25 ml/kg over 30 min. Blood samples (4 ml) were taken every 5 min during the first 120 min, and thereafter the sampling rate was every 10 min until the end of the experiment at 240 min. A standard bladder catheter connected to a drip counter to monitor urine excretion continuously was used. The data were analysed by empirical calculations as well as by a mathematical model. RESULTS: Maximum urinary output rate was found to be 19 (13-31) ml/min. The subjects were likely to accumulate three times as much of the infused fluid peripherally as centrally; 1/µ = 2.7 (2.0-5.7). Elimination efficacy, E(eff), was 24 (5-35), and the basal elimination k(b) was 1.11 (0.28-2.90). The total time delay T(tot) of urinary output was estimated as 17 (11-31) min. CONCLUSION: The experimental results showed a large variability in spite of a homogenous volunteer group. It was possible to compute the infusion amount, plasma dilution and simultaneous urinary output for each consecutive time point and thereby the empirical peripheral fluid accumulation. The variability between individuals may be explained by differences in tissue and hormonal responses to fluid boluses, which needs to be further explored.

End-tidal carbon dioxide monitoring during bag valve ventilation: the use of a new portable device.

BACKGROUND: For healthcare providers in the prehospital setting, bag-valve mask (BVM) ventilation could be as efficacious and safe as endotracheal intubation. To facilitate the evaluation of efficacious ventilation, capnographs have been further developed into small and convenient devices able to provide end- tidal carbon dioxide (ETCO2). The aim of this study was to investigate whether a new portable device (EMMA™) attached to a ventilation mask would provide ETCO2 values accurate enough to confirm proper BVM ventilation. METHODS: A prospective observational trial was conducted in a single level-2 centre. Twenty-two patients under general anaesthesia were manually ventilated. ETCO2 was measured every five minutes with the study device and venous PCO2 (PvCO2) was simultaneously measured for comparison. Bland- Altman plots were used to compare ETCO2, and PvCO2. RESULTS: The patients were all hemodynamically and respiratory stable during anaesthesia. End-tidal carbon dioxide values were corresponding to venous gases during BVM ventilation under optimal conditions. The bias, the mean of the differences between the two methods (device versus venous blood gases), for time points 1-4 ranges from -1.37 to -1.62. CONCLUSION: The portable device, EMMA™ is suitable for determining carbon dioxide in expired air (kPa) as compared to simultaneous samples of PvCO2. It could therefore, be a supportive tool to asses the BVM ventilation in the demanding prehospital and emergency setting.

Hypoproteinemia does not alter plasma volume expansion in response to a 0.9% saline bolus in awake sheep.

OBJECTIVE: To test the hypothesis that hypoproteinemia reduces plasma volume expansion produced by a bolus of crystalloid solution given to awake sheep. DESIGN: Prospective and observational. SETTING: Laboratory. SUBJECTS: Five female merino sheep (n = 5) weighing 37 ± 3 kg were anesthetized. INTERVENTIONS: Each animal was subjected to a 5-day test period: day 1: 50 mL/min 0.9% saline infusion over 20 mins. Days 2-4: daily plasmapheresis and replacement of the shed plasma with 6 L of 0.9% saline were performed in increments. MEASUREMENTS AND MAIN RESULTS: Fractional plasma volume expansion after rapid infusion of saline on days 1 and 5 was calculated from changes in hemoglobin concentration. There was a significant reduction in total plasma protein concentration after plasmapheresis (p < .05). Colloid osmotic pressures were also significantly lowered (p < .05). A crystalloid infusion of 0.9% saline did not alter any of these values compared with baseline. The hemodynamic measurements did not show significant differences between the experiments. The plasma volume expansion reached approximately 20% at the end of infusion and stayed at 10-15% during the experiments. No difference was found in plasma volume expansion produced by a bolus of 50 mL/min of 0.9% in the hypoproteinemic state when compared with the euproteinemic state (p = .61). No difference in cumulative urinary output was found between the two states. CONCLUSIONS: In contrast to our hypothesis, severe acute hypoproteinemia does not reduce plasma volume expansion in response to 50 mL/min 0.9% saline infusion in nonspleenectomized sheep when compared with the resultant plasma volume expansion after a 50 mL/min of 0.9% infusion in the euproteinemic state.

Pharmacokinetic aspects of fluid therapy.

Peri-operative fluid therapy continues to be an exercise in empiricism, with nagging questions about efficacy and complications. Pharmacokinetics is used for studying the time dependency of administered drugs. Volume kinetics is a pharmacokinetic approach describing the peak effects and clearance of intravenously infused fluids. It clarifies the absorption, distribution, metabolism and excretion of an intravenous fluid bolus. This could possibly allow for more rational design of intravenous fluid paradigms to improve clinical fluid therapy. This chapter briefly summarizes currently accepted principles of fluid therapy, discusses the general approach to kinetic analysis of fluid therapy, reviews currently available data defining kinetic responses to fluid therapy, and speculates about future applications of this approach.

Arteriovenous differences in plasma dilution and the distribution kinetics of lactated ringer's solution.

BACKGROUND: Conventional concept suggests that infused crystalloid fluid is first distributed in the plasma volume and then, since the capillary permeability for fluid is very high, almost instantly equilibrates with the extracellular fluid space. We challenge whether this view is consistent with findings based on volume kinetic analysis. METHODS: Fifteen volunteers received an IV infusion of 15 mL/kg of lactated Ringer's solution during 10 min. Simultaneous arterial and venous blood hemoglobin (Hgb) samples were obtained and Hgb concentrations measured. The arteriovenous (AV) difference in Hgb dilution in the forearm was determined and a volume kinetic model was fitted to the series of Hgb concentrations in arterial and venous blood. RESULTS: The AV difference in plasma dilution was only positive during the infusion and for 2.5 min thereafter, which represents the period of net flow of fluid from plasma to tissue. Kinetic analysis showed that volume expansion of the peripheral fluid space began to decrease 14 min (arterial blood) and 20 min (venous blood) after the infusion ended. Distribution of lactated Ringer's solution apparently occurs much faster in the forearm than in the body as a whole. Therefore, the AV difference in the arm does not accurately reflect the distribution of Ringer's solutions or whole-body changes in plasma volume. CONCLUSIONS: The relatively slow whole-body distribution of lactated Ringer's solution, which boosts the plasma volume expansion during and for up to 30 min after an infusion, is probably governed by a joint effect of capillary permeability and differences in tissue perfusion between body regions.

Population volume kinetics predicts retention of 0.9% saline infused in awake and isoflurane-anesthetized volunteers.

BACKGROUND: In previous work, extravascular expansion was observed to be enhanced by isoflurane anesthesia in sheep when a crystalloid bolus was administered. The aim of the current study was to further elaborate these investigations to humans and to explore the use of population kinetics in the analysis of fluid shifts. METHODS: Eleven healthy volunteers participated in two experiments each, either awake or isoflurane anesthetized, during which they received 25 ml/kg saline, 0.9%, intravenously over 20 min. Plasma dilution data were derived from repeated sampling of hemoglobin concentration, and population pharmacokinetic analysis was conducted using the WinNonMix 2.0.1 software (Pharsight Corporation, Mountain View, CA). Plasma hormones were measured, and hemodynamic values were monitored. RESULTS: Fluid infusion during isoflurane anesthesia was followed by a higher cardiac output, lower arterial pressure, and lower urinary excretion as compared with the awake protocol (P < 0.05). Albumin dilution was greater than hemoglobin concentration-derived plasma dilution, which indicates a transcapillary leak of albumin. A two-compartment model with an isoflurane-depressed, intercompartmental distribution parameter predicted that more than 50% of the infused volume was retained in the peripheral compartment at 180 min in both protocols. Isoflurane markedly increased the plasma levels of renin and aldosterone, whereas vasopressin was mostly unchanged. CONCLUSION: Fluid retention after rapid infusion of 0.9% saline was prominent in both awake and isoflurane-anesthetized subjects. Altered kinetics of infused 0.9% saline during isoflurane anesthesia was expressed as reduced clearance and a slower distribution, resulting in a small but significant increase in fluid accumulation in the body fluid compartments. These changes may be due to the associated decreasing of mean arterial pressure and increased release of renin and aldosterone.

Intravascular fluid administration and hemodynamic performance during open abdominal surgery.

We studied whether central hemodynamics measured by a pulmonary artery catheter can serve as a pharmacodynamic expression of fluid therapy in 10 patients undergoing open abdominal surgery. We examined how closely hemodynamic variables follow plasma dilution, which is an index of plasma volume expansion, during and after an IV infusion of 25 mL/kg of lactated Ringer's solution over 45 min. Pulmonary artery wedge pressure and central venous pressure responded to IV fluid with an increase that correlated with accompanying plasma dilution. Six of 10 patients showed a decrease in cardiac output that was probably secondary to an increase in peripheral vascular resistance (nonresponders), whereas the rest increased cardiac output (responders). Volume kinetic analysis suggested that 54% of the infused fluid resided in the central fluid space at the end of the infusion and 25% at the end of the study in the responders compared with 25% and 3%, respectively, in nonresponders. In conclusion, half of the patients undergoing open abdominal surgery responded to crystalloid fluid with a decrease in cardiac output. Pulmonary artery wedge pressure and central venous pressure responded more consistently to different degrees of plasma dilution, which can be simulated for various fluid regimens using volume kinetics.

Isoflurane inhibits compensatory intravascular volume expansion after hemorrhage in sheep.

After hemorrhage, blood volume is partially restored by transcapillary refill, a process of spontaneous compensatory intravascular volume expansion that we hypothesized would be inhibited by anesthesia. Six chronically instrumented sheep were subjected to four randomly ordered experiments while conscious or during anesthesia with isoflurane. After plasma volume measurement (indocyanine green), 15% or 45% of the blood volume was withdrawn. To quantify transcapillary refill, mass balance and kinetic calculations utilized repeated measurements of hemoglobin concentration, assuming that transcapillary refill would dilute hemoglobin concentration. After 15% hemorrhage, mean arterial blood pressure remained stable in both conscious and isoflurane-anesthetized sheep (normotensive hemorrhage) but decreased after 45% hemorrhage (hypotensive hemorrhage). After either normotensive or hypotensive hemorrhage, transcapillary refill occurred more rapidly during the first 40 min than during the next 140 min (P < 0.001). In conscious sheep, at 180 min, 57% and 42% of the bled volume had been restored after normotensive and hypotensive hemorrhage, respectively, in contrast to only 13% and 27% (P < 0.001) in isoflurane-anesthetized sheep. A novel kinetic model implicated hemodynamic factors in rapid, early transcapillary refill and decreased plasma oncotic pressure in subsequent slower filling. We conclude that isoflurane inhibits transcapillary refill after both normotensive and hypotensive hemorrhage in sheep.

Optoacoustic monitoring of blood hemoglobin concentration: a pilot clinical study.

The optoacoustic technique is noninvasive, has high spatial resolution, and potentially can be used to measure the total hemoglobin concentration ([THb]) continuously and accurately. We performed in vitro measurements in blood and in vivo tests in healthy volunteers. Our clinical protocol included rapid infusion of intravenous saline to simulate rapid change in the [THb] during fluid therapy or surgery. Optoacoustic measurements were made from the wrist area overlying the radial artery for more than 1 h. The amplitude of the optoacoustic signal generated in the radial artery closely followed the [THb] measured directly in concurrently collected blood samples.