Intraoperative Intravascular Effect of Lactated Ringer’s Solution and Hyperoncotic Albumin During Hemorrhage in Cystectomy Patients

Abstract

BACKGROUND: 

The intraoperative effect of 20% albumin on plasma volume during surgery involving major blood loss has not been explored extensively due to methodological difficulties. Crystalloids poorly expand the plasma volume, and using a colloid might then be a way to avoid fluid overload. As doubts have been raised about synthetic colloids, albumin solutions are currently used more extensively. This study presents a methodological development showing how plasma volume expansion can be studied in surgical settings with the coinfusion of 20% albumin and lactated Ringer’s solution.

METHODS: 

In this single-arm, single-center feasibility study, an intravenous (i.v.) infusion of 3 mL·kg·BW⁻¹ of 20% albumin was administered over 30 minutes to 23 cystectomy patients during the bleeding phase in addition to lactated Ringer’s solution to correct blood loss. Blood samples were measured at regular intervals over a period of 300 minutes to estimate the blood volume expansion resulting from simultaneous infusions of lactated Ringer’s and 20% albumin solutions, using a regression equation and the area under the volume–time curve method.

RESULTS: 

Mean hemorrhage was 974 mL (standard deviation [SD] ± 381). The regression method showed strong correlation (r² = 0.58) between blood loss minus blood volume expansion and the independent effects of the infused volume of lactated Ringer’s and 20% albumin solutions. The mean plasma volume expansion attributable to the infusion of lactated Ringer’s solution amounted to 0.38 (95% confidence interval [CI], 0.31–0.49) of the infused volume; for the 20% albumin, it was 1.94 mL/mL (95% CI, 1.41–2.46 mL/mL) over 5 hours on average (regression method). The mean within-patient change was 0.20 mL/mL (± 0.06 mL/mL) for the lactated Ringer’s solution and 2.20 mL/mL (±1.31 mL/mL) for the 20% albumin using the area under the volume–time curve method.

CONCLUSIONS: 

Blood volume expansion averaged 1.9–2.2 times the infused volume of 20% albumin during surgery associated with hemorrhage of around 1000 mL. This effect was long standing and approximately 5 times stronger than for the lactated Ringer’s solution. Twenty percent albumin boosts the plasma volume expansion of lactated Ringer’s solution to as high as 40% of the infused volume on the average, which is an effect that lasts at least 5 hours.

KEY POINTS

• Question: How effective is the plasma volume expansion of an intravenous infusion of 3 mL/kg of 20% albumin combined with lactated Ringer’s solution during an intraoperative bleeding period?
• Findings: Twenty percent albumin expanded the plasma volume by 1.9–2.2 times the infused volume if calculated with the regression method or the area under the volume–time curve method, respectively, over 5 hours of surgery and a mean hemorrhage volume of approximately 1000 mL.
• Meaning: Intraoperative administration of 20% albumin during hemorrhage is a potent plasma volume expander with a long-lasting effect.

Intraoperative fluid treatment is performed with either crystalloids or iso-oncotic colloids. Because crystalloids quickly equilibrate between the intravascular and interstitial volume, they are mainly administered to treat dehydration and temporary volume deficits. In contrast, iso-oncotic colloids remain intravascularly for a prolonged period, resulting in a long-lasting plasma volume expansion. Doubts have been raised about synthetic colloids, as they may have a deleterious effect on renal and coagulation functions,^1,2 and albumin is therefore used more extensively.³ The 20% albumin is of particular interest in major surgery because the total amount of fluid can be kept low.

The “Revised Starling mechanism” holds that interstitial fluid cannot be recruited by raising the plasma oncotic pressure and that capillary leakage of albumin increases from the inflammation induced by major surgery.⁴ In volunteers, 20% albumin effectively increased the plasma volume by recruiting 3.4 times as much fluid from noncirculating sources to the circulating blood than the infused volume, resulting in a long-lasting plasma volume expansion.⁵ This effect agrees well with the traditional Frank Starling law, which holds that raising the plasma oncotic pressure recruits fluid to the circulating blood.⁶ However, usefulness of 20% albumin during ongoing major surgery is difficult to study by traditional methods because measurements are confounded by hemorrhage and the frequent use of multiple types of infusion fluids.

Here we aimed to estimate the plasma volume expansion of 20% albumin in a surgical setting with major hemorrhage and the need for large amounts of infusion fluid judged by the within-patient change. For this purpose, we chose radical cystectomy with urinary diversion. This surgical procedure has 3 stages, the first one being pelvic lymph node dissection, which lasts 1–2 hours and during which minimal bleeding occurs. The bladder is removed during the second stage, which lasts approximately 1 hour and is associated with relevant blood loss (500–1200 mL). Finally, urinary diversion is performed, which lasts 2–3 hours and is a nonbleeding stage.⁷

We aimed to explore new ways to study the within-patient change of infusion fluids during major, lengthy surgery. The primary objective was to examine the within-patient change of 20% albumin on plasma volume expansion in the framework of blood loss replacement during the bleeding stage. We expected that 20% albumin could have a potent influence on the plasma volume. Furthermore, we hypothesized that 20% albumin will sustain the administration of lactated Ringer’s solution as blood loss replacement therapy.

METHODS

Approval

This investigator-initiated, open-label, single-arm, single-center feasibility study was approved by the Swiss government’s local ethics committee (cantonal ethics committee KEK Bern, Switzerland, KEKBE ID 2018-02351, chairperson Professor C. Seiler), prospectively registered at ClinicalTrials.gov (NCT03848507, principal investigator P. Y. Wuethrich, date of registration: February 20, 2019) and conducted in compliance with the Declaration of Helsinki and good clinical practice. The study was performed at the Department of Urology, University Hospital Bern (Bern, Switzerland). The full trial protocol can be accessed on request. All patients gave preoperative written informed consent to participate. This manuscript adheres to the applicable STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) guidelines.

Patients planned for pelvic lymph node dissection, open radical cystectomy, and urinary diversion were screened for inclusion in the Department of Urology of the Bern University Hospital. Inclusion criteria were age >18 years and nonemergency surgery. Surgery was standardized and performed by 2 highly experienced senior consultants. Exclusion criteria were renal dysfunction (Kidney Disease Outcomes Quality Initiative stage 3 or higher), history of heart failure, known hypersensitivity or allergy to exogenous albumin, pregnancy, breastfeeding, known or suspected drug or alcohol abuse, participation in another study with investigational drug within the 30 days preceding and during the present study, and enrollment of the investigator, family members, employees, and other dependent persons.

The recruitment was performed during the preoperative assessment for surgery during the ambulatory visit at the Department of Urology or at latest the day before surgery on the urological ward by one of the research members (L.M.L., D.E., P.Y.W.).

End Points

We aimed to estimate the plasma volume expansion over 300 minutes and to mathematically separate the plasma volume expansion resulting from lactated Ringer’s solution (as a baseline infusion and 1:1 volume substitution to blood loss in milliliters) from 20% albumin, which was infused in a volume of 3 mL/kg over 30 minutes to combat hypovolemia during removal of the bladder (ie, cystectomy stage, with a approximately 60-minute-long bleeding phase).

Time Course and Intervention

A cannula was placed in 1 radial artery for monitoring of the blood pressure and pulse pressure variation (PPV), heart rate, oxygen saturation, end-tidal concentration of anesthetic gas (desflurane) and carbon dioxide, and neuromuscular transmission. Cardiac output (CO) and stroke volume (SV) were measured with a CardioQ esophageal probe (Deltex Medical, Chichester, United Kingdom) and plethysmography variability index with a Radical-7 Pulse CO-Oximeter (Masimo International, Neuchatel, Switzerland).

To prevent preoperative dehydration, all patients were encouraged to drink 800 mL of a carbo-loading solution (Preload, Nestlé Health Science, Vevey, Switzerland) the evening before and 400 mL up to 2 hours before arrival at the operating theater. No intravenous (i.v.) colloids, albumin, or crystalloids were administered within 12 hours before surgery. After insertion of an epidural catheter at the low thoracic level, induction of anesthesia (fentanyl 2 µg/kg bolus, propofol 2 mg/kg, and rocuronium 0.6–0.9 mg/kg intravenously to facilitate endotracheal intubation) and maintenance of anesthesia (desflurane) were performed according to our daily practice. Epidural anesthesia was started after endotracheal intubation with a bolus of 3 mL of lidocaine 2%, followed by a continuous infusion of bupivacaine 0.25% at a rate of 6–8 mL/h. Central venous cannulation was performed in the right internal jugular vein.

An infusion of norepinephrine, starting at a rate of 0.03 µg·kg⁻¹·minute⁻¹, was given to maintain the mean arterial pressure (MAP) >65 mm Hg. If PPV was >10, mini-fluid challenges of 100 mL of lactated Ringer’s solution were administered until normovolemia was restored and removal of the bladder began. Baseline i.v. fluid administration was performed according to our daily practice with baseline maintenance of 1 mL·kg⁻¹·hour⁻¹ of lactated Ringer’s solution (lactated Ringer’s solution [sodium {Na}: 130.9 mmol/L, K: 5.4 mmol/L, Cl: 111.7 mmol/L, Ca 1.84 mmol/L, L-lactate: 28.3 mmol/L], Fresenius Kabi, Kriens, Switzerland) during the pelvic lymph node dissection and cystectomy.^8,9

The 20% albumin solution (Albumin CSL 20%, CSL Behring, Bern, Switzerland, ATC Code: B05AA01, license number 52476 [Swissmedic]) was a sterile aqueous solution for i.v. use, with a sodium content of around 125 mmol/L, with additional 16 mmol/L sodium caprylate and 16 mmol/L sodium N-acetyltryptophanate. The amount used in this study was based on the study design and results of Zdolsek et al.⁵ A constant infusion of 3 mL/kg 20% albumin was started (based on ideal body weight) and continued at a constant rate over 30 minutes via an Infusomat until removal of the bladder (ie, the bleeding stage of surgery) was started. Blood loss was assessed by weighing sponges and suction content at regular intervals (15 minutes), and lost blood was replaced with the lactated Ringer’s solution in a 1:1 ratio during the bleeding phase.¹⁰ The baseline infusion rate was thereafter increased to 3 mL·kg⁻¹·hour⁻¹ of lactated Ringer’s solution until the end of surgery.

Postoperative baseline i.v. hydration consisted primarily of 1000 mL of lactated Ringer’s solution and 500 mL of glucose 5% per day until resumption of normal food intake.¹¹ In case of hypotension, an additional bolus of 250–500 mL of lactated Ringer’s solution was administered. Immediately postoperatively, patients were offered clear fluids. An oral liquid diet, as well as active mobilization, was started on postoperative day 1.

Measurements

Venous blood (5 mL) was drawn from the proximal lumen of the central venous catheter using a plastic syringe both just before (time 0 minutes) and at 10, 20, 30, 40, 50, 60, 75, 90, 120, 180, 210, 240, and 300 minutes after the start of the albumin infusion (Figure 1). Before each sampling, a small volume of blood was drawn from the cannula and re-administered after the sampling was finished and flushed with around 2 mL of 0.9% saline to prevent clotting.

Figure 1.: Timeline for the intervention and experiment. Induction of anesthesia began at –180 (180 min before the start of the infusion of 20% albumin). At –120 min, surgery started with the pelvic lymph node dissection (nonbleeding phase). From 0 to 60 min, removal of the bladder was performed (bleeding phase). From 0 to 30 min, 3 mL/kg 20% albumin was infused (red). Blood sampling started at 0 min with samplings every 10 min for the first 60 min (0–60 min), then every 15 min for the next 30 min, then every 30 min for the next 60 min, and finally every 60 min until the 300-min time point (ie, end of surgery). Hemodynamic variables were recorded at the same time as the blood samples were collected. Additional urine samples were taken at 60 and 300 min.

Hemodynamic parameters CO and SV, perfusion index, and plethysmography variability index were recorded at the same time intervals as blood samples were drawn.

Routine analyses of blood samples were conducted in the hospital’s central laboratory. The blood hemoglobin (Hb) concentration was sampled in ethylendiamintetraacetat (EDTA) tubes and analyzed on a Sysmex XN (Sysmex Corp, Kobe, Hyogo, Japan). The coefficient of variance for this analysis was 0.7% as ensured by duplicate samples that had been drawn at baseline.

Plasma was sampled in a lithium-heparin plasma gel tube and used for measurement of the sodium, potassium, creatinine, and albumin concentrations at 0, 60, and 300 minutes after the start of the 20% albumin solution and analyzed on a Cobas 800 ISE and c702 (Roche Diagnostics, Basel, Switzerland).

Analysis/Calculations

Two mathematical approaches were implemented to evaluate how much the blood volume usage expands when using 20% albumin. The first was a regression method that studies the linear correlation between blood volume expansion and the cumulative volumes of infused lactated Ringer’s solution and 20% albumin, as well as the cumulative recorded blood loss. All measurements were pooled into a single analysis.^12,13

The blood volume expansion was estimated from the hemodilution with correction blood sampling and hemorrhage.^14–16 The latter was assumed to occur to 3/4 during a mean duration of 60 minutes in the period when the bladder was removed (see our previous publication¹⁷). The calculations were performed as follows: the initial blood volume (BV₀) was first obtained using Nadler’s formula, where the total blood volume before the infusion of 20% albumin (BV₀) was derived from the height (h) in meters, body weight (w) in kilograms, and sex.¹⁸

The blood volume at a later time 1 was calculated by first estimating the total Hb mass in the circulation at baseline [Hbmass(0)] as being equal to the product of BV(0) and the blood Hb concentration at baseline Hb(0). Losses from Hbmass were then subtracted for each measurement, and the BV(1) was obtained by dividing this difference by a freshly taken Hb.^19,20 Hence

The result was then compared to the amount of infused fluids (lactated Ringer’s solution and 20% albumin separately) and the estimated volume of blood loss up to that point in time.

The second approach is a previously unpublished area method. The area under the volume–time curve for the blood volume changes and the surgical hemorrhage (including the sampled blood volume) was calculated between 0 and 300 minutes for each patient separately, based on the figure for total surgical blood loss and blood sampling, assuming that 3/4 of the surgical blood loss occurs during the first 60 minutes.⁷ The expected area under the curve (AUC) for each infusion of lactated Ringer’s solution was then calculated by volume kinetics based on previously published kinetic constants derived from 10 volunteers after 900 mL had been withdrawn, assuming that the loss of 1 mL of blood caused hypovolemia of 1 mL.²¹ We then calculated the AUC for the estimated total blood volume expansion over time, for lactated Ringer’s solution, and for the hemorrhage using the function implemented in MATLAB R2019b (Math Works Inc, Natick, MA). The AUC for lactated Ringer’s solution was given directly by this calculation, while the area for 20% albumin was obtained as the difference between the blood volume expansion and the sum of the (negative) value for blood loss and the (positive) value for the lactated Ringer’s solution.

The plasma volume–expanding capacity of lactated Ringer’s solution was finally obtained as the AUC divided by the product of the infused volume and the length of the observation period (300 minutes).

The plasma volume–expanding capacity of 20% albumin was obtained as the residual area after subtracting the AUCs for lactated Ringer’s solution and the BV expansion from the AUC for the hemorrhage. Likewise, this residual was divided with the amount of infused 20% albumin and the length of the observation period (300 minutes). The division with time is needed to account for that the AUC has the dimension of volume and time. This calculation yielded the average blood volume expansion that could be attributable to 20% albumin during the 5-hour experiment. A value for the expansion of lactated Ringer’s solution was also obtained but relates to the simulation based on kinetic data from a previous study.²¹

Statistics

Laboratory data are presented as mean ± standard deviation (SD) if being normally distributed. Within-patient differences in hemodynamic variables (MAP, heart rate, SV, CO, and plethysmography variability index) between the measurement points were screened by using repeated-measures analysis of variance (RM ANOVA), and pairwise comparisons with baseline then performed by application of Bonferroni corrections (all data points compared with baseline, ie, time point “0,” with adjustment of the P level due to multiple comparisons [n = 12]) was performed automatically using the SPSS Statistics for Windows (version 26.0, IBM Corp, Armonk, NY). The linear regression analysis was assessed among blood loss, blood volume change, and infused volumes of lactated Ringer’s solution and 20% albumin, where r is the correlation coefficient (simple regression) and r² the coefficient of determination (multiple regression). The significance level was 0.05 for each hypothesis.

This feasibility study was exploratory and no power calculation per se was performed because there were no preliminary data on which to base such an analysis. Based on previous data, we assumed that the SD of the plasma volume expansion would be about 5%. With N = 20, we were able to estimate a 95% confidence interval for within-patient change in 20% albumin of width 4.38 and half-width (or precision) of 2.19.²² In addition, considering a dropout frequency of a bit more than 20%, 25 patients needed to be finally recruited.

RESULTS

Twenty-five patients were enrolled, 2 of them were excluded before data analysis due to unplanned changes in surgical technique (n = 2). Twenty-three patients, 4 women and 19 men, were included in the final analysis. Fourteen of them had an ASA physical status of III and 9 of 23 had a physical status of II. Mean age was 67.8 years (±8.6 years), body weight 77.1 kg (±12.7 kg), and body mass index (BMI) 26.3 kg·m⁻² (±3.3 kg·m⁻²). Mean duration of surgery was 376 minutes (±53 minutes), and mean blood loss was 974 mL (±381 mL). Mean preoperative plasma albumin value was 36.1 g/L (±3.4 g/L), mean plasma osmolality 286.1 mOsmol/kg (±6.2 mOsmol/kg), and mean plasma creatinine was 95 µmol·L⁻¹ (±24 µmol·L⁻¹).

Patients received mean continuous administration of norepinephrine of 0.06 µg·kg⁻¹·BW⁻¹·minute⁻¹ (±0.02 µg·kg⁻¹·BW⁻¹·minute⁻¹), mean 20% albumin of 220 mL (±29 mL), and mean lactated Ringer’s solution of 2095 mL (±679 mL) during experimental time.

Table 1. - Laboratory Data From Baseline, 60 min, 300 min, and on POD 1, Presented as Mean and SD

	0 min	60 min	300 min	POD 1
S-osmolality (mOsmol/kg)	287 ± 7	289 ± 7	289 ± 5	284 ± 6
S-creatinine (µmol/L)	98 ± 22	99 ± 25	100 ± 25	100 ± 27
S-K (mmol/L)	4.3 ± 0.5	4.9 ± 0.5	4.9 ± 0.5	4.7 ± 0.6
S-Na (mmol/L)	139.7 ± 2.3	139.3 ± 2.5	139.1 ± 1.7	142.0 ± 2.7
U-creatinine (mmol/L)	8.5 ± 4.6	Na	12.1 ± 4.8	9.4 ± 5.7
U-Na (mmol/L)	104 ± 37	Na	64 ± 28	79 ± 32
U-K (mmol/L)	38 ± 20	Na	115 ± 54	65 ± 31
U-osmolality (mOsmol/kg)	482 ± 146	Na	545 ± 141	549 ± 175
Hb (g/L)	123 ± 16	108 ± 11	106 ± 9	89 ± 12
Albumin (g/L)	36.2 ± 3.2			32.1 ± 4.5

Abbreviations: Hb, hemoglobin; Na, sodium; POD, postoperative day; SD, standard deviation.

Figure 2.: Hemodynamic variables over time, given as mean and SD. A, Stroke volume. B, Cardiac output. C, Plethysmography variability index (pleth variability index). D, MAP. E, PPV. F, HR. *Significant variations from baseline over time (RM ANOVA and pairwise comparisons with baseline, performed by application of Bonferroni corrections). HR indicates heart rate; MAP, mean arterial pressure; PPV, pulse pressure variation; RM ANOVA, repeated-measures analysis of variance.

There was a mild increase in MAP (P = .01) at the time points 120 and 180 minutes, heart rate (P = .001) at the time point 40 minutes, SV (P = .01) at the time points 90 and 240 minutes, and CO (P = .01) at the time point 90 minutes compared with baseline (Bonferroni post hoc test following RM ANOVA), while there were no statistically significant differences in the plethysmography variability index between points in time (P = .61; RM ANOVA; Figure 2). On postoperative day 1, mean fluid balance was positive (+895 mL [±337 mL]), and mean weight gain was 1100 g (±839 g). Plasma creatinine values did not change significantly over time (P = .638; Table 1).

Regression Method

Table 2. - Independent Blood Volume–Expanding Effects of Lactated Ringer’s Solution and 20% Albumin When Given Together During Major Surgery

	r 2 = 0.58			P < .0001
	β Coefficient Table
Count 319	Best Estimates	95% CI	Standard Error	t	P
Intercept	−39.3
Lactated Ringer’s solution (mL)	0.38	0.31–0.45	0.036	10.63	<.0001
20% albumin (mL)	1.94	1.41–2.46	0.266	7.28	<.0001

The blood volume–expanding effect was taken as the blood loss plus the blood volume expansion. One milliliter of lactated Ringer’s solution had a mean blood volume–expanding effect of 0.38 mL (95% CI, 0.31–0.45) during the study period. Likewise, infusing 1 mL of 20% albumin increased the blood volume by 1.94 mL (95% CI, 0.266–7.28).

Abbreviation: CI, confidence interval.

Multiple regression analysis showed that the infused volumes of lactated Ringer’s solution and 20% albumin explained about 58% (r² = 0.58) of the variability in the outcome of blood loss minus the blood volume expansion. Accordingly, the plasma volume expansion for the lactated Ringer’s solution was 0.38 mL/mL and for 20% albumin 1.94 mL/mL infused fluid on the average during the 5 hours of the study (both P < .001). Details about this regression analysis are given in Table 2.

Area Under the Curve Method

The total area under the blood volume expansion curve over time was 110 L*minute (±43 L*minute) for lactated Ringer’s solution, 157 L*minute (±106 L*minute) for 20% albumin, 34 L*minute (±71 L*minute) for the blood volume, and −231 mL*minute (±96 mL*minute) for the blood loss. The estimated average blood volume expansion was 0.20 mL/mL (±0.06 mL/mL) for the lactated Ringer’s solution and 2.20 mL/mL (±1.31 mL/mL) for the 20% albumin. The blood volume changes showed that, on average, the patients tended toward balanced normovolemia intraoperatively (Figure 3).

Figure 3.: Blood volume change (green line) as the result of the plasma volume expansion of the lactated Ringer’s solution and 20% albumin, derived from changes in hemoglobin value measurement, in 23 patients undergoing cystectomy. The within-patient change of the lactated Ringer’s solution is given by the difference in the area under the curve between the hemorrhage (red) and lactated Ringer’s solution (blue) lines. The within-patient change of 20% albumin is given by the area under the curve between the lactated Ringer’s solution (blue) and blood volume change (green) lines. SD indicates standard deviation.

Figure 4.: The volume of infused lactated Ringer’s solution versus the difference in the hemorrhage and blood volume change. As the average blood volume was practically unchanged during the surgeries, the plot illustrates how strongly the lactated Ringer’s solution boosted the blood volume when coinfused with 3 mL/kg of 20% albumin. About half (49.9%) of the infused lactated Ringer’s solution then expanded the blood volume.

Figure 4 shows what the blood volume expansion of lactated Ringer’s solution would be if 20% albumin were regarded as a booster substance to Ringer infusion. The correlation coefficient for the relationship between the amount of infused lactated Ringer’s solution versus the sum of the hemorrhage volume and the blood volume change was r = 0.71 (95% confidence interval [CI], 0.63–0.78). About 40% of the lactated Ringer’s solution is retained over time when coinfused with 20% albumin (300 minutes).

DISCUSSION

Overall, we observed effective and long-lasting blood volume expansion with the administration of 20% albumin (1.94 mL/mL infused fluid) combined with lactated Ringer’s solution (0.38 mL/mL infused fluid) intraoperatively. Twenty percent albumin expanded the plasma volume by between 1.9 and 2.2 times the infused volume if calculated with the regression method or the AUC method, respectively, over 5 hours of surgery and with a mean hemorrhage volume of approximately 1000 mL. The blood volume expansion resulting from infusion of lactated Ringer’s solution was no more than 20%–40% of the infused volume depending on the calculation method.

The changes associated with 20% albumin in this intraoperative setting are quite similar to findings made in volunteers and after major abdominal surgery, where it amounts to twice the amount of fluid infused volume.

CO, SV, mean arterial blood pressure, and plethysmography variability index were clinically stable over experimental time, which supports the statement that hemodynamics were stable surrogating normovolemia. There was a good correlation between the amount of infused lactated Ringer’s solution versus the sum of the hemorrhage volume and the blood volume change (Figure 4). This comparison is interesting because the overall changes in blood volume were practically 0; we can then estimate how much lactated Ringer’s solution was needed to compensate for blood loss when coinfused with 3 mL/kg of 20% albumin. Almost a mean of 50% of the lactated Ringer’s solution was retained intravascularly during 5 hours when boosted with the hyperoncotic albumin during the first 30 minutes, which is a surprisingly good effect. The time course of the changes in fluid effect depicted in Figure 3 even suggests that the supportive effect of 20% albumin on the blood volume becomes even better as the plasma volume expansion due to the lactated Ringer’s solution decreases during the last 2 hours of surgery.

The effective oncotic pressure of an albumin solution depends on its albumin content: in the case of 20% albumin, it is approximately 4 times that of human plasma. Albumin is a very soluble, globular protein, accounting for 70–80% of the colloid osmotic pressure of plasma, which is the predominant reason for its clinical use, and thus it retains more water intravascularly. The combined administration of lactated Ringer’s solution (in a 1:1 ratio) and 20% albumin (3 mL/kg) to replace losses due to intraoperative hemorrhage could be a valuable option in terms of fluid management, reducing positive fluid balance. This is of importance as postoperative positive fluid balance of more than 2–3 L has been associated with delayed return of bowel function after major abdominal surgery and increased morbidity.^19,23,24

We observed that 40% of the lactated Ringer’s solution was maintained intravascularly and that the within-patient change of 20% albumin did not differ much between our study and studies conducted in volunteers. We may speculate that, in our patients, the endothelial barrier was not seriously damaged. The benefit of 20% albumin seems to be the restoration of optimal colloid osmotic pressure, a better intravascular effect of the fluid administered (crystalloids), and the relatively low total amount of fluid and lactated Ringer’s solution needed to maintain normovolemia and a well-maintained hemodynamic profile.

The intraoperative administration of hyperoncotic albumin has been a topic of research for decades. The rationale behind this was that a hyperoncotic substance could prevent the intraoperative formation of edema. This is of relevance in surgery where the ileum is usually used for reconstruction. An edematous bowel makes bowel anastomosis more difficult to perform and carries a greater risk of dehiscence and infection.^20,25,26 Prien et al⁶ showed that the administration of 20% albumin prevents the formation of edema of the intestine during major gastrointestinal surgery because the 20% albumin helps avoid colloid osmotic pressure decrease. Moreover, the administration of 20% albumin in volunteers and after major surgery showed that plasma volume expansion occurred by recruitment of fluid from the interstitium.^5,27

Limitations

Both methods used here to study the plasma volume expansion of infusion fluids are based on the assumptions that the blood volume can be predicted by anthropometric regression equations, that Hb molecules are distributed evenly throughout the circulating blood volume, and that the blood loss is assessed accurately by weighing sponges and measuring the content of suction bottles. Suboptimal calculation of the blood volume cannot be excluded even if correction for blood samples was made and patients were assumed to be normovolemic at the time the bladder was removed. The blood volume at baseline was estimated by Nadler’s anthropometric formula, which is based on 155 isotope measurements in men and women with body weights ranging from 36 to 177 kg.²⁶ The average blood volume in their study was close to 5 L, which is quite similar to our patients. However, the regression method we used is quite insensitive to moderate errors in the assumed baseline blood volume. If we assume blood volumes of 5.0 and 4.5 L and hemorrhage of 0.5, a change in blood Hb from 15 to 12 g/dL will only distort the estimated blood volume change by 100 mL. The present 2 approaches are also forgiving for errors in time and yet offer fair and clinically useful answers about within-patient change in plasma volume expansion in complex scenarios with ongoing hemorrhage and simultaneous infusion of 2 fluids having quite different characteristics.

The plasma volume expansion of infusion fluids can be assessed in several ways, none of which is perfect in all situations. Isotope dilution requires a steady state with regard to the fluid balance during the equilibration period, which can be difficult to guarantee. Moreover, changes over time can be difficult to show. Volume kinetics requires very precise data on blood loss at each measurement, requiring 20–30 samples during an experiment. Volume kinetics cannot yet resolve the effects of 2 fluids given simultaneously, although it is possible if fluids are given sequentially.²⁸

Two different types of calculations used in the present study (the regression and the area methods) yielded a similar blood volume expansion effect for 20% albumin (190% vs 220%, respectively), while the discrepancy was markedly greater for lactated Ringer’s solution (38% vs 20%). The reason for the lower within-patient change, as suggested by the AUC method, might be that plasma volume expansion resulting from the lactated Ringer’s solution was inferred from previous experiments performed by Drobin and Hahn.²¹ These other data were derived in the presence of hemorrhage of 900 mL, which is similar to the average amount of bleeding in the present study, but were observed in conscious young volunteers instead of in older anesthetized patients.

The administration of hyperoncotic albumin to treat shock and hypovolemia has been associated with poorer renal outcome.²⁹ Warnings have been raised against the treatment of dehydrated patients with hyperoncotic albumin. This observation could not be confirmed in the present setting, but the number of patients was low. The urine osmolality and the urinary concentration of creatinine were normal before surgery, showing that fluid retention due to dehydration was not present. Further concentration of the urine during the study was not impressive and can probably be explained solely by the reduced urine flow due to anesthesia-induced reduction of the arterial pressure.³⁰ The lack of a more marked increase in the urinary biomarkers of renal fluid retention at the end of surgery confirms that the kidneys excreted urine at a fairly normal rate and could hardly have experienced hypovolemic stress.

CONCLUSIONS

The infusion of 20% albumin during surgery with hemorrhage of around 1000 mL expanded blood volume by twice the infused volume, which is approximately 5 times more than for lactated Ringer’s solution. These results suggest that 20% albumin is a potent blood volume expander with a long-lasting effect in this setting. The results can also demonstrate that the infusion of 3 mL/kg of 20% albumin boosts the blood volume expansion of lactated Ringer’s solution to as high as 40% of the infused volume on the average during major abdominal surgery lasting 5 hours.

ACKNOWLEDGMENTS

We acknowledge the editorial assistance of Jeannie Wurz, BA, Medical Editor, Department of Anaesthesiology and Pain Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.

DISCLOSURES

Name: Lukas M. Löffel, MD.

Contribution: This author helped write applications, organize and collect the patient data, and cowrite the manuscript.

Name: Robert G. Hahn, MD, PhD.

Contribution: This author helped plan the study, analyze the data, design graphs and tables, and cowrite the manuscript.

Name: Dominique Engel, MD.

Contribution: This author helped organize and collect the patient data and cowrite the manuscript.

Name: Patrick Y. Wuethrich, MD.

Contribution: This author helped plan the study, write applications, collect the patient data, analyze the data, cowrite the paper, and submitted the manuscript.

This manuscript was handled by: Tong J. Gan, MD.