Effects of pentafraction and hetastarch plasma expansion on lung and soft tissue transvascular fluid filtration

Effects of pentafraction and hetastarch plasma expansion on lung and soft tissue transvascular fluid filtration Gregory A. Myers, MD, Robert L. Conhaim, PhD, David J. Rosenfeld, BA, and Bruce A. Harms, MD, Madison, Wis.

Background. Hetastarch and pentafraction are high molecular weight starch solutions designed to augment plasma oncotic pressure. Although clinical utilization of hetastarch has been limited by reported coagulation abnormalities, pentafraction is a newer derivative that appears to have few adverse hemostatic effects. We examined the ability of pentafraction to modulate lung and soft tissue transvascular fluid filtration under hypoproteinemic conditions compared with hetastarch and Ringer's lactate (LR). Methods. Awake, protein-depleted sheep (n = 79) were prepared with lung and soft tissue lymph fistulas, and comparable infusions of 5% pentafraction (n = 6), 6% hetastarch (n = 6), or L R (n = 7) were administered. Plasma and lymph samples were collected during 24-hour period to determine changes in protein concentrations, plasma-to-lymph oncotic gradients, and lung (QL) and soft tissue (Qs) lymph flows. Results. Qj~ and Qs rose nearly twofold after protein depletion alone. LR infusion increased QL and Qs to 8.7 +_ 1.7 and 3.1 +_ 0.6 times normoproteinemic baseline, respectively (p < 0.05). In contrast, hetastarch and pentafraction infusion limited the increase in QL to 4.2 +. I. 1 and 4.0 + 0.8 times normoproteinemic baseline, respectively (p < 0.05 versus LR) and did not significantly increase Q,s,. Hetastarch and pentafraction infusions increase plasma oncotic pressure by nearly 6 mm Hg, which significantly widened the plasma-to-lymph oncotic pressure gradients above preinfusion baseline by 4.7 +_ O. 7 and 3.4 +_ 0.4 mm Hg in lung and 4.6 + O. 7 and 3.2 +_ 0.4 mm Hg in soft tissue, respectively (p < 0.05). Conclusions. Both hetastarch and pentafraction limit transvascular fluid filtration under hypoproteinemic conditions by augmenting plasma oncotic pressure and the plasma-to-lymph oncotic pressure gradient. Because of fewer adverse hemostatic effects pentafraction may be an improvement over current therapies in critical care fluid management. (SURGERY 1995; l 17:340-9.) From the Department of Surgery, University of Wisconsin-Madison, and William S. Middleton Memorial Veterans Hospital, Madison, Wis.

PROGRESSION OF TRANSVASCULAR FLUID filtration to clinically significant pulmonary and soft tissue edema can complicate fluid resuscitation after blood loss from major trauma or surgery. Fluid filtration within the pulmonary and systemic microcirculations is influenced by a number of factors that include (1) microvascular hydrostatic pressures, (2) oncotic pressure gradients, and (3) the filtration characteristics of organ specific microcirculations. Transient elevations of microvascuSupportedbygrants fromthe NationalInstitutesofHealth (HL46236) and the Department of Veterans Affairs. Accepted for publication July 25, 1994. Reprint requests: Bruce A. Harms, MD, Department of Surgery, University of Wisconsin Hospital and Clinics, 600 Highland Ave., Madison, WI 53792.

11/.56/61329 340

SURGERY

lar hydrostatic pressure occur when fluid infusion exceeds requirements for stable hemodynamic parameters and can precipitate marked increases in both pulmonary and soft tissue fluid flux. i, z Hypoproteinemia lowers plasma oncotie pressure and enhances fluid filtration in the lung and soft tissue independent of alterations in microvascular porosity or hydrostatic pressures. 2"9 Hypoproteinemia may develop quickly with rapid protein-free fluid replacement after significant blood loss and may persist during the posttraumatic hypermetabolie state. The effects on transvascular filtration are compounded when elevations in hydrostatic pressure coexist with hypoproteinemia. 2, 7, s Hydroxyethyl starch plasma volume expanders such as hetastarch have previously been shown to blunt pulmonary transvascular fluid filtration during hypoproteinemic conditions compared with crystalloid infusion. 8

Surgery Volume 117, Number 3

The high average molecular weight of hetastarch (450 kd) limits its escape from the circulation, which augments plasma volume and restores plasma oncotic pressure. Unfortunately, the larger molecular weight fractions among the heterogeneous spectrum of starch molecules present in hetastarch (20 to 2000 kd) have been implicated in clotting abnormalities that have markedly limited the clinical use of hetastarch) ~ Pentafraction is a newer synthetic hydroxyethyl starch solution with an average molecular weight of 200 kd and a narrower molecular weight spectrum (40 to 1250 kd) than hetastarch. We previously demonstrated the ability of pentafraction infusion to limit transvascular filtration compared with crystalloid.4 However, little information is available on the osmotic effectiveness of pentafraction compared with other colloid solutions. Despite the smaller average size of starch molecules compared with hetastarch, pentafraction may impart similar plasma osmotic pressures and limitation of transvascular fluid filtration. In addition, pentafraction has a relative lack of adverse effects on hemostatic parameters, which may be attributable to the exclusion of most larger molecular fractions found in hetastarchJ ~ In this respect pentafraction may be an improvement over hetastareh in critical care fluid management. Our aim in this study was to investigate the effects of intravenous pentafraction administration on transvascular fluid flux compared with similar infusions of hetastareh and Ringer's lactate (LR). To better evaluate differences among these solutions and the relationship between microvascular pressures and fluid filtration, infusions were administered to produce supranormal cardiac filling pressures, as might occur clinically with overaggressive fluid resuscitation or after postoperative remobilization of third-spaced fluid. To further simulate the difficulties encountered in the management of the critically ill patient, the effects of volume expansion with these solutions were studied under hypoproteinemic conditions. The efficacy of pentafraction as a resuscitation fluid was assessed with regard to its ability to augment hemodynamic parameters, restore plasma oncotic activity and the plasma-to-interstitial oncotic gradient, and to limit transvascular fluid filtration as reflected by pulmonary and soft tissue lymph flow. METHODS

Animal preparation. Nineteen adult sheep (35 to 50 kg) were surgically prepared with chronic lung and soft tissue lymph fistulas. By use of the method of Staub et al. n the efferent lymphatic of the caudal mediastinal lymph node was cannulated through a right thoracotomy incision, and the Silastic silicone rubber cannula (no. 602-015; Dow Corning Corp., Midland, Mich.) was externalized for continuous collection of lung lymph. The node was then ligated at its proximal end

Myers et al.

341

near the diaphragm, and tributary diaphragmatic lymphatics were cauterized to eliminate contamination from systemic lymph. 12 To allow for the continuous collection of soft tissue lymph, a prefemoral efferent lymphatic vessel draining the skin and subcutaneous tissue in the lower abdomen and flank was also cannulated, as described by Demling et al) 3 Animals were instrumented with carotid and central venous access lines and a Swan-Ganz thermodilution catheter (American Edwards Laboratories Inc, Anasco, Puerto Rico). Each animal was placed in a metabolic cage and was given free access to food and water throughout the study. Experimental protocol. Each animal was given a 5-day recuperation period after operation to allow for normalization of hemodynamic parameters and lymph flows. Lymph and plasma samples were then collected every 30 minutes for 4 hours to determine normoproteinemic baseline (NormBaseline) lymph flows and protein concentrations. Serial batch plasmapheresis during a 3-day period was performed to establish a chronic protein depleted state. The day after plasmapheresis was completed, lymph and plasma samples were collected every 30 minutes for 2 hours to determine hypoproteinemic baseline (HypoBaseline) lymph flows, protein concentrations, and oncotic pressures. HypoBaseline hemodynamic data were also collected during this 2-hour period. Each animal then received a 2-hour infusion of 6% hetastarch (n = 6), 5% pentafraction (n = 6) (pentafraction and hetastarch [Hespan] were supplied by Dupont Pharmaceuticals, Wilmington, Del.), or LR (n = 7). For each infusion the rate was carefully adjusted to maintain the pulmonary arterial wedge pressure 5 to 6 mm Hg above HypoBaseline values during the 2-hour period of volume expansion. By this means hydrostatic pressure was controlled and equivalent among the three infusion groups. This permitted analysis of the effect of each solution on the plasma-to-lymph oncotic gradient and the resulting influence on transvascular fluid flux. After the start of each infusion (hour 0) lymph and blood samples were collected every 30 minutes for 6 hours and at 12 hours and 24 hours to determine lymph flows, protein concentrations, and oncotic pressures. Mean aortic (AOP), pulmonary arterial (PAP), pulmonary arterial wedge (PAWP), and central venous pressures (CVP) were measured by using calibrated pressure transducers (Gould Inc., Cardiovascular Products, Oxnard, Calif.) and recorded on a multichannel physiograph with continuous digital display ( E / M ; Honeywell Electronics, Chicago, Ill.). Pulmonary and " soft tissue microvascular pressures were calculated as follows: PMVLung = PAWP + 0.4(PAP - PAWP) 1 and PMvso~t = CVP + 0.1 (AOP - CVP). All pressures were referenced to the level of the humeral tuberosity, which we considered to be level with the left atrium.

342

Myers et al.

Surgery March 7995

Table I. Hemodynamic parameters at NormBaseline, HypoBaseline, and at peak response after hetastarch, pentafraction, and LR infusions

PAWP (ram Hg) Hetastarch NormBaseline HypoBaseline Peak Increase Pentafraction NormBaseline HypoBaseline Peak Increase LR NormBaseline HypoBaseline Peak Increase

PMVLung

(mm He)

PMvsof~ (ram Hg)

6.7 6.1 12.1 6.0

_+ 0.7 +_ 1.0 _+ 1.2" _+ 0.5

10.1 + 0.9 10.7 + 1.0 18.5 -+ 1.6" 7.7 _+ 0.9

11.7 11.2 20.3 8.6

_+ 1.1 _+ 1.4 _+ 1.1" -+ 1.0

7.2 7.9 13.6 5.7

_+ 1.1 _+ 0.7 _+ 0.8* 4- 0.3

12.7 13.0 19.2 6.1

_+ 0.9 -+ 1.2 _+ 0.9* _+ 0.6

13.8 14.2 20.7 6.5

+_ 1.3 +_ 1.1 + 1.9" 4- 1.0

6.7 8.1 13.4 5.2

_+ 1.3 _ 1.1 + 0.9* _ 0.4

11.7 13.1 19.0 6.0

_+ 0.9 _ 1.1 + 1.3" + 0.6

13.2 --- 1.2 14.9 _ 1.1 21.9 __+0.9* 6.6 +- 0.7

Values are mean + SEM. *Significantly different from HypoBaseline (p < 0.05).

To quantitate pulmonary and soft tissue lymph flow, lymph samples were collected for 30-minute periods in heparinized graduated cylinders and measured to the nearest 0.1 ml. Corresponding samples of arterial blood were collected for measurement of total protein concentration and oncotic pressures. Plasma and lymph oncotic pressures were measured by using an oncometer (Wescor 4420; Weseor, Inc., Logan, Utah) equipped with a 10,000 molecular weight membrane. All samples were measured at room temperature after calibration of the oncometer with a bovine serum albumin standard. Total protein concentrations in both plasma and lymph were quantitated by using the Lowry assay. 14 Plasma protein depletion. The reduction in plasma protein concentration in each animal was accomplished by serial batch plasmapheresis. This method has been shown to be a consistent and effective technique for the establishment of long-term protein depletion with recovery of plasma and lymph proteins occurring gradually during 2 to 3 days. z'9 Demling et al. 5 and Kramer et al. 9 have previously shown that in animals not receiving additional intravenous solutions, an initial plasma protein reduction of 40% to 50% produces a hypoproteinemic state for 48 to 72 hours in plasma, up to 48 hours in lung lymph, and more than 72 hours in soft tissue lymph. We subjected each animal to 3 consecutive days of plasmapharesis to establish a 28% to 33% reduction in plasma protein concentration at HypoBaseline. An average of 4 to 6 units of whole blood per day from each animal underwent plasmapheresis. Arterial blood was collected in 450 ml citrate-phosphate-

dextrose-adenine blood packs containing 63 ml of anticoagulant solution (Fenwal Inc., Ashland, Mass.). After centrifugation (3000 rpm for 10 minutes) plasma was extracted aseptically and discarded, and packed cells were promptly returned to each animal. LR was infused throughout plasmapheresis to maintain arterial and central venous pressures at baseline values. After the completion of the third day of plasmapheresis, the animals were allowed to equilibrate hemodynamically overnight (18 hours) and received no intravenous liquids until the infusion studies were begun on the following day. Statistical analysis. All values are expressed as mean _+ SEM. A paired Student's t test was used to evaluate changes from HypoBaseline within each infusion group. Mean values among the study groups at a given time period were compared by using a single factor analysis of variance followed by Fisher's protected least significant difference test. A p value of <0.05 was considered statistically significant. A computer based statistics program was used to perform all tests (StatView II; Abacus Concepts Inc., Berkeley, Calif.).

RESULTS Hemodynamic parameters. NormBaseline, HypoBaseline, and peak values of PAWP, PMVLung, and PMvsoft are shown in Table I. HypoBaseline hemodynamic values did not significantly differ from those at NormBaseline. During the 2-hour infusion period 1780 _+ 95 ml of hetastarch, 1500 +_ 81 ml of pentafraction, and 6600 + 134 ml of LR were administered. These infusions produced similar increases in PAW (6.0 + 1.2, 5.7 _ 0.3, and 5.2 + 0.4 mm Hg for hetastarch, pentafraction, and LR, respectively). Mean PMVLungand PMvsoft were not significantly different among the infusion groups at peak response or at any point during the study periods. Plasma and l y m p h protein response. Protein concentrations in plasma and pulmonary and soft tissue lymph under normoproteinemic and hypoproteinemic conditions and in response to hetastarch, pentafraction, and LR infusions are shown in Table II. Plasmapheresis decreased NormBaseline plasma protein concentration (PT) by approximately one third for each of the three study groups (p < 0.05). Pulmonary (LT) and soft tissue (ST) lymph protein concentrations also fell significantly below NormBaseline in response to plasmapheresis (p < 0.05). HypoBaseline PT values for the three study groups were similar (hetastarch, 45.8 -+ 5.6 gm/L; pentafraction, 40.3 + 1.9 gin/L; and LR, 40.0 -+ 2.3 gm/L; Table II). After 2 hours of hetastarch or pentafraction infusion PT fell to 64% (29.4 + 3.7 g m / L ) and 67% (27.0 +_ 1.1 g m / L ) of HypoBaseline levels, respectively, and remained significantly below HypoBaseline for 12 hours (p < 0.05). PT values were

Surgery Volume 117, Number 3

Myers et al.

343

Table II. Protein concentrations (gm/L) in plasma, lung lymph, and soft tissue lymph under normoproteinemic conditions, hypoproteinemic conditions, and in response to infusions of hetastarch, pentafraction, or LR

Hetastarch

Norm63.2_+1.1" Baseline Hypo45.8 _+5.6 Baseline Hours after infusion 1 35.0_+2.3 2 29.4 _+3.7" t 3 25.8-+ 3.8"~ 4 28.4 _+2.4" t 5 30.0 _+3.4" t 6 30.0_+4.0*t 12 34.1 _+4.7*t 24 37.4_+ 3.1t

Plasma

Lung lymph

Pentafraction

Pentafraction

LR

Hetastarch

Soft tissue lymph LR

Hetastarch

Pentafraction

LR

64.0_+2.1" 54.7_+1.9" 38.2_+1.5" 40.1_+1.8" 37.9_+1.9" 27.4-+0.9* 30.8_+5.0* 23.6_+1.8" 40.3_+1.9

40.0_+2.3 22.1_+1.7 18.2_+1.3 19.3_+1.5 8.8_+0.6 10.5_+0.8 8.3_+1.7

28.3_+1.3" 27.0_+1.1" 28.3-+1.0"t 27.8___3.4t 30.5_+2.8 31.5_+2.6" 33.3_+2.1"t 38.6_+2.5t

32.7_+2.5* 22.1_+1.7~ 31.8_+2.8" 20.1_+1.6"~ 37.2_+2.6* 20.8-1.0t 37.7_+2.8 20.8_+0.9 36.6-+1.1 22.6+1.4 t 38.5-+2.5 21.9_+1.2 44.5_+1.8" 23.1-+1.6 49.3_+2.1" 28.4_+1.6"

15.5___1.2"t 15.3+1.3" t 17.0_+2.3t 18.0-+2.4t 18.0___1.4t 19.8_+1.9 22.0_+2.0* 22.5_+1.9"

12.4_+1.6" 7.8_+1.5 11.6_+1.4" 7.7_+1.8 11.7_+1.2" 8.5_+2.4 14.3_+2.2" 8.8-+2.7 13.0-+0.8" 9.9_+2.7 17.0_+1.8 10.2_+2.9 18.4_+2.5 10.1-+1.5 24.9-+2.3* 11.4_+0.1

10.0_+0.8 9.5_+0.6 9.5_+0.8 9.0+1.2 10.0_+1.3 10.3_+1.1 13.8_+2.3 12.1_+2.1

7.9_+1.8 6.6_+1.4" 7.6_+1.8" 7.5-+2.1" 5.9_+0.7* 7.4_+1.5" 8.0_+1.6 8.2-+1.7

Values are mean + SEM. *Significantly different from HypoBaseline (p < 0.05). tSignificantly different from LR (p < 0.05). /;Significant difference between hetastareh and pentafraction (p < 0.05).

similar for hetastarch and pentafraction throughout the 24-hour study period except at 3 hours, when PT had fallen to 25.8 + 3.8 g m / L after hetastarch infusion, which was significantly less than the decrease to 28.3 _+ 1.0 g m / L after pentafraction infusion (p < 0.05). Volume expansion with LR also significantly lowered PT, which fell to 79% (31.8 +_ 2.8 gm/L) of HypoBaseline level after 2 hours (p < 0.05). However, PT rapidly returned to 96% (37.7 _+ 2.8 gm/ dl) of HypoBaseline within 4 hours. Twelve hours after LR infusion PT exceeded HypoBaseline values (44.5 _+ 1.8 gm/L; p < 0.05) as the animals began to recover from protein depletion. In contrast, PT never surpassed HypoBaseline values after hetastarch or pentafraction infusions because of the dilutional effect of the starch molecules. Values for LT were similar among the three study groups at HypoBaseline and averaged 19.5 _+ 0.9 g m / L (Table II). Hetastarch infusion did not significantly change LT. Volume expansion with pentafraction resulted in a mild but significant reduction in LT to 84% (15.3 _+ 1.3 gm/L) of HypoBaseline after 2 hours (p < 0.05), with immediate recovery to HypoBaseline level after completion of the infusion. In contrast, LT decreased to 60% (11.6 _+ 1.4 gm/L) of HypoBaseline (p < 0.05) 2 hours after starting LR infusion and did not return to preinfusion value until after 6 hours. Twenty-four hours after completion of hetastarch, pentafraction, and LR infusions, LT for each of these study groups had increased to values greater than HypoBaseline (28.4 _+ 1.6, 22.5 _+ 1.9, and 24.9 _+ 2.3 gm/L,

respectively; p < 0.05), again because of partial recovery from protein depletion. ST did not differ significantly among the starch and LR groups at any point in the study (Table II). ST remained comparable to HypoBaseline after volume expansion with either hetastarch or pentafraction. In contrast, however, S T fell significantly to 79% (6.6 _+ 1.4 gm/L) of HypoBaseline 2 hours after starting LR infusion (p < 0.05) and did not return to HypoBaseline level until after 12 hours. Lung and soft tissue lymph flow. Lymph flows for lung (QL) and soft tissue (Qs) for each of the study groups are reported as multiples of their NormBaseline values (QL' and Qs'), which averaged 3.2 _+ 0.9 and 2.7 _+ 0.4 ml/30 min, respectively (Fig. 1). Protein depletion increased QL and Qs to 2.3 _ 0.3 and 1.8 _+ 0.2 times their respective NormBaseline values (p < 0.05). No significant differences were noted in Q L / Q L ' or Q s / Q s ' among the three infusion groups at HypoBaseline. LR infusion markedly increased Q L / Q L ' from 3.0 _+ 0.6 at HypoBaseline to a peak value of 8.7 _+ 1.7 at 2 hours (p < 0.05) (Fig. 1, A). QL/QL' remained significantly elevated above HypoBaseline for 6 hours after LR infusion. Volume expansion with hetastarch or pentafraction also raised Q L / Q L ' from 1.9 _+ 0.6 and 1.8 +- 0.6 at HypoBaseline, respectively, to peak values of 4.2 _+ 1.1 and 4.0 _+ 0.8 at 2 hours (p < 0.05); these values returned to HypoBaseline by 4 hours. No differences were noted between hetastarch and pentafraction with respect to QL/QL', but the increase in lung lymph

344 Myers et al.

Surgery March 1995

A

lo

Ii

o

$~.,~

~

/ it , N

EE

/,t

~o

"~

LR

.

-LNI

2

I Iniusi~

Norm-

HypoBaseline Baseline

S

,

,

2

4

6

2

4

//

, 12

//

, 24

4

Norm-

Baseline

Hypo-

Baseline

6

12

24

Hours

Fig. 1. Lung (A) and soft tissue (B) lymph flows relative to NormBaseline before and after infusion of hetastarch, pentafraction, or LR. Lung and soft tissue lymph flows at HypoBaseline were significantly greater than NormBaseline for all three groups (p < 0.05). *Significantly different from HypoBaseline (p < 0.05). tSignificantly different from LR (p < 0.05).

flow produced by the two starch solutions was significantly less than that obtained with LR throughout the 12-hour period after volume expansion (p < 0.05). In response to LR infusion, Q s / Q s ' increased significantly from 1.8 + 0.2 at HypoBaseline to a peak value of 3.1 + 0.6 after 3 hours (p < 0.05) and then returned to HypoBaseline after 6 hours (Fig. 1, B). In contrast, no significant change occurred in Q s / Q s ' throughout the 24-hour period after volume expansion with hetastarch or pentafraction. Oncotlc pressures. After protein depletion plasma oncotic pressures (~-p) among the starch and LR infusion groups significantly decreased from a pooled average of 19.7 + 0.4 mm Hg at NormBaseline to 10.8 + 0.4 mm Hg at HypoBaseline (p < 0.05) (Fig. 2). Plasmapheresis also decreased lung lymph oncotie

pressure ('/rL) from a pooled average of 14.0 + 0.5 to to 5.2 _+ 0.3 mm Hg (p < 0.05) and soft tissue lymph oncotic pressure (Trs) from 7.9 +_ 0.7 to 2.6 -+ 0.4 mm Hg (p < 0.05). Volume expansion with hetastarch or pentafraction resulted in prompt and sustained increases in 7rp to average values of 16.7 _ 0.5 and 16.2 _ 0.8 mm Hg, respectively (p < 0.05), throughout the 24-hour period after infusion (Fig. 2, A). In contrast, after LR infusion ~rp fell to an average of 8.3 _+ 0.7 mm Hg during the first 4 hours (p < 0.05) and then returned to HypoBaseline level by 5 hours. In response to hetastarch infusion "itE rose continuously throughout the 24-hour study period, climbing by nearly 6 mm Hg above HypoBaseline to 11.6 +_ 0.5 mm Hg (p < 0.05; Fig. 2, B). After pentafraction infusion

Surgery Volume l l 7, Number 3

~rL rose by 5 mm Hg above HypoBaseline to 9.9 _ 1.4 mm Hg at 24 hours (p < 0.05). Infusion with LR resulted in a 2 mm Hg decrease in ZrL to 2.4 + 0.5 mm Hg at 3 hours (p < 0.05), with gradual recovery to HypoBaseline level by 12 hours. A small but steady increase in ~rs occurred in response to both hetastarch and pentafraction infusions, reaching 4.9 _+ 1.1 and 5.9 + 1.9 mm Hg, respectively, after 24 hours (p < 0.05; Fig. 2, C). In contrast, LR infusion produced a mild decrease in ~rs to 0.8 _+ 0.3 mm Hg after 6 hours (p < 0.05), returning to near HypoBaseline level by 12 hours. Oncotic pressure gradients. NormBaseline plasmato-lymph oncotic gradients for lung and soft tissue 0rp~rL; ~rp-~rs) were similar among the hetastarch, pentafraction, and LR groups with pooled averages of 5.9 + 0.5 and 11.5 + 0.7 mm Hg, respectively (Fig. 3). Protein-depletion decreased a'p-~rL to 5.6 _+ 0.3 mm Hg and ~rp-~rs to 8.0 -+ 0.5 mm Hg. After volume expansion with hetastarch or pentafraction the two starches responded similarly, producing a dramatic widening of 7rp-TrL to 10.1 _+ 1.0 and 9.4 + 0.8 mm Hg, respectively, at 3 hours (p < 0.05), with a gradual return to HypoBaseline level by 24 hours. Hetastarch and pentafraction infusions also resulted in a similar widening of 7rp-~rs to 13.9 + 0.9 and 12.8 _+ 0.7 mm Hg, respectively, at 3 hours (p < 0.05), with subsequent narrowing to HypoBaseline level by 24 hours. In contrast, LR infusion (p < 0.05) produced no changes in either ~rp-~rL or ~rv-~'S, because plasma and lymph oncotic pressures fell concomitantly. DISCUSSION

Fluid management of critically ill patients after traumatic injury and operative procedures with major blood loss can be complicated by excessive transvascular fluid filtration. This effect is important because of the potential for pulmonary and soft tissue edema. Accumulation of fluid in the pulmonary interstitium or alveoli can alter airway and vascular resistance, resulting in ventilation/perfusion mismatch and impaired gas exchange.15 Soft tissue edema can likewise be deleterious by decreasing tissue oxygen tension, which increases the risk of infection and impairs wound healing. 16, 17 The physiologic basis for transvascular fluid filtration is described by the Starling-Landis equation 18, i9 QL = KF[(PMv -- PPMV) --a0rMV -- ~rVMV)], where QL is the filtration rate and P and ~r are the hydrostatic and oncotic pressures in the microvascular (MV) and perimicrovascular (PMV) compartments, respectively. The protein reflection coefficient for the microvascular filtration barrier (range, 0 to 1) is represented by a, and K1% the filtration coefficient, is a measure of the resistance to fluid passage from the intravascular space to the

345

Myers et al.

22

20

~-~

18

II/O#~'t

~ ~4 o. .-"~ ~

el

*t

*~"

I ,t ~t,,(~t ,~.,~)t .(~. ,.-~t t ,~ *t t

"

-7.*/

4

NormBaseline

B

Baseline

is 14

I

lu n u

12

.,

Y...)'

4", l

"'

10

u,,r

=E s o. .J

~

6

+

4

•

I \T

I

v T

T

I~

2 Infusion*

NormBaseline

C

i+

8 7

.,,. I'+"~

,

*

.4

*

t

; z

Baseline

+ T

0.

i:-P

4

"E EE _~

a

I =

l

*t

I

i:

Y]]

I,~ NormBaseline

HypoBseeline

2

4

6

]. 12

24

Hours

Fig. 2. Oneotic pressure in plasma (A), lung lymph (B), and soft tissue lymph (C) before and after infusion of hetastarch, pentafraction, or LR. Plasma and lymph oncotic pressures at HypoBaseline were significantly less than NormBaseline for all three infusion groups (p < 0.05). *Significantly different from HypoBaseline (p < 0.05). tSignificantly different from LR (p < 0.05).

interstitium. Under normal conditions the hydrostatic gradient from the vascular to interstitial space exceeds the opposing oncotic gradient, which results in net filtration from the circulation equal to the lymph flow. Transvascular fluid filtration in critically ill patients

346

Myers et al.

Surgery March 1995

A

12

t ~tT 10

~ . 0 ~ ~rt *t

8 6 4

HET PEN

LR Infusion Norm.

Baseline

B

, 2

HypoBaseline

' 4

' 6

II

' 12

II

24

~r

16 14

A

12

9IE E

10

---oo

8

o.

6 4 Infusion

NormBaseline

HypoBasellne

2

,

,

4

6

//

, 12

//

,

24

Hours

Fig. 3. "/l'p-./i-L (A) and '/rp-'/l"S (B) oncotic gradients before and after infusion of hetastarch, pentafraction, or LR. *Significantly different from HypoBaseline (p < 0.05). tSignificantly different from LR (p < 0.05).

is affected by the magnitude of plasma volume expansion and acute or preexisting hypoproteinemia. Microvascular hydrostatic pressure may be augmented in response to excessive plasma volume expansion caused by overresucitation, rapid intravenous infusion, or postoperative remobilization of third-spaced fluid. The impact of hydrostatic forces was demonstrated by Erdmann et al, 1 who described increased pulmonary fluid filtration and accumulation of extravascular lung water in response to increases in left atrial and pulmonary microvascular pressures. Hypoproteinemia is another compounding factor that is frequently observed in patients with severely burns or who had suffered trauma or after surgical procedures with major blood loss. z0' Zl Resuscitation of these patients with protein-free crystalloid solution may further reduce ~rp through a dilution of plasma proteins. Even in the absence of volume expansion, we observed an increase in QL and Qs as a result of protein depletion alone, which has been previ-

ously reported in response to both acute and chronic hypoproteinemia, z'9 The relative importance of hypoproteinemia was demonstrated by Kramer et al., 2 who found that a decrease in ~rp resulted in twice the increase in QL compared with an equivalent increase in mierovascular hydrostatic pressure. Furthermore, the effects were cumulative; an elevation in mierovascular pressure during hypoproteinemia increased pulmonary lymph flow more than at normal plasma protein concentrations. In our present comparison of pentafraction, hetastarch, and LR infusions under hypoproteinemic conditions, QL and Qs increased in all three study groups because of the elevation in hydrostatic pressures during volume expansion. However, the two starch solutions markedly limited this increase in plasma-to-interstitial fluid flux in both lung and soft tissue (Fig. 1). The lower lymph flows produced by pentafraction and hetastarch were not due to differences in hydrostatic

Surgery Volume 117, Number 3

pressures because the experimental protocol was designed to maintain a similar 5 to 6 mm Hg increase in PAWP for all three infusion groups, resulting in nearly identical PMVLungand PMvsoft. The restricted transvascular filtration after pentafraction and hetastarch volume expansion was the result of partial restoration of plasma oncotic activity that had been lost with protein depletion. Although hetastarch and pentafraction infusions further reduced PT to two thirds of preinfusion level (Table II), this dilutional effect was due to the addition of oncotically active starch macromolecules to the circulation. The net result was an increase in rrp of nearly 6 mm Hg, which persisted for the entire 24 hours after each starch infusion (Fig. 2). ~'L and a's also increased after either starch infusion, but the response was more gradual. As a result the plasma-to-lymph oncotic gradients were increased in both lung and soft tissue for up to 24 hours (Fig. 3). Thus although an elevated capillary hydrostatic pressure augmented lymph flows after hetastarch and pentafraction infusions, the concomitant increase in plasma-to-lymph oncotic gradients directly opposed this effect and attenuated the response. In contrast to pentafraction and hetastarch, LR reduced 7rp by more than 2 mm Hg during the 4 hours after starting infusion because of dilution of plasma proteins (Fig. 2). 7rL and 7rs decreased in a similar manner because the increase in hydrostatic pressure during LR infusion enhanced filtration of protein-free fluid into the interstitium and diluted lymph protein concentrations. As a result plasma-to-lymph oncotic gradients did not change after LR infusion (Fig. 3). Thus the rise in PMV with LR volume expansion was unopposed by increases in the oneotic gradients and produced profound increases in fluid flux. The osmotic effectiveness of hetastarch and pentafraction infusions was further shown by the volumes needed to maintain a 5 to 6 mm Hg increase in PAWP. During the 2-hour infusion period it was necessary to administer an average of 1.7 L of hetastareh and 1.5 L of pentafraction. In contrast, because of its dilutional effect and increased transvascular flux, an average of more than 6.6 L of LR was needed to sustain a similar elevation in filling pressure. Because macromolecular filtration is inversely proportional to molecular mass, an ideal resuscitation fluid should have high molecular weight particles that are too large to readily pass through transvascular pathways, thus retaining their osmotic effect within the vascular space. Hetastarch and pentafraction are hydroxyethyl starch solutions composed of heterogeneous populations of starch molecules with wide molecular weight ranges (hetastarch, 20 to 3000 kd; pentafraction, 40 to 1250 kd) and high average molecular weights (hetastarch, 450 kd; pentafraction, 200 kd) that are considerably larger than

Myers et al.

347

that of the most prevalent plasma protein, albumin (69 kd). However, our results suggest that these starches do partially filter from the circulation, because 7rL and 7rs rose steadily after volume expansion with either of the starch solutions (Fig. 2). The increase in "/rL was probably in part due to recovery from protein depletion, because at 12 hours LT had increased above preinfusion levels in both starch groups (Table II). However, recovery of interstitial proteins does not explain the rise in lrs or the early increase in 7rL. We previously demonstrated filtration of high molecular weight starches in a comparison of volume expansion with pentafraction and LR. 4 After infusion, concentrations of pentafraction in lung lymph were 35% of those in plasma at 3 hours and 44% at 12 hours. Accumulation of pentafraction in soft tissue lymph was more delayed, because pentafraction concentration was only 19% of that in plasma by 12 hours. We did not measure hetastarch concentrations in lymph fluid, but the increase in lymph oncotic pressures after infusion of the two starches in the present study suggests that the filtration of hetastarch and of pentafraction were similar (Fig. 2). Differences in pulmonary and soft tissue filtration for various resuscitation fluids have been previously described.4, 7 In the present study rrL increased immediately after starting the starch infusions and rose by an average of nearly 5 mm Hg at 24 hours (Fig. 2). In contrast, a lag was noted in the increase in ~rs, which only reached 2 to 3 mm Hg above preinfusion levels at 24 hours, suggesting less filtration of starch within the soft tissue. This resulted in greater widening of a'p-Trs compared with 7 r p - ' / r L (Fig. 3) and a greater increase in QL (approaching 4-fold) compared with Qs, which increased only 2-fold and failed to reach statistical significance (Fig. 1). These differences in filtration may represent variability in the fluid conductivity and macromolecular permeability of the pulmonary and soft tissue microcirculations. Furthermore, the pulmonary microcirculation receives the entire cardiac output, whereas the soft tissue microcirculation at rest receives only a fraction of this blood flow. Thus differences in perfusion may in part account for the more rapid accumulation of starches in the pulmonary interstitium compared with soft tissue. Although hetastarch and pentafraction infusions initially increased "/rp-Tr L and 7rp-Trs by nearly 4 mm Hg and 6 mm Hg (Fig. 3), respectively, these increases were limited by their partial filtration, because "/rL and 7rs rose concomitantly with 7rp (Fig. 2). Presumably, it is the smaller molecular weight particles among the heterogeneous population of starch molecules that filter. This effect is analogous to our previous investigation with autogenous plasma infusion in protein-depleted sheep, which resulted in a marked increase in pulmonary

348

Myers et al.

lymph flow and minimal widening of the plasma to pulmonary interstitial oncotic gradient. 7 This was probably due to the relatively small average size of plasma proteins, which led to their prompt filtration from the intravascular to pulmonary interstitial space. Dextran 70 is another colloid solution with relatively small macromolecules (average molecular weight, 70 kd). In a previous investigation with this solution, concentrations of dextran 70 in lung lymph reached 74% of those in plasma within 1 hour of infusion. 2z As a result dextran infusion failed to increase lrp-lrL. The smaller average molecular weight of pentafraction compared with hetastarch resulted in little difference in the osmotic effectiveness of the two solutions. Similar volumes of pentafraction and hetastarch were required to produce the same elevation in PMV. Furthermore, the augmentation of a-p (Fig. 2) and attenuation of lymph flows (Fig. 1) were identical after either starch infusion. The narrower molecular weight spectrum of pentafraction excludes most of the smaller starch fractions found in hetastarch, which presumably results in a similar proportion of macromolecules in pentafraction and hetastarch solutions that are too large to cross the filtration barrier. The lymphatic system has a finite capacity to transport fluid and protein that filters from the circulation. Pulmonary edema results when filtration exceeds this capacity and fluid begins to accumulate, first in the interstitium and ultimately in the air spaces of the lung. 15 Although the increase in pulmonary lymph flow that we measured after LR infusion was more than twice that of pentafraction or hetastarch, it is not clear whether this degree of filtration caused any accumulation of extravascular lung water. In previous studies in an ovine model of acute hemorrhagic shock, extravascular lung water did not increase after resuscitation with hetastarch, 5% albumin, or LR, even though LR caused a significant reduction in lrv and in the gradient between 7rp and PAWP. z3"25 However, these studies did not address the effects of long-term protein depletion or associated cardiopulmonary injury, which are factors that influence transvascular filtration in critically ill patients. In awake normoproteinemic sheep Erdmann et al. 1 showed that lung water began to accumulate when PMV approached 30 mm Hg. In the present study P MV never exceeded 22 mm Hg, but protein depletion in our animals reduced a'p, which lowered the threshold value of PMV at which interstitial edema would develop. Pentafraction and hetastarch augmented 7rp, opposing the effect of an increase in hydrostatic pressure, whereas LR further reduced ~-p through protein dilution. Therefore LR infusion is more likely to elevate PMV above the edema threshold. In the setting of chronic protein depletion and cardiopulmonary dysfunction, the twofold difference in

Surgery March 1995

pulmonary fluid flux between LR and the starches could account for significant lung fluid accumulation. Additional investigation is needed to evaluate the effects of pentafraction, hetastarch, and LR on extravascular lung water under the influence of these confounding factors. Despite the theoretic advantage of colloid solutions in limiting pulmonary transvascular fluid filtration and subsequent edema, prospective clinical trials with albumin therapy in critically ill patients have failed to show a beneficial effect on pulmonary function compared with crystalloid. In a population of surgical patients with severe pulmonary insufficiency (shunt fraction >20%), Metildi et al. 26 found that 5% albumin therapy failed to increase 7ri, or a-p-PAWP gradient. Furthermore, no differences were noted in pulmonary function, length of stay in intensive care unit, or survival in patients receiving albumin compared to those who received LR. Weaver et al. 27 randomly selected patients who had suffered major trauma to receive 150 grams of daily supplemental intravenous albumin during their postresuscitation course. These patients required significantly more positive end-expiratory pressure and prolonged ventilatory support and had greater fraction of inspired oxygen to Pao2 ratios compared with patients who did not receive albumin. In this study, however, albumin therapy also caused significantly higher CVP, PAWP, and calculated plasma volumes, which increase the tendency for transvascular filtration and obscure the comparison between the albumin and control groups. The lack of a pulmonary protective effect with albumin therapy in these clinical trials may be related to its low molecular weight. A previous investigation with labeled intravenous albumin in sheep indicated rapid equilibration between plasma and lymph, with a half-life of less than 2Vz hours. 22 This again emphasizes the importance of macromolecular size, because albumin is readily able to filter into the interstitium, resulting in little effective change in the transvascular osmotic gradient. The theoretic benefit of the hydroxyethyl starch solutions in critical care fluid management relates to their high average molecular weights and more restricted filtration. Unfortunately, the clinical application of hetastarch has been limited by several adverse effects on hemostasis and coagulation. Hetastarch prolongs partial prothrombin time and bleeding time and reduces circulating plasma levels of factor VIII. 9 The potential advantage of pentafraction as a volume expander is that it lacks the larger molecular weight fractions found in hetastarch that may contribute to coagulopathy. Pentafraction is a derivative of pentastarch, which has been shown to have no adverse effects on bleeding time and little effect on partial prothrombin time and plasma factor VIII levels. 9

Surgery Volume 17 7, Number 3

In s u m m a r y , we found pentafraction and hetastarch to be c o m p a r a b l e resuscitation fluids that produced a sustained elevation in h e m o d y n a m i c filling p a r a m e ters w i t h substantially less t r a n s v a s c u l a r fluid flux c o m p a r e d w i t h L R . Restricted t r a n s v a s c u l a r filtration of these high m o l e c u l a r weight starch molecules augments i n t r a v a s c u l a r osmotic pressure and the p l a s m a to-interstitial oncotic gradients in l u n g and soft tissue, thus opposing the effect of a concomitant increase in m i c r o v a s c u l a r hydrostatic pressure. In the fluid m a n a g e m e n t of critically ill patients, especially the freq u e n t l y encountered patient w i t h h y p o p r o t e i n e m i a , pentafraction and hetastarch have the potential to e n h a n c e vascular filling p a r a m e t e r s w h i l e l i m i t i n g progression to soft tissue and p u l m o n a r y e d e m a and the associated m o r b i d i t y and mortality. Pentafraction, in particular, as a result of few k n o w n adverse effects on hemostasis and coagulation, m a y be an i m p r o v e d option over c u r r e n t modalities in critical care fluid m a n a g e ment. We thank B. Imm and G. Johnson for their assistance with these studies. REFERENCES

1. Erdmann AJ III, Vaughan TR, Brigham KL, Woolverton WC, Staub NC. Effect of increased vascular pressure on lung fluid balance in unanesthetized sheep. Circ Res 1975;37:271-84. 2. Kramer GC, Harms BA, Bodai BI, Renkin EM, Demling RH. Effects of hypoproteinemia and increased vascular pressure on lung fluid balance in sheep. J Appl Physiol 1983;55:1514-22. 3. Conhaim RL, Harms BA. A simplified two-pore filtration model explains the effects of hypoproteinemia on lung and soft tissue lymph flux in awake sheep. Microvasc Res 1992;44:1426. 4. Conhaim RL, Rosenfeld D J, Schreiber MA, Baaske DM, Harms BA. Effects of intravenous pentafraction on lung and soft tissue liquid exchange in hypoproteinemie sheep. Am J Physiol 1993;265:H1536-42. 5. Demling RH, Harms BA, Kramer GC, Gunther R. Acute versus sustained hypoproteinemia and post-traumatic pulmonary edema. SURGERY1982;92:79-86. 6. Dodek PM, Rice TW, Bonsignore MR, Yamada S, Staub NC. Effects of plasmapheresis and hypoproteinemia on lung liquid conductance in awake sheep. Circ Res 1986;58:269-80. 7. Harms BA, Pahl AC, Radosevieh DG, Starling JR. The effects of hypoproteinemia and volume expansion on lung and soft tissue transvascular fluid filtration. SURGERY1989;105:605-14. 8. Harms BA, Rosenfeld D J, Pahl AC, Conhaim RL, Starling JR. Pulmonary transvascular fluid filtration response to hypoproteinemia and Hespan infusion. J Surg Res 1990;48:408-14. 9. Kramer GC, Harms BA, Bodai BI, Demling RH, Renkin EM.

Myers et al.

349

Mechanisms for redistribution of plasma protein following acute protein depletion. Am J Physiol 1982;243:H803-9. 10. Strauss RG, Stansfield C, Henriksen RA, Villhauer PJ. Pentastarch may cause fewer effects on coagulation than hetastarch. Transfusion 1988;28:257-60. 11. Staub NC, Bland RD, Brigham KL, Demling RH, Erdmann AJ III. Preparation of chronic lung lymph fistula in sheep. J Surg Res 1975;19:315-20. 12. Drake R, Adair R, Traber D, Gabel J. Contamination of caudal mediastinal node efferent lymph in sheep. Am J Physiol 1981;241:H354-7. 13. Demling RH, Smith M, Gunther R, Wandzilak T, Pederson NC. Use of a chronic prefemoral fistula for monitoring systemic capillary integrity in unanesthetized sheep. J Surg Res 1981; 31:144-6. 14. Lowry OH, Rosebrough N J, Farr AL, Randall RJ. Protein measurement with the Folin phenol reagent. J Biol Chem 1951; 193:265-75. 15. Demling RH, Wilson RF. Decision making in surgical critical care. Toronto: B C Decker, 1988;30-5. 16. Heughen C, Niinikoski J, Hunt TK. Effect of excessive infusion of saline solution on tissue oxygen transport. Surg Gynecol Obstet 1972;135:257-60. 17. Hunt TK, Pai MP. The effect of varying ambient oxygen tensions on wound metabolism and collagen synthesis. Surg Gynecol Obstet 1972;135:561-7. 18. Starling EH. On the absorption of fluids from the connective tissue spaces. J Physiol 1896;19:312-26. 19. Landis EM, Papenheimer JR. Exchange of substances through the capillary walls. In: Hamilton WF, Dow P, eds. Handbook of physiology circulation; vol 2. Washington: American Physiology Society, 1963:961-1034. 20. Daniels JC, Larson DL, Abston S, Ritzmann SE. Serum protein profiles in thermal burns. J Trauma 1974;14:137-62. 21. Howland WS, Schweitzer O, Ragasa J, Jascott D. Colloid oneotic pressure and levels of albumin and total protein during major surgical procedure. Surg Gyneeol Obstet 1976;143:592-6. 22. Arakawa M, Jerome EH, Enzan K, Grady M, Staub NC. Effects of Dextran 70 on hemodynamics and lung liquid and protein exchange in awake sheep. Microvase Res 1992;44:14-26. 23. Gallagher T J, Banner M J, Barnes PA. Large volume erystalloid resuscitation does not increase extravascular lung water. Anesth Analg 1985;64:323-6. 24. Layon AJ, Gallagher TJ. Effects of hetastareh resuscitation on extravaseular lung water and cardiopulmonary parameters in a sheep model of hemorrhagic shock. Resuscitation 1987;15:25765. 25. Layon AJ, Gallagher TJ. Five percent human albumin in lactated Ringer's solution for resuscitation from hemorrhagic shock: efficacy and cardiopulmonary consequences. Crit Care Med 1990;18:410-3. 26. Metildi LA, Shackford SR, Virgilio RW, Peters RM. Crystalloid versus colloid in fluid resuscitation of patients with severe pulmonary insufficiency. Surg Gynecol Obstet 1984;3:207-12. 27. Weaver DW, Ledgerwood AM, Lueas CE, Higgins R, Bouwman DL, Johnson SD. Pulmonary effects of albumin resuscitation for severe hypovolemic shock. Arch Surg 1978;113:387-92.