Pulmonary transvascular fluid filtration response to hypoproteinemia and Hespan infusion.

Management of major blood loss utilizing protein-free fluids for volume replacement frequently results in plasma protein depletion and plasma volume expansion. These factors can increase pulmonary transvascular fluid filtration which may lead to life-threatening pulmonary edema. We studied the combined effects of plasma protein depletion and plasma volume expansion on lung lymph flow (QL) in awake sheep prepared with chronic lung lymph fistulae. Animals were first chronically protein-depleted by batch plasmapheresis and then infused for 2 hr with either lactated Ringer's (Hypo/LR; n = 7) or 6% hydroxyethyl starch (Hespan) (Hypo/HES; n = 6). Control normoproteinemic animals (Norm/LR; n = 13) only received lactated Ringer's. Hypoproteinemia alone resulted in an average 2-fold increase in QL over normoproteinemic baseline levels (P less than or equal to 0.05). Infusion of LR into hypoproteinemic animals caused a 7.9-fold increase in QL (P less than or equal to 0.05). By comparison, HES infusion under similar hypoproteinemic conditions limited the increase in QL to 3.2-fold over baseline. We attributed this reduced rise in QL to Hespan's high oncotic pressure, which dramatically widened (by 4-5 mm Hg) the pulmonary-to-lymph oncotic pressure gradient. We did not observe this with LR infusion, or in previous studies employing intravenous infusion of plasma protein. Thus, the oncotic pressure of Hespan appears to significantly limit pulmonary fluid filtration during hypoproteinemia compared to LR. We do not believe that these effects are the results of any changes in microvascular porosity.     

Effects of interleukin-2 on pulmonary and systemic transvascular fluid filtration

Interleukin-2 (IL-2) therapy for patients with advanced cancer may be compromised by dose-limiting and life-threatening pulmonary and systemic edema. We studied the effects of bolus IL-2 infusion on lung and soft-tissue transvascular fluid and protein filtration in six sheep with chronic lung and soft-tissue lymphatic cannulation. Changes in lung (QL) and soft-tissue (QS) lymph flow were used as indicators of transvascular fluid filtration. A dose of 100,000 U/kg IL-2 was administered every 8 hours for 3 days. A significant increase (p less than or equal to 0.05) in both QL and QS was observed after each IL-2 infusion, with maximal flow occurring 2 to 3 hours after infusion. After 72 hours of IL-2 infusion, a fourfold maximal increase in QL occurred, which recovered to near-baseline values within 24 hours. Elevations in QL and QS were not associated with increases in pulmonary arterial or pulmonary arterial wedge pressures, but these elevations were associated with significant (p less than or equal to 0.05) increases in cardiac output (7.7 +/- 0.5 to 11.4 +/- 0.4 L/min) and a consistent decrease in systemic vascular resistance. A significant increase in lung lymph/plasma protein ratio (0.49 +/- 0.06 to 0.93 +/- 0.04 for albumin) revealed a marked increase in pulmonary microvascular porosity. This change, however, was not observed in the systemic microcirculation. Serum concentrations of tumor necrosis factor did not increase with the observed changes in pulmonary microvascular porosity. We conclude that IL-2 increases both pulmonary and systemic microvascular fluid flux. In addition, there is a marked increase in pulmonary, but not systemic, protein permeability that is not a consequence of changes mediated by tumor necrosis factor.     

Lung vascular injury with protease infusion. Relationship to plasma fibronectin.

Fibronectin exists in a soluble form in plasma and in an insoluble form in tissues. Plasma fibronectin can modulate phagocytic function as well as incorporate into the tissue matrix where it is believed to influence microvascular integrity and tissue repair. The temporal alterations in plasma and lung lymph fibronectin were studied in relation to increased pulmonary vascular permeability induced by protease infusion. The acute sheep lung lymph fistula model was used. A 39% decrease in plasma fibronectin (control = 421 +/- 67 micrograms/ml) was observed 2.5 hours (255 +/- 43 micrograms/ml) after protease infusion. There was an elevation of lymph fibronectin early after protease infusion, followed by a progressive decline. Concomitant with the decrease in plasma fibronectin, an increase in lymph flow (QL) of greater than 200% (from a control of 6.7 +/- 1.0 ml/hr to 13.9 +/- 1.4 ml/hr) was observed within 2.5 hours. Also, there was a sustained elevation in the total protein lymph/plasma concentration (L/P) ratio, which was maximal at 2.5 hours. The transvascular protein clearance (TVPC = QL X L/P) was 4.5 +/- 0.7 ml/hr at the control period and 13.1 +/- 2.0 ml/hr by 2.5 hours. This was indicative of increased flux of protein-rich fluid across the pulmonary endothelial barrier. Lung vascular permeability stabilized after 2.5 hours as manifested by a slowly declining L/P ratio. Thus, plasma fibronectin deficiency may contribute to the etiology of increased lung vascular permeability with protease infusion. Since the progressive decline in plasma fibronectin was not reflected in a proportional increase in lymph fibronectin, plasma fibronectin may have sequestered in tissues such as the lung, or perhaps in reticuloendothelial cells during the injury phase. Whether the progressive decrease in plasma fibronectin reflects its incorporation into the endothelial barrier matrix where it may mediate stabilization of the pulmonary microvascular barrier remains to be determined.     

Effect of nonprotein colloid on postburn edema formation in soft tissues and lung

We studied the effect of a nonprotein colloid solution--namely low molecular weight dextran (LMWD)--on edema formation in burned and nonburned soft tissue and lung. Adult sheep with lung and bilateral flank lymph fistulas were given a unilateral 25% to 30% full-thickness burn under ketamine anesthesia and followed for 72 hours. Resuscitation (24-hour period) was performed with lactated Ringer solution (LR) (n = 9) or 10% LMWD in saline (n = 8) to restore baseline vascular pressures and cardiac output. Interstitial edema and microvascular protein permeability were monitored by lymph flow (QL) and lymph to plasma protein ratio, respectively. With LR, QL values in nonburned skin and lung were increased twofold to threefold in the first 24 hours, while with LMWD, values remained at baseline. The nonburn edema with LR was due to the burn-induced hypoproteinemia state. The prevention of this process with LMWD was due to the generation of a twofold to threefold increase in the plasma to interstitial colloid osmotic pressure (COP) gradient. Burn QL was increased fivefold in both groups despite a higher COP gradient with LMWD. Net fluid requirements for the first 24 hours were 75 and 35 ml/kg for animals treated with LR and LMWD, respectively. After cessation of dextran administration in the second 24 hours, the COP gradients for the two groups were equal but QL in nonburned skin and net fluid requirements now increased significantly in the LMWD group. The development of nonburn edema was believed to be due to the persistent hypoproteinemic state. We conclude that edema formation in nonburned tissues, which is due to hypoproteinemia, accounts for a substantial amount of the net fluid requirements after thermal injury. This process can be prevented by infusion of a nonprotein colloid as long as the COP gradient is increased. Edema in burned tissue appears to be unaffected by changes in COP.     

Pulmonary and systemic fluid filtration after continuous versus bolus interleukin-2 infusion

Interleukin-2 has been widely investigated as adjuvant therapy for advanced cancer and is administered by either bolus or continuous infusion. We compared the effects of bolus and continuous interleukin-2 infusion on pulmonary (QL) and systemic microvascular fluid filtration in 11 adult sheep prepared with chronic lung and soft-tissue lymph fistulas. Interleukin-2 was administered as a bolus infusion (100,000 units/kg) every 8 hours for 3 days or as a continuous infusion at the same dose for 3 days. No significant changes in pulmonary hydrostatic pressures or pulmonary vascular resistance were noted after either bolus or continuous interleukin-2 infusion. However, significantly decreased (p less than or equal to 0.05) systemic vascular resistances were observed in both groups. QL increased steadily throughout the infusion period in both groups, peaking at three times baseline on the third infusion day. The plasma/interstitial protein clearance (QL X lymph/plasma protein ratio) rose similarly in both groups, indicating increased barrier permeability. Increased lymphocyte clearance into lung lymph occurred by day 3 but was not associated with lymphocytic sequestration in the lung interstitium. We conclude that pulmonary and systemic microvascular fluid and protein flux exhibit similar changes after bolus or continuous interleukin-2 infusion. These changes are associated with increased clearance of lymphocytes into lung lymph that are not sequestered in the pulmonary interstitium after infusions of shorter duration.     

The effect of plasma oncotic pressure on the pulmonary microcirculation after hemorrhagic shock.

Plasma oncotic pressure is considered to be an important factor in controlling lung water after hemorrhagic shock. However, it is the gradient between plasma and interstitial oncotic pressure which affects the pulmonary transvascular fluid filtration rate, Qf. Our objective was to determine the effect of decreasing plasma oncotic pressure, pip, on Qf, on interstitial oncotic pressure pii, and on the oncotic gradient. Chronic lung lymph fistulas were created in 16 sheep. Lymph flow, a reliable index of Qf, plasma and lymph (equal to interstitial) oncotic pressures, and vascular pressures were monitored in unanesthetized sheep, before and during hemorrhagic shock (50% blood volume), during resuscitation (3 hours), and during recovery (24 hours). Resuscitation was either with shed blood or lactated Ringer's solution in sufficient quantity to return left atrial pressure and cardiac output to baseline levels. During resuscitation with blood, lymph flow increased by 115%. The pip remained constant, while pii decreased, increasing the oncotic gradient. Crystalloid resuscitation produced on increase in lymph flow equal to that in the blood group at 120% over baseline; however, pip decreased by 50%, producing an oncotic gradient 4 mm Hg less than that of blood group. This was not reflected by a difference in Qf between the groups. During recovery Qf returned to baseline in the blood group and in most of the crystalloid group, as the oncotic gradient returned to baseline, despite a significant decrease in pip due to a compensatory decrease in pii. We conclude that during resuscitation Qf does not appear to be increased by a decrease in the oncotic gradient. During recovery a major decrease in pip can be compensated for rapidly by a decrease in pii, leading to no change in interstitial fluid content.     

Understanding and extending the Starling principle

The Starling Principle states that fluid movements between blood and tissues are determined by differences in hydrostatic and colloid osmotic (oncotic) pressures between plasma inside microvessels and fluid outside them. The Revised Starling Principle recognizes that, because microvessels are permeable to macromolecules, a balance of pressures cannot halt fluid exchange. In most tissues, steady oncotic pressure differences between plasma and interstitial fluid depend on low levels of steady filtration from plasma to tissues for which the Revised Principle provides the theory. Plasma volume is normally maintained by fluid losses from filtration being matched by fluid gains from lymph. Steady state fluid uptake into plasma only occurs in tissues such as intestinal mucosa and renal peri-tubular capillaries where a protein-free secretion of adjacent epithelia contributes significantly to interstitial fluid volume and keeps interstitial oncotic pressure low. Steady filtration rates in different tissues are disturbed locally by reflex changes in capillary pressure and perfusion. The rapid overall decline in capillary pressure after acute blood loss initiates rapid fluid uptake from tissue to plasma, that is, autotransfusion. Fluid uptake is transient, being rapid at first then attenuating but low levels may continue for more than an hour. The Revised Principle highlights the role of oncotic pressure of small volumes of interstitial fluid within a sub-compartment surrounding the microvessels rather than the tissue's mean interstitial fluid oncotic pressure. This maximizes oncotic pressure differences when capillary pressure are high and enhances initial absorption rates when pressures are low, accelerating short-term regulation of plasma volume.     

Burn edema is accentuated by a moderate smoke inhalation injury in sheep.

We determined the lung and systemic response of a moderate smoke inhalation injury combined with a 15% total body surface third-degree burn compared with a burn alone and inhalation alone. Adult sheep were prepared with chronic lung and bilateral prefemoral soft tissue lymph fistula. The burn was confined to one side. Physiologic parameters, lymph flow (QL), and lymph/plasma protein ratio were monitored. Oxidant changes were measured as lipid peroxidation by circulating and lymph-conjugated dienes and lung tissue malondialdehyde. Animals were resuscitated with lactated Ringer's solution during the 24-hour study period to restore and maintain vascular filling pressures and cardiac index. We found net 24-hour fluid balance for burn-inhalation injuries to be 4.1 +/- 1.2 L compared with burn alone of 2.9 +/- 0.9 L and inhalation alone of 2.4 +/- 0.5 L, a significant difference. Protein-rich burn tissue QL increased by fivefold to sixfold with burn alone compared with more than tenfold with burn-inhalation injury. A twofold increase in both lung and nonburn soft tissue QL was also seen in the combined injury not seen with burn alone. Arterial blood gases decreased only at 12 hours. Plasma conjugated dienes were increased in all groups, whereas burn lymph values were increased only in combined insult. In addition, lung malondialdehyde content at 24 hours was 155 +/- 11 nmol/gm with burn-inhalation injury compared with 62 +/- 8 nmol/L for burn alone, 55 +/- 9 nmol/L in inhalation alone, and 45 +/- 4 nmol/L for controls. However, no alveolar flooding was noted in any group. We conclude that a modest smoke inhalation (carboxyhemoglobin of 25%) added to a 15% total body surface burn markedly increases the degree of burn edema, as well as nonburn soft tissue and lung QL, compared with burn alone, indicating increased plasma to interstitial fluid transport in these tissues as well. Increased burn tissue lipid peroxidation products corresponded with the increased burn fluid losses. The increased lung lipid peroxidation also indicates further lung oxidant activity as well.     

Increased plasma oncotic pressure inhibits pulmonary fluid transport when pulmonary pressures are elevated

Hydrostatic and oncotic pressures are the primary determinants of fluid movement across the pulmonary vascular membrane. The precise role of oncotic pressure in regulating transvascular fluid exchange especially when hydrostatic pressure is high is not known. Awake, adult sheep were instrumented for pressure monitoring and the collection of pulmonary lymph. A left atrial (LA) balloon catheter was utilized to control LA pressure. Statistically significant increases in lymph protein flux were seen with infusion of saline and elevated pulmonary microvascular pressure (Pmv) over elevated Pmv alone (15.3 +/- 1.23 versus 11.2 +/- 1.09 mg/min) concomitant with a decrease in plasma colloid oncotic pressure (COP) (14.9 +/- 0.5 versus 16.9 +/- 0.5 mm/Hg). The protein flux seen with elevated Pmv and saline infusion was blunted when plasma was infused (13.8 +/- 1.58 mg/min) and the plasma COP augmented (18.1 +/- 0.05 mg Hg) but was not statistically different. We conclude that under conditions of stable membrane permeability and elevated Pmv, the plasma COP appears to be an important mechanism for protection against pulmonary edema.     

Role of thermal injury-induced hypoproteinemia on fluid flux and protein permeability in burned and nonburned tissue

We studied the role of hypoproteinemia, induced by a major burn injury, on the edema process in burned and nonburned tissues including the lung in the adult sheep. We used lymph flow (QL) and the lymph-plasma (L/P) protein ratio as indicators of the rate of fluid and protein flux across the microcirculation and into the interstitium. We compared the response after a full-thickness burn to 30% of total body surface plus resuscitation by means of lactated Ringer's solution (n = 8) with a comparable degree of hypoproteinemia produced by plasmapheresis with vascular hydrostatic pressure and cardiac output kept constant. We measured lung QL and soft tissue (prefemoral) QL from both the burned and nonburned areas. A twofold increase in QL and a decrease in the L/P ratio was seen in both lung and nonburned tissue in both burn and plasmapheresis animals, indicating the postburn response to be due to hypoproteinemia with no increase in protein permeability. The QL in burned tissue was increased five to ten times with an increase in the L/P ratio. Four burned sheep were resuscitated with pooled plasma. Restoration of plasma proteins eliminated the increase in QL in lung and nonburned tissue but had no effect on the burn response. In summary, burn-induced hypoproteinemia plays a major role in the edema process in nonburned tissues and is corrected by restoration of plasma proteins. Edema in burned tissue does not appear to be related to this process.     

Lung vascular permeability after reversal of fibronectin deficiency in septic sheep. Correlation with patient studies.

Plasma fibronectin deficiency and opsonic dysfunction exist in critically ill septic surgical, trauma, and burn patients with multiple organ failure. Fibronectin deficiency can be reversed by infusion of fresh plasma cryoprecipitate. The influence of therapy with human cryoprecipitate on lung vascular permeability in septic sheep with plasma fibronectin deficiency following surgery was evaluated. Additionally, selected studies on pulmonary function in septic surgical and trauma patients after infusion of plasma cryoprecipitate were completed. In patients, ventilation-perfusion balance appeared to improve as measured by the multiple inert gas elimination technique. With the lung lymph fistula preparation in fibronectin deficient sheep, infusion of human plasma cryoprecipitate (10 units; 250 ml) delayed the onset and minimized the increase in lung vascular permeability during postoperative Pseudomonas sepsis (5 X 10(9) bacteria, I.V.; 5 X 10(10) bacteria, I.P.). For example, in a first group of sheep, the transvascular protein clearance (TPC) at 2 hrs in septic sheep (n = 4) treated with only saline (volume control) was 20.1 +/- 3.1 ml/hr, compared to 11.23 +/- 0.83 ml/hr in the sheep (n =a 4) treated with fibronectin-rich cryoprecipitate (p less than 0.05). In a second group of sheep, cryoprecipitate depleted of fibronectin by affinity chromatography was used as the control solution. It also did not manifest this protective effect with respect to lung vascular permeability. Thus, at 2 hrs the lymph flow (Qlym) was 30.2 ml/hr and the transvascular protein clearance (TPC) was 18.0 ml/hr in septic sheep given fibronectin-deficient cryoprecipitate. In contrast, in the fibronectin-rich cryoprecipitate treated sheep, the Qlym was 14.8 ml/hr and the TPC was 8.12 ml/hr. It is suggested that fibronectin may influence lung vascular integrity during sepsis following surgery and trauma.     

The dynamics of vascular volume and fluid shifts of lactated Ringer's solution and hypertonic-saline-dextran solutions infused in normovolemic sheep

Infusions of hyperosmotic-hyperoncotic solutions such as hypertonic saline dextran (HSD) are used in Europe for resuscitation of traumatic shock and perioperative volume support as an adjunct to conventional isotonic crystalloids. Whereas plasma volume expansion of HSD has been measured at single time points after the intravascular volume expansion, the detailed time course of fluid shifts during and after infusions have not been reported. We compared the time course of volume expansion during and after 30-min infusions of 4 mL/kg HSD and 25 mL/kg lactated Ringer's solution (LR) in normovolemic conscious splenectomized sheep. Peak plasma volume (Evans blue and hemoglobin dilution) expansion was similar for HSD (7.8 +/- 0.9 mL/kg) and the larger sixfold volume of LR (7.2 +/- 0.5 mL/kg). However, 30 min after the 30-min infusion (T60), plasma expansion remained larger after HSD (5.1 +/- 0.9 mL/kg) than after LR (1.7 +/- 0.6 mL/kg). Both solutions caused an equivalent diuresis. Intravascular volume expansion efficiency (VEE), defined as milliliter plasma expansion/milliliter fluid infused at 0 (T30), 30 (T60), and 60 (T90) min after infusion ended was 1.8, 1.3, and 0.8, respectively for HSD, whereas LR provided a VEE of only 0.27, 0.07, and 0.07. The relative expansion efficiency of HSD versus LR, calculated as the ratio (VEE(HSD)/VEE(LR)), was 7-fold that of LR at the end of infusion T30, and 20-fold at T60, but decreased to 9-fold by T120. Intravascular volume dynamic studies of different volume expanders in animals and patients may provide anesthesiologists with a new tool for monitoring the effectiveness of fluid therapy. IMPLICATIONS: Hypertonic saline dextran (HSD) is a new plasma expander recently approved for clinical use in Europe. We compared the plasma volume expansion of HSD versus lactated Ringers (LR) in normovolemic sheep. After a 30 min infusion, HSD was 7 times as effective at expanding volume as an equal volume of LR, but for the next 90 minutes the relative effectiveness of HSD increased to 10-20 times.     

Influences of different resuscitation regimens on acute early weight gain in extensively burned patients

Dissatisfaction with the massive weight gain that commonly followed crystalloid resuscitation of extensively burned patients dictated the need for a study to determine if acute weight gain could be minimized with an alternative form of resuscitation. Three groups of ten patients each with statistically similar age and burn size (mean BSA 46 per cent) were resuscitated with lactated Ringer's solution (LR), hypertonic saline solution (HPT), or fresh frozen plasma (FFP). The volume of infused fluid and the patient weight gain were measured over the first 48 h of treatment. The mean urine output of the three groups was comparable (P greater than 0.05). The volume of infused resuscitation fluid to maintain urine output was a mean of 4.8 ml/kg/per cent BSA in the LR group, 3.16 in the HPT group and 2.68 in the FFP group. The difference in infusion rate between the FFP group and the LR group was statistically significant (P less than 0.01). All patients gained weight with resuscitation. The median percentage weight gain at the end of the first day of treatment was 10.69 per cent in the LR group, 7.88 per cent in the HPT group and 2.38 per cent in the FFP group. Weight gain at the end of the second day of treatment was 13.9 per cent in the LR group, 11.99 per cent in the HPT group, and 4.37 per cent in the FFP group. The differences between FFP, HPT and LR groups were statistically significant (P less than 0.01). In our study the use of fresh frozen plasma for resuscitation of extensively burned patients has been associated with minimal weight gain and minimal oedema. We believe that fresh frozen plasma resuscitation is an attractive alternative to crystalloid infusion and that further comparative studies should be performed.     

Early lung dysfunction after major burns: role of edema and vasoactive mediators

We determined the effect of a body burn on pulmonary function. Full-thickness burns varying in size from 25 to 70% of total body surface (TBS), were produced in sheep. Resuscitation was performed with lactated Ringer's. We noted an increase in lung transvascular fluid flux as measured by lymph flow, Q1, during the resuscitation period, varying from one- to threefold over baseline with the degree of increase directly proportional to the burn size. The increase in QL could be totally explained by the degree of hypoproteinemia which was also proportional to burn size. Transient pulmonary hypertension 20 +/- 4 to 26 +/- 5 mm Hg and a decrease in PaO2 from 90 +/- 5 to 83 +/- 6 torr occurred in the 50 and 70% burns as well as a significant decrease in lung compliance. These alterations were not due to pulmonary edema as there was no increase in measured lung water. Also, the increase in QL could be prevented by using a combination of Dextran and protein for resuscitation but this had no effect on the hypertension or hypoxia. Burn lymph and venous plasma thromboxane levels were increased during this period of lung dysfunction. Ibuprofen 12.5 mg/kg preburn and 12.5 mg/kg every 2 hours postburn decreased the degree of dysfunction suggesting a cause and effect relationship.     

Mécanismes des échanges d'eau: équations de Starling

This review considers the main mathematical models used in the understanding of transvascular fluid exchanges and oedema formation. Models by Starling, Kedem-Katchalsky and Wiederhielm are briefly described. The main factors which determine the value of the physical parameters involved in these models are the osmotic and interstitial pressures in plasma and tissue. With regard to the regulation of interstitial osmotic pressure, the importance of the presence of mucopolysaccharidic gel in the interstitial compartment creating an exclusion volume for proteins diffusing from plasma is underlined, as well as the importance of lymphatic flow, a parameter neglected in several models of transcapillary exchanges. Consequences of variations in venous hydrostatic pressure, plasma oncotic pressure, endothelial permeability are discussed using the described models. In case of changes combining an increase in venous pressure and permeability and a decrease in plasma oncotic pressure, the importance of correcting venous pressure relatively to protein supply is discussed.     

Pulmonary dysfunction secondary to soft-tissue endotoxin

Our purpose was to determine whether peripheral soft tissues produce and release prostanoids in response to local sepsis, and whether this mediator release can produce pulmonary dysfunction. Escherichia coli endotoxin (2 micrograms/kg in 100 mL of saline) was injected below the hide of the flank in seven unanesthetized sheep. In three additional sheep, ibuprofen (12.5 mg/kg of body weight) was injected with the endotoxin. Thromboxane B2 and 6-keto-PGF1 alpha (prostacyclin) levels were measured in tissue lymph draining the flank, lung lymph, pulmonary artery (Ppa), and aortic plasma. One hour after endotoxin administration, mean PaO2 decreased from 90 to 74 mm Hg and Ppa increased from 22 to 35 mm Hg. Lung lymph flow (QL) increased only 50% with QL being protein poor. No increase in lung or peripheral soft-tissue vascular permeability was noted. Tissue lymph (TxB2) increased from 220 +/- 114 to greater than 10,000 pg/mL with levels in Ppa plasma increasing from 300 +/- 128 to 595 +/- 124 pg/mL and aortic plasma from 270 +/- 141 to 410 +/- 104 pg/mL. Lung lymph TxB2 paralleled aortic values. Peak levels of 6-keto-PGF1 alpha in systemic lymph exceeded 2,000 pg/mL while levels in lung lymph remained relatively constant. The pulmonary injury and the increase in TxB2 was prevented by ibuprofen. We conclude that the response of soft tissue to local endotoxin is to release thromboxane in quantities sufficient to raise plasma levels and to produce hypoxia and pulmonary hypertension. The lung dysfunction is not produced by an increase in lung water or vascular permeability.     

Revised Starling equation and the glycocalyx model of transvascular fluid exchange: an improved paradigm for prescribing intravenous fluid therapy

I.V. fluid therapy does not result in the extracellular volume distribution expected from Starling's original model of semi-permeable capillaries subject to hydrostatic and oncotic pressure gradients within the extracellular fluid. Fluid therapy to support the circulation relies on applying a physiological paradigm that better explains clinical and research observations. The revised Starling equation based on recent research considers the contributions of the endothelial glycocalyx layer (EGL), the endothelial basement membrane, and the extracellular matrix. The characteristics of capillaries in various tissues are reviewed and some clinical corollaries considered. The oncotic pressure difference across the EGL opposes, but does not reverse, the filtration rate (the 'no absorption' rule) and is an important feature of the revised paradigm and highlights the limitations of attempting to prevent or treat oedema by transfusing colloids. Filtered fluid returns to the circulation as lymph. The EGL excludes larger molecules and occupies a substantial volume of the intravascular space and therefore requires a new interpretation of dilution studies of blood volume and the speculation that protection or restoration of the EGL might be an important therapeutic goal. An explanation for the phenomenon of context sensitivity of fluid volume kinetics is offered, and the proposal that crystalloid resuscitation from low capillary pressures is rational. Any potential advantage of plasma or plasma substitutes over crystalloids for volume expansion only manifests itself at higher capillary pressures.     

Effect of albumin infusion on pulmonary microvascular fluid and protein transport

The effect of human albumin infusion on the dynamics of fluid and protein transport across the pulmonary microcirculation was studied. Lung lymph flow ($\text{Q}\text{?}{}_{\mathrm{<mtext>L</mtext>}}$) from a chronic lung lymph fistula in unanesthetized sheep was used as a reliable indicator of transvascular fluid filtration rate ($\text{Q}\text{?}{}_{\mathrm{<mtext>L</mtext>}}$). Lymph protein content was considered equal to interstitial protein content. Pulmonary vascular pressures, $\text{Q}\text{?}{}_{\mathrm{<mtext>L</mtext>}}$, lymph and plasma proteins were continuously monitored. After a 4-hr baseline period, 50g of human, salt-poor albumin (400 cc) was infused over 0.5-hr. A hypersensitivity reaction occurred, in four studies, reflected in a large increase in pulmonary artery pressure and $\text{Q}\text{?}{}_{\mathrm{<mtext>L</mtext>}}$. Mean data for the remaining six studies are summarized for baseline, after albumin infusion and 2 and 4 hr postinfusion. Microvascular pressure (P_mr, mm Hg) for the four periods was 8, 12, 8, and 8, while plasma colloid osmotic pressure (π_mv, mm Hg) was 21, 27, 24, and 24, respectively. Interstitial colloid osmotic pressure (π_mv) was 11, 11, 13, and 14 mm Hg. $\text{Q}\text{?}{}_{\mathrm{<mtext>L</mtext>}}$ was unchanged over the entire study period. We found that albumin infusion produced an immediate increase in plasma oncotic pressure and a transient increase in P_mv. However, the colloid osmotic gradient between the interstitium and plasma returned to baseline by 4 hr despite a continued increase in plasma proteins as interstitial protein content increased in an equal manner. These data suggest a very transient, if any, decrease in lung extravascular fluid after albumin infusion.     

Sampling of lung interstitial fluid in intact dog

This paper reports a method of sampling fluid from the peribronchial-perivascular space (PBVS) of the lungs in intact closed chest dogs. The PBVS was sampled by introducing a wick catheter into the PBVS through a mediastinoscope. The right lymph duct was cannulated by the method of Vriem and Ohkuda [J. Appl. Physiol.: Respirat. Environ. Exercise Physiol. 54: 199, 1983] for collection of lymph to compare to peribronchial fluid. The colloid osmotic pressure (COP) of PVBS and right lymph duct fluid (RLDF) were compared in a series of dogs infused with lactated Ringer's solution (LR) and lactated Ringer's combined with three other conditions: left atrial balloon inflation (LRB), oleic acid infusion (LRO), and oleic acid infusion and left atrial balloon inflation (LROB). Prior to LR infusion, the volume of samples of fluid from the PBVS wicks was inadequate for measuring COP (less than 4 microliters). This difference was significantly only in the later samples at 3, 4, and 5 hr in the LR and LRB groups. In the LRO and LROB groups, protein content and amount of fluid sampled were greater than in the LR and LRB groups, but the mean COPs of the wick PBVS and RLDF were not significantly different. This method of directly sampling interstitial fluid from the lungs of dogs without thoracotomy confirms the high COP of fluid from the lung interstitium. This method of PBVS fluid sampling is potentially feasible in a human patient undergoing mediastinoscopy.     

Pure oxygen breathing increases sheep lung microvascular permeability

Sheep that breathe pure oxygen via a tracheostomy develop progressive respiratory failure and die within four days. The characteristic terminal findings include an increased water content of the lung, a decrease in lung compliance, and severe hypercarbia. To sequentially assess alterations of lung transvascular fluid dynamics during prolonged oxygen breathing the authors measured lung lymph flow (Q lymph), protein transport (Q protein), and pulmonary vascular pressures in five sheep with chronic lung lymph fistulas. No significant changes of lung transvascular fluid dynamics occurred during the first 60 hours of oxygen breathing, although an increasing trend of Q lymph and Q protein was demonstrable. However, after 72 hours of oxygen breathing, Q lymph, Q protein, and extravascular lung water had increased significantly without any change of pulmonary vascular pressures. The authors conclude that the toxic effects of oxygen on the lungs of sheep include a delayed but marked increase of pulmonary microvascular permeability to protein and fluid.