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The Synergistic Effects of Pentoxifylline on Systemic and Regional Perfusion After Hemorrhage and Hypertonic Resuscitation

Cruz, Ruy J. Jr MD, PhD*; Yada-Langui, Margareth M. PhD; de Figueiredo, Luiz F. Poli MD, PhD*; Sinosaki, Sueli MSc; e Silva, Mauricio Rocha MD, PhD*†

doi: 10.1213/01.ane.0000204255.35494.f2
Critical Care and Trauma: Research Report

Small volumes of hypertonic saline solution ([HS] 7.5% NaCl) produce systemic and microcirculatory benefits in hemorrhaged animals. Pentoxifylline (PTX) has beneficial effects when administrated after hemorrhagic shock. We tested the hypothesis that the combination of HS and PTX in the initial treatment of hemorrhagic shock provides synergistic hemodynamic benefits. Twenty-four dogs were bled to a target arterial blood pressure of 40 mm Hg and randomized into 3 groups: lactated Ringer’s solution (33 mL/kg; n = 6); HS (7.5% NaCl 4 mL/kg; n = 9); and HS+PTX (7.5% NaCl 4 mL/kg + PTX 15 mg/kg; n = 9). Systemic hemodynamics were measured by Swan-Ganz and arterial catheters. Gastric mucosal-arterial Pco2 gradient (Dg-aPco2; gas tonometry), portal vein blood flow (ultrasonic flowprobe), and systemic and regional O2-derived variables were also evaluated. HS induced a partial increase in mean arterial blood pressure, cardiac output, and portal vein blood flow. In the HS+PTX group, we observed a significant, but transitory, increase in systemic oxygen delivery (180 ± 17 versus 141 ± 13 mL/min) in comparison to HS alone. PTX infusion during hypertonic resuscitation promoted a significant reduction in Dg-aPco2 (41.8 ± 4.8 to 25.7 ± 3.9 mm Hg) when compared with isolated HS infusion (48.2 ± 6.4 to 39.4 ± 5.5 mm Hg). We conclude that PTX as an adjunct drug during hypertonic resuscitation improves cardiovascular performance and gastric mucosal oxygenation.

IMPLICATIONS: Pentoxifylline (PTX) has beneficial effects when administrated after hemorrhagic shock, restoring cardiac output and improving splanchnic perfusion. We tested the hypothesis that a combination of small volumes of hypertonic saline solution and PTX in the initial treatment of hemorrhagic shock provides synergistic hemodynamic benefits.

Research Division, Heart Institute, *InCor and †LIM-11, University of São Paulo School of Medicine, Brazil

Supported, in part, by Fundação de Amparo a Pesquisa do Estado de São Paulo, São Paulo, Brazil, grant FAPESP – 98/15658-0.

Accepted for publication December 15, 2005.

Address correspondence and reprint requests to Ruy J. Cruz Jr., MD, PhD, Rua Marivaldo Fernandes 140, São Paulo, Brazil. Address e-mail to expcruzjr@incor.usp.br.

Resuscitation of patients in shock continues to present a challenge in trauma management. A variety of fluids have been tested to restore intravascular volume and improve the systemic and regional perfusion. Hypertonic saline (HS) solution (7.5% NaCl) has been widely studied and has shown several benefits over the standard of care, lactated Ringer’s (LR) resuscitation, for the treatment of different conditions, including hemorrhagic, cardiogenic, and septic shock (1–3). Hemodynamic benefits after hypertonic resuscitation are associated with HS’s potent plasmatic expansion capacity, through which fluid shifts from the intracellular compartment, improving the systemic and microcirculatory blood flow (1,4). Additionally, HS decreases lung injury and bacterial translocation and attenuates neutrophil margination and cellular immune dysfunction that occurs after hemorrhagic shock (5–7). Clinical trials of posttraumatic hypotension showed that HS is safe and indicated that there are potential benefits of hypertonic solutions in hypotensive trauma patients who require surgery (8,9). However, these salutary effects of hypertonic resuscitation were not clearly demonstrated in other studies (10–12).

Other strategies, such as the use of drugs in conjunction with fluid resuscitation, have been tested to modulate the organ dysfunction triggered by trauma and hemorrhage. In this regard, pentoxifylline (PTX), a methylxanthine derivative, has beneficial effects when administrated after hemorrhagic shock. Some studies indicate that PTX treatment restores depressed cardiac output (CO) and improves intestinal blood flow, as well as hepatic perfusion, after hemorrhage and resuscitation (13–16). The salutary effects of PTX can be related not only to its hemorheologic properties, but also to the inhibition of inflammatory cytokines, such as tumor necrosis factor-α and interleukin-6. Our group (7) demonstrated that both HS and PTX significantly attenuated bacterial translocation and lung injury after hemorrhagic shock. We also demonstrated that hypertonic resuscitation and PTX infusion after hemorrhagic shock downregulates polymorphonuclear neutrophil-endothelial cell interactions and lung ICAM-1 expression (17).

Therefore, it seems plausible to assume that the combination of PTX and HS may have synergistic hemodynamic and metabolic benefits in the early phase of fluid resuscitation. The aim of this study was to test the hypothesis that the combination of HS and PTX provides additional benefits for the initial treatment of hemorrhagic shock, with significant improvement in systemic and regional perfusion when compared with LR and isolated hypertonic resuscitation.

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Methods

The experimental protocol was approved by the IRB of the Heart Institute, University of São Paulo Medical School, in adherence with the “Principles of Laboratory Animal Care” formulated by the National Society for Medical Research.

The present study was performed using 24 male mongrel dogs, weighing 15.8 ± 0.8 kg. The dogs were fasted for 12 h before the study, with free access to water. Anesthesia was induced by morphine sulfate (1.5 mg IM), followed by an IV injection of sodium pentobarbital 25 mg/kg. Additional doses of sodium pentobarbital (2 mg/kg) were used whenever required. After endotracheal intubation, the dog’s lungs were mechanically ventilated. The ventilator was adjusted to achieve an initial arterial Pco2 at 40 ± 5 mm Hg, with a 1.0 inspired oxygen fraction throughout the experiment. A heating pad was used to maintain body core temperature. Every dog received a single bolus injection of 50 mg of ranitidine. A urinary bladder catheter was placed for urinary drainage.

The right common femoral artery was dissected, and a catheter was introduced to measure mean arterial blood pressure (MAP) at the abdominal aorta and to collect arterial blood samples. Through the contralateral femoral artery, a polyethylene cannula (P240) was introduced to allow blood withdrawal according to our pressure-controlled hemorrhagic shock model. A catheter placed in the inferior vena cava, inserted through the right femoral vein, was used for the injection of the treatment solutions.

A 7.5F flow-directed thermodilution fiberoptic pulmonary artery catheter with thermal filament (CCOmbo 744H7.5F; Baxter Edwards Critical Care, Irvine, CA) was introduced through the right external jugular vein, and its tip was placed in the pulmonary artery, guided by pressure monitoring and wave tracings. This catheter was connected to a cardiac computer (Vigilance; Baxter Edwards Critical Care) to measure mean pulmonary arterial pressure (MPAP) and CO and to collect mixed venous samples for blood gas analysis. All pressure-measuring catheters were connected to pressure transducers (Transpac Disposable Transducer; Abbott, Chicago, IL) and then to a Biopac Data Acquisition System (Model-MP100; Biopac Systems, Goleta, CA) for continuous recording of systemic and pulmonary artery pressures.

Through a median laparotomy, the spleen was removed, and a fluid-filled polyethylene catheter was placed into the portal vein through the splenic vein to draw blood samples. A transit time ultrasonic flowprobe was positioned around the portal vein and connected to a flowmeter (T206 Transonic Volume Flowmeter; Transonic Systems, Inc, Ithaca, NY). An orogastric tube was inserted in the stomach, and gastric lavage was performed using warm isotonic saline solution until a clear fluid solution was obtained. A 16F-TRIP® tonometry catheter was then introduced orally and placed along the greater gastric curvature. This catheter was connected to a gas capnometer (Tonocap TC-200; Tonometrics, Datex-Egstrom, Helsinki, Finland) for gastric Pco2 measurement.

After completion of the surgical preparation, 30 min were allowed for stabilization, after which baseline (BL) measurements were obtained. A controlled hemorrhagic shock was induced by blood withdrawal through the left femoral artery cannula at a fixed rate of 20 mL/min using an electronic pump until a MAP of 40 mm Hg was achieved (SH0). Additional blood was withdrawn or injected when required to maintain MAP at these levels for 30 additional min (SH30). Dogs were then assigned to 3 experimental groups: LR (33 mL/kg; n = 6), HS (7.5% NaCl 4 mL/kg; n = 9), and HS+PTX (7.5% NaCl 4 mL/kg + PTX 15 mg/kg; n = 9). The LR solution was infused for 20 min and the other tested solutions as a single bolus for a 5-min period. The volume of LR was set to match a sodium load similar to HS and HS+PTX groups. No other drug, fluid, or intervention was used thereafter. The dogs were observed for 60 min (T0 to T60) and then killed with an overdose of pentobarbital and potassium chloride.

Total shed blood was measured at the end of the hemorrhage period. MPAP, MAP, and portal vein blood flow (PBVF) were continuously recorded. CO was determined using 3-mL bolus injections of isotonic saline at 20°C. Each determination was the arithmetic mean of 3 consecutive measurements when their differences did not exceed 10%.

Arterial, portal, and mixed venous base deficit, pH value, Pco2, oxygen tension, oxygen saturation, hemoglobin, hematocrit, and bicarbonate levels were obtained at BL, 30 min after shock period, and 20 and 60 min after treatment. All blood samples were analyzed immediately after their collection by a Stat Profile Ultra Analyzer (Nova Biomedical, Waltham, MA).

Three Pco2 gradients were analyzed during the experimental protocol: pulmonary artery-arterial, portal vein-arterial, and gastric mucosal-arterial gradients (Dpa-aPco2, Dpv-aPco2, and Dg-aPco2, respectively). Systemic and splanchnic oxygen delivery, consumption, and extraction (DO2syst, Vo2syst, O2ERsyst, DO2splanc, Vo2 splanc, and O2ERsplanc, respectively) were calculated using standard formulas.

Results are presented as mean ± sem. Statistical analysis was performed using Statistic Package for Social Sciences for Windows software (version 10.0; SPSS, Chicago, IL). Differences among groups were analyzed using repeated-measure analysis of variance and post hoc Tukey test. Statistical significance was considered as P < 0.05.

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Results

During BL measurements, no significant differences among groups were detected regarding measured or calculated hemodynamic and metabolic variables. Total shed blood volume was 33.3 ± 1.4 mL/kg for the LR group, 30.5 ± 2.5 mL/kg for the HS group, and 30.5 ± 2.6 mL/kg for the HS+PTX group (Fig. 1; P = 0.226). Graded hemorrhage induced major hemodynamic changes typical of hemorrhagic shock. There were significant reductions in MAP, MPAP, CO, PVBF, base excess, and splanchnic and systemic DO2. A reduction in hemoglobin levels was observed during this period. Systemic and splanchnic O2ER, gastric mucosal Pco2, as well as three other calculated Pco2 gradients presented a marked increase after hemorrhage in all studied groups, without significant differences among them. No significant changes in systemic or splanchnic Vo2 were detected during the shock period (Figs. 2–4; Tables 1 and 2).

Figure 1

Figure 1

Figure 2

Figure 2

Figure 3

Figure 3

Figure 4

Figure 4

Table 1

Table 1

Table 2

Table 2

Fluid replacement was associated with a significant, sustained, but partial restoration of MAP and CO in all groups. MAP in the LR group was significantly higher when compared with the HS and HS+PTX groups during the first 30 min after the end of LR infusion (T20 to T50). A complete restoration of arterial pH values in all groups was observed at the end of experiment.

A significant improvement in PVBF was observed in all groups. PVBF was significantly higher in the HS+PTX group at T5. The PVBF in the LR group was significantly higher from T20 to T50 when compared with the other two studied groups. Fluid resuscitation promoted a partial restoration in DO2splanc and O2ERsplanc (Table 2). Vo2splanc did not present any significant change during the shock or treatment period. A complete restoration of Dpv-aPco2 to BL was observed in all groups. The Dg-aPco2 in the HS+PTX group presented a marked and significant reduction in the first 20 min of treatment. By the end of the experiment, Dg-aPco2 was lower in the HS+PTX group than in the group receiving HS alone. Hemoglobin levels showed a significant reduction after fluid resuscitation in all studied groups (Figs. 2–4; Tables 1 and 2).

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Discussion

This is the first study evaluating the potential benefits of the combination of HS solution (4 mL/kg) and PTX on systemic and splanchnic oxygen use in a large animal model of hemorrhagic shock. Our most striking finding relates to the substantial improvement in mucosal perfusion, evaluated tonometrically in animals treated with HS and PTX. In addition, fluid resuscitation with HS and PTX showed a significant, but transitory, increase in cardiac performance and DO2syst when compared with isolated hypertonic resuscitation.

It should be noted that the isolated hypertonic resuscitation, and even the proposed strategy (HS+PTX), did not provide any hemodynamic or metabolic benefits over the standard of care, LR resuscitation, one hour after fluid resuscitation. However, we believe that hypertonic resuscitation is an attractive strategy for the treatment of posttraumatic hypotension in the prehospital scenario when time is limited; the same hemodynamic and metabolic benefits can be achieved with a small volume of HS (280 mL versus 2200 mL). Bickell et al. (18) have shown that the volume of Ringer’s acetate solution infused in the prehospital setting in 309 hypotensive patients with penetrating torso injuries was approximately 900 mL (870 ± 667 mL), which is usually insufficient to treat severe hypotension.

In the present study, hemorrhage promoted an approximately 75% reduction in both PVBF and DO2splanc. Despite this reduction, Vo2splanc was maintained by a substantial increase in oxygen extraction. During this period of regional hypoperfusion, the splanchnic Vo2 remained stable, but a significant increase in both systemic and regional lactate was observed, which can be ascribed to the onset of anaerobic metabolism. Other studies (19,20) also demonstrated the presence of tissue hypoxia and, subsequently, activation of anaerobic metabolism, without any change in Vo2. The occurrence of hypoxia during a preserved splanchnic Vo2 could be explained by a blood flow redistribution within intestinal layers, with an improved perfusion in the muscular and serosal layers, rendering the mucosal layer hypoxic but with low impact on global mesenteric Vo2 (19). Supporting this hypothesis, we found the increase in Dg-aPco2 was double the increase observed in the Dpv-aPco2 gradient, reflecting the more profound effect of hypoperfusion on the mucosal layer versus the mesenteric bed as a whole.

During the shock period, we observed a significant increase in systemic and regional Pco2 in all studied groups. As noted above (Fig. 4), fluid replacement induced a significant reduction in the systemic gradient of Pco2 (Dpa-aPco2), which correlated with the increase of CO, reflecting that mixed venous hypercarbia and an increase in venous-arterial Pco2 gradient are reliable markers of systemic hypoperfusion, as previously demonstrated in different types of shock (21,22). Twenty minutes after the start of fluid resuscitation, a significant increase in the CO was observed in the LR group, effects that can be explained by the infusion of a larger volume in this group (almost eight times) when compared with HS alone. At the same time point (T20), we observed a higher CO (1.4 ± 0.1 versus 1.1 ± 0.1 L/min) and DO2syst (180 ± 17 versus 141 ± 13 mL/min) in the HS+PTX group when compared with isolated hypertonic resuscitation. The significant improvement in cardiac performance in the HS+PTX group can be attributed solely to the pharmacological properties of PTX because a similar volume was injected (4 mL/kg) in both groups (i.e., HS+PTX and HS groups). The precise mechanism responsible for these salutary effects of PTX administration remains unknown. However, we can propose three different hypotheses to explain the significant increase in CO in animals that received PTX as an adjunct to hypertonic resuscitation.

First, through its ability to enhance red blood cell deformability, PTX can have improved blood flow and DO, leading to vasodilatation and decreased afterload (23). Second, it PTX downregulates tumor necrosis factor-α synthesis, a potent myocardial depressor released after hemorrhage and resuscitation (24). Third, PTX’s hemorheologic properties and ability to increase endothelium-derived nitric oxide may have improved the coronary blood flow, and therefore increased left ventricular contractility (23). It should be noted that these hemodynamic benefits of PTX on cardiovascular performance have been reported (14–16).

In our laboratory, Coimbra et al. (25) demonstrated a complete cardiac index restoration to preshock levels in dogs treated with systemic PTX and LR when compared with LR alone. In the same study, it was shown that intrapulmonary artery PTX injection is associated with a further improvement in cardiac performance when compared with systemic PTX infusion. However, some important differences between these studies and our experimental protocol should be analyzed.

Initially, in the aforementioned studies, the hemodynamic benefits of PTX were observed after crystalloid fluid replacement. We were able to show that the salutary action of PTX on cardiovascular performance is also maintained during hypertonic resuscitation. Moreover, these authors used a different resuscitation strategy. In their studies, PTX infusion was performed in 2 steps: a bolus injection followed by a continuous infusion for a period ranging from 45 to 90 minutes. For logistic reasons, we did not include the continuous infusion in our protocol. Our goal was to evaluate the initial effects of an alternative formulation of hypertonic solution that could be easily performed in the prehospital setting for the treatment of posttraumatic hypotension. The benefits of hypertonic solutions on macro-hemodynamic variables during fluid resuscitation are associated mainly with the plasma-expanding properties of these solutions. The initial volume expansion represents approximately 2.75 mL of plasma for each milliliter of 7.5% NaCl injected, whereas with standard isotonic solutions, an expansion ratio of 0.33 mL is observed for each milliliter injected (1,26). The main sources for the observed plasma expansion after 7.5% NaCl injection are the red blood cells and the endothelium, which lose approximately 8% of their volumes directly to the intravascular compartment (27). Apart from the volume expansion, these events result in important hemodynamic effects on the microcirculation, because the edema in the red blood cells and endothelium are of critical importance in terms of viscosity and hydraulic resistance in the microcirculation (1,27). The potential benefits of HS infusion on reduction of endothelial edema during fluid resuscitation, coupled with the hemorheologic properties of PTX, may explain the significant improvement on gastric mucosal blood flow (i.e., lower Dg-aPco2) when compared with LR, despite less PVBF and DO2splanc in this group 20 minutes after fluid replacement initiation (T20).

We found that PTX infusion in conjunction with hypertonic resuscitation significantly increased mucosal oxygenation when compared with HS alone. The improvement in mucosal perfusion can be partially attributed to the increase in CO and PVBF; however, other mechanisms should be considered. Besides its hemorheologic properties, PTX induces a significant reduction in the leukocytes’ adhesiveness and promotes a restoration of depressed vascular contractility and endothelial function, improving the microcirculatory blood flow in splanchnic circulation (28). As pointed out before, hypertonic solutions are associated with hemodynamic improvement in microcirculation, but isotonic solutions are not. Nevertheless, in our study, isolated HS solution infusion did not present any additional benefit over LR for gastric mucosal oxygenation. Similarly, Braz et al. (29) found that resuscitation with HS or HS dextran after controlled hemorrhage in dogs did not improve intramucosal pH values, but LR, infused in three times the shed blood volume, did. However, it may be that our bolus infusion of HS solution represented roughly 15% of shed blood volume, and in our study, LR was infused at a fixed rate of 33 mL/kg, which approached a 1:1 ratio, as shown in Figure 1. Therefore, our dogs were not fully resuscitated with fluids, and this is a possible explanation for the maintenance of a comparable Dg-aPco2 in the HS and LR groups at the end of the resuscitation period. Furthermore, it has to be emphasized that the mucosal-arterial Pco2 gradient presents limitations for detecting intestinal dysoxia during anemic hypoxia (30).

There are limitations in our experimental model, as is true for all controlled and uncontrolled hemorrhage models. Trauma victims’ clinical presentations are complex, transport conditions may vary, and prehospital and emergency room protocols differ. Resuscitation tends to be a continuing process, whereas in our study, dogs followed a strict protocol of fluid replacement, with no additional interventions. There were no deaths during our experimental protocol despite a blood loss more than 40% of initial blood volume. In addition, we deliberately used a short observation time to address the immediate impact of fluid resuscitation and how long this initial response would last. We recognize that this protocol impairs our capability to analyze delayed responses, including the development of multiple organ dysfunction and survival. Further investigation is required, including longer follow-up periods, to determine the moment when both systemic and splanchnic perfusions are fully restored, as well as the effects of other interventions such as additional fluid replacement after bolus injection and continuous PTX infusion.

In summary, in this model of controlled hemorrhagic shock, PTX as an adjunct drug during hypertonic resuscitation improved cardiovascular performance and gastric mucosal oxygenation. However, further evaluations are required to appraise the real impact of this alternative resuscitation strategy on organ dysfunction and survival after hemorrhagic shock.

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