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Anesth Analg 2004;98:1439-1446
© 2004 International Anesthesia Research Society
doi: 10.1213/01.ANE.0000111106.98535.FD

CRITICAL CARE AND TRAUMA

Intraarterial Pulmonary Pentoxifylline Improves Cardiac Performance and Oxygen Utilization After Hemorrhagic Shock: A Novel Resuscitation Strategy

Raul Coimbra, MD PhD*, Alvaro Razuk-Filho, MD PhD{dagger}, Margareth M. Yada-Langui, BS{ddagger}, and Mauricio Rocha-e-Silva, MD PhD{ddagger}

*Division of Trauma, Department of Surgery, University of California San Diego School of Medicine, San Diego, California; {dagger}Santa Casa School of Medicine, São Paulo, Brazil; and {ddagger}Research Division, Heart Institute (InCor), University of São Paulo, São Paulo, Brazil

Address correspondence and reprint requests to Raul Coimbra, MD, PhD, Division of Trauma, Surgical Critical Care, and Burns, University of California San Diego School of Medicine, 200 W. Arbor Dr., #8896, San Diego, CA 921038896. Address e-mail to rcoimbra{at}ucsd.edu


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
The role of pentoxifylline (PTX) as a resuscitation adjunct in hemorrhagic shock is unclear. PTX infusion into the pulmonary artery and its effects on cardiac performance and oxygen utilization have not been defined. We hypothesized that pulmonary PTX is superior to systemic PTX or lactated Ringer’s (LR) solution alone. The effects of LR solution, systemic PTX, and pulmonary PTX on cardiac performance and oxygen utilization in a hemorrhagic shock model in dogs were compared. Animals were bled to a mean arterial blood pressure (MAP) of 40 mm Hg maintained for 30 min and randomized into 3 resuscitation groups: LR solution (2x shed blood), systemic PTX (10 mg/kg bolus IV) in addition to LR solution (2x shed blood) + PTX (5 mg/kg for 45 min IV), and pulmonary PTX (10 mg/kg bolus + 5 mg/kg for 45 min via a pulmonary artery catheter) plus LR solution (2x shed blood, IV). Arterial blood gases, hemoglobin levels, MAP, cardiac index, systemic vascular resistance index, pulmonary vascular resistance index, oxygen delivery, oxygen consumption, and oxygen extraction ratio (O2ER) were measured serially. No differences in blood loss, hemoglobin, and MAP were observed. Pulmonary PTX increased cardiac index to levels more than baseline (P = 0.012) and decreased systemic vascular resistance index and pulmonary vascular resistance index to levels less than baseline (P < 0.0001). Pulmonary PTX increased oxygen delivery and oxygen consumption to baseline levels. Postresuscitation O2ER levels in LR-treated animals remained more than baseline (P < 0.0001). Systemic and pulmonary PTX significantly decreased O2ER compared with shock levels. PTX resuscitation is superior compared with LR solution alone. Intraarterial pulmonary PTX administration is safe, and improves cardiac performance as well as O2 utilization.

IMPLICATIONS: This study shows that a novel route (via the pulmonary circulation) used to administer pentoxifylline after hemorrhagic shock leads to superior cardiac performance in comparison with administration via lactated Ringer’s solution or IV systemic pentoxifylline.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Bleeding is an important cause of early death after major trauma. In addition, the consequences of hemorrhagic shock, such as sepsis and multiple organ dysfunction syndrome, are responsible for a significant number of late deaths after injury (1,2).

Prompt fluid resuscitation decreases the duration of shock, and theoretically should decrease the inflammatory response observed after hemorrhage and trauma, which has been considered of utmost importance for the development of sepsis and multiple organ dysfunction syndrome. Recent evidence suggests that resuscitation with lactated Ringer’s (LR) solution causes increased neutrophil activation which is associated with increased organ injury, particularly in the lung (3–6). Alternative resuscitation regimens have been tested in an attempt to modulate the inflammatory response after shock and trauma (7–10).

Pentoxifylline (PTX), a methylxanthine derivative and phosphodiesterase inhibitor, exerts its actions through its hemorheologic properties, changing the shape of red cells, thus leading to better microcirculatory blood flow. Additionally, PTX modulates the inflammatory response by decreasing tumor necrosis factor (TNF)-{alpha} synthesis (11–13). Numerous clinical and laboratory studies have demonstrated impaired cardiac performance after trauma-hemorrhage. It has also been shown that systemic administration of PTX restores cardiac output and microcirculatory blood flow after shock (14–16).

Although there are numerous clinical studies using PTX in a great variety of disease processes, the data in hemorrhagic shock are scarce and the experimental designs are prone to criticism, because most of the studies have used PTX in isolation and not as an adjunct to fluid resuscitation. There is a lack of knowledge regarding the potential use and benefits of PTX as an adjunct to fluid resuscitation after hemorrhagic shock. There are no studies investigating the effects of PTX on the hemodynamic variables and oxygen utilization variables after hemorrhagic shock and adequate fluid resuscitation using a large animal model. PTX may be a useful adjunct to fluid resuscitation in clinical practice and many trauma patients may benefit from a resuscitation regimen with PTX. In addition, others have shown that PTX also attenuates pulmonary vasomotor dysfunction in acute lung injury and causes pulmonary vasodilatation in states of pulmonary hypertension (17–19).

With that in mind, we explored the use of PTX through an alternate route, in the pulmonary artery, as an adjunct to fluid resuscitation after hemorrhagic shock.

The present study was designed to test the hypothesis that infusion of PTX into the pulmonary artery as an adjunct to systemic LR solution resuscitation would improve cardiac performance and oxygen utilization after hemorrhagic shock compared with systemic PTX and LR solution alone.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
The study protocol was approved by the IRB of the INCOR—Heart Institute of the University of São Paulo, Brazil. The experiments were conducted in accordance with the "Guide for the Care and Use of Laboratory Animals" published by the National Institutes of Health.

Animals
Eighteen adult male mongrel dogs (15–20 kg) were quarantined in quiet light-cycled rooms for 1 wk before the experiments. Animals were fasted for 16 h for solids and 6 h for liquids before anesthesia.

Anesthesia was induced by morphine sulfate (1.5 mg IM), followed by sodium pentobarbital (25 mg/kg) IV. After endotracheal intubation, animals were allowed to breathe spontaneously on a T-piece with humidified supplemental oxygen (5 L/min). Additional doses of sodium pentobarbital (2 mg/kg) were administered when necessary.

Vascular Access and Hemodynamic Monitoring
A 5F flow-directed catheter (Baxter Healthcare Corporation, Irvine, CA) was introduced into the right external jugular vein through a cutdown and its tip was advanced into the pulmonary artery under fluoroscopic guidance. The catheter was attached to a pressure transducer and connected to a TSD 104 DA VREF1 and VREF2 polygraph (Biopac System Inc., Goleta, CA). Hemodynamic data were recorded using specific software (Acknowledge MP 100 NSW).

The left common carotid artery was cannulated with an 8F polyethylene catheter connected to a pressure transducer (model 1920; Hewlett-Packard Corporation, Palo Alto, CA). The left femoral vein was also cannulated with an 8F polyethylene catheter and used for fluid administration. The left femoral artery was cannulated with a similar catheter and used for blood withdrawal (bleeding). A 4F Foley catheter was inserted into the urinary bladder to monitor the urinary output throughout the experiment.

Measured Variables
Heart rate, mean arterial blood pressure (MAP), pulmonary artery pressure, and right atrium pressure were constantly measured throughout the experiment. Cardiac output was measured by the thermodilution technique and allowed the calculation of the following variables: cardiac index (CI), pulmonary vascular resistance index (PVRI), and systemic vascular resistance index (SVRI).

Arterial and venous blood samples were analyzed by using a Stat Profile Ultra Analyzer (Nova Biomedical, Waltham, MA) for hemoglobin, blood gas measurements, and oxygen content in the mixed venous blood.

Oxygen delivery (DO2), oxygen consumption (VO2), and oxygen extraction ratio (O2ER) were calculated by standard equations based on hemodynamic variables and blood analysis.

Experimental Design
After the surgical preparation, animals were allowed to stabilize for 30 min, and basal hemodynamic measurements as well as arterial and venous blood gas analyses and hemoglobin measurements were obtained.

We used a pressure-controlled hemorrhagic shock model. Briefly, animals were bled through a left femoral artery catheter for 15 min until a MAP of 40 mm Hg was reached. They were maintained in shock for 30 min and then randomized into 3 fluid resuscitation groups: systemic LR solution (n = 6), systemic PTX (n = 6), and pulmonary PTX (n = 6). The resuscitation strategy used in each group is described in detail in Table 1.


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  		Table 1. Resuscitation Strategy According to the Type of Fluid
 
Hemodynamic and blood variables were measured before shock (baseline; t = 0 min), at the end of the shock period (shock; t = 45 min), and at the end of the experiment (postresuscitation; t = 105 min) (Fig. 1).



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  		Figure 1. Experimental protocol. MAP = mean arterial blood pressure.

 
Results are presented as mean ± SEM. Statistical analysis was performed using the SPPS version 10.0 software for Windows (SPSS, Inc., Chicago, IL). Data were analyzed by analysis of variance for multiple intragroup comparisons and with the Student’s t-test for intergroup comparisons. P < 0.05 was considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Hemoglobin Levels and Blood Loss
No differences were observed among groups regarding the amount of blood drawn (Table 2).


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  		Table 2. Blood Loss, Base Deficit, and Arterial Partial Pressure of Oxygen (PaO2) and Carbonic Gas (PCO2)
 
Hemoglobin levels at the end of the shock period remained stable and comparable to baseline levels. This was likely attributable to the fact that the animals were not splenectomized. Splenic contraction that occurs during shock was probably responsible for the maintenance of hemoglobin levels during the shock period despite the fact that bleeding was occurring. After fluid resuscitation, hemoglobin levels decreased consistently in all three groups. No differences among groups were observed (Fig. 2).



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  		Figure 2. At the end of the shock period, hemoglobin levels remained similar to baseline, likely because of splenic contraction. Postresuscitation (post resus) hemoglobin levels decreased uniformly in all groups by approximately 50% compared with baseline levels. No differences among groups were observed. LR = lactated Ringer’s, PTX = pentoxifylline.

 
Base Deficit, and Partial Pressure of Oxygen and Carbonic Gas in the Arterial Blood
Shock caused significant metabolic acidosis in all groups, characterized by increased base deficit levels. Shock was also accompanied by mild hyperventilation. Fluid resuscitation caused almost complete correction of base deficit in all groups. No differences were observed among groups regarding volume of blood loss, base deficit, and arterial partial pressure of oxygen and carbonic gas (Table 2).

MAP
MAP decreased during shock in all groups. Fluid resuscitation restored MAP to baseline levels in all groups. No differences among groups were observed (Fig. 3).



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  		Figure 3. All resuscitation regimens restored mean arterial blood pressure to levels similar to baseline. No differences among groups were observed. Post resus = postresuscitation, LR = lactated Ringer’s, PTX = pentoxifylline.

 
CI
CI decreased during shock consistently in all groups. LR solution and systemic PTX restored CI to baseline levels. Pulmonary PTX increased CI to levels more than baseline (P = 0.012) and caused the largest increase in CI compared with systemic PTX and LR solution alone (P < 0.05) (Fig. 4A).



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  		Figure 4. Hemodynamic variables. A, Fluid resuscitation with lactated Ringer’s (LR) solution and systemic pentoxifylline (PTX) restores shock-induced decreased cardiac index to baseline levels. Pulmonary PTX resuscitation caused an increase in cardiac index to levels significantly more than baseline and more than LR solution resuscitation. *P = 0.012 pulmonary PTX baseline versus postresuscitation (post resus) levels. $P = 0.013 postresuscitation LR solution versus pulmonary PTX. B, Systemic vascular resistance index (SVRI) levels. Shock caused significant increases in SVRI in all groups. LR solution and systemic PTX resuscitation decreased SVRI to baseline levels. Pulmonary PTX decreased SVRI to levels less than baseline and significantly less than in LR-resuscitated animals. *P < 0.0001 pulmonary PTX baseline versus postresuscitation. $P = 0.02 postresuscitation LR solution versus pulmonary PTX. C, Pulmonary vascular resistance index (PVRI) levels. Increased PVRI levels returned to baseline after LR solution and systemic PTX resuscitation. Pulmonary PTX decreased PVRI to levels less than baseline and significantly less than LR-treated animals. *P < 0.0001 pulmonary PTX baseline versus postresuscitation. $P = 0.03 postresuscitation LR solution versus pulmonary PTX.

 
SVRI
SVRI consistently increased during shock in all groups. LR solution and systemic PTX resuscitation restored SVRI to baseline levels. Pulmonary PTX significantly decreased SVRI to levels less than baseline (P < 0.0001). Also, postresuscitation SVRI levels were lower in pulmonary PTX-resuscitated animals compared with their LR solution counterparts (P = 0.02) (Fig. 4B).

PVRI
PVRI levels increased during shock in all groups. LR solution and systemic PTX resuscitation caused a decrease in PVRI to baseline levels. Pulmonary PTX significantly decreased PVRI to levels less than baseline (P < 0.0001). Postresuscitation PVRI levels were lower in pulmonary PTX-resuscitated animals compared with LR-resuscitated animals (P = 0.03) (Fig. 4C).

DO2
DO2 levels consistently decreased during shock in all groups. LR solution and systemic PTX resuscitation were unable to restore DO2 to baseline levels. Pulmonary PTX significantly increased DO2 to baseline levels. Postresuscitation DO2 levels were higher in pulmonary PTX-resuscitated animals compared with their LR solution counterparts (P = 0.004). No postresuscitation differences in DO2 levels were observed between pulmonary PTX and systemic PTX, as well as between systemic PTX and LR-treated animals (Fig. 5A).



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  		Figure 5. Oxygen utilization variables. A, Oxygen delivery levels were not restored to baseline levels after either lactated Ringer’s (LR) solution or systemic pentoxifylline (PTX) resuscitation. Pulmonary PTX significantly increased oxygen delivery to baseline levels and to levels more than in LR-treated animals. *P < 0.0001 LR solution baseline versus postresuscitation (post resus). $P = 0.05 systemic PTX baseline versus postresuscitation. **P = 0.004 postresuscitation LR solution versus pulmonary PTX. B, Oxygen consumption levels remained unchanged during shock. Oxygen consumption levels after pulmonary PTX resuscitation were significantly more than in LR-treated animals. *P = 0.05 postresuscitation LR solution versus pulmonary PTX. C, Oxygen extraction ratio (O2ER) increased during shock and decreased after fluid resuscitation in all groups. O2ER levels in LR-treated animals were significantly more than baseline. O2ER levels significantly decreased after systemic and pulmonary PTX resuscitation, which were no different than baseline levels. O2ER after pulmonary PTX treatment was less than in LR-treated animals. *P = 0.038 postresuscitation LR solution versus pulmonary PTX. $P < 0.0001 LR solution baseline versus postresuscitation.

 
VO2
VO2 levels were unchanged in LR-resuscitated animals compared with baseline and shock values. A trend toward increased VO2 after systemic PTX resuscitation in comparison to VO2 levels during shock was observed. Pulmonary PTX significantly increased VO2 to baseline levels. Postresuscitation VO2 levels were higher in pulmonary PTX-resuscitated animals compared with their LR solution counterparts (P = 0.05). No postresuscitation differences in VO2 levels were observed between pulmonary PTX and systemic PTX, as well as between systemic PTX- and LR-treated animals (Fig. 5B).

O2ER
O2ER consistently increased during shock in all groups. Fluid resuscitation decreased O2ER in all groups. Postresuscitation O2ER levels in LR-treated animals remained significantly more than baseline levels (P < 0.0001). Systemic and pulmonary PTX resuscitation caused a significant decrease in O2ER compared with shock levels, which were no different than baseline levels. O2ER after pulmonary PTX treatment was less than LR solution (P = 0.038) and no different than systemic PTX (Fig. 5C).


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
PTX (1-[5-oxohexyl]-3,7-dimethylxanthine), a methylxanthine derivative and nonspecific phosphodiesterase inhibitor, has been used for the treatment of intermittent claudication in patients with peripheral and cerebrovascular atherosclerotic disease because of its ability to change the shape of red blood cells, improving microcirculatory blood flow (20).

PTX used as an adjunct to fluid resuscitation in the treatment of hemorrhagic shock improves tissue oxygenation (21) and intestinal blood flow (16), decreases shock-induced bacterial translocation and subsequent tissue damage (7), and improves animal survival (22).

Clinical studies have found that PTX treatment reduces mortality rates and attenuates symptoms associated with sepsis in neonates (23) and improves cardiopulmonary function in septic shock patients (24). No adverse effects of PTX on hemodynamic variables have been identified in hemorrhagic shock models (7,14,25).

In the present study, we assessed the effects of PTX infused in the pulmonary circulation on the macro-hemodynamic variables. This novel strategy was compared with conventional systemic infusion of LR solution and a combination of LR solution and PTX infused systemically. We demonstrated, in this animal model, that fluid resuscitation with LR solution and systemic PTX restored CI to preshock levels. Pulmonary PTX resuscitation increased CI to values that were significantly more than baseline, as well as more than LR solution and systemic PTX. Because there were no differences in hemoglobin levels (hemoglobin decreased after fluid resuscitation consistently and equally) and in heart rate among groups (data not shown), it seems that the superiority of pulmonary PTX was the result of increased stroke volume, or cardiac contractility, or both.

Crystalloid resuscitation after trauma and hemorrhage has been shown to decrease left ventricular contractility (15). PTX improved cardiac performance through positive inotropic and chronotropic effects in a rat model of hemorrhagic shock (15). Increased CI to levels more than normal, achieved in this study, could justify the significant decrease in SVRI and PVRI observed after pulmonary PTX resuscitation. A potential vasodilatory effect of PTX secondary to the release of endogenous vasodilators contributing to a decrease in afterload and improved cardiac performance cannot be excluded. Although we did not observe significant differences between systemic PTX and pulmonary PTX in terms of CI levels, those levels were increased after pulmonary PTX resuscitation. Pulmonary PTX resuscitation may cause the release of endogenous and constitutive vasodilators (e.g., nitric oxide [NO]) from the pulmonary circulation during its first pass through the lung vasculature. Although this is an attractive theory, the short half-life of NO would not explain the observed lower systemic vascular resistance, because this molecule is rapidly taken up by hemoglobin. Alternatively, PTX might differentially affect smooth muscle relaxation in the systemic and pulmonary vasculature. Other potential explanations for the observed results would include cyclooxygenase formation and possible release of prostacyclin from the vascular tissue leading to vasodilatation. Further studies are necessary to test these hypotheses.

During shock, VO2 levels sustained a mild decrease, but values were not statistically different from baseline, whereas DO2 values decreased significantly in all groups. This was compensated by an increase in O2ER. DO2 decreased as a result of reduced CI because hemoglobin levels were unchanged and oxygen saturation remained stable (data not shown).

After fluid resuscitation, VO2 increased proportionally to increases in DO2. This was observed to a larger extent in pulmonary PTX-resuscitated animals as compared with the LR solution group. Systemic PTX increased DO2 levels after shock, but this resuscitation regimen was unable to restore DO2 to baseline levels. As DO2 levels increased after fluid resuscitation, O2ER decreased. However, LR solution resuscitation was unable to decrease O2ER to baseline levels. The same occurred with systemic PTX resuscitation, although the difference did not reach statistical significance. Improvements in cardiac performance (CI) and blood flow (decreased SVRI and PVRI) after pulmonary PTX resuscitation may be the reason for better oxygen utilization in that group of animals.

One of the most important effects of PTX on the inflammatory cascade is the consistent decrease in TNF-{alpha} synthesis (11–13,26). Myocardial depression may be related to increased synthesis of shock-related inflammatory mediators such as TNF-{alpha} (15,27,28). Other possible mechanisms by which PTX may improve cardiac performance would be through its hemorheologic properties and its effects on NO synthesis. By these mechanisms, it is possible that PTX facilitates microcirculatory blood flow and tissue oxygenation, and causes macro-circulation vasodilatation, leading to increased blood flow and decreased afterload, besides decreasing the production of neutrophil-derived free radicals (29–31).

Improvements in cardiac performance after the use of PTX have been reported in disease states other than hemorrhagic shock, such as sepsis and pulmonary hypertension (17–19,24,32,33).

The short observation period (45 minutes after fluid resuscitation) is one of the limitations of the present study. Furthermore, beneficial hemodynamic effects may not have an impact on long-term outcome (morbidity and mortality), although we and others have demonstrated decreased tissue injury (lung, liver, kidney, and intestines) and decreased bacterial translocations after PTX resuscitation (7,14–17,21). In addition, the small number of animals contributed to some degree of variability in the data and could have caused a type II error. The controlled hemorrhage model chosen for the study is a classic and very consistent model, used in several studies. Most studies using large animals use only five or six animals in each group. We opted to use a classic and consistent model using a small number of animals at a reasonable cost instead of using a model that is not as consistent or using different species in which complex hemodynamic monitoring is difficult. Eventually increasing the number of animals in each group would allow us to identify more profound differences between systemic and pulmonary PTX.

The initial enthusiasm regarding the use of PTX in hemorrhagic shock several years ago has decreased because of mixed results. Deficiencies in the knowledge base about the utility of PTX in hemorrhagic shock are probably related to variations in experimental design in previous studies, in which PTX was administered without adequate fluid expansion (34,35). Studies using adequate resuscitation regimens showed beneficial effects of the use of PTX (7,14,15,25).

This is the first study, using a large animal model of hemorrhagic shock, to propose an alternate route of administration of PTX and to examine in detail its hemodynamic effects. We conclude that pulmonary PTX improved cardiac performance based on increased CI to levels more than baseline and more than those levels observed in systemic PTX- and LR-resuscitated animals. These experiments suggest that PTX is safe, both hemodynamically and metabolically, for use as an adjunct to fluid resuscitation in hemorrhagic shock.

Using the pulmonary route for infusion of PTX in patients who develop acute pulmonary hypertension after severe trauma and hemorrhagic shock may prove useful. However, extrapolation of the results obtained in the present study to the clinical setting should be limited. Well designed clinical trials examining the utility of PTX as an adjunct to conventional fluid resuscitation are lacking. These studies are necessary to evaluate PTX’s usefulness in the modulation of the inflammatory response, as well as in improving hemodynamics and decreasing organ dysfunction.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication November 19, 2003.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press