Every year, 5000 to 10,000 patients die in the United States by smoke inhalation, 23,000 patients get injured, and about 5000 of these are firefighters (1). Acute lung injury (ALI) after smoke inhalation trauma is frequently associated with multiple nonpulmonary organ failure (2), along with pneumonia and sepsis, which in turn is a major cause of morbidity and mortality in thermally injured patients (3, 4).
Every year, more than 750,000 patients in the United States develop sepsis, and approximately 30% of these patients die (5). More than 75% of these deaths occur within the first 24 h after establishing the diagnosis and result mainly from persistent arterial hypotension. The remaining deaths occur after successful treatment of this hypotension and result from the development of multiple organ failure, resulting in reperfusion injury and/or irreversible damage sustained during the period of hypotension (6).
Clinically relevant models, such as the one described, are urgently needed to improve treatment strategies for victims of smoke inhalation and/or sepsis based on the findings of such models and potential treatment strategies. Our group developed this two-hit ovine model of hyperdynamic septic shock that involves the insufflation of the lungs with cotton smoke followed by the instillation of Pseudomonas aeruginosa (using a bronchoscope) (7). It has been shown in this model that bacteria can translocate from the lung to the systemic circulation, thereby causing infections after smoke inhalation injury, which are associated with severe organ failure, systemic hypotension, hyperdynamic circulation, drop in white blood cell count, and an increase in core body temperature. This model matches the criteria of sepsis, as described by Bone et al. (8), and has shown to be of high clinical relevance (9, 10). However, the exact mechanisms that underlie the pathogenesis of this process are still not completely understood. We performed this study to assess the contribution of maldistribution of blood flow to the development of nonpulmonary organ dysfunction after acute lung injury associated with septic shock and to validate regional microvascular blood flow (RMBF) to various organs in this large-animal model of sepsis, using colored microspheres before injury and at certain intervals during the 24-h study period. Because Murakami et al. (7) have reported that the nitrate-nitrite ([NOx] total amount of nitric oxide [NO] metabolites) levels are not significantly elevated in smoke inhalation without bacterial challenge, but that an increase in NOx levels could be anticipated in septic shock, we measured the NOx levels a) to clearly describe the model, and b) to differentiate NOx levels between the combined smoke and septic challenge compared with the injury caused by tracheotomy or artificial ventilation in the noninjured group. The findings in this unique animal model may provide an important insight into the pathophysiology of the combination injury.
MATERIALS AND METHODS
Animal care and use
The Institutional Animal Care and Use Committee of the University of Texas Medical Branch approved this study. The guidelines of the National Institutes of Health for the care and use of experimental animals were carefully followed. Animals were individually housed in metabolic cages and were studied in the awake state. The Investigational Intensive Care Unit at the University of Texas Medical Branch is an approved Association for Assessment and Accreditation of Laboratory Animal Care international facility.
Sixteen female Merino sheep (33 ± 2 kg) were included in this study. For the operative procedures, sheep were anesthetized, and chronically instrumented for hemodynamic monitoring as described previously (7, 11, 12). Briefly, the right femoral artery was cannulated, and a polyvinylchloride catheter (Intracath, 16-G, 24 inches, Becton Dickinson Vascular Access, Sandy, Utah) was positioned in the descending aorta. A 7-French Swan-Ganz thermodilution catheter (model 93A-131-7F, Edwards Critical Care Division, Irvine, Calif) was inserted into the right jugular vein through an 8.5-French percutaneous introducer sheath (Edwards Lifescience, Irvine, Calif) and was advanced into the common pulmonary artery. Through a left-sided thoracotomy at the level of the fifth intercostal space, a Silastic catheter (0.062-inch inner diameter, 0.125-inch outer diameter, Dow-Corning, Midland, Mich) was positioned in the left atrium. After the operative procedure, the animals were allowed to recover for 7 days. During this time, they had free access to food and water.
One day before the experiment started, catheters were connected to pressure transducers (model PX3X3, Baxter Edwards Critical Care Division) with continuous flushing devices. Electronically calculated mean pressures were recorded on a monitor with graphic and digital displays (model 7830A, Hewlett Packard, Santa Clara, Calif). Cardiac output (CO) was determined using the thermal dilution technique and displayed on a CO computer (COM-1; Baxter Edwards Critical Care Division). Pressures were measured while the sheep were standing and calm. Zero calibrations were taken at the olecranon joint of the front leg while the animals were in a standing position. Core body temperature was measured with the thermistor of the Swan-Ganz catheter. Ten milliliters of 5% dextrose solution at 1°C to 3°C served as the thermal indicator. Arterial blood gas samples were analyzed at 37°C using a conventional blood gas analyzer (Synthesis 15, Instrumentation Laboratories, Lexington, Mass) and were corrected for core body temperature. Carboxyhemoglobin (COHb) saturation was measured using a CO oximeter (model IL482, Instrumentation Laboratories). Oxygen delivery, oxygen consumption, and oxygen extraction were calculated using standard equations.
After a baseline (BL) measurement, sheep were randomly allocated to either the control group (uninjured, n = 8) or the smoke/sepsis (SS) group (injured, n = 8). Thereafter, a tracheotomy was performed under ketamine anesthesia (10 mg/kg). Anesthesia was then maintained using 1.5% to 2.5% halothane (Vedco Inc., St. Joseph, Mo) in oxygen. The SS animals were subjected to smoke inhalation injury, according to an established protocol (7). Briefly, the animals were insufflated with 4 × 12 breaths of cotton smoke (<40°C). The smoke was generated and delivered by a modified bee smoker that was filled with 40 g of burning cotton toweling and attached to the tracheotomy tube via a modified endotracheal tube. The tube contained an indwelling thermistor from a Swan-Ganz catheter. The control group received 4 × 12 breaths of room air through the bee smoker. Arterial COHb plasma concentrations were determined after each set of smoke or air inhalation and served as an index of lung injury.
After smoke inhalation, an experimental bacterial solution was instilled into the lung lobes of animals in the SS group using a bronchoscope (model PF-P40, Olympus America Inc., Melville, NY). Live P. aeruginosa (5 × 1011 colony-forming units, strain 12/4/4), which were isolated and cultured from a male burn patient at Brooke Army Medical Center, San Antonio, Texas, were suspended in 30 mL of saline and instilled into the right lower and middle lobes (10 mL each) and the left lower lobe (10 mL). The control group received only the vehicle (30 mL of normal saline) instilled in the same way. Anesthesia was then discontinued, and the sheep were allowed to awaken (7).
All animals were mechanically ventilated (Servo-Ventilator 900C, Siemens, Elema, Sweden) with a tidal volume of 15 mL/kg and a respiratory rate adjusted to maintain arterial carbon dioxide tension (PaCO2) 5 mmHg below the value obtained during spontaneous ventilation. This approach allows invasive ventilation without using anesthetics in sheep (7, 13). Positive end-expiratory pressure remained on a fixed level of 6 cm H2O to avoid ventilation-related differences in the study groups (14). These ventilator settings were chosen in accordance with those originally described by Murakami et al. (7).
All animals were fluid resuscitated, initially started with an infusion rate of 2 mL · kg−1 · h−1 lactated Ringer's solution. The infusion rate was then adjusted to maintain hematocrit at BL. During the study period, all animals had free access to food, but not to water, to precisely control the fluid balance.
The determination of regional blood flow was performed using colored microspheres. Approximately 5 million microspheres (15.0 ± 0.1 μm) were injected into the left atrium at BL, 3, 6, 12, and 24 h, whereas reference blood was withdrawn from the femoral arterial catheter at a constant rate of 10 mL/min. The color of the microspheres was randomized for each injection (2, 15-17).
After completion of the experiment, the animals were anesthetized with ketamine (15 mg/kg) and sacrificed by i.v. injection of 60 mL saturated potassium chloride. Immediately after death, representative transmural tissue samples were obtained from the distal trachea, pancreas, spleen, both kidneys (cortex), and ileum, and from the skin and skeletal muscle. In addition, brain tissue was taken from different cerebral areas, such as cortex cerebri, medulla oblongata, cerebellum, thalamus, pons, basal ganglia, and hippocampus. All these tissue samples were analyzed by Interactive Medical Technologies, Ltd. (Los Angeles, Calif), by determining the weight of each tissue sample, digesting the entire sample in a high concentration of NaOH, and measuring the total number of different colored spheres using flow cytometry. Regional blood flow in mL min−1 g−1 was then calculated using the following formula: regional blood flow = total tissue spheres/([tissue weight, g] × [reference spheres/mL/min]) (2).
Measurement of plasma nitrate-nitrite formation
The concentration of NOx in plasma was measured intermittently. Plasma samples were subjected to NOx reduction using vanadium (III) as a reducing agent in a commercial instrument (model 745, Antek Instruments, Houston, Tex). The resulting NO was measured with a chemiluminescent NO analyzer (model 7020, Antek Instruments) and was recorded by dedicated software as the NO content (in μmol/L), as previously described (7).
For statistical analysis, Sigma Stat 2.03 software (SPSS, Inc., Chicago, Ill) was used. After confirming normal distribution (Kolmogorov-Smirnov test), a two-way analysis of variance for repeated measurements with appropriate Student-Newman-Keuls post hoc comparisons was used to detect differences within and between groups. Significance was assumed when P < 0.05. Data are presented as means ± SEM.
Injury and survival
The arterial COHb determined immediately after the fourth set of smoke exposure averaged 74% ± 3% in the SS group, reflecting a severe smoke inhalation injury. The control group, which was not exposed to smoke inhalation, showed a COHb level of 6% ± 1% after receiving 4 × 12 breaths of room air through the bee smoker.
With aggressive fluid administration, all animals survived the 24-h study period.
Hemodynamic variables and blood studies
Cardiovascular variables (Fig. 1) were stable in control animals. In the SS group, CO and heart rate increased significantly after 24 h versus BL and versus the control group (P ≤ 0.001, each). This was associated with a significant drop in mean arterial pressure (MAP) and systemic vascular resistance index (SVRI) (P ≤ 0.001, each). Cardiac output is also shown as mean percentage of BL in Table 2. Left atrial pressure and central venous pressure are presented in Table 1. Whereas oxygen delivery significantly increased over time (P ≤ 0.05), oxygen consumption and oxygen extraction remained stable in both groups (Table 1). The saturation of oxygen decreased in the SS group versus BL (P≤ 0.05) and was significantly lower than in the control group (P ≤ 0.001). Arterial carbon dioxide tension was kept below BL for the entire study period, resulting in a slight increase of arterial pH (apH) in both groups (Table 1).
The PaO2/FiO2 - ratio < 200 (Table 1) decreased significantly in the SS group compared with those of the BL and control animals (P ≤ 0.001) and met the criteria for acute respiratory distress syndrome (ratio of partial pressure of oxygen in arterial blood and fraction of inspired oxygen <200) within 3 h. Mean pulmonary artery pressure increased over time and was significantly higher in the SS group than in the control group (P ≤ 0.05, Table 1). In addition, a significant increase of pulmonary artery occlusion pressure compared with BL could be observed in both groups (P ≤ 0.05, Table 1).
Regional microvascular blood flow
Blood flow in the trachea, below the tracheotomy tube (Table 2, P ≤ 0.001), and in skeletal muscle (Fig. 2, P ≤ 0.01) dramatically increased in SS animals during the entire experiment versus BL and versus controls. In addition, RMBF in the skin showed a significant increase compared with controls after 12 h (P ≤ 0.05). Whereas the pancreas displayed a significant drop in RMBF versus BL and controls (P ≤ 0.05), no statistical differences were observed in renal cortex, spleen, and ileum.
All investigated cerebral structures showed a significant increase in RMBF versus BL and versus control animals after 24 h (Fig. 3 and Table 2).
The present study investigated the effects of acute respiratory distress syndrome resulting from smoke inhalation injury and septic shock on global hemodynamics and microvascular blood flow. The major findings were a significant increase of RMBF of trachea, skeletal muscle, and skin, and a decrease in pancreatic blood flow. Whereas blood flow of renal cortex, spleen, and ileum remained unchanged, there was an increase of RMBF in all investigated cerebral structures.
The early stage of septic shock is usually associated with a hypotensive-hyperdynamic circulation characterized by an increase in CO and a decrease in MAP and SVRI (18). The sheep model is suitable for studying the effects of smoke inhalation and sepsis because it closely mimics the pathophysiology of human sepsis, as demonstrated by the increase in CO and heart rate and the decrease in MAP in this study. This two-hit model would lead to decreased RMBF to most, if not all, vital organs, thereby mimicking the anticipated mechanisms for the development of multiorgan dysfunction syndrome. The primary mechanism through which septic shock develops from the two-hit model described in this manuscript is bacterial translocation from the alveolar capsule into circulation with subsequent development of bacteremia. This is in line with previous publications based on this model (2, 7, 13, 19, 20).
During sepsis, the efficacy of catecholamines often gradually decreases over time because of adrenergic receptor and postreceptor abnormalities (21, 22). When aggressive volume challenge fails to restore a sufficient perfusion pressure, vasopressor agents have to be administered to prevent irreversible organ dysfunction, or even death (23). In the present study, all animals were fluid resuscitated to maintain hematocrit at BL to ensure adequate intravascular volume replacement. Therefore, we can exclude that changes in regional blood flow resulted from under-resuscitation or intravascular volume depletion (2). This resuscitation strategy led to filling pressures similar to those recommended by Rivers et al. (24) and is comparable to pulmonary artery occlusion pressure-guided resuscitation algorithms.
The dramatic increase in tracheal blood flow was anticipated, given the degree of direct inflammatory damage by smoke inhalation at this site. These findings are in accordance with the results of Schenarts et al. (2), who investigated the effects of isolated smoke inhalation on regional blood flow without septic challenge in sheep. Blood flow to the pancreas was significantly depressed. This finding is especially important because Haglund (25) reported that pancreatic hypoperfusion may induce ischemic reperfusion injury and lead to the development of pancreatitis, thereby aggravating the systemic inflammatory response. These findings are similar to those of Booke et al. (26), who also reported a decrease in pancreatic blood flow in an ovine model of hyperdynamic sepsis caused by continuous i.v. administration of P. aeruginosa bacteria. In our study, there was also a significant increase in blood flow to the skeletal muscle, indicating that the blood was redistributed to the muscle mass.
It is well known that ALI is frequently associated with alterations in nonpulmonary organ function (27-29). Nonpulmonary organ failure may in part explain why the respiratory complications of inhalation injury have become the major cause of mortality in thermally injured patients (30). Schenarts et al. (2) demonstrated in smoke inhalation injury that the blood flow decreased in the ileum, spleen, and pancreas, with only a slight decline in CO and SVRI. In this study, however, blood flow of renal cortex, spleen, and ileum remained unchanged in a hypotensive, hyperdynamic model, which compensates the decrease in RMBF most likely related to the increase in CO. These findings are supported by the findings of Booke et al. (26, 31) and Bone et al. (32), using a sheep model of continuous infusion of P. aeruginosa bacteria. The authors reported about differences between the models and the importance to clearly describe an animal model suitable to transfer these findings to clinical practice. In this regard, it is noteworthy to mention that preliminary studies of our group (data not shown) indicated that the instillation of P. aeruginosa bacteria (in the dosage used in this model) into the lungs without smoke inhalation did not induce ALI within 24 h.
Langenberg et al. (33) investigated the two English language electronic reference libraries to examine changes in renal blood flow in sepsis. In the absence of human data, the authors evaluated 159 animal studies with different models regarding renal blood flow measurements and reported that these blood flow measurements may vary substantially. In fact, renal blood flow was depressed in 99 studies and unchanged or increased in 60 studies. The authors concluded that the widely held paradigm that when CO is typically increased in human sepsis, renal blood flow is decreased and is pivotal to acute renal failure, might require reassessment, what is in accordance to the findings of our group.
Perfusion abnormalities are an overall phenomenon in severe sepsis and septic shock, leading to organ and neurological dysfunction. Changes in mental status occur early in sepsis and are associated with increased rates of morbidity and mortality (34). Although cerebral dysfunction often occurs, the pathophysiological background is still not fully understood. In this view, some studies demonstrated cerebral blood flow to be unchanged (35), whereas others reported either an increase in ovine cerebral blood flow (36, 37) or a decrease in cerebral blood flow in a canine sepsis model (38). These different findings may be related to the type of sepsis induction (endotoxin versus bacteria, bolus versus continuous infusion, etc.) (39). In this study, an additional smoke inhalation injury was used to complicate the septic challenge and resulted in an increase of RMBF in all cerebral structures. All animals in our study were hyperventilated to study the sheep in awake state and to exclude that sedative or narcotic drugs may lower cerebral blood flow (16). The unchanged cerebral blood flow in the control group proves that the ventilation-related decrease in PaCO2 and increase in apH had no influence on cerebral blood flow in this model because PaCO2 and apH were similar between groups. In addition, Terborg et al. (40) have shown that septic shock severely reduces the CO2-induced vasomotor reactivity, independent of changes in MAP. In the latter and in our study, MAP did not reach the lower level of autoregulation caused by fluid resuscitation.
Nitric oxide is considered a potent cerebral vasodilator and leads to cell damage by peroxynitrite formation (41, 42). In our study, plasma NOx levels increased in both groups in the first 6 h of the experiment. Whereas plasma NOx levels in the control group decreased after 6 h, the SS group showed a continuous increase in plasma NOx until the end of the experiment. This may have contributed to some extent to cerebral vasodilation. The short increase in NOx in the control group was most likely related to the injury of the tracheotomy and/or mechanical ventilation. We did not measure tissue NOx levels because previous investigations have already shown that the intracellular increase of NOx and peroxynitrite positively correlate with the plasma NOx levels in this model (7, 43, 44).
Pollard et al. (45) demonstrated that an endotoxin-related vasodilation in healthy human volunteers did not influence cerebral blood flow. In animal models, however, septic shock may produce a more severe and dose-dependent systemic insult, which causes a gross systemic reaction with a predominantly destructive cytokine response (46). The disturbance in cerebral blood flow during sepsis appears to have a multifactor genesis, involving receptor and postreceptor abnormalities (18); the vasodilating effects of NO (42) and an impairment of cerebral autoregulation, which can be caused by systemic involvement, perhaps associated with a flow maldistribution syndrome (45). Because cerebral blood flow might be pressure dependent if cerebral autoregulation is impaired and MAP is frequently decreased in sepsis, cerebral blood flow could be reduced. In our study, however, the blood flow was increased and apparently increased proportionally with the increase in CO.
A limitation of our study is that we cannot guarantee that our findings can be transferred to human beings. Another limitation might be the large variance of regional tissue perfusion observed in this study, most likely caused by inconsistencies in CO of the awake ventilated ewes.
It is becoming increasingly apparent that potential therapies for septic shock may appear highly efficacious in an animal model and yet fail in clinical trials. Therefore, the efficacy of an experimental therapy should be investigated in several models to determine its potential clinical use. Chronic large-animal models, such as the one described in this study, may be advantageous to verify results of experimental therapies in other species. We believe that this model closely approximates the physiological derangements seen in human patients affected by septic shock and will be useful for the investigation of both the pathophysiology and potential therapy for septic shock.
The authors thank the staff of the Investigational Intensive Care Unit at the University of Texas Medical Branch for their valuable assistance. The 1st and 2nd author contributed equally to this study and publication.
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