George W. Machiedo

Endotoxemia and bacteremia during hemorrhagic shock. The link between trauma and sepsis

Previous investigations of a treated model of hemorrhagic shock in the rat indicated the frequent occurrence of bacteremia that appeared to derive from the gut. This paper determines the incidence of bacteremia and endotoxemia during the acute shock period and compares this with similar observations in humans in varying degrees of shock. Studies in 26 rats indicated that bacteremia and endotoxemia was present in 50% and 87%, respectively, by the end of 2 hours at a mean arterial pressure of 30 mmHg. Observations in 50 patients admitted to the trauma unit showed that positive bacterial blood cultures were present in 56% when the admission systolic blood pressure was 80 mmHg or less (p < 0.01 compared with either of the other groups). Endotoxemia was noticed in two such patients. Direct access of bacteria and endotoxin to the blood stream may occur during hemorrhagic or traumatic shock and is the probable cause of subsequent sepsis in traumatized patients when no other source is apparent.

The gut as source of sepsis after hemorrhagic shock

In a model of severe hemorrhagic shock in rats, blood culture findings became positive within 2 to 4 hours of shock. The organisms cultured were primarily gram-negative. To test the hypothesis that the gut was the source of the bacteria, E. coli labeled with carbon-14 oleic acid were fed to rats undergoing hemorrhagic shock. Their plasma was then assayed for carbon-14 activity. Seven of the 14 shocked animals demonstrated increased plasma carbon-14 activity during or after shock. The mortality rate was 100 percent 80 hours postshock, and all animals had E. coli on subsequent blood culture. The seven rats without increased plasma carbon-14 activity had a survival rate of 83 percent postshock. Sham-shocked animals did not exhibit plasma carbon-14 levels greater than the background levels. These data suggest that bacterial translocation occurs during hemorrhagic shock and that the gut is the source of the bacteremia seen during hemorrhagic shock.

Intestinal permeability correlates with severity of injury in trauma patients

BACKGROUND Increased intestinal permeability (IP) and the release of toxic intraluminal materials have been implicated in the systemic inflammatory response syndrome (SIRS) and multiple organ failure (MOF) observed in patients after severe trauma. Previous studies of intestinal permeability have failed to demonstrate a correlation between early measurements of IP and indicators of injury severity. This study examines the relationship between standard measures of injury severity and the early (day 1) and delayed (day 4) changes in IP. Associations between IP and the development of SIRS, MOF, and infectious complications were also studied. METHODS The metabolically inactive markers lactulose (L) and mannitol (M) were used to measure IP in 29 consecutive patients who sustained injuries that required admission to the surgical intensive care unit and in 10 healthy control subjects. Measurements were made within 24 hours of admission and on hospital day 4. Severity of injury was assessed by A Severity Characterization of Trauma (ASCOT), Trauma and Injury Severity Score (TRISS), Injury Severity Score (ISS), Revised Trauma Score (RTS), and Acute Physiology and Chronic Health Evaluation (APACHE) II score. Postinjury infections and parameters of SIRS and MOF were recorded. RESULTS The IP of healthy volunteers (L/M, 0.025 +/- 0.008) was within the normal range (L/M < or = 0.03), whereas the average IP in injured patients was increased both within 24 hours (L/M, 0.139 +/- 0.172) and on the fourth hospital day (L/M, 0.346 +/- 0.699). No significant correlation between severity of injury and increased IP was seen within 24 hours of injury. A significant correlation was seen on hospital day 4, however, with all severity indices measured (ASCOT: r = 0.93, R2 = 0.87, p < 0.001; TRISS: r = 0.93, R2 = 0.87, p < 0.001; ISS: r = 0.84, R2 = 0.70, p < 0.001; RTS: r = 0.68, R2 = 0.47, p = 0.002; APACHE II score: r = 0.51, R2 = 0.26, p = 0.04). Patients with markedly increased IP (L/M > or = 0.100) experienced a significant increase in the development of SIRS (83 vs. 44%; p = 0.03) and subsequent infectious complications (58 vs. 13%; p = 0.01) and showed close correlation with the multiple organ dysfunction scores (r = 0.87, R2 = 0.76, p < 0.001). CONCLUSION These observations demonstrate that the increased IP observed after trauma correlates with severity of injury only after 72 to 96 hours and not within the initial 24 hours of injury. A large increase in IP is associated with the development of SIRS, multiple organ dysfunction, and an increased incidence of infectious complications.

Hemorrhage lowers the threshold for intra-abdominal hypertension-induced pulmonary dysfunction.

BACKGROUND Intra-abdominal hypertension has been associated with pulmonary and cardiac dysfunctions. We have noted in the clinical scenario of hemorrhagic shock and resuscitation that avoidance of even moderate levels of increased intra-abdominal pressure, using prophylactic decompression, improves outcomes when compared with patients who were decompressed when intra-abdominal pressures went over 20 cm H2O. We hypothesized that prior hemorrhage and resuscitation exacerbates the cardiopulmonary dysfunction associated with intra-abdominal hypertension. METHODS Ten anesthetized pigs underwent placement of arterial and pulmonary artery catheters and a Silastic intra-abdominal catheter for measuring and manipulating intra-abdominal pressure. Group 1 animals (n = 5) were subjected to increasing intra-abdominal pressures at 10 mm Hg increments up to a level of 40 mm Hg. Group 2 animals (n = 5) were exposed to a severe hemorrhage and resuscitation before the increasing intra-abdominal pressure protocol. RESULTS Compared with baseline, hemorrhage and resuscitation caused a significant deterioration in cardiac output at intra-abdominal pressures of 10 mm Hg and above. Oxygenation was reduced at 30 and 40 mm Hg. These changes were not seen in group 1 animals. A significant difference was found between groups 1 and 2 in VT, PaCO2, and PaCO2/FIO2 ratio at an intra-abdominal pressure of 20 mm Hg. This difference was not seen at lower or higher pressures. CONCLUSIONS Prior hemorrhage and resuscitation caused an earlier decline in cardiopulmonary function in the setting of increased intra-abdominal pressure. These data suggest that, when interpreting intra-abdominal pressures, the clinical scenario must be considered. Prior hemorrhage and resuscitation produce the adverse consequences of intra-abdominal hypertension at lower pressures than when intra-abdominal hypertension is the only insult.

Effect of Hemorrhage on Superior Mesenteric Artery Flow during Increased Intra-abdominal Pressures

BACKGROUND Elevations in intra-abdominal pressure (IAP) adversely affect organ function. Prior hemorrhage and resuscitation exacerbates the cardiac and pulmonary effects of IAP. We have recently shown that superior mesenteric artery flow (SMAF) is reduced with increasing IAP. This study was designed to determine whether and how hemorrhage and resuscitation affects SMAF with increasing IAP. METHODS Ten pigs were divided into two groups after placement of a Doppler flow probe around the proximal SMA and insertion of a pulmonary artery (PA) catheter. Group 1 underwent intraperitoneal infusion of fluid to increase IAP to 10, 20, 30, and 40 mm Hg followed by a 20-minute equilibration period at each IAP. Group 2 was hemorrhaged 20% of circulating volume followed by standard resuscitation. After equilibration, this group had IAP increased in the same manner as group 1. Cardiac output (CO), PA pressures, and SMAF were recorded 1 hour after laparotomy and after equilibration at each IAP. Comparisons were made using repeated measures of analysis of variance, Students t test, and linear regression analysis. RESULTS In group 2, a reduction in SMAF was noted at 30 and 40 mm Hg of IAP when compared with baseline (p = 0.009). This reduction was not seen in group 1. There was also a significant (p = 0.001) reduction in CO between baseline and all levels of increased IAP in group 2. This decrease was again not seen in group 1. The correlation between CO and SMAF in group 2 was r = 0.74, r2 = 0.55, p = 0.0001. There was no significant correlation between CO and SMAF in group 1. CONCLUSION SMAF and CO are reduced with increasing IAP to a greater degree when preceded by hemorrhage and resuscitation. Although there is a strong correlation between the reductions in CO and SMAF, the reduction in SMAF is greater than the reduction in CO. This finding suggests that optimizing cardiac function alone during periods of even moderate levels of increased IAP may be inadequate to normalize SMAF. This lends further support for early abdominal decompression in the treatment of trauma patients with increased IAP.

Occurrence of bacteremia during and after hemorrhagic shock.

In recent research, hemorrhagic shock and septic shock have been studied as two separate entities. We have developed a treated model of hemorrhagic shock in which unrestrained and unanesthetized rats are bled to a mean arterial pressure of 30 torr until 80% of the maximum shed volume must be returned. Rats are maintained preshock and treated post shock with a 20% glucose-electrolyte solution. Survival of these animals is 62% at 24 hours post shock and all animals are dead at 72 hours post shock. Blood cultures obtained during shock become positive at 2 hours into the shock period and are significant compared to controls at 3 to 5 hours of shock (p less than 0.0001). Blood cultures obtained after the period of shock are significantly positive at 24 and 48 hours post shock (p less than 0.05) compared to controls. Intrashock cultures are monomicrobial; the majority of post-shock cultures are polymicrobial. All cultured organisms are normal rat enteric flora. Histologic changes of renal failure are also demonstrated post shock. We suggest that bacterial invasion, possibly from the gut, plays a role in the sepsis seen in patients following severe hemorrhagic shock. Sepsis may precede rather than follow the immune incompetence which accompanies shock.

Hormonally active women tolerate shock-trauma better than do men: a prospective study of over 4000 trauma patients.

Objective:To test the hypothesis that comparably injured women, especially those in the hormonally active age groups, would manifest a better preserved hemodynamic response and tissue perfusion after major trauma than do men. Summary Background Data:The notion that premenopausal women are more resistant than men to shock and trauma has been shown in numerous preclinical models. However, human studies on the effects of gender on outcome after shock-trauma are less clear, and none has examined the effect of gender on the immediate postinjury response to major trauma. Methods:Prospective series of all patients at a Level I trauma center from January 2000 to December 2005. Study patients were all patients arriving to the trauma area of the emergency department and having a serum lactate drawn within 30 minutes of arrival. Demographic data, injury severity indices, blood utilization, and lactate levels were recorded. Lactate was used as a marker of the hemodynamic response to injury, because it has been shown to be an excellent and accurate indicator of inadequate tissue perfusion. Results:A total of 5192 patients were eligible for the study of which 4106 fulfilled the study requirements and were enrolled. Initial serum lactate levels were significantly lower in premenopausal (age 14–44) and perimenopausal (age 45–54) women than in men of the same age groups (P < 0.001), even though the Injury Severity Score of the women was significantly higher than that of the men (24 vs. 18; P < 0.1). When patients were stratified into major injury groups as well as groups receiving blood transfusions, the premenopausal women were also found to have lower initial serum lactate levels and receive less blood, while having a greater magnitude of injury as reflected in their Injury Severity Score. Conclusion:The data firmly establishes a proof of principle that hormonally active human women have a better physiologic response to similar degrees of shock and trauma than do their male counterparts. These gender-based differences should be taken into account in designing studies evaluating the response to shock-trauma.

OXYGEN FREE RADICALS : EFFECT ON RED CELL DEFORMABILITY IN SEPSIS

ObjectiveTo examine the effect of α-tocopherol, a free radical scavenger, on RBC deformability, mixed venous hemoglobin saturation (Svo2), arterial-venous oxygen content difference (C[a-v]o2), pHv, and survival during sepsis. DesignRandomized controlled study. InterventionsSprague-Dawley rats were randomized to three groups: sham, cecal ligation and puncture, or α-tocopherol/cecal ligation and puncture (pretreatment with α-tocopherol before cecal ligation and puncture). Measurements and Main ResultsThe cecal ligation and puncture group had a significantly (p < .05) higher Svo2 and lower C(a-v)o2, pHv, and survival rate when compared with α-tocopherol/cecal ligation and puncture and sham groups. No difference in pHa existed between groups. ConclusionsThe α-tocopherol treatment improves survival in sepsis. RBC deformability during sepsis is prevented by α-tocopherol, suggesting that free radicals may cause the decrease in RBC deformability. This study provides indirect evidence that decreased RBC deformability may play a role in the physiologic peripheral shunting and decreased mi-crocirculatory flow that occurs during sepsis. (Crit Care Med 1991; 19:732)

Organ distribution of gut-derived bacteria caused by bowel manipulation or ischemia

Translocation of carbon-14-labeled Escherichia coli from the gut was studied at the specified times in the following groups of rats: Group 1, 5 hours after ligation of the superior mesenteric artery; Group 2, 5 hours after laparotomy and exposure of the superior mesenteric artery with gentle removal and replacement of the intestines; and Group 3, 5 hours after handling but no surgical manipulation. Both living and dead bacteria were administered by means of gavage, and the effect of viability, intestinal ischemia without reperfusion, and bowel manipulation on the translocation of enteric bacteria was assessed. We demonstrated that (1) even gentle bowel manipulation causes bacteremia as great as that associated with ligation of the superior mesenteric artery; (2) dead E. coli are absorbed into the blood in the presence of bowel manipulation or ischemia but less effectively than are live E. coli; (3) live bacteria are found in highest concentration in the lung and in descending order in the liver, kidney, heart, and spleen; (4) dead bacteria absorbed from the gut are found in highest concentration in the kidney and the liver. Lesser amounts are found in the lung, spleen, and heart.

Does the bacteremia observed in hemorrhagic shock have clinical significance? A study in germ-free animals.

We have recently reported the rapid appearance of bacteria and endotoxin in the blood of rats and of trauma patients in the course of 30 minutes to 2 hours of hemorrhagic shock. The current study was designed to determine the effect of this bacteremia and endotoxemia on survival. Thirty-three conventional (C:group 1) and 36 germ-free (GF:group 2) Sprague Dawley rats were subjected to our previously described model of treated hemorrhagic shock. Survival in the GF group was significantly better than the C group at 24, 48, and 72 hours after shock. Endotoxin levels were elevated in 88% of C group during shock and in 28% of GF group. The gut of the GF animal contains endotoxin (26 ng/gm of stool) as does the sterile food supply (393 ng/gm of rat chow).