Hypotensive resuscitation versus standard fluid resuscitation for the management of trauma patients in hemorrhagic shock: The safety phase of a randomized controlled trial

Trauma is a leading cause of death worldwide, and is thus a major public health concern. Improving current resuscitation strategies may help to reduce morbidity and mortality from trauma, and clinical research plays an important role in addressing these issues. This thesis is a secondary analysis of data that was collected for a randomized clinical trial being conducted at Ben Taub General Hospital. The trial is designed to compare a hypotensive resuscitation strategy to standard fluid resuscitation for the early treatment of trauma patients in hemorrhagic shock. This thesis examines the clinical outcomes from the first 90 subjects enrolled in the study, with the primary aim of assessing the safety of hypotensive resuscitation within the trauma population. ^ Patients in hemorrhagic shock who required emergent surgery were randomized to one of two arms of the study. Those in the experimental (LMAP) arm were managed with a hypotensive resuscitation strategy in which the target mean arterial pressure was 50mmHg. Those in the control (HMAP) arm were managed with standard fluid resuscitation to a target mean arterial pressure of 65mmHg. Patients were followed for 30 days. Mortality, post-operative complications, and other clinical data were prospectively gathered by the Ben Taub surgical staff and then secondarily analyzed for the purpose of this thesis.^ Subjects in the LMAP group had significantly lower early post-operative mortality compared to those in the HMAP group. 30-day mortality was also lower in the LMAP group, although this did not reach statistical significance. There were no statistically significant differences between the two groups with regards to development of ischemic, hematologic or infectious complications, length of hospitalization, length of ICU stay or duration of mechanical ventilation. ^ Based upon the data presented in this thesis, it appears that hypotensive resuscitation is a safe strategy for use in the trauma population. Specifically, hypotensive resuscitation reduced the risk of early post-operative death from coagulopathic bleeding and did not result in an increased risk of ischemic or other post-operative complications. The preliminary results described in this thesis provide convincing evidence support the continued investigation and use of hypotensive resuscitation in a trauma setting.^

Reversal of acute coagulopathy during hypotensive resuscitation using small-volume 7.5% NaCl adenocaine and Mg2+ in the rat model of severe hemorrhagic shock

OBJECTIVE: : Acute traumatic coagulopathy occurs early in hemorrhagic trauma and is a major contributor to mortality and morbidity. Our aim was to examine the effect of small-volume 7.5% NaCl adenocaine (adenosine and lidocaine, adenocaine) and Mg on hypotensive resuscitation and coagulopathy in the rat model of severe hemorrhagic shock. DESIGN: : Prospective randomized laboratory investigation. SUBJECTS: : A total of 68 male Sprague Dawley Rats. INTERVENTION: : Post-hemorrhagic shock treatment for acute traumatic coagulopathy. MEASUREMENTS AND METHODS: : Nonheparinized male Sprague-Dawley rats (300-450 g, n = 68) were randomly assigned to either: 1) untreated; 2) 7.5% NaCl; 3) 7.5% NaCl adenocaine; 4) 7.5% NaCl Mg; or 5) 7.5% NaCl adenocaine/Mg. Hemorrhagic shock was induced by phlebotomy to mean arterial pressure of 35-40 mm Hg for 20 mins (~40% blood loss), and animals were left in shock for 60 mins. Bolus (0.3 mL) was injected into the femoral vein and hemodynamics monitored. Blood was collected in Na citrate (3.2%) tubes, centrifuged, and the plasma snap frozen in liquid N2 and stored at -80°C. Coagulation was assessed using activated partial thromboplastin times and prothrombin times. RESULTS: : Small-volume 7.5% NaCl adenocaine and 7.5% NaCl adenocaine/Mg were the only two groups that gradually increased mean arterial pressure 1.6-fold from 38-39 mm Hg to 52 and 64 mm Hg, respectively, at 60 mins (p < .05). Baseline plasma activated partial thromboplastin time was 17 ± 0.5 secs and increased to 63 ± 21 secs after bleeding time, and 217 ± 32 secs after 60-min shock. At 60-min resuscitation, activated partial thromboplastin time values for untreated, 7.5% NaCl, 7.5% NaCl/Mg, and 7.5% NaCl adenocaine rats were 269 ± 31 secs, 262 ± 38 secs, 150 ± 43 secs, and 244 ± 38 secs, respectively. In contrast, activated partial thromboplastin time for 7.5% NaCl adenocaine/Mg was 24 ± 2 secs (p < .05). Baseline prothrombin time was 28 ± 0.8 secs (n = 8) and followed a similar pattern of correction. CONCLUSIONS: : Plasma activated partial thromboplastin time and prothrombin time increased over 10-fold during the bleed and shock periods prior to resuscitation, and a small-volume (~1 mL/kg) IV bolus of 7.5% NaCl AL/Mg was the only treatment group that raised mean arterial pressure into the permissive range and returned activated partial thromboplastin time and prothrombin time clotting times to baseline at 60 mins.

Continuous measurement of cerebral oxygen saturation (rSO 2) for assessment of cardiovascular status during hemorrhagic shock in a swine model

Background: Early trauma care is dependent on subjective assessments and sporadic vital sign assessments. We hypothesized that near-infrared spectroscopy-measured cerebral oxygenation (regional oxygen saturation [rSO 2]) would provide a tool to detect cardiovascular compromise during active hemorrhage. We compared rSO 2 with invasively measured mixed venous oxygen saturation (SvO2), mean arterial pressure (MAP), cardiac output, heart rate, and calculated pulse pressure. Methods: Six propofol-anesthetized instrumented swine were subjected to a fixed-rate hemorrhage until cardiovascular collapse. rSO 2 was monitored with noninvasively measured cerebral oximetry; SvO2 was measured with a fiber optic pulmonary arterial catheter. As an assessment of the time responsiveness of each variable, we recorded minutes from start of the hemorrhage for each variable achieving a 5%, 10%, 15%, and 20% change compared with baseline. Results: Mean time to cardiovascular collapse was 35 minutes ± 11 minutes (54 ± 17% total blood volume). Cerebral rSO 2 began a steady decline at an average MAP of 78 mm Hg ± 17 mm Hg, well above the expected autoregulatory threshold of cerebral blood flow. The 5%, 10%, and 15% decreases in rSO 2 during hemorrhage occurred at a similar times to SvO2, but rSO 2 lagged 6 minutes behind the equivalent percentage decreases in MAP. There was a higher correlation between rSO 2 versus MAP (R =0.72) than SvO2 versus MAP (R =0.55). Conclusions: Near-infrared spectroscopy- measured rSO 2 provided reproducible decreases during hemorrhage that were similar in time course to invasively measured cardiac output and SvO2 but delayed 5 to 9 minutes compared with MAP and pulse pressure. rSO 2 may provide an earlier warning of worsening hemorrhagic shock for prompt interventions in patients with trauma when continuous arterial BP measurements are unavailable. © 2012 Lippincott Williams & Wilkins.

Microcirculatory parameters after isotonic and hypertonic colloidal fluid resuscitation in acute hemorrhagic shock

BACKGROUND: Volume resuscitation is one of the primary therapeutic goals in hemorrhagic shock, but data on microcirculatory effects of different colloidal fluid resuscitation regimen are sparse. We investigated sublingual mucosal microcirculatory parameters during hemorrhage and after fluid resuscitation with gelatin, hydroxyethyl starch, or hypertonic saline and hydroxyethyl starch in pigs. METHODS: To induce hemorrhagic shock, 60% of calculated blood volume was withdrawn. Microvascular blood flow was assessed by laser Doppler velocimetry. Microcirculatory hemoglobin oxygen saturation was measured with a tissue reflectance spectrophotometry, and side darkfield imaging was used to visualize the microcirculation and to quantify the flow quality. Systemic hemodynamic variables, systemic acid base and blood gas variables, and lactate measurements were recorded. Measurements were performed at baseline, after hemorrhage, and after fluid resuscitation with a fixed volume regimen. RESULTS: Systemic hemodynamic parameters returned or even exceeded to baseline values in all three groups after fluid resuscitation, but showed significantly higher filling pressures and cardiac output values in animals treated with isotonic colloids. Microcirculatory parameters determined in gelatin and hydroxyethyl starch resuscitated animals, and almost all parameters except microvascular hemoglobin oxygen saturation in animals treated with hypertonic saline and hydroxyethyl starch, were restored after treatment. DISCUSSION: Hemorrhaged pigs can be hemodynamically stabilized with either isotonic or hypertonic colloidal fluids. The main finding is an adequate restoration of sublingual microcirculatory blood flow and flow quality in all three study groups, but only gelatin and hydroxyethyl starch improved microvascular hemoglobin oxygen saturation, indicating some inadequate oxygen supply/demand ratio maybe due to a better restoration of systemic hemodynamics in isotonic colloidal resuscitated animals.

Impact of epinephrine and norepinephrine on two dynamic indices in a porcine hemorrhagic shock model

Abstract BACKGROUND: Pulse pressure variations (PPVs) and stroke volume variations (SVVs) are dynamic indices for predicting fluid responsiveness in intensive care unit patients. These hemodynamic markers underscore Frank-Starling law by which volume expansion increases cardiac output (CO). The aim of the present study was to evaluate the impact of the administration of catecholamines on PPV, SVV, and inferior vena cava flow (IVCF). METHODS: In this prospective, physiologic, animal study, hemodynamic parameters were measured in deeply sedated and mechanically ventilated pigs. Systemic hemodynamic and pressure-volume loops obtained by inferior vena cava occlusion were recorded. Measurements were collected during two conditions, that is, normovolemia and hypovolemia, generated by blood removal to obtain a mean arterial pressure value lower than 60 mm Hg. At each condition, CO, IVCF, SVV, and PPV were assessed by catheters and flow meters. Data were compared between the conditions normovolemia and hypovolemia before and after intravenous administrations of norepinephrine and epinephrine using a nonparametric Wilcoxon test. RESULTS: Eight pigs were anesthetized, mechanically ventilated, and equipped. Both norepinephrine and epinephrine significantly increased IVCF and decreased PPV and SVV, regardless of volemic conditions (p < 0.05). However, epinephrine was also able to significantly increase CO regardless of volemic conditions. CONCLUSION: The present study demonstrates that intravenous administrations of norepinephrine and epinephrine increase IVCF, whatever the volemic conditions are. The concomitant decreases in PPV and SVV corroborate the fact that catecholamine administration recruits unstressed blood volume. In this regard, understanding a decrease in PPV and SVV values, after catecholamine administration, as an obvious indication of a restored volemia could be an outright misinterpretation.

A peptide inhibitor of C-jun N-terminal kinase modulates hepatic damage and the inflammatory response after hemorrhagic shock and resuscitation

Hemorrhage and resuscitation (H/R) leads to phosphorylation of mitogen-activated stress kinases, an event that is associated with organ damage. Recently, a specific, cell-penetrating, protease-resistant inhibitory peptide of the mitogen-activated protein kinase c-JUN N-terminal kinase (JNK) was developed (D-JNKI-1). Here, using this peptide, we tested if inhibition of JNK protects against organ damage after H/R. Male Sprague-Dawley rats were treated with D-JNKI-1 (11 mg/kg, i.p.) or vehicle. Thirty minutes later, rats were hemorrhaged for 1 h to a MAP of 30 to 35 mmHg and then resuscitated with 60% of the shed blood and twice the shed blood volume as Ringer lactate. Tissues were harvested 2 h later. ANOVA with Tukey post hoc analysis or Kruskal-Wallis ANOVA on ranks, P < 0.05, was considered significant. c-JUN N-terminal kinase inhibition decreased serum alanine aminotransferase activity as a marker of liver injury by 70%, serum creatine kinase activity by 67%, and serum lactate dehydrogenase activity by 60% as compared with vehicle treatment. The histological tissue damage observed was blunted after D-JNKI-1 pretreatment both for necrotic and apoptotic cell death. Hepatic leukocyte infiltration and serum IL-6 levels were largely diminished after D-JNKI-1 pretreatment. The extent of oxidative stress as evaluated by immunohistochemical detection of 4-hydroxynonenal was largely abrogated after JNK inhibition. After JNK inhibition, activation of cJUN after H/R was also reduced. Hemorrhage and resuscitation induces a systemic inflammatory response and leads to end-organ damage. These changes are mediated, at least in part, by JNK. Therefore, JNK inhibition deserves further evaluation as a potential treatment option in patients after resuscitated blood loss.

The early systemic and gastrointestinal oxygenation effects of hemorrhagic shock resuscitation with hypertonic saline and hypertonic saline 6% dextran-70: A comparative study in dogs

The smaller volemic state from hypertonic (7.5%) saline (HS) solution administration in hemorrhagic shock can determine lesser systemic oxygen delivery and tissue oxygenation than conventional plasma expanders. In a model of hemorrhagic shock in dogs, we studied the systemic and gastrointestinal oxygenation effects of HS and hyperoncotic (6%) dextran-70 in combination with HS (HSD) solutions in comparison with lactated Ringer's (LR) and (6%) hydroxyethyl starch (HES) solutions. Forty-eight mongrel dogs were anesthetized, mechanically ventilated, and subjected to splenectomy. A gastric air tonometer was placed. in the stomach for intramucosal gastric CO2 (Pgco(2)) determination and for the calculation of intramucosal. pH (pHi):[pHi = pHa - log(Pgco(2)/Paco(2))].The dogs were hemorrhaged (42% of blood volume) to hold mean arterial blood pressure at 40-50 mm Hg over 30 min and were then resuscitated with LR (n = 12) in a 3:1 relation to removed blood volume; HS (n = 12), 6 mL / kg; HSD (n = 12), 6 mL / kg; and HES (mean molecular weight, 200 kDa; degree of substitution, 0.5) (n = 12) in a 1:1 relation to the removed blood volume. Hemodynamic, systemic, and gastric oxygenation variables were measured at baseline, after 30 min of hemorrhage, and 5, 60, and 120 min after intravascular fluid resuscitation. After fluid resuscitation, HS showed significantly lower arterial pH and mixed venous Po-2 and higher systemic oxygen uptake index and systemic oxygenation extraction than LR and HES (P < 0.05), whereas HSD showed significantly lower arterial pH than LR and HES (P < 0.05). Only HS and HSD did not return arterial pH and pHi to control levels (P < 0.05). In conclusion, all solutions improved systemic and gastrointestinal oxygenation after hemorrhagic shock in dogs. However, the HS solution showed the worst response in comparison to LR and HES solutions in relation to systemic oxygenation, whereas HSD showed intermediate values. HS and HSD solutions did not return regional oxygenation to control values.

Early hemodynamic and renal effects of hemorrhagic shock resuscitation with lactated Ringer's solution, hydroxyethyl starch, and hypertonic saline with or without 6% dextran-70

Background. Considering the renal effects of fluid resuscitation in hemorrhaged patients, the choice of fluid has been a source of controversy. In a model of hemorrhagic shock, we studied the early hemodynamic and renal effects of fluid resuscitation with lactated Ringer's (LR), 6% hydroxyethyl starch (HES), and 7.5% hypertonic saline (HS) with or without 6% dextran-70 (HSD).Materials and methods. Forty-eight dogs were anesthetized and submitted to splenectomy. An estimated 40% blood volume was removed to maintain mean arterial pressure (MAP) at 40 mm Hg for 30 min. The dogs were divided into four groups: LR, in a 3:1 ratio to removed blood volume; HS, 6 mL kg(-1); HSD, 6 mL kg(-1); and HES in a 1:1 ratio to removed blood volume. Hemodynamics and renal function were studied during shock and 5, 60, and 120 min after fluid replacement.Results. Shock treatment increased MAP similarly in all groups. At 5 min, cardiac filling pressures and cardiac performance indexes were higher for LR and HES but, after 120 min, there were no differences among groups. Renal blood flow and glomerular filtration rate (GFR) were higher in LR at 60 min but GFR returned to baseline values in all groups at 120 min. Diuresis was higher for LR at 5 min and for LR and HES at 60 min. There were no differences among groups in renal variables 120 min after treatment.Conclusions. Despite the immediate differences in hemodynamic responses, the low-volume resuscitation fluids, HS and HSD, are equally effective to LR and HES in restoring renal performance 120 min after hemorrhagic shock treatment. (c) 2006 Elsevier B.V. All rights reserved.

The Effects of 6% Hydroxyethyl Starch-Hypertonic Saline in Resuscitation of Dogs with Hemorrhagic Shock

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Does the Choice of the Halogenated Anesthetic Influence Renal Function during Hemorrhagic Shock and Resuscitation?

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LESION OF THE ANTEROVENTRAL 3RD VENTRICLE REGION IMPAIRS THE RECOVERY OF ARTERIAL-PRESSURE INDUCED BY HYPERTONIC SALINE IN RATS SUBMITTED TO HEMORRHAGIC-SHOCK

The effect of intravenous infusion of hypertonic saline (HS, 7.5% NaCl) on the recovery of mean arteria pressure (MAP) after hemorrhage was studied in sham-operated rats and in rats with electrolytic lesion of the anteroventral third ventricle (AV3V) region (4 h, 4 and 20 days). Rats anesthetized with thiopental sodium were bled (about 2.8 ml/100 g) until the MAP was stabilized at the level of 60 mmHg for 30 min. In sham-lesioned rats, MAP increased to 90 mmHg and became stable near this level after intravenous infusion of 7.5% NaCl (4 ml/kg b.wt.). In AV3V-lesioned rats, the same infusion induced a smaller increase in MAP (80 mmHg) and the MAP returned to pre-infusion levels within 30 min. These results show that the AV3V region plays an important role in the recovery of arterial pressure induced by hypertonic saline in rats submitted to hemorrhagic shock.