Effects of isovolemic resuscitation with hemoglobin-based oxygen carrier Hemoglobin glutamer-200 (bovine) on systemic and mesenteric perfusion and oxygenation in a canine model of hemorrhagic shock: a comparison with 6% hetastarch solution and shed blood.

OBJECTIVE: To study Hemoglobin glutamer-200 bovine (Hb-200), 6% hetastarch (HES) and shed whole blood (WB) resuscitation in canine hemorrhagic shock. STUDY DESIGN: Prospective laboratory investigation. Animals Twelve adult dogs [29 +/- 1 kg (mean +/- SD)]. METHODS: Anesthetized dogs were instrumented for recording systemic and mesenteric hemodynamic parameters and withdrawal of arterial, mixed and mesenteric venous blood, in which hematological, oxygenation, blood gas and acid-bases variables were determined. Recordings were made before [baseline (BL)], after 1 hour of hypovolemia and immediately and 3 hours post-resuscitation with 30 mL kg(-1) of either Hb-200, HES, or WB. RESULTS: Blood withdrawal (average 34 +/- 2 mL kg(-1)) caused significant hemodynamic changes, metabolic acidosis and hyperlactatemia characteristic for hemorrhagic shock. Only WB transfusion restored all variables. Hemoglobin glutamer-200 bovine infusion returned most hemodynamic parameters including cardiac output and mesenteric arterial blood flow to BL but increased mean arterial pressure above BL (p < 0.05). However, Hb-200 failed to restore total Hb and arterial oxygen content (CaO2), leaving systemic (DO2I) and mesenteric O2 delivery (DO2Im) below BL (p < 0.05). Nevertheless, acid-base variables recovered completely after Hb-200 resuscitation, and met-hemoglobin (Met-Hb) levels increased (p < 0.05). Hetastarch resuscitation returned hemodynamic variables to or above BL but further decreased total Hb and CaO2, preventing recovery of sDO2I and mDO2I (p < 0.05). Thus, systemic and mesenteric O2 extraction stayed above BL (p < 0.05) while acid-base variables recovered to BL, although slower than in Hb-200 and WB groups (p < 0.05). CONCLUSIONS AND CLINICAL RELEVANCE: Resuscitation with Hb-200 seemed to resolve metabolic acidosis and lactatemia more rapidly than HES, but not WB; yet it is not superior to HES in improving DO2I and DO2Im. The hyperoncotic property of solutions like Hb-200 that results in rapid volume expansion with more homogenous microvascular perfusion and the ability to facilitate diffusive O2 transfer accelerating metabolic recovery may be the key mechanisms underlying their beneficial effects as resuscitants.

Effects of haemoglobin-based oxygen carrier hemoglobin glutamer-200 (bovine) on intestinal perfusion and oxygenation in a canine hypovolaemia model.

The objective of this investigation was to study the effects of the first marketed haemoglobin-based oxygen carrier, Hemoglobin glutamer-200 (bovine) (Hb-200) (Oxyglobin) on splanchnic perfusion and oxygenation in a canine model of acute hypovolaemia. Twelve anaesthetized dogs [mean weight 30.8 (S.D. 1.4) kg] were instrumented for recordings of heart rate (HR), mean arterial pressure (MAP), central venous pressure (CVP), cardiac output and cranial mesenteric arterial (CMA) and venous blood flows (CMV). Total and plasma haemoglobin (Hb), oxygen content and saturation, lactate concentration, pH and blood gases were analysed in arterial, mixed venous and mesenteric venous blood samples. Measurements were made before (baseline) and after 1 h of haemorrhage, after which animals were resuscitated with either shed blood (controls) or Hb-200 until HR, MAP and CVP returned to prehaemorrhage levels. Recordings were repeated immediately and 3 h after termination of fluid resuscitation, after which organ specimens were obtained for microscopic examination. Haemorrhage (average 32 ml kg(-1)) reduced MAP to 50 mm Hg, increased HR and systemic vascular resistance (SVR), and was accompanied in both the systemic and the splanchnic circulation by significant decreases in blood flow, Hb content and oxygen delivery (DO2), and lactic acidosis. In controls, all variables recovered to baseline after isovolaemic resuscitation with shed blood. In dogs resuscitated with a small volume of Hb-200 (10 ml kg(-1)), HR, MAP, CVP and CMA and CMV blood flows returned to baseline. However, cardiac output, total Hb, oxygen content and systemic and mesenteric DO2 remained depressed while SVR increased further. Mesenteric and systemic acid-base status recovered in both groups, and there was no difference in microscopic tissue damage between groups. Thus, Hb-200 reconstituted splanchnic perfusion and oxidative metabolism in spite of pronounced systemic vasoconstriction and insufficient restoration of CO and DO2; it may improve diffusive oxygen transport in the microvasculature by virtue of haemodilution and its high efficiency in the uptake and release of oxygen.

The effects of hemoglobin glutamer-200 (bovine) on the microcirculation in a canine hypovolemia model: a noninvasive computer-assisted intravital microscopy study.

UNLABELLED: We sought to correlate in vivo microvascular, systemic function, hemodynamic, and oxygenation changes in autologous shed blood (n = 4) and hemoglobin glutamer-200 (Hb-200) (n = 4) resuscitations in hypovolemic dogs. Hemorrhage (approximately 40% blood loss) reduced mean arterial pressure to approximately 50 mm Hg and caused significant (P < 0.01) decreases in hematocrit, total hemoglobin, mean pulmonary arterial pressure, cardiac output, and oxygen delivery and significant (P < 0.01) increases in heart rate, systemic vascular resistance, and lactic acidosis. Significant (P < 0.01) changes in conjunctival microvascular variables also occurred, including a 19% decrease in venular diameter and 79% increase in average blood flow velocity. Shed blood resuscitation returned microvascular, systemic function, hemodynamic, and oxygenation variables to prehemorrhagic baseline values. In contrast, Hb-200 failed to restore hematocrit, total hemoglobin, cardiac output, oxygen delivery index, and systemic venous resistance to baseline, but it restored other systemic functions and all hemodynamic and microvascular changes. In addition, Hb-200 resuscitation in hypovolemic dogs (approximately 40% blood loss) did not cause extreme hemodilution or fatal outcome. This study confirms that real-time (in vivo) microvascular studies, which were conducted only in small rodent models in the past, can be performed simultaneously with systemic function, hemodynamic, and oxygenation studies in a large animal model for relevant data correlation. IMPLICATIONS: This is the first time that changes in the blood circulation have been studied, quantified, and correlated with systemic function, hemodynamic, and oxygenation changes in shock and during shock treatment in a large animal model. This study was performed by a new technology developed in-house to noninvasively and quantitatively study blood vessels in real time.

Coronary-bronchial blood flow and airway dimensions in exercise-induced syndromes.

1. We have an incomplete understanding of integrative cardiopulmonary control during exercise and particularly during the postexercise period, when symptoms and signs of myocardial ischaemia and exercise-induced asthma not present during exercise may appear. 2. The hypothesis is advanced that baroreflex de-resetting during exercise recovery is normally associated with (i) a dominant sympathetic vasoconstrictor effect in the coronary circulation, which, when associated with obstructive coronary disease, may initiate a potentially positive-feedback cardiocardiac sympathetic reflex (variable myocardial ischaemia with symptoms and signs); and (ii) a dominant parasympathetic bronchoconstrictor effect in the presence of bronchovascular dilatation, which, when associated with raised mediator release in the bronchial wall, reinforces the tendency for airway obstruction (variable dyspnoea results). 3. There is a need for new techniques to examine hypotheses concerning autonomic control, during and after exercise, of the coronary and bronchial circulations and the dimensions of airways. Accordingly, a new ultrasonic instrument has been designed named an 'Airways Internal Diameter Assessment (AIDA) Sonomicrometer'. It combines pulsed Doppler flowmetry with transit-time sonomicrometry of airway circumference and single-crystal sonomicrometry of airway wall thickness. Initial evaluation suggests it is relatively easy to apply during thoracotomy in recovery animals. The component devices are linear and will measure target variables with excellent accuracy. 4. In anaesthetized sheep, intubated with controlled ventilation, intravenous isoproterenol causes large increases in bronchial blood flow, a fall in arterial pressure and a reduction in airway circumference. This may reflect the dominant action of reflex vagal activity over direct beta-adrenoceptor inhibition of bronchial smooth muscle, the reflex source being baroreflex secondary to the fall in arterial pressure. These findings provide insight into the integrative mechanisms underlying the paradoxical negative effects sometimes observed when beta-adrenoceptor agonists are used in asthma.

Inadequacy of low-volume resuscitation with hemoglobin-based oxygen carrier hemoglobin glutamer-200 (bovine) in canine hypovolemia.

Stroma-free hemoglobin-based oxygen carriers (HBOC) have been developed to overcome problems associated with transfusion of allogeneic blood. We have studied the efficacy of the first licensed veterinary blood substitute, hemoglobin glutamer-200 bovine (Oxyglobin; Biopure, Cambridge, MA, USA, Hb-200), in a canine model of acute hypovolemia and examined whether clinically commonly used criteria are adequate to guide fluid resuscitation with this product. Twelve anesthetized dogs were instrumented for measurements of physiological variables including hemodynamic, oxygenation, and blood gas and acid-base parameters. Dogs were bled to a mean arterial pressure (MAP) of 50 mmHg for 1 h followed by resuscitation with either shed blood (controls) or Hb-200 until heart rate (HR), MAP and central venous pressure (CVP) returned to baseline. Recordings were repeated immediately and 3 h after termination of fluid resuscitation. Hemorrhage (average 32 mL/kg) caused significant decreases in total hemoglobin (Hb), mean pulmonary arterial pressure (PAP), cardiac output (CO) and oxygen delivery (DO2I), increases in HR and systemic vascular resistance (SVRI), and lactic acidosis. In controls, only re-transfusion of all shed blood returned HR, MAP and CVP to prehemorrhage values, whereas in other dogs this endpoint was reached with infusion of 10 mL/kg Hb-200. Unlike blood transfusion, Hb-200 infusion failed to return CI and DO2I to baseline and to increase arterial oxygen content (CaO2) and total Hb; SVRI further increased. Thus, commonly used criteria (HR, MAP, CVP) to guide transfusion therapy in patients posthemorrhage prove insufficient when HBOCs with pronounced vasoconstrictive action are used and lead to inadequate volume repletion.

Plasma and lymph pharmacokinetics of recombinant human interleukin-2 and polyethylene glycol-modified interleukin-2 in pigs.

Modification of recombinant human interleukin-2 (IL-2) with polyethylene glycol (PEG-IL-2) decreases clearance and might favor absorption into the lymphatics, due to its increased molecular weight. In the present study, we compared the plasma and lymph concentrations of IL-2 and PEG-IL-2 in Yorkshire pigs. The IL-2 regimens were i.v. bolus (0.1-1.6 x 10(6) I.U., MIU/kg), 15-min i.v. infusion (0.1 MIU/kg), or s.c. bolus (0.1-3.0 MIU/kg). The PEG-IL-2 doses were 15-min i.v. infusion (0.01 MIU/kg) or s.c. bolus (0.01-0. 10 MIU/kg). Lymph and plasma data were analyzed using noncompartmental methods and NONMEM. Bioavailability of IL-2 was route- and dose-dependent. Bioavailability of i.v. bolus doses of >/=0.16 MIU/kg was complete but only 39% at 0.1 MIU/kg. For the infusion and s.c. doses, bioavailability was 28 and 42%, respectively. Noncompartmental and NONMEM estimates of clearance and volume of distribution at steady state agreed: 300 ml/h/kg and 570 ml/kg, respectively, for IL-2. The ratio of the area under the curve in lymph and plasma increased from 0.67 to 3.4 when comparing i.v. and s.c. routes, and the s.c. delivery advantage (ratio of dose-normalized ratio of the area under the curve in lymph after s.c. and i.v. administration) was 6.6 to 16. For PEG-IL-2, bioavailability was 100%, clearance was 5.9 ml/h/kg, and volume of distribution at steady state was 370 ml/kg. The ratio of the area under the curve in lymph and plasma increased from 0.33 (i.v.) to 1. 2 (s.c.), and the s.c. delivery advantage was 3.8. Subcutaneous dosing would be favored over i.v. dosing, and IL-2 would be favored over PEG-IL-2 to maximize lymph and minimize plasma exposure. Because IL-2 efficacy may be related to lymph concentrations, dosing regimens can now be designed to test this hypothesis.

Bovine respiratory syncytial virus-specific IgE is associated with interleukin-2 and -4, and interferon-gamma expression in pulmonary lymph of experimentally infected calves.

OBJECTIVE: To study the local immune response of calves to bovine respiratory syncytial virus (BRSV) infection with emphasis on IgE production and cytokine gene expression in pulmonary lymph. ANIMALS: Twelve 6- to 8-week-old Holstein bull calves. Six similar control calves were mock infected to obtain control data. PROCEDURE: Lymphatic cannulation surgery was performed on 12 calves to create a long-term thoracic lymph fistula draining to the exterior. Cannulated calves were exposed to virulent BRSV by aerosol. Lymph fluid collected daily was assayed for BRSV and isotype-specific IgE antibody, total IgG, IgA, IgM, and protein concentrations. Interleukin-4 (IL-4), interleukin-2 (IL-2), and interferon-gamma were semi-quantitated by reverse transcription-polymerase chain reaction (RT-PCR). Cell counts and fluorescence-activated cell scanner (FACSCAN) analysis of T-cell subsets were performed on lymph cells. RESULTS: Calves had clinical signs of respiratory tract disease during days 5 to 10 after infection and shed virus. Bovine respiratory syncytial virus-specific IgE in infected calves was significantly increased over baseline on day 9 after infection. Mean virus-specific IgE concentrations strongly correlated with increases in severity of clinical disease (r = 0.903). Expression of IL-2, IL-4, and interferon-gamma was variably present in infected and control calves, with IL-4 expression most consistent during early infection. CONCLUSIONS AND CLINICAL RELEVANCE: Infection with BRSV was associated with production of BRSV-specific IgE, and IL-4 message was commonly found in lymph cells of infected calves. This finding supports the concept that BRSV-induced pathophysiology involves a T helper cell type-2 response. Effective therapeutic and prophylactic strategies could, therefore, be developed using immunomodulation to shift the immune response more toward a T helper cell type-1 response.

The effect of a dynamic pressure-redistributing bed support surface upon systemic lymph flow and composition.

INTRODUCTION: It has been postulated that lymphatic insufficiency may have a key role in pressure ulcer development. Our hypothesis is that the particular dynamic action of the Airwave mattress directly improves lymphatic circulation compared to conventional hospital mattresses. METHODS: Seven anesthetized sheep (40-48 kg) prepared with chronic prefemoral lymph fistulas and vascular catheters were first placed on a standard hospital mattress. Following 30 minutes of equilibration, a 2 hr control period was started measuring lymph flow and vascular pressures. The standard mattress was then exchanged for an active Airwave mattress (Pegasus Egerton, Ltd.) and after 30 minutes of equilibration monitored as above. After 2.5 hr, the support surface was then switched back to the standard mattress and monitored as before. Data are mean +/- sem. RESULTS: Initially, on the standard mattress, lymph flow was 1.0 +/- 0.2 ml/30 min and increased significantly more than 3 fold on the Aireave mattress to 3.7 +/- 0.7 ml/30 min. Upon return to the standard mattress, lymph flow decreased to 1.2 +/- 0.2 ml/30 min. Hemodynamic variables and arterial blood gases were constant. Lymphatic protein transport increased significantly from 1.3 +/- 0.3 micrograms/min to 4.3 +/- 1.0 micrograms/min when placed on the test mattress and decreased when returned to the standard mattress to 1.3 +/- 0.2 micrograms/min. Similar rates of lymph flow were seen upon a variant of the Airwave mattress (Cairwave Therapy System). CONCLUSIONS: Results support the hypothesis that the Airwave's action increased the lymph flow compared to a standard hospital mattress. The dynamic cycle may act to aid the pumping action of lymphatics by reducing pressure which would otherwise collapse and compress lymphatics leading to local edema and tissue swelling.

Evaluation of severe disease induced by aerosol inoculation of calves with bovine respiratory syncytial virus.

OBJECTIVE: To develop a model of bovine respiratory syncytial virus (BRSV) infection that induces severe disease similar to that seen in some cattle with naturally acquired BRSV infection. ANIMALS: 25 male Holstein calves, 8 to 16 weeks old. PROCEDURE: 17 calves were given a low-passage field isolate of BRSV by aerosolization; 8 control calves were given supernatant from noninfected cell culture. Disease was characterized by evaluating clinical signs, virus isolation and pulmonary function tests, and results of blood gas analysis, gross and histologic postmortem examination, and microbiologic testing. RESULTS: Cumulative incidence of cough, harsh lung sounds, adventitious sounds, and dyspnea and increases in rectal temperature and respiratory rate were significantly greater in infected calves. Three infected calves developed extreme respiratory distress and were euthanatized 7 days after inoculation. Virus was isolated from nasal swab specimens from all infected calves but not from mock infected calves. On day 7 after inoculation, mean PaO2 and PaCO2 were significantly lower, and pulmonary resistance was significantly higher, in infected calves. During necropsy, infected calves had varying degrees of necrotizing and proliferative bronchiolitis and alveolitis with syncytial formation. The 3 calves euthanatized on day 7 had emphysematous bullae in the caudal lung lobes; 1 had unilateral pneumothorax. CONCLUSION AND CLINICAL RELEVANCE: Severe disease similar to that seen in some cattle with naturally acquired BRSV infection can be induced in calves with a single aerosol exposure of a low-passage clinical isolate of BRSV. Our model will be useful for studying the pathogenesis of BRSV infection and for evaluating vaccines and therapeutics.

A bovine model of vaccine enhanced respiratory syncytial virus pathophysiology.

A critical issue has been the observation that vaccination of children with a formalin-inactivated respiratory syncytial virus (RSV) vaccine is associated with disease enhancement. We have taken advantage of bovine RSV and our experience with this disease in calves to develop a natural model that parallels human disease. Using formalin-inactivated bovine RSV vaccine calves were either sham-vaccinated/infected, vaccinated/infected, or vaccinated/sham-infected and their clinical signs, pulmonary function, and histological lung lesions quantitatively scored. Interestingly there was significantly greater disease in vaccinated/infected calves and histological lesions in calves were similar to those of affected children. Finally, we note that vaccination did not induce neutralizing antibodies, but IgG antibodies were detected by ELISA. Our model of RSV enhanced disease is important because it provides quantifiable evidence of disease severity that can be applied to evaluate the mechanisms of immunopathology and the safety of candidate RSV vaccines.

Intraosseous resuscitation of hemorrhagic shock in a pediatric animal model using a low sodium hypertonic fluid.

OBJECTIVE: To study the efficacy of a low sodium hypertonic resuscitation fluid for resuscitation of severe hemorrhage in a pediatric animal, using the intraosseous route. DESIGN: Prospective, randomized, controlled animal study. SETTING: University physiology laboratory. SUBJECTS: Seventeen immature (6- to 9-wk-old) piglets, weighing 10.6 +/- 0.4 kg, were studied under anesthesia. INTERVENTIONS: A new 2400 mosm/L hypertonic fluid, "Isosal" was formulated with reduced (3.45%) sodium content compared with a 2400-mosm/L (7.5%) hypertonic saline solution. This formulation was accomplished by substituting glucose and mixed amino acids for sodium. Piglets were subjected to 1 hr of hemorrhage, reducing the cardiac output to 50% of baseline value. Resuscitation was carried out through the intraosseous route with an initial 6 mL/kg bolus of either hypertonic saline, Isosal, or lactated Ringer's solution. After the initial bolus, additional test fluid was given to maintain the cardiac output at baseline value for a 2-hr period. MEASUREMENTS AND MAIN RESULTS: Total resuscitation volumes, hemodynamic variables, and electrolytes were measured. Intraosseous vascular access was easily established in all animals, and fluid resuscitation was carried out effectively through this route. Resuscitation volumes were significantly lower for both of the hypertonic fluids (12.7 +/- 1.2 mL/kg for hypertonic saline, and 12.5 +/- 1.7 mL/kg for Isosal solution) compared with lactated Ringer's solution (75.3 +/- 11.6 mL/kg) (p = .01). Both hypertonic saline and Isosal solution resulted in an immediate supranormal response in cardiac output that lasted 20 mins. In contrast, when lactated Ringer's solution was used, multiple boluses were required over a 20-min period to normalize cardiac output. Serum sodium was significantly higher in the hypertonic saline group compared with the Isosal or lactated Ringer's groups (p = .001). CONCLUSIONS: Isosal solution was as effective as hypertonic saline in "small volume" resuscitation of severe hemorrhagic shock in a pediatric animal model through the intraosseous route, and produced significantly less hypernatremia when compared with hypertonic saline.

Markedly increased lymphatic removal of hyaluronan from skin after major thermal injury.

Hyaluronam (HYA) (formerly hyaluronic acid) is an important constituent of the interstitial matrix in skin. Following major burn injury plasma HYA is known to increase markedly. The present study investigated to what extent the lymphatic removal of HYA from skin is affected following major burn injuries. Under ketamine anaesthesia a 30 per cent full thickness scald injury was inflicted on sheep previously provided with a chronic prefemoral lymph fistula. Animals were resuscitated for 24 h using lactated Ringer's infusion as needed to restore and maintain cardiac output within +/- 10 per cent of baseline. Following burn injury, lymph flow from thermally injured tissue gradually increased to 10-25 times above baseline. The baseline HYA concentration in lymph was 4.3 +/- 1.1 micrograms/ml; the HYA concentration in lymph was not significantly altered postinjury. The lymphatic HYA flux (flow x concentration) increased postinjury to 5-30 times control. The HYA concentration in plasma was 162 +/- 12 ng/ml at baseline; postinjury plasma HYA peaked at two to three times baseline at 4-8 h after the injury. At 24 h postinjury plasma HYA was reduced compared to baseline. In conclusion, after major burn injury the lymphatic transport of HYA from the injured area into the systemic circulation increased markedly, leading to elevated plasma concentrations of this high molecular weight connective tissue component.

The renal effects of 7.5% NaCl-6% dextran-70 versus lactated Ringer's resuscitation of hemorrhage in dehydrated sheep.

A small volume of 7.5% NaCl/6% Dextran-70 (HSD) can rapidly expand the plasma volume, but concerns exist regarding its adverse effects on renal function in the dehydrated state. Sheep were thirsted for 4 days (13% plasma volume contraction), and subjected to a fixed-pressure shock model (mean arterial pressure of 50 mmHg for 2 h), followed by resuscitation with either HSD (4 mL/kg) or lactated Ringer's solution (LR; 37 mL/kg). Mean arterial pressure was restored to 90%, cardiac output to 125% and 120%, and plasma volume to 78% and 72% of baseline in LR and HSD groups, respectively. Glomerular filtration rate improved to 100% of baseline following HSD compared with 82% following LR. No significant urinary 70,000 molecular weight dextran was observed, suggesting an intact renal glomerular membrane. These data suggest that small volume HSD resuscitation is effective, even with pre-existing dehydration. In addition, renal function is not compromised by HSD resuscitation of hemorrhaged, dehydrated animals.

Thoracic lymphatic cannulation for the study of pulmonary immune responses in lung lymph of calves.

OBJECTIVE: To develop a system for analysis of immune response variables in the lymph draining the lung and to establish baseline data for clinically normal calves. DESIGN: Surgery was performed on 6 calves to insert a cannula into the efferent lymphatic duct of the caudal mediastinal lymph node to create a long-term thoracic lymph fistula draining to the exterior. Lymph was collected daily, and on the fifth postoperative day, calves were exposed to an aerosol of cell culture medium (mock infection). For the next 10 days, lymph was collected for analysis and, on the tenth day, necropsy was performed. ANIMALS: Six 6- to 8-week-old Holstein bull calves. PROCEDURES: Daily lymph samples were evaluated for: flow rate; total and differential cell counts; and IgG, IgM, IgA, IgE, and protein concentrations. On days -4, -1, 1, 4, 7, and 10, cells were stained and quantitated by fluorescence-activated cell sorter analysis for T, B, CD4+, and CD8+ cells. Blood lymphocytes were evaluated on days -1 and 10 for comparison. RESULTS: Flow was established for up to 25 days, with a mean rate between 11 and 22 ml/h. Protein concentrations in lymph and plasma did not indicate a protein drain. Although mean lymphocyte counts reflected a slight gradual decrease in lymph lymphocytes, this effect was not apparent in every calf, nor was the effect seen in blood lymphocytes. There were no significant changes in IgG, IgM, IgA, or IgE concentration, with the exception of IgA concentration in 1 calf that developed an abscess at the cannulation site. The T-cell subset absolute numbers of CD4+ and CD8+ cells decreased slightly over time, but the CD4(+)-to-CD8+ cell ratio remained almost constant at near 2. CONCLUSIONS: Creation of a thoracic lymphatic fistula appears to be a useful technique for studying effects of lung infection on immunologic variables, with potential application to bacterial and viral respiratory tract diseases. CLINICAL RELEVANCE: Thoracic lymphatic cannulation can be used in studies to determine pathogenic mechanisms in respiratory tract disease and to develop more effective vaccines against respiratory tract pathogens.

Effector of hemodynamics during laparoscopy: CO2 absorption or intra-abdominal pressure?

Controversy has been raised about the effects of systemic carbon dioxide accumulation versus the intra-abdominal pressure on hemodynamics during laparoscopy. We compared the acid-base and hemodynamic changes during pneumoperitoneum in a randomized cross-over study between CO2 and nitrogen gases to test the hypothesis that the CO2 absorbed during laparoscopy, rather than the 15 mmHg intra-abdominal pressure created, accounted for these changes. Eight adult pigs were anesthetized and ventilated with a fixed minute ventilation. Metabolic function was measured from analysis of expired flow by a metabolic measurement cart. After baseline periods, animals were randomized into two groups, for 2 hr of either CO2 or nitrogen pneumoperitoneum at 15 mmHg intra-abdominal pressure, followed by 1 hr of recovery. After at least a 48-hr recovery period, the experiment was repeated with the other gas. Metabolic data revealed that there was a significant absorption of CO2 gas across the peritoneal epithelium during CO2 pneumoperitoneum. Animals insufflated with CO2 gas experienced a 75% increase in pulmonary CO2 excretion, with significant acidemia and hypercapnia, whereas there were no acid-base disturbances in those with nitrogen insufflation. Oxygen consumption remained essentially unchanged in both groups, even during pneumoperitoneum. CO2 pneumoperitoneum was also associated with systemic and pulmonary arterial hypertension and a reduction in stroke volume of up to 15%. Pneumoperitoneum alone did not compromise hemodynamics. Pneumoperitoneum using CO2 gas during laparoscopy resulted in systemic CO2 absorption across the peritoneum. This led to acidemia, hypercapnea, and depressed hemodynamics. The intra-abdominal pressure routinely used during laparoscopic surgery did not affect metabolic function, acid-base balance, or hemodynamics in the experimental model.

Comparison of 7.5% NaCl/6% dextran-70 resuscitation of hemorrhage between euhydrated and dehydrated sheep.

7.5% NaCl/6% dextran-70 (HSD) has been shown to be an effective, small volume resuscitation fluid following hemorrhage (HEM) in euhydrated (E) sheep. However, there is controversy whether hypertonic solutions would be effective in dehydrated (D) animals. Therefore, we used two groups (E and 4 days D) of chronically instrumented ewes to evaluate the responses to HSD following HEM. All sheep were bled and maintained at 50 mmHg mean arterial pressure (MAP) for 2 h, then resuscitated with a 4 mL/kg bolus of HSD. Dehydration did not affect baseline MAP, heart rate (HR), or total peripheral resistance (TPR), whereas cardiac output (CO: E, 5.28 +/- .31; D, 4.00 +/- .31 L/min), stroke volume (SV: E, 61 +/- 4; D, 44 +/- 4 mL/beat), urine flow rate (V: E, .51 +/- .11; D, .34 +/- .07 mL/min), and sodium excretion (UNa V: E, 22 +/- 8; D, 6 +/- 2 microEq/min) were reduced and plasma sodium (PNa: E, 150 +/- 3; D, 157 +/- 2 mEq/L) and protein (PTP E, 7.8 +/- .1; D, 8.8 +/- .6 g/dL) were elevated. The only difference between groups during HEM were HR (E, 98 +/- 8; D, 150 +/- 17 bpm), SV (E, 31 +/- 3; D, 14 +/- 2), and TPR (E, 23 +/- 2; D, 32 +/- 3). Resuscitation with HSD restored MAP (E, 92 +/- 3; D, 92 +/- 2), CO (E, 6.2 +/- .3; D, 4.2 +/- .2), and TPR (E, 15 +/- 1; D, 23 +/- 1) to baseline values. SV was increased above hemorrhage values but was not restored to baseline values in either group (E, 50 +/- 7; D, 27 +/- 3). HR increased further following HSD (E, 143 +/- 11; D, 158 +/- 5). PNa was raised 10 and 16 mEq/L in the E and D sheep, respectively, following HSD infusion, but no adverse effects associated with elevated PNa were observed in either group. Thus, HSD was effective in restoring MAP, CO, and TPR to baseline values in D sheep but it was at the expense of a lower SV and a higher HR than in E sheep.

High level of arginine vasopressin and 7.5% NaCl/6% dextran-70 solution: cardiovascular and renal effects.

A marked diuresis has been observed following resuscitation of hypotensive hemorrhaged animals with small volume hypertonic saline/dextran (HSD), 7.5% NaCl/6% dextran-70. We tested the hypothesis that high arginine vasopressin (AVP) levels associated with severe hemorrhage may exacerbate the diuretic effect of HSD infusion in euvolemic sheep. Following AVP infusion, a significant bradycardia (55% of baseline) and decreased cardiac output (62% of baseline) was observed (p < or = .05). Urine output increased during AVP infusion (25.4 +/- 2.3 ml/20 min) compared to control group (10.5 +/- 1.0 ml/20 min) (p < or = .0001). With HSD volume expansion, urine flow in the AVP group was initially 1.7 times greater than the control group (104.8 +/- 10 ml/20 min vs. 60.2 +/- 15 ml/20 min) (p < or = .05). High serum levels of AVP (600 +/- 33 pg/ml) may contribute to the diuresis seen with HSD resuscitation and possibly contribute to the bradycardia observed with severe hemorrhage.

Liver hemodynamics during portal venous endotoxemia in swine.

The acute hemodynamic response of the liver to portal endotoxemia was measured in six isoflurane anesthetized pigs in which volume support was used to maintain normal cardiac output. After baseline monitoring, bacterial endotoxin (LPS) was infused over 1 hr into a mesenteric vein at a rate of 1 microgram.kg-1.hr-1, and monitoring was continued for 1 hr postinfusion. Peak vasoconstriction occurred during LPS infusion in both the hepatic artery (resistance increases 349% of baseline, P < 0.05) and the liver's portal circulation (resistance increases 159% of baseline, P < 0.05). Increased vascular resistance was also detected in lung (increases 433% of baseline) and intestine (increases 130% of baseline) at the midpoint of the LPS infusion. The non-splanchnic circulation, defined for our analysis as all of the peripheral circulation except the portal and hepatic arterial circulation, generally exhibited little change in vascular resistance during LPS infusion. LPS was incompletely cleared by the liver, but secondary clearance by the lung prevented large increases in the LPS concentration of arterial blood. During the first hour postinfusion, the systemic vascular resistance subsequently decreased to near normal in all vascular beds, with the exception of the liver's portal circulation. A sustained and secondary increase in vascular resistance of the liver's portal circulation and portal vein pressure occurred during the first hour after LPS infusion. We conclude that most of the vasoconstriction in the acute response to portal endotoxemia occurs in the liver and lung, organs directly exposed to elevated levels of endotoxins.