Optoacoustic monitoring of cerebral venous blood oxygenation though intact scalp in large animals.

Monitoring (currently invasive) of cerebral venous blood oxygenation is a key to avoiding hypoxia-induced brain injury resulting in death or severe disability. Noninvasive, optoacoustic monitoring of cerebral venous blood oxygenation can potentially replace existing invasive methods. To the best of our knowledge, we report for the first time noninvasive monitoring of cerebral venous blood oxygenation through intact scalp that was validated with invasive, "gold standard" measurements. We performed an in vivo study in the sheep superior sagittal sinus (SSS), a large midline cerebral vein, using our novel, multi-wavelength optoacoustic system. The study results demonstrated that: 1) the optoacoustic signal from the sheep SSS is detectable through the thick, intact scalp and skull; 2) the SSS signal amplitude correlated well with wavelength and actual SSS blood oxygenation measured invasively using SSS catheterization, blood sampling, and measurement with "gold standard" CO-Oximeter; 3) the optoacoustically predicted oxygenation strongly correlated with that measured with the CO-Oximeter. Our results indicate that monitoring of cerebral venous blood oxygenation may be performed in humans noninvasively and accurately through the intact scalp using optoacoustic systems because the sheep scalp and skull thickness is comparable to that of humans whereas the sheep SSS is much smaller than that of humans.

Optoacoustic monitoring of cerebral venous blood oxygenation through extracerebral blood.

There is strong clinical evidence that controlling cerebral venous oxygenation (oxyhemoglobin saturation) is critically important for patients with severe traumatic brain injury as well as for patients undergoing cardiac surgery. However, the only available method for cerebral venous blood oxygenation monitoring is invasive and requires catheterization of the internal jugular vein. We designed and built a novel optoacoustic monitor of cerebral venous oxygenation as measured in the superior sagittal sinus (SSS), the large midline cerebral vein. To the best of our knowledge, optical monitoring of cerebral venous blood oxygenation through overlying extracerebral blood is reported for the first time in this paper. The system was capable of detecting SSS signals in vivo at 700, 800, and 1064 nm through the thick (5-6 mm) sheep skull containing the circulating blood. The high (submillimeter) in-depth resolution of the system provided identification of the SSS peaks in the optoacoustic signals. The SSS peak amplitude closely followed the actual SSS blood oxygenation measured invasively using catheterization, blood sampling, and "gold standard" CO-Oximetry. Our data indicate the system may provide accurate measurement of the SSS blood oxygenation in patients with extracerebral blood over the SSS.

Noninvasive monitoring of cerebral blood oxygenation in ovine superior sagittal sinus with novel multi-wavelength optoacoustic system.

Noninvasive monitoring of cerebral blood oxygenation with an optoacoustic technique offers advantages over current invasive and noninvasive methods. We report the results of in vivo studies in the sheep superior sagittal sinus (SSS), a large central cerebral vein. We changed blood oxygenation by increasing and decreasing the inspired fraction of oxygen (FiO(2)). Optoacoustic measurements from the SSS were performed at wavelengths of 700, 800, and 1064 nm using an optical parametric oscillator as a source of pulsed near-infrared light. Actual oxygenation of SSS blood was measured with a CO-Oximeter in blood samples drawn from the SSS through a small craniotomy. The amplitude of the optoacoustic signal induced in the SSS blood at lambda = 1064 nm closely followed the changes in blood oxygenation, at lambda = 800 nm was almost constant, and at lambda = 700 nm was changing in the opposite direction, all in accordance with the absorption spectra of oxy- and deoxyhemoglobin. The optoacoustically predicted oxygenation correlated well with actual blood oxygenation in sheep SSS (R(2) = 0.965 to 0.990). The accuracy was excellent, with a mean difference of 4.8% to 9.3% and a standard deviation of 2.8% to 4.2%. To the best of our knowledge, this paper reports for the first time accurate measurements of cerebral venous blood oxygenation validated against the "gold standard" CO-Oximetry method.

In vivo monitoring of blood oxygenation in large veins with a triple-wavelength optoacoustic system.

A noninvasive optoacoustic technique could be a clinically useful alternative to existing, invasive methods for cerebral oxygenation monitoring. Recently we proposed to use an optoacoustic technique for monitoring cerebral blood oxygenation by probing large cerebral and neck veins including the superior sagittal sinus and the internal jugular vein. In these studies we used a multi-wavelength optoacoustic system with a nanosecond optical parametric oscillator as a light source and a custom-made optoacoustic probe for the measurement of the optoacoustic signals in vivo from the area of the sheep neck overlying the external jugular vein, which is similar in diameter and depth to the human internal jugular vein. Optoacoustic signals induced in venous blood were measured with high resolution despite the presence of a thick layer of tissues (up to 10 mm) between the external jugular vein and the optoacoustic probe. Three wavelengths were chosen to provide accurate and stable measurements of blood oxygenation: signals at 700 nm and 1064 nm demonstrated high correlation with actual oxygenation measured invasively with CO-Oximeter ("gold standard"), while the signal at 800 nm (isosbestic point) was independent of blood oxygenation and was used for calibration.

Accurate, noninvasive measurement of total hemoglobin concentration with optoacoustic technique.

The measurement of total hemoglobin concentration is currently invasive and time consuming. The optoacoustic technique may provide accurate and noninvasive measurements of total hemoglobin concentration by probing blood vessels. We studied the influence of blood vessel diameter and lateral displacement of the optoacoustic probe on accuracy of total hemoglobin concentration measurements with this technique.

Improved right heart function with a compliant inflow artificial lung in series with the pulmonary circulation.

BACKGROUND: We previously reported a 50% incidence of immediate right heart failure using a rigidly housed, noncompliant inflow artificial lung in series with the pulmonary circulation in a healthy ovine survival model. Three device modifications resulted: (1) an inflow cannula compliance chamber, (2) an inlet blood flow separator, and (3) modification of the artificial lung outlet geometry, all to reduce resistance and mimic the compliance of the pulmonary vascular bed. METHODS: In 7 sheep, arterial grafts were anastomosed end-to-side to the proximal and distal main pulmonary artery, with the paracorporeal artificial lung interposed. A pulmonary artery snare between anastomoses diverted full pulmonary blood flow through the artificial lung for up to 72 hours. RESULTS: Six of 7 sheep exhibited good cardiac function throughout the test period: mean central venous pressure was 6.8 mm Hg (range, 4 to 11 mm Hg), mean cardiac output, 4.17 +/- 0.12 L/min (range, 2.4 to 6.3 L/min); before and after device mean pulmonary arterial pressure, 21.8 and 18.5 mm Hg, and left atrial pressure, 10.8 mm Hg. CONCLUSIONS: This modified artificial lung prototype with an inflow compliance chamber, blood flow separator, and modified outlet geometry has greatly improved cardiac function and initial survival in our healthy ovine model.

Veno-venous perfusion-induced systemic hyperthermia: case report with perfusion considerations.

Cancer cells are more susceptible to destruction by heat than are their normal counterparts. However, optimization of this hyperthermic susceptibility for selective cancer cell kill has been difficult to define and technically difficult to achieve. A whole-body hyperthermic technique veno-venous perfusion-induced systemic hyperthermia (VV-PISH) was designed in in vitro and in swine experiments to achieve selective hyperthermic cancer cell destruction. In this case report, VV-PISH is studied for its safety and therapeutic efficiency in a Food and Drug Administration (FDA) approved phase-I study, where hyperthermia is used to treat advanced (Stage III B or IV) lung cancer. VV-PISH, utilizing the ThermoChem HT system in an extracorporeal circuit, was used to induce hyperthermia to 42.5 degrees C sustained for 120 min. Cooling returned the body temperature to 37 degrees C. After completion of the treatment, the patient was transferred to the intensive care unit on a ventilator, norepinephrine and diuretics. The patient remained somnolent for 36 h, developed pulmonary congestion requiring an additional 48 h before extubation, was transferred to the intermediate unit on day 4 and discharged in good condition on day 8. He did experience hyperthermia-related shrinkage of his lung cancer; however, he succumbed 270 days after this treatment from further progression of this disease. Hyperthermia is not a benign therapy; management techniques have been developed that have ameliorated many of the problems associated with extremely high temperatures, but pathophysiology still exists. Using these techniques, VV-PISH can be safety implemented, albeit not without temporary sequelae and further hospitalization.

Hemodynamic stability during arteriovenous carbon dioxide removal for adult respiratory distress syndrome: a prospective randomized outcomes study in adult sheep.

To evaluate the ability of arteriovenous carbon dioxide removal (AVCO2R) to maintain hemodynamic stability during treatment of adult respiratory distress syndrome (ARDS), we used our smoke/burn, LD40 sheep model of ARDS. With onset of ARDS (PaO2/FiO2 < 200) animals were randomized to AVCO2R (n = 20) or SHAM (n = 8). With AVCO2R, the carotid artery (10-14 F) and jugular vein (14-16 F) were cannulated; SHAM received identical management, sparing the vessels. AVCO2R maintained stable hemodynamics compared to SHAM at 48 hours; heart rate (114.8+/-6.1 vs. 110.1+/-11.0 beats/min.), mean arterial pressure (112+/-5.1 vs. 107.0+/-8.5 mm Hg), cardiac output (7.4+/-0.5 vs. 7.5+/-0.9 L/min.), pulmonary arterial pressure (26+/-2.4 vs. 21+/-1.3 mm Hg), pulmonary arterial wedge pressure (14.1+/-1.8 vs. 14.0+/-1.2 mm Hg), and central venous pressure (7+/-1.6 vs. 8+/-0.9 mm Hg). At 48 hours, AVCO2R allowed significant reductions (p<0.05) in minute ventilation (13.6+/-2.5 to 7.6+/-0.8 L/min); tidal volume (TV) (389.4+/-24.1 to 295.0+/-10.1 ml); peak inspiratory pressure (PIP) (25.4+/-9.2 to 18.8+/-2.5 cm H2O); RR (27.5+/-0.7 to 21.6+/-1.8 breaths/min); and FiO2 (0.96+/-0.00 to 0.48+/-0.2) while normocapnia was maintained. AVCO2R is an effective method of CO2 removal during severe respiratory failure that is hemodynamically well tolerated.

Percutaneous extracorporeal arteriovenous carbon dioxide removal improves survival in respiratory distress syndrome: a prospective randomized outcomes study in adult sheep.

OBJECTIVE: Arteriovenous carbon dioxide removal (AVCO(2)R) uses a simple arteriovenous shunt for CO(2) removal to minimize barotrauma/volutrauma from mechanical ventilation. We performed a prospective randomized outcomes study of AVCO(2)R in our new, clinically relevant model of respiratory distress syndrome. METHODS: Adult sheep (n = 18) received an LD(50) severe smoke inhalation and 40% third-degree burn. When respiratory distress syndrome developed (PaO (2)/FIO (2) < 200 at 40 to 48 hours), animals were randomized to the AVCO(2)R (n = 9) or sham group (n = 9) for 7 days. Ventilator management protocols mandated reductions in minute ventilation, first tidal volume to peak inspiratory pressure less than 30 cm H(2)O, then respiratory rate when PaCO (2) was less than 40 mm Hg. PaO (2) was kept above 60 mm Hg by adjusting FIO (2). When FIO (2) was 0.21, animals were weaned. RESULTS: The study required 2946 animal-hours of critical care with 696 AVCO(2)R hours. One died in each group during model development. AVCO(2)R flow from 820 mL/min to 970 mL/min (11% to 14% cardiac output) removed CO(2) at a rate of 92 to 116 mL/min (mean 103 mL/min; 93%-97% of CO(2) production). Heart rate, mean arterial pressure, cardiac output, and pulmonary arterial wedge pressure remained relatively constant. Within 48 hours, AVCO(2)R allowed significant ventilator reductions versus baseline in the following measurements: tidal volume (420 to 270 mL), peak inspiratory pressure (25 to 14 cm H(2)O), minute ventilation (13 to 5 L/min), respiratory rate (26 to 16 breaths/min), and FIO (2) (0.88 to 0.35). Ventilator-free days with AVCO(2)R were 3.9 versus 0.2 (P <.01) for sham animals, and ventilator-dependent days with AVCO(2)R were 2.4 versus 6.2 (P <.01) for the 3 sham survivors. All 8 AVCO(2)R animals and 3 of 8 sham animals survived 7 days after randomization. CONCLUSIONS: Percutaneous AVCO(2)R achieved significant reduction in airway pressures, increased ventilator-free days, decreased ventilator-dependent days, and improved survival in a sheep model of respiratory distress syndrome.

Anatomic study of the pulmonary artery as a conduit for an artificial lung.

Our group is developing an artificial lung as a bridge to transplant. We evaluated the sheep pulmonary artery (PA) for the presence or absence of a septum, which may increase PA resistance and affect artificial lung flow. We also measured the PA size to determine whether it is a suitable conduit for artificial lung implantation using a PA-PA shunt. Adult Suffolk ewes in two groups were studied. Group 1 consisted of animals (n = 12, 30-43 kg) prepared for thoracotomy. Group 2 (n = 21, 30-43 kg) consisted of postmortem dissections. In both groups, the length and girth of the PA was measured. The heart and lungs were removed on all postmortem animals (group 2), the ductus arteriosum was crosscut, and the common PA was incised. The average length of the PA in live animals was 5.5 cm and the average diameter was 2.2 cm. The average length of the PA in postmortem animals was 4.8 cm and the average diameter was 2.0 cm. All pulmonary arteries were aseptate, and the ligamentum arteriosum in each PA was not patent. We conclude that the PA is not a source of increased resistance and is a suitable conduit for artificial lung implantation in the PA-PA configuration.

Safety and efficacy of a heparin removal device: a prospective randomized preclinical outcomes study.

BACKGROUND: Systemic protamine sulfate for heparin reversal after cardiopulmonary bypass (CPB) is associated with uncommon, but life-threatening adverse reactions. METHODS: In a prospective randomized 3-day outcomes study, a heparin removal device (HRD) group (n = 12; 60-, 80-, 100-kg subgroups) was compared with a matched systemic Protamine group (Protamine; n = 6) for safety and efficacy using an adult swine model of CPB (60 minutes, 28 degrees C). RESULTS: HRD run time was 25 to 38 minutes depending on weight without complications. After HRD, heparin concentration decreased from 4.77 +/- 0.17 to 0.45 +/- 0.06 U/mL (activated clotting time [ACT] 776 +/- 83 to 180 +/- 12 seconds), and in Protamine, 3.94 +/- 0.63 to 0.13 +/- 0.02 U/mL (ACT 694 +/- 132 to 101 +/- 5 seconds) (p = 0.01 between groups, but no significant differences 60 minutes later). No significant difference between HRD and Protamine to 72 hours was seen in plasma-free hemoglobin C3a, heparin concentration, thromboelastogram index, platelet count, activated partial thromboplastin time, anti-thrombin III, fibrinogen, ACT, and tissue histology. CONCLUSIONS: In a prospective randomized outcomes study, HRD achieved predictable reversal of systemic heparinization after CPB with no difference in safety or outcomes compared with protamine.

Low-dose versus high-dose heparinization during arteriovenous carbon dioxide removal.

The purpose of this study was to compare low-dose (LD) and high-dose (HD) systemic heparinization in a prospective randomized study of arteriovenous carbon dioxide removal (AVCO2R) during acute respiratory distress syndrome, using a commercially available heparin-coated oxygenator. Adult sheep (n = 13) received an LD50 smoke inhalation and 40% TBSA third degree cutaneous flame burn injury. At 40-48 h post-injury, animals underwent cannulation of the carotid artery and jugular vein and were then randomized to HD heparin (activated clotting time, ACT > 300s, n = 6) and LD heparin (ACT < 200s, n =7) and placed on AVCO2R for approximately 72 h using an oxygenator with the Trillium Bio-Passive Surface. Mean ACTs were significantly different, as expected (HD: 446 +/- 26s, LD: 213 +/- 12s, p < 0.05). AVCO2R shunt flow averaged approximately 13% of cardiac output with mean CO2 removal similar in HD and LD, p = NS. The hematocrit, platelet count, and fibrin degradation products for the two groups were not different. No differences in thrombosis or bleeding were noted. In conclusion, LD systemic heparin (ACT < 200s) with a heparin-coated oxygenator does not increase thrombogenicity during AVCO2R for smoke/burn-induced severe lung injury in sheep.

Venovenous perfusion-induced systemic hyperthermia: hemodynamics, blood flow, and thermal gradients.

BACKGROUND: Thermal events during extracorporeal venovenous perfusion-induced systemic hyperthermia (VV-PISH) were studied and related to determination of whole-body and regional thermal isoeffect doses. METHODS: Swine (n = 6, 77+/-4.5 kg) were heated to a target temperature of 43 degrees C for 120 minutes using VV-PISH. Colored microspheres were injected during preheat, heat induction, maintenance, cool down, and after decannulation. The esophageal, tympanic, rectal, pulmonary artery, bladder, bone marrow, kidney, brain, blood, lung, and airway temperatures were recorded continuously. The thermal dose, thermal exchange, metabolic heat production, heat loss to the environment, the change in body heat, and the thermal isoeffect dose were studied at 15-minute intervals. RESULTS: VV-PISH increased heart rate and cardiac output and caused a redistribution of blood flow favoring the thoracoabdominal organs. Greatest thermal exchange occurred during the heating phase (total 2,162+/-143 kJ), metabolic heat production contributed in all phases (274+/-9 kJ), the greatest change in body heat occurred during heating (1,310+/-309 kJ) with a total delivered thermal dose of 298+/-21 kJ, and the total whole body thermal isoeffect dose at 100+/-5 minutes. CONCLUSIONS: VV-PISH is feasible, is capable of transferring sufficient heat, causes a redistribution of blood flow favoring the thoracoabdominal organs, and facilitates calculation of whole-body and regional thermal isoeffect doses.

New clinically relevant sheep model of severe respiratory failure secondary to combined smoke inhalation/cutaneous flame burn injury.

OBJECTIVES: To develop a predictable, dose-dependent, clinically relevant model of severe respiratory failure associated with a 40% total body surface area, full-thickness (third-degree) cutaneous flame burn and smoke inhalation injury in adult sheep. DESIGN: Model development. SETTING: Research laboratory. SUBJECTS: Adult female sheep (n = 22). INTERVENTIONS: Animals were divided into three groups, determined by the number of smoke breaths administered (24, 36, 48) for a graded inhalation injury. The smoke was insufflated into a tracheostomy with a modified bee smoker at airway temperatures <40 degrees C. All animals concurrently received a 40% total body surface area (third-degree) cutaneous flame burn to the body (flanks). After injury, the animals were placed on volume-controlled ventilation to achieve PaO2 >60 mm Hg and PaCO2 <40 mm Hg. Arterial blood gases and ventilator settings were monitored every 6 hrs postinjury for up to 7 days. MEASUREMENTS AND MAIN RESULTS: All animals survived the induction of injury. In the 24 smoke breath/40% total body surface area burn (24/40) group, PaO2/F(IO2) never decreased below 300, and peak inspiratory pressure was consistently <14 cm H2O with normal arterial blood gases throughout the observation period. With 36 smoke breaths/40% total body surface area burn (36/40) (n = 7), all animals had PaO2/F(IO2) of <200 and peak inspiratory pressure of 26 cm H2O within 40-48 hrs, as 30% died during the study period. With 48 smoke breaths/40% total body surface area burn (48/40) (n = 12), all animals developed respiratory distress syndrome (RDS) in 24-30 hrs, but none survived the experimental period. CONCLUSIONS: Development of RDS by smoke and cutaneous flame bum injury depends on smoke inhalation dose. A combination of 36 breaths of smoke and a 40% total body surface area (third-degree) cutaneous flame burn injury can induce severe RDS (PaO2/F(IO2) <200) within 40-48 hrs to allow evaluation of various treatment modalities of RDS.

Effects of pentobarbital and isoflurane on conditioned learning after transient global cerebral ischemia in rabbits.

BACKGROUND: The acquisition of a conditioned eyeblink response has been used extensively to study the neurologic substrates of learning and memory. We examined the effects of the anesthetics isoflurane and pentobarbital, or hypothermia (30 degrees C), on the ability of rabbits to acquire an eyeblink conditioned response after 6.5 min of cerebral ischemia. METHODS: New Zealand white rabbits (n = 48) were randomly assigned to sham, normothermic, hypothermic, isoflurane, or pentobarbital groups. In the normothermic, hypothermic, isoflurane, and pentobarbital groups, 6.5 min of global cerebral ischemia was produced. In animals randomized to the isoflurane and pentobarbital groups, a pattern of burst suppression was achieved on the electroencephalogram before the start of the ischemic episode. Animals in the hypothermia group were cooled to 30 degrees C before ischemia. Seven days after ischemia, eyeblink training was started using an audible tone presented for 100 ms as the conditioned stimulus. The unconditioned stimulus was an air puff directed at the cornea. The delay between the end of conditioned stimulus and the start of the unconditioned stimulus (the trace interval) was 300 ms in duration. A conditioned response was defined as an eyeblink that was initiated during the trace interval. Eighty trials per day and 15 days of training were delivered. RESULTS: Neurologic deficits were greatest in the normothermia group, and these animals also had fewer conditioned responses than those in the sham, hypothermia, or pentobarbital groups. Animals in the isoflurane group had an intermediate number of conditioned responses that was not significantly different from the normothermia group. CONCLUSIONS: This study demonstrates that a brief episode of cerebral ischemia results in the impairment of associative learning. Hypothermia and burst-suppressive doses of pentobarbital were able to improve neurobehavioral outcome as measured by ability to acquire a trace conditioned response.

Development of a human to murine orthotopic xenotransplanted lung cancer model.

The goal was to develop a clinically relevant animal model that could be used to assess the efficacy of therapeutic interventions in lung cancer. Two cell lines, noncancerous control (BEAS2-B, immortalized human bronchial-epithelial cell line) and cancerous (BZR-T33, H-ras transformed BEAS2-B) were implanted into nude (athymic) mice. Two groups (n = 10 each) received dorsoscapular subcutaneous injection of 10(6) cells from either cell line. BEAS2-B cells were nontumorigenic, whereas mice with BZR-T33 cells had tumors (9,510 +/- 4,307 mm3) confirmed by histology, and a significantly smaller body weight (BZR-T33, 28.5 +/- 0.49 vs. BEAS2-B, 30.7 +/- 0.75 g, p < .05). The next phase evaluated invasion/metastasis. Two groups (n = 10 each) received 10(6) cells from either cell line injected into tail veins. Animals receiving BZR-T33 cells had a smaller body weight, palpable lung masses (67%), obvious tail masses (44%), and average tumor burden (1,120 +/- 115 mm3), and histology revealed invasion of lung tissue and interstitial hemorrhage. In development of the orthotopic xenotransplanted model, mice (2 groups, n = 10 each) received 10(6) cells from either cell line implanted into the lungs through a tracheotomy. Animals with BZR-T33 cells did not survive past 59 days and had a smaller body weight, increased lung weight, lung masses (100%), and metastatic loci (30%). Magnetic resonance imaging (MRI) confirmed the presence of masses in intubated live mice, later confirmed by histology. In summary, the H-ras transfected cell line developed lung masses following tail-vein injection and endotracheal seeding. Evaluation by MRI allows for a comprehensive model with significant potential in the study of lung cancer.

Laboratory testing of femoral venous cannulae: effect of size, position and negative pressure on flow.

Femoral venous cannulae (17-28 French) were tested to compare flows obtained by their placement in a simulated inferior vena cava (IVC) or right atrium (RA) and by varying drainage pressures using gravity siphon drainage or a centrifugal pump in the venous line. The circuit consisted of conventional tubing and equipment including a segment of thin-walled latex tubing to simulate the IVC connected to a flexible reservoir to simulate the RA. The test fluid was a 40% glycerin solution. Flow was measured at height differentials of 30-60 cm (cannula-to-inlet of hard-shell venous reservoir) and with a -10 to -80 mmHg negative pressure created by the centrifugal pump. A roller pump returned the test fluid to a flexible bag to maintain a filling pressure of 0-1 mmHg. Flow increased modestly with an increasing height differential. When negative pressure was applied with the centrifugal pump, flow increased 10% and 18% (IVC and RA positions, respectively) compared to gravity siphon drainage conditions. There also was a tendency for flow to plateau or cease when the centrifugal pump was used at higher levels of negative pressure or when larger cannulae were used. We conclude: (1) position of smaller cannulae in the RA yield better flows than when the cannulae are larger and placed in the IVC; (2) smaller-sized cannulae are capable of achieving higher flows when the centrifugal pump is used; (3) cannulae must be properly positioned to achieve maximum flow; (4) the centrifugal pump will augment flow, but should be regulated to avoid extreme negative pressures; and (5) cannula design has no demonstrable effect on flow.

Effects of hypothermia and lamotrigine on trace-conditioned learning after global cerebral ischemia in rabbits.

Acquisition of the trace-conditioned eye blink response (CR) is mediated by a variety of brain structures, including the cerebellum, the hippocampus, and brain stem nuclei. We examined the effects of a neuronal sodium channel antagonist (lamotrigine) on the ability of rabbits to acquire an eye blink CR after 6.5 min of cerebral ischemia. New Zealand white rabbits (n = 31) were randomly assigned to sham (S), normothermic ischemia (N), hypothermic (30 degrees C) ischemia-(H), or lamotrigine (50 mg/kg) treated (L) groups. In the N, H, and L groups, 6.5 min of global cerebral ischemia was produced using an inflatable neck tourniquet. Trace conditioning was started on the 7th postischemic day. The conditioned stimulus consisted of a tone (85 dB, 6 kHz) presented for 100 ms. The unconditioned stimulus was an air puff (150 ms duration) directed at the cornea. The interval between the end of the conditioned stimulus and the start of the unconditioned stimulus (the trace interval, TI) was 300 ms in duration. A trace-conditioned response was defined as an eye blink that was initiated during the TI. Eighty trials were delivered daily for 15 days. Neurologic deficits were greatest in the N group, and these animals had fewer CRs (149 +/- 157) than animals in the S (509 +/- 214) or H (461 +/- 149) groups (P < 0.05 by analysis of variance). Animals in the L group had a total number of CRs (380 +/- 253) that was intermediate between the S and N groups. Histologic evidence of neural injury was greatest in the N group. This study demonstrates that a brief episode of cerebral ischemia results in the impairment of this test of neurobehavioral function. Both hypothermia and lamotrigine were able to attenuate the impairment of eye blink trace-conditioned responses produced by cerebral ischemia.

Reduced ventilator pressure and improved P/F ratio during percutaneous arteriovenous carbon dioxide removal for severe respiratory failure.

OBJECTIVE: To evaluate the effect of percutaneous arteriovenous carbon dioxide removal (AVCO2R) on ventilator pressures and P/F ratio in a clinically relevant large-animal model of severe respiratory failure. SUMMARY BACKGROUND DATA: AVCO2R was developed as a simple arteriovenous shunt with a commercially available low-resistance gas exchange device of sufficient surface area for near-total CO2 removal. With an AV shunt 10% to 15% of cardiac output, AVCO2R allows a reduction in ventilator airway pressures without hypercapnia or the complex circuitry and monitoring required for conventional ECMO. METHODS: AVCO2R was applied to a new, clinically relevant large-animal model of severe respiratory failure created by smoke inhalation and cutaneous flame bum injury. Adult sheep (n = 9, 38+/-6 kg) received a 40% total body surface area, third-deinsufflation. After injury, all animals were placed on volume-controlled mechanical ventilation to achieve PaO2 > 60 mmHg and PacO2 < 40 mmHg. Animals were placed on AVCO2R within 40 to 48 hours of injury when the PaO2/FiO2 was <200. Animals underwent cannulation of the carotid artery and jugular vein with percutaneous 10F arterial and 14F venous cannulas. Shunt flow was continuously monitored using an ultrasonic flow probe and calculated as a percentage of cardiac output. RESULTS: AVCO2R flows of 800 to 900 ml/min (11% to 13% cardiac output) achieved 77 to 104 ml/min of CO2 removal (95% to 97% total CO2 production) while maintaining normocapnia. Significant reductions in ventilator settings were tidal volume, 421.3+/-39.8 to 270.0+/-6.3 ml; peak inspiratory pressure, 24.8+/-2.4 to 13.7+/-0.7 cm H2O; minute ventilation, 12.7+/-1.4 to 6.2+/-0.8 L/min; respiratory rate, 25.4+/-1.3 to 18.4+/-1.8 breaths/min; and FiO2, 0.88+/-0.1 to 0.39+/-0.1. The P/F ratio increased from 151.5+/-40.0 at baseline to 320.0+/-17.8 after 72 hours. CONCLUSIONS: Percutaneous AVCO2R allows near-total CO2 removal and significant reductions in ventilator pressures with improvement in the P/F ratio.

Significant reduction in circuit pressure with modified plasma separation chamber for a heparin removal device.

The heparin removal device (HRD), using plasma separation and poly-L-lysine (PLL) affinity adsorption, has been shown to be an effective alternative to protamine after cardiopulmonary bypass (CPB). Previous designs of the HRD used standard Luer-Lok ((phi = 2.3 mm) port connections between the extracorporeal tubing and the plasma separation chambers, which resulted in excessively high circuit pressures (> 750 mm Hg) at an HRD flow of 1,400 ml/min. To reduce circuit pressures, we enlarged the connection ports to phi = 4.2 mm, keeping other circuit components and sorbent amounts unchanged. The modified circuit HRD was divided into the SMALL PORT group (phi = 2.3 mm, A = 4.15 mm2) and the LARGE PORT group (phi = 4.2 mm, A = 13.85 mm2) in adult swine (70+/-5 kg) given 300 U/kg heparin. A dual lumen cannula was inserted into the right atrium and connected to the HRD. Inlet pressure ranged from 749+/-42 to 795+/-57 mm Hg in the SMALL PORT group during the HRD run at 1,400 ml/min, whereas it ranged from 345+/-5 to 372+/-34 mm Hg in the LARGE PORT group (p < 0.01 between groups). Likewise, the chamber pressure ranged from 447+/-21 to 452+/-27 mm Hg in the SMALL PORT group and from 190+/-14 to 204+/-19 mm Hg in the LARGE PORT group (p < 0.01 between groups). There were no significant differences in ACT between groups. We conclude that enlarged chamber ports significantly lower circuit pressures for the HRD without changing heparin removal capability.