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Biomedical subjects

Colleen M Fitzpatrick

Publications and source records attributed to Colleen M Fitzpatrick.

11 recordsLinked to original sources
PubMed2005

Prolonged low-volume resuscitation with HBOC-201 in a large-animal survival model of controlled hemorrhage.

BACKGROUND: Military guidelines call for two 500-mL boluses of Hextend for resuscitation in far-forward environments. This study compared a hemoglobin-based oxygen carrier (HBOC-201; Hemopure) to Hextend when used to treat hemorrhagic shock in situations of delayed definitive care military operations. METHODS: Yorkshire swine (55-65 kg) were hemorrhaged to a mean arterial blood pressure (MAP) of 30 mmHg. Hypotension was maintained for 45 minutes followed by resuscitation with either Hextend (HEX) (n = 8) or HBOC-201 (HBOC) (n = 8). Over 8 hours, animals received up to 1,000 mL of either fluid in an effort to sustain an MAP of 60 mmHg. At the end of 8 hours, HEX animals received 2 L of lactated Ringer's solution followed by shed blood. HBOC animals received 4 L of lactated Ringer's solution only. Animals were killed and necropsied on postprocedure day 5. Hemodynamic data were collected during shock and resuscitation. Complete blood counts, amylase, lactate, coagulation studies, and renal and liver function were measured throughout the experiment. RESULTS: Equivalent volumes were hemorrhaged from each group (HBOC, 44.3 +/- 2.2 mL/kg; HEX, 47.4 +/- 3.0 mL/kg). The HBOC group achieved the goal MAP (HBOC, 60.0 +/- 2.3 mmHg; HEX, 46.4 +/- 2.3 mmHg; p < 0.01) and required less volume during the initial 8 hours (HBOC, 12.4 +/- 1.4 mL/kg; HEX, 17.3 +/- 0.3 mL/kg; p < 0.01). The HBOC group had lower SvO2 (HBOC, 46.3 +/- 2.4%; HEX, 50.7 +/- 2.5%; p = 0.12) and cardiac output (HBOC, 5.8 +/- 0.4 L/min; HEX, 7.2 +/- 0.6 L/min; p = 0.05), but higher systemic vascular resistance (HBOC, 821.4 +/- 110.7 dynes . s . cm-5; HEX, 489.6 +/- 40.6 dynes . s . cm-5; p = 0.01). Base excess, pH, lactate, and urine output did not differ between groups. HEX group survival was 50% (four of eight) versus 88% for the HBOC group (seven of eight). All animals survived the initial 8 hours. Animals surviving 5 days displayed no clinical or laboratory evidence of organ dysfunction in either group. CONCLUSION: HBOC-201 more effectively restored and maintained perfusion pressures with lower volumes, and allowed for improved survival. These data suggest that hemoglobin-based oxygen carriers are superior to the current standard of care for resuscitation in far-forward military operations.

Alanine Transaminase↗
PubMed2005

Endothelial dysfunction after lactated Ringer's solution resuscitation for hemorrhagic shock.

BACKGROUND: Endothelial dysfunction is presumed to occur after hemorrhagic shock and resuscitation. This study uses a novel large-animal model to evaluate the effects of diverse resuscitation regimens on endothelial function. METHODS: Twenty-seven adult domestic pigs (Sus scrofa) were used in this study. Control pigs (n = 3) underwent instrumentation alone. The remaining pigs experienced controlled hemorrhagic shock to a mean arterial blood pressure of 30 +/- 5 mm Hg for 45 minutes. Pigs were resuscitated to their baseline mean arterial blood pressure +/-5 mm Hg with either shed blood (SB; n = 8), lactated Ringers solution (40 mL/kg) followed by shed blood (LRSB; n = 8), or lactated Ringers solution alone (LR; n = 8). At baseline, 1 and 4 hours after resuscitation, acetylcholine (5, 10, and 15 microg/min) was infused into the proximal iliac artery to measure endothelial dependent relaxation (EDR). Sodium nitroprusside was infused to determine endothelial independent relaxation at the end of the study to insure smooth muscle vasomotor integrity. External iliac artery luminal diameter was measured using motion-mode ultrasonography. Statistical analysis was performed using repeated-measures analysis of variance with Tukey's post-hoc analysis. RESULTS: All pigs survived the experiment. Pigs required ninefold more resuscitation with LR (370.58 +/- 29 mL/kg) versus SB (41.45 +/- 3.5 mL/kg) or LRSB (76.4 +/- 1.1 mL/kg) (p < 0.05). EDR for LR pigs 1 hour after initiation of resuscitation (R1) was 70.4 +/- 14.4% compared with 94.2 +/- 13.4% for SB and 106.1 +/- 8.2% for LRSB (p < 0.05). At 4 hours after resuscitation (R4), systolic luminal diameters were larger in the SB (0.45 +/- 0.01 cm) and LRSB (0.51 +/- 0.02 cm) groups compared with LR (0.41 +/- 0.03 cm) (LRSB versus LR; p = 0.01). At R4, EDR for the LR group was 78.3 +/- 10.7% compared with SB (101.4 +/- 8.3%) and LRSB (106.4 +/- 7.4%) (p < 0.05). Infusion of sodium nitroprusside confirmed integrity of smooth muscle vasorelaxation. Analysis of serum nitric oxide levels revealed decreased values after resuscitation with LR (9.44 +/- 0.76 mol/L) compared with SB (26.3 +/- 7.8 mol/L) and LRSB (16.3 +/- 1.0 mol/L) (p = not significant). CONCLUSION: This is the first description of a large-animal model to evaluate EDR after hemorrhagic shock. Resuscitation with LR requires significantly larger volumes than SB or LRSB. LR resuscitation leads to endothelial dysfunction, as determined by decreased EDR, versus SB or LRSB. Resuscitation with blood products may preserve nitric oxide bioactivity when compared with crystalloid resuscitation in the setting of hemorrhagic shock.

Animals↗
PubMed2005

Bilateral brachial artery occlusion decreases internal carotid artery volume flow: a simple adjunct for cerebral protection?

PURPOSE: To investigate if a decrease in internal carotid artery (ICA) blood flow occurs with bilateral brachial artery occlusion (BBO), which may improve the effectiveness of cerebral protection devices during carotid interventions. METHODS: Thirty-two asymptomatic patients (21 men; mean age 67 years) with carotid atherosclerosis between 15% and 79% were enrolled in the study. Carotid duplex ultrasound was followed by volume flow rate (VF) determination in the right ICA, external carotid (ECA), and vertebral arteries. After baseline values were obtained, BBO was induced by bilateral arm pressure cuff inflation to 30 mmHg over the systolic pressure for no more than 3 minutes. VF measurements were repeated. RESULTS: Seventeen patients (responders) had an ICA VF decrease from 406+/-109 mL/min (+/-SD) to 303+/-90 mL/min (p=0.005), while 15 patients (nonresponders) had no significant change in their ICA VF (340+/-192 versus 447+/-267 mL/min, p=0.22). In responders, ECA VF increased (190+/-65 to 232+/-125 mL/min), as did vertebral VF (77+/-53 to 95+/-60 mL/min; p>0.05). The ratio of ICA/ECA VF dropped from 2.13 to 1.31 in responders, but did not change in nonresponders. No patient exhibited any neurological symptoms during the study. Post cuff volume flows approximated baseline values. Cerebral magnetic resonance angiograms obtained in 10 responders revealed a complete circle of Willis in 8 (80%), while only 1 (16%) of 6 nonresponders had a complete pathway. CONCLUSIONS: A transient decrease in ICA VF, with concomitant elevations of the ECA and vertebral VFs, occurs with occlusion of the brachial arteries in the setting of a complete circle of Willis. Since no flow reversal occurs, this maneuver is insufficient to provide complete cerebral protection, but it may improve the effectiveness of cerebral protection devices and serve as an adjunctive maneuver in selected cases. Furthermore, changes in ICA VF may prove to be a noninvasive test for evaluating the integrity of the circle of Willis.

Adult↗
PubMed2005

Carotid revascularization in the presence of contralateral carotid artery occlusion is safe and durable.

OBJECTIVE: Complete occlusion of the contralateral carotid artery has been thought to increase the risk of carotid endarterectomy (CEA). This study was conducted to determine whether contralateral occlusion (CO) leads to a higher rate of complications among patients undergoing CEA or alters long-term outcomes. METHODS: All CEAs (N = 221) performed at our institution between September 1997 and June 2002 were reviewed. Patients were divided into two groups, i.e., CO and contralateral patency. Statistical analyses were performed using Fisher's exact test for nominal values and the t test for continuous variables. Life-table analyses were performed for patency and survival. RESULTS: Complete data and follow-up results were available for 170 of the 221 operations performed during the study period. CO was present in 16 cases (9.4%). Preoperative demographic features, indications for surgery, and operative techniques did not vary between study groups; there was increased use of general anesthesia (p = 0.05) in the CO group. No surgical deaths occurred. The perioperative stroke rates were not statistically different between groups (CO group, 6.3%; contralateral patency group, 2.6%; p = 0.39). Long-term patency and stroke-free survival rates at 5 years exceeded 90% and did not vary significantly between groups. CONCLUSION: Patients undergoing CEA with occlusion of the contralateral carotid artery do not have unique preoperative demographic features or indications. Contralateral carotid artery occlusion does not increase risk or alter long-term outcomes after CEA. Carotid revascularization can be safely performed in tertiary military centers.

Aged↗
PubMed2004

Cardioprotection in chronically hypoxic rabbits persists on exposure to normoxia: role of NOS and KATP channels.

Hypoxia from birth increases resistance to myocardial ischemia in infant rabbits. We hypothesized that increased cardioprotection in hearts chronically hypoxic from birth persists following development in a normoxic environment and involves increased activation of nitric oxide synthase (NOS) and ATP-dependent K (K(ATP)) channels. Resistance to myocardial ischemia was determined in rabbits raised from birth to 10 days of age in a normoxic (Fi(O(2)) = 0.21) or hypoxic (Fi(O(2)) = 0.12) environment and subsequently exposed to normoxia for up to 60 days of age. Isolated hearts (n = 8/group) were subjected to 30 min of global ischemia followed by 35 min of reperfusion. At 10 days of age, resistance to myocardial ischemia (percent recovery postischemic recovery left ventricular developed pressure) was higher in chronically hypoxic hearts (68 +/- 4%) than normoxic controls (43 +/- 4%). At 10 days of age, N(G)-nitro-L-arginine methyl ester (200 microM) and glibenclamide (3 microM) abolished the cardioprotective effects of chronic hypoxia (45 +/- 4% and 46 +/- 5%, respectively) but had no effect on normoxic hearts. At 30 days of age resistance to ischemia in normoxic hearts declined (36 +/- 5%). However, in hearts subjected to chronic hypoxia from birth to 10 days and then exposed to normoxia until 30 days of age, resistance to ischemia persisted (63 +/- 4%). L-NAME or glibenclamide abolished cardioprotection in previously hypoxic hearts (37 +/- 4% and 39 +/- 5%, respectively) but had no effect on normoxic hearts. Increased cardioprotection was lost by 60 days. We conclude that cardioprotection conferred by adaptation to hypoxia from birth persists on subsequent exposure to normoxia and is associated with enhanced NOS activity and activation of K(ATP) channels.

Adaptation, Physiological↗
PubMed2004

Resuscitation with a blood substitute causes vasoconstriction without nitric oxide scavenging in a model of arterial hemorrhage.

BACKGROUND: The purpose of this study was to determine if a hemoglobin-based oxygen carrier, HBOC-201 (Hemopure, Biopure Corp), alters endothelial function and nitric oxide physiology when used for hemorrhagic shock. STUDY DESIGN: Female swine (Sus scrofa) underwent catheterization of the femoral, circumflex iliac, and pulmonary arteries. Control animals (n = 3) underwent instrumentation only. Study animals underwent hemorrhage to mean arterial pressure of 30 +/- 5 mmHg, were maintained for 45 minutes, and resuscitated to the baseline mean arterial pressure for 4 hours. Resuscitation fluids included: shed blood (SB) (n = 8), lactated Ringers plus shed blood (LRSB) (n = 8), and HBOC (n = 8). At baseline, 1, and 4 hours after resuscitation, acetylcholine was infused into the proximal iliac artery and endothelial-dependent relaxation was measured with M-mode ultrasonography. Nitric oxide levels were determined using a chemiluminescent assay. RESULTS: HBOC, SB, and LRSB provided equivalent survival and resuscitation as measured by mean arterial pressures (65.3 +/- 2.48 mmHg); pulmonary artery mean pressures (15.8 +/- 0.84 mmHg); and lactate levels (1.22 +/- 0.19 mmol/L). HBOC group animals required the lowest resuscitation volume (SB, 41.5 +/- 3.5 mL/kg; LRSB, 76.4 +/- 1.1 mL/kg, HBOC, 14.6 +/- 2.1 mL/kg, p < 0.001). Response to acetylcholine was normal in the SB and LRSB groups, but the HBOC group had diminished acetylcholine response (29.5% endothelial-dependent relaxation end resuscitation, p < 0.001). Arterial nitric oxide levels did not differ between study groups (p = 0.69). CONCLUSIONS: HBOC might be an alternative resuscitation agent in patients with hemorrhagic shock. Resuscitation with HBOC requires less volume than blood or crystalloid. These data suggest HBOC-201 has a vasoconstrictive effect that cannot be attributed soley to nitric oxide scavenging.

Animals↗
PubMed2004

Thrombus-induced endothelial dysfunction: Hemoglobin and fibrin decrease nitric oxide bioactivity without altering eNOS.

BACKGROUND: Arterial thrombosis is associated with endothelial dysfunction. The purpose of this study was to determine which components of thrombus induce endothelial dysfunction and to determine their effect on endothelial nitric oxide synthase (eNOS) activity and expression. MATERIALS AND METHODS: Human aortic endothelial cells were grown to confluence. Group 1 consisted of control cells exposed to media. Group 2 was exposed to cellular components of thrombus, including erythrocytes (RBCs) (1.5, 3, and 6 x 10(4) cells/ml) and platelets (0.5, 1, and 2 x 10(5) platelets/ml). Group 3 was exposed to extracellular thrombus components, including hemoglobin (1.25, 2.5, and 5.0 g/dl), thrombin (0.4, 4.0, and 10.0 units/ml), and fibrin. The exposure time was 20 h. Nitric oxide (NO) levels were measured following exposure. Global cellular integrity was evaluated by MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) conversion. eNOS mRNA expression was measured using semiquantitative PCR and eNOS protein activity evaluated via a l-citrulline conversion assay. Studies were done in replicates of six and expressed as percentages of controls. RESULTS: NO levels decreased following exposure to hemoglobin (1.25 g/dl = 59 +/- 5%, 2.5 g/dl = 38 +/- 3%, 5 g/dl = 37 +/- 6%, P < 0.001). MTS metabolism was likewise suppressed (1.25 g/dl = 57 +/- 2%, 2.5 g/dl = 55 +/- 3%, 5 g/dl = 44 +/- 6%, P < 0.001). Fibrin diminished NO levels (37 +/- 5%, P < 0.01) and MTS metabolism (49 +/- 5%, P < 0.01). RBCs and platelets had no effect on NO production or MTS metabolism (P > 0.05). Thrombin's effect was concentration dependent, inhibiting nitric oxide production at low doses while stimulating it at high doses (P < 0.01). All thrombin doses enhanced MTS metabolism (P < 0.05). eNOS activity was not altered by fibrin, thrombin, or hemoglobin exposure (P > 0.05). Moreover, eNOS mRNA expression was unaffected (P > 0.05). CONCLUSIONS: Intact cellular components of thrombus do not cause endothelial dysfunction in vitro. However, free hemoglobin and fibrin diminish NO bioactivity, likely via scavenging. Thrombin affects NO levels in a concentration-dependent manner. Neither eNOS expression nor eNOS activity is diminished, indicating that thrombus does not cause permanent changes in NO generation capability.

Aorta↗
PubMed2003

Cellular redistribution of inducible Hsp70 protein in the human and rabbit heart in response to the stress of chronic hypoxia: role of protein kinases,.

Many infants who undergo cardiac surgery have a congenital cyanotic defect where the heart is chronically perfused with hypoxemic blood. Infant hearts adapt to chronic hypoxemia by activation of intracellular protein kinase signal transduction pathways. However, the involvement of heat shock protein 70 in adaptation to chronic hypoxemia and its role in protein kinase signaling pathways is unknown. We determined expression of message and subcellular protein distribution for inducible (Hsp70i) and constitutive heat shock protein 70 (Hsc70) in chronically hypoxic and normoxic infant human and rabbit hearts and their relationship to protein kinases. In chronically hypoxic human and rabbit hearts message levels for Hsp70i were elevated 4- to 5-fold compared with normoxic hearts, Hsp70i protein was redistributed from the particulate to the cytosolic fraction. In normoxic infants Hsp70i protein was distributed almost equally between the cytosolic and particulate fractions. Hsc70 message and subcellular distribution of Hsc70 protein were unaffected by chronic hypoxia. We then determined if protein kinases influence Hsp70i protein subcellular distribution. In rabbit hearts SB203580 and chelerythrine reduced Hsp70i message levels, whereas SB203580, chelerythrine, and curcumin reversed the subcellular redistribution of Hsp70i protein caused by chronic hypoxia, with no effect in normoxic hearts, indicating regulation of Hsp70i message and subcellular distribution of Hsp70i protein in chronically hypoxic rabbit hearts is influenced by protein kinase C and mitogen-activated protein kinases, specifically p38 MAPK and JNK. We conclude the Hsp70 signal transduction pathway plays an important role in adaptation of infant human and rabbit hearts to chronic hypoxemia.

Alkaloids↗
PubMed2003

Caval and ureteral obstruction secondary to an inflammatory abdominal aortic aneurysm.

Inflammatory abdominal aortic aneurysms (IAAA) represent 3% to 10% of all abdominal aortic aneurysms. Obstructive uropathy is a well-described feature of IAAAs, but venous complications are unusual secondary to IAAA. The authors report a patient presenting with acute renal failure and deep venous thrombosis secondary to an IAAA. We believe this represents the first case of an IAAA manifesting as combined inferior vena cava compression and associated obstructive uropathy. Successful operative repair was performed. With resolution of the retroperitoneal inflammation, long-term follow-up revealed spontaneous release of both ureteral and caval compression.

Aged↗
PubMed2002

Delayed cardioprotection by isoflurane: role of K(ATP) channels.

Isoflurane mimics the cardioprotective effect of acute ischemic preconditioning with an acute memory phase. We determined whether isoflurane can induce delayed cardioprotection, the involvement of ATP-sensitive potassium (K(ATP)) channels, and cellular location of the channels. Neonatal New Zealand White rabbits at 7-10 days of age (n = 5-16/group) were exposed to 1% isoflurane-100% oxygen for 2 h. Hearts exposed 2 h to 100% oxygen served as untreated controls. Twenty-four hours later resistance to myocardial ischemia was determined using an isolated perfused heart model. Isoflurane significantly reduced infarct size/area at risk (means +/- SD) by 50% (10 +/- 5%) versus untreated controls (20 +/- 6%). Isoflurane increased recovery of preischemic left ventricular developed pressure by 28% (69 +/- 4%) versus untreated controls (54 +/- 6%). The mitochondrial K(ATP) channel blocker 5-hydroxydecanoate (5-HD) completely (55 +/- 3%) and the sarcolemmal K(ATP) channel blocker HMR 1098 partially (62 +/- 3%) attenuated the cardioprotective effects of isoflurane. The combination of 5-HD and HMR-1098 completely abolished the cardioprotective effect of isoflurane (56 +/- 5%). We conclude that both mitochondrial and sarcolemmal K(ATP) channels contribute to isoflurane-induced delayed cardioprotection.

Adenosine Triphosphate↗