Scott T. Johnson

N-acetylcysteine improves the hemodynamics and oxidative stress in hypoxic newborn pigs reoxygenated with 100% oxygen.

Neonatal asphyxia may lead to cardiac and renal complications perhaps mediated by oxygen free radicals. Using a model of neonatal hypoxia-reoxygenation, we tested the hypothesis that N-acetylcysteine (NAC) would improve cardiac function and renal blood flow. Eighteen piglets (aged 1-4 days old, weighing 1.4-2.2 kg) were anesthetized and acutely instrumented for continuous monitoring of pulmonary and renal artery flow (cardiac index [CI] and renal artery flow index [RAFI], respectively) and mean blood pressure. Alveolar hypoxia was induced for 2 h, followed by resuscitation with 100% oxygen for 1 h and 21% oxygen for 3 h. Animals were randomized to sham-operated, hypoxic control, and NAC treatment (i.v. bolus of 150 mg/kg given at 10 min of reoxygenation followed by 100 mg/kg per h infusion) groups. Myocardial and renal tissue glutathione content and lipid hydroperoxide levels were assayed, and histology was examined. After 2 h of hypoxia, all animals were acidotic (pH 6.96 ± 0.04) and in cardiogenic shock with depressed renal blood flow. Upon reoxygenation, CI and RAFI increased but gradually deteriorated later. The NAC treatment prevented the decreased CI, stroke volume, mean blood pressure, systemic oxygen delivery, RAFI, and renal oxygen delivery at 2 to 4 h of reoxygenation observed in hypoxic controls (versus shams, all P < 0.05). The myocardial and renal tissue glutathione content was significantly higher in the NAC treatment group (versus controls). The CI and RAFI at 4 h of reoxygenation correlated with the tissue glutathione redox ratio (r = 0.5 and 0.6, respectively, P < 0.05). There were no significant differences in heart rate, pulmonary artery pressure, systemic oxygen uptake, and tissue lipid hydroperoxide levels between groups. No histologic injury was found in the heart or kidney. In this porcine model of neonatal hypoxia and 100% reoxygenation, NAC improved cardiac function and renal perfusion, with improved tissue glutathione content.

The hemodynamic effects of dobutamine during reoxygenation after hypoxia: a dose-response study in newborn pigs.

Asphyxiated neonates usually have myocardial stunning and hypotension and require inotropic support. A randomized controlled study was designed to examine the dose-response effect of dobutamine (5-20 &mgr;g·kg−1·min−1) on systemic and regional circulations and oxygen metabolism in a neonatal swine model of hypoxia/reoxygenation. Thirty-eight anesthetized newborn piglets were acutely instrumented for continuous monitoring of heart rate, systemic and pulmonary arterial pressures, and pulmonary (surrogate for cardiac index), right common carotid, and superior mesenteric and left renal arterial flows. After stabilization, they were exposed to normocapnic alveolar hypoxia (10%-15% oxygen) for 2 h followed by reoxygenation with 100% oxygen for 1 h, then 21% for 3 h. Piglets were block randomized to receive dobutamine infusion (5, 10, or 20 &mgr;g·kg−1·min−1) or saline (control) at 2 to 4 h of reoxygenation (n = 8 each). A nonasphyxiated, sham-operated group was included (n = 6). Blood samples were collected for blood gas analysis, arterial and venous co-oximetry, and plasma lactate concentration determination. At 2-h reoxygenation after hypoxia, there was hypotension (systemic arterial pressure, 27 to 36 mmHg) and myocardial dysfunction (cardiac index from 178-209 to 134-156 mL·kg−1·min−1). Cardiac index improved significantly with 20 &mgr;g·kg−1·min−1 of dobutamine (P < 0.05) and modestly in the treatment groups of 5 and 10 &mgr;g·kg−1·min−1 (P < 0.1) (at 120 min, 172 ± 35, 160 ± 30, and 158 ± 56 mL·kg−1·min−1 vs. 119 ± 33 mL·kg−1·min−1 of controls, respectively), with corresponding increases in stroke volume. Pulmonary vascular resistance was lower in all dobutamine-treated groups (vs. controls, P < 0.05) There were no differences in heart rate, systemic and pulmonary arterial pressures, systemic vascular resistance, and regional flows between groups. The group of 20 &mgr;g·kg−1·min−1 of dobutamine also had higher systemic oxygen delivery (at 120 min, 18 ± 5 vs. 11 ± 3 O2 mL·kg−1·min−1 of controls, P < 0.05) with no significant differences in systemic oxygen consumption and regional oxygen delivery between groups. After the reoxygenation of newborn piglets with severe hypoxia, high dose of dobutamine is effective to treat myocardial stunning and low cardiac output with no significant effect on blood pressure or regional circulation. Further clinical studies are needed to confirm these findings in the human neonate.

Combined hepatic and inferior vena cava resection for colorectal metastases

Surgical resection continues to offer the only hope for cure of colorectal cancer metastatic to the liver. Tumor involvement of the vena cava is often viewed as a contraindication to surgical resection. Whereas proven technically feasible, the survival advantages of en bloc liver and vena cava resection remain unclear. We reviewed all patients at a tertiary care center who had resection of colorectal liver metastases, including those with vena cava resections. Eleven patients had en bloc liver and vena cava resection between 1988 and 2002; during the same time period, 97 patients underwent isolated liver resection. There were no perioperative deaths in the 11 patients. All resections had negative histological margins. Mean follow-up was 33 months from the date of surgery. Median disease-free survival of the group having caval resections was 9 months, whereas median survival was 34 months. When compared to the cohort of isolated hepatic resections, the group undergoing caval resections experienced a significantly reduced diseasefree survival of 18.6 vs. 9.1 months, respectively (P = 0.03); however, there was no difference in overall survival between the two groups at 55.2 vs. 34.3 months, respectively (P = 0.20). Colorectal liver metastases involving the vena cava should be considered for surgical resection.

The effect of dobutamine on platelet aggregatory function in newborn piglets with hypoxia and reoxygenation.

Dobutamine, a &bgr;-adrenoceptor agonist that is often used to treat myocardial dysfunction in asphyxiated neonates, may act on the adrenoceptors of platelets resulting in activation. Little information is available on the effect and mechanistic pathway of dobutamine on the platelet aggregatory function in neonatal asphyxia. Newborn piglets were acutely instrumented and exposed to hypoxia for 2 h and reoxygenation for 4 h. Piglets were randomized to receive dobutamine infusion (5, 10, or 20 µg/kg per min) or saline (hypoxic-control) at 2 to 4 h of reoxygenation (n = 8 each), and sham-operated animals were not exposed to hypoxia and reoxygenation (n = 6). Platelet number, collagen-stimulated whole blood aggregation, and plasma concentrations of thromboxane B2 were studied. The effects of &agr;- and &bgr;-adrenoceptor antagonists (phentolamine and propranolol, respectively) on platelet aggregation to in vitro administration of dobutamine (3µM) were also examined. Shock and metabolic acidosis developed similarly in all hypoxia-reoxygenated groups. At 4 h of reoxygenation, platelet numbers in all groups decreased, with no differences among groups. Platelet aggregation deteriorated significantly with a rightward shift of concentration-response curve in piglets receiving 10 and 20 µg/kg per min of dobutamine. The group that received 20 µg/kg per min of dobutamine had increased plasma thromboxane B2 concentrations from baseline (P < 0.05). The platelet aggregatory response induced by 3 µM of dobutamine was improved by the coadministration of the &bgr;-but not the &agr;-adrenoceptor antagonist. We observed platelet aggregatory dysfunction in hypoxic-reoxygenated newborn piglets treated with high-dose dobutamine. Further investigation is needed to examine the differential effects of dobutamine and hypoxia-reoxygenation in platelet aggregation in newborns.

Temporal platelet aggregatory function in hypoxic newborn piglets reoxygenated with 18%, 21%, and 100% oxygen.

Thromboembolic and bleeding complications are common after asphyxia. We studied the temporal effects of different oxygen concentrations used in resuscitating hypoxic newborn piglets on platelet aggregatory function. Alveolar normocapnic hypoxia (fractional inspired oxygen concentration = 0.15) was induced in piglets (1-4 d, 1.7-2.5 kg) for 2 h, followed by reoxygenation with 18%, 21%, or 100% oxygen for 1 h and then 21% for 2 h (n = 8-9 per group). Control piglets underwent surgery with no hypoxia-reoxygenation (n = 5). Platelet counts and collagen-stimulated (2-10 &mgr;g/mL) whole blood aggregation were studied at normoxic baseline and at 3 h, 2 d, and 4 d of recovery. Platelet activation markers including plasma thromboxane B2 and matrix metalloproteinase 2 and 9 levels were measured. At 2 h hypoxia (mean PaO2 30-35 mmHg), all piglets were hypotensive and acidotic (mean pH 7.19-7.24). In 100% reoxygenation piglets, the concentration-response curves of collagen-stimulated platelet aggregation were significantly shifted upward at 3 h and 2 d of recovery with no differences in the collagen concentration required to induce 50% of maximum aggregation, and this normalized to baseline on 4 d. In the 18% and 21% reoxygenated groups, there were no changes in platelet aggregation during the experiment. Platelet counts were not different between groups and over time. Hypoxic-reoxygenated piglets had increased plasma thromboxane B2 (100% group) and matrix metalloproteinase-2 levels (21% and 100% groups) (versus respective baseline, P < 0.05), with no difference between experimental groups. These findings suggest transient platelet activation in hypoxic newborn piglets resuscitated with 100% but not with 18% and 21% oxygen, of which the clinical significance requires further investigation.

Cerebral Amino Acid Profiles after Hypoxia-Reoxygenation and N-Acetylcysteine Treatment in the Newborn Piglet

Background: Neonatal hypoxia-ischemia (HI) is a common clinical occurrence. Recently, much evidence has been gathered to suggest that oxygen free radicals are implicated in the pathogenesis of hypoxia-reoxygenation injury through the initiation and propagation of toxic cascades including glutamate excitotoxicity and the manifestation of post-HI neurologic disorders. Following HI, excessive free radicals are formed and antioxidant defenses are diminished. N-acetylcysteine (NAC) is a clinically available antioxidant and has been previously shown to reduce oxidative stress and scavenge free radicals in multiple models of brain injury. Objectives: Using an acutely instrumented swine model of neonatal hypoxia-reoxygenation, the objective of the present study was to examine the neurochemical effects of NAC administration in 5 brain regions exquisitely vulnerable to severe hypoxia. Methods: In a blinded fashion, newborn piglets (1–4 d, 1.4–2.2 kg) were block randomized into surgical sham (SHAM), hypoxic control (HC) and NAC-treated (H-NAC) groups. Both HC and H-NAC piglets were subject to 2 h of alveolar hypoxia (paO2 = 20–40 mm Hg) and then resuscitated with 100% O2 for 1 h followed by 21% for an additional 3 h. Results: Our results show that two hours of severe hypoxemia causes metabolic acidosis and significant changes in cerebral amino acids including glutamate, aspartate and alanine, in all brain regions investigated including the cortex, basal ganglia and thalamus. The administration of NAC 10 min into the reoxygenation period and subsequently continued as an infusion, maintains post-resuscitation amino acid neurochemistry at the levels observed in SHAM piglets. Conclusions: In newborn piglets that have sustained brain injury related to hypoxia/reoxygenation, the administration of NAC does not disrupt cerebral amino acid balance and maintains cerebral amino acid homeostasis.

Design of a Consensus-Derived Synoptic Operative Report for Lung Cancer Surgery

BACKGROUND For lung cancer surgery, a narrative operative report is the standard reporting procedure, whereas a synoptic-style report is increasingly utilized by healthcare professionals in various specialties with great success. A synoptic operative report more succinctly and accurately captures vital information and is rapidly generated with good intraobserver reliability. The objective of this study was to systematically develop a synoptic operative report for lung cancer surgery following a modified Delphi consensus model with the support of the Canadian thoracic surgery community. METHODS Using online survey software, thoracic surgeons and related physicians were asked to suggest and rate data elements for a synoptic report following the modified Delphi consensus model. The consensus exercise-derived template was forwarded to a small working group, who further refined the definition and priority designation of elements until the working group had reached a satisfactory consensus. RESULTS In all, 139 physicians were invited to participate in the consensus exercise, with 36.7%, 44.6%, and 19.5% response rates, respectively, in the three rounds. Eighty-nine elements were agreed upon at the conclusion of the exercise, but 141 elements were forwarded to the working group. The working group agreed upon a final data set of 180 independently defined data elements, with 72 mandatory and 108 optional elements for implementation in the final report. CONCLUSIONS This study demonstrates the process involved in developing a multidisciplinary, consensus-based synoptic lung cancer operative report. This novel report style is a quality improvement initiative to improve the capture, dissemination, readability, and potential utility of critical surgical information.

Effects of N-Acetylcysteine on Intestinal Reoxygenation Injury in Hypoxic Newborn Piglets Resuscitated with 100% Oxygen

Background: Neonatal asphyxia may lead to the development of ischemia-reperfusion induced intestinal injury, which is related to oxygen-derived free radical production. N-Acetylcysteine (NAC) is a thiol-containing antioxidant which increases intracellular stores of glutathione. Objectives: Using a swine model of neonatal hypoxia-reoxygenation, we examined whether administration of NAC after resuscitation improved intestinal perfusion and reduced intestinal damage. Methods: Twenty-four piglets (1–4 days old, 1.4–2.2 kg) were anesthetized and acutely instrumented for continuous monitoring of superior mesenteric arterial flow and oxygen delivery. Alveolar hypoxia was induced for 2 h, followed by resuscitation with 100% oxygen for 1 h and 21% oxygen for 3 h. Animals were randomized to sham-operated, hypoxic control and NAC treatment (150 mg/kg i.v. at 0 or 10 min of reoxygenation followed by infusion 100 mg/kg/h) groups. During hypoxia-reoxygenation, intestinal tissue glutathione content, caspase-3 activity and reoxygenation injury were examined. Results: After 2 h of hypoxia, piglets were acidotic and hypotensive, with significantly depressed blood flow and oxygen delivery to the small intestine. Upon reoxygenation, hemodynamics recovered as did oxygen supply to the small intestine. After 4 h of reoxygenation, the NAC treatment improved mesenteric flow and oxygen delivery. Despite reducing the increase in caspase-3 activities after hypoxia-reoxygenation by NAC treatment, no significant differences in the glutathione content and histological grading of ileal injury were found among the experimental groups. Conclusions: In newborn piglets with hypoxia-reoxygenation, NAC may improve mesenteric blood flow and oxygen delivery without significant effect on tissue glutathione content. The protective role of NAC in the reoxygenated intestine after severe hypoxia warrants further investigation.

Systemic and regional hemodynamic effects of high-dose epinephrine infusion in hypoxic piglets resuscitated with 100% oxygen.

Shock and poor regional perfusion are common in asphyxiated neonates. We compared the systemic and regional hemodynamic effects of high-dose epinephrine (E) with those of dopamine combined with low-dose epinephrine (DE) infusions in a neonatal model of hypoxia-reoxygenation. Neonatal piglets (1-3 days, 1.5-2.5 kg) were acutely instrumented to continuously monitor systemic arterial pressure (SAP), pulmonary artery pressure, cardiac index (CI), and blood flows at the left common carotid, superior mesenteric, and renal arteries. Either epinephrine (1 &mgr;g · kg−1 · min−1) or dopamine (10 &mgr;g · kg−1 · min−1) and epinephrine (0.2 &mgr;g · kg−1 · min−1) were given for 2 h in hypoxic piglets resuscitated with 100% oxygen (n = 8 per group) in a randomized blinded fashion. Control piglets received hypoxia and reoxygenation but no catecholamine infusion (n = 7). Alveolar hypoxia (PaO2, 33-37 mmHg) caused reduced CI (89-92 vs. 171-186 mL · kg−1 · min−1 of baseline, P < 0.05), hypotension (SAP, 28-32 mmHg) with pH 7.05 to 7.10, and decreased regional flows. Upon reoxygenation, CI and SAP improved but gradually deteriorated to 131 to 136 mL · kg−1 · min−1 and 41 to 49 mmHg at 2 h of reoxygenation, respectively. E and DE administration similarly improved CI (167 ± 60 and 166 ± 55 vs. 121 ± 35 mL · kg−1 · min−1 of controls) and SAP (53 ± 7 and 56 ± 10 vs. 39 ± 8 mmHg of controls), respectively, and the pulmonary vascular resistance (vs. controls, all P < 0.05). Heart rate and pulmonary artery pressure were not different between groups. Systemic oxygen delivery and consumption were increased in E- and DE-treated groups with no difference in extraction ratio between groups. There were no differences in regional blood flows and oxygen delivery between groups. After hyperlactatemia with hypoxia, plasma lactate levels decreased with no difference between groups. Epinephrine given as the sole agent is as effective as dopamine and low-dose epinephrine combined in treating shock and hypotension that follow the resuscitation of hypoxic neonatal piglets, with no reduction in regional perfusion.

Angiostatins decrease in the kidney of newborn piglets after hypoxia-reoxygenation

Little is known about the expression of kidney angiostatin in the hypoxia and reoxygenation of neonates. In this study, we compared the effect of 21% and 100% reoxygenation on kidney levels of angiostatin and its related factors in newborn piglets subjected to hypoxia-reoxygenation. Newborn piglets were subjected to 2h hypoxia followed by 1h of reoxygenation with either 21% or 100% oxygen and observed for 4days. There were 3 isoforms (38, 43 and 50kDa) of angiostatins identified in the kidney tissue of newborn piglets with the 38kDa being the major isoform (~60%). The 38kDa, but not 43 and 50kDa, angiostatin isoform correlated significantly with the levels of total angiostatin and plasminogen (r=0.95 and r=0.58, respectively). On day 4 of recovery in 100% hypoxic-reoxygenated group, there were decreases in kidney tissue levels of plasminogen, total angiostatin, angiostatin (38 and 43kDa, but not 50kDa), whereas no significant changes were found in the 21% hypoxic-reoxygenated group when compared to the sham-operated piglets with no hypoxia-reoxygenation. Both 21% and 100% hypoxic-reoxygenated groups did not show significant changes in kidney tissue levels of 50kDa angiostatin, MMP-2, MMP-9 and HIF-1alpha. In comparison to 21% oxygen, neonatal resuscitation with 100% oxygen decreased the kidney tissue levels of plasminogen and angiostatin that may play a role in neonatal kidney injury and altered renal development in adulthood.