Hypothermic low-flow cardiopulmonary bypass impairs pulmonary and right ventricular function more than circulatory arrest.

BACKGROUND: Hypothermic circulatory arrest (HCA) is used during surgical treatment of certain congenital heart defects. The possibility of ischemic neurologic injury associated with HCA has led some surgeons to use low-flow cardiopulmonary bypass (CPB) during the hypothermic interval (hypothermic low flow [HLF]). This study investigates the inflammatory response to HCA and HLF, and reports the consequences of this response on pulmonary and right ventricular function. METHODS: Piglets (3.1 to 6.6 kg) were cooled to 16 degrees to 18 degrees C using CPB, and randomized: HCA for 60 minutes (n = 7), or HLF (50 cc.kg(-1).min(-1)) for 60 minutes (n = 6). The piglets were rewarmed to 36 degrees C and weaned from CPB. Serum tumor necrosis factor-alpha (TNF-alpha) concentration, percent lung water, and pulmonary and cardiac function were measured before and after CPB. RESULTS: Tumor necrosis factor-alpha was higher after HLF (2,990.5 +/- 884.5 pg/mL), compared with HCA (347.6 +/- 89.2 pg/mL; p = 0.03). The percent lung water was higher after HLF (84.8% +/- 0.3%) than HCA (82.0% +/- 0.4%; p < 0.001). The alveolar to arterial oxygen gradient was worse after HLF (457 +/- 42 mm Hg) than HCA (285.8 +/- 45 mm Hg; p = 0.02). Pulmonary vascular resistance was greater after HLF (36.08 +/- 8.28 mm Hg.mL(-1).m(-2).min(-1)) than HCA (14.55 +/- 3.46 mm Hg. mL(-1).m(-2).min(-1); p = 0.049). The right ventricular pressure waveform peak derivative, corrected for systolic pulmonary artery pressure, was lower after HLF (14.1 +/- 1.4 sec(-1)), than HCA (23.8 +/- 2.7 sec(-1); p = 0.01). CONCLUSIONS: Hypothermic low flow extends exposure to CPB, and is associated with an increased inflammatory response compared with HCA. The greater inflammatory response after HLF may result in substantial nonneurologic morbidity in the postoperative period, demonstrated by pulmonary and right ventricular dysfunction. Interventions that attenuate the inflammatory response to CPB may prevent pulmonary and right ventricular dysfunction after HLF.

Cardiac output augmentation during hypoxemia improves cerebral metabolism after hypothermic cardiopulmonary bypass.

BACKGROUND: Hypothermic circulatory arrest (HCA) impairs cerebral oxygen delivery (CDO2) and cerebral oxygen consumption (CMRO2), which are further reduced by perioperative hypoxemia. This study investigates if continuous hypothermic low-flow cardiopulmonary bypass (HLF) or intermittent hypothermic low-flow cardiopulmonary bypass (IHLF) can prevent reductions in CDO2 and CMRO2 during hypoxemia. METHODS: Eighteen neonatal piglets, cooled to 16 degrees to 18 degrees C with cardiopulmonary bypass (CPB), were randomly assigned into three groups: HCA, HLF (50 cc.kg(-1).min(-1)), or IHLF (1 minute of HLF for every 15 minutes of HCA). After 60 minutes of hypothermia, normothermic CPB (100 cc.kg(-1).min(-1)) was established and cerebral perfusion data measured at hyperoxemia (PaO2 150 to 250 mm Hg), hypoxemia (PaO2 50 to 60 mm Hg), and severe hypoxemia (PaO2 30 to 40 mm Hg), and with increased CPB flow (200 cc.kg(-1).min(-1)) during severe hypoxemia. RESULTS: The CMRO2 (in mL O2.100 g(-1).min(-1)) was lower after HCA (2.5 +/- 0.3), compared with HLF (4.1 +/- 0.5, p = 0.02) and IHLF (6.2 +/- 0.8, p = 0.002). Within groups, the change from hyperoxemia to severe hypoxemia resulted in decreased CMRO2: HCA (1.3 +/- 0.2, p = 0.004), HLF (3.0 +/- 0.5, p = 0.01), and IHLF (2.9 +/- 0.5, p = 0.01). During severe hypoxemia, increasing CPB flow (from 100 cc.kg(-1).min(-1) to 200 cc.kg(-1).min(-1)) improved CMRO2: HCA (1.9 +/- 0.5, p = 0.05), HLF (4.2 +/- 0.5, p = 0.05), and IHLF (7.4 +/- 0.5, p = 0.04). CONCLUSIONS: Hypoxemia reduces CDO2 and CMRO2 despite the method of hypothermic CPB. Increased CPB flow during hypoxemia can restore both CDO2 and CMRO2 to values found with hyperoxemia and slower CPB flows. Augmenting cardiac output during periods of perioperative hypoxemia may prevent cerebral injury after exposure to hypothermic cardiopulmonary bypass.

Using a miniaturized circuit and an asanguineous prime to reduce neutrophil-mediated organ dysfunction following infant cardiopulmonary bypass.

BACKGROUND: Contemporary infant cardiopulmonary bypass circuits require a blood prime. Blood, especially when stored, generates an inflammatory response, and may contribute to organ dysfunction following cardiopulmonary bypass. We determined whether using a miniaturized circuit and an asanguineous prime attenuated the post-bypass inflammatory response, and improved right ventricular and pulmonary function. METHODS: Sixteen infant piglets were placed into 3 groups based on prime components: group I (fresh blood), group II (stored blood), and group III (miniaturized circuit and asanguineous prime). Piglets were placed on cardiopulmonary bypass (100 mL.kg(-1).min(-1)), cooled to 18 degrees C, and underwent continuous perfusion (50 mL.kg(-1).min(-1)) for 30 minutes. They were rewarmed and separated from bypass. Serum tumor necrosis factor-alpha, right ventricular function, and pulmonary function were measured before and 30 minutes after bypass. Neutrophil priming activity in fresh and stored donor blood was also assessed. RESULTS: Animals in group III had significantly improved cardiopulmonary function than the groups receiving blood (right ventricular cardiac index [mL.kg(-1).min(-1)]: group I [18.8 +/- 4.8], group II [21.5 +/- 6.2], and group III [81.2 +/- 11.4], p < 0.001; and pulmonary vascular resistance index [dynes.mL(-1).kg(-1)]: group I [1169 +/- 409], group II [1610 +/- 486], and group III [214 +/- 63], p = 0.03). Tumor necrosis factor-alpha (pg.mL(-1)) was lower in group III (1465 +/- 39) than in the groups receiving blood (3940 +/- 777), p = 0.002. Neutrophil priming activity (nmol.min(-1)) was also higher in stored blood (3.7 +/- 6) than in fresh blood (1.9 +/- 0.2), p = 0.02. CONCLUSIONS: We have devised a unique miniaturized circuit that allows an asanguineous prime without hemodilution in an infant swine model. The employment of this circuit attenuates the post-bypass inflammatory response and has salutary effects on cardiopulmonary function.

Postoperative hypoxemia exacerbates potential brain injury after deep hypothermic circulatory arrest.

BACKGROUND: Deep hypothermic circulatory arrest (DHCA) is often used in infants undergoing the Norwood procedure. These infants are hypoxic after surgery. Previous investigations into the cerebral metabolic response and oxygen utilization after DHCA examined animals with normal arterial oxygenation. This study reports the cerebral metabolic consequences if hypoxemic conditions are present after DHCA. METHODS: Eighteen neonatal piglets were randomly assigned to three groups. The control group was ventilated; the cardiopulmonary bypass group underwent 60 minutes of normothermic cardiopulmonary bypass, and the DHCA group underwent cardiopulmonary bypass and 60 minutes of DHCA (16 degrees to 18 degrees C) followed by rewarming. Hemodynamic and cerebral perfusion data were measured at an arterial partial pressure of oxygen (PaO2) of 150 to 250 mm Hg, and then at moderate hypoxemia (PaO2, 50 to 60 mm Hg) and severe hypoxemia (PaO2, 25 to 35 mm Hg). RESULTS: Cerebral oxygen delivery decreased by 44% from PaO2 150 to 250 mm Hg to severe hypoxemia (p < 0.001). Cerebral oxygen extraction increased from moderate hypoxemia to severe hypoxemia in the control (57.9% +/- 3.7% to 71.8% +/- 3.8%; p = 0.002) and cardiopulmonary bypass groups (61.2% +/- 2.6% to 70.6% +/- 1.2%; p = 0.035); however, the cerebral oxygen extraction of the DHCA group did not increase under these conditions (82.8% +/- 1.8% to 77.9% +/- 4.3%; p = 0.32). The cerebral metabolic rate of oxygen consumption of the DHCA group decreased from PaO2 150 to 250 mm Hg to severe hypoxemia (1.86 +/- 0.20 to 0.99 +/- 0.24 mL O2 x 100 g(-1) x min(-1); p = 0.02), whereas the cerebral metabolic rate of oxygen consumption did not change under these conditions in the control and cardiopulmonary bypass groups. CONCLUSIONS: Under hypoxemic conditions cerebral metabolic rate of oxygen consumption deteriorates after DHCA. Infants exposed to DHCA may be at greater risk of brain injury when postoperative hypoxemia is present. Because maximal cerebral oxygen extraction after DHCA occurs at moderate hypoxemia, techniques that increase cerebral oxygen delivery may reduce the risk of hypoxic brain injury.

Blunt cardiac injury.

In summary, the incidence of BCI following blunt thoracic trauma patients has been reported between 20% and 76%, and no gold standard exists to diagnose BCI. Diagnostic tests should be limited to identify those patients who are at risk of developing cardiac complications as a result of BCI. Therapeutic interventions should be directed to treat the complications of BCI. Finally, the prognosis and outcome of BCI patients is encouraging

Routine mechanical ventricular assist following the Norwood procedure--improved neurologic outcome and excellent hospital survival.

BACKGROUND: Although excellent survival following the Norwood procedure for palliation of hypoplastic left heart syndrome (HLHS) is being achieved by some, most centers, especially the ones with small surgical volume and limited experience, continue to struggle with initial results. Survivors often showed evidence of significant neurologic injury. The early postoperative care is labor-intensive as attempts are made to balance the systemic and pulmonary circulation for these infants. We report our experience with routine use of mechanical circulatory assist to support the increased cardiac output requirements present following Norwood procedure. METHODS: Eighteen consecutive infants undergoing Norwood operation for HLHS (Oregon Health & Science University [OHSU] 13; University of Louisville [UL] 5) were placed on a ventricular assist device (VAD) immediately following modified ultrafiltration in the operating room using the cardiopulmonary bypass (CPB) cannulas that were in the right atrium and the neoaorta. VAD flows were maintained at approximately 200 mL x kg(-1) x min(-1) and the patients were transported to the intensive care unit (ICU). Patients operated at OHSU also received neurodevelopmental testing before their Glenn procedure, approximately 4 to 6 months following their Norwood operation. RESULTS: All patients were stable on VAD support and no attempt was made to balance the systemic and pulmonary circulation. The ventilator was manipulated to achieve systemic Pa0(2) between 30 and 45 mm Hg and PaC0(2) between 35 and 45 mm Hg. Evidence of hypoperfusion (increasing lactates) was managed by increasing the VAD flow. Lactates normalized [< 2 mmol/L]) by 1.8 +/- 1.1 days following surgery. Average time of VAD support was 3.1 +/- 1.0 (range, 2 to 5 days) and average time until chest closure was 3.4 +/- 1.5 (range, 2 to 8 days). There were two cases of postoperative bleeding (11.1%) requiring reexploration and one case of mediastinitis (5.5%) in a patient who has now gone on to successful Glenn. Sixteen of the eighteen patients survived (hospital survival mean 89% with a 95% confidence interval of 63.9% to 98.1%; 12/13 OHSU [92.3%]; 4/5 UL [80%]). Neurodevelopmental testing using the Mullen Scales of Early Learning and the Vineland Adaptive Behavior Scale were normal for all infants tested. CONCLUSIONS: Routine postoperative use of VAD can support the increased cardiac output demands of infants following Norwood operation and results in a stable postoperative convalescence that does not require aggressive ventilator or inotrope manipulation. Although not a panacea, this strategy can simplify postoperative management, lead to excellent hospital survival, and possibly augment cerebral oxygen delivery, resulting in improved neurologic outcomes for this challenging group of patients.

Extracellular signal-regulated kinase and phosphoinositol-3 kinase mediate IGF-1 induced proliferation of fetal sheep cardiomyocytes.

Growth of the fetal heart involves cardiomyocyte enlargement, division, and maturation. Insulin-like growth factor-1 (IGF-1) is implicated in many aspects of growth and is likely to be important in developmental heart growth. IGF-1 stimulates the IGF-1 receptor (IGF1R) and downstream signaling pathways, including extracellular signal-regulated kinase (ERK) and phosphoinositol-3 kinase (PI3K). We hypothesized that IGF-1 stimulates cardiomyocyte proliferation and enlargement through stimulation of the ERK cascade and stimulates cardiomyocyte differentiation through the PI3K cascade. In vivo administration of Long R3 IGF-1 (LR3 IGF-1) did not stimulate cardiomyocyte hypertrophy but led to a decreased percentage of cells that were binucleated in vivo. In culture, LR3 IGF-1 increased myocyte bromodeoxyuridine (BrdU) uptake by three- to five-fold. The blockade of either ERK or PI3K signaling (by UO-126 or LY-294002, respectively) completely abolished BrdU uptake stimulated by LR3 IGF-1. LR3 IGF-1 did not increase footprint area, but as expected, phenylephrine stimulated an increase in binucleated cardiomyocyte size. We conclude that 1) IGF-1 through IGF1R stimulates cardiomyocyte division in vivo; hyperplastic growth is the most likely explanation of IGF-1 stimulated heart growth in vivo; 2) IGF-1 through IGF1R does not stimulate binucleation in vitro or in vivo; 3) IGF-1 through IGF1R does not stimulate hypertrophy either in vivo or in vitro; and 4) IGF-1 through IGF1R requires both ERK and PI3K signaling for proliferation of near-term fetal sheep cardiomyocytes in vitro.

Fetal anemia leads to augmented contractile response to hypoxic stress in adulthood.

In response to chronic fetal anemia, coronary blood flow, maximal coronary conductance, and coronary reserve increase. We sought to determine whether chronic fetal anemia alters left ventricular (LV) function in adulthood. We studied adult sheep that had been made anemic for 20 days in utero by phlebotomy. They were transfused just before birth. At 7 mo of age, LV function was measured by pressure-volume loops at rest and during hypoxic stress. The in utero anemia group (n = 8) did not differ from controls (n = 5) with respect to hematocrit, heart and body weight, or baseline hemodynamic parameters. However, the effect of hypoxia (relative to baseline) on multiple indexes of systolic function was different between the two groups. End-systolic elastance increased in the in utero anemia group (baseline to hypoxia) by 4.15 +/- 3.47 mmHg/ml (mean +/- SD) but changed little in controls (0.24 +/- 0.45), which shows that the response to hypoxia was significantly different (P < 0.01) between groups. Similarly, the maximum derivative of LV pressure with respect to time increased in the in utero anemia group (486 +/- 340 mmHg/s,) but on average fell in the controls (-503 +/- 211 mmHg/s) with the response again being significantly different (P < 0.03). We conclude that in sheep, perinatal anemia can alter cardiac responses to hypoxic stress in the adult long after restoration of normocythemia.

Total correction of tetralogy of Fallot in the first year of life: late results.

BACKGROUND: Correction of tetralogy of Fallot in patients less than 1 year of age offers the advantage of a more normal development; but in the majority of cases exposes the patient to the possibly of a higher mortality with one-stage primary repair, and to the long-term effects of a transannular patch, which is often necessary. METHODS: A retrospective review of total correction of tetralogy of Fallot performed in 63 consecutive patients at less than 1 year of age was made. Risk factors for operative mortality and functional status at follow-up were analyzed. Follow-up was obtained from clinic appointments and telephone questionnaires. RESULTS: The operative mortality was 6%, with three late deaths. Aortic cross-clamp time more than 60 minutes (p = 0.023), cardiopulmonary bypass time more than 90 minutes (p = 0.016), and frequent preoperative respiratory tract infection symptoms (p = 0.008) affected operative survival; whereas age less than 3.0 months or weight less than 6.0 kg did not. Mean follow-up is 11.6 years (+/- 0.6 years, standard error). Actuarial survival is 89% (+/- 4%) and freedom from reoperation is 96% (+/- 4%) at up to 20 years after correction. Eighty-seven percent of patients have normal echocardiographic right ventricular function. Only 4 patients have greater than moderate pulmonary regurgitation by echocardiography. Three of these four patients are asymptomatic. At more than 15 years postoperatively, 88% of patients have good-to-excellent functional status. CONCLUSIONS: Early correction of tetralogy of Fallot at less than 1 year of age can have a low operative mortality and provide excellent asymptomatic long-term survival.