W. T. McBride

Plasma and Urinary Cytokine Homeostasis and Renal Dysfunction during Cardiac Surgery

BackgroundCardiac surgery induces changes in plasma cytokines. Proinflammatory cytokines have been associated with a number of renal diseases. The proinflammatory cytokines interleukin 8 (IL-8), tumor necrosis factor &agr; (TNF&agr;), and interleukin 1&bgr; (IL-1&bgr;) are smaller than the antiinflammatory cytokines interleukin 10 (IL-10), interleukin 1 receptor antagonist (IL-1ra), and TNF soluble receptor 2 (TNFsr2), and thus undergo glomerular filtration more readily. Accordingly, this study investigated the relation between plasma and urinary cytokines and proximal renal dysfunction during cardiac surgery. MethodsTwenty patients undergoing coronary artery bypass grafting with cardiopulmonary bypass (CPB) were studied. Blood and urine samples were analyzed for proinflammatory and antiinflammatory cytokines. Proximal tubular dysfunction was measured using urinary N-acetyl-&bgr;-d-glucosaminidase (NAG)/creatinine and &agr;1-microglobulin/creatinine ratios. ResultsPlasma IL-8, IL-10, IL-1ra, and TNFsr2 values were significantly elevated compared with baseline. Urinary IL-1ra and TNFsr2 were significantly elevated. Urinary NAG/creatinine and &agr;1-microglobulin/creatinine ratios were also elevated. Plasma TNF&agr; at 2 h correlated with urinary NAG/creatinine ratio at 2 and 6 h (P < 0.05) and with urinary IL-1ra at 2 h (P < 0.05). Plasma IL-8 at 2 h correlated with NAG/creatinine at 6 h (P < 0.05). Urinary IL-1ra correlated with urinary NAG/creatinine ratio after cross-clamp release and 2 and 6 h after CPB (P < 0.05). ConclusionsCardiac surgery using CPB leads to changes in plasma and urinary cytokine homeostasis that correlate with renal proximal tubular dysfunction. This dysfunction may be related to the renal filtration of proinflammatory mediators. Renal autoprotective mechanisms may involve the intrarenal generation of antiinflammatory cytokines.

Methylprednisolone Increases Urinary Nitrate Concentrations and Reduces Subclinical Renal Injury During Infrarenal Aortic Ischemia Reperfusion.

Objective:This study tests the hypothesis that methylprednisolone may influence eNOS activity in renal arterial and venous vascular beds and impede subclinical renal injury. Summary Background Data:Acute renal failure is a major complication of cardiovascular surgery. Renal damage arises in part from excessive vasoconstriction mediated by an imbalance of vasoconstrictive ET-1 and vasodilatory NO produced by eNOS. While methylprednisolone may reduce subclinical renal injury as measured by urinary N-acetyl-beta-D-glucosaminidase (β-NAG), its effects upon eNOS activity in renal arterial and venous vascular beds, reflected by urinary nitrate levels, is unclear. Methods:A porcine model of normotensive, euvolemic infrarenal aortic ischaemia-reperfusion was used. Forty-two pigs underwent a 60-minute laparotomy followed by 150 minutes of infrarenal ischemia and 180 minutes of reperfusion. Animals were randomized to receive methylprednisolone 30 mg/kg or placebo after induction of general anesthesia. Urinary β-NAG levels were assessed as an index of subclinical renal injury, whereas urinary nitrate was assessed as an indicator of eNOS activity in renal arterial and venous vascular beds. Results:Methylprednisolone treatment did not influence mean arterial, central venous, or pulmonary artery wedge pressures but suppressed plasma IL-6 levels. After the ischemia-induced rise from preanaesthetic baseline levels, urinary β-NAG levels declined to significantly lower values in the MP group, indicative of MP renal protection (P < 0.05). Conversely, urinary nitrate levels indicative of vascular e-NOS activity remained significantly and persistently higher in MP-treated animals (P < 0.05). Conclusion:This study, in a porcine model of renal ischaemia-reperfusion injury, shows the benefits of methylprednisolone pretreatment in enhancing urinary nitrate levels indicative of vascular eNOS activity and the reduction of urinary β-NAG levels, which represent subclinical renal injury.

A clinical ,renal and immunological assessment of Surface-Modifying Additive treated (SMART) cardiopulmonary bypass circuits

Biocompatible cardiopulmonary bypass (CPB) circuits aim to reduce contact activation and its physiological consequences. We investigated the hypothesis that use of Surface Modifying Additive (SMA)-treated circuits (Sorin Group Ltd) compared with non-SMA circuits would be associated with preservation of blood pressure during CPB and modulation of perioperative subclinical renal function (urinary α-1-microglobulin (α-1-m)) and plasma and urinary cytokine changes. In a study of low-risk CABG patients (n=40), randomized to SMA (n=20) versus non-SMA circuits (n=20), we found better preserved blood pressure at CPB initiation in SMA patients (p <0.05), particularly in ACE-inhibited SMA patients (n=11) versus ACE-inhibited non-SMA patients (n=10) (p <0.05). Plasma anti-inflammatory IL-10, as well as urinary α-1-m, were elevated 48 hours postoperatively (p <0.05). SMA patients also had lower blood loss (p <0.05). SMA circuits have some clinical benefit, especially in ACE-inhibited patients.

Cytokine phenotype, genotype, and renal outcomes at cardiac surgery

BACKGROUND Cardiac surgery modulates pro- and anti-inflammatory cytokine balance involving plasma tumour necrosis factor alpha (TNFα) and interleukin-10 (IL-10) together with urinary transforming growth factor beta-1 (TGFβ1), interleukin-1 receptor antagonist (IL1ra) and tumour necrosis factor soluble receptor-2 (TNFsr2). Effects on post-operative renal function are unclear. We investigated if following cardiac surgery there is a relationship between cytokine (a) phenotype and renal outcome; (b) genotype and phenotype and (c) genotype and renal outcome. Since angiotensin-2 (AG2), modulates TGFβ1 production, we determined whether angiotensin converting enzyme insertion/deletion (ACE I/D) genotype affects urinary TGFβ1 phenotype as well as renal outcome. METHODS In 408 elective cardiac surgery patients we measured pre- and 24 h post-operative urinary TGFβ-1, IL1ra and TNFsr2 and pre- and 2 h post-operative plasma TNFα and IL-10. Post-operative responses were compared for each cytokine in patients grouped according to presence or absence of renal dysfunction defined as a drop from baseline eGFR of greater than 25% (as calculated by the method of modification of diet in renal disease (MDRD)) occurring (1) within the first 24 and (2) 48 postoperative hours (early renal dysfunction), (3) on the fifth postoperative day (late renal dysfunction) or (4) at any time throughout the 5 day postoperative period (early and late combined). Patient genotype was determined for TNF/G-308A, TGFβ1-509 C/T, IL10/G-1082A and ACE I/D. RESULTS Post-operative plasma IL-10 and urinary TGFβ1 responses were significantly higher in patients who developed early renal dysfunction. IL1ra and TNFsr2 responses were significantly lower 24h post-operatively in patients who developed late renal dysfunction. Genotype did not alter cytokine phenotype or outcome. CONCLUSIONS/INFERENCES: Cytokine profiling may help predict early and late renal dysfunction. Genotypes studied did not alter phenotype or outcome.

The Hemodynamic and Respiratory Effects of Cuirass Ventilation in Healthy Volunteers: Part 1

OBJECTIVE Negative-pressure ventilation (NPV) by external cuirass (RTX; Deminax Medical Instruments Limited, London, UK) in intubated patients after cardiac surgery improves hemodynamics measured by pulmonary artery catheter (PAC)-based methods, with an increased cardiac output (CO) and stroke volume (SV), without changing the heart rate (HR). The less-invasive pressure recording analytical method (PRAM) (Mostcare; Vytech Health srl, Padova, Italy) allows radial artery-based monitoring of the CO, SV, SV variation, and cardiac cycle efficiency (CCE). The authors investigated the hypothesis that NPV improves PRAM-based hemodynamics and arterial blood gas analysis in spontaneously breathing subjects. DESIGN A clinical investigation. SETTING A teaching hospital. PARTICIPANTS Ten healthy volunteers. INTERVENTIONS Subjects underwent 5 consecutive experimental ventilation modalities lasting 5 minutes: (1) baseline (no cuirass ventilation), (2) mode 1: cuirass ventilation with a continuous negative pressure of -20 cmH(2)O, (3) first rest period (no cuirass ventilation), (4) mode 2: cuirass ventilation in control mode of 12 breaths/min at -20 cmH(2)O, and (5) second rest period. MEASUREMENTS AND MAIN RESULTS PRAM parameters were analyzed throughout the final minute of each experimental modality, which concluded with arterial blood gas sampling. Both NPV modes significantly reduced HR without changing CO or systemic vascular resistance. Mode 1 significantly increased CCE and decreased SVV. PO(2) decreased in both rest modes compared with baseline. This was prevented by NPV. In 5 smokers, PO(2) significantly increased in the control mode compared with first rest period. The control mode NPV improved oxygenation with a reduced PCO(2) and reciprocally increased pH. CONCLUSIONS Five minutes of NPV improves hemodynamics and oxygenation in healthy subjects.

The Hemodynamic and Respiratory Effects of Continuous Negative and Control-Mode Cuirass Ventilation in Recently Extubated Cardiac Surgery Patients: Part 2

OBJECTIVE Negative-pressure ventilation (NPV) by external cuirass (RTX; Deminax Medical Instruments Limited, London, UK) in intubated patients after cardiac surgery improves hemodynamics measured by pulmonary artery catheter (PAC)-based methods with increased cardiac output (CO) and stroke volume (SV) without changing the heart rate (HR). The less-invasive pressure recording analytical method (PRAM) (MostCare; Vytech Health srl, Padova, Italy) allows radial artery monitoring of CO, SV, SV variation, and cardiac cycle efficiency (CCE). The authors investigated the hypothesis that NPV improves PRAM-based hemodynamics and arterial blood gas analysis in extubated cardiac surgery patients. DESIGN A clinical investigation. SETTING A teaching hospital. PARTICIPANTS Twenty recently extubated cardiac surgery patients. INTERVENTIONS Five consecutive experimental ventilation modalities lasted 5 minutes: (1) baseline (no cuirass ventilation), (2) mode 1 (cuirass ventilation with a continuous negative pressure of -20 cmH(2)O), (3) rest 1 (no cuirass ventilation), (4) mode 2 (cuirass ventilation in the control mode of 12 breaths/min at -20 cmH(2)O, and (5) rest 2. MEASUREMENTS AND MAIN RESULTS PRAM parameters were analyzed throughout the final minute of each experimental modality, concluding with arterial blood gas sampling. NPV was well tolerated. HR was unchanged. Mode 2 SV was higher than baseline and rest 2. Mode 2 CO was higher than rest 2. Rest 2 systolic blood pressure was lower than rest 1 and mode 2. Increased CCE with NPV was not significant (p = 0.0696). Oxygenation and PCO(2) were unchanged although mode 2 pH increased. CONCLUSIONS Extubated sedated cardiac surgery patients comfortably tolerated NPV with unchanged HR. SV and pH increased.

J Stephen D Allen

Shortly after qualifying J Stephen D Allen (“Steve”) decided to specialise in anaesthesia, and his intellect and energy were quickly recognised. His subspecialty interests lay in critical care medicine and cardiothoracic anaesthesia. He was awarded an MD …

A comparison of pressure recording analytical method (PRAM) with pulmonary artery catheter (PAC) based cardiac output (CO) method: O-34

Reference Reduction Reduction value 10% 25% Mortality (%) 3.8 38.3 5.7 ICU stay (days) 2.6 5.3 6.5 1.0 Length of stay (days) 9.1 7.0 929 149 Renal failure (%) 1.16 128.8 19.4 Gastrointestinal (GI) complications(%) 1.14 131.2 19.8 Deep wound infection (DWI)(%) 1.1 135.9 20.5 Mechanical Ventilation (VAM) 24 h (%) 4.1 35.4 5.46 Low Cardiac Output (LCO)(%) 5 28.8 4.4 Post Op. Myocardial Infarct (POMI)(%) 7.7 18.2 2.8 IABP use (%) 1.3 114.8 17.3 FEV1 Reduction (%) 60 1.1 19 GI complications renal failure (%) 2.30 64.3 9.7 Pulmonary infection DWI VAM 24 h 14.2 9.2 1.4 ICU stay 7 days(%) POMI LCO IABP (%) 14.0 9.4 1.4

Methylprednisolone reduces plasma macrophage colony stimulating factor (mcsf) at cardiac surgery: O-30

(MCSF) is elevated during trauma, impairs DC maturation and migration and is associated with infective complications and poor outcome [1]. We wished to determine if MCSF increases at cardiac surgery and if there is associated poor clinical outcome as assessed by impaired renal function. Method: From a large data base of 300 low risk patients, with normal preoperative renal function, undergoing cardiac surgery at our institution, we selected 20 patients who developed renal dysfunction as defined by serum creatinine 125 mol/L or a serum creatinine rise (delta creatinine) 35 mol/L during a 5 day postoperative period. This group was compared with 20 patients who had normal renal function throughout. Plasma samples for cytokine analysis were obtained at pre-anaesthetic baseline (sample A) and at 2 and 24 hr post CPB (Samples B and C respectively). MCSF was measured in both groups. Within group comparison with T0 was with repeated measures ANOVA followed by paired T-Test. Between group analysis at each sampling time was with one way ANOVA and Bonferroni Multiple Comparisons Test. Results: There was a very significant increase from baseline (P 0.01) at 2 and 24 hours post CPB in both groups. No between group difference was observed.

Preoperative ACE inhibition and renal dysfunction following cardiac surgery: 105

Discussion: Perioperative rapid increases in urinary nitrate may reflect systemic eNOS activation and provide early evidence of an evolving inflammatory response. Since glucocorticoid beneficial anti-inflammatory effects appear to be eNOS dependent [2], urinary nitrate measurement may help determine the minimal steroid dose necessary for significant anti-inflammatory effects. References: 1 Bhagat K, Hingorani AD, Palacios M, et al. Cytokine-induced venodilatation in humans in vivo: eNOS masquerading as iNOS. Cardiovasc Res 1999; 41(3): 754–764. 2 Hafezi-Moghadam A, Simoncini T, Yang E, et al. Acute cardiovascular protective effects of corticosteroids are mediated by non-transcriptional activation of endothelial nitric oxide synthase. Nat Med 2002; 8(5): 473–479.