Brachial artery reactivity in patients with severe sepsis: an observational study

Orren Wexler, Mary A M Morgan, Michael S Gough, Sherry D Steinmetz, Cynthia M Mack, Denise C Darling, Kathleen P Doolin, Michael J Apostolakos, Brian T Graves, Mark W Frampton, Xucai Chen, Anthony P Pietropaoli, Orren Wexler, Mary A M Morgan, Michael S Gough, Sherry D Steinmetz, Cynthia M Mack, Denise C Darling, Kathleen P Doolin, Michael J Apostolakos, Brian T Graves, Mark W Frampton, Xucai Chen, Anthony P Pietropaoli

Abstract

Introduction: Ultrasound measurements of brachial artery reactivity in response to stagnant ischemia provide estimates of microvascular function and conduit artery endothelial function. We hypothesized that brachial artery reactivity would independently predict severe sepsis and severe sepsis mortality.

Methods: This was a combined case-control and prospective cohort study. We measured brachial artery reactivity in 95 severe sepsis patients admitted to the medical and surgical intensive care units of an academic medical center and in 52 control subjects without acute illness. Measurements were compared in severe sepsis patients versus control subjects and in severe sepsis survivors versus nonsurvivors. Multivariable analyses were also conducted.

Results: Hyperemic velocity (centimeters per cardiac cycle) and flow-mediated dilation (percentage) were significantly lower in severe sepsis patients versus control subjects (hyperemic velocity: severe sepsis = 34 (25 to 48) versus controls = 63 (52 to 81), P < 0.001; flow-mediated dilation: severe sepsis = 2.65 (0.81 to 4.79) versus controls = 4.11 (3.06 to 6.78), P < 0.001; values expressed as median (interquartile range)). Hyperemic velocity, but not flow-mediated dilation, was significantly lower in hospital nonsurvivors versus survivors (hyperemic velocity: nonsurvivors = 25 (16 to 28) versus survivors = 39 (30 to 50), P < 0.001; flow-mediated dilation: nonsurvivors = 1.90 (0.68 to 3.41) versus survivors = 2.96 (0.91 to 4.86), P = 0.12). Lower hyperemic velocity was independently associated with hospital mortality in multivariable analysis (odds ratio = 1.11 (95% confidence interval = 1.04 to 1.19) per 1 cm/cardiac cycle decrease in hyperemic velocity; P = 0.003).

Conclusions: Brachial artery hyperemic blood velocity is a noninvasive index of microvascular function that independently predicts mortality in severe sepsis. In contrast, brachial artery flow-mediated dilation, reflecting conduit artery endothelial function, was not associated with mortality in our severe sepsis cohort. Brachial artery hyperemic velocity may be a useful measurement to identify patients who could benefit from novel therapies designed to reverse microvascular dysfunction in severe sepsis and to assess the physiologic efficacy of these treatments.

Figures

Figure 1
Figure 1
Enrollment algorithm for severe sepsis patients.
Figure 2
Figure 2
Brachial artery reactivity in severe sepsis patients versus control subjects: hyperemic velocity (a) and flow-mediated dilation (b). Box plots show the median (horizontal line), 25th, and 75th percentiles (lower and upper limits of the box). The dots represent outliers beyond the whiskers that designate the 10th and 90th percentiles. Comparisons made with the Wilcoxon rank-sum test.
Figure 3
Figure 3
Brachial artery reactivity in severe sepsis survivors versus nonsurvivors: hyperemic velocity (a) and flow-mediated dilation (b). Box plots show the median (horizontal line), 25th, and 75th percentiles (lower and upper limits of the box). The dots represent outliers beyond the whiskers that designate the 10th and 90th percentiles. Comparisons made with the Wilcoxon rank-sum test.
Figure 4
Figure 4
Kaplan-Meier survival probability plots for quartiles of hyperemic velocity (a) and flow-mediated dilation (b). No subjects were lost to follow-up. The log-rank test was used to evaluate the statistical significance of the trend in survival per quartile of brachial artery reactivity.

References

    1. DeBacker D, Creteur J, Preiser JC, Dubois MJ, Vincent JL. Microvascular blood flow in patients with sepsis. Am J Respir Crit Care Med. 2002;166:98–104. doi: 10.1164/rccm.200109-016OC.
    1. Shepherd JT. In: Handbook of Physiology: The Cardiovascular System. Geiger SR, Abboud FM, Shepherd JT, editor. III. Bethesda, MD: American Physiological Society; 1983. Peripheral circulation and organ blood flow; pp. 319–371.
    1. Kanatsuka H, Sekiguchi N, Sato K, Akai K, Wang Y, Komaru T, Ashikawa K, Takishima T. Microvascular sites and mechanisms responsible for reactive hyperemia in the coronary circulation of the beating canine heart. Circ Res. 1992;71:912–922. doi: 10.1161/01.RES.71.4.912.
    1. Koller A, Kaley G. Role of endothelium in reactive dilation of skeletal muscle arterioles. Am J Physiol. 1990;259:H1313–H1316.
    1. Engelke KA, Halliwill JR, Proctor DN, Dietz NM, Joyner MJ. Contribution of nitric oxide and prostaglandins to reactive hyperemia in human forearm. J Appl Physiol. 1996;81:1807–1814.
    1. Carlsson I, Sollevi A, Wennmalm A. The role of myogenic relaxation, adenosine and prostaglandins in human forearm reactive hyperaemia. J Physiol (Lond) 1987;389:147–161.
    1. Meredith IT, Currie KE, Anderson TJ, Roddy MA, Ganz P, Creager MA. Postischemic vasodilation in human forearm is dependent on endothelium-derived nitric oxide. Am J Physiol. 1996;270:H1435–H1440.
    1. Neviere R, Mathieu D, Chagnon JL, Lebleu N, Millien JP, Wattel F. Skeletal muscle microvascular blood flow and oxygen transport in patients with severe sepsis. Am J Respir Crit Care Med. 1996;153:191–195.
    1. Hartl WH, Gunther B, Inthorn D, Heberer G. Reactive hyperemia in patients with septic conditions. Surgery. 1988;103:440–444.
    1. Astiz ME, DeGent GE, Lin RY, Rackow EC. Microvascular function and rheologic changes in hyperdynamic sepsis. Crit Care Med. 1995;22:265–271.
    1. Astiz ME, Tilly E, Rackow ED, Weil MH. Peripheral vascular tone in sepsis. Chest. 1991;99:1072–1075. doi: 10.1378/chest.99.5.1072.
    1. Anderson TJ, Charbonneau F, Title LM, Buithieu J, Rose MS, Conradson H, Hildebrand K, Fung M, Verma S, Lonn EM. Microvascular function predicts cardiovascular events in primary prevention: long-term results from the Firefighters and Their Endothelium (FATE) study. Circulation. 2011;123:163–169. doi: 10.1161/CIRCULATIONAHA.110.953653.
    1. Huang AL, Silver AE, Shvenke E, Schopfer DW, Jahangir E, Titas MA, Shpilman A, Menzoian JO, Watkins MT, Raffetto JD, Gibbons G, Woodson J, Shaw PM, Dhadly M, Eberhardt RT, Keaney JF Jr, Gokce N, Vita JA. Predictive value of reactive hyperemia for cardiovascular events in patients with peripheral arterial disease undergoing vascular surgery. Arterioscler Thromb Vasc Biol. 2007;27:2113–2119. doi: 10.1161/ATVBAHA.107.147322.
    1. Philpott AC, Lonn E, Title LM, Verma S, Buithieu J, Charbonneau F, Anderson TJ. Comparison of new measures of vascular function to flow mediated dilatation as a measure of cardiovascular risk factors. Am J Cardiol. 2009;103:1610–1615. doi: 10.1016/j.amjcard.2009.01.376.
    1. Vita JA, Keaney JF Jr, Larson MG, Keyes MJ, Massaro JM, Lipinska I, Lehman BT, Fan S, Osypiuk E, Wilson PWF, Vasan RS, Mitchell GF, Benjamin EJ. Brachial artery vasodilator function and systemic inflammation in the Framingham Offspring Study. Circulation. 2004;110:3604–3609. doi: 10.1161/01.CIR.0000148821.97162.5E.
    1. Widlansky ME, Vita JA, Keyes MJ, Larson MG, Hamburg NM, Levy D, Mitchell GF, Osypiuk EW, Vasan RS, Benjamin EJ. Relation of season and temperature to endothelium-dependent flow-mediated vasodilation in subjects without clinical evidence of cardiovascular disease (from the Framingham Heart Study) Am J Cardiol. 2007;100:518–523. doi: 10.1016/j.amjcard.2007.03.055.
    1. Philpott A, Anderson TJ. Reactive hyperemia and cardiovascular risk. Arterioscler Thromb Vasc Biol. 2007;27:2065–2067. doi: 10.1161/ATVBAHA.107.149740.
    1. Skarda DE, Mulier KE, Myers DE, Taylor JH, Beilman GJ. Dynamic near-infrared spectroscopy measurements in patients with severe sepsis. Shock. 2007;27:348–353. doi: 10.1097/01.shk.0000239779.25775.e4.
    1. Young JD, Cameron EM. Dynamics of skin blood flow in human sepsis. Intensive Care Med. 1995;21:669–674. doi: 10.1007/BF01711546.
    1. Davis JS, Yeo TW, Thomas JH, McMillan M, Darcy CJ, McNeil YR, Cheng AC, Celermajer DS, Stephens DP, Anstey NM. Sepsis-associated microvascular dysfunction measured by peripheral arterial tonometry: an observational study. Critical Care (Lond) 2009;13:R155. doi: 10.1186/cc8055.
    1. Haisjackl M, Hasibeder W, Klaunzer S, Altenberger H, Koller W. Diminished reactive hyperemia in the skin of critically ill patients. Crit Care Med. 1990;18:813–818. doi: 10.1097/00003246-199008000-00003.
    1. Doerschug KC, Delsing AS, Schmidt GA, Haynes WG. Impairments in microvascular reactivity are related to organ failure in human sepsis. Am J Physiol Heart Circ Physiol. 2007;293:H1065–H1071. doi: 10.1152/ajpheart.01237.2006.
    1. Creteur J, Carollo T, Soldati G, Buchele G, De Backer D, Vincent JL. The prognostic value of muscle StO2 in septic patients. Intensive Care Med. 2007;33:1549–1556. doi: 10.1007/s00134-007-0739-3.
    1. Shapiro NL, Arnold RC, Sherwin R, O'Connor J, Najarro G, Singh S, Lundy D, Nelson T, Trzeciak SW, Jones AE. The association of near-infrared spectroscopy-derived tissue oxygen measurements with sepsis syndromes, organ dysfunction and mortality in emergency department patients with sepsis. Critical Care. 2011;15:R223. doi: 10.1186/cc10463.
    1. Trzeciak S, Cinel I, Dellinger P, Shapiro NI, Arnold RC, Parrillo JE, Hollenberg SM. Resuscitating the microcirculation in sepsis: the central role of nitric oxide, emerging concepts for novel therapies, and challenges for clinical trials. Acad Emerg Med. 2008;15:399–413. doi: 10.1111/j.1553-2712.2008.00109.x.
    1. Corretti MC, Anderson TJ, Benjamin EJ, Celermajer D, Charbonneau F, Creager MA, Deanfield J, Drexler H, Gerhard-Herman M, Herrington D, Vallance P, Vita J, Vogel R. Guidelines for the ultrasound assessment of endothelial-dependent flow-mediated vasodilation of the brachial artery: a report of the International Brachial Artery Reactivity Task Force. J Am Coll Cardiol. 2002;39:257–265.
    1. Joannides R, Haefeli WE, Linder L, Richard V, Bakkali EH, Thuillez C, Luscher TF. Nitric oxide is responsible for flow-dependent dilatation of human peripheral conduit arteries in vivo. Circulation. 1995;91:1314–1319. doi: 10.1161/01.CIR.91.5.1314.
    1. Luiking YC, Poeze M, Ramsay G, Deutz NEP. Reduced citrulline production in sepsis is related to diminished de novo arginine and nitric oxide production. Am J Clin Nutr. 2009;89:142–152.
    1. Gough MS, Morgan MAM, Mack CM, Darling DC, Frasier LM, Doolin KP, Apostolakos MJ, Stewart JC, Graves BT, Arning E, Bottiglieri T, Mooney RA, Frampton MW, Pietropaoli AP. The ratio of arginine to dimethylarginines is reduced and predicts outcomes in patients with severe sepsis. Crit Care Med. 2011;39:1351–1358. doi: 10.1097/CCM.0b013e318212097c.
    1. Morgan MM, Frasier LM, Stewart JC, Mack CM, Gough MS, Graves BT, Apostolakos MJ, Doolin KP, Darling DC, Frampton MW, Pietropaoli AP. Artery-to-vein differences in nitric oxide metabolites are diminished in sepsis. Crit Care Med. 2010;38:1069–1077. doi: 10.1097/CCM.0b013e3181d16a3e.
    1. Vaudo G, Marchesi S, Siepi D, Brozzetti M, Lombardini R, Pirro M, Alaeddin A, Roscini AF, Lupattelli G, Mannarino E. Human endothelial impairment in sepsis. Atherosclerosis. 2008;197:747–752. doi: 10.1016/j.atherosclerosis.2007.07.009.
    1. Thijssen DHJ, Black MA, Pyke KE, Padilla J, Atkinson G, Harris RA, Parker B, Widlansky ME, Tschakovsky ME, Green DJ. Assessment of flow-mediated dilation in humans: a methodological and physiological guideline. Am J Physiol Heart Circ Physiol. pp. H2–H12.
    1. Morgan MM, Stewart JC, Mack CM, Graves BT, Frasier LM, Steinmetz SD, Doolin KP, Darling DC, Apostolakos MJ, Frampton MW, Pietropaoli AP. Flow-mediated brachial artery dilation is impaired in sepsis syndrome. Am J Respir Crit Care Med. 2008;177:A118.
    1. Bone RC, Balk RA, Cerra FB, Dellinger RP, Fein AM, Knaus WA, Schein RM, Sibbald WJ. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Chest. 1992;101:1644–1655. doi: 10.1378/chest.101.6.1644.
    1. Kaplan EL, Meier P. Non-parametric estimation from incomplete observations. J Am Statist Assoc. 1958;53:457–481. doi: 10.2307/2281868.
    1. Bernard GR, Wheeler AP, Arons MM, Morris PE, Paz HL, Russell JA, Wright PE. A trial of antioxidants N-acetylcysteine and procysteine in ARDS: the Antioxidant in ARDS Study Group. Chest. 1997;112:164–172. doi: 10.1378/chest.112.1.164.
    1. Knaus WA, Draper EA, Wagner DP, Zimmerman JE. APACHE II: A severity of disease classification system. Crit Care Med. 1985;13:818–829. doi: 10.1097/00003246-198510000-00009.
    1. Vincent JL, Moreno R, Takala J, Willatts S, De Mendonca A, Bruining H, Reinhart CK, Suter PM, Thijs LG. The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure: On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine. Intensive Care Med. 1996;22:707–710. doi: 10.1007/BF01709751.
    1. Celermajer DS, Sorensen KE, Gooch VM, Spiegelhalter DJ, Miller OI, Sullivan ID, Lloyd JK, Deanfield JE. Non-invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis. Lancet. 1992;340:1111–1115. doi: 10.1016/0140-6736(92)93147-F.
    1. Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis. 1987;40:373–383. doi: 10.1016/0021-9681(87)90171-8.
    1. Celermajer DS, Sorensen KE, Bull CM, Robinson J, Deanfield JE. Endothelium dependent dilation in the systemic arteries of asymptomatic subjects relates to coronary risk factors and their interaction. J Am Coll Cardiol. 1994;24:468–474.
    1. Matthews JN, Altman DG. Interaction 3: how to examine heterogeneity. BMJ. 1996;313:862. doi: 10.1136/bmj.313.7061.862.
    1. Afifi A, Clark VA, May S. Computer-aided Multivariate Analysis. 4. Boca Raton: Chapman & Hall/CRC Press; 2004.
    1. DeLong ER, DeLong DM, Clarke-Pearson DL. Comparing the areas under two or more correlated receiver operating characteristic curves: a nonparametric approach. Biometrics. 1988;44:837–845. doi: 10.2307/2531595.
    1. Bland JM, Altman DG. Statistical methods for assessing agreement between two methods of clinical measurement. Lancet. 1986;1:307–310.
    1. McGinn T, Wyer PC, Newman TB, Keitz S, Leipzig R, Guyatt G. Tips for learners of evidence-based medicine: 3. Measures of observer variability (kappa statistic).[Erratum appears in CMAJ 2005, 173:18] CMAJ. 2004;171:1369–1373. doi: 10.1503/cmaj.1031981.
    1. Spronk PE, Zandstra DF, Ince C. Bench-to-bedside review: sepsis is a disease of the microcirculation. Crit Care (London) 2004;8:462–468. doi: 10.1186/cc2894.
    1. Heyland DK, Dhaliwal R, Suchner U, Berger MM. Antioxidant nutrients: a systematic review of trace elements and vitamins in the critically ill patient. Intensive Care Med. 2005;31:327–337. doi: 10.1007/s00134-004-2522-z.
    1. Tousoulis D, Antoniades C, Tentolouris C, Tsioufis C, Toutouza M, Toutouzas P, Stefanadis C. Effects of combined administration of vitamins C and E on reactive hyperemia and inflammatory process in chronic smokers. Atherosclerosis. 2003;170:261–267. doi: 10.1016/S0021-9150(03)00250-8.
    1. Spronk PE, Ince C, Gardien MJ, Mathura KR, Oudemans-van Straaten HM, Zandstra DF. Nitroglycerin in septic shock after intravascular volume resuscitation. Lancet. 2002;360:1395–1396. doi: 10.1016/S0140-6736(02)11393-6.
    1. Angus DC. Caring for the critically ill patient: challenges and opportunities. JAMA. 2007;298:456–458. doi: 10.1001/jama.298.4.456.
    1. Cohen J, Guyatt G, Bernard GR, Calandra T, Cook D, Elbourne D, Marshall J, Nunn A, Opal S. New strategies for clinical trials in patients with sepsis and septic shock. Crit Care Med. 2001;29:880–886. doi: 10.1097/00003246-200104000-00039.
    1. Kirschenbaum LA, Astiz ME, Rackow EC, Saha DC, Lin R. Microvascular response in patients with cardiogenic shock. Crit Care Med. 2000;28:1290–1294. doi: 10.1097/00003246-200005000-00005.
    1. Johnson JM, Taylor WF, Shepherd AP, Park MK. Laser-Doppler measurement of skin blood flow: comparison with plethysmography. J Appl Physiol. 1984;56:798–803. doi: 10.1063/1.334009.
    1. Nohria A, Gerhard-Herman M, Creager MA, Hurley S, Mitra D, Ganz P, Nohria A, Gerhard-Herman M, Creager MA, Hurley S, Mitra D, Ganz P. Role of nitric oxide in the regulation of digital pulse volume amplitude in humans. J Appl Physiol. 2006;101:545–548. doi: 10.1152/japplphysiol.01285.2005.
    1. De Blasi RA, Ferrari M, Natali A, Conti G, Mega A, Gasparetto A. Noninvasive measurement of forearm blood flow and oxygen consumption by near-infrared spectroscopy. J Appl Physiol. 1994;76:1388–1393.
    1. Brennan JM, Blair JE, Hampole C, Goonewardena S, Vasaiwala S, Shah D, Spencer KT, Schmidt GA. Radial artery pulse pressure variation correlates with brachial artery peak velocity variation in ventilated subjects when measured by internal medicine residents using hand-carried ultrasound devices. Chest. 2007;131:1301–1307. doi: 10.1378/chest.06-1768.
    1. Tschakovsky ME, Shoemaker JK, Hughson RL. Beat-by-beat forearm blood flow with Doppler ultrasound and strain-gauge plethysmography. J Appl Physiol. 1995;79:713–719.
    1. Green S, Thorp R, Reeder EJ, Donnelly J, Fordy G, Green S. Venous occlusion plethysmography versus Doppler ultrasound in the assessment of leg blood flow during calf exercise. Eur J Appl Physiol. pp. 1889–1900.
    1. Schmidt GA. ICU ultrasound: the coming boom. Chest. 2009;135:1407–1408. doi: 10.1378/chest.09-0502.
    1. Witte DR, Westerink J, de Koning EJ, van der Graaf Y, Grobbee DE, Bots ML. Is the association between flow-mediated dilation and cardiovascular risk limited to low-risk populations? J Am Coll Cardiol. 2005;45:1987–1993. doi: 10.1016/j.jacc.2005.02.073.
    1. Hijmering ML, Stroes ESG, Olijhoek J, Hutten BA, Blankestijn PJ, Rabelink TJ. Sympathetic activation markedly reduces endothelium-dependent, flow-mediated vasodilation. J Am Coll Cardiol. 2002;39:683–688. doi: 10.1016/S0735-1097(01)01786-7.
    1. Benjamin EJ, Larson MG, Keyes MJ, Mitchell GF, Vasan RS, Keaney JF Jr, Lehman BT, Fan S, Osypiuk E, Vita JA. Clinical correlates and heritability of flow-mediated dilation in the community: the Framingham Heart Study. Circulation. 2004;109:613–619. doi: 10.1161/01.CIR.0000112565.60887.1E.
    1. Duffy MJ, Mullan BA, Craig TR, Shyamsundar M, MacSweeney RE, Thompson G, Stevenson M, McAuley DF. Impaired endothelium-dependent vasodilatation is a novel predictor of mortality in intensive care. Crit Care Med. 2011;39:629–635. doi: 10.1097/CCM.0b013e318206bc4a.
    1. Bernard GR, Vincent JL, Laterre PF, LaRosa SP, Dhainaut JF, Lopez-Rodriguez A, Steinbrub JS, Garber GE, Helterbrand JD, Ely W, Fisher CJ. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med. 2001;344:699–709. doi: 10.1056/NEJM200103083441001.

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