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    • THE CARDIO-PULMONARY EFFECTS OF VASOPRESSIN COMPARED TO NOREPINEPHRINE IN SEPTIC SHOCK Anthony C. Gordon, Nan Wang, Keith R. Walley, Deborah Ashby and James A. Russell Chest; Prepublished online April 19, 2012; DOI 10.1378/chest.11-2604 The online version of this article, along with updated information and services can be found online on the World Wide Web at: http://chestjournal.chestpubs.org/content/early/2012/04/18/chest.11-2604 Chest is the official journal of the American College of Chest Physicians. It has been published monthly since 1935. Copyright2012by the American College of Chest Physicians, 3300 Dundee Road, Northbrook, IL 60062. All rights reserved. No part of this article or PDF may be reproduced or distributed without the prior written permission of the copyright holder. (http://chestjournal.chestpubs.org/site/misc/reprints.xhtml) ISSN:0012-3692 CHEST Papers in Press are peer-reviewed, accepted articles that have not yet been published in an issue of the journal and have not yet been edited or typeset. The final version may contain substantive or nonsubstantive changes. These articles are indexed by PubMed, but any references to an in-press article must include the digital object identifier (DOI) and date of in-press publication. CHEST Papers in Press are not under media or public embargo once the appear online. For inquriires, please contact the AACP Media Relations Department at (847) 498-1400 or media@chestnet.org.Downloaded from chestjournal.chestpubs.org at McGill University Libraries on June 15, 2012 Copyright © 2012 American College of Chest Physicians
    • Page 1 of 32 Word count: 2706 Abstract word count: 249 THE CARDIO-PULMONARY EFFECTS OF VASOPRESSIN COMPARED TO NOREPINEPHRINE IN SEPTIC SHOCK. Running head: Cardio-pulmonary effects of vasopressin Authors: Anthony C Gordon1 MD, Nan Wang2 PhD, Keith R Walley3 MD, Deborah Ashby2 PhD, James A Russell3 MD Emails: anthony.gordon@imperial.ac.uk n.wang@imperial.ac.uk keith.walley@hli.ubc.ca deborah.ashby@imperial.ac.uk jim.russell@hli.ubc.ca Institutions: 1. Section of Anaesthetics, Pain Medicine and Intensive Care, Faculty of Medicine, Imperial College London, UK. 2. Imperial Clinical Trials Unit, School of Public Health, Faculty of Medicine, Imperial College London, UK. 3. Critical Care Research Laboratories, Institute for Heart + Lung Health, St. Paul’s Hospital and University of British Columbia, Vancouver, British Columbia, Canada V6Z 1Y6. Corresponding author: Dr Anthony Gordon Clinical Senior Lecturer & Consultant, Critical Care Medicine 11N, Imperial College / Charing Cross Hospital Fulham Palace Road 1 Downloaded from chestjournal.chestpubs.org at McGill University Libraries on June 15, 2012 Copyright © 2012 American College of Chest Physicians
    • Page 2 of 32London W6 8RF,UKTel: +44 20 3313 0657Fax: +44 20 3311 1975Email: anthony.gordon@imperial.ac.ukKEY WORDS: Vasopressin, norepinephrine, septic shock, hemodynamics, cardiacoutputConflicts of interest:Drs. Russell, Walley, and Gordon have previously served as officers for and holdstock in Sirius Genomics, which has submitted a patent, owned by the University ofBritish Columbia and licensed to Sirius Genomics, that is related to the genetics ofvasopressin. The University of British Columbia has also submitted a patent related tothe use of vasopressin in septic shock. Drs. Russell, Walley, and Gordon are named asinventors on this patent. Drs. Russell and Walley have received consulting fees fromFerring, which manufactures vasopressin.Drs Wang and Ashby have no conflicts of interest. 2 Downloaded from chestjournal.chestpubs.org at McGill University Libraries on June 15, 2012 Copyright © 2012 American College of Chest Physicians
    • Page 3 of 32 Abstract Background: Vasopressin is known to be an effective vasopressor in the treatment of septic shock but uncertainty remains about its effect on other hemodynamic parameters. Methods: We examined the cardio-pulmonary effects of vasopressin compared to norepinephrine in 779 adult patients who had septic shock recruited to the Vasopressin and Septic Shock Trial (VASST). More detailed cardiac output data was analyzed for the subset of 241 patients managed with a pulmonary artery catheter and data was collected for the first 96 hours after randomization. We compared the effects of vasopressin versus norepinephrine in all patients and also according to severity of shock (< or ≥ 15µg/min of norepinephrine) and cardiac output at baseline. Results: Equal blood pressures were maintained in both treatment groups with a significant reduction in norepinephrine requirements in the vasopressin treated patients. The major haemodynamic difference between the two groups was a significant reduction in heart rate in the vasopressin treated patients (p < 0.0001) and this was most pronounced in the less severe shock stratum (treatment x shock stratum interaction, p = 0.03). There were no other major cardio-pulmonary differences between treatment groups, including no difference in cardiac index or stroke volume index between vasopressin and norepinephrine treated patients. There was significantly greater use of inotropic drugs in the vasopressin group compared to the norepinephrine group. Conclusions: Vasopressin treatment in septic shock is associated with a significant reduction in heart rate but no change in cardiac output or other measures of perfusion. (Controlled Trials number, ISRCTN94845869.) 3 Downloaded from chestjournal.chestpubs.org at McGill University Libraries on June 15, 2012 Copyright © 2012 American College of Chest Physicians
    • Page 4 of 32Abbreviation listAPACHE – Acute Physiology and Chronic Health EvaluationAVP – Arginine vasopressinCI – Cardiac IndexCOPD - chronic obstructive pulmonary diseaseCVP - central venous pressureECG – ElectrocardiogramFiO2 – Fraction of inspired oxygenHR – Heart rateLVSWI – left ventricular stroke work indexMAP – mean arterial pressureMPAP - mean pulmonary artery pressureNE- norepinephrineNYHA - New York Heart AssociationPA – Pulmonary ArteryPaO2 – Arterial partial pressure of oxygenPAOP - pulmonary artery occlusion pressureRPP – Rate pressure productSBP - Systolic blood pressureSIRS - Systemic inflammatory response syndromeSVI – stroke volume indexSvO2 – Mixed venous oxygen saturationVASST - Vasopressin and Septic Shock Trial 4 Downloaded from chestjournal.chestpubs.org at McGill University Libraries on June 15, 2012 Copyright © 2012 American College of Chest Physicians
    • Page 5 of 32 Introduction: When cardiovascular failure develops due to sepsis, mortality rates are high1. As well as treating the underlying infection with antibiotics and source control, the mainstay of treatment of septic shock is cardiovascular resuscitation using intravenous fluid, and vasopressor and/or inotropic drugs2. In recent years there has been increasing interest in vasopressin treatment as an adjunct to other catecholamine vasopressors. The rationale behind its use is that there is commonly a relative vasopressin deficiency in septic shock3 and patients appear sensitive to administration of low-dose vasopressin infusions4. In several small studies, often unblinded, vasopressin infusion has invariably been shown to increase blood pressure and spare catecholamine use5-8. The effect of vasopressin on cardiac output is less clear with reports that it may reduce8, increase7 or have no effect on cardiac output5,6,9. There have also been concerns that higher doses of vasopressin (generally > 0.05 U/min) are associated with cardiac arrest10. In contrast norepinephrine, the most commonly used catecholamine vasopressor11, has both α and β-adrenoreceptor effects and so increases blood pressure but also may increase heart rate, cause arrhythmias and has been associated with mesenteric and cutaneous ischemia12,13. The Vasopressin and Septic Shock Trial (VASST) was a large double-blind randomized, controlled trial comparing low-dose vasopressin to norepinephrine in addition to standard vasopressors in the treatment of established adult septic shock14. In the whole study population there was no significant difference in mortality rates between the treatment groups (28-day mortality, 35.4% in the vasopressin group vs. 39.3% in the norepinephrine group, p=0.26). However, in the a priori stratum of less severe shock (defined as 5-15µg/min of norepinephrine at baseline) there was a significantly lower 28-day mortality in vasopressin group compared to the 5 Downloaded from chestjournal.chestpubs.org at McGill University Libraries on June 15, 2012 Copyright © 2012 American College of Chest Physicians
    • Page 6 of 32norepinephrine group (26.5% vs. 35.7%, respectively, p=0.05). In the more severeshock stratum (≥15µg/min of norepinephrine at baseline) there was no difference inmortality rates (44.0% vs. 42.5%, p=0.76 in the vasopressin and norepinephrinegroups respectively). We, therefore, planned to study the cardio-pulmonary effects of vasopressincompared to norepinephrine in VASST. Specifically we tested the hypothesis thatthere is no difference in cardiac output and other measures of hemodynamics betweenvasopressin and norepinephrine. To further explore efficacy and safety questionsabout vasopressin and norepinephrine, we also compared hemodynamics ofvasopressin versus norepinephrine in the strata of patients who had less and moresevere septic shock (as defined originally in VASST). Finally, because vasopressorsmay decrease cardiac output especially in patients who have a low cardiac output, wecompared the effects of vasopressin versus norepinephrine in patients according tocardiac output at baseline. 6 Downloaded from chestjournal.chestpubs.org at McGill University Libraries on June 15, 2012 Copyright © 2012 American College of Chest Physicians
    • Page 7 of 32 Methods: Patients and protocol The VASST study has been previously reported14 and was conducted between July 2001 and April 2006. Research ethics board approval was granted at the coordinating center (University of British Columbia / St Paul Hospital, P99-0175) and all participants or their legal representatives gave informed consent. In summary, this was a multi-center randomized double-blind controlled trial of vasopressin versus norepinephrine in addition to standard vasopressors for the treatment of septic shock. Patients were greater than 16 years of age and had septic shock, defined by the presence of two or more of the systemic inflammatory response syndrome (SIRS) criteria15, proven or suspected infection, new dysfunction of at least one organ, and hypotension despite adequate fluid resuscitation requiring vasopressor support of at least 5 µg/min of norepinephrine (or equivalent) for six hours. Important clinical exclusion criteria were unstable coronary syndromes, severe chronic heart disease (New York Heart Association class III and IV) and vasospastic diathesis. Patients were randomized to receive a blinded infusion of study drug, either vasopressin (0.01 - 0.03 U/min) or norepinephrine (5 – 15 µg/min). The study drug and all other vasopressors were titrated and weaned according to protocols. The initial target mean arterial pressure was 65 – 75 mmHg. All other cardiovascular management including cardiac output monitoring, setting of cardiac output goals, fluid and inotropic therapy were at the local treating physician’s discretion. Data analysis & statistics Basic cardio-pulmonary variables (blood pressure, heart rate, central venous pressure, PaO2/FiO2 and pH) and inotrope use (dobutamine, milrinone and epinephrine) were collected in all patients in the study and are reported for all patients in this analysis. If a pulmonary artery (PA) catheter was in situ details of pulmonary 7 Downloaded from chestjournal.chestpubs.org at McGill University Libraries on June 15, 2012 Copyright © 2012 American College of Chest Physicians
    • Page 8 of 32artery pressures, cardiac output and mixed venous saturations were collected for thefirst 96 after randomization.Comparison of baseline data between patients who had or did not have a PA catheterwas carried out by chi-squared test or t-test as appropriate. Longitudinal data wereanalyzed using linear mixed effect models (PROC MIXED in SAS Enterprise Guide4.3) comparing treatment effect over time adjusting for any imbalance at baseline andwithout imputation for missing data variables. The analysis was done first for allpatients and then repeated for each shock stratum. The p-values of fixed effects(treatment, shock stratum and their interaction) were provided by the F-test or two-sided t-test as appropriate. The numbers of patients receiving inotropes was analyzedusing a generalized linear mixed effect model with logit link (PROC GENMOD inSAS Enterprise Guide 4.3) and p-values of fixed effects and their interaction (baselineadjusted) were provided by the Chi-square test. A p-value less than 0.05 wasconsidered significant. 8 Downloaded from chestjournal.chestpubs.org at McGill University Libraries on June 15, 2012 Copyright © 2012 American College of Chest Physicians
    • Page 9 of 32 Results: In total 779 patients were randomized and infused with the blinded study drugs. Cardiac output monitoring was used in 156 patients at baseline and was instituted after randomization in a further 85 patients (total = 241, or 31% of patients in VASST) and was equally balanced between the two treatment groups (vasopressin n=123 and norepinephrine n=118, p = 0.97). The baseline characteristics of those patients managed with and without a PA catheter are shown in table 1. Patients who had a PA catheter had several markers of more severe organ dysfunction including more renal dysfunction, lower pH, higher lactate and were receiving higher doses of norepinephrine and phenylephrine at baseline compared to patients who did not have a PA catheter. As specified in the protocol vasopressor drugs were titrated to maintain similar mean arterial pressure in the vasopressin and norepinephrine treatment groups (table 2). As expected vasopressin treatment resulted in a significant reduction in norepinephrine requirements. The most noticeable cardiovascular difference in the whole population was a rapid and significant drop in heart rate after starting the vasopressin infusion (table 2). This was most pronounced in the less severe shock stratum (table 4) and the interaction statistic examining the treatment x shock stratum interaction was significant (p=0.03). There was no difference in cardiac index, stroke volume index or left ventricular stroke work index associated with vasopressin treatment in the whole population or in either the more or less severe shock strata. Similarly there was no difference in markers of oxygen delivery, namely SvO2, pH or serum lactate levels between treatment groups (tables 2-5). However, there was significantly greater use of inotropic drugs in the vasopressin group compared to the norepinephrine group, particularly in the more severe shock stratum where significantly more patients were 9 Downloaded from chestjournal.chestpubs.org at McGill University Libraries on June 15, 2012 Copyright © 2012 American College of Chest Physicians
    • Page 10 of 32treated with inotropic agents and there was a trend for a higher mean dose ofdobutamine (the most commonly used inotrope) to be infused in the vasopressingroup compared to the norepinephrine group. As any deterioration in cardiac function is likely to be most clinicallyimportant in those who have a low cardiac output we also divided the patients bycardiac index quartile at baseline. There was no difference in cardiac index over timebetween treatment groups in any of the quartiles (Figure 1A-D) including those whohad the lowest cardiac outputs (1st quartile CI ≤2.9l/min/m2). Details of other cardio-pulmonary variables are shown in tables 2-5. Therewas no difference in mean pulmonary artery pressure (MPAP), pulmonary arteryocclusion pressure (PAOP) or central venous pressure (CVP) between treatmentgroups other than a higher CVP in the vasopressin treated patients in the less severeshock stratum. Although this difference was statistically significant the actualdifference was small (generally < 1mmHg between vasopressin and norepinephrinepatients). In view of the complexities and inter-relationship of changes in heart rate,cardiac output, and inotrope use between vasopressin and norepinephrine treatmentwe calculated the rate-pressure product (HR x SBP) as an indicator of myocardialworkload and oxygen consumption. This fell rapidly and was significantly lower inthe vasopressin treated patients compared to the norepinephrine-treated patients andthis decline in rate-pressure product was more marked in the less severe shockstratum, although the interaction statistic did not reach significance (p = 0.10). 10 Downloaded from chestjournal.chestpubs.org at McGill University Libraries on June 15, 2012 Copyright © 2012 American College of Chest Physicians
    • Page 11 of 32 Discussion: The effect of vasopressin on cardiac output is one of the main concerns about using vasopressin in the treatment of septic shock, especially in those patients with poor cardiac function. In this study we have demonstrated that vasopressin therapy was not associated with a significant decrease in cardiac output compared to norepinephrine but there was greater use of inotropic drugs in the vasopressin compared to the norepinephrine treatment group, particularly in the more severe shock subgroup. The main cardiovascular effect of vasopressin infusion was a marked decrease in heart rate rather than a reduction in stroke volume index, and this reduction in heart rate was most striking in the less severe shock stratum. There were no differences between vasopressin and norepinephrine in the other cardio-pulmonary variables measured including markers of global perfusion, cardiac filling pressures, pulmonary artery pressures and oxygenation. In general, maintenance of a high cardiac output in critical care16 and specifically sepsis17 is associated with a better outcome and is one of the important targets of early goal directed therapy18. However, the use of inotropic drugs to boost cardiac output and oxygen delivery in established septic shock has been shown to lead to an increased mortality rate19. Tachycardia is also thought to have adverse effects on the myocardium as it both increases myocardial oxygen demand as well as reducing myocardial oxygen supply due to the reduction in myocardial perfusion in the shortened diastole. In previous studies a high heart rate has been associated with higher mortality rates in septic shock20,21. It is interesting that the greater decrease of heart rate was seen in vasopressin patients in the less severe shock stratum in whom there was a significant reduction in mortality with vasopressin compared to norepinephrine treatment. 11 Downloaded from chestjournal.chestpubs.org at McGill University Libraries on June 15, 2012 Copyright © 2012 American College of Chest Physicians
    • Page 12 of 32 We calculated the rate-pressure product in an attempt to summarize thebalance of myocardial workload and oxygen consumption, a higher numberparticularly >11,00022, being associated with an increased risk of myocardialischemia23. There was a significant reduction in the rate-pressure product and theproportion of patients who had a rate-pressure product >11,000 in the vasopressin-treated patients (compared to norepinephrine-treated patients) and this may reflect animprovement in the balance of myocardial oxygen supply and demand. However,there were no differences in myocardial ischemia or infarction between treatmentgroups in the primary VASST analysis or in subsequent post-hoc subgroup analysesof troponin levels or ischemic ECG changes24,25. These effects of vasopressin vs. norepinephrine on hemodynamics agree withmany of the previously published smaller studies. Vasopressin has been associatedwith a reduction in heart rate in several studies7,8. There are two possibilities for thiseffect. If the normal baroreceptor response is still intact (particularly in the less severeshock stratum) the normal physiological response to the vasopressin-inducedvasoconstriction would be a drop in heart rate if stroke volume is maintained,therefore balancing cardiac output in order to maintain the same blood pressure. Theother explanation may be due to the well-described catecholamine-sparing effect ofvasopressin. Although norepinephrine is described as an α-adrenoreceptor agonist itdoes have some β-adrenoreceptor activity and thus a reduction in the rate of infusionof norepinephrine may lead to a reduction in heart rate. This may be an importantcharacteristic of vasopressin. Recent work has demonstrated that increasedcatecholamine vasopressor load is associated with mortality and other adverse eventsonce a mean arterial pressure of 70mmHg is obtained21. At the time of recruitmentinto VASST the average mean arterial pressure was ~72mmHg and the meannorepinephrine infusion rate was ~20µg/min. Norepinephrine requirements reduced 12 Downloaded from chestjournal.chestpubs.org at McGill University Libraries on June 15, 2012 Copyright © 2012 American College of Chest Physicians
    • Page 13 of 32 significantly in the vasopressin treated patients. The idea of decatecholaminization, reducing both endogenous and exogenous adrenergic stimulation, is now thought to be an important treatment strategy26 and the use of beta-blockers in septic shock is being considered27,28. The early use of vasopressin or specific V1a receptor agonists in early septic shock may be another possible treatment strategy29. Adhering to the lower limits of a blood pressure targets may also help reduce vasopressor load30. A reduction in cardiac output associated with vasopressin has previously been reported8 although other controlled trials have shown no effect5,6,9 and others even an increase in cardiac output7. The divergent results between studies may reflect differences in doses and methods of vasopressin administration, concomitant intravenous fluid resuscitation and inotropic infusions. We administered low-dose vasopressin (maximum dose 0.03U/min) by continuous infusion after adequate fluid resuscitation, and then titrated up the infusion while decreasing catecholamine vasopressors to maintain the target blood pressure. The fact that there was no difference in stroke volume index between treatment groups suggests that vasopressin treatment is not significantly decreasing cardiac contractility and that any effect on cardiac output is due to an effect on heart rate. Reassuringly there was no associated fall in cardiac output with vasopressin in those patients who had poor cardiac function (as defined by the lowest cardiac index quartile at baseline); however, it is important to note that there was a significantly greater proportion of patients who received inotropic agent infusions amongst vasopressin treated patients. While this greater use of inotropic agents could have been due to changes in cardiac output or markers of perfusion, our data do not show such a difference between the vasopressin and norepinephrine groups. This is in agreement with another recent study that reported that infusions of vasopressin or terlipressin, in addition to norepinephrine in septic shock, did not affect microcirculatory flow31. Despite previous reports that low-dose 13 Downloaded from chestjournal.chestpubs.org at McGill University Libraries on June 15, 2012 Copyright © 2012 American College of Chest Physicians
    • Page 14 of 32vasopressin may reduce pulmonary artery pressures32, we saw no effect ofvasopressin on these pressures. There are of course strengths and limitations of this study. The data comefrom a large multi-center double-blind randomized controlled trial in which infusionand weaning of vasopressin and norepinephrine was controlled by protocol, and thusprovide us with the most extensive data set to date in which to compare the effects ofvasopressin to norepinephrine infusion in septic shock. However, PA catheters wereonly inserted in a small subgroup (31%) of patients, and their use and the use ofinotropic agents was uncontrolled. As can be seen clearly from table 1, PA catheterswere inserted in sicker patients with higher APACHE II scores, more organdysfunction and requiring higher doses of vasopressors. Therefore they are notrepresentative of the whole population of patients with septic shock. However, if thereare any adverse hemodynamic effects of vasopressin they are more likely to bepresent in these sicker patients. This is a post-hoc subgroup analysis and thereforeshould only be hypothesis-generating, informing further research studies, rather thanused to inform clinical practice. It is also important to consider the inclusion andexclusion criteria for the trial. Patients were recruited who had established and treatedseptic shock for at least 6 hours. Patients had already been fluid resuscitated and theblinded study drug (vasopressin or norepinephrine) was substituted for existingvasopressors and thus it is not a direct comparison of the two vasopressors onsystemic hemodynamics when used as initial therapy in septic shock. Adequate fluidresuscitation prior to starting vasopressin or any vasopressin analogue is importantand detrimental cardiovascular effects might occur if the patient is fluid deplete. Alsopatients with severe chronic heart disease and patients with acute coronary syndromeswere excluded from VASST. Further evidence about the effect of vasopressininfusion in these groups of patients is required. 14 Downloaded from chestjournal.chestpubs.org at McGill University Libraries on June 15, 2012 Copyright © 2012 American College of Chest Physicians
    • Page 15 of 32 Conclusions: Vasopressin treatment in septic shock is associated with a significant reduction in heart rate but no change in cardiac output or measures of perfusion. Nonetheless, more patients in the vasopressin-treated than the norepinephrine-treated group also received inotropic agent infusions. Any effect of vasopressin on cardiac output seems due to this decrease in heart rate rather than an effect on stroke volume index. Finally, there were no adverse effects on cardiac output of vasopressin versus norepinephrine even in those patients with the poorest cardiac function (as reflected by lowest cardiac index quartile at baseline). 15 Downloaded from chestjournal.chestpubs.org at McGill University Libraries on June 15, 2012 Copyright © 2012 American College of Chest Physicians
    • Page 16 of 32Acknowledgments:Funding: Dr Gordon is a UK National Institute for Health Research (NIHR) ClinicianScientists award holder, and is grateful for funding from the NIHR comprehensiveBiomedical Research Centre funding stream. The VASST trial was funded by a grant(MCT 44152) from the Canadian Institutes of Health Research.Author contributions: All authors provided intellectual input to the research andmanuscript. Dr Gordon acts as a guarantor of the paper, taking responsibility for theintegrity of the work as a whole.Drs Gordon, Walley and Russell contributed to the study conception and design,acquisition of data, analysis and interpretation of data, statistical analysis, drafting ofthe manuscript, and critical revision of the manuscript for important intellectualcontent.Drs Wang and Ashby contributed to the analysis and interpretation of data, statisticalanalysis, and critical revision of the manuscript for important intellectual content. 16 Downloaded from chestjournal.chestpubs.org at McGill University Libraries on June 15, 2012 Copyright © 2012 American College of Chest Physicians
    • Page 17 of 32 References: 1 Alberti C, Brun-Buisson C, Goodman SV, et al. Influence of systemic inflammatory response syndrome and sepsis on outcome of critically ill infected patients. American Journal of Respiratory and Critical Care Medicine 2003; 168:77-84 2 Dellinger RP, Levy MM, Carlet JM, et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008. Critical care medicine 2008; 36:296-327 3 Landry DW, Levin HR, Gallant EM, et al. Vasopressin deficiency contributes to the vasodilation of septic shock. Circulation 1997; 95:1122-1125 4 Landry DW, Levin HR, Gallant EM, et al. Vasopressin pressor hypersensitivity in vasodilatory septic shock. Crit Care Med 1997; 25:1279-1282 5 Malay MB, Ashton RC, Jr., Landry DW, et al. Low-dose vasopressin in the treatment of vasodilatory septic shock. J Trauma 1999; 47:699-703; discussion 703-695 6 Patel BM, Chittock DR, Russell JA, et al. Beneficial effects of short-term vasopressin infusion during severe septic shock. Anesthesiology 2002; 96:576-582 7 Dunser MW, Mayr AJ, Ulmer H, et al. Arginine vasopressin in advanced vasodilatory shock: a prospective, randomized, controlled study. Circulation 2003; 107:2313-2319 8 Lauzier F, Levy B, Lamarre P, et al. Vasopressin or norepinephrine in early hyperdynamic septic shock: a randomized clinical trial. Intensive Care Med 2006; 32:1782-1789 9 Morelli A, Ertmer C, Rehberg S, et al. Continuous terlipressin versus vasopressin infusion in septic shock (TERLIVAP): a randomized, controlled pilot study. Crit Care 2009; 13:R130 10 Holmes CL, Walley KR, Chittock DR, et al. The effects of vasopressin on hemodynamics and renal function in severe septic shock: a case series. Intensive Care Med 2001; 27:1416-1421 11 Torgersen C, Dunser MW, Schmittinger CA, et al. Current approach to the haemodynamic management of septic shock patients in European intensive care units: a cross-sectional, self-reported questionnaire-based survey. European journal of anaesthesiology 2011; 28:284-290 17 Downloaded from chestjournal.chestpubs.org at McGill University Libraries on June 15, 2012 Copyright © 2012 American College of Chest Physicians
    • Page 18 of 3212 Krejci V, Hiltebrand LB, Sigurdsson GH. Effects of epinephrine, norepinephrine, and phenylephrine on microcirculatory blood flow in the gastrointestinal tract in sepsis. Critical care medicine 2006; 34:1456-146313 Hayes MA, Yau EH, Hinds CJ, et al. Symmetrical peripheral gangrene: association with noradrenaline administration. Intensive Care Med 1992; 18:433-43614 Russell JA, Walley KR, Singer J, et al. Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl J Med 2008; 358:877-88715 Bone RC, Sibbald WJ, Sprung CL. The ACCP-SCCM consensus conference on sepsis and organ failure. Chest 1992; 101:1481-148316 Shoemaker WC, Appel PL, Kram HB, et al. Prospective trial of supranormal values of survivors as therapeutic goals in high-risk surgical patients. Chest 1988; 94:1176-118617 Abraham E, Bland RD, Cobo JC, et al. Sequential cardiorespiratory patterns associated with outcome in septic shock. Chest 1984; 85:75-8018 Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 2001; 345:1368-137719 Hayes MA, Timmins AC, Yau EH, et al. Elevation of systemic oxygen delivery in the treatment of critically ill patients. N Engl J Med 1994; 330:1717-172220 Parker MM, Shelhamer JH, Natanson C, et al. Serial cardiovascular variables in survivors and nonsurvivors of human septic shock: heart rate as an early predictor of prognosis. Critical care medicine 1987; 15:923-92921 Dunser MW, Ruokonen E, Pettila V, et al. Association of arterial blood pressure and vasopressor load with septic shock mortality: a post hoc analysis of a multicenter trial. Critical care 2009; 13:R18122 Roy WL, Edelist G, Gilbert B. Myocardial ischemia during non-cardiac surgical procedures in patients with coronary-artery disease. Anesthesiology 1979; 51:393-39723 Robinson BF. Relation of heart rate and systolic blood pressure to the onset of pain in angina pectoris. Circulation 1967; 35:1073-108324 Mehta S, Granton J, Cook D, et al. Troponin and CKMB trends in patients with septic shock randomized to vasopressin (VP) or Norepinephrine (NE). Am J Respir Crit Care Med 2009; 179:A1564 18 Downloaded from chestjournal.chestpubs.org at McGill University Libraries on June 15, 2012 Copyright © 2012 American College of Chest Physicians
    • Page 19 of 32 25 Gordon AC, Mehta S, Lapinsky S, et al. Comparison of vasopressin- versus norepinephrine-associated ischemic ECG changes in septic shock. Intensive Care Med 2009; 35:S114 26 Brame AL, Singer M. Stressing the obvious? An allostatic look at critical illness. Critical care medicine 2010; 38:S600-607 27 Rudiger A. Beta-block the septic heart. Critical care medicine 2010; 38:S608-612 28 http://clinicaltrials.gov/ct2/show/NCT01231698:Accessed 30-January 2012 29 Rehberg S, Ertmer C, Vincent JL, et al. Role of selective V1a receptor agonism in ovine septic shock. Critical care medicine 2011; 39:119-125 30 Takala J. Should we target blood pressure in sepsis? Critical care medicine 2010; 38:S613-619 31 Morelli A, Donati A, Ertmer C, et al. Effects of vasopressinergic receptor agonists on sublingual microcirculation in norepinephrine-dependent septic shock. Critical care 2011; 15:R217 32 Holmes CL, Patel BM, Russell JA, et al. Physiology of vasopressin relevant to management of septic shock. Chest 2001; 120:989-1002 19 Downloaded from chestjournal.chestpubs.org at McGill University Libraries on June 15, 2012 Copyright © 2012 American College of Chest Physicians
    • Page 20 of 32LegendFigure 1 Cardiac index over time in patients who had PA catheters by cardiac indexquartile at baseline. A - 1st quartile CI ≤2.9 l/min/m2 at baseline. B- 2nd quartile CI2.91-3.7 l/min/m2 at baseline. C - 3rd quartile CI 3.71-4.5 l/min/m2 at baseline. D - 4thquartile CI >4.5 l/min/m2 at baseline. The grey circles represent the vasopressin-treated patients and the black squares norepinephrine-treated patients. The treatment(vasopressin vs. norepinephrine) effect on CI over time was p=0.99 in the firstquartile, p=0.26 in the second quartile, p=0.43 in the third quartile, p=0.36 in thefourth quartile. 20 Downloaded from chestjournal.chestpubs.org at McGill University Libraries on June 15, 2012 Copyright © 2012 American College of Chest Physicians
    • Page 21 of 32 TABLE 1. DEMOGRAPHICS AND BASELINE CHARACTERISTICS OF PATIENTS WHO HAD OR DID NOT HAVE PA CATHETERS CHARACTERISTIC NO PA PA P-VALUE CATHETER CATHETER N (%) N (%) (N = 538) (N = 241) Age (years) 59.9 ± 16.5 62.0 ± 15.6 0.10 Sex – Male 329 (61.2) 146 (60.6) 0.88 Recent surgical history 185 (34.4) 98 (40.7) 0.09 APACHE II score 26.6 ± 7.6 28.2 ± 6.4 0.004 Ethnicity – Caucasian 453 (84.2) 203 (84.2) 0.99 Pre-existing conditions Ischemic Heart Disease 85 (15.8) 48 (19.9) 0.16 Congestive Heart Failure 43 (8.0) 15 (6.2) 0.38 COPD 93 (17.3) 34 (14.1) 0.27 Chronic Renal Failure 60 (11.2) 28 (11.6) 0.85 Diabetes 110 (20.4) 55 (22.8) 0.45 Liver Disease 66 (12.3) 22 (9.1) 0.20 Alcoholism 75 (13.9) 33 (13.7) 0.93 Injection Drug Abuse 29 (5.4) 5 (2.1) 0.04 Cancer 131 (24.3) 58 (24.1) 0.93 Immunocompromised 100 (18.6) 39 (16.2) 0.42 Solid Organ Transplant 25 (4.6) 6 (2.5) 0.15 Steroid use 109 (20.3) 59 (24.5) 0.19 Recent Trauma 25 (4.6) 14 (5.8) 0.49 New Organ Failure Respiratory 465 (86.4) 218 (90.5) 0.11 Renal 344 (63.9) 178 (73.9) 0.006 Hematology/Coagulation 130 (24.2) 72 (29.9) 0.09 Neurologic 134 (24.9) 56 (23.2) 0.62 Cardio-pulmonary variables Systolic Blood Pressure (mmHg) 109 ± 16 109 ± 17 0.84 Mean Arterial Pressure (mmHg) 72.9 ± 9.9 72.4 ± 8.6 0.52 Arterial pH 7.32 ± 0.10 7.30 ± 0.10 <0.001 Central venous pressure (mmHg) 14.2 ± 4.9 15.4 ± 5.1 0.002 Serum lactate (mmol/L) 3.1 ± 2.9 4.2 ± 3.5 <0.001 PaO2/FiO2 (mmHg) 207 ± 94 192 ± 92 0.05 More severe shock subgroup (>15µg/min 256 (47.6) 145 (60.2) 0.001 norepinephrine at randomization) Vasoactive Drug Dosage at randomization Norepinephrine (µg/min) 19.1 ± 19.7 24.0 ± 20.8 0.003 Phenylephrine (µg/min) 139 ± 81 182 ± 80 0.002 Epinephrine (µg/min) 14.5 ± 18.0 9.0 ± 7.7 0.18 Dobutamine (µg/kg/min) 5.4 ± 4.8 6.5 ± 4.1 0.30 Milrinone (µg/kg/min) 0.40 ± 0.37 0.30 ± 0.13 0.36 Plus-minus values are means ± SD. PA denotes pulmonary artery catheter, COPD - chronic obstructive pulmonary disease, and APACHE II - Acute Physiology and Chronic Health Evaluation II 21 Downloaded from chestjournal.chestpubs.org at McGill University Libraries on June 15, 2012 Copyright © 2012 American College of Chest Physicians
    • Page 22 of 32 Table 2: Cardio-pulmonary variables over time comparing vasopressin versus norepinephrine in all patients (n=779). # 0hrs 6 hrs 12 hrs 24 hrs 36 hrs 48 hrs 60 hrs 72 hrs 84 hrs 96 hrs p MAP (mmHg) NE 73.2 ± 9.9 75.5 ± 10.1 75.0 ± 10.2 75.9 ± 11.8 76.7 ± 11.1 76.2 ± 12.8 80.3 ± 12.7 79.2 ± 13.7 81.1 ± 14.7 82.1 ± 13.7 0.80Downloaded from chestjournal.chestpubs.org at McGill University Libraries on June 15, 2012 AVP 72.4 ± 9.1 73.4 ± 9.1 74.2 ± 9.6 75.9 ± 10.9 75.2 ± 11.3 76.4 ± 11.4 79.6 ± 12.7 80.1 ± 13.6 82.7 ± 14.0 83.0 ± 14.9 Total NE infusion rate^ (µ g/min) NE 15.9 (9.0-25.0) 17.0 (12.0-33.0) 15.0 (10.0-29.8) 12.5 (3.0-22.0) 15.0 (7.5-28.9) 10.0 (3.1-21.0) 7.5 (2.0-19.2) 5.0 (0.0-15.0) 2.5 (0.0-12.5) 0.0 (0.0-9.0) <0.0001 AVP 14.0 (8.0- 25.0) 8.0 (3.0-17.0) 6.0 (2.0-14.4) 4.0 (0.0-10.0) 6.0 (2.0-14.0) 3.1 (0.0-9.6) 1.0 (0.0-5.9) 0.0 (0.0-2.0) 0.0 (0.0-2.0) 0.0 (0.0-1.1) HR (bpm) Copyright © 2012 American College of Chest Physicians NE 100 ± 20 99 ± 19 96 ± 19 95 ± 20 96 ± 19 95 ± 20 92 ± 19 92 ± 19 91 ± 19 92 ± 18 <0.0001 AVP 100 ± 21 93 ± 20 90 ± 21 90 ± 21 90 ± 22 90 ± 21 88 ± 20 89 ± 20 88 ± 19 90 ± 21 CVP (mmHg) NE 14.4 ± 5.0 14.9 ± 5.2 14.2 ± 4.9 14.4 ± 5.7 14.6 ± 5.1 14.4 ± 5.5 14.0 ± 4.9 13.6 ± 4.7 13.4 ± 4.5 13.1 ± 4.9 0.14 AVP 14.8 ± 5.0 15.0 ± 5.0 15.1 ± 5.6 15.2 ± 5.3 14.9 ± 4.8 15.0 ± 5.0 15.0 ± 4.9 14.4 ± 4.9 13.8 ± 4.5 13.4 ± 4.9 pH NE 7.31 ± .10 7.32 ± .11 7.33 ± .10 7.35 ± .09 7.34 ± .10 7.35 ± .09 7.37 ± .09 7.38 ± .07 7.39 ± .08 7.39 ± .08 0.66 AVP 7.32 ± .10 7.32 ± .11 7.34 ± .09 7.35 ± .08 7.34 ± .09 7.35 ± .09 7.36 ± .09 7.38 ± .07 7.39 ± .07 7.40 ± .08 Lactate (mmol/l) NE 2.3 (1.5-4.6) 2.5 (1.5-4.5) 2.2 (1.4-4.0) 1.8 (1.2-2.9) 1.7 (1.2-2.4) 0.63 AVP 2.3 (1.4-4.0) 2.4 (1.7-5.2) 2.1 (1.4-3.8) 1.8 (1.3-2.8) 1.7 (1.2-2.4) PaO2/FiO2 (mmHg) NE 199 ± 94 207 ± 97 213 ± 94 217 ± 91 218 ± 98 218 ± 89 231 ± 99 229 ± 103 231 ± 100 227 ± 88 0.79 AVP 206 ± 93 217 ± 114 219 ± 97 217 ± 91 222 ± 96 223 ± 109 226 ± 94 227 ± 94 233 ± 89 229 ± 93 N receiving any inotropes (existing / new) NE 74 68 (57 / 11) 73 (58 / 11) 55 (47 / 8) 67 (66 / 1) 56 (48 / 8) 51 (47 / 4) 45 (41 / 4) 55 (48 / 7) 50 (45 / 5) 0.02 AVP 80 86 (70 / 16) 94 (81 / 13) 88 (83 / 5) 93 (91 / 2) 85 (81 / 4) 78 (73 / 5) 67 (61 / 6) 66 (62 / 4) 53 (52 / 1) Mean dose dobutamine§ (µ g/kg/min) NE 5.1 ± 3.7 6.2 ± 10.3 4.4 ± 3.0 4.5 ± 5.2 3.7 ± 2.4 5.3 ± 7.5 3.7 ± 1.9 3.4 ± 1.5 3.4 ± 1.9 3.7 ± 1.8 0.06 AVP 6.4 ± 5.2 6.4 ± 5.0 6.9 ± 6.4 6.3 ± 6.4 6.3 ± 5.0 6.5 ± 6.8 5.2 ± 4.7 5.5 ± 6.2 4.9 ± 4.5 5.7 ± 4.4 RPP (/100) NE 109 ± 23 112 ± 24 109 ± 25 109 ± 27 110 ± 27 109 ± 27 110 ± 27 110 ± 28 112 ± 30 115 ± 28 <0.0001 AVP 108 ± 24 100 ± 24 99 ± 26 101 ± 28 99 ± 27 102 ± 27 105 ± 31 108 ± 32 109 ± 31 112 ± 35 RPP >110 (%) NE 47.6 49.3 46.9 44.4 45.7 44.5 46.1 47.2 48.5 51.2 AVP 44.9 33.0 30.9 34.5 31.3 32.0 35.2 44.1 44.0 48.8 <0.0001 22
    • Page 23 of 32 Values are means ± SD and median (interquartile range) for NE dose and serum lactate levels. # p-value is comparing difference over time between treatment groups. The abbreviations are NE – norepinephrine, AVP – vasopressin, MAP – mean arterial pressure, HR – heart rate, CVP – central venous pressure, RPP – rate pressure product (divided by 100). ^NE dose is calculated for all patients who were receiving NE at baseline. §Dobutamine dose is calculated for patients receiving dobutamine at that time point.Downloaded from chestjournal.chestpubs.org at McGill University Libraries on June 15, 2012 Copyright © 2012 American College of Chest Physicians 23
    • Page 24 of 32 Table 3 Detailed cardio-pulmonary variables over time comparing vasopressin versus norepinephrine in patients who had a PA catheter (n=241) # 0hrs 6 hrs 12 hrs 24 hrs 36 hrs 48 hrs 60 hrs 72 hrs 84 hrs 96 hrs p SvO2 (%) NE 68.6 ± 14.4 69.5 ± 14.3 68.4 ± 13.8 69.8 ± 15.6 66.9 ± 14.2 66.4 ± 15.9 62.9 ± 17.4 63.3 ± 17.7 65.3 ± 17.1 62.3 ± 17.4 0.92Downloaded from chestjournal.chestpubs.org at McGill University Libraries on June 15, 2012 AVP 67.0 ± 15.7 64.0 ± 17.0 68.3 ± 13.8 66.2 ± 14.6 67.7 ± 15.8 67.3 ± 13.0 65.0 ± 16.8 65.4 ± 14.4 64.2 ± 14.8 65.7 ± 15.0 CI (l/min/m2) NE 3.95 ± 1.26 3.92 ± 1.22 3.70 ± 1.14 3.67 ± 1.02 3.61 ± 1.23 3.62 ± 1.27 3.46 ± 1.18 3.82 ± 1.40 3.49 ± 1.15 3.53 ± 1.10 0.87 AVP 3.82 ± 1.31 3.51 ± 1.39 3.46 ± 1.29 3.70 ± 1.57 3.46 ± 1.45 3.65 ± 1.45 3.52 ± 1.46 3.59 ± 1.39 3.47 ± 1.48 3.65 ± 1.61 SVI (ml/min/m2) NE 39.8 ± 14.3 39.9 ± 11.9 37.8 ± 11.7 40.2 ± 11.9 37.5 ± 11.9 39.9 ± 14.0 38.4 ± 12.9 40.4 ± 13.6 39.6 ± 11.8 39.8 ± 11.9 0.53 AVP 37.5 ± 12.5 37.2 ± 14.3 36.3 ± 12.7 39.0 ± 14.6 37.5 ± 14.9 39.1 ± 14.8 38.9 ± 15.1 39.5 ± 13.7 38.7 ± 13.0 40.0 ± 13.5 Copyright © 2012 American College of Chest Physicians LVSWI (g/m2) NE 28.5 ± 11.7 31.2 ± 11.9 29.8 ± 12.5 31.7 ± 12.2 29.4 ± 12.4 31.3 ± 12.8 32.5 ± 13.4 33.2 ± 13.2 32.0 ± 11.5 34.8 ± 12.3 0.72 AVP 26.6 ± 10.3 28.8 ± 11.9 27.7 ± 11.7 30.2 ± 14.0 29.3 ± 13.6 31.5 ± 14.7 31.4 ± 15.3 31.5 ± 14.2 31.6 ± 10.9 32.0 ± 12.5 PAOP (mmHg) NE 17.3 ± 5.7 17.9 ± 5.3 17.7 ± 4.8 18.9 ± 6.1 18.7 ± 5.7 19.4 ± 7.2 17.9 ± 5.3 18.7 ± 6.4 19.2 ± 8.3 18.9 ± 5.2 0.32 AVP 20.6 ± 5.9 19.2 ± 5.0 19.6 ± 6.7 20.2 ± 6.0 19.0 ± 5.8 19.1 ± 5.9 19.5 ± 6.4 19.5 ± 6.8 19.4 ± 5.6 19.5 ± 6.3 MPAP (mmHg) NE 28.0 ± 6.7 29.4 ± 6.3 29.0 ± 5.9 29.4 ± 8.7 29.4 ± 6.6 29.8 ± 7.1 28.6 ± 6.9 30.0 ± 7.7 28.9 ± 7.8 30.4 ± 7.3 0.82 AVP 30.3 ± 6.7 30.2 ± 8.2 29.9 ± 8.2 29.7 ± 6.3 29.8 ± 8.0 30.1 ± 7.1 29.8 ± 7.8 29.9 ± 7.3 28.7 ± 6.3 29.8 ± 7.4 Values are means ± SD. # p-value is comparing difference over time between treatment groups. The abbreviations are NE – norepinephrine, AVP – vasopressin, SvO2 mixed venous saturation, CI – cardiac index, SVI – stroke volume index, LVSWI – left ventricular stroke work index, PAOP – pulmonary artery occlusion pressure, MPAP – mean pulmonary arterial pressure. 24
    • Page 25 of 32 Table 4: Cardio-pulmonary variables over time comparing vasopressin versus norepinephrine in all patients in the more and less severe shock strata. # * 0hrs 6 hrs 12 hrs 24 hrs 36 hrs 48 hrs 60 hrs 72 hrs 84 hrs 96 hrs p value p value interaction MAP (mmHg)Downloaded from chestjournal.chestpubs.org at McGill University Libraries on June 15, 2012 More severe NE 71.7 ± 10.5 74.5 ± 10.4 74.8 ± 10.3 74.6 ± 11.3 76.0 ± 11.9 74.8 ± 12.6 79.7 ± 11.4 77.8 ± 11.8 79.7 ± 14.0 81.7 ± 12.6 0.73 AVP 71.4 ± 8.8 72.4 ± 9.5 73.6 ± 10.2 74.8 ± 11.3 73.9 ± 11.9 75.1 ± 11.7 76.9 ± 12.3 78.5 ± 13.6 82.8 ± 14.0 81.7 ± 14.8 Less severe 0.51 NE 74.7 ± 9.1 76.6 ± 9.7 75.2 ± 10.0 77.2 ± 12.2 77.5 ± 10.2 77.6 ± 12.9 80.9 ± 13.8 80.7 ± 15.2 82.4 ± 15.2 82.4 ± 14.8 0.55 AVP 73.3 ± 9.3 74.4 ± 8.6 74.9 ± 9.0 77.0 ± 10.4 76.5 ± 10.5 77.6 ± 10.9 82.1 ± 12.6 81.3 ± 13.5 82.7 ± 14.0 84.0 ± 14.9 Total NE Copyright © 2012 American College of Chest Physicians infusion rate^ (µ g/min) More severe NE 22.7 (16.0-37.8) 27.0 (15.5-45.0) 23.0 (15.0-40.0) 17.6 (7.5-27.0) 21.2 (15.0-37.0) 17.0 (28.6-7.5) 15.0 (4.0-23.0) 6.5 (0.0-17.0) 2.5 (0.0-13.0) 0.0 (0.0-10.0) <0.0001 AVP 24.0 (17.0-35.0) 15.0 (8.0-28.0) 12.7 (4.0-26.2) 6.0 (0.0-18.0) 12.0 (4.0-24.0) 5.7 (0.0-16.0) 2.5 (0.0-10.6) 0.0 (0.0-5.3) 0.0 (0.0-3.7) 0.0 (0.0-2.0) Less severe 0.16 NE 10.0 (7.0-12.0) 12.5 (7.5-16.6) 10.0 (5.0-15.0) 5.0 (1.5-15.0) 10.0 (5.0-15.0) 5.0 (2.0-15.0) 5.0 (0.0-15.0) 2.5 (0.0-10.0) 1.1 (0.0-11.0) 0.0 (0.0-7.5) <0.0001 AVP 9.0 (6.0-11.0) 5.0 (1.0-8.0) 4.0 (0.0-6.0) 2.0 (0.0-6.0) 3.7 (0.0-7.0) 1.5 (0.0-6.0) 0.0 (0.0-3.9) 0.0 (0.0-2.0) 0.0 (0.0-2.0) 0.0 (0.0-0.5) HR (bpm) More severe NE 100 ± 20 99 ± 19 96 ± 19 95 ± 20 96 ± 19 95 ± 20 92 ± 19 92 ± 19 91 ± 19 92 ± 18 0.02 AVP 100 ± 21 93 ± 20 90 ± 21 90 ± 21 90 ± 22 90 ± 21 88 ± 20 89 ± 20 88 ± 19 90 ± 21 Less severe 0.03 NE 97 ± 19 97 ± 18 96 ± 20 95 ± 21 95 ± 19 95 ± 20 93 ± 19 95 ± 20 94 ± 20 95 ± 20 <0.0001 AVP 95 ± 18 88 ± 19 85 ± 19 86 ± 20 84 ± 20 88 ± 21 87 ± 21 89 ± 20 87 ± 19 92 ± 22 CVP (mmHg) More severe NE 14.7 ± 5.1 15.5 ± 5.4 14.7 ± 5.0 14.9 ± 5.8 15.1 ± 5.5 15.1 ± 6.0 14.6 ± 5.5 14.1 ± 5.2 14.2 ± 5.0 13.6 ± 5.2 0.57 AVP 15.6 ± 5.1 15.7 ± 4.8 15.9 ± 6.0 15.9 ± 5.4 15.5 ± 4.9 15.7 ± 5.3 15.1 ± 4.9 14.7 ± 4.7 13.9 ± 4.5 13.6 ± 5.1 Less severe 0.02 NE 14.2 ± 4.8 14.2 ± 4.8 13.7 ± 4.8 13.8 ± 4.8 14.0 ± 4.5 13.6 ± 4.8 13.3 ± 4.1 13.1 ± 4.2 12.6 ± 3.9 12.7 ± 4.4 0.007 AVP 14.0 ± 4.8 14.3 ± 5.2 14.3 ± 5.0 14.5 ± 5.1 14.2 ± 4.6 14.4 ± 4.7 14.9 ± 4.9 14.1 ± 5.1 13.6 ± 4.7 13.2 ± 4.8 pH More severe NE 7.29 ± 0.11 7.29 ± 0.12 7.31 ± 0.11 7.33 ± 0.10 7.32 ± 0.10 7.34 ± 0.10 7.36 ± 0.09 7.37 ± 0.07 7.38 ± 0.08 7.39 ± 0.08 0.91 AVP 7.29 ± 0.10 7.29 ± 0.12 7.32 ± 0.10 7.33 ± 0.09 7.32 ± 0.10 7.34 ± 0.10 7.35 ± 0.10 7.37 ± 0.07 7.39 ± 0.07 7.39 ± 0.08 Less severe 0.76 NE 7.35 ± 0.08 7.35 ± 0.09 7.35 ± 0.10 7.36 ± 0.08 7.36 ± 0.09 7.37 ± 0.08 7.38 ± 0.08 7.39 ± 0.08 7.40 ± 0.07 7.40 ± 0.09 0.59 AVP 7.35 ± 0.08 7.35 ± 0.09 7.36 ± 0.08 7.37 ± 0.07 7.36 ± 0.08 7.37 ± 0.08 7.38 ± 0.08 7.39 ± 0.07 7.40 ± 0.07 7.40 ± 0.08 Lactate (mmol/l) More severe 25
    • Page 26 of 32 NE 3.0 (1.7-5.4) 2.9 (1.8-5.8) 2.5 (1.6-4.6) 1.8 (1.3-3.1) 1.7 (1.3-2.5) 0.51 AVP 3.3 (2.0-6.1) 3.5 (1.9-6.3) 2.9 (1.8-5.6) 2.1 (1.5-3.3) 1.8 (1.3-2.7) Less severe 0.69 NE 1.9 (1.3-3.7) 1.9 (1.4-3.2) 1.7 (1.2-2.8) 1.7 (1.2-2.6) 1.6 (1.2-2.2) 0.95 AVP 1.6 (1.1-2.5) 2.1 (1.3-2.5) 1.7 (1.2-2.3) 1.6 (1.2-2.1) 1.7 (1.1-2.2)Downloaded from chestjournal.chestpubs.org at McGill University Libraries on June 15, 2012 PaO2/FiO2 (mmHg) More severe NE 188 ± 95 197 ± 101 207 ± 98 211 ± 92 213 ± 100 216 ± 89 229 ± 96 226 ± 95 233 ± 102 229 ± 83 0.74 0.81 AVP 194 ± 95 206 ± 118 209 ± 104 212 ± 91 211 ± 98 224 ± 129 219 ± 98 230 ± 92 237 ± 92 233 ± 93 Less severe Copyright © 2012 American College of Chest Physicians NE 210 ± 92 218 ± 92 220 ± 89 223 ± 90 224 ± 94 221 ± 90 233 ± 103 231 ± 111 228 ± 98 225 ± 94 0.99 AVP 217 ± 90 229 ± 108 229 ± 88 223 ± 91 233 ± 93 223 ± 84 232 ± 90 225 ± 95 229 ± 87 225 ± 93 N receiving any inotropes (existing/new) More severe NE 54 53 (44 / 9) 53 (44 / 9) 40 (34 / 6) 50 (49 / 1) 41 (37 / 4) 39 (37 / 2) 30 (29 / 1) 34 (31 / 3) 34 (30 / 4) 0.03 AVP 62 67 (55 / 12) 72 (64 / 8) 65 (62 / 3) 72 (70 / 2) 64 (61 / 3) 56 (54 / 2) 46 (41 / 5) 45 (43 / 2) 37 (37 / 0) Less severe 0.69 NE 20 15 (13 / 2) 20 (14 / 6) 15 (13 / 2) 17 (17 / 0) 15 (11 / 4) 12 (10 / 2) 15 (12 / 3) 21 (17 / 4) 16 (15 / 1) 0.27 AVP 18 19 (15 / 4) 22 (17 / 5) 23 (21 / 2) 21 (21 / 0) 21 (20 / 1) 22 (19 / 3) 21 (20 / 1) 21 (19 / 2) 16 (15 / 1) Mean dose dobutamine§ (µ g/kg/min) More severe NE 5.1 ± 3.7 6.5 ± 11.9 3.7 ± 1.9 4.5 ± 6.2 3.5 ± 1.9 5.2 ± 8.6 3.6 ± 2.0 3.5 ± 1.6 3.6 ± 2.0 3.7 ± 1.9 0.07 AVP 7.0 ± 5.7 6.9 ± 5.4 7.1 ± 6.9 6.8 ± 7.1 6.6 ± 5.4 7.1 ± 7.5 5.6 ± 5.1 5.6 ± 4.8 5.6 ± 5.0 6.4 ± 4.9 Less severe 0.59 NE 5.1 ± 4.0 5.3 ± 4.0 5.8 ± 4.4 4.5 ± 1.4 4.3 ± 3.4 5.4 ± 2.0 5.2 ± 9.0 3.1 ± 1.4 3.1 ± 1.6 3.6 ± 1.3 0.66 AVP 4.1 ± 1.8 4.6 ± 2.3 5.7 ± 3.2 4.3 ± 2.2 4.7 ± 2.2 4.4 ± 2.8 4.0 ± 2.7 5.2 ± 9.0 3.5 ± 2.5 4.1 ± 2.7 RPP (/100) More severe NE 110 ± 24 112 ± 24 109 ± 25 106 ± 25 109 ± 26 105 ± 25 107 ± 25 105 ± 27 108 ± 28 111 ± 27 0.05 AVP 112 ± 26 103 ± 22 103 ± 26 103 ± 26 103 ± 26 102 ± 25 102 ± 26 106 ± 31 109 ± 30 108 ± 32 Less severe 0.10 NE 108 ± 23 111 ± 24 109 ± 25 111 ± 28 112 ± 27 112 ± 29 114 ± 29 116 ± 28 116 ± 31 118 ± 29 <0.0001 AVP 104 ± 23 96 ± 25 95 ± 25 100 ± 29 96 ± 28 103 ± 30 109 ± 5 110 ± 33 109 ± 32 116 ± 37 RPP >110 (%) More severe NE 49.0 53.8 47.6 41.2 43.9 40.2 40.5 36.5 41.4 48.4 0.04 AVP 50.7 38.4 36.3 38.0 36.8 31.4 32.2 41.5 42.9 44.8 Less severe 0.12 26
    • Page 27 of 32 NE 46.2 44.5 46.1 47.7 47.5 48.9 51.7 57.7 55.4 53.9 <0.0001 AVP 39.0 27.5 25.6 31.0 25.7 32.6 38.0 46.2 44.8 52.2 Values are means ± SD and median (interquartile range) for NE dose and serum lactate levels. # p-value is comparing difference over time between treatment groups; *p-value is testing for a treatment group x shock subgroup interaction. The abbreviations are NE – norepinephrine, AVP –Downloaded from chestjournal.chestpubs.org at McGill University Libraries on June 15, 2012 vasopressin, MAP – mean arterial pressure, HR – heart rate, CVP – central venous pressure, RPP – rate pressure product (divided by 100). ^Median NE dose is calculated for all patients who were receiving NE at baseline. §Mean dobutamine dose is calculated for patients receiving dobutamine at that time point Copyright © 2012 American College of Chest Physicians 27
    • Page 28 of 32 Table 5: Detailed cardio-pulmonary variables over time comparing vasopressin versus norepinephrine in patients who had a PA catheter in the more and less severe shock strata. # ## 0hrs 6 hrs 12 hrs 24 hrs 36 hrs 48 hrs 60 hrs 72 hrs 84 hrs 96 hrs p value p valueDownloaded from chestjournal.chestpubs.org at McGill University Libraries on June 15, 2012 interaction SvO2 (%) More severe NE 67.4 ± 16.7 68.9 ± 15.6 67.4 ± 14.2 70.7 ± 13.1 66.9 ± 12.8 67.7 ± 12.6 61.4 ± 16.7 62.5 ± 16.4 61.8 ± 17.5 63.1 ± 14.7 0.99 AVP 62.2 ± 16.3 58.5 ± 18.1 64.7 ± 14.8 61.2 ± 15.2 64.7 ± 15.2 63.9 ± 14.0 60.6 ± 18.1 59.8 ± 15.5 58.8 ± 15.5 61.4 ± 16.5 Less severe 0.97 NE 69.8 ± 11.6 70.3 ± 12.6 69.9 ± 13.4 68.5 ± 18.9 67.0 ± 16.7 64.7 ± 19.8 66.1 ± 19.0 64.5 ± 20.2 70.3 ± 15.8 60.4 ± 22.9 0.95 Copyright © 2012 American College of Chest Physicians AVP 74.1 ± 11.8 73.4 ± 9.5 72.8 ± 11.0 70.8 ± 12.7 71.4 ± 16.1 71.7 ± 10.2 70.3 ± 13.7 71.9 ± 10.3 73.9 ± 6.4 74.2 ± 5.6 CI (l/min/m2) More severe NE 3.96 ± 1.14 3.67 ± 0.99 3.59 ± 1.26 3.55 ± 1.05 3.41 ± 1.22 3.47 ± 1.28 3.36 ± 1.16 3.54 ± 1.29 3.33 ± 1.16 3.22 ± 0.90 0.32 AVP 3.76 ± 1.27 3.51 ± 1.37 3.41 ± 1.19 3.65 ± 1.52 3.26 ± 1.31 3.53 ± 1.45 3.31 ± 1.42 3.47 ± 1.25 3.30 ± 1.21 3.64 ± 1.57 Less severe 0.15 NE 3.95 ± 1.41 4.36 ± 1.45 3.86 ± 0.93 3.83 ± 0.99 3.95 ± 1.19 3.83 ± 1.24 3.64 ± 1.23 4.18 ± 1.47 3.72 ± 1.11 4.01 ± 1.26 0.30 AVP 3.93 ± 1.39 3.50 ± 1.44 3.55 ± 1.45 3.81 ± 1.69 3.80 ± 1.64 3.87 ± 1.45 3.85 ± 1.47 3.74 ± 1.56 3.73 ± 1.82 3.65 ± 1.74 SVI (ml/min/m2) More severe NE 39.8 ± 14.3 39.9 ± 11.9 37.8 ± 11.7 40.2 ± 11.9 37.5 ± 11.9 39.9 ± 14.0 38.4 ± 12.9 40.4 ± 13.6 39.6 ± 11.8 39.8 ± 11.9 0.36 AVP 37.5 ± 12.5 37.2 ± 14.3 36.3 ± 12.7 39.0 ± 14.6 37.5 ± 14.9 39.1 ± 14.8 38.9 ± 15.1 39.5 ± 13.7 38.7 ± 13.0 40.0 ± 13.5 Less severe 0.66 NE 41.4 ± 16.8 46.9 ± 12.7 40.2 ± 38.6 42.8 ± 11.5 42.3 ± 11.1 42.5 ± 14.7 40.6 ± 11.2 43.4 ± 12.3 41.4 ± 9.2 43.1 ± 10.4 0.86 AVP 40.8 ± 14.6 38.4 ± 15.7 38.6 ± 14.9 42.7 ± 16.2 42.6 ± 17.5 42.6 ± 16.0 41.9 ± 15.5 41.1 ± 15.3 42.2 ± 16.1 41.0 ± 14.9 LVSWI (g/m2) More severe NE 27.8 ± 11.7 28.8 ± 12.0 28.3 ± 14.5 30.4 ± 14.8 26.7 ± 13.4 30.1 ± 15.1 31.3 ± 14.9 31.2 ± 14.3 31.7 ± 12.4 33.9 ± 14.5 0.62 AVP 25.3 ± 8.0 27.7 ± 10.6 25.3 ± 8.3 27.1 ± 11.1 26.4 ± 9.9 28.3 ± 12.6 28.4 ± 12.8 30.8 ± 11.9 30.1 ± 9.3 31.6 ± 13.6 Less severe 0.16 NE 29.5 ± 11.8 35.8 ± 10.3 32.1 ± 8.5 33.4 ± 7.9 33.5 ± 9.5 32.9 ± 9.0 34.5 ± 10.7 35.5 ± 11.6 32.3 ± 10.5 36.4 ± 7.45 0.16 AVP 28.4 ± 12.9 30.9 ± 14.2 31.6 ± 15.4 34.9 ± 16.7 34.2 ± 17.4 37.3 ± 16.7 36.9 ± 18.2 32.5 ± 17.2 34.2 ± 13.1 32.8 ± 10.6 PAOP (mmHg) More severe NE 17.4 ± 6.0 18.1 ± 6.3 18.2 ± 5.4 19.1 ± 7.2 18.9 ± 5.6 19.3 ± 7.8 17.6 ± 4.7 18.1 ± 7.1 19.1 ± 7.7 18.8 ± 5.9 0.20 AVP 20.6 ± 4.7 19.9 ± 4.2 19.5 ± 4.4 20.6 ± 5.2 18.9 ± 4.9 19.8 ± 5.1 20.6 ± 6.2 19.1 ± 4.2 19.9 ± 6.0 19.2 ± 6.8 Less severe 0.39 NE 17.2 ± 5.3 17.7 ± 6.2 16.9 ± 3.7 18.5 ± 4.4 18.3 ± 5.9 19.6 ± 6.3 18.3 ± 6.2 19.5 ± 5.5 19.4 ± 9.1 19.1 ± 3.5 0.97 AVP 20.5 ± 7.4 17.7 ± 6.2 19.8 ± 9.6 19.5 ± 7.2 19.0 ± 7.3 17.7 ± 7.0 17.4 ± 6.3 20.0 ± 9.5 18.7 ± 5.2 20.0 ± 5.3 28
    • Page 29 of 32 MPAP (mmHg) More severe NE 27.3 ± 7.2 29.9 ± 7.4 29.8 ± 6.5 30.7 ± 10.4 30.1 ± 7.5 30.4 ± 8.0 28.7 ± 7.4 29.5 ± 8.6 29.2 ± 8.1 30.5 ± 8.4 0.10 AVP 29.6 ± 6.4 30.1 ± 7.2 29.2 ± 6.2 29.6 ± 6.0 29.2 ± 7.4 29.6 ± 6.1 29.2 ± 7.2 29.7 ± 7.1 28.2 ± 6.1 27.6 ± 5.6Downloaded from chestjournal.chestpubs.org at McGill University Libraries on June 15, 2012 Less severe 0.02 NE 28.9 ± 6.0 28.7 ± 4.3 27.8 ± 4.6 27.5 ± 4.2 28.2 ± 4.8 28.9 ± 5.6 28.5 ± 6.2 30.6 ± 6.4 28.6 ± 7.4 30.2 ± 4.9 0.12 AVP 31.2 ± 7.0 30.3 ± 9.7 30.9 ± 10.6 29.8 ± 7.0 30.9 ± 8.8 31.0 ± 8.6 30.9 ± 8.8 30.2 ± 7.6 29.6 ± 6.7 34.3 ± 8.6 Values are means ± SD. # p-value is comparing difference over time between treatment groups; *p-value is testing for a treatment group x shock subgroup interaction. The abbreviations are NE – norepinephrine, AVP – vasopressin, SvO2 mixed venous saturation, CI – cardiac index, SVI – stroke volume index, LVSWI – left ventricular stroke work index, PAOP – pulmonary artery occlusion pressure, MPAP – mean pulmonary arterial pressure, Copyright © 2012 American College of Chest Physicians 29
    • Page 31 of 32 Figure 1 A B Downloaded from chestjournal.chestpubs.org at McGill University Libraries on June 15, 2012 Copyright © 2012 American College of Chest Physicians
    • Page 32 of 32Figure 1CD Downloaded from chestjournal.chestpubs.org at McGill University Libraries on June 15, 2012 Copyright © 2012 American College of Chest Physicians
    • THE CARDIO-PULMONARY EFFECTS OF VASOPRESSIN COMPARED TO NOREPINEPHRINE IN SEPTIC SHOCK Anthony C. Gordon, Nan Wang, Keith R. Walley, Deborah Ashby and James A. Russell Chest; Prepublished online April 19, 2012; DOI 10.1378/chest.11-2604 This information is current as of June 15, 2012Updated Information & ServicesUpdated Information and services can be found at:http://chestjournal.chestpubs.org/content/early/2012/04/18/chest.11-2604Permissions & LicensingInformation about reproducing this article in parts (figures, tables) or in its entirety can be foundonline at:http://www.chestpubs.org/site/misc/reprints.xhtmlReprintsInformation about ordering reprints can be found online:http://www.chestpubs.org/site/misc/reprints.xhtmlCitation AlertsReceive free e-mail alerts when new articles cite this article. To sign up, select the "Services" link tothe right of the online article.Images in PowerPoint formatFigures that appear in CHEST articles can be downloaded for teaching purposes in PowerPointslide format. See any online figure for directions.CHEST Papers in Press are peer-reviewed, accepted articles that have not yet beenpublished in an issue of the journal and have not yet been edited or typeset. The finalversion may contain substantive or nonsubstantive changes. These articles are indexed byPubMed, but any references to an in-press article must include the digital object identifier(DOI) and date of in-press publication.CHEST Papers in Press are not under media or public embargo once the appear online.For inquriires, please contact the AACP Media Relations Department at (847) 498-1400 ormedia@chestnet.org. Downloaded from chestjournal.chestpubs.org at McGill University Libraries on June 15, 2012 Copyright © 2012 American College of Chest Physicians