Neumonia y Sistema Cardiovascular Lancet 13.pdf

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496 www.thelancet.com Vol 381 February 9, 2013

Acute pneumonia and the cardiovascular system

Vicente F Corrales-Medina, Daniel M Musher, Svetlana Shachkina, Julio A Chirinos

Although traditionally regarded as a disease confined to the lungs, acute pneumonia has important effects on thecardiovascular system at all severities of infection. Pneumonia tends to affect individuals who are also at highcardiovascular risk. Results of recent studies show that about a quarter of adults admitted to hospital with pneumoniadevelop a major acute cardiac complication during their hospital stay, which is associated with a 60% increase inshort-term mortality. These findings suggest that outcomes of patients with pneumonia can be improved byprevention of the development and progression of associated cardiac complications. Before this hypothesis can betested, however, an adequate mechanistic understanding of the cardiovascular changes that occur during pneumonia,and their role in the trigger of various cardiac complications, is needed. In this Review, we summarise knowledgeabout the burden of cardiac complications in adults with acute pneumonia, the cardiovascular response to thisinfection, the potential effects of commonly used cardiovascular and anti-infective drugs on these associations, andpossible directions for future research.

IntroductionPneumonia an cariac isease are leaing causes ofmorbiity an mortality worlwie.15 Community-acquire pneumonia affects more than 5 million aults,an causes 11 million hospital amissions an morethan 60 000 eaths every year in the USA.1,2 Cariacisease affects more than 30 million US aults an leasto 5 million hospital amissions an more than300 000 eaths every year.3,6 Disease burens in Europeare similar.4,5,7 Pneumonia an cariac isease oftencoexist in the same patients.8 For example, more thanhalf of elerly patients amitte to hospital withpneumonia also have a chronic cariac isoreranassociation that will become more prevalent as the

population continues to age.8

Investigators have reporte a high incience of cariaccomplications uring the course of community-acquirepneumonia, an have shown that these events areinepenently associate with increase short-termmortality.9 In view of this association, full appreciation ofthe magnitue of this problem an an unerstaning ofthe cariovascular consequences of this infection areimportant. In this Review, we summarise the presentknowlege about the buren of cariac complications inault patients with pneumonia, the cariovascularresponse to acute pneumonia, an the potential effects ofcommonly use cariovascular an anti-infective rugson these associations. We also iscuss potential areas for

future research.

Burden of cardiac complications in patients withpneumoniaFor several ecaes, investigators have note that acuterespiratory infections, incluing pneumonia, oftenprecee the evelopment of acute cariac events, an acausal relation has been propose.10,11 For acute coronarysynromes specifically, this association satisfies most ofBrafor Hills criteria for causality an is iscusseelsewhere.11,12 The high prevalence of cariac arrhythmiasafter an episoe of pneumonia an the temporality of thisassociation also suggest a causal role for pneumonia in

cases of pneumonia-associate arrhythmias.9

Although asimilar argument can be mae for the association betweenpneumonia an heart failure, this relation is probablymore complex. Results of clinical stuies suggest thatpatients with heart failure have reuce immunologicalresponses, an experimental evience inicates thatpulmonary congestion can promote the growth ofcommon bacteria such as Streptococcus pneumoniae(pneumococcus) an Staphylococcus aureus in the lungs.1315Epiemiological ata also suggest that pre-existing heartfailure is a risk factor for the evelopment of pneumonia. 16Therefore, the causeeffect relation between pneumoniaan heart failure might be biirectional. A causal relationbetween infections in other organs, such as the urinary or

gastrointestinal tracts, an acute cariac events has alsobeen suggeste, but has not yet been characterise.17,18

Although acute cariac events have been recognise asimportant complications in patients with pneumonia

Lancet 2013; 381: 496505

Published Online

January 16, 2012

http://dx.doi.org/10.1016/

S0140-6736(12)61266-5

Department of Medicine,

University of Ottawa, ON,

Canada (V F Corrales-Medina MD,

S Shachkina MD); Ottawa

Hospital Research Institute,

ON, Canada

(V F Corrales-Medina,

S Shachkina); Departments of

Medicine and Molecular

Virology and Microbiology,

Baylor College of Medicine,Houston, TX, USA

(Prof D M Musher MD); Medical

Care Line, Infectious Disease

Section, Michael E DeBakey VA

Medical Center, Houston, TX,

USA (D M Musher);Division of

Cardiology, University of

Pennsylvania,PA, USA

(J A Chirinos MD);and

Philadelphia VA Medical Center,

PA, USA (J A Chirinos)

Correspondence to:

Dr Vicente F Corrales-Medina,

Department of Medicine,

University of Ottawa,

1053 Carling Avenue, CPC 470,

Ottawa, ON, K1Y 4E9, [email protected]

Search strategy and selection criteria

We searched Medline (from 1946 to May 15, 2012), Scopus

(from 1950 to May 15, 2012), and Embase (from 1947 to

May 15, 2012) databases, using detailed search strategies

(appendix). We developed search methods to capture clinical

and experimental evidence of cardiac complications in patients

with pneumonia, and the effects of pneumonia on the human

cardiovascular system, the consequences of commonly used

cardiovascular drugs on the outcomes of patients withpneumonia, and the effects of available antibiotics on the

cardiovascular system. Only articles in English, Spanish, Russian,

German, French, and Chinese were included. Articles in

languages other than English were translated by medical

doctors proficient in those languages. Then, relevant articles

were reviewed in their entirety and discussed by the

investigators to establish their relevance to this Review.When

appropriate, we preferred to cite comprehensive reviews of the

literature rather than many individual reports. Similarly, our

Review focuses on conceptual syntheses of data, rather than

detailed descriptions of original research.

See Online for appendix


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www.thelancet.com Vol 381 February 9, 2013 497

since the early 20th century, the magnitue of this problemhas only recently begun to be appreciate fully.19 A meta-analysis of 25 stuies reporting the incience of cariacevents within 30 ays of pneumonia iagnosis reportecumulative rates of new or worsening heart failure (14%,

range 733%), new or worsening arrhythmias (5%, range111%), an the acute coronary synromes myocarialinfarction or unstable angina (5%, range 111%) in patientsamitte to hospital with pneumonia.20 Most stuies,however, i not use clear efinitions for the outcomesinvestigate, relie on retrospective chart review for theirascertainment, or were restricte to high-risk populations(eg, veterans, patients with iabetes, an elerly patients).In their 2012 analysis of a prospective multicentre cohortof 2344 unselecte patients with community-acquirepneumonia (1343 inpatients an 944 outpatients), Corrales-Meina an colleagues reporte the 30-ay incience ofwell-efine cariac complications.9 In this cohort, new orworsening heart failure, new or worsening arrhythmias,

an myocarial infarction occurre in, respectively, 21%,10%, an 3% of inpatients, an 14%, 10%, an 01% ofoutpatients. Overall, cariac complications (efine as anyof the aforementione events) occurre in 27% of in-patients an 2% of outpatients.9 Cariac arrest occursin up to 3% of patients amitte to hospital withcommunity-acquire pneumonia.21

The occurrence of two or more types of cariac event ina patient with pneumonia is not uncommon an hasbeen reporte in 2040% of patients who evelop cariaccomplications.9,19 In this setting, the recognition ofmyocarial infarction is usually precee by the iagnosisof other cariac events (69% of patients). 9 Conversely,

new or worsening heart failure an arrhythmias are thefirst recognise, or only, pneumonia-associate cariacevent in most cases (85% an 69%, respectively).9

Risk for cariac complications is higher in the first feways after a pneumonia iagnosis, with about 90% of

these events recognise within 7 ays of iagnosis, anmore than half ientifie within the first 24 h (figure 1).9,22Risk factors for cariac complications inclue oler age(about 86% of cariac complications occur in peopleage 60 years), nursing home resience, pre-existingcariovascular isease, an greater severity of pneumoniaat presentation.9,22,23 Nonetheless, about a thir ofpneumonia-associate cariac complications occur inpatients with no history of clinical cariac isease, aquarter of cases are in patients consiere to be at low riskon the basis of their pneumonia severity inex score, anabout three-quarters of cases arise in patients thought notto nee intensive care after their first assessment.9,19,21,24

Cariac complications have an important effect on the

clinical course of patients with pneumonia. In patientsamitte to hospital with pneumonia who experienceclinical failure to treatment, about a thir o so because ofcariac complications.25 Diagnostic criteria for myocarialinfarction are present in as many as 50% of patients withpneumonia who nee intensive care unit treatmentwithin 24 h of amission to hospital. 23 Cariac compli-cations are also the irect or unerlying cause of eath in27% of pneumonia-associate eaths.26 Death within30 ays of pneumonia iagnosis is five times morecommon in patients who evelop cariac complicationsthan in those who o not.9 Even after ajustment forbaseline risk, cariac complications are associate with a

Figure 1: Timing of cardiac complications in patients with community-acquired pneumonia

Cardiac complications included any of the following cardiac events: new or worsening heart failure, new or worsening arrhythmias, or myocardial infarction. Data

from the Pneumonia Patient Outcomes Research Team cohort study. Adapted from Corrales-Medina et al,9 with permission of Wolters Kluwer Health.

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 300

5

10

15

20

25

30

35

40

45

50

55

Patientswithcardiaccomplications(%;n=377)

Day of cardiac complications relative to day of pneumonia diagnosis


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60% increase in pneumonia-associate short-termmortality,9 an lea to one in four reamissions afterhospitalisation for pneumonia.27

Effects of pneumonia on the cardiovascularsystemThe present unerstaning of the human cariovascularresponse to infections, incluing pneumonia, is erivemainly from stuies of critically ill patients with septicshock. This isorer is characterise by inability of the

peripheral vasculature to constrict espite increaseconcentrations of catecholamines an increase activityof the reninangiotensinalosterone system;28 myo-carial systolic an iastolic ysfunction, mainly of theleft ventricle, with some myocarial injury manifeste byincrease serum troponin concentrations in the absenceof recognisable acute coronary synromes;29,30 cariacautonomic ysfunction;31 substantial changes in haemo-stasis, mainly riven by activation of the extrinsiccoagulation pathway an suppression of fibrinolysis;32impairment of the haemostatic functions of the vascularenothelium;28,29 an renal ysfunction, which pre-sumably arises from many of the preceing processes orother primary insults to the kineys.33 Comprehensive

iscussions about the cariovascular system in septicshock are publishe elsewhere an are not the focus ofthis Review.28,29,33 Although septic shock occurs in aminority of patients with pneumonia (complicating theisease in about 4% of those requiring hospitalamission),34 in this Review we will concentrate onevience from stuies of patients with pneumonia whoare not necessarily critically ill. The table presents asummary of this evience.

Vascular endothelium and peripheral vesselsPatients with pneumonia have transiently raise serumconcentrations of enothelin-1, an enothelium-specific

vasoconstricting peptie.40 Circulating concentrations ofenothelin-1 at hospital amission are associate withseverity an prognosis of pneumonia, a fining alsoreporte for arenomeullin, another peptie prouceby enothelial cells but with vasoilatory effects.41Transientisturbances of vascular responses to restoration of blooflow (ie, reactive hyperaemia) an to nitric oxie uringthe acute phase of pneumonia also suggest some vascularysfunction associate with this infection.35

A ecrease in peripheral vascular resistance is thenorm uring the acute phase of pneumonia in youngan mile-age people.3639 However, increase peri-pheral vascular resistance only partly responsive tovolume expansion can occur in up to a thir of mile-age patients.37,38 This fining suggests that vasoactiveresponses leaing to increase cariac afterloa (ie,

increase peripheral vascular resistance) can also presentin elerly iniviuals with pneumonia, which is poten-tially counterprouctive in patients with chronicimpairment of myocarial function.6 Further stuies areneee to characterise the systemic vascular response toacute pneumonia in elerly patients.

MyocardiumA transient ecrease in left ventricular function occurs inup to a thir of mile-age people with pneumonia, evenwithout a history of cariac, renal, hepatic, or chronicpulmonary iseases, an has also been escribe in young,otherwise healthy, populations.37,38,42 Serum concentrationsof B-type natriuretic peptie an atrial natriuretic peptie

increase uring the acute phase of pneumonia, an themagnitue of this increase is associate with the severityan outcome of the infection.4446 The extent to which leftventricular ysfunction uring pneumonia is seconary toirect epressant effects of circulating inflammatorymeiators (ie, cytokines, enotoxins, or both), with orwithout vascular responses affecting cariac afterloa orpreloa, is unclear. Increase resistive afterloa occurs insome patients with pneumonia,37,38 whereas pulsatileafterloa, which can change unfavourably in response toother acute inflammatory stimuli an is highly relevant forventriculararterial interactions,6668 has not been assessein this setting.

Increase serum troponin concentrations without

recognisable acute coronary synromes are also wellescribe across the range of pneumonia severity.47Whether these raise concentrations represent amanifestation of otherwise unrecognise myocarialinfarctions or non-ischaemic myocarial injury is un-known. Myocarial ischaemia can result from coronaryocclusion, focal spasm, severe iffuse microvascularysfunction, or hypoxaemia, with or without increasemetabolic emans in patients with pre-existing coronarystenosis.11 However, the low incience of clinically apparentmyocarial ischaemic events compare with that of heartfailure in patients with pneumonia suggests that non-ischaemic mechanisms (ie, loa changes, neurohormonal

Effect of pneumonia

Vascular endothelium and

peripheral vessels

Impaired reactive hyperaemia response and response to nitric oxide;35

decreased peripheral vascular resistance in most young adults, butincreased peripheral vascular resistance in up to a third of middle-agedadults (no data available for elderly patients);3639 increasedconcentrations of endothelin-1 and adrenomedullin40,41

Myocardium Depression of left ventricular function;37,38,42 myocarditis;43 increased

concentrations of troponins, BNP, and ANP4447

Cardiac rhythm Acute cardiac arrhythmias20,48,49

Coronary arteries Possible acute inflammatory changes in atherosclerotic plaques;5052

possible coronary vasoconstriction53

Pulmonary circulation Increased pulmonary artery pressures54

Cardiac autonomic function Impairment of cardiovascular autonomic reflexes55

Coagulation Increased procoagulant activity5658

Renal function and fluid and

sodium balance

Increased production of vasopressin;41,59,60 decreased ACE activity;6163

water retention;59 acute kidney injury64,65

BNP=B-type natriuretic peptide. ANP=atrial natriuretic peptide. ACE=angiotensin-converting enzyme.

Table: Effects of pneumonia on the cardiovascular system


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hyperactivity, or non-ischaemic myocarial injury) aremore often the cause.9

Non-ischaemic myocarial injury can result from acutemyocaritis. Many agents that cause pneumonia alsocause myocaritismainly viruses such as influenzavirus, respiratory syncytial virus, aenovirus, an entero-viruses, but also bacteria incluing Mycoplasma

pneumoniae, Chlamydophila pneumoniae, Staphylococcusaureus, pneumococcus, an Legionella spphave alsobeen implicate.6973 Stuies using PCR-base iagnostictests suggest a viral cause in about a thir of aults withcommunity-acquire pneumonia.69 A etaile autopsystuy of 67 patients with lobar pneumonia showe patho-logical evience of myocaritis in 39% of patients.43

Because of the iffi culties in the non-invasive iagnosisof myocarial inflammation, the precise incience of

myocaritis in non-fatal pneumonia is unknown.Techniques such as T2-weighte an post-gaoliniumelaye-enhancement cariac MRI, however, arepromising for non-invasive iagnosis.74

Cardiac rhythmNew or worsening cariac arrhythmias, especially atrialfibrillation, are well-characterise complications of acutepneumonia.20 The fact that acute pneumonia can cause awie range of acute changes in the surface electro-cariogram of patients has also long been recognise.48,49Whether these changes result mainly from a irect effectof pneumonia on the cariac conuction system, con-comitant myocarial isorers such as ischaemia or

myocaritis, or pericarial involvement by pneumonia-proucing organisms is unknown.

Coronary arteriesAnimal moels have shown that C pneumoniae can initiatean accelerate atherosclerosis in mice.75 This organism hasalso been ientifie in atherosclerotic plaques of humanbeings, but no causal association has been shown.75 Acomprehensive iscussion of the possible role ofC pneumoniae in the pathogenesis of human atherosclerosisis beyon the scope of this Review an can be founelsewhere.75 However, the possibility that C pneumoniaecan trigger acute coronary synromes in the short termafter causing pneumonia has not yet been investigate.

Stuies of apolipoprotein E-eficient mice have shownthat influenza can promote acute inflammation, smoothmuscle cell proliferation, an fibrin eposition inatherosclerotic plaques of these animals.50,51 A small post-mortem stuy of patients with sepsis of various causessuggeste increase inflammatory infiltrates in theircoronary atherosclerotic plaques an aventitia comparewith patients ying from non-infectious causes.52 On thebasis of these results, investigators have propose thatacute infections can affect the stability of coronaryatherosclerotic plaques in human beings.11 Animalsinfecte with C pneumoniae an influenza virus showincrease coronary vasoconstricting responses.53

Pulmonary circulationHypoxaemia, the consoliate lung parenchyma, an theaaptive local regulatory mechanisms to reucepulmonary ventilationperfusion mismatches (ie, shunts)can affect resistance to bloo flow through the pulmonaryvasculature in patients with acute pneumonia.76 Stuiesof young an mile-age patients have shown thatpneumonia can increase pulmonary artery pressuresproportional to the egree of ventilatory restriction anhypoxaemia.54

Cardiac autonomic functionElerly patients with acute pneumonia show transientimpairments of their cariovascular autonomic reflexes,as shown by a reuce heart rate response to the Valsalvamanoeuvre, a more pronounce fall of systolic bloo

pressure on staning, an impaire rise in iastolicbloo pressure on sustaine han grip.55

CoagulationAlmost 90% of patients who are amitte to hospital forpneumonia have increase coagulation activation, asmanifeste by at least one of the following: increaseantithrombin activity, ecrease factor IX activity,increase thrombinantithrombin complex concen-trations, increase d-imer concentrations, or increaseplasminogen activator inhibitor concentrations.56Patients with acute coronary synromes complicate bypneumonia have higher platelet-aggregating activity annon-responsiveness to aspirin than o patients with

acute coronary synromes not complicate by theinfection, suggesting that acute pneumonia also resultsin pro-aggregant platelet ysfunction.77 When plasmafrom patients with pneumonia is injecte into mice, theplasma inuces lethal thrombosis-inucing activity,which has also been escribe in patients with avancelung cancer.57,58 This effect, however, isappears if plasmais taken from patients after treatment for pneumonia. 57

The enothelial ysfunction of pneumonia probably alsoencompasses impairment of enothelial anti-coagulantproperties, contributing further to a pro-coagulant state.78

Renal function and fluid and sodium balancePneumonia is a well-recognise cause of the synrome

of inappropriate antiiuretic hormone secretion.79

Pneumonia-inuce increases in serum vasopressinwith impairment of renal water excretion occur even ineuvolaemic patients with normal plasma soiumconcentrations in the absence of recognise clinicalcariac, liver, renal, or chronic lung isease.59 Bothextreme hyponatraemia an amounts of copeptin onamission to hospital (copeptin is the C-terminalfragment of the vasopressin precursor, which inicatesvasopressin prouction) are strong preictors of iseaseseverity an mortality in patients with community-acquire pneumonia.41,60,80 The lungs are a major site forexpression of angiotensin-converting enzyme (ACE).61,81


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During pneumonia, serum ACE activity decreasestransiently, but the extent of change does not seem topredict high disease severity or poor outcomes, evenwith consideration of the variance associated with thegenetic ACE insertion/deletion polymorphism.6163 Thespecific activity of aldosterone during acute pneumonia,however, has not been characterised. Acute kidneyinjury develops in as many as 34% of patients withpneumonia during their hospital stay, and is associated

with high short-term mortality.64

Although sodium andwater retention from renal dysfunction probablycontribute to new or worsening heart failure in somepatients with pneumonia, this possibility has not yetbeen investigated.

Integrated mechanistic model for cardiaccomplications in patients with pneumoniaIntroductionOn the basis of present knowledge already discussed, thefollowing pathophysiological model for cardiaccomplications in patients with pneumonia can beproposed (figure 2).

New or worsening heart failureSeveral mechanisms can contribute to myocardialdysfunction in patients with pneumonia. Circulatinginflammatory mediators (ie, cytokines and/or endo-toxins) or direct infection of cardiomyocytes withpneumonia-causing organisms, or both these mechan-isms, can lead to non-ischaemic myocardial injury.Acute myocardial ischaemia secondary to acute coronarysyndromes or demand ischaemia can also occur.

Transient disturbances of endothelial function andvascular tone, driven by the systemic response toinfection, can increase left ventricular afterload byincreasing the peripheral microvascular resistance (ie,systemic vascular resistance) or the pulse wavereflections from medium and large arteries (thepulsatile component of left ventricular afterload). Thesystemic inflammatory response to pneumonia can alsoresult in acute kidney injury and impaired sodium andwater metabolism, leading to volume overload. Thiseffect can be exacerbated by the administration ofantibiotics or other drugs with high sodium content orlarge infusion volumes. Patients with impaired cardiac

Figure 2: Proposed pathophysiological mechanisms contributing to cardiac complications in patients with acute pneumonia

VQ=ventilationperfusion mismatch. SVR=systemic vascular resistance. Image of heart and lungs at the bottom of the figure reproduced with permission from

Peter Gardiner at clinicalskills.net.

Pneumonia

Endothelialdysfunction

Pulsatileventricular

afterloadSVR

Impaired gas exchange

VQ

mismatch

Impaired electrolyteand water metabolism;

acute kidney injury

Non-ischaemicmyocardial/pericardial injury

Myocardial

ischaemia/infarction

Arrhythmia

Coronaryvasoconstriction

Heart failure

Bacterial/viral infection ofmyocardium/pericardium

Systemic inflammatory

response

Volume overload

Arrhythmogenic drugs

Sympathetic activation

Hypoxaemia

Procoagulant state

Plaque instability and rupture

Intravenoussodium

administration


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function at baseline are especially sensitive to theseeffects. Cariac arrhythmias can also trigger new orworsening heart failure by interfering with the effectivesynchronisation of the cariac cycle an the coorinatecontraction of cariomyocytes.

Myocardial ischaemia or infarctionPneumonia results in impaire gas exchange across thealveoli of inflame lung parenchyma an ventilationperfusion mismatching, which can lea to hypoxaemia.The systemic response to pneumonia also increasessympathetic activity, causing sinus tachycaria. Anincrease heart rate not only increases myocarial oxygenrequirements but also shortens the iastolic perio,uring which coronary perfusion occurs. The net resultis a ecrease in the ratio of myocarial metabolic supply

to eman, which can lea to eman ischaemia,especially in the presence of pre-existing coronary arteryisease. The metabolic consequences of cariactachyarrhythmias an the compensatory sympathetichyperactivity of heart failure can contribute to this effect.The systemic inflammatory response to pneumonia canalso increase the inflammatory activity within coronaryatherosclerotic plaques, making them unstable anprone to rupture. This same pneumonia-riven systemicinflammatory response causes enothelial ysfunctionan increases the procoagulant activity of the bloo,which can contribute to the formation of an occlusivethrombus over a rupture coronary plaque. Enothelialysfunction can also change the coronary vascular tone

(ie, vasoconstriction), contributing further to myocarialischaemia an infarction.

New or worsening cardiac arrhythmiasIn patients with pneumonia, new or worsening cariacarrhythmias can result from myocarial or pericarialinjury, or both, from ischaemic (acute coronary syn-romes, eman ischaemia, or both) an non-ischaemiccauses (irect bacterial or viral infection with or withoutsystemic inflammatory mechanisms). Cariac arrhyth-mias can also result from strain-inuce changes in theelectrical properties of cariomyocytes an the compen-satory sympathetic hyperactivity recore in heart failure.Some antibiotics, such as macrolies an fluoroquino-

lones, also have arrhythmogenic potential (see later).

Effects of commonly used cardiovascular drugson the course of pneumoniaAspirinIn a large retrospective cohort stuy (n=1007) ofunselecte patients with pneumonia amitte to hospital,investigators reporte a non-statistically significant 37%reuction in short-term mortality in those patients usingaspirin,82 whereas in a smaller (n=127) stuy of elerlypatients with severe community-acquire pneumonia,the investigators showe a significant association betweenuse of antiplatelet rugs (84% low-ose aspirin) an

reuce nee for intensive care an shorter hospitalstays.83 Only one prospective, bline controlle stuy hasassesse the effect of aspirin in patients with pneumo-coccal pneumonia.84 However, this stuy was toounerpowere to show any meaningful ifference in itsrelatively young population (67 patients, 54% of whomwere


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Beta-blockersA large observational cohort stuy showe that previoususe of beta-blockers was associate with increase 30-aymortality an nee for mechanical ventilation in patientswith community-acquire pneumonia.82 Ranomisetrials of the effect of beta-blockers on the incience ofcariac complications in patients with pneumonia arenot available.

Diuretics, calcium channel blockers, and othervasodilatorsNo stuies have reporte on the effect of iuretics,calcium channel blockers, or other vasoilators on theoutcomes of patients with pneumonia.

Cardiovascular effects of common antibiotics

Intravenous formulations of some beta-lactam antibioticscontain substantial amounts of soium an nee frequentosing, which might be a relevant consieration inpatients with pre-existing heart failure. Typical regimensof aqueous benzylpenicillin (5 million units intravenouslyevery 6 h) or piperacillintazobactam (3375 g intra-venously every 6 h), for example, can provie aily soiumloas equivalent to 13 g an 08 g, respectively; however,when soium from the normal saline use for infusion ofthese rugs is consiere, aily soium loas can be ashigh as 33 g an 14 g, respectively. Macrolies have anti-inflammatory activity, an a beneficial reuction ofinflammation-riven effects of pneumonia on thecariovascular system has been hypothesise.85 However,

macrolies can also inuce QT prolongation an, rarely,polymorphic ventricular tachyarrhythmia (ie, torsaes epointes)an effect also attribute to fluoroquinolones.97 Alarge retrospective stuy suggeste that, when comparewith patients taking amoxicillin, patients receivingazithromycin have a small but statistically significantincrease in their short-term risk of cariovascular eath(47 aitional events per 1 million courses of azithromycintreatment), especially in patients with high baselinecariovascular risk.97 A similar tren was also note forlevofloxacin, but was not statistically significant in thisanalysis.97 Vancomycin, when infuse rapily, inucesantigenantiboy-inepenent release of histamine frommast cells an basophils, causing peripheral vasoilation

that results in pruritus an an erythematous rash over theface, neck, upper chest, an arms (re man synrome)an, occasionally, severe hypotension.98 This reaction canbe mostly prevente with longer infusion times (1 h)an, if neee, prophylactic aministration of anti-histamines.98,99 Although experimental stuies havesuggeste potential cariovascular actions of several otherantibiotics, these finings have not translate intoclinically meaningful effects.100

Implications for clinical practiceClinicians an public health offi cials shoul optimiserates of influenzal an pneumococcal vaccination,

especially in elerly patients an iniviuals with chroniccariac isorers. Because more than 50% of cariaccomplications are recognise at or within 24 h ofpresentation with acute pneumonia, a thorough investi-gation for the presence of cariac complications shoul bepart of the initial assessment of patients presenting withthis infection. Clinicians shoul specifically investigatepre-existing cariovascular isease an symptoms orsigns of ecompensate heart failure, cariac arrhythmias,an acute coronary synromes. A 12-lea electrocariogramshoul be consiere seriously, both for the assessment ofprevalent abnormalities an for comparison purposes, incase cariac complications are suspecte later. Measure-ment of serum B-type natriuretic peptie concentrationscan be consiere when the presence of new or worseningheart failure cannot be establishe on clinical grouns

alone. Further cariac testing (ie, echocariogram, ormeasurement of serum cariac troponin concentrations)shoul be guie by clinical suspicion, an is notrecommene routinely or as a screening tool to etectearly subclinical abnormalities in this setting. Specialattention shoul be pai to patients with clustering of riskfactors for cariac complications. These investigationsshoul complement assessment of pneumonia severity(using valiate methos such as the pneumonia severityinex or CURB-65 scores), as recommene by existingguielines, in site-of-care ecisions for these patients(inpatient vs outpatient, an general meical war vsintensive care unit).1,7 In patients with prolonge QTcinterval, alternative antibiotic regimens that o not inclue

macrolies or fluoroquinolones shoul be consiere,especially when pharmacokinetic or pharmacoynamicinteractions with other meications known to prolong theQT interval (class Ia an class III antiarrhythmics,cisaprie, antipsychotics, an tricyclic antiepressants)are likely, or when uncorrecte hypokalaemia or hypo-magnesaemia is present. In hospital inpatients, ailyclinical assessment of cariovascular status, incluingweight measurement an careful assessment of fluibalance, shoul be one. In patients with signs of volumeoverloa, especially in those with a history of pre-existingheart failure, antibiotic alternatives with low soiumcontents an infusion volumes shoul be chosen. In viewof the high incience of cariac complications in patients

amitte to hospital with pneumonia, a high inex ofsuspicion for these events shoul be applie, especially forpatients with a suboptimal clinical response. In patientswho evelop cariac complications, the investigation anmanagement of these events shoul follow stanarclinical practice an proceures, but shoul also beinforme by the pathophysiological consierations is-cusse earlier (figure 2). For example, physicians shoulbe aware that increase serum concentrations of cariactroponins without recognisable acute coronary synromeare not infrequent in the setting of pneumonia. At hospitalischarge, the patients immunisation status againstinfluenza an pneumococcus, cariovascular risk profile,


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an cariovascular meications shoul be reviewe anupate as appropriate.

Areas for future researchThe panel lists some suggeste goals for futureresearch. Previous investigations have focuse mainlyon characterisation of pneumonia-associate temporalchanges in istinct elements of the cariovascularsystem (ie, left ventricular function, peripheral vascularresistance, neuroenocrine system, an water ansoium balance) without consieration of potentialinteractions between them or their role in triggeringcariac complications in patients with this infection;therefore, more integrative mechanistic stuies areneee. For example, although several pathophysio-logical processes might lea to new or worsening heart

failure in patients with pneumonia (figure 2), istinc-tion between non-ischaemic myocarial injury, meta-bolic supplyeman mismatch, changes in ventricularafterloa, excessive neurohormonal activation, or acombination of these factors as the main mechanismriving the evelopment of this complication will be ofgreat importance in the esign of strategies to preventits occurrence. This rationale also applies to otherpneumonia-associate cariac complications. Becausemost pneumonia-associate cariac complicationsoccur in non-critically ill an elerly patients, thesemechanistic stuies shoul inclue these populations.Future investigations shoul also improve our ability torisk stratify patients with pneumonia for the occurrence

of cariac complications with the evelopment ofvaliate preiction algorithms, which shoul beapplicable in research an clinical settings. This newinformation shoul guie interventions aime atprevention of pneumonia-associate cariac compli-cations in high-risk groups, while characterising theireffect on all-cause morbiity, mortality, health-careutilisation, an cost. Finally, methos to promote thesynthesis an issemination of this knowlege in amanner that translates effectively into positive changesin clinical practice are also essential.

ConclusionsPneumonia is usually consiere to be an acute process

confine to the lungs, unless the isease is complicateby severe sepsis. However, pneumonia affects essentialparts of the cariovascular system, which is probablyresponsible for the substantial buren of acute cariaccomplications that has been ocumente thoroughly inlarge cohorts. In view of the high incience of cariaccomplications in patients with pneumonia an theeffect on mortality, the possibility of improving theoutcomes of these patients by prevention, earlyetection, an early treatment of these events shoul bepursue. However, before targete interventions can beesigne an teste aequately, a better unerstaningof the mechanistic pathways unerlying this association

is neee. Meanwhile, awareness of this associationshoul inform clinical practice in the provision of carefor patients with pneumonia.

Contributors

VFC-M, DMM, an JAC were responsible for conception of the Review.VFC-M an JAC esigne the search strategies an initially screene thecitations ientifie by the literature search. VFC-M, DMM, SS, an JACcritically reviewe an interprete the selecte literature. VFC-M wrote theinitial raft. VFC-M, DMM, SS, an JAC critically reviewe an eite the

manuscript. All authors take responsibility for the integrity of the work.Conflicts of interest

We eclare that we have no conflicts of interest.

Acknowledgments

We thank Alexanra Davis, librarian at The Ottawa Hospital, for herassistance in the esign of our search strategies an the retrieval ofselecte articles. We also acknowlege Yoko S Schreiber anBing Wang, from the Division of Infectious Diseases at the Universityof Ottawa, for their assistance with the translation of articles in French,German, an Chinese; an Wahee Raja an Zubair A Khan, from theDivisions of Internal Meicine at Texas Tech University HealthSciences Center an Cooper University Hospital, respectively, for theirhelpful assistance uring the literature search process. VFC-M issupporte by a Research Priority Grant from the Department ofMeicine of The Ottawa Hospital, an a Junior Investigator Awar ofthe Ottawa Hospital Research Institute.

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Panel: Suggested goals for future research

To characterise the role of changes in preload, afterload (resistive and pulsatile),

pulmonary vasculature, myocardial ischaemia, myocardial inflammation, and

disturbances of the water and sodium balance in the development of heart failure in

patients with pneumonia

To characterise the role of coronary thrombosis, focal spasm, diffuse microvascular

dysfunction, acute hypoxaemia, or increased myocardial metabolic demands, or a

combination of these factors, in the development of acute cardiac ischaemic events in

patients with pneumonia

To characterise the mechanisms responsible for the development of clinically

significant cardiac arrhythmias in patients with pneumonia

To characterise the cardiovascular effects of pneumonia in non-critically ill

elderly patients

To develop suitable prediction tools to identify pneumonia patients at high risk of

cardiac complications, for use in clinical practice and research

To test mechanistically informed interventions to prevent the development andprogression of cardiac complications in high-risk patients with pneumonia and

characterise the effect of these strategies on pneumonia-associated morbidity,

mortality, health-care utilisation, and costs


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