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Νεφροπάθεια απο Σκιαγραφικά (Contrast induced Nephropathy - CIN) Οξεια Νεφρική Βλάβη απο Σκιαγραφικά (Contrast induced Αcute Kidney Injury – CI-AKI 37o Πανελλήνιο Καρδιολογικό Συνέδριο Ελληνική Καρδιολογική Εταιρεία Αθήνα 20-22 Οκτωβρίου 2016 Βλάσιος Ν. Πυργάκης MD FESC FACC Συντ/στής Διευθυντής Καρδιολογική Κλινική Γ . Ν. Αθηνών «Γ . ΓΕΝΝΗΜΑΤΑΣ» 1

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Νεφροπάθεια απο Σκιαγραφικά (Contrast induced Nephropathy - CIN)

Οξεια Νεφρική Βλάβη απο Σκιαγραφικά (Contrast induced Αcute Kidney Injury – CI-AKI)

37o Πανελλήνιο Καρδιολογικό Συνέδριο Ελληνική Καρδιολογική Εταιρεία

Αθήνα 20-22 Οκτωβρίου 2016

Βλάσιος Ν. Πυργάκης MD FESC FACC

Συντ/στής Διευθυντής Καρδιολογική Κλινική

Γ. Ν. Αθηνών «Γ. ΓΕΝΝΗΜΑΤΑΣ»

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✓ first description , as “ ischuria renalis” by William Heberden in 1802

✓ “Acute Bright’s disease” in William Osler’s Textbook for Medicine (1909)

✓ “war nephritis” during the First World War ✓ “acute renal failure (ARF) ” by Homer W. Smith in his

textbook “The kidney-structure and function in health and disease” (1951)

Eknoyan G. Emergence of the concept of acute renal failure. Am J Nephrol 2002; 22: 225–230. Davies F, Weldon R. A contribution to the study of ‘‘war nephritis’’. Lancet 1917; ii: 118–120. Bywaters EGL, Beall D. Crush injuries with impairment of renal function. BMJ 1947; 1: 427–432

the syndrome of (potentially reversible) rapid worsening of renal excretory function

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✓no consensus on the diagnostic criteria (biochemical or clinical)

✓> 35 different definitions in the literature

confusion, wide variation in reported incidence

Kellum JA, Levin N, Bouman C, et al. Developing a consensus classification system for acute renal failure. Curr Opin Crit Care 2002; 8: 509–514.

need for a uniform definition

ARF

Acute Kidney Injury (AKI)

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the new consensus term for Acute Renal Failure (ARF)

RIFLE criteria for diagnosis of AKI

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SCr &

Bellomo R, Ronco C, Kellum JA, et al. Acute renal failure - definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care 2004; 8: R204–212

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Mehta RL, Kellum JA et al. Acute Kidney Injury Network: report of an initiative to improve outcomes in acute kidney injury. Crit Care 2007; 11: R31.

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KDIGO criteria mixing of the RIFLE and AKIN criteria

AKI Definition

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Staging of AKI

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Conceptual model for AKI

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Murray PT, Devarajan P, Levey AS, et al. A framework and key research questions in AKI diagnosis and staging in different environments. Clin J Am Soc Nephrol 2008; 3: 864–868

stage 1 stage 2 stage 3

the term AKI encompasses the entire spectrum of the syndrome of acute worsening of renal function, from subclinical renal injury to severe Kidney failure

pathophysiology of AKI (mechanism via which AKI increases risk of death)

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Ratliff BB, Rabadi MM, Vasko R, Yasuda K, Goligorsky MS: Messengers without borders: mediators of systemic inflammatory response in AKI. J Am Soc Nephrol 24: 529–536, 2013 Grams ME, Rabb H: The distant organ effects of AKI. Kidney Int 81: 942–948, 2012

“AKI is a paradigm of a localized damage triggering systemic inflammatory disease,” when that inflammatory response is severe or prolonged, it may involve other organs (heart, lungs, and liver)

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complications of AKI

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AKI affects short and long term prognosis

Bihorac A, Brennan M, Ozrazgat-Baslanti T, et al. National surgical quality improvement program underestimates the risk associated with mild and moderate postoperative acute kidney injury. Crit Care Med. 2013;41(11):2570-2583.

27.841 adults undergoing major surgery

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Contrast induced Nephropathy (CIN) or Contrast-induced AKI (CI-AKI)

definition

an iatrogenic ΑΚΙ that follows intravascular administration of radio-opaque contrast media (CM) in susceptible individuals

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CI-AKI

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CI-AKI

➢ the diagnosis and staging of CI-AKI should be based on KDIGO Recommendations

DIAGNOSIS

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CI-AKI

time course

SCr

✓ increases within 24-48 hrs after contrast administration ✓ peaks at 3 to 5 days ✓ returns to baseline in 1-3 weeks

18 PATHOPHYSIOLOGY

Intravascular CM

✓ concentrated tri-iodinated benzene compounds that are radio-opaque as a result of their associated iodine moieties

✓ all CM agents are cytotoxic this may be compounded by the

ionic strength osmolality viscosity of each specific agent

CI-AKI

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CI-AKI

PATHOPHYSIOLOGY

higher osmolality (greater particle concentration in solution)

vascular symptoms of warmth and pain during injection incidence of CI-AKI

Rear R, et al. Heart 2016;0:1–11

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CI-AKI

PATHOPHYSIOLOGY

Rear R, et al. Heart 2016;0:1–11

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pathogenesis of CI-AKI from the point of injection into the coronary arteries, iodinated CM triggers a series of hemodynamic responses and direct cellular injury as it reaches the kidneys

Brown JR, McCullough PA. Contrast nephropathy and kidney injury. In: Thompson CA, editor. Textbook of Cardiovascular Intervention. London, UK: Springer-Verlag, 2014:53–63.

epidemiology of CI-AKI

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✓ first described in 1950s (fatal ARF following iv pyelography in patients with renal disease arising from multiple myeloma)

✓ the 3rd most common cause of hospital-acquired AKI (decreased renal perfusion(1st) and nephrotoxic medications(2nd)

11% of cases

✓ affects 1% - 2% of the general population

Hou SH, Bushinsky DA, Wish JB, et al. Hospital-acquired renal insufficiency: a prospective study. Am J Med 1983;74:243–8. Nash K, Hafeez A, Hou S. Hospital-acquired renal insufficiency. Am J Kidney Dis 2002;39:930–6. Mehran R, Nikolsky E. Contrast-induced nephropathy: definition, epidemiology, and patients at risk. Kidney Int Suppl 2006: S11–15.

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epidemiology of CI-AKI

✓ in patients with normal renal function : low (1–2%) ✓ in patients with “risk factors for AKI” : very high

Rudnick MR, Goldfarb S, Tumlin J. Contrast-induced nephropathy: is the picture any clearer? Clin J Am Soc Nephrol 2008; 3: 261–262

risk for CI-AKI

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Risk factors for CI - AKI

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Risk factors for CI - AKI

➢ all patients who are considered for a procedure that requires intravascular administration of iodinated CM should be assessed for the risk of CI-AKI (Not Graded)

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risk assesment of CI-AKI

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Characteristics of predictive models for CI-AKI

Mehran R, Aymong ED, Nikolsky E et al. A simple risk score for prediction of contrast-induced nephropathy after PCI: development and initial validation. J Am Coll Cardiol 2004; 44: 1393–1399

Mehran Risk score28

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CI-AKI

in high risk patients : ➢ a baseline sCr should be determined before the intervention - a repeat sCr is performed 12 and 72 h after administration of contrast media. (2D)

the change of SCr 12 h after contrast is the best predictor of CI-AKI (P> 0.001) (a 5% increase of SCr yields a 75% sensitivity and 72% specificity for early detection)

Ribichini F, Graziani M, Gambaro G, et al. Early creatinine shifts predict contrast-induced nephropathy and persistent renal damage after angiography. Am J Med 2010; 123: 755–763.

prevention of CI-AKI

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prevention of CI-AKI

in patients at increased risk for CI-AKI :

➢ Consider alternative imaging methods (Not Graded )

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prevention of CI-AKI

✓ The risk of CIN increases by 12% for each 100 mL of contrast used beyond the first 100 mL

in patients at increased risk for CI-AKI : ➢ Use the lowest possible dose of contrast medium (Not Graded ) (contrast volumes target : <4 mL/kg or V/CrCl <3.7:1)

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✓A single invasive approach (CA followed by ad hoc PCI)

if a second CM procedure is necessitated ✓ delay until adequate clearance of CM and recovery from any

renal injury has occurred, which may be up to 2 weeks or as long as is clinically acceptable

prevention of CI-AKI

volume of CM should be minimized

prevention of CI-AKI

may counteract intrarenal hemodynamic alterations and direct tubulotoxic effects caused by CM

mechanisms : ✓ suppression of vasopressin ✓ inhibition of the renin angiotensin axis ✓ increased synthesis of vasodilatory renal prostaglandins ✓ reduced cellular damage by dilution of the contrast medium ✓ may diminish increasd tubular fluid viscosity by radiocontrast media

hydration 34

prevention of CI-AKI

➢ I.V hydration with either isotonic NaCl or NaHCO3 solutions is recommended (1A )

➢ the oral use of fluids alone is not recommended (1C )

35 hydration

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Stacul F, van der Molen AJ, Reimer P, et al., Contrast Media Safety Committee of European Society of Urogenital R. Contrast induced nephropathy: updated ESUR contrast media safety committee guidelines. Eur Radiol 2011;21:2527–41.

prevention of CI-AKI

hydration

prevention of CI-AKI

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Zoungas S, Ninomiya T, Huxley R et al. Systematic review: sodium bicarbonate treatment regimens for the prevention of contrast-induced nephropathy. Ann Intern Med 2009; 151: 631–638

Bicarbonate vs. saline and risk of CI-AKI

prevention of CI-AKI

➢ use either iso-osmolar or low-osmolar, rather than high-osmolar iodinated contrast media (1B )

38 Selection of a Contrast Agent

prevention of CI-AKI

➢ the use of oral NAC, together with i.v. isotonic salines is recommended (2D )

N-acetylcysteine (NAC) NAC has a protective effect on CI-AKI when administered before the onset of renal insult

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prevention of CI-AKI

➢ We suggest not using theophylline to prevent CI-AKI (2C )

pre-interventional administration might be helpful BUT • possibility of cardiovascular side-effects • interactions with numerous drugs

Theophylline

Upton RA. Pharmacokinetic interactions between theophylline and other medication (Part II). Clin Pharmacokinet 1991; 20: 135–150. Upton RA. Pharmacokinetic interactions between theophylline and other medication (Part I). Clin Pharmacokinet 1991; 20: 66–80.

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prevention of CI-AKI

StatinsYoshida S, Kamihata H, Nakamura S, et al. Prevention of contrast-induced nephropathy by chronic pravastatin treatment in patients with CVD and renal insufficiency. J Cardiol 2009; 54: 192–198.

chronic pravastatin treatment is independently related to decreased risk of CI-AKI

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hemodialysis or hemofiltration

Reinecke H, Fobker M, Wellmann J, et al. A randomized controlled trial comparing hydration therapy to additional hemodialysis (IHD) or N-acetylcysteine for the prevention of contrast medium-induced nephropathy: the Dialysis-versus-Diuresis (DVD) Trial. Clin Res Cardiol 2007; 96: 130–139.

The frequency of CI-AKI from 48 to 72 hours after catheterization : • 6.1% in the fluids-only group • 15.9% with IHD • 5.3% in the NAC group (P. 0.008)

IHD, for the prevention of CI-AKI provided no any outcome benefit but showed evidence for probable harm

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prevention of CI-AKI

prevention of CI-AKI

➢ We suggest not using prophylactic intermittent hemodialysis (IHD) or hemofiltration (HF) for contrast-media removal in patients at increased risk for CI-AKI. (2C)

43 Effects of hemodialysis or hemofiltration

prevention of CI-AKI

• reduces the incidence ( - 38%) of AKI

➢ insulin therapy targeting plasma glucose 110–149 mg/dl is recommended (2C )

tight glycemic control

furosemide vs. control on all-cause mortality

Ho KM, Power BM. Benefits and risks of furosemide in AKI. Anaesthesia 2010; 65: 283–293

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prevention of CI-AKI

Diuretics in AKI

furosemide vs. control on need for RRT

Ho KM, Power BM. Benefits and risks of furosemide in AKI. Anaesthesia 2010; 65: 283–293

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prevention of CI-AKI

Diuretics in AKI

Diuretics in AKI

➢ to prevent AKI ➢ to treat AKI (except in the management of volume overload) (1B )

is not recommended

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prevention of CI-AKI

prevention of CI-AKI

Low-dose dopamine (1–3 m g/kg/min) to healthy individuals causes : ✓ renal vasodilation ✓ natriuresis ✓ increased GFR

because of these effects, it has been given as prophylaxis for AKI

48 Vasodilator therapy: dopamine

Effect of low-dose dopamine on mortality. Friedrich JO, Adhikari N, Herridge MS et al. Meta-analysis: low-dose dopamine increases urine output but does not prevent death. Ann Intern Med 2005; 142: 510–524

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Effect of low-dose dopamine on need for RRT. Friedrich JO, Adhikari N, et al. Meta-analysis: low-dose dopamine increases urine output but does not prevent renal dysfunction. Ann Intern Med 2005; 142: 510–524

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Vasodilator therapy: dopamine

➢ low-dose dopamine to prevent or treat AKI is not recommended (1A )

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prevention of CI-AKI

withdrawal of Nephrotoxic medications

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prevention of CI-AKI

withdrawal of Metformin

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prevention of CI-AKI

• risk of lactic acidosis • indicators for metformin-induced lactic acidosis :

arterial pH <7.35 blood lactate >5 mmol/L (45 mg/dL) detectable plasma metformin concentration

✓ metformin should be suspended before angiography or PCI, and resumed 48 hours later, subject to adequate renal function

prevention of CI-AKI- Future directions

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✓ Technology to minimize contrast quantity avoiding over injection accurately recording contrast volumes

✓ novel nontoxic radio-opaque contrast media (we are aware of no such new molecular entities in development)

✓Attempts to render iodine-based radiocontrast less toxic ( the use of cyclodextrin, makes contrast stay in the urinary space and less likely to penetrate the kidney tissue and cause damage)

✓ the development of cellular protectants

PA McCullough, JP Choi, GA Feghali, et al. J Am Coll Cardiol; 2016 Sep 27; 68 (13)1465-1473;

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New Biomarkers in the Early Diagnosis and Prognosis

none of the new biomarkers is available for routine clinical use

CI-AKI- Future directions

CI –AKI in patients with ACS

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CI-AKI

n= 954729 2009-11 1253 sites

The most important factors associated with increased rates of CI-AKI in pts undergoing PCI : ➢STEMI ➢cardiogenic shock ➢eGFR <30 ml/min/1.73 m2

Tsai TT, Patel UD, Chang TI, et al. Contemporary incidence, predictors, and outcomes of AKI in patients undergoing PCIs : insights from the NCDR Cath-PCI Registry. J Am Coll Cardiol Intv 2014;7: 1–9.

the risk of AKI is higher in the patients with the greatest need for urgent PCI

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epidemiology of CI-AKI

Tsai TT, Patel UD, Chang TI, et al. Contemporary incidence, predictors, and outcomes of acute kidney injury in patients undergoing PCI: insights from the NCDR Cath-PCI Registry. J Am Coll Cardiol Intv 2014;7: 1–9.

incidence of ACS-associated AKI

Narula A, Mehran R, Weisz G, et al. Contrast-induced acute kidney injury after primary percutaneous coronary intervention: results from the HORIZONS-AMI substudy. Eur Heart J 2014;35:1533–40.

incidence of CI-AKI in patients who underwent PPCI : 16%

the true incidence of AKI was underestimated in all these studies due to the exclusion of patients who died early, thus not allowing at least two consecutive daily sCr values to be collected

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AKI in Elderly Patients With Non-ST ACS

Anna Toso, Stefano de Servi, Mario Leoncini. Angiology 01/2015; 66(9)

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Association Between AKI and In-Hospital Mortality in pts undergoing PCI Judith Kooiman, Milan Seth, et al. Circ Cardiovasc Interv. 2015;8:e002212 (N=112687 PCIs)

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Association Between AKI and In-Hospital Mortality in Patients Undergoing PCI. Judith Kooiman, MSc; Milan Seth, MS; Brahmajee K. et al. Circ Cardiovasc Interv. 2015;8:e002212

mortality is proportionate to preprocedural AKI risk (calculated using the Cath-PCI National Cardiovascular Data Registry risk model : includes 8 variables: age, cardiogenic shock, previous congestive HF, peripheral vascular disease, chronic lung disease, eGFR, NYHA IV HF, and PCI status)

Association Between AKI and In-Hospital Mortality in Patients Undergoing PCI

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mortality at 30 days and 1- year after MI related AKI

Incidence and Mortality of Acute Kidney Injury after MI: A Comparison between KDIGO and RIFLE Criteria Fernando B. Rodrigues1, Rosana G. Bruetto2, Ulysses S. Torres2, Ana P. Otaviano3, Dirce M. T. Zanetta4., Emmanuel A. Burdmann PLoS ONE 8(7): e69998. doi:10.1371/journal.pone.0069998

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Re-infarction rate in ACS-related AKI

➢ 1 year 15.4% with AKI vs 7.0% without AKI (RR 2.05; 95% CI 1.61-2.61)

➢ 5 years (RR 1.75 )

Coca SG, Yusuf B, Shlipak MG, et al. Long-term risk of mortality and other adverse outcomes after acute kidney injury: a systematic review and meta-analysis. Am J Kidney Dis 2009; 53: 961-973.

MIMI+ AKI

AKI

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Patient outcomes, by diagnostic group

(6th year)

“an AKI exposure is potentially worse for an individual than is a STEMI exposure”

CI -AKI

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Amin AP, Salisbury AC, McCullough PA, et al. Trends in the incidence of acute kidney injury in patients hospitalized with acute myocardial infarction. Arch Intern Med 2012;172:246–53

in 33249 patients hospitalized with AMI

the rate of AKI (KDIGO definition) in AMI pts 26.6% in 2000 19.7% in 2008 (26% reduction)

still formidable

AKI

Calculating the cost. Interview with Marion Kerr. Health Service J 2011; 3(suppl 1).

the cost of AKI to the NHS (excluding AKI in the community)

➢ 434 - 620.000.000 GBP/ per year ➢ more than expenditure on breast cancer or lung + skin

cancer combined

AKI

• Many physicians who refer patients for contrast procedures and some who perform the procedure themselves are not fully informed about the risk of CI-AKI

• less than half of referring physicians are aware of potential risk factors of CI-AKI

Contrast-Induced Nephropathy author heading Author: Renu Bansal, MD; Chief Editor: Vecihi Batuman, MD, FASN

AKI

…..most cardiology textbooks and recent guidelines do not draw much attention, on AKI in patients with ACS. …..while recommendations exist for the management of fairly rare ACS-associated complications ( papillary muscle rupture or Dressler syndrome : <2% of patients) , no information is given about AKI, despite its high incidence

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Πίνοντας ήλιο κορινθιακό Διαβάζοντας τα μάρμαρα Δρασκελίζοντας αμπέλια θάλασσες Σημαδεύοντας με το καμάκι Ένα τάμα ψάρι που γλιστρά Βρήκα τα φύλλα που ο ψαλμός του ήλιου αποστηθίζει Τη ζωντανή στεριά που ο πόθος χαίρεται Ν' ανοίγει. Πίνω νερό κόβω καρπό Χώνω το χέρι μου στις φυλλωσιές του ανέμου Οι λεμονιές αρδεύουνε τη γύρη της καλοκαιριάς Τα πράσινα πουλιά σκίζουν τα όνειρά μου Φεύγω με μια ματιά Ματιά πλατιά όπου ο κόσμος

ΟΔΥΣΣΕΑΣ ΕΛΥΤΗΣ

Πίνοντας ήλιο κορινθιακό

Η ποιητική συλλογή Ήλιος ο Πρώτος του Οδυσσέα Ελύτη γράφτηκε και κυκλοφόρησε μέσα στην Κατοχή (1943), περιέχει ωστόσο αισιόδοξα ποιήματα που, σε πείσμα της δύσκολης εποχής, υμνούσαν τη χαρά της ζωής, τον έρωτα, τη φύση και το ελληνικό φως.