Early Goal Directed Therapy Using a Physiological Holistic View. The ANDROMEDA-SHOCK Study

NCT03078712 | Completed DMC

• 1 other identifier: 161130002
• Study Type: interventional
• Target: 424
• Locations: 1 country
• Sites: 1

Brief Summary

Septic shock is a highly lethal condition associated with a mortality risk of 30 to 60%. Optimizing tissue perfusion and oxygenation is the aim to decrease mortality and morbidity in septic shock patients. Persistent hyperlactatemia after initial resuscitation is particularly difficult to interpret, although optimizing systemic blood flow might reverse ongoing hypoperfusion. Nevertheless, if persistent hyperlactatemia is caused by non-hypoperfusion-related mechanisms, then sustained efforts aimed at increasing cardiac output (CO) could lead to detrimental effects of excessive fluids or inotropes. Another potential alternative resuscitation target is peripheral perfusion as assessed by capillary refill time (CRT), mottling score or central-to-toe temperature differences. Reversal of abnormal peripheral perfusion might represent improvement in tissue hypoperfusion with the advantage of a faster recovery than lactate. Hypothesis: Peripheral perfusion guided resuscitation in septic shock is associated with lower mortality, less organ dysfunctions, less mechanical ventilation (MV), less vasopressor load, and less renal replacement therapies than a lactate-targeted resuscitation strategy. Main Objective To test if peripheral perfusion targeted resuscitation in septic shock is associated with lower 28-day mortality than a lactate targeted resuscitation. Design: Multicenter, Parallel Assignment randomized controlled study, conducted under supervision of an independent Data Safety Monitoring Board (DSMB). Interventions:

1. 1.Active Comparator- Peripheral Perfusion guided resuscitation
2. 2.Active Comparator- Lactate guided resuscitation

Conditions

Septic Shock; Hyperlactatemia; Peripheral Perfusion

Keywords

Septic Shock; Lactate; Capillary Refill Time; Fluid Responsiveness; Mortality

Outcome Measures

Primary Outcomes (1)

• All-cause of mortality

  All cause of mortality.

  28 days

Secondary Outcomes (4)

• Need of mechanical ventilation

  28 days

• Need of renal replacement therapies (RRT)

  28 days

• Days free of MV, vasopressors and RRT

  28 days

• Variations in Sequential Organ failure Assessment (SOFA)

  At 8, 24, 48 and 72 hours

Other Outcomes (5)

• Acute kidney injury (AKI)

  28 days

• Intra-abdominal hypertension

  28 days

• Fluid balances

  At 8, 24, 48 and 72 hours

Study Arms (2)

Peripheral Perfusion guided resuscitation

ACTIVE COMPARATOR

Resuscitation will be aimed at normalization of capillary refill time.

Other: Peripheral Perfusion guided resuscitation

Lactate guided resuscitation

ACTIVE COMPARATOR

Resuscitation will be aimed at normalization or significant decrease in lactate levels.

Other: Lactate guided resuscitation

Interventions

Peripheral Perfusion guided resuscitation OTHER

Sequential approach with fluids (guided by dynamic predictors of fluid responsiveness), vasopressors titration, and inodilators according to peripheral perfusion.

Peripheral Perfusion guided resuscitation

Lactate guided resuscitation OTHER

Sequential approach with fluids (guided by dynamic predictors of fluid responsiveness), vasopressors titration, and inodilators according to lactate decrease.

Lactate guided resuscitation

Eligibility Criteria

• Age: 18 Years - 90 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Septic shock diagnosed at ICU admission according to the Sepsis-3 Consensus Conference, (basically septic patients with hypotension requiring norepinephrine (NE) to maintain a mean arterial pressure (MAP) of ≥ 65 mmHg, and serum lactate levels \> 2 mmol/l after initial fluid resuscitation with at least 20/ml kg in one hour.

You may not qualify if:

• Pregnancy
• Anticipated surgery or dialysis procedure during the first 8h after septic shock diagnosis
• Do-not-resuscitate status
• Child B or C liver cirrhosis
• Active bleeding
• Acute hematological malignancy
• Severe concomitant acute respiratory distress syndrome (ARDS)
• More than 4h after officially meeting septic shock criteria

Sponsors & Collaborators

• Pontificia Universidad Catolica de Chile: lead

Study Sites (1)

Pontificia Universidad Católica de Chile

Santiago, Santiago Metropolitan, 7500000, Chile

Location

Related Publications (40)

• Vincent JL, De Backer D. Circulatory shock. N Engl J Med. 2013 Oct 31;369(18):1726-34. doi: 10.1056/NEJMra1208943. No abstract available.

  PMID: 24171518 BACKGROUND

• Cecconi M, De Backer D, Antonelli M, Beale R, Bakker J, Hofer C, Jaeschke R, Mebazaa A, Pinsky MR, Teboul JL, Vincent JL, Rhodes A. Consensus on circulatory shock and hemodynamic monitoring. Task force of the European Society of Intensive Care Medicine. Intensive Care Med. 2014 Dec;40(12):1795-815. doi: 10.1007/s00134-014-3525-z. Epub 2014 Nov 13.

  PMID: 25392034 BACKGROUND

• Dougnac AL, Mercado MF, Cornejo RR, Cariaga MV, Hernandez GP, Andresen MH, Bugedo GT, Castillo LF; Grupo Chileno del Estudio de la Sepsis. [Prevalence of severe sepsis in intensive care units. A national multicentric study]. Rev Med Chil. 2007 May;135(5):620-30. doi: 10.4067/s0034-98872007000500010. Epub 2007 Jul 9. Spanish.

  PMID: 17657331 BACKGROUND

• Hernandez G, Bruhn A, Castro R, Regueira T. The holistic view on perfusion monitoring in septic shock. Curr Opin Crit Care. 2012 Jun;18(3):280-6. doi: 10.1097/MCC.0b013e3283532c08.

  PMID: 22473257 BACKGROUND

• Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, Sevransky JE, Sprung CL, Douglas IS, Jaeschke R, Osborn TM, Nunnally ME, Townsend SR, Reinhart K, Kleinpell RM, Angus DC, Deutschman CS, Machado FR, Rubenfeld GD, Webb S, Beale RJ, Vincent JL, Moreno R; Surviving Sepsis Campaign Guidelines Committee including The Pediatric Subgroup. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock, 2012. Intensive Care Med. 2013 Feb;39(2):165-228. doi: 10.1007/s00134-012-2769-8. Epub 2013 Jan 30.

  PMID: 23361625 BACKGROUND

• Garcia-Alvarez M, Marik P, Bellomo R. Sepsis-associated hyperlactatemia. Crit Care. 2014 Sep 9;18(5):503. doi: 10.1186/s13054-014-0503-3.

  PMID: 25394679 BACKGROUND

• Tapia P, Soto D, Bruhn A, Alegria L, Jarufe N, Luengo C, Kattan E, Regueira T, Meissner A, Menchaca R, Vives MI, Echeverria N, Ospina-Tascon G, Bakker J, Hernandez G. Impairment of exogenous lactate clearance in experimental hyperdynamic septic shock is not related to total liver hypoperfusion. Crit Care. 2015 Apr 22;19(1):188. doi: 10.1186/s13054-015-0928-3.

  PMID: 25898244 BACKGROUND

• Hernandez G, Pedreros C, Veas E, Bruhn A, Romero C, Rovegno M, Neira R, Bravo S, Castro R, Kattan E, Ince C. Evolution of peripheral vs metabolic perfusion parameters during septic shock resuscitation. A clinical-physiologic study. J Crit Care. 2012 Jun;27(3):283-8. doi: 10.1016/j.jcrc.2011.05.024. Epub 2011 Jul 27.

  PMID: 21798706 BACKGROUND

• Hernandez G, Castro R, Romero C, de la Hoz C, Angulo D, Aranguiz I, Larrondo J, Bujes A, Bruhn A. Persistent sepsis-induced hypotension without hyperlactatemia: is it really septic shock? J Crit Care. 2011 Aug;26(4):435.e9-14. doi: 10.1016/j.jcrc.2010.09.007. Epub 2010 Dec 3.

  PMID: 21126850 BACKGROUND

• Hernandez G, Bruhn A, Castro R, Pedreros C, Rovegno M, Kattan E, Veas E, Fuentealba A, Regueira T, Ruiz C, Ince C. Persistent Sepsis-Induced Hypotension without Hyperlactatemia: A Distinct Clinical and Physiological Profile within the Spectrum of Septic Shock. Crit Care Res Pract. 2012;2012:536852. doi: 10.1155/2012/536852. Epub 2012 Apr 18.

  PMID: 22570774 BACKGROUND

• Hernandez G, Regueira T, Bruhn A, Castro R, Rovegno M, Fuentealba A, Veas E, Berrutti D, Florez J, Kattan E, Martin C, Ince C. Relationship of systemic, hepatosplanchnic, and microcirculatory perfusion parameters with 6-hour lactate clearance in hyperdynamic septic shock patients: an acute, clinical-physiological, pilot study. Ann Intensive Care. 2012 Oct 15;2(1):44. doi: 10.1186/2110-5820-2-44.

  PMID: 23067578 BACKGROUND

• Hernandez G, Boerma EC, Dubin A, Bruhn A, Koopmans M, Edul VK, Ruiz C, Castro R, Pozo MO, Pedreros C, Veas E, Fuentealba A, Kattan E, Rovegno M, Ince C. Severe abnormalities in microvascular perfused vessel density are associated to organ dysfunctions and mortality and can be predicted by hyperlactatemia and norepinephrine requirements in septic shock patients. J Crit Care. 2013 Aug;28(4):538.e9-14. doi: 10.1016/j.jcrc.2012.11.022. Epub 2013 Apr 6.

  PMID: 23566729 BACKGROUND

• Hernandez G, Bruhn A, Luengo C, Regueira T, Kattan E, Fuentealba A, Florez J, Castro R, Aquevedo A, Pairumani R, McNab P, Ince C. Effects of dobutamine on systemic, regional and microcirculatory perfusion parameters in septic shock: a randomized, placebo-controlled, double-blind, crossover study. Intensive Care Med. 2013 Aug;39(8):1435-43. doi: 10.1007/s00134-013-2982-0. Epub 2013 Jun 6.

  PMID: 23740284 BACKGROUND

• Ospina-Tascon GA, Bautista-Rincon DF, Umana M, Tafur JD, Gutierrez A, Garcia AF, Bermudez W, Granados M, Arango-Davila C, Hernandez G. Persistently high venous-to-arterial carbon dioxide differences during early resuscitation are associated with poor outcomes in septic shock. Crit Care. 2013 Dec 13;17(6):R294. doi: 10.1186/cc13160.

  PMID: 24330804 BACKGROUND

• Ospina-Tascon GA, Umana M, Bermudez W, Bautista-Rincon DF, Hernandez G, Bruhn A, Granados M, Salazar B, Arango-Davila C, De Backer D. Combination of arterial lactate levels and venous-arterial CO2 to arterial-venous O 2 content difference ratio as markers of resuscitation in patients with septic shock. Intensive Care Med. 2015 May;41(5):796-805. doi: 10.1007/s00134-015-3720-6. Epub 2015 Mar 20.

  PMID: 25792204 BACKGROUND

• Ospina-Tascon GA, Umana M, Bermudez WF, Bautista-Rincon DF, Valencia JD, Madrinan HJ, Hernandez G, Bruhn A, Arango-Davila C, De Backer D. Can venous-to-arterial carbon dioxide differences reflect microcirculatory alterations in patients with septic shock? Intensive Care Med. 2016 Feb;42(2):211-21. doi: 10.1007/s00134-015-4133-2. Epub 2015 Nov 17.

  PMID: 26578172 BACKGROUND

• Hernandez G, Tapia P, Alegria L, Soto D, Luengo C, Gomez J, Jarufe N, Achurra P, Rebolledo R, Bruhn A, Castro R, Kattan E, Ospina-Tascon G, Bakker J. Effects of dexmedetomidine and esmolol on systemic hemodynamics and exogenous lactate clearance in early experimental septic shock. Crit Care. 2016 Aug 2;20(1):234. doi: 10.1186/s13054-016-1419-x.

  PMID: 27480413 BACKGROUND

• Hernandez G, Luengo C, Bruhn A, Kattan E, Friedman G, Ospina-Tascon GA, Fuentealba A, Castro R, Regueira T, Romero C, Ince C, Bakker J. When to stop septic shock resuscitation: clues from a dynamic perfusion monitoring. Ann Intensive Care. 2014 Oct 11;4:30. doi: 10.1186/s13613-014-0030-z. eCollection 2014.

  PMID: 25593746 BACKGROUND

• Malbrain ML, Marik PE, Witters I, Cordemans C, Kirkpatrick AW, Roberts DJ, Van Regenmortel N. Fluid overload, de-resuscitation, and outcomes in critically ill or injured patients: a systematic review with suggestions for clinical practice. Anaesthesiol Intensive Ther. 2014 Nov-Dec;46(5):361-80. doi: 10.5603/AIT.2014.0060.

  PMID: 25432556 BACKGROUND

• Marik PE. Iatrogenic salt water drowning and the hazards of a high central venous pressure. Ann Intensive Care. 2014 Jun 21;4:21. doi: 10.1186/s13613-014-0021-0. eCollection 2014.

  PMID: 25110606 BACKGROUND

• Gu WJ, Zhang Z, Bakker J. Early lactate clearance-guided therapy in patients with sepsis: a meta-analysis with trial sequential analysis of randomized controlled trials. Intensive Care Med. 2015 Oct;41(10):1862-3. doi: 10.1007/s00134-015-3955-2. Epub 2015 Jul 8. No abstract available.

  PMID: 26154408 BACKGROUND

• Jansen TC, van Bommel J, Schoonderbeek FJ, Sleeswijk Visser SJ, van der Klooster JM, Lima AP, Willemsen SP, Bakker J; LACTATE study group. Early lactate-guided therapy in intensive care unit patients: a multicenter, open-label, randomized controlled trial. Am J Respir Crit Care Med. 2010 Sep 15;182(6):752-61. doi: 10.1164/rccm.200912-1918OC. Epub 2010 May 12.

  PMID: 20463176 BACKGROUND

• Jones AE, Shapiro NI, Trzeciak S, Arnold RC, Claremont HA, Kline JA; Emergency Medicine Shock Research Network (EMShockNet) Investigators. Lactate clearance vs central venous oxygen saturation as goals of early sepsis therapy: a randomized clinical trial. JAMA. 2010 Feb 24;303(8):739-46. doi: 10.1001/jama.2010.158.

  PMID: 20179283 BACKGROUND

• Bakker J, de Backer D, Hernandez G. Lactate-guided resuscitation saves lives: we are not sure. Intensive Care Med. 2016 Mar;42(3):472-474. doi: 10.1007/s00134-016-4220-z. Epub 2016 Feb 1. No abstract available.

  PMID: 26831675 BACKGROUND

• Vallee F, Vallet B, Mathe O, Parraguette J, Mari A, Silva S, Samii K, Fourcade O, Genestal M. Central venous-to-arterial carbon dioxide difference: an additional target for goal-directed therapy in septic shock? Intensive Care Med. 2008 Dec;34(12):2218-25. doi: 10.1007/s00134-008-1199-0. Epub 2008 Jul 8.

  PMID: 18607565 BACKGROUND

• Lima A, Bakker J. Clinical assessment of peripheral circulation. Curr Opin Crit Care. 2015 Jun;21(3):226-31. doi: 10.1097/MCC.0000000000000194.

  PMID: 25827585 BACKGROUND

• van Genderen ME, Engels N, van der Valk RJ, Lima A, Klijn E, Bakker J, van Bommel J. Early peripheral perfusion-guided fluid therapy in patients with septic shock. Am J Respir Crit Care Med. 2015 Feb 15;191(4):477-80. doi: 10.1164/rccm.201408-1575LE. No abstract available.

  PMID: 25679107 BACKGROUND

• Hernandez G, Teboul JL. Is the macrocirculation really dissociated from the microcirculation in septic shock? Intensive Care Med. 2016 Oct;42(10):1621-1624. doi: 10.1007/s00134-016-4416-2. Epub 2016 Jun 11. No abstract available.

  PMID: 27289357 BACKGROUND

• Jhanji S, Stirling S, Patel N, Hinds CJ, Pearse RM. The effect of increasing doses of norepinephrine on tissue oxygenation and microvascular flow in patients with septic shock. Crit Care Med. 2009 Jun;37(6):1961-6. doi: 10.1097/CCM.0b013e3181a00a1c.

  PMID: 19384212 BACKGROUND

• Jhanji S, Lee C, Watson D, Hinds C, Pearse RM. Microvascular flow and tissue oxygenation after major abdominal surgery: association with post-operative complications. Intensive Care Med. 2009 Apr;35(4):671-7. doi: 10.1007/s00134-008-1325-z. Epub 2008 Oct 21.

  PMID: 18936911 BACKGROUND

• Dubin A, Pozo MO, Casabella CA, Palizas F Jr, Murias G, Moseinco MC, Kanoore Edul VS, Palizas F, Estenssoro E, Ince C. Increasing arterial blood pressure with norepinephrine does not improve microcirculatory blood flow: a prospective study. Crit Care. 2009;13(3):R92. doi: 10.1186/cc7922. Epub 2009 Jun 17.

  PMID: 19534818 BACKGROUND

• De Backer D, Creteur J, Dubois MJ, Sakr Y, Koch M, Verdant C, Vincent JL. The effects of dobutamine on microcirculatory alterations in patients with septic shock are independent of its systemic effects. Crit Care Med. 2006 Feb;34(2):403-8. doi: 10.1097/01.ccm.0000198107.61493.5a.

  PMID: 16424721 BACKGROUND

• Lima A, van Genderen ME, van Bommel J, Klijn E, Jansem T, Bakker J. Nitroglycerin reverts clinical manifestations of poor peripheral perfusion in patients with circulatory shock. Crit Care. 2014 Jun 19;18(3):R126. doi: 10.1186/cc13932.

  PMID: 24946777 BACKGROUND

• Dunser MW, Takala J, Brunauer A, Bakker J. Re-thinking resuscitation: leaving blood pressure cosmetics behind and moving forward to permissive hypotension and a tissue perfusion-based approach. Crit Care. 2013 Oct 8;17(5):326. doi: 10.1186/cc12727.

  PMID: 24103466 BACKGROUND

• Brunauer A, Kokofer A, Bataar O, Gradwohl-Matis I, Dankl D, Bakker J, Dunser MW. Changes in peripheral perfusion relate to visceral organ perfusion in early septic shock: A pilot study. J Crit Care. 2016 Oct;35:105-9. doi: 10.1016/j.jcrc.2016.05.007. Epub 2016 May 12.

  PMID: 27481743 BACKGROUND

• Ait-Oufella H, Bakker J. Understanding clinical signs of poor tissue perfusion during septic shock. Intensive Care Med. 2016 Dec;42(12):2070-2072. doi: 10.1007/s00134-016-4250-6. Epub 2016 Feb 4. No abstract available.

  PMID: 26846520 BACKGROUND

• Bhatt DL, Mehta C. Adaptive Designs for Clinical Trials. N Engl J Med. 2016 Jul 7;375(1):65-74. doi: 10.1056/NEJMra1510061. No abstract available.

  PMID: 27406349 BACKGROUND

• Kattan E, Ospina-Tascon GA, Teboul JL, Castro R, Cecconi M, Ferri G, Bakker J, Hernandez G; ANDROMEDA-SHOCK Investigators. Systematic assessment of fluid responsiveness during early septic shock resuscitation: secondary analysis of the ANDROMEDA-SHOCK trial. Crit Care. 2020 Jan 23;24(1):23. doi: 10.1186/s13054-020-2732-y.

  PMID: 31973735 DERIVED

• Hernandez G, Ospina-Tascon GA, Damiani LP, Estenssoro E, Dubin A, Hurtado J, Friedman G, Castro R, Alegria L, Teboul JL, Cecconi M, Ferri G, Jibaja M, Pairumani R, Fernandez P, Barahona D, Granda-Luna V, Cavalcanti AB, Bakker J; The ANDROMEDA SHOCK Investigators and the Latin America Intensive Care Network (LIVEN); Hernandez G, Ospina-Tascon G, Petri Damiani L, Estenssoro E, Dubin A, Hurtado J, Friedman G, Castro R, Alegria L, Teboul JL, Cecconi M, Cecconi M, Ferri G, Jibaja M, Pairumani R, Fernandez P, Barahona D, Cavalcanti AB, Bakker J, Hernandez G, Alegria L, Ferri G, Rodriguez N, Holger P, Soto N, Pozo M, Bakker J, Cook D, Vincent JL, Rhodes A, Kavanagh BP, Dellinger P, Rietdijk W, Carpio D, Pavez N, Henriquez E, Bravo S, Valenzuela ED, Vera M, Dreyse J, Oviedo V, Cid MA, Larroulet M, Petruska E, Sarabia C, Gallardo D, Sanchez JE, Gonzalez H, Arancibia JM, Munoz A, Ramirez G, Aravena F, Aquevedo A, Zambrano F, Bozinovic M, Valle F, Ramirez M, Rossel V, Munoz P, Ceballos C, Esveile C, Carmona C, Candia E, Mendoza D, Sanchez A, Ponce D, Ponce D, Lastra J, Nahuelpan B, Fasce F, Luengo C, Medel N, Cortes C, Campassi L, Rubatto P, Horna N, Furche M, Pendino JC, Bettini L, Lovesio C, Gonzalez MC, Rodruguez J, Canales H, Caminos F, Galletti C, Minoldo E, Aramburu MJ, Olmos D, Nin N, Tenzi J, Quiroga C, Lacuesta P, Gaudin A, Pais R, Silvestre A, Olivera G, Rieppi G, Berrutti D, Ochoa M, Cobos P, Vintimilla F, Ramirez V, Tobar M, Garcia F, Picoita F, Remache N, Granda V, Paredes F, Barzallo E, Garces P, Guerrero F, Salazar S, Torres G, Tana C, Calahorrano J, Solis F, Torres P, Herrera L, Ornes A, Perez V, Delgado G, Lopez A, Espinosa E, Moreira J, Salcedo B, Villacres I, Suing J, Lopez M, Gomez L, Toctaquiza G, Cadena Zapata M, Orazabal MA, Pardo Espejo R, Jimenez J, Calderon A, Paredes G, Barberan JL, Moya T, Atehortua H, Sabogal R, Ortiz G, Lara A, Sanchez F, Hernan Portilla A, Davila H, Mora JA, Calderon LE, Alvarez I, Escobar E, Bejarano A, Bustamante LA, Aldana JL. Effect of a Resuscitation Strategy Targeting Peripheral Perfusion Status vs Serum Lactate Levels on 28-Day Mortality Among Patients With Septic Shock: The ANDROMEDA-SHOCK Randomized Clinical Trial. JAMA. 2019 Feb 19;321(7):654-664. doi: 10.1001/jama.2019.0071.

  PMID: 30772908 DERIVED

• Hernandez G, Cavalcanti AB, Ospina-Tascon G, Zampieri FG, Dubin A, Hurtado FJ, Friedman G, Castro R, Alegria L, Cecconi M, Teboul JL, Bakker J; ANDROMEDA-SHOCK Study Investigators. Early goal-directed therapy using a physiological holistic view: the ANDROMEDA-SHOCK-a randomized controlled trial. Ann Intensive Care. 2018 Apr 23;8(1):52. doi: 10.1186/s13613-018-0398-2.

  PMID: 29687277 DERIVED

MeSH Terms

Conditions

Shock, Septic; Hyperlactatemia

Condition Hierarchy (Ancestors)

Sepsis; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Shock; Metabolic Diseases; Nutritional and Metabolic Diseases; Signs and Symptoms

Study Officials

• Glenn Hernandez, PhD

  Pontificia Universidad Catolica de Chile

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Tenured Professor

Study Record Dates

• First Submitted: March 6, 2017
• First Posted: March 13, 2017
• Study Start: March 1, 2017
• Primary Completion: March 15, 2018
• Study Completion: June 30, 2018
• Last Updated: July 23, 2018

Record last verified: 2018-07

Locations

CL (1)